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STEROID DERIVATIVE REGULATORS, METHOD FOR PREPARING THE SAME, AND USES THEREOF

20220017565 · 2022-01-20

    Inventors

    Cpc classification

    International classification

    Abstract

    Steroid derivative regulators, a method for preparing the same, and uses thereof are described. Specifically, a compound as shown in formula (I), a preparation method therefor, a pharmaceutical composition containing the compound, and uses thereof as a regulator of GABA A receptor for treating depression, convulsion, Parkinson's disease, and nervous system diseases are described, wherein the substituents of the formula (I) are as defined in the description.

    ##STR00001##

    Claims

    1. A compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: ##STR00230## wherein: X is selected from the group consisting of —CR.sub.17— and —N—; Y is selected from the group consisting of —CR.sub.23R.sub.24—, —S(CH.sub.2).sub.n1—, —P(CH.sub.2).sub.n1—, —O(CH.sub.2).sub.n1—, —(CH.sub.2).sub.n1NR.sub.22—, ##STR00231## R.sup.x, R.sub.y, R.sup.z and R.sup.f are identical or different and are each independently selected from the group consisting of hydrogen atom, deuterium atom, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, thiol, nitro, hydroxy, cyano, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, —(CH.sub.2).sub.n1R.sub.23, —(CH.sub.2).sub.n1OR.sub.23, —(CH.sub.2).sub.n1SR.sub.23, —(CH.sub.2).sub.n1C(O)R.sub.23, —(CH.sub.2).sub.n1C(O)OR.sub.23, —(CH.sub.2).sub.n1S(O).sub.m1R.sub.23, —(CH.sub.2).sub.n1NR.sub.23R.sub.24, —(CH.sub.2).sub.n1C(O)NR.sub.23R.sub.24, —(CH.sub.2).sub.n1NR.sub.23C(O)R.sub.24 and —(CH.sub.2).sub.n1NR.sub.23S(O).sub.m1R.sub.24, wherein the alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each optionally substituted by one or more substituents selected from the group consisting of deuterium atom, alkyl, haloalkyl, halogen, amino, thiol, oxo, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —(CH.sub.2).sub.n1R.sub.25, —(CH.sub.2).sub.n1OR.sub.25, —(CH.sub.2).sub.n1SR.sub.25, —(CH.sub.2).sub.n1C(O)R.sub.25, —(CH.sub.2).sub.n1C(O)OR.sub.25, —(CH.sub.2).sub.n1S(O).sub.m1R.sub.25, —(CH.sub.2).sub.n1NR.sub.25R.sub.26, —(CH.sub.2).sub.n1C(O)NR.sub.25R.sub.26, —(CH.sub.2).sub.n1C(O)NHR.sub.25, —(CH.sub.2).sub.n1NR.sub.25C(O)R.sub.26 and —(CH.sub.2).sub.n1NR.sub.25S(O).sub.m1R.sub.26; or, any two adjacent or non-adjacent groups or two identical groups of R.sup.x, R.sup.y, R.sup.z and R.sup.f are bonded to form a cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted by one or more substituents selected from the group consisting of deuterium atom, alkyl, haloalkyl, halogen, amino, oxo, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —(CH.sub.2).sub.n1R.sub.23, —(CH.sub.2).sub.n1OR.sub.23, —(CH.sub.2).sub.n1SR.sub.23, —(CH.sub.2).sub.n1C(O)R.sub.23, —(CH.sub.2).sub.n1C(O)OR.sub.23, —(CH.sub.2).sub.n1S(O).sub.m1R.sub.23, —(CH.sub.2).sub.n1NR.sub.23R.sub.24, —(CH.sub.2).sub.n1C(O)NR.sub.23R.sub.24, —(CH.sub.2).sub.n1NR.sub.23C(O)R.sub.24 and —(CH.sub.2).sub.n1NR.sub.23S(O).sub.m1R.sub.24; or, any two adjacent groups of R.sup.x, R.sup.y, R.sup.z and R.sup.f form a double bond; R.sub.21 is selected from the group consisting of hydrogen atom, deuterium atom, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxy, cyano, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, —(CH.sub.2).sub.n1R.sub.23, —(CH.sub.2).sub.n1OR.sub.23, —(CH.sub.2).sub.n1SR.sub.23, —(CH.sub.2).sub.n1C(O)R.sub.23, —(CH.sub.2).sub.n1C(O)OR.sub.23, —(CH.sub.2).sub.n1S(O).sub.m1R.sub.23, —(CH.sub.2).sub.n1NR.sub.23R.sub.24, —(CH.sub.2).sub.n1C(O)NR.sub.23R.sub.24, —(CH.sub.2).sub.n1NR.sub.23C(O)R.sub.24 and —(CH.sub.2).sub.n1NR.sub.23S(O).sub.m1R.sub.24, wherein the alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each optionally substituted by one or more substituents selected from the group consisting of deuterium atom, alkyl, haloalkyl, halogen, amino, oxo, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —(CH.sub.2).sub.n1R.sub.25, —(CH.sub.2).sub.n1OR.sub.25, —(CH.sub.2).sub.n1SR.sub.25, —(CH.sub.2).sub.n1C(O)R.sub.25, —(CH.sub.2).sub.n1C(O)OR.sub.25, —(CH.sub.2).sub.n1S(O).sub.m1R.sub.25, —(CH.sub.2).sub.n1NR.sub.25R.sub.26, —(CH.sub.2).sub.n1C(O)NR.sub.25R.sub.26, —(CH.sub.2).sub.n1C(O)NHR.sub.25, —(CH.sub.2).sub.n1NR.sub.25C(O)R.sub.26 and —(CH.sub.2).sub.n1NR.sub.25S(O).sub.m1R.sub.26; when X is —CR.sub.17—, then R.sub.17 is selected from the group consisting of a bond, hydrogen atom, deuterium atom, alkyl, deuterated alkyl, haloalkyl, hydroxy, amino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each optionally substituted by one or more substituents selected from the group consisting of deuterium atom, substituted or unsubstituted alkyl, halogen, hydroxy, substituted or unsubstituted amino, oxo, nitro, cyano, alkenyl, alkynyl, alkoxy, hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl; or, R.sub.17 and any group of R.sup.x, R.sup.y, R.sup.z and R.sup.f are bonded to form a cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted by one or more substituents selected from the group consisting of deuterium atom, alkyl, haloalkyl, halogen, amino, oxo, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —(CH.sub.2).sub.n1R.sub.23, —(CH.sub.2).sub.n1OR.sub.23, —(CH.sub.2).sub.n1SR.sub.23, —(CH.sub.2).sub.n1C(O)R.sub.23, —(CH.sub.2).sub.n1C(O)OR.sub.23, —(CH.sub.2).sub.n1S(O).sub.m1R.sub.23, —(CH.sub.2).sub.n1NR.sub.23R.sub.24, —(CH.sub.2).sub.n1C(O)NR.sub.23R.sub.24, —(CH.sub.2).sub.n1NR.sub.23C(O)R.sub.24 and —(CH.sub.2).sub.n1NR.sub.23S(O).sub.m1R.sub.24; R.sub.22 is selected from the group consisting of hydrogen atom, deuterium atom, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxy, cyano, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, —(CH.sub.2).sub.n1R.sub.23, —(CH.sub.2).sub.n1OR.sub.23, —(CH.sub.2).sub.n1SR.sub.23, —(CH.sub.2).sub.n1C(O)R.sub.23, —(CH.sub.2).sub.n1C(O)OR.sub.23, —(CH.sub.2).sub.n1S(O).sub.m1R.sub.23, —(CH.sub.2).sub.n1NR.sub.23R.sub.24, —(CH.sub.2).sub.n1C(O)NR.sub.23R.sub.24, —(CH.sub.2).sub.n1NR.sub.23C(O)R.sub.24 and —(CH.sub.2).sub.n1NR.sub.23S(O).sub.m1R.sub.24, wherein the alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each optionally substituted by one or more substituents selected from the group consisting of deuterium atom, alkyl, haloalkyl, halogen, amino, oxo, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —(CH.sub.2).sub.n1R.sub.25, —(CH.sub.2).sub.n1OR.sub.25, —(CH.sub.2).sub.n1SR.sub.25, —(CH.sub.2).sub.n1C(O)R.sub.25, —(CH.sub.2).sub.n1C(O)OR.sub.25, —(CH.sub.2).sub.n1S(O).sub.m1R.sub.25, —(CH.sub.2).sub.n1NR.sub.25R.sub.26, —(CH.sub.2).sub.n1C(O)NR.sub.25R.sub.26, —(CH.sub.2).sub.n1C(O)NHR.sub.25, —(CH.sub.2).sub.n1NR.sub.25C(O)R.sub.26 and —(CH.sub.2).sub.n1NR.sub.25S(O).sub.m1R.sub.26; R.sub.23, R.sub.24, R.sub.25 and R.sub.26 are identical or different and are each independently selected from the group consisting of hydrogen atom, deuterium atom, alkyl, deuterated alkyl, haloalkyl, hydroxy, amino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each optionally substituted by one or more substituents selected from the group consisting of deuterium atom, substituted or unsubstituted alkyl, halogen, hydroxy, substituted or unsubstituted amino, oxo, nitro, cyano, alkenyl, alkynyl, alkoxy, hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl; m is an integer of 0, 1, 3, 4, 5, 6, 7, 8, 9 or 10; n is an integer of 0, 1, 2 or 3; o is an integer of 0, 1, 2, 3, 4 or 5; p is an integer of 0, 1, 2, 3, 4, 5 or 6; q is an integer of 0, 1, 2, 3, 4, 5 or 6; m.sub.1 is an integer of 0, 1 or 2; and n.sub.1 is an integer of 0, 1, 2, 3, 4 or 5.

    2. The compound of formula (I), the stereoisomer thereof, or the pharmaceutically acceptable salt thereof according to claim 1, being a compound of formula (I-1), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: ##STR00232## wherein: R.sub.1, R.sub.2, R.sub.4, R.sub.5, R.sub.6, R.sub.7, R.sub.11, R.sub.12, R.sub.15a, R.sub.15b, R.sub.16a, R.sub.16b, R.sub.18 and R.sub.19 are identical or different and are each independently selected from the group consisting of hydrogen atom, deuterium atom, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxy, cyano, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, —(CH.sub.2).sub.n1R.sub.23, —(CH.sub.2).sub.n1OR.sub.23, —(CH.sub.2).sub.n1SR.sub.23, —(CH.sub.2).sub.n1C(O)R.sub.23, —(CH.sub.2).sub.n1C(O)OR.sub.23, —(CH.sub.2).sub.n1S(O).sub.m1R.sub.23, —(CH.sub.2).sub.n1S(O)NR.sub.23, —(CH.sub.2).sub.n1NR.sub.23R.sub.24, —(CH.sub.2).sub.n1C(O)NR.sub.23R.sub.24, —(CH.sub.2).sub.n1NR.sub.23C(O)R.sub.23 and —(CH.sub.2).sub.n1NR.sub.23S(O).sub.m1R.sub.24, wherein the alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each optionally substituted by one or more substituents selected from the group consisting of deuterium atom, alkyl, haloalkyl, halogen, amino, oxo, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —(CH.sub.2).sub.n1R.sub.25, —(CH.sub.2).sub.n1OR.sub.25, —(CH.sub.2).sub.n1SR.sub.25, —(CH.sub.2).sub.n1C(O)R.sub.25, —(CH.sub.2).sub.n1C(O)OR.sub.25, —(CH.sub.2).sub.n1S(O).sub.m1R.sub.25, —(CH.sub.2).sub.n1NR.sub.25R.sub.26, —(CH.sub.2).sub.n1C(O)NR.sub.25R.sub.26, —(CH.sub.2).sub.n1C(O)NHR.sub.25, —(CH.sub.2).sub.n1NR.sub.25C(O)R.sub.26 and —(CH.sub.2).sub.n1NR.sub.25S(O).sub.m1R.sub.26; or, any two adjacent or non-adjacent groups of R.sub.1, R.sub.2, R.sub.4, R.sub.5, R.sub.6, R.sub.7, R.sub.11, R.sub.12, R.sub.15a, R.sub.15b, R.sub.16a, R.sub.16b, R.sub.18 and R.sub.19 are bonded to form a cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted by one or more substituents selected from the group consisting of deuterium atom, alkyl, haloalkyl, halogen, amino, oxo, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —(CH.sub.2).sub.n1R.sub.25, —(CH.sub.2).sub.n1OR.sub.25, —(CH.sub.2).sub.n1SR.sub.25, —(CH.sub.2).sub.n1C(O)R.sub.25, —(CH.sub.2).sub.n1C(O)OR.sub.25, —(CH.sub.2).sub.n1S(O).sub.m1R.sub.25, —(CH.sub.2).sub.n1NR.sub.25R.sub.26, —(CH.sub.2).sub.n1C(O)NR.sub.25R.sub.26, —(CH.sub.2).sub.n1C(O)NHR.sub.25, —(CH.sub.2).sub.n1NR.sub.25C(O)R.sub.26 and —(CH.sub.2).sub.n1NR.sub.25S(O).sub.m1R.sub.26; R.sub.3a and R.sub.3b are identical or different and are each independently selected from the group consisting of hydrogen atom, deuterium atom, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, thiol, nitro, hydroxy, cyano, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, —(CH.sub.2).sub.n1R.sub.23, —(CH.sub.2).sub.n1OR.sub.23, —(CH.sub.2).sub.n1SR.sub.23, —(CH.sub.2).sub.n1C(O)R.sub.23, —(CH.sub.2).sub.n1C(O)OR.sub.23, —(CH.sub.2).sub.n1S(O).sub.m1R.sub.23, —(CH.sub.2).sub.n1S(O)NR.sub.23, —(CH.sub.2).sub.n1NR.sub.23R.sub.24, —(CH.sub.2).sub.n1C(O)NR.sub.23R.sub.24, —(CH.sub.2).sub.n1NR.sub.23C(O)R.sub.23 and —(CH.sub.2).sub.n1NR.sub.23S(O).sub.m1R.sub.24, wherein the alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each optionally substituted by one or more substituents selected from the group consisting of deuterium atom, alkyl, haloalkyl, halogen, amino, thiol, oxo, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —(CH.sub.2).sub.n1R.sub.25, —(CH.sub.2).sub.n1OR.sub.25, —(CH.sub.2).sub.n1SR.sub.25, —(CH.sub.2).sub.n1C(O)R.sub.25, —(CH.sub.2).sub.n1C(O)OR.sub.25, —(CH.sub.2).sub.n1S(O).sub.m1R.sub.25, —(CH.sub.2).sub.n1NR.sub.25R.sub.26, —(CH.sub.2).sub.n1C(O)NR.sub.25R.sub.26, —(CH.sub.2).sub.n1C(O)NHR.sub.25, —(CH.sub.2).sub.n1NR.sub.25C(O)R.sub.26 and —(CH.sub.2).sub.n1NR.sub.25S(O).sub.m1R.sub.26; X, Y, R.sub.21-R.sub.26, n, m.sub.1 and n.sub.1 are as defined in claim 1.

    3. The compound of formula (I), the stereoisomer thereof, or the pharmaceutically acceptable salt thereof according to claim 2, being a compound of formula (III), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: ##STR00233## wherein: Y, R.sub.1, R.sub.2, R.sub.3a, R.sub.3b, R.sub.4, R.sub.5, R.sub.6, R.sub.7, R.sub.11, R.sub.12, R.sub.15a, R.sub.15b, R.sub.16a, R.sub.16b, R.sub.18, R.sub.19, R.sub.21 and n are as defined in claim 2.

    4. The compound of formula (I), the stereoisomer thereof, or the pharmaceutically acceptable salt thereof according to claim 1, being a compound of formula (IV), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: ##STR00234## wherein: Y is selected from the group consisting of ##STR00235## R.sub.3a is selected from the group consisting of hydrogen atom, deuterium atom, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, thiol, nitro, hydroxy, cyano, alkenyl and alkynyl; R.sub.5 is selected from the group consisting of hydrogen atom, deuterium atom, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxy, cyano, alkenyl and alkynyl; R.sub.15a is selected from the group consisting of hydrogen atom, deuterium atom, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxy, cyano, alkenyl and alkynyl; R.sub.16a is selected from the group consisting of hydrogen atom, deuterium atom, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxy, cyano, alkenyl and alkynyl; or, R.sub.15a and R.sub.16a are bonded to form a cycloalkyl or heterocyclyl, wherein the cycloalkyl or heterocyclyl is optionally substituted by one or more substituents selected from the group consisting of hydrogen atom, deuterium atom, alkyl, haloalkyl, halogen, amino, oxo, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; R.sub.19 is selected from the group consisting of hydrogen atom, deuterium atom, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, thiol, hydroxy, cyano, alkenyl, alkynyl, hydroxyalkyl, —(CH.sub.2).sub.n1OR.sub.23, —(CH.sub.2).sub.n1SR.sub.23, —(CH.sub.2).sub.n1C(O)OR.sub.23, —(CH.sub.2).sub.n1S(O).sub.m1R.sub.23, —(CH.sub.2).sub.n1S(O)(═NR.sub.23)R.sub.24 and —(CH.sub.2).sub.n1C(O)NR.sub.23R.sub.24; or, R.sub.5 and R.sub.19 are bonded to form a cycloalkyl or heterocyclyl, wherein the cycloalkyl or heterocyclyl is optionally substituted by one or more substituents selected from the group consisting of hydrogen atom, deuterium atom, alkyl, haloalkyl, halogen, amino, oxo, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; R.sub.21 is selected from the group consisting of hydrogen atom, deuterium atom, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxy, cyano, alkenyl, alkynyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, —(CH.sub.2).sub.n1R.sub.23, —(CH.sub.2).sub.n1OR.sub.23, —(CH.sub.2).sub.n1SR.sub.23, —(CH.sub.2).sub.n1C(O)R.sub.23, —(CH.sub.2).sub.n1C(O)OR.sub.23, —(CH.sub.2).sub.n1S(O).sub.m1R.sub.23, —(CH.sub.2).sub.n1NR.sub.23R.sub.24, —(CH.sub.2).sub.n1C(O)NR.sub.23R.sub.24, —(CH.sub.2).sub.n1NR.sub.23C(O)R.sub.24 and —(CH.sub.2).sub.n1NR.sub.23S(O).sub.m1R.sub.24, wherein the alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each optionally substituted by one or more substituents selected from the group consisting of deuterium atom, alkyl, haloalkyl, halogen, amino, oxo, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —(CH.sub.2).sub.n1R.sub.25, —(CH.sub.2).sub.n1OR.sub.25, —(CH.sub.2).sub.n1SR.sub.25, —(CH.sub.2).sub.n1C(O)R.sub.25, —(CH.sub.2).sub.n1C(O)OR.sub.25, —(CH.sub.2).sub.n1S(O).sub.m1R.sub.25, —(CH.sub.2).sub.n1NR.sub.25R.sub.26, —(CH.sub.2).sub.n1C(O)NR.sub.25R.sub.26, —(CH.sub.2).sub.n1C(O)NHR.sub.25, —(CH.sub.2).sub.n1NR.sub.25C(O)R.sub.26 and —(CH.sub.2).sub.n1NR.sub.25S(O).sub.m1R.sub.26; R.sub.23, R.sub.24, R.sub.25 and R.sub.26 are identical or different and are each independently selected from the group consisting of hydrogen atom, deuterium atom, alkyl, deuterated alkyl, haloalkyl, hydroxy, amino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each optionally substituted by one or more substituents selected from the group consisting of deuterium atom, substituted or unsubstituted alkyl, halogen, hydroxy, substituted or unsubstituted amino, oxo, nitro, cyano, alkenyl, alkynyl, alkoxy, hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl; n is an integer of 1 or 2; m.sub.1 is an integer of 0, 1 or 2; and n.sub.1 is an integer of 0, 1, 2, 3, 4 or 5.

    5. The compound of formula (I), the stereoisomer thereof, or the pharmaceutically acceptable salt thereof according to claim 3, being a compound of formula (III-A), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: ##STR00236## wherein: Z is selected from the group consisting of —CR.sub.23R.sub.24—, —(CH.sub.2).sub.n1NR.sub.23—, —(CH.sub.2).sub.n1O(CH.sub.2).sub.n2— and —O—; ring C is selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each optionally substituted by one or more substituents selected from the group consisting of deuterium atom, alkyl, haloalkyl, halogen, amino, oxo, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —(CH.sub.2).sub.n1R.sub.25, —(CH.sub.2).sub.n1OR.sub.25, —(CH.sub.2).sub.n1SR.sub.25, —(CH.sub.2).sub.n1C(O)R.sub.25, —(CH.sub.2).sub.n1C(O)OR.sub.25, —(CH.sub.2).sub.n1S(O).sub.m1R.sub.25, —(CH.sub.2).sub.n1NR.sub.25R.sub.26, —(CH.sub.2).sub.n1C(O)NR.sub.25R.sub.26, —(CH.sub.2).sub.n1C(O)NHR.sub.25, —(CH.sub.2).sub.n1NR.sub.25C(O)R.sub.26 and —(CH.sub.2).sub.n1NR.sub.25S(O).sub.m1R.sub.26; each R.sub.c is identical or different and each is independently selected from the group consisting of hydrogen atom, deuterium atom, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxy, cyano, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, —(CH.sub.2).sub.n1R.sub.23, —(CH.sub.2).sub.n1OR.sub.23, —(CH.sub.2).sub.n1SR.sub.23, —(CH.sub.2).sub.n1C(O)R.sub.23, —(CH.sub.2).sub.n1C(O)OR.sub.23, —(CH.sub.2).sub.n1S(O).sub.m1R.sub.23, —(CH.sub.2).sub.n1S(O)NR.sub.23, —(CH.sub.2).sub.n1NR.sub.23R.sub.24, —(CH.sub.2).sub.n1C(O)NR.sub.23R.sub.24, —(CH.sub.2).sub.n1NR.sub.23C(O)R.sub.23 and —(CH.sub.2).sub.n1NR.sub.23S(O).sub.m1R.sub.24, wherein the alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each optionally substituted by one or more substituents selected from the group consisting of deuterium atom, alkyl, haloalkyl, halogen, amino, oxo, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —(CH.sub.2).sub.n1R.sub.25, —(CH.sub.2).sub.n1OR.sub.25, —(CH.sub.2).sub.n1SR.sub.25, —(CH.sub.2).sub.n1C(O)R.sub.25, —(CH.sub.2).sub.n1C(O)OR.sub.25, —(CH.sub.2).sub.n1S(O).sub.m1R.sub.25, —(CH.sub.2).sub.n1NR.sub.25R.sub.26, —(CH.sub.2).sub.n1C(O)NR.sub.25R.sub.26, —(CH.sub.2).sub.n1C(O)NHR.sub.25, —(CH.sub.2).sub.n1NR.sub.25C(O)R.sub.26 and —(CH.sub.2).sub.n1NR.sub.25S(O).sub.m1R.sub.26; z is an integer of 0, 1, 3, 4 or 5; n2 is an integer of 0, 1, 3, 4 or 5; and R.sub.3a, R.sub.3b, R.sub.5, R.sub.19, R.sub.23-R.sub.26, n, m.sub.1 and n.sub.1 are as defined in claim 3.

