This application claims the benefit of Indian provisional application no
623/CHE/2015 filed on 9th February 2015 which is hereby incorporated by reference in its
entirety.
FIELD OF THE INVENTION
The present invention relates to C-3 novel triterpenone with C-28 reverse amide
derivatives and related compounds, compositions useful for therapeutic treatment of viral
diseases and particularly HIV mediated diseases.
BACKGROUND OF THE INVENTION
The Human Immunodeficiency Virus (HIV) has now been established as the
causative agent of the Acquired Immunodeficiency Syndrome (AIDS) for over 20 years
(Science 1983, 220,868-871; N.Eng. J.Med. 1984, 3 11, 1292-1297). AIDS is characterized by
the destruction of the immune system, particularly of CD4+T-cells. HIV is a retrovirus, and
the HIV life cycle encompasses several crucial steps, starting from the attachment of the virus
to the host cell membrane and finishing with the release of progeny virons from the cell.
The natural compound betulinic acid, isolated from Syzygium clavifolium and several
other plant species was found to possess anti-HIV activity. Chemical modifications were
undertaken by several research groups in an attempt to identify potent anti-HIV agents by
making semi-synthetic analogs of betulinic acid, leading to the discovery of bevirimat as a
compound with a novel mechanism of action (J. Nat. Prod. 199457(2):243-7; J . Med. Chem.
1996,39(5), 1016). Further studies shown that bevirimat acts by disrupting Gag processing
(Proc. Natl. Acad. Sci. USA 2003, 100(23): 13555-60; Antimicrob. Agents. Chemother.
2001,45(4), 1225-30; J . Virol. 2004,78(2): 922-9; J . Biol. Chem. 2005,280(5 1):42149-55; J .
Virol. 2006,80(12): 5716-22) and to be a first-in-class maturation inhibitor with a potent
activity against HIV-1. Bevirimat went up to phase 2 clinical trials, in clinic despite optimal
plasma concentrations, not all patients given bevirimat have a robust viral load reduction. It
was reported that non-respondant patients had more frequent base line Gag polymorphisms
near the capsid SP-1 cleavage site than responders. (HIV gag polymorphism determines
treatment response to bevirimat. XVII international HIV drug resistance work shop June 10-
14, 2008, Sitges, Spain).
Encouraged by these developments, medicinal chemists started exploring betulinic
acid derivatives and related compounds intensively for their therapeutic activities. For
example, WO 2014/093941 describes pharmaceutical compositions of betulin derivatives;
WO 2009/082819 describes preparation of 17-amino lupane derivatives as anti-HIV agents;
WO 2013/1 17137 describes lupane triterpenoids derivatives and pharmaceutical use thereof;
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
201 1/100308 describes preparation of betulin derivatives for treatment of HIV-1; WO
2013/090664 describes preparation of betulin derivatives for the treatment of HIV; WO
2013/091 144 describes preparation of propenoate derivatives of betulin useful for the
treatment of HIV; WO 2013/090683 describes preparation of betulin propenoate derivatives
for the treatment of HIV.
Given the fact of the world wide epidemic level of AIDS, there is a strong continued
need for new effective drugs for treatment of HIV infected patients, disease conditions and/or
disorders mediated by HIV by discovering new compounds with novel structures and/or
mechanism of action(s).
SUMMARY OF THE INVENTION
The present invention relates to the compounds of the formula (1)
,
substituted or unsubstituted Ci-C alkyl, or substituted or unsubstituted C -C cycloalkyl);
R2 can be hydrogen, substituted or unsubstituted Ci-C alkyl, substituted or
unsubstituted C2-C6 alkoxylalkoxy or substituted or unsubstituted Ci-C6 amino alkyl;
R and R4 can be independently selected from substituted or unsubstituted Ci-C6 alkyl,
substituted or unsubstituted amine, substituted or unsubstituted C -C8 cycloalkyl, substituted
or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl or R and R4 can be
taken together with the carbon atom to which they are attached to form substituted or
unsubstituted C -C8 cycloalkyl, epoxide, oxetane or azetidine;
R5 and R6 can be independently selected from hydrogen, substituted or unsubstituted
Ci-C alkyl and R5 and can be taken together with the carbon atom to which they are
attached to form substituted or unsubstituted C -C cycloalkyl or R5 and can be together
represent oxo;
R 7 can be hydrogen, substituted or unsubstituted Ci-C6 alkyl, substituted or
unsubstituted Ci-C alkoxy, substituted or unsubstituted amino, substituted or unsubstituted
Ci-C amino alkyl, substituted or unsubstituted C -C cycloalkyl, substituted or unsubstituted
C6 -Ci2 aryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaryl,
or -S(0) 2Rb; wherein the substituents can be independently selected from one or more Rm;
Rm can be halo, Ci-C alkyl, haloalkyl, amino, -C(0)OR , substituted or unsubstituted
heterocyclyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted
heteroaryl or -S(0) 2Rb;
R and Re can be independently selected from substituted or unsubstituted Ci-C6 alkyl
or substituted or unsubstituted C -Ci2 aryl;
'n' can be an integer selected from 0, lor 2;
pharmaceutically acceptable salts, pharmaceutically acceptable solvates,
pharmaceutically acceptable hydrates, tautomers, stereoisomers, ester prodrugs, or
combination thereof.
It should be understood that the formula (1) structurally encompasses all
stereoisomers, including enantiomers, diastereomers, racemates, and combinations thereof
which may be contemplated from the chemical structure of the genus described herein.
It should be understood that the formula (1) structurally encompasses all tautomers.
Also contemplated are prodrugs of the compounds of the formula (1), including ester
prodrugs.
to one embodiment, there is provided a compound of formula (1), wherein
According to another embodiment, there is provided a compound of formula (1),
wherein R2 is hydrogen.
According to yet another embodiment there is provided a compound of formula (1),
wherein R and R 4 are methyl.
According to yet another embodiment there is provided a compound of formula (1),
wherein R and R4 together with the carbon atom to which they are attached to form
substituted or unsubstituted C -6 cycloalkyl.
According to yet another embodiment there is provided a compound of formula (1),
wherein the above said C - cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.
According to yet another embodiment there is provided a compound of formula (1),
wherein R5 and are hydrogen.
According to yet another embodiment there is provided a compound of formula (1),
wherein R5 and are methyl.
According to yet another embodiment there is provided a compound of formula (1),
wherein R5 and together with the carbon atom to which they are attached form C -6
cycloalkyl.
According to yet another embodiment there is provided a compound of formula (1),
wherein the above said C - cycloalkyl is cyclopropyl and cyclopentyl.
According to yet another embodiment there is provided a compound of formula (1),
wherein R5 and together represent oxo.
According to yet another embodiment, there is provided a compound of formula (1),
wherein R is substituted phenyl; wherein the substituents are chloro, methyl, fluoro,
trifluoromethyl, morpholine, methylsulfonyl, 4-Methyl-lH-imidazole, oxazole, 1,3,4-
Oxadiazole, thiomorpholine 1,1 -dioxide or 4-methylthiomorpholine 1,1 -dioxide.
According to yet another embodiment there is provided a compound of formula (1),
wherein R7 is substituted pyridine; wherein the substituents are methyl, amino, morpholine or
chloro.
According to yet another embodiment there is provided a compound of formula (1),
wherein R is pyrrolidine.
According to yet another embodiment, there is provided a compound of formula (1),
wherein R is pyrrolidine which is substituted with -C(0)OR c; wherein R is tertiary butyl.
According to yet another embodiment there is provided a compound of formula (1),
wherein R is pyrazine.
According to yet another embodiment there is provided a compound of formula (1),
wherein R is pyrazine which is substituted with methyl.
According to yet another embodiment there is provided a compound of formula
wherein R is furan which is substituted with methyl.
According to yet another embodiment there is provided a compound of formula
wherein R7 is piperazine which is substituted with ethyl.
According to yet another embodiment there is provided a compound of formula
wherein R is quinoline.
According to yet another embodiment there is provided a compound of formula
wherein R is piperidine.
According to yet another embodiment, there is provided a compound of formula
wherein R7 is thiomorpholine 1,1-dioxide.
According to yet another embodiment there is provided a compound of formula
wherein R is lH-benzo[d]imidazole.
According to yet another embodiment, there is provided a compound of formula
wherein R is lH-benzo[d]imidazole which is substituted with methyl pyridine.
According to yet another embodiment there is provided a compound of formula
wherein R is lH-benzo[d]imidazole which is substituted with pyrazine.
According to yet another embodiment there is provided a compound of formula
wherein R is thiazole which is substituted with methyl or amino.
According to yet another embodiment there is provided a compound of formula
wherein R is imidazole which is substituted with methyl.
According to yet another embodiment there is provided a compound of formula
wherein R is pyrazole which is substituted with isopropyl.
According to yet another embodiment there is provided a compound of formula
wherein R is isoxazole which is substituted with methyl.
According to yet another embodiment, there is provided a compound of formula
wherein R is 1,3,4-Oxadiazole which is substituted with methyl.
According to yet another embodiment there is provided a compound of formula
wherein R is pyrimidine.
According to yet another embodiment, there is provided a compound of formula
wherein R is pyrazolo[l ,5-a]pyrimidine.
According to yet another embodiment, there is provided a compound of formula
wherein R is - S(0) 2Rb; wherein R is methyl or 4-chloro phenyl.
According to yet another embodiment, there is provided a compound of formula
wherein R7 is N,N-dimethyl amino.
According to yet another embodiment there is provided a compound of formula (1),
wherein R is tertiary butyl.
According to yet another embodiment there is provided a compound of formula (1),
wherein R is tertiary butoxy.
According to yet another embodiment there is provided a compound of formula (1),
wherein R7 is cyclohexyl.
According to yet another embodiment, there is provided a compound of formula (1),
wherein 'n' is 0 .
According to yet another embodiment, there is provided a compound of formula (1),
wherein 'n' is 1.
According to yet another embodiment, there is provided a compound of formula (1),
wherein 'n' is 2 .
Accordingly, one other aspect of the present invention provides compounds of
formula ( 1A):
wherein,
R2, R5, , R and 'n' are same as defined in claim 1;
pharmaceutically acceptable salts, pharmaceutically acceptable solvates,
pharmaceutically acceptable hydrates, tautomers, stereoisomers, ester prodrugs, or
combination thereof.
It should be understood that the formula (1A) structurally encompasses all
stereoisomers, including enantiomers, diastereomers, racemates, and combinations thereof
which may be contemplated from the chemical structure of the genus described herein.
It should be understood that the formula ( 1A) structurally encompasses all tautomers.
Also contemplated are prodrugs of the compounds of the formula (1A), including
ester prodrugs.
According to one embodiment, there is provided a compound of formula (1A),
wherein R2 is hydrogen.
According to one embodiment, there is provided a compound of formula (1A),
wherein R5 and R 6 are hydrogen.
According to one embodiment, there is provided a compound of formula (1A),
wherein R5 and are methyl.
According to one embodiment, there is provided a compound of formula (1A),
wherein R5 and together represent oxo.
According to one embodiment, there is provided a compound of formula (1A),
wherein R5 and together with the carbon atom to which they are attached to form C -
cycloalkyl.
According to one embodiment, there is provided a compound of formula (1A),
wherein the above said C - cycloalkyl is cyclopropyl, cyclopentyl or cyclohexyl.
According to yet another embodiment, there is provided a compound of formula ( 1A),
wherein R is substituted phenyl; wherein the substituents are chloro, methyl, fluoro,
trifluoromethyl, morpholine, methylsulfonyl, 4-Methyl-lH-imidazole, oxazole, 1,3,4-
Oxadiazole, thiomorpholine 1,1-dioxide or 4-methylthiomorpholine 1,1-dioxide.
According to yet another embodiment there is provided a compound of formula ( 1A),
wherein R7 is substituted pyridine, wherein the substituents are methyl, amino, morpholine or
chloro.
According to yet another embodiment there is provided a compound of formula ( 1A),
wherein R is pyrrolidine.
According to yet another embodiment, there is provided a compound of formula ( 1A),
wherein R is pyrrolidine which is substituted with -C(0)OR c; wherein R is tertiary butyl.
According to yet another embodiment there is provided a compound of formula ( 1A),
wherein R is pyrazine.
According to yet another embodiment there is provided a compound of formula ( 1A),
wherein R is pyrazine which is substituted with methyl.
According to yet another embodiment there is provided a compound of formula ( 1A),
wherein R is furan which is substituted with methyl.
According to yet another embodiment there is provided a compound of formula ( 1A),
wherein R is piperazine which is substituted with ethyl.
According to yet another embodiment there is provided a compound of formula ( 1A),
wherein R is quinoline.
According to yet another embodiment there is provided a compound of formula ( 1A),
wherein R is piperidine.
According to yet another embodiment, there is provided a compound of formula ( 1A),
wherein R7 is thiomorpholine 1,1 -dioxide.
