BICYCLIC COMPOUNDS AND USE THEREOF

Abstract

The present invention relates to a compound as represented by formula (I). The present invention also provides compositions and formulations containing such compounds, and methods for using and preparing such compounds.

##STR00001##

Claims

1. A compound of formula (I), or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex, or solvate thereof, ##STR00220## wherein, represents a single bond or a double bond; L is a bond, —O—, —NH—, —(CR.sub.dR.sub.c).sub.n—, —S—, —S(═O)—, —S(═O).sub.2—, —C═C—, —C≡C— or C.sub.3-C.sub.5 cycloalkyl, X.sub.1 and X.sub.2 are each independently selected from C or N; X.sub.3 is CR.sub.f or NR.sub.f; X.sub.4 is CR.sub.j or NR.sub.j; and at least one of X.sub.1, X.sub.2, X.sub.3 or X.sub.4 is N; R.sub.1 is selected from C.sub.1-C.sub.10 alkyl, C.sub.2-C.sub.10 alkenyl, C.sub.2-C.sub.10 alkynyl, C.sub.1-C.sub.10 alkoxyl, C.sub.6-C.sub.10 aryl, 5-18 membered heteroaryl, C.sub.3-C.sub.10 cycloalkyl, or 3-10 membered heterocyclyl; wherein the 5-18 membered heteroaryl and 3-10 membered heterocyclyl optionally comprising 1, 2 or 3 hetero atoms independently selected from N, O or S; the C.sub.1-C.sub.10 alkyl, C.sub.2-C.sub.10 alkenyl, C.sub.2-C.sub.10 alkynyl, C.sub.1-C.sub.10 alkoxyl, C.sub.6-C.sub.10 aryl, 5-18 membered heteroaryl, C.sub.3-C.sub.10 cycloalkyl and 3-10 membered heterocyclyl are each optionally substituted with one or more halogen, —OH, —CN, oxo, amino, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxyl, C.sub.2-C.sub.6 alkenyl, C.sub.3-C.sub.5 cycloalkyl, C.sub.2-C.sub.6 alkynyl, C.sub.1-C.sub.6 haloalkyl, —C.sub.1-C.sub.6 alkylene-OR.sub.c, —C.sub.0-C.sub.6 alkylene-C═OR.sub.c, —NO.sub.2, —OR.sub.c, —SR.sub.c, —NR.sub.aR.sub.b, —C(═O)R.sub.c, —C(═O)OR.sub.c, —C(═O)NR.sub.aR.sub.b, —NC(═O)R.sub.c, —S(═O)R.sub.c, —S(═O).sub.2R.sub.c, —S(═O).sub.2NR.sub.aR.sub.b, —S(═O)(═NR.sub.a)R.sub.b, —P(═O)NR.sub.aR.sub.b and/or —P(═S)NR.sub.aR.sub.b; R.sub.2 is selected from H, deuterium, halogen, —CN, —OH, ═N—OH, C.sub.1-C.sub.5 haloalkyl, amino, C.sub.1-C.sub.10 alkoxyl, —O—C(═O)—C.sub.1-3 alkyl, —C(═O)—O—C.sub.1alkyl or —NR.sub.aR.sub.b; R.sub.3 is selected from H, deuterium, halogen, —CN, —OH, —N—OH, C.sub.1-C.sub.10 alkyl, C.sub.2-C.sub.10 alkenyl, C.sub.1-C.sub.5 haloalkyl, C.sub.1-C.sub.10 alkoxyl, —O—C(═O)—C.sub.1-C.sub.3 alkyl, —C(═O)—O—C.sub.1-C.sub.3 alkyl or C.sub.2-C.sub.10 alkynyl, the C.sub.1-C.sub.10 alkyl, C.sub.2-C.sub.10 alkenyl, C.sub.1-C.sub.5 haloalkyl, C.sub.1-C.sub.10 alkoxyl, —O—C(═O )—C.sub.1-C.sub.3 alkyl, —C(═O)—O—C.sub.1-C.sub.3 alkyl are each optionally substituted with one or more H, halogen, —CN, —OH, amino, C.sub.1-C.sub.5 alkyl, C.sub.2-C.sub.6 alkenyl and/or C.sub.1-C.sub.5 haloalkyl; or R.sub.2 and R.sub.3 together form an oxo group; R.sub.4 and R.sub.5 are each independently selected from H, halogen, —OH, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxyl, C.sub.1-C.sub.6 haloalkyl, C.sub.2-C.sub.10 alkenyl, C.sub.2-C.sub.10 alkynyl, C.sub.3-C.sub.5 cycloalkyl or 3-6 membered heterocyclyl, the C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxyl, C.sub.1-C.sub.6 haloalkyl, C.sub.2-C.sub.10 alkenyl, C.sub.2-C.sub.10 alkynyl, C.sub.3-C.sub.5 cycloalkyl and 3-6 membered heterocyclyl are each optionally substituted with one or more halogen, —CN, —OH, amino, C.sub.1-C.sub.5 alkyl, C.sub.2-C.sub.6 alkenyl and/or C.sub.1-C.sub.5 haloalkyl; or R.sub.4 and R.sub.5 together with the C atom to which they are attached form a substituted or unsubstituted cyclopropyl; R.sub.6 is selected from H, —CN, halogen, —OH, —NO.sub.2, —NH.sub.2, oxo, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxyl, C.sub.1-C.sub.6 haloalkyl, C.sub.2-C.sub.10 alkenyl, C.sub.2-C.sub.10 alkynyl, C.sub.3-C.sub.5 cycloalkyl or 3-6 membered heterocyclyl; the C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxyl, C.sub.1-C.sub.6 haloalkyl, C.sub.2-C.sub.10 alkenyl, C.sub.2-C.sub.10 alkynyl, C.sub.3-C.sub.5 cycloalkyl and 3-6 membered heterocyclyl are each optionally substituted with one or more H, halogen, —CN, —OH, amino, oxo, C.sub.1-C.sub.5 alkyl, C.sub.2-C.sub.6 alkenyl and/or C.sub.1-C.sub.5 haloalkyl; or two R.sub.6 together with the C atom to which they are attached form a substituted. or unsubstituted C.sub.3-C.sub.5 cycloalkyl or 3-5 membered heterocyclyl; or R.sub.6 and R.sub.5 together with the C atom to which they are attached form a substituted or unsubstituted C.sub.3-C.sub.4 cycloalkyl; R.sub.d and R.sub.e are each independently selected from H, halogen, CN, —NR.sub.aR.sub.b, C.sub.1-C.sub.10 alkyl and C.sub.3-C.sub.10 cycloalkyl; or R.sub.d and R.sub.e together form an oxo group; R.sub.f is selected from absent, H, —CN, halogen, C.sub.1-C.sub.10 alkyl, C.sub.1-C.sub.10 haloalkyl, C.sub.3-C.sub.10 cycloalkyl, oxo, or —NR.sub.aR.sub.b; the C.sub.1-C.sub.10 alkyl, C.sub.1-C.sub.10 haloalkyl and C.sub.3-C.sub.10 cycloalkyl are each optionally substituted with one or more H, halogen, —CN, —OH, amino, C.sub.1-C.sub.5 allyl, C.sub.2-C.sub.6 alkenyl and/or C.sub.3-C.sub.5 haloalkyl; R.sub.j is selected from H, —NO.sub.2, —CN, halogen, C.sub.1-C.sub.10 alkyl, C.sub.2-C.sub.10 alkenyl, C.sub.2-C.sub.10 alkynyl, haloalkyl, cycloalkyl, C.sub.3-C.sub.10 cycloalkyl, 3-10 membered heterocyclyl, C.sub.6-C.sub.10 aryl, 5-10 membered heteroaryl, —C.sub.1-C.sub.6 alkylene-OR.sub.c, —OR.sub.c, —SR.sub.c, —NR.sub.aR.sub.b, —C(═O)R.sub.c, —C(═O)OR.sub.c, —C(═O)NR.sub.aR.sub.b, —NC(═O)R.sub.c, —S(═O)R.sub.c, —S(═O).sub.2R.sub.c, —S(═O).sub.2NR.sub.aR.sub.b, —S(═O)(═NR.sub.a)R.sub.b, P(═O)R.sub.aR.sub.b, or P(═S)R.sub.aR.sub.b; wherein the 5-10 membered heteroaryl and 3-10 membered heterocyclyl optionally comprising 1, 2 or 3 heteroatoms independently selected from N, O or S; the C.sub.1-C.sub.10 alkyl, C.sub.2-C.sub.10 alkenyl, C.sub.2-C.sub.10 alkynyl, C.sub.1-C.sub.10 haloalkyl, C.sub.3-C.sub.10 cycloalkyl, 3-10 membered heterocyclyl, C.sub.6-C.sub.10 aryl and 5-10 membered heteroaryl are each optionally substituted with one or more halogen, hydroxyl, amino, P(═O)Me.sub.2, P(═S)Me.sub.2, —S(═O).sub.2—C.sub.1-C.sub.3 alkyl, —S(═O).sub.2—C.sub.3-C.sub.5 cycloalkyl, —S(═O)—C.sub.1-C.sub.3 alkyl, —S(═O)—C.sub.3-C.sub.5 cycloalkyl, CN, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxyl and/or C.sub.1-C.sub.6 haloalkyl; R.sub.a, R.sub.b and R.sub.c are each independently selected from H, C.sub.1-C.sub.10 alkyl, C.sub.1-C.sub.10 haloalkyl, C.sub.2-C.sub.10 alkenyl, C.sub.2-C.sub.10 alkynyl, C.sub.3-C.sub.10 cycloalkyl, 3-10 membered heterocyclyl, C.sub.6-C.sub.10 aryl or 5-10 membered heteroaryl; n is 1, 2 or 3; m is 0, 1, 2, 3 or 4.

2. The compound, or the stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex, or solvate of claim 1, wherein, the compound is of formula (II): ##STR00221## wherein, one and only one of X.sub.1 or X.sub.2 is N, and the other is C.

3. The compound, or the stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex, or solvate of claim 1, wherein, the R.sub.2 is selected from halogen, —CN, —OH, or ═N—OH.

4. The compound or the stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex, or solvate of claim 1, wherein, the R.sub.3 is selected from H, deuterium, C.sub.1-C.sub.10 alkyl, or C.sub.2-C.sub.10 alkenyl, the C.sub.1-C.sub.10 alkyl and C.sub.2-C.sub.10 alkenyl are each optionally substituted with H, halogen, —CN, —OH, amino, or C.sub.1-C.sub.5 haloalkyl; or R.sub.2 and R.sub.3 together form an oxo group.

5. The compound or the stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex, or solvate of claim 1, wherein, the R.sub.3 is selected from H, deuterium, or C.sub.1-C.sub.3 alkyl, the C.sub.1-C.sub.3 alkyl and C.sub.2-C.sub.5 alkenyl are each optionally substituted with H, halogen, —CN, —OH, amino, or C.sub.1-C.sub.5 haloalkyl; or R.sub.2 and R.sub.3 together form an oxo group.

6. The compound or the stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex, or solvate of claim 1, wherein, R.sub.4 and R.sub.5 are each independently selected from H, halogen or C.sub.1-C.sub.6 alkyl, the C.sub.1-C.sub.6 alkyl is optionally substituted H, halogen, —CN, —OH, amino, or oxo.

7. The compound or the stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex, or solvate of claim 1, wherein, R.sub.4 and R.sub.5 are each independently selected from H or halogen.

8. The compound or the stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex, or solvate of claim 1, wherein, the compound is of formula (IV-1), formula (IV-2) or formula (V), ##STR00222## wherein, one and only one of X.sub.1 or X2 is N, and the other is C.

9. (canceled)

10. The compound or the stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex, or solvate of claim 1, wherein, L is a bond, —CH.sub.2—, —S(═O).sub.2—, —C═C—, —C═O—, —C≡C— or —3.sub.1-C.sub.5 cycloalkyl.

11. The compound or the stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex, or solvate of claim 1, wherein, X.sub.3 is CR.sub.f.

12. The compound or the stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex, or solvate of claim 1, wherein, L is a bond.

13. The compound or the stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex, or solvate of claim 1, wherein, the compound is of formula (VI-1), formula (V1-2), formula (VI-3), formula (VI-4) or formula (VI-5): ##STR00223##

14. The Compound or the stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex, or solvate of claim 1, wherein, R.sub.6 is H, —CN, halogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxyl or C.sub.1-C.sub.6 haloalkyl, the C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy and C.sub.1-C.sub.6 haloalkyl are each optionally substituted with one or more halogen, —CN, —OH oxo and/or amino.

15. The compound or the stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex, or solvate of claim 1, wherein, R.sub.6 is H, halogen or C.sub.1-C.sub.6 alkyl, the C.sub.1-C.sub.6 alkyl is optionally substituted with. one or more H, halogen, —CN, —OH, oxo and/or amino.

16. The compound or the stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex, or solvate of claim 1, wherein, the R.sub.f is selected from H, —CN, halogen, —NH.sub.2, C.sub.1-C.sub.3 alkyl, cyclopropyl or C.sub.1-C.sub.3 haloalkyl, the C.sub.1-C.sub.3 alkyl, cyclopropyl or C.sub.1-C.sub.3 haloalkyl are each optionally substituted with one or more H, halogen, —CN, —OH, amino, C.sub.1-C.sub.3 alkyl, C.sub.2-C.sub.4 alkenyl and/or C.sub.1-C.sub.3 haloalkyl.

17. The compound or the stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex, or solvate of claim 1, wherein, R.sub.f is selected from H, —CN, halogen, C.sub.1-C.sub.3 alkyl or C.sub.1-C.sub.3 haloalkyl.

18. The compound or the stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex, or solvate of claim 1, wherein, R.sub.f is C.sub.6-C.sub.10 aryl, 5-18 membered heteroaryl or C.sub.3-C.sub.10 cycloalkyl; the 5-18 membered heteroaryl optionally comprising 1, 2 or 3 heteroatoms independently selected from N, O or S.

19. The compound or the stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex, or solvate of claim 1, wherein, R.sub.f is C.sub.6-C.sub.8 aryl, 5-8-membered heteroaryl or C.sub.3-C.sub.6 cycloalkyl, the 5-8-membered heteroaryl optionally comprising 1, 2 or 3heteroatoms independently selected from N, O or S, the C.sub.6-C.sub.8 aryl, 5-8 membered heteroaryl or C.sub.3-C.sub.6 cycloalkyl are each optionally substituted with one or more halogen, —OH, —CN, oxo, amino, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxyl, C.sub.1-C.sub.6 haloalkyl, —C.sub.1-C.sub.6 alkylene-OR.sub.c, C.sub.0-C.sub.6 alkylene-C═O—R.sub.c, —NO.sub.2, C(═O)OR.sub.c and/or —S(═O).sub.2R.sub.c.

20. The compound or the stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex, or solvate of claim 1, wherein, R.sub.f is phenyl, 5-6 membered heteroaryl or C.sub.3-C.sub.6 cycloalkyl, the 5-6 membered heteroaryl optionally comprising 1, 2 or 3 heteroatoms independently selected from N, O or S; the phenyl, 5-6 membered heteroaryl and C.sub.3-C.sub.6 cycloalkyl are each optionally substituted with one or more halogen, —CN and/or C.sub.1-C.sub.4 haloalkyl.

21. The compound or the stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex, or solvate of claim 1, wherein, the R.sub.j is selected from H, —CN, halogen, C.sub.1-C.sub.10 alkyl, C.sub.2-C.sub.10 alkenyl, C.sub.1-C.sub.10 haloalkyl, C.sub.3-C.sub.10 cycloalkyl, C.sub.6-C.sub.10 aryl, 5-10 membered heteroaryl, —S(═O)R.sub.c, —C.sub.1-C.sub.6 alkylene-OR.sub.c, —S(═O).sub.2R.sub.c or P(═O)R.sub.aR.sub.b; the 5-10 membered heteroaryl optionally comprising 1, 2 or 3 heteroatoms independently selected from N, O or S; the C.sub.1-C.sub.10 alkyl, C.sub.2-C.sub.10 alkenyl, C.sub.1-C.sub.10 haloalkyl, C.sub.3-C.sub.10 cycloalkyl, C.sub.6-C.sub.10 aryl, 5-10 membered heteroaryl are each optionally substituted with one or more halogen, hydroxyl, P(═O)Me.sub.2, P(═S)Me.sub.2, —S(═O).sub.2-C.sub.1-C.sub.3alkyl, —S(═O).sub.2-C.sub.3-C.sub.5cycloalkyl, —S(═O)-C.sub.1-C.sub.3alkyl, —(═O)-C.sub.3-C.sub.5alkyl, —S(═O).sub.2-C.sub.3-C.sub.5cycloalkyl, —S(═O)-C.sub.1-C.sub.3alkyl, —S(═O)-C.sub.3-C.sub.5cycloalkyl, CN, C.sub.1-C.sub.6 alkyl and/or C.sub.1-C.sub.6 haloalkyl; the R.sub.a and R.sub.b independently selected from H, C.sub.1-C.sub.4 alkyl; the R.sub.c is selected from H, C.sub.1-C.sub.3 alkyl or C.sub.1-C.sub.3 haloalkyl.

22. The compound or the stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex, or solvate of claim 1, wherein, the R.sub.j is selected from H, halogen, —CN, C.sub.1-C.sub.4 haloalkyl, C.sub.3-C.sub.5 cycloalkyl, 5-membered heteroaryl, S(═O)R.sub.c, —S(═O).sub.2R.sub.c, —S(═O)(═NR.sub.a) R.sub.b or P(═O)Me.sub.2, the 5-membered heteroaryl optionally comprising 1, 2 or 3 heteroatoms independently selected from N, O or S; the C.sub.3-C.sub.5 cycloalkyl, 5-membered heteroaryl are each optionally substituted with one or more halogen, hydroxyl, C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3 alkoxyl and/or C.sub.1-C.sub.3 haloalkyl; the R.sub.a and R.sub.b independently selected from H, C.sub.1-C.sub.4 alkyl; the R.sub.c is selected from H, C.sub.1-C.sub.3 alkyl or C.sub.1-C.sub.3 haloalkyl,

23. The compound or the stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex, or solvate of claim 1, wherein, the R.sub.j is selected from C.sub.1-C.sub.4haloalkyl, CN, —S(═O).sub.2R.sub.c or 5-membered heteroaryl, the 5-membered heteroaryl optionally comprising 1, 2 or 3 heteroatoms independently selected from N, O or S; the 5-membered heteroaryl is optionally substituted with one or more halogen, C.sub.1-C.sub.3alkyl and/or C.sub.1-C.sub.3haloalkyl; the R.sub.c is selected from H, C.sub.1-C.sub.3 alkyl or C.sub.1-C.sub.3 haloalkyl.