    6. The compound of formula (I), the stereoisomer thereof, or the pharmaceutically acceptable salt thereof according to claim 1, being a compound of formula (V), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: ##STR00237## wherein: R.sub.1, R.sub.2, R.sub.4, R.sub.5, R.sub.6, R.sub.7, R.sub.11, R.sub.12, R.sub.15a, R.sub.15b, R.sub.16a, R.sub.16b, R.sub.18 and R.sub.19 are identical or different and are each independently selected from the group consisting of hydrogen atom, deuterium atom, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxy, cyano, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, —(CH.sub.2).sub.n1R.sub.23, —(CH.sub.2).sub.n1OR.sub.23, —(CH.sub.2).sub.n1SR.sub.23, —(CH.sub.2).sub.n1C(O)R.sub.23, —(CH.sub.2).sub.n1C(O)OR.sub.23, —(CH.sub.2).sub.n1S(O).sub.m1R.sub.23, —(CH.sub.2).sub.n1S(O)NR.sub.23, —(CH.sub.2).sub.n1NR.sub.23R.sub.24, —(CH.sub.2).sub.n1C(O)NR.sub.23R.sub.24, —(CH.sub.2).sub.n1NR.sub.23C(O)R.sub.23 and —(CH.sub.2).sub.n1NR.sub.23S(O).sub.m1R.sub.24, wherein the alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each optionally substituted by one or more substituents selected from the group consisting of deuterium atom, alkyl, haloalkyl, halogen, amino, oxo, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —(CH.sub.2).sub.n1R.sub.25, —(CH.sub.2).sub.n1OR.sub.25, —(CH.sub.2).sub.n1SR.sub.25, —(CH.sub.2).sub.n1C(O)R.sub.25, —(CH.sub.2).sub.n1C(O)OR.sub.25, —(CH.sub.2).sub.n1S(O).sub.m1R.sub.25, —(CH.sub.2).sub.n1NR.sub.25R.sub.26, —(CH.sub.2).sub.n1C(O)NR.sub.25R.sub.26, —(CH.sub.2).sub.n1C(O)NHR.sub.25, —(CH.sub.2).sub.n1NR.sub.25C(O)R.sub.26 and —(CH.sub.2).sub.n1NR.sub.25S(O).sub.m1R.sub.26; or, any two adjacent or non-adjacent groups of R.sub.1, R.sub.2, R.sub.4, R.sub.5, R.sub.6, R.sub.7, R.sub.11, R.sub.12, R.sub.15a, R.sub.15b, R.sub.16a, R.sub.16b, R.sub.18 and R.sub.19 are bonded to form a cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted by one or more substituents selected from the group consisting of deuterium atom, alkyl, haloalkyl, halogen, amino, oxo, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —(CH.sub.2).sub.n1R.sub.25, —(CH.sub.2).sub.n1OR.sub.25, —(CH.sub.2).sub.n1SR.sub.25, —(CH.sub.2).sub.n1C(O)R.sub.25, —(CH.sub.2).sub.n1C(O)OR.sub.25, —(CH.sub.2).sub.n1S(O).sub.m1R.sub.25, —(CH.sub.2).sub.n1NR.sub.25R.sub.26, —(CH.sub.2).sub.n1C(O)NR.sub.25R.sub.26, —(CH.sub.2).sub.n1C(O)NHR.sub.25, —(CH.sub.2).sub.n1NR.sub.25C(O)R.sub.26 and —(CH.sub.2).sub.n1NR.sub.25S(O).sub.m1R.sub.26; R.sub.3a and R.sub.3b are identical or different and are each independently selected from the group consisting of hydrogen atom, deuterium atom, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, thiol, nitro, hydroxy, cyano, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, —(CH.sub.2).sub.n1R.sub.23, —(CH.sub.2).sub.n1OR.sub.23, —(CH.sub.2).sub.n1SR.sub.23, —(CH.sub.2).sub.n1C(O)R.sub.23, —(CH.sub.2).sub.n1C(O)OR.sub.23, —(CH.sub.2).sub.n1S(O).sub.m1R.sub.23, —(CH.sub.2).sub.n1S(O)NR.sub.23, —(CH.sub.2).sub.n1NR.sub.23R.sub.24, —(CH.sub.2).sub.n1C(O)NR.sub.23R.sub.24, —(CH.sub.2).sub.n1NR.sub.23C(O)R.sub.23 and —(CH.sub.2).sub.n1NR.sub.23S(O).sub.m1R.sub.24, wherein the alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each optionally substituted by one or more substituents selected from the group consisting of deuterium atom, alkyl, haloalkyl, halogen, amino, thiol, oxo, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —(CH.sub.2).sub.n1R.sub.25, —(CH.sub.2).sub.n1OR.sub.25, —(CH.sub.2).sub.n1SR.sub.25, —(CH.sub.2).sub.n1C(O)R.sub.25, —(CH.sub.2).sub.n1C(O)OR.sub.25, —(CH.sub.2).sub.n1S(O).sub.m1R.sub.25, —(CH.sub.2).sub.n1NR.sub.25R.sub.26, —(CH.sub.2).sub.n1C(O)NR.sub.25R.sub.26, —(CH.sub.2).sub.n1C(O)NHR.sub.25, —(CH.sub.2).sub.n1NR.sub.25C(O)R.sub.26 and —(CH.sub.2).sub.n1NR.sub.25S(O).sub.m1R.sub.26; and X, R.sub.17, R.sub.21 and n is as defined in claim 1.

    7. The compound of formula (I), the stereoisomer thereof, or the pharmaceutically acceptable salt thereof according to claim 5, being a compound of formula (V-7) or (V-8), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: ##STR00238## wherein: ring A is selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each optionally substituted by one or more substituents selected from the group consisting of deuterium atom, alkyl, haloalkyl, halogen, amino, oxo, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —(CH.sub.2).sub.n1R.sub.25, —(CH.sub.2).sub.n1OR.sub.25, —(CH.sub.2).sub.n1SR.sub.25, —(CH.sub.2).sub.n1C(O)R.sub.25, —(CH.sub.2).sub.n1C(O)OR.sub.25, —(CH.sub.2).sub.n1S(O).sub.m1R.sub.25, —(CH.sub.2).sub.n1NR.sub.25R.sub.26, —(CH.sub.2).sub.n1C(O)NR.sub.25R.sub.26, —(CH.sub.2).sub.n1C(O)NHR.sub.25, —(CH.sub.2).sub.n1NR.sub.25C(O)R.sub.26 and —(CH.sub.2).sub.n1NR.sub.25S(O).sub.m1R.sub.26; each R.sub.a is identical or different and each is independently selected from the group consisting of hydrogen atom, deuterium atom, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxy, cyano, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, —(CH.sub.2).sub.n1R.sub.23, —(CH.sub.2).sub.n1OR.sub.23, —(CH.sub.2).sub.n1SR.sub.23, —(CH.sub.2).sub.n1C(O)R.sub.23, —(CH.sub.2).sub.n1C(O)OR.sub.23, —(CH.sub.2).sub.n1S(O).sub.m1R.sub.23, —(CH.sub.2).sub.n1S(O)NR.sub.23, —(CH.sub.2).sub.n1NR.sub.23R.sub.24, —(CH.sub.2).sub.n1C(O)NR.sub.23R.sub.24, —(CH.sub.2).sub.n1NR.sub.23C(O)R.sub.23 and —(CH.sub.2).sub.n1NR.sub.23S(O).sub.m1R.sub.24, wherein the alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each optionally substituted by one or more substituents selected from the group consisting of deuterium atom, alkyl, haloalkyl, halogen, amino, oxo, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —(CH.sub.2).sub.n1R.sub.25, —(CH.sub.2).sub.n1OR.sub.25, —(CH.sub.2).sub.n1SR.sub.25, —(CH.sub.2).sub.n1C(O)R.sub.25, —(CH.sub.2).sub.n1C(O)OR.sub.25, —(CH.sub.2).sub.n1S(O).sub.m1R.sub.25, —(CH.sub.2).sub.n1NR.sub.25R.sub.26, —(CH.sub.2).sub.n1C(O)NR.sub.25R.sub.26, —(CH.sub.2).sub.n1C(O)NHR.sub.25, —(CH.sub.2).sub.n1NR.sub.25C(O)R.sub.26 and —(CH.sub.2).sub.n1NR.sub.25S(O).sub.m1R.sub.26; R.sub.19 is selected from the group consisting of hydrogen atom, alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxy, cyano, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, —(CH.sub.2).sub.n1R.sub.23, —(CH.sub.2).sub.n1OR.sub.23, —(CH.sub.2).sub.n1SR.sub.23, —(CH.sub.2).sub.n1C(O)R.sub.23, —(CH.sub.2).sub.n1C(O)OR.sub.23, —(CH.sub.2).sub.n1S(O).sub.m1R.sub.23, —(CH.sub.2).sub.n1S(O)NR.sub.23, —(CH.sub.2).sub.n1NR.sub.23R.sub.24, —(CH.sub.2).sub.n1C(O)NR.sub.23R.sub.24, —(CH.sub.2).sub.n1NR.sub.23C(O)R.sub.23, —(CH.sub.2).sub.n1S(O)(═NR.sub.23)R.sub.24 and —(CH.sub.2).sub.n1NR.sub.23S(O).sub.m1R.sub.24, wherein the alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each optionally substituted by one or more substituents selected from the group consisting of deuterium atom, alkyl, haloalkyl, halogen, amino, oxo, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —(CH.sub.2).sub.n1R.sub.25, —(CH.sub.2).sub.n1OR.sub.25, —(CH.sub.2).sub.n1SR.sub.25, —(CH.sub.2).sub.n1C(O)R.sub.25, —(CH.sub.2).sub.n1C(O)OR.sub.25, —(CH.sub.2).sub.n1S(O).sub.m1R.sub.25, —(CH.sub.2).sub.n1NR.sub.25R.sub.26, —(CH.sub.2).sub.n1C(O)NR.sub.25R.sub.26, —(CH.sub.2).sub.n1C(O)NHR.sub.25, —(CH.sub.2).sub.n1NR.sub.25C(O)R.sub.26 and —(CH.sub.2).sub.n1NR.sub.25S(O).sub.m1R.sub.26; x is an integer of 0, 1, 3, 4 or 5; Z, R.sub.23-R.sub.26, m.sub.1 and n.sub.1 are as defined in claim 5.

    8. The compound of formula (I), the stereoisomer thereof, or the pharmaceutically acceptable salt thereof according to claim 1, being a compound of formula (III-B), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: ##STR00239## wherein: R.sub.5 is selected from the group consisting of hydrogen atom, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl and C.sub.1-6 alkoxy; R.sub.19 is selected from the group consisting of hydrogen atom, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.1-6 alkoxy, —(CH.sub.2).sub.n1OR.sub.23 and —(CH.sub.2).sub.n1SR.sub.23; R.sub.c is selected from the group consisting of hydrogen atom, cyano and C.sub.1-6 alkyl; z is an integer of 0, 1 or 2; and n is 0, 1 or 2.

    9. The compound of formula (I), the stereoisomer thereof, or the pharmaceutically acceptable salt thereof according to claim 4, being a compound of formula (IV-A) or (IV-B), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: ##STR00240## wherein: R.sub.3a is selected from the group consisting of C.sub.1-6 alkyl, C.sub.1-6 haloalkyl and C.sub.1-6 alkoxy; R.sub.19 is selected from the group consisting of cyano, halogen, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.1-6 alkoxy, —(CH.sub.2).sub.n1OR.sub.23, —(CH.sub.2).sub.n1S(O).sub.m1R.sub.23, —(CH.sub.2).sub.n1S(O)(═NR.sub.23)R.sub.24 and —(CH.sub.2).sub.n1SR.sub.23; R.sub.a is selected from the group consisting of hydrogen atom, cyano, halogen, nitro, alkyl, alkoxy, haloalkyl, cycloalkyl, hydroxyalkyl, heterocyclyl, heteroaryl, —(CH.sub.2).sub.n1CR.sub.23R.sub.24R.sub.25, —(CH.sub.2).sub.n1SR.sub.23, —(CH.sub.2).sub.n1C(O)OR.sub.23, —(CH.sub.2).sub.n1S(O).sub.m1R.sub.23, —(CH.sub.2).sub.n1S(O)(═NR.sub.23)R.sub.24 and —(CH.sub.2).sub.n1C(O)NR.sub.23R.sub.24, wherein the alkyl, cycloalkyl, heterocyclyl and heteroaryl are each optionally substituted by one or more substituents selected from the group consisting of hydrogen atom, alkyl, halogen, cyano, hydroxy, cycloalkyl, heterocyclyl and heteroaryl; x is an integer of 0, 1 or 2; and R.sub.5, R.sub.23, R.sub.24, m.sub.1 and n.sub.1 are as defined in claim 4.

    10. The compound of formula (I), the stereoisomer thereof, or the pharmaceutically acceptable salt thereof according to claim 1, being a compound of formula (VII), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: ##STR00241## wherein: R.sub.1a and R.sub.1b are identical or different and are each selected from the group consisting of hydrogen atom, deuterium atom, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxy, cyano, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, —(CH.sub.2).sub.n1R.sub.23, —(CH.sub.2).sub.n1OR.sub.23, —(CH.sub.2).sub.n1SR.sub.23, —(CH.sub.2).sub.n1C(O)R.sub.23, —(CH.sub.2).sub.n1C(O)OR.sub.23, —(CH.sub.2).sub.n1S(O).sub.m1R.sub.23, —(CH.sub.2).sub.n1S(O)NR.sub.23, —(CH.sub.2).sub.n1NR.sub.23R.sub.24, —(CH.sub.2).sub.n1C(O)NR.sub.23R.sub.24, —(CH.sub.2).sub.n1NR.sub.23C(O)R.sub.23 and —(CH.sub.2).sub.n1NR.sub.23S(O).sub.m1R.sub.24, wherein the alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each optionally:=substituted by one or more substituents selected from the group consisting of deuterium atom, alkyl, haloalkyl, halogen, amino, oxo, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —(CH.sub.2).sub.n1R.sub.25, —(CH.sub.2).sub.n1OR.sub.25, —(CH.sub.2).sub.n1SR.sub.25, —(CH.sub.2).sub.n1C(O)R.sub.25, —(CH.sub.2).sub.n1C(O)OR.sub.25, —(CH.sub.2).sub.n1S(O).sub.m1R.sub.25, —(CH.sub.2).sub.n1NR.sub.25R.sub.26, —(CH.sub.2).sub.n1C(O)NR.sub.25R.sub.26, —(CH.sub.2).sub.n1C(O)NHR.sub.25, —(CH.sub.2).sub.n1NR.sub.25C(O)R.sub.26 and —(CH.sub.2).sub.n1NR.sub.25S(O).sub.m1R.sub.26; Z is selected from the group consisting of Z is selected from the group consisting of —CR.sub.23R.sub.24—, —NR.sub.23—, —(CH.sub.2).sub.n1O(CH.sub.2).sub.n2— and —O—; ring A is selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each optionally substituted by one or more substituents selected from the group consisting of deuterium atom, alkyl, haloalkyl, halogen, amino, oxo, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —(CH.sub.2).sub.n1R.sub.25, —(CH.sub.2).sub.n1OR.sub.25, —(CH.sub.2).sub.n1SR.sub.25, —(CH.sub.2).sub.n1C(O)R.sub.25, —(CH.sub.2).sub.n1C(O)OR.sub.25, —(CH.sub.2).sub.n1S(O).sub.m1R.sub.25, —(CH.sub.2).sub.n1NR.sub.25R.sub.26, —(CH.sub.2).sub.n1C(O)NR.sub.25R.sub.26, —(CH.sub.2).sub.n1C(O)NHR.sub.25, —(CH.sub.2).sub.n1NR.sub.25C(O)R.sub.26 and —(CH.sub.2).sub.n1NR.sub.25S(O).sub.m1R.sub.26; each R.sub.a is identical or different and each is independently selected from the group consisting of hydrogen atom, deuterium atom, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxy, cyano, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, —(CH.sub.2).sub.n1R.sub.23, —(CH.sub.2).sub.n1OR.sub.23, —(CH.sub.2).sub.n1SR.sub.23, —(CH.sub.2).sub.n1C(O)R.sub.23, —(CH.sub.2).sub.n1C(O)OR.sub.23, —(CH.sub.2).sub.n1S(O).sub.m1R.sub.23, —(CH.sub.2).sub.n1S(O)NR.sub.23, —(CH.sub.2).sub.n1NR.sub.23R.sub.24, —(CH.sub.2).sub.n1C(O)NR.sub.23R.sub.24, —(CH.sub.2).sub.n1NR.sub.23C(O)R.sub.23 and —(CH.sub.2).sub.n1NR.sub.23S(O).sub.m1R.sub.24, wherein the alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each optionally substituted by one or more substituents selected from the group consisting of deuterium atom, alkyl, haloalkyl, halogen, amino, oxo, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —(CH.sub.2).sub.n1R.sub.25, —(CH.sub.2).sub.n1OR.sub.25, —(CH.sub.2).sub.n1SR.sub.25, —(CH.sub.2).sub.n1C(O)R.sub.25, —(CH.sub.2).sub.n1C(O)OR.sub.25, —(CH.sub.2).sub.n1S(O).sub.m1R.sub.25, —(CH.sub.2).sub.n1NR.sub.25R.sub.26, —(CH.sub.2).sub.n1C(O)NR.sub.25R.sub.26, —(CH.sub.2).sub.n1C(O)NHR.sub.25, —(CH.sub.2).sub.n1NR.sub.25C(O)R.sub.26 and —(CH.sub.2).sub.n1NR.sub.25S(O).sub.m1R.sub.26; R.sub.23, R.sub.24, R.sub.25 and R.sub.26 are identical or different and are each independently selected from the group consisting of hydrogen atom, deuterium atom, alkyl, deuterated alkyl, haloalkyl, hydroxy, amino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each optionally further substituted by one or more substituents selected from the group consisting of deuterium atom, substituted or unsubstituted alkyl, halogen, hydroxy, substituted or unsubstituted amino, oxo, nitro, cyano, alkenyl, alkynyl, alkoxy, hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl; m.sub.1 is an integer of 0, 1 or 2; and n.sub.1 is an integer of 0, 1, 2, 3, 4 or 5; and x is an integer of 0, 1, 3, 4 or 5.

    11. The compound of formula (I), the stereoisomer thereof, or the pharmaceutically acceptable salt thereof according to claim 7, being a compound of formula (VIII), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: ##STR00242## wherein: ring A, Z, R.sub.a and x are as defined in claim 7.

    12. The compound of formula (I), the stereoisomer thereof, or the pharmaceutically acceptable salt thereof according to claim 1, being a compound of formula (IX), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: ##STR00243## wherein: Z is selected from the group consisting of —CR.sub.23R.sub.24—, —(CH.sub.2).sub.n1NR.sub.23—, —(CH.sub.2).sub.n1O(CH.sub.2).sub.n2— and —O—; ring B is selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are each optionally substituted by one or more substituents selected from the group consisting of deuterium atom, alkyl, haloalkyl, halogen, amino, oxo, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —(CH.sub.2).sub.n1R.sub.25, —(CH.sub.2).sub.n1OR.sub.25, —(CH.sub.2).sub.n1SR.sub.25, —(CH.sub.2).sub.n1C(O)R.sub.25, —(CH.sub.2).sub.n1C(O)OR.sub.25, —(CH.sub.2).sub.n1S(O).sub.m1R.sub.25, —(CH.sub.2).sub.n1NR.sub.25R.sub.26, —(CH.sub.2).sub.n1C(O)NR.sub.25R.sub.26, —(CH.sub.2).sub.n1C(O)NHR.sub.25, —(CH.sub.2).sub.n1NR.sub.25C(O)R.sub.26 and —(CH.sub.2).sub.n1NR.sub.25S(O).sub.m1R.sub.26; each R.sub.b is identical or different and each is selected from the group consisting of hydrogen atom, deuterium atom, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxy, cyano, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, —(CH.sub.2).sub.n1R.sub.23, —(CH.sub.2).sub.n1OR.sub.23, —(CH.sub.2).sub.n1SR.sub.23, —(CH.sub.2).sub.n1C(O)R.sub.23, —(CH.sub.2).sub.n1C(O)OR.sub.23, —(CH.sub.2).sub.n1S(O).sub.m1R.sub.23, —(CH.sub.2).sub.n1S(O)NR.sub.23, —(CH.sub.2).sub.n1NR.sub.23R.sub.24, —(CH.sub.2).sub.n1C(O)NR.sub.23R.sub.24, —(CH.sub.2).sub.n1NR.sub.23C(O)R.sub.23 and —(CH.sub.2).sub.n1NR.sub.23S(O).sub.m1R.sub.24, wherein the alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each optionally substituted by one or more substituents selected from the group consisting of deuterium atom, alkyl, haloalkyl, halogen, amino, oxo, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —(CH.sub.2).sub.n1R.sub.25, —(CH.sub.2).sub.n1OR.sub.25, —(CH.sub.2).sub.n1SR.sub.25, —(CH.sub.2).sub.n1C(O)R.sub.25, —(CH.sub.2).sub.n1C(O)OR.sub.25, —(CH.sub.2).sub.n1S(O).sub.m1R.sub.25, —(CH.sub.2).sub.n1NR.sub.25R.sub.26, —(CH.sub.2).sub.n1C(O)NR.sub.25R.sub.26, —(CH.sub.2).sub.n1C(O)NHR.sub.25, —(CH.sub.2).sub.n1NR.sub.25C(O)R.sub.26 and —(CH.sub.2).sub.n1NR.sub.25S(O).sub.m1R.sub.26; and y is an integer of 0, 1, 2, 3 or 4.

    13. The compound of formula (I), the stereoisomer thereof, or the pharmaceutically acceptable salt thereof according to claim 1, being a compound of formula (XI), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: ##STR00244## wherein: R.sub.21 is selected from the group consisting of hydrogen atom, deuterium atom, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxy, cyano, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, —(CH.sub.2).sub.n1R.sub.23, —(CH.sub.2).sub.n1OR.sub.23, —(CH.sub.2).sub.n1SR.sub.23, —(CH.sub.2).sub.n1C(O)R.sub.23, —(CH.sub.2).sub.n1C(O)OR.sub.23, —(CH.sub.2).sub.n1S(O).sub.m1R.sub.23, —(CH.sub.2).sub.n1NR.sub.23R.sub.24, —(CH.sub.2).sub.n1C(O)NR.sub.23R.sub.24, —(CH.sub.2).sub.n1NR.sub.23C(O)R.sub.24 and —(CH.sub.2).sub.n1NR.sub.23S(O).sub.m1R.sub.24, wherein the alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each optionally substituted by one or more substituents selected from the group consisting of deuterium atom, alkyl, haloalkyl, halogen, amino, oxo, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —(CH.sub.2).sub.n1R.sub.25, —(CH.sub.2).sub.n1OR.sub.25, —(CH.sub.2).sub.n1SR.sub.25, —(CH.sub.2).sub.n1C(O)R.sub.25, —(CH.sub.2).sub.n1C(O)OR.sub.25, —(CH.sub.2).sub.n1S(O).sub.m1R.sub.25, —(CH.sub.2).sub.n1NR.sub.25R.sub.26, —(CH.sub.2).sub.n1C(O)NR.sub.25R.sub.26, —(CH.sub.2).sub.n1C(O)NHR.sub.25, —(CH.sub.2).sub.n1NR.sub.25C(O)R.sub.26 and —(CH.sub.2).sub.n1NR.sub.25S(O).sub.m1R.sub.26; R.sub.23-R.sub.26, m.sub.1 and n.sub.1 are as defined in claim 1.

    14. The compound of formula (I), the stereoisomer thereof, or the pharmaceutically acceptable salt thereof according to claim 1, being a compound of formula (X), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: ##STR00245## wherein: M is selected from the group consisting of —CR.sub.23— and oxygen atom; Y is selected from the group consisting of —S(CH.sub.2).sub.n1—, ##STR00246## R.sub.21 is selected from the group consisting of hydrogen atom, deuterium atom, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxy, cyano, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, —(CH.sub.2).sub.n1R.sub.23, —(CH.sub.2).sub.n1OR.sub.23, —(CH.sub.2).sub.n1SR.sub.23, —(CH.sub.2).sub.n1C(O)R.sub.23, —(CH.sub.2).sub.n1C(O)OR.sub.23, —(CH.sub.2).sub.n1S(O).sub.m1R.sub.23, —(CH.sub.2).sub.n1NR.sub.23R.sub.24, —(CH.sub.2).sub.n1C(O)NR.sub.23R.sub.24, —(CH.sub.2).sub.n1NR.sub.23C(O)R.sub.24 and —(CH.sub.2).sub.n1NR.sub.23S(O).sub.m1R.sub.24, wherein the alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each optionally substituted by one or more substituents selected from the group consisting of deuterium atom, alkyl, haloalkyl, halogen, amino, oxo, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —(CH.sub.2).sub.n1R.sub.25, —(CH.sub.2).sub.n1OR.sub.25, —(CH.sub.2).sub.n1SR.sub.25, —(CH.sub.2).sub.n1C(O)R.sub.25, —(CH.sub.2).sub.n1C(O)OR.sub.25, —(CH.sub.2).sub.n1S(O).sub.m1R.sub.25, —(CH.sub.2).sub.n1NR.sub.25R.sub.26, —(CH.sub.2).sub.n1C(O)NR.sub.25R.sub.26, —(CH.sub.2).sub.n1C(O)NHR.sub.25, —(CH.sub.2).sub.n1NR.sub.25C(O)R.sub.26 and —(CH.sub.2).sub.n1NR.sub.25S(O).sub.m1R.sub.26; R.sub.22-R.sub.26, m.sub.1 and n.sub.1 are as defined in claim 1.

    15. The compound of formula (I), the stereoisomer thereof, or the pharmaceutically acceptable salt thereof according to claim 7, wherein the ring A is selected from the group consisting of: ##STR00247## ##STR00248##

    16. The compound of formula (I), the stereoisomer thereof, or the pharmaceutically acceptable salt thereof according to claim 5, wherein R.sub.c selected from the group consisting of hydrogen atom, cyano, halogen, nitro, C.sub.1-6 alkyl, C.sub.2-6 alkynyl, C.sub.1-6 alkoxy, C.sub.1-6 haloalkyl, C.sub.3-6 cycloalkyl, C.sub.1-6 hydroxyalkyl, 5 to 10 membered heterocyclyl, 5 to 10 membered heteroaryl, —(CH.sub.2),10R.sub.23, —(CH.sub.2).sub.n1SR.sub.23, —(CH.sub.2).sub.n1C(O)R.sub.23, —(CH.sub.2).sub.n1C(O)NR.sub.23R.sub.24, —(CH.sub.2).sub.n1C(O)OR.sub.23 and —(CH.sub.2).sub.n1S(O).sub.m1R.sub.23, wherein the C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.1-6 haloalkyl, C.sub.3-6 cycloalkyl, C.sub.1-6 hydroxyalkyl, wherein the 5 to 10 membered heterocyclyl and 5 to 10 membered heteroaryl are each optionally substituted by one or more substituents selected from the group consisting of hydrogen atom, C.sub.1-6 alkyl, halogen, cyano, hydroxy, C.sub.3-6 cycloalkyl, C.sub.1-6 hydroxyalkyl, 5 to 10 membered heterocyclyl and 5 to 10 membered heteroaryl; R.sub.23 and R.sub.24 are each independently selected from the group consisting of hydrogen atom, C.sub.1-6 alkyl and 3 to 8 membered heterocyclyl.