According to yet another embodiment there is provided a compound of formula ( 1A),
wherein R7 is lH-benzo[d]imidazole.
According to yet another embodiment there is provided a compound of formula ( 1A),
wherein R is lH-benzo[d]imidazole which is substituted with methyl pyridine or pyrazine.
According to yet another embodiment there is provided a compound of formula ( 1A),
wherein R is thiazole which is substituted with methyl or amino.
According to yet another embodiment there is provided a compound of formula ( 1A),
wherein R is imidazole which is substituted with methyl.
According to yet another embodiment there is provided a compound of formula ( 1A),
wherein R is pyrazole which is substituted with isopropyl.
According to yet another embodiment there is provided a compound of formula ( 1A),
wherein R is isoxazole which is substituted with methyl.
According to yet another embodiment, there is provided a compound of formula ( 1A),
wherein R is 1,3,4-oxadiazole which is substituted with methyl.
According to yet another embodiment there is provided a compound of formula ( 1A),
wherein R7 is pyrimidine.
According to yet another embodiment, there is provided a compound of formula ( 1A),
wherein R is pyrazolo[l ,5-a]pyrimidine.
According to yet another embodiment, there is provided a compound of formula ( 1A),
wherein R is - S(0) 2Rb; wherein R is methyl or 4-chloro phenyl.
According to yet another embodiment, there is provided a compound of formula ( 1A),
wherein R is N,N-dimethyl amino.
According to yet another embodiment, there is provided a compound of formula ( 1A),
wherein R is tertiary butyl.
According to yet another embodiment, there is provided a compound of formula ( 1A),
wherein R is tertiary butoxy.
According to yet another embodiment, there is provided a compound of formula ( 1A),
wherein R7 is cyclohexyl.
According to yet another embodiment, there is provided a compound of formula ( 1A),
wherein 'n' is 0 .
According to yet another embodiment, there is provided a compound of formula ( 1A),
wherein 'n' is 1.
According to yet another embodiment, there is provided a compound of formula ( 1A),
wherein 'n' is 2 .
Accordingly, one other aspect of the present invention provides compounds of
formula (IB):
wherein,
R2, 5, R , R and 'n' are same as defined in claim 1;
X can be selected from -0-, -CH20-, -CH2N-, or (-CH2-)m;
'm' can be an integer selected from 1, 2, 3 or 4;
pharmaceutically acceptable salts, pharmaceutically acceptable solvates,
pharmaceutically acceptable hydrates, tautomers, stereoisomers, ester prodrugs, or
combination thereof.
It should be understood that the formula (IB) structurally encompasses all
stereoisomers, including enantiomers, diastereomers, racemates, and combinations thereof
which may be contemplated from the chemical structure of the genus described herein.
It should be understood that the formula (IB) structurally encompasses all tautomers.
Also contemplated are prodrugs of the compounds of the formula (IB), including
ester prodrugs.
According to one embodiment, there is provided a compound of formula (IB),
wherein R2 is hydrogen.
According to one embodiment, there is provided a compound of formula (IB),
wherein X is -CH2- .
According to one embodiment, there is provided a compound of formula (IB),
wherein R5 and R together represent oxo.
According to another embodiment, there is provided a compound of formula (IB),
wherein R is phenyl which is substituted with chloro, methyl or fluoro.
According to another embodiment, there is provided a compound of formula (IB),
wherein R is pyridyl which is substituted with methyl or morpholine.
According to another embodiment, there is provided a compound of formula (IB),
wherein R7 is pyrimidine.
According to another embodiment, there is provided a compound of formula (IB),
wherein 'n' is 1.
According to another embodiment, there is provided a compound of formula (IB),
wherein 'm' is 1.
According to another embodiment, there is provided a compound of formula (IB),
wherein 'm' is 2 .
According to another embodiment, there is provided a compound of formula (IB),
wherein 'm' is 3 .
According to another embodiment, there is provided a compound of formula (IB),
wherein 'm' is 4 .
Below are the representative compounds, which are illustrative in nature only and are
not intended to limit to the scope of the invention (Nomenclature has been generated from
ChemBioDraw Ultra 13.0 version):
(lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-3a-(2-(4-chlorobenzamido)-2-
methylpropanamido)-l-isopropyl-5a,5b,8,8,l la-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,
9,10,1 1,1 la,l lb, 12,13, 13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2-
dimethylcyclobutane-l-carboxylic acid (Compound 1),
(lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-3a-(2-(l-(4-chlorophenyl)
cyclopropane-l-carboxamido)-2-methylpropanamido)-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-octadecahydro-2H-cyclopenta[a]
chrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-l-carboxylic acid (Compound 2),
(lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-3a-(2-benzamido-2-methyl
propanamido)-l-isopropyl-5a,5b,8,8,l la-pentamethyl-2-oxo-3,3a,4,5,5a, 5b,6,7,7a,8,9,10,1 1,
l la,l lb,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2-dimethyl
cyclobutane-l-carboxylic acid (Compound 3),
(lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-3a-(2-(3,4-dichlorobenzamido)
-2-methylpropanamido)-l-isopropyl-5a,5b,8,8,l la-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,
8,9,10,1 1,1 la,l lb, 12,13, 13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-
2,2-dimethylcyclobutane-l-carboxylic acid (Compound 4),
(lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-l-isopropyl-5a,5b,8,8,l lapentamethyl-
3a-(2-methyl-2-(pyrazine-2-carboxamido)propanamido)-2-oxo-3,3a,4,5,5a,5b,
6,7,7a,8,9,10,1 1,1 la,l lb, 12,13, 13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)
carbonyl)-2,2-dimethylcyclobutane-l-carboxylic acid (Compound 5),
(lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-3a-(2-(6-aminonicotinamido)-
2-methylpropanamido)-l-isopropyl-5a,5b,8,8,l la-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,
8,9,10,1 1,1 la,l lb, 12,13, 13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-
2,2-dimethylcyclobutane-l-carboxylic acid (Compound 6),
(lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-l-isopropyl-5a,5b,8,8,l lapentamethyl-
3a-(2-methyl-2-(5-methylpyrazine-2-carboxamido)propanamido)-2-oxo-3,3a,
4,5, 5a,5b,6,7,7a,8,9,10,1 1,1 la,l lb, 12,13, 13a-octadecahydro-2H-cyclopenta[a]chrysen-9-
yl)oxy)carbonyl)-2,2-dimethylcyclobutane-l-carboxylic acid (Compound 7),
(lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-3a-(2-((S)-l-(tert-butoxy
carbonyl)pyrrolidine-2-carboxamido)-2-methylpropanamido)-l-isopropyl-5a,5b,8,8,l lapentamethyl-
2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,l l,l la,l lb,12,13,13a-octadecahydro-2Hcyclopenta[
a]chrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-l-carboxylic acid
(Compound 8),
(lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-3a-(2-(2-(4-ethylpiperazin-lyl)
acetamido)-2-methylpropanamido)-l-isopropyl-5a,5b,8,8,l la-pentamethyl-2-oxo-
3,3a,4,5,5a,5b,6,7,7a,8, 9,10,1 1,1 la,l lb, 12,13, 13a-octadecahydro-2H-cyclo penta[a]chrysen-
9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-l-carboxylic acid (Compound 9),
(lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-l-isopropyl-5a,5b,8,8,l lapentamethyl-
3a-(2-methyl-2-(2-(piperidin-l-yl)acetamido)propanamido)-2-oxo-3,3a,4,5,5a,
5b, 6,7,7a,8, 9,10,1 1,1 la,l lb, 12,13, 13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)
carbonyl)-2,2-dimethylcyclobutane-l-carboxylic acid (Compound 10),
(lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-3a-(2-(2-amino-2-methyl
propanamido)-2-methylpropanamido)-l-isopropyl-5a,5b,8,8,l la-pentamethyl-2-oxo-3,3a,4,5,
5a,5b,6,7,7a,8,9,10,1 1,1 la,l lb, 12,13, 13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)
carbonyl)-2,2-dimethylcyclobutane-l-carboxylic acid hydrochloride (Compound 11),
(lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-3a-(2-(lH-benzo[d]imidazole-
5-carboxamido)-2-methylpropanamido)-l-isopropyl-5a,5b,8,8,l la-pentamethyl-2-oxo-3,3a,4,
5,5a,5b,6,7,7a,8, 9,10,1 1,1 la,l lb, 12,13, 13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)
oxy)carbonyl)-2,2-dimethylcyclobutane-l-carboxylic acid (Compound 12),
(lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-l-isopropyl-5a,5b,8,8,l lapentamethyl-
3a-(2-methyl-2-(2-(6-methylpyridin-3-yl)-lH-benzo[d]imidazole-5-
carboxamido)propanamido)-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8, 9,10,1 1,1 la,l lb, 12,13, 13aoctadecahydro-
2H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-lcarboxylic
acid (Compound 13),
(lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-3a-(2-(2,4-dimethylthiazole-5-
carboxamido)-2-methylpropanamido)-l-isopropyl-5a,5b,8,8,l la-pentamethyl-2-oxo-3,3a,4,
5,5a,5b,6,7,7a,8, 9,10,1 1,1 la,l lb, 12,13, 13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)
oxy)carbonyl)-2,2-dimethylcyclobutane-l -carboxylic acid (Compound 14),
(lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-l-isopropyl-5a,5b,8,8,l lapentamethyl-
3a-(2-methyl-2-(2-(pyrazin-2-yl)-lH-benzo[d]imidazole-5-carboxamido)propan
amido)-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-cyclo
penta[a]chrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-l -carboxylic acid (Compound
15),
(lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-l-isopropyl-5a,5b,8,8,l lapentamethyl-
3a-(2-methyl-2-(l-methyl-lH-imidazole-2-carboxamido)propanamido)-2-oxo-
3,3a,4,5,5a,5b,6,7,7a,8, 9,10,1 1,1 la,l lb, 12,13, 13a-octadecahydro-2H-cyclopenta[a]chrysen-
9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-l -carboxylic acid (Compound 16),
(lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-l-isopropyl-3a-(2-(3-isopropyllH-
pyrazole-5-carboxamido)-2-methylpropanamido)-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-cyclopenta[a]chrysen-9-yl)
oxy)carbonyl)-2,2-dimethylcyclobutane-l -carboxylic acid (Compound 17),
(lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-l-isopropyl-5a,5b,8,8,l lapentamethyl-
3a-(2-methyl-2-(4-mo holinobenzamido)propanamido)-2-oxo-3,3a,4,5,5a,5b,
6,7,7a,8,9,10,1 1,1 la,l lb, 12,13, 13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)
carbonyl)-2,2-dimethylcyclobutane-l-carboxylic acid (Compound 18),
(lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-3a-(2-(3,5-dimethylisoxazole-
4-carboxamido)-2-methylpropanamido)-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-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)
oxy)carbonyl)-2,2-dimethylcyclobutane-l -carboxylic acid (Compound 19),
(lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-l-isopropyl-5a,5b,8,8,l lapentamethyl-
3a-(2-methyl-2-(4-(4-methyl-lH-imidazol-l-yl)benzamido)propanamido)-2-
oxo-3,3a,4,5,5a,5b,6,7,7a,8, 9,10,1 1,1 la,l lb, 12,13, 13a-octadecahydro-2H-cyclopenta[a]
chrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-l -carboxylic acid (Compound 20),
(lS,3R)-3-((((3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-3a-(2-(4-chlorobenzamido)-2-
methylpropanamido)-l-isopropyl-5a,5b,8,8,l la-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,
9,10,1 1,1 la,l lb, 12,13, 13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2-
dimethylcyclobutane-l-carboxylic acid (Compound 21),
(lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-3a-(2-(4-fluorobenzamido)-2-
methylpropanamido)-l-isopropyl-5a,5b,8,8,l la-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,
9,10,1 1,1 la,l lb, 12,13, 13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl) oxy)carbonyl)-2,2-
dimethylcyclobutane-l-carboxylic acid (Compound 22),
(lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-l-isopropyl-5a,5b,8,8,l lapentamethyl-
