WO2011007230A2 - Lupeol-type triterpene derivatives as antivirals - Google Patents

Lupeol-type triterpene derivatives as antivirals Download PDF

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Publication number
WO2011007230A2
WO2011007230A2 PCT/IB2010/001677 IB2010001677W WO2011007230A2 WO 2011007230 A2 WO2011007230 A2 WO 2011007230A2 IB 2010001677 W IB2010001677 W IB 2010001677W WO 2011007230 A2 WO2011007230 A2 WO 2011007230A2
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prop
pentamethyl
cyclopenta
icosahydro
substituted
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PCT/IB2010/001677
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French (fr)
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WO2011007230A3 (en
Inventor
Bandi Parthasaradhi Reddy
Vedula Manohar Sharma
Kura Rathnakar Reddy
Musku Madhanmohan Reddy
Nelli Yella Reddy
Lanka Vl Subrahmanyam
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Hetero Research Foundation
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Priority to CN201080031744.XA priority Critical patent/CN102656180B/en
Priority to EP10734556.3A priority patent/EP2454270B1/en
Priority to KR1020147000436A priority patent/KR20140016428A/en
Priority to MX2012000565A priority patent/MX2012000565A/en
Priority to BR112012000769A priority patent/BR112012000769A2/en
Priority to AP2012006081A priority patent/AP2012006081A0/en
Priority to RU2012104993/04A priority patent/RU2561604C2/en
Priority to CA2767642A priority patent/CA2767642C/en
Publication of WO2011007230A2 publication Critical patent/WO2011007230A2/en
Publication of WO2011007230A3 publication Critical patent/WO2011007230A3/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J63/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by expansion of only one ring by one or two atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J63/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by expansion of only one ring by one or two atoms
    • C07J63/008—Expansion of ring D by one atom, e.g. D homo steroids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J69/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by contraction of only one ring by one atom and expansion of only one ring by one atom

Definitions

  • the present invention relates to novel lupeol-type triterpene derivatives and related compounds, compositions useful for therapeutic treatment of viral diseases and particularly HIV mediated diseases.
  • HIV Human Immunodeficiency Virus
  • ADDS Acquired Immunodeficiency Syndrome
  • HIV is a retrovirus, and the HIV life cycle encompasses several crucial steps, starting from the attachment of the virus to the host cell membrane and finishing with the release of progeny virons from the cell.
  • betulinicacid acid isolated from Syzygium clavifolium and several other plant species was found to possess anti-HIV activity.
  • 20040204389 describes anti-HIV agents with dual sites of action; WO 2007/00241 1 describes antiviral compounds; CN 1861627 describes antitumor agents; WO 2006053255 describes novel betulin derivatives, preparation thereof and use thereof; WO 2009/082818 describes novel C-21 keto lupine derivatives preparation and use thereof; and WO 2006105356 describes methods of manufacturing bioactive 3- esters of betulinic aldehyde and betulinic acid.
  • WO 2009/082819, WO 2009/100532 disclosed 17 ⁇ lupine derivatives as anti-HIV agents.
  • WO 2007141383 describes betulin derivatives as antifeedants for plant pests
  • US 6670345 describes use of betulinic acid and its derivatives for inhibiting cancer growth and process for the manufacture of betulinic acid
  • WO 2002091858 describes anxiolytic marcgraviaceae compositions containing betulinic acid, betulinic acid derivatives, and methods of preparation and use
  • WO 2000046235 describes preparation of novel betulinic acid derivatives for use as cancer growth inhibitors
  • WO 2007141392 describes cosmetic and pharmaceutical compositions comprising betulonic acid and betulin derivatives.
  • the present invention relates to the compounds of the formula (1):
  • R can be H, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocyclyl and preferably R can be substituted by R a ;
  • R' can be H, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted alkyloxy, or substituted or unsubstituted aryloxy and preferably R' can be substituted by R a ;
  • X and Xi are independently can be selected from a bond, -O-, -NR"-, -C(O)-, -C(O) 2 -,-(CH 2 )n-, or -C(O)NR"-;
  • Z and Zi are independently can be selected from a bond, -C(O)-, -(CH 2 ) n -, - O-, -S-, -SO 2 -, or -NR"-;
  • n can be an integer 0-2;
  • n can be an integer 0-2;
  • Ri can be H, C(O) 2 R", or substituted or unsubstituted alkyl
  • RT can be H, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, or substituted or unsubstituted cycloalkyl;
  • R a can be H, OH, halogen, NR", C(O) 2 R", CH 2 OR", C(O)NR" or substituted or unsubstituted alkyl; and each R" can be independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocyclyl; and a proviso that one of the R or R' is substituted or unsubstituted 4 or 5 membered cycloalkyl group, and if R or R' is 4 membered cycloalkyl group then at least one of the carbon atom of the 4 membered cycloalkyl group must be substituted by two identical groups and which are selected from alkyl or halogen wherein most preferably alkyl is methyl and halo is fluorine.
  • compositions of the formula (1) are also contemplated.
  • pharmaceutically acceptable solvates, including hydrates, of the compounds of the formula (1) are contemplated.
  • formula (1) structurally encompasses all stereoisomers, including enantiomers, diastereomers, racemates, and combinations therof, which may be contemplated from the chemical structure of the genus described herein.
  • prodrugs of the compounds of the formula (1) including ester prodrugs.
  • a compound of formula (1) wherein R is substituted or unsubstituted cyclopentyl. According to one embodiment, there is provided a compound of formula (1), wherein R is substituted or unsubstituted alkyl.
  • R is H, -C((CH 3 ) 2 )-CO 2 H, -C((CH 3 ) 2 )-CH2-CO 2 H, -CH 2 -CH2-CO 2 H, - CH2-CO 2 H and CH 3 .
  • X 1 is -C(O)NR"- and -C(O) 2 -.
  • R can be substituted or unsubstituted alkyl or substituted or unsubstituted cycloalkyl; wherein cycloalkyl is a 4 or 5 membered ring system and substituents in each occurrence is independently selected from H, halo, Ci-C 4 alkyl, CO-O-R b , - CH2-O-R b , CO-NHRb, or CON(R b ) 2 ; and preferably substituted or unsubstituted alkyl of R A can be selected from:
  • R A ' can be H, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, and preferably R A ' can be substituted by R a ;
  • X 1 A can be a bond, -O-, -NR"-, -C(O)-, -C(O) 2 -, or -C(O)NR"-;
  • Zi A can be a bond, -C(O)-, -O-, -S-, -SO 2 -, or -NR"-;
  • R a can be H, OH, halogen, NR", C(O) 2 R", CH 2 OR", C(O)NR" or substituted or unsubstituted alkyl;
  • R b can be H, or substituted or unsubstituted alkyl
  • each R" can be independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocyclyl; and a proviso that one of the R A or R A ' is substituted or unsubstituted 4 or 5 membered cycloalkyl group, and if R A or R A ' is 4 membered cycloalkyl group then at least one of the carbon atom of the 4 membered cycloalkyl group must be substituted by two identical groups and which are selected from alkyl or halogen wherein most preferably alkyl is methyl and halo is fluorine.
  • compositions of the formula (IA) are also contemplated.
  • pharmaceutically acceptable solvates, including hydrates, of the compounds of the formula (IA) are contemplated.
  • formula (IA) structurally encompasses all stereoisomers, including enatiomers and diastereomers, which may be contemplated from the chemical structure of the genus described herein.
  • prodrugs of the compounds of the formula (IA), including ester prodrugs are also contemplated.
  • R 2 can be H, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted cycloalkyl and preferably R 2 can be substituted by R a ;
  • R 2 ' can be H, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted alkyloxy, or substituted or unsubstituted aryloxy and preferably R 2 ' can be substituted by R a ;
  • X 2 and X 2 ' are independently can be selected from a bond, -O-, -NR"-, -C(O)- , -C(O) 2 -,-(CH 2 ) n -, or -C(O)NR"-;
  • n can be 0-3;
  • Z 2 and Z 2 ' are independently can be selected from a bond, -C(O)-, -O-, or - NR"-;
  • R a can be H, OH, halogen, N(R") 2 , C(O)R", C(O) 2 R", CH 2 OR", C(0)N(R") 2 or substituted or unsubstituted alkyl;
  • each R" can be independently selected from H, -[CH(R"')] P C(O) 2 R"', substituted or unsubstituted alkyl, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocyclyl;
  • p can be 0-3;
  • each R"' can be independently selected from H, substituted or unsubstituted alkyl, or substituted or unsubstituted cycloalkyl; and a proviso that one of the R 2 or R 2 ' is substituted or unsubstituted 4 or 5 membered cycloalkyl group, and if R 2 or R 2 ' is 4 membered cycloalkyl group then at least one of the carbon atom of the 4 membered cycloalkyl group must be substituted by two identical groups and which are selected from alkyl or halogen wherein most preferably alkyl is methyl and halo is fluorine.
  • compositions of the formula (2) are also contemplated.
  • pharmaceutically acceptable solvates, including hydrates, of the compounds of the formula (2) are contemplated.
  • prodrugs of the compounds of the formula (2) including ester prodrugs.
  • a compound of formula (2) wherein X 2 is a bond, -C(O)- and -C(O)-CH 2 -.
  • R 2 is H, -C((CH 3 ) 2 )-CO 2 H, -C((CH 3 ) 2 )-CH2-CO 2 H, -CH 2 -CH2-CO 2 H, - CH2-CO 2 H and CH 3 .
  • a compound of formula (2) wherein X 2 ' is a bond, -C(O) 2 - and -C(O)N R"-.
  • R a is substituted or unsubstituted alkyl and C(O)R".
  • R" is OH, -[CH(R"')] p C(O) 2 Me, -[CH(R'")] P C(O) 2 H, benzyl, morpholine, piperidine, ethyl piperidine-4-carboxylate, N-ethyl piperazine, and pyrrolidine.
  • one more aspect of the present invention provides the compounds of formula (2A):
  • X M l can be a bond, or -C(O)-;
  • X ⁇ A2 can be a bond, O or NH; R ,Al can be H, substituted or unsubstituted alkyl, substituted or unsubstituted
  • R A2 can be H, substituted or unsubstituted alkyl, substituted or unsubstituted amino, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted aryl and preferably R A2 can be substituted by R ; and
  • each R can be substituted or unsubstituted alkyl, substituted or unsubstituted heterocyclyl, wherein heterocycle is nitrogen containing heterocycle and is bonded through nitrogen atom, substituted or unsubstituted N contained heterocyclylalkyl (wherein alkyl is bonded to ring nitrogen atom of heterocycle), substituted or unsubstituted aralkyl or substituted or unsubstituted phenyl.
  • compositions of the formula (2A) are also contemplated.
  • pharmaceutically acceptable solvates, including hydrates, of the compounds of the formula (2A) are contemplated.
  • prodrugs of the compounds of the formula (2A), including ester prodrugs are also contemplated.
  • a compound of formula (2A) wherein X A I is a bond and -C(O)-. According to one embodiment, there is provided a compound of formula (2A), wherein R AI is H and substituted or unsubstituted alkyl.
  • R A1 is H, -C((CH 3 ) 2 )-CO 2 H, -C((CH 3 ) 2 )-CH2-CO 2 H, -CH 2 -CH2- CO 2 H, -CH2-CO 2 H and CH 3 .
  • R 3a can be H, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted alkyloxy, or substituted or unsubstituted aryloxy and preferably R 3a can be substituted by R a ;
  • X 3 can be selected from a bond, -O-, -NR"-, -C(O)-, -C(O) 2 -,-(CH 2 ) n -, or - C(O)NR"-;
  • n can be 0-3;
  • Z 3 can be selected from a bond, -O-, or -NR"-;
  • R a can be H, OH, halogen, N(R") 2 , C(O)R", C(O) 2 R", CH 2 OR", C(O)N(R") 2 or substituted or unsubstituted alkyl;
  • each R" can be independently selected from H, -[CH(R"')] P C(O) 2 R" ⁇ substituted or unsubstituted alkyl, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocyclyl;
  • p can be 0-3;
  • each R'" can be independently selected from H, substituted or unsubstituted alkyl, or substituted or unsubstituted cycloalkyl; and a proviso that R 3a is substituted or unsubstituted 4 or 5 membered cycloalkyl group, and if R 3a is 4 membered cycloalkyl group then at least one of the carbon atom of the 4 membered cycloalkyl group must be substituted by two identical groups and which are selected from alkyl or halogen wherein most preferably alkyl is methyl and halo is fluorine.
  • compositions of the formula (3) are also contemplated.
  • pharmaceutically acceptable solvates, including hydrates, of the compounds of the formula (3) are contemplated.
  • prodrugs of the compounds of the formula (3) including ester prodrugs.
  • a- or pharmaceutically acceptable salts, solvates, including hydrates and prodrugs of compounds are also contemplated.
  • the present invention also provides a pharmaceutical composition that includes at least one compound of described herein and at least one pharmaceutically acceptable excipient (such as a pharmaceutically acceptable carrier or diluent).
  • the pharmaceutical composition comprises a therapeutically effective amount of at least one compound described herein.
  • the compound(s) present in the composition may be associated with a pharmaceutically acceptable excipient (such as a carrier or a diluent) or may be diluted by a carrier, or enclosed within a carrier which may be in the form of a capsule, sachet, paper, or other container.
  • the compounds and pharmaceutical compositions described herein are useful in the treatment of diseases, conditions and/or disorders mediated by viral infections.
  • the present invention further provides a method of treating a disease, condition and/or disorder mediated by viral infections in a subject in need thereof by administering to the subject one or more compounds described herein in the amount effective to cause that infection.
  • the invention provides a method for preventing, ameliorating or treating a HIV mediated disease, disorder or syndrome in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of the invention.
  • the invention further provides a method, wherein the HIV mediated disease, disorder or syndrome is like AIDS, AIDS related complex, or a syndrome characterized by symptoms such as pesistant generalized limphadenopathy, fever and weight loss, or an etroviral infection genetically related to AIDS.
  • Anti HIV inhibitory potential of the compounds of present invention may be demonstrated by any one or more methodologies known in the art, such as by using the assays described in Mosmann T, December 1983, Journal of immunological methods, 65 (1-2), 55-63 and SPC Cole, cancer chemotherapy and Pharmacology, 1986, 17, 259-263. Detailed Description of the Invention
  • the present invention provides lupeol-type triterpene derivatives and related compounds, which may be used as antiviral particularly as anti-HIV compounds and processes for the synthesis of these compounds.
  • Pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, diastereomers, together with pharmaceutically acceptable carriers, excipients or diluents, which can be used for the treatment of diseases, condition and/or disorders mediated by viral infections, are also provided.
  • halogen or halo includes fluorine, chlorine, bromine, or iodine.
  • alkyl refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to eight carbon atoms, and which is attached to the rest of the molecule by a single bond, e.g., methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n- pentyl, and 1,1-dimethylethyl (t-butyl).
  • alkenyl refers to an aliphatic hydrocarbon group containing a carbon-carbon double bond and which may be a straight or branched chain having from 2 to about 10 carbon atoms, e.g., ethenyl, 1-propenyl, 2-propenyl (allyl), iso- propenyl, 2-methyl- 1-propenyl, 1-butenyl, and 2-butenyl.
  • halo alkyl is used to denote a group comprised of an alkyl group substituted with halogen atom, where alkyl group is as defined above and halogen is used to denote fluorine, chlorine, bromine or iodine, an example of such group is trifluoromethyl, difluoromethyl.
  • acyl group is used to denote a linear or branched aliphatic acyl group (preferably a C 2 - 6 alkanoyl group) or an aromatic acyl group, which contains 2 to 10 carbon atoms.
  • examples include an acetyl group, a propionyl group, a pivaloyl group, a butyryl group, an isobutyryl group, a valeryl group and a benzoyl group, with an acetyl group being preferred.
  • alkoxy group is used to denote a linear or branched alkoxy group containing 1 to 6 carbon atoms. Preferred are C 1 .4 alkoxy groups including a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, an n- butoxy group, an isobutoxy group and a tert-butoxy group.
  • alkoxycarbonyl group is used to denote a structure composed of a linear or branched C 1 . 5 alkoxy group and a carbonyl group. Preferred are C 2 .
  • alkoxycarbonyl groups including a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, an isopropoxycarbonyl group and a butoxycarbonyl group.
  • a methoxycarbonyl group is preferred.
  • cycloalkyl denotes a non-aromatic mono or multicyclic ring system of from 3 to about 12 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • multicyclic cycloalkyl groups include, but are not limited to, perhydronapththyl, adamantyl and norbornyl groups, bridged cyclic groups and spirobicyclic groups, e.g., spiro (4,4) non-2-yl.
  • cycloalkenyl refers to a cyclic ring-containing radical having from 3 to about 8 carbon atoms with at least one carbon-carbon double bond, such as cyclopropenyl, cyclobutenyl, and cyclopentenyl.
  • cycloalkylalkyl refers to a cyclic ring-containing radical having from 3 to about 8 carbon atoms directly attached to an alkyl group.
  • the cycloalkylalkyl group may be attached to the main structure at any carbon atom in the alkyl group that results in the creation of a stable structure.
  • Non-limiting examples of such groups include cyclopropylmethyl, cyclobutylethyl, and cyclopentylethyl.
  • aryl refers to an aromatic radical having from 6 to 14 carbon atoms such as phenyl, naphthyl, tetrahydronapthyl, indanyl, and biphenyl.
  • arylalkyl refers to an aryl group as defined above directly bonded to an alkyl group as defined above, e.g., -CH 2 C 6 H 5 and -C 2 H 5 C 6 H 5 .
  • Substituted refers to 1-3 substituents on the same position or on different positions with the same groups or different groups.
  • Alkynyl refers to alkynyl groups having from 2 to 6 carbon atoms and having at least one alkynyl saturation ,example for such group includes acetylenyl, propargyl.
  • heterocyclyl and “heterocyclic ring” refer to a stable 3- to 15- membered ring radical which consists of carbon atoms and from one to five heteroatoms selected from nitrogen, phosphorus, oxygen and sulfur.
  • the heterocyclic ring radical may be a monocyclic, bicyclic or tricyclic ring system, which may include fused, bridged or spiro ring systems, and the nitrogen, phosphorus, carbon, oxygen or sulfur atoms in the heterocyclic ring radical may be optionally oxidized to various oxidation states.
  • the nitrogen atom may be optionally quateraized; and the ring radical may be partially or fully saturated (i.e., heterocyclic or heteroaryl).
  • heterocyclic ring radicals include, but are not limited to, tetrazoyl, tetrahydroisouinolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2- oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolinyl, oxazolidinyl, triazolyl, isoxazolyl, isoxasolidinyl, morpholinyl, thiazolyl, thiazolinyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl, isoindolyl, is
  • heterocyclylalkyl refers to a heterocyclic ring radical directly bonded to an alkyl group.
  • the heterocyclylalkyl radical may be attached to the main structure at any carbon atom in the alkyl group that results in the creation of a stable structure.
  • heteroaryl refers to an aromatic heterocyclic ring radical.
  • the heteroaryl ring radical may be attached to the main structure at any heteroatom or carbon atom that results in the creation of a stable structure.
  • heteroarylalkyl refers to a heteroaryl ring radical directly bonded to an alkyl group.
  • the heteroarylalkyl radical may be attached to the main structure at any carbon atom in the alkyl group that results in the creation of a stable structure.
  • R ⁇ R y and R z are independently selected from hydrogen, substituted or unsubstituted alkyl, haloalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted cycloalky
  • prodrug means a compound that is transformed in vivo to yield a compound of Formula (I), (IA), (2), (2A) or a pharmaceutically acceptable salt, hydrate or solvate, or metabolite of the compound.
  • the transformation may occur by various mechanisms, such as through hydrolysis in blood.
  • a discussion of the use of prodrugs is provided by T. Higuchi and W. Stella, "Pro-drugs as Novel Delivery Systems," Vol. 14 of the A. C. S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and
  • treating or “treatment” of a state, disease, disorder or condition includes:
  • the benefit to a subject receiving treatment is either statistically significant or at least perceptible to the subject or to the physician.
  • subject includes mammals (especially humans) and other animals, such as domestic animals (e.g., household pets including cats and dogs) and non-domestic animals (such as wildlife).
  • domestic animals e.g., household pets including cats and dogs
  • non-domestic animals such as wildlife.
  • a “therapeutically effective amount” means the amount of a compound that, when administered to a subject for treating a state, disease, disorder or condition, is sufficient to effect such treatment.
  • the “therapeutically effective amount” will vary depending on the compound, the state, disease, disorder or condition and its severity and the age, weight, physical condition and responsiveness of the subject receiving treatment.
  • the compounds of the present invention may form salts.
  • Non-limiting examples of pharmaceutically acceptable salts forming part of this invention include salts derived from inorganic bases salts of organic bases salts of chiral bases, salts of natural amino acids and salts of non-natural amino acids.
  • Certain compounds of the present invention are capable of existing in stereoisomeric forms (e.g., diastereomers, enantiomers, racemates, and combinations thereof). With respect to the overall compounds described by the Formula (1), (IA), (2) or (2A), the present invention extends to these stereoisomeric forms and to mixtures thereof.
  • solvates includes hydrates and other solvents of crystallization (such as alcohols).
  • the compounds of the present invention may form solvates with low molecular weight solvents by methods known in the art.
  • compositions provided in the present invention include at least one compound described herein and at least one pharmaceutically acceptable excipient (such as a pharmaceutically acceptable carrier or diluent).
  • pharmaceutically acceptable excipient such as a pharmaceutically acceptable carrier or diluent.
  • the contemplated pharmaceutical compositions include a compound(s) described herein in an amount sufficient to treat viral infection in a subject.
  • the subjects contemplated include, for example, a living cell and a mammal, including human.
  • the compound of the present invention may be associated with a pharmaceutically acceptable excipient (such as a carrier or a diluent) or be diluted by a carrier, or enclosed within a carrier which can be in the form of a capsule, sachet, or other container.
  • suitable carriers include, but are not limited to, water, salt solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, peanut oil, olive oil, gelatin, lactose, terra alba, sucrose, dextrin, magnesium carbonate, sugar, cyclodextrin, amylose, magnesium stearate, talc, gelatin, agar, pectin, acacia, stearic acid or lower alkyl ethers of cellulose, silicic acid, fatty acids, fatty acid amines, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, polyoxyethylene, hydroxymethylcellulose and polyvinylpyrrolidone.
  • the carrier or diluent may include a sustained release material, such as, for example, glyceryl monostearate or glyceryl distearate, alone or mixed with a wax.
  • a sustained release material such as, for example, glyceryl monostearate or glyceryl distearate, alone or mixed with a wax.
  • the pharmaceutical composition may also include one or more pharmaceutically acceptable auxiliary agents, wetting agents, emulsifying agents, suspending agents, preserving agents, salts for influencing osmotic pressure, buffers, sweetening agents, flavoring agents, colorants, or any combination of the foregoing.
  • the pharmaceutical composition of the invention may be formulated so as to provide quick, sustained, or delayed release of the active ingredient after administration to the subject by employing procedures known in the art.
  • compositions described herein may be prepared, e.g., as described in Remington: The Science and Practice of Pharmacy, 20 th Ed., 2003 (Lippincott Williams & Wilkins).
  • the active compound can be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier, which may be in the form of an ampoule, capsule, sachet, or other container.
  • the carrier serves as a diluent, it may be a solid, semi-solid, or liquid material that acts as a vehicle, excipient, or medium for the active compound.
  • the active compound can be adsorbed on a granular solid container, for example, in a sachet.
  • compositions may be, for example, capsules, tablets, aerosols, solutions, suspensions, liquids, gels, or products for topical application.
  • the route of administration may be any route which effectively transports the active compound to the appropriate or desired site of action.
  • Suitable routes of administration include, but are not limited to, oral, nasal, pulmonary, buccal, subdermal, intradermal, transdermal, parenteral, rectal, depot, subcutaneous, intravenous, intraurethral, intramuscular, intranasal, ophthalmic (such as with an ophthalmic solution) or topical (such as with a topical ointment).
  • the oral route is preferred.
  • Solid oral formulations include, but are not limited to, tablets, capsules (soft or hard gelatin), dragees (containing the active ingredient in powder or pellet form), troches and lozenges. Tablets, dragees, or capsules having talc and/or a carbohydrate carrier or binder or the like are particularly suitable for oral application. Preferable carriers for tablets, dragees, or capsules include lactose, cornstarch, and/or potato starch. A syrup or elixir can be used in cases where a sweetened vehicle can be employed.
  • a typical tablet that may be prepared by conventional tabletting techniques may contain: (1) Core: Active compound (as free compound or salt thereof), 250 mg colloidal silicon dioxide (Aerosil®), 1.5 mg microcrystalline cellulose (Avicel®), 70 mg modified cellulose gum (Ac-Di-Sol®), and 7.5 mg magnesium stearate; (2) Coating: HPMC, approx. 9 mg Mywacett 9-40 T and approx. 0.9 mg acylated monoglyceride.
  • Liquid formulations include, but are not limited to, syrups, emulsions, soft gelatin and sterile injectable liquids, such as aqueous or non-aqueous liquid suspensions or solutions.
  • injectable solutions or suspensions preferably aqueous solutions with the active compound dissolved in polyhydroxylated castor oil.
  • Antiviral HFV activity and cytotoxicity of compounds present invention can be measured in parallel by following the methods published in the literature.
  • the cytotoxic effect of compounds can be analyzed by measuring the proliferation of cells using the 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyl tetrazlium bromide (MTT) staining.
  • MTT 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyl tetrazlium bromide
  • the purple -blue MTT formazan precipitate will be dissolved in a triplex reagent containing 10% SDS, 5% isobutanol and 10 mmol/lit HCl.
  • the activity of mitochondria, reflecting cellular growth and viability, will be evaluated by measuring the optical density at 570 nm on micro titer plate.
  • IxIO 6 Sup-Tl cells with 100% cell viability will be seeded in RPMI 1640, 0.1% FBS four 12 well plates.
  • Increasing concentrations of Epap-1 peptides will be added to the cells and will be infected with HIVl 93 M joi each at final concentration of virus equivalent to 2 ng of p24 per ml.
  • the infected cells will be incubated at 37 C and 5% CO2 incubator for 2 hours. After 2hrs the cells will be pelleted at 350 g for 10 min, supernatant will be discarded and cell will be held with RPMI 1640 containing 10% FBS.
  • the cells will be resuspended in the same medium with increasing concentrations of Epap-1 peptides and will be incubated for 96 hours. The cells will be supplemented with peptides at every 24 hours. The supernatants will be collected after 96 hours and analyzed using P24 antigen capture assay kit (SAIC Fredrick). The infection in the absence of Epap-1 will be considered to be 0% inhibition Azidothymidine (AZT) will be taken as positive control.
  • SAIC Fredrick P24 antigen capture assay kit
  • Action of compound on virus entry and quantification of virus entered can be done in terms of GFP expression by the following the methods published J. Virol. 72, 6988 ( 1998) by in Cecilia et al., and Analytical Biochemistry Volume 360, Issue 2, 15 January 2007. Pages 315-317 (Dyavar S. Ravi and Debashis Mitra).
  • cells will be seeded in to wells of 24 well plates 1 day prior to the experiment.
  • the cells will be transfected with Tat-reporter.
  • the virus inoculum will be adjusted to 1,000-4,000 TCED 50/ ml in assay medium (DMEM, 10%FCS,glutamine and antibiotics ), 50 ⁇ l aliquots will be incubated with serial dilutions of compounds (50 ⁇ l ) for lhr at 37°C.
  • the reporter expression will be quantified at appropriate time calculated inhibitory doses referrers to the concentration of these agents in this preincubation mixture.
  • the present invention provides compounds and pharmaceutical formulations thereof that are useful in the treatment of diseases, conditions and/or disorders mediated by viral infections.
  • the connection between therapeutic effect and antiviral is illustrated.
  • the present invention further provides a method of treating a disease, condition and/or disorder mediated by viral infections in a subject in need thereof by administering to the subject a therapeutically effective amount of a compound or a pharmaceutical composition of the present invention.
  • HIV infection HBV, HCV
  • a retroviral infection genetically related to HIV HIV
  • AIDS inflammatory disease
  • respiratory disorders including adult respiratory distress syndrome (ARDS), bronchitis, chronic bronchitis, chronic obstructive pulmonary disease, cystic fibrosis, asthma, emphysema, rhinitis and chronic sinusitis
  • ARDS adult respiratory distress syndrome
  • bronchitis chronic bronchitis
  • cystic fibrosis asthma
  • emphysema chronic obstructive pulmonary disease
  • cystic fibrosis asthma
  • emphysema chronic obstructive pulmonary disease
  • cystic fibrosis asthma
  • emphysema chronic obstructive pulmonary disease
  • chronic fibrosis cystic fibrosis
  • asthma emphysema
  • rhinitis chronic sinusitis
  • the compounds of the present invention can obtain more advantageous effects than additive effects in the prevention or treatment of the above diseases when using suitably in combination with the above drugs. Also, the administration dose can be decreased in comparison with administration of either drug alone, or adverse effects of co administrated drugs other than antiviral can be avoided or declined.
  • the compounds described herein may be prepared by techniques known in the art.
  • the compounds described herein may be prepared by following the reaction sequence as depicted in Scheme- 1 to 6. Further, in the following schemes, where specific bases, acids, reagents, solvents, coupling agents, etc., are mentioned, it is understood that other bases, acids, reagents, solvents, coupling agents etc., known in the art may also be used and are therefore included within the present invention. Variations in reaction conditions, for example, temperature and/or duration of the reaction, which may be used as known in the art, are also within the scope of the present invention. All the stereo isomers of the compounds in these schemes, unless otherwise specified, are also encompassed within the scope of this invention.
  • Compounds of the present invention can be synthesized from naturally occurring Betulinic acid, Ceanothic acid, Moronic acid, or Oleanolic acid.
  • Key intermediates required for synthesizing analogues are either commercially available, or can be prepared by the methods published in the literature.
  • the key intermediates in the present invention were prepared by modifying the procedures published in Journal of organic chemistry 2000, 65, 3934-3940; Tetrahedron: asymmetry 2008, 19, 302-308; or Tetrahedron: asymmetry 2003, 14, 217-223.
  • the compound of Formula (7) (wherein, P is a protecting group (for example alkyl or aralkylyl protecting methyl, ethyl, propyl, isopropyl, benzyl or tertiorybutyl) can be prepared as shown in Scheme 1.
  • P is a protecting group
  • vebinone was oxidized with an oxidizing agent like ruthenium chloride/sodium periodate in a solvent system like CC14-ACN-H2O to give the carboxylic acid of compounds of formula 1.
  • the carboxylic acid of compounds of formula 1 is protected with a protecting agent to give the acid protected compounds of formula 2.
  • a protecting group is introduced by reacting alkyl halides in the presence of a base like potassium carbonate or cesium carbonate or by reacting a compound of formula 1 with alcohols in the presence of a dehydrating agent like DCC/DMAP or refluxing in the presence of an acid catalyst.
  • a dehydrating agent like DCC/DMAP or refluxing in the presence of an acid catalyst.
  • a wide range of solvents can be used to conduct this reaction including DMF, THF, DCM, toluene or the like.
  • a compound of the formula 2 on Schmidt rearrangement promoted by treatment with sodium azide and methane sulphonic acid or the like, gives protected amino acid compounds of formula 3.
  • the N-acyl of compounds of formula 3 is hydrogenolysed in the presence of Pd-C/EtOAc or the like to give the N-acyl amino acid of compounds of formula 4.
  • the N-acyl amino acid of compounds of formula 4 can be acid hydrolyzed in the presence of hydrogen chloride or the like and treated with BOC anhydride in the appropriate reagent to give corresponding carbamate, more particularly, the tertiary butyl carbamate of compounds of formula 5.
  • the tertiary butyl carbamate of compounds of formula 5 can be benzylated to give the tertiary butyl carbamate of benzylated compounds of formula 6 in presence of cesium carbonate or the like in the solvents such as DMF or the like.
  • the tertiary butyl carbamate of benzylated compounds of formula 6 can be treated for BOC removal in the presence of TFA in solvents such as, DCM or the like to give the salt of benzylated of compound of formula 7.
  • the steps of providing a triterpene betulinic acid or ceanotheic acid comprising a C-3 alcohol, C-28 and or C2- carboxyl acid of compound 13 or 14 include: reacting a C-3 alcohol with a suitable ester forming reagents like anhydrides, acid halides or mixed anhydrides in the presence of a base like triethyl amine, diisopropyl ethyl mine, or pyridine in an inert solvent like DCM, toluene, THF or a basic solvent like pyridine with or without addition of a catalyst like DMAP.
  • a C-3 alcohol of compounds of the formula 10 can be protected by an acetyl group in the presence of acetic anhydride in solvents such as pyridine or the like, to give the C-3 acetyl of compounds of formula 11.
  • Converting the C-3 acetyl compound of formula 11 to C-28 carboxylic halide of formula 12 in presence of acid halides such as thionyl chloride, oxalyl chloride, phosphorous bromide, phosphorous oxy bromide or the like occurs in an inert solvent like benzene or DCM or the like.
  • the compounds of Formula (21), (wherein, R" is as defined above) can be prepared by following the procedures published as shown in Scheme 1.
  • Commercially available verbenone can be oxidized with an oxidizing agent like ruthenium chloride/sodium periodate in a solvent system like CCI 4 -ACN-H2O to give the carboxylic acid of compounds of formula 15.
  • Curtius rearrangement with sodium azide or (PhO)2P(O)N3, followed by N-protection affords the N-protected aminoketone of formula 17.
  • a halo form reaction using substrate 17 under NaOBr, dioxane with aq conditions give compounds of formula 18.
  • the acid compounds of formula 18 can be reacted with compounds of formula 19 to give the N-protected compounds of formula 20 in presence of coupling reagents such as l-Ethyl-3-(3- Dimethylaminopropyl)carbodiimide (EDCI), 1-hydroxybenzotrazolehydrate
  • coupling reagents such as l-Ethyl-3-(3- Dimethylaminopropyl)carbodiimide (EDCI), 1-hydroxybenzotrazolehydrate
  • HOBT O-benzotrazol-l-yl-N,N,N',N'-tetramethyluroniumhexafluorophosphate
  • a base for example, triethylamine, diisopropylethylamine, sodium carbonate, potassium carbonate, or the like in the solvents, for example, ethylactate, dichloromethane, acetonitrile, tetrahydrofuran, dioxane or mixtures thereof.
  • the N-protected compounds of formula 20 can be deprotected to give the deprotected amine compounds of formula 21 in presence of hydrogenating agents such as, for example, Pd-C/EtOAc or the like.
  • Ethyl-3-(3-Dimethylaminopropyl)carbodiimide EDCI
  • 1- hydroxybenzotrazolehydrate HOBT
  • O-benzotrazol-l-yl-N,N,N',N'- tetramethyluroniumhexafluorophosphate HBTU
  • N-protected compounds of formula F can be deprotected to give the deprotected amine compounds of formula G in presence of acids such as, for example, trifluoroacetic acid, HCl or the like.
  • the compounds of Formula (28) (Formula (2), when Z 2 is O) can be prepared as shown in Scheme 5.
  • the C-3 hydroxy-protected compounds of formula 22 can be converted to C-28 carboxylic halide compounds of formula 23 in presence of acid halides such as thionyl chloride, oxalyl chloride, phosphorous bromide, phosphorous oxy bromide or the like can be performed in an inert solvent like benzene or DCM or the like without added solvent.
  • C-28 carboxylic halide of the C- 3 oxy-protected compounds of formula 23 can be reacted with the amine compounds of formula 24 in the presence of triethyl amine or the like in an inert solvents such as DCM or the like to give the O-protected compounds of formula 25.
  • the O-protected compounds of formula 25 can be hydrolyzed to give the hydroxyl compounds of formula 26 in presence of base such as, for example, metal hydroxides, metal caronates or bicarbonates in MeOH, EtOH or MeOH-THF or the like solvents.
  • the hydroxy compounds of formula 26 can be reacted with acid anhydride compounds, half protected diacids or their mixed anhydrides or acid chlorides of formula 27 to give the final compound of formula 28 [Formula (2), when Z 2 is O and Z 2 ' and X 2 ' are C(O)] in the presence a base like triethyl amine, 4-Dimethylaminopyridine, diisopropyl ethyl mine or pyridine or the like in the solvents such as for example, DCM, toluene, THF or the like.
  • the compounds of Formula (35) (Formula (2A), when X A1 is C(O)) can be prepared by the above procedure as shown in Scheme 6.
  • the C-3 hydroxy-protected compounds of formula 29 can be converted to C-28 carboxylic halide of the C-3 oxy-protected compounds of formula 30 in presence of acid halides such as thionyl chloride, oxalyl chloride, phosphorous bromide, phosphorous oxy bromide or the like can be performed in an inert solvent like benzene or DCM or the like without added solvent.
  • C-28 carboxylic halide of the C-3 oxy-protected compounds of formula 30 can be reacted with the amine compounds of formula 31 in the presence of triethyl amine or the like in an inert solvents such as DCM or the like to give the
  • O-protected compounds of formula 32 can be hydrolyzed to give the hydroxyl compounds of formula 33 by hydrolyzing with a base like metal hydroxide, metal carbonates or bicarbonates and the like in a protic solvent like alcohol or a combination of solvents for example, MeOH :THF or the like.
  • the hydroxyl compounds of formula 33 can be reacted with acid anhydride compounds of formula 34 or partially protected diacids or mixed anhydrides, acid halides to give the final compound of formula (35) (Formula (2A), when X A1 is C(O)) in the presence a base like triethyl amine, 4-Dimethylaminopyridine, diisopropyl ethyl mine or pyridine or the like in the solvents such as for example, DCM, toluene, THF or the like.
  • reaction mixture was acidified with IN HCl and extracted with EtOAc, the organic layer was washed with water, brine and dried over Na 2 SO 4 . Organic layer was concentrated under reduced pressure then the resulting crude was purified by silica gel column ( 100-200 mesh, elution: 30% EtOAc in Hexane) to afford the title compound as off white solid.
  • reaction mixture was washed with methyl t- butyl ether (3 x 150 ml), the aqueous layer was adjusted p H (2-3) with IN HCl and the aqueous layer was extracted with EtOAc and dried over Na 2 SO 4 and the solvent was evaporated to afford title compound as an off white liquid.
  • Step 1 Synthesis of ( 1 S,3R)-3-acetyl-2,2-dimethyIcyclob ⁇ tanecarbonyl azide:
  • Step 1 1.147 g, 5.88 mmol
  • toluene (20 ml) benzyl alcohol (0.95 ml mmol, 8.82 mmol) was added at room temperature and stirred at reflux temperature for about 4 hours.
  • the solvent was evaporated under reduced pressure and the resulting crude was purified by silicagel column (60/120 mesh, elution: 5% EtOAc in Hexane) to afford the title compound as a liquid.
  • NaOBr solution A solution of NaOH (9.4 g, 233.6 mmol) in H 2 O (180 ml) Br 2 (3.3 ml, 63.72 mmol) was added at 0 0 C slowly, the yellow colored NaOBr solution formed which was used immediately for the reaction.
  • Step 4 Synthesis of benzyl (lS,3R)-2,2-dimethyl-3-(morpholine-4- carbonyl)cyclobutylcarbamate: To a stirred solution of (lR,3S)-3-(benzyloxycarbonylamino)-2,2- dimethylcyclobutanecarboxylic acid (Step 3, 0.9 g, 3.25 mmol) in DCM (5 ml) EDCI (0.747 g, 3.89 mmol) and HOBt (0.527 g, 3.89 mmol) were added at about 0 0 C, after 10 minutes morpholine (0.6 ml, 6.5 mmol) and Et 3 N (2.3 ml, 16.26 mmol) were added drop wise and the reaction mixture was stirred at room temperature for about 8 hours.
  • Step 5 Synthesis of ((lR,3S)-3-amino-2,2- dimethylcyclobutyl)(morpholino)methanone:
  • Step 2 Synthesis of ((lR,3S)-3-amino-2,2-dimethylcyclobutyl)(piperidin-l- yl)methanone:
  • Step 1 Synthesis of benzyl (lS,3R)-2,2-dimethyl-3-(pyrrolidine-l- carbonyl)cyclobutylcarbamate:
  • reaction mixture was diluted with DCM and washed with water, saturated NaHCO 3 solution, water, IN HCl, water and saturated brine and the organic layer was concentrated under reduced pressure, the resulting crude purified by silica gel column (100-200 mesh, elution 20% EtOAC in hexane) to afford the title compound as an off white solid.
  • Step 1 Synthesis of tert-butyl (lR,3S)-2,2-dimethyl-3-(morpholine-4- carbonyljcyclobutylcarbamate:
  • Step 1 synthesis of (lS,3R)-tert-butyl 3-acetyl-2,2-dimethylcyclobutanecarboxylate:
  • Step 2 Synthesis of ( 1 R,3S)-3-(tert-butoxycarbonyl)-2 ,2- dimethylcyclobutanecarboxylic acid:
  • NaOBr solution A solution of NaOH (57.0 g, 1426.9 mmol) in H 2 O (910 ml), Br 2 (19 ml, 371.6 mmol) were added at 0 0 C slowly, the yellow colored NaoBr solution formed which was used immediately for the reaction.
  • Step 3 Synthesis of (1R,3S)-1 -benzyl 3-tert-butyl 2,2-dimethylcyclobutane- 1 ,3- dicarboxylate:
  • step 3 To a solution of (IR, 3S)-I -benzyl 3-tert-butyl 2,2-dimethylcyclobutane- 1,3- dicarboxylate (step 3, 1.0 g) dioxane-HCl (10 ml) was added at about O 0 C under nitrogen atmosphere. The reaction mixture was stirred for about 12 hours at room temperature. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was washed with brine, dried over Na 2 SO 4 and concentrated under reduced pressure to give crude product, which upon column chromatography to afford the title compound (800 mg, 97.2 % Yield).
  • Step 1 Synthesis of tert-butyl (lS,4R)-4-(hydroxymethyl)cyclopent-2- enylcarbamate:
  • Step 2 Synthesis of tert-butyl (lR,3S)-3-(hydroxymethyl)cyclopentylcarbamate:
  • step 1 To a stirred solution of tert-butyl (lS,4R)-4-(hydroxymethy!)cyclopent-2- enylcarbamate (step 1, about 10.0 g) in ethanol ( 150 ml) 10 % palladium on carbon (about 1.0 g ) was added and kept under hydrogen atmosphere. Reaction mass was stirred for about 16 hours. Completion of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through high-flow bed and washed with ethanol. The filtrate was concentrated under reduced pressure to furnish the title compound (7.5 g) as a light yellow liquid. ES Mass: 215 [M+l] 216(100%).
  • Step 3 Synthesis of (( 1 S,3R)-3-(tert-butoxycarbonylamino)cyclopentyl)methyl 4- methylbenzenesulfonate:
  • step 3 To a stirred solution of ((lS,3R)-3-(tert- butoxycarbonylamino)cyclopentyl)methyl 4-methylbenzenesulfonate (step 3, about 0.5 g) in DCM (50 ml), potassium carbonate (about 0.3 g) was added at room temperature and cooled to about 0 0 C. After ten minutes, morpholine (1 ml) was added and stirred the reaction at room temperature for about 6 hours. Completion of the reaction was monitored by TLC. The reaction mixture was neutralized and extracted with DCM, the organic layer was dried over Na 2 SO 4 and concentrated under reduced pressure to furnish the title compound (0. 60 g) as a light yellow liquid.
  • Step 1 Synthesis of ((lR,4S)-4-(tert-butoxycarbonylamino)cyclopent-2-enyl)methyl 4-methylbenzenesulfonate:
  • Step 2 Synthesis of tert-butyl (IS, 4R)-4-(morpholinomethyI ) cyclopent-2- envlcarbamate:
  • step 1 To a stirred solution of ((lR,4S)-4-(tert-butoxycarbonylamino)cyclopent-2- enyl)methyl 4-methylbenzenesulfonate (step 1, about 0.5 g) in DCM (50 ml) potassium carbonate (about 0.3 g) was added at room temperature and cooled to about 0 0 C. After ten minutes, morpholine (3 ml) was added and stirred the reaction at room temperature for about 6 hours then completion of the reaction monitored by TLC. The reaction mixture was neutralized and extracted with DCM, the organic layer was dried over Na 2 SO 4 and concentrated under reduced pressure to furnish the title compound (0.5 g) as light yellow liquid.
  • Step 1 Synthesis of ((lS,3R)-3- ⁇ tert-butoxycarbonylamino)cyc ⁇ opentyl)methyl 4- methylbenzenesulfonate:
  • Step 2 Synthesis of tert-butyl (lR,3S)-3-((4-benzylpiperidin-l- yl)methyl)cyclopentylcarbamate
  • step 1 To a stirred solution of ((lR,4S)-4-(tert-butoxycarbonylamino)cyclopent-2- enyl)methyl 4-methylbenzenesulfonate (step 1, about 0.5 g) in DCM (50 ml), potassium carbonate (about 0.3 g) was added at room temperature and cooled to about 0 0 C. After ten minutes, 4-benzylpiperidine (0.17g) was added and stirred the reaction at room temperature for about 6 hours .Completion of the reaction was monitored by TLC. The reaction mixture was neutralized and extracted with DCM, the organic layer was dried over Na 2 SO 4 and concentrated under reduced pressure to furnish the title compound (0.45 g) as light yellow liquid.
  • step 2 N-(( lR,3S)-3-((4-benzylpiperidin-l-yloxy)methyl)cyclopentyl)-3,3- dimethylbutanamide (step 2, 0.5g) was treated with trifluroacetic acid (3ml) and the obtained compound of (lR,3S)-3-((4-benzylpiperidin-l- yloxy)methyl)cyclopentanamine (0.25g) was used directly for synthesizing final compounds in the example section without further purification.
  • Step 1 Synthesis of tert-butyl (lR,3S)-3-((4-ethylpiperazin-l- yl)methyl)cyclopentylcarbamate:
  • Step 2 Synthesis of ( 1 R,3S)-3-((4-ethylpiperazin- 1 -yl) methyljcyclopentanamine:
  • step 1 N-((lR,3S)-3-((4-ethylpiperazin- l-yl)methyl)cyclo ⁇ entyl)-3,3- dimethylbutanamide (step 1, 0.5 g) was treated with trifluroacetic acid and the obtained compound of (lR,3S)-3-((4-ethylpiperazin-l-yl)methyl)cyclopentanamine was used directly for synthesizing final compounds in example section without further purification.
  • Step 2 Synthesis o/(lR,3S)-3-((3-methylpiperidin-l-yl)methyl)cyclopentanamine:
  • step 1 (step 1, 0.2 g) was treated with trifluroacetic acid and the obtained compound of
  • Step 1 Synthesis of 1 -tert-butyl 4-ethyl piperidine-1, 4-diearboxylate:
  • Step 1 Synthesis of l-(tert-butoxycarbonyl)-4-ethy ⁇ pipe ⁇ d ⁇ ne-4-carboxylic acid:
  • Step-1 Synthesis of benzyl (lS,3R)-3-(4-ethylpiperazine-l-carbonyl)-2,2- dimethylcyclobutylcarbamate:
  • Step 2 Synthesis of ((lR,3S)-3- ⁇ nino-2,2-dimethylcyelobutyl)(4-ethylpiperazin-l- yl)methanone:
  • Step-2 Synthesis of ((lS,3R)-3-amino-2,2-dimethylcyclobutyl)(4-ethylpiperazin-l- yl)methanone.
  • trifluoro acetic acid ((lS,3R)-3-amino-2,2-dimethylcyclobutyl)(4-ethylpiperazin-l- yl)methanone.
  • Step 1 Synthesis of ethyl l-((lR,3S)-3-(benzyloxycarbonylamino)-2,2- dimethylcyclobutanecarbonyl)piperidine-4-carboxylate:
  • Step 2 Synthesis of ethyl l-((lR,3S)-3-amino-2,2- dimethylcyclobutanecarbonyl)piperidine-4-carboxylate:
  • step 1 To a solution of ethyl l-((lR,3S)-3-(benzyloxycarbonylamino)-2,2- dimethylcyclobutanecarbonyl)piperidine-4-carboxylate (step 1, 1.30 g) in ethyl acetate (50 ml), Pd/C (100 mg) was added carefully under argon atmosphere. Then the reaction mixture was stirred for overnight under hydrogen conditions. After completion of the reaction (monitored by TLC), diluted with ethyl acetate, filtered on celite, washed with ethyl acetate. The combined organic extracts were concentrated under reduced pressure to give crude product which was preceded for next step without further purification and analysis.
  • Example 1 Preparation of (lR,3aS,5aR.5bR,7aR,9S,l laR.l lbR.13aR,13bR)-9- acetoxy-5a,5b,8,8, 1 1 a-pentamethyl- 1 -(prop- 1 -en-2- vDicosah ydro- 1 H- cyclopenta[alchrysene-3a-carboxylic acid:
  • reaction mixture poured in to ice water and extracted with EtOAc and washed with water, brine and dried over Na 2 SO 4 , the solvent was evaporated and purified by silica gel column (100-200, elution 10% EtOAc in hexane) to afford title compound as a off white solid.
  • Example 4 Preparation of ( 1 R,3aS,5aR,5bR.7aR.9S , 11 aR, 1 1 bR.13aR.13bR)-9- ((lR.3S)-3-carboxy-2,2-dimethylcyclobutanecarbonyloxy)-5a,5b,8,8,l la- pentamethyl- 1 -(prop- 1 -en-2- vDicosahydro- 1 H-cyclopenta[alchrysene-3a-carboxylic acid:
  • Example 7 Preparation of ⁇ R.3aS,5aR,5bR,7aR,9S,l laR,l lbR.13aR.13bR)-3a- ((lS,3R)-2,2-dimethyI-3-(mo ⁇ holine-4-carbonyl)cvclobutylcarbamoyl)-
  • reaction mixture was diluted with DCM and washed with water, IN HCl, water brine and dried with Na 2 SO 4 , the solvent was evaporated and purified by silica gel column (100-200 mesh, elution 10% EtOAc in hexane) to afford the title compound as an off white solid.
  • Example 8 Preparation of (lR.3aS,5aR.5bR,7aR,9S.l laR.l lbR,13aR.13bR)-N- ((lS,3R)-2,2-dimethyl-3-(mo ⁇ holine-4-carbonyl)cvclobutyl)-9-hvdroxy- 5a,5b,8,8, 11 a-pentamethyl- 1 -(prop- 1 -en-2-yl )icosahydro- 1 H-cyclopentafalchrysene-
  • Example 9 Preparation of 4-(( lR,3aS.5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)-3a- ((lS,3R)-2,2-dimethyl-3-(mo ⁇ holine-4-carbonyl)cyclobutylcarbamoyl)- 5a,5b,8,8J la-pentamethyl-l-(prop-l-en-2-yl)icosahvdro-lH-cyclopentafalchrvsen-
  • Example 13 Preparation of (lRJaS.SaR.SbRJaR ⁇ S.l laR.l lbR.naR.nbRVSa- ((lS,3R)-2,2-dimethyl-3-(pyrrolidine-l-carbonyl)cvclobutylcarbamoyl)- 5a,5b,8,8, 1 1 a-pentamethyl- 1 -(prop- 1 -en-2-yPicosahydro- 1 H-cyclopentaf alchrysen- 9-yl acetate:
  • Example 14 Preparation of (lR.3aS.5aR.5bRJaR,9S.l laR.l lbR.13aR.13bR)-N- ((lS,3R)-2,2-dimethyl-3-(pyrrolidine-l-carbonyl)cvclobutyl)-9-hvdroxy-
  • Example 15 Preparation of 4-(dR,3aS,5aR,5bR,7aR,9S,l laR.l lbR.13aR,13bRV 3a-((lS,3R)-2,2-dimethyl-3-(pyrrolidine-l-carbonyl)cyclobutylcarbamoyl)-
  • Example 17 Preparation of (lR.3aS.5aR,5bR,7aR.9S,l laR,l lbR,13aR,13bR)-N- ((lR.3S)-2.2-dimethyl-3-(mor ⁇ holine-4-carbonyl)cvclobutyl)-9-hvdroxy-
  • Example 18 Preparation of (lR,3aS,5aR,5bR,7aR,9S.l laR,l lbR.13aR,13bR)-9- ((lS,3R)-3-(benzyloxycarbonyl)-2,2-dimethylcvclobutanecarbonyloxy)- 5a,5b,8,8, 11 a-pentamethyl- 1 -(prop- 1 -en-2-yl)icosahydro- 1 H-cyclopenta[alchrysene- 3a-carboxylic acid:
  • Example 19 Preparation of (lR,3aS,5aR,5bR.7aR.9S,l laR,l lbR.13aR,13bR)-9- ((lS3R)-3-carboxy-2,2-dimethylcyclobutanecarbonyloxy)-5a,5b,8,8.11a- pentamethyl- 1 -(prop- 1 -en-2-yl)icosahvdro- 1 H-cyclopentaf alchrvsene-Sa-carboxylic acid:
  • Example 20 Preparation of (lR.3aS.5aR.5bR,7aR,9S.l laR.l lbR.13aR.13bR)- 5a.5b,8,8, 11 a-pentamethyl-3a-(( 1 R,3S)-3- morpholinomethyDc yclopentylcarbamoyl)- 1 -(prop- 1 -en-2-yl)icosahydro- 1 H- cyclopentafalchrysen-9-yl acetate:
  • Example 21 Preparation of (lR,3aS.5aR,5bR.7aR.9S.l laR.l lbR,13aR.13bRV 5a,5b.8,8.1 1a-pentamethyl-3a-((lS,4R)-4-(mo ⁇ holinomethyl)cyclopent-2- en ylcarbamoyl)- 1 -(prop- 1 -en-2-yl)-icosah ydro- 1 H-cyclopenta[alchrysen-9-yl acetate:
  • Example 22 Preparation of ((lR,5aR.5bR.7aR,9S,l laR.l lbR.13aR,13bRV9- hvdroxy-5a.5b.8.8, 11 a-pentamethyl- 1 -(prop- l-en-2-yl)icosahvdro- IH- cyclopenta[alchrysen-3a-yl)(3-(3-isopropyl-5-methyl-4H-l,2,4-triazol-4-yl)-8- azabicyclo[3.2.11octan-8-yl)methanone:
  • Example 23 Preparation of (lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)-9- hydroxy-5a,5b,8,8,l la-pentamethyl-N-((lR,3S)-3-(moipholinomethyl)cvclopentyl)- 1 -(prop- 1 -en-2-yl)icosahvdro- 1 H-cyclopenta[alchrysene-3a-carboxamide:
  • Example 25 Preparation of ((lR.5aR,5bRJaR,9S,l laR,l lbR, 13aR.13bR)-9- hydroxy-5a,5b,8,8,l la-pentamethyl-1 -(prop- l-en-2-yl)icosahydro- IH- cyclopenta[alchrvsen-3a-yl)(3-(3-isopropyl-5-methyl-4H-l ,2,4-triazol-4-yl)-8- azabicyclo[3.2.11octan-8-yl)methanone:
  • Example 26 Preparation of (lR.3aS.5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)-9- hydroxy-5a,5b,8,8,l la-pentamethyl-N-((lS,4R)-4-(moipholinomethyl)cyclopent-2- enyl)- 1 -(prop- 1 -en-2-yl)icosahvdiO- 1 H-cyclopenta[a1chrysene-3a-carboxamide:
  • Example 27 Preparation of (lR.3aS,5aR,5bR.7aR.9S.l laR.l lbR,13aR.13bR)-3a- (4-(hydroxymethyl)cyclopent-2-enylcarbamoyl)-5a,5b.8.8,l la-pentamethyl-l-(prop- 1 -en-2- vPicosah ydro- 1 H-cvcIopenta[alchrysen-9-vl acetate:
  • Example 28 Preparation of ( lR,3aS,5aR,5bR,7aR.9S.l laR.l lbR,13aR,13bR)-9- hydroxy-N-(4-(hydiOxymethyl)cyclopent-2-enyl)-5a,5b,8,8, 1 1 a-pentamethyl- 1 -
  • Example 29 Preparation of ( lR,3aS.5aR,5bR.7aR.9S.l laR,l lbR.13aR.13bR)-3a- ((2S,3R)-4-((3S,4aS,8aS)-3-(tert-butylcarbamoyl)octahvdroisoquinolin-2(lH)-yl)-3- hvdroxy- 1 -phen ylbutan-2-ylcarbamoyl)-5a,5b,8.8, 11 a-pentameth yl- 1 -(prop- 1 -en-2- yl)icosahvdro-lH-cvclopentara1chrvsen-9-yl acetate:
  • the reaction mixture was evaporated under reduced pressure, the residue was taken in water and extracted with DCM. The organic layer was dried over Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 5% methanol in DCM as eluent to furnish the title compound (0.34 g) as a white solid.
  • Example 31 Preparation of (lR,3aS.5aR,5bR.7aR.9S,l laR.l lbR.13aR.13bR)-3a- (( 1 R,3S)-3-((4-benzylpiperidin- 1 -yDmethyDcyclopentylcarbamoyD-Sa.Sb. ⁇ . ⁇ , 1 1 a- pentameth yl- 1 -(prop- 1 -en-2-yl)icosah ydro- 1 H-cyclopenta[a1chrysen-9-yl acetate: To a stirred solution of (lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)-9- acetoxy-5a,5b,8,8, 11 a-pentamethyl- 1 -(prop- 1 -en-2-yl)icosahydr
  • Example 32 Preparation of (lRJaS.SaR.SbRJaR ⁇ SJ laR.l lbR.OaR.BbR)- ⁇ (( 1 R.3S)-3-((4-benzylpiperidin- 1 - yl)methyl)cvclopentyl)-9-hvdrox v-5a,5b.8,8.1 1 a- pentamethyl-l-(prop-l-en-2-yl)icosahvdro-lH-cvclopenta[alchrysene-3a- carboxamide:
  • the reaction mixture was diluted with ethyl acetate (30 ml).
  • the organic layer was washed with 5% aqueous HCl, washed with water followed by brine solution, dried over Na 2 SO 4 and concentrated under reduced pressure.
  • the residue was purified by silica gel column chromatography using 5% MeOH in DCM as eluent to furnish the title compound (0.1 g) as a white solid.
  • Example 34 Preparation of (lR.3aS,5aR.5bR,7aR,9S.l laR.l lbR,13aR.13bR)-3a- ((lR,3S)-3-((4-ethylpiperazin-l-yl)methyl)cvclopentylcarbamoyl)-5a,5b,8,8,l la- pentamethyl- 1 -(prop- 1 -en-2-yl)icosah vdro- 1 H-c vclopentaraichrysen-9- yl acetate:
  • Example 35 Preparation of ( lR,3aS,5aR.5bR.7aR,9S,l laR.l lbR,13aR.13bR)-N- (( lR,3S)-3-((4-ethylpiperazin-l-yl)methyl)cvclopentyl)-9-hvdroxy-5a,5b,8,8,l la- pentamethyl- 1 -(prop- 1 -en-2-yl)icosahydro- 1 H-cyclopentaralchi'ysene-3a- carboxamide:
  • Example 36 Preparation of 4-((lR.3aS,5aR,5bR.7aR.9S,l laR,l lbR.13aR,13bR)- 3a-((lR,3S)-3-((4-ethylpiperazin-l-yl)methyl)cvclopentylcarbamoyl)-5a,5b,8,8,l la- pentamethyl- 1 -(prop- 1 -en-2-yl)icosahvdro- 1 H-cyclopenta[alchrysen-9-yloxy)-2,2- dimethyl-4-oxobutanoic acid:
  • Step 1 Synthesis of methyl 3-((IS,3R)-3-(tert-butoxycarbonylamino)-2,2- dimethylcyclobutanecarboxamido)propanoate:
  • the reaction mixture was diluted with DCM and washed with water and saturated NaHCO 3 solution, then washed with aqueous IN HCl, then washed with water and saturated brine, and the organic layer was concentrated under reduced pressure, the resulting crude was purified by silica gel column (100-200 mesh, elution 70% EtOAC in hexane) to afford the title compound as solid.
  • Step 2 synthesis of methyl 3-((lS,3R)-3-amino-2,2- dimethylcyclobutanecarboxamido)propanoate:
  • Step 3 Preparation of methyl 3-((lS,3R)-3- ((lR,3aS,5aR,5bR,7aR,9S,l IaRJ JbR,13aR,13bR)-9-acetoxy-5a,5b,8,8,l Ia- pentamethyl- 1 -(prop- 1 -en-2-yl)icosahydro- lH-cyclopenta[a] chrysene-3a- carboxamido)-2,2-dimethylcyclobutanecarboxamido)propanoate:
  • reaction mixture was diluted with DCM and washed with water, IN HCl, water brine and dried over Na 2 SO 4 , the solvent was evaporated and purified by silica gel column (100-200 mesh, elution 25% EtOAc in hexane) to afford the compound as a off white solid.
  • Step 1 Synthesis of (S)-methyl 2-((lS,3R)-3-(tert-butoxycarbonylamino)-2,2- dimethylcyclobutanecarboxamido)-3-methylbutanoate:
  • the reaction mixture was diluted with DCM and washed with water and saturated NaHCO 3 solution, then washed with aqueous IN HCl, then washed with water and saturated brine, and the organic layer was concentrated under reduced pressure, the resulting crude was purified by silica gel column (100-200 mesh, elution 70% EtOAC in hexane) to afford the title compound as a solid.
  • Step 2 Synthesis of (S)-methyl 2-((lS,3R)-3-amino-2,2- dimethylcyclobutanecarboxamido)-3-methylbutanoate:
  • step I 2,2-dimethylcyclobutanecarboxamido)-3-methylbutanoate (step I, 0.430 g, 1.21 mmol) in TFA: DCM (1 :4) (4 ml) at 0 °C-room temperature for about 1 hour. After completion of the reaction, the solvent was evaporated and the crude was dissolved in DCM and basified with Et 3 N (1.0 ml, 7.25 mmol) then the resulting solution as such used for next reaction immediately. Wt: 0.309 g (Based on 100% yield calculated and proceeded for next reaction).
  • Step 3 Preparation of (S)-methyl 2-((lS,3R)-3- ((lR,3aS,5aR,5bR,7aR,9S,l IaRJ lbR,13aR,13bR)-9-acetoxy-5a,5b,8,8,l Ja- pentamethyl-l-(prop-l-en-2-yl)icosahydro-lH-cyclopenta[a]ch ⁇ ysene-3a- carboxamido)-2,2-dimethylcyclobutanecarboxamido)-3-methylbutanoate:
  • reaction mixture was diluted with DCM and washed with aqueous IN HCl, then water and brine, and dried over Na 2 SO 4 , the solvent was evaporated and purified by silica gel column (100-200 mesh, elution 30% EtOAc in hexane) to afford the title compound as an off white solid.
  • Step 1 Synthesis of (S)-methyl 2-((lS,3R)-3-(tert-butoxycarbonylamino)-2,2- dimethylcyclobutanecarboxamido)-4-methylpentanoate:
  • Step 2 Synthesis of (S)-methyl 2-((lS,3R)-3-amino-2,2- dimethylcyclobutanecarboxamido)-4-methylpentanoate:
  • reaction mixture was diluted with DCM and washed with water, IN HCl, water, brine and dried over Na 2 SO 4 , the solvent was evaporated and purified by silica gel column (100-200 mesh, elution 25% EtOAc in hexane) to afford the title compound as an off white solid.
