WO2017149518A1 - C-3 novel triterpene with c-17 amine derivatives as hiv inhibitors - Google Patents

C-3 novel triterpene with c-17 amine derivatives as hiv inhibitors Download PDF

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WO2017149518A1
WO2017149518A1 PCT/IB2017/051272 IB2017051272W WO2017149518A1 WO 2017149518 A1 WO2017149518 A1 WO 2017149518A1 IB 2017051272 W IB2017051272 W IB 2017051272W WO 2017149518 A1 WO2017149518 A1 WO 2017149518A1
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substituted
unsubstituted
amino
icosahydro
cyclopenta
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PCT/IB2017/051272
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French (fr)
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Parthasaradhi Reddy BANDI
Rathnakar Reddy KURA
David Krupadanam GAZULA LEVI
Panduranga Reddy ADULLA
Venkati MUKKERA
Sudhakar NEELA
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Hetero Labs Limited
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C219/00—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C219/24—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups or amino groups bound to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
    • C07D207/09—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/12—Oxygen or sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/56—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D211/72—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D211/78—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
    • C07D265/30—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
    • C07D279/10—1,4-Thiazines; Hydrogenated 1,4-thiazines
    • C07D279/12—1,4-Thiazines; Hydrogenated 1,4-thiazines not condensed with other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • C07D295/125—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/13—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/46—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings substituted on the ring sulfur atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/04—Systems containing only non-condensed rings with a four-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/02—Ortho- or ortho- and peri-condensed systems
    • C07C2603/52—Ortho- or ortho- and peri-condensed systems containing five condensed rings

Definitions

  • the present invention relates to C-3 novel triterpene with C-17 amine derivatives and related compounds, compositions useful for therapeutic treatment of viral diseases and particularly HIV mediated diseases.
  • HIV Human Immunodeficiency Virus
  • AIDS Acquired Immunodeficiency Syndrome
  • 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.
  • betulinic 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. 1994, 57(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.
  • Bevirimat went up to phase 2 clinical trials, in clinic despite optimal plasma concentrations, not all patients given Bevirimat have a robust viral load reduction. It was reported that non-respondant patients had more frequent base line Gag polymorphisms near the capsid SP-1 cleavage site than responders. (HIV gag polymorphism determines treatment response to bevirimat. XVII international HIV drug resistance work shop June 10-14, 2008, Sitges, Spain).
  • WO 2014/105926 disclosed novel betulinic acid proline derivatives as HIV inhibitors
  • WO 2014/130810 describes preparation of C3 alkyl and alkenyl modified betulinic acid derivatives useful in the treatment of HIV
  • WO 2014/123889 describes preparation of triterpenoid derivatives for use as HIV maturation inhibitors
  • WO 2013/160810 disclosed novel betulinic acid derivatives as HIV inhibitors
  • WO 2013/169578 describes C-17 bicyclic amines of triterpenoids with HIV maturation inhibitory activity and their preparation
  • WO 2013/123019 describes C-3 cycloalkenyl triterpenoids with HIV maturation inhibitory activity
  • WO 2013/043778 describes novel betulinic acid derivatives with antiviral activity
  • WO 2013/035943 describes betulinic acid and derivatives thereof having anti-aging activity
  • WO 2012/106190 describes preparation of C17 and C3 modified triter
  • WO 2006/053255 describes preparation of betulin derivatives for use in pharmaceutical compositions which inhibit the transmission of viral infection;
  • WO 2004/089357 describes anti-fungal formulation of triterpene and essential oil;
  • Bioorganic & Medicinal Chemistry Letters (2003), 13(20), 3549-3552 describes lupane triterpenes and derivatives with antiviral activity;
  • Russian Journal of Bioorganic Chemistry (2003), 29(6), 594-600 describes synthesis and antiviral activity of ureides and carbamates of betulinic acid and its derivatives;
  • Journal of Medicinal Chemistry (1996), 39(5), 1056-68 describes betulinic acid derivatives: a new class of human immunodeficiency virus type 1 specific inhibitors with a new mode of action;
  • Oxidation Communications (1987), 10(3-4), 305-12 describes oxidative decarboxylations. II. oxidative decarboxylation of acetyl betulinic acid.
  • the present invention relates to the com ounds of the formula (I):
  • R b is hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted cycloalkyl
  • R 2 is alkyl, alkenyl or substituted or unsubstituted cycloalkyl; wherein the substituent is alkyl;
  • R 3 is hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted cycloalkyl; wherein the substituent is heterocyclyl or alkylamino;
  • R4 and R5 independently are hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl; wherein the substituent is alkylamino; alternatively, R 4 and R5 are taken together with the N-atom to which they are attached to form substituted or unsubstituted 3-15 membered heterocyclyl; wherein the substituent is one or more R a ;
  • R a is independently selected from substituted or unsubstituted alkyl, substituted or unsubstituted aminoalkyl, halogen, hydroxyl, haloalkyl, hydroxyalkyl, substituted or unsubstituted amino, -N(H)-S0 2 -R c , -S0 2 -R c , -C(0)-R d , or -C(0)0-R e ;
  • R c , R d and R e independently are substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted alkylamino, substituted or unsubstituted amino, or substituted or unsubstituted arylalkyl; and
  • 'n' is an integer selected from 1-4 both inclusive;
  • the present invention relates to pharmaceutical composition
  • pharmaceutical composition comprising C-3 novel triterpene with C-17 amine derivatives and related compounds of formula (I) and processes for preparing thereof.
  • the present invention relates to C-3 novel triterpene with C-17 amine derivatives and related compounds, compositions useful for therapeutic treatment of viral diseases and particularly HIV mediated diseases.
  • the present invention relates to C-3 novel triterpene with C-17 amine derivatives and related compounds, compositions useful for therapeutic treatment of viral diseases and particularly HIV mediated diseases.
  • the resent invention relates to compounds of formula (I):
  • R b is hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted cycloalkyl
  • R 2 is alkyl, alkenyl or substituted or unsubstituted cycloalkyl; wherein the substituent is alkyl;
  • R 3 is hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted cycloalkyl; wherein the substituent is heterocyclyl or alkylamino;
  • R4 and R5 independently are hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl; wherein the substituent is alkylamino; alternatively, R 4 and R5 are taken together with the N-atom to which they are attached to form substituted or unsubstituted 3-15 membered heterocyclyl; wherein the substituent is one or more R a ;
  • R a is independently selected from substituted or unsubstituted alkyl, substituted or unsubstituted aminoalkyl, halogen, hydroxyl, haloalkyl, hydroxyalkyl, substituted or unsubstituted amino, -N(H)-S0 2 -R c , -S0 2 -R c , -C(0)-R d , or -C(0)0-R e ;
  • R c , R d and R e independently are substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted alkylamino, substituted or unsubstituted amino, or substituted or unsubstituted arylalkyl;
  • 'n' is an integer selected from 1-4 both inclusive;
  • the resent invention relates to compounds of formula (IA):
  • R b is hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted cycloalkyl
  • R 2 is alkyl, alkenyl or substituted or unsubstituted cycloalkyl; wherein the substituent is alkyl;
  • R 3 is hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted cycloalkyl; wherein the substituent is heterocyclyl or alkylamino;
  • R4 and R5 independently are hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl; wherein the substituent is alkylamino; alternatively, R 4 and R5 are taken together with the N-atom to which they are attached to form substituted or unsubstituted 3-15 membered heterocyclyl; wherein the substituent is one or more R a ;
  • R a is independently selected from substituted or unsubstituted alkyl, substituted or unsubstituted aminoalkyl, halogen, hydroxyl, haloalkyl, hydroxyalkyl, substituted or unsubstituted amino, -N(H)-S0 2 -R c , -S0 2 -R c , -C(0)-R d , or -C(0)0-R e ; and
  • R c , R d and R e independently are substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted alkylamino, substituted or unsubstituted amino, or substituted or unsubstituted arylalkyl; or
  • the present invention relates to compounds of formula
  • R 2 is alkyl, alkenyl or substituted or unsubstituted cycloalkyl; wherein the substituent is alkyl;
  • R 3 is hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted cycloalkyl; wherein the substituent is heterocyclyl or alkylamino;
  • R4 and R5 independently are hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl; wherein the substituent is alkylamino; alternatively, R 4 and R5 are taken together with the N-atom to which they are attached to form substituted or unsubstituted 3-15 membered heterocyclyl; wherein the substituent is one or more R a ;
  • R a is independently selected from substituted or unsubstituted alkyl, substituted or unsubstituted aminoalkyl, halogen, hydroxyl, haloalkyl, hydroxyalkyl, substituted or unsubstituted amino, -N(H)-S0 2 -R c , -S0 2 -R c , -C(0)-R d , or -C(0)0-R e ;
  • R c , R d and R e independently are substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted alkylamino, substituted or unsubstituted amino, or substituted or unsubstituted arylalkyl;
  • 'n' is an integer selected from 1-4 both inclusive;
  • prodrugs of the compounds of the formula (I) includes esters of the compounds.
  • R 3 is hydrogen, or substituted or unsubstituted alkyl; wherein the substituent is heterocyclyl or alkylamino.
  • R 4 and R5 are hydrogen or substituted or unsubstituted alkyl; wherein the substituent is alkylamino.
  • R 4 and R5 are taken together with the N-atom to which they are attached to form substituted or unsubstituted 3-15 membered heterocyclyl; wherein the substituent is one or more R a .
  • R a is substituted or unsubstituted alkyl, substituted or unsubstituted aminoalkyl, halogen, hydroxyl, hydroxyalkyl, substituted or unsubstituted amino, haloalkyl, -N(H)-S0 2 -R c , -S0 2 -R c , -C(0)-R d or -C(0)0-R e .
  • R c , R d and R e are substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted alkylamino, substituted or unsubstituted amino or substituted or unsubstituted arylalkyl.
  • the compounds of formula (I) can also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds.
  • the present invention also embraces isotopically-labeled variants of the present invention which are identical to those recited herein, but for the fact that one or more atoms of the compound are replaced by an atom having the atomic mass or mass number different from the predominant atomic mass or mass number usually found in nature for the atom. All isotopes of any particular atom or element as specified are contemplated within the scope of the compounds of the invention, and their uses.
  • the present invention is meant to include all suitable isotopic variations of the compounds of generic formula (I).
  • H isotopic forms of hydrogen
  • protium 1H
  • deuterium 2 H
  • Protium is the predominant hydrogen isotope found in nature. Enriching for deuterium may provide certain therapeutic advantages, such as increasing in vivo half -life or reducing dosage requirements, or may provide a compound useful as a standard for characterization of biological samples.
  • Isotopically-enriched compounds of formula (I) can be prepared without undue experimentation by conventional techniques well known to those skilled in the art or by processes analogous to those described in the Schemes and Examples herein using appropriate isotopically-enriched reagents and/or intermediates.
  • a compound of formula (I) has one or more of its hydrogen atoms replaced with deuterium.
  • the compounds of formula (I) structurally encompasses all stereoisomers, enantiomers and diastereomers, and pharmaceutically acceptable salts that may be contemplated from the chemical structure of the general formula (I) described herein.
  • the absolute configuration at an asymmetric atom is specified by either R or S.
  • Resolved compounds whose absolute configuration is not known can be designated by (+) or (-) depending on the direction in which they rotate plane polarized light.
  • a specific stereoisomer is identified, this means that said stereoisomer is substantially free, i.e. associated with less than 50%, preferably less than 20%, more preferably less than 5%, in particularly less than 2% or 1 % of the other isomers.
  • the prodrugs of present invention are the compounds of formula (I) and its pharmaceutically acceptable salts, stereoisomers, solvates thereof containing an hydroxyl group; wherein hydrogen atom of the hydroxyl group are replaced with (Ci-C 6 )alkanoyloxymethyl, l-((Ci-C 6 )alkanoyloxy)ethyl, 1 -methyl- l-((Ci- C 6 )alkanoyloxy)ethyl, (Ci-C 6 )alkoxycarbonyloxymethyl, N-(Ci-C 6 )alkoxycarbonyl aminomethyl, succinoyl, (Ci-C 6 )alkanoyl, a-amino(Ci-C 4 )alkyl, a-amino(Ci-C 4 )alkylene- aryl, arylacyl and a-aminoacyl, where each a -aminoacyl group is independently selected from
  • the prodrugs of present invention are the compounds of formula (I) and its pharmaceutically acceptable salts, stereoisomers, hydrates, solvates thereof containing an amine group; wherein one or more hydrogen atoms of the amine group is replaced with (Ci-C 6 )alkylcarbonyl, (Ci-C 6 )alkoxycarbonyl, aminocarbonyl, (C3-C 6 )cycloalkylcarbonyl, benzylcarbonyl and the like.
  • the present invention also provides a pharmaceutical composition that includes at least one compound according to formula (I) 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 according to formula (I).
  • 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, 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 a therapeutically effective amount to treat that infection, specifically in the form of a pharmaceutical composition.
  • the present invention relates to combinations comprising a compound of the formula (I) and a second therapeutic agent that is an anti-HIV agent, an anti-HCV agent or anti-TB agents.
  • the present invention relates to pharmaceutical compositions comprising the compound of formula (I) and one or more second anti-HIV agents and their pharmaceutically acceptable salts and stereoisomers thereof.
  • the present invention relates to combinations comprising a compound of the formula (I) and one or more second anti-HIV agents selected from the group consisting of Protease inhibitors, Integrase inhibitors, Nucleoside Reverse Transcriptase inhibitors, Non-Nucleoside Reverse Transcriptase Inhibitors, Fusion/Entry inhibitors, Pharmacokinetic enhancers, and combinations thereof.
  • second anti-HIV agents selected from the group consisting of Protease inhibitors, Integrase inhibitors, Nucleoside Reverse Transcriptase inhibitors, Non-Nucleoside Reverse Transcriptase Inhibitors, Fusion/Entry inhibitors, Pharmacokinetic enhancers, and combinations thereof.
  • the present invention relates to methods of treatment of HIV infection, AIDS, and AIDS-related conditions by administering to a subject a compound of formula (I) and one or more second therapeutic agents selected from the group consisting of Protease inhibitors, Integrase inhibitors, Nucleoside Reverse Transcriptase inhibitors, Non-Nucleoside Reverse Transcriptase Inhibitors, Fusion/Entry inhibitors, Pharmacokinetic enhancers, and combinations thereof.
  • the present invention relates to combinations comprising a compound of the formula (I) and one or more second anti-HIV agents wherein the second anti-HIV agent is Abacavir, Didanosine, Emtricitabine, Lamivudine, Stavudine, Tenofovir disoproxil Fumarate, Tenofovir Alafenamide Fumarate, Zidovudine, Efavirenz, Etravirine, Nevirapine, Rilpivirine, Atazanavir, Darunavir, Fosamprenavir, Indinavir, Nelfinavir, Ritonavir, Cobicistat, Saquinavir, Tipranavir, Enfuvirtide, Maraviroc, Fostemsavir, Dolutegravir, Elvitegravir, Raltegravir, Bictegravir, Cabotegravir or a combination thereof.
  • the second anti-HIV agent is Abacavir, Didanosine, Emtricitabine, Lamivudi
  • the present 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 persistent generalized lymphadenopathy, fever and weight loss, or a retroviral 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 Mossman T, December 1983, Journal of immunological methods, 65 (1- 2), 55-63 and SPC Cole, cancer chemotherapy and Pharmacology, 1986, 17, 259-263.
  • halogen or halo includes fluorine, chlorine, bromine, or iodine.
  • amino refers to -NH 2 .
  • 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).
  • Examples of C 2 -C 6 alkenyl groups include, but are not limited to ethylene, prop-l-ene, but-1- ene, but-2-ene, pent-l-ene, pent-2-ene, hex-l-ene, hex-2-ene and the like.
  • alkylamino refers to alkyl group as defined above attached via amino linkage to the rest of the molecule. Representative examples of those groups are -NHCH 3 , - N(CH 3 ) 2 and the like.
  • hydroxyl refers to -OH group.
  • amino acid refers to a straight or branched hydrocarbon chain containing an amine group, a carboxylic acid group, and a side-chain that is specific to each amino acid and which is attached through the nitrogen atom of the amine group to the rest of the molecule by a single bond, e.g., alanine, valine, isoleucine, leucine, phenylalanine, or tyrosine.
  • aminoalkyl refers to any amino derivative of an alkyl radical more specifically dimethylamino ethyl and dimethylamino methyl.
  • cycloalkyl denotes a non-aromatic or saturated mono or multicyclic ring system of from 3 to about 12 carbon atoms, such as but are not limited to, 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.
  • aryl refers to an aromatic radical having from 6 to 14 carbon atoms such as but are not limited to, 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 .
  • haloalkyl refers to alkyl group (as defined above) is substituted with one or more halogens.
  • a monohaloalkyl radical for example, may have a chlorine, bromine, iodine or fluorine atom.
  • Dihalo and polyhaloalkyl radicals may have two or more of the same or different halogen atoms.
  • haloalkyl examples include, but are not limited to, chloromethyl, dichloromethyl, trichloromethyl, dichloroethyl, dichloropropyl, fluoromethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl, heptafluoropropyl, difluoro chloromethyl, dichloro fluoromethyl, difluoroethyl, difluoropropyl and the like.
  • hydroxyalkyl or "hydroxylalkyl” means alkyl substituted with one or more hydroxyl groups, wherein the alkyl groups are as defined above.
  • Examples of “hydroxyalkyl” include but are not limited to hydroxymethyl, hydroxyethyl, hydroxypropyl, propan-2-ol and the like.
  • heterocyclyl and “heterocyclic ring” and “heterocycle” 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 quaternized; 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, azetidinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolinyl, oxazolidinyl, triazolyl, isoxazolyl, isoxasolidinyl, morpholinyl, thiazolyl, thiazol
  • 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.
  • substituted refers to 1-3 substituents on the same position or on different positions with the same groups or different groups.
  • Stereoisomer or “Stereoisomers” refer to compounds that differ in the chirality of one or more stereo centers. Stereoisomers include enantiomers and diastereomers.
  • Regioisomer or “Positional isomer” refer to that have the same carbon skeleton and the same functional groups but differ from each other in the location of the functional groups on or in the carbon chain.
  • prodrug denotes a derivative of a compound, which derivative, when administered to warm -blooded animals, e.g. humans, is converted into the compound (drug).
  • the enzymatic and/or chemical hydrolytic cleavage of the compounds of the present invention occurs in such a manner that the proven drug form (parent carboxylic acid drug) is released, and the moiety or moieties split off remain nontoxic or are metabolized so that nontoxic metabolic products are produced.
  • a carboxylic acid group can be esterified, e.g., with a methyl group or ethyl group to yield an ester.
  • an ester When an ester is administered to a subject, the ester is cleaved, enzymatically or non-enzymatically, reductively, oxidatively, or hydrolytically, to reveal the anionic group.
  • An anionic group can be esterified with moieties (e.g., acyloxymethyl esters) which are cleaved to reveal an intermediate compound which subsequently decomposes to yield the active compound.
  • moieties e.g., acyloxymethyl esters
  • 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.
  • 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 (I), 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.
  • 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, peanut oil, olive oil, gelatin, lactose, terra alba, sucrose, dextrin, magnesium carbonate, sugar, amylose, magnesium stearate, talc, gelatin, agar, pectin, acacia, stearic acid, lower alkyl ethers of cellulose, silicic acid, fatty acids, fatty acid amines, fatty acid monoglycerides and diglycerides, fatty acid esters, and polyoxyethylene.
  • 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.
  • the pharmaceutical 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 ampule, capsule, or sachet.
  • 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 pharmaceutical compositions may be in conventional forms, for example, capsules, tablets, solutions, suspensions, injectables or products for topical application. Further, the pharmaceutical composition of the present invention may be formulated so as to provide desired release profile.
  • 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 specifically suitable.
  • 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. Exemplary 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 tableting techniques.
  • 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 specifically aqueous solutions with the active compound dissolved in polyhydroxylated castor oil.
  • 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.
  • 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).
  • ARDS adult respiratory distress syndrome
  • bronchitis chronic bronchitis
  • chronic obstructive pulmonary disease cystic
  • 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 available 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 below schemes. 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 stereoisomers 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 Betulin.
  • 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 2010, 75, 1285-1288; Journal of organic chemistry 2000, 65, 3934-3940; Tetrahedron: asymmetry 2008, 19, 302-308; or Tetrahedron: asymmetry 2003, 14, 217-223.
  • Another embodiment of the present invention provides process for preparation of the compounds of general formula (I) are set forth in the below generalized schemes.
  • One of skill in the art will recognize that below generalised schemes can be adapted to produce the compounds of general formula (I) and pharmaceutically acceptable salts of compounds of general formula (I) according to the present invention. Wherein all symbols/variables are as defined earlier unless otherwise stated.
  • the compounds of formula 4 (R 4 and R5 are same as defined above) can be prepared as described in Scheme 1.
  • the amino compounds of formula 1 can be reacted with the halo alcohol compounds of formula 2 to give the amino alcohol compounds of formula 3 in the presence of bases such as cesium carbonate (CS2CO3), sodium carbonate (Na 2 C0 3 ), potassium carbonate (K 2 C0 3 ) or the like in the presence of suitable solvents such as acetonitrile (ACN), acetone [(CH 3 ) 2 CO] or the like.
  • bases such as cesium carbonate (CS2CO3), sodium carbonate (Na 2 C0 3 ), potassium carbonate (K 2 C0 3 ) or the like
  • suitable solvents such as acetonitrile (ACN), acetone [(CH 3 ) 2 CO] or the like.
  • the amino alcohol compounds of formula 3 can be converted to the halo amino compounds of formula 4 in the presence of reagents such as thionyl chloride (SOCl 2 ), oxalyl chloride (COCl) 2 or the like in the presence of catalysts such as ⁇ , ⁇ -dimethyl formamide (DMF) or the like in the presence of suitable solvents such as dichloromethane (CH 2 C1 2 ), chloroform (CHC1 3 ) or the like.
  • reagents such as thionyl chloride (SOCl 2 ), oxalyl chloride (COCl) 2 or the like
  • catalysts such as ⁇ , ⁇ -dimethyl formamide (DMF) or the like in the presence of suitable solvents such as dichloromethane (CH 2 C1 2 ), chloroform (CHC1 3 ) or the like.
  • the compounds of formula (I) (wherein, Ri, R 3 , R4 and R5 are same as defined above; Pi and P 2 are protecting groups such as acetyl, benzyl or the like) can be prepared as described in Scheme 2.
  • the C-28 acid compounds of formula 5 (as described in our PCT publication WO 2013/160810 A2) can be converted to the carbamate compounds of formula 6 in the presence of reagents such as diphenylphosphoryl azide (DPPA), (4- methoxyphenyl)methanol or the like in the solvents such as dichloromethane (DCM), 1,4- dioxane or the like in the presence of bases such as triethylamine (TEA), diisopropyl ethyl amine (DIPEA) or the like.
  • DPPA diphenylphosphoryl azide
  • DCM dichloromethane
  • TAA triethylamine
  • DIPEA diisopropyl ethyl amine
  • the carbamate compounds of formula 6 can be converted to C-17 amine compounds of formula 7 in the presence of solvents such as 1,4-dioxane in HC1 or the like.
  • the C-17 amine compounds of formula 7 can be reacted with the halo amino compounds of formula 4 to give the corresponding C-17 substituted amine compounds of formula 8 in the presence of bases such as potassium phosphate (K 3 P0 4 ), sodium phosphate (Na 3 P0 4 ) or the like in the solvents such as acetonitrile (ACN) or the like in the presence of catalysts such as potassium iodide (KI), sodium iodide (Nal) or the like.
  • bases such as potassium phosphate (K 3 P0 4 ), sodium phosphate (Na 3 P0 4 ) or the like
  • solvents such as acetonitrile (ACN) or the like
  • catalysts such as potassium iodide (KI), sodium iodide (Nal) or the like.
  • the C-3 protected compounds of formula 8 can be deprotected to give the C-3 hydroxy compounds of formula 9 in the presence of bases such as lithium hydroxide (LiOH), sodium hydroxide (NaOH) or the like in the solvents such as tetrahydrofuran (THF), methanol (MeOH), ethanol (EtOH), water or the like.
  • bases such as lithium hydroxide (LiOH), sodium hydroxide (NaOH) or the like in the solvents such as tetrahydrofuran (THF), methanol (MeOH), ethanol (EtOH), water or the like.
  • the C-3 hydroxy compounds of formula 9 can be reacted with the compounds of formula 10 to give the C-3 protected compounds of formula 11 in the presence of catalysts such as ⁇ , ⁇ '-Dicyclohexylcarbodiimide (DCC), 4-Dimethylaminopyridine (DMAP) or the like in the solvents such as dichloromethane (DCM), chloroform (CHC1 3 ) or the like.
  • the C-3 protected compounds of formula 11 can be deprotected to give the corresponding acid compounds of the present invention formula (I) in the presence of palladium on carbon (Pd/C) in hydrogen gas (3 ⁇ 4 gas) or the like in the solvents such as ethylacetate (EtOAc), methanol (MeOH) or the like.
  • the compounds of formula (I) (wherein, Ri, R4 and R 5 are same as defined above; Pi and P 2 are protecting groups such as acetyl, benzyl or the like) can be prepared as described in Scheme 3.
  • the C-28 acid compounds of formula 12 (as described in our PCT publication WO 2013/160810 A2) can be converted to the C-17 isocyanato compounds of formula 13 in the presence of reagents such as diphenylphosphoryl azide (DPPA) or the like in the presence of bases such as triethylamine (TEA) or the like in the solvents such as 1,4-dioxane or the like.