24. The compound or the stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex, or solvate of claim 1, wherein, the compound is selected from: 1-(3-chloro-5-fluorophenyl)-5,5-difluoro-3-iodo-1,5,6,7-tetrahydro-4H-indol-4-one; 1-(3-chloro-5-fluorophenyl)-5,5-difluoro-3-iodo-4,5,6,7-tetrahydro-1H-indol-4-ol; 5,5-difluoro-3-iodo-1-(4-(trifluoromethyl)phenyl)-1,5,6,7-tetrahydro-4H-indol-4-one; 5,5-difluoro-3-iodo-1-(4-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydro-1H-indol-4-ol; 5-(5,5-difluoro-4-hydroxyl-3-iodo-4,5,6,7-tetrahydro-1H-indol-1-yl)-2-fluorobenzonitrile; 1-(3-chloro-5-fluorophenyl)-5,5-difluoro-3-(trifluoromethyl)-1,5,6,7-tetrahydro-4H-indol-4-one; 1-(3-chloro-5-fluorophenyl)-5,5-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol; 1-(3,5-difluorophenyl)-5,5-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol; 5,5-difluoro-1-phenyl-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol; 1-(3,5-difluorophenyl)-5,5-difluoro-3-(trifluoromethyl)-1,5,6,7-tetrahydro-4H-indol-4-one; 5,5-difluoro-1-phenyl-3-(trifluoromethyl)-1,5,6,7-tetrahydro-4H-indol-4-one; 3-(5,5-difluoro-4-hydroxyl-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)-5-fluorobenzonitrile; 4-(5,5-difluoro-4-hydroxyl-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)benzonitrile; 5,5-difluoro-1-(4-fluoro-3-methoxyphenyl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol; 1-(3-chlorophenyl)-5,5-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol; 5,5-difluoro-1-(3-fluorophenyl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol; 1-(5-chloropyridin-3-yl)-5,5-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol; 5,5-difluoro-1-(2-fluorophenyl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol; 3-(5,5-difluoro-4-hydroxyl-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)benzonitrile; 1-(3,5-dichlorophenyl)-5,5-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol; 1-(4-chlorophenyl)-5,5-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol; 1-(3-bromo-5-fluorophenyl)-5,5-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol; 5,5-difluoro-1-(pyridin-3-yl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol; 5,5-difluoro-1-(3-fluoro-5-(trifluoromethyl)phenyl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol; 5,5-difluoro-3-(trifluoromethyl)-1-(4-trifluoromethyl)phenyl)-4,5,6,7-tetrahydro-1H-indol-4-ol; 5,5-difluoro-1-(p-tolyl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol; 5,5-difluoro-1-(3-fluoro-5-hydroxyphenyl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol; 1-(3-chloro-5-fluorobenzyl)-5,5-difluoro-3-(trifluoromethyl)-1,5,6,7-tetrahydro-4H-indol-4-one; 1-(3-chloro-5-fluorobenzyl)-5,5-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol; 5,5-difluoro-1-benzyl-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol; 1-((3,3-difluorocyclobutyl)methyl)-5,5-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol; (5,5-difluoro-4-hydroxyl-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)(3,3-difluorocyclobutyl)methanone; 1-(3,5-difluorophenyl)-5,5-difluoro-1,5,6,7-tetrahydro-4H-indol-4-one; 1-(3,5-difluorophenyl)-5,5-difluoro-4,5,6,7-tetrahydro-1H-indol-4-ol; 1-cyclohexyl-5,5-difluoro-3-(trifluoromethyl)-1,5,6,7-tetrahydro-4H-indol-4-one; 1-cyclohexyl-5,5-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol; 1-(3,5-difluorophenyl)-(3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol; 3-fluoro-5-(3-(methylsulfonyl)-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl)benzonitrile; 3-fluoro-5-(4-hydroxyl-3-(methylsulfonyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)benzonitrile; 1-(3,5-difluorophenyl)-(4-hydroxyl-4,5,6,7-tetrahydro-1H-indole-3-carbonitrile; 3-fluoro-5-(4-(hydroxyl-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)benzonitrile; 1-(3-chloro-5-fluorophenyl)-3-(trifluoromethyl)-1,5,6,7-tetrahydro-4H-indol-4-one; 3-fluoro-5-(4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)benzonitrile; 1-(3,3-difluorocyclobutyl-5,5-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol; 1-(3,3-difluorocyclobutyl)-5,5-difluoro-3-(methylsulfonyl)-4,5,6,7-tetrahydro-1H-indol-4-ol; 2-fluoro-5-(4-hydroxyl-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)benzonitrile; 1-(3,5-difluorophenyl)-3-(1-methyl-1H-pyrazol-5-yl)-4,5,6,7-tetrahydro-1H-indol-4-ol; (S)-1-(3-chloro-5-fluorophenyl)-5,5-difluoro-3-(thiophen-2-yl)-4,5,6,7-tetrahydro-1H-indol-4-ol; 1-(4-fluorobenzyl)-3-(1-methyl-1H-pyrazol-5-yl)-4,5,6,7-tetrahydro-1H-indol-4-ol; 1-(3,5-difluorophenyl)-5,5-difluoro-3-(thiophen-2-yl)-4,5,6,7-tetrahydro-1H-indol-4-ol; 1-(3-chloro-5-fluorophenyl)-5,5-difluoro-3-(1-methyl-1H-pyrrol-2-yl)-4,5,6,7-tetrahydro-1H-indol-4-ol; 1-(3-chloro-5-fluorophenyl)-3-cyclopropyl-5,5-difluoro-4,5,6,7-tetrahydro-1H-indol-4-ol; 1-(3-chloro-5-fluorophenyl)-5,5-difluoro-3-(furan-2-yl)-4,5,6,7-tetrahydro-1H-indol-4-ol; 5-(5,5-difluoro-4-hydroxyl-3-(thiazol-5-yl)-4,5,6,7-tetrahydro-1H-indol-1-yl)-2-fluorobenzonitrile; 1-(3-chloro-5-fluorophenyl)-5,5-difluoro-3-(furan-3-yl)-1,5,6,7-tetrahydro-4H-indol-4-one; 1-(3-chloro-5-fluorophenyl)-5,5-difluoro-3-(furan-3-yl)-4,5,6,7-tetrahydro-1H-indol-4-ol; 1-(3-chloro-5-fluorophenyl)-5,5-difluoro-3-(1H-pyrazol-3-yl)-4,5,6,7-tetrahydro-1H-indol-4-ol; 1-(3-chloro-5-fluorophenyl)-5,5-difluoro-3-(5-methyl-1H-pyrazol-3-yl)-4,5,6,7-tetrahydro-1H-indol-4-ol; 1-(3-chloro-5-fluorophenyl)-5,5-difluoro-3-(1-methyl-1H-pyrazol-5-yl)-4,5,6,7-tetrahydro-1H-indol-4-ol; 1-(3-chloro-5-fluorophenyl)-5,5-difluoro-3-(thiophen-3-yl)-4,5,6,7-tetrahydro-1H-indol-4-ol; 1-(3-chloro-5-fluorophenyl)-5,5-difluoro-3-methyl-4,5,6,7-tetrahydro-1H-indol-4-ol; 1-(3-chloro-5-fluorophenyl)-5,5-difluoro-3-(thiazol-4-yl)-4,5,6,7-tetrahydro-1H-indol-4-ol; 1-(3-chloro-5-fluorophenyl)-5,5-difluoro-3-(thiazol-5-yl)-4,5,6,7-tetrahydro-1H-indol-4-ol; (S)-1-(3,5-difluorophenyl)-5,5-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol; 1-(3-chloro-5-fluorophenyl)-3-(difluoromethyl)-5,5-difluoro-4,5,6,7-tetrahydro-1H-indol-4-ol; 1-(3-chloro-5-fluorophenyl)-5,5-difluoro-3-vinyl-4,5,6,7-tetrahydro-1H-indol-4-ol; 1-(3-chloro-5-fluorophenyl)-5,5-difluoro-3-(hydroxymethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol; 3-(3-chloro-5-fluorophenyl)-7-fluoro-1-(trifluoromethyl)-5,6,7,8-tetrahydroindolizin-8-ol; 5-(7,7-difluoro-8-hydroxyl-1-(trifluoromethyl)-5,6,7,8-tetrahydroindolizin-3-yl)-2-fluorobenzonitrile; (S)-5-(7,7-difluoro-8-hydroxyl-1-(trifluoromethyl)-5,6,7,8-tetrahydroindolizin-3-yl-2-fluorobenzonitrile; 3-(3-chloro-5-fluorophenyl)-7,7-difluoro-1-(trifluoromethyl)-5,6,7,8-tetrahydroindolizin-8-ol; 7-fluoro-3-phenyl-1-(trifluoromethyl)-5,6,7,8-tetrahydroindolizin-8-ol; 3-(3,5-difluorophenyl)-7-fluoro-1-(trifluoromethyl)-5,6,7,8-tetrahydroindolizin-8-ol; 7-fluoro-3-(4-fluoro-3(trifluoromethyl)phenyl-1-(trifluoromethyl)-5,6,7,8-tetrahydroindolizin-8-ol; 2-fluoro-5-(7-fluoro-8-hydroxyl-1-(trifluoromethyl)-5,6,7,8-tetrahydroindolizin-3-yl)benzonitrile; 3-(3,5-difluorophenyl)-7,7-difluoro-1-(trifluoromethyl)-5,6,7,8-tetrahydroindolizin-8-ol; 3-(7,7-difluoro-8-hydroxyl-1-(trifluoromethyl)-5,6,7,8-tetrahydroindolizin-3-yl)-5-fluorobenzonitrile; (E)-3-(2-cyclohexylvinyl)-7,7-difluoro-1-(trifluoromethyl)-5,6,7,8-tetrahydroindolizin-8-ol; 3-(cyclopropylethynyl)-7,7-difluoro-1-(trifluoromethyl)-5,6,7,8-tetrahydroindolizin-8-ol; 3-(3-(difluoromethyl)-4-fluorophenyl)-7,7-difluoro-1-(trifluoromethyl)-5,6,7,8-tetrahydroindolizin-8-ol; 7,7-difluoro-1-(trifluoromethyl)-3-(3,4,5-trifluorophenyl)-5,6,7,8-tetrahydroindolizin-8-ol; 7,7-difluoro-3-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(trifluoromethyl)-5,6,7,8-tetrahydroindolizin-8-ol; 3-(3-(difluoromethyl)-4-fluorophenyl)-7,7-difluoro-1-(trifluoromethyl)-6,7-dihydroindolizin-8(5H)-one; 7,7-difluoro-1-(trifluoromethyl)-3-(3,4,5-trifluorophenyl)-6,7-dihydroindolizin-8(5H)-one; 7,7-difluoro-3-(4-fluoro-3trifluoromethyl)phenyl)-1-(trifluoromethyl)-6,7-dihydroindolizin-8(5H)-one; 7,7-difluoro-3-(1-phenylcyclopropyl)-1-(trifluoromethyl)-5,6,7,8-tetrahydroindolizin-8-ol; 7,7-difluoro-3-(phenylethynyl)-1-(trifluoromethyl)-5,6,7,8-tetrahydroindolizin-8-ol; (1-(3-chloro-3-fluorophenyl)-5,5-difluoro-4-hydroxyl-4,5,6,7-tetrahydro-1H-indol-3-yl)dimethylphosphine oxide; (S)-5-(5,5-difluoro-4-hydroxyl-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)-2-fluorobenzonitrile; 1-(3-chloro-5-fluorophenyl)-5,5-difluoro-4-hydroxyl-4,5,6,7-tetrahydro-1H-indol-3-carbonitrile; 1-(3-chloro-5-fluorophenyl)-5,6-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol; 5,5-difluoro-1(4-fluoro-3-(hydroxymethyl)phenyl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol; 5,5-difluoro-1-(6-fluoropyridin-2-yl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol; 5-(5,5-difluoro-4-hydroxyl-4-methyl-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)-2-fluorobenzonitrile; 5-(5,5-difluoro-4-hydroxyl-6,6-dimethyl-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)-2-fluorobenzonitrile; 2-fluoro-5-(5-fluoro-4-hydroxyl-6,6-dimethyl-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)-benzonitrile; (4S,5S)-1-(3-(difluoromethyl)-4-fluorophenyl)-5-fluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol; (4R,5R)-1-(3-(difluoromethyl)-4-fluorophenyl)-5-fluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol; (4S,5R)-1-(3-(difluoromethyl)-4-fluorophenyl)-5-fluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol; (4R,5S)-1-(3-(difluoromethyl)-4-fluorophenyl)-5-fluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol; 1-(3-chloro-5-fluorophenyl)-2,5,5-trifluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol; (S)-2-chloro-1-(3-chloro-5-fluorophenyl-5,5-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol; 1-(3-difluoromethyl)-4-fluorophenyl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol; 1-(3-chloro-5-fluorophenyl)-5,5-difluoro-3-(methylsulfonyl)-4,5,6,7-tetrahydro-1H-indol-4-ol; 3-(5,5-difluoro-4-hydroxyl-3-(methylsulfonyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)-5-fluorobenzonitrile; 3-(3-difluoromethyl)-5,5-difluoro-4-hydroxyl-4,5,6,7-tetrahydro-1H-indol-1-yl)-5-fluorobenzonitrile; 3-(3-difluoromethyl)sulfonyl)-5,5-difluoro-4-hydroxyl-4,5,6,7-tetrahydro-1H-indol-1-yl)-5-fluorobenzonitrile; 1-(3-chloro-5-fluorophenyl)-3,5,5-trifluoro-4,5,6,7-tetrahydro-1H-indol-4-ol; 1-(3-chloro-5-fluorophenyl)-5,5-difluoro-4-hydroxyl-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indole-2-carbonitrile; (R)-1-(3-chloro-5-fluorophenyl-5,5-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol; (S)-1-(3-chloro-5-fluorophenyl-5,5-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol; 1-(3,5-difluorophenyl)-5,5-difluoro-3-(methylsulfonyl)-4,5,6,7-tetrahydro-1H-indol-4-ol; 1-(3,5-difluorophenyl)-5,5-difluoro-3-(methylsulfonyl)-1,5,6,7-tetrahydro-4H-indol-4-one; 3-(3-chloro-5-fluorophenyl)-6,6-difluoro-1-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-7-ol; 1-(3-chloro-4-fluorophenyl)-5,5-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol; 5-(5,5-difluoro-4-hydroxyl-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1)-2-fluorobenzonitrile; 4-(5,5-difluoro-4-hydroxyl-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1)-2-fluorobenzonitrile; 5,5-difluoro-1-(1-methyl-1H-pyrrol-2-yl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol; 2-chloro-4-(5,5-difluoro-4-hydroxyl-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)benzonitrile; 4-(5,5-difluoro-4-hydroxyl-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)phthalonitrile; 5,5-difluoro-1-(furan-2-yl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol; 2-cyano-5-(5,5-difluoro-4-hydroxyl-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)benzoic acid; 2-acetyl-4-(5,5-difluoro-4-hydroxyl-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)benzonitrile; 1-(3-chloro-5-fluorophenyl)-5,6-difluoro-3-(methylsulfonyl)-4,5,6,7-tetrahydro-1H-indol-4-ol; 1-(4-chlorophenyl)-5,6-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol; 2-fluoro-5-((4S)-5-fluoro-4-hydroxyl-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)benzonitrile; 5,6-difluoro-1-(5-fluoropyridin-3-yl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol; 5,5-difluoro-1-(5-fluoropyridin-3-yl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol; (S)-5-(5,5-difluoro-4-hydroxyl-3-(methylsulfonyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)-2-fluorobenzonitrile; 1-(3-chloro-5-fluorophenyl)-5,5-difluoro-3-((S)-methylsulfinyl)-4,5,6,7-tetrahydro-1H-indol-4-ol; 1-(3-chloro-5-fluorophenyl)-5,5-difluoro-3-((R)-methylsulfinyl)-4,5,6,7-tetrahydro-1H-indol-4-ol; 2-chloro-5-(5,5-difluoro-4-hydroxyl-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)benzonitrile; 1-(4-chloro-3-nitrophenyl)-5,5-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol; 3-fluoro-5-(5-fluoro-4-hydroxyl-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)benzonitrile; 1-(3-amino-5-fluorophenyl)-5-fluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol; 1-(3-chloro-5-fluorophenyl)-5,7-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol; 1-(3-chloro-5-fluorophenyl)-5-fluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol; 1-(3-chloro-5-fluorophenyl)-5-fluoro-2-methyl-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol; 1-(3-chloro-5-fluorophenyl)-5,5-difluoro-3-phenyl)-1,5,6,7-tetrahydro-4H-indol-4-one; 1-(3-chloro-5-fluorophenyl)-5,5-difluoro-3-phenyl)-4,5,6,7-tetrahydro-1H-indol-4-ol; (S)-2-bromo-1-(3,5-difluorophenyl)-5,5-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol; 5,5-difluoro-1-(thiophen-3-yl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol; 5,5-difluoro-3-(trifluoromethyl)-1-(3,4,5-trifluorophenyl)-4,5,6,7-tetrahydro-1H-indol-4-ol; 1-(3,5-dichloro-4-fluorophenyl)-5,5-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol; 3-(3-chloro-5-fluorophenyl)-6,7-difluoro-1-(trifluoromethyl)-5,6,7,8-tetrahydroindolizin-8-ol; 3-(3-chloro-5-fluorophenyl)-6,7-difluoro-1-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-8-ol; 3-(3-chloro-5-fluorophenyl)-5,6-difluoro-1-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-7-ol; 3-(3-chloro-5-fluorophenyl)-5,6-difluoro-1-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-7-ol; 3-chloro-5-(5,5-difluoro-4-hydroxyl-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)benzonitrile; 4-(5,5-difluoro-4-hydroxyl-3-(trifluoromethyl-4,5,6,7-tetrahydro-1H-indol-1-yl)-2-methoxybenzonitrile; 5,5-difluoro-1-(4-fluoro-3-(trifluoromethyl)phenyl)-3-trifluoromethyl-4,5,6,7-tetrahydro-1H-indol-4-ol; 4-(5,5-difluoro-4-hydroxyl-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)-2-(trifluoromethyl)benzonitrile; 5,5-difluoro-1-(3-fluoro-4-methoxyphenyl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol; 5,5-difluoro-1-(pyridin-4-yl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol; 5,5-difluoro-1-(4-fluorophenyl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol; 5,5-difluoro-1-(3-(methylsulfonyl)phenyl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol; 5,5-difluoro-1-(2-methoxypyridin-4-yl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol; 4-(5,5-difluoro-4-hydroxyl-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)-picolinonitrile; 1-(3,4-difluorophenyl)-5,5-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol; 5,5-difluoro-1-(2-fluoropyridin-4-yl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol; 1-(3-cyano-4-fluorophenyl)-5,5-difluoro-4-hydroxyl-4,5,6,7-tetrahydro-1H-indole-3-carbonitrile; (S)-4-(5,5-difluoro-4-hydroxyl-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)phthalonitrile; 1-(3-(difluoromethyl)-4-fluorophenyl)-5,5-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol; 5,5-difluoro-1-(4-fluoro-3-methylphenyl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol; 5,5-difluoro-1-(6-fluoropyridin-3-yl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol; 5,5-difluoro-1-(5-fluoropyridin-2-yl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol; 1-(2-chloropyridin-4-yl)-5,5-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol; (S)-1-(3-(difluoromethyl)-4-fluorophenyl)-5,5-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol; (R)-1-(3-(difluoromethyl)-4-fluorophenyl)-5,5-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol; (R)-5-(5,5-difluoro-4-hydroxyl-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)-2-fluorobenzonitrile; 5-(5,5-difluoro-4-hydroxyl-3-(trifluoromethyl)-4-vinyl-4,5,6,7-tetrahydro-1H-indol-1-yl)-2-fluorobenzonitrile; (S)-5-(5,5-difluoro-4-hydroxyl-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)nicotinonitrile; 5,5-difluoro-1-(4-fluorophenyl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-carbonitrile; 5-(5,5-difluoro-4-hydroxyl-6-methyl-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)-2-fluorobenzonitrile; 5-((4S)-5,5-difluoro-4-hydroxyl-6-methyl-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)-2-fluorobenzonitrile; (E)-5,5-difluoro-1-styryl-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol; (E)-5,5-difluoro-1-styryl-3-(trifluoromethyl)-1,5,6,7-tetrahydro-4H-indol-4-one; 1-(phenylsulfonyl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol; (E)-1-(2-cyclohexylvinyl)-5,5-difluoro-3-(trifluoromethyl)-1,5,6,7-tetrahydro-4H-indol-4-one; 5,5-difluoro-1-(phenylsulfonyl)-3-(trifluoromethyl)-1,5,6,7-tetrahydro-4H-indol-4-one; 5,5-difluoro-1-(phenylsulfonyl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol; (E)-1-(2-cyclohexylvinyl)-5,5-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol; 5-(5,5-difluoro-4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)-2-fluorobenzonitrile; 5-(5,5-difluoro-4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1yl)-2-fluorobenzaldehyde; 1-(3-(difluoromethyl)-4-fluorophenyl)-5,5-difluoro-3-(trifluoromethyl)-1,5,6,7-tetrahydro-4H-indol-4-one; 2-fluoro-5-(5-fluoro-4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)benzaldehyde; 1-(3-(difluoromethyl)-4-fluorophenyl)-5-fluoro-3-(trifluoromethyl)-1,5,6,7-tetrahydro-4H-indol-4-one; 3-fluoro-5-(5-fluoro-4-hydroxyl-3-(methylsulfonyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)benzonitrile; 3-(3-chloro-5-fluorophenyl)-7,7-difluoro-1-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-8-ol; 3-(3-chloro-5-fluorophenyl)-6,6-difluoro-1-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-7-ol; (S)-1-(3,5-difluorophenyl)-5,5-difluoro-3-(methylsulfonyl)-2-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol; (S)-2-fluoro-5-(4,5,5-trifluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)benzonitrile; (R)-2-fluoro-5-(4,5,5-trifluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)benzonitrile; (Z)-5-(5,5-difluoro-4-(hydroxyimino)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)-2-fluorobenzonitrile; or (S)-5-(5,5-difluoro-4-hydroxyl-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl-4-d)-2-fluorobenzonitrile.

26. (canceled)

27. (canceled)

28. (canceled)

29. (canceled)

30. A method for treating or preventing HIF-2α mediated disease, wherein, comprising administering a therapeutically effective amount of the compound of claim 1, or the pharmaceutical composition to a subject.

31. The method of claim 30, wherein, the disease mediated by HIF-2α is VHL syndrome, autoimmune disease, inflammatory disease and/or cancer.

32. The method of claim 31, wherein, the cancer is selected from glioma, pheochromocytoma, paraganglioma, colon cancer, rectal cancer, prostate cancer, lung cancer, pancreatic cancer, liver cancer, kidney cancer, cervical cancer, uterine cancer, stomach cancer, ovarian cancer, breast cancer, skin cancer, brain cancer, meningioma, neurocytoma, meningioma and medulloblastoma.

33. The method of claim 30, wherein the cancer is selected from hematological cancer, lymphoma, multiple myeloma, digestive system tumor, reproductive system tumor, brain tumor, nervous system tumor, neoplasm.

Description

EXAMPLES

[0392] In order to make the present invention easier to understand, the present invention was described in detail with reference to the examples. These examples are only for illustrative purposes and are not limited to the scope of application of the present invention. The experimental methods in the present invention, unless otherwise specified, all are conventional methods. The experimental materials used in the present invention are purchased from the market unless otherwise specified.

[0393] Unless otherwise specified, all parts and percentages are by weight and all temperatures are in degrees Celsius.

[0394] The following abbrevations have been used in the examples: [0395] CuI: Cuprous iodide; [0396] DAST; Diethylaminosulfur trifluoride; [0397] DCM: Dichloromethane; [0398] DMF: Dimethylformamide; [0399] DMSO: Dimethyl sulfoxide; [0400] EA: Ethyl Acetate; [0401] ESI-MS: Electrospray ionization mass spectrometry; [0402] K.sub.2CO.sub.3: Potassium carbonate; [0403] NaH: Sodium hydride; [0404] LDA: Lithium diisopropylamide; [0405] LiHMDS: Lithium bis(trimethylsilyl)amide; [0406] m-CPBA: m-chloroperoxybenzoic acid; [0407] MtBE: Methyl tert-butyl ether; [0408] Na.sub.2SO.sub.4: Sodium sulfate; [0409] NaBH.sub.4: Sodium borohydride; [0410] NBS: N-bromosuccinimide; [0411] NFSI: N-Fluorobisbenzenesulfonamide; [0412] NIS: N-Iodosuccinimide; [0413] NMP: N-Methylpyrrolidone; [0414] PE: Petroleum ether; [0415] Pd.sub.2(dba).sub.3: Tris(dibenzylideneacetone)dipalladium; [0416] Pd(dppf)Cl.sub.2: 1,1′-Bis(diphenylphosphino)ferrocene]palladium dichloride; [0417] Pd(PPh.sub.3).sub.4): Tetrakis(triphenylphosphine)palladium; [0418] Prep-TLC: Preparative Thin Layer Chromatography; [0419] SelectFlour: 1-Chloromethyl-4-fluoro-1,4-azabicyclo[2.2.2]octanebis(tetrafluoro borate); [0420] TBAF: Tetrabutylammonium fluoride; [0421] TEA: Triethylamine; [0422] THF: Tetrahydrofuran; [0423] Xanophos: 4,5-Bis(diphenylphosphine)-9,9-dimethylxanthene; [0424] TLC: Thin layer chromatography; [0425] ESI-MS: Electrospray ionization mass spectrometry; [0426] LCMSort C-MS: liquid chromatography mass spectrometry; [0427] .sup.1H NMR: hydrogen-1 nuclear magnetic resonance; [0428] [(R,R)-T.sub.5-DPEN]RuCl(p-cymene): Chlorine {[(1R,2R)-(−)-2-amino-1,2-diphenylethyl](4-toluenesulfonyl)amino}(P-isopropyltoluene)ruthenium(II)

Synthesis of Intermediate M1(5,5-difluoro-3-iodo-1,5,6,7-tetrahydro-4H-indol-4-one)

[0429] ##STR00011##

Step 1: Synthesis of Compound M1-1

[0430] 6,7-dihydro-1H-indol-4(5H)-one (13.5 g) was dissolved in DMF (100 mL) under N.sub.2 protection, 60% NaH (4.4 g) was added slowly in an ice bath after stirred for 0.5 h, triisopropylchlorosilane (21.2 g) was added. The reaction mixture was stirred at 0° C. for 3 h, the reaction mixture was poured into a mixture of water and ice (500 mL), extracted with EA (500 mL*2), washed with saturated sodium chloride solution (500 mL*2) dried, concentrated to give a crude product, which was purified by column chromatography (EA/PE=1:10) to afford the target compound M1-1 (20.3 g). ESI-MS m/z: 292.10 [M+H].sup.+.