  • Step 1 Synthesis of tert-butyl (lR,3S)-2,2-dimethyl-3-(pyrrolidine-l- carbonyl)cyclobutylcarbamate:
  • reaction mixture was diluted with DCM and washed with water and saturated NaHCO 3 solution, then washed withaqueous IN HCl, then water and saturated brine, and the organic layer was concentrated under reduced pressure, the resulting crude residue was stirred in hexane and the resulting solid was obtained which was filtered and dried under vacuum.
  • Step 2 Synthesis of ((lS,3R)-3-amino-2,2-dimethylcyclobutyl)(pyrrolidin-l- yl)methanone:
  • Example 45 Preparation of 4-((lR,3aS,5aR.5bR,7aR,9S,l laR.l lbR.13aR.13bRV 3a-((lR,3S)-2,2-dimethyl-3-(pyrrolidine-l-carbonyl)cyclobutylcarbamoyl)- 5a,5b,8,8, 11 a-pentamethyl- 1 -(prop- 1 -en-2-yl)icosahydro- lH-cyclopenta[alchrvsen- 9-yloxy)-2,2-dimethyl-4-oxobutanoic acid:
  • reaction mixture was diluted with EtOAc, washed with aquepus IN HCl, them washed with water and brine, and dried over Na 2 SO 4 , the solvent was evaporated and purified by silica gel column
  • Step 1 Synthesis of tert-butyl (lR,3S)-2,2-dimethyl-3-(piperidine-l- carbonyl)cyclobutylcarbamate:
  • reaction mixture was diluted with DCM and washed with water, sat. NaHCO 3 solution, water, IN HCl, water, saturated brine and the organic layer was concentrated under reduced pressure, the resulting crude residue was stirred in hexane and the resulting solid was obtained which was filtered and dried under vacuum to afford the title compound.
  • Step 3 Preparation of (lR,3aS,5aR,5bR,7aR,9S,llaR,llbR,13aR,13bR)-3a-
  • reaction mixture was diluted with DCM and washed with aqueous IN HCl, then washed with water and brine, and dried over Na 2 SO 4 then the solvent was evaporated and purified by silica gel column (100-200 mesh, elution 15% EtOAc in hexane) to afford the title compound as an off white solid.
  • Example 50 Preparation of (lR,3aS.5aR.5bR.7aR.9S.l laR.l lbR,13aR.13bR)-9- hvdroxy-5a,5b.8.8.11a-pentamethyl-N-((lR.3S)-3-((3-methylpiperidin-l- yl)methyl)cvclopentyl)- 1 -(prop- 1 -en-2-yl)icosahvdro- lH-cyclopenta[alchrysene-3a- carboxamide: (lR,3aS,5aR,5bR,7aR,9S,l IaR, 1 lbR,13aR,13bR)-5a,5b,8,8,l Ia- pentamethyl-3a-((lR,3S)-3-((3-methylpiperidin-l-yl)methyl)cyclopentylcarbamoyl
  • the reaction mixture was diluted with ethyl acetate (30 ml).
  • the organic layer was washed with 5% aqueous HCl, washed with water followed by brine solution, dried over Na 2 SO 4 and concentrated under reduced pressure.
  • the residue was purified by silica gel column chromatography using 5% MeOH in DCM as eluent to furnish the title compound (0.1 g) as a white solid.
  • Example 52 Preparation of (lR,3aS,5aR.5bR,7aR.9S.l laR,llbR.13aR.13bR)-3a- (4-ethylpiperazine- 1 -carbonyl)-5a,5b,8,8.11 a-pentamethyl- 1 -(prop- 1 -en-2- yl)icosahvdro-lH-cvclopenta[alchrysen-9-yl acetate:
  • Step 1 Synthesis of 1-tert-butyl 4-ethyl piperidine-1 ,4-dicarboxylate:
  • Step 2 Synthesis of 1-tert-butyl 4-ethyl 4-benzylpiperidine- 1 ,4-dicarboxylate:
  • Step 4 Preparation of ethyl 4-((lR,3aS,5aR,5bR,7aR,9S,llaR,llbR,13aR,13bR)-9- acetoxy-5a,5b,8,8,lla-pentamethyl-l-(prop-l-en-2-yl)icosahydro-lH- cyclopenta[a]chrysene-3a-carbonyl)-l-benzylcyclohexanecarboxylate:
  • reaction mixture was diluted with EtOAc, washed with water, IN HCl, water, brine and dried over Na 2 SO 4 then the solvent was evaporated and purified by silica gel column (100-200 mesh, elution 20% EtOAc in hexane) to afford the title compound as a white solid.
  • reaction mixture was stirred at reflux temperature for about 12 hours.
  • water (20 mL) was added and extracted with ethyl acetate.
  • the combined organic layers were washed with aqueous IN HCl, then brineand water, then dried over sodium sulfate, concentrated under reduced pressure to give crude compound.
  • the so obtained crude product was purified by column chromatography to give the title compound as a white solid. Wt: 0.800 g: Yield: 61 %.
  • Example 62 Preparation of 4-( ⁇ R.3aS.5aR.5bR.7aR,9S.l laR,l lbR.13aR,13bR)- 3a-((lS,3R)-2,2-dimethyl-3-(piperidine-l-carbonyl)cyclobutylcarbamoyl)- 5a,5b,8,8, 11 a-pentamethyl- 1 -(prop- 1 -en-2-yl)icosahydro- lH-cyclopentaraichrysen- 9-yloxy)-4-oxobutanoic acid:
  • reaction mixture was stirred at reflux temperature for 12 hours. After completion of the reaction (monitored by TLC), water (20 mL) was added and extracted with ethyl acetate. The combined organic layers were washed with aqueous IN HCl, then brine, and water, and subsequently dried over sodium sulfate, concentrated under reduced pressure to give crude compound. The so obtained crude product was purified by column chromatography to give the title compound as a white solid.
  • Example 66 Preparation of (lR,3aS,5aR,5bR,7aR,9SJ laR,l lbR.13aR.13bR)-3a- ((lS,3R)-3-(4-ethylpiperazine-l-carbonyl)-2,2-dimethylcyclobutylcarbamoyl)- 5a,5b,8,8, 11 a-pentamethyl- 1 -(prop- 1 -en-2-yl)icosahydro- lH-cyclopenta[alchrysen- 9-yl acetate:
  • Oxallyl chloride was added To a cooled solution of (lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)-9-acetoxy-5a,5b,8,8,lla- pentamethyl-l-(prop-l-en-2-yl)icosahydro-lH-cyclopenta[a]chrysene-3a-carboxylic acid (835 mg) in DCM (20 mL) at 0 0 C and the reaction mass was allowed to stir at room temperature for about 6 hours.
  • Example 68 Preparation of 4-((lR.3aS.5aR.5bR.7aR.9S.l laR.l lbR.13aR,13bR)- 3a-((lS,3R)-3-(4-ethylpiperazine-l-carbonyl)-2,2-dimethylcyclobutylcarbamoyl)- 5a,5b,8,8,Ua-pentamethyl-l-(prop-l-en-2-yl)icosahydro-lH-cvclopentaralchrvsen- 9-yloxy)-2,2-dimethyl-4-oxobutanoic acid:
  • reaction mixture was refluxed for 14 hours. After completion of the reaction (monitored by TLC), it was diluted with EtOAc, the organic layer was washed with aqueous IN HCl, then washed with water and brine, and dried with Na 2 SO 4 . The solvent was evaporated and purified by silica gel column (100-200, elution 35% EtOAc in hexane) to afford 90 mg of title compound (60.8 % yield) as an off white solid with 81.67% HPLC purity.
  • Example 69 Preparation of (lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR.13aR,13bR)-3a- ((lR,3S)-3-(4-ethylpiperazine-l -carbon yl)-2,2-dimethylcvclobutylcarbamoyl)- 5a,5b,8,8,l la-pentamethyl-l-(prop-l-en-2-yl)icosahydro-lH-cyclopenta[a1chrvsen-

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Abstract

The invention relates to novel lupeol-type triterpene derivatives and related compounds, and pharmaceutical compositions useful for therapeutic treatment of viral diseases and particularly HIV mediated diseases.

Description

LUPEOJΛTYPE TRITERPENE DERIVATIVES AS ANTIVIRALS
This application claims the benefit of Indian Provisional Patent Application Nos. 1670/CHE/2009 filed on 14th July 2009 and 587/CHE/2010 filed on 8th March 2010; and US Provisional Patent Application No. US 61/251,933 filed on 15th Oct
2009, all of which are incorporated herein by reference in their entirety.
Field of the Invention
The present invention relates to novel lupeol-type triterpene derivatives and related compounds, compositions useful for therapeutic treatment of viral diseases and particularly HIV mediated diseases.
Background of the Invention
The Human Immunodeficiency Virus (HIV) has now been established as the causative agent of the Acquired Immunodeficiency Syndrome (ADDS) for over 20 years (Science 1983, 220,868-871; N.Eng.J.Med.1984,311,1292-1297). AIDS is characterized by the destruction of the immune system, particularly of CD4+T-cells.
HIV is a retrovirus, and the HIV life cycle encompasses several crucial steps, starting from the attachment of the virus to the host cell membrane and finishing with the release of progeny virons from the cell.
The natural compound betulinicacid acid, isolated from Syzygium clavifolium and several other plant species was found to possess anti-HIV activity.
Chemical modifications were undertaken by several research groups in an attempt to identify potent anti-HIV agents by making semi-synthetic analogs of betulinic acid, leading to the discovery of bevirimat as a compound with a novel mechanism of action (J. Nat. Prod. 199457(2):243-7; J. Med. Chem. 1996,39(5), 1016 ) .Further studies shown that bevirimat acts by disrupting Gag processing (Proc. Natl. Acad.
Sci. USA 2003,100(23): 13555-60; Antimicrob. Agents. Chemother. 2001,45(4),1225-30;J. Virol. 2004,78(2): 922-9; J. Biol. Chem. 2005,280(51):42149-55; J. Virol. 2006,80(12): 5716-22) and to be a first-in-class maturation inhibitor with a potent activity against HIV-I.
Encouraged by these developments, medicinal chemists started exploring betulinic acid derivatives and related compounds intensively for their therapeutic activities. For example, the patent publication WO 2008057420 describes extended triteipene derivatives as antiretroviral agents; WO 2007141391 describes Betulin derived compounds useful as antiprotozoal agents; WO 2007141390 describes preparation of betulin derived compounds as antiviral agents; WO 2008127364 describes preparation of betulinic acid derivatives for use in antiviral and anticancer pharmaceutical compositions; US 20080207573 describes preparation of triterpene derivatives for therapeutic use in the treatment of viral infections; WO 2007141389 describes preparation of betulin derived compounds as antibacterial agents; US
20040204389 describes anti-HIV agents with dual sites of action; WO 2007/00241 1 describes antiviral compounds; CN 1861627 describes antitumor agents; WO 2006053255 describes novel betulin derivatives, preparation thereof and use thereof; WO 2009/082818 describes novel C-21 keto lupine derivatives preparation and use thereof; and WO 2006105356 describes methods of manufacturing bioactive 3- esters of betulinic aldehyde and betulinic acid.
Similarly WO 2009/082819, WO 2009/100532 disclosed 17 β lupine derivatives as anti-HIV agents.
Some more references disclose betulinic acid related compounds. For example, WO 2007141383 describes betulin derivatives as antifeedants for plant pests; US 6670345 describes use of betulinic acid and its derivatives for inhibiting cancer growth and process for the manufacture of betulinic acid; WO 2002091858 describes anxiolytic marcgraviaceae compositions containing betulinic acid, betulinic acid derivatives, and methods of preparation and use; WO 2000046235 describes preparation of novel betulinic acid derivatives for use as cancer growth inhibitors and WO 2007141392 describes cosmetic and pharmaceutical compositions comprising betulonic acid and betulin derivatives.
Given the fact of the world wide epidemic level of AIDS, there is a strong continued need for new effective drugs for treatment of HIV infected patentis, disease conditions and/or disorders mediated by HIV by discovering new compounds with novel structures and/or mechanism of action(s).
Summary of the Invention
The present invention relates to the compounds of the formula (1):
Figure imgf000004_0001
Formula (1)
wherein,
R can be H, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocyclyl and preferably R can be substituted by Ra;
R' can be H, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted alkyloxy, or substituted or unsubstituted aryloxy and preferably R' can be substituted by Ra;
X and Xi are independently can be selected from a bond, -O-, -NR"-, -C(O)-, -C(O)2-,-(CH2)n-, or -C(O)NR"-;
Z and Zi are independently can be selected from a bond, -C(O)-, -(CH2)n-, - O-, -S-, -SO2-, or -NR"-;
Z' can be H, substituted or unsubstituted alkyl or Z and Z' can be together with the attached carbon to form oxo (C=O) and when Z and Z' together with the attached carbon then X and R are absent;
n can be an integer 0-2;
m can be an integer 0-2;
" =-^" can be single bond or double bond;
Ri can be H, C(O)2R", or substituted or unsubstituted alkyl;
RT can be H, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, or substituted or unsubstituted cycloalkyl;
R3' and R3" are independently can be selected from H, or substituted or unsubstituted alkyl and when " =^" is single bond then one of R3' or R3" is absent;
Ra can be H, OH, halogen, NR", C(O)2R", CH2OR", C(O)NR" or substituted or unsubstituted alkyl; and each R" can be independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocyclyl; and a proviso that one of the R or R' is substituted or unsubstituted 4 or 5 membered cycloalkyl group, and if R or R' is 4 membered cycloalkyl group then at least one of the carbon atom of the 4 membered cycloalkyl group must be substituted by two identical groups and which are selected from alkyl or halogen wherein most preferably alkyl is methyl and halo is fluorine.
Pharmaceutically acceptable salts of the compounds of the formula (1) are also contemplated. Likewise, pharmaceutically acceptable solvates, including hydrates, of the compounds of the formula (1) are contemplated.
It should be understood that formula (1) structurally encompasses all stereoisomers, including enantiomers, diastereomers, racemates, and combinations therof, which may be contemplated from the chemical structure of the genus described herein.
Also contemplated are prodrugs of the compounds of the formula (1), including ester prodrugs.
According to one embodiment, there is provided a compound of formula (1), wherein X is -C(O)-.
According to one embodiment, there is provided a compound of formula (1), wherein X is -C(O)NR"-.
According to one embodiment, there is provided a compound of formula (1), wherein X is a bond.
According to one embodiment, there is provided a compound of formula (1), wherein Z is O.
According to one embodiment, there is provided a compound of formula (1), wherein Z' is H.
According to one embodiment, there is provided a compound of formula (1), wherein R is H.
According to one embodiment, there is provided a compound of formula (1), wherein R is substituted or unsubstituted cyclobutyl.
According to one embodiment, there is provided a compound of formula (1), wherein R is substituted or unsubstituted cyclopentyl. According to one embodiment, there is provided a compound of formula (1), wherein R is substituted or unsubstituted alkyl.
According to one embodiment, there is provided a compound of formula (1), wherein R is H, -C((CH3)2)-CO2H, -C((CH3)2)-CH2-CO2H, -CH2-CH2-CO2H, - CH2-CO2H and CH3.
According to one embodiment, there is provided a compound of formula (1), wherein Zj is a bond.
According to one embodiment, there is provided a compound of formula (1), wherein X1 is -C(O)NR"- and -C(O)2-.
According to one embodiment, there is provided a compound of formula (1), wherein R' is H.
According to one embodiment, there is provided a compound of formula (1 ), wherein R' is substituted or unsubstituted alkyl.
According to one embodiment, there is provided a compound of formula ( 1), wherein R' is substituted or unsubstituted cyclobutyl.
According to one embodiment, there is provided a compound of formula (1), wherein R' is substituted or unsubstituted cyclopentyl.
According to one embodiment, there is provided a compound of formula (1), wherein R" is H.
According to one embodiment, there is provided a compound of formula ( 1 ), wherein Ri is H.
According to one embodiment, there is provided a compound of formula ( 1), wherein R2 is propene.
According to one embodiment, there is provided a compound of formula (1), wherein " =-^" is single bond;
According to one embodiment, there is provided a compound of formula ( 1), wherein n is 0.
According to one embodiment, there is provided a compound of formula (1), wherein m is 0 and 1.
Accordingly, one aspect of the present invention provides compounds of formula ( IA):
Figure imgf000007_0001
Formula (IA)
wherein,
R can be substituted or unsubstituted alkyl or substituted or unsubstituted cycloalkyl; wherein cycloalkyl is a 4 or 5 membered ring system and substituents in each occurrence is independently selected from H, halo, Ci-C4 alkyl, CO-O-Rb, - CH2-O-Rb, CO-NHRb, or CON(Rb)2; and preferably substituted or unsubstituted alkyl of RA can be selected from:
Figure imgf000007_0002
RA' can be H, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, and preferably RA' can be substituted by Ra;
X1 A can be a bond, -O-, -NR"-, -C(O)-, -C(O)2-, or -C(O)NR"-;
ZiA can be a bond, -C(O)-, -O-, -S-, -SO2-, or -NR"-;
Ra can be H, OH, halogen, NR", C(O)2R", CH2OR", C(O)NR" or substituted or unsubstituted alkyl;
Rb can be H, or substituted or unsubstituted alkyl; and
each R" can be independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocyclyl; and a proviso that one of the RA or RA' is substituted or unsubstituted 4 or 5 membered cycloalkyl group, and if RA or RA' is 4 membered cycloalkyl group then at least one of the carbon atom of the 4 membered cycloalkyl group must be substituted by two identical groups and which are selected from alkyl or halogen wherein most preferably alkyl is methyl and halo is fluorine.
Pharmaceutically acceptable salts of the compounds of the formula (IA) are also contemplated. Likewise, pharmaceutically acceptable solvates, including hydrates, of the compounds of the formula (IA) are contemplated.
It should be understood that formula (IA) structurally encompasses all stereoisomers, including enatiomers and diastereomers, which may be contemplated from the chemical structure of the genus described herein.
Also contemplated are prodrugs of the compounds of the formula (IA), including ester prodrugs.
According to one embodiment, there is provided a compound of formula (IA), wherein RA is substituted or unsubstituted cyclobutyl.
According to one embodiment, there is provided a compound of formula (IA), wherein RA is CH2-C((CH3)2)-CO2H, and CH3.
According to one embodiment, there is provided a compound of formula (IA), wherein RA' is substituted or unsubstituted cyclobutyl.
According to one embodiment, there is provided a compound of formula
(IA), wherein RA' is H, CH2-C((CH3)2)-CO2H, and CH3.
Also the present invention relates to the compounds of the formula (2):
Figure imgf000008_0001
Formula (2)
wherein,
R2 can be H, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted cycloalkyl and preferably R2 can be substituted by Ra;
R2' can be H, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted alkyloxy, or substituted or unsubstituted aryloxy and preferably R2' can be substituted by Ra;
X2 and X2' are independently can be selected from a bond, -O-, -NR"-, -C(O)- , -C(O)2-,-(CH2)n-, or -C(O)NR"-;
n can be 0-3;
Z2 and Z2' are independently can be selected from a bond, -C(O)-, -O-, or - NR"-;
Ra can be H, OH, halogen, N(R")2, C(O)R", C(O)2R", CH2OR", C(0)N(R")2 or substituted or unsubstituted alkyl;
each R" can be independently selected from H, -[CH(R"')]PC(O)2R"', substituted or unsubstituted alkyl, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocyclyl;
p can be 0-3; and
each R"' can be independently selected from H, substituted or unsubstituted alkyl, or substituted or unsubstituted cycloalkyl; and a proviso that one of the R2 or R2' is substituted or unsubstituted 4 or 5 membered cycloalkyl group, and if R2 or R2' is 4 membered cycloalkyl group then at least one of the carbon atom of the 4 membered cycloalkyl group must be substituted by two identical groups and which are selected from alkyl or halogen wherein most preferably alkyl is methyl and halo is fluorine.
Pharmaceutically acceptable salts of the compounds of the formula (2) are also contemplated. Likewise, pharmaceutically acceptable solvates, including hydrates, of the compounds of the formula (2) are contemplated.
It should be understood that the formula (2) structurally encompasses all stereoisomers, including enatiomers and diastereomers, which may be contemplated from the chemical structure of the genus described herein.
Also contemplated are prodrugs of the compounds of the formula (2), including ester prodrugs.
According to one embodiment, there is provided a compound of formula (2), wherein Z2 is O.
According to one embodiment, there is provided a compound of formula (2), wherein X2 is a bond, -C(O)- and -C(O)-CH2-. According to one embodiment, there is provided a compound of formula (2), wherein R2 is H, -C((CH3)2)-CO2H, -C((CH3)2)-CH2-CO2H, -CH2-CH2-CO2H, - CH2-CO2H and CH3.
According to one embodiment, there is provided a compound of formula (2), wherein R2 is substituted or unsubstituted cyclobutyl.
According to one embodiment, there is provided a compound of formula (2), wherein Z2' is a bond.
According to one embodiment, there is provided a compound of formula (2), wherein X2' is a bond, -C(O)2- and -C(O)N R"-.
According to one embodiment, there is provided a compound of formula (2), wherein R2' is H, substituted or unsubstituted cyclobutyl and ethyl piperidine-4- carboxylate.
According to one embodiment, there is provided a compound of formula (2), wherein R" is H.
According to one embodiment, there is provided a compound of formula (2), wherein Ra is substituted or unsubstituted alkyl and C(O)R". In this embodiment, preferably R" is OH, -[CH(R"')]pC(O)2Me, -[CH(R'")]PC(O)2H, benzyl, morpholine, piperidine, ethyl piperidine-4-carboxylate, N-ethyl piperazine, and pyrrolidine.
According to one embodiment, there is provided a compound of formula (2), wherein R"' is H, methyl, isopropyl and isobutyl.
According to one embodiment, there is provided a compound of formula (2), wherein p is 1 and 2.
Accordingly, one more aspect of the present invention provides the compounds of formula (2A):
Figure imgf000010_0001
Formula (2A)
wherein,
X M l can be a bond, or -C(O)-;
X ΛA2 can be a bond, O or NH; R ,Al can be H, substituted or unsubstituted alkyl, substituted or unsubstituted
Figure imgf000011_0001
RA2 can be H, substituted or unsubstituted alkyl, substituted or unsubstituted amino, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted aryl and preferably RA2 can be substituted by R ; and
each R can be substituted or unsubstituted alkyl, substituted or unsubstituted heterocyclyl, wherein heterocycle is nitrogen containing heterocycle and is bonded through nitrogen atom, substituted or unsubstituted N contained heterocyclylalkyl (wherein alkyl is bonded to ring nitrogen atom of heterocycle), substituted or unsubstituted aralkyl or substituted or unsubstituted phenyl.
Pharmaceutically acceptable salts of the compounds of the formula (2A) are also contemplated. Likewise, pharmaceutically acceptable solvates, including hydrates, of the compounds of the formula (2A) are contemplated.
It should be understood that the formula (2A) structurally encompasses all stereoisomers, including enatiomers, diastereomers, racemates, and combinations thereof which may be contemplated from the chemical structure of the genus described herein.
Also contemplated are prodrugs of the compounds of the formula (2A), including ester prodrugs.
According to one embodiment, there is provided a compound of formula (2A), wherein XA I is a bond and -C(O)-. According to one embodiment, there is provided a compound of formula (2A), wherein RAI is H and substituted or unsubstituted alkyl.
According to one embodiment, there is provided a compound of formula (2A), wherein RA1 is H and substituted or unsubstituted cycloalkyl.
According to one embodiment, there is provided a compound of formula (2A), wherein RA1 is H, -C((CH3)2)-CO2H, -C((CH3)2)-CH2-CO2H, -CH2-CH2- CO2H, -CH2-CO2H and CH3.
According to one embodiment, there is provided a compound of formula (2A), wherein XA2 is a bond and NH.
According to one embodiment, there is provided a compound of formula
(2A), wherein RA2
Figure imgf000012_0001
Figure imgf000012_0002
Also the present invention relates to the intermediate compounds of the formula (3):
Figure imgf000012_0003
Formula (3)
wherein,
R3a can be H, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted alkyloxy, or substituted or unsubstituted aryloxy and preferably R3a can be substituted by Ra;
X3 can be selected from a bond, -O-, -NR"-, -C(O)-, -C(O)2-,-(CH2)n-, or - C(O)NR"-;
n can be 0-3;
Z3 can be selected from a bond, -O-, or -NR"-;
Ra can be H, OH, halogen, N(R")2, C(O)R", C(O)2R", CH2OR", C(O)N(R")2 or substituted or unsubstituted alkyl;
each R" can be independently selected from H, -[CH(R"')]PC(O)2R"\ substituted or unsubstituted alkyl, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocyclyl;
p can be 0-3; and
each R'" can be independently selected from H, substituted or unsubstituted alkyl, or substituted or unsubstituted cycloalkyl; and a proviso that R3a is substituted or unsubstituted 4 or 5 membered cycloalkyl group, and if R3a is 4 membered cycloalkyl group then at least one of the carbon atom of the 4 membered cycloalkyl group must be substituted by two identical groups and which are selected from alkyl or halogen wherein most preferably alkyl is methyl and halo is fluorine.
Pharmaceutically acceptable salts of the compounds of the formula (3) are also contemplated. Likewise, pharmaceutically acceptable solvates, including hydrates, of the compounds of the formula (3) are contemplated.
It should be understood that the formula (3) structurally encompasses all stereoisomers, including enantiomers, diastereomers, racemates, and combinations thereof, which may be contemplated from the chemical structure of the genus described herein.
Also contemplated are prodrugs of the compounds of the formula (3), including ester prodrugs.
Below are the representative compounds, which are illustrative in nature only and are not intended to limit to the scope of the invention (Nomenclature has been generated from Chem. Draw Ultra 1 1.0 version): (lR,3aS,5aR,5bR,7aR,9S,l IaR1I lbR,13aR,13bR)-9-acetoxy-5a,5b,8,8,l Ia- pentamethyl- l-(prop- 1 -en-2-yl)icosahydro- 1 H-cyclopenta[a]chrysene-3a-carboxylic acid (Compound 1),
( 1 S,3R)-benzyl 3-(( 1 R,3aS,5aR,5bR,7aR,9S, 11 aR, 1 IbR, 13aR, 13bR)-9- acetoxy-5a,5b,8,8, 11 a-pentamethyl- 1 -(prop- 1 -en-2-yl)icosahydro- 1 H- cyclopenta[a]chrysene-3a-carboxamido)-2,2-dimethylcyclobutanecarboxylate (Compound 2),
(lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)-9-((lR,3S)-3-(tert- butoxycarbonyl)-2,2-dimethylcyclobutanecarbonyloxy)-5a,5b,8,8,l la-pentamethyl- l-(prop-l-en-2-yl)icosahydro-lH-cyclopenta[a]chrysene-3a-carboxylic acid
(Compound 3),
( 1 R,3aS,5aR,5bR,7aR,9S, 11 aR, 1 IbR, 13aR, 13bR)-9-(( 1 R,3S)-3-carboxy- 2,2-dimethylcyclobutanecarbonyloxy)-5a,5b,8,8, 11 a-pentamethyl- 1 -(prop- 1 -en-2- yl)icosahydro-lH-cyclopenta[a]chi7sene-3a-carboxylic acid (Compound 4),
(lS,3R)-3-((lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)-9-hydroxy-
5a,5b,8,8, 11 a-pentamethyl- 1 -(prop- 1 -en-2-yl)icosahydro- 1 H-cyclopenta[a]chrysene- 3a-carboxamido)-2,2-dimethylcyclobutanecarboxylic acid (Compound 5),
(lR,2S,3aR,5aR,5bR,7aS,10R,12aR,12bR)-2-(3-carboxy-3- methylbutanoyloxy)-3,3,5a,5b, 12b-pentamethyl- 10-(prop- 1 -en-2- yl)icosahydrodicyclopenta[a,i]phenanthrene-l,7a-dicarboxylic acid (Compound 6),
( 1 R,3aS,5aR,5bR,7aR,9S, 11 aR, 1 IbR.13aR, 13bR)-3a-(( 1 S,3R)-2,2-dimethyl- 3-(moφholine-4-carbonyl)cyclobutylcarbamoyl)-5a,5b,8,8,l 1 a-pentamethyl- 1 - (prop-l-en-2-yl)icosahydro-lH-cyclopenta[a]chrysen-9-yl acetate (Compound 7),
( 1 R,3aS,5aR,5bR,7aR,9S, 11 aR, 1 1 bR, 13aR, 13bR)-N-(( 1 S,3R)-2,2-dimethyl- 3-(morpholine-4-carbonyl)cyclobutyl)-9-hydroxy-5a,5b, 8, 8, 1 1 a-pentamethyl- 1-
(prop- 1 -en-2-yl)icosahydro- 1 H-cyclopenta[a]chrysene-3a-carboxamide (Compound 8),
4-(( 1 R,3aS,5aR,5bR,7aR,9S, 1 1 aR, 1 1 bR, 13aR, 13bR)-3a-(( 1 S,3R)-2,2- dimethyl-3-(moφholine-4-carbonyl)cyclobutylcarbamoyl)-5a,5b,8,8,l la- pentamethyl- 1 -(prop- 1 -en-2-yl)icosahydro- 1 H-cyclopenta[a]chrysen-9-yloxy)-2,2- dimethyl-4-oxobutanoic acid (Compound 9),
( lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)-3a-((lS,3R)-2,2-dimethyl- 3-(piperidine- 1 -carbonyl)cyclobutylcarbamoyl)-5a,5b,8,8, 1 1 a-pentamethyl- 1 -(prop- l-en-2-yl)icosahydro-lH-cyclopenta[a]chrysen-9-yl acetate (Compound 10), ( 1 R,3aS,5aR,5bR,7aR,9S, 11 aR, 1 IbR, 13aR, 13bR)-N-(( 1 S,3R)-2,2-dimethyl- 3-(piperidine-l-carbonyl)cyclobutyl)-9-hydroxy-5a,5b,8,8,l la-pentamethyl-l-(prop- l-en-2-yl)icosahydro-lH-cyclopenta[a]chrysene-3a-carboxamide (Compound 11),
4-(( 1 R,3aS,5aR,5bR,7aR,9S, 11 aR, 1 IbR, 13aR, 13bR)-3a-(( 1 S,3R)-2,2- dimethyl-3-(piperidine-l-carbonyl)cyclobutylcarbamoyl)-5a,5b,8,8,l la- pentamethyl- 1 -(prop- 1 -en-2-yl)icosahydro- 1 H-cyclopenta[a]chrysen-9-yloxy)-2,2- dimethyl-4-oxobutanoic acid (Compound 12),
(lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)-3a-((lS,3R)-2,2-dimethyl- 3-(pyrrolidine-l-carbonyl)cyclobutylcarbamoyl)-5a,5b,8,8,l la-pentamethyl-l- (prop-l-en-2-yl)icosahydro-lH-cyclopenta[a]chrysen-9-yl acetate (Compound 13),
(lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)-N-((lS,3R)-2,2-dimethyl- 3-(pyπOlidine-l-carbonyl)cyclobutyl)-9-hydroxy-5a,5b,8,8,l la-pentamethyl-l- (prop- 1 -en-2-yl)icosahydro- 1 H-cyclopenta[a]chrysene-3a-carboxamide (Compound 14),
4-((lR,3aS,5aR,5bR,7aR,9S,l IaR7I lbR,13aR,13bR)-3a-((lS,3R)-2,2- dimethyl-3-(pyrrolidine-l-carbonyl)cyclobutylcarbamoyl)-5a,5b,8,8,l la- pentamethyl- 1 -(prop- 1 -en-2-yl)icosahydro- 1 H-cyclopenta[a]chrysen-9-yloxy)-2,2- dimethyl-4-oxobutanoic acid (Compound 15),
( 1 R,3aS,5aR,5bR,7aR,9S, 11 aR, 1 IbR, 13aR, 13bR)-3a-(( 1 R,3S)-2,2-dimethyl- 3-(morpholine-4-carbonyl)cyclobutylcarbamoyl)-5a,5b,8,8,l la-pentamethyl-l-
(prop-l-en-2-yl)icosahydro-lH-cyclopenta[a]chrysen-9-yl acetate (Compound 16),
( 1 R,3aS,5aR,5bR,7aR,9S, 1 1 aR, 1 IbR, 13aR, 13bR)-N-(( 1 R,3S)-2,2-dimethyl- 3-(moφholine-4-carbonyl)cyclobutyl)-9-hydroxy-5a,5b,8,8,l la-pentamethyl-l- (prop-l-en-2-yl)icosahydro-lH-cyclopenta[a]chrysene-3a-carboxamide (Compound 17),
(lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)-9-((lS,3R)-3- (benzyloxycarbonyl)-2,2-dimethylcyclobutanecarbonyloxy)-5a,5b,8,8,l la- pentamethyl- l-(prop-l-en-2-yl)icosahydro-lH-cyclopenta[a]chrysene-3a-carboxylic acid (Compound 18),
(lR,3aS,5aR,5bR,7aR,9S,l laR.l lbR,13aR,13bR)-9-((lS,3R)-3-carboxy-
2,2-dimethylcyclobutanecarbonyloxy)-5a,5b,8,8, 1 1 a-pentamethyl- 1 -(prop- 1 -en-2- yl)icosahydro-lH-cyclopenta[a]chrysene-3a-carboxylic acid (Compound 19), (lR,3aS,5aR,5bR,7aR,9S,l laR.l lbR,13aR,13bR)-5a,5b,8,8,l Ia- pentamethyl-3a-(( 1 R,3S)-3-moφholinomethyl)cyclopentylcarbamoyl)- 1 -(prop- 1 -en- 2-yl)icosahydro-lH-cyclopenta[a]chrysen-9-yl acetate (Compound 20),
( 1 R,3aS,5aR,5bR,7aR,9S, 1 1 aR, 1 IbR, 13aR, 13bR)-5a,5b,8,8, 1 1 a- pentamethyl-3a-((lS,4R)-4-(moφholinomethyl)cyclopent-2-enylcarbamoyl)-l-
(prop-l-en-2-yl)-icosahydro-lH-cyclopenta[a]chrysen-9-yl acetate (Compound 21),
((lR,5aR,5bR,7aR,9S,l IaR1I lbR,13aR,13bR)-9-hydroxy-5a,5b,8,8,l Ia- pentamethyl- 1 -(prop- 1 -en-2-yl)icosahydro- 1 H-cyclopenta[a]chrysen-3a-yl)(3-(3- isopiOpyl-5-methyl-4H-l,2,4-triazol-4-yl)-8-azabicydo[3.2J]octan-8-yl)methanone (Compound 22),
(lR,3aS,5aR,5bR,7aR,9S,l IaR5I lbR,13aR,13bR)-9-hydroxy-5a,5b,8,8,l Ia- pentamethyl-N-(( 1 R,3S)-3-(morpholinomethyl)cyclopentyl)- 1 -(prop- 1 -en-2- yl)icosahydro-lH-cyclopenta[a]chrysene-3a-carboxamide (Compound 23),
2,2-dimethyl-4-oxo-4-((lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)- 5a,5b,8,8,l la-pentamethyl-3a-((lR,3S)-3-
(moφholinomethyl)cyclopentylcarbamoyl)- 1 -(prop- 1 -en-2-yl)icosahydro- 1 H- cyclopenta[a]chrysen-9-yloxy)butanoic acid (Compound 24),
((lR,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)-9-hydroxy-5a,5b,8,8,l la- pentamethyl-l-(piOp-l-en-2-yl)icosahydro-lH-cyclopenta[a]chi-ysen-3a-yl)(3-(3- isopropyl-S-methyl^H-l^^-triazol^-ylj-S-azabicycloP^. lloctan-S-ylJmethanone
(Compound 25),
( 1 R,3aS,5aR,5bR,7aR,9S, 1 1 aR, 1 IbR, 13aR, 13bR)-9-hydroxy-5a,5b,8,8, 11 a- pentamethyl-N-((lS,4R)-4-(moφholinomethyl)cyclopent-2-enyl)-l-(prop-l-en-2- yl)icosahydro- 1 H-cyclopenta[a]chrysene-3a-carboxamide (Compound 26),
(lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)-3a-(4-
(hydroxymethyl)cyclopent-2-enylcarbamoyl)-5a,5b,8,8, 11 a-pentamethyl- 1 -(prop- 1 - en-2-yl)icosahydro-lH-cyclopenta[a]chrysen-9-yl acetate (Compound 27),
(lR,3aS,5aR,5bR,7aR,9S,l IaRJ lbR,13aR,13bR)-9-hydroxy-N-(4- (hydroxymethyl)cyclopent-2-enyl)-5a,5b,8,8, 1 1 a-pentamethyl- 1 -(prop- 1 -en-2- yl)icosahydro-lH-cyclopenta[a]chrysene-3a-carboxamide (Compound 28),
(lR,3aS,5aR,5bR,7aR,9S,l IaR, 1 lbR,13aR,13bR)-3a-((2S,3R)-4- ((3S,4aS,8aS)-3-(tert-butylcarbamoyl)octahydroisoquinolin-2( lH)-yl)-3-hydroxy-l- phenylbutan-2-ylcarbamoyl)-5a,5b,8,8, 1 1 a-pentamethyl- 1 -(prop- 1 -en-2- yl)icosahydro-lH-cyclopenta[a]chrysen-9-yl acetate (Compound 29), (3S,4aS,8aS)-N-tert-butyl-2-((2R,3S)-2-hydroxy-3-
((lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)-9-hydroxy-5a,5b,8,8,l Ia- pentamethyl- 1 -(prop- 1 -en-2-yl)icosahydro- 1 H-cyclopenta[a]chrysene-3a- carboxamido)-4-phenylbutyl)decahydroisoquinoline-3-carboxamide (Compound 30),
( 1 R,3aS,5aR,5bR,7aR,9S, 1 1 aR, 1 IbR, 13aR, 13bR)-3a-(( 1 R,3S)-3-((4- benzylpiperidin- 1 -y^methy^cyclopentylcarbamoylVSa.Sb^δ, 1 1 a-pentamethyl- 1 - (prop-l-en-2-yl)icosahydro-lH-cyclopenta[a]chrysen-9-yl acetate (Compound 31),
(lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)-N-((lR,3S)-3-((4- benzylpiperidin- 1 -yl)methyl)cyclopentyl)-9-hydroxy-5a,5b,8,8, 11 a-pentamethyl- 1 -
(prop- 1 -en-2-yl)icosahydro- 1 H-cyclopenta[a]chrysene-3a-carboxamide (Compound 32),
5-(( 1 R,3aS,5aR,5bR,7aR,9S, 11 aR, 1 IbR, 13aR, 13bR)-3a-(( 1 R,3S)-3-((4- benzylpiperidin- 1 -ylJmethylJcyclopentylcarbamoy^-Sa.Sb.δ.S, 1 1 a-pentamethyl- 1 - (prop-l-en-2-yl)icosahydro-lH-cyclopenta[a]chrysen-9-yloxy)-5-oxopentanoic acid
(Compound 33),
( lR,3aS,5aR,5bR,7aR,9S, 11 aR, 1 IbR, 13aR, 13bR)-3a-(( lR,3S)-3-((4- ethylpiperazin- 1 -yl)methyl)cyclopentylcarbamoyl)-5a,5b,8,8, 1 1 a-pentamethyl- 1 - (prop-l-en-2-yl)icosahydro-lH-cyclopenta[a]chrysen-9-yl acetate (Compound 34), ( 1 R,3aS,5aR,5bR,7aR,9S, 1 1 aR, 11 bR, 13aR, 13bR)-N-(( 1 R,3S)-3-((4- ethylpiperazin- 1 -yl)methyl)cyclopentyl)-9-hydroxy-5a,5b,8,8, 11 a-pentamethyl- 1 - (prop- 1 -en-2-yl)icosahydro- 1 H-cyclopenta[a]chrysene-3a-carboxamide (Compound 35),
4-((lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)-3a-((lR,3S)-3-((4- ethylpiperazin- 1 -y^methyOcyclopentylcarbamoy^-Sa.Sb.S.δ, 1 1 a-pentamethyl- 1 -
(prop-l-en-2-yl)icosahydro-lH-cyclopenta[a]chrysen-9-yloxy)-2,2-dimethyl-4- oxobutanoic acid (Compound 36),
Methyl 3-((lS,3R)-3-((lR,3aS,5aR,5bR,7aR,9S,l laR.l lbR,13aR,13bR)-9- acetoxy-5a,5b,8,8, 11 a-pentamethyl- 1 -(prop- 1 -en-2-yl)icosahydro- 1 H- cyclopenta[a]chrysene-3a-carboxamido)-2,2-dimethylcyclobutanecarboxamido) propanoate (Compound 37),
3-(( 1 S,3R)-3-(( 1 R,3aS,5aR,5bR,7aR,9S, 1 1 aR, 11 bR, 13aR, 13bR)-9-hydroxy- 5a,5b,8,8, 1 1 a-pentamethyl- 1 -(prop- 1 -en-2-yl)icosahydro- 1 H-cyclopenta[a]chrysene- 3a-carboxamido)-2,2-dimethylcyclobutanecarboxamido)propanoic acid (Compound 38),
(S)-methyl 2-((lS,3R)-3-((lR,3aS,5aR,5bR,7aR,9S,l IaR5I IbR, 13aR, BbR)- 9-acetoxy-5a,5b,8,8, 11 a-pentamethyl- 1 -(prop- 1 -en-2-yl)icosahydro- 1 H- cyclopenta[a]chrysene-3a-carboxamido)-2,2-dimethylcyclobutanecarboxamido)-3- methylbutanoate (Compound 39),
(S)-2-(( 1 S,3R)-3-(( 1 R,3aS,5aR,5bR,7aR,9S, 11 aR, 1 IbR, 13aR, 13bR)-9- hydroxy-5a,5b,8,8, 1 1 a-pentamethyl- 1 -(prop- 1 -en-2-yl)icosahydro- 1 H- cyclopenta[a]chrysene-3a-carboxamido)-2,2-dimethylcyclobutanecarboxamido)-3- methylbutanoic acid (Compound 40),
(S)-methyl 2-((lS,3R)-3-((lR,3aS,5aR,5bR,7aR,9S,l IaR5I lbR,13aR,13bR)- 9-acetoxy-5a,5b,8,8, 11 a-pentamethyl- 1 -(prop- 1 -en-2-yl)icosahydro- 1 H- cyclopenta[a]chrysene-3a-carboxamido)-2,2-dimethylcyclobutanecarboxamido)-4- methylpentanoate (Compound 41),
(S)-2-((lS,3R)-3-((lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)-9- hydroxy-5a,5b,8,8, 1 1 a-pentamethyl- 1 -(prop- 1 -en-2-yl)icosahydro- 1 H- cyclopenta[a]chrysene-3a-carboxamido)-2,2-dimethylcyclobutanecarboxamido)-4- methylpentanoic acid (Compound 42),
( 1 R,3aS,5aR,5bR,7aR,9S, 1 IaR, 1 1 bR, 13aR, 13bR)-3a-(( 1 R,3S)-2,2-dimethyl- 3-(pyπ-olidine- 1 -carbonyl)cyclobutylcarbamoyl)-5a,5b,8,8, 11 a-pentamethyl- 1 -
(prop-l-en-2-yl)icosahydro-lH-cyclopenta[a]chrysen-9-yl acetate (Compound 43),
( 1 R,3aS,5aR,5bR,7aR,9S, 11 aR, 1 IbR, 13aR, 13bR)-N-(( 1 R,3S)-2,2-dimethyl- 3-(pyrrolidine- 1 -carbonyl)cyclobutyl)-9-hydroxy-5a,5b,8,8, 1 1 a-pentamethyl- 1 - (prop-l-en-2-yl)icosahydro-lH-cyclopenta[a]chrysene-3a-carboxamide (Compound 44),
4-(( lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)-3a-((lR,3S)-2,2- dimethyl-3-(pyrrolidine-l-carbonyl)cyclobutylcarbamoyl)-5a,5b,8,8,l Ia- pentamethyl- 1 -(prop- 1 -en-2-yl)icosahydro- 1 H-cyclopenta[a]chrysen-9-yloxy)-2,2- dimethyl-4-oxobutanoic acid (Compound 45),
(lR,3aS,5aR,5bR,7aR,9S,l laR.l lbR,13aR,13bR)-3a-((lR,3S)-2,2-dimethyl-
3-(piperidine- 1 -carbonyl)cyclobutylcarbamoyl)-5a,5b,8,8, 1 1 a-pentamethyl- 1 -(prop- l-en-2-yl)icosahydro-lH-cyclopenta[a]chrysen-9-yl acetate (Compound 46), ( lR,3aS,5aR,5bR,7aR,9S, 1 IaR, 1 IbR, BaR, 13bR)-N-(( 1 R,3S)-2,2-dimethyl- 3-(piperidine- 1 -carbonyl)cyclobutyl)-9-hydroxy-5a,5b,8,8, 11 a-pentamethyl- 1 -(prop- l-en-2-yl)icosahydro-lH-cyclopenta[a]chrysene-3a-carboxamide (Compound 47),
4-((lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)-3a-((lR,3S)-2,2- dimethyl-3-(piperidine-l-carbonyl)cyclobutylcarbamoyl)-5a,5b,8,8,l la- pentamethyl-l-(prop-l-en-2-yl)icosahydro-lH-cyclopenta[a]chrysen-9-yloxy)-2,2- dimethyl-4-oxobutanoic acid (Compound 48),
(lR,3aS,5aR,5bR,7aR,9S,l IaR5I lbR,13aR,13bR)-5a,5b,8,8,l Ia- pentamethyl-3a-((lR,3S)-3-((3-methylpiperidin-l-yl)methyl)cydopentylcarbarnoyl)- l-(prop-l-en-2-yl)icosahydro-lH-cyclopenta[a]chrysen-9-yl acetate (Compound
49),
( 1 R,3aS,5aR,5bR,7aR,9S, 1 1 aR, 1 IbR, 13aR, 13bR)-9-hydroxy-5a,5b,8,8, 11 a- pentamethyl-N-(( 1 R,3S)-3-((3-methylpiperidin- 1 -yl)methyl)cyclopentyl)- 1 -(prop- 1 - en-2-yl)icosahydro- 1 H-cyclopenta[a]chrysene-3a-carboxamide (Compound 50), 2,2-dimethyl-4-oxo-4-(( 1 R,3aS,5aR,5bR,7aR,9S, 11 aR, 1 IbR, BaR, 13bR)-
5a,5b,8,8, 1 1 a-pentamethyl-3a-(( 1 R,3S)-3-((3-methylρiperidin- 1 - yl)methyl)cyclopentylcarbamoyl)- 1 -(prop- 1 -en-2-yl)icosahydro- 1 H- cyclopenta[a]chrysen-9-yloxy)butanoic acid (Compound 51),
( 1 R,3aS,5aR,5bR,7aR,9S, 11 aR, 1 IbR, 13aR, 13bR)-3a-(4-ethylpiperazine- 1 - carbonyl)-5a,5b,8,8, 1 1 a-pentamethyl- 1 -(prop- 1 -en-2-yl)icosahydro- 1 H- cyclopenta[a]chrysen-9-yl acetate (Compound 52),
4-ethylpiperazin- 1 -yl)(( 1 R,3aS,5aR,5bR,7aR,9S, 11 aR, 1 1 bR, 13aR, 13bR)-9- hydroxy-5a,5b,8,8, 11 a-pentamethyl- 1 -(prop- 1 -en-2-yl)icosahydro- 1 H- cyclopenta[a]chrysen-3a-yl)methanone (Compound 53),
3-(((lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)-3a-(4-ethylpiperazine-
1 -carbonyl)-5a,5b,8,8, 11 a-pentamethyl- 1 -(prop- 1 -en-2-yl)icosahydro- 1 H- cyclopenta[a]chrysen-9-yloxy)carbonyl)-2,2-dimethylcyclobutanecarboxylic acid (Compound 54),
Ethyl 4-((lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)-9-acetoxy- 5a,5b,8,8, 1 1 a-pentamethyl- 1 -(prop- 1 -en-2-yl)icosahydro- 1 H-cyclopenta[a]chrysene-
3a-carbonyl)-l-benzylcyclohexanecarboxylate (Compound 55),
Ethyl l-benzyl-4-(( lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)-9- hydroxy-5a,5b,8,8,l 1 a-pentamethyl- 1 -(prop- l-en-2-yl)icosahydro- IH- cyclopenta[a]chrysene-3a-carbonyl)cyclohexanecarboxylate (Compound 56), 4-(( 1 R,3aS,5aR,5bR,7aR,9S, 11 aR, 1 IbR, 13aR, 13bR)-3a-(4-benzyl-4- (ethoxycarbonyl)piperidine- 1 -carbonyl)-5a,5b,8,8, 11 a-pentamethyl- 1 -(prop- l-en-2- yl)icosahydro-lH-cyclopenta[a]chrysen-9-yloxy)-2,2-dimethyl-4-oxobutanoic acid (Compound 57),
(lS,3R)-l-tert-butyl 3-((lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)-
3a-((lR,3S)-2,2-dimethyl-3-(piperidine-l-carbonyl)cyclobutylcarbamoyl)- 5a,5b,8,8, 11 a-pentamethyl- 1 -(prop- 1 -en-2-yl)icosahydro- 1 H-cyclopenta[a]chrysen- 9-yl) 2,2-dimethylcyclobutane-l,3-dicarboxylate (Compound 58),
(lS,3R)-3-(((lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)-3a-((lR,3S)- 2,2-dimethyl-3-(piperidine- 1 -carbonyl)cyclobutylcarbamoyl)-5a,5b,8,8, 1 1 a- pentamethyl- 1 -(prop- 1 -en-2-yl)icosahydro- 1 H-cyclopenta[a]chrysen-9- yloxy)carbonyl)-2,2-dimethylcyclobutanecarboxylic acid (Compound 59),
(lS,3R)-l-tert-butyl 3-((lR,3aS,5aR,5bR,7aR,9S,l IaR1I lbR,13aR,13bR)- 3a-((lS,3R)-2,2-dimethyl-3-(morpholine-4-carbonyl)cyclobutylcarbamoyl)- 5a,5b,8,8, 1 1 a-pentamethyl- 1 -(prop- 1 -en-2-yl)icosahydro- 1 H-cyclopenta[a]chrysen-
9-yl) 2,2-dimethylcyclobutane-l,3-dicarboxylate (Compound 60),
(lS,3R)-3-(((lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)-3a-((lS,3R)- 2,2-dimethyl-3-(moφholine-4-carbonyl)cyclobutylcarbamoyl)-5a,5b,8,8, 11 a- pentamethyl- l-(prop-l-en-2-yl)icosahydro-lH-cyclopenta[a]chrysen-9- yloxy)carbonyl)-2,2-dimethylcyclobutanecarboxylic acid (Compound 61),
4-(( 1 R,3aS,5aR,5bR,7aR,9S, 1 1 aR, 11 bR, 13aR, 13bR)-3a-(( 1 S,3R)-2,2- dimethy]-3-(piperidine-l-carbonyl)cyclobutylcarbamoyl)-5a,5b,8,8,l la- pentamethyl- 1 -(prop- 1 -en-2-yl)icosahydro- 1 H-cyclopenta[a]chrysen-9-yloxy)-4- oxobutanoic acid (Compound 62),
(lS,3R)-l-tert-butyl 3-((lR,3aS,5aR,5bR,7aR,9S,l laR,l IbR1BaR, BbR)-
3a-((lS,3R)-2,2-dimethyl-3-(piperidine-l-carbonyl)cyclobutylcarbamoyl)- 5a, 5b, 8,8, 11 a-pentamethyl- 1 -(prop- l-en-2-yl)icosahydro-lH-cyclopenta[a]chrysen- 9-yl) 2,2-dimethylcyclobutane-l ,3-dicarboxylate (Compound 63),
(lS,3R)-3-(((lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)-3a-((lS,3R)- 2,2-dimethyl-3-(piperidine-l-carbonyl)cyclobutylcarbamoyl)-5a,5b,8,8,l la- pentamethyl- 1 -(prop- 1 -en-2-yl)icosahydro- 1 H-cyclopenta[a]chrysen-9- yloxy)carbonyl)-2,2-dimethylcyclobutanecarboxylic acid (Compound 64),
5-((lR,3aS,5aR,5bR,7aR,9S,l IaR1I lbR,13aR,13bR)-3a-((lS,3R)-2,2- dimethyl-3-(piperidine-l -carbonyl)cyclobutylcarbamoyl)-5a, 5b, 8,8,1 Ia- pentamethyl- 1 -(prop- 1 -en-2-yl)icosahydro- 1 H-cyclopenta[a]chrysen-9-yloxy)-5- oxopentanoic acid (Compound 65),
(lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)-3a-((lS,3R)-3-(4- ethylpiperazine-l-carbonyl)-2,2-dimethylcyclobutylcarbamoyl)-5a,5b,8,8,l la- pentamethyl- 1 -(prop- 1 -en-2-yl)icosahydro- 1 H-cyclopenta[a]chrysen-9-yl acetate
(Compound 66),
(lR,3aS,5aR,5bR,7aR,9S,l IaR, 1 lbR,13aR,13bR)-N-((lS,3R)-3-(4- ethylpiperazine-l-carbonyl)-2,2-dimethylcyclobutyl)-9-hydiOxy-5a,5b,8,8,l la- pentamethyl- 1 -(prop- 1 -en-2-yl)icosahydro- 1 H-cyclopenta[a]chrysene-3a- carboxamide (Compound 67),
4-((lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)-3a-((lS,3R)-3-(4- ethylpiperazine-l-carbonyl)-2,2-dimethylcyclobutylcarbamoyl)-5a,5b, 8,8,1 Ia- pentamethyl- 1 -(prop- 1 -en-2-yl)icosahydro- 1 H-cyclopenta[a]chrysen-9-yloxy)-2,2- dimethyl-4-oxobutanoic acid (Compound 68),
(lR,3aS,5aR,5bR,7aR,9S,l IaR1I lbR,13aR,13bR)-3a-((lR,3S)-3-(4- ethylpiperazine- 1 -carbonyl)-2,2-dimethylcyclobutylcarbamoyl)-5a,5b,8,8, 1 1 a- pentamethyl-l-(prop-l-en-2-yl)icosahydro-lH-cyclopenta[a]chrysen-9-yl acetate (Compound 69),
(lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR.13bR)-N-((lR,3S)-3-(4- ethylpiperazine-l-carbonyl)-2,2-dimethylcyclobutyl)-9-hydroxy-5a,5b,8,8,l Ia- pentamethyl- 1 -(prop- 1 -en-2-yl)icosahydro- 1 H-cyclopenta[a]chrysene-3a- carboxamide (Compound 70),
4-((lR,3aS,5aR,5bR,7aR,9S,l IaR1I lbR,13aR,13bR)-3a-((lR,3S)-3-(4- ethylpiperazine-l-carbonyl)-2,2-dimethylcyclobutylcarbamoyl)-5a,5b,8,8,l Ia- pentamethyl- 1 -(prop- 1 -en-2-yl)icosahydro- 1 H-cyclopenta[a]chrysen-9-yloxy)-2,2- dimethyl-4-oxobutanoic acid (Compound 71),
Ethyl 1 -(( 1 R,3aS,5aR,5bR,7aR,9S, 11 aR, 1 IbR113aR, 13bR )-9-acetoxy-
5a,5b, 8,8,11 a-pentamethyl- 1 -(prop- l-en-2-yl)icosahydro-lH-cyclopenta[a]chrysene- 3a-carbonyl)-4-ethylpiperidine-4-carboxylate (Compound 72),
Ethyl 4-ethyl-l-((lR,3aS,5aR,5bR,7aR,9S,l IaR1I lbR,13aR,13bR)-9- hydroxy-5a,5b,8,8, 1 1 a-pentamethyl- 1 -(prop- 1 -en-2-yl)icosahydro- 1 H- cyclopenta[a]chrysene-3a-carbonyl)piperidine-4-carboxylate (Compound 73),
4-(( 1 R,3aS,5aR,5bR,7aR,9S, 1 1 aR, 1 1 bR, 13aR, 13bR)-3a-(4-
(ethoxycarbonyl)-4-ethylpiperidine- 1 -carbonyl)-5a,5b,8,8, 1 1 a-pentamethyl- 1 -(prop- 1 -en-2-yl)icosahydro- 1 H-cyclopenta[a]chrysen-9-yloxy)-2,2-dimethyl-4- oxobutanoic acid (Compound 74),
(lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)-3a-(4-cyano-4- phenylpiperidine- 1 -carbonyl)-5a,5b,8,8, 11 a-pentamethyl- 1 -(prop- 1 -en-2- yl)icosahydro-lH-cyclopenta[a]chrysen-9-yl acetate (Compound 75),
l-((lR,3aS,5aR,5bR,7aR,9S,l IaR5I lbR,13aR,13bR)-9-hydroxy- 5a,5b,8,8, 11 a-pentamethyl- 1 -(prop- 1 -en-2-yl)icosahydro- 1 H-cyclopenta[a]chrysene- 3a-carbonyl)-4-phenylpiperidine-4-carbonitrile (Compound 76),
4-(( 1 R,3aS,5aR,5bR,7aR,9S, 11 aR, 1 IbR, 13aR, 13bR)-3a-(4-cyano-4- phenylpiperidine- 1 -carbonyl)-5a,5b,8,8, 11 a-pentamethyl- 1 -(prop- 1 -en-2- yl)icosahydro- 1 H-cyclopenta[a]chrysen-9-yloxy)-2,2-dimethyl-4-oxobutanoic acid (Compound 77),
Tert-butyl 2-(6-(2-((lR,3aS,5aR,5bR,7aR,9S,l IaR1I IbR, BaR, 13bR)-9- acetoxy-5a,5b,8,8, 1 1 a-pentamethyl- 1 -(prop- 1 -en-2-yl)icosahydro- 1 H- cyclopenta[a]chrysene-3a-carboxamido)ethyl)-2,2-dimethyl-l,3-dioxan-4-yl)acetate
(Compound 78),
Tert-butyl 2-(6-(2-(( 1 R,3aS,5aR,5bR,7aR,9S, 1 1 aR, 1 1 bR, 13aR, 13bR)-9- hydroxy-5a,5b,8,8, 1 1 a-pentamethyl- 1 -(prop- 1 -en-2-yl)icosahydro- 1 H- cyclopenta[a]chrysene-3a-carboxamido)ethyl)-2,2-dimethyl- 1 ,3-dioxan-4-yl )acetate (Compound 79),
4-(( lR,3aS,5aR,5bR,7aR,9S, 1 IaR, 1 IbR, 13aR, 13bR)-3a-(2-(6-(2-tert- butoxy-2-oxoethyl)-2,2-dimethyl- 1 ,3-dioxan-4-yl)ethylcarbamoyl)-5a,5b,8,8, 1 1 a- pentamethyl- 1 -(prop- 1 -en-2-yl)icosahydro- 1 H-cyclopenta[a]chrysen-9-yloxy)-2,2- dimethyl-4-oxobutanoic acid (Compound 80),
7-(( 1 R,3aS,5aR,5bR,7aR,9S, 1 1 aR, 11 bR, 13aR, 13bR)-9-(3-carboxy-3- methylbutanoyloxy)-5a,5b,8,8, 1 1 a-pentamethyl- 1 -(prop- 1 -en-2-yl)icosahydro- 1 H- cyclopenta[a]chrysene-3a-carboxamido)-3,5-dihydroxyheptanoic acid (Compound 81),
5-((lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)-3a-((lR,3S)-3-((4- benzylpiperidin- 1 -y^methyOcyclopentylcarbamoy^-Sa.Sb^δ, 11 a-pentamethyl- 1 -
(prop-l-en-2-yl)icosahydro-lH-cyclopenta[a]chrysen-9-yloxy)-3,3-dimethyl-5- oxopentanoic acid (Compound 82), ((lR,3aS,5aR,5bR,7aR,9S,l IaR, 1 lbR,13aR,13bR)-9-acetoxy-5a,5b,8,8,l Ia- pentamethyl-l-(prop-l-en-2-yl)icosahydro-lH-cyclopenta[a]chrysene-3a-carbonyl)- 4-ethylpiperidine-4-carboxylic acid (Compound 83),
4-ethyl- 1 -(( 1 R,3aS,5aR,5bR,7aR,9S , 11 aR, 11 bR, 13aR, 13bR)-9-hydroxy- 5a,5b,8,8, 11 a-pentamethyl- 1 -(prop- 1 -en-2-yl)icosahydro- lH-cyclopenta[a]chrysene-
3a-carbonyl)piperidine-4-carboxylic acid (Compound 84),
l-((lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)-9-(3-carboxy-3- methylbutanoyloxy)-5a,5b,8,8, 11 a-pentamethyl- 1 -(prop- 1 -en-2-yl)icosahydro- 1 H- cyclopenta[a]chrysene-3a-carbonyl)-4-ethylpiperidine-4-carboxylic acid (Compound 85),
l-(((lS,3R)-3-((lR,3aS,5aR,5bR,7aR,9S,l IaR1I lbR,13aR,13bR)-9-(3- cai'boxy-3-methylbutanoyloxy)-5a,5b,8,8, 11 a-pentamethyl- 1 -(prop- l-en-2- yl)icosahydro- 1 H-cyclopenta[a]chrysene-3a- carbonyl)cyclopentyl)methyl)piperidine-4-carboxylic acid (Compound 86),
4-((lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)-3a-((lR,3S)-3-
(benzyloxycarbonyl)-2,2-dimethylcyclobutylcarbamoyl)-5a,5b,8,8, 11 a-pentamethyl- 1 -(prop- 1 -en-2-yl)icosahydro- 1 H-cyclopenta[a]chrysen-9-yloxy)-2,2-dimethyl-4- oxobutanoic acid (Compound 87),
( 1 S,3R)-3-(( 1 S,3aS,5aR,5bR,7aR,9S, 11 aR, 1 IbR, 13aR, 13bR)-9-(3-carboxy- 3-methylbutanoyloxy)- 1 -isopropyl-5a,5b,8,8, 1 1 a-pentamethylicosahydro- 1 H- cyclopenta[a]chrysene-3a-carboxamido)-2,2-dimethylcyclobutanecarboxylic acid (Compound 88),
(lR,3S)-l-benzyl 3-((lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)-3a- ((lS,3R)-3-(4-(ethoxycarbonyl)piperidine-l-carbonyl)-2,2- dimethylcyclobutylcarbamoyl)-5a,5b,8,8, 1 1 a-pentamethyl- 1 -(prop- 1 -en-2- yl)icosahydro- 1 H-cyclopenta[a]chrysen-9-yl) 2,2-dimethylcyclobutane- 1 ,3- dicarboxylate (Compound 89),
(lR,3S)-3-(((lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)-3a-(( lS,3R)- 3-(4-(ethoxycarbonyl)piperidine-l-carbonyl)-2,2-dimethylcyclobutylcarbamoyl)- 5a,5b,8,8, 11 a-pentamethyl- 1 -(prop- 1 -en-2-yl)icosahydro- 1 H-cyclopenta[a]chrysen-
9-yloxy)carbonyl)-2,2-dimethylcyclobutanecarboxylic acid (Compound 90),
( lR,3S)-l-benzyl 3-((lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)-3a- ((lR,3S)-3-(benzyloxycarbonyl)-2,2-dimethylcyclobutylcarbamoyl)-5a,5b,8,8,l Ia- pentamethyl- 1 -(prop- 1 -en-2-yl)icosahydro- 1 H-cyclopenta[a]chi'ysen-9-yl) 2,2- dimethylcyclobutane-l,3-dicarboxylate (Compound 91),
( 1 S,3R)-3-(( 1 R,3aS,5aR,5bR,7aR,9S, 11 aR, 1 IbR, 13aR, 13bR)-9-(( 1 S,3R)-3- carboxy-2,2-dimethylcyclobutanecarbonyloxy)-5a,5b,8,8, 1 1 a-pentamethyl- 1 -(prop- 1 -en-2-yl)icosahydro- 1 H-cyclopenta[a]chrysene-3a-carboxamido)-2,2- dimethylcyclobutanecarboxylic acid (Compound 92),
( 1 R.3S)- 1 -benzyl 3-(( 1 R,3aS,5aR,5bR,7aR,9S, 11 aR, 1 IbR, 13aR, 13bR)-3a- (4-(ethoxycarbonyl)piperidine- 1 -carbonyl)-5a,5b,8,8, 11 a-pentamethyl- 1 -(prop- 1 -en- 2-yl)icosahydro- 1 H-cyclopenta[a]chrysen-9-yl) 2,2-dimethylcyclobutane- 1,3- dicarboxylate (Compound 93),
5-((lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)-3a-((lR,3S)-3-((4- benzylpiperidin- 1 -yOmethyOcyclopentylcarbamoy^-Sa.Sb^δ, 11 a-pentamethyl- 1 - (prop-l-en-2-yl)icosahydro-lH-cyclopenta[a]chrysen-9-yloxy)-3,3-dimethyl-5- oxopentanoic acid (Compound 94),
2,2-dimethyl-4-oxo-4-((lR,3aS,5aR,5bR,7aR,9S,l IaR, 1 lbR,13aR,13bR)-
5a,5b,8,8,l la-pentamethyl-3a-((lS,4R)-4-(morpholinomethyl)cyclopent-2- enylcarbamoyl)- 1 -(prop- 1 -en-2-yl)icosahydro- 1 H-cyclopenta[a]chrysen-9- yloxy)butanoic acid (Compound 95),
4-oxo-4-((lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)-5a,5b,8,8,l la- pentamethyl-3a-(3-(piperidin- 1 -ylmethyl)cyclopentylcarbamoyl)- 1 -(prop- 1 -en-2- yl)icosahydro-lH-cyclopenta[a]chrysen-9-yloxy)butanoic acid (Compound 96), ( 1 R,3aS,5aR,5bR,7aR,9S, 1 1 aR, 1 IbR, 13aR, 13bR)-N-(2,2-dimethyl-3-(3- moφholino-3-oxopropylcarbamoyl)cyclobutyl)-9-hydroxy-5a,5b,8,8, 11 a- pentamethyl- 1 -(prop- 1 -en-2-yl)icosahydro- lH-cyclopenta[a]chrysene-3a- carboxamide (Compound 97),
(lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)-N-(2,2-dimethyl-3-(3- oxo-3-(pyrrolidin- 1 -y^propylcarbamoy^cyclobutyO-θ-hydroxy-Sa.Sb^.δ, 1 1 a- pentamethyl- 1 -(prop- 1 -en-2-yl)icosahydro- 1 H-cyclopenta[a]chrysene-3a- carboxamide (Compound 98),
4-((lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)-3a-((lR,3S)-3-((4- benzylpiperidin- 1 -yl)methyl)cyclopentylcarbamoyl)-5a,5b,8,8, 1 1 a-pentamethyl- 1 - (prop-l-en-2-yl)icosahydro-lH-cyclopenta[a]chi'ysen-9-yloxy)-2,2-dimethyl-4- oxobutanoic acid (Compound 99), or pharmaceutically acceptable salts, solvates, including hydrates and prodrugs of compounds are also contemplated.
