Prodrugs of neuroactive steroids

Abstract

The present application relates to novel compounds that are prodrugs of brexolone, ganaxolone and zuranolone; pharmaceutical compositions comprising one or more compounds and salts thereof disclosed herein, and pharmaceutically acceptable excipients; and compounds and salts thereof disclosed herein for use in treating GABA-related diseases in mammals, especially humans. A Use in diseases or conditions related to receptor function, such as major depressive disorder (MDD) and postpartum depression (PPD).

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of and priority to U.S. Provisional Application No. 62 / 982,717, filed on February 27, 2020; the provisional application is incorporated herein by reference in its entirety. Technical Field

[0003] The present application relates to novel compounds that are prodrugs of brexanolone, ganaxolone and zuranolone; pharmaceutical compositions comprising one or more of the disclosed compounds and salts thereof, and a pharmaceutically acceptable excipient; and the disclosed compounds and salts thereof for use in treating GABA-related diseases in mammals, especially humans. A Use in diseases and conditions associated with receptor function, such as major depressive disorder (MDD) and postpartum depression (PPD). Background Art

[0004] Neuroactive steroids (NAS) include neurosteroids (NS) that are synthesized de novo in the brain as cholesterol metabolites, as well as steroids synthesized in the adrenal glands and gonads. The main target of NAS is the inhibitory gamma-aminobutyric acid (GABA) system. GABA is the main inhibitory neurotransmitter in the nervous system and activates two types of receptors GABA A and GABA B GABA works by binding to GABA receptors. A Receptor binding regulates neuronal excitability and rapid mood changes, and can affect a wide range of brain circuits and conditions related to GABA function, which are central to multiple behavioral states, such as anxiety levels, panic, stress responses, seizures, sleep, vigilance, and memory.

[0005] Given its critical role in neuronal circuit function, GABA A The receptor is the target of many clinically relevant drugs. Brenosolone (also known as allopregnanolone), ganaxolone, and zolanolide are GABA A A known positive allosteric modulator (PAM) of the receptor, which prolongs the GABA A Allopregnanolone (chemical name brexanolone) is an endogenous hormone produced from progesterone through the sequential action of 5α-reductase and 3α-hydroxysteroid oxidoreductase (3α-HSOR), while ganaxolone and zulresso are synthetic analogs of allopregnanolone designed to improve its physicochemical properties and overcome its metabolic propensity. Zulresso TMZulresso is a soluble intravenous formulation of allopregnanolone, approved by the FDA on March 19, 2019 for the treatment of PPD. Zulresso has demonstrated unique therapeutic effects, including rapid onset of action, high remission rates, and sustained effects after treatment ends. However, there are limitations to the administration of Zulresso, which requires continuous intravenous infusion for 60 hours. In addition, loss of consciousness has been observed in clinical studies, which is partly attributed to the sudden change in brexanolone concentration during the infusion. Although ganaxolone has improved metabolic stability, ganaxolone needs to be administered at high doses when taken orally, and has limited bioavailability. For some diseases, such as the treatment of PPD, ganaxolone also requires continuous intravenous infusion.

[0006] Therefore, there is still a need to develop drugs with improved pharmaceutical or pharmacokinetic properties that can function as GABA A New compounds that are modulators of receptors. Summary of the invention

[0007] In one aspect, the present disclosure provides a compound of formula (I):

[0008]

[0009] or a pharmaceutically acceptable salt thereof, wherein:

[0010] R 1a and R 1b are each independently hydrogen or methyl;

[0011] Q is methyl or

[0012] L is selected from the group consisting of absence, alkyl, -O-, and -N(R 2 )-groups composed of;

[0013] W is selected from the group consisting of absence, alkyl, and -O-;

[0014] Y is selected from the group consisting of alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, saturated or unsaturated cycloalkyl, saturated or unsaturated heterocyclyl, aryl, heteroaryl, -OC(O)OR 3 、-OC(O)R 4 and –NR 5 R 6 wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, saturated or unsaturated cycloalkyl, saturated or unsaturated heterocyclyl, aryl and heteroaryl are optionally substituted with one or more groups independently selected from the group consisting of oxo, halogen, cyano, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, saturated or unsaturated cycloalkyl, saturated or unsaturated heterocyclyl, aryl and heteroaryl;

[0015] R2 , R 3 , R 4 and R 5 each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, saturated or unsaturated cycloalkyl, saturated or unsaturated heterocyclyl, aryl and heteroaryl, wherein said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, saturated or unsaturated cycloalkyl, saturated or unsaturated heterocyclyl, aryl and heteroaryl are optionally substituted with one or more groups independently selected from the group consisting of oxo, halogen, cyano, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, saturated or unsaturated cycloalkyl, saturated or unsaturated heterocyclyl, aryl and heteroaryl;

[0016] R 6 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, and -C(O)R 7 ;and

[0017] R 7 selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, saturated or unsaturated cycloalkyl, saturated or unsaturated heterocyclyl, aryl and heteroaryl, wherein said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, saturated or unsaturated cycloalkyl, saturated or unsaturated heterocyclyl, aryl and heteroaryl are optionally substituted with one or more groups independently selected from the group consisting of oxo, halogen, cyano, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, saturated or unsaturated cycloalkyl, saturated or unsaturated heterocyclyl, aryl and heteroaryl, provided that when L is —O— or —N(R 2 )-, W is not -O-, when W is -O-, Y is not -NR 5 NR 6 , and when W is -O-, Y is -C(O)OR 3 or -C(O)R 4 .

[0018] In another aspect, provided is a compound of formula (Ia):

[0019]

[0020] or a pharmaceutically acceptable salt thereof, wherein R 1b and Y are as defined in formula (I).

[0021] In another aspect, provided is a compound of formula (Ib):

[0022]

[0023] or a pharmaceutically acceptable salt thereof, wherein R 1b, W and Y are as defined in the above formula (I), and n is an integer from 1 to 10.

[0024] In another aspect, provided is a compound of formula (Ic-1):

[0025]

[0026] or a pharmaceutically acceptable salt thereof, wherein R 1b , W and Y are as defined in formula (I).

[0027] In another aspect, provided is a compound of formula (Ic-2):

[0028]

[0029] or a pharmaceutically acceptable salt thereof, wherein W and Y are as defined in formula (I).

[0030] In another aspect, provided is a compound of formula (Id-1):

[0031]

[0032] or a pharmaceutically acceptable salt thereof, wherein R 1b , R 2 , W and Y are as defined in formula (I).

[0033] In another aspect, provided is a compound of formula (Id-2):

[0034]

[0035] or a pharmaceutically acceptable salt thereof, wherein R 2 , W and Y are as defined in formula (I).

[0036] On the other hand, a pharmaceutical composition is provided, comprising one or more compounds of Formula (I), Formula (Ia), Formula (Ib), Formula (Ic-1), Formula (Ic-2), Formula (Id-1), Formula (Id-2) or pharmaceutically acceptable salts thereof, and at least one pharmaceutically acceptable excipient.

[0037] In another aspect, a method for treating a subject in need thereof with GABA is provided. A A method for treating a disease or condition associated with receptor function, the method comprising administering to a subject a therapeutically effective amount of a compound of Formula (I), Formula (Ia), Formula (Ib), Formula (Ic-1), Formula (Ic-2), Formula (Id-1), or Formula (Id-2), or a pharmaceutically acceptable salt thereof.

[0038] In another aspect, a method for treating a subject in need thereof with GABA is provided. AA method for treating a disease or condition associated with receptor function, the method comprising administering to a subject a therapeutically effective amount of a composition comprising a compound of formula (I), formula (Ia), formula (Ib), formula (Ic-1), formula (Ic-2), formula (Id-1), or formula (Id-2), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0039] In another aspect, provided is a compound of formula (I), formula (Ia), formula (Ib), formula (Ic-1), formula (Ic-2), formula (Id-1), formula (Id-2) or a pharmaceutically acceptable salt thereof for use in treating GABA A Diseases or conditions associated with receptor function.

[0040] In another aspect, a compound of formula (I), formula (Ia), formula (Ib), formula (Ic-1), formula (Ic-2), formula (Id-1), formula (Id-2) or a pharmaceutically acceptable salt thereof is provided for use in the manufacture of a compound for treating GABA A Use in medicaments for diseases or conditions associated with receptor function.

[0041] On the other hand, provided is a compound of Formula (I), Formula (Ia), Formula (Ib), Formula (Ic-1), Formula (Ic-2), Formula (Id-1), Formula (Id-2) or a pharmaceutically acceptable salt thereof, which is administered simultaneously, separately or sequentially with one or more additional agents.

[0042] In another aspect, there is provided a method for treating A A kit for treating a disease or condition associated with receptor function, the kit comprising a compound of Formula (I), (Ia), (Ib), (Ic-1), (Ic-2), (Id-1), (Id-2) or a pharmaceutically acceptable salt thereof, a container, and an optional package insert or label indicating treatment. The kit may also comprise a second compound or formulation comprising a second agent that can be used to treat the disease or condition. DETAILED DESCRIPTION

[0043] Reference will now be made in detail to certain embodiments of the present disclosure, examples of which are illustrated in the accompanying structures and formulas. Although the present invention will be described in conjunction with the enumerated embodiments, it should be understood that they are not intended to limit the present invention to those embodiments. On the contrary, the present disclosure is intended to cover all alternatives, modifications and equivalents, which may be included within the scope of the present invention as defined by the claims. Those skilled in the art will recognize many methods and materials similar or equivalent to the methods and materials described herein, which can be used in the practice of the present invention. The present invention is by no means limited to the methods and materials described. If one or more incorporated documents and similar materials are different or contradictory from the present application, including but not limited to defined terms, term usage, described technology, etc., the present application shall prevail.

[0044] It should be understood that certain features of the present disclosure described in the context of separate embodiments for the sake of clarity may also be provided in combination with a single embodiment. Conversely, various features of the present disclosure described in the context of a single embodiment for the sake of brevity may also be provided separately or in any suitable sub-combination.

[0045] definition

[0046] The definitions of specific functional groups and chemical terms are described in more detail below. For the purposes of this disclosure, chemical elements are identified according to the CAS version of the periodic table, Handbook of Chemistry and Physics, 75th edition, inside cover, and specific functional groups are generally defined as described therein. In addition, the general principles of organic chemistry and specific functional moieties and reactivity are described in Organic Chemistry, Thomas Sorrell, 2nd edition, University Science Books, Sausalito, 2006; Smith and March March's Advanced Organic Chemistry, 6th edition, John Wiley & Sons, Inc., New York, 2007; Larock, Comprehensive Organic Transformations, 3rd edition, VCH Publishers, Inc., New York, 2018; Carruthers, Some Modern Methods of Organic Synthesis, 4th edition, Cambridge University Press, Cambridge, 2004; The entire contents of each of them are incorporated herein by reference.

[0047] Linking substituents are described in various places of this disclosure. Where a structure clearly requires a linking group, the Markush variables listed for the group are understood to be linking groups, and the group to be linked is linked to the linking group at any position as long as valence permits. For example, if a structure requires a linking group and the Markush group definition for the variable lists "alkyl", it is understood that "alkyl" represents a linking alkylene group.

[0048] When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent may be bonded to any atom in the ring. When substituents are listed without indicating the atom via which such substituent is bonded to the rest of the compound of a given formula, then such substituent may be bonded via any atom in such formula. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0049] When any variable (such as R i ) occurs more than once in any constituent or formula of a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be comprised of 0-2 R i Partially substituted, the group may optionally be substituted with up to two R i Partially substituted, and R i In each occurrence, independently selected from R i Additionally, combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0050] As will be understood by one of ordinary skill in the art, use of the term "about" indicates a value slightly exceeding the recited value, ie, plus or minus 0.1% to 10%.

[0051] As used herein, the term “C i -C j " represents a range of carbon atoms, wherein i and j are integers, and the range of carbon atoms includes the endpoints (i.e., i and j) and every integer point therebetween, and wherein j is greater than i. For example, C 1 -C 6 In some embodiments, the term "C 1 -C 12 ” means 1 to 12, especially 1 to 10, especially 1 to 8, especially 1 to 6, especially 1 to 5, especially 1 to 4, especially 1 to 3 or especially 1 to 2 carbon atoms.

[0052] As used herein, the term "alkyl", whether used as part of another term or independently, refers to a saturated straight or branched chain hydrocarbon group, which may be optionally substituted independently with one or more substituents as described below. i-j Alkyl (or "C i -C j "alkyl" refers to an alkyl group having i to j carbon atoms. In some embodiments, the alkyl group contains 1 to 12 carbon atoms. In some embodiments, the alkyl group contains 1 to 11 carbon atoms. In some embodiments, the alkyl group contains 1 to 11 carbon atoms, 1 to 10 carbon atoms, 1 to 9 carbon atoms, 1 to 8 carbon atoms, 1 to 7 carbon atoms, 1 to 6 carbon atoms, 1 to 5 carbon atoms, 1 to 4 carbon atoms, 1 to 3 carbon atoms, or 1 to 2 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl, ethyl, 1-propyl (n-propyl), 2-propyl (isopropyl), 1-butyl (n-butyl), , 2-methyl-1-propyl (isobutyl), 2-butyl (sec-butyl), 2-methyl-2-propyl (tert-butyl), 1-pentyl (n-pentyl), 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, 3,3-dimethyl-2-butyl, 1-heptyl, 1-octyl, etc. "C 1-12 Examples of "alkyl" include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, and dodecyl. 1-6 Examples of "alkyl" are methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, 3,3-dimethyl-2-butyl, and the like.

[0053] The alkyl group may be further substituted with substituents which independently replace one or more hydrogen atoms on one or more carbons of the alkyl group. Examples of such substituents may include, but are not limited to, acyl, alkyl, alkenyl, alkynyl, halogen, hydroxy, alkoxy, haloalkyl, haloalkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, phosphate, phosphonate, phosphite, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), amido (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfonyl, sulfonate, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, nitro, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety. Alkenyl, alkynyl, saturated or partially unsaturated cycloalkyl, heteroalkyl, heterocyclyl, arylalkyl, heteroarylalkyl, heterocyclylalkyl, cycloalkylalkyl, aryl and heteroaryl groups as described below may also be similarly substituted.

[0054] As used herein, the term "alkenyl", whether as part of another term or used independently, refers to a straight or branched hydrocarbon group having at least one carbon-carbon double bond, which may be optionally substituted independently by one or more substituents described herein, and includes groups with "cis" and "trans" orientations, or "E" and "Z" orientations. In some embodiments, the alkenyl group contains 2 to 12 carbon atoms. In some embodiments, the alkenyl group contains 2 to 11 carbon atoms. In some embodiments, the alkenyl group contains 2 to 11 carbon atoms, 2 to 10 carbon atoms, 2 to 9 carbon atoms, 2 to 8 carbon atoms, 2 to 7 carbon atoms, 2 to 6 carbon atoms, 2 to 5 carbon atoms, 2 to 4 carbon atoms, 2 to 3 carbon atoms, and in some embodiments, the alkenyl group contains 2 carbon atoms. Examples of alkenyl groups include, but are not limited to, vinyl (ethylenyl / vinyl), propenyl, butenyl, pentenyl, 1-methyl-2butene-1-yl, 5-hexenyl, etc.

[0055] As used herein, the term "alkynyl", whether as part of another term or used independently, refers to a straight or branched hydrocarbon group having at least one carbon-carbon triple bond, which may be optionally independently substituted with one or more substituents described herein. In some embodiments, alkenyl contains 2 to 12 carbon atoms. In some embodiments, alkynyl contains 2 to 11 carbon atoms. In some embodiments, alkynyl contains 2 to 11 carbon atoms, 2 to 10 carbon atoms, 2 to 9 carbon atoms, 2 to 8 carbon atoms, 2 to 7 carbon atoms, 2 to 6 carbon atoms, 2 to 5 carbon atoms, 2 to 4 carbon atoms, 2 to 3 carbon atoms, and in some embodiments, alkynyl contains 2 carbon atoms. Examples of alkynyl include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, etc.

[0056] As used herein, the term "alkoxy" whether used as part of another term or by itself, refers to an alkyl group as previously defined attached to the parent molecular group through an oxygen atom. i-j Alkoxy (or "C i -C j In some embodiments, the alkoxy group contains 1 to 10 carbon atoms. In some embodiments, the alkoxy group contains 1 to 9 carbon atoms. In some embodiments, the alkoxy group contains 1 to 8 carbon atoms, 1 to 7 carbon atoms, 1 to 6 carbon atoms, 1 to 5 carbon atoms, 1 to 4 carbon atoms, 1 to 3 carbon atoms, or 1 to 2 carbon atoms. "C 1-6 Examples of "alkoxy" include, but are not limited to, methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), tert-butoxy, neopentoxy, n-hexyloxy, and the like.

[0057] As used herein, the term "aryl", whether used as part of another term or independently, refers to monocyclic and polycyclic systems having a total of 5 to 20 ring members, wherein at least one ring in the system is an aromatic ring and wherein each ring in the system contains 3 to 12 ring members. Examples of "aryl" include, but are not limited to, phenyl, biphenyl, naphthyl, anthracenyl, etc., which may carry one or more substituents. Also included within the scope of the term "aryl", as used herein, are groups in which an aromatic ring is fused to one or more additional rings. In the case of a polycyclic system, only one ring needs to be an aromatic ring (e.g., 2,3-dihydroindole), although all rings can be aromatic rings (e.g., quinoline). The second ring may also be fused or bridged. Examples of polycyclic aryls include, but are not limited to, benzofuranyl, indanyl, phthalimide, naphthimide, phenanthridinyl, or tetrahydronaphthyl, etc. Aryl may be substituted with substituents as described above at one or more ring positions.

[0058] As used herein, the terms "cycloalkyl", "carbocyclyl" and "carbocycle" are interchangeable and, whether used as part of another term or independently, refer to monovalent, saturated, partially unsaturated or fully unsaturated monocyclic and polycyclic ring systems in which all ring atoms are carbon and contain at least three ring-forming carbon atoms. In some embodiments, a cycloalkyl group may contain 3 to 12 ring-forming carbon atoms (C 3- C 12 ), 3 to 10 ring carbon atoms (C 3- C 10 ), 3 to 9 ring carbon atoms (C 3- C 9 ), 3 to 8 ring carbon atoms (C 3- C 8 ), 3 to 7 ring carbon atoms (C 3- C 7 ), 3 to 6 ring carbon atoms (C 3- C 6 ), 3 to 5 ring carbon atoms (C 3- C 5 ), 4 to 12 ring carbon atoms (C 4- C 12 ), 4 to 10 ring carbon atoms (C 4- C 10 ), 4 to 9 ring carbon atoms (C 4- C 9 ), 4 to 8 ring carbon atoms (C 4- C 8 ), 4 to 7 ring carbon atoms (C 4- C 7 ), 4 to 6 ring carbon atoms (C 4- C 6 ), 4 to 5 ring carbon atoms (C 4- C 5 ). The cycloalkyl group may be saturated or unsaturated. The cycloalkyl group may be substituted. In some embodiments, the cycloalkyl group may be a saturated cyclic alkyl group. In some embodiments, the cycloalkyl group may be an unsaturated cyclic alkyl group containing at least one double bond or triple bond in its ring system.

[0059] In some embodiments, the cycloalkyl group may be a saturated or unsaturated monocyclic carbocyclic ring system, examples of which include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, and cyclododecyl.

[0060] In some embodiments, cycloalkyl can be a saturated or unsaturated polycyclic (e.g., bicyclic and tricyclic) carbocyclic system, which can be arranged as a condensed ring, a spirocyclic or a bridged ring system. As used herein, the term "condensed ring" refers to a ring system with two rings sharing two adjacent atoms, the term "spirocyclic" refers to a ring system with two rings connected by a single common atom, and the term "bridged ring" refers to a ring system with two rings sharing three or more atoms. Examples of fused carbocyclic groups include, but are not limited to, naphthyl, benzopyrenyl, anthracenyl, acenaphthenyl, fluorenyl, etc. Examples of spiro carbocyclic groups include, but are not limited to, spiro [5.5] undecyl, spiropentadienyl, spiro [3.6]-decyl, etc. Examples of bridged carbocyclic groups include, but are not limited to, bicyclo[1,1,1]pentenyl, bicyclo[2,2,1]heptenyl, bicyclo[2.2.1]heptenyl, bicyclo[2.2.2]octanyl, bicyclo[3.3.1]nonanyl, bicyclo[3.3.3]undecyl, and the like.

[0061] As used herein, the term "cyano" refers to -CN.

[0062] As used herein, the term "halo" or "halogen" refers to an atom selected from fluorine (or fluoro), chlorine (or chloro), bromine (or bromo) and iodine (or iodo).

[0063] As used herein, the term "heteroalkyl" refers to an alkyl group in which at least one carbon atom is substituted by a heteroatom selected from N, O, S and P. A heteroalkyl group may be a carbon group or a heteroatom group (i.e., a heteroatom may appear in the middle or at the end of the group), and may be optionally substituted independently by one or more substituents described herein. The term "heteroalkyl" includes alkoxy and heteroalkoxy.

[0064] As used herein, the term "heteroalkenyl" refers to an alkenyl group in which at least one carbon atom is substituted with a heteroatom selected from N, O, S and P. The heteroalkenyl group may be a carbon group or a heteroatom group (i.e., the heteroatom may appear in the middle or at the terminal of the group), and may be optionally substituted independently with one or more substituents described herein.

[0065] As used herein, the term "heteroalkynyl" refers to an alkynyl group in which at least one carbon atom is substituted with a heteroatom selected from N, O, S and P. The heteroalkynyl group may be a carbon group or a heteroatom group (i.e., the heteroatom may appear in the middle or at the terminal end of the group), and may be optionally substituted independently with one or more substituents described herein.

[0066] As used herein, the term "heteroatom" refers to nitrogen, oxygen, sulfur, or phosphorus, and includes any oxidized form of the nitrogen or sulfur and any quaternized form of a basic nitrogen.

[0067] As used herein, the term "heteroaryl", whether used as part of another term or independently, refers to an aryl group having one or more heteroatoms, such as one or more heteroatoms selected from the group consisting of N, O and S, in addition to carbon atoms. Examples of heteroaryl groups include, but are not limited to, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, benzofuranyl and pteridinyl. Heteroaryl also includes groups in which a heteroaromatic ring is fused to one or more aryl, alicyclic or heterocyclyl rings, with the attachment base or point of attachment being on the heteroaromatic ring. Non-limiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzothiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolyl, tetrahydroisoquinolyl, and pyrido[2,3-b]-1,4-oxazin-3(4H)-one. In some embodiments, the term "5- to 10-membered heteroaryl" refers to a 5- to 6-membered heteroaryl ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, sulfur, or phosphorus, or an 8- to 10-membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, sulfur, and phosphorus. In certain embodiments, the term "5- to 12-membered heteroaryl" refers to a 5- to 6-membered heteroaryl ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, sulfur, and phosphorus, or an 8- to 12-membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, sulfur, and phosphorus.

[0068] As used herein, the term "heterocycle" or "heterocyclyl" refers to a saturated or unsaturated carbocyclic group, wherein one or more ring atoms are independently selected from heteroatoms of oxygen, sulfur, nitrogen, phosphorus, etc., and the remaining ring atoms are carbon, wherein one or more ring atoms may be optionally independently substituted by one or more substituents. In some embodiments, the heterocyclic group is a saturated heterocyclic group. In some embodiments, the heterocyclic group is an unsaturated heterocyclic group having one or more double bonds in its ring system. In some embodiments, the heterocyclic group may contain any oxidized form of carbon, nitrogen, sulfur or phosphorus, and any quaternized form of basic nitrogen. "Heterocyclic group" also includes groups in which the heterocyclic group is fused to a saturated, partially unsaturated or completely unsaturated (i.e., aromatic) carbocyclic or heterocyclic ring. Where possible, the heterocyclic group may be carbon-connected or nitrogen-connected. In some embodiments, the heterocyclic ring is carbon-connected. In some embodiments, the heterocyclic ring is nitrogen-connected. For example, the group derived from pyrrole may be pyrrole-1-yl (nitrogen-connected) or pyrrole-3-yl (carbon-connected). Furthermore, a group derived from imidazole may be imidazol-1-yl (nitrogen attached) or imidazol-3-yl (carbon attached).

