BICYCLIC COMPOUND AND APPLICATION THEREOF

Abstract

The present invention relates to a compound as shown in formula (I). The present invention also provides a composition and preparation containing the compound, and a method for using and preparing the compound.

##STR00001##

Claims

1. A compound as shown in formula (I), or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex or solvate thereof, ##STR00148## wherein represents a single bond or double bond; X.sub.1, X.sub.2, X.sub.3 and X.sub.4 are each independently selected from C or N, and at least one of X.sub.1, X.sub.2, X.sub.3 and X.sub.4 is N; W is selected from C, N, O or S; 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 alkoxy, C.sub.6-C.sub.10 aryl, 5- to 18-membered heteroaryl, C.sub.5-C.sub.10 cycloalkyl, or 5- to 10-membered heterocyclyl; wherein the 5- to 18-membered heteroaryl and 5- to 10-membered heterocyclyl contain 1, 2 or 3 heteroatoms each independently selected from N, O and 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 alkoxy, C.sub.6-C.sub.10 aryl, 5- to 18-membered heteroaryl, C.sub.5-C.sub.10 cycloalkyl and 5- to 10-membered heterocyclyl can be optionally substituted with one or more substituents selected from H, halogen, OH, CN, oxo, amino, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, 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, cyano-substituted C.sub.1-C.sub.6 alkyl, cyano-substituted C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 haloalkoxy, C.sub.1-C.sub.6 alkylene-OR.sub.c, C.sub.1-C.sub.6 alkylene-COR.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)R.sub.aR.sub.b or P(S)R.sub.aR.sub.b; R.sub.3 is selected from H, deuterium, halogen, NO.sub.2, NR.sub.aR.sub.b, CN, 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 alkoxy, OC(O)C.sub.1-3 alkyl, C(O)OC.sub.1-3 alkyl or C.sub.2-C.sub.10 alkynyl, wherein 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 alkoxy, OC(O)C.sub.1-3 alkyl, C(O)OC.sub.1-3 alkyl, and C.sub.2-C.sub.10 alkynyl can be optionally substituted with one or more substituents selected from H, halogen, CN, OH, amino, C.sub.1-C.sub.5 alkyl, C.sub.1-C.sub.6 alkoxy, C.sub.2-C.sub.6 alkenyl or C.sub.1-C.sub.5 haloalkyl; R.sub.4 and R.sub.5 are each independently selected from H, halogen, NO.sub.2, OH, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, 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- to 6-membered heterocyclyl; the C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, 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- to 6-membered heterocyclyl can be optionally substituted with one or more substituents selected from H, halogen, CN, OH, amino, oxo, C.sub.1-C.sub.5 alkyl, C.sub.1-C.sub.6 alkoxy, C.sub.2-C.sub.6 alkenyl or C.sub.1-C.sub.5 haloalkyl; or R.sub.4 and R.sub.5 together form oxo; or R.sub.4 and R.sub.5 together with the C atom to which they are attached form substituted or unsubstituted cyclopropyl; R.sub.6 is selected from H, CN, halogen, NO.sub.2, OH, NO.sub.2, NR.sub.aR.sub.b, oxo, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, 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- to 6-membered heterocyclyl; the C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, 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- to 6-membered heterocyclyl can be optionally substituted with one or more substituents selected from H, halogen, CN, OH, amino, oxo, C.sub.1-C.sub.5 alkyl, C.sub.1-C.sub.6 alkoxy, C.sub.2-C.sub.6 alkenyl or C.sub.1-C.sub.5 haloalkyl; or two R.sub.6 together with the C atom to which they are attached form substituted or unsubstituted C.sub.3-C.sub.5 cycloalkyl or 3- to 5-membered heterocyclyl; or R.sub.6 and R.sub.5 together with the C atom to which they are attached form substituted or unsubstituted C.sub.3-C.sub.4 cycloalkyl; R.sub.f is absent or selected from 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 can be optionally substituted with one or more substituents selected from H, halogen, CN, OH, amino, C.sub.1-C.sub.5 alkyl, C.sub.1-C.sub.6 alkoxy, C.sub.2-C.sub.6 alkenyl or C.sub.1-C.sub.5 haloalkyl; R.sub.1 is selected from C.sub.1-C.sub.6 alkylene-C(O)R.sub.c, C.sub.1-C.sub.6 alkylene-C(O)OR.sub.c, C.sub.2F.sub.5, C(O)R.sub.c, C(O)OR.sub.c, SR, S(O)R.sub.c, S(O).sub.2R, or S(O)(NR.sub.a)R.sub.c, wherein the C.sub.1-C.sub.6 alkylene can be optionally substituted with one or more substituents selected from H, halogen, cyano, C.sub.1-C.sub.4 alkyl, C.sub.2-C.sub.4 alkenyl, C.sub.2-C.sub.4 alkynyl, C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.4 alkoxy and C.sub.1-C.sub.4 haloalkoxy; R.sub.a and R.sub.b are each independently selected from H, CN, C.sub.1-C.sub.10 alkyl, C.sub.1-C.sub.10 haloalkyl, C.sub.1-C.sub.10 alkoxy, C.sub.2-C.sub.10 alkenyl, C.sub.2-C.sub.10 alkynyl, C.sub.3-C.sub.10 cycloalkyl, 3- to 10-membered heterocyclyl, C.sub.6-C.sub.10 aryl or 5- to 10-membered heteroaryl; R.sub.c is selected from C.sub.1-C.sub.10 alkyl, C.sub.1-C.sub.10 alkoxy, C.sub.3-C.sub.6 cycloalkyl and NR.sub.aR.sub.b, wherein the C.sub.1-C.sub.10 alkyl, C.sub.1-C.sub.10 alkoxy and C.sub.3-C.sub.6 cycloalkyl can be optionally substituted with one or more substituents selected from H, halogen, CN, NH.sub.2, oxo, C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.4 haloalkoxy, and C.sub.3-C.sub.6 cycloalkyl; n is 0 or 1; m is 0, 1, 2, 3 or 4; provided that the compound is not: 3-fluoro-5-(4-hydroxyl-3-(methylsulfonyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)benzonitrile; 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) sulfonyl)-5,5-difluoro-4-hydroxyl-4,5,6,7-tetrahydro-1H-indol-1-yl)-5-fluorobenzonitrile; 1-(3,5-difluorophenyl)-5,5-difluoro-3-(methylsulfonyl)-4,5,6,7-tetrahydro-1H-indol-4-ol; 1-(3-chloro-5-fluorophenyl)-5,6-difluoro-3-(methylsulfonyl)-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)-methylsulfoxyl)-4,5,6,7-tetrahydro-1H-indol-4-ol; 1-(3-chloro-5-fluorophenyl)-5,5-difluoro-3-((R)-methylsulfoxyl)-4,5,6,7-tetrahydro-1H-indol-4-ol; 3-fluoro-5-(5-fluoro-4-hydroxyl-3-(methylsulfonyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)benzonitrile; (S)-1-(3,5-difluorophenyl)-5,5-difluoro-3-(methylsulfonyl)-2-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol; 2-chloro-5-(5,5-difluoro-4-hydroxyl-3-(methylsulfonyl)-5,6-dihydrocyclopenta[b]pyrrol-1(4H)-yl)benzonitrile; and 1-(3-chloro-5-fluorophenyl)-3-((difluoromethyl)sulfonyl)-5,5-difluoro-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-ol.

2. (canceled)

3. The compound, or the stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex or solvate thereof according to claim 1, wherein the compound is as shown in formula (III-1), formula (III-2), formula (III-3) or formula (III-4) ##STR00149##

4. (canceled)

5. The compound, or the stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex or solvate thereof according to claim 1, wherein the R.sub.3 is selected from H, deuterium or C.sub.1-C.sub.3 alkyl.

6. The compound, or the stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex or solvate thereof according to claim 1, wherein the R.sub.3 is H or deuterium.

7. The compound, or the stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex or solvate thereof according to 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, wherein the C.sub.1-C.sub.6 alkyl can be optionally substituted with one or more substituents selected from H, halogen, CN, OH, amino or oxo.

8. (canceled)

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

10. (canceled)

11. The compound, or the stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex or solvate thereof according to claim 1, wherein R.sub.6 is H, halogen or C.sub.1-C.sub.6 alkyl, wherein the C.sub.1-C.sub.6 alkyl can be optionally substituted with one or more substituents selected from H, halogen, CN, OH, oxo, or amino.

12. The compound, or the stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex or solvate thereof according to claim 1, wherein R.sub.6 is H or halogen.

13-14. (canceled)

15. The compound, or the stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex or solvate thereof according to claim 1, wherein the R.sub.f is selected from H, CN or halogen.

16. The compound, or the stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex or solvate thereof according to claim 1, wherein the W is C or O.

17-19. (canceled)

20. The compound, or the stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex or solvate thereof according to claim 1, wherein the R.sub.1 is phenyl, pyridyl, naphthyl, 10-membered heteroaryl, C.sub.8-C.sub.10 cycloalkyl or 8- to 10-membered heterocyclyl, wherein the 10-membered heteroaryl and 8- to 10-membered heterocyclyl optionally contain 1 or 2 N heteroatoms, and the phenyl, pyridyl, naphthyl, 10-membered heteroaryl, C.sub.8-C.sub.10 cycloalkyl or 8- to 10-membered heterocyclyl can be optionally substituted with one or more substituents selected from halogen, cyano or C.sub.1-C.sub.6 haloalkyl.

21. (canceled)

22. The compound, or the stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex or solvate thereof according to claim 1, wherein the RR is selected from C.sub.2F.sub.5, C.sub.1-C.sub.6 haloalkylene-C(O)R.sub.c, C.sub.1-C.sub.6 haloalkylene-C(O)OR.sub.c, C(O)OR.sub.c, C(O)R.sub.c, SR, S(O).sub.2R, or S(O)(NR.sub.a)R.sub.c, wherein, the R.sub.c is selected from C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, C.sub.3-C.sub.6 cycloalkyl and NH.sub.2, wherein the C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy and C.sub.3-C.sub.6 cycloalkyl can be optionally substituted with one or more substituents selected from H, halogen, CN, NH.sub.2, C.sub.1-C.sub.4 haloalkyl or C.sub.3-C.sub.6 cycloalkyl.

23. (canceled)

24. The compound, or the stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex or solvate thereof according to claim 1, wherein the R.sub.c is selected from C.sub.1-C.sub.6 alkyl, wherein the C.sub.1-C.sub.6 alkyl can be optionally substituted with one or more substituents selected from H, halogen or CN.

25-26. (canceled)

27. The compound, or the stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex or solvate thereof according to claim 1, wherein the R.sub.j is selected from ##STR00150## ##STR00151##

28. The compound, or the stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex or solvate thereof according to claim 1, wherein the compound is as shown in formula (IX-1) or formula (IX-2), ##STR00152##