3a-(2-methyl-2-(4-methylbenzamido)propanamido)-2-oxo-3,3a,4,5,5a,5b,6,7,
7a,8,9,10,1 1,1 la,l lb, 12,13, 13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)
-2,2-dimethylcyclobutane-l-carboxylic acid (Compound 23),
(lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-3a-(2-(furan-3-carboxamido)-
2-methylpropanamido)-l-isopropyl-5a,5b,8,8,l la-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,
9,10,1 1,1 la,l lb, 12,13, 13a-octadecahydro-2H-cyclopenta[a] chrysen-9-yl) oxy)carbonyl)-2,2-
dimethylcyclobutane-l-carboxylic acid (Compound 24),
(lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-l-isopropyl-5a,5b,8,8,l lapentamethyl-
3a-(2-methyl-2-(4-(trifluoromethyl)benzamido)propanamido)-2-oxo-3,3a,4,5,
5a,5b,6,7,7a,8,9,10,1 1,1 la,l lb, 12,13, 13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)
carbonyl)-2,2-dimethylcyclobutane-l-carboxylic acid (Compound 25),
(lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-3a-(2-(furan-2-carboxamido)-
2-methylpropanamido)-l-isopropyl-5a,5b,8,8,l la-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,
8,9,10,1 1,1 la,l lb, 12,13, 13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-
2,2-dimethylcyclobutane-l-carboxylic acid (Compound 26),
(lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-l-isopropyl-5a,5b,8,8,l lapentamethyl-
3a-(2-methyl-2-(l -phenylcyclopentane-1 -carboxamido)propanamido)-2-oxo-
3,3a,4,5,5a,5b,6,7,7a,8, 9,10,1 1,1 la,l lb, 12,13, 13a-octadecahydro-2H-cyclopenta[a]chrysen-
9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-l-carboxylic acid (Compound 27),
(lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-l-isopropyl-5a,5b,8,8,l lapentamethyl-
3a-(2-methyl-2-(quinoline-2-carboxamido)propanamido)-2-oxo-3,3a,4,5,5a,5b,
6,7,7a,8,9,10,1 1,1 la,l lb, 12,13, 13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)
carbonyl)-2,2-dimethylcyclobutane-l-carboxylic acid (Compound 28),
(lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-l-isopropyl-5a,5b,8,8,l lapentamethyl-
3a-(2-methyl-2-(3-methylpicolinamido)propanamido)-2-oxo-3,3a,4,5,5a,5b,
6,7,7a,8,9,10,1 1,1 la,l lb, 12,13, 13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)
carbonyl)-2,2-dimethylcyclobutane-l-carboxylic acid (Compound 29),
(lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-l-isopropyl-5a,5b,8,8,l lapentamethyl-
3a-(2-methyl-2-(2-methylfuran-3-carboxamido)propanamido)-2-oxo-3,3a,4,5,
5a,5b,6,7,7a,8,9,10,1 1,1 la,l lb, 12,13, 13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)
carbonyl)-2,2-dimethylcyclobutane-l-carboxylic acid (Compound 30),
(lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-l-isopropyl-5a,5b,8,8,l lapentamethyl-
3a-(2-methyl-2-(2-mo holinonicotinamido)propanamido)-2-oxo-3,3a,4,5,5a,5b,
6,7,7a,8,9,10,1 1,1 la,l lb, 12,13, 13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)
carbonyl)-2,2-dimethylcyclobutane-l-carboxylic acid (Compound 31),
(lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-l-isopropyl-5a,5b,8,8,l lapentamethyl-
3a-(2-methyl-2-(pyrimidine-2-carboxamido)propanamido)-2-oxo-3,3a,4,5,5a,5b,
6,7,7a,8,9,10,1 1,1 la,l lb, 12,13, 13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)
carbonyl)-2,2-dimethylcyclobutane-l-carboxylic acid (Compound 32),
(lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-3a-(2-(2,5-dimethylfuran-3-
carboxamido)-2-methylpropanamido)-l-isopropyl-5a,5b,8,8,l la-pentamethyl-2-oxo-3,3a,4,5,
5a,5b,6,7,7a,8,9,10,1 1,1 la,l lb, 12,13, 13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)
carbonyl)-2,2-dimethylcyclobutane-l-carboxylic acid (Compound 33),
(lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-3a-(2-(2-(l,l-dioxidothio
mo holino)acetamido)-2-methylpropanamido)-l-isopropyl-5a,5b,8,8,l la-pentamethyl-2-
oxo-3,3a,4,5,5a,5b,6,7,7a,8, 9,10,1 1,1 la,l lb, 12,13, 13a-octadecahydro-2H-cyclopenta[a]
chrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-l-carboxylic acid (Compound 34),
(lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-l-isopropyl-5a,5b,8,8,l lapentamethyl-
3a-(2-methyl-2-(piperidine-4-carboxamido)propanamido)-2-oxo-3,3a,4,5,5a,5b,
6,7,7a,8,9,10,1 1,1 la,l lb, 12,13, 13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)
carbonyl)-2,2-dimethylcyclobutane-l-carboxylic acid hydrochloride (Compound 35),
(lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-3a-(2-((S)-2-amino-3-methyl
butanamido)-2-methylpropanamido)-l-isopropyl-5a,5b,8,8,l la-pentamethyl-2-oxo-3,3a,4,5,
5a,5b,6,7,7a,8,9,10,1 1,1 la,l lb, 12,13, 13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)
carbonyl)-2,2-dimethylcyclobutane-l-carboxylic acid hydrochloride (Compound 36),
(lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-3a-(l-(4-chlorobenzamido)
cyclopropane-l-carboxamido)-l-isopropyl-5a,5b,8,8,l la-pentamethyl-2-oxo-3,3a,4,5,5a,5b,
6,7,7a,8,9,10,1 1,1 la,l lb, 12,13, 13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)
carbonyl)-2,2-dimethylcyclobutane-l-carboxylic acid (Compound 37),
(lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-l-isopropyl-5a,5b,8,8,l lapentamethyl-
3a-(l-(6-methylnicotinamido)cyclopropane-l-carboxamido)-2-oxo-3,3a,4,5,5a,
5b, 6,7,7a,8, 9,10,1 1,1 la,l lb, 12,13, 13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)
carbonyl)-2,2-dimethylcyclobutane-l-carboxylic acid (Compound 38),
(lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-3a-(l-(4-fluorobenzamido)
cyclopropane-l-carboxamido)-l-isopropyl-5a,5b,8,8,l la-pentamethyl-2-oxo-3,3a,4,5,5a,5b,
6,7,7a,8,9,10,1 1,1 la,l lb, 12,13, 13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)
carbonyl)-2,2-dimethylcyclobutane-l-carboxylic acid (Compound 39),
(lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-l-isopropyl-5a,5b,8,8,l lapentamethyl-
3a-(l-(4-methylbenzamido)cyclopropane-l-carboxamido)-2-oxo-3,3a,4,5,5a,5b,
6,7,7a,8,9,10,1 1,1 la,l lb, 12,13, 13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)
carbonyl)-2,2-dimethylcyclobutane-l-carboxylic acid (Compound 40),
(lS,3R)-3-((((3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-3a-(l-(4-chlorobenzamido)
cyclopropane-l-carboxamido)-l-isopropyl-5a,5b,8,8,l la-pentamethyl-2-oxo-3,3a,4,5,5a,5b,
6,7,7a,8,9,10,1 1,1 la,l lb, 12,13, 13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)
carbonyl)-2,2-dimethylcyclobutane-l-carboxylic acid (Compound 41),
(lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-3a-(l-(4-chlorobenzamido)
cyclobutane-l-carboxamido)-l-isopropyl-5a,5b,8,8,l la-pentamethyl-2-oxo-3,3a,4,5,5a,5b,
6,7,7a,8,9,10,1 1,1 la,l lb, 12,13, 13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)
carbonyl)-2,2-dimethylcyclobutane-l-carboxylic acid (Compound 42),
(lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-l-isopropyl-5a,5b,8,8,l lapentamethyl-
3a-(l-(6-methylnicotinamido)cyclobutane-l-carboxamido)-2-oxo-3,3a,4,5,5a,
5b, 6,7,7a,8, 9,10,1 1,1 la,l lb, 12,13, 13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)
carbonyl)-2,2-dimethylcyclobutane-l-carboxylic acid (Compound 43),
(lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-l-isopropyl-5a,5b,8,8,l lapentamethyl-
2-oxo-3a-(l-(pyrimidine-2-carboxamido)cyclobutane-l-carboxamido)-3,3a,4,5,
5a,5b,6,7,7a,8,9,10,1 1,1 la,l lb, 12,13, 13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)
carbonyl)-2,2-dimethylcyclobutane-l-carboxylic acid (Compound 44),
(lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-l-isopropyl-5a,5b,8,8,l lapentamethyl-
3a-(l-(2-mo holinonicotinamido)cyclobutane-l-carboxamido)-2-oxo-3,3a,4,5,
5a,5b,6,7,7a,8,9,10,1 1,1 la,l lb, 12,13, 13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)
carbonyl)-2,2-dimethylcyclobutane-l-carboxylic acid (Compound 45),
(lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-3a-(l-(4-chlorobenzamido)
cyclopentane-l-carboxamido)-l-isopropyl-5a,5b,8,8,l la-pentamethyl-2-oxo-3,3a,4,5,5a,5b,
6,7,7a,8,9,10,1 1,1 la,l lb, 12,13, 13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)
carbonyl)-2,2-dimethylcyclobutane-l-carboxylic acid (Compound 46),
(lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-l-isopropyl-5a,5b,8,8,l lapentamethyl-
3a-(l-(6-methylnicotinamido)cyclopentane-l-carboxamido)-2-oxo-3,3a,4,5,5a,
5b, 6,7,7a,8, 9,10,1 1,1 la,l lb, 12,13, 13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)
carbonyl)-2,2-dimethylcyclobutane-l-carboxylic acid (Compound 47),
(lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-3a-(l-(4-chlorobenzamido)
cyclohexane-l-carboxamido)-l-isopropyl-5a,5b,8,8,l la-pentamethyl-2-oxo-3,3a,4,5,5a,5b,
6,7,7a,8,9,10,1 1,1 la,l lb, 12,13, 13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)
carbonyl)-2,2-dimethylcyclobutane-l-carboxylic acid (Compound 48),
(lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-l-isopropyl-5a,5b,8,8,l lapentamethyl-
3a-(l-(6-methylnicotinamido)cyclohexane-l-carboxamido)-2-oxo-3,3a,4,5,5a,
5b, 6,7,7a,8, 9,10,1 1,1 la,l lb, 12,13, 13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)
carbonyl)-2,2-dimethylcyclobutane-l-carboxylic acid (Compound 49),
(lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-l-isopropyl-5a,5b,8,8,l lapentamethyl-
3a-(l-(4-methylbenzamido)cyclohexane-l-carboxamido)-2-oxo-3,3a,4,5,5a,5b,
6,7,7a,8,9,10,1 1,1 la,l lb, 12,13, 13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)
carbonyl)-2,2-dimethylcyclobutane-l-carboxylic acid (Compound 50),
(lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-l-isopropyl-5a,5b,8,8,l lapentamethyl-
3a-(2-methyl-2-(4-(methylsulfonyl)benzamido)propanamido)-2-oxo-3,3a,4,5,5a,
5b, 6,7,7a,8, 9,10,1 1,1 la,l lb, 12,13, 13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)
carbonyl)-2,2-dimethylcyclobutane-l-carboxylic acid (Compound 51),
(lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-l-isopropyl-5a,5b,8,8,l lapentamethyl-
3a-(2-methyl-2-((S)-piperidine-3-carboxamido)propanamido)-2-oxo-3,3a,4,5,5a,
5b, 6,7,7a,8, 9,10,1 1,1 la,l lb, 12,13, 13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)
carbonyl)-2,2-dimethylcyclobutane-l-carboxylic acid hydrochloride (Compound 52),
(1R,3 S)-3-((((3aR,5aR,5bR,7aR,9S, 1laR, 1IbR, 13aS)-3a-(2-(2-(4-chlorophenyl)
acetamido)-2-methylpropanamido)-l-isopropyl-5a,5b,8,8,l la-pentamethyl-2-oxo-3,3a,4,5,
5a,5b,6,7,7a,8,9,10,1 1,1 la,l lb, 12,13, 13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)
carbonyl)-2,2-dimethylcyclobutane-l-carboxylic acid (Compound 53),
(lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-l-isopropyl-5a,5b,8,8,l lapentamethyl-
3a-(2-methyl-2-(pyrazolo[l,5-a]pyrimidine-3-carboxamido)propanamido)-2-
oxo-3,3a,4,5,5a,5b,6,7,7a,8, 9,10,1 1,1 la,l lb, 12,13, 13a-octadecahydro-2H-cyclopenta[a]
chrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-l-carboxylic acid (Compound 54),
(lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-3a-(2-(2-aminothiazole-4-
carboxamido)-2-methylpropanamido)-l-isopropyl-5a,5b,8,8,l la-pentamethyl-2-oxo-3,3a,4,5,
5a,5b,6,7,7a,8,9,10,1 1,1 la,l lb, 12,13, 13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)
carbonyl)-2,2-dimethylcyclobutane-l-carboxylic acid (Compound 55),
(lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-l-isopropyl-5a,5b,8,8,l lapentamethyl-
3a-(2-methyl-2-(4-(5-methyl-l,3,4-oxadiazol-2-yl)benzamido)propanamido)-2-
oxo-3,3a,4,5,5a,5b,6,7,7a,8, 9,10,1 1,1 la,l lb, 12,13, 13a-octadecahydro-2H-cyclopenta[a]
chrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-l-carboxylic acid (Compound 56),
(lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-3a-(2-(4-(l,l-dioxidothio
mo holino)benzamido)-2-methylpropanamido)-l-isopropyl-5a,5b,8,8,l la-pentamethyl-2-
oxo-3,3a,4,5,5a,5b,6,7,7a,8, 9,10,1 1,1 la,l lb, 12,13, 13a-octadecahydro-2H-cyclopenta[a]
chrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-l-carboxylic acid (Compound 57),
(lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-3a-(2-(4-((l,l-dioxidothio
mo holino)methyl)benzamido)-2-methylpropanamido)-l-isopropyl-5a,5b,8,8,l la-penta
methyl-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-cyclo