Also below are the some representative compounds (shown in Table 1), which are illustrative in nature only and are not intended to limit to the scope of the invention:
Table 1
a-
Figure imgf000025_0001
Figure imgf000026_0001
or pharmaceutically acceptable salts, solvates, including hydrates and prodrugs of compounds are also contemplated.
The present invention also provides a pharmaceutical composition that includes at least one compound of described herein and at least one pharmaceutically acceptable excipient (such as a pharmaceutically acceptable carrier or diluent). Preferably, the pharmaceutical composition comprises a therapeutically effective amount of at least one compound described herein. The compound(s) present in the composition may be associated with a pharmaceutically acceptable excipient (such as a carrier or a diluent) or may be diluted by a carrier, or enclosed within a carrier which may be in the form of a capsule, sachet, paper, or other container.
The compounds and pharmaceutical compositions described herein are useful in the treatment of diseases, conditions and/or disorders mediated by viral infections.
The present invention further provides a method of treating a disease, condition and/or disorder mediated by viral infections in a subject in need thereof by administering to the subject one or more compounds described herein in the amount effective to cause that infection.
Also provided herein are processes for preparing compounds described herein.
The invention provides a method for preventing, ameliorating or treating a HIV mediated disease, disorder or syndrome in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of the invention. The invention further provides a method, wherein the HIV mediated disease, disorder or syndrome is like AIDS, AIDS related complex, or a syndrome characterized by symptoms such as pesistant generalized limphadenopathy, fever and weight loss, or an etroviral infection genetically related to AIDS.
Anti HIV inhibitory potential of the compounds of present invention may be demonstrated by any one or more methodologies known in the art, such as by using the assays described in Mosmann T, December 1983, Journal of immunological methods, 65 (1-2), 55-63 and SPC Cole, cancer chemotherapy and Pharmacology, 1986, 17, 259-263. Detailed Description of the Invention
The present invention provides lupeol-type triterpene derivatives and related compounds, which may be used as antiviral particularly as anti-HIV compounds and processes for the synthesis of these compounds. Pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, diastereomers, together with pharmaceutically acceptable carriers, excipients or diluents, which can be used for the treatment of diseases, condition and/or disorders mediated by viral infections, are also provided.
The following definitions apply to the terms as used herein:
The terms "halogen" or "halo" includes fluorine, chlorine, bromine, or iodine.
The term "alkyl" refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to eight carbon atoms, and which is attached to the rest of the molecule by a single bond, e.g., methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n- pentyl, and 1,1-dimethylethyl (t-butyl).
The term "alkenyl" refers to an aliphatic hydrocarbon group containing a carbon-carbon double bond and which may be a straight or branched chain having from 2 to about 10 carbon atoms, e.g., ethenyl, 1-propenyl, 2-propenyl (allyl), iso- propenyl, 2-methyl- 1-propenyl, 1-butenyl, and 2-butenyl.
The term "halo alkyl" is used to denote a group comprised of an alkyl group substituted with halogen atom, where alkyl group is as defined above and halogen is used to denote fluorine, chlorine, bromine or iodine, an example of such group is trifluoromethyl, difluoromethyl.
The term "acyl group" is used to denote a linear or branched aliphatic acyl group (preferably a C2-6 alkanoyl group) or an aromatic acyl group, which contains 2 to 10 carbon atoms. Examples include an acetyl group, a propionyl group, a pivaloyl group, a butyryl group, an isobutyryl group, a valeryl group and a benzoyl group, with an acetyl group being preferred.
The term "alkoxy group" is used to denote a linear or branched alkoxy group containing 1 to 6 carbon atoms. Preferred are C 1.4 alkoxy groups including a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, an n- butoxy group, an isobutoxy group and a tert-butoxy group. The term "alkoxycarbonyl group" is used to denote a structure composed of a linear or branched C 1.5 alkoxy group and a carbonyl group. Preferred are C2.5 alkoxycarbonyl groups including a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, an isopropoxycarbonyl group and a butoxycarbonyl group. Among them, a methoxycarbonyl group is preferred.
The term "cycloalkyl" denotes a non-aromatic mono or multicyclic ring system of from 3 to about 12 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Examples of multicyclic cycloalkyl groups include, but are not limited to, perhydronapththyl, adamantyl and norbornyl groups, bridged cyclic groups and spirobicyclic groups, e.g., spiro (4,4) non-2-yl.
The term "cycloalkenyl" refers to a cyclic ring-containing radical having from 3 to about 8 carbon atoms with at least one carbon-carbon double bond, such as cyclopropenyl, cyclobutenyl, and cyclopentenyl.
The term "cycloalkylalkyl" refers to a cyclic ring-containing radical having from 3 to about 8 carbon atoms directly attached to an alkyl group. The cycloalkylalkyl group may be attached to the main structure at any carbon atom in the alkyl group that results in the creation of a stable structure. Non-limiting examples of such groups include cyclopropylmethyl, cyclobutylethyl, and cyclopentylethyl.
The term "aryl" refers to an aromatic radical having from 6 to 14 carbon atoms such as phenyl, naphthyl, tetrahydronapthyl, indanyl, and biphenyl.
The term "arylalkyl" refers to an aryl group as defined above directly bonded to an alkyl group as defined above, e.g., -CH2C6H5 and -C2H5C6H5.
"Substituted" refers to 1-3 substituents on the same position or on different positions with the same groups or different groups.
"Alkynyl" refers to alkynyl groups having from 2 to 6 carbon atoms and having at least one alkynyl saturation ,example for such group includes acetylenyl, propargyl.
The terms "heterocyclyl" and "heterocyclic ring" refer to a stable 3- to 15- membered ring radical which consists of carbon atoms and from one to five heteroatoms selected from nitrogen, phosphorus, oxygen and sulfur. For purposes of this invention, the heterocyclic ring radical may be a monocyclic, bicyclic or tricyclic ring system, which may include fused, bridged or spiro ring systems, and the nitrogen, phosphorus, carbon, oxygen or sulfur atoms in the heterocyclic ring radical may be optionally oxidized to various oxidation states. In addition, the nitrogen atom may be optionally quateraized; and the ring radical may be partially or fully saturated (i.e., heterocyclic or heteroaryl). Examples of such heterocyclic ring radicals include, but are not limited to, tetrazoyl, tetrahydroisouinolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2- oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolinyl, oxazolidinyl, triazolyl, isoxazolyl, isoxasolidinyl, morpholinyl, thiazolyl, thiazolinyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl, isoindolyl, indolinyl, isoindolinyl, octahydroindolyl, octahydroisoindolyl, quinolyl, isoquinolyl, decahydroisoquinolyl, benzimidazolyl, thiadiazolyl, benzothiazolyl, benzooxazolyl, furyl, tetrahydrofurtyl, tetrahydropyranyl, thienyl, benzothienyl, thiamorpholinyl, thiamoφholinyl sulfoxide, thiamoφholinyl sulfone, dioxaphospholanyl, oxadiazolyl. The heterocyclic ring radical may be attached to the main structure at any heteroatom or carbon atom that results in the creation of a stable structure.
The term "heterocyclylalkyl" refers to a heterocyclic ring radical directly bonded to an alkyl group. The heterocyclylalkyl radical may be attached to the main structure at any carbon atom in the alkyl group that results in the creation of a stable structure.
The term "heteroaryl" refers to an aromatic heterocyclic ring radical. The heteroaryl ring radical may be attached to the main structure at any heteroatom or carbon atom that results in the creation of a stable structure.
The term "heteroarylalkyl" refers to a heteroaryl ring radical directly bonded to an alkyl group. The heteroarylalkyl radical may be attached to the main structure at any carbon atom in the alkyl group that results in the creation of a stable structure.
Unless otherwise specified, the term "substituted" as used herein refers to substitution with any one or any combination of the following substituents: hydroxy, halogen, carboxyl, cyano, nitro, oxo (=O), thio (=S), substituted or unsubstituted alkyl, haloalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclylalkyl ring, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic ring, substituted or unsubstiuted guanidine, -COOR\ -C(O)R\ -C(S)R\ -C(O)NRxRy, -C(O)ONRxRy, -NRxCONRyRz, -N(Rx)SORy, -N(Rx)SO2Ry, -(=N- N(Rx)Ry), -NRxC(O)ORy, -NRxRy, -NRxC(O)Ry, -NRxC(S)Ry, -NRxC(S)NRyRz, - SONRxRy, -SO2NRxRy, -ORX, -ORxC(O)NRyR2, -ORxC(O)ORy, -OC(O)RX, -
OC(O)NRxRy, -RxNRyC(O)Rz, -RxORy, -RxC(O)ORy, -RxC(O)NRyRz, -RxC(O)Ry, - RxOC(O)Ry, -SRX, -SORX, -SO2RX, and -ONO2, wherein R\ Ry and Rz are independently selected from hydrogen, substituted or unsubstituted alkyl, haloalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted heterocyclylalkyl ring, substituted or unsubstituted heteroarylalkyl, or substituted or unsubstituted heterocyclic ring. The substituents in the aforementioned "substituted" groups cannot be further substituted. For example, when the substituent on "substituted alkyl" is "substituted aryl", the substituent on "substituted aryl" cannot be "substituted alkenyl".
The term "prodrug" means a compound that is transformed in vivo to yield a compound of Formula (I), (IA), (2), (2A) or a pharmaceutically acceptable salt, hydrate or solvate, or metabolite of the compound. The transformation may occur by various mechanisms, such as through hydrolysis in blood. A discussion of the use of prodrugs is provided by T. Higuchi and W. Stella, "Pro-drugs as Novel Delivery Systems," Vol. 14 of the A. C. S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and
Pergamon Press, 1987.
The term "treating" or "treatment" of a state, disease, disorder or condition includes:
(1) preventing or delaying the appearance of clinical symptoms of the state, disease, disorder or condition developing in a subject that may be afflicted with or predisposed to the state, disease, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disease, disorder or condition; (2) inhibiting the state, disease, disorder or condition, i.e., arresting or reducing the development of the state, disease, disorder or condition or at least one clinical or subclinical symptom thereof; or
(3) relieving the state, disease, disorder or condition, i.e., causing regression of the state, disease, disorder or condition or at least one of its clinical or subclinical symptoms.
The benefit to a subject receiving treatment is either statistically significant or at least perceptible to the subject or to the physician.
The term "subject" includes mammals (especially humans) and other animals, such as domestic animals (e.g., household pets including cats and dogs) and non-domestic animals (such as wildlife).
A "therapeutically effective amount" means the amount of a compound that, when administered to a subject for treating a state, disease, disorder or condition, is sufficient to effect such treatment. The "therapeutically effective amount" will vary depending on the compound, the state, disease, disorder or condition and its severity and the age, weight, physical condition and responsiveness of the subject receiving treatment.
The compounds of the present invention may form salts. Non-limiting examples of pharmaceutically acceptable salts forming part of this invention include salts derived from inorganic bases salts of organic bases salts of chiral bases, salts of natural amino acids and salts of non-natural amino acids. Certain compounds of the present invention are capable of existing in stereoisomeric forms (e.g., diastereomers, enantiomers, racemates, and combinations thereof). With respect to the overall compounds described by the Formula (1), (IA), (2) or (2A), the present invention extends to these stereoisomeric forms and to mixtures thereof. To the extent prior art teaches synthesis or separation of particular stereoisomers, the different stereoisomeric forms of the present invention may be separated from one another by the methods known in the art, or a given isomer may be obtained by stereospecific or asymmetric synthesis. Tautomeric forms and mixtures of compounds described herein are also contemplated.
Pharmaceutically acceptable solvates includes hydrates and other solvents of crystallization (such as alcohols). The compounds of the present invention may form solvates with low molecular weight solvents by methods known in the art. Pharmaceutical Compositions
The pharmaceutical compositions provided in the present invention include at least one compound described herein and at least one pharmaceutically acceptable excipient (such as a pharmaceutically acceptable carrier or diluent). Preferably, the contemplated pharmaceutical compositions include a compound(s) described herein in an amount sufficient to treat viral infection in a subject.
The subjects contemplated include, for example, a living cell and a mammal, including human. The compound of the present invention may be associated with a pharmaceutically acceptable excipient (such as a carrier or a diluent) or be diluted by a carrier, or enclosed within a carrier which can be in the form of a capsule, sachet, or other container.
Examples of suitable carriers include, but are not limited to, water, salt solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, peanut oil, olive oil, gelatin, lactose, terra alba, sucrose, dextrin, magnesium carbonate, sugar, cyclodextrin, amylose, magnesium stearate, talc, gelatin, agar, pectin, acacia, stearic acid or lower alkyl ethers of cellulose, silicic acid, fatty acids, fatty acid amines, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, polyoxyethylene, hydroxymethylcellulose and polyvinylpyrrolidone.
The carrier or diluent may include a sustained release material, such as, for example, glyceryl monostearate or glyceryl distearate, alone or mixed with a wax.
The pharmaceutical composition may also include one or more pharmaceutically acceptable auxiliary agents, wetting agents, emulsifying agents, suspending agents, preserving agents, salts for influencing osmotic pressure, buffers, sweetening agents, flavoring agents, colorants, or any combination of the foregoing. The pharmaceutical composition of the invention may be formulated so as to provide quick, sustained, or delayed release of the active ingredient after administration to the subject by employing procedures known in the art.
The pharmaceutical compositions described herein may be prepared, e.g., as described in Remington: The Science and Practice of Pharmacy, 20th Ed., 2003 (Lippincott Williams & Wilkins). For example, the active compound can be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier, which may be in the form of an ampoule, capsule, sachet, or other container. When the carrier serves as a diluent, it may be a solid, semi-solid, or liquid material that acts as a vehicle, excipient, or medium for the active compound. The active compound can be adsorbed on a granular solid container, for example, in a sachet.
The pharmaceutical compositions may be, for example, capsules, tablets, aerosols, solutions, suspensions, liquids, gels, or products for topical application.
The route of administration may be any route which effectively transports the active compound to the appropriate or desired site of action. Suitable routes of administration include, but are not limited to, oral, nasal, pulmonary, buccal, subdermal, intradermal, transdermal, parenteral, rectal, depot, subcutaneous, intravenous, intraurethral, intramuscular, intranasal, ophthalmic (such as with an ophthalmic solution) or topical (such as with a topical ointment). The oral route is preferred.
Solid oral formulations include, but are not limited to, tablets, capsules (soft or hard gelatin), dragees (containing the active ingredient in powder or pellet form), troches and lozenges. Tablets, dragees, or capsules having talc and/or a carbohydrate carrier or binder or the like are particularly suitable for oral application. Preferable carriers for tablets, dragees, or capsules include lactose, cornstarch, and/or potato starch. A syrup or elixir can be used in cases where a sweetened vehicle can be employed.
A typical tablet that may be prepared by conventional tabletting techniques may contain: (1) Core: Active compound (as free compound or salt thereof), 250 mg colloidal silicon dioxide (Aerosil®), 1.5 mg microcrystalline cellulose (Avicel®), 70 mg modified cellulose gum (Ac-Di-Sol®), and 7.5 mg magnesium stearate; (2) Coating: HPMC, approx. 9 mg Mywacett 9-40 T and approx. 0.9 mg acylated monoglyceride.
Liquid formulations include, but are not limited to, syrups, emulsions, soft gelatin and sterile injectable liquids, such as aqueous or non-aqueous liquid suspensions or solutions.
For parenteral application, particularly suitable are injectable solutions or suspensions, preferably aqueous solutions with the active compound dissolved in polyhydroxylated castor oil.
Methods of screening
Antiviral HFV activity and cytotoxicity of compounds present invention can be measured in parallel by following the methods published in the literature. The cytotoxic effect of compounds can be analyzed by measuring the proliferation of cells using the 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyl tetrazlium bromide (MTT) staining. Cells (5 x 103 cells /well) will be incubated in in 96 well plates in the presence or absence of compounds. At the end of treatment, 20μl of MTT (5mg/ml in PBS) will be added to each well and incubated for an additional 4 hours at 370C. The purple -blue MTT formazan precipitate will be dissolved in a triplex reagent containing 10% SDS, 5% isobutanol and 10 mmol/lit HCl. The activity of mitochondria, reflecting cellular growth and viability, will be evaluated by measuring the optical density at 570 nm on micro titer plate.
Action of compounds on replication of HIV in Sup-Tl cells can be determined by the method published by Roda Rani et al., 2006 (Archives of
Biochemistry and Biophysics, Volume 456, Issue 1, 1 December 2006, Pages 79- 92).
Briefly, IxIO6 Sup-Tl cells with 100% cell viability will be seeded in RPMI 1640, 0.1% FBS four 12 well plates. Increasing concentrations of Epap-1 peptides will be added to the cells and will be infected with HIVl 93 M joi each at final concentration of virus equivalent to 2 ng of p24 per ml. The infected cells will be incubated at 37 C and 5% CO2 incubator for 2 hours. After 2hrs the cells will be pelleted at 350 g for 10 min, supernatant will be discarded and cell will be held with RPMI 1640 containing 10% FBS. The cells will be resuspended in the same medium with increasing concentrations of Epap-1 peptides and will be incubated for 96 hours. The cells will be supplemented with peptides at every 24 hours.The supernatants will be collected after 96 hours and analyzed using P24 antigen capture assay kit (SAIC Fredrick). The infection in the absence of Epap-1 will be considered to be 0% inhibition Azidothymidine (AZT) will be taken as positive control.
Action of compound on virus entry and quantification of virus entered can be done in terms of GFP expression by the following the methods published J. Virol. 72, 6988 ( 1998) by in Cecilia et al., and Analytical Biochemistry Volume 360, Issue 2, 15 January 2007. Pages 315-317 (Dyavar S. Ravi and Debashis Mitra).
Briefly, cells will be seeded in to wells of 24 well plates 1 day prior to the experiment. The cells will be transfected with Tat-reporter. The virus inoculum will be adjusted to 1,000-4,000 TCED 50/ ml in assay medium (DMEM, 10%FCS,glutamine and antibiotics ), 50 μl aliquots will be incubated with serial dilutions of compounds (50 μl ) for lhr at 37°C. The reporter expression will be quantified at appropriate time calculated inhibitory doses referrers to the concentration of these agents in this preincubation mixture.
Other relevant references useful for screening antiviral HIV activity are: Averett, D. R.1989. Anti-HIV compound assessment by two novel high capacity assays. J. Virol. Methods 23: 263-276; Schwartz, O., et al.1998; A rapid and simple colorimeric test fror the study of anti HIV agents. AEDS Res. and Human Retroviruses, 4(6):441-447; Daluge, S. M., et al. 1994. 5-Chloro-2',3'-deoxy- 3'fluorouridine (935U83), a selective anti human immunodeficiency virus agent with an improved metabolic and toxicological profile; Antimicro. Agents and Chemotherapy, 38(7): 1590-1603; H.Mitsuya and S.Border, Inhibition of the in vitro infectivity and cytopathic effect of human T-lymphotropic virus type lymphadenopathy-associated virus (HLTV-iπ/LAV) by 2,3'-dideoxynucleosides, Proc. Natl. Acad. Sci. USA,83,191 1-15(1986); Pennington et al., Peptides 1990; Meek T. D et al., Inhibition of HIV-I protease in infected T-limphocytes by synthetic peptide analogues, Nature, 343, p90 (1990); Weislow et al., J. Natl. Cancer
Inst. 81, 577-586, 1989; T. Mimoto et al ., J. Med. Chem., 42, 1789-1802, 1999; Uckun et al 1998, Antimicobial Agents and Chemotherapy 42:383; for P24 antigen assay Erice et al., 1993, Antimicrob. Ag. Chemotherapy 37: 385-383; Koyanagi et al., Int. J. Cancer, 36, 445-451, 1985; Balzarini et al. AIDS (1991), 5, 21-28; Connor et al., Journal of virology, 1996, 70, 5306-5311 ; Popik et al., Journal of virology,
2002, 76, 4709-4722; Harrigton et al., Journal of Virology Methods, 2000, 88, 111- 1 15; Roos et al., Virology 2000, 273, 307-315; Fedyuk N.V. et al; Problems of Virology 1992, (3)P135; Mosmann T, December 1983, Journal of immunological methods, 65 (1-2), 55-63 ; SPC Cole, cancer chemotherapy and Pharmacology, 1986, 17, 259-263.
Methods of Treatment
The present invention provides compounds and pharmaceutical formulations thereof that are useful in the treatment of diseases, conditions and/or disorders mediated by viral infections. The connection between therapeutic effect and antiviral is illustrated. For example, PCT publication Nos. WO 01//07646, WO 01/65957, or
WO 03/037908; US publication Nos. US 4,598,095 or US 2002/0068757; EP publication Nos. EP0989862 or EP 0724650; Bioorganic & Medicinal Chemistry Letters, 16, (6), 1712-1715, 2006; and references cited therein, all of which are incorporated herein by reference in their entirety and for the puipose stated. The present invention further provides a method of treating a disease, condition and/or disorder mediated by viral infections in a subject in need thereof by administering to the subject a therapeutically effective amount of a compound or a pharmaceutical composition of the present invention.
Diseases, conditions, and/or disorders that are mediated by viral infections are believed to include, but are not limited to, HIV infection, HBV, HCV, a retroviral infection genetically related to HIV, AIDS, inflammatory disease, respiratory disorders (including adult respiratory distress syndrome (ARDS), bronchitis, chronic bronchitis, chronic obstructive pulmonary disease, cystic fibrosis, asthma, emphysema, rhinitis and chronic sinusitis), inflammatory bowel disease
(including Crohn's disease and ulcerative colitis), multiple sclerosis, rheumatoid arthritis, graft rejection (in particular but not limited to kidney and lung allografts), endometriosis, type I diabetes, renal diseases, chronic pancreatitis, inflammatory lung conditions, chronic heart failure and bacterial infections (in particular but not limited to tuberculosis).
The compounds of the present invention can obtain more advantageous effects than additive effects in the prevention or treatment of the above diseases when using suitably in combination with the above drugs. Also, the administration dose can be decreased in comparison with administration of either drug alone, or adverse effects of co administrated drugs other than antiviral can be avoided or declined.
Methods of Preparation
The compounds described herein may be prepared by techniques known in the art. In addition, the compounds described herein may be prepared by following the reaction sequence as depicted in Scheme- 1 to 6. Further, in the following schemes, where specific bases, acids, reagents, solvents, coupling agents, etc., are mentioned, it is understood that other bases, acids, reagents, solvents, coupling agents etc., known in the art may also be used and are therefore included within the present invention. Variations in reaction conditions, for example, temperature and/or duration of the reaction, which may be used as known in the art, are also within the scope of the present invention. All the stereo isomers of the compounds in these schemes, unless otherwise specified, are also encompassed within the scope of this invention. Compounds of the present invention can be synthesized from naturally occurring Betulinic acid, Ceanothic acid, Moronic acid, or Oleanolic acid. Key intermediates required for synthesizing analogues are either commercially available, or can be prepared by the methods published in the literature. For example, the key intermediates in the present invention were prepared by modifying the procedures published in Journal of organic chemistry 2000, 65, 3934-3940; Tetrahedron: asymmetry 2008, 19, 302-308; or Tetrahedron: asymmetry 2003, 14, 217-223.
Scheme 1
Figure imgf000038_0001
The compound of Formula (7), (wherein, P is a protecting group (for example alkyl or aralkylyl protecting methyl, ethyl, propyl, isopropyl, benzyl or tertiorybutyl) can be prepared as shown in Scheme 1. Commercially available vebinone was oxidized with an oxidizing agent like ruthenium chloride/sodium periodate in a solvent system like CC14-ACN-H2O to give the carboxylic acid of compounds of formula 1. The carboxylic acid of compounds of formula 1 is protected with a protecting agent to give the acid protected compounds of formula 2.
A protecting group is introduced by reacting alkyl halides in the presence of a base like potassium carbonate or cesium carbonate or by reacting a compound of formula 1 with alcohols in the presence of a dehydrating agent like DCC/DMAP or refluxing in the presence of an acid catalyst. A wide range of solvents can be used to conduct this reaction including DMF, THF, DCM, toluene or the like. A compound of the formula 2, on Schmidt rearrangement promoted by treatment with sodium azide and methane sulphonic acid or the like, gives protected amino acid compounds of formula 3. The N-acyl of compounds of formula 3 is hydrogenolysed in the presence of Pd-C/EtOAc or the like to give the N-acyl amino acid of compounds of formula 4. The N-acyl amino acid of compounds of formula 4 can be acid hydrolyzed in the presence of hydrogen chloride or the like and treated with BOC anhydride in the appropriate reagent to give corresponding carbamate, more particularly, the tertiary butyl carbamate of compounds of formula 5. The tertiary butyl carbamate of compounds of formula 5 can be benzylated to give the tertiary butyl carbamate of benzylated compounds of formula 6 in presence of cesium carbonate or the like in the solvents such as DMF or the like. The tertiary butyl carbamate of benzylated compounds of formula 6 can be treated for BOC removal in the presence of TFA in solvents such as, DCM or the like to give the salt of benzylated of compound of formula 7.
Lieben degradation of the methyl ketone functional group of compound of formula 2 by using aqueous sodium hypobromite in the solvent such as, dioxane or the like, furnish compound of formula 8. 2,4,6-trichloro benzoyl ester compound of formula 9 was obtained by reacting benzoylchloride in presence of DIPEA or the like in solvents such as THF, or the like.
cycloburyl]
— is no bond, Z is O, X [ is R2 is iso-propylene, R
Figure imgf000039_0001
Compounds 13 and 14 of general formula (1), (wherein, P, R, R', X and Xi, Z and Zi, Z', n, m, "— -", Ri, R21 R3' and R3", R\ and R" are same as defined above) can be prepared as described in Scheme 2. The steps of providing a triterpene betulinic acid or ceanotheic acid comprising a C-3 alcohol, C-28 and or C2- carboxyl acid of compound 13 or 14 include: reacting a C-3 alcohol with a suitable ester forming reagents like anhydrides, acid halides or mixed anhydrides in the presence of a base like triethyl amine, diisopropyl ethyl mine, or pyridine in an inert solvent like DCM, toluene, THF or a basic solvent like pyridine with or without addition of a catalyst like DMAP. For example a C-3 alcohol of compounds of the formula 10 can be protected by an acetyl group in the presence of acetic anhydride in solvents such as pyridine or the like, to give the C-3 acetyl of compounds of formula 11. Converting the C-3 acetyl compound of formula 11 to C-28 carboxylic halide of formula 12 in presence of acid halides such as thionyl chloride, oxalyl chloride, phosphorous bromide, phosphorous oxy bromide or the like occurs in an inert solvent like benzene or DCM or the like. Reacting a C-28 carboxylic halide of formula 12 with a compound of formula 7 in the presence of triethyl amine or the like occurs in an inert solvent such as DCM or the like to give the compounds of formula 13 [Formula (1), when n and m is 0, " " is no bond, Z is O, X] is NH, Z' and R1 is H, X and Zi is CO, R2 is iso-propylene, R is methyl, and R' is substituted cyclobutyl].
Esterifying a C-3 alcohol of the compound of the formula 10 by reacting with the compound of formula 9 gives a compound of formula 14 [Formula (IA), when ZiA is CO, X) A is O, RA' is H, and RA is substituted cyclobutyl] in presence of a base like triethylamine in the solvents such as DCM or THF.
Scheme 3
Figure imgf000040_0001
The compounds of Formula (21), (wherein, R" is as defined above) can be prepared by following the procedures published as shown in Scheme 1. Commercially available verbenone can be oxidized with an oxidizing agent like ruthenium chloride/sodium periodate in a solvent system like CCI4-ACN-H2O to give the carboxylic acid of compounds of formula 15. Curtius rearrangement with sodium azide or (PhO)2P(O)N3, followed by N-protection affords the N-protected aminoketone of formula 17. A halo form reaction using substrate 17 under NaOBr, dioxane with aq conditions give compounds of formula 18. The acid compounds of formula 18 can be reacted with compounds of formula 19 to give the N-protected compounds of formula 20 in presence of coupling reagents such as l-Ethyl-3-(3- Dimethylaminopropyl)carbodiimide (EDCI), 1-hydroxybenzotrazolehydrate
(HOBT), O-benzotrazol-l-yl-N,N,N',N'-tetramethyluroniumhexafluorophosphate (HBTU) or the like and a base for example, triethylamine, diisopropylethylamine, sodium carbonate, potassium carbonate, or the like in the solvents, for example, ethylactate, dichloromethane, acetonitrile, tetrahydrofuran, dioxane or mixtures thereof. The N-protected compounds of formula 20 can be deprotected to give the deprotected amine compounds of formula 21 in presence of hydrogenating agents such as, for example, Pd-C/EtOAc or the like.
is NH and
Figure imgf000041_0001
Compounds of Formula (G), (wherein, R" is as defined above) can be prepared by following the procedures published as shown in Scheme 4. The acid compounds of formula E can be reacted with compounds of formula 19 to give the
N-protected compounds of formula F in presence of coupling reagents such as 1-
Ethyl-3-(3-Dimethylaminopropyl)carbodiimide (EDCI), 1- hydroxybenzotrazolehydrate (HOBT), O-benzotrazol-l-yl-N,N,N',N'- tetramethyluroniumhexafluorophosphate (HBTU) or the like and a base for example,
DMAP, triethylamine, diisopropylethylamine, sodium carbonate, potassium carbonate, or the like in the solvents, for example, ethylactate, dichloromethane, acetonitrile, tetrahydrofuran, dioxane or mixtures thereof. The N-protected compounds of formula F can be deprotected to give the deprotected amine compounds of formula G in presence of acids such as, for example, trifluoroacetic acid, HCl or the like.
Figure imgf000042_0001
28
The compounds of Formula (28) (Formula (2), when Z2 is O) can be prepared as shown in Scheme 5. The C-3 hydroxy-protected compounds of formula 22 can be converted to C-28 carboxylic halide compounds of formula 23 in presence of acid halides such as thionyl chloride, oxalyl chloride, phosphorous bromide, phosphorous oxy bromide or the like can be performed in an inert solvent like benzene or DCM or the like without added solvent. C-28 carboxylic halide of the C- 3 oxy-protected compounds of formula 23 can be reacted with the amine compounds of formula 24 in the presence of triethyl amine or the like in an inert solvents such as DCM or the like to give the O-protected compounds of formula 25. The O-protected compounds of formula 25 can be hydrolyzed to give the hydroxyl compounds of formula 26 in presence of base such as, for example, metal hydroxides, metal caronates or bicarbonates in MeOH, EtOH or MeOH-THF or the like solvents. The hydroxy compounds of formula 26 can be reacted with acid anhydride compounds, half protected diacids or their mixed anhydrides or acid chlorides of formula 27 to give the final compound of formula 28 [Formula (2), when Z2 is O and Z2' and X2' are C(O)] in the presence a base like triethyl amine, 4-Dimethylaminopyridine, diisopropyl ethyl mine or pyridine or the like in the solvents such as for example, DCM, toluene, THF or the like.
Figure imgf000043_0001
The compounds of Formula (35) (Formula (2A), when XA1 is C(O)) can be prepared by the above procedure as shown in Scheme 6. The C-3 hydroxy-protected compounds of formula 29 can be converted to C-28 carboxylic halide of the C-3 oxy-protected compounds of formula 30 in presence of acid halides such as thionyl chloride, oxalyl chloride, phosphorous bromide, phosphorous oxy bromide or the like can be performed in an inert solvent like benzene or DCM or the like without added solvent. C-28 carboxylic halide of the C-3 oxy-protected compounds of formula 30 can be reacted with the amine compounds of formula 31 in the presence of triethyl amine or the like in an inert solvents such as DCM or the like to give the
O-protected compounds of formula 32. The O-protected compounds of formula 32 can be hydrolyzed to give the hydroxyl compounds of formula 33 by hydrolyzing with a base like metal hydroxide, metal carbonates or bicarbonates and the like in a protic solvent like alcohol or a combination of solvents for example, MeOH :THF or the like. The hydroxyl compounds of formula 33 can be reacted with acid anhydride compounds of formula 34 or partially protected diacids or mixed anhydrides, acid halides to give the final compound of formula (35) (Formula (2A), when XA1 is C(O)) in the presence a base like triethyl amine, 4-Dimethylaminopyridine, diisopropyl ethyl mine or pyridine or the like in the solvents such as for example, DCM, toluene, THF or the like. Experimental
The present invention is further illustrated by the following examples, which are not to be construed in any way as imposing limitations upon the scope of this disclosure, but rather are intended to be illustrative only. On the contrary, it is to be clearly understood that resort may be had to various other embodiments, modifications, and equivalents thereof which, after reading the description herein, may suggest themselves to one of ordinary skill in the art without departing from the spirit of the present invention. Thus, the skilled artisan will appreciate how the experiments and Examples may be further implemented as disclosed by variously altering the following examples, substituents, reagents, or conditions.
Intermediates
Intermediate 1: Synthesis of ( lS,3R)-3-acetyl-2,2-dimethylcyclobutanecarboxylic acid:
Figure imgf000044_0001
A stirred solution of verbenone (about 10 g, 66.57 mmol) in CCl4: ACN:
H2O ( 140 ml) NaIO4 ( 56.9 g, 266.3 mmol) followed by RuCl3-H2O (catalytic) were added at O0C and allowed to stir at room temperature for about 12 hours. After completion of the reaction (monitored by TLC), reaction mixture was diluted with EtOAc (about 200 ml), filtered through celite bed and the organic layer was separated, the aqueous layer extracted with EtOAc (100 ml x 2) combined the organic layers dried with Na2SO4 and concentrated under reduced pressure. The resulting crude was stirred in hexane. Solid was filtered and dried under vacuum (8.56 g). 1H NMR (300 MHZ, CDCl3): δ 2.91-2.77 (m, 2H), 2.63 (q, IH, J = 9Hz), 2.07 (s, 3H), 1.86-1.95 (m, IH), 1.40 (s, 3H), 0.97 (s, 3H). Mass: [M+l]+ 171 (10%), [M+Na]+ 193 (72%). IR (KBr, cm 1): 3218, 1737, 1694, 1467, 1368, 1283, 1174,
1080, 836, 703. M.R: 109.5 0C -120.7 0C.
Intermediate 2j_ Synthesis of_ (lS,3R)-benz.yl 3-acetyl-2,2- dimethylcyclobutanecarboxylate:
Figure imgf000044_0002
A stirred solution of (lS,3R)-3-acetyl-2,2-dimethylcyclobutanecarboxylic acid ( 6.0 g, 35.29 mmol) in DMF ( 20 ml) at O0C, Cs2CO3 (13.8 g, 42.34 mmol)followed by BnBr ( 5.06 ml, 42.34 mmol) were added slowly portion wise. The reaction was stirred at room temperature for about 2 hours. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with EtOAc (100 ml) and washed with water (50 ml), brine (50 ml) and dried with Na2SO4. The solvent was evaporated and purified by silica gel column (60-120, elution 4%
EtOAc in hexane) to afford title compound as a pale yellow syrup. Wt: 5.6 g; Yield: 61.5 %; 1H NMR (300 MHZ, CDCl3): δ 7.42-7.31 (m, 5H), 5.13 (s, 2H), 2.93-2.81 (m, 2H), 2.68 (q, IH, J = 10.5 Hz,), 2.05 (s, 3H)1 1.97-1.88 (m, IH), 1.43 (s, 3H), 0.87 (s, 3H); Mass: [M+l]+ 261(20%), [M+Na]+283 (87%); IR (KBr, cm"1): 2889, 1732, 1708, 1498, 1456, 1329, 1279, 1183, 1027, 954, 752, 698.
Intennediate 3: Synthesis of (lS,3R)-benzyl 3-acetamido-2,2- dimethylcyclobutanecarboxylate:
Figure imgf000045_0001
A stirred solution of (lS,3R)-benzyl 3-acetyl-2,2- dimethylcyclobutanecarboxylate ( 1.5 g, 5.76 mmol) in monoglyme ( 18.75 ml) at - 45° C, NaN3 ( 1.12 g, 17.30 mmol), MeSO3H (10.5 ml), were added drop wise slowly and the reaction was allowed to stir at room temperature for about 48 hours. After completion of the reaction (monitored by TLC), the reaction mixture was neutralized with aqueous ammonia solution. Solvent was evaporated and diluted with DCM.
Organic layer was washed with water, brine dried over Na2SO4. The solvent was evaporated under reduced pressure and the resulting crude purified by silica gel column (60/120mesh, elution: 30% EtOAc in Hexane) to afford the title compound as off white solid. Wt: 1.3 g; Yield: 82.2 %; 1H NMR (300 MHZ, CD3OD): δ 7.42-7.31 (m, 5H), 5.59 (d, IH, J = 5.7 Hz), 5.12 (s, 2H), 4.13 (q, IH, J = 9.3 Hz), 2.69-2.63 (m,
IH), 2.38-2.34 (m, IH), 2.13-2.06 (m, IH), 2.05 (s, 3H), 1.30 (s, 3H), 0.86 (s, 3H). Mass: [M+ 1]+ 276 (100%), [M+Na]+ 298 (66%); ER (KBr, cm"1): 3270, 2963, 2866, 1728, 1647, 1571, 1455, 1303, 1 151, 1071, 1019, 961 , 755, 742; M.R: 85.6 0C -97.5 0C.
Intermediate 4± Synthesis g£ ( lS,3R)-3-acetamido-2,2- dimethylcyclobutanecarboxylic acid;
Figure imgf000046_0001
A stirred solution of (lS,3R)-benzyl 3-acetamido-2,2- dimethylcyclobutanecarboxylate ( 0.650 g, 2.36 mmol) in EtOAc ( 10 ml) at room temperature, 10 % Pd/C (catalytic amount) were added and the reaction mixture was stirred under H2 gas atmosphere at room temperature for about 1 hour. After completion of the reaction (monitored by TLC), the reaction mixture was filtered through celite bed. The obtained filtrate was concentrated under reduced pressure to afford title compound as an off white solid. Wt: 0.240 g; Yield: 54.9%; 1H NMR (300 MHZ, CD3OD): δ 8.09 (d, J = 3.0 Hz, IH), 4.08-3.96 (m, IH), 2.62-2.58 (m, IH), 2.20 -2.15 (m, 2H), 1.93 (s, 3H), 1.26 (s, 3H), 0.92 (s, 3H); Mass: [M+l]+ 186
(70%), [M+Na]+ 208 (93%). IR (KBr, cm"1): 3349, 2962, 1697, 1624, 1557, 1428, 1377, 1257, 1075, 988, 920, 736; M.R: 194.7 0C -216.2 0C.
Intermediate 5: Synthesis of (lS,3R)-3-(tert-butoxycarbonylamino)-2,2- dimethylcvclobutanecarboxylic acid:
Figure imgf000046_0002
A stirred suspension of (lS,3R)-3-acetamido-2,2- dimethylcyclobutanecarboxylic acid ( 0.5 g, 2.702 mmol) in 3N HCl (about 8 ml) was refluxed for about 2 hours. After completion of the reaction (monitored by TLC), the solvent was evaporated and basified (PH = 8-9) with 2N NaOH. Dioxane (3 ml), followed by (Boc)2O (1.24 ml, 5.405 mmol) were added at about 00C. The reaction was allowed to stir at room temperature for about 16 hours. After completion of the reaction (monitored by TLC), the reaction mixture was acidified with IN HCl and extracted with EtOAc, the organic layer was washed with water, brine and dried over Na2SO4. Organic layer was concentrated under reduced pressure then the resulting crude was purified by silica gel column ( 100-200 mesh, elution: 30% EtOAc in Hexane) to afford the title compound as off white solid. Wt: 0.500 g; Yield: 72.6%; 1H NMR (300 MHZ, CD3OD): δ 3.75-3.704 (m, IH), 2.55-2.52 (m, IH), 2.19-2.06 (m, 2H), 1.43 (s, 9H), 1.25 (s, 3H), 0.92 (s, 3H); Mass: [M+Na]+ 266 (100%); IR (KBr, cm' 1): 3300, 3249, 2967, 1701, 1643, 1479, 1403, 1265, 1 159, 1 109, 1029, 858, 778;
M.R: 142.8 0C -149.0 0C. Intermediate 6: Synthesis of (lS,3R)-benzyl 3-(tert-butoxycarbonylamino)-2,2- dimethylcyclobutanecarboxylate:
V o
BocHN— O>— A.
V OBn
A stirred solution of (lS,3R)-3-(teit-butoxycarbonylamino)-2,2- dimethylcyclobutanecarboxylic acid ( 0.5 g, 2.05 mmol) in DMF (about 5 ml),
Cs2CO3 (0.804 g, 2.47 mmol) and BnBr (0.3 ml, 2.47 mmol) were added slowly portion wise at about O0C, then the reaction was stirred at room temperature for about 2 hours. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with EtOAc and washed with water, brine and dried over Na2SO4. The solvent was evaporated and purified by silica gel column (60-120 mesh, elution 4% EtOAc in hexane) to afford title compound as a pale yellow syrup. Wt: 0.35 g; Yield: 51%; 1H NMR (300 MHZ, CDCl3): δ 7.39-7.28 (m, 5H), 5.12 (Brs, 2H), 4.60 (Brs, IH), 3.88-3.79 (m, IH), 2.65-2.53 (m, IH), 2.38-2.27 (m, IH), 2.01-1.99 (m, IH), 1.43 (s, 9H), 1.28 (s, 3H), 0.86 (s, 3H); IR (KBr, cm '):3387, 2962, 1710, 1523, 1456, 1366, 1253, 1173, 1079, 1009, 979, 746, 698.
Intermediate 7: Synthesis of(lS,3R)-benz.yl 3-amino-2,2- dimethylcyclobutanecarboxylate trifluoroacetic acid:
Figure imgf000047_0001
( 1 S,3R)-benzyl-(tert-butoxycarbonylamino)-2,2- dimethylcyclobutanecarboxylate (about 0.210 g, 0.63 mmol) was stirred in TFA:DCM (1 :4) (3 ml) solution at O0C and allowed to reach room temperature in 30 minutes. After completion of the reaction the solvent was evaporated and the crude was dissolved in DCM and basified with Et3N (about 0.26 ml, 1.89 mmol) then the resulting solution used immediately as such for the next reaction.
Intermediate 8: Synthesis of (lSJR)-tert-butyl 3-acetyI-2,2- dimethylcvclobutanecarboxylate:
Figure imgf000047_0002
To a stirred ice cooled solution of (lS,3R)-3-acetyl-2,2- dimethylcyclobutanecarboxylic acid ( 3.0 g, 17.65 mmol) in THF (5 ml), t-BuOH
(5.1 ml. 52.94 mmol) and DMAP (0.036 g, 0.176 mmol) in THF (3 ml) were added followed by DCC (4.4 g, 21.2 mmol) in dry THF (2 ml) was added slowly. Then the reaction was stirred at room temperature for about 36 hours. After completion of the reaction (monitored by TLC), the reaction mixture was filtered through a celite bed and washed with DCM. The filtrate was washed with 5% HCl, water, aqueous NaHCO3 and dried over Na2SO4. The solvent was evaporated and purified by silica gel column (60-120, elution 10% EtOAc in hexane) to afford title compound as a pale yellow syrup. Wt: 2.4 g; Yield: 60 %; 1H NMR (300 MHZ, CDCl3): δ 2.84 (m, IH), 2.70-2.51 (m, 2H), 2.06 (s, 3H), 1.89-1.80 (m, IH), 1.41 (s, 12H), 0.93 (s, 3H); Mass: [M+Na]+ 249 (100%).
Intennediate 9: Synthesis of (lR,3S)-3-(tert-butoxycarbonyl)-2,2- dimethylcyclobutanecarboxylic acid
Figure imgf000048_0001
A stirred solution of (lS,3R)-tert-butyl 3-acetyl-2,2- dimethylcyclobutanecarboxylate (2.4 g, 10.62 mmol) in dioxane (270 ml) aqueous NaOBr solution (about 180 ml) was added slowly at about O0C and stirred at the same temperature for about 3 hours then allowed to stirred at room temperature for about 4 hours (the yellow colored solution turned to white color). After completion of the reaction (monitored by TLC), the reaction mixture was washed with methyl t- butyl ether (3 x 150 ml), the aqueous layer was adjusted pH (2-3) with IN HCl and the aqueous layer was extracted with EtOAc and dried over Na2SO4 and the solvent was evaporated to afford title compound as an off white liquid. Wt: 1.9 g; Yield: 78 %; 1H NMR (300 MHZ, CDCl3): δ 2.82-2.67 (m, 2H), 2.57-2.50 (m, IH), 2.04-1.98 (m, IH), 1.42 (s, 9H), 1.34 (s, 3H), 1.05 (s, 3H); IR (KBr, cm"1): 3205, 1731, 1694,
1460, 1371, 1236, 1 157, 1108, 846, 721 ; Mass: [M+Na]+ 251 (40%).
Intennediate 10: Synthesis of (lR,3S)-3-(tert-butoxycarbonyl)-2,2- dimethylcyclobutanecarboxylic 2, 4, 6-trichlorobenzoic anhydride
Figure imgf000048_0002
To a stirred solution of (lR,3S)-3-(tert-butoxycarbonyl)-2,2- dimethylcyclobutanecarboxylic acid (about 0.450 g, 1.97 mmol) and DIPEA (about 1.01 ml, 5.92 mmol) in THF (about 4 ml) and 2,4,6-trichloro benzoyl chloride (0.35 ml, 2.17 mmol) were added at 00C and the reaction mixture was allowed to stir at room temperature for about 6 hours, after completion of the reaction (monitored by TLC), the solvent was evaporated and crude product proceeded as such for the next reaction.
Intermediate LJj Synthesis of. ((lR,3S)-3-amino-2,2- dimethylcvclobutyl)(morpholino)methanone:
Figure imgf000049_0001
Step 1: Synthesis of ( 1 S,3R)-3-acetyl-2,2-dimethyIcyclobιιtanecarbonyl azide:
Figure imgf000049_0002
A stirred solution of (lS,3R)-3-acetyl-2,2-dimethylcyclobutanecarboxylic acid (1.0 g, 5.88 mmol) in acetone (20 ml), Et3N (1.6 ml, 1 1.76 mmol) and ethyl chloroformate (1.12 ml, 1 1.76 mmol) were added slowly by portion wise at about 0 0C and stirred for about 3 hours. After completion of the reaction (monitored by
TLC), NaN3 (0.84 g, 12.93 mmol) dissolved in minimum amount of water was added to reaction mixture at 0 0C and the reaction mixture was allowed to stir at room temperature for about 1.5 hours. After completion of the reaction (monitored by TLC), the reaction mixture was extracted with DCM and washed with water, brine and dried over Na2SO4 and benzyl alcohol (0.95 ml, 8.82 mmol) then the solvent was evaporated and the crude product was processed for next reaction immediately without characterization (considering as 100% yield proceeded for next reaction). Crude wt: 1.147 g (100% yield). Step 2: Synthesis of benzyl (lS,3R)-3-acetyl-2,2-dimethylcyclobutylcarbamate:
<κ V-/ X V-NHCbz
A stirred solution of (lS,3R)-3-acetyl-2,2-dimethylcyclobutanecarbonyl azide
(Step 1, 1.147 g, 5.88 mmol) in toluene (20 ml) benzyl alcohol (0.95 ml mmol, 8.82 mmol) was added at room temperature and stirred at reflux temperature for about 4 hours. After completion of the reaction (monitored by TLC), the solvent was evaporated under reduced pressure and the resulting crude was purified by silicagel column (60/120 mesh, elution: 5% EtOAc in Hexane) to afford the title compound as a liquid. Wt: 1.3 g; Yield: 81.2 %; 1H NMR (300 MHz, CDCl3): δ 7.38-7.29 (m, 5H), 5.08 (q, 2H, 7 = 12 Hz), 4.80 (d, IH, J = 8.0 Hz), 3.92 (q, IH, J = 9.3 Hz), 2.77-2.71 (m, IH), 2.16-2.08 (m, IH), 2.07 (s, 3H), 1.40 (s, 3H), 0.82 (s, 3H); Mass: [M+l]+ 276
(10%), [M+Na]+ 298 (100%); IR (KBr, cm 1): 3338, 2956, 2927, 1703, 1648, 1530, 1460, 1370, 1282, 1254, 1 183, 1042, 944.
Step 3: Synthesis of (lR,3S)-3-(benzyloxycarbonylamino)-2,2- dimethylcyclobutanecarboxylic acid:
Figure imgf000050_0001
To a stirred solution of benzyl (lS,3R)-3-acetyl-2,2- dimethylcyclobutylcarbamate (Step 2, 1.3 g, 4.72 mmol) in dioxane (90 ml): water (30 ml) aq. NaOBr solution (80 ml) was added slowly at about -5 0C and stirred at the same temperature for about 5 hours. After completion of the reaction (monitored by TLC), the reaction mixture was washed with methyl t-butyl ether and the aqueous layer was adjusted pH (2-3) with IN HCl and extracted with EtOAc, dried over Na2SO4 and the solvent was evaporated then the resulting crude was purified by silica gel column (100-200 mesh, elution: 20% EtOAc in Hexane) to afford the title compound as a semi solid. Wt: 1.2 g: Yield: 92%; 1H NMR (300 MHZ, CDCl3): δ
7.38-7.31 (m, 5H), 5.09 (q, 2H, J = 10.8 Hz), 4.89 (d, IH, J = 8.4 Hz), 3.98-3.89 (m, IH), 2.64-2.53 (m, IH), 2.51-2.26 (m, 2H), 1.32 (s, 3H), 0.98 (s, 3H).
IR (KBr, cm"1): 341 1, 3351, 2961, 1705, 1532, 1456, 1412, 1343, 1256, 1044, 1003, 776, 697; Mass: [M+Na]+ 300 (100%).
NaOBr solution: A solution of NaOH (9.4 g, 233.6 mmol) in H2O (180 ml) Br2 (3.3 ml, 63.72 mmol) was added at 0 0C slowly, the yellow colored NaOBr solution formed which was used immediately for the reaction.
Step 4: Synthesis of benzyl (lS,3R)-2,2-dimethyl-3-(morpholine-4- carbonyl)cyclobutylcarbamate:
Figure imgf000050_0002
To a stirred solution of (lR,3S)-3-(benzyloxycarbonylamino)-2,2- dimethylcyclobutanecarboxylic acid (Step 3, 0.9 g, 3.25 mmol) in DCM (5 ml) EDCI (0.747 g, 3.89 mmol) and HOBt (0.527 g, 3.89 mmol) were added at about 0 0C, after 10 minutes morpholine (0.6 ml, 6.5 mmol) and Et3N (2.3 ml, 16.26 mmol) were added drop wise and the reaction mixture was stirred at room temperature for about 8 hours. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with DCM and washed with water, saturated NaHCO3 solution, water, IN HCl, water and saturated brine and the organic layer was concentrated under reduced pressure, the resulting crude purified by silica gel column (100-200 mesh, elution 90% EtOAC in hexane) to afford the title compound as a syrup. Wt:
0.6 g; Yield: 53.4%; 1H NMR (300 MHz, CD3OD): δ 7.40-7.22 (m, 5H), 5.19 (d, IH, J = 8.7 Hz), 5.08 (q, 2H, J = 12.0 Hz), 3.95 (q, IH, J = 9.0 Hz), 3.79-3.38 (m, 8H), 2.80 (t, IH, J = 8.4 Hz), 2.49-2.35 (m, IH), 2.34-2.20 (m, IH), 1.33 (s, 3H), 0.89 (s, 3H); Mass: : [M+l]+ 347 (10%), [M+Na]+ 346 (100%).
Step 5: Synthesis of ((lR,3S)-3-amino-2,2- dimethylcyclobutyl)(morpholino)methanone:
Figure imgf000051_0001
To a stirred solution of benzyl ( lS,3R)-2,2-dimethyl-3-(morpholine-4- carbonyl)cyclobutylcarbamate (step 4, 0.60 g, 1.73 mmol) in EtOAc (10 ml) 10 %
Pd/C (catalytic amount) was added at room temperature and the reaction mixture was stirred under H2 gas atmosphere at room temperature for about 12 hours. After completion of the reaction (monitored by TLC) the reaction mixture was filtered through a celite bed, the obtained filtrate was concentrated under reduced pressure to afford free amine as a liquid which was proceeded as such for the next reaction without characterization. Wt: 0.331 g: Yield: 90%.
Intermediate 12: Synthesis of ((lR,3S)-3-amino-2,2-dimethylcyclobutyl)(piperidin- l-yl)methanone:
Figure imgf000051_0002
Step 1: Synthesis of benzyl (lS,3R)-2,2-dimethyl-3-(piperidine-l- ca rbonyl)cyclobutylca rbama te:
Figure imgf000052_0001
To a stirred solution of (lR,3S)-3-(benzyloxycarbonylamino)-2,2- dimethylcyclobutanecarboxylic acid (Intermediate 1-Step 3, 0.650 g, 2.346 mmol) in
DCM (5 ml) EDCI (0.674 g, 3.519 mmol) and HOBt (0.475 g, 3.519 mmol) were added at 0 0C, after 10 minutes piperidine (0.46 ml, 4.692 mmol) and Et3N (0.65 ml, 4.692 mmol) were added drop wise and the reaction mixture was stirred at room temperature for about 12 hours. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with DCM and washed with water, saturated
NaHCO3 solution, water, IN HCl, water and saturated brine and the organic layer was concentrated under reduced pressure. The resulting crude was purified by a silica gel column (100-200 mesh, elution 20% EtOAC in hexane) to afford the title compound as an off white solid. Wt: 0.393 g; Yield: 48.6%; 1H NMR (300 MHz, CDCl3): δ 7.40-7.28 (m, 5H), 5.18-4.99 (m, 3H), 3.97-3.87 (m, IH), 3.77-3.67 (m,
IH), 3.49-3.28 (m, 3H), 2.83 (t, IH, J = 8.4 Hz), 2.47-2.20 (m, 2H), 3.65-3.41 (m, 6H), 1.35 (s, 3H), 0.87 (s, 3H); Mass: : [M+l]+ 345 (10%), [M+Na]+ 367 (100%); IR (KBr, cm"1): 3315, 3013, 2931, 2855, 1719, 1622, 1534, 1443, 1369, 1255, 1236, 1219, 1 125, 1040, 853, 746, 697; M.R: 145.2 0C -150.8 0C.
Step 2: Synthesis of ((lR,3S)-3-amino-2,2-dimethylcyclobutyl)(piperidin-l- yl)methanone:
Figure imgf000052_0002
10 % Pd/C (catalytic amount) was added to a stirred solution of benzyl (lS,3R)-2,2-dimethyl-3-(piperidine-l-carbonyl)cyclobutylcarbamate (step 1, 0.393 g, 1.14 mmol) in EtOAc (10 ml) at room temperature and the reaction mixture was stirred under H2 gas atmosphere at room temperature for about 12 hours. After completion of the reaction (monitored by TLC) the reaction mixture was filtered through celite bed, the obtained filtrate was concentrated under reduced pressure to afford free amine as a liquid which was proceeded as such for next reaction without characterization. Wt: 0.230 g: Yield: 95%. Intermediate 13: Synthesis of ((lR,3S)-3-amino-2,2-dimethylcvclobutyl)(pyrrolidin- l-yl)methanone:
Figure imgf000053_0001
Step 1: Synthesis of benzyl (lS,3R)-2,2-dimethyl-3-(pyrrolidine-l- carbonyl)cyclobutylcarbamate:
CbzHN— <T y—*(
To a stirred solution of (lR,3S)-3-(benzyloxycarbonylamino)-2,2- dimethylcyclobutanecarboxylic acid (Intermediate 1-Step 3, 0.650 g, 2.346 mmol) in DCM (5 ml) EDCI (0.674 g, 3.519 mmol) and HOBt (0.475 g, 3.519 mmol) were added at about 0 0C, after 10 minutes pyrrolidine (0.40 ml, 4.692 mmol) and Et3N (0.65 ml, 4.692 mmol) were added drop wise and the reaction mixture was stirred at room temperature for about 12 hours. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with DCM and washed with water, saturated NaHCO3 solution, water, IN HCl, water and saturated brine and the organic layer was concentrated under reduced pressure, the resulting crude purified by silica gel column (100-200 mesh, elution 20% EtOAC in hexane) to afford the title compound as an off white solid. Wt: 0.600 g; Yield: 77.5%; 1H NMR (300 MHz, CDCl3): δ 7.40-7.28 (m, 5H), 5.18-4.99 (m, 3H), 3.97-3.87 (m, IH), 3.77-3.67 (m, IH), 3.49-3.28 (m, 3H), 2.83 (t, IH, J = 8.4 Hz), 2.47-2.20 (m, 2H), 3.65-3.41
(m, 6H), 1.35 (s, 3H), 0.87 (s, 3H); Mass: : [M+ 1]+ 331 (20%), [M+Na]+ 353 (100%); IR (KBr, cm"1): 3304, 3035, 2954, 1716, 1618, 1529, 1497, 1439, 1387, 1368, 131 1, 1253, 1222, 1 159, 1041, 912, 753. Step 2: Synthesis of ((lR,3S)-3-amino-2,2-dimethylcyclobutyl)(pyrroJidin-l- yl)methanone:
Figure imgf000053_0002
To a stirred solution of benzyl (lS,3R)-2,2-dimethyl-3-(pyrrolidine-l- carbonyl)cyclobutylcarbamate (Step 1, 0.600 g, 1.818 mmol) in EtOAc (10 ml) 10 % Pd/C (catalytic amount) was added at room temperature and the reaction mixture was stirred under H2 gas atmosphere at room temperature for about 12 hours. After completion of the reaction (monitored by TLC), the reaction mixture was filtered through a celite bed, the obtained filtrate was concentrated under reduced pressure to afford free amine as a liquid which was processed as such for the next reaction without characterization. Wt: 0.282 g: Yield: 80%.
Intermediate 14: Synthesis of ((lS,3R)-3-amino-2,2- dimethylcvclobutyl)(morpholino)methanone:
Figure imgf000054_0001
Step 1: Synthesis of tert-butyl (lR,3S)-2,2-dimethyl-3-(morpholine-4- carbonyljcyclobutylcarbamate:
Figure imgf000054_0002
To a stirred solution of (lS,3R)-3-(tert-butoxycarbonylamino)-2,2- dimethylcyclobutanecarboxylic acid (Intermediate 1-Step 3, 0.3 g, 1.23 mmol) in DCM (5 ml) EDCI (0.237 g, 1.23 mmol) and HOBt (0.167 g, 1.23 mmol) were added at about 0 0C, after 10 minutes morpholine (0.2 ml, 2.469 mmol) and Et3N
(0.9 ml, 6.2 mmol) were added drop wise and the reaction mixture was stirred at room temperature for about 16 hours. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with DCM and washed with water, saturated NaHCO3 solution, water, IN HCl, water and saturated brine and the organic layer was concentrated under reduced pressure, the resulting crude purified by a silica gel column (100-200 mesh, elution 90% EtOAC in hexane) to afford the title compound as a syrup. Wt: 0.205 g; Yield: 53.1%; 1H NMR (300 MHz, CDCl3): 5 4.75 (d, IH, J = 8.4 Hz), 3.90-3.40 (m, 8H), 2.83-2.74 (m, IH), 2.40-2.21 (m, 2H), 1.43 (s, 9H), 1.32 (s, 3H), 0.89 (s, 3H).
Step 2: Synthesis of ((lS,3R)-3-amino-2,2- dimethylcyclobutyl)(morphoHno)methanone:
Figure imgf000054_0003
Tert-butyl (lR,3S)-2,2-dimethyl-3-(morpholine-4- carbonyl)cyclobutylcarbamate (Step 1, 0.260 g, 0.833 mmol) was taken in TFA:
DCM (1 :4) (3 ml) at 0 °C-room temperature and stirred for 1 hour. After completion of the reaction the solvent was evaporated and the crude dissolved in DCM and basified with Et3N (0.7 ml, 5.0 mmol). The resulting solution as such used for next reaction immediately. Wt: 0.176 g. Intermediate 15: Synthesis of (lS,3R)-3-(benzyIoxycarbonyl)-2,2- dimethylcvclobutanecarboxylic acid:
Figure imgf000055_0001
Step 1: synthesis of (lS,3R)-tert-butyl 3-acetyl-2,2-dimethylcyclobutanecarboxylate:
Figure imgf000055_0002
To a stirred ice cooled solution of (lS,3R)-3-acetyl-2,2- dimethylcyclobutanecarboxylic acid (16.0 g, 94.1 17 mmol) in THF (160 ml) DMAP (1.148 g, 9.409 mmol) and DCC (23.265 g, 1 12.93 mmol) were added .followed by t-butyl alcohol (27.63 ml, 282.34 mmol) was added drop wise. The reaction mixture was stirred at room temperature for 36 hours. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with EtOAc and filtered through a celite bed and washed with EtOAc. The filtrate was as such concentrated and purified by silica gel column (100-200 mesh, elution 10% EtOAc in hexane) to afford the title compound as a solid. Wt: 15.0 g: Yield: 70%; 1H NMR (300 MHz, CDCl3): δ 2.86-2.74 (m, IH), 2.70-2.50 (m, 2H), 2.04 (s, 3H), 1.89-1.78 (m, IH), 1.42, 1.40 (2s, 12H), 0.91 (s, 3H); Mass: [M+Na]+ 249 (100%).