29. A compound, or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex or solvate thereof, wherein the compound is selected from: 1) 5-(5,5-difluoro-4-hydroxyl-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)-2,3-difluorobenzonitrile; 2) 5,5-difluoro-1-(4-fluoro-3-(fluoromethyl)phenyl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol; 3) (S)-4-(5,5-difluoro-4-hydroxyl-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)-2-(difluoromethyl)benzonitrile; 4) (S)-5-(3-((difluoromethyl)sulfonyl)-5,5-difluoro-4-hydroxyl-4,5,6,7-tetrahydro-1H-indol-1-yl)-2-fluorobenzonitrile; 5) (S)-1-(3-(difluoromethyl)-4-fluorophenyl)-5,5-difluoro-3-(methylsulfonyl)-4,5,6,7-tetrahydro-1H-indol-4-ol; 6) (S)-1-(3-(difluoromethyl)-4-fluorophenyl)-3-((difluoromethyl)sulfonyl)-5,5-difluoro-4,5,6,7-tetrahydro-1H-indol-4-ol; 7) (S)-3-((S)-(difluoromethyl)sulfinyl)-5,5-difluoro-1-(4-fluoro-3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydro-1H-indol-4-ol; 8) (S)-3-((R)-(difluoromethyl) sulfinyl)-5,5-difluoro-1-(4-fluoro-3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydro-1H-indol-4-ol; 9) 5-(5,5-difluoro-4-hydroxyl-3-(perfluoroethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)-2-fluorobenzonitrile; 10) (S)-5-(5,5-difluoro-4-hydroxyl-3-((trifluoromethyl) sulfonyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)-2-fluorobenzonitrile; 11) (S)-5-(5,5-difluoro-3-((fluoromethyl)sulfonyl)-4-hydroxyl-4,5,6,7-tetrahydro-1H-indol-1-yl)-2-fluorobenzonitrile; 12) (S)-1-(3-(difluoromethyl)-4-fluorophenyl)-5,5-difluoro-3-((trifluoromethyl)sulfonyl)-4,5,6,7-tetrahydro-1H-indol-4-ol; 13) (S)-2-((5,5-difluoro-1-(4-fluoro-3-(trifluoromethyl)phenyl)-4-hydroxyl-4,5,6,7-tetrahydro-1H-indol-3-yl)sulfonyl)acetonitrile; 14) (S)-1-(3-(difluoromethyl)-4-fluorophenyl)-5,5-difluoro-3-((fluoromethyl) sulfonyl)-4,5,6,7-tetrahydro-1H-indol-4-ol; 15) 2-(1-(3-cyano-4-fluorophenyl)-5,5-difluoro-4-hydroxyl-4,5,6,7-tetrahydro-1H-indol-3-yl)-2,2-difluoroacetamide; 16) (S)-3-(ethylsulfonyl)-5,5-difluoro-1-(4-fluoro-3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydro-1H-indol-4-ol; 17) 5-(3-(cyanodifluoromethyl)-5,5-difluoro-4-hydroxyl-4,5,6,7-tetrahydro-1H-indol-1-yl)-2-fluorobenzonitrile; 18)N(((S)-1-(3-cyano-4-fluorophenyl)-5,5-difluoro-4-hydroxyl-4,5,6,7-tetrahydro-1H-indol-3-yl)(methyl)(oxo)-16-sulfino)cyanamide; 19) (S)-2-((1-(3-(difluoromethyl)-4-fluorophenyl)-5,5-difluoro-4-hydroxyl-4,5,6,7-tetrahydro-1H-indol-3-yl)sulfonyl)acetonitrile; 20) (S)-5,5-difluoro-1-(4-fluoro-3-(trifluoromethyl)phenyl)-3-(methylsulfonyl)-4,5,6,7-tetrahydro-1H-indol-4-ol; 21) (S)-3-((difluoromethyl) sulfonyl)-5,5-difluoro-1-(4-fluoro-3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydro-1H-indol-4-ol; 22) (S)-5-(3-((difluoromethyl)sulfonyl)-2,5,5-trifluoroether-4-hydroxyl-4,5,6,7-tetrahydro-1H-indol-1-yl)-2-fluorobenzonitrile; 23) (S)-5,5-difluoro-1-(4-fluoro-3-(trifluoromethyl)phenyl)-3-((trifluoromethyl)sulfonyl)-4,5,6,7-tetrahydro-1H-indol-4-ol; 24) 1-(3-chloro-4-fluorophenyl)-5,5-difluoro-3-(methylsulfonyl)-4,5,6,7-tetrahydro-1H-indol-4-ol; 25) 1-(3-chloro-4-fluorophenyl)-3-((difluoromethyl) sulfonyl)-5,5-difluoro-4,5,6,7-tetrahydro-1H-indol-4-ol; 26) (R)-1-(3-(difluoromethyl)-4-fluorophenyl)-3-((difluoromethyl) sulfonyl)-5,5-difluoro-4,5,6,7-tetrahydro-1H-indol-4-ol; 27) (S)-2-chloro-5-(5,5-difluoro-4-hydroxyl-3-(methylsulfonyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)benzonitrile; 28) (S)-2-chloro-5-(3-((difluoromethyl)sulfonyl)-5,5-difluoro-4-hydroxyl-4,5,6,7-tetrahydro-1H-indol-1-yl)benzonitrile; 29) (S)-4-(5,5-difluoro-4-hydroxyl-3-(methylsulfonyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)-2-(difluoromethyl)benzonitrile; 30) (S)-5,5-difluoro-1-(4-fluoro-3-(trifluoromethyl)phenyl)-3-((fluoromethyl) sulfonyl)-4,5,6,7-tetrahydro-1H-indol-4-ol; 31) (S)-4-(5,5-difluoro-4-hydroxyl-3-((trifluoromethyl) sulfonyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)-2-(trifluoromethyl)benzonitrile; 32) (R)-1-(3-(difluoromethyl)-4-fluorophenyl)-3-((difluoromethyl) sulfonyl)-4,5,6,7-tetrahydro-1H-indol-4-ol; 33) (S)-1-(3-chloro-4-fluorophenyl)-5,5-difluoro-3-((trifluoromethyl)sulfonyl)-4,5,6,7-tetrahydro-1H-indol-4-ol; 34) (S)-4-(3-((difluoromethyl)sulfonyl)-5,5-difluoro-4-hydroxyl-4,5,6,7-tetrahydro-1H-indol-1-yl)-2-(trifluoromethyl)benzonitrile; 35) (S)-4-(5,5-difluoro-4-hydroxyl-3-((trifluoromethyl) sulfonyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)-2-(difluoromethyl)benzonitrile; 36) (S)-4-(5,5-difluoro-3-((fluoromethyl)sulfonyl)-4-hydroxyl-4,5,6,7-tetrahydro-1H-indol-1-yl)-2-(trifluoromethyl)benzonitrile; 37) (S)-1-(3-chloro-4-fluorophenyl)-5,5-difluoro-3-((fluoromethyl) sulfonyl)-4,5,6,7-tetrahydro-1H-indol-4-ol; 38) (S)-4-(5,5-difluoro-4-hydroxyl-3-(methylsulfonyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)phthalonitrile; 39) (S)-4-(3-((difluoromethyl)sulfonyl)-5,5-difluoro-4-hydroxyl-4,5,6,7-tetrahydro-1H-indol-1-yl)phthalonitrile; 40) (S)-2-chloro-5-(5,5-difluoro-4-hydroxyl-3-((trifluoromethyl) sulfonyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)benzonitrile; 41) 4-(5,5-difluoro-4-hydroxyl-3-(perfluoroethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)-2-(difluoromethyl)benzonitrile; 42) (S)-4-(5,5-difluoro-4-hydroxyl-3-((trifluoromethyl) sulfonyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)phthalonitrile; 43) (S)-2-(difluoromethyl)-4-(3-((difluoromethyl) sulfonyl)-5,5-difluoro-4-hydroxyl-4,5,6,7-tetrahydro-1H-indol-1-yl)benzonitrile; 44) (S)-4-(5,5-difluoro-3-((fluoromethyl)sulfonyl)-4-hydroxyl-4,5,6,7-tetrahydro-1H-indol-1-yl)-2-(difluoromethyl)benzonitrile; 45) (S)-4-(5,5-difluoro-3-((fluoromethyl)sulfonyl)-4-hydroxyl-4,5,6,7-tetrahydro-1H-indol-1-yl)phthalonitrile; 46) (S)-4-(5,5-difluoro-4-hydroxyl-3-(perfluoroethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)phthalonitrile; 47) 2-(((S)-1-(3-(difluoromethyl)-4-fluorophenyl)-5,5-difluoro-4-hydroxyl-4,5,6,7-tetrahydro-1H-indol-3-yl)sulfonyl)-2-fluoroacetonitrile; 48) ethyl (S)-2-(1-(3-(difluoromethyl)-4-fluorophenyl)-5,5-difluoro-4-hydroxyl-4,5,6,7-tetrahydro-1H-indol-3-yl)-2,2-difluoroacetate; 49) (S)-2-(1-(3-(difluoromethyl)-4-fluorophenyl)-5,5-difluoro-4-hydroxyl-4,5,6,7-tetrahydro-1H-indol-3-yl)-2,2-difluoroacetonitrile; 50) (S)-2-(1-(3-(difluoromethyl)-4-fluorophenyl)-5,5-difluoro-4-hydroxyl-4,5,6,7-tetrahydro-1H-indol-3-yl)-2,2-difluoroacetamide; 51) (S)-1-(3-(difluoromethyl)-4-fluorophenyl)-5,5-difluoro-3-(thiazol-2-yl)-4,5,6,7-tetrahydro-1H-indol-4-ol; 52) (R)-1-(3-(difluoromethyl)-4-fluorophenyl)-3-((trifluoromethyl)sulfonyl)-4,5,6,7-tetrahydro-1H-indol-4-ol; 53) (S)-1-(3-(difluoromethyl)-4-fluorophenyl)-5,5-difluoro-3-(oxazol-2-yl)-4,5,6,7-tetrahydro-1H-indol-4-ol; 54) (S)-2-((1-(3-(difluoromethyl)-4-fluorophenyl)-5,5-difluoro-4-hydroxyl-4,5,6,7-tetrahydro-1H-indol-3-yl) sulfonyl)-2,2-difluoroacetonitrile; 55) 2-(((S)-5,5-difluoro-1-(4-fluoro-3-(trifluoromethyl)phenyl)-4-hydroxyl-4,5,6,7-tetrahydro-1H-indol-3-yl)sulfonyl)-2-fluoroacetonitrile; 56) (S)-(1-(3-(difluoromethyl)-4-fluorophenyl)-5,5-difluoro-4-hydroxyl-4,5,6,7-tetrahydro-1H-indol-3-yl)dimethylphosphine oxide methyl; 57) 2-(((S)-1-(3-(difluoromethyl)-4-fluorophenyl)-5,5-difluoro-4-hydroxyl-4,5,6,7-tetrahydro-1H-indol-3-yl)sulfonyl) propanenitrile; 58) (S)-1-((1-(3-(difluoromethyl)-4-fluorophenyl)-5,5-difluoro-4-hydroxyl-4,5,6,7-tetrahydro-1H-indol-3-yl) sulfonyl)cyclopropane-1-nitrile; 59)N(((S)-1-(3-(difluoromethyl)-4-fluorophenyl)-5,5-difluoro-4-hydroxyl-4,5,6,7-tetrahydro-1H-indol-3-yl)(methyl)(oxo)-16-sulfino)cyanamide; 60) ethyl (S)-1-(3-(difluoromethyl)-4-fluorophenyl)-5,5-difluoro-4-hydroxyl-4,5,6,7-tetrahydro-1H-indole-3-carboxylate; 61) (R)-1-(3-(difluoromethyl)-4-fluorophenyl)-5,5-difluoro-3-((fluoromethyl) sulfonyl)-4,5,6,7-tetrahydro-1H-indol-4-ol; 62) (S)-1-(3-(difluoromethyl)-4-fluorophenyl)-5,5-difluoro-4-hydroxyl-4,5,6,7-tetrahydro-1H-indole-3-carboxamide; 63) (4S,5R)-1-(3-(difluoromethyl)-4-fluorophenyl)-3-((difluoromethyl)sulfonyl)-5-fluoro-4,5,6,7-tetrahydro-1H-indol-4-ol; 64) (4S,5S)-1-(3-(difluoromethyl)-4-fluorophenyl)-3-((difluoromethyl) sulfonyl)-5-fluoro-4,5,6,7-tetrahydro-1H-indol-4-ol; 65) (R)-2-(difluoromethyl)-4-(4-hydroxyl-3-((trifluoromethyl)sulfonyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)benzonitrile; 66) (S)-4-(5,5-difluoro-4-hydroxyl-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)-3-fluorobenzonitrile; 67) (4S)1-(3-(difluoromethyl)-4-fluorophenyl)-5,5-difluoro-3-((fluoromethyl) sulfinyl)-4,5,6,7-tetrahydro-1H-indol-4-ol; 68) (S)-1-((R)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-1-yl-yl)-5,5-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol; 69) (S)-1-((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-1-yl-yl)-5,5-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol; 70) (S)-1-(2,4-difluorobenzyl)-5,5-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol; 71) (S)-2-((5,5-difluoro-4-hydroxyl-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)methyl)-5-fluorobenzonitrile; 72) (S)-1-(2,4-difluorophenyl)-5,5-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol; 73)N(((S)-1-(3-(difluoromethyl)-4-fluorophenyl)-5,5-difluoro-4-hydroxyl-4,5,6,7-tetrahydro-1H-indol-3-yl)(oxy)(trifluoromethyl)-16-sulfino)cyanamide; 74)N-((difluoromethyl)((S)-1-(3-(difluoromethyl)-4-fluorophenyl)-5,5-difluoro-4-hydroxyl-4,5,6,7-tetrahydro-1H-indol-3-yl)(oxo)-16-sulfino)cyanamide; 75) (S)-2-(5-(5,5-difluoro-4-hydroxyl-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)-2-fluorophenyl)acetonitrile; 76) (S)-4-(5,5-difluoro-4-hydroxyl-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)-2-(fluoromethyl)benzonitrile; 77) (S)-1-(3-(difluoromethyl)-4-fluorophenyl)-5,5-difluoro-3-((fluoromethyl) sulfonyl)-1,4,5,6-tetrahydrocyclopentadiene[b]pyrrol-4-ol; 78) (S)-1-(3-(difluoromethyl)-4-fluorophenyl)-5,5-difluoro-3-(methylsulfonyl)-1,4,5,6-tetrahydrocyclopentadiene[b]pyrrol-4-ol; 79) (S)-1-(3-(difluoromethyl)-4-fluorophenyl)-3-((difluoromethyl)sulfonyl)-5,5-difluoro-1,4,5,6-tetrahydrocyclopentadiene[b]pyrrol-4-ol; 80) (S)-1-(3-(difluoromethyl)-4-fluorophenyl)-5,5-difluoro-3-((trifluoromethyl)sulfonyl)-1,4,5,6-tetrahydrocyclopentadiene[b]pyrrol-4-ol; 81) (S)-5-(5,5-difluoro-4-hydroxyl-3-((trifluoromethyl)sulfonyl)-5,6-dihydrocyclopentadiene[b]pyrrol-1(4H)-yl)-yl2-fluorobenzonitrile; 82) (S)-3-(3-(difluoromethyl)-4-fluorophenyl)-7,7-difluoro-1-((trifluoromethyl)sulfonyl)-5,6,7,8-tetrahydroindol-8-ol; 83) (S)-3-(3-(difluoromethyl)-4-fluorophenyl)-7,7-difluoro-1-((trifluoromethyl)sulfonyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-8-ol; 84) (7R,8S)-3-(3-(difluoromethyl)-4-fluorophenyl)-7-fluoro-1-((trifluoromethyl)sulfonyl)-5,6,7,8-tetrahydroindolizin-8-ol; 85) 1-(3-(difluoromethyl)-4-fluorophenyl)-5,5-difluoro-3-((trifluoromethyl)sulfonyl)-1,4,5,7-tetrahydropyran[3,4-b]pyrrol-4-ol; 86) 2-(difluoromethyl)-4-((4S,5R)-3-((difluoromethyl)sulfonyl)-5-fluoro-4-hydroxyl-4,5,6,7-tetrahydro-1H-indol-1-yl)benzonitrile; 87) 2-(difluoromethyl)-4-((4S,5R)-5-fluoro-4-hydroxyl-3-((trifluoromethyl)sulfonyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)benzonitrile; 88) (S)-5,5-difluoro-1-(imidazo[1,2-a]pyridin-8-yl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol; 89) (4S,5R)-1-(3-(difluoromethyl)-4-fluorophenyl)-5-fluoro-3-((trifluoromethyl)sulfonyl)-4,5,6,7-tetrahydro-1H-indol-4-ol; 90) (S)-8-(5,5-difluoro-3-((fluoromethyl)sulfonyl)-4-hydroxyl-4,5,6,7-tetrahydro-1H-indol-1-yl)-5-fluoro-1-naphthonitrile; 91) (S)-3-((difluoromethyl)sulfonyl)-5,5-difluoro-1-(4-fluoro-5,6,7,8-tetrahydronaphthalen-1-yl)-4,5,6,7-tetrahydro-1H-indol-4-ol; 92) (S)-5,5-difluoro-1-(quinolin-8-yl)-3-((trifluoromethyl)sulfonyl)-4,5,6,7-tetrahydro-1H-indol-4-ol; 93) (4S)-1-(6,8-difluoro-1,2,3,4-tetrahydronaphthalen-1-yl)-5,5-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol; 94) (4S)-1-(6,8-difluoro-1,2,3,4-tetrahydronaphthalen-1-yl)-5,5-difluoro-3-((trifluoromethyl)sulfonyl)-4,5,6,7-tetrahydro-1H-indol-4-ol; 95) (4S)-1-(6,8-difluoro-1,2,3,4-tetrahydronaphthalen-1-yl)-3-((difluoromethyl) sulfonyl)-5,5-difluoro-4,5,6,7-tetrahydro-1H-indol-4-ol; 96) 1-(6,8-difluoro-1,2,3,4-tetrahydronaphthalen-1-yl)-5,5-difluoro-3-((fluoromethyl) sulfonyl)-4,5,6,7-tetrahydro-1H-indol-4-ol; 97) (4S)1-(5,7difluoro-2,3-dihydro-1H-inden-1-yl)-5,5-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol; 98) (4S)-5,5-difluoro-1-(5,6,7,8-tetrahydroquinolin-8-yl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol; 99) (4S)-5,5-difluoro-3-(methylsulfonyl)-1-(5,6,7,8-tetrahydroquinolin-8-yl)-4,5,6,7-tetrahydro-1H-indol-4-ol; 100) 5,5-difluoro-3-((fluoromethyl)sulfonyl)-1-(5,6,7,8-tetrahydroquinolin-8-yl)-4,5,6,7-tetrahydro-1H-indol-4-ol; 101) (4S)-3-((difluoromethyl) sulfonyl)-5,5-difluoro-1-(5,6,7,8-tetrahydroquinolin-8-yl)-4,5,6,7-tetrahydro-1H-indol-4-ol; 102) (4S)-5,5-difluoro-1-(5,6,7,8-tetrahydroquinolin-8-yl)-3-((trifluoromethyl)sulfonyl)-4,5,6,7-tetrahydro-1H-indol-4-ol; 103) 2-(difluoromethyl)-4-(5-fluoro-4-hydroxyl-3-((trifluoromethyl)thio)-4,5,6,7-tetrahydro-1H-indol-1-yl)benzonitrile; 104) 2-(difluoromethyl)-4-(5-fluoro-4-hydroxyl-3-((trifluoromethyl)sulfonyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)benzonitrile; 105) 2-fluoro-5-(5-fluoro-4-hydroxyl-3-(trifluoromethyl)-4,7-dihydropyran[3,4-b]pyrrol-1(5H)-yl)benzonitrile; 106) 2-fluoro-5-(2,5,5-trifluoro-4-hydroxyl-3-(thien-2-yl)-4,5,6,7-tetrahydro-1H-indol-1-yl)benzonitrile; or 107) 2-(difluoromethyl)-4-(5-fluoro-4-hydroxyl-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)benzonitrile.

30. A pharmaceutical composition, comprising a therapeutically effective amount of at least one of the compounds according to claim 1 and at least one pharmaceutically acceptable excipient.