penta[a]chrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-l-carboxylic acid (Compound
58),
(1R,3 S)-3-((((3aR,5aR,5bR,7aR,9S, 1laR, 1IbR, 13aS)-3a-(2-(2-(dimethylamino)
acetamido)-2-methylpropanamido)-l-isopropyl-5a,5b,8,8,l la-pentamethyl-2-oxo-3,3a,4,5,5a,
5b, 6,7,7a,8, 9,10,1 1,1 la,l lb, 12,13, 13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)
carbonyl)-2,2-dimethylcyclobutane-l-carboxylic acid (Compound 59),
(lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-l-isopropyl-5a,5b,8,8,l lapentamethyl-
3a-(2-methyl-2-(6-methylpicolinamido)propanamido)-2-oxo-3,3a,4,5,5a,5b,
6,7,7a,8,9,10,1 1,1 la,l lb, 12,13, 13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)
carbonyl)-2,2-dimethylcyclobutane-l-carboxylic acid (Compound 60),
(lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-l-isopropyl-5a,5b,8,8,l lapentamethyl-
3a-(2-methyl-2-(6-methylnicotinamido)propanamido)-2-oxo-3,3a,4,5,5a,5b,
6,7,7a,8,9,10,1 1,1 la,l lb, 12,13, 13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)
carbonyl)-2,2-dimethylcyclobutane-l-carboxylic acid (Compound 61),
(lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-l-isopropyl-5a,5b,8,8,l lapentamethyl-
3a-(2-methyl-2-pivalamidopropanamido)-2-oxo-3,3a,4,5,5a,5b,6, 7,7a,8,9,10,l 1,
l la,l lb,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2-dimethyl
cyclobutane-l-carboxylic acid (Compound 62),
sodium (lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-l-isopropyl-5a,5b,8,8,
l la-pentamethyl-3a-(2-methyl-2-(methylsulfonamido)propanamido)-2-oxo-3,3a,4,5,5a,5b,
6,7,7a,8,9,10,1 1,1 la,l lb, 12,13, 13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)
carbonyl)-2,2-dimethylcyclobutane-l-carboxylate (Compound 63),
(1R,3 S)-3-((((3aR,5aR,5bR,7aR,9S, 1laR, 1IbR, 13aS)-3a-(2-((ethoxycarbonyl)amino)
-2-methylpropanamido)-l-isopropyl-5a,5b,8,8,l la-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,
8,9,10,1 1,1 la,l lb, 12,13, 13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-
2,2-dimethylcyclobutane-l-carboxylic acid (Compound 64),
(1R,3 S)-3-((((3aR,5aR,5bR,7aR,9S, 1laR, 1IbR, 13aS)-3a-(2-((4-chlorophenyl)
sulfonamido)-2-methylpropanamido)-l-isopropyl-5a,5b,8,8,l la-pentamethyl-2-oxo-3,3a,4,5,
5a,5b,6,7,7a,8,9,10,1 1,1 la,l lb, 12,13, 13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)
carbonyl)-2,2-dimethylcyclobutane-l-carboxylic acid (Compound 65),
(lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-3a-(2-(cyclohexanecarbox
amido)-2-methylpropanamido)-l-isopropyl-5a,5b,8,8,l la-pentamethyl-2-oxo-3,3a,4,5,5a,5b,
6,7,7a,8,9,10,1 1,1 la,l lb, 12,13, 13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)
carbonyl)-2,2-dimethylcyclobutane-l-carboxylic acid (Compound 66),
(lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-l-isopropyl-5a,5b,8,8,l lapentamethyl-
3a-(2-methyl-2-((pyridin-2-ylmethyl)amino)propanamido)-2-oxo-3,3a,4,5,5a,
5b, 6,7,7a,8, 9,10,1 1,1 la,l lb, 12,13, 13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)
carbonyl)-2,2-dimethylcyclobutane-l-carboxylic acid (Compound 67),
(1R,3 S)-3-((((3aR,5aR,5bR,7aR,9S, 1laR, 1IbR, 13aS)-3a-(2-((4-chlorobenzyl)amino)-
2-methylpropanamido)-l-isopropyl-5a,5b,8,8,l la-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,
8,9,10,1 1,1 la,l lb, 12,13, 13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-
2,2-dimethylcyclobutane-l-carboxylic acid (Compound 68),
(lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-3a-(2-(((l-(4-chlorophenyl)
cyclopropyl)methyl)amino)-2-methylpropanamido)-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-octadecahydro-2H-cyclopenta[a]
chrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-l-carboxylic acid (Compound 69),
(1R,3 S)-3-((((3aR,5aR,5bR,7aR,9S, 1laR, 1IbR, 13aS)-3 a-(2-(5 -chloropicolinamido)-
2-methylpropanamido)-l-isopropyl-5a,5b,8,8,l la-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,
8,9,10,1 1,1 la,l lb, 12,13, 13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-
2,2-dimethylcyclobutane-l-carboxylic acid (Compound 70),
(lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-l-isopropyl-5a,5b,8,8,l lapentamethyl-
3a-(2-methyl-2-(3-(6-methylpyridin-3-yl)ureido)propanamido)-2-oxo-3,3a,4,5,
5a,5b,6,7,7a,8,9,10,1 1,1 la,l lb, 12,13, 13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)
carbonyl)-2,2-dimethylcyclobutane-l-carboxylic acid (Compound 71),
(lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-l-isopropyl-5a,5b,8,8,l lapentamethyl-
3a-(2-methyl-2-(3-(6-methylpyridin-2-yl)ureido)propanamido)-2-oxo-3,3a,4,5,
5a,5b,6,7,7a,8, 9,10,1 1,1 la,l lb, 12,13, 13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)
carbonyl)-2,2-dimethylcyclobutane-l-carboxylic acid (Compound 72),
(lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-3a-(2-((2-(dimethylamino)
ethyl)amino)-2-methylpropanamido)-l-isopropyl-5a,5b,8,8,l la-pentamethyl-2-oxo-3,3a,4,5,
5a,5b,6,7,7a,8, 9,10,1 1,1 la,l lb, 12,13, 13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)
carbonyl)-2,2-dimethylcyclobutane-l-carboxylic acid (Compound 73),
(lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-3a-(2-amino-2-methylpropan
amido)-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-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2-dimethyl
cyclobutane-l-carboxylic acid hydrochloride (Compound 74),
(1R,3 S)-3-((((3aR,5aR,5bR,7aR,9S, 1laR, 1IbR, 13aS)-3a-(2-((tert-butoxycarbonyl)
amino)-2-methylpropanamido)-l-isopropyl-5a,5b,8,8,l la-pentamethyl-2-oxo-3,3a,4,5,5a,5b,
6,7,7a,8,9,10,1 1,1 la,l lb, 12,13, 13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)
carbonyl)-2,2-dimethyl cyclobutane-l-carboxylic acid (Compound 75),
(lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-l-isopropyl-5a,5b,8,8,l lapentamethyl-
3a-(2-methyl-2-((S)-pyrrolidine-2-carboxamido)propanamido)-2-oxo-3,3a,4,5,
5a,5b,6,7,7a,8, 9,10,1 1,1 la,l lb, 12,13, 13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)
carbonyl)-2,2-dimethylcyclobutane-l-carboxylic acid hydrochloride (Compound 76), or
pharmaceutically acceptable salts, solvates, including hydrates and prodrugs of compounds
are also contemplated.
The present invention also provides a pharmaceutical composition that includes at
least one compound as described herein and at least one pharmaceutically acceptable
excipient (such as a pharmaceutically acceptable carrier or diluent). Specifically, the
pharmaceutical composition comprises a therapeutically effective amount of at least one
compound 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
cause that infection, specifically in the form of a pharmaceutical composition.
Also provided herein are processes for preparing compounds described herein.
The invention provides a method for preventing; ameliorating or treating a HIV
mediated disease, disorder or syndrome in a subject in need thereof comprising administering
to the subject a therapeutically effective amount of a compound of the invention. The
invention further provides a method, wherein the HIV mediated disease, disorder or
syndrome is like AIDS, AIDS related complex, or a syndrome characterized by symptoms
such as 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 Mossman T, December 1983, Journal of immunological methods, 65 (1-
2), 55-63 and SPC Cole, cancer chemotherapy and Pharmacology, 1986, 17, 259-263.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides C-3 novel triterpenone with C-28 reverse amide
derivatives and related compounds, which may be used as antiviral particularly as anti-HIV
compounds and processes for the synthesis of these compounds. Pharmaceutically acceptable
salts, pharmaceutically acceptable solvates, enantiomers, diastereomers of the derivatives,
together with pharmaceutically acceptable carriers, excipients or diluents, which can be used
for the treatment of diseases, condition and/or disorders mediated by viral infections, are also
provided.
The following definitions apply to the terms as used herein:
The terms "halogen" or "halo" includes fluorine, chlorine, bromine, or iodine.
The term "alkyl" refers to a straight or branched hydrocarbon chain radical consisting
solely of carbon and hydrogen atoms, containing no unsaturation, having from one to eight
carbon atoms, and which is attached to the rest of the molecule by a single bond, e.g., methyl,
ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl, and 1,1 -dimethylethyl (t-butyl).
The term "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).
The term "alkoxylalkoxy" refers to a straight or branched hydrocarbon chain with
oxygen radical consisting carbon atom, hydrogen atom and alkoxy groups, 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., 2-
(methyloxy)ethyloxy, 2-(ethyloxy)ethyloxy, 2-(n-propyloxy)ethyloxy, and 3- (isopropylo
xy)butylo xy.
The term "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.
The term "amino acid" refers to a straight or branched hydrocarbon chain containing
an amine group, a carboxylic acid group, and a side-chain that is specific to each amino acid
and which is attached through the nitrogen atom of the amine group to the rest of the
molecule by a single bond, e.g., alanine, valine, isoleucine, leucine, phenylalanine, or
tyrosine.
The term "amino alkyl" refers to any amino derivative of an alkyl radical more
specifically dimethylamino.
The term "cycloalkyl" denotes a non-aromatic mono or multicyclic ring system of
from 3 to about 12 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, and
cyclohexyl. Examples of multicyclic cycloalkyl groups include, but are not limited to,
perhydronapththyl, adamantyl and norbornyl groups, bridged cyclic groups and spirobicyclic
groups, e.g., spiro (4,4) non-2-yl.
The term "aryl" refers to an aromatic radical having from 6 to 14 carbon atoms such
as phenyl, naphthyl, tetrahydronapthyl, indanyl, and biphenyl.
The term "haloalkyl" refers to alkyl group (as defined above) is substituted with one
or more halogens. A monohaloalkyl radical, for example, may have a chlorine, bromine,
iodine or fluorine atom. Dihalo and polyhaloalkyl radicals may have two or more of the same
or different halogen atoms. Examples of haloalkyl include, but are not limited to,
chloromethyl, dichloromethyl, trichloromethyl, dichloroethyl, dichloropropyl, fluoromethyl,
difluoromethyl, trifluoromethyl, pentafluoroethyl, heptafluoropropyl, difluoro chloromethyl,
dichloro fluoromethyl, difluoroethyl, difluoropropyl and the like.
The terms "heterocyclyl" and "heterocyclic ring" refer to a stable 3- to 15-membered
ring radical which consists of carbon atoms and from one to five heteroatoms selected from
nitrogen, phosphorus, oxygen and sulfur. For purposes of this invention, the heterocyclic ring
radical may be a monocyclic, bicyclic or tricyclic ring system, which may include fused,
bridged or spiro ring systems, and the nitrogen, phosphorus, carbon, oxygen or sulfur atoms
in the heterocyclic ring radical may be optionally oxidized to various oxidation states. In
addition, the nitrogen atom may be optionally quaternized; and the ring radical may be
partially or fully saturated (i.e., heterocyclic or heteroaryl). Examples of such heterocyclic
ring radicals include, but are not limited to, tetrazoyl, tetrahydroisouinolyl, piperidinyl,
piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepinyl, azepinyl,
pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl,
oxazolinyl, oxazolidinyl, triazolyl, isoxazolyl, isoxasolidinyl, morpholinyl, thiazolyl,
thiazolinyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl, isoindolyl,
indolinyl, isoindolinyl, octahydroindolyl, octahydroisoindolyl, quinolyl, isoquinolyl,
decahydroisoquinolyl, benzimidazolyl, thiadiazolyl, benzothiazolyl, benzooxazolyl, furyl,
tetrahydrofurtyl, tetrahydropyranyl, thienyl, benzothienyl, thiamorpholinyl, thiamorpholinyl
sulfoxide, thiamorpholinyl sulfone, dioxaphospholanyl, oxadiazolyl and l,4-Thiazine-l,ldione.