Step 2: Synthesis of ( 1 R,3S)-3-(tert-butoxycarbonyl)-2 ,2- dimethylcyclobutanecarboxylic acid:
Figure imgf000055_0003
A stirred solution of (IS ,3R)-tert-butyl 3-acetyl-2 ,2- dimethylcyclobutanecarboxylate (step 1, 15.0 g, 66.371 mmol) in dioxane (1450 ml), aq. NaOBr solution (920 ml) was added slowly drop wise at about 0 0C and stirred for about 3 hours and again stirred at room temperature for about 4 hours. After completion of the reaction (monitored by TLC), the reaction mixture was washed with methyl t-butyl ether. The aqueous layer was adjusted pH (2-3) with IN
HCl and extracted with EtOAc, the organic layer was washed with water and brine, dried over Na2Sθ4..The solvent was evaporated to afford the title acid as an off white solid. Wt: 7.2 g: Yield: 47.5 %; 1H NMR (300 MHz, CDCl3): δ 2.83-2.68 (m, 2H), 2.59-2.48 (m, IH), 2.08-1.97 (m, IH), 1.44 (s, 9H), 1.34 (s, 3H), 1.06 (s, 3H); IR (KBr, cm"1): 3207, 2873, 1731, 1694, 1472, 1462, 1371, 1312, 1286, 1251, 1179, 1157, 1108, 1090, 1017, 904, 846, 742, 721, 620; Mass: [M+Na]+ 251 (100%); M.R:
1 19.1-123.00C.
NaOBr solution: A solution of NaOH (57.0 g, 1426.9 mmol) in H2O (910 ml), Br2 (19 ml, 371.6 mmol) were added at 0 0C slowly, the yellow colored NaoBr solution formed which was used immediately for the reaction.
Step 3: Synthesis of (1R,3S)-1 -benzyl 3-tert-butyl 2,2-dimethylcyclobutane- 1 ,3- dicarboxylate:
Figure imgf000056_0001
To a stirred solution of (lR,3S)-3-(tert-butoxycarbonyl)-2,2- dimethylcyclobutanecarboxylic acid (step 2, 0.200 g) in DMF (5 ml) Cs2CO3 (0.371 g) was added at about O0C under nitrogen atmosphere. After 30 minutes, BnBr (0.11 ml) was added by drop wise to the reaction mixture and stirred for about 2 hours at room temperature. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was washed with brine, dried over MgSO4 and concentrated under reduced pressure to give crude product which upon column chromatography afforded the title compound (150 mg, 53.9 % Yield). 1H NMR (300 MHz, CDCl3): δ 7.37-7.34 (5H, m), 5.12 (2H, d, J = 3.9 Hz), 2.80 (IH, t, J = 8.1 Hz), 2.768-2.52 (2H, m), 2.0 (IH, m), 1.44 (9H, m), 1.32 (3H, s), 0.953 (3H, s); Mass: [M+Na]+ 341.2 (100%).
Step 4: Synthesis of (lS,3R)-3-(benzyloxycarbonyl)-2,2- dimethylcyclobutanecarboxylic acid:
BnO ^ OH
To a solution of (IR, 3S)-I -benzyl 3-tert-butyl 2,2-dimethylcyclobutane- 1,3- dicarboxylate (step 3, 1.0 g) dioxane-HCl (10 ml) was added at about O0C under nitrogen atmosphere. The reaction mixture was stirred for about 12 hours at room temperature. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure to give crude product, which upon column chromatography to afford the title compound (800 mg, 97.2 % Yield). 1H NMR (300 MHz, CDCl3): δ 7.35 (5H, s), 5.12 (2H, d, J = 2.7 Hz), 2.84 (2H, m), 2.63 (IH, m), 2.0 (IH, m), 1.35 (3H, s), 0.99
(3H, s); Mass: [M+H]+ 263.1 (20%), 285.1 [M+Na]+.
Intermediate 16: Synthesis of 3-(morpholinornethyl)cyclopentanamine:
Figure imgf000057_0001
Step 1: Synthesis of tert-butyl (lS,4R)-4-(hydroxymethyl)cyclopent-2- enylcarbamate:
Figure imgf000057_0002
To a stirred solution of ((lS,4R)-4-aminocyclopent-2-enyl)methanol 2,3- dihydroxysuccinate salt (about 10.0 g, 38.02 mmol) in THF ( 100 ml) sodium carbonate (about 6.38 g, 76.04 mmol) was added at room temperature and cooled to about 0 0C. After ten minutes, di-tert-butyl dicarbonate (about 9.1 g, 41.82) was added and stirred the reaction at room temperature for about 12 hours. Completion of the reaction monitored by TLC. Reaction mixture was diluted with water and extracted with DCM, the organic layer was dried over Na2SO4 and concentrated under reduced pressure to furnish the title compound (1 1.5 g) as light yellow liquid.
ES Mass: 213 [M+ 1] 214(100%).
Step 2: Synthesis of tert-butyl (lR,3S)-3-(hydroxymethyl)cyclopentylcarbamate:
Figure imgf000057_0003
To a stirred solution of tert-butyl (lS,4R)-4-(hydroxymethy!)cyclopent-2- enylcarbamate (step 1, about 10.0 g) in ethanol ( 150 ml) 10 % palladium on carbon (about 1.0 g ) was added and kept under hydrogen atmosphere. Reaction mass was stirred for about 16 hours. Completion of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through high-flow bed and washed with ethanol. The filtrate was concentrated under reduced pressure to furnish the title compound (7.5 g) as a light yellow liquid. ES Mass: 215 [M+l] 216(100%).
Step 3: Synthesis of (( 1 S,3R)-3-(tert-butoxycarbonylamino)cyclopentyl)methyl 4- methylbenzenesulfonate:
Figure imgf000058_0001
To a stirred solution of tert-butyl (lR,3S)-3- (hydroxymethyl)cyclopentylcarbamate (Step 2, about 4.5 g, 21.12 mmol) in DCM (50 ml), triethyl amine (about 9.5 ml, 68.1 mmol) was added at room temperature and cooled to about 0 0C. After ten minutes, 4-methylbenzene-l-sulfonyl chloride
(about 6.0 g) was added and stirred the reaction at room temperature for about 6 hours. Completion of the reaction was monitored by TLC. The reaction mixture was neutralized with saturated NaHCO3 and extracted with DCM, the organic layer was dried over Na2SO4 and concentrated under reduced pressure to furnish the title compound (5.5 g) as light yellow liquid. IH NMR (300 MHz, CDC13): 1.45 (s, 9H);
246-2.55 (m, 4H); 2.90-2.91 (m, IH); 3.95-3.98 (m, 2H); 4.59-4.70 (m, 2H); 5.66- 5.77 (m, 2H); 7.34-7.37 (d, J=9Hz, 2H); 7.77-7.80 (d, J=9Hz, 2H); ES Mass: 369 [M+l] 370(100%). Step 4: Synthesis of tert-butyl (lR,3S)-3-(morpholinomethyl)cyclopentylcarbamate:
Figure imgf000058_0002
To a stirred solution of ((lS,3R)-3-(tert- butoxycarbonylamino)cyclopentyl)methyl 4-methylbenzenesulfonate (step 3, about 0.5 g) in DCM (50 ml), potassium carbonate (about 0.3 g) was added at room temperature and cooled to about 0 0C. After ten minutes, morpholine (1 ml) was added and stirred the reaction at room temperature for about 6 hours. Completion of the reaction was monitored by TLC. The reaction mixture was neutralized and extracted with DCM, the organic layer was dried over Na2SO4 and concentrated under reduced pressure to furnish the title compound (0. 60 g) as a light yellow liquid. IH NMR (300 MHz, CDC13): 1.24 -1.29 (m, IH); 1.39-1.40 (s, 9H); 2.29- 2.60 (m, 7H); 2.79-2.80 (m, IH); 3.70-3.73 (m, 4H); 4.63 (S, IH); 5.37-5.39 (d, J=6Hz, IH); 5.72-5.81 (m, 2H); ES Mass:283 (100%) [M+l].
Step 5: Synthesis of(lR,3S)-3-(morpholinomethyl)cyclopentanamine:
Figure imgf000059_0001
Tert-butyl (lR,3S)-3-(morpholinomethyl)cyclopentylcarbamate (Step 4, 0.6) was treated with trifluroacetic acid (2 ml) and the obtained compound of 3- (morpholinomethyl)cyclopentanamine was used directly for synthesizing final compounds given in example section without further purification.
Intermediate 17: Synthesis of (lS,4R)-4-(moφholinomethyl)cyclopent-2-enamine:
Figure imgf000059_0002
Step 1: Synthesis of ((lR,4S)-4-(tert-butoxycarbonylamino)cyclopent-2-enyl)methyl 4-methylbenzenesulfonate:
Figure imgf000059_0003
To a stirred solution of tert-butyl (lS,4R)-4-(hydroxymethyl)cyclopent-2- enylcarbamate (Intermediate 6-step 2, about 4.5 g, 21.12 mmol) in DCM (50 ml) triethyl amine (about 9.5 ml, 68.1 mmol) was added at room temperature and cooled to about 0 0C. After ten minutes, 4-methylbenzene-l-sulfonyl chloride (about 6.0 g) was added and stirred the reaction at room temperature for about 6 hours and completion of the reaction was monitored by TLC. Reaction mixture was neutralized with saturated NaHCO3 and extracted with DCM, the organic layer was dried over Na2SO4 and concentrated under reduced pressure to furnish the title compound (5.5 g) as a light yellow liquid. 1H NMR (300 MHz, CDCl3): 1.45(s,9H); 246-2.55 (m,4H) ; 2.90-2.91 (m,lH); 3.95-3.98 (m,2H); 4.59-4.70 (m,2H); 5.66-5.77 (m,2H);
7.34-7.37 (d,J=9Hz,2H); 7.77-7.80 (d,J=9Hz,2H).
Step 2: Synthesis of tert-butyl (IS, 4R)-4-(morpholinomethyI ) cyclopent-2- envlcarbamate:
Figure imgf000060_0001
To a stirred solution of ((lR,4S)-4-(tert-butoxycarbonylamino)cyclopent-2- enyl)methyl 4-methylbenzenesulfonate (step 1, about 0.5 g) in DCM (50 ml) potassium carbonate (about 0.3 g) was added at room temperature and cooled to about 0 0C. After ten minutes, morpholine (3 ml) was added and stirred the reaction at room temperature for about 6 hours then completion of the reaction monitored by TLC. The reaction mixture was neutralized and extracted with DCM, the organic layer was dried over Na2SO4 and concentrated under reduced pressure to furnish the title compound (0.5 g) as light yellow liquid. 1H NMR (300 MHz, CDCl3 : 1.24 -1.29 (m,lH); 1.39-1.40 ( s,9H); 2.29-2.60 (m.7H); 2.79-2.80 (m,lH); 3.70-3.73 (m, 4H);
4.63 (S,1H); 5.37-5.39 (d,J=6Hz,lH);5.72-5.81 (m,2H); ES Mass:283 (100%), [M+l].
Step 3: Synthesis of ( 1 S,4R)-4-(morpholinomethyl)cyclopent-2-enamine:
Figure imgf000060_0002
Tert-butyl (lR,3S)(moφholinomethyl)cyclopentylcarbamate (step 2) was treated with trifluroacetic acid and the obtained compound of (lS,4R)-4- (morpholinomethyl)cyclopent-2-enamine was used directly for synthesizing the final compounds in the example section without further purification.
Intermediate 3_8j Synthesis of ( 1 R,3S)-3-((4-benzylpiperidin- 1 - yloxy)methyl)cyclopentanamine:
Figure imgf000060_0003
Step 1: Synthesis of ((lS,3R)-3-{tert-butoxycarbonylamino)cyc\opentyl)methyl 4- methylbenzenesulfonate:
Figure imgf000060_0004
To a stirred solution of N-((1R, 3S)-3-(hydroxymethyl) cyclopentyl)-3, 3- dimethylbutanamide (Intermediate 16-step 2, 4.5 g, 21.12. mmol) in DCM (50 ml) triethyl amine (about 9.5 ml, 68.1 mmol) was added at room temperature and cooled to about 0 0C. After ten minutes, 4-methylbenzene-l-sulfonyl chloride (about 6.0 g) was added and stirred the reaction at room temperature for about 6 hours and completion of the reaction was monitored by TLC. Reaction mixture was neutralized with saturated NaHCO3 and extracted with DCM, the organic layer was dried over
Na2SO4 and concentrated under reduced pressure to furnish the title compound (5.5 g) as a light yellow liquid. 1H NMR (300 MHz, CDCl3): 1.45 (s, 9H); 2.46-2.55 (m, 4H); 2.90-2.91 (m, IH); 3.95-3.98 (m, 2H); 4.59-4.70 (m, 2H); 5.66-5.77 (m, 2H); 7.34-7.37 (d, J=9Hz, 2H); 7.77-7.80 (d, J=9Hz, 2H).
Step 2: Synthesis of tert-butyl (lR,3S)-3-((4-benzylpiperidin-l- yl)methyl)cyclopentylcarbamate
Figure imgf000061_0001
To a stirred solution of ((lR,4S)-4-(tert-butoxycarbonylamino)cyclopent-2- enyl)methyl 4-methylbenzenesulfonate (step 1, about 0.5 g) in DCM (50 ml), potassium carbonate (about 0.3 g) was added at room temperature and cooled to about 0 0C. After ten minutes, 4-benzylpiperidine (0.17g) was added and stirred the reaction at room temperature for about 6 hours .Completion of the reaction was monitored by TLC. The reaction mixture was neutralized and extracted with DCM, the organic layer was dried over Na2SO4 and concentrated under reduced pressure to furnish the title compound (0.45 g) as light yellow liquid. 1H NMR (300 MHz, CDCl3 : 1.24 -1.29 (m, IH); 1.39-1.40 (s, 9H); 2.29-2.60 (m, 7H); 2.79-2.80 (m, IH); 3.70-3.73 (m, 4H); 4.63 (S, IH); 5.37-5.39 (d, J=6Hz, IH); 5.72-5.81 (m, 2H). Step 3: Synthesis of (lR,3S)-3-((4-benzylpiperidin-l- yloxy)methyl)cyclopentanamine:
Figure imgf000061_0002
N-(( lR,3S)-3-((4-benzylpiperidin-l-yloxy)methyl)cyclopentyl)-3,3- dimethylbutanamide (step 2, 0.5g) was treated with trifluroacetic acid (3ml) and the obtained compound of (lR,3S)-3-((4-benzylpiperidin-l- yloxy)methyl)cyclopentanamine (0.25g) was used directly for synthesizing final compounds in the example section without further purification.
Intermediate 19: Synthesis of (lR,3S)-3-((4-ethylpiperazin-l-yl) methvDcyclopentanamine:
Figure imgf000062_0001
Step 1: Synthesis of tert-butyl (lR,3S)-3-((4-ethylpiperazin-l- yl)methyl)cyclopentylcarbamate:
Figure imgf000062_0002
To a stirred solution of ((lS,3R)-3-(tert- butoxycarbonylamino)cyclopentyl)methyl 4-methylbenzenesulfonate (Intermediate 18-step 2, about 0.5g) in DCM (50 ml) potassium carbonate (about 0.3 g) was added at room temperature and cooled to about 0 0C. After ten minutes, 1 -ethyl piperazine (0.23g) was added and stirred the reaction at room temperature for about 6 hours then completion of the reaction monitored by TLC. The reaction mixture was neutralized and extracted with DCM, the organic layer was dried over Na2SO4 and concentrated under reduced pressure to furnish the title compound (0.3 g) as a pale yellow solid. 1H NMR (300 MHz, CDCl3 : 1.09 -1.24 (m, 3H); 1.39 (s, 9H); 2.29- 2.60 (m, 4H); 2.79-2.80 (m, 10H); 3.06-3.18 (m, 6H); 3.70-3.73 (m, IH); ES Mass:
312 (100%) [M+l].
Step 2: Synthesis of ( 1 R,3S)-3-((4-ethylpiperazin- 1 -yl) methyljcyclopentanamine:
N-((lR,3S)-3-((4-ethylpiperazin- l-yl)methyl)cycloρentyl)-3,3- dimethylbutanamide (step 1, 0.5 g) was treated with trifluroacetic acid and the obtained compound of (lR,3S)-3-((4-ethylpiperazin-l-yl)methyl)cyclopentanamine was used directly for synthesizing final compounds in example section without further purification. Intermediate 20: Synthesis of (lR,3S)-3-((3-methylpiperidin-l- yl)methyl)cyclopentanamine:
Figure imgf000062_0003
Step 1: Synthesis of tert-butyl (lR,3S)-3-((3-methylpiperidin-l- yl)methyl)cyclopentylcarbamate:
χvHN~o~
To a stirred solution of ((lS,3R)-3-(tert- butoxycarbonylamino)cyclopentyl)methyl 4-methylbenzenesulfonate (Intermediate
18-step 2, about 0.5g) in DCM (50 ml) potassium carbonate (about 0.3 g) was added at room temperature and cooled to about 0 0C. After ten minutes, 3-methylpiperidine (0.21 g) was added and stirred the reaction at room temperature for about 6 hours and completion of the reaction was monitored by TLC. The reaction mixture was neutralized and extracted with DCM, the organic layer was dried over Na2SO4 and concentrated under reduced pressure to furnish the title compound (0.29 g) as a pale yellow solid. 1H NMR (300 MHz, CDCl3 1.08-1.09(m, 3H ); 1.24 -1.29 (m, IH); 1.39-1.40 (s, 9H); 2.29-2.60 (m, 6H); 2.79-2.80 (m, 8H); 3.70-3.73 (m, 4H); ES Mass: 297 (100%), [M+l].
Step 2: Synthesis o/(lR,3S)-3-((3-methylpiperidin-l-yl)methyl)cyclopentanamine:
Tert-butyl ( 1 R,3S)-3-((3-methylpiperidin- 1 -yl)methyl)cyclopentylcarbamate
(step 1, 0.2 g) was treated with trifluroacetic acid and the obtained compound of
(lR,3S)-3-((3-methylpiperidin-l-yl)methyl)cyclopentanamine was used directly for synthesizing the final compounds in the example section without further purification.
Intermediate 21: Synthesis of ethyl 4-ethylpiperidine-4-carboxylate:
Figure imgf000063_0001
Step 1: Synthesis of 1 -tert-butyl 4-ethyl piperidine-1, 4-diearboxylate:
Figure imgf000063_0002
Et
To a stirred solution of ethyl piperidine-4-carboxylate (10.0 g, 63.69 mmol) in 50 ml THF sodium bicarbonate (8.0 g, 95.5 mmol) was added at room temperature and cooled to 0 0C. After ten minutes, di-tert-butyl dicarbonate (15.27 g, 70.05 mmol) was added and stirred the reaction at room temperature for 14 hours. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with DCM, the organic layer was dried over Na2SO4 and concentrated under reduced pressure to furnish the title compound (1 1.4 g) as a light yellow liquid. 1H NMR (300 MHz, CDCl3): 1.23-1.28 (t, 3H); 1.45 (s, 9H); 1.60-1.68 (m, 3H); 1.85-1.90 (d, J=15Htz, 2H); 2.41-2.46 (m, IH); 2.83-2.87 (m, 2H); 4.04-4.17 (m, 3H); ES Mass: 258 (100%), [M+l]. Step 2: Synthesis of 1-tert-butyl 4-ethyl 4-benzylpiperidine-l,4-dicarboxylate:
Figure imgf000064_0001
Diisopropyl ethylamine (6.5 ml) in dry THF (25 ml) was cooled to -10 0C then N-butyl lithium (1.6 molar, 23 ml) was added drop wise under nitrogen atmosphere and maintain the reaction at -10 0C for 45 minutes then cool the reaction to - 750C for 15 minutes then 1-tert-butyl 4-ethyl piperidine-l,4-dicarboxylate
(Above step 1, 5 g in 30 ml THF) was added and stirred the reaction at same temp for 30 minutes, again raise the reaction temperature to -35 0C and stirred for 45 minutes then again cool the reaction to - 750C then ethyl iodide (3.5 g in 20 ml THF)was added drop wise and slowly allowed the reaction to room temperature and stirred the reaction at room temperature for about 12 hours. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with saturated ammonium chloride and extracted with ethyl acetate. The organic layer was washed with saturated NaHCO3 followed by brine and the organic layer dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 3% ethyl acetate in hexane as eluent to furnish the title compound as a light yellow color liquid.Η NMR (300 MHz, CDCl3): 1.16-1.18 (t, 3H); 1.44 (s, 9H); 2.07-2.1 1 (m, 2H); 2.28 (s, IH); 2.82 (s, 2H); 2.92-2.95 (m, IH); 3.46-3.52 (m, 3H); 4.09-4.11 (m, 2H); ES Mass: 308 (100%) [M+Na]. Step 3: Synthesis of ethyl 4-ethylpiperidine-4-carboxylate:
To a stirred solution of 1-tert-butyl 4-ethyl 4-ethylpiperidine-l ,4- dicarboxylate (above step 2, 4.5 g, 12.96 mmol) in 50 ml DCM was cooled to 0 0C. After ten minutes trifluro acetic acid (6.0 g) was added and stirred the reaction at room temperature for about 6 hours. Upon completion of the reaction (monitored by TLC), the reaction mixture was neutralized with saturated NaHCO3 and extracted with DCM, the organic layer was dried over Na2SO4 and concentrated under reduced pressure to furnish the title compound (2.3 g) as a light yellow liquid. 1H NMR (300
MHz, CDCl3): 1.19-1.24 (t, 3H); 1.48-1.58 (m, 2H); 2.14-2.18 (m, 2H); 2.64-2.73 (m, 2H); 2.86 (s, 2H); 3.01-3.07 (m, 4H); 4.10-4.17 (m, 2H); 7.07-7.10 (m, 2H); 7.24-7.30 (m, 3H); ES Mass: 186 (100%), [M+ 1]. Intermediate 22: Synthesis of 4-ethylpiperidine-4-carboxylic acid:
Figure imgf000065_0001
Step 1: Synthesis of l-(tert-butoxycarbonyl)-4-ethy\pipeήd\ne-4-carboxylic acid:
Figure imgf000065_0002
To a stirred solution of 1-tert-butyl 4-ethyl 4-ethylpiperidine-l,4- dicarboxylate (Intermediate 21-step 2, 10.0 g, 63.69. mmol) in 50 ml ethanol was added potassium hydroxide (8.0 g, 95.5 mmol) and the contents were refluxed for 16 hours. Upon completion of the reaction (monitored by TLC), the reaction mixture was diluted with water, acidified with 5% HCl and extracted with DCM. The organic layer was dried over Na2SO4 and concentrated under reduced pressure to furnish the title compound (8.2 g) as a light yellow liquid. 1H NMR (300 MHz,
CDCl3): 1.44 (s, 9H); 2.07-2.11 (m, 2H); 2.28 (s, IH); 2.82 (s, 2H); 2.92-2.95 (m, IH); 3.46-3.52 (m, 3H); ES Mass: 280 (100%), [M+Na].
Step 2: Synthesis of4-ethylpiperidine-4-carboxylic acid:
To a stirred solution of l-(tert-butoxycarbonyl)-4-ethylpiperidine-4- carboxylic acid (above step 1, 4.5 g, 12.96 mmol) in DCM (50 ml) was cooled to O0C. After ten minutes, trifluro acetic acid (6.0 g) was added and stirred the reaction at room temperature for about 6 hours. Upon completion of the reaction (monitored by TLC), the reaction mixture was neutralized with saturated NaHCO3 and extracted with DCM. The organic layer was dried over Na2SO4 and concentrated under reduced pressure to furnish the title compound (2.3 g) as a light yellow liquid. 1H NMR (300 MHz, CDCl3): 1.48-1.58 (m, 2H); 2.14-2.18 (m, 2H); 2.64-2.73 (m, 2H); 2.86 (s, 2H); 3.01-3.07 (m, 4H); ES Mass: 158 (100%), [M+l].
Intermediate 23: Synthesis of ((lR,3S)-3-amino-2,2-dimethylcyclobutvI)(4- ethylpiperazin- 1 -vPmethanone:
Figure imgf000066_0001
Step-1: Synthesis of benzyl (lS,3R)-3-(4-ethylpiperazine-l-carbonyl)-2,2- dimethylcyclobutylcarbamate:
Figure imgf000066_0002
To a stirred solution of (lR,3S)-3-(benzyloxycarbonylamino)-2,2- dimethylcyclobutanecarboxylic acid (1.0 g) in DCM (30 ml) at 0 0C EDCI (800 mg) and HOBt (700 mg) were added, after 10 minutes N-Ethylpiperazine (800 mg) and Et3N (3 ml) were added drop wise and the reaction mass was allowed to stir at room temperature for 8 hours. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with DCM and washed with water, saturated NaHCO3 solution, water, IN HCl, water and saturated brine. The organic layer was concentrated under reduced pressure then the resulting crude was purified by silica gel column (100-200 mesh, elution 90% EtOAC in hexane) to afford the title compound as a syrup. Wt: 780 mg; Yield: 57.9%. 1H NMR and Mass complies with the required product.
Step 2: Synthesis of ((lR,3S)-3-ωnino-2,2-dimethylcyelobutyl)(4-ethylpiperazin-l- yl)methanone:
To a stirred solution of benzyl ( lS,3R)-3-(4-ethylpiperazine-l-carbonyl)-2,2- dimethylcyclobutylcarbamate (above step 1 , 780 mg) in EtOAc (20 ml) 10 % Pd/C (catalytic amount) was added at room temperature and the reaction mixture was stirred under H? gas atmosphere for 12 hours. After completion of the reaction (monitored by TLC), the reaction mixture was filtered through a celite bed and the obtained filtrate concentrated under reduced pressure to afford the title compound as a liquid which was proceeded as such for next reaction without characterization. Yield has been calculated as 100%.
Intermediate 24: Synthesis of ((lS,3R)-3-amino-2.2-dimethylcvclobutyl)(4- ethylpiperazin-l-vDmethanone. trifluoro acetic acid:
Figure imgf000067_0001
Stepl: Synthesis of tert-butyl (lR,3S)-3-(4-ethyIpiperazine-l-carbonyl)-2,2- dimethylcyclobutylcarbamate:
Figure imgf000067_0002
To a stirred solution of (lS,3R)-3-(tert-butoxycarbonylamino)-2,2- dimethylcyclobutanecarboxylic acid (2 g, 8.23 mmol) in DCM (50 ml) EDCI (946 mg, 9.876 mmol) and HOBt (756 mg, 9.876 mmol) were added at 0 0C, after 10 minutes N-Ethyl piperazine (939 mg, 16.46 mmol) and Et3N (3 niL, 41.15 mmol) were added drop wise and the reaction mass was allowed to stir at room temperature for 12 hours. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with DCM and washed with water, saturated NaHCO3 solution, water, IN HCl, water and saturated brine and the organic layer was concentrated under reduced pressure. The resulting crude residue was stirred in hexane and obtained solid was filtered. Wt: 1.6 g; Yield: 70 %. 1H NMR (300 MHz, CDCl3): δ 4.77 (d, IH, J = 8.4 Hz), 3.89-3.78 (m, IH), 3.6-3.46 (m, 3H), 2.80 (m, IH), 2.60-
2.40 (m, 8H), 1.80 (m, IH), 1.43 (s, 9H), 1.12 (s, 3H), 1.2 (t, 3H), 0.87 (s, 3H); Mass: [M+l]+ 340 (25%), [M+Na]+ 362 (100%).
Step-2: Synthesis of ((lS,3R)-3-amino-2,2-dimethylcyclobutyl)(4-ethylpiperazin-l- yl)methanone. trifluoro acetic acid:
A solution of tert-butyl ( lR,3S)-3-(4-ethylpiperazine-l-carbonyl)-2,2- dimethylcyclobutylcarbamate ( 1.6 g, 4.7 mmol) in TFA:DCM (1 :2) (50 mL) stirred at room temperature for 1 hour. After completion of the reaction (monitored by TLC), the solvent was evaporated, the crude dissolved in DCM and basified with Et3N (20 ml) then the resulting solution as such used for the next reaction. Intermediate 25: Synthesis of ethyl l-(YlR.3S)-3-amino-2.2- dimethylcyclobutanecarbonyl)piperidine-4-carboxylate:
Figure imgf000068_0001
Step 1: Synthesis of ethyl l-((lR,3S)-3-(benzyloxycarbonylamino)-2,2- dimethylcyclobutanecarbonyl)piperidine-4-carboxylate:
Figure imgf000068_0002
To a stirred solution of (lR,3S)-3-(benzyloxycarbonylamino)-2,2- dimethylcyclobutanecarboxylic acid (1.5 g, 5.415 mmol) in DCM (20 ml) EDCI (1.55 g, 8.122 mmol) and HOBt (1.24 g, 8.122 mmol) were added at O 0C after 10 minutes, 4-ethylpiperidinecarboxylate (1.0 g, 6.498 mmol) and Et3N (3.75 ml,
27.075 mmol) were added drop wise and the reaction mass was allowed to stir at room temperature for 12 hours. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with DCM and washed with water, saturated NaHCO3 solution, water, IN HCl, water and saturated brine and the organic layer was concentrated under reduced pressure, the resulting crude residue was stirred in hexane, and the obtained solid was filtered and dried under vacuum. Wt: 1.3 g; Yield: 57.7 %. 1H NMR (300 MHz, CDCl3): δ 7.35 (5H, s), 5.194-5.058 (3H, m), 4.5O6-4.3(1H, m), 4.19-4.1 1 (2H, m), 3.98-3.78 (2H, m), 3.15-3.00 ( IH, m), 2.9-2.7 (2H, m), 2.6-2.2 (3H, m), 2.0-1.8 (2H, m), 1.741.5 (2H, m), 1.26 (3H, s), 1.2 (3H, m), 0.85 (3H, s); Mass: : [M+l]+ 417 (10%), [M+Na]+ 439 (100%).
Step 2: Synthesis of ethyl l-((lR,3S)-3-amino-2,2- dimethylcyclobutanecarbonyl)piperidine-4-carboxylate:
To a solution of ethyl l-((lR,3S)-3-(benzyloxycarbonylamino)-2,2- dimethylcyclobutanecarbonyl)piperidine-4-carboxylate (step 1, 1.30 g) in ethyl acetate (50 ml), Pd/C (100 mg) was added carefully under argon atmosphere. Then the reaction mixture was stirred for overnight under hydrogen conditions. After completion of the reaction (monitored by TLC), diluted with ethyl acetate, filtered on celite, washed with ethyl acetate. The combined organic extracts were concentrated under reduced pressure to give crude product which was preceded for next step without further purification and analysis.
Examples Example 1: Preparation of (lR,3aS,5aR.5bR,7aR,9S,l laR.l lbR.13aR,13bR)-9- acetoxy-5a,5b,8,8, 1 1 a-pentamethyl- 1 -(prop- 1 -en-2- vDicosah ydro- 1 H- cyclopenta[alchrysene-3a-carboxylic acid:
Figure imgf000069_0001
Ac2O (about 0.93 ml, 9.87 mmol) was added to a stirred solution of (1 R,3aS,5aR,5bR,7aR,9S, 11 aR, 1 1 bR, 13aR, 13bR)-9-hydroxy-5a,5b,8,8, 1 1 a- pentamethyl- 1 -(prop- 1 -en-2-yl)icosahydro- 1 H-cyclopenta[a]chrysene-3a-carboxylic acid (Betulinic acid, about 0.3 g, 0.657 mmol) and DMAP (about 0.167 g, 1.32 mmol) in pyridine (about 15 ml) at about 0 0C then the reaction mixture was slowly warmed to room temperature and refluxed for about 24 hours. After completion of the reaction (monitored by TLC), the reaction mixture poured in to ice water and extracted with EtOAc and washed with water, brine and dried over Na2SO4, the solvent was evaporated and purified by silica gel column (100-200, elution 10% EtOAc in hexane) to afford title compound as a off white solid. Wt: 0.196 g; Yield: 59.8 %; 1H NMR (300 MHZ, CDCl3): δ 4.74 (s, IH), 4.61 (s, IH), 4.50-4.44 (m, IH), 3.02-2.97 (m, IH), 3.01-2.12 (m, 2H), 2.04 (s, 3H), 1.99-1.92 (m, 2H), 1.69 (s,
3H), 1.68-1.57 (m, 6H), 1.56-1.32 (m, 10H), 1.31-1.01 (m, 5H), 0.97, 0.93 (2s , 6H), 0.85 (Brs, 9H); Mass: [M-I]" 497 (100%); IR (KBr, cm"1 ): 3296, 2945, 1736, 1694, 1464, 1368, 1247, 1 196, 1 161, 1024, 980, 884, 777, 543; M.R: 283.7 0C - 290.1 0C; HPLC: 97.17%.
Example 2j Preparation of (lS,3R)-benzyl 3^
((lR,3aS.5aR.5bR,7aR,9S,l laR.l lbR.13aR.13bR)-9-acetoxy-5a,5b,8.8,l Ia- pentamethyl- 1 -(prop- 1 -en-2- vPicosah vdro- 1 H-cvclopenta[alchrysene-3a- carboxarnido)-2,2-dimethylcvclobutanecarboxvlate:
Figure imgf000070_0001
2M solution ooff ( (CCOOCCll))2? in DCM was added to (lR,3aS,5aR,5bR,7aR,9S,l IaR1I lbR,13aR,13bR)-9-acetoxy-5a,5b,8,8,l Ia- pentamethyl-l-(prop-l-en-2-yl)icosahydro-lH-cyclopenta[a]chrysene-3a-carboxylic acid (Example 1, about 0.150 g, 0.301 mmol) at about O0C and the reaction mixture was stirred at about 15-200C for about 2 hours. After completion of the reaction (monitored by TLC), the solvent was evaporated under nitrogen atmosphere and dissolved in DCM (3 ml). To this solution, solution of Intermediate 7 (about 0.140 g, 0.602 mmol) in DCM and Et3N (about 0.2 ml, 0.904 mmol) were added slowly at about -50C and allowed to stir at room temperature for 16 hours. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with DCM and washed with water, brine and dried over Na2SO4, the solvent was evaporated and purified by silica gel column (100-200 mesh, elution 10% EtOAc in hexane) to afford the title compound as an off white solid. Wt: 0.110 g; Yield: 51.4 %; 1H NMR (300 MHZ, CDCl3): δ 7.38-7.32 (m, 5H), 5.65 (d, IH, J = 10.5 Hz), 5.13 (dd,
2H, J = 12.3, 19.2 Hz), 4.72 (s, IH), 4.58 (s, IH), 4.51-4.42 (m, IH), 4.12 (q, IH, J = 9.0 Hz), 3.16-3.13 (m, IH), 2.72-2.68 (m, IH), 2.52-2.41 (m, IH), 2.38-2.29 (m, IH), 2.04 (s, 3H), 1.95-1.88 (m, 2H), 1.77-1.48 (m, 14H), 1.46-1.32 (m, 7H), 1.31 (s, 3H), 1.29-1.22 (m, 3H), 1.18-1.13 (m, IH), 0.95 (s, 3H), 0.92 (s, 3H), 0.85-0.82 (m, 12H); Mass: [M+l]+ 714 (100%); IR (KBr, cm"1): 3406, 2950, 1734, 1664, 1456,
1369, 1247, 1 172, 1079, 1023, 979, 884, 750, 698; M.R: 1 13.3 0C -1 19.8 0C; HPLC: 93.86%.
Example 3: Preparation of (lR,3aS.5aR.5bR.7aR.9S,l IaRJ lbR,13aR,13bR)-9- ((lR,3S)-3-(tert-butoxycarbonyl)-2,2-dimethylcvclobutanecarbonyloxy)-
5a,5b,8,8, 1 1 a-pentamethyl- 1 -(prop- 1 -en-2-yl)icosahydro- 1 H-cyclopenta[alchrysene- 3a-carboxvlic acid:
Figure imgf000071_0001
To a stirred solution of (lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)-9- hydroxy-5a,5b,8,8, 1 1 a-pentamethyl- 1 -(prop- 1 -en-2-yl)icosahydro- 1 H- cyclopenta[a]chrysene-3a-carboxylic acid (Betulinic acid, about 0.1 g, 0.22 mmol) in THF:Toluene (about 6 ml) (lR,3S)-3-(tert-butoxycarbonyl)-2,2- dimethylcyclobutanecarboxylic 2,4,6-trichlorobenzoic anhydride (Intermediate 10, about 0.955 g, 2.20 mmol) and DMAP (0.054 g, 0.44 mmol) were added and refluxed for about 12 hours and the solvent was evaporated then dry Pyridine (about 6 ml) was added and refluxed for about 16 hours. After completion of the reaction
(monitored by TLC), the reaction mixture was diluted with DCM and washed with water, dried over Na2SO4 and concentrated under reduced pressure. The resulting crude was purified Silica gel column chromatography (100-200 Mesh, Elution: 5 % EtOAc in Hexane) to afford the title compound as a white solid. Wt: 0.050 g; Yield: 34.2%; 1H NMR (300 MHZ, CD3OD): δ 4.74 (s, IH), 4.61 (s, IH), 4.47-4.43 (m,
IH), 3.03-2.97 (m, IH), 2.77-2.64 (m, 2H), 2.58-2.54 (m, IH), 2.29-2.24 (m, 2H), 2.03--1.94 (m, 3H), 1.69 (s, 5H), 1.64-1.50 (m, 9H), 1.44 (s, 12 H), 1.38-1.21 (m, 8H), 1.00 (s, 3H), 0.97 (s, 3H), 0.93 (s, 3H), 0.84, 0.83 (2s, 9H), 0.80-0.77 (m, IH); Mass: [M+Na]+ 689 (100 %); IR (KBr, cm"1): 2937, 2344, 1733, 1698, 1464, 1376, 1237, 1153, 1 107, 982, 882; M. Range : 222.7-223.6 0C; HPLC: 95.04 % at RT
17.45 minutes.
Example 4: Preparation of ( 1 R,3aS,5aR,5bR.7aR.9S , 11 aR, 1 1 bR.13aR.13bR)-9- ((lR.3S)-3-carboxy-2,2-dimethylcyclobutanecarbonyloxy)-5a,5b,8,8,l la- pentamethyl- 1 -(prop- 1 -en-2- vDicosahydro- 1 H-cyclopenta[alchrysene-3a-carboxylic acid:
Figure imgf000072_0001
To a stirred solution of (lR,3aS,5aR,5bR,7aR,9S,l IaR1I lbR,13aR,13bR) -9- ((lR,3S)-3-(tert-butoxycarbonyl)-2,2-dimethylcyclobutanecarbonyloxy)- 5a,5b,8,8, 1 la-pentamethyl- 1 -(prop- 1 -en-2-yl)icosahydro- 1 H-cyclopenta
[a]chrysene-3a-carboxylic acid (Example 3, about 0.160 g, 0.239 mmol) in 2M HCl in Dioxane (10 ml) was stirred at room temperature for about 12 hours. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with EtOAc and washed with water, the organic layer dried over Na2SO4 and concentrated under reduced pressure. The resulting crude was purified by Silica gel column chromatography (100-200 Mesh, Elution: 20 % EtOAc in Hexane) to afford the title compound as a white solid. Wt: 0.086 g; Yield: 59.0%; 1H NMR (300 MHZ, CDCl3): δ 4.74 (s, IH), 4.61 (s, IH), 4.47-4.43 (m, IH), 3.03-2.97 (m, IH), 2.87- 2.74 (m, 2H), 2.63-2.51 (m, IH), 2.31-2.24 (m, 2H), 2.19-1.90 (m, 3H), 1.69 (s, 3H), 1.78-1.68 (m, 5H), 1.52-1.41 (m, 12 H), 1.29-1.02 (m, 9H), 0.97 (s, 3H), 0.93 (s, 3H), 0.85 (s, 9H); Mass: [M+Na]+ 633 (100 %); IR (KBr, cm"1): 3427, 2951, 1730, 1706, 1698, 1456, 1376, 1242, 1 190, 1 107, 1020, 885; M.Range: 282.5-289.3 0C; HPLC: 92.2 % at RT 8.76 minutes.
Example 5: Preparation of (1S.3RV3-
(( 1 R.3aS,5aR,5bR,7aR.9S. l laR.l l bR.13aR, 13bRV9-h vdroxy-5a.5b.8,8, 11 a- pentamethyl-l-(prop-l-en-2-yl)icosahvdro-lH-cvclopentafalchrvsene-3a- carboxamido)-2,2-dimethylcvclobutanecarboxylic acid:
Figure imgf000072_0002
To a solution of (lS,3R)-benzyl 3-
(( 1 R,3aS,5aR,5bR,7aR,9S, 1 1 aR, 1 1 bR, 13aR, 13bR)-9-acetoxy-5a,5b,8,8, 1 1 a- pentamethyl- 1 -(prop- 1 -en-2-yl)icosahydro- lH-cyclopenta[a]chrysene-3a- carboxamido)-2,2-dimethylcyclobutanecarboxylate (Example 2, about 0.140 g, 0.196 mmol) in MeOH:THF (2: 1) (6 ml) at 0 0C, 2N NaOH (2 ml) was added and allowed to stir at room temperature for about 6 hours. After completion of the reaction (monitored by TLC), the solvent was evaporated and acidified with 2N HCl, the aqueous layer was extracted with ethyl acetate and dried with Na2SO4. The solvent was evaporated and purified by silica gel column (100-200 mesh, elution 50% EtOAc in hexane) to afford the title compound as an off white solid.Wt: 0.105 g: Yield: 92 %. 1H NMR (300 MHZ, CDCl3): δ 5.64 (d, IH, J = 7.8 Hz), 4.72 (s, IH), 4.58 (s, IH), 4.15 (q, IH, J = 9.3 Hz), 3.18 (dd, IH, J = 5.1, 10.8 Hz), 3.14- 3.08 (m, IH), 2.71-2.64 (m, IH), 2.52-2.41 (m, IH), 2.40-2.28 (m, IH), 2.10-1.88
(m, 4H), 1.78-1.64 (m, 9H), 1.62-1.51 (m, 3H), 1.49-1.41 (m, 4H), 1.39-1.32 (m, 7H), 1.28-1.22 (m, 4H), 0.98 (s, 3H), 0.97 (s, 3H), 0.96 (s, 3H), 0.93 (s, 3H), 0.81 (s, 3H), 0.75 (s, 3H);Mass: [M+l]+ 582 (10%), [M+Na]+ 604 (100%);IR (KBr, cm"1): 3454, 3407, 2949, 2869, 1716, 1709, 1642, 1459, 1243, 1 191, 1009, 885, 787; M.R: 174.6 0C -187.0 0C; HPLC: 90.33%.
Example 6: Preparation of (lR.2S.3aR.5aR.5bR.7aS.10R.12aR,12bR)-2-(3-carboxy- 3-methylbutanoyloxy)-3,3,5a,5b,12b-pentamethyl-10-(prop-l-en-2- vDicosahydrodicyclopentara jlphenanthrene- 1 ,7a-dicarboxvlic acid:
Figure imgf000073_0001
To a stirred solution of ceanotheic acid (about 0.22 mmol) in dry Pyridine (about 6 ml) dimethylsuccinic anhydride (about 3.30 mmol) and DMAP (0.44 mmol) were added and contents were re fluxed for about 16 hours. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with DCM and washed with water, the organic layer dried with Na2SO4 and concentrated under reduced pressure. The resulting crude was purified by Silica gel column chromatography (100-200 Mesh, Elution: 5 % EtOAc in Hexane) to afford the title compound as a white solid. Wt: 0.050 g: Yield: 34.2%. 1H NMR (300 MHZ, CDCl3): δ 5.08 (s, IH), 4.62 (s, IH), 4.48 (s, IH), 2.92-2.87 (m, IH), 0.9-1.9 (m, 44H); [M+Na]+ 637.40 (100%).
Example 7: Preparation of αR.3aS,5aR,5bR,7aR,9S,l laR,l lbR.13aR.13bR)-3a- ((lS,3R)-2,2-dimethyI-3-(moφholine-4-carbonyl)cvclobutylcarbamoyl)-
5a.5b,8,8, 1 1 a-pentamethyl- 1 -(prop- 1 -en-2-yl)icosahydro- 1 H-cyclopenta[alchrvsen- 9-yl acetate:
Figure imgf000074_0001
To a (lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)-9-acetoxy- 5a,5b,8,8, 11 a-pentamethyl- 1 -(prop- 1 -en-2-yl )icosahydro- 1 H-cyclopenta[a]chrysene-
3a-carboxylic acid (0.4 g, 0.803 mmol) in DCM (1 ml) 2M solution of (COCl)2 in DCM (4 ml, 8.03 mmol) was added at about 0 0C and the reaction mixture was stirred at room temperature for about 3 hours. After completion of the reaction (monitored by TLC) the solvent was evaporated under nitrogen atmosphere and dissolved in DCM (4 ml), which was added to a solution of ((lR,3S)-3-amino-2,2- dimethylcyclobutyl)(morpholino)methanone (Intermediate 1 1, 0.306 g, 1.45 mmol) in DCM (5 ml) and Et3N (0.22 ml, 1.61 mmol) at about 0 0C and allowed to stir at room temperature for about 16 hours. After completion of the reaction (monitored by TLC) the reaction mixture was diluted with DCM and washed with water, IN HCl, water brine and dried with Na2SO4, the solvent was evaporated and purified by silica gel column (100-200 mesh, elution 10% EtOAc in hexane) to afford the title compound as an off white solid. Wt: 0.380 g: Yield: 68.4 %; 1H NMR (300 MHz, CDCl3): δ 5.88 (d, IH), 4.73 (s, IH), 4.58 (s, IH), 4.51-4.42 (m, IH), 4.17-4.06 (m, IH), 3.80-3.41 (m, 7H), 3.17-3.08 (m, IH), 2.93-2.84 (m, IH), 2.50-2.29 (m, 2H), 2.05 (s, 3H), 1.99-1.86 (m, 3H), 1.80-1.02 (m, 22 H), 0.95, 0.92 (s, 9H), 0.83 (s,
15H); Mass: [M+Na]+ 693 (100%); M.R: 144.80C -156.2 0C.
Example 8: Preparation of (lR.3aS,5aR.5bR,7aR,9S.l laR.l lbR,13aR.13bR)-N- ((lS,3R)-2,2-dimethyl-3-(moφholine-4-carbonyl)cvclobutyl)-9-hvdroxy- 5a,5b,8,8, 11 a-pentamethyl- 1 -(prop- 1 -en-2-yl )icosahydro- 1 H-cyclopentafalchrysene-
3a-carboxamide:
Figure imgf000075_0001
To a solution of (lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)-3a- ((lS,3R)-2,2-dimethyl-3-(moφholine-4-carbonyl)cyclobutylcarbamoyl)- 5a,5b,8,8, 1 1 a-pentamethyl- 1 -(prop- 1 -en-2-yl)icosahydro- 1 H-cyclopenta[a]chrysen- 9-yl acetate (Example 7, 0.380 g, 0.55 mmol) in MeOH:THF (2: 1) (6 ml) NaOH
(2N, 2 ml) was added at about 0 0C and allowed to stir at room temperature for about 16 hours. After completion of the reaction (monitored by TLC) the volatiles was evaporated and the aqueous layer was extracted with ethyl acetate and dried with Na2SO4. The solvent was evaporated and purified by silica gel column (100-200 mesh, elution 15% EtOAc in hexane) to afford the title compound as an off white solid. Wt: 0.320 g: Yield: 89.6 %; 1H NMR (300 MHz, CDCl3): δ 5.88 (d, IH, J = 8.1 Hz), 4.73 (s, IH), 4.58 (s, IH), 4.18-4.07 (m, IH), 3.80-3.41 (m, 7H), 3.21-3.08 (m, 2H), 2.91-2.83 (m, IH), 2.50-2.29 (m, 3H), 1.98-1.87 (m, 2H), 1.80-1.10 (m, 26 H), 0.95-0.92 (s, 12H), 0.99-0.68 (s, 9H); Mass: [M+l]+ 651 (100%), [M+Na]+ 673 (70%); IR (KBr, cm'1): 3367, 2856, 2926, 1714, 1634, 1493, 1463, 1375, 1270,
1241, 1 1 15, 1040, 983, 884, 756, 665; M.R: 262.5 0C -267.8 0C; HPLC: 90.7%.
Example 9: Preparation of 4-(( lR,3aS.5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)-3a- ((lS,3R)-2,2-dimethyl-3-(moφholine-4-carbonyl)cyclobutylcarbamoyl)- 5a,5b,8,8J la-pentamethyl-l-(prop-l-en-2-yl)icosahvdro-lH-cyclopentafalchrvsen-
9-yloxy)-2,2-dimethyl-4-oxobutanoic acid:
Figure imgf000075_0002
To a stirred solution of (lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)-N- ((lS,3R)-2,2-dimethyl-3-(moφholine-4-carbonyl)cyclobutyl)-9-hydroxy- 5a,5b,8,8, 1 1 a-pentamethyl- 1 -(prop- 1 -en-2-yl)icosahydro- 1 H-cyclopenta[a]chrysene-
3a-carboxamide (Example 8, 0.250 g, 0.385 mmol) 2,2-Dimethylsuccinic anhydride (0.26 ml, 2.31 mmol) and DMAP (0.094 g, 0.77 mmol) in pyridine ( 10 ml) were added at room temperature then the reaction mixture was refluxed for about 16 hours. After completion of the reaction (monitored by TLC) the reaction mixture was diluted with EtOAc, the organic layer was washed with water, IN HCl, water, brine and dried with Na2SO4, the solvent was evaporated and purified by silica gel column (100-200, elution 35% EtOAc in hexane) to afford the title compound as a off white solid. Wt: 0.140 g: Yield: 46.8 %; 1H NMR (300 MHz, CDCl3): δ 5.95 (d, IH), 4.73 (s, IH), 4.58 (s, IH), 4.52-4.43 (m, IH), 4.19-4.09 (m, IH), 3.82-3.40 (m,
8H), 3.17-3.04 (m, IH), 2.92-1.82 (m, IH), 2.71-2.29 (m, 6H), 2.00-1.91 (m, 3H), 1.80-1.09 (m, 28H), 1.00-0.77 (m, 21H); Mass: [M+l]+ 779 (100%), [M+Na]+ 801 (15%); IR (KBr, cm"1): 3419, 2952, 2867, 1757, 1733, 1729, 1638, 1631, 1460, 1452, 1376, 1243, 1180, 1 117, 1067, 978, 879, 775; M.R: 248.7 0C -252.6 0C; HPLC: 87.7%
Figure imgf000076_0001
(( lS,3R)-2,2-dimethyl-3-(piperidine-l-carbonyl)cvclobutylcarbamoyl)- 5a,5b,8,8, 11 a-pentamethyl- 1 -(prop- 1 -en-2-yl)icosahydro- 1 H-cyclopenta[alchrysen- 9-yl acetate:
Figure imgf000076_0002
To a stirred solution of (lR,3aS,5aR,5bR,7aR,9S,l IaR1I lbR,13aR,13bR)-9- acetoxy-5a,5b,8,8, 11 a-pentamethyl- 1 -(prop- 1 -en-2-yl)icosahydro- 1 H- cyclopenta[a]chrysene-3a-carboxylic acid (0.4 g, 0.803 mmol) in DCM (1 ml) (COCl)2 (0.69 ml, 8.03 mmol) in DCM (4 ml) was added at about 0 0C and the reaction mixture was stirred at room temperature for about 3 hours. After completion of the reaction (monitored by TLC) the solvent was evaporated under nitrogen atmosphere and dissolved in DCM (4 ml), which was added to a stirred solution of ((lR,3S)-3-amino-2,2-dimethylcyclobutyl)(piperidin-l-yl)methanone (Intermediate 12, 0.306 g, 1.45 mmol) in DCM (5 ml) and Et3N (0.22 ml, 1.61 mmol) at about 0
0C and allowed to stir at room temperature for about 16 hours. After completion of the reaction (monitored by TLC) the reaction mixture was diluted with DCM and washed with water, IN HCl, water, brine and dried over Na2SO4, the solvent was evaporated and purified by silica gel column (100-200 mesh, elution 10% EtOAc in hexane) to afford the title compound as an off white solid. Wt: 0.380 g: Yield: 68.4
%; δ 5.94 (d, IH, J = 7.8 Hz), 4.74 (s, IH), 4.59 (s, IH), 4.54-4.41 (m, IH), 4.17- 4.05 (m, IH), 3.74-3.62 (m, IH), 3.37 (brs, 2H), 3.18-3.07 (m, IH), 2.89 (t, IH, 7.8 Hz), 2.51-2.40 (m, IH), 2.39-2.28 (m, 2H), 2.04 (s, 3H), 2.01-1.84 (m, 2H), 1.81- 1.75 (m, IH), 1.74-1.45 (m, 7H), 1.44-1.21 (m, 15H), 1.21-1.09 (m, 2H), 0.95, 0.93 (s, 9H), 0.83-0.82 (m, 12H); Mass: [M+Na]+ 714 (100%); IR (KBr, cm"1): 3372, 2943, 2864, 1736, 1730, 1652, 1636, 1623, 1501, 1459, 1444, 1369, 1248, 1192,
1024, 979, 881, 853.
Example 11: Preparation of (lR.3aS,5aR.5bR,7aR,9S,l laR.l lbR.13aR,13bR)-N- (( 1 S,3R)-2,2-dimethyl-3-(piperidine- 1 -carbon yl)cvclobutyl)-9-hydroxy- 5a,5b,8,8.11 a-pentamethyl- 1 -(prop- 1 -en-2-yl)icosahydro- 1 H-cyclopenta[alchrysene-
3a-carboxamide:
Figure imgf000077_0001
To a stirred solution of ( lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)- 3a-((lS,3R)-2,2-dimethyl-3-(piperidine-l-carbonyl)cyclobutylcarbamoyl)- 5a,5b,8,8, 1 1 a-pentamethyl- 1 -(prop- 1 -en-2-yl)icosahydro- 1 H-cyclopenta[a]chrysen-
9-yl acetate (Example 10, 0.340 g, 0.492 mmol) in MeOH:THF (2: 1) (6 ml) NaOH (2N, 2 ml) was added at about 0 0C and allowed to stir at room temperature for about 16 hours. After completion of the reaction (monitored by TLC) the volatiles were evaporated and the aqueous layer was extracted with ethyl acetate and the organic layer was washed with water, brine and dried with Na2SO4. The solvent was evaporated and purified by silica gel column (100-200 mesh, elution 15% EtOAc in hexane) to afford the title compound as an off white solid. Wt: 0.190 g: Yield: 59 %; 1H NMR (300 MHz, CDCl3): δ 5.94 (d, IH, J = 7.8 Hz), 4.73 (s, IH), 4.58 (s, IH), 4.17-4.13 (m, IH), 3.73-3.59 (m, IH), 3.54-3.41 (m, IH), 3.40-3.30 (m, 2H), 3.22- 3.04 (m, 2H), 2.93-2.83 (m, IH), 2.52-2.23 (m, 3H), 2.00-1.82 (m, 2H), 1.79-1.42
(m, 15H), 1.41-1.1 1 (m, 17H), 0.96, 0.93 (s, 10H), 0.82, 0.80 (s, 6H), 0.75 (s, 3H).0.71-0.62 (m, IH); Mass: [M+l]+ 649 ( 100%), [M+Na]+ 671 (60%); IR (KBr, cm" 1): 3450, 2937, 2862, 2587, 2126, 1622, 1459, 1373, 1251, 1 192, 1049, 1024, 882, 853; M.R: 110.0 0C -1 16.3 0C; HPLC: 97.2%.
Example 12: Preparation of 4-((lR.3aS.5aR.5bR.7aR.9S.l laR.l lbR.13aR.13bR)-
3a-(( lS,3R)-2,2-dimethyl-3-(piperidine-l-carbonyl)cyclobutylcarbamoyl)- 5a,5b,8,8, 11 a-pentamethyl- 1 -(prop- 1 -en-2-yl)icosahvdro- 1 H-c vclopentaf alchrysen- 9-yloxy)-2,2-dimethyl-4-oxobutanoic acid:
Figure imgf000078_0001
To a stirred solution of (lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)-N- (( lS,3R)-2,2-dimethyl-3-(piperidine-l -carbon yl)cyclobutyl)-9-hydroxy-
5a,5b,8,8, 1 1 a-pentamethyl- 1 -(prop- 1 -en-2-yl)icosahydro- 1 H-cyclopenta[a]chrysene- 3a-carboxamide (Example 1 1, 0.110 g, 1.697 mmol) 2,2-Dimethylsuccinic anhydride (0.2 ml, 1.697 mmol) and DMAP (0.044 g, 0.338 mmol) in pyridine (5 ml) were added at room temperature then the reaction mixture was refluxed for about 16 hours. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with EtOAc, washed with water, IN HCl, water, brine and dried with Na2SO4, the solvent was evaporated and purified by silica gel column (100-200 mesh, elution 15% EtOAc in hexane) to afford the title compound as an off white solid. Wt: 0.080 g: Yield: 61%; 1H NMR (300 MHz, CDCl3): δ 6.01 (d, IH, J = 8.4 Hz), 4.72 (s, IH), 4.58 (s, IH), 4.53-4.43 (m, IH), 4.16-4.08 (m, IH), 3.71-3.62 (m,
2H), 3.54-3.35 (m, 3H), 3.18-3.06 (m, IH), 2.93-2.87 (m, IH), 2.66 (d, IH, J = 15.9 Hz), 2.56 (d, IH, J = 15.9 Hz), 2.50-2.27 (m, 2H), 1.99-1.88 (m, 2H), 1.80-1.00 (m, 46H), 0.94, 0.92, 0.83 (s, 12H); Mass: [M+l]+ 777 (100%), [M+Na]+ 799 (80%); IR (KBr, cm"1 ): 3411, 2944, 2867, 1733, 1730, 1625, 1467, 1445, 1368, 1253, 1220, 1192, 1022, 977, 884, 767; M.R: 139.5 0C -141.5 0C; HPLC: 96.7%.
Example 13: Preparation of (lRJaS.SaR.SbRJaR^S.l laR.l lbR.naR.nbRVSa- ((lS,3R)-2,2-dimethyl-3-(pyrrolidine-l-carbonyl)cvclobutylcarbamoyl)- 5a,5b,8,8, 1 1 a-pentamethyl- 1 -(prop- 1 -en-2-yPicosahydro- 1 H-cyclopentaf alchrysen- 9-yl acetate:
Figure imgf000078_0002
To a stirred solution of (lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)-9- acetoxy-5a,5b,8,8, 1 1 a-pentamethyl- 1 -(prop- 1 -en-2-yl)icosahydro- 1 H- cyclopenta[a]chrysene-3a-carboxylic acid (0.3 g, 0.602 mmol) in DCM (1 ml) a solution of (COCl)2 (0.52 ml, 6.02 mmol) in DCM (4 ml) was added at about 0 0C and the reaction mixture was allowed to stir at room temperature for about 3 hours. After completion of the reaction (monitored by TLC), the solvent was evaporated under nitrogen atmosphere and dissolved in DCM (4 ml), which was added to a stirred solution of ((lR,3S)-3-amino-2,2-dimethylcyclobutyl)(pyrrolidin-l- yl)methanone (Intermediate 13, 0.288 g, 1.023 mmol) in DCM (5 ml) and Et3N
(0.16 ml, 1.204 mmol) at about 0 0C and allowed to stir at room temperature for about 16 hours. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with DCM and washed with water, IN HCl, water, brine and dried over Na2SO4, the solvent was evaporated and purified by silica gel column (100-200 mesh, elution 20% EtOAc in hexane) to afford the title compound as an off white solid. Wt: 0.230 g; Yield: 56.5 %; 1H NMR (300 MHz, CDCl3): δ 6.38 (d, IH, J = 8.4 Hz), 4.73 (s, IH), 4.58 (s, IH), 4.50-4.42 (m, IH), 4.13-4.02 (m, IH), 3.56- 3.28 (m, 5H), 3.18-3.07 (m, IH), 2.79 (t, IH, J = 7.2 Hz), 2.55-2.33 (m, 2H), 2.27- 2.18 (m, IH), 2.04 (s, 3H), 2.00-1.74 (m, 8H), 1.72-1.10 (m, 20H), 0.95, 0.92, 0.88, 0.83 (s, 22H); Mass: [M+Na]+ 714 (100%); IR (KBr, cm"1): 3372, 2943, 2864, 1736,
1730, 1652, 1636, 1623, 1501, 1459, 1444, 1369, 1248, 1 192, 1024, 979, 881, 853; M.R: 125.4 0C -135.5 0C.
Example 14: Preparation of (lR.3aS.5aR.5bRJaR,9S.l laR.l lbR.13aR.13bR)-N- ((lS,3R)-2,2-dimethyl-3-(pyrrolidine-l-carbonyl)cvclobutyl)-9-hvdroxy-
5a,5b,8,8, 1 1 a-pentamethyl- 1 -(prop- 1 -en-2-yl )icosahydro- 1 H-cyclopenta[a1chrysene- 3a-carboxamide:
Figure imgf000079_0001
To a stirred solution of (lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)- 3a-(( 1 S,3R)-2,2-dimethyl-3-(pyiτolidine- 1 -carbonyl)cyclobutylcarbamoyl)-
5a, 5b, 8, 8, 11 a-pentamethyl- 1 -(prop- 1 -en-2-yl)icosahydro- 1 H-cyclopenta[a]chrysen- 9-yl acetate (Example 13, 0.230 g, 0.340 mmol) in MeOH:THF (2: 1) (9 ml) NaOH (2N, 3 ml) was added at about 0 0C and allowed to stir at room temperature for about 16 hours. After completion of the reaction (monitored by TLC), the volatiles were evaporated and the aqueous layer was extracted with ethyl acetate and the organic layer was washed with water, brine and dried with Na2SO4. The solvent was evaporated and purified by silica gel column (100-200 mesh, elution 15% EtOAc in hexane) to afford the title compound as an off white solid. Wt: 0.150 g: Yield: 69.5 %; 1H NMR (300 MHz, CDCl3): δ 6.39 (d, IH, J = 8.4 Hz), 4.73 (s, IH), 4.57 (s, IH), 4.13-4.03 (m, IH), 3.58-3.28 (m, 4H), 3.21-3.07 (m, 2H), 2.79 (t, IH, J = 7.2 Hz), 2.57-2.33 (m, 2H), 2.27-2.18 (m, IH), 2.04-1.72 (m, 8H), 1.70-1.10 (m, 23H), 0.95, 0.92, 0.88, 0.83, 0.80, 0.75 (s, 21H); Mass: [M+l]+ 635 (100%), [M+Na]+ 657
(90%); IR (KBr, cm"1): 3489, 2947, 2869, 1637, 1615, 1441, 1376, 1357, 1250, 1 194, 1050, 881, 717; M.R: 172.4 0C -173.8 0C; HPLC: 96.79%.
