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

20210139530 · 2021-05-13

    Inventors

    Cpc classification

    International classification

    Abstract

    Steroid derivative regulators, a method for preparing the same, and uses thereof are described. Specifically, a compound of formula (I), a preparation method therefor, a pharmaceutical composition containing the compound, and uses thereof as a regulator the of GABA.sub.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: ##STR00333## 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—, ##STR00334## R.sup.x, R.sup.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, alkenyl, 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.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.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—, R.sub.17 is 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; 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: ##STR00335## 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 are as defined in claim 1.

    3. The compound of formula (I), the stereoisomer thereof, or the pharmaceutically acceptable salt thereof according to claim 1, being a compound of formula (I-A), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: ##STR00336## wherein: Y is selected from the group consisting of —S(CH.sub.2).sub.n1—, ##STR00337## 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; R.sub.5, R.sub.6, R.sub.15a, R.sub.15b, R.sub.16a, R.sub.16b 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, alkenyl, 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.5, R.sub.6, R.sub.15a, R.sub.15b, R.sub.16a, R.sub.16b 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.17 is 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; or, R.sub.17 and any group of R.sub.16a and R.sub.16b 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.n1C(O)R.sub.23, and —(CH.sub.2).sub.n1NR.sub.23S(O).sub.m1R.sub.24; 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, alkenyl, 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.n1C(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.n1C(O)R.sub.23, —(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; n is an integer of 0, 1, 2 or 3; and R.sub.22-R.sub.26, m.sub.4 and n.sub.4 are as defined in claim 1.

    4. The compound of formula (I), the stereoisomer thereof, or the pharmaceutically acceptable salt thereof according to claim 2, being a compound of formula (I-2), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: ##STR00338## 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.

    5. The compound of formula (I), the stereoisomer thereof, or the pharmaceutically acceptable salt thereof according to claim 4, being a compound of formula (IV-1), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: ##STR00339## wherein: Z is selected from the group consisting of —CR.sub.23R.sub.24—, —NR.sub.23— and —O—, and preferably methylene; ring A 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.a 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.22, —(CH.sub.2).sub.n1C(O)OR.sub.22, —(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 x is an integer of 0, 1, 3, 4 or 5; and 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, RU, R.sub.12, R.sub.15a, R.sub.15b, R.sub.16a, R.sub.16b, R.sub.18, R.sub.19, R.sub.23-R.sub.26, n, m.sub.1 and n.sub.1 are as defined in claim 4.

    6. The compound of formula (I), the stereoisomer thereof, or the pharmaceutically acceptable salt thereof according to claim 4, being a compound of formula (I-2-A) or (I-2-B), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: ##STR00340## wherein: 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.17, R.sub.18, R.sub.19, R.sub.21 and n are as defined in claim 4; ring A, Z, Ra and x are as defined in claim 4.

    7. The compound of formula (IV-1), the stereoisomer thereof, or the pharmaceutically acceptable salt thereof according to claim 5, being a compound of formula (IV-2), (IV-3), (IV-4) or (IV-5), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: ##STR00341## wherein: 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.21, R.sub.15a, R.sub.15b, R.sub.16a, R.sub.16b, R.sub.17, R.sub.18, R.sub.19, R.sub.21 and n are as defined in claim 4; ring A, Z, Ra and x 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 (IV), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: ##STR00342## wherein: Z is selected from the group consisting of —CR.sub.23R.sub.24—, —(CH.sub.2).sub.n1NR.sub.23— and —(CH.sub.2).sub.n1O(CH.sub.2).sub.n2—, and preferably methylene; ring A 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, alkenyl, alkoxy, haloalkoxy, hydroxy alkyl, cycloalkyl, heterocyclyl, aryl, 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.sup.a 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)R.sub.24, —(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, cycloalkyl, heterocyclyl, aryl, 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.15a is selected from the group consisting of hydrogen atom, alkyl, haloalkyl, alkoxy, halogen, amino, hydroxy, 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.n1S(O).sub.m1R.sub.22 and —(CH.sub.2).sub.n1NR.sub.23R.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, alkenyl, alkoxy, haloalkoxy, hydroxy alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; R.sub.16a is selected from the group consisting of hydrogen atom, alkyl, haloalkyl, alkoxy, halogen, amino, hydroxy, 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.n1S(O).sub.m1R.sub.23 and —(CH.sub.2).sub.n1NR.sub.23R.sub.24; or, R.sub.15a and R.sub.16a form a cycloalkyl or heterocyclyl, wherein the cycloalkyl or heterocyclyl 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, cycloalkyl, heterocyclyl, aryl and heteroaryl, and R.sub.15a and R.sub.16a are not hydrogen at the same time; R.sub.23 and R.sub.24 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 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, cycloalkyl, heterocyclyl, aryl, 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; and R.sub.25-R.sub.26, m.sub.1 and n.sub.1 are as defined in claim 1.

    9. The compound of formula (I), the stereoisomer thereof, or the pharmaceutically acceptable salt thereof according to claim 8, being a compound of formula (IV-A), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: ##STR00343## R.sub.15a is selected from the group consisting of hydrogen atom, alkyl, haloalkyl, alkoxy, halogen, amino, hydroxy, 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.n1S(O).sub.m1R.sub.23 and —(CH.sub.2).sub.n1NR.sub.23R.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, alkenyl, alkoxy, haloalkoxy, hydroxy alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; ring A, Z, R.sup.a, R.sub.23-R.sub.24, np, n.sub.t and x are as defined in claim 8.

    10. The compound of formula (I), the stereoisomer thereof, or the pharmaceutically acceptable salt thereof according to claim 1, being a compound of formula (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: ##STR00344## wherein: 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, alkenyl, 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)R.sub.24, —(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, cycloalkyl, heterocyclyl, aryl, 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.15a, R.sub.15b, R.sub.16a and R.sub.16b 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)R.sub.24, —(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, cycloalkyl, heterocyclyl, aryl, 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 R.sub.15a, R.sub.15b, R.sub.16a and R.sub.16b are not hydrogen at the same time; or, any two adjacent or non-adjacent groups of R.sub.15a, R.sub.15b, R.sub.16a and R.sub.16b 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, cycloalkyl, heterocyclyl, aryl, 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, 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)R.sub.24, —(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; R.sub.21, R.sub.23-R.sub.26, m.sub.1 and n.sub.1 are as defined in claim 1.

    11. 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: ##STR00345## wherein: R.sub.15a, R.sub.16a and R.sub.21 are as defined in claim 2.

    12. The compound of formula (I), the stereoisomer thereof, or the pharmaceutically acceptable salt thereof according to claim 5, being a compound of formula (V), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: ##STR00346## wherein: R.sub.15a, R.sub.16a, R.sup.a and x are as defined in claim 5.

    13. The compound of formula (I), the stereoisomer thereof, or the pharmaceutically acceptable salt thereof according to claim 12, being a compound of formula (V-A), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: ##STR00347## wherein: R.sub.15a, R.sub.16a, R.sup.a and x are as defined in claim 12.

    14. The compound of formula (I), the stereoisomer thereof, or the pharmaceutically acceptable salt thereof according to claim 8, being a compound of formula a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: ##STR00348## wherein: each R.sup.d 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)R.sub.24, —(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; y is an integer of 0, 1, 3 or 4; ring A, Z, R.sup.a, R.sub.23-R.sub.26, m.sub.1, n.sub.1 and x are as defined in claim 8.

    15. The compound of formula (I), the stereoisomer thereof, or the pharmaceutically acceptable salt thereof according to claim 14, being a compound of formula (VI-A), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: ##STR00349## wherein: ring A, Z, R.sup.a, R.sup.d, R.sub.23-R.sub.26, m.sub.1, n.sub.1, x and y are as defined in claim 14.

    16. 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: ##STR00350## wherein: Y is selected from the group consisting of —S(CH.sub.2).sub.n1—, ##STR00351## 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, alkenyl, 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.

    17. The compound of formula (I), the stereoisomer thereof, or the pharmaceutically acceptable salt thereof according to claim 1, being a compound of formula (VIII), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: ##STR00352## 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, alkenyl, 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.

    18. 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: ##STR00353## wherein: Y is selected from the group consisting of —S(CH.sub.2).sub.n1—, ##STR00354## 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, alkenyl, 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; and n is an integer of 0, 1 or 2; R.sub.22-R.sub.26, m.sub.1 and n.sub.1 are as defined in claim 1.

    19. 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: ##STR00355## wherein: M is selected from the group consisting of —CR.sub.23— and oxygen; Y is selected from the group consisting of —S(CH.sub.2).sub.n1—, ##STR00356## 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, alkenyl, 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.

    20. The compound of formula, the stereoisomer thereof, or the pharmaceutically acceptable salt thereof according to claim 5, wherein the ring A is selected from the group consisting of: ##STR00357## ##STR00358##

    21. The compound of any formula, 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—; Y is selected from the group consisting of —C(O)—, —C(O)CH.sub.2—, —C(O)O—, —C(O)CH.sub.2NH—, —C(O)CH.sub.2O—, —SCH.sub.2—, —S(O)CH.sub.2—, —S(O).sub.2CH.sub.2—, —P(O)R.sub.23—, —C(O)NH— and —C(O)NHSO.sub.2—; R.sup.a is selected from the group consisting of hydrogen atom, halogen, amino, cyano, nitro, C.sub.1-6 alkyl, C.sub.2-6 alkynyl, C.sub.3-6 cycloalkyl, C.sub.1-6 haloalkyl, C.sub.3-8 halocycloalkyl, C.sub.1-6 alkoxy, C.sub.1-6 hydroxyalkyl, —(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.n1C(O)NR.sub.23R.sub.24 and —(CH.sub.2).sub.n1S(O).sub.m1R.sub.23, wherein the C.sub.1-6 alkyl, C.sub.2-6 alkynyl, C.sub.3-6 cycloalkyl, C.sub.1-6 haloalkyl, C.sub.3-6 halocycloalkyl, C.sub.1-6 alkoxy and C.sub.1-6 hydroxyalkyl are each optionally substituted by one or more substituents selected from the group consisting of hydrogen atom, halogen, cyano, hydroxy, C.sub.1-6 alkyl, C.sub.3-6 cycloalkyl and 3 to 6 membered heterocyclyl; R.sup.d is selected from the group consisting of hydrogen atom, halogen, amino, cyano, nitro, C.sub.1-6 alkyl, C.sub.2-6 alkynyl, C.sub.3-6 cycloalkyl, C.sub.1-6 haloalkyl, C.sub.3-8 halocycloalkyl, C.sub.1-6 alkoxy and C.sub.1-6 hydroxyalkyl; R.sub.23 and R.sub.24 are identical or different and are each independently selected from the group consisting of C.sub.1-6 alkyl, C.sub.3-8 cycloalkyl and 3 to 8 membered heterocyclyl, wherein the C.sub.1-6 alkyl, C.sub.3-8 cycloalkyl and 3 to 8 membered heterocyclyl are each optionally father substituted by one or more substituents selected from the group consisting of deuterium atom, halogen, hydroxy, C.sub.1-3 alkyl, amino, oxo, nitro, cyano, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 alkoxy, C.sub.1-6 hydroxyalkyl, C.sub.3-8 cycloalkyl, —(CH.sub.2).sub.n1NR.sub.25R.sub.26, 3 to 8 membered heterocyclyl, 6 to 10 membered aryl and 5 to 12 membered heteroaryl.

    22. The compound of any formula, the stereoisomer thereof, or the pharmaceutically acceptable salt thereof according to claim 2, wherein: R.sub.15a is selected from the group consisting of hydrogen atom, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.1-6 alkoxy, halogen, amino, hydroxy, C.sub.3-8 cycloalkyl, C.sub.3-8 halocycloalkyl, 3 to 8 membered heterocyclyl, 6 to 10 membered aryl, 5 to 12 membered heteroaryl —(CH.sub.2).sub.n1R.sub.23, —(CH.sub.2).sub.n1OR.sub.23, —(CH.sub.2).sub.n1C(O)OR.sub.23, —(CH.sub.2).sub.n1SR.sub.23, —(CH.sub.2).sub.n1S(O).sub.m1R.sub.23 and —(CH.sub.2).sub.n1NR.sub.23R.sub.24, wherein the C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.1-6 alkoxy, C.sub.3-8 cycloalkyl, C.sub.3-8 halocycloalkyl, 3 to 8 membered heterocyclyl, 6 to 10 membered aryl and 5 to 12 membered heteroaryl are each optionally substituted by one or more substituents selected from the group consisting of hydrogen atom, halogen, cyano, hydroxy, nitro, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.3-6 cycloalkyl, —(CH.sub.2).sub.n1NR.sub.25R.sub.26 and 3 to 6 membered heterocyclyl; R.sub.16a is selected from the group consisting of hydrogen atom, halogen, cyano, C.sub.1-6 alkyl and C.sub.1-6 haloalkyl; or, R.sub.15a and R.sub.16a ears form a C.sub.3-8 cycloalkyl, wherein the C.sub.3-8 cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of hydrogen atom, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl and halogen, and R.sub.15a and R.sub.16a are not hydrogen at the same time; R.sub.23 and R.sub.24 are identical or different and are each independently selected from the group consisting of hydrogen atom, C.sub.1-6 alkyl, C.sub.3-8 cycloalkyl and 3 to 8 membered heterocyclyl, wherein the C.sub.1-6 alkyl, C.sub.3-8 cycloalkyl and 3 to 8 membered heterocyclyl are each optionally father substituted by one or more substituents selected from the group consisting of deuterium atom, halogen, hydroxy, C.sub.1-3 alkyl, amino, oxo, nitro, cyano, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 alkoxy, C.sub.1-6 hydroxyalkyl, C.sub.3-8 cycloalkyl, —(CH.sub.2).sub.n1NR.sub.25R.sub.26, 3 to 8 membered heterocyclyl, 6 to 10 membered aryl and 5 to 12 membered heteroaryl.

    23. The compound of formula (I), the stereoisomer thereof, or the pharmaceutically acceptable salt thereof according to claim 1, selected from the group consisting of: ##STR00359## ##STR00360## ##STR00361## ##STR00362## ##STR00363## ##STR00364## ##STR00365## ##STR00366## ##STR00367## ##STR00368## ##STR00369## ##STR00370## ##STR00371## ##STR00372## ##STR00373## ##STR00374## ##STR00375## ##STR00376## ##STR00377## ##STR00378## ##STR00379## ##STR00380## ##STR00381## ##STR00382## ##STR00383## ##STR00384## ##STR00385## ##STR00386## ##STR00387## ##STR00388## ##STR00389## ##STR00390## ##STR00391## ##STR00392## ##STR00393## ##STR00394## ##STR00395## ##STR00396## or a pharmaceutically acceptable salt thereof.

    24. 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.

    25. A method of regulating GABAA receptor in a subject in need thereof, comprising administering the pharmaceutical composition according to claim 24 to the subject.

    26. 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 24 in treating a CNS-related disease, wherein the CNS-related disease is selected from the group consisting of steep 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 or tinnitus.

    Description

    DETAILED DESCRIPTION OF THE INVENTION

    [0175] The present invention will be further described with reference to the following examples, but the examples should not be considered as limiting the scope of the present invention.

    EXAMPLES

    [0176] 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 shifts (δ) 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).

    [0177] 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).

    [0178] 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.

    [0179] The raw 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.

    [0180] Unless otherwise stated, all reactions of the present invention were carried out under continuous magnetic stirring under a dry nitrogen or argon atmosphere, the solvent was dry, and the reaction temperature was in degrees Celsius.

    Example 1

    1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-Hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)ethan-1-one

    [0181] ##STR00072##

    Step 1: Preparation of (3R,5R,8R,9R,10S,13S,14S)-3-hydroxy-3,13-dimethyl-16-(phenylsulfinyl)hexadecahydro-17H-cyclopenta[a]phenanthren-17-one

    [0182] ##STR00073##

    [0183] Potassium tert-butoxide (2.3 g, 20.7 mmol) was dissolved in anhydrous tetrahydrofuran (200 mL), and the reaction system was purged with nitrogen. (3R,5R,8R,9R,10S,13S,14S)-3-Hydroxy-3,13-dimethylhexadecahydro-17H-cyclopenta[a]phenanthren-17-one (3 g, 10.3 mmol) was added to the above solution to obtain an orange solution, which was then stirred at 25° C. for 10 minutes. Methyl benzenesulfinate (3.2 g, 20.7 mmol) was added, and then the reaction solution was stirred at 30° C. for half an hour. Water (100 mL) was added to the reaction solution to quench the reaction, and the aqueous phase was extracted with ethyl acetate (100 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtrated and concentrated. The resulting crude product was purified by column chromatography (petroleum ether/ethyl acetate: 50/1-3/1) to obtain (3R,5R,8R,9R,10S,13S,14S)-3-hydroxy-3,13-dimethyl-16-(phenylsulfinyl)hexadecahydro-17H-cyclopenta[a]phenanthren-17-one (3.5 g, yield: 82%).

    Step 2: Preparation of (3R,5R,8R,9R,10S,13S,14S)-3-hydroxy-3,13-dimethyl-1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetradecahydro-17H-cyclopenta[a]phenanthren-17-one

    [0184] ##STR00074##

    [0185] (3R,5R,8R,9R,10S,13S,14S)-3-Hydroxy-3,13-dimethyl-16-(phenylsulfinyl)hexadecahydro-17H-cyclopenta[a]phenanthren-17-one (3.5 g, 8.5 mmol) was dissolved in xylene (50 mL), and the reaction system was purged with nitrogen. Sodium carbonate (24.7 g, 0.17 mol) was added, and then the reaction solution was stirred at 140° C. overnight. The reaction solution was filtrated, and the organic phase was concentrated. The resulting crude product was purified by column chromatography (petroleum ether/ethyl acetate: 50/1-3/1) to obtain (3R,5R,8R,9R,10S,13S,14S)-3-hydroxy-3,13-dimethyl-1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetradecahydro-17H-cyclopenta[a]phenanthren-17-one (1.5 g, yield: 62%).

    [0186] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.53 (dd, J=5.9, 1.2 Hz, 1H), 6.03 (dd, J=6.0, 3.2 Hz, 1H), 2.42-2.33 (m, 1H), 1.90-1.79 (m, 4H), 1.76-1.66 (m, 2H), 1.58-1.48 (m, 5H), 1.47-1.37 (m, 4H), 1.36-1.23 (m, 7H), 1.08 (s, 3H).

    Step 3: Preparation of (2R,4aS,4bR,6aS,7aS,8aS,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethylhexadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7(1H)-one

    [0187] ##STR00075##

    [0188] Trimethyl sulfoxide (0.92 g, 4.2 mmol) was dissolved in anhydrous dimethyl sulfoxide (10 mL), and the reaction system was purged with nitrogen. Sodium hydride (168 mg, 4.2 mmol) was added, and then the reaction solution was stirred for 1 hour. A solution of (3R,5R,8R,9R,10S,13S,14S)-3-hydroxy-3,13-dimethyl-1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetradecahydro-17H-cyclopenta[a]phenanthren-17-one (1.0 g, 3.5 mmol) in dimethyl sulfoxide (5 mL) was added, and then the reaction solution was stirred at room temperature overnight. Water (50 mL) was added to the reaction solution to quench the reaction, and the aqueous phase was extracted with ethyl acetate (50 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtrated and concentrated. The resulting crude product was purified by column chromatography (petroleum ether/ethyl acetate: 50/1-3/1) to obtain (2R,4aS,4bR,6aS,7aS,8aS,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethylhexadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7(1H)-one (0.75 g, yield: 71%).

    [0189] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 2.06-2.00 (m, 1H), 1.97-1.91 (m, 1H), 1.88-1.79 (m, 3H), 1.78-1.67 (m, 6H), 1.63-1.54 (m, 2H), 1.48-1.39 (m, 3H), 1.37-1.25 (m, 9H), 1.15-1.05 (m, 2H), 0.96 (s, 3H).

    Step 4: Preparation of (2R,4aS,4bR,6aS,7aS,8aR,8bR,8cR,10aR)-7-ethylidene-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-2-ol

    [0190] ##STR00076##

    [0191] PPh.sub.3EtBr (14.8 g, 40 mmol) was dissolved in anhydrous dimethyl sulfoxide (50 mL), and the reaction system was purged with nitrogen. Sodium hydride (1.6 g, 40 mmol) was added, and then the reaction solution was stirred at room temperature for 1 hour. (2R,4aS,4bR,6aS,7aS,8aS,8bR,8cR,10aR)-2-Hydroxy-2,6a-dimethylhexadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7(1H)-one (0.6 g, 2.0 mmol) was added, and then the reaction solution was stirred at 100° C. overnight. The reaction solution was cooled to room temperature. Water (200 mL) was added to the reaction solution to quench the reaction, and the aqueous phase was extracted with ethyl acetate (200 mL×2). The organic phases were combined, dried over anhydrous sodium sulfate, filtrated and concentrated. The resulting crude product was purified by column chromatography (petroleum ether/ethyl acetate: 50/1-3/1) to obtain (2R,4aS,4bR,6aS,7aS,8aR,8bR,8cR,10aR)-7-ethylidene-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-2-ol (0.5 g, yield: 81%).

    Step 5: Preparation of (2R,4aS,4bR,6aS,7aS,8aR,8bR,8cR,10aR)-7-(1-hydroxyethyl)-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-2-ol

    [0192] ##STR00077##

    [0193] (2R,4aS,4bR,6aS,7aS,8aR,8bR,8cR,10aR)-7-Ethylidene-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-2-ol (0.4 g, 1.3 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL). The solution was cooled to 0° C., and then BH.sub.3/THF (12.7 mL, 12.7 mmol) was added dropwise. The reaction solution was stirred at room temperature for 3 hours, and TLC showed that the reaction was completed. The reaction solution was cooled to 0° C., and then 3 M aqueous NaOH solution (4 mL) was slowly added, followed by the addition of H.sub.2O.sub.2 (3 mL). The reaction solution was stirred at room temperature for 2 hours, and TLC showed that the reaction was completed. Ethyl acetate (50 mL) was added, and then the reaction solution was washed with saturated aqueous Na.sub.2S.sub.2O.sub.3 solution (30 mL) and water (30 mL) successively. The organic phase was dried over anhydrous sodium sulfate, filtrated and concentrated to obtain the crude product (0.4 g, yield: 100%, crude), which was used directly in the next step.

    Step 6: Preparation of 1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)ethan-1-one

    [0194] ##STR00078##

    [0195] (2R,4aS,4bR,6aS,7aS,8aR,8bR,8cR,10aR)-7-(1-Hydroxyethyl)-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-2-ol (0.4 g, 1.2 mmol) was dissolved in dichloromethane (20 mL). PCC (0.52 g, 40 mmol) was added, and then the reaction solution was stirred at room temperature for 2 hours. The reaction solution was filtrated, and the organic phase was concentrated. The resulting crude product was purified by column chromatography (petroleum ether/ethyl acetate: 50/1-3/1) to obtain 1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)ethan-1-one (0.35 g, yield: 83%).

    [0196] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 2.74 (d, J=4.1 Hz, 1H), 2.21 (s, 3H), 1.97-1.91 (m, 1H), 1.87-1.62 (m, 7H), 1.56-1.50 (m, 1H), 1.44-1.21 (m, 15H), 1.12-1.00 (m, 1H), 0.90-0.83 (m, 1H), 0.72 (s, 3H), 0.44-0.36 (m, 1H).

    Example 2

    Preparation of 1-(2-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile

    [0197] ##STR00079##

    Step 1: Preparation of 2-bromo-1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethylocta decahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)ethan-1-one

    [0198] ##STR00080##

    [0199] 1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-Hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)ethan-1-one (70 mg, 0.21 mmol) was dissolved in methanol (3 mL). A drop of hydrogen bromide was added to the solution, followed by the addition of liquid bromine (41 mg, 0.25 mmol), and then the reaction solution was stirred at room temperature for 1 hour. Water (20 mL) was added to the reaction solution, and the aqueous phase was extracted with ethyl acetate (20 mL×2). The organic phases were combined, dried over anhydrous sodium sulfate, filtrated and concentrated to obtain the crude product (87 mg, yield: 100%, crude), which was used directly in the next step.

    Step 2: Preparation of 1-(2-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile

    [0200] ##STR00081##

    [0201] 2-Bromo-1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)ethan-1-one (87 mg, 0.21 mmol), 1H-pyrazole-4-carbonitrile (59 mg, 0.64 mmol) and potassium carbonate (145 mg, 1.05 mmol) were dissolved in tetrahydrofuran (2 mL), and the resulting reaction solution was stirred at room temperature overnight. The reaction solution was filtrated, and the filtrate was concentrated. The resulting crude product was purified by high performance liquid chromatography to obtain 1-(2-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile (33 mg, yield: 37%).

    [0202] MS m/z (ESI): 404.2 [M−H.sub.2O+H].sup.+.

    [0203] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.88 (s, 1H), 7.82 (s, 1H), 5.24-5.13 (m, 2H), 2.84 (d, J=2.7 Hz, 1H), 1.98-1.92 (m, 1H), 1.87-1.77 (m, 4H), 1.76-1.66 (m, 3H), 1.57-1.51 (m, 1H), 1.46-1.24 (m, 15H), 1.12-1.02 (m, 1H), 1.00-0.96 (m, 1H), 0.78 (s, 3H), 0.54-0.46 (m, 1H).

    Example 3 and Example 4

    Preparation of 1-(2-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-oxoethyl)-1H-pyrazole-3-carbonitrile (3)

    1-(2-((2R,4aS,4bR,6aS,7R,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-oxoethyl)-1H-pyrazole-3-carbonitrile (4)

    [0204] ##STR00082## ##STR00083##

    [0205] 2-Bromo-1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)ethan-1-one (80 mg, 0.19 mmol), 1H-pyrazole-3-carbonitrile (55 mg, 0.58 mmol) and potassium carbonate (131 mg, 0.95 mmol) were dissolved in tetrahydrofuran (3 mL), and the resulting reaction solution was stirred at room temperature overnight. The reaction solution was filtrated, and the filtrate was concentrated. The resulting crude product was purified by high performance liquid chromatography to obtain 1-(2-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-oxoethyl)-1H-pyrazole-3-carbonitrile (34.7 mg, yield: 42%) and 1-(2-((2R,4aS,4bR,6aS,7R,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-oxoethyl)-1H-pyrazole-3-carbonitrile (3.7 mg, yield: 4.5%).

    Example 3

    [0206] MS m/z (ESI): 404.2 [M−H.sub.2O+H].sup.+

    [0207] .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), 5.29-5.13 (m, 2H), 2.83 (d, J=2.9 Hz, 1H), 1.97-1.92 (m, 1H), 1.86-1.79 (m, 4H), 1.73-1.64 (m, 3H), 1.58-1.52 (m, 1H), 1.43-1.27 (m, 15H), 1.12-0.96 (m, 2H), 0.79 (s, 3H), 0.53-0.44 (m, 1H).

    Example 4

    [0208] MS m/z (ESI): 404.2 [M−H.sub.2O+H].sup.+.

    [0209] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.52 (d, J=2.4 Hz, 1H), 6.75 (d, J=2.4 Hz, 1H), 5.11-4.96 (m, 2H), 2.92 (s, 1H), 1.93-1.87 (m, 1H), 1.82-1.74 (m, 2H), 1.72-1.62 (m, 4H), 1.51 (s, 1H), 1.46-1.24 (m, 15H), 1.18-1.09 (m, 2H), 1.04 (s, 3H), 0.89-0.84 (m, 1H), 0.46-0.40 (m, 1H).

    Example 5

    1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-Hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-(4-(trifluoromethyl)-1H-pyrazol-1-yl)ethan-1-one

    [0210] ##STR00084##

    Step 1: Preparation of 1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-(4-(trifluoromethyl)-1H-pyrazol-1-yl)ethan-1-one

    [0211] ##STR00085##

    [0212] 2-Bromo-1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)ethan-1-one (60 mg, 0.15 mmol), 4-(trifluoromethyl)-1H-pyrazole (60 mg, 0.44 mmol) and potassium carbonate (104 mg, 0.75 mmol) were dissolved in tetrahydrofuran (3 mL), and the resulting reaction solution was stirred at room temperature overnight. The reaction solution was filtrated, and the filtrate was concentrated. The resulting crude product was purified by high performance liquid chromatography to obtain 1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-(4-(trifluoromethyl)-1H-pyrazol-1-yl)ethan-1-one (22.2 mg, yield: 33%).

    [0213] MS m/z (ESI): 465.3 [M+H].sup.+.

    [0214] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.74 (s, 1H), 7.73 (s, 1H), 5.25-5.09 (m, 2H), 2.83 (d, J=3.6 Hz, 1H), 2.00-1.91 (m, 1H), 1.89-1.79 (m, 4H), 1.78-1.65 (m, 3H), 1.58-1.52 (m, 1H), 1.47-1.22 (m, 15H), 1.15-0.95 (m, 2H), 0.79 (s, 3H), 0.52-0.44 (m, 1H).

    Example 6

    1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-Hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-(3-(trifluoromethyl)-1H-pyrazol-1-yl)ethan-1-one

    [0215] ##STR00086##

    Step 1: Preparation of 1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-(3-(trifluoromethyl)-1H-pyrazol-1-yl)ethan-1-one

    [0216] ##STR00087##

    [0217] 2-Bromo-1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)ethan-1-one (80 mg, 0.2 mmol), 3-(trifluoromethyl)-1H-pyrazole (80 mg, 0.6 mmol) and potassium carbonate (138 mg, 1.0 mmol) were dissolved in tetrahydrofuran (5 mL), and the resulting reaction solution was stirred at room temperature overnight. The reaction solution was filtrated, and the filtrate was concentrated. The resulting crude product was purified by high performance liquid chromatography to obtain 1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-(3-(trifluoromethyl)-1H-pyrazol-1-yl)ethan-1-one (17 mg, yield: 18%).

    [0218] MS m/z (ESI): 447.3 [M−H.sub.2O+H].sup.+.

    [0219] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.49 (d, J=1.9 Hz, 1H), 6.60 (d, J=1.9 Hz, 1H), 5.27-5.13 (m, 2H), 2.83 (d, J=3.7 Hz, 1H), 1.99-1.90 (m, 1H), 1.89-1.76 (m, 4H), 1.75-1.61 (m, 3H), 1.58-1.50 (m, 1H), 1.50-1.21 (m, 15H), 1.13-0.96 (m, 2H), 0.79 (s, 3H), 0.52-0.45 (m, 1H).

    Example 7 and Example 8

    1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-Hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-(2H-1,2,3-triazol-2-yl)ethan-1-one (7)

    1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-Hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-(1H-1,2,3-triazol-1-yl)ethan-1-one (8)

    [0220] ##STR00088##

    Step 1: Preparation of 1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-(2H-1,2,3-triazol-2-yl)ethan-1-one (7) and

    1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-(1H-1,2,3-triazol-1-yl)ethan-1-one (8)

    [0221] ##STR00089##

    [0222] 2-Bromo-1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)ethan-1-one (80 mg, 0.19 mmol), 1H-1,2,3-triazole (40 mg, 0.58 mmol) and potassium carbonate (131 mg, 0.95 mmol) were dissolved in tetrahydrofuran (3 mL), and the resulting reaction solution was stirred at room temperature overnight. The reaction solution was filtrated, and the filtrate was concentrated. The resulting crude product was purified by high performance liquid chromatography to obtain 1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-(2H-1,2,3-triazol-2-yl)ethan-1-one (7) (9.2 mg, yield: 12%) and 1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-(1H-1,2,3-triazol-1-yl)ethan-1-one (8) (17.8 mg, yield: 23%).

    Example 7

    [0223] MS m/z (ESI): 380.3 [M−H.sub.2O+H].sup.+.

    [0224] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.69 (s, 2H), 5.55-5.36 (m, 2H), 2.82 (d, J=4.1 Hz, 1H), 1.99-1.92 (m, 1H), 1.87-1.74 (m, 4H), 1.73-1.52 (m, 5H), 1.47-1.26 (m, 14H), 1.14-0.98 (m, 2H), 0.84 (s, 3H), 0.52-0.43 (m, 1H).

    Example 8

    [0225] MS m/z (ESI): 398.3 [M+H].sup.+.

    [0226] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.76 (s, 1H), 7.66 (s, 1H), 5.52-5.35 (m, 2H), 2.87 (d, J=3.9 Hz, 1H), 2.02-1.92 (m, 1H), 1.89-1.78 (m, 4H), 1.76-1.65 (m, 3H), 1.59-1.52 (m, 1H), 1.48-1.23 (m, 15H), 1.15-0.98 (m, 2H), 0.80 (s, 3H), 0.56-0.45 (m, 1H).

    Example 9 and Example 10

    1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-Hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-(2H-tetrazol-2-yl)ethan-1-one (9)

    1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-Hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-(1H-tetrazol-1-yl)ethan-1-one (10)

    [0227] ##STR00090##

    Step 1: Preparation of 1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-(2H-tetrazol-2-yl)ethan-1-one (9) and

    1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-(1H-tetrazol-1-yl)ethan-1-one (10)

    [0228] ##STR00091##

    [0229] 2-Bromo-1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)ethan-1-one (50 mg, 0.12 mmol), 1H-tetrazole (26 mg, 0.37 mmol) and potassium carbonate (83 mg, 0.6 mmol) were dissolved in tetrahydrofuran (3 mL), and the resulting reaction solution was stirred at room temperature overnight. The reaction solution was filtrated, and the filtrate was concentrated. The resulting crude product was purified by high performance liquid chromatography to obtain 1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-(2H-tetrazol-2-yl)ethan-1-one (9) (11.6 mg, yield: 24%) and 1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-(1H-tetrazol-1-yl)ethan-1-one (10) (4.4 mg, yield: 9%).

