OA18389A - C-3 novel triterpenone with C-28 reverse amide derivatives as HIV inhibitors. - Google Patents
C-3 novel triterpenone with C-28 reverse amide derivatives as HIV inhibitors. Download PDFInfo
- Publication number
- OA18389A OA18389A OA1201700317 OA18389A OA 18389 A OA18389 A OA 18389A OA 1201700317 OA1201700317 OA 1201700317 OA 18389 A OA18389 A OA 18389A
- Authority
- OA
- OAPI
- Prior art keywords
- octadecahydro
- oxo
- isopropyl
- chrysen
- cyclopenta
- Prior art date
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- 150000001408 amides Chemical class 0.000 title claims abstract description 6
- 241000580858 Simian-Human immunodeficiency virus Species 0.000 title claims abstract 6
- 230000002401 inhibitory effect Effects 0.000 title description 10
- 239000003112 inhibitor Substances 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 314
- 201000010099 disease Diseases 0.000 claims abstract description 54
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 22
- 230000001404 mediated Effects 0.000 claims abstract description 18
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- 230000001225 therapeutic Effects 0.000 claims abstract description 6
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 claims description 186
- 241000282619 Hylobates lar Species 0.000 claims description 125
- -1 chrysen-9-yl Chemical group 0.000 claims description 110
- 239000002253 acid Substances 0.000 claims description 80
- 239000011734 sodium Substances 0.000 claims description 76
- 239000000203 mixture Substances 0.000 claims description 53
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 37
- 125000000217 alkyl group Chemical group 0.000 claims description 22
- 125000004432 carbon atoms Chemical group C* 0.000 claims description 20
- 239000000969 carrier Substances 0.000 claims description 16
- 239000000651 prodrug Substances 0.000 claims description 16
- 229940002612 prodrugs Drugs 0.000 claims description 16
- 239000011780 sodium chloride Substances 0.000 claims description 16
- WZUBYJLFSCGSNR-UHFFFAOYSA-N 2,2-dimethylcyclobutane-1-carboxylic acid Chemical compound CC1(C)CCC1C(O)=O WZUBYJLFSCGSNR-UHFFFAOYSA-N 0.000 claims description 15
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- 125000001424 substituent group Chemical group 0.000 claims description 14
- 201000009910 diseases by infectious agent Diseases 0.000 claims description 12
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- 125000004435 hydrogen atoms Chemical class [H]* 0.000 claims description 11
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 10
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 10
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- 125000001072 heteroaryl group Chemical group 0.000 claims description 10
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 9
- 125000000623 heterocyclic group Chemical group 0.000 claims description 9
- 230000003612 virological Effects 0.000 claims description 9
- 239000003085 diluting agent Substances 0.000 claims description 8
- 150000004677 hydrates Chemical class 0.000 claims description 8
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 8
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- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 6
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- 125000003277 amino group Chemical group 0.000 claims description 4
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- 200000000018 inflammatory disease Diseases 0.000 claims description 3
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- 238000002474 experimental method Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- YCKRFDGAMUMZLT-UHFFFAOYSA-N fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 1
- 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 238000005755 formation reaction Methods 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 229940075507 glyceryl monostearate Drugs 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 125000006343 heptafluoro propyl group Chemical group 0.000 description 1
- 230000003301 hydrolyzing Effects 0.000 description 1
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 description 1
- 230000002757 inflammatory Effects 0.000 description 1
- 239000002054 inoculum Substances 0.000 description 1
- 229940079866 intestinal antibiotics Drugs 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007915 intraurethral administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N iodine atom Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 125000001261 isocyanato group Chemical group *N=C=O 0.000 description 1
- 125000005956 isoquinolyl group Chemical group 0.000 description 1
- 239000011344 liquid material Substances 0.000 description 1
- 239000006193 liquid solution Substances 0.000 description 1
- 239000006194 liquid suspension Substances 0.000 description 1
- 238000011068 load Methods 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000035800 maturation Effects 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- PJROXVOPRSDRGX-UHFFFAOYSA-N methyl 4-(4-methylimidazol-1-yl)benzoate Chemical compound C1=CC(C(=O)OC)=CC=C1N1C=C(C)N=C1 PJROXVOPRSDRGX-UHFFFAOYSA-N 0.000 description 1
- NLWBJPPMPLPZIE-UHFFFAOYSA-N methyl 4-(bromomethyl)benzoate Chemical compound COC(=O)C1=CC=C(CBr)C=C1 NLWBJPPMPLPZIE-UHFFFAOYSA-N 0.000 description 1
- QDHHCQZDFGDHMP-UHFFFAOYSA-N monochloramine Chemical compound ClN QDHHCQZDFGDHMP-UHFFFAOYSA-N 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 201000006417 multiple sclerosis Diseases 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N o-xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 125000005060 octahydroindolyl group Chemical group N1(CCC2CCCCC12)* 0.000 description 1
- 125000005061 octahydroisoindolyl group Chemical group C1(NCC2CCCCC12)* 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 239000002997 ophthalmic solution Substances 0.000 description 1
- 229940005935 ophthalmologic Antibiotics Drugs 0.000 description 1
- 230000003287 optical Effects 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 230000003204 osmotic Effects 0.000 description 1
- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- 125000000160 oxazolidinyl group Chemical group 0.000 description 1
- 125000005968 oxazolinyl group Chemical group 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 125000005476 oxopyrrolidinyl group Chemical group 0.000 description 1
- MYMOFIZGZYHOMD-UHFFFAOYSA-N oxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 239000001814 pectin Substances 0.000 description 1
- 229920001277 pectin Polymers 0.000 description 1
- 235000010987 pectin Nutrition 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 125000006340 pentafluoro ethyl group Chemical group FC(F)(F)C(F)(F)* 0.000 description 1
- 201000003450 persistent generalized lymphadenopathy Diseases 0.000 description 1
- 230000000275 pharmacokinetic Effects 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- NQRYJNQNLNOLGT-UHFFFAOYSA-N piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 1
- 230000036470 plasma concentration Effects 0.000 description 1
- 125000006684 polyhaloalkyl group Polymers 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002685 pulmonary Effects 0.000 description 1
- KYQCOXFCLRTKLS-UHFFFAOYSA-N pyrazine Chemical group C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- HBDYSKVKXMUPKV-UHFFFAOYSA-N pyridine;trioxochromium;hydrochloride Chemical compound [H+].[Cl-].O=[Cr](=O)=O.C1=CC=NC=C1 HBDYSKVKXMUPKV-UHFFFAOYSA-N 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000000171 quenching Effects 0.000 description 1
- LOAUVZALPPNFOQ-UHFFFAOYSA-N quinaldic acid Chemical compound C1=CC=CC2=NC(C(=O)O)=CC=C21 LOAUVZALPPNFOQ-UHFFFAOYSA-N 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- VBICKXHEKHSIBG-UHFFFAOYSA-N rac-1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 1
- 239000002516 radical scavenger Substances 0.000 description 1
- 239000003638 reducing agent Substances 0.000 description 1
- 238000006268 reductive amination reaction Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000000241 respiratory Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 230000004043 responsiveness Effects 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 239000012056 semi-solid material Substances 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- YOQDYZUWIQVZSF-UHFFFAOYSA-N sodium borohydride Substances [BH4-].[Na+] YOQDYZUWIQVZSF-UHFFFAOYSA-N 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000001187 sodium carbonate Substances 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000010262 sodium metabisulphite Nutrition 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- IXCOLRNWVTZDBE-UHFFFAOYSA-M sodium;2-(dimethylamino)-1-hydroxyethanesulfonate Chemical compound [Na+].CN(C)CC(O)S([O-])(=O)=O IXCOLRNWVTZDBE-UHFFFAOYSA-M 0.000 description 1
- ODGROJYWQXFQOZ-UHFFFAOYSA-N sodium;boron(1-) Chemical compound [B-].[Na+] ODGROJYWQXFQOZ-UHFFFAOYSA-N 0.000 description 1
- 239000011343 solid material Substances 0.000 description 1
- 238000004611 spectroscopical analysis Methods 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 230000000707 stereoselective Effects 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 125000005017 substituted alkenyl group Chemical group 0.000 description 1
- 125000000547 substituted alkyl group Chemical group 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 125000000446 sulfanediyl group Chemical group *S* 0.000 description 1
- 125000004434 sulfur atoms Chemical group 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 230000002459 sustained Effects 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- LCTNGUBCJIEBSU-UHFFFAOYSA-N tert-butyl 2-(1,1-dioxo-1,4-thiazinan-4-yl)acetate Chemical compound CC(C)(C)OC(=O)CN1CCS(=O)(=O)CC1 LCTNGUBCJIEBSU-UHFFFAOYSA-N 0.000 description 1
- UXBSQSRIOSLILI-UHFFFAOYSA-N tert-butyl 2-piperidin-1-ylacetate Chemical compound CC(C)(C)OC(=O)CN1CCCCC1 UXBSQSRIOSLILI-UHFFFAOYSA-N 0.000 description 1
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000002769 thiazolinyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 231100000583 toxicological profile Toxicity 0.000 description 1
- 230000032258 transport Effects 0.000 description 1
- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 description 1
- 201000008827 tuberculosis Diseases 0.000 description 1
- 201000006704 ulcerative colitis Diseases 0.000 description 1
- 239000004474 valine Substances 0.000 description 1
- 230000004580 weight loss Effects 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
- FUOOLUPWFVMBKG-UHFFFAOYSA-N α-aminoisobutanoic acid Chemical compound CC(C)(N)C(O)=O FUOOLUPWFVMBKG-UHFFFAOYSA-N 0.000 description 1
Abstract
The invention relates to C-3 novel triterpenone with C-17 reverse amide derivatives, related compounds, and pharmaceutical compositions useful for the therapeutic treatment of viral diseases and particularly HIV mediated diseases.
Description
The présent invention relates to C-3 novel triterpenone with C-17 reverse amide dérivatives and related compounds, compositions useful for therapeutic treatment of viral diseases and particularly HTV mediated diseases.
BACKGROUND OF THE INVENTION
The Human Immunodeficiency Virus (HIV) has now been established as the causative agent of the Acquired Immunodeficiency Syndrome (AIDS) for over 20 years (Science 1983, 220,868-871; N.Eng.J.Med.1984, 311, 1292-1297). AIDS is characterized by the destruction ofthe 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 15 membrane and finishing with the release of progeny virons from the cell.
The naturel 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-HTV agents by making semi-synthetic analogs of betulinic acid, leading to the discovery of bevirimat as a 20 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. Viral. 2004,78(2): 922-9; J. Biol. Chem. 2005,280(51):42149-55; J. Virol. 2006,80(12): 5716-22) and to be a first-in-class maturation inhibitor with a potent 25 activity against HIV-1. Bevirimat went up to phase 2 clinical trials, in clinic despite optimal plasma concentrations, not ail patients given bevirimat hâve a robust viral load réduction. It was reported that non-respondant patients had more frequent base line Gag polymorphisme near the capsid SP-1 cleavage site than responders. (HIV gag polymorphism détermines treatment response to bevirimat. XVII international HIV drug résistance work shop June 1030 14, 2008, Sitges, Spain).
Encouraged by these developments, médicinal chemists started exploring betulinic acid dérivatives and related compounds intensively for their therapeutic activities. For example, WO 2014/093941 describes pharmaceutical compositions of betulin dérivatives; WO 2009/082819 describes préparation of 17-amino lupane dérivatives as anti-HIV agents; WO
2013/117137 descnbes lupane tnterpenoids denvatives and pharmaceutical use thereof; WO 2013/020245 descnbes carbonyl denvatives of betulin; WO 2009/082818 descnbes préparation of C21-keto lupane denvatives for the treatment of HIV infections; WO 2011/100308 describes préparation of betulin dérivatives for treatment of HIV-1; WO 2013/090664 describes préparation of betulin denvatives for the treatment of HIV; WO 2013/091144 describes préparation ofpropenoate denvatives of betulin useful for the treatment of HIV; WO 2013/090683 describes préparation of betulin propenoate denvatives for the treatment of HIV.
Given the fact of the world wide épidémie 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 présent invention relates to the compounds of the formula (1)
wherein,
Ri can be substituted
or unsubstituted Ci-Cô alkyl,
V or HOOCT^
HOOC
substituted or unsubstituted Ci-Cô alkyl, or substituted or unsubstituted C3-C8 cycloalkyl);
R2 can be hydrogen, substituted or unsubstituted Ci-Cô alkyl, substituted or unsubstituted C2-C6 alkoxylalkoxy or substituted or unsubstituted Ci-Cô amino alkyl;
(wherein Ra can be hydrogen,
R3 and R4 can be independently selected from substituted or unsubstituted Ci-Cô alkyl, substituted or unsubstituted amine, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl or R3 and R4 can be taken together with the carbon atom to which they are attached to form substituted or unsubstituted C3-C8 cycloalkyl, epoxide, oxetane or azetidine;
R5 and Rô can be independently selected from hydrogen, substituted or unsubstituted Ci-Cô alkyl and R5 and Rôcan be taken together with the carbon atom to which they are attached to form substituted or unsubstituted C3-C8 cycloalkyl or R5 and Rô can be together represent oxo;
R7 can be hydrogen, substituted or unsubstituted Ci-Cô alkyl, substituted or unsubstituted Ci-Cô alkoxy, substituted or unsubstituted amino, substituted or unsubstituted CiCô amino alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted CôC12 aryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaryl, or S(O)2Rb; wherein the substituents can be independently selected from one or more Rm;
Rm can be halo, Ci-Cô alkyl, haloalkyl, amino, -C(O)ORc, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted heteroaryl or -S(O)2Rb;
Rb and Rc can be independently selected from substituted or unsubstituted Ci-Cô alkyl or substituted or unsubstituted Cô-Ci2 aryl;
‘n’ can be an integer selected from 0, lor 2;
pharmaceutically acceptable salts, pharmaceutically acceptable solvatés, pharmaceutically acceptable hydrates, tautomers, stereoisomers, ester prodrugs, or combination thereof.
It should be understood that the formula (1) structurally encompasses ail 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 ail tautomers.
Also contemplated are prodrugs of the compounds of the formula (1), including ester prodrugs.
According to one embodiment, there is provided a compound of formula (1), wherein
Ri is
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 R3 and R4 are methyl.
According to yet another embodiment there is provided a compound of formula (1), wherein R3 and R4 together with the carbon atom to which they are attached to form substituted or unsubstituted C3-6 cycloalkyl.
According to yet another embodiment there is provided a compound of formula (1), wherein the above said C3-6 cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.
According to yet another embodiment there is provided a compound of formula (1), wherein R5 and Rô are hydrogen.
According to yet another embodiment there is provided a compound of formula (1), wherein R5 and Rô are methyl.
According to yet another embodiment there is provided a compound of formula (1), wherein R5 and Rô together with the carbon atom to which they are attached form C3-6 cycloalkyl.
According to yet another embodiment there is provided a compound of formula (1), wherein the above said C3-6 cycloalkyl is cyclopropyl and cyclopentyl.
According to yet another embodiment there is provided a compound of formula (1), wherein Rs and Rô together represent oxo.
According to yet another embodiment, there is provided a compound of formula (1), wherein R7 is substituted phenyl; wherein the substituents are chlore, methyl, fluoro, trifluoromethyl, morpholine, methylsulfonyl, 4-Methyl-lH-imidazole, oxazole, 1,3,4Oxadiazole, 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 chlore.
According to yet another embodiment there is provided a compound of formula (1), wherein R7 is pyrrolidine.
According to yet another embodiment, there is provided a compound of formula (1), wherein R7 is pyrrolidine which is substituted with -C(O)ORc; wherein Rc is tertiary butyl.
According to yet another embodiment there is provided a compound of formula (1), wherein R7 is pyrazîne.
According to yet another embodiment there is provided a compound of formula (1), wherein R7 is pyrazîne which is substituted with methyl.
According to yet another embodiment there is provided a compound of formula (1), wherein R7 is fùran which is substituted with methyl.
According to yet another embodiment there is provided a compound of formula (1), wherein R7 is piperazine which is substituted with ethyl.
According to yet another embodiment there is provided a compound of formula (1), wherein R7 is quinoline.
According to yet another embodiment there is provided a compound of formula (1), wherein R7 is piperidine.
According to yet another embodiment, there is provided a compound of formula (1), wherein R7 is thiomorpholine 1,1-dioxide.
According to yet another embodiment there is provided a compound of formula (1), wherein R7 is lH-benzo[d]imidazole.
According to yet another embodiment, there is provided a compound of formula (1), wherein R7 is lH-benzo[d]imidazole which is substituted with methyl pyridine.
According to yet another embodiment there is provided a compound of formula (1), wherein R7 is lH-benzo[d]imidazole which is substituted with pyrazine.
According to yet another embodiment there is provided a compound of formula (1), wherein R7 is thiazole which is substituted with methyl or amino.
According to yet another embodiment there is provided a compound of formula (1), wherein R7 is imidazole which is substituted with methyl.
According to yet another embodiment there is provided a compound of formula (1), wherein R7 is pyrazole which is substituted with isopropyl.
According to yet another embodiment there is provided a compound of formula (1), wherein R7 is isoxazole which is substituted with methyl.
According to yet another embodiment, there is provided a compound of formula (1), wherein R7 is 1,3,4-Oxadiazole which is substituted with methyl.
According to yet another embodiment there is provided a compound of formula (1), wherein R7 is pyrimidine.
According to yet another embodiment, there is provided a compound of formula (1), wherein R7 is pyrazolo[l,5-a]pyrimidine.
According to yet another embodiment, there is provided a compound of formula (1), wherein R7 is -S(O)2Rb; wherein Rb is methyl or 4-chloro phenyl.
According to yet another embodiment, there is provided a compound of formula (1), wherein R7 is Ν,Ν-dimethyl amino.
According to yet another embodiment there is provided a compound of formula (1), wherein R7 is tertiary butyl.
According to yet another embodiment there is provided a compound of formula (1), wherein R7 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 présent invention provides compounds of formula (IA):
wherein,
R2, R5, R«, R7 and ‘n’ are same as defined in formula 1;
pharmaceutically acceptable salts, pharmaceutically acceptable solvatés, pharmaceutically acceptable hydrates, tautomers, stereoisomers, ester prodrugs, or combination thereof.
It should be understood that the formula (IA) structurally encompasses ail 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 (IA) structurally encompasses ail tautomers.
Also contemplated are prodrugs of the compounds of the formula (1 A), including ester prodrugs.
According to one embodiment, there is provided a compound of formula (IA), wherein R2 is hydrogen.
According to one embodiment, there is provided a compound of formula (1 A), wherein Ré and Ré are hydrogen.
According to one embodiment, there is provided a compound of formula (IA), wherein
Ré and Ré are methyl.
According to one embodiment, there is provided a compound of formula ( 1 A), wherein
R5 and Ré together represent oxo.
According to one embodiment, there is provided a compound of formula (1 A), wherein Ré and Ré together with the carbon atom to which they are attached to form C3-6 cycloalkyl.
According to one embodiment, there is provided a compound of formula (IA), wherein 10 the above said C3-6 cycloalkyl is cyclopropyl, cyclopentyl or cyclohexyl.