Step 2: Synthesis of Compound M1-2

[0431] Compound M1-1 (13.5 g) was dissolved in DMF (100 mL) under N.sub.2 protection, NIS (11.5 g) was added in portions, stirred at room temperature for 7 h, the reaction mixture was poured into a mixture of water and ice (500 mL), extracted with EA (500 mL*2), washed with saturated sodium chloride solution (500 mL*2), dried, concentrated to give a crude product, which was purified by column chromatography (EA/PE=1:10) to afford the target compound MI1-2 (8.7 g). ESI-MS m/z: 418.10 [M+H].sup.+.

Step 3: Synthesis of Compound M1-3

[0432] Compound M1-2 (5.5 g) was dissolved in THF (50 mL), cooled to −78° C., a solution of LiHMDS in THF (1.0 M, 35.6 mL) was added slowly, after stirred at room temperature for 0.5 h, NFSI (8.72 g) in THF (50 mL) was added, and stirred was continued at room temperature for 2 h, the reaction was quenched by the addition of saturated ammonium chloride, extracted twice with EA, washed twice with saturated sodium chloride solution, dried, concentrated to give a crude product, which was purified by column chromatography (EA/PE=1:10) to afford the target compound M1-3 (2.1 g). ESI-MS m/z: 454.10 [M+H].sup.+.

Step 4: Synthesis of Compound M1

[0433] Compound M1-3 (2.1 g) was dissolved in a mixture of THF (20 mL) and water (20 mL), K.sub.2CO.sub.3 (1.27 g) was added under room temperature, stirred at room temperature for 3 h. The reaction mixture was poured into water, extracted with EA, the organic layer was washed with sodium chloride solution, dried over Na.sub.2SO.sub.4, concentrated to give a crude product, which was purified by column chromatography (100% DCM) to afford the target compound M1 (0.5 g). ESI-MS m/z: 297.99 [M+H].sup.+. .sup.1H NMR (500 MHz, DMSO-d6):δ 12.05 (s, 1H), 7.12 (d, J=2.3 Hz, 1H), 2.98 (t, J=6.2 Hz, 2H), 2.60-2.53 (m, 2H).

Synthesis of Intermediate M2 (5,5-difluoro-3-(trifluoromethyl)-1,5,6,7-tetrahydro-4H-indol-4-one)

[0434] ##STR00012##

[0435] M1 (12 g), cuprous iodide (7.8 g), methyl fluorosulfonyl difluoroacetate (24 g) were added into DMF (120 mL), the atmosphere was evacuated and replaced with nitrogen, the reaction was heated to 130° C. under nitrogen protection, stirred overnight. TLC and LCMS showed that no starting material remained, the temperature was cooled down, the reaction mixture was diluted with EA, the organic layer was washed with saturated sodium chloride solution, dried over Na.sub.2SO.sub.4, concentrated to give a crude product, which was purified by column chromatography (EA/PE=1:5) to afford the target compound M2 (8.4 g). ESI-MS m/z: 238.0 [M+H].sup.+. .sup.1H NMR (500 MHz, DMSO) δ 12.37 (s, 1H), 7.56 (s, 1H), 3.03 (t, J=6.1 Hz, 2H), 2.68-2.55 (m, 2H).

Synthesis of Intermediate M3 (5-fluoro-3-(trifluoromethyl)-1,5,6,7-tetrahydro-4H-indol-4-one)

[0436] ##STR00013##

Step 1: Synthesis of Compound M3-1

[0437] Compound M1-2 (834 mg), cuprous iodide (380 mg), NMP (20 mL) and methyl fluorosulfonyl difluoroacetate (1.15 g) were added to 50 mL single-neck bottle sequentially heated to 120° C. stirred for 6 h, the reaction mixture was diluted with EA, washed three times with water and once with saturated brine, dried, concentrated to give a crude product, which was purified by column chromatography (DCM=100%) to afford the target compound M 3-1 (264 mg) ESI-MS m/z: 204.08 [M+H].sup.+.

Step 2: Synthesis of Compound M3

[0438] Compound M3-1 (264 mg) was dissolved in ultra-dry THF (20 mL) under N.sub.2 protection, cooled to −78° C., a solution of LDA in THF (1 M, 2.5 mL) was added slowly, after stirred for 0.5 h, NFSI (491 mg) in THF (5 mL) was added, stirring was continued at −78° C. for 2 h. The reaction was quenched by the addition of saturated ammonium chloride, extracted twice with EA, washed twice with saturated sodium chloride solution, dried, concentrated to give a crude product, which was purified by column chromatography (DCM=100%) to afford the target compound M3 (147 mg). ESI-MS m/z: 222.12 [M+H].sup.+.

Synthesis of Intermediate M4 (3-bromo-7-fluoro-1-(trifluoromethyl)-6,7-indoline-8(5H)-one) and Intermediate M5 (3-bromo-7,7-difluoro-1-(trifluoromethyl)-6,7-indoline-8(5H)-one)

[0439] ##STR00014##

Step 1: Synthesis of Compound M4-1

[0440] 3-bromo-1H-pyrrole-2-carboxylate methylester (20.4 g) and methyl 4-bromobutyrate (19.8 g) were dissolved in DMF (100 mL) under N.sub.2 protection, cesium carbonate (65.2 g) was added, after stirred at room temperature for 4 h, the reaction solution was poured into a mixture of ice and water (500 mL), extracted with EA, washed with saturated sodium chloride solution (500 mL*2), dried over anhydrous sodium sulfate, concentrated to give a crude product, which was purified by column chromatography (EA/PE=1:10) to afford the target compound M4-1 (28.3 g). ESI-MS m/z: 304.10 [M+H].sup.+.

Step 2: Synthesis of Compound M4-2

[0441] Compound M4-1 (15.2 g) was dissolved in THF (100 mL) under N.sub.2 protection, solution of potassium tert-butoxide in THF (1.0 M, 60 mL) was added dropwise in an ice bath, stirred at 0° C. for 3 h and then cooled to −78° C., solution of NFSI (18.9 g) in THF (50 mL) was added, stirring at −78° C. was continued for another 1 h, the reaction was quenched by the addition of saturated ammonium chloride, extracted with EA, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated to give a crude product, which was purified by column chromatography (EA/PE=1:5) to afford the target compound M4-2 (9.1 g). ESI-MS m/z: 277.15 [M+H].sup.+.

Step 3: Synthesis of Compound M4-3

[0442] Compound M4-2 (8.3 g) was dissolved in DMF (100 mL) under N.sub.2 protection, palladium acetate (3.3 g), CuI (11.4 g) and methyl fluorosulfonyl difluoroacetate (23 g) were added, stirred at 100° C. for 3 h, extracted with EA, the organic layer was washed with saturated sodium chloride solution, dried over Na.sub.2SO.sub.4, concentrated to give a crude product, which was purified by column chromatography (EA/PE=1:4) to afford the target compound M4-3 (4.23 g). ESI-MS m/z: 279.20 [M+H].sup.+.

Step 4: Synthesis of Compound M4-4

[0443] Compound M4-3 (4.23 g) was dissolved in a mixture of ethanol (20 mL) and M aqueous hydrochloric acid (20 mL), the reaction mixture was heated at reflux for 3 h. Concentrated under reduced pressure to remove ethanol, the residue was extracted with EA (100 mL*2), the organic layer was washed with saturated sodium chloride solution (100 mL*2), dried over Na.sub.2SO.sub.4, concentrated to give a crude product, which was purified by column chromatography (EA/PE=1:4) to afford the target compound M4-4 (2.1 g). ESI-MS m/z: 221.20 [M+H].sup.+.

Step 5: Synthesis of Compound M4

[0444] Compound M4-4 (2.1 g) was dissolved in acetonitrile (20 mL), NBS (1.8 g) was added at room temperature, the reaction mixture was heated at reflux for 4 h, quenched by the addition of water, extracted with EA, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated to give a crude product, which was purified by column chromatography (EA/PE=1:3) to afford the target compound M4 (2.5 g). ESI-MS m/z: 300.10 [M+H].sup.+.

Step 6: Synthesis of Compound M5

[0445] Compound M4 (1.3 g) was dissolved in THF (50 mL), cooled to −78° C., solution of LiHMDS in THF (1.0 M, 6 mL) was added dropwise, after stirred for 0.5 h, solution of NFSI (1.5 g) in THF (10 mL) was added dropwise, continued stirring for 2 h, the reaction was quenched by the addition of saturated ammonium chloride, extracted twice with EA, washed twice with saturated sodium chloride solution, dried, concentrated to give a crude product, which was purified by column chromatography (EA/PE=1:3) to afford the target compound M5 (2.1 g). ESI-MS m/z: 318.14 [M+H].sup.+.

Synthesis of Intermediate M6 (5,6-difluoro-3-(trifluoromethyl)-1,5,6,7-tetrahydro-4H-indol-4-one

[0446] ##STR00015##

Step 1: Synthesis of Compound M6-11

[0447] 1,3-dimethoxy-5-fluorobenzene (15.6 g) was dissolved in tert-butanol (25 mL) and THF (15 mL) under N.sub.2 protection, the mixture was added to liquid ammonia solution (650 mL), metal lithium (1.75 g) was added in batches, the blue solution was stirred at −65° C. for 3 h, solid ammonium chloride was added, until the blue color was disappeared, the temperature was allowed to rise to evaporate and remove the liquid ammonia, the residue was diluted with petroleum ether, washed with water, and washed with saturated brine, dried and concentrated to afford the target product M6-11 (10 g).

Step 2: Synthesis of Compound M6-12

[0448] Compound M6-11 (10 g) was dissolved in THF (100 mL), hydrochloric acid (1 N, 100 mL) was added, stirred at room temperature overnight, diluted with EA, extracted three times, dried and concentrated to afford the target product M6-12 (10 g). ESI-MS m/z: 129.10 [M+H].sup.+.

Step 3: Synthesis of Compound M6-21

[0449] Compound 2-bromo-1,1-dimethoxyethane (82.4 mL) was dissolved in DMSO (14 mL), sodium azide (1.95 g) and potassium iodide (0.33 g) were added, heated to 90° C. and stirred for 5 days, cooled to room temperature, the reaction was diluted with water and ether, the water layer was extracted three times with ether, dried and concentrated to afford M6-21 (30 g).

Step 4: Synthesis of Compound M6-13

[0450] Compound M6-21 (5.73 g) was dissolved in THF (150 mL), M6-12 (3.86 g) and triphenylphosphine (11.8 g) were added, heated to reflux overnight, cooled to room temperature, concentrated, and purified by column chromatography to afford M6-13 (7.24 g).

Step 5: Synthesis of Compound M6-14

[0451] Compound M6-13 (7.24 g) was dissolved in dichloromethane (100 mL), the reaction mixture was cooled to 0° C., trifluoroacetic acid (5 mL) was added, stirred at room temperature overnight, concentrated, and purified by column chromatography to afford M6-14 (5 g).

Step 6: Synthesis of Compound M6-15

[0452] Refer to the preparation method of compound M1-1 to obtain M6-15.

Step 7: Synthesis of Compound M6-16

[0453] Refer to the preparation method of compound M1-1 to obtain M6-16.

Step 8: Synthesis of Compound M6-17

[0454] Refer to the preparation method of step 2 in compound M3 to obtain M6-17.

Step 9: Synthesis of Compound M6-18

[0455] Refer to the preparation method of intermediate M2 to obtain M6-18.

Step 10: Synthesis of Compound M6

[0456] Refer to the preparation method of step 4 in intermediate M1 to obtain M6.

EXAMPLE 1 AND EXAMPLE 2

Synthesis of 1-(3-chloro-5-fluorophenyl)-5,5-difluoro-3-iodo-1,5,6,7-tetrahydro-4H-indol-4-one (Compound A13) and 1-(3-chloro-5-fluorophenyl)-5,5-difluoro-3-iodo-4,5,6,7-tetrahydro-1H-indol-4-ol (Compound A2)

[0457] ##STR00016##

Step 1: Synthesis of Compound A13

[0458] Compound M1 (300 mg) was dissolved in DCM (20 mL), copper acetate (90 mg), 3-chloro-5-fluorophenylboronic acid (350 mg) and TEA (404 mg) were added, stirred at room temperature overnight. The reaction mixture was diluted with DCM, washed twice with saturated brine, dried, concentrated to give a crude product, which was purified by column chromatography (EA/PE=1:5) to afford the target compound A13 (255 mg). ESI-MS m/z: 426.09 [M+H].sup.+.

Step 1: Synthesis of Compound A2

[0459] Compound A13 (43 mg) was dissolved in methanol (2 mL), NaBH.sub.4 (8 mg) was added in an ice bath, stirred at 0° C. for 1 h. Ice water was added and the mixture was extracted with EA, the organic layer was washed with with brine, dried over Na.sub.2SO.sub.4, concentrated to give a crude product, which was purified by Prep-TLC (EA/PE=1:5) to afford the target compound A2 (34 mg). ESI-MS m/z: 409.90 [M+H−H.sub.2O].sup.+.

[0460] Using a method substantially similar to example 1, such as replacing

##STR00017##

with

##STR00018##

etc., to prepare the following example.

TABLE-US-00001 Example number Structure Chemical name ESI-MS 3 [00019] 5,5-difluoro-3-iodo-1-(4- (trifluoromethyl)phenyl)- 1,5,6,7-tetrahydro-4H-indol- 4-one [M + H].sup.+: 442.06 4 [00020] 5,5-difluoro-3-iodo-1-(4- (trifluoromethyl)phenyl)- 4,5,6,7-tetrahydro-1H-indol- 4-ol [M + H − H.sub.2O].sup.+: 425.90 5 [00021] 5-(5,5-difluoro-hydroxy-3- iodo-4,5,6,7-tetrahydro-1H- indol-1-yl)-2- fluorobenzonitrile [M + H − H.sub.2O].sup.+: 401.01

EXAMPLE 6 AND EXAMPLE 7

Synthesis of 1-(3-chloro-5-fluorophenyl)-5,5-difluoro-3-(trifluoromethyl)-1,5,6,7-tetrahydro-4H-indol-4-one (Compound A18) and 1-(3-chloro-5-fluorophenyl)-5,5-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol (Compound A1)

[0461] ##STR00022##

Step 1: Synthesis of Compound A18

[0462] Compound A13 (255 mg) was dissolved in DMF (5 mL) under nitrogen protection, Pd.sub.2(dba).sub.3 (165 mg), CuI (114 mg) and methyl fluorosulfonyldifluoroacetate (230 mg) were added, stirred at 100° C. for 3 hours, the reaction mixture was extracted with ethyl acetate, the organic layer was washed with brine, dried over Na.sub.2SO.sub.4, and concentrated to obtain the crude product, which was purified by column chromatography (EA/PE=1:5) to obtain the target compound A18 (176 mg). ESI-MS m/z: 368.20 [M+H].sup.+.

Step 2: Synthesis of Compound A1

[0463] Compound A18 (147 mg) was dissolved in methanol (4 mL), NaBH.sub.4 (30 mg) was added in an ice bath, after stirring at 0° C. for 1 hour, ice water was added, the mixture was extracted with ethyl acetate, the organic layer was washed with brine, dried over Na.sub.2SO.sub.4, concentrated to obtain crude product, which was purified by Prep-TLC (EA/PE=1:5) to obtain the target compound A1 (118 mg). ESI-MS m/z: 352.11 [M+H−H.sub.2O].sup.+.

[0464] Using a method substantially similar to example 1-example 7, such as replacing

##STR00023##

with

##STR00024##

etc., to prepare the following example.

TABLE-US-00002 Example number Structure Chemical name ESI-MS 8 [00025] 1-(3,5-difluorophenyl-5,5- difluoro-3-(trifluoromethyl)- 4,5,6,7-tetrahydro-1H-indol-4-ol [M + H − H.sub.2O].sup.+: 336.05 9 [00026] 5,5-difluoro-1-phenyl-3- (trifluoromethyl)-4,5,6,7- tetrahydro-1H-indol-1-ol [M + H − H.sub.2O].sup.+: 300.10 10 [00027] 1-(3,5-difluorophenyl)-5,5- difluoro-3-(trifluoromethyl)- 1,5,6,7-tetrahydro-4H-indol-4-one [M + H].sup.+: 352.11 11 [00028] 5,5-difluoro-1-phenyl-3- (trifluoromethyl)-1,5,6,7- tetrahydro-4H-indol-4-one [M + H].sup.+: 316.12 12 [00029] 3-(5,5-difluoro-4-hydroxy-3- (trifluoromethyl)-4,5,6,7- tetrahydro-1H-indol-1-yl)-5- fluorobenzonitrile [M + H − H.sub.2O].sup.+: 343.10 13 [00030] 4-(5,5-difluoro-4-hydroxy-3 (trifluoromethyl)-4,5,6,7- tetrahydro-1H-indol-1- yl)benzonitrile [M + H − H.sub.2O].sup.+: 382.98 14 [00031] 5,5-difluoro-1-4-fluoro-3- methoxyphenyl)-3- (trifluoromethyl)-4,5,6,7- tetrahydro-1H-indol-4-ol [M + H − H.sub.2O].sup.+: 348.08 15 [00032] l-(3-chlorophenyl)-5,5-difluoro- 3-(trifluoromethyl)-4,5,6,7- tetrahydro-1H-indol-4-ol [M + H − H.sub.2O].sup.+: 334.04:336.04 16 [00033] 5,5-difluoro-1-3-fluorophenyl)- 3-(trifluoromethyl)-4,5,6,7- tetrahydro-1H-indol-4-ol [M + H − H.sub.2O].sup.+: 318.15 17 [00034] 1-(5-chloropyridin-3-yl)-5,5- difluoro-3-(trifluoromethyl) 4,5,6,7-tetrahydro-1H-indol-4-ol [M + H].sup.+: 353.11 18 [00035] 5,5-difluoro-1-(2-fluorophenyl)- 3-(trifluoromethyl)-4,5,6,7- tetrahydro-1H-indol-4-ol [M + H − H.sub.2O].sup.+: 318.12 19 [00036] 3-(5,5-difluoro-4-hydroxy-3- (trifluoromethyl)-4,5,6,7- tetrahydro-1H-indol-1- yl)benzonitrile [M + H − H.sub.2O].sup.+: 325.08 20 [00037] 1-(3,5-dichlorophenyl)-5,5- difluoro-3-(trifluoromethyl)- 4,5,6,7-tetrahydro-1H-indol-4-ol [M + H − H.sub.2O].sup.+: 368.11 21 [00038] 1-(4-chlorophenyl)-5,5-difluoro- 3-(trifluoromethyl)-4,5,6,7- tetrahydro-lH-indol-4-ol [M + H − H.sub.2O].sup.+: 334.11 22 [00039] 1-(3-bromo-5-flucrophenyl)-5,5- difluoro-3-(trifluoromethyl- 4,5,6,7-tetrahydro-1H-indol-4-ol [M + H − H.sub.2O].sup.+: 395.92 23 [00040] 5,5-difluoro-1-(pyridin-3-yl)-3- (trifluoromethyl)-4,5,6,7- tetrahydro-1H-indol-4-ol [M + H].sup.+: 319.10 24 [00041] 5,5-difluoro-1-(3-fluoro-5- (trifluoromethylphenyl)-3- (trifluoromethyl)-4,5,6,7- tetrahydro-1H-indol-4-ol [M + H − H.sub.2O].sup.+: 386.00 25 [00042] 5,5-difluoro-3-(trifluoromethyl)- 1-(4-(trifluoromethylphenyl)- 4,5,6,7-tetrahydro-1H-indol-4-ol [M + H − H.sub.2O].sup.+: 368.25 26 [00043] 5,5-difluoro-1-(p-tolyl)-1-3- (trifluoromethyl)-4,5,6,7- tetrahydro-1H-indol-4-ol [M + H − H.sub.2O].sup.+: 314.16 27 [00044] 5,5-difluoro-1-13-fluoro-5- hydroxyphenyl)-3- (trifluoromethyl)-4,5,6,7- tetrahydro-1H-indol-4-ol [M + H − H.sub.2O].sup.+: 334.00

EXAMPLE 28 AND EXAMPLE 29

Synthesis of 1-(3-chloro-5-fluorobenzyl)-5,5-difluoro-3-(trifluoromethyl)-1,5,6,7-tetrahydro-4H-indol-4-one (Compound a19) and 1-(3-chloro-5-(fluorobenzyl)-5,5-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol (Compound A3)

[0465] ##STR00045##

Step 1: Synthesis of Compound 3-1

[0466] Intermediate M1 (300 mg) was dissolved in DMF (10 mL), K.sub.2CO.sub.3 (276 mg) and 3-chloro-5-fluorobenzyl bromide (245 mg) were added, stirred at room temperature for two hours. The reaction mixture was poured into water, extracted twice with ethyl acetate, washed twice with saturated brine, dried, and concentrated to obtain the crude product, which was purified by column chromatography (EA/PE=1:7) to obtain the target compound 3-1 (307 mg). ESI-MS m/z: 440.10 [M+H].sup.+.

Step 1: Synthesis of Compound A19

[0467] Compound 3-1 (307 mg) was dissolved in DMF (5 mL) under nitrogen protection, Pd.sub.2(dba).sub.2 (192 mg), CuI (133 mg) and methyl fluorosulfonyldifluoroacetate (265 mg) were added, stirred at 100° C. for three hours, the reaction solution was extracted with ethyl acetate, the organic layer was washed with brine, dried over Na.sub.2SO.sub.4, and concentrated to obtain the crude product, which was purified by column chromatography (EA/PE=1:10) to obtain the target compound A19 (186 mg). ESI-MS m/z: 382.20 [M+H].sup.+.