    Example 9

    [0230] MS m/z (ESI): 381.2 [M−H.sub.2O+H].sup.+

    [0231] .sup.1H NMR (400 MHz, CDCl.sub.3) δ8.58 (s, 1H), 5.74-5.62 (m, 2H), 2.88 (d, J=3.8 Hz, 1H), 1.97-1.91 (m, 1H), 1.87-1.79 (m, 4H), 1.75-1.64 (m, 3H), 1.58-1.55 (m, 1H), 1.45-1.35 (m, 7H), 1.34-1.24 (m, 8H), 1.14-1.01 (m, 2H), 0.85 (s, 3H), 0.56-0.48 (m, 1H).

    Example 10

    [0232] MS m/z (ESI): 399.3 [M+H].sup.+

    [0233] .sup.1H NMR (400 MHz, CDCl.sub.3) δ8.77 (s, 1H), 5.57-5.39 (m, 2H), 2.90 (s, 1H), 2.00-1.91 (m, 1H), 1.88-1.79 (m, 4H), 1.76-1.65 (m, 3H), 1.59-1.56 (m, 1H), 1.46-1.37 (m, 7H), 1.35-1.24 (m, 8H), 1.13-0.99 (m, 2H), 0.79 (s, 3H), 0.58-0.49 (m, 1H).

    Example 11

    1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-Hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-(4-(methylsulfonyl)piperazin-1-yl)ethan-1-one

    [0234] ##STR00092##

    [0235] 2-Bromo-1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)ethan-1-one (50 mg, 0.12 mmol), 1-(methylsulfonyl)piperazine (60 mg, 0.36 mmol) and potassium carbonate (83 mg, 0.6 mmol) were dissolved in tetrahydrofuran (3 mL), and the resulting reaction solution was stirred at room temperature overnight. The reaction solution was filtrated, and the filtrate was concentrated. The resulting crude product was purified by high performance liquid chromatography to obtain 1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-(4-(methylsulfonyl)piperazin-1-yl)ethan-1-one (13.7 mg, yield: 23%).

    [0236] MS m/z (ESI): 493.2 [M+H].sup.+.

    [0237] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 3.63 (br, 2H), 3.47 (br, 4H), 2.93 (br, 4H), 2.82 (s, 3H), 2.73 (s, 1H), 1.90-1.88 (m, 1H), 1.86-1.81 (m, 2H), 1.81-1.70 (m, 3H), 1.70-1.64 (m, 2H), 1.57-1.50 (m, 1H), 1.41 (s, 5H), 1.34-1.22 (m, 10H), 1.12-0.99 (m, 1H), 0.92-0.85 (m, 1H), 0.73 (s, 3H), 0.49-0.39 (m, 1H).

    Example 12

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

    [0238] ##STR00093##

    Step 1: Preparation of (3R,5R,8R,9R,10S,13S,14S,16R)-16-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-17H-cyclopenta[a]phenanthren-17-one

    [0239] ##STR00094##

    [0240] Trimethylsilyl triflate (5.6 mL, 31.0 mmol) was added dropwise to a solution of (3R,5R,8R,9R,10S,13S,14S)-3-hydroxy-3,13-dimethylhexadecahydro-17H-cyclopenta[a]phenanthren-17-one (3 g, 10.3 mmol) and triethylamine (36.0 mL, 258.2 mmol) in toluene (45 mL), and the resulting reaction solution was heated to reflux for 2 hours. The reaction solution was cooled, washed with saturated sodium bicarbonate, and extracted with n-hexane. The organic phase was concentrated to dryness to obtain the crude product (((3R,5R,8R,9R,10S,13S,14S)-3,13-dimethyl-2,3,4,5,6,7,8,9,10,11,12,13,14,15-tetradecahydro-1H-cyclopenta[a]phenanthrene-3,17-diyl)bis(oxy))bis(trimethylsilane). A selective fluorine reagent (4.0 g, 11.4 mmol) was added to a solution of (((3R,5R,8R,9R,10S,13S,14S)-3,13-dimethyl-2,3,4,5,6,7,8,9,10,11,12,13,14,15-tetradecahydro-1H-cyclopenta[a]phenanthrene-3,17-diyl)bis(oxy))bis(trimethylsilane) in N,N-dimethylformamide (25 mL), and the resulting reaction solution was stirred at room temperature for 2 hours to obtain (3R,5R,8R,9R,10S,13S,14S,16R)-16-fluoro-3,13-dimethyl-3-((trimethylsilyl)oxy)hexadecahydro-17H-cyclopenta[a]phenanthren-17-one. A solution of tetrabutylammonium fluoride in tetrahydrofuran (11.4 mL, 1 M) was added, and the resulting reaction solution was stirred at room temperature overnight. The reaction solution was extracted with ethyl acetate, and washed with saturated saline three times. The organic phase was concentrated to dryness, and the resulting crude product was purified by column chromatography (petroleum ether:ethyl acetate=6:4) to obtain (3R,5R,8R,9R,10S,13S,14S,16R)-16-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-17H-cyclopenta[a]phenanthren-17-one (2.0 g, yield: 50.9%).

    [0241] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 5.09 (dd, J=50.6, 7.5 Hz, 1H), 2.18-1.58 (m, 10H), 1.54-1.01 (m, 14H), 0.92 (s, 3H).

    [0242] .sup.19F NMR (376 MHz, CDCl.sub.3) δ −192.59.

    Step 2: Preparation of (3R,5R,8R,9R,10S,13S,14S,16R)-17-ethylidene-16-fluoro-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-3-ol

    [0243] ##STR00095##

    [0244] Sodium hydride (123 mg, 3.08 mmol, 60% w/w) was added to a solution of ethyltriphenylphosphonium bromide (1.2 g, 3.24 mmol) in dimethyl sulfoxide (20 mL) in batches under a nitrogen atmosphere, and the resulting reaction solution was stirred at room temperature for 1 hour. (3R,5R,8R,9R,10S,13S,14S,16R)-16-Fluoro-3-hydroxy-3,13-dimethylhexadecahydro-17H-cyclopenta[a]phenanthren-17-one (200 mg, 0.65 mmol) was added, and the reaction solution was heated to 70° C. under a nitrogen atmosphere overnight. The reaction solution was cooled, and saturated saline was added. 1 N hydrochloric acid was added to adjust pH to 6, and the reaction solution was extracted with ethyl acetate. The organic phase was washed with saturated saline, and concentrated to dryness to obtain a crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate=7:3) to obtain (3R,5R,8R,9R,10S,13S,14S,16R)-17-ethylidene-16-fluoro-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-3-ol (80 mg, yield: 38.5%).

    [0245] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 5.71-5.59 (m, 1H), 5.12 (dt, J=57.2, 7.0 Hz, 1H), 2.27-2.11 (m, 2H), 1.92-1.24 (m, 21H), 1.22-1.09 (m, 4H), 1.06 (s, 3H).

    [0246] .sup.19F NMR (376 MHz, CDCl.sub.3) δ −153.69.

    Step 3: Preparation of (3R,8R,9R,10S,13S,14S,16R,17S)-16-fluoro-17-(1-hydroxyethyl)-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-3-ol

    [0247] ##STR00096##

    [0248] (3R,5R,8R,9R,10S,13S,14S,16R)-17-Ethylidene-16-fluoro-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-3-ol (80 mg, 0.25 mmol) was dissolved in anhydrous tetrahydrofuran (50 mL). A solution of borane in tetrahydrofuran (1 M, 2.5 mL) was added dropwise at room temperature, and the resulting reaction solution was stirred at room temperature for 1 hour. The reaction solution was cooled with ice water, and sodium hydroxide solution (3 M, 1 mL) was slowly added dropwise to release a large amount of gas. Hydrogen peroxide (25%, 0.58 mL) was slowly added dropwise, and then the reaction solution was stirred at room temperature for 2 hours. The reaction solution was extracted with ethyl acetate, washed with sodium thiosulfate solution and saturated saline, and dried to obtain (3R,8R,9R,10S,13S,14S,16R,17S)-16-fluoro-17-(1-hydroxyethyl)-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-3-ol (80 mg), which was used directly in the next step.

    [0249] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 5.47-5.16 (m, 1H), 4.22-4.05 (m, 1H), 2.42-2.17 (m, 1H), 1.94-0.93 (m, 27H), 0.87 (s, 3H).

    [0250] .sup.19F NMR (376 MHz, CDCl.sub.3) δ −178.27.

    Step 4: Preparation of 1-((3R,8R,9R,10S,13S,14S,16R,17S)-16-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one

    [0251] ##STR00097##

    [0252] Pyridinium chlorochromate (102 mg, 0.47 mmol) was added to a solution of (3R,8R,9R,10S,13S,14S,16R,17S)-16-fluoro-17-(1-hydroxyethyl)-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-3-ol (80 mg) in acetone (2 mL), and the resulting reaction solution was reacted at 60° C. for 6 hours. The reaction solution was concentrated to dryness, and the resulting residue was purified by column chromatography (petroleum ether:ethyl acetate=5:2) to obtain 1-((3R,8R,9R,10S,13S,14S,16R,17S)-16-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one (22 mg, yield: 25%).

    [0253] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 5.64-5.35 (m, 1H), 2.44-2.09 (m, 6H), 1.97-1.75 (m, 4H), 1.74-1.00 (m, 20H), 0.98-0.68 (m, 2H).

    [0254] .sup.19F NMR (376 MHz, CDCl.sub.3) δ −168.20.

    Example 13

    1-(2-((3R,5R,8R,9R,10S,13S,14S,15R)-3-Hydroxy-3,13,15-trimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile

    [0255] ##STR00098##

    Step 1: (3R,5R,8R,9R,10S,13S,14S,15R)-3-Hydroxy-3,13,15-trimethylhexadecahydro-17H-cyclopenta[a]phenanthren-17-one

    [0256] ##STR00099##

    [0257] 3.0 M methylmagnesium bromide (8.5 mL, 25.5 mmol) and 20 mL of anhydrous tetrahydrofuran were added to a dry 100 mL round bottom flask. The reaction system was purged with nitrogen, and cooled to 0° C. Cuprous iodide (3.94 g, 20.7 mmol) was added, and then the reaction solution was stirred at 0° C. for 1 hour. (3R,5R,8R,9R,10S,13S,14S)-3-Hydroxy-3,13-dimethyl-1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetradecahydro-17H-cyclopenta[a]phenanthren-17-one (2 g, 6.9 mmol) was dissolved in 10 ml of anhydrous tetrahydrofuran, and the resulting solution was slowly added dropwise to the reaction system. The reaction solution was stirred for 3 hours, and TLC showed that the reaction was completed. Saturated ammonium chloride solution was added to quench the reaction, and the reaction solution was extracted with ethyl acetate. The organic phase was washed with water and saturated saline, dried over anhydrous sodium sulfate, filtrated and concentrated by rotary evaporation to dryness. The resulting crude product was purified by column chromatography (petroleum ether:ethyl acetate=2:1) to obtain (3R,5R,8R,9R,10S,13S,14S,15R)-3-hydroxy-3,13,15-trimethylhexadecahydro-17H-cyclopenta[a]phenanthren-17-one (1.56 g, yield: 75%).

    [0258] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 2.51-2.42 (m, 2H), 2.24 (d, J=17.6 Hz, 1H), 1.89-1.63 (m, 7H), 1.54-1.18 (m, 16H), 1.10 (d, J=7.6 Hz, 3H), 1.03 (s, 3H).

    Step 2

    (3R,5R,8R,9R,10S,13S,14S,15R,E)-17-Ethylidene-3,13,15-trimethylhexadecahydro-1H-cyclopenta[a]phenanthren-3-ol

    [0259] ##STR00100##

    [0260] Ethyltriphenylphosphonium bromide (18.5 g, 50 mmol) was dissolved in anhydrous dimethyl sulfoxide (50 mL), and the reaction system was purged with nitrogen. Sodium hydride (2.0 g, 50 mmol) was added, and then the reaction solution was stirred at room temperature for 1 hour. (3R,5R,8R,9R,10S,13S,14S,15R)-3-Hydroxy-3,13,15-trimethylhexadecahydro-17H-cyclopenta[a]phenanthren-17-one (1.52 g, 5 mmol) was added, and then the reaction solution was stirred at 100° C. overnight. The reaction solution was cooled to room temperature. Water (200 mL) was added to the reaction solution to quench the reaction, and the aqueous phase was extracted with ethyl acetate (200 mL×2). The organic phases were combined, dried over anhydrous sodium sulfate, filtrated and concentrated. The resulting crude product was purified by column chromatography (petroleum ether/ethyl acetate: 50/1-3/1) to obtain (3R,5R,8R,9R,10S,13S,14S,15R,E)-17-ethylidene-3,13,15-trimethylhexadecahydro-1H-cyclopenta[a]phenanthren-3-ol (1.37 g, yield: 86%).

    Step 3: (3R,5R,8R,9R,10S,13S,14S,15R,17S)-17-((R)-1-Hydroxyethyl)-3,13,15-trimethylhexadecahydro-1H-cyclopenta[a]phenanthren-3-ol

    [0261] ##STR00101##

    [0262] (3R,5R,8R,9R,10S,13S,14S,15R,E)-17-Ethylidene-3,13,15-trimethylhexadecahydro-1H-cyclopenta[a]phenanthren-3-ol (1.37 g, 4.33 mmol) was dissolved in anhydrous tetrahydrofuran (50 mL). The solution was cooled to 0° C., and then BH.sub.3/THF (43 mL, 43 mmol) was added dropwise. The reaction solution was stirred at room temperature for 3 hours, and TLC showed that the reaction was completed. The reaction solution was cooled to 0° C., and then 3 M aqueous NaOH solution (40 mL) was slowly added, followed by the addition of H.sub.2O.sub.2 (30 mL). The reaction solution was stirred at room temperature for 2 hours, and TLC showed that the reaction was completed. Ethyl acetate (50 mL) was added, and then the reaction solution was washed with saturated aqueous Na.sub.2S.sub.2O.sub.3 solution (30 mL) and water (30 mL) successively. The organic phase was dried over anhydrous sodium sulfate, filtrated and concentrated to obtain the crude product (1.37 g), which was used directly in the next step.

    Step 4: 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

    [0263] ##STR00102##

    [0264] (3R,5R,8R,9R,10S,13S,14S,15R,17S)-17-((R)-1-Hydroxyethyl)-3,13,15-trimethyl hexadecahydro-1H-cyclopenta[a]phenanthren-3-ol (1.37 g, crude) was dissolved in dichloromethane (30 mL). PCC (1.8 g, 8.66 mmol) was added, and then the reaction solution was stirred at room temperature for 2 hours. The reaction solution was filtrated, and the organic phase was concentrated. The resulting crude product was purified by column chromatography (petroleum ether/ethyl acetate: 1/1) to obtain 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 (780 mg, yield of two steps: 54.3%).

    [0265] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 2.49 (dd, J=8.8, 10.4 Hz, 1H), 2.14-2.03 (m, 5H), 1.95-1.79 (m, 5H), 1.69-1.06 (m, 18H), 0.96 (d, J=12 Hz, 3H), 0.78 (s, 3H).

    Step 5: 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

    [0266] ##STR00103##

    [0267] 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 (333 mg, 1 mmol) was dissolved in methanol (10 mL). A drop of hydrogen bromide was added to the solution, followed by the addition of liquid bromine (176 mg, 1.1 mmol) was added, and then the reaction solution was stirred at room temperature for 1 hour. Water (20 mL) was added to the reaction solution, and the aqueous phase was extracted with ethyl acetate (20 mL×2). The organic phases were combined, dried over anhydrous sodium sulfate, filtrated and concentrated to obtain the crude product (413 mg, crude), which was used directly in the next step.

    Step 6: 1-(2-((3R,5R,8R,9R,10S,13S,14S,15R)-3-Hydroxy-3,13,15-trimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile

    [0268] ##STR00104##

    [0269] 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 (82 mg, 0.2 mmol), 1H-pyrazole-4-carbonitrile (28 mg, 0.3 mmol) and potassium carbonate (54 mg, 0.3 mmol) were dissolved in anhydrous tetrahydrofuran (5 mL), and the resulting reaction solution was stirred at room temperature overnight. The reaction solution was filtrated, and the filtrate was concentrated. The resulting crude product was purified by high performance liquid chromatography to obtain 1-(2-((3R,5R,8R,9R,10S,13S,14S,15R)-3-hydroxy-3,13,15-trimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile (41 mg, yield: 48%).

    [0270] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.86 (S, 1H), 7.81 (s, 1H), 5.01 (d, J=17.9 Hz, 1H), 4.90 (d, J=17.9 Hz, 1H), 2.62-2.48 (m, 1H), 2.30-2.06 (m, 3H), 2.04-1.75 (m, 7H), 1.75-1.04 (m, 15H), 0.99 (d, J=7.1 Hz, 3H), 0.84 (s, 3H).

    [0271] MS m/z (ESI): 424.6 [M+H].sup.+.

    Example 14 and Example 15

    1-(2-((3R,5R,10S,13S,16R)-16-Fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile (14)

    1-(2-((3R,5R,10S,13S,16S)-16-Fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile (15)

    [0272] ##STR00105##

    [0273] Example 14 and Example 15 were synthesized by the following specific scheme:

    ##STR00106##

    [0274] Example 14: MS m/z (ESI): 428.3 [M+1].sup.+.

    [0275] Example 15: MS m/z (ESI): 428.3 [M+1].sup.+.

    Example 16 and Example 17

    1-(2-((3R,5R,10S,13S,16R)-3-Hydroxy-3,13-dimethyl-16-(trifluoromethyl)hexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile (16)

    1-(2-((3R,5R,10S,13S,16S)-3-Hydroxy-3,13-dimethyl-16-(trifluoromethyl)hexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile (17)

    [0276] ##STR00107##

    [0277] Example 16 and Example 17 were synthesized by the following specific scheme:

    ##STR00108##

    [0278] Example 16: MS m/z (ESI): 478.3 [M+1].sup.+.

    [0279] Example 17: MS m/z (ESI): 478.3 [M+1].sup.+.

    Example 18

    2-(4-Chloro-1H-pyrazol-1-yl)-1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)ethan-1-one

    [0280] ##STR00109##

    [0281] In accordance with Example 5, 2-bromo-1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethylocta decahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)ethan-1-one and 4-chloro-1H-pyrazole were used as the starting materials, accordingly, 2-(4-chloro-1H-pyrazol-1-yl)-1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)ethan-1-one (21.9 mg, yield: 26%) was obtained.

    [0282] MS m/z (ESI): 431.2 [M+H].sup.+

    [0283] .sup.1H NMR (400 MHz, CDCl.sub.3) δ7.45 (d, J=11.8 Hz, 2H), 5.17-5.01 (m, 2H), 2.81 (d, J=3.5 Hz, 1H), 1.99-1.91 (m, 1H), 1.86-1.79 (m, 3H), 1.77-1.62 (m, 3H), 1.57-1.49 (m, 3H), 1.44-1.20 (m, 14H), 1.12-0.96 (m, 2H), 0.78 (s, 3H), 0.51-0.44 (m, 1H).

    Example 19

    (2R,4aS,4bR,6aS,7S,8bR,8cR,10aR)-2-Hydroxy-2,6a-dimethyl-N-phenyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthrene-7-carboxamide

    [0284] ##STR00110##

    [0285] Example 19 was synthesized by the following specific scheme:

    ##STR00111##

    [0286] MS m/z (ESI): 408.3 [M+1].sup.+.

    Example 20

    1-(2-((3R,5R,8R,9R,10S,13S,14S,17S)-3-Hydroxy-15-(isopropylamino)-3,13-dimethyl hexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile

    [0287] ##STR00112##

    [0288] Example 20 was synthesized by the following specific scheme:

    ##STR00113##

    [0289] MS m/z (ESI): 467.3 [M+1].sup.+.

    Example 21

    1-(2-((3R,5R,8R,9R,10S,13R,14S,17S)-3-Hydroxy-15-(isopropylsulfonyl)-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile

    [0290] ##STR00114##

    [0291] Example 21 was synthesized by the following specific scheme:

    ##STR00115##

    [0292] MS m/z (ESI): 516.3 [M+1].sup.+.

    Example 23

    1-(2-((2R,4aS,4bR,6aS,7S,8bR,8cR,10aR)-2-Hydroxy-2-(methoxymethyl)-6a-methyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile

    [0293] ##STR00116##

    [0294] Example 23 was synthesized by the following specific scheme:

    ##STR00117##

    [0295] MS m/z (ESI): 452.3 [M+1].sup.+.

    Example 24

    1-((2R,4aS,4bR,6aS,7S,8bR,8cR,10aR)-2-Hydroxy-2-(methoxymethyl)-6a-methyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-(4-methyl-1H-pyrazol-1-yl)ethan-1-one

    [0296] ##STR00118##

    [0297] MS m/z (ESI): 441.3 [M+1].sup.+.

    Example 25

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

    [0298] ##STR00119##

    [0299] Example 25 was synthesized by the following specific scheme:

    ##STR00120## ##STR00121##

    [0300] MS m/z (ESI): 466.3 [M+1].sup.+.

    Example 26

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

    [0301] ##STR00122##

    [0302] MS m/z (ESI): 466.3 [M+1].sup.+.

    Example 33 and Example 34

    3-Cyclopropyl-1-(2-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile (33)

    5-Cyclopropyl-1-(2-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile (34)

    [0303] ##STR00123## ##STR00124##

    [0304] In accordance with Example 5, 2-bromo-1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethylocta decahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)ethan-1-one and 5-cyclopropyl-1H-pyrazole-4-carbonitrile were used as the starting materials, accordingly, 3-cyclopropyl-1-(2-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile (33) (19.2 mg, yield: 21%) and 5-cyclopropyl-1-(2-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile (34) (3.0 mg, yield: 3.3%) were obtained.

    Example 33

    [0305] MS m/z (ESI): 462.3 [M+H].sup.+

    [0306] .sup.1H NMR (400 MHz, CDCl.sub.3) δ7.73 (s, 1H), 5.14-4.98 (m, 2H), 2.80 (d, J=2.2 Hz, 1H), 2.05-1.89 (m, 2H), 1.86-1.78 (m, 4H), 1.75-1.64 (m, 3H), 1.58-1.52 (m, 2H), 1.46-1.33 (m, 7H), 1.33-1.20 (m, 7H), 1.14-0.92 (m, 6H), 0.76 (s, 3H), 0.53-0.43 (m, 1H).

    Example 34

    [0307] MS m/z (ESI): 462.3 [M+H].sup.+

    [0308] .sup.1H NMR (400 MHz, CDCl.sub.3) δ7.69 (s, 1H), 5.33-5.13 (m, 2H), 2.85 (d, J=3.8 Hz, 1H), 2.00-1.92 (m, 1H), 1.86-1.79 (m, 3H), 1.76-1.62 (m, 4H), 1.60-1.51 (m, 2H), 1.45-1.34 (m, 7H), 1.34-1.22 (m, 7H), 1.17-0.94 (m, 7H), 0.81 (s, 3H), 0.54-0.45 (m, 1H).

    Example 37A and Example 37B

    1-(2-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-Hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-oxoethyl)-3-methyl-1H-pyrazole-4-carbonitrile (37A)

    1-(2-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-Hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-oxoethyl)-5-methyl-1H-pyrazole-4-carbonitrile (37B)

    [0309] ##STR00125## ##STR00126##

    [0310] In accordance with Example 5, 2-bromo-1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethylocta decahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)ethan-1-one and 3-methyl-1H-pyrazole-4-carbonitrile were used as the starting materials, accordingly, a mixture of Example 37A and Example 37B (approximately 3:1) (25.9 mg, white solid, yield: 39.3%) was obtained. The mixture was further separated by preparative chromatography to obtain 1-(2-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-oxoethyl)-3-methyl-1H-pyrazole-4-carbonitrile (37A) and 1-(2-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-oxoethyl)-5-methyl-1H-pyrazole-4-carbonitrile (37B).

    [0311] Example 37A: MS m/z (ESI): 436.3[M+H].sup.+

    [0312] Example 37B: MS m/z (ESI): 436.3[M+H].sup.+

    Example 40

    2-((2,4-Difluorophenyl)amino)-1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)ethan-1-one

    [0313] ##STR00127##

    [0314] In accordance with Example 5, 2-bromo-1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethylocta decahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)ethan-1-one and 2,4-difluoroaniline were used as the starting materials, accordingly, 2-((2,4-difluorophenyl)amino)-1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)ethan-1-one (3.9 mg, white solid, yield: 3.9%) was obtained.

    [0315] MS m/z (ESI): 458.3[M+H].sup.+

    [0316] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 6.84-6.75 (m, 2H), 6.65-6.59 (m, 1H), 4.12 (dd, J.sub.1=5.2 Hz, J.sub.2=24.8 Hz, 2H), 3.61-3.27 (br, 1H), 2.80 (d, J=3.6 Hz, 1H), 2.01-1.77 (m, 10H), 1.76-1.56 (m, 3H), 1.53-1.46 (m, 1H), 1.28-1.19 (m, 10H), 1.00-0.93 (m, 2H), 0.73 (m, 3H), 0.50-0.44 (m, 1H).

    Example 41 and Example 42

    1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-Hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-(2H-pyrazolo[3,4-c]pyridin-2-yl)ethan-1-one

    1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-Hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-(1H-pyrazolo[3,4-c]pyridin-1-yl)ethan-1-one

    [0317] ##STR00128## ##STR00129##

    [0318] In accordance with Example 5, 2-bromo-1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethylocta decahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)ethan-1-one and 1H-pyrazolo[3,4-c]pyridine were used as the starting materials, accordingly, 1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-(2H-pyrazolo[3,4-c]pyridin-2-yl)ethan-1-one (41) (5.4 mg, yield: 6.2%) and 1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-(1H-pyrazolo[3,4-c]pyridin-1-yl)ethan-1-one (42) (7.0 mg, yield: 8%) were obtained.

    Example 41

    [0319] MS m/z (ESI): 448.3 [M+H].sup.+

    [0320] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 9.43 (s, 1H), 8.39 (s, 1H), 8.19 (d, J=6.4 Hz, 1H), 8.08 (d, J=6.4 Hz, 1H), 5.77-5.61 (m, 2H), 2.96 (s, 1H), 2.01-1.92 (m, 1H), 1.88-1.81 (m, 4H), 1.74-1.69 (m, 3H), 1.59-1.55 (m, 2H), 1.48-1.43 (m, 5H), 1.33-1.27 (m, 9H), 1.10-1.05 (m, 2H), 0.85 (s, 3H), 0.60-0.54 (m, 1H).

    Example 42

    [0321] MS m/z (ESI): 448.3 [M+H].sup.+

    [0322] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 9.16 (s, 1H), 8.34 (d, J=5.8 Hz, 1H), 8.25 (s, 1H), 7.87 (d, J=5.2 Hz, 1H), 5.72-5.60 (m, 2H), 2.96 (d, J=3.9 Hz, 1H), 2.01-1.94 (m, 1H), 1.87-1.81 (m, 4H), 1.75-1.67 (m, 3H), 1.58-1.52 (m, 2H), 1.44-1.39 (m, 5H), 1.33-1.25 (m, 9H), 1.12-1.02 (m, 2H), 0.86 (s, 3H), 0.56-0.50 (m, 1H).

    Example 46

    2-(4-Fluoro-1H-pyrazol-1-yl)-1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)ethan-1-one

    [0323] ##STR00130##

    [0324] In accordance with Example 5, 2-bromo-1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethylocta decahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)ethan-1-one and 4-fluoropyrazole were used as the starting materials, accordingly, 2-(4-fluoro-1H-pyrazol-1-yl)-1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)ethan-1-one (6.2 mg, white solid, yield: 7.7%) was obtained.

    [0325] MS m/z (ESI): 415.2[M+H].sup.+

    [0326] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.37 (d, J=4.0 Hz, 1H), 7.32 (d, J=4.0 Hz, 1H), 5.03 (d, J=3.6 Hz, 2H), 2.80 (d, J=3.6 Hz, 1H), 2.01-1.93 (m, 2H), 1.85-1.80 (m, 3H), 1.73-1.61 (m, 6H), 1.41-1.32 (m, 9H), 1.27 (s, 3H), 1.12-1.02 (m, 2H), 0.99-0.96 (m, 1H), 0.78 (s, 3H), 0.50-0.44 (m, 1H).

    Example 51

    Ethyl 1-(2-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-oxoethyl)-1H-pyrazole-4-carboxylate

    [0327] ##STR00131##

    [0328] In accordance with Example 5, 2-bromo-1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethylocta decahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)ethan-1-one and ethyl 1H-pyrazole-4-carboxylate were used as the starting materials, accordingly, ethyl 1-(2-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-oxoethyl)-1H-pyrazole-4-carboxylate (29.6 mg, white solid, yield: 43%) was obtained.

    [0329] MS m/z (ESI): 469.3 [M+H].sup.+

    [0330] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.95 (s, 2H), 5.32-4.99 (m, 2H), 4.36-4.24 (m, 2H), 2.83 (s, 1H), 1.99-1.92 (m, 1H), 1.87-1.79 (m, 3H), 1.72-1.52 (m, 6H), 1.49-1.16 (m, 17H), 1.14-0.96 (m, 2H), 0.83 (s, 3H), 0.53-0.44 (m, 1H).

    Example 53, Example 54A and Example 54B

    1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-Hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-(5-methoxy-2H-benzo[d][1,2,3]triazol-2-yl)ethan-1-one (53)

    1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-Hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-(6-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)ethan-1-one (54A)

    1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-Hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)ethan-1-one (54B)

    [0331] ##STR00132## ##STR00133##

    [0332] In accordance with Example 5, 2-bromo-1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethylocta decahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)ethan-1-one and 6-methoxy-1H-benzo[d][1,2,3]triazole were used as the starting materials, accordingly, 1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-(5-methoxy-2H-benzo[d][1,2,3]triazol-2-yl)ethan-1-one (11.8 mg, yield: 13.6%) and a mixture of Example 54A and Example 54B (approximately 1:1) (34 mg, yield: 39%) were obtained. The mixture was further separated by preparative chromatography to obtain 1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-(6-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)ethan-1-one (54A) and 1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)ethan-1-one (54B).

    Example 53

    [0333] MS m/z (ESI): 478.3 [M+H].sup.+

    [0334] .sup.1H NMR (400 MHz, CDCl.sub.3) δ7.74 (d, J=10.1 Hz, 1H), 7.14-7.03 (m, 2H), 5.73-5.59 (m, 2H), 3.88 (s, 3H), 2.88 (d, 0.7=4.1 Hz, 1H), 2.01-1.93 (m, 1H), 1.86-1.78 (m, 4H), 1.74-1.63 (m, 3H), 1.55-1.51 (m, 1H), 1.46-1.25 (m, 15H), 1.15-1.00 (m, 2H), 0.88 (s, 3H), 0.53-0.45 (m, 1H).

    Example 54A

    [0335] MS m/z (ESI): 478.3 [M+H].sup.+

    Example 54B

    [0336] MS m/z (ESI): 478.3 [M+H].sup.+

    Example 59

    1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-3-Hydroxy-3,13,15-trimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(4-(trifluoromethyl)-1H-pyrazol-1-yl)ethan-1-one

    [0337] ##STR00134##

    [0338] 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 (82 mg, 0.2 mmol), 4-(trifluoromethyl)-1H-pyrazole (41 mg, 0.3 mmol) and potassium carbonate (54 mg, 0.3 mmol) were dissolved in anhydrous tetrahydrofuran (5 mL), and the resulting reaction solution was stirred at room temperature overnight. The reaction solution was filtrated, and the filtrate was concentrated. The resulting crude product was purified by high performance liquid chromatography to obtain 1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-3,13,15-trimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(4-(trifluoromethyl)-1H-pyrazol-1-yl)ethan-1-one (24.6 mg, yield: 26%).

    [0339] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.72 (s, 2H), 5.00 (d, J=16 Hz, 1H), 4.90 (d, J=16 Hz, 1H), 2.58-2.54 (m, 1H), 1.88-1.83 (m, 2H), 1.69-1.58 (m, 5H), 1.50-1.25 (m, 19H), 0.98 (d, J=8.0 Hz, 3H), 0.85 (s, 3H).

    [0340] MS m/z (ESI): 467.3 [M+H].sup.+

    Example 60

    1-(2-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-3-Hydroxy-3,13,15-trimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-1H-pyrazole-3-carbonitrile (60)

    [0341] ##STR00135##

    Step 1: Preparation of 1-(2-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-3,13,15-trimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-1H-pyrazole-3-carbonitrile

    [0342] ##STR00136##

    [0343] In accordance with Example 5, 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, 1-(2-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-3,13,15-trimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-1H-pyrazole-3-carbonitrile (12.5 mg, yield: 20.2%) was obtained.

    [0344] MS m/z (ESI): 424.1[M+H].sup.+.

    [0345] .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), 5.07-4.84 (m, 2H), 2.55 (t, J=8.1 Hz, 1H), 2.33-1.06 (m, 25H), 0.98 (d, J=7.0 Hz, 3H), 0.84 (s, 3H).

    Example 61 and Example 132

    1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-3-Hydroxy-3,13,15-trimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(2H-1,2,3-triazol-2-yl)ethan-1-one (61)

    1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-3-Hydroxy-3,13,15-trimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(1H-1,2,3-triazol-1-yl)ethan-1-one (132)

    [0346] ##STR00137##

    Step 1: Preparation of 1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-3,13,15-trimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(2H-1,2,3-triazol-2-yl)ethan-1-one and

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

    [0347] ##STR00138##

    [0348] In accordance with Example 5, 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, 1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-3,13,15-trimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(2H-1,2,3-triazol-2-yl)ethan-1-one (9.5 mg, yield: 16.3%) and 1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-3,13,15-trimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(1H-1,2,3-triazol-1-yl)ethan-1-one (13 mg, yield: 22.3%) were obtained.

    Example 61

    [0349] MS m/z (ESI): 400.2[M+H].sup.+.