According to yet another embodiment, there is provided a compound of formula (1 A), wherein R7 is substituted phenyl; wherein the substituents are chloro, methyl, fluoro, trifluoromethyl, morpholine, methylsulfonyl, 4-Methyl-lH-imidazole, oxazole, 1,3,4Oxadiazole, thiomorpholine 1,1-dioxide or 4-methylthiomorpholine 1,1-dioxide.
According to yet another embodiment there is provided a compound of formula (IA), 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 (IA), wherein R7 is pyrrolidine.
According to yet another embodiment, there is provided a compound of formula (1 A), wherein R7 is pyrrolidine which is substituted with -C(O)ORc; wherein Rc is tertiary butyl.
According to yet another embodiment there is provided a compound of formula (IA), wherein R7 is pyrazine.
According to yet another embodiment there is provided a compound of formula (IA), 25 wherein R7 is pyrazine which is substituted with methyl.
According to yet another embodiment there is provided a compound of formula (IA), wherein R7 is fûran which is substituted with methyl.
According to yet another embodiment there is provided a compound of formula (IA), wherein R7 is piperazine which is substituted with ethyl.
According to yet another embodiment there is provided a compound of formula (1 A), wherein R7 is quinoline.
According to yet another embodiment there is provided a compound of formula (IA), wherein R7 is piperidine.
According to yet another embodiment, there is provided a compound of formula (1 A), wherein R7 is thiomorpholine 1,1-dioxide.
According to yet another embodiment there is provided a compound of formula (IA), wherein R7 is lH-benzo[d]imidazole.
According to yet another embodiment there is provided a compound of formula (IA), wherein R7 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 (IA), wherein R7 is thiazole which is substituted with methyl or amino.
According to yet another embodiment there is provided a compound of formula (IA), wherein R7 is imidazole which is substituted with methyl.
According to yet another embodiment there is provided a compound of formula (IA), wherein R7 is pyrazole which is substituted with isopropyl.
According to yet another embodiment there is provided a compound of formula (IA), wherein R7 is isoxazole which is substituted with methyl.
According to yet another embodiment, there is provided a compound of formula (1 A), wherein R7 is 1,3,4-oxadiazole which is substituted with methyl.
According to yet another embodiment there is provided a compound of formula (IA), wherein R7 is pyrimidine.
According to yet another embodiment, there is provided a compound of formula (1 A), wherein R7 is pyrazolo[l,5-a]pyrimidine.
According to yet another embodiment, there is provided a compound of formula (1 A), wherein R7 is -S(O)2Rbî wherein Rb is methyl or 4-chloro phenyl.
According to yet another embodiment, there is provided a compound of formula (IA), wherein R7 is Ν,Ν-dimethyl amino.
According to yet another embodiment, there is provided a compound of formula (1 A), wherein R7 is tertiary butyl.
According to yet another embodiment, there is provided a compound of formula (1 A), wherein R7 is tertiary butoxy.
According to yet another embodiment, there is provided a compound of formula (1 A), wherein R7 is cyclohexyl.
According to yet another embodiment, there is provided a compound of formula (IA), wherein ‘n’ is 0.
According to yet another embodiment, there is provided a compound of formula (1 A), wherein ‘n’ is 1.
According to yet another embodiment, there is provided a compound of formula (1 A), wherein ‘n’ is 2.
Accordingly, one other aspect of the présent invention provides compounds of formula (IB):
wherein,
R2, Rs, Rô, R? and ‘n’ are same as defined in formula 1;
X can be selected from -O-, -CH2O-, -CH2N-, or (-CH2-)m;
‘m’ can be an integer selected from 1,2,3 or 4;
pharmaceutically acceptable salts, pharmaceutically acceptable solvatés, pharmaceutically acceptable hydrates, tautomers, stereoisomers, ester prodrugs, or combination thereof.
It should be understood that the formula (IB) structurally encompasses ail stereoisomers, including enantiomers, diastereomers, racemates, and combinations thereof which may be contemplated from the chemical structure ofthe genus described herein.
It should be understood that the formula (IB) structurally encompasses ail tautomers.
Also contemplated are prodrugs ofthe compounds ofthe formula (IB), including ester prodrugs.
According to one embodiment, there is provided a compound of formula (IB), wherein R2 is hydrogen.
According to one embodimenL there is provided a compound of formula (IB), wherein X1S-CH2-.
According to one embodimenL there is provided a compound of formula (IB), wherein R5 and Rfi together represent oxo.
According to another embodiment, there is provided a compound of formula (IB), wherein R7 is phenyl which is substituted with chloro, methyl or fluoro.
According to another embodiment, there is provided a compound of formula (IB), wherein R7 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), 10 wherein ‘m’is 3.
According to another embodiment, there is provided a compound of formula (IB), wherein ‘m’is 4.
Below are the représentative 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,llaR,llbR,13aS)-3a-(2-(4-chlorobenzamido)-2methylpropanamido)-l-isopropyl-5a,5b,8,8,lla-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,
9,10,11,11 a, 11 b, 12,13,13a-octadecahydro-2H-cyclopenta[a] chrysen-9-yl)oxy)carbonyl)-2,2dimethylcyclobutane-l-carboxylic acid (Compound 1), (lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-3a-(2-(l-(4-chlorophenyl) cyclopropane-1 -carboxamido)-2-methylpropanamido)-l -isopropyl-5a,5b,8,8,11 a-pentamethyl -2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,l 1,1 la, 1 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,l 1, lia, 11b, 12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2-dimethyl cyclobutane-1-carboxylic acid (Compound 3), (lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,llaR,llbR,13aS)-3a-(2-(3,4-dichlorobenzamido) -2-methylpropanamido)-l-isopropyl-5a,5b,8,8,lla-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,
8,9,10,11,1 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,l 1,11 a, 1 lb,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy) carbonyl)-2,2-dimethylcyclobutane-l-carboxylic acid (Compound 5), ( 1 R,3 S)-3-((((3aR,5aR,5bR,7aR,9S, 11 aR, 11 bR, 13aS)-3a-(2-(6-aminonicotinamido)2-methylpropanamido)-l-isopropyl-5a,5b,8,8,lla-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,
8,9,10,11,11 a, 11 b, 12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-y l)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,l 1,11 a, 1 lb,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-910 yl)oxy)carbonyl)-2,2-dimethylcyclobutane-l-carboxylic acid (Compound 7), (lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,llaR,llbR,13aS)-3a-(2-((S)-l-(tert-butoxy carbonyl)pyrrolidine-2-carboxamido)-2-methylpropanamido)-l-isopropyl-5a,5b,8,8,llapentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,l 1,1 la, 1 lb,12,13,13a-octadecahydro-2Hcyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-1 -carboxylic acid (Compound 8), (lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,llaR,llbR,13aS)-3a-(2-(2-(4-ethylpiperazin-lyl)acetamido)-2-methylpropanamido)-l-isopropyl-5a,5b,8,8,lla-pentamethyl-2-oxo3,3a,4,5,5a,5b,6,7,7a,8,9,10,l 1,11 a, 1 lb, 12,13,13a-octadecahydro-2H-cyclo penta[a]chrysen9-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,l 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), (1 R,3 S)-3-((((3aR,5aR,5bR,7aR,9S, 11 aR, 11 bR, 13aS)-3a-(2-(2-amino-2-methyl propanamido)-2-methylpropanamido)-l -isopropyl-5a,5b,8,8,11 a-pentamethyl-2-oxo-3,3a,4,5,
5a,5b,6,7,7a,8,9,10,l 1,11 a,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,llaR,llbR,13aS)-3a-(2-(lH-benzo[d]imidazole5-carboxamido)-2-methylpropanamido)-l -isopropyl-5a,5b,8,8,11 a-pentamethyl-2-oxo-3,3a,4,
5,5a,5b,6,7,7a,8,9,10,l 1,11 a,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-3 a-(2-methyl-2-(2-(6-methylpyridin-3-yl)-1 H-benzo[d] imidazole-5 carboxamido)propanamido)-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,l 1,11 a,l lb,12,13,13a
octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-lcarboxylic acid (Compound 13), (lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,llaR,llbR,13aS)-3a-(2-(2,4-dimethylthiazole-5carboxamido)-2-methylpropanamido)-l-isopropyl-5a,5b,8,8,lla-pentamethyl-2-oxo-3,3a,4,
5,5a,5b,6,7,7a,8,9,10,l 1,1 la,l lb,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl) 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 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 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-oxo3,3a,4,5,5a,5b,6,7,7a,8,9,10,l 1,1 la,l lb,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen15 9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-l-carboxylic acid (Compound 16), ( 1 R,3S)-3-((((3aR,5aR,5bR,7aR,9S, 11 aR, 11 bR, 13aS)-1 -isopropyl-3a-(2-(3-isopropyllH-pyrazole-5-carboxamido)-2-methylpropanamido)-5a,5b,8,8,11 a-pentamethyl-2-oxo-3,3a, 4,5,5a,5b,6,7,7a,8,9,10,l 1,1 la,l lb,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl) 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-morpholinobenzamido)propanamido)-2-oxo-3,3a,4,5,5a,5b, 6,7,7a,8,9,10,l 1,1 la,l lb,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy) carbonyl)-2,2-dimethylcyclobutane-l-carboxylic acid (Compound 18), ( 1 R,3S)-3-((((3aR,5aR,5bR,7aR,9S, 11 aR, 11 bR, 13aS)-3a-(2-(3,5-dimethylisoxazole25 4-carboxamido)-2-methylpropanamido)-l-isopropyl-5a,5b,8,8,lla-pentamethyl-2-oxo-3,3a, 4,5,5a,5b,6,7,7a,8,9,10,l 1,1 la,l lb,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl) 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)-230 oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,l 1,1 la,l lb,12,13,13a-octadecahydro-2H-cyclopenta[a] chrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-l-carboxylic acid (Compound 20), (lS,3R)-3-((((3aR,5aR,5bR,7aR,9S,llaR,llbR,13aS)-3a-(2-(4-chlorobenzamido)-2methylpropanamido)-l-isopropyl-5a,5b,8,8,lla-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,
9,10,1l,lla,l lb,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2dimethylcyclobutane-l-carboxylic acid (Compound 21), (lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,llaR,llbR,13aS)-3a-(2-(4-fluorobenzamido)-2methylpropanamido)-l -isopropyl-5a,5b,8,8,11 a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,
9,10,11,1 la,llb,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl) oxy)carbonyl)-2,2dimethylcyclobutane-l-carboxylic acid (Compound 22), (lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-l-isopropyl-5a,5b,8,8,llapentamethyl-3a-(2-methyl-2-(4-methylbenzamido)propanamido)-2-oxo-3,3a,4,5,5a,5b,6,7, 7a,8,9,10,l 1,1 la,l lb,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)
-2,2-dimethylcyclobutane-l-carboxylic acid (Compound 23), (lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,llaR,llbR,13aS)-3a-(2-(furan-3-carboxamido)2-methylpropanamido)-l-isopropyl-5a,5b,8,8,lla-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,
9.10.11.1 la,l lb,12,13,13a-octadecahydro-2H-cyclopenta[a] chrysen-9-yl) oxy)carbonyl)-2,2dimethylcyclobutane-l-carboxylic acid (Compound 24), (lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-l-isopropyl-5a,5b,8,8,1 lapentamethyl-3a-(2-methyl-2-(4-(trifluoromethyl)benzamido)propanamido)-2-oxo-3,3a,4,5, 5a,5b,6,7,7a,8,9,10,l 1,1 la,l lb,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy) carbonyl)-2,2-dimethylcyclobutane-l-carboxylic acid (Compound 25), ( 1 R,3 S)-3-((((3aR,5aR,5bR,7aR,9S, 11 aR, 11 bR, 13aS)-3a-(2-(furan-2-carboxamido)20 2-methylpropanamido)-l -isopropyl-5a,5b,8,8,11 a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,
8.9.10.11.1 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,8,8,1 lapentamethyl-3a-(2-methyl-2-( 1 -phenylcyclopentane-1 -carboxamido)propanamido)-2-oxo25 3,3a,4,5,5a,5b,6,7,7a,8,9,10,l 1,1 la,l lb,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen9-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,l 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,l 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),
(1 R,3S)-3-((((3aR,5aR,5bR,7aR,9S, 11 aR, 11 bR, 13aS)-1 -isopropyl-5a,5b,8,8,11 apentamethyl-3a-(2-methyl-2-(2-methylfuran-3-carboxamido)propanamido)-2-oxo-3,3a,4,5, 5a,5b,6,7,7a,8,9,10,l 1,1 la,l lb,12,13,13a-octadecahydro-2H-cycIopenta[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-morpholinonicotinamido)propanamido)-2-oxo-3,3a,4,5,5a,5b, 6,7,7a,8,9,10,l 1,1 la,l lb,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)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 la10 pentamethyl-3a-(2-methyl-2-(pyrimidine-2-carboxamido)propanamido)-2-oxo-3,3a,4,5,5a,5b, 6,7,7a,8,9,10,l 1,1 la,l lb,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy) carbonyl)-2,2-dimethylcyclobutane-l-carboxylic acid (Compound 32), ( 1 R,3S)-3-((((3aR,5aR,5bR,7aR,9S, 11 aR, 11 bR, 13aS)-3a-(2-(2,5-dimethylfuran-3carboxamido)-2-methylpropanamido)-l-isopropyl-5a,5b,8,8,lla-pentamethyl-2-oxo-3,3a,4,5,
5a,5b,6,7,7a,8,9,10,l 1,1 la, 1 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,llaR,llbR,13aS)-3a-(2-(2-(l,l-dioxidothio morpholino)acetamido)-2-methylpropanamido)-l-isopropyl-5a,5b,8,8,lla-pentamethyl-2oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,l 1,11 a, 1 lb,12,13,13a-octadecahydro-2H-cyclopenta[a] chrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-1 -carboxylic acid (Compound 34), (lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-l-isopropyl-5a,5b,8,8,1 lapentamethyl-3a-(2-methyl-2-(piperidine-4-carboxamido)propanamido)-2-oxo-3,3a,4,5,5a,5b, 6,7,7a,8,9,10,l 1,1 la,l lb,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy) carbonyl)-2,2-dimethyl cyclobutane-1 -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,8,9,10,11,11 a, 11 b, 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,llaR,llbR,13aS)-3a-(l-(4-chlorobenzamido) cyclopropane-l-carboxamido)-l-isopropyl-5a,5b,8,8,lla-pentamethyl-2-oxo-3,3a,4,5,5a,5b, 6,7,7a,8,9,10,11,11 a, 11 b, 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,l 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,llaR,llbR,13aS)-3a-(l-(4-fluorobenzamido) cyclopropane-l-carboxamido)-l-isopropyl-5a,5b,8,8,lla-pentamethyl-2-oxo-3,3a,4,5,5a,5b,
6,7,7a, 8,9,10,11,11 a, 11 b, 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,l 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), (1 S,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,lla-pentamethyl-2-oxo-3,3a,4,5,5a,5b, 6,7,7a,8,9,10,11,11 a, 11 b, 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,lla-pentamethyl-2-oxo-3,3a,4,5,5a,5b, 6,7,7a, 8,9,10,11,11 a, 11 b, 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,8,8,1 la20 pentamethyl-3a-(l-(6-methylnicotinamido)cyclobutane-l-carboxamido)-2-oxo-3,3a,4,5,5a, 5b,6,7,7a, 8,9,10,11,1 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, 25 5a,5b,6,7,7a,8,9,10,l 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-morpholinonicotinamido)cyclobutane-l-carboxamido)-2-oxo-3,3a,4,5, 5a,5b,6,7,7a,8,9,10,l 1,1 la, 1 lb,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy) 30 carbonyl)-2,2-dimethylcyclobutane-l-carboxylic acid (Compound 45), (1 R,3 S)-3-((((3aR,5aR,5bR,7aR,9S, 11 aR, 11 bR, 13aS)-3a-(l -(4-chlorobenzamido) cyclopentane-l-carboxamido)-l-isopropyl-5a,5b,8,8,lla-pentamethyl-2-oxo-3,3a,4,5,5a,5b, 6,7,7a,8,9,10,11,11 a, 11 b, 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,llaR,llbR,13aS)-l-isopropyl-5a,5b,8,8,llapentamethyl-3a-(l-(6-methylnicotinamido)cyclopentane-l-carboxamido)-2-oxo-3,3a,4,5,5a, 5b,6,7,7a,8,9,10,l 1,1 la,l lb,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)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,lla-pentamethyl-2-oxo-3,3a,4,5,5a,5b, 6,7,7a,8,9,10,l 1,1 la,1 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 la10 pentamethyl-3a-(l-(6-methylnicotinamido)cyclohexane-l-carboxamido)-2-oxo-3,3a,4,5,5a, 5b,6,7,7a,8,9,10,11,1 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, 15 6,7,7a,8,9,10,11,11 a, 11 b, 12,13,13 a-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,l 1,1 la,l lb,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy) 20 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,8,8,1 lapentamethyl-3a-(2-methyl-2-((S)-piperidine-3-carboxamido)propanamido)-2-oxo-3,3a,4,5,5a, 5b,6,7,7a,8,9,10,l 1,1 la,l lb,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy) carbonyl)-2,2-dimethylcyclobutane-l-carboxylic acid hydrochloride (Compound 52), 25 (lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-3a-(2-(2-(4-chlorophenyl) acetamido)-2-methylpropanamido)-l -isopropyl-5a,5b,8,8,11 a-pentamethyl-2-oxo-3,3a,4,5, 5a,5b,6,7,7a,8,9,10,l 1,1 la,l lb,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)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,8,8,1 la30 pentamethyl-3a-(2-methyl-2-(pyrazolo[ 1,5-a]pyrimidine-3-carboxamido)propanamido)-2oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,1 la,l lb,12,13,13a-octadecahydro-2H-cyclopenta[a] chrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-l-carboxylic acid (Compound 54), (1 R,3 S)-3-((((3aR,5aR,5bR,7aR,9S, 11 aR, 11 bR, 13aS)-3a-(2-(2-aminothiazole-4carboxamido)-2-methylpropanamido)-l -isopropyl-5a,5b,8,8,11 a-pentamethyl-2-oxo-3,3a,4,5,
5a»5b,6,7,7a»8,9,10,l 1,1 la, 1 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)-25 oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,l 1,1 la, 1 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,llaR,llbR,13aS)-3a-(2-(4-(l,l-dioxidothio morpholino)benzamido)-2-methylpropanamido)-l-isopropyl-5a,5b,8,8,lla-pentamethyl-2oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,l 1,11 a,l lb,12,13,13a-octadecahydro-2H-cyclopenta[a] 10 chrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-l-carboxylic acid (Compound 57), (lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,llaR,llbR,13aS)-3a-(2-(4-((l,l-dioxidothio morpholino)methyl)benzamido)-2-methylpropanamido)-l-isopropyl-5a,5b,8,8,lla-penta methyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,l 1,1 la, 1 lb,12,13,13a-octadecahydro-2H-cyclo penta[a]chrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-l-carboxylic acid (Compound 15 58), (lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,llaR,llbR,13aS)-3a-(2-(2-(dimethylamino) acetamido)-2-methylpropanamido)-l-isopropyl-5a,5b,8,8,lla-pentamethyl-2-oxo-3,3a,4,5,5a, 5b,6,7,7a,8,9,10,11,11 a, 11 b, 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,8,9,10,11,11 a, 11 b, 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 la25 pentamethyl-3a-(2-methyl-2-(6-methylnicotinamido)propanamido)-2-oxo-3,3a,4,5,5a,5b,
6,7,7a,8,9,10,11,11 a, 11 b, 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,llapentamethyl-3a-(2-methyl-2-pivalamidopropanamido)-2-oxo-3,3a,4,5,5a,5b,6, 7,7a,8,9,10,11, 30 11 a, 1 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, lla-pentamethyl-3a-(2-methyl-2-(methylsulfonamido)propanamido)-2-oxo-3,3a,4,5,5a,5b,
6,7,7a,8,9,10,l 1,1 la,l lb,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy) carbonyl)-2,2-dimethylcyclobutane-l-carboxylate (Compound 63), (1 R,3S)-3-((((3aR,5aR,5bR,7aR,9S, 1 laR, 11 bR, 13aS)-3a-(2-((ethoxycarbonyl)amino) -2-methylpropanamido)-l-isopropyl-5a,5b,8,8,11 a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,
8,9,10,11,1 la,l lb,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)2,2-dimethylcyclobutane-l-carboxylic acid (Compound 64), ( 1 R,3S)-3-((((3aR,5aR,5bR,7aR,9S, 11 aR, 11 bR, 13aS)-3a-(2-((4-chlorophenyl) sulfonamido)-2-methylpropanamido)-l-isopropyl-5a,5b,8,8,lla-pentamethyl-2-oxo-3,3a,4,5, 5a,5b,6,7,7a,8,9,10,l 1,1 la,l lb,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy) 10 carbonyl)-2,2-dimethylcyclobutane-l-carboxylic acid (Compound 65), (lR,3S)-3-((((3aR,5aR,5bR,7aR,9S, 11 aR, 11 bR, 13aS)-3a-(2-(cyclohexanecarbox amido)-2-methylpropanamido)-l-isopropyl-5a,5b,8,8,lla-pentamethyl-2-oxo-3,3a,4,5,5a,5b, 6,7,7a,8,9,10,l 1,1 la,l lb,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)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,l 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), (1 R,3S)-3-((((3aR,5aR,5bR,7aR,9S, 11 aR, 11 bR, 13aS)-3a-(2-((4-chlorobenzyl)amino)20 2-methylpropanamido)-l-isopropyl-5a,5b,8,8,lla-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,
8,9,10,11,11 a, 11 b, 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, 11 aR, 11 bR, 13aS)-3a-(2-(((l -(4-chlorophenyl) cyclopropyl)methyl)amino)-2-methylpropanamido)-l -isopropyl-5a,5b,8,8,11 a-pentamethyl25 2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,l 1,1 la,l lb,12,13,13a-octadecahydro-2H-cyclopenta[a] chrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-l-carboxylic acid (Compound 69), (lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,llaR,llbR,13aS)-3a-(2-(5-chloropicolinamido)2-methylpropanamido)-l -isopropyl-5a,5b,8,8,11 a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,
8,9,10,11,1 la,l lb,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)30 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,8,8,1 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,l 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,l 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 IbR, 13aS)-3a-(2-((2-(dimethylamino) ethyl)amino)-2-methylpropanamido)-l -isopropyl-5a,5b,8,8,11 a-pentamethyl-2-oxo-3,3a,4,5, 5a,5b,6,7,7a,8,9,10,l 1,1 la,l lb,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy) carbonyl)-2,2-dimethylcyclobutane-l-carboxylic acid (Compound 73), ( 1 R,3S)-3-((((3aR,5aR,5bR,7aR,9S, 11 aR, 11 bR, 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 1,1 la, b, 12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2-dimethyl cyclobutane-l-carboxylic acid hydrochloride (Compound 74), (lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,llaR,llbR,13aS)-3a-(2-((tert-butoxycarbonyl) amino)-2-methylpropanamido)-l-isopropyl-5a,5b,8,8,lla-pentamethyl-2-oxo-3,3a,4,5,5a,5b, 15 6,7,7a,8,9,10,l 1,1 la,l lb,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy) carbonyl)-2,2-dimethylcyclobutane-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,l 1,1 la,l lb,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy) 20 carbonyl)-2,2-dimethylcyclobutane-l-carboxylic acid hydrochloride (Compound 76), or pharmaceutically acceptable salts, solvatés, including hydrates and prodrugs of compounds are also contemplated.