Step 3: Synthesis of Compound A3

[0468] Compound A19 (186 mg) was dissolved in methanol (4 mL), NaBH.sub.4 (56 mg) was added in an ice bath, after stirring at 0° C. for 1 hour, ice water was added, the mixture was extracted with ethyl acetate, the organic layer was washed with brine, dried over Na.sub.2SO.sub.4 and concentrate to obtain the crude product, which was purified by Prep-TLC (EA/PE=1:5) to obtain the target compound A3 (158 mg). ESI-MS m/z: 366.22 [M+H−H.sub.2O].sup.+.

[0469] Using a method substantially similar to example 1-example 28, such as replacing

##STR00046##

with

##STR00047##

etc., to prepare the following example.

TABLE-US-00003 Example number Structure Chemical name ESI-MS 30 [00048] 5,5-difluoro-1-benzyl-3- (trifluorometlyl)-4,5,6,7-tetrahydro- 1H-indol-4-ol [M + H − H.sub.2O].sup.+: 314.14 31 [00049] 1-((3,3-difluorocyclobutyl)methyl)- 5,5-difluoro-3-(trifluoromethyl)- 4,5,6,7-tetrahydro-1H-indol-4-ol [M + H − H.sub.2O].sup.+: 328.10 32 [00050] (5,5-difluoro-4-hydroxy-3- (trifluoromethyl-4,5,6,7-tetrahydro- 1H-indol-1-yl)(3,3- difluorocyclobutyl)methanone [M + H − H.sub.2O].sup.+: 342.07

EXAMPLE 33 AND EXAMPLE 34

Synthesis of 1-(3,5-difluorophenyl)-5,5-difluoro-1,5,6,7-tetrahydro-4H-indol-4-one (Compound A12) and 1-(3,5-difluorophenyl)-5,5-difluoro-4,5,6,7-tetrahydro-1H-indol-4-ol (Compound A4)

[0470] ##STR00051##

Step 1: Synthesis of Compound 4-1

[0471] Compound M1-1 (2.91 g) was dissolved in THF (40 mL) under nitrogen protection, cooled to −78° C. LiHMDS in tetrahydrofuran solution (1.0 M, 28 mL) was added slowly and dropwised, after stirred for 0.5 h, a solution of NFSI (6.6 g) in tetrahydrofuran (40 mL) was added slowly and dropwise, kept stirring at −78° C. for two hours. The reaction mixture was quenched by the addition of saturated aqueous ammonium chloride solution, extracted twice with ethyl acetate, washed twice with saturated brine, dried, and concentrated to obtain the crude compound 4-1 (2.8 g), which was directly used in the next step.

Step 2: Synthesis of Compound 4-2

[0472] The crude compound 4-1 (2.8 g) was dissolved in a mixed solvent of THF (20 mL)/H.sub.2O (20 mL), K.sub.2CO.sub.3 (2.76 g) was added at room temperature, and stirring was continued for three hours. The reaction mixture was extracted with ethyl acetate, the organic layer was washed with brine, dried over Na.sub.2SO.sub.4, and concentrated to obtain the crude product, which was purified by column chromatography (DCM=100%) to obtain the target compound 4-2 (512 mg). ESI-MS m/z: 172.12 [M+H].sup.+.

Step 3: Synthesis of Compound A12

[0473] Compound 4-2 (171 mg) was dissolved in DCM (50 mL), copper acetate (90 mg), 3,5-difluorophenylboronic acid (316 mg), TEA (404 mg) were added, stirred at room temperature overnight, the reaction mixture was diluted with dichloromethane, washed twice with saturated brine, dried, filtered, and concentrated to obtain the crude product, which was purified by column chromatography (EA/PE=1:5) to obtain the target compound A12 (170 mg). ESI-MS m/z: 294.08 [M+H].sup.+.

Step 4: Synthesis of Compound A4

[0474] Compound A12 (170 mg) was dissolved in methanol (4 mL), NaBH.sub.4 (46 mg) was added in an ice bath, after stirred at 0° C. for 1 hour, ice water was added, the mixture was extracted with ethyl acetate, and the organic layer was washed with brine, dried over Na.sub.2SO.sub.4 and concentrate to obtain the crude product, which was purified by Prep-TLC (EA/PE=1:5) to obtain the target compound A4 (137 mg). ESI-MS m/z: 268.13 MS [M+H−H.sub.2O].sup.+.

EXAMPLE 35 AND EXAMPLE 36

Synthesis of 1-cyclohexyl-5,5-difluoro-3-(trifluoromethyl)-1,5,6,7-tetrahydro-4H-indol-4-one (Compound A20) and 1-cyclohexyl-5,5-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol (Compound A5)

[0475] ##STR00052##

Step 1: Synthesis of Compound 5-1

[0476] Compound M1-2 (19 g), THF (150 mL) and TBAF (13.09 g) were added to a 500 ml single-necked flask sequentially, and the reaction was carried out at room temperature for 30 min. The residue was obtained by concentrating under reduced pressure, PE/EA (V:V=1:1, 100 ml) was added to the residue, suction filtration after stirring, and the obtained filter cake was rinsed twice with EA to give the compound 5-1 (5.2 g).

Step 2: Synthesis of Compound 5-2

[0477] Compound 5-1 (500 mg), cesium carbonate (2.5 g), cyclohexyl 4-methylbenzensulfonate (1.2 g) and DMF (10 mL) were added to a 50 ml single-necked bottle sequentially, the temperature was raised to 100° C., and stirred overnight. The reaction mixture was diluted with EA, washed with water 3 times and with saturated sodium chloride solution once, dried, concentrated to obtain the crude product, which was purified by column chromatography to obtain the target compound 5-2 (230 mg).

Step 3: Synthesis of Compound 5-3

[0478] Using the preparation method similar to compound A19, replacing compound 3-1 with compound 5-2, the target compound 5-3 was prepared.

Step 4: Synthesis of Compound A20

[0479] Using the preparation method similar to Step 3 of intermediate M1, replacing compound M1-2 with compound 5-3, the target compound A20 was prepared.

Step 5: Synthesis of Compound A5

[0480] Using the preparation method similar to compound A4, replacing compound A12 with compound A20, the target compound A5 was prepared. LCMS: 306.18 [M+H−H.sub.2O].sup.+.

EXAMPLE 37

Synthesis of 1-(3,5-difluorophenyl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol (Compound A6)

[0481] ##STR00053##

Step 1: Synthesis of Compound 6-1

[0482] Using the preparation method similar to intermediate M4, replacing M4-4 with M1-1, the target compound 6-1 was prepared.

Step 2: Synthesis of Compound 6-2

[0483] TBAF (21 mL, 1 M in THF) was added into the solution of compounds 6-1 (2.6 g) in THF (30 mL) at room temperature, stirred for 1 hour, the reaction solution was concentrated, diluted with water, extracted with EA, and concentrated to obtain crude product, the crude product was purified by silica gel column (EA:PE=70%) to obtain the target compound 6-2 (1.1 g).

Step 3: Synthesis of Compound 6-3

[0484] Potassium carbonate (968 mg), 1,3,5-trifluorobenzene (617 mg) were added into a solution of compound 6-2 (500 mg) in DMF (10 mL) at room temperature, then warmed to 100° C. and stirred overnight, the reaction mixture was quenched with water, diluted with ethyl acetate, and concentrated to obtain the crude product, which was purified by column chromatography (EA:PE=17%) to obtain the target compound 6-3 (400 mg).

Step 4: Synthesis of Compound 6-4

[0485] Compound 6-3 (100 mg), cuprous iodide (111.18 mg), NMP (3 mL) and methyl fluorosulfonyl difluoroacetate (112.15 mg) were added to a 25 ml single-neck bottle sequentially, the temperature was raised to 120° C., stirred for 6 h, the reaction mixture was diluted with EA, washed three times with water, washed once with saturated brine, dried, and concentrated to obtain the crude product, which was purified by Prep-TLC (DCM:PE=2:1) to obtain the target compound 6-4 (9.8 mg). ESI-MS m/z: 332.06 [M+H].sup.+.

Step 5: Synthesis of Compound A6

[0486] Using the preparation method similar to M3, replacing compound M3-1 with compound 6-4, the target compound A6 was prepared. LCMS: [M+H−H.sub.2O].sup.+: 300.09.

EXAMPLE 38 AND EXAMPLE 39

Synthesis of 3-fluoro-5-(3-(methylsulfonyl)-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl)benzonitrile (Compound A24) and 3-fluoro-5-(4-hydroxyl-3-(methylsulfonyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)benzonitrile (Compound A8)

[0487] ##STR00054##

Step 1: Synthesis of Compound 8-1

[0488] Potassium carbonate (1000 mg) and 3,5-difluorobenzonitrile (700 mg) were added to a solution of compound 5-1 (500 mg) in DMF (10 mL) at room temperature, then warmed to 100° C. and stirred overnight, the reaction mixture was quenched with water, diluted with ethyl acetate, and concentrated to obtain the crude product, which was purified by column chromatography (EA:PE=17%) to obtain the target compound 8-1 (350 mg).

Step 2: Synthesis of Compound 8-2

[0489] Compound 8-1 (380 mg), methyl 3-sulfanyl propionate (240 mg), Xantphas (116 mg) and Pd.sub.2(dba).sub.3 (89 mg) were added to toluene (10 mL), stirred at 70° C. overnight, concentrated to obtain a residue, the residue was purified by column chromatography to obtain the target compound 8-2 (232 mg).

Step 3: Synthesis of Compound 8-3

[0490] Potassium tert-butoxide (43 mg) was added to a solution of compound 8-2 (120 mg) in THF (10 mL) at −78° C., stirred until the starting material disappeared, and iodomethane (92 mg) was added, stirred for 5 hours, the reaction was quenched with saturated ammonium chloride, extracted with ethyl acetate, and concentrated to obtain the crude product, which was purified by column chromatography to obtain the target compound 8-3 (71 mg).

Step 4: Synthesis of Compound A24

[0491] m-CPBA (223 mg) was added to a solution of compound 8-3 (130 mg) in dichloromethane (10 mL) at room temperature, stirred at room temperature for 10 hours, the reaction mixture was extracted with aqueous sodium thiosulfate solution and diluted with dichloromethane, washed with aqueous sodium bicarbonate solution, and saturated brine, dried, and concentrated to obtain the crude product, which was purified by column chromatography to obtain the target compound A24 (71 mg). ESI-MS m/z: 333.20 [M+H].sup.+.

Step 5: Synthesis of Compound A8

[0492] Using the preparation method similar to compound A2, replacing compound A13 with compound 8-4, the target compound 8 was prepared. ESI-MS m/z: 317.11 [M+H−H.sub.2O].sup.+.

EXAMPLE 40

Synthesis of 1-(3,5-difluorophenyl)-4-hydroxyl-4,5,6,7-tetrahydro-1H-indol-3-carbonitrile (Compound A25)

[0493] ##STR00055##

Step 1: Synthesis of Compound A25-1

[0494] Potassium carbonate (900 mg), 1,3,5-trifluorobenzene (600 mg) were added to a solution of compound 5-1 (450 mg) in DMF (10 mL) at room temperature, then warmed to 100° C. and stirred overnight, the reaction mixture was quenched with water, diluted with ethyl acetate, and concentrated to obtain the crude product, which was purified by column chromatography (EA:PE=17%) to obtain the target compound A25-1 (400 mg).

Step 2: Synthesis of Compound 25-2

[0495] Compound A25-1 (200 mg) was dissolved in DMF (5 mL), Zn(CN).sub.2 (117 mg) and Pd(PPh.sub.3).sub.4 (58 mg) were added under nitrogen protection, the reaction mixture was stirred at 120° C. for 2 hours, extracted with ethyl acetate, the organic layer was washed with brine, dried over Na.sub.2SO.sub.4, and concentrated to obtain the crude product, which was purified by column chromatography (EA/PE=1:3) to obtain the target compound A25-2 (120 mg).

Step 3: Synthesis of Compound A25

[0496] Compound A25-2 (100 mg) was dissolved in a mixed solution of THF (2 mL) and H.sub.2O (1 mL), NaBH.sub.4 (18 mg) was added in an ice bath, stirred at 0° C. for 1 hour. The reaction solution was added ice water, and extracted with ethyl acetate, the organic layer was washed with brine, dried over Na.sub.2SO.sub.4, concentrated to obtain the crude product, which was purified by Prep-TLC (EA/PE=1:3) to obtain the target compound A25 (15 mg). ESI-MS m/z: 257.10 [M+H−H.sub.2O].sup.+.

[0497] Using the method substantially similar to example 1-example 40 to obtain the following compounds

TABLE-US-00004 Example number Structure Chemical name ESI-MS 41 [00056] 3-fluoro-5-(4-hydroxy-3- (trifluoromethyl)-4,5,6,7- tetrahydo-1H-indol-1- yl)benzonitrile [M + H − H.sub.2O].sup.+: 307.12 42 [00057] 1-(3-chloro-5-fluorophenyl)-3- (trifluoromethyl)-1,5,6,7- tetrahydro-4H-indol-4-one [M + H].sup.+: 332.06 43 [00058] 3-fluoro-5-(4-oxo-3- (trifluoromethyl)-4,5,6,7- tetrahydro-1H-indol-1- yl)benzonitrile [M + H].sup.+: 323.12 44 [00059] 1-(3,3-difluorocyclobutyl)-5,5- difluoro-3-(trifluoromethyl)- 4,5,6,7-tetrahydro-1H-indol-4-ol [M + H − H.sub.2O].sup.+: 314.08 45 [00060] 1-(3,3-difluorocyclobutyl)-5,5- difluoro-3-(methylsulfonyl)-4,5,6,7- tetrahydro-1H-indol-1-4-ol [M + H − H.sub.2O].sup.+: 324.08 46 [00061] 2-fluoro-5-(4-hydroxy-3- (trifluoromethyl)-4,5,6,7- tetrahydro-1H-indol-1- yl)benzonitrile [M + H − H.sub.2O].sup.+: 307.10

EXAMPLE 47

Synthesis of 1-(3,5-fluorophenyl)-3-(1-methyl)-1H-pyrazol-5-yl)-4,5,6,7-tetrahydro-1H-indol-4-ol (Compound A7)

[0498] ##STR00062##

Step 1: Synthesis of Compound 7-1

[0499] Pd(dppf)Cl.sub.2 (12.52 mg), K.sub.2CO.sub.3 (42.38 mg), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-3-yl)pyrazole (38.28 mg) were added to a mixed solution of compound 6-3 (50 mg) in dioxane (2 mL)/H.sub.2O (0.5 mL) at room temperature, the atmosphere was replaced with nitrogen three times, and microwaved at 100° C. for 1 h, the reaction mixture was diluted with water, extracted with ethyl acetate, dried and concentrated to obtain the target compound 7-1 (40 mg).

Step 2: Synthesis of Compound A7

[0500] Using the preparation method similar to compound A2, replacing compound A13 with compound 7-1, the target compound A7 was prepared ESI-MS m/z: 312.14 [M+H].sup.+.

EXAMPLE 48

Synthesis of (S)-1-(3-chloro-5-fluorophenyl)-5,5-difluoro-3-(thiophen-2-yl)-4,5,6,7-tetrahydro-1H-indol-4-ol (Compound A65)

[0501] ##STR00063##

Step 1: Synthesis of Compound A65-1

[0502] Compound A13 (100 mg), 2-thiopheneboronic acid (36 mg), Pd(PPh.sub.3).sub.4 (30 mg), potassium carbonate (97 mg) were added into dioxane (5 mL) and water (1 mL), the reaction was carried out at 90° C. overnight under N.sub.2 protection, and then diluted with ethyl acetate, washed with saturated brine, dried over sodium sulfate, concentrated, and prepared by Prep-TLC to obtain the target product A65-1 (60 mg). ESI-MS m/z: [M+H].sup.+ 382.05 .

Step 1: Synthesis of Compound A65

[0503] Compound A65-1 (60 mg) was dissolved in dichloromethane (2 mL), cooled in an ice-water bath, [(R,R)-Ts-DPEN]RuCl(p-cymene) (10 mg), TEA (32 mg)) and formic acid (23 mg) were added, stirred at room temperature overnight, the reaction mixture was diluted with dichloromethane, washed with saturated brine, the organic phase was spin-dried, and purified by Prep-TLC to obtain the target product A65 (23 mg). ESI-MS m/z: [M+H−H.sub.2O] .sup.+: 366.11. .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 7.53-7.45 (m, 3H), 7.43-7.36 (m, 2H), 7.33 (d, J=3.5 Hz, 1H), 7.08 (dd, J=5.1, 3.5 Hz, 1H), 6.01 (d, J=6.5 Hz, 1H), 5.75 (s, 1H), 4.60 (d, J=6.2 Hz, 1H), 2.90 (ddd, J=17.0, 11.3, 6.3 Hz, 1H), 2.80 (dd, J=16.2, 6.4 Hz, 1H), 2.19-2.11 (m, 1H).

EXAMPLE 49

Synthesis of 1-(4-fluorobenzyl)-3-(1-methyl-1H-pyrazol-5-yl)-4,5,6,7-tetrahydro-1H-indol-4-ol (Compound A79)

[0504] ##STR00064##

Step 1: Synthesis of Compound A 79-1

[0505] Compound M1-2 (19 g), THF (150 mL) and TBAF (13.09 g) were added to a 500 ml single-necked flask sequentially, the reaction was carried out at room temperature for 30 min. Concentrated under reduced pressure to get a residue, and PE/EA (V: V=1:1, 100 ml) was added to the residue, suction filtration after stirring, and the obtained filter cake was rinsed twice with EA to obtain compound A79-1 (5.2 g).

Step 1: Synthesis of Compound A79-2

[0506] Compound A79-1 (300 mg) was dissolved in DMF (10 mL), K.sub.2CO.sub.3 (276 mg) and 4-fluorobenzyl bromide (260 mg) were added, the mixture was stirred at room temperature for two hours. The reaction mixture was poured into water, washed with ethyl acetate, extracted twice with EA, washed twice with saturated brine, dried, and concentrated to obtain the crude product, which was purified by column chromatography (EA/PE=1.7) to obtain the target compound A79-2 (200 mg).

Step 3: Synthesis of Compound A 79-3

[0507] Pd(dppf)Cl.sub.2 (44 mg), K.sub.2CO.sub.3 (112 mg), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)pyrazole (112 mg) were added into a mixed solution of compound A79-2 (100 mg) in dioxane (2 mL)/H.sub.2O (0.5 mL), the atmosphere was replaced with nitrogen three times. The reaction was carried out at 100° C. for 6 hours, the reaction mixture was diluted with water, extracted with ethyl acetate, dried, concentrated to obtain the target compound A79-3 (40 mg).

Step 4: Synthesis of Compound A 79

[0508] Using the preparation method similar to compound A2, it was prepared by reduction of sodium borohydride. LCMS: 308.21 [M+H−H.sub.2O].sup.+.

[0509] Using a method substantially similar to example 1-49, such as replacing

##STR00065##

with

##STR00066##

etc., to prepare the following example.

TABLE-US-00005 Example number Structure Chemical name ESI-MS 50 [00067] 1-(3,5-difluorophenyl)-5,5- difluoro-3-(thiophen-2-yl)-4,5,6,7- tetrahydro-1H-indol-4-ol [M + H − H.sub.2O].sup.+: 350.10 51 [00068] 1-(3-chloro-5-fluorophenyl)-5,5- difluoro-3-(1-methyl-1H-pyrrol-2- yl)-4,5,6,7-tetrahydro-1H-indol-4- ol [M + H].sup.+: 381.10 52 [00069] 1-(3-chloro-5-fluorophenyl)-3- cyclopropyl-5,5-difluoro-4,5,6,7- tetrahydro-1H-indol-4-ol [M + H − H.sub.2O].sup.+: 324.10 53 [00070] 1-(3-chloro-5-fluorophenyl)-5,5- difluoro-3-(furan-2-yl)-4,5,6,7- tetrahydro-1H-indol-4-ol [M + H − H.sub.2O].sup.+: 350.18 54 [00071] 5-(5,5-difluoro-4-hydroxy-3- (thiazol-5-yl)-4,5,6,7-tetrahydro- 1H-indol-1-yl)-2-fluorobenzonitrile [M + H].sup.+: 376.30 55 [00072] 1-(3-chloro-5-fluorophenyl)-3,5- difluoro-3-(furan-3-yl)-1,5,6,7- tetrahydro-4H-indol-4-one [M + H].sup.+: 366.17 56 [00073] 1-(3-chloro-5-fluorophenyl)-5,5- difluoro-3-(furan-3-yl)-4,5,6,7- tetrahydro-1H-indol-4-ol [M + H − H.sub.2O].sup.+: 350.18 57 [00074] 1-(3-chloro-5-fluoroprophenyl)-5,5- difluoro-3-(1H-pyrazol-3-yl)- 4,5,6,7-tetrahydro-1H-indol-4-ol [M + H − H.sub.2O].sup.+: 350.11 58 [00075] 1-(3-chloro-5-fluorophenyl)-5,5- difluoro-3-(5-methyl-1H-pyrazol- 3-yl)-4,5,6,7-tetrahydro-1H-indol- 4-ol [M + H − H.sub.2O].sup.+: 365.24 59 [00076] 1-(3-chloro-5-fluorophenyl)-5,5- difluoro-3-(1-methyl-1H-pyrazol- 5-yl)-4,5,6,7-tetrahydro-1H-indol- 4-ol [M + H].sup.+: 382.16 60 [00077] 1-(3-chloro-5-fluorophenyl)-5,5- difluoro-3-(thiophen-3-yl)-4,5,6,7- tetrahydro-1H-indol-4-ol [M + H − H.sub.2O].sup.+: 366.08 61 [00078] 1-(3-chloro-5-(fluorophenyl)-5,5- difluoro-3-methyl-4,5,6,7- tetrahydro-1H-indol-4-ol [M + H − H.sub.2O].sup.+: 298.13 62 [00079] 1-(3-chloro-5-fluorophenyl)-5,5- difluoro-3-(thiazol-4-yl)-4,5,6,7- tetrahydro-1H-indol-4-ol [M + H − H.sub.2O].sup.+: 367.00 63 [00080] 1-(3-chloro-5-fluorophenyl)-5,5- difluoro-3-(thiazol-5-yl)-4,5,6,7- tetrahydro-1H-indol-4-ol [M + H − H.sub.2O].sup.+: 367.00

EXAMPLE 64

Synthesis of (S)-1-(3,5-difluorophenyl)-5,5-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol (Compound A9)

[0510] ##STR00081##

Step 1: Synthesis of Compound 9-1

[0511] Compound M1 (300 mg) was dissolved in DCM (20 mL), copper acetate (90 mg), 3,5-difluorophenylboronic acid (350 mg) and TEA (404 mg) were added, and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with dichloromethane, washed twice with saturated brine, dried, concentrated to obtain the crude product, which was purified by column chromatography (EA/PE=1.5) to obtain the target compound 9-1 (230 mg). ESI-MS m/z: 409.11 [M+H].sup.+.