    17. The compound of formula (I), the stereoisomer thereof, or the pharmaceutically acceptable salt thereof according to claim 5, wherein: Z is selected from the group consisting of —CH.sub.2—, —CH.sub.2NH—, —CH.sub.2O—, —CH.sub.2—, —NH— and —NHSO.sub.2—; R.sub.3a is selected from the group consisting of C.sub.1-6 alkyl, C.sub.1-6 haloalkyl and C.sub.1-6 alkoxy; R.sub.5 is selected from the group consisting of hydrogen atom, halogen, cyano, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl and C.sub.1-6 alkoxy; R.sub.19 is selected from the group consisting of cyano, halogen, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.1-6 alkoxy, —(CH.sub.2).sub.n1OR.sub.23, —(CH.sub.2).sub.n1S(O).sub.m1R.sub.23, —(CH.sub.2).sub.n1S(O)(═NR.sub.23)R.sub.24 and —(CH.sub.2).sub.n1SR.sub.23; or, a C.sub.3-6 cycloalkyl, is formed between any two adjacent groups of R.sub.5 and R.sub.19.

    18. The compound of formula (I), the stereoisomer thereof, or the pharmaceutically acceptable salt thereof according to claim 1, selected from the group consisting of: ##STR00249## ##STR00250## ##STR00251## ##STR00252## ##STR00253## ##STR00254## ##STR00255## ##STR00256## ##STR00257## ##STR00258## ##STR00259## ##STR00260## ##STR00261## ##STR00262## ##STR00263## ##STR00264## ##STR00265## ##STR00266## ##STR00267## ##STR00268## ##STR00269## ##STR00270## ##STR00271## ##STR00272## ##STR00273## ##STR00274## ##STR00275## ##STR00276## ##STR00277## ##STR00278## ##STR00279## ##STR00280## ##STR00281## ##STR00282## ##STR00283## ##STR00284## ##STR00285## or a pharmaceutically acceptable salt thereof.

    19. A pharmaceutical composition, comprising a therapeutically effective amount of the compound of formula (I), the stereoisomer thereof, or the pharmaceutically acceptable salt thereof according to claim 1, and one or more pharmaceutically acceptable carriers, diluents or excipients.

    20. A method of regulating GABA.sub.A receptor in a subject in need thereof, comprising administering the pharmaceutical composition according to claim 19 to the subject.

    21. A method of treating a CNS-related disease in a subject in need thereof, comprising administering to the subject a therapeutically amount of the pharmaceutical composition according to claim 19, wherein the CNS-related disease is selected from the group consisting of sleep disorder, mood disorder, schizophrenia spectrum disorder, spasmodic disorder, memory disorder and/or cognitive disorder, dyskinesia, personality disorder, autism spectrum disorder, pain, traumatic brain injury, vascular disease, substance abuse disorder and/or withdrawal syndrome, and tinnitus.

    Description

    DETAILED DESCRIPTION OF THE INVENTION

    [0166] The present invention is further described in combination with the following examples, which are not intended to limit the scope of the present invention.

    EXAMPLES

    [0167] The structures of the compounds of the present invention were identified by nuclear magnetic resonance (NMR) and/or liquid chromatography-mass spectrometry (LC-MS). NMR chemical shifts (8) are given in parts per million (ppm). NMR was determined by a Bruker AVANCE-400 machine. The solvents for determination were deuterated-dimethyl sulfoxide (DMSO-d.sub.6), deuterated-methanol (CD.sub.3OD) and deuterated-chloroform (CDCl.sub.3), and the internal standard was tetramethylsilane (TMS).

    [0168] Liquid chromatography-mass spectrometry (LC-MS) was determined on an Agilent 1200 Infinity Series mass spectrometer. High performance liquid chromatography (HPLC) was determined on an Agilent 1200DAD high pressure liquid chromatograph (Sunfire C18 150×4.6 mm chromatographic column), and a Waters 2695-2996 high pressure liquid chromatograph (Gimini C18 150×4.6 mm chromatographic column).

    [0169] Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate was used as the thin-layer silica gel chromatography (TLC) plate. The dimension of the silica gel plate used in TLC was 0.15 mm to 0.2 mm, and the dimension of the silica gel plate used in product purification was 0.4 mm to 0.5 mm. Yantai Huanghai 200 to 300 mesh silica gel was generally used as a carrier for column chromatography.

    [0170] The starting materials used in the examples of the present invention are known and commercially available, or can be synthesized by adopting or according to known methods in the art.

    [0171] Unless otherwise stated, all reactions of the present invention were carried out under continuous magnetic stirring in a dry nitrogen or argon atmosphere, the solvent was dry, and the reaction temperature was in degrees Celsius.

    Example 1

    1-((3R,5R,8S,10R,13S,14S,17S)-10-Fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one

    [0172] ##STR00066##

    Step 1: (8S,9S,10S,13S,14S)-10-Fluoro-13-methyl-7,8,9,10,11,12,13,14,15,16-decahydro-3H-cyclopenta[a]phenanthrene-3,17(6H)-dione

    [0173] ##STR00067##

    [0174] (8R,9S,13S,14S)-3-Hydroxy-13-methyl-6,7,8,9,11,12,13,14,15,16-decahydro-17H-cyclopenta[a]phenanthren-17-one (2.7 g, 10 mmol) and acetonitrile (100 mL) were added successively to a 100 mL three-necked flask, followed by the addition of 1 chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (3.6 g, 10 mmol) under stirring. The reaction solution was heated to 45° C. in an oil bath, and reacted for 5 hours. The reaction solution was cooled to room temperature and concentrated. The resulting residue was dissolved in dichloromethane (100 mL), and washed with saturated saline (30 mL×3). The organic phase was dried over anhydrous sodium sulfate, filtrated and concentrated by rotary evaporation to dryness. The crude product was purified by column chromatography (petroleum ether/ethyl acetate: 3/1) to obtain (8S,9S,10S,13S,14S)-10-fluoro-13-methyl-7,8,9,10,11,12,13,14,15,16-decahydro-3H-cyclopenta[a]phenanthrene-3,17(6H)-dione (1.8 g, light yellow solid, yield: 62.5%).

    [0175] MS m/z (ESI): 289.1[M+H].sup.+.

    [0176] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.12-7.05 (m, 1H), 6.30-6.19 (m, 1H), 6.04 (s, 1H), 2.70-2.60 (m, 1H), 2.52-2.45 (m, 2H), 2.16-1.86 (m, 7H), 1.65-1.18 (m, 5H), 0.98 (s, 3H).

    [0177] .sup.19F NMR (376 MHz, CDCl.sub.3) δ −165.20.

    Step 2: (5R,8S,9S,10R,13S,14S)-10-Fluoro-13-methyltetradecahydro-3H-cyclopenta[a]phenanthrene-3,17(2H)-dione

    [0178] ##STR00068##

    [0179] (8S,9S,10S,13S,14S)-10-Fluoro-13-methyl-7,8,9,10,11,12,13,14,15,16-decahydro-3H-cyclopenta[a]phenanthrene-3,17(6H)-dione (1.8 g, 6.25 mmol) was dissolved in ethanol (50 mL) in a 100 mL single-necked flask. After stirring at room temperature for 2-3 minutes, to the solution was added the catalyst Pd/barium sulfate (300 mg). After completion of the addition, the reaction solution was stirred at room temperature under a hydrogen atmosphere for 5 hours. The reaction solution was filtrated, and dissolved in 20 mL of dichloromethane to precipitate a white solid. The mixture was filtrated, and the filtrate was concentrated by rotary evaporation to dryness. The crude product was purified by column chromatography (petroleum ether/ethyl acetate: 3/1) to obtain (5R,8S,9S,10R,13S,14S)-10-fluoro-13-methyltetradecahydro-3H-cyclopenta[a]phenanthrene-3,17(2H)-dione (600 mg, white solid, yield: 32.9%).

    [0180] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 2.63-2.45 (m, 2H), 2.43-2.33 (m, 3H), 2.30-1.80 (m, 8H), 1.75-1.55 (m, 5H), 1.45-1.35 (m, 3H), 1.25-1.18 (m, 1H), 0.94 (s, 3H).

    [0181] .sup.19F NMR (376 MHz, CDCl.sub.3) δ −159.89.

    Step 3: (3R,5R,8S,10R,13S,14S)-10-Fluoro-3-hydroxy-3,13-dimethylhexadecahydro-17H-cyclopenta[a]phenanthren-17-one

    [0182] ##STR00069##

    [0183] 2,6-Di-tert-butyl-4-methylphenol (1.45 g, 6.6 mmol) was dissolved in anhydrous toluene (15 mL) in a 100 mL three-necked flask. The solution was cooled to 0-5° C. in an ice bath, and trimethylaluminum (1.7 mL, 2 M, 3.3 mmol) was added dropwise under a nitrogen atmosphere. After completion of the addition, the reaction solution was naturally warmed to room temperature, and stirred for 1 hour. The reaction solution was cooled to −78° C., and then a solution of (5R,8S,9S,10R,13S,14S)-10-fluoro-13-methyltetradecahydro-3H-cyclopenta[a]phenanthrene-3,17(2H)-dione (320 mg, 1.1 mmol) in toluene (5 mL) was added dropwise to the above reaction solution. The reaction solution was reacted at −78° C. for 1 hour. After methylmagnesium bromide (1.0 mL, 3 M, 3 mmol) was added dropwise, the reaction solution was reacted at −78° C. for 1 hour. The reaction was quenched with saturated aqueous ammonium chloride solution, and the reaction solution was extracted with ethyl acetate (20 mL) to precipitate a large amount of white solid. The mixture was filtrated, and the filtrate was separated into two phases. The organic phase was dried over anhydrous sodium sulfate, and concentrated by rotary evaporation to dryness. The resulting residue was purified by column chromatography (petroleum ether/ethyl acetate: 2/1) to obtain (3R,5R,8S,10R,13S,14S)-10-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-17H-cyclopenta[a]phenanthren-17-one (250 mg, white solid, yield: 74.0%).

    [0184] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 2.46 (dd, J=19.3, 8.7 Hz, 1H), 2.17-1.72 (m, 8H), 1.71-1.44 (m, 10H), 1.38 (s, 3H), 1.34-1.11 (m, 3H), 0.90 (s, 3H).

    [0185] .sup.19F NMR (376 MHz, CDCl.sub.3) δ −158.16.

    Step 4: (3R,5R,8S,10R,13S,14S)-17-Ethylidene-10-fluoro-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-3-ol

    [0186] ##STR00070##

    [0187] Potassium tert-butoxide (500 mg, 4.5 mmol) and tetrahydrofuran (15 mL) were added successively to a 100 mL three-necked flask. The reaction solution was cooled to 0° C., and ethyltriphenylphosphine bromide (1.82 g, 4.8 mmol) was added in batches. The reaction solution was stirred at 60° C. for 2 hours, and then (3R,5R,8S,10R,13S,14S)-10-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-17H-cyclopenta[a]phenanthren-17-one (250 mg, 0.75 mmol) was added to the above reaction solution. The reaction solution was reacted at 60° C. for 8 hours. The reaction was quenched with saturated ammonium chloride solution, and then the reaction solution was extracted with ethyl acetate (20 mL) and washed with saturated saline (10 mL×2). The organic phase was dried over anhydrous sodium sulfate, filtrated and concentrated by rotary evaporation to dryness. The resulting residue was purified by column chromatography (petroleum ether/ethyl acetate: 5/1) to obtain (3R,5R,8S,10R,13S,14S)-17-ethylidene-10-fluoro-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-3-ol (110 mg, white solid, yield: 42%).

    [0188] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 5.15-5.08 (m, 1H), 2.40-1.80 (m, 8H), 1.65-1.45 (m, 13H), 1.36 (s, 3H), 1.31-1.05 (m, 4H), 0.89 (s, 3H).

    [0189] .sup.19F NMR (376 MHz, CDCl.sub.3) δ −157.91.

    Step 5: (3R,5R,8S,10R,13S,14S)-10-Fluoro-17-(1-hydroxyethyl)-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-3-ol

    [0190] ##STR00071##

    [0191] (3R,5R,8S,10R,13S,14S)-17-Ethylidene-10-fluoro-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-3-ol (110 mg, 0.35 mmol) was dissolved in dry tetrahydrofuran (5 mL). A complex of borane and tetrahydrofuran (1.1 mL, 1 M, 1.05 mmol) was added at room temperature. After completion of the addition, the reaction solution was stirred for 1 hour. The reaction solution was cooled in an ice-water bath, and NaOH (10%, 1.5 mL) was slowly added dropwise to produce a lot of gas. Hydrogen peroxide (30%, 2 mL) was slowly added dropwise, and the reaction solution was stirred at room temperature for 1 hour. The reaction solution was extracted with ethyl acetate (10 mL×2), and washed with 10% sodium thiosulfate solution. The organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain (3R,5R,8S,10R,13S,14S)-10-fluoro-17-(1-hydroxyethyl)-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-3-ol (100 mg, white solid).

    Step 6: 1-((3R,5R,8S,10R,13S,14S,17S)-10-Fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one

    [0192] ##STR00072##

    [0193] (3R,5R,8S,10R,13S,14S)-10-Fluoro-17-(1-hydroxyethyl)-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-3-ol (100 mg, 0.3 mmol) was dissolved in dichloromethane (5 mL). Pyridinium chlorochromate (130 mg, 0.6 mmol) was added, and the reaction solution was stirred at room temperature for 12 hours. The reaction solution was filtrated and concentrated under reduced pressure. The resulting residue was purified by column chromatography (petroleum ether/ethyl acetate: 5/1) to obtain 1-((3R,5R,8S,10R,13S,14S,17S)-10-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one (80 mg, white solid, yield: 81%).

    [0194] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 2.53 (t, J=9.0 Hz, 1H), 2.23-2.16 (m, 1H), 2.12 (s, 3H), 2.10-1.83 (m, 5H), 1.73-1.42 (m, 12H), 1.38 (s, 3H), 1.35-1.02 (m, 4H), 0.64 (s, 3H).

    Example 2

    1-(2-((3R,5R,8S,9S,10R,13S,14S,17S)-10-Fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile

    [0195] ##STR00073##

    Step 1: 2-Bromo-1-((3R,5R,8S,10R,13S,14S,17S)-10-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one

    [0196] ##STR00074##

    [0197] 1-((3R,5R,8S,10R,13S,14S,17S)-10-Fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one (80 mg, 0.25 mmol) was dissolved in methanol (5 mL). 3 Drops of hydrogen bromide and 3 drops of liquid bromine were added. After stirring at room temperature for 12 hours, the reaction solution was added to ice-water, and extracted with ethyl acetate (10 mL×2). The organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 2-bromo-1-((3R,5R,8S,10R,13S,14S,17S)-10-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one (80 mg, 81%), which was used directly in the next step.

    Step 2: 1-(2-((3R,5R,8S,9S,10R,13S,14S,17S)-10-Fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile

    [0198] ##STR00075##

    [0199] 2-Bromo-1-((3R,5R,8S,10R,13S,14S,17S)-10-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one (80 mg, 0.2 mmol) was dissolved in tetrahydrofuran (5 mL). 4-Cyanopyrazole (46 mg, 0.5 mmol) and potassium carbonate (84 mg, 0.6 mmol) were added, and the reaction solution was stirred at room temperature for 5 hours. The reaction solution was filtrated and concentrated, and the resulting residue was purified by prep-HPLC to obtain the product (25 mg, white solid, yield: 30.3%).

    [0200] MS m/z (ESI): 428.3[M+H].sup.+.

    [0201] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.87 (s, 1H), 7.81 (s, 1H), 5.10-4.83 (m, 2H), 2.60 (t, J=8.8 Hz, 1H), 2.28-2.18 (m, 1H), 2.15-2.07 (m, 2H), 2.05-1.75 (m, 5H), 1.69-1.45 (m, 10H), 1.38 (s, 3H), 1.35-1.23 (m, 3H), 1.19-1.07 (m, 1H), 0.70 (s, 3H).

    [0202] .sup.19F NMR (376 MHz, CDCl.sub.3) δ −158.28.

    Example 3 and Example 4

    1-(2-((3R,5R,8S,9S,10R,13S,14S,17S)-10-Fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-1H-pyrazole-3-carbonitrile (3)

    1-(2-((3R,5R,8S,9S,10R,13S,14S,17R)-10-Fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-1H-pyrazole-3-carbonitrile (4)

    [0203] ##STR00076##

    [0204] 2-Bromo-1-((3R,5R,8S,10R,13S,14S,17S)-10-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one (80 mg, 0.2 mmol) was dissolved in tetrahydrofuran (5 mL). 3-Cyanopyrazole (46 mg, 0.5 mmol) and potassium carbonate (84 mg, 0.6 mmol) were added, and the reaction solution was stirred at room temperature for 5 hours. The reaction solution was filtrated and concentrated, and the resulting residue was purified by prep-HPLC to obtain the product 1-(2-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-1H-pyrazole-3-carbonitrile (3) (18 mg, white solid, yield: 21.9%) and the product 1-(2-((3R,5R,8S,9S,10R,13S,14S,17R)-10-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-1H-pyrazole-3-carbonitrile (4) (5 mg, white solid, yield: 6.0%).

    Example 3

    [0205] MS m/z (ESI): 428.1[M+H].sup.+.

    [0206] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.50 (d, J=2.4 Hz, 1H), 6.74 (d, J=2.4 Hz, 1H), 5.15-4.85 (m, 2H), 2.60 (t, J=8.9 Hz, 1H), 2.26-2.16 (m, 1H), 2.05-1.90 (m, 2H), 1.85-1.73 (m, 3H), 1.67-1.43 (m, 12H), 1.38 (s, 3H), 1.38-1.25 (m, 3H), 1.18-1.06 (m, 1H), 0.71 (s, 3H).

    [0207] .sup.19F NMR (376 MHz, CDCl.sub.3) δ −158.21.

    Example 4

    [0208] MS m/z (ESI): 428.1 [M+H].sup.+.

    [0209] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.50 (d, J=2.4 Hz, 1H), 6.76 (d, J=2.4 Hz, 1H), 5.15-4.85 (m, 2H), 2.78 (dd, J=8.0, 2.8 Hz, 1H), 2.10-1.73 (m, 7H), 1.70-1.36 (m, 11H), 1.35 (s, 3H), 1.32-1.10 (m, 4H), 0.98 (s, 3H).

    [0210] .sup.19F NMR (376 MHz, CDCl.sub.3) δ −158.42.

    Example 5 and Example 6

    1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-Fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(3-(trifluoromethyl)-1H-pyrazol-1-yl)ethan-1-one (5)

    1-((3R,5R,8S,9S,10R,13S,14S,17R)-10-Fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(3-(trifluoromethyl)-1H-pyrazol-1-yl)ethan-1-one (6)

    [0211] ##STR00077##

    [0212] In accordance with Step 2 of Example 2, 2-bromo-1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one was used as the starting material, accordingly, the products 1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(1H-tetrazol-1-yl)ethan-1-one (5) (35.5 mg, white solid, yield: 43%) and 1-((3R,5R,8S,9S,10R,13S,14S,17R)-10-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(3-(trifluoromethyl)-1H-pyrazol-1-yl)ethan-1-one (6) (12.3 mg, white solid, yield: 14.9%) were obtained.

    Example 5

    [0213] MS m/z (ESI): 471.3[M+H].sup.+.

    [0214] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.48 (s, 1H), 6.59 (d, J=2.1 Hz, 1H), 5.05-4.92 (m, 2H), 2.59 (t, J=8.8 Hz, 1H), 2.25-2.15 (m, 1H), 2.15-2.05 (m, 2H), 2.03-1.69 (m, 5H), 1.70-1.41 (m, 12H), 1.38 (s, 3H), 1.06 (m, 4H), 0.71 (s, 3H).

    Example 6

    [0215] MS m/z (ESI): 471.3[M+H].sup.+.

    [0216] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.48 (d, J=1.3 Hz, 1H), 6.61 (d, J=2.3 Hz, 1H), 5.07-4.90 (m, 2H), 2.77 (dd, J=7.9, 3.0 Hz, 1H), 2.12-1.72 (m, 9H), 1.72-1.38 (m, 11H), 1.34 (s, 3H), 1.33-1.04 (m, 4H), 0.96 (s, 3H).

    Example 7 and Example 8

    1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-Fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(4-(trifluoromethyl)-1H-pyrazol-1-yl)ethan-1-one (7)

    1-((3R,5R,8S,9S,10R,13S,14S,17R)-10-Fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(4-(trifluoromethyl)-1H-pyrazol-1-yl)ethan-1-one (8)

    [0217] ##STR00078##

    [0218] In accordance with Step 2 of Example 2, 2-bromo-1-((3R,5R,8S,10R,13S,14S,17S)-10-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one was used as the starting material, accordingly, the product 1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(4-(trifluoromethyl)-1H-pyrazol-1-yl)ethan-1-one (7) (22 mg, white solid, yield: 32.9%) and the product 1 ((3R,5R,8S,9S,10R,13S,14S,17R)-10-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(4-(trifluoromethyl)-1H-pyrazol-1-yl)ethan-1-one (8) (8 mg, white solid, yield: 11.5%) were obtained.

    Example 7

    [0219] MS m/z (ESI): 471.2[M+H].sup.+.

    [0220] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.72 (s, 2H), 5.05-4.85 (m, 2H), 2.60 (t, J=8.0 Hz, 1H), 2.30-2.15 (m, 1H), 2.15-2.05 (m, 2H), 2.01-1.93 (m, 2H), 1.92-1.83 (m, 1H), 1.81-1.71 (m, 2H), 1.71-1.43 (m, 10H), 1.38 (s, 3H), 1.35-1.25 (m, 3H), 1.19-1.10 (m, 1H), 0.71 (s, 3H).

    [0221] .sup.19F NMR (376 MHz, CDCl.sub.3) δ −56.44, −158.26.

    Example 8

    [0222] MS m/z (ESI): 471.3[M+H].sup.+.

    [0223] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.74 (s, 1H), 7.73 (s, 1H), 5.29-5.19 (m, 2H), 2.79 (dd, J=7.9, 2.7 Hz, 1H), 2.10-2.03 (m, 1H), 1.95-1.75 (m, 6H), 1.65-1.25 (m, 17H), 1.19-1.10 (m, 1H), 0.98 (s, 3H).

    [0224] .sup.19F NMR (376 MHz, CDCl.sub.3) δ −56.42, −158.43.

    Example 9 and Example 10

    1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-Fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(1H-1,2,3-triazol-1-yl)ethan-1-one (9)

    1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-Fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(2H-1,2,3-triazol-2-yl)ethan-1-one (10)

    [0225] ##STR00079##

    [0226] In accordance with Step 2 of Example 2, 2-bromo-1-((3R,5R,8S,10R,13S,14S,17S)-10-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one was used as the starting material, accordingly, the product 1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(1H-1,2,3-triazol-1-yl)ethan-1-one (9) (32 mg, white solid, yield: 32.9%) and the product 1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(2H-1,2,3-triazol-2-yl)ethan-1-one (10) (20 mg, white solid, yield: 20.5%) were obtained.

    Example 9

    [0227] MS m/z (ESI): 404.2[M+H].sup.+.

    [0228] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.76 (s, 1H), 7.65 (s, 1H), 5.30-5.13 (m, 2H), 2.65 (t, J=8.0 Hz, 1H), 2.25-2.15 (m, 1H), 2.13-2.03 (m, 2H), 2.05-1.75 (m, 5H), 1.68-1.43 (m, 10H), 1.38 (s, 3H), 1.35-1.25 (m, 3H), 1.19-1.10 (m, 1H), 0.71 (s, 3H).

    [0229] .sup.19F NMR (376 MHz, CDCl.sub.3) δ −158.26.

    Example 10

    [0230] MS m/z (ESI): 404.2[M+H].sup.+.

    [0231] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.69 (s, 2H), 5.24 (s, 2H), 2.57 (t, J=8.0 Hz, 1H), 2.27-2.16 (m, 1H), 2.15-2.07 (m, 2H), 2.05-1.75 (m, 5H), 1.68-1.43 (m, 10H), 1.38 (s, 3H), 1.35-1.25 (m, 3H), 1.19-1.05 (m, 1H), 0.74 (s, 3H).

    [0232] .sup.19F NMR (376 MHz, CDCl.sub.3) δ −158.24.

    Example 11

    1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-Fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(4-methyl-1H-pyrazol-1-yl)ethan-1-one

    [0233] ##STR00080##

    [0234] In accordance with Step 2 of Example 2, 2-bromo-1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one was used as the starting material, accordingly, the product 1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(4-methyl-1H-pyrazol-1-yl)ethan-1-one (11) (24 mg, white solid, yield: 29%) was obtained.