    [0350] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.68 (s, 2H), 5.29-5.15 (m, 2H), 2.52 (t, J=8.0 Hz, 1H), 2.17-1.29 (m, 24H), 1.15-1.05 (m, 1H), 0.97 (d, J=7.0 Hz, 3H), 0.87 (s, 3H).

    Example 132

    [0351] MS m/z (ESI): 400.2[M+H].sup.+.

    [0352] .sup.1H NMR (400 MHz, CDCl.sub.3) δ7.77 (s, 1H), 7.65 (s, 1H), 5.32-5.02 (m, 2H), 2.60 (t, 0.7=9.1 Hz, 1H), 2.30-2.12 (m, 2H), 1.99-1.27 (m, 22H), 1.17-1.06 (m, 1H), 0.99 (d, J=6.9 Hz, 3H), 0.84 (s, 3H).

    Example 62

    1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-3-Hydroxy-3,13,15-trimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(5-methyl-2H-tetrazol-2-yl)ethan-1-one (62)

    [0353] ##STR00139##

    Step 1: Preparation of 1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-3,13,15-trimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(5-methyl-2H-tetrazol-2-yl)ethan-1-one

    [0354] ##STR00140##

    [0355] In accordance with Example 5, 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, 1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-3,13,15-trimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(5-methyl-2H-tetrazol-2-yl)ethan-1-one (4.7 mg, yield: 7%) was obtained.

    [0356] MS m/z (ESI): 415.3[M+H].sup.+

    [0357] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 5.36 (s, 2H), 2.57 (s, 3H), 2.27-2.11 (m, 2H), 2.00-198 (m, 1H), 1.87-1.83 (m, 5H), 1.77-1.57 (m, 6H), 1.52-1.30 (m, 12H), 1.11 (s, 2H), 0.98 (d, J=7.0 Hz, 3H), 0.88 (s, 3H).

    Example 63

    1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-3-Hydroxy-3,13,15-trimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(2H-tetrazol-2-yl)ethan-1-one

    [0358] ##STR00141##

    [0359] 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 (82 mg, 0.2 mmol), 2H-tetrazole (21 mg, 0.3 mmol) and potassium carbonate (54 mg, 0.3 mmol) were dissolved in anhydrous tetrahydrofuran (5 mL), and the resulting reaction solution was stirred at room temperature overnight. The reaction solution was filtrated, and the filtrate was concentrated. The resulting crude product was purified by high performance liquid chromatography to obtain 1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-3,13,15-trimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(2H-tetrazol-2-yl)ethan-1-one (15.7 mg, yield: 20%).

    [0360] MS m/z (ESI): 401.3 [M+H].sup.+

    [0361] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.58 (s, 1H), 4.46 (s, 2H), 2.62-2.58 (m, 1H), 1.89-1.84 (m, 2H), 1.70-1.26 (m, 23H), 0.99 (d, J=8.0 Hz, 3H), 0.88 (s, 3H).

    Example 64

    2-(2,4-Difluorophenoxy)-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 (64)

    [0362] ##STR00142##

    Step 1: Preparation of 2-(2,4-difluorophenoxy)-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 (64)

    [0363] ##STR00143##

    [0364] In accordance with Example 5, 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, 2-(2,4-difluorophenoxy)-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 (34 mg, yield: 45%) was obtained.

    [0365] MS m/z (ESI): 461.3[M+H].sup.+

    [0366] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 6.91-6.82 (m, 2H), 6.77 (ddd, J=9.1, 5.3, 1.6 Hz, 1H), 4.56 (q, J=16.7 Hz, 2H), 2.74-2.68 (m, 1H), 2.27-2.14 (m, 1H), 2.13-1.99 (m, 1H), 1.95-1.74 (m, 4H), 1.74-1.61 (m, 3H), 1.57 (s, 3H), 1.52-1.35 (m, 4H), 1.36-1.18 (m, 6H), 1.21-1.00 (m, 3H), 0.98 (d, J=7.2 Hz, 3H), 0.82 (s, 3H).

    Example 69

    3-Cyclopropyl-1-(2-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-3,13,15-trimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile (69)

    [0367] ##STR00144##

    Step 1: Preparation of 3-cyclopropyl-1-(2-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-3,13,15-trimethyl hexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile (69)

    [0368] ##STR00145##

    [0369] In accordance with Example 5, 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, 3-cyclopropyl-1-(2-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-3,13,15-trimethyl hexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile (30 mg, yield: 41%) was obtained.

    [0370] MS m/z (ESI): 464.3[M+H].sup.+

    [0371] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.71 (s, 1H), 4.82 (q, J=17.9 Hz, 2H), 2.51-2.46 (m, 1H), 2.27-2.18 (m, 1H), 2.19-2.08 (m, 1H), 2.04-1.91 (m, 2H), 1.90-1.80 (m, 4H), 1.68-1.60 (m, 4H), 1.57 (s, 3H), 1.51-1.29 (m, 8H), 1.18-1.03 (m, 3H), 1.02-0.95 (m, 7H), 0.82 (s, 3H).

    Example 71

    1-(2-((3R,5R,8R,9R,10S,13S,14S,15S)-15-Cyclopropyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile

    [0372] ##STR00146##

    Step 1: (3R,5R,8R,9R,10S,13S,14S,15S)-15-Cyclopropyl-3-hydroxy-3,13-dimethylhexadecahydro-17H-cyclopenta[a]phenanthren-17-one

    [0373] ##STR00147##

    [0374] 1.0 M cyclopropylmagnesium bromide (12.7 mL, 12.7 mmol) and 20 mL of anhydrous tetrahydrofuran were added to a dry 100 mL round bottom flask. The reaction system was purged with nitrogen, and cooled to 0° C. Cuprous iodide (1.97 g, 10.4 mmol) was added, and then the reaction solution was stirred at 0° C. for 1 hour. (3R,5R,8R,9R,10S,13S,14S)-3-Hydroxy-3,13-dimethyl-1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetradecahydro-17H-cyclopenta[a]phenanthren-17-one (1 g, 3.5 mmol) was dissolved in 10 ml of anhydrous tetrahydrofuran, and the resulting solution was slowly added dropwise to the reaction system. The reaction solution was stirred for 3 hours, and TLC showed that the reaction was completed. Saturated ammonium chloride solution was added to quench the reaction, and the reaction solution was extracted with ethyl acetate. The organic phase was washed with water and saturated saline, dried over anhydrous sodium sulfate, filtrated and concentrated by rotary evaporation to dryness. The resulting crude product was purified by column chromatography (eluent: petroleum ether:ethyl acetate=2:1) to obtain (3R,5R,8R,9R,10S,13S,14S,15S)-15-cyclopropyl-3-hydroxy-3,13-dimethylhexadecahydro-17H-cyclopenta[a]phenanthren-17-one (1.11 g, 96%).

    [0375] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 2.45-2.30 (m, 2H), 1.85-1.76 (m, 9H), 1.59-1.52 (m, 5H), 1.59-1.27 (m, 12H), 1.11-0.98 (m, 1H), 0.67-0.64 (m, 1H), 0.47-0.43 (m, 1H), 0.22-0.18 (m, 1H), 0.09-0.07 (m, 1H).

    Step 2: (3R,5R,8R,9R,10S,13S,14S,15S,E)-15-Cyclopropyl-17-ethylidene-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-3-ol

    [0376] ##STR00148##

    [0377] Ethyltriphenylphosphonium bromide (12.5 g, 33 mmol) was dissolved in anhydrous dimethyl sulfoxide (50 mL), and the reaction system was purged with nitrogen. Sodium hydride (1.32 g, 33 mmol) was added, and then the reaction solution was stirred at room temperature for 1 hour. (3R,5R,8R,9R,10S,13S,14S,15S)-15-Cyclopropyl-3-hydroxy-3,13-dimethylhexadecahydro-17H-cyclopenta[a]phenanthren-17-one (1.1 g, 3.3 mmol) was added, and then the reaction solution was stirred at 60° C. overnight. The reaction solution was cooled to room temperature. Water (200 mL) was added to the reaction solution to quench the reaction, and the aqueous phase was extracted with ethyl acetate (200 mL×2). The organic phases were combined, dried over anhydrous sodium sulfate, filtrated and concentrated. The resulting crude product was purified by column chromatography (petroleum ether/ethyl acetate: 50/1-3/1) to obtain (3R,5R,8R,9R,10S,13S,14S,15S,E)-15-cyclopropyl-17-ethylidene-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-3-ol (0.67 g, yield: 59%).

    [0378] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 5.15-5.09 (m, 1H), 2.45-2.38 (m, 1H), 2.38-2.18 (m, 2H), 1.90-1.07 (m, 28H), 0.86-0.78 (m, 1H), 0.56-0.50 (m, 1H), 0.38-0.32 (m, 1H), 0.12-0.02 (m, 2H).

    Step 3: (3R,5R,8R,9R,10S,13S,14S,15S,17S)-15-Cyclopropyl-17-((R)-1-hydroxyethyl)-3,13-di methylhexadecahydro-1H-cyclopenta[a]phenanthren-3-ol

    [0379] ##STR00149##

    [0380] (3R,5R,8R,9R,10S,13S,14S,15S,E)-15-Cyclopropyl-17-ethylidene-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-3-ol (0.67 g, 1.96 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL). The solution was cooled to 0° C., and then BH.sub.3/THF (9.8 mL, 9.8 mmol) was added dropwise. The reaction solution was stirred at room temperature for 3 hours, and TLC showed that the reaction was completed. The reaction solution was cooled to 0° C., and then 3 M aqueous NaOH solution (10 mL) was slowly added, followed by the addition of 30% hydrogen peroxide (8 mL). The reaction solution was stirred at room temperature for 2 hours, and TLC showed that the reaction was completed. Ethyl acetate (50 mL) was added, and then the reaction solution was washed with saturated aqueous Na.sub.2S.sub.2O.sub.3 solution (30 mL) and water (30 mL) successively. The organic phase was dried over anhydrous sodium sulfate, filtrated and concentrated to obtain the crude product (0.71 g), which was used directly in the next step.

    Step 4 1-((3R,5R,8R,9R,10S,13S,14S,15S,17S)-15-Cyclopropyl-3-hydroxy-3,13-dimethylhexa decahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one

    [0381] ##STR00150##

    [0382] (3R,5R,8R,9R,10S,13S,14S,15S,17S)-15-Cyclopropyl-17-((R)-1-hydroxyethyl)-3, 13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-3-ol (0.71 g, crude) was dissolved in dichloromethane (20 mL). Pyridinium chlorochromate (1.27 g, 5.88 mmol) was added, and then the reaction solution was stirred at room temperature for 2 hours. The reaction solution was filtrated, and the organic phase was concentrated. The resulting crude product was purified by column chromatography (petroleum ether/ethyl acetate: 1/1) to obtain 1-((3R,5R,8R,9R,10S,13S,14S,15S,17S)-15-cyclopropyl-3-hydroxy-3,13-dimethylhexa decahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one (480 mg, yield of two steps: 68.3%).

    [0383] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 2.45-2.40 (m, 1H), 2.18-2.10 (m, 4H), 1.99-1.03 (m, 24H), 0.84-0.79 (m, 4H), 0.60-0.53 (m, 1H), 0.43-0.38 (m, 1H), 0.14-0.02 (m, 2H).

    Step 5: 2-Bromo-1-((3R,5R,8R,9R,10S,13S,14S,15S,17S)-15-cyclopropyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one

    [0384] ##STR00151##

    [0385] 1-((3R,5R,8R,9R,10S,13S,14S,15S,17S)-15-Cyclopropyl-3-hydroxy-3,13-dimethyl hexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one (107 mg, 0.3 mmol) was dissolved in methanol (5 mL). A drop of hydrogen bromide was added to the solution, followed by the addition of liquid bromine (56 mg, 0.35 mmol), and then the reaction solution was stirred at room temperature for 1 hour. Water (20 mL) was added to the reaction solution, and the aqueous phase was extracted with ethyl acetate (20 mL×2). The organic phases were combined, dried over anhydrous sodium sulfate, filtrated and concentrated to obtain the crude product (120 mg, crude), which was used directly in the next step.

    Step 6: 1-(2-((3R,5R,8R,9R,10S,13S,14S,15S)-15-Cyclopropyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile

    [0386] ##STR00152##

    [0387] 1-((3R,5R,8R,9R,10S,13S,14S,15S,17S)-15-Cyclopropyl-3-hydroxy-3,13-dimethyl hexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one (60 mg, 0.14 mmol), 1H-pyrazole-4-carbonitrile (28 mg, 0.3 mmol) and potassium carbonate (54 mg, 0.3 mmol) were dissolved in anhydrous tetrahydrofuran (5 mL), and the resulting reaction solution was stirred at room temperature overnight. The reaction solution was filtrated, and the filtrate was concentrated. The resulting crude product was purified by high performance liquid chromatography to obtain 1-(2-((3R,5R,8R,9R,10S,13S,14S,15S)-15-cyclopropyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile (31 mg, yield: 49%).

    [0388] MS m/z (ESI): 450.3 [M+H].sup.+

    [0389] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.86 (S, 1H), 7.81 (s, 1H), 5.02 (d, J=16.0 Hz, 1H), 4.92 (d, J=16.0 Hz, 1H), 2.51-2.47 (m, 1H), 2.09-1.71 (m, 9H), 1.48-1.10 (m, 16H), 0.90 (s, 3H), 0.83-0.79 (m, 1H), 0.62-0.58 (m, 1H), 0.45-0.40 (m, 1H), 0.14-0.11 (m, 1H), 0.05-0.02 (m, 1H).

    Example 72

    1-(2-((3R,5R,8R,9R,10S,13S,14S,15S,17S)-15-Cyclopropyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-1H-pyrazole-3-carbonitrile (72)

    [0390] ##STR00153##

    Step 1: Preparation of 1-(2-((3R,5R,8R,9R,10S,13S,14S,15S,17S)-15-cyclopropyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-1H-pyrazole-3-carbonitrile

    [0391] ##STR00154##

    [0392] In accordance with Example 5, 1-((3R,5R,8R,9R,10S,13S,14S,15S,17S)-15-cyclopropyl-3-hydroxy-3,13-dimethylhexa decahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one was used as the starting material, accordingly, 1-(2-((3R,5R,8R,9R,10S,13S,14S,15S,17S)-15-cyclopropyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-1H-pyrazole-3-carbonitrile (20 mg, yield 20%) was obtained.

    [0393] MS m/z (ESI): 432.2[M−H.sub.2O+H].sup.+10 .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.49 (d, J=2.4 Hz, 1H), 6.73 (d, J=2.4 Hz, 1H), 4.98 (dd, 0.7=40.0, 17.8 Hz, 2H), 2.52-2.45 (m, 1H), 2.24-2.13 (m, 1H), 2.11-2.03 (m, 1H), 2.04-1.95 (m, 2H), 1.90-1.82 (m, 2H), 1.75-1.66 (m, 2H), 1.54-1.23 (m, 16H), 1.18-1.05 (m, 2H), 0.93-0.79 (m, 4H), 0.63-0.55 (m, 1H), 0.45-0.37 (m, 1H), 0.18-0.09 (m, 1H), 0.08-0.01 (m, 1H).

    Example 73 and Example 145 1-((3R,5R,8R,9R,10S,13S,14S,15S,17S)-15-Cyclopropyl-3-hydroxy-3,13-dimethylhexa decahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(2H-1,2,3-triazol-2-yl)ethan-1-one (73)

    1-((3R,5R,8R,9R,10S,13S,14S,15S,17S)-15-Cyclopropyl-3-hydroxy-3,13-dimethylhexa decahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(1H-1,2,3-triazol-1-yl)ethan-1-one (145)

    [0394] ##STR00155##

    Step 1: Preparation of

    1-((3R,5R,8R,9R,10S,13S,14S,15S,17S)-15-cyclopropyl-3-hydroxy-3,13-dimethylhexa decahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(2H-1,2,3-triazol-2-yl)ethan-1-one and

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

    [0395] ##STR00156##

    [0396] In accordance with Example 5, 1-((3R,5R,8R,9R,10S,13S,14S,15S,17S)-15-cyclopropyl-3-hydroxy-3,13-dimethylhexa decahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one was used as the starting material, accordingly, 1-((3R,5R,8R,9R,10S,13S,14S,15S,17S)-15-cyclopropyl-3-hydroxy-3,13-dimethylhexa decahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(2H-1,2,3-triazol-2-yl)ethan-1-one (7.6 mg, yield: 7.8%) and 1-((3R,5R,8R,9R,10S,13S,14S,15S,17S)-15-cyclopropyl-3-hydroxy-3,13-dimethylhexa decahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(1H-1,2,3-triazol-1-yl)ethan-1-one (11.6 mg, yield: 11.9%) were obtained.

    Example 73

    [0397] MS m/z (ESI): 408.3[M−H.sub.2O+H].sup.+

    [0398] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.68 (s, 2H), 5.24 (s, 2H), 2.49-2.42 (m, 1H), 2.23-2.14 (m, 1H), 2.10-1.94 (m, 3H), 1.91-1.81 (m, 3H), 1.75-1.66 (m, 2H), 1.48-1.24 (m, 15H), 1.17-1.04 (m, 2H), 0.94 (s, 3H), 0.86-0.76 (m, 1H), 0.63-0.54 (m, 1H), 0.45-0.38 (m, 1H), 0.14-0.01 (m, 2H).

    Example 145

    [0399] MS m/z (ESI): 426.3[M+H].sup.+

    [0400] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.78 (s, 1H), 7.67 (s, 1H), 5.22 (dd, J=47.1, 17.8 Hz, 2H), 2.59-2.50 (m, 1H), 2.25-2.15 (m, 1H), 2.14-1.98 (m, 2H), 1.96-1.79 (m, 3H), 1.76-1.58 (m, 6H), 1.56-1.25 (m, 12H), 1.22-1.04 (m, 2H), 0.91 (s, 3H), 0.87-0.77 (m, 1H), 0.62-0.55 (m, 1H), 0.47-0.36 (m, 1H), 0.18-0.02 (m, 2H).

    Example 74

    1-((3R,5R,8R,9R,10S,13S,14S,15S,17S)-15-Cyclopropyl-3-hydroxy-3,13-dimethylhexa decahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(5-methyl-2H-tetrazol-2-yl)ethan-1-one (74)

    [0401] ##STR00157##

    Step 1: Preparation of 1-((3R,5R,8R,9R,10S,13S,14S,15S,17S)-15-cyclopropyl-3-hydroxy-3,13-dimethylhexa decahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(5-methyl-2H-tetrazol-2-yl)ethan-1-one

    [0402] ##STR00158##

    [0403] In accordance with Example 5, 1-((3R,5R,8R,9R,10S,13S,14S,15S,17S)-15-cyclopropyl-3-hydroxy-3,13-dimethylhexa decahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one was used as the starting material, accordingly, 1-((3R,5R,8R,9R,10S,13S,14S,15S,17S)-15-cyclopropyl-3-hydroxy-3,13-dimethylhexa decahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(5-methyl-2H-tetrazol-2-yl)ethan-1-one (8.5 mg, yield: 9%) was obtained.

    [0404] MS m/z (ESI): 441.3[M+H].sup.+

    [0405] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 5.36 (s, 2H), 2.57 (s, 3H), 2.54-2.47 (m, 1H), 2.25-2.15 (m, 1H), 2.13-1.95 (m, 3H), 1.92-1.79 (m, 3H), 1.77-1.66 (m, 2H), 1.50-1.24 (m, 15H), 1.18-1.05 (m, 2H), 0.94 (s, 3H), 0.87-0.78 (m, 1H), 0.63-0.55 (m, 1H), 0.45-0.37 (m, 1H), 0.17-0.02 (m, 2H).

    Example 81

    1-(2-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-15-Ethyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile (81)

    [0406] ##STR00159##

    Step 1: (3R,5R,8R,9R,10S,13S,14S,15R)-15-Ethyl-3-hydroxy-3,13-dimethylhexadecahydro-17H-cyclopenta[a]phenanthren-17-one

    [0407] ##STR00160##

    [0408] Tetrahydrofuran (15 mL) was added to a 100 mL three-neck flask, and ethyl magnesium bromide (10 mL, 1M, 10 mmol) was then added at 0° C. under a nitrogen atmosphere, followed by the addition of cuprous iodide (1.6 g, 8.4 mmol). The reaction solution was stirred at 0° C. for 1 hour. (3R,5R,8R,9R,10S,13S,14S)-3-Hydroxy-3,13-dimethyl-1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetradecahydro-17H-cyclopenta[a]phenanthren-17-one (800 mg, 2.8 mmol) was dissolved in tetrahydrofuran (5 mL), and the resulting solution was slowly added dropwise to the reaction solution, which was then stirred at 0° C. for 4 hours. Saturated aqueous ammonium chloride solution was added to quench the reaction, and the reaction solution was extracted with ethyl acetate (20 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 resulting crude product was purified by column chromatography (petroleum ether/ethyl acetate: 3/1) to obtain (3R,5R,8R,9R,10S,13S,14S,15R)-15-ethyl-3-hydroxy-3,13-dimethylhexadecahydro-17H-cyclopenta[a]phenanthren-17-one (750 mg, yield: 84.9%).

    [0409] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 2.37-2.30 (m, 1H), 2.15-2.02 (m, 2H), 1.91-1.31 (m, 17H), 1.27 (s, 3H), 1.24-1.03 (m, 4H), 0.98 (s, 3H), 0.90 (t, J=7.3 Hz, 3H).

    Step 2: (3R,5R,8R,9R,10S,13S,14S,15R)-15-Ethyl-17-ethylidene-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-3-ol

    [0410] ##STR00161##

    [0411] Dimethyl sulfoxide (20 mL) was added to a 100 mL three-neck flask, and ethyltriphenylphosphonium bromide (8.7 g, 23.5 mmol) was then added under a nitrogen atmosphere. Sodium hydride (60%) (940 mg, 23.5 mmol) was added in batches, and the reaction solution was stirred at room temperature for 1 hour. (3R,5R,8R,9R,10S,13S,14S,15R)-15-Ethyl-3-hydroxy-3,13-dimethylhexadecahydro-17H-cyclopenta[a]phenanthren-17-one (750 mg, 2.35 mmol) was dissolved in dimethyl sulfoxide (5 mL), and the resulting solution was slowly added dropwise to the reaction solution, which was then stirred under a nitrogen atmosphere at 80° 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 (50 mL). The organic phase was washed with saline (20 mL×3), dried over anhydrous sodium sulfate, filtrated and concentrated by rotary evaporation to dryness. The resulting crude product was purified by column chromatography (petroleum ether/ethyl acetate: 3/1) to obtain (3R,5R,8R,9R,10S,13S,14S,15R)-15-ethyl-17-ethylidene-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-3-ol (580 mg, yield: 71.7%).

    [0412] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 5.22-5.06 (m, 1H), 2.54-2.39 (m, 1H), 2.28-2.09 (m, 2H), 1.96-1.80 (m, 4H), 1.78-1.59 (m, 6H), 1.55-1.33 (m, 11H), 1.26 (s, 3H), 1.20-1.08 (m, 3H), 1.05 (s, 3H), 0.82 (t, J=7.3 Hz, 3H).

    Step 3: (3R,5R,8R,9R,10S,13S,14S,15R,17R)-15-Ethyl-17-(1-hydroxyethyl)-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-3-ol

    [0413] ##STR00162##

    [0414] In accordance with Step 3 of Example 71, (3R,5R,8R,9R,10S,13S,14S,15R)-15-ethyl-17-ethylidene-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-3-ol was used as the starting material, accordingly, (3R,5R,8R,9R,10S,13S,14S,15R,17R)-15-ethyl-17-(1-hydroxyethyl)-3,13-dimethylhexa decahydro-1H-cyclopenta[a]phenanthren-3-ol (600 mg, yield: 98.1%) was obtained.

    Step 4: 1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-15-Ethyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one

    [0415] ##STR00163##

    [0416] In accordance with Step 4 of Example 71, (3R,5R,8R,9R,10S,13S,14S,15R,17R)-15-ethyl-17-(1-hydroxyethyl)-3,13-dimethylhexa decahydro-1H-cyclopenta[a]phenanthren-3-ol was used as the starting material, accordingly, 1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-15-ethyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one (500 mg, yield: 83.8%) was obtained.

    [0417] 1H NMR (400 MHz, CDCl.sub.3) δ 2.51 (t, 0.7=8.0 Hz, 1H), 2.12 (s, 3H), 2.00-1.30 (m, 20H), 1.28 (s, 3H), 1.25-1.00 (m, 4H), 0.84 (t, J=12 Hz, 3H), 0.73 (s, 3H).

    Step 5: 2-Bromo-1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-15-ethyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one

    [0418] ##STR00164##

    [0419] In accordance with Step 5 of Example 71, 1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-15-ethyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one was used as the starting materials, accordingly, 2-bromo-1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-15-ethyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one (500 mg, yield: 81.4%) was obtained.

    Step 6: 1-(2-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-15-Ethyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile

    [0420] ##STR00165##

    [0421] In accordance with Step 6 of Example 71, 2-bromo-1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-15-ethyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one was used as the starting material, accordingly, 1-(2-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-15-ethyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile (24 mg, yield: 38.8%) was obtained.

    [0422] MS m/z (ESI): 438.2[M+H]+.

    [0423] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.86 (s, 1H), 7.81 (s, 1H), 5.08-4.78 (m, 2H), 2.58 (t, J=8.0 Hz, 1H), 2.07-1.29 (m, 20H), 1.28 (s, 3H), 1.27-1.06 (m, 4H), 0.85 (t, J=7.3 Hz, 3H), 0.79 (s, 3H).

    Example 91

    2-(4-Chloro-1H-pyrazol-1-yl)-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 (91)

    [0424] ##STR00166##

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

    [0425] ##STR00167##

    [0426] In accordance with Example 5, 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, 2-(4-chloro-1H-pyrazol-1-yl)-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 (10 mg, yield: 14%) was obtained.

    [0427] MS m/z (ESI): 433.3[M+H].sup.+

    [0428] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.45 (s, 1H), 7.41 (s, 1H), 4.86 (q, J=17.9 Hz, 2H), 2.61-2.44 (m, 1H), 2.30-2.07 (m, 2H), 2.02-1.91 (m, 1H), 1.86-1.80 (m, 4H), 1.76-1.57 (m, 4H), 1.51-1.38 (m, 6H), 1.37-1.20 (m, 6H), 1.20-1.03 (m, 2H), 0.98 (d, J=7.1 Hz, 3H), 0.83 (s, 3H).

    Example 92 and Example 93

    2-(5-Fluoro-2H-benzo[d][1,2,3]triazol-2-yl)-1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR, 10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)ethan-1-one (92)

    2-(5-Fluoro-1H-benzo[d][1,2,3]triazol-1-yl)-1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR, 10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)ethan-1-one (93A) and

    2-(6-Fluoro-1H-benzo[d][1,2,3]triazol-1-yl)-1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR, 10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)ethan-1-one (93B)

    [0429] ##STR00168## ##STR00169##

    [0430] In accordance with Example 5, 2-bromo-1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethylocta decahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)ethan-1-one and 5-fluoro-2H-benzo[d][1,2,3]triazole were used as the starting materials, accordingly, 2-(5-fluoro-2H-benzo[d][1,2,3]triazol-2-yl)-1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)ethan-1-one (11.5 mg, white solid, yield: 12.7%) and a mixture of Example 93A and Example 93B (about 3:2) (21.6 mg, white solid, yield: 23.9%) were obtained. The mixture was further separated by preparative chromatography to obtain 2-(5-fluoro-1H-benzo[d][1,2,3]triazol-1-yl)-1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)ethan-1-one and 2-(6-fluoro-1H-benzo[d][1,2,3]triazol-1-yl)-1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)ethan-1-one.

    Example 92

    [0431] MS m/z (ESI): 466.2[M+H].sup.+

    [0432] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.87 (dd, J.sub.2=9.2 Hz, J.sub.2=4.8 Hz, 1H), 7.47 (dd, J.sub.2=9.2 Hz, J.sub.2=2.0 Hz, 1H), 7.23-7.18 (m, 1H), 5.73 (dd, J.sub.1=17.6 Hz, J.sub.2=4.4 Hz, 2H), 2.90 (d, J=4.0 Hz, 1H), 1.99-1.96 (m, 1H), 1.85-1.81 (m, 4H), 1.74-1.63 (m, 3H), 1.57-1.38 (m, 10H), 1.30-1.11 (m, 6H), 1.14-1.01 (m, 2H), 0.88 (s, 3H), 0.53-0.48 (m, 1H).

    Example 93A

    [0433] MS m/z (ESI): 466.2[M+H].sup.+

    Example 93B

    [0434] MS m/z (ESI): 466.2[M+H].sup.+

    Example 94

    2-(2,4-Difluorophenoxy)-1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2, 6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)ethan-1-one

    [0435] ##STR00170##

    [0436] In accordance with Example 5, 2-bromo-1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethylocta decahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)ethan-1-one and 2,4-difluorophenol were used as the starting materials, accordingly, 2-(2,4-difluorophenoxy)-1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2, 6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)ethan-1-one (27.4 mg, white solid, yield: 38.6%) was obtained.

    [0437] MS m/z (ESI): 441.2 [M+H].sup.+

    [0438] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 6.93-6.80 (m, 2H), 6.79-6.74 (m, 1H), 4.77 (dd, J.sub.1=16.8 Hz, J.sub.2=3.6 Hz, 2H), 2.93 (d, J=3.2 Hz, 1H), 1.89-1.76 (m, 5H), 1.75-1.60 (m, 3H), 1.55-1.50 (m, 1H), 1.46-1.41 (m, 6H), 1.27-1.11 (m, 9H), 0.98-0.95 (m, 1H), 0.94-0.89 (m, 1H), 0.76 (s, 3H), 0.46-0.39 (m, 1H).

    Example 95

    1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-Hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-(4-methyl-1H-pyrazol-1-yl)ethan-1-one

    [0439] ##STR00171##

    [0440] In accordance with Example 5, 2-bromo-1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethylocta decahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)ethan-1-one and 4-methylpyrazole were used as the starting materials, accordingly, 1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-(4-methyl-1H-pyrazol-1-yl)ethan-1-one (12.6 mg, white solid, yield: 15.7%) was obtained.

    [0441] MS m/z (ESI): 411.3[M+H].sup.+

    [0442] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.44 (s, 1H), 7.26 (s, 1H), 5.23 (m, 2H), 2.83 (d, J=4.4 Hz, 1H), 2.13 (s, 3H), 1.98-1.85 (m, 2H), 1.83-1.69 (m, 9H), 1.60-1.56 (m, 1H), 1.40-1.27 (m, 12H), 1.09-1.01 (m, 2H), 0.80 (s, 3H), 0.48-0.45 (m, 1H).

    Example 96

    2-((4-Fluorophenyl)amino)-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

    [0443] ##STR00172##

    Step 1: Preparation of 2-((4-fluorophenyl)amino)-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

    [0444] ##STR00173##

    [0445] 2-Bromo-1-((3R,5R,8R,10S,13S,14S,15R,17S)-3-hydroxy-3,13,15-trimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one (50 mg, 0.12 mmol) was dissolved in tetrahydrofuran (3 mL). 4-Fluoroaniline (42 mg, 0.2 mmol) and triethylamine (60 mg, 0.6 mmol) were added, and the reaction solution was stirred at room temperature for 12 hours. The reaction solution was concentrated, and the resulting residue was purified by high performance liquid chromatography to obtain 2-((4-fluorophenyl)amino)-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 (7 mg, white solid, yield: 13%).

    [0446] MS m/z (ESI): 442.3[M+H].sup.+.

    [0447] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 6.95-6.86 (m, 2H), 6.59-6.53 (m, 2H), 3.95-3.85 (m, 2H), 2.55-2.47 (m, 1H), 2.25-2.15 (m, 2H), 1.90-1.80 (m, 5H), 1.75-1.25 (m, 18H), 1.00 (d, 0.7=8.0 Hz, 3H), 0.81 (s, 3H).

    Example 97

    2-((4-Fluorophenyl)amino)-1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)ethan-1-one

    [0448] ##STR00174##

    [0449] In accordance with Example 5, 2-bromo-1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethylocta decahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)ethan-1-one and p-fluoroaniline were used as the starting materials, and N,N-dimethylformamide was used as the solvent, accordingly, 2-((4-fluorophenyl)amino)-1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)ethan-1-one (14.9 mg, yellow oil, yield: 26.7%) was obtained.

    [0450] MS m/z (ESI): 440.2[M+H].sup.+

    [0451] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.00-6.95 (m, 2H), 6.91-6.83 (m, 2H), 4.19 (dd, J.sub.1=20.0 Hz, J.sub.2=2.8 Hz, 2H), 2.80 (d, 0.7=4.0 Hz, 1H), 1.92-1.58 (m, 14H), 1.45-1.40 (m, 8H), 1.27 (s, 3H), 1.09-0.91 (m, 2H), 0.69 (s, 3H), 0.48-0.43 (m, 1H).

    Example 98

    1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-Hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-(1H-imidazol-1-yl)ethan-1-one

    [0452] ##STR00175##

    [0453] In accordance with Example 63, 2-bromo-1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethylocta decahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)ethan-1-one and imidazole were used as the starting materials, accordingly, 1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-(1H-imidazol-1-yl)ethan-1-one (23.3 mg, white solid, yield: 34.4%) was obtained.

    [0454] MS m/z (ESI): 397.2[M+H].sup.+

    [0455] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.48 (s, 1H), 7.12 (s, 1H), 6.88 (s, 1H), 4.98-4.87 (m, 2H), 2.82 (d, J=2.8 Hz, 1H), 1.94-1.91 (m, 1H), 1.85-1.81 (m, 4H), 1.70-1.53 (m, 10H), 1.41-1.28 (m, 9H), 1.13-0.95 (m, 2H), 0.78 (s, 3H), 0.52-0.46 (m, 1H).