  • the C-17 isocyanato compounds of formula 13 can be converted to the C-17 amine hydrochloride compounds of formula 14 in the presence of reagents such as cone. HC1 or the like in the solvents such as 1,4-dioxane or the like.
  • the C-17 amine hydrochloride compounds of formula 14 can be converted to the C-17 protected amine compounds of formula 15 in the presence of reagents such as di-tert-butyl dicarbonate [(Boc) 2 0] or the like in the presence of bases such as sodium bicarbonate (NaHC0 3 ) or the like in the solvents such as 1,4-dioxane: H 2 0 or the like.
  • the C-3 hydroxy compounds of formula 15 can be protected with the compounds of formula 16 to give the C-3 protected compounds of formula 17 in the presence of catalysts such as ⁇ , ⁇ '-Dicyclohexylcarbodiimide (DCC), 4- Dimethylaminopyridine (DMAP) or the like in the solvents such as dichloromethane (DCM) or the like.
  • DCC ⁇ , ⁇ '-Dicyclohexylcarbodiimide
  • DMAP 4- Dimethylaminopyridine
  • the C-17 protected amine compounds of formula 17 can be converted to the C-17 amine trifluoroacetic acid compounds of formula 18 in the presence of reagents such as trifluoro acetic acid (TFA) or the like in the solvents such as dichloromethane (DCM) or the like.
  • TFA trifluoro acetic acid
  • DCM dichloromethane
  • the C-17 amine trifluoroacetic acid compounds of formula 18 can be reacted with the halo amino compounds of formula 4 to give the corresponding C-17 substituted amine compounds of formula 19 in the presence of bases such as potassium phosphate (K 3 P0 4 ) or the like in the solvents such as acetonitrile (ACN) or the like in the presence of catalysts such as potassium iodide (KI) or the like.
  • bases such as potassium phosphate (K 3 P0 4 ) or the like in the solvents such as acetonitrile (ACN) or the like in the presence of catalysts such as potassium iodide (KI) or the like.
  • the C-3 protected compounds of formula 19 can be deprotected to give the corresponding acid compounds of the present invention formula (I) in the presence of reagents such as palladium acetate [Pd(OAc) 2 ], triethylsilylhydride (Et 3 SiH) or the like in the solvents such as tetrahydrofuran (THF) or the like.
  • reagents such as palladium acetate [Pd(OAc) 2 ], triethylsilylhydride (Et 3 SiH) or the like in the solvents such as tetrahydrofuran (THF) or the like.
  • step 1 To a stirred solution of 4-(2-hydroxyethyl)thiomorpholine 1,1-dioxide (step 1, 2.5 g, 13.88 mmol, 1.0 eq) in DCM (25 ml) at 0 °C then added thionyl chloride (5.06 mL, 69.44 mmol, 5.0 eq) followed by DMF (Cat.). The reaction mixture was heated to 40 °C for overnight. After completion of the reaction (monitored by TLC), the solvent was evaporated in vacuo providing a crude residue was diluted with DCM and washed with saturated sodium bicarbonate solution.
  • Step 1 Synthesis of 2-morpholinoethan- -ol.
  • Step 2 Synthesis of 4-(2-chloroethyl)morpholine: To a stirred solution of 2-morpholinoethan-l-ol (step 1, 2.5 g, 13.88 mmol, 1.0 eq) in DCM (25 ml) at 0 °C then added thionyl chloride (5.06 mL, 69.44 mmol, 5.0 eq) followed by DMF (Cat.). The reaction mixture was heated to 40 °C for overnight. After completion of the reaction (monitored by TLC), the solvent was evaporated in vacuo providing a crude residue, which was diluted with DCM and washed with saturated sodium bicarbonate solution.
  • Step 1 Synthesis of 2-(4-(methylsulfonyl)piperazin-l -yl)ethan-l -ol:
  • step 1 To a stirred solution of 2-(4-(methylsulfonyl)piperazin-l-yl)ethan-l-ol (step 1, 2.5 g, 12.02 mmol, 1.0 eq) in DCM (25 ml) at 0 °C then added thionyl chloride (4.38 mL, 60.10 mmol, 5.0 eq) followed by DMF (Cat.). The reaction mixture was heated to 40 °C for overnight. After completion of the reaction (monitored by TLC), the solvent was evaporated in vacuum providing a crude residue which was diluted with DCM and washed with saturated sodium bicarbonate solution.
  • Step 1 Synthesis of tert-butyl 4-oxopiperidine-l-carboxylate:
  • Step 2 Synthesis of tert-butyl 4,4-difluoropi eridine-l -carboxylate:
  • step 1 To a stirred solution of tert-butyl 4-oxopiperidine-l-carboxylate (step 1, 6.0 g, 30.15 mmol, 1.0 eq) in DCM (60 mL) was added diethylaminosulfmtrifiuoride (DAST) (5.97 mL, 45.22 mmol, 1.5 eq) at 0 °C.
  • DAST diethylaminosulfmtrifiuoride
  • the reaction mixture was stirred at same temperature for about 6 hours. TLC indicated starting material was consumed and the desired product was observed.
  • the reaction mixture was poured into ice cold water and extracted with DCM. The organic layer was washed with water, brine solution and the organic layer was dried with Na 2 S0 4 .
  • step 2 To a tert-butyl 4,4-difluoropiperidine- 1-carboxylate (step 2, 6.0 g, 27.15 mmol, 1.0 eq) was added dioxane hydrochloride (60 ml). The reaction mixture was stirred for about 2 hours. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture was concentrated gave the hydrochloride salt product (4.2 g) as a white solid.
  • Step 4 Synthesis of 2-(4,4-difluoropiperidin-l -yl)ethan-l -ol:
  • Step 5 Synthesis of 1 -(2-chloroethyl)-4,4-difluoropiperidine:
  • Step 1 Synthesis of tert-butyl piperazine-l -carboxylate:
  • Step 2 Synthesis of tert-butyl 4-(isopropylsulfonyl)piperazine-l -carboxylate :
  • step 1 To a stirred solution of tert-butyl 4-oxopiperazine- 1 -carboxylate (step 1, 10.0 g, 53.76 mmol, 1.0 eq) in DCM (100 mL) was added propane-2-sulfonyl chloride (8.5 g, 59.14 mmol, 1.1 eq) followed by TEA (8.9 mL, 64.51 mmol, 1.2 eq) at room temperature and stirred for about 12 hours at same temperature. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture was diluted with water and extracted with DCM. The organic layer was washed with water, brine solution and was dried with Na 2 S0 4 .
  • Step 4 Synthesis of 2-(4-(isopropylsulfonyl)piperazin-l -yl)ethan-l -ol:
  • Step 5 Synthesis of l-(2-chloroethyl)-4-(isopropylsulfonyl)piperazine:
  • Step 1 Synthesis of tert-butyl piperazine- 1 -carboxylate:
  • Step 2 Synthesis of tert-butyl 4-benzoylpiperazine-l-carboxylate:
  • Step 4 Synthesis of (4-(2-hydroxyethyl)piperazin-l -yl)(phenyl)methanone:
  • step 4 To a stirred solution of (4-(2-hydroxyethyl)piperazin-l-yl)(phenyl)methanone (step 4, 7.0 g, 29.78 mmol, 1.0 eq) in DCM (70 mL) at 0 °C added thionyl chloride (10.87 mL, 148.93 mmol, 5.0 eq) followed by DMF (Cat.). The reaction mixture was heated to 40 °C and stirred for overnight. After completion of the reaction (monitored by TLC), the solvent was evaporated in vacuum providing a crude residue was diluted with DCM and washed with saturated sodium bicarbonate solution.
  • Step 1 Synthesis of tert-butyl piperazine-1 -carboxylate:
  • Step 2 Synthesis of tert-butyl 4-(N,N-dimethylsulfamoyl)piperazine-l -carboxylate:
  • step 1 To a stirred solution of tert-butyl piperazine-1 -carboxylate (step 1, 10.0 g, 53.56 mmol, 1.0 eq) in DCM (100 mL) was added ⁇ , ⁇ -dimethylsulfamoyl chloride (6.3 mL, 59.13 mmol, 1.1 eq) followed by TEA (8.9 mL, 64.51 mmol, 1.2 eq) at room temperature and stirred for about 12 hours at same temperature. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture was diluted with water and extracted with DCM. The organic layer was washed with water, brine solution and was dried over Na 2 S0 4 .
  • step 2 A solution of tert-butyl 4-(N,N-dimethylsulfamoyl)piperazine-l-carboxylate (step 2, 14.5 g, 49.48 mmol, 1.0 eq) in dioxane hydrochloride (145 ml) was stirred at room temperature for about 2 hours. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture was concentrated gave the hydrochloride salt product (9.5 g) as a white solid.
  • Step 4 Synthesis of 4-(2-hydroxyethy -N,N-dimethylpiperazine-l -sulfonamide:
  • Step 5 Synthesis of 4-(2-chloroethyl)-N,N-dimethylpiperazine-l -sulfonamide:
  • step 4 To a stirred solution of 4-(2-hydroxyethyl)-N,N-dimethylpiperazine-l-sulfonamide (step 4, 8.0 g, 33.75 mmol, 1.0 eq) in DCM (100 mL) at 0 °C then added thionyl chloride (12.32 mL, 168.75 mmol, 5.0 eq) followed by DMF (Cat.). The reaction mixture was heated to 40 °C for overnight. After completion of the reaction (monitored by TLC), the solvent was evaporated in vacuum providing a crude residue which was diluted with DCM and washed with saturated sodium bicarbonate solution.
  • Step 1 Synthesis of tert-butyl piperazine-1 -carboxylate:
  • Step 2 Synthesis of tert-butyl 4-(dimeth lcarbamoyl)piperazine-l -carboxylate:
  • step 1 To a stirred solution of tert-butyl piperazine-1 -carboxylate (step 1, 10.0 g, 53.76 mmol, 1.0 eq) in DCM (100 mL) was added dimethylcarbamic chloride (7.39 mL, 80.64 mmol, 1.5 eq) followed by TEA (11.18 mL, 80.64 mmol, 1.5 eq) at room temperature and stirred for about 12 hours at same temperature. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture was diluted with water and extracted with DCM. The organic layer was washed with water, brine solution and was dried over Na 2 S0 4 .
  • Step 3 Synthesis of N,N-dimethylpipera ine-l -carboxamide.
  • HCl salt A solution of tert-butyl 4-(dimethylcarbamoyl)piperazine-l-carboxylate (step 2, 13.5 g, 52.52 mmol, 1.0 eq) in dioxane hydrochloride (135 ml) was stirred at room temperature for about 2 hours. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture was concentrated gave the hydrochloride salt product (8.2 g) as a white solid.
  • Step 4 Synthesis of 4-(2-hydroxyethy -N,N-dimethylpiperazine-l -carboxamide:
  • Step 5 Synthesis of 4-(2-chloroethyl)-N,N-dimethylpiperazine-l -carboxamide:
  • step 4 To a stirred solution of 4-(2-hydroxyethyl)-N,N-dimethylpiperazine-l -carboxamide (step 4, 7.0 g, 34.82 mmol, 1.0 eq) in DCM (100 mL) at 0 °C added thionyl chloride (12.71 mL, 174.12 mmol, 5.0 eq) followed by DMF (Cat.). The reaction mixture was heated to 40 °C and stirred for overnight. After completion of the reaction (monitored by TLC), the solvent was evaporated in vacuum providing a crude residue which was diluted with DCM and washed with saturated sodium bicarbonate solution.
  • Step 1 Synthesis of tert-butyl piperazine-1 -carboxylate:
  • Step 2 Synthesis of tert-butyl 4-(phenylsulfonyl)piperazine-l -carboxylate:
  • step 1 To a stirred solution of tert-butyl piperazine-1 -carboxylate (step 1, 10.0 g, 53.76 mmol, 1.0 eq) in DCM (100 mL) was added benzenesulfonyl chloride (7.62 mL, 59.13 mmol, 1.1 eq) followed by TEA (8.9 mL, 64.51 mmol, 1.2 eq) at room temperature and stirred for about 12 hours at same temperature. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture was diluted with water and extracted with DCM. The organic layer was washed with water, brine solution and was dried over Na 2 S0 4 . Filtrate was concentrated to get the crude residue which was purified by column chromatography by using 5% EtOAc in hexane as an eluent to obtain the desired product
  • Step 3 Synthesis of 1 -(phenylsulfonyl)piperazine.
  • HCl salt A solution of tert-butyl 4-(phenylsulfonyl)piperazine-l-carboxylate (step 2, 14.0 g, 42.9 mmol, 1.0 eq) in dioxane hydrochloride (112 niL). The reaction mixture was stirred at room temperature for about 2 hours. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture was concentrated gave the hydrochloride salt product (8.0 g) as a white solid.
  • Step 4 Synthesis of 2-(4-(phenylsulfonyl)piperazin-l -yl)ethan-l -ol:
  • Step 5 Synthesis of 1 -(2-chloroethyl)-4-(phenylsulfonyl)piperazine:
  • step 4 To a stirred solution of 2-(4-(phenylsulfonyl)piperazin-l-yl)ethan-l-ol (step 4, 8.5 g, 31.4 mmol, 1.0 eq) in DCM (85 mL) at 0 °C then added thionyl chloride (11.4 mL, 157.0 mmol, 5.0 eq) followed by DMF (Cat.). The reaction mixture was heated to 40 °C and stirred for overnight. After completion of the reaction (monitored by TLC), the solvent was evaporated in vacuum providing a crude residue which was diluted with DCM and washed with saturated sodium bicarbonate solution.
  • Step 1 Synthesis of tert-butyl piperazine-1 -carboxylate:
  • Step 2 Synthesis of tert-butyl 4-(ben lsulfonyl)piperazine-l -carboxylate:
  • step 1 To a stirred solution of tert-butyl piperazine-1 -carboxylate (step 1, 10.0 g, 53.7 mmol,
  • Step 3 Synthesis of 1 -(benzylsulfon l)piperazine.
  • HCl salt A solution of tert-butyl 4-(benzylsulfonyl)piperazine-l-carboxylate (step 2, 13.0 g, 38.2 mmol, 1.0 eq) in dioxane hydrochloride (104 niL) was stirred at room temperature for about 2 hours. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture was concentrated gave the hydrochloride salt product (7.7 g, yield: 84.0%) as a white solid.
  • Step 4 Synthesis of 2-(4-(benzylsulfonyl)piperazin-l -yl)ethan-l -ol:
  • Step 5 Synthesis of 1 -(benzylsulfonyl)-4-(2-chloroethyl)piperazine:
  • Step 1 Synthesis of (lR,3aS,5aR,5bR, 7aR,9S,llaR,llbR,13aR,13bR)-3a-((((4-methoxy benzyl )oxy )carbonyl)amino)-5a,5b, 8,8,1 la-pentamethyl-1 -( 1 -methylcyclopropyl)icosahydro- lH-cyclopenta[a ]chrysen-9-yl acetate:
  • reaction mixture was refluxed for about 3 hours and then added (4-methoxyphenyl)methanol (5.3 mL, 39.06 mmol, 1.0 eq). The reaction mixture was continued refluxing under nitrogen atmosphere and stirred for about 4 hours. After completion of the reaction (monitored by TLC), the solvent was evaporated in vacuo providing a crude residue which was recrystallized in acetonitrile to obtain the desired product (17.8 g, yield: 70.0%) as a white solid.
  • Step 2 Synthesis of (lR,3aS,5aR,5bR, 7aR,9S,llaR,llbR,13aR,13bR)-3a-amino-5a,5b,8,8, 1 la-penta methyl-1 -(1 -methylcyclopropyl)icosahydro-lH-cyclopenta[a] chrysen-9-yl acetate.
  • Step 1 Synthesis of (lR,3aS,5aR,5bR, 7aR,9S,llaR,llbR,13aR,13bR)-3a-isocyanato-5a,5b,8, 8,lla-pentamethyl-l-(prop-l-en- -yl)icosahydro-lH-cyclopenta[a]chrysen-9-yl acetate:
  • reaction mixture was heated to reflux and continued for about 3 hours. After completion of the reaction (monitored by TLC), the reaction mixture was cooled to room temperature and the solvent was evaporated in vacuo providing a crude residue, which was diluted with DCM, washed with water, brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to give the residue.
  • the crude product was purified via silica gel column chromatography using EtOAc in n-hexane (10:90) as an eluent to afford the desired compound (9.0 g, yield: 90%) as a white solid.
  • Step 3 Synthesis of tert-butyl ((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-3aH-cyclopenta[a]chrysen-3a-yl) carbamate:
  • reaction mixture was stirred for overnight at room temperature. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with EtOAc, washed with water, brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to give the residue.
  • the crude product was purified via silica gel column chromatography by using EtOAc in n-hexane (15:85) as an eluent to afford the desired compound (7.0 g, yield: 84.3%) as a white solid.
  • Step 4 Synthesis of 1 -benzyl 3-((lR,3aS,5aR,5bR, 7aR,9S,llaR,llbR,13aR,13bR)-3a-((tert- butoxycarbonyl)amino)-5a,5b,8,8,lla-pentamethyl-l-(prop-l-en-2-yl)icosahydro-lH-cyclo penta[a] chrysen-9-yl) (lR,3S -2,2-dimethylcyclobutane-l,3-dicarboxylate:
  • reaction mixture was diluted with DCM, washed with water, saturated NaHC0 3 solution, brine and dried over Na 2 S0 4 .
  • the solvent was evaporated under reduced pressure to give the residue.
  • the crude product was purified via silica gel column chromatography by using EtOAc in n-hexane (5:95) as an eluent to afford the desired compound (9.0 g, yield: 87.2%) as a white solid.
  • Step 5 Synthesis of l-((lR,3aS,5aR,5bR, 7aR,9S,llaR,llbR,13aR,13bR)-3a-amino- 5a,5b,8,8,lla-pentamethyl-l-(prop-l-en-2-yl)icosahydro-lH-cyclopenta[a]chrysen-9-yl) 3- benzyl (lS,3R)-2,2-dimethylcyclobutane-l,3-dicarboxylate trifluoroacetic acid salt:
  • Step 1 Synthesis of (lR,3aS,5aR,5bR,7aR,9S,llaR,llbR,13aR,13bR)-3a-((tert- butoxycarbonyl)amino)-5a,5b,8,8,lla-pentamethyl-l-(l-methylcyclopropyl)icosahydro-lH- cyclopenta[a ]chrysen-9-yl acetate:
  • Step 2 Synthesis of tert-butyl ((lR,3aS,5aR,5bR,7aR,9S,llaR,llbR,13aR,13bR)-9-hydroxy- 5a,5b, 8,8,1 la-pentamethyl-1 -( 1 -methylcyclopropyl)icosahydro-3aH-cyclopenta[a Jchrysen- 3a-yl)carbamate:
  • reaction mixture was stirred at room temperature for about 12 hours. TLC indicated starting material was consumed and the desired product was observed.
  • the reaction mixture was diluted with water and extracted with DCM. The organic layer was washed with water and dried over Na 2 S0 4 . The organic layer was evaporated under reduced pressure and the crude was purified by recrystallization in acetone and water (1:3) gave the desired product (5.0 g, yield: 98.0%) as a white solid.
  • Step 3 Synthesis of 1 -benzyl 3-((lR,3aS,5aR,5bR, 7aR,9S,llaR,llbR,13aR,13bR)-3a-((tert- butoxy carbonyl)amino)-5a,5b,8,8,lla-pentamethyl-l-(l-methylcyclopropyl)icosahydro-lH- cyclopenta [a]chrysen-9-yl) (l -2,2-dimethylcyclobutane-l,3-dicarboxylate:
  • Step 4 Synthesis of l-((lR,3aS,5aR,5bR, 7aR,9S,llaR,llbR,13aR,13bR)-3a-amino- 5a,5b,8,8,lla-penta methyl-l-(l-methylcyclopropyl)icosahydro-lH-cyclopenta[a]chrysen-9- yl) 3-benzyl (lS,3R)-2,2-dimethylcyclobutane-l,3-dicarboxylate hydrochloride:
  • Example 1 Preparation of (lR,3S)-3-((((lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)- 3 a-((2-( 1,1 -dioxidothiomorpholino)ethyl)amino)-5 a,5b,8 , 8 J 1 a-pentamethyl- 1 -( 1 -methyl cvclopropyl)icosahvdro-lH-cvclopentaralchrvsen-9-yl)oxy)carbonyl)-2,2-dimethylcvclo butane- 1-carboxvlic acid
  • Step 1 Synthesis of (lR,3aS,5aR,5bR, 7aR,9S,llaR,llbR,13aR,13bR)-3a-((2-(l,l-dioxidothio morpholino )ethyl)amino)-5a,5b, 8,8,11 a-pentamethyl- 1 -( 1 -methylcyclopropyl)icosahydro-lH- cyclopenta[a] chrysen-9-yl acetate:
  • reaction mixture was heated to 120 °C under nitrogen atmosphere and stirred for about 20 hours. After completion of the reaction (monitored by TLC), the reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated gave the crude residue which was purified by column chromatography by using 2% methanol in DCM as an eluent to afford the desired compound (0.700 g, yield: 52.0%) as a white solid.
  • Step 2 Synthesis of 4-(2-(((lR,3aS,5aR,5bR,7aR,9S,llaR,llbR,13aR,13bR)-9-hydroxy-5a, 5b,8,8,lla-pentamethyl-l-(l-methylcyclopropyl)icosahydro-3aH-cyclopenta[a]chrysen-3a- yl)amino)ethyl)thiomorpholine 1 1-dioxide:
  • reaction mixture was stirred at room temperature for about 12 hours. TLC indicated starting material was consumed and the desired product was observed.
  • the reaction mixture was diluted with water and extracted with DCM. Organic layer was washed with water and dried with Na 2 S0 4 . The organic layer was evaporated under reduced pressure and the crude was purified by column chromatography by using 4% MeOH in DCM as an eluent gave the desired product (0.450 g, yield: 69.0%) as a white solid.
  • Step 3 Synthesis of 1 -benzyl 3-((lR,3aS,5aR,5bR,7aR,9S,llaR,llbR,13aR,13bR)-3a-((2-(l,l -dioxidothiomorpholino )ethyl)amino )-5a,5b, 8,8,1 la-pentamethyl-1 -( 1 -methylcyclopropyl) icosahydro-lH-cyclopenta[a]chrysen-9-yl) (lR,3S)-2,2-dimethylcyclobutane-l,3- dicarboxylate:
  • the reaction mixture was cooled to 0 °C then added DCC (0.307 g, 1.5 mmol, 2.0 eq) followed by DMAP (0.018 g, 0.15 mmol, 0.2 eq).
  • DCC 0.307 g, 1.5 mmol, 2.0 eq
  • DMAP 0.15 mmol, 0.2 eq
  • the reaction mixture was raised to room temperature and stirred for overnight. TLC indicated starting material was consumed and the desired product was observed.
  • the reaction mixture was evaporated under reduced pressure and diluted with water.
  • the aqueous layer was extracted with CH 2 CI 2 .
  • the organic layer was washed with water and brine solution.
  • the combined organic layers were dried over Na 2 S0 4 , filtered and evaporated under reduced pressure.
  • Step 4 Synthesis of (lR,3S)-3-((((lR,3aS,5aR,5bR,7aR,9S,llaR,llbR,13aR,13bR)-3a-((2- ( 1,1 -dioxidothiomorpholino)ethyl)amino)-5a,5b, 8, 8,1 la-pentamethyl-1 -(1-methylcyclo propyl)icosahydro-lH-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-l- carboxylic acid:
  • reaction mixture was stirred in hydrogen atmosphere at room temperature for overnight. After completion of the reaction (monitored by TLC), the reaction mixture was filtered through a pad of celite ® and was washed with MeOH and DCM. The filtrate was evaporated under reduced pressure, the crude residue was purified by column chromatography by using 4% methanol in DCM as an eluent gave the desired compound (0.116 g, yield: 44.0%) as a white solid.
  • Step 1 Synthesis of 1 -benzyl 3-((lR,3aS,5aR,5bR,7aR,9S,llaR,llbR,13aR,13bR)-3a-((2-(l,l -dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,lla-pentamethyl-l-(prop-l-en-2-yl) icosahydro-lH-cyclopenta[a]chrysen-9-yl) (lR,3S)-2,2-dimethylcyclobutane-l,3 dicarboxylate:
  • the reaction mixture was heated to 120 °C and continued for about 18 hours. After completion of the reaction (monitored by TLC), the reaction mixture was filtered through celite and the cake was washed with DCM (twice). The filtrate was concentrated under reduced pressure gave the residue.
  • the crude product was purified via silica gel column chromatography by using MeOH in DCM (2:98) as an eluent to afford the desired compound (0.89 g, yield: 76.2%) as a white solid.
  • Step 2 Synthesis of (lR,3S)-3-((((lR,3aS,5aR,5bR,7aR,9S,llaR,llbR,13aR,13bR)-3a-((2- (1 ,1 -dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,l 1 a-pentamethyl-1 -(prop-1 -en-2-yl) icosahydro-lH-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-l- carboxylic acid:
  • reaction mixture was heated to 70 °C and stirring was continued for about 3 hours. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with EtOAc, washed with water, saturated NaHC03 solution, brine and dried over Na2S04. The solvent was evaporated under reduced pressure and purified by silica gel column using 5% MeOH in DCM as an eluent to afford the title compound (0.37 g, yield: 51.89%) as a white solid.