The présent invention also provides a pharmaceutical composition that includes at least one compound as described herein and at least one pharmaceutically acceptable excipient (such 25 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) présent 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 présent invention further provides a method of treating a disease, condition and/or disorder mediated by viral infections in a subject in need thereof by administering to the subject one or more compounds described herein in a therapeutically effective amount to treat that infection, specifically in the form of a pharmaceutical composition.
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 présent invention may be demonstrated by any one or more méthodologies known in the art, such as by using the assays described in Mossman T, December 1983, Journal of immunological methods, 65 (1-2), 55-63 and SPC Cole, cancer chemotherapy and Pharmacology, 1986,17, 259-263.
DETAILED DESCRIPTION OF THE INVENTION
The présent invention provides C-3 novel triterpenone with C-17 reverse amide dérivatives 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 solvatés, enantiomers, diastereomers of the dérivatives, 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 définitions 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 molécule 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 molécule 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 molécule 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 dérivatives of ammonia, wherein one or more hydrogen atoms hâve 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 10 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 spécifie to each amino acid and which is attached through the nitrogen atom of the amine group to the rest of the molécule 15 by a single bond, e.g., alanine, valine, isoleucine, leucine, phenylalanine, or tyrosine.
The term “amino alkyl” refers to any amino dérivative of an alkyl radical more specificaîly dimethylamino.
The term “cycloalkyl” dénotés 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 norbomyl 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 hâve a chlorine, bromine, iodine or fluorine atom. Dihalo and polyhaloalkyl radicals may hâve 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 consiste of carbon atoms and from one to five heteroatoms selected from nitrogen, phosphores, oxygen and sulfûr. 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, phosphores, 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 quatemized; 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 Iimited to, tetrazoyl, tetrahydroisouinolyl, piperidinyl, piperazinyl, 2oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepinyl, azepinyl, pyrrolyl, 4piperidonyl, 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 création 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 création of a stable structure.
The term “heteroaryl” refers to an aromatic heterocyclic ring radical. Examples of such heteroaryl include, but are not Iimited to pyridyl, pyrazinyl, furanyl, quinolinyl, tetrazoyl, triazolyl, 1,3-Diaza-lH-indenyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, pyrazolo[l,5a]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 création 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 dénotés a dérivative of a compound, which dérivative, when administered to warm -blooded animais, e.g. humans, is converted into the compound (drug). The enzymatic and/or chemical hydrolytic cleavage of the compounds of the présent 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 esterifîed, 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 esterifîed with moieties (e.g., acyloxymethyl esters) which are cleaved to reveal an intermediate compound which subsequently décomposés 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 ofthe A.C.S. Symposium Sériés, 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 clînical symptoms of the state, disease, disorder or condition developing in a subject that may be afïlïcted with or predisposed to the state, disease, disorder or condition but does not yet expérience 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 régression 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 animais, such as domestic animais (e.g., household pets including cats and dogs) and non-domestic animais (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 âge, weight, physical condition 5 and responsiveness of the subject receiving treatment.
The compounds of the présent 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 naturel amino acids and salts ofnon-naturel amino acids. Certain compounds ofthe présent invention are capable of existing 10 in stéréo isomeric forms (e.g., diastereomers, enantiomers, racemates, and combinations thereof). With respect to the overall compounds described by the Formula (1), the présent invention extends to these stéréo isomeric forms and to mixtures thereof. To the extent prior art teaches synthesis or séparation of particular stereoisomers, the different stéréo isomeric forms of the présent invention may be separated from one another by the methods known in 15 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 solvatés includes hydrates and other solvents of crystallization (such as alcohols). The compounds of the présent invention may form solvatés with low molecular weight solvents by methods known in the art.
PHARMACEUTICAL COMPOSITIONS
The pharmaceutical compositions provided in the présent 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 25 infection in a subject.
The subjects contemplated include, for example, a living cell and a mammal, including human. The compound of the présent 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, sait solutions, alcohols, polyethylene glycols, peanut oil, olive oil, gelatin, lactose, terra alba, sucrose, dextrin, magnésium carbonate, sugar, amylose, magnésium stéarate, 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 ingrédient after administration to the subject by employing procedures known in the art.
The pharmaceutical compositions described herein may be prepared, e.g., as described 10 in Remington: The Science and Practice of Pharmacv. 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 présent 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 ofaction. Suitable routes ofadministration include, but are not limited to, oral, nasal, pulmonary, buccal, subdermal, intradermal, transdermal, parentéral, 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 ingrédient 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, comstarch, and/or potato starch. A syrup or élixir can be used in cases 30 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, émulsions, soft gelatin and stérile injectable liquids, such as aqueous or non-aqueous liquid suspensions or solutions.
For parentéral 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 présent 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 prolifération of cells using the 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyl tetrazlium bromide (MTT) staining. Cells (5 x 103 cells /well) will be incubated in in 96 well plates in the presence or absence of 10 compounds. At the end of treatment, 20μ1 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 réplication 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, lxlO6 Sup-Tl cellswith 100%cell viabilitywîllbeseededinRPMI 1640,0.1% FBS four 12 well plates. Increasing concentrations of Epap-1 peptides will be added to the cells 20 and will be infected with HIV1 93 in 101 each at final concentration of virus équivalent to 2 ng of p24 per ml. The infected cells will be incubated at 37°C and 5% CO2 incubator for 2 hours. After 2 hours the cells will be pelleted at 350 g for 10 minutes, supematant 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 25 96 hours. The cells will be supplemented with peptides at every 24 hours. The supematants 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 30 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).
Bnefly, cells will be seeded m to wells of 24 well plates 1 day pnor to the expenment. The cells will be transfected with Tat-reporter. The virus inoculum will be adjusted to 1,0004,000 TCID 50/ml in assay medium (DMEM, 10% FCS, glutamine and antibiotics), 50 μΐ aliquots will be incubated with serial dilutions of compounds (50 μΐ) 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 référencés usefiil 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 sélective 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,83,1911-15(1986); Pennington et al., Peptides 1990; Meek T.D et al., Inhibition of HTV-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, 70,5306-5311; Popik et al., Journal of virology, 2002, 76, 4709-4722; Harrigton et al., Journal of Virology Methods, 2000, 88, 111-115; 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, HTV 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. HTV-1 p24 antigen capture assay, enzyme immunoassay for détection of Human immunodeficiency Virus Type 1 (HIV-1) p24 in tissue culture media - Advanced bio science laboratories, Inc kit procedure.
METHODS OF TREATMENT
The présent invention provides compounds and pharmaceutical formulations thereof that are usefiil 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 & Médicinal Chemistry Letters, 16, (6), 1712-1715, 2006; and référencés cited 5 therein, ail of which are incorporated herein by reference in their entirety and for the purpose stated.
The présent 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 10 présent 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 disoiders (including adult respiratory distress syndrome (ARDS), bronchitis, chronic bronchitis, chronic 15 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 diabètes, rénal diseases, chronic pancreatitis, inflammatory lung conditions, chronic heart failure and bacterial infections (in particular but 20 not limited to tuberculosis).
The compounds of the présent invention can obtain more advantageous effects than additive effects in the prévention 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 25 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 spécifie bases, acids, 30 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 présent invention. Variations in reaction conditions, for example, température and/or duration of the reaction, which may be used as known in the art, are also
within the scope of the présent invention. Ail the stereoisomers of the compounds in these schemes, unless otherwise specified, are also encompassed within the scope of this invention.
Compounds of the présent invention can be synthesized from naturally occurring
Betulinic acid or Betulin. Key intermediates required for synthesizing analogues are either 5 commercially available, or can be prepared by the methods published in the literature. For example, the key intermediates in the présent invention were prepared by modifying the procedures published in Journal of organic chemistiy 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-l
' R, R,1* r<°OH.
wherein Formula 1, » « u..P
JQ Rr'c'a .QO*. or Rr c
The compounds of formula 1 (wherein, R2, R3, R4, Rs, Rô and R7 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), 15 diisopropylethylamine (DIPEA), pyridine or the like in the solvents such as dichloromethane (DCM), chloroform (CHCI3), toluene, tetrahydrofùran (THF) or the like with or without
addition of catalysts such as dimethyl amino pyridine (DMAP) or the like to give the C-3 & C28 protected alcohol compounds of formula (ii) (Pi and P2 areprotecting 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 (AC2O) 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 (Na2Cr2Ch), sodium acetate (NaOAc), acetic acid (AcOH), acetic anhydride (AC2O) 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: éthanol (EtOH) (1:1) or with reagents like Aluminum isopropoxide (Al(i-Pro)3) in solvents like 2-propanol or the like. The C-28 alcohol compounds of formula (v) can be converted to give the C-28 aldéhyde compounds of formula (vi) in the presence of pyridinium chlorochromate (PCC), pyridinium dichromate (PDC), Dess-martin periodinane (DMP) or Swem oxidation conditions in the solvents such as dichloromethane (DCM) or the like. The C-28 aldéhyde 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 (NaCICh) 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 (NaH2PO4) or the like in the combination of solvents such as tert-butanol (t-BuOH), tetrahydrofuran (THF) and water (H2O) 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 ofoxidizing 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 (NaH2PO4) and the bases like NaHCO3 in combination of solvents like Tetrahydrofuran (THF) and water (H2O) The C-28 acid compounds of formula (vii) can be converted to the C-17 carbamate compounds of formula (viii) by using the reagents like diphenylphosphoryl azide (DPPA) or ethylchloroformate and sodium azide (NaN3) in the presence of bases such as triethylamine (TEA), Ν,Ν-Diisopropylethylamine (DIPEA) in solvents such as 1,2-DCE, THF or Toluene in the presence of alcohols such as 4methoxybenzyl alcohol (PMBOH), tert-butyl alcohol (t-BuOH) or the like. The C-17 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 (CHCI3) or the like to give the amine compounds of formula (ix). The C-17 amine compounds of formula (ix) can be reacted with the acid compounds of formula (x) in the presence of coupling reagents such as O-(7-Azabenzotriazol-l-yl)-N,N,N’,N’tetramethyluroniumhexafluorophosphate (HATU), O-(Benzotriazol-1 -yl)-N,N,N’,N’ 5 tetramethyluroniumhexafluoro phosphate (HBTU), l-Ethyl-3-(3dimethylaminopropyl)carbodiimide (EDCI), 1-Hydroxybenzo triazole (HOBt) or the like in the presence of bases such as triethylamine (TEA), Ν,Ν-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-17 amide compounds of formula (xi). The C-3 protected alcohol 10 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 (H2O) (4:2:1) (or) 1,4-dioxane: water (H2O) (4:1) or the like. The C-3 alcohol compounds of formula (xii) can be reacted with the acid compounds of formula 15 (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), Ν,Ν-Diisopropylethylamine (DIPEA) and catalysts such as 4dimethylaminopyridine (DMAP) in the solvents such as 1,2-dichloroethane (1,220 DCE), dichloromethane (DCM) or the like.
(b) acid alcohol coupling in the presence ofcoupling reagents such EDCI, HOBt in the presence of bases such as triethylamine (TEA), Ν,Ν-Diisopropylethylamine (DIPEA) and catalysts such as 4-dimethylaminopyridine (DMAP) in the solvents such as dichloromethane (DCM) and Ν,Ν-dimethylformamide (DMF) or the like.
The C-17 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-17 substituted amine compounds of formula (xv). The C-17 substituted amine compounds of formula (xv) can be reacted with the compounds of formula (xvi) to form C-3 ester compounds of formula 30 (xvii) in different ways like
a) acid and amine coupling in the presence of coupling reagents such as O-(7Azabenzotriazol-1 -yl)-N,N,N’,N’-tetra methyluroniumhexafluorophosphate (HATU), O-(Benzotriazol-1 -yl)-N,N,N’ ,N’ -tetramethyl uroniumhexafluorophosphate (HBTU), l-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 aldéhyde in the presence of reducing agents such as sodium triacetoxyborohydride (STAB) or Sodium borohydride or, sodium cyanoborohydride (NaCNBH3) or the like in the solvents such as 1,2-dichloroethane (1,2-DCE), tetrahydrofuran (THF), Methanol (MeOH), Acetonitrile (CH3CN) or the like.
c) acid chloride and amine coupling in the presence ofbases 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 (NaCNBH3) 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 spécification may be summarized herein below with their particular meaning: DIPEA (Ν,Ν-Diisopropylethylamine); °C (degree Celsius); δ (delta); ppm (parts per million); % (percentage); DMSO-de (Deuterated DMSO); d (Doublet); dd (Doublet of doublet); EtOH (Ethanol); EtOAc (Ethyl acetate); g or gr (gram); H or H2 (Hydrogen); HCl (Hydrochloric acid); h or hr. (Hours); HATU (0-(7-Azabenzotriazol-1-yl)Ν,Ν,Ν’,Ν’-tetramethyluroniumhexafluoro phosphate); Hz (Hertz); HPLC (High-performance liquid chromatography); mmol (Milli mol); M (Molar); ml (Millilitre); mg (Milli gram); m (Multiplet); mm (Millimètre); MHz (Mégahertz); ESI-MS (Electron spray Ionization Mass spectra); min (Minutes); mM (Milli molar); NaOH (Sodium hydroxide); N2 (Nitrogen); NMR (Nuclear magnetic résonance 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)2O (Di-tert-butyl dicarbonate); DCM (dichloromethane); DMF (N,N18389 dimethyl formamide); DMAP (4-(Dimethylamino)pyndine); eq (équivalent); Ltr or L (Liter); CDCh (Deuterated chloroform); J (Coupling constant); Jab (Coupling constant); NaHzPCU (Sodium dihydrogen phosphate); Na(OAc)3BH3 (Sodium triacetoxyborohydride); AcOH (Acetic acid); NaCNBtb (Sodium cyanoborohydride); ABq (AB quartet); CS2CO3 (Césium carbonate); Cul (Copper(I) iodide); MTBE (Methyl tert-butyl ether); HBr (Hydrogen bromide); AC2O (Acetic anhydride); NaHCCh (Sodium bicarbonate); Na2SC>4 (Sodium sulphate); 1,2DCE (1,2-dichloroethane); HBTU (O-(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 (2,2bis(diphenylphosphino)-l, 1 -binaphthyl).
EXPERIMENTAL
The présent 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 équivalents 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 présent 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: Préparation of l-ii3aR.5aR,5bR.7aR.9S.llaR,llbR,13aS)-3a-(2-amino-2methvlpropanamido’)-l-isopropvl-5a.5b.8.8.11a-pentamethvl-2-oxo-3.3a.4.5.5a.5b.6.7.7a.8.9.