    [0235] MS m/z (ESI): 417.3[M+H].sup.+.

    [0236] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.35 (s, 1H), 7.18 (s, 1H), 4.90-4.79 (m, 2H), 2.56 (t, J=8.9 Hz, 1H), 2.27-2.13 (m, 1H), 2.11 (s, 3H), 2.06-1.80 (m, 4H), 1.80-1.40 (m, 11H), 1.38 (s, 3H), 1.35-1.19 (m, 5H), 1.18-1.03 (m, 1H), 0.71 (s, 3H).

    Example 12 and Example 13

    1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-Fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(2H-tetrazol-2-yl)ethan-1-one (12)

    1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-Fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(1H-tetrazol-1-yl)ethan-1-one (13)

    [0237] ##STR00081##

    [0238] In accordance with Step 2 of Example 2, 2-bromo-1-((3R,5R,8S,10R,13S,14S,17S)-10-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one was used as the starting material, accordingly, the products 1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(2H-tetrazol-2-yl)ethan-1-one (12) (12 mg, white solid, yield: 16%) and 1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(1H-tetrazol-1-yl)ethan-1-one (13) (9 mg, white solid, yield: 12%) were obtained.

    Example 12

    [0239] MS m/z (ESI): 405.2[M+H].sup.+.

    [0240] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.57 (s, 1H), 5.46 (s, 2H), 2.64 (t, J=8.0 Hz, 1H), 2.28-2.19 (m, 1H), 2.18-2.07 (m, 2H), 2.05-1.75 (m, 4H), 1.71-1.43 (m, 11H), 1.38 (s, 3H), 1.34-1.26 (m, 3H), 1.21-1.11 (m, 1H), 0.75 (s, 3H).

    Example 13

    [0241] MS m/z (ESI): 405.2[M+H].sup.+.

    [0242] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.75 (s, 1H), 5.35-5.15 (m, 2H), 2.67 (t, J=8.0 Hz, 1H), 2.30-2.19 (m, 1H), 2.15-2.07 (m, 1H), 2.05-1.75 (m, 4H), 1.68-1.45 (m, 11H), 1.39 (s, 3H), 1.35-1.25 (m, 4H), 1.20-1.10 (m, 1H), 0.71 (s, 3H).

    Example 14 and Example 15

    2-(2H-Benzo[d][1,2,3]triazol-2-yl)-1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one (15)

    2-(1H-Benzo[d][1,2,3]triazol-1-yl)-1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one

    [0243] ##STR00082##

    [0244] In accordance with Step 2 of Example 2, 2-bromo-1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one was used as the starting material, accordingly, the products 2-(2H-benzo[d][1,2,3]triazol-2-yl)-1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one (14) (11 mg, yield: 14%) and 2-(1H-benzo[d][1,2,3]triazol-1-yl)-1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one (15) (31 mg, yield: 41%) were obtained.

    Example 14

    [0245] MS m/z (ESI): 453.3[M+H].sup.+.

    [0246] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.88 (dd, J=6.6, 3.0 Hz, 2H), 7.40 (dd, J=6.6, 3.0 Hz, 2H), 5.53 (t, J=4.7 Hz, 2H), 2.64 (t, J=8.9 Hz, 1H), 2.34-1.41 (m, 16H), 1.38 (s, 3H), 1.35-0.97 (m, 6H), 0.78 (s, 3H).

    Example 15

    [0247] MS m/z (ESI): 453.3[M+H].sup.+.

    [0248] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.11 (d, J=7.5 Hz, 1H), 7.50 (t, J=7.5 Hz, 1H), 7.46-7.30 (m, 2H), 5.42 (s, 2H), 2.70 (t, J=8.5 Hz, 1H), 2.35-1.42 (m, 16H), 1.38 (s, 3H), 1.35-1.01 (m, 6H), 0.77 (s, 3H).

    Example 16 and Example 17

    1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-Fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(2H-pyrazolo[3,4-c]pyridin-2-yl)ethan-1-one (16)

    1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-Fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(1H-pyrazolo[3,4-c]pyridin-1-yl)ethan-1-one (17)

    [0249] ##STR00083##

    [0250] In accordance with Step 2 of Example 2, 2-bromo-1-((3R,5R,8S,10R,13S,14S,17S)-10-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one was used as the starting material, accordingly, the products 1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(1H-tetrazol-1-yl)ethan-1-one (16) (9.2 mg, white solid, yield: 10.5%) and 1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(2H-tetrazol-2-yl)ethan-1-one (17) (16 mg, white solid, yield: 18.3%) were obtained.

    Example 16

    [0251] MS m/z (ESI): 454.2[M+H].sup.+.

    [0252] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 9.33 (s, 1H), 8.19 (s, 1H), 8.13 (s, 1H), 7.72 (s, 1H), 5.42-5.25 (m, 2H), 2.70 (t, J=8.0 Hz, 1H), 2.30-2.10 (m, 3H), 2.05-1.85 (m, 8H), 1.70-1.45 (m, 7H), 1.39 (s, 3H), 1.32-1.25 (m, 3H), 0.90-0.85 (m, 1H), 0.75 (s, 3H).

    Example 17

    [0253] MS m/z (ESI): 454.2[M+H].sup.+.

    [0254] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.88 (s, 1H), 8.36 (s, 1H), 8.13 (s, 1H), 7.71 (s, 1H), 5.32-5.25 (m, 2H), 2.69 (t, J=8.0 Hz, 1H), 2.25-2.10 (m, 3H), 2.05-1.75 (m, 5H), 1.70-1.45 (m, 10H), 1.39 (s, 3H), 1.35-1.25 (m, 3H), 1.20-1.10 (m, 1H), 0.76 (s, 3H).

    Example 18, Example 19 and Example 20

    2-(5-Fluoro-2H-benzo[d][1,2,3]triazol-2-yl)-1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one (18)

    2-(6-Fluoro-1H-benzo[d][1,2,3]triazol-1-yl)-1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one (19)

    2-(5-Fluoro-1H-benzo[d][1,2,3]triazol-1-yl)-1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one (20)

    [0255] ##STR00084##

    [0256] In accordance with Step 2 of Example 2, 2-bromo-1-((3R,5R,8S,10R,13S,14S,17S)-10-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one was used as the starting material, accordingly, 2-(5-fluoro-2H-benzo[d][1,2,3]triazol-2-yl)-1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one (18) (20 mg, white solid, yield: 14.9%), 2-(6-fluoro-1H-benzo[d][1,2,3]triazol-1-yl)-1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one (19) (18 mg, white solid, yield: 13.1%) and 2-(5-fluoro-1H-benzo[d][1,2,3]triazol-1-yl)-1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one (20) (19 mg, white solid, yield: 13.9%) were obtained.

    Example 18

    [0257] MS m/z (ESI): 472.3[M+H].sup.+.

    [0258] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.86 (dd, J=9.3, 4.7 Hz, 1H), 7.47 (dd, J=8.7, 1.9 Hz, 1H), 7.21 (m, 1H), 5.55-5.45 (m, 2H), 2.65 (t, J=8.8 Hz, 1H), 2.32-2.08 (m, 3H), 2.04-1.45 (m, 15H), 1.38 (s, 3H), 1.35-1.23 (m, 3H), 1.20-1.10 (m, 1H), 0.78 (s, 3H).

    Example 19

    [0259] MS m/z (ESI): 472.3[M+H].sup.+.

    [0260] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.04 (dd, J=8.9, 4.4 Hz, 1H), 7.20-7.10 (m, 1H), 6.99 (d, J=7.6 Hz, 1H), 5.45-5.35 (m, 2H), 2.69 (d, J=8.7 Hz, 1H), 2.31-2.08 (m, 3H), 2.04-1.45 (m, 15H), 1.39 (s, 3H), 1.35-1.25 (m, 3H), 1.20-1.10 (m, 1H), 0.76 (s, 3H).

    Example 20

    [0261] MS m/z (ESI): 472.3[M+H].sup.+.

    [0262] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.71 (d, J=7.9 Hz, 1H), 7.35-7.28 (m, 2H), 5.45-5.35 (m, 2H), 2.69 (d, J=8.7 Hz, 1H), 2.31-2.08 (m, 3H), 2.04-1.45 (m, 15H), 1.39 (s, 3H), 1.35-1.25 (m, 3H), 1.20-1.10 (m, 1H), 0.76 (s, 3H).

    Example 21 and Example 22

    1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-Fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(4,5,6,7-tetrahydro-2H-indazol-2-yl)ethan-1-one (21)

    1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-Fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(4,5,6,7-tetrahydro-1H-indazol-1-yl)ethan-1-one (22)

    [0263] ##STR00085##

    [0264] In accordance with Step 2 of Example 2, 2-bromo-1-((3R,5R,8S,10R,13S,14S,17S)-10-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one was used as the starting material, accordingly, 1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(4,5,6,7-tetrahydro-2H-indazol-2-yl)ethan-1-one (21) (15.0 mg, white solid, yield: 27.2%) and 1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(4,5,6,7-tetrahydro-1H-indazol-1-yl)ethan-1-one (22) (8.0 mg, white solid, yield: 12.1%) were obtained.

    Example 21

    [0265] MS m/z (ESI): 457.2[M+H].sup.+.

    [0266] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.10 (s, 1H), 4.90-4.85 (m, 2H), 2.72-2.66 (m, 2H), 2.62-2.52 (m, 3H), 2.25-1.40 (m, 22H), 1.37 (s, 3H), 1.33-1.23 (m, 3H), 1.17-1.07 (m, 1H), 0.71 (s, 3H).

    Example 22

    [0267] MS m/z (ESI): 457.2[M+H].sup.+.

    [0268] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.31 (s, 1H), 4.85-4.75 (m, 2H), 2.60-2.50 (m, 3H), 2.45-2.39 (m, 2H), 2.25-1.40 (m, 22H), 1.37 (s, 3H), 1.33-1.23 (m, 3H), 1.15-1.05 (m, 1H), 0.71 (s, 3H).

    Example 23

    1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-Fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-((4-fluorophenyl)amino)ethan-1-one

    [0269] ##STR00086##

    [0270] 2-Bromo-1-((3R,5R,8S,10R,13S,14S,17S)-10-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one (80 mg, 0.2 mmol) was dissolved in tetrahydrofuran (5 mL). 4-Fluoroaniline (42 mg, 0.4 mmol) and triethylamine (60 mg, 0.6 mmol) were added, and the reaction solution was stirred at room temperature for 5 hours. The reaction solution was concentrated, and the resulting residue was purified by prep-HPLC to obtain the product (18 mg, white solid, yield: 21%).

    [0271] MS m/z (ESI): 446.3[M+H].sup.+.

    [0272] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 6.94-6.88 (m, 2H), 6.58-6.53 (m, 2H), 3.96-3.85 (m, 2H), 2.57 (t, J=8.0 Hz, 1H), 2.30-2.20 (m, 1H), 2.15-2.06 (m, 1H), 2.05-1.71 (m, 6H), 1.68-1.43 (m, 10H), 1.38 (s, 3H), 1.34-1.20 (m, 3H), 1.18-1.07 (m, 1H), 0.68 (s, 3H).

    Example 24

    1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-Fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-((2-fluorophenyl)amino)ethan-1-one

    [0273] ##STR00087##

    [0274] In accordance with Example 23, 2-bromo-1-((3R,5R,8S,10R,13S,14S,17S)-10-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one was used as the starting material, accordingly, the product 1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-((2-fluorophenyl)amino)ethan-1-one (11 mg, white solid, yield: 20.5%) was obtained.

    [0275] MS m/z (ESI): 446.2[M+H].sup.+.

    [0276] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.04-6.92 (m, 2H), 6.71-6.61 (m, 1H), 6.60-6.52 (m, 1H), 4.03-3.86 (m, 2H), 2.58 (t, J=8.8 Hz, 1H), 2.33-1.44 (m, 18H), 1.38 (s, 3H), 1.33-1.05 (m, 4H), 0.69 (s, 3H).

    Example 25

    1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-Fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-((3-fluorophenyl)amino)ethan-1-one

    [0277] ##STR00088##

    [0278] In accordance with Example 23, 2-bromo-1-((3R,5R,8S,10R,13S,14S,17S)-10-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one was used as the starting material, accordingly, the product 1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-((3-fluorophenyl)amino)ethan-1-one (4.5 mg, white solid, yield: 7.0%) was obtained.

    [0279] MS m/z (ESI): 446.2[M+H].sup.+.

    [0280] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.15-7.07 (m, 1H), 6.51-6.38 (m, 2H), 6.30 (d, J=11.4 Hz, 1H), 3.98-3.85 (m, 2H), 2.57 (t, J=8.8 Hz, 1H), 2.12-1.64 (m, 18H), 1.38 (s, 3H), 1.30-1.26 (m, 3H), 1.18-1.11 (m, 1H), 0.68 (s, 3H).

    Example 26

    2-((2,4-Difluorophenyl)amino)-1-((3R,5R,8S,10R,13S,14S,17S)-10-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one

    [0281] ##STR00089##

    [0282] 2-Bromo-1-((3R,5R,8S,10R,13S,14S,17S)-10-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one (80 mg, 0.193 mmol) was dissolved in tetrahydrofuran (3 mL). 2,4-Difluoroaniline (37 mg, 0.289 mmol) and potassium carbonate (53 mg, 0.438 mmol) were added, and the reaction solution was stirred at room temperature for 16 hours. Water (15 mL) was added, and the reaction solution was extracted with ethyl acetate (20 mL×3). The organic phases were combined, washed with saturated saline (15 mL), dried over anhydrous sodium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by preparative chromatography to obtain a white solid, 2-((2,4-difluorophenyl)amino)-1-((3R,5R,8S,10R,13S,14S,17S)-10-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one (7 mg, yield: 7.8%).

    [0283] MS m/z (ESI): 464.2[M+H].sup.+.

    [0284] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 6.84-6.70 (m, 2H), 6.50-6.45 (m, 1H), 3.98-3.88 (m, 2H), 2.57 (t, J=8.9 Hz, 1H), 2.31-2.19 (m, 1H), 2.10 (m, 1H), 2.04-1.74 (m, 7H), 1.51-1.44 (m, 5H), 1.38 (s, 3H), 1.37-1.20 (m, 8H), 1.13 (m, 2H), 0.69 (s, 3H).

    Example 27

    5-Fluoro-2-((2-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)amino)benzonitrile

    [0285] ##STR00090##

    [0286] 2-Amino-5-fluorobenzonitrile (147 mg, 1.08 mmol) was dissolved in tetrahydrofuran (5 mL) at 0° C. Sodium hydride (29 mg, 0.72 mmol) was added, and the reaction solution was stirred at 0° C. for 40 minutes. A mixed solution of 2-bromo-1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one (150 mg, 0.36 mmol) and tetrahydrofuran (2 mL) was added, and the reaction solution was stirred at 0° C. for 30 minutes. Water (20 mL) was added, and the reaction solution was extracted with ethyl acetate (20 mL×3). The organic phases were combined, washed with saturated saline (30 mL), dried over anhydrous sodium sulfate and filtrated. The filtrate was concentrated under reduced pressure to dryness, and the resulting residue was purified by preparative chromatography to obtain 5-fluoro-2-((2-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)amino)benzonitrile (10 mg, white solid, yield: 6%).

    [0287] MS m/z (ESI): 471.2 [M+H].sup.+.

    [0288] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.62 (dd, J=9.6, 3.0 Hz, 1H), 7.10-7.01 (m, 1H), 6.62 (dd, J=9.1, 4.5 Hz, 1H), 4.90-4.73 (m, 2H), 2.58 (t, J=8.8 Hz, 1H), 2.28-1.78 (m, 9H), 1.65-1.58 (m, 3H), 1.61-1.44 (m, 4H), 1.38 (s, 3H), 1.31-1.26 (m, 4H), 1.15-1.09 (m, 2H), 0.90-0.86 (m, 2H), 0.73 (s, 3H).

    Example 28

    1-((3S,5R,8S,9S,10R,13S,14S,17S)-10-Fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-((3-fluoropyridin-4-yl)amino)ethan-1-one

    [0289] ##STR00091##

    [0290] 4-Amino-3-fluoropyridine (32.4 mg, 0.28 mmol) and 2-bromo-1-((3S,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one (60 mg, 0.14 mmol) were dissolved in N,N-dimethylformamide (5 mL). Triethylamine (42.5 mg, 0.42 mmol) was added, and the reaction solution was stirred at room temperature overnight. 5 mL of water was added, and the reaction solution was extracted with ethyl acetate (30 mL×3). The organic phase was washed with saturated saline (20 mL) once, dried over anhydrous sodium sulfate and concentrated by rotary evaporation to dryness. The resulting residue was purified by prep-HPLC to obtain the product 1-((3S,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-((3-fluoropyridin-4-yl)amino)ethan-1-one (6.1 mg, white solid, yield: 9.7%). MS m/z (ESI): 447.2[M+H].sup.+.

    Example 29

    1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-Fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(pyridazin-4-yloxy)ethan-1-one

    [0291] ##STR00092##

    [0292] In accordance with Step 2 of Example 2, 2-bromo-1-((3R,5R,8S,10R,13S,14S,17S)-10-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one was used as the starting material, accordingly, the product 1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(pyridazin-4-yloxy)ethan-1-one (19 mg, white solid, yield 30.5%) was obtained.

    [0293] MS m/z (ESI): 431.2[M+H].sup.+.

    [0294] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.92 (s, 1H), 7.72 (s, 1H), 6.60 (s, 1H), 4.99-4.73 (m, 2H), 2.67-2.54 (m, 1H), 2.32-1.49 (m, 18H), 1.38 (s, 3H), 1.31-1.01 (m, 4H), 0.71 (s, 3H).

    Example 30 and Example 32

    5-Fluoro-2-(2-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethoxy)benzonitrile (30)

    5-Fluoro-2-(2-((3R,5R,8S,9S,10R,13S,14S,17R)-10-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethoxy)benzonitrile (32)

    [0295] ##STR00093##

    [0296] In accordance with Step 2 of Example 2, 2-bromo-1-((3R,5R,8S,10R,13S,14S,17S)-10-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one was used as the starting material, accordingly, the products 5-fluoro-2-(2-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethoxy)benzonitrile (30) (14.5 mg, white solid, yield: 21.2%) and 5-fluoro-2-(2-((3R,5R,8S,9S,10R,13S,14S,17R)-10-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethoxy)benzonitrile (32) (13.5 mg, white solid, yield: 19.8%) were obtained.

    Example 30

    [0297] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.31 (dd, J=7.4, 3.1 Hz, 1H), 7.25-7.18 (m, 1H), 6.74 (dd, J=9.3, 4.0 Hz, 1H), 4.69-4.53 (m, 2H), 2.90 (t, J=8.7 Hz, 1H), 2.32-1.43 (m, 18H), 1.37 (s, 3H), 1.31-1.03 (m, 4H), 0.70 (s, 3H).

    Example 32

    [0298] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.37-7.32 (m, 1H), 7.25-7.17 (m, 2H), 5.67-5.40 (m, 2H), 3.40 (t, J=8.9 Hz, 1H), 2.44-1.08 (m, 25H), 0.73 (s, 3H).

    Example 31

    3-Fluoro-4-(2-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethoxy)benzonitrile

    [0299] ##STR00094##

    [0300] In accordance with Step 2 of Example 2, 2-bromo-1-((3R,5R,8S,10R,13S,14S,17S)-10-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one was used as the starting material, accordingly, the product 3-fluoro-4-(2-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethoxy)benzonitrile (13 mg, white solid, yield 19.0%) was obtained.

    [0301] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.50-7.34 (m, 2H), 6.86 (t, J=8.4 Hz, 1H), 4.76-4.59 (m, 2H), 2.79 (t, J=8.9 Hz, 1H), 2.29-1.42 (m, 17H), 1.38 (s, 3H), 1.34-1.07 (m, 5H), 0.70 (s, 3H).

    Example 33

    4-(2-((3R,5R,8S,9S,10R,13S,14S,17S)-10-Fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethoxy)benzonitrile

    [0302] ##STR00095##

    [0303] In accordance with Step 2 of Example 2, 2-bromo-1-((3R,5R,8S,10R,13S,14S,17S)-10-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one was used as the starting material, accordingly, the product 4-(2-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethoxy)benzonitrile (27.5 mg, white solid, yield: 41.9%) was obtained.

    [0304] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.60 (d, J=8.8 Hz, 2H), 6.92 (d, J=8.8 Hz, 2H), 4.65-4.52 (m, 2H), 2.77 (t, J=8.7 Hz, 1H), 2.24-1.49 (m, 18H), 1.38 (s, 3H), 1.32-1.25 (m, 3H), 1.18-1.06 (m, 1H), 0.71 (s, 3H).

    Example 34

    4-Fluoro-3-(2-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethoxy)benzonitrile

    [0305] ##STR00096##

    [0306] In accordance with Step 2 of Example 2, 2-bromo-1-((3R,5R,8S,10R,13S,14S,17S)-10-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one was used as the starting material, accordingly, the product 4-fluoro-3-(2-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethoxy)benzonitrile (32 mg, white solid, yield: 46.9%) was obtained.

    [0307] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.36-7.27 (m, 1H), 7.20 (dd, J=10.6, 8.4 Hz, 1H), 7.11 (dd, J=7.6, 1.9 Hz, 1H), 4.76-4.51 (m, 2H), 2.77 (t, J=8.9 Hz, 1H), 2.24-1.51 (m, 18H), 1.38 (s, 3H), 1.32-1.23 (m, 3H), 1.19-1.06 (m, 1H), 0.71 (s, 3H).

    Example 35

    2-Fluoro-4-(2-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethoxy)benzonitrile

    [0308] ##STR00097##

    [0309] In accordance with Step 2 of Example 2, 2-bromo-1-((3R,5R,8S,10R,13S,14S,17S)-10-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one was used as the starting material, accordingly, the product 2-fluoro-4-(2-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethoxy)benzonitrile (23 mg, white solid, yield: 33.7%) was obtained.

    [0310] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.36-7.27 (m, 1H), 7.20 (dd, J=10.6, 8.4 Hz, 1H), 7.11 (dd, J=7.6, 1.9 Hz, 1H), 4.76-4.51 (m, 2H), 2.77 (t, J=8.9 Hz, 1H), 2.24-1.51 (m, 18H), 1.38 (s, 3H), 1.32-1.23 (m, 3H), 1.19-1.06 (m, 1H), 0.71 (s, 3H).

    Example 36

    2-(2,4-Difluorophenoxy)-1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one

    [0311] ##STR00098##

    [0312] In accordance with Step 2 of Example 2, 2-bromo-1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-3,13,15-trimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one was used as the starting material, accordingly, the product 2-(2,4-difluorophenoxy)-1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one (16.4 mg, white solid, yield: 24.4%) was obtained.

    [0313] .sup.1H NMR (400 MHz, Chloroform-d) δ 6.95-6.83 (m, 2H), 6.82-6.69 (m, 1H), 4.67-4.45 (m, 2H), 2.81 (t, J=8.8 Hz, 1H), 2.36-2.16 (m, 1H), 2.14-2.04 (m, 1H), 2.03-1.78 (m, 4H), 1.76-1.69 (m, 1H), 1.65-1.44 (m, 11H), 1.37 (s, 3H), 1.32-1.21 (m, 3H), 1.19-0.99 (m, 1H), 0.69 (s, 3H).

    Example 37

    2-(4-Chloro-1H-pyrazol-1-yl)-1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one

    [0314] ##STR00099##

    [0315] In accordance with Step 2 of Example 2, 2-bromo-1-((3R,5R,8S,10R,13S,14S,17S)-10-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one was used as the starting material, accordingly, the product 2-(4-chloro-1H-pyrazol-1-yl)-1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one (22 mg, white solid, yield: 34.9%) was obtained.

    [0316] MS m/z (ESI): 437.2[M+H].sup.+.

    [0317] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.46 (s, 1H), 7.42 (s, 1H), 5.04-4.62 (m, 2H), 2.57 (t, J=8.8 Hz, 1H), 2.31-1.45 (m, 18H), 1.38 (s, 3H), 1.33-1.23 (m, 3H), 1.18-1.05 (m, 1H), 0.70 (s, 3H).

    Example 38 and Example 39

    1-(2-((3R,5R,8S,9S,10R,13S,14S,17S)-10-Fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-3-methyl-1H-pyrazole-4-carbonitrile (38)

    1-(2-((3R,5R,8S,9S,10R,13S,14S,17S)-10-Fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-5-methyl-1H-pyrazole-4-carbonitrile (39)

    [0318] ##STR00100##

    [0319] In accordance with Step 2 of Example 2, 2-bromo-1-((3R,5R,8S,10R,13S,14S,17S)-10-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one was used as the starting material, accordingly, the products 1-(2-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-3-methyl-1H-pyrazole-4-carbonitrile (38) (16.5 mg, white solid, yield: 19.5%) and 1-(2-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-5-methyl-1H-pyrazole-4-carbonitrile (39) (9.5 mg, white solid, yield: 11%) were obtained.