  • Example 13 Preparation of (lR,3S)-3-((((lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)- 3a-((2-(4,4-difluoropiperidin-l-yl)ethyl)amino)-5a,5b,8,8 J la-pentamethyl-l-d- methylcvclopropyl)icosahvdro-lH-cvclopentaralchrvsen-9-yl)oxy)carbonyl)-2,2- dimethylcyclobutane-l-carboxylic acid:
  • Step 1 Synthesis of 1-benzyl 3-((lR,3aS,5aR,5bR, 7aR,9S,llaR,llbR,13aR,13bR)-3a-((2- (4,4-difluoropiperidin-l-yl)ethyl)amino)-5a,5b,8,8 la ⁇ entamethyl-l-(l-methylcyclopropyl) icosahydro-lH-cyclopenta[a]chrysen-9-yl) (lR,3S)-2,2-dimethylcyclobutane-l,3- dicarboxylate:
  • reaction mixture was heated to 120 °C under nitrogen atmosphere and stirred for about 20 hours. After completion of the reaction (monitored by TLC), the reaction mixture was cooled to room temperature and filtered. Filtrate was concentrated gave the crude residue which was purified by column chromatography by using 2% methanol in DCM as an eluent to afford the title compound (0.5 g, yield: 41.0%) as a white solid.
  • Step 2 Synthesis of (lR,3S)-3-((((lR,3aS,5aR,5bR,7aR,9S,llaR,nbR,13aR,13bR)-3a-((2- (4,4-difluoropiperidin-l-yl)ethyl)amino)-5a,5b,8,8 la ⁇ entamethyl-l-(l-methylcyclopropyl) icosahydro-lH-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-l- carboxylic acid:
  • step 1 ((2-(4,4-difluoropiperidin-l-yl)ethyl)amino)-5a,5b, 8,8,1 la-pentamethyl- 1-(1- methylcyclopropyl)icosahydro-lH-cyclopenta[a]chrysen-9-yl) (lR,3S)-2,2- dimethylcyclobutane-l,3-dicarboxylate (step 1, 0.500 g, 0.60 mmol, 1.0 eq) in ethylacetate (10 mL) and methanol (5 mL) was added palladium carbon (0.032g, 0.30 mmol, 0.5 eq). The reaction mixture was stirred in hydrogen atmosphere at room temperature for overnight.
  • reaction mixture was filtered through a pad of celite and was washed with MeOH and DCM. The filtrate was evaporated under reduced pressure, the crude residue was purified by column chromatography by using 4% methanol and DCM as an eluent to give the desired compound (0.043 g, yield: 10.0%) as a white solid.
  • the compounds described herein can be tested for their antiviral activity following procedures known to a person of ordinary skill in the art. For example, the following protocols can be employed for testing the compounds. These protocols are illustrative and do not limit to the scope of the invention.
  • MT2 cells were infected with HIV-1 strain 92HT599 (15TCID 50/ 30000 cells).
  • the infected cells were plated at the concentration of -30 000 cells per well in 96 well plate.
  • Test compound was added to the micro plate in defined format with the final concentration of DMSO (vehicle) is not more than 1%.
  • Incubation was carried out in C0 2 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 controls).
  • IC 50 values of the compounds of formula (I) are summarized in the below Table- 1A, wherein the compounds according to compound of formula (I) possess antiviral activity IC 50 value less than or equal to 10 nM referred herein as "A” and IC 50 value greater than 10 nM referred herein as "B”.
  • Table- 1 A Table- 1 A
  • HIV-1 p24 antigen capture assay enzyme immunoassay for detection of Human immunodeficiency Virus Type 1 (HIV-1) p24 in tissue culture media - Advanced bio science laboratories, Inc kit procedure.

Abstract

The present invention relates to to C-3 novel triterpene with C-17 amine derivatives of formula (I); or pharmaceutically acceptable salts, solvates, hydrates, tautomers, stereoisomers, prodrugs, compositions or combination thereof, wherein R1, R2, R3, R4, R5 and 'n' are as defined herein. The present invention also relates to pharmaceutical compositions comprising compounds of formula (I) and process for preparing them, and their use for the treatment of viral diseases and particularly HIV mediated diseases.

Description

C-3 NOVEL TRITERPENE WITH C-17 AMINE DERIVATIVES AS HIV
INHIBITORS
This application claims the benefit of Indian provisional application no 201641007671 filed on 4th March 2016 which is hereby incorporated by reference in its entirety.
FIELD OF THE INVENTION
The present invention relates to C-3 novel triterpene with C-17 amine 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 (AIDS) 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 betulinic 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. 1994, 57(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-1. Bevirimat went up to phase 2 clinical trials, in clinic despite optimal plasma concentrations, not all patients given Bevirimat have a robust viral load reduction. It was reported that non-respondant patients had more frequent base line Gag polymorphisms near the capsid SP-1 cleavage site than responders. (HIV gag polymorphism determines treatment response to bevirimat. XVII international HIV drug resistance work shop June 10-14, 2008, Sitges, Spain). Encouraged by these developments, medicinal chemists started exploring betulinic acid derivatives and related compounds intensively for their therapeutic activities. For example, WO 2014/105926 disclosed novel betulinic acid proline derivatives as HIV inhibitors; WO 2014/130810 describes preparation of C3 alkyl and alkenyl modified betulinic acid derivatives useful in the treatment of HIV; WO 2014/123889 describes preparation of triterpenoid derivatives for use as HIV maturation inhibitors; WO 2013/160810 disclosed novel betulinic acid derivatives as HIV inhibitors; WO 2013/169578 describes C-17 bicyclic amines of triterpenoids with HIV maturation inhibitory activity and their preparation; WO 2013/123019 describes C-3 cycloalkenyl triterpenoids with HIV maturation inhibitory activity; WO 2013/043778 describes novel betulinic acid derivatives with antiviral activity; WO 2013/035943 describes betulinic acid and derivatives thereof having anti-aging activity; WO 2012/106190 describes preparation of C17 and C3 modified triterpenoids with HIV maturation inhibitory activity; CN 102399254 describes novel pentacyclic triterpenoid derivatives, their preparation method and application for preventing and treating diabetes, cardiovascular disease, cerebrovascular disease and tumor; WO 2011/007230 describes preparation of lupeol-type triterpene derivatives as antiviral agents; WO 2010/032123 describes preparation of triterpenoid compounds for pharmaceutical use; Journal of Medicinal Chemistry (2010), 53(1), 178-190 describes structure-activity relationship study of betulinic acid, a novel and selective TGR5 agonist, and its synthetic derivatives: potential impact in diabetes; WO 2009/100532 describes preparation of 17 -lupane derivatives for the treatment of HIV infection; CN 101367861 describes preparation method and application of 2-hydroxy- 3-deoxy-pentacyclic triterpene compounds and derivatives; WO 2008/138200 describes preparation of lupane derivatives as NMDA and MC receptor antagonists exhibiting neuroprotective and memory enhancing activities; WO 2008/127364 describes preparation of betulinic acid derivatives for use in antiviral and anticancer pharmaceutical compositions.
Some additional references disclose betulinic acid related compounds. For example, WO 2006/053255 describes preparation of betulin derivatives for use in pharmaceutical compositions which inhibit the transmission of viral infection; WO 2004/089357 describes anti-fungal formulation of triterpene and essential oil; Bioorganic & Medicinal Chemistry Letters (2003), 13(20), 3549-3552 describes lupane triterpenes and derivatives with antiviral activity; Russian Journal of Bioorganic Chemistry (2003), 29(6), 594-600 describes synthesis and antiviral activity of ureides and carbamates of betulinic acid and its derivatives; Journal of Medicinal Chemistry (1996), 39(5), 1056-68 describes betulinic acid derivatives: a new class of human immunodeficiency virus type 1 specific inhibitors with a new mode of action; Oxidation Communications (1987), 10(3-4), 305-12 describes oxidative decarboxylations. II. oxidative decarboxylation of acetyl betulinic acid.
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 patients, 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
In one aspect, the present invention relates to the com ounds of the formula (I):
Figure imgf000004_0001
Formula (I)
wherein,
Figure imgf000004_0002
0 F3C CF3 (wherein Rb is hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted cycloalkyl);
R2 is alkyl, alkenyl or substituted or unsubstituted cycloalkyl; wherein the substituent is alkyl;
R3 is hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted cycloalkyl; wherein the substituent is heterocyclyl or alkylamino;
R4 and R5 independently are hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl; wherein the substituent is alkylamino; alternatively, R4 and R5 are taken together with the N-atom to which they are attached to form substituted or unsubstituted 3-15 membered heterocyclyl; wherein the substituent is one or more Ra;
Ra is independently selected from substituted or unsubstituted alkyl, substituted or unsubstituted aminoalkyl, halogen, hydroxyl, haloalkyl, hydroxyalkyl, substituted or unsubstituted amino, -N(H)-S02-Rc, -S02-Rc, -C(0)-Rd, or -C(0)0-Re; Rc, Rd and Re independently are substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted alkylamino, substituted or unsubstituted amino, or substituted or unsubstituted arylalkyl; and
'n' is an integer selected from 1-4 both inclusive; or
pharmaceutically acceptable salts, solvates, hydrates, tautomers, stereoisomers, prodrugs, or combination thereof.
In another aspect, the present invention relates to pharmaceutical composition comprising C-3 novel triterpene with C-17 amine derivatives and related compounds of formula (I) and processes for preparing thereof.
In yet another aspect, the present invention relates to C-3 novel triterpene with C-17 amine derivatives and related compounds, compositions useful for therapeutic treatment of viral diseases and particularly HIV mediated diseases.
DETAILED DESCRIPTION OF THE INVENTION
In one embodiment, the present invention relates to C-3 novel triterpene with C-17 amine derivatives and related compounds, compositions useful for therapeutic treatment of viral diseases and particularly HIV mediated diseases.
Each embodiment is provided by way of explanation of the invention, and not by way of limitation of the invention. In fact, it will be apparent to those skilled in the art that various modifications and variations can be made to the compounds, compositions, and methods described herein without departing from the scope or spirit of the invention. For instance, features illustrated or described as part of one embodiment can be applied to another embodiment to yield a still further embodiment. Thus it is intended that the present invention include such modifications and variations and their equivalents. Other objects, features, and aspects of the present invention are disclosed in, or are obvious from, the following detailed description. It is to be understood by one of ordinary skill in the art that the present discussion is a description of exemplary embodiments only, and is not to be construed as limiting the broader aspects of the present invention.
In one embodiment, the resent invention relates to compounds of formula (I):
Figure imgf000005_0001
Formula (I) wherei
Figure imgf000006_0001
0 F3C CF3 (wherein Rb is hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted cycloalkyl);
R2 is alkyl, alkenyl or substituted or unsubstituted cycloalkyl; wherein the substituent is alkyl;
R3 is hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted cycloalkyl; wherein the substituent is heterocyclyl or alkylamino;
R4 and R5 independently are hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl; wherein the substituent is alkylamino; alternatively, R4 and R5 are taken together with the N-atom to which they are attached to form substituted or unsubstituted 3-15 membered heterocyclyl; wherein the substituent is one or more Ra;
Ra is independently selected from substituted or unsubstituted alkyl, substituted or unsubstituted aminoalkyl, halogen, hydroxyl, haloalkyl, hydroxyalkyl, substituted or unsubstituted amino, -N(H)-S02-Rc, -S02-Rc, -C(0)-Rd, or -C(0)0-Re;
Rc, Rd and Re independently are substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted alkylamino, substituted or unsubstituted amino, or substituted or unsubstituted arylalkyl; and
'n' is an integer selected from 1-4 both inclusive; or
pharmaceutically acceptable salts, solvates, hydrates, tautomers, stereoisomers, prodrugs, or combination thereof.
In another embodiment, the resent invention relates to compounds of formula (IA):
Figure imgf000006_0002
wherein,
Figure imgf000007_0001
0 F3C CF3 (wherein Rb is hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted cycloalkyl);
R2 is alkyl, alkenyl or substituted or unsubstituted cycloalkyl; wherein the substituent is alkyl;
R3 is hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted cycloalkyl; wherein the substituent is heterocyclyl or alkylamino;
R4 and R5 independently are hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl; wherein the substituent is alkylamino; alternatively, R4 and R5 are taken together with the N-atom to which they are attached to form substituted or unsubstituted 3-15 membered heterocyclyl; wherein the substituent is one or more Ra;
Ra is independently selected from substituted or unsubstituted alkyl, substituted or unsubstituted aminoalkyl, halogen, hydroxyl, haloalkyl, hydroxyalkyl, substituted or unsubstituted amino, -N(H)-S02-Rc, -S02-Rc, -C(0)-Rd, or -C(0)0-Re; and
Rc, Rd and Re independently are substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted alkylamino, substituted or unsubstituted amino, or substituted or unsubstituted arylalkyl; or
pharmaceutically acceptable salts, solvates, hydrates, tautomers, stereoisomers, prodrugs, or combination thereof.
In yet another embodiment, the present invention relates to compounds of formula
(IB):
Figure imgf000007_0002
wherein,
R2 is alkyl, alkenyl or substituted or unsubstituted cycloalkyl; wherein the substituent is alkyl;
R3 is hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted cycloalkyl; wherein the substituent is heterocyclyl or alkylamino; R4 and R5 independently are hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl; wherein the substituent is alkylamino; alternatively, R4 and R5 are taken together with the N-atom to which they are attached to form substituted or unsubstituted 3-15 membered heterocyclyl; wherein the substituent is one or more Ra;
Ra is independently selected from substituted or unsubstituted alkyl, substituted or unsubstituted aminoalkyl, halogen, hydroxyl, haloalkyl, hydroxyalkyl, substituted or unsubstituted amino, -N(H)-S02-Rc, -S02-Rc, -C(0)-Rd, or -C(0)0-Re;
Rc, Rd and Re independently are substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted alkylamino, substituted or unsubstituted amino, or substituted or unsubstituted arylalkyl; and
'n' is an integer selected from 1-4 both inclusive; or
pharmaceutically acceptable salts, solvates, hydrates, tautomers, stereoisomers, prodrugs, or combination thereof.
It should be understood that the formula (I), (IA) and (IB) structurally encompasses all stereoisomers, including enantiomers, diastereomers, racemates, and combinations thereof which may be contemplated from the chemical structure of the genus described herein.
It should be understood that the formula (I), (IA) and (IB) structurally encompasses all tautomers.
Also contemplated that the prodrugs of the compounds of the formula (I) includes esters of the compounds.
The embodiments below are illustrative of the present invention and are not intended to limit the claims to the specific embodiments exemplified.
According to one embodiment, specifically provided are compounds of formula (I), wherein Ri
Figure imgf000008_0001
According to another embodiment, specifically provided are compounds of formula (I), wherein R2 is isopropylene.
According to yet another embodiment, specifically provided are compounds of formula (I), wherein R2 is methylcyclopropyl.
According to yet another embodiment, specifically provided are compounds of formula (I), wherein R3 is hydrogen.
According to yet another embodiment, specifically provided are compounds of formula (I), wherein 'n' is 2. According to yet another embodiment, specifically provided are compounds of formula (I), wherein R4 and R5 are taken together with the N-atom to which they are attached to form substituted or unsubstituted 3-15 membered heterocyclyl.
According to preceding embodiment, specifically provided are compounds of formula (I), wherein the said heterocyclyl is morpholine.
According to one of preceding embodiment, specifically provided are compounds of formula (I), wherein the said heterocyclyl is thiomorpholine 1,1-dioxide.
According to one of preceding embodiment, specifically provided are compounds of formula (I), wherein the said heterocyclyl is substituted piperazine; wherein the substituents
Figure imgf000009_0001
According to one of preceding embodiment, specifically provided are compounds of formula (I), wherein the said heterocyclyl is substituted piperidine; wherein the substituent is one or more fluoro.
In certain embodiments of formula (I), R3 is hydrogen, or substituted or unsubstituted alkyl; wherein the substituent is heterocyclyl or alkylamino.
In certain embodiments of formula (I), R4 and R5 are hydrogen or substituted or unsubstituted alkyl; wherein the substituent is alkylamino.
In certain embodiments of formula (I), R4 and R5 are taken together with the N-atom to which they are attached to form substituted or unsubstituted 3-15 membered heterocyclyl; wherein the substituent is one or more Ra.
In certain embodiments of formula (I), Ra is substituted or unsubstituted alkyl, substituted or unsubstituted aminoalkyl, halogen, hydroxyl, hydroxyalkyl, substituted or unsubstituted amino, haloalkyl, -N(H)-S02-Rc, -S02-Rc, -C(0)-Rd or -C(0)0-Re.
In certain embodiments of formula (I), Rc, Rd and Re are substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted alkylamino, substituted or unsubstituted amino or substituted or unsubstituted arylalkyl.
In certain embodiments, the compounds of formula (I) can also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the present invention also embraces isotopically-labeled variants of the present invention which are identical to those recited herein, but for the fact that one or more atoms of the compound are replaced by an atom having the atomic mass or mass number different from the predominant atomic mass or mass number usually found in nature for the atom. All isotopes of any particular atom or element as specified are contemplated within the scope of the compounds of the invention, and their uses. The present invention is meant to include all suitable isotopic variations of the compounds of generic formula (I). For example, different isotopic forms of hydrogen (H) include protium ( 1H) and deuterium ( 2 H). Protium is the predominant hydrogen isotope found in nature. Enriching for deuterium may provide certain therapeutic advantages, such as increasing in vivo half -life or reducing dosage requirements, or may provide a compound useful as a standard for characterization of biological samples.
Isotopically-enriched compounds of formula (I) can be prepared without undue experimentation by conventional techniques well known to those skilled in the art or by processes analogous to those described in the Schemes and Examples herein using appropriate isotopically-enriched reagents and/or intermediates. In one embodiment, a compound of formula (I) has one or more of its hydrogen atoms replaced with deuterium.
The representative compounds according to the present invention including the compounds disclosed in the experimental section are illustrative in nature only and are not intended to limit to the scope of the invention. (Nomenclature wherever applicable has been generated from ChemBioDraw Ultra 13.0 version).
(lR,3S)-3-((((lR,3aS,5aR,5bR,7aR,9S,l laR, l lbR, 13aR, 13bR)-3a-((2-(l,l- dioxidothiomo holino)ethyl)amino)-5a,5b,8,8,l la-pentamethyl-l-(l-methyl
cyclopropyl)icosahydro-lH-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclo butane- 1-carboxylic acid (Example 1),
(lR,3S)-2,2-dimethyl-3-((((lR,3aS,5aR,5bR,7aR,9S, l laR,l lbR,13aR,13bR)- 5a,5b,8,8, l la-pentamethyl-l-(l-methylcyclopropyl)-3a-((2- mo holinoethyl)amino)icosahydro-lH-cyclopenta[a]chrysen-9- yl)oxy)carbonyl)cyclobutane- 1-carboxylic acid (Example 2), (lR,3S)-2,2-dimethyl-3-((((lR,3aS,5aR,5bR,7aR,9S, l laR,l lbR,13aR,13bR)-
5a,5b, 8,8, 1 la-pentamethyl-l-(l-methylcyclopropyl)-3a-((2-(4-(methylsulfonyl)piperazin-l- yl)ethyl)amino)icosahydro-lH-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)cyclobutane-l- carboxylic acid (Example 3),
(lR,3S)-3-((((lR,3aS,5aR,5bR,7aR,9S,l laR, l lbR, 13aR, 13bR)-3a-((2-(l,l- dioxidothiomo holino)ethyl)amino)-5a, 5b, 8, 8, 11 a-pentamethyl- 1 -(prop- 1 -en-2- yl)icosahydro-lH-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-l- carboxylic acid (Example 4), (lR,3S)-2,2-dimethyl-3-((((lR,3aS,5aR,5bR,7aR,9S, l laR,l lbR,13aR,13bR)- 5a,5b, 8,8, 1 la-pentamethyl-3a-((2-mo holinoethyl)amino)-l-(prop-l-en-2-yl)icosahydro-lH- cyclopenta[a]chrysen-9-yl)oxy)carbonyl)cyclobutane-l-carboxylic acid (Example 5),
(lR,3S)-2,2-dimethyl-3-((((lR,3aS,5aR,5bR,7aR,9S, l laR,l lbR,13aR,13bR)- 5a,5b, 8,8, 1 la-pentamethyl-3a-((2-(4-(methylsulfonyl)piperazin- l-yl)ethyl)amino)- l-(prop- 1- en-2-yl)icosahydro-lH-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)cyclobutane-l-carboxylic acid (Example 6),
(1R,3 S)-3-((((lR,3aS,5aR,5bR,7aR,9S, 1 laR, 1 IbR, 13aR, 13bR)-3a-((2-(4-(N,N- dimethylsulfamoyl)piperazin-l-yl)ethyl)amino)-5a,5b, 8,8,1 la-pentamethyl-l-(prop- l-en-2- yl)icosahydro-lH-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-l- carboxylic acid (Example 7),
(1R,3 S)-3-((((lR,3aS,5aR,5bR,7aR,9S, 1 laR, 1 IbR, 13aR, 13bR)-3a-((2-(4- (dimethylcarbamoyl)piperazin- 1 -yl)ethyl)amino)-5a, 5b, 8, 8, 11 a-pentam ethyl- 1 -(prop- 1 -en-2- yl)icosahydro-lH-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-l- carboxylic acid (Example 8),
(1R,3 S)-3-((((lR,3aS,5aR,5bR,7aR,9S, 1 laR, 1 IbR, 13aR, 13bR)-3a-((2-(4- benzoylpiperazin- 1 -yl)ethyl)amino)-5a, 5b, 8, 8, 11 a-pentam ethyl- 1 -(prop- 1 -en-2- yl)icosahydro-lH-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-l- carboxylic acid (Example 9),
(1R,3 S)-3-((((lR,3aS,5aR,5bR,7aR,9S, 1 laR, 1 IbR, 13aR, 13bR)-3a-((2-(4- (isopropylsulfonyl)piperazin-l-yl)ethyl)amino)-5a,5b, 8,8,11 a-pentam ethyl- l-(prop- l-en-2- yl)icosahydro-lH-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-l- carboxylic acid (Example 10),
(1R,3 S)-3-((((lR,3aS,5aR,5bR,7aR,9S, 1 laR, 1 IbR, 13aR, 13bR)-3a-((2-(4- (benzylsulfonyl)piperazin-l-yl)ethyl)amino)-5a,5b,8,8, l la-pentamethyl-l-(prop-l-en-2- yl)icosahydro-lH-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-l- carboxylic acid (Example 11),
(lR,3S)-2,2-dimethyl-3-((((lR,3aS,5aR,5bR,7aR,9S, l laR,l lbR,13aR,13bR)- 5a,5b,8,8, l la-pentamethyl-3a-((2-(4-(phenylsulfonyl)piperazin-l-yl)ethyl)amino)-l-(prop-l- en-2-yl)icosahydro-lH-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)cyclobutane-l-carboxylic acid (Example 12),
(1R,3 S)-3-((((lR,3aS,5aR,5bR,7aR,9S, 1 laR, 1 IbR, 13aR, 13bR)-3a-((2-(4,4- difluoropiperidin-l-yl)ethyl)amino)-5a,5b,8,8,l la-pentamethyl-l-(l-methylcyclopropyl) icosahydro-lH-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-l- carboxylic acid (Example 13),
(1R,3 S)-3-((((lR,3aS,5aR,5bR,7aR,9S, 1 laR, 1 IbR, 13aR, 13bR)-3a-((2-(4- (isopropylsulfonyl)piperazin-l-yl)ethyl)amino)-5a,5b,8,8,l la-pentamethyl-l-(l- methylcyclopropyl)icosahydro-lH-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2- dimethylcyclobutane-l-carboxylic acid (Example 14),
(1R,3 S)-3-((((lR,3aS,5aR,5bR,7aR,9S, 1 laR, 1 IbR, 13aR, 13bR)-3a-((2-(4- benzoylpiperazin-l-yl)ethyl)amino)-5a,5b, 8,8,1 la-pentam ethyl- 1-(1- methylcyclopropyl)icosahydro-lH-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2- dimethylcyclobutane-l-carboxylic acid (Example 15),
(lR,3S)-2,2-dimethyl-3-((((lR,3aS,5aR,5bR,7aR,9S, l laR,l lbR,13aR,13bR)- 5a,5b, 8,8, 1 la-pentamethyl-l-(l-methylcyclopropyl)-3a-((2-(4-(phenylsulfonyl)piperazin-l- yl)ethyl)amino)icosahydro-lH-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)cyclobutane-l- carboxylic acid (Example 16), and
(1R,3 S)-3-((((lR,3aS,5aR,5bR,7aR,9S, 1 laR, 1 IbR, 13aR, 13bR)-3a-((2-(4- (benzylsulfonyl)piperazin-l-yl)ethyl)amino)-5a,5b,8,8, l la-pentamethyl-l-(l- methylcyclopropyl)icosahydro-lH-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2- dimethylcyclobutane-l-carboxylic acid (Example 17); or pharmaceutically acceptable salts, solvates, hydrates, tautomers, stereoisomers, prodrugs, or combinations of compounds are also contemplated.
In further yet another embodiment, the compounds of formula (I) structurally encompasses all stereoisomers, enantiomers and diastereomers, and pharmaceutically acceptable salts that may be contemplated from the chemical structure of the general formula (I) described herein.
The absolute configuration at an asymmetric atom is specified by either R or S. Resolved compounds whose absolute configuration is not known can be designated by (+) or (-) depending on the direction in which they rotate plane polarized light. When a specific stereoisomer is identified, this means that said stereoisomer is substantially free, i.e. associated with less than 50%, preferably less than 20%, more preferably less than 5%, in particularly less than 2% or 1 % of the other isomers. Thus when a compound of formula (I) is for instance specified as (R), this means that the compound is substantially free of (S) isomer; when the compound of formula (I) is for instance specified as E, this means that the compound is free of the Z isomer; when the compound of formula (I) is for instance specified as cis isomer, this means that the compound is free of the trans isomer.