The heterocyclic ring radical may be attached to the main structure at any heteroatom
or carbon atom that results in the creation of a stable structure.
The term "heterocyclylalkyl" refers to a heterocyclic ring radical directly bonded to
an alkyl group. The heterocyclylalkyl radical may be attached to the main structure at any
carbon atom in the alkyl group that results in the creation of a stable structure.
The term "heteroaryl" refers to an aromatic heterocyclic ring radical. Examples of
such 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.
"Substituted" refers to 1-3 substituents on the same position or on different positions
with the same groups or different groups. Unless otherwise specified, the term "substituted"
as used herein refers to substitution with any one or any combination of the following
substituents: hydroxy, halogen, carboxyl, cyano, nitro, oxo (=0), thio (=S), substituted or
unsubstituted alkyl, haloalkyl, substituted or unsubstituted alkoxy, substituted or
unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl,
substituted or unsubstituted arylalkyl, substituted or unsubstituted cycloalkyl, s substituted or
unsubstituted amino, substituted or unsubstituted heteroaryl, substituted or unsubstituted
heterocyclylalkyl ring, substituted or substituted or unsubstituted heterocyclic ring. The
substituents in the aforementioned "substituted" groups cannot be further substituted. For
example, when the substituent on "substituted alkyl" is "substituted aryl", the substituent on
"substituted aryl" cannot be "substituted alkenyl".
The term "prodrug" denotes a derivative of a compound, which derivative, when
administered to warm -blooded animals, e.g. humans, is converted into the compound (drug).
The enzymatic and/or chemical hydrolytic cleavage of the compounds of the present
invention occurs in such a manner that the proven drug form (parent carboxylic acid drug) is
released, and the moiety or moieties split off remain nontoxic or are metabolized so that
nontoxic metabolic products are produced. For example, a carboxylic acid group can be
esterified, e.g., with a methyl group or ethyl group to yield an ester. When an ester is
administered to a subject, the ester is cleaved, enzymatically or non-enzymatically,
reductively, oxidatively, or hydrolytically, to reveal the anionic group. An anionic group can
be esterified with moieties (e.g., acyloxymethyl esters) which are cleaved to reveal an
intermediate compound which subsequently decomposes to yield the active compound. A
discussion of the use of prodrugs is provided by T. Higuchi and W. Stella, "Pro-drugs as
Novel Delivery Systems," Vol. 14 of the A.C.S. Symposium Series, and in Bioreversible
Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and
Pergamon Press, 1987.
The term "treating" or "treatment" of a state, disease, disorder or condition includes:
(1) preventing or delaying the appearance of clinical symptoms of the state,
disease, disorder or condition developing in a subject that may be afflicted with or
predisposed to the state, disease, disorder or condition but does not yet experience or display
clinical or subclinical symptoms of the state, disease, disorder or condition;
(2) inhibiting the state, disease, disorder or condition, i.e., arresting or
reducing the development of the state, disease, disorder or condition or at least one clinical or
subclinical symptom thereof; or
(3) relieving the state, disease, disorder or condition, i.e., causing regression of
the state, disease, disorder or condition or at least one of its clinical or subclinical symptoms.
The benefit to a subject receiving treatment is either statistically significant or at least
perceptible to the subject or to the physician.
The term "subject" includes mammals (especially humans) and other animals, such as
domestic animals (e.g., household pets including cats and dogs) and non-domestic animals
(such as wildlife).
A "therapeutically effective amount" means the amount of a compound that, when
administered to a subject for treating a state, disease, disorder or condition, is sufficient to
effect such treatment. The "therapeutically effective amount" will vary depending on the
compound, the state, disease, disorder or condition and its severity and the age, weight,
physical condition and responsiveness of the subject receiving treatment.
The compounds of the present invention may form salts. Non-limiting examples of
pharmaceutically acceptable salts forming part of this invention include salts derived from
inorganic bases salts of organic bases salts of chiral bases, salts of natural amino acids and
salts of non-natural amino acids. Certain compounds of the present invention are capable of
existing in stereo isomeric forms (e.g., diastereomers, enantiomers, racemates, and
combinations thereof). With respect to the overall compounds described by the Formula (1),
the present invention extends to these stereo isomeric forms and to mixtures thereof. To the
extent prior art teaches synthesis or separation of particular stereoisomers, the different stereo
isomeric forms of the present invention may be separated from one another by the methods
known in the art, or a given isomer may be obtained by stereospecific or asymmetric
synthesis. Tautomeric forms and mixtures of compounds described herein are also
contemplated.
Pharmaceutically acceptable solvates includes hydrates and other solvents of
crystallization (such as alcohols). The compounds of the present invention may form solvates
with low molecular weight solvents by methods known in the art.
PHARMACEUTICAL COMPOSITIONS
The pharmaceutical compositions provided in the present invention include at least
one compound described herein and at least one pharmaceutically acceptable excipient (such
as a pharmaceutically acceptable carrier or diluent). Specifically, the contemplated
pharmaceutical compositions include a compound(s) described herein in an amount sufficient
to treat viral infection in a subject.
The subjects contemplated include, for example, a living cell and a mammal,
including human. The compound of the present invention may be associated with a
pharmaceutically acceptable excipient (such as a carrier or a diluent) or be diluted by a
carrier, or enclosed within a carrier which can be in the form of a capsule, sachet, or other
container.
Examples of suitable carriers include, but are not limited to, water, salt solutions,
alcohols, polyethylene glycols, peanut oil, olive oil, gelatin, lactose, terra alba, sucrose,
dextrin, magnesium carbonate, sugar, amylose, magnesium stearate, talc, gelatin, agar, pectin,
acacia, stearic acid, lower alkyl ethers of cellulose, silicic acid, fatty acids, fatty acid amines,
fatty acid monoglycerides and diglycerides, fatty acid esters, and polyoxyethylene.
The carrier or diluent may include a sustained release material, such as, for example,
glyceryl monostearate or glyceryl distearate, alone or mixed with a wax.
The pharmaceutical composition may also include one or more pharmaceutically
acceptable auxiliary agents, wetting agents, emulsifying agents, suspending agents,
preserving agents, salts for influencing osmotic pressure, buffers, sweetening agents,
flavoring agents, colorants, or any combination of the foregoing. The pharmaceutical
composition of the invention may be formulated so as to provide quick-, sustained-, or
delayed-release of the active ingredient after administration to the subject by employing
procedures known in the art.
The pharmaceutical compositions described herein may be prepared, e.g., as described
in Remington: The Science and Practice of Pharmacy , 20th Ed., 2003 (Lippincott Williams &
Wilkins). For example, the active compound can be mixed with a carrier, or diluted by a
carrier, or enclosed within a carrier, which may be in the form of an ampule, capsule, or
sachet. When the carrier serves as a diluent, it may be a solid, semi-solid, or liquid material
that acts as a vehicle, excipient, or medium for the active compound.
The pharmaceutical compositions may be in conventional forms, for example,
capsules, tablets, solutions, suspensions, injectables or products for topical application.
Further, the pharmaceutical composition of the present invention may be formulated so as to
provide desired release profile.
The route of administration may be any route which effectively transports the active
compound to the appropriate or desired site of action. Suitable routes of administration
include, but are not limited to, oral, nasal, pulmonary, buccal, subdermal, intradermal,
transdermal, parenteral, rectal, depot, subcutaneous, intravenous, intraurethral, intramuscular,
intranasal, ophthalmic (such as with an ophthalmic solution) or topical (such as with a topical
ointment). The oral route is specifically suitable.
Solid oral formulations include, but are not limited to, tablets, capsules (soft or hard
gelatin), dragees (containing the active ingredient in powder or pellet form), troches and
lozenges. Tablets, dragees, or capsules having talc and/or a carbohydrate carrier or binder or
the like are particularly suitable for oral application. Exemplary carriers for tablets, dragees,
or capsules include lactose, cornstarch, and/or potato starch. A syrup or elixir can be used in
cases where a sweetened vehicle can be employed.
A typical tablet that may be prepared by conventional tableting techniques.
Liquid formulations include, but are not limited to, syrups, emulsions, soft gelatin and
sterile injectable liquids, such as aqueous or non-aqueous liquid suspensions or solutions.
For parenteral application, particularly suitable are injectable solutions or
suspensions, specifically aqueous solutions with the active compound dissolved in
polyhydroxylated castor oil.
METHODS OF SCREENING
Antiviral HIV activity and cytotoxicity of compounds present invention can be
measured in parallel by following the methods published in the literature.
The cytotoxic effect of compounds can be analyzed by measuring the proliferation of
cells using the 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyl tetrazlium bromide (MTT) staining.
Cells (5 x 10 cells /well) will be incubated in in 96 well plates in the presence or absence of
compounds. At the end of treatment, 20m1 of MTT (5mg/ml in PBS) will be added to each
well and incubated for an additional 4 hours at 37°C. The purple-blue MTT formazan
precipitate will be dissolved in a triplex reagent containing 10% SDS, 5% isobutanol and 10
mmol/lit HCl. The activity of mitochondria, reflecting cellular growth and viability, will be
evaluated by measuring the optical density at 570 nm on micro titer plate.
Action of compounds on replication of HIV in Sup-Tl cells can be determined by the
method published by Roda Rani et al., 2006 (Archives of Biochemistry and Biophysics,
Volume 456, Issue 1, 1 December 2006, Pages 79-92).
Briefly, lxlO 6 Sup-Tl cells with 100% cell viability will be seeded in RPMI 1640,
0 .1% FBS four 12 well plates. Increasing concentrations of Epap-1 peptides will be added to
the cells and will be infected with HIV1 I IOI each at final concentration of virus equivalent
to 2 ng of p24 per ml. The infected cells will be incubated at 37°C and 5% C0 2 incubator for
2 hours. After 2 hours the cells will be pelleted at 350 g for 10 minutes, supernatant will be
discarded and cell will be held with RPMI 1640 containing 10%> FBS. The cells will be
resuspended in the same medium with increasing concentrations of Epap-1 peptides and will
be incubated for 96 hours. The cells will be supplemented with peptides at every 24 hours.
The supernatants will be collected after 96 hours and analyzed using P24 antigen capture
assay kit (SAIC Fredrick). The infection in the absence of Epap-1 will be considered to be
0%> inhibition Azidothymidine (AZT) will be taken as positive control.
Action of compound on virus entry and quantification of virus entered can be done in
terms of GFP expression by the following the methods published J . Virol. 72, 6988 (1998) by
in Cecilia et al., and Analytical Biochemistry Volume 360, Issue 2, 15 January 2007, Pages
315-317 (Dyavar S. Ravi and Debashis Mitra).
Briefly, cells will be seeded in to wells of 24 well plates 1 day prior to the experiment.
The cells will be transfected with Tat-reporter. The virus inoculum will be adjusted to 1,000-
4,000 TCID 50/ml in assay medium (DMEM, 10% FCS, glutamine and antibiotics), 50 mΐ
aliquots will be incubated with serial dilutions of compounds (50 mΐ ) for 1 hour at 37°C. The
reporter expression will be quantified at appropriate time calculated inhibitory doses referrers
to the concentration of these agents in this preincubation mixture.
Other relevant references useful for screening antiviral HIV activity are: Averett,
D.R.1989. Anti-HIV compound assessment by two novel high capacity assays. J . Virol.
Methods 23: 263-276; Schwartz, O., et al.1998; A rapid and simple colorimeric test fror the
study of anti HIV agents. AIDS Res. and Human Retroviruses, 4(6):441-447; Daluge, S. M.,
et al. 1994. 5-Chloro-2',3'-deoxy-3'fluorouridine (935U83), a selective anti human
immunodeficiency virus agent with an improved metabolic and toxicological profile;
Antimicro. Agents and Chemotherapy, 38(7): 1590-1603; H.Mitsuya and S.Border,
Inhibition of the in vitro infectivity and cytopathic effect of human T-lymphotropic virus type
lymphadenopathy-associated virus (HLTV-III/LAV) by 2,3'-dideoxynucleosides, Proc. Natl.
Acad. Sci. USA,83, 191 1-15(1986); Pennington et al., Peptides 1990; Meek T.D et al.,
Inhibition of HIV-1 protease in infected T-limphocytes by synthetic peptide analogues,
Nature, 343, p90 (1990); Weislow et al., J . Natl. Cancer Inst. 81, 577-586, 1989; T. Mimoto
et al ., J . Med. Chem., 42, 1789-1802, 1999; Uckun et al 1998, Antimicrobial Agents and
Chemotherapy 42:383; for P24 antigen assay Erice et al., 1993, Antimicrob. Ag.