10,1 L1 la,l lb,12.13.13a-octadecahvdro-2H-cvclopentaralchrvsen-9-vD 3-benzyl (1S.3RI-2.2 -dimethvlcvclobutane-l,3-dicarboxvlate:
Step 1: Synthesis of ((lR,3aS,5aR,5bR,7aR,9S,llaR,llbR,13aR,13bR)-9-acetoxy-5a,5b,8,8, lla-pentamethyl-l-(prop-l-en-2-yl)icosahydro-3aH-cyclopenta[a]chrysen-3a-yl)methyl acetate:
AcO
OAc
A mixture of (lR,3aS,5aR,5bR,7aR,9S,llaR,llbR,13aR,13bR)-3a-(hydroxymethyl)5a,5b,8,8,11 a-pentamethyl-1 -(prop-1 -en-2-yl)icosahydro-1 H-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. 'H NM R (300 MHz, CDCh): δ 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,llaR,llbR,13aS)-9-acetoxy-l-isopropyl-5a,5b,8, 8, lla-pentamethyl-2,3,4,5,5a, 5b, 6,7,7a, 8,9,10,11,1 la,11b,12,13,13a-octadecahydro-3aHcyclopenta[a]chrysen-3a-yl)methyl acetate:
AcO'
OAc
HBr in acetic acid (800 ml, 33%), was added to a suspension of (flR,3aS,5aR,5bR, 7aR,9S, 11 aR, 11 bR, 13aR, 13b7?)-9-acetoxy-5a,5b,8,8,11 a-pentamethyl-1 -(prop-1 -en-2-yl) icosahydro-3a/7-cyclo penta[«]chrysen-3a-yl)methyl acetate (step 1, 400 g, 0.76 mol, 1.0 eq) in toluene (800 ml), AC2O (800 ml) and acetic acid (800 ml) previously heated at 105 °C. The reaction mixture was stirred and heated at this température 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 CH2CI2 (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% éthanol and CH2CI2 to obtain the desired product (256 g, yield: 64%) as a white solid. *H NMR (300 MHz, CDCI3): δ 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,llaR,llbR,13aS)-9-acetoxy-l-isopropyl-5a,5b,8,
8,11 a-pentamethyl-2-oxo-2,3,4,5,5a, 5b, 6,7,7a,8,9,10,11,lia,11b,12,13,13a-octadecahydro3aH-cyclopenta[a] chrysen-3a-yl)methyl acetate:
To a stirred solution of ((3aS,5aR,5b/?,7aÆ,95,l la/?, 11 b/?,l3aS)-9-acetoxy-lisopropyl-5a,5b,8,8,l la-pentamethyl-2,3,4,5,5a,5b,6,7,7a,8,9,10,l 1,1 la,l lb,12,13,13a-octa decahydro-3a/7-cyclopenta[n]chrysen-3a-yl)methyI 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), Ac2O (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 précipitâtes that formed were collected by filtration were dried under vacuum to obtain the desired product (81 g, yield: 79%) as a white solid. *H NMR (300 MHz, CDCh): δ 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,llaR,llbR,13aS)-3a-(hydroxymethyl)-l-isopropyl -5a,5b,8,8,1 la-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,l 1,1 la,l lb,12,13,13a-octa decahydro-2H-cyclopenta[a]chrysen-9-yl acetate:
To a stirred solution of ((3a7?,5aR,5bR,7aR,95,11 aR, 11 b/?,l 3aS)-9-acetoxy-l isopropyl-5a,5b,8,8,l la-pentamethyl-2-oxo-2,3,4,5,5a,5b,6,7,7a,8,9,10,l 1,1 la,l lb,12,13,13a -octadecahydro-3a7/-cyclopenta[a]chrysen-3a-yl)methyl acetate (step 3, 70 g, 0.129 mol, 1.0 eq) in éthanol (2 L) : toluene (2 L) was added potassium hydroxide (8.72 g, 0.155 mol, 1.2 eq) and stirred at room température 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 précipitâtes 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. *H NMR (300 MHz, CDCfi): δ 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, 1 H); ESI-MS: m/z 521.3 (M+Na)+.
Step 5: Synthesis of (3aR,5aR,5bR,7aR,9S,llaR,llbR,13aS)-3a-formyl-l-isopropyl-5a,5b,8,
8,1 la-pentamethyl-2-oxo-3,3a, 4,5,5a, 5 b, 6,7,7a,8,9,10,11,lia,11 b, 12,13,13a-octadecahydro2H-cyclopenta[a] chrysen-9-yl acetate:
To a solution of (3a7?,5a7?,5b/?,7a7?,95,lla7?,llb.R,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 1,1 la,l lb,12,13, 13a-octadecahydro-27/-cyclopenta[a]chrysen-9-ylacetate (step 4,52.0 g, 0.104 mol, 1.0 eq) in CH2CI2 (2 L) at room température was added pyridinîumchlorochromate (67.5 g, 0.313 mol, 3.0 eq) and silicagel (100-200 mesh) (67.5 g). The reaction mixture was stirred at room température 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, dned over sodium sulphate and evaporated under reduced pressure to give a crude product, which was triturated with éthanol, solid was filtered and dried under vacuum to obtain the desired product (41.4 g, yield: 80%) as a white solid. ’HNMR (300 MHz, CDCh): δ 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, 3 H), 0.98-0.75 (m, 12H).
Step 6: Synthesis of (3aR,5aR,5bR,7aR,9S,llaR,llbR,13aS)-9-acetoxy-l-isopropyl-5a,5b,8,
8,1 la-pentamethyl-2-oxo-2,3,4,5,5 a, 5b, 6,7,7a,8,9,10,11,lia,11b,12,13,13a-octadecahydro3aH-cyclopenta[a]chrysene-3a-carboxyïic acid:
,OH
To an ice-cooled solution of (3aR,5aR,5bR,7aR,9S,llaR,llbR,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 1,1 la, 11 b,l 2,13, 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 ofNaCICh (71.86 g, 797.58 mmol, 12.0 eq) in 385 ml of water followed by NaH2PO4 (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 température 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. ‘H NMR (300 MHz, CDCb): δ 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,llaR,llbR,13aS)-l-isopropyl-3a-((((4-methoxy benzyl)oxy)carbonyl)amino)-5a, 5b, 8,8,1 la-pentamethyl-2-oxo-3,3 a, 4,5,5a, 5b, 6,7,7a, 8,9,10, 11, lla,llb,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl acetate:
To a stirred solution of (3aR,5aR,5bR,7aR,9S,llaR,llbR,13aS)-9-acetoxy-lisopropyl-5a,5b,8,8,11 a-pentamethyl-2-oxo-2,3,4,5,5a,5b,6,7,7a,8,9,10,11,11 a, 11 b, 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 température, 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 containîng the product were combined and concentrated under reduced pressure to give the desired product (38.0 g, yield: 91.1%) as a white solid. ’H NMR (300 MHz, CDCh): δ 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,llaR,llbR,13aS)-3a-amino-l-isopropyl-5a,5b,8,8, 1 la-pentamethyl-2-oxo-3,3a,4,5,5a, 5b, 6,7,7a, 8,9,10,11,1 la, 11b, 12,13,13a-octadecahydro2H-cyclopenta[a]chrysen-9-ylacetate:
To a stirred solution of (3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-l-isopropyl-3a-((((4methoxybenzyl)oxy)carbonyl)amino)-5a,5b,8,8,11 a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,
8,9,10,11,1 la,llb,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 température for ovemight. 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 NaHCCh 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 5 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 NMR (300 MHz, CDCh): δ 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 of2-((tert-butoxycarbonyl)amino)-2-methylpropanoic acid:
b“hn^-oh
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 (ΒοφΟ (95.13 g, 436.38 mmol, 1.5 eq). The reaction mixture was allowed to stir at room température for ovemight. 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 HCl and then extracted with DCM (3x300 ml). The combined organic extracts were washed with water (300 ml), brine (100 ml) solution, dried over NaîSCh, filtered and evaporated under reduced pressure. The residue was stirred with n-hexane (300 ml) at room température 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 of2-carboxypropan-2-aminium chloride (15.0 g, 145.63 mmol) 25 in 1,4-dioxane (75 mL), added 2N NaOH solution (75 mL), (ΒοφΟ (47.62 g, 218.44 mmol) at 0 °C and stirred the reaction mixture for about 12 hours at room température. 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 HCl (pH-2-3) and extracted with CH2CI2 (2x200 mL). The combined organic extracts 30 were washed with water, dried over Na2SÜ4, filtered and evaporated under reduced pressure.
The crude residue was purified by silicagel column chromatography by using 30% EtOAc: nHexane as an eluent to afford the desired product (15.0 g, yield: 50.74%) as an off white solid.
H NMR (300 MHz, DMSO): δ 12.18 (s, 1H), 7.05 (s, 1H), 1.36 (s, 9H), 1.29 (s, 6H); ES Mass: 226.06 [M+Na]+.
Step 10: Synthesis of (3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-3a-(2-((tert-butoxycarbonyl) amino)-2-methylpropanamido)-l-isopropyl-5a,5b,8,8,lla-pentamethyl-2-oxo-3,3a,4,5,5a,5b,
6,7,7a, 8,9,10,11,1 la, 11b, 12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl acetate:
Method 1: To a stirred solution of 2-((tert-butoxycarbonyl)amino)-2-methylpropanoic acid (step 9,4.539 g, 22.36 mmol, 1.2 eq) in 1,2-DCE (200 ml) was added HATU (10.62 g, 27.95 mmol, 1.5 eq) followed by DIPEA (19.3 ml, 111.79 mmol, 6.0 eq). The reaction mixture was stirred at room température for about 30 minutes, then (3aR,5aR,5bR,7aR,9S,llaR,llbR, 13aS)-3a-amino-l-isopropyl-5a,5b,8,8,lla-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10, ll,lla,llb,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl acetate (step 8, 9.0 g, 18.63 mmol, 1.0 eq) was added and stirred at same température for ovemight. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture was evaporated under reduced pressure, diluted with water (90 ml) and extracted with DCM (3x135 ml). The combined organic extracts were washed with 0.5N HCl (90 ml), water (90 ml) and brine (45 ml) solution. The organic layer was dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified by silicagel column chromatography by using 0-2% methanol in dichloromethane gradient. The fractions containing the product were combined and concentrated under reduced pressure to give the desired product (11.0 g, yield: 88.7%) as an off-white solid. ’H NMR (300 MHz, CDCh): δ ppm 4.91 (brs, 1H), 4.49 (dd, J = 10.5, 5.7 Hz, 1H), 3.20-3.08 (m, 1H), 2.86 (m, 1H), 2.68 (d, J= 18.6 Hz, 1H), 2.39-2.32 (m, 1H), 2.27 (d, J= 18.6 Hz, 1H), 2.05 (s, 3H), 1.98-1.86 (m, 2H), 1.84 (m, 1H), 1.81-1.52 (m, 6H), 1.49 (s, 3H), 1.47 (s, 3H), 1.42 (s, 9H), 1.39-1.34 (m, 3H), 1.29-1.19 (m, 7H), 1.18-1.13 (m, 1H), 1.17 (s, 3H), 1.10-1.01 (m, 2H), 0.92 (s, 3H), 0.91 (s, 3H), 0.856 (s, 3H), 0.85 (s, 3H), 0.80 (m, 1H); ESI-MS: m/z 691.5 (M+Na)+.
Method 2: To a stirred solution of 2-((tert-butoxycarbonyl)amino)-2-methylpropanoic acid (step 9, 7.56 g, 37.21 mmol, 1.2 eq) in DMF (150 ml) was added EDCI (9.24 g 48.3 mmol 1.5 eq) followed by DMAP (11.8 g 96.77 mmol 3eq) at 0 °C. The reaction mixture was stirred at room température for about 30 minutes, then (3aR,5aR,5bR,7aR,9S,llaR,llbR, 13aS)-3aamino-1-isopropyl-5a,5b,8,8,11 a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10, ll,lla,llb,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl acetate (step 8, 15.0 g, 31.0 mmol, 1.0 eq) was added and stirred at room température for about 4 hours. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture was diluted with ice water (450 ml) and white solid was obtained. The solid was filtered, dissolved in DCM, washed with water and brine solution. The organic layer was dried over Na2SO4, evaporated under reduced pressure to give the desired product (17.5 g, yield: 80%) as an off-white solid.
Step 11: Synthesis of tert-butyl (l-(((3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-9-hydroxy-lisopropyl-5a,5b,8,8,lla-pentamethyl-2-oxo-2,3,4,5,5a,5b,6,7,7a,8,9,10,ll,lla,llb,12,13,13a -octadecahydro-3aH-cyclopenta[a]chrysen-3a-yl)amino)-2-methyl-l-oxopropan-2-yl) carbamate:
To a stirred solution of (3aR,5aR,5bR,7aR,9S,llaR,llbR,13aS)-3a-(2-((tert-butoxy carbonyl)amino)-2-methylpropanamido)-l-isopropyl-5a,5b,8,8,lla-pentamethyl-2-oxo-3,3a, 4,5,5a,5b,6,7,7a,8,9,10,11,1 la,l lb,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl acetate (step 10, 11.0 g, 16.45 mmol, 1.0 eq) in MeOH (110 ml), THF (55 ml) and water (28 ml) at 0 °C was added NaOH (6.582 g, 164.57 mmol, 10.0 eq). The mixture was removed from the ice bath and was stirred at room température for ovemight. 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 (165 ml) and extracted with DCM (3x165 ml). The combined organic extracts were washed with water (110 ml), brine solution (50 ml), dried over sodium sulfate, filtered and evaporated under reduced pressure. 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 (10.0 g, yield: 96.92%) as a yellow solid. ‘H NMR (300 MHz, CDCh): δ ppm 7.0 (brs, 1H), 4.85 (brs, 1H), 3.28-3.08 (m, 2H), 2.86 (m, 1H), 2.68 (d, J= 18.6 Hz, 1H), 2.38-2.31 (m, 1H), 2.27 (d, J= 18.6 Hz, 1H), 1.97-1.73 (m, 4H), 1.70-1.65 (m, 3H), 1.64-1.53 (m, 3H), 1.49 (s, 3H), 1.46 (s, 3H), 1.42 (s, 9H), 1.40-1.25 (m, 5H), 1.25 (s, 3H), 1.22 (s, 3H), 1.17 (s, 3H), 1.10-1.02 (m, 1H), 0.97 (s, 3H), 0.94 (s, 3H), 0.89 (s, 3H), 0.77 (s, 3H), 0.75-0.68 (m, 1H); ESI-MS: m/z 649.5 (M+Na)+.
Step 12: Synthesis of 1-benzyl 3-((3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-3a-(2-((tert-butoxy carbonyl)amino)-2-methylpropanamido)-l-isopropyl-5a,5b,8,8,lla-pentamethyl-2-oxo-3,3a, 4,5,5a,5b,6,7,7a,8,9,10,11, lia, 11b, 12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl) (1 R, 3S)-2,2-dimethylcyclobutane-l, 3-dicarboxylate:
BnO<
.NHBoc
Method 1: To a stirred solution of tert-butyl (l-(((3aR,5aR,5bR,7aR,9S,llaR,llbR,13aS)-9hydroxy-l-isopropyl-5a,5b,8,8,l la-pentamethyl-2-oxo-2,3,4,5,5a,5b,6,7,7a,8,9,10,l 1,1 la, b, 12,13,13a-octadecahydro-3aH-cyclopenta[a]chrysen-3a-yl)amino)-2-methyl-l -oxo propan-2-yl)carbamate (step 11, 10.0 g, 15.95 mmol, 1.0 eq) in DCM (100 ml) at 0 °C under nitrogen atmosphère was added EtîN (11.12 ml, 79.75 mmol, 5.0 eq), DMAP (0.969 g, 7.975 mmol, 0.5 eq), (lS,3R)-3-((benzyloxy)carbonyl)-2,2-dimethylcyclobutane-l-carboxylic acid (prepared as described in WO 2011/007230 A2, 6.27 g, 23.92 mmol, 1.5 eq) and 2,4,6trichlorobenzoyl chloride (4.98 ml, 31.89 mmol, 2.0 eq). The mixture was removed from the ice bath and was stirred at room température for ovemight. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture was evaporated under reduced pressure, diluted with water (100 ml) and extracted with DCM (3x100 ml). The combined organic extracts were washed with 0.5N HCl (100 ml), water (100 ml), brine solution (50 ml), dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by silicagel column chromatography by using 0-10% MeOH in DCM gradient. The fractions containing the product were combined and concentrated under reduced pressure to give the desired product (10.0 g, yield: 71.9%) as an off-white solid. ’H NMR (300 MHz, CDCI3): δ ppm 7.38-7.32 (m, 5H), 6.96 (brs, 1H), 5.15, 5.09 (ABq, Jab= 12.3 Hz, 2H), 4.84 (brs, 1H), 4.45 (dd, J= 11.1,4.5 Hz, 1H), 3.20-3.08 (m, 1H), 2.88-2.58 (m, 5H), 2.40-2.33 (m, 1H), 2.27 (d, J= 18.6 Hz, 1H), 2.09-2.02 (m, 1H), 2.0-1.82 (m, 3H), 1.81-1.70 (m, 3H), 1.65-
1.54 (m, 4H), 1.49 (s, 3H), 1.46 (s, 3H), 1.42 (s, 9H), 1.40-1.30 (m, 3H), 1.34 (s, 3H), 1.301.17 (m, 8H), 1.14 (s, 3H), 1.11-1.0 (m, 1H), 0.97 (s, 3H), 0.93 (s, 3H), 0.91 (s, 3H), 0.86 (s,
3H), 0.85 (s, 3H), 0.79 (m, 1H).
Method 2: To a stirred solution of (1 S,3R)-3-((benzyloxy)carbonyl)-2,2-dimethylcyclo butane1-carboxylic acid (prepared as described in WO 2011/007230 A2, 0.54 g, 3.89 mmol, 1.5 eq) in DMF (20 ml) at 0 °C under nitrogen atmosphère was added EDCI (0.99 g, 5.18 mmol, 2 eq), HOBT (0.52 g, 3.89 mmol, 1.5 eq), DMAP (0.15 g, 1.29 mmol, 0.5eq), added Triethylamine
(1.08 ml 7.78 mmol, 3 eq) and stîrred it for about 30 minutes. Then added tert-butyl (1(((3aR,5aR,5bR,7aR,9S,llaR,llbR,13aS)-9-hydroxy-l-isopropyl-5a,5b,8,8,llapentamethyl-2-oxo-2,3,4,5,5a,5b,6,7,7a,8,9,10,l 1,1 la,l lb,12,13,13a-octadecahydro-3aHcyclopenta[a]chrysen-3a-yl)amino)-2-methyl-l-oxopropan-2-yl)carbamate (step 11, 2.0 g, 5 2.59 mmol, 1 eq). The reaction mixture was stirred at room température for about 14 hours.