Example 15: Preparation of 4-(dR,3aS,5aR,5bR,7aR,9S,l laR.l lbR.13aR,13bRV 3a-((lS,3R)-2,2-dimethyl-3-(pyrrolidine-l-carbonyl)cyclobutylcarbamoyl)-
5a,5b,8,8 , 11 a-pentamethyl- 1 -(prop- 1 -en-2- vDicosahydro- 1 H-c vclopenta[alchrysen- 9-yloxy)-2,2-dimethyl-4-oxobutanoic acid:
Figure imgf000080_0001
To a stirred solution of (!R,3aS,5aR,5bR,7aR,9S,l IaR1I lbR,13aR,13bR)-N- ((lS,3R)-2,2-dimethyl-3-(pyrrolidine-l-carbonyl)cyclobutyl)-9-hydroxy-
5a,5b,8,8, 11 a-pentamethyl- 1 -(prop- 1 -en-2-yl)icosahydro- 1 H-cyclopenta[a]chrysene- 3a-carboxamide (Example 14, 0.15 g) in dry pyridine (5 ml) dimethyl succinamide (0.302 g) was added followed by DMAP (0.057 g) and the reaction mixture was refluxed for about 20 hours. After the completion of the reaction (monitored by TLC), the mixture was diluted with ethyl acetate, washed with water and brine solution. The combined organic layers were dried over Na2SO4, concentrated under reduced pressure to afford the title crude compound as a gummy solid. The crude compound was purified by silica-gel column chromatography using 100-200 mesh and hexane and ethyl acetate mixtures as mobile phase. 1H NMR (300 MHZ, CDCl3): δ 6.42 (IH, d, J = 8.1 Hz), 4.72(1H, s), 4.5787 ( IH, s), 4.51 (IH, m), 4.1
(IH, m), 3.42-3.5 (3H, m), 3.3-3.4 ( IH, m), 3.08-3.15 (IH, m), 2.8 ( IH, m), 2.2-2.7 (7H, m), 1.8-2.0 (HH, m), 1.2-1.78 (24H, m), 0.95 (6H, m), 0.8 (1OH, m); IR (KBr, cm"1): 3246, 2950, 2873, 2381, 1725, 1620, 1459, 1 193, 1 154, 909, 722; Mass: [M+H]+ 763 (10%), 785 [M+Na]+; Melting Range: 1 10-1 140C.
Example 16: Preparation of (lR,3aS,5aR,5bR,7aR,9S.l laR,l lbR,13aR.13bR)-3a-
((lR,3S)-2,2-dimethyl-3-(morpholine-4-carbonyl)cvclobutylcarbamoyl)- 5a,5b,8,8, 11 a-pentamethyl- 1 -(prop- 1 -en-2- vPicosahydro- 1 H-cyclopentafalchrysen- 9-yl acetate:
Figure imgf000081_0001
To a solution of (lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)-9- acetoxy-5a,5b,8,8, 11 a-pentamethyl- 1 -(prop- 1 -en-2-yl)icosahydro- 1 H- cyclopenta[a]chrysene-3a-carboxylic acid (0.270 g, 0.542 mmol) in DCM (1 ml) 2M solution of (COCl)2 in DCM (2.71 ml, 5.42 mmol) was added at about 0 0C and the reaction mixture was stirred at room temperature for about 3 hours. After completion of the reaction (monitored by TLC), the solvent was evaporated under nitrogen atmosphere and dissolved in DCM (4 ml), which was added to a solution of
((lS,3R)-3-amino-2,2-dimethylcyclobutyl)(moφholino)methanone (Intermediate 14, 0.172 g, 0.0813 mmol) in DCM at 0 0C and allowed to stir at room temperature for about 16 hours. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with DCM and washed with water, IN HCl, water, brine and dried over Na2SO4, the solvent was evaporated and purified by silica gel column
(100-200 mesh, elution 15% EtOAc in hexane) to afford the title compound as an off white solid. Wt: 0.310 g: Yield: 82 %; 1H NMR (300 MHz, CDCl3): δ 5.83 (d, IH, J = 7.8 Hz), 4.72 (s, IH), 4.58 (s, IH), 4.51-4.40 (m, IH), 4.19-4.08 (m, IH), 3.81- 3.40 (m, 8H), 3.18-3.05 (m, IH), 2.90-2.82 (m, IH), 2.54-2.21 (m, 3H), 2.04 (s, 3H), 1.99-1.83 (m, 2H), 1.80-1.12 (m, 27H), 1.08-1.70 (s, 18H); Mass: [M+l]+ 693
(15%), [M+Na]+ 715 (28%); IR (KBr, cm"1): 3388, 2954, 2867, 1716, 1659, 1633, 1524, 1449, 1366, 1271, 1235, 1 1 19, 1038, 980, 892; M.R: 71.6 0C -78.9 0C.
Example 17: Preparation of (lR.3aS.5aR,5bR,7aR.9S,l laR,l lbR,13aR,13bR)-N- ((lR.3S)-2.2-dimethyl-3-(morρholine-4-carbonyl)cvclobutyl)-9-hvdroxy-
5a,5b,8,8, 1 1 a-pentamethyl- 1 -(prop- 1 -en-2- vDicosahydro- 1 H-cvclopentaf alchrysene- 3a-carboxamide:
Figure imgf000081_0002
To a stirred solution of (lR.SaS^aR^bRJaR^S.l laR.l lbR.πaR.lSbR)- 3a-((lR,3S)-2,2-dimethyl-3-(moφholine-4-carbonyl)cyclobutylcarbamoyl)- 5a,5b,8,8, 11 a-pentamethyl- 1 -(prop- 1 -en-2-yl)icosahydro- 1 H-cyclopenta[a]chrysen- 9-yl acetate (Example 16, 0.300 g, 0.43 mmol) in MeOH:THF (2: 1) (15 ml), 2N NaOH (5 ml) was added at about 0 0C and allowed to stir at room temperature for about 16 hours. After completion of the reaction (monitored by TLC), the volatiles were evaporated and the aqueous layer was extracted with ethyl acetate and dried over Na2SO4. The solvent was evaporated and purified by silica gel column (100- 200 mesh, elution 15% EtOAc in hexane) to afford the title compound as an off white solid. Wt: 0.230 g: Yield: 81.8 %; 1H NMR (300 MHz, CDCl3): δ 5.83 (d, IH,
J = 7.8 Hz), 4.72 (s, IH), 4.57 (s, IH), 4.18-4.07 (m, IH), 3.80-3.41 (m, 8H), 3.22- 3.05 (m, 2H), 2.86 (t, IH, J = 8.1 Hz), 2.52-2.23 (m, 3H), 1.99-1.87 (m, 2H), 1.79- 1.11 (m, 28H), 0.93, 0.89, 0.81, 0.74 (s, 18H); Mass: [M+l]+ 673 (100); YR (KBr, cm"1): 3419, 2951, 2864, 1624, 1527, 1459, 1374, 1271, 1249, 1112, 1068, 1044, 875, 861; M.R: 213.5 0C -216.5 0C; HPLC: 95.6%.
Example 18: Preparation of (lR,3aS,5aR,5bR,7aR,9S.l laR,l lbR.13aR,13bR)-9- ((lS,3R)-3-(benzyloxycarbonyl)-2,2-dimethylcvclobutanecarbonyloxy)- 5a,5b,8,8, 11 a-pentamethyl- 1 -(prop- 1 -en-2-yl)icosahydro- 1 H-cyclopenta[alchrysene- 3a-carboxylic acid:
Figure imgf000082_0001
To a stirred solution of (lS,3R)-3-(benzyloxycarbonyl)-2,2- dimethylcyclobutanecarboxylic acid (Intermediate 15, 1.5 g) in THF (10 ml) DIPEA (2.215 g) was added under nitrogen atmosphere at about O0C then 2,4,6- trichlorobenzoyl chloride (1.346 g) was added and stirred the reaction mixture for about 3 hours. After completion of the reaction (anhydride formation), which was monitored by TLC, the reaction mixture was concentrated under reduced pressure and directly used for the next reaction.
To a stirred solution of (lR,3aS,5aR,5bR,7aR,9S,l IaR5I lbR,13aR,13bR)-9- hydroxy-5a,5b,8,8, 1 1 a-pentamethyl- 1 -(prop- 1 -en-2-yl)icosahydro- 1 H- cyclopenta[a]chrysene-3a-carboxylic acid ( 1.3 g) in pyridine (10 ml) DMAP (0.57 g) was added followed by the crude reaction mixture (anhydride formation). The reaction mixture was stirred at reflux temperature for about 12 hours. After completion of the reaction (monitored by TLC), the mixture was cooled to room temperature, diluted with EtOAc, washed with dil HCl, water, followed by brine and dried over Na2SO4, and concentrated under reduced pressure. The crude reaction mixture was purified by column chromatography using hexane and ethyl acetate mixtures as an eluent to afford the title compound (300 mg, 15 % yield). 1H NMR (300 MHz, CDCl3): δ 7.37-7.33 (5H, m), 5.16 (2H, m), 4.73 (IH, s), 4.61 (IH, s), 4.45-4.36 (IH, m), 3.65-3.6 (IH, m), 3.1-2.90 (IH, m), 2.85-2.6 (3H, m), 2.4 (IH, m), 2.3-1.9 (5H, m), 1.8 -1.3 (17H, m), 1.26 (4H, m), 1.24 (3H, s), 1.22 (2H, m), 1.16 (3H, s), 1.14 (3H, s), 1.00 (2H, m), 0.8 (6H, s); Mass: [M+Na]+ 723 (15 %); IR
(KBr, cm"1): 3427, 2953, 17330, 1730, 1459, 1376, 1277, 1236, 1187, 1107, 1034, 940, 882.
Example 19: Preparation of (lR,3aS,5aR,5bR.7aR.9S,l laR,l lbR.13aR,13bR)-9- ((lS3R)-3-carboxy-2,2-dimethylcyclobutanecarbonyloxy)-5a,5b,8,8.11a- pentamethyl- 1 -(prop- 1 -en-2-yl)icosahvdro- 1 H-cyclopentaf alchrvsene-Sa-carboxylic acid:
Figure imgf000083_0001
To a stirred solution of (lR,3aS,5aR,5bR,7aR,9S,l IaR1I lbR,13aR,13bR)-9- ((lS,3R)-3-(benzyloxycarbonyl)-2,2-dimethylcyclobutanecarbonyloxy)-
5a,5b,8, 8,1 1 a-pentamethyl-1 -(prop- l-en-2-yl)icosahydro-lH-cyclopenta[a]chrysene- 3a-carboxylic acid (Example 18, 0.25 g) in dry DCM (10 ml) Et3N (5.77 ml) and Et3SiH (0.057 g) were added at about O0C then Pd(OAc)2 (0.005 g) was added under nitrogen conditions and the reaction mixture was stirred at reflux temperatures for over night. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with DCM, and concentrated under reduced pressure, purified by column chromatography to afford the title compound (80 mg, 36.86 % Yield). 1H NMR (300 MHz, CDCl3): δ 4.73 (IH, s), 4.54 ( IH, s), 4.4-4.36 (IH, m), 3.0-2.90 (IH, m), 2.80-2.65 (2H, m), 2.6 (2H, m), 2.3-2.1 (3H, m), 2.0-1.88 (4H, m), 1.64 (5H, m), 1.61 (2H, m), 1.6-1.4 (4H, m), 1.39-1.3 (4H, m), 1.32 (6H, s), 1.3-1.02 (4H, m), 1.00 (3H, s),0.91 (3H, s), 0.89 (3H, s), 0.809 (3H, s), 0.790 (3H, s), 0.751 (3H, s); Mass: [M+Na]+ 633 (75 %); IR (KBr, cm"1): 3400, 2949, 1732, 1703, 1459, 1389, 1364, 1264, 121 1, 1 139, 1126, 1106, 1020, 942, 889. Melting Range: 308-31O0C.
Example 20: Preparation of (lR.3aS.5aR.5bR,7aR,9S.l laR.l lbR.13aR.13bR)- 5a.5b,8,8, 11 a-pentamethyl-3a-(( 1 R,3S)-3- morpholinomethyDc yclopentylcarbamoyl)- 1 -(prop- 1 -en-2-yl)icosahydro- 1 H- cyclopentafalchrysen-9-yl acetate:
Figure imgf000084_0001
To a stirred solution of (lR,3aS,5aR,5bR,7aR,9S,l IaR, 1 lbR,13aR,13bR)-9- acetoxy-5a,5b,8,8, 1 1 a-pentamethyl- 1 -(prop- 1 -en-2-yl)icosahydro- 1 H- cyclopenta[a]chrysene-3a-carboxylic acid (0.8 g, 1.6 mmol) (Prepared as described in J.Med.Chem. 2009. 52, 3248-3258) in 50 ml DCM was added Oxolyl chloride (2 ml, 15.87 mmol) and stirred at room temperature for about 6 hours and completion of the reaction was monitored by TLC. The reaction mixture was concentrated under reduced pressure and the residue was taken in DCM (15 ml) then kept under N2 atmosphere.
To a stirred solution of (lR,3S)-3-(moφholinomethyl)cyclopentanamine (0.3 g, 19.8 mmol) in DCM (50 ml) triethyl amine (2 ml, 19.8 mmol) was added at about 0 0C and stirred for about 15 minutes then above prepared acid chloride was added and stirred continually at room temperature for about 8 hours and completion of reaction monitored by TLC. The reaction mixture was neutralized with saturated NaHCO3 and extracted with DCM, the organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 5% methanol in DCM as eluent to furnish the title compound (0.5 g) as a white solid. 1H NMR (300 MHz, CDCl3): 0.88-0.96(m,9H) ; 1.25-1.39
(m,HH) ; 1.43- 1.88 (m, 24H ) ; 2.07 (s,3H) ; 2.21-2.47(m,8H) ; 2.86-3.10(m,3H) ;3.15-3.72 (m,7H) ; 4.60(s,lH) ; 4.74(s,lH); ES Mass: 665[M+1] (100%).
Example 21 : Preparation of (lR,3aS.5aR,5bR.7aR.9S.l laR.l lbR,13aR.13bRV 5a,5b.8,8.1 1a-pentamethyl-3a-((lS,4R)-4-(moφholinomethyl)cyclopent-2- en ylcarbamoyl)- 1 -(prop- 1 -en-2-yl)-icosah ydro- 1 H-cyclopenta[alchrysen-9-yl acetate:
Figure imgf000085_0001
To a stirred solution of (lR,3aS,5aR,5bR,7aR,9S,l IaR5I IbR, 13aR,13bR)-9- acetoxy-5a,5b,8,8, 11 a-pentamethyl- 1 -(prop- 1 -en-2-yl)icosahydro- 1 H- cyclopenta[a]chrysene-3a-carboxylic acid (0.8 g, 1.6 mmol) in DCM (50 ml) oxalyl chloride (2 ml, 15.87 mmol) was added at room temperature and completion of the reaction monitored by TLC. The reaction mixture was concentrated under reduced pressure and the residue was taken in DCM (15 ml) then kept under N2 atmosphere.
To a stirred solution of (lS,4R)-4-(moφholinomethyl)cyclopent-2-enamine (0.3 g, 19.8 mmol) in DCM (50 ml) triethyl amine (2 ml, 19.8 mmol) was added at about 0 0C and stirred for about 15 minutes then above prepared acid chloride was added and stirred continually at room temperature for about 8 hours and completion of reaction monitored by TLC. The reaction mixture was neutralized with saturated NaHCO3 and extracted with DCM, the organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 5% methanol in DCM as eluent to furnish the title compound
(0.5 g) as a white solid. 1H NMR (300 MHz, CDCl3): 0.88-0.96 (m, 9H); 1.25-1.39 (m, HH); 1.43- 1.88 (m, 24H); 2.07 (s, 3H); 2.21-2.47 (m, 8H); 2.86-3.10 (m, 3H); 3.15-3.72 (m, 7H); 4.60 (s, IH); 4.74 (s, IH); 5.52-5.55 (m, IH); 5.69-5.70 (m, IH); 5.72-5.91 (m, IH); ES Mass: 622 [M+Na] 645(100%).
Example 22: Preparation of ((lR,5aR.5bR.7aR,9S,l laR.l lbR.13aR,13bRV9- hvdroxy-5a.5b.8.8, 11 a-pentamethyl- 1 -(prop- l-en-2-yl)icosahvdro- IH- cyclopenta[alchrysen-3a-yl)(3-(3-isopropyl-5-methyl-4H-l,2,4-triazol-4-yl)-8- azabicyclo[3.2.11octan-8-yl)methanone:
Figure imgf000085_0002
To a stirred solution of ( lR,3aS,5aR,5bR,7aR,9S,l IaR1I lbR,13aR,13bR)-9- acetoxy-5a,5b,8,8, 1 1 a-pentamethyl- 1 -(prop- 1 -en-2-yl)icosahydro- 1 H- cyclopenta[a]chrysene-3a-carboxylic acid ( (0.8 g, 1.6 mmol) in DCM (50 ml) oxalyl chloride (2 ml, 15.87 mmol) was added at room temperature and completion of the reaction monitored by TLC. The reaction mixture was concentrated under reduced pressure and the residue was taken in DCM (15 ml) then kept under N2 atmosphere.
To a stirred solution of 3-(3-isopropyl-5-methyl-4H-l,2,4-triazol-4-yl)-8- azabicyclo[3.2.1]octane (0.3 g, 19.8 mmol) in DCM (50 ml) triethyl amine (2 ml,
19.8 mmol) was added at about 0 0C and stirred for about 15 minutes then above prepared acid chloride was added and stirred continually at room temperature for about 8 hours and completion of reaction monitored by TLC. The reaction mixture was neutralized with saturated NaHCO3 and extracted with DCM, the organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 5% methanol in DCM as eluent to furnish the title compound (0.5 g) as a white solid. 1H NMR (300 MHz, CDCl3): 0.76-0.99 (m, 16H); 1.25-1.85 (m, 35H); 2.03-2.28 (m, 6H); 2.47 (s, 3H); 2.86-3.10 (m, 3H); 3.18 (s, IH); 4.60 (s, IH); 4.74 (s, IH); ES Mass: 715 (100%), [M+l].
Example 23: Preparation of (lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)-9- hydroxy-5a,5b,8,8,l la-pentamethyl-N-((lR,3S)-3-(moipholinomethyl)cvclopentyl)- 1 -(prop- 1 -en-2-yl)icosahvdro- 1 H-cyclopenta[alchrysene-3a-carboxamide:
Figure imgf000086_0001
( 1 R,3aS,5aR,5bR,7aR,9S, 11 aR, 1 IbR, 13aR, 13bR)-5a,5b,8,8, 1 1 a- pentamethyl-3a-(( 1 R,3S)-3-(moφholinomethyl)cyclopentylcarbamoyl)- 1 -(prop- 1 - en-2-yl)icosahydro-lH-cyclopenta[a]chrysen-9-yl acetate (Example 20, 0.22 g ) in MeOH:THF (8:8 ml) and cooled the contents to 0 0C then sodium hydroxide (0.05g in 4ml water) was added and the contents were stirred for about 6 hours at room temperature then completion of the reaction was monitored by TLC. The reaction mixture was evaporated under reduced pressure, the residue was taken in water and extracted with DCM. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 5% methanol in DCM as an eluent to furnish the title compound (0.14 g) as a white solid. 1H NMR (300 MHz, CDCl3): 0.88-0.96 (m,
9H); 1.25-1.39 (m, HH); 1.43- 1.88 (m, 24H) 2.21-2.47 (m, 8H); 2.86-3.10 (m, 3H); 3.15-3.72 (m, 7H); 4.60 (s, IH); 4.74 (s, IH); ES Mass: 622 (100%), [M+Na] 645; HPLC: 98.6 %.
Example 24j Preparation of 2,2-dimethyl-4-oxo-4- (( 1 R,3aS.5aR.5bR.7aR,9S.11 aR.1 IbR.13aR.13bR)-5a.5b.8.8.11 a-pentamethyl-3a-
(( 1 R,3S)-3-(morpholinometh vDcyclopentylcarbamoyl)- 1 -(prop- 1 -en-2- vPicosahydro- 1 H-c yclopenta[alchrvsen-9-yloxy)butanoic acid:
To a stirred solution of (lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)- 5a,5b,8,8,l la-pentamethyl-3a-((lR,3S)-3-
(morpholinomethyl)cyclopentylcarbamoyl)- 1 -(prop- 1 -en-2-yl)icosahydro- 1 H- cyclopenta[a]chrysen-9-yl acetate (Example 23, 0.15 g, 0.24 mmol) in pyridine (5 ml) dimethyl amino pyridine (0.32 g, 0.48 mmol) and 3,3-dimethyldihydrofuran-2,5- dione (1.3 ml) were added and the contents were refluxed for about 16 hours and completion of the reaction monitored by TLC. The reaction mixture was diluted with ethyl acetate (30 ml). The organic layer was washed with 5% aqueous HCl, washed with water followed by brine solution, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 5% MeOH in DCM as eluent to furnish the title compound (0.1 g) as a white solid. 1H NMR (300 MHz, CDCl3): 0.95-1.16 (m, 19H); 1.23-1.78 (m, 23H); 2.15-
2.59 (m, IH); 2.77-3.58 (m, HH); 4.33-4.70 (m, 4H); 5.58-5.60 (s, IH); 5.78- 5.80 (s, IH); 7.44-7.47 (s, IH); ES Mass: [M+l] 750 (100%); HPLC: 98.08%.
Example 25: Preparation of ((lR.5aR,5bRJaR,9S,l laR,l lbR, 13aR.13bR)-9- hydroxy-5a,5b,8,8,l la-pentamethyl-1 -(prop- l-en-2-yl)icosahydro- IH- cyclopenta[alchrvsen-3a-yl)(3-(3-isopropyl-5-methyl-4H-l ,2,4-triazol-4-yl)-8- azabicyclo[3.2.11octan-8-yl)methanone:
Figure imgf000087_0001
(lR,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)-3a-(3-(3-isopropyl-5-methyl- 4H- 1 ,2,4-triazol-4-yl)-8-azabicyclo[3.2.1 ]octane-8-carbonyl)-5a,5b,8,8, 1 1 a- pentamethyl- 1 -(prop- 1 -en-2-yl)icosahydro- 1 H-cyclopenta[a]chrysen-9-yl acetate
(Example 22, 0.2g) in MeOH: THF (8: 8 ml) and cooled the contents to 0 0C then sodium hydroxide (0.05 g in 4ml water) was added and the contents were stirred for about for about 6 hours at room temperature and completion of the reaction was monitored by TLC. The reaction mixture was evaporated under reduced pressure, the residue was taken in water and extracted with DCM. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 5% methanol in DCM as eluent to furnish the title compound (0.14g) as a white solid. 1H NMR (300 MHz, CDCl3): 0.76-0.99 (m, 16H); 1.25-1.85 (m, 35H); 2.03-2.28 (m, 6H); 2.47 (s, 3H); 2.86-3.10 (m, 3H); 3.18 (s, IH); 4.60 (s, IH); 4.74 (s, IH); ES Mass: [M+] 672 (100%), [M+l] 673; HPLC: 95.5 %.
Example 26: Preparation of (lR.3aS.5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)-9- hydroxy-5a,5b,8,8,l la-pentamethyl-N-((lS,4R)-4-(moipholinomethyl)cyclopent-2- enyl)- 1 -(prop- 1 -en-2-yl)icosahvdiO- 1 H-cyclopenta[a1chrysene-3a-carboxamide:
Figure imgf000088_0001
( 1 R,3aS,5aR,5bR,7aR,9S, 11 aR, 1 IbR, 13aR, 13bR)-5a,5b,8,8, 1 1 a- pentamethyl-3a-((lS,4R)-4-(moφholinomethyl)cyclopent-2-enylcarbamoyl)-l- (prop-l-en-2-yl)icosahydro-lH-cyclopenta[a]chrysen-9-yl acetate (Example 21, 0.22 g) in MeOH:THF (8:8 ml) and cooled the contents to 0 0C then sodium hydroxide (0.05g in 4ml water) was added and the contents were stirred for about 6 hours at room temperature then completion of the reaction was monitored by TLC. The reaction mixture was evaporated under reduced pressure, the residue was taken in water and extracted with DCM. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 5% methanol in DCM as eluent to furnish the title compound
(0.14 g) as a white solid. 1H NMR (300 MHz, CDCl3): 0.88-0.96 (m, 9H); 1.25-1.39 (m, HH); 1.43- 1.88 (m, 24H); 2.21-2.47 (m, 8H); 2.86-3.10 (m, 3H); 3.15-3.72 (m, 7H); 4.60 (s, IH); 4.74 (s, IH); 5.52-5.55 (m, IH); 5.69-5.70 (m, IH); 5.72-5.91 (m, IH); ES Mass: 620 ( 100%), [M+l] 621 ; HPLC: 96.98%. Example 27: Preparation of (lR.3aS,5aR,5bR.7aR.9S.l laR.l lbR,13aR.13bR)-3a- (4-(hydroxymethyl)cyclopent-2-enylcarbamoyl)-5a,5b.8.8,l la-pentamethyl-l-(prop- 1 -en-2- vPicosah ydro- 1 H-cvcIopenta[alchrysen-9-vl acetate:
Figure imgf000089_0001
To a stirred solution of (IR1SaS1SaR1SbRJaR^S1I IaR1I lbR,13aR,13bR)-9- acetoxy-5a,5b,8,8, 11 a-pentamethyl- 1 -(prop- 1 -en-2-yl)icosahydro- 1 H- cyclopenta[a]chrysene-3a-carboxylic acid (0.8 g, 1.6 mmol) in DCM (50 ml) oxalyl chloride (1.02 ml, 8.02 mmol) was added at room temperature and completion of the reaction monitored by TLC. The reaction mixture was concentrated under reduced pressure and the residue was taken in DCM (15 ml) then kept under N2 atmosphere.
To a stirred solution of ((lR,4S)-4-aminocyclopent-2-enyl)methanol (0.22 g , 1.92 mmol) in DCM (50 ml) triethyl amine (2 ml, 19.8 mmol) was added at about 0 0C and stirred for about 15 minutes then above prepared acid chloride was added and stirred continually at room temperature for about 8 hours and completion of reaction monitored by TLC. The reaction mixture was neutralized with saturated
NaHCO3 and extracted with DCM1 the organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 5% methanol in DCM as eluent to furnish the title compound (0.56 g) as a white solid. 1H NMR (300 MHz1 CDCl3): 0.88-0.96(m, 9H); 1.25-1.39 (m, HH); 1.43- 1.88 (m, 14H); 2.07 (s, 3H); 2.21-2.47 (m, 8H); 2.86-3.10 (m, 3H);
3.15-3.72 (m, 7H); 4.60 (s, IH); 4.74 (s, IH); 5.52-5.55 (m, IH); 5.69-5.70 (m, IH); 5.72-5.91 (m, IH); ES Mass: 593 [M+Na] 616(100%).
Example 28: Preparation of ( lR,3aS,5aR,5bR,7aR.9S.l laR.l lbR,13aR,13bR)-9- hydroxy-N-(4-(hydiOxymethyl)cyclopent-2-enyl)-5a,5b,8,8, 1 1 a-pentamethyl- 1 -
(prop-l-en-2-yl)icosahvdro-lH-cvclopentafa1chrysene-3a-carboxamide:
Figure imgf000089_0002
(lR,3aS,5aR,5bR,7aR,9S,l IaR1I lbR,13aR,13bR)-3a-(4-
(hydroxymethyl)cyclopent-2-enylcarbamoyl)-5a,5b,8,8, 11 a-pentamethyl- 1 -(prop- 1 - en-2-yl)icosahydro-lH-cyclopenta[a]chrysen-9-yl acetate (Example 27, 0.22 g) in MeOH:THF (8:8 ml) and cooled the contents to 0 0C then sodium hydroxide (0.05g in 4 ml water) was added and the contents were stirred for about 6 hours at room temperature then completion of the reaction was monitored by TLC. The reaction mixture was evaporated under reduced pressure, the residue was taken in water and extracted with DCM. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 5% methanol in DCM as eluent to furnish the title compound (0.14 g) as a white solid. 1H NMR (300 MHz, CDCl3): 0.76-0.99 (m, 16H); 1.25- 1.85 (m, 35H); 2.03-2.28 (m, 6H); 2.47 (s, 3H); 2.86-3.10 (m, 3H); 3.18 (s, IH); 4.60 (s, IH); 4.74 (s, IH); ES Mass: 551 (100%), [M+l] 551 ; HPLC: 96.94 %.
Example 29: Preparation of ( lR,3aS.5aR,5bR.7aR.9S.l laR,l lbR.13aR.13bR)-3a- ((2S,3R)-4-((3S,4aS,8aS)-3-(tert-butylcarbamoyl)octahvdroisoquinolin-2(lH)-yl)-3- hvdroxy- 1 -phen ylbutan-2-ylcarbamoyl)-5a,5b,8.8, 11 a-pentameth yl- 1 -(prop- 1 -en-2- yl)icosahvdro-lH-cvclopentara1chrvsen-9-yl acetate:
Figure imgf000090_0001
To a stirred solution of (lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)-9- acetoxy-5a,5b,8, 8,1 1 a-pentamethyl-1 -(prop- l-en-2-yl)icosahydro- IH- cyclopenta[a]chrysene-3a-carboxylic acid (0.5 g, 1.0 mmol) in DCM (50 ml) oxalyl chloride (1 ml, 7.93 mmol) was added at room temperature and completion of the reaction monitored by TLC. The reaction mixture was concentrated under reduced pressure and the residue was taken in DCM (15 ml) then kept under N2 atmosphere.
To a stirred solution of (3S,4aS,8aS)-2-((2R,3S)-3-amino-2-hydroxy-4- phenylbutyl)-N-tert-butyldecahydroisoquinoline-3-carboxamide (0.44 g , 1.1 mmol) in DCM (50 ml) triethyl amine (0.4 ml, 3.01 mmol) was added at about 0 0C and stirred for about 15 minutes then above prepared acid chloride was added and stirred continually at room temperature for about 8 hours and completion of the reaction was monitored by TLC. The reaction mixture was neutralized with saturated NaHCO3 and extracted with DCM, the organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 5% methanol in DCM as eluent to furnish the title compound (0.68 g) as a white solid. 1H NMR (300 MHz, CDCl3): 0.57- 0.97 (m, 19H); 1.18- 1.21 (m, 8H); 1.25- 1.41 (m, 12H); 1.49-1.62 (m, 8H); 1.65- 1.82 (m, 10H); 1.85- 1.98 (m, 4H); 2.01 (s, 3H); 2.56-2.69 (m, 2H); 2.88-3.06 (m, 3H); 3.29-3.38 (m, IH); 3.89-3.90 (m, IH); 4.25-4.70 (m, 4H); 5.78 (s, IH); 6.12-6.15 (d, J= 9Hz, IH); 7.19-7.29 (m, 6H); ES Mass: 881 (100%), [M+l] 882.
Example 30: Preparation of (3S.4aS,8aS)-N-tert-butyl-2-((2R.3S)-2-hydroxy-3-
(( 1 R.3aS.5aR,5bR,7aR,9S, 11 aR.1 1 bR, 13aR, 13bR)-9-hydroxy-5a,5b.8,8.1 1 a- pentamethyl- 1 -(prop- 1 -en-2-yl)icosah ydro- 1 H-cyclopenta[alchrysene-3a- carboxamido)-4-phenylbutyl)decahydroisoquinoline-3-carboxamide:
Figure imgf000091_0001
( lR,3aS,5aR,5bR,7aR,9S, 1 1 aR, 1 IbR, 13aR, 13bR)-3a-((2S,3R)-4-
((3S,4aS,8aS)-3-(tert-butylcarbamoyl)octahydroisoquinolin-2(lH)-yl)-3-hydroxy-l- phenylbutan-2-ylcarbamoyl)-5a,5b,8,8, 11 a-pentamethyl- 1 -(prop- 1 -en-2- yl)icosahydro-lH-cyclopenta[a]chrysen-9-yl acetate (Example 29, 0.5g) in MeOH:THF (8:8 ml) and cooled the contents to 0 0C then sodium hydroxide (0.12 g in 4ml water) was added and the contents were stirred for about 6 hours at room temperature, and the completion of the reaction was monitored by TLC. The reaction mixture was evaporated under reduced pressure, the residue was taken in water and extracted with DCM. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 5% methanol in DCM as eluent to furnish the title compound (0.34 g) as a white solid. 1H NMR (300 MHz, CDCl3): 0.57- 0.97 (m, 19H); 1.18- 1.21 (m, 8H); 1.25- 1.41 (m, 12H); 1.49-1.62 (m, 8H); 1.65- 1.82 (m, 10H); 1.85- 1.98 (m, 4H); 2.56-2.69 (m, 2H); 2.88-3.06 (m, 3H); 3.29-3.38 (m, IH); 3.89-3.90 (m, IH); 4.25-4.70 (m, 4H); 5.78 (s, IH); 6.12-6.15 (d, J= 9Hz, IH); 7.19-7.29 (m,
6H); ES Mass: 839 (100%), [M+l] 840.
Example 31 : Preparation of (lR,3aS.5aR,5bR.7aR.9S,l laR.l lbR.13aR.13bR)-3a- (( 1 R,3S)-3-((4-benzylpiperidin- 1 -yDmethyDcyclopentylcarbamoyD-Sa.Sb.δ.δ, 1 1 a- pentameth yl- 1 -(prop- 1 -en-2-yl)icosah ydro- 1 H-cyclopenta[a1chrysen-9-yl acetate:
Figure imgf000091_0002
To a stirred solution of (lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)-9- acetoxy-5a,5b,8,8, 11 a-pentamethyl- 1 -(prop- 1 -en-2-yl)icosahydro- 1 H- cyclopenta[a]chrysene-3a-carboxylic acid (0.5 g, 1.04 mmol) (Prepared as described in J.Med.Chem. 2009. 52, 3248-3258) in 50 ml DCM was added Oxolyl chloride (2 ml, 15.87 mmol) and stirred at room temperature for about 6 hours and completion of the reaction monitored by TLC. The reaction mixture was concentrated under reduced pressure and the residue was taken in DCM (15 ml) then kept under N2 atmosphere.
To a stirred solution of (lR,3S)-3-((4-benzylpiperidin-l- yloxy)methyl)cyclopentanamine (0.43 g, 1.5 mmol) in DCM (50 ml) triethyl amine
(0.3 ml, 3.12 mmol) was added at about 0 0C and stirred for about 15 minutes then the above prepared acid chloride was added and stirred continually at room temperature for about 8 hours and completion of the reaction was monitored by TLC. The reaction mixture was neutralized with saturated NaHCO3 and extracted with DCM, the organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 5% methanol in DCM as eluent to furnish the title compound (0.4 g) as a white solid. 1H NMR (300 MHz, CDCl3): 0.57- 0.97 (m, 19H); 1.18- 1.21 (m, 8H); 1.25- 1.41 (m, 12H); 1.49-1.62 (m, 8H); 1.65- 1.82 (m, 10H); 1.85- 1.98 (m, 4H); 2.56-2.69 (m, 2H); 2.88-3.06 (m, 3H); 3.29-3.38 (m, IH); 3.89-3.90 (m, IH); 4.25-4.70 (m, 4H);
5.78 (s, IH); 6.12-6.15 (d, J= 9Hz, IH); 7.19-7.29 (m, 6H); ES Mass: 753 (100%).
Example 32: Preparation of (lRJaS.SaR.SbRJaR^SJ laR.l lbR.OaR.BbR)-^ (( 1 R.3S)-3-((4-benzylpiperidin- 1 - yl)methyl)cvclopentyl)-9-hvdrox v-5a,5b.8,8.1 1 a- pentamethyl-l-(prop-l-en-2-yl)icosahvdro-lH-cvclopenta[alchrysene-3a- carboxamide:
Figure imgf000092_0001
(2S,4aR,4bR,6aR,7R,8S,10aR,10bR,12aR)-8-((lR,3S)-3-((4- benzylpiperidin- 1 -yl)methyl)cyclopentylcarbamoyl)- 1 , 1 ,4a,8, 10a, 1 Ob-hexamethyl-7- (2-methylallyl)octadecahydrochrysen-2-yl acetate (Example 31, 0.5 g) in
MeOH:THF (8:8 ml) and cooled the contents to 0 0C then sodium hydroxide (0.12g in 4ml water) was added and the contents were stirred for about 6 hours at room temperature then completion of the reaction was monitored by TLC. The reaction mixture was evaporated under reduced pressure, the residue was taken in water and extracted with DCM. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 5% methanol in DCM as eluent to furnish the title compound
(0.34 g) as a white solid. 1H NMR (300 MHz, CDCl3): 0.57- 0.97 (m, 19H); 1.18- 1.21 (m, 8H); 1.25- 1.41 (m, 12H); 1.49-1.62 (m, 8H); 1.65- 1.82 (m, 10H); 1.85- 1.98 (m, 4H); 2.56-2.69 (m, 2H); 2.88-3.06 (m, 3H); 3.29-3.38 (m, IH); 3.89-3.90 (m, IH); 4.25-4.70 (m, 4H); 5.78 (s, IH); MASS: 711 (100%).
Example 33: Preparation of S-αiRJaS.SaR.SbRJaR^S.l laR.l lbR.naR.DbR)-
3a-((lR,3S)-3-((4-benzylpiperidin-l-yl)methyl)cyclopentylcarbamoyl)-
5a.5b,8,8, 11 a-pentamethyl- 1 -(prop- 1 -en-2- yl )icosahydro- 1 H-c vclopentafaichrvsen-
9-yloxy)-5-oxopentanoic acid:
Figure imgf000093_0001
To a stirred solution of (lR,3aS,5aR,5bR,7aR.9S,l laR,l lbR,13aR,13bR)-N- (( 1 R,3S)-3-((4-benzylpiperidin- 1 -yl)methyl)cyclopentyl)-9-hydroxy-5a,5b,8,8, 11 a- pentamethyl-l-(prop-l-en-2-yl)icosahydro-lH-cyclopenta[a]chrysene-3a- carboxamide (Example 32, 0.24 mmol) in pyridine (5 ml) dimethyl amino pyridine (0.32 g, 0.48 mmol) and glutaric anhydride (1.3 ml) were added and the contents were refluxed for about 16 hours and completion of the reaction monitored by TLC. The reaction mixture was diluted with ethyl acetate (30 ml). The organic layer was washed with 5% aqueous HCl, washed with water followed by brine solution, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 5% MeOH in DCM as eluent to furnish the title compound (0.1 g) as a white solid. 1H NMR (300 MHz, CDCl3): 0.82- 0.95(m,17H)l .13-3.01 (m, 48H); 3.05-3.12(m,4H), 3.13-3.54(m,2H),4.18-4.21 (m,lH),4.45-4.17(m,lH),4.58(s,lH), 4.72 (s, IH); 6.28-6.30 (m, 1H),7.1 1- 7.13(m,2H),7.14-7.22(m, lH),7.24-7.29(m,2H); ES Mass: [M+]825 (100%); HPLC: 90 %. Example 34: Preparation of (lR.3aS,5aR.5bR,7aR,9S.l laR.l lbR,13aR.13bR)-3a- ((lR,3S)-3-((4-ethylpiperazin-l-yl)methyl)cvclopentylcarbamoyl)-5a,5b,8,8,l la- pentamethyl- 1 -(prop- 1 -en-2-yl)icosah vdro- 1 H-c vclopentaraichrysen-9- yl acetate:
Figure imgf000094_0001
To a stirred solution of (lR,3aS,5aR,5bR,7aR,9S,l IaR5I lbR,13aR,13bR)-9- acetoxy-5a,5b,8,8, 11 a-pentamethyl- 1 -(prop- 1 -en-2-yl)icosahydro- 1 H- cyclopenta[a]chrysene-3a-carboxylic acid (0.5 g, 1.04 mmol) (Prepared as described in J.Med.Chem. 2009, 52, 3248-3258) in 50 ml DCM was added Oxolyl chloride (2 ml, 15.87 mmol) and stirred at room temperature for about 6 hours and completion of the reaction monitored by TLC. The reaction mixture was concentrated under reduced pressure and the residue was taken in DCM (15 ml) then kept under N2 atmosphere.
To a stirred solution of (lR,3S)-3-((4-ethylpiperazin-l- yl)methyl)cyclopentanamine (0.43 g, 1.5 mmol) in DCM (50 ml) triethyl amine (0.3 ml, 3.12 mmol) was added at about 0 0C and stirred for about 15 minutes then the above prepared acid chloride was added and stirred continually at room temperature for about 8 hours and completion of reaction monitored by TLC. The reaction mixture was neutralized with saturated NaHCO3 and extracted with DCM, the organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 5% methanol in
DCM as eluent to furnish the title compound (0.56 g) as a white solid. 1H NMR (300 MHz, CDCl3): 0.57- 0.97 (m, 19H); 1.18-1.21 (m, 8H); 1.25- 1.41 (m, 12H); 1.49- 1.62 (m, 8H); 1.65- 1.82 (m, 10H); 1.85-1.98 (m, 4H); 2.56-2.69 (m, 2H); 2.88-3.06 (m, 3H); 3.29-3.38 (m, IH); 3.89-3.90 (m, IH); 4.25-4.70 (m, 4H); 5.78 (s, IH); 6.12-6.15 (d, J= 9Hz, IH); 7.19-7.29 (m, 6H); MASS: 692 (100%).
Example 35: Preparation of ( lR,3aS,5aR.5bR.7aR,9S,l laR.l lbR,13aR.13bR)-N- (( lR,3S)-3-((4-ethylpiperazin-l-yl)methyl)cvclopentyl)-9-hvdroxy-5a,5b,8,8,l la- pentamethyl- 1 -(prop- 1 -en-2-yl)icosahydro- 1 H-cyclopentaralchi'ysene-3a- carboxamide:
Figure imgf000095_0001
lR,3aS,5aR,5bR,7aR,9S,l IaR5I lbR,13aR,13bR)-3a-((lR,3S)-3-((4- ethylpiperazin- 1 -yl)methyl)cyclopentylcarbamoyl)-5a,5b,8,8, 11 a-pentamethyl- 1 - (prop-l-en-2-yl)icosahydiO-lH-cyclopenta[a]chrysen-9-yl acetate (Example 34, 0.5 g) in MeOH:THF (8:8 ml) and cooled the contents to 0 0C then sodium hydroxide
(0.12 g in 4ml water) was added and the contents were stirred for about 6 hours at room temperature then completion of the reaction was monitored by TLC. The reaction mixture was evaporated under reduced pressure, the residue was taken in water and extracted with DCM. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 5% methanol in DCM as eluent to furnish the title compound (0.34 g) as a white solid. 1H NMR (300 MHz, CDCl3): 0.57- 0.97 (m, 19H); 1.18- 1.21 (m, 8H); 1.25- 1.41 (m, 12H); 1.49-1.62 (m, 8H); 1.65- 1.82 (m, 10H); 1.85- 1.98 (m, 4H); 2.56-2.69 (m, 2H); 2.88-3.06 (m, 3H); 3.29-3.38 (m, IH); 3.89-3.90 (m, IH); 4.25-4.70 (m, 4H); 5.78 (s, IH); MASS: 650 (100%).
Example 36: Preparation of 4-((lR.3aS,5aR,5bR.7aR.9S,l laR,l lbR.13aR,13bR)- 3a-((lR,3S)-3-((4-ethylpiperazin-l-yl)methyl)cvclopentylcarbamoyl)-5a,5b,8,8,l la- pentamethyl- 1 -(prop- 1 -en-2-yl)icosahvdro- 1 H-cyclopenta[alchrysen-9-yloxy)-2,2- dimethyl-4-oxobutanoic acid:
Figure imgf000095_0002
To a stirred solution Of (IR1SaS5SaR7SbRJaR^S5I IaRJ IbR5BaR1ISbR)-N- ((lR53S)-3-((4-ethylpiperazin-l-yl)methyl)cyclopentyl)-9-hydroxy-5a55b,8,8,l la- pentamethyl- 1 -(prop- 1 -en-2-yl)icosahydro- 1 H-cyclopenta[a]chrysene-3a- carboxamide (Example 35, 0.24 mmol) in pyridine (5 ml) dimethyl amino pyridine
(0.32 g, 0.48 mmol) and 3,3-dimethyldihydrofuran-2,5-dione (1.3 ml) were added and the contents were refluxed for about 16 hours and completion of the reaction was monitored by TLC. The reaction mixture was diluted with ethyl acetate (30 ml). The organic layer was washed with 5% aqueous HCl5 washed with water followed by brine solution, dried over Na2SO4 and concentrated under reduced pressure. The 7 residue was purified by silica gel column chromatography using 5% MeOH in DCM as eluent to furnish the title compound (0.1 g) as a white solid. 1H NMR (300 MHz, CDCl3): 0.80- 0.95(m,16H)1.23-1.90 (m, 41H); 2.03-3.08(m,16H), 4.13-4.18 (m,lH),4.46(s,lH),4.58(s,lH), 4.72 (s, IH); 5.61-5.63 (m, IH); ES Mass: [M+l] 778 (100%); HPLC: 78.4%.
Example 37j Preparation of methyl 3-((lS,3R)-3-
(( 1 R.3aS.5aR,5bR.7aR.9S.1 1 aR, 1 IbR.13aR, 13bR)-9-acetoxy-5a,5b.8.8, 1 1 a- pentamethyl-l-(prop-l-en-2-yl)icosahvdro-lH-cyclopenta[alchi-ysene-3a- carboxamido)-2,2-dimethylcyclobutanecarboxamido)piOpanoate:
Figure imgf000096_0001
Step 1: Synthesis of methyl 3-((IS,3R)-3-(tert-butoxycarbonylamino)-2,2- dimethylcyclobutanecarboxamido)propanoate:
Figure imgf000096_0002
To a stirred solution of (lS,3R)-3-(tert-butoxycarbonylamino)-2,2- dimethylcyclobutanecarboxylic acid (0.3 g, 1.234 mmol) in DCM (5 ml) EDCI (0.284 g, 1.48 mmol) and HOBt (0.2 g, 1.48 mmol) were added at about 0 0C. after 10 minutes methyl 3-aminopropanoate hydrochloride (0.254 g, 2.47 mmol) and Et3N (0.9 ml, 6.17 mmol) in DCM (5 ml) were added drop wise and the reaction mass was allowed to stir at room temperature for about 16 hours. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with DCM and washed with water and saturated NaHCO3 solution, then washed with aqueous IN HCl, then washed with water and saturated brine, and the organic layer was concentrated under reduced pressure, the resulting crude was purified by silica gel column (100-200 mesh, elution 70% EtOAC in hexane) to afford the title compound as solid. Wt: 0.336 g; Yield: 88.9%; 1H NMR (300 MHz, CDCl3): δ 5.89 (brs, IH), 4.79 (d, IH, J = 8.1 Hz), 3.88-3.73 (m, IH), 3.70 (s, 3H), 3.59-3.42 (m, 2H), 2.54- 2.51 (m, 2H), 2.39-2.20 (m, 2H), 2.1 1-1.99 (m, IH), 1.43 (s, 9H), 1.26 (s, 3H), 0.87 (s, 3H); Mass: [M+Na]+ 351 (100%); IR (KBr, cm 1): 3359, 3319, 2973, 1737, 1696, 1667, 1539, 1454, 1366, 1271 , 1254, 1 176, 1051, 1024, 782, 683; M.R: 98.60C -
100.2 0C. Step 2: synthesis of methyl 3-((lS,3R)-3-amino-2,2- dimethylcyclobutanecarboxamido)propanoate:
Figure imgf000097_0001
A stirred solution of methyl 3-((lS,3R)-3-(tert-butoxycarbonylamino)-2,2- dimethylcyclobutanecarboxamido)propanoate (step 1, 0.336 g, 1.024 mmol) in TFA: DCM (1:4) (4 ml) at 0°C-room temperature for about 1 hour and after completion of the reaction, the solvent was evaporated and the crude dissolved in DCM and basified with Et3N (0.87 ml, 6.29 mmol) then the resulting solution as such used for the next reaction. Wt: 0.233 g (Based on 100% yield calculated and proceeded for next reaction).
Step 3: Preparation of methyl 3-((lS,3R)-3- ((lR,3aS,5aR,5bR,7aR,9S,l IaRJ JbR,13aR,13bR)-9-acetoxy-5a,5b,8,8,l Ia- pentamethyl- 1 -(prop- 1 -en-2-yl)icosahydro- lH-cyclopenta[a] chrysene-3a- carboxamido)-2,2-dimethylcyclobutanecarboxamido)propanoate:
To a stirred solution of (lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)-9- acetoxy-5a,5b,8,8, 11 a-pentamethyl- 1 -(prop- 1 -en-2-yl)icosahydro- 1 H- cyclopenta[a]chrysene-3a-carboxylic acid (0.25 g, 0.502 mmol) (Prepared as described in J.Med.Chem. 2009. 52, 3248-3258) in DCM (1 ml) Oxolyl chloride (2 M) in DCM (2.5 ml, 5.02 mmol) was added and stirred at room temperature for about 3 hours and completion of the reaction was monitored by TLC then the solvent was evaporated under a nitrogen atmosphere and dissolved in DCM (4 ml), which was added to a solution of methyl 3-((lS,3R)-3-amino-2,2- dimethylcyclobutanecarboxamido) propanoate (step 2) in DCM (5 ml) at about 0 C and allowed to stir at room temperature for 16 hours. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with DCM and washed with water, IN HCl, water brine and dried over Na2SO4, the solvent was evaporated and purified by silica gel column (100-200 mesh, elution 25% EtOAc in hexane) to afford the compound as a off white solid. Wt: 0.150 g: Yield: 35.2 %; 1H NMR (300 MHz, CDCl3): δ 5.99 (d, IH, J = 8.1 Hz), 5.90 (t, IH, J = 6.0 Hz), 4.73 (s, IH), 4.58 (s, IH), 4.50-4.41 (m, IH), 4.14-4.04 (m, IH), 3.70 (s, 3H), 3.59-3.43 (m, 3H), 3.17-3.08 (m, IH), 2.59-2.22 (m, 6H), 2.19-2.06 (m, IH), 2.04 (s, 3H), 1.99-1.87 (m, 2H), 1.80-1.12 (m, 25H), 0.96-0.73 (s, 18H); Mass: [M+Na]+ 731 (100%); IR (KBr, cm"1): 3375, 2952, 1736, 1656, 1516, 1439, 1369, 1247, 1178, 1074, 1027, 980, 885; M.R: 87.90C -90.70C.
Example 3_8j Preparation of 3-(dS.3R)-3-
((lR.3aS,5aR,5bR,7aR.9S.l laR.l lbR,13aR.13bR)-9-hvdroxy-5a.5b,8,8.1 Ia- pentameth yl- 1 -(prop- 1 -en-2- vDicosahydro- 1 H-c yclopenta[alchrysene-3a- carboxamido)-2,2-dimethylcvclobutanecarboxamido)propanoic acid:
Figure imgf000098_0001
To a stirred solution of methyl 3-((lS,3R)-3-
((lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)-9-acetoxy-5a,5b,8,8,l Ia- pentamethyl-l-(prop-l-en-2-yl)icosahydro-lH-cyclopenta[a]chrysene-3a- carboxamido)-2,2-dimethylcyclobutanecarboxamido)piOpanoate (Example 37, 0.150 g, 0.21 1 mmol) in MeOH:THF (2: 1) (7.5 ml), 2N NaOH (2.5 ml) was added at about
0 0C and allowed to stir at room temperature for about 16 hours. After completion of the reaction (monitored by TLC), the volatile was evaporated. The reaction mixture was acidified with IN HCl, filtered, washed with water and dried under vacuum to afford the title compound as an off white solid. Wt: 0.030 g: Yield: 21.7 %; 1H NMR (300 MHz, DMSO-d6): δ 7.61 (brm, IH), 7.54 (d, IH, J = 7.2 Hz), 4.63 (s,
IH), 4.52 (s, IH), 2.90-2.80 (m, IH), 3.20-3.08 (m, 3H), 3.00-2.89 (m, 3H), 2.68- 2.54 (m, 2H), 2.40-2.18 (m, 5H), 1.90-1.74 (m, 2H), 1.70-1.00 (m, 28H), 0.90, 0.86, 0.84, 0.75, 0.72, 0.64 (s, 15H); Mass: [M+l]+ 653 (2%), [M+Na]+ 675 (100%); IR (KBr, cm 1): 3408, 2947, 2868, 1724, 1652, 1636, 1523, 1376, 1250, 1194, 1108, 1074, 1033, 983, 881, 730; M.R: 188.6 0C -200.1 0C; HPLC: 99.35%.
Example 39: Preparation of (S)-methyl 2-((lS.3R)-3-
((lR.3aS,5aR.5bR.7aR,9S,l laR.l lbR.13aR.13bR)-9-acetoxy-5a,5b.8.8.1 Ia- pentamethyl- 1 -(prop- 1 -en-2- vDicosahydro- 1 H-cyclopenta[alchrvsene-3a- carboxamido)-2,2-dimethylcvclobutanecarboxamido)-3-methylbutanoate:
Figure imgf000099_0001
Step 1: Synthesis of (S)-methyl 2-((lS,3R)-3-(tert-butoxycarbonylamino)-2,2- dimethylcyclobutanecarboxamido)-3-methylbutanoate:
Figure imgf000099_0002
To a stirred solution of (lS,3R)-3-(tert-butoxycarbonylamino)-2,2- dimethylcyclobutanecarboxylic acid (0.350 g, 1.44 mmol) in DCM (5 ml) EDCI (0.331 g, 1.73 mmol) and HOBt (0.234 g, 1.73 mmol) were added at about 0 0C. After 10 minutes, (S)-methyl 2-amino-3-methylbutanoate hydrochloride (0.720, 8.64 mmol) and Et3N (1.2 ml, 6.17 mmol) in DCM (5 ml) were added drop wise and the reaction mass was allowed to stir at room temperature for about 16 hours. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with DCM and washed with water and saturated NaHCO3 solution, then washed with aqueous IN HCl, then washed with water and saturated brine, and the organic layer was concentrated under reduced pressure, the resulting crude was purified by silica gel column (100-200 mesh, elution 70% EtOAC in hexane) to afford the title compound as a solid. Wt: 0.440 g; Yield: 85.9%; 1H NMR (300 MHz, CDCl3): δ 5.62 (d, IH, J = 8.4 Hz), 4.77 (d, IH, J = 8.4 Hz), 4.70-4.60 (m, IH), 4.89-4.71 (m, IH), 3.72 (s, 3H), 2.46- 2.21 (m, 2H), 2.18-1.99 (m, IH), 1.70-1.50 (m, IH), 1.42 (s, 9H), 1.31 (s, 3H), 0.94-0.90 (s, 9H); Mass: The related mass peak was not observed; ER (KBr, cm"1): 3345, 3314, 2960, 1753, 1690, 1664, 1529, 1456, 1366, 1271, 1172,
1049, 1028, 986, 873.
Step 2: Synthesis of (S)-methyl 2-((lS,3R)-3-amino-2,2- dimethylcyclobutanecarboxamido)-3-methylbutanoate:
Figure imgf000099_0003
A stirred solution of (S)-methyl 2-((lS,3R)-3-(tert-butoxycarbonylamino)-
2,2-dimethylcyclobutanecarboxamido)-3-methylbutanoate (step I, 0.430 g, 1.21 mmol) in TFA: DCM (1 :4) (4 ml) at 0 °C-room temperature for about 1 hour. After completion of the reaction, the solvent was evaporated and the crude was dissolved in DCM and basified with Et3N (1.0 ml, 7.25 mmol) then the resulting solution as such used for next reaction immediately. Wt: 0.309 g (Based on 100% yield calculated and proceeded for next reaction).
Step 3: Preparation of (S)-methyl 2-((lS,3R)-3- ((lR,3aS,5aR,5bR,7aR,9S,l IaRJ lbR,13aR,13bR)-9-acetoxy-5a,5b,8,8,l Ja- pentamethyl-l-(prop-l-en-2-yl)icosahydro-lH-cyclopenta[a]chιysene-3a- carboxamido)-2,2-dimethylcyclobutanecarboxamido)-3-methylbutanoate:
To a stirred solution of (lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)-9- acetoxy-5a,5b,8,8, 1 1 a-pentamethyl- 1 -(prop- 1 -en-2-yl)icosahydro- 1 H- cyclopenta[a]chrysene-3a-carboxylic acid (0.350 g, 0.702 mmol) (Prepared as described in J.Med.Chem. 2009. 52, 3248-3258) in DCM (1 ml) Oxolyl chloride (2 M) in DCM (3.51 ml, 0.702 mmol) was added at 0 0C and stirred at room temperature for about 3 hours and completion of the reaction monitored by TLC then the solvent was evaporated under nitrogen atmosphere and dissolved in DCM (4 ml), which was added to a solution of (S)-methyl 2-((lS,3R)-3-amino-2,2- dimethylcyclobutanecarboxamido)-3-methylbutanoate (Step 2, 0.27 g) in DCM (5 ml) at 0 0C and allowed to stir at room temperature for about 16 hours. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with DCM and washed with aqueous IN HCl, then water and brine, and dried over Na2SO4, the solvent was evaporated and purified by silica gel column (100-200 mesh, elution 30% EtOAc in hexane) to afford the title compound as an off white solid. Wt: 0.300 g: Yield: 35.2 %; 1H NMR (300 MHz, CDCl3): δ 5.87 (d, IH, J = 8.1 Hz), 5.56 (d, IH, 7 = 8.1 Hz), 4.72 (s, IH), 4.61 (s, IH), 4.50-4.40 (m, IH), 4.18- 4.08 (m, IH), 3.74 (s, 3H), 3.17-3.07 (m, IH), 2.53-2.40 (m, 2H), 2.38-2.24 (m, IH), 2.19-2.04 (m, IH), 2.03 (s, 3H), 1.99-1.84 (m, 2H), 1.79-1.1 1 (m, 21H), 1.09-0.74
(m, 32H); Mass: [M+Na]+ 759 (100%).
Example 40; Preparation of (S)-2-((lS.3R)-3-
(( lR.3aS,5aR,5bR,7aR,9S, 1 IaR, 1 IbR, 13aR, 13bR)-9-hvdroxy-5a.5b.8.8.1 1 a- pentamethyl- 1 -(prop- 1 -en-2-yl)icosahvdro- 1 H-cvclopentaf a1chrysene-3a- carboxamido)-2,2-dimethylcvclobutanecarboxamido)-3-methylbutanoic acid:
Figure imgf000100_0001
To a stirred solution of (S)-methyl 2-((lS,3R)-3- (( 1 R,3aS,5aR,5bR,7aR,9S , 11 aR, 1 1 bR, 13aR, 13bR)-9-acetoxy-5a,5b,8,8, 1 1 a- pentamethyl- 1 -(prop- 1 -en-2-yl)icosahydro- 1 H-cyclopenta[a]chrysene-3a- carboxamido)-2,2-dimethylcyclobutanecarboxamido)-3-methylbutanoate (Example 39, 0.300 g, 0.407 mmol) in MeOH: THF (2: 1) (7.5 ml) 2N NaOH (2.5 ml) was added at 0 0C and allowed to stir at room temperature for about 16 hours. After completion of the reaction (monitored by TLC), the volatile was evaporated and the reaction mixture was acidified with IN HCl, filtered, washed with water and dried under vacuum to afford the title compound as an off white solid. Wt: 0.180 g: Yield: 64.9 %; 1H NMR (300 MHz, DMSO-d6): δ 7.55 (d, 2H, J = 6.6 Hz), 4.62 (s, IH),
4.51 (s, IH), 4.20-4.1 1 (m, IH), 3.91-3.82 (m, IH), 3.00-2.98 (m, 2H), 2.71-2.56 (m, IH), 2.48-2.39 (m, IH), 2.37-2.18 (m, 2H), 1.92-1.76 (m, 2H), 1.69-1.15 (m, 32H), 0.93-0.76 (m, 15H), 0.85 (s, 3H), 0.84 (s, 3H); Mass: [M+Na]+ 703 (100); IR (KBr, cm"1): 3321, 2951, 1713, 1631, 1532, 1460, 1386, 1252, 1 169, 1 108, 1044, 983, 882; M.R: 203.9 0C -205.0 0C; HPLC: 97.3%.
Example 41 : Preparation of (S)-methyl 2-((lS,3R)-3-
(( 1 R,3aS,5aR,5bR.7aR.9S, 1 1 aR.1 1 bR, 13aR, 13bR)-9-acetoxy-5a,5b,8,8, 11 a- pentamethyl- 1 -(prop- 1 -en-2-yl)icosahydro- 1 H-cyclopentaralchrysene-Sa- carboxamido)-2,2-dimethylcvclobutanecarboxamido)-4-methylpentanoate:
Figure imgf000101_0001
Step 1: Synthesis of (S)-methyl 2-((lS,3R)-3-(tert-butoxycarbonylamino)-2,2- dimethylcyclobutanecarboxamido)-4-methylpentanoate:
Figure imgf000101_0002
To a stirred solution of (lS,3R)-3-(tert-butoxycarbonylamino)-2,2- dimethylcyclobutanecarboxylic acid (0.350 g, 1.44 mmol) in DCM (5 ml) EDCI (0.331 g, 1.73 mmol) and HOBt (0.234 g, 1.73 mmol) were added at O0C. After 10 minutes, (S)-methyl 2-amino-4-methylpentanoate hydrochloride (0.780, 4.32 mmol) and Et3N (1.2 ml, 8.64 mmol) in DCM (5 ml) were added drop wise and the reaction mass was allowed to stir at room temperature for about 16 hours. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with DCM and washed with water, sat. NaHCO3 solution, water, IN HCl, water and saturated brine and the organic layer was concentrated under reduced pressure, the resulting crude was purified by silica gel column (100-200 mesh, elution 65% EtOAC in hexane) to afford the title compound as a solid. Wt: 0.210 g; Yield: 39.4%; 1H NMR (300
MHz, CDCl3): δ 5.56 (d, IH), 4.75 (d, IH, J = 9Hz), 4.70-4.60 (m, IH), 3.88-3.79 (m, IH), 3.73 (s, 3H), 2.48-2.25 (m, 2H), 2.14-1.99 (m, IH), 1.70-1.48 (m, 3H), 1.43 (s, 9H), 1.32 (s, 3H), 0.95-0.91 (m, 9H); Mass: [M+Na]+ 393 (100%); IR (KBr, cm" !): 3344, 2960, 2873, 1743, 1689, 1664, 1531, 1458, 1366, 1271, 1174, 1050, 1028, 873, 827, 744; M.R: 100.5 0C -103.9 0C.
Step 2: Synthesis of (S)-methyl 2-((lS,3R)-3-amino-2,2- dimethylcyclobutanecarboxamido)-4-methylpentanoate:
Figure imgf000102_0001
A stirred solution of (S)-methyl 2-((lS,3R)-3-(tert-butoxycarbonylamino)-
2,2-dimethylcyclobutanecarboxamido)-4-methylpentanoate (step 1, 0.200 g, 0.54 mmol) in TFA: DCM (1:4) (4 ml) at 0 °C-room temperature for about 1 hour. After completion of the reaction, the solvent was evaporated and the crude was dissolved in DCM and basified with Et3N (0.5 ml, 3.24 mmol) then the resulting solution as such used for next reaction immediately. Wt: 0.145 g (Based on 100% yield calculated and proceeded for next reaction).