31-33. (canceled)

34. A method for treating and/or preventing a HIF-2-mediated disease, comprising administering a therapeutically effective amount of the compound according to claim 1 to a subject to be treated, wherein, the HIF-2-mediated disease is VHL syndrome, an autoimmune disease, an inflammatory disease and/or cancer.

35. (canceled)

36. The method according to claim 35, wherein the cancer is selected from bone cancer, pancreatic cancer, skin cancer, head and neck cancer, malignant melanoma, ovarian cancer, rectal cancer, gastric cancer, uterine cancer, cervical cancer, endometrial cancer, lymphoma, esophageal cancer, colon cancer, thyroid cancer, prostate cancer, sarcoma, leukemia, bladder cancer, kidney cancer, glioma, epidermal cystadenoma, squamous cell carcinoma, pheochromocytoma, lung cancer, liver cancer, breast cancer, exothelioma, neurocytoma, paraganglioma, blastoma, endocrine tumor, meningioma and medulloblastoma.

37. A method for preparing the compound according to claim 28, comprising subjecting an intermediate compound as shown in formula (A-1) or a compound as shown in formula (A-2) to an oxidation reaction to form a compound as shown in formula (IX-1) or formula (IX-2), ##STR00153## wherein R.sub.1, R.sub.4, R.sub.5, R.sub.6, R.sub.f, R.sub.c, R.sub.a and m are as defined in claim 1; and/or comprising preparing the compound as shown in formula (A-1) by the method of scheme 1 or scheme 2, ##STR00154## wherein R.sub.1, R.sub.4, R.sub.5, R.sub.6, R.sub.f, R.sub.c, R.sub.a and m are as defined in claim 1; ##STR00155## wherein R.sub.1, R.sub.4, R.sub.5, R.sub.6, R.sub.f, R.sub.c, R.sub.a and m are as defined in claim 1; and/or comprising preparing the compound as shown in formula (A-2) by the method of scheme 3, scheme 4, scheme 5 or scheme 6, ##STR00156## wherein R.sub.1, R.sub.4, R.sub.5, R.sub.6, R.sub.f, R.sub.c and m are as defined in claim 1; ##STR00157## wherein R.sub.1, R.sub.4, R.sub.5, R.sub.6, R.sub.f and m are as defined in claim 1, and X is halogen; ##STR00158## wherein R.sub.1, R.sub.4, R.sub.5, R.sub.6, R.sub.f, R.sub.c and m are as defined in claim 1, and X is halogen; ##STR00159## wherein R.sub.1, R.sub.4, R.sub.5, R.sub.6, R.sub.f, R.sub.c, and m are as defined in claim 1, X.sub.1 is -TIPS, -Trt or -TBDPS, and R.sub.102 is H or C.sub.1-3 alkyl, or two R.sub.102 together with the O atoms to which they are attached form a 5-membered heterocycle containing two oxygen atoms and one boron atom, and the 5-membered heterocycle can be optionally substituted with one or more C.sub.1-3 alkyl; and/or comprising preparing the compound as shown in formula (C-1) by the method of scheme 7, ##STR00160## wherein R.sub.1, R.sub.4, R.sub.5, R.sub.6, R.sub.f and m are as defined in claim 1, X is halogen, X.sub.1 is -TIPS, -Trt or -TBDPS, and R.sub.102 is H or C.sub.1-3 alkyl, or two R.sub.102 together with the O atoms to which they are attached form a 5-membered heterocycle containing two oxygen atoms and one boron atom, and the 5-membered heterocycle can be optionally substituted with one or more C.sub.1-3 alkyl; and/or comprising preparing the compound as shown in formula (B-1) by the method of scheme 8, scheme 9 or scheme 10, ##STR00161## wherein R.sub.1, R.sub.4, R.sub.5, R.sub.6, R.sub.f, R.sub.c, and m are as defined in claim 1, X is halogen, and R.sub.101 is C.sub.1-10 alkyl; ##STR00162## wherein R.sub.1, R.sub.4, R.sub.5, R.sub.6, R.sub.f, R.sub.c, and m are as defined in claim 1, and X is halogen; ##STR00163## wherein R.sub.1, R.sub.4, R.sub.5, R.sub.6, R.sub.f, R.sub.c, and m are as defined in claim 1, and R.sub.102 is H or C.sub.1-3 alkyl, or two R.sub.102 together with the O atoms to which they are attached form a 5-membered heterocycle containing two oxygen atoms and one boron atom, and the 5-membered heterocycle can be optionally substituted with one or more C.sub.1-3 alkyl; and/or comprising preparing a compound as shown in formula (G-5) by the method of scheme 11, ##STR00164## wherein R.sub.4, R.sub.5, R.sub.6, R.sub.f, R.sub.c, and m are as defined in claim 1, X is halogen, and X.sub.2 is -Boc or benzenesulfonyl.

38. A compound, or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex or solvate thereof, wherein the compound is selected from the following structure: ##STR00165## ##STR00166## wherein R.sub.1, R.sub.4, R.sub.5, R.sub.6, R.sub.f, R.sub.c, R.sub.a and m are as defined in claim 1, X is halogen, X.sub.1 is -TIPS, -Trt or -TBDPS, X.sub.2 is -Boc or benzenesulfonyl, R.sub.101 is C.sub.1-10 alkyl, and R.sub.102 is H or C.sub.1-3 alkyl, or two R.sub.102 together with the O atoms to which they are attached form a 5-membered heterocycle containing two oxygen atoms and one boron atom, and the 5-membered heterocycle can be optionally substituted with one or more C.sub.1-3 alkyl.

39. The compound, or the stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex or solvate thereof according to claim 1, wherein the R.sub.1 is phenyl, and wherein the phenyl can be optionally substituted with one or more substituents selected from halogen, CN, CH.sub.2F, CHF.sub.2, CF.sub.3, CH.sub.2CHF.sub.2 or CH.sub.2CF.sub.3.

40. A method for treating and/or preventing a HIF-2-mediated disease, comprising administering a therapeutically effective amount of the pharmaceutical composition according to claim 30 to a subject to be treated, wherein, the HIF-2-mediated disease is VHL syndrome, an autoimmune disease, an inflammatory disease and/or cancer.

Description

DETAILED DESCRIPTION OF EMBODIMENTS

[0268] In order to make the present invention to be easily understood, the present invention will be described in details below with reference to examples. These examples are only for illustration and are not intended to limit the application scope of the present invention. The experimental methods in the present invention are all conventional methods unless otherwise specified. Unless otherwise specified, the experimental materials used in the present invention are commercially available.

[0269] Unless otherwise specified, all fractions and percentages are by weight and all temperatures are in degrees Celsius.

The Following Abbreviations are Used in the Examples

[0270] CuI: Cuprous iodide; [0271] DAST: Diethylamine sulfur trifluoride; [0272] DCM: Dichloromethane; [0273] DIEA: N,N-diisopropylethylamine; [0274] DMF: N,N-dimethylformamide; [0275] DMSO: Dimethyl sulfoxide; [0276] EA: Ethyl acetate; [0277] ESI-MS: Electrospray ionization mass spectrometry; [0278] K.sub.2CO.sub.3: Potassium carbonate; [0279] NaH: Sodium hydride; [0280] LDA: Diisopropylaminolithium; [0281] LiHMDS: Lithium bis(trimethylsilyl)amide; [0282] m-CPBA: m-Chloroperbenzoic acid; [0283] MtBE: Methyl tert-butyl ether; [0284] Na.sub.2SO.sub.4: Sodium sulfate; [0285] NaBH.sub.4: Sodium borohydride; [0286] NBS: N-bromosuccinimide; [0287] NFSI: N-Fluorobisbenzenesulfonamide; [0288] NIS: N-iodosuccinimide; [0289] NMP: N-Methylpyrrolidone; [0290] PE: Petroleum ether; [0291] Pd.sub.2(dba).sub.3: Tris(dibenzylideneacetone)dipalladium; [0292] Pd(dppf)Cl.sub.2: 1,1-Bis(diphenylphosphino)ferrocene]palladium dichloride; [0293] Pd(PPh.sub.3).sub.4: Tetrakis(triphenylphosphino)palladium; [0294] Prep-TLC: Preparative thin layer chromatography; [0295] TMSC.sub.2F.sub.5: (Pentafluoroethyl)trimethylsilane; [0296] TBAF: Tetrabutylammonium fluoride; [0297] TEA: Triethylamine; [0298] THF: Tetrahydrofuran; [0299] Xantphos: 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene; [0300] TLC: Thin layer chromatography; [0301] ESI-MS: Electrospray ionization mass spectrometry; [0302] LCMS or LC-MS: Liquid chromatography-mass spectrometry; [0303] .sup.1H NMR: Nuclear magnetic resonance hydrogen spectrum; [0304] [(R,R)-Ts-DPEN]RuCl(p-cymene): Chloro{[(1R,2R)-()-2-amino-1,2-diphenylethyl](4-toluenesulfonyl)amino}(p-cymene)ruthenium(II).

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

##STR00036##

Step 1: Synthesis of Compound M1-1

[0305] Under nitrogen protection, 6,7-dihydro-1H-indol-4(5H)-one (13.5 g) was suspended in THF (100 mL), and DBU (33.44 g) and triisopropylsilyl chloride (21.2 g) were slowly added dropwise at room temperature. The mixture was stirred at room temperature for 3 hours. MTBE (100 mL) and 10% aqueous citric acid solution (100 mL) were added to the reaction liquid and the mixture was subjected to liquid separation. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to obtain the target compound M1-1 (20.3 g), which was used directly in the next step.

[0306] ESI MS m/z: 292.10[M+H].sup.+.

Step 2: Synthesis of Compound M1-2

[0307] Under nitrogen protection, compound M1-1 (13.5 g) was dissolved in acetonitrile (100 mL), and NIS (11.5 g) was added in batches. The mixture was reacted at room temperature for 5 hours. The resulting reaction mixture was cooled, and the precipitated solid was filtered, rinsed with methanol (50 mL*2) and dried to obtain the target compound M1-2 (15.4 g).

[0308] ESI-MS m/z: 418.10 [M+H].sup.+.

Step 3: Synthesis of Compound M1

[0309] Compound M1-2 (4.2 g) and NFSI (7.9 g) were suspended in THF (100 mL) and cooled to 78 C., and 1.0 M LiHMDS tetrahydrofuran solution (28.2 mL) was slowly added dropwise. After stirring at 60 C. for 2 hours, saturated ammonium chloride aqueous solution (200 mL) was added to the reaction liquid, and the mixture was extracted twice with ethyl acetate, washed twice with saturated sodium chloride aqueous solution, dried and concentrated to obtain a crude product, which was rinsed with methanol to obtain the target compound M1 (2.1 g).

[0310] ESI-MS m/z: 297.99 [M+H].sup.+.

[0311] .sup.1H NMR (500 MHz, DMSO-d6): 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)

##STR00037##

[0312] M1 (12 g), cuprous iodide (7.8 g), and methyl fluorosulfonyldifluoroacetate (24 g) were added to NMP (120 mL). The reaction system was replaced with nitrogen, and the mixture was heated to 120 C. under nitrogen protection. The reaction was allowed to proceed overnight. TLC and LCMS showed that no raw material remained. The mixture was cooled down and diluted with ethyl acetate. The organic phase was washed with saturated sodium chloride aqueous solution, dried over sodium sulfate, and concentrated to obtain a crude product, which was purified by column chromatography (EA/PE=1:5) to obtain the target compound M2 (8.4 g).

[0313] ESI-MS m/z: 238.00 [MH].sup..

[0314] .sup.1H NMR (500 MHz, DMSO) 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)

##STR00038##

Step 1: Synthesis of Compound M3-1

[0315] Compound M1-2 (834 mg), cuprous iodide (380 mg), NMP (20 mL) and methyl fluorosulfonyldifluoroacetate (1.15 g) were added to a 50 mL single-necked bottle in sequence, the mixture was heated to 120 C., and the reaction was carried out for 6 h. The reaction mixture was diluted with EA, washed three times with water, washed once with saturated sodium chloride aqueous solution, dried, and concentrated to obtain a crude product, which was purified by column chromatography (DCM=100%) to obtain the target compound M3-1 (264 mg).

[0316] ESI-MS m/z: 204.08[M+H+].sup.+.

Step 2: Synthesis of Compound M3

Method I:

[0317] Under nitrogen protection, compound M3-1 (264 mg) was dissolved in ultra-dry tetrahydrofuran (20 mL), cooled to 78 C., and 1.0 M LDA tetrahydrofuran solution (2.5 mL) was slowly added dropwise. After stirring for half an hour, NFSI (491 mg)tetrahydrofuran solution (5 mL) was added dropwise, and stirring was continued at 78 C. for two hours. Saturated ammonium chloride aqueous solution was added to the reaction mixture to quench the reaction, and the resulting mixture was extracted twice with ethyl acetate, washed twice with saturated sodium chloride aqueous solution, dried and concentrated to obtain a crude product, which was purified by column chromatography (DCM=100%) to obtain the target compound M3 (147 mg).

Method II:

[0318] Under nitrogen protection, compound M3-1 (200 mg) was dissolved in methanol (3 mL), NFSI (465 mg) was added, and the mixture was refluxed at 70 C. overnight. After the reaction was completed, the mixture was concentrated and purified by column chromatography (DCM=100%) to obtain the target compound M3 (173 mg).

[0319] ESI-MS m/z: 222.12[M+H+].sup.+.

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

##STR00039##

Step 1: Synthesis of Compound M4-1

[0320] Under nitrogen protection, methyl 3-bromo-1H-pyrrole-2-carboxylate (20.4 g) and methyl 4-bromobutyrate (19.8 g) were dissolved in DMF (100 mL), and cesium carbonate (65.2 g) was added. After stirring at room temperature for 4 hours, the reaction liquid was poured into an ice-water mixture (500 mL), extracted with ethyl acetate, washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product, which was purified by column chromatography (EA/PE=1:10) to obtain the target compound M4-1 (28.3 g).

[0321] ESI-MS m/z: 304.10[M+H].sup.+.

Step 2: Synthesis of Compound M4-2

[0322] Under nitrogen protection, compound M4-1 (15.2 g) was dissolved in THE (100 mL), and 1.0 M potassium tert-butoxide tetrahydrofuran solution (60 mL) was slowly added dropwise in an ice bath. After stirring at 0 C. for 3 hours, the mixture was cooled to 78 C., and a solution of NFSI (18.9 g) in tetrahydrofuran (50 mL) was added dropwise. The reaction was continued at 78 C. for 1 hour. After the reaction was quenched by adding saturated ammonium chloride aqueous solution, the mixture was extracted with ethyl acetate, washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product, which was purified by column chromatography (EA/PE=1:5) to obtain the target compound M4-2 (9.1 g).

[0323] ESI-MS m/z: 277.15 [M+H].sup.+.

Step 3: Synthesis of Compound M4-3

[0324] Under nitrogen protection, compound M4-2 (8.3 g) was dissolved in DMF (100 mL), palladium acetate (3.3 g), CuI (11.4 g) and methyl fluorosulfonyldifluoroacetate (23 g) were added. The mixture was stirred at 100 C. for 3 hours and extracted with ethyl acetate, and the organic layer was washed with brine, dried over Na.sub.2SO.sub.4 and concentrated to obtain a crude product, which was purified by column chromatography (EA/PE=1:4) to obtain the target compound M4-3 (4.23 g).

[0325] ESI-MS m/z: 279.20 [M+H].sup.+.