    Example 99 and Example 100

    1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-Hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-(4,5,6,7-tetrahydro-1H-indazol-1-yl)ethan-1-one

    1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-Hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-(4,5,6,7-tetrahydro-2H-indazol-2-yl)ethan-1-one

    [0456] ##STR00176## ##STR00177##

    [0457] In accordance with Example 5, 2-bromo-1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethylocta decahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)ethan-1-one and 4,5,6,7-tetrahydro-2H-indazole were used as the starting materials, accordingly, 1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-(4,5,6,7-tetrahydro-1H-indazol-1-yl)ethan-1-one (99) (5.5 mg, white solid, yield: 6.8%) and 1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-(4,5,6,7-tetrahydro-2H-indazol-2-yl)ethan-1-one (100) (3.1 mg, white solid, yield: 3.8%) were obtained.

    Example 99

    [0458] MS m/z (ESI): 415.3[M+H].sup.+

    [0459] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.12 (s, 1H), 5.14-5.05 (m, 2H), 2.80 (d, J=4.0 Hz, 1H), 2.69 (t, 0.7=6.0 Hz, 2H), 2.56 (t, J=6.0 Hz, 2H), 1.97-1.93 (m, 1H), 1.85-1.61 (m, 12H), 1.55-1.52 (m, 2H), 1.43-1.21 (m, 13H), 1.11-0.94 (m, 2H), 0.79 (s, 3H), 0.48-0.42 (m, 1H).

    Example 100

    [0460] MS m/z (ESI): 415.3[M+H].sup.+

    [0461] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.50 (s, 1H), 5.74-5.35 (m, 2H), 2.89 (d, J=4.0 Hz, 1H), 2.58 (t, J=6.0 Hz, 2H), 2.48 (t, J=6.0 Hz, 2H), 1.96-1.91 (m, 1H), 1.80-1.72 (m, 8H), 1.40-1.22 (m, 19H), 1.12-0.99 (m, 2H), 0.82 (s, 3H), 0.51-0.45 (m, 1H).

    Example 101

    1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-Hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-(5-methyl-1H-tetrazol-1-yl)ethan-1-one

    [0462] ##STR00178##

    [0463] In accordance with Example 5, 2-bromo-1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethylocta decahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)ethan-1-one and 5-methyl-1H-4-tetrazole were used as the starting materials, accordingly, 1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-(5-methyl-1H-tetrazol-1-yl)ethan-1-one (19 mg, white solid, yield: 23.5%) was obtained.

    [0464] MS m/z (ESI): 413.2[M+H].sup.+

    [0465] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 5.58 (dd, J.sub.1=17.6 Hz, J.sub.2=7.6 Hz, 2H), 2.86 (d, J=4.0 Hz, 1H), 2.57 (s, 3H), 1.96-1.93 (m, 1H), 1.89-1.61 (m, 8H), 1.55-1.22 (m, 14H), 1.14-0.97 (m, 3H), 0.84 (s, 3H), 0.47-0.53 (m, 1H).

    Example 102

    2-(4-(Azetidine-1-carbonyl)-1H-pyrazol-1-yl)-1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)ethan-1-one

    [0466] ##STR00179##

    [0467] In accordance with Example 5, 2-bromo-1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethylocta decahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)ethan-1-one and azetidin-1-yl(1H-pyrazol-4-yl)methanone were used as the starting materials, accordingly, 2-(4-(azetidine-1-carbonyl)-1H-pyrazol-1-yl)-1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR 15,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)ethan-1-one (10.0 mg, yield: 14.3%) was obtained.

    [0468] MS m/z (ESI): 480.3 [M+H].sup.+

    [0469] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.85-7.80 (m, 1H), 7.80-7.74 (m, 1H), 5.20-5.05 (m, 2H), 4.53-4.10 (m, 4H), 2.82 (d, J=3.3 Hz, 1H), 2.44-2.31 (m, 2H), 1.98-1.90 (m, 1H), 1.86-1.79 (m, 3H), 1.74-1.64 (m, 3H), 1.57-1.53 (m, 2H), 1.44-1.24 (m, 15H), 1.13-0.97 (m, 2H), 0.79 (s, 3H), 0.51-0.44 (m, 1H).

    Example 103

    1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-Hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-(4-nitro-1H-pyrazol-1-yl)ethan-1-one

    [0470] ##STR00180##

    [0471] In accordance with Example 5, 2-bromo-1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethylocta decahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)ethan-1-one and 4-nitro-1H-pyrazole were used as the starting materials, accordingly, 1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-(4-nitro-1H-pyrazol-1-yl)ethan-1-one (32.5 mg, yield: 60%) was obtained.

    [0472] MS m/z (ESI): 424.2 [M+H—H.sub.2O].sup.+

    [0473] .sup.1H NMR (400 MHz, CDCl.sub.3) δ8.20 (s, 1H), 8.09 (s, 1H), 5.26-5.09 (m, 2H), 2.85 (s, 1H), 1.98-1.91 (m, 1H), 1.87-1.79 (m, 4H), 1.74-1.65 (m, 3H), 1.56-1.52 (m, 2H), 1.47-1.35 (m, 7H), 1.34-1.24 (m, 7H), 1.13-0.97 (m, 2H), 0.79 (s, 3H), 0.55-0.47 (m, 1H).

    Example 104

    (3R,5R,8R,9R,10S,13S,14S,16R,17S)-17-Acetyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-16-carbonitrile (104)

    [0474] ##STR00181##

    Step 1: Preparation of (3R,5R,8R,9R,10S,13S,14S,16R,17S)-17-acetyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-16-carbonitrile

    [0475] ##STR00182##

    [0476] 1-((3R,5R,8R,9R,10S,13S,14S)-3-Hydroxy-3,13-dimethyl-2,3,4,5,6,7,8,9,10,11,12, 13,14,15-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one (270 mg, 0.853 mmol), ammonium chloride (250 mg, 4.69 mmol) and 18-crown-6 (23 mg, 0.853 mmol) were added to a mixed solution of dimethyl sulfoxide (7 mL) and water (2 mL) at 85° C., followed by the addition of a mixed solution of sodium cyanide (230 mg, 4.69 mmol), dimethyl sulfoxide (4 mL) and water (1 mL). The reaction solution was stirred at 85° C. for 16 hours. Water (30 mL) was added, and then 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 column chromatography (petroleum ether/ethyl acetate=1:1) to obtain (3R,5R,8R,9R,10S,13S,14S,16R,17S)-17-acetyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-16-carbonitrile as a white solid (250 mg, yield: 85%).

    Example 105

    1-(2-((3R,5R,8R,9R,10S,13S,14R,17S)-3-Hydroxy-3,13-dimethyl-15-(nitromethyl)hexa decahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile

    [0477] ##STR00183##

    [0478] Example 105 was synthesized by the following specific scheme:

    ##STR00184##

    [0479] MS m/z (ESI): 469.3 [M+1].sup.+.

    Example 121

    3-Cyclopropyl-1-(2-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile

    [0480] ##STR00185##

    Step 1: Preparation of 3-cyclopropyl-1-(2-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile

    [0481] ##STR00186##

    [0482] In accordance with Example 5, 2-bromo-1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethylocta decahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)ethan-1-one was used as the starting material, accordingly, 3-cyclopropyl-1-(2-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile (19.2 mg, yield: 21%) was obtained.

    [0483] MS m/z (ESI): 462.3 [M+H].sup.+

    [0484] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.73 (s, 1H), 5.13-4.95 (m, 2H), 2.80 (d, J=2.2 Hz, 1H), 2.04-1.89 (m, 2H), 1.86-1.79 (m, 3H), 1.76-1.63 (m, 3H), 1.58-1.49 (m, 3H), 1.46-1.21 (m, 14H), 1.12-0.93 (m, 6H), 0.76 (s, 3H), 0.51-0.43 (m, 1H).

    Example 122

    1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-Hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-(4-(methylthio)-1H-pyrazol-1-yl)ethan-1-one (122)

    [0485] ##STR00187##

    Step 1: Preparation of 1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-(4-(methylthio)-1H-pyrazol-1-yl)ethan-1-one

    [0486] ##STR00188##

    [0487] In accordance with Example 5, 2-bromo-1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethylocta decahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)ethan-1-one was used as the starting material, accordingly, 1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-(4-(methylthio)-1H-pyrazol-1-yl)ethan-1-one (8.7 mg, yield: 16%) was obtained.

    [0488] MS m/z (ESI): 443.2 [M+H].sup.+

    [0489] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.54 (s, 1H), 7.45 (s, 1H), 5.17-5.00 (m, 2H), 2.81 (d, J=3.8 Hz, 1H), 2.35 (s, 3H), 1.99-1.91 (m, 1H), 1.88-1.76 (m, 4H), 1.73-1.63 (m, 3H), 1.55-1.50 (m, 1H), 1.43-1.18 (m, 15H), 1.12-0.97 (m, 2H), 0.79 (s, 3H), 0.50-0.41 (m, 1H).

    Example 123 and Example 124

    1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-Hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-(4-(methylsulfinyl)-1H-pyrazol-1-yl)ethan-1-one (123) and

    1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-(4-(methylsulfonyl)-1H-pyrazol-1-yl)ethan-1-one (124)

    [0490] ##STR00189##

    Step 1: Preparation of 1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-(4-(methylsulfinyl)-1H-pyrazol-1-yl)ethan-1-one and

    1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-(4-(methylsulfonyl)-1H-pyrazol-1-yl)ethan-1-one

    [0491] ##STR00190##

    [0492] 1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-Hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-(4-(methylthio)-1H-pyrazol-1-yl)ethan-1-one (80 mg, 0.18 mmol) was dissolved in dichloromethane (10 mL), and the solution was cooled to −78° C. m-Chloroperoxybenzoic acid (55 mg, 0.27 mmol) was added, and the reaction solution was stirred for 1 hour. Water (10 mL) was added, and then the reaction solution was washed with saturated aqueous sodium bicarbonate solution (10 mL). The organic phase was separated, dried over anhydrous sodium sulfate, filtrated and concentrated by rotary evaporation to dryness. The resulting crude product was purified by high performance liquid chromatography to obtain 1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-(4-(methylsulfinyl)-1H-pyrazol-1-yl)ethan-1-one (17.2 mg, yield: 20%) and 1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-(4-(methylsulfonyl)-1H-pyrazol-1-yl)ethan-1-one (20.4 mg, yield: 25%).

    Example 123

    [0493] MS m/z (ESI): 441.3 [M−H.sub.2O+H].sup.+

    [0494] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.85 (s, 1H), 7.83 (s, 1H), 5.30-5.09 (m, 2H), 2.91 (s, 3H), 2.85-2.82 (m, 1H), 1.98-1.90 (m, 1H), 1.87-1.78 (m, 3H), 1.75-1.50 (m, 8H), 1.47-1.21 (m, 12H), 1.13-0.96 (m, 2H), 0.79 (s, 3H), 0.54-0.45 (m, 1H).

    Example 124

    [0495] MS m/z (ESI): 457.2 [M−H.sub.2O+H].sup.+

    [0496] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.94 (s, 1H), 7.87 (s, 1H), 5.26-5.10 (m, 2H), 3.14 (s, 3H), 2.85 (d, J=2.7 Hz, 1H), 1.98-1.91 (m, 1H), 1.87-1.79 (m, 3H), 1.76-1.64 (m, 3H), 1.59-1.52 (m, 1H), 1.50-1.18 (m, 16H), 1.15-0.96 (m, 2H), 0.79 (s, 3H), 0.55-0.46 (m, 1H).

    Example 125

    3-Fluoro-4-(2-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-oxoethoxy)benzonitrile (125)

    [0497] ##STR00191##

    Step 1: Preparation of 3-fluoro-4-(2-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-oxoethoxy)benzonitrile

    [0498] ##STR00192##

    [0499] In accordance with Example 5, 2-bromo-1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethylocta decahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)ethan-1-one was used as the starting material, accordingly, 3-fluoro-4-(2-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-oxoethoxy)benzonitrile (12.5 mg, yield: 18%) was obtained.

    [0500] MS m/z (ESI): 448.2 [M−H.sub.2O+H].sup.+

    [0501] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.43-7.33 (m, 2H), 6.91-6.84 (m, 1H), 4.91 (s, 2H), 2.96-2.88 (m, 1H), 1.90-1.76 (m, 4H), 1.75-1.62 (m, 3H), 1.55-1.26 (m, 17H), 1.12-1.04 (m, 1H), 0.98-0.92 (m, 1H), 0.78 (s, 3H), 0.50-0.41 (m, 1H).

    Example 126

    5-Fluoro-2-(2-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-oxoethoxy)benzonitrile (126)

    [0502] ##STR00193##

    Step 1: Preparation of 5-fluoro-2-(2-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-oxoethoxy)benzonitrile

    [0503] ##STR00194##

    [0504] In accordance with Example 5, 2-bromo-1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethylocta decahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)ethan-1-one was used as the starting material, accordingly, 5-fluoro-2-(2-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-oxoethoxy)benzonitrile (11.4 mg, yield: 10%) was obtained.

    [0505] MS m/z (ESI): 448.2 [M−H.sub.2O+H].sup.+

    [0506] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.34-7.28 (m, 1H), 7.25-7.18 (m, 1H), 6.78-6.72 (m, 1H), 4.91-4.78 (m, 2H), 2.99 (d, 0.7=3.3 Hz, 1H), 1.91-1.78 (m, 4H), 1.76-1.64 (m, 3H), 1.57-1.25 (m, 17H), 1.08-0.92 (m, 2H), 0.78 (s, 3H), 0.50-0.40 (m, 1H).

    Example 127

    1-(2-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-Hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-oxoethyl)-1H-pyrazole-3,5-dicarbonitrile (127)

    [0507] ##STR00195##

    Step 1: Preparation of 1-(2-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-oxoethyl)-1H-pyrazole-3,5-dicarbonitrile

    [0508] ##STR00196##

    [0509] In accordance with Example 5, 2-bromo-1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethylocta decahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)ethan-1-one was used as the starting material, accordingly, 1-(2-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-oxoethyl)-1H-pyrazole-3,5-dicarbonitrile (18.0 mg, yield: 31.8%) was obtained.

    [0510] MS m/z (ESI): 429.2 [M−H.sub.2O+H].sup.+

    [0511] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.21 (S, 1H), 5.38 (q, J=18.0 Hz, 2H), 2.87 (d, J=3.0 Hz, 1H), 1.97-1.91 (m, 1H), 1.88-1.75 (m, 4H), 1.76-1.64 (m, 3H), 1.58-1.51 (m, 1H), 1.48-1.26 (m, 15H), 1.15-0.99 (m, 2H), 0.83 (s, 3H), 0.58-0.48 (m, 1H).

    Example 128

    1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-Hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-(4-(oxazol-2-yl)-1H-pyrazol-1-yl)ethan-1-one (128)

    [0512] ##STR00197##

    Step 1: Preparation of 1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-(4-(oxazol-2-yl)-1H-pyrazol-1-yl)ethan-1-one

    [0513] ##STR00198##

    [0514] In accordance with Example 5, 2-bromo-1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethylocta decahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)ethan-1-one was used as the starting material, accordingly, 1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-(4-(oxazol-2-yl)-1H-pyrazol-1-yl)ethan-1-one (16.0 mg, yield: 14%) was obtained.

    [0515] MS m/z (ESI): 464.3 [M+H].sup.+

    [0516] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.89 (s, 1H), 7.79 (s, 1H), 7.73 (s, 1H), 7.13 (s, 1H), 5.27-5.13 (m, 2H), 2.85 (d, J=4.0 Hz, 1H), 2.01-1.93 (m, 1H), 1.87-1.65 (m, 11H), 1.58-1.50 (m, 1H), 1.44-1.22 (m, 11H), 1.14-0.98 (m, 2H), 0.81 (s, 3H), 0.53-0.44 (m, 1H).

    Example 129

    1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-Hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-(pyridazin-4-yloxy)ethan-1-one (129)

    [0517] ##STR00199##

    Step 1: Preparation of 1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-(pyridazin-4-yloxy)ethan-1-one

    [0518] ##STR00200##

    [0519] In accordance with Example 5, 2-bromo-1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethylocta decahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)ethan-1-one was used as the starting material, accordingly, 1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-(pyridazin-4-yloxy)ethan-1-one (16.0 mg, yield: 26%) was obtained.

    [0520] MS m/z (ESI): 425.3 [M+H].sup.+

    [0521] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.88 (s, 1H), 7.61 (d, J=6.8 Hz, 1H), 6.53 (d, J=6.8 Hz, 1H), 5.17-4.85 (m, 2H), 2.83 (s, 1H), 1.99-1.90 (m, 1H), 1.88-1.78 (m, 3H), 1.76-1.54 (m, 10H), 1.46-1.25 (m, 10H), 1.14-0.95 (m, 2H), 0.79 (s, 3H), 0.55-0.46 (m, 1H).

    Example 130

    1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-Hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-((2-(trifluoromethyl)pyrimidin-5-yl)oxy)ethan-1-one

    [0522] ##STR00201##

    Step 1: Preparation of 1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-((2-(trifluoromethyl)pyrimidin-5-yl)oxy)ethan-1-one

    [0523] ##STR00202##

    [0524] In accordance with Example 5, 2-bromo-1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethylocta decahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)ethan-1-one was used as the starting material, accordingly, 1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-((2-(trifluoromethyl)pyrimidin-5 10-yl)oxy)ethan-1-one (23.0 mg, yield: 38.3%) was obtained.

    [0525] MS m/z (ESI): 493.2[M+H].sup.+1H NMR (400 MHz, CDCl.sub.3) δ 8.45 (s, 2H), 5.01 (s, 2H), 2.86 (s, 1H), 1.89 (m, 1H), 1.83 (m, 4H), 1.75 (dm, 1H), 1.68 (m, 2H), 1.57 (m, 1H), 1.38 (m, 8H), 1.31 (m, 2H), 1.28 (s, 3H), 1.26-1.20 (m, 1H), 1.13-1.03 (m, 1H), 0.96 (m, 1H), 0.80 (s, 3H), 0.48 (m, 1H).

    Example 131

    1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-3-Hydroxy-3,13,15-trimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(3-(trifluoromethyl)-1H-pyrazol-1-yl)ethan-1-one (131)

    [0526] ##STR00203##

    Step 1: 1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-3-Hydroxy-3,13,15-trimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(3-(trifluoromethyl)-1H-pyrazol-1-yl)ethan-1-one

    [0527] ##STR00204##

    [0528] In accordance with Example 5, 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, 1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-3,13,15-trimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(3-(trifluoromethyl)-1H-pyrazol-1-yl)ethan-1-one (20.5 mg, yield: 30.1%) was obtained.

    [0529] MS m/z (ESI): 467.2[M+H].sup.+.

    [0530] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.49-7.43 (m, 1H), 6.59 (d, J=2.4 Hz, 1H), 5.14-4.85 (m, 2H), 2.54 (t, J=8.1 Hz, 1H), 2.26-2.08 (m, 2H), 2.02-1.93 (m, 1H), 1.90-1.79 (m, 4H), 1.74-1.59 (m, 3H), 1.57-1.19 (m, 14H), 1.21-1.04 (m, 1H), 0.98 (d, J=7.0 Hz, 3H), 0.84 (s, 3H).

    Example 133

    2-(4-(Azetidine-1-carbonyl)-1H-pyrazol-1-yl)-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 (133)

    [0531] ##STR00205##

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

    [0532] ##STR00206##

    [0533] In accordance with Example 5, 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, 2-(4-(azetidine-1-carbonyl)-1H-pyrazol-1-yl)-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 (12.0 mg, yield: 21%) was obtained.

    [0534] MS m/z (ESI): 482.3[M+H].sup.+.

    [0535] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.78 (s, 2H), 5.00-4.77 (m, 2H), 4.38-4.25 (m, 4H), 2.54 (t, J=7.6 Hz, 1H), 2.43-2.32 (m, 2H), 2.26-2.08 (m, 2H), 1.98-1.96 (m, 1H), 1.88-1.83 (m, 3H), 1.69-1.62 (m, 5H), 1.48-1.42 (m, 4H), 1.38-1.26 (m, 9H), 1.16-1.07 (m, 2H), 0.98 (d, J=7.0 Hz, 3H), 0.84 (s, 3H).

    Example 134

    3-Chloro-1-(2-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-3,13,15-trimethylhexa decahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile (134)

    [0536] ##STR00207##

    Step 1: Preparation of 3-chloro-1-(2-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-3,13,15-trimethylhexa decahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile

    [0537] ##STR00208##

    [0538] In accordance with Example 5, 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 3-chloro-1-(2-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-3,13,15-trimethylhexa decahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile (37 mg, yield: 55.3%) was obtained.

    [0539] MS m/z (ESI): 456.2[M−H]−.

    [0540] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.81 (s, 1H), 5.03-4.75 (m, 2H), 2.54 (t, J=8.0 Hz, 1H), 2.31-2.13 (m, 2H), 1.93-1.06 (m, 23H), 0.99 (d, 0.7=7.1 Hz, 3H), 0.83 (s, 3H).

    Example 135

    1-(2-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-3-Hydroxy-3,13,15-trimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-1H-pyrazole-3,5-dicarbonitrile (135)

    [0541] ##STR00209##

    Step 1: Preparation of 1-(2-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-3,13,15-trimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-1H-pyrazole-3,5-dicarbonitrile

    [0542] ##STR00210##

    [0543] In accordance with Example 5, 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 1-(2-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-3,13,15-trimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-1H-pyrazole-3,5-dicarbonitrile (18 mg, yield 27.5%) was obtained.

    [0544] MS m/z (ESI): 447.2[M−H].sup.−.

    [0545] .sup.1H NMR (400 MHz, CDCl.sub.3) δ7.20 (s, 1H), 5.23-5.07 (m, 2H), 2.68-2.52 (m, 1H), 2.28-1.36 (m, 21H), 1.28 (s, 3H), 1.18-1.08 (m, 1H), 1.00 (d, J=6.9 Hz, 3H), 0.88 (s, 3H).

    Example 136

    3-(2-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-3-Hydroxy-3,13,15-trimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)thiazolidine-2,4-dione (136)

    [0546] ##STR00211##

    Step 1: Preparation of 3-(2-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-3,13,15-trimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)thiazolidine-2,4-dione

    [0547] ##STR00212##

    [0548] In accordance with Example 5, 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, 3-(2-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-3,13,15-trimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)thiazolidine-2,4-dione (24.0 mg, yield: 31.5%) was obtained.

    [0549] MS m/z (ESI): 430.2 [M−H.sub.2O+H].sup.+

    [0550] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 4.37 (s, 2H), 4.04-3.98 (m, 2H), 2.56-2.49 (m, 1H), 2.22-2.03 (m, 2H), 1.91-1.81 (m, 4H), 1.73-1.61 (m, 3H), 1.47-1.26 (m, 15H), 1.17-1.05 (m, 2H), 0.97 (d, J=7.1 Hz, 3H), 0.81 (s, 3H).

    Example 137

    1-(2-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-15-Ethyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-1H-pyrazole-3-carbonitrile (137)

    [0551] ##STR00213##

    Step 1: Preparation of 1-(2-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-15-ethyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-1H-pyrazole-3-carbonitrile

    [0552] ##STR00214##

    [0553] In accordance with Example 5, 2-bromo-1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-15-ethyl-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,8R,9R,10S,13S,14S,15R,17S)-15-ethyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-1H-pyrazole-3-carbonitrile (16 mg, yield: 25.9%) was obtained.

    [0554] MS m/z (ESI): 438.2[M+H].sup.+.

    [0555] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.49 (d, J=2.5 Hz, 1H), 6.73 (d, J=2.4 Hz, 1H), 5.22-4.78 (m, 2H), 2.57 (t, J=8.0 Hz, 1H), 2.15-1.30 (m, 20H), 1.28 (s, 3H), 1.16-1.03 (m, 4H), 0.84 (t, J=7.3 Hz, 3H), 0.79 (s, 3H).

    Example 138

    1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-15-Ethyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(3-(trifluoromethyl)-1H-pyrazol-1-yl)ethan-1-one (138)

    [0556] ##STR00215##

    Step 1: Preparation of 1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-15-ethyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(3-(trifluoromethyl)-1H-pyrazol-1-yl)ethan-1-one

    [0557] ##STR00216##

    [0558] In accordance with Example 5, 2-bromo-1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-15-ethyl-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,8R,9R,10S,13S,14S,15R,17S)-15-ethyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(3-(trifluoromethyl)-1H-pyrazol-1-yl)ethan-1-one (23 mg, yield: 33.9%) was obtained.

    [0559] MS m/z (ESI): 481.3[M+H].sup.+.

    [0560] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.47 (d, J=4.0 Hz, 1H), 6.59 (d, J=4.0 Hz 1H), 5.07-4.89 (m, 2H), 2.56 (t, J=9.3 Hz, 1H), 2.20-1.29 (m, 20H), 1.28 (s, 3H), 1.27-1.03 (m, 4H), 0.84 (t, J=7.3 Hz, 3H), 0.80 (s, 3H).

    Example 139

    1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-15-Ethyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(5-methyl-2H-tetrazol-2-yl)ethan-1-one (139)

    [0561] ##STR00217##

    Step 1: Preparation of 1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-15-ethyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(5-methyl-2H-tetrazol-2-yl)ethan-1-one

    [0562] ##STR00218##

    [0563] In accordance with Example 5, 2-bromo-1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-15-ethyl-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,8R,9R,10S,13S,14S,15R,17S)-15-ethyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(5-methyl-2H-tetrazol-2-yl)ethan-1-one (13.5 mg, yield: 22.3%) was obtained.

    [0564] MS m/z (ESI): 429.3[M+H].sup.+.

    [0565] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 5.39-5.29 (m, 2H), 2.63-2.57 (m, 1H), 2.56 (s, 3H), 2.10-1.30 (m, 20H), 1.28 (s, 3H), 1.27-1.05 (m, 4H), 0.87-0.81 (m, 6H).

    Example 140 and Example 141

    1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-15-Ethyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(1H-1,2,3-triazol-1-yl)ethan-1-one (140)

    1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-15-Ethyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(2H-1,2,3-triazol-2-yl)ethan-1-one (141)

    [0566] ##STR00219##

    Step 1: Preparation of 1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-15-ethyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(1H-1,2,3-triazol-1-yl)ethan-1-one and

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

    [0567] ##STR00220##

    [0568] In accordance with Example 5, 2-bromo-1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-15-ethyl-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,8R,9R,10S,13S,14S,15R,17S)-15-ethyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(1H-1,2,3-triazol-1-yl)ethan-1-one (17 mg, yield: 29.1%) and 1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-15-ethyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(2H-1,2,3-triazol-2-yl)ethan-1-one (9.2 mg, yield: 15.7%) were obtained.

    Example 140

    [0569] MS m/z (ESI): 414.3[M+H].sup.+.

    [0570] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.77 (s, 1H), 7.67 (s, 1H), 5.37-5.09 (m, 2H), 2.62 (t, J=9.2 Hz, 1H), 2.28-1.20 (m, 25H), 1.16-1.05 (m, 2H), 0.85 (t, J=7.3 Hz, 3H), 0.80 (s, 3H).

    Example 141

    [0571] MS m/z (ESI): 414.3[M+H].sup.+.

    [0572] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.68 (s, 2H), 5.28-5.20 (m, 2H), 2.54 (t, J=8.0 Hz, 1H), 1.99-1.23 (m, 25H), 1.13-1.06 (m, 2H), 0.88-0.78 (m, 6H).

    Example 142

    1-(2-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-15-Ethyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-1H-pyrazole-3,5-dicarbonitrile (142)

    [0573] ##STR00221##

    Step 1: Preparation of 1-(2-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-15-ethyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-1H-pyrazole-3,5-dicarbonitrile

    [0574] ##STR00222##

    [0575] In accordance with Example 5, 2-bromo-1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-15-ethyl-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,8R,9R,10S,13S,14S,15R,17S)-15-ethyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-1H-pyrazole-3,5-dicarbonitrile (5 mg, yield: 9.2%) was obtained.

    [0576] MS m/z (ESI): 463.2[M+H].sup.+.

    [0577] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.21 (s, 1H), 5.29-5.02 (m, 2H), 2.61 (t, J=9.3 Hz, 1H), 2.24-1.34 (m, 19H), 1.28 (s, 3H), 1.26-1.02 (m, 5H), 0.92-0.76 (m, 6H).

    Example 143

    1-(2-((3R,5R,8R,9R,10S,13S,14S,15S,17S)-15-Cyclopropyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-1H-pyrazole-3,5-dicarbonitrile (143)

    [0578] ##STR00223##

    Step 1: Preparation of 1-(2-((3R,5R,8R,9R,10S,13S,14S,15S,17S)-15-cyclopropyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-1H-pyrazole-3,5-dicarbonitrile

    [0579] ##STR00224##

    [0580] In accordance with Example 5, 1-((3R,5R,8R,9R,10S,13S,14S,15S,17S)-15-cyclopropyl-3-hydroxy-3,13-dimethylhexa decahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one was used as the starting material, accordingly, 1-(2-((3R,5R,8R,9R,10S,13S,14S,15S,17S)-15-cyclopropyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-1H-pyrazole-3,5-dicarbonitrile (19.6 mg, yield: 18%) was obtained.

    [0581] MS m/z (ESI): 473.2[M−H].sup.−

    [0582] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.20 (s, 1H), 5.24-5.09 (m, 2H), 2.58-2.50 (m, 1H), 2.26-2.07 (m, 2H), 2.06-1.95 (m, 2H), 1.90-1.80 (m, 2H), 1.78-1.66 (m, 2H), 1.58-1.22 (m, 16H), 1.19-1.06 (m, 2H), 0.94 (s, 3H), 0.87-0.78 (m, 1H), 0.64-0.56 (m, 1H), 0.45-0.39 (m, 1H), 0.18-0.02 (m, 2H).

    Example 144

    1-((3R,5R,8R,9R,10S,13S,14S,15S,17S)-15-Cyclopropyl-3-hydroxy-3,13-dimethylhexa decahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(3-(trifluoromethyl)-1H-pyrazol-1-yl)ethan-1-one (144)

    [0583] ##STR00225##

    Step 1: Preparation of 1-((3R,5R,8R,9R,10S,13S,14S,15S,17S)-15-cyclopropyl-3-hydroxy-3,13-dimethylhexa decahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(3-(trifluoromethyl)-1H-pyrazol-1-yl)ethan-1-one

    [0584] ##STR00226##

    [0585] In accordance with Example 5, 1-((3R,5R,8R,9R,10S,13S,14S,15S,17S)-15-cyclopropyl-3-hydroxy-3,13-dimethylhexa decahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one was used as the starting material, accordingly, 1-((3R,5R,8R,9R,10S,13S,14S,15S,17S)-15-cyclopropyl-3-hydroxy-3,13-dimethylhexa decahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(3-(trifluoromethyl)-1H-pyrazol-1-yl)ethan-1-one (18.0 mg, yield: 23%) was obtained.

    [0586] MS m/z (ESI): 491.3[M−H].sup.−

    [0587] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.47 (d, J=2.0 Hz, 1H), 6.59 (d, J=2.0 Hz, 1H), 5.08-4.90 (m, 2H), 2.53-2.42 (m, 1H), 2.24-1.94 (m, 4H), 1.91-1.79 (m, 3H), 1.78-1.66 (m, 2H), 1.52-1.22 (m, 15H), 1.18-1.02 (m, 2H), 0.91 (s, 3H), 0.88-0.76 (m, 1H), 0.65-0.54 (m, 1H), 0.48-0.36 (m, 1H), 0.18-0.00 (m, 2H).

    Example 146

    1-((3R,5R,8R,9R,10S,13S,14S,15S,17S)-15-Cyclopropyl-3-hydroxy-3,13-dimethylhexa

    [0588] decahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(2H-tetrazol-2-yl)ethan-1-one (146)

    ##STR00227##

    Step 1: Preparation of 1-((3R,5R,8R,9R,10S,13S,14S,15S,17S)-15-cyclopropyl-3-hydroxy-3,13-dimethylhexa decahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(2H-tetrazol-2-yl)ethan-1-one

    [0589] ##STR00228##

    [0590] In accordance with Example 5, 1-((3R,5R,8R,9R,10S,13S,14S,15S,17S)-15-cyclopropyl-3-hydroxy-3,13-dimethylhexa decahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one was used as the starting material, accordingly, 1-((3R,5R,8R,9R,10S,13S,14S,15S,17S)-15-cyclopropyl-3-hydroxy-3,13-dimethylhexa decahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(2H-tetrazol-2-yl)ethan-1-one (12.9 mg, yield: 13.2%) was obtained.

    [0591] MS m/z (ESI): 409.3[M−H.sub.2O+H].sup.+

    [0592] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.57 (s, 1H), 5.46 (s, 2H), 2.58-2.47 (m, 1H), 2.24-1.94 (m, 4H), 1.93-1.80 (m, 3H), 1.77-1.66 (m, 2H), 1.50-1.21 (m, 15H), 1.18-1.06 (m, 2H), 0.95 (s, 3H), 0.87-0.78 (m, 1H), 0.64-0.55 (m, 1H), 0.46-0.38 (m, 1H), 0.17-0.01 (m, 2H).

    Example 147

    3-Chloro-1-(2-((3R,5R,8R,9R,10S,13S,14S,15S,17S)-15-cyclopropyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile (147)

    [0593] ##STR00229##

    Step 1: Preparation of 3-chloro-1-(2-((3R,5R,8R,9R,10S,13S,14S,15S,17S)-15-cyclopropyl-3-hydroxy-3,13-di methylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile

    [0594] ##STR00230##

    [0595] In accordance with Example 5, 1-((3R,5R,8R,9R,10S,13S,14S,15S,17S)-15-cyclopropyl-3-hydroxy-3,13-dimethylhexa decahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one was used as the starting material, accordingly, 3-chloro-1-(2-((3R,5R,8R,9R,10S,13S,14S,15S,17S)-15-cyclopropyl-3-hydroxy-3,13-di methylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile (13.5 mg, yield: 17.4%) was obtained.