[0069] In some embodiments, the term "3 to 12 membered heterocyclyl" refers to a 3 to 12 membered saturated or partially unsaturated monocyclic or polycyclic heterocyclic ring system having 1 to 3 heteroatoms independently selected from nitrogen, oxygen or sulfur. Condensed rings, spirocyclic rings and bridged ring systems are also included within the scope of this definition. Examples of monocyclic heterocyclyls include, but are not limited to, oxetane, 1,1-dioxothietanylpyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, thiazolyl, piperidinyl, piperazinyl, morpholinyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, pyridonyl, pyrimidonyl, pyrazinonyl, pyrimidonyl, pyridazinonyl, pyrrolidinyl, triazinonyl, etc. Examples of fused heterocyclic groups include, but are not limited to, phenyl fused rings or pyridyl fused rings, such as quinolyl, isoquinolyl, quinoxalinyl, quinolizinyl, quinazolinyl, azaindolyl, pteridinyl, chromenyl, isochromenyl, indolyl, isoindolyl, indolizinyl, indazolyl, purinyl, benzofuranyl, isobenzofuranyl, benzimidazolyl, benzothienyl, benzothiazolyl, carbazolyl, phenazinyl, phenothiazinyl, phenanthridinyl, imidazo[1,2-a]pyridinyl, [1,2,4]triazolo[4,3-a]pyridinyl, [1,2,3]triazolo[4,3-a]pyridinyl, etc. Examples of spiro heterocyclic groups include, but are not limited to, spiropyranyl, spirooxazinyl, etc. Examples of bridged heterocyclic groups include, but are not limited to, morpholinyl, hexamethylenetetramine, 3-azabicyclo[3.1.0]hexane, 8-azabicyclo[3.2.1]octane, 1-azabicyclo[2.2.2]octane, 1,4-diazabicyclo[2.2.2]octane (DABCO), and the like.

[0070] As used herein, the term "hydroxyl" or "hydroxy" refers to an -OH group.

[0071] As used herein, the term "partially unsaturated" refers to a group that includes at least one double or triple bond. The term "partially unsaturated" is intended to include rings having multiple sites of unsaturation, but is not intended to include aromatic (ie, fully unsaturated) moieties.

[0072] As used herein, whether or not the term "optionally" is added in front, the term "substituted" means that one or more hydrogens of the specified part are replaced by suitable substituents. It should be understood that "replacement" or "substituted" includes implicit prerequisites, that is, such substitutions meet the allowed valence of the substituted atom, and the substitution produces a stable or chemically feasible compound, for example, it will not spontaneously undergo a transformation such as rearrangement, cyclization, elimination, etc. Unless otherwise specified, the "optionally substituted" group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure can be substituted by more than one substituent selected from a specified group, the substituent may be the same or different at each position. It will be understood by those skilled in the art that, if appropriate, the substituent itself may be substituted. Unless specifically stated as "unsubstituted", the chemical moieties mentioned herein should be understood to include substituted variants. For example, mentioning an "aryl" group or part implicitly includes substituted and unsubstituted variants.

[0073] Compounds of the Disclosure

[0074] The present disclosure provides novel compounds of formula (I) and pharmaceutically acceptable salts thereof, synthetic methods for preparing the compounds, pharmaceutical compositions containing them, and various uses of the disclosed compounds in treating diseases and conditions.

[0075] In one aspect, the present disclosure provides compounds of formula (I):

[0076]

[0077] or a pharmaceutically acceptable salt thereof, wherein:

[0078] R 1a and R 1b are each independently hydrogen or methyl;

[0079] Q is methyl or

[0080] L is selected from the group consisting of absence, alkyl, -O- and -N(R 2 )-groups composed of;

[0081] W is selected from the group consisting of absence, alkyl and -O-;

[0082] Y is selected from the group consisting of alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, saturated or unsaturated cycloalkyl, saturated or unsaturated heterocyclyl, aryl, heteroaryl, -OC(O)OR 3 、-OC(O)R 4 and-NR 5 R 6wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, saturated or unsaturated cycloalkyl, saturated or unsaturated heterocyclyl, aryl and heteroaryl are optionally substituted with one or more groups independently selected from the group consisting of oxo, halogen, cyano, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, saturated or unsaturated cycloalkyl, saturated or unsaturated heterocyclyl, aryl and heteroaryl;

[0083] R 2 , R 3 , R 4 and R 5 each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, saturated or unsaturated cycloalkyl, saturated or unsaturated heterocyclyl, aryl and heteroaryl, wherein said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, saturated or unsaturated cycloalkyl, saturated or unsaturated heterocyclyl, aryl and heteroaryl are optionally substituted with one or more groups independently selected from the group consisting of oxo, halogen, cyano, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, saturated or unsaturated cycloalkyl, saturated or unsaturated heterocyclyl, aryl and heteroaryl;

[0084] R 6 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, and -C(O)R 7 ;and

[0085] R 7 Selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, saturated or unsaturated cycloalkyl, saturated or unsaturated heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, saturated or unsaturated cycloalkyl, saturated or unsaturated heterocyclyl, aryl and heteroaryl are optionally substituted with one or more groups independently selected from the group consisting of oxo, halogen, cyano, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, saturated or unsaturated cycloalkyl, saturated or unsaturated heterocyclyl, aryl and heteroaryl.

[0086] In some embodiments of Formula (I), when L is -O- or -N(R 2 )-, W is not -O-, when W is -O-, Y is not -NR 5 NR 6 , and when W is -O-, Y is -C(O)OR 3 or -C(O)R 4 In some embodiments, when L is -O- or -N(R 2 )-, W is not -O-. In some embodiments, when W is -O-, Y is not -NR 5 NR6 In some embodiments, when W is -O-, Y is -C(O)OR 3 or -C(O)R 4 .

[0087] In some embodiments, R 1a and R 1b In some embodiments, R 1a and R 1b In some embodiments, R 1a is hydrogen, and R 1b In some embodiments, one R 1a is a methyl group, and R 1b It's hydrogen.

[0088] In some embodiments, Q is methyl. In some embodiments, Q is

[0089] In some embodiments, R 1a and R 1b are hydrogen, and Q is methyl. In some embodiments, R 1a and R 1b are methyl, and Q is methyl. In some embodiments, R 1a is hydrogen, R 1b is a methyl group, and Q is In some embodiments, R 1a is methyl, R 1b is hydrogen, and Q is

[0090] In some embodiments, L is absent. In some embodiments, L is alkyl, such as C 1 -C 12 Alkyl, C 1 -C 11 Alkyl, C 1 -C 10 Alkyl, C 1 -C 9 Alkyl, C 1 -C 8 Alkyl, C 1 -C 7 Alkyl, C 1 -C 6 Alkyl, C 1 -C 5 Alkyl, C 1 -C 4 Alkyl, C 1 -C 3 Alkyl or C 1 -C 2In certain embodiments, L is C 1 -C 7 In certain embodiments, L is C 1 -C 6 In some embodiments, L is -O-. In some embodiments, L is -N(R 2 )-, and R 2 is selected from the group consisting of: hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, and heteroalkynyl. In some embodiments, L is -N(R 2 )-, and R 2 is hydrogen or alkyl. In some embodiments, alkyl is methyl or ethyl. In some embodiments, alkyl is methyl.

[0091] In some embodiments, W is absent. In some embodiments, W is alkyl, such as C 1 -C 12 Alkyl, C 1 -C 11 Alkyl, C 1 -C 10 Alkyl, C 1 -C 9 Alkyl, C 1 -C 8 Alkyl, C 1 -C 7 Alkyl, C 1 -C 6 Alkyl, C 1 -C 5 Alkyl, C 1 -C 4 Alkyl, C 1 -C 3 Alkyl or C 1 -C 2 In certain embodiments, W is C 1 -C 6 In some embodiments, W is -O-.

[0092] In some embodiments, L is absent and W is absent. In some embodiments, L is alkyl and W is absent or is -O-. In certain embodiments, L is C 1 -C 6 alkyl, and W is absent or -O-. In some embodiments, L is C 1 -C 6 In some embodiments, L is -O- and W is absent or is alkyl. In some embodiments, L is -O- and W is alkyl. In some embodiments, L is -O- and W is C 1 -C6 In some embodiments, L is -O-, and W is alkyl. In some embodiments, L is -O-, and W is C 1 In some embodiments, L is -N(R 2 )-, W is an alkyl group, and R 2 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, and heteroalkynyl. In certain embodiments, L is -N(R 2 )-, W is an alkyl group, and R 2 is hydrogen. In certain embodiments, L is -N(R 2 )-, W is an alkyl group, and R 2 is an alkyl group, such as C 1 -C 6 Alkyl, C 1 -C 5 Alkyl, C 1 -C 4 Alkyl, C 1 -C 3 Alkyl or C 1 -C 2 In certain embodiments, L is -N(R 2 )-, W is C 1 -C 6 Alkyl, and R 2 is H, methyl, ethyl, n-propyl or n-butyl. In some embodiments, L is -N(R 2 )-, W is C 1 -C 6 Alkyl, and R 2 In some embodiments, L is -N(R 2 )-, W is C 1 -C 6 Alkyl, and R 2 It's H.

[0093] In some embodiments, Y is selected from the group consisting of: alkyl, saturated or unsaturated cycloalkyl, saturated or unsaturated heterocyclic, -OC(O)OR 3 、-OC(O)R 4 and –NR 5 R 6 wherein the alkyl, saturated or unsaturated cycloalkyl and saturated or unsaturated heterocyclyl are optionally substituted with one or more groups independently selected from the group consisting of oxo, halogen, cyano, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, saturated or unsaturated cycloalkyl, saturated or unsaturated heterocyclyl, aryl and heteroaryl, provided that when W is -O-, Y is -C(O)OR 3 or -C(O)R4 In certain embodiments, Y is an alkyl group, such as C 1 -C 12 Alkyl, C 1 -C 11 Alkyl, C 1 -C 10 Alkyl, C 1 -C 9 Alkyl, C 1 -C 8 Alkyl, C 1 -C 7 Alkyl, C 1 -C 6 Alkyl, C 1 -C 5 Alkyl, C 1 -C 4 Alkyl, C 1 -C 3 Alkyl or C 1 -C 2 In certain embodiments, Y is C 1 -C 8 alkyl.

[0094] In some embodiments, L is absent or is -O-, W is absent, and Y is alkyl, such as C 1 -C 8 Alkyl, C 1 -C 7 Alkyl, C 1 -C 6 Alkyl, C 1 -C 5 Alkyl, C 1 -C 4 Alkyl, C 1 -C 3 Alkyl or C 1 -C 2 In some embodiments, L is absent or is -O-, W is absent, and Y is n-propyl, isobutyl, n-butyl, tert-butyl, n-pentyl, neopentyl, n-hexyl, or n-heptyl.

[0095] In some embodiments, Y is an optionally substituted saturated or unsaturated cycloalkyl, such as 3 to 10 yuan saturated cycloalkyl, 3 to 9 yuan saturated cycloalkyl, 3 to 8 yuan saturated cycloalkyl, 3 to 7 yuan saturated cycloalkyl, 3 to 6 yuan saturated cycloalkyl, 3 to 5 yuan saturated cycloalkyl, 5 to 10 yuan unsaturated cycloalkyl, 5 to 9 yuan unsaturated cycloalkyl, 5 to 8 yuan unsaturated cycloalkyl, 5 to 7 yuan unsaturated cycloalkyl, or 5 to 6 yuan unsaturated cycloalkyl. In certain embodiments, Y is an optionally substituted 3 to 6 yuan saturated cycloalkyl or 5 to 6 yuan unsaturated cycloalkyl. In some embodiments, Y is cyclopentyl or cyclopentenyl. In certain embodiments, Y is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, and cyclohexadienyl.

[0096] In some embodiments, L is alkyl, W is absent, and Y is an optionally substituted saturated or unsaturated cycloalkyl. 1 -C 6 alkyl, W is absent, and Y is an optionally substituted 3 to 6 membered saturated cycloalkyl or 5 to 6 membered unsaturated cycloalkyl.

[0097] In some embodiments, Y is an optionally substituted saturated or unsaturated heterocyclic group, such as 3 to 10 yuan saturated heterocyclic group, 3 to 9 yuan saturated heterocyclic group, 3 to 8 yuan saturated heterocyclic group, 3 to 7 yuan saturated heterocyclic group, 3 to 6 yuan saturated heterocyclic group, 3 to 5 yuan saturated heterocyclic group, 5 to 10 yuan unsaturated heterocyclic group, 5 to 9 yuan unsaturated heterocyclic group, 5 to 8 yuan unsaturated heterocyclic group, 5 to 7 yuan unsaturated heterocyclic group or 5 to 6 yuan unsaturated heterocyclic group. In some embodiments, saturated or unsaturated heterocyclic group is optionally substituted by one or more groups independently selected from oxo, halogen, cyano, alkyl, alkenyl and alkynyl. In certain embodiments, Y is 3 to 6 yuan saturated heterocyclic group or 5 to 6 yuan unsaturated heterocyclic group, which is optionally substituted by one or more groups independently selected from oxo, halogen, cyano, alkyl, alkenyl and alkynyl. In some embodiments, Y is an unsaturated heterocyclic group. In some embodiments, the unsaturated heterocyclic group is a 5- or 6-membered unsaturated heterocyclic group. In some embodiments, the unsaturated heterocyclic group is a 5-membered heterocyclic group with one or two oxygen atoms. In some embodiments, the unsaturated heterocyclic group is a 5-membered heterocyclic group with two oxygen atoms. In some embodiments, the 5-membered heterocyclic group with two oxygen atoms is optionally substituted with one or more oxo groups or alkyl groups. In some embodiments, the optionally substituted heterocyclic group is

[0098] In some embodiments, L is alkyl or -O-, W is absent or is alkyl, and Y is an optionally substituted saturated or unsaturated heterocyclyl. 1 -C 6 Alkyl or –O-, W is absent or C 1 -C 6 In some embodiments, L is -O-, W is alkyl, and Y is a 3- to 6-membered saturated heterocyclic group or a 5- to 6-membered unsaturated heterocyclic group, which is optionally substituted by one or more groups independently selected from oxo, halogen, cyano, alkyl, alkenyl, and alkynyl. In some embodiments, L is -O-, W is alkyl, and Y is an unsaturated heterocyclic group. In some embodiments, L is -O-, W is C 1 -C 6 alkyl, and Y is an unsaturated heterocyclic group. In some embodiments, L is -O-, W is C 1 In some embodiments, L is -O-, W is an alkyl group, and Y is an unsaturated heterocyclic group. In some embodiments, L is -O-, W is an alkyl group, and Y is an unsaturated 5- or 6-membered heterocyclic group. 1 -C 6 alkyl, and Y is an unsaturated 5- or 6-membered heterocyclic group. In some embodiments, L is -O-, W is C 1 alkyl (i.e., methylene), and Y is an unsaturated 5- or 6-membered heterocyclic group. In some embodiments, L is -O-, W is an alkyl group, and Y is an unsaturated In some embodiments, L is -O-, W is C 1 -C 6 alkyl, and Y is In some embodiments, L is -O-, W is C 1 alkyl (i.e., methylene), and Y is

[0099] In some embodiments, L is -N(R 2 )-, where R 2 is hydrogen or -methyl, W is alkyl, and Y is unsaturated In some embodiments, L is -N(R 2 )-, where R 2 is hydrogen or -methyl, W is C 1 -C 6 alkyl, and Y is In some embodiments, L is -N(R 2 )-, where R 2 is hydrogen or -methyl, W is C 1 alkyl (i.e., methylene), and Y is

[0100] In some embodiments, Y is -OC(O)OR 3 , where R 3 is an alkyl group, such as C 1 -C 6 Alkyl, C 1 -C 5 Alkyl, C 1 -C 4 Alkyl, C 1 -C 3 Alkyl or C 1 -C 2 In certain embodiments, Y is -OC(O)OR 3 , where R 3 is methyl, ethyl, n-propyl, isopropyl, n-butyl or tert-butyl. 3 is methyl, ethyl or isopropyl. In some embodiments, R 3 is methyl or isopropyl. 3 is optionally substituted aryl, for example optionally substituted phenyl.

[0101] In certain embodiments, L is alkyl, W is -O-, and Y is -C(O)R 3 , where R 3 It is C 1 -C 6 In some embodiments, C 1 -C 6 Alkyl is methyl or isopropyl. In some embodiments, L is -O-, W is alkyl, and Y is -OC(O)OR 3 , where R 3 In some embodiments, L is -O-, W is C 1 -C 6 alkyl, and Y is -OC(O)OR 3 , where R 3 In some embodiments, L is -O-, W is C 2 -C 3 alkyl, and Y is -OC(O)OR 3 , where R 3 In some embodiments, L is -O-, W is alkyl, and Y is -OC(O)OR 3 , where R 3 It is C 1 -C 6 In some embodiments, L is -O-, W is C 1 -C 6 alkyl, and Y is -OC(O)OR 3 , where R3 It is C 1 -C 6 In some embodiments, L is -O-, W is C 2 -C 3 alkyl, and Y is -OC(O)OR 3 , where R 3 It is C 1 -C 6 In some embodiments, L is -O-, W is alkyl, and Y is -OC(O)OR 3 , where R 3 is methyl or isopropyl. In some embodiments, L is -O-, W is C 1 -C 6 alkyl, and Y is -OC(O)OR 3 , where R 3 is methyl or isopropyl. In some embodiments, L is -O-, W is C 2 -C 3 alkyl, and Y is -OC(O)OR 3 , where R 3 It is methyl or isopropyl.

[0102] In some embodiments, Y is -OC(O)R 4 , where R 4 is an alkyl group, such as C 1 -C 6 Alkyl, C 1 -C 5 Alkyl, C 1 -C 4 Alkyl, C 1 -C 3 Alkyl or C 1 -C 2 In certain embodiments, Y is -OC(O)R 4 , where R 4 is methyl, ethyl, n-propyl, isopropyl, n-butyl or tert-butyl. 4 It is methyl or isopropyl.

[0103] In certain embodiments, L is -O- or -N(R 2 )-, W is alkyl, and Y is -OC(O)R 4 , where R 2 is hydrogen or alkyl, and R 4 In certain embodiments, L is -O- or -N(R 2 )-, W is C 1 -C 6 alkyl, and Y is -OC(O)R4 , where R 2 is hydrogen or alkyl, and R 4 In certain embodiments, L is -O- or -N(R 2 )-, W is C 2 -C 3 alkyl, and Y is -OC(O)R 4 , where R 2 is hydrogen or alkyl, and R 4 In certain embodiments, L is -O- or -N(R 2 )-, W is alkyl, and Y is -OC(O)R 4 , where R 2 is hydrogen or C 1 -C 6 Alkyl, R 4 It is C 1 -C 6 In certain embodiments, L is -O- or -N(R 2 )-, W is C 1 -C 6 alkyl, and Y is -OC(O)R 4 , where R 2 is hydrogen or C 1 -C 6 Alkyl, R 4 It is C 1 -C 6 In certain embodiments, L is -O- or -N(R 2 )-, W is C 2 -C 3 alkyl, and Y is -OC(O)R 4 , where R 2 is hydrogen or C 1 -C 6 Alkyl, R 4 It is C 1 -C 6 In certain embodiments, L is -O- or -NN(R 2 )-, W is alkyl, and Y is -OC(O)R 4 , where R 2 is hydrogen or Me, R 4 is methyl, ethyl or isopropyl. In certain embodiments, L is -O- or -N(R 2 )-, W is C 1 -C 6 alkyl, and Y is -OC(O)R 4 , where R 2 is hydrogen or Me, R 4is methyl, ethyl or isopropyl. In certain embodiments, L is -O- or -N(R 2 )-, W is C 2 -C 3 alkyl, and Y is -OC(O)R 4 , where R 2 is hydrogen or Me, R 4 is methyl, ethyl or isopropyl. In some embodiments, L is -O-. In some embodiments, L is -N(R 2 )-. In some embodiments, R 2 is hydrogen or methyl. 4 It is methyl or isopropyl.

[0104] In some embodiments, Y is -NR 5 R 6 , where R 5 is hydrogen or alkyl, R 6 Yes-C(O)R 7 , and R 7 In certain embodiments, Y is -NR 5 R 6 , where R 5 is hydrogen or C 1 -C 6 Alkyl, R 6 Yes-C(O)R 7 , and R 7 It is C 1 -C 6 Alkyl or C 1 -C 6 In some embodiments, R 5 is hydrogen or methyl, R 6 Yes-C(O)R 7 , and R 7 Yes-CH 3 、-CH(CH 3 ) 2 、-OCH 3 or -OCH(CH 3 ) 2 In some embodiments, R 5 is hydrogen or methyl, and R 6 is -C(O)CH 3 、-C(O)CH(CH 3 ) 2 、-C(O)OCH 3 or -C(O)OCH(CH 3 ) 2 .

[0105] In some embodiments, L is -O-, W is alkyl, and Y is -NR 5 R 6 , where R 5 is hydrogen or alkyl, R 6 Yes-C(O)R 7 , R 7 In certain embodiments, L is -O-, W is C 1 -C 6 Alkyl, Y is –NR 5 R 6 , where R 5 is hydrogen or C 1 -C 6 Alkyl, R 6 Yes-C(O)R 7 , and R 7 It is C 1 -C 6 Alkyl or C 1 -C 6 In certain embodiments, L is -O-, W is C 1 -C 6 Alkyl, Y is –NR 5 R 6 , where R 5 is hydrogen or methyl, and R 6 is -C(O)CH 3 、-C(O)CH(CH 3 ) 2 、-C(O)OCH 3 or -C(O)OCH(CH 3 ) 2 In certain embodiments, L is -O-, W is alkyl, and Y is -NR 5 R 6 , where R 5 Is H or C 1 -C 3 Alkyl, R 6 Yes-C(O)R 7 , and R 7 In certain embodiments, L is -O-, W is C 1 -C 6 alkyl, and Y is –NR 5 R 6 , where R 5 Is H or C 1 -C 3 Alkyl, R 6 Yes-C(O)R 7 , and R 7 In certain embodiments, L is -O-, W is C2 -C 3 alkyl, and Y is –NR 5 R 6 , where R 5 Is H or C 1 -C 3 Alkyl, R 6 Yes-C(O)R 7 , and R 7 In certain embodiments, L is -O-, W is alkyl, and Y is -NR 5 R 6 , where R 5 Is H or C 1 -C 3 Alkyl, R 6 Yes-C(O)R 7 , and R 7 It is C 1 -C 6 Alkyl or C 1 -C 6 In certain embodiments, L is -O-, W is C 1 -C 6 alkyl, and Y is –NR 5 R 6 , where R 5 Is H or C 1 -C 3 Alkyl, R 6 Yes-C(O)R 7 , and R 7 It is C 1 -C 6 Alkyl or C 1 -C 6 In certain embodiments, L is -O-, W is C 2 -C 3 alkyl, and Y is –NR 5 R 6 , where R 5 Is H or C 1 -C 3 Alkyl, R 6 Yes-C(O)R 7 , and R 7 It is C 1 -C 6 Alkyl or C 1 -C 6 In certain embodiments, L is -O-, W is alkyl, and Y is -NR 5 R 6 , where R 5 Is H or C 1 -C3 Alkyl, R 6 Yes-C(O)R 7 , and R 7 It is C 1 -C 3 Alkyl or C 1 -C 3 In certain embodiments, L is -O-, W is C 1 -C 6 alkyl, and Y is –NR 5 R 6 , where R 5 Is H or C 1 -C 3 Alkyl, R 6 Yes-C(O)R 7 , and R 7 It is C 1 -C 3 Alkyl or C 1 -C 3 In certain embodiments, L is -O-, W is C 2 -C 3 alkyl, and Y is –NR 5 R 6 , where R 5 Is H or C 1 -C 3 Alkyl, R 6 Yes-C(O)R 7 , and R 7 It is C 1 -C 3 Alkyl or C 1 -C 3 In certain embodiments, L is -O-, W is alkyl, and Y is -NR 5 R 6 , where R 5 Is H or C 1 -C 3 Alkyl, R 6 Yes-C(O)R 7 , and R 7 Yes-CH 3 、-CH(CH 3 ) 2 、-OCH 3 or -OCH(CH 3 ) 2 In certain embodiments, L is -O-, W is C 1 -C 6 alkyl, and Y is –NR 5 R 6 , where R 5 Is H or C1 -C 3 Alkyl, R 6 Yes-C(O)R 7 , and R 7 Yes-CH 3 、-CH(CH 3 ) 2 、-OCH 3 or -OCH(CH 3 ) 2 In certain embodiments, L is -O-, W is C 2 -C 3 alkyl, and Y is –NR 5 R 6 , where R 5 Is H or C 1 -C 3 Alkyl, R 6 Yes-C(O)R 7 , and R 7 Yes-CH 3 、-CH(CH 3 ) 2 、-OCH 3 or -OCH(CH 3 ) 2 .

[0106] In some embodiments, the compounds of the present disclosure have Formula (Ia):

[0107]

[0108] Where R 1b and Y are as defined above in formula (I).

[0109] In certain embodiments, R 1b is hydrogen or methyl, Y is alkyl, such as C 1 -C 12 Alkyl, C 1 -C 11 Alkyl, C 1 -C 10 Alkyl, C 1 -C 9 Alkyl, C 1 -C 8 Alkyl, C 1 -C 7 Alkyl, C 1 -C 6 Alkyl, C 1 -C 5 Alkyl, C 1 -C 4 Alkyl, C 1 -C 3Alkyl or C 1 -C 2 alkyl.

[0110] In some embodiments, the compounds of the present disclosure have Formula (Ib):

[0111]

[0112] in is optionally substituted with an alkyl group (eg, methyl, ethyl or isopropyl), n is an integer from 1 to 5, and R 1b , W and Y are as defined above in formula (I).