In further yet another embodiment, the prodrugs of present invention are the compounds of formula (I) and its pharmaceutically acceptable salts, stereoisomers, solvates thereof containing an hydroxyl group; wherein hydrogen atom of the hydroxyl group are replaced with (Ci-C6)alkanoyloxymethyl, l-((Ci-C6)alkanoyloxy)ethyl, 1 -methyl- l-((Ci- C6)alkanoyloxy)ethyl, (Ci-C6)alkoxycarbonyloxymethyl, N-(Ci-C6)alkoxycarbonyl aminomethyl, succinoyl, (Ci-C6)alkanoyl, a-amino(Ci-C4)alkyl, a-amino(Ci-C4)alkylene- aryl, arylacyl and a-aminoacyl, where each a -aminoacyl group is independently selected from the naturally occurring L-amino acids, or glycosyl (the radical resulting from the removal of a hydroxyl group of the hemiacetal form of a carbohydrate).
In further yet another embodiment, the prodrugs of present invention are the compounds of formula (I) and its pharmaceutically acceptable salts, stereoisomers, hydrates, solvates thereof containing an amine group; wherein one or more hydrogen atoms of the amine group is replaced with (Ci-C6)alkylcarbonyl, (Ci-C6)alkoxycarbonyl, aminocarbonyl, (C3-C6)cycloalkylcarbonyl, benzylcarbonyl and the like.
The present invention also provides a pharmaceutical composition that includes at least one compound according to formula (I) and at least one pharmaceutically acceptable excipient (such as a pharmaceutically acceptable carrier or diluent). Specifically, the pharmaceutical composition comprises a therapeutically effective amount of at least one compound according to formula (I). 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, 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 a therapeutically effective amount to treat that infection, specifically in the form of a pharmaceutical composition.
In another aspect, the present invention relates to combinations comprising a compound of the formula (I) and a second therapeutic agent that is an anti-HIV agent, an anti-HCV agent or anti-TB agents.
In another aspect, the present invention relates to pharmaceutical compositions comprising the compound of formula (I) and one or more second anti-HIV agents and their pharmaceutically acceptable salts and stereoisomers thereof.
In another aspect, the present invention relates to combinations comprising a compound of the formula (I) and one or more second anti-HIV agents selected from the group consisting of Protease inhibitors, Integrase inhibitors, Nucleoside Reverse Transcriptase inhibitors, Non-Nucleoside Reverse Transcriptase Inhibitors, Fusion/Entry inhibitors, Pharmacokinetic enhancers, and combinations thereof.
The present invention relates to methods of treatment of HIV infection, AIDS, and AIDS-related conditions by administering to a subject a compound of formula (I) and one or more second therapeutic agents selected from the group consisting of Protease inhibitors, Integrase inhibitors, Nucleoside Reverse Transcriptase inhibitors, Non-Nucleoside Reverse Transcriptase Inhibitors, Fusion/Entry inhibitors, Pharmacokinetic enhancers, and combinations thereof.
In another aspect, the present invention relates to combinations comprising a compound of the formula (I) and one or more second anti-HIV agents wherein the second anti-HIV agent is Abacavir, Didanosine, Emtricitabine, Lamivudine, Stavudine, Tenofovir disoproxil Fumarate, Tenofovir Alafenamide Fumarate, Zidovudine, Efavirenz, Etravirine, Nevirapine, Rilpivirine, Atazanavir, Darunavir, Fosamprenavir, Indinavir, Nelfinavir, Ritonavir, Cobicistat, Saquinavir, Tipranavir, Enfuvirtide, Maraviroc, Fostemsavir, Dolutegravir, Elvitegravir, Raltegravir, Bictegravir, Cabotegravir or a combination thereof.
In another aspect of the present 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 persistent generalized lymphadenopathy, fever and weight loss, or a retroviral 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 Mossman T, December 1983, Journal of immunological methods, 65 (1- 2), 55-63 and SPC Cole, cancer chemotherapy and Pharmacology, 1986, 17, 259-263.
The following definitions apply to the terms as used herein:
The terms "halogen" or "halo" includes fluorine, chlorine, bromine, or iodine.
The term "amino" refers to -NH2.
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 a hydrocarbon chain that may be a straight chain or branched chain, containing the indicated number of carbon atoms having at least one -C=C-, for example, a C2-C6 alkenyl group may have from 2 to 6 (inclusive) -C=C- atoms in it. Examples of C2-C6 alkenyl groups include, but are not limited to ethylene, prop-l-ene, but-1- ene, but-2-ene, pent-l-ene, pent-2-ene, hex-l-ene, hex-2-ene and the like.
The term "alkylamino" refers to alkyl group as defined above attached via amino linkage to the rest of the molecule. Representative examples of those groups are -NHCH3, - N(CH3)2 and the like.
The term "hydroxyl" refers to -OH group.
The term "amino acid" refers to a straight or branched hydrocarbon chain containing an amine group, a carboxylic acid group, and a side-chain that is specific to each amino acid and which is attached through the nitrogen atom of the amine group to the rest of the molecule by a single bond, e.g., alanine, valine, isoleucine, leucine, phenylalanine, or tyrosine.
The term "aminoalkyl" refers to any amino derivative of an alkyl radical more specifically dimethylamino ethyl and dimethylamino methyl.
The term "cycloalkyl" denotes a non-aromatic or saturated mono or multicyclic ring system of from 3 to about 12 carbon atoms, such as but are not limited to, 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 "aryl" refers to an aromatic radical having from 6 to 14 carbon atoms such as but are not limited to, 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.
The term "haloalkyl" refers to alkyl group (as defined above) is substituted with one or more halogens. A monohaloalkyl radical, for example, may have a chlorine, bromine, iodine or fluorine atom. Dihalo and polyhaloalkyl radicals may have two or more of the same or different halogen atoms. Examples of haloalkyl include, but are not limited to, chloromethyl, dichloromethyl, trichloromethyl, dichloroethyl, dichloropropyl, fluoromethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl, heptafluoropropyl, difluoro chloromethyl, dichloro fluoromethyl, difluoroethyl, difluoropropyl and the like.
The term "hydroxyalkyl" or "hydroxylalkyl" means alkyl substituted with one or more hydroxyl groups, wherein the alkyl groups are as defined above. Examples of "hydroxyalkyl" include but are not limited to hydroxymethyl, hydroxyethyl, hydroxypropyl, propan-2-ol and the like.
The terms "heterocyclyl" and "heterocyclic ring" and "heterocycle" 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 quaternized; 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, azetidinyl, 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, furanyl, tetrahydrofuranyl, tetrahydropyranyl, thienyl, benzothienyl, tetrahydrothiophenyl 1,1 -dioxide, thiamorpholinyl, thiomorpholinyl 1,1-dioxide, thiamorpholinyl sulfone, dioxaphospholanyl, 2-oxa-6-azaspiro[3.3]heptane, 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. "Substituted" refers to 1-3 substituents on the same position or on different positions with the same groups or different groups. 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 (=0), thio (=S), methyl sufonyl, isopropyl sufonyl, phenyl carbonyl, dimethylamino carbonyl, phenyl sulfonyl, benzyl sulfonyl, dimethylamino sufonyl, substituted or unsubstituted alkyl, haloalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclylalkyl ring.
The term "Stereoisomer" or "Stereoisomers" refer to compounds that differ in the chirality of one or more stereo centers. Stereoisomers include enantiomers and diastereomers.
The term "Tautomer" refer to alternate forms of a compound that differ in the position of a proton, such as but are not limited to, enol-keto, imine-enamine tautomers, or the like or the Tautomeric forms of heteroaryl groups containing a ring atom attached to both a ring - NH- moiety and a ring =N- moiety or the like such as but are not limited to, pyrazoles, imidazoles, benzimidazoles, triazoles, and tetrazoles.
The term "Regioisomer" or "Positional isomer" refer to that have the same carbon skeleton and the same functional groups but differ from each other in the location of the functional groups on or in the carbon chain.
The term "prodrug" denotes a derivative of a compound, which derivative, when administered to warm -blooded animals, e.g. humans, is converted into the compound (drug). The enzymatic and/or chemical hydrolytic cleavage of the compounds of the present invention occurs in such a manner that the proven drug form (parent carboxylic acid drug) is released, and the moiety or moieties split off remain nontoxic or are metabolized so that nontoxic metabolic products are produced. For example, a carboxylic acid group can be esterified, e.g., with a methyl group or ethyl group to yield an ester. When an ester is administered to a subject, the ester is cleaved, enzymatically or non-enzymatically, reductively, oxidatively, or hydrolytically, to reveal the anionic group. An anionic group can be esterified with moieties (e.g., acyloxymethyl esters) which are cleaved to reveal an intermediate compound which subsequently decomposes to yield the active compound. 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 (I), 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 stereo specific 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). Specifically, 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, peanut oil, olive oil, gelatin, lactose, terra alba, sucrose, dextrin, magnesium carbonate, sugar, amylose, magnesium stearate, talc, gelatin, agar, pectin, acacia, stearic acid, lower alkyl ethers of cellulose, silicic acid, fatty acids, fatty acid amines, fatty acid monoglycerides and diglycerides, fatty acid esters, and polyoxyethylene.
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 ampule, capsule, or sachet. 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 pharmaceutical compositions may be in conventional forms, for example, capsules, tablets, solutions, suspensions, injectables or products for topical application. Further, the pharmaceutical composition of the present invention may be formulated so as to provide desired release profile.
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 specifically suitable.
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. Exemplary 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 tableting techniques.
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, specifically aqueous solutions with the active compound dissolved in polyhydroxylated castor oil.
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. EP 0989862 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 purpose 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 available 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 below schemes. 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 stereoisomers 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 Betulin. 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 2010, 75, 1285-1288; Journal of organic chemistry 2000, 65, 3934-3940; Tetrahedron: asymmetry 2008, 19, 302-308; or Tetrahedron: asymmetry 2003, 14, 217-223.
Another embodiment of the present invention provides process for preparation of the compounds of general formula (I) are set forth in the below generalized schemes. One of skill in the art will recognize that below generalised schemes can be adapted to produce the compounds of general formula (I) and pharmaceutically acceptable salts of compounds of general formula (I) according to the present invention. Wherein all symbols/variables are as defined earlier unless otherwise stated.
General Synthetic Procedures:
Scheme-1:
Figure imgf000022_0001
The compounds of formula 4 (R4 and R5 are same as defined above) can be prepared as described in Scheme 1. The amino compounds of formula 1 can be reacted with the halo alcohol compounds of formula 2 to give the amino alcohol compounds of formula 3 in the presence of bases such as cesium carbonate (CS2CO3), sodium carbonate (Na2C03), potassium carbonate (K2C03) or the like in the presence of suitable solvents such as acetonitrile (ACN), acetone [(CH3)2CO] or the like. The amino alcohol compounds of formula 3 can be converted to the halo amino compounds of formula 4 in the presence of reagents such as thionyl chloride (SOCl2), oxalyl chloride (COCl)2 or the like in the presence of catalysts such as Ν,Ν-dimethyl formamide (DMF) or the like in the presence of suitable solvents such as dichloromethane (CH2C12), chloroform (CHC13) or the like.
Scheme-2:
Figure imgf000022_0002
The compounds of formula (I) (wherein, Ri, R3, R4 and R5 are same as defined above; Pi and P2 are protecting groups such as acetyl, benzyl or the like) can be prepared as described in Scheme 2. The C-28 acid compounds of formula 5 (as described in our PCT publication WO 2013/160810 A2) can be converted to the carbamate compounds of formula 6 in the presence of reagents such as diphenylphosphoryl azide (DPPA), (4- methoxyphenyl)methanol or the like in the solvents such as dichloromethane (DCM), 1,4- dioxane or the like in the presence of bases such as triethylamine (TEA), diisopropyl ethyl amine (DIPEA) or the like. The carbamate compounds of formula 6 can be converted to C-17 amine compounds of formula 7 in the presence of solvents such as 1,4-dioxane in HC1 or the like. The C-17 amine compounds of formula 7 can be reacted with the halo amino compounds of formula 4 to give the corresponding C-17 substituted amine compounds of formula 8 in the presence of bases such as potassium phosphate (K3P04), sodium phosphate (Na3P04) or the like in the solvents such as acetonitrile (ACN) or the like in the presence of catalysts such as potassium iodide (KI), sodium iodide (Nal) or the like. The C-3 protected compounds of formula 8 can be deprotected to give the C-3 hydroxy compounds of formula 9 in the presence of bases such as lithium hydroxide (LiOH), sodium hydroxide (NaOH) or the like in the solvents such as tetrahydrofuran (THF), methanol (MeOH), ethanol (EtOH), water or the like. The C-3 hydroxy compounds of formula 9 can be reacted with the compounds of formula 10 to give the C-3 protected compounds of formula 11 in the presence of catalysts such as Ν,Ν'-Dicyclohexylcarbodiimide (DCC), 4-Dimethylaminopyridine (DMAP) or the like in the solvents such as dichloromethane (DCM), chloroform (CHC13) or the like. The C-3 protected compounds of formula 11 can be deprotected to give the corresponding acid compounds of the present invention formula (I) in the presence of palladium on carbon (Pd/C) in hydrogen gas (¾ gas) or the like in the solvents such as ethylacetate (EtOAc), methanol (MeOH) or the like.
Scheme-3:
Figure imgf000023_0001
■» The compounds of formula (I) (wherein, Ri, R4 and R5 are same as defined above; Pi and P2 are protecting groups such as acetyl, benzyl or the like) can be prepared as described in Scheme 3. The C-28 acid compounds of formula 12 (as described in our PCT publication WO 2013/160810 A2) can be converted to the C-17 isocyanato compounds of formula 13 in the presence of reagents such as diphenylphosphoryl azide (DPPA) or the like in the presence of bases such as triethylamine (TEA) or the like in the solvents such as 1,4-dioxane or the like. The C-17 isocyanato compounds of formula 13 can be converted to the C-17 amine hydrochloride compounds of formula 14 in the presence of reagents such as cone. HC1 or the like in the solvents such as 1,4-dioxane or the like. The C-17 amine hydrochloride compounds of formula 14 can be converted to the C-17 protected amine compounds of formula 15 in the presence of reagents such as di-tert-butyl dicarbonate [(Boc)20] or the like in the presence of bases such as sodium bicarbonate (NaHC03) or the like in the solvents such as 1,4-dioxane: H20 or the like. The C-3 hydroxy compounds of formula 15 can be protected with the compounds of formula 16 to give the C-3 protected compounds of formula 17 in the presence of catalysts such as Ν,Ν'-Dicyclohexylcarbodiimide (DCC), 4- Dimethylaminopyridine (DMAP) or the like in the solvents such as dichloromethane (DCM) or the like. The C-17 protected amine compounds of formula 17 can be converted to the C-17 amine trifluoroacetic acid compounds of formula 18 in the presence of reagents such as trifluoro acetic acid (TFA) or the like in the solvents such as dichloromethane (DCM) or the like. The C-17 amine trifluoroacetic acid compounds of formula 18 can be reacted with the halo amino compounds of formula 4 to give the corresponding C-17 substituted amine compounds of formula 19 in the presence of bases such as potassium phosphate (K3P04) or the like in the solvents such as acetonitrile (ACN) or the like in the presence of catalysts such as potassium iodide (KI) or the like. The C-3 protected compounds of formula 19 can be deprotected to give the corresponding acid compounds of the present invention formula (I) in the presence of reagents such as palladium acetate [Pd(OAc)2], triethylsilylhydride (Et3SiH) or the like in the solvents such as tetrahydrofuran (THF) or the like.
Abbreviations: The abbreviations used in the entire specification may be summarized herein below with their particular meaning: 1H NMR (Proton Nuclear Magnetic Resonance); Hz (hertz); MHz (megahertz); CDC1 (Deuterated chloroform); DMSO-d6 (Deuterated Dimethylsulfoxide); DMSO (Dimethylsulfoxide); δ (delta); ppm (parts per million); s (singlet); d (doublet); m (multiplet); q (quartet); J (coupling constant); ml or mL (milliliter); °C (degree Celsius); mol (mole(s)); mmol (millimole(s)); M (molar); N (Normal); mg (milligram(s)); g (gram(s)); mm (millimeter(s)); DIPEA (Ν,Ν-Diisopropylethylamine); % (percentage); EtOH (ethanol); EtOAc (Ethyl acetate); H or H2 (hydrogen); HC1 (Hydrochloric acid); h or hr (hours); HPLC (High-performance liquid chromatography); ESI-MS (Electrospray ionization mass spectrometry); m/z (mass-to-charge ratio); (M+H)+ (parent mass spectrum peak plus H+); (M+Na)+ (parent mass spectrum peak plus sodium"1"); min (Minutes); mM (millimolar); NaOH (Sodium hydroxide); N2 (Nitrogen); TEA (triethylamine); TLC (Thin Layer Chromatography); THF (Tetrahydrofuran); CH3CN (acetonitrile); H20 (water); tert (tertiary), TFA/CF3COOH (Trifluoro acetic acid); t (triplet); IC (Inhibitory concentration), nM (Nano molar); pH (Pouvoir hydrogen); (Boc)20 (di-tert- butyl dicarbonate); DCC (Dicyclohexyl carbodimide), K2C03 (Potassium Carbonate), DCM or CH2C12 (dichloromethane); KI (Potassium iodide), DMF (N,N-dimethylformamide); DMAP (4-(Dimethylamino)pyridine); eq (equivalent); Ltr or L (Liter(s)); AcOH (Acetic acid); ABq (AB quartet); NaHC03 (Sodium bicarbonate); Na2S04 (Sodium sulfate); KOH (Potassium hydroxide); MeOH (methanol); EDCI (l-Ethyl-3-(3- dimethylaminopropyl)carbodiimide); HOBt (1-Hydroxybenzotriazole); RB flask (round bottom flask).
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: Preparation of 4-(2-chloroethyl)thiomorpholine 1,1 -dioxide:
Figure imgf000025_0001
Step 1: Synthesis of4-(2-hydroxyethyl)thiomorpholine 1,1-dioxide:
Figure imgf000025_0002
To a stirred solution of 2-bromoethan-l-ol (11.78 mL, 165.92 mmol, 7.0 eq) in acetonitrile (68 ml) was added potassium carbonate (9.8 g, 71.10 mmol, 3.0 eq). The reaction mixture was stirred for about 30 minutes at room temperature then added thiomorpholine 1,1- dioxide (3.2 g, 23.70 mmol, 1.0 eq). The reaction mixture was refluxed for overnight. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated to get crude residue which was purified by column chromatography by using 3% MeOH in DCM as an eluent to afford the desired compound (2.5 g, yield: 60.0%) as a brown colour liquid. 1H NMR (DMSO-d6, 300 MHz): δ 4.50 (t, 1H), 3.51 (q, 2H), 3.07 (m, 4H), 2.95 (m, 4H) and 2.58 (t, 2H); Mass: [M+H]+ 180.19 (10%).
Step 2: Synthesis of4-(2-chloroethyl)thiomorpholine 1,1-dioxide:
To a stirred solution of 4-(2-hydroxyethyl)thiomorpholine 1,1-dioxide (step 1, 2.5 g, 13.88 mmol, 1.0 eq) in DCM (25 ml) at 0 °C then added thionyl chloride (5.06 mL, 69.44 mmol, 5.0 eq) followed by DMF (Cat.). The reaction mixture was heated to 40 °C for overnight. After completion of the reaction (monitored by TLC), the solvent was evaporated in vacuo providing a crude residue was diluted with DCM and washed with saturated sodium bicarbonate solution. Organic layer was concentrated in vacuo to give crude residue which was purified by column chromatography by using 3% MeOH and DCM as an eluent to afford the desired compound (2.0 g, yield: 74.0%) as a white solid. 1H NMR (DMSO-d6, 300 MHz): δ 3.70 (t, 2H), 3.08 (m, 4H), 3.01 (m, 4H) and 2.87 (t, 2H); Mass: [M+H]+ 198.10 (30%). Intermediate 2: Preparation of 4-(2-chloroethyl)morpholine:
Figure imgf000026_0001
Step 1: Synthesis of 2-morpholinoethan- -ol.
Figure imgf000026_0002
To a stirred solution of 2-bromoethan-l-ol (11.78 mL, 165.92 mmol, 7.0 eq) in acetonitrile (68 ml) was added potassium carbonate (9.8 g, 71.10 mmol, 3.0 eq). The reaction mixture was stirred for about 30 minutes at room temperature then added morpholine (3.2 g, 23.70 mmol, 1.0 eq). The reaction mixture was refluxed for overnight. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated to get crude residue which was purified by column chromatography by using 3% MeOH in DCM as an eluent to afford the desired compound (2.5 g, yield: 60.0%) as a brown colour liquid. 1H NMR (DMSO-d6, 300 MHz): δ 4.37 (s, 1H), 3.56 (m, 4H), 3.49 (m, 2H) and 2.38-2.33 (m, 6H); Mass: [M+H]+ 131.98 (80%).
Step 2: Synthesis of 4-(2-chloroethyl)morpholine: To a stirred solution of 2-morpholinoethan-l-ol (step 1, 2.5 g, 13.88 mmol, 1.0 eq) in DCM (25 ml) at 0 °C then added thionyl chloride (5.06 mL, 69.44 mmol, 5.0 eq) followed by DMF (Cat.). The reaction mixture was heated to 40 °C for overnight. After completion of the reaction (monitored by TLC), the solvent was evaporated in vacuo providing a crude residue, which was diluted with DCM and washed with saturated sodium bicarbonate solution. Organic layer was concentrated under reduced preesure gave crude residue which was purified by column chromatography by using 3% MeOH in DCM as an eluent to afford the desired compound (2.0 g, yield: 74.0%) as a colour less liquid. 1H NMR (DMSO-d6, 300
MHz): δ 3.69 (t, J = 6.9 Hz, 2H), 3.57 (m, J = 4.5 Hz, 4H), 2.64 (t, J = 6.9 Hz, 2H) and 2.43 (t, J = 4.5 Hz, 4H); Mass: [M+H]+ 149.95 (10%).
Intermediate 3: Preparation of l-(2-chloroeth l)-4-(methylsulfonyl)piperazine:
Figure imgf000027_0001
Step 1: Synthesis of 2-(4-(methylsulfonyl)piperazin-l -yl)ethan-l -ol:
Figure imgf000027_0002
To a stirred solution of potassium carbonate (10.09 g, 73.17 mmol, 3.0 eq) in acetonitrile (60 mL) was added 2-bromoethan-l-ol (6.9 mL, 97.56 mmol, 4.0 eq). The reaction mixture was stirred for about 30 minutes at room temperature then added 1- (methylsulfonyl)piperazine (4.0 g, 24.39 mmol, 1.0 eq). The reaction mixture was refluxed for overnight. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated to get crude residue which was purified by column chromatography by using 3% MeOH in DCM as an eluent to afford the desired compound (2.5 g, yield: 49.0%) as a brown colour liquid. 1H NMR (DMSO-d6, 300 MHz): δ 4.41 (bs, 2H), 3.52 (m, 2H), 3.39 (s, 3H), 3.10 (m, 3H), 2.89-2.85 (m, 2H) and 2.51-2.40 (m, 4H); Mass: [M+H]+ 208.71 (100%). Step 2: Synthesis of 1 -(2-chloroethyl)-4-(methylsulfonyl)piperazine:
To a stirred solution of 2-(4-(methylsulfonyl)piperazin-l-yl)ethan-l-ol (step 1, 2.5 g, 12.02 mmol, 1.0 eq) in DCM (25 ml) at 0 °C then added thionyl chloride (4.38 mL, 60.10 mmol, 5.0 eq) followed by DMF (Cat.). The reaction mixture was heated to 40 °C for overnight. After completion of the reaction (monitored by TLC), the solvent was evaporated in vacuum providing a crude residue which was diluted with DCM and washed with saturated sodium bicarbonate solution. Organic layer was concentrated in vacuum gave the crude residue which was purified by column chromatography by using 2% MeOH in DCM as an eluent to afford the desired compound (1.2 g, yield: 44.0%) as a brown colour liquid. 1H NMR (DMSO-d6, 300 MHz): δ 3.71 (t, J = 6.6 Hz, 2H), 3.11 (t, J = 4.8 Hz, 4H), 2.887 (s, 3H), 2.71 (t, J = 6.9 Hz, 2H) and 2.50 (m, 4H); Mass: [M+H]+ 226.65 (100%).
Intermediate 4: Preparation of Synthesi -(2-chloroethyl)-4,4-difluoropiperidine:
Figure imgf000028_0001
Step 1: Synthesis of tert-butyl 4-oxopiperidine-l-carboxylate:
Figure imgf000028_0002
To a stirred solution of piperidin-4-one.hydrochloride (10.0 g, 65.09 mmol, 1.0 eq) in THF (100 ml) and water (100 mL) was added sodium bicarbonate (16.40 g, 195.29 mmol, 3.0 eq) at 10 °C followed by (Boc)20 (15.6 g, 71.60 mmol, 1.1 eq). The reaction mixture was stirred at room temperature for overnight. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture was diluted with water and extracted with DCM. The combined organic layers were washed with water, brine solution and was dried over Na2S04. The organic layer was concentrated to get the crude residue which was purified by column chromatography by using 30% EtOAc and hexane as an eluent to obtain the desired product (8.5 g, yield: 65.0%) as a white solid. 1H NMR (DMSO-d6, 300 MHz): δ 3.62 (m, 4H), 2.36 (m, 4H) and 1.42 (s, 9H); Mass: [M+H] 200.37 (10%).