Step 4: Synthesis of Compound M4-4

[0326] Compound M4-3 (4.23 g) was dissolved in a mixed solvent of ethanol (20 mL) and 6 M aqueous hydrochloric acid solution (20 mL), and the reaction was allowed to reflux for 3 hours. The mixture was concentrated under reduced pressure and the ethanol was removed by rotary evaporation, and the residue was extracted with ethyl acetate (100 mL*2). The organic layer was washed with brine (100 mL*2), then dried over Na.sub.2SO.sub.4 and concentrated to obtain a crude product, which was purified by column chromatography (EA/PE=1:4) to obtain the target compound M4-4 (2.1 g).

[0327] ESI-MS m/z: 221.20 [M+H].sup.+.

Step 5: Synthesis of Compound M4

[0328] Compound M4-4 (2.1 g) was dissolved in acetonitrile (20 mL), NBS (1.8 g) was added at room temperature, and the reaction liquid was refluxed for 4 hours, quenched with water, extracted with ethyl acetate, washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product, which was purified by column chromatography (EA/PE=1:3) to obtain the target compound M4 (2.5 g).

[0329] ESI-MS m/z: 300.10 [M+H].sup.+.

Step 6: Synthesis of Compound M5

[0330] Compound M4 (1.3 g) was dissolved in THE (50 mL), cooled to 78 C., and 1.0 M LiHMDS tetrahydrofuran solution (6 mL) was slowly added dropwise. After stirring for half an hour, a solution of NFSI (1.5 g) in tetrahydrofuran (10 mL) was added dropwise. The mixture was stirred for another two hours. Saturated ammonium chloride aqueous solution was added to quench the reaction. The mixture was extracted twice with ethyl acetate, washed twice with saturated sodium chloride aqueous solution, dried, and concentrated to obtain a crude product, which was purified by column chromatography (EA/PE=1:3) to obtain the target compound M5 (0.8 g).

Example 1 Synthesis of 5-(5,5-difluoro-4-hydroxyl-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)-2,3-difluorobenzonitrile (compound B1)

##STR00040##

Step 1: Synthesis of Compound B1-1

[0331] Potassium acetate (0.76 g), 1,1-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (0.21 g), bis(pinacolato)diboron (1.31 g), and 5-bromo-2,3-difluorobenzonitrile (0.56 g) were dissolved in dioxane (6 mL) and dimethyl sulfoxide (0.05 mL). The reaction system was replaced with nitrogen, and the mixture was stirred at 95 C. overnight. After the reaction was completed, ethyl acetate and water were added. The mixture was subjected to liquid separation, washed with saturated sodium chloride aqueous solution, dried and concentrated to obtain a crude product B1-1 (0.7 g), which was directly used in the next step.

Step 2: Synthesis of Compound B1-2

[0332] Copper acetate (0.31 g), 4A molecular sieve (0.5 g), compound M2 (0.47 g) and compound B1-1 (0.7 g) were placed in a reaction bottle, and DMF (1 mL) and triethylamine (0.71 mL) were added. The reaction system was replaced with oxygen, and the mixture was stirred at 80 C. overnight, cooled to room temperature, filtered, diluted with ethyl acetate, washed with water and saturated sodium chloride aqueous solution, dried, concentrated, and purified by column chromatography to obtain the target compound B1-2 (0.07 g).

Step 3: Synthesis of Compound B1

[0333] Compound B1-2 (0.07 g) was dissolved in methanol (1 mL) and tetrahydrofuran (1 mL), and cooled in an ice-water bath. Sodium borohydride (0.02 g) was added, and stirred at room temperature overnight, and ethyl acetate and water were added after the reaction was completed. The mixture was washed with saturated sodium chloride aqueous solution, dried, concentrated, and purified by Prep-TLC to obtain the target compound B1 (0.07 g).

[0334] ESI-MS m/z: 423.21 [M+HCOO.sup.].sup..

Example 2 Synthesis of 5,5-difluoro-1-(4-fluoro-3-(fluoromethyl)phenyl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol (compound B2)

##STR00041##

[0335] 5,5-Difluoro-1-(4-fluoro-3-(hydroxymethyl)phenyl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol (100 mg) was dissolved in dichloromethane (2 mL), and cooled in an ice-water bath, and DAST (48 mg) was added. After stirring in an ice-water bath for 1 hour, saturated sodium bicarbonate was added to the reaction liquid, and the mixture was diluted with dichloromethane. The mixture was subjected to liquid separation, and the organic phase was washed with saturated sodium chloride aqueous solution, dried, and concentrated, and purified by Prep-TLC to obtain the target compound B2 (10 mg).

[0336] ESI-MS m/z: 350.10[M+H.sub.2O-H+].sup.+.

Example 3 Synthesis of (S)-4-(5,5-difluoro-4-hydroxyl-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)-2-(difluoromethyl)benzonitrile (compound B3)

##STR00042##

Step 1: Synthesis of Compound B3-1

[0337] Potassium acetate (224 mg), 1,1-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (42 mg), bis(pinacolato)diboron (305 mg), and 4-bromo-2-(difluoromethyl)benzonitrile (265 mg) were dissolved in dioxane (6 mL), and the mixture was stirred at 80 C. overnight under nitrogen protection. After the reaction was completed, ethyl acetate and water were added to the reaction liquid. The mixture was subjected to liquid separation, washed with saturated sodium chloride aqueous solution, dried and concentrated to obtain a crude product, which was purified by column chromatography to obtain compound B3-1 (165 mg).

Step 2: Synthesis of Compound B3-2

[0338] DCM (5 mL) and diisopropylethylamine (0.13 mL) were added to a mixture of copper acetate (92 mg), 4A molecular sieve (100 mg), compound M2 (61 mg) and compound B3-1 (50 mg). The reaction system was replaced with oxygen, and the mixture was stirred at room temperature overnight, filtered, concentrated, and purified by column chromatography to obtain the target compound B3-2 (64 mg).

Step 3: Synthesis of Compound B3

[0339] To a solution of compound B3-2 (64 mg) in dichloromethane, triethylamine (0.05 mL), chloro {[(1R,2R)-()-2-amino-1,2-diphenylethyl](4-toluenesulfonyl)amino}(p-cymene)ruthenium(II) (10 mg) and formic acid (23 mg) were added, stirred at room temperature overnight, concentrated, and purified by column chromatography to obtain the target compound B3 (35 mg).

[0340] ESI-MS m/z: 437.24 [M+HCOO.sup.].sup..

Example 4 Synthesis of (S)-5-(3-((difluoromethyl)sulfonyl)-5,5-difluoro-4-hydroxyl-4,5,6,7-tetrahydro-1H-indol-1-yl)-2-fluorobenzonitrile (compound A3)

##STR00043##

Step 1: Synthesis of Compound A3-1

[0341] To a solution of compound M2 (0.9 g) in DCM (50 mL) were added copper acetate (0.55 g), 3-cyano-4-fluorophenylboronic acid (1.0 g) and TEA (1.2 g), and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with dichloromethane, washed twice with saturated sodium chloride aqueous solution, dried, and concentrated to obtain a crude product, which was purified by column chromatography (EA/PE=1:5) to obtain the target compound A3-1 (0.92 g).

Step 2: Synthesis of Compound A3-2

[0342] A mixture of compound A3-1 (1.26 g), methyl 3-mercaptopropionate (0.73 g), Xantphos (0.35 g), tri(dibenzylideneacetone)dipalladium (0.28 g), DIEA (1.5 mL) and toluene (40 mL) was stirred at 70 C. overnight. After the reaction was completed, the mixture was concentrated to obtain a crude product, which was purified by column chromatography to obtain the target compound A3-2 (1.10 g).

Step 3: Synthesis of Compound A3-3

[0343] To a solution of compound A3-2 (0.40 g) in tetrahydrofuran (10 mL) was added a 1.0 M solution of potassium tert-butoxide in tetrahydrofuran (1.5 mL) at 78 C. After stirring for 10 minutes, diethyl bromofluoromethylphosphonate (0.40 g) was added. After stirring for 2 hours, water was added to quench the reaction. The reaction liquid was heated to room temperature and stirring was continued overnight. The reaction solution was diluted with water and ethyl acetate. The organic phase was washed with saturated sodium chloride aqueous solution, dried, and concentrated to obtain a crude product, which was purified by column chromatography (EA/PE=1:3) to obtain the target compound A3-3 (0.18 g).

Step 4: Synthesis of Compound A3-4

[0344] To a mixture of compound A3-3 (0.15 g), acetonitrile (1 mL), dichloromethane (1 mL) and water (2 mL) was added ruthenium trichloride (0.01 g) and sodium periodate (0.5 g) and the mixture was stirred at room temperature for 2 h. After the reaction was completed, the reaction liquid was diluted with ethyl acetate, washed with water and saturated sodium chloride aqueous solution, dried, and concentrated to obtain a crude product, which was purified by column chromatography (EA/PE=1:3) to obtain the target compound A3-4 (0.1 g).

Step 5: Synthesis of Compound A3

[0345] Triethylamine (0.08 mL), chloro{[(1R,2R)-()-2-amino-1,2-diphenylethyl](4-toluenesulfonyl)amino}(P-cymene)ruthenium(II) (0.04 g) and formic acid (0.04 g) were added to a solution of compound A3-4 (0.12 g) in dichloromethane, and the mixture was stirred at room temperature overnight. The reaction liquid was diluted with dichloromethane, washed with water and saturated sodium chloride aqueous solution, dried, and concentrated to obtain a crude product, which was purified by column chromatography (EA/PE=1:3) to obtain the target compound A3 (0.09 g).

[0346] ESI-MS m/z: 451.16 [M+HCOO.sup.].sup..

Example 5 Synthesis of (S)-1-(3-(difluoromethyl)-4-fluorophenyl)-5,5-difluoro-3-(methylsulfonyl) 4,5,6,7-tetrahydro-1H-indol-4-ol (compound A4)

##STR00044## ##STR00045##

Step 1: Synthesis of Compound A4-1

[0347] (4-Fluoro-3-formylphenyl)boronic acid (2.0 g), compound M2 (3.5 g), copper acetate (2.5 g) and triethylamine (5.0 mL) were added to dichloromethane (40 mL) respectively, and the mixture was stirred at room temperature overnight under an oxygen atmosphere. After the reaction was completed, the reaction liquid was diluted with dichloromethane, washed twice with saturated sodium chloride aqueous solution, dried, filtered, and concentrated to obtain a crude product, which was purified by column chromatography (EA/PE=1:3) to obtain the target compound A4-1 (1.8 g).

[0348] ESI-MS m/z: 420.0 [M+H].sup.+.

Step 2: Synthesis of Compound A4-2

[0349] DAST (700 mg) was added to a solution of compound A4-1 (500 mg) in dichloromethane (10 mL) and the mixture was stirred at room temperature overnight. After the reaction was completed, the reaction liquid was diluted with dichloromethane and quenched with saturated sodium bicarbonate. The organic phase was washed with water, dried, filtered, and concentrated to obtain a crude product, which was purified by column chromatography (EA/PE=1:3) to obtain the target compound A4-2 (150 mg).

[0350] ESI-MS m/z: 442.0 [M+H].sup.+.

Step 3: Synthesis of Compound A4-3

[0351] A mixture of compound A4-2 (0.88 g), methyl 3-mercaptopropionate (0.36 g), Xantphos (0.23 g), tri(dibenzylideneacetone)dipalladium (0.18 g), DIEA (0.66 mL) and toluene (5 mL) was stirred at 70 C. overnight. After the reaction was completed, the mixture was concentrated to obtain a crude product, which was purified by column chromatography to obtain the target compound A4-3 (0.8 g).

[0352] ESI-MS m/z: 434.0 [M+H].sup.+.

Step 4: Synthesis of Compound A4-4

[0353] Compound A4-3 (0.30 g) was dissolved in tetrahydrofuran (10 mL), and the reaction solution was cooled to 78 C. and stirred for half an hour. A 1.0 M solution of potassium tert-butoxide in tetrahydrofuran (1.0 mL) was then added, and stirred for 10 minutes. Iodomethane (0.09 mL) was added, and the stirring was continued at 78 C. for 2 hours. The reaction liquid was diluted with water and ethyl acetate, and the organic phase was washed with saturated sodium chloride aqueous solution, dried and concentrated to obtain a crude product, which was purified by column chromatography (EA/PE=1:3) to obtain the target compound A4-4 (0.20 g).

[0354] ESI-MS m/z: 362.0 [M+H].sup.+.

Step 5: Synthesis of Compound A4-5

[0355] Potassium peroxymonosulfonate (0.71 g) was added to a mixture of compound A4-4 (0.2 g), acetonitrile (10 mL) and water (2 mL), and the mixture was stirred at 60 C. for 2 h. After the reaction was completed, the reaction liquid was diluted with ethyl acetate, washed with water and saturated sodium chloride aqueous solution, dried, and concentrated to obtain a crude product, which was purified by column chromatography (EA/PE=1:3) to obtain the target compound A4-5 (0.18 g).

[0356] ESI-MS m/z: 394.0 [M+H].sup.+.

Step 6: Synthesis of Compound A4

[0357] To a solution of A4-5 (0.06 g) in dichloromethane (3 mL) were added triethylamine (0.03 g), chloro{[(1R,2R)-()-2-amino-1,2-diphenylethyl](4-toluenesulfonyl)amino}(P-cymene)ruthenium(II) (0.01 g) and formic acid (0.02 g), and the mixture was stirred at room temperature overnight. The reaction liquid was diluted with dichloromethane, washed with water and saturated sodium chloride aqueous solution, dried, and concentrated to obtain a crude product, which was purified by column chromatography (EA/PE=1:3) to obtain the target compound A4 (0.03 g).

[0358] ESI-MS m/z: 451.16 [M+H.sup.+-H.sub.2O].sup.+.

Example 6 Synthesis of (S)-1-(3-(difluoromethyl)-4-fluorophenyl)-3-((difluoromethyl)sulfonyl)-5,5-difluoro-4,5,6,7-tetrahydro-1H-indol-4-ol (compound A5)

##STR00046##

Step 1: Synthesis of Compound A5-1

[0359] Compound A4-3 (0.20 g) was dissolved in tetrahydrofuran (10 mL), and the solution was cooled to 78 C. and stirred for half an hour. A 1.0 M solution of potassium tert-butoxide in tetrahydrofuran (0.7 mL) was added, and the mixture was stirred for 10 minutes. Diethyl bromofluoromethylphosphonate (0.20 g) was then added, and stirring was continued at 78 C. for 2 hours. The reaction liquid was diluted with water and ethyl acetate, and the organic phase was washed with saturated sodium chloride aqueous solution, dried and concentrated, and purified by column chromatography to obtain the target compound A5-1 (0.15 g).

[0360] ESI-MS m/z: 398.0 [M+H].sup.+.

Step 2: Synthesis of Compound A5-2

[0361] To a mixture of compound A5-1 (0.15 g), acetonitrile (2 mL), dichloromethane (2 mL) and water (4 mL) were added ruthenium trichloride (0.01 g) and sodium periodate (0.24 g), and the mixture was stirred at room temperature for 2 h. After the reaction was completed, the reaction liquid was diluted with ethyl acetate, washed with water and saturated sodium chloride aqueous solution, dried, concentrated, and purified by column chromatography to obtain the target compound A5-2 (0.08 g).

Step 3: Synthesis of Compound A5

[0362] To a solution of compound A5-2 (0.08 g) in dichloromethane (3 mL) were added triethylamine (0.05 mL), chloro{[(1R,2R)-()-2-amino-1,2-diphenylethyl](4-toluenesulfonyl)amino}(P-cymene)ruthenium(II) (0.01 g) and formic acid (0.03 g), and the mixture was stirred at room temperature overnight. The reaction liquid was diluted with dichloromethane, washed with water and saturated sodium chloride aqueous solution, dried, and concentrated, and purified by column chromatography to obtain the target compound A5 (0.03 g).