    Example 38

    [0320] MS m/z (ESI): 442.2[M+H].sup.+.

    [0321] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.75 (s, 1H), 4.96-4.79 (m, 2H), 2.65-2.54 (m, 1H), 2.38 (s, 3H), 2.17-1.58 (m, 18H), 1.38 (s, 3H), 1.33-1.24 (m, 3H), 1.18-1.06 (m, 1H), 0.70 (s, 3H).

    Example 39

    [0322] MS m/z (ESI): 442.2[M+H].sup.+.

    [0323] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.71 (s, 1H), 4.86-4.80 (m, 2H), 2.61-2.54 (m, 1H), 2.33 (s, 3H), 2.23-1.55 (m, 18H), 1.38 (s, 3H), 1.30-1.27 (m, 3H), 1.15-1.11 (m, 1H), 0.71 (s, 3H).

    Example 40

    3-Cyclopropyl-1-(2-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile

    [0324] ##STR00101##

    [0325] In accordance with Step 2 of Example 2, 2-bromo-1-((3R,5R,8S,10R,13S,14S,17S)-10-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one was used as the starting material, accordingly, the product 3-cyclopropyl-1-(2-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile (15 mg, white solid, yield: 22.2%) was obtained.

    [0326] MS m/z (ESI): 468.2[M+H].sup.+.

    [0327] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.72 (s, 1H), 4.92-4.72 (m, 2H), 2.57 (t, J=8.8 Hz, 1H), 2.26-1.40 (m, 19H), 1.38 (s, 3H), 1.37-1.05 (m, 4H), 1.05-0.91 (m, 4H), 0.69 (s, 3H).

    Example 41 and Example 42

    1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-Fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(5-methyl-2H-tetrazol-2-yl)ethan-1-one (41)

    1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-Fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(5-methyl-1H-tetrazol-1-yl)ethan-1-one (42)

    [0328] ##STR00102##

    [0329] In accordance with Step 2 of Example 2, 2-bromo-1-((3R,5R,8S,10R,13S,14S,17S)-10-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one was used as the starting material, accordingly, the products 1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(5-methyl-2H-tetrazol-2-yl)ethan-1-one (41) (23 mg, white solid, yield: 22.8%) and 1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(5-methyl-1H-tetrazol-1-yl)ethan-1-one (42) (6.5 mg, white solid, yield: 6.5%) were obtained.

    Example 41

    [0330] MS m/z (ESI): 419.2[M+H].sup.+.

    [0331] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 5.46-5.27 (m, 2H), 2.63 (d, J=8.5 Hz, 1H), 2.57 (s, 3H), 2.31-1.46 (m, 18H), 1.38 (s, 3H), 1.35-1.03 (m, 4H), 0.75 (s, 3H).

    Example 42

    [0332] MS m/z (ESI): 419.2[M+H].sup.+.

    [0333] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 5.19-5.02 (m, 2H), 2.66 (t, J=8.5 Hz, 1H), 2.48 (s, 3H), 2.30-1.48 (m, 18H), 1.39 (s, 3H), 1.33-1.07 (m, 4H), 0.72 (s, 3H).

    Example 43

    1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-Fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(thiazol-2-ylamino)ethan-1-one

    [0334] ##STR00103##

    [0335] In accordance with Step 2 of Example 2, 2-bromo-1-((3R,5R,8S,10R,13S,14S,17S)-10-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one was used as the starting material, accordingly, the product 1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(thiazol-2-ylamino)ethan-1-one (13 mg, white solid, yield: 20.7%) was obtained.

    [0336] MS m/z (ESI): 435.2[M+H].sup.+.

    [0337] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 6.37 (d, J=4.9 Hz, 1H), 5.92 (d, J=4.9 Hz, 1H), 4.70-4.46 (m, 2H), 2.68 (t, J=8.9 Hz, 1H), 2.32-1.46 (m, 17H), 1.37 (s, 3H), 1.35-1.20 (m, 4H), 1.16-1.06 (m, 1H), 0.70 (s, 3H).

    Example 44

    1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-Fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-((1-methyl-1H-pyrazol-4-yl)amino)ethan-1-one

    [0338] ##STR00104##

    [0339] In accordance with Example 23, 2-bromo-1-((3R,5R,8S,10R,13S,14S,17S)-10-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one was used as the starting material, accordingly, the product 1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-((1-methyl-1H-pyrazol-4-yl)amino)ethan-1-one (8.2 mg, white solid, yield: 13.2%) was obtained.

    [0340] MS m/z (ESI): 432.3[M+H].sup.+.

    [0341] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.30 (s, 1H), 7.26 (s, 1H), 3.94-3.88 (m, 2H), 3.83 (s, 3H), 2.52 (t, J=8.7 Hz, 1H), 2.27-1.46 (m, 16H), 1.37 (s, 3H), 1.33-1.05 (m, 6H), 0.65 (s, 3H).

    Example 45

    1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-Fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(isoxazol-4-ylamino)ethan-1-one

    [0342] ##STR00105##

    [0343] In accordance with Step 2 of Example 2, 2-bromo-1-((3R,5R,8S,10R,13S,14S,17S)-10-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one was used as the starting material, accordingly, the product 1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(isoxazol-4-ylamino)ethan-1-one (8.5 mg, white solid, yield 14.0%) was obtained.

    [0344] MS m/z (ESI): 419.2[M+H].sup.+.

    [0345] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.08 (s, 1H), 7.91 (s, 1H), 3.85-3.65 (m, 2H), 2.53 (t, J=8.7 Hz, 1H), 2.23-1.72 (m, 8H), 1.51-1.13 (m, 17H), 0.67 (s, 3H).

    Example 46, Example 47 and Example 48

    1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-Fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(5-methoxy-2H-benzo[d][1,2,3]triazol-2-yl)ethan-1-one (46)

    1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-Fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(6-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)ethan-1-one (47)

    1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-Fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)ethan-1-one (48)

    [0346] ##STR00106##

    [0347] In accordance with Step 2 of Example 2, 2-bromo-1-((3R,5R,8S,10R,13S,14S,17S)-10-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one was used as the starting material, accordingly, the products 1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(5-methoxy-2H-benzo[d][1,2,3]triazol-2-yl)ethan-1-one (46) (13.5 mg, white solid, yield: 11.6%), 1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(6-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)ethan-1-one (47) (14 mg, white solid, yield: 12.0%) and 1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)ethan-1-one (48) (14 mg, white solid, yield: 12.0%) were obtained.

    Example 46

    [0348] MS m/z (ESI): 484.2[M+H].sup.+.

    [0349] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.75-7.70 (m, 1H), 7.11-7.04 (m, 2H), 5.49-5.40 (m, 2H), 3.88 (s, 3H), 2.62 (t, J=8.8 Hz, 1H), 2.30-1.46 (m, 18H), 1.38 (s, 3H), 1.34-1.10 (m, 4H), 0.78 (s, 3H).

    Example 47

    [0350] MS m/z (ESI): 484.2[M+H].sup.+.

    [0351] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.39 (d, J=2.2 Hz, 1H), 7.22 (d, J=9.0 Hz, 1H), 7.15 (dd, J=9.0, 2.2 Hz, 1H), 5.39-5.35 (m, 2H), 3.90 (s, 3H), 2.70-2.64 (m, 1H), 2.26-1.45 (m, 18H), 1.38 (s, 3H), 1.32-1.12 (m, 4H), 0.76 (s, 3H).

    Example 48

    [0352] MS m/z (ESI): 484.2[M+H].sup.+.

    [0353] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.92 (d, J=9.1 Hz, 1H), 7.01 (dd, J=9.1, 2.2 Hz, 1H), 6.60 (d, J=2.2 Hz, 1H), 5.35-5.31 (m, 2H), 3.87 (s, 3H), 2.73-2.65 (m, 1H), 2.26-1.46 (m, 18H), 1.38 (s, 3H), 1.34-1.10 (m, 4H), 0.77 (s, 3H).

    Example 49

    1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-Fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(pyrimidin-5-yloxy)ethan-1-one

    [0354] ##STR00107##

    [0355] In accordance with Step 2 of Example 2, 2-bromo-1-((3R,5R,8S,10R,13S,14S,17S)-10-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one was used as the starting material, accordingly, the product 1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(pyrimidin-5-yloxy)ethan-1-one (10.3 mg, white solid, yield: 20.0%) was obtained.

    [0356] MS m/z (ESI): 431.2[M+H].sup.+.

    [0357] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.92 (s, 1H), 8.44 (s, 2H), 4.78-4.63 (m, 2H), 2.75-2.70 (m, 1H), 2.29-2.20 (m, 1H), 2.15-2.05 (m, 3H), 2.02-1.93 (m, 3H), 1.92-1.82 (m, 1H), 1.81-1.73 (m, 2H), 1.62-1.60 (m, 2H), 1.59-1.43 (m, 6H), 1.38 (s, 3H), 1.35-1.25 (m, 3H), 1.20-1.07 (m, 1H), 0.72 (s, 3H).

    Example 50

    1-(2-((3R,5R,8S,9S,10R,13S,14S,17S)-10-Fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-1H-pyrazole-3,5-dicarbonitrile

    [0358] ##STR00108##

    [0359] In accordance with Step 2 of Example 2, 2-bromo-1-((3R,5R,8S,10R,13S,14S,17S)-10-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one was used as the starting material, accordingly, the product 1-(2-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-1H-pyrazole-3,5-dicarbonitrile (26 mg, white solid, yield: 39.7%) was obtained.

    [0360] MS m/z (ESI): 451.2[M−H].sup.−.

    [0361] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.21 (s, 1H), 5.19-5.14 (m, 2H), 2.63 (t, J=8.9 Hz, 1H), 2.29-1.49 (m, 18H), 1.38 (s, 3H), 1.32-1.30 (m, 3H), 1.20-1.10 (m, 1H), 0.75 (s, 3H).

    Example 51

    3-Chloro-1-(2-((3R,5R,8S,10R,13S,14S,17S)-10-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile

    [0362] ##STR00109##

    [0363] In accordance with Step 2 of Example 2, 2-bromo-1-((3R,5R,8S,10R,13S,14S,17S)-10-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one was used as the starting material, accordingly, the product 3-chloro-1-(2-((3R,5R,8S,10R,13S,14S,17S)-10-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile (12 mg, white solid, yield: 22%) was obtained.

    [0364] MS m/z (ESI): 462.2 [M+H].sup.+.

    [0365] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.82 (s, 1H), 4.98-4.85 (m, 2H), 2.58 (t, J=8.5 Hz, 1H), 2.26-2.18 (m, 1H), 2.15-1.75 (m, 7H), 1.66-1.45 (m, 10H), 1.40-1.25 (m, 7H), 1.15-1.09 (m, 1H), 0.70 (s, 3H).

    Example 52

    1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-Fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(4-(oxazol-2-yl)-1H-pyrazol-1-yl)ethan-1-one

    [0366] ##STR00110##

    Step 1: Preparation of 2-(1H-pyrazol-4-yl)oxazole

    [0367] ##STR00111##

    [0368] A mixture of 1H-pyrazole-4-carbaldehyde (0.8 g, 8.33 mmol), 1-((isocyanomethyl)sulfonyl)-4-methylbenzene (1.79 g, 9.16 mmol), potassium carbonate (2.53 g, 18.33 mmol) and methanol (20 mL) were stirred at 70° C. for 16 hours. The reaction solution was concentrated under reduced pressure to dryness, and the resulting residue was purified by column chromatography (dichloromethane/methanol=10:1) to obtain a white solid, 2-(1H-pyrazol-4-yl)oxazole (160 mg, yield: 14%).

    [0369] MS m/z (ESI): 136.2 [M+H].sup.+.

    [0370] .sup.1H NMR (400 MHz, DMSO) δ 13.19 (s, 1H), 8.30 (s, 1H), 8.15 (s, 1H), 7.83 (s, 1H), 7.26 (s, 1H).

    Step 2: 1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-Fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(4-(oxazol-2-yl)-1H-pyrazol-1-yl)ethan-1-one

    [0371] ##STR00112##

    [0372] A mixture of 2-bromo-1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one (60 mg, 0.14 mmol), 2-(1H-pyrazol-4-yl)oxazole (28 mg, 0.21 mmol), potassium carbonate (39 mg, 0.28 mmol) and tetrahydrofuran (3 mL) were stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure to dryness, and the resulting residue was purified by preparative chromatography to obtain 1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(4-(oxazol-2-yl)-1H-pyrazol-1-yl)ethan-1-one (13 mg, white solid, yield: 20%).

    [0373] MS m/z (ESI): 470.2 [M+H].sup.+.

    [0374] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.85 (s, 1H), 7.76 (s, 1H), 7.69 (s, 1H), 7.13 (s, 1H), 4.99-4.89 (m, 2H), 2.61 (t, J=8.8 Hz, 1H), 2.28-2.18 (m, 1H), 2.15-2.08 (m, 2H), 2.03-1.82 (m, 4H), 1.78-1.76 (m, 2H), 1.64-1.62 (m, 3H), 1.52-1.43 (m, 5H), 1.38 (s, 3H), 1.31-1.26 (m, 4H), 1.16-1.11 (m, 2H), 0.73 (s, 3H).

    Example 53 and Example 54

    1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-Fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(6-(2-hydroxypropan-2-yl)-1H-benzo[d]imidazol-1-yl)ethan-1-one (53)

    1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-Fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(5-(2-hydroxypropan-2-yl)-1H-benzo[d]imidazol-1-yl)ethan-1-one (54)

    [0375] ##STR00113##

    [0376] In accordance with Step 2 of Example 2, 2-bromo-1-((3R,5R,8S,10R,13S,14S,17S)-10-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one was used as the starting material, accordingly, 1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(6-(2-hydroxypropan-2-yl)-1H-benzo[d]imidazol-1-yl)ethan-1-one (53) (20 mg, white solid, yield: 27.1%) and 1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(5-(2-hydroxypropan-2-yl)-1H-benzo[d]imidazol-1-yl)ethan-1-one (54) (15 mg, white solid, yield: 20.3%) were obtained.

    Example 53

    [0377] MS m/z (ESI): 511.3 [M+H].sup.+.

    [0378] .sup.1H NMR (400 MHz, Chloroform-d) δ 7.93 (s, 1H), 7.87 (s, 1H), 7.51 (d, J=8.5 Hz, 1H), 7.14 (d, J=8.5 Hz, 1H), 4.96-4.84 (m, 2H), 2.64 (t, J=8.7 Hz, 1H), 2.31-2.17 (m, 1H), 2.16-2.06 (m, 2H), 2.04-1.93 (m, 2H), 1.92-1.75 (m, 2H), 1.71-1.43 (m, 15H), 1.39 (s, 3H), 1.35-1.20 (m, 5H), 1.18-1.05 (m, 1H), 0.75 (s, 3H).

    Example 54

    [0379] MS m/z (ESI): 511.3 [M+H].sup.+.

    [0380] .sup.1H NMR (400 MHz, Chloroform-d) δ 8.19 (s, 1H), 7.77 (d, J=8.5 Hz, 1H), 7.46 (s, 1H), 7.39 (d, J=8.1 Hz, 1H), 5.12-4.89 (m, 2H), 2.68 (t, J=8.2 Hz, 1H), 2.31-2.06 (m, 7H), 2.04-1.47 (m, 15H), 1.38 (s, 3H), 1.35-1.21 (m, 5H), 1.20-1.02 (m, 1H), 0.75 (s, 3H).

    Example 55

    1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-Fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(4-(methylthio)-1H-pyrazol-1-yl)ethan-1-one

    [0381] ##STR00114##

    [0382] In accordance with Step 2 of Example 2, 2-bromo-1-((3R,5R,8S,10R,13S,14S,17S)-10-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one was used as the starting material, accordingly, the product 1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(4-(methylthio)-1H-pyrazol-1-yl)ethan-1-one (25 mg, white solid, yield: 38%) was obtained.

    [0383] MS m/z (ESI): 449.2 [M+H].sup.+.

    [0384] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.53 (s, 1H), 7.43 (s, 1H), 4.95-4.85 (m, 2H), 2.58 (t, J=8.9 Hz, 1H), 2.35 (s, 3H), 2.25-2.17 (m, 1H), 2.10 (d, J=11.4 Hz, 2H), 2.02-1.82 (m, 4H), 1.77-1.74 (m, 2H), 1.68-1.42 (m, 9H), 1.38 (s, 3H), 1.35-1.21 (m, 4H), 1.17-1.04 (m, 1H), 0.71 (s, 3H).

    Example 56

    1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-Fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(4-(methylsulfinyl)-1H-pyrazol-1-yl)ethan-1-one

    [0385] ##STR00115##

    [0386] 1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-Fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(4-(methylthio)-1H-pyrazol-1-yl)ethan-1-one (35 mg, 0.078 mmol) was dissolved in dichloromethane (3 mL). m-Chloroperoxybenzoic acid (17 mg, 0.0858 mmol) was added, and the reaction solution was stirred at −78° C. for 2 hours. The reaction was quenched with saturated sodium sulfite solution, and the reaction solution was extracted with ethyl acetate (20 mL×3). The organic phases were combined, washed with saturated saline (30 mL), dried over anhydrous sodium sulfate and filtrated. The filtrate was concentrated under reduced pressure to dryness, and the resulting residue was purified by preparative chromatography to obtain a white solid, 1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(4-(methylsulfinyl)-1H-pyrazol-1-yl)ethan-1-one (25 mg, white solid, yield: 69%).

    [0387] MS m/z (ESI): 465.2 [M+H].sup.+.

    [0388] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.81 (d, J=4.6 Hz, 2H), 4.96-4.85 (m, 2H), 2.90 (s, 3H), 2.61 (t, J=8.7 Hz, 1H), 2.27-2.17 (m, 1H), 2.13-2.07 (m, 2H), 2.04-1.73 (m, 4H), 1.66-1.62 (m, 4H), 1.50-1.48 (m, 5H), 1.38 (s, 3H), 1.33-1.22 (m, 5H), 1.14-1.11 (m, 2H), 0.71 (s, 3H).

    Example 57

    1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-Fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(4-(methylsulfonyl)-1H-pyrazol-1-yl) ethan-1-one

    [0389] ##STR00116##

    [0390] 1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-Fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(4-(methylthio)-1H-pyrazol-1-yl)ethan-1-one (15 mg, 0.033 mmol) was dissolved in dichloromethane (3 mL). T m-Chloroperoxybenzoic acid (17 mg, 0.1 mmol) was added, and the reaction solution was stirred at room temperature for 6 hours. The reaction solution was concentrated under reduced pressure to dryness, and the resulting residue was purified by preparative chromatography to obtain 1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(4-(methylsulfonyl)-1H-pyrazol-1-yl)ethan-1-one (10 mg, white solid, yield: 63%).

    [0391] MS m/z (ESI): 481.2 [M+H].sup.+.

    [0392] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.93 (s, 1H), 7.87 (s, 1H), 4.99-4.90 (m, 2H), 3.13 (s, 3H), 2.62 (t, J=8.7 Hz, 1H), 2.24-2.20 (m, 1H), 2.12-2.09 (m, 2H), 2.03-1.74 (m, 5H), 1.66-1.63 (m, 4H), 1.53-1.42 (m, 6H), 1.38 (s, 3H), 1.28-1.26 (m, 3H), 1.15 (m, 1H), 0.89-0.86 (m, 1H), 0.71 (s, 3H).

    Example 58

    1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-Fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(4-nitro-1H-pyrazol-1-yl)ethan-1-one

    [0393] ##STR00117##

    [0394] In accordance with Step 2 of Example 2, 2-bromo-1-((3R,5R,8S,10R,13S,14S,17S)-10-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one was used as the starting material, accordingly, the product 1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(4-nitro-1H-pyrazol-1-yl)ethan-1-one (39 mg, white solid, yield: 60.3%) was obtained.

    [0395] MS m/z (ESI): 448.2[M+H].sup.+.

    [0396] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.18 (s, 1H), 8.08 (s, 1H), 5.08-4.81 (m, 2H), 2.62 (t, J=8.7 Hz, 1H), 2.30-1.46 (m, 16H), 1.38 (s, 3H), 1.34-1.04 (m, 6H), 0.71 (s, 3H).

    Example 59

    Ethyl 1-(2-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-1H-pyrazole-4-carboxylate

    [0397] ##STR00118##

    [0398] In accordance with Step 2 of Example 2, 2-bromo-1-((3R,5R,8S,10R,13S,14S,17S)-10-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one was used as the starting material, accordingly, the product ethyl 1-(2-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-1H-pyrazole-4-carboxylate (32 mg, white solid, yield: 46.6%) was obtained.

    [0399] MS m/z (ESI): 475.3[M+H].sup.+.

    [0400] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.94 (s, 1H), 7.92 (s, 1H), 5.04-4.80 (m, 2H), 4.38-4.19 (m, 2H), 2.60 (t, J=8.7 Hz, 1H), 2.27-1.45 (m, 21H), 1.38 (s, 3H), 1.37-1.25 (m, 3H), 1.20-1.07 (m, 1H), 0.71 (s, 3H).

    Example 60

    1-(2-((3R,5R,8S,9S,10R,13S,14S,17S)-10-Fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-N,N-dimethyl-1H-pyrazole-4-carboxamide

    [0401] ##STR00119##

    [0402] In accordance with Step 2 of Example 2, 2-bromo-1-((3R,5R,8S,10R,13S,14S,17S)-10-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one was used as the starting material, accordingly, the product 1-(2-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-N,N-dimethyl-1H-pyrazole-4-carboxamide (10 mg, white solid, yield: 14.6%) was obtained.

    [0403] MS m/z (ESI): 474.3[M+H].sup.+.

    [0404] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.75 (s, 2H), 5.09-4.82 (m, 2H), 3.16 (s, 6H), 2.69-2.53 (m, 1H), 2.30-1.45 (m, 18H), 1.38 (s, 3H), 1.32-1.05 (m, 4H), 0.72 (s, 3H).

    Example 61

    N-Ethyl-1-(2-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-N-methyl-1H-pyrazole-4-carboxamide

    [0405] ##STR00120##

    [0406] In accordance with Step 2 of Example 2, 2-bromo-1-((3R,5R,8S,10R,13S,14S,17S)-10-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one was used as the starting material, accordingly, the product N-ethyl-1-(2-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-N-methyl-1H-pyrazole-4-carboxamide (14 mg, white solid, yield: 19.8%) was obtained.

    [0407] MS m/z (ESI): 488.3[M+H].sup.+.

    [0408] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.76 (s, 1H), 7.73 (s, 1H), 5.02-4.80 (m, 2H), 3.66-3.44 (m, 2H), 3.28-2.93 (m, 3H), 2.60 (t, J=8.6 Hz, 1H), 2.30-1.45 (m, 18H), 1.38 (s, 3H), 1.34-1.06 (m, 7H), 0.71 (s, 3H).

    Example 62

    2-(4-(Azetidine-1-carbonyl)-1H-pyrazol-1-yl)-1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one

    [0409] ##STR00121##

    [0410] In accordance with Step 2 of Example 2, 2-bromo-1-((3R,5R,8S,10R,13S,14S,17S)-10-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one was used as the starting material, accordingly, the product 2-(4-(azetidine-1-carbonyl)-1H-pyrazol-1-yl)-1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one (12 mg, white solid, yield: 17.1%) was obtained.

    [0411] MS m/z (ESI): 486.2[M+H].sup.+.

    [0412] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.87 (s, 1H), 7.76 (s, 1H), 5.02-4.82 (m, 2H), 4.39-4.21 (m, 4H), 2.59 (t, J=8.5 Hz, 1H), 2.46-1.59 (m, 20H), 1.38 (s, 3H), 1.34-1.19 (m, 3H), 1.17-1.05 (m, 1H), 0.71 (s, 3H).

    Example 63 and Example 64

    2-(4-Cyclopropyl-2H-1,2,3-triazol-2-yl)-1-((3R,5R,8S,10R,13S,14S,17S)-10-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one (63)

    2-(4-Cyclopropyl-1H-1,2,3-triazol-1-yl)-1-((3R,5R,8S,10R,13S,14S,17S)-10-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one (64)

    [0413] ##STR00122##

    Step 1: Preparation of 4,5-dibromo-2H-1,2,3-triazole

    [0414] ##STR00123##

    [0415] Liquid bromine (3 mL) was slowly added to a solution of 2H-1,2,3-triazole (3 g, 43.43 mmol) in water (30 mL) at 0° C. to precipitate a light yellow solid. The reaction solution was stirred at room temperature for 16 hours and then filtrated. The filter cake was washed with water (20 mL), and dried to obtain 4,5-dibromo-2H-1,2,3-triazole (5.7 g, white solid, yield: 58%), which was used directly in the next step without purification.

    [0416] MS m/z (ESI): 227.2[M+H].sup.+.

    Step 2: Preparation of 4-bromo-2H-1,2,3-triazole

    [0417] ##STR00124##

    [0418] 4,5-Dibromo-2H-1,2,3-triazole (5.7 g, 25.13 mmol) was suspended in water (50 mL). Sodium sulfite (9.5 g, 75.38 mmol) was added, and the reaction solution was stirred at 100° C. for 3 days. The reaction solution was cooled to room temperature, and extracted with ethyl acetate (30 mL×6). The organic phases were combined, washed with saturated saline (100 mL), dried over anhydrous sodium sulfate and filtrated. The filtrate was concentrated under reduced pressure to dryness to obtain 4-bromo-2H-1,2,3-triazole (3 g, white solid, yield: 81%).