[0113] In certain embodiments, R 1b is hydrogen or methyl, and W is absent or is -O-. In certain embodiments, R 1b is hydrogen or methyl, W is absent or is -O-, and Y is a saturated or unsaturated cycloalkyl, a saturated or unsaturated heterocyclyl or -OC(O)OR 3 , where R 3 is hydrogen or alkyl, wherein the cycloalkyl and heterocyclyl groups are optionally substituted with one or more groups independently selected from oxo, halogen, cyano, alkyl, alkenyl, and alkynyl. 1b is hydrogen or methyl, W is absent or is -O-, and Y is a 3- to 6-membered saturated or unsaturated cycloalkyl group, a 3- to 6-membered saturated or unsaturated heterocyclic group, or -OC(O)OR 3 , where R 3 is hydrogen or C 1 -C 6 Alkyl, wherein the cycloalkyl and heterocyclyl are optionally substituted with one or more groups independently selected from oxo, halogen, cyano, alkyl, alkenyl and alkynyl.

[0114] In some embodiments, the compounds of the present disclosure have Formula (Ic-1) or Formula (Ic-2):

[0115]

[0116] Where R 1b , W and Y are as defined above in formula (I).

[0117] In certain embodiments, R 1b R is hydrogen or methyl, and W is absent or is alkyl. 1b is hydrogen or methyl, W is absent or is alkyl, and Y is selected from alkyl, saturated or unsaturated heterocyclic, -OC(O)R 4 and –NR 5 R 6 The group consisting of R 4 and R5 are each selected from the group consisting of hydrogen, alkyl, alkenyl and alkynyl, R 6 Yes-C(O)R 7 , and R 7 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl and alkoxy, wherein the alkyl, alkenyl, alkynyl, alkoxy and saturated or unsaturated heterocyclyl are optionally substituted with one or more groups independently selected from the group consisting of oxo, halogen, cyano, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, saturated or unsaturated cycloalkyl, saturated or unsaturated heterocyclyl, aryl and heteroaryl. In certain embodiments, R 1b is hydrogen or methyl, W is alkyl, and Y is selected from unsaturated heterocyclic groups, -OC(O)R 4 and –NR 5 R 6 The group consisting of R 4 and R 5 are each selected from the group consisting of hydrogen, alkyl, alkenyl and alkynyl, R 6 Yes-C(O)R 7 , and R 7 Selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl and alkoxy, wherein the alkyl, alkenyl, alkynyl, alkoxy and saturated or unsaturated heterocyclyl are optionally substituted with one or more groups independently selected from the group consisting of oxo, halogen, cyano, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, saturated or unsaturated cycloalkyl, saturated or unsaturated heterocyclyl, aryl and heteroaryl.

[0118] In certain embodiments, R 1b is hydrogen or methyl, W is C 1 -C 6 alkyl, and Y is selected from the group consisting of: optionally substituted with one or more oxo groups, -OC(O)R 4 and –NR 5 R 6 A substituted 5- to 6-membered unsaturated heterocyclic group, wherein R 4 and R 5 Each is hydrogen or C 1 -C 6 Alkyl, R 6 Yes-C(O)R 7 , and R 7 It is C 1 -C 6 Alkyl or C 1 -C 6 Alkoxy.

[0119] In some embodiments, the compounds of the present disclosure have Formula (Id-1) or Formula (Id-2):

[0120]

[0121] Where R 1b , R 2 , W and Y are as defined above in formula (I).

[0122] In certain embodiments, R 1b is hydrogen or methyl, and R 2 is hydrogen or alkyl. 1b is hydrogen or methyl, and R 2 is hydrogen or methyl.

[0123] In certain embodiments, R 1b is hydrogen or methyl, R 2 is hydrogen or alkyl, and W is alkyl. 1b is hydrogen or methyl, R 2 is hydrogen or alkyl, W is alkyl, and Y is -OC(O)R 4 , where R 4 is selected from the group consisting of hydrogen, alkyl, alkenyl and alkynyl. 1b is hydrogen or methyl, R 2 is hydrogen or C 1 -C 6 Alkyl, W is C 1 -C 6 alkyl, and Y is -OC(O)R 4 , where R 4 is hydrogen or C 1 -C 6 alkyl.

[0124] In certain embodiments, the present disclosure provides compounds of Table 1.

[0125] In another aspect, the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof selected from the group consisting of:

[0126] Hexanoic acid [(3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl] ester,

[0127] Heptanoic acid [(3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl] ester,

[0128] Octanoic acid (3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthrene-3-yl ester,

[0129] Hexanoic acid [(3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-3,10,13-trimethyl-1,2,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydrocyclopenta[a]phenanthrene-3-yl] ester,

[0130] Heptanoic acid [(3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-3,10,13-trimethyl-1,2,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydrocyclopenta[a]phenanthrene-3-yl] ester, octanoic acid [(3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-3,10,13-trimethyl-1,2,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydrocyclopenta[a]phenanthrene-3-yl] ester, 3-cyclopentylpropionic acid [(3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-1 0,13-Dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl]ester, 3-Cyclopentylacetic acid [(3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl]ester, 3-Cyclopentylacetic acid [(3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl]ester, ,14,15,16,17-tetradecahydrocyclopenta[a]phenanthrene-3-yl] ester, 2-cyclopentylacetic acid [(3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-3,10,13-trimethyl-1,2,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydrocyclopenta[a]phenanthrene-3-yl] ester, 3-cyclopent-3-ene-1-ylpropionic acid [(3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl] Esters, 3-cyclopent-3-en-1-yl propanoic acid [(3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-3,10,13-trimethyl-1,2,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydrocyclopenta[a]phenanthrene-3-yl] ester, 3-(5-oxotetrahydrofuran-2-yl) propanoic acid [(3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl] ester, 4-acetoxybutyric acid [(3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl] ester, 4-(2-methylpropanoyloxy)butanoic acid [(3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl] ester, 5-acetoxypentanoic acid [(3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl] ester [(3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl] ester, 5-acetoxy-2-methyl-pentanoic acid [(3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl] ester, 3-[[(3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-10,13-dimethyl-2,3,4,5 ,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl]oxycarbonyloxy]propyl ester, 2-[[(3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl]oxycarbonyloxy]ethyl 2-methylpropanoate, [(3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl]oxycarbonyloxy]ethyl carbonate 16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl] ester (5-methyl-2-oxo-1,3-dioxol-4-yl) methyl ester, [(3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl] ester butyl carbonate, 2-[[(3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl] ester butyl carbonate,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl]oxycarbonylamino]ethyl ester, 2-[[(3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl]oxycarbonyl-methyl-amino]ethyl 2-methylpropanoate,

[0131] [(3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl] 2-(2-methylpropionylamino)ethyl carbonate),

[0132] (3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthrene-3-yl carbonate (2-(N-methylisobutyramido)ethyl)

[0133] [(3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl] 2-(methoxycarbonylamino)ethyl carbonate,

[0134] [(3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl] 2-(methoxycarbonyl-N-methylamino)ethyl carbonate,

[0135] (3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-3,10,13-trimethylhexahydro-1H-cyclopenta[a]phenanthrene-3-yl carbonate ((5-methyl-2-oxo-1,3-dioxol-4-yl)methyl) carbonate,

[0136] 2-(((((3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-3,10,13-trimethylhexahydro-1H-cyclopenta[a]phenanthrene-3-yl)oxy)carbonyl)(methyl)amino)ethyl isobutyrate,

[0137] 2-(((((3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-3,10,13-trimethylhexahydro-1H-cyclopenta[a]phenanthrene-3-yl)oxy)carbonyl)oxy)ethyl isobutyrate,

[0138] (3R,5R,8R,9R,10S,13S,14S,17S)-17-(2-(4-cyano-1H-pyrazol-1-yl)acetyl)-3,13-dimethylhexahydro-1H-cyclopenta[a]phenanthrene-3-yl carbonate ((5-methyl-2-oxo-1,3-dioxol-4-yl)methyl) carbonate,

[0139] isobutyric acid 2-(((((3R,5R,8R,9R,10S,13S,14S,17S)-17-(2-(4-cyano-1H-pyrazol-1-yl)acetyl)-3,13-dimethylhexahydro-1H-cyclopenta[a]phenanthren-3-yl)oxy)carbonyl)(methyl)amino)ethyl isobutyrate, and isobutyric acid 2-(((((3R,5R,8R,9R,10S,13S,14S,17S)-17-(2-(4-cyano-1H-pyrazol-1-yl)acetyl)-3,13-dimethylhexahydro-1H-cyclopenta[a]phenanthren-3-yl)oxy)carbonyl)oxy)ethyl ester.

[0140] Exemplary compounds of formula (I) are listed in Table 1 below.

[0141] Table 1

[0142]

[0143]

[0144]

[0145]

[0146]

[0147]

[0148]

[0149] The compounds provided herein are described with reference to general formulae and specific compounds. In addition, the compounds of the present disclosure may exist in a variety of different forms or derivatives, all of which are within the scope of the present disclosure. These include, for example, tautomers, stereoisomers, racemic mixtures, regioisomers, salts, prodrugs, solvated forms, different crystal forms or polymorphs, and active metabolites.

[0150] The compounds of the present disclosure may contain one or more asymmetric centers and therefore may exist in various stereoisomeric forms, such as enantiomers and / or diastereomers. Therefore, the compounds of the present invention and compositions thereof may be in the form of individual enantiomers, diastereomers or geometric isomers, or may be in the form of a mixture of stereoisomers. In certain embodiments, the compounds of the present disclosure are enantiomerically pure compounds. In certain embodiments, a mixture of enantiomers or diastereomers is provided.

[0151] The term "enantiomer" refers to two stereoisomers of a compound that are non-superimposable mirror images of one another. The term "diastereomer" refers to a pair of optical isomers that are not mirror images of one another. Diastereomers have different physical properties, such as melting points, boiling points, spectral properties, and reactivity.

[0152] In addition, as described herein, certain compounds may have one or more double bonds that can exist as Z or E isomers (unless otherwise specified). The present disclosure additionally includes compounds as individual isomers that are substantially free of other isomers, and alternatively as mixtures of various isomers, such as racemic mixtures of enantiomers. In addition to the above compounds themselves, the present disclosure also includes compositions comprising one or more compounds.

[0153] As used herein, the term "isomer" includes any and all geometric isomers and stereoisomers. For example, "isomer" includes cis and trans isomers, E- and Z-isomers, R- and S-enantiomers, diastereomers, (D)-isomers, (L)-isomers, racemic mixtures thereof, and other mixtures thereof within the scope of the present invention. For example, in some embodiments, a stereoisomer may be provided substantially free of one or more corresponding stereoisomers, and may also be referred to as "stereochemically enriched".

[0154] Where a particular enantiomer is preferred, it may be provided in some embodiments substantially free of the opposite enantiomer, and may also be referred to as "optically enriched". As used herein, "optically enriched" means that the compound is composed of a significantly greater proportion of one enantiomer. In certain embodiments, the compound is composed of at least about 90% by weight of the preferred enantiomer. In other embodiments, the compound is composed of at least about 95%, 98%, or 99% by weight of the preferred enantiomer. The preferred enantiomer may be separated from the racemic mixture or prepared by asymmetric synthesis by any method known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts. See, e.g., Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen, SH et al., Tetrahedron 33:2725 (1977); Eliel, EL Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, SH Tables of Resolving Agents and Optical Resolutions, p. 268 (EL Eliel, ed., Univ. of Notre Dame Press, Notre Dame, IN 1972).

[0155] Compounds of the present disclosure can also exist in different tautomeric forms, and all such forms are included in the scope of the present disclosure. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies, which can interconvert through low energy barriers. For example, proton tautomers (also referred to as prototropic tautomers) include interconversions by proton migration, such as keto-enols, amide-imidic acids, lactams-lactams, imines-enamine isomerizations, and protons can occupy two or more positions of heterocyclic systems. The cyclic form (e.g., 1H- and 3H-imidazoles, 1H-, 2H- and 4H-1,2,4-triazoles, 1H- and 2H-isoindoles, and 1H- and 2H-pyrazoles). Valence tautomers include interconversions by reorganizing some bonded electrons. Tautomers can reach equilibrium or spatial locking into a form by appropriate substitution. Unless otherwise specified, compounds of the present disclosure identified as a specific tautomeric form by name or structure are intended to include other tautomeric forms.

[0156] The compounds of the present disclosure may be formulated into or in the form of pharmaceutically acceptable salts. Unless otherwise specified, the compounds provided herein include pharmaceutically acceptable salts of such compounds.

[0157] As used herein, the term "pharmaceutically acceptable" means that a substance or composition is chemically and / or toxicologically compatible with the other ingredients making up the formulation and / or the subject to be treated therewith.

[0158] As used herein, unless otherwise indicated, the term "pharmaceutically acceptable salt" includes salts that retain the biological effectiveness of the free acids and bases of the specified compound and are not biologically or otherwise undesirable. Pharmaceutically acceptable salt forms contemplated include, but are not limited to, mono-, di-, tri-, tetra-, etc. Pharmaceutically acceptable salts are non-toxic in the amounts and concentrations to which they are administered. The preparation of such salts can facilitate pharmacological use by changing the physical characteristics of the compound without preventing it from exerting its physiological effects. Useful changes in physical properties include lowering the melting point to facilitate transmucosal administration and increasing solubility to facilitate administration of higher concentrations of the drug.

[0159] Pharmaceutically acceptable salts include acid addition salts, such as those containing sulfate, chloride, hydrochloride, fumarate, maleate, phosphate, sulfamate, acetate, citrate, lactate, tartrate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, cyclohexylsulfamate and quinate. Pharmaceutically acceptable salts can be obtained from acids such as hydrochloric acid, maleic acid, sulfuric acid, phosphoric acid, sulfamate, acetic acid, citric acid, lactic acid, tartaric acid, malonic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclohexylsulfamate, fumaric acid and quinic acid.

[0160] Pharmaceutically acceptable salts also include basic addition salts, such as those containing benzathine, chloroprocaine, choline, diethanolamine, ethanolamine, tert-butylamine, ethylenediamine, meglumine, procaine, aluminum, calcium, lithium, magnesium, potassium, sodium, ammonium, alkylamines, and zinc (when an acidic functional group, such as a carboxylic acid or phenol, is present). For example, see Remington's Pharmaceutical Sciences, 19th edition, Mack Publishing Co., Easton, PA, Vol. 2, p. 1457, 1995; "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" Stahl and Wermuth, Wiley-VCH, Weinheim, Germany, 2002. Such salts can be prepared using the appropriate corresponding bases.

[0161] Pharmaceutically acceptable salts can be prepared by standard techniques. For example, the free base form of the compound can be dissolved in a suitable solvent, such as an aqueous or alcoholic solution containing a suitable acid, and then separated by evaporating the solution. Thus, if the particular compound is a base, the desired pharmaceutically acceptable salt can be prepared by any suitable method available in the art, such as treating the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc., or an organic acid, such as acetic acid; maleic acid; succinic acid; mandelic acid; fumaric acid; malonic acid; pyruvic acid; oxalic acid; glycolic acid; salicylic acid; pyranosidic acid, such as glucuronic acid or galacturonic acid; α-hydroxy acids, such as citric acid or tartaric acid; amino acids, such as aspartic acid or glutamic acid; aromatic acids, such as benzoic acid or cinnamic acid; sulfonic acids, such as p-toluenesulfonic acid or ethanesulfonic acid, etc.

[0162] Similarly, if the particular compound is an acid, the desired pharmaceutically acceptable salt may be prepared by any suitable method, for example, by treating the free acid with an inorganic or organic base, such as an amine (primary, secondary or tertiary), an alkali metal hydroxide or an alkaline earth metal hydroxide, etc. Illustrative examples of suitable salts include organic salts derived from amino acids (e.g., L-glycine, L-lysine and L-arginine), ammonia, primary, secondary and tertiary amines, and cyclic amines, such as hydroxyethylpyrrolidine, piperidine, morpholine or piperazine, and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.

[0163] It should also be understood that the compounds of the present disclosure may exist in unsolvated forms, solvated forms (eg, hydrated forms), and solid forms (eg, crystalline or polymorphic forms), and that the present disclosure is intended to include all such forms.

[0164] As used herein, the term "solvate" or "solvated form" refers to a solvent-added form containing a stoichiometric or non-stoichiometric amount of solvent. Some compounds tend to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thereby forming a solvate. If the solvent is water, the solvate formed is a hydrate; and if the solvent is an alcohol, the solvate formed is an alcoholate. Hydrates are formed by the reaction of one or more water molecules with one water molecule to maintain its molecular state as H 2 The solvate is formed by the combination of molecules of substances O. Examples of solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine.

[0165] As used herein, the terms "crystal form", "crystalline form", "polymorph" and "polymorph" are used interchangeably and refer to crystal structures in which a compound (or a salt or solvate thereof) can crystallize in different crystal packing arrangements, all of which have the same elemental composition. Different crystal forms typically have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability and solubility. Recrystallization solvent, crystallization rate, storage temperature and other factors may cause one crystal form to dominate. Polymorphs of a compound can be prepared by crystallization under different conditions.

[0166] The present disclosure is also intended to include all isotopes of atoms in the compounds. Atomic isotopes include atoms with the same atomic number but different mass numbers. For example, unless otherwise specified, hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine, or iodine in the compounds of the present disclosure are intended to also include their isotopes, such as but not limited to 1 H. 2 H. 3 H. 11 C. 12 C. 13 C. 14 C. 14 N. 15 N. 16 O. 17 O. 18 O. 31 P. 32 P. 32 S. 33 S. 34 S. 36 S. 17 F. 18 F. 19 F. 35 Cl, 37 Cl, 79 Br, 81 Br, 124 I. 127 I and 131 I. In some embodiments, hydrogen includes protium, deuterium, and tritium. In some embodiments, carbon includes 12 C and 13 C.

[0167] Synthesis of Compounds of the Disclosure

[0168] The synthesis schemes of the compounds provided herein, including the synthesis of pharmaceutically acceptable salts thereof, are described in the synthetic schemes of the embodiments. The compounds provided herein can be prepared using any known organic synthesis techniques, and can be synthesized according to any of many possible synthetic routes, and therefore these schemes are only illustrative and do not mean to limit other possible methods that can be used to prepare the compounds provided herein. In addition, the steps in the schemes are for better explanation and can be changed as appropriate. The embodiments of the compounds in the embodiments are synthesized for research purposes and for the purpose of possible submission to regulatory agencies.

[0169] The reaction of preparing the disclosed compound can be carried out in a suitable solvent, which can be easily selected by a technician in the field of organic synthesis. Suitable solvents can be at a temperature at which the reaction is carried out, for example, at a temperature within the range of the freezing temperature of the solvent to the boiling temperature of the solvent, and do not react with the starting material (reactant), intermediate or product. A given reaction can be carried out in a solvent or a mixture of more than one solvent. According to the specific reaction steps, a solvent suitable for the specific reaction steps can be selected by a person skilled in the art.

[0170] The preparation of compounds of the present disclosure may involve the protection and deprotection of various chemical groups. Those skilled in the art can easily determine the need for protection and deprotection and the selection of appropriate protecting groups. The chemical properties of protecting groups can be found in, for example, TW Greene and PGM Wuts, Protective Groups in Organic Synthesis, 3rd edition, Wiley & Sons, Inc., New York (1999), which is incorporated herein by reference in its entirety.

[0171] The reaction can be monitored according to any suitable method known in the art. For example, product formation can be monitored by spectroscopic means, such as nuclear magnetic resonance spectroscopy (e.g. 1 H or 13C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), mass spectrometry, or by chromatographic methods, such as high performance liquid chromatography (HPLC), liquid chromatography-mass spectrometry (LCMS), or thin layer chromatography (TLC). One skilled in the art can purify compounds by a variety of methods, including high performance liquid chromatography (HPLC) ("Preparative LC-MS Purification: Improved Compound Specific Method Optimization" Karl F. Blom, Brian Glass, Richard Sparks, Andrew P. Combs J. Combi. Chem. 2004, 6 (6), 874-883, which is incorporated herein by reference in its entirety) and normal phase silica chromatography.

[0172] The structures of the compounds in the examples were characterized by nuclear magnetic resonance (NMR) and / or liquid chromatography-mass spectrometry (LC-MS). NMR chemical shifts (δ) are expressed in 10 -6 (ppm) are given. On a Varian or Bruker instrument (400 MHz), in CDCl 3 , CD 3 OD or DMSO-d 6 Recording in solution 1 H-NMR spectra (reported in ppm).

[0173] MS measurements were performed using a Shimadzu 2010 mass spectrometer or an Agilent 6110A MSD or 1969A TOF mass spectrometer using electrospray, chemical and electron impact ionization methods in a range of instruments.

[0174] Known starting materials of the present disclosure can be synthesized by using or according to methods known in the art, or can be purchased from commercial suppliers such as Aldrich Chemical Company, Adamas-beta, TCI or Accela ChemBio Co., Ltd, and used without further purification unless otherwise stated. Tetrahydrofuran (THF), N,N-dimethylformamide (DMF), dichloromethane (DCM), dichloroethane (DCE), dioxane and 1,1,2,2-tetrachloroethane were purchased from Aldrich, packed in Sure sealed bottles and used as received.

[0175] Unless otherwise stated, the reactions of the present disclosure were carried out in anhydrous solvents and the reaction flasks were typically fitted with rubber septa for the introduction of substrates and reagents via syringe. Glassware was oven dried and / or heat dried.

[0176] For the purpose of illustration, the general synthetic route for preparing the compounds of the present disclosure and key intermediates is shown below. For a more detailed description of each reaction step, see the Examples section below. It will be appreciated by those skilled in the art that other synthetic routes can be used to synthesize the compounds of the present invention. Although specific starting materials and reagents are described in the scheme and discussed below, other starting materials and reagents can be easily substituted to provide a variety of derivatives and / or reaction conditions. In addition, many compounds prepared by the following methods can be further modified according to the present disclosure using conventional chemistry well known to those skilled in the art.

[0177] In some embodiments, the compound of formula (I) provided herein is prepared by reacting brexanolone with a compound of formula (II):

[0178]

[0179] wherein L, W and Y are as defined above.

[0180] Scheme 1 illustrates an exemplary synthesis of compounds of formula (I) starting from the reaction of brexanolone with a compound of formula (II).

[0181]

[0182] In some embodiments, the compounds of Formula (I) provided herein are prepared according to Scheme 2.

[0183]

[0184] As will be appreciated by those skilled in the art, the compounds of the present disclosure may be synthesized by routes other than those explicitly disclosed herein.

[0185] Properties of the compounds disclosed herein

[0186] In one aspect, the present disclosure provides a compound of formula (I), formula (Ia), formula (Ib), formula (Ic-1), formula (Ic-2), formula (Id-1), formula (Id-2) or a pharmaceutically acceptable salt thereof, which is used as GABA A Receptor modulators.

[0187] In some embodiments, the compounds of the present disclosure are prodrug compounds that, upon administration to a subject, are chemically transformed by one or more metabolic processes to release an active pharmacological agent in vivo.

[0188] Thus, in some embodiments, the compounds of the present disclosure are converted to bryanolone, ganaxolone, or zuranoone after administration. In some embodiments, the compounds of the present disclosure are converted to bryanolone, ganaxolone, or zuranoone after oral administration. In some embodiments, the compounds of the present disclosure are converted to bryanolone, ganaxolone, or zuranoone after parenteral administration. In some embodiments, the compounds of the present disclosure are converted to bryanolone, ganaxolone, or zuranoone in the blood. In some embodiments, the release rate of bryanolone, ganaxolone, or zuranoone within 1 hour after the compound of the present disclosure is contacted with the blood is not less than 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, or 10%. In some embodiments, the release rate of brenolanolone, ganaxolone or zulanolanolone is no less than 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20% or 10% within 2 hours after the compound of the present disclosure is contacted with the blood.

[0189] In some embodiments, compounds of the present disclosure exhibit a thermodynamic aqueous solubility (at pH 7.4) of at least 0.1 μM, at least 0.5 μM, at least 1 μM, at least 1.5 μM, at least 2 μM, at least 2.5 μM, at least 3 μM, at least 3.5 μM, at least 4 μM, at least 4.5 μM, at least 5 μM, at least 5.5 μM, at least 6 μM, at least 6.5 μM, at least 7 μM, at least 8 μM, at least 9 μM, at least 10 μM, at least 15 μM, at least 20 μM, or even greater. In some embodiments, the compounds of the present disclosure exhibit thermodynamic aqueous solubility (at pH 7.4) in the range of 0.1-20 μM, e.g., 0.1-18 μM, 0.1-16 μM, 0.1-14 μM, 0.1-12 μM, 0.1-10 μM, 0.1-9 μM, 0.1-8 μM, 0.1-7 μM, 0.1-6 μM, 0.1-5 μM, 0.1-4 μM, 0.1-3 μM, 0.1-2 μM, 1-20 μM, 2-20 μM, 2-15 μM, 2-10 μM, 2-9 μM, 2-8 μM, 2-7 μM, 2-6 μM, 2-5 μM, 2-4 μM, etc.