[0363] ESI-MS m/z: 414.05 [M+H.sup.+-H.sub.2O].sup.+.

Example 7 and example 8 Synthesis of (S)-3-((S)-(difluoromethyl)sulfinyl)-5,5-difluoro-1-(4-fluoro-3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydro-1H-indol-4-ol (compound A13, presumed) and (S)-3-((R)-(difluoromethyl)sulfinyl)-5,5-difluoro-1-(4-fluoro-3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydro-1H-indol-4-ol (compound A14, presumed)

##STR00047## ##STR00048##

Step 1: Synthesis of Compound A13-11

[0364] 3-Cyano-4-fluorophenylboronic acid was replaced with 3-trifluoromethyl-4-fluorophenylboronic acid and compound A13-11 was obtained with reference to the method of step 1 of example 4.

Step 2: Synthesis of Compound A13-12

[0365] Compound A3-1 was replaced with compound A13-11 and compound 13-12 was obtained with reference to the method of step 2 of example 4.

Step 3: Synthesis of Compound 13-1

[0366] Compound A3-2 was replaced with compound 13-11 and compound 13-1 was obtained with reference to the method of step 3 of example 4.

Step 4: Synthesis of Compound A13-2

[0367] To a mixed solution of compound A13-1 (120 mg) in acetonitrile (2 mL) and water (2 mL) was added potassium peroxymonosulfonate (210 mg), and the mixture was stirred at 65 C. overnight. After the reaction was completed, the mixture was cooled, diluted with ethyl acetate, washed with water and saturated sodium chloride aqueous solution, dried, concentrated, and purified by column chromatography to obtain the target compound A13-2 (90 mg).

[0368] ESI-MS m/z: 430.0 [MH.sup.+].sup..

Step 5: Synthesis of Compounds A13 and A14

[0369] To a solution of A13-2 (100 mg) in dichloromethane (5 mL) were added chloro {[(1R,2R)-()-2-amino-1,2-diphenylethyl](4-toluenesulfonyl)amino}(p-cymene)ruthenium(II) (10 mg), triethylamine (0.06 mL) and formic acid (0.03 g), and the mixture was stirred at room temperature overnight. The reaction liquid was diluted with dichloromethane, washed with water and saturated sodium chloride aqueous solution, dried, and concentrated, and the crude product was purified by HPLC (Luna PREP C.sub.18, mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile (35% to 70%), flow rate: 40 mL/min, detection wavelength: 254 nm, temperature: room temperature), and the front peak was collected as the target compound A13 (20 mg), and the back peak was collected as the target compound A14 (20 mg).

[0370] ESI-MS m/z: 416.07 [M+H.sup.+-H.sub.2O].sup.+.

Example 9 Synthesis of 5-(5,5-difluoro-4-hydroxyl-3-(perfluoroethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)-2-fluorobenzonitrile (compound A10)

##STR00049##

Step 1: Synthesis of Compound A10-1

[0371] TMSC.sub.2F.sub.5 (0.11 mL) and pyridine (0.12 mL) were added to a mixed solution of A3-1 (130 mg), cuprous iodide (0.12 g), silver fluoride (0.08 g) and dimethyl sulfoxide (2 mL), and stirred at 80 C. overnight. The reaction liquid was diluted with ethyl acetate, washed with water and saturated sodium chloride aqueous solution, dried, concentrated, and purified by column chromatography to obtain the target compound A10-1 (100 mg).

Step 2: Synthesis of Compound A10

[0372] Compound A10-1 (100 mg) was dissolved in methanol (1 mL) and tetrahydrofuran (1 mL), and the mixture was cooled to 0 C. in an ice-water bath. Sodium borohydride (30 mg) was added, and the reaction was allowed to react at room temperature overnight. The reaction liquid was diluted with water, and extracted with ethyl acetate, and the organic phase was washed with saturated sodium chloride aqueous solution, dried, concentrated, and purified by column chromatography (EA/PE=1:3) to obtain the target compound A10 (90 mg).

[0373] ESI-MS m/z: 455.17 [M+HCOO.sup.].sup..

Example 10 Synthesis of (S)-5-(5,5-difluoro-4-hydroxyl-3-((trifluoromethyl)sulfonyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)-2-fluorobenzonitrile (compound A11)

##STR00050##

Step 1: Synthesis of Compound A11-1

[0374] N,N-dimethylacetamide (2 mL) was added to a mixture of copper(I) thiophene-2-carboxylate (270 mg), compound A3-1 (400 mg) and silver trifluoromethanethiol (300 mg), and the mixture was stirred at 100 C. overnight. The mixture was cooled to room temperature, and the reaction liquid was diluted with ethyl acetate, washed with water and saturated sodium chloride aqueous solution, dried, concentrated, and purified by column chromatography (EA/PE=1:3) to obtain the target compound A11-1 (210 mg).

[0375] ESI-MS m/z: 389.0 [MH.sup.+].sup..

Step 2: Synthesis of Compound A11-2

[0376] To a mixture of compound A11-1 (100 mg) in acetonitrile (2 mL), dichloromethane (2 mL) and water (4 mL), ruthenium trichloride (0.01 g) and sodium periodate (0.22 g) were added and stirred at room temperature for 2 h. After the reaction was completed, the reaction liquid was diluted with ethyl acetate, washed with water and saturated sodium chloride aqueous solution, dried, concentrated, and purified by column chromatography (EA/PE=1:3) to obtain the target compound A11-2 (70 mg).

[0377] ESI-MS m/z: 421.0 [MH.sup.+].sup..

Step 3: Synthesis of Compound A11

[0378] To a solution of compound A11-2 (50 mg) in dichloromethane (5 mL) were added chloro {[(1R,2R)-()-2-amino-1,2-diphenylethyl](4-toluenesulfonyl)amino}(p-cymene)ruthenium(II) (10 mg), triethylamine (0.03 mL) and formic acid (30 mg), and the mixture was stirred at room temperature overnight. The reaction liquid was diluted with dichloromethane, washed with water and saturated sodium chloride aqueous solution, dried, and concentrated, and purified by column chromatography (EA/PE=1:3) to obtain the target compound A11 (10 mg).

[0379] ESI-MS m/z: 469.10 [M+HCOO.sup.].sup..

Example 11 Synthesis of (S)-5-(5,5-difluoro-3-((fluoromethyl)sulfonyl)-4-hydroxyl-4,5,6,7-tetrahydro-1H-indol-1-yl)-2-fluorobenzonitrile (compound A16)

##STR00051##

Step 1: Synthesis of Compound A16-1

[0380] To a solution of compound A3-2 (120 mg) in tetrahydrofuran (10 mL) was added a 1.0 M solution of potassium tert-butoxide in tetrahydrofuran (0.44 mL) at 78 C. After stirring for 10 minutes, fluoroiodomethane (70 mg) was added and stirring was continued for 2 hours. The reaction liquid was diluted with water and ethyl acetate. The organic phase was washed with saturated sodium chloride aqueous solution, dried, concentrated, and purified by column chromatography (EA/PE=1:3) to obtain the target compound A16-1 (80 mg).

[0381] ESI-MS m/z: 353.0 [MH.sup.+].sup..

Step 2: Synthesis of Compound A16-2

[0382] Potassium peroxymonosulfonate (0.63 g) was added to a mixed solution of compound A16-1 (60 mg) in acetonitrile (3 mL) and water (3 mL), and the reaction solution was stirred at 60 C. overnight. After the reaction was completed, the reaction liquid was diluted with ethyl acetate, washed with water and saturated sodium chloride aqueous solution, dried, concentrated, and purified by column chromatography (EA/PE=1:3) to obtain the target compound A16-2 (50 mg).

[0383] ESI-MS m/z: 385.0 [MH.sup.+].sup..

Step 3: Synthesis of Compound A16

[0384] To a solution of compound A16-2 (70 mg) in dichloromethane (5 mL) were added triethylamine (0.05 mL), chloro{[(1R,2R)-()-2-amino-1,2-diphenylethyl](4-toluenesulfonyl)amino}(p-cymene)ruthenium(II) (10 mg), and formic acid (20 mg), and the mixture was stirred at room temperature overnight. The reaction liquid was diluted with dichloromethane, washed with water and saturated sodium chloride aqueous solution, dried, and concentrated, and purified by column chromatography (EA/PE=1:3) to obtain the target compound A16 (30 mg).

[0385] ESI-MS m/z: 433.16 [M+HCOO.sup.].sup..

Example 12 Synthesis of (S)-1-(3-(difluoromethyl)-4-fluorophenyl)-5,5-difluoro-3-((trifluoromethyl)sulfonyl)-4,5,6,7-tetrahydro-1H-indol-4-ol (compound A17)

##STR00052##

Step 1: Synthesis of Compound A17-1

[0386] N,N-dimethylacetamide (5 mL) was added to a mixture of copper(I) thiophene-2-carboxylate (140 mg), compound A4-2 (220 mg) and silver trifluoromethanethiol (160 mg), and the mixture was stirred at 100 C. overnight. The mixture was cooled to room temperature, and the reaction liquid was diluted with ethyl acetate, washed with water and saturated sodium chloride aqueous solution, dried, concentrated, and purified by column chromatography to obtain the target compound A17-1 (160 mg).

[0387] ESI-MS m/z: 416.0 [M+H.sup.+].sup.+.

Step 2: Synthesis of Compound A17-2

[0388] To a mixture of compound A17-1 (0.17 g) in acetonitrile (3 mL), dichloromethane (3 mL) and water (6 mL), ruthenium trichloride (0.01 g) and sodium periodate (0.44 g) were added and stirred at room temperature overnight. After the reaction was completed, the reaction liquid was diluted with ethyl acetate, washed with water and saturated sodium chloride aqueous solution, dried, concentrated, and purified by column chromatography (EA/PE=1:3) to obtain the target compound A17-2 (0.07 g).

[0389] ESI-MS m/z: 446.0 [MH.sup.+].sup..

Step 3: Synthesis of Compound A17

[0390] To a solution of A17-2 (70 mg) in dichloromethane (5 mL) were added chloro{[(1R,2R)-()-2-amino-1,2-diphenylethyl](4-toluenesulfonyl)amino}(p-cymene)ruthenium(II) (10 mg), triethylamine (0.04 mL) and formic acid (0.02 g), and the mixture was stirred at room temperature overnight. The reaction liquid was diluted with dichloromethane, washed with water and saturated sodium chloride aqueous solution, dried, and concentrated, and purified by column chromatography (EA/PE=1:3) to obtain the target compound A17 (60 mg).

[0391] ESI-MS m/z: 494.12 [M+HCOO.sup.].sup..

Example 13 Synthesis of (S)-2-((5,5-difluoro-1-(4-fluoro-3-(trifluoromethyl)phenyl)-4-hydroxyl-4,5,6,7-tetrahydro-1H-indol-3-yl)sulfonyl)acetonitrile (compound A18)

##STR00053##

Step 1: Synthesis of Compound A18-2

[0392] To a solution of A18-1 (160 mg) in tetrahydrofuran (10 mL) was added a 1.0 M solution of potassium tert-butoxide in tetrahydrofuran (0.5 mL) at 78 C. After stirring for 10 minutes, bromoacetonitrile (60 mg) was added and stirring was continued for 2 hours. The reaction liquid was diluted with water and ethyl acetate. The organic phase was washed with saturated sodium chloride aqueous solution, dried, concentrated, and purified by column chromatography (EA/PE=1:3) to obtain the target compound A18-2 (120 mg).

[0393] ESI-MS m/z: 405 [M+H.sup.+].sup.+.

Step 2: Synthesis of Compound A18-3

[0394] Potassium peroxymonosulfonate (457 mg) was added to a mixture of compound A18-2 (120 mg) in acetonitrile (3 mL) and water (3 mL), and the reaction solution was stirred at 60 C. for 2 h. After the reaction was completed, the reaction liquid was diluted with ethyl acetate, washed with water and saturated sodium chloride aqueous solution, dried, concentrated, and purified by column chromatography (EA/PE=1:3) to obtain the target compound A18-3 (100 mg).

[0395] ESI-MS m/z: 435 [MH.sup.+].sup..

Step 3: Synthesis of Compound A18

[0396] To a solution of compound A18-3 (100 mg) in dichloromethane (5 mL) were added triethylamine (0.06 mL), chloro{[(1R,2R)-()-2-amino-1,2-diphenylethyl](4-toluenesulfonyl)amino}(p-cymene)ruthenium(II) (10 mg), and formic acid (30 mg), and the mixture was stirred at room temperature overnight. The reaction liquid was diluted with dichloromethane, washed with water and saturated sodium chloride aqueous solution, dried, and concentrated, and purified by column chromatography (EA/PE=1:3) to obtain the target compound A18 (50 mg).

[0397] ESI-MS m/z: 437.12 [MH.sup.].sup..

Example 14 Synthesis of (S)-1-(3-(difluoromethyl)-4-fluorophenyl)-5,5-difluoro-3-((fluoromethyl)sulfonyl)-4,5,6,7-tetrahydro-1H-indol-4-ol (compound A19)

##STR00054##

Step 1: Synthesis of Compound A19-1

[0398] To a solution of compound A4-3 (270 mg) in tetrahydrofuran (10 mL) was added a 1.0 M solution of potassium tert-butoxide in tetrahydrofuran (1.0 mL) at 78 C. After stirring for 10 minutes, fluoroiodomethane (0.15 g) was added and stirring was continued for 2 hours while keeping the temperature unchanged. The reaction liquid was diluted with water and ethyl acetate. The organic phase was washed with saturated sodium chloride aqueous solution, dried, concentrated, and purified by column chromatography (EA/PE=1:3) to obtain the target compound A19-1 (180 mg).

[0399] ESI-MS m/z: 380 [M+H.sup.+].sup.+.

Step 2: Synthesis of Compound A19-2

[0400] Potassium peroxymonosulfonate (1.85 g) was added to a solution of compound A19-1 (190 mg) in acetonitrile (4 mL) and water (4 mL), and the reaction solution was stirred at 60 C. for 3 h. After the reaction was completed, the reaction liquid was diluted with ethyl acetate, washed with water and saturated sodium chloride aqueous solution, dried, concentrated, and purified by column chromatography (EA/PE=1:3) to obtain the target compound A19-2 (150 mg).

[0401] ESI-MS m/z: 412 [M+H.sup.+].sup.+.

Step 3: Synthesis of Compound A19

[0402] To a solution of compound A19-2 (150 mg) in dichloromethane (5 mL) were added triethylamine (0.11 mL), chloro{[(1R,2R)-()-2-amino-1,2-diphenylethyl](4-toluenesulfonyl)amino}(p-cymene)ruthenium(II) (20 mg), and formic acid (50 mg), and the mixture was stirred at room temperature overnight. The reaction liquid was diluted with dichloromethane, washed with water and saturated sodium chloride aqueous solution, dried, and concentrated, and purified by column chromatography (EA/PE=1:3) to obtain the target compound A19 (90 mg).

[0403] ESI-MS m/z: 458.11 [M+HCOO.sup.].sup..

Example 15 Synthesis of 2-(1-(3-cyano-4-fluorophenyl)-5,5-difluoro-4-hydroxyl-4,5,6,7-tetrahydro-1H-indol-3-yl)-2,2-difluoroacetamide (compound A20)

##STR00055##

Step 1: Synthesis of Compound A20-1

[0404] To a solution of ethyl difluorobromoacetate (100 mg) in dimethyl sulfoxide (1 mL), copper powder (30 mg) and compound A3-1 (100 mg) were added, and the mixture was stirred at 95 C. overnight. The mixture was cooled to room temperature, and the reaction liquid was diluted with ethyl acetate, washed with water and saturated sodium chloride aqueous solution, dried, concentrated, and purified by column chromatography to obtain the target compound A20-1 (70 mg).