Step 2: Synthesis of Compound A 9-2

[0512] Compound 9-1 (230 mg) was dissolved in DMF (5 mL) under nitrogen protection, Pd.sub.2(dba).sub.4 (165 mg), CuI (114 mg) and methyl fluorosulfonyldifluoroacetate (230 mg) were added, stirred at 100° C. for 3 hours, extracted with ethyl acetate, the organic layer was washed with brine, dried over Na.sub.2SO.sub.4, concentrated to obtain the crude product, the crude product was purified by column chromatography (EA/PE=1.5) to obtain the target compound 9-2 (150 mg). ESI-MS m/z: 352.20 [M+H].sup.+.

Step 3: Synthesis of Compound A9

[0513] Compound 9-2 (150 mg) was dissolved in dichloromethane (5 mL), formic acid (0.03 mL) and triethylamine (1.05 mL) were added, the reaction mixture was sparged with nitrogen, [(R,R)-Ts-DPEN]RuCl(p-cymene)] (12 mg) was added, the reaction mixture was stirred at room temperature under nitrogen protection overnight, concentrated, and the crude product was purified by Prep-TLC (EA/PE=1.5) to obtain the target compound A9 (100 mg). LC-MS: 336.20 [M+H−H.sub.2O].sup.+.

EXAMPLE 65

Synthesis of 1-(3-chloro-5-fluorophenyl)-3-(difluoromethyl)-5,5-difluoro-4,5,6,7-tetrahydro-1H-indol-4-ol (Compound A29)

[0514] ##STR00082##

Step 1: Synthesis of Compound A29-1

[0515] Compound A13 (400 mg) was dissolved in a mixed solvent of dioxane (5 mL) and H.sub.2O (5 mL) under nitrogen protection, Pd(PPh.sub.3).sub.4 (109 mg), K.sub.2CO.sub.3 (390 mg) and vinyl borate pinacol ester (217 mg), stirred at 90° C. overnight, extracted with ethyl acetate, the organic layer was washed with brine, dried over Na.sub.2SO.sub.4, and concentrated to obtain the crude product, which was purified by column chromatography (EA/PE=1.5) to obtained the target compound A29-1 (210 mg). ESI-MS m/z: 326.03 [M+H].sup.+.

Step 2: Synthesis of Compound A29-2

[0516] Compound A29-1 (210 mg) was dissolved in a mixed solvent of THF (5 mL) and H.sub.2O (5 mL), NaIO.sub.4 (414 mg) and potassium osmate (20 mg) were added, stirred at room temperature for 2 hours, extracted with ethyl acetate, the organic layer was washed with brine, dried over Na.sub.2SO.sub.4, and concentrated to obtain the crude product, which was purified by Prep-TLC (EA/PE=1.4) to obtain the target compound A29-2 (45 mg). ESI-MS m/z: 328.10 [M+H].sup.+.

Step 3: Synthesis of Compound A29-3

[0517] Compound 29-2 (80 mg) was dissolved in dichloromethane (4 mL) under nitrogen protection, and DAST (98 mg) was added in an ice bath, after the dropwise addition, the mixture was warmed to room temperature and stirred overnight. The reaction mixture was quenched with saturated sodium bicarbonate, extracted with ethyl acetate, the organic layer was washed with brine, dried over Na.sub.2SO.sub.4, and concentrated to obtain the crude product, which was purified by Prep-TLC (EA/PE=1.4) to obtain the target compound A29-3 (45 mg). ESI-MS m/z: 350.05 [M+H].sup.+.

Step 4: Synthesis of Compound A29

[0518] Compound A29-3 (45 mg) was dissolved in a mixed solvent of THF (5 mL) and H.sub.2O (5 mL), NaBH.sub.4 (20 mg) was added in an ice bath, the reaction was carried out at 90° C. for 0.5 hour, extracted with ethyl acetate, the organic layer was washed with brine, dried over Na.sub.2SO.sub.4, and concentrated to obtain the crude product, which was purified by Prep-TLC (EA/PE=1.3) to obtain the target compound A29 (30 mg). ESI-MS m/z: 334.04 [M+H−H.sub.2O].sup.+.

EXAMPLE 66

Synthesis of 1-(3-chloro-5-fluorophenyl)-5,5-difluoro-3-vinyl-4,5,6,7-tetrahydro-1H-indol-4-ol (Compound D12)

[0519] ##STR00083##

[0520] Compound D12 was obtained by reduction of A29-1 with sodium borohydride using a preparation method similar to that of compound A2. ESI-MS m/z: [M+H−H.sub.2O].sup.+ 310.17.

EXAMPLE 67

Synthesis of 1-(3-chloro-5-fluorophenyl)-5,5-difluoro-3-(hydroxymethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol (Compound D20)

[0521] ##STR00084##

[0522] Compound D20 was obtained by reduction of A29-2 with sodium borohydride using a similar preparation method to compound A2. ESI-MS m/z: [M+H−H.sub.2O] .sup.+: 314.00.

EXAMPLE 68

Synthesis of 3-(3-chloro-5-fluorophenyl)-7-fluoro-1-(trifluoromethyl)-5,6,7,8-tetrahydroindolizin-8-ol (Compound D70)

[0523] ##STR00085##

Step 1: Synthesis of Compound D70-1

[0524] Compound M4 (300 mg) and (3-chloro-5-fluorophenyl)boronic acid (260 mg) were dissolved in a mixed solvent of 1,4-dioxane (5 mL) and water (1 mL) under nitrogen protection, Pd(PPh.sub.3).sub.4 (110 mg) and potassium carbonate (276 mg) were added, the reaction mixture was stirred in an oil bath at 90° C. for 0.5 hours, the reaction solution was extracted twice with ethyl acetate, washed twice with saturated brine, dried and concentrate to obtain the crude product, which was purified by column chromatography (EA/PE=1.2) to obtain the target compound D70-1 (185 mg). ESI-MS m/z: 350.09 [M+H].sup.+.

Step 2: Synthesis of Compound D70

[0525] Compound D70-1 (120 mg) was dissolved in methanol (4 mL), NaBH.sub.4 (76 mg) was added in an ice bath. After stirred at 0° C. for 1 hour, ice water was added, the mixture was extracted with ethyl acetate, and the organic layer was washed with brine, dried over Na.sub.2SO.sub.4, and concentrated to obtain the crude product, which was purified by Prep-TLC (EA/PE=1.2) to obtain the target compound D70 (96 mg). ESI-MS m/z: 334.01 [M+H].sup.+.

EXAMPLE 69 AND EXAMPLE 70

Synthesis of 5-(7,7-difluoro-8-hydroxyl-1-(trifluoromethyl)-5,6,7,8-tetrahydroindolizin-3-yl)-2-fluorobenzonitrile (Compound D79) and (S)-5-(7,7-difluoro-8-hydroxyl-1-(trifluoromethyl)-5,6,7,8-tetrahydroindolizin-3-yl)-2-fluorobenzonitrile (Compound D76)

[0526] ##STR00086##

Step 1: Synthesis of Compound D76-1

[0527] Compound M5 (317 mg) and (3-cyano-4-fluorophenyl)boronic acid (248 mg) were dissolved in a mixed solvent of 1,4-dioxane (5 mL) and water (1 mL) under nitrogen protection, Pd(PPh.sub.3).sub.4 (110 mg) and potassium carbonate (276 mg) were added, the reaction mixture was stirred in an oil bath at 90° C. for 0.5 h, extracted twice with ethyl acetate, washed twice with saturated brine, dried and concentrated to obtain the crude product, which was purified by column chromatography (EA/PE=1.2) to obtain the target compound D76-1 (215 mg). ESI-MS m/z: 358.45 [M+H].sup.+.

Step 2: Synthesis of Compound D79

[0528] Compound D76-1 (100 mg) was dissolved in methanol (4 mL), NaBH.sub.4 (38 mg) was added in an ice bath, after stirring at 0° C. for 1 hour, ice water was added, the reaction mixture was extracted with ethyl acetate, the organic layer was washed with brine, dried over Na.sub.2SO.sub.4, concentrated to give the crude product, which was purified by Prep-TLC (EA/PE=1.3) to give the compound D79 (72 mg). ESI-MS m/z: 343.11 [M+H−H.sub.2O].sup.+.

Step 3: Synthesis of Compound D76

[0529] Compound D76-1 (100 mg) was dissolved in dichloromethane (5 mL), formic acid (0.03 mL) and triethylamine (1.05 mL) were added, the reaction mixture was sparged with nitrogen, [(R,R)-Ts-DPEN]RuCl(p-cymene) (12 mg) was stirred at room temperature under nitrogen protection overnight, concentrated, the crude product was purified by Prep-TLC (EA/PE=1:3) to obtain the target compound D76 (68 mg). LC-MS m/z: 343.09 [M+H−H.sub.2O].sup.+.

[0530] Using a method substantially similar to example 1-example 70, such as replacing

##STR00087##

with

##STR00088##

etc., to prepare the following example.

TABLE-US-00006 Example number Structure Chemical name ESI-MS 71 [00089] 3-(3-chloro-5-fluoropheny1)-7,7- difluoro-1-(trifluoromethyl)- 5,6,7,8-tetrahydroindolizin-8-ol [M + H − H.sub.2O].sup.+: 352.03 72 [00090] 7-fluoro-3-phenyl-1- (trifluoromethyl)-5,6,7,8- tetrahydroindolizin-8-ol [M + H − H.sub.2O].sup.+: 282.04 73 [00091] 3-(3,5-difluorophenyl)-7-fluoro-1- (trifluoromethyl)-5,6,7,8- tetrahydroindolizin-8-ol [M + H − H.sub.2O].sup.+: 318.08 74 [00092] 7-fluoro-3-(4-fluoro-3- (trifluoromethyl)phenyl)-1- (trifluoromethyl)-5,6,7,8- tetrahydroindolizin-8-ol [M + H − H.sub.2O].sup.+: 368.23 75 [00093] 2-fluoro-5-(7-fluoro-8-hydroxy-1- (trifluoromethyl)-5,6,7,8- tetrahydroindolizin-3- yl)benzonitrile [M + H − H.sub.2O].sup.+: 325.00 76 [00094] 3-(3,5-difluorophenyl)-7,7- difluoro-1-(trifluoromethyl)- 5,6,7,8-tetrahydroindolizin-8-ol [M + H − H.sub.2O].sup.+: 335.97 77 [00095] 3-(7,7-difluoro-8-hydroxy-1- (trifluoromethyl)-5,6,7,8- tetrahydroindolizin-3-yl)-5- fluorobenzonitrile [M + H − H.sub.2O].sup.+: 343.13 78 [00096] (E)-3-(2-cyclohexylvinyl)-7,7- difluoro-1-(trifluoromethyl)- 5,6,7,8-tetrahydroindolizin-8-ol [M + H − H.sub.2O].sup.+: 332.16 79 [00097] 3-(cyclopropylethynyl)-7,7- difluoro-1-(trifluoromethyl)- 5,6,7,8-tetrahydroindolizin-8-ol [M + H − H.sub.2O].sup.+: 228.08 80 [00098] 3-(3-(difluoromethyl)-4- fluorophenyl)-7,7-difluoro-1- (trifluoromethyl)-5,6,7,8- tetrahydroindolizin-8-ol [M + H − H.sub.2O].sup.+: 368.16 81 [00099] 7,7-difluoro-1-(trifluoromethyl)- 3-(3,4,5-trifluorophenyl)-5,6,7,8- tetrahydroindolizin-8-ol [M + H − H.sub.2O].sup.+: 354.03 82 [00100] 7,7-difluoro-3-(4-fluoro-3- (trifluoromethyl)phenyl)-1- (trifluoromethyl)-5,6,7,8- tetrahydroindolizin-8-ol [M + H − H.sub.2O].sup.+: 386.15 83 [00101] 3-(3-(difluoromethyl)-4- fluorophenyl)-7,7-difluoro-1- (trifluoromethyl)-6,7- dihydroindolizin-8(5H)-one [M + H − H.sub.2O].sup.+: 383.02 84 [00102] 7,7-difluoro-1-(trifluoromethyl)- 3-(3,4,5-trifluorophenyl)-6,7- dihydroindolizin-8(5H)-one [M + H − H.sub.2O].sup.+: 370.05 85 [00103] 7,7-difluoro-3-(4-fluoro-3- (trifluoromethyl)phenyl)-1- (trifluoromethyl)-6,7- dihydroindolizin-8(5H)-one [M + H].sup.+: 402.06 86 [00104] 7,7-difluoro-3-(1- phenylcyclopropyl)-1- (trifluoromethyl)-5,6,7,8- tetrahydroindolizin-8-ol [M + H − H.sub.2O].sup.+: 358.14 87 [00105] 7,7-difluoro-3-(phenylethynyl)-1- (trifluoromethyl)-5,6,7,8- tetrahydroindolizin-8-ol [M + H − H.sub.2O].sup.+: 324.13

EXAMPLE 88

Synthesis of 1-(3,5-difluorophenyl)-5,5-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-4-ol (Compound D80)

[0531] ##STR00106##

Step 1: Synthesis of Compound D80-1

[0532] Carbonyldimidazole (32.4 g) was dissolved in 100 mL of chloroform under nitrogen protection, a solution (50 mL) of trifluoroacetic anhydride (32.4 g) in chloroform was added slowly and dropwise in an ice bath, the temperature was warmed to room temperature, a mixture of cyclohexane-1,3-dione (11.2 g) and imidazole (6.8 g) in chloroform (50 mL) was added, continued stirring for 2 h, the reaction mixture was washed with 1M dilute hydrochloric acid solution and saturated brine respectively, dried over anhydrous sodium sulfate, concentrated to obtain a crude product, and the crude product was purified by column chromatography (EA/PE=1.4) to obtain the target compound D80-1 (13.3 g). ESI-MS m/z: 209.15 [M+H].sup.+.

Step 2: Synthesis of Compound D80-2

[0533] Compound D80-1 (2.08 g) was dissolved in ethanol (100 mL) under nitrogen protection, (3.5-difluorophenyl)hydrazine (1.44 g) was added, after refluxed for 3 hours, the reaction solution was concentrated to obtain the crude product, which was purified by column chromatography (EA/PE=1.3) to obtain the target compound D80-2 (1.9 g). ESI-MS m/z: 317.45 [M+H].sup.+.

Step 3: Synthesis of Compound D80-3

[0534] Compound D80-2 (316 mg), 3-methoxypropylamine (534 mg) and pivalic acid (21 mg) were dissolved in a mixture of toluene (20 mL) and cyclohexane (10 mL) under nitrogen protection, refluxed overnight; the reaction solution was spin-dried to obtain the crude target compound D80-3 (326 mg), which was directly used in the next step without purification. ESI-MS m/z: 388.41 [M+H].sup.+.

Step 4: Synthesis of Compound D80-4

[0535] Compound D80-3 (326 mg) was dissolved in acetonitrile (20 mL). SelectFlour (656 mg) was added and the reaction was refluxed for hours, cooled to room temperature, the reaction mixture was treated with 1 M dilute hydrochloric acid (20 mL), and stirred at room temperature for 1 hour, concentrated under reduced pressure to obtain a residue, the residue was partitioned between ethyl acetate and water, the organic layer was washed with brine, dried over Na.sub.2SO.sub.4, concentrated to give crude product, which was purified by column chromatography (EA/PE=1.3) to obtain the target compound D80-4 (213 mg). ESI-MS m/z: 353.10 [M+H].sup.+.

Step 5: Synthesis of Compound D80

[0536] Compound D80-4 (100 mg) was dissolved in methanol (4 mL), NaBH.sub.4 (42 mg) was added in an ice bath, after stirred at 0° C. for 1 hour, ice water was added, the reaction mixture was extracted with ethyl acetate, the organic layer was washed with brine, dried over Na.sub.2SO.sub.4, and concentrated to obtain the crude product, which was purified by Prep-TLC (EA/PE=1.3) to obtain the target compound 80 (81 mg). ESI-MS m/z: 337.23 [M+H−H.sub.2O].sup.+.

[0537] Using a method substantially similar to example 88, substituting different aromatic hydrazine and the following example is obtained.

TABLE-US-00007 Example number Structure Chemical name ESI-MS 89 [00107] 5,5-difluoro-1-(4-fluorophenyl)- 3-(trifluoromethyl)-4,5,6,7- tetrahydro-1H-indazol-4-ol [M + H].sup.+: 337.05 90 [00108] 1-(3-chloro-5-fluorophenyl)-5,5- difluoro-3-(trifluoromethyl)- 4,5,6,7-tetrahydro-1H-indazol-4- ol [M + H].sup.+: 371.03 91 [00109] 3-fluoro-5-(4-hydroxy-3- (trifluoromethyl)-4,5,6,7- tetrahydro-1H-indazol-1- yl)benzonitrile [M − H].sup.+: 322.04 92 [00110] 3-(5,5-difluoro-4-hydroxy-3- (trifluoromethyl)-4,5,6,7- tetrahydro-1H-indazol-1-yl-5- fluorobenzonitrile [M + H].sup.+: 361.95 93 [00111] 1-(4-fluorobenzyl)-3- (methylsulfonyl)-1,5,6,7- tetrahydro-4H-indazol-4-one [M + H].sup.+: 323.18

EXAMPLE 94

Synthesis of (1-(3-chloro-5-fluorophenyl)-5,5-difluoro-4-hydroxyl-4,5,6,7-tetrahydro-1H-indol-3-yl)dimethylphosphine oxide (Compound A50)

[0538] ##STR00112##

Step 1: Synthesis of Compound A50-1

[0539] Compound A13 (864 mg), dimethylphosphine oxide (200 mg), K.sub.3PO.sub.4 (520 mg), Xantphos (118 mg) and palladium acetate (46 mg) were added to DMF (15 mL), and the reaction mixture was stirred at 150° C. overnight under nitrogen protection, after the reaction was completed, the reaction mixture was cooled, added to water, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over sodium sulfate, concentrated, and purified by column chromatography to obtain the target product A50-1 (300 mg).

Step 2: Synthesis of Compound A50

[0540] Using a similar preparation method to compound A2, it was obtained by sodium borohydride reduction reaction. ESI-MS m/z: 360.05 [M+H−H.sub.2O].sup.+. .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 7.57-7.43 (m, 4H), 6.21 (d, J=4.8 Hz, 1H), 4.84 (q, J=7.1 Hz, 1H), 2.87-2.73 (m, 2H), 2.34-2.14 (m, 2H), 1.68 (d, J=13.6 Hz, 6H).

EXAMPLE 95

Synthesis of (S)-5-(5,5-difluoro-4-(hydroxyl-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)-2-fluorobenzonitrile (A61)

[0541] ##STR00113##

Step 1: Synthesis of Compound A61-1

[0542] Compound M2 (214 mg) was dissolved in DCM (10 mL), copper acetate (108 mg), 4-fluoro-3-cyanophenylboronic acid (100 mg), TEA (0.25 mL) were added, the reaction mixture was stirred overnight under oxygen atmosphere, diluted with dichloromethane, washed twice with saturated brine, dried, filtered, and concentrated to obtain the crude product, which was purified by column chromatography (EA/PE=1.3) to obtain the target compound A61-1 (120 mg). ESI-MS m/z: 359.05 [M+H].sup.+.

Step 2: Synthesis of Compound A61

[0543] Compound A61-1 (120 mg) was dissolved in dichloromethane (3 mL), formic acid (0.04 mL) and triethylamine (0.1 mL) were added, the reaction mixture was sparged with nitrogen. [(R,R)-Ts-DPEN]RuCl(p-cymene) (22 mg) was added, the reaction mixture was stirred at room temperature overnight under nitrogen protection, concentrated, and the crude product was purified by Prep-TLC (EA/PE=1.3) to obtain the target compound A61 (90 mg, ee>96%). ESI-MS m/z: 343.05 [M+H−H.sub.2O].sup.+.

EXAMPLE 96

Synthesis of 1-(3-chloro-5-fluorophenyl)-5,5-difluoro-4-hydroxyl-4,5,6,7-tetrahydro-1H-indol-3-carbonitrile (Compound A73)

[0544] ##STR00114##

Step 1: Synthesis of Compound A73-1

[0545] Compound A13 (212 mg) was dissolved in DMF (5 mL), Zn(CN).sub.2 (117 mg) and Pd(PPh.sub.3).sub.4 (58 mg) were added under nitrogen protection, the reaction mixture was stirred at 120° C. for 2 hours, extracted with ethyl acetate, the organic layer was washed with brine, dried over Na.sub.2SO.sub.4, and concentrated to obtain the crude product, which was purified by column chromatography (EA/PE=1.3) to obtain the target compound A73-1 (137 mg). ESI-MS m/z: 325.08 [M+H].sup.+.

Step 2: Synthesis of Compound A73

[0546] Compound A73-1 (100 mg) was dissolved in a mixed solvent of THF (2 mL) and H.sub.2O (1 mL), NaBH.sub.4 (18 mg) was added in an ice bath, stirred at 0° C. for 1 hour. Ice water was added, the reaction mixture was extracted with ethyl acetate, the organic layer was washed with brine, dried over Na.sub.2SO.sub.4, and concentrated to obtain the crude product, which was purified by Prep-TLC (EA/PE=1.3) to obtain the target compound A73 (13 mg). ESI-MS m/z: 309.12 [M+H−H.sub.2O].sup.+.