[0190] In some embodiments, the compounds of the present disclosure have a lipophilicity as measured by Log D in the range of 0.5-7, e.g., 1-7, 1.5-7, 2-7, 2.5-7, 3-7, 4-7, 1.5-6, 2-6, 2.5-6, 3-6, 3.5-6, 4-6, 1-5, 1.5-5, 2-5, 2.5-5, 3-5, 3.5-5, 4-5, 4.5-5, etc.

[0191] In some embodiments, the compounds of the present disclosure exhibit a plasma half-life (t half-life) of not less than 10 minutes, not less than 20 minutes, not less than 30 minutes, not less than 40 minutes, not less than 50 minutes, not less than 60 minutes, not less than 70 minutes, not less than 80 minutes, not less than 90 minutes, not less than 100 minutes, not less than 110 minutes, not less than 120 minutes, not less than 130 minutes, not less than 140 minutes, not less than 150 minutes, not less than 160 minutes, not less than 170 minutes, not less than 180 minutes, not less than 190 minutes, or not less than 200 minutes. 1 / 2 ), as measured in the assays described in the Examples below.

[0192] In some embodiments, compounds of the present disclosure exhibit a hepatic S9 half-life of no less than 10 minutes, no less than 20 minutes, no less than 30 minutes, no less than 40 minutes, or no less than 50 minutes, as measured in the assays described in the Examples below.

[0193] Therefore, the compounds of formula (I), formula (Ia), formula (Ib), formula (Ic-1), formula (Ic-2), formula (Id-1), formula (Id-2) and pharmaceutically acceptable salts thereof are used as prodrugs of NAS, in particular, by releasing brexolone, ganaxolone or zuranolone to regulate GABA A receptor function, and thus modulates GABA function.

[0194] As used herein, the term "modulate" or "modulation" refers to GABA A Inhibition or enhancement of receptor function. A "modulator" may be, for example, GABA A Agonist, partial agonist, antagonist or partial antagonist of a receptor.

[0195] Pharmaceutical composition

[0196] The present disclosure provides a pharmaceutical composition comprising one or more compounds of Formula (I), Formula (Ia), Formula (Ib), Formula (Ic-1), Formula (Ic-2), Formula (Id-1), Formula (Id-2) or pharmaceutically acceptable salts thereof. In some embodiments, the pharmaceutical composition of the present disclosure comprises a compound selected from Formula (I), Formula (Ia), Formula (Ib), Formula (Ic-1), Formula (Ic-2), Formula (Id-1), Formula (Id-2) or pharmaceutically acceptable salts thereof. In some embodiments, the pharmaceutical composition of the present disclosure comprises a first compound selected from Formula (I), Formula (Ia), Formula (Ib), Formula (Ic-1), Formula (Ic-2), Formula (Id-1), Formula (Id-2) or a pharmaceutically acceptable salt thereof and one or more additional compounds having the same formula, wherein the first compound and the additional compound are not the same molecule.

[0197] In some embodiments, pharmaceutical compositions comprise one or more compounds of the present disclosure, or pharmaceutically acceptable salts thereof, and at least one pharmaceutically acceptable carrier or excipient.

[0198] As used herein, a "pharmaceutical composition" is a formulation containing a compound of the present disclosure in a form suitable for administration to a subject. In some embodiments, the pharmaceutical composition is in bulk or unit dosage form.

[0199] As used herein, the term "unit dosage form" refers to physically discrete units suitable as single doses for a subject, each unit containing a predetermined amount of active material calculated to produce the desired therapeutic effect, and a suitable pharmaceutical excipient. The unit dosage form is any of a variety of forms, including, for example, tablets, capsules, pills, powders, granules, sachets, cachets, lozenges, suspensions, emulsions, solutions, syrups, aerosols (as solids or in liquid media), sprays, ointments, pastes, creams, lotions, gels, patches, inhalants, or suppositories. The amount of active ingredient (e.g., a formulation of a disclosed compound or a salt, hydrate, solvate, or isomer thereof) in a unit dosage composition is a therapeutically effective amount and varies according to the specific treatment involved. Those skilled in the art will appreciate that it is sometimes necessary to make routine changes to the dosage according to the age and condition of the patient. The dosage will also depend on the route of administration.

[0200] The pharmaceutical compositions of the present disclosure can be administered by a variety of routes, including, but not limited to, oral (enteral), parenteral (by injection), rectal, transdermal, intradermal, intrathecal, subcutaneous (SC), intravenous (IV), intramuscular (IM), and intranasal (e.g., nasal spray).

[0201] In some embodiments, the compounds of the present disclosure are admixed under sterile conditions with a pharmaceutically acceptable excipient and any needed preservatives, buffers, or propellants.

[0202] As used herein, the term "pharmaceutically acceptable excipient" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, etc. The use of such media and agents for pharmaceutically active substances is well known in the art. Unless any conventional media or agents are incompatible with the active ingredient, it is expected to be used in therapeutic compositions. In addition, various adjuvants commonly used in the art may be included. These and other such compounds are described in the literature, such as Merck Index, Merck & Company, Rahway, NJ. "Pharmaceutically acceptable excipients" used in the specification and claims include one and more than one such excipient. The term "pharmaceutically acceptable excipient" also includes "pharmaceutically acceptable carrier" and "pharmaceutically acceptable diluent".

[0203] The specific excipient, carrier or diluent will depend on the mode and purpose of applying the compound of the present disclosure. The solvent is usually selected based on the solvent that is considered safe for mammalian administration by those skilled in the art. Generally speaking, safe solvents are non-toxic aqueous solvents, such as water and other non-toxic solvents that are soluble or miscible in water. Suitable aqueous solvents include water, ethanol, propylene glycol, polyethylene glycol (e.g., PEG 400, PEG 300), etc. and mixtures thereof. Acceptable excipients, diluents and carriers, and stabilizers are nontoxic to recipients at the dosages and concentrations employed, and include buffers such as phosphate, citrate, and other organic acids; antioxidants, including ascorbic acid and methionine; preservatives (e.g., octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride; benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less than about 10 residues); proteins such as serum albumin, gelatin or immunoglobulins; hydrophilic polymers such as polyvinyl pyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine or lysine; monosaccharides, disaccharides and other carbohydrates, including glucose, mannose, dextrin, starch, hydroxyethyl starch; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose or sorbitol; salt-forming counterions such as sodium ions; metal complexes (e.g., Zn-protein complexes); and / or nonionic surfactants such as TWEEN TM 、PLURONICS TMOr polyethylene glycol (PEG). Compositions may also include one or more stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifiers, glidants, processing aids, colorants, sweeteners, aromatics, flavoring agents and other known additives to provide a fine appearance of a drug (i.e., a compound of the present disclosure or its pharmaceutical composition) or to help manufacture a pharmaceutical product (i.e., a medicament). Active pharmaceutical ingredients may also be embedded in microcapsules (e.g., hydroxymethylcellulose or gelatin-microcapsules and poly-(methyl methacrylate) microcapsules) prepared, for example, by coagulation techniques or by interfacial polymerization, embedded in colloidal drug delivery systems (e.g., liposomes, albumin microspheres, microemulsions, nanoparticles and nanocapsules) or embedded in coarse emulsions. Such technology is disclosed in Remington's Pharmaceutical Sciences, 16th edition, Osol, A. (1980). "Liposomes" are small vesicles composed of various types of lipids, phospholipids and / or surfactants that can be used to deliver drugs (e.g., compounds disclosed herein and optional chemotherapeutic agents) to mammals. The components of liposomes are typically arranged in a bilayer form, similar to the lipid arrangement of biological membranes.

[0204] Pharmaceutical compositions of compounds of the present disclosure can be formulated according to specific routes of administration and dosage forms. Pharmaceutical compositions are typically formulated to achieve a physiologically compatible pH, such as a pH of about 3 to about 11, about 3 to about 10, about 3 to about 9, about 3 to about 8, about 3 to about 7, about 4 to about 11, about 4 to about 10, about 4 to about 9, about 4 to about 8, about 4 to about 7, about 5 to about 11, about 5 to about 10, about 5 to about 9, about 5 to about 8, or about 5 to about 7. In some embodiments, the pharmaceutical composition is formulated to achieve a pH of about 5 to about 7.

[0205] In some embodiments, the pharmaceutical compositions of the present disclosure may be formulated to provide a therapeutically effective amount of a compound provided herein.

[0206] As used herein, the term "therapeutically effective amount" refers to an amount sufficient to provide a therapeutic benefit in the treatment of a disease, disorder or condition or to delay or minimize one or more symptoms associated with the disease, disorder or condition. The therapeutically effective amount of a compound means the amount of a therapeutic agent alone or in combination with other therapies, which provides a therapeutic benefit in the treatment of a disease, disorder or condition. The term "therapeutically effective amount" may include an amount that improves overall treatment, reduces or avoids symptoms or causes of a disease or condition, or enhances the therapeutic efficacy of another therapeutic agent. The precise effective amount of the compound actually administered will typically be determined by a physician according to the relevant circumstances, including the condition to be treated, the selected route of administration, the compound actually administered, the age, weight and response of individual patients, the severity of patient symptoms, etc.

[0207] In some embodiments, the pharmaceutical composition of the present disclosure can be formulated for parenteral or oral administration. For example, the pharmaceutical composition of the present disclosure can be formulated into a solid, a liquid solution, an emulsion or a suspension. In some embodiments, the pharmaceutical composition of the present disclosure can be formulated for pulmonary administration. For example, the pharmaceutical composition of the present disclosure can be formulated into a liquid or a powder. In some embodiments, the pharmaceutical composition of the present disclosure can be formulated into a lyophilized solid, which is reconstituted with a physiologically compatible solvent before administration. In some embodiments, the pharmaceutical composition of the present disclosure can be formulated into a form suitable for the following: oral use (e.g., tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), topical use (e.g., as creams, ointments, gels or aqueous or oily solutions or suspensions), administration by inhalation (e.g., as finely divided powders or liquid aerosols), administration by insufflation (e.g., as finely divided powders).

[0208] In some embodiments, the pharmaceutical compositions of the present disclosure may also be administered chronically ("chronic administration"). As used herein, the term "chronic administration" refers to administration of a compound or a pharmaceutical composition thereof over a long period of time, such as within 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, etc., or may continue indefinitely, such as for the rest of the subject's life. In certain embodiments, chronic administration is intended to provide a constant level of the compound in the blood, such as within a therapeutic window over a long period of time.

[0209] In some embodiments, the pharmaceutical compositions of the present disclosure may also be administered in sustained release form or from a sustained release drug delivery system. A description of representative sustained release materials can be found in Remington's Pharmaceutical Sciences.

[0210] In some embodiments, the pharmaceutical composition of the present disclosure can be formulated into a long-acting formulation for administration by injection, which comprises a therapeutically effective amount of one or more compounds provided herein and a pharmaceutically acceptable excipient, wherein the pharmaceutically acceptable excipient is water and one or more compounds are suspended therein. In some embodiments, the long-acting formulation is administered by intramuscular injection. In some embodiments, the long-acting formulation is administered by subcutaneous injection. In some embodiments, the pharmaceutical composition formulated into a long-acting formulation may further include one or more additional medicaments selected from the group consisting of a wetting agent, a suspending agent, a preservative, a buffer and an isotonic agent.

[0211] Depending on the method for administering the drug, the pharmaceutical composition (or formulation) applied can be packaged in a variety of ways. For example, the article for distribution may include a container in which the pharmaceutical composition is stored in an appropriate form. Suitable containers are well known to those skilled in the art and include materials such as bottles (plastic and glass), pouches, ampoules, plastic bags, metal cylinders, etc. The container may also include a tamper-proof assembly to prevent inadvertent contact with the package contents. In addition, a label describing the container contents is affixed to the container. The label may also include appropriate warnings. The composition may also be packaged in unit dose or multidose containers, such as sealed ampoules and vials, and may be stored under freeze drying (lyophilization) conditions, requiring only the addition of a sterile liquid carrier for injection, such as water, just before use. Extemporaneous injection solutions and suspensions are prepared by sterile powders, granules and tablets of the aforementioned types.

[0212] In some embodiments, the pharmaceutical compositions of the present disclosure are formulated into unit dosage forms. Such single dosage forms or unit dosage forms are expected to be administered once, twice, three times, four times or more per day. In certain embodiments, the pharmaceutical compositions of the present disclosure can be formulated to provide 0.01-50 mg / kg, 0.05-50 mg / kg, 0.1-50 mg / kg, 0.5-50 mg / kg, 1-50 mg / kg, 2-50 mg / kg, 3-50 mg / kg, 4-50 mg / kg, 5-50 mg / kg, 0.01-40 mg / kg, 0.05-40 mg / kg, 0.1-40 mg / kg , 0.5-40mg / kg, 1-40mg / kg, 2-40mg / kg, 3-40mg / kg, 4-40mg / kg, 5-40mg / kg, 0.01-30mg / kg, 0.05- 30mg / kg, 0.1-30mg / kg, 0.5-30mg / kg, 1-30mg / kg, 2-30mg / kg, 3-30mg / kg, 4-30mg / kg, 5-30mg / kg , 0.01-20mg / kg, 0.05-20mg / kg, 0.1-20mg / kg, 0.5-20mg / kg, 1-20mg / kg, 2-20mg / kg, 3-20mg / kg, 4-20mg / kg, 5-20mg / kg, 0.01-15mg / kg, 0.05-15mg / kg, 0.1-15mg / kg, 0.5-15mg / kg, 1-15mg / kg, 2 In some embodiments, the unit dose is administered once a day. In other embodiments, the unit dose is administered twice a day. In other embodiments, the unit dose is administered three times a day. In other embodiments, the unit dose is administered four times a day.

[0213] In some embodiments, the pharmaceutical composition of the present disclosure is administered to obtain an effective amount of the compound of the present disclosure. For example, the amount of the compound of the present disclosure may be in the following range: about 0.1-1000mg, about 1-1000mg, about 10-1000mg, about 50-1000mg, about 100-1000mg, about 200-1000mg, about 300-1000mg, about 400-1000mg, about 500-1000mg, about 0.1-900mg, about 0.1-800mg, about 0.1-700mg, about 0.1-600mg, about 0.1-500mg, about 1-500mg, about 10-500mg, about 50-500mg, about 100-500mg, about 200-500mg, about 300-500mg, or about 400-500mg. In some embodiments, the pharmaceutical compositions of the present disclosure are administered to obtain an amount of about 200-500 mg of the compound of the present disclosure.

[0214] In some embodiments, the compounds of the present disclosure may be administered as the sole active agent, or they may be administered in combination with one or more additional active ingredients. Those skilled in the art will recognize that a variety of active ingredients may be combined with the compounds of the present disclosure. In some embodiments, the additional active ingredients of the pharmaceutical combination formulation or dosing regimen have complementary activities with the compounds of the present disclosure, so that they do not adversely affect each other. Such ingredients are appropriately present in an amount effective for the intended purpose.

[0215] In some embodiments, the additional active ingredients can increase the bioavailability of the compounds provided herein, reduce and / or alter the metabolism of the compounds provided herein, inhibit the excretion of the compounds provided herein, and / or alter the distribution of the compounds provided herein in the body.

[0216] Additional therapeutically active agents include, for example, small organic molecules, such as pharmaceutical compounds (e.g., compounds approved by the U.S. Food and Drug Administration as provided in the Code of Federal Regulations (CFR)), peptides, proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoproteins, mucins, lipoproteins, synthetic polypeptides or proteins, small molecules linked to proteins, glycoproteins, steroids, nucleic acids, DNA, RNA, nucleotides, nucleosides, oligonucleotides, antisense oligonucleotides, lipids, hormones, vitamins, and cells.

[0217] The compounds of Formula (I), (Ia), (Ib), (Ic-1), (Ic-2), (Id-1), (Id-2) or pharmaceutically acceptable salts thereof and the additional active ingredients may be administered together in a single pharmaceutical composition or separately, and when administered separately, this may occur simultaneously or sequentially in any order. Such sequential administration may be spaced shortly in time or spaced long in time. The amounts of the compounds of Formula (I), (Ia), (Ib), (Ic-1), (Ic-2), (Id-1), (Id-2) and the additional active ingredients and the relative times of administration will be selected to achieve the desired combined therapeutic effect.

[0218] Suitable dosages of any of the above co-administered agents are those currently used and may be lowered due to the combined action (synergy) of the newly identified agent and other chemotherapeutic agents or treatments.

[0219] As used herein, the term "combination" refers to simultaneous, separate or sequential administration. In some embodiments, "combination" refers to simultaneous administration. In some embodiments, "combination" refers to separate administration. In some embodiments, "combination" refers to sequential administration. In the case of sequential or separate administration, delaying the administration of the second component should not result in loss of the beneficial effects of the combination.

[0220] Therefore, in another aspect, a combination of a compound of Formula (I), Formula (Ia), Formula (Ib), Formula (Ic-1), Formula (Ic-2), Formula (Id-1), Formula (Id-2) or a pharmaceutically acceptable salt thereof and one or more additional active ingredients is provided.

[0221] On the other hand, a pharmaceutical composition is provided, comprising a combination of a compound of formula (I), formula (Ia), formula (Ib), formula (Ic-1), formula (Ic-2), formula (Id-1), or formula (Id-2) or a pharmaceutically acceptable salt thereof and one or more additional active ingredients, and a pharmaceutically acceptable excipient.

[0222] On the other hand, a kit is provided, comprising a compound of Formula (I), Formula (Ia), Formula (Ib), Formula (Ic-1), Formula (Ic-2), Formula (Id-1), Formula (Id-2) or a pharmaceutically acceptable salt thereof in combination with one or more additional active ingredients.

[0223] In another aspect, a kit is provided, comprising:

[0224] (a) a compound of Formula (I), Formula (Ia), Formula (Ib), Formula (Ic-1), Formula (Ic-2), Formula (Id-1), Formula (Id-2), or Formula (Id-2), or a pharmaceutically acceptable salt thereof, in a first unit dosage form;

[0225] (b) an additional active ingredient selected from those listed above in a second unit dosage form; and

[0226] (c) a container for containing the first and second unit dosage forms.

[0227] Treatment

[0228] In one aspect, due to the effects of the compounds of the present disclosure on GABA A The modulatory activity of the GABA receptor provides a method for treating a subject in need thereof. A A method for treating a disease or condition associated with receptor function, the method comprising administering to a subject a therapeutically effective amount of a compound of Formula (I), Formula (Ia), Formula (Ib), Formula (Ic-1), Formula (Ic-2), Formula (Id-1), or Formula (Id-2), or a pharmaceutically acceptable salt thereof.

[0229] In another aspect, a method for treating a subject in need thereof with GABA is provided. A A method for treating a disease or condition associated with receptor function, the method comprising administering to a subject a composition comprising a therapeutically effective amount of a compound of formula (I), formula (Ia), formula (Ib), formula (Ic-1), formula (Ic-2), formula (Id-1), or formula (Id-2), or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

[0230] In one aspect, a method for treating a neurological disease or condition in a subject in need thereof is provided, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), Formula (Ia), Formula (Ib), Formula (Ic-1), Formula (Ic-2), Formula (Id-1), Formula (Id-2), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0231] As used herein, the term "subject in need thereof" is a subject suffering from a disorder related to GABA. A A subject with a disease or condition associated with receptor function. "Subject" includes a warm-blooded animal. In some embodiments, the warm-blooded animal is a mammal. In some embodiments, the warm-blooded animal is a human.

[0232] with GABA AExemplary diseases or conditions associated with receptor function include, but are not limited to, sleep disorders (e.g., insomnia), mood disorders (e.g., depression (e.g., postpartum depression (PPD), major depressive disorder (MDD)), dysthymic disorder (e.g., minor depression), bipolar disorder (e.g., I and / or II), anxiety disorders (e.g., generalized anxiety disorder (GAD), social anxiety disorder), stress, post-traumatic stress disorder (PTSD), obsessive-compulsive disorder (e.g., obsessive-compulsive disorder (OCD)), schizophrenia spectrum disorders (e.g., schizophrenia, schizoaffective disorder), convulsive disorders (e.g., epilepsy (e.g., status epilepticus (SE), seizures), memory and / or cognitive disorders (e.g., attention disorders (e.g., attention deficit hyperactivity disorder (ADHD)), dementia (e.g., Alzheimer's type dementia, Lewy body dementia, vascular dementia), movement disorders (e.g., Huntington's disease, Parkinson's disease), personality disorders (e.g., antisocial personality disorder, obsessive-compulsive personality disorder), autism spectrum disorders (ASD) (e.g., autism, monogenic causes of autism, e.g., synaptophathy's, e.g., Rett syndrome, fragile X syndrome, Angelman syndrome), pain (e.g., neuropathic pain, injury-related pain syndrome, acute pain, chronic pain), traumatic brain injury (TBI), vascular disease (e.g., stroke, ischemia, vascular malformations), substance abuse disorders and / or withdrawal syndromes (e.g., other than opiates, cocaine and / or alcohol), tinnitus, and essential tremor (ET).

[0233] In some embodiments of the present method, the disease is anxiety, major depressive disorder, postpartum disorder, Alzheimer's disease, Parkinson's disease, epilepsy, focal seizures, PCDH19 pediatric epilepsy, pediatric genetic epilepsy, CDKL5 deficiency (CDD), catamenial epilepsy, infantile spasms, fragile X syndrome, depression, postpartum depression or premenstrual syndrome. In some embodiments, the disease is CDD, MDD, PPD, essential tremor, PTSD, SE, ESE, fragile X syndrome, Parkinson's disease or refractory depression.

[0234] In one aspect, the compounds of Formula (I), Formula (Ia), Formula (Ib), Formula (Ic-1), Formula (Ic-2), Formula (Id-1), Formula (Id-2), and pharmaceutically acceptable salts thereof can be used for therapy, such as treatment of GABA-related A Diseases or conditions associated with receptor function. In some embodiments, the therapy is for use in mammals, including humans and non-human mammals.

[0235] As used herein, the term "therapy" is intended to have the normal meaning of treating a disease to completely or partially alleviate one or more of its symptoms, or to correct or compensate for potential pathology, so as to achieve a beneficial or desired clinical outcome. For the purposes of this disclosure, beneficial or desired clinical outcomes include, but are not limited to, alleviation of symptoms, reduction of disease range, stable (i.e., non-deterioration) disease state, delay or slowing of disease progression, improvement or alleviation of disease state, and alleviation (whether partially or completely), whether detectable or undetectable. "Therapy" may also mean to extend survival compared to the expected survival without treatment. People who need therapy include people who have already suffered from a condition or illness, and people who are susceptible to a condition or illness or people who want to prevent a condition or illness. Unless there are specific indications to the contrary, the term "therapy" also includes prevention. The terms "therapeutic" and "therapeutically" should be interpreted in a corresponding manner.

[0236] As used herein, the term "prevention" is intended to have its normal meaning and includes primary prevention, which prevents the development of a disease, and secondary prevention, where a disease has already developed and the patient is temporarily or permanently protected from an exacerbation or worsening of the disease or the development of new symptoms associated with the disease.

[0237] The term "treat" is used synonymously with "therapy." Similarly, the term "treatment" may be viewed as "applying therapy," where "therapy" is as defined herein.

[0238] Therefore, in one aspect, provided is a compound of Formula (I), Formula (Ia), Formula (Ib), Formula (Ic-1), Formula (Ic-2), Formula (Id-1), Formula (Id-2) or a pharmaceutically acceptable salt thereof for use in therapy.

[0239] In some embodiments, a compound of Formula (I), Formula (Ia), Formula (Ib), Formula (Ic-1), Formula (Ic-2), Formula (Id-1), Formula (Id-2) or a pharmaceutically acceptable salt thereof is provided for use as a medicament.

[0240] In some embodiments, compounds of Formula (I), (Ia), (Ib), (Ic-1), (Ic-2), (Id-1), (Id-2), or (Id-2), or pharmaceutically acceptable salts thereof, are provided for use in treating diseases or conditions that are related, alone or in part, to GABA function.

[0241] In some embodiments, a compound of formula (I), formula (Ia), formula (Ib), formula (Ic-1), formula (Ic-2), formula (Id-1), formula (Id-2) or a pharmaceutically acceptable salt thereof is provided for use in the manufacture of a method for treating GABA A Medicaments for diseases or conditions associated with receptor function.

[0242] In some embodiments, provided are compounds of Formula (I), (Ia), (Ib), (Ic-1), (Ic-2), (Id-1), (Id-2), or a pharmaceutically acceptable salt thereof for use in the manufacture of a medicament for treating depression, such as PPD and MDD, Alzheimer's dementia, and Parkinson's disease.

[0243] For the treatment of the present invention with GABA A The compounds of the present disclosure for diseases or conditions associated with receptor function can be used as monotherapy. As used herein, the term "monotherapy" refers to the administration of a single active or therapeutic compound to a subject in need thereof. In some embodiments, monotherapy will involve administering a therapeutically effective amount of one or more compounds of the present disclosure or a pharmaceutically acceptable salt thereof to a subject in need of such treatment.

[0244] Depending on the particular disease or condition being treated, the treatments described herein may be combined with GABA A Methods for treating diseases or conditions associated with receptor function may include, in addition to administering the compounds of the present disclosure, one or more additional therapies, such as conventional surgery, radiation therapy, chemotherapy, or a combination of such additional therapies. As used herein, the term "combination therapy" refers to the administration of a combination of multiple active compounds.