Step 2: Synthesis of Compound A20-2

[0405] To a solution of compound A20-1 (70 mg) in methanol (1 mL) was added 7 mol/L ammonia methanol solution (0.49 mL), and the mixture was stirred at room temperature for 4 hours. The reaction liquid was concentrated to obtain the target compound A20-2, which was used directly in the next step without further purification.

[0406] ESI-MS m/z: 384.1 [M+H.sup.+].sup.+.

Step 3: Synthesis of Compound A20

[0407] A20-2 (70 mg) was dissolved in methanol (1 mL) and tetrahydrofuran (1 mL). After cooling in an ice-water bath, sodium borohydride (20 mg) was added and the reaction was allowed to react at room temperature overnight. After the reaction was completed, the reaction liquid was diluted with ethyl acetate, washed with water and saturated sodium chloride aqueous solution, dried, concentrated, and purified by column chromatography (EA/PE=1:3) to obtain the target compound A20 (40 mg).

[0408] ESI-MS m/z: 430.0 [M+HCOO.sup.].sup..

Example 16 Synthesis of 1-(4-fluoro-3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydro-4,5,6,7-tetrahydro-1H-indol-4-ol (compound A21)

##STR00056##

Step 1: Synthesis of Compound A21-1

[0409] To a solution of compound A18-1 (180 mg) in tetrahydrofuran (10 mL) was added a 1.0 M solution of potassium tert-butoxide in tetrahydrofuran (0.6 mL) at 78 C. After stirring for 10 minutes, iodoethane (90 mg) was added. The reaction solution was stirred for 2 hours. The reaction liquid was diluted with water and ethyl acetate. The organic phase was washed with saturated sodium chloride aqueous solution, dried, concentrated, and purified by column chromatography (EA/PE=1:3) to obtain the target compound A21-1 (150 mg).

[0410] ESI-MS m/z: 394 [M+H.sup.+].sup.+.

Step 2: Synthesis of Compound A21-2

[0411] Potassium peroxymonosulfonate (0.7 g) was added to a mixture of compound A21-1 (150 mg), acetonitrile (5 mL) and water (5 mL), and stirred at 60 C. for 2 h. After the reaction was completed, the reaction liquid was diluted with ethyl acetate, washed with water and saturated sodium chloride aqueous solution, dried, concentrated, and purified by column chromatography (EA/PE=1:3) to obtain the target compound A21-2 (150 mg).

[0412] ESI-MS m/z: 424 [MH.sup.+].sup..

Step 3: Synthesis of Compound A21

[0413] To a solution of compound A21-2 (150 mg) in dichloromethane (5 mL) were added triethylamine (0.10 mL), chloro{[(1R,2R)-()-2-amino-1,2-diphenylethyl](4-toluenesulfonyl)amino}(p-cymene)ruthenium(II) (20 mg), and formic acid (50 mg), and the mixture was stirred at room temperature overnight. The reaction liquid was diluted with dichloromethane, washed with water and saturated sodium chloride aqueous solution, dried, and concentrated, and purified by column chromatography (EA/PE=1:3) to obtain the target compound A21 (60 mg).

[0414] ESI-MS m/z: 472.15 [M+HCOO.sup.].sup..

Example 17 Synthesis of 5-(3-(cyanodifluoromethyl)-5,5-difluoro-4-hydroxyl-4,5,6,7-tetrahydro-1H-indol-1-yl)-2-fluorobenzonitrile (compound A22)

##STR00057##

Step 1: Synthesis of Compound A22-1

[0415] A solution of compound A20-2 (0.7 g) in dichloromethane (2 mL) was cooled to 0 C., and then triethylamine (0.07 mL) and trifluoroacetic anhydride (0.07 mL) were added. The mixture was stirred at 50 C. overnight and concentrated to obtain the target compound A22-1, which was used directly in the next step without further purification.

Step 2: Synthesis of Compound A22

[0416] Sodium borohydride (20 mg) was added to a solution of compound A22-1 (60 mg) in methanol (1 mL) and tetrahydrofuran (1 mL), and the mixture was reacted at room temperature overnight. The reaction liquid was diluted with ethyl acetate, washed with water and saturated sodium chloride aqueous solution, dried, concentrated, and purified by column chromatography (EA/PE=1:3) to obtain the target compound A22 (20 mg).

[0417] ESI-MS m/z: 412.0 [M+HCOO.sup.].sup..

Example 18 Synthesis of N(((S)-1-(3-cyano-4-fluorophenyl)-5,5-difluoro-4-hydroxyl-4,5,6,7-tetrahydro-1H-indol-3-yl)(methyl)(oxo)-16-sulfino)cyanamide (compound A23)

##STR00058##

Step 1: Synthesis of Compound A23-1

[0418] To a solution of compound A3-2 (180 mg) in tetrahydrofuran (10 mL) was added a 1.0 M solution of potassium tert-butoxide in tetrahydrofuran (0.7 mL) at 78 C. After stirring for 10 minutes, iodomethane (90 mg) was added. The reaction solution was stirred for another 2 hours. The reaction liquid was diluted with water and ethyl acetate. The organic phase was washed with saturated sodium chloride aqueous solution, dried, concentrated, and purified by column chromatography (EA/PE=1:3) to obtain the target compound A23-1 (116 mg).

[0419] ESI-MS m/z: 337 [M+H.sup.+].sup.+.

Step 2: Synthesis of Compound A23-2

[0420] To a solution of compound A23-1 (200 mg) in acetonitrile (5 mL) were added cyanamide (40 mg) and iodobenzene diacetate (250 mg), and the mixture was stirred at room temperature overnight, and concentrated. The reaction liquid was diluted with ethyl acetate, washed with water and saturated sodium chloride aqueous solution, dried, concentrated, and purified by column chromatography (EA/PE=1:3) to obtain the target compound A23-2 (120 mg).

[0421] ESI-MS m/z: 377 [M+H.sup.+].sup.+.

Step 3: Synthesis of Compound A23-3

[0422] To a mixture of compound A23-2 (120 mg) dissolved in acetonitrile (2 mL), dichloromethane (2 mL) and water (4 mL), ruthenium trichloride (10 mg) and sodium periodate (370 mg) were added and stirred at room temperature for 4 hours. After the reaction was completed, the reaction liquid was diluted with ethyl acetate, washed with water and saturated sodium chloride aqueous solution, dried, concentrated, and purified by column chromatography (EA/PE=1:3) to obtain the target compound A23-3 (40 mg).

[0423] ESI-MS m/z: 393.0[M+H.sup.+].sup.+.

Step 4: Synthesis of Compound A23

[0424] To a solution of compound A23-3 (40 mg) in dichloromethane (5 mL) were added chloro {[(1R,2R)-()-2-amino-1,2-diphenylethyl](4-toluenesulfonyl)amino}(p-cymene)ruthenium(II) (10 mg), triethylamine (0.03 mL) and formic acid (14 mg), and the mixture was stirred at room temperature overnight. The reaction liquid was diluted with dichloromethane, washed with water and saturated sodium chloride aqueous solution, dried, concentrated, and purified by column chromatography to obtain the target compound A23 (10 mg).

[0425] ESI-MS m/z: 395.11 [M+H.sup.+].sup.+.

Example 19 Synthesis of (S)-2-((1-(3-(difluoromethyl)-4-fluorophenyl)-5,5-difluoro-4-hydroxyl-4,5,6,7-tetrahydro-1H-indol-3-yl)sulfonyl)acetonitrile (compound A24)

##STR00059##

Step 1: Synthesis of Compound A24-1

[0426] To a solution of A4-3 (0.86 g) in tetrahydrofuran (20 mL) was added a 1.0 M solution of potassium tert-butoxide in tetrahydrofuran (3.0 mL) at 78 C. After stirring for 10 minutes, bromoacetonitrile (0.36 g) was added. The reaction mixture was stirred for another 2 hours. The reaction liquid was diluted with water and ethyl acetate. The organic phase was washed with saturated sodium chloride aqueous solution, dried, concentrated, and purified by column chromatography to obtain the target compound A24-1 (0.38 g).

[0427] ESI-MS m/z: 387 [M+H.sup.+].sup.+.

Step 2: Synthesis of Compound A24-2

[0428] Potassium peroxymonosulfonate (3.6 g) was added to a mixture of compound A24-1 (0.38 g) in acetonitrile (6 mL) and water (6 mL), and the mixture was stirred at 60 C. overnight. After the reaction was completed, the reaction liquid was diluted with ethyl acetate, washed with water and saturated sodium chloride aqueous solution, dried, concentrated, and purified by column chromatography (EA/PE=1:3) to obtain the target compound A24-2 (0.34 g).

[0429] ESI-MS m/z: 417 [MH.sup.+].sup..

Step 3: Synthesis of Compound A24

[0430] To a solution of compound A24-2 (0.34 g) in dichloromethane (10 mL) were added triethylamine (0.23 mL), chloro{[(1R,2R)-()-2-amino-1,2-diphenylethyl](4-toluenesulfonyl)amino}(P-cymene)ruthenium(II) (0.08 g) and formic acid (0.11 g), and the mixture was stirred at room temperature overnight. The reaction liquid was diluted with dichloromethane, washed with water and saturated sodium chloride aqueous solution, dried, concentrated, and purified by column chromatography (EA/PE=1:3) to obtain the target compound A24 (0.18 g).

[0431] ESI-MS m/z: 419 [MH.sup.].sup..

[0432] The following examples were prepared using methods substantially similar to those of examples 1-19.