Step 2: Synthesis of tert-butyl 4,4-difluoropi eridine-l -carboxylate:
Figure imgf000028_0003
To a stirred solution of tert-butyl 4-oxopiperidine-l-carboxylate (step 1, 6.0 g, 30.15 mmol, 1.0 eq) in DCM (60 mL) was added diethylaminosulfmtrifiuoride (DAST) (5.97 mL, 45.22 mmol, 1.5 eq) at 0 °C. The reaction mixture was stirred at same temperature for about 6 hours. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture was poured into ice cold water and extracted with DCM. The organic layer was washed with water, brine solution and the organic layer was dried with Na2S04. The filtrate was concentrated to get the crude residue which was purified by column chromatography by using 10% EtOAc and hexane as an eluent to obtain the desired product (6.0 g, yield: 90.0%) as a white solid. 1H NMR (DMSO-d6, 300 MHz): δ 3.45-3.41 (m, 4H), 1.98-1.85 (m, 4H) and 1.40 (s, 9H); Mass: [M+H]+ 222.53 (20%).
Step 3: Synthesis of 4,4-difluoropiperidine. HCl salt:
Figure imgf000029_0001
To a tert-butyl 4,4-difluoropiperidine- 1-carboxylate (step 2, 6.0 g, 27.15 mmol, 1.0 eq) was added dioxane hydrochloride (60 ml). The reaction mixture was stirred for about 2 hours. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture was concentrated gave the hydrochloride salt product (4.2 g) as a white solid. 1H NMR (DMSO-d6, 300 MHz): δ 3.22-3.18 (m, 4H) and 2.31-2.18 (m, 4H); Mass: [M+H]+ 121.85 (100%).
Step 4: Synthesis of 2-(4,4-difluoropiperidin-l -yl)ethan-l -ol:
Figure imgf000029_0002
To a stirred solution of 2-bromoethan-l-ol (9.5 mL, 133.75 mmol, 5.0 eq) in acetonitrile (42 ml) was added potassium carbonate (11.07 g, 80.25 mmol, 3.0 eq). The reaction mixture was stirred for about 30 minutes at room temperature then added 4,4- difluoropiperidine. HCl salt (step 3, 4.2 g, 26.75 mmol, 1.0 eq) in acetonitrile (20 mL). The reaction mixture was refluxed for overnight. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture was cooled to room temperature, and filtered. Filtrate was concentrated to get the crude residue which was purified by column chromatography by using 2% MeOH and DCM as an eluent to obtain the desired product (3.0 g, yield: 68.0%) as a colour less liquid. 1H NMR (DMSO-d6, 300 MHz): δ 4.43 (m, 1H), 3.51-3.46 (m, 2H), 2.53-2.41 (m, 4H), 1.98-1.85 (m, 4H) and 1.98-1.90 (m, 2H); Mass: [M+H]+ 165.97 (30%).
Step 5: Synthesis of 1 -(2-chloroethyl)-4,4-difluoropiperidine:
To a stirred solution of 2-(4,4-difluoropiperidin-l-yl)ethan-l-ol (step 4, 3.8 g, 23.03 mmol, 1.0 eq) in DCM (38 mL) at 0 °C then added thionyl chloride (8.4 mL, 115.15 mmol, 5.0 eq) followed by DMF (Cat.). The reaction mixture was heated to 40 °C for overnight. After completion of the reaction (monitored by TLC), the solvent was evaporated in vacuum providing a crude residue was diluted with DCM and washed with saturated sodium bicarbonate solution. The organic layer was concentrated in vacuum gave the crude residue which was purified by column chromatography by using 30% EtOAc and hexane as an eluent to obtain the desired product (2.0 g, yield: 50.0%) as a brown colour liquid. 1H NMR (DMSO-d6, 300 MHz): δ 3.70 (t, 2H), 2.73 (t, 2H), 2.59-2.55 (m, 4H) and 1.99-1.91 (m, 4H); Mass: [M+H]+ 184.91 (10%).
Intermediate 5: Preparation of l-(2-chloroethyl)-4-(isopropylsulfonyl)piperazine:
Figure imgf000030_0001
Step 1: Synthesis of tert-butyl piperazine-l -carboxylate:
H
N
I
Boc
The solution of piperazine (100 g, 1176.04 mmol, 1.0 eq) in DCM (2 lit.) was cooled with ice bath then added Boc anhydride (117.7 mL, 529.4 mmol, 0.45 eq) in DCM (2 lit) drop wise. Then reaction mixture was stirred at same temperature for about 2 hours. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture was filtered, filtrate was washed with bicarbonate solution and the organic layer was dried with Na2S04. The organic layer was concentrated to get the crude residue which was purified by column chromatography by using 10% EtOAc and hexane as an eluent to obtain the desired product (80.0 g, yield: 37.0%) as a white solid. 1H NMR (DMSO-d6, 300 MHz): δ 3.62 (m, 4H), 2.36 (m, 4H) and 1.42 (s, 9H).
Step 2: Synthesis of tert-butyl 4-(isopropylsulfonyl)piperazine-l -carboxylate :
Figure imgf000030_0002
To a stirred solution of tert-butyl 4-oxopiperazine- 1 -carboxylate (step 1, 10.0 g, 53.76 mmol, 1.0 eq) in DCM (100 mL) was added propane-2-sulfonyl chloride (8.5 g, 59.14 mmol, 1.1 eq) followed by TEA (8.9 mL, 64.51 mmol, 1.2 eq) at room temperature and stirred for about 12 hours at same temperature. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture was diluted with water and extracted with DCM. The organic layer was washed with water, brine solution and was dried with Na2S04. The filtrate was concentrated to get the crude residue which was purified by column chromatography by using 30% EtOAc and hexane as an eluent to obtain the desired product (12.0 g, yield: 76.0%) as a white solid. 1H NMR (DMSO-d6, 300 MHz): δ 3.51-3.41 (m, 6H), 2.13-2.10 (m, 4H), 1.23-1.21 (d, 5H) and 1.40 (s, 9H); Mass: [M+H]+ 293.53 (60%). Step 3: Synthesis of 1 -(isopropylsulfonyl)piperazine. HCl salt:
Figure imgf000031_0001
A solution of tert-butyl 4-(isopropylsulfonyl)piperazine-l-carboxylate (step 2, 12.0 g, 36.58 mmol, 1.0 eq) in dioxane hydrochloride (120 ml) was stirred at room temperature for about 2 hours. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture was concentrated gave the hydrochloride salt product (7.8 g) as a white solid. 1H NMR (DMSO-d6, 300 MHz): δ 3.51-3.41 (m, 6H), 2.13-2.10 (m, 4H) and 1.23-1.21 (d, 6H); Mass: [M+H]+ 193.14 (100%).
Step 4: Synthesis of 2-(4-(isopropylsulfonyl)piperazin-l -yl)ethan-l -ol:
Figure imgf000031_0002
To a stirred solution of 2-bromoethan-l-ol (12.13 mL, 171.05 mmol, 5.0 eq) in acetonitrile (50 ml) was added potassium carbonate (14.16 g, 102.63 mmol, 3.0 eq) and the reaction mixture was stirred for about 30 minutes at room temperature then added 1- (isopropylsulfonyl)piperazine.HCl salt (step 3, 7.8 g, 34.21 mmol, 1.0 eq) in acetonitrile (28 mL). The reaction mixture was refluxed for overnight. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture was cooled to room temperature, and filtered. The filtrate was concentrated to get the crude residue which was purified by column chromatography by using 2% MeOH and DCM as an eluent to obtain the desired product (4.7 g, yield: 58.0%) as a colour less liquid. 1H NMR (DMSO-d6, 300 MHz): δ 4.40-4.37 (t, 1H), 3.52-3.46 (q, 2H), 3.36 (m, 1H), 3.22-3.19 (m, 4H), 2.45-2.41 (m, 6H) and 1.22-1.19 (d, 6H); Mass: [M+H]+ 236.92 (100%).
Step 5: Synthesis of l-(2-chloroethyl)-4-(isopropylsulfonyl)piperazine:
To a stirred solution of 2-(4-(isopropylsulfonyl)piperazin-l-yl)ethan-l-ol (step 4, 4.7 g, 19.91 mmol, 1.0 eq) in DCM (50 mL) at 0° C then added thionyl chloride (7.2 mL, 99.57 mmol, 5.0 eq) followed by DMF (Cat.). The reaction mixture was heated to 40 °C for overnight. After completion of the reaction (monitored by TLC), the solvent was evaporated in vacuum providing a crude residue was diluted with DCM and washed with saturated sodium bicarbonate solution. The organic layer was concentrated in vacuum gave the crude residue which was to purified by column chromatography by using 2% MeOH and DCM as an eluent to obtain the desired product (4.0 g, yield: 80.0%) as a brown colour liquid. 1H NMR (DMSO-d6, 300 MHz): δ 3.70-3.65 (t, 2H), 3.34-3.27 (m, 1H), 3.24-3.21 (m, 8H), 2.70-2.66 (t, 2H) and 1.22-1.20 (d, 6H); Mass: [M+H]+ 254.69 (80%).
Intermediate 6: Preparation of (4-(2-chloroeth l)piperazin-l-yl)(phenyl)methanone:
Figure imgf000032_0001
Step 1: Synthesis of tert-butyl piperazine- 1 -carboxylate:
Figure imgf000032_0002
To a stirred solution of piperazine (100 g, 1176.04 mmol, 1.0 eq) in DCM (2 lit.) was cooled with ice bath, then added Boc anhydride (117.7 mL, 529.4 mmol, 0.45 eq) in DCM (2 lit) drop wise. The reaction mixture was stirred at same temperature for about 2 hours. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture was filtered, filtrate was washed with bicarbonate solution and the organic layer was dried with Na2S04. The organic layer was concentrated to get crude the residue which was purified by column chromatography by using 10% EtOAc and hexane as an eluent to obtain the desired product (80.0 g, yield: 37.0%) as a white solid. 1H NMR (DMSO-d6, 300 MHz): δ 3.23 (t, 4H), 2.98 (s, 1H), 2.62 (t, 4H) and 1.39 (s, 9H); Mass: [M+H]+ 186.25 (50%).
Step 2: Synthesis of tert-butyl 4-benzoylpiperazine-l-carboxylate:
Figure imgf000032_0003
A solution of tert-butyl piperazine- 1 -carboxylate (10.0 g, 53.76 mmol, 1.0 eq) in DMF (80 mL) was treated sequentially with HOBt (12.33 g, 80.64 mmol, 1.5 eq) and EDCI (30.8 g, 161.28 mmol, 3.0 eq) and benzoic acid (7.2 g, 59.13 mmol, 1.1 eq). The suspension was stirred for about 15 minutes, then TEA (37.29 mL, 268.81 mmol, 5.0 eq) was added and the mixture was stirred for about 12 hours. The reaction mixture was quenched by pouring into 50 mL of DCM, water and extracting with DCM and washed with water, and a portion of brine. The solution was then dried over Na2S04, filtered and concentrated. The residue was purified by column chromatography by using 2% MeOH and DCM as an eluent to obtain the desired product (14.0 g, yield: 89.0%) as a white solid. 1H NMR (DMSO-d6, 300 MHz): δ 7.46-7.39 (m, 5H), 3.57 (t, 4H), 2.70 (t, 4H) and 1.40 (s, 9H); Mass: [M+H]+ 290.75 (20%). Step 3: Synthesis of ' phenyl(piperazin-l -yl)methanone. HCl salt:
Figure imgf000033_0001
A solution of tert-butyl 4-benzoylpiperazine-l-carboxylate (step 2, 14.0 g, 48.27 mmol, 1.0 eq) in dioxane hydrochloride (140 ml) was stirred at room temperature for about 2 hours. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture was concentrated gave the hydrochloride salt product (9.0 g) as a white solid. 1H NMR (DMSO-d6, 300 MHz): δ 9.38 (s, 1H), 7.46 (m, 5H), 3.68 (t, 4H) and 3.13 (t, 4H); Mass: [M+H]+ 191.33 (90%).
Step 4: Synthesis of (4-(2-hydroxyethyl)piperazin-l -yl)(phenyl)methanone:
Figure imgf000033_0002
To a stirred solution of 2-bromoethan-l-ol (13.44 mL, 189.47 mmol, 5.0 eq) in acetonitrile (50 ml) was added potassium carbonate (15.68 g, 113.68 mmol, 3.0 eq). The reaction mixture was stirred for about 30 minutes at room temperature then added phenyl(piperazin-l-yl)methanone.HCl salt (step 3, 7.2 g, 37.39 mmol, 1.0 eq) in acetonitrile (22 mL). The reaction mixture was refluxed for overnight. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated to get the crude residue which was purified by column chromatography by using 2% MeOH and DCM as an eluent to obtain the desired product (7.0 g, yield: 78.0%) as a colour less liquid. 1H NMR (DMSO-d6, 300 MHz): δ 7.45-7.35 (m, 5H), 4.48-4.43 (q, 2H), 3.59-3.47 (m, 2H), 3.32-3.20 (m, 5H) and 2.43-2.39 (m, 4H); Mass: [M+H]+ 235.37 (100%).
Step 5: Synthesis of (4-(2-chloroethyl)piperazin-l-yl)(phenyl)methanone:
To a stirred solution of (4-(2-hydroxyethyl)piperazin-l-yl)(phenyl)methanone (step 4, 7.0 g, 29.78 mmol, 1.0 eq) in DCM (70 mL) at 0 °C added thionyl chloride (10.87 mL, 148.93 mmol, 5.0 eq) followed by DMF (Cat.). The reaction mixture was heated to 40 °C and stirred for overnight. After completion of the reaction (monitored by TLC), the solvent was evaporated in vacuum providing a crude residue was diluted with DCM and washed with saturated sodium bicarbonate solution. The organic layer was concentrated in vacuum gave the crude residue which was purified by column chromatography by using 2% MeOH and DCM as an eluent to obtain the desired product (4.0 g, yield: 53.0%) as a brown colour liquid. 1H NMR (DMSO-d6, 300 MHz): δ 7.45-7.37 (m, 5H), 3.71-3.63 (q, 2H), 3.59-3.47 (m, 2H), 3.32-3.20 (m, 4H) and 2.43-2.39 (m, 4H). Mass: [M+H]+ 252.89 (100%).
Intermediate 7: Preparation of 4-(2-chloroethyl)-N,N-dimethylpiperazine-l -sulfonamide:
Figure imgf000034_0001
Step 1: Synthesis of tert-butyl piperazine-1 -carboxylate:
Figure imgf000034_0002
To a stirred solution of piperazine (100 g, 1176.04 mmol, 1.0 eq) in DCM (2 lit.) was cooled with ice bath, then added Boc anhydride (117.7 mL, 529.4 mmol, 0.45 eq) in DCM (2 lit) drop wise. Then reaction mixture was stirred at same temperature for about 2 hours. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture was filtered, filtrate was washed with bicarbonate solution and was dried over Na2S04. The organic layer was concentrated to get the crude residue which was purified by column chromatography by using 10% EtOAc in hexane as an eluent to obtain the desired compound (80.0 g, yield: 37.0%) as a white solid. 1H NMR (DMSO-d6, 300 MHz): δ 3.62 (m, 4H), 2.36 (m, 4H) and 1.42 (s, 9H); Mass: [M+H]+ 187.37 (70%).
Step 2: Synthesis of tert-butyl 4-(N,N-dimethylsulfamoyl)piperazine-l -carboxylate:
Boc-N N-S ,?
N— ' O N—
/
To a stirred solution of tert-butyl piperazine-1 -carboxylate (step 1, 10.0 g, 53.56 mmol, 1.0 eq) in DCM (100 mL) was added Ν,Ν-dimethylsulfamoyl chloride (6.3 mL, 59.13 mmol, 1.1 eq) followed by TEA (8.9 mL, 64.51 mmol, 1.2 eq) at room temperature and stirred for about 12 hours at same temperature. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture was diluted with water and extracted with DCM. The organic layer was washed with water, brine solution and was dried over Na2S04. Filtrate was concentrated to get the crude residue which was purified by column chromatography by using 30% EtOAc in hexane as an eluent to obtain the desired product (14.5 g, yield: 92.0%) as a white solid. 1H NMR (DMSO-d6, 300 MHz): δ 3.37-3.33 (m, 4H), 3.13-3.09 (m, 4H), 2.76 (s, 6H) and 1.40 (s, 9H); Mass: [M+H]+ 293.53 (60%). Step 3: Synthesis of N,N-dimethylpiperazine-l -sulfonamide. HCl salt: CIH.HN N-Sx
f d N—
/
A solution of tert-butyl 4-(N,N-dimethylsulfamoyl)piperazine-l-carboxylate (step 2, 14.5 g, 49.48 mmol, 1.0 eq) in dioxane hydrochloride (145 ml) was stirred at room temperature for about 2 hours. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture was concentrated gave the hydrochloride salt product (9.5 g) as a white solid. 1H NMR (DMSO-d6, 300 MHz): δ 9.37 (s, 1H), 3.38-3.34 (m, 4H), 3.15-3.11 (m, 4H) and 2.78 (s, 6H); Mass: [M+H]+ 193.91 (100%).
Step 4: Synthesis of 4-(2-hydroxyethy -N,N-dimethylpiperazine-l -sulfonamide:
Figure imgf000035_0001
To a stirred solution of 2-bromoethan-l-ol (17.53 mL, 247.77 mmol, 5.0 eq) in acetonitrile (50 ml) was added potassium carbonate (20.43 g, 148.66 mmol, 3.0 eq). The reaction mixture was stirred for about 30 minutes at room temperature then added N,N- dimethylpiperazine-1- sulfonamide. HQ salt (step 3, 7.8 g, 49.55 mmol, 1.0 eq) in acetonitrile (50 mL). The reaction mixture was refluxed for overnight. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture was cooled to room temperature, and filtered. The filtrate was concentrated to get the crude residue which was purified by column chromatography by using 2% MeOH in DCM as an eluent to obtain the desired product (8.0 g, yield: 68.0%) as a colour less liquid. 1H NMR (DMSO-d6, 300 MHz): δ 4.45 (t, 1H), 3.51-3.45 (m, 2H), 3.14-3.10 (m, 4H), 2.75 (s, 6H) and 2.46-2.38 (m, 6H); Mass: [M+H]+ 238.47 (80%).
Step 5: Synthesis of 4-(2-chloroethyl)-N,N-dimethylpiperazine-l -sulfonamide:
To a stirred solution of 4-(2-hydroxyethyl)-N,N-dimethylpiperazine-l-sulfonamide (step 4, 8.0 g, 33.75 mmol, 1.0 eq) in DCM (100 mL) at 0 °C then added thionyl chloride (12.32 mL, 168.75 mmol, 5.0 eq) followed by DMF (Cat.). The reaction mixture was heated to 40 °C for overnight. After completion of the reaction (monitored by TLC), the solvent was evaporated in vacuum providing a crude residue which was diluted with DCM and washed with saturated sodium bicarbonate solution. The organic layer was concentrated in vacuum gave the crude residue which was purified by column chromatography by using 2% MeOH in DCM as an eluent to obtain the desired product (4.0 g, yield: 46.0%) as a off white solid. 1H NMR (DMSO-d6, 300 MHz): δ 3.70-3.66 (t, 2H), 3.15-3.12 (m, 4H), 2.76 (s, 6H), 2.70-2.65 (t, 2H) and 2.50-2.84 (m, 4H); Mass: [M+H]+ 255.69 (80%). ntermediate 8: Preparation of 4-(2-chloroethyl)-N,N-dimethylpiperazine-l-carboxamide:
Figure imgf000036_0001
Step 1: Synthesis of tert-butyl piperazine-1 -carboxylate:
Figure imgf000036_0002
A solution of piperazine (100 g, 1176.04 mmol, 1.0 eq) in DCM (2 lit.) was cooled with ice bath, then added Boc anhydride (117.7 mL, 529.4 mmol, 0.45 eq) in DCM (2 lit) drop wise. The reaction mixture was stirred at same temperature for about 2 hours. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture was filtered, filtrate was washed with bicarbonate solution and was dried over Na2S04. The organic layer was concentrated to get the crude residue which was purified by column chromatography by using 10% EtOAc in hexane as an eluent to obtain the desired product (80.0 g, yield: 37.0%) as a white solid. 1H NMR (DMSO-d6, 300 MHz): 3.23 (t, 4H), 2.98 (s, 1H), 2.62 (t, 4H) and 1.39 (s, 9H); Mass: [M+H]+ 186.30 (100%).
Step 2: Synthesis of tert-butyl 4-(dimeth lcarbamoyl)piperazine-l -carboxylate:
Figure imgf000036_0003
To a stirred solution of tert-butyl piperazine-1 -carboxylate (step 1, 10.0 g, 53.76 mmol, 1.0 eq) in DCM (100 mL) was added dimethylcarbamic chloride (7.39 mL, 80.64 mmol, 1.5 eq) followed by TEA (11.18 mL, 80.64 mmol, 1.5 eq) at room temperature and stirred for about 12 hours at same temperature. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture was diluted with water and extracted with DCM. The organic layer was washed with water, brine solution and was dried over Na2S04. Filtrate was concentrated to get the crude residue which was purified by column chromatography by using 2% MeOH in DCM as an eluent to obtain the desired product (13.5 g, yield: 97.0%) as a white solid. 1H NMR (DMSO-d6, 300 MHz): δ 3.57-3.52 (m, 4H), 3.26-3.20 (m, 4H) and 1.07 (s, 6H) and 1.05 (s, 9H); Mass: [M+H-boc]+ 158.30 (100%).
Step 3: Synthesis of N,N-dimethylpipera ine-l -carboxamide. HCl salt:
Figure imgf000036_0004
A solution of tert-butyl 4-(dimethylcarbamoyl)piperazine-l-carboxylate (step 2, 13.5 g, 52.52 mmol, 1.0 eq) in dioxane hydrochloride (135 ml) was stirred at room temperature for about 2 hours. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture was concentrated gave the hydrochloride salt product (8.2 g) as a white solid. 1H NMR (DMSO-d6, 300 MHz): δ 3.33-3.29 (t, 4H), 3.06-3.02 (m, 1H), 2.73 (m, 4H) and 1.40 (s, 6H); Mass: [M+H]+ 158.11 (100%).
Step 4: Synthesis of 4-(2-hydroxyethy -N,N-dimethylpiperazine-l -carboxamide:
Figure imgf000037_0001
To a stirred solution of 2-bromoethan-l-ol (18.56 mL, 262.81 mmol, 5.0 eq) in acetonitrile (50 ml) was added potassium carbonate (21.67 g, 157.68 mmol, 3.0 eq). The reaction mixture was stirred for about 30 minutes at room temperature then added N,N- dimethylpiperazine- 1 -carboxamide. HC1 salt (step 3, 6.36 g, 52.56 mmol, 1.0 eq) in acetonitrile (50 mL). The reaction mixture was refluxed for overnight. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture was cooled to room temperature, and filtered. The filtrate was concentrated to get the crude residue which was purified by column chromatography by using 4% MeOH in DCM as an eluent to obtain the desired product (7.0 g, yield: 66.0%) as a colour less liquid. 1H NMR (DMSO-d6, 300 MHz): δ 4.45 (m, 1H), 3.52-3.46 (m, 2H), 3.39 (m, 4H), 3.09-3.05 (m, 2H), 2.71 (s, 6H) and 2.40-2.37 (m, 4H); Mass: [M+H]+ 201.38 (100%).
Step 5: Synthesis of 4-(2-chloroethyl)-N,N-dimethylpiperazine-l -carboxamide:
To a stirred solution of 4-(2-hydroxyethyl)-N,N-dimethylpiperazine-l -carboxamide (step 4, 7.0 g, 34.82 mmol, 1.0 eq) in DCM (100 mL) at 0 °C added thionyl chloride (12.71 mL, 174.12 mmol, 5.0 eq) followed by DMF (Cat.). The reaction mixture was heated to 40 °C and stirred for overnight. After completion of the reaction (monitored by TLC), the solvent was evaporated in vacuum providing a crude residue which was diluted with DCM and washed with saturated sodium bicarbonate solution. The organic layer was concentrated in vacuum gave the crude residue which was purified by column chromatography by using 2% MeOH in DCM as an eluent to obtain the desired product (2.5 g, yield: 33.0%) as a brown colour liquid. 1H NMR (DMSO-d6, 300 MHz): δ 4.66-4.40 (m, 2H), 3.71-3.66 (m, 2H), 3.10-3.07 (m, 4H), 2.72 (s, 6H) and 2.67-2.43 (m, 4H); Mass: [M+H]+ 219.92 (100%). Intermediate 9: Preparation of l-(2-chloroethyl)-4-(phenylsulfonyl)piperazine:
Figure imgf000038_0001
Step 1: Synthesis of tert-butyl piperazine-1 -carboxylate:
Figure imgf000038_0002
To a stirred solution of piperazine (100 g, 1176.04 mmol, 1.0 eq) in DCM (2 lit was cooled with ice bath, then added Boc anhydride (117.7 niL, 529.4 mmol, 0.45 eq) in DCM (2 lit) drop wise. The reaction mixture was stirred at same temperature for about 2 hours. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture was filtered, filtrate was washed with bicarbonate solution and was dried over Na2S04. The organic layer was concentrated to get the crude residue which was purified by column chromatography by using 10% EtOAc in hexane as an eluent to obtain the desired product (80.0 g, yield: 37.0%) as a white solid. 1H NMR (DMSO-d6, 300 MHz)
4H), 2.36 (m, 4H) and 1.42 (s, 9H); Mass: [M+H]+ 187.37 (10%).