    [0596] MS m/z (ESI): 482.2[M−H].sup.−

    [0597] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.82 (s, 1H), 5.01-4.76 (m, 2H), 2.55-2.41 (m, 1H), 2.22-1.94 (m, 4H), 1.91-1.77 (m, 3H), 1.76-1.66 (m, 2H), 1.56-1.24 (m, 15H), 1.18-1.04 (m, 2H), 0.90 (s, 3H), 0.87-0.75 (m, 1H), 0.64-0.53 (m, 1H), 0.46-0.38 (m, 1H), 0.17-0.02 (m, 2H).

    Example 148

    3-(2-((3R,5R,8R,9R,10S,13S,14S,15S,17S)-15-Cyclopropyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)thiazolidine-2,4-dione (148)

    [0598] ##STR00231##

    Step 1: Preparation of 3-(2-((3R,5R,8R,9R,10S,13S,14S,15S,17S)-15-cyclopropyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)thiazolidine-2,4-dione

    [0599] ##STR00232##

    [0600] In accordance with Example 5, 1-((3R,5R,8R,9R,10S,13S,14S,15S,17S)-15-cyclopropyl-3-hydroxy-3,13-dimethylhexa decahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one was used as the starting material, accordingly, 3-(2-((3R,5R,8R,9R,10S,13S,14S,15S,17S)-15-cyclopropyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)thiazolidine-2,4-dione (10.0 mg, yield: 13%) was obtained.

    [0601] MS m/z (ESI): 456.2[M−H.sub.2O+H].sup.+

    [0602] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 4.38 (s, 2H), 4.04 (s, 2H), 2.51-2.43 (m, 1H), 2.24-2.00 (m, 4H), 1.91-1.80 (m, 3H), 1.75-1.67 (m, 2H), 1.49-1.27 (m, 15H), 1.17-1.05 (m, 2H), 0.88 (s, 3H), 0.84-0.78 (m, 1H), 0.62-0.53 (m, 1H), 0.46-0.36 (m, 1H), 0.15-0.01 (m, 2H).

    Example 149

    1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-15-Ethyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(2H-tetrazol-2-yl)ethan-1-one (149)

    [0603] ##STR00233##

    Step 1: Preparation of 1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-15-ethyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(2H-tetrazol-2-yl)ethan-1-one

    [0604] ##STR00234##

    [0605] In accordance with Example 5, 2-bromo-1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-15-ethyl-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,8R,9R,10S,13S,14S,15R,17S)-15-ethyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(2H-tetrazol-2-yl)ethan-1-one (11 mg, white solid, yield: 18.8%) was obtained.

    [0606] MS m/z (ESI): 397.2[M−H.sub.2O+H].sup.+

    [0607] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.57 (s, 1H), 5.50-5.41 (m, 2H), 2.62 (t, J=8.5 Hz, 1H), 2.29-1.30 (m, 20H), 1.28 (s, 3H), 1.27-1.05 (m, 4H), 0.85-0.82 (m, 6H).

    Example 150

    1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-3-Hydroxy-3,13,15-trimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-((2-(trifluoromethyl)pyrimidin-5-yl)oxy)ethan-1-one (150)

    [0608] ##STR00235##

    Step 1: Preparation of 1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-3-Hydroxy-3,13,15-trimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-((2-(trifluoromethyl)pyrimidin-5-yl)oxy)ethan-1-one

    [0609] ##STR00236##

    [0610] In accordance with Example 5, 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, 1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-3,13,15-trimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-((2-(trifluoromethyl)pyrimidin-5-yl)oxy)ethan-1-one (16.1 mg, yield: 19%) was obtained.

    [0611] MS m/z (ESI): 477.3[M−H.sub.2O+H].sup.+

    [0612] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.44 (s, 2H), 4.85-4.71 (m, 2H), 2.67-2.57 (m, 1H), 2.30-2.10 (m, 2H), 1.93-1.81 (m, 4H), 1.74-1.61 (m, 3H), 1.48-1.23 (m, 15H), 1.18-1.06 (m, 2H), 1.00 (d, J=7.1 Hz, 3H), 0.87 (s, 3H).

    Example 151

    1-((3R,5R,8R,9R,10S,13S,14S,15S,17S)-15-Cyclopropyl-3-hydroxy-3,13-dimethylhexa decahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-((2-(trifluoromethyl)pyrimidin-5-yl)oxy)ethan-1-one (151)

    [0613] ##STR00237##

    Step 1: Preparation of 1-((3R,5R,8R,9R,10S,13S,14S,15S,17S)-15-cyclopropyl-3-hydroxy-3,13-dimethylhexa decahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-((2-(trifluoromethyl)pyrimidin-5-yl)oxy)ethan-1-one

    [0614] ##STR00238##

    [0615] In accordance with Example 5, 1-((3R,5R,8R,9R,10S,13S,14S,15S,17S)-15-cyclopropyl-3-hydroxy-3,13-dimethylhexa decahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one was used as the starting material, accordingly, 1-((3R,5R,8R,9R,10S,13S,14S,15S,17S)-15-cyclopropyl-3-hydroxy-3,13-dimethylhexa decahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-((2-(trifluoromethyl)pyrimidin-5-yl)oxy)ethan-1-one (22.9 mg, yield: 27.6%) was obtained.

    [0616] MS m/z (ESI): 503.3[M−H.sub.2O+H].sup.+

    [0617] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.44 (s, 2H), 4.87-4.69 (m, 2H), 2.62-2.50 (m, 1H), 2.25-1.96 (m, 3H), 1.92-1.84 (m, 3H), 1.77-1.66 (m, 2H), 1.54-1.23 (m, 15H), 1.18-1.04 (m, 2H), 0.93 (s, 3H), 0.87-0.78 (m, 1H), 0.65-0.56 (m, 1H), 0.49-0.38 (m, 1H), 0.20-0.02 (m, 2H).

    Example 152

    3-(2-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-Hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-oxoethyl)thiazolidine-2,4-dione (152)

    [0618] ##STR00239##

    Step 1: Preparation of 3-(2-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-oxoethyl)thiazolidine-2,4-dione

    [0619] ##STR00240##

    [0620] In accordance with Example 5, 2-bromo-1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethylocta decahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)ethan-1-one was used as the starting material, accordingly, 3-(2-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-oxoethyl)thiazolidine-2,4-dione (7.1 mg, yield: 9.3%) was obtained.

    [0621] MS m/z (ESI): 446.2[M+H].sup.+

    [0622] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 4.66-4.50 (m, 2H), 4.04 (s, 2H), 2.78 (d, J=4.0 Hz, 1H), 1.98-1.92 (m, 1H), 1.85-1.52 (m, 11H), 1.44-1.24 (m, 12H), 1.13-0.97 (m, 2H), 0.77 (s, 3H), 0.49-0.41 (m, 1H).

    Example 157

    1-((8S,9S,13S,14S,17S)-3-Hydroxy-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-17-yl)ethan-1-one (157)

    [0623] ##STR00241##

    Step 1: Preparation of (8R,9S,13S,14S)-3-(benzyloxy)-13-methyl-6,7,8,9,11,12,13,14,15,16-decahydro-17H-cyclopenta[a]phenanthren-17-one

    [0624] ##STR00242##

    [0625] (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 (4.1 g, 15 mmol) and a solution of dichloromethane/methanol (1/1, 50 mL) were added to a 100 mL three-neck flask, followed by the addition of potassium carbonate (6.2 g, 45 mmol) and benzyl bromide (7.6 g, 45 mmol). The reaction solution was refluxed at 65° C. for 5 hours. The reaction solution was cooled, filtrated and washed with methanol. The reaction solution was concentrated, and the resulting residue was purified by column chromatography with petroleum ether/ethyl acetate (1/3) to obtain (8R,9S,13S,14S)-3-(benzyloxy)-13-methyl-6,7,8,9,11,12,13,14,15,16-decahydro-17H-cyclopenta[a]phenanthren-17-one (5 g, yield: 93%).

    [0626] 1H NMR (400 MHz, CDCl.sub.3) δ 7.45-7.29 (m, 5H), 7.20 (d, J=8.5 Hz, 1H), 6.79 (dd, J=8.6, 2.7 Hz, 1H), 6.73 (d, J=2.6 Hz, 1H), 5.04 (s, 2H), 2.95-2.85 (m, 2H), 2.50 (dd, J=18.8, 8.5 Hz, 1H), 2.43-2.36 (m, 1H), 2.30-2.23 (m, 1H), 2.20-1.94 (m, 4H), 1.63-1.40 (m, 6H), 0.91 (s, 3H).

    Step 2: Preparation of (8S,9S,13S,14S)-3-(benzyloxy)-17-ethylidene-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthrene

    [0627] ##STR00243##

    [0628] Potassium tert-butoxide (7.8 g, 70 mmol) was suspended in tetrahydrofuran (100 mL). Ethyltriphenylphosphonium bromide (26.3 g, 70 mmol) was slowly added at 0° C., and the reaction solution was stirred at 60° C. for 2 hours. (8R,9S,13S,14S)-3-(Benzyloxy)-13-methyl-6,7,8,9,11,12,13,14,15,16-decahydro-17H-cyclopenta[a]phenanthren-17-one (5 g, 14 mmol) was added to the above reaction solution. After reacting at 60° C. for 2 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. The organic phase was washed with saturated saline, dried, filtrated and concentrated. The resulting residue was purified by column chromatography with petroleum ether to obtain (8S,9S,13S,14S)-3-(benzyloxy)-17-ethylidene-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthrene (5 g, yield: 96%).

    Step 3: Preparation of 1-((8S,9S,13S,14S)-3-(benzyloxy)-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-17-yl)ethan-1-ol

    [0629] ##STR00244##

    [0630] (8S,9S,13S,14S)-3-(Benzyloxy)-17-ethylidene-13-methyl-7,8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta[a]phenanthrene (2.5 g, 6.9 mmol) was dissolved in anhydrous tetrahydrofuran (50 mL). A solution of borane in tetrahydrofuran (1 M, 20 mL) was added dropwise at room temperature, and the resulting reaction solution was stirred at room temperature for 1 hour. The reaction solution was cooled with ice water, and sodium hydroxide solution (10%, 15 mL) was slowly added dropwise to release a large amount of gas. Hydrogen peroxide (30%, 20 mL) was slowly added dropwise, and the reaction solution was stirred at room temperature for 2 hours. The reaction solution was extracted with ethyl acetate, washed with sodium thiosulfate solution and saturated saline, and dried to obtain the product (2.5 g), which was used directly in the next step. Step 4: Preparation of 1-((8S,9S,13S,14S,17S)-3-(benzyloxy)-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-17-yl)ethan-1-one

    ##STR00245##

    [0631] 1-((8S,9S,13S,14S)-3-(Benzyloxy)-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-17-yl)ethan-1-ol (2.5 g, 6.5 mmol) was dissolved in dichloromethane (30 mL). Pyridinium chlorochromate (2.06 g, 9.6 mmol) was added, and the reaction solution was stirred at room temperature for 12 hours. The reaction solution was filtrated and concentrated by rotary evaporation to dryness. The resulting residue was purified by column chromatography with petroleum ether/ethyl acetate (1/5) to obtain 1-((8S,9S,13S,14S,17S)-3-(benzyloxy)-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-17-yl)ethan-1-one (1.6 g, yield: 65%).

    [0632] 1H NMR (400 MHz, CDCl.sub.3) δ 7.44-7.28 (m, 5H), 7.20 (d, J=8.6 Hz, 1H), 6.78 (dd, J=8.5, 2.6 Hz, 1H), 6.72 (d, J=2.6 Hz, 1H), 5.03 (s, 2H), 2.90-2.80 (m, 2H), 2.61 (t, J=9.1 Hz, 1H), 2.40-2.17 (m, 4H), 2.15 (s, 3H), 1.96-1.27 (m, 9H), 0.65 (s, 3H).

    Step 5: Preparation of 1-((8S,9S,13S,14S,17S)-3-hydroxy-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-17-yl)ethan-1-one

    [0633] ##STR00246##

    [0634] 1-((8S,9S,13S,14S,17S)-3-(Benzyloxy)-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-17-yl)ethan-1-one (200 mg, 0.52 mmol) was dissolved in methanol/tetrahydrofuran (5 mL/5 mL). Palladium hydroxide on activated carbon (30 mg, 20%) was added, and the reaction solution was reacted under a hydrogen atmosphere at 45° C. for 12 hours to obtain the final product 1-((8S,9S,13S,14S,17S)-3-hydroxy-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-17-yl)ethan-1-one (50 mg, yield: 32%).

    [0635] MS m/z (ESI):298.1 [M]+.

    [0636] 1H NMR (400 MHz, CDCl.sub.3) δ 7.15 (d, J=8.4 Hz, 1H), 6.63 (dd, J=8.4, 2.6 Hz, 1H), 6.56 (d, J=2.6 Hz, 1H), 4.62 (s, 1H), 2.92-2.74 (m, 2H), 2.62 (t, J=9.1 Hz, 1H), 2.40-2.17 (m, 4H), 2.16 (s, 3H), 1.95-1.30 (m, 9H), 0.65 (s, 3H).

    Example 158

    1-((8S,9S,13S,14S,17S)-3-Hydroxy-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-17-yl)-2-(1H-1,2,3-triazol-1-yl)ethan-1-one (158)

    [0637] ##STR00247##

    Step 1: Preparation of 1-((8S,9S,13S,14S,17S)-3-(benzyloxy)-2-bromo-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-17-yl)-2-bromoethan-1-one

    [0638] ##STR00248##

    [0639] 1-((8S,9S,13S,14S,17S)-3-(Benzyloxy)-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-17-yl)ethan-1-one (300 mg, 0.78 mmol) was dissolved in methanol (15 mL). Five drops of hydrogen bromide solution was added, followed by the dropwise addition of liquid bromine (255 mg, 1.6 mmol). After stirring at room temperature for 2 hours, the reaction solution was poured into ice water, and extracted with ethyl acetate. The organic phase was washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated by rotary evaporation to dryness to obtain 300 mg of the product 1-((8S,9S,13S,14S,17S)-3-(benzyloxy)-2-bromo-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-17-yl)-2-bromoethan-1-one, which was used directly in the next step.

    Step 2: Preparation of 1-((8S,9S,13S,14S,17S)-3-(benzyloxy)-2-bromo-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-17-yl)-2-(1H-1,2,3-triazol-1-yl)ethan-1-one

    [0640] ##STR00249##

    [0641] 1-((8S,9S,13S,14S,17S)-3-(Benzyloxy)-2-bromo-13-methyl-7,8,9,11,12,13,14,15, 16,17-decahydro-6H-cyclopenta[a]phenanthren-17-yl)-2-bromoethan-1-one (300 mg, 0.55 mmol) was dissolved in tetrahydrofuran (10 mL). Cesium carbonate (536 mg, 1.65 mmol) and 1,2,3-triazole (190 mg, 2.7 mmol) were added, and the reaction solution was reacted at 35° C. for 5 hours. The reaction solution was filtrated and concentrated. The resulting residue was purified by column chromatography with petroleum ether/ethyl acetate (1/1) to obtain 1-((8S,9S,13S,14S,17S)-3-(benzyloxy)-2-bromo-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-17-yl)-2-(1H-1,2,3-triazol-1-yl)ethan-1-one (70 mg, yellow solid, yield: 20%).

    [0642] MS m/z (ESI): 534.1/536.1 (50/50) [M+H]+.

    Step 3: Preparation of 1-((8S,9S,13S,14S,17S)-3-hydroxy-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-17-yl)-2-(1H-1,2,3-triazol-1-yl)ethan-1-one

    [0643] ##STR00250##

    [0644] 1-((8S,9S,13S,14S,17S)-3-(Benzyloxy)-2-bromo-13-methyl-7,8,9,11,12,13,14,15, 16,17-decahydro-6H-cyclopenta[a]phenanthren-17-yl)-2-(1H-1,2,3-triazol-1-yl)ethan-1-one (70 mg, 0.13 mmol) was dissolved in methanol/tetrahydrofuran (5 mL/5 mL). Palladium hydroxide on activated carbon (30 mg, 20%) was added, and the reaction solution was reacted under a hydrogen atmosphere at 45° C. for 12 hours. The reaction solution was filtrated, and concentrated to obtain 1-((8S,9S,13S,14S,17S)-3-hydroxy-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-17-yl)-2-(1H-1,2,3-triazol-1-yl)ethan-1-one (30 mg, white solid, yield: 62.6%).

    [0645] MS m/z (ESI):366.1 [M+H]+.

    [0646] 1H NMR (400 MHz, CDCl.sub.3) δ 7.78 (s, 1H), 7.67 (s, 1H), 7.15 (d, J=8.0 Hz, 1H), 6.65 (dd, 0.7=6.4, 2.4 Hz, 1H), 6.60-6.56 (m, 1H), 5.40-5.15 (m, 2H), 5.04 (s, 1H), 2.89-2.70 (m, 3H), 2.40-2.21 (m, 3H), 1.96-1.27 (m, 10H), 0.71 (s, 3H).

    Example 159

    ((3R,5R,8R,9R,10S,13S,14S,17S)-3-Hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)dimethylphosphine oxide (159)

    [0647] ##STR00251##

    Step 1: Preparation of (3R,5R,8R,9R,10S,13S,14S)-3-((tert-butyldimethylsilyl)oxy)-3,13-dimethylhexadecahydro-17H-cyclopenta[a]phenanthren-17-one

    [0648] ##STR00252##

    [0649] (3R,5R,8R,9R,10S,13S,14S)-3-Hydroxy-3,13-dimethylhexadecahydro-17H-cyclopenta[a]phenanthren-17-one (5 g, 17 mmol) (Shanghai Yinling Pharmaceutical Technology Co., Ltd.), 2,6-lutidine (4.5 g, 42.5 mmol) and anhydrous dichloromethane (80 mL) were successively added to a 100 mL round bottom flask. The reaction system was cooled to 0° C. in an ice water bath, and tert-butyldimethylsilyl trifluoromethanesulfonate (9 g, 34 mmol) was added dropwise. The reaction system was warmed up to room temperature and stirred overnight. TLC showed that the reaction was completed. The reaction solution was diluted with dichloromethane. The organic phase was washed with water and saturated saline, dried over anhydrous sodium sulfate, filtrated and concentrated by rotary evaporation to dryness. The resulting crude product was purified by column chromatography (petroleum ether:ethyl acetate=20:1) to obtain (3R,5R,8R,9R,10S,13S,14S)-3-((tert-butyldimethylsilyl)oxy)-3,13-dimethylhexadecahydro-17H-cyclopenta[a]phenanthren-17-one (6.2 g, yield: 90.1%).

    [0650] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 2.37 (dd, J=18.8, 8.0 Hz, 1H), 2.06-1.97 (m, 1H), 1.90-1.84 (m, 1H), 1.75-1.68 (m, 5H), 1.59-1.55 (m, 1H), 1.47-0.89 (m, 17H), 0.80 (s, 3H), 0.79 (s, 9H), 0.00 (m, 6H).

    Step 2: Preparation of (3R,5R,8R,9R,10S,13S,14S)-3-((tert-butyldimethylsilyl)oxy)-3,13-dimethyl-2,3,4,5,6,7, 8,9,10,11,12,13,14,15-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl trifluoromethanesulfonate

    [0651] ##STR00253##

    [0652] (3R,5R,8R,9R,10S,13S,14S)-3-(tert-butyldimethylsilyl)oxy)-3,13-dimethylhexadecahydro-17H-cyclopenta[a]phenanthren-17-one (1.2 g, 3 mmol) and 50 ml of anhydrous tetrahydrofuran were successively added to a 100 mL round bottom flask. The reaction system was cooled to −78° C., and a solution of potassium hexamethyldisilazide in tetrahydrofuran (3 mL, 3 mmol) was added dropwise to the reaction system. The reaction solution was stirred at −78° C. for 1 hour, and then N-phenylbis(trifluoromethanesulfonimide) (1.29 g, 3.6 mmol) dissolved in 5 ml of anhydrous tetrahydrofuran was added dropwise to the reaction system. After completion of the addition, the reaction solution was warmed naturally up to room temperature and stirred overnight. After completion of the reaction, saturated ammonium chloride solution was added to quench the reaction, and the reaction solution was extracted with ethyl acetate. The organic phase was washed with water and saturated saline, dried over anhydrous sodium sulfate, filtrated and concentrated by rotary evaporation to dryness. The resulting crude product was purified by column chromatography (eluent: petroleum ether) to obtain (3R,5R,8R,9R,10S,13S,14S)-3-((tert-butyldimethylsilyl)oxy)-3,13-dimethyl-2,3,4,5,6,7,8,9,10,11,12,13,14,15-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl trifluoromethanesulfonate (1.4 g, yield: 87%).

    [0653] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 5.56 (s, 1H), 2.27-2.18 (m, 1H), 2.00-1.93 (m, 1H), 1.80-1.61 (m, 7H), 1.49-1.23 (m, 15H), 0.97 (s, 3H), 0.86 (s, 9H), 0.08 (s, 6H).

    Step 3: Preparation of ((3R,5R,8R,9R,10S,13S,14S)-3-((tert-butyldimethylsilyl)oxy)-3,13-dimethyl-2,3,4,5,6,7,8,9,10,11,12,13,14,15-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl)dimethylphosphine oxide

    [0654] ##STR00254##

    [0655] (3R,5R,8R,9R,10S,13S,14S)-3-((tert-butyldimethylsilyl)oxy)-3,13-dimethyl-2,3,4,5,6,7,8,9,10,11,12,13,14,15-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl trifluoromethanesulfonate (840 mg, 1.57 mmol), dimethylphosphine oxide (146 mg, 1.89 mmol), palladium diacetate (35 mg, 0.16 mmol), 1,4-bis(diphenylphosphino)butane (69 mg, 0.16 mmol), N,N-diisopropylethylamine (1.6 g, 12.6 mmol) and 10 ml of anhydrous dimethyl sulfoxide were successively added to a 100 mL round bottom flask. The reaction system was purged with nitrogen, slowly warmed up to 120° C. and stirred overnight. After completion of the reaction, the reaction system was cooled to room temperature. Water was added to quench the reaction, and the reaction solution was extracted with ethyl acetate. The organic phase was washed with water and saturated saline, dried over anhydrous sodium sulfate, filtrated and concentrated by rotary evaporation to dryness. The resulting crude product was purified by column chromatography (eluent: dichloromethane/methanol=10/1) to obtain ((3R,5R,8R,9R,10S,13S,14S)-3-((tert-butyldimethylsilyl)oxy)-3,13-dimethyl-2,3,4,5,6,7,8,9,10,11,12,13,14,15-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl)dimethylphosphine oxide (642 mg, yield: 88%).

    [0656] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 6.54 (dd, 0.7=10.8, 1.6 Hz, 1H), 2.33-2.27 (m, 1H), 2.11-2.01 (m, 2H), 1.66-1.58 (m, 12H), 1.48-1.1.13 (m, 15H), 1.00 (s, 3H), 0.86 (s, 9H), 0.07 (s, 6H).

    Step 4: Preparation of ((3R,5R,8R,9R,10S,13S,14S)-3-hydroxy-3,13-dimethyl-2,3,4,5,6,7,8,9,10,11,12,13,14,15-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl)dimethylphosphine oxide

    [0657] ##STR00255##

    [0658] ((3R,5R,8R,9R,10S,13S,14S)-3-((tert-butyldimethylsilyl)oxy)-3,13-dimethyl-2,3,4,5,6,7,8,9,10,11,12,13,14,15-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl)dimeth ylphosphine oxide (642 mg, 1.38 mmol) was dissolved in 5 mL of anhydrous tetrahydrofuran in a 100 mL round bottom flask, and a 1.0 M solution of tetrabutylammonium fluoride in tetrahydrofuran (5 mL) was added to the reaction system. The reaction solution was stirred at 60° C. overnight. After completion of the reaction, the reaction system was cooled to room temperature. Water was added to quench the reaction, and the reaction solution was extracted with ethyl acetate. The organic phase was washed with water and saturated saline, dried over anhydrous sodium sulfate, filtrated and concentrated by rotary evaporation to dryness. The resulting crude product was purified by column chromatography (eluent:dichloromethane/methanol=10/1) to obtain ((3R,5R,8R,9R,10S,13S,14S)-3-hydroxy-3,13-dimethyl-2,3,4,5,6,7,8,9,10,11,12,13,14,15-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl)dimethylphosphine oxide (170 mg, yield: 35%).

    [0659] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 6.57-6.54 (m, 1H), 2.45 (br, 1H), 2.35-2.28 (m, 1H), 2.12-2.00 (m, 2H), 1.87-1.70 (m, 4H), 1.67-1.14 (m, 23H), 1.00 (s, 3H).

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

    [0660] ##STR00256##

    [0661] ((3R,5R,8R,9R,10S,13S,14S)-3-Hydroxy-3,13-dimethyl-2,3,4,5,6,7,8,9,10,11,12,13,14,15-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl)dimethylphosphine oxide (100 mg, 0.29 mmol), palladium on carbon (100 mg, 10%) and 10 mL of ethyl acetate were added to a 100 mL round bottom flask. The reaction system was purged with hydrogen three times, and reacted at 1 atmosphere overnight. After completion of the reaction, the reaction solution was filtrated through celite to remove excess palladium on carbon, and the filtrate was concentrated by rotary evaporation to dryness. The resulting crude product was purified by high performance liquid chromatography to obtain ((3R,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)dimethylphosphine oxide (39.5 mg, yield: 39%).

    [0662] MS m/z (ESI): 353.3 [M+H].sup.+.

    [0663] .sup.1H NMR (400 MHz, CDCl.sub.3)<5 2.13-1.62 (m, 22H), 1.35-1.27 (m, 8H), 1.16-1.06 (m, 4H), 0.99 (s, 3H).

    Example 160

    ((3R,5R,8R,9R,10S,13S,14S,17S)-3-Hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)diphenylphosphine oxide (160)

    [0664] ##STR00257##

    Step 1: Preparation of ((3R,5R,8R,9R,10S,13S,14S)-3-((tert-butyldimethylsilyl)oxy)-3,13-dimethyl-2,3,4,5,6,7,8,9,10,11,12,13,14,15-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl)diphenylphosphine oxide

    [0665] ##STR00258##

    [0666] (3R,5R,8R,9R,10S,13S,14S)-3-((tert-butyldimethylsilyl)oxy)-3,13-dimethyl-2,3,4, 5,6,7,8,9,10,11,12,13,14,15-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl trifluoromethanesulfonate (350 mg, 0.65 mmol), diphenylphosphine oxide (158 mg, 0.78 mmol), palladium diacetate (35 mg, 0.16 mmol), 1,4-bis(diphenylphosphino)butane (69 mg, 0.16 mmol), N,N-diisopropylethylamine (660 mg, 5.2 mmol) and 10 ml of anhydrous dimethyl sulfoxide were successively added to a 100 mL round bottom flask. The reaction system was purged with nitrogen, slowly warmed up to 120° C. and stirred overnight. After completion of the reaction, the reaction system was cooled to room temperature. Water was added to quench the reaction, and the reaction solution was extracted with ethyl acetate. The organic phase was washed with water and saturated saline, dried over anhydrous sodium sulfate, filtrated and concentrated by rotary evaporation to dryness. The resulting crude product was purified by column chromatography (eluent: dichloromethane/methanol=10/1) to obtain ((3R,5R,8R,9R,10S,13S,14S)-3-((tert-butyldimethylsilyl)oxy)-3,13-dimethyl-2,3,4,5,6,7,8,9,10,11,12,13,14,15-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl)diphenylphosphine oxide (290 mg, 76%).

    [0667] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.85-7.80 (m, 2H), 7.67-7.62 (m, 2H), 7.59-7.40 (m, 6H), 6.01-5.98 (m, 1H), 2.31-2.25 (m, 1H), 2.09-2.02 (m, 2H), 1.89-1.10 (m, 21H), 1.07 (s, 3H), 0.86 (s, 9H), 0.07 (s, 6H).

    Step 2: Preparation of ((3R,5R,8R,9R,10S,13S,14S)-3-hydroxy-3,13-dimethyl-2,3,4,5,6,7,8,9,10,11,12,13,14,15-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl)diphenylphosphine oxide

    [0668] ##STR00259##

    [0669] ((3R,5R,8R,9R,10S,13S,14S)-3-((tert-butyldimethylsilyl)oxy)-3,13-dimethyl-2,3,4,5,6,7,8,9,10,11,12,13,14,15-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl)diphenylphosphine oxide (270 mg, 0.46 mmol) was dissolved in 5 mL of anhydrous tetrahydrofuran in a 100 mL round bottom flask, and a 1.0 M solution of tetrabutylammonium fluoride in tetrahydrofuran (5 mL) was added to the reaction system. The reaction solution was stirred at 60° C. overnight. After completion of the reaction, the reaction system was cooled to room temperature. Water was added to quench the reaction, and the reaction solution was extracted with ethyl acetate. The organic phase was washed with water and saturated saline, dried over anhydrous sodium sulfate, filtrated and concentrated by rotary evaporation to dryness. The resulting crude product was purified by column chromatography (eluent: dichloromethane/methanol=10/1) to obtain ((3R,5R,8R,9R,10S,13S,14S)-3-hydroxy-3,13-dimethyl-2,3,4,5,6,7,8,9,10,11,12,13,14,15-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl)diphenylphosphine oxide (120 mg, yield: 55%).

    [0670] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 6.57-6.54 (m, 1H), 2.45 (br, 1H), 2.35-2.28 (m, 1H), 2.12-2.00 (m, 2H), 1.87-1.70 (m, 4H), 1.67-1.14 (m, 26H), 1.00 (s, 3H).

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

    [0671] ##STR00260##

    [0672] ((3R,5R,8R,9R,10S,13S,14S)-3-Hydroxy-3,13-dimethyl-2,3,4,5,6,7,8,9,10,11,12,13,14,15-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl)diphenylphosphine oxide (120 mg, 0.25 mmol), palladium on carbon (120 mg, 10%) and 10 mL of ethyl acetate were added to a 100 mL round bottom flask. The reaction system was purged with hydrogen three times, and reacted at 1 atmosphere overnight. After completion of the reaction, the reaction solution was filtrated through celite to remove excess palladium on carbon, and the filtrate was concentrated by rotary evaporation to dryness. The resulting crude product was purified by high performance liquid chromatography to obtain ((3R,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)diphenylphosphine oxide (40 mg, yield: 33%).

    [0673] MS m/z (ESI): 477.3 [M+H].sup.+.

    [0674] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.91-7.83 (m, 4H), 7.54-7.44 (m, 6H), 2.37-2.15 (m, 2H), 2.11-2.09 (m, 1H), 2.07-1.95 (m, 6H), 1.84-1.04 (m, 22H).

    [0675] .sup.31P NMR (162 MHz, CDCl.sub.3) δ 30.00.

    Example 161

    1-((3R,6R,8S,10S,13S,14S,17S)-3-Hydroxy-3,13-dimethylhexadecahydro-6,10-(epoxy methano)cyclopenta[a]phenanthren-17-yl)ethan-1-one (161)

    [0676] ##STR00261##

    Step 1: Preparation of (8R,10R,13S,14S)-10,13-dimethyl-17-oxo-2,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-yl acetate

    [0677] ##STR00262##

    [0678] (8R,10R,13S,14S)-10,13-Dimethyl-1,6,7,8,9,10,11,12,13,14,15,16-dodecahydro-3H-cyclopenta[a]phenanthrene-3,17(2H)-dione (19.0 g, 66.43 mmol) was dissolved in ethyl acetate (500 mL), and acetic anhydride (100 mL) and perchloric acid (0.5 mL) were added. The reaction solution was stirred at room temperature for 1 hour, and TLC showed that the reaction was completed. Saturated sodium carbonate solution (300 mL) was added to the reaction solution. The organic phase was washed with saturated sodium carbonate solution (300 mL*2) and saturated saline (300 mL), dried over anhydrous sodium sulfate and concentrated. The resulting residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether=0-40%) to obtain (8R,10R,13S,14S)-10,13-dimethyl-17-oxo-2,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-yl acetate (13.0 g, yield: 59.7%).

    [0679] 1H NMR (400 MHz, CDCl3) δ: 5.71 (s, 1H), 5.42 (t, J=2.4 Hz, 1H), 2.51-2.43 (m, 2H), 2.34-2.27 (m, 1H), 2.18-2.04 (m, 5H), 2.00-1.69 (m, 6H), 1.62-1.27 (m, 5H), 1.13-1.06 (m, 1H), 1.03 (s, 3H), 0.92 (s, 3H).

    Step 2: Preparation of (8R,10R,13S,14S)-6-hydroxy-10,13-dimethyl-1,6,7,8,9,10,11,12,13,14,15,16-dodecahydro-3H-cyclopenta[a]phenanthrene-3,17(2H)-dione

    [0680] ##STR00263##

    [0681] (8R,10R,13S,14S)-10,13-Dimethyl-17-oxo-2,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-yl acetate (5.0 g, 15.24 mmol) was dissolved in ethanol (180 mL), and m-chloroperoxybenzoic acid (5.0 g, 24.71 mmol) was added. The reaction solution was stirred at room temperature for 3 hours, and LC/MS showed that the reaction was completed. Saturated sodium carbonate solution (200 mL) was added, and then the reaction solution was extracted with ethyl acetate (300 mL). The organic phase was washed with saturated sodium carbonate solution (200 mL*2) and saturated saline (200 mL), dried over anhydrous sodium sulfate and concentrated to obtain (8R,10R,13S,14S)-6-hydroxy-10,13-dimethyl-1,6,7,8,9,10,11,12,13,14,15,16-dodecahydro-3H-cyclopenta[a]phenanthrene-3,17(2H)-dione (3.5 g, yield: 76.0%).

