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WO2017115329A1 - Nouveaux dérivés de triterpénone en c-3 en tant qu'inhibiteurs du vih - Google Patents

Nouveaux dérivés de triterpénone en c-3 en tant qu'inhibiteurs du vih Download PDF

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Publication number
WO2017115329A1
WO2017115329A1 PCT/IB2016/058104 IB2016058104W WO2017115329A1 WO 2017115329 A1 WO2017115329 A1 WO 2017115329A1 IB 2016058104 W IB2016058104 W IB 2016058104W WO 2017115329 A1 WO2017115329 A1 WO 2017115329A1
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oxo
oxy
chrysen
dimethylcyclobutane
lar
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Inventor
Parthasaradhi Reddy BANDI
Rathnakar Reddy KURA
David Krupadanam GAZULA LEVI
Panduranga Reddy ADULLA
Bhaskar Reddy KASIREDDY
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Hetero Research Foundation
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Hetero Research Foundation
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J63/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by expansion of only one ring by one or two atoms
    • C07J63/008—Expansion of ring D by one atom, e.g. D homo steroids

Definitions

  • the present invention relates to C-3 novel triterpenone 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 2013/160810 disclosed novel betulinic acid derivatives as HIV inhibitors
  • WO 2011/007230 describes preparation of lupeol-type triterpene derivatives as antiviral agents
  • WO 2014/093941 describers pharmaceutical compositions of betulin derivatives
  • WO 2009/082819 describes preparation of 17-amino lupane derivatives as anti-HIV agents
  • WO 2013/020245 describes carbonyl derivatives of betulin
  • WO 2009/082818 describes preparation of C21-keto lupane derivatives for the treatment of HIV Infections
  • WO 2011/100308 describes preparation of betulin derivatives for treatment of HIV-1
  • WO 2013/090664 describes preparation of betulin derivatives for the treatment of HIV
  • WO 2013/117137 describes lupan
  • WO 2013/090683 describes preparation of betulin propenoate derivatives for the treatment of HIV
  • WO 2013/020246 describes preparation of methylene derivatives of betulin useful for the treatment of HIV
  • WO 2010/132334 describes C3, 28-disubstituted betulinic acid derivatives as Anti-HIV agents
  • US 2011/0152229 describes betulinic acid derivatives as anti-HIV agents
  • WO 2008/057420 describes extended triterpene derivatives as antiretroviral agents
  • WO 2013/123019 describes C-3 cycloalkenyl triterpenoids with HIV maturation inhibitory activity
  • WO 2007/141392 describes compositions comprising betulonic acid
  • WO 2007/141391 describes betulin derived compounds useful as antiprotozoal agents
  • WO 2007/141390 describes the preparation of betulin derived compounds as antiviral agents
  • WO 2007/141389 describes preparation of betulin derived compounds as antibacterial agents
  • the present invention relates to the compounds of the formula (I):
  • Ci-C 6 alkyl optionally substituted Ci-C 6 alkyl
  • R a is hydrogen, optionally substituted Ci-C 6 alkyl, or optionally substituted C3-C8 cycloalkyl);
  • R 2 at each occurrence are independently selected from hydrogen, alkyl, halo, haloalkyl;
  • R 3 at each occurrence are independently selected from hydrogen, halo, haloalkyl, alkyl, or -OR t ,; wherein R is hydrogen, or selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, alkoxylalkyl, - C(0)alkyl, -C(0)aryl, -C(0)heteroaryl, -C(0)cycloalkyl, -C(0)arylalkyl, -
  • R4 is selected from hydrogen, optionally substituted alkyl, or -C(0)R c ; wherein the optional substituents are selected from amino, alkylamino, dialkylamino, alkoxy, hydroxy, heterocyclyl, heteroaryl, acyl(alkyl)amino, cycloalkyl, aryl (optionally substituted with halo, alkylamino, or dialkylaminoalkyl), hydroxy alkylamino, alkoxy alkylamino, alkoxyalkylaminoalkyl, -C(0)OH, -C(0)N(H)alkyl, -C(0)N(CH 3 ) 2 , -C(0)NH 2 , -NHC(0)0- alkyl, -N(CH 3 )C(0)Oalkyl, -N(CH 3 )alkoxy, -NHC(0)alkyl, -N(CH 3 )C(0)alkyl, - C(0)N(H)cycloalkyl
  • R5 and R 6 are independently selected from hydrogen, hydroxy, optionally substituted Ci-C 6 alkyl, halo, haloalkyl, optionally substituted hydroxyalkyl, or optionally substituted aminoalkyl; alternatively R5 and R 6 can be taken together with the carbon atom to which they are attached to form optionally substituted 3-8 membered cycloalkyl, optionally substituted 3- 8 membered heterocyclyl; or R5 and R 6 together represent an oxo; wherein the optional substituents are independently selected from one or more R d ;
  • W is absent, -NR 8 - -NR 8 (CO)-, -NR 8 (CR 8 R 8a )i_ 3 - or -NR 8 S(0) 2 -;
  • R 7 is hydrogen, -C(0)OH, amino, optionally substituted aminoacid, optionally substituted Q-C 6 alkyl, optionally substituted alkoxy, optionally substituted amine, optionally substituted aminoalkyl, -NHC(0)aryl, -NHC(0)heterocyclyl, -NHC(0)cycloalkyl, optionally substituted C 6 -Ci2 aryl, aryloxy, optionally substituted 3-8 membered cycloalkyl, optionally substituted 4-15 membered heterocyclyl, or optionally substituted 4-15 membered heteroaryl; wherein the substituents can be independently selected from one or more R e ;
  • R 8 and R 8a at each occurrence are hydrogen, or selected from the group consisting of optionally substituted alkyl, optionally substituted acyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl; alternatively R 8 and R 8a are taken together with the carbon atom to which they are attached to form an optionally substituted 3-8 membered cycloalkyl, optionally substituted 3-8 membered heterocyclyl; or R 8 and R 8a together represent an oxo; wherein the optional substituents at each occurrence are selected from one or more R d ;
  • R c is selected from alkyl, aminoalkyl, dialkylaminoalkyl, alkylaminoalkyl, alkoxyalkyl, -C(0)dialkylaminoalkyl, -C(0)N(CH 3 ) 2 , -C(0)OH, -C(0)NH 2 , hydroxyalkyl, heterocyclyl, aryl, arylalkyl, heterocyclylalkyl, cycloalkyl, or cycloalkylalkyl;
  • R d is alkyl, amino, halolalkyl, hydroxy, alkoxy or halogen
  • R e is alkyl, hydroxy, alkoxy, alkoxyalkoxy, amino, acyl, optionally substituted aryl, alkoxycarbonyl, alkylsulfonyl, dialkylaminoalkoxy, optionally substituted 3-8 membered cycloalkyl, optionally substituted heterocyclyl, optionally substituted 3-8 membered cycloalkylalkyl, optionally substituted 3-8 membered arylalkyl, optionally substituted 3-8 membered heterocyclylalkyl, optionally substituted 3-8 membered heterocyclylalkoxy, optionally substituted 3-8 membered heterocyclyloxy, hydroxy, -C(0)OH, oxo, -S(0) 2 NH 2 , haloalkyl, haloalkyloxy or halo; wherein the optional substituents are alkyl, amino, halo, haloalkyl, hydroxy, alkoxy, aryl, cycloal
  • 'm' is an integer selected from lor 2;
  • 'n' is an integer selected from 0, 1, 2, 3, 4 or 5;
  • the present invention relates to pharmaceutical composition comprising C-3 novel triterpenone derivatives and related compounds of formula (I) and processes for preparing thereof.
  • the present invention relates to C-3 novel triterpenone 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 triterpenone derivatives and related compounds, compositions useful for therapeutic treatment of viral diseases and particularly HIV mediated diseases.
  • the present invention relates to compounds of formula (I):
  • Ri is optionally substituted Ci-C 6 alkyl
  • R a is hydrogen, optionally substituted Ci-C 6 alkyl, or optionally substituted C3-C8 cycloalkyl);
  • R 2 at each occurrence are independently selected from hydrogen, alkyl, halo, or haloalkyl;
  • R 3 at each occurrence are independently selected from hydrogen, halo, haloalkyl, alkyl, or -OR b ,; wherein R b is hydrogen, or selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, alkoxylalkyl, - C(0)alkyl, -C(0)aryl, -C(0)heteroaryl, -C(0)cycloalkyl, -C(0)arylalkyl, - C(0)heterocyclylalkyl, -C(0)cycloalkylalkyl, or
  • R4 is selected from hydrogen, optionally substituted alkyl, or -C(0)R c ; wherein the optional substituents are selected from amino, alkylamino, dialkylamino, alkoxy, hydroxy, heterocyclyl, heteroaryl, acyl(alkyl)amino, cycloalkyl, aryl (optionally substituted with halo, alkylamino, or dialkylaminoalkyl), hydroxy alkylamino, alkoxy alkylamino, alkoxyalkylaminoalkyl, -C(0)OH, -C(0)N(H)alkyl, -C(0)N(CH 3 ) 2 , -C(0)NH 2 , -NHC(0)0- alkyl, -N(CH 3 )C(0)Oalkyl, -N(CH 3 )alkoxy, -NHC(0)alkyl, -N(CH 3 )C(0)alkyl, - C(0)N(H)cycloalkyl
  • R5 and R 6 are independently selected from hydrogen, hydroxy, optionally substituted Ci-C 6 alkyl, halo, haloalkyl, optionally substituted hydroxyalkyl, or optionally substituted aminoalkyl; alternatively R5 and R 6 can be taken together with the carbon atom to which they are attached to form optionally substituted 3-8 membered cycloalkyl, optionally substituted 3- 8 membered heterocyclyl; or R5 and R 6 together represent an oxo; wherein the optional substituents are independently selected from one or more R d ;
  • W is absent, -NR 8 - -NR 8 (CO)-, -NR 8 (CR 8 R 8a )i- - or -NR 8 S(0) 2 -;
  • R 7 is hydrogen, -C(0)OH, amino, optionally substituted aminoacid, optionally substituted Ci-C 6 alkyl, optionally substituted alkoxy, optionally substituted amine, optionally substituted aminoalkyl, -NHC(0)aryl, -NHC(0)heterocyclyl, -NHC(0)cycloalkyl, optionally substituted C 6 -Ci 2 aryl, aryloxy, optionally substituted 3-8 membered cycloalkyl, optionally substituted 4-15 membered heterocyclyl, or optionally substituted 4-15 membered heteroaryl; wherein the substituents can be independently selected from one or more R e ; R 8 and R 8a at each occurrence are hydrogen, or selected from the group consisting of optionally substituted alkyl, optionally substituted acyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally
  • R c is selected from alkyl, aminoalkyl, dialkylaminoalkyl, alkylaminoalkyl, alkoxyalkyl, -C(0)dialkylaminoalkyl, -C(0)N(CH 3 ) 2 , -C(0)OH, -C(0)NH 2 , hydroxyalkyl, heterocyclyl, aryl, arylalkyl, heterocyclylalkyl, cycloalkyl, or cycloalkylalkyl;
  • R d is alkyl, amino, halolalkyl, hydroxy, alkoxy or halogen
  • R e is alkyl, hydroxy, alkoxy, alkoxyalkoxy, amino, acyl, optionally substituted aryl, alkoxycarbonyl, alkylsulfonyl, dialkylaminoalkoxy, optionally substituted 3-8 membered cycloalkyl, optionally substituted heterocyclyl, optionally substituted 3-8 membered cycloalkylalkyl, optionally substituted 3-8 membered arylalkyl, optionally substituted 3-8 membered heterocyclylalkyl, optionally substituted 3-8 membered heterocyclylalkoxy, optionally substituted 3-8 membered heterocyclyloxy, hydroxy, -C(0)OH, oxo, -S(0) 2 NH 2 , haloalkyl, haloalkyloxy or halo; wherein the optional substituents are alkyl, amino, halo, haloalkyl, hydroxy, alkoxy, aryl, cycloal
  • 'm' is an integer selected from lor 2;
  • 'n' is an integer selected from 0, 1, 2, 3, 4 or 5;
  • the present invention relates to compounds of formula (IA)
  • R is hydrogen, or selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, alkoxylalkyl, -C(0)alkyl, -C(0)aryl optionally substituted with halo, -C(0)arylalkyl, or
  • R a is hydrogen, optionally substituted Ci-C 6 alkyl, or optionally substituted C3-C8 cycloalkyl);
  • R 2 and R 3 are independently hydrogen or alkyl
  • R4 is selected from hydrogen, optionally substituted alkyl, or -C(0)R c ; wherein the optional substituents are selected from amino, alkylamino, dialkylamino, alkoxy, hydroxy, heterocyclyl, heteroaryl, acyl(alkyl)amino, cycloalkyl, aryl (optionally substituted with halo, alkylamino, or dialkylaminoalkyl), hydroxy alkylamino, alkoxy alkylamino, alkoxyalkylaminoalkyl, -C(0)OH, -C(0)N(H)alkyl, -C(0)N(CH 3 ) 2 , -C(0)NH 2 , -NHC(0)0- alkyl, -N(CH 3 )C(0)Oalkyl, -N(CH 3 )alkoxy, -NHC(0)alkyl, -N(CH 3 )C(0)alkyl, - C(0)N(H)cycloalkyl
  • R5 and R 6 are independently selected from hydrogen, hydroxy, optionally substituted Ci-C 6 alkyl, halo, haloalkyl, optionally substituted hydroxyalkyl, or optionally substituted aminoalkyl; alternatively R5 and R 6 can be taken together with the carbon atom to which they are attached to form optionally substituted 3-8 membered cycloalkyl, optionally substituted 3- 8 membered heterocyclyl; or R5 and R 6 together represent an oxo; wherein the optional substituents are independently selected from one or more R d ;
  • W is absent, -NR 8 - -NR 8 (CO)-, -NR 8 (CR 8 R 8a )i_ 3 - or -NR 8 S(0) 2 -;
  • R 7 is hydrogen, -C(0)OH, amino, optionally substituted aminoacid, optionally substituted Ci-C 6 alkyl, optionally substituted alkoxy, optionally substituted amine, optionally substituted aminoalkyl, -NHC(0)aryl, -NHC(0)heterocyclyl, -NHC(0)cycloalkyl, optionally substituted C 6 -Ci 2 aryl, aryloxy, optionally substituted 3-8 membered cycloalkyl, optionally substituted 4- 15 membered heterocyclyl, or optionally substituted 4-15 membered heteroaryl; wherein the substituents can be independently selected from one or more R e ;
  • R 8 and R 8a at each occurrence are hydrogen, or selected from the group consisting of optionally substituted alkyl, optionally substituted acyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl; alternatively R 8 and R 8a are taken together with the carbon atom to which they are attached to form an optionally substituted 3-8 membered cycloalkyl, optionally substituted 3-8 membered heterocyclyl; or R 8 and R 8a together represent an oxo; wherein the optional substituents at each occurrence are selected from one or more R d ;
  • R c is selected from alkyl, aminoalkyl, dialkylaminoalkyl, alkylaminoalkyl, alkoxyalkyl, -C(0)dialkylaminoalkyl, -C(0)N(CH 3 ) 2 , -C(0)OH, -C(0)NH 2 , hydroxyalkyl, heterocyclyl, aryl, arylalkyl, heterocyclylalkyl, cycloalkyl, or cycloalkylalkyl;
  • R d is alkyl, amino, halolalkyl, hydroxy, alkoxy or halogen
  • R e is alkyl, hydroxy, alkoxy, alkoxyalkoxy, amino, acyl, optionally substituted aryl, alkoxycarbonyl, alkylsulfonyl, dialkylaminoalkoxy, optionally substituted 3-8 membered cycloalkyl, optionally substituted heterocyclyl, optionally substituted 3-8 membered cycloalkylalkyl, optionally substituted 3-8 membered arylalkyl, optionally substituted 3-8 membered heterocyclylalkyl, optionally substituted 3-8 membered heterocyclylalkoxy, optionally substituted 3-8 membered heterocyclyloxy, hydroxy, -C(0)OH, oxo, -S(0) 2 NH 2 , haloalkyl, haloalkyloxy or halo; wherein the optional substituents are alkyl, amino, halo, haloalkyl, hydroxy, alkoxy, aryl, cycloal
  • 'n' is an integer selected from 0, 1, 2, 3, 4 or 5;
  • the present invention relates to compounds of formula (IB)
  • Ri is optionally substituted Ci-C 6 alkyl
  • R a is hydrogen, optionally substituted Ci-C 6 alkyl, or optionally substituted C3-C8 cycloalkyl);
  • R4 is selected from hydrogen, optionally substituted alkyl, or -C(0)R c ; wherein the optional substituents are selected from amino, alkylamino, dialkylamino, alkoxy, hydroxy, heterocyclyl, heteroaryl, acyl(alkyl)amino, cycloalkyl, aryl (optionally substituted with halo, alkylamino, or dialkylaminoalkyl) , hydroxy alkylamino , alkoxy alkylamino , alkoxyalkylaminoalkyl, -C(0)OH, -C(0)N(H)alkyl, -C(0)N(CH 3 ) 2 , -C(0)NH 2 , -NHC(0)0- alkyl, -N(CH 3 )C(0)Oalkyl, -N(CH 3 )alkoxy, -NHC(0)alkyl, -N(CH 3 )C(0)alkyl, - C(0)N(H)cycl
  • R5 and R 6 are independently selected from hydrogen, hydroxy, optionally substituted Ci-C 6 alkyl, halo, haloalkyl, optionally substituted hydroxyalkyl, or optionally substituted aminoalkyl; alternatively R5 and R 6 can be taken together with the carbon atom to which they are attached to form optionally substituted 3-8 membered cycloalkyl, optionally substituted 3- 8 membered heterocyclyl; or R5 and R 6 together represent an oxo; wherein the optional substituents are independently selected from one or more R d ;
  • W is absent, -NR 8 - -NR 8 (CO)-, -NR 8 (CR 8 R 8a )i_ 3 - or -NR 8 S(0) 2 -;
  • R 7 is hydrogen, -C(0)OH, amino, optionally substituted aminoacid, optionally substituted Ci-C 6 alkyl, optionally substituted alkoxy, optionally substituted amine, optionally substituted aminoalkyl, -NHC(0)aryl, -NHC(0)heterocyclyl, -NHC(0)cycloalkyl, optionally substituted C 6 -Ci 2 aryl, aryloxy, optionally substituted 3-8 membered cycloalkyl, optionally substituted 4-15 membered heterocyclyl, or optionally substituted 4-15 membered heteroaryl; wherein the substituents can be independently selected from one or more R e ;
  • R 8 and R 8a at each occurrence are hydrogen, or selected from the group consisting of optionally substituted alkyl, optionally substituted acyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl; alternatively R 8 and R 8a are taken together with the carbon atom to which they are attached to form an optionally substituted 3-8 membered cycloalkyl, optionally substituted 3-8 membered heterocyclyl; or R 8 and R 8a together represent an oxo; wherein the optional substituents at each occurrence are selected from one or more R d ;
  • R c is selected from alkyl, aminoalkyl, dialkylaminoalkyl, alkylaminoalkyl, alkoxyalkyl, -C(0)dialkylaminoalkyl, -C(0)N(CH 3 ) 2 , -C(0)OH, -C(0)NH 2 , hydroxyalkyl, heterocyclyl, aryl, arylalkyl, heterocyclylalkyl, cycloalkyl, or cycloalkylalkyl;
  • R d is alkyl, amino, halolalkyl, hydroxy, alkoxy or halogen
  • R e is alkyl, hydroxy, alkoxy, alkoxyalkoxy, amino, acyl, optionally substituted aryl, alkoxycarbonyl, alkylsulfonyl, dialkylaminoalkoxy, optionally substituted 3-8 membered cycloalkyl, optionally substituted heterocyclyl, optionally substituted 3-8 membered cycloalkylalkyl, optionally substituted 3-8 membered arylalkyl, optionally substituted 3-8 membered heterocyclylalkyl, optionally substituted 3-8 membered heterocyclylalkoxy, optionally substituted 3-8 membered heterocyclyloxy, hydroxy, -C(0)OH, oxo, -S(0) 2 NH 2 , haloalkyl, haloalkyloxy or halo; wherein the optional substituents are alkyl, amino, halo, haloalkyl, hydroxy, alkoxy, aryl, cycloal
  • 'n' is an integer selected from 0, 1, 2, 3, 4 or 5;
  • Ri is optionally substituted Ci-C 6 alkyl
  • R a is hydrogen, optionally substituted Ci-C 6 alkyl, or optionally substituted C3-C8 cycloalkyl);
  • R4 is selected from hydrogen, optionally substituted alkyl, or -C(0)R c ; wherein the optional substituents are selected from amino, alkylamino, dialkylamino, alkoxy, hydroxy, heterocyclyl, heteroaryl, acyl(alkyl)amino, cycloalkyl, aryl (optionally substituted with halo, alkylamino, or dialkylaminoalkyl) , hydroxy alkylamino , alkoxy alkylamino , alkoxyalkylaminoalkyl, -C(0)OH, -C(0)N(H)alkyl, -C(0)N(CH 3 ) 2 , -C(0)NH 2 , -NHC(0)0- alkyl, -N(CH 3 )C(0)Oalkyl, -N(CH 3 )alkoxy, -NHC(0)alkyl, -N(CH 3 )C(0)alkyl, - C(0)N(H)cycl
  • R5 and R 6 are independently selected from hydrogen, hydroxy, optionally substituted Ci-C 6 alkyl, halo, haloalkyl, optionally substituted hydroxyalkyl, or optionally substituted aminoalkyl; alternatively R5 and R 6 can be taken together with the carbon atom to which they are attached to form optionally substituted 3-8 membered cycloalkyl, optionally substituted 3- 8 membered heterocyclyl; or R5 and R 6 together represent an oxo; wherein the optional substituents are independently selected from one or more R d ;
  • W is absent, -NR 8 - -NR 8 (CO)-, -NR 8 (CR 8 R 8a )i_ 3 - or -NR 8 S(0) 2 -;
  • R 7 is hydrogen, -C(0)OH, amino, optionally substituted aminoacid, optionally substituted Ci-C 6 alkyl, optionally substituted alkoxy, optionally substituted amine, optionally substituted aminoalkyl, -NHC(0)aryl, -NHC(0)heterocyclyl, -NHC(0)cycloalkyl, optionally substituted C 6 -Ci 2 aryl, aryloxy, optionally substituted 3-8 membered cycloalkyl, optionally substituted 4-15 membered heterocyclyl, or optionally substituted 4-15 membered heteroaryl; wherein the substituents can be independently selected from one or more R e ;
  • R 8 and R 8a at each occurrence are hydrogen, or selected from the group consisting of optionally substituted alkyl, optionally substituted acyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl; alternatively R 8 and R 8a are taken together with the carbon atom to which they are attached to form an optionally substituted 3-8 membered cycloalkyl, optionally substituted 3-8 membered heterocyclyl; or R 8 and R 8a together represent an oxo; wherein the optional substituents at each occurrence are selected from one or more R d ; R c is selected from alkyl, aminoalkyl, dialkylaminoalkyl, alkylaminoalkyl, alkoxyalkyl, -C(0)dialkylaminoalkyl, -C(0)N(CH 3
  • R d is alkyl, amino, halolalkyl, hydroxy, alkoxy or halogen
  • R e is alkyl, hydroxy, alkoxy, alkoxyalkoxy, amino, acyl, optionally substituted aryl, alkoxycarbonyl, alkylsulfonyl, dialkylaminoalkoxy, optionally substituted 3-8 membered cycloalkyl, optionally substituted heterocyclyl, optionally substituted 3-8 membered cycloalkylalkyl, optionally substituted 3-8 membered arylalkyl, optionally substituted 3-8 membered heterocyclylalkyl, optionally substituted 3-8 membered heterocyclylalkoxy, optionally substituted 3-8 membered heterocyclyloxy, hydroxy, -C(0)OH, oxo, -S(0) 2 NH 2 , haloalkyl, haloalkyloxy or halo; wherein the optional substituents are alkyl, amino, halo, haloalkyl, hydroxy, alkoxy, aryl, cycloal
  • 'n' is an integer selected from 0, 1, 2, 3, 4 or 5;
  • the present invention relates to compounds of formula (ID)
  • R a is hydrogen, optionally substituted Ci-C 6 alkyl, or optionally substituted C 3 -C 8 cycloalkyl;
  • R 2 at each occurrence are independently selected from hydrogen, alkyl, halo, or haloalkyl;
  • R 3 at each occurrence are independently selected from hydrogen, halo, haloalkyl, alkyl, or -OR t ,; wherein R is hydrogen, or selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, alkoxylalkyl, - C(0)alkyl, -C(0)aryl, -C(0)heteroaryl, -C(0)cycloalkyl, -C(0)arylalkyl, - C(0)heterocyclylalkyl, -C(0)cycloalkylalkyl, I , or o ; alternatively, R 2 and R 3 taken together with the carbon atom to which they are attached form an oxo;
  • R4 is selected from hydrogen, optionally substituted alkyl, or -C(0)R c ; wherein the optional substituents are selected from amino, alkylamino, dialkylamino, alkoxy, hydroxy, heterocyclyl, heteroaryl, acyl(alkyl)amino, cycloalkyl, aryl (optionally substituted with halo, alkylamino, or dialkylaminoalkyl), hydroxy alkylamino, alkoxy alkylamino, alkoxyalkylaminoalkyl, -C(0)OH, -C(0)N(H)alkyl, -C(0)N(CH 3 ) 2 , -C(0)NH 2 , -NHC(0)0- alkyl, -N(CH 3 )C(0)Oalkyl, -N(CH 3 )alkoxy, -NHC(0)alkyl, -N(CH 3 )C(0)alkyl, - C(0)N(H)cycloalkyl
  • R5 and R 6 are independently selected from hydrogen, hydroxy, optionally substituted Ci-C 6 alkyl, halo, haloalkyl, optionally substituted hydroxyalkyl, or optionally substituted aminoalkyl; alternatively R5 and R 6 can be taken together with the carbon atom to which they are attached to form optionally substituted 3-8 membered cycloalkyl, optionally substituted 3- 8 membered heterocyclyl; or R5 and R 6 together represent an oxo; wherein the optional substituents are independently selected from one or more R d ;
  • W is absent, -NR 8 - -NR 8 (CO)-, -NR 8 (CR 8 R 8a )i_ 3 - or -NR 8 S(0) 2 -;
  • R 7 is hydrogen, -C(0)OH, amino, optionally substituted aminoacid, optionally substituted Ci-C 6 alkyl, optionally substituted alkoxy, optionally substituted amine, optionally substituted aminoalkyl, -NHC(0)aryl, -NHC(0)heterocyclyl, -NHC(0)cycloalkyl, optionally substituted C 6 -Ci 2 aryl, aryloxy, optionally substituted 3-8 membered cycloalkyl, optionally substituted 4-15 membered heterocyclyl, or optionally substituted 4-15 membered heteroaryl; wherein the substituents can be independently selected from one or more R e ;
  • R 8 and R 8a at each occurrence are hydrogen, or selected from the group consisting of optionally substituted alkyl, optionally substituted acyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl; alternatively R 8 and R 8a are taken together with the carbon atom to which they are attached to form an optionally substituted 3-8 membered cycloalkyl, optionally substituted 3-8 membered heterocyclyl; or R 8 and R 8a together represent an oxo; wherein the optional substituents at each occurrence are selected from one or more R d ; R c is selected from alkyl, aminoalkyl, dialkylaminoalkyl, alkylaminoalkyl, alkoxyalkyl, -C(0)dialkylaminoalkyl, -C(0)N(CH 3
  • R d is alkyl, amino, halolalkyl, hydroxy, alkoxy or halogen
  • R e is alkyl, hydroxy, alkoxy, alkoxyalkoxy, amino, acyl, optionally substituted aryl, alkoxycarbonyl, alkylsulfonyl, dialkylaminoalkoxy, optionally substituted 3-8 membered cycloalkyl, optionally substituted heterocyclyl, optionally substituted 3-8 membered cycloalkylalkyl, optionally substituted 3-8 membered arylalkyl, optionally substituted 3-8 membered heterocyclylalkyl, optionally substituted 3-8 membered heterocyclylalkoxy, optionally substituted 3-8 membered heterocyclyloxy, hydroxy, -C(0)OH, oxo, -S(0) 2 NH 2 , haloalkyl, haloalkyloxy or halo; wherein the optional substituents are alkyl, amino, halo, haloalkyl, hydroxy, alkoxy, aryl, cycloal
  • 'm' is an integer selected from lor 2;
  • 'n' is an integer selected from 0, 1, 2, 3, 4 or 5;
  • Ri is wherein R a is hydrogen, optionally substituted Ci-C 6 alkyl, or optionally substituted C 3 -C 8 cycloalkyl.
  • R 2 at each occurrence is selected from hydrogen or alkyl; and R 3 at each occurrence is selected from hydrogen, alkyl, or - ORt,; wherein R is hydrogen, or selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, alkoxylalkyl, -C(0)alkyl, -
  • R is hydrogen, or selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, alkoxylalkyl, -C(0)alkyl, -C(0)aryl, -C(0)heteroaryl, (0)cycloalkyl, -C(0)arylalkyl, -C(0)heterocyclylalkyl, -C(0)cycloalkylalkyl, I
  • R 2 is hydrogen, and R 3 is -OR b ,; wherein R is hydrogen or alkyl
  • R 4 is hydrogen or optionally substituted alkyl.
  • the optional substituents are selected from amino, alkylamino, dialkylamino, alkoxy, hydroxy, heterocyclyl, heteroaryl, acyl(alkyl)amino, cycloalkyl, aryl (optionally substituted with halo, or dialkylaminoalkyl), hydroxy alkylamino, alkoxy alkylamino, alkoxyalkylaminoalkyl, -C(0)OH, -C(0)N(H)alkyl, -C(0)N(CH 3 ) 2 , -C(0)NH 2 , -NHC(0)Oalkyl, -N(CH 3 )C(0)Oalkyl, -N(CH 3 )alkoxy, - NHC(0)alkyl, -N(CH 3 )C(0)alkyl, -C(0)N(H)cycloalkyl, -C(0)N(H)cycloalkylalkyl, or - C(0)he
  • R5 and R 6 independently are hydrogen or alkyl.
  • R5 and R 6 are taken together with the carbon atom to which they are attached represent an oxo.
  • R5 and R 6 are taken together with the carbon atom to which they are attached to form cycloalkyl or heterocyclyl ring.
  • R 8 and R 8a at each occurrence are hydrogen, or optionally substituted alkyl, or optionally substituted acyl; alternatively R 8 and R 8a are taken together with the carbon atom to which they are attached to form an optionally substituted 3-8 membered cycloalkyl, optionally substituted 3-8 membered heterocyclyl; or R 8 and R 8a together represent an oxo.
  • the optional substituents at each occurrence is selected from one or more R ⁇ ; wherein R is hydrogen or halogen.
  • R 7 is hydrogen
  • R 7 is -C(0)OH, optionally substituted Ci-C 6 alkyl, optionally substituted alkoxy, optionally substituted amine, optionally substituted aminoalkyl, -NHC(0)aryl, -NHC(0)heterocyclyl, NHC(0)cycloalkyl, optionally substituted C 6 -Ci2 aryl, aryloxy, optionally substituted 3-8 membered cycloalkyl, optionally substituted 4-15 membered heterocyclyl, optionally substituted 4-15 membered heteroaryl.
  • the optional substituents at each occurrence is selected from one or more R e ; wherein R e is alkyl, hydroxy, alkoxy, alkoxyalkoxy, amino, acyl, optionally substituted aryl, alkoxycarbonyl, alkylsulfonyl, dialkylaminoalkoxy, optionally substituted 3-8 membered cycloalkyl, optionally substituted heterocyclyl, optionally substituted 3-8 membered cycloalkylalkyl, optionally substituted 3-8 membered arylalkyl, optionally substituted 3-8 membered heterocyclylalkyl, optionally substituted 3-8 membered heterocyclylalkoxy, optionally substituted 3-8 membered heterocyclyloxy, hydroxy, -C(0)OH, oxo, -S(0) 2 NH2, haloalkyl, haloalkyloxy or halo.
  • 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, stereo siomers, 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, stereosiomers, 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 as described herein and at least one pharmaceutically acceptable excipient (such as a pharmaceutically acceptable carrier or diluent).
  • the pharmaceutical composition comprises a therapeutically effective amount of at least one compound described herein.
  • the compound(s) present in the composition may be associated with a pharmaceutically acceptable excipient (such as a carrier or a diluent) or may be diluted by a carrier, or enclosed within a carrier which may be in the form of a capsule, sachet, 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, Fosetemsavir, Dolutegravir, Elvitegravir, Raltegravir, Bictegravir, Cobetagravir or a combination thereof.
  • the second anti-HIV agent is Abacavir, Didanosine, Emtricitabine, Lami
  • 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 il2), 55-63 and SPC Cole, cancer chemotherapy and Pharmacology, 1986, 17, 259-263.
  • 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).
  • 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.
  • alkylamino refers to alkyl group as defined above attached via amino linkage to the rest of the molecule. Representative examples of those groups are -NH 2 , - NHCH 3 , -N(CH 3 ) 2 and the like.
  • aminoalkyl refers to any amino derivative of an alkyl radical more specifically dimethylamino ethyl and dimethylamino methyl.
  • aryl refers to an aromatic radical having from 6 to 14 carbon atoms such as phenyl, naphthyl, tetrahydronapthyl, indanyl, and biphenyl.
  • alkoxy refers to a straight or branched hydrocarbon chain with oxygen radical consisting carbon and hydrogen atoms, containing saturation or unsaturation, having from one to eight carbon atoms, and which is attached through oxygen atom to the rest of the molecule by a single bond, e.g., methyloxy, ethyloxy, n-propyloxy, 1-methylethyloxy (isopropyloxy), n-butyloxy, n-pentyloxy, and 1,1-dimethylethyloxy (t-butyloxy).
  • amine refers to an organic compounds and functional groups that contain a basic nitrogen atom with a lone pair.
  • Amines are derivatives of ammonia, wherein one or more hydrogen atoms have been replaced by a substituent such as an alkyl or aryl group these may respectively be called alkylamines and arylamines; amines in which both types of substituent are attached to one nitrogen atom may be called alkylarylamines.
  • Important amines include amino acids, trimethylamine, and aniline.
  • aminoalkyl refers to any amino derivative of an alkyl radical specifically methylamino.
  • alkylaminoalkyl refers aminoalkyl radicals having the nitrogen atom substituted with an alkyl radical.
  • dialkylamino refers -N(alkyl)alkyl; wherein alkyl is as defined above.
  • dialkylaminoalkyl refers to alkylamino groups attached to an alkyl group. Examples include, but are not limited to, ⁇ , ⁇ -dimethylaminomethyl, N,N- dimethylaminoethyl ⁇ , ⁇ -dimethylaminopropyl, and the like.
  • hydroxyalkylamino group denotes an (HO-alkyl) 2 -N- group or HO-alkyl-
  • acyl refers to a group R-CO- wherein R is an optionally substituted alkyl group defined above.
  • R is an optionally substituted alkyl group defined above.
  • 'acyl' groups are, but not limited to, CH 3 CO-, CH 3 CH 2 CO- , CH 3 CH 2 CH 2 CO- or (CH 3 ) 2 CHCO-.
  • acyl(alkyl)amino means -N(Ci-C 6 alkyl)acyl; wherein alkyl and acyl are as defined above.
  • alkoxyalkyl refers to the alkyl group as defined above, which is attached to the alkoxy group as defined above.
  • alkoxycarbonyl means an alkoxy-C(O)- group, in which the alkyl group as defined above.
  • alkoxy alkylamino means alkoxyalkyl group attached to an amino group wherein the alkoxyalkyl and amino are defined as above.
  • alkoxyalkylaminoalkyl means alkoxyalkyl group attached to an aminoalkyl group wherein the alkoxyalkyl and aminoalkyl are defined as above.
  • aryloxy refers to an aryl group as defined above attached via an oxygen linkage to the rest of the molecule.
  • Examples of aryloxy moiety include, but are not limited to phenoxy and naphthoxy. Unless set forth or recited to the contrary, all aryloxy groups described herein may be substituted or unsubstituted.
  • cycloalkyl denotes a non-aromatic mono or multicyclic ring system of from 3 to about 12 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • multicyclic cycloalkyl groups include, but are not limited to, perhydronapththyl, adamantyl and norbornyl groups, bridged cyclic groups and spirobicyclic groups, e.g., spiro (4,4) non-2-yl.
  • cycloalkylalkyl alone or in combination with other term(s) means alkyl substituted with cycloalkyl group, wherein the terms “alkyl” and “cycloalkyl” are as defined above.
  • alkylsulfonyl means a -S0 2 R radical where 'R' is alkyl as defined above, e.g., methylsulfonyl, ethylsulfonyl, and the like.
  • halogen or halo includes fluorine, chlorine, bromine, or iodine.
  • 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.
  • hydroxy means -OH.
  • haloalkoxy refers the radical -O-haloalkyl, wherein the haloalkyl is as defined above.
  • Representative examples of haloalkoxy include, but are not limited to, fluoromethoxy, trifluoromethoxy and 2-fluoroethoxy.
  • 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” 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, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolinyl, oxazolidinyl, triazolyl, isoxazolyl, isoxasolidinyl, morpholinyl, thiazolyl, thiazolinyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl, isoindolyl, iso
  • heteroaryl refers to an aromatic heterocyclic ring radical.
  • heteroaryl include, but are not limited to pyridyl, pyrazinyl, furanyl, quinolinyl, tetrazoyl , triazolyl, 1,3-Diaza-lH-indenyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, pyrazolo[l,5-a]pyrimidinyl, 1,3,4-Oxadiazolyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl, isoindolyl, indolinyl and isoindolinyl.
  • the heteroaryl ring radical may be attached to the main structure at any heteroatom or carbon atom that results in the creation of a stable structure.
  • arylalkyl or “heterocyclylalkyl” refers to an alkyl group which is further substituted by aryl or heterocyclyl respectively, wherein aryl, heterocyclyl and alkyl are as above defined.
  • Heterocyclyloxy refers to the group -O-heterocyclyl. wherein the heterocyclyl groups are as defined above.
  • heterocyclylalkoxy refers to a heterocyclyl group attached to the parent molecular moiety through an alkoxy group. Wherein heterocyclyl and alkoxy groups are same as defined above. "Substituted” refers to 1-3 substituents on the same position or on different positions with the same groups or different groups.
  • 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 stereo isomeric 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 stereo isomeric 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.
  • 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.
  • 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, ⁇ 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 cyst
  • 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 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 (10 TCID 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. Percentage inhibition was calculated with reference to control values (vehicle controls).
  • 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.
  • 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 C-3 & C-28 di hydroxy groups in compounds of formula (1) can be protected in different ways like (a) With a suitable ester forming reagent such as anhydride with or without addition of a base or a catalyst under heating conditions or (b) with a suitable ester forming reagents such as anhydrides or acid halides or mixed anhydrides in the presence of a base such as triethylamine (TEA) or N,N-diisopropylethylamine (DIPEA) or pyridine or the like in a solvent such as dichloromethane (DCM) or tetrahydrofuran (THF) or toluene or the like with or without addition of a catalyst such as 4-(Dimethylamino)pyridine (DMAP) under heating conditions to give C-3 & C-28 di hydroxy protected compounds of formula (2).
  • a base such as triethylamine (TEA) or N,N-diisopropylethylamine (
  • the compounds of formula (3) can be prepared by the reaction of compounds of formula (2) with hydrogen bromide (HBr) in acetic acid (AcOH), acetic acid (AcOH) and acetic anhydride (Ac 2 0) in a suitable solvent such as toluene or benzene.
  • the compounds of formula (3) can be converted to the compounds of formula (4) with reagents such as sodium dichromate dihydrate (Na 2 Cr 2 0 7 .2H 2 0), sodium acetate (NaOAc), acetic acid (AcOH) and acetic anhydride (Ac 2 0) in a suitable solvent such as toluene or benzene.
  • the C-28 protecting group in compound (4) can be selectively deprotected to the C-28 hydroxy compounds of formula (5) in the presence of a base such as potassium hydroxide (KOH) in the combination of solvents such as toluene: ethanol (EtOH) (1 :1) or with a reagent like Aluminium isopropoxide [Al(OCH(CH 3 ) 2 ) 3 ] in a solvent such as 2-propanol or the like.
  • a base such as potassium hydroxide (KOH)
  • solvents such as toluene: ethanol (EtOH) (1 :1)
  • EtOH ethanol
  • Aluminium isopropoxide Al(OCH(CH 3 ) 2 ) 3
  • the C-28 hydroxy compounds of formula (5) can be converted to the C-28 aldehyde compounds of formula (6) in the presence of an oxidizing agent such as pyridinium chlorochromate (PCC) or pyridinium dichromate (PDC) or Dess-Martin periodinane (DMP) or Swern oxidation conditions in a solvent such as dichloromethane (DCM) or the like.
  • an oxidizing agent such as pyridinium chlorochromate (PCC) or pyridinium dichromate (PDC) or Dess-Martin periodinane (DMP) or Swern oxidation conditions in a solvent such as dichloromethane (DCM) or the like.
  • PCC pyridinium chlorochromate
  • PDC pyridinium dichromate
  • DMP Dess-Martin periodinane
  • Swern oxidation conditions in a solvent such as dichloromethane (DCM) or the like.
  • the C-3 esters of compounds of formula (9) can be prepared by the reaction of compound (7) with acids of compounds of formula (8) in different ways like
  • a coupling reagent such as 1-ethyl- 3-(3-dimethylaminopropyl)carbodiimide (EDCI) and a catalyst such as 4-
  • DMAP Dimethylaminopyridine
  • DCM dichloromethane
  • DMF N,N-dimethylformamide
  • the compounds of formula (9) can be converted to the C-28 hydroxy compounds of formula (10) in the presence of chiral ligand N,N'-bis(isobornyl)ethylenediamine, derived from (S)-camphor reagent like nitromethane, base like ⁇ , ⁇ -diisopropylethylamine and a catalyst such as copper(I) acetate [Cu(OAc)] in the combination of solvents such as toluene and ie/ -butanol (t-BuOH).
  • the primary amines of compounds of formula (11) can be prepared by reducing the nitro group in compounds of formula (10) with a reagent like Nickel(II) chloride hexahydrate (NiCl 2 - 6H 2 0) and a reducing agent such as sodium borohydride (NaBH 4 ) in a suitable solvent such as methanol (MeOH) or the like.
  • the secondary amines of compounds of formula (13) can be prepared by the reductive amination of compounds of formula (11) with aldehydes of compounds of formula (12) in the presence of a reducing agent such as sodium triacetoxyborohydride (STAB) or the like in a solvent such as tetrahydrofuran (THF) or the like.
  • the compounds of formula 15 can be prepared by the reductive amination of compounds (13) and (14) with a reducing agent such as sodium cyanoborohydride (NaCNBH 3 ) or the like in the presence of a base such as triethylamine (TEA) or ⁇ , ⁇ -diisopropylethylamine (DIPEA) or the like in a solvent such as methanol (MeOH) or the like.
  • a reducing agent such as sodium cyanoborohydride (NaCNBH 3 ) or the like in the presence of a base such as triethylamine (TEA) or ⁇ , ⁇ -diisopropylethylamine (DIPEA) or the like in a solvent such as methanol (MeOH) or the like.
  • a reducing agent such as sodium cyanoborohydride (NaCNBH 3 ) or the like
  • a base such as triethylamine (TEA) or ⁇ , ⁇ -di
  • the compounds of formula (I) can be prepared by hydrolysing the ester group in compounds of formula (15) or (16) in the presence of aqueous solution of inorganic bases such as potassium carbonate (K 2 C0 3 ) or sodium hydroxide (NaOH) or potassium hydroxide (KOH) or the like in the combination of solvents such as tetrahydrofuran (THF): methanol (MeOH) or the like.
  • inorganic bases such as potassium carbonate (K 2 C0 3 ) or sodium hydroxide (NaOH) or potassium hydroxide (KOH) or the like in the combination of solvents such as tetrahydrofuran (THF): methanol (MeOH) or the like.
  • the amides of compounds of formula (18) can be prepared by coupling of compounds (17) and compounds of formula (11) in the presence of coupling reagents such as 0-(7- Azabenzotriazol-l-yl)-N,N,N ⁇ N'-tetramethyluroniumhexafluorophosphate (HATU) or O- (Benzotriazol-l-yl)-N,N,N ⁇ N'-tetramethyluroniurnhexafluorophosphate (HBTU) or 1-Ethyl- 3-(3-dimethylaminopropyl)carbodiimide (EDCI) and 1-Hydroxybenzotriazole (HOBt) in the presence of a base such as triethylamine (TEA) or ⁇ , ⁇ -Diisopropylethylamine (DIPEA) in a suitable solvent such as ⁇ , ⁇ -dimethylformamide (DMF) or 1,2-dichloroethane (1,2-D
  • the compounds of formula (I) can be prepared by hydrolysing the ester group in compounds of formula (18) in the presence of aqueous solution of inorganic bases such as sodium hydroxide (NaOH) or potassium hydroxide (KOH) or the like in the combination of solvents such as tetrahydrofuran (THF): methanol (MeOH) or the like.
  • inorganic bases such as sodium hydroxide (NaOH) or potassium hydroxide (KOH) or the like
  • solvents such as tetrahydrofuran (THF): methanol (MeOH) or the like.
  • the protected amines of compounds of formula (18b) can be prepared by the reaction of (Boc) 2 0 in the presence of a base such as triethylamine (TEA) or N,N- Diisopropylethylamine (DIPEA) in a suitable solvent such as DCM (Dichloromethane).
  • a base such as triethylamine (TEA) or N,N- Diisopropylethylamine (DIPEA) in a suitable solvent such as DCM (Dichloromethane).
  • the compounds of formula (18c) can be prepared by acetylation with acetic anhydride in the presence of catalyst such as DMAP, and base such as TEA (triethylamine) in a suitable solvent such as DCM or THF. Upon deprotection of compound 18c in the presence of TFA in DCM or HC1 in 1,4-dioxane results in the formation of compound of formula (18d).
  • Example-I-1 Preparation of (lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-3a-((R)- 2-((4-chlorobenzyl)(2-(dimethylamino)ethyl)amino)-l-hydroxyethyl)-l-isopropyl-5a,5b,8,8, l la-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,l l,l la,l lb,12,13,13a-octadecahvdro-2H -cyclopentaralchrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-l-carboxylic acid:
  • Step 1 Synthesis of ((lR,3aS,5aR,5bR,7aR,9S,llaR,llbR,13aR,13bR)-9-acetoxy-5a,5b,8,8, lla-pentamethyl-l-(prop-l-en-2-yl)icosahydro-3aH-cyclopenta[a]chrysen-3a-yl)methyl acetate:
  • Step 2 Synthesis of ((3aS,5aR,5bR,7aR,9S,llaR,llbR,13aS)-9-acetoxy-l-isopropyl-5a,5b,8, 8,lla-pentamethyl-2,3,4,5,5a,5b,6, 7,7a,8,9,10,ll,lla,llb,12,13,13a-octadecahydro-3aH- cyclopenta[a]chrysen-3a-yl)methyl acetate:
  • HBr in acetic acid (800 ml, 33%), was added to a suspension of ⁇ R, &S,5aR,5bR, 7a ?,95,l la ?,l lb ?,13a ?,13b ?)-9-acetoxy-5a,5b,8,8,l la-pentamethyl-l-(prop-l-en-2-yl) icosahydro-3aH-cyclopenta[a]chrysen-3a-yl)methyl acetate (step 1, 400 g, 0.76 mol, 1.0 eq) in toluene (800 ml), Ac 2 0 (800 ml) and acetic acid (800 ml) previously heated at 105 °C.
  • Step 3 Synthesis of ((3aR,5aR,5bR, 7aR,9S,llaR,llbR,13aS)-9-acetoxy-l-isopropyl-5a,5b,8, 8,lla-pentamethyl-2-oxo-2,3,4,5,5a,5b,6, 7,7a,8,9,10,ll,lla,llb,12,13,13a-octadecahydro- 3aH-cyclopenta[a]chrysen-3a-yl)methyl acetate:
  • Step 4 Synthesis of (3aR,5aR,5bR,7aR,9S,llaR,llbR,13aS)-3a-(hydroxymethyl)-l-isopropyl -5 a, 5b, 8, 8, 1 la-pentamethyl-2-oxo-3,3a,4, 5, 5 a, 5b, 6, 7,7a,8,9,10,ll,lla,llb,12,13,l 3 a -octa decahydro-2H-cyclopenta[a ]chrysen-9-yl acetate:
  • Step 5 Synthesis of (3aR,5aR,5bR,7aR,9S,llaR,llbR,13aS)-3a-formyl-l-isopropyl-5a,5b,8, 8,lla-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6, 7,7a,8,9,10,ll,lla,llb,12,13,13a-octadecahydro- 2H-cyclopenta[a ]chrysen-9-yl acetate:
  • reaction mixture was stirred at room temperature for about 1 hour. TLC indicated starting material was consumed and the desired product was observed.
  • the reaction mixture was diluted with water (50 ml) and extracted with CH 2 CI 2. The combined organic layers were washed with saturated sodium bicarbonate solution, dried over sodium sulphate and evaporated under reduced pressure to give a crude product, which was triturated with ethanol, solid was filtered and dried under vacuum to obtain the desired product (41.4 g, yield: 80%) as a white solid.
  • Step 6 Synthesis of (3aR,5aR,5bR, 7aR,9S,l laR,l lbR,l 3aS)-9-hydroxy-l -isopropyl-5a,5b,8,
  • the reaction was warmed to approximately 45-55 °C and maintained for about 14 hours. The reaction was then treated with water (6 ml) and heated at 45 °C for about 30 minutes. The reaction was then cooled to room temperature and evaporated under vacuum at 40 °C to 60 ml. Dichloromethane (200 ml) was added and the reaction was treated with IN HC1 (100 ml), mixed thoroughly, organic layer was separated and evaporated to 40 ml. Acetonitrile (160 ml) was added and heated at 60 °C, thus forming a clear solution.
  • Step 7 Synthesis of 1-benzyl 3-((3aR,5aR,5bR, 7aR,9S,llaR,llbR,13aS)-3a-formyl-l-iso propyl-5a,5b,8,8,lla-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7, 7a,8,9,10,ll,lla,llb,12,13,13a- octadecahydro-2H-cyclopenta[a]chrysen-9-yl) (lR,3S)-2,2-dimethylcyclobutane-l,3- dicarboxylate:
  • reaction mixture was allowed to stir at room temperature for overnight. TLC indicated starting material was consumed and the desired product was observed.
  • the reaction mixture was diluted with water (300 ml) and extracted with CH 2 C1 2 (2x300 ml). The combined organic extracts were dried over Na 2 S0 4 , filtered and evaporated under reduced pressure. The residue was purified by silicagel column chromatography by using 0-1% MeOH in DCM gradient. The fractions containing the expected product were combined and concentrated under reduced pressure to obtain the desired product (7.0 g, yield: 91%) as a white solid.
  • Step 8 Synthesis of 1-benzyl 3-((3aR,5aR,5bR, 7aR,9S,llaR,llbR,13aS)-3a-((R)-l-hydroxy- 2-nitroethyl)-l-isopropyl-5a,5b,8, 8,1 la-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6, 7,7a,8,9, 10,11, lla,llb,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)(lR,3S)-2,2-dimethylcyclo butane -1,3 -dicarboxy late:
  • reaction was next allowed to cool to 7-13 °C, then charged nitro methane (28.8 g, 472.5 mmol, 55 eq) and N,N-diisopropylethylamine (4.5 ml, 25.7 mmol, 3.0 eq) and allowed to stir at 7-13°C for approximately 4 days. TLC indicated starting material was consumed and the desired product was observed.
  • Step 9 Synthesis of l-((3aR,5aR,5bR,7aR,9S,llaR,llbR,13aS)-3a-((R)-2-amino-l-hydroxy ethyl)-l-isopropyl-5a,5b,8,8,lla-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7, 7a,8,9,10,ll,lla,llb, 12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)3-benzyl(lS,3R)-2,2-dimethylcyclo butane -1,3 -dicarboxylate :
  • Step 10 Synthesis of 1-benzyl 3-((3aR,5aR,5bR,7aR,9S,llaR,llbR,13aS)-3a-((R)-2-((4- chlorobenzyl) mino)-l-hydroxyethyl)-l-isopropyl-5a,5b,8,8,lla-pentamethyl-2-oxo-3,3a,4,5, 5a,5b,6,7, 7a,8,9,10,ll,lla,llb,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl) ( lR,3S)-2,2-dimethylcyclo butane- 1 ,3 -dicarboxylate:
  • Step 11 Synthesis of 1-benzyl 3-((3aR,5aR,5bR,7aR,9S,llaR,llbR,13aS)-3a-((R)-2-((4- chlorobenzyl)(2-( dimethylamino )ethyl)amino )-l -hy droxy ethyl)- 1 -isopropyl-5a,5b,8, 8,11a- pentamethyl-2-oxo-3, 3 a, 4, 5, 5 a, 5b, 6, 7, 7a,8,9,10,ll,lla,llb,12,13,l 3a-octadecahydro-2H- cyclopenta[a] chrysen- -yl) ( 1 R,3S )-2,2-dimethylcyclobutane-l ,3 -dicarboxylate :
  • Step 12 Synthesis of (lR,3S)-3-((((3aR,5aR,5bR, 7aR,9S,llaR,llbR,13aS)-3a-((R)-2-((4- chlorobenzyl)(2-( dimethylamino )ethyl)amino )-l -hy droxy ethyl)- 1 -isopropyl-5a,5b,8, 8,11a- pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7, 7a,8,9,10,ll,lla,llb,12,13,13a-octadecahydro-2H- cyclopenta[a] chrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-l-carboxylic acid:
  • reaction mixture was evaporated under reduced pressure, diluted with water (50 ml) and pH adjusted to 7.0 with IN HC1 and extracted with DCM (3x100 ml). The combined organic extracts were dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by silicagel column chromatography by using 10% MeOH: DCM and 0.2% triethylamine as an eluent to obtain the desired product (50 mg) as a white solid.
  • Example 1-2 Preparation of (lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-3a-((R)- 2-(2-(4-chlorobenzamido)-2-methylpropanamido)- 1 -hydroxyethyl)- 1 -isopropyl- 5a,5b,8,8,l la-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,l l,l la,l lb,12,13,13a- octadecahydro-2H-cyclopentaralchrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-l- carboxylic acid:
  • Step 1 Synthesis of 1-benzyl 3-((3aR,5aR,5bR, 7aR,9S,llaR,llbR,13aS)-3a-((R)-2-(2-(4- chlorobenzamido )-2-methylpropanamido)-l -hydroxyethyl)-!
  • Step 2 Synthesis of (lR,3S)-3-((((3aR,5aR,5bR, 7aR,9S,llaR,llbR,13aS)-3a-((R)-2-(2-(4- chlorobenzamido )-2-methylpropanamido)-l -hydroxyethyl)-!
  • reaction mixture was stirred at room temperature for overnight. TLC indicated starting material was consumed and the desired product was observed.
  • the organic phase was evaporated under reduced pressure, the reaction mixture was diluted with water (10 ml), cooled to 0 °C, ptl adjusted to 6.0 with IN HC1 and stirred for about 15 minutes. The precipitates formed were collected by filtration, washed with water (10 ml) and dried in vacuo. The obtained solid was dissolved in DCM (20 ml), dried over sodium sulphate, filtered and concentrated under reduced pressure. The residue was washed with ethyl acetate (10 ml), acetonitrile (20 ml) was added and heated to reflux for about 30 minutes.
  • Example 1-3 Preparation of (lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-3a-((R)- 2-amino-l-hvdroxyethyl)-l-isopropyl-5a,5b,8,8 J la-pentamethyl-2-oxo- 3,3a,4,5,5a,5b,6,7,7a,8,9,10,l l,l la,l lb,12,13,13a-octadecahvdro-2H-cvclopentaralchrvsen- 9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane- 1-carboxylic acid:
  • the compounds of formula (19) can be prepared by the reaction of compounds of formula (6) with a reagent like niromethane in the presence of a base such as triethylamine (TEA) or ⁇ , ⁇ -diisopropylethylamine (DIPEA).
  • a base such as triethylamine (TEA) or ⁇ , ⁇ -diisopropylethylamine (DIPEA).
  • TEA triethylamine
  • DIPEA ⁇ , ⁇ -diisopropylethylamine
  • the hydroxy group in compound (19) can be acetylated in the presence of a catalyst such as /?ara-toluenesulfonic acid monohydrate (pTSA) with a suitable reagent such as acetic anhydride or the like.
  • pTSA /?ara-toluenesulfonic acid monohydrate
  • the compounds of formula (21) can be prepared by chopping the acetoxy group in compound (20) in the presence of a reducing agent such as sodium borohydride (NaBH 4 ) in solvents such as methanol or combination of methanol (MeOH) and Tetrahydrofuran (THF).
  • a reducing agent such as sodium borohydride (NaBH 4 ) in solvents such as methanol or combination of methanol (MeOH) and Tetrahydrofuran (THF).
  • the acids of compounds of formula (22) can be prepared by the reaction of compounds of formula (21) with reagents such as sodium nitrite (NaN0 2 ) and acetic acid (CH 3 COOH) in a solvent such as Dimethylsulfoxide (DMSO) or the like.
  • DMSO Dimethylsulfoxide
  • the amides of compounds of formula (24) can be prepared by coupling of compounds (22) and (23) in the presence of coupling reagents such as 0-(7-Azabenzotriazol- l-yl)-N,N,N',N'-tetramethyluroniumhexafluorophosphate (HATU) or 0-(Benzotriazol-l-yl)-N,N,N ⁇ N'-tetramethyluroniumhexafluorophosphate (HBTU) or 1- Ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI) and 1-Hydroxybenzotriazole (HOBt) in the presence of a base such as triethylamine (TEA) or N,N-Diisopropylethylamine (DIPEA) in a suitable solvent such as ⁇ , ⁇ -dimethylformamide (DMF) or 1,2-dichloroethane (1,2-DCE).
  • the C-3 hydroxy compound (25) can be prepared by deprotection at C-3 of compound (24) in the presence of a base such as NaOH or KOH in the combination of solvents such as MeOH, THF and H 2 0 (4:2: 1).
  • the C-3 esters of compounds of formula (26) can be prepared by the reaction of compound (25) with compound (8) with a reagent such as 2,4,6-trichlorobenzoyl chloride, in the presence of a base such as triethylamine (TEA) or ⁇ , ⁇ -Diisopropylethylamine (DIPEA) and a catalyst such as 4-dimethylaminopyridine (DMAP) in solvents such as dichloromethane (DCM) or 1,2-dichloroethane (1,2-DCE) or the like.
  • a base such as NaOH or KOH in the combination of solvents such as MeOH, THF and H 2 0 (4:2: 1).
  • the ester group in compounds of formula (26) can be hydrolysed in the presence of aqueous solution of inorganic bases such as sodium hydroxide (NaOH) or potassium hydroxide (KOH) or the like in the combination of solvents such as tetrahydrofuran (THF): methanol (MeOH) (1: 1) to give compounds of formula (I).
  • the sodium salt of compounds of formula (I) can be prepared by the reaction of compound (I) in the presence of a base such as sodium hydroxide (NaOH) in a mixture of solvents such as methanol (MeOH) and water (H 2 0).
  • Example II-l Preparation of sodium (lR,3S)-3-((((3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aS)- 3a-(2-((4-chlorobenzyl)(2-(dimethylamino)ethyl)amino)-2-oxoethyl)-l-isopropyl- 5a,5b,8,8,l la-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,l l,l la,l lb,12,13,13a- octadecahvdro-2H-cvclopentaralchrvsen-9-yl)oxy)carbonyl)-2,2-dimethylcvclobutane-l- carboxylate:
  • Step 1 Synthesis of (3aR,5aR,5bR,7aR,9S,llaR,llbR,13aS)-3a-(l-hydroxy-2-nitroethyl)-l- isopropyl-5a, 5b, 8, 8, 11 a-pentamethyl-2-oxo-
  • Step 2 Synthesis of l-((3aR,5aR,5bR,7aR,9S,llaR,llbR,13aS)-9-acetoxy-l-isopropyl- 5 a, 5b, 8,8,11a -pentamethyl-2-oxo -2,3,4,5, 5 a, 5b, 6, 7, 7a, 8, 9, 10,11,1 la, lib, 12, 13, 13 a- octadecahydro-3aH-cyclopenta[a]chrysen-3a-yl)-2-nitroethyl acetate:
  • Step 3 Synthesis of (3aR,5aR,5bR,7aR,9S,llaR,llbR,13aS)-l-isopropyl-5a,5b,8,8,lla- pentamethyl-3a-(2-nitroethyl)-2-oxo-3,3a,4,5,5a,5b,6,7, 7a,8,9,10,ll,lla,llb,12,13,13a- octadecahydro-2H-cyclopenta[a ]chrysen-9-yl acetate:
  • Step 4 Synthesis of 2-((3aS,5aR,5bR, 7aR,9S,llaR,llbR,13aS)-9-acetoxy-l-isopropyl- 5 a, 5b, 8,8,11a -pentamethyl-2-oxo -2,3,4,5, 5 a, 5b, 6, 7, 7a, 8, 9, 10,11,1 la, lib, 12, 13, 13 a- octadecahydro-3aH-cyclopenta[a ]chrysen-3a-yl)acetic acid:
  • Step 5 Synthesis of (3aS,5aR,5bR, 7aR,9S,llaR,llbR,13aS)-3a-(2-((4-chlorobenzyl)(2- (dimethylamino)ethyl)amino)-2-oxoethyl)-l-isopropyl-5a,5b,8,8,lla-pentamethyl-2-oxo-
  • step 4 2,3,4,5, 5a,5b,6,7,7a,8, 9, 10, 11, 11a, l ib, 12,13, 13a-octadecahydro-3aH-cyclopenta[a]chrysen- 3a-yl)acetic acid (step 4, 2.4 g, 4.56 mmol, 1.0 eq) in DMF (10 ml) were added HBTU (2.59 g, 6.84 mmol, 1.5 eq) followed by DIPEA (3.96 ml, 22.81 mmol, 5.0 eq).
  • reaction mixture was stirred at room temperature for about 10 minutes, then N 1 -(4-chlorobenzyl)- N 2 ,N 2 -dimethylethane-l,2-diamine (Intermediate 1, 1.45 g, 6.84 mmol, 1.5 eq) in DMF (20 ml) was added and 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 (200 ml) and extracted with ethyl acetate (3x100 ml). The combined organic extracts were dried over Na 2 S0 4 , filtered and evaporated under reduced pressure.
  • Step 6 Synthesis of N-(4-chlorobenzyl)-N-(2-(dimethylamino)ethyl)-2- ( ( 3aS, 5aR, 5bR, 7aR, 9S, 11 aR, 11 bR, 13aS ) -9-hydroxy-l -isopropyl-5a, 5b, 8, 8, 1 la-pentamethyl- 2 -oxo -2, 3, 4, 5, 5 a, 5b, 6,7, 7a,8,9,10,ll,lla,llb,12,13,13a -octadecahydro -3aH- cyclopenta[a]chrysen-3a-yl)acetamide:
  • reaction mixture was allowed to stir at room temperature for about 6 hours. TLC indicated starting material was consumed and the desired product was observed.
  • the organic phase was evaporated under reduced pressure, the reaction mixture was diluted with water (50 ml) and extracted with DCM (3x100 ml). The combined organic extracts were washed with water (50 ml), dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by silicagel column chromatography by using 5% MeOH in DCM as an eluent to obtain the title compound (1.0 g, yield: 59%) as a white solid.
  • Step 7 Synthesis of l-benzyl3-((3aS,5aR,5bR, 7aR,9S,llaR,llbR,13aS)-3a-(2-((4- chlorobenzyl)(2-( dimethylamino )ethyl)amino )-2-oxoethyl)-l -isopropyl-5a,5b, 8,8,11a- pentamethyl-2-oxo-3, 3 a, 4, 5, 5 a, 5b, 6, 7, 7a,8,9,10,ll,lla,llb,12,13,l 3a-octadecahydro-2H- cyclopenta[a] chryse -9-yl) (lR,3S)-2,2-dimethylcyclobutane-l,3-dicarboxylate:
  • reaction mixture was flushed with nitrogen and allowed to stir at room temperature for overnight. TLC indicated starting material was consumed and the desired product was observed.
  • the reaction mixture was diluted with water (50 ml) and extracted with DCM (3x50 ml). The combined organic extracts were washed with water (25 ml), dried over Na 2 S0 4 , filtered and evaporated under reduced pressure. The residue was purified by silicagel column chromatography by using 3% MeOH in DCM as an eluent to obtain the title compound (1.2 g, yield: 88.8%) as a white solid.
  • Step 8 Synthesis of (lR,3S)-3-((((3aS,5aR,5bR, 7aR,9S,llaR,llbR,13aS)-3a-(2-((4- chlorobenzyl)(2-( dimethylamino )ethyl)amino )-2-oxoethyl)-l -isopropyl-5a,5b, 8,8,11a- pentamethyl-2-oxo-3, 3 a, 4, 5, 5 a, 5b, 6, 7, 7a,8,9,10,ll,lla,llb,12,13,l 3a-octadecahydro-2H- cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-l-carboxylic acid:
  • reaction mixture was stirred at room temperature for overnight. TLC indicated starting material was consumed and the desired product was observed.
  • the organic phase was evaporated under reduced pressure, the reaction mixture was diluted with water (30 ml), cooled to 0 °C, pH adjusted to 6.0 with IN HC1 and extracted with DCM (3x100 ml). The combined organic extracts were dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by silicagel column chromatography by using 8% MeOH in DCM as an eluent to obtain the title compound (0.3 g, yield: 28%) as a white solid.
  • Step 9 Synthesis of sodium (lR,3S)-3-((((3aS,5aR,5bR, 7aR,9S,llaR,llbR,13aS)-3a-(2-((4- chlorobenzyl)(2-( dimethylamino )ethyl)amino )-2-oxoethyl)-l -isopropyl-5a,5b, 8,8,11a- pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7, 7a,8,9,10,ll,lla,llb,12,13,13a-octadecahydro-2H- cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-l-carboxylate:
  • reaction mixture was stirred at room temperature for about 2 hours and then distilled out about 90% methanol under reduced pressure. Hexane (5 ml) and ethyl acetate (5 ml) were added and the reaction mixture was stirred at room temperature for overnight. The reaction mixture was filtered, solid was washed with hexane (5 ml) followed by ethyl acetate (5 ml) and dried under vacuum to obtain the title compound (0.160 g, yield: 55%) as a white solid.
  • Example II-2 Preparation of sodium (lR,3S)-3-((((3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aS)- 3a-(2-(((l-(4-chlorophenyl)cyclopropyl)methyl)(2-(dimethylamino)ethyl)amino)-2- oxoethyl)-l-isopropyl-5a,5b,8,8 J la-pentamethyl-2-oxo-
  • Step 1 Synthesis of (3aS,5aR,5bR,7aR,9S,llaR,llbR,13aS)-3a-(2-(((l-(4- chlorophenyl)cyclopropyl)methyl)(2-(dimethylamino)ethyl)amino
  • reaction mixture was stirred at room temperature for about 10 minutes, then N 1 -((l-(4- chlorophenyl)cyclopropyl)methyl)-N 2 ,N 2 -dimethylethane-l,2-diamine (Intermediate 2, 1.32 g, 5.239 mmol, 1.2 eq) was added and stirred at room temperature for overnight. TLC indicated starting material was consumed and the desired product was observed.
  • the reaction mixture was combined with another 200 mg batch of same reaction, diluted with water (350 ml) and extracted with ethyl acetate (3x50 ml). The combined organic extracts were washed with water (100 ml), dried over Na 2 S0 4 , filtered and evaporated under reduced pressure.
  • Step 2 Synthesis of N-((l-(4-chlorophenyl)cyclopropyl)methyl)-N-(2-(dimethylamino)ethyl)- 2-(( 3aS, 5aR, 5bR, 7aR, 9S, 11 aR, 11 bR, 13aS)-9-hydroxy-l -isopropyl-5a, 5b, 8,8,11a- pentamethyl-2-oxo-2, 3, 4, 5, 5 a, 5b, 6, 7, 7a,8,9,10,ll,lla,llb,12,13,l 3a-octadecahydro-3aH- cyclopenta[a]chrysen-3a-yl)acetamide:
  • reaction mixture was removed from the ice bath and was stirred at room temperature for overnight. TLC indicated starting material was consumed and the desired product was observed.
  • the organic phase was evaporated under reduced pressure, the reaction mixture was diluted with water (50 ml) and extracted with DCM (3x50 ml). The combined organic extracts were washed with water (50 ml) and brine solution (50 ml). The organic layer was dried with sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by silicagel column chromatography by using 0-7% MeOH in DCM gradient. The fractions containing the expected product were combined and concentrated under reduced pressure to obtain the title compound (2.2 g, yield: 93.22%) as an off-white solid.
  • Step 3 Synthesis of 1-benzyl 3-((3aS,5aR,5bR,7aR,9S,llaR,llbR,13aS)-3a-(2-(((l-(4- chlorophenyl)cyclopropyl)methyl)(2-(dimethylamino)ethyl)amino
  • reaction mixture was removed from the ice bath and 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 (25 ml) and extracted with DCM (3x30 ml). The combined organic extracts were washed with 0.5N HC1 (15 ml), water (30 ml) and brine solution (10 ml). The organic layer was dried over Na 2 S0 4 , filtered and evaporated under reduced pressure. The residue was purified by silicagel column chromatography by using 3-4% MeOH in DCM gradient. The fractions containing the expected product were combined and concentrated under reduced pressure to obtain the title compound (1.8 g, yield: 56%) as an off-white solid.
  • Step 4 Synthesis of (lR,3S)-3-((((3aS,5aR,5bR,7aR,9S,llaR,llbR,13aS)-3a-(2-(((l-(4- chlorophenyl)cyclopropyl)methyl)(2-(dimethylamino)ethyl)amino)-2-oxoethyl)-l-isopropyl- 5 a, 5b, 8,8,11a -pentamethyl-2-oxo -3,3 a, 4, 5, 5 a, 5b, 6,7, 7a, 8, 9, 10,11,1 la, lib, 12, 13,13 a- octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-l- carboxylic acid:
  • reaction mixture was diluted with water (10 ml), cooled to 0 °C, pU adjusted to 6.0 with IN HCl and extracted with DCM (3x25 ml).
  • the combined organic extracts were washed with water (10 ml), dried over sodium sulfate, filtered and evaporated under reduced pressure.
  • the residue was purified by silicagel column chromatography by using 0-8% MeOH in DCM gradient. The fractions containing the expected product were combined and concentrated under reduced pressure to obtain the title compound (0.135 g, yield: 74.4%) as a white solid.
  • Step 5 Synthesis of sodium (lR,3S)-3-((((3aS,5aR,5bR,7aR,9S,llaR,llbR,13aS)-3a-(2-(((l- (4-chlorophenyl)cyclopropyl)methyl)(2-(dimethylamino)ethyl)amino)-2-oxoethyl)-l- isopropyl-5a, 5b, 8, 8, 11 a-pentamethyl-2-oxo- 3,3a,4,5,5a,5b,6,7, 7a,8,9,10,ll,lla,llb,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen- 9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-l-carboxylate:
  • the compounds of formula (27) can be prepared by the reaction of compounds of formula (9) with a reagent like niromethane in the presence of a base such as triethylamine (TEA) or ⁇ , ⁇ -diisopropylethylamine (DIPEA).
  • a base such as triethylamine (TEA) or ⁇ , ⁇ -diisopropylethylamine (DIPEA).
  • TEA triethylamine
  • DIPEA ⁇ , ⁇ -diisopropylethylamine
  • the hydroxy group in compound (27) can be acetylated in the presence of a catalyst such as /?ara-toluenesulfonic acid monohydrate (pTSA) with a suitable reagent such as acetic anhydride to give compound (28).
  • pTSA /?ara-toluenesulfonic acid monohydrate
  • suitable reagent such as acetic anhydride
  • the compounds of formula (29) can be prepared by chopping the acetoxy group in compound (28) in the presence of a reducing agent such as sodium borohydride (NaBH 4 ) in solvents such as methanol or combination of methanol (MeOH) and Tetrahydrofuran (THF).
  • a reducing agent such as sodium borohydride (NaBH 4 ) in solvents such as methanol or combination of methanol (MeOH) and Tetrahydrofuran (THF).
  • the amines of compounds of formula (30) can be prepared by reducing the nitro group in compounds of formula (29) with a reagent such as Nickel(II) chloride hexahydrate (NiCl 2 -6H 2 0) and reducing agent such as sodium borohydride (NaBH 4 ) in the combination of solvents such as methanol (MeOH) and dichloromethane (DCM) or methanol (MeOH) and tetrahydrofuran (THF).
  • a reagent such as Nickel(II) chloride hexahydrate (NiCl 2 -6H 2 0) and reducing agent such as sodium borohydride (NaBH 4 )
  • solvents such as methanol (MeOH) and dichloromethane (DCM) or methanol (MeOH) and tetrahydrofuran (THF).
  • the compounds of formula (32) can be prepared by coupling of compounds (30) and (31) with coupling reagents such as 0-(7-Azabenzotriazol-l-yl)- ⁇ , ⁇ , ⁇ ', ⁇ '-tetramethyluroniumhexafluorophosphate (HATU) or O-(Benzotriazol-l-yl)- ⁇ , ⁇ , ⁇ ', ⁇ '-tetramethyluroniumhexafluorophosphate (HBTU) or l-Ethyl-3-(3- dimethylaminopropyl)carbodiimide (EDCI) and 1-Hydroxybenzotriazole (HOBt) in the presence of a base such as triethylamine (TEA) or ⁇ , ⁇ -Diisopropylethylamine (DIPEA) in a suitable solvent such as ⁇ , ⁇ -dimethylformamide (DMF) or 1,2-dichloroethane (1,2-DCE).
  • the compounds of formula (34) can be prepared by the reaction of compound 29 with KMn0 4 , MgS0 4 and aq. KOH solution in the presence of acetone and methanol.
  • the obtained compound (34) further undergoes reductive amination with compound 35 in the presence of acetic acid and STAB in solvents like 1,2-dichloroethane and the like to give compound of formula (32).
  • the compounds of formula (I) can be prepared by hydrolysing the ester group in compounds of formula (32) in the presence of aqueous solution of inorganic bases such as sodium hydroxide (NaOH) or potassium hydroxide (KOH) or the like in the combination of solvents such as tetrahydrofuran (THF): methanol (MeOH) or the like.
  • inorganic bases such as sodium hydroxide (NaOH) or potassium hydroxide (KOH) or the like
  • solvents such as tetrahydrofuran (THF): methanol (MeOH) or the like.
  • any of the compounds of the above scheme can form HC1 salt in the presence of acidic medium such as HC1 in 1,4-dioxane or HC1 in MeOH or the like.
  • acidic medium such as HC1 in 1,4-dioxane or HC1 in MeOH or the like.
  • Example III- 1 Preparation of (lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-3a-(2-(2- (4-chlorobenzamido)-2-methylpropanamido)ethyl)- l-isopropyl-5a,5b,8,8 J la-pentamethyl-2- oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,l l,l la,l lb,12,13,13a-octadecahvdro-2H- cyclopentaralchryse -9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-l-carboxylic acid:
  • Step 1 Synthesis of 1-benzyl 3-((3aR,5aR,5bR, 7aR,9S,llaR,llbR,13aS)-3a-(l-hydroxy-2- nitroethyl)-l-isopropyl-5a,5b,8,8,lla-pentamethyl-2-oxo-
  • 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 evaporated under reduced pressure.
  • the crude compound was triturated with n-hexane (50 ml), solid was filtered and dried under vacuum to obtain the title compound (5.0 g, yield: 76.6%) as a white solid.
  • Step 2 Synthesis of l-((3aR,5aR,5bR,7aR,9S,llaR,llbR,13aS)-3a-(l-acetoxy-2-nitroethyl)- 1 -isopropyl-5a,5b, 8,8,11 a-pentamethyl-2-oxo- 3,3a,4,5,5a,5b,6,7, 7a,8,9,10,ll,lla,llb,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen- 9-yl) 3 -benzyl (lS,3R)-2,2-dimethylcyclobutane-l,3-dicarboxylate:
  • Step 3 Synthesis of 1-benzyl 3-((3aR,5aR,5bR, 7aR,9S,llaR,llbR,13aS)-l-isopropyl- 5a,5b,8,8,lla-pentamethyl-3a-(2-nitroethyl)-2-oxo-
  • Step 4 Synthesis of l-((3aR,5aR,5bR, 7aR,9S,llaR,llbR,13aS)-3a-(2-aminoethyl)-l- isopropylSa, 5b, 8, 8, 11 a-pentamethyl-2-oxo-
  • Step 5 Synthesis of 1-benzyl 3-((3aR,5aR,5bR,7aR,9S,llaR,llbR,13aS)-3a-(2-(2-(4- chlorobenzamido)-2-methylpropanamido)ethyl)-l-isopropyl-5a,5b,8,8,lla-pentamethyl-2- oxo -3,3 a, 4, 5, 5 a, 5b, 6, 7,7a,8,9,10,ll,lla,llb,12,13,l 3a-octadecahydro-2H- cyclopenta[a] chrysen-9- -2,2-dimethylcyclobutane-l ,3 -dicarboxylate :
  • reaction mixture was stirred at room temperature for about 30 minutes, then l-((3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-3a- (2-aminoethyl)- l-isopropyl-5a,5b, 8,8,1 la-pentamethyl-2-oxo-
  • Step 6 Synthesis of (lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,llaR,llbR,13aS)-3a-(2-(2-(4- chlorobenzamido)-2-methylpropanamido)ethyl)-l-isopropyl-5a,5b,8,8,lla-pentamethyl-2- oxo -3,3 a, 4, 5, 5 a, 5b, 6, 7,7a,8,9,10,ll,lla,llb,12,13,l 3a-octadecahydro-2H- cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-l-carboxylic acid:
  • reaction mixture was stirred at room temperature for overnight. TLC indicated starting material was consumed and the desired product was observed.
  • the organic phase was evaporated under reduced pressure, the reaction mixture was diluted with water (10 ml), cooled to 0 °C, ptl adjusted to 5.0 with IN HCl and extracted with DCM (3x50 ml). The combined organic extracts were washed with water (50 ml), dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by silicagel column chromatography by using 80-95% ethyl acetae in hexane gradient. The fractions containing the expected product were combined and concentrated under reduced pressure to obtain the solid.
  • Example III-2 Preparation of (lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-3a-(2- aminoethyl)-l-isopropyl-5a,5b,8,8 J la-pentamethyl-2-oxo- 3,3a,4,5,5a,5b,6,7,7a,8,9,10,l l,l la,l lb,12,13,13a-octadecahvdro-2H-cvclopentaralchrvsen- 9-yl)oxy)carbonyl)-2,2-dimethylcvclobutane- 1-carboxylic acid hydrochloride:
  • Step 1 Synthesis of 1-benzyl 3-((3aR,5aR,5bR,7aR,9S,llaR,llbR,13aS)-3a-(2-((tert- butoxycarbonyl)amino)ethyl)-l-isopropyl-5a,5b,8,8,lla-pentamethyl-2-oxo- 3,3a,4,5,5a,5b,6,7, 7a,8,9,10,ll,lla,llb,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen- 9-yl) (lR,3S)-2,2-dimethylcyclobutane-l,3-dicarboxylate:
  • reaction mixture was stirred at room temperature for overnight. After completion of the reaction monitored by TLC, the reaction mixture was diluted with ethyl acetate (100 ml). The organic layer was washed with 0.5N HCl (50 ml), water (50 ml) and brine solution (50 ml). The organic layer was dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by silicagel column chromatography by using 0-2% MeOH in DCM gradient. The fractions containing the expected product were combined and concentrated under reduced pressure to obtain the title compound (0.650 g, yield: 81.4%) as an off-white solid.
  • Step 2 Synthesis of (lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,llaR,llbR,13aS)-3a-(2-((tert- butoxycarbonyl)amino)ethyl)-l-isopropyl-5a,5b,8,8,lla-pentamethyl-2-oxo- 3,3a,4,5,5a,5b,6,7, 7a,8,9,10,ll,lla,llb,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen- 9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-l-carboxylic acid'.
  • Step 3 Synthesis of (lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,llaR,llbR,13aS)-3a-(2-aminoethyl)- 1 -isopropyl-5a,5b, 8,8,11 a-pentamethyl-2-oxo-
  • 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 concentrated under reduced pressure, washed with MTBE (30 ml) and hexane (30 ml). The resulting solid was refluxed with MTBE (30 ml) for about 1 hour. The mixture was cooled to room temperature, filtered, solid was washed with MTBE (20 ml) and dried under vacuum to obtain the title compound (0.055 g, yield: 30.1%) as an off-white solid.
  • Example III-3 Preparation of (lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-3a-(2-(2- amino-2-methylpropanamido)ethyl)-l-isopropyl-5a,5b,8,8 J la-pentamethyl-2-oxo- 3,3a,4,5,5a,5b,6,7,7a,8,9,10,l l,l la,l lb,12,13,13a-octadecahvdro-2H-cvclopentaralchrvsen- 9-yl)oxy)carbonyl)-2,2-dimethylcvclobutane- 1-carboxylic acid hydrochloride:
  • Step 1 Synthesis of 1-benzyl 3-((3aR,5aR,5bR,7aR,9S,llaR,llbR,13aS)-3a-(2-(2-((tert- butoxycarbonyl)amino)-2-methylpropanamido)ethyl)-l-isopropyl-5a,5b,8,8,lla-pentamethyl- 2 -oxo-3, 3 a, 4, 5, 5 a, 5b, 6,7, 7a,8,9,10,ll,lla,llb,12,13,13a -octadecahydro -2H- cyclopenta[a] chrysen- -yl) ( 1 R,3S )-2,2-dimethylcyclobutane-l ,3 -dicarboxylate :
  • reaction mixture was stirred at room temperature for 30 minutes, then l-((3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)- 3a-(2-aminoethyl)- l-isopropyl-5a,5b, 8,8,1 la-pentamethyl-2-oxo-
  • Step 2 Synthesis of (lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,llaR,nbR,13aS)-3a-(2-(2-((tert- butoxycarbonyl)amino)-2-methylpropanamido)ethyl)-l-isopropyl-5a,5b,8,8,lla-pentamethyl- 2 -oxo-3, 3 a, 4, 5, 5 a, 5b, 6,7, 7a,8,9,10,ll,lla,llb,12,13,13a -octadecahydro -2H- cyclopenta[a]chryse -9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-l-carboxylic acid:
  • step 1 ((tert-butoxycarbonyl)amino)-2-methylpropanamido)ethyl)-l-isopropyl-5a,5b, 8,8,1 la- pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,l 1,1 la,l lb, 12,13, 13a-octadecahydro-2H- cyclopenta[a]chrysen-9-yl) (lR,3S)-2,2-dimethylcyclobutane-l,3-dicarboxylate (step 1, 1.0 g, 1.112 mmol, 1.0 eq) in MeOH (10 ml) and THF (10 ml) was added aqueous 2.5N KOH solution (3.3 ml, 8.34 mmol, 7.5 eq).
  • Step 3 Synthesis of (lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,llaR,llbR,13aS)-3a-(2-(2-amino-2- methylpropanamido)ethyl)-l-isopropyl-5a,5b,8,8,lla-pentamethyl-2-oxo- 3,3a,4,5,5a,5b,6,7, 7a,8,9,10,ll,lla,llb,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen- 9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-l-carboxylic acid hydrochloride:
  • Example III-4 Preparation of (lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-3a-(2- ((4-chlorobenzyl)amino)ethyl)-l-isopropyl-5a,5b,8,8 J la-pentamethyl-2-oxo- 3,3a,4,5,5a,5b,6,7,7a,8,9,10,l l,l la,l lb,12,13,13a-octadecahvdro-2H-cvclopentaralchrvsen- 9-yl)oxy)carbonyl)-2, -dimethylcyclobutane- 1-carboxylic acid hydrochloride:
  • Step 1 Synthesis of 1-benzyl 3-((3aR,5aR,5bR,7aR,9S,llaR,llbR,13aS)-3a-(2-((tert- butoxycarbonyl)(4-chlorobenzyl) mino)ethyl)-l-isopropyl-5a,5b,8,8,lla-pentamethyl-2-oxo- 3,3a,4,5,5a,5b,6,7, 7a,8,9,10,ll,lla,llb,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen- 9-yl) ( lR,3S)-2,2-dimethylcyclobutane-l,3-dicarboxylate:
  • reaction mixture was stirred at room temperature for about 2 hours, then cooled to -5 °C and sodium borohydride (0.0159 g, 0.420 mmol, 0.4 eq) was added in small portions during 10 minutes.
  • the reaction mixture was stirred at the same temperature for about 30 minutes, di-ie/ -butyl dicarbonate (0.29 ml, 1.260 mmol, 1.2 eq) was added, warmed to room temperature and stirred for about 1 hour. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with ice water (50 ml) and extracted with ethyl acetate (2x100 ml).
  • Step 2 Synthesis of (lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,llaR,llbR,13aS)-3a-(2-((tert- butoxycarbonyl)(4-chlorobenzyl)amino)ethyl)-l-isopropyl-5a,5b,8,8,lla-pentamethyl-2-oxo- 3,3a,4,5,5a,5b,6,7, 7a,8,9,10,ll,lla,llb,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen- 9-yl)oxy)carbonyl)-2, -dimethylcyclobutane-l-carboxylic acid:
  • reaction mixture was stirred at room temperature for overnight. After completion of the reaction (monitored by TLC), the reaction mixture was evaporated under reduced pressure. The mixture was cooled to 0 °C, water (10 ml) was added, pU adjusted to 5.0 with IN HC1 and extracted with DCM (2x100 ml). The combined organic extracts were dried over sodium sulfate, filtered and evaporated under reduced pressure. The obtained solid was purified by silicagel column chromatography by using 0-5% MeOH in DCM gradient. The fractions containing the expected product were combined and concentrated under reduced pressure to obtain the title compound (0.400 g, yield: 63.2%) as an off-white solid.
  • Step 3 Synthesis of (lR,3S)-3-((((3aR,5aR,5bR, 7aR,9S,llaR,nbR,13aS)-3a-(2-((4- chlorobenzyl)amino)ethyl)-l-isopropyl-5a,5b,8,8,lla-pentamethyl-2-oxo- 3,3a,4,5,5a,5b,6,7, 7a,8,9,10,ll,lla,llb,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen- 9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-l-carboxylic acid hydrochloride:
  • reaction mixture was stirred at room temperature for overnight. After completion of the reaction (monitored by TLC), The reaction mixture was evaporated under reduced pressure. The residue was washed with MTBE (30 ml), followed by hexane (30 ml) to obtain the solid. To this solid compound, MTBE (30 ml) was added and refluxed for about 1 hour. The mixture was cooled to room temperature, solid was filtered, washed with MTBE (20 ml) and dried under vacuum to obtain the title compound (0.065 g, yield: 46.8%) as an off-white solid.

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Abstract

La présente invention concerne de nouveaux dérivés de triterpénone en C-3 de formule (I) ; (I) ou des sels pharmaceutiquement acceptables, des solvates pharmaceutiquement acceptables, des hydrates pharmaceutiquement acceptables, des tautomères, des stéréo-isomères, des promédicaments, des compositions ou une combinaison de ceux-ci, dans laquelle R1, R2, R3, R4, R5, R6, R7, W, ̔m ̕ et 'n ̕ sont définis dans la description. La présente invention concerne également des compositions pharmaceutiques comprenant des composés de formule (I) et un procédé pour les préparer, et leur utilisation dans le traitement de maladies virales et en particulier de maladies médiées par le VIH.
PCT/IB2016/058104 2015-12-30 2016-12-30 Nouveaux dérivés de triterpénone en c-3 en tant qu'inhibiteurs du vih Ceased WO2017115329A1 (fr)

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10370405B2 (en) * 2015-03-16 2019-08-06 Hetero Labs Limited C-3 novel triterpenone with C-28 amide derivatives as HIV inhibitors
WO2019150300A1 (fr) 2018-02-02 2019-08-08 Glaxosmithkline Intellectual Property (No.2) Limited Formes cristallines d'acide 4-(((3ar,5ar,5br,7ar,9s,11ar,11br,13as)-3a-((r)-2-((4-chlorobenzyl)(2-(diméthylamino)éthyl)amino)-1-hydroxyéthyl)-1-isopropyl-5a,5b,8,8,11a-pentaméthyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadécahydro-2h-cyclopenta[a]chrysén-9-yl)oxy)-2,2-diméthyl-4-oxobutanoïque
US10533035B2 (en) 2015-02-09 2020-01-14 Hetero Labs Ltd. C-3 novel triterpenone with C-17 reverse amide derivatives as HIV inhibitors
WO2020056553A1 (fr) * 2018-09-17 2020-03-26 海门华祥医药科技有限公司 Procédé de préparation d'un composé hétérocyclique et de ses sels
US20220144882A1 (en) * 2019-02-11 2022-05-12 Hetero Labs Limited Novel triterpenone derivatives as hiv inhibitors

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009082818A1 (fr) * 2008-01-03 2009-07-09 Virochem Pharma Inc. Préparation de nouveaux dérivés de c-21-céto lupane et leur utilisation
WO2011007230A2 (fr) * 2009-07-14 2011-01-20 Hetero Research Foundation Dérivés de triterpène de type lupéol comme antiviraux
WO2011100308A1 (fr) * 2010-02-11 2011-08-18 Glaxosmithkline Llc Dérivés de bétuline
WO2014105926A1 (fr) * 2012-12-31 2014-07-03 Hetero Research Foundation Nouveaux dérivés proline de l'acide bétulinique utilisés comme inhibiteurs du vih

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009082818A1 (fr) * 2008-01-03 2009-07-09 Virochem Pharma Inc. Préparation de nouveaux dérivés de c-21-céto lupane et leur utilisation
WO2011007230A2 (fr) * 2009-07-14 2011-01-20 Hetero Research Foundation Dérivés de triterpène de type lupéol comme antiviraux
WO2011100308A1 (fr) * 2010-02-11 2011-08-18 Glaxosmithkline Llc Dérivés de bétuline
WO2014105926A1 (fr) * 2012-12-31 2014-07-03 Hetero Research Foundation Nouveaux dérivés proline de l'acide bétulinique utilisés comme inhibiteurs du vih

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US10533035B2 (en) 2015-02-09 2020-01-14 Hetero Labs Ltd. C-3 novel triterpenone with C-17 reverse amide derivatives as HIV inhibitors
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
WO2019150300A1 (fr) 2018-02-02 2019-08-08 Glaxosmithkline Intellectual Property (No.2) Limited Formes cristallines d'acide 4-(((3ar,5ar,5br,7ar,9s,11ar,11br,13as)-3a-((r)-2-((4-chlorobenzyl)(2-(diméthylamino)éthyl)amino)-1-hydroxyéthyl)-1-isopropyl-5a,5b,8,8,11a-pentaméthyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadécahydro-2h-cyclopenta[a]chrysén-9-yl)oxy)-2,2-diméthyl-4-oxobutanoïque
WO2020056553A1 (fr) * 2018-09-17 2020-03-26 海门华祥医药科技有限公司 Procédé de préparation d'un composé hétérocyclique et de ses sels
US20220144882A1 (en) * 2019-02-11 2022-05-12 Hetero Labs Limited Novel triterpenone derivatives as hiv inhibitors
US12378281B2 (en) * 2019-02-11 2025-08-05 Hetero Labs Limited Triterpenone derivatives as HIV inhibitors

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