[0245] Additional therapies may be administered separately from the compounds of the present disclosure, as part of a multiple dosage regimen. Alternatively, these additional therapies may be part of a single dosage form, mixed with the compounds of the present disclosure in a single composition.

[0246] In some embodiments, the compounds of the present disclosure may be administered simultaneously, sequentially, or separately with conventional surgery, radiation therapy, or chemotherapy treatments.

[0247] Example

[0248] The following examples are included for illustrative purposes. However, it should be understood that these examples do not limit the present invention and are intended only to set forth methods for implementing the present disclosure. Those skilled in the art will recognize that the chemical reactions described can be readily adapted to prepare many other compounds of the present disclosure, and alternative methods for preparing compounds of the present disclosure are considered to be within the scope of the present disclosure. For example, the synthesis of non-exemplary compounds according to the present disclosure can be successfully carried out by modifications that are obvious to those skilled in the art, such as by appropriately protecting interfering groups, by utilizing other suitable reagents known in the art other than those described, and / or by making conventional modifications to the reaction conditions. Alternatively, other reactions disclosed herein or known in the art will be considered to have applicability to preparing other compounds of the present disclosure.

[0249] Example 1

[0250] Hexanoic acid [(3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl] ester

[0251]

[0252] A mixture of 1-[(3R,5S,8R,9S,10S,13S,14S,17S)-3-hydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-17-yl]ethanone (500 mg, 1.57 mmol, 1.0 equiv) was dissolved in DCM (10 mL). Hexanoyl chloride (275 mg, 2.04 mmol, 0.285 mL, 1.3 equiv), pyridine (248 mg, 3.14 mmol, 0.253 mL, 2.0 equiv) and DMAP (9.6 mg, 0.079 mmol, 0.05 equiv) were added. The reaction mixture was stirred at 20 °C for 12 h. The reaction mixture was washed with H 2 O (30 ml) and extracted with DCM (30 mL x 3). The combined organic layers were washed with brine (50 mL) and purified by Na 2 SO 4 The residue was purified by flash silica gel chromatography ( 20g Silica Flash Column, eluted with 0-10% ethyl acetate / petroleum ether gradient at 35 mL / min) to give [(3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl]hexanoate (550 mg, 84.1% yield) as a white solid. LCMS (ESI) m / z: C 27 H 44 O 3 Calculated value 416.33, experimental value 415.4 (MH) - . 1 H NMR (400 MHz, CDCl 3)δ(ppm)5.01(s,1H),2.54-2.49(m,1H),2.31-2.26(m,2H),2.19-2.10(m,4H),2.01-1.98(m,1 H),1.73-1.59(m,8H),1.52-1.11(m,16H),0.99-0.88(m,4H),0.83-0.72(m,4H),0.60(s,3H). 13 C NMR (100 MHz, CDCl 3 )δ(ppm)209.64,173.32,69.63,63.80,56.71,54.09,44.21,40.05,39.03,35.77,35.39,34.78,32.9 1,32.84,31.86,31.51,31.28,28.23,26.08,24.82,24.33,22.72,22.35,20.76,13.96,13.43,11.31.

[0253] Example 2

[0254] Heptanoic acid [(3R,5S,8R,9S,10S,13S,14S,17S)-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl] ester

[0255]

[0256] Heptanoic acid [(3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl] ester was prepared according to the same procedure as in Example 1, except that hexanoyl chloride was replaced with heptanoyl chloride (550 mg, 80.5% yield). LCMS (ESI) m / z: C 28 H 46 O 3 Calculated value 430.34, experimental value 429.3 (MH) - . 1 H NMR (400 MHz, CDCl 3)δ(ppm)5.02(s,1H),2.54-2.50(m,1H),2.32-2.28(m,2H),2.17-2.11(m,4H),2.02-2.00(m,1 H),1.71-1.61(m,8H),1.48-1.15(m,18H),0.93-0.89(m,4H),0.83-0.76(m,4H),0.61(s,3H). 13 C NMR (101 MHz, CDCl 3 )δ(ppm)209.69,173.38,69.69,63.86,56.78,54.16,44.26,40.11,39.09,35.82,35.45,34.87,32.9 7,32.90,31.91,31.54,28.85,28.28,26.13,25.16,24.38,22.79,22.57,20.81,14.09,13.47,11.35.

[0257] Example 3

[0258] Octanoic acid (3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthrene-3-yl ester

[0259]

[0260] Octanoic acid [(3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl] ester was prepared according to the same procedure as Example 1, except that hexanoyl chloride was replaced with octanoyl chloride (550 mg, 78.0% yield). LCMS (ESI) m / z: C 29 H 48 O 3 Calculated value 444.36, experimental value 443.4 (MH) - . 1 H NMR (400 MHz, CDCl 3)δ(ppm)5.02(s,1H),2.54-2.49(m,1H),2.32-2.19(m,2H),2.17-2.11(m,4H),2.02-1.99(m,1 H),1.71-1.57(m,8H),1.52-1.15(m,20H),0.93-0.87(m,4H),0.81-0.76(m,4H),0.60(s,3H). 13 C NMR (100 MHz, CDCl 3 )δ(ppm)173.37,69.69,63.86,56.78,54.17,44.25,40.11,39.08,35.82,35.44,34.86,32.98,32.90,31 .90,31.77,29.13,31.54,29.03,28.28,26.13,25.20,24.37,22.79,22.66,20.81,14.12,13.46,11.35.

[0261] Example 4

[0262] Hexanoic acid [(3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-3,10,13-trimethyl-1,2,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydrocyclopenta[a]phenanthrene-3-yl] ester

[0263]

[0264] Hexanoic acid [(3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-3,10,13-trimethyl-1,2,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydrocyclopenta[a]phenanthrene-3-yl] ester was prepared according to the same procedure as in Example 1 except that 1-[(3R,5S,8R,9S,10S,13S,14S,17S)-3-hydroxy-10,13-dimethyl-2,3, 4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-17-yl]ethanone was changed to 1-[(3R,5S,8R,9S,10S,13S,14S,17S)-3-hydroxy-3,10,13-trimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-17-yl]ethanone (176 mg, 44.8% yield). 1 H NMR (400 MHz, CDCl 3)δ(ppm)2.54-2.50(m,1H),2.27-2.18(m,4H),2.11(s,3H),2.02-1.98(m,1H),1.93-1.89(m,1H),1.70-1.57( m,6H),1.51-1.44(m,4H),1.41-1.11(m,15H),0.95-0.88(m,4H),0.77(s,3H),0.75-0.69(m,1H),0.60(s,3H). 13 C NMR (100 MHz, CDCl 3 )δ(ppm)209.72,173.27,81.63,63.86,56.76,54.28,44.29,41.09,39.10,39.08,35.76,35.49,35.33,3 4.12,32.26,31.98,31.54,31.40,28.01,26.39,25.00,24.38,22.79,22.44,21.01,14.03,13.48,11.70.

[0265] Example 5

[0266] Heptanoic acid [(3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-3,10,13-trimethyl-1,2,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydrocyclopenta[a]phenanthrene-3-yl] ester

[0267]

[0268] [(3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-3,10,13-trimethyl-1,2,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydrocyclopenta[a]phenanthrene-3-yl]heptanoate was prepared according to the same procedure as in Example 1 except that 1-[(3R,5S,8R,9S,10S,13S,14S,17S)-3-hydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydrocyclopenta[a]phenanthrene-3-yl]heptanoate was used as the 7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-17-yl]ethanone was replaced with 1-[(3R,5S,8R,9S,10S,13S,14S,17S)-3-hydroxy-3,10,13-trimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-17-yl]ethanone, and hexanoyl chloride was replaced with heptanoyl chloride (350 mg, 51.8% yield). LCMS (ESI) m / z: C 29 H 48 O 3 Calculated value 444.36, experimental value 443.4 (MH) - . 1 H NMR (400 MHz, CDCl 3 )δ(ppm)2.54-2.50(m,1H),2.28-2.19(m,4H),2.12(s,3H),2.02-1.99(m,1H),1.93-1.90(m,1H),1.71-1.57(m,7H),1. 51-1.46(m,4H),1.43-1.32(m,10H),1.27-1.32(m,6H),0.95-0.86(m,4H),0.77(s,3H),0.74-0.70(m,1H),0.61(s,3H). 13 C NMR (100 MHz, CDCl 3 )δ(ppm)209.21,172.76,81.11,63.36,56.25,53.78,43.77,40.59,38.59,38.57,35.30,34.97,34.80,33.6 1,31.73,31.46,31.09,31.03,28.40,27.49,25.87,24.78,23.86,22.27,22.09,20.50,13.61,12.96,11.19.

[0269] Example 6

[0270] Octanoic acid [(3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-3,10,13-trimethyl-1,2,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydrocyclopenta[a]phenanthrene-3-yl] ester

[0271]

[0272] Octanoic acid [(3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-3,10,13-trimethyl-1,2,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydrocyclopenta[a]phenanthrene-3-yl] ester was prepared according to the same procedure as in Example 1, except that hexanoyl chloride was replaced with octanoyl chloride and 1-[(3R,5S,8R,9S,10S,13S,14S,17S)-3-hydroxy-10,13-dimethyl- Methyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-17-yl]ethanone was replaced with 1-[(3R,5S,8R,9S,10S,13S,14S,17S)-3-hydroxy-3,10,13-trimethyl-1,2,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydrocyclopenta[a]phenanthrene-17-yl]ethanone (350 mg, 50.2% yield). 1 H NMR (400 MHz, CDCl 3 )δ(ppm)2.54-2.50(m,1H),2.27-2.17(m,7H),2.02-1.94(m,1H),1.93-1.90( m,1H),1.71-1.15(m,29H),0.95-0.85(m,4H),0.77-0.70(m,4H),0.61(s,3H). 13 C NMR (100 MHz, CDCl 3 )δ(ppm)209.74,173.29,81.65,63.89,56.78,54.32,44.29,41.11,39.09,35.83,35.49,35.33,34.13,32.2 9,31.98,31.83,31.56,29.23,29.14,28.01,26.40,25.36,24.38,22.79,22.72,21.03,14.15,13.48,11.72.

[0273] Example 7

[0274] 3-Cyclopentylpropionic acid [(3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl] ester

[0275]

[0276] 3-Cyclopentylpropanoic acid [(3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl] ester was prepared according to the same procedure as in Example 1, except that hexanoyl chloride was replaced by 3-cyclopentylpropanoyl chloride. 1 H NMR (400 MHz, CDCl 3 )δ(ppm)5.02(bs,1H),2.54-2.50(m,1H),2.32-2.28(m,2H),2.17-2.11(m,4H),2.02-2.00(m, 1H),1.71-1.61(m,8H),1.48-1.15(m,18H),0.93-0.89(m,4H),0.83-0.76(m,4H),0.61(s,3H). 13 C NMR (100 MHz, CDCl 3 )δ(ppm)209.70,172.91,69.64,63.84,56.76,54.17,44.26,41.06,40.13,39.08,37.15,36.72,3 5.45,33.02,32.98,32.44,31.94,31.58,28.28,26.05,25.05,24.38,22.90,20.81,13.47,11.35.

[0277] Example 8

[0278] 3-Cyclopentylacetate [(3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl]

[0279]

[0280] Step 1: Preparation of 2-cyclopentylacetyl chloride

[0281]

[0282] To a solution of 2-cyclopentylacetic acid (0.80 g, 6.24 mmol, 0.784 mL, 1.0 eq) in DCM (10 mL) was added DMF (38.0 mg, 0.51 mmol, 0.040 mL, 0.1 eq) followed by dropwise addition of SOCl at 0 °C. 2 (1.86 g, 15.60 mmol, 1.13 mL, 2.5 eq.) The mixture was stirred at 20° C. for 2 hours and then concentrated. The resulting crude product, 2-cyclopentylacetyl chloride (900 mg, light yellow oil), was used in the next reaction without further purification.

[0283] Step 2: Preparation of 3-cyclopentylacetate [(3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl] ester

[0284]

[0285] 3-Cyclopentylacetate [(3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl] ester was prepared according to the same procedure as Example 1, except that hexanoyl chloride was replaced with 2-cyclopentylacetyl chloride (126 mg, 31.2% yield). LCMS (ESI) m / z: C 28 H 44 O 3 Calculated value 428.33, found value 429.33 (M+H) + . 1 H NMR (400 MHz, CDCl 3 )δ(ppm)5.04(s,1H),2.53(t,J=8.0Hz,1H),2.38-2.11(m,6H),1.82-1.84(m ,1H),1.94-1.08(m,27H),1.01-0.89(m,1H),0.86-0.72(m,4H),0.61(s,3H). 13 C NMR (100 MHz, CDCl 3)δ(ppm)209.79,172.96,69.67,63.88,56.76,54.17,44.28,41.05,40.14,39.92,39.07,36.73,36.2 6,35.83,35.47,32.91,32.45,32.43,31.94,28.29,26.16,25.07,25.05,24.38,20.82,13.48,11.36.

[0286] Example 9

[0287] 3-Cyclopentylpropionic acid [(3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-3,10,13-trimethyl-1,2,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydrocyclopenta[a]phenanthrene-3-yl] ester

[0288]

[0289] 3-Cyclopentylpropanoic acid [(3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-3,10,13-trimethyl-1,2,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydrocyclopenta[a]phenanthrene-3-yl] ester was prepared according to the same procedure as in Example 1, except that hexanoyl chloride was replaced with 3-cyclopentylpropanoyl chloride and 1-[(3R,5S,8R,9S,10S,13S,14S,17S)-3-hydroxy-10 ,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-17-yl]ethanone was replaced with 1-[(3R,5S,8R,9S,10S,13S,14S,17S)-3-hydroxy-3,10,13-trimethyl-1,2,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydrocyclopenta[a]phenanthrene-17-yl]ethanone (90.0 mg, 13.0% yield). 1 H NMR (400 MHz, CDCl 3 )δ(ppm)2.53(t,J=8.0Hz,1H),2.27-2.12(m,7H),2.04-1.79(m,4H),1.74-1.14(m,27H),0.94-0.83(m,2H),0.81-0.66(m,4H),0.61(s,3H). 13 C NMR (100 MHz, CDCl 3)δ(ppm)209.22,172.32,81.14,63.34,56.24,53.82,43.78,41.50,40.56,38.57,38.47,36.25,34.99,3 4.82,33.62,32.00,31.96,31.90,31.50,31.03,27.50,25.86,24.55,23.87,22.26,20.50,12.97,11.19.

[0290] Example 10

[0291] 2-Cyclopentylacetate [(3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-3,10,13-trimethyl-1,2,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydrocyclopenta[a]phenanthrene-3-yl]

[0292]

[0293] 2-Cyclopentylacetate [(3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-3,10,13-trimethyl-1,2,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydrocyclopenta[a]phenanthrene-3-yl] ester was prepared according to the same procedure as in Example 1, except that hexanoyl chloride was replaced with 2-cyclopentylacetyl chloride and 1-[(3R,5S,8R,9S,10S,13S,14S,17S)-3-hydroxy-10 ,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-17-yl]ethanone was replaced with 1-[(3R,5S,8R,9S,10S,13S,14S,17S)-3-hydroxy-3,10,13-trimethyl-1,2,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydrocyclopenta[a]phenanthrene-17-yl]ethanone (106 mg, 26.5% yield). LCMS (ESI) m / z: C 29 H 46 O 3 Calculated value 442.34, found value 443.3 (M+H) + . 1 H NMR (400 MHz, CDCl 3)δ(ppm)2.53(t,J=8.0Hz,1H),2.32-2.08(m,8H),2.05-1.79(m,4H),1.74-1.10(m,24H),0.99-0.85(m,2H),0.82-0.66(m,4H),0.61(s,3H). 13 C NMR (100 MHz, CDCl 3 )δ(ppm)209.73,172.84,81.66,63.87,56.76,54.34,44.30,42.03,41.09,39.10,38.99,36.77,35.52,35.3 4,34.15,32.53,32.48,32.43,32.03,31.56,28.03,26.92,26.39,25.06,24.39,22.79,21.02,13.49,11.72.

[0294] Embodiment 11

[0295] 3-Cyclopent-3-en-1-ylpropanoic acid [(3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl] ester

[0296]

[0297] Step 1: Preparation of ethyl 3-(cyclopent-3-en-1-yl)propanoate

[0298]

[0299] To a solution of diethyl malonate (1.27 g, 7.93 mmol, 1.20 mL, 2.0 equiv) in anhydrous DMF (10 mL) was added NaH (317 mg, 7.93 mmol, 60%, 2.0 equiv) at 0°C, and then the resulting reaction mixture was stirred at 25°C for 30 min. A solution of 4-methylbenzenesulfonic acid cyclopent-3-en-1-ylmethylmethyl ester (1.0 g, 3.96 mmol, 1.0 equiv) in anhydrous DMF (5 mL) was added dropwise to the above mixture at 25°C and the resulting reaction mixture was stirred at 60°C for 12 h. The reaction mixture was combined with another batch. The reaction mixture was washed with H 2 O (50 mL) and extracted with EtOAc (60 mL×3). The combined organic layers were washed with brine (100 mL), 2 SO 4Dry, filter and concentrate. The crude product was purified by flash silica gel chromatography ( 20g Purification by HPLC-MS / MS (HPLC-MS / MS) using a 0-10% ethyl acetate / petroleum ether gradient at 35 mL / min gave diethyl 2-(cyclopent-3-en-1-ylmethyl)malonate (1.7 g, 7.07 mmol, 89.3% yield) as a colorless oil.

[0300] To diethyl 2-(cyclopent-3-en-1-ylmethyl)malonate (800 mg, 3.33 mmol, 1 eq.) was dissolved in DMA (10 mL) and H 2 To the mixture in 2% CO (1 mL), LiCl (706 mg, 16.65 mmol, 5.0 equiv) was added. The reaction mixture was stirred at 135 °C for 12 h. The reaction mixture was combined with another batch. The reaction mixture was washed with H 2 O (30 mL) and extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine (50 mL) and purified by Na 2 SO 4 Dry, filter and concentrate. The crude product was purified by flash silica gel chromatography ( 20g Purification by HPLC-MS / MS (HPLC-MS / MS) using a 0-10% ethyl acetate / petroleum ether gradient at 30 mL / min gave ethyl 3-cyclopent-3-en-1-ylpropanoate (750 mg, 4.46 mmol, 67.0% yield) as a brown oil. 1 H NMR (400 MHz, CDCl 3 )δ(ppm)5.67(m,2H),4.21-4.10(m,2H),2.52-2.45(m,2H),2.40-2.30(m,2H) ,2.28-2.21(m,1H),2.01-1.92(m,2H),1.80-1.71(m,2H),1.28-1.24(m,3H).

[0301] Step 2: Preparation of 3-(cyclopent-3-en-1-yl)propanoyl chloride

[0302]

[0303] To ethyl 3-cyclopent-3-en-1-ylpropanoate (750 mg, 4.46 mmol, 1.0 eq.) was dissolved in THF (5 mL) and H 2To the mixture in 4% CO (5 mL), NaOH (892 mg, 22.29 mmol, 5.0 equiv) was added. The reaction mixture was stirred at 25 °C for 1 h and then acidified with HCl (1 N, 20 mL). 2 O (30 ml) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (50 mL) and purified by Na 2 SO 4 Dry, filter and concentrate. The obtained crude product 3-cyclopent-3-en-1-ylpropanoic acid (600 mg, 96.0% yield, brown oil) was used in the next reaction without further purification.

[0304] To a mixture of 3-cyclopent-3-en-1-ylpropanoic acid (100 mg, 0.713 mmol, 1.0 equiv) in DCM (5 mL) and DMF (0.05 mL) was added SOCl at 0 °C. 2 (170 mg, 1.43 mmol, 0.103 mL, 2.0 equiv.) The reaction mixture was then stirred at 20°C for 3 hours. The reaction mixture was concentrated under reduced pressure to give 3-cyclopent-3-en-1-ylpropanoyl chloride (120 mg, crude material, light yellow oil), which was used in the next reaction without further purification.

[0305] Step 3: Preparation of 3-cyclopent-3-en-1-yl propanoic acid [(3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl] ester

[0306]

[0307] 3-Cyclopent-3-en-1-ylpropanoic acid [(3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl] ester was prepared according to the same procedure as Example 1, except that hexanoyl chloride was replaced with 3-cyclopent-3-en-1-ylpropanoyl chloride (117 mg, 41.8% yield). 1 H NMR (400 MHz, CDCl 3)δ(ppm)5.87(s,2H),5.02(s,1H),2.54-2.49(m,3H),2.34-2.17(m,4H),2.11(s,3H),2.02-1.95(m,3H),1 .77-1.60(m,8H),1.52-1.37(m,6H),1.30-1.12(m,6H),1.00-0.91(m,1H),0.83-0.76(m,4H),0.60(s,3H). 13 C NMR (100 MHz, CDCl 3 )δ(ppm)209.66,173.30,129.81,69.79,63.86,56.77,54.15,44.26,40.12,39.08,38.67,38.64,37.18,3 5.83,35.46,33.72,32.99,32.89,31.91,31.58,31.53,28.28,26.13,24.38,22.79,20.81,13.47,11.35.

[0308] Example 12

[0309] 3-Cyclopent-3-en-1-ylpropanoic acid [(3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-3,10,13-trimethyl-1,2,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydrocyclopenta[a]phenanthrene-3-yl] ester

[0310]

[0311] 3-Cyclopent-3-en-1-ylpropanoic acid [(3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-3,10,13-trimethyl-1,2,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydrocyclopenta[a]phenanthrene-3-yl] ester was prepared according to the same procedure as in Example 1, except that hexanoyl chloride was replaced with 3-cyclopent-3-en-1-ylpropanoyl chloride and 1-[(3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-3,10,13-trimethyl-1,2,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydrocyclopenta[a]phenanthrene-3-yl] 3-Hydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-17-yl]ethanone was replaced with 1-[(3R,5S,8R,9S,10S,13S,14S,17S)-3-hydroxy-3,10,13-trimethyl-1,2,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydrocyclopenta[a]phenanthrene-17-yl]ethanone (101 mg, 21.1% yield). 1 H NMR (400 MHz, CDCl 3 )δ(ppm)5.68(m,2H),2.55-2.48(m,3H),2.32-2.13(m,5H),2.12(s,3H),2.03-1.91(m,4H) ,1.75-1.61(m,5H),1.51-1.11(m,15H),0.98-0.86(m,2H),0.78-0.70(m,4H),0.61(s,3H). 13 C NMR (100 MHz, CDCl 3 )δ(ppm)209.72,173.16,129.80,81.72,63.85,56.72,54.25,44.26,41.08,39.04,38.65,37.15,35.4 6,35.29,34.57,34.16,32.24,31.86,31.66,31.25,27.97,26.34,26.25,24.35,22.76,13.43,11.67.

[0312] Embodiment 13

[0313] 3-(5-oxotetrahydrofuran-2-yl)propanoic acid [(3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl] ester

[0314]

[0315] Step 1: Preparation of 4-oxopimelic acid dichloride

[0316]

[0317] To a mixture of 4-oxopimelic acid (1.0 g, 5.74 mmol, 1.0 equiv) in DCM (10 mL) at 0 °C was added DMF (0.05 mL) followed by SOCl 2 (1.71 g, 14.36 mmol, 1.04 mL, 2.5 equiv.). The reaction mixture was stirred at 20 °C for 3 h. The reaction mixture was concentrated to give 4-oxopimeloyl chloride (1.3 g, crude) as a light yellow oil, which was used in the next step without further purification.

[0318] Step 2: Preparation of 7-[[(3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl]oxy]-4,7-dioxo-heptanoic acid

[0319]

[0320] 7-[[(3R,5S,8R,9S,10S,13S,14S,17S)-17-Acetyl-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl]oxy]-4,7-dioxo-heptanoic acid was prepared according to the same procedure as Example 1, except that hexanoyl chloride was replaced with 4-oxopimelic acid dichloride (1.0 g, 40.0% yield). 1 H NMR (400 MHz, CDCl 3 )δ(ppm)5.01(bs,1H),2.85-2.75(m,4H),2.69-2.61(m,4H),2.53(t,J=8.0Hz,1H),2.2 3-2.00(m,5H),1.78-1.10(m,19H),1.03-0.90(m,1H),0.83-0.80(m,4H),0.61(s,3H).

[0321] Step 3: Preparation of 3-(5-oxotetrahydrofuran-2-yl)propanoic acid [(3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl] ester

[0322]

[0323] To a mixture of 7-[[(3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl]oxy]-4,7-dioxo-heptanoic acid (500 mg, 1.05 mmol, 1.0 equiv) (59.8 mg, 1.58 mmol, 1.5 equiv) in DCM (5 mL) and MeOH (5 mL) was added NaBH 4 The reaction mixture was stirred at 20 °C for 12 hours and then concentrated to give 7-[[(3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl]oxy]-4-hydroxy-7-oxo-heptanoic acid (500 mg, 99.6% yield, crude) as a light yellow oil, which was used in the next step without further purification.