    [0419] MS m/z (ESI): 148.2 [M+H].sup.+, 150.2 [M+2+H].sup.+.

    Step 3: Preparation of 4-bromo-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole

    [0420] ##STR00125##

    [0421] Sodium hydride (760 mg, 18.9 mmol) was slowly added to a solution of 4-bromo-2H-1,2,3-triazole (2 g, 13.51 mmol) in tetrahydrofuran (20 mL) at 0° C., and the reaction solution was stirred at 0° C. for 0.5 hour. 2-(Trimethylsilyl)ethoxymethyl chloride (2.48 g, 14.86 mmol) was added dropwise. After completion of the addition, the reaction solution was stirred at room temperature for 2 hours. The reaction was quenched with water (50 mL), and the reaction solution was extracted with ethyl acetate (30 mL×3). The organic phases were combined, washed with saturated saline (50 mL), dried over anhydrous sodium sulfate and filtrated. The filtrate was concentrated under reduced pressure to dryness, and the resulting residue was purified by column chromatography to obtain 4-bromo-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole (1.4 g, white solid, yield: 38%).

    [0422] MS m/z (ESI): 278.2 [M+H].sup.+, 280.2 [M+2+H].sup.+.

    Step 4: Preparation of 4-cyclopropyl-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole

    [0423] ##STR00126##

    [0424] 4-Bromo-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole (0.5 g, 1.79 mmol) and potassium cyclopropyltrifluoroborate (530 mg, 3.58 mmol) were dissolved in 1,4-dioxane (10 mL). [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.5 g, 1.79 mmol) and sodium carbonate (0.5 g, 1.79 mmol) were added. After purging with nitrogen three times, the reaction solution was stirred under a nitrogen atmosphere at 100° C. for 16 hours. The reaction solution was filtrated through celite, and the filtrate was concentrated under reduced pressure to obtain a residue. To the residue was added water (30 mL), and the mixture was extracted with ethyl acetate (30 mL×3). The organic phases were combined, washed with saturated saline (50 mL), dried over anhydrous sodium sulfate and filtrated. The filtrate was concentrated under reduced pressure to dryness, and the resulting residue was purified by column chromatography (petroleum ether/ethyl acetate=4:1) to obtain 4-cyclopropyl-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole (70 mg, light yellow oil, yield: 16%).

    [0425] MS m/z (ESI): 240.2 [M+H].sup.+.

    Step 5: Preparation of 4-cyclopropyl-2H-1,2,3-triazole

    [0426] ##STR00127##

    [0427] 4-Cyclopropyl-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole (50 mg, 0.208 mmol) was dissolved in dichloromethane (1 mL). Trifluoroacetic acid (1 mL) was added, and the reaction solution was stirred at room temperature for 3 hours. Water (10 mL) was added, and then saturated sodium carbonate solution was added to the reaction solution to adjust pH=8, and the reaction solution was extracted with ethyl acetate (20 mL×3). The organic phases were combined, washed with saturated saline (50 mL), dried over anhydrous sodium sulfate and filtrated. The filtrate was concentrated under reduced pressure to dryness to obtain 4-cyclopropyl-2H-1,2,3-triazole (35 mg, white solid, crude product).

    [0428] MS m/z (ESI): 110.2 [M+H].sup.+.

    Step 6: Preparation of 2-(4-cyclopropyl-2H-1,2,3-triazol-2-yl)-1-((3R,5R,8S,10R,13S,14S,17S)-10-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one (63) and 2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-1-((3R,5R,8S,10R,13S,14S,17S)-10-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one (64)

    [0429] ##STR00128##

    [0430] Potassium carbonate (80 mg, 0.579 mmol) was added to a mixed solution of 2-bromo-1-((3R,5R,8S,10R,13S,14S,17S)-10-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one (80 mg, 0.193 mmol) and tetrahydrofuran (3 mL), and the reaction solution was stirred at room temperature for 16 hours. Water (20 mL) was added, and the reaction solution was extracted with ethyl acetate (20 mL×3). The organic phases were combined, washed with saturated saline (30 mL), dried over anhydrous sodium sulfate and filtrated. The filtrate was concentrated under reduced pressure to dryness, and the resulting residue was purified by preparative chromatography to obtain a white solid, 2-(4-cyclopropyl-2H-1,2,3-triazol-2-yl)-1-((3R,5R,8S,10R,13S,14S,17S)-10-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one (63) (34 mg, white solid, yield: 39.8%) and a white solid, 2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-1-((3R,5R,8S,10R,13S,14S,17S)-10-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one (64) (14 mg, white solid, yield: 16.4%).

    Example 63

    [0431] MS m/z (ESI): 444.2 [M+H].sup.+.

    [0432] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.35 (s, 1H), 5.15-5.05 (m, 2H), 3.91 (d, J=3.0 Hz, 1H), 2.61-2.47 (m, 1H), 2.25-2.08 (m, 4H), 2.04-1.81 (m, 5H), 1.78-1.71 (m, 2H), 1.54-1.42 (m, 6H), 1.37 (s, 3H), 1.33-1.20 (m, 4H), 1.18-1.04 (m, 2H), 0.99-0.96 (m, 2H), 0.80-0.75 (m, 2H), 0.73 (s, 3H).

    Example 64

    [0433] MS m/z (ESI): 444.2 [M+H].sup.+.

    [0434] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.35 (s, 1H), 5.16-5.06 (m, 2H), 3.91 (d, J=3.0 Hz, 1H), 2.54 (t, J=8.8 Hz, 1H), 2.24-2.09 (m, 4H), 2.04-1.81 (m, 5H), 1.78-1.70 (m, 2H), 1.54-1.42 (m, 6H), 1.37 (s, 3H), 1.31-1.22 (m, 4H), 1.18-1.04 (m, 2H), 0.99-0.96 (m, 2H), 0.80-0.76 (m, 2H), 0.73 (s, 3H).

    Example 66

    1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-Fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-((2-(trifluoromethyl)pyrimidin-5-yl)oxy)ethan-1-one

    [0435] ##STR00129##

    [0436] In accordance with Step 2 of Example 2, 2-bromo-1-((3R,5R,8S,10R,13S,14S,17S)-10-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one was used as the starting material, accordingly, the product 1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-((2-(trifluoromethyl)pyrimidin-5-yl)oxy)ethan-1-one (39.2 mg, white solid, yield: 65.5%) was obtained.

    [0437] MS m/z (ESI): 499.2[M+H].sup.+.

    [0438] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.45 (s, 2H), 4.84-4.70 (m, 2H), 2.68 (t, J=8.9 Hz, 1H), 2.23 (m, 1H), 2.09 (d, J=10.8 Hz, 1H), 1.98 (t, J=12.6 Hz, 3H), 1.91-1.83 (m, 1H), 1.79 (t, J=8.4 Hz, 2H), 1.60-1.52 (m, 4H), 1.48 (dd, J=19.5, 12.9 Hz, 5H), 1.38 (s, 3H), 1.35-1.21 (m, 4H), 1.20-1.05 (m, 1H), 0.73 (s, 3H).

    Example 67

    3-(2-((3R,5R,8S,9S,10R,13S,14S,17S)-10-Fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)thiazolidine-2,4-dione

    [0439] ##STR00130##

    [0440] In accordance with Step 2 of Example 2, 2-bromo-1-((3R,5R,8S,10R,13S,14S,17S)-10-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one was used as the starting material, accordingly, the product 3-(2-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)thiazolidine-2,4-dione (18.5 mg, white solid, yield: 28.3%) was obtained.

    [0441] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 4.43-4.32 (m, 2H), 4.03 (s, 2H), 2.56 (t, J=8.7 Hz, 1H), 2.21-1.54 (m, 18H), 1.37 (s, 3H), 1.32-1.25 (m, 3H), 1.17-1.08 (m, 1H), 0.68 (s, 3H).

    Example 68

    (1R,3R,5R)-2-(2-((3R,5R,8S,10R,13S,14S,17S)-10-Fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-2-azabicyclo[3.1.0]hexane-3-carbonitrile

    [0442] ##STR00131##

    Step 1: Preparation of tert-butyl (1R,3R,5R)-3-cyano-2-azabicyclo[3.1.0]hexane-2-carboxylate

    [0443] ##STR00132##

    [0444] Trifluoroacetic anhydride (5 mL, 35.3 mmol) was slowly added dropwise to a suspension of tert-butyl (1R,3R,5R)-3-carbamoyl-2-azabicyclo[3.1.0]hexane-2-carboxylate (2 g, 8.85 mmol) and pyridine (25 mL) at −20° C. After stirring at −20° C. for 1 hour, the reaction solution was warmed up to room temperature, and stirred for 8 hours. Ice-water was added to quench the reaction, and the reaction solution was extracted with ethyl acetate (30 mL×3). The organic phases were combined, washed with dilute hydrochloric acid (10%) and saturated saline, dried over anhydrous sodium sulfate and filtrated. The filtrate was concentrated under reduced pressure to dryness, and the resulting residue was purified by column chromatography (petroleum ether/ethyl acetate=4:1) to obtain tert-butyl (1R,3R,5R)-3-cyano-2-azabicyclo[3.1.0]hexane-2-carboxylate (1.5 g, white solid, yield: 83%).

    [0445] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 4.71 (dd, J=41.1, 9.6 Hz, 1H), 3.58 (d, J=33.8 Hz, 1H), 2.63-2.47 (m, 1H), 2.35 (d, J=12.7 Hz, 1H), 1.70-1.60 (m, 1H), 1.52 (s, 9H), 1.02 (s, 1H), 0.90-0.81 (m, 1H).

    Step 2: Preparation of (1R,3R,5R)-2-azabicyclo[3.1.0]hexane-3-carbonitrile

    [0446] ##STR00133##

    [0447] Tert-butyl (1R,3R,3R)-3-cyano-2-azabicyclo[3.1.0]hexane-2-carboxylate (0.8 g, 3.85 mmol) was dissolved in dioxane (2 mL). Hydrochloric acid-dioxane (8 mL) was added, and the reaction solution was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure to dryness, to the resulting residue was added water (50 mL), and the mixture was extracted with dichloromethane/methanol=10:1. The organic phases were combined, washed with saturated saline, dried over anhydrous sodium sulfate and filtrated. The filtrate was concentrated under reduced pressure to dryness to obtain (1R,3R,5R)-2-azabicyclo[3.1.0]hexane-3-carbonitrile (0.5 g, brown oil, crude product).

    Step 3: Preparation of (1R,3R,5R)-2-(2-((3R,5R,8S,10R,13S,14S,17S)-10-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-2-azabicyclo[3.1.0]hexane-3-carbonitrile

    [0448] ##STR00134##

    [0449] In accordance with Step 2 of Example 2, 2-bromo-1-((3R,5R,8S,10R,13S,14S,17S)-10-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one was used as the starting material, accordingly, the product (1R,3R,5R)-2-(2-((3R,5R,8S,10R,13S,14S,17S)-10-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-2-azabicyclo[3.1.0]hexane-3-carbonitrile (12 mg, white solid, yield: 23%) was obtained.

    [0450] MS m/z (ESI): 443.2 [M+H].sup.+.

    [0451] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 4.08 (s, 2H), 3.70 (s, 2H), 2.49 (t, J=8.7 Hz, 1H), 2.24-2.16 (m, 2H), 2.12-1.82 (m, 11H), 1.74-1.70 (m, 2H), 1.60-1.48 (m, 6H), 1.37 (s, 3H), 1.31-1.25 (m, 6H), 1.12-1.07 (m, 1H), 0.65 (s, 3H).

    Example 69

    1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-Fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-((1-methyl-1H-pyrazol-4-yl)oxy)ethan-1-one

    [0452] ##STR00135##

    [0453] In accordance with Step 2 of Example 2, 2-bromo-1-((3R,5R,8S,10R,13S,14S,17S)-10-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one was used as the starting material, accordingly, the product 1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-((1-methyl-1H-pyrazol-4-yl)oxy)ethan-1-one (20 mg, white solid, yield: 32.0%) was obtained.

    [0454] MS m/z (ESI): 433.3[M+H].sup.+.

    [0455] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.21 (s, 1H), 7.08 (s, 1H), 4.48-4.28 (m, 2H), 3.82 (s, 3H), 2.74 (t, J=8.9 Hz, 1H), 2.22-1.50 (m, 18H), 1.37 (s, 3H), 1.30-1.10 (m, 4H), 0.68 (s, 3H).

    Example 70

    7-(2-((3R,5R,8S,9S,10R,13S,14S,17S)-10-Fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethoxy)quinolone 1-oxide

    [0456] ##STR00136##

    Step 1: Preparation of 1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(quinolin-7-yloxy)ethan-1-one

    [0457] ##STR00137##

    [0458] In accordance with Step 2 of Example 2, 2-bromo-1-((3R,5R,8S,10R,13S,14S,17S)-10-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one was used as the starting material, accordingly, the product 1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(quinolin-7-yloxy)ethan-1-one (60.0 mg, white solid, yield 52.1%) was obtained.

    [0459] MS m/z (ESI): 480.2[M+H].sup.+.

    Step 2: Preparation of 7-(2-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethoxy)quinolone 1-oxide

    [0460] ##STR00138##

    [0461] 1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-Fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(quinolin-7-yloxy)ethan-1-one (60 mg, 0.125 mmol) and dichloromethane (10 ml) were added to a 100 ml single-neck flask, followed by the addition of m-chloroperoxybenzoic acid (78 mg, 0.313 mmol). The reaction solution was stirred at room temperature overnight. The reaction solution was washed with saturated sodium bicarbonate solution and concentrated. The crude product obtained after concentration was purified by prep-HPLC to obtain 7-(2-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethoxy)quinolone 1-oxide (29.2 mg, white solid, yield 47.1%).

    [0462] MS m/z (ESI): 496.2[M+H].sup.+.

    [0463] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.59 (d, J=6.0 Hz, 1H), 7.97 (d, J=2.2 Hz, 1H), 7.83 (d, J=9.0 Hz, 1H), 7.78 (d, J=8.3 Hz, 1H), 7.43 (dd, J=9.0, 2.4 Hz, 1H), 7.26-7.20 (m, 1H), 4.87-4.73 (m, 2H), 2.83-2.75 (m, 1H), 2.33-2.21 (m, 1H), 2.13-2.07 (m, 1H), 2.06-1.95 (m, 4H), 1.94-1.84 (m, 2H), 1.82-1.74 (m, 2H), 1.62-1.42 (m, 8H), 1.38 (s, 3H), 1.35-1.25 (m, 3H), 1.20-1.06 (m, 1H), 0.75 (s, 3H).

    Example 71

    N-(2-((3S,5R,8S,9S,10R,13S,14S,17S)-10-Fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)benzenesulfonamide

    [0464] ##STR00139##

    [0465] Benzenesulfonamide (28 mg, 0.18 mmol) was dissolved in N,N-dimethylformamide (5 mL). Sodium hydride (7.2 mg, 0.18 mmol) was added at 0° C., and the reaction solution was stirred at 0° C. for 0.5 hour. 2-Bromo-1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one (50 mg, 0.12 mmol) was added at 0° C., and the reaction solution was stirred at room temperature overnight. 5 mL of water was added, and the reaction solution was extracted with ethyl acetate (30 mL×3). The organic phase was washed with saturated saline (20 mL) once, dried over anhydrous sodium sulfate and concentrated by rotary evaporation to dryness. The resulting residue was purified by prep-HPLC to obtain the product (7.1 mg, white solid, yield: 12%).

    [0466] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.86 (d, J=7.2 Hz, 2H), 7.58 (t, J=7.4 Hz, 1H), 7.51 (t, J=7.5 Hz, 2H), 5.48 (s, 1H), 3.87-3.68 (m, 2H), 2.36 (t, J=8.9 Hz, 1H), 2.06-2.08 (m, 2H), 1.94-1.97 (m, 2H), 1.90-1.80 (m, 1H), 1.71-1.62 (m, 4H), 1.52-1.39 (m, 6H), 1.37 (s, 3H), 1.34-1.25 (m, 4H), 1.24-1.01 (m, 3H), 0.38 (s, 3H).

    Example 72

    (3R,5R,8S,9S,10R,13S,14S,17S)-10-Fluoro-N-(4-fluorophenyl)-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-carboxamide

    [0467] ##STR00140##

    Step 1: Preparation of (3R,5R,8S,9S,10R,13S,14S)-10-fluoro-3,13-dimethyl-17-methylenehexadecahydro-1H-cyclopenta[a]phenanthren-3-ol

    [0468] ##STR00141##

    [0469] Potassium tert-butoxide (4.36 g, 38.961 mmol) was added to a solution of methyltriphenylphosphonium bromide (13.9 g, 38.961 mmol) and tetrahydrofuran (50 mL), and the reaction solution was stirred at 65° C. for 1 hour. A mixed solution of (3R,5R,8S,9S,10R,13S,14S)-10-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-17H-cyclopenta[a]phenanthren-17-one (2 g, 6.494 mmol) and tetrahydrofuran (30 mL) was added dropwise. After stirring at 65° C. for 1 hour, the reaction solution was cooled to room temperature. Water was added to quench the reaction, and the reaction solution was extracted with ethyl acetate (50 mL×3). The organic phases were combined, washed with saturated saline, dried over anhydrous sodium sulfate and filtrated. The filtrate was concentrated under reduced pressure to dryness, and the resulting residue was purified by column chromatography (petroleum ether/ethyl acetate=10:1) to obtain (3R,5R,8S,9S,10R,13S,14S)-10-fluoro-3,13-dimethyl-17-methylenehexadecahydro-1H-cyclopenta[a]phenanthren-3-ol (1.8 g, white solid, yield: 90%).

    Step 2: Preparation of (3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-17-(hydroxymethyl)-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-3-ol

    [0470] ##STR00142##

    [0471] (3R,5R,8S,9S,10R,13S,14S)-10-Fluoro-3,13-dimethyl-17-methylenehexadecahydro-1H-cyclopenta[a]phenanthren-3-ol (0.5 g, 1.634 mmol) was dissolved in tetrahydrofuran (8 mL). Borane-tetrahydrofuran (8.2 mL, 8.169 mmol) was added dropwise, and the reaction solution was stirred at room temperature for 1.5 hours. The reaction solution was cooled to 0° C., and a solution of sodium hydroxide (327 mg, 8.169 mmol) in water (3 mL) was added. Hydrogen peroxide (3 mL, 30%) was slowly added dropwise, and the reaction solution was stirred at room temperature for 1.5 hours. Water (50 mL) was added, and the reaction solution was extracted with ethyl acetate (50 mL×3). The organic phases were combined, washed with saturated saline, dried over anhydrous sodium sulfate and filtrated. The filtrate was concentrated under reduced pressure to dryness to obtain (3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-17-(hydroxymethyl)-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-3-ol (600 mg, crude product).

    Step 3: Preparation of (3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-carboxylic acid

    [0472] ##STR00143##

    [0473] Pyridinium dichromate (4.6 g, 12.34 mmol) was added to a mixture of (3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-17-(hydroxymethyl)-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-3-ol (400 mg, 1.234 mmol), N,N-dimethylformamide (15 mL) and water (1 mL), and the reaction solution was stirred at room temperature for 16 hours. Saturated sodium sulfite solution (50 mL) was added to quench the reaction, and the reaction solution was extracted with ethyl acetate (40 mL×3). The organic phases were combined, washed with saturated saline, dried over anhydrous sodium sulfate and filtrated. The filtrate was concentrated under reduced pressure to dryness to obtain a light yellow solid, (3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-carboxylic acid (400 mg, light yellow solid, crude product).

    [0474] .sup.1H NMR (400 MHz, DMSO) δ 11.92 (s, 1H), 4.38 (s, 1H), 2.90-2.70 (m, 2H), 2.05-1.52 (m, 9H), 1.39-1.19 (m, 15H), 0.61 (s, 3H).

    Step 4: Preparation of (3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-N-(4-fluorophenyl)-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-carboxamide

    [0475] ##STR00144##

    [0476] A mixture of (3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-carboxylic acid (200 mg, 0.592 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethylurea hexafluorophosphate (270 mg, 0.71 mmol), triethylamine (119 mg, 1.18 mmol) and dichloromethane (5 mL) was stirred at room temperature for 30 minutes. p-Fluoroaniline (79 mg, 0.71 mmol) was added, and the reaction solution was stirred at room temperature for 3 hours. Water (30 mL) was added, and the reaction solution was extracted with dichloromethane (40 mL×3). The organic phases were combined, washed with saturated saline, dried over anhydrous sodium sulfate and filtrated. The filtrate was concentrated under reduced pressure to dryness, and the resulting residue was purified by preparative chromatography to obtain (3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-N-(4-fluorophenyl)-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-carboxamide (25 mg, white solid, yield: 10%).

    [0477] MS m/z (ESI): 432.2 [M+H].sup.+.

    [0478] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.51-7.41 (m, 2H), 7.05-6.95 (m, 2H), 2.43-2.17 (m, 2H), 2.14-1.80 (m, 8H), 1.72-1.69 (m, 3H), 1.51-1.11 (m, 15H), 0.93 (s, 3H).

    Example 73

    2-((4-Fluoro-2-methoxyphenyl)amino)-1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one

    [0479] ##STR00145##

    [0480] In accordance with Example 23, 2-bromo-1-((3R,5R,8S,10R,13S,14S,17S)-10-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one was used as the starting material, accordingly, the product 2-((4-fluoro-2-methoxyphenyl)amino)-1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one (29 mg, white solid, yield: 42.2%) was obtained.

    [0481] MS m/z (ESI): 476.3[M+H].sup.+.

    [0482] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 6.61-6.49 (m, 2H), 6.40-6.31 (m, 1H), 3.91 (d, J=6.3 Hz, 2H), 3.87-3.82 (m, 3H), 2.58 (t, J=8.8 Hz, 1H), 2.31-1.42 (m, 18H), 1.38 (s, 3H), 1.35-1.03 (m, 4H), 0.69 (s, 3H).

    Example 79A

    1-(2-((3R,5R,8S,9S,10R,13S,14S,17S)-10-(Fluoromethyl)-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile

    [0483] ##STR00146##

    [0484] Example 79A was synthesized by the following specific scheme:

    ##STR00147## ##STR00148##

    Example 82A

    1-(2-((3R,5R,8S,9S,10R,13S,14S,17S)-10-(Difluoromethyl)-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile

    [0485] ##STR00149##

    [0486] Example 82A was synthesized by the following specific scheme:

    ##STR00150## ##STR00151## ##STR00152##

    Example 90

    1-(2-((2R,4aR,4bS,6aS,8bS, 8cR,10aR)-2-Hydroxymethyl-4a-(methoxymethyl)-2,6a-dimethylhexadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile

    [0487] ##STR00153##

    [0488] Example 90 was synthesized by the following specific scheme:

    ##STR00154## ##STR00155##

    [0489] MS m/z (ESI): 465.3 [M].sup.+.

    Example 91

    1-(2-((2R,4aR,4bS,6aS,8bS, 8cR,10aR)-2-Hydroxymethyl-4a-(methoxymethyl)-2,6a-dimethylhexadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-oxoethyl)-1H-pyrazole-3-carbonitrile

    [0490] ##STR00156##

    [0491] MS m/z (ESI): 465.3 [M].sup.+.

    Example 92

    1-(2-((2R,4aR,4bS,6aS,8bS, 8cR,10aR)-2-thiomethyl-4a-(methoxymethyl)-2,6a-dimethylhexadecahydrocyclopenta[4,5]cyclopenta[1,2-α]phenanthren-7-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile

    [0492] ##STR00157##

    [0493] Example 92 was synthesized by the following specific scheme:

    ##STR00158## ##STR00159##

    [0494] MS m/z (ESI): 469.3 [M].sup.+.

    Example 93

    2-(5-Chloro-1H-benzo[d][1,2,3]triazol-1-yl)-1-((3R,5R,8S,9S,10R,13S,14S,17S)-3-((methylthio)methyl)hexahydrodecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one

    [0495] ##STR00160##

    [0496] MS m/z (ESI): 529.3 [M].sup.+.

    Example 94

    2-(4,5-Difluoro-1H-benzo[d][1,2,3]triazol-1-yl)-1-((3R,5R,8S,9S,10R,13S,14S,17S)-3-hydroxy-3,13-dimethyl-10-((methylthio)methyl)hexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one

    [0497] ##STR00161##

    [0498] MS m/z (ESI): 531.3 [M].sup.+.

    Example 95

    2-(3H-[1,2,3]Triazolo[4,5-b]pyridin-3-yl)-1-((3R,5R,8S,9S,10R,13S,14S,17S)-3-hydroxy-3,13-dimethyl-10-((methylthio)methyl)hexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one

    [0499] ##STR00162##

    [0500] MS m/z (ESI): 496.3 [M].sup.+.