Chemotherapy 37: 385-383; Koyanagi et al., Int. J . Cancer, 36, 445-451, 1985; Balzarini et
al. AIDS (1991), 5, 21-28; Connor et al., Journal of virology, 1996, 70, 5306-531 1; Popik et
al., Journal of virology, 2002, 76, 4709-4722; Harrigton et al., Journal of Virology Methods,
2000, 88, 111-1 15; Roos et al.,Virology 2000, 273, 307-315; Fedyuk N.V. et al; Problems of
Virology 1992, (3)P135; Mosmann T, December 1983, Journal of immunological methods,
65 (1-2), 55-63 ; SPC Cole, cancer chemotherapy and Pharmacology, 1986, 17, 259-263,
Antiviral methods and protocols (Eds: D Kinchington and R. F. Schinazi) Humana Press Inc.,
2000, HIV protocols (Eds: N. L. Michael and J . H. Kim) Humana Press Inc, 1999, DAIDS
Virology manual from HIV laboratories, Publication NIH-97-3838, 1997, 4 . HIV-1 p24
antigen capture assay, enzyme immunoassay for detection of Human immunodeficiency
Virus Type 1 (HIV-1) p24 in tissue culture media - Advanced bio science laboratories, Inc kit
procedure.
METHODS OF TREATMENT
The present invention provides compounds and pharmaceutical formulations thereof
that are useful in the treatment of diseases, conditions and/or disorders mediated by viral
infections. The connection between therapeutic effect and antiviral is illustrated. For
example, PCT publication Nos. WO 01//07646, WO 01/65957, or WO 03/037908; US
publication Nos. US 4,598,095 or US 2002/0068757; EP publication Nos. EP 0989862 or EP
0724650; Bioorganic & Medicinal Chemistry Letters, 16, (6), 1712-1715, 2006; and
references cited therein, all of which are incorporated herein by reference in their entirety and
for the purpose stated.
The present invention further provides a method of treating a disease, condition
and/or disorder mediated by viral infections in a subject in need thereof by administering to
the subject a therapeutically effective amount of a compound or a pharmaceutical
composition of the present invention.
Diseases, conditions, and/or disorders that are mediated by viral infections are
believed to include, but are not limited to, HIV infection, HBV infection, HCV infection, a
retroviral infection genetically related to HIV, AIDS, inflammatory disease, respiratory
disorders (including adult respiratory distress syndrome (ARDS), bronchitis, chronic
bronchitis, chronic obstructive pulmonary disease, cystic fibrosis, asthma, emphysema,
rhinitis and chronic sinusitis), inflammatory bowel disease (including Crohn's disease and
ulcerative colitis), multiple sclerosis, rheumatoid arthritis, graft rejection (in particular but not
limited to kidney and lung allografts), endometriosis, type I diabetes, renal diseases, chronic
pancreatitis, inflammatory lung conditions, chronic heart failure and bacterial infections (in
particular but not limited to tuberculosis).
The compounds of the present invention can obtain more advantageous effects than
additive effects in the prevention or treatment of the above diseases when using suitably in
combination with the available drugs. Also, the administration dose can be decreased in
comparison with administration of either drug alone, or adverse effects of co administrated
drugs other than antiviral can be avoided or declined.
METHODS OF PREPARATION
The compounds described herein may be prepared by techniques known in the art. In
addition, the compounds described herein may be prepared by following the reaction
sequence as depicted in Scheme 1. Further, in the following schemes, where specific bases,
acids, reagents, solvents, coupling agents, etc., are mentioned, it is understood that other
bases, acids, reagents, solvents, coupling agents etc., known in the art may also be used and
are therefore included within the present invention. Variations in reaction conditions, for
example, temperature and/or duration of the reaction, which may be used as known in the art,
are also within the scope of the present invention. All the stereoisomers of the compounds in
these schemes, unless otherwise specified, are also encompassed within the scope of this
invention.
Compounds of the present invention can be synthesized from naturally occurring
Betulinic acid or betulinal. Key intermediates required for synthesizing analogues are either
commercially available, or can be prepared by the methods published in the literature. For
example, the key intermediates in the present invention were prepared by modifying the
procedures published in Journal of organic chemistry 2010, 75, 1285-1288; Journal of
organic chemistry 2000, 65, 3934-3940; Tetrahedron: asymmetry 2008, 19, 302-308; or
Tetrahedron: asymmetry 2003, 14, 217-223.
Scheme-1
The compounds of formula 1 (wherein, R2, R , R4, R5, R6 and R 7 are same as defined
above) can be prepared as described in Scheme 1. The C-3 & C-28 di alcohol compounds of
formula (i) can be reacted with a suitable acetate forming reagents such as anhydrides, acid
halides, mixed anhydrides or the like in the presence of bases such as triethylamine (TEA),
diisopropylethylamine (DIPEA), pyridine or the like in the solvents such as dichloromethane
(DCM), chloroform (CHC1 ), toluene, tetrahydrofuran (THF) or the like with or without
addition of catalysts such as dimethyl amino pyridine (DMAP) or the like to give the C-3 &
C-28 protected alcohol compounds of formula (ii) (Pi and P2 are protecting groups such as
acetyl, benzyl or the like). The C-3 & C-28 protected alcohol compounds of formula (ii) with
terminal double bond can be migrated to the E-ring compounds of formula (iii) in the
presence of hydrogen bromide (HBr) in acetic acid (AcOH), acetic acid (AcOH) and acetic
anhydride (Ac20 ) in solvents like toluene, benzene, xylene or the like. The E-ring compounds
of formula (iii) can be converted to give the Enone compounds of formula (iv) in the presence
of sodium dichromate (Na2Cr20 7), sodium acetate (NaOAc), acetic acid (AcOH), acetic
anhydride (Ac20 ) in solvents like toluene, benzene or the like. The Enone C-28 compounds
of formula (iv) can be deprotected to give the C-28 alcohol compounds of formula (v) in the
presence of potassium hydroxide (KOH) or the like in the combination of solvents such as
toluene: ethanol (EtOH) (1:1) or with reagents like Aluminum isopropoxide (Al(i-Pro) ) in
solvents like 2-propanol or the like. The C-28 alcohol compounds of formula (v) can be
converted to give the C-28 aldehyde compounds of formula (vi) in the presence of pyridinium
chlorochromate (PCC), pyridinium dichromate (PDC), Dess-martin periodinane (DMP) or
Swern oxidation conditions in the solvents such as dichloromethane (DCM) or the like. The
C-28 aldehyde compounds of formula (vi) can be converted to give the C-28 acid compounds
of formula (vii) in the presence of oxidising agents such as sodium chlorite (NaC102) or the
like in the presence of a scavenger such as 2-methyl-2-butene or the like in the presence of a
buffer reagent such as sodiumdihydrogen phosphate (NaH2P0 4) or the like in the
combination of solvents such as tert-butanol (t-BuOH), tetrahydrofuran (THF) and water
(H20 ) or the like. The C-28 alcohol compounds of formula (v) can be converted in one pot
method to C-28 acid compounds of formula (vii) in the presence of oxidizing agents such as
2,2,6,6-Tetramethyl-l-piperidinyloxy, free radical, 2,2,6,6-Tetramethylpiperidine 1-oxyl
(TEMPO), Sodium hypochlorite (NaOCl) and Sodium chlorite (NaC102) in the presence of
buffer reagent such as sodiumdihydrogen phosphate (NaH2P0 4) and the bases like NaHC0
in combination of solvents like Tetrahydrofuran (THF) and water (H20 ) The C-28 acid
compounds of formula (vii) can be converted to the C-28 carbamate compounds of formula
(viii) by using the reagents like diphenylphosphoryl azide (DPPA) or ethylchloroformate and
sodium azide (NaN ) in the presence of bases such as triethylamine (TEA), N,NDiisopropylethylamine
(DIPEA) in solvents such as 1,2-DCE, THF or Toluene in the
presence of alcohols such as 4-methoxybenzyl alcohol (PMBOH), tert-butyl alcohol (t-
BuOH) or the like. The C-28 carbamate compounds of formula (viii) can be cleaved in the
presence of acid medium such as trifluoroacetic acid (TFA), HCl/l,4-dioxane or the like in
the solvents such as dichloromethane (DCM) or chloroform (CHC1 ) or the like to give the
amine compounds of formula (ix). The C-28 amine compounds of formula (ix) can be reacted
with the acid compounds of formula (x) in the presence of coupling reagents such as 0-(7-
Azabenzotriazol- 1-yl)-N,N,N' ,N' -tetramethyluroniumhexafluorophosphate (HATU), O-
(Benzotriazol-l-yl)-N,N,N',N'-tetramethyluroniumhexafluoro phosphate (HBTU), l-Ethyl-3-
(3-dimethylaminopropyl)carbodiimide (EDCI), 1-Hydroxybenzo triazole (HOBt) or the like
in the presence of bases such as triethylamine (TEA), N,N-Diisopropylethylamine (DIPEA)
or the like in the solvents such as 1,2-dichloroethane (1,2-DCE), dimethylformamide (DMF)
or the like to give the C-28 amide compounds of formula (xi). The C-3 protected alcohol
compounds of formula (xi) can be deprotected to give the C-3 alcohol compounds of formula
(xii) in the presence of inorganic bases such as Lithium hydroxide (LiOH), sodium hydroxide
(NaOH), potassium hydroxide (KOH) or the like in the solvents such as methanol (MeOH):
tetrahydrofuran (THF): water (H20 ) (4:2:1) (or) 1,4-dioxane: water (H20 ) (4:1) or the like.
The C-3 alcohol compounds of formula (xii) can be reacted with the acid compounds of
formula (xiii) to give the C-3 ester compounds of formula (xiv) in different ways like
(a) Acid and alcohol coupling in the presence of coupling reagents such as 2,4,6-
trichlorobenzyl chloride, or the like in the presence of bases such as triethylamine
(TEA), N,N-Diisopropylethylamine (DIPEA) and catalysts such as 4-
dimethylaminopyridine (DMAP) in the solvents such as 1,2-dichloroethane (1,2-
DCE), dichloromethane (DCM) or the like.
(b) acid alcohol coupling in the presence of coupling reagents such EDCI, HOBt in
the presence of bases such as triethylamine (TEA), N,N-Diisopropylethylamine
(DIPEA) and catalysts such as 4-dimethylaminopyridine (DMAP) in the solvents
such as dichloromethane (DCM) and N,N-dimethylformamide (DMF) or the like.
The C-28 substituted N-protected compounds of formula (xiv) can be deprotected in the
presence of deprotecting agents such as trifluoroacetic acid (TFA) or HCl/l,4-dioxane or the
like in the solvents such as dichloromethane (DCM) or the like to give the C-28 substituted
amine compounds of formula (xv). The C-28 substituted amine compounds of formula (xv)
can be reacted with the compounds of formula (xvi) to form C-3 ester compounds of formula
(xvii) in different ways like
a) acid and amine coupling in the presence of coupling reagents such as 0-(7-
Azabenzotriazol- 1-yl)-N,N,N' ,N' -tetra methyluroniumhexafluorophosphate (HATU),
0-(Benzotriazol-l-yl)-N,N,N',N'-tetram ethyl uroniumhexafluorophosphate (HBTU),
1-Ethyl-3 -(3 -dimethylaminopropyl)carbodiimide (EDCI), 1-Hydroxybenzotriazole
(HOBt) or the like in the presence of bases such as triethylamine (TEA), N,NDiisopropylethylamine
(DIPEA) or the like in the solvents such as 1,2-dichloroethane
(1,2-DCE), dimethylformamide (DMF) or the like.
b) reductive amination of amine and aldehyde in the presence of reducing agents such as
sodium triacetoxyborohydride (STAB) or Sodium borohydride or sodium
cyanoborohydride (NaC BH ) or the like in the solvents such as 1,2-dichloroethane
(1,2-DCE), tetrahydrofuran (THF), Methanol (MeOH), Acetonitrile (CH CN) or the
like.
c) acid chloride and amine coupling in the presence of bases such as triethylamine
(TEA), or diisopropylethylamine (DIPEA) or the like in the solvents such as
dichloromethane (DCM) or the like.
d) amine and sodium sulphite adduct coupling in the presence of reductive agents such
as sodium cyano borohydride (NaC BH ) or the like in the presence of bases such as
triethylamine (TEA) or the like in the solvents such as methanol (MeOH) or the like.
e) Amine and isocyanato coupling in the presence of bases such as triethylamine (TEA),
diisopropylethylamine (DIPEA) or the like in the solvents such as tetrahydrofuran
(THF) or the like.
The ester compounds of formula (xvii) can be hydrolysed to give the acid compounds
of formula 1 in the presence of aqueous solution of inorganic bases such as Lithium
hydroxide (LiOH), sodium hydroxide (NaOH) or potassium hydroxide (KOH) or the like in
the combination of solvents such as tetrahydrofuran (THF): methanol (MeOH) (1:1) or the
like.