[0324] To a mixture of 7-[[(3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl]oxy]-4-hydroxy-7-oxo-heptanoic acid (500 mg, 1.05 mmol, 1 eq) in DCM (10 mL) was added HCl (8 M, 10.0 mL, 76 eq). The reaction mixture was stirred at 25 °C for 2 h and then washed with H 2 O (30 mL) and extracted with DCM (30 mL x 3). The combined organic layers were washed with brine (50 mL) and purified by Na 2 SO 4 Dry, filter and concentrate. The crude product was purified by flash silica gel chromatography ( 20g Silica Flash Column, eluted with 0-50% ethyl acetate / petroleum ether gradient at 35 mL / min) to give 3-(5-oxotetrahydrofuran-2-yl)propanoic acid [(3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl] ester (228 mg, 46.9% yield, 99% purity) as a white solid. LCMS (ESI) m / z: C 28 H 42 O 5 Calculated value 458.30, experimental value 481.3 (M+Na) + . 1 H NMR (400 MHz, CDCl 3 )δ(ppm)5.05(s,1H),4.60-4.53(m,1H),2.59-2.46(m,5H),2.42-2.34(m,1H),2.20-2.12(m,4H),2.06-1.87(m, 4H),1.74-1.61(m,6H),1.54-1.39(m,6H),1.30-1.14(m,6H),1.01-0.91(m,1H),0.84-0.77(m,4H),0.61(s,3H). 13 CNMR (100MHz, CDCl 3 )δ(ppm)209.71,176.83,172.08,79.74,79.72,70.40,70.34,63.81,56.68,54.01,44.22,40.04,39.00,35.7 8,35.41,32.86,31.85,31.52,30.78,30.68,30.63,28.72,28.20,27.88,25.98,24.33,22.74,13.43,11.31.

[0325] Embodiment 14

[0326] 4-Acetoxybutyric acid [(3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl] ester

[0327]

[0328] Step 1: Preparation of 4-acetoxybenzyl butyrate

[0329]

[0330] To a mixture of tetrahydrofuran-2-one (2.0 g, 23.23 mmol, 1.77 mL, 1.0 equiv) in MeOH (25 mL) was added tetrabutylammonium hydroxide (6.03 g, 23.23 mmol, 7.53 mL, 1.0 equiv), and the resulting mixture was stirred at 70 ° C for 2 hours. The mixture was then concentrated, and the residue was dissolved in DMF (25 mL), and BnBr (3.97 g, 23.23 mmol, 2.76 mL, 1.0 equiv) was slowly added. The resulting mixture was stirred at 25 ° C for 16 hours. The mixture was then diluted with EtOAc (250 mL) and washed with water (50 mL×3). The organic layer was separated and purified by Na 2 SO 4 Dry, filter and concentrate. The crude product was purified by flash silica gel chromatography ( 20g Silica Flash Column, eluted with 0-40% ethyl acetate / petroleum ether gradient at 35 mL / min) to give 4-hydroxybutyric acid benzyl ester (2.2 g, 11.33 mmol, 48.8% yield, 100% purity) as a colorless oil. LCMS (ESI) m / z: C 11 H 14 O 3 Calculated value 194.09, found value 195.1 (M+H) + . 1 HNMR (400 MHz, DMSO-d 6 )7.39-7.16(m,5H),5.08(s,2H),4.26(t,J=6.8Hz,1H),3.41-3.40(m,2H),2.40-2.37(m,2H),1.70-1.66(m,2H).

[0331] To a mixture of benzyl 4-hydroxybutyrate (400 mg, 2.06 mmol, 1.0 equiv) in DCM (10 mL) at 0 °C were added DMAP (37.7 mg, 0.309 mmol, 0.15 equiv), Et 3 N (208 mg, 2.06 mmol, 0.287 mL, 1.0 equiv) and acetyl acetate (210 mg, 2.06 mmol, 0.193 mL, 1.0 equiv), and the mixture was then heated at 25 °C under N 2The mixture was diluted with water (30 mL), then extracted with EtOAc (30 mL×3), and the organic layer was washed with brine (50 mL) and purified by Na 2 SO 4 Dry, filter and concentrate. The residue was purified by flash silica gel chromatography ( 4g Silica Flash Column, eluted with 0-10% ethyl acetate / petroleum ether gradient at 30 mL / min) to give 4-acetoxybutyric acid benzyl ester (410 mg, 84.3% yield, 100% purity) as a colorless oil. LCMS (ESI) m / z: C 13 H 16 O 4 Calculated value 236.1, found value 237.1 (M+H) + ,259.2(M+Na) + . 1 H NMR (400 MHz, CDCl 3 )7.40-7.33(m,5H),5.13(s,2H),4.13-4.09(m,3H),2.48-2.43(m,2H),2.03(s,3H),2.00-1.96(m,2H).

[0332] Step 2: Preparation of 4-chloro-4-oxobutyl acetate

[0333]

[0334] In N 2 To a solution of benzyl 4-acetoxybutyrate (410 mg, 1.74 mmol, 1 eq) in EtOAc (10 mL) was added Pd / C (50 mg, 10% on carbon). The resulting suspension was degassed under vacuum and washed with H 2 The mixture was stirred at 25 °C under H 2 (15 psi) for 3 h. The reaction mixture was filtered, and the filtrate was concentrated to give 4-acetoxybutyric acid (300 mg, crude) as a colorless oil, which was used directly in the next step without further purification.

[0335] At 0°C in N 2 To a mixture of 4-acetoxybutyric acid (150 mg, 1.03 mmol, 1 eq.) in DCM (5 mL) was added SOCl 2(246 mg, 2.07 mmol, 0.15 mL, 2.0 equiv), and then the mixture was stirred at 25° C. atmosphere for 16 h. The mixture was concentrated to give 4-chloro-4-oxobutyl acetate (160 mg, crude) as a colorless oil, which was used directly in the next step without further purification.

[0336] Step 3: Preparation of 4-acetoxybutyric acid [(3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl] ester

[0337]

[0338] 4-Acetoxybutyric acid [(3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl] ester was prepared according to the same procedure as Example 1, except that hexanoyl chloride was replaced with 4-chloro-4-oxobutyl acetate (68.4 mg, 16.8% yield, 100% purity). LCMS (ESI) m / z: C 27 H 42 O 5 Calculated value 446.40, experimental value 469.1 (M+Na) + . 1 H NMR (400 MHz, CDCl 3 )δ(ppm)5.04(d,J=2.8Hz,1H),4.12(t,J=6.4Hz,2H),2.53(t,J=8.8Hz,1H),2.39(t,J=7.4Hz,2 H),2.23-1.91(m,10H),1.71-1.16(m,18H),1.02-0.90(m,1H),0.83-0.80(m,4H),0.61(s,3H). 13 C NMR (100 MHz, CDCl 3 )δ(ppm)209.72,172.28,171.03,70.19,63.83,63.55,56.73,54.07,44.25,40.09,39.05,35.80,35.4 1,32.91,32.84,31.85,31.55,31.31,28.23,26.08,24.36,24.13,22.76,20.96,20.79,13.46,11.33.

[0339] Embodiment 15

[0340] 4-(2-methylpropionyloxy)butanoic acid [(3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl] ester

[0341]

[0342] Step 1: Preparation of 4-chloro-4-oxobutyl isobutyrate

[0343] 4-Chloro-4-oxobutyl isobutyrate was prepared following the same procedure as for the preparation of 4-chloro-4-oxobutyl acetate from benzyl 4-hydroxybutyrate, except that acetyl acetate was replaced with isobutyryl chloride.

[0344] Step 2: Preparation of 4-(2-methylpropanoyloxy)butanoic acid [(3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl] ester

[0345]

[0346] 4-(2-methylpropanoyloxy)butanoic acid [(3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl] ester was prepared according to the same procedure as Example 1, except that hexanoyl chloride was replaced with 4-chloro-4-oxobutyl isobutyrate (114 mg, 28.9% yield, 100% purity). LCMS (ESI) m / z: C 29 H 46 O 5 Calculated value 474.33, experimental value 497.2 (M+Na) + . 1 HNMR (400MHz, CDCl 3)δ(ppm)5.04(s,1H),4.12(t,J=6.4Hz,2H),2.61-2.50(m,2H),2.41(t,J=7.2Hz,2H),2.22-2.12(m,1H),2. 24-2.06(m,3H),2.03-1.95(m,3H),1.75-1.03(m,23H),1.03-0.90(m,1H),0.83-0.76(m,4H),0.61(s,3H). 13 C NMR (100 MHz, CDCl 3 )δ(ppm)209.71,177.05,172.30,70.18,63.83,63.27,56.73,54.06,44.24,40.07,39.04,35.79,35.41,3 3.96,32.91,32.83,31.84,31.54,31.25,28.22,26.07,24.35,24.21,22.75,20.78,19.01,13.45,11.33.

[0347] Example 16

[0348] 5-Acetoxypentanoic acid [(3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl] ester

[0349]

[0350] Step 1: Preparation of 5-acetoxypentanoic acid

[0351]

[0352] To pentane-1,5-diol (3.0 g, 28.81 mmol, 3.03 mL, 1.0 equiv), Et 3 To a mixture of N (4.37 g, 43.21 mmol, 6.01 mL, 1.5 eq) in DCM (40 mL) was added acetyl chloride (2.26 g, 28.81 mmol, 2.06 mL, 1.0 eq), and then the mixture was stirred at 25 °C under N 2 The mixture was diluted with water (30 mL) and then extracted with DCM (30 mL x 2). The combined organic layers were combined and purified by Na 2 SO 4 Dry, filter and concentrate. The crude product was purified by flash silica gel chromatography ( 20g The resulting mixture was purified by HPLC-MS / MS (HPLC-MS / ... 1 H NMR (400 MHz, CDCl 3 )4.07(t,J=6.8Hz,2H),3.65(t,J=6.4Hz,2H),2.04(s,3H),1.68-1.58(m,4H),1.47-1.39(m,2H).

[0353] To a mixture of 5-hydroxypentyl acetate (260 mg, 1.78 mmol, 1.0 eq) in DMF (8 mL) was added PDC (2.01 g, 5.34 mmol, 3.0 eq). The resulting mixture was stirred at 25 °C for 16 hours. The reaction mixture was combined with another batch, diluted with EtOAc (100 mL), and then washed with water (30 mL x 3). The organic layer was separated and purified by Na 2 SO 4 Dry, filter and concentrate. The crude product was purified by flash silica gel chromatography ( 4g The product was purified by HPLC-MS / MS (HPLC-MS / ... 1 H NMR (400 MHz, CDCl 3 )4.09(t,J=6.0Hz,2H),2.45-2.37(m,2H),2.06(s,3H),1.77-1.60(m,4H).

[0354] Step 2: Preparation of (5-chloro-5-oxo-pentyl) acetate

[0355]

[0356] To a mixture of 5-acetoxypentanoic acid (160 mg, 1.00 mmol, 1.0 equiv) in DCM (6 mL) was added SOCl 2 (238 mg, 2.00 mmol, 0.145 mL, 2.0 equiv) and DMF (14.6 mg, 0.200 mmol, 0.015 mL, 0.2 equiv), and the mixture was then heated at 25 °C under N 2The mixture was stirred for 16 hours under an atmosphere of CHCl. ​​The mixture was concentrated to obtain the compound (5-chloro-5-oxo-pentyl) acetate (180 mg, crude material) as a yellow oil, which was used directly in the next step without further purification.

[0357] Step 3: Preparation of 5-acetoxypentanoic acid [(3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl] ester

[0358]

[0359] 5-Acetoxypentanoic acid [(3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl] ester was prepared according to the same procedure as in Example 1, except that hexanoyl chloride was replaced with (5-chloro-5-oxo-pentyl) acetate (202 mg, 43% yield, 99.3% purity). LCMS (ESI) m / z: C 28 H 44 O 5 Calculated value 460.32, experimental value 483.3 (M+Na) + . 1 H NMR (400 MHz, CDCl 3 )δ(ppm)5.04(s,1H),4.14-4.08(m,2H),2.53(t,J=8.9Hz,1H),2.37-2.34(m,2H),2.22-2.12(m,4H),2.0 6-2.00(m,4H),1.73-1.63(m,9H),1.54-1.13(m,13H),1.00-0.90(m,1H),0.83-0.77(m,4H),0.61(s,3H). 13 C NMR (100 MHz, CDCl 3 )209.75,172.75,171.17,69.98,64.01,63.82,56.72,54.10,44.24,40.09,39.03,35.80,35.41,34.24,32.93,32.85,31.87,31.54,28.23,28.01,26.10,24.35,22.75,21.57,20.99,20.78,13.45,11.33.

[0360] Embodiment 17

[0361] 5-Acetoxy-2-methyl-pentanoic acid [(3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl] ester

[0362]

[0363] Step 1: Preparation of diethyl 2-(3-(benzyloxy)propyl)-2-methylmalonate

[0364]

[0365] To a mixture of diethyl 2-methylmalonate (2.28 g, 13.09 mmol, 2.24 mL, 1.0 equiv) in THF (35 mL) at 0 °C was added NaH (1.05 g, 26.19 mmol, 60.0%, 2.0 equiv) followed by 3-bromopropoxymethylbenzene (3.0 g, 13.09 mmol, 1.0 equiv) in THF (5 mL), and the mixture was then heated at 25 °C under N 2 Stir under atmosphere for 16 hours. The mixture was quenched with water (60 mL), and the resulting mixture was extracted with EtOAc (60 mL×3). The combined organic layers were purified by Na 2 SO 4 Dry, filter and concentrate. The residue was purified by flash silica gel chromatography ( 40g The product was purified by SilicaFlash Column with a gradient of 0-30% ethyl acetate / petroleum ether at 35 mL / min to afford diethyl 2-(3-benzyloxypropyl)-2-methyl-malonate (2.29 g, 54.3% yield) as a colorless oil.

[0366] Step 2: Preparation of 5-(Benzyloxy)-2-methylpentanoic acid

[0367]

[0368] A mixture of 2-(3-benzyloxypropyl)-2-methyl-malonic acid diethyl ester (2.39 g, 7.41 mmol, 1.0 equiv.), KOH (2.50 g, 44.48 mmol, 6.0 equiv.) in EtOH (40 mL) was stirred at 90 ° C for 5 hours. The mixture was diluted with water (70 mL) and extracted with 2-methoxy-2-methylpropane (50 mL×2). The aqueous layer was acidified to pH=1 with HCl (1 M) and extracted with EtOAc (100 mL×4). The combined organic layers were washed with brine (80 mL) and purified by Na 2 SO 4 Drying, filtration and concentration gave 2-(3-benzyloxypropyl)-2-methyl-malonic acid (2.0 g, crude) as a yellow oil. LCMS (ESI) m / z: C 14 H 18 O 5 Calculated value 266.12, experimental value 288.9 (M+Na) + .

[0369] A mixture of 2-(3-benzyloxypropyl)-2-methyl-malonic acid (2 g, 7.51 mmol, 1 eq.) and DMAP (183 mg, 1.50 mmol, 0.2 eq.) in toluene (40 mL) was stirred at 125 °C for 5 h. The mixture was concentrated and purified by flash silica gel chromatography ( 10g Silica Flash Column, eluted with 0-50% ethyl acetate / petroleum ether gradient at 35 mL / min) to give 5-benzyloxy-2-methyl-pentanoic acid (720 mg, 38.0% yield, 88% purity) as a yellow oil. LCMS (ESI) m / z: C 13 H 18 O 3 Calculated value 222.13, experimental value 245.0 (M+Na) + .

[0370] Step 3: Preparation of 5-benzyloxy-2-methyl-pentanoic acid [(3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl] ester

[0371]

[0372] 1-[(3R,5S,8R,9S,10S,13S,14S,17S)-3-hydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-17-yl]ethanone (1.03 g, 3.24 mmol, 1.0 equiv), 5-benzyloxy-2-methyl-pentanoic acid (720 mg, 3.24 mmol, 1.0 equiv), DMAP (79.2 mg, 0.65 mmol, 0.2 equiv), EDCI (931 mg, 4.86 mmol, 1.5 equiv) and Et 3 A mixture of N (1.47 g, 14.58 mmol, 2.03 mL, 4.5 equiv) in DCM (20 mL) was stirred at 25 °C for 16 h. The mixture was concentrated. The residue was purified by flash silica gel chromatography ( 40g Silica Flash Column, 0-15% ethyl acetate / petroleum ether gradient elution at 35 mL / min). The compound 5-benzyloxy-2-methyl-pentanoic acid [(3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl] ester (610 mg, 1.15 mmol, 35.5% yield) was obtained as a colorless oil. LCMS (ESI) m / z: C 34 H 50 O 4 Calculated value 522.37, found value 523.4 (M+H) + .

[0373] Step 4: Preparation of (3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthrene-3-yl 5-hydroxy-2-methylpentanoate

[0374]

[0375] In N 2To a solution of 5-benzyloxy-2-methyl-pentanoic acid [(3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl] ester (100 mg, 0.19 mmol, 1.0 equiv) in EtOAc (10 mL) was added Pd / C (10%, 20.0 mg). The suspension was degassed under vacuum and heated to 40 ℃ with H 2 The mixture was stirred at 25 °C under H 2 The reaction mixture was filtered and the filtrate was concentrated to give 5-hydroxy-2-methyl-pentanoic acid [(3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl] ester (80.0 mg, 96.7% yield) as a colorless oil, which was used in the next reaction without further purification.

[0376] Step 5: Preparation of 5-acetoxy-2-methyl-pentanoic acid [(3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl] ester

[0377]

[0378] To a mixture of 5-hydroxy-2-methyl-pentanoic acid [(3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl] ester (80.0 mg, 0.19 mmol, 1.0 equiv) in DCM (6 mL) was added acetyl chloride (43.6 mg, 0.55 mmol, 0.040 mL, 3.0 equiv) and pyridine (73.1 mg, 0.93 mmol, 0.075 mL, 5.0 equiv). The mixture was then stirred at 25 °C under N 2 Stir under atmosphere for 4 hours. Concentrate the mixture. The residue is purified by flash silica gel chromatography ( 20g Silica Flash Column, 0-20% ethyl acetate / petroleum ether gradient elution at 30 mL / min). The compound 5-acetoxy-2-methyl-pentanoic acid [(3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl] ester (60.2 mg, 68.6% yield) was obtained as a colorless solid. LCMS (ESI) m / z: C 29 H 46 O 5 Calculated value 474.33, experimental value 497.2 (M+Na) + . 1 H NMR (400 MHz, CDCl 3 )δ(ppm)5.03(s,1H),4.07(t,J=6.4Hz,2H),2.55-2.42(m,2H),2.21-2.12(m,4H),2.06-1.99(m ,4H),1.78-1.64(m,8H),1.55-1.13(m,16H),1.00-0.89(m,1H),0.82-0.75(m,4H),0.61(s,3H). 13 C NMR (100 MHz, CDCl 3 )δ(ppm)209.78,175.72,171.15,69.75,64.26,63.82,56.69,54.16,44.23,40.21,39.43,39.00,35.80,35.41,33.00,32.8 7,32.84,31.90,31.54,30.10,30.03,28.25,26.31,26.11,26.05,24.34,22.74,20.99,20.78,17.27,17.16,13.44,11.31.

[0379] Embodiment 18

[0380] 3-[[(3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl]oxycarbonyloxy]propyl acetate

[0381]

[0382] Step 1: Preparation of 3-benzyloxypropyl chloroformate

[0383]

[0384] To a solution of triphosgene (8.93 g, 30.08 mmol, 5.0 equiv) in toluene (20 mL) was added pyridine (714 mg, 9.02 mmol, 0.728 mL, 1.5 equiv) at 0°C. Then 3-benzyloxypropan-1-ol (1.0 g, 6.02 mmol, 0.952 mL, 1.0 equiv) was added and the mixture was stirred at 25°C for 3 hours. The mixture was diluted with DCM (40 mL) and washed with water (10 mL x 3). The organic layer was concentrated to give 3-benzyloxypropyl chloroformate (150 mg, 52.4% yield) as a colorless oil. 1 H NMR (400MHz, CD 3 Cl) δ (ppm) 7.42-7.34 (m, 5H), 4.55 (s, 2H), 4.90 (t, J = 6.4Hz, 2H), 3.60 (t, J = 6.0Hz, 2H), 2.07-2.03 (m, 2H).

[0385] Step 2: Preparation of [(3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl] 3-benzyloxypropyl carbonate

[0386]

[0387] A solution of 1-[(3R,5S,8R,9S,10S,13S,14S,17S)-3-hydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-17-yl]ethanone (100 mg, 0.31 mmol, 1.0 equiv) and DMAP (8 mg, 0.63 mmol, 0.2 equiv) and pyridine (124 mg, 1.57 mmol, 0.126 mL, 5.0 equiv) in DCM (2 mL) was stirred at 50 °C for 5 min, and 3-benzyloxypropyl chloroformate (108 mg, 0.471 mmol, 1.5 equiv) in DCM (1 mL) was added at 0 °C. The mixture was then stirred at 20 °C for 16 h. The mixture was diluted with water (5 mL) and extracted with EtOAc (10 mL x 3). The organic layer was concentrated. The residue was purified by flash silica gel chromatography ( 4g Silica Flash Column, eluted with 0-10% ethyl acetate / petroleum ether gradient at 20 mL / min) to give [(3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl] 3-benzyloxypropyl carbonate (100 mg, 62.4% yield) as a white solid. LCMS (ESI) m / z: C 32 H 46 O 5 Calculated value 510.33, experimental value 533.4 (M+Na) + .

[0388] Step 3: Preparation of [(3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl] carbonate 3-hydroxypropyl ester

[0389]

[0390] To a solution of [(3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl] 3-benzyloxypropyl carbonate (90 mg, 0.18 mmol, 1.0 equiv) in EtOAc (3 mL) was added Pd(OH) 2 / C (100 mg, 20% purity). The mixture was degassed and washed with H 2 Purge 3 times and keep at 25 °C in H 2 (15 psi) for 16 h. The mixture was filtered and the filtrate was concentrated. The residue was purified by flash silica gel chromatography ( 4g The product was purified by HPLC-MS / MS with 5% paraformaldehyde (HPLC-MS / MS) and purified by HPLC-MS / MS with 1% paraformaldehyde (HPLC-MS / MS) (50 mg, 67.5% yield) using a 5% paraformaldehyde silica flash column and gradient elution with 0-25% ethyl acetate / petroleum ether at 20 mL / min to afford [(3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl] 3-hydroxypropyl carbonate as a white solid (50 mg, 67.5% yield). 1 H NMR (400MHz, CD3 Cl)δ(ppm)4.91(s,1H),4.31(t,J=6.0Hz,2H),4.75(dd,J1=6.4Hz,J2=11.6Hz,2H),2.53(t,J=8.8Hz,1H),2.21-2.09(m,4H),2.07-1.84( m,5H),4.24-4.17(m,4H),2.55-2.53(m,1H),2.17-1.78(m,11H),1.75-1.50(m,6H),1.45-1.12(m,12H),1.04-0.80(m,5H),0.61(s,3H).

[0391] Step 4: Preparation of 3-[[(3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl]oxycarbonyloxy]propyl acetate

[0392]

[0393] To a solution of [(3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl] 3-hydroxypropyl carbonate (50.0 mg, 0.119 mmol, 1.0 equiv) in DCM (5 mL), pyridine (38.0 mg, 0.48 mmol, 0.038 mL, 4.0 equiv) and DMAP (8.0 mg, 0.059 mmol, 0.5 equiv) was added acetyl chloride (19.0 mg, 0.24 mmol, 0.017 mL, 2.0 equiv). The mixture was then stirred at 25 °C for 16 h. The mixture was diluted with DCM (10 mL) and washed with water (5 mL x 3) and brine (5 mL). The organic layer was dried (anhydrous Na 2 SO 4 ) and concentrated in vacuo. The crude product was purified by flash silica gel chromatography ( 4g Silica Flash Column, eluted with 0-20% ethyl acetate / petroleum ether gradient at 20 mL / min) to give 3-[[(3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl]oxycarbonyloxy]propyl acetate as a white solid (11.2 mg, 19.8% yield, 97% purity). LCMS (ESI) m / z: C 27 H 42 O 6 Calculated value 462.3, experimental value 480.4 (M+NH 4 ) + . 1 H NMR (400MHz, CD 3 Cl)δ(ppm)4.90(s,1H),4.24-4.17(m,4H),2.55-2.53(m,1H),2.17-1.78(m,11H),1.72-1.17(m,17H),0.84-0.80(m,5H),0.61(s,3H). 13 CNMR (100MHz, CDCl 3 )δ(ppm)209.73,171.02,154.76,74.50,64.21,63.84,60.95,56.76,53.87,44.26,39.69,3 9.08,35.78,35.46,32.82,32.65,31.75,28.20,28.04,26.06,24.38,20.79,13.47,11.32.