Step 3: Preparation of (S)-methyl 2-((lS,3R)-3-
((1R, 3aS, 5aR, 5bR, 7aR, 9S, 1 IaR, 11 bR, 13aR, 13bR)-9-acetoxy-5a, 5b, 8,8,11a- pentamethyl-l-(prop-l-en-2-yl)icosahydro-lH-cyclopenta[a]chrysene-3a- carboxamido)-2,2-dimethylcyclobutanecarboxamido)-4-methylpentanoate:
To a stirred solution of (lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)-9- acetoxy-5a,5b,8,8,l la-pentamethyl-l-(prop-l-en-2-yl)icosahydro-lH- cyclopenta[a]chrysene-3a-carboxylic acid (0.200 g, 0.401 mmol) (Prepared as described in J.Med.Chem. 2009. 52, 3248-3258) in DCM (1 ml) Oxolyl chloride (2
M) in DCM (2.0 ml, 4.016 mmol) was added at 0 0C and stirred at room temperature for about 3 hours and completion of the reaction monitored by TLC then the solvent was evaporated under nitrogen atmosphere and dissolved in DCM (4 ml), which was added to a solution of the above (S)-methyl 2-((lS,3R)-3-amino-2,2- dimethylcyclobutane carboxamido)-4-methylpentanoate (step 2, 0.16 g) in DCM (5 ml) at 0 0C and allowed to stir at room temperature for about 16 hours. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with DCM and washed with water, IN HCl, water, brine and dried over Na2SO4, the solvent was evaporated and purified by silica gel column (100-200 mesh, elution 25% EtOAc in hexane) to afford the title compound as an off white solid. Wt: 0.195 g: Yield: 64.7 %; 1H NMR (300 MHz, CDCl3): δ 5.88 (d, IH, J = 8.1 Hz), 5.68 (d, IH, J = 8.7 Hz) 4.72 (s, IH), 4.57 (s, IH), 4.50-4.42 (m, IH), 4.18-4.09 (m, IH), 3.75 (s, 3H), 3.17-3.05 (m, IH), 2.57-2.43 (m, 2H), 2.38-2.29 (m, IH), 2.20-2.08 (m,
2H), 2.04 (s, 3H), 1.99-1.88 (m, 2H), 1.79-1.09 (m, 30H), 0.98-0.78 (m, 24H).
Example 42j Preparation of (S)-2-((lS,3R)-3-
(( 1 R,3aS,5aR,5bR,7aR,9S, 11 aR, 1 IbR, 13aR.13bR)-9-hydroxy-5a,5b,8,8, 11 a- pentamethyl- 1 -(prop- 1 -en-2- vDicosahydro- 1 H-cyclopentafalchrysene-S a- carboxamido)-2,2-dimethylcvclobutanecarboxamido)-4-methylpentanoic acid:
Figure imgf000103_0001
To a stirred solution of (S)-methyl 2-((lS,3R)-3- ((lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)-9-acetoxy-5a,5b,8,8,l la- pentamethyl- 1 -(prop- 1 -en-2-yl)icosahydro- 1 H-cyclopenta[a]chrysene-3 a- carboxamido)-2,2-dimethylcyclobutanecarboxamido)-4-methylpentanoate (Example 41, 0.190 g, 0.253 mmol) in MeOH:THF (2: 1) (7.5 ml) 2N NaOH (2.5 ml) was added at 0 0C and allowed to stir at room temperature for about 16 hours. After completion of the reaction (monitored by TLC), the volatiles were evaporated and the reaction mixture was acidified with IN HCl, extracted with EtOAc, dried over
Na2SO4 then the organic layer was concentrated and dried under vacuum to afford the title compound as an off white solid. Wt: 0.100 g: Yield: 56.7%; 1H NMR (300 MHz, DMSO-d6): δ 7.69 (d, IH, / = 8.1 Hz), 7.54 (d, IH, J = 6.6 Hz), 4.62 (s, IH), 4.51 (s, IH), 4.29-4.18 (m, 2H), 3.95-3.84 (m, IH), 3.01-2.88 (m, 2H), 2.34-2.18 (m, 3H), 1.91-1.72 (m, 3H), 1.69-1.10 (m, 31H), 0.96-0.58 (m, 23H); Mass: [M+l]+ 694
(10%), [M+Na]+ 717 (100%); IR (KBr, cm"1): 3454, 2950, 1726, 1634, 1523, 1466, 1369, 1266, 1207, 1195, 1157, 1044, 1009, 922, 882, 722; M.R: 192.4 0C -213.8 0C; HPLC: 95.97%.
Example 43: Preparation of (lR.3aS.5aR.5bR.7aR.9S,l laR.l lbR,13aR.13bR)-3a- ((lR,3S)-2,2-dimethyl-3-(pyrrolidine-l-carbonyl)cyclobutylcarbamoyl)-
5a,5b, 8,8,1 la-pentamethyl-l-(prop-l-en-2-yl)icosahvdro-lH-cyclopentara1chrvsen- 9-vl acetate:
Figure imgf000104_0001
Step 1: Synthesis of tert-butyl (lR,3S)-2,2-dimethyl-3-(pyrrolidine-l- carbonyl)cyclobutylcarbamate:
Figure imgf000104_0002
To a stirred solution of (lS,3R)-3-(tert-butoxycarbonylamino)-2,2- dimethylcyclobutanecarboxylic acid (0.700 g, 2.88 mmol) in DCM (20 ml) EDCI (0.660 g, 3.456 mmol) and HOBt (0.529 g, 3.456 mmol) were added at about 0 0C and after 10 minutes, pyrrolidine (0.47 ml, 5.761 mmol) and Et3N (1.42 ml, 14.403 mmol) were added drop wise and the reaction mass was allowed to stir at room temperature for about 12 hours. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with DCM and washed with water and saturated NaHCO3 solution, then washed withaqueous IN HCl, then water and saturated brine, and the organic layer was concentrated under reduced pressure, the resulting crude residue was stirred in hexane and the resulting solid was obtained which was filtered and dried under vacuum. Wt: 0.400 g; Yield: 46.9%; 1H NMR (300 MHz, CDCl3): δ 5.00 (d, IH, J = 7.5 Hz), 3.89-3.77 (m, IH), 3.57-3.29 (m, 4H), 2.78-2.68 (m, IH), 2.31-2.22 (m, 2H), 1.98-1.78 (m, 4H), 1.43 (s, 9H), 1.35 (s, 3H), 0.89 (s, 3H); Mass: : [M+l]+ 297 (40%), [M+Na]+ 319 (100%); IR (KBr, cm"'):
3312, 2977, 2956, 1709, 1621, 1606, 1526, 1442, 1365, 1348, 1283, 1267, 1176, 1106, 1046, 1009, 912, 877; M.R: 164.8 0C -165.5 0C.
Step 2: Synthesis of ((lS,3R)-3-amino-2,2-dimethylcyclobutyl)(pyrrolidin-l- yl)methanone:
Figure imgf000105_0001
A solution of tert-butyl (lR,3S)-2,2-dimethyl-3-(pyrrolidine-l- carbonyl)cyclobutylcarbamate (step 1, 0.400 g, 1.351 mmol) in TFA: DCM (1:2) (3 ml) stirred at 0 °C-room temperature for about 1 hour. After completion of the reaction, the solvent was evaporated and the crude was dissolved in DCM and basified with Et3N (1.124 ml, 8.108 mmol) the resulting solution as such used for next reaction immediately. Wt: 0.264 g (Based on 100% yield calculated and proceeded for next reaction). Step 3: Preparation of (lR,3aS,5aR,5bR, 7aR,9S,llaR,llbR,13aR,13bR)-3a-
((lR,3S)-2,2-dimethyl-3-(pyrrolidine-l-carbonyl)cyclobutylcarbamoyl)- 5a,5b, 8, 8, lla-pentamethyl-l-(prop-l -en-2-yl)icosahydro-lH-cyclopenta[a]chrysen- 9-yl acetate:
To a stirred solution of QR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)-9- acetoxy-5a,5b, 8,8, l la-pentamethyl-1 -(prop- l-en-2-yl)icosahydro- IH- cyclopenta[a]chrysene-3a-carboxylic acid (0.336 g, 0.674 mmol) (Prepared as described in J.Med.Chem. 2009. 52, 3248-3258) in DCM (1 ml) Oxolyl chloride (0.58 ml, 6.746 mmol) in DCM (3.15 ml) was added at 0 0C and stirred at room temperature for about 3 hours and completion of the reaction monitored by TLC then the solvent was evaporated under nitrogen atmosphere and dissolved in DCM
(4 ml), which was added to the above stirred solution of ((lS,3R)-3-amino-2,2- dimethylcyclobutyl)(pyrrolidin-l-yl)methanone (step 2, 0.264 g, 1.349 mmol) at 0 0C and allowed to stir at room temperature for about 16 hours. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with DCM and washed with aqueous IN HCl, then washed with water and brine, and dried over
Na2SO4, the solvent was evaporated and purified by silica gel column (100-200 mesh, elution 15% EtOAc in hexane) to afford the title compound as an off white solid. Wt: 0.350 g: Yield: 76.7 %; 1H NMR (300 MHz, CDCl3): δ 6.28 (d, IH), 4.72 (s, IH), 4.58 (s, IH), 4.51-4.06 (m, 2H), 3.56-3.27 (m, 8H), 3.18-3.08 (m, IH), 2.91- 2.74 (m, 2H), 2.60-2.46 (m, 2H), 2.37-2.20 (m, 3H), 2.08 (s, 3H), 1.99-1.11 (m,
26H), 1.00-0.75 (s, 18H); Mass: [M+Na]+ 699 (100%); IR (KBr, cm"1): 3268, 3077, 2955, 2873, 1734, 1716, 1618, 1549, 1455, 1452, 1371, 1344, 1242, 1180, 1150, 1033, 980, 869; M.R: 94.9 0C -101.2 0C.
Exampl 44: Preparation of (lR,3aS,5aR,5bR,7aR,9S.l laR.l lbRJ3aR.13bR)-N- (( 1 R,3S)-2,2-dimethyl-3-(pyrrolidine- 1 -carbon yl)cyclobutylV9-hydroxy-
5a,5b,8,8,l la-pentamethyl-l-(prop-l-en-2-yl)icosahvdro-lH-cyclopentara1chrysene- 3a-carboxamide:
Figure imgf000106_0001
To a stirred solution of (lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)- 3a-((lR,3S)-2,2-dimethyl-3-(pyrrolidine-l-carbonyl)cyclobutylcarbamoyl)-
5a,5b,8,8,l la-pentamethyl-l-(prop-l-en-2-yl)icosahydro-lH-cyclopenta[a]chrysen- 9-yl acetate (Example 43, 0.350 g, 0.517 mmol) in MeOH:THF (2:1) (30 ml) 2N NaOH (10 ml) was added at 0 0C and allowed to stir at room temperature for about 16 hours. After completion of the reaction (monitored by TLC), the volatile was evaporated and the aqueous layer was extracted with ethyl acetate and the organic layer was washed with water, brine and dried over Na2SO4 then the solvent was evaporated and the resulting crude was stirred in hexane and the resulting solid was obtained which was filtered and dried under vacuum to afford the title compound. Wt: 0.220 g: Yield: 67 %; 1H NMR (300 MHz, CDCl3): δ 6.27 (d, IH, J = 8.1 Hz), 4.72 (s, IH), 4.57 (s, IH), 4.17-4.07 (m, IH), 3.56-3.11 (m, 4H), 3.19-3.09 (m, 2H),
2.82-2.76 (m, IH), 2.57-2.43 (m, IH), 2.39-2.18 (m, 2H), 2.01-1.72 (m, 7H), 1.67 (s, 3H), 1.61-1.11 (m, 22H), 0.96, 0.93, 0.87, 0.81, 0.74 (s, 18H); Mass: [M+l]+ 635 (5%), [M+Na]+ 657 (100%); IR (KBr, cm"1): 3390, 3071, 2947, 2869, 1617, 1455, 1369, 1341, 1250, 1194, 1168, 1108, 1034, 921, 880; M.R: 176.3 0C -180.9 0C; HPLC: 98.9%.
Example 45: Preparation of 4-((lR,3aS,5aR.5bR,7aR,9S,l laR.l lbR.13aR.13bRV 3a-((lR,3S)-2,2-dimethyl-3-(pyrrolidine-l-carbonyl)cyclobutylcarbamoyl)- 5a,5b,8,8, 11 a-pentamethyl- 1 -(prop- 1 -en-2-yl)icosahydro- lH-cyclopenta[alchrvsen- 9-yloxy)-2,2-dimethyl-4-oxobutanoic acid:
Figure imgf000107_0001
2,2-Dimethylsuccinic anhydride (0.303 g, 2.365 mmol) was added to a stirred solution of (lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)-N-((lR,3S)- 2,2-dimethyl-3-(pyrrolidine- 1 -carbony^cyclobutyl^-hydroxy-Sa.Sb^δ, 11 a- pentamethyl- 1 -(prop- 1 -en-2-yl)icosahydro- lH-cyclopenta[a]chrysene-3a- carboxamide (Example 44, 0.150 g, 0.236 mmol) and DMAP (0.057 g, 0.473 mmol) in pyridine (10 ml) at room temperature and refluxed for about 24 hours. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with EtOAc, washed with aquepus IN HCl, them washed with water and brine, and dried over Na2SO4, the solvent was evaporated and purified by silica gel column
(100-200 mesh, elution 20% EtOAc in hexane) to afford the title compound as an off white solid. Wt: 0.045 g: Yield: 24.4%; 1H NMR (300 MHz, CDCl3): δ 6.33 (d, IH, 7 = 7.8 Hz), 4.73 (s, IH), 4.57 (s, IH), 4.53-4.46 (m, IH), 4.16-4.07 (m, IH), 3.54- 3.30 (m, 4H), 3.18-3.08 (m, IH), 2.82-2.42 (m, 6H), 2.34-2.27 (m, 2H), 2.08-1.78 (m, 8H), 1.78-1.10 (m, 30H), 098-0.71 (s, 18H); Mass: [M+ 1]+ 763 (30%), [M+Na]+
785 (100%); IR (KBr, cm"1): 3407, 2951, 2346, 2273, 1726, 1619, 1453, 1192, 1019, 879; HPLC: 96.0%; M.R: 134.8 0C -145.0 0C.
Example 46: Preparation of (lR.3aS.5aR.5bR.7aR.9S.l laR.l lbR.13aR.13bR)-3a- (( lR,3S)-2,2-dimethyl-3-(piperidine-l -carbon vDcyclobutylcarbamoyl)-
5a,5b,8,8,l la-pentamethyl-l-(prop-l-en-2-yl)icosahydro-lH-cvclopentara1chrysen- 9-vl acetate:
Figure imgf000107_0002
Step 1: Synthesis of tert-butyl (lR,3S)-2,2-dimethyl-3-(piperidine-l- carbonyl)cyclobutylcarbamate:
Figure imgf000107_0003
To a stirred solution of (lS,3R)-3-(tert-butoxycarbonylamino)-2,2- dimethylcyclobutanecarboxylic acid (0.500 g, 2.057 mmol) in DCM (20 ml) EDCI (0.472 g, 2.469 mmol) and HOBt (0.378 g, 2.469 mmol) were added at 0 0C and after 10 minutes, piperidine (0.4 ml, 4.115 mmol) and Et3N (1.42 ml, 10.288 mmol) were added drop wise and the reaction mass was allowed to stir at room temperature for about 12 hours. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with DCM and washed with water, sat. NaHCO3 solution, water, IN HCl, water, saturated brine and the organic layer was concentrated under reduced pressure, the resulting crude residue was stirred in hexane and the resulting solid was obtained which was filtered and dried under vacuum to afford the title compound. Wt: 0.400 g; Yield: 62.79%; 1H NMR (300 MHz, CDCl3): δ 4.77 (d, IH, J = 8.4 Hz), 3.89-3.78 (m, IH), 3.77-3.67 (m, IH), 3.49-3.28 (m, 3H), 2.87-2.76 (m, IH), 2.40-2.18 (m, 2H), 1.70-1.46 (m, 6H), 1.43 (s,
9H), 1.33 (s, 3H), 0.87 (s, 3H); Mass: : [M+l]+ 311 (35%), [M+Na]+ 333 (100%); IR (KBr, cm"1): 3337, 2939, 1712, 1628, 1522, 1456, 1445, 1388, 1353, 1366, 1288, 1264, 1254, 1217, 1172, 1047, 1026, 1013, 976; M.R: 176.00C -178.0 0C. Step 2: Synthesis of ((lS,3R)-3-amino-2,2-dimethylcyclobutyl)(piperidin-l- yl)methanone:
Figure imgf000108_0001
A solution of tert-butyl (lR,3S)-2,2-dimethyl-3-(piperidine-l- carbonyl)cyclobutylcarbamate (step 1, 0.500 g, 1.612 mmol) in TFA: DCM (1:2) (3 ml) stirred at 0 °C-room temperature for about 1 hour. After completion of the reaction (monitored by TLC), the solvent was evaporated and the crude was dissolved in DCM and basified with Et3N (1.34 ml, 9.677 mmol) then the resulting solution as such used for the next reaction. Wt: 0.338 g (Based on 100% yield calculated and proceeded for next reaction).
Step 3: Preparation of (lR,3aS,5aR,5bR,7aR,9S,llaR,llbR,13aR,13bR)-3a-
((lR,3S)-2,2-dimethyl-3-(piperidine-l-carbonyl)cyclobutylcarbamoyl)- 5a,5b,8,8,lla-pentamethyl-l-(prop-l-en-2-yl)icosahydro-lH-cyclopenta[a]chrysen- 9-yl acetate:
To a stirred solution of (lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)-9- acetoxy-5a,5b,8,8, 11 a-pentamethyl- 1 -(prop- 1 -en-2-yl)icosahydro- 1 H- cyclopenta[a]chrysene-3a-carboxylic acid (0.410 g, 0.823 mmol) (Prepared as described in J.Med.Chem. 2009. 52, 3248-3258) in DCM (1 ml) Oxolyl chloride (0.71 ml, 8.232 mmol) in DCM (3.42 ml) was added at O 0C and stirred at room temperature for about 3 hours and completion of the reaction was monitored by TLC, then the solvent was evaporated under nitrogen atmosphere and dissolved in DCM (4 ml), which was added to a stirred solution of ((lS,3R)-3-amino-2,2- dimethylcyclobutyl)(piperidin-l-yl)methanone (step 2, 0.328 g, 1.56 mmol) at 0 C and allowed to stir at room temperature for about 16 hours. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with DCM and washed with aqueous IN HCl, then washed with water and brine, and dried over Na2SO4 then the solvent was evaporated and purified by silica gel column (100-200 mesh, elution 15% EtOAc in hexane) to afford the title compound as an off white solid. Wt: 0.400 g; Yield: 71.9 %; 1H NMR (300 MHz, CDCl3): δ 5.85 (d, IH), 4.72 (s, IH), 4.58 (s, IH), 4.50-4.41 (m, IH), 4.18-4.07 (m, IH), 3.78-3.67 (m, IH), 2.50- 2.30 (m, 3H), 3.19-3.07 (m, IH), 2.88 (t, IH, J = 8.1 Hz), 2.54-2.13 (m, 3H), 2.04 (s, 3H), 2.00-1.86 (m, 2H), 1.80-1.11 (m, 33H), 0.95, 0.93, 0.87, 0.83, 0.81 (s, 18H); Mass: [M+H]+ 691 (100%), [M+Na]+ 713 (25%); IR (KBr, cm"1): 3395, 2943, 2864,
1736, 1734, 1624, 1444, 1370, 1248, 1192, 1154, 1024, 979, 884; M.R: 140.2 0C - 145.8 0C.
Example 47: Preparation of αR.3aS.5aR,5bRJaR,9S.l laR.l lbR,13aR.13bRVN- C(lR.3S)-2.2-dimethyl-3-(ρiperidine-l -carbon yl)cvclobutyl)-9-hvdroxy-
5a,5b,8,8, 11 a-pentamethyl- 1 -(prop- 1 -en-2-yDicosahydro- lH-cvclopentaFaichrvsene- 3a-carboxamide:
Figure imgf000109_0001
To a stirred solution of (IR5SaS5SaR5SbRJaR^S5I IaR5HbR5HaR5ISbR)- 3a-((lR,3S)-2,2-dimethyl-3-(piperidine-l -carbon yl)cyclobutylcarbamoyl)-
5a,5b,858511 a-pentamethyl- 1 -(prop- 1 -en-2-yl)icosahydro- 1 H-cyclopenta[a]chrysen- 9-yl acetate (Example 46, 0.400 g, 0.579 mmol) in MeOH:THF (2: 1) (30 ml) 2N NaOH (10 ml) was added at 0 0C and allowed to stir at room temperature for about 16 hours. After completion of the reaction (monitored by TLC)5 the volatile was evaporated and the aqueous layer was extracted with ethyl acetate and the organic layer was washed with water, brine and dried over Na2SO4 then the solvent was evaporated and the resulting crude stirred in hexane and the resulting solid was obtained which was filtered and dried under vacuum to afford the title compound. Wt: 0.280 g; Yield: 74.6 %; 1H NMR (300 MHz, CDCl3): δ 5.86 (d, IH, 7 = 8.1 Hz), 4.72 (s, IH), 4.57 (s, IH), 4.18-4.06 (m, IH), 3.78-3.68 (m, IH), 3.52-3.30 (m, 3H), 3.23-3.08 (m, 2H), 2.92-2.86 (m, IH), 2.52-2.20 (m, 3H), 2.01-1.88 (m, 2H), 1.80- 1.12 (m, 33H), 0.96, 0.93, 0.87, 0.81, 0.74 (s, 18H); Mass: [M+l]+ 649 (5%),
[M+Na]+ 671 (100%); IR (KBr, cm"1): 3353, 2937, 2858, 1635, 1618, 1533, 1459, 1390, 1262, 1250, 1148, 1048, 1033, 1020, 983, 883; M.R: 177 0C -188.7 0C; HPLC: 95.72%. Example 48: Preparation of 4-((lR,3aS,5aR,5bR,7aR.9S.l laR,l lbR,13aR,13bR)-
3a-((lR,3S)-2,2-dimethyl-3-(piperidine-l-carbonyl)cvclobutylcarbamoyl)- 5a,5b,8,8,l la-pentamethyl-l-(prop-l-en-2-yl)icosahydro-lH-cyclopentaralchrysen- 9-yloxy)-2,2-dimethyl-4-oxobutanoic acid:
Figure imgf000110_0001
To a stirred solution of (lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)-N-
((lR,3S)-2,2-dimethyl-3-(piperidine-l-carbonyl)cyclobutyl)-9-hydroxy- 5a,5b,8,8,l la-pentamethyl-l-(prop-l-en-2-yl)icosahydro-lH-cyclopenta[a]chrysene- 3a-carboxamide (Example 47, 0.190 g, 0.293 mmol) 2,2-Dimethylsuccinic anhydride (0.375 g, 2.932 mmol) and DMAP (0.071 g, 0.586 mmol) in pyridine (10 ml) were added at room temperature and refluxed for about 24 hours. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with EtOAc, washed with aqueous IN HCl, then water and brine, and dried over Na2SO4 then the solvent was evaporated and purified by silica gel column (100-200 mesh, elution 20% EtOAc in hexane) to afford the title compound as an off white solid. Wt: 0.090 g; Yield: 39.6%; 1H NMR (300 MHz, CDCl3): δ 5.96 (d, IH, J =
8.1 Hz), 4.72 (s, IH), 4.58 (s, IH), 4.52-4.44 (m, IH), 4.16-4.07 (m, IH), 3.79-3.58 (m, IH), 3.50-3.31 (m, 3H), 3.18-3.07 (m, IH), 2.91-2.87 (m, IH), 2.71-2.56 (m, 2H), 2.56-2.37 (m, 2H), 2.30-2.19 (m, IH), 2.01-1.81 (m, 3H), 1.80-1.10 (m, 35H), 0.95, 0.93, 0.88, 0.87 (s, 21H); Mass: [M+l]+ 777 (30%), [M+Na]+ 799 (100%); IR (KBr, cm"1): 3400, 2947, 2868, 1733, 1622, 1456, 1390, 1369, 1320, 1252, 1231,
1192, 1150, 1021, 978, 881; HPLC: 97.37%; M.R: 168.5 0C -176.9 0C. Example 49: Preparation of (lR.3aS.5aR.5bR.7aR.9S.l laR.l lbR.13aR.13bRV 5a.5b,8,8,lla-pentamethyl-3a-(αR,3SV3-(('3-methylpiperidin-l- yPmethvPc vclopentylcarbamoyl)- 1 -(prop- 1 -en-2-yl)icosahydro- 1 H- cyclopenta[a1chrysen-9-yl acetate:
Figure imgf000111_0001
To a stirred solution of (lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)-9- acetoxy-5a,5b58,8, 11 a-pentamethyl- 1 -(prop- 1 -en-2-yl)icosahydro- IH- cyclopenta[a]chrysene-3a-carboxylic acid (0.5 g, 1.04 mmol) (Prepared as described in J.Med.Chem. 2009. 52, 3248-3258) in 50 ml DCM ,Oxallyl chloride (2 ml, 15.87 mmol) was added and stirred at room temperature for about 6 hours. Completion of the reaction was monitored by TLC. The reaction mixture was concentrated under reduced pressure. The residue was taken in DCM (15 ml) then kept under N2 atmosphere. (lR,3S)-3-((3-methylpiperidin-l-yl)methyl)cyclopentanamine
(Intermediate 10, 0.21 g) in DCM, triethyl amine (0.3 ml, 3.12 mmol) was added at 0 0C and stirred for about 15 minutes followed by above prepared acid chloride was added and stirred at room temperature for about 8 hours. Completion of the reaction was monitored by TLC. The reaction mixture was neutralized with sat. NaHCO3 and extracted with DCM, the organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 50% ethyl acetate in hexane as eluent to furnish the title compound as a white solid. 1H NMR (300 MHz, CDCl3): 0.57- 0.97 (m, 19H); 1.18- 1.21 (m, 8H); 1.25- 1.41 (m, 12H); 1.49-1.62 (m, 8H); 1.65- 1.82 (m, 10H); 1.85- 1.98 (m, 4H); 2.56-2.69 (m, 2H); 2.88-3.06 (m, 3H); 3.29-3.38 (m, IH); 3.89-3.90 (m, IH); 4.25-4.70 (m, 4H); 5.78 (s, IH); 6.12-6.15 (m, IH); MASS: 763 (100%).
Example 50: Preparation of (lR,3aS.5aR.5bR.7aR.9S.l laR.l lbR,13aR.13bR)-9- hvdroxy-5a,5b.8.8.11a-pentamethyl-N-((lR.3S)-3-((3-methylpiperidin-l- yl)methyl)cvclopentyl)- 1 -(prop- 1 -en-2-yl)icosahvdro- lH-cyclopenta[alchrysene-3a- carboxamide:
Figure imgf000111_0002
(lR,3aS,5aR,5bR,7aR,9S,l IaR, 1 lbR,13aR,13bR)-5a,5b,8,8,l Ia- pentamethyl-3a-((lR,3S)-3-((3-methylpiperidin-l-yl)methyl)cyclopentylcarbamoyl)- l-(prop-l-en-2-yl)icosahydro-lH-cyclopenta[a]chrysen-9-yl acetate (Example 49, 0.5g) in MeoH: THF (8: 8 ml) and cooled the contents to 0 0C then sodium hydroxide (0.12g in 4ml water) was added and stirred for about 6 hours at room temperature. Completion of the reaction (monitored by TLC), the reaction mixture was evaporated under reduced pressure and the residue was taken in water, and extracted with DCM, the organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 5% methanol in DCM as eluent to furnish the title compound
(0.3Ig) as a white solid. 1H NMR (300 MHz, CDCl3): 0.57- 0.97 (m, 19 H); 1.18- 1.21 (m, 8H); 1.25- 1.41 (m,12H); 1.49-1.62 (m,8H); 1.65- 1.82 (m, 10H); 1.85- 1.98 (m,4H); 2.56-2.69 (m,2H); 3.29-3.38 (m,lH); 3.89-3.90 (m,lH); 4.25-4.70 (m,4H); 5.78 (s,lH); MASS: 635(100%).
Example 5Jj Preparation of 2,2-dimethyl-4-oxo-4-
((lR,3aS,5aR,5bR.7aR.9S,l laR.l lbR.13aR,13bR)-5a.5b,8.8,l la-pentamethyl-3a- (( 1 R,3S)-3-((3-methyrpiperidin- 1 -yl)methyl)cyclopentylcarbamoyl)- 1 -(prop- 1 -en-2- yl)icosahvdro-lH-cvclopentaFalchrvsen-9-yloxy)butanoic acid:
Figure imgf000112_0001
To a stirred solution of (lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)-9- hydroxy-5a,5b,8,8,l la-pentamethyl-N-((lR,3S)-3-((3-methylpiperidin-l- yl)methyl)cyclopentyl)- 1 -(prop- 1 -en-2-yl)icosahydro- 1 H-cyclopenta[a]chrysene-3a- carboxamide (Example -50, 0.24 mmol) in pyridine (5 ml) dimethyl amino pyridine (0.32 g, 0.48 mmol) and 3,3-dimethyldihydrofuran-2,5-dione (1.3 ml) were added and the contents were refluxed for about 16 hours and completion of the reaction monitored by TLC. The reaction mixture was diluted with ethyl acetate (30 ml). The organic layer was washed with 5% aqueous HCl, washed with water followed by brine solution, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 5% MeOH in DCM as eluent to furnish the title compound (0.1 g) as a white solid. 1H NMR (300 MHz, CDCl3): 0.80- 0.95(m,l 6H) 1.23- 1.90 (m, 41H); 2.03-3.08(m,16H), 4.13-4.18 (m,lH),4.46(s,lH),4.58(s,lH), 4.72 (s, IH); 5.61-5.63 (m, IH); ES Mass: [M+ 1] 778 (100%); HPLC: 78.4%.
Example 52: Preparation of (lR,3aS,5aR.5bR,7aR.9S.l laR,llbR.13aR.13bR)-3a- (4-ethylpiperazine- 1 -carbonyl)-5a,5b,8,8.11 a-pentamethyl- 1 -(prop- 1 -en-2- yl)icosahvdro-lH-cvclopenta[alchrysen-9-yl acetate:
Figure imgf000113_0001
To a stirred solution of (lR53aS,5aR,5bR,7aR,9S5l IaR5I lbR,13aR,13bR)-9- acetoxy-5a,5b, 8,8, 11 a-pentamethyl- 1 -(prop- l-en-2-yl)icosahydro-lH- cyclopenta[a]chrysene-3a-carboxylic acid (0.5 g, 1.04 mmol) (Prepared as described in J.Med.Chem. 2009. 52, 3248-3258) in 50 ml DCM, Oxallyl chloride (2 ml, 15.87 mmol) was added and stirred at room temperature for about 6 hours and completion of the reaction monitored by TLC. The reaction mixture was concentrated under reduced pressure and the residue was taken in DCM (15 ml) then kept under N2 atmosphere.
1-ethylpiperazine (0.23 g , 1.24 mmol) in DCM (50 ml) triethyl amine (0.3 ml, 3.12 mmol) was added at 0 0C and stirred for about 15 minutes followed by above prepared acid chloride was added and stirred at room temperature for about 8 hours. Upon completion of the reaction (monitored by TLC), the reaction mixture was neutralized with sat. NaHCO3 and extracted with DCM5 the organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 50% ethyl acetate in hexane as eluent to furnish the title compound. 1H NMR (300 MHz, CDCl3): 0.57- 0.97 (m, HH); 1.18- 1.21 (m, 8H); 1.25- 1.41 (m,10H); 1.49-1.62 (m, 8H); 1.65- 1.82 (m, 10H); 1.85- 1.98 (m, 4H); 2.56-2.69 (m, 2H); 2.88-3.06 (m, 3H); 3.89-3.90 (m, IH);
4.25-4.70 (m, 4H); 5.78 (s, IH); 6.12-6.15 (m, IH); ES Mass: 595 (100%) [M+l].
Example 53j Preparation of 4-ethylpiperazin- 1 - ylX(lR.3aS.5aR.5bR.7aR,9S.l laR.l lbR.13aR.13bRV9-hvdroxy-5a,5b.8,8.11a- pentamethyl- 1 -(prop- 1 -en-2-yl)icosahvdro- lH-cyclopentara1chrysen-3a- vPmethanone:
Figure imgf000114_0001
( 1 R,3aS ,5aR,5bR,7aR,9S , 11 aR, 1 IbR, 13aR, 13bR)-3a-(4-ethylpiperazine- 1 - carbonyl)-5a,5b,8,8, 11 a-pentamethyl- 1 -(prop- 1 -en-2-yl)icosahydro- IH- cyclopenta[a]chrysen-9-yl acetate (Example 52, 0.5 g) in MeOH: THF (8: 8 ml) and cooled the contents to 0 0C, then sodium hydroxide (0.16g in 4ml water) was added and stirred for about 6 hours at room temperature. Completion of the reaction was monitored by TLC, the reaction mixture was evaporated under reduced pressure and the residue was taken in water, and extracted with DCM. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 5% methanol in DCM as eluent to furnish the title compound (0.31 g) as a white solid. 1H NMR (300 MHz, CDCl3): 0.57- 0.97 (m, 12 H); 1.18- 1.21 (m, 8H); 1.25- 1.41 (m, 10H); 1.49-1.62 (m, 8H); 1.65- 1.82 (m, 10H); 1.85- 1.98 (m, 4H); 2.56-2.69 (m, 2H); 3.29-3.38 (m, IH); 3.89-3.90 (m, IH); 4.25-4.70 (m, 4H); 5.78 (s, IH); MASS 552 (100%).
Example 54: Preparation of 3-(((lR,3aS,5aR,5bRJaR,9S,l laRJ lbRJ3aRa3bR)-
3a-(4-ethylpiperazine- 1 -carbon yl)-5a,5b, 8, 8, 11 a-pentamethyl- 1 -(prop- l-en-2- yl)icosahydro-lH-cyclopentaralchrysen-9-yloxy)carbonyl)-2,2- dimethylcvclobutanecarboxvlic acid:
Figure imgf000114_0002
To a stirred solution of 3-(tert-butoxycarbonyl)-2,2- dimethylcyclobutanecarboxylic acid (0.5g, 0.24 mmol) in THF (15 ml) Diisopropylethylamine (0.32g 0.48, mmol) was added and cool the contents to 0 0C then 2,4,6-trichloro benzoyl chloride (1.3 ml) was added and stirred at room temperature for about 4 hours. Completion of the reaction was monitored by TLC.
The reaction mixture was concentrated under reduced pressure. The residue was taken in pyridine (15 ml) under N2 atmosphere which was added to A- ethylpiperazin- 1 -yl)(( 1 R,3aS,5aR,5bR,7aR,9S , 11 aR, 1 IbR, 13aR, 13bR)-9-hydroxy- 5a,5b,8,8, 11 a-pentamethyl- 1 -(prop- 1 -en-2-yl)icosahydro- lH-cyclopenta[a]chrysen- 3a-yl)methanone (Example 47, 0.25 g.15 mmol ) and dimethyl amino pyridine (0.02 g, 22 mmol ).The contents were refluxed for about 16 hours. Completion of the reaction was monitored by TLC, the reaction mixture was diluted with 30 ml ethyl acetate. The organic layer was washed with 5% aqueous HCl, washed with water followed by brine sol, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 5% MeOH in
DCM as eluent to furnish the title compound as white solid (0.12 g). 1H NMR (300 MHz, CDCl3): 0.95-1.16 (m, 17H); 1.21-1.86 (m, 19 H); 2.25- 2.48 (m, HH); 2.77- 3.58 (m, 16H); 4.33-4.70 (m, 4H); 5.58-5.60 (s, IH); 5.78- 5.80 (s, IH); 7.44-7.47 (s, IH); ES Mass: 707 (100%).
Example 55j Preparation of. ethyl 4^
(( lR,3aS.5aR.5bR.7aR.9S.11 aR.1 IbR, 13aR, 13bR)-9-acetoxy-5a,5b.8.8, 11 a- pentamethyl- 1 -(prop- l-en-2-yl)icosahydro- lH-cyclopentara1chrvsene-3a-carbonyl)- 1 -benzylcyclohexanecarboxylate:
Figure imgf000115_0001
Step 1: Synthesis of 1-tert-butyl 4-ethyl piperidine-1 ,4-dicarboxylate:
Boc
COOEt
To a stirred solution of ethyl piperidine-4-carboxylate (10.0 g, 63.69 mmol) in THF (50 ml) Sodium bicarbonate (8.0 g, 95.5 mmol) was added at room temperature and cooled to O0C. After ten minutes, di-tert-butyl dicarbonate (15.27 g,
70.05 mmol) was added and stirred the reaction mixture at room temperature for about 14 hours. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water, extracted with DCM and the organic layer was dried over Na2SO4 then concentrated under reduced pressure to furnish the title compound (11.4 g) as a light yellow liquid. 1H NMR (300 MHz, CDCl3): 1.23-1.28 (t, 3H);
1.45 (s, 9H); 1.60-1.68 (m, 3H); 1.85-1.90 (d, J=15Htz, 2H); 2.41-2.46 (m, IH); 2.83-2.87 (m, 2H); 4.04-4.17 (m, 3H); ES Mass: 258 (100%) [M+l].
Step 2: Synthesis of 1-tert-butyl 4-ethyl 4-benzylpiperidine- 1 ,4-dicarboxylate:
Figure imgf000116_0001
Diisopropyl ethylamine (6.5 ml) in dry THF (25 ml) cooled the contents to about -10 0C then N-butyl lithium (1.6 M, 23 ml) was added drop wise under nitrogen atmosphere and maintain the same temperature for about 45 minutes and cooled to about - 750C for about 15 minutes then 1-tert-butyl 4-ethyl piperidine-1,4- dicarboxylate (step 1, 5 g) in THF (30 ml) was added and stirred for about 30 minutes then increase the reaction temperature to -35 0C and stirred for about 45 minutes and again cooled to -750C then benzyl bromide (3.5 g in 20 ml THF) was added drop wise and slowly allowed the reaction to room temperature and stirred the reaction for about 12 hours. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with saturated ammonium chloride and extracted with ethyl acetate. The organic layer was washed with sat. NaHCO3 followed by brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 3% ethyl acetate in hexane as eluent to furnish the title compound as a light yellow colour liquid. 1H NMR (300
MHz, CDCl3): 1.16-1.18 (t, 3H); 1.44 (s, 9H); 2.07-2.11 (m, 2H); 2.28 (s, IH); 2.82 (s, 2H); 2.92-2.95 (m, IH); 3.46-3.52 (m, 3H); 4.09-4.11 (m, 2H); 7.03-7.06 (m, 2H); 7.23-7.24 (m, 3H); ES Mass: 370 (100%) [M+Na]. Step 3: Synthesis of ethyl 4-benzylpiperidine-4-carboxylate:
Figure imgf000116_0002
A solution of 1-tert-butyl 4-ethyl 4-benzylpiperidine-l,4-dicarboxylate (step 2, 4.5 g, 12.96 mmol) in DCM (50 ml) was cooled to 0 0C. After ten minutes, trifluroacetic acid (6.0 g) was added and stirred the reaction at room temperature for about 6 hours. After completion of the reaction (monitored by TLC), the reaction mixture was neutralized with sat. NaHCO3, extracted with DCM, dried over Na2SO4 and concentrated under reduced pressure to furnish the title compound (2.3 g) as a light yellow liquid. 1H NMR (300 MHz, CDCl3): 1.19-1.24 (t, 3H); 1.48-1.58 (m, 2H); 2.14-2.18 (m, 2H); 2.64-2.73 (m, 2H); 2.86 (s, 2H); 3.01-3.07 (m, 4H); 4.10- 4.17 (m, 2H); 7.07-7.10 (m, 2H); 7.24-7.30 (m, 3H); ES Mass: 248 (100%) [M+l]. Step 4: Preparation of ethyl 4-((lR,3aS,5aR,5bR,7aR,9S,llaR,llbR,13aR,13bR)-9- acetoxy-5a,5b,8,8,lla-pentamethyl-l-(prop-l-en-2-yl)icosahydro-lH- cyclopenta[a]chrysene-3a-carbonyl)-l-benzylcyclohexanecarboxylate:
To a stirred solution of (lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)-9- acetoxy-5a,5b,8,8,l la-pentamethyl-l-(prop-l-en-2-yl)icosahydro-lH- cyclopenta[a]chrysene-3a-carboxylic acid (1.0 g, 2.08 mmol) (Prepared as described in J.Med.Chem. 2009. 52, 3248-3258) in 50 ml DCM Oxolyl chloride (2 ml, 15.87 mmol) was added and stirred at room temperature for about 6 hours and completion of the reaction was monitored by TLC. The reaction mixture was concentrated under reduced pressure and the residue was taken in DCM (15 ml) and then kept under N2 atmosphere.
Ethyl 4-benzylpiperidine-4-carboxylate (step 3, 0.49 g, 2.08 mmol) in DCM (50 ml) triethyl amine (0.3 ml, 3.12 mmol) was added at O0C and stirred for about 15 minutes, followed by above prepared acid chloride. Reaction was continued at room temperature for about 8 hours. Completion of the reaction was monitored by TLC. The reaction mixture was neutralized with sat. NaHCO3 and extracted with DCM, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 50% ethyl acetate in hexane as eluent to furnish the title compound as a white solid (0.9 g). 1H NMR (300 MHz, CDCl3): 0.57- 0.97 (m, 19H); 1.18- 1.21 (m, 8H); 1.25- 1.41 (m, 12H); 1.49-1.62 (m, 8H); 1.65-1.82 (m, 10H); 1.85- 1.98 (m, 4H); 2.56-2.69 (m, 2H); 2.88-3.06 (m, 3H); 3.29-3.38 (m, IH); 3.89-3.90 (m, IH); 4.12-4.23 (m, 2H); 4.44-4.47 (m, IH); 4.56 (s, IH); 4.7 l(s, IH); 7.03-7.05 (m, 2H); 7.23-7.25 (m, 3H); ES Mass: 728 (100%) [M+l].
Example 56: Preparation of Ethyl l-benzyl-4-
((lR,3aS,5aR,5bR,7aR,9S,l laR.l lbR.13aR.13bRV9-hvdroxy-5a,5b.8,8,l la- pentamethyl- 1 -(prop- 1 -en-2-yl)icosahydro- lH-cyclopentaraichrysene-Sa- carbonvDcvclohexanecarboxylate:
Figure imgf000117_0001
Ethyl 4-((lR,3aS,5aR,5bR,7aR,9S,l IaR5I lbR,13aR,13bR)-9-acetoxy-
5a,5b,8,8, 11 a-pentamethyl- 1 -(prop- 1 -en-2-yl)icosahydro- lH-cyclopenta[a]chrysene- 3a-carbonyl)-l-benzylcyclohexanecarboxylate (Example 55 , 0.9g) was taken in MeOH: THF (8: 8 ml) and cooled the contents to 0 0C then sodium hydroxide (0.28g in 4ml water) was added and stirred for about 6 hours at room temperature.
Completion of the reaction was monitored by TLC. The reaction mixture was evaporated under reduced pressure and the residue was taken in water, extracted with DCM, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 5% methanol in DCM as eluent to furnish the title compound (0.45g) as a white solid. 1H NMR (300 MHz,
CDCl3): 0.57- 0.97 (m, 19H); 1.18- 1.21 (m, 8H); 1.25- 1.41 (m, 12H); 1.49-1.62 (m, 8H); 1.65- 1.82 (m, 10H); 1.85- 1.98 (m, 4H); 2.56-2.69 (m, 2H); 3.29-3.38 (m, IH); 3.89-3.90 (m, IH); 4.12-4.23 (m, 2H) 4.56 (s, IH ); 4.71(s, IH); 7.03-7.05 (m, 2H); 7.23-7.25 (m, 3H); MASS: 685 (100%).
Example 57: Preparation of 4-((lR,3aS.5aR.5bR,7aR.9S.l laR,l lbR,13aR,13bR)-
3a-(4-benzyl-4-(ethoxycarbonyl')piperidine-l-carbonyl)-5a,5b,8<8,l la-pentamethyl- l-(prop-l-en-2-yl)icosahvdro-lH-cyclopentaralchrysen-9-yloxy)-2t2-dimethyl-4- oxobutanoic acid:
Figure imgf000118_0001
To a stirred solution of Ethyl 1 -benzyl -4-
((lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)-9-hydroxy-5a,5b,8,8,l la- pentamethyl- 1 -(prop- 1 -en-2-yl)icosahydro- 1 H-cyclopenta[a]chrysene-3 a- carbonyl)cyclohexanecarboxylate (Example 56, 0.25 g, 0.36 mmol), 2,2- dimethylsuccinic anhydride (0.375 g, 2.932 mmol) and DMAP (0.071 g, 0.586 mmol) in pyridine (10 ml) were added at room temperature and refluxed for about 24 hours. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with EtOAc, washed with water, IN HCl, water, brine and dried over Na2SO4 then the solvent was evaporated and purified by silica gel column (100-200 mesh, elution 20% EtOAc in hexane) to afford the title compound as a white solid.
Wt: 0.26 g; 1H NMR (300 MHz, CDCl3): 0.57- 0.97 (m, 16 H); 1.18- 1.21 (m, 14H); 1.25- 1.41 (m, 12H); 1.49-1.62 (m, 8H); 1.65- 1.82 (m, 10H); 1.85- 1.98 (m, 4H); 2.56-2.69 (m, 4H); 3.29-3.38 (m, IH); 3.89-3.90 (m, IH); 4.12-4.23 (m, 2H); 4.56 (s, IH); 4.71 (s, IH); 7.03-7.05 (m, 2H); 7.23-7.25 (m, 3H); ES Mass: 814 (100%) [M+l]. Example 58: Preparation of (lS,3R)-l-tert-butyl 3-
((lR,3aS,5aR,5bR,7aR,9S,l laR.l lbR.13aR.13bRV3a-((lR,3SV2.2-dimethyl-3- (piperidine- 1 -carbonyl)cyclobutylcarbamoyl)-5a,5b,8,8, 11 a-pentamethyl- 1 -(prop- 1 - en-2-yl)icosahvdro- lH-cyclopentaralchrysen-9-yl) 2,2-dimethylcyclobutane- 1 ,3- dicarboxylate:
Figure imgf000119_0001
To a solution of (lR,3S)-3-(tert-butoxycarbonyl)-2,2- dimethylcyclobutanecarboxylic 2,4,6-trichlorobenzoic anhydride (1.117 g) in pyridine (20 ml) (lR,3aS,5aR,5bR,7aR,9S,l IaR5I lbR,13aR,13bR)-N-((lR,3S)-2,2- dimethyl-3-(piperidine- 1 -carbonyl)cyclobutyl)-9-hydroxy-5a,5b,8,8, Ha- pentamethyl- 1 -(prop- 1 -en-2-yl)icosahydro- 1 H-cyclopenta[a]chrysene-3a- carboxamide (Example 47, 1.0 g) in pyridine was added, followed by DMAP (376 mg). Thus obtained reaction mixture was stirred at reflux temperature for about 12 hours. After completion of the reaction (monitored by TLC), water (20 mL) was added and extracted with ethyl acetate. The combined organic layers were washed with IN HCl, brine, and water, dried over sodium sulfate, concentrated under reduced pressure to give crude compound. The so obtained crude product was purified by column chromatography to give title compound as a white solid. Wt: 800 mg : Yield: 61%. 1H NMR (300 MHz, CDCl3): δ 5.94 (d, IH, J = 8.1 Hz), 4.729 (s, IH), 4.580 (s, IH), 4.434 (m, IH), 4.154 (m, IH), 3.70 (m, 3H), 3.44 (m, 4H), 3.1 (m, IH), 2.93-2.2 (m, HH), 2.00 (m, 4H), 1.80-1.10 (m, 38 H), 0.95 (s, 6H), 0.93
(3H), 0.89 (s, 9H), 0.82 (m, IH); Mass: [M+H+]+ 860.45 (100%).
Example 59j Preparation of (lS,3R)-3-
(((lR.3aS.5aR.5bR.7aR.9S.l laR.l lbR.13aR.13bR)-3a-((lR,3SV2,2-dimethyl-3- (piperidine-l-carbonyl)cvclobutylcarbarnoyl)-5a,5b,8,8,l la-pentamethyl-l-(prop-l- en-2-yl)icosahvdro-lH-cyclopentaralchrvsen-9-yloxy)carbonyl)-2,2- dimethylcyclobutanecarboxylic acid:
Figure imgf000120_0001
To a cooled (O0C) HCl in 1,4-dioxane solution (10 mL) (lS,3R)-l-tert-butyl 3-(( 1 R,3aS,5aR,5bR,7aR,9S, 11 aR, 1 IbR, 13aR, 13bR)-3a-(( lR,3S)-2,2-dimethyl-3- (piperidine- 1 -carbonyl)cyclobutylcarbamoyl)-5a,5b,8,8, 1 la-pentamethyl- 1 -(prop- 1 - en-2-yl)icosahydro-lH-cyclopenta[a]chrysen-9-yl) 2,2-dimethylcyclobutane-l,3- dicarboxylate (Example 58, 800 mg) was added and allowed to warm to room temperature. Stirred at room temperature for about 12 hours and check the TLC. After completion of the reaction (monitored by TLC) water was added and extracted with EtOAc. The combined organic layers were dried over sodium sulfate, evaporated under reduced pressure, purified over silica-gel column chromatography to yield the title compound as a white solid. Wt: 0.200 g: Yield: 30 %. 1H NMR (300 MHz, CDCl3): δ 5.98 (d, IH, J = 8.1 Hz), 4.725 (s, IH), 4.582 (s, IH), 4.44 (m, IH), 4.11 (m, IH), 3.70-3.00 (m, 6H), 2.902-2.76 (m, 4H), 2.60-1.85 (m, 10H), 1.81-1.10 (m, 34H), 0.96 (s, 3H), 0.93 (s, 6H), 0.87 (s, 9H), 0.82 (m, IH); Mass: [M+H+]+ 803.25 (20%), 825.5 (100 %) [M+Na+]+; IR (KBr, cm"1): 3400, 2949, 2866, 1734, 1638, 1625, 1500, 1463, 1369, 1251, 1233, 1191, 1107, 1088, 977, 882, 542; M.R: 186.2-238.1 0C; HPLC: 95.25 %.
Example 60: Preparation of (lS,3R)-l-tert-butyl 3-
((lR.3aS.5aR.5bR.7aR.9SJ laR,l lbR,13aRJ3bR)-3a-((lS,3R)-2,2-dimethyl-3- (morpholine-4-carbonyl)cvclobutylcarbamoyl)-5a,5b,8,8, 11 a-pentamethyl- 1 -(prop- l-en-2-yl)icosahydro-lH-cvclopenta[alchrysen-9-yl) 2,2-dimethylcyclobutane-l,3- dicarboxylate:
Figure imgf000120_0002
To a solution of (lR,3S)-3-(tert-butoxycarbonyl)-2,2- dimethylcyclobutanecarboxylic 2,4,6-trichlorobenzoic anhydride (1.115 g) in pyridine (lR,3aS,5aR,5bR,7aR,9S,l IaR5I lbR,13aR,13bR)-N-((lS,3R)-2,2- dimethyl-3-(morpholine-4-carbonyl)cyclobutyl)-9-hydroxy-5a,5b,8,8, l la- pentamethyl- 1 -(prop- 1 -en-2-yl)icosahydro- lH-cyclopenta[a]chrysene-3a- carboxamide (Example 8, 1.0 gr) in pyridine was added, followed by DMAP (375 mg). Thus obtained reaction mixture was stirred at reflux temperature for about 12 hours. After completion of the reaction (monitored by TLC), water (20 mL) was added and extracted with ethyl acetate. The combined organic layers were washed with aqueous IN HCl, then brineand water, then dried over sodium sulfate, concentrated under reduced pressure to give crude compound. The so obtained crude product was purified by column chromatography to give the title compound as a white solid. Wt: 0.800 g: Yield: 61 %. 1H NMR (300 MHz, CDCl3): δ 5.9 (d, IH, J = 8.1 Hz), 4.7356 (s, IH), 4.590 (s, IH), 4.43 (m, IH), 4.15 (m, IH), 3.80-3.44 (m, 9H), 3.11 (m, IH), 2.87 (m, IH), 2.8-2.3 (m, 6H), 2.0-1.80 (m, 3H), 1.80-1.10 (m,
34 H), 0.98 (s, 3H), 0.95 (s, 6H), 0.8 (s, 9H), 0.78 (m, 2H); Mass: [M+H+]+ 861.45 (100%), [M+Na]+ 884.6 (30%).
Example 6Jj Preparation of. (lS,3R)-3- (((lR,3aS.5aR,5bR,7aR.9S,l laR,l lbR.13aR,13bR)-3a-((lS,3R)-2,2-dimethyl-3-
(morpholine-4-carbonyl)cvclobutylcarbamoyl)-5a,5b,8,8,l la-pentamethyl-l-(prop- l-en-2-yl)icosahydro-lH-cvclopenta[alchrvsen-9-yloxy)carbonyl)-2,2- dimethylcyclobutanecarboxylic acid:
Figure imgf000121_0001
To a cooled (O0C) HCl in 1,4-dioxane solution (lS,3R)-l-tert-butyl 3-
(( lR,3aS ,5aR,5bR,7aR,9S , 11 aR, 1 IbR, 13aR, 13bR)-3a-(( 1 S,3R)-2,2-dimethyl-3- (morpholine-4-carbonyl)cyclobutylcarbamoyl)-5a,5b,8,8, 1 la-pentamethyl- l-(prop- l-en-2-yl)icosahydro-lH-cyclopenta[a]chrysen-9-yl) 2,2-dimethylcyclobutane-l,3- dicarboxylate (Example 60, 900 mg) was added and allowed to warm to room temperature. Stirred at room temperature for about 12 hours and check the TLC. After completion of the reaction (monitored by TLC), water was added and extracted with EtOAc. The combined organic layers were dried over sodium sulfate, evaporated under reduced pressure, purified over silica-gel column chromatography to yield the title compound as a white solid. Wt: 0.220 g: Yield: 30 %. 1H NMR (300 MHz, CDCl3): δ 5.988 (d, IH, J = 7.8 Hz), 4.736 (s, IH), 4.586 (s, IH), 4.43 (m,
IH), 4.15 (m, IH), 3.80-3.44 (m, 8H), 3.12 (m, IH), 2.902-2.76 (m, 4H), 2.650-2.3 (m, 8H), 2.1-1.80 (m, 3H), 1.80-1.10 (m, 28 H), 0.98 (s, 3H), 0.95 (s, 6H), 0.8 (s, 9H), 0.78 (m, IH); Mass: [M+H+]+ 806.5 (100%); IR (KBr, cm"1): 3447, 2953, 2869, 1736, 1723, 1645, 1626, 1500, 1463, 1369, 1271, 1239, 1191, 1117, 1038, 975, 882, 722, 573; M.R: 255.5 0C -266.5 0C; HPLC: 92.86 %.
Example 62: Preparation of 4-(αR.3aS.5aR.5bR.7aR,9S.l laR,l lbR.13aR,13bR)- 3a-((lS,3R)-2,2-dimethyl-3-(piperidine-l-carbonyl)cyclobutylcarbamoyl)- 5a,5b,8,8, 11 a-pentamethyl- 1 -(prop- 1 -en-2-yl)icosahydro- lH-cyclopentaraichrysen- 9-yloxy)-4-oxobutanoic acid:
Figure imgf000122_0001
To a stirred solution of (lR,3aS,5aR,5bR,7aR,9S,HaR,l lbR,13aR,13bR)-N- ((lS,3R)-2,2-dimethyl-3-(piperidine-l-carbonyl)cyclobutyl)-9-hydroxy- 5a,5b,8,8,l la-pentamethyl-l-(prop-l-en-2-yl)icosahydro-lH-cyclopenta[a]chrysene- 3a-carboxamide (Example 11, 500 mg) in dry pyridine (10 mL) succinic anhydride
(771.6 mg) was added followed by DMAP (188.53 mg). Reflux the reaction mixture for 20 hours, after completing the reaction (monitored by TLC), diluted with ethyl acetate, and washed with water and brine solutions. The combined organic layers were dried over Na2SO4, concentrated under reduced pressure to afford title compound as a gummy solid. The crude compound was purified by silica-gel column chromatography using 100-200 mesh and hexane and ethyl acetate mixtures as a mobile phase to give 250 mg (43.5 % yield) of title compound with 5.95 % purity by HPLC. 1H NMR (300 MHZ, CDCl3): δ 6.027 (IH, d, J = 8.1 Hz), 4.738 (IH, s), 4.585 (IH, s), 4.52 (IH, m), 4.13 (IH, m), 3.66 (IH, m), 3.512 (IH, m), 3.38 (2H, m), 3.12 (IH, m), 2.95 (2H, m), 2.55-2.7 (7H, m), 2.25-2.54 (5H, m), 1.9 (3H, m), 1.2-1.8 (28H, m), 0.953 (3H, s), 0.924 (3H, s), 0.827 (9H, m), 0.754 (2H, m); IR (KBr, cm"1): 3403, 2946, 2867, 1802, 1733, 1619, 1449, 1370, 1293, 1253, 1228, 1162, 1110, 991, 934, 880, 826; Mass: [M+H]+ 749.55 (40%), 771.55 [M+Na]+ (100 %). Example 63: Preparation of (lS.3R)-l-tert-butyl 3-
((lR,3aS,5aR,5bRJaR,9SJ laR.l lbR.13aR.13bR)-3a-((lS,3R)-2,2-dimethyl-3- (piperidine- 1 -carbonyDcyclobutylcarbamovD-Sa^b&δ, 11 a-pentamethyl- 1 -(prop- 1 - en-2-yl)icosahydro-lH-cvclopentaralchrysen-9-yl) 2,2-dimethylcvclobutane-l,3- dicarboxylate:
Figure imgf000123_0001
To a solution of (lR,3S)-3-(tert-butoxycarbonyl)-2,2- dimethylcyclobutanecarboxylic 2,4,6-trichlorobenzoic anhydride (1.34 g)) in pyridine (20 mL) (lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)-N-((lS,3R)-2,2- dimethyl-3-(piperidine-l-carbonyl)cyclobutyl)-9-hydroxy-5a,5b,8,8,l la- pentamethyl- 1 -(prop- 1 -en-2-yl)icosahydro- lH-cyclopenta[a]chrysene-3a- carboxamide (Example 11, 1 g) in pyridine was added followed by DMAP (375 mg). Thus obtained reaction mixture was stirred at reflux temperature for 12 hours. After completion of the reaction (monitored by TLC), water (20 mL) was added and extracted with ethyl acetate. The combined organic layers were washed with aqueous IN HCl, then brine, and water, and subsequently dried over sodium sulfate, concentrated under reduced pressure to give crude compound. The so obtained crude product was purified by column chromatography to give the title compound as a white solid. 1H NMR (300 MHZ, CDCl3): δ 6.02 (IH, d, J = 8.1 Hz), 4.74 (IH, s), 4.59 (IH, s), 4.42 (IH, m), 4.11 (IH, m), 3.66 (IH, m), 3.5 (IH, m), 3.4 (2H, m), 3.1 (IH, m), 2.95-2.75 (4H, m), 2.6-2.3 (5H, m), 1.9 (2H, m), 1.8 (IH, m), 1.68 (3H, s),
1.64-1.12 (28H, m), 1.11 (12H, s), 1.05 (6H, s), 0.83 (12H, s), 0.75 (IH, m); Mass: [M+H]+ 787.2 (100%).
Example 64j Preparation of (lS,3R)-3- ((( lR,3aS.5aR.5bR.7aR,9S, 1 IaR.1 IbR.13aR.13bR)-3a-(( lS,3R)-2,2-dimethyl-3-
(piperidine- 1 -carbonyl)cvclobutylcarbamoyl)-5a,5b,8,8, 11 a-pentamethyl- 1 -(prop- 1 - en-2-yl)icosahvdro-lH-cyclopenta[alchrvsen-9-yloxy)carbonyl')-2,2- dimethylcyclobutanecarbox ylic acid :
Figure imgf000124_0001
To a cooled HCl in 1,4-dioxane solution (15 niL) (lS,3R)-l-tert-butyl 3- ((lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)-3a-((lS,3R)-2,2-dimethyl-3-
(piperidine- 1 -carbon yl)cyclobutylcarbamoyl)-5 a,5b,8,8, 11 a-pentamethyl- 1 -(prop- 1 - en-2-yl)icosahydro-lH-cyclopenta[a]chrysen-9-yl) 2,2-dimethylcyclobutane-l,3- dicarboxylate (Example 63, 800 mg) was added and allowed to warm to room temperature. Stirred at room temperature for 12 hours and check the TLC. After completion of the reaction (monitored by TLC), water was added and extracted with
EtOAc. The combined organic layers were dried over sodium sulfate, evaporated under reduced pressure, purified over silica-gel column chromatography to yield the title compound (350 mg) as a white solid. 1H NMR (300 MHZ, CDCl3): δ 6.02 (IH, d, J = 8.1 Hz), 4.734 (IH, s), 4.587 (IH, s), 4.44 (IH, m), 4.14 (IH, m), 3.66 (IH, m), 3.5 (IH, m), 3.4 (2H, m), 3.1 (IH, m), 2.95-2.75 (3H, m), 2.6-2.3 (5H, m), 1.9
(2H, m), 1.8 (IH, m), 1.68 (3H, s), 1.64-1.12 (35H, m), 1.05 (6H, s), 0.83 (12H, s), 0.75 (IH, m); Mass: [M+H]+ 803.7 (100%), 825.7 (50) [M+Na]+; IR (KBr, cm"1): 3426, 2947, 2866, 2346, 1734, 1625, 1466, 1369, 1252, 1232, 1190, 1107, 1022, 983, 883 and 651 cm"1; M.P. 257.7-269 0C.
Example 65: Preparation of 5-f(lR.3aS.5aR.5bR.7aR.9S.l laR.l lbR,13aR,13bRV
3a-((lS,3R)-2,2-dimethyl-3-(piperidine-l-carbonyl)cyclobutylcarbamoyl)- 5a,5b,8,8 J l a-pentamethyl- 1 -(prop- l-en-2-yl)icosahydro-lH-cyclopentaralchrysen- 9-yloxy)-5-oxopentanoic acid:
Figure imgf000124_0002
To a stirred solution of 5-((lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)- 3a-((lS,3R)-2,2-dimethyl-3-(piperidine-l-carbonyl)cyclobutylcarbamoyl)- 5a,5b,8,8, 11 a-pentamethyl- 1 -(prop- 1 -en-2-yl)icosahydro- 1 H-cyclopenta[a]chrysen- 9-yloxy)-5-oxopentanoic acid (Example 11, 500 mg) in dry pyridine (10 mL) glutaric anhydride (880.14 mg) was added followed by DMAP (188.53 mg). Reflux the reaction mixture for 20 hours. After completing the reaction as monitored by TLC, diluted with ethyl acetate, washed with water and brine solutions. The combined organic layers were dried over Na2SO4, concentrated under reduced pressure to afford crude title compound as a gummy solid. The crude compound was purified by silica-gel column chromatography using 100-200 mesh and hexane and ethyl acetate mixtures as mobile phase to give 350 mg (59.5 % yield) of title compound with 91.4 % purity by HPLC. 1H NMR (300 MHZ, CDCl3): δ 6.07 (IH, d, J = 8.1 Hz), 4.729 (IH, s), 4.58 (IH, s), 4.50 (IH, m), 4.132 (IH, m), 3.71 (2H, m), 3.5 (IH, m), 3.4 (2H, m), 3.147 (IH, m), 2.90 (IH, m), 2.3-2.55 (1OH, m), 2.0 (6H, m), 1.2-1.8 (29H, m), 0.94 (3H, s), 0.92 (3H, s), 0.85 (1OH, m), 0.75 (IH, m); IR (KBr, cm'1): 3395, 2950, 2868, 1712, 1603, 1509, 1517, 1445, 1412, 1390, 1375, 1304, 1253, 1206, 1065, 977, 920, 784; Mass: [M+H]+ 763.55 (50%), 785.6 [M+Na]+ (100 %).