EXAMPLE 97

Synthesis of 1-(3-chloro-5-fluorophenyl)-5,5-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol (Compound A90)

[0547] ##STR00115##

Step 1: Synthesis of Compound A90-1

[0548] Compound M6 (214 mg) was dissolved in DCM (10 mL), copper acetate (108 mg), 3-chloro-5-fluorophenylboronic acid (105 mg), TEA (0.25 mL) were added, the reaction mixture was stirred overnight under oxygen atmosphere, diluted with dichloromethane, washed twice with saturated brine, dried, filtered, and concentrated to obtain the crude product, which was purified by column chromatography (EA/PE=1.3) to obtain the target compound A90-1 (83 mg). ESI-MS m/z: 368.07 [M+H].sup.+.

Step 2: Synthesis of Compound A90

[0549] Compound A90-1 (104 mg) was dissolved in methanol (4 mL), NaBH.sub.4 (42 mg) was added in an ice bath, after stirring at 0° C. for 1 hour, ice water was added, the reaction mixture was extracted with ethyl acetate, and the organic layer was washed with brine, dried over Na.sub.2SO.sub.4, and concentrated to obtain the crude product, which was purified by Prep-TLC (EA/PE=1.3) to obtain the target compound A90 (63 mg). ESI-MS m/z: 352.07 [M+H−H.sub.2O].sup.+.

EXAMPLE 98

Synthesis of 5,5-difluoro-1-(4-fluoro-3-(hydroxymethyl)phenyl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol (Compound D37)

[0550] ##STR00116##

Step 1: Synthesis of Compound D37-1

[0551] Compound M2 (2.14 g) was dissolved in DCM (20 mL), copper acetate (1.08 g), 4-fluoro-3-aldolphenylboronic acid (1.0 g), TEA (2.48 mL) were added, the reaction mixture was stirred at room temperature overnight under oxygen atmosphere, diluted with dichloromethane, washed twice with saturated brine, dried, filtered and concentrated to obtain the crude product, which was purified by column chromatography (EA/PE=1.3) to obtain the target compound D37-1 (1.1 g). ESI-MS m/z: 362.08 [M+H].sup.+.

Step 2: Synthesis of Compound D37

[0552] Compound D37-1 (350 mg) was dissolved in MeOH (5 mL), sodium borohydride (0.15 g) was added in portions, stirred at room temperature for 6 hours, monitored by LC-MS and TLC, after the reaction was completed, the reaction solution was poured into water, extracted with ethyl acetate, dried and spin-dried, the crude product was purified by column chromatography to give D37 (100 mg). ESI-MS m/z: 348.05 [M+H−H.sub.2O].sup.+.

EXAMPLE 99

Synthesis of 5,5-difluoro-1-(6-fluoropyridin-2-yl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol (Compound D40)

[0553] ##STR00117##

Step 1: Synthesis of Compound D40-1

[0554] Potassium carbonate (866 mg) and 2,6-difluoropyridine (481 mg) were added to a solution of compound M2 (500 mg) in DMF (10 mL) at room temperature, then warmed to 100° C. and stirred overnight, the reaction mixture was quenched by the addition of water, diluted with ethyl acetate, and concentrated to obtain the crude product, which was purified by column chromatography (EA/PE=17%) to obtain the target compound D40-1 (400 mg). ESI-MS m/z: 335.05 [M+H].sup.+.

Step 2: Synthesis of Compound D40

[0555] Using a similar preparation method to compound A2, it was obtained by sodium borohydride reduction reaction. ESI-MS m/z: 319.25 [M+H−H.sub.2O].sup.+.

EXAMPLE 100

Synthesis of 5-(5,5-difluoro-4-hydroxyl-4-methyl-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)-2-fluorobenzonitrile (Compound D46)

[0556] ##STR00118##

Step 1: Synthesis of Compound D46

[0557] Compound A61-1 (36 mg) was dissolved in tetrahydrofuran (5 mL) under nitrogen protection, methylmagnesium chloride (3.0 M, 0.3 mL) was added dropwise in an ice bath, the reaction mixture was stirred at 0° C. for 3 hours, and quenched with 1 M dilute hydrochloric acid, the reaction solution was extracted twice with ethyl acetate, washed twice with saturated brine, dried, and concentrated to obtain the crude product, which was purified by column Pre-TLC (EA/PE=1.3) to obtain the target compound D46 (13 mg). ESI-MS m/z: 357.18 [M+H−H.sub.2O].sup.+. .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 8.20-8.17 (m, 1H), 7.94-7.91 (m, 1H), 7.69 (t, J=9.0 Hz, 1H), 7.61 (s, 1H), 2.83-2.59 (m, 2H), 2.45-2.16 (m, 2H), 1.53 (s, 3H).

EXAMPLE 101

Synthesis of 5-5,5-difluoro-4-hydroxyl-6,6-dimethyl-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)-2-fluorobenzonitrile (Compound D49)

[0558] ##STR00119## ##STR00120##

Step 1: Synthesis of Compound D49-1

[0559] Ethyl trifluoroacetoacetate (25.02 g) was dissolved in glacial acetic acid (38 mL) in an ice bath, an aqueous solution (25 mL) of sodium nitrite (9.37 g) was added in portions, and then the reaction was stirred at 20° C. for 2 hours, concentrated under reduced pressure, water and ethyl acetate were added, the layers were separated, the organic layer was washed with brine, dried over Na.sub.2SO.sub.4, and concentrated to obtain the target compound D49-1 (22 g). ESI-MS m/z: 212.03 [M+H].sup.+.

Step 2: Synthesis of Compound D49-2

[0560] 5,5-dimethyl-1,3-cyclohexanedione (6.0 g) was dissolved in glacial acetic acid (30 mL), heated to 60° C., an aqueous solution (20 mL) of compound D49-1 (9.12 g) was added, zinc powder (5.59 g) was added in batches, heated to 90° C. and stirred for 16 hours after the addition, water and ethyl acetate were added to the reaction system, separated, and the aqueous phase was extracted twice with ethyl acetate, the combined organic phases were washed twice with saturated aqueous sodium bicarbonate solution, dried over Na.sub.2SO.sub.4, and concentrated to obtain the crude product, which was purified by column chromatography (EA/PE=1.3) to obtain the target compound D49-2 (2.2 g, 22.2%) ESI-MS m/z: 232.10 [M+H].sup.+.

Step 3: Synthesis of Compound D49-3

[0561] Compound D49-2 (2.2 g) was dissolved in tetrahydrofuran (30 mL) under nitrogen protection, sodium hydride (0.457 g) was added in portions in an ice bath, the reaction was carried out at 0° C. for 0.5 h, and then a solution of triisopropylchlorosilane (2.75 g) in tetrahydrofuran (5 mL) was added, and the stirring was continued for 1 hour. The reaction solution was poured into ice water to quench, extracted with ethyl acetate, washed with water dried over Na.sub.2SO.sub.4, and concentrated to obtain the crude product, which was purified by column chromatography (EA/PE=1:3) to obtain the target compound D49-3 (2.93 g, 79.5%). ESI-MS m/z: 388.10 [M+H].sup.+.

Step 4: Synthesis of Compound D49-4

[0562] Compound 49-3 (1.05 g) was dissolved in tetrahydrofuran (20 mL) under nitrogen protection, cooled to −78° C., and LiHMDS in tetrahydrofuran solution (1.0 M, 7.33 mL) was added slowly and dropwise, after stirring for half an hour, a solution of NFSI (1.79 g) in tetrahydrofuran (10 mL) was added dropwise, and kept stirring at −78° C. for two hours. The reaction mixture was quenched by the addition of saturated aqueous ammonium chloride solution, extracted twice with ethyl acetate, and washed twice with saturated brine, dried and concentrated to obtain the crude product, which was purified by column chromatography (DCM=100%) to obtain the target compound D49-4 (0.73 g, 55.2%). ESI-MS m/z: 425.05 [M+H].sup.+.

Step 5: Synthesis of Compound D49-5

[0563] The crude compound D49-4 (0.73 g) was dissolved in a mixed solvent of THF (20 mL)/water (20 mL), K.sub.2CO.sub.3 (0.48 g) was added at room temperature, and stirring was continued for three hours. The reaction mixture was extracted with ethyl acetate, the organic layer was washed with brine, dried over Na.sub.2SO.sub.4, and concentrated to obtain the crude product, which was purified by column chromatography (DCM=100%) to obtain the target compound D49-5 (402 mg). ESI-MS m/z: 268.12 [M+H].sup.+.

Step 6: Synthesis of Compound D49-6

[0564] Compound D-49-5 (402 mg) was dissolved in DCM (20 mL), copper acetate (275 mg), 3,5-difluorophenylboronic acid (494 mg), TEA compound (304 mg) were added, the reaction mixture was stirred at room temperature overnight, diluted with dichloromethane, washed twice with saturated brine, dried, filtered, and concentrated to obtain the crude product, which was purified by column chromatography (EA/PE=1:3) to obtain the target compound D49-6 (512 mg). ESI-MS m/z: 387.08 [M+H].sup.+.

Step 7: Synthesis of Compound D49

[0565] Compound D49-6 (50 mg) was dissolved in methanol (4 mL), NaBH.sub.4 (15 mg) was added in an ice bath, after stirring at 0° C. for 1 hour, ice water was added, the reaction mixture was extracted with ethyl acetate, and the organic layer was washed with brine, dried over Na.sub.2SO.sub.4, concentrated to obtain the crude product, which was purified by Prep-TLC (EA/PE=1:4) to obtain the target compound D49 (37 mg, 73.7%). ESI-MS m/z: 371.10 [M+H−H.sub.2O].sup.+.

EXAMPLE 102

Synthesis of 2-fluoro-5-(5-fluoro-4-hydroxyl-6,6-dimethyl-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)benzonitrile (Compound D50)

[0566] ##STR00121##

Step 1: Synthesis of Compound D50-1

[0567] Compound D49-1 (1.0 g) was dissolved in tetrahydrofuran (20 mL) under nitrogen protection, cooled to −78° C., LDA in tetrahydrofuran solution (1.0 M, 3.9 mL) was added slowly and dropwise, after stirred for half an hour. A solution of NFSI (895 mg) in THF (10 mL) was added dropwise, and kept stirring at −78° C. for two hours. The reaction was quenched by the addition of saturated aqueous ammonium chloride, extracted twice with ethyl acetate, washed twice with saturated brine, dried and concentrated to obtain the crude product, which was purified by column chromatography (DCM=100%) to obtain the target compound D50-1 (550 mg). ESI-MS m/z: 406.12 [M+H].sup.+.

Step 2: Synthesis of Compound D50-2

[0568] The crude compound D50-1 (550 mg) was dissolved in mixed solvent of THF (10 mL)/water (10 mL), K.sub.2CO.sub.3 (375 mg) was added at room temperature, and stirring was continued for three hours. The reaction mixture was extracted with ethyl acetate, the organic layer was washed with brine, dried over Na.sub.2SO.sub.4, concentrated to obtain the crude product, which was purified by column chromatography (DCM=100%) to obtain the target compound D50-2 (208 mg). ESI-MS m/z: 205.06 [M+H].sup.+.

Step 3: Synthesis of Compound D50-3

[0569] Compound D50-2 (208 mg) was dissolved in DCM (15 mL), copper acetate (150 mg), 3,5-difluorophenylboronic acid (206 mg), TEA compound (168 mg) were added, stirred at room temperature overnight, the reaction mixture was diluted with dichloromethane, washed twice with saturated brine, dried, filtered, and concentrated to obtain the crude product, which was purified by column chromatography (EA/PE=1:3) to obtain the target compound D50-3 (217 mg). ESI-MS m/z: 369.10 [M+H].sup.+.

Step 4: Synthesis of Compound D50

[0570] Compound D50-3 (100 mg) was dissolved in methanol (4 mL), NaBH.sub.4 (21 mg) was added in an ice bath, after stirred at 0° C. for 1 hour, ice water was added, the reaction mixture was extracted with ethyl acetate, the organic layer was washed with brine, dried over Na.sub.2SO.sub.4, concentrated to obtain the crude product, which was purified by Prep-TLC (EA/PE=1:4) to obtain the target compound D50 (82 mg). ESI-MS m/z: 353.12 [M+H−H.sub.2O].sup.+.

EXAMPLE 103

Synthesis of the Mixture (4S,5S)-1-(3-(difluoromethyl)-4-fluorophenyl)-5-fluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol and (4R,5R)-1-(3-(difluoromethyl)-4-fluorophenyl)-5-fluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol (Compound D51-A, Assumed Structure)

EXAMPLE 104

Synthesis of (4S,5R)-1-(3-(difluoromethyl)-4-fluorophenyl)-5-fluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol (Compound D51-B, Assumed Structure)

EXAMPLE 105

Synthesis of (4R,5S)-1-(3-(difluoromethyl)-4-fluorophenyl)-5-fluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol (Compound D51-C, Assumed Structure)

[0571] ##STR00122##

Step 1: Synthesis of Compound D51-1

[0572] Compound M3 (147 mg) was dissolved in DCM (15 mL), copper acetate (120 mg), 4-fluoro-3-aldophenylboronic acid (167 mg), TEA (136 mg) were added, stirred at room temperature overnight. The reaction mixture was diluted with dichloromethane, washed twice with saturated brine, dried, filtered, and concentrated to obtain the crude product, which was purified by column chromatography (EA/PE=1:3) to obtain the target compound D51-1 (152 mg). ESI-MS m/z: 344.08 [M+H].sup.+.

Step 2: Synthesis of Compound D51-2

[0573] Compound 51-1 (152 mg) was dissolved in DCM (10 mL), DAST (214 mg) was added in an ice bath, stirred at 0° C. for 3 hours, diluted with dichloromethane, washed twice with saturated brine, dried, and filtered, concentrated to obtain the crude product, which was purified by column chromatography (EA/PE=1:3) to obtain the target compound D5102 (129 mg). ESI-MS m/z: 344.08 [M+H].sup.+.

Step 3: Synthesis of Compound D51

[0574] Compound 51-2 (350 mg) was dissolved in MeOH (5 mL), sodium borohydride (0.15 mg) was added in batches, stirred at room temperature for 6 hours, monitored by LC-MS and TLC, after the reaction was completed, the reaction solution was poured into water, extracted with ethyl acetate, dried, spin-dried, the crude product was chromatographed to give D51 (300 mg). D51 was separated by chiral preparation (column type: Daicel CHIRALPAK® IF 250*25 min, 5 μm; mobile phase A: n-hexane, Mobile phase B: ethanol, mobile phase A, mobile phase B-90:10 (V/V); detection wavelength: 254 nM; flow rate: 15 mL/min; column temperature: RT; running time: 25 min; column pressure: 35 Bar) to obtain three elution peaks.

[0575] D51-A (10 mg) was the first eluting peak, Rt=75 min, ESI-MS m/z: 350.12 [M+H−H.sub.2O].sup.+, .sup.1H NMR (500 MHz, DMSO) δ 7.77-7.67 (m, 2H), 7.53-7.59 (m, 2H), 7.23 (5, J=53.9 Hz, 1H), 5.44 (d, J=6.7 Hz, 1H), 4.80 (d, J=47.3 Hz, 1H), 4.64 (s, 1H), 2.64-2.54 (m, 1H), 2.48-2.51 (m, 1H), 2.18-1.94 (m, 2H). D51-B (70 mg) was the second eluting peak, Rt×11 min, ESI-MS m/z: 35.12 [M+H−H.sub.2O].sup.+. .sup.1H NMR (500 MHz, DMSO) δ 7.71 (dd, J=5.7, 2.8 Hz, 2H), 7.62-7.49 (m, 2H), 7.23 (5, J=53.9 Hz, 1H), 5.19 (d, J=6.1 Hz, 1H), 4.92-4.69 (m, 2H), 2.77-2.60 (m, 1H), 2.60-2.51 (m, 1H), 2.26-2.07 (m, 1H), 1.85-1.90 (m, 1H). D51-C (80 mg) was the third eluting peak, Rt=14.5 min, ESI-MS m/z: 350.12 [M+H−H.sub.2O].sup.+. .sup.1H NMR (500 MHz, DMSO) δ 7.71 (dd, J=5.7, 2.8 Hz, 2H), 7.62-7.99 (m, 2H), 7.23 (5, J=53.9 Hz, 1H), 51.9 (d, J=6.1 Hz, 1H), 4.92-4.69 (m, 2H), 2.77-2.60 (m, 1H), 2.60-2.51 (m, 1H), 2.26-2.07 (m, 1H), 1.85-1.90 (m, 1H).

EXAMPLE 106

Synthesis of 1-(3-chloro-5-fluorophenyl)-2,5,5-trifluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol (Compound A41)

[0576] ##STR00123##

Step 1: Synthesis of Compound A41-1

[0577] Compound 1-2 (106 mg) was dissolved in acetonitrile (5 mL) under nitrogen protection, Selectfluor (133 mg) was added, the reaction mixture was stirred at 80° C. for 2 hours, extracted with ethyl acetate, the organic layer was washed with brine, dried over Na.sub.2SO.sub.4, concentrated to obtain the crude product, which was purified by Prep-TLC (EA/PE=1:3) to obtain the target compound A41-1 (79 mg).

Step 2: Synthesis of Compound A41

[0578] Compound A41-1 (79 mg) was dissolved in a mixed solvent of THF (2 mL) and H.sub.2O (1 mL), NaBH.sub.4 (16 mg) was added in an ice bath, stirred at 0° C. for 1 hour. The reaction mixture was added ice water, extracted with ethyl acetate. The organic layer was washed with brine, dried over Na.sub.2SO.sub.4, and concentrated to obtain the crude product, which was purified by Prep-TLC (EA/PE=1:3) to obtain the target compound A41 (45 mg). ESI-MS m/z: 370.02 [M+H−H.sub.2O].sup.+. .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 7.72-7.67 (m, 2H), 7.66-7.62 (m, 1H), 6.22 (d, J=6.4 Hz, 1H), 4.55 (q, J=6.6 Hz, 1H), 2.61-2.57 (m, 2H), 2.41-2.24 (m, 1H), 2.19-2.10 (m, 1H).

EXAMPLE 107

Synthesis of (S)-2-chloro-1-(3-chloro-54-fluorophenyl)-5,5-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol (Compound A75)

[0579] ##STR00124##

Step 1: Synthesis of Compound A75-1

[0580] Compound 1-2 (106 mg) was dissolved in acetonitrile (5 mL) under nitrogen protection, NCS (50 mg) was added, stirred at 80° C. for 2 h, the reaction mixture was extracted with ethyl acetate, the organic layer was washed with brine, dried over Na.sub.2SO.sub.4, concentrated to obtain the crude product, which was purified by Prep-TLC (EA/PE=1:3) to obtain the target compound A75-1 (81 mg). ESI-MS m/z: 401.9 [M+H].sup.+.

Step 2: Synthesis of Compound A75

[0581] Compound A75-1 (40 mg) was dissolved in dichloromethane (3 mL), formic acid (0.01 mL) and triethylamine (0.03 mL) were added, the reaction mixture was sparged with nitrogen, and [(R,R)-Ts-DPEN]RuCl(p-cymene) (12 mg) was added, stirred at room temperature under nitrogen protection overnight, concentrated, and the crude product was purified by Prep-TLC (EA/PE=1:3) to obtain the target compound A75 (15 mg). ESI-MS m/z: 387.85 [M+H−H.sub.2O].sup.+.

EXAMPLE 108

Synthesis of 1-(3-(difluoromethyl)-4-fluorophenyl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol (Compound D95)

[0582] ##STR00125##

Step 1: Synthesis of Compound D95-1

[0583] (4-Fluoro-3-formylphenyl)boronic acid (2.0 g), compound M3-1 (3.63 g), copper acetate (2.16 g) and triethylamine (4.97 mL) were added to dichloromethane (40 mL)), the reaction mixture was stirred at room temperature under an oxygen atmosphere overnight, after the reaction was completed, the reaction mixture was diluted with dichloromethane, washed twice with saturated brine, dried, filtered, and concentrated to obtain a crude product, which was purified by column chromatography (EA/PE=1:3) to obtain the target compound D95-1 (2.1 g). ESI-MS m/z: 326.10 [M+H].sup.+.

Step 2: Synthesis of Compound D95-2

[0584] Compound D95-1 (500 mg) was added to dichloromethane (10 mL), DAST (520 mg) was added, stirred at room temperature, after the reaction was completed, the reaction mixture was diluted with dichloromethane, quenched with saturated sodium bicarbonate, the organic phase was washed with water, dried, filtered, concentrated to obtain the crude product, which was purified by column chromatography (EA/PE=1:3) to obtain the target compound D95-2 (163 mg). ESI-MS m/z: 348.05 [M+H].sup.+.

Step 3: Synthesis of Compound D95

[0585] Compound D95-2 (100 mg) was added to a mixed solution of tetrahydrofuran (2 mL) and water (1 mL), sodium borohydride (80 mg) was added in an ice-water bath, the reaction mixture was stirred at room temperature overnight, diluted with ethyl acetate, washed with saturated brine, the organic layer was dried, and purified by the HPLC to obtain the target product D95 (50 mg). ESI-MS m/z: 305.10 [M+H].sup.+.

[0586] Through different raw materials and/or intermediates, using a preparation method similar to example 1-example 108, the following example was obtained.