TLC indicated starting material was consumed and the desired product was observed. The reaction mixture was quenched with ice cold water then filtered through Buchner fùnnel. The solid was separated, then the solid compound was dissolved in DCM, washed with sodium bicarbonate, water, brine solution then dried over sodium sulfate and concentrated under 10 reduced pressure to give a crude compound. The crude compound was purified by flash silica column chromatography by using 100-200 silica gel, then the product was eluted at 2% MeOH in DCM (1.5 g, yield: 65.21%) as an off-white solid.
Step 13: Synthesis of l-((3aR,5aR,5bR,7aR,9S,llaR,llbR,13aS)-3a-(2-amino-2-methyl propanamido)-l-isopropyl-5a, 5b, 8,8,1 la-pentamethyl-2-oxo-3,3 a, 4,5,5a, 5b, 6,7,7a, 8,9,10,
11,1 la,1 lb,12,13,13a-octadecahydro-2H-cyclopenta[a] chrysen-9-yl)3-benzyl (lS,3R)-2,2-di methylcyclobutane-l,3-dicarboxylate:
To a stirred solution of 1-benzyl 3-((3aR,5aR,5bR,7aR,9S,llaR,llbR,13aS)-3a-(2((tert-butoxycarbonyl)amino)-2-methylpropanamido)-l-isopropyl-5a,5b,8,8,lla-pentamethyl2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,l 1,1 la,l lb,12,13,13a-octadecahydro-2H-cyclopenta[a] chrysen-9-yl) (lR,3S)-2,2-dimethylcyclobutane-l,3-dicarboxylate (step 12, 10.0 g, 11.47 mmol, 1.0 eq) in DCM (80 ml) was added trifluoroacetic acid (20 ml). The reaction mixture was stirred at room température for about 14 hours. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture was evaporated under reduced pressure, cooled to 0 °C, pH adjusted to 8.0 with saturated sodium bicarbonate solution 25 and extracted with DCM (3x100 ml). The combined organic extracts were dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by sîlicagel column chromatography by using 0-5% methanol in dichloromethane gradient. The fractions containing the product were combined and concentrated under reduced pressure to give the desired product (8.0 g, yield: 90.4%) as an off-white solid. ’H NMR (300 MHz, CDCh): δ ppm
7.99 (brs, 1H), 7.38-7.32 (m, 5H), 5.15, 5.09 (ABq, Jab = 12.3 Hz, 2H), 4.45 (dd, J= 11.1,4.5
Hz, 1H), 3.20-3.09 (m, 1H), 2.89-2.61 (m, 5H), 2.43-2.35 (m, 1H), 2.30 (d, J= 18.6 Hz, 1H), 2.10-1.92 (m, 3H), 1.90-1.65 (m, 4H), 1.53-1.40 (m, 4H), 1.40-1.30 (m, 12H), 1.27-1.15 (m, 8H), 1.12 (s, 3H), 1.09-1.01 (m, 1H), 0.96 (s, 3H), 0.94 (s, 3H), 0.91 (s, 3H), 0.86 (s, 3H), 0.85 (s, 3H), 0.79 (m, 1H); ESI-MS: m/z 771.6 (M+H)+.
Intermediate 2: Préparation of l-(('3aR.5aR,5bR,7aR.9S,llaR.l lbR.13aS)-3a-(2-ammo-2methylpropanamidoï-l -isonropyl-5a.5b.8.8.11 a-pentamethyl-2-oxo-3.3a.4.5.5a.5b.6.7.7a,8.9.
10.11.1 la.l lb.l2J3.13a-octadecahvdro-2H-cvclopentara1chrvsen-9-vn 3-benzyl i!R.3S)-2.2
Step 1; Synthesis of (lR,3S)-3-((benzyloxy)carbonyl)-2,2-dimethylcyclobutane-l~carboxylic
2,4,6-trichlorobenzoic anhydride:
BnOOC
To a stirred solution of (lR,3S)-3-((benzyloxy)carbonyl)-2,2-dimethylcyclobutane-lcarboxylic acid (prepared as described in WO 2014/105926 Al, 1.0 g, 3.812 mmol, 1.0 eq) in THF (10 ml) at 0 °C under nitrogen atmosphère was added triethylamine (1.59 ml, 11.436 mmol, 3.0 eq) followed by 2,4,6-trichlorobenzoyl chloride (0.71 ml, 4.574 mmol, 1.2 eq). The reaction mixture was allowed to stir at room température for about 4 hours. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture was evaporated under reduced pressure to obtain the desired product (1.8 g) as an oil, which is used as such for next step without further purification.
Step 2: Synthesis of 1-benzyl 3-((3aR,5aR,5bR,7aR,9S,llaR,llbR,13aS)-3a-(2-((tert-butoxy carbonyl)amino)-2-methylpropanamido)-l-isopropyl-5a,5b,8,8,lla-pentamethyl-2-oxo-3,3a, 4,5,5a,5b,6,7,7a,8,9,10,U,lla,llb,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl) (IS, 3R)-2,2-dimethylcyclobutane-l, 3-dicarboxylate:
To a stirred solution of tert-butyl (Î-(((3aR,5aR,5bR,7aR,9S,llaR,llbR,13aS)-9hydroxy-l-isopropyl-5a,5b,8,8,l la-pentamethyl-2-oxo-2,3,4,5,5a,5b,6,7,7a,8,9,10,l 1,1 la, 11 b, 12,13,13a-octadecahydro-3aH-cyclopenta[a]chrysen-3a-yl)amino)-2-methyl-l -oxo
propan-2-yl)carbamate (Intermediate 1-step 11, 1.5 g, 2.392 mmol, 1.0 eq) in Toluene (15 ml) at 0 °C under nitrogen atmosphère was added DMAP (0.730 g, 5.981 mmol, 2.5 eq) and (lR,3S)-3-((benzyloxy)carbonyl)-2,2-dimethylcyclobutane-l-carboxylic 2,4,6-trichloro benzoic anhydride (step 1, 1.685 g, 3.588 mmol, 1.5 eq) dissolved in toluene (15 ml). The 5 reaction mixture was allowed to stir at room température for about 30 minutes and then heated to reflux for ovemight. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture was evaporated under reduced pressure, diluted with water (20 ml) and extracted with DCM (3x30 ml). The combined organic extracts were washed with water (20 ml), brine solution (20 ml), dried over sodium sulfate, filtered and evaporated under 10 reduced pressure. The residue was purified by silicagel column chromatography by using 03% methanol in dichloromethane gradient. The fractions containing the expected product were combined and concentrated under reduced pressure to obtain the desired product (1.0 g, yield: 48.07%) as a white solid. *H NMR (300 MHz, CDCh): δ ppm 7.35 (m, 5H), 5.15, 5.10 (ABq, Jab = 12.3 Hz, 2H), 4.46 (dd, J= 11.1,4.5 Hz, 1H), 3.20-3.08 (m, 1H), 3.0-2.58 (m, 5H), 2.4015 2.23 (m, 2H), 2.12-2.02 (m, 1H), 1.98-1.82 (m, 2H), 1.80-1.67 (m, 2H), 1.65-1.53 (m, 7H),
1.50 (s, 3H), 1.47 (s, 3H), 1.43 (s, 9H), 1.40-1.30 (m, 4H), 1.33 (s, 3H), 1.24 (d, J= 6.9 Hz, 3H), 1.21 (d, J= 6.9 Hz, 3H), 1.14 (s, 3H), 1.08-1.0 (m, 1H), 0.97-0.90 (m, 9H), 0.87-0.78 (m, 7H); ESI-MS: m/z 893.54 (M+Na)+.
Step 3: Synthesis of l-((3aR,5aR,5bR,7aR,9S,llaR,llbR,13aS)-3a-(2-amino-2-methylpropan 20 amido)-l-isopropyl-5a, 5 b, 8,8,11 a-pentamethyl-2-oxo-3,3 a, 4,5,5a, 5b, 6,7,7a, 8,9,10,11,11a, llb,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl) 3-benzyl (lR,3S)-2,2-dimethyl cyclobutane-1,3-dicarboxylate:
To a stirred solution of 1-benzyl 3-((3aR,5aR,5bR,7aR,9S,llaR,llbR,13aS)-3a-(2((tert-butoxycarbonyl)amino)-2-methylpropanamido)-l-isopropyl-5a,5b,8,8,lla-pentamethyl25 2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,l 1,1 la,l lb,12,13,13a-octadecahydro-2H-cyclopenta[a] chrysen-9-yl) (lS,3R)-2,2-dimethylcyclobutane-l,3-dicarboxylate (step 2, 1.0 g, 1.148 mmol, 1.0 eq) in DCM (8 ml) was added trifluoroacetic acid (2 ml). The reaction mixture was stirred at room température for ovemight. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture was evaporated under reduced pressure, 30 diluted with water (10 ml), cooled to 0 °C, pH adjusted to 8.0 with saturated sodium bicarbonate solution and extracted with DCM (3x50 ml). The combined organic extracts were washed with water (30 ml), dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by silicagel column chromatography by using 0-5% methanol in dichloromethane gradient. The fractions containing the expected product were combined and concentrated under reduced pressure to give the desired product (0.8 g, yield: 90.3%) as a white solid.
Intermediate 3: Préparation of l-(ï3aR.5aR.5bR.7aR.9S.l laR.l lbR.13aS)-3a-(l-aminocyclo Dropane-l-carboxamido~)-l-isoproDvl-5a.5b,8,8.1 la-pentamethyl-2-oxo-3.3a.4.5.5a,5b,6.7,7a.
8.9,10.11.1 la.l lb.l2.13.13a-octadecahvdro-2H-cvclopentaralchrysen-9-vl) 3-benzvl (1S.3R) -2,2-dimethylcyclobutane-1.3-dicarboxylate:
BnOOC
Step 1: Synthesis of l-((tert-butoxycarbonyl)amino)cyclopropane-l-carboxylic acid:
HOOC^NHBoc
To a stirred solution of 1-aminocyclopropane-l-carboxylic acid (30 g, 149.25 mmol, 1.0 eq) in 1,4-dioxane (300 ml) at 0 °C was added 2N NaOH solution (300 ml) followed by (Boc)2O (48.80 gr, 223.88 mmol, 1.5 eq). The reaction mixture was allowed to stir at room température for ovemight. 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 HCl and then extracted with DCM (3x300 ml). The combined organic extracts were washed with water (300 ml), brine (100 ml) solution, dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was stirred with n-hexane (300 ml) at room température for about 30 minutes, the obtained solid was filtered and dried under vacuum to obtain the desired product (32.0 g, yield: 53.60%) as a white solid. ’H NMR (300 MHz, DMSO-dô): δ ppm 12.26 (brs, 1H), 7.40 (s, 1H), 1.36 (s, 9H), 1.25 (d, J= 12 Hz, 2H), 0.95-0.91 (d, J= 12 Hz, 2H); ESI-MS: m/z 226.43 (M+Na)+.
Step 2: Synthesis of (3aR,5aR,5bR,7aR,9S,llaR,llbR,13aS)-3a-(l-((tert-butoxycarbonyl) amino)cyclopropane-l-carboxamido)-l-isopropyl-5a,5b,8,8,lla-pentamethyl-2-oxo-3,3a,4,5, 5a, 5b, 6,7,7a,8,9,10,11,lia,11b,12,13,13a-octadecahydro-2H-cyclopenta[a] chrysen-9-yl acetate:
To a stirred solution of l-((tert-butoxycarbonyl)amino)cyclopropane-l-carboxylic acid (step 1,12.48 g, 62.08 mmol, 1.5 eq) in DMF (150 ml) at 0 °C under nitrogen atmosphère was added EDCI (15.90 g, 82.81 mmol, 2 eq), HOBT (8.38 g, 62.11 mmol, 1.5 eq), DMAP (2.52 g, 20.70 mmol, 0.5 eq), and added Triethylamine (17.28 ml, 124.22 mmol, 3 eq) and stirred it for about 30 minutes. Then added (3aR,5aR,5bR,7aR,9S,llaR,llbR,13aS) -3a-amino-lisopropyl-5a,5b,8,8,l la-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,l 1,11a, llb,12,13,13a-octadecahydro-2H-cyclopenta[a] chrysene-9-yl acetate (Intermediate 1-step 8, 20.0 g, 41.40 mmol, 1 eq) and the reaction mixture was stirred at room température for about 14 hours. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture was quenched with ice cold water then filtered through Buchner fiinnel then solid was separated, then that solid compound was dissolved in DCM and washed with sodium bicarbonate, water, brine solution then dried over sodium sulfate and concentrated under reduced pressure to give a crude compound. The crude compound was purified by flash silica column chromatography (100-200 silica gel) using 1.5% MeOH in DCM as an eluent to obtain the desired product (20.0 g, yield: 72.72%) as an off pale yellow colour solid. ’H NMR (300 MHz, DMSO-de): δ ppm 7.37-7.20 (m, 1H), 7.02-6.81 (m, 1H), 4.41-4.36 (m, 1H), 4.063.99 (m, 1H), 3.74-3.47 (m, 1H), 3.23-3.10 (m, 1H), 2.97-2.89 (m, 1H), 2.80-2.73 (m, 1H), 2.38-2.27 (m, 2H), 2.20-2.14 (m, 2H), 1.90 (m, 3H), 1.86-1.49 (m, 8H), 1.39-1.34 (m, 9H), 1.28-1.17 (m, 3H), 1.15-1.09 (m, 9H), 0.99-0.94 (m, 3H), 0.89-0.87 (m, 6H), 0.83-0.80 (s, 9H); ESI-MS: m/z 689.43 (M+Na)+.
Step 3: Synthesis of tert-butyl (l-(((3aR,5aR,5bR,7aR,9S,llaR,llbR,13aS)-9-hydroxy-lisopropyl-5a, 5b, 8,8,1 la-pentamethyl-2-oxo-2,3,4,5,5a, 5b, 6,7,7a,8,9,10,11,lia,11 b, 12,13, 13a-octadecahydro-3aH-cyclopenta[a]chrysen-3a-yl)carbamoyl)cyclopropyl)carbamate:
p
NH
NHBoc
To a stirred solution of (3aR,5aR,5bR,7aR,9S,llaR,llbR,13aS)-3a-(l-((tert-butoxy carbonyl)amino)cyclopropane-l-carboxamido)-l-isopropyl-5a,5b,8,8,lla-pentamethyl-2oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,l 1,1 la,l lb,12,13,13a-octadecahydro-2H-cyclopenta[a] chrysen-9-yl acetate (step 2,20 g, 30.03 mmol, 1.0 eq) în MeOH (200 ml), THF (100 ml) and water (50 ml) at 0 °C was added NaOH (12.01 g, 300.30 mmol, 10.0 eq). The mixture was removed from the ice bath and was stirred at room température for ovemight. 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 (180 ml) and extracted with DCM (3x180 ml). The combined organic extracts were washed with water (100 ml), brine solution (50 ml), dried over sodium sulfate, filtered and evaporated under reduced pressure. 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 (16.0 g, yield: 85.5%) as a white solid. ’H NMR (300 MHz, DMSO-de): δ ppm 8.32 (m, 1H), 7.20 (m, 1H), 4.32-4.31 (m, 1H), 3.72-3.67 (m, 1H), 3.12-2.75 (m, 3H), 2.38-2.09 (m, 4H), 1.85 (m, 4H), 1.65-1.23 (m, 19H), 1.13-1.08 (m, 10H), 0.95-0.83 (m, 13H), 0.66 (s, 3H); ESI-MS: m/z 647.43 (M+Na)+.
Step 4: Synthesis of 1-benzyl 3-((3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-3a-(l-((tert-butoxy carbonyl)amino)cyclopropane-l-carboxamido)-l-isopropyl-5a,5b,8,8,lla-pentamethyl-2oxo-3,3a, 4,5,5a, 5b, 6,7,7a,8,9,10,U,lla,Ub,12,l 3,13a-octadecahydro-2H-cycïopenta[a] chrysen-9-yl) (1 R, 3S)-2,2-dimethylcyclobutane-l, 3-dicarboxylate:
BnOOC’
NHBoc
To a stirred solution of (lS,3R)-3-((benzyloxy)carbonyl)-2,2-dimethylcyclobutane-lcarboxylic acid (prepared as described in WO 2011/007230 A2, 10.07 g, 38.46 mmol, 1.5 eq) in DMF (120 ml) at 0 °C under nitrogen atmosphère was added EDCI (9.84 g, 51.28 mmol, 2 eq), HOBT (5.19 g, 38.46 mmol, 1.5 eq), DMAP (1.56 g, 12.82 mmol, 0.5 eq) and added Triethylamine (10.70 ml, 76.92 mmol, 3 eq) and stirred it for about 30 minutes. Then added tert-butyl (l-(((3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-9-hydroxy-l-isopropyl-5a,5b,8,8,l lapentamethyl-2-oxo-2,3,4,5,5a,5b,6,7,7a,8,9,10,l 1,1 la,l lb,12,13,13a-octadecahydro-3aHcyclopenta[a]chrysen-3a-yl)carbamoyl)cyclopropyl)carbamate (step 3, 16.0 g, 25.64 mmol,l eq) and the reaction mixture was stirred at room température for about 14 hours. TLC indicated
starting material was consumed and the desired product was observed. The reaction mixture was quenching with ice cold water then filtered through Buchner funnel then solid was separated, then that solid compound was dissolved in DCM, washed with sodium bicarbonate, water and brine solution then dried over sodium sulfate and concentrated under reduced 5 pressure to give a crude compound. The crude compound was purified by flash silica column chromatography (100-200 silica gel) using 2% MeOH in DCM gradient. The fractions contaîning the product were combined and concentrated under reduced pressure to give the desired product (18.0 g, yield: 80.89%) as an off-white solid. 'H NMR (300 MHz, DMSO-dâ): δ ppm 7.36-7.34 (m, 5H), 7.32-7.20 (m, 2H), 5.14, 5.08 (ABq, Jab = 12.3 Hz, 2H), 4.35 (m, 10 1H), 3.74-3.69 (m, 2H), 3.12-2.84 (m, 5H), 2.38-2.14 (m, 4H), 1.96-1.90 (m, 3H), 1.73-1.1.58 (m, 8H), 1.39-1.36 (m, 14H), 1.13-1.09 (m, 14H), 0.89-0.81 (m, 16H); ESI-MS: m/z 891.32 (M+Na)+.
Step 5: Synthesis of l-((3aR,5aR,5bR,7aR,9S,llaR,llbR,13aS)-3a-(l-aminocyclopropane-lcarboxamido)-l-isopropyl-5a,5b,8,8,lla-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,ll, 15 lla,llb,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl) 3-benzyl (lS,3R)-2,2-di methylcyclobutane-l,3-dicarboxylate:
To a stirred solution of 1-benzyl 3-((3aR,5aR,5bR,7aR,9S,llaR,llbR,13aS)-3a-(l((tert-butoxycarbonyl)amino)cyclopropane-l-carboxamido)-l-isopropyl-5a,5b,8,8,llapentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11 a, 11 b, 12,13,13a-octadecahydro-2H20 cyclopenta[a]chrysen-9-yl) (lR,3S)-2,2-dimethylcyclobutane-l,3-dicarboxylate (step 4, 18 g, 20.73 mmol, 1.0 eq) in DCM (160 ml) was added trifluoroacetic acid (36 ml). The reaction mixture was stirred at room température for about 3 hours. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture was slowly poured in to cold sodium bicarbonate solution, pH adjusted to 8.0 then filtered through celite pad and the filtrate was extracted with DCM (3x200 ml). The combined organic layer was washed with water (200 ml), dried over sodium sulfate, and evaporated under reduced pressure to give the desired product (13.0 g, yield: 81.76%) as an off-white solid. *HNMR (300 MHz, DMSO-dâ): δ ppm 7.36-7.34 (m, 5H), 7.32-7.20 (m, 2H), 5.14, 5.08 (ABq, Jab = 12.3 Hz, 2H), 4.35 (m, 1H), 3.74-3.69 (m, 2H), 3.12-2.84 (m, 5H), 2.38-2.14 (m, 4H), 1.96-1.90 (m, 3H), 1.73-1.58 (m, 7H), 1.39-1.36 (m, 7H), 1.13-1.09 (m, 14H), 0.89-0.81 (m, 16H); ESI-MS: m/z 791.52 (M+Na)+.
Intermediate 4: Préparation of l-((3aR.5aR.5bR.7aR,9S,llaR.llbR,13aS)-3a-(l-aminocvclo propane-l-carboxamido)-l-isopropyl-5a,5b.8.8.11a-pentamethvl-2-oxo-3.3a,4.5.5a.5b.6.7.7a.
8,9,10,11,1 la,l lb.l2.13.13a-octadecahydro-2H-cvclopentaralchrvsen-9-vl) 3-benzyl il R, 3 S) -2,2-dimethylcyclobutane-l,3-dicarboxylate:
BnOOC
Step 1: Synthesis of 1-benzyl 3-((3aR,5aR,5bR,7aR,9S,llaR,llbR,13aS)-3a-(l-((tert-butoxy carbonyl)amino)cyclopropane-l-carboxamido)-l-isopropyl-5a,5b,8,8,lla-pentamethyl-2oxo-3,3a,4,5,5a,5 b, 6,7,7a,8,9,10,11,lia,11b, 12,13,13a-octadecahydro-2H-cyclopenta[a] chrysen-9-yl) (1 S, 3R)-2,2-dimethylcyclobutane-l, 3-dicarboxylate:
BnOOC
NHBoc
To a stirred solution of (lR,3S)-3-((benzyloxy)carbonyl)-2,2-dimethylcyclobutane-lcarboxylic acid (prepared as described in WO 2014/105926 Al, 10.11 g, 38.46 mmol, 1.5 eq) in DMF (120 ml) at 0 °C under nitrogen atmosphère was added EDCI (14.76 g, 76.92 mmol, 2 eq), HOBT (7.78 g, 57.66 mmol, 1.5 eq), DMAP (2.3 g, 19.22 mmol, 0.5 eq) and added Triethylamine (15.53 ml, 115.32 mmol, 3 eq) and stirred it for about 30 minutes. Then added tert-butyl (l-(((3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-9-hydroxy-l-isopropyl-5a,5b,8,8,l lapentamethyl-2-oxo-2,3,4,5,5a,5b,6,7,7a,8,9,10,l 1,1 la, 1 lb,12,13,13a-octadecahydro-3aHcyclopenta[a]chrysen-3a-yl)carbamoyl)cyclopropyl)carbamate (Intermediate 3-step 3, 16.0 g, 25.64 mmol, 1 eq). The reaction mixture was stirred at room température for about 14 hours. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture was quenched with ice cold water then filtered through Buchner tunnel then solid was separated, then that solid compound was dissolved in DCM and washed with sodium bicarbonate, water and brine solution then dried over sodium sulfate and concentrated under reduced pressure to give a crude compound. The crude compound was purified by flash silica column chromatography (100-200 silica gel) using 2% MeOH in DCM gradient. The fractions containing the product were combined and concentrated under reduced pressure to give the desired product (18.0 g, yield: 80.89%) as an off-white solid. *H NMR (300 MHz, DMSO-dô): δ ppm 8.32 (m, 1H), 7.20 (m, 1H), 4.32-4.31 (m, 1H), 3.72-3.67 (m, 1H), 3.12-2.75 (m, 3H),
2.38-2.09 (m, 4H), 1.85 (m, 4H), 1.65-1.23 (m, 19H), 1.13-1.08 (m, 10H), 0.95-0.83 (m, 13H),
0.66 (s, 3H); ESI-MS: m/z 647.43 (M+Na)+.
Step 2: Synthesis of l-((3aR,5aR,5bR,7aR,9S,llaR,llbR,13aS)-3a-(l-aminocyclopropane-lcarboxamido)-l-isopropyl-5a,5b,8,8,lla-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,ll, lia, 11b, 12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl) 3-benzyl (lR,3S)-2,2-di methylcyclobutane-l,3-dicarboxylate:
To a stirred solution of 1-benzyl 3-((3aR,5aR,5bR,7aR,9S,llaR,llbR,13aS)-3a-(l((tert-butoxycarbonyl)amino)cyclopropane-l-carboxamido)-l-isopropyl-5a,5b,8,8,lla-penta methyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,l 1,1 la,l lb,12,13,13a-octadecahydro-2H-cyclo penta[a]chrysen-9-yl) (lS,3R)-2,2-dimethylcyclobutane-l,3-dicarboxylate (step 1,18 g, 20.73 mmol, 1.0 eq) in DCM (160 ml) was added trifluoroacetic acid (36 ml). The reaction mixture was stirred at room température for about 3 hours. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture was slowly poured in to cold sodium bicarbonate solution, pH adjusted to 8.0 then filtered through celite pad, the fîltrate was extracted with DCM (3x200 ml). The combined organic layer was washed with water (200 ml), dried over sodium sulfate, and evaporated under reduced pressure give the desired product (13.0 g, yield: 81.76%) as an off-white solid. *H NMR (300 MHz, DMSO-dô): δ ppm 7.36-7.34 (m, 5H), 7.32-7.20 (m, 2H), 5.14, 5.08 (ABq, Jab = 12.3 Hz, 2H), 4.35 (m, 1H), 3.74-3.69 (m, 2H), 3.12-2.84 (m, 5H), 2.38-2.14 (m, 4H), 1.96-1.90 (m, 3H), 1.73-1.58 (m, 7H), 1.39-1.36 (m, 7H), 1.13-1.09 (m, 14H), 0.89-0.81 (m, 16H); ESI-MS: m/z 791.52 (M+Na)+.
Intermediate 5: Préparation of l-((3aR.5aR,5bR,7aR.9S.llaR.llbR.13aS)-3a-(l-aminocvclo butane-l-carboxamido)-l-isopropyl-5a.5b.8.8.11a-pentamethvl-2-oxo-3.3a.4.5.5a.5b.6.7.7a.
8.9.10.11.11 a, 11 b, 12.13.13a-octadecahvdro-2H-cyclopentaralchrvsen-9-vB 3-benzyl ( 1 S.3R) -2.2-dimethvlcvclobutane-l,3-dicarboxvlate:
BnOOC’
Step 1: Synthesis of l-((tert-butoxycarbonyl)amino)cyclobutane-l-carboxylic acid:
HOOCL· .NHBoc
To a stirred solution of 1-aminocyclobutane-l-carboxylic acid (30 g, 139.53 mmol, 1.0 eq) in 1,4-dioxane (300 ml) at 0 °C was added 2NNaOH solution (300 ml) followed by (BocjîO (45.62 g, 209.30 mmol, 1.5 eq). The reaction mixture was allowed to stir at room température for ovemight. 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 HCl and then extracted with DCM (3x300 ml). The combined organic extracts were washed with water (300 ml), brine (100 ml) solution, dried over NaîSCh, filtered and evaporated under reduced pressure. The residue was stirred with n-hexane (300 ml) at room température for about 30 minutes, the obtained solid was filtered and dried under vacuum to give the desired product (35.0 g, yield: 62.41%) as a white solid. lH NMR (300 MHz, DMSO-de): δ ppm 12.19 (brs, 1H), 7.70-7.16 (m, 1H), 2.45-2.36 (m, 2H), 2.12-2.03 (m, 2H), 1.86-1.78 (m, 2H), 1.36 (brs, 9H); ESI-MS: m/z 238.13 (M+Na)+.
Step 2: Synthesis of (3aR,5aR,5bR,7aR,9S,llaR,llbR,13aS)-3a-(l-((tert-butoxycarbonyl) amino)cyclobutane-l-carboxamido)-l-isopropyl-5a,5b,8,8,lla-pentamethyl-2-oxo-3,3a,4,5, 5a,5b, 6,7,7a, 8,9,10,11,1 la,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl acetate:
To a stirred solution of l-((tert-butoxycarbonyl)amino)cyclobutane-l-carboxylic acid (step 1,13.35 g, 62.11 mmol, 1.5 eq) in DMF (160 ml) at 0 °C under nitrogen atmosphère was added EDCI (15.90 g, 82.81 mmol, 2 eq), HOBT (8.38 g, 62.11 mmol, 1.5 eq), DMAP (2.52 g, 20.70 mmol, 0.5 eq), and added Triethylamine (17.28 ml 124.22 mmol, 3 eq) and stirred it for about 30 minutes. Then added (3aR,5aR,5bR,7aR,9S,llaR,llbR,13aS)-3a-amino-lisopropyl-5a,5b, 8,8,1 la-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,l 1,11 a, 1 lb, 12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl acetate (Intermediate 1-step 8,20.0 g, 41.40 mmol, 1 eq) and the reaction mixture was stirred at room température for about 14 hours. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture was quenched with ice cold water then filtered through Buchner fiinnel then solid was separated, then that solid compound was dissolved in DCM and washed with sodium bicarbonate, water and brine solution then dried over sodium sulfate and concentrated under reduced pressure to give a crude compound. The crude compound was purified by flash silica column chromatography (100-200 silica gel) usmg 2% MeOH m DCM gradient. The fractions containing the product were combined and concentrated under reduced pressure to give the desired product (22.0 g, yield: 78.15%) as an off-pale yellow solid. *H NMR (300 MHz, DMSO-de): δ ppm 7.37-7.20 (m, 1H), 7.02-6.81 (m, 1H), 4.40-4.35 (m, 1H), 4.06-3.98 (m, 1H), 3.73-3.49 (m, 1H), 3.25-3.14 (m, 1H), 2.97-2.90 (m, 1H), 2.82-2.74 (m, 1H), 2.45-2.36 (m, 2H), 2.31-2.26 (m, 2H), 2.16-2.10 (m, 2H), 1.92 (m, 3H), 1.86-1.43 (m, 8H), 1.38-1.33 (m, 9H), 1.27-1.18 (m, 3H), 1.15-1.11 (m, 9H), 0.99-0.95 (m, 3H), 0.90-0.86 (m, 6H), 0.84-0.81 (s, 9H); ESI-MS: m/z 703.43 (M+Na)+.
Step 3: Synthesis of tert-butyl (l-(((3aR,5aR,5bR,7aR,9S,llaR,llbR,13aS)-9-hydroxy-lisopropyl-5a, 5b, 8,8,1 la-pentamethyl-2-oxo-2,3,4,5,5a, 5b, 6,7,7a, 8,9,10,11,1 la,1 lb,12,13,13a -octadecahydro-3aH-cyclopenta[a]chrysen-3a-yl)carbamoyl)cyclobutyl)carbamate:
H<
To a stirred solution of (3aR,5aR,5bR,7aR,9S,llaR,llbR,13aS)-3a-(l-((tert-butoxy carbonyl)amino)cyclobutane-1 -carboxamido)-1 -isopropyl-5a,5b,8,8,11 a-pentamethyl-2-oxo3,3a,4,5,5a,5b,6,7,7a,8,9,10,l 1,11 a, 1 lb,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen9-yl acetate (step 2,22 g, 32.35 mmol, 1.0 eq) in MeOH (180 ml), THF (90 ml) and water (50 ml) at 0 °C was added NaOH (12.94 g, 323.52 mmol, 10.0 eq). The mixture was removed from the ice bath and was stirred at room température for ovemight. 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 (180 ml) and extracted with DCM (3x180 ml). The combined organic extracts were washed with water (100 ml), brine solution (50 ml), dried over sodium sulfate, filtered and evaporated under reduced pressure. 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 (18 g, yield: 87.20%) as a white solid. Ή NMR (300 MHz, DMSO-de): δ ppm 8.35 (m, 1H), 7.22 (m, 1H), 4.34-4.30 (m, 1H), 3.75-3.68 (m, 1H), 3.14-2.77 (m, 3H), 2.52-2.43 (m, 2H), 2.40-2.11 (m, 4H), 1.89 (m, 4H), 1.69-1.33 (m, 19H), 1.15-1.11 (m, 10H), 0.99-0.85 (m, 13H), 0.68 (s, 3H); ESI-MS: m/z 661.42 (M+Na)+.
Step 4: Synthesis of 1-benzyl 3-((3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-3a-(l-((tert-butoxy carbonyl)amino)cyclobutane-l-carboxamido)-l-isopropyl-5a,5b,8,8,lla-pentamethyl-2-oxo3,3 a, 4,5,5a, 5b, 6,7,7a, 8,9,10,11,1 la,11b, 12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen9-yl) (lR,3S)-2,2-dimethylcyclobutane-l,3-dicarboxylate:
To a stirred solution of (lS,3R)-3-((benzyloxy)carbonyl)-2,2-dimethylcyclobutane-lcarboxylic acid (prepared as described in WO 2011/007230 A2, 11.08 g, 42.31 mmol, 1.5 eq) in DMF (120 ml) at 0 °C under nitrogen atmosphère was added EDCI (16.25 g, 84.63 mmol, 2 eq), HOBT (5.71 g, 42.31 mmol, 1.5 eq), DMAP (1.72 g, 14.10 mmol, 0.5 eq), and added 10 triethylamine (11.77 ml, 84.63 mmol, 3 eq) and stirred it for about 30 minutes. Then added tert-butyl (l-(((3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-9-hydroxy-l-isopropyI-5a,5b,8,8,l lapentamethyl-2-oxo-2,3,4,5,5a,5b,6,7,7a,8,9,10,11,1 la,l lb, 12,13,13a-octadecahydro-3aHcyclopenta[a]chrysen-3a-yl)carbamoyl)cyclobutyl)carbamate (step 3, 18 g, 28.21 mmol,l eq). The reaction mixture was stirred at room température for about 14 hours. TLC indicated 15 starting material was consumed and the desired product was observed. The reaction mixture was quenched with îce cold water then filtered through Buchner fùnnel then solid was separated, then that solid compound was dissolved in DCM and washed with sodium bicarbonate, water and brine solution then dried over sodium sulfate and concentrated under reduced pressure to give a crude compound. The crude compound was purified by flash silica 20 column chromatography (100-200 silica gel) using 2% MeOH in DCM gradient. The fractions containing the product were combined and concentrated under reduced pressure to give the desired product (18 g, yield: 72.58%) as an off-white solid. *H NMR (300 MHz, DMSO-dô): δ ppm 7.37-7.35 (m, 5H), 7.31-7.22 (m, 2H), 5.15, 5.09 (ABq, Jab = 12.3 Hz, 2H), 4.34-4.30 (m, 1H), 3.77-3.70 (m, 2H), 3.14-2.87 (m, 5H), 2.47-2.38 (m, 2H), 2.32-2.16 (m, 4H), 1.9925 1.95 (m, 3H), 1.75-1.60 (m, 8H), 1.38-1.30 (m, 14H), 1.20-1.11 (m, 14H), 0.90-0.83 (m, 16H);
ESI-MS: m/z 905.43 (M+Na)+.
Step 5: Synthesis of l-((3aR,5aR,5bR,7aR,9S,llaR,llbR,13aS)-3a-(l-aminocyclobutane-lcarboxamido)-l-isopropyl-5a, 5b, 8,8,1 la-pentamethyl-2-oxo-3,3a, 4,5,5a, 5b, 6,7,7a, 8,9,10,11, lia,11b,12,13, 13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl) 3-benzyl (lS,3R)-2,2-di 30 methylcyclobutane-1,3-dicarboxylate:
To a stirred solution of 1-benzyl 3-((3aR,5aR,5bR,7aR,9S,llaR,llbR,13aS)-3a-(l((tert-butoxycarbonyl)amino)cyclobutane-l-carboxamido)-l-isopropyl-5a,5b,8,8,lla-penta methyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,l 1,11 a, 1 lb,12,13,13a-octadecahydro-2H-cyclo penta[a]chrysen-9-yl) (lR,3S)-2,2-dimethylcyclobutane-l,3-dicarboxylate (step 4,18 g, 22.95 mmol, 1.0 eq) in DCM (160 ml) was added trifluoroacetic acid (36 ml). The reaction mixture was stirred at room température for about 3 hours. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture was slowly poured in to cold sodium bicarbonate solution, pH adjusted to 8.0 then filtered through celite pad, the filtrate was extracted with DCM (3x200 ml). The combined organic layer was washed with water (200 ml), dried over sodium sulfate, and evaporated under reduced pressure to give the desired product (14 g, yield: 87.77%) as an off-white solid. ’H NMR (300 MHz, DMSO-dé): δ ppm 7.34-7.32 (m, 5H), 7.31-7.22 (m, 2H), 5.15,5.09 (ABq, Jab = 12.3 Hz, 2H), 4.34-4.32 (m, 1H), 3.77-3.70 (m, 2H), 3.14-2.85 (m, 5H), 2.46-2.41 (m, 2H), 2.38-2.14 (m, 4H), 1.97-1.91 (m, 3H), 1.74-1.60 (m, 7H), 1.40-1.38 (m, 7H), 1.14-1.11 (m, 14H), 0.89-0.83 (m, 16H); ESIMS: m/z 805.32 (M+Na)+.
Intermediate 6: Préparation of l-((3aR.5aR.5bR.7aR,9S.llaR.llbR.13aS)-3a-fl-aminocvclo pentane-l-carboxamido)-l-isopropvl-5a.5b.8.8.11a-pentamethvl-2-oxo-3,3a.4.5.5a.5b.6.7.7a. 8,9.10.11.1 la.l lb,12.13.13a-octadecahvdro-2H-cvclopentaralchrvsen-9-vD 3-benzvl (1S.3R) -2.2-dimethvlcvclobutane-1.3-dicarboxvlate:
BnOOC*^
Step 1: Synthesis of l-((tert-butoxycarbonyl)amino)cyclopentane-l-carboxyUc acid:
HOOCL^NHBoc
To a stirred solution of 1-aminocyclopentane-l-carboxylic acid (10 g, 77.51 mmol, 1.0 eq) in 1,4-dioxane (100 ml) at 0 °C was added 2N NaOH solution (100 ml) followed by (ΒοφΟ (25.34 g, 116.27 mmol, 1.5 eq). The reaction mixture was allowed to stir at room température for ovemight. 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 HCl and then extracted with DCM (3x300 ml). The combined organic extracts were washed with water (300 ml), brine (100 ml) solution, dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was stirred with n-hexane (300 ml) at room température for about 30 minutes, the obtained solid was filtered and dried under vacuum to obtain the desired product (10.0 g, yield: 56.33%) as a white solid. *H NMR (300 MHz, DMSO-d6): δ ppm 12.11 (s, 1H), 7.10-6.86 (m, 1H), 1.94-1.84 (m, 4H), 1.62-1.58 (m, 4H), 1.36 (s, 9H); ESI-MS: m/z 252.02 (M+Na)+.
Step 2: Synthesis of (3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-3a-(l-((tert-butoxycarbonyl) amino)cyclopentane-l-carboxamido)-l-isopropyl-5a, 5b, 8,8, lla-pentamethyl-2-oxo-3,3a, 4,5, 5a,5b, 6,7,7a,8,9,10,11,lia,11b, 12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl acetate:
To a stirred solution of l-((tert-butoxycarbonyl)amino)cyclopentane-l-carboxylic acid (step 1, 8.5 g, 37.11 mmol, 1.5 eq) in DMF (100 ml) at 0 °C under nitrogen atmosphère was added EDCI ( 9.54 g, 49.68 mmol, 2 eq), HOBT (5.03 g, 37.26 mmol, 1.5 eq), DMAP (1.51 g, 12.42 mmol, 0.5 eq), and added Triethylamine (10.36 ml 74.53 mmol, 3 eq) and stirred it for about 30 minutes. Then added (3aR,5aR,5bR,7aR,9S,llaR,llbR,13aS)-3a-amino-lisopropyl-5a,5b,8,8,l la-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,l 1,1 la, 11 b, 12,13, 13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl acetate (Intermediate 1-step 8, 12 g, 24.84 mmol,l eq). The reaction mixture was stirred at room température for about 14 hours. TLC indicated starting matériel was consumed and the desired product was observed. The reaction mixture was quenched with ice cold water then filtered through Buchner fùnnel then solid was separated, then that solid compound was dissolved in DCM and washed with sodium bicarbonate, water and brine solution then dried over sodium sulfate and concentrated under reduced pressure to give a crude compound. The crude compound was purified by flash silica column chromatography (100-200 silica gel) using 2% MeOH in DCM gradient. The fractions containing the product were combined and concentrated under reduced pressure to give the desired product (10 g, yield: 58.00%) as an off-white solid. ’H NMR (300 MHz, DMSO-de): δ ppm 7.10 (brs, 1H), 6.89 (brs, 1H), 4.42-4.36 (m, 1H), 3.74-3.66 (m, 1H), 3.12-3.08 (m, 2H), 2.83-2.79 (m, 1H), 2.35-2.26 (m, 2H), 2.11-1.81 (m, 11H), 1.56-1.47 (m, 9H), 1.35-1.23 (m, 13H), 1.14-1.07 (m, 11H), 0.90-0.80 (m, 10H), 0.76 (brs, 3H); ESI-MS: m/z 717.52 (M+Na)+.
Step 3: Synthesis of tert-butyl (l-(((3aR,5aR,5bR,7aR,9S,llaR,llbR,13aS)-9-hydroxy-lisopropyl-5a, 5b, 8,8,1 la-pentamethyl-2-oxo-2,3,4,5,5a,5b, 6,7,7a,8,9,10,11,lia,11 b, 12,13, 13a-octadecahydrù-3aH-cyclopenta[a]chrysen-3a-yl)carbamoyl)cyclopentyl)carbamate:
To a stirred solution of (3aR,5aR,5bR,7aR,9S,llaR,llbR,13aS)-3a-(l-((tert-butoxy carbonyl)amino)cyclopentane-l-carboxamido)-l-isopropyl-5a,5b,8,8,lla-pentamethyl-2-oxo3,3a,4,5,5a,5b,6,7,7a,8,9,10,l 1,1 la,l lb,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen9-yl acetate (step 2, 10 g, 14.40 mmol, 1.0 eq) in MeOH (60 ml), THF (30 ml) and water (15 ml) at 0 °C was added NaOH (5.76 g, 144.0 mmol, 10.0 eq). The mixture was removed from the ice bath and was stirred at room température for ovemight. 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 (180 ml) and extracted with DCM (3x180 ml). The combined organic extracts were washed with water (100 ml), brine solution (50 ml), dried over sodium sulfate, filtered and evaporated under reduced pressure. 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 (7 g, yield: 75.26%) as a white solid. ’HNMR(300MHz, DMSO-de): δ ppm 7.09(brs, 1H), 6.89 (brs, 1H), 4.31-4.29 (m, 1H), 3.17-3.15 (m, 1H), 3.11-2.98 (m, 2H), 2.82-2.79 (m, 1H), 2.35-2.27 (m, 2H), 2.11-1.81 (m, 9H), 1.57-1.47 (m, 9H), 1.35-1.23 (m, 12H), 1.19-1.06 (m, 11H), 0.94-0.82 (m, 11H), 0.66 (brs, 3H); ESI-MS: m/z 675.72 (M+Na)+.
Step 4: Synthesis of 1-benzyl 3-((3aR,5aR,5bR,7aR,9S,llaR,llbR,l3aS)-3a-(l-((tert-butoxy carbonyl)amino)cyclopentane-l-carboxamido)-l-isopropyl-5a,5b,8,8,lla-pentamethyl-2oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,ll,lla,llb,12,13,13a-octadecahydro-2H-cyclopenta[a] chrysen-9-yl) (lR,3S)-2,2-dimethylcyclobutane-l,3-dicarboxylate:
To a stirred solution of (1 S,3R)-3-((benzyloxy)carbonyl)-2,2-dimethyl cyclobutane-1carboxylic acid (prepared as described in WO 2011/007230 A2,4.2 g, 16.03 mmol, 1.5 eq) in DMF (60 ml) at 0 °C under nitrogen atmosphère was added EDCI (4.12 g, 21.47 mmol, 2 eq), HOBT (2.17 g, 16.10 mmol, 1.5 eq), DMAP (0.65 g, 5.36 mmol, 0.5 eq), and added 5 Triethylamine (4.48 ml 32.20 mmol, 3 eq) and stirred it for about 30 minutes. Then added tertbutyl (l-(((3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-9-hydroxy-l-isopropyl-5a,5b,8,8,l lapentamethyl-2-oxo-2,3,4,5,5a,5b,6,7,7a,8,9,10,l 1,1 la, 1 lb,12,13,13a-octadecahydro-3aHcyclopenta[a]chrysen-3a-yl)carbamoyl)cyclopentyl)carbamate (step 3,7 g, 10.73 mmol, 1 eq). The réaction mixture was stirred at room température for about 14 hours. TLC indicated 10 starting material was consumed and the desired product was observed. The reaction mixture was quenched with ice cold water then filtered through Buchner funnel then solid was separated, then that solid compound was dissolved in DCM and washed with sodium bicarbonate, water and brine solution then dried over sodium sulfate and concentrated under reduced pressure to give a crude compound. The crude compound was purified by flash silica 15 column chromatography (100-200 silica gel) using 2% MeOH in DCM gradient. The fractions containing the product were combined and concentrated under reduced pressure to give the desired product (6 g, yield: 62.41%) as an off-white solid. ’H NMR (300 MHz, DMSO-dô): δ ppm 7.37-7.32 (m, 5H), 7.10 (s, 1H), 6.89 (s, 1H), 5.14, 5.08 (ABq, Jab = 12.3 Hz, 2H), 4.384.32 (m, 1H), 3.61-3.59 (m, 1H), 3.12-3.07 (m, 1H), 2.97-2.80 (m, 3H), 2.38-2.31 (m, 4H), 20 2.22-1.88 (m, 6H), 1.81-1.77 (m, 5H), 1.69-1.57 (m, 8H), 1.35 (m, 10H), 1.26-1.23 (m, 7H),
1.14-1.03 (m, 11H), 0.89-0.78 (m, 14H); ESI-MS: m/z 919.45 (M+Na)+.
Step 5: Synthesis of l-((3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-3a-(l-aminocyclopentane-lcarboxamido)-l-isopropyl-5a, 5 b, 8,8,1 la-pentamethyl-2-oxo-3,3a, 4,5,5a, 5 b, 6,7,7a, 8,9,10,11, lia,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl) 3-benzyl (IS,3R)-2,2-di 25 methylcyclobutane-1,3-dicarboxylate:
To a stirred solution of 1-benzyl 3-((3aR,5aR,5bR,7aR,9S,llaR,llbR,13aS)-3a-(l((tert-butoxycarbonyl)amino)cyclopentane-l -carboxamido)-l -isopropyl-5a,5b,8,8,11 apentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,l 1,1 la,l lb,12,13,13a-octadecahydro-2Hcyclopenta[a]chrysen-9-yl) (lR,3S)-2,2-dimethylcyclobutane-l,3-dicarboxylate (step 4, 6.0 g, 30 6.69 mmol, 1.0 eq) in DCM (60 ml) was added trifluoroacetic acid (12 ml). The reaction mixture was stirred at room température for about 3 hours. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture was slowly poured in to cold sodium bicarbonate solution, pH adjusted to 8.0 then filtered through celite pad and the filtrate was extracted with DCM (3x200 ml). The combined organic layer was washed with water (200 ml), dried over sodium sulfate, and evaporated under reduced pressure to give the desired product (4.0 g, yield: 75.47%) as an off-white solid. *H NMR (300 MHz, DMSO-dô): δ ppm 7.36-7.35 (m, 5H), 7.10 (s, 1H), 5.14, 5.08 (ABq, Jab = 12.3 Hz, 2H), 4.38-4.32 (m, 1H), 3.61-3.59 (m, 1H), 3.12-3.07 (m, 1H), 2.97-2.80 (m, 3H), 2.38-2.31 (m, 4H), 2.22-1.88 (m, 6H), 1.81-1.77 (m, 5H), 1.69-1.35 (m, 11H), 1.26-1.23 (m, 7H), 1.14-1.03 (m, 11H), 0.890.78 (m, 14H); ESI-MS: m/z 819.32 (M+Na)+.
Intermediate 7: Préparation of l-(i3aR.5aR.5bR.7aR.9S.llaR.llbR.13aS’)-3a-(l-aminocvclo hexane-l-carboxamido')-l-isopropvl-5a.5b.8.8.11a-pentamethvl-2-oxo-3.3a.4.5.5a.5b.6.7.7a.
8.9.10.11.1 la,l lb.l2.13.13a-octadecahydro-2H-cvcloDentaralchrvsen-9-vl) 3-benzvl (1S.3R) -2.2-dimethvlcvclobutane-1.3-dicarboxvlate:
BnOOC*
Step 1: Synthesis of l-((tert-butoxycarbonyl)amino)cycïohexane-l-carboxylic acid:
HOOC^NHBoc
To a stirred solution of 1-aminocyclohexane-l-carboxylic acid (10 g, 69.93 mmol, 1.0 eq) in 1,4-dioxane (300 ml) at 0 °C was added 2NNaOH solution (100 ml) followed by (Boc)2O (22.86 g, 104.89 mmol, 1.5 eq). The reaction mixture was allowed to stir at room température for ovemight. 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 HCl and then extracted with DCM (3x300 ml). The combined organic extracts were washed with water (300 ml), brine (100 ml) solution, dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was stirred with n-hexane (300 ml) at room température for about 30 minutes, the obtained solid was filtered and dried under vacuum to afford the desired product (11.0 g, yield: 64.74%) as a white solid. ’H NMR (300 MHz, DMSO-dô): δ ppm 12.08 (s, 1H), 6.88 (s, 1H),
1.92-1.88 (m,2H), 1.62-1.56 (m,2H), 1.45-1.43 (m,4H), 1.36 (s, 9H), 1.25-1.19 (m,2H); ESIMS: m/z 266.32 (M+Na)+.
Step 2: Synthesis of (3aR,5aR,5bR,7aR,9S,llaR,llbR,13aS)-3a-(l-((tert-butoxycarbonyl) amino)cyclohexane-l-carboxamido)-l-isopropyl-5a,5b,8,8,lla-pentamethyl-2-oxo-3,3a,4,5,
5a, 5b, 6,7,7a,8,9,10,11,1 la,1 lb,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl acetate:
To a stirred solution of l-((tert-butoxycarbonyl)amino)cyclohexane-l-carboxylic acid (step 1, 9.05 g, 37.26 mmol, 1.5 eq) in DMF (120 ml) at 0 °C under nitrogen atmosphère was added HBTU (18.83 g, 49.68 mmol, 2 eq), DMAP (1.51 g, 12.42 mmol, 0.5eq), and added Dîîsopropylethylamine (12.81 ml, 74.53 mmol, 3 eq) and stirred it for about 10 minutes. Then added (3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-3a-amino-l-isopropyl-5a,5b,8,8,l lapentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,l 1,1 la, 1 lb,12,13,13a-octadecahydro-2H10 cyclopenta[a]chrysen-9-yl acetate (Intermediate 1-step 8,12 g, 24.84 mmol, 1 eq). The réaction mixture was stirred at room température for about 14 hours. TLC indicated starting material was consumed and the desired product was observed. The réaction mixture was evaporated under reduced pressure, the réaction mixture was diluted with water (200 ml), and extracted with DCM (3x200 ml). The combined organic extracts were washed with water (300 ml), sodium bicarbonate, and brine solution, then dried over sodium sulfate, filtered and concentrated under reduced pressure to give a crude compound, The crude compound was purified by flash silica column chromatography (100-200 silica gel) using 2% MeOH in DCM as an eluent. The fractions containing the product were combined and concentrated under reduced pressure to give the desired product (12 g, yield: 68.22%) as an off-white solid. ’H
NMR (300 MHz, DMSO-de): δ ppm 7.04 (brs, 1H), 6.53 (brs, 1H), 4.41-4.37 (m, 1H), 3.693.58 (m, 1H), 3.12-3.07 (m, 1H), 2.89-2.82 (m, 1H), 2.73-2.68 (m, 2H), 2.37-2.27 (m, 3H), 2.11-2.05 (m, 2H), 2.02-1.95 (m, 3H), 1.88-1.80 (m, 3H), 1.74-1.71 (m, 6H), 1.60-1.55 (m, 3H), 1.47 (s, 8H), 1.42-1.41 (m, 7H), 1.35-1.23 (m, 3H), 1.39-1.11 (m, 10H), 1.09-1.07 (m, 7H), 1.04-0.80 (m, 5H); ESI-MS: m/z 731.44 (M+Na)+.
Step 3: Synthesis of tert-butyl (l-(((3aR,5aR,5bR,7aR,9S,llaR,llbR,13aS)-9-hydroxy-lisopropyl-5a,5b, 8,8,1 la-pentamethyl-2-oxo-2,3,4,5,5a, 5b, 6,7,7a,8,9,10,11,1 la,11 b, 12,13,13a -octadecahydro-3aH-cyclopenta[a]chrysen-3a-yl)carbamoyl)cyclohexyl)carbamate:
To a stirred solution of (3aR,5aR,5bR,7aR,9S,llaR,llbR,13aS)-3a-(l-((tert-butoxy carbonyl)amino)cyclohexane-1 -carboxamido)-1 -isopropyl-5a,5b,8,8,11 a-pentamethyl-2-oxo3,3a,4,5,5a,5b,6,7,7a,8,9,10,l 1,1 la,l lb,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen9-yl acetate (step 2,12 g, 16.94 mmol, 1.0 eq) in MeOH (120 ml), THF (60 ml) and water (30 ml) at 0 °C was added NaOH (6.77 g, 169.4 mmol, 10.0 eq). The mixture was removed from the ice bath and was stirred at room température for ovemight. 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 (180 ml) and extracted with DCM (3x180 ml). The combined organic extracts were washed with water (100 ml), brine solution (50 ml), dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by silicagel column chromatography by using 0-3% methanol in dichloromethane gradient. The fractions containîng the product were combined and concentrated under reduced pressure to give the desired product (9 g, yield: 79.78%) as a white solid. ’H NMR (300 MHz, DMSO-d6): δ ppm 7.04 (s, 1H), 6.53 (s, 1H), 4.31-4.30 (m, 1H), 3.11-2.99 (m, 3H), 2.86-2.82 (m, 1H), 2.32-2.28 (m, 2H), 2.11 (m, 1H), 1.89-1.85 (m, 4H), 1.65-1.56 (m, 5H), 1.45 (brs, 9H), 1.35-1.28 (brs, 12H), 1.13-0.99 (m, 14H), 0.94-0.82 (m, 9H), 0.66 (s, 3H); ESI-MS: m/z 689.50 (M+Na)+.
Step 4: Synthesis of 1-benzyl 3-((3aR,5aR,5bR,7aR,9S,llaR,llbR,13aS)-3a-(l-((tert-butoxy carbonyl)amino)cyclohexane-l-carboxamido)-l-isopropyl-5a,5b,8,8,l la-pentamethyl-2-oxo3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,1 la,l lb,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen9-yl) (lR,3S)-2,2-dimethylcyclobutane-l,3-dicarboxylate:
To a stirred solution of (lS,3R)-3-((benzyloxy)carbonyl)-2,2-dimethylcyclobutane-lcarboxylic acid (prepared as described in WO 2011/007230 A2,5.31 g, 20.27 mmol, 1.5 eq) in DMF (100 ml) at 0 °C under nitrogen atmosphère was added EDCI (5.18 g, 27.02 mmol, 2 eq), HOBT (2.73 g, 20.27 mmol, 1.5 eq), DMAP (0.82 g, 6.75 mmol, 0.5 eq), and added
Triethylamine (5.63 ml, 40.54 mmol, 3 eq) and stirred it for about 30 minutes. Then added tertbutyl (l-(((3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-9-hydroxy-l-isopropyl-5a,5b,8,8,l lapentamethyl-2-oxo-2,3,4,5,5a,5b,6,7,7a,8,9,10,l 1,1 la,l lb,12,13,13a-octadecahydro-3aHcyclopenta[a]chrysen-3a-yl)carbamoyl)cyclohexyl)carbamate (step 3, 9.0 g, 13.51 mmol, 1 eq). The reaction mixture was stirred at room température for about 14 hours. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture was quenched with ice cold water then filtered through Buchner funnel then solid was separated, then that solid compound was dissolved in DCM and washed with sodium bicarbonate, water and brine solution then dried over sodium sulfate and concentrated under 10 reduced pressure to give a crude compound. The crude compound was purified by flash silica column chromatography (100-200 silica gel) using 2% MeOH in DCM as an eluent. The fractions containing the product were combined and concentrated under reduced pressure to give the desired product (8 g, yield: 65.09%) as an off-white solid. ’H NMR (300 MHz, DMSOd6): δ ppm 8.13 (s, 1H), 7.36-7.35 (m, 5H), 7.34 (s, 1H), 5.14,5.08 (ABq, Jab = 12.3 Hz, 2H), 15 4.38-4.32 (m, 1H), 3.13-3.09 (m, 1H), 3.00-2.67 (m, 4H), 2.38-2.25 (m, 5H), 1.96-1.90 (m,
5H), 1.69-1.40 (m, 21H), 1.36 (brs, 9H), 1.15-1.03 (m, 14H), 0.92-0.81 (m, 13H); ESI-MS: m/z 933.63 (M+Na)+.
Step 5: Synthesis of l-((3aR,5aR,5bR,7aR,9S,llaR,llbR,13aS)-3a-(l-aminocyclohexane-lcarboxamido)-l -isopropyl-5a, 5b,8,8,11 a-pentamethyl-2-oxo-3,3a, 4,5,5a, 5b, 6,7,7a, 8,9,10,11, 20 lla,llb,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl) 3-benzyl (lS,3R)-2,2dimethylcyclobutane-l,3-dicarboxylate:
To a stirred solution of 1-benzyl 3-((3aR,5aR,5bR,7aR,9S,llaR,llbR,13aS)-3a-(l((tert-butoxycarbonyl)amino)cyclohexane-l-carboxamido)-l-isopropyl-5a,5b,8,8,lla-penta methyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11 a, 11 b, 12,13,13a-octadecahydro-2H-cyclo penta[a]chrysen-9-yl) (lR,3S)-2,2-dimethylcyclobutane-l,3-dicarboxylate (step 4, 8.0 g, 8.79 mmol, 1.0 eq) in DCM (80 ml) was added trifluoroacetic acid (16 ml). The reaction mixture was stirred at room température for about 3 hours. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture was slowly poured in to cold sodium bicarbonate solution, pH adjusted to 8.0 then filtered through celite pad, the 30 filtrate was extracted with DCM (3x200 ml). The combined organic layer was washed with water (200 ml), dried over sodium sulfate, and evaporated under reduced pressure to give the desired product (6.0 g, yield: 84.26%) as an off-white solid. ’H NMR (300 MHz, DMSO-dô): δ ppm 8.13 (s, 1H), 7.36-7.35 (m, 5H), 5.14, 5.08 (ABq, Jab = 12.3 Hz, 2H), 4.38-4.32 (m,
1H), 3.13-3.09 (m, 1H), 3.00-2.67 (m, 4H), 2.38-2.25 (m, 5H), 1.96-1.90 (m, 5H), 1.69-1.23 (m, 23H), 1.15-1.03 (m, 14H), 0.92-0.81 (m, 13H); ESI-MS: m/z 833.55 (M+Na)+. Intermediate 8: Préparation of l-(4-chlorophenvl)cvclopropane-l-carboxvlic acid:
Step 1: Synthesis of l-(4-chlorophenyl)cyclopropane-l-carbonitrile:
A suspension of 55% sodium hydride (25.27 g, 1052.9 mmol, 5.3 eq) and THF (200 ml) under nitrogen atmosphère was heated to 40 °C and a solution of 2-(4-chlorophenyl) acetonitrile (30.0 g, 198.67 mmol, 1.0 eq) in THF (50 ml) was added dropwise over about 30 minutes. The mixture was stirred at 40 °C for about 30 minutes and a solution of 1,2dibromoethane (74.3 g, 397.35 mmol, 2.0 eq) in THF (50 ml) was added dropwise over about 30 minutes. The reaction mixture was stirred at 40 °C for about 1 hour. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture was cooled to 0 °C, quenched with ice water (250 ml) and extracted with ethyl acetate (3x400 ml). The combined organic extracts were washed with brine solution (400 ml), dried over sodium sulfate, filtered and evaporated under reduced pressure to obtain the desired product (30.0 g) as a semi solid, which is used as such for next step without further purification. *H NMR (300 MHz, CDCh): δ ppm 7.33 (d, J= 8.7 Hz, 2H), 7.24 (d, J= 8.7 Hz, 2H), 1.78-1.71 (m, 2H), 1.42-1.35 (m, 2H).
Step 2: Synthesis of l-(4-chlorophenyl)cyclopropane-l-carboxylic acid:
ci
COOH
A stirred solution of l-(4-chlorophenyl)cyclopropane-l-carbonitrile (step 1, 30.0 g, 169.49 mmol, 1.0 eq), sodium hydroxide (20.3 g, 508.47 mmol, 3.0 eq), diethylene glycol (120 ml) and water (35.4 ml) was refluxed for about 18 hours. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture was poured into water (1800 ml) and acidified to pH 4.0 with concentrated HCl (54 ml). The generated crystals were collected by filtration and dried under vacuum to obtain the desired product (30.0 g, yield: 90.3%) as a pale-brown color solid. ’H NMR (300 MHz, DMSO-dô); δ ppm 12.40 (brs, 1H), 7.34 (m, 4H), 1.48-1.42 (m, 2H), 1.16-1.10 (m, 2H).
Intermediate 9: Préparation of 2,2,2-trifluoroacetate sait of 2-(4-ethylpiperazin-l-yl)acetic
acid: | /~\ /—N N—\ HOOC '—' ' CF3COOH |
Step 1: Synthesis of tert-butyl 2-(4-ethylpiperazin-l-yl)acetate:
To a stirred solution of 1-ethylpiperazine (5.0 g, 43.78 mmol, 1.0 eq) in DCM (100 ml) at 0 °C was added EtîN (30.4 ml, 218.93 mmol, 5.0 eq) followed by tert-butyl 2-chloroacetate (9.41 ml, 65.68 mmol, 1.5 eq). The reaction mixture was stirred at room température for ovemight. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture was diluted with water (150 ml) and extracted with DCM (3x150 ml). The combined organic extracts were washed with water (100 ml), brine solution (50 ml), dried over Na2SO4, filtered and evaporated under reduced pressure to obtain the desired product (9.0 g, yield: 90.09%) as a solid, which is used as such for next step without further purification. ESI-MS: m/z 229.09 (M+H)+.
Step 2: Synthesis of 2,2,2-trifluoroacetate sait of2-(4-ethylpiperazin-l-yl)acetic acid:
To a stirred solution of tert-butyl 2-(4-ethylpiperazin-l-yl) acetate (step 1,9.0 g, 39.414 mmol, 1.0 eq) in DCM (72 ml) at 0 °C was added TFA (18 ml). The reaction mixture was allowed to stir at room température for ovemight. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture was evaporated under reduced pressure to obtain the desired product (11.2 g) as a solid, which is used as such for next step without further purification. ESI-MS: m/z 173.18 (M-TFA+H)+.
Intermediate 10: Préparation of l-fcarboxvmethvDpiperidin-l-ium 2,2,2-trifluoroacetate:
CF3COO- /_ )
HOOC H '—'
Step 1: Synthesis of tert-butyl 2-(piperidin-l-yl)acetate:
To a stirred solution of piperidine (5.0 g, 58.71 mmol, 1.0 eq) in DCM (75 ml) at 0 °C was added triethylamine (29.7 g, 293.55 mmol, 5.0 eq) followed by tert-butyl 2-chloroacetate (12.62 ml, 88.07 mmol, 1.5 eq). The reaction mixture was stirred at room température for ovemight. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture was diluted with water (200 ml) and extracted with DCM (3x100 ml). The combined organic extracts were washed with water (100 ml), brine solution (50 ml), dried over NazSCh, filtered and concentrated under reduced pressure to obtain the desired product (10.0 g, yield: 85.47%) as a solid, which is used as such for next step without further purification.
Step 2: Synthesis of l-(carboxymethyl)piperidin-l-ium 2,2,2-trifluoroacetate:
To a stirred solution oftert-butyl 2-(piperidin-l-yl)acetate (step 1,10.0 g, 50.17 mmol, 1.0 eq) in DCM (80 ml) at 0 °C was added trifluoroacetic acid (20 ml). The reaction mixture was allowed to stir at room température for ovemight. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture was evaporated under reduced pressure to obtain the desired product (12.9 g) as a solid, which is used as such for next step without further purification. ESI-MS: m/z 144.03 (M-TFA+H)+.
Intermediate 11: Préparation of 2-(6-methylpyridin-3-vl')-lH-benzordlimidazole-5-carboxvlic acid:
Step 1: Synthesis of methyl 2-(6-methylpyridin-3-yl)-lH-benzo[d]imidazole-5-carboxylate:
To a stirred solution of 6-methylnicotinic acid (1.23 g, 9.026 mmol, 1.5 eq) in DMF (10 ml) was added HBTU (3.47 g, 9.026 mmol, 1.5 eq), DIPEA (4.12 ml, 24.070 mmol, 4.0 eq) followed by methyl 3,4-diaminobenzoate (1.0 g, 6.017 mmol, 1.0 eq). The reaction mixture was stirred at room température for about 5 hours. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture was diluted with water (50 ml) and extracted with Ethyl acetate (2x100 ml). The combined organic extracts were dried over Na2SÜ4, filtered and evaporated under reduced pressure. The residue was mixed with acetic acid (5 ml) and heated at 60 °C for ovemight. Acetic acid was removed under reduced pressure and the residue was treated with 10 ml of 5N sodium hydroxide solution. The resulting solid was filtered and was washed with water and dried under vacuum to obtain the desired product (0.804 g, yield: 50%) as an off-white solid. *H NMR (300 MHz, DMSO-dô): δ ppm 13.4 (brs, 1H), 9.24 (d, J= 1.5 Hz, 1H), 8.41 (dd, J= 8.1,2.1 Hz, 1H), 8.21 (brs, 1H), 7.87 (dd, J= 8.4, 1.2 Hz, 1H), 7.71 (d, J= 8.4 Hz, 1H), 7.48 (d, J= 8.1 Hz,, 1H), 3.88 (s, 3H), 2.56 (s, 3H); ESI-MS: m/z 267.93 (M+H)+.
Step 2: Synthesis of2-(6-methylpyridin-3-yl)-lH-benzo[d]imidazole-5-carboxylic acid:
To a stirred solution of methyl 2-(6-methylpyridin-3-yl)-lH-benzo[d]imidazole-5carboxylate (step 1, 0.8 g, 2.993 mmol, 1.0 eq) in MeOH (8 ml) and THF (8 ml) was added aqueous 2.5N KOH solution (8.98 ml, 22.447 mmol, 7.5 eq). The reaction mixture was stirred at room température for ovemight. TLC indicated starting material was consumed and the desired product was observed. The organic phase was evaporated under reduced pressure and diluted with water (15 ml), cooled to 0 °C, pH adjusted to 6.0 with IN HCl and extracted with 20% MeOH: DCM (4x50 ml). The combined organic extracts were washed with water (2x50 ml), dried over sodium sulfate, filtered and evaporated under reduced pressure to obtain to obtain the desired product (0.5 g, yield: 65.9%) as an off white solid. ’H NMR (300 MHz, DMSO-de): δ ppm 13.38 (brs, 1H), 12.78 (brs, 1H), 9.24 (d, J= 1.5 Hz, 1H), 8.41 (dd, J= 8.1, 1.8 Hz, 1H), 8.25 (brs, 1H), 7.85 (m, 1H), 7.78-7.60 (m, 1H), 7.48 (d, J= 8.1 Hz, 1H), 2.56 (s, 3H); ESI-MS: m/z 253.85 (M+H)+.
Intermediate 12: Préparation of2-(pvrazin-2-vT)-lH-benzordlimidazole-5-carboxylic acid:
o
Step 1: Synthesis of methyl 2-(pyrazin-2-yl)-lH-benzo[d]îmidazole-5-carboxylate:
o
To a stirred solution of pyrazine-2-carboxylic acid (1.120 g, 9.026 mmol, 1.5 eq) in DMF (10 ml) was added HBTU (3.42 g, 9.026 mmol, 1.5 eq) followed by DIPEA (4.12 ml, 24.07 mmol, 4.0 eq). The reaction mixture was stirred at room température for about 30 minutes, then methyl 3,4-diaminobenzoate (1.0 g, 6.017 mmol, 1.0 eq) was added and stirred at room température for ovemight. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture was diluted with ice cooled water (50 ml) and stirred at room température for about 15 minutes. The précipitâtes formed were collected by filtration, washed with water (50 ml) and dried under vacuum to obtain the solid. The resulting solid was purified by silicagel column chromatography by using 0-7% methanol in dichloromethane gradient. The fractions containing the expected product were combined and concentrated under reduced pressure to obtain the desired product (0.400 g, yield: 26.3%) as an off-white solid. Ή NMR (300 MHz, DMSO-de): δ ppm 9.52 (d, J= 1.2 Hz, 1H), 8.78-8.69 (m,2H), 8.25(d,J=0.9Hz, 1H), 7.79(dd, J= 8.7,1.2Hz, 1H), 7.67(d, J=8.4Hz, 1H), 3.87 (s, 3H); ESI-MS: m/z 254.99 (M+H)+.
Step 2: Synthesis of2-(pyrazin-2-yl)-lH-benzo[d]imidazole-5-carboxylic acid:
To a stirred solution of methyl 2-(pyrazin-2-yl)-lH-benzo[d]imidazole-5-carboxylate (step 1, 0.400 g, 1.573 mmol, 1.0 eq) in MeOH (4 ml) and THF (4 ml) was added aqueous 2.5N KOH solution (4.71 ml, 11.79 mmol, 7.5 eq). The reaction mixture was stirred at room température for ovemight. TLC indicated starting material was consumed and the desired product was observed. The organic phase was evaporated under reduced pressure, diluted with water (5 ml), cooled to 0 °C, pH adjusted to 6.0 with IN HCl and extracted with 20% methanol in dichloromethane (4x50 ml). The combined organic extracts were washed with water (2x50 ml), dried over sodium sulfate, filtered and evaporated under reduced pressure to obtain the desired product (0.373 g, yield: 98%) as an off white solid. ’H NMR (300 MHz, DMSO-dô): δ ppm 13.68 (brs, 1H), 12.72 (brs, 1H), 9.53 (d, J= 1.2 Hz, 1H), 8.88-8.80 (m, 2H), 8.33-8.20 (m, 1H), 7.79-7.60 (m, 2H).
Intermediate 13: Préparation of 4-(4-methvl-lH-imidazol-l-vl)benzoic acid:
o
Step 1: Synthesis of methyl 4-(4-methyl-lH-imidazol-l-yl)benzoate:
o
To a stirred solution of methyl 4-bromobenzoate (8.0 g, 37.20 mmol, 1.0 eq) in DMF (150 ml) was added CS2CO3 (24.24 g, 74.4 mmol, 2.0 eq) and 4-methyl-lJ/-imidazole (4.58 g, 55.8 mmol, 1.5 eq). The reaction mixture was bubbled through nitrogen for about 20 minutes, then Cul (3.542 g, 18.6 mmol, 0.5 eq) was added and the mixture was again bubbled through nitrogen for about 40 minutes. The reaction mixture was heated at 100 °C for about 72 hours. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture was allowed cool to room température and filtered through celite. The filtrate was evaporated under reduced pressure and the residue was purified by silicagel column chromatography by using 40% EtOAc in hexane eluent. The fractions containing the expected product were combined and concentrated under reduced pressure to obtain the desired product (2.413 g, yield: 30%) as an off-white solid. ’H NMR (300 MHz, CDCI3): δ ppm 8.14 (d, J= 8.7 Hz, 2H), 7.85 (s, 1H), 7.44 (d, J= 8.7 Hz, 2H), 7.07 (s, 1H), 3.94 (s, 3H), 2.30 (s, 3H); ESIMS: m/z 217.09 (M+H)+.
Step 2: Synthesis of 4-(4-methyl-lH-imidazol-l-yl)benzoic acid:
To a stirred solution of methyl 4-(4-methyl-lJ7-imidazol-l-yl)benzoate (step 1, 2.0 g, 9.248 mmol, 1.0 eq) in methanol (20 ml) was added IN NaOH (75 ml, 73.99 mmol, 8.0 eq). The reaction mixture was stirred at room température for ovemight. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture was cooled to 0 °C, pH adjusted to 7.0 with IN HCl and evaporated under reduced pressure to afford the desired product (1.5 g, yield: 80.2%) as a white solid. *H NMR (300 MHz, CDCh): δ ppm 9.50 (d, J= 1.5 Hz, 1H), 8.27 (d, J= 8.7 Hz, 2H), 7.90 (s, 1H), 7.84 (d, J= 8.7 Hz, 2H), 2.47 (s, 3H); ESI-MS: m/z 203.12 (M+H)+.
Intermediate 14: Préparation of 2-aminothiazole-4-carboxylic acid:
r-s ho^An>-nh2 o
To a stirred solution of ethyl 2-aminothiazole-4-carboxylate (1.5 g, 8.71 mmol, 1.0 eq) in éthanol (15 ml) at 0 °C was added IN NaOH solution (69.68 ml, 69.68 mmol, 8.0 eq). The réaction mixture was stirred at room température for ovemight. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture was evaporated under reduced pressure to obtain the desired compound (3.0 g) as an off-white solid. Intermediate 15: Préparation of4-(5-methvl-L3,4-oxadiazol-2-vDbenzoic acid:
o
Step 1: Synthesis of methyl 4-(2-acetylhydrazine-l-carbonyl)benzoate:
MeOOC
To a stirred solution of 4-(methoxycarbonyl)benzoic acid (5.0 g, 27.74 mmol, 1.0 eq) in DMF (50 ml) was added HBTU (15.7 g, 41.62 mmol, 1.5 eq), followed by triethyl amine (15.4 ml, 110.98 mmol, 4.0 eq). The reaction mixture was stirred at room température for about 30 minutes then acetic hydrazide (3.0 g, 41.62 mmol, 1.5 eq) was added and stirred at room température for ovemight. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture was diluted with water (500 ml) and extracted with EtOAc (2x200 ml). The combined organic extracts were dried over NazSCL, filtered and evaporated under reduced pressure to obtain the desired compound (5.0 g, yield: 76%) as a colourless liquid. ‘H NMR (300 MHz, DMSO-d6): δ ppm 10.5 (s, 1H), 9.97 (s, 1H), 8.07 (d, J = 8.1 Hz, 2H), 7.98 (d, J= 8.4 Hz, 2H), 3.89 (s, 3H), 2.73 (s, 3H);
Step 2: Synthesis of methyl 4-(5-methyl-l,3,4-oxadiazol-2-yl)benzoate:
To a stirred solution of methyl 4-(2-acetylhydrazine-l-carbonyl)benzoate (step 1, 5.0 g, 21.186 mmol, 1.0 eq) in DCM (50 ml) at 0 °C was added triethyl amine (14.77 ml, 105.82 mmol, 5.0 eq) followed by para-toluenesulphonyl chloride (6.0 g, 31.779 mmol, 1.5 eq). The reaction mixture was allowed to stir at room température for ovemight. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture was diluted with DCM (200 ml) and washed with water (2x100 ml). The combined organic extracts were dried over Na2SO4, filtered and evaporated under reduced pressure. The crude compound (3.0 g) was used as such for next step without further purification. ’H NMR (300 MHz, CDCb): δ ppm 8.17 (d, J= 8.7 Hz, 2H), 8.09 (d, J= 8.7 Hz, 2H), 3.95 (s, 3H), 2.64 (s, 3H).
Step 3: Synthesis of 4-(5-methyl-l,3,4-oxadiazol-2-yl)benzoic acid:
To a stirred solution of methyl 4-(5-methyl-l,3,4-oxadiazol-2-yl)benzoate (step 2, 3.0 g, 13.761 mmol, 1.0 eq) in MeOH (30 ml) was added aqueous IN NaOH solution (110 ml, 110