    [0682] MS m/z (ESI): 303.0 [M+H].sup.+.

    Step 3: Preparation of (8R,10R,13S,14S)-6-hydroxy-10,13-dimethyltetradecahydro-3H-cyclopenta[a]phenanthrene-3,17(2H)-dione

    [0683] ##STR00264##

    [0684] (8R,10R,13S,14S)-6-Hydroxy-10,13-dimethyl-1,6,7,8,9,10,11,12,13,14,15,16-dodecahydro-3H-cyclopenta[a]phenanthrene-3,17(2H)-dione (8.0 g, 26.5 mmol) was dissolved in pyridine (50 mL), and 10% Pd Lindlar's catalyst (2.0 g) was added to the above solution. The reaction system was equipped with a hydrogen balloon and purged with hydrogen three times, and stirred at room temperature for 16 hours. The reaction solution was filtrated, and the filter cake was washed with ethyl acetate (30 mL). The filtrate was diluted with ethyl acetate (200 mL), and washed with 1N hydrochloric acid (100 mL*2). The organic phase was washed with saturated saline (100 mL), dried over anhydrous sodium sulfate and concentrated. The resulting residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether=1:1) to obtain (8R,10R,13S,14S)-6-hydroxy-10,13-dimethyltetradecahydro-3H-cyclopenta[a]phenanthrene-3,17(2H)-dione (2.0 g, yield: 25.0%).

    [0685] 1H NMR (400 MHz, DMSO-r/6) δ: 4.60 (s, 1H), 3.51 (m, 1H), 2.45-2.31 (m, 3H), 2.06-1.82 (m, 7H), 1.69-1.51 (m, 5H), 1.48-1.23 (m, 5H), 1.14 (s, 3H), 0.82 (s, 3H).

    Step 4: Preparation of (6R,8R,10S,13S,14S)-13-methyltetradecahydro-6,10-(epoxymethano)cyclopenta[a]phenanthrene-3,17-dione

    [0686] ##STR00265##

    [0687] (8R,10R,13S,14S)-6-Hydroxy-10,13-dimethyltetradecahydro-3H-cyclopenta[a]phenanthrene-3,17(2H)-dione (1.0 g, 3.29 mmol) was dissolved in benzene (50 mL)/pyridine (0.8 mL), and lead tetraacetate (7.3 g, 16.5 mmol) was added to the above solution. The reaction solution was stirred under an incandescent lamp (500W) for 2 hours, and the reaction was then stopped. Ethyl acetate (100 mL) was added to the reaction solution to precipitate a large amount of solid, and the reaction solution was then filtrated. The filtrate was washed with 1N hydrochloric acid (50 mL*2). The organic phase was washed with saturated saline (50 mL), dried over anhydrous sodium sulfate and concentrated. The resulting residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether=1:2) to obtain (6R,8R,10S,13S,14S)-13-methyltetradecahydro-6,10-(epoxymethano)cyclopenta[a]phenanthrene-3,17-dione (600 mg, yield: 60.0%).

    [0688] 1H NMR (400 MHz, CDCl.sub.3) δ: 4.25-4.22 (m, 1H), 4.06 (d, J=8.4 Hz, 1H,), 3.39 (d, J=8.4 Hz, 1H), 2.63-2.44 (m, 3H), 2.35-2.06 (m, 5H), 1.98-1.80 (m, 4H), 1.72-1.24 (m, 8H), 0.96 (s, 3H).

    Step 5: Preparation of (3R,6R,8R,10S,13S,14S)-3-hydroxy-3,13-dimethyltetradecahydro-6,10-(epoxymethano)cyclopenta[a]phenanthren-17(1H)-one

    [0689] ##STR00266##

    [0690] 2,6-Di-tert-butyl-p-methylphenol (3.5 g, 15.9 mmol) and toluene (35 mL) were added to a three-neck flask. 2M trimethylaluminum (4 mL, 8 mmol) was added dropwise at 0-10° C. under a nitrogen atmosphere. After completion of the addition, the reaction solution was stirred at room temperature for 1 hour. The reaction solution was cooled to −78° C. in a dry ice/acetone bath, and (6R,8R,10S,13S,14S)-13-methyltetradecahydro-6,10-(epoxymethano)cyclopenta[a]phenanthrene-3,17-dione (0.8 g, 2.65 mmol) dissolved in toluene (30 mL) was added dropwise, and then the reaction solution was reacted at −78° C. for 1 hour. 3M methylmagnesium bromide (2.3 mL, 6.9 mmol) was added, and then the reaction solution was reacted at −78° C. for 1 hour. Saturated ammonium chloride solution (50 mL) was added, and then the reaction solution was extracted with ethyl acetate (120 mL). The organic phase was washed with saturated saline (50 mL), dried over anhydrous sodium sulfate and concentrated. The resulting residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether=1:1) to obtain (3R,6R,8R,10S,13S,14S)-3-hydroxy-3,13-dimethyltetradecahydro-6,10-(epoxymethano)cyclopenta[a]phenanthren-17(1H)-one (400 mg, yield: 47.5%).

    [0691] 1H NMR (400 MHz, CDCl.sub.3) δ: 4.15-4.12 (m, 1H), 3.96 (d, J=8.0 Hz, 1H), 3.32 (d, J=8.0 Hz, 1H), 2.48-2.41 (m, 1H), 2.13-2.03 (m, 1H), 1.92-1.79 (m, 5H), 1.75-1.63 (m, 3H), 1.60-1.43 (m, 6H), 1.38-1.10 (m, 7H), 0.92 (s, 3H).

    Step 6: Preparation of (3R,6R,8S,10S,13S,14S)-17-ethylidene-3,13-dimethylhexadecahydro-6,10-(epoxymethano)cyclopenta[a]phenanthren-3-ol

    [0692] ##STR00267##

    [0693] Ethyltriphenylphosphonium bromide (11.65 g, 31.4 mmol) was dissolved in dimethyl sulfoxide (25 mL). 60% sodium hydrogen (1.26 g, 31.4 mmol) was added, and then the reaction solution was stirred at room temperature under a nitrogen atmosphere for 1 hour. (3R,6R,8R,10S,13S,14S)-3-Hydroxy-3,13-dimethyltetradecahydro-6,10-(epoxymethano)cyclopenta[a]phenanthren-17(1H)-one (0.5 g, 1.57 mmol) dissolved in dimethyl sulfoxide (5 mL) was added, and then the reaction solution was heated to 60° C. and reacted for 16 hours. Saturated ammonium chloride solution (50 mL) was added, and then the reaction solution was extracted with ethyl acetate (60 mL). The organic phase was washed with saturated sodium carbonate solution (50 mL*2) and saturated saline (50 mL) successively, dried over anhydrous sodium sulfate and concentrated. The resulting residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether=1:3) to obtain (3R,6R,8S,10S,13S,14S)-17-ethylidene-3,13-dimethylhexadecahydro-6,10-(epoxymethano)cyclopenta[a]phenanthren-3-ol (350 mg, yield 67.6%).

    [0694] 1H NMR (400 MHz, CDCl.sub.3) δ: 5.12-5.09 (m, 1H), 4.15-4.12 (m, 1H), 3.96 (d, J=8.0 Hz, 1H), 3.26 (d, J=8.0 Hz, 1H), 2.39-2.13 (m, 3H), 1.91-1.85 (m, 3H), 1.70-1.50 (m, 12H), 1.30-1.07 (m, 8H), 0.91 (s, 3H).

    Step 7: Preparation of (3R,6R,8S,10S,13S,14S,17S)-17-((S)-1-hydroxyethyl)-3,13-dimethylhexadecahydro-6,10-(epoxymethano)cyclopenta[a]phenanthren-3-ol

    [0695] ##STR00268##

    [0696] (3R,6R,8S,10S,13S,14S)-17-Ethylidene-3,13-dimethylhexadecahydro-6,10-(epoxy methano)cyclopenta[a]phenanthren-3-ol (250 mg, 0.76 mmol) was dissolved in tetrahydrofuran (8 mL), and the solution was cooled to 0° C. A solution of borane in tetrahydrofuran (1 M, 15 mL, 15 mmol) was added, and the reaction solution was stirred at room temperature for 3 hours. The reaction solution was cooled to 0° C., and sodium hydroxide (3M, 10 mL) was added dropwise. After completion of the dropwise addition, hydrogen peroxide (30%, 8 mL) was added, and the reaction solution was stirred at room temperature for 1 hour. The reaction solution was diluted with ethyl acetate (60 mL), and washed with saturated sodium thiosulfate solution (30 mL). The organic phase was washed with saturated saline (50 mL), dried over anhydrous sodium sulfate, and concentrated to obtain (3R,6R,8S,10S,13S,14S,17S)-17-((S)-1-hydroxyethyl)-3,13-dimethylhexadecahydro-6,10-(epoxymethano)cyclopenta[a]phenanthren-3-ol (260 mg, yield: 100%), which was used directly in the next step without further purification.

    Step 8: Preparation of 1-((3R,6R,8S,10S,13S,14S,17S)-3-hydroxy-3,13-dimethylhexadecahydro-6,10-(epoxy methano)cyclopenta[a]phenanthren-17-yl)ethan-1-one

    [0697] ##STR00269##

    [0698] (3R,6R,8S,10S,13S,14S,17S)-17-((S)-1-hydroxyethyl)-3,13-dimethylhexadecahydro-6,10-(epoxymethano)cyclopenta[a]phenanthren-3-ol (260 mg, 0.75 mmol) was dissolved in dichloromethane (10 mL), and the solution was cooled to 0° C. PCC (322 mg, 1.5 mmol) was added, and then the reaction solution was stirred at room temperature for 3 hours. TLC showed that the reaction was completed. The reaction solution was filtrated, and the filter cake was washed with ethyl acetate (20 mL). The filtrate was diluted with ethyl acetate (30 mL), and washed with saturated sodium thiosulfate solution (30 mL). The organic phase was washed with saturated saline (50 mL), dried over anhydrous sodium sulfate and concentrated. The resulting residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether=1:2) to obtain 1-((3R,6R,8S,10S,13S,14S,17S)-3-hydroxy-3,13-dimethylhexadecahydro-6,10-(epoxy methano)cyclopenta[a]phenanthren-17-yl)ethan-1-one (150 mg, yield: 57.8%).

    [0699] 1H NMR (400 MHz, CDCl.sub.3) δ: 4.14-4.12 (m, 1H), 3.94 (d, J=7.6 Hz, 1H), 3.27 (d, J=7.6 Hz, 1H), 2.53 (t, J=8.8 Hz, 1H), 2.18-2.04 (m, 5H), 1.91-1.86 (m, 3H), 1.70-1.49 (m, 10H), 1.34-1.49 (m, 8H), 0.66 (s, 3H).

    Example 162

    1-(2-((3R,6R,8S,10S,13S,14S,17S)-3-Hydroxy-3,13-dimethylhexadecahydro-6,10-(epoxymethano)cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile (162)

    [0700] ##STR00270##

    Step 1: Preparation of 2-bromo-1-((3R,6R,8S,10S,13S,14S,17S)-3-hydroxy-3,13-dimethylhexadecahydro-6,10-(epoxy methano)cyclopenta[a]phenanthren-17-yl)ethan-1-one

    [0701] ##STR00271##

    [0702] 1-((3R,6R,8S,10S,13S,14S,17S)-3-Hydroxy-3,13-dimethylhexadecahydro-6,10-(epoxymethano)cyclopenta[a]phenanthren-17-yl)ethan-1-one (135 mg, 0.39 mmol) was dissolved in methanol (6 mL). A drop of hydrogen bromide was added, followed by the addition of 5 drops of liquid bromine under stirring at room temperature, and then the reaction solution was stirred at room temperature for 1 hour. TLC showed that the reaction was completed. Saturated sodium bicarbonate solution (30 mL) was added, and then the reaction solution was extracted with ethyl acetate (50 mL). The organic phase was washed with saturated saline (50 mL), dried over anhydrous sodium sulfate, and concentrated to obtain 2-bromo-1-((3R,6R,8S,10S,13S,14S,17S)-3-hydroxy-3,13-dimethylhexadecahydro-6,10-(epoxymethano)cyclopenta[a]phenanthren-17-yl)ethan-1-one (160 mg, yield: 96.5%), which was used directly in the next step without further purification. Step 2: Preparation of 1-(2-((3R,6R,8S,10S,13S,14S,17S)-3-hydroxy-3,13-dimethylhexadecahydro-6,10-(epoxymethano)cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile

    ##STR00272##

    [0703] 2-Bromo-1-((3R,6R,8S,10S,13S,14S,17S)-3-hydroxy-3,13-dimethylhexadecahydro-6,10-(epoxymethano)cyclopenta[a]phenanthren-17-yl)ethan-1-one (85 mg, 0.2 mmol) and 4-cyanopyrazole (92 mg, 1.0 mmol) were dissolved in tetrahydrofuran (5 mL), and potassium carbonate (138 mg, 1.0 mmol) was added. The reaction solution was stirred at room temperature for 16 hours, and TLC and LCMS showed that the reaction was completed. The reaction solution was filtrated and concentrated. The resulting residue was purified by flash preparative chromatography to obtain 1-(2-((3R,6R,8S,10S,13S,14S,17 S)-3-hydroxy-3,13-dimethylhexadecahydro-6,10-(epoxymethano)cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile (29.7 mg, yield: 34.0%).

    [0704] MS m/z (ESI): 438.3 [M+H]+.

    [0705] 1H NMR (400 MHz, CDCl3) δ: 7.87 (s, 1H), 7.81 (s, 1H), 5.01-4.87 (m, 2H), 4.15-4.12 (m, 1H), 3.93 (d, J=8.4 Hz, 1H), 3.28 (d, J=8.4 Hz, 1H), 2.60 (t, 0.7=6.8 Hz, 1H), 2.22-2.08 (m, 2H), 1.91-1.49 (m, 13H), 1.39-1.24 (m, 6H), 1.19-1.13 (m, 2H), 0.72 (s, 3H).

    Example 163

    1-(2-((3R,6R,8S,10S,13S,14S,17S)-3-Hydroxy-3,13-dimethylhexadecahydro-6,10-(epoxymethano)cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-1H-pyrazole-3-carbonitrile (163)

    [0706] ##STR00273##

    Preparation of 1-(2-((3R,6R,8S,10S,13S,14S,17S)-3-Hydroxy-3,13-dimethylhexadecahydro-6,10-(epoxymethano)cyclopenta)[a]phenanthren-17-yl)-2-oxoethyl)-1H-pyrazole-3-carbonitrile

    [0707] ##STR00274##

    [0708] 2-Bromo-1-((3R,6R,8S,10S,13S,14S,17S)-3-hydroxy-3,13-dimethylhexadecahydro-6,10-(epoxymethano)cyclopenta[a]phenanthren-17-yl)ethan-1-one (80 mg, 0.19 mmol) and 3-cyanopyrazole (88 mg, 0.95 mmol) were dissolved in tetrahydrofuran (5 mL), and potassium carbonate (130 mg, 0.95 mmol) was added. The reaction solution was stirred at room temperature for 16 hours, and TLC and LCMS showed that the reaction was completed. The reaction solution was filtrated and concentrated. The resulting residue was purified by flash preparative chromatography to obtain 1-(2-((3R,6R,8S,10S,13S,14S,17S)-3-Hydroxy-3,13-dimethylhexadecahydro-6,10-(epoxymethano)cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-1H-pyrazole-3-carbonitrile (36.5 mg, yield: 44.4%).

    [0709] MS m/z (ESI): 438.3 [M+H]+.

    [0710] 1H NMR (400 MHz, CDCl.sub.3) δ: 7.49 (d, J=2.0 Hz, 1H), 7.76 (d, J=2.0 Hz, 1H), 5.10-4.90 (m, 2H), 4.15-4.12 (m, 1H), 3.94 (d, J=8.0 Hz, 1H), 3.28 (d, J=8.0 Hz, 1H), 2.60 (t, 0.7=8.8 Hz, 1H), 2.21-2.09 (m, 2H), 1.91-1.50 (m, 13H), 1.39-1.24 (m, 6H), 1.19-1.13 (m, 2H), 0.72 (s, 3H).

    Example 164

    1-((3R,6R,8S,10S,13S,14S,17S)-3-Hydroxy-3,13-dimethylhexadecahydro-6,10-(epoxy methano)cyclopenta[a]phenanthren-17-yl)-2-(4-(trifluoromethyl)-1H-pyrazol-1-yl)ethan-1-one (164)

    [0711] ##STR00275##

    Preparation of 1-((3R,6R,8S,10S,13S,14S,17S)-3-hydroxy-3,13-dimethylhexadecahydro-6,10-(epoxy methano)cyclopenta[a]phenanthren-17-yl)-2-(4-(trifluoromethyl)-1H-pyrazol-1-yl)ethan

    [0712] ##STR00276##

    [0713] 2-Bromo-1-((3R,6R,8S,10S,13S,14S,17S)-3-hydroxy-3,13-dimethylhexadecahydro-6,10-(epoxymethano)cyclopenta[a]phenanthren-17-yl)ethan-1-one (80 mg, 0.19 mmol) and 4-trifluoromethylpyrazole (128 mg, 0.95 mmol) were dissolved in tetrahydrofuran (5 mL), and potassium carbonate (130 mg, 0.95 mmol) was added. The reaction solution was stirred at room temperature for 16 hours, and TLC and LCMS showed that the reaction was completed. The reaction solution was filtrated and concentrated. The resulting residue was purified by flash preparative chromatography to obtain 1-((3R,6R,8S,10S,13S,14S,17S)-3-hydroxy-3,13-dimethylhexadecahydro-6,10-(epoxy methano)cyclopenta[a]phenanthren-17-yl)-2-(4-(trifluoromethyl)-1H-pyrazol-1-yl)ethan-1-one (29.5 mg, yield: 32.7%).

    [0714] MS m/z (ESI): 481.2 [M+H]+.

    [0715] 1H NMR (400 MHz, CDCl.sub.3) δ: 7.72 (s, 2H), 5.01-4.87 (m, 2H), 4.15-4.12 (m, 1H), 3.94 (d, 0.7=8.0 Hz, 1H), 3.28 (d, 0.7=8.0 Hz, 1H), 2.60 (t, J=8.8 Hz, 1H), 2.22-2.09 (m, 2H), 1.91-1.49 (m, 13H), 1.39-1.24 (m, 6H), 1.19-1.13 (m, 2H), 0.73 (s, 3H).

    Example 165

    1-(2-((1S,4aS,4bR,6aR,8R,10aS,10bR,12aS)-8-Hydroxy-8,12a-dimethyloctadecahydrochrysen-1-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile (165)

    [0716] ##STR00277##

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

    [0717] ##STR00278##

    [0718] (3R,5R,8R,9R,10S,13S,14S)-3-Hydroxy-3,13-dimethylhexadecahydro-17H-cyclopenta[a]phenanthren-17-one (580 mg, 2.0 mmol) was dissolved in acetic anhydride (15 mL). Pyridine (158 mg, 2.0 mmol) was added, and the reaction solution was reacted under a N.sub.2 atmosphere at 80° C. overnight. The reaction solution was concentrated under reduced pressure to remove acetic anhydride. H.sub.2O (20 mL) was added to the resulting residue, and then the mixture was extracted with EA (15 mL×3). The EA phases were combined, washed successively with H.sub.2O (20 mL) and saturated saline (20 mL), dried over anhydrous Na.sub.2SO.sub.4, and concentrated under reduced pressure. The resulting residue was purified by column chromatography to obtain (3R,5R,8R,9R,10S,13S,14S)-3,13-dimethyl-17-oxohexadecahydro-1H-cyclopenta[a]phenanthren-3-yl acetate (560 mg, yield: 84%).

    [0719] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 2.44 (dd, J=19.2, 8.1 Hz, 1H), 2.24-2.06 (m, 1H), 1.97 (s, 3H), 1.96-1.76 (m, 8H), 1.71-1.57 (m, 3H), 1.55 (s, 3H), 1.55-0.99 (m, 10H), 0.87 (s, 3H).

    Step 2: Preparation of ethyl 2-((3R,5R,8R,9R,10S,13S,14S)-3-acetoxy-17-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-diazoacetate

    [0720] ##STR00279##

    [0721] (3R,5R,8R,9R,10S,13S,14S)-3,13-Dimethyl-17-oxohexadecahydro-1H-cyclopenta[a]phenanthren-3-yl acetate (400 mg, 1.2 mmol) and ethyl diazoacetate (206 mg, 1.8 mmol) were dissolved in THF (15 mL). The reaction solution was cooled to −70° C., and LDA (2 mL) was added dropwise. After completion of the dropwise addition, the reaction solution was reacted at the same temperature for 1 hour. A solution of AcOH (400 mg) in ether (20 mL) was added, and the reaction solution was warmed up to room temperature, and H.sub.2O (50 mL) was added. The reaction solution was extracted with ether (25 mL×2). The ether phases were combined, washed successively with H.sub.2O (50 mL), saturated NaHCO.sub.3 solution (30 mL) and saturated saline (30 mL), dried over anhydrous Na.sub.2SO.sub.4, and concentrated under reduced pressure to dryness. The resulting residue was purified by column chromatography to obtain ethyl 2-((3R,5R,8R,9R,10S,13S,14S)-3-acetoxy-17-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-diazoacetate (500 mg, yield: 93%).

    [0722] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 4.70 (bs, 1H), 4.36-4.17 (m, 2H), 2.24-2.11 (m, 1H), 2.00 (s, 3H), 1.96-1.87 (m, 2H), 1.85-1.83 (m, 4H), 1.74-1.58 (m, 4H), 1.55 (s, 3H), 1.52-1.35 (m, 2H), 1.32 (t, J=7.1 Hz, 3H), 1.29-1.17 (m, 4H), 1.17-0.94 (m, 5H), 0.92 (s, 3H), 0.91-0.81 (m, 1H).

    Step 3: Preparation of ethyl (4aS,4bR,6aR,8R,10aS,10bR,12aS)-8-acetoxy-8,12a-dimethyl-1-oxooctadecahydrochrysene-2-carboxylate

    [0723] ##STR00280##

    [0724] Ethyl 2-((3R,5R,8R,9R,10S,13S,14S)-3-acetoxy-17-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-diazoacetate (500 mg, 1.1 mmol) was dissolved in ethylene glycol dimethyl ether (10 mL). Rhodium acetate dimer (5.0 mg) was added, and the reaction solution was reacted under a N.sub.2 atmosphere at room temperature for 0.5 hour. The reaction solution was filtrated to remove the insoluble matter, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to obtain ethyl (4aS,4bR,6aR,8R,10aS,10bR,12aS)-8-acetoxy-8,12a-dimethyl-1-oxooctadecahydrochrysene-2-carboxylate (436 mg, yield: 93%).

    [0725] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 12.35 (s, 0.82H), 4.13 (q, J=7.1 Hz, 2H), 3.63 (dd, J=13.5, 6.0 Hz, 0.15H), 2.27 (dd, J=16.2, 6.1 Hz, 1H), 2.14-1.96 (m, 2H), 1.89 (s, 3H), 1.88-1.65 (m, 7H), 1.58 (dd, J=20.4, 10.4 Hz, 3H), 1.48 (s, 3H), 1.36-1.13 (m, 8H), 1.11-1.04 (m, 2H), 1.03 (s, 3H), 0.99-0.88 (m, 3H).

    Step 4: Preparation of (4aS,4bR,6aR,8R,10aS,10bR,12aS)-8-hydroxy-8,12a-dimethylhexadecahydrochrysen-1 (2H)-one

    [0726] ##STR00281##

    [0727] KOH (4.0 g) was dissolved in methanol (60 mL). Ethyl (4aS,4bR,6aR,8R,10aS,10bR,12aS)-8-acetoxy-8,12a-dimethyl-1-oxooctadecahydrochrysene-2-carboxylate (400 mg) was added, and then the reaction solution was heated to reflux under a N.sub.2 atmosphere for 1 hour. The reaction solution was cooled to room temperature, and poured into ice water (150 mL). After stirring for 20 minutes, the reaction solution was filtrated. The filter cake was washed with a small amount of water and acetone, and dried to obtain (4aS,4bR,6aR,8R,10aS,10bR,12aS)-8-hydroxy-8,12a-dimethylhexadecahydrochrysen-1 (2H)-one (320 mg).

    [0728] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 2.61 (td, 0.7=14.0, 6.8 Hz, 1H), 2.25-2.15 (m, 1H), 2.11-2.00 (m, 1H), 1.87 (dd, J=9.8, 7.7 Hz, 2H), 1.84-1.70 (m, 5H), 1.67-1.57 (m, 3H), 1.56-1.47 (m, 2H), 1.45-1.27 (m, 7H), 1.26 (s, 3H), 1.20-1.10 (m, 1H), 1.08 (s, 3H), 1.07-0.91 (m, 2H).

    Step 5: Preparation of (2R,4aS,4bR,6aS,10aS,10bR,12aR)-7-ethylidene-2,6a-dimethyloctadecahydrochrysen-2-ol

    [0729] ##STR00282##

    [0730] In accordance with Step 4 of Example 1, (4aS,4bR,6aR,8R,10aS,10bR,12aS)-8-hydroxy-8,12a-dimethylhexadecahydrochrysen-1 (2H)-one was used as the starting material, accordingly, (2R,4aS,4bR,6aS,10aS,10bR,12aR)-7-ethylidene-2,6a-dimethyloctadecahydrochrysen-2-ol (288 mg) was obtained.

    Step 6: Preparation of (2R,4aS,4bR,6aS,7S,10aS,10bR,12aR)-7-(1-hydroxyethyl)-2,6a-dimethyloctadecahydrochrysen-2-ol

    [0731] ##STR00283##

    [0732] In accordance with Step 5 of Example 1, (2R,4aS,4bR,6aS,10aS,10bR,12aR)-7-ethylidene-2,6a-dimethyloctadecahydrochrysen-2-ol was used as the starting material, accordingly, (2R,4aS,4bR,6aS,7S,10aS,10bR,12aR)-7-(1-hydroxyethyl)-2,6a-dimethyloctadecahydro chrysen-2-ol (150 mg, containing a small amount of impurities) was obtained, which was used directly in the next step without purification.

    Step 7: Preparation of 1-((1S,4aS,4bR,6aR,8R,10aS,10bR,12aS)-8-hydroxy-8,12a-dimethyloctadecahydrochrysen-1-yl)ethan-1-one

    [0733] ##STR00284##

    [0734] In accordance with Step 6 of Example 1, (2R,4aS,4bR,6aS,7S,10aS,10bR,12aR)-7-(1-hydroxy ethyl)-2,6a-dimethyloctadecahydro chrysen-2-ol was used as the starting material, accordingly, 1-((1S,4aS,4bR,6aR,8R,10aS,10bR,12aS)-8-hydroxy-8,12a-dimethyloctadecahydrochrysen-1-yl)ethan-1-one (80 mg, containing a small amount of impurities) was obtained, which was used directly in the next step without purification.

    Step 8: Preparation of 2-bromo-1-((1S,4aS,4bR,6aR,8R,10aS,10bR,12aS)-8-hydroxy-8,12a-dimethyloctadecahydrochrysen-1-yl)ethan-1-one

    [0735] ##STR00285##

    [0736] In accordance with Step 1 of Example 2, 1-((1S,4aS,4bR,6aR,8R,10aS,10bR,12aS)-8-hydroxy-8,12a-dimethyloctadecahydrochrysen-1-yl)ethan-1-one was used as the starting material, accordingly, 2-bromo-1-((1S,4aS,4bR,6aR,8R,10aS,10bR,12aS)-8-hydroxy-8,12a-dimethyloctadecahydrochrysen-1-yl)ethan-1-one (50 mg, containing a small amount of impurities) was obtained, which was used directly in the next step without purification.

    Step 9: Preparation of 1-(2-((1S,4aS,4bR,6aR,8R,10aS,10bR,12aS)-8-hydroxy-8,12a-dimethyloctadecahydrochrysen-1-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile

    [0737] ##STR00286##

    [0738] In accordance with Example 5, 2-bromo-1-((1S,4aS,4bR,6aR,8R,10aS,10bR,12aS)-8-hydroxy-8,12a-dimethyloctadecahydrochrysen-1-yl)ethan-1-one was used as the starting material, accordingly, 1-(2-((1S,4aS,4bR,6aR,8R,10aS,10bR,12aS)-8-hydroxy-8,12a-dimethyloctadecahydrochrysen-1-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile (5.5 mg) was obtained.

    [0739] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.87 (s, 1H), 7.83 (s, 1H), 5.06-4.88 (m, 2H), 2.47 (d, J=4.9 Hz, 1H), 1.90-1.81 (m, 2H), 1.78-1.67 (m, 5H), 1.58-1.50 (m, 6H), 1.41-1.34 (m, 4H), 1.29-1.24 (m, 9H), 0.99 (s, 3H), 0.96-0.83 (m, 3H).

    Example 166

    1-((2-((3R,5R,8R,9R,10S,13S,14S,17S)-3-Hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethoxy)methyl)cyclopropane-1-carbonitrile (166)

    [0740] ##STR00287##

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

    [0741] ##STR00288##

    [0742] 2-Bromo-1-((3R,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one (80 mg, 0.2 mmol), 1-(hydroxymethyl)cyclopropane-1-carbonitrile (29 mg, 0.3 mmol) and potassium carbonate (138 mg, 1.0 mmol) were dissolved in N,N-dimethylacetamide (3 mL), and the resulting reaction solution was stirred at 70° C. overnight. Water (20 mL) was added to the reaction solution, and the water phase was extracted with ethyl acetate (20 mL×2). The organic phases were combined, dried over anhydrous sodium sulfate, filtrated and concentrated. The resulting crude product was purified by column chromatography (petroleum ether/ethyl acetate: 50/1-3/1) to obtain 1-((2-((3R,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethoxy)methyl)cyclopropane-1-carbonitrile (10 mg, yield: 12%).

    [0743] 1H NMR (400 MHz, CDCl.sub.3) δ 4.21-4.09 (m, 2H), 3.53 (s, 2H), 2.61-2.54 (m, 1H), 2.21-2.12 (m, 1H), 1.90-1.78 (m, 4H), 1.75-1.61 (m, 4H), 1.49-1.40 (m, 5H), 1.34-1.26 (m, 13H), 1.10-1.04 (m, 4H), 0.63 (s, 3H).

    Example 167

    1-((((3R,5R,8R,9R,10S,13S,14S,17S)-3-Hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)thio)methyl)-1H-pyrazole-4-carbonitrile

    [0744] ##STR00289##

    Step 1: Preparation of (3R,5R,8R,9R,10S,13S,14S)-3-((tert-butyldimethylsilyl)oxy)-3,13-dimethylhexadecahydro-17H-cyclopenta[a]phenanthrene-17-thione

    [0745] ##STR00290##

    [0746] (3R,5R,8R,9R,10S,13S,14S)-3-((tert-butyldimethylsilyl)oxy)-3,13-dimethylhexadecahydro-17H-cyclopenta[a]phenanthren-17-thione (1.2 g, 3 mmol), 2,4-bis(p-methoxy phenyl)-1,3-dithiadiphosphetane-2,4-sulfide (971 mg, 2.4 mmol) and 20 mL anhydrous toluene were successively added to a dry 100 mL round bottom flask. The reaction system was purged with argon, heated to reflux and stirred overnight. After completion of the reaction, the reaction solution was filtrated through neutral alumina, and the filtrate was concentrated by rotary evaporation to dryness. The resulting crude product was purified by column chromatography (eluent: petroleum ether/ethyl acetate=50/1) to obtain

    [0747] (3R,5R,8R,9R,10S,13S,14S)-3-((tert-butyldimethylsilyl)oxy)-3,13-dimethylhexadecahydro-17H-cyclopenta[a]phenanthrene-17-thione (860 mg, 68%).

    [0748] .sup.1H NMR (400 MHzm CDCl.sub.3) δ 2.90 (dd, J=8.4, 21.6 Hz, 1H), 2.63-2.55 (m, 1H), 1.97-1.93 (m, 2H), 1.73-1.17 (m, 22H), 0.84 (s, 3H), 0.79 (s, 9H), 0.07 (s, 6H).

    Step 2: Preparation of (3R,5R,8R,9R,10S,13S,14S)-3-((tert-butyldimethylsilyl)oxy)-3,13-dimethylhexadecahydro-17H-cyclopenta[a]phenanthrene-17-thiol

    [0749] ##STR00291##

    [0750] (3R,5R,8R,9R,10S,13S,14S)-3-((tert-butyldimethylsilyl)oxy)-3,13-dimethylhexadecahydro-17H-cyclopenta[a]phenanthrene-17-thione (860 mg, 2 mmol) and 30 ml of anhydrous tetrahydrofuran were added to a dry 100 mL round bottom flask. The reaction system was cooled to 0° C., and 1.0 M tri-tert-butoxy lithium aluminum hydride (6 mL, 6 mmol) was added dropwise. The reaction solution was stirred at 0° C. for 2 hours, and stirred at room temperature for 1 hour. TLC showed that the reaction was completed. Saturated sodium bicarbonate solution was added to carefully quench the reaction, and the reaction solution was extracted with dichloromethane. The organic phases were combined, washed with water and saturated saline, dried over anhydrous sodium sulfate, filtrated, and concentrated by rotary evaporation to dryness to obtain the crude product, which was used directly in the next step without purification.

    [0751] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 2.60-2.58 (m, 1H), 2.10-2.07 (m, 1H), 1.72-0.98 (m, 25H), 0.79 (s, 9H), 0.64 (s, 3H), 0.04 (s, 6H).