The abbreviations used in the entire specification may be summarized herein below
with their particular meaning: DIPEA (N,N-Diisopropylethylamine); °C (degree Celsius); d
(delta); ppm (parts per million); % (percentage); DMSO-d6 (Deuterated DMSO); d (Doublet);
dd (Doublet of doublet); EtOH (Ethanol); EtOAc (Ethyl acetate); g or gr (gram); H or H2
(Hydrogen); HC1 (Hydrochloric acid); h or hr. (Hours); HATU (0-(7-Azabenzotriazol-l-yl)-
N,N,N' ,N '-tetramethyluroniumhexafluoro phosphate); Hz (Hertz); HPLC (High-performance
liquid chromatography); mmol (Milli mol); M (Molar); ml (Millilitre); mg (Milli gram); m
(Multiplet); mm (Millimetre); MHz (Megahertz); ESI-MS (Electron spray Ionization Mass
spectra); min (Minutes); mM (Milli molar); NaOH (Sodium hydroxide); N2 (Nitrogen); NMR
(Nuclear magnetic resonance spectroscopy); S (Singlet); TEA (Triethyl amine); TLC (Thin
Layer Chromatography); THF (Tetrahydrofuran); tert (Tertiary), TFA/CF3COOH (Trifluoro
acetic acid); t (Triplet); IC (Inhibitory concentration), nM (Nano molar); pH (Pouvoir
hydrogen); (Boc)20 (Di-tert-butyl dicarbonate); DCM (dichloromethane); DMF (N,Ndimethyl
formamide); DMAP (4-(Dimethylamino)pyridine); eq (equivalent); Ltr or L (Liter);
CDCI 3 (Deuterated chloroform); J (Coupling constant); JAB (Coupling constant); NaH2P0 4
(Sodium dihydrogen phosphate); Na(OAc) 3BH (Sodium triacetoxyborohydride); AcOH
(Acetic acid); NaCNBH (Sodium cyanoborohydride); ABq (AB quartet); Cs2C0 (Cesium
carbonate); Cul (Copper(I) iodide); MTBE (Methyl tert-butyl ether); HBr (Hydrogen
bromide); Ac20 (Acetic anhydride); NaHC0 3 (Sodium bicarbonate); Na2S0 4 (Sodium
sulphate); 1,2-DCE (1,2-dichloroethane); HBTU (0-(Benzotriazol-l-yl)-N,N,N',N'-
tetramethyluroniumhexafluoro phosphate); KOH (Potassium hydroxide); MeOH (methanol);
EDCI (l-Ethyl-3-(3-dimethylaminopropyl)carbodiimide); HOBt (1-Hydroxybenzotriazole);
brs (broad singlet); DPPA (Diphenyl phosphoryl azide) and BINAP (2,2'-
bis(diphenylphosphino)- 1,1'-binaphthyl).
EXPERIMENTAL
The present invention is further illustrated by the following examples, which are not
to be construed in any way as imposing limitations upon the scope of this disclosure, but
rather are intended to be illustrative only. On the contrary, it is to be clearly understood that
resort may be had to various other embodiments, modifications, and equivalents thereof
which, after reading the description herein, may suggest themselves to one of ordinary skill in
the art without departing from the spirit of the present invention. Thus, the skilled artisan will
appreciate how the experiments and examples may be further implemented as disclosed by
variously altering the following examples, substituents, reagents, or conditions.
INTERMEDIATES
Intermediate 1 : Preparation of l - 3aR 5aR 5bR aR 9S l laR.l lbR.13aS)-3a-(2-amino-2-
methylpropanamido)-l-isopropyl-5a,5b,8,8,l la-pentamethyl-2-oxo-3,3aA5,5a,5b,6,7,7a,8,9,
10.11.11a. 1lb. 12.13.13a-octadecahvdro-2H-cvclopentara1chrvsen-9 -vn 3-benzyl (1S.3RV2.2
-dimethylcyclobutane- L3-dicarboxylate:
Step 1: Synthesis of ((!R,3aS,5aR,5bR, 7aR,9S,l laR,l lbR,13aR,13bR)-9-acetoxy-5a,5b,8,8,
1la-pentamethyl-l-(prop-l-en-2-yl)icosahydro-3aH-cyclopentafaJchrysen-3a-yl )methyl
acetate:
A mixture of (lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)-3a-(hydroxymethyl)-
5a,5b,8,8,l la-pentamethyl-l-(prop-l-en-2-yl)icosahydro-lH-cyclopenta[a]chrysen-9-ol (400
g, 0.904 mol, 1.0 eq) and acetic anhydride (3.4 Ltr) were heated at 140 °C for about 3 hours.
TLC indicated starting material was consumed and the desired product was observed. The
reaction mixture was cooled to 0 °C, solid was filtered, washed with water (2 Ltr) and dried
under vacuum to obtain the desired product (400 g, yield: 84%) as an off-white solid. 1H
MR (300 MHz, CDC1 ) : d ppm 4.68 (d, 1H), 4.59 (s, 1H), 4.50-4.43 (m, 1H), 4.25 (d, J =
11.1 Hz, 1H), 3.85 (d, J = 11.1 Hz, 1H), 2.50-2.40 (m, 1H), 2.07 (s, 3H), 2.04 (s, 3H), 2.01-
1.71 (m, 4H), 1.70-1.62 (m, 4H), 1.68 (s, 3H), 1.61-1.43 (m, 4H), 1.43-1.36 (m, 4H), 1.33-
1.18 (m, 3H), 1.18-1.09 (m, 1H), 1.08-0.94 (m, 3H), 1.03 (s, 3H), 0.97 (s, 3H), 0.88-0.75 (m,
10H).
Step 2: Synthesis of ((3aS,5aR,5bR, 7aR,9S,l laR,l lbR,13aS)-9-acetoxy-l-isopropyl-5a,5b,8,
8,1la-pentamethyl-2, 3,4,5,5a, 5b, 6, 7, 7a, 8,9,10, 11,11a, lib, 12, 13, 13a-octadecahydro-3aHcyclopenta[
a]chrysen-3a-yl)methyl acetate:
HBr in acetic acid (800 ml, 33%), was added to a suspension of ((l R,3aS,5aR,5bR,
7aR,9 ,11aR,1IbR,13aR,13bR)-9-acetoxy-5a,5b, 8,8,11a-pentamethyl- 1-(prop- 1-en-2-yl)
icosahydro-3a J-cyclo penta[a]chrysen-3a-yl)m ethyl acetate (step 1, 400 g, 0.76 mol, 1.0 eq)
in toluene (800 ml), Ac20 (800 ml) and acetic acid (800 ml) previously heated at 105 °C. The
reaction mixture was stirred and heated at this temperature for about 1.5 hours. After cooling
down, sodium acetate (480 g) was added and the resulting reaction mixture was evaporated to
dryness. The residue was taken up in CH2C 12 (1200 ml) and the organic phase was washed
with water (2x500 ml), dried over sodium sulphate, filtered and evaporated under reduced
pressure. The residue was recrystallized over 95% ethanol and CH2C 12 to obtain the desired
product (256 g, yield: 64%) as a white solid. 1H NMR (300 MHz, CDC1 ) : d ppm 4.52-4.45
(m, 1H), 4.03 (d, J = 10.8 Hz, 1H), 3.98 (d, J = 10.8 Hz, 1H), 3.19-3.08 (m, 1H), 2.46-2.38
(m, 1H), 2.28-2.22 (m, 2H), 2.05 (s, 3H), 2.04 (s, 3H), 2.01-1.83 (m, 2H), 1.78-1.63 (m, 6H),
1.57-1.44 (m, 3H), 1.43-1.08 (m, 8H), 1.06 (s, 3H), 1.02-0.88 (m, 12H), 0.84 (s, 3H), 0.83 (s,
3H) and 0.78 (m, 1H).
Step 3: Synthesis of ((3aR,5aR,5bR, 7aR,9S, 1laR, 1IbR, 13aS)-9-acetoxy-l-isopropyl-5a,5b,8,
8,1la-pentamethyl-2-oxo-2, 3, 4,5, 5a, 5b, 6, 7, 7a, 8,9,10, 11,11a, lib, 12, 13, 13a-octadecahydro-
3aH-cyclopentafaJ chrysen-3a-yl)methyl acetate:
To a stirred solution of ((3aS,5?LR,5bR,7?LR,9S,l l aR ,l lbR ,13a,S)-9-acetoxy-lisopropyl-
5a,5b,8,8,l la-pentamethyl-2,3,4,5,5a,5b,6,7,7a,8,9,10,l l,l la,l lb,12,13,13a-octa
decahydro-3a J -cyclopenta[a]chrysen-3a-yl)methyl acetate (step 2, 100 g, 0.190 mol, 1.0 eq)
in Toluene (1280 ml) was added sodium acetate (88.96 g, 1.08 mol, 5.7 eq), sodium
dichromate dihydrate (67.9 g, 0.228 mol, 1.2 eq), Ac20 (414 ml) and AcOH (1700 ml) and
heated at 60 °C for about 14 hours. TLC indicated starting material was consumed and the
desired product was observed. After cooling down, the reaction mixture diluted with water
(500 ml) and extracted with ethyl acetate (1000 ml). The organic phase was washed
successively with saturated solution of sodium carbonate (1x500 ml) and brine (2x200 ml)
solution. The organic layer was dried over sodium sulphate, filtered and concentrated under
reduced pressure. The residue was triturated with methanol and the precipitates that formed
were collected by filtration were dried under vacuum to obtain the desired product (81 g,
yield: 79%) as a white solid. 1H NMR (300 MHz, CDC1 ) : d ppm 4.47 (dd, J = 10.2, 6.0 Hz,
1H), 4.31 (d, J = 10.8 Hz, 1H), 4.03 (d, J = 10.8 Hz, 1H), 3.22-3.12 (m, 1H), 2.85 (dd, J =
12.3, 3.3 Hz, 1H), 2.36 (d, J = 18.6 Hz, 1H), 2.03 (s, 3H), 1.97 (s, 3H), 1.93-1.88 (m, 2H),
1.88-1.62 (m, 6H), 1.61-1.28 (m, 8H), 1.27-1.22 (m, 1H), 1.21-1.12 (m, 9H), 1.09-0.97 (m,
1H), 0.91 (s, 3H), 0.90 (s, 3H), 0.83 (s, 3H), 0.82 (s, 3H) and 0.77-0.75 (m, 1H); ESI-MS:
m/z 563.4 (M+Na) +
Step 4: Synthesis of (3aR,5aR,5bR, 7aR,9S, 1laR, 1IbR, 13aS)-3a-(hydroxymethyl)-l-isopropyl
-5a,5b, 8,8,1la-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6, 7, 7a,8,9, 10,11,1 la,l lb, 12,13, 13a-octa
decahydro-2H-cyclopentafaJchrysen-9-yl acetate:
To a stirred solution of ((3aR,5aR,5bR,7aR,9S,l l aR,l lbR,13a,S)-9-acetoxy-lisopropyl-
5a,5b,8,8,l la-pentamethyl-2-oxo-2,3,4,5,5a,5b,6,7,7a,8,9,10,l l,l la,l lb,12,13,13a
-octadecahydro-3a J-cyclopenta[a]chrysen-3a-yl)methyl acetate (step 3, 70 g, 0.129 mol, 1.0
eq) in ethanol (2 L) : toluene (2 L) was added potassium hydroxide (8.72 g, 0.155 mol, 1.2
eq) and stirred at room temperature for about 2 hours. TLC indicated starting material was
consumed and the desired product was observed. The reaction mixture was neutralized with
aqueous IN HCl to pH adjusted to 7.0 and evaporated to dryness. The obtained residue was
taken up in water (200 ml) and a small amount of acetone (20 ml). The precipitates formed
were collected by filtration, washed with water and dried in vacuo to obtain the desired
product (51 g, yield: 79%) as a white solid. 1H NMR (300 MHz, CDC1 ) : d ppm 4.49 (dd, J =
10.5, 6.0 Hz, 1H), 3.73 (d, J = 10.5 Hz, 1H), 3.67 (d, J = 10.5 Hz, 1H), 3.25-3.14 (m, 1H),
2.78 (dd, J = 12.3, 3.0 Hz, 1H), 2.43 (d, J = 18.6 Hz, 1H), 2.05 (s, 3H), 2.02-1.65 (m, 8H),
1.60-1.25 (m, 8H), 1.24-1.17 (m, 7H), 1.13 (s, 3H), 1.12-0.97 (m, 1H), 0.94 (s, 3H), 0.92 (s,
3H), 0.86 (s, 3H), 0.85 (s, 3H), 0.80 (m, 1H); ESI-MS: m/z 521.3 (M+Na) +.