TABLE-US-00008 Example number Structure Chemical name ESI-MS 109 [00126] 1-(3-chloro-5-fluorophenyl)-5,5- difluoro-3-(methylsulfonyl)- 4,5,6,7-tetrahydro-1H-indol-4-ol [M + H − H.sub.2O].sup.+: 362.02 110 [00127] 3-(5,5-difluoro-4-hydroxy-3- (methylsulfonyl-4,5,6,7- tetrahydro-1H-indol-1-yl)-5- fluorobenzonitrile [M + H − H.sub.2O].sup.+: 353.06 111 [00128] 3-(3-(difluoromethyl-5,5- difloro-4-hydroxy-4,5,6,7- tetrahydro-1H-indol-1-yl)-5- fluorobenzonitrile [M + H − H.sub.2O].sup.+: 325.10 112 [00129] 3-(3-((difluoromethyl)sulfonyl)- 5,5-difluoro-4-hydroxy-4,5,6,7- tetrahydro-1H-indol-1-yl)-5- fluorobenzonitrile [M + H − H.sub.2O].sup.+: 389.06 113 [00130] 1-(3-chloro-5-fluorophenyl)- 3,5,5-trifluoro-4,5,6,7- tetrahydro-1H-indol-4-ol [M + H − H.sub.2O].sup.+: 302.4 114 [00131] 1-(3-chloro-5-fluorophenyl)-5,5- difluoro-4-hydroxy-3- (trifluoromethyl)-4,5,6,7- tetrahydro-1H-indole-2- carbonitrile [M + H − H.sub.2O].sup.+: 377.03 115 [00132] (R)-1-3-chloro-5- fluorophenyl)-5,5-difluoro-3- (trifluoromethyl)-4,5,6,7- tetrahydro-1H-indol-4-ol [M + H − H.sub.2O].sup.+: 352.00 116 [00133] (S)-1-(3-chloro-5-fluorophenyl)- 5,5-difluoro-3-(trifluoromethyl)- 4,5,6,7-tetrahydro-1H-indol-4-ol [M + H − H.sub.2O].sup.+: 352.00 117 [00134] 1-(3,5-difluorophenyl)-5,5- difluoro-3-(methylsulfonyl)- 4,5,6,7-tetrahydro-1H-indol-4-ol [M + H − H.sub.2O].sup.+: 346.20 118 [00135] 1-(3,5-difluorophenyl)-5,5- difluoro-3-(methylsulfonyl)- 1,5,6,7-tetrahydro-4H-indol-4- one [M + H].sup.+: 362.18 119 [00136] 3-(3-chloro-5-fluorophenyl)-6,6- difluoro-1-trifluoromethyl- 4,5,6,7-tetrahydro-1H-indol-7-ol [M + H − H.sub.2O].sup.+: 352.10 120 [00137] 1-(3-chloro-4-fluorophenyl)-5,5- difluoro-3-(trifluoromethyl)- 4,5,6,7-tetrahydro-1H-indol-4-ol [M + H − H.sub.2O].sup.+: 352.00 121 [00138] 5-(5,5-difluoro-4-hydroxy-3- (trifluoromethyl)-4,5,6,7- tetrahydro-1H-indol-1-yl-2- fluorobenzonitrile [M + H − H.sub.2O].sup.+: 343.05 122 [00139] 4-(5,5-difluoro-4-hydroxy-3- (trifluoromethyl)-4,5,6,7- tetrahydro-1H-indol-1-yl)-2- fluorobenzonitrile [M + H − H.sub.2O].sup.+: 342.95 123 [00140] 5,5-difluoro-1-(1-methyl-1H- pyrrol-2-yl)-3-(trifluoromethyl)- 4,5,6,7-tetrahydro-1H-indol-4-ol [M + H − H.sub.2O].sup.+: 303.09 124 [00141] 2-chloro-4-(5,5-difluoro-4- hydroxy-3-(trifluoromethyl)- 4,5,6,7-tetrahydro-1H-indol-1- yl)benzonitrile [M + H − H.sub.2O].sup.+: 358.95 125 [00142] 4-(5,5-difluoro-4-hydroxy-3- (trifluoromethyl)-4,5,6,7- tetrahydro-1H-indol-1- yl)phthalonitrile [M + H − H.sub.2O].sup.+: 350.00 126 [00143] 5,5-difluoro-1-furan-2-yl)-3- (trifluoromethyl)-4,5,6,7- tetrahydro-1H-indol-4-ol [M + H − H.sub.2O].sup.+: 290.06 127 [00144] 2-cyano-5-(5,5-difluoro-4- hydroxy-3-(trifluoromethyl)- 4,5,6,7-tetrahydro-1H-indol-1- yl)benzoic acid [M + H − H.sub.2O].sup.+: 369.07 128 [00145] 2-acetyl-4-(5,5-difluoro-4- hydroxy-3-(trifluoromethyl)- 4,5,6,7-tetrahydro-1H-indol-1- yl)benzonitrile [M + H − H.sub.2O].sup.+: 367.09 129 [00146] 1-(3-chloro-5-fluorophenyl)-5,6- difluoro-3-methylsulfonyl)- 4,5,6,7-tetrahydro-1H-indol-4-ol [M + H − H.sub.2O].sup.+: 362.02 130 [00147] l-(4-chlorophenyl)-5,6-difluoro- 3-(trifluoromethyl)-4,5,6,7- tetrahydro-1H-indol-4-ol [M + H − H.sub.2O].sup.+: 334.04 131 [00148] 2-fluoro-5-((4S)-5-fluoro-4- hydroxy-3-(trifluoromethyl)- 4,5,6,7-tetrahydro-1H-indol-1- yl)benzonitrile [M + H − H.sub.2O].sup.+: 325.17 132 [00149] 5,6-difluoro-1-(5-fluoropyridin- 3-yl)-3-(trifluoromethyl)- 4,5,6,7-tetranydro-1H-indol-4-ol [M + H − H.sub.2O].sup.+: 319.00 133 [00150] 5,5-difluoro-1-(5-(fluoropyridin- 3-y1)-3-(trifluoromethyl)- 4,5,6,7-tetrahydro-1H-indol-4-ol [M + H − H.sub.2O].sup.+: 318.95 134 [00151] (S)-5-(5,5-difluoro-4-hydroxy-3- (methylsulfonyl)-4,5,6,7- tetrahydro-1H-indol-1-yl)-2- fluorobenzonitrile [M + H − H.sub.2O].sup.+: 352.95 135 [00152] 1-(3-chloro-5-fluorophenyl-5,5- difluoro-3-((S)-methylsulfinyl)- 4,5,6,7-tetrahydro-1H-indol-4-ol [M + H].sup.+: 364.16 136 [00153] 1-(3-chloro-5-fluorophenyl-5,5- difluoro-3-((R)-methylsulfinyl)- 4,5,6,7-tetrahydro-1H-indol-4-ol [M + H].sup.+: 364.13 137 [00154] 2-chloro-5-(5,5-difluoro-4- hydroxy-3-trifluoromethyl)- 4,5,6,7-tetrahydro-1H-indol-1- yl)benzonitrile [M + H − H.sub.2O].sup.+: 359.04 138 [00155] 1-(4-chloro-1-nitrophenyl)-5,5- difluoro-3-(trifluoromethyl)- 4,5,6,7-tetrahydro-1H-indol-4-ol [M + H − H.sub.2O].sup.+: 379.00 139 [00156] 3-fluoro-5-(5-fluoro-4-hydroxy- 3-(trifluoromethyl)-4,5,6,7- tetrahydro-1H-indol-1- yl)benzonitrile [M + H − H.sub.2O].sup.+: 325.00 140 [00157] 1-(3-amino-5-fluorophenyl)-5- fluoro-3-(trifluoromethyl)- 4,5,6,7-tetrahydro-1H-indol-4-ol [M + H − H.sub.2O].sup.+: 315.09 141 [00158] 1-(3-chloro-5-fluorophenyl)-5,7- difluoro-3-trifluoromethyl)- 4,5,6,7-tetrahydro-1H-indol-4-ol [M + H − H.sub.2O].sup.+: 352.03 142 [00159] 1-(3-chloro-5-fluorophenyl)-5- fluoro-3-(trifluoromethyl)- 4,5,6,7-tetrahydro-1H-indol-4-ol [M + H − H.sub.2O].sup.+: 334.11 143 [00160] 1-(3-chloro-5-fluorophenyl)-5- fluoro-2-methyl-3- (trifluoromethyl)-4,5,6,7- tetrahydro-1H-indol-4-ol [M + H − H.sub.2O].sup.+: 348.06 144 [00161] 1-(3-chloro-5-fluorophenyl)-5,5- difluoro-3-phenyl-1,5,6,7- tetrahydro-4H-indol-4-one [M + H].sup.+: 376.23 145 [00162] 1-(3-chloro-5-fluorophenyl-5,5- difluoro-3-phenyl-4,5,6,7- tetrahydro-1H-indol-4-ol [M + H − H.sub.2O].sup.+: 360.17 146 [00163] (S)-2-bromo-1-(3,5- dilfuorophenyl)-5,5-difluoro-3- (trifluoromethyl)-4,5,6,7- tetrahydro-1H-indol-4-ol [M + H − H.sub.2O].sup.+: 433.93/431.94 147 [00164] 5,5-difluoro-1-(thiophen-3-yl)- 3-(trifluoromethyl)-4,5,6,7- tetrahydro-1H-indol-4-ol [M + H − H.sub.2O].sup.+: 306.08 148 [00165] 5,5-difluoro-3-(trifluoromethyl- 1-(3,4,5-trifluorophenyl- 4,5,6,7-tetrahydro-1H-indol-4-ol [M + H − H.sub.2O].sup.+: 354.15 149 [00166] 1-(3,5-dichloro-4-fluorophenyl- 5,5-difluoro-3-(trifluoromethyl)- 4,5,6,7-tetrahydro-1H-indol-4-ol [M + H − H.sub.2O].sup.+: 386.00 150 [00167] 1-(3-chloro-5-fluorophenyl)-6,7- difluoro-1-trifluoromethyl)- 5,6,7,8-tetrahydroindolizin-8-ol [M + H − H.sub.2O].sup.+: 352.03 151 [00168] 3-(3-chloro-5-fluorophenyl)-6,7- difluoro-1-trifluoromethyl- 5,6,7,8-tetrahydroimidazol[1.5- a]pyridin-8-ol [M + H − H.sub.2O].sup.+: 353.03 152 [00169] 3-(3-chloro-5-fluorophenyl)-5,6- difluoro-1-(trifluoromethyl)- 4,5,6,7-tetrahydro-1H-indol-7-ol [M + H − H.sub.2O].sup.+: 352.03 153 [00170] 3-(3-chloro-5-fluorophenyl)-5,6- difluoro-1-(trifluoromethyl)- 4,5,6,7-tetrahydro-1H-indazol-7- ol [M + H − H.sub.2O].sup.+: 353.03 154 [00171] 3-chloro-5-(5,5-difluoro-4- hydroxy-3-(trifluoromethyl)- 4,5,6,7-tetrahydro-1H-indol-1- yl)benzonitrile [M + H − H.sub.2O].sup.+: 359.00 155 [00172] 4-(5,5-difluoro-4-hydroxy-3- (trifluoromethyl)-4,5,6,7- tetrahydro-1H-indol-1-yl-2- methoxybenzonitrile [M + H − H.sub.2O].sup.+: 354.95 156 [00173] 5,5-difluoro-1-(4-fluoro-3- (trifluoromethyl)phenyl)-3- (trifluoromethy)-4,5,6,7- tetrahydro-1H-indol-4-ol [M + H − H.sub.2O].sup.+: 386.12 157 [00174] 4-(5,5-difluoro-4-hydroxy-3- (trifluoromethyl)-4,5,6,7- tetrahydro-1H-indol-1-yl)-2- (trifluoromethyl)benzonitrile [M + H − H.sub.2O].sup.+: 392.05 158 [00175] 5,5-difluoro-1-(3-fluoro-4- methoxyphenyl)-3- (trifluoromethyl)-4,5,6,7- tetrahydro-1H-indol-4-ol [M + H − H.sub.2O].sup.+: 348.18 159 [00176] 5,5-difluoro-1-(pyridin-4-yl)-3- (trifluoromethyl)-4,5,6,7- tetrahydro-1H-indol-4-ol [M + H − H.sub.2O].sup.+: 319.00 160 [00177] 5,5-difluoro-1-(4-fluorophenyl)- 3-(trifluoromethyl)-4,5,6,7- tetrahydro-1H-indol-4-ol [M + H − H.sub.2O].sup.+: 318.02 161 [00178] 5,5-difluoro-1-(3- (methylsulfonyl)phenyl)-3- (trifluoromethyl)-4,5,6,7- tetrahydro-1H-indol-4-ol [M + H − H.sub.2O].sup.+: 378.00 162 [00179] 5,5-difluoro-1-(2- methoxypyridin-4-yl)-3- (trifluoromethyl)-4,5,6,7- tetrahydro-1H-indol-4-ol [M + H − H.sub.2O].sup.+: 349.35 163 [00180] 4-(5,5-difluoro-4-hydroxy-3- (trifluoromethyl)-4,5,6,7- tetrahydro-1H-indol-1- yl)picolinonitrile [M + H − H.sub.2O].sup.+: 344.00 164 [00181] 1-(3,4-difluorophenyl)-5,5- difluoro-3-trifluoromethyl)- 4,5,6,7-tetrahydro-1H-indol-4-ol [M + H − H.sub.2O].sup.+: 336.23 165 [00182] 5,5-difluoro-1-(2-fluoropyridin- 4-yl)-3-(trifluoromethyl)- 4,5,6,7-tetrahydro-1H-indol-4-ol [M + H − H.sub.2O].sup.+: 337.00 166 [00183] 1-(3-cyano-4-fluorophenyl)-5,5- difluoro-4-hydroxy-4,5,6,7- tetrahydro-1H-indole-3- carbonitrile [M + H − H.sub.2O].sup.+: 299.95 167 [00184] (S)-4-(5,5-difluoro-4-hydroxy-3- (trifluoromethyl)-4,5,6,7- tetrahydro-1H-indol-1- yl)phthalonitrile [M + H − H.sub.2O].sup.+: 350.00 168 [00185] 1-(3-(difluoromethyl)-4- fluorophenyl)-5,5-difluoro-3- (trifluoromethyl)-4,5,6,7- tetrahydro-1H-indol-4-ol [M + H − H.sub.2O].sup.+: 368.00 169 [00186] 5,5-difluoro-1-(4-fluoro-3- methylphenyl)-3- (trifluoromethyl)-4,5,6,7- tetrahydro-1H-indol-4-ol [M + H − H.sub.2O].sup.+: 332.30 170 [00187] 5,5-difluoro-1-(6-fluoropyridin- 3-yl-3-(trifluoromethyl)- 4,5,6,7-tetrahydro-1H-indol-4-ol [M + H − H.sub.2O].sup.+: 319.15 171 [00188] 5,5-difluoro-1-(5-fluoropyridin- 2-yl)-3-(trifluoromethyl)- 4,5,6,7-tetrahydro-1H-indol-4-ol [M + H − H.sub.2O].sup.+: 319.15 172 [00189] 1-(2-chloropyridin-4-yl)-5,5- difluoro-3-(trifluoromethyl)- 4,5,6,7-tetrahydro-1H-indol-4-ol [M + H − H.sub.2O].sup.+: 335.00 173 [00190] (S)-1-(3-(difluoromethyl)-4- fluorophenyl)-5,5-difluoro-3- (trifluoromethyl)-4,5,6,7- tetrahydro-1H-indol-4-ol [M + HCOOH − H].sup.−: 430.05 174 [00191] (R)-1-(3-(difluoromethyl)-4- fluorophenyl)-5,5-difluoro-3- (trifluoromethyl)-4,5,6,7- tetrahydro-1H-indol-4-ol [M + HCOOH − H].sup.−: 430.2 175 [00192] (R)-5-(5,5-difluoro-4-hydroxy- 3-(trifluoromethyl)-4,5,6,7- tetrahydro-1H-indol-1-yl)-2- fluorobenzonitrile [M + HCOOH − H].sup.−: 405.07 176 [00193] 5-(5,5-difluoro-4-hydroxy-3- (trifluoromethyl)-4-vinyl- 4,5,6,7-tetrahydro-1H-indol-1- yl)-2-fluorobenzonitrile [M + H − H.sub.2O].sup.+: 369.20 177 [00194] (S)-5-(5,5-difluoro-4-hydroxy-3- (trifluoromethyl)-4,5,6,7- tetrahydro-1H-indol-1- yl)nicotinonitrile [M + H].sup.+: 344.07 178 [00195] 5,5-difluoro-1-(4-fluorophenyl)- 3-(trifluoromethyl)-4,5,6,7- tetrahydro-1H-indole-4- carbonitrile [M + H].sup.+: 345.06 179 [00196] 5-(5,5-difluoro-4-hydroxy-6- methyl-3-(trifluoromethyl)- 4,5,6,7-tetrahydro-1H-indol-1- yl)-2-fluorobenzonitrile [M + H − H.sub.2O].sup.+: 357.00 180 [00197] 5-((4S)-5,5-difluoro-4-hydroxy- 6-methyl-3-trifluoromethyl)- 4,5,6,7-tetrahydro-1H-indol-1- yl)-2-fluorobenzonitrile [M + H − H.sub.2O].sup.+: 357.02 181 [00198] (E)-5,5-difluoro-1-styryl-3- (trifluoromethyl)-4,5,6,7- tetrahydro-1H-indol-4-ol [M + H − H.sub.2O].sup.+: 326.09 182 [00199] (E)-5,5-difluoro-1-styryl-3- (trifluoromethyl)-1,5,6,7- tetrahydro-4H-indol-one [M + H].sup.+: 342.12 183 [00200] 1-(phenylsulfonyl)-3- (trifluoromethyl)-4,5,6,7- tetrahydro-1H-indol-4-ol [M + H].sup.+: 346.03 184 [00201] (E)-1-(2-cyclohexylvinyl)-5,5- difluoro-3-(trifluoromethyl)- 1,5,6,7-tetrahydro-4H-indol-4- one [M + H].sup.+: 348.13 185 [00202] 5,5-difluoro-1-(phenylsulfonyl)- 3-(trifluoromethyl)-1,5,6,7- tetrahydro-4H-indol-4-one [M + H].sup.+: 380.03 186 [00203] 5,5-difluoro-1-(phenylsulfonyl)- 3-(trifluoromethyl)-4,5,6,7- tetrahydro-1H-indol-4-ol [M + H − H.sub.2O].sup.+: 364.04 187 [00204] (E)-1-(2-cyclohexylvinyl)-5,5- difluoro-3-trifluoromethyl)-1- 4,5,6,7-tetradydro-1H-indol-4-ol [M + H − H.sub.2O].sup.+: 332.15 188 [00205] 5-(5,5-difluoro-4-oxo-3- (trifluoromethyl)-4,5,6,7- tetrahydro-1H-indol-1-yl)-2- fluorobenzonitrile [M + H].sup.−: 359.05 189 [00206] 5-(5,5-difluoro-4-oxo-3- (trifluoromethyl)-4,5,6,7- tetrahydro-1H-indol-1-yl)-2- fluorobenzaldehyde [M + H].sup.−: 362.06 190 [00207] 1-(3-(difluoromethyl)-4- fluorophenyl)-5,5-difluoro-3- (trifluoromethyl)-1,5,6,7- tetrahydro-4H-indol-4-one [M − H].sup.−: 382.06 191 [00208] 2-fluoro-5-(5-(fluoro-4-oxo-3- (trifluoromethyl)-4,5,6,7- tetrahydro-1H-indol-1- yl)benzaldehyde [M + H].sup.+: 344.06 192 [00209] 1-(3-(difluoromethyl)-4- fluorophenyl)-5-fluoro-3- (trifluoromethyl)-1,5,6,7- tetahydro-4H-indol-4-one [M − H].sup.−: 364.07 193 [00210] 3-fluoro-5-(5-fluoro-4-hydroxy- 3-(methylsulfonyl)-4,5,6,7- tetrahydro-1H-indol-1- yl)benzonitrile [M + H − H.sub.2O].sup.+: 335.07 194 [00211] 3-(3-chloro-5-fluorophenyl)-7,7- difluoro-1-(trifluoromethyl)- 5,6,7,8-tetrahydroimidazo[1.5- a]pyridin-8-ol [M + H − H.sub.2O].sup.+: 353.07 195 [00212] 3-(3-chloro-5-fluorophenyl)-6,6- difluoro-1-trifluoromethyl)- 4,5,6,7-tetrahydro-1H-indazol-7- ol [M + H − H.sub.2O].sup.+: 353.07 204 [00213] (S)-1-(3,5-difluorophenyl)-5,5- difluoro-3-(methylsulfonyl)-2- (trifluoromethyl)-4,5,6,7- tetrahydro-1H-indol-4-ol [M + H − H.sub.2O].sup.+: 414.04

EXAMPLE 197 AND EXAMPLE 197

Synthesis of (S)-2-fluoro-5-(4,5,5-trifluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)benzonitrile (Compound D54, Assumed) and (R)-2-fluoro-5-(4,5,5-trifluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)benzonitrile (Compound D55, Assumed)

[0587] ##STR00214##

Step 1: Synthesis of Compound D54-1

[0588] A58 (360 mg) was dissolved in 20 mL of dichloromethane under nitrogen protection, DAST (412 mg) was added slowly and dropwise in an ice bath, the reaction was carried out at 0° C. for 2 hours, quenched by the addition of ice water, the organic layer was washed with saturated sodium bicarbonate and saturated brine successively, dried over anhydrous sodium sulfate and concentrated to obtain the crude product, the crude product was purified by column chromatography (EA/PE=1:3) to obtain the target compound D54-1 (285 mg). ESI-MS m/z: 362.30 [M+H].sup.+.

Step 2: Synthesis of Compound D54 and D55

[0589] Compound D54-1 was separated and purified by chiral preparation column (column type Daicel CHIRALPAK® IF 250*20 mm, 5 μm, mobile phase A: n-hexane, mobile phase B: ethanol; mobile phase A: mobile phase B-85: 15 (V/V), detection wavelength 254 mm, flow rate: 15 mL/mm; column temperature: RT; running time: 28 min, example D54 was the first eluting peak, Rt=16.5 min, ESI-MS m/z: 325.00 [M+H−H.sub.2O].sup.+: .sup.1H NMR (500 MHz, DMSO) δ 8.14-8.16 (m, 1H), 7.89-7.92 (m, 1H), 7.73-7.67 (m, 1H), 7.59 (s, 1H), 5.23 (d, J=6.0 Hz, 1H), 4.88-4.70 (m, 2H), 2.56-2.76 (m, 2H), 2.23-2.13 (m, 1H), 1.85-1.92 (m, 1H); example D55 was the second eluting peak, Rt=20 min, ESI-MS m/z: 325.00 [M+H−H.sub.2O].sup.+.

EXAMPLE 198

Synthesis of (Z)-5-(5,5-difluoro-4-(hydroxyimino)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)-2-fluorobenzonitrile (Compound D56)

[0590] ##STR00215##

Step 1: Synthesis of Compound D56

[0591] Compound A58 (36 mg) and hydroxylamine hydrochloride (14 mg) were dissolved in 10 mL or ethanol, refluxed for 5 hours, concentrated to obtain the crude product, which was purified by Pre-TLC (EA/PE=1:3) to obtain the target compound D56 (16 mg) ESI-MS m/z: 392.08 [M+H−H.sub.2O].sup.+.