    Example 96

    1-(2-((3R,5R,8S,9S,10R,13S,14S,17S)-3-Hydroxy-3,13-dimethyl-10-((methylsulfonyl)methyl)hexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile

    [0501] ##STR00163##

    ##STR00164##

    [0502] MS m/z (ESI): 501.3 [M].sup.+.

    Example 97

    1-(2-((3R,5R,8S,9S,10R,13S,14S,17S)-3-Hydroxy-3,13-dimethyl-10-((S-methylsulfonimidoyl)methyl)hexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile

    [0503] ##STR00165##

    [0504] MS m/z (ESI): 500.3 [M].sup.+.

    [0505] MS m/z (ESI): 456.3 [M].sup.+.

    Example 114

    1-(2-((3R,5R,8S,9S,10R,13S,14S,17S)-10-Fluoro-3-hydroxy-3-(methoxymethyl)-13-methylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile

    [0506] ##STR00166##

    Step 1: (5R,8S,10R,13S,14S)-10-Fluoro-13-methyltetradecahydrospiro[cyclopenta[a]phenanthrene-3,2′-oxiran]-17(2H)-one

    [0507] ##STR00167##

    [0508] Trimethylsulfoxonium iodide (2.65 g, 12 mmol) and tetrahydrofuran (50 mL) were added successively to a 100 mL three-neck flask, followed by the addition of potassium tert-butoxide (1.35 g, 12 mmol) under stirring. The reaction solution was stirred at room temperature for 0.5 hour. (5R,8S,9S,10R,13S,14S)-10-Fluoro-13-methyltetradecahydro-3H-cyclopenta[a]phenanthrene-3,17(2H)-dione (3.0 g, 10 mmol) was added, and the reaction solution was reacted at room temperature for 2 hours. Saturated aqueous ammonium chloride solution was added to quench the reaction, and the reaction solution was extracted with ethyl acetate (30 mL). The organic phase was washed with saline (10 mL×3), dried over anhydrous sodium sulfate, filtrated and concentrated by rotary evaporation to dryness. The crude product was purified by column chromatography (petroleum ether/ethyl acetate: 3/1) to obtain (5R,8S,10R,13S,14S)-10-fluoro-13-methyltetradecahydrospiro[cyclopenta[a]phenanthrene-3,2′-oxiran]-17(2H)-one (2.5 g, light yellow solid, yield: 79.5%).

    [0509] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 2.72-2.67 (m, 2H), 2.52-2.43 (m, 1H), 2.31-1.06 (m, 21H), 0.92 (s, 3H).

    Step 2: (3R,5R,8S,10R,13S,14S)-10-Fluoro-3-hydroxy-3-(methoxymethyl)-13-methylhexadecahydro-17H-cyclopenta[a]phenanthren-17-one

    [0510] ##STR00168##

    [0511] (5R,8S,10R,13S,14S)-10-Fluoro-13-methyltetradecahydrospiro[cyclopenta[a]phenanthrene-3,2′-oxiran]-17(2H)-one (2.5 g, 7.5 mmol) was dissolved in methanol (50 mL) in a 100 mL single-neck flask. After the solution was stirred at room temperature for 2-3 minutes, sodium methoxide (1.25 g, 22.5 mmol) was added. After completion of the addition, the reaction solution was stirred at 60° C. for 5 hours. The reaction solution was cooled to room temperature, saturated aqueous ammonium chloride solution was added to quench the reaction, and the reaction solution was extracted with ethyl acetate (30 mL). The organic phase was washed with saline (10 mL×3), dried over anhydrous sodium sulfate, filtrated and concentrated by rotary evaporation to dryness. The crude product was purified by column chromatography (petroleum ether/ethyl acetate: 3/1) to obtain (3R,5R,8S,10R,13S,14S)-10-fluoro-3-hydroxy-3-(methoxymethyl)-13-methylhexadecahydro-17H-cyclopenta[a]phenanthren-17-one (1.6 g, light yellow solid, yield: 57.9%).

    [0512] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 3.39 (s, 3H), 3.21 (s, 2H), 2.51-2.40 (m, 1H), 2.37-1.04 (m, 21H), 0.90 (s, 3H).

    Step 3: (3R,5R,8S,10R,13S,14S)-17-Ethylidene-10-fluoro-3-(methoxymethyl)-13-methylhexadecahydro-1H-cyclopenta[a]phenanthren-3-ol

    [0513] ##STR00169##

    [0514] In accordance with Step 4 of Example 1, (3R,5R,8S,10R,13S,14S)-10-fluoro-3-hydroxy-3-(methoxymethyl)-13-methylhexadecahydro-17H-cyclopenta[a]phenanthren-17-one was used as the starting material, accordingly, the product (3R,5R,8S,10R,13S,14S)-17-ethylidene-10-fluoro-3-(methoxymethyl)-13-methylhexadecahydro-1H-cyclopenta[a]phenanthren-3-ol (600 mg, white solid, yield: 36.2%) was obtained.

    [0515] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 5.18-4.96 (m, 1H), 3.39 (s, 3H), 3.20 (s, 2H), 2.44-0.99 (m, 25H), 0.90 (s, 3H).

    Step 4: (3R,5R,8S,10R,13S,14S,17R)-10-Fluoro-17-(1-hydroxyethyl)-3-(methoxymethyl)-13-methylhexadecahydro-1H-cyclopenta[a]phenanthren-3-ol

    [0516] ##STR00170##

    [0517] In accordance with Step 5 of Example 1, (3R,5R,8S,10R,13S,14S)-17-ethylidene-10-fluoro-3-(methoxymethyl)-13-methylhexadecahydro-1H-cyclopenta[a]phenanthren-3-ol was used as the starting material, accordingly, the product (3R,5R,8S,10R,13S,14S,17R)-10-fluoro-17-(1-hydroxyethyl)-3-(methoxymethyl)-13-methylhexadecahydro-1H-cyclopenta[a]phenanthren-3-ol (600 mg, white solid, yield: 95.1%) was obtained.

    Step 5: 1-((3R,5R,8S,10R,13S,14S,17S)-10-Fluoro-3-hydroxy-3-(methoxymethyl)-13-methylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one

    [0518] ##STR00171##

    [0519] In accordance with Step 6 of Example 1, (3R,5R,8S,10R,13S,14S,17R)-10-fluoro-17-(1-hydroxyethyl)-3-(methoxymethyl)-13-methylhexadecahydro-1H-cyclopenta[a]phenanthren-3-ol was used as the starting material, accordingly, the product 1-((3R,5R,8S,10R,13S,14S,17S)-10-fluoro-3-hydroxy-3-(methoxymethyl)-13-methylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one (500 mg, white solid, yield: 83.7%) was obtained.

    [0520] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 3.40 (s, 3H), 3.21 (s, 2H), 2.56-2.47 (m, 1H), 2.39-2.16 (m, 4H), 2.12 (s, 3H), 2.07-0.98 (m, 18H), 0.65 (s, 3H).

    Step 6: 2-Bromo-1-((3R,5R,8S,10R,13S,14S,17S)-10-fluoro-3-hydroxy-3-(methoxymethyl)-13-methylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one

    [0521] ##STR00172##

    [0522] In accordance with Step 1 of Example 2, 1-((3R,5R,8S,10R,13S,14S,17S)-10-fluoro-3-hydroxy-3-(methoxymethyl)-13-methylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one was used as the starting material, accordingly, the product 2-bromo-1-((3R,5R,8S,10R,13S,14S,17S)-10-fluoro-3-hydroxy-3-(methoxymethyl)-13-methylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one (500 mg, white solid, yield: 82.2%) was obtained.

    Step 7: 1-(2-((3R,5R,8S,9S,10R,13S,14S,17S)-10-Fluoro-3-hydroxy-3-(methoxymethyl)-13-methylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile

    [0523] ##STR00173##

    [0524] In accordance with Step 2 of Example 2, 2-bromo-1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxy-3-(methoxymethyl)-13-methylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one was used as the starting material, accordingly, the product 1-(2-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxy-3-(methoxymethyl)-13-methylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile (11 mg, white solid, yield: 17.8%) was obtained.

    [0525] MS m/z (ESI): 458.3[M+H].sup.+.

    [0526] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.87 (s, 1H), 7.82 (s, 1H), 5.04-4.90 (m, 2H), 3.40 (s, 3H), 3.22 (s, 2H), 2.58 (t, J=8.9 Hz, 1H), 2.22-1.01 (m, 22H), 0.71 (s, 3H).

    Example 115

    1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-Fluoro-3-hydroxy-3-(methoxymethyl)-13-methylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(4-(trifluoromethyl)-1H-pyrazol-1-yl)ethan-1-one

    [0527] ##STR00174##

    [0528] In accordance with Step 2 of Example 2, 2-bromo-1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxy-3-(methoxymethyl)-13-methylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one was used as the starting material, accordingly, the product 1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxy-3-(methoxymethyl)-13-methylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(4-(trifluoromethyl)-1H-pyrazol-1-yl)ethan-1-one (25 mg, white solid, yield: 37.0%) was obtained. MS m/z (ESI): 501.2[M+H].sup.+.

    [0529] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.74 (s, 2H), 5.05-4.82 (m, 2H), 3.40 (s, 3H), 3.22 (s, 2H), 2.59 (t, J=8.6 Hz, 1H), 2.45-1.05 (m, 22H), 0.72 (s, 3H).

    Example 116

    1-(2-((3R,5R,8S,9S,10R,13S,14S,17S)-10-Fluoro-3-hydroxy-3-(methoxymethyl)-13-methylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-1H-pyrazole-3-carbonitrile

    [0530] ##STR00175##

    [0531] In accordance with Step 2 of Example 2, 2-bromo-1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxy-3-(methoxymethyl)-13-methylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one was used as the starting material, accordingly, the product 1-(2-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxy-3-(methoxymethyl)-13-methylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-1H-pyrazole-3-carbonitrile (19 mg, white solid, yield: 30.8%) was obtained. MS m/z (ESI): 458.3[M+H].sup.+.

    [0532] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.50 (d, J=2.4 Hz, 1H), 6.74 (d, J=2.4 Hz, 1H), 5.03-4.88 (m, 2H), 3.39 (s, 3H), 3.22 (s, 2H), 2.59 (t, J=8.8 Hz, 1H), 2.38-1.05 (m, 22H), 0.71 (s, 3H).

    Example 117

    1-(2-((3R,5S,8S,9S,10S,13S,14 S,17S)-3-Hydroxy-3,13-dimethyltetradecahydro-6H-5,10-methanocyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile

    [0533] ##STR00176##

    [0534] Step 1: ((8R,9S,10S,13S,14S)-13-Methyl-3,17-dioxo-1,2,3,6,7,8,9,11,12,13,14,15,16,17-tetradecahydro-10H-cyclopenta[a]phenanthren-10-yl)methyl 4-methylbenzenesulfonate

    ##STR00177##

    [0535] Pyridine (20 mL) and (8R,9S,10S,13S,14S)-10-(hydroxymethyl)-13-methyl-1,6,7,8,9,10,11,12,13,14,15,16-dodecahydro-3H-cyclopenta[a]phenanthrene-3,17(2H)-dione (6.0 g, 20 mmol) were added successively to an 100 mL three-neck flask, followed by the addition of 4-methylbenzenesulfonyl chloride (11.4 g, 60 mmol) under stirring. The reaction solution was stirred at room temperature for 12 hours, then poured into an ice-water bath to precipitate a white solid. The solid was filtrated out, washed with water and dried to obtain the product ((8R,9S,10S,13S,14S)-13-methyl-3,17-dioxo-1,2,3,6,7,8,9,11,12,13,14,15,16,17-tetradecahydro-10H-cyclopenta[a]phenanthren-10-yl)methyl 4-methylbenzenesulfonate (8.0 g, white solid, yield: 88%).

    [0536] MS m/z (ESI): 457.2[M+H].sup.+.

    [0537] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.75 (d, J=8.0 Hz, 2H), 7.36 (d, J=8.0 Hz, 2H), 5.87 (s, 1H), 4.39-4.23 (m, 2H), 2.52-2.47 (m, 1H), 2.46 (s, 3H), 2.38-2.25 (m, 5H), 2.12-1.70 (m, 7H), 1.65-1.40 (m, 2H), 1.30-1.05 (m, 4H), 0.89 (s, 3H).

    Step 2: (5S,8R,9S,10S,13S,14S)-13-Methyldodecahydro-17H-5,10-methanocyclopenta[a]phenanthrene-3,17(4H)-dione

    [0538] ##STR00178##

    [0539] ((8R,9S,10S,13S,14S)-13-Methyl-3,17-dioxo-1,2,3,6,7,8,9,11,12,13,14,15,16,17-tetradecahydro-10H-cyclopenta[a]phenanthren-10-yl)methyl 4-methylbenzenesulfonate (7.1 g, 15.5 mmol), acetic acid (300 mL) and water (300 mL) were added to a 100 mL single-neck flask. After the reaction solution was stirred at room temperature for 2-3 minutes, zinc powder (35 g, 538 mmol) was added. After completion of the addition, the reaction solution was reacted at 120° C. for 1.5 hours. The reaction solution was filtrated, and the filtrate was concentrated by rotary evaporation to dryness. The crude product was purified by column chromatography (petroleum ether/ethyl acetate: 35/1) to obtain (5S,8R,9S,10S,13S,14S)-13-methyldodecahydro-17H-5,10-methanocyclopenta[a]phenanthrene-3,17(4H)-dione (2.5 g, white solid, yield: 56%).

    [0540] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 2.56-2.53 (m, 2H), 2.49-2.27 (m, 2H), 2.14-1.70 (m, 9H), 1.55-0.90 (m, 8H), 0.89 (s, 3H), 0.55 (d, J=6.0 Hz, 1H), 0.45 (d, J=6.0 Hz, 1H).

    Step 3: (3R,5S,8R,9S,10S,13S,14S)-3-Hydroxy-3,13-dimethyltetradecahydro-17H-5,10-methanocyclopenta[a]phenanthren-17-one

    [0541] ##STR00179##

    [0542] In accordance with Step 3 of Example 1, (5S,8R,9S,10S,13S,14S)-13-methyldodecahydro-17H-5,10-methanocyclopenta[a]phenanthrene-3,17(4H)-dione was used as the starting material, accordingly, the product (3R,5S,8R,9S,10S,13S,14S)-3-hydroxy-3,13-dimethyltetradecahydro-17H-5,10-methanocyclopenta[a]phenanthren-17-one (white solid, yield: 52%) was obtained.

    [0543] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 2.47-2.39 (m, 1H), 2.10-1.25 (m, 16H), 1.19 (s, 3H), 1.15-0.85 (m, 4H), 0.86 (s, 3H), 0.42 (s, 2H).

    Step 4: (3R,5S,8S,9S,10S,13S,14S)-17-Ethylidene-3,13-dimethyltetradecahydro-6H-5,10-methanocyclopenta[a]phenanthren-3-ol

    [0544] ##STR00180##

    [0545] In accordance with Step 4 of Example 1, (3R,5S,8R,9S,10S,13S,14S)-3-hydroxy-3,13-dimethyltetradecahydro-17H-5,10-methanocyclopenta[a]phenanthren-17-one was used as the starting material, accordingly, the product (3R,5S,8S,9S,10S,13S,14S)-17-ethylidene-3,13-dimethyltetradecahydro-6H-5,10-methanocyclopenta[a]phenanthren-3-ol (white solid, yield: 61.5%) was obtained.

    [0546] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 5.15-5.08 (m, 1H), 2.40-1.20 (m, 18H), 1.19 (s, 3H), 1.16-0.87 (m, 6H), 086 (s, 3H), 0.43 (d, J=4.4 Hz, 1H), 0.35 (d, J=4.4 Hz, 1H).

    Step 5: (3R,5S,8S,9S,10S,13S,14S)-17-(1-Hydroxyethyl)-3,13-dimethyltetradecahydro-6H-5,10-methanocyclopenta[a]phenanthren-3-ol

    [0547] ##STR00181##

    [0548] In accordance with Step 5 of Example 1, (3R,5S,8S,9S,10S,13S,14S)-17-ethylidene-3,13-dimethyltetradecahydro-6H-5,10-methanocyclopenta[a]phenanthren-3-ol was used as the starting material, accordingly, the product (3R,5 S,8 S,9S,10S,13S,14S)-17-(1-hydroxyethyl)-3,13-dimethyltetradecahydro-6H-5,10-methanocyclopenta[a]phenanthren-3-ol (white solid, yield: 100%) was obtained.

    Step 6: 1-((3R,5S,8S,9S,10S,13S,14S,17S)-3-Hydroxy-3,13-dimethyltetradecahydro-6H-5,10-methanocyclopenta[a]phenanthren-17-yl)ethan-1-one

    [0549] ##STR00182##

    [0550] In accordance with Step 6 of Example 1, (3R,5S,8S,9S,10S,13S,14S)-17-(1-hydroxyethyl)-3,13-dimethyltetradecahydro-6H-5,10-methanocyclopenta[a]phenanthren-3-ol was used as the starting material, accordingly, the product 1-((3R,5S,8S,9S,10S,13S,14S,17S)-3-hydroxy-3,13-dimethyltetradecahydro-6H-5,10-methanocyclopenta[a]phenanthren-17-yl)ethan-1-one (white solid, yield: 71%) was obtained.

    [0551] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 2.54 (t, J=8.0 Hz, 1H), 2.12 (s, 3H), 2.10-1.25 (m, 17H), 1.19 (s, 3H), 1.15-0.72 (m, 4H), 0.60 (s, 3H), 0.41 (d, J=4.4 Hz, 1H), 0.36 (d, J=4.4 Hz, 1H).

    Step 7: 2-Bromo-1-((3R,5S,8S,9S,10S,13S,14S,17S)-3-hydroxy-3,13-dimethyltetradecahydro-6H-5,10-methanocyclopenta[a]phenanthren-17-yl)ethan-1-one

    [0552] ##STR00183##

    [0553] In accordance with Step 1 of Example 2, 1-((3R,5S,8S,9S,10S,13S,14S,17S)-3-hydroxy-3,13-dimethyltetradecahydro-6H-5,10-methanocyclopenta[a]phenanthren-17-yl)ethan-1-one was used as the starting material, accordingly, the product 2-bromo-1-((3R,5S,8S,9S,10S,13S,14S,17S)-3-hydroxy-3,13-dimethyltetradecahydro-6H-5,10-methanocyclopenta[a]phenanthren-17-yl)ethan-1-one (white solid, yield: 100%) was obtained.

    Step 8: 1-(2-((3R,5S,8S,9S,10S,13S,14S,17S)-3-Hydroxy-3,13-dimethyltetradecahydro-6H-5,10-methanocyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile

    [0554] ##STR00184##

    [0555] In accordance with Step 2 of Example 2, 2-bromo-1-((3R,5S,8S,9S,10S,13S,14S,17S)-3-hydroxy-3,13-dimethyltetradecahydro-6H-5,10-methanocyclopenta[a]phenanthren-17-yl)ethan-1-one was used as the starting material, accordingly, the product 1-(2-((3R,5S,8S,9S,10S,13S,14S,17S)-3-hydroxy-3,13-dimethyltetradecahydro-6H-5,10-methanocyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile (18 mg, white solid, yield: 21.9%) was obtained.

    [0556] MS m/z (ESI): 404.2 [M-17].sup.+.

    [0557] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.86 (s, 1H), 7.81 (s, 1H), 5.05-4.85 (m, 2H), 2.61 (t, J=8.8 Hz, 1H), 2.25-2.15 (m, 1H), 2.10-1.95 (m, 2H), 1.90-1.25 (m, 15H), 1.19 (s, 3H), 1.15-1.05 (m, 1H), 0.90-0.80 (m, 2H), 0.66 (s, 3H), 0.43-0.38 (m, 2H).

    Example 118

    1-(2-((3R,5S,8S,9S,10S,13S,14 S,17S)-3-Hydroxy-3,13-dimethyltetradecahydro-6H-5,10-methanocyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-1H-pyrazole-3-carbonitrile

    [0558] ##STR00185##

    [0559] In accordance with Step 2 of Example 2, 2-bromo-1-((3R,5S,8S,9S,10S,13S,14S,17S)-3-hydroxy-3,13-dimethyltetradecahydro-6H-5,10-methanocyclopenta[a]phenanthren-17-yl)ethan-1-one was used as the starting material, accordingly, the product 1-(2-((3R,5S,8S,9S,10S,13S,14S,17S)-3-hydroxy-3,13-dimethyltetradecahydro-6H-5,10-methanocyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-1H-pyrazole-3-carbonitrile (10.5 mg, white solid, yield: 15.4%) was obtained.

    [0560] MS m/z (ESI): 404.2 [M−H.sub.2O+H].sup.+.

    [0561] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.48 (d, J=2.4 Hz, 1H), 6.73 (d, J=2.4 Hz, 1H) 5.10-4.85 (m, 2H), 2.61 (t, J=8.9 Hz, 1H), 2.24-1.98 (m, 3H), 1.90-1.25 (m, 15H), 1.16 (s, 3H), 1.15-1.05 (m, 1H), 0.90-0.80 (m, 2H), 0.67 (s, 3H), 0.43-0.37 (m, 2H).

    Example 119

    1-((3R,5 S,8 S,9S,10S,13S,14S,17S)-3-Hydroxy-3,13-dimethyltetradecahydro-6H-5,10-methanocyclopenta[a]phenanthren-17-yl)-2-(4-(trifluoromethyl)-1H-pyrazol-1-yl)ethan-1-one

    [0562] ##STR00186##

    [0563] In accordance with Step 2 of Example 2, 2-bromo-1-((3R,5S,8S,9S,10S,13S,14S,17S)-3-hydroxy-3,13-dimethyltetradecahydro-6H-5,10-methanocyclopenta[a]phenanthren-17-yl)ethan-1-one was used as the starting material, accordingly, the product 1-((3R,5S,8S,9S,10S,13S,14S,17S)-3-hydroxy-3,13-dimethyltetradecahydro-6H-5,10-methanocyclopenta[a]phenanthren-17-yl)-2-(4-(trifluoromethyl)-1H-pyrazol-1-yl)ethan-1-one (10.5 mg, white solid, yield: 15.4%) was obtained.

    [0564] MS m/z (ESI): 465.2 [M+H].sup.+.

    [0565] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.72 (s, 2H), 5.10-4.85 (m, 2H), 2.61 (t, J=8.9 Hz, 1H), 2.26-1.98 (m, 3H), 1.90-1.25 (m, 15H), 1.19 (s, 3H), 1.15-1.05 (m, 1H), 0.90-0.80 (m, 2H), 0.67 (s, 3H), 0.43-0.37 (m, 2H).

    Example 120 and Example 121

    1-((3R,5 S,8 S,9S,10S,13S,14S,17S)-3-Hydroxy-3,13-dimethyltetradecahydro-6H-5,10-methanocyclopenta[a]phenanthren-17-yl)-2-(1H-1,2,3-triazol-1-yl)ethan-1-one (120)

    1-((3R,5 S,8 S,9S,10S,13S,14S,17S)-3-Hydroxy-3,13-dimethyltetradecahydro-6H-5,10-methanocyclopenta[a]phenanthren-17-yl)-2-(1H-1,2,3-triazol-1-yl)ethan-1-one (121)

    [0566] ##STR00187##

    [0567] In accordance with Step 2 of Example 2, 2-bromo-1-((3R,5S,8S,9S,10S,13S,14S,17S)-3-hydroxy-3,13-dimethyltetradecahydro-6H-5,10-methanocyclopenta[a]phenanthren-17-yl)ethan-1-one was used as the starting material, accordingly, the products 1-((3R,5S,8S,9S,10S,13S,14S,17S)-3-hydroxy-3,13-dimethyltetradecahydro-6H-5,10-methanocyclopenta[a]phenanthren-17-yl)-2-(1H-1,2,3-triazol-1-yl)ethan-1-one (120) (7.2 mg, white solid, yield: 12.2%) and 1 ((3R,5S,8S,9S,10S,13S,14S,17S)-3-hydroxy-3,13-dimethyltetradecahydro-6H-5,10-methanocyclopenta[a]phenanthren-17-yl)-2-(1H-1,2,3-triazol-1-yl)ethan-1-one (121) (10 mg, white solid, yield: 17.1%) were obtained.

    Example 120

    [0568] MS m/z (ESI): 398.2[M+H].sup.+.

    [0569] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.68 (s, 2H), 5.26-5.20 (m, 2H), 2.59 (t, J=8.0 Hz, 1H), 2.24-1.95 (m, 3H), 1.90-1.25 (m, 15H), 1.19 (s, 3H), 1.15-1.05 (m, 1H), 0.90-0.80 (m, 2H), 0.70 (s, 3H), 0.43-0.37 (m, 2H).

    Example 121

    [0570] MS m/z (ESI): 398.2[M+H].sup.+.

    [0571] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.76 (s, 1H), 7.65 (s, 1H), 5.35-5.10 (m, 2H), 2.66 (t, J=8.0 Hz, 1H), 2.25-1.97 (m, 3H), 1.90-1.25 (m, 15H), 1.20 (s, 3H), 1.13-1.05 (m, 1H), 0.90-0.80 (m, 2H), 0.67 (s, 3H), 0.43-0.36 (m, 2H).