TABLE-US-00001 Example number Structural formula Compound name ESI-MS 20 [00060] (S)-5,5-Difluoro-1-(4-fluoro-3- (trifluoromethyl)phenyl)-3- (methylsulfonyl)-4,5,6,7- tetrahydro-1H-indol-4-ol [M + HCOO.sup.].sup.: 458 21 [00061] (S)-3- ((Difluoromethyl)sulfonyl)-5,5- difluoro-1-(4-fluoro-3- (trifluoromethyl)phenyl)- 4,5,6,7-tetrahydro-1H-indol-4- ol [M + HCOO.sup.].sup.: 494 22 [00062] (S)-5-(3- ((Difluoromethyl)sulfonyl)- 2,5,5-trifluoroether-4-hydroxyl- 4,5,6,7-tetrahydro-1H-indol-1- yl)-2-fluorobenzonitrile [M + HCOO.sup.].sup.: 469 23 [00063] (S)-5,5-Difluoro-1-(4-fluoro-3- (trifluoromethyl)phenyl)-3- ((trifluoromethyl)sulfonyl)- 4,5,6,7-tetrahydro-1H-indol-4- ol [M + HCOO.sup.].sup.: 512 24 [00064] 1-(3-Chloro-4-fluorophenyl)- 5,5-difluoro-3- (methylsulfonyl)-4,5,6,7- tetrahydro-1H-indol-4-ol [M + HCOO.sup.].sup.: 424 25 [00065] 1-(3-Chloro-4-fluorophenyl)-3- ((difluoromethyl)sulfonyl)-5,5- difluoro-4,5,6,7-tetrahydro-1H- indol-4-ol [M + HCOO.sup.].sup.: 460 26 [00066] (R)-1-(3-(Difluoromethyl)-4- fluorophenyl)-3- ((difluoromethyl)sulfonyl)-5,5- difluoro-4,5,6,7-tetrahydro-1H- indol-4-ol [M + HCOO.sup.].sup.: 476 27 [00067] (S)-2-Chloro-5-(5,5-difluoro-4- hydroxyl-3-(methylsulfonyl)- 4,5,6,7-tetrahydro-1H-indol-1- yl)benzonitrile [M + HCOO.sup.].sup.: 431 28 [00068] (S)-2-Chloro-5-(3- ((difluoromethyl)sulfonyl)-5,5- difluoro-4-hydroxyl-4,5,6,7- tetrahydro-1H-indol-1- yl)benzonitrile [M + HCOO.sup.].sup.: 467 29 [00069] (S)-4-(5,5-Difluoro-4-hydroxyl- 3-(methylsulfonyl)-4,5,6,7- tetrahydro-1H-indol-1-yl)-2- (difluoromethyl)benzonitrile [M + HCOO.sup.].sup.: 447 30 [00070] (S)-5,5-Difluoro-1-(4-fluoro-3- (trifluoromethyl)phenyl)-3- ((fluoromethyl)sulfonyl)- 4,5,6,7-tetrahydro-1H-indol-4- ol [M + HCOO.sup.].sup.: 476 31 [00071] (S)-4-(5,5-Difluoro-4-hydroxyl- 3-((trifluoromethyl)sulfonyl)- 4,5,6,7-tetrahydro-1H-indol-1- yl)-2- (trifluoromethyl)benzonitrile [M + HCOO.sup.].sup.: 519 32 [00072] (R)-1-(3-(Difluoromethyl)-4- fluorophenyl)-3- ((difluoromethyl)sulfonyl)- 4,5,6,7-tetrahydro-1H-indol-4- ol [M + HCOO.sup.].sup.: 440 33 [00073] (S)-1-(3-Chloro-4- fluorophenyl)-5,5-difluoro-3- ((trifluoromethyl)sulfonyl)- 4,5,6,7-tetrahydro-1H-indol-4- ol [M + HCOO.sup.].sup.: 478 34 [00074] (S)-4-(3- ((Difluoromethyl)sulfonyl)-5,5- difluoro-4-hydroxyl-4,5,6,7- tetrahydro-1H-indol-1-yl)-2- (trifluoromethyl)benzonitrile [M + HCOO.sup.].sup.: 501 35 [00075] (S)-4-(5,5-Difluoro-4-hydroxyl- 3-((trifluoromethyl)sulfonyl)- 4,5,6,7-tetrahydro-1H-indol-1- yl)-2- (difluoromethyl)benzonitrile [M + HCOO.sup.].sup.: 501 36 [00076] (S)-4-(5,5-Difluoro-3- ((fluoromethyl)sulfonyl)-4- hydroxyl-4,5,6,7-tetrahydro- 1H-indol-1-yl)-2- (trifluoromethyl)benzonitrile [M + HCOO.sup.].sup.: 483 37 [00077] (S)-1-(3-Chloro-4- fluorophenyl)-5,5-difluoro-3- ((fluoromethyl)sulfonyl)- 4,5,6,7-tetrahydro-1H-indol-4- ol [M + HCOO.sup.].sup.: 442 38 [00078] (S)-4-(5,5-Difluoro-4-hydroxyl- 3-(methylsulfonyl)-4,5,6,7- tetrahydro-1H-indol-1- yl)phthalonitrile [M + HCOO.sup.].sup.: 422 39 [00079] (S)-4-(3- ((Difluoromethyl)sulfonyl)-5,5- difluoro-4-hydroxyl-4,5,6,7- tetrahydro-1H-indol-1- yl)phthalonitrile [M + HCOO.sup.].sup.: 458 40 [00080] (S)-2-Chloro-5-(5,5-difluoro-4- hydroxyl-3- ((trifluoromethyl)sulfonyl)- 4,5,6,7-tetrahydro-1H-indol-1- yl)benzonitrile [M + HCOO.sup.].sup.: 485 41 [00081] 4-(5,5-Difluoro-4-hydroxyl-3- (perfluoroethyl)-4,5,6,7- tetrahydro-1H-indol-1-yl)-2- (difluoromethyl)benzonitrile [M + HCOO.sup.].sup.: 487 42 [00082] (S)-4-(5,5-Difluoro-4-hydroxyl- 3-((trifluoromethyl)sulfonyl)- 4,5,6,7-tetrahydro-1H-indol-1- yl)phthalonitrile [M + HCOO.sup.].sup.: 476 43 [00083] (S)-2-(Difluoromethyl)-4-(3- ((difluoromethyl)sulfonyl)-5,5- difluoro-4-hydroxyl-4,5,6,7- tetrahydro-1H-indol-1- yl)benzonitrile [M + H.sup.+].sup.+: 483 44 [00084] (S)-4-(5,5-Difluoro-3- ((fluoromethyl)sulfonyl)-4- hydroxyl-4,5,6,7-tetrahydro- 1H-indol-1-yl)-2- (difluoromethyl)benzonitrile [M + HCOO.sup.].sup.: 465 45 [00085] (S)-4-(5,5-Difluoro-3- ((fluoromethyl)sulfonyl)-4- hydroxyl-4,5,6,7-tetrahydro- 1H-indol-1-yl)phthalonitrile [M + HCOO.sup.].sup.: 440 46 [00086] (S)-4-(5,5-Difluoro-4-hydroxyl- 3-(perfluoroethyl)-4,5,6,7- tetrahydro-1H-indol-1- yl)phthalonitrile [M + HCOO.sup.].sup.: 462 47 [00087] 2-(((S)-1-(3-(Difluoromethyl)- 4-fluorophenyl)-5,5-difluoro-4- hydroxyl-4,5,6,7-tetrahydro- 1H-indol-3-yl)sulfonyl)-2- fluoroacetonitrile [M H.sup.].sup.: 437 48 [00088] Ethyl (S)-2-(1-(3- (difluoromethyl)-4- fluorophenyl)-5,5-difluoro-4- hydroxyl-4,5,6,7-tetrahydro- 1H-indol-3-yl)-2,2- difluoroacetate [M + HCOO.sup.].sup.: 484 49 [00089] (S)-2-(1-(3-(Difluoromethyl)-4- fluorophenyl)-5,5-difluoro-4- hydroxyl-4,5,6,7-tetrahydro- 1H-indol-3-yl)-2,2- difluoroacetonitrile [M + HCOO.sup.].sup.: 437 50 [00090] (S)-2-(1-(3-(Difluoromethyl)-4- fluorophenyl)-5,5-difluoro-4- hydroxyl-4,5,6,7-tetrahydro- 1H-indol-3-yl)-2,2- difluoroacetamide [M H.sup.].sup.: 409 51 [00091] (S)-1-(3-(Difluoromethyl)-4- fluorophenyl)-5,5-difluoro-3- (thiazol-2-yl)-4,5,6,7- tetrahydro-1H-indol-4-ol [M + H.sup.+].sup.+: 401 52 [00092] (R)-1-(3-(Difluoromethyl)-4- fluorophenyl)-3- ((trifluoromethyl)sulfonyl)- 4,5,6,7-tetrahydro-1H-indol-4- ol [M + H.sup.+-H.sub.2O].sup.+: 396 53 [00093] (S)-1-(3-(Difluoromethyl)-4- fluorophenyl)-5,5-difluoro-3- (oxazol-2-yl)-4,5,6,7- tetrahydro-1H-indol-4-ol [M + H.sup.+].sup.+: 401 54 [00094] (S)-2-((1-(3-(Difluoromethyl)- 4-fluorophenyl)-5,5-difluoro-4- hydroxyl-4,5,6,7-tetrahydro- 1H-indol-3-yl)sulfonyl)-2,2- difluoroacetonitrile [M H.sup.+].sup.: 455 55 [00095] 2-(((S)-5,5-Difluoro-1-(4- fluoro-3- (trifluoromethyl)phenyl)-4- hydroxyl-4,5,6,7-tetrahydro- 1H-indol-3-yl)sulfonyl)-2- fluoroacetonitrile [M H.sup.+].sup.: 455 56 [00096] (S)-(1-(3-(Difluoromethyl)-4- fluorophenyl)-5,5-difluoro-4- hydroxyl-4,5,6,7-tetrahydro- 1H-indol-3-yl) dimethylphosphine oxide methyl [M + H.sup.+].sup.+: 394 57 [00097] 2-(((S)-1-(3-(Difluoromethyl)- 4-fluorophenyl)-5,5-difluoro-4- hydroxyl-4,5,6,7-tetrahydro- 1H-indol-3-yl)sulfonyl) propanenitrile [M H.sup.+].sup.: 433 58 [00098] (S)-1-((1-(3-(Difluoromethyl)- 4-fluorophenyl)-5,5-difluoro-4- hydroxyl-4,5,6,7-tetrahydro- 1H-indol-3-yl)sulfonyl) cyclopropane-1-nitrile [M + HCOO.sup.].sup.: 491 59 [00099] N-(((S)-1-(3-(Difluoromethyl)- 4-fluorophenyl)-5,5-difluoro-4- hydroxyl-4,5,6,7-tetrahydro- 1H-indol-3-yl)(methyl)(oxo)- 16-sulfino)cyanamide [M + H.sup.+].sup.+: 420 60 [00100] Ethyl (S)-1-(3- (difluoromethyl)-4- fluorophenyl)-5,5-difluoro-4- hydroxyl-4,5,6,7-tetrahydro- 1H-indole -3-carboxylate [M + H.sup.+-H.sub.2O].sup.+: 372 61 [00101] (R)-1-(3-(Difluoromethyl)-4- fluorophenyl)-5,5-difluoro-3- ((fluoromethyl)sulfonyl)- 4,5,6,7-tetrahydro-1H-indol-4- ol [M + HCOO.sup.].sup.: 458 62 [00102] (S)-1-(3-(Difluoromethyl)-4- fluorophenyl)-5,5-difluoro-4- hydroxyl-4,5,6,7-tetrahydro- 1H-indole -3-carboxamide [M + H+-H.sub.2O].sup.+: 343 63 [00103] (4S,5R)-1-(3-(Difluoromethyl)- 4-fluorophenyl)-3- ((difluoromethyl)sulfonyl)-5- fluoro-4,5,6,7-tetrahydro-1H- indol-4-ol [M + HCOO.sup.].sup.: 458 64 [00104] (4S,5S)-1-(3-(Difluoromethyl)- 4-fluorophenyl)-3- ((difluoromethyl)sulfonyl)-5- fluoro-4,5,6,7-tetrahydro-1H- indol-4-ol [M + HCOO.sup.].sup.: 458 65 [00105] (R)-2-(Difluoromethyl)-4-(4- hydroxyl-3- ((trifluoromethyl)sulfonyl)- 4,5,6,7-tetrahydro-1H-indol-1- yl)benzonitrile [M + HCOO.sup.].sup.: 458 66 [00106] (S)-4-(5,5-Difluoro-4-hydroxyl- 3-(trifluoromethyl)-4,5,6,7- tetrahydro-1H-indol-1-yl)-3- fluorobenzonitrile [M + HCOO.sup.].sup.: 405 67 [00107] (4S)-1-(3-(Difluoromethyl)-4- fluorophenyl)-5,5-difluoro-3- ((fluoromethyl)sulfinyl)- 4,5,6,7-tetrahydro-1H-indol-4- ol [M + HCOO.sup.].sup.: 442 68 [00108] (S)-1-((R)-6,8-Difluoro-1,2,3,4- tetrahydronaphthalen-1-yl-yl)- 5,5-difluoro-3- (trifluoromethyl)-4,5,6,7- tetrahydro-1H-indol-4-ol [M + H.sup.+-H.sub.2O].sup.+: 390 69 [00109] (S)-1-((S)-6,8-Difluoro-1,2,3,4- tetrahydronaphthalen-1-yl-yl)- 5,5-difluoro-3- (trifluoromethyl)-4,5,6,7- tetrahydro-1H-indol-4-ol [M + H.sup.+-H.sub.2O].sup.+: 390 70 [00110] (S)-1-(2,4-Difluorobenzyl)-5,5- difluoro-3-(trifluoromethyl)- 4,5,6,7-tetrahydro-1H-indol-4- ol [M + H.sup.+-H.sub.2O].sup.+: 350 71 [00111] (S)-2-((5,5-Difluoro-4- hydroxyl-3-(trifluoromethyl)- 4,5,6,7-tetrahydro-1H-indol-1- yl)methyl)-5-fluorobenzonitrile [M + H.sup.+-H.sub.2O].sup.+: 357 72 [00112] (S)-1-(2,4-Difluorophenyl)-5,5- difluoro-3-(trifluoromethyl)- 4,5,6,7-tetrahydro-1H-indol-4- ol [M + H.sup.+-H.sub.2O].sup.+: 336 73 [00113] N-(((S)-1-(3-(Difluoromethyl)- 4-fluorophenyl)-5,5-difluoro-4- hydroxyl-4,5,6,7-tetrahydro- 1H-indol-3- yl)(oxy)(trifluoromethyl)-16- sulfino)cyanamide [M + H.sup.+-H.sub.2O].sup.+: 456 74 [00114] N-((Difluoromethyl)((S)-1-(3- (difluoromethyl)-4- fluorophenyl)-5,5-difluoro-4- hydroxyl-4,5,6,7-tetrahydro- 1H-indol-3-yl)(oxo)-16- sulfino)cyanamide [M + H.sup.+-H.sub.2O].sup.+: 438 75 [00115] (S)-2-(5-(5,5-Difluoro-4- hydroxyl-3-(trifluoromethyl)- 4,5,6,7-tetrahydro-1H-indol-1- yl)-2-fluorophenyl)acetonitrile [M + H.sup.+-H.sub.2O].sup.+: 357 76 [00116] (S)-4-(5,5-Difluoro-4-hydroxyl- 3-(trifluoromethyl)-4,5,6,7- tetrahydro-1H-indol-1-yl)-2- (fluoromethyl)benzonitrile [M + H.sup.+-H.sub.2O].sup.+: 357 77 [00117] (S)-1-(3-(Difluoromethyl)-4- fluorophenyl)-5,5-difluoro-3- ((fluoromethyl)sulfonyl)- 1,4,5,6- tetrahydrocyclopentadiene[b] pyrrol-4-ol [M + H.sup.+-H.sub.2O].sup.+: 382 78 [00118] (S)-1-(3-(Difluoromethyl)-4- fluorophenyl)-5,5-difluoro-3- (methylsulfonyl)-1,4,5,6- tetrahydrocyclopentadiene[b] pyrrol-4-ol [M + H+-H.sub.2O].sup.+: 364 79 [00119] (S)-1-(3-(Difluoromethyl)-4- fluorophenyl)-3- ((difluoromethyl)sulfonyl)-5,5- difluoro-1,4,5,6- tetrahydrocyclopentadiene[b] pyrrol-4-ol [M + H.sup.+-H.sub.2O].sup.+: 400 80 [00120] (S)-1-(3-(Difluoromethyl)-4- fluorophenyl)-5,5-difluoro-3- ((trifluoromethyl)sulfonyl)- 1,4,5,6- tetrahydrocyclopentadiene[b] pyrrol-4-ol [M + H.sup.+-H.sub.2O].sup.+: 418 81 [00121] (S)-5-(5,5-Difluoro-4-hydroxyl- 3-((trifluoromethyl)sulfonyl)- 5,6- dihydrocyclopentadiene[b] pyrrol-1(4H)-yl)-yl2- fluorobenzonitrile [M + H.sup.+-H.sub.2O].sup.+: 393 82 [00122] (S)-3-(3-(Difluoromethyl)-4- fluorophenyl)-7,7-difluoro-1- ((trifluoromethyl)sulfonyl)- 5,6,7,8-tetrahydroindol-8-ol [M + H.sup.+-H.sub.2O].sup.+: 432 83 [00123] (S)-3-(3-(Difluoromethyl)-4- fluorophenyl)-7,7-difluoro-1- ((trifluoromethyl)sulfonyl)- 5,6,7,8-tetrahydroimidazo[1,5- a]pyridin-8-ol [M + H.sup.+].sup.+: 451 84 [00124] (7R,8S)-3-(3-(Difluoromethyl)- 4-fluorophenyl)-7-fluoro-1 - ((trifluoromethyl)sulfonyl)- 5,6,7,8-tetrahydroindolizin-8-ol [M + H.sup.+-H.sub.2O].sup.+: 414 85 [00125] 1-(3-(Difluoromethyl)-4- fluorophenyl)-5,5-difluoro-3- ((trifluoromethyl)sulfonyl)- 1,4,5,7-tetrahydropyran[3,4- b]pyrrol-4-ol [M + H.sup.+-H.sub.2O].sup.+: 434 86 [00126] 2-(Difluoromethyl)-4-((4S,5R)- 3-((difluoromethyl)sulfonyl)-5- fluoro-4-hydroxyl-4,5,6,7- tetrahydro-1H-indol-1- yl)benzonitrile [M + H.sup.+-H.sub.2O].sup.+: 403 87 [00127] 2-(Difluoromethyl)-4-((45,5R)- 5-fluoro-4-hydroxyl-3- ((trifluoromethyl)sulfonyl)- 4,5,6,7-tetrahydro-1H-indol-1- yl)benzonitrile M + HCOO.sup.].sup.+: 451.11 88 [00128] (S)-5,5-Difluoro-1- (imidazo[1,2-a]pyridin-8-yl)-3- (trifluoromethyl)-4,5,6,7- tetrahydro-1H-indol-4-ol [M + H.sup.+].sup.+: 358 89 [00129] (4S,5R)-1-(3-(Difluoromethyl)- 4-fluorophenyl)-5-fluoro-3- ((trifluoromethyl)sulfonyl)- 4,5,6,7-tetrahydro-1H-indol-4- ol [M + H.sup.+-H.sub.2O].sup.+: 414 90 [00130] (S)-8-(5,5-Difluoro-3- ((fluoromethyl)sulfonyl)-4- hydroxyl-4,5,6,7-tetrahydro- 1H-indol-1-yl)-5-fluoro-1- naphthonitrile [M + H.sup.+-H.sub.2O].sup.+: 421 91 [00131] (S)-3- ((Difluoromethyl)sulfonyl)-5,5- difluoro-1-(4-fluoro-5,6,7,8- tetrahydronaphthalen-1-yl)- 4,5,6,7-tetrahydro-1H-indol-4- ol [M + H.sup.+-H.sub.2O].sup.+: 418 92 [00132] (S)-5,5-Difluoro-1-(quinolin-8- yl)-3- ((trifluoromethyl)sulfonyl)- 4,5,6,7-tetrahydro-1H-indol-4- ol [M + H.sup.+].sup.+: 433 93 [00133] (4S)-1-(6,8-Difluoro-1,2,3,4- tetrahydronaphthalen-1-yl)-5,5- difluoro-3-(trifluoromethyl)- 4,5,6,7-tetrahydro-1H-indol-4- ol [M + H.sup.+-H.sub.2O].sup.+: 390 94 [00134] (4S)-1-(6,8-Difluoro-1,2,3,4- tetrahydronaphthalen-1-yl)-5,5- difluoro-3- ((trifluoromethyl)sulfonyl)- 4,5,6,7-tetrahydro-1H-indol-4- ol [M + H.sup.+-H.sub.2O].sup.+: 454 95 [00135] (4S)-1-(6,8-Difluoro-1,2,3,4- tetrahydronaphthalen-1-yl)-3- ((difluoromethyl)sulfonyl)-5,5- difluoro-4,5,6,7-tetrahydro-1H- indol-4-ol [M + H.sup.+-H.sub.2O].sup.+: 436 96 [00136] 1-(6,8-Difluoro-1,2,3,4- tetrahydronaphthalen-1-yl)-5,5- difluoro-3- ((fluoromethyl)sulfonyl)- 4,5,6,7-tetrahydro-1H-indol-4- ol [M + H.sup.+-H.sub.2O].sup.+: 418 97 [00137] (4S)-1-(5,7Difluoro-2,3- dihydro-1H-inden-1-yl)-5,5- difluoro-3-(trifluoromethyl)- 4,5,6,7-tetrahydro-1H-indol-4- ol [M + H.sup.+-H.sub.2O].sup.+: 376 98 [00138] (4S)-5,5-Difluoro-1-(5,6,7,8- tetrahydroquinolin-8-yl)-3- (trifluoromethyl)-4,5,6,7- tetrahydro-1H-indol-4-ol [M + H.sup.+-H.sub.2O].sup.+: 355 99 [00139] (4S)-5,5-Difluoro-3- (methylsulfonyl)-1-(5,6,7,8- tetrahydroquinolin-8-yl)- 4,5,6,7-tetrahydro-1H-indol-4- ol [M + H.sup.+-H.sub.2O].sup.+: 365 100 [00140] 5,5-Difluoro-3- ((fluoromethyl)sulfonyl)-1- (5,6,7,8-tetrahydroquinolin-8- yl)-4,5,6,7-tetrahydro-1H- indol-4-ol [M + H.sup.+-H.sub.2O].sup.+: 383 101 [00141] (4S)-3- ((Difluoromethyl)sulfonyl)-5,5- difluoro-1-(5,6,7,8- tetrahydroquinolin-8-yl)- 4,5,6,7-tetrahydro-1H-indol-4- ol [M + H.sup.+-H.sub.2O].sup.+: 401 102 [00142] (4S)-5,5-Difluoro-1-(5,6,7,8- tetrahydroquinolin-8-yl)-3- ((trifluoromethyl)sulfonyl)- 4,5,6,7-tetrahydro-1H-indol-4- ol [M + H.sup.+-H.sub.2O].sup.+: 419 103 [00143] 2-(Difluoromethyl)-4-(5-fluoro- 4-hydroxyl-3- ((trifluoromethyl)thio)-4,5,6,7- tetrahydro-1H-indol-1- yl)benzonitrile [M + HCOO.sup.].sup.: 451.1 104 [00144] 2-(Difluoromethyl)-4-(5-fluoro- 4-hydroxyl-3- ((trifluoromethyl)sulfonyl)- 4,5,6,7-tetrahydro-1H-indol-1- yl)benzonitrile [M + HCOO.sup.].sup.: 483.1 105 [00145] 2-Fluoro-5-(5-fluoro-4- hydroxyl-3-(trifluoromethyl)- 4,7-dihydropyran[3,4-b]pyrrol- 1(5H)-yl)benzonitrile [M + HCOO.sup.].sup.: 389.1 106 [00146] 2-Fluoro-5-(2,5,5-trifluoro-4- hydroxyl-3-(thien-2-yl)-4,5,6,7- tetrahydro-1H-indol-1- yl)benzonitrile [M + HCOO.sup.].sup.: 437.1 107 [00147] 2-(Difluoromethyl)-4-(5-fluoro- 4-hydroxyl-3-(trifluoromethyl)- 4,5,6,7-tetrahydro-1H-indol-1- yl)benzonitrile [M + HCOO.sup.].sup.: 419.1