Example 66: Preparation of (lR,3aS,5aR,5bR,7aR,9SJ laR,l lbR.13aR.13bR)-3a- ((lS,3R)-3-(4-ethylpiperazine-l-carbonyl)-2,2-dimethylcyclobutylcarbamoyl)- 5a,5b,8,8, 11 a-pentamethyl- 1 -(prop- 1 -en-2-yl)icosahydro- lH-cyclopenta[alchrysen- 9-yl acetate:
Figure imgf000125_0001
Oxallyl chloride was added To a cooled solution of (lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)-9-acetoxy-5a,5b,8,8,lla- pentamethyl-l-(prop-l-en-2-yl)icosahydro-lH-cyclopenta[a]chrysene-3a-carboxylic acid (835 mg) in DCM (20 mL) at 0 0C and the reaction mass was allowed to stir at room temperature for about 6 hours. After completion of the reaction (monitored by TLC) the solvent was evaporated under nitrogen atmosphere and dissolved in DCM, which was added to a solution of ((lR,3S)-3-amino-2,2-dimethylcyclobutyl)(4- ethylpiperazin-l-yl)methanone (500 mg) in DCM and Et3N (6 mL) at 0 0C and allowed to stir at room temperature for about 12 hours. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with DCM and washed with water, IN HCl, water brine and dried with Na2SO4, the solvent was evaporated and purified by silica-gel column (100-200 mesh, elution 10% EtOAc in hexane) to afford the title compound as an off white solid. Wt: 760 mg: Yield: 67.3 %. 1H NMR (300 MHz, CDCl3): δ 5.88 (d, J = 8.1 Hz, IH), 4.737 (d, J = 1.5 Hz,
IH), 4.58 (d, J = 1.5 Hz, , IH), 4.49-4.438 (m, IH), 4.10 (m, IH), 3.80-3.41 (m, 4H), 3.17-3.08 (m, IH), 2.9 (m, IH), 2.60-2.295 (m, 9H), 2.04 (s, 3H), 1.90 (m, 2H), 1.80-1.02 (m, 30 H), 0.95, 0.92 (s, 6H), 0.83 (s, 12H); Mass: [M+H+]+720 (100%). Example 67: Preparation of (lR.3aS.5aR,5bR,7aR.9S,l laR.l lbR.13aR.13bR)-N-
((lS,3R)-3-("4-ethylpiperazine-l-carbonyl)-2,2-dimethylcyclobutyl)-9-hydroxy- 5a,5b,8,8,l la-pentamethyl-l-(prop-l-en-2-yl)icosahvdro-lH-cvclopenta[alchrvsene- 3a-carboxamide:
Figure imgf000126_0001
A solution of (lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)-3a-
((lS,3R)-3-(4-emylpiperazine-l-carbonyl)-2,2-dimethylcyclobutylcarbamoyl)- 5a,5b,8,8,l la-pentamethyl-l-(prop-l-en-2-yl)icosahydro-lH-cyclopenta[a]chrysen- 9-yl acetate (Example 66, 0.760 g) in MeOH:THF (2:1) (45 ml) at 0 0C, 2N NaOH (15 ml) were added and allowed to stir at room temperature for about 16 hours. After completion of the reaction (monitored by TLC), the volatiles were evaporated, the aqueous layer extracted with ethyl acetate and dried with Na2SO4. The solvent was evaporated and purified by silica gel column (100-200 mesh, elution 15% EtOAc in hexane) to afford the title compound as a white solid. Wt: 0.500 g: Yield: 69.9 %; 1H NMR (300 MHz, CDCl3): δ 5.90 (d, J = 8.1 Hz, IH), 4.728 (s, IH), 4.57 (s, IH), 4.10 (m, IH), 3.80-3.41 (m, 4H), 3.20-3.10 (m, 2H), 2.9 (m, IH), 2.60-2.295
(m, 9H), 2.1 (m, 2H), 1.90 (m, IH), 1.80-1.02 (m, 22 H), 0.95, 0.92 (s, 6H), 0.83 (s, 3H), 0.80 (s, 3H). Mass: [M+H+]+ 679 (100%); IR (KBr, cm"1): 3445, 2946, 2867, 1634, 1459, 1463, 1376, 1270, 1242, 1126, 1043, 983, 883, 768, 656; M.R: 122.0 0C -155.1 0C; HPLC: 94.8 %. Example 68: Preparation of 4-((lR.3aS.5aR.5bR.7aR.9S.l laR.l lbR.13aR,13bR)- 3a-((lS,3R)-3-(4-ethylpiperazine-l-carbonyl)-2,2-dimethylcyclobutylcarbamoyl)- 5a,5b,8,8,Ua-pentamethyl-l-(prop-l-en-2-yl)icosahydro-lH-cvclopentaralchrvsen- 9-yloxy)-2,2-dimethyl-4-oxobutanoic acid:
Figure imgf000127_0001
2,2-Dimethylsuccinic anhydride (238 mg) was added to a stirred solution of ( 1 R,3aS,5aR,5bR,7aR,9S, 11 aR, 1 IbR, 13aR, 13bR)-N-(( 1 S,3R)-3-(4-ethylpiperazine- l-carbonyl)-2,2-dimethylcyclobutyl)-9-hydroxy-5a,5b,8,8,l la-pentamethyl-l-(prop- l-en-2-yl)icosahydro-lH-cyclopenta[a]chrysene-3a-carboxamide (Example 67, 125 mg) and DMAP (45 mg) in dry pyridine (10 mL) at room temperature. After addition, the reaction mixture was refluxed for 14 hours. After completion of the reaction (monitored by TLC), it was diluted with EtOAc, the organic layer was washed with aqueous IN HCl, then washed with water and brine, and dried with Na2SO4. The solvent was evaporated and purified by silica gel column (100-200, elution 35% EtOAc in hexane) to afford 90 mg of title compound (60.8 % yield) as an off white solid with 81.67% HPLC purity. 1H-NMR (300 MHz, CDCl3): δ 5.92 (d, J = 7.8 Hz, IH), 4.73 (s, IH), 4.58 (s, IH), 4.52-4.44 (m, IH), 4.19-4.09 (m, IH), 3.90 (m, 2H), 3.7 (m, 2H), 3.15-3.04 (m, IH), 2.87-2.82 (m, 6H), 2.60 (m, 3H), 2.5- 2.3 (m, 3H), 2.00-1.91 (m, 3H), 1.75-1.10 (m, 36H), 0.947, 0.914, 0.900 (s, 18H); Mass: [M+l]+ 806 (100%); IR (KBr, cm"1): 3394, 2957, 2873, 1724, 1623, 1455,
1374, 1367, 1244, 1188, 1146, 980, 883, 765; M.R: 63.8 0C -122.5 0C.
Example 69: Preparation of (lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR.13aR,13bR)-3a- ((lR,3S)-3-(4-ethylpiperazine-l -carbon yl)-2,2-dimethylcvclobutylcarbamoyl)- 5a,5b,8,8,l la-pentamethyl-l-(prop-l-en-2-yl)icosahydro-lH-cyclopenta[a1chrvsen-
9-yl acetate:
Figure imgf000127_0002
A solution of (COCl)2 in DCM was added to a stirred solution of ( lR,3aS,5aR,5bR,7aR,9S, 11 aR, 1 IbR, 13aR, 13bR)-9-acetoxy-5a,5b,8,8, 11 a- pentamethyl- 1 -(prop- 1 -en-2-yl)icosahydro- 1 H-cyclopenta[a]chrysene-3a-carboxylic acid (651 mg) in DCM (10 mL) at 0 0C and the reaction mass was allowed to stir at room temperature for about 3 hours. After completion of the reaction (monitored by
TLC), the solvent was evaporated under nitrogen atmosphere and dissolved in DCM, which was added to a stirred solution of ((lS,3R)-3-amino-2,2- dimethylcyclobutyl)(4-ethylpiperazin-l-yl)methanone itrifluoro acetic acid salt (900 mg) at 0 0C and allowed to stir at room temperature for about 16 hours. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with DCM and washed with aqueous IN HCl, then washed with water and brine, and then dried with Na2SO4, the solvent was evaporated and purified by silica gel column (100-200 mesh, elution 15% EtOAc in hexane) to afford the title compound as an off white solid. Wt: 550 mg. 1H NMR (300 MHz, CDCl3): δ 5.80 (d, J = 6.5 Hz, IH), 4.73 (s, IH), 4.58 (s, IH), 4.50-4.41 (m, IH), 4.2-4.10 (m, IH), 3.78-3.67
(m, 3H), 3.6-3.50 (m, 4H), 3.5-3.4 (m, 7H), 3.1 (m, IH), 3.0 (m, 2H), 2.9 (m, IH), 2.60-2.40 (m, 6H), 2.0 (3H, s), 1.9-1.86 (m, 2H), 1.80-1.2 (m, 18H), 0.95, 0.93, 0.87, 0.83, 0.81, (s, 24H). Example 70: Preparation of (lR,3aS,5aR,5bR.7aR.9S.l laR.l lbR.13aR.13bR)-N-
((lR,3S)-3-(4-ethylpiperazine-l-carbonyl)-2,2-dimethylcvclobutyl)-9-hydroxy- 5a,5b,8.8, 11 a-pentamethyl- 1 -(prop- 1 -en-2-yl)icosahvdro- lH-cyclopentaFalchrysene- 3a-carboxamide:
Figure imgf000128_0001
To a stirred solution of (lR^aS^aR^bRJaR^SJ laRJ lbRJSaRJSbR)-
3a-((lR,3S)-3-(4-ethylpiperazine-l-carbonyl)-2,2-dimethylcyclobutylcarbamoyl)- 5a,5b,8,8, 11 a-pentamethyl- 1 -(prop- 1 -en-2-yl)icosahydro- 1 H-cyclopenta[a]chrysen- 9-yl acetate (Example 69, 550 mg) in MeOH:THF (2:1) at 0 0C temperature 2N NaOH (4 mL) was added and allowed to stir at room temperature for about 16 hours. After completion of the reaction (monitored by TLC), the volatiles was evaporated, the aqueous layer was extracted with ethyl acetate and the organic layer was washed with water, brine and dried with Na2SO4. The solvent was evaporated and the resulting crude was stirred in hexane to get crude solid. The solid crude was purified over silica-gel column chromatography to afford the title compound. Wt: 200 mg, Yield: 93.3 %. 1H NMR (300 MHz, CDCl3): δ 5.86 (d, IH, J = 8.1 Hz), 4.72 (s, IH), 4.57 (s, IH), 4.18-4.06 (m, IH), 3.78-3.68 (m, IH), 3.52-3.30 (m, 3H), 3.23-3.08 (m,
2H), 2.92-2.86 (m, IH), 2.52-2.20 (m, 3H), 2.01-1.88 (m, 2H), 1.80-1.12 (m, 33H), 0.96, 0.93, 0.87, 0.81, 0.74 (s, 18H); Mass: [M+l]+ 649 (5%), [M+Na]+ 671 (100%); IR (KBr, cm"1): 3353, 2937, 2858, 1635, 1618, 1533, 1459, 1390, 1262, 1250, 1148, 1048, 1033, 1020, 983, 883; M.R: 177 0C -188.7 0C; HPLC: 95.72%.
Example 71: Preparation of 4-((lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR.13aR.13bR)-
3a-((lR,3S)-3-(4-ethylpiperazine-l-carbonyl)-2,2-dimethylcvclobutylcarbamoyl)- 5a,5b,8,8,l la-pentamethyl-l-(prop-l-en-2-yl)icosahydro-lH-cyclopenta[a1chrysen- 9-yloxy)-2,2-dimethyl-4-oxobutanoic acid: (Prepared as desribed in above procedure):
Figure imgf000129_0001
1H-NMR (300 MHz, CDCl3): δ 5.91 (d, J = 7.8 Hz, IH), 4.73 (s, IH), 4.58 (s, IH), 4.53-4.44 (m, m), 4.19-4.10 (m, IH), 3.90 (m, 2H), 3.7 (m, 2H), 3.15-3.04 (m, IH), 2.87-2.82 (m, 6H), 2.60 (m, 3H), 2.5-2.3 (m, 3H), 2.00-1.91 (m, 3H), 1.75-1.10 (m, 36H), 0.947, 0.914, 0.900 (s, 18H); Mass: [M+l]+ 806 (100%); IR (KBr, cm"1):
3390, 2956, 2873, 1724, 1623, 1458, 1374, 1367, 1244, 1188, 1146, 980, 883, 765.
Example 72j Preparation of ethyl I^
((lR,3aS,5aR.5bR.7aR.9S.l laR,l lbR,13aR,13bR)-9-acetoxy-5a.5b.8.8.11a- pentamethyl-l-(prop-l-en-2-yl)icosahydro-lH-cyclopentaralchrysene-3a-carbonyl)-
4-ethylpiperidine-4-carboxylate:
Figure imgf000129_0002
To a stirred solution of (lR,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)-9- acetoxy-5a,5b,8,8, 11 a-pentamethyl- 1 -(prop- 1 -en-2-yl)icosahydro- IH- cyclopenta[a]chrysene-3a-carboxylic acid (2.0 g, 4.01 mmol) in DCM (50 ml) oxalyl chloride (4 ml, 15.87 mmol) was added at room temperature. Completion of the reaction as shown on TLC, reaction mixture was concentrated under reduced pressure. The residue was taken in DCM (15 ml) and kept under N2 atmosphere.
Ethyl 4-benzylpiperidine-4-carboxylate (0.74 g, 4.01 mmol) in DCM (50 ml) triethyl amine (1 ml) was added at O0C and stirred for about 15 minutes followed by above prepared acid chloride and the reaction was continued at room temperature for about 8 hours. After completion of the reaction (monitored by TLC), the reaction mixture was neutralized with saturated NaHCO3 and extracted with DCM, the organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 50% ethyl acetate in hexane as an eluent to furnish the title compound as a white solid (1.8 g). 1H NMR (300 MHz, CDCl3): 0.57- 0.97 (m, 19H); 1.18- 1.21 (m, 8H); 1.25- 1.41 (m, 12H); 1.49-1.62 (m, 8H); 1.65- 1.82 (m, 10H); 1.85- 1.98 (m, 4H); 2.56-2.69 (m, 2H); 2.88-3.06 (m, 3H); 3.29-3.38 (m, IH); 3.89-3.90 (m, IH); 4.12-4.23 (m, 2H);
4.44-4.47 (m, IH); 4.56 (s, IH); 4.7 l(s, IH); 7.03-7.05 (m, 2H); 7.23-7.25 (m, 3H); ES Mass: 666 (100%), [M+l].
Example 73j Preparation of. ethyl 4-ethyl-l- ((lR.3aS,5aR,5bR,7aR,9SJ laR,l lbR,13aRJ3bR)-9-hvdroxy-5a,5b,8,8 J la- pen tameth yl- 1 -(prop- l-en-2-yl)icosahydro- lH-cyclopentaraichrysene-Sa- carbonyl)piperidine-4-carboxylate:
Figure imgf000130_0001
Ethyl l-((lR,3aS,5aR,5bR,7aR,9S,l IaR5I lbR,13aR,13bR)-9-acetoxy- 5a,5b,8,8, 11 a-pentamethyl- 1 -(prop- 1 -en-2-yl)icosahydro- lH-cyclopenta[a]chrysene-
3a-carbonyl)-4-ethylpiperidine-4-carboxylate (Example 72, 2.0 g) was taken in
MeOH: THF (8: 8 ml) and cooled the contents to 0 0C then sodium hydroxide (1.5 g in 4ml water) was added and the contents were stirred for about 6 hours at room temperature. After completion of the reaction (monitored by TLC), the reaction mixture was evaporated under reduced pressure. The residue was taken in water and extracted with DCM; the organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 5% methanol in DCM as eluent to furnish the title compound (1.45 g) as a white solid. 1H NMR (300 MHz, CDCl3): 0.57- 0.97 (m, 19H); 1.18- 1.21 (m, 8H); 1.25- 1.41 (m, 12H); 1.49-1.62 (m, 10H); 1.65- 1.82 (m, 10H); 1.85- 1.98 (m, 4H); 2.56-2.69 (m, 2H); 3.29-3.38 (m, IH); 3.89-3.90 (m, IH); 4.15-4.18
(m, 2H); 4.56 (s, IH ); 4.71 (s, IH ); MASS: 624 (100%).
Example 74: Preparation of 4-((lR,3aS,5aR,5bR.7aR,9S,l laR.l lbR,13aR,13bR)- 3a-(4-(ethoxycarbonyl)-4-ethylpiperidine-l-carbonyl)-5a,5b,8,8J la-pentamethyl-l- (prop- 1 -en-2-yl)icosahydro- lH-cyclopentara1chrysen-9-yloxy)-2,2-dimethyl-4- oxobutanoic acid:
Figure imgf000131_0001
To a stirred solution of ethyl 4-ethyl-l-
(( lR,3aS,5aR,5bR,7aR,9S, 11 aR, 1 IbR, 13aR, 13bR)-9-hydroxy-5a,5b,8,8, 11 a- pentamethyl- 1 -(prop- 1 -en-2-yl)icosahydro- 1 H-cyclopenta[a]chrysene-3 a- carbonyl)piperidine-4-carboxylate (Example 73, 0.5 g, 0.80 mmol) in pyridine (5 ml) dimethyl amino pyridine (0.2 g, 1.6 mmol) was added then 3,3- dimethyldihydrofuran-2,5-dione (0.82 ml) was added and the contents were refluxed for about 16 hours. Completion of the reaction was monitored by TLC, the reaction mixture was diluted with ethyl acetate (30 ml) and the organic layer was washed with 5% aqueous HCl, washed with water followed by brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 5% MeOH in DCM as eluent to furnish the title compound (0.25 g) as a white solid. 1H NMR (300 MHz, CDCl3): 0.95-1.16 (m, 19 H); 1.23- 1.78 ( m, 23H); 2.15- 2.59 (m, HH); 2.77-3.58 (m, 16H); 4.33-4.70 (m, 4H); 5.58-
5.60 (s, IH); 5.78 - 5.80 (s, IH); 7.44-7.47 (s, IH); ES Mass: 753; (100%), [M+l].
Example 75: Preparation of (lR.3aS.5aR.5bR,7aR,9SJ laR,l lbR,13aR,13bR)-3a- (4-c vano-4-phen ylpiperidine- 1 -carbon yl)-5 a,5b,8 ,8, 11 a-pentamethyl- 1 -(prop- 1 -en- 2-yl)icosahvdro-lH-cvclopentaralchrvsen-9-yl acetate:
Figure imgf000132_0001
To a stirred solution of (lR,5aR,5bR,7aR,9S,l IaR5I lbR,13aR,13bR)-9- acetoxy-5a,5b5858,l la-pentamethyl-l-(prop-l-en-2-yl)icosahydro-lH- cyclopenta[a]chrysene-3a-carboxylic acid (1.0 g, 2.08 mmol) in DCM (50 ml) oxalyl chloride (4 ml, 15.87 mmol) was added at room temperature. Upon completion of the reaction as shown on TLC, the reaction mixture was concentrated under reduced pressure. The residue was taken in DCM (15 ml) and kept under N2 atmosphere.
4-phenylpiperidine-4-carbonitrile (0.49 g, 2.08 mmol) in DCM (50 ml) triethyl amine (0.3 ml, 3.12 mmol) was added at 0 0C and stirred for about 15 minutes then the above prepared acid chloride was added and reaction was continued at room temperature for about 8 hours. Upon completion of the reaction (monitored by TLC), the reaction mixture was neutralized with saturated NaHCO3 and extracted with DCM, the organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 50% ethyl acetate in hexane as eluent to furnish the title compound (0.9 g). 1H NMR (300 MHz5 CDCl3): 0.57- 0.97 (m, 19 H); 1.18- 1.21 (m, 8H); 1.25- 1.41 (m, 12H); 1.49-1.62 (m, 8H); 1.65- 1.82 (m, 10H); 1.85-1.98 (m, 4H); 2.56-2.69 (m, 2H); 2.88-3.06 (m, 3H); 3.29-3.38 (m, IH); 3.89-3.90 (m, IH); 4.12-4.23 (m, 2H) 4.44-4.47 (m, IH); 4.56 (s, IH); 4.71(s, IH); 7.03-7.05 (m, 2H); 7.23-7.25 (m, 3H); ES Mass: 667 (100%), [M+l].
Example 76: Preparation of l-((lR,3aS,5aR.5bR,7aR,9S.l laR.l lbR,13aR,13bR)-9- hydroxy-5a,5b,8,8J la-pentamethyl-l-(prop-l-en-2-yl)icosahydro-lH- cvclopenta[a1chrvsene-3a-carbonyl)-4-phenylpiperidine-4-carbonitrile:
Figure imgf000132_0002
(lR,3aS,5aR,5bR,7aR,9S, 1 IaR5I IbR513aR,13bR)-3a-(4-cyano-4- phenylpiperidine- 1 -carbon yl)-5a,5b, 8,8, 11 a-pentamethyl- 1 -(prop- 1 -en-2- yl)icosahydro-lH-cyclopenta[a]chrysen-9-yl acetate (Example 75, 2.0 g) was taken in MeOH: THF (8: 8 ml) and cooled the contents to 0 0C then sodium hydroxide (1.5 g in 4ml water) was added and the contents were stirred for about 6 hours at room temperature. After completion of the reaction (monitored by TLC), the reaction mixture was evaporated under reduced pressure and the residue was taken in water and extracted with DCM, the organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 5% methanol in DCM as eluent to furnish the title compound (1.45g) as a white solid. 1U NMR (300 MHz, CDCl3): 0.57- 0.97 (m, 19 H); 1.18- 1.21 (m, 8H); 1.25-1.41 (m, 12H); 1.49-1.62 (m, 10H); 1.65-1.82 (m, 10H); 1.85- 1.98 (m, 4H); 2.56-2.69 (m, 2H); 3.29-3.38 (m, IH); 3.89-3.90 (m, IH); 4.15-4.18 (m, 2H); 4.56 (s, IH); 4.7 l(s, IH); MASS: 624 (100%).
Example 77: Preparation of 4-(qR,3aS,5aR.5bR.7aR,9S,l laR,l lbRq3aR,13bRy 3a-(4-cyano-4-phenylpiperidine- 1 -carbon vD-5a,5b,8, 8, 11 a-pentamethyl- 1 -(prop- 1 - en-2-yl)icosahydro-lH-cyclopentaralchrysen-9-yloxy)-2,2-dimethyl-4-oxobutanoic acid:
Figure imgf000133_0001
To a stirred solution of ((1R5SaS5SaR5SbRJaR^S5I IaR5I IbR5BaR5ISbR)- 9-hydroxy-5a,5b,8,8, 11 a-pentamethyl- 1 -(prop- 1 -en-2-yl)icosahydro- IH- cyclopenta[a]chrysene-3a-carbonyl)-4-phenylpiperidine-4-carbonitrile (Example 76, 0. 5g, 0.80 mmol) in pyridine (5 ml) dimethyl amino pyridine (0.2 g, 1.6 mmol) was added then 3,3-dimethyldihydrofuran-2,5-dione (0.82 ml) was added and the contents were refluxed for about 16 hours. Upon completion of the reaction (monitored by TLC)5 the reaction mixture was diluted with ethyl acetate (30 ml). The organic layer was washed with 5% aqueous HCl, washed with water followed by brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 5% MeOH in DCM as eluent to furnish the title compound (0.25 g) as a white solid. 1H NMR (300 MHz5 CDCl3): 0.95-1.16 (m, 19 H); 1.23-1.78 (m, 23H); 2.15- 2.59 (m, HH); 2.77-3.58 (m, 16H); 4.33-4.70 (m, 4H); 5.58-5.60 (s, IH); 5.78- 5.80 (s, IH); 7.44-7.47 (s, IH); ES Mass: 753 (100%), [M+l]. Example 78: Preparation of tert-butyl 2-(6-(2-
(( lR,3aS.5aR.5bR.7aR.9S.11 aR.1 IbR.13aR, 13bR)-9-acetoxy-5a.5b.8.8, 11 a- pentamethyl- 1 -(prop- 1 -en-2-yl)icosahydro- 1 H-cyclopentaralchrysene-3 a- carboxamido)ethyl)-2,2-dimethyl- 1 ,3-dioxan-4-yl)acetate:
Figure imgf000134_0001
To a stirred solution of (lR,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)-9- acetoxy-5a,5b,8,8, 11 a-pentamethyl- 1 -(prop- 1 -en-2-yl)icosahydro- IH- cyclopenta[a]chrysene-3a-carboxylic acid (1.0 g, 2.08 mmol) in DCM (50 ml) oxalyl chloride (4 ml, 15.87 mmol) was added at room temperature. Completion of the reaction as shown on TLC, the reaction mixture was concentrated under reduced pressure. The residue was taken in DCM (15 ml) and kept under N2 atmosphere.
Tert-butyl 2-(6-(2-aminoethyl)-2,2-dimethyl-l,3-dioxan-4-yl)acetate (0.49 g, 2.08 mmol) in DCM (50 ml) triethyl amine (0.3 ml, 3.12 mmol) was added at 0 0C and stirred for about 15 minutes, then the above prepared acid chloride was added and the reaction was continued at room temperature for about 8 hours. Completion of the reaction was monitored by TLC, and the reaction mixture was neutralized with saturated NaHCO3 and extracted with DCM, and the organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 50% ethyl acetate in hexane as eluent to furnish the title compound (0.9 g). 1H NMR (300 MHz, CDCl3): 0.57- 0.97 (m, 19
H); 1.18- 1.21 (m, 8H); 1.25- 1.41 (m,12H); 1.49-1.62 (m,8H); 1.65- 1.82 (m, 10H); 1.85- 1.98 (m,4H); 2.56-2.69 (m,2H); 2.88-3.06 (m,3H); 3.29-3.38 (m,lH); 3.89- 3.90 (m,lH); 4.12-4.23 (m,4H) 4.44-4.47 (m,lH); 4.56 (s,lH ); 4.71(s,lH); ES Mass: 754; (100%), [M+l].
Example 79j Preparation of tert-butyl 2-(6-(2-
((lR.3aS.5aR.5bR.7aR.9S.l laR.l lbR.13aR.13bR)-9-hvdroxy-5a.5b.8.8.11a- pentamethyl- 1 -(prop- 1 -en-2- vDicosahydro- 1 H-c yclopentaralchrysene-3 a- carboxamido)ethyl)-2,2-dimethyl- 1 ,3-dioxan-4-vl)acetate:
Figure imgf000135_0001
Tert-butyl 2-(6-(2-((lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)-9- hydroxy-5a,5b,8,8,l la-pentamethyl-l-(prop-l-en-2-yl)icosahydro-lH- cyclopenta[a]chrysene-3a-carboxamido)ethyl)-2,2-dimethyl-l,3-dioxan-4-yl)acetate (Example 78, 2.0 g) was taken in MeOH: THF (8: 8 ml) and cooled the contents to 0
0C then sodium hydroxide (1.5 g in 4ml water) was added and contents were stirred for 6 hours at room temperature. Completion of the reaction was monitored by TLC, reaction mixture was evaporated under reduced pressure and the residue was taken in water and extracted with DCM, the organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 5% methanol in DCM as eluent to furnish the title compound (1.45 g) as a white solid. 1H NMR (300 MHz, CDCl3): 0.57-0.97 (m, 19 H); 1.18- 1.21 (m, 8H); 1.25-1.41 (m,12H); 1.49-1.62 (m, 10H); 1.65-1.82 (m, 10H); 1.85- 1.98 (m, 4H); 2.56-2.69 (m, 2H); 3.29-3.38 (m, IH); 3.89-3.90 (m, IH); 4.15-4.18 (m, 2H); 4.56 (s, IH); 4.71 (s, IH); MASS: 712 (100%).
Example 80: Preparation of 4-((lR,3aS.5aR.5bR.7aR.9S.l laR.l lbR.13aR.13bRV 3a-(2-(6-(2-tert-butoxy-2-oxoethyl)-2,2-dimethyl-l,3-dioxan-4-yl)ethylcarbamoyl)- 5a,5b,8,8,l la-pentamethyl-l-(prop-l-en-2-yl)icosahvdro-lH-cyclopenta[a1chrvsen- 9-yloxy)-2,2-dimethyl-4-oxobutanoic acid:
Figure imgf000135_0002
To a stirred solution of tert-butyl 2-(6-(2-
(( 1 R,3aS,5aR,5bR,7aR,9S, 11 aR, 1 IbR, 13aR, 13bR)-9-hydroxy-5a,5b,8,8, 11 a- pentamethyl- 1 -(prop- 1 -en-2-yl)icosahydro- 1 H-cyclopenta[a]chrysene-3 a- carboxamido)ethyl)-2,2-dimethyl-l,3-dioxan-4-yl)acetate (Example 79, 0. 5g, 0.80 mmol) in pyridine (5 ml), dimethyl amino pyridine (0.2 g, 1.6 mmol) and 3,3- dimethyldihydrofuran-2,5-dione (0.82 ml) were added. Contents were refluxed for about 16 hours. After completion of the reaction, the reaction mixture was diluted with ethyl acetate (30 ml). The organic layer was washed with 5% aqueous HCl,
L 34 water followed by brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 5% MeOH in DCM as eluent to furnish the title compound (0.25 g) as a white solid. 1H NMR (300 MHz, CDCl3): 0.95-1.16 (m,19 H); 1.23-1.78 ( m, 23 H ); 2.15- 2.59 (m.HH ); 2.77-3.58 (m, 16H) ; 4.33-4.70 (m,4H ); 5.58-5.60 (s,lH ); 5.78- 5.80
(s,lH); 7.44-7.47 (s,lH); ES Mass: 806 [M+Na].
Example 81: Preparation of 7-(( lR.3aS,5aR,5bR,7aR,9S,l IaR.1 IbRJ 3aR,l 3bRV 9-(3-carboxy-3-methylbutanoyloxy)-5a,5b,8,8,l la-pentamethyl-l-(prop-l-en-2- yl)icosahvdro-lH-cvclopentara1chrysene-3a-carboxamido)-3,5-dihvdroxyheptanoic acid:
Figure imgf000136_0001
4-((lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)-3a-(2-(6- (carboxymethyl)-2,2-dimethyl-l,3-dioxan-4-yl)ethylcarbamoyl)-5a,5b,8,8,l la- pentamethyl-l-(prop-l-en-2-yl)icosahydro-lH-cyclopenta[a]chrysen-9-yloxy)-2,2- dimethyl-4-oxobutanoic acid (Example 80, 0.3 g) was taken in MeOH (3 ml) and cooled the contents to 0 0C then Aq HCl (0.5 ml) was added and the contents were stirred for 6 hours at room temperature. After completion of the reaction (monitored by TLC), the reaction mixture was evaporated under reduced pressure. The residue was taken in water and extracted with DCM, the organic layer was dried over
Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 5% methanol in DCM as eluent to furnish the title compound (0.08 g) as a white solid. 1H NMR (300 MHz, CDCl3): 0.57-0.97 (m, 19H); 1.18-1.21 (m, 8H); 1.25-1.41 (m, 12H); 1.49-1.62 (m, 8H); 1.65- 1.82 (m, 10H); 1.85- 1.98 (m, 4H); 2.56-2.69 (m, 2H); 2.88-3.06 (m, 3H); 3.29-3.38 (m, IH);
3.89-3.90 (m, IH); 4.44-4.47 (m, IH); 4.56 (s, IH); 4.71(s, IH); Mass: 744 [M+l].
Example 82: Preparation of 5-(αR.3aS.5aR.5bR,7aR,9S.l laR.l lbR,13aR.13bR)- 3a-((lR,3S)-3-((4-benzylpiperidin-l-yl)methyl)cvclopentylcarbamoyl)- 5a,5b,8,8.11 a-pentamethyl- 1 -(prop- 1 -en-2-yl)icosahvdro- lH-cyclopentafalchrysen-
9-yloxy)-3.3-dimethyl-5-oxopentanoic acid:
Figure imgf000137_0001
To a stirred solution of (IR5SaS1SaR1SbRJaR^SJ IaR5I IbR1ISaR5ISbR)- N-((lR,3S)-3-((4-benzylpiperidin-l-yl)methyl)cyclopentyl)-9-hydroxy- 5a,5b,8,8,l la-pentamethyl-l-(prop-l-en-2-yl)icosahydro-lH-cyclopenta[a]chrysene- 3a-carboxamide (Example 32, 0. 5g, 0.80 mmol) in pyridine (5 ml), dimethyl amino pyridine (0.2 g, 1.6 mmol) was added, followed by 4,4-dimethyldihydro-2H-pyran- 2,6(3H)-dione (0.82 ml) was added. The contents were refluxed for 16 hours. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with ethyl acetate (30 ml). The organic layer was washed with 5% aqueous HCl, water followed by brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 5% MeOH in DCM as eluent to furnish the title compound (0.25 g) as a white solid. 1H NMR (300 MHz, CDC13): 0.80-0.95 (m, 17H); 1.14-1.67 (m, 23H); 1.82-2.02 (m, 15H); 2.23-3.50 (m, 15H); 4.21-4.45 (m, 2H); 4.57 (s, IH); 4.72 (s, IH); 6.28-6.30 (m, IH); 7.11-7.13 (m, 2H); 7.14-7.22 (m, IH); 7.24-7.29 (m, 2H); ES Mass: 841
(100%), [M+l].
Example 83: Preparation of ((lR,3aS.5aR.5bR.7aR,9S.l laR.l lbR.13aR.13bR)-9- acetoxy-5a,5b.8,8, l la-pentamethyl-1 -(prop- l-en-2-yl)icosahydro-lH- cyclopentaralchrvsene-3a-carbonyl)-4-ethylpiperidine-4-carboxylic acid:
Figure imgf000137_0002
To a stirred solution of (lR55aR55bR,7aR,9S5l IaR5I IbR513aR,13bR)-9- acetoxy-5a,5b,8,8, 11 a-pentamethyl- 1 -(prop- 1 -en-2-yl)icosahydro- IH- cyclopenta[a]chrysene-3a-carboxylic acid (2.0 g, 4.01 mmol) in DCM (50 ml) oxallyl chloride (4 ml, 15.87 mmol) was added at room temperature. Upon completion of the reaction as shown on TLC, the reaction mixture was concentrated under reduced pressure. The residue was taken in DCM (15 ml) and kept under N2 atmosphere. 4-ethylpiperidine-4-carboxylic acid (0.74 g, 4.01 mmol) in DCM (50 ml) triethyl amine (1 ml) was added at O0C and stirred for 15 minutes followed by above prepared acid chloride and the reaction was continued at room temperature for about 8 hours. After completion of reaction monitored by TLC, the reaction mixture was neutralized with saturated NaHCO3 and extracted with DCM. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 50% ethyl acetate in hexane as eluent to furnish the title compound (1.8 g). 1H NMR (300 MHz, CDCl3): 0.57- 0.97 (m, 19 H); 1.18- 1.21 (m, 8H); 1.25- 1.41 (m, 12H); 1.49-1.62 (m, 8H); 1.65-1.82 (m, 10H); 1.85-1.98 (m, 4H); 2.56-2.69 (m, 2H); 2.88-3.06 (m, 3H); 3.29-3.38 (m,
IH); 3.89-3.90 (m, IH); 4.12-4.23 (m, 2H); 4.44-4.47 (m, IH); 4.56 (s, IH); 4.71 (s, IH); 7.03-7.05 (m, 2H); 7.23-7.25 (m, 3H); ES Mass: 660 (100%), [M+Na].
Example 84j Preparation of 4-ethyl-l- ((lR.3aS.5aR,5bR.7aR,9S.l laR.l lbR,13aR.13bR)-9-hvdroxy-5a,5K8,8,l la- pentamethyl- 1 -(prop- 1 -en-2-yl)icosahydro- lH-cyclopentaf alchrvsene-3a- carbonyl)ρiρeridine-4-carboxylic acid:
Figure imgf000138_0001
l-((lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)-9-acetoxy- 5a,5b,8,8, 11 a-pentamethyl- 1 -(prop- 1 -en-2-yl)icosahydro- lH-cyclopenta[a]chrysene-
3a-carbonyl)-4-ethylpiperidine-4-carboxylic acid (Example 83, 2.0 g) was taken in MeOH: THF (8: 8 ml) and cooled the contents to O0C then sodium hydroxide (1.5 g in 4 ml water) was added and the contents were stirred for 6 hours at room temperature. Completion of the reaction was monitored by TLC. The reaction mixture was evaporated under reduced pressure and the residue was taken in water and extracted with DCM, the organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 5% methanol in DCM as eluent to furnish the title compound (1.45 g) as a white solid.1H NMR (300 MHz, CDCl3): 0.57- 0.97 (m, 19H); 1.18- 1.21 (m, 8H); 1.25- 1.41 (m, 12H); 1.49-1.62 (m, 10H); 1.65- 1.82 (m, 10H); 1.85- 1.98 (m, 4H); 2.56-2.69 (m, 2H); 3.29-3.38 (m, IH); 3.89-3.90 (m, IH); 4.15-4.18 (m, 2H); 4.56 (s, IH); 4.71 (s, IH); MASS: 595 (100%).
Example 85: Preparation of l-((lR,3aS.5aR,5bR:7aR,9S.l laR.l lbR,13aR.13bR)-9- (3-carboxy-3-methylbutanoyloxy)-5a,5b,8.8, 11 a-pentamethyl- 1 -(prop- 1 -en-2- yl)icosahydro-lH-cyclopentaralchrvsene-3a-carbonyl)-4-ethylpiperidine-4- carboxylic acid:
Figure imgf000139_0001
To a stirred solution of 4-ethyl-l- ((lR,3aS,5aR,5bR,7aR,9S,l laR,llbR,13aR,13bR)-9-hydroxy-5a,5b,8,8,l la- pentamemyl-l-(prop-l-en-2-yl)icosahydro-lH-cyclopenta[a]chrysene-3a- carbonyl)piperidine-4-carboxylic acid (Example 84, 0.5 g, 0.80 mmol) in pyridine (5 ml) dimethyl amino pyridine (0.2 g, 1.6 mmol) and 3,3-dimethyldihydrofuran- 2,5-dione (0.82 ml) were added. The contents were refluxed for about 16 hours. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with ethyl acetate (30 ml). The organic layer was washed with 5% aqueous HCl, water followed by brine then dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 5% MeOH in DCM as eluent to furnish the title compound (0.25 g) as a white solid. 1H NMR (300 MHz, CDCl3): 0.95-1.16 (m, 19H); 1.23-1.78 (m, 23 H); 2.15-
2.59 (m, 11H); 2.77-3.58 (m, 16H); 4.33-4.70 (m, 4H); 5.58-5.60 (s, IH); 5.78- 5.80 (s, IH); 7.44-7.47 (s, IH); ES Mass: 725 (100%), [M+l].
Example 86j Preparation of 1-(((1S,3RV3- ((lR,3aS,5aR.5bR.7aR.9S,l laR.l lbR.13aR.13bR)-9-(3-carboxy-3- methylbutanoyloxy)-5a,5b,8,8,l la-pentamethyl-l -(prop- l-en-2-yl)icosahydro- IH- cyclopenta[alchrvsene-3a-carbonyl)cyclopentyl)methyl)piperidine-4-carboxylic acid:
Figure imgf000140_0001
To a stirred solution of l-(((lS,3R)-3-
((lR,3aS,5aR,5bR,7aR,9S,l IaR5I lbR,13aR,13bR)-9-hydroxy-5a,5b,8,8,l Ia- pentamethyl- 1 -(prop- 1 -en-2-yl)icosahydro- 1 H-cyclopenta[a]chrysene-3 a- carbonyl)cyclopentyl)methyl)piperidine-4-carboxylic acid (0.5 g, 0.80 mmol) in pyridine (5 ml) dimethyl amino pyridine (0.2 g, 1.6 mmol) and 3,3- dimethyldihydrofuran-2,5-dione (0.82 ml) were added and the contents were refluxed for about 16 hours. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with ethyl acetate (30 ml), the organic layer was washed with 5% aqueous HCl, then water followed by brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 5% MeOH in DCM as eluent to furnish the title compound (0.25 g) as a white solid. 1H NMR (300 MHz, CDCl3): 0.95-1.16 (m, 19H); 1.23- 1.78 (m, 23H); 2.15-2.59 (m, HH); 2.77-3.58 (m, 16H); 4.33-4.70 (m, 4H); 5.58- 5.60 (s, IH); 5.78- 5.80 (s, IH); 7.44-7.47 (s, IH); ES Mass: 778 (100%), [M+l].
Example 87: Preparation of 4-((lR,3aS.5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)- 3a-((lR,3S)-3-(benzyloxycarbonyl)-2,2-dimethylcyclobutylcarbamoyl)- 5a,5b,8,8, 11 a-pentamethyl- 1 -(prop- 1 -en-2-yl)icosahydro- 1 H-cyclopenta[alchrvsen- 9-yloxy)-2,2-dimethyl-4-oxobutanoic acid:
Figure imgf000140_0002
Step 1: synthesis of (lS,3R)-benzyl 3-
((lR,3aS,5aR,5bR,7aR,9S,llaR,llbR,13aR,13bR)-9-hydroxy-5a,5b,8,8,lla- pentamethyl-l-(prop-l-en-2-yl)icosahydro-lH-cyclopenta[a]chrysene-3a- carboxamido)-2,2-dimethylcyclobutanecarboxylate:
Figure imgf000141_0001
A stirred solution of (lS,3R)-3-
((lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)-9-hydroxy-5a,5b,8,8,l la- pentamethyl- 1 -(prop- 1 -en-2-yl)icosahydro- 1 H-cyclopenta[a]chrysene-3 a- carboxamido)-2,2-dimethylcyclobutanecarboxylic acid (Example 5, 2.0 g, 3.844 mmol) in DMF (15 ml) Cs2CO3 (1.45 g, 4.473 mmol) and benzyl bromide (0.51 ml, 3.843 mmol) were added slowly portion wise at 0 0C . After addition, the reaction was stirred at room temperature for 2 hours. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with EtOAc (100 ml) and washed with water (50 ml), brine (50 ml) and dried over Na2SO4 then the solvent was evaporated and purified by silica gel column (60-120, elution 4% EtOAc in hexane) to afford the title compound as a white solid. 1H NMR and Mass complies with the product structure and forwarded to next step. Step 2: Preparation of 4-((lR,3aS,5aR,5bR, 7aR,9S,l IaRJ IbRJ 3aR,13bR)-3a-
((1R, 3S)-3-(benzyloxycarbonyl)-2,2-dimethylcyclobutylcarbamoyl)-5a, 5b, 8,8,11a- pentamethyl-l-(prop-l-en-2-yl)icosahydro-lH-cyclopenta[a]chrysen-9-yloxy)-2,2- dimethyl-4-oxobutanoic acid:
To a stirred solution of (lS,3R)-benzyl 3- ((lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)-9-hydroxy-5a,5b,8,8,l la- pentamethyl- 1 -(prop- l-en-2-yl)icosahydro- lH-cyclopenta[a]chrysene-3a- carboxamido)-2,2-dimethylcyclobutanecarboxylate (above step 1, 500 mg) in dry pyridine (10 ml) dimethyl Succinic anhydride (953 mg) was added followed by DMAP 181 mg) then reflux the reaction mixture for 20 hours. After completing the reaction (monitored by TLC), diluted with ethyl acetate and washed with water and brine. The combined organic layers were dried over Na2SO4, concentrated under reduced pressure to afford the crude compound as a gummy solid. The crude compound was purified by silica- gel column chromatography using 100-200 mesh and hexane and ethyl acetate mixtures as mobile phase to get the title compound. Wt: 400 mg, Yield: 67.1 %. 1H NMR (300 MHZ, CDCl3): δ 7.36 (5H, s), 5.70 (IH, d, J = 7.8 Hz), 5.136 (2H, d, J = 5.7 Hz), 4.723(1H, s), 4.58 (IH, s), 4.57-4.47 (IH, m), 4.14-4.11 (IH, m), 3.10-3.09 (IH, m), 2.71-2.60 (4H, m), 2.52-2.31 (2H, m), 2.15-2.00 (IH, m), 1.93-1.89 (2H, m), 1.80-1.17 (31H, m), 0.95 (6H, m), 0.91 (3H, s), 0.882 (3H, s), 0.856 (3H, s), 0.820 (3H, s), 0.786 (IH, m); IR (KBr, cm"1): 3406, 3069, 2951, 1734, 1664, 1642, 1509, 1499, 1474, 1456, 1391, 1234, 1184, 1150,
977, 881, 697; Mass: [M+H]+ 800.6 (10%), 822.65 [M+Na]+; Melting Range: 64.7- 100.40C
Example 88j Preparation of dS,3R)-3- (QS,3aS,5aR,5bR,7aR,9S.l laR,l lbR,13aR,13bR)-9-(3-carboxy-3- methylbutanoyloxy)- l-isopropyl-5a,5b,8,8, 11 a-pentamethylicosahydro- IH- cyclopentaralchrvsene-3a-carboxamido)-2,2-dimethylcyclobutanecarboxylic acid:
Figure imgf000142_0001
To a stirred solution of 4- ((lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)-3a-((lR,3S)-3-
(benzyloxycarbonyl)-2,2-dimethylcyclobutylcarbamoyl)-5a,5b,8,8, 11 a-pentamethyl- l-(prop-l-en-2-yl)icosahydro-lH-cyclopenta[a]chrysen-9-yloxy)-2,2-dimethyl-4- oxobutanoic acid (Example 87, 200 mg) in EtOAc (20 ml) at room temperature 10 % Pd/C (catalytic amount) were added and the reaction mixture was stirred under H2 gas atmosphere at room temperature for 12 hours. After completion of the reaction
(monitored by TLC), the reaction mixture was filtered through a celite bed and the obtained filtrate was concentrated under reduced pressure to afford the debenzylated title compound as a white solid. Wt: 0.100 g: Yield: 56.2 %. 1H NMR (300 MHz, CDCl3): δ 5.77 (d, J = 7.8 Hz, IH), 4.54-4.507 (m, IH), 4.157-4.13 (m, IH), 2.9- 2.80 (m, IH), 2.7-2.61 (m, 3H), 2.60-2.20 (m, 5H), 2.00-1.93 (m, IH), 1.80-1.10 (m,
30H), 0.95 (s, 6H), 0.941 (s, 3H), 0.88 (s, 6H), 0.84 (d, J = 7.6 Hz, 6H), 0.832 (s, 3H), 0.823 (s, 3H); IR (KBr, cm"1): 3403, 2956, 2620, 1710, 1652, 1648, 1509, 1474, 1367, 1245, 1194, 1148, 1000, 978, 877, 620, 509; M.R: 150.1 0C -282.9 0C. Example 89j Preparation of (1R.3SV1 -benzyl 3^
((lR.3aS.5aR.5bR.7aR.9S.l laR.l lbR.13aR,13bRV3a-f(lS.3RV3-(4- (ethoxycarbonyl)piperidine-l-carbonylV2,2-dimethylcyclobutylcarbarnoyl)- 5a,5b,8,8, 1 la-pentamethyl- 1 -(prop- 1 -en-2-yDicosahydro- 1 H-cyclopentaralchrysen- 9-yl) 2,2-dimethylcvclobutane- 1.3-dicarboxylate:
Figure imgf000143_0001
To a cooled solution of (lR,3aS55aR55bR57aR,9S,l IaR5I lbR513aR,13bR)-9- ((lS,3R)-3-(benzyloxycarbonyl)-2,2-dimethylcyclobutanecarbonyloxy)- 5a,5b,8585l la-pentamethyl- 1 -(prop- l-en-2-yl)icosahydro-lH-cyclopenta[a]chrysene- 3a-carboxylic acid (Example 18, 1.0 g) in dry DCM (15 ml) oxallyl chloride (1.24 ml) was added drop wise to the reaction mixture under nitrogen and stirred for 2 hours. After completion of the reaction (monitored by TLC), the solvent was evaporated under reduced pressure to get crude compound as a white solid. This crude acid chloride was dissolved in dry DCM and was added to a mixture of ethyl l-((lR,3S)-3-amino-2,2-dimethylcyclobutanecarbonyl)piperidine-4-carboxylate
(678 mg) and triethyl amine (0.5 ml). The reaction mixture was stirred at room temperature for over night. After completion of the reaction, the mixture was diluted with DCM5 washed with water, brine and dried over Na2SO4, concentrated under reduced pressure, purified over silica-gel column chromatography to afford the title compound (700 mg). Yield: 51 %. 1H NMR (300 MHZ5 CDCl3): δ 7.353 (5H5 m),
5.958 -5.80 (IH5 m), 5.12 (2H5 d, J = 3.90 Hz)5 4.73 (IH5 m), 4.586 (IH5 s), 4.5-4.35 (2H5 m), 4.20-4.11 (2H,m), 3.80 (lH,m), 3.20-3.02 (2H,m), 2.898-2.75(4H,m), 2.70- 2.6 (lH,m), 2.59-2.40 (2H,m), 2.38-2.28(2H,m), 1.96-1.80(5H,m), 1.79- 1.10(32H,m), 0.961(6H,s), 0.952(6H,s)5 0.926(6H,s), 0.840(3H,s), 0.829(3H,s), 0.728(lH,m); FAB Mass : 988[M+Na]+; IR (KBr, cm"1): 3403, 2952, 1733, 1656,
1652, 1639, 1509, 1497, 1463, 1455, 1375, 1263, 1235, 1184, 1108, 1021, 983, 882, 750 and 697; M.R: 138.10C- 154.20C; HPLC: 91.21%.
Example 90. ; Preparation of (1R.3SV3- (((lR.3aS,5aR.5bR.7aR,9SJ laR.l lbR.13aR.13bR)-3a-((lS.3R)-3-(4-
(ethoxycarbonyl)piperidine-l-carbonyl)-2,2-dimethylcvclobutylcarbamoyl)- 5a,5b,8,8J la-pentamemyl-l-(prop-l-en-2-yl)icosahvdro-lH-cyclopentaralchrvsen- 9-yloxy)carbonyl)-2,2-dimethylcvclobutanecarboxylic acid:
Figure imgf000144_0001
To a stirred solution of (lR,3S)-l-benzyl 3- ((lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)-3a-((lS,3R)-3-(4-
(ethoxycarbonyl)piperidine-l-carbonyl)-2,2-dimethylcyclobutylcarbamoyl)- 5a,5b,8,8, 11 a-pentamethyl- 1 -(prop- 1 -en-2-yl)icosahydπ> 1 H-cyclopenta[a]chrysen- 9-yl) 2,2-dimethylcyclobutane-l,3-dicarboxylate (Example 89, 200 mg) in dry DCM (10 ml) triethyl amine (0.1 ml) and Et3SiH (48.1 mg) were added at O0C then Pd(OAc)2 (5 mg) was added under nitrogen conditions. The reaction mixture was stirred at reflux temperatures for over night. After completion of the reaction (monitored by TLC), diluted with DCM and concentrated under reduced pressure then purified by column chromatography to get the title compound (150 mg, 83.3 % Yield). 1H NMR (300 MHz, CDCl3): δ 6.152-6.09 (IH, m), 4.736 (IH, s), 4.58 (IH, s), 4.52-4.35 (2H, m), 4.19-4.12 (3H, m), 3.85-3.80 (IH, m), 3.18-3.08 (2H, m)
2.95-2.86 (4H, m), 2.66-2.20 (7H, m), 2.10 (IH, m), 2.05-1.89 (7H, m), 1.80-1.14 (31H, m), 1.059 (3H, s), 0.955 (3H, s), 0.930 (3H, s), 0.918-0.884 (HH, m), 0.846 (IH, m). Mass (ESI): 897.70 [M+Na] (50%); IR (KBr, cm"1): 3403, 2954, 2869, 1733, 1603, 1456, 1459, 1376, 1236, 1185, 1041, 983, 943 and 883; MR: 780C- 125.20C; HPLC: 93.94%.
Example 9Jj Preparation of (lR,3S)-l-benzyl 3^
((lR,3aS,5aR,5bR.7aR.9S.l laR,l lbR,13aR,13bR)-3a-f(lR.3S)-3- (benzyloxycarbonyl)-2,2-dimethylcyclobutylcarbamoyl)-5a.5b,8,8 J 1 a-pentamethyl- 1 -(prop- 1 -en-2-yl)icosahvdro- 1 H-c yclopentaralchrysen-9-yl) 2,2- dimethylcyclobutane- 1 ,3-dicarboxylate:
Figure imgf000144_0002
To a stirred solution of (lS,3R)-3-(benzyloxycarbonyl)-2,2- dimethylcyclobutanecarboxylic acid (525 mg, 2.003 mmol) and diisopropyl ethyl amine (1.027 ml, 6.0 mmol) in THF (10 ml) 2,4,6-trichloro benzoyl chloride (0.313 ml, 2.00 mmol) was added at 0 0C temperature and the reaction mixture was allowed to stir at room temperature for 6 hours, After completion of the reaction (monitored by TLC), the solvent was evaporated and crude anhydride was dissolved in dry pyridine (10 ml) then (lS,3R)-benzyl 3-
((lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)-9-hydroxy-5a,5b,8,8,l la- pentamethyl- 1 -(prop- 1 -en-2-yl)icosahydro- 1 H-cyclopenta[a]chrysene-3 a- carboxamido)-2,2-dimethylcyclobutanecarboxylate (Example 87-step 1, 0.7 g, 1.641 mmol) in pyridine (10 ml) was added followed by DMAP (catalytic) and refluxed for 12 hours and the solvent was evaporated. The reaction mixture was diluted with DCM and washed with water, the organic layer was dried with Na2SO4 and concentrated under reduced pressure. The resulting crude purified by silica gel column chromatography (100-200 Mesh, Elution: 5 % EtOAc in Hexane) to afford the title compound as a white solid. 1H NMR (300 MHZ, CD3OD): δ 7.35 (1OH, s), 5.65 (IH, d, J =8.1 Hz), 5.13 (4H, d, J = 3.6 Hz), 4.72 (IH, s), 4.57 (IH, s), 4.47- 4.43 (IH, m), 4.2-4.09 (IH, m), 3.2-3.0 (IH, m), 2.81-2.61 (5H, m), 2.46-2.317 (3H, m), 1.877 (3H, s), 1.713-1.14 (25H, m), 0.954 (6H, s), 0.95 (3H, s), 0.914 (3H, s), 0.892 (3H, s), 0.880 (3H, s), 0.851 (3H, s), 0.782 (IH, m); FAB Mass: [M+Na]+ 940
(100 %); IR (KBr, cm 1): 3410, 2954, 2869, 1733, 1664, 1498, 1459, 1456, 1234, 1184, 1020, 883, 697; M.Range: 71.9- 111.3 0C.
Example 92j Preparation of (lS,3R)-3- ((lR.3aS,5aR.5bR,7aR.9S,l laR,l lbR.13aR.13bR)-9-((lS.3R)-3-carboxy-2.2- dimethylcvclobutanecarbonyloxy)-5a,5b,8,8,l la-pentamethyl-l-(prop-l-en-2- yl)icosahydro-lH-cyclopentara1chrvsene-3a-carboxamido')-2,2- dimethylcvclobutanecarboxylic acid:
Figure imgf000145_0001
To a stirred solution of (lR,3S)-l-benzyl 3- ((lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)-3a-((lR,3S)-3- (benzyloxycarbonyl)-2,2-dimethylcyclobutylcarbamoyl)-5a,5b,8,8, 11 a-pentamethyl- l-(prop-l-en-2-yl)icosahydro-lH-cyclopenta[a]chrysen-9-yl) 2,2- dimethylcyclobutane-l.S-dicarboxylate (Example 91, 350 mg) in dry DCM (10 ml) triethyl amine (0.1 ml) and Et3SiH (88.5 mg) were added at O0C then Pd (OAc)2 (5 mg) was added under nitrogen conditions and the reaction mixture was stirred at reflux temperatures for over night. After completion of the reaction (monitored by TLC), diluted with DCM and concentrated under reduced pressure then purified by column chromatography to get the title compound as a white solid. 1H NMR (300
MHZ, CD3OD): δ 5.86 (IH, d, J =8.1 Hz), 4.732 (IH, s), 4.585 (IH, s), 4.54-4.43 (IH, m), 4.2-4.09 (IH, m), 3.2-3.0 (2H, m), 2.80-2.71 (2H, m), 2.46-2.3 (5H, m), 2.00-1.87 (3H, m), 1.83-1.134 (30H, m), 0.978 (6H, s), 0.948 (3H, s), 0.914 (3H, s), 0.884 (3H, s), 0.880 (3H, s), 0.851 (3H, s), 0.782 (IH, m); FAB Mass: [M+Na]+ 759 (100 %); IR (KBr, cm"1): 3405, 2955, 2870, 1726, 1658, 1652, 1638, 1463, 1390,
1234, 1192, 1019, 879, 727, 621; M.Range: 102.3-158.2 0C.
Example 93: Preparation of. (lR,3S)-l-benzyl 3_i
((lR,3aS,5aR,5bR.7aR.9S.l laR,l lbR,13aR.13bR)-3a-(4- (ethoxycarbonyl)piperidine-l-carbonyl)-5a,5b,8,8,l la-pentamethyl-l-(prop-l-en-2- yl)icosahvdro-lH-cyclopentaralchrvsen-9-yl) 2,2-dimethylcvclobutane- 1,3- dicarboxvlate:
Figure imgf000146_0001
A solution of (COCl)2 (0.493 ml, 5.71 mmol) in DCM (5 ml) was added to a stirred solution of (lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)-9-((lS,3R)-3-
(benzyloxycarbonyl)-2,2-dimethylcyclobutanecarbonyloxy)-5a,5b,8,8, Ha- pentamethyl-l-(prop-l-en-2-yl)icosahydro-lH-cyclopenta[a]chrysene-3a-carboxylic acid (Example 18, 0.400 g, 0.0.571 mmol) in DCM (10 ml) at O0C. The reaction mass was allowed to stir at room temperature for 3 hours. After completion of the reaction (monitored by TLC), the solvent was evaporated under nitrogen atmosphere and dissolved in DCM (10 ml), which was added to a stirred solution of 4- ethylpiperidinecarboxylate (0.179 g, 1.142 mmol) at 00C and allowed to stir at room temperature for 16 hours. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with DCM and washed with water, IN HCl, water brine and dried with Na2SO4, the solvent was evaporated and purified by silica gel column (100-200 mesh, elution 15% EtOAc in hexane) to afford the title compound as an off white solid. Wt: 0.400 g: Yield: 83.5 %. 1H NMR (300 MHz, CDCl3): δ 7.363-7.34 (5H, m), 5.12 (2H, d, J= 3.9 Hz), 4.72 (IH, d, 7 = 1.5 Hz), 4.51 (IH, d, J = 1.5 Hz), 4.44 (IH, m), 4.25 (IH, m), 4.2 (2H, m), 2.98-2.73 (5H, m), 2.63 (IH, m), 2.51 (IH, m) 2.1-2.0 (2H, m), 2.09-1.8 (6H, m), 1.65-1.10 (30H, m), 0.959 (6H, s), 0.949 (3H, s), 0.928 (9H, s), 0.838 (IH, m); Mass (ESI): 862.70 [M+Na] (20%); IR (KBr, cm"1): 3434, 2950, 2867, 2366, 1734, 1631, 1456, 1411, 1390, 1376, 1319, 1264, 1234, 1182, 1168, 1039, 916, 881, 748, 697 cm-1; MR: 57.9 0C - 92.9 0C; HPLC: 94.30%.
The following compounds have been prepared by above procedures and the starting C3-OH compounds have been taken from above compounds.
Example 94: 5-((lR,3aS,5aR,5bR,7aR,9S,l laR.l lbR,13aR,13bR)-3a-((lR,3S)-3- ((4-benzylpiperidin-l-yl)methyl)cyclopentylcarbamoyl)-5a,5b,8,8J la-pentamethyl-
1 -(prop- 1 -en-2-yl)icosahydro- lH-cvclopenta[alchrysen-9-yloxy)-3,3-dimethyl-5- oxopentanoic acid:
Figure imgf000147_0001
1K NMR (300 MHz, CDCl3): δ7.24-7.29(2H,m),7.14-7.22(lH,m), 7.11-7.13 (2H, m),6.28-6.30 (IH, m), 4.72 (lH,s), 4.57 (IH, s), 4.2 1-4.45(2H, m), 2.23-2.50
(15H, m), 1.82-2.02 (15H, m), 1.14-1.67(23H, m), 0.80-095 (17H, m); Mass (ESI): 854 [M+l] (100%); IR (KBr, cm"1): 3423,3066, 2947, 1724, 1656,1639, 1509, 1375, 1232, 1151, MR: 112 - 1600C; HPLC: 97.36%. Example 95j 2,2-dimethyl-4-oxo-4-
((lR3aS.5aR,5bR.7aR.9S.l laR,l lbR,13aR.13bR)-5a,5b,8,8,l la-pentamethvl-3a- (Y 1 S ,4R)-4-(moφholinomethyl)cyclopent-2-enylcarbamoyl)- 1 -(prop- 1 -en-2- vDicosahydro- lH-cvclopentaralchrysen-9-yloxy)butanoic acid:
Figure imgf000148_0001
1H NMR (300 MHz, CDCl3): δ 0.95-1.16 (m, 19H), 1.23-1.78 (m, 23H), 2.15-2.59 (m, 1 IH), 2.77-3.58 (m, 1 IH), 4.33-4.70 (m, 4H), 5.58-5.60 (s, IH), 5.78-5.80 (s,
IH), 7.44-7.47 (s, IH); ES Mass: 749 (100%); HPLC: 99.6%.
Example 96: 4-oxo-4-((lR.3aS.5aR<5bR,7aR,9S.l laR.l lbR.13aR.13bR)- 5a,5b,8,8,l la-pentamethyl-3a-(3-(piperidin-l-ylmethyl)cyclopentylcarbanioyl)-l- (prop- 1 -en-2- vDicosahydro- 1 H-cyclopenta[alchrysen-9- yloxy)butanoic acid:
Figure imgf000148_0002
HlNMR (300MHz, CDC13) : 0.95-1.16 (m, 19H), 1.23-1.78 (m, 23H), 2.15-2.59 (m, HH), 2.77-3.58 (m, 16H), 4.33-4.70 (m, 4H), 5.58-5.60 (s, IH), 5.78-5.80 (s, IH); IRcm 1: 3391, 2951, 2866, 2731, 2556, 1726, 1630, 1356, 1244, 1185, 1137, 1004; Mass: 749[M+1] (100%); HPLC: 90%.