[0394] Embodiment 19

[0395] 2-[[(3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl]oxycarbonyloxy]ethyl 2-methylpropanoate

[0396]

[0397] Step 1: Preparation of [(3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl] 2-hydroxyethyl carbonate

[0398]

[0399] Carbonic acid [(3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl] ester 3-hydroxyethyl ester was prepared according to the method of [(3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl] ester S,14S,17S)-17-acetyl-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl] ester 2-hydroxypropyl ester was prepared by the same procedure except that 3-benzyloxypropanol was replaced with 2-benzyloxyethanol (1.2 g, 87.2% yield, colorless oil). The crude material was used directly in the next step. 1 HNMR (400MHz, CDCl 3 )δ(ppm)4.93(s,1H),4.27(dd,J1=6.0Hz,J2=4.4Hz,2H),3.90-3.86(m,2H),2.54(t,J=9.2Hz,1H),2.20-2.12(m, 4H),2.04-1.96(m,2H),1.91-1.82(m,1H),1.76-1.50(m,9H),1.48-1.11(m,9H),1.00-0.82(m,4H),0.61(s,3H).

[0400] Step 2: Preparation of 2-[[(3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl]oxycarbonyloxy]ethyl 2-methylpropanoate

[0401]

[0402] In N 2To a solution of [(3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl]carbonate 2-hydroxyethyl ester (130 mg, 0.32 mmol, 1.0 eq) in DCM (5 mL) was added pyridine (101 mg, 1.28 mmol, 0.103 mL, 4.0 eq), DMAP (4.0 mg, 0.032 mmol, 0.1 eq) and 2-methylpropanoyl chloride (41.0 mg, 0.38 mmol, 0.040 mL, 1.2 eq) under atmospheric pressure. The mixture was then stirred at 20°C for 16 hours. The mixture was diluted with water (3 mL) and extracted with EtOAc (8 mL×3). The combined organic layers were washed with brine (50 mL), 2 SO 4 Dry, filter and concentrate. The crude product was purified by flash silica gel chromatography ( 12g Silica Flash Column, eluted with 0-15% ethyl acetate / petroleum ether gradient at 20 mL / min) to give 2-[[(3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl]oxycarbonyloxy]ethyl 2-methylpropanoate (46.5 mg, 30.2% yield, 99% purity) as a white solid. LCMS (ESI) m / z: C 28 H 44 O 6 Calculated value 476.31, experimental value 494.3 (M+NH 4 ) + ,499.2(M+Na) + . 1 H NMR (400 MHz, CDCl 3)δ(ppm)4.91(s,1H),4.36-4.34(m,2H),4.34-4.31(m,2H),2.63-2.56(m,1H),2.55- 2.51(m,1H),2.19-2.12(m,4H),2.02-1.96(m,1H),1.87-1.84(d,J=13.6Hz,2H),1.6 9-1.63(m,4H),1.613(s,2H),1.54-1.50(m,4H),1.40-1.39(m,2H),1.29-1.22(m,3H ),1.19-1.16(m,8H),1.00-0.90(m,1H),0.86-0.82(m,1H),0.80(s,3H),0.61(s,3H). 13 C NMR (100 MHz, CDCl 3 )δ(ppm)209.25,176.41,154.10,74.31,64.73,63.31,61.45,56.25,53.35,43.75,39.15,38.56,35.2 5,34.92,33.35,32.26,32.11,31.23,31.05,27.67,25.51,23.87,22.28,20.27,18.43,12.97,10.82.

[0403] Embodiment 20

[0404] Methyl [(3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl] carbonate (5-methyl-2-oxo-1,3-dioxol-4-yl)

[0405]

[0406] Method 1

[0407] Step 1: Preparation of [(3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl]chloroformate

[0408]

[0409] To a solution of triphosgene (3.49 g, 11.77 mmol, 2.5 eq) in toluene (20 mL) was added pyridine (559 mg, 7.06 mmol, 0.57 mL, 1.5 eq) at 0°C. The mixture was stirred at 0°C for 15 minutes, and 1-[(3R,5S,8R,9S,10S,13S,14S,17S)-3-hydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-17-yl]ethanone (1.50 g, 4.71 mmol, 1.0 eq) was added, and the resulting mixture was stirred at 25°C for 5 hours. The mixture was then diluted with water (15 mL) and extracted with DCM (20 mL x 3). The organic layers were combined, washed with brine (15 mL), and dried (Na 2 SO 4 ) and concentrated in vacuo to afford [(3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl]chloroformate (1.1 g, 2.89 mmol, 61.3% yield) as a colorless solid which was used directly in the next step without further purification.

[0410] Step 2: Preparation of [(3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl] (5-methyl-2-oxo-1,3-dioxol-4-yl) methyl carbonate

[0411]

[0412] To a solution of 4-(hydroxymethyl)-5-methyl-1,3-dioxol-2-one (150 mg, 1.15 mmol, 1.0 equiv), DMAP (14.0 mg, 0.12 mmol, 0.1 equiv) and DIPEA (298 mg, 2.31 mmol, 0.40 mL, 2.0 equiv) in DCM (9 mL) was added [(3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl]chloroformate (571 mg, 1.50 mmol, 1.3 equiv) at room temperature. The resulting mixture was stirred at room temperature for 16 hours. The mixture was then diluted with water (15 mL) and extracted with EtOAc (20 mL x 3). The organic layers were combined, dried (anhydrous Na 2 SO 4 ) and concentrated in vacuo. The crude product was purified by flash silica gel chromatography ( 4g Silica Flash Column, eluted with 0-15% ethyl acetate / petroleum ether gradient at 20 mL / min) to give the desired product. The product was further purified by trituration with MeOH at 25°C, and the solid was dried in vacuo to give [(3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl] ester (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl carbonate (276 mg, 0.57 mmol, 49.5% yield, 98% purity).

[0413] Method 2:

[0414] Step 1: Preparation of [(3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl] carbonate (4-nitrophenyl)

[0415]

[0416] To a solution of 1-[(3R,5S,8R,9S,10S,13S,14S,17S)-3-hydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-17-yl]ethanone (3.0 g, 9.42 mmol, 1.0 eq) in THF (50 mL) was added DMAP (2.30 g, 18.8 mmol, 2.0 eq) and (4-nitrophenyl) chloroformate (3.80 g, 18.84 mmol, 2 eq). The reaction mixture was stirred at 25 °C for 16 h. iPrOH (1.13 g, 18.8 mmol, 1.44 mL, 2.0 eq) was then added and the resulting mixture was stirred at 25 °C for 2 h. The mixture was diluted with EtOAc (70 mL) and washed with water (40 mL × 3) and brine (50 mL). The organic layer was concentrated. The crude product was wet-milled with iPrOH (25 mL) for 5 minutes at 25 ° C. The resulting mixture was filtered, and the filter cake was dried under reduced pressure to obtain [(3R, 5S, 8R, 9S, 10S, 13S, 14S, 17S) -17- acetyl -10, 13- dimethyl -2,3,4,5,6,7,8,9,11,12,14,15,16,17- tetrahydro -1H- cyclopenta [a] phenanthrene -3- base] ester (4- nitrophenyl) ester (3.90 g, 87% yield) as a white solid. 1 H NMR (400 MHz, CDCl 3 )δ(ppm)8.31-8.28(m,2H),7.43-7.38(m,2H),5.05(s,1H),2.56-2.52(t,J=8.8 Hz,1H),2.21-1.93(m,6H),1.76-1.13(m,17H),1.04-0.84(m,5H),0.62(s,3H).

[0417] Step 2: Preparation of [(3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl] (5-methyl-2-oxo-1,3-dioxol-4-yl) methyl carbonate

[0418]

[0419] To a solution of [(3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl]carbonate (4-nitrophenyl) (14.0 g, 28.4 mmol, 98% purity, 1.0 eq) and 4-(hydroxymethyl)-5-methyl-1,3-dioxol-2-one (7.38 g, 56.7 mmol, 2.0 eq) in THF (100 mL) was added DMAP (693 mg, 5.67 mmol, 0.2 eq). The mixture was stirred at 50° C. for 16 h. The mixture was diluted with EtOAc (200 mL) and washed with water (80 mL x 2). The organic layer was washed with brine (80 mL) and purified by Na 2 SO 4 The mixture was dried, filtered and concentrated. The crude residue was triturated with iPrOH (70 mL) at 25 ° C for 30 minutes. The mixture was filtered and the filter cake was dried under reduced pressure to give [(3R, 5S, 8R, 9S, 10S, 13S, 14S, 17S) -17- acetyl -10, 13- dimethyl -2,3,4,5,6,7,8,9,11,12,14,15,16,17- tetrahydro -1H- cyclopenta [a] phenanthrene -3- base] ester (5- methyl -2- oxo -1,3- dioxol -4- base) methyl carbonate (11.1 g, 82% yield) as a pale yellow solid.

[0420] LCMS (ESI) m / z: C 27 H 38 O 7 Calculated value 474.26, found value 475.3 (M+H) + ,492.3(M+NH 4 ) + . 1 HNMR (400MHz, CD 3 Cl)δ(ppm)4.93(s,1H),4.88(s,2H),2.56-2.51(t,J=9.2Hz,1H),2.20-2.12(m,7H),2.02-1.99(d,J=12Hz,1H),1.8 7-1.83(d,J=16.4Hz,1H),1.72-1.50(m,8H),1.43-1.14(m,9H),0.98-0.88(m,1H),0.75-0.79(m,4H),0.61(s,3H). 13 C NMR (100 MHz, CDCl 3)δ(ppm)209.72,154.22,152.00,140.53,133.16,75.66,63.81,56.66,53.86,44.24,39.67,39.05 ,35.76,35.44,32.77,32.59,31.72,31.58,28.17,26.03,24.38,22.81,20.79,13.47,11.32,9.43.

[0421] Embodiment 21

[0422] Butyl [(3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl] carbonate

[0423]

[0424] [(3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl]butyl carbonate was prepared according to the method of Acyl-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl] ester (5-methyl-2-oxo-1,3-dioxol-4-yl) methyl ester was prepared by the same procedure except that 4-(hydroxymethyl)-5-methyl-1,3-dioxol-2-one was replaced with butan-1-ol. LCMS (ESI) m / z: C 26 H 42 O 4 Calculated value 418.31, found value 419.3 (M+H) + . 1 H NMR (400 MHz, CDCl 3)δ(ppm)4.89(s,1H),4.15-4.12(t,J=6.8Hz,2H),2.55-2.51(t,J=8.8Hz,1H),2.19-2.12(m,4H),2.02-1.99(d,J=11.2Hz,1H),1 .87-1.83(d,J=16.4Hz,1H),1.71-1.50(m,10H),1.44-1.11(m,11H),0.97-0.93(t,J=7.2Hz,4H),0.87-0.80(m,4H),0.61(s,3H). 13 C NMR (100 MHz, CDCl 3 )δ(ppm)209.82,154.94,74.12,67.55,63.78,56.71,53.78,44.23,39.59,39.03,35.71,35.38,3 2.77,32.59,31.69,31.54,30.71,28.15,26.00,24.33,22.72,20.73,18.94,13.69,13.44,11.28.

[0425] Embodiment 22

[0426] 2-[[(3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl]oxycarbonylamino]ethyl 2-methylpropanoate

[0427]

[0428] Step 1: Preparation of N-(2-hydroxyethyl)carbamic acid [(3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl] ester

[0429]

[0430] N-(2-Hydroxyethyl)carbamate [(3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl]] ester was prepared according to the method of [(3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl]] ester. 10,13-Dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl]methyl ester (5-methyl-2-oxo-1,3-dioxol-4-yl) was prepared by the same procedure except that 4-(hydroxymethyl)-5-methyl-1,3-dioxol-2-one was replaced by 2-aminoethanol (650 mg, 61.1% yield).

[0431] Step 2: Preparation of 2-[[(3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl]oxycarbonylamino]ethyl 2-methylpropanoate

[0432]

[0433] 2-[[(3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl]oxycarbonylamino]ethyl 2-methylpropanoate was prepared following the same procedure as for 2-[[(3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl]oxycarbonylamino]ethyl 2-methylpropanoate , except that [(3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl]carbonate 2-hydroxyethyl ester was replaced with [(3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl] N-(2-hydroxyethyl)carbamate (382 mg, 44.6% yield). LCMS (ESI) m / z: C 28 H 45 NO 5 Calculated value 475.33, experimental value 498.3 (M+Na) + . 1 H NMR (400 MHz, CDCl 3 )δ(ppm)4.93(s,1H),4.86(bs,1H),4.18-4.15(t,J=5.6Hz,2H),3.48-3.44(m,2H),2.62-2.50(m,2H),2.12-2.20(m ,4H),2.04-2.00(m,1H),1.78-1.63(m,5H),1.48-1.18(m,19H),0.99-0.90(m,1H),0.81-0.75(m,4H),0.61(s,3H). 13 C NMR (100MHz, CD 3Cl)δ(ppm)209.74,177.10,156.22,70.58,63.82,63.28,56.77,54.13,44.23,40.06,39.96,39.06,35. 78,35.40,33.88,33.05,32.86,31.89,31.52,28.22,26.28,24.33,22.73,20.76,18.97,13.44,11.31.

[0434] Embodiment 23

[0435] 2-[[(3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl]oxycarbonyl-methyl-amino]ethyl 2-methylpropanoate

[0436]

[0437] Step 1: Preparation of N-(2-hydroxyethyl)-N-methyl-carbamic acid [(3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl] ester

[0438]

[0439] N-(2-Hydroxyethyl)-N-methyl-carbamic acid [(3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl] ester was prepared according to the method of [(3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl] carbonate

[0147] The same procedure was used to prepare 5-(methyl-2-oxo-1,3-dioxol-4-yl)methyl 4-(10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl]ester except that 4-(hydroxymethyl)-5-methyl-1,3-dioxol-2-one was replaced by 2-(methylamino)ethanol (400 mg, 72.8% yield).

[0440] Step 2: Preparation of 2-[[(3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl]oxycarbonyl-methyl-amino]ethyl 2-methylpropanoate

[0441]

[0442] 2-Methylpropionic acid 2-[[(3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl]oxycarbonyl-methyl-amino]ethyl ester was prepared according to the same procedure as for the preparation of 2-methylpropionic acid 2-[[(3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl]oxycarbonyl-methyl-amino]ethyl ester, The difference is that [(3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl] carbonate 2-hydroxyethyl ester was changed to [(3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl] N-(2-hydroxyethyl)-N-methyl-carbamic acid (280 mg, 59.4% yield). LCMS (ESI) m / z: C 29 H 47 NO 5 Calculated value 489.35, experimental value 512.3 (M+Na) + . 1 HNMR (400MHz, CDCl 3)δ(ppm)4.95(s,1H)4.24-4.21(t,J=5.6Hz,2H),3.59-3.48(m,2H),2.98(s,3H),2.60-2.50(m,2H),2.20 -2.12(m,4H),2.05-2.00(m,1H),1.77-1.18(m,24H),0.99-0.88(m,1H),0.80-0.73(m,4H),0.61(s,3H). 13 C NMR (100 MHz, CDCl 3 )δppm 209.15,176.36,155.43,70.41,63.35,61.77,56.21,53.83,47.26,43.74,39.94,38.54,35.34,35.0 9,34.94,34.51,33.45,32.78,32.64,31.00,27.75,25.90,23.84,22.27,20.32,18.44,12.94,10.89.

[0443] Embodiment 24

[0444] Carbonate [(3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl] 2-(2-methylpropionylamino)ethyl ester

[0445]

[0446] Preparation of [(3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl] 2-(2-methylpropionylamino)ethyl carbonate

[0447]

[0448] To a solution of 2-aminoethanol (200 mg, 3.27 mmol, 1.0 eq) in DCM (5 mL) was added TEA (993 mg, 9.81 mmol, 1.37 mL, 3.0 eq) followed by 2-methylpropanoyl chloride (453 mg, 4.25 mmol, 0.444 mL, 1.3 eq) in DCM (5 mL) at 0° C. The reaction mixture was stirred at 25° C. for 16 h. Then DMAP (200 mg, 1.64 mmol, 0.5 eq) and [(3R, 5S, 8R, 9S, 10S, 13S, 14S, 17S)-17-acetyl-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl]chloroformate (623 mg, 1.64 mmol, 0.5 eq) in DCM (5 mL) were added, and the mixture was stirred at 25 °C for 16 hours. The mixture was diluted with DCM (40 mL), and the organic layer was washed with water (30 mL) and brine (30 mL). The organic layer was purified by Na 2 SO 4 The residue was purified by flash silica gel chromatography ( 12g Silica Flash Column, 0-40% ethyl acetate / petroleum ether gradient elution at 35 mL / min). The compound was wet-milled with hexane (10 mL) at 25 °C for 16 hours. The mixture was filtered, and the filter cake was wet-milled with hexane / EtOAc (5 mL / 0.5 mL) at 25 °C for 1 hour, then the mixture was filtered, and the filter cake was dried to give [(3R, 5S, 8R, 9S, 10S, 13S, 14S, 17S)-17-acetyl-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl] ester 2-(2-methylpropionylamino)ethyl ester (254 mg, 16.3% yield) as a white solid. LCMS (ESI) m / z: C 28 H 45 NO 5 Calculated value 475.33, experimental value 498.2 (M+Na) + . 1 H NMR (400 MHz, CDCl 3)δ(ppm)5.86(br s,1H),4.92(br s,1H),4.23(t,J=5.2Hz,2H),3.57(q,J=5.6Hz,2H),2.53(t,J=8.8Hz,1H),2.37-2.35(m,1H),2.22-2.08(m,4H),2.06-1 .97(m,1H),1.90-1.80(m,1H),1.75-1.62(m,4H),1.58-1.09(m,19H),1.04-0.89(m,1H),0.88-0.75(m,4H),0.61(s,3H). 13 C NMR (100 MHz, CDCl 3 )δ(ppm)209.71,177.09,154.79,74.91,66.58,63.80,56.73,53.88,44.23,39.75,39.04,38.66,35.7 5,35.59,35.40,32.74,32.64,31.74,31.52,28.16,25.99,24.35,22.77,20.76,19.54,13.45,11.30.

[0449] Embodiment 25

[0450] (3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthrene-3-yl carbonate (2-(N-methylisobutyramido)ethyl)

[0451]

[0452] (3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthrene-3-yl (2-(N-methylisobutyramido)ethyl) carbonate was prepared according to the same procedure as for [(3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl] 2-(2-methylpropionamido)ethyl carbonate, except that 2-aminoethanol was replaced with 2-(methylamino)ethanol (193 mg, 11.8% yield). LCMS (ESI) m / z: C 29 H 47 NO 5 Calculated value 489.35, experimental value 512.3 (M+Na) +. 1 H NMR (400 MHz, DMSO-d 6 )δ(ppm)4.77(br d,J=8.8Hz,1H),4.21-4.13(m,2H),3.62-3.52(m,2H),3.02(s,2H),2.84-2.80(m,2H),2.56(br t,J=8.4Hz,1H),2.03-1.91(m,2H),1.68-1.17(m,20H),0.99-0.96(m,8H),0.76-0.72(m,4H),0.50(s,3H). 13 C NMR (100 MHz, DMSO-d 6 )δ(ppm)208.57,176.14,153.99,73.79,64.13,62.66,55.93,53.64,47.52,45.90,43.50,38.15,35.37,34.8 8,32.99,32.34,31.47,31.19,29.35,,28.81,27.72,25.39,23.90,22.17,20.32,19.62,19.06,13.16,11.04.

[0453] Embodiment 26

[0454] 2-(Methoxycarbonylamino)ethyl carbonate [(3R,5S,8R,9S,10S,13S,14S,17S)-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl] ester

[0455]

[0456] Carbonate [(3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl] 2-(methoxycarbonylamino)ethyl ester was prepared according to the method of [(3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl] ester 2-(methoxycarbonylamino)ethyl ester 14S,17S)-17-acetyl-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl] ester 2-(2-methylpropionylamino)ethyl ester. Prepared by the same procedure except that 2-aminoethanol 2-methylpropanoyl chloride was replaced by methyl chloroformate (109 mg, 17.9% yield). LCMS (ESI) m / z: C 26 H 41 NO 6 Calculated value 463.29, experimental value 486.3 (M+Na) + . 1 H NMR (400 MHz, CDCl 3 )δ(ppm)5.04(bs,1H),4.91(s,1H)4.22-4.20(t,J=5.2Hz,2H),3.69(s,3H)3.51-3.49(d,J=5.2Hz,2H)2.55-2.51(t,J=8.8Hz,1H),2.20-2.12( m,4H),2.03-2.00(m,1H),1.87-1.83(d,J=14.8Hz,1H)1.70-1.60(m,5H ),1.55-1.14(m,12H),0.99-0.95(m,1H),0.87-0.79(m,4H)0.61(s,3H). 1 H NMR (400 MHz, DMSO-d 6 )δ(ppm)7.33-7.30(t,J=5.2Hz 1H),4.78(s,1H)4.05-4.03(t,J=5.2Hz,2H),3.52(s,3H),3.22-3.21(d,J=5.2Hz,2H),2.58-2.54(t,J =8.8Hz,1H),2.07-1.95(m,4H),1.69-1.09(m,18H),0.93-0.89(m,1H),0.86-0.71(m,4H),0.50(s,3H). 13 C NMR (100 MHz, DMSO-d 6)δ(ppm)209.02,157.24,154.49,74.13,66.31,63.15,56.38,54.01,51.80,43.98,38.63,3 5.83,35.38,32.82,32.67,31.93,31.66,28.21,25.87,24.39,22.66,20.80,13.63,11.51.

[0457] Embodiment 27

[0458] 2-(Methoxycarbonyl-N-methylamino)ethyl carbonate [(3R,5S,8R,9S,10S,13S,14S,17S)-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl] ester

[0459]

[0460] Carbonic acid [(3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl] ester 2-(methoxycarbonyl-N-methyl-amino)ethyl ester was prepared according to the method of [(3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl] ester )-17-acetyl-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl] ester 2-(2-methylpropionylamino)ethyl ester was prepared by the same procedure except that 2-aminoethanol 2-methylpropionyl chloride was replaced by methyl chloroformate and 2-aminoethanol was replaced by 2-(methylamino)ethanol (143 mg, 23.1% yield). LCMS (ESI) m / z: C 27 H 43 NO 6 Calculated value 477.31, experimental value 500.3 (M+Na) + . 1 H NMR (400 MHz, DMSO-d 6)δ(ppm)4.77(s,1H),4.17-4.15(t,J=5.2Hz,2H),3.57(s,3H),3.48-3.47(d,J=4.8Hz,2H),2.84(s,3H),2.58-2 .54(t,J=8.8Hz,1H),2.07-1.94(m,5H),1.68-1.09(m,19H),0.92-0.86(m,1H),0.76-0.70(m,4H),0.50(s,3H). 13 C NMR (100 MHz, DMSO-d 6 )δ(ppm)208.52,156.13,153.94,73.68,64.25,62.63,55.87,53.50,52.27,47.29,46.81,43.47,38.1 1,35.33,34.86,34.17,32.32,32.13,31.42,31.16,27.70,25.37,23.88,22.15,20.30,13.13,11.00.

[0461] Plasma stability

[0462] Pooled frozen plasma was thawed in a 37°C water bath before the experiment. Plasma was centrifuged at 4000 rpm for 5 minutes and any clots, if any, were removed. If necessary, the pH was adjusted to 7.4 ± 0.1.

[0463] Preparation of test compounds and positive control (propantheline bromide): 1 mM intermediate solution was prepared by diluting 10 μL of stock solution with 90 μL MeOH; 1 mM positive control propantheline intermediate was prepared by diluting 10 μL of stock solution with 90 μL ultrapure water. 100 μM dosing solution was prepared by diluting 20 μL of intermediate solution (1 mM) with 180 μL MeOH. 2 μL of dosing solution (100 μM) was added to 98 μL of blank plasma to reach a final concentration of 2 μM in duplicate, and the samples were incubated in a water bath at 37°C. At each time point (0, 10, 30, 60 and 120 minutes), 400 μL of stop solution (0.1% FA / MeOH containing 200 ng / mL tolbutamide and 200 ng / mL labetalol) was added to precipitate proteins and mixed thoroughly. The sample plate was centrifuged at 4,000 rpm for 10 minutes. An aliquot of the supernatant (100 μL) was transferred from each well to another plate.

[0464] Data Analysis: The % of test compound remaining in plasma after incubation was calculated using the following equation:

[0465] Remaining % = 100 × (PAR at designated cultivation time / PAR at T0)

[0466] Where PAR is the peak area ratio of the analyte to the internal standard (IS) (LC / MS / MS mobile phase conditions: water containing 0.1% formic acid / acetonitrile containing 0.1% formic acid. The designated incubation time points are T0 (0 min), Tn (n=0, 10, 30, 60, 120 min).