[0433] The .sup.1H NMR data for some of the exemplary compounds are as shown below:

[0434] .sup.1H NMR (500 MHz, CDCl.sub.3) 7.91 (d, J=8.3 Hz, 1H), 7.71 (s, 1H), 7.56 (d, J=8.2 Hz, 1H), 7.21 (s, 1H), 7.00 (dd, J=70.0, 38.6 Hz, 1H), 4.93 (t, J=6.2 Hz, 1H), 2.92-2.81 (m, 1H), 2.74-2.64 (m, 1H), 2.60-2.45 (m, 1H), 2.30-2.20 (m, 1H). (Example 3)

[0435] .sup.1H NMR (500 MHz, CDCl.sub.3) 7.67 (dd, J=5.2, 2.7 Hz, 1H), 7.62 (ddd, J=8.9, 4.4, 2.8 Hz, 1H), 7.50 (s, 1H), 7.46-7.40 (m, 1H), 6.39 (t, J=54.0 Hz, 1H), 5.06 (t, J=6.3 Hz, 1H), 3.11 (s, 1H), 2.83-2.70 (m, 1H), 2.62 (ddd, J=16.3, 6.3, 2.3 Hz, 1H), 2.55-2.38 (m, 1H), 2.31-2.19 (m, 1H). (Example 4)

[0436] .sup.1H NMR (500 MHz, DMSO) 7.85-7.75 (m, 2H), 7.65 (s, 1H), 7.57 (t, J=9.2 Hz, 1H), 7.23 (t, J=53.9 Hz, 1H), 6.35 (d, J=6.0 Hz, 1H), 4.85-4.80 (m, 1H), 3.24 (s, 3H), 2.80-2.70 (m, 1H), 2.70-2.59 (m, 1H), 2.35-2.25 (m, 1H), 2.20-2.10 (m, 1H). (Example 5)

[0437] .sup.1H NMR (500 MHz, CDCl.sub.3) 7.62 (dd, J=5.7, 2.7 Hz, 1H), 7.58 (d, J=9.2 Hz, 1H), 7.52-7.44 (m, 1H), 7.35 (t, J=8.9 Hz, 1H), 7.08-6.78 (m, 1H), 5.03 (dt, J=7.5, 3.7 Hz, 1H), 3.02 (d, J=7.4 Hz, 1H), 2.85-2.73 (m, 1H), 2.67-2.43 (m, 2H), 2.35-2.18 (m, 1H).

Example 12

[0438] .sup.1H NMR (500 MHz, CDCl.sub.3) 7.60 (dd, J=5.8, 2.7 Hz, 1H), 7.49-7.43 (m, 2H), 7.32 (t, J=8.9 Hz, 1H), 6.94 (dd, J=59.6, 49.5 Hz, 1H), 5.47 (dd, J=47.2, 9.8 Hz, 1H), 5.25-5.07 (m, 2H), 3.00 (d, J=3.4 Hz, 1H), 2.76 (ddd, J=16.5, 10.5, 6.1 Hz, 1H), 2.64 (ddd, J=16.3, 6.2, 2.7 Hz, 1H), 2.55-2.37 (m, 1H), 2.31-2.16 (m, 1H). (Example 14)

[0439] .sup.1H NMR (500 MHz, CDCl.sub.3) 7.63-7.58 (m, 1H), 7.56 (s, 1H), 7.51-7.42 (m, 1H), 7.33 (t, J=8.9 Hz, 1H), 6.94 (t, J=54.5 Hz, 1H), 5.15 (s, 1H), 4.63 (d, J=16.4 Hz, 1H), 4.17 (d, J=16.4 Hz, 1H), 2.90 (s, 1H), 2.83-2.61 (m, 2H), 2.53-2.16 (m, 2H). (Example 19)

[0440] .sup.1H NMR (500 MHz, CDCl.sub.3) 7.52 (s, J=6.3 Hz, 1H), 7.28-7.24 (m, 1H), 7.19 (d, J=0.9 Hz, 1H), 7.02 (dt, J=8.3, 2.1 Hz, 1H), 6.39 (t, J=54.0 Hz, 1H), 5.05 (t, J=6.4 Hz, 1H), 3.08 (s, 1H), 2.85-2.75 (m, 1H), 2.70 (ddd, J=16.4, 6.3, 2.4 Hz, 1H), 2.56-2.38 (m, 1H), 2.32-2.17 (m, 1H). (Example 23)

[0441] .sup.1H NMR (500 MHz, CDCl.sub.3) 7.41 (dd, J=6.2, 2.6 Hz, 1H), 7.36 (s, 1H), 7.29 (t, J=8.5 Hz, 1H), 7.21 (ddd, J=8.7, 4.0, 2.7 Hz, 1H), 5.14 (t, J=6.4 Hz, 1H), 3.25 (s, 3H), 3.21 (d, J=2.2 Hz, 1H), 2.80-2.59 (m, 2H), 2.55-2.35 (m, 1H), 2.28-2.19 (m, 1H). (Example 24)

[0442] .sup.1H NMR (500 MHz, CDCl.sub.3) 7.74-7.67 (m, 2H), 7.55 (dd, J=8.6, 2.6 Hz, 1H), 7.51 (s, 1H), 6.38 (t, J=54.0, 1H), 5.10-5.02 (m, 1H), 3.11 (d, J=3.4 Hz, 1H), 2.85-2.75 (m, 1H), 2.64 (ddd, J=16.3, 6.2, 2.4 Hz, 1H), 2.57-2.36 (m, 1H), 2.33-2.20 (m, 1H). (Example 28)

[0443] .sup.1H NMR (500 MHz, CDCl.sub.3) 7.96 (d, J=8.3 Hz, 1H), 7.76 (s, 1H), 7.61 (dd, J=8.3, 2.1 Hz, 1H), 7.47 (s, 1H), 7.03 (t, J=67.7 Hz, 1H), 5.22-5.15 (m, 1H), 3.21 (d, J=3.0 Hz, 1H), 2.92-2.82 (m, 1H), 2.73 (ddd, J=16.2, 6.0, 2.9 Hz, 1H), 2.56-2.40 (m, 1H), 2.34-2.24 (m, 1H). (Example 29)

[0444] .sup.1H NMR (500 MHz, CDCl.sub.3) 8.00 (d, J=8.3, 1H), 7.81 (d, J=9.4, 1H), 7.79-7.68 (m, 1H), 7.53 (s, 1H), 5.51 (dd, J=47.2, 9.9 Hz, 1H), 5.25-5.05 (m, 2H), 3.00 (s, 1H), 2.94-2.79 (m, 1H), 2.75-2.65 (m, 1H), 2.56-2.38 (m, 1H), 2.31-2.22 (m, 1H). (Example 45)

[0445] .sup.1H NMR (500 MHz, CDCl.sub.3) 7.97 (d, J=8.4 Hz, 1H), 7.78 (d, J=2.1 Hz, 1H), 7.71 (dd, J=8.4, 2.2 Hz, 1H), 7.14 (s, 1H), 4.89 (t, J=5.9 Hz, 1H), 2.92-2.83 (m, 1H), 2.69 (dd, J=16.1, 6.4 Hz, 1H), 2.63-2.42 (m, 2H), 2.34-2.17 (m, 1H). (Example 46)

Pharmacological Experiments

VEGFA ELISA Assay (IC.SUB.50.)

[0446] 786-O cells in the logarithmic growth phase were inoculated into a 96-well plate at a cell concentration of 65,000 cells per ml of culture liquid, 180 L per well. The compounds were diluted to the corresponding concentrations, and 20 L of compound solutions of various concentrations were added to the corresponding cell wells, so that the final concentrations of the compounds were 1.5 nM, 4.6 nM, 13.7 nM, 41.2 nM, 123.5 nM, 370.4 nM, 1111.1 nM, 3333.3 nM, and 10000 nM, respectively. After culturing for 24 h, the cell culture supernatant was collected and the VEGFA concentration was determined using an ELISA kit (purchased from Abeam). Finally, the reaction was terminated and the absorbance value of each well was measured at a wavelength of 450 nm using an ELISA reader. The IC.sub.50 values were calculated by GraphPadPrism. CellTiter-Glo reagent was used to measure cell viability.

[0447] The IC.sub.50 data of the exemplary examples are provided in Table 1, where A stands for IC.sub.500.5 M; B stands for 0.5 M<IC.sub.501.5 M; C stands for 1.5 M<IC.sub.50<10 M, and D stands for IC.sub.50>10 M.

TABLE-US-00002 TABLE 1 Example number IC.sub.50 (M) 1 A 2 0.0083 3 0.003 4 0.098 5 0.072 6 0.011 9 0.047 10 A 11 0.027 12 0.010 13 B 14 0.040 15 B 16 0.537 17 A 18 A 19 B 20 0.039 21 0.012 22 0.086 23 0.011 24 0.072 25 0.063 26 0.628 27 A 28 0.118 29 0.174 30 0.045 31 0.021 32 0.062 33 0.041 34 A 35 0.018 36 0.108 37 A 39 0.140 40 A 41 A 42 0.074 43 A 44 A 45 A 46 A 47 0.008 48 1.621 49 0.099 51 1.250 52 0.046 57 A 58 0.639 59 0.109 61 A 62 A 63 0.050 64 0.033 65 0.030 72 B 105 C 106 0.015 107 0.034

Luciferase Assay

[0448] The luciferase LUC gene was stably transfected into 786-0 cells (purchased from ATCC) using Lipofectamine 3000 transfection reagent (purchased from Invitrogen) to construct HIF2 reporter gene cells (786-O-HIF2-Luc cells). The experiment was performed when 786-O-HIF2-Luc cells were in the logarithmic growth phase, the culture medium (RPMI MEDIUM 1640, purchased from Invitrogen) was discarded, and the cells were rinsed three times with PBS; trypsin (TrypLE, purchased from Invitrogen) was added to digest the cells, and the digestion was terminated with culture medium, 10% fetal bovine serum, 1% penicillin, and streptomycin. The cells were collected by centrifugation, and washed twice with PBS to remove phenol red in the culture medium. The cells were resuspended to an appropriate concentration. The cell density and viability were measured, to ensure that the cells with a viability of at least 90% were used in the assay.

[0449] The compounds at a gradient concentration were transferred into 384 wells using Echo550 (non-contact acoustic pipetting system, purchased from Labcyte), 25 nL/well. The cells were seeded into 384-well plates, with 4500 cells/well and 25 L of culture medium, and the final concentrations of the compounds were 10000 nM, 3333 nM, 1111 nM, 370 nM, 123 nM, 41.1 nM, 13.7 nM, 4.6 nM, 1.5 nM, and 0.5 nM, respectively. The cells were cultured for 18-20 h under conditions of 37 C. and 5% CO.sub.2. Steady-Glo luciferase assay system (purchased from Promega) was added to a 384-well plate, 25 L/well. Luminescence values were detected using Envision. The inhibition rate % was calculated based on the RLU (Record Luminescence) signal value of each well, and then the IC.sub.50 values of the corresponding compounds were calculated by fitting using Graphpad 8.0.

[0450] The IC.sub.50 data of the exemplary examples are provided in Table 2, where A stands for IC.sub.500.1 M; B stands for 0.1 M<IC.sub.500.5 M; and C stands for IC.sub.50>0.5 M.

TABLE-US-00003 TABLE 2 Example number IC.sub.50 (M) 6 0.038 11 B 12 A 14 0.054 23 0.040 32 B 33 0.052 35 0.010 52 0.045 59 B 107 A

In Vivo PK

[0451] Compounds were formulated with 5% DMSO, 5% Solutol and 90% NaCl. SD rats and Balb/c mice were selected for drug administration. The intravenous dose was 1 mg/kg and the oral dose was 5 mg/kg. Blood was collected from the eye sockets at 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 7 h, and 24 h. After blood collection, centrifugation was performed at 4000 rpm for 10 min, and the supernatant was taken. 200 L of internal standard solution was added to 30 L of the supernatant for precipitation, and the mixture was vortexed and centrifuged at 12000 rpm for 10 min. 100 L of the supernatant solution was taken and mixed with purified water in a 1:1 ratio for sample injection. The concentration of compounds in plasma was detected by a high performance liquid chromatography-mass spectrometer and the internal standard quantitative method was used to quantify the concentration of compounds in plasma samples. After measuring the compound concentration, relevant pharmacokinetic parameters including Cmax and AUC were calculated using Winnonln software. The experiment reveals that the exemplary compounds of the present invention have good in vivo PK properties.