Example 97: (lR,3aS,5aR,5bR,7aR.9S.l laR.l lbR.13aR.13bR)-N-(2,2-dimethyl-3- (3-morpholino-3-oxopropylcarbamoyl)cyclobutyl)-9-hydroxy-5a,5b,8,8, Ha- pentamethyl- 1 -(prop- 1 -en-2-yl)icosahydro- lH-cyclopentaralchrysene-Sa- carboxamide:
Figure imgf000148_0003
HlNMR (300MHz, CDC13): 0.87-0.96 (m, 20H), 1.22-1.89 (m, 23H), 1.89-2.08 (m, 8H), 2.34-2.52 (m, 4H), 3.12-3.16 (m, 2H), 3.40-3.43 (m, 2H), 3.55-3.66 (m, 8H), 4.09 (m, IH), 4.58 (s, IH), 4.73 (s, IH), 6.072-6.10 (d, IH, J=8.4Hz), 6.21-6.24 (m, IH); IRcm"1: 3372, 2945, 2865, 1656, 1652, 1646, 1509, 1375, 1271, 1235, 1161,
1034, 754; Mass: 744[M+Na] (100%); HPLC: 89% Example 98: (lR.3aS.5aR.5bR.7aR.9S.l laR.l lbR.13aR.13bRVN-f2.2-dimethyl-3- (3-oxo-3-(pyrrolidin-l-yl)propylcarbamoyl)cyclobutyl)-9-hydroxy-5a,5b,8,8J la- pentamethyl-l-('prop-l-en-2-yl')icosahvdro-lH-cvclopenta[alchrysene-3a- carboxamide:
Figure imgf000149_0001
HlNMR (300 MHz, CDC13): 0.74-0.95 (m, 23H), 1.22-1.38 (m, 12H), 1.49-1.67 (m, 13H), 1.84-2.37 (m, 7H), 2.37-2.47 (m, 5H), 3.12-3.60 (m, 6H), 4.05-4.08 (m, IH), 4.58 (s, IH), 4.72 (s, IH), 6.13-6.15 (d, IH, J=8.4Hz), 6.44-6.48 (m, IH); IRcm"1: 3355, 2948, 2869, 1638, 1513, 1452, 1376, 1250, 1046, 881, 752; Mass:
728[M+Na] (100%); HPLC: 84%.
Example 99: 4-(( lR,3aS,5aR.5bR.7aR.9S, 1 IaR, 1 IbR , 13aR, 13bR)-3a-(( lR.3S)-3- ((4-benzylpiperidin-l-yl)methyl)cvclopentylcarbamoyl)-5a,5b,8,8,l la-pentamethyl- l-(prop-l-en-2-yl)icosahvdro-lH-cvclopentaFa1chrysen-9-yloxy)-2,2-dimethyl-4- oxobutanoic acid:
Figure imgf000149_0002
Hl NMR (300 MHz, CDC13): 0.80-0.95 (m, 17H), 1.14-1.67 (m, 23H), 1.82-2.02
(m, 15H), 2.23-3.50 (m, 15H), 4.21-4.45 (m, 2H), 4.57 (s, IH), 4.72 (s, IH), 6.28- 6.30 (m, IH), 7.11-7.13 (m, 2H), 7.14-7.22 (m, IH), 7.24-7.29 (m, 2H); IRcm"1:
3416, 2944, 2869, 2179, 1733, 1729, 1640, 1466, 1365, 1033, 1055, 977; Mass:
840[M+l] (100%); HPLC: 83.13%.
Pharmacological activity
The compounds described herein can be tested for their activity for antiviral following any procedures known to a person of ordinary skill in the art. For example, the following protocols may be employed for testing the compounds.
These protocols are illustrative and do not limit to the scope of the invention. Example 100: Evaluation of compounds cytotoxicity on Sup-Tl cells:
Reduction of 3-(4,5-dimethylthiozol-2-yl)-2,5-diphenyltetrazolium bromide (MTT, sigma) is chosen as an optimal end point of cell viability measurement (Mosmann, 1983; Cole, 1986; Alley et al., 1988)T! Cells (O.2xlO6 cells per well) are seeded in 96-well plates. Increasing concentrations of compound are added to the cells and incubated at 370C for about 14 hours in a CO2 Incubator with 5% CO2. The media is replaced with a fresh growth medium along with 20 μL of 5 mg /ml 3-(4,5- dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT, Sigma). After incubation for about 4 hours in a humidified atmosphere, the media is removed and 200 μL of 0.1 N acidic isopropyl alcohol is added to the wells to dissolve the MTT- formazan crystals. The absorbance is recorded at 570 nm, immediately after the development of purple colour. Each experiment is conducted in triplicate and the data are represented as average, with standard deviation. Percent viability of the cells is computed with reference to the absorbance of reduced MTT in the experiments conducted in absence of any compound.
Cell line: Sup-Tl
Results:
Figure imgf000150_0001
Example 101: Evaluation of compounds cytotoxicity on Molt-4 cells:
10 mM stock solution of the test compound was made in DMSO and stored at -2O0C for further use. During the day of the experiment working stocks were made by serial dilution with DMSO. The final concentration of DMSO in the test media is
1%.
MTT assay was performed in a 96 well format using Molt-4 cell line (Human acute T lymphoblastic leukemia) - a suspension culture maintained in RPMI with
10% FBS media. Approximately 0.03 million cells are seeded/well and the plate was incubated for 16 hours. Following incubation, cells are treated with a test compound at a defined concentration in triplicates and incubation was continued for another 24 hours. At the end of the incubation, MTT reagent was added (10 μl, 5mg/ml stock) to the plate and continued incubation for additional 4 hours. Reaction was terminated by addition of 200 μl 0.1N acidic propanol. The colour developed was measured by a plate reader using 590 nM filters. The percent viability was calculated by comparing mean absorbance value of sample with the control (Vehicle alone).
Cell line: Molt-4
Results:
Figure imgf000151_0001
Example 102: P24 assay for Anti-HIV activity:
Viral p24 is measured after about 72 hours of post infection in presence of drugs using an ABL p24 ELISA kit. 0.5 million cells/well are taken into the 24 well plates and added increasing concentrations of drugs. 1 ng/ml of HIV-I virus was added to each well and incubated for overnight at 370C (370C and 5% CO2). After about 16 hours incubation the media was changed and fresh media was added and cultured for about 72 hours. P24 was quantified at the 4th day of post-infection using an ABL kit according to manufacturer's instructions.
Results:
Percent inhibition of HIV- 193IN 101 replication in Sup-Tl cells
Figure imgf000151_0002
Figure imgf000152_0001
Example 103: Determining the anti HIV-l(IC50) and cytotoxicity against Infectious HIV- 1 strain (92-HT 599):
MT2 cells were infected with the HIV-I strain 92-HT599 (10TCID50/30000 cells). The infected cells are plated at the concentration of 30000 cells per well in a 96 well assay micro plate. A test compound was added to the micro plate in a defined format with the final concentration of DMSO (vehicle) being not more than 1%. Incubation was carried out in a CO2 incubator for 96 hours for viral infection. At the end of incubation period an aliquot from each well was taken for p24 estimation. The quantitation of p24 is an index for antiviral activity of the compound. Percent inhibition was calculated with reference to control values (vehicle).
P24 estimation was carried out using an Advance Biosciences kit as per the procedure as detailed by supplier.
Compound preparation:
10 mm stock was made by dissolving test compound in DMSO. Subsequent dilutions were made with DMSO to make necessary working stocks (100X).
Results:
Figure imgf000152_0002
Figure imgf000152_0003
Figure imgf000153_0001
Example 104: Evaluation of compounds for their anti-HFV-1 ICsns and cytotoxicities (CCso) using three infectious HIV-I strains (NL4-3, IIIB and CNHN24) in MT2 cells:
Assay Procedures:
Compound Preparation:
Compound was dissolved in DMSO to make 30 mM stock. Then the 3OmM stock is further diluted to 4 mM using DMSO. The 4mM stock was used as the top concentration to carry out an 11 -point, 3-fold dilution scheme using DMSO in a 96- well plate to make the compound dose plate. Compounds in the dose plate were transferred to a new 96-well plate (working plate) containing PBS with 0.05% pluronic acid. From this working plate, the compound solution was transferred to the 384-well assay plates.
Control compounds used in compound control wells were prepared and added to assay plates individually.
Assay Methods:
MT2 cells were mixed with HIV-I strain NL4-3(or IIIB, or CNHN24) and the cell/virus mixture was added to the aforementioned antivirus assay plates. After incubation in a 370C, 5% CO2 incubator, the supernatant from the assay plate was transferred to a new 384-well plate containing the indicator cells with a fire fly luciferase gene under HIV-I LTR control. The expression level of lucif erase was related to HIV-I infectivity and was measured by Bright-Glo kit (Promega).
For cytotoxicity assay the same amount of MT2 cells as in antivirus assay but without HIV-I virus were added to the cytotoxicity plates. The cytotoxicity was measured by Cell Titer-Glo cell viability assay (Promega).
Therapeutic index (TI) was determined by taking ratio of CC50/IC50
Results:
Figure imgf000154_0001
Figure imgf000155_0001
Figure imgf000155_0002
Example 105: Evaluation of compounds for their anti -HIV-I ICsns and cytotoxicities (CCso) using three infectious HIV-I strains (NL4-3. MB and CNHN241 in PBMC cells:
Compound Preparation:
Compound was dissolved in DMSO to make 3OmM stock. Then the 3OmM stock was further diluted to 4mM using DMSO. The 4mM stock was used as the top concentration to carry out an 11 -point, 3-fold dilution scheme using DMSO in a 96- well plate to make the compound dose plate. Compounds in the dose plate were transferred to a new 96-well plate (working plate) containing PBS with 0.05% pluronic acid. From this working plate the compound solution was transferred to the 384-well assay plates.
Control compounds for cpd control wells were prepared and added to assay plates individually.
Assay Method:
PBMC cells were isolated from human whole blood using Histopaque-
1077(Sigma, #10771) and frozen down and kept in liquid nitrogen tank. Two days before the assay PBMC was recovered and cultured in medium containing PHA-P (Sigma,#L1668).On the day of assay PBMC cells were pelleted down and resuspended in medium containing IL-2(Sigma, #17908), then the cells were mixed with HIV-I strain NL4-3, MOI=0.01(or IIIB, or CNHN24) and the ceiyvirus mixture was added to the aforementioned antivirus assay plates. After incubation in a 37 C, 5% CO2 incubator, the supernatant from the assay plate was transferred to a new 384-well plate containing the indicator cells with a fire fly luciferase gene under HΓV-1 LTR control. The expression level of luciferase was related to HIV-I infectivity and was measured by Bright-Glo kit (Promega).
For the cytotoxicity assay, the same amount of PBMC cells as in the antivirus assay but without the HIV-I virus, was added to the cytotoxicity plates. The cytotoxicity was measured by a CellTiter-Glo cell viability assay (Promega).
Results:
Figure imgf000156_0001
References:
1. Mosmann T, December 1983, Journal of immunological methods, 65 (1-2), 55-63.
2. SPC Cole, cancer chemotherapy and Pharmacology, 1986, 17, 259-263.
3. Antiviral methods and protocols (Eds: D.Kinchington and RFSchinazi), Humana press Inc, 2000]
4. HlV protocols (Eds: NL Michael and JHKin), Humana press Inc, 1999]
5. DAIDS virology manual for HIV laboratories, publication NIH-97-38-38, 1997
6. HIV-I p24 antigen capture assay, enzyme immuno assay for deduction of HIV-I p24 in tissue culture media-Advance bioscience laboratories Inc., kit procedure. Although the invention herein has been described with reference to particular embodiments, it is to be understood that these embodiments are merely illustrative of the principles and applications of the present invention. It is therefore to be understood that numerous modifications may be made to the illustrative embodiments and that other arrangements may be devised without departing from the spirit and scope of the present invention as described above.
All publications and patent applications cited in this application are herein incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated herein by reference.

Claims

WE CLAIM:
1. A compound of the formula (I):
Figure imgf000158_0001
Formula (1)
wherein,
R is H, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocyclyl and preferably R is substituted by Ra;
R' is H, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted alkyloxy, or substituted or unsubstituted aryloxy and preferably R' can be substituted by Ra;
X and Xi are independently selected from a bond, -O-, -NR"-, -C(O)-, - C(O)2-,-(CH2)n-, or -C(O)NR"-;
Z and Zi are independently selected from a bond, -(CH2)n-, -C(O)-, -O-, - S-, -SO2-, or -NR"-;
Z' is H, substituted or unsubstituted alkyl or Z and Z' are together with the attached carbon to form oxo (C=O) and when Z and Z' together with the attached carbon then X and R are absent;
n is an integer 0-2;
m is an integer 0-2;
" =^^" is single bond or double bond;
Ri is H, C(O)2R", or substituted or unsubstituted alkyl; R2 is H, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, or substituted or unsubstituted cycloalkyl;
R3' and R3" are independently selected from H, or substituted or unsubstituted alkyl and when " ^=" is single bond then one of R3' or R3" is absent;
Rais H, OH, halogen, NR", C(O)2R", CH2OR", C(O)NR" or substituted or unsubstituted alkyl; and
each R" is independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocyclyl; and a proviso that one of the R or R' is substituted or unsubstituted 4 or 5 membered cycloalkyl group, and if R or R' is 4 membered cycloalkyl group then at least one of the carbon atom of the 4 membered cycloalkyl group must be substituted by two identical groups and which are selected from alkyl or halogen wherein most preferably alkyl is methyl and halo is fluorine, an analog thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable solvate thereof, a pharmaceutically acceptable hydrate thereof, an N-oxide thereof, a tautomer thereof, a regioisomer thereof, a stereoisomer thereof, a prodrug thereof or a polymorph thereof.
2. The compound according to claim 1, which is a compound of the formula (IA):
Figure imgf000159_0001
Formula (IA)
wherein, RA is substituted or unsubstituted alkyl or substituted or unsubstituted cycloalkyl; wherein cycloalkyl is a 4 or 5 membered ring system and substituents in each occurrence is independently selected from H, halo, C1-C4 alkyl, CO-O-Rb, -CH2-O-Rb, CO-NHRb, or CON(Rb)2; and preferably substituted or unsubstituted alkyl of R is selected from:
Figure imgf000160_0001
RA' is H, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, and preferably RA' can be substituted by Ra;
XiA is a bond, -O-, -NR"-, -C(O)-, -C(O)2-, or -C(O)NR"-;
Z1A is a bond, -C(O)-, -O-, -S-, -SO2-, or -NR"-;
Ra is H, OH, halogen, NR", C(O)2R", CH2OR", C(O)NR" or substituted or unsubstituted alkyl;
Rb is H, or substituted or unsubstituted alkyl; and
each R" is independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocyclyl; and a proviso that one of the RΛ or RA' is substituted or unsubstituted 4 or 5 membered cycloalkyl group, and if RΛ or RA' is 4 membered cycloalkyl group then at least one of the carbon atom of the 4 membered cycloalkyl group wherein at least one of the carbon atom of the cycloalkyl group must be substituted by two identical groups and which are selected from alkyl or halogen wherein most preferably alkyl is methyl and halo is fluorine, an analog thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable solvate thereof, a pharmaceutically acceptable hydrate thereof, an N-oxide thereof, a tautomer thereof, a regioisomer thereof, a stereoisomer thereof, a prodrug thereof or a polymorph thereof.
3. The compound according to claim 1, which is a compound of the formula (2):
Figure imgf000161_0001
Formula (2)
wherein,
R2 is H, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted cycloalkyl and preferably R2 can be substituted by Ra;
R2' is H, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted alkyloxy, or substituted or unsubstituted aryloxy and preferably R2' is substituted by Ra;
X2 and X2' are independently selected from a bond, -O-, -NR"-, -C(O)-, - C(O)2-,-(CH2)n-, or -C(O)NR"-;
n is 0-3;
Z2 and Z2' are independently selected from a bond, -C(O)-, -0-, or -NR"-;
Ra is H, OH, halogen, N(R")2, C(O)R", C(O)2R", CH2OR", C(O)N(R")2 or substituted or unsubstituted alkyl;
each R" is independently selected from H, -[CH(R"')]PC(O)2R"', substituted or unsubstituted alkyl, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocyclyl; p is 0-3; and
each R'" is independently selected from H, substituted or unsubstituted alkyl, or substituted or unsubstituted cycloalkyl; and a proviso that one of the R2 or R2' is substituted or unsubstituted 4 or 5 membered cycloalkyl group, and if R2 or R2' is 4 membered cycloalkyl group then at least one of the carbon atom of the 4 membered cycloalkyl group must be substituted by two identical groups and which are selected from alkyl or halogen wherein most preferably alkyl is methyl and halo is fluorine an analog thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable solvate thereof, a pharmaceutically acceptable hydrate thereof, an N-oxide thereof, a tautomer thereof, a regioisomer thereof, a stereoisomer thereof, a prodrug thereof or a polymorph thereof.
4. A compound of the formula (2A):
Figure imgf000162_0001
Formula (2A)
wherein,
X T-AAl1 is a bond, or -C(O)-;
X rtΛ&Z is a bond, O or NH;
R >A1 is H, substituted or unsubstituted alkyl, substituted or unsubstituted
Figure imgf000162_0002
Figure imgf000163_0001
RA2 is H, substituted or unsubstituted alkyl, substituted or unsubstituted amino, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted aryl and preferably RA2 is substituted by R ; and
each R is substituted or unsubstituted alkyl, substituted or unsubstituted heterocyclyl, wherein heterocycle is nitrogen containing heterocycle and is bonded through nitrogen atom, substituted or unsubstituted N contained heterocyclylalkyl (wherein alkyl is bonded to ring nitrogen atom of heterocycle), substituted or unsubstituted aralkyl or substituted or unsubstituted phenyl, an analog thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable solvate thereof, a pharmaceutically acceptable hydrate thereof, an N- oxide thereof, a tautomer thereof, a regioisomer thereof, a stereoisomer thereof, a prodrug thereof or a polymorph thereof.
5. A compound selected from the group consisting of:
(lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)-9-acetoxy-
5a,5b,8, 8, 11 a-pentamethyl-1 -(prop- l-en-2-yl)icosahydro- IH- cyclopenta[a]chrysene-3a-carboxylic acid,
( 1 S,3R)-benzyl 3-(( 1 R,3aS,5aR,5bR,7aR,9S, 11 aR, 11 bR, 13aR, 13bR)-9- acetoxy-5a,5b,8,8, 11 a-pentamethyl-1 -(prop- l-en-2-yl)icosahydro- IH- cyclopenta[a]chrysene-3a-carboxamido)-2,2-dimethylcyclobutanecarboxylate, ( 1 R,3aS,5aR,5bR,7aR,9S, 1 1 aR, 11 bR, 13aR, 13bR)-9-(( 1 R,3S)-3-(tert- butoxycarbonyl)-2,2-dimethylcyclobutanecarbonyloxy)-5a,5b,8,8, Ha- pentamethyl-l-(prop-l-en-2-yl)icosahydro-lH-cyclopenta[a]chrysene-3a- carboxylic acid, (lR,3aS,5aR,5bR,7aR,9S,llaR,llbR,13aR,13bR)-9-((lR,3S)-3-carboxy- 2,2-dimethylcyclobutanecarbonyloxy)-5a,5b,8,8,l la-pentamethyl-l-(prop-l-en-2- yl)icosahydro-lH-cyclopenta[a]chrysene-3a-carboxylic acid,
(lS,3R)-3-((lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)-9-hydroxy- 5a,5b,8,8,lla-pentamethyl-l-(prop-l-en-2-yl)icosahydro-lH- cyclopenta[a]chrysene-3a-carboxamido)-2,2-dimethylcyclobutanecarboxylic acid,
( 1 R,2S,3aR,5aR,5bR,7aS, 1 OR, 12aR, 12bR)-2-(3-carboxy-3- methylbutanoyloxy)-3,3,5a,5b, 12b-pentamethyl- 10-(prop- 1 -en-2- yl)icosahydrodicyclopenta[a,i]phenanthrene-l,7a-dicarboxylic acid,
(lR,3aS,5aR,5bR,7aR,9S, 1 IaR, 1 IbR, 13aR, 13bR)-3a-((l S,3R)-2,2- dimethyl-3-(moφholine-4-carbonyl)cyclobutylcarbamoyl)-5a,5b,8,8,l la- pentamethyl- 1 -(prop- 1 -en-2-yl)icosahydro- lH-cyclopenta[a]chrysen-9-yl acetate,
(lR,3aS,5aR,5bR,7aR,9S,l laR,llbR,13aR,13bR)-N-((lS,3R)-2,2- dimethyl-3-(morpholine-4-carbonyl)cyclobutyl)-9-hydroxy-5a,5b,8,8,l la- pentamethyl-l-(prop-l-en-2-yl)icosahydro-lH-cyclopenta[a]chrysene-3a- carboxamide,
4-((lR,3aS,5aR,5bR,7aR,9S,llaR,llbR,13aR,13bR)-3a-((lS,3R)-2,2- dimethyl-3-(morpholine-4-carbonyl)cyclobutylcarbamoyl)-5a,5b,8,8,l la- pen tamethyl- 1 -(prop- 1 -en-2-yl)icosahydro- 1 H-cyclopenta[a]chrysen-9-yloxy)- 2,2-dimethyl-4-oxobutanoic acid,
(lR,3aS,5aR,5bR,7aR,9S,l IaR1I lbR,13aR,13bR)-3a-((lS,3R)-2,2- dimethyl-3-(piperidine-l-carbonyl)cyclobutylcarbamoyl)-5a,5b,8,8,l la- pentamethyl- 1 -(prop- 1 -en-2-yl)icosahydro- 1 H-cyclopenta[a]chrysen-9-yl acetate,
( 1 R,3aS,5aR,5bR,7aR,9S, 11 aR, 11 bR, 13aR, 13bR)-N-(( 1 S,3R)-2,2- dimethyl-3-(piperidine-l-carbonyl)cyclobutyl)-9-hydroxy-5a,5b,8,8,lla- pentamethyl-l-(prop-l-en-2-yl)icosahydro-lH-cyclopenta[a]chrysene-3a- carboxamide,
4-((lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)-3a-((lS,3R)-2,2- dimethyl-3-(piperidine-l-carbonyl)cyclobutylcarbamoyl)-5a,5b,8,8,l la- pentamethyl-l-(prop-l-en-2-yl)icosahydro-lH-cyclopenta[a]chrysen-9-yloxy)- 2,2-dimethyl-4-oxobutanoic acid, (lR,3aS,5aR,5bR,7aR,9S,l laR,llbR,13aR,13bR)-3a-((lS,3R)-2,2- dimethyl-3-(pyrrolidine-l-carbonyl)cyclobutylcarbamoyl)-5a,5b,8,8,lla- pentamethyl- 1 -(prop- 1 -en-2-yl)icosahydro- 1 H-cyclopenta[a]chrysen-9-yl acetate,
( lR,3aS,5aR,5bR,7aR,9S, 11 aR, 1 IbR, 13aR, 13bR)-N-(( 1 S,3R)-2,2- dimethyl-3-(pyrrolidine- 1 -carbonytycyclobutyl^-hydroxy-Sa^bAS, Ha- pentamethyl-l-(prop-l-en-2-yl)icosahydro-lH-cyclopenta[a]chrysene-3a- carboxamide,
4-((lR,3aS,5aR,5bR,7aR,9S,l IaR5I IbR, 13aR,l 3bR)-3a-((l S,3R)-2,2- dimethyl-3-(pyrrolidine- l-carbonyl)cyclobutylcarbamoyl)-5a,5b,8, 8, 1 la- pen tamethyl- 1 -(prop- 1 -en-2-yl)icosahydro- 1 H-cyclopenta[a]chrysen-9-yloxy)- 2,2-dimethyl-4-oxobutanoic acid,
(lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)-3a-((lR,3S)-2,2- dimethyl-3-(moφholine-4-carbonyl)cyclobutylcarbamoyl)-5a,5b,8,8,lla- pentamethyl-l-(prop-l-en-2-yl)icosahydro-lH-cyclopenta[a]chrysen-9-yl acetate,
( 1 R,3aS,5aR,5bR,7aR,9S, 11 aR, 11 bR, 13aR, 13bR)-N-(( lR,3S)-2,2- dimethyl-3-(morpholine-4-carbonyl)cyclobutyl)-9-hydroxy-5a,5b,8,8,l la- pentamethyl-l-(prop-l-en-2-yl)icosahydro-lH-cyclopenta[a]chrysene-3a- carboxamide,
( 1 R,3aS,5aR,5bR,7aR,9S, 11 aR, 11 bR, 13aR, 13bR)-9-(( 1 S,3R)-3- (benzyloxycarbonyl)-2,2-dimethylcyclobutanecarbonyloxy)-5a,5b,8,8,lla- pentamethyl-l-(prop-l-en-2-yl)icosahydro-lH-cyclopenta[a]chrysene-3a- carboxylic acid,
( 1 R,3aS,5aR,5bR,7aR,9S, 11 aR, 11 bR, 13aR, 13bR)-9-((l S,3R)-3-carboxy- 2,2-dimethylcyclobutanecarbonyloxy)-5a,5b,8,8,l la-pentamethyl-l-(prop-l-en-2- yl)icosahydro-lH-cyclopenta[a]chrysene-3a-carboxylic acid,
(lR.SaS.SaR.SbRJaR.QS.l laR.llbR.lSaR.lSbR^Sa.Sb.S.β.l la- pentamethyl-3a-((lR,3S)-3-moφholinomethyl)cyclopentylcarbamoyl)-l-(prop-l- en-2-yl)icosahydro-lH-cyclopenta[a]chrysen-9-yl acetate,
(lR,3aS,5aR,5bR,7aR,9S,l laR.l IbR513aR,13bR)-5a,5b,8,8,l Ia- pentamethyl-3a-((lS,4R)-4-(morpholinomethyl)cyclopent-2-enylcarbamoyl)-l- (prop-l-en-2-yl)-icosahydro-lH-cyclopenta[a]chrysen-9-yl acetate, ((lR,5aR,5bR,7aR,9S,l laR,llbR,13aR,13bR)-9-hydroxy-5a,5b,8,8,lla- pentamethyl-l-(prop-l-en-2-yl)icosahydro-lH-cyclopenta[a]chrysen-3a-yl)(3-(3- isopropyl-S-methyMH-l^^-triazoM-yty-S-azabicycloP^.ljoctan-S- yl)methanone,
(lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)-9-hydroxy- 5a,5b,8,8,l la-pentamethyl-N-((lR,3S)-3-(moφholinomethyl)cyclopentyl)-l- (prop-l-en-2-yl)icosahydro-lH-cyclopenta[a]chrysene-3a-carboxamide,
2,2-dimethyl-4-oxo-4-((lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)- 5a,5b,8,8,l la-pentamethyl-3a-((lR,3S)-3-
(morpholinomethyl)cyclopentylcarbamoyl)- 1 -(prop- 1 -en-2-yl)icosahydro- 1 H- cyclopenta[a]chrysen-9-yloxy)butanoic acid,
((I R,5aR,5bR,7aR,9S, 11 aR, 11 bR, 13aR, 13bR)-9-hydroxy-5a,5b,8,8, 11 a- pentamethyl-l-(prop-l-en-2-yl)icosahydro-lH-cyclopenta[a]chrysen-3a-yl)(3-(3- isopropyl-S-methyl^H-l^^-triazol^-y^-S-azabicyclofS^.lJoctan-δ- yl)methanone,
(lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)-9-hydroxy- 5a,5b,8,8,l la-pentamethyl-N-((lS,4R)-4-(morpholinomethyl)cyclopent-2-enyl)- l-(prop-l-en-2-yl)icosahydro-lH-cyclopenta[a]chrysene-3a-carboxamide,
(lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)-3a-(4-
(hydroxymethyl)cyclopent-2-enylcarbamoyl)-5a,5b,8,8,l la-pentamethyl-l-(prop- l-en-2-yl)icosahydro-lH-cyclopenta[a]chrysen-9-yl acetate,
(lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)-9-hydroxy-N-(4- (hydroxymethyl)cyclopent-2-enyl)-5a,5b,8,8,l la-pentamethyl-l-(prop-l-en-2- yl)icosahydro-lH-cyclopenta[a]chrysene-3a-carboxamide,
(lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)-3a-((2S,3R)-4- ((3S,4aS,8aS)-3-(tert-butylcarbamoyl)octahydroisoquinolin-2(lH)-yl)-3-hydroxy- l-phenylbutan-2-ylcarbamoyl)-5a,5b,8,8,l la-pentamethyl-l-(prop-l-en-2- yl)icosahydro-lH-cyclopenta[a]chrysen-9-yl acetate,
(3S,4aS,8aS)-N-tert-butyl-2-((2R,3S)-2-hydroxy-3- (( lR,3aS,5aR,5bR,7aR,9S, 1 1 aR, 11 bR, 13aR, 13bR)-9-hydroxy-5a,5b,8,8, 11 a- pentamethyl- 1 -(prop- 1 -en-2-yl)icosahydro- 1 H-cyclopenta[a]chrysene-3a- carboxamido)-4-phenylbutyl)decahydroisoquinoline-3-carboxamide,
(lR,3aS,5aR,5bR,7aR,9S,l laR,llbR,13aR,13bR)-3a-((lR,3S)-3-((4- benzylpiperidin- 1 -yOmethyOcyclopentylcarbamoy^-Sa.Sb^^, 11 a-pentamethyl- l-(prop-l-en-2-yl)icosahydro-lH-cyclopenta[a]chrysen-9-yl acetate,
(lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)-N-((lR,3S)-3-((4- benzylpiperidin-l-yOmethy^cyclopentyl^-hydroxy-Sa^b^Λl la-pentamethyl- 1 -(prop- 1 -en-2-yl)icosahydro- 1 H-cyclopenta[a]chrysene-3 a-carboxamide,
5-((lR,3aS,5aR,5bR,7aR,9S,l laR,llbR,13aR,13bR)-3a-((lR,3S)-3-((4- benzylpiperidin-l-y^methy^cyclopentylcarbamoy^-Sa^b.S^J la-pentamethyl- l-(prop-l-en-2-yl)icosahydro-lH-cyclopenta[a]chrysen-9-yloxy)-5-oxopentanoic acid,
( lR,3aS,5aR,5bR,7aR,9S, 1 IaR, 1 IbR, 13aR, 13bR)-3a-((lR,3S)-3-((4- ethylpiperazin- 1 -yl )methyl )cyclopentylcarbamoyl )-5a,5b,8,8,l l a-pentamethyl- 1 - (prop-l-en-2-yl)icosahydro-lH-cyclopenta[a]chrysen-9-yl acetate,
(lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)-N-((lR,3S)-3-((4- ethylpiperazin-l-yl)methyl)cyclopentyl)-9-hydroxy-5a,5b,8,8,l la-pentamethyl-l- (prop-l-en-2-yl)icosahydro-lH-cyclopenta[a]chrysene-3a-carboxamide,
4-((l R,3aS,5aR,5bR,7aR,9S, 11 aR, 11 bR, 13aR, 13bR)-3a-(( lR,3S)-3-((4- ethylpiperazin-l-y^methy^cyclopentylcarbamoyO-Sa.Sb^^^ la-pentamethyl-l- (prop-l-en-2-yl)icosahydro-lH-cyclopenta[a]chrysen-9-yloxy)-2,2-dimethyl-4- oxobutanoic acid,
Methyl 3-((lS,3R)-3-((lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)- 9-acetoxy-5a,5b,8,8,l la-pentamethyl-l-(prop-l-en-2-yl)icosahydro-lH- cyclopenta[a]chrysene-3a-carboxamido)-2,2-dimethylcyclobutanecarboxamido) propanoate,
3-((lS,3R)-3-((lR,3aS,5aR,5bR,7aR,9S,l IaR5I lbR,13aR,13bR)-9- hydroxy-Sa.Sb^^J la-pentamethyl-l-Cprop-l-en^-yl^cosahydro-lH- cyclopenta[a]chrysene-3a-carboxamido)-2,2- dimethylcyclobutanecarboxamido)propanoic acid, (S)-methyl 2-((lS,3R)-3-
((lR,3aS,5aR,5bR,7aR59S,l IaR5I lbR,13aR513bR)-9-acetoxy-5a,5b,8,85l Ia- pentamethyl-l-(prop-l-en-2-yl)icosahydro-lH-cyclopenta[a]chrysene-3a- carboxamido)-2,2-dimethylcyclobutanecarboxamido)-3-methylbutanoate,
(S)-2-(( 1 S,3R)-3-((lR,3aS,5aR,5bR,7aR,9S, 11 aR, 1 IbR, 13aR, 13bR)-9- hydroxy-5a,5b,8,8,lla-pentamethyl-l-(prop-l-en-2-yl)icosahydro-lH- cyclopenta[a]chrysene-3a-carboxamido)-2,2-dimethylcyclobutanecarboxamido)- 3-methylbutanoic acid,
(S)-methyl 2-((lS,3R)-3-
((lR,3aS,5aR,5bR,7aR,9S,l IaR5I lbR,13aR,13bR)-9-acetoxy-5a,5b,8,8,l Ia- pentamethyl-l-(prop-l-en-2-yl)icosahydro-lH-cyclopenta[a]chrysene-3a- carboxamido)-2,2-dimethylcyclobutanecarboxamido)-4-methylpentanoate,
(S)-2-((lS,3R)-3-((lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)-9- hydroxy-5a,5b, 8, 8, 11 a-pentamethyl- 1 -(prop- 1 -en-2-yl)icosahydro- 1 H- cyclopenta[a]chrysene-3a-carboxamido)-2,2-dimethylcyclobutanecarboxamido)- 4-methylpentanoic acid,
(lR,3aS,5aR,5bR,7aR59S,l IaR5I IbR5BaR513bR)-3a-((lR,3S)-2,2- dimethyl-3-(pyrrolidine-l-carbonyl)cyclobutylcarbamoyl)-5a,5b,8,8,l la- pentamethyl- 1 -(prop- 1 -en-2-yl)icosahydro- lH-cyclopenta[a]chrysen-9-yl acetate,
( 1 R,3aS,5aR,5bR,7aR,9S, 11 aR, 11 bR, 13aR, 13bR)-N-(( 1 R,3S)-2,2- dimethyl-3-(pyrrolidine- 1 -carbonyl)cyclobutyl)-9-hydroxy-5a,5b,8,8, l la- pentamethyl-l-(prop-l-en-2-yl)icosahydro-lH-cyclopenta[a]chrysene-3a- carboxamide,
4-((l R,3aS,5aR,5bR,7aR,9S, 11 aR, 1 IbR, 13aR, 13bR)-3a-((lR,3S)-2,2- dimethyl-3-(pyrrolidine-l-carbonyl)cyclobutylcarbamoyl)-5a,5b,8,8,l la- pentamethyl-l-(prop-l-en-2-yl)icosahydro-lH-cyclopenta[a]chrysen-9-yloxy)- 2,2-dimethyl-4-oxobutanoic acid,
(lR,3aS,5aR,5bR,7aR,9S,l IaR5I lbR,13aR,l 3bR)-3a-((lR,3S)-2,2- dimethyl-3-(piperidine-l-carbonyl)cyclobutylcarbamoyl)-5a,5b,8,8,l la- pen tamethyl- 1 -(prop- 1 -en-2-yl)icosahydro- 1 H-cyclopenta[a] chry sen-9-yl acetate, ( lR,3aS,5aR,5bR,7aR,9S, 11 aR, 1 IbR, 13aR, 13bR)-N-(( lR,3S)-2,2- dimethyl-3-(piperidine-l-carbonyl)cyclobutyl)-9-hydroxy-5a,5b,8,8,l la- pentamethyl-l-(prop-l-en-2-yl)icosahydro-lH-cyclopenta[a]chrysene-3a- carboxamide,
4-((lR,3aS,5aR,5bR,7aR,9S,l laR,llbR,13aR,13bR)-3a-((lR,3S)-2,2- dimethyl-3-(piperidine-l-carbonyl)cyclobutylcarbamoyl)-5a,5b,8,8,lla- pentamethyl- 1 -(prop- 1 -en-2-yl)icosahydro- lH-cyclopenta[a]chrysen-9-yloxy)- 2,2-dimethyl-4-oxobutanoic acid,
(lR,3aS,5aR,5bR,7aR,9S,l IaR, 1 lbR,13aR,13bR)-5a,5b,8,8,l Ia- pentamethyl-3a-((lR,3S)-3-((3-methylpiperidin-l- yl)methyl)cyclopentylcarbamoyl)- 1 -(prop- 1 -en-2-yl)icosahydro- IH- cyclopenta[a] chrysen-9-yl acetate,
(lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)-9-hydroxy- 5a,5b,8,8,l la-pentamethyl-N-((lR,3S)-3-((3-methylpiperidin-l- yl)methyl)cyclopentyl)-l-(prop-l-en-2-yl)icosahydro-lH-cyclopenta[a]chrysene- 3a-carboxamide,
2,2-dimethyl-4-oxo-4-((lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)- 5a,5b,8,8,l la-pentamethyl-3a-((lR,3S)-3-((3-methylpiperidin-l- yl)methyl)cyclopentylcarbamoyl)- 1 -(prop- 1 -en-2-yl)icosahydro- 1 H- cyclopenta[a] chrysen-9-yloxy)butanoic acid,
(lR,3aS,5aR,5bR,7aR,9S,l IaR1I lbR,13aR,13bR)-3a-(4-ethylpiperazine- l-carbonyl)-5a,5b,8,8,l la-pentamethyl-l-(prop-l-en-2-yl)icosahydro-lH- cyclopenta[a]chrysen-9-yl acetate,
4-ethylpiperazin-l-yl)((lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)- 9-hydroxy-5a,5b,8,8,l la-pentamethyl-l-(prop-l-en-2-yl)icosahydro-lH- cyclopenta[a]chrysen-3a-yl)methanone,
3-(((lR,3aS,5aR,5bR,7aR,9S,l laR,l IbR513aR,13bR)-3a-(4- ethylpiperazine- 1 -carbonyl)-5a,5b,8,8, 11 a-pentamethyl- 1 -(prop- 1 -en-2- yl)icosahydro-lH-cyclopenta[a]chrysen-9-yloxy)carbonyl)-2,2- dimethylcyclobutanecarboxylic acid, Ethyl 4-((lR,3aS,5aR,5bR,7aR,9S,l laR,llbR,13aR,13bR)-9-acetoxy- 5a,5b,8,8, 11 a-pentamethyl- 1 -(prop- 1 -en-2-yl)icosahydro- IH- cyclopenta[a]chrysene-3a-carbonyl)-l-benzylcyclohexanecarboxylate,
Ethyl 1 -benzyl-4-(( 1 R,3aS ,5aR,5bR,7aR,9S, 11 aR, 11 bR, 13aR, 13bR)-9- hydroxy-5a,5b,8,8,l la-pentamethyl-l-(prop-l-en-2-yl)icosahydro-lH- cyclopenta[a]chrysene-3a-carbonyl)cyclohexanecaτboxylate,
4-((lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)-3a-(4-benzyl-4- (ethoxycarbonyl)piperidine-l-carbonyl)-5a,5b,8,8,l la-pentamethyl-l-(prop-l-en- 2-yl)icosahydro-lH-cyclopenta[a]chrysen-9-yloxy)-2,2-dimethyl-4-oxobutanoic acid,
(lS,3R)-l-tert-butyl 3-((1R5SaS5SaR5SbRJaR^S5I IaR5I IbRaSaR5BbR)- 3a-((lR,3S)-2,2-dimethyl-3-(piperidine-l-carbonyl)cyclobutylcarbamoyl)- 5a,5b,8,8,l la-pentamethyl-l-(prop-l-en-2-yl)icosahydro-lH- cyclopenta[a]chrysen-9-yl) 2,2-dimethylcyclobutane- 1 ,3-dicarboxylate,
( 1 S,3R)-3-((( 1 R53aS,5aR,5bR,7aR59S511 aR, 11 bR, 13aR, 13bR)-3a- ((lR,3S)-2,2-dimethyl-3-(piperidine-l-carbonyl)cyclobutylcarbamoyl)- 5a,5b,8,8, 11 a-pentamethyl- 1 -(prop- 1 -en-2-yl)icosahydro- IH- cyclopenta[a]chrysen-9-yloxy)carbonyl)-2,2-dimethylcyclobutanecarboxylic acid,
( 1 S,3R)- 1 -tert-butyl 3-(( 1 R,3aS,5aR,5bR,7aR,9S, 11 aR, 11 bR, 13aR, 13bR)- 3a-((lS,3R)-252-dimethyl-3-(morpholine-4-carbonyl)cyclobutylcarbamoyl)- 5a,5b,8,8, 11 a-pentamethyl- 1 -(prop- 1 -en-2-yl)icosahydro- IH- cyclopenta[a]chrysen-9-yl) 2,2-dimethylcyclobutane- 1,3-dicarboxylate,
( lS,3R)-3-(((l R,3aS,5aR,5bR,7aR,9S,l IaR, 1 IbR513aR,l 3bR)-3a- ((lS,3R)-2,2-dimethyl-3-(morpholine-4-carbonyl)cyclobutylcarbamoyl)- 5a,5b,8,8, 11 a-pentamethyl- 1 -(prop- 1 -en-2-yl)icosahydro- IH- cyclopenta[a]chrysen-9-yloxy)carbonyl)-2,2-dimethylcyclobutanecarboxylic acid,
4-((lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)-3a-((lS,3R)-2,2- dimethyl-3-(piperidine- 1 -carbonyl)cyclobutylcarbamoyl)-5a,5b,8,8, l la- pentamethyl-l-(prop-l-en-2-yl)icosahydro-lH-cyclopenta[a]chrysen-9-yloxy)-4- oxobutanoic acid, (lS,3R)-l-tert-butyl 3-
((lR,3aS,5aR,5bR,7aR,9S,llaR,l lbR,13aR,13bR)-3a-((lS,3R)-2,2-dimethyl-3- (piperidine- 1 -carbonyl)cyclobutylcarbamoyl)-5a,5b,8,8, 11 a-pentamethyl- 1 -(prop- l-en-2-yl)icosahydro-lH-cyclopenta[a]chrysen-9-yl) 2,2-dimethylcyclobutane- 1 ,3-dicarboxylate,
(lS,3R)-3-(((lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)-3a- (( IS, 3R)-2,2-dimethyl-3-(piperidine-l -carbon yl)cyclobutylcarbamoyl)- 5a,5b,8,8, 11 a-pentamethyl- 1 -(prop- 1 -en-2-yl)icosahydro- 1 H- cyclopenta[a]chrysen-9-yloxy)carbonyl)-2,2-dimethylcyclobutanecarboxylic acid,
5-((lR,3aS,5aR,5bR,7aR,9S,l laR,llbR,13aR,13bR)-3a-((lS,3R)-2,2- dimethyl-3-(piperidine-l-carbonyl)cyclobutylcarbamoyl)-5a,5b,8,8,l la- pentamethyl- 1 -(prop- 1 -en-2-yl)icosahydro- lH-cyclopenta[a]chrysen-9-yloxy)-5- oxopentanoic acid,
(lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)-3a-((lS,3R)-3-(4- ethylpiperazine-l-carbonyl)-2,2-dimethylcyclobutylcarbamoyl)-5a,5b,8,8,l la- pentamethyl-1 -(prop-1 -en-2-yl)icosahydro-lH-cyclopenta[a]chrysen-9-yl acetate,
( 1 R,3aS,5aR,5bR,7aR,9S, 11 aR, 11 bR, 13aR, 13bR)-N-(( 1 S,3R)-3-(4- ethylpiperazine-l-carbonyl)-2,2-dimethylcyclobutyl)-9-hydroxy-5a,5b, 8, 8,1 la- pen tamethyl-1 -(prop-1 -en-2-yl)icosahydro-lH-cyclopenta[a]chrysene-3a- carboxamide,
4-((lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)-3a-((lS,3R)-3-(4- ethylpiperazine-l-carbonyl)-2,2-dimethylcyclobutylcarbamoyl)-5a,5b,8,8,l la- pentamethyl-1 -(prop-1 -en-2-yl)icosahydro-lH-cyclopenta[a]chrysen-9-yloxy)- 2,2-dimethyl-4-oxobutanoic acid,
(lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)-3a-((lR,3S)-3-(4- ethylpiperazine-l-carbonyl)-2,2-dimethylcyclobutylcarbamoyl)-5a,5b,8,8,l la- pen tamethyl-1 -(prop-1 -en-2-yl)icosahydro-lH-cyclopenta[a]chrysen-9-yl acetate,
(lR,3aS,5aR,5bR,7aR,9S,l laR,llbR,13aR,13bR)-N-((lR,3S)-3-(4- ethylpiperazine-l-carbonyl)-2,2-dimethylcyclobutyl)-9-hydroxy-5a,5b,8,8,l la- pentamethyl-1 -(prop-1 -en-2-yl)icosahydro-lH-cyclopenta[a]chrysene-3a- carboxamide, 4-((lR,3aS,5aR,5bR,7aR,9S,l laR,llbR,13aR,13bR)-3a-((lR,3S)-3-(4- ethylpiperazine-1 -carbon yl)-2,2-dimethylcyclobutylcarbamoyl)-5a,5b,8,8,l Ia- pentamethyl- 1 -(prop- 1 -en-2-yl)icosahydro- 1 H-cyclopenta[a]chrysen-9-yloxy)- 2,2-dimethyl-4-oxobutanoic acid,
Ethyl l-((lR,3aS,5aR,5bR,7aR,9S,l laR,llbR,13aR,13bR)-9-acetoxy- 5a,5b,8, 8,11 a-pentamethyl-1 -(prop- l-en-2-yl)icosahydro- IH- cyclopenta[a]chrysene-3a-carbonyl)-4-ethylpiperidine-4-carboxylate,
Ethyl 4-ethyl- 1 -(( 1 R,3aS ,5aR,5bR,7aR,9S, 11 aR, 11 bR, 13aR, 13bR)-9- hydroxy-5a,5b, 8,8, 11 a-pentamethyl- 1 -(prop- 1 -en-2-yl)icosahydro- 1 H- cyclopenta[a]chrysene-3a-carbonyl)piperidine-4-carboxylate,
4-((lR,3aS,5aR,5bR,7aR,9S,l IaR5I lbR,13aR,13bR)-3a-(4- (ethoxycarbonyl)-4-ethylpiperidine-l -carbon yl)-5a,5b,8, 8, 11 a-pentamethyl- 1 - (prop-l-en-2-yl)icosahydro-lH-cyclopenta[a]chrysen-9-yloxy)-2,2-dimethyl-4- oxobutanoic acid,
(lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)-3a-(4-cyano-4- phenylpiperidine- 1 -carbonyl)-5a,5b,8,8, 11 a-pentamethyl- 1 -(prop- 1 -en-2- yl)icosahydro- 1 H-cyclopenta[a] chrysen-9-yl acetate,
l-((lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)-9-hydroxy- 5a,5b,8,8,l la-pentamethyl-l-(prop-l-en-2-yl)icosahydro-lH- cyclopenta[a]chrysene-3a-carbonyl)-4-phenylpiperidine-4-carbonitrile,
4-(( 1 R,3aS,5aR,5bR,7aR,9S, 11 aR, 11 bR, 13aR, 13bR)-3a-(4-cyano-4- phenylpiperidine-l-carbonyl)-5a,5b,8, 8, 11 a-pentamethyl-1 -(prop- l-en-2- yl)icosahydro-lH-cyclopenta[a]chrysen-9-yloxy)-2,2-dimethyl-4-oxobutanoic acid,
Tert-butyl 2-(6-(2-((lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)-9- acetoxy-5a,5b,8, 8, 11 a-pentamethyl-1 -(prop- 1 -en-2-yl)icosahydro-lH- cyclopenta[a]chrysene-3a-carboxamido)ethyl)-2,2-dimethyl-l,3-dioxan-4- yl)acetate,
Tert-butyl 2-(6-(2-(( 1 R,3aS,5aR,5bR,7aR,9S, 11 aR, 1 1 bR, 13aR, 13bR)-9- hydroxy-5a,5b,8, 8, 11 a-pentamethyl-1 -(prop- 1 -en-2-yl)icosahydro- IH- cyclopenta[a]chrysene-3a-carboxamido)ethyl)-2,2-dimethyl-l,3-dioxan-4- yl)acetate,
4-(( 1 R,3aS,5aR,5bR,7aR,9S , 11 aR, 11 bR, 13aR, 13bR)-3a-(2-(6-(2-tert- butoxy-2-oxoethyl)-2,2-dimethyl-l,3-dioxan-4-yl)ethylcarbamoyl)-5a,5b,8,8,l la- pentamethyl-l-(prop-l-en-2-yl)icosahydro-lH-cyclopenta[a]chrysen-9-yloxy)- 2,2-dimethyl-4-oxobutanoic acid,
7-((lR,3aS,5aR,5bR,7aR,9S, 11 aR, 1 IbR, 13aR,l 3bR)-9-(3-carboxy-3- methylbutanoyloxy)-5a,5b, 8, 8, 11 a-pentamethyl- 1 -(prop- l-en-2-yl)icosahydro- lH-cyclopenta[a]chrysene-3a-carboxamido)-3,5-dihydroxyheptanoic acid,
5-((lR,3aS,5aR,5bR,7aR,9S,l IaR5I lbR,13aR,13bR)-3a-((lR,3S)-3-((4- benzylpiperidin-l-yOmethy^cyclopentylcarbamoy^-Sa^b^SJ la-pentamethyl- l-(prop-l-en-2-yl)icosahydro-lH-cyclopenta[a]chrysen-9-yloxy)-3,3-dimethyl-5- oxopentanoic acid,
((lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)-9-acetoxy- 5a,5b,8,8,l la-pentamethyl-l-(prop-l-en-2-yl)icosahydro-lH- cyclopenta[a]chrysene-3a-carbonyl)-4-ethylpiperidine-4-carboxylic acid,
4-ethyl-l-((lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)-9-hydroxy- 5a,5b,8,8, 11 a-pentamethyl- 1 -(prop- 1 -en-2-yl)icosahydro- 1 H- cyclopenta[a]chrysene-3a-carbonyl)piperidine-4-carboxylic acid,
1 -(( 1 R,3aS,5aR,5bR,7aR,9S, 11 aR, 1 IbR, 13aR, 13bR)-9-(3-carboxy-3- methylbutanoyloxy)-5a,5b,8,8,l la-pentamethyl-l-(prop-l-en-2-yl)icosahydro- lH-cyclopenta[a]chrysene-3a-carbonyl)-4-ethylpiperidine-4-carboxylic acid,
1 -(((1 S,3R)-3-((lR,3aS,5aR,5bR,7aR,9S, 11 aR, 1 IbR, 13aR, 13bR)-9-(3- carboxy-3-meth ylbutanoyloxy)-5a,5b,8, 8, 11 a-pentamethyl- 1 -(prop- l-en-2- yl)icosahydro-lH-cyclopenta[a]chrysene-3a- carbonyl)cyclopentyl)methyl)piperidine-4-carboxylic acid,
4-((lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)-3a-((lR,3S)-3- (benzyloxycarbonyl)-2,2-dimethylcyclobutylcarbamoyl)-5a,5b,8,8, 11 a- pentamethyl-l-(prop-l-en-2-yl)icosahydro-lH-cyclopenta[a]chrysen-9-yloxy)- 2,2-dimethyl-4-oxobutanoic acid, (lS,3R)-3-((lS,3aS,5aR,5bR,7aR,9S,l laR,llbR,13aR,13bR)-9-(3- carboxy-3-methylbutanoyloxy)-l-isopropyl-5a,5b,8,8,l la- pentamethylicosahydro-lH-cydopenta[a]chrysene-3a-carboxamido)-2,2- dimethylcyclobutanecarboxylic acid,
(lR,3S)-l-benzyl 3-((lR,3aS55aR55bR,7aR59S,l IaR5I lbR,13aR,13bR)- 3a-(( 1 S,3R)-3-(4-(ethoxycarbonyl)piperidine- 1 -carbonyl)-2,2- dimethylcyclobutylcarbamoyl)-5a,5b,8,8,lla-pentamethyl-l-(prop-l-en-2- yl)icosahydro-lH-cyclopenta[a]chrysen-9-yl) 2,2-dimethylcyclobutane-l,3- dicarboxylate,
(lR,3S)-3-(((lR,3aS,5aR,5bR,7aR,9S,llaR,l lbR,13aR,13bR)-3a- ((lS,3R)-3-(4-(ethoxycarbonyl)piperidine-l-carbonyl)-2,2- dimethylcyclobutylcarbamoyl)-5a,5b,8,8, 11 a-pentamethyl- 1 -(prop- 1 -en-2- yl)icosahydro- 1 H-cyclopenta[a] chrysen-9-yloxy)carbonyl)-2,2- dimethylcyclobutanecarboxylic acid,
(lR,3S)-l-benzyl 3-((1R5SaS5SaR5SbRJaR^S5HaR5I IbR5ISaR5ISbR)- 3a-((lR,3S)-3-(benzyloxycarbonyl)-2,2-dimethylcyclobutylcarbamoyl)- 5a55b58,8,l la-pentamethyl-l-(prop-l-en-2-yl)icosahydro-lH- cyclopenta[a]chrysen-9-yl) 2,2-dimethylcyclobutane-l,3-dicarboxylate,
(lS53R)-3-((lR53aS,5aR55bR,7aR,9S5l laR,l lbR,13aR,13bR)-9-((lS53R)- 3-carboxy-252-dimethylcyclobutanecarbonyloxy)-5a55b5858,l la-pentamethyl-l- (prop-l-en-2-yl)icosahydro-lH-cyclopenta[a]chrysene-3a-carboxamido)-2,2- dimethylcyclobutanecarboxylic acid,
( 1 R,3S)- 1 -benzyl 3-(( 1 R53aS,5aR,5bR57aR59S, HaR5I l bR, 13aR, 13bR)- 3a-(4-(ethoxycarbonyl)piperi dine- l-carbonyl)-5a,5b,8,8, 11 a-pentamethyl- 1- (prop- 1 -en-2-yl)icosahydro- 1 H-cyclopenta[a]chrysen-9-yl) 2,2- dimethylcyclobutane- 1 ,3-dicarboxylate,
5-((lR,3aS55aR55bR57aR59S,l laR,l lbR,13aR,13bR)-3a-((lR53S)-3-((4- benzylpiperidin-l-yl)methyl)cyclopentylcarbamoyl)-5a55b58,8,l la-pentamethyl- l-(prop-l-en-2-yl)icosahydro-lH-cyclopenta[a]chrysen-9-yloxy)-3,3-dimethyl-5- oxopentanoic acid, 2,2-dimethyl-4-oxo-4-((lR,3aS,5aR,5bR,7aR,9S,l laR,llbR,13aR,13bR)- 5a,5b,8,8,l la-pentamethyl-3a-((lS,4R)-4-(morpholinomethyl)cyclopent-2- enylcarbamoyl)- 1 -(prop- 1 -en-2-yl)icosahydro- 1 H-cyclopenta[a]chrysen-9- yloxy)butanoic acid,
4-oxo-4-(( 1 R,3aS,5aR,5bR,7aR,9S, 11 aR, 1 IbR, 13aR, 13bR)-5a,5b,8,8, 11 a- pentamethyl-3a-(3-(piperidin- 1 -ylmethyOcyclopentylcarbamoyl)- 1 -(prop- 1 -en-2- yl)icosahydro- 1 H-cyclopenta[a] chrysen-9-yloxy)butanoic acid,
( lR,3aS,5aR,5bR,7aR,9S, 11 aR, 11 bR, 13aR, 13bR)-N-(2,2-dimethyl-3-(3- moφholino-3-oxopropylcarbamoyl)cyclobutyl)-9-hydroxy-5a,5b,8,8,l la- pentamethyl- 1 -(prop- 1 -en-2-yl)icosahydro- lH-cyclopenta[a]chrysene-3a- carboxamide,
(lR,3aS,5aR,5bR,7aR,9S,l IaR1I lbR,13aR,13bR)-N-(2,2-dimethyl-3-(3- oxo-3-(pyrrolidin-l -yl)propylcarbamoyl)cyclobutyl)-9-hydroxy-5a,5b,8,8, Ha- pentamethyl-l-(prop-l-en-2-yl)icosahydro-lH-cyclopenta[a]chrysene-3a- carboxamide,
4-((lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)-3a-((lR,3S)-3-((4- benzylpiperidin-l-y^methy^cydopentylcarbamoylVSa^b^^l la-pentamethyl- 1 -(prop- 1 -en-2-yl)icosahydro- 1 H-cyclopenta[a] chrysen-9-yloxy)-2,2-dimethyl-4- oxobutanoic acid,
(lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR)-9-((3R)-3-(benzyloxycarbonyl)- 2,2-dimethylcyclobutanecarbonyloxy)-5a,5b,8,8, 11 a-pentamethyl-1 -(prop- 1 -en-2- yl)icosahydro-lH-cyclopenta[a]chrysene-3a-carboxylic acid,
(lR,3aS,5aR,5bR,7aR,9S,l laR,llbR)-9-((3R)-3-(tert-butylcarbamoyl)- 2,2-dimethylcyclobutanecarbonyloxy)-5a,5b,8,8, 11 a-pentamethyl-1 -(prop- l-en-2- yl)icosahydro-lH-cyclopenta[a]chrysene-3a-carboxylic acid,
(lR,3aS,5aR,5bR,7aR,9S,l IaR5I lbR)-9-((3R)-3-(tert- butoxycarbonylamino)-2,2-dimethylcyclobutanecarbonyloxy)-5a,5b,8,8, Ha- pentamethyl- 1 -(prop- 1 -en-2-yl)icosahydro- 1 H-cyclopenta[a]chrysene-3a- carboxylic acid, ( 1 R,3aS ,5aR,5bR,7aR,9S, 11 aR, 11 bR)-9-((3R)-3-(ethoxycarbonylamino)- 2,2-dimethylcyclobutanecarbonyloxy)-5a,5b,8,8,lla-pentamethyl-l-(prop-l-en-2- yl)icosahydro- lH-cyclopenta[a]chrysene-3a-carboxylic acid,
(lR)-3-(((lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR)-3a- (carboxymethylcarbamoyl)-5a,5b,8,8,l la-pentamethyl-l-(prop-l-en-2- yl)icosahydro-lH-cyclopenta[a]chrysen-9-yloxy)carbonyl)-2,2- dimethylcyclobutanecarboxylic acid,
(lR)-3-(((lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR)-3a-(l-carboxy-3- methylbutylcarbamoyl)-5a,5b,8,8,l la-pentamethyl-l-(prop-l-en-2-yl)icosahydro- lH-cyclopenta[a]chrysen-9-yloxy)carbonyl)-2,2-dimethylcyclobutanecarboxylic acid,
( 1 R,3aS,5aR,5bR,7aR,9S, 11 aR, 11 bR)-9-((3R)-3-( 1 , 1 -difluoroethyl)-2,2- dimethylcyclobutanecarbonyloxy)-5a,5b,8,8,l la-pentamethyl-l-(prop-l-en-2- yl)icosahydro-lH-cyclopenta[a]chrysene-3a-carboxylic acid,
(IR)-S-(KlR1SaS1SaR^bRJaR1QS1I IaRJ IbR)-Sa-(I- carboxyethylcarbamoyO-Sa.Sb^δJ la-pentamethyl-l-φrop-l-en^- yl)icosahydro- 1 H-cyclopenta[a] chrysen-9-yloxy)carbonyl)-2,2- dimethylcyclobutanecarboxylic acid,
(lR)-3-(((lR,3aS,5aR,5bR,7aR,9S,l IaR5I lbR)-3a-(l-carboxy-2,2- dimethylpropylcarbamoyl)-5a,5b,8,8,l la-pentamethyl-l-(prop-l-en-2- yl)icosahydro-lH-cyclopenta[a]chrysen-9-yloxy)carbonyl)-2,2- dimethylcyclobutanecarboxylic acid,
4-((lR,3aS,5aR,5bR,7aR,9S,l IaR, 1 lbR)-9-(3-carboxy-2,2- dimethylpropanoyloxy)-5a,5b,8,8,l la-pentamethyl-l-(prop-l-en-2-yl)icosahydro- lH-cyclopenta[a]chrysene-3a-carboxamido)-3,3-difluorocyclopentanecarboxylic acid,
(lR)-3-(((lR,3aS,5aR,5bR,7aR,9S,l IaR5I lbR)-3a-(4-(2- carboxyethyl)piperidine-l-carbonyl)-5a,5b,8, 8,11 a-pentamethyl-1 -(prop- l-en-2- yl)icosahydro- 1 H-cyclopenta[a]chrysen-9-yloxy)carbonyl)-2,2- dimethylcyclobutanecarboxylic acid, 4-(( 1 R,3aS,5aR,5bR,7aR,9S, 11 aR, 1 lbR)-9-(3-carboxy-3- methylbutanoyloxy)-5a,5b,8,8,lla-pentamethyl-l-(prop-l-en-2-yl)icosahydro- lH-cyclopenta[a]chrysene-3a-carboxamido)-3,3-difluorocyclopentanecarboxylic acid,
( 1 R,2S,3aR,5aR,5bR,7aS , 1 OR, 12aR, 12bR)-7a-( 1 -carboxy-2,2- dimethylpropylcarbamoyl)-2-(3-carboxy-3-methylbutanoyloxy)-3,3,5a,5b,12b- pentamethyl-10-(prop-l-en-2-yl)icosahydrodicyclopenta[a,i]phenanthrene-l- carboxylic acid,
( 1 R,2S,3aR,5aR,5bR,7aS , 1 OR, 12aR, 12bR)-2-(3-carboxy-3- methylbutanoyloxy)-7a-(l-carboxyethylcarbamoyl)-3,3,5a,5b,12b-pentamethyl- 10-(prop- 1 -en-2-yl)icosahydrodicyclopenta[a,i]phenanthrene- 1 -carboxylic acid, and pharmaceutically acceptable salts thereof.
6. An Intermediate compound of the formula (3):
Figure imgf000177_0001
Formula (3)
wherein,
R3a is H, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted alkyloxy, or substituted or unsubstituted aryloxy and preferably R3a is substituted by Ra;
X3 is selected from a bond, -O-, -NR"-, -C(O)-, -C(O)2-,-(CH2)n-, or - C(O)NR"-;
n is 0-3;
Z3 is selected from a bond, -0-, or -NR"-;
Ra is H, OH, halogen, N(R")2, C(O)R", C(O)2R", CH2OR", C(O)N(R")2 or substituted or unsubstituted alkyl; each R" is independently selected from H, -[CH(R"')]PC(O)2R"', substituted or unsubstituted alkyl, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocyclyl;
p is 0-3; and
each R'" is independently selected from H, substituted or unsubstituted alkyl, or substituted or unsubstituted cycloalkyl; and a proviso that R3a is substituted or unsubstituted 4 or 5 membered cycloalkyl group, and if R3a is 4 membered cycloalkyl group then at least one of the carbon atom of the 4 membered cycloalkyl group must be substituted by two identical groups and which are selected from alkyl or halogen wherein most preferably alkyl is methyl and halo is fluorine, an analog thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable solvate thereof, a pharmaceutically acceptable hydrate thereof, an N-oxide thereof, a tautomer thereof, a regioisomer thereof, a stereoisomer thereof, a prodrug thereof or a polymorph thereof.
7. A pharmaceutical composition comprising a compound according to any one of claims 1-5 and a pharmaceutically acceptable excipient.
8. The pharmaceutical composition according to claim 7, wherein the pharmaceutically acceptable excipient is a carrier or diluent.
9. A method for preventing, ameliorating or treating a viral mediated disease, disorder or syndrome in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1-5.
10. The method according to claim 9, wherein the viral mediated disease, disorder or syndrome is HIV infection, HBV, HCV, a retroviral infection genetically related to AIDS, respiratory disorders (including adult respiratory distress syndrome (ARDS)), inflammatory disease.
11. A method of treating HIV in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1-5.
12. A method for preventing, ameliorating or treating a viral mediated disease, disorder or syndrome in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound according to claim 7.
13. The method according to claim 12, wherein the viral mediated disease, disorder or syndrome is HIV infection, HBV, HCV, a retroviral infection genetically related to AIDS, respiratory disorders (including adult respiratory distress syndrome (ARDS)), inflammatory disease.
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