    Biological Assay and Evaluation

    [0572] The present invention is further described below in combination with the following test examples, which are not intended to limit the scope of the present invention.

    [0573] I. GABA.sub.A Receptor Binding Ability Test of the Compounds of the Present Invention

    [0574] 1.1 Experimental objective: The objective of this test example is to measure the ability of the compounds to allosterically inhibit the binding of the ion channel blocker (tert-butylbicyclophosphorothionate (TBPS)) to the GABA-A receptor.

    [0575] Experimental Instruments:

    TABLE-US-00001 Instruments/Consumables Supplier Model Vortex mixer IKA MS3 basic Electric thermostat incubator Shanghai Yiheng DHP-9032 Instrument Co., Ltd. TopCount PerkinElmer NTX Universal Harvester Perkin Elmer UNIFILTER-96 High-speed floor-standing Thermo LYNX 4000 centrifuge Glass tissue homogenizer Nanjing Luanyu Glass 50 ml Instrument Co., Ltd. Sprague-Dawley Rat Pharmaron Protease inhibitor roche 11836170001 1.1 ml deep 96-well plate Axygen P-DW-11-C round bottom ULTIMA GOLD Perkin Elmer 77-16061 UNIFILTER-96 Perkin Elmer 6005177 GF/B filter plate Polyethylenimine Sigma 408727 (PEI), branched

    [0576] 1.2 Experimental Procedures

    [0577] 1.2.1 Extraction of Cerebral Cortex Cell Membrane:

    [0578] 1. The cerebral cortex of male Sprague-Dawley rat was isolated.

    [0579] 2. A pre-chilled 0.32 M sucrose solution (one tablet of protease inhibitor was added per 100 ml) was added to the cerebral cortex (the volume of sucrose solution was 10 times the volume of the cerebral cortex). The mixture was crushed with a 50 ml glass tissue homogenizer in batches and mixed well.

    [0580] 3. The mixture was centrifuged at 1500 g, 4° C. for 10 minutes, and the supernatant was collected.

    [0581] 4. The mixture was centrifuged at 20000 g, 4° C. for 30 minutes, and the supernatant was discarded.

    [0582] 5. The precipitate was resuspended with the pre-chilled phosphate buffer saline (PBS) (one tablet of protease inhibitor was added per 100 ml). An average of 4 ml of PBS was added per rat, and the mixture was mixed well with a glass tissue homogenizer.

    [0583] 6. The mixture was centrifuged at 10000 g, 4° C. for 10 minutes, and the supernatant was discarded.

    [0584] 7. Steps 5 and 6 were repeated three times.

    [0585] 8. Finally, the precipitate was resuspended with 4 volumes of PBS. The resulting solution was dispensed, frozen in liquid nitrogen, and stored at −80° C.

    [0586] 9. The protein concentration was measured by the bicinchoninic acid (BCA) method.

    [0587] 1.2.2 .sup.35S-TBPS Binding Assay

    [0588] 1. 230 μL of PBS was added to each well of a well plate with 1.1 ml volume.

    [0589] 2. 60 μL of the cerebral cortex cell membrane (5 μg/μL) solution was added to each well, and the mixture was mixed well.

    [0590] 3. The test compound (3 μL per well) was added, and the plate was incubated at 25° C. for 5 minutes. The DMSO concentration was 1%. The initial compound concentration was 1 NM, and a 3-fold dilution in gradient was carried out to obtain a total of 8 gradients and 2 replicates. 1% DMSO was used as a negative control, and 10 μM P026-2 was used as a positive control.

    [0591] 4. GABA was added at a final concentration of 5 NM, and incubated at 25° C. for 5 minutes. 1 mM GABA solution was formulated, and 1.5 μL of the solution was added to each well.

    [0592] 5. .sup.35S-TBPS was added at a final concentration of 2 nM. The concentration of isotope mother solution was 9.7 NM. After dilution with PBS for 100 times, 6 μL of the diluted isotope solution was added to each well.

    [0593] 6. The plate was incubated at 4° C. for 20 hours.

    [0594] 7. The FilterMate GF/C plate was pre-treated with 0.5% PEI, and incubated at 4° C. for 1 hour.

    [0595] 8. The FilterMate GF/C plate was washed with Universal Harvester twice, 50 ml PBS each time.

    [0596] 9. The reaction solution was transferred to the GF/C plate, and each well was washed 4 times with 900 μL PBS.

    [0597] 10. The washed GF/C plate was placed at 55° C. and dried for 10 minutes.

    [0598] 11. 40 μL of scintillation solution was added to each well, and the CPM value was read with TopCount.

    [0599] 1.2.3 Experimental Data Processing Method:

    [0600] In the experiment, the CPM (counts per minute) value was read with TopCount. According to the readings of the High control (DMSO) and the Low control (10 μM of the positive compound) experimental groups, the % inhibition was calculated based on the following formula:


    % Inhibition=100×(CPM.sub.High control−CPM.sub.Sample)/(CPM.sub.High control−CPM.sub.Low control)

    [0601] The IC.sub.50 of the compound was calculated according to the following 4-parameter nonlinear logic formula:


    Y=Bottom+(Top−Bottom)/(1+10{circumflex over ( )}((Log IC50−X)*Hill Slope)),

    [0602] wherein:

    [0603] X represents the log of compound concentration,

    [0604] Y represents the % Inhibition.

    [0605] The effect of the compound of the present invention on the TBPS binding activity was determined by the above test, and the measured IC50 values are shown in Table 1.

    TABLE-US-00002 TABLE 1 IC.sub.50 of the compounds of the present invention on inhibiting the TBPS binding activity Compound .sup.35S-TBPS bindng Compound .sup.35S-TBPS No. test (nM) No. bindng test (nM) 1 42.4 35 15.1 2 11.8 36 13.7 3 10.9 37 17.0 5 8.3 38 34.0 7 12.4 40 12.0 10 5.3 41 13.6 11 41.3 45 34.4 12 13.5 46 5.6 14 10.4 47 7.3 15 8.7 48 7.3 16 40.0 49 48.0 18 10.0 50 12.5 19 15.2 51 14.3 21 36.1 52 23.0 23 30.9 55 42.5 24 10.2 58 37.8 25 6.7 59 9.4 26 10.5 62 7.1 27 7.5 63 25.8 30 7.2 64 24.8 31 11.1 66 27.0 33 13.8 70 7.6 34 9.3 71 49.0

    [0606] Conclusion: The compounds of the present invention have a significant inhibitory effect on the TBPS binding activity.

    [0607] II. Pharmacokinetic Assay in Balb/c Mice

    [0608] 1. Test Objective:

    [0609] Balb/c mice were used as test animals. The pharmacokinetic behavior in mice (plasma and brain tissue) of the compounds of Example 2, Example 5, Example 7, Example 12, Example 18, Example 23, Example 26, Example 38, Example 41, Example 50, Example 51 and Example 66 orally administrated at a dose of 5 mg/kg was studied.

    [0610] 2. Test Protocol:

    [0611] 2.1 Test Compounds:

    [0612] Compounds of Example 2, Example 5, Example 7, Example 12, Example 18, Example 23, Example 26, Example 38, Example 41, Example 50, Example 51 and Example 66 of the present invention, prepared by the applicant.

    [0613] 2.2 Test Animals:

    [0614] Male Balb/c mice were purchased from Shanghai Jiesijie Laboratory Animal Co., LTD, with Certificate No.: SCXK (Shanghai) 2013-0006 NO. 311620400001794.

    [0615] 2.3 Administration:

    [0616] Each group had 24 male Balb/c mice. After an overnight fast, Balb/c mice were administrated p.o. with the test compound at an administration dose of 5 mg/kg and an administration volume of 10 mL/kg.

    [0617] 2.4 Sample Collection:

    [0618] 0.2 ml of blood was taken from the heart before administration and at 0, 0.5, 1, 2, 4, 6, 8 and 24 hours after administration. The samples were stored in EDTA-K.sub.2 tubes, and centrifuged for 6 minutes at 4° C., 6000 rpm to separate the plasma. The plasma samples were stored at −80° C. The mice were sacrificed with CO.sub.2, and the whole brain tissue was taken out, weighed, placed in a 2 mL centrifuge tube and stored at −80° C.

    [0619] 2.5 Sample Process:

    [0620] 1) 160 μL of acetonitrile was added to 40 μL of the plasma sample for precipitation, and then the mixture was centrifuged for 5-20 minutes at 3500×g.

    [0621] 2) 90 μL of acetonitrile containing the internal standard (100 ng/mL) was added to 30 μL of the plasma and brain homogenate samples for precipitation, and then the mixture was centrifuged for 8 minutes at 13000 rpm.

    [0622] 3) 70 μL of the treated supernatant was taken and added to 70 μL of water, and mixed by vortex for 10 minutes. 20 μL of the mixture was taken to analyze the concentration of the test compound by LC/MS/MS. LC/MS/MS analysis instrument: AB Sciex API 4000 Qtrap.

    [0623] 2.6 Liquid Chromatography Analysis [0624] Liquid chromatography condition: Shimadzu LC-20AD pump. [0625] Chromatographic column: Agilent ZORBAX XDB-C18 (50×2.1 mm, 3.5 μm); Mobile phase: Eluent A was 0.1% formic acid in water, and Eluent B was acetonitrile. [0626] Flow rate: 0.4 mL/min [0627] Elution time: 0-4.0 minutes the eluent is as follows:

    TABLE-US-00003 Time/minute Eluent A Eluent B 0.01 90% 10% 0.5 90% 10% 0.8  5% 95% 2.4  5% 95% 2.5 90% 10% 4.0 Stop

    [0628] 3. Test Results and Analysis

    [0629] The main parameters of pharmacokinetics were calculated by WinNonlin 6.1. The results of pharmacokinetic test in mice are shown in Table 2 below:

    TABLE-US-00004 TABLE 2 Results of pharmacokinetic test in mice Pharmacokinetic test (5 mg/kg) Plasma Mean Peak time concentration Area under curve Area under curve Half-life residence time Example No. t.sub.max(ng/mL) C.sub.max(ng/mL) AUC.sub.0-t(ng/mL × h) AUC.sub.0-∞(ng/mL × h) t.sub.1/2(h) MRT(h) Example 2 1.0 846.3 2655.8 2707.2 1.49 2.49 plasma Example 2 1.0 655.0 1765.2 1794.9 1.49 2.26 brain tissue Example 5 0.5 242.0 515.2 524.1 1.16 1.94 plasma Example 5 0.5 233.7 470.9 485.5 0.94 1.74 brain tissue Example 7 1.0 888.3 3779.8 3782.8 1.73 3.67 plasma Example 7 1.0 1263.3 5106.0 5514.3 1.89 3.37 brain tissue Example 12 0.5 5160.0 4288.5 4294.4 1.17 0.86 plasma Example 12 0.5 583.0 422.6 424.5 0.20 0.73 brain tissue Example 18 1.0 236 1518.1 1544.3 4.2 5.5 plasma Example 18 1.0 281.7 2141.1 2186.8 4.7 6.1 brain tissue Example 23 0.5 408.0 544.7 555.7 1.08 1.78 plasma Example 23 0.5 558.0 1067.1 1126.7 1.36 2.42 brain tissue Example 26 0.5 232.3 767 771.5 2.57 4.08 plasma Example 26 0.5 172.3 722.9 828.4 2.06 3.84 brain tissue Example 38 0.5 1113.7 1945.1 1974.3 1.08 1.7 plasma Example 38 0.5 746.7 1216.1 1230.2 1.14 1.6 brain tissue Example 41 0.5 1226.7 1144.4 1147.4 0.72 0.94 plasma Example 41 0.5 625.3 553.5 559.5 0.35 0.91 brain tissue Example 50 1.0 324.0 1080.7 1097.3 1.11 2.36 plasma Example 50 1.0 656.0 2215.1 2265.7 1.10 2.48 brain tissue Example 51 0.5 711.2 1955.1 2079.5 1.93 2.65 plasma Example 51 1.0 512.3 1625.9 1796.0 2.19 3.28 brain tissue Example 66 0.5 917.7 6040.9 6124.7 4.39 5.54 plasma Example 66 1.0 2006.0 14940.0 15020.9 3.60 5.01 brain tissue

    [0630] It can be seen from the results of the pharmacokinetic test in mice in the table that the compounds of the examples of the present invention showed good metabolic properties, and both the exposure AUC and the maximum blood drug concentration C.sub.max performed well.

    [0631] III. In Vivo Pharmacodynamic Test in the Forced Swimming Model in Mice

    [0632] 3.1 Experimental Objective

    [0633] The antidepressant effect of the compound was evaluated by the forced swimming model in mice.

    [0634] 3.2 Main Instruments and Reagents of the Experiment

    [0635] 3.2.1 Instruments

    [0636] Forced swimming device (JLBehv-FSC-4, Shanghai Jiliang Software Technology Co., Ltd.).

    [0637] 3.2.2 Reagents

    [0638] Sodium carboxymethyl cellulose (CMC-Na, SLBV9664, Sigma)

    [0639] Tween 80 (BCBV8843, Sigma)

    [0640] 3.2.3 Test Compounds

    [0641] Compounds of Example 2, Example 5, Example 7, Example 18, Example 23, Example 26 and Example 50 of the present invention, prepared by the applicant.

    [0642] 3.3 Experimental Procedures

    [0643] 3.3.1 Adaptation:

    [0644] Male ICR mice (25-35 g) were adapted in the test environment for 3 days before the forced swimming test.

    [0645] 3.3.2 Grouping and Administration:

    [0646] According to the test design, the mice were randomly grouped on the day before the test according to body weight, with 12 mice in each group. Before the test, the compounds of each example were administrated intragastrically according to the Tmax thereof in the brain in mice pharmacokinetic test as follows:

    [0647] 1) Model group (0.5% CMC-Na+1% Tween 80 solution, p.o., 10 mL/kg);

    [0648] 2) Compounds of Example 2, Example 5, Example 7, Example 18, Example 23, Example 26 and Example 50 (10 mg/kg, p.o., 10 mL/kg).

    [0649] When being administrated, the compounds of each example were suspended in 0.5% CMC-Na-1% Tween 80 solution to the desired concentration.

    [0650] 3.3.2 Forced Swimming Test:

    [0651] 0.5-1 hour after administration, ICR mice were placed in a forced swimming device (transparent glass drum (water depth 18 cm, water temperature 25-26° C.), one mouse per tank) and forced to swim for 6 minutes. The forced swimming device recorded the floating time of the ICR mice during the entire 6 minutes, and the data of the latter four minutes were used for data analysis. The mice were taken out immediately after the swimming test, wiped dry and put back in their original cages.

    [0652] Note: The criterion for determining the immobility time is that the mouse stops struggling in water and floats, and there are only slight limb movements to keep the head floating on the water.

    [0653] 3.4 Data Analysis


    Floating time percentage=100*floating time/240 s.

    [0654] 3.5 Test Data:

    TABLE-US-00005 Example No. Dose (mpk) Mean (immobility, s) Mean (immobility, %) Vehicle / 163.70 68.22 Example 2 10 87.34 36.39 Example 5 10 65.07 27.11 Example 7 10 141.58 58.99 Example 18 10 146.86 61.19 Example 23 10 68.51 28.55 Example 26 10 128.30 53.46 Example 50 10 101.07 42.11

    [0655] 3.6 Test Results

    [0656] It can be seen from the above results that the compounds of the examples of the present application can significantly shorten the cumulative immobility time of the forced-swimming mice, and have a significant antidepressant effect.

    [0657] The immobility time during the latter four minutes of the compound of Example 2 was significantly different compared with that of the model group; and the immobility time during the latter four minutes of the compounds of Example 5, Example 23 and Example 50 was very significantly different compared with that of the model group.

    [0658] IV. In Vivo Pharmacodynamic Test in the PTZ-Induced Epilepsy Model in Mice

    [0659] 4.1 Test Objective

    [0660] The PTZ-induced epilepsy model in CD-1 mice was established, and the antiepileptic effect of the compounds of Example 5 and Example 23 was evaluated using this model.

    [0661] 4.2 Test Method

    [0662] 4.2.1 Test Animals

    [0663] 30 male CD-1 mice were purchased from Beijing Vital River Laboratory Animal Technology Co. Ltd. The test animals were adapted at the animal room in the third building of Shanghai ChemPartner Co., Ltd for 7 days before the test. The average body weight of the animals on the test day was 32.2±0.2 grams. Feeding environment: 5 animals/cage, room temperature 23±2° C., 12/12 hours of light and dark cycle, free access to food and water.

    [0664] The mice were randomly grouped for the test on the test day.

    [0665] 4.2.2 Test Compounds

    [0666] Compounds of Example 5 and Example 23 (prepared by the applicant). The test compounds were stored in a refrigerator at 4° C.

    TABLE-US-00006 TABLE 3 Test reagent information Article Batch Total Store Name number number Property Supplier weight Purity condition pentylenetetrazol P6500 SLBD3876V White Sigma 25 g 100% −20° C. (PTZ) crystal refrigeration Sodium 9004-32-4 LAB0R36 White Beijing J&K 100 G 800 cps Room carboxymethyl solid Scientific Co., temperature/dry/in cellulose Ltd. the dark Tween-80 9005-65-6 P1279207 Transparent GENERAL- 500 mL 100% Room liquid REAGENT ® temperature/dry Hydroxypropyl 19184C OP1901A White Seebio 500 g >98% 2-8° C. β-cyclodextrin powder Biotech refrigeration 0.9% sodium H37022749 H18010314 Transparent Shandong Hualu 500 mL 100% Room chloride liquid Pharmaceutical temperature/dry injection Co., Ltd.

    [0667] 4.2.1 Test Equipments [0668] 1 ml sterile disposable syringe with needle (purchased from Zhejiang Kangdelai Medical Devices Co., Ltd.) [0669] Pipette: Eppendorf Research Plus (100-1000 μL) [0670] Vortex mixer: Kylin-Bell Vortex 5 [0671] Ultrasonic instrument: JL-360 ultrasonic cleaner [0672] Balance: METTLER TOLEDO XS204 precision balance [0673] Balance: METTLER TOLEDO XS6002S electronic balance [0674] Plexiglass box: 25 cm length*15 cm width*15 cm height with one opaque side wall, custom made by Suzhou Fengshi Laboratory Animal Equipment Co., Ltd [0675] 3-channel timer: Oregon/Model NO. WB-388

    [0676] 4.2.2 Test Animal Grouping

    [0677] 1) Vehicle/PTZ: 0.5% CMC-Na+1% Tween-80 (10 ml/kg, p.o.), administrated 0.5 hr before the PTZ administration; PTZ (120 ml/kg, s.c.), administrated before the test;

    [0678] 2) 3 mg/kg of the compounds of Examples/PTZ: the compounds of Example 5 and Example 23 (3 mg/kg, 10 ml/kg, p.o.), administrated 0.5 hr before the PTZ administration; PTZ (120 ml/kg, s.c.), administrated before the test.

    [0679] 4.3 Experimental Procedures

    [0680] 4.3.1 Solvent Formulation

    [0681] 1) 0.5% CMC-NA+1% Tween-80 (administration volume: 10 mL/kg):

    [0682] 1 g of sodium carboxymethyl cellulose was precisely weighed and added to a 250 mL solvent bottle, then 150 mL of double-distilled water was added. The mixture was stirred at room temperature for 4 hours with a magnetic stirrer to obtain a uniform and clear solution. 2 mL of Tween-80 was slowly added, and the mixture was stirred at room temperature for 3 hours to obtain a uniform and clear solution. The solution was slowly transferred to a 200 mL volumetric flask, and double distilled water was added to the constant volume of 200 mL. The solution was transferred to a 250 mL solvent bottle, and stirred for 1 hour with a magnetic stirrer to obtain a uniform and clear solution.

    [0683] 2) 30% hydroxypropyl-β-cyclodextrin:

    [0684] 30.6122 g of hydroxypropyl-β-cyclodextrin (purity: 98%) was precisely weighed and added to a 100 mL solvent bottle, then 60 mL of double-distilled water was added. The mixture was mixed by vortex for 3 minutes, and treated by ultrasound at room temperature for 15 minutes to obtain a uniform and clear solution. Double distilled water was added to the constant volume of 100 mL, mixed by vortex for 1 minute, and treated by ultrasound at room temperature for 5 minutes to obtain a uniform and clear solution.

    [0685] 4.3.2 Test Compound Formulation

    [0686] 1) 12 mg/mL PTZ (dose: 120 mg/kg; administration volume: 10 mL/kg):

    [0687] 248 mg of PTZ was precisely weighed and added to a 40 mL brown flask, then 20.667 mL of physiological saline was added. The mixture was mixed by vortex for 2 minutes, and treated by ultrasound at room temperature for 2 minutes to obtain a uniform and clear solution (concentration: 12 mg/mL).

    [0688] 2) 0.3 mg/mL of the compounds of Example 5 or Example 23 (dose: 3 mg/kg; administration volume: 10 mL/kg):

    [0689] A certain amount of 0.5% CMC-NA+1% Tween-80 was taken and added to a flask containing a certain amount of the compounds of Example 5 or Example 23. The mixture was mixed by vortex for 3 minutes, and treated by ultrasound at room temperature for 15 minutes to obtain a uniform suspension (concentration: 0.3 mg/mL).

    [0690] 4.3.3 Test Method

    [0691] 1) The test animals were transferred to the operating room to adapt to the environment 1 hour before the test;

    [0692] 2) The animals were randomly grouped, marked and weighed;

    [0693] 3) The compounds of Example 5 and Example 23 were administrated respectively 1 hour before the PTZ administration, or 0.5% CMC-NA+1% Tween-80, the compounds of Example 5 and Example 23 were administrated respectively 0.5 hour before the PTZ administration;

    [0694] 4) PTZ (120 mg/kg) was administrated subcutaneously before the test observation, and this time point was recorded as the observation start point;

    [0695] 5) After the administration of PTZ, the animal was immediately placed in the observation box and observed for 30 minutes, and the followings were recorded: a) the incubation period of the first clonic seizure, b) the incubation period of the first generalized tonic seizure, c) the number of clonic seizures, d) the number of generalized tonic seizures, e) the time when the animal died, 6) if the animal did not have seizures during the 30-minute observation period, the incubation period was recorded as 1800 sec and the number of seizures was recorded as 0. [0696] Clonic seizure: generalized clonic seizure in animals lasts for more than 3 seconds, and is accompanied by a fall; [0697] Tonic seizure: the limbs straightens 90° to the body;

    [0698] 6) The possible side effects induced by the drug after the administration were observed and recorded, which can be divided into four levels: [0699] None: normal [0700] Mild sedation [0701] Moderate sedation [0702] Severe sedation

    [0703] 7) The test was carried out from 12:00 am to 16:30 pm.

    [0704] 4.4 Adaptation to the Environment

    [0705] The test animals were transferred to the operating room to adapt to the environment 1 hour before the test.

    [0706] 4.5 Grouping and Administration

    [0707] The mice were randomly grouped, marked and weighed; 10 mice per group. The test compound was administrated orally at an administration volume of 10 mL/kg 30-60 minutes before the PTZ administration.

    [0708] 4.6 PTZ Modeling and Testing

    [0709] PTZ (120 mg/kg) was administrated subcutaneously before the test observation, and this time point was recorded as the observation start point; after the administration of PTZ, the animal was immediately placed in the observation box and observed for 30 minutes, and the followings were recorded: a) the incubation period of the first clonic seizure, b) the incubation period of the first generalized tonic seizure, c) the number of clonic seizures, d) the number of generalized tonic seizures, e) the time when the animal died. If the animal did not have seizures during the 30-minute observation period, the incubation period was recorded as 1800 sec and the number of seizures was recorded as 0.

    [0710] 4.7 Data Analysis

    [0711] All measurement data were expressed as Mean±SEM, and analysed with Prism 6.0 statistical software.

    [0712] 4.8 Test Data:

    TABLE-US-00007 Incubation Number Incubation period of the of Time when period of the Number generalized generalized the animal clonic of clonic tonic seizure tonic died Mortality Dose seizure (sec) seizures (sec) seizures (sec) rate Example No. (mpk) Mean ± SEM Mean Mean Mean Mean (%) Vehicle / 331.4 ± 61.2 2.1 ± 0.2  821.6 ± 107.7 1.0 ± 0.0  839.8 ± 108.0 100%   5 3  644.5 ± 122.0 1.8 ± 0.3 1576.7 ± 108.8 0.4 ± 0.2 1623.0 ± 105.5 40% 23 3 366.5 ± 21.1 1.8 ± 0.2 1519.9 ± 117.9 0.4 ± 0.2 1527.7 ± 114.6 40%

    [0713] 4.9 Test Results

    [0714] The compounds of the examples significantly prolonged the incubation period of clonic seizure and generalized tonic seizure and reduced the number of clonic seizures and generalized tonic seizures, compared with the control group. The compounds of the examples can protect 60% of animals from death, significantly prolong the incubation period of death, and have a good antiepileptic effect.

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