Step 2: Synthesis of tert-butyl 4-(phenylsulfonyl)piperazine-l -carboxylate:
Figure imgf000038_0003
To a stirred solution of tert-butyl piperazine-1 -carboxylate (step 1, 10.0 g, 53.76 mmol, 1.0 eq) in DCM (100 mL) was added benzenesulfonyl chloride (7.62 mL, 59.13 mmol, 1.1 eq) followed by TEA (8.9 mL, 64.51 mmol, 1.2 eq) at room temperature and stirred for about 12 hours at same temperature. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture was diluted with water and extracted with DCM. The organic layer was washed with water, brine solution and was dried over Na2S04. Filtrate was concentrated to get the crude residue which was purified by column chromatography by using 5% EtOAc in hexane as an eluent to obtain the desired product
(14.0 g, yield: 80.0%) as a white solid. 1H NMR (DMSO-d6, 300 MHz): δ 7.77-7.63 (m, 5H), 3.40-4.37 (m, 4H), 2.85-2.82 (m, 4H) and 1.33 (m, 9H); Mass: [M+H]+ 327.03 (20%).
Step 3: Synthesis of 1 -(phenylsulfonyl)piperazine. HCl salt:
Figure imgf000038_0004
A solution of tert-butyl 4-(phenylsulfonyl)piperazine-l-carboxylate (step 2, 14.0 g, 42.9 mmol, 1.0 eq) in dioxane hydrochloride (112 niL). The reaction mixture was stirred at room temperature for about 2 hours. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture was concentrated gave the hydrochloride salt product (8.0 g) as a white solid. 1H NMR (DMSO-d6, 300 MHz): δ 9.18 (s, 1H), 7.81- 7.68 (m, 5H) and 3.14 (m, 8H); Mass: [M+H]+ 226.14 (100%).
Step 4: Synthesis of 2-(4-(phenylsulfonyl)piperazin-l -yl)ethan-l -ol:
Figure imgf000039_0001
To a stirred solution of 2-bromoethan-l-ol (13.2 mL, 179.6 mmol, 5.0 eq) in acetonitrile (81 mL) was added potassium carbonate (14.8 g, 107.7 mmol, 3.0 eq). The reaction mixture was stirred for about 30 minutes at room temperature then added 1- (phenylsulfonyl)piperazine.HCl salt (step 3, 8.0 g, 35.9 mmol, 1.0 eq) in acetonitrile (28 mL). The reaction mixture was refluxed for overnight. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture was cooled to room temperature, and filtered. Filtrate was concentrated to get the crude residue which was purified by column chromatography by using 2% MeOH in DCM as an eluent to obtain the desired product (8.5 g, yield: 88.0%) as a colour less liquid. 1H NMR (DMSO-d6, 300 MHz): δ 7.74-7.66 (m, 5H), 4.38 (t, 1H), 3.43-3.37 (t, 2H), 2.86-2.84 (m, 4H), 2.44-2.60 (m, 2H) and 2.52-2.50 (m, 4H); Mass: [M+H]+ 270.66 (100%).
Step 5: Synthesis of 1 -(2-chloroethyl)-4-(phenylsulfonyl)piperazine:
To a stirred solution of 2-(4-(phenylsulfonyl)piperazin-l-yl)ethan-l-ol (step 4, 8.5 g, 31.4 mmol, 1.0 eq) in DCM (85 mL) at 0 °C then added thionyl chloride (11.4 mL, 157.0 mmol, 5.0 eq) followed by DMF (Cat.). The reaction mixture was heated to 40 °C and stirred for overnight. After completion of the reaction (monitored by TLC), the solvent was evaporated in vacuum providing a crude residue which was diluted with DCM and washed with saturated sodium bicarbonate solution. The organic layer was concentrated in vacuum gave the crude residue which was purified by column chromatography by using 2% MeOH in DCM as an eluent to obtain the desired product (7.0 g, yield: 78.0%) as a white solid. 1H NMR (DMSO-d6, 300 MHz): δ 7.75-7.67 (m, 5H), 3.63-3.58 (t, 2H), 2.86-2.84 (m, 4H), 2.44-2.60 (m, 2H) and 2.52-2.50 (m, 4H); Mass: [M+H]+ 289.06 (30%).
Intermediate 10: Preparation of l-(benzylsulfonyl)-4-(2-chloroethyl)piperazine:
Figure imgf000040_0001
Step 1: Synthesis of tert-butyl piperazine-1 -carboxylate:
Figure imgf000040_0002
To a stirred solution of piperazine (100 g, 1176.04 mmol, 1.0 eq) in DCM (2 lit.) was cooled with ice bath, then added Boc anhydride (117.7 mL, 529.4 mmol, 0.45 eq) in DCM (2 lit) drop wise. The reaction mixture was stirred at same temperature for about 2 hours. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture was filtered, filtrate was washed with bicarbonate solution and was dried over Na2S04. The organic layer was concentrated to get the crude residue which was purified by column chromatography by using 10% EtOAc in hexane as an eluent to obtain the desired product (80.0 g, yield: 37.0%) as a white solid. 1H NMR (DMSO-d6, 300 MHz): δ 3.62 (m, 4H), 2.36 (m, 4H) and 1.42 (s, 9H); Mass: [M+H]+ 187.37 (10%).
Step 2: Synthesis of tert-butyl 4-(ben lsulfonyl)piperazine-l -carboxylate:
Figure imgf000040_0003
To a stirred solution of tert-butyl piperazine-1 -carboxylate (step 1, 10.0 g, 53.7 mmol,
1.0 eq) in DCM (100 mL) was added phenylmethanesulfonyl chloride (11.2 mL, 59.1 mmol,
1.1 eq) followed by TEA (8.9 mL, 64.5 mmol, 1.2 eq) at room temperature and stirred for about 12 hours at same temperature. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture was diluted with water and extracted with DCM. The organic layer was washed with water, brine solution and was dried over Na2S04. Filtrate was concentrated to get the crude residue which was purified by column chromatography by using 1% EtOAc in hexane as an eluent to obtain the desired product (13.0 g, yield: 71.0%) as a white solid. 1H NMR (DMSO-d6, 300 MHz): δ 7.39-7.37 (m, 5H), 4.42 (s, 2H), 3.40-4.37 (m, 4H), 3.09 (m, 4H) and 1.40 (m, 9H); Mass: [M+H]+ 340.88 (30%).
Step 3: Synthesis of 1 -(benzylsulfon l)piperazine. HCl salt:
Figure imgf000040_0004
A solution of tert-butyl 4-(benzylsulfonyl)piperazine-l-carboxylate (step 2, 13.0 g, 38.2 mmol, 1.0 eq) in dioxane hydrochloride (104 niL) was stirred at room temperature for about 2 hours. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture was concentrated gave the hydrochloride salt product (7.7 g, yield: 84.0%) as a white solid. 1H NMR (DMSO-d6, 300 MHz): δ 9.33 (S, 1H), 7.40-7.37 (m, 5H), 4.54 (s, 2H), 3.3-3.32 (t, 4H) and 3.07-3.04 (m, 4H); Mass: [M+H]+ 240.14 (20%).
Step 4: Synthesis of 2-(4-(benzylsulfonyl)piperazin-l -yl)ethan-l -ol:
Figure imgf000041_0001
To a stirred solution of 2-bromoethan-l-ol (11.8 mL, 160.4 mmol, 5.0 eq) in acetonitrile (77 mL) was added potassium carbonate (13.2 g, 96.2 mmol, 3.0 eq). The reaction mixture was stirred for about 30 minutes at room temperature then added 1- (benzylsulfonyl)piperazine.HCl salt (step 3, 7.7 g, 32.0 mmol, 1.0 eq) in acetonitrile (20 mL). The reaction mixture was refluxed for overnight. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture was cooled to room temperature and filtered. Filtrate was concentrated to get the crude residue which was purified by column chromatography by using 2% MeOH in DCM as an eluent to obtain the desired product (9.0 g, yield: 98.0%) as a colour less liquid. 1HNMR (DMSO-d6, 300 MHz): δ 7.39-7.36 (m, 5H), 4.43 (m, 3H), 3.50-3.44 (t, 2H), 3.09-3.06 (m, 4H) and 2.41-2.36 (m, 6H); Mass: [M+H]+ 284.98 (100%).
Step 5: Synthesis of 1 -(benzylsulfonyl)-4-(2-chloroethyl)piperazine:
To a stirred solution of 2-(4-(benzylsulfonyl)piperazin-l-yl)ethan-l-ol (step 4, 9.0 g, 31.6 mmol, 1.0 eq) in DCM (90 mL) at 0 °C then added thionyl chloride (11.5 mL, 158.4 mmol, 5.0 eq) followed by DMF (Cat.). The reaction mixture was heated to 40 °C and stirred for overnight. After completion of the reaction (monitored by TLC), the solvent was evaporated in vacuum providing a crude residue which was diluted with DCM and washed with saturated sodium bicarbonate solution. The organic layer was concentrated in vacuum gave the crude residue which was purified by column chromatography by using 2% MeOH in DCM as an eluent to obtain the desired product (6.0 g, yield: 62.0%) as a white solid. 1H
NMR (DMSO-d6, 300 MHz): δ 7.40-7.39 (m, 5H), 4.42 (s, 2H), 3.69-3.64 (t, 2H), 3.09-3.07 (m, 4H), 2.67-2.63 (m, 2H) and 2.47-2.43 (m, 4H); Mass: [M+H]+ 303.27 (100%). Intermediate 11: Synthesis of (lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)-3a-amino- 5a,5b,8,8, 1 la-penta methyl- l-(l-methylcvclopropyl)icosahvdro-lH-cvclopentaralchrvsen-9- yl acetate. HC1 salt:
Figure imgf000042_0001
Step 1: Synthesis of (lR,3aS,5aR,5bR, 7aR,9S,llaR,llbR,13aR,13bR)-3a-((((4-methoxy benzyl )oxy )carbonyl)amino)-5a,5b, 8,8,1 la-pentamethyl-1 -( 1 -methylcyclopropyl)icosahydro- lH-cyclopenta[a ]chrysen-9-yl acetate:
Figure imgf000042_0002
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-(l-methylcyclopropyl)icosahydro-3aH-cyclopenta[a]chrysene- 3a-carboxylic acid (prepared as described in WO 2013/160810 A2, 20.0 g, 39.06 mmol, 1.0 eq) in DCM (200 mL, 10 vol.) then added diphenylphosphoryl azide (11.4 mL, 50.70 mmol, 1.3 eq) followed by triethylamine (13.54 mL, 97.65 mmol, 2.5 eq). The reaction mixture was refluxed for about 3 hours and then added (4-methoxyphenyl)methanol (5.3 mL, 39.06 mmol, 1.0 eq). The reaction mixture was continued refluxing under nitrogen atmosphere and stirred for about 4 hours. After completion of the reaction (monitored by TLC), the solvent was evaporated in vacuo providing a crude residue which was recrystallized in acetonitrile to obtain the desired product (17.8 g, yield: 70.0%) as a white solid. 1H NMR (DMSO-d6, 300 MHz): δ 7.32 (d, = 8.7 Hz, 2H), 6.97 (d, = 8.7 Hz, 2H), 4.35 (s, 2H), 3.76 (s, 3H), 2.08 (m, 2H), 1.99 (s, 3H), 1.85-1.51 (m, 10H), 1.47-1.03 (m, 11H), 0.95-0.80 (m, 22H), 0.39 (t, 2H) and 0.29 (t, 2H); Mass: [M+H]+ 648.43 (50%).
Step 2: Synthesis of (lR,3aS,5aR,5bR, 7aR,9S,llaR,llbR,13aR,13bR)-3a-amino-5a,5b,8,8, 1 la-penta methyl-1 -(1 -methylcyclopropyl)icosahydro-lH-cyclopenta[a] chrysen-9-yl acetate. HCl salt:
To a stirred solution of (lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)-3a-((((4- methoxybenzyl)oxy)carbonyl)amino)-5a,5b,8,8,l la-pentamethyl-l-(l- methylcyclopropyl)icosahydro-lH-cyclopenta[a]chrysen-9-yl acetate (step 1, 1.5 g, 2.12 mmol, 1.0 eq) in 1,4-dioxane.HCl (15 ml) and stirred for overnight. TLC indicated starting material was consumed and the desired product was observed. Then the reaction mixture was evaporated directly under vacuum to give the residue. The residue was recrystallized by acetonitrile gave the pure desired compound (1.05 g, yield: 91.0%) as a white solid. 1H NMR (DMSO-d6, 300 MHz): δ 7.53 (s, 2H), 4.50 (q, 1H), 2.08-1.93 (m, 5H), 1.85-1.51 (m, 10H), 1.47-1.03 (m, 11H), 0.95-0.80 (m, 20H), 0.39 (t, 2H) and 0.29 (t, 2H); Mass: [M+H]+ 484.43 (50%).
Intermediate 12: Preparation of l-((lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)-3a- amino-5a,5b,8,8 J la-pentamethyl-l-(prop-l-en-2-yl)icosahvdro-lH-cvclopentaralchrvsen-9- yl) 3-benzyl (lS,3R)-2,2-dimethylcvclobutane-l 3-dicarboxylate trifluoroacetic acid salt:
Figure imgf000043_0001
Step 1: Synthesis of (lR,3aS,5aR,5bR, 7aR,9S,llaR,llbR,13aR,13bR)-3a-isocyanato-5a,5b,8, 8,lla-pentamethyl-l-(prop-l-en- -yl)icosahydro-lH-cyclopenta[a]chrysen-9-yl acetate:
Figure imgf000043_0002
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-3aH-cyclopenta[a]chrysene-3a- carboxylic acid (prepared as described in WO 2013/160810 A2, 10.0 g, 20.1 mmol) in 1,4- dioxane (100 mL) were added TEA (8.4 ml, 60.3 mmol) and diphenylphosphoryl azide (8.6 ml, 40.2 mmol). The reaction mixture was heated to reflux and continued for about 3 hours. After completion of the reaction (monitored by TLC), the reaction mixture was cooled to room temperature and the solvent was evaporated in vacuo providing a crude residue, which was diluted with DCM, washed with water, brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to give the residue. The crude product was purified via silica gel column chromatography using EtOAc in n-hexane (10:90) as an eluent to afford the desired compound (9.0 g, yield: 90%) as a white solid. 1H NMR (CDC13, 300 MHz): δ 4.74 (s, 1H), 4.63 (s, 1H), 4.49-4.44 (m, 1H), 2.58-2.49 (m, 1H), 2.15-2.02 (m, 1H), 2.04 (s, 3H), 1.88-1.05 (m, 27H), 0.99-0.77 (m, 14H). Step 2: Synthesis of (lR,3aS,5aR,5bR, 7aR,9S,llaR,llbR,13aR,13bR)-3a-amino-
5a,5b,8,8,lla-pentamethyl-l-(prop-l-en-2-yl)icosahydro-lH-cyclopenta[a]chrysen-9-ol hydrochloride:
Figure imgf000044_0001
To a stirred solution (lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)-3a-isocyanato
-5a,5b,8,8,l la-pentamethyl-l-(prop-l-en-2-yl)icosahydro-lH-cyclopenta[a]chrysen-9-yl acetate (step 1, 9.0 g, 18.18 mmol) in 1,4-dioxane (100 mL) was added Cone. HC1 (21 ml). The reaction mixture was heated to 60 °C and continued for about 16 hours. After completion of the reaction (monitored by TLC), the reaction mixture was cooled to room temperature and the reaction mixture was concentrated under reduced pressure to give (lR,3aS,5aR,5bR,7aR,9S, l laR, l lbR, 13aR, 13bR)-3a-amino-5a,5b,8,8,l la-pentamethyl-l- (prop-l-en-2-yl)icosahydro-lH-cyclopenta[a]chrysen-9-ol hydrochloride (8.0 g). This was used as such for next reaction without any further purification.
Step 3: Synthesis of tert-butyl ((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-3aH-cyclopenta[a]chrysen-3a-yl) carbamate:
Figure imgf000044_0002
To a stirred solution of (lR,3aS,5aR,5bR,7aR,9S, l laR, llbR,13aR,13bR)-3a-amino- 5a,5b,8,8, l la-pentamethyl-l-(prop-l-en-2-yl)icosahydro-lH-cyclopenta[a]chrysen-9-ol hydrochloride (step 2, 8.0 g, 16.22 mmol) in 1,4-dioxane (80 ml) and water (25 ml) at 0 °C, were added NaHC03 (4.1 g, 48.68 mmol) and (Boc)20 (5.6 ml, 24.34 mmol). The reaction mixture was stirred for overnight at room temperature. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with EtOAc, washed with water, brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to give the residue. The crude product was purified via silica gel column chromatography by using EtOAc in n-hexane (15:85) as an eluent to afford the desired compound (7.0 g, yield: 84.3%) as a white solid. 1H NMR (CDCI3, 300 MHz): δ 4.72 (s, 1H), 4.63 (s, 1H), 4.31 (s, 1H), 3.21 (m, 1H), 2.56-2.33 (m, 3H), 2.04-1.89 (m, 1H), 1.68-1.25 (m, 29H) and 1.07-0.67 (m, 20H). Step 4: Synthesis of 1 -benzyl 3-((lR,3aS,5aR,5bR, 7aR,9S,llaR,llbR,13aR,13bR)-3a-((tert- butoxycarbonyl)amino)-5a,5b,8,8,lla-pentamethyl-l-(prop-l-en-2-yl)icosahydro-lH-cyclo penta[a] chrysen-9-yl) (lR,3S -2,2-dimethylcyclobutane-l,3-dicarboxylate:
Figure imgf000045_0001
To a stirred solution of tert-butyl ((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-3aH-cyclopenta[a] chrysen-3a-yl)carbamate (step 3, 7.0 g, 13.61 mmol) and (lS,3R)-3-((benzyloxy)carbonyl)- 2,2-dimethylcyclobutane-l-carboxylic acid (prepared as described in WO 2011/007230 A2, 5.35 g, 20.42 mmol) and DMAP (0.3 g, cat) in DCM (70 ml), was slowly added DCC (5.6 g, 27.23 mmol) in DCM (30 ml) at 0 °C 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, washed with water, saturated NaHC03 solution, brine and dried over Na2S04. The solvent was evaporated under reduced pressure to give the residue. The crude product was purified via silica gel column chromatography by using EtOAc in n-hexane (5:95) as an eluent to afford the desired compound (9.0 g, yield: 87.2%) as a white solid. 1H NMR (CDC13, 300 MHz): δ 7.36 (m, 5H), 5.12 (ABq, J=12.3 Hz, 2H), 4.72 (s, 1H), 4.61 (s, 1H), 4.45-4.40 (m, 1H), 4.32 (s, 1H), 2.84-2.32 (m, 6H), 2.07-1.89 (m, 2H), 1.68-1.23 (m, 39H) and 1.06-0.76 (m, 15H).
Step 5: Synthesis of l-((lR,3aS,5aR,5bR, 7aR,9S,llaR,llbR,13aR,13bR)-3a-amino- 5a,5b,8,8,lla-pentamethyl-l-(prop-l-en-2-yl)icosahydro-lH-cyclopenta[a]chrysen-9-yl) 3- benzyl (lS,3R)-2,2-dimethylcyclobutane-l,3-dicarboxylate trifluoroacetic acid salt:
To a stirred solution of 1-benzyl 3-((lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR) -3a-((tert-butoxycarbonyl)amino)-5a,5b,8,8,l la-pentamethyl-l-(prop-l-en-2-yl)icosahydro- lH-cyclopenta[a]chrysen-9-yl) (lR,3S)-2,2-dimethylcyclobutane-l,3-dicarboxylate (step 4, 1.0 g, 1.29 mmol) in DCM (10 ml), was added TFA (2.5 ml) and stirred for about 2 hours. After completion of the reaction (monitored by TLC), the reaction mixture was concentrated under reduced pressure to afford the desired product (1.018 g, yield: 100%) which was carried to the next step without any further purification. Intermediate 13: Synthesis of l-((lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)-3a- amino-5a,5b,8,8 J la-pentamethyl-l-(l-methylcvclopropyl)icosahvdro-lH- cyclopentaralchrysen-9-yl) 3-benzyl (lS,3R)-2,2-dimethylcyclobutane-l,3-dicarboxylate hydrochloride:
Figure imgf000046_0001
Step 1: Synthesis of (lR,3aS,5aR,5bR,7aR,9S,llaR,llbR,13aR,13bR)-3a-((tert- butoxycarbonyl)amino)-5a,5b,8,8,lla-pentamethyl-l-(l-methylcyclopropyl)icosahydro-lH- cyclopenta[a ]chrysen-9-yl acetate:
Figure imgf000046_0002
To a stirred solution of (lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)-3a-amino- 5a,5b,8,8,l la-pentamethyl-l-(l-methylcyclopropyl)icosahydro-lH-cyclopenta[a]chrysen-9- yl acetate (Intermediate 1-step 2, 5.0 g, 10.35 mmol, 1.0 eq) ) in THF (75 ml) and water (75 mL) was added sodium bicarbonate (2.60 g, 31.05 mmol, 3.0 eq). at 10 °C followed by (Boc)20 (2.4 g, 11.38 mmol, 1.1 eq). The reaction mixture was stirred at room temperature for overnight. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture was diluted with water and extracted with DCM. Organic layer was washed with water, brine solution and was dried over Na2S04. The organic layer was concentrated to get the crude residue which was purified by column chromatography using 5% EtOAc in hexane as an eluent to afford the title compound (5.5 g, yield: 91.0%) as a white solid. 1H NMR (DMSO-d6, 300 MHz): δ 5.53 (m, 1H), 4.40 (m, 1H), 2.13-2.06 (m, 1H), 1.99 (s, 3H), 1.80-1.63 (m, 5H), 1.45-1.28 (m, 18H), 1.21-1.11 (m, 4H), 0.97-0.79 (m, 20H), 0.66 (s, 4H), 0.38 (m, 2H) and 0.22 (m, 2H); Mass: [M+Na]+ 606.40 (100%).
Step 2: Synthesis of tert-butyl ((lR,3aS,5aR,5bR,7aR,9S,llaR,llbR,13aR,13bR)-9-hydroxy- 5a,5b, 8,8,1 la-pentamethyl-1 -( 1 -methylcyclopropyl)icosahydro-3aH-cyclopenta[a Jchrysen- 3a-yl)carbamate:
Figure imgf000047_0001
To a stirred solution of (lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)-3a-((tert- butoxycarbonyl)amino)-5a,5b,8,8,l la-pentamethyl-l-(l-methylcyclopropyl)icosahydro-lH- cyclopenta[a]chrysen-9-yl acetate (step 1, 5.5 g, 9.43 mmole, 1.0 eq) in THF (55 mL), methanol (55 mL) and water (20 mL) was added LiOH (3.6 g, 94.33 mmole, 10.0 eq). The reaction mixture was stirred at room temperature for about 12 hours. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture was diluted with water and extracted with DCM. The organic layer was washed with water and dried over Na2S04. The organic layer was evaporated under reduced pressure and the crude was purified by recrystallization in acetone and water (1:3) gave the desired product (5.0 g, yield: 98.0%) as a white solid. 1H NMR (DMSO-d6, 300 MHz): δ 5.53 (m, 1H), 4.27 (m, 1H), 2.99 (m, 1H), 2.27-1.58 (m, 6H), 1.45-1.28 (m, 18H), 1.21-1.11 (m, 4H), 0.97-0.79 (m, 20H), 0.66 (s, 4H), 0.38 (m, 2H) and 0.22 (m, 2H); Mass: [M+Na]+ 564.38 (100%).
Step 3: Synthesis of 1 -benzyl 3-((lR,3aS,5aR,5bR, 7aR,9S,llaR,llbR,13aR,13bR)-3a-((tert- butoxy carbonyl)amino)-5a,5b,8,8,lla-pentamethyl-l-(l-methylcyclopropyl)icosahydro-lH- cyclopenta [a]chrysen-9-yl) (l -2,2-dimethylcyclobutane-l,3-dicarboxylate:
Figure imgf000047_0002
To a stirred solution of tert-butyl ((lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)- 9-hydroxy-5a,5b,8,8,l la-pentamethyl-l-(l-methylcyclopropyl)icosahydro-3aH-cyclopenta[a] chrysen-3a-yl)carbamate (step 2, 5.0 g, 9.24 mmol, 1.0 eq) in DCM (50 mL) was cooled to 0 °C then added EDCI.HC1 salt (8.8 g, 46.21 mmol, 5.0 eq) followed by DMAP (3.38 g, 27.72 mmol, 3.0 eq) and added (lS,3R)-3-((benzyloxy)carbonyl)-2,2-dimethylcyclobutane-l- carboxylic acid (prepared as described in WO 2011/007230 A2, 3.63g, 13.86 mmol, 1.5 eq). The reaction mixture was raised to room temperature and stirred for overnight. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture was evaporated under reduced pressure and diluted with water. The aqueous layer was extracted with CH2C12. The organic layer was washed with water and brine solution. The combined organic layers were dried over Na2S04, filtered and evaporated under reduced pressure. The crude residue was purified by column chromatography using 5% EtOAc in hexane as an eluent to afford the title compound (5.5 g, yield: 75.0%) as a white solid. 1H NMR (DMSO-d6, 300 MHz): δ 7.36 (m, 5H), 5. 54 (s, 1H), 5.14 (q, 2H), 4.37 (t, 1H), 2.96- 2.80 (m, 2H), 2.41-2.26 (m, 2H), 2.01-1.80 (m, 4H), 1.71-1.25 (m, 30H), 1.12-1.09 (m, 1H), 1.02 (s, 3H), 0.95-0.80 (m, 20H), 0.39 (m, 2H), and 0.29 (m, 2H); Mass: [M+Na]+ 808.50 (100%).