EXAMPLE 199

Synthesis of 2-fluoro-5-(5-fluoro-4-hydroxyl-2-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)benzonitrile (Compound D58)

[0592] ##STR00216##

Step 1: Synthesis of Compound D58-1

[0593] 1,3-cyclohexanedione (1.10 g) was dissolved in an aqueous solution (4 mL) of potassium hydroxide (0.57 g) in an ice bath, a solution of 3-bromo-1,1,1-trifluoroacetone (1.85 g) in methanol (10 mL) was added dropwise, stirred for 2 h and the methanol was spin-dried, water (5 mL) and 2-fluoro-5-aminobenzonitrile (1.2 g) were added to adjust the pH to 0, the reaction was refluxed for 14 h. The reaction mixture was spin-dried and extracted with ethyl acetate, the organic layer was washed with brine, dried over Na.sub.2SO.sub.4, and concentrated to obtain the crude product, which was purified by column chromatography (EA/PE=1:3) to obtain the target compound D58-1 (254 mg, 8%). ESI-MS m/z: 323.07 [M+H].sup.+. .sup.1H NMR (500 MHz, CDCl.sub.3) δ 7.66 (dd, J=14.2, 11.6 Hz, 1H), 7.61 (dd, J=8.4, 4.0 Hz, 1H), 7.41 (t, J=8.4 Hz, 1H), 7.10 (s, 1H), 2.57-2.44 (m, 4H), 2.22-2.12 (m, 2H).

Step 2: Synthesis of Compound D58-2

[0594] Compound D58-1 (60 mg) and NFSI (90 mg) were dissolved in tetrahydrofuran (2.00 mL) under nitrogen protection, the temperature was cooled to −78° C. and lithium diisopropylamide (0.25 mL, 2.00 mol/L) was added, stirred for 2 hours. The reaction mixture was quenched with saturated ammonium chloride, extracted with ethyl acetate, and concentrated to obtain the crude product, which was purified by column chromatography (EA/PE=1:2) to obtain the target compound D58-2 (40 mg, 59%). ESI-MS m/z: 341.06 [M+H].sup.+.

Step 3: Synthesis of Compound D58

[0595] Compound D58-2 (40 mg) was dissolved in a mixed solvent of methanol (1 mL) and tetrahydrofuran (1 mL), sodium borohydride (10 mg) was added in an ice bath, and the mixture was stirred at room temperature for 2 hours. Water and ethyl acetate were added, the organic layer was concentrated to obtain the crude product, which was purified by column chromatography (EA/PE=1:2) to obtain the target compound D58 (20 mg). ESI-MS m/z: 336.20 [M+H−H.sub.2O].sup.+.

EXAMPLE 200

Synthesis of (S)-5-(5,5-difluoro-4-hydroxyl-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl-4-d)-2-fluorobenzonitrile (Compound D74)

[0596] ##STR00217##

Step 1: Synthesis of Compound D74

[0597] Compound A61-1 (120 mg) was dissolved in dichloromethane (3 mL), deuterated formic acid (0.04 mL) and triethylamine (0.1 mL) were added, the reaction mixture was sparged with nitrogen, and [(R,R)-Ts-DPEN]RuCl(p-cymene) (22 mg) was added, the mixture was stirred at room temperature under nitrogen protection overnight, concentrated, and the crude product was purified by Prep-TLC (EA/PE=1:3) to obtain the target compound D74 (70 mg, 33>96%). ESI-MS m/z: 406.07 [M+COOH—H].sup.+. .sup.1H NMR (500 MHz, DMSO) δ 8.22 (dd, J=5.4, 2.7 Hz, 1H), 8.02-7.85 (m, 1H), 7.80-7.49 (m, 2H), 6.16-5.82 (m, 1H), 2.86-2.60 (m, 2H), 2.42-2.26 (m, 1H), 2.26-2.06 (m, 1H).

EXAMPLE 201

Synthesis of 6-(3-chloro-5-fluorophenyl)-8-(trifluoromethyl)-5,6-dihydro-4-H-isoxazolo[5,4-e]indole (Compound D100)

[0598] ##STR00218##

Step 1: Synthesis of Compound D100-1

[0599] Compound M3-1 (203 mg) was dissolved in DCM (20 mL), copper acetate (180 mg), 3-chloro-5-fluorophenylboronic acid (261 mg) and TEA (202 mg) were added, and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with dichloromethane, washed twice with saturated brine, dried and concentrated to obtain the crude product, which was purified by Pre-TLC (EA/PE=1:3) to obtain the target compound D100-1 (275 mg). ESI-MS m/z: 332.05 [M+H].sup.+.

Step 2: Synthesis of Compound D100-21

[0600] Compound D100-1 (100 mg) was dissolved in ethanol (5 mL) under nitrogen protection, cooled to 0° C., sodium ethoxide (20 mg) was added, and ethyl formate (23 mg) was added dropwise after stirring for 10 minutes, stirred overnight at room temperature. The reaction solution was spin-dried and diluted with ethyl acetate, washed twice with saturated brine, dried, and concentrated to obtain the crude product, which was purified by column chromatography (EA/PE=1:3) to obtain the target compound D100-2 (35 mg). ESI-MS m/z: 360.17 [M+H].sup.+.

Step 3: Synthesis of Compound D100

[0601] Compound D100-2 (100 mg) was dissolved in acetic acid (5 mL), hydroxylamine hydrochloride (23 mg) was added, and the mixture was stirred at room temperature for 5 hours. The reaction solution was poured into water, extracted with ethyl acetate, washed twice with saturated brine, dried, concentrated to obtain the crude product, which was purified by Pre-TLC (EA/PE=1:3) to obtain the target compound D100 (42 mg). ESI-MS m/z: 358/12 [M+H].sup.+. .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 8.49 (s, 1H), 7.82 (s, 1H), 7.67-7.56 (m, 3H), 2.96 (t, J=8.5 Hz, 2H), 2.83 (g, J=8.5 Hz, 2H).

EXAMPLE 202

Synthesis of 6-(3-chloro-5-fluorophenyl)-8-(trifluoromethyl)-1,4,5,6-tetrahydropyrrolo-[2,3-g]indazole (Compound D101)

[0602] ##STR00219##

Step 1: Synthesis of Compound D101

[0603] Compound D100-2 (100 mg) was dissolved in acetic acid (5 mL), hydrazine hydrate (30 uL) was added, and the mixture was stirred at room temperature for 5 hours. The reaction solution was poured into water, extracted with ethyl acetate, washed twice with saturated brine, dried, concentrated to obtain the crude product, which was purified by Pre-TLC (EA/PE=1:3) to obtain the target compound D101 (30 mg). ESI-MS m/z: 356.12 [M+H].sup.+.

[0604] .sup.1H NMR data for some exemplary compounds are shown below:

[0605] .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 8.13-8.11 (m, 1H), 7.88-7.85 (m, 1H), 7.74-7.62 (m, 1H), 7.26 (s, 1H), 5.89 (d, J=6.4 Hz, 1H), 5.76 (s, 2H), 4.31-4.27 (m, 1H), 2.84-2.77 (m, 1H), 2.80-2.74 (m, 1H), 2.39-2.32 (m, 1H), 2.12 (s, 1H) (Example 5)

[0606] .sup.1H NMR (500 MHz, CDCl.sub.3) δ 7.18 (d, J=8.6 Hz, 1H), 7.13 (s, 2H), 6.96 (d, J=8.6 Hz, 1H), 4.94-4.88 (m, 1H), 2.85-2.78 (m, 1H), 2.74-2.67 (m, 1H), 2.63-2.40 (m, 2H), 2.26-2.16 (m, 1H) (Example 7).

[0607] .sup.1H NMR (500 MHz, DMSO-d.sub.6) 67 7.67 (s, 1H), 7.42-7.30 (m, 3H), 6.07 (d, J=6.7 Hz, 1H), 4.59 (q, J=6.6 Hz, 1H), 2.91-2.69 (m, 2H), 2.44-2.23 (m, 1H), 2.17-2.12 (m, 1H) (Example 8).

[0608] .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 7.59-7.42 (m, 6H), 6.01 (d, J=6.8 Hz, 1H), 4.59 (q, J=6.9 Hz, 1H), 2.81-2.60 (m, 2H), 2.46-2.29 (m, 1H), 2.16-2.09 (m, 1H) (Example 9)

[0609] .sup.1H NMR (500 MHz, CDCl-d.sub.3) δ 7.41-7.34 (m, 2H), 7.25 (dt, J=8.6, 2.1 Hz, 1H), 7.09 (s, 1H), 4.88-4.92 (m, 1H), 2.80-2.70 (m, 1H), 2.66-2.59 (m, 1H), 2.55 (d, J=2.5 Hz, 1H), 2.51-2.12 (m, 2H) (Example 12).

[0610] .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 7.96 (s, 1H), 7.62-7.47 (m, 3H), 3.36 (s, 3H), 3.09 (t, J=6.0 Hz, 2H), 2.69-2.58 (m, 2H) (Example 15).

[0611] .sup.1H NMR (500 MHz, DMSO) δ 7.33-7.17 (m, 3H), 7.07) (d, J=2.9 Hz, 1H), 6.23 (d, J=3.0 Hz, 1H), 5.69 (d, J=6.6 Hz, 1H), 4.61-4.53 (m, 1H), 2.92-2.75 (m, 2H), 2.41-2.24 (m, 1H), 2.20-2.08 (m, 1H) (Example 34).

[0612] .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ0 8.14-8.13 (m, 1H), 7.91-7.89 (m, 1H), 7.69 (t, J=9.0 Hz, 1H), 7.52 (s, 1H), 4.78 (d, J=6.3 Hz, 1H), 4.70-4.68 (m, 1H), 2.50-2.38 (m, 1H), 1.92-1.85 (m, 1H), 1.82-1.68 (m, 2H), 1.71-1.63 (m 1H) (Example 46).

[0613] .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 7.53-7.45 (m, 3H), 7.43-7.36 (m, 2H), 7.33 (d, J=3.5 Hz, 1H), 7.08 (dd, J=5.1, 3.5 Hz, 1H), 6.01 (d, J=6.5 Hz, 1H), 5.75 (s, 1H), 4.60 (d, J=6.2 Hz, 1H), 2.90 (ddd, J=17.0, 11.3, 6.3 Hz, 1H), 2.80 (dd, J=16.2, 6.4 Hz, 1H), 2.19-2.11 (m, 1H) (Example 48).

[0614] .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 7.53-7.45 (m, 3H), 7.43-7.36 (m, 2H), 7.33 (d, J=3.5 Hz, 1H), 7.08 (dd, J=5.1, 3.5 Hz, 1H), 6.01 (d, J=6.5 Hz, 1H), 5.75 (s, 1H), 4.60 (d, J=6.2 Hz, 1H), 2.90 (ddd, J=17.0, 11.3, 6.3 Hz, 1H), 2.80 (dd, J=16.2, 6.4 Hz, 1H), 2.19-2.11 (m, 1H) (Example 59)

[0615] .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 7.67 (s, 1H), 7.43-7.36 (m, 3H), 6.07 (d, J=6.7 Hz, 1H), 4.67-4.52 (m, 1H), 2.93-2.69 (m, 2H), 2.44-2.27 (m, 1H), 2.19-2.10 (m, 1H) (Example 64)

[0616] .sup.1H NMR (500 MHz, DMSO) δ 8.30-8.24 (m, 1H), 8.04-7.98 (m, 1H), 7.81-7.68 (m, 2H), 6.13 (d, J=6.6 Hz, 1H), 4.70-4.60 (m, 1H), 2.89-2.70 (m, 2H), 2.50-2.31 (m, 1H), 2.25-2.13 (m, 1H) (Example 95)

[0617] .sup.1H NMR (500 MHz, DMSO) δ 7.75-7.58 (m, 3H), 6.22 (d, J=6.4 Hz, 1H), 4.58-4.50 (m, 1H), 2.70-2.52 (m, 2H), 2.43-2.24 (m, 1H), 2.20-2.10 (m, 1H) (Example 106).

[0618] .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 7.69 (s, 1H), 7.62-7.54 (m, 3H), 6.37 (d, J=6.1 Hz, 1H), 4.82 (q, J=6.5 Hz, 1H), 3.24 (s, 3H), 2.85-2.79 (m, 1H), 2.75-2.70 (m, 1H), 2.29 (d, J=8.9 Hz, 1H), 2.16 (s, 1H) (Example 109).

[0619] .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 7.68 (d, J=1.6 Hz, 1H), 7.60-7.40 (m, 3H), 6.07 (d, J=6.6 Hz, 1H), 4.59 (q, J=6.8 Hz, 1H), 2.88-2.81 (m, 1H), 2.84-2.70 (m, 2H), 2.42-2.38 (m, 1H), 2.17-2.12 (m, 1H) (Example 115).

[0620] .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 7.96 (s, 1H), 7.62-7.47 (m, 3H), 3.36 (s, 3H), 3.09 (t, J=6.0 Hz, 2H), 2.69-2.58 (m, 2H) (Example 118).

[0621] .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 7.88-7.84 (m, 1H), 7.67-7.48 (m, 3H), 6.03 (d, J=7.0 Hz, 1H), 4.62-4.55 (m, 1H), 2.84-2.62 (m, 2H), 2.44-2.26 (m, 1H), 2.20-2.10 (m, 1H) (Example 120).

[0622] .sup.1H NMR (500 MHz, DMSO) δ 7.88-7.84 (m, 1H), 7.67-7.48 (m, 3H), 6.03 (d, J=7.0 Hz, 1H), 4.62-4.55 (m, 1H)) 2.84-2.62 (m, 2H), 2.44-2.26 (m, 1H), 2.20-2.10 (m, 1H) (Example 124).

[0623] .sup.1H NMR (500 MHz, DMSO) δ 7.83-7.70 (m, 1H), 7.65-7.55 (m, 2H), 7.36-7.42 (m, 1H), 6.05 (d, J=6.6 Hz, 1H), 4.52-4.55 (m, 1H), 2.80-2.60 (m 2H), 2.45-2.26 (m, 1H), 2.20-2.05 (m, 1H) (Example 137).

[0624] .sup.1H NMR (500 MHz, DMSO) δ 7.59-7.49 (m, 3H), 7.37 (t, J=8.7 Hz, 2H), 6.01 (d, J=6.8 Hz, 1H), 4.62-4.53 (m, 1H), 2.76-2.59 (m, 2H), 2.44-2.27 (m, 1H), 2.18-2.08 (m, 1H) (Example 160).

[0625] .sup.1H NMR (500 MHz, DMSO) δ 7.83-7.70 (m, 1H), 7.65-7.55 (m, 1H), 7.36-7.42 (m, 1H), 6.05 (d, J=6.6 Hz, 1H), 4.52-4.55 (m, 1H), 2.80-2.60 (m, 2H), 2.45-2.26 (m, 1H), 2.20-2.05 (m, 1H) (Example 164)

[0626] .sup.1H NMR (500 MHz, CDCl.sub.3) δ 7.55 (m, 7.56-7.54, 1H), 7.43-7.40 (m, 1H), 7.30-7.28 (m, 1H), 7.12 (d, J=1.4 Hz, 1H), 7.04-6.82 (m, 1H), 4.93 (q, J=5.4 Hz, 1H), 2.78-2.72 (m, 1H), 2.66-2.61 (m, 1H), 2.55-2.42 (m, 2H), 2.25-2.17 (m, 1H) (Example 168).

[0627] .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 9.10 (d, J=1.8 Hz, 1H), 9.05 (d, J=2.5 Hz, 1H), 8.63 (t, J=2.2 Hz, 1H), 7.77 (d, J=1.6 Hz, 1H), 6.11 (d, J=6.7 Hz, 1H), 4.60 (q, J=6.7 Hz, 1H), 2.86-2.72 (m, 2H), 2.16 (s, 1H) (Example 177)

[0628] .sup.1H NMR (500 MHz, CDCl.sub.3) δ 7.53-7.45 (m, 2H), 7.32 (t, J=8.4 Hz, 1H), 7.04 (d, J=1.4 Hz, 1H), 4.92 (q, J=9.8 Hz, 1H), 2.55-2.43 (m, 2H), 2.38-2.28 (m, 1H), 2.24 (dd, J=8.4, 2.3 Hz, 1H), 0.02 (d, J=34.9 Hz, 3H) (Example 179).

[0629] .sup.1H NMR (500 MHz, CDCl.sub.3) δ 7.42-7.35 (m, 5H), 7.34-7.29 (m, 1H), 7.13 (d, J=14.4 Hz, 1H), 6.69 (d, J=14.4 Hz, 1H), 4.88 (t, J=6.6 Hz, 1H), 2.96-2.80 (m, 2H), 2.63-2.46 (m, 1H), 2.45-2.41 (m, 1H), 2.32-2.24 (m, 1H) (Example 181).

[0630] .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 8.04-8.02 (m, 1H), 7.82 (d, J=1.6 Hz, 1H), 7.74 (t, J=9.0 Hz, 1H), 5.71-5.61 (m, 1H), 2.92-2.76 (m, 2H), 2.43-2.36 (m, 2H) (Example 196).

Pharmacological Experiments

VEGFA ELISA Assay (IC.SUB.50.)

[0631] 786-O cells in exponential growth phase were seeded in 96-well plate, the cell concentration was 65,000 cells per milliliter of culture medium, 180 ul per well. Compounds were serial diluted to the indicated concentration, and 20 ul compound solutions of different concentrations were added to the corresponding cell wells. The final compound concentrations were as follows (nM): 1.5, 4.6, 13.7, 41.2, 123.5, 370.4, 1111.1, 3333.3, 10000. After 24 hours of incubation, the cell culture supernatant was taken, and the VEGFA concentration was determined using an ELISA kit (purchased from abcam). Finally, the reaction was terminated, and the light absorbance value of each well was measured using a microplate reader at a wavelength of 45 nm, and IC.sub.50 was calculated by GraphPad Prism. Cell Titer-Glo reagent was used to measure cell viability.

[0632] The IC.sub.50 data of the exemplary Example are provided in Table 1, wherein A means IC.sub.50≤0.5 μM; B means 0.5 μM<IC.sub.50≤1.5 μM; C means 1.5 μM<IC.sub.50≤10 μM; D means IC.sub.50>1.5 μM.

TABLE-US-00009 TABLE 1 Example No. IC.sub.50 (μM) 5 B 6 B 7 0.0307 12 0.0675 13 A 15 0.0188 19 A 20 A 22 0.0554 24 A 29 C 37 A 41 B 48 0.0456 51 B 53 A 54 B 64 A 68 A 69 0.0442 70 0.0454 71 0.0138 75 A 76 A 77 0.0162 88 D 90 D 92 D 93 D 95 0.0145 96 A 97 A 100 A 103 0.0441 104 0.0062 106 A 107 A 108 A 109 A 116 0.0277 120 0.0389 121 0.031  122 0.0426 124 0.0085 125 0.034  130 A 131 A 132 A 133 B 134 A 137 0.0421 139 A 141 A 142 A 145 C 148 A 154 A 156 0.0156 160 0.0461 164 A 167 A 168 0.0084 170 B 173 0.0178 174 B 178 A 179 B 180 B 181 C 190 B 193 A 196 A 197 A 200 0.0056 201 D 202 D

Luciferase Assay

[0633] Luciferase LUC gene was transfected into 786-O cells (purchased from ATCC) using Lipofectamine 3000 Transfection Reagent (purchased from Invitrogen) to construct HIF2α reporter cells (786-O-HIF2α-Luc cells). Experiments were performed when 786-O-HIF2α-Luc cells were in logarithmic growth phase, culture medium (RPMI MEDIUM 1640, purchased from Invitrogen) was abandoned, the cells were rinsed with PBS three times; trypsin (TrypLE, purchased from invitrogen) was added to digest cells, the digestion was terminated by washing the cells with culture medium, 10% fetal bovine serum, 1% penicillin and streptomycin. The cells were collected by centrifugation, rinsed twice with PBS to remove the phenol red in the medium, and then resuspended the cells to an appropriate concentration, and detected the cell density and viability, and made sure the cell viability is above 90% before it can be used for experiments.

[0634] The gradient concentration compound was transferred into 384-well plate, 25 nl/well using Echo 550 (non-contact sonic pipetting system, purchased from Labcyte); the cells were seeded in 384-well plate, 4500 cells/well, with 25 μl of culture medium, to make the final concentrations as follows: 10000, 3333, 1111, 370, 123, 41.1, 13.7, 4.6, 1.5, 0.5 nM. Cells were incubated at 37° C., 5% CO.sub.2 for 18-20 h; Steady-Glo™ Luciferase Assay System (purchased from Promega) was added to 384 well-plate, 25 μl/well; the luminescence value was detected with Envision. The % inhibition rate was calculated according to the RLU (Record Luminescence) signal value of each well, and then the IC.sub.50 of the corresponding compound was calculated by Graphpad 8.0.

[0635] The IC.sub.50 data of the exemplary Example are provided in Table 2, wherein A means IC.sub.50≤0.5 μM; B means 0.5 μM<IC.sub.50≤1.5 μM, C means 1.5 μM<IC.sub.50≤10 μM, D means IC.sub.50>1.50 μM.

TABLE-US-00010 TABLE 2 Example No. IC.sub.50 (μM) 7 0.0577 12 A 15 A 19 A 20 A 37 A 48 A 64 A 69 0.067  70 0.0842 75 A 95 0.0376 103 A 104 0.0220 106 A 116 0.0532 120 0.0757 121 0.0985 124 A 125 A 131 A 148 A 156 0.0705 167 0.0699 168 0.0305 173 0.0159 196 A 200 0.0335

Pharmacokinetics Tset In Vivo

[0636] Compounds was dissolved in 5% DMSO, 5% Solutoland 90% NaCLSD rats and Balb/c mice were selected as animals for administration, the intravenous dose was 1 mg/kg, the oral dose was 5 mg/kg, orbital blood was collected at 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 7 h, and 24 h, respectively. After blood collection, supernatant was collected by centrifugation at 4000 rpm for 10 min, 200 μL internal standard solutions were added to 30 μL supernatant for precipitation, after vortexing, supernatant was collected by centrifugation at 12,000 rpm for 10 min, 100 μL supernatant solutions and purified water were mixed at a ratio of 1:1 and injected. The compound concentration in plasma was detected by high performance liquid chromatography-mass spectrometry, and the compound concentration in plasma samples was quantitatively analyzed by internal standard method. After the compound concentration was measured, relevant pharmacokinetic parameters including Cmax, AUC, etc. were calculated by Winnonin software. Experiments have found that the exemplary compounds of the present invention have better PK properties in vivo.