[0467] Liver S9 stability

[0468] Intermediate solution: dilute 5 μL of compound or control (7-ethoxycoumarin) from stock solution (10 mM) with 495 μL MeOH (concentration: 100 μM, 1% DMSO, 99% MeOH). Stop solution: cold ACN (including 100 ng / mL tolbutamide and labetalol as internal standards). Add 2 μL of test compound or control working solution / well to all plates (T0, T5, T10, T20, T30, T60, NCF60) except matrix blank. Add 600 μL / well stop solution (cold, at 4°C, including 100 ng / mL tolbutamide / 100 ng / mL labetalol) to stop the T0 plate, which is then placed on ice. Distribute 840 μL / well S9 solution to 96-well plates as reservoirs according to the plate map. Then add 100 μL / well to each plate with Apricot. In addition to NCF60 and T0, S9 solution and compound were cultivated at 37°C for about 10 minutes. After S9 solution and 98 μL PB buffer were added to NCF60, they were cultivated without preheating at 37°C and timer 1 was started. After 60 minutes, 600 μL / well stop solution was added to terminate the reaction. After preheating, 760 μL / well cofactor solution was distributed to 96-well plates as a reservoir according to the plate map. Then 98 μL / well was added to each plate with Apricot to initiate the reaction. Cultivated at 37°C, timer 2 was started, and 600 μL / well stop solution (cold, at 4°C, including 100 ng / mL tolbutamide and labetalol) was added to terminate the reaction. The sample was centrifuged at 4000 rpm for 20 minutes. During centrifugation, 300 μL of HPLC water was added to 8× new 96-well plates, followed by the transfer of 100 μL of supernatant, mixed with water for LC / MS / MS, and transferred to Bioanalytical Services for LC-MS / MS analysis. Calculation of t using the first-order kinetic equation 1 / 2 And CL: first-order kinetic equation:

[0469]

[0470]

[0471] CLint(S9) =Vd·k e

[0472] Vd=1mL / mg

[0473] The stability results of exemplary compounds in human plasma and human liver S9 are listed in Table 2 below.

[0474] Table 2. Stability results of exemplary compounds in human plasma and human liver S9.

[0475]

[0476] Half-life range: A: >200 minutes; B: 50-200 minutes; C: <50 minutes.

[0477] The foregoing description is considered to be merely illustrative of the principles of the present disclosure. In addition, since many modifications and variations will be apparent to those skilled in the art, it is not desirable to limit the present invention to the precise configurations and processes shown above. Therefore, all suitable modifications and equivalents are considered to be within the scope of the present invention as defined by the appended claims.

[0478] The words "comprise", "comprises", "includes", "including", "including" when used in the present description and the following claims are intended to specify the presence of stated features, integers, components or steps, but they do not exclude the presence or addition of one or more other features, integers, components, steps or groups thereof.

[0479] The present invention is further described by the following numbered embodiments:

[0480] 1. A compound of formula (I),

[0481]

[0482] or a pharmaceutically acceptable salt thereof, wherein:

[0483] R 1a and R 1b are each independently hydrogen or methyl;

[0484] Q is methyl or

[0485] L is selected from the group consisting of absence, alkyl, -O-, and -N(R 2 )-groups composed of;

[0486] W is selected from the group consisting of absence, alkyl, and -O-;

[0487] Y is selected from the group consisting of alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, saturated or unsaturated cycloalkyl, saturated or unsaturated heterocyclyl, aryl, heteroaryl, -OC(O)OR 3 、-OC(O)R 4 and-NR 5 R 6 wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, saturated or unsaturated cycloalkyl, saturated or unsaturated heterocyclyl, aryl and heteroaryl are optionally substituted with one or more groups independently selected from the group consisting of oxo, halogen, cyano, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, saturated or unsaturated cycloalkyl, saturated or unsaturated heterocyclyl, aryl and heteroaryl;

[0488] R 2 , R 3 , R 4 and R 5 each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, saturated or unsaturated cycloalkyl, saturated or unsaturated heterocyclyl, aryl and heteroaryl, wherein said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, saturated or unsaturated cycloalkyl, saturated or unsaturated heterocyclyl, aryl and heteroaryl are optionally substituted with one or more groups independently selected from the group consisting of oxo, halogen, cyano, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, saturated or unsaturated cycloalkyl, saturated or unsaturated heterocyclyl, aryl and heteroaryl;

[0489] R 6 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, and -C(O)R 7 ;and

[0490] R 7 selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, alkoxy, saturated or unsaturated cycloalkyl, saturated or unsaturated heterocyclyl, aryl and heteroaryl, wherein said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, alkoxy, saturated or unsaturated cycloalkyl, saturated or unsaturated heterocyclyl, aryl and heteroaryl are optionally substituted with one or more groups independently selected from the group consisting of oxo, halogen, cyano, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, saturated or unsaturated cycloalkyl, saturated or unsaturated heterocyclyl, aryl and heteroaryl, provided that when L is —O— or —N(R 2 )-, W is not -O-, when W is -O-, Y is not -NR 5 NR 6 , and when W is -O-, Y is -C(O)OR 3 or -C(O)R4 .

[0491] 2. A compound of formula (I) or a pharmaceutically acceptable salt thereof as described in Embodiment 1, wherein R 1a and R 1b It's all hydrogen.

[0492] 3. A compound of formula (I) or a pharmaceutically acceptable salt thereof as described in Embodiment 1, wherein R 1a and R 1b They are all methyl.

[0493] 4. A compound of formula (I) or a pharmaceutically acceptable salt thereof as described in Embodiment 1, wherein R 1a is methyl and R 1b is hydrogen, or R 1a is hydrogen and R 1b It's methyl.

[0494] 5. A compound of formula (I) or a pharmaceutically acceptable salt thereof as described in any one of embodiments 1-4, wherein Q is methyl.

[0495] 6. A compound of formula (I) or a pharmaceutically acceptable salt thereof as described in any one of embodiments 1-4, wherein Q is

[0496] 7. A compound of formula (I) or a pharmaceutically acceptable salt thereof as described in any one of embodiments 1-6, wherein L is absent.

[0497] 8. A compound of formula (I) or a pharmaceutically acceptable salt thereof as described in any one of embodiments 1-6, wherein L is an alkyl group.

[0498] 9. A compound of formula (I) or a pharmaceutically acceptable salt thereof as described in any one of embodiments 1-6, wherein L is -O-.

[0499] 10. A compound of formula (I) or a pharmaceutically acceptable salt thereof as described in any one of embodiments 1-6, wherein L is -N(R 2 )-, and R 2 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, and heteroalkynyl.

[0500] 10a. A compound of formula (I) or a pharmaceutically acceptable salt thereof as described in Embodiment 10, wherein L is -N(R 2 )-, and R 2 is hydrogen or an alkyl group.

[0501] 10b. A compound of formula (I) or a pharmaceutically acceptable salt thereof as described in Embodiment 10 or 10a, wherein the alkyl group is C 1 -C6 alkyl.

[0502] 10c. A compound of formula (I) or a pharmaceutically acceptable salt thereof as described in embodiment 10b, wherein said C 1 -C 6 The alkyl group is methyl.

[0503] 11. A compound of formula (I) or a pharmaceutically acceptable salt thereof as described in any one of embodiments 1-10b, wherein W is absent.

[0504] 12. A compound of formula (I) or a pharmaceutically acceptable salt thereof as described in any one of embodiments 1-10b, wherein W is alkyl.

[0505] 12a. A compound of formula (I) or a pharmaceutically acceptable salt thereof as described in Embodiment 12, wherein the alkyl group is C 1 -C 7 alkyl.

[0506] 13. A compound of formula (I) or a pharmaceutically acceptable salt thereof as described in any one of embodiments 1-10b, wherein W is -O-.

[0507] 14. A compound of formula (I) or a pharmaceutically acceptable salt thereof as described in Embodiment 1, wherein L is absent and W is absent.

[0508] 15. A compound of formula (I) or a pharmaceutically acceptable salt thereof as described in Embodiment 1, wherein L is alkyl, and W is absent or is -O-.

[0509] 16. A compound of formula (I) or a pharmaceutically acceptable salt thereof as described in Embodiment 1, wherein L is -O-, and W is absent or is alkyl.

[0510] 16a. A compound of formula (I) or a pharmaceutically acceptable salt thereof as described in Embodiment 1, wherein L is -O-, and W is alkyl.

[0511] 17. A compound of formula (I) or a pharmaceutically acceptable salt thereof as described in Embodiment 1, wherein L is -N(R 2 )-, W is an alkyl group, and R 2 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, and heteroalkynyl.

[0512] 17a. A compound of formula (I) or a pharmaceutically acceptable salt thereof as described in Embodiment 1, wherein L is -N(R 2 )-, W is an alkyl group, and R 2 is selected from the group consisting of hydrogen or alkyl.

[0513] 17b. A compound of formula (I) or a pharmaceutically acceptable salt thereof as described in any one of embodiments 16-17a, wherein the alkyl group is C 1 -C 6 alkyl.

[0514] 18. A compound of formula (I) or a pharmaceutically acceptable salt thereof as described in any one of the preceding embodiments, wherein Y is selected from the group consisting of: an alkyl group, a saturated or unsaturated cycloalkyl group, a saturated or unsaturated heterocyclic group, -OC(O)OR 3 (or -C(O)OR when W is -O- 3 )、-OC(O)R 4 and –NR 5 R 6 wherein the alkyl, saturated or unsaturated cycloalkyl and saturated or unsaturated heterocyclyl are optionally substituted by one or more groups independently selected from the group consisting of oxo, halogen, cyano, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, saturated or unsaturated cycloalkyl, saturated or unsaturated heterocyclyl, aryl and heteroaryl.

[0515] 18a. A compound of formula (I) or a pharmaceutically acceptable salt thereof as described in any one of the preceding embodiments, wherein Y is an unsaturated heterocyclic group, -OC(O)OR 3 (or -C(O)OR when W is -O- 3 )、-OC(O)R 4 and –NR 5 R 6 , wherein the unsaturated heterocyclic group is optionally substituted with one or more groups independently selected from oxo, halogen, cyano, alkyl, alkenyl, alkynyl and heteroalkyl.

[0516] 18b. A compound of formula (I) or a pharmaceutically acceptable salt thereof as described in any one of embodiments 1-18a, wherein Y is an optionally substituted unsaturated 5- or 6-membered heterocyclic group having 1 or 2 oxygen atoms.

[0517] 18c. A compound of formula (I) or a pharmaceutically acceptable salt thereof as described in any one of embodiments 1-18b, wherein Y is

[0518] 18d. A compound of formula (I) or a pharmaceutically acceptable salt thereof as described in any one of embodiments 1-18a, wherein Y is -OC(O)R 4 .

[0519] 18e. A compound of formula (I) or a pharmaceutically acceptable salt thereof as described in embodiment 18d, R 4 It is C 1 -C 6 alkyl.

[0520] 18f. A compound of formula (I) or a pharmaceutically acceptable salt thereof as described in embodiment 18e, wherein said C 1 -C 6 The alkyl group is methyl, ethyl or isopropyl.

[0521] 18g. A compound of formula (I) or a pharmaceutically acceptable salt thereof as described in any one of embodiments 1-18a, wherein Y is -NR 5 R 6 .

[0522] 18h. A compound of formula (I) or a pharmaceutically acceptable salt thereof as described in embodiment 18g, wherein R 5 is H or alkyl and R 6 Yes-C(O)R 7 .

[0523] 18i. A compound of formula (I) or a pharmaceutically acceptable salt thereof as described in embodiment 18h, wherein R 7 It is C 1 -C 6 Alkyl or C 1 -C 6 Alkoxy.

[0524] 18j. A compound of formula (I) or a pharmaceutically acceptable salt thereof as described in embodiment 18i, wherein C 1 -C 6 Alkyl is -CH 3 or -CH(CH 3 ) 2 And C 1 -C 6 Alkoxy is -OCH 3 or -OCH(CH 3 ) 2 .

[0525] 19. A compound of formula (I) or a pharmaceutically acceptable salt thereof as described in Embodiment 1, wherein the compound has formula (Ia):

[0526]

[0527] 20. A compound of formula (I) or a pharmaceutically acceptable salt thereof as described in Embodiment 19, wherein Y is an alkyl group.

[0528] 21. A compound of formula (I) or a pharmaceutically acceptable salt thereof as described in Embodiment 1, wherein the compound has formula (Ib):

[0529]

[0530] in Optionally C 1 -C 6 The alkyl group is substituted, and n is an integer in the range of 1-5.

[0531] 22. A compound of formula (I) or a pharmaceutically acceptable salt thereof as described in Embodiment 21, wherein W is -O-.

[0532] 23. A compound of formula (I) or a pharmaceutically acceptable salt thereof as described in embodiment 21 or 22, wherein Y is a saturated or unsaturated cycloalkyl group, a saturated or unsaturated heterocyclic group, or -C(O)OR 3 , and R 3 is alkyl, wherein the cycloalkyl and heterocyclyl are optionally substituted with one or more groups independently selected from oxo, halogen, cyano, alkyl, alkenyl and alkynyl.

[0533] 23a. A compound of formula (I) or a pharmaceutically acceptable salt thereof as described in Embodiment 22 or 23, wherein Y is -C(O)OR 3 And R 3 It is C 1 -C 6 alkyl.

[0534] 23b. A compound of formula (I) or a pharmaceutically acceptable salt thereof as described in Embodiment 23 or 23a, wherein Y is a 5- or 6-membered saturated or unsaturated cycloalkyl group (eg, cyclopentyl or cyclopentenyl).

[0535] 23c. A compound of formula (I) or a pharmaceutically acceptable salt thereof as described in any one of embodiments 23-23b, wherein Y is a 5- or 6-membered heterocyclyl.

[0536] 24. A compound of formula (I) or a pharmaceutically acceptable salt thereof as described in Embodiment 1, wherein the compound has formula (Ic-1) or formula (Ic-2):

[0537]

[0538] 25. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to embodiment 1, wherein the compound has formula (Id-1) or formula (Id-2):

[0539]

[0540] 26. A compound of formula (I) or a pharmaceutically acceptable salt thereof as described in embodiment 24 or 25, wherein R 1b It's hydrogen.

[0541] 27. A compound of formula (I) or a pharmaceutically acceptable salt thereof as described in embodiment 24 or 25, wherein R1b It's methyl.

[0542] 28. A compound of formula (I) or a pharmaceutically acceptable salt thereof as described in any one of embodiments 24-27, wherein R 2 is H, alkyl (e.g. C 1 -C 6 Alkyl), alkenyl (e.g. C 2 -C 6 alkenyl) or alkynyl (e.g. C 2 -C 6 alkynyl).

[0543] 29. A compound of formula (I) or a pharmaceutically acceptable salt thereof as described in any one of embodiments 24-27, wherein R 2 Is H or C 1 -C 6 alkyl.

[0544] 30. A compound of formula (I) or a pharmaceutically acceptable salt thereof as described in any one of embodiments 24-29, wherein W is optionally substituted alkyl.

[0545] 31. A compound of formula (I) or a pharmaceutically acceptable salt thereof as described in embodiment 30, wherein the optionally substituted alkyl is C 1 -C 6 alkyl.

[0546] 32. A compound of formula (I) or a pharmaceutically acceptable salt thereof as described in embodiment 30, wherein the optionally substituted alkyl is C 1 -C 3 alkyl.

[0547] 33. A compound of formula (I) or a pharmaceutically acceptable salt thereof as described in any one of embodiments 24-32, wherein Y is an unsaturated heterocyclic group, -OC(O)OR 3 、-OC(O)R 4 and –NR 5 R 6 , wherein the unsaturated heterocyclic group is optionally substituted with one or more groups independently selected from oxo, halogen, cyano, alkyl, alkenyl, alkynyl and heteroalkyl.

[0548] 34. A compound of formula (I) or a pharmaceutically acceptable salt thereof as described in any one of embodiments 24-33, wherein Y is an optionally substituted unsaturated 5- or 6-membered heterocyclic group having 1 or 2 oxygen atoms.

[0549] 35. A compound of formula (I) or a pharmaceutically acceptable salt thereof as described in any one of embodiments 24-33, wherein Y is

[0550] 36. A compound of formula (I) or a pharmaceutically acceptable salt thereof as described in any one of embodiments 24-33, wherein Y is -OC(O)R 4 .

[0551] 37. A compound of formula (I) or a pharmaceutically acceptable salt thereof as described in Embodiment 36, wherein R 4 It is C 1 -C 6 alkyl.

[0552] 38. A compound of formula (I) or a pharmaceutically acceptable salt thereof as described in embodiment 37, wherein said C 1 -C 6 The alkyl group is methyl, ethyl or isopropyl.

[0553] 39. A compound of formula (I) or a pharmaceutically acceptable salt thereof as described in any one of embodiments 24-33, wherein Y is -NR 5 R 6 .

[0554] 40. A compound of formula (I) or a pharmaceutically acceptable salt thereof as described in embodiment 39, wherein R 5 is H or alkyl and R 6 Yes-C(O)R 7 .

[0555] 41. A compound of formula (I) or a pharmaceutically acceptable salt thereof as described in embodiment 40, wherein R 7 It is C 1 -C 6 Alkyl or C 1 -C 6 Alkoxy.

[0556] 41a. A compound of formula (I) or a pharmaceutically acceptable salt thereof as described in embodiment 41, wherein C 1 -C 6 Alkyl is -CH 3 or -CH(CH 3 ) 2 And C 1 -C 6 Alkoxy is -OCH 3 or -OCH(CH 3 ) 2 .

[0557] 42. A compound of formula (I) or a pharmaceutically acceptable salt thereof as described in any one of embodiments 24-33, wherein Y is -OC(O)OR 3 .

[0558] 42a. A compound of formula (I) or a pharmaceutically acceptable salt thereof as described in Embodiment 42, R 3 is an alkyl group (e.g. C 1 -C 6 alkyl) or aryl (phenyl), each of which is optionally substituted.

[0559] 43. A compound or a pharmaceutically acceptable salt thereof as described in any one of the preceding technical solutions, wherein the compound is selected from the group consisting of:

[0560] Hexanoic acid [(3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl] ester,

[0561] Heptanoic acid [(3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl] ester,

[0562] Octanoic acid (3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthrene-3-yl ester,

[0563] Hexanoic acid [(3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-3,10,13-trimethyl-1,2,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydrocyclopenta[a]phenanthrene-3-yl] ester, heptanoic acid [(3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-3,10,13-trimethyl-1,2,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydrocyclopenta[a]phenanthrene-3-yl] ester, 3-Trimethyl-1,2,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydrocyclopenta[a]phenanthrene-3-yl] ester, 3-cyclopentylpropionic acid [(3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl] ester, 3-cyclopentylacetic acid [(3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16 ,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl] ester, 3-cyclopentylpropionic acid [(3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-3,10,13-trimethyl-1,2,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydrocyclopenta[a]phenanthrene-3-yl] ester, 2-cyclopentylacetic acid [(3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-3,10,13-trimethyl-1,2,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydrocyclopenta[a]phenanthrene-3-yl] ester, 3-cyclopent-3-ene-1-yl Propionic acid [(3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl] ester, 3-cyclopent-3-en-1-yl propionic acid [(3R,5S ,8R,9S,10S,13S,14S,17S)-17-acetyl-3,10,13-trimethyl-1,2,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydrocyclopenta[a]phenanthrene-3-yl]ester, 3-(5-oxotetrahydrofuran-2-yl)propanoic acid [(3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl] ester, 4-acetoxybutyric acid [(3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl] ester 0,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl] ester, 4-(2-methylpropionyloxy)butanoic acid [(3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-10,13-dimethyl-2,3,4,5,6, 7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl] ester, 5-acetoxypentanoic acid [(3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl] ester Tetrahydro-1H-cyclopenta[a]phenanthrene-3-yl] ester, 5-acetoxy-2-methyl-pentanoic acid [(3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl] ester,

[0564] 3-[[(3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl]oxycarbonyloxy]propyl acetate, 2-[[(3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl]oxycarbonyloxy]ethyl 2-methylpropanoate,

[0565] [(3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl] ester (5-methyl-2-oxo-1,3-dioxol-4-yl) methyl carbonate,

[0566] Carbonic acid [(3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl]butyl ester, 2-[[(3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl]butyl ester ,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl]oxycarbonylamino]ethyl ester, 2-[[(3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl]oxycarbonyl-methyl-amino]ethyl 2-methylpropanoate,

[0567] [(3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl] 2-(2-methylpropionylamino)ethyl carbonate),

[0568] (3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthrene-3-yl carbonate (2-(N-methylisobutyramido)ethyl)

[0569] [(3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl] 2-(methoxycarbonylamino)ethyl carbonate,

[0570] [(3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl] 2-(methoxycarbonyl-N-methylamino)ethyl carbonate, (3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-3,10,13-trimethylhexahydro-1H-cyclopenta[a]phenanthrene-3-yl carbonate ((5-methyl-2-oxo-1,3-dioxol-4-yl)methyl) carbonate,

[0571] 2-(((((3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-3,10,13-trimethylhexahydro-1H-cyclopenta[a]phenanthrene-3-yl)oxy)carbonyl)(methyl)amino)ethyl isobutyrate,

[0572] 2-(((((3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-3,10,13-trimethylhexahydro-1H-cyclopenta[a]phenanthrene-3-yl)oxy)carbonyl)oxy)ethyl isobutyrate,

[0573] (3R,5R,8R,9R,10S,13S,14S,17S)-17-(2-(4-cyano-1H-pyrazol-1-yl)acetyl)-3,13-dimethylhexahydro-1H-cyclopenta[a]phenanthrene-3-yl carbonate ((5-methyl-2-oxo-1,3-dioxol-4-yl)methyl) carbonate,

[0574] isobutyric acid 2-(((((3R,5R,8R,9R,10S,13S,14S,17S)-17-(2-(4-cyano-1H-pyrazol-1-yl)acetyl)-3,13-dimethylhexahydro-1H-cyclopenta[a]phenanthren-3-yl)oxy)carbonyl)(methyl)amino)ethyl isobutyrate, and isobutyric acid 2-(((((3R,5R,8R,9R,10S,13S,14S,17S)-17-(2-(4-cyano-1H-pyrazol-1-yl)acetyl)-3,13-dimethylhexahydro-1H-cyclopenta[a]phenanthren-3-yl)oxy)carbonyl)oxy)ethyl ester.

[0575] 44. A pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof as described in any one of the preceding embodiments, and at least one pharmaceutically acceptable excipient.

[0576] 45. A method of treating a subject in need thereof with GABA A A method for treating a disease or condition associated with receptor function, the method comprising administering to a subject a therapeutically effective amount of a compound of formula (I) as described in any one of embodiments 1 to 43, or a pharmaceutically acceptable salt thereof.

[0577] 46. ​​The method of embodiment 45, wherein the disease or condition is selected from the group consisting of sleep disorders, mood disorders, dementia, schizophrenia spectrum disorders, convulsive disorders, anxiety disorders, autism spectrum disorders, memory and / or cognitive disorders, movement disorders, personality disorders, autism spectrum disorders, pain, traumatic brain injury, vascular disease, substance abuse disorders, withdrawal syndrome, and tinnitus.

[0578] 46a. The method of embodiment 46, wherein the sleep disorder is insomnia, the mood disorder is depression, the dementia is Alzheimer's type dementia, the convulsive disorder is epilepsy, and the movement disorder is Parkinson's disease.

[0579] 46b. The method of embodiment 46, wherein the disease is selected from the group consisting of CDD, MDD, PPD, essential tremor, PTSD, SE, ESE, fragile X syndrome, Parkinson's disease, or refractory depression.

[0580] 47. A compound of formula (I) or a pharmaceutically acceptable salt thereof as described in any one of embodiments 1 to 43 for use in treating GABA A Diseases or conditions associated with receptor function.

[0581] 48. A compound of formula (I) or a pharmaceutically acceptable salt thereof as described in any one of embodiments 1 to 43 in the manufacture of a drug for treating GABA A Use in a medicament for a disease or condition associated with receptor function.

[0582] 49. A compound of formula (I) or a pharmaceutically acceptable salt thereof as described in any one of embodiments 1 to 43 for use in treating GABA A A disease or condition associated with receptor function, wherein the compound of formula (I) is administered simultaneously, separately or sequentially with one or more additional pharmaceutical agents.

Claims

1. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:

2. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein: The compound is:

3. A pharmaceutical composition comprising the compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

4. A composition comprising the compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition according to claim 3 in the preparation of a composition for treating a subject with GABA A Use of the receptor in a medicament for a disease or condition associated with receptor function.

5. The use of claim 4, wherein the disease or condition is selected from the group consisting of sleep disorders, mood disorders, schizophrenia spectrum disorders, convulsive disorders, autism spectrum disorders, memory and / or cognitive disorders, movement disorders, personality disorders, autism spectrum disorders, pain, traumatic brain injury, vascular disease, substance abuse disorders and withdrawal syndrome.

6. The use according to claim 5, wherein the sleep disorder is insomnia, the mood disorder is depression, the memory and / or cognitive disorder is Alzheimer's dementia, the convulsive disorder is epilepsy, and the movement disorder is Parkinson's disease.

7. The use of claim 4, wherein the disease is selected from the group consisting of CDKL5 deficiency (CDD), major depressive disorder (MDD), postpartum depression (PPD), essential tremor, post-traumatic stress disorder (PTSD), status epilepticus (SE), electroencephalographic status epilepticus (ESE), fragile X syndrome, Parkinson's disease, refractory depression and tinnitus.

8. The use of claim 4, wherein the disease or condition is major depressive disorder (MDD), postpartum depression (PPD) or epilepsy.

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