Step 4: Synthesis of l-((lR,3aS,5aR,5bR, 7aR,9S,llaR,llbR,13aR,13bR)-3a-amino- 5a,5b,8,8,lla-penta methyl-l-(l-methylcyclopropyl)icosahydro-lH-cyclopenta[a]chrysen-9- yl) 3-benzyl (lS,3R)-2,2-dimethylcyclobutane-l,3-dicarboxylate hydrochloride:
To a stirred solution of 1 -benzyl 3-
((lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)-3a-((tert-butoxycarbonyl)amino)- 5a,5b,8,8,l la-pentamethyl-l-(l-methylcyclopropyl)icosahydro-lH-cyclopenta[a]chrysen-9- yl) (lR,3S)-2,2-dimethylcyclobutane-l,3-dicarboxylate (step 3, 5.5 g, 7.00 mmol, 1.0 eq) in dioxane hydrochloride (55 ml). The reaction mixture was stirred for about 2 hours. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture was concentrated to afford the title compound (2.8 g, yield: 58.0%) as a white solid. 1H NMR (DMSO-d6, 300 MHz): δ 7.44 (s, 2H), 7.35 (m, 5H), 5.13 (q, 2H), 4.37 (t, 1H), 2.96-2.80 (m, 2H), 2.41-2.26 (m, 2H), 2.01-1.80 (m, 4H), 1.71-1.25 (m, 21H), 1.12-1.09 (m, 1H), 1.02 (s, 3H), 0.95-0.80 (m, 20H), 0.39 (m, 2H), and 0.29 (m, 2H); Mass: [M+H]+ 685.51 (10%).
EXAMPLES
Example 1: Preparation of (lR,3S)-3-((((lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)- 3 a-((2-( 1,1 -dioxidothiomorpholino)ethyl)amino)-5 a,5b,8 , 8 J 1 a-pentamethyl- 1 -( 1 -methyl cvclopropyl)icosahvdro-lH-cvclopentaralchrvsen-9-yl)oxy)carbonyl)-2,2-dimethylcvclo butane- 1-carboxvlic acid
Figure imgf000048_0001
Step 1: Synthesis of (lR,3aS,5aR,5bR, 7aR,9S,llaR,llbR,13aR,13bR)-3a-((2-(l,l-dioxidothio morpholino )ethyl)amino)-5a,5b, 8,8,11 a-pentamethyl- 1 -( 1 -methylcyclopropyl)icosahydro-lH- cyclopenta[a] chrysen-9-yl acetate:
Figure imgf000049_0001
To a stirred solution of (lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)-3a-amino- 5a,5b,8,8,l la-pentamethyl-l-(l-methylcyclopropyl)icosahydro-lH-cyclopenta[a]chrysen-9- yl acetate (Intermediate 11, 1.0 g, 2.07 mmol, 1.0 eq) in acetonitrile (25 mL) then added 4-(2- chloroethyl)thiomorpholine 1,1-dioxide (Intermediate 1, 1.02 g, 5.17 mmol, 2.5 eq) followed by potassium phosphate tribasic (2.6 g, 12.42 mmol, 6 eq) and potassium iodide (1.37 g, 8.28 mmol, 4.0 eq) at room temperature under nitrogen atmosphere. The reaction mixture was heated to 120 °C under nitrogen atmosphere and stirred for about 20 hours. After completion of the reaction (monitored by TLC), the reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated gave the crude residue which was purified by column chromatography by using 2% methanol in DCM as an eluent to afford the desired compound (0.700 g, yield: 52.0%) as a white solid. 1H NMR (DMSO-d6, 300 MHz): δ 4.32 (m, 1H), 3.04 (m, 4H), 2.89 (m, 4H), 2.56 (m, 3H), 2.41 (m, 2H), 2.04 (s, 3H), 1.90-1.56 (m, 6H), 1.5- 1.08 (m, 14H), 0.98-0.79 (m, 19H), 0.66 (s, 4H), 0.32 (m, 2H) and 0.23 (m, 2H); Mass: [M+H]+ 645.47 (100%).
Step 2: Synthesis of 4-(2-(((lR,3aS,5aR,5bR,7aR,9S,llaR,llbR,13aR,13bR)-9-hydroxy-5a, 5b,8,8,lla-pentamethyl-l-(l-methylcyclopropyl)icosahydro-3aH-cyclopenta[a]chrysen-3a- yl)amino)ethyl)thiomorpholine 1 1-dioxide:
Figure imgf000049_0002
To a stirred solution of (lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)-3a-((2-(l,l- dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,l la-pentamethyl-l-(l-methylcyclopropyl) icosahydro-lH-cyclopenta[a]chrysen-9-yl acetate (step 1, 0.700 g, 1.08 mmol, 1.0 eq) in THF (10 mL), methanol (10 mL) and water (3 mL) was added LiOH (0.450 g, 10.8 mmol, 10.0 eq). The reaction mixture was stirred at room temperature for about 12 hours. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture was diluted with water and extracted with DCM. Organic layer was washed with water and dried with Na2S04. The organic layer was evaporated under reduced pressure and the crude was purified by column chromatography by using 4% MeOH in DCM as an eluent gave the desired product (0.450 g, yield: 69.0%) as a white solid. 1H NMR (DMSO-d6, 300 MHz): δ 4.32 (m, 1H), 3.04 (m, 4H), 2.89 (m, 4H), 2.56 (m, 3H), 2.41 (m, 2H), 1.90-1.56 (m, 7H), 1.5-1.08 (m, 14H), 0.98-0.79 (m, 19H), 0.66 (s, 4H), 0.32 (m, 2H) and 0.23 (m, 2H); Mass: [M+Na] 625.38 (100%).
Step 3: Synthesis of 1 -benzyl 3-((lR,3aS,5aR,5bR,7aR,9S,llaR,llbR,13aR,13bR)-3a-((2-(l,l -dioxidothiomorpholino )ethyl)amino )-5a,5b, 8,8,1 la-pentamethyl-1 -( 1 -methylcyclopropyl) icosahydro-lH-cyclopenta[a]chrysen-9-yl) (lR,3S)-2,2-dimethylcyclobutane-l,3- dicarboxylate:
Figure imgf000050_0001
To a stirred solution of 4-(2-(((lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)-9- hydroxy-5a,5b,8,8,l la-pentamethyl-l-(l-methylcyclopropyl)icosahydro-3aH-cyclopenta[a] chrysen-3a-yl)amino)ethyl)thiomorpholine 1,1 -dioxide (step 2, 0.450 g, 0.746 mmol, 1.0 eq) in DCM (10 mL) then added (lS,3R)-3-((benzyloxy)carbonyl)-2,2-dimethylcyclobutane-l- carboxylic acid (prepared as described in WO 2011/007230 A2, 0.293 g, 1.12 mmol, 1.5 eq). The reaction mixture was cooled to 0 °C then added DCC (0.307 g, 1.5 mmol, 2.0 eq) followed by DMAP (0.018 g, 0.15 mmol, 0.2 eq). The reaction mixture was raised to room temperature and stirred for overnight. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture was evaporated under reduced pressure and diluted with water. The aqueous layer was extracted with CH2CI2. The organic layer was washed with water and brine solution. The combined organic layers were dried over Na2S04, filtered and evaporated under reduced pressure. The crude residue was purified by column chromatography by using 4% MeOH in DCM as an eluent to obtain the desired product (0.400 g, yield: 63.0%) as a white solid. 1H NMR (DMSO-d6, 300 MHz): δ 7.36 (m, 5H), 5.10 (q, 2H), 4.37 (t, 1H), 3.04 (m, 4H), 2.89 (m, 4H), 2.78-2.71 (m, 2H), 2.35-2.27 (m, 3H), 1.89-1.78 (m, 5H), 1.72-1.44 (m, 9H), 1.36-1.09 (m, 13H), 0.99-0.72 (m, 26H), 0.33 (m, 2H), and 0.23 (m, 2H); Mass: [M+H]+ 847.63 (10%).
Step 4: Synthesis of (lR,3S)-3-((((lR,3aS,5aR,5bR,7aR,9S,llaR,llbR,13aR,13bR)-3a-((2- ( 1,1 -dioxidothiomorpholino)ethyl)amino)-5a,5b, 8, 8,1 la-pentamethyl-1 -(1-methylcyclo propyl)icosahydro-lH-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-l- carboxylic acid:
To a solution of 1-benzyl 3-((lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)-3a- ((2-(l,l-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,l la-pentamethyl-l-(l-meth propyl)icosahydro-lH-cyclopenta[a]chrysen-9-yl) (lR,3S)-2,2-dimethylcyclobutane-l,3- dicarboxylate (step 3, 0.4 g, 0.47 mmol, 1.0 eq) in ethylacetate (10 niL) and methanol (5 mL) was added palladium on carbon (0.028 g, 0.236 mmol, 0.5 eq). The reaction mixture was stirred in hydrogen atmosphere at room temperature for overnight. After completion of the reaction (monitored by TLC), the reaction mixture was filtered through a pad of celite® and was washed with MeOH and DCM. The filtrate was evaporated under reduced pressure, the crude residue was purified by column chromatography by using 4% methanol in DCM as an eluent gave the desired compound (0.116 g, yield: 44.0%) as a white solid. 1H NMR (CDC13, 300 MHz): δ 12.40 (s, 1H), 4.37 (t, 1H), 3.04 (m, 4H), 2.89 (m, 4H), 2.78-2.71 (m, 2H), 2.35- 2.27 (m, 3H), 1.89-1.78 (m, 5H), 1.72-1.44 (m, 9H), 1.36-1.09 (m, 13H), 0.99-0.72 (m, 26H), 0.33 (m, 2H), and 0.23 (m, 2H); Mass: [M+H] 757.68 (100%); HPLC: 99.32%.
The below examples 2-3 were prepared by procedure similar to the one described in example- 1 with appropriate variations in reactants, quantities of reagents and reaction conditions.
Figure imgf000051_0001
99.55%.
Example 4: Preparation of (lR,3S)-3-((((lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)- 3a-((2-(l J-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8 J la-pentamethyl-l-(prop-l-en-2- yl)icosahydro-lH-cyclopentaralchrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-l- carboxylic acid:
Figure imgf000052_0001
Step 1: Synthesis of 1 -benzyl 3-((lR,3aS,5aR,5bR,7aR,9S,llaR,llbR,13aR,13bR)-3a-((2-(l,l -dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,lla-pentamethyl-l-(prop-l-en-2-yl) icosahydro-lH-cyclopenta[a]chrysen-9-yl) (lR,3S)-2,2-dimethylcyclobutane-l,3 dicarboxylate:
Figure imgf000052_0002
To a stirred solution of l-((lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)-3a- amino-5a,5b,8,8,l la-pentamethyl-l-(prop-l-en-2-yl)icosahydro-lH-cyclopenta[a]chrysen-9- yl) 3-benzyl (lS,3R)-2,2-dimethylcyclobutane-l,3-dicarboxylate trifluoroacetic acid salt (Intermediate 12, 1.0 g, 1.27 mmol) and 4-(2-chloroethyl)thiomorpholine 1,1 -dioxide (Intermediate 1, 1.75 g, 8.9 mmol) in ACN (30 ml), were added K3P04 (1.62 g, 7.63 mmol) and KI (0.84 g, 5.1 mmol). The reaction mixture was heated to 120 °C and continued for about 18 hours. After completion of the reaction (monitored by TLC), the reaction mixture was filtered through celite and the cake was washed with DCM (twice). The filtrate was concentrated under reduced pressure gave the residue. The crude product was purified via silica gel column chromatography by using MeOH in DCM (2:98) as an eluent to afford the desired compound (0.89 g, yield: 76.2%) as a white solid. 1H NMR (CDC13, 300 MHz): δ 7.35 (m, 5H), 5.12 (ABq, J=12.3 Hz, 2H), 4.69 (s, 1H), 4.52 (s, 1H), 4.45-4.41 (m, 1H), 3.09- 2.45 (m, 15H), 2.05-1.22 (m, 31H) and 1.08-0.76 (m, 19H).
Step 2: Synthesis of (lR,3S)-3-((((lR,3aS,5aR,5bR,7aR,9S,llaR,llbR,13aR,13bR)-3a-((2- (1 ,1 -dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,l 1 a-pentamethyl-1 -(prop-1 -en-2-yl) icosahydro-lH-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-l- carboxylic acid:
To a stirred solution of 1-benzyl 3-((lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR) -3a-((2-(l,l-dioxidothiomorpholino)ethyl)amino)-5a,5b, 8,8,1 la-pentamethyl-l-(prop-l-en-2- yl)icosahydro-lH-cyclopenta[a]chrysen-9-yl) (lR,3S)-2,2-dimethylcyclobutane-l,3-di carboxylate (step 1, 0.8 g, 0.96 mmol) in THF (15 ml), were added N(Et)3 (0.5 ml, 3.8 mmol), triethyl silane (0.5 ml, 3.1 mmol) and Pd(OAc)2 (0.07 g, cat). The reaction mixture was heated to 70 °C and stirring was continued for about 3 hours. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with EtOAc, washed with water, saturated NaHC03 solution, brine and dried over Na2S04. The solvent was evaporated under reduced pressure and purified by silica gel column using 5% MeOH in DCM as an eluent to afford the title compound (0.37 g, yield: 51.89%) as a white solid. 1H MR (DMSO-d6, 300 MHz): δ 4.68 (s, 1H), 4.54 (s, 1H), 4.36-4.31 (m, 1H), 3.06 (m, 4H), 2.92 (m, 4H), 2.82-2.27 (m, 7H), 1.91-1.23 (m, 28H) and 0.99-0.81 (m, 22H); ESI Mass: 743.65 [M+H]+.
The below examples 5-12 were prepared by procedure similar to the one described in example-4 with appropriate variations in reactants, quantities of reagents and reaction conditions in presence of suitable solvents. The physiochemical properties of the compounds are also contemplated herein.
Figure imgf000053_0001
Figure imgf000054_0001
1H NMR (CDCI3, 300 MHz): δ 12.13
J s /1 (s, 1H), 7.40-7.36 (m, 5H), 4.76-4.31
(m, 5H), 3.09 (m, 6H), 2.81-2.72 (m,
11 4H), 2.36-2.23 (m, 7H), 1.89-1.02
(m, 28H) and 0.90-0.78 (m, 22H);
HOOCT
Mass: [M+H]+ 848.67 (100%); HPLC: 93.29%.
1H NMR (CDCI3, 300 MHz): δ 12.13 (s, 1H), 7.77-7.66 (m, 5H), 4.60-4.49 (m, 3H), 2.89-2.72 (m, 7H), 2.32-
12 2.25 (m, 4H), 1.90-1.05 (m, 30H),
ΗΟΟ(Τ 0.92-0.73 (m, 22H) and 0.50 (s, 3H);
Mass: [M+H]+ 834.67 (100%); HPLC: 96.12%.
Example 13: Preparation of (lR,3S)-3-((((lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)- 3a-((2-(4,4-difluoropiperidin-l-yl)ethyl)amino)-5a,5b,8,8 J la-pentamethyl-l-d- methylcvclopropyl)icosahvdro-lH-cvclopentaralchrvsen-9-yl)oxy)carbonyl)-2,2- dimethylcyclobutane-l-carboxylic acid:
Figure imgf000055_0001
Step 1: Synthesis of 1-benzyl 3-((lR,3aS,5aR,5bR, 7aR,9S,llaR,llbR,13aR,13bR)-3a-((2- (4,4-difluoropiperidin-l-yl)ethyl)amino)-5a,5b,8,8 la^entamethyl-l-(l-methylcyclopropyl) icosahydro-lH-cyclopenta[a]chrysen-9-yl) (lR,3S)-2,2-dimethylcyclobutane-l,3- dicarboxylate:
Figure imgf000055_0002
To a stirred solution of l-((lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)-3a- amino-5a,5b,8,8,l la-pentamethyl-l-(l-methylcyclopropyl)icosahydro-lH- cyclopenta[a]chrysen-9-yl) 3-benzyl (lS,3R)-2,2-dimethylcyclobutane-l,3-dicarboxylate hydrochloride (Intermediate 13, 1.0 g, 1.45 mmol, 1.0 eq) ) in acetonitrile (20 mL) then added l-(2-chloroethyl)-4,4-difluoropiperidine (Intermediate 4, 0.667 g, 3.65 mmol, 2.5 eq) followed by potassium phosphate tribasic (1.6385 g, 8.75 mmol, 6 eq) and potassium iodide (0.97 g, 5.83 mmol, 4.0 eq) at room temperature under nitrogen atmosphere. The reaction mixture was heated to 120 °C under nitrogen atmosphere and stirred for about 20 hours. After completion of the reaction (monitored by TLC), the reaction mixture was cooled to room temperature and filtered. Filtrate was concentrated gave the crude residue which was purified by column chromatography by using 2% methanol in DCM as an eluent to afford the title compound (0.5 g, yield: 41.0%) as a white solid. 1H NMR (DMSO-d6, 300 MHz): δ 7.36 (m, 5H), 5.10 (q, 2H), 4.36 (t, 1H), 3.41-3.37 (m, 4H), 3.05 (m, 2H), 2.83-2.63 (m, 5H), 2.35-2.27 (m, 2H), 1.97-1.83 (m, 8H), 1.71-1.26 (m, 20H), 1.11-1.02 (m, 2H), 0.93-0.82 (m, 25H), 0.43 (m, 2H), and 0.26 (m, 2H); Mass: [M+H]+ 833.51 (100%).
Step 2: Synthesis of (lR,3S)-3-((((lR,3aS,5aR,5bR,7aR,9S,llaR,nbR,13aR,13bR)-3a-((2- (4,4-difluoropiperidin-l-yl)ethyl)amino)-5a,5b,8,8 la^entamethyl-l-(l-methylcyclopropyl) icosahydro-lH-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-l- carboxylic acid:
To a solution of 1-benzyl 3-((lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)-3a-
((2-(4,4-difluoropiperidin-l-yl)ethyl)amino)-5a,5b, 8,8,1 la-pentamethyl- 1-(1- methylcyclopropyl)icosahydro-lH-cyclopenta[a]chrysen-9-yl) (lR,3S)-2,2- dimethylcyclobutane-l,3-dicarboxylate (step 1, 0.500 g, 0.60 mmol, 1.0 eq) in ethylacetate (10 mL) and methanol (5 mL) was added palladium carbon (0.032g, 0.30 mmol, 0.5 eq). The reaction mixture was stirred in hydrogen atmosphere at room temperature for overnight. After completion of the reaction (monitored by TLC), the reaction mixture was filtered through a pad of celite and was washed with MeOH and DCM. The filtrate was evaporated under reduced pressure, the crude residue was purified by column chromatography by using 4% methanol and DCM as an eluent to give the desired compound (0.043 g, yield: 10.0%) as a white solid. 1H NMR (CDC13, 300 MHz): δ 12.15 (s, 1H), 4.38 (t, 1H), 3.41-3.37 (m, 4H), 3.05 (m, 2H), 2.83-2.63 (m, 5H), 2.35-2.27 (m, 2H), 1.97-1.83 (m, 8H), 1.71-1.26 (m, 20H), 1.11-1.02 (m, 2H), 0.93-0.82 (m, 25H), 0.43 (m, 2H), and 0.26 (m, 2H); Mass: [M+H]+ 743.68 (60%); HPLC: 93.07%. The below examples 14-17 were prepared by procedure similar to the one described in example- 13 with appropriate variations in reactants, quantities of reagents, reaction conditions, in presence of suitable solvents. The physiochemical properties of the compounds are also contemplated herein.
Figure imgf000057_0001
29H), 0.94-0.79 (m, 22H), 0.32 (m,
2H), and 0.23 (m, 2H); Mass: [M+H]+ 861.84 (100%); HPLC: 96.49%.
The below compounds were prepared by procedure similar to the one described in above synthetic procedures with appropriate variations in reactants, quantities of reagents and reaction conditions.
Table 1
Figure imgf000058_0001
(lR,3S)-2,2-dimethyl-3-
((((lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)- 5a,5b,8,8,l l a-pentamethyl- 1 - ( 1 -methylcyclopropyl) - 3 a- ((2- (pyrrolidin-l-yl)ethyl)amino)icosahydro-lH-
Figure imgf000059_0001
cyclopenta[a]chrysen-9-yl)oxy)carbonyl)cyclobutane-l- carboxylic acid
(lR,3S)-3-
((((lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)-3a- ((2-(2-(hydroxymethyl)pyrrolidin-l-yl)ethyl)amino)- 5a,5b,8,8,l l a-pentamethyl- 1 - ( 1 - methylcyclopropyl)icosahydro-lH-cyclopenta[a]chrysen-9-
Figure imgf000059_0002
yl)oxy)carbonyl)-2,2-dimethylcyclobutane- 1 -carboxylic acid
(lR,3S)-3-
((((lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)-3a- ((2-(3 -hydroxypyrrolidin- 1 -yl)ethyl)amino)-5a,5b, 8 ,8,11a- pentamethyl- 1 -( 1 -methylcyclopropyl)icosahydro- 1H-
Figure imgf000059_0003
cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2- dimethylcyclobutane- 1 -carboxylic acid
(lR,3S)-3-
((((lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)-3a- ((2-(3-aminopyrrolidin-l-yl)ethyl)amino)-5a,5b,8,8,l la- pentamethyl- 1 -( 1 -methylcyclopropyl)icosahydro- 1H-
Figure imgf000059_0004
cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2- dimethylcyclobutane- 1 -carboxylic acid
(lR,3S)-2,2-dimethyl-3-
((((lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)- 5a,5b,8,8,l l a-pentamethyl- 1 - ( 1 -methylcyclopropyl) - 3 a- ((2- (3-(methylsulfonamido)pyrrolidin-l-
Figure imgf000059_0005
yl)ethyl)amino)icosahydro-lH-cyclopenta[a]chrysen-9- yl)oxy)carbonyl)cyclobutane- 1 -carboxylic acid (lR,3S)-2,2-dimethyl-3-
((((lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)- 5a,5b,8,8,l l a-pentamethyl- 1 - ( 1 -methylcyclopropyl) - 3 a- ((2- (2-oxopyrrolidin-l-yl)ethyl)amino)icosahydro-lH-
Figure imgf000060_0001
cyclopenta[a]chrysen-9-yl)oxy)carbonyl)cyclobutane-l- carboxylic acid
(lR,3S)-3-
((((lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)-3a- ((2-(3 ,3 -difluoropyrrolidin- 1 -yl)ethyl)amino)- 5a,5b,8,8,l l a-pentamethyl- 1 - ( 1 - methylcyclopropyl)icosahydro-lH-cyclopenta[a]chrysen-9- yl)oxy)carbonyl)-2,2-dimethylcyclobutane- 1 -carboxylic acid
(lR,3S)-2,2-dimethyl-3-
((((lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)- 5a,5b,8,8,l la-pentamethyl-l-(l-methylcyclopropyl)-3a-((2- (2-methylpyrrolidin-l-yl)ethyl)amino)icosahydro-lH- cyclopenta[a]chrysen-9-yl)oxy)carbonyl)cyclobutane-l- carboxylic acid
(lR,3S)-3-
((((lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)-3a- ((2-(2,5-dimethylpyrrolidin-l-yl)ethyl)amino)- 5a,5b,8,8,l l a-pentamethyl- 1 - ( 1 - methylcyclopropyl)icosahydro-lH-cyclopenta[a]chrysen-9- yl)oxy)carbonyl)-2,2-dimethylcyclobutane- 1 -carboxylic acid
(lR,3S)-3-
((((lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)-3a- ((2-(3-(hydroxymethyl)pyrrolidin-l-yl)ethyl)amino)- 5a,5b,8,8,l l a-pentamethyl- 1 - ( 1 - methylcyclopropyl)icosahydro-lH-cyclopenta[a]chrysen-9- yl)oxy)carbonyl)-2,2-dimethylcyclobutane- 1 -carboxylic acid (lR,3S)-3-
((((lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)-3a- ((2-(3-(aminomethyl)pyrrolidin-l-yl)ethyl)amino)- 5a,5b,8,8,l l a-pentamethyl- 1 - ( 1 - methylcyclopropyl)icosahydro-lH-cyclopenta[a]chrysen-9-
Figure imgf000061_0001
yl)oxy)carbonyl)-2,2-dimethylcyclobutane- 1 -carboxylic acid
(lR,3S)-3-
((((lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)-3a-
Η Λ H 0 ((2-(( 1 , 1 -dioxidotetrahydrothiophen-3- yl)amino)ethyl)amino)-5a,5b,8,8,l la-pentamethyl-l-(l- methylcyclopropyl)icosahydro-lH-cyclopenta[a]chrysen-9-
OH
yl)oxy)carbonyl)-2,2-dimethylcyclobutane- 1 -carboxylic acid
(lR,3S)-3-
((((lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)-3a- ((2-(3,3-difluoropiperidin-l-yl)ethyl)amino)-5a,5b,8,8,l la- pentamethyl- 1 -( 1 -methylcyclopropyl)icosahydro- 1H-
OH cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2- dimethylcyclobutane- 1 -carboxylic acid
(lR,3S)-3-
((((lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)-3a- ((2-(4-fluoropiperidin-l-yl)ethyl)amino)-5a,5b,8,8,l la- pentamethyl- 1 -( 1 -methylcyclopropyl)icosahydro- 1H-
OH cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2- dimethylcyclobutane- 1 -carboxylic acid
(lR,3S)-3-
((((lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)-3a- ((2-(2- (hydroxymethyl)piperidin- 1 - yl)ethyl) amino) - 5a,5b,8,8,l l a-pentamethyl- 1 - ( 1 - methylcyclopropyl)icosahydro-lH-cyclopenta[a]chrysen-9-
Figure imgf000061_0002
yl)oxy)carbonyl)-2,2-dimethylcyclobutane- 1 -carboxylic acid (lR,3S)-2,2-dimethyl-3-
((((lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)- 5a,5b,8,8,l la-pentamethyl-l-(l-methylcyclopropyl)-3a-((2- (4-(methylsulfonyl)piperidin-l-yl)ethyl)amino)icosahydro-
Figure imgf000062_0001
lH-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)cyclobutane- 1-carboxylic acid
(lR,3S)-3-
((((lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)-3a- ((2-(4-hydroxy-4-methylpiperidin-l-yl)ethyl)amino)- 5a,5b,8,8,l l a-pentamethyl- 1 - ( 1 - methylcyclopropyl)icosahydro-lH-cyclopenta[a]chrysen-9- yl)oxy)carbonyl)-2,2-dimethylcyclobutane- 1 -carboxylic acid
(lR,3S)-3-
((((lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)-3a- ((2-(4-hydroxypiperidin-l-yl)ethyl)amino)-5a,5b,8,8,l la- pentamethyl- 1 -( 1 -methylcyclopropyl)icosahydro- 1H- cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2- dimethylcyclobutane- 1 -carboxylic acid
(lR,3S)-3-
((((lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)-3a- ((2-(4-aminopiperidin-l-yl)ethyl)amino)-5a,5b,8,8,l la- pentamethyl- 1 -( 1 -methylcyclopropyl)icosahydro- 1H- cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2- dimethylcyclobutane- 1 -carboxylic acid
(lR,3S)-2,2-dimethyl-3-
((((lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)- 5a,5b,8,8,l l a-pentamethyl- 1 - ( 1 -methylcyclopropyl) - 3 a- ((2- (4-(trifluoromethyl)piperidin- 1 -yl)ethyl)amino)icosahydro- lH-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)cyclobutane- 1 -carboxylic acid (lR,3S)-2,2-dimethyl-3-
((((lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)- 5a,5b,8,8,l l a-pentamethyl- 1 - ( 1 -methylcyclopropyl) - 3 a- ((2- (4-methylpiperidin- l-yl)ethyl)amino)icosahydro- 1H-
Figure imgf000063_0001
cyclopenta[a]chrysen-9-yl)oxy)carbonyl)cyclobutane-l- carboxylic acid
(lR,3S)-3-
((((lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)-3a- ((2-(4- (hydroxymethyl)piperidin- 1 - yl)ethyl) amino) - 5a,5b,8,8,l l a-pentamethyl- 1 - ( 1 - methylcyclopropyl)icosahydro-lH-cyclopenta[a]chrysen-9- yl)oxy)carbonyl)-2,2-dimethylcyclobutane- 1 -carboxylic acid
(lR,3S)-3-
((((lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)-3a- ((2-((2R,6S)-2,6-dimethylpiperidin-l-yl)ethyl)amino)- 5a,5b,8,8,l l a-pentamethyl- 1 - ( 1 - methylcyclopropyl)icosahydro-lH-cyclopenta[a]chrysen-9- yl)oxy)carbonyl)-2,2-dimethylcyclobutane- 1 -carboxylic acid
(lR,3S)-3-
((((lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)-3a- ((2-(3,5-dimethylpiperidin-l-yl)ethyl)amino)- 5a,5b,8,8,l l a-pentamethyl- 1 - ( 1 - methylcyclopropyl)icosahydro-lH-cyclopenta[a]chrysen-9- yl)oxy)carbonyl)-2,2-dimethylcyclobutane- 1 -carboxylic acid
(lR,3S)-2,2-dimethyl-3-
((((lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)- 5a,5b,8,8,l l a-pentamethyl- 1 - ( 1 -methylcyclopropyl) - 3 a- ((2- thiomorpholinoethyl)amino)icosahydro-lH- cyclopenta[a]chrysen-9-yl)oxy)carbonyl)cyclobutane-l- carboxylic acid (lR,3S)-3-
((((lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)-3a- ((2-(2,6-dimethyl- 1 , 1 -dioxidothiomorpholino)ethyl)amino)- 5a,5b,8,8,l l a-pentamethyl- 1 - ( 1 - methylcyclopropyl)icosahydro-lH-cyclopenta[a]chrysen-9-
Figure imgf000064_0001
yl)oxy)carbonyl)-2,2-dimethylcyclobutane- 1 -carboxylic acid
(lR,3S)-3-
((((lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)-3a- ((2-(4,4-bis(ethoxycarbonyl)piperidin-l-yl)ethyl)amino)- 5a,5b,8,8,l l a-pentamethyl- 1 - ( 1 - methylcyclopropyl)icosahydro-lH-cyclopenta[a]chrysen-9-
Figure imgf000064_0002
yl)oxy)carbonyl)-2,2-dimethylcyclobutane- 1 -carboxylic acid
(lR,3S)-2,2-dimethyl-3-
J ((((lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)- 5a,5b,8,8,l l a-pentamethyl- 1 - ( 1 -methylcyclopropyl) - 3 a- ((2- ((S)-3-methylmorpholino)ethyl)amino)icosahydro-lH- cyclopenta[a]chrysen-9-yl)oxy)carbonyl)cyclobutane-l- carboxylic acid
(lR,3S)-3-
((((lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)-3a- ((2-((S)-3-(hydroxymethyl)morpholino)ethyl)amino)- 5a,5b,8,8,l l a-pentamethyl- 1 - ( 1 - methylcyclopropyl)icosahydro-lH-cyclopenta[a]chrysen-9- yl)oxy)carbonyl)-2,2-dimethylcyclobutane- 1 -carboxylic acid
(lR,3S)-3-
((((lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)-3a- ((2-(2,2-dimethylmorpholino)ethyl)amino)-5a,5b,8,8, 1 la- pentamethyl- 1 -( 1 -methylcyclopropyl)icosahydro- 1H-
Figure imgf000064_0003
cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2- dimethylcyclobutane- 1 -carboxylic acid (lR,3S)-3-
((((lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)-3a- ((2-(3,5-dimethylmorpholino)ethyl)amino)-5a,5b,8,8, 1 la- pentamethyl- 1 -( 1 -methylcyclopropyl)icosahydro- 1H-
Figure imgf000065_0001
cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2- dimethylcyclobutane- 1 -carboxylic acid
(lR,3S)-3-
((((lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)-3a- ((2-(2,6-dimethylmorpholino)ethyl)amino)-5a,5b,8,8, 1 la- pentamethyl- 1 -( 1 -methylcyclopropyl)icosahydro- 1H-
OH cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2- dimethylcyclobutane- 1 -carboxylic acid
(lR,3S)-3-
((((lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)-3a- ((2-(dimethylamino)ethyl)amino)-5a,5b,8,8,l la- pentamethyl- 1 -( 1 -methylcyclopropyl)icosahydro- 1H-
OH cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2- dimethylcyclobutane- 1 -carboxylic acid
(lR,3S)-3-
J? ((((lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)-3a- ((2-(diisopropylamino)ethyl)amino)-5a,5b,8,8,l la- pentamethyl- 1 -( 1 -methylcyclopropyl)icosahydro- 1H-
OH cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2- dimethylcyclobutane- 1 -carboxylic acid
(lR,3S)-3-
((((lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)-3a- ((2-((2-(dimethylamino)ethyl)amino)ethyl)amino)- 5a,5b,8,8,l l a-pentamethyl- 1 - ( 1 - methylcyclopropyl)icosahydro-lH-cyclopenta[a]chrysen-9-
Figure imgf000065_0002
yl)oxy)carbonyl)-2,2-dimethylcyclobutane- 1 -carboxylic acid (lR,3S)-3-
((((lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)-3a- ((3-( 1 , 1 -dioxidothiomorpholino)propyl)amino)- 5a,5b,8,8,l l a-pentamethyl- 1 - ( 1 - methylcyclopropyl)icosahydro-lH-cyclopenta[a]chrysen-9-
Figure imgf000066_0001
yl)oxy)carbonyl)-2,2-dimethylcyclobutane- 1 -carboxylic acid
(lR,3S)-3-
((((lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)-3a- ((4-( 1 , 1 -dioxidothiomorpholino)butyl)amino)- 5a,5b,8,8,l l a-pentamethyl- 1 - ( 1 - methylcyclopropyl)icosahydro-lH-cyclopenta[a]chrysen-9- yl)oxy)carbonyl)-2,2-dimethylcyclobutane- 1 -carboxylic acid
(lR,3S)-3-
((((lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)-3a- ΓΛ r ((2-(2-oxa-6-azaspiro[3.3]heptan-6-yl)ethyl)amino)- 5a,5b,8,8,l l a-pentamethyl- 1 - ( 1 - methylcyclopropyl)icosahydro-lH-cyclopenta[a]chrysen-9- yl)oxy)carbonyl)-2,2-dimethylcyclobutane- 1 -carboxylic acid
(lR,3S)-3-
J? ((((lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)-3a- (bis(2-(dimethylamino)ethyl)amino)-5a,5b,8,8,l la- pentamethyl- 1 -( 1 -methylcyclopropyl)icosahydro- 1H- cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2- dimethylcyclobutane- 1 -carboxylic acid
(lR,3S)-3-
J? ((((lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)-3a- (bis(2-(pyrrolidin-l-yl)ethyl)amino)-5a,5b,8,8,l la- pentamethyl- 1 -( 1 -methylcyclopropyl)icosahydro- 1H- cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2- dimethylcyclobutane- 1 -carboxylic acid (lR,3S)-3-
((((lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)-3a- (bis(2-(l,l-dioxidothiomorpholino)ethyl)amino)- 5a,5b,8,8,l l a-pentamethyl- 1 - ( 1 - methylcyclopropyl)icosahydro-lH-cyclopenta[a]chrysen-9-
Figure imgf000067_0001
yl)oxy)carbonyl)-2,2-dimethylcyclobutane- 1 -carboxylic acid, and
(lR,3S)-3-
((((lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)-3a- (bis(2-morpholinoethyl)amino)-5a,5b,8,8, 1 la-pentamethyl- l-(l-methylcyclopropyl)icosahydro-lH-
Figure imgf000067_0002
cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2- dimethylcyclobutane-1 -carboxylic acid.
PHARMACOLOGICAL ACTIVITY
The compounds described herein can be tested for their antiviral activity following procedures known to a person of ordinary skill in the art. For example, the following protocols can be employed for testing the compounds. These protocols are illustrative and do not limit to the scope of the invention.
Example 18: Evaluation of compounds antiviral activity:
MT2 cells were infected with HIV-1 strain 92HT599 (15TCID 50/ 30000 cells). The infected cells were plated at the concentration of -30 000 cells per well in 96 well plate. Test compound was added to the micro plate in defined format with the final concentration of DMSO (vehicle) is not more than 1%. Incubation was carried out in C02 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 controls).
P-24 estimation was carried out using Advance biosciences kit as per the procedure detailed by supplier.
The IC50 values of the compounds of formula (I) are summarized in the below Table- 1A, wherein the compounds according to compound of formula (I) possess antiviral activity IC50 value less than or equal to 10 nM referred herein as "A" and IC50 value greater than 10 nM referred herein as "B". Table- 1 A
Figure imgf000068_0001
References:
1. Antiviral methods and protocols (Eds: D Kinchington and R F Schinazi) Humana Press Inc., 2000.
2. HIV protocols (Eds: N L Michael and J H Kim) Humana Press Inc, 1999.
3. DAIDS Virology manual from HIV laboratories, Publication NIH-97-3838, 1997.
4. HIV-1 p24 antigen capture assay, enzyme immunoassay for detection of Human immunodeficiency Virus Type 1 (HIV-1) p24 in tissue culture media - Advanced bio science 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

Claims:
Figure imgf000069_0001
Formula (I)
wherein,
Figure imgf000069_0002
o F3C CF3 (wherein Rb is hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted cycloalkyl);
R2 is alkyl, alkenyl or substituted or unsubstituted cycloalkyl; wherein the substituent is alkyl;
R3 is hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted cycloalkyl; wherein the substituent is heterocyclyl or alkylamino;
R4 and R5 independently are hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl; wherein the substituent is alkylamino; alternatively, R4 and R5 are taken together with the N-atom to which they are attached to form substituted or unsubstituted 3-15 membered heterocyclyl; wherein the substituent is one or more Ra;
Ra is independently selected from substituted or unsubstituted alkyl, substituted or unsubstituted aminoalkyl, halogen, hydroxyl, haloalkyl, hydroxyalkyl, substituted or unsubstituted amino, -N(H)-S02-Rc, -S02-Rc, -C(0)-Rd, or -C(0)0-Re;
Rc, Rd and Re independently are substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted alkylamino, substituted or unsubstituted amino, or substituted or unsubstituted arylalkyl; and
'n' is an integer selected from 1-4 both inclusive; or
pharmaceutically acceptable salts, solvates, hydrates, tautomers, stereoisomers, prodrugs, or combination thereof.
2. The compound according to claim 1, is a compound of the formula (IA): Formula (IA)
wherein,
Figure imgf000070_0001
(wherein Rb is hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted cycloalkyl);
R2 is alkyl, alkenyl or substituted or unsubstituted cycloalkyl; wherein the substituent is alkyl;
R3 is hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted cycloalkyl; wherein the substituent is heterocyclyl or alkylamino;
R4 and R5 independently are hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl; wherein the substituent is alkylamino; alternatively, R4 and R5 are taken together with the N-atom to which they are attached to form substituted or unsubstituted 3- 15 membered heterocyclyl; wherein the substituent is one or more Ra;
Ra is independently selected from substituted or unsubstituted alkyl, substituted or unsubstituted aminoalkyl, halogen, hydroxyl, haloalkyl, hydroxyalkyl, substituted or unsubstituted amino, -N(H)-S02-Rc, -S02-Rc, -C(0)-Rd, or -C(0)0-Re; and
Rc, Rd and Re independently are substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted alkylamino, substituted or unsubstituted amino, or substituted or unsubstituted arylalkyl; or
pharmaceutically acceptable salts, solvates, hydrates, tautomers, stereoisomers, prodrugs, or combination thereof.
3. The compound according to claim 1, is a compound of the formula (IB):
Figure imgf000071_0001
wherein,
R2 is alkyl, alkenyl or substituted or unsubstituted cycloalkyl; wherein the substituent is alkyl;
R3 is hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted cycloalkyl; wherein the substituent is heterocyclyl or alkylamino;
R4 and R5 independently are hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl; wherein the substituent is alkylamino; alternatively, R4 and R5 are taken together with the N-atom to which they are attached to form substituted or unsubstituted 3-15 membered heterocyclyl; wherein the substituent is one or more Ra;
Ra is independently selected from substituted or unsubstituted alkyl, substituted or unsubstituted aminoalkyl, halogen, hydroxyl, haloalkyl, hydroxyalkyl, substituted or unsubstituted amino, -N(H)-S02-Rc, -S02-Rc, -C(0)-Rd, or -C(0)0-Re;
Rc, Rd and Re independently are substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted alkylamino, substituted or unsubstituted amino, or substituted or unsubstituted arylalkyl; and
'n' is an integer selected from 1-4 both inclusive; or
pharmaceutically acceptable salts, solvates, hydrates, tautomers, stereoisomers, prodrugs, or combination thereof.
4. The compound according to claim 1-2, wherein Ri is HO N/ ^ .
5. The compound according to claim 1-4, wherein R2 is ""v or ^
6. The compound according to claim 1-5, wherein R3 is hydrogen.
7. The compound according to claim 1-6, wherein R4 and R5 are taken together with the N-atom to which they are attached to form substituted or unsubstituted 3-15 membered heterocyclyl.
8. The compound according to claim 7, wherein heterocyclyl is substituted or unsubstituted with one or more Ra, wherein Ra is halogen, -S02-Rc or -C(0)-Rd-
9. The compound according to claim 8, wherein Rc is alkyl(methyl, isopropyl), aryl (phenyl), arylalkyl(benzyl), alkylamino(dimethylamino) and Rd is aryl (phenyl), and alkylamino(dimethylamino) .
10. A compound selected from the group consisting of:
(lR,3S)-3-((((lR,3aS,5aR,5bR,7aR,9S,l laR, l lbR, 13aR, 13bR)-3a-((2-(l,l- dioxidothiomo holino)ethyl)amino)-5a,5b,8,8,l la-pentamethyl-l-(l-methyl
cyclopropyl)icosahydro-lH-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclo butane- 1-carboxylic acid,
(lR,3S)-2,2-dimethyl-3-((((lR,3aS,5aR,5bR,7aR,9S, l laR,l lbR,13aR,13bR)- 5a,5b,8,8, l la-pentamethyl-l-(l-methylcyclopropyl)-3a-((2- mo holinoethyl)amino)icosahydro-lH-cyclopenta[a]chrysen-9- yl)oxy)carbonyl)cyclobutane- 1 -carboxylic acid,
(lR,3S)-2,2-dimethyl-3-((((lR,3aS,5aR,5bR,7aR,9S, l laR,l lbR,13aR,13bR)- 5a,5b, 8,8, 1 la-pentamethyl-l-(l-methylcyclopropyl)-3a-((2-(4-(methylsulfonyl)piperazin-l- yl)ethyl)amino)icosahydro-lH-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)cyclobutane-l- carboxylic acid,
(lR,3S)-3-((((lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)-3a-((2-(l,l- dioxidothiomo holino)ethyl)amino)-5a, 5b, 8, 8, 11 a-pentamethyl- 1 -(prop- 1 -en-2- yl)icosahydro-lH-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-l- carboxylic acid,
(lR,3S)-2,2-dimethyl-3-((((lR,3aS,5aR,5bR,7aR,9S, l laR, l lbR,13aR,13bR)- 5a,5b, 8,8, 1 la-pentamethyl-3a-((2-mo holinoethyl)amino)- l-(prop-l-en-2-yl)icosahydro- 1H- cyclopenta[a]chrysen-9-yl)oxy)carbonyl)cyclobutane- 1-carboxylic acid,
(lR,3S)-2,2-dimethyl-3-((((lR,3aS,5aR,5bR,7aR,9S, l laR,l lbR,13aR,13bR)- 5a,5b, 8,8, 1 la-pentamethyl-3a-((2-(4-(methylsulfonyl)piperazin- l-yl)ethyl)amino)- l-(prop- 1- en-2-yl)icosahydro-lH-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)cyclobutane- 1-carboxylic acid,
(1R,3 S)-3-((((lR,3aS,5aR,5bR,7aR,9S, 1 laR, 1 IbR, 13aR, 13bR)-3a-((2-(4-(N,N- dimethylsulfamoyl)piperazin-l-yl)ethyl)amino)-5a,5b, 8,8,11 a-pentamethyl- 1 -(prop- l-en-2- yl)icosahydro-lH-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-l- carboxylic acid, (1R,3 S)-3-((((lR,3aS,5aR,5bR,7aR,9S, 1 laR, 1 IbR, 13aR, 13bR)-3a-((2-(4- (dimethylcarbamoyl)piperazin- 1 -yl)ethyl)amino)-5a, 5b, 8, 8, 11 a-pentam ethyl- 1 -(prop- 1 -en-2 yl)icosahydro-lH-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-l- carboxylic acid,
(1R,3 S)-3-((((lR,3aS,5aR,5bR,7aR,9S, 1 laR, 1 IbR, 13aR, 13bR)-3a-((2-(4- benzoylpiperazin- 1 -yl)ethyl)amino)-5a, 5b, 8, 8, 11 a-pentam ethyl- 1 -(prop- 1 -en-2- yl)icosahydro-lH-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-l- carboxylic acid,
(1R,3 S)-3-((((lR,3aS,5aR,5bR,7aR,9S, 1 laR, 1 IbR, 13aR, 13bR)-3a-((2-(4- (isopropylsulfonyl)piperazin-l-yl)ethyl)amino)-5a,5b,8,8,l la-pentamethyl-l-(prop-l-en-2- yl)icosahydro-lH-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-l- carboxylic acid,
(1R,3 S)-3-((((lR,3aS,5aR,5bR,7aR,9S, 1 laR, 1 IbR, 13aR, 13bR)-3a-((2-(4- (benzylsulfonyl)piperazin-l-yl)ethyl)amino)-5a,5b,8,8, l la-pentamethyl-l-(prop-l-en-2- yl)icosahydro-lH-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-l- carboxylic acid,
(lR,3S)-2,2-dimethyl-3-((((lR,3aS,5aR,5bR,7aR,9S, l laR,l lbR,13aR,13bR)- 5a,5b,8,8, l la-pentamethyl-3a-((2-(4-(phenylsulfonyl)piperazin-l-yl)ethyl)amino)-l-(prop-l en-2-yl)icosahydro-lH-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)cyclobutane-l -carboxylic acid,
(1R,3 S)-3-((((lR,3aS,5aR,5bR,7aR,9S, 1 laR, 1 IbR, 13aR, 13bR)-3a-((2-(4,4- difluoropiperidin-l-yl)ethyl)amino)-5a,5b,8,8,l la-pentamethyl-l-(l-methylcyclopropyl) icosahydro-lH-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-l- carboxylic acid,
(1R,3 S)-3-((((lR,3aS,5aR,5bR,7aR,9S, 1 laR, 1 IbR, 13aR, 13bR)-3a-((2-(4- (isopropylsulfonyl)piperazin-l-yl)ethyl)amino)-5a,5b,8,8,l la-pentamethyl-l-(l- methylcyclopropyl)icosahydro-lH-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2- dimethylcyclobutane- 1 -carboxylic acid,
(1R,3 S)-3-((((lR,3aS,5aR,5bR,7aR,9S, 1 laR, 1 IbR, 13aR, 13bR)-3a-((2-(4- benzoylpiperazin-l-yl)ethyl)amino)-5a,5b, 8,8,11 a-pentam ethyl- 1-(1- methylcyclopropyl)icosahydro-lH-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2- dimethylcyclobutane- 1 -carboxylic acid,
(lR,3S)-2,2-dimethyl-3-((((lR,3aS,5aR,5bR,7aR,9S, l laR,l lbR,13aR,13bR)- 5a,5b,8,8, l la-pentamethyl-l-(l-methylcyclopropyl)-3a-((2-(4-(phenylsulfonyl)piperazin-l- yl)ethyl)amino)icosahydro-lH-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)cyclobutane-l- carboxylic acid, and
(1R,3 S)-3-((((lR,3aS,5aR,5bR,7aR,9S, 1 laR, 1 IbR, 13aR, 13bR)-3a-((2-(4- (benzylsulfonyl)piperazin-l-yl)ethyl)amino)-5a,5b,8,8, l la-pentamethyl-l-(l- methylcyclopropyl)icosahydro-lH-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2- dimethyl cyclobutane-1 -carboxylic acid; or pharmaceutically acceptable salts, solvates, hydrates, tautomers, stereoisomers, prodrugs, or combination thereof.
11. A pharmaceutical composition comprising a compound according to any one of claims 1-10 and at least one pharmaceutically acceptable excipient.
12. The pharmaceutical composition according to claim 11, wherein the pharmaceutically acceptable excipient is a carrier or diluent.
13. 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 1-10.
14. The method according to claim 13, wherein the viral mediated disease, disorder or syndrome is HIV infection, HBV infection, HCV infection, a retroviral infection genetically related to AIDS, respiratory disorders (including adult respiratory distress syndrome (ARDS)), inflammatory disease, or a combination thereof.
15. 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 1-10.
16. The method according to claim 13 and 15, wherein the subject is a mammal including human.
17. Use of a compound according to any of claims 1-10, in the manufacture of a medicament for the treatment of viral mediated diseases.
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US11034718B2 (en) 2015-02-09 2021-06-15 Hetero Labs Limited C-3 novel triterpenone with C-17 reverse amide derivatives as HIV inhibitors
US10370405B2 (en) * 2015-03-16 2019-08-06 Hetero Labs Limited C-3 novel triterpenone with C-28 amide derivatives as HIV inhibitors
WO2020006510A1 (en) * 2018-06-29 2020-01-02 Dfh Therapeutics Triterpene amine derivatives
AU2019292599B2 (en) * 2018-06-29 2022-03-03 Dfh Therapeutics Triterpene amine derivatives
US11236122B2 (en) 2018-06-29 2022-02-01 Dfh Therapeutics Triterpene amine derivatives
CN113727989A (en) * 2019-02-11 2021-11-30 熙德隆制药有限公司 Novel triterpene derivatives as HIV inhibitors
WO2020165741A1 (en) 2019-02-11 2020-08-20 Hetero Labs Limited Novel triterpene derivatives as hiv inhibitors
EP4248960A2 (en) 2019-02-11 2023-09-27 Hetero Labs Limited Novel triterpene derivatives as hiv inhibitors
EP4248960A3 (en) * 2019-02-11 2024-01-03 Hetero Labs Limited Novel triterpene derivatives as hiv inhibitors
CN113727989B (en) * 2019-02-11 2024-02-13 熙德隆制药有限公司 Novel triterpene derivatives as HIV inhibitors
WO2021161206A1 (en) * 2020-02-11 2021-08-19 Hetero Labs Limited Novel triterpene derivatives as hiv inhibitors
CN115380040A (en) * 2020-02-11 2022-11-22 熙德隆制药有限公司 Novel triterpene derivatives as HIV inhibitors
EP4103579A4 (en) * 2020-02-11 2024-05-01 Hetero Labs Ltd Novel triterpene derivatives as hiv inhibitors
WO2023030667A1 (en) 2021-09-03 2023-03-09 Hovione Scientia Process for the preparation of chloroalkyl substituted cyclic amines

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