    Step 3: Preparation of 1-(hydroxymethyl)-1H-pyrazole-4-carbonitrile

    [0752] ##STR00292##

    [0753] 1H-Pyrazole-4-carbonitrile (930 mg, 10 mmol), 30% aqueous formaldehyde solution (8 g, 100 mmol) and 10 mL of methanol were added to a 100 mL round bottom flask. The reaction system was stirred at room temperature overnight. The reaction solution was concentrated by rotary evaporation to dryness to obtain 1-(hydroxymethyl)-1H-pyrazole-4-carbonitrile (900 mg, 73%).

    [0754] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.05 (s, 1H), 7.87 (s, 1H), 4.96-4.80 (m, 2H).

    Step 4: Preparation of 1-(chloromethyl)-1H-pyrazole-4-carbonitrile

    [0755] ##STR00293##

    [0756] 1-(Hydroxymethyl)-1H-pyrazole-4-carbonitrile (900 mg, 7.3 mmol), triethylamine (1.5 g, 14.6 mmol) and 20 ml of dichloromethane were added to a 100 mL round bottom flask. P-Toluenesulfonyl chloride (2.1 g, 11 mmol) was added in batches under stirring, and the reaction system was stirred at room temperature overnight. Water was added to quench the reaction, and the reaction solution was extracted with dichloromethane. The organic phase was washed with water and saturated saline, dried over anhydrous sodium sulfate, filtrated and concentrated by rotary evaporation to dryness. The resulting crude product was purified by column chromatography (eluent: petroleum ether/ethyl acetate=10/1) to obtain 1-(chloromethyl)-1H-pyrazole-4-carbonitrile (790 mg, 76.7%).

    [0757] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.08 (s, 1H), 7.89 (s, 1H), 5.87 (s, 2H).

    Step 5: Preparation of 1-((((3R,5R,8R,9R,10S,13S,14S,17S)-3-((tert-butyldimethylsilyl)oxy)-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)thio)methyl)-1H-pyrazole-4-carbonitrile

    [0758] ##STR00294##

    [0759] (3R,5R,8R,9R,10S,13S,14S)-3-((tert-butyldimethylsilyl)oxy)-3,13-dimethylhexadecahydro-17H-cyclopenta[a]phenanthrene-17-thiol (210 mg, 0.5 mmol), 1-(chloromethyl)-1H-pyrazole-4-carbonitrile (72 mg, 0.6 mmol), potassium carbonate (136 mg, 1 mmol), sodium iodide (10 mg, catalytic amount) and 5 ml of anhydrous N,N-dimethylformamide were added to a dry 100 mL round bottom flask. The reaction system was heated to 60° C. and stirred overnight. The reaction solution was cooled to room temperature. Water was added to quench the reaction, and the reaction solution was extracted with dichloromethane. The organic phase was washed with water and saturated saline, dried over anhydrous sodium sulfate, filtrated and concentrated by rotary evaporation to dryness. The resulting crude product was purified by column chromatography (petroleum ether/ethyl acetate=10/1) to obtain 1-((((3R,5R,8R,9R,10S,13S,14S,17S)-3-((tert-butyldimethylsilyl)oxy)-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)thio)methyl)-1H-pyrazole-4-carbonitrile (170 mg, yield: 64.5%).

    [0760] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.10 (s, 1H), 7.79 (s, 1H), 5.18 (dd, J=14.4, 19.2 Hz, 2H), 2.62 (t, J=12 Hz, 1H), 2.05-1.98 (m, 2H), 1.90-0.90 (m, 24H), 0.86 (s, 9H), 0.72 (s, 3H), 0.07 (s, 6H).

    Step 6: 1-((((3R,5R,8R,9R,10S,13S,14S,17S)-3-Hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)thio)methyl)-1H-pyrazole-4-carbonitrile

    [0761] ##STR00295##

    [0762] 1-((((3R,5R,8R,9R,10S,13S,14S,17S)-3-((tert-butyldimethylsilyl)oxy)-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)thio)methyl)-1H-pyrazole-4-carbonitrile (170 mg, 0.32 mmol) was dissolved in 5 mL of anhydrous tetrahydrofuran in a 100 mL round bottom flask, and a 1.0 M solution of tetrabutylammonium fluoride in tetrahydrofuran (5 mL) was added to the reaction system. The reaction solution was stirred at 60° C. overnight. After completion of the reaction, the reaction system was cooled to room temperature. Water was added to quench the reaction, and the reaction solution was extracted with ethyl acetate. The organic phase was washed with water and saturated saline, dried over anhydrous sodium sulfate, filtrated and concentrated by rotary evaporation to dryness. The resulting crude product was purified by column chromatography (eluent: petroleum ether/ethyl acetate=l/l) to obtain 1-((((3R,5R,8R,9R,10S,13S,14S,17S)-3-Hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)thio)methyl)-1H-pyrazole-4-carbonitrile (100 mg, 75%).

    [0763] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.09 (s, 1H), 7.79 (s, 1H), 5.28-5.02 (m, 2H), 2.58 (t, J=9.4 Hz, 1H), 2.12-1.93 (m, 1H), 1.89-0.94 (m, 26H), 0.72 (s, 3H).

    Example 168 and Example 169

    1-(((S)-((3R,5R,8R,9R,10S,13S,14S,17S)-3-Hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)sulfinyl)methyl)-1H-pyrazole-4-carbonitrile (168)

    1-(((R)-((3R,5R,8R,9R,10S,13S,14S,17S)-3-Hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)sulfinyl)methyl)-1H-pyrazole-4-carbonitrile (169)

    [0764] ##STR00296##

    [0765] 1-((((3R,5R,8R,9R,10S,13S,14S,17S)-3-Hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)thio)methyl)-1H-pyrazole-4-carbonitrile (25 mg, 0.06 mmol) was dissolved in 5 mL of anhydrous dichloromethane in a 100 mL round bottom flask, tert-chloroperoxybenzoic acid (15 mg, 0.073 mmol) was added at −20° C., and the reaction solution was stirred at this temperature for 1 hour. After completion of the reaction, saturated sodium bicarbonate solution was added to quench the reaction, and the reaction solution was extracted with ethyl acetate. The organic phase was washed with water and saturated saline, dried over anhydrous sodium sulfate, filtrated and by rotary evaporation concentrated to dryness. The resulting crude product was purified by high performance liquid chromatography to obtain 1-(((S)-((3R,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)sulfinyl)methyl)-1H-pyrazole-4-carbonitrile (7.5 mg, 29%) and 1-(((R)-((3R,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)sulfinyl)methyl)-1H-pyrazole-4-carbonitrile (6.5 mg, yield: 25%).

    Example 168

    [0766] MS m/z (ESI): 430.3 [M+H].sup.+

    [0767] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.06 (s, 1H), 7.90 (s, 1H), 5.21 (d, J=12.0 Hz, 1H), 5.03 (d, J=12.0 Hz, 1H), 2.54 (t, J=9.2 Hz, 1H), 2.12-1.93 (m, 2H), 1.85-1.02 (m, 25H), 0.89 (s, 3H).

    Example 169

    [0768] MS m/z (ESI): 430.3 [M+H].sup.+

    [0769] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.10 (s, 1H), 7.91 (s, 1H), 5.18 (d, J=13.6 Hz, 1H), 5.03 (d, J=13.6 Hz, 1H), 2.32 (t, J=8.8 Hz, 1H), 2.05-1.94 (m, 2H), 1.85-1.12 (m, 25H), 1.05 (s, 3H).

    Example 170

    1-((((3R,5R,8R,9R,10S,13S,14S,17S)-3-Hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)sulfonyl)methyl)-1H-pyrazole-4-carbonitrile (170)

    [0770] ##STR00297##

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

    [0771] ##STR00298##

    [0772] 1-((((3R,5R,8R,9R,10S,13S,14S,17S)-3-Hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)thio)methyl)-1H-pyrazole-4-carbonitrile (25 mg, 0.06 mmol) was dissolved in 5 mL of anhydrous dichloromethane in a 100 mL round bottom flask. M-chloroperoxybenzoic acid (30 mg, 0.15 mmol) was added at 0° C., and the reaction solution was stirred at room temperature for 2 hours. After completion of the reaction, saturated sodium bicarbonate solution was added to quench the reaction, and the reaction solution was extracted with ethyl acetate. The organic phase was washed with water and saturated saline, dried over anhydrous sodium sulfate, filtrated and concentrated by rotary evaporation to dryness. The resulting crude product was purified by preparative high performance liquid chromatography to obtain 1-((((3R,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)sulfonyl)methyl)-1H-pyrazole-4-carbonitrile (9.1 mg, 34%).

    [0773] MS m/z (ESI): 446.3 [M+H].sup.+

    [0774] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.13 (s, 1H), 7.89 (s, 1H), 5.24 (d, J=14.8 Hz, 1H), 5.02 (d, J=14.8 Hz, 1H), 2.88 (t, J=9.2 Hz, 1H), 2.24-2.18 (m, 1H), 2.11-1.92 (m, 3H), 1.84-1.00 (s, 26H).

    Example 171

    ((3R,5R,8R,9R,10S,13S,14S,17S)-3-Hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)methylphenylphosphine oxide (171)

    [0775] ##STR00299##

    [0776] Step 1: Preparation of ((3R,5R,8R,9R,10S,13S,14S)-3-((tert-butyldimethylsilyl)oxy)-3,13-dimethyl-2,3,4,5,6,7,8,9,10,11,12,13,14,15-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl)methylphenylphosphine oxide

    ##STR00300##

    [0777] (3R,5R,8R,9R,10S,13S,14S)-3-((tert-butyldimethylsilyl)oxy)-3,13-dimethyl-2,3,4,5,6,7,8,9,10,11,12,13,14,15-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl trifluoromethanesulfonate (230 mg, 0.43 mmol), methylphenylphosphine oxide (92 mg, 0.64 mmol), palladium diacetate (10 mg, 0.04 mmol), 1,4-bis(diphenylphosphino)butane (18 mg, 0.04 mmol), N,N-diisopropylethylamine (443 mg, 3.4 mmol) and 10 mL anhydrous dimethyl sulfoxide were successively added to a 100 mL round bottom flask. The reaction system was purged with nitrogen, slowly warmed up to 120° C. and stirred overnight. After completion of the reaction, the reaction system was cooled to room temperature. Water was added to quench the reaction, and the reaction solution was extracted with ethyl acetate. The organic phase was washed with water and saturated saline, dried over anhydrous sodium sulfate, filtrated and concentrated by rotary evaporation to dryness. The resulting crude product was purified by column chromatography (eluent: dichloromethane/methanol=10/1) to obtain ((3R,5R,8R,9R,10S,13S,14S)-3-((tert-butyldimethylsilyl)oxy)-3,13-dimethyl-2,3,4,5,6,7,8,9,10,11,12,13,14,15-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl)methylphenylphosphine oxide (170 mg, 75%).

    [0778] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.77-7.72 (m, 2H), 7.55-7.48 (m, 3H), 6.53-6.50 (m, 1H), 2.44-1.16 (m, 27H), 1.00 (s, 3H), 0.86 (s, 9H), 0.05 (s, 6H).

    Step 2: Preparation of ((3R,5R,8R,9R,10S,13S,14S)-3-hydroxy-3,13-dimethyl-2,3,4,5,6,7,8,9,10,11,12,13,14,15-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl)methylphenylphosphine oxide

    [0779] ##STR00301##

    [0780] ((3R,5R,8R,9R,10S,13S,14S)-3-((tert-butyldimethylsilyl)oxy)-3,13-dimethyl-2,3,4,5,6,7,8,9,10,11,12,13,14,15-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl)methyl phenylphosphine oxide (170 mg, 0.32 mmol) was dissolved in 5 mL of anhydrous tetrahydrofuran in a 100 mL round bottom flask, and a 1.0 M solution of tetrabutylammonium fluoride in tetrahydrofuran (5 mL) was added to the reaction system. The reaction solution was stirred at 60° C. overnight. After completion of the reaction, the reaction system was cooled to room temperature. Water was added to quench the reaction, and the reaction solution was extracted with ethyl acetate. The organic phase was washed with water and saturated saline, dried over anhydrous sodium sulfate, filtrated and concentrated by rotary evaporation to dryness. The resulting crude product was purified by column chromatography (eluent: dichloromethane/methanol=10/1) to obtain ((3R,5R,8R,9R,10S,13S,14S)-3-hydroxy-3,13-dimethyl-2,3,4,5,6,7,8,9,10,11,12,13,14,15-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl)methylphenylphosphine oxide (50 mg, 38%).

    Step 3: Preparation of ((3R,5R,8R,9R,10S,13S,14S,17S)-3-Hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)methylphenylphosphine oxide

    [0781] ##STR00302##

    [0782] ((3R,5R,8R,9R,10S,13S,14S)-3-Hydroxy-3,13-dimethyl-2,3,4,5,6,7,8,9,10,11,12,13,14,15-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl)methylphenylphosphine oxide (50 mg, 0.12 mmol), palladium on carbon (50 mg, 10%) and 10 mL of ethyl acetate were added to a 100 mL round bottom flask. The reaction system was purged with hydrogen three times, and reacted at 1 atmosphere overnight. After completion of the reaction, the reaction solution was filtrated through celite to remove excess palladium on carbon, and the filtrate was concentrated by rotary evaporation to dryness. The resulting crude product was purified by high performance liquid chromatography to obtain ((3R,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)methylphenylphosphine oxide (10 mg, 20%).

    [0783] MS m/z (ESI): 415.3 [M+H].sup.+.

    [0784] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.79-7.74 (m, 2H), 7.55-7.50 (m, 3H), 2.41-2.34 (m, 1H), 2.03-1.60 (m, 12H), 1.55-0.73 (m, 21H).

    Example 172

    1-((3R,5R,8R,9R,10S,13S,14S)-13-Methyl-3-(methylamino)hexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one hydrochloride

    [0785] ##STR00303##

    Step 1: Preparation of (3S,5R,8R,9R,10S,13S,14S)-3-hydroxy-13-methylhexadecahydro-17H-cyclopenta[a]phenanthren-17-one

    [0786] ##STR00304##

    [0787] (5R,8R,9R,10S,13S,14S)-13-Methyltetradecahydro-3H-cyclopenta[a]phenanthrene-3,17(2H)-dione (5.90 g, 21.50 mmol) was dissolved in anhydrous tetrahydrofuran (150 mL) at −78° C. The reaction system was purged with nitrogen, and potassium triisobutylborohydride (1.0 M in THF, 32.25 mL, 32.25 mmol) was added dropwise to the reaction system. The reaction solution was reacted at −78° C. for 3 hours. Aqueous sodium hydroxide solution (10 wt %, 56.6 mL) and hydrogen peroxide (82.6 mL) were successively added dropwise, and then the reaction solution was stirred at room temperature for half an hour. Saturated sodium thiosulfate (100 mL) was added, and then the reaction solution was stirred at room temperature for 10 minutes. The reaction solution was extracted with ethyl acetate (100 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtrated and concentrated by rotary evaporation to dryness. The resulting crude product was purified by flash column chromatography (petroleum ether:ethyl acetate: 4:1) to obtain (3S,5R,8R,9R,10S,13S,14S)-3-hydroxy-13-methylhexadecahydro-17H-cyclopenta[a]phenanthren-17-one (5.0 g, white solid, yield: 84%).

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

    [0788] ##STR00305##

    [0789] Sodium hydride (1.45 g, 36.18 mmol, 60% in mineral oil) was added in batches to a solution of ethyltriphenylphosphonium bromide (13.44 g, 36.18 mmol) in dimethyl sulfoxide (100 mL) under a nitrogen atmosphere. The reaction solution was stirred at room temperature for 1 hour, and a solution of (3S,5R,8R,9R,10S,13S,14S)-3-hydroxy-13-methylhexadecahydro-17H-cyclopenta[a]phenanthren-17-one (2.0 g, 7.24 mmol) in dimethyl sulfoxide (40 mL) was added dropwise. The reaction solution was heated to 60° C. overnight under a nitrogen atmosphere. The reaction solution was cooled to room temperature. Saturated saline (200 mL) was added, and then the reaction solution was extracted with dichloromethane (50 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtrated and concentrated by rotary evaporation to dryness. The resulting crude product was purified by flash column chromatography (petroleum ether:ethyl acetate: 10:1) to obtain (3S,5R,8R,9R,10S,13S,14S)-17-ethylidene-13-methylhexadecahydro-1H-cyclopenta[a]phenanthren-3-ol (1.60 g, white solid, yield: 76.7%).

    [0790] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 5.14-5.08 (m, 1H), 4.13-4.11 (m, 1H), 2.40-2.33 (m, 1H), 2.28-2.11 (m, 3H), 1.91-1.83 (m, 1H), 1.74-1.58 (m, 8H), 1.47-1.38 (m, 5H), 1.38-1.34 (m, 2H), 1.29-1.07 (m, 7H), 0.88 (s, 3H).

    Step 3: Preparation of (3S,5R,8R,9R,10S,13S,14S)-17-ethylidene-13-methylhexadecahydro-1H-cyclopenta[a]phenanthren-3-yl methanesulfonate

    [0791] ##STR00306##

    [0792] (3S,5R,8R,9R,10S,13S,14S)-17-Ethylidene-13-methylhexadecahydro-1H-cyclopenta[a]phenanthren-3-ol (0.40 g, 1.39 mmol) was dissolved in dichloromethane (20 mL) at room temperature. Pyridine (0.33 g, 4.16 mmol) and methanesulfonyl chloride (0.32 g, 2.77 mmol) were successively added dropwise, and then the reaction solution was reacted at room temperature overnight. After completion of the reaction, the reaction solution was diluted with dichloromethane (40 mL), and washed with saturated saline (10 mL×3). The organic phase was dried over anhydrous sodium sulfate, filtrated and concentrated by rotary evaporation to dryness. The resulting crude product was purified by flash column chromatography (petroleum ether:ethyl acetate: 10:1) to obtain (3S,5R,8R,9R,10S,13S,14S)-17-ethylidene-13-methylhexadecahydro-1H-cyclopenta[a]phenanthren-3-yl methanesulfonate (0.30 g, white solid, yield: 59%).

    Step 4: Preparation of (3R,5R,8R,9R,10S,13S,14S)-17-ethylidene-N,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-3-amine

    [0793] ##STR00307##

    [0794] (3S,5R,8R,9R,10S,13S,14S)-17-Ethylidene-13-methylhexadecahydro-1H-cyclopenta[a]phenanthren-3-yl methanesulfonate (0.20 g, 0.55 mmol) was added to a microwave reaction tube (10 mL) at room temperature, and methylamine alcohol solution (3 mL) was added dropwise to the reaction system. The microwave reaction tube was sealed, and heated to 80° C. overnight. The reaction solution was cooled to room temperature and concentrated by rotary evaporation to dryness. The resulting residue was dissolved in ethyl acetate (20 mL). The organic phases were washed with saturated saline (20 mL×3), combined, dried over anhydrous sodium sulfate, filtrated and concentrated by rotary evaporation to dryness. The resulting crude product was purified by flash column chromatography (dichloromethane:methanol:triethylamine: 300:10:3) to obtain (3R,5R,8R,9R,10S,13S,14S)-17-ethylidene-N,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-3-amine (70 mg, colorless oil, yield: 42.4%).

    [0795] MS m/z (ESI): 302.5 [M+H].sup.+.

    Step 5: Preparation of 1-((3R,5R,8R,9R,10S,13S,14S)-13-methyl-3-(methylamino)hexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-ol

    [0796] ##STR00308##

    [0797] (3R,5R,8R,9R,10S,13S,14S)-17-Ethylidene-N,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-3-amine (0.07 g, 0.23 mmol) was dissolved in anhydrous tetrahydrofuran (3 mL) in an ice bath, and then a solution of borane in tetrahydrofuran (1.0 M in THF, 2.32 mL, 2.32 mmol) was added dropwise. The reaction solution was reacted for 3 hours. Sodium hydroxide solution (3N, 1 mL) and hydrogen peroxide (0.3 mL) were successively added dropwise, and then the reaction solution was stirred at room temperature for half an hour. The reaction solution was diluted with ethyl acetate (20 mL), and washed with saturated saline (10 mL×3). The organic phase was dried over anhydrous sodium sulfate, filtrated and concentrated by rotary evaporation to dryness to obtain the crude product 1-((3R,5R,8R,9R,10S,13S,14S)-13-methyl-3-(methylamino)hexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-ol (40 mg, colorless oil, crude product).

    [0798] MS m/z (ESI): 320.5 [M+H].sup.+.

    Step 6: Preparation of 1-((3R,5R,8R,9R,10S,13S,14S)-13-methyl-3-(methylamino)hexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one

    [0799] ##STR00309##

    [0800] 1-((3R,5R,8R,9R,10S,13S,14S)-13-Methyl-3-(methylamino)hexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-ol (40 mg, 0.125 mmol) was dissolved in dichloromethane (5 mL) at room temperature. Pyridinium chlorochromate (54 mg, 0.25 mmol) was added, and then the reaction solution was reacted at room temperature for 3 hours. The reaction solution was diluted with dichloromethane (20 mL), and washed with saturated sodium thiosulfate (10 mL×3). The organic phase was dried over anhydrous sodium sulfate, filtrated and concentrated by rotary evaporation to dryness. The resulting crude product was purified by column chromatography (dichloromethane:methanol:30:1) to obtain 1-((3R,5R,8R,9R,10S,13S,14S)-13-methyl-3-(methylamino)hexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one (15 mg, white solid, yield: 37.7%).

    [0801] MS m/z (ESI): 318.5 [M+H].sup.+

    [0802] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 3.61-3.55 (m, 1H), 2.55-2.50 (m, 1H), 2.47 (s, 3H), 2.11 (s, 3H), 2.01-1.92 (m, 3H), 1.78-1.56 (m, 8H), 1.43-1.01 (m, 13H), 0.61 (s, 3H).

    Example 173

    1-((3R,8R,9R,10S,13S,14S,16R,17S)-16-Fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one (173)

    [0803] ##STR00310##

    Step 1: Preparation of (3R,5R,8R,9R,10S,13S,14S,16R)-16-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-17H-cyclopenta[a]phenanthren-17-one

    [0804] ##STR00311##

    [0805] Trimethylsilyl triflate (5.6 mL, 31.0 mmol) was added dropwise to a solution of (3R,5R,8R,9R,10S,13S,14S)-3-hydroxy-3,13-dimethylhexadecahydro-17H-cyclopenta[a]phenanthren-17-one (3 g, 10.3 mmol) and triethylamine (36.0 mL, 258.2 mmol) in toluene (45 mL), and the resulting reaction solution was heated to reflux for 2 hours. The reaction solution was cooled, washed with saturated sodium bicarbonate, and extracted with n-hexane. The organic phase was concentrated to dryness to obtain the crude product (((3R,5R,8R,9R,10S,13S,14S)-3,13-dimethyl-2,3,4,5,6,7,8,9,10,11,12,13,14,15-tetradecahydro-1H-cyclopenta[a]phenanthrene-3,17-diyl)bis(oxy))bis(trimethylsilane). A selective fluorine reagent (4.0 g, 11.4 mmol) was added to a solution of (((3R,5R,8R,9R,10S,13S,14S)-3,13-dimethyl-2,3,4,5,6,7,8,9,10,11,12,13,14,15-tetradecahydro-1H-cyclopenta[a]phenanthrene-3,17-diyl)bis(oxy))bis(trimethylsilane) in N,N-dimethylformamide (25 mL), and the resulting reaction solution was stirred at room temperature for 2 hours to obtain (3R,5R,8R,9R,10S,13S,14S,16R)-16-fluoro-3,13-dimethyl-3-((trimethylsilyl)oxy)hexadecahydro-17H-cyclopenta[a]phenanthren-17-one. A solution of tetrabutylammonium fluoride in tetrahydrofuran (11.4 mL, 1 M) was added, and the resulting reaction solution was stirred at room temperature overnight. The reaction solution was extracted with ethyl acetate, and washed with saturated saline three times. The organic phase was concentrated to dryness, and the resulting crude product was purified by column chromatography (petroleum ether:ethyl acetate=6:4) to obtain (3R,5R,8R,9R,10S,13S,14S,16R)-16-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-17H-cyclopenta[a]phenanthren-17-one (2.0 g, yield: 50.9%).

    [0806] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 5.09 (dd, J=50.6, 7.5 Hz, 1H), 2.18-1.58 (m, 10H), 1.54-1.01 (m, 14H), 0.92 (s, 3H).

    [0807] .sup.19F NMR (376 MHz, CDCl.sub.3) δ −192.59.

    Step 2: Preparation of (3R,5R,8R,9R,10S,13S,14S,16R)-17-ethylidene-16-fluoro-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-3-ol

    [0808] ##STR00312##

    [0809] Sodium hydride (123 mg, 3.08 mmol, 60% w/w) was added to a solution of ethyltriphenylphosphonium bromide (1.2 g, 3.24 mmol) in dimethyl sulfoxide (20 mL) in batches under a nitrogen atmosphere, and the resulting reaction solution was stirred at room temperature for 1 hour. (3R,5R,8R,9R,10S,13S,14S,16R)-16-Fluoro-3-hydroxy-3,13-dimethylhexadecahydro-17H-cyclopenta[a]phenanthren-17-one (200 mg, 0.65 mmol) was added, and the reaction solution was heated to 70° C. under a nitrogen atmosphere overnight. The reaction solution was cooled, and saturated saline was added. 1 N hydrochloric acid was added to adjust pH to 6, and the reaction solution was extracted with ethyl acetate. The organic phase was washed with saturated saline, and concentrated to dryness to obtain a crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate=7:3) to obtain (3R,5R,8R,9R,10S,13S,14S,16R)-17-ethylidene-16-fluoro-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-3-ol (80 mg, yield: 38.5%).

    [0810] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 5.71-5.59 (m, 1H), 5.12 (dt, J=57.2, 7.0 Hz, 1H), 2.27-2.11 (m, 2H), 1.92-1.24 (m, 21H), 1.22-1.09 (m, 4H), 1.06 (s, 3H).

    [0811] .sup.19F NMR (376 MHz, CDCl.sub.3) δ −153.69.

    Step 3: Preparation of (3R,8R,9R,10S,13S,14S,16R,17S)-16-fluoro-17-(1-hydroxyethyl)-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-3-ol

    [0812] ##STR00313##

    [0813] (3R,5R,8R,9R,10S,13S,14S,16R)-17-Ethylidene-16-fluoro-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-3-ol (80 mg, 0.25 mmol) was dissolved in anhydrous tetrahydrofuran (50 mL). A solution of borane in tetrahydrofuran (1 M, 2.5 mL) was added dropwise at room temperature, and the resulting reaction solution was stirred at room temperature for 1 hour. The reaction solution was cooled with ice water, and sodium hydroxide solution (3 M, 1 mL) was slowly added dropwise to release a large amount of gas. Hydrogen peroxide (25%, 0.58 mL) was slowly added dropwise, and the reaction solution was stirred at room temperature for 2 hours. The reaction solution was extracted with ethyl acetate, washed with sodium thiosulfate solution and saturated saline, and dried to obtain (3R,8R,9R,10S,13S,14S,16R,17S)-16-fluoro-17-(1-hydroxyethyl)-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-3-ol (80 mg), which was used directly in the next step.

    [0814] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 5.47-5.16 (m, 1H), 4.22-4.05 (m, 1H), 2.42-2.17 (m, 1H), 1.94-0.93 (m, 27H), 0.87 (s, 3H).

    [0815] .sup.19F NMR (376 MHz, CDCl.sub.3) δ −178.27.

    Step 4: Preparation of 1-((3R,8R,9R,10S,13S,14S,16R,17S)-16-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one

    [0816] ##STR00314##

    [0817] Pyridinium chlorochromate (102 mg, 0.47 mmol) was added to a solution of (3R,8R,9R,10S,13S,14S,16R,17S)-16-fluoro-17-(1-hydroxyethyl)-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-3-ol (80 mg) in acetone (2 mL), and the resulting reaction solution was reacted at 60° C. for 6 hours. The reaction solution was concentrated to dryness, and the resulting residue was purified by column chromatography (petroleum ether:ethyl acetate=5:2) to obtain 1-((3R,8R,9R,10S,13S,14S,16R,17S)-16-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one (22 mg, yield: 25%).

    [0818] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 5.64-5.35 (m, 1H), 2.44-2.09 (m, 6H), 1.97-1.75 (m, 4H), 1.74-1.00 (m, 20H), 0.98-0.68 (m, 2H).

    [0819] .sup.19F NMR (376 MHz, CDCl.sub.3) δ −168.20.

    Example 174

    1-((2aR,4R,6aS,6bR,8aS,8bS,9aS,10aS,10bR)-4-Hydroxy-4,8a-dimethylhexadecahydrocyclopropa[3,4]cyclopenta[1,2-a]phenanthren-8b(2H)-yl)ethan-1-one (174)

    [0820] ##STR00315##

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

    [0821] ##STR00316##

    [0822] 1-((3R,5R,8R,9R,10S,13S,14S,17S)-3-Hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one (600 mg, 1.872 mmol) was dissolved in carbon tetrachloride (10 mL). N-Bromosuccinimide (666 mg, 3.744 mmol) and benzoyl peroxide (48 mg, 0.187 mmol) were added, and then the reaction solution was stirred at 80° C. for 2 hours. The reaction solution was cooled to room temperature. Water (30 mL) was added, and then 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, and the resulting residue was purified by column chromatography (petroleum ether/ethyl acetate=8/1) to obtain 1-((3R,5R,8R,9R,10S,13S,14S,17R)-17-bromo-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one (light yellow solid, 400 mg, yield: 54%).

    [0823] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 3.09-3.01 (m, 1H), 2.38 (s, 3H), 2.32-2.20 (m, 1H), 2.10-1.98 (m, 1H), 1.97-1.72 (m, 7H), 1.71-1.58 (m, 1H), 1.57-0.94 (m, 15H), 0.89-0.81 (m, 1H), 0.76 (s, 3H).

    Step 2: Preparation of 1-((3R,5R,8R,9R,10S,13S,14S)-3-hydroxy-3,13-dimethyl-2,3,4,5,6,7,8,9,10,11,12,13,14,15-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one

    [0824] ##STR00317##

    [0825] 1-((3R,5R,8R,9R,10S,13S,14S,17R)-17-Bromo-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one (400 mg, 1 mmol) was dissolved in anhydrous toluene (10 mL). 1,8-Diazabicycloundec-7-ene (913 mg, 6 mmol) was added, and then the reaction solution was stirred at 110° C. for 16 hours. The reaction solution was cooled to room temperature. Water (20 mL) was added, and then 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, and the resulting residue was purified by column chromatography (petroleum ether/ethyl acetate=4/1) to obtain 1-((3R,5R,8R,9R,10S,13S,14S)-3-hydroxy-3,13-dimethyl-2,3,4,5,6,7,8,9,10,11,12,13,14,15-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one (colorless oil, 160 mg, yield: 51%).

    [0826] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 6.69 (dd, J=3.1, 1.7 Hz, 1H), 2.41-2.28 (m, 2H), 2.25 (s, 3H), 2.07-1.93 (m, 1H), 1.89-1.76 (m, 3H), 1.71-1.69 (m, 4H), 1.53-1.41 (m, 5H), 1.37-1.29 (m, 4H), 1.27 (s, 3H), 1.24-1.07 (m, 3H), 0.89 (s, 3H).

    Step 3: Preparation of 1-((2aR,4R,6aS,6bR,8aS,8bS,9aS,10aS,10bR)-4-hydroxy-4,8a-dimethylhexadecahydrocyclopropa[3,4]cyclopenta[1,2-a]phenanthren-8b(2H)-yl)ethan-1-one

    [0827] ##STR00318##

    [0828] Sodium hydride (45 mg, 1.136 mmol, 60%) was suspended in dimethyl sulfoxide (2 mL). Trimethyl sulfoxide (100 mg, 0.451 mmol) was added, and then the reaction solution was stirred at room temperature for 1 hour. A mixed solution of 1-((3R,5R,8R,9R,10S,13S,14S)-3-hydroxy-3,13-dimethyl-2,3,4,5,6,7,8,9,10,11,12,13,14,15-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one (90 mg, 0.284 mmol) and tetrahydrofuran (2 mL) was added, and then the reaction solution was stirred at room temperature for 16 hours. Water (15 mL) was added, and then the reaction solution was extracted with ethyl acetate (10 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 column chromatography (petroleum ether/ethyl acetate=4/1) to obtain 1-((2aR,4R,6aS,6bR,8aS,8bS,9aS,10aS,10bR)-4-hydroxy-4,8a-dimethylhexadecahydrocyclopropa[3,4]cyclopenta[1,2-a]phenanthren-8b(2H)-yl)ethan-1-one (colorless oil, 40 mg, yield: 43%).

    [0829] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 2.26-2.18 (m, 1H), 1.95 (s, 3H), 1.92-1.85 (m, 1H), 1.81 (m, 2H), 1.72-1.53 (m, 5H), 1.46-1.29 (m, 7H), 1.29-1.17 (m, 7H), 1.16-1.00 (m, 3H), 0.94 (s, 3H), 0.91-0.78 (m, 2H).

    Example 175

    1-(2-((2aR,4R,6aS,6bR,8aS,8bS,9aS,10aS,10bR)-4-Hydroxy-4,8a-dimethylhexadecahydrocyclopropa[3,4]cyclopenta[1,2-a]phenanthren-8b(2H)-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile (175)

    [0830] ##STR00319##

    Step 1: Preparation of 2-bromo-1-((2aR,4R,6aS,6bR,8aS,8bS,9aS,10aS,10bR)-4-hydroxy-4,8a-dimethylhexadecahydrocyclopropa[3,4]cyclopenta[1,2-a]phenanthren-8b(2H)-yl)ethan-1-one

    [0831] ##STR00320##

    [0832] 1-((2aR,4R,6aS,6bR,8aS,8bS,9aS,10aS,10bR)-4-Hydroxy-4,8a-dimethylhexadecahydrocyclopropa[3,4]cyclopenta[1,2-a]phenanthren-8b(2H)-yl)ethan-1-one (40 mg, 0.121 mmol) was dissolved in methanol (2 mL). A drop of hydrogen bromide and two drops of liquid bromine were added, and then the reaction solution was stirred at room temperature for 1.5 hours. Water (15 mL) was added, and then the reaction solution was extracted with ethyl acetate (10 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 to obtain 2-bromo-1-((2aR,4R,6aS,6bR,8aS,8bS,9aS,10aS,10bR)-4-hydroxy-4,8a-dimethylhexadecahydrocyclopropa[3,4]cyclopenta[1,2-a]phenanthren-8b(2H)-yl)ethan-1-one (50 mg, crude product).

    Step 2: Preparation of 1-(2-((2aR,4R,6aS,6bR,8aS,8bS,9aS,10aS,10bR)-4-hydroxy-4,8a-dimethylhexadecahydrocyclopropa[3,4]cyclopenta[1,2-a]phenanthren-8b(2H)-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile

    [0833] ##STR00321##

    [0834] 2-Bromo-1-((2aR,4R,6aS,6bR,8aS,8bS,9aS,10aS,10bR)-4-hydroxy-4,8a-dimethylhexadecahydrocyclopropa[3,4]cyclopenta[1,2-a]phenanthren-8b(2H)-yl)ethan-1-one (40 mg, 0.098 mmol) was dissolved in tetrahydrofuran (5 mL). 4-Cyanopyrazole (11 mg, 0.0118 mmol) and potassium carbonate (27 mg, 0.196 mmol) were added, and then the reaction solution was stirred at room temperature for 16 hours. Water (15 mL) was added, and then the reaction solution was extracted with ethyl acetate (10 mL×2). The organic phases were combined, washed with saturated saline (20 mL), dried over anhydrous sodium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the resulting crude product was purified by high performance liquid chromatography to obtain 1-(2-((2aR,4R,6aS,6bR,8aS,8bS,9aS,10aS,10bR)-4-hydroxy-4,8a-dimethylhexadecahydrocyclopropa[3,4]cyclopenta[1,2-a]phenanthren-8b(2H)-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile (18 mg, yield: 44%).

    [0835] MS m/z (ESI): 422.2[M+H].sup.+.

    [0836] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.76 (s, 1H), 7.74 (s, 1H), 5.11 (d, J=18.0 Hz, 1H), 4.91 (d, J=18.0 Hz, 1H), 3.61-3.49 (m, 1H), 2.96 (d, J=8.7 Hz, 1H), 2.17-2.05 (m, 2H), 1.90-1.70 (m, 5H), 1.68-1.5 (m, 7H), 1.45-1.35 (m, 5H), 1.34-1.01 (m, 7H), 0.65 (s, 3H).

    Example 176

    1-((2aR,4R,6aS,6bR,8aS,8bS,9aS,10aS,10bR)-4-Hydroxy-4,8a-dimethylhexadecahydrocyclopropa[3,4]cyclopenta[1,2-a]phenanthren-8b(2H)-yl)-2-(4-(trifluoromethyl)-1H-pyrazol-1-yl)ethan-1-one (176)

    [0837] ##STR00322##

    Step 1: Preparation of 1-((2aR,4R,6aS,6bR,8aS,8bS,9aS,10aS,10bR)-4-hydroxy-4,8a-dimethylhexadecahydrocyclopropa[3,4]cyclopenta[1,2-a]phenanthren-8b(2H)-yl)-2-(4-(trifluoromethyl)-1H-pyrazol-1-yl)ethan-1-one

    [0838] ##STR00323##

    [0839] 2-Bromo-1-((2aR,4R,6aS,6bR,8aS,8bS,9aS,10aS,10bR)-4-hydroxy-4,8a-dimethylhexadecahydrocyclopropa[3,4]cyclopenta[1,2-a]phenanthren-8b(2H)-yl)ethan-1-one (40 mg, 0.098 mmol) was dissolved in tetrahydrofuran (5 mL). 3-Cyanopyrazole (11 mg, 0.0118 mmol) and potassium carbonate (27 mg, 0.196 mmol) were added, and then the reaction solution was stirred at room temperature for 16 hours. Water (15 mL) was added, and then the reaction solution was extracted with ethyl acetate (10 mL×2). The organic phases were combined, washed with saturated saline (20 mL), dried over anhydrous sodium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the resulting crude product was purified by high performance liquid chromatography to obtain 1-((2aR,4R,6aS,6bR,8aS,8bS,9aS,10aS,10bR)-4-hydroxy-4,8a-dimethylhexadecahydrocyclopropa[3,4]cyclopenta[1,2-a]phenanthren-8b(2H)-yl)-2-(4-(trifluoromethyl)-1H-pyrazol-1-yl)ethan-1-one (18 mg, yield: 44%).

    [0840] MS m/z (ESI): 465.2[M+H].sup.+

    [0841] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.74 (s, 1H), 7.70 (s, 1H), 4.90 (d, J=17.3 Hz, 1H), 4.71 (d, J=17.3 Hz, 1H), 2.18 (m, 1H), 2.10-2.03 (m, 1H), 1.81 (m, 3H), 1.76-1.58 (m, 4H), 1.57-1.32 (m, 10H), 1.26 (s, 3H), 1.19-1.00 (m, 4H), 0.98 (s, 3H), 0.92 (m, 2H).

    Example 177

    1-(2-((2aR,4R,6aS,6bR,8aS,8bS,9aR,10aS,10bR)-4-Hydroxy-4,8a-dimethylhexadecahydro-8bH-naphtho[2′,1′:4,5]indeno[1,2-b]oxiren-8b-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile (177)

    [0842] ##STR00324##

    Step 1: Preparation of 1-((2aR,4R,6aS,6bR,8aS,8bS,9aR,10aS,10bR)-4-hydroxy-4,8a-dimethylhexadecahydro-8bH-naphtho[2′,1′:4,5]indeno[1,2-b]oxiren-8b-yl)ethan-1-one

    [0843] ##STR00325##

    [0844] 1-((3R,5R,8R,9R,10S,13S,14S)-3-Hydroxy-3,13-dimethyl-2,3,4,5,6,7,8,9,10,11,12,13,14,15-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one (80 mg, 0.242 mmol) was dissolved in methanol (5 mL) and water (1 mL). Hydrogen peroxide (1.3 mL) and sodium hydroxide (30 mg, 0.75 mmol) were added, and then the reaction solution was stirred at 0° C. for 16 hours. Water (15 mL) was added, and then the reaction solution was extracted with ethyl acetate (15 mL×3). The organic phases were combined, washed with saturated saline (20 mL), dried over anhydrous sodium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (petroleum ether/ethyl acetate=4/1) to obtain 1-((2aR,4R,6aS,6bR,8aS,8bS,9aR,10aS,10bR)-4-hydroxy-4,8a-dimethylhexadecahydro-8bH-naphtho[2′,1′:4,5]indeno[1,2-b]oxiren-8b-yl)ethan-1-one (60 mg, yield: 75%).

    [0845] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 3.66 (s, 1H), 2.03 (s, 3H), 1.94 (m, 1H), 1.87-1.75 (m, 3H), 1.74-1.61 (m, 3H), 1.47 (m, 2H), 1.43-1.37 (m, 4H), 1.35-1.30 (m, 3H), 1.25 (s, 6H), 1.17-1.07 (m, 3H), 1.03 (s, 3H).

    Step 2: Preparation of 2-bromo-1-((2aR,4R,6aS,6bR,8aS,8bS,9aR,10aS,10bR)-4-hydroxy-4,8a-dimethylhexadecahydro-8bH-naphtho[2′,1′:4,5]indeno[1,2-b]oxiren-8b-yl)ethan-1-one

    [0846] ##STR00326##

    [0847] 1-((2aR,4R,6aS,6bR,8aS,8bS,9aR,10aS,10bR)-4-Hydroxy-4,8a-dimethylhexadecahydro-8bH-naphtho[2′,1′:4,5]indeno[1,2-b]oxiren-8b-yl)ethan-1-one (50 mg, 0.15 mmol) was dissolved in methanol (3 mL). A drop of hydrogen bromide and two drops of liquid bromine were added, and then the reaction solution was stirred at room temperature for 8 hours. Water (10 mL) was added, and then the reaction solution was extracted with ethyl acetate (10 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 to obtain 2-bromo-1-((2aR,4R,6aS,6bR,8aS,8bS,9aR,10aS,10bR)-4-hydroxy-4,8a-dimethylhexadecahydro-8bH-naphtho[2′,1′:4,5]indeno[1,2-b]oxiren-8b-yl)ethan-1-one (60 mg, crude product).

    Step 3: Preparation of 1-(2-((2aR,4R,6aS,6bR,8aS,8bS,9aR,10aS,10bR)-4-hydroxy-4,8a-dimethylhexadecahydro-8bH-naphtho[2′,1′:4,5]indeno[1,2-b]oxiren-8b-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile

    [0848] ##STR00327##

    [0849] 2-Bromo-1-((2aR,4R,6aS,6bR,8aS,8bS,9aR,10aS,10bR)-4-hydroxy-4,8a-dimethyl hexadecahydro-8bH-naphtho[2′,1′:4,5]indeno[1,2-b]oxiren-8b-yl)ethan-1-one (60 mg, 0.146 mmol) was dissolved in tetrahydrofuran (3 mL). 4-Cyanopyrazole (20 mg, 0.219 mmol) and potassium carbonate (60 mg, 0.438 mmol) were added, and then the reaction solution was stirred at room temperature for 16 hours. Water (15 mL) was added, and then the reaction solution was extracted with ethyl acetate (10 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 crude product was purified by high performance liquid chromatography to obtain 1-(2-((2aR,4R,6aS,6bR,8aS,8bS,9aR,10aS,10bR)-4-hydroxy-4,8a-dimethylhexadecahydro-8bH-naphtho[2′,1′:4,5]indeno[1,2-b]oxiren-8b-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile (18 mg, yield: 29%).

    [0850] MS m/z (ESI): 424.2[M+H].sup.+

    [0851] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.84 (s, 1H), 7.82 (s, 1H), 5.07 (d, J=18.3 Hz, 1H), 4.87 (d, J=18.3 Hz, 1H), 3.85 (s, 1H), 2.03 (dd, J=13.1, 5.6 Hz, 1H), 1.94-1.91 (m, 1H), 1.84-1.78 (m, 3H), 1.76-1.64 (m, 3H), 1.52-1.28 (m, 10H), 1.26 (s, 4H), 1.19-1.09 (m, 3H), 1.07 (s, 3H).

    Example 178

    (3R,5R,8R,9R,10S,13S,14S,16R,17S)-3-Hydroxy-3,13-dimethyl-17-(2-(4-(trifluoromethyl)-1H-pyrazol-1-yl)acetyl)hexadecahydro-1H-cyclopenta[a]phenanthrene-16-carbonitrile (178)

    [0852] ##STR00328##

    Step 1: Preparation of (3R,5R,8R,9R,10S,13S,14S,16R,17S)-17-(2-bromoacetyl)-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-16-carbonitrile

    [0853] ##STR00329##

    [0854] (3R,5R,8R,9R,10S,13S,14S,16R,17S)-17-Acetyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-16-carbonitrile (120 mg, 0.349 mmol) was dissolved in methanol (3 mL). Liquid bromine (83 mg, 0.524 mmol) and a drop of hydrogen bromide were added, and then the reaction solution was stirred at room temperature for 5 hours. Water (30 mL) was added, and then 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 to obtain (3R,5R,8R,9R,10S,13S,14S,16R,17S)-17-(2-bromoacetyl)-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-16-carbonitrile (140 mg, crude product).

    Step 2: Preparation of (3R,5R,8R,9R,10S,13S,14S,16R,17S)-3-hydroxy-3,13-dimethyl-17-(2-(4-(trifluoromethyl)-1H-pyrazol-1-yl)acetyl)hexadecahydro-1H-cyclopenta[a]phenanthrene-16-carbonitrile

    [0855] ##STR00330##

    [0856] A mixture of (3R,5R,8R,9R,10S,13S,14S,16R,17S)-17-(2-bromoacetyl)-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-16-carbonitrile (100 mg, 0.23 mmol), 4-(trifluoromethyl)-1H-pyrazole (63 mg, 0.46 mmol), potassium carbonate (95 mg, 0.69 mmol) and tetrahydrofuran (5 mL) was stirred at room temperature for 16 hours. Water (20 mL) was added, and then 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 crude product was purified by high performance liquid chromatography to obtain (3R,5R,8R,9R,10S,13S,14S,16R,17S)-3-hydroxy-3,13-dimethyl-17-(2-(4-(trifluoromethyl)-1H-pyrazol-1-yl)acetyl)hexadecahydro-1H-cyclopenta[a]phenanthrene-16-carbonitrile (25 mg, yield: 23%).

    [0857] MS m/z (ESI): 478.2[M+H].sup.+.

    [0858] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.76 (s, 1H), 7.74 (s, 1H), 5.01 (dd, J=77.6, 18.0 Hz, 2H), 3.65-3.36 (m, 1H), 2.96 (d, J=8.7 Hz, 1H), 2.18-2.04 (m, 2H), 1.89-1.71 (m, 5H), 1.69-1.60 (m, 5H), 1.46-1.39 (m, 5H), 1.32-1.25 (m, 5H), 1.24-1.03 (m, 3H), 0.65 (s, 3H).

    Example 179

    2-(1-Hydroxy-4-aminoadamantane)-1-((3R,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one (179)

    [0859] ##STR00331##

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

    [0860] ##STR00332##

    [0861] In accordance with Example 5, 2-bromo-1-((3R,5R,8R,10S,13S,14S,17S)-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one was used as the starting material, accordingly, 2-(1-hydroxy-4-aminoadamantane)-1-((3R,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one (7.5 mg, yield: 10.2%) was obtained.

    [0862] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 3.55 (d, J=2.8 Hz, 2H), 2.72 (s, 1H), 2.50 (t, J=8.9 Hz, 1H), 2.29-0.93 (m, 40H), 0.64 (s, 3H).

    Biological Assay and Evaluation

    [0863] 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.

    [0864] 1. GABA.sub.A Receptor Binding Ability Test of the Compound of the Present Invention

    [0865] 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.

    [0866] 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 50 ml Glass Instrument Co., Ltd. Sprague-Dawley Rat Pharmaron Protease inhibitor roche 11836170001 1.1 ml deep 96-well plate, round Axygen P-DW-11-C bottom ULTIMA GOLD Perkin Elmer 77-16061 UNIFILTER-96 GF/B filter plate Perkin Elmer 6005177 Polyethylenimine (PEI), branched Sigma 408727

    1.2 Experimental Procedures

    [0867] 1.2.1 Extraction of Cerebral Cortex Cell Membrane:

    [0868] 1. The cerebral cortex of male Sprague-Dawley rat was isolated.

    [0869] 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.

    [0870] 3. The mixture was centrifuged at 1500 g, 4° C. for 10 minutes, and the supernatant was collected.

    [0871] 4. The mixture was centrifuged at 20000 g, 4° C. for 30 minutes, and the supernatant was discarded.

    [0872] 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 by a glass tissue homogenizer.

    [0873] 6. The mixture was centrifuged at 10000 g, 4° C. for 10 minutes, and the supernatant was discarded.

    [0874] 7. Steps 5 and 6 were repeated three times.

    [0875] 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.

    [0876] 9. The protein concentration was measured by the bicinchoninic acid (BCA) method.

    [0877] 1.2.2 .sup.35S-TBPS binding assay

    [0878] 1. 230 μL of PBS was added to each well of a well plate with 1.1 ml volume.

    [0879] 2. 60 μL of the cerebral cortex cell membrane (5 μg/μL) solution was added to each well, and the mixture was mixed well.

    [0880] 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 μM, 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.

    [0881] 4. GABA was added at a final concentration of 5 μM, 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.

    [0882] 5. .sup.35S-TBPS was added at a final concentration of 2 nM. The concentration of isotope mother solution was 9.7 μM. After dilution with PBS for 100 times, 6 μL of the diluted isotope solution was added to each well.

    [0883] 6. The plate was incubated at 4° C. for 20 hours.

    [0884] 7. The FilterMate GF/C plate was pre-treated with 0.5% PEI, and incubated at 4° C. for 1 hour.

    [0885] 8. The FilterMate GF/C plate was washed with Universal Harvester twice, 50 ml PBS each time.

    [0886] 9. The reaction solution was transferred to the GF/C plate, and each well was washed 4 times with 900 μL of PBS.

    [0887] 10. The washed GF/C plate was placed at 55° C. and dried for 10 minutes.

    [0888] 11. 40 μL of scintillation solution was added to each well, and the CPM value was read with TopCount.

    [0889] 1.2.3 Experimental Data Processing Method:

    [0890] 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)

    [0891] 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)*HillSlope)),

    [0892] wherein:

    [0893] X represents the log of compound concentration,

    [0894] Y represents the % Inhibition.

    [0895] The effect of the compound of the present invention on the TBPS binding activity was determined by the above test, and the measured IC.sub.50 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 Example .sup.35S-TBPS bindng test No. (nM)  1 15.0  2 24.3  3 14.9  5 13.5  6 3.1  7 14.7  8 42  9 21.3  13 4.6  18 6.4  33 18.3  34 28.1  37A 15.4  37B 15.4  41 22.7  42 38.3  46 28.7  51 5.0  52 65  53 12.3  54A 11.8  54B 11.8  59 6.2  60 8.2  62 5.4  63 6.1  64 8.6  69 7.6  71 7.5  91 9.6  92 10.8  93A 3.0  93B 3.0  94 10.2  95 34.1  97 30.2  98 37.8 101 11.4 102 65 103 10.2 121 18.3 122 46.0 125 30.7 126 4.9 127 6.1 128 15.8 130 4.2 131 8.0 132 24.6 133 17.8 134 6.7 135 4.3 136 26.5 137 16.2 138 25.2 139 27.0 140 33.1 141 23.9 142 16.2 143 28.5 144 18.6 145 16.9 146 21.4 147 24.4 149 25.6 150 8.8 151 26.2 166 38.4

    [0896] Conclusion: The compounds of the examples of the present invention have a significant inhibitory effect on the TBPS binding activity.

    [0897] II. Pharmacokinetic Assay in Balb/c Mice

    [0898] 1. Test Objective:

    [0899] Balb/c mice were used as test animals. The pharmacokinetic behavior in mice (plasma and brain tissue) of the compounds of Examples 2, 3, 5, 6, 9, 13, 59, 60, 61, 63, 71-74, 81, 103, 130, 134, 135, 137, 138, 140, 141, 143, 145 and 146 orally administered at a dose of 5 mg/kg was studied.

    [0900] 2. Test Protocol

    [0901] 2.1 Test Compounds:

    [0902] Compounds of Examples 59, 60, 61, 63, 71-74, 81, 103, 130, 134, 135, 137, 138, 140, 141, 143, 145 and 146 of the present invention, prepared by the applicant.

    [0903] 2.2 Test Animals:

    [0904] Male Balb/c mice were purchased from Shanghai Jiesijie Laboratory Animal Co., LTD, with Certificate No.: SCXK (Shanghai) 2013-0006 N0.311620400001794.

    [0905] 2.3 Administration:

    [0906] Each group had 24 male Balb/c mice. After an overnight fast, Balb/c mice were administered p.o. with the test compound at an administration dose of 5 mg/kg and an administration volume of 10 mL/kg.

    [0907] 2.4 Sample Collection:

    [0908] 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.

    [0909] 2.5 Sample Processing:

    [0910] 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.

    [0911] 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.

    [0912] 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.

    [0913] 2.6 Liquid Chromatography Analysis [0914] Liquid chromatography condition: Shimadzu LC-20AD pump. [0915] Chromatographic column: Agilent ZORBAX XDB-C18 (50×2.1 mm, 3.5 μm); [0916] Mobile phase: Eluent A was 0.1% formic acid in water, and Eluent B was acetonitrile. [0917] Flow rate: 0.4 mL/min [0918] 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

    [0919] 3. Test Results and Analysis

    [0920] 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) Peak Plasma Area under Area under Mean time concentration curve curve residence Example t.sub.max C.sub.max AUC.sub.0-t AUC.sub.0-∞ Half-life time No. (ng/mL) (ng/mL) (ng/mL × h) (ng/mL × h) t.sub.1/2(h) MRT(h) 2 plasma 0.5 1099.3 1360.5 1374.2 0.54 1.21 2 brain 0.5 636.7 839.7 913.0 2.84 2.39 tissue 3 plasma 0.5 673.3 569.7 573.8 0.50 1.01 3 brain 0.5 690.3 718.9 721.8 0.50 1.10 tissue 5 plasma 0.5 461.0 1241.5 1254.2 5.12 4.80 5 brain 0.5 1406.3 2303.0 3067.4 4.72 5.53 tissue 6 plasma 0.5 219.0 409.0 483.8 3.19 4.03 6 brain 0.5 464.0 917.2 964.3 1.90 2.40 tissue 9 plasma 0.5 663.7 774.9 778.0 0.9 1.1 9 brain 0.5 605.3 677.0 679.9 0.5 0.9 tissue 13 plasma 1.0 1210 5057.2 5065.8 2.5 3.6 13 brain 1.0 1060.0 4731.4 4744.7 2.5 3.9 tissue 59 plasma 0.5 553.7 1305.0 1316.9 2.99 4.15 59 brain 1.0 678.0 2642.7 2680.6 3.18 4.81 tissue 60 plasma 0.5 719.7 1704.9 1772.1 1.64 1.43 60 brain 1.0 998.0 2403.0 2498.4 2.37 2.35 tissue 61 plasma 0.5 524.7 588.5 604.6 3.27 1.48 61 brain 0.5 710.7 657.1 676.0 3.95 1.41 tissue 63 plasma 0.5 335.3 599 604.3 2.58 2.42 63 brain 0.5 486 602.6 617.9 0.72 1.21 tissue 71 plasma 1.0 508.3 1577.3 1758.8 2.04 3.50 71 brain 1.0 382.7 1127.8 1275.4 2.00 3.66 tissue 72 plasma 0.5 1146.3 2967.0 2972.0 2.79 3.71 72 brain 0.5 723.7 2051.0 2237.3 2.12 3.17 tissue 73 plasma 0.5 1303.3 2430.5 2482.0 1.40 2.06 73 brain 0.5 635.7 1098.1 1117.6 1.31 1.91 tissue 74 plasma 0.5 2136.7 7156.4 8601.3 3.06 4.59 74 brain 1.0 1523.3 5846.2 6511.2 2.28 3.82 tissue 81 plasma 1.0 1146.7 4643.8 5922.3 2.64 4.96 81 brain 1.0 296.2 1439.7 2234.7 5.59 7.97 tissue 103 plasma 1.0 386 1034.8 1060.9 1.19 2.12 103 brain 1.0 626.3 1676.2 1706.2 1.12 2.07 tissue 130 plasma 0.5 307.3 1391.8 1560 2.21 3.83 130 brain 0.5 563.2 2308.8 2625.8 2.49 3.88 tissue 134 plasma 0.5 1750.0 4627.3 5132.2 1.78 3.31 134 brain 1.0 892.0 3205.7 3501.3 1.59 3.22 tissue 135 plasma 2.0 640.3 4103.8 4110.3 2.06 4.38 135 brain 2.0 724.0 3736.7 4450.7 2.82 4.71 tissue 137 plasma 1.0 762.7 2785.0 3792.4 3.85 5.88 137 brain 1.0 613.0 2126.5 3162.6 6.02 7.58 tissue 138 plasma 0.5 432.0 661.7 729.8 1.66 2.83 138 brain 0.5 314.0 772.7 934.8 1.47 2.38 tissue 140 plasma 0.5 2483.3 5982.0 6106.9 1.19 2.22 140 brain 0.5 1738.0 4327.1 4539.1 1.21 2.10 tissue 141 plasma 0.5 1633.3 3545.3 3634.6 1.35 2.55 141 brain 0.5 1048.0 2153.2 2251.2 1.68 2.68 tissue 143 plasma 0.5 1650.0 6287.8 6492.4 1.70 3.08 143 brain 2.0 812.0 8818.0 9215.1 3.95 7.81 tissue 145 plasma 1.0 2986.7 13411.8 13415.2 1.75 3.47 145 brain 1.0 1480.0 4821.6 5273.3 2.09 3.40 tissue 146 plasma 1.0 2086.7 7785.5 8000.6 1.45 2.97 146 brain 1.0 1966.0 8677.8 12488.1 4.66 6.73 tissue

    [0921] It can be seen from the results of the pharmacokinetic test of mice in the table that the compounds of the examples of the present invention showed good metabolic properties, and both the exposure amount AUC and the maximum blood drug concentration C.sub.max performed well.

    [0922] III. In Vivo Pharmacodynamic Test in the Forced Swimming Model in Mice

    [0923] 3.1 Experimental Objective

    [0924] The antidepressant effect of the compound was evaluated by the forced swimming model in mice.

    [0925] 3.2 Main Instruments and Reagents of the Experiment

    [0926] 3.2.1 Instruments

    [0927] Forced swimming device (JLBehv-FSC-4, Shanghai Jiliang Software Technology Co., Ltd.).

    [0928] 3.2.2 Reagents

    [0929] Sodium carboxymethyl cellulose (CMC-Na, SLBV9664, Sigma)

    [0930] Tween 80 (BCBV8843, Sigma)

    [0931] 3.2.3 Test Compounds

    [0932] Compounds of Example 2, Example 3, Example 5, Example 6, Example 9, Example 13, Examples 59-63, Examples 71-74, Example 103, Example 135, Example 137, Example 145 and Example 146 of the present invention, prepared by the applicant.

    [0933] 3.3 Experimental Procedures

    [0934] 3.3.1 Adaptation:

    [0935] Male ICR mice (25-35 g) were adapted in the test environment for 3 days before the forced swimming test.

    [0936] 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 administered intragastrically according to the Tmax thereof in the brain in mice pharmacokinetic test as follows:

    [0937] 1) Model group (0.5% CMC-Na-1% Tween 80 solution, p.o., 10 mL/kg);

    [0938] 2) Compounds of Example 2, Example 3, Example 5, Example 6, Example 9, Examples 59-63, Examples 71-73, Example 103, Example 135, Example 137, Example 145 and Example 146 (10 mg/kg. p.o., 10 mL/kg); Example 13 and Example 74 (5 mg/kg, p.o., 5 mL/kg).

    [0939] When being administered, the compounds of each example were suspended in 0.5% CMC-Na+1% Tween 80 solution to the desired concentration.

    [0940] 3.3.2 Forced Swimming Test:

    [0941] 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.

    [0942] 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.

    [0943] 3.4 Data Analysis

    [0944] Floating time percentage=100*floating time/240s.

    [0945] 3.5 Test Data:

    TABLE-US-00005 Dose Mean Mean Example No. (mpk) (immobility, s) (immobility, %) Vehicle / 163.70 68.22 Example 2 10 130.22 54.26 Example 3 10 68.39 28.50 Example 5 10 143.81 59.93 Example 13 5 138.22 57.60 Example 60 10 84.90 35.30 Example 61 10 85.8 35.75 Example 71 10 134.21 55.92 Example 72 10 85.77 35.74 Example 73 10 70.96 29.57 Example 74 5 91.21 38.00 Example 137 10 88.61 36.92 Example 145 5 73.72 30.72 Example 146 5 80.5 33.54

    [0946] 3.6 Test Results

    [0947] 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.

    [0948] The immobility time during the latter four minutes of the compounds of Example 3, Example 60, Example 61, Example 72, Example 73, Example 137 and Example 146 was significantly different compared with that of the model group.

    [0949] IV. In Vivo Pharmacodynamic Test in the PTZ-Induced Epilepsy Model in Mice

    [0950] 4.1 Test Objective

    [0951] The PTZ-induced epilepsy model in CD-1 mice was established, and the antiepileptic effect of the compounds of Example 3, Example 60, Example 61 and Example 74 was evaluated using this model.

    [0952] 4.2 Test method

    [0953] 4.2.1 Test animals

    [0954] 50 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.

    [0955] The mice were randomly grouped for the test on the test day.

    [0956] 4.2.2 Test Compounds

    [0957] Compounds of Example 3, Example 60, Example 61 and Example 74 (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 pentylene- P6500 SLBD3876V White Sigma 25 g 100% −20° C. tetrazol crystal refrigeration (PTZ) Sodium 9004-32-4 LAB0R36 White Beijing J&K 100 G 800 cps Room carboxy- solid Scientific temperature/ methyl Co., Ltd. dry/in cellulose the dark Tween-80 9005-65-6 P1279207 Transparent GENERAL- 500 mL 100% Room liquid REAGENT ® temperature/ dry Hydroxy- 19184C OP1901A White Seebio 500 g ≥98%  2-8° C. propyl powder Biotech refrigeration β-cyclodextrin 0.9% H37022749 H18010314 Transparent Shandong 500 mL 100% Room sodium liquid Hualu temperature/ chloride Pharmaceutical dry injection Co., Ltd.

    [0958] 4.2.1 Test Equipments [0959] 1 ml sterile disposable syringe with needle (purchased from Zhejiang Kangdelai Medical Devices Co., Ltd.) [0960] Pipette: Eppendorf Research Plus (100-1000 μL) [0961] Vortex mixer: Kylin-Bell Vortex 5 [0962] Ultrasonic instrument: JL-360 ultrasonic cleaner [0963] Balance: METTLER TOLEDO XS204 precision balance [0964] Balance: METTLER TOLEDO XS6002S electronic balance [0965] Plexiglass box: 25 cm length*15 cm width*15 cm hight with one opaque side wall, custom made by Suzhou Fengshi Laboratory Animal Equipment Co., Ltd [0966] 3-channel timer: Oregon/Model NO. WB-388.

    [0967] 4.2.2 Test Animal Grouping

    [0968] 1) Vehicle/PTZ: 0.5% CMC-Na+1% Tween-80 (10 ml/kg, p.o.), administered 0.5 hr before the PTZ administration; PTZ (120 ml/kg, s.c.), administered before the test;

    [0969] 2) 3 mg/kg of the compounds of Examples/PTZ: the compounds of Example 3, Example 60, Example 61 and Example 74 (3 mg/kg, 10 ml/kg, p.o.), administered 0.5 hr before the PTZ administration; PTZ (120 ml/kg, s.c.), administered before the test.

    [0970] 4.3 Experimental Procedures

    [0971] 4.3.1 Solvent Formulation

    [0972] 1) 0.5% CMC-Na+1% Tween-80 (administration volume: 10 mL/kg):

    [0973] 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.

    [0974] 2) 30% hydroxypropyl-β-cyclodextrin:

    [0975] 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.

    [0976] 4.3.2 Test Compound Formulation

    [0977] 1) 12 mg/mL PTZ (dose: 120 mg/kg; administration volume: 10 mL/kg):

    [0978] 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).

    [0979] 2) 0.3 mg/mL of the compounds of Example 5 or Example 23 (dose: 3 mg/kg; administration volume: 10 mL/kg):

    [0980] 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).

    [0981] 4.3.3 Test Method

    [0982] 1) The test animals were transferred to the operating room to adapt to the environment 1 hour before the test;

    [0983] 2) The animals were randomly grouped, marked and weighed;

    [0984] 3) The compounds of Example 3, Example 60, Example 61 and Example 74 were administered respectively 1 hour before the PTZ administration, or 0.5% CMC-Na+1% Tween-80, the compounds of Example 3, Example 60, Example 61 and Example 74 were administered respectively 0.5 hour before the PTZ administration;

    [0985] 4) PTZ (120 mg/kg) was administrated subcutaneously before the test observation, and this time point was recorded as the observation start point;

    [0986] 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. [0987] Clonic seizure: generalized clonic seizure in animals lasts for more than 3 seconds, and is accompanied by a fall; [0988] Tonic seizure: the limbs straightens 90° to the body;

    [0989] 6) The possible side effects induced by the drug after the administration were observed and recorded, which can be divided into four levels: [0990] None: normal [0991] Mild sedation [0992] Moderate sedation [0993] Severe sedation

    [0994] 7) The test was carried out from 12:00 am to 16:30 μm.

    [0995] 4.4 Adaptation to the Environment

    [0996] The test animals were transferred to the operating room to adapt to the environment 1 hour before the test.

    [0997] 4.5 Grouping and Administration

    [0998] The mice were randomly grouped, marked and weighed; 10 mice per group. The test compound was administered orally at an administration volume of 10 mL/kg 30-60 minutes before the PTZ administration.

    [0999] 4.6 PTZ Modeling and Testing

    [1000] 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.

    [1001] 4.7 Data Analysis

    [1002] All measurement data were expressed as Mean±SEM, and analysed with Prism 6.0 statistical software.

    [1003] 4.7 Test Data:

    TABLE-US-00007 Incubation Incubation period of the Number of Time when period of the Number generalized generalized the animal clonic seizure of clonic tonic seizure tonic died Mortality Example Dose (sec) seizures (sec) seizures (sec) rate 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%  3 3 902.9 ± 200.8 1.3 ± 0.3 1736.0 ± 63.2  0.1 ± 0.1 1739.8 ± 60.2  10% 60 3 1308.1 ± 170.1  0.5 ± 0.2 1800.0 ± 0.0  0.0 ± 0.0 1800.0 ± 0.0   0% 61 3 841.4 ± 179.8 1.9 ± 0.4 1497.4 ± 124.3 0.5 ± 0.2 1573.1 ± 117.9 40% 74 3 635.4 ± 149.9 1.8 ± 0.3 1506.8 ± 149.8 0.3 ± 0.2 1618.1 ± 121.3 30%

    [1004] 4.9 Test Results

    [1005] 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%-100% of animals from death, significantly prolong the incubation period of death, and have a good antiepileptic effect.