Step 5: Synthesis of (3aR,5aR,5bR, 7aR,9S,l laR,l lbR,13aS)-3a-formyl-l-isopropyl-5a,5b,8,
8,1la-pentamethyl-2-oxo-3, 3a, 4,5, 5a, 5b, 6, 7, 7a, 8,9,10, 11,11a, lib, 12, 13, 13a-octadecahydro-
2H-cyclopenta[a] chrysen-9-yl acetate:
To a solution of (3aR,5aR,5bR,7aR,9^,l l aR,l lbR,13a5)-3a-(hydroxymethyl)-lisopropyl-
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-2 H-cyclopenta[a]chrysen-9-ylacetate (step 4, 52.0 g, 0.104 mol, 1.0 eq)
in CH2CI2 (2 L) at room temperature was added pyridiniumchlorochromate (67.5 g, 0.313
mol, 3.0 eq) and silicagel (100-200 mesh) (67.5 g). The 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 CH2CI2. 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. 1H NMR (300 MHz, CDC1 ) :
d ppm 9.31 (s, 1H), 4.52-4.44 (m, 1H), 3.32-3.18 (m, 1H), 2.60-2.50 (m, 1H), 2.43-2.33 (m,
2H), 2.12-2.0 (m, 2H), 2.05 (s, 3H), 2.0-1.80 (m, 2H), 1.80-1.65 (m, 3H), 1.53-1.18 (m, 15H),
1.12-1.0 (m, 2H), 1.03 (s, 3H), 0.98-0.75 (m, 12H).
Step 6: Synthesis of (3aR,5aR,5bR, 7aR,9S,l laR,l lbR,13aS)-9-acetoxy-l-isopropyl-5a,5b,8,
8,1la-pentamethyl-2-oxo-2, 3, 4,5, 5a, 5b, 6, 7, 7a, 8,9,10, 11,11a, lib, 12, 13, 13a-octadecahydro-
3aH-cyclopenta[a]chrysene-3a-carboxylic acid:
To an ice-cooled solution of (3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-3a-formyl-lisopropyl-
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-cyclopenta[a]chrysen-9-yl acetate (step 5, 33.0 g, 66.465 mmol, 1.0
eq) in t-butanol (330 ml), THF (500 ml) and 2-methyl 2-butene (60 ml) was added slowly a
solution of NaC10 2 (71.86 g, 797.58 mmol, 12.0 eq) in 385 ml of water followed by
NaH2P0 4 (79.75 g, 664.65 mmol, 10.0 eq) in 390 ml of water (390 ml) over 15 minutes.
After stirring at 0 °C for about 10 minutes, the reaction mixture was warmed to room
temperature and stirred for about 1 hour. TLC indicated starting material was consumed and
the desired product was observed. The reaction mixture was diluted with water (100 ml) and
extracted with ethyl acetate (3x500 ml). The combined organic extracts were dried over
sodium sulfate, filtered and evaporated under reduced pressure. The residue was triturated
with n-hexane, solid formed was collected by filtration and dried under vacuum to obtain the
desired product (33.1 g, yield: 97.3%) as a white solid. 1H NMR (300 MHz, CDC1 ) : d ppm
4.49 (dd, J = 10.2, 5.7 Hz, 1H), 3.27-3.18 (m, 1H), 2.78-2.71 (m, 1H), 2.58 (d, J = 18.9 Hz,
1H), 2.50-2.43 (m, 1H), 2.19 (d, J = 18.6 Hz, 1H), 2.05 (s, 3H), 2.02-1.82 (m, 3H), 1.81-1.51
(m, 5H), 1.51-1.25 (m, 6H), 1.22 (d, J = 1.5 Hz, 3H), 1.20 (d, J = 1.5 Hz, 3H), 1.17-1.09 (m,
1H), 1.05 (s, 3H), 1.03-0.98 (m, 1H), 0.94 (s, 3H), 0.91 (s, 3H), 0.85 (s, 3H), 0.84 (s, 3H),
0.80 (m, 1H); ESI-MS: m/z 535.42 (M+Na) +.
Step 7: Synthesis of (3aR,5aR,5bR, 7aR,9S,l laR,l lbR,13aS)-l-isopropyl-3a-((((4-methoxy
benzyl)oxy)carbonyl)amino)-5a, 5b, 8,8,1la-pentamethyl-2-oxo-3, 3a, 4,5,5a, 5b, 6, 7, 7a, 8,9,10,
11, 11a, lib, 12, 13, 13a-octadecahydro-2H-cyclopenta[a] chrysen-9-yl acetate:
To a stirred solution of (3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-9-acetoxy-lisopropyl-
5a,5b,8,8,l la-pentamethyl-2-oxo-2,3,4,5,5a,5b,6,7,7a,8,9,10,l l,l la,l lb,12,13,13a
-octadecahydro-3aH-cyclopenta[a]chrysene-3a-carboxylic acid (step 6, 33.0 g, 64.45 mmol,
1.0 eq) in 1,2-dichloroethane (500 ml) was added triethyl amine (22.43 ml, 161.13 mmol, 2.5
eq), followed by diphenylphosphonic azide (18.0 ml, 83.78 mmol, 1.3 eq). After 15 minutes
stirring at room temperature, the solution was heated to reflux for about 100 minutes. After
which it was converted completely to the isocyanate by TLC, p-methoxybenzyl alcohol (9.9
ml, 83.78 mmol, 1.3 eq) was added and reflux was continued for about 4 hours. TLC
indicated starting material was consumed and the desired product was observed. The reaction
mixture was evaporated under reduced pressure and the residue was purified by silicagel
column chromatography by using 0-3% methanol in dichloromethane gradient. The fractions
containing the product were combined and concentrated under reduced pressure to give the
desired product (38.0 g, yield: 91.1%) as a white solid. 1H MR (300 MHz, CDC1 ) : d ppm
7.30 (d, J = 8.7 Hz, 2H), 6.87 (d, J = 8.7 Hz, 2H), 4.98 (s, 2H), 4.83 (s, 1H), 4.48 (dd, J =
10.5, 6.0 Hz, 1H), 3.80 (s, 3H), 3.22-3.0 (m, 1H), 2.82-2.58 (m, 2H), 2.55-2.20 (m, 2H), 2.05
(s, 3H), 1.98-1.60 (m, 7H), 1.58-1.30 (m, 7H), 1.28-1.12 (m, 8H), 1.07 (s, 3H), 0.92 (m, 6H),
0.85-0.78 (m, 7H); ESI-MS: m/z 670.51 (M+Na) +.
Step 8: Synthesis of (3aR,5aR,5bR, 7aR,9S,l laR,l lbR,13aS)-3a-amino-l-isopropyl-5a,5b,8,8,
1la-pentamethyl-2-oxo-3, 3a, 4,5,5a, 5b, 6, 7, 7a, 8,9, 10,11, 11a, lib, 12,13, 13a-octadecahydro-
2H-cyclopentaf Jchrysen-9-yl acetate :
To a stirred solution of (3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-l-isopropyl-3a-((((4-
methoxybenzyl)oxy)carbonyl)amino)-5a,5b,8,8,l la-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,
8,9,10,1 1,1 la,l lb, 12,13, 13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl acetate (step 7,
38.0 g, 58.73 mmol, 1.0 eq) in DCM (320 ml) at 0 °C was added TFA (80 ml). The 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
evaporated under reduced pressure, water (100 ml) was added, cooled to 0 °C, pH adjusted to
8.0 with saturated NaHC0 solution and extracted with DCM (3x600 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 a 0-3%
methanol in dichloromethane gradient. The fractions containing the product were combined
and concentrated under reduced pressure to obtain the desired product (26.0 g, yield: 91.87%)
as a white solid. H MR (300 MHz, CDC1 ) : d ppm 4.48 (m, 1H), 3.20-3.05 (m, 1H), 2.33
(d, J = 18.6 Hz, 1H), 2.23 (d, J = 18.6 Hz, 1H), 2.05 (s, 3H), 1.98-1.72 (m, 4H), 1.72-1.50 (m,
7H), 1.46-1.26 (m, 5H), 1.26-1.0 (m, 11H), 0.93 (s, 3H), 0.91 (s, 3H), 0.86 (s, 3H), 0.85 (s,
3H), 0.80 (m, 1H).
Step 9: Synthesis of 2-((tert-butoxycarbonyl)amino)-2-methylpropanoic acid:
Method 1 : To a stirred solution of 2-Amino-2-methylpropanoic acid (30 g, 290.92 mmol, 1.0
eq) in 1,4-dioxane (300 ml) at 0 °C was added 2N NaOH solution (300 ml) followed by
(Boc)20 (95.13 g, 436.38 mmol, 1.5 eq). The reaction mixture was allowed to stir 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), cooled to 0 °C, pH adjusted to 5 with IN
HC1 and then extracted with DCM (3x300 ml). The combined organic extracts were washed
with water (300 ml), brine (100 ml) solution, dried over Na2S0 4, filtered and evaporated
under reduced pressure. The residue was stirred with n-hexane (300 ml) at room temperature
for about 30 minutes. The obtained solid was filtered and dried under vacuum to obtain the
desired product (38.0 g, yield: 64.4%) as a white solid.
Method 2 : To a stirred solution of 2-carboxypropan-2-aminium chloride (15.0 g, 145.63
mmol) in 1,4-dioxane (75 mL), added 2N NaOH solution (75 mL), (Boc)20 (47.62 g, 218.44
mmol) at 0 °C and stirred the reaction mixture for about 12 hours at room temperature. TLC
indicated starting material was consumed and the desired product was observed. The reaction
mixture was washed with EtOAc (200 mL) to remove the impurities, then aqueous part was
acidified with IN HC1 (pH-2-3) and extracted with CH2C 12 (2x200 mL). The combined
organic extracts were washed with water, dried over Na2S0 4, filtered and evaporated under
reduced pressure. The crude residue was purified by silicagel column chromatography by
using 30% EtOAc: n-Hexane as an eluent to afford the desired product (15.0 g, yield:
50.74%) as an off white solid. 1H NMR (300 MHz, DMSO): d 12.18 (s, 1H), 7.05 (s, 1H),
1.36 (s, 9H), 1.29 (s, 6H); ES Mass: 226.06 [M+Na]+.

We Claim:
1. A compound of the formula (1):
Formula
wherein,
(wherein Ra is selected from hydrogen, substituted or unsubstituted Ci-C6 alkyl,
or substituted or unsubstituted C -C cycloalkyl);
R2 is selected from hydrogen, substituted or unsubstituted Ci-C alkyl;
R and R 4 are independently selected from substituted or unsubstituted Ci-C6 alkyl,
substituted or unsubstituted amine, substituted or unsubstituted C -C8 cycloalkyl and R and
R4 are taken together with the carbon atom to which they are attached to form substituted or R2, R5, R5, R and 'n' are same as defined in claim 1;
X is selected from -0-, -CH20-, -CH2N-, -or (-CH2-)m
'm' is an integer selected from 1, 2, 3 or 4 .
5 . A compound selected from the group consisting of:(lS,3R)-3-((((3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-3a-(l-(4-chlorobenzamido)
cyclopropane-l-carboxamido)-l-isopropyl-5a,5b,8,8,l la-pentamethyl-2-oxo-3,3a,4,5,5a,5b,
6,7,7a,8,9,10,1 1,1 la,l lb, 12,13, 13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)
carbonyl)-2,2-dimethylcyclobutane-l-carboxylic acid, or pharmaceutically acceptable salts,
solvates, including hydrates and prodrugs of compounds are also contemplated.
7 . A pharmaceutical composition comprising a compound according to any one of
claims 1-6 and at least one pharmaceutically acceptable excipient.
8 . The pharmaceutical composition according to claim 7, wherein the
pharmaceutically acceptable excipient is a carrier or diluent.
9 . A method for preventing, ameliorating or treating a viral mediated disease, disorder
or syndrome in a subject in need thereof comprising administering to the subject a
therapeutically effective amount o f a compound according to any one of claims 1-6.
10. The method according to claim 9, wherein the viral mediated disease, disorder or
syndrome is HIV infection, HBV infection , HCV infection , a retroviral infection genetically
related to AIDS, respiratory disorders (including adult respiratory distress syndrome
(ARDS)), inflammatory disease, or a combination thereof.
11. A method of treating HIV in a subject in need thereof comprising administering to
the subject a therapeutically effective amount o f a compound according to any one of claims
1- 6 .
12. A method for preventing, ameliorating or treating a viral mediated disease,
disorder or syndrome in a subject in need thereof comprising administering to the subject the
pharmaceutical composition according to claim 11 comprising a therapeutically effective
amount of the compound.
13. The method according to claim 12, wherein the viral mediated disease, disorder or
syndrome is HIV infection, HBV infection, HCV infection, a retroviral infection genetically
related to AIDS, respiratory disorders (including adult respiratory distress syndrome
(ARDS)), inflammatory disease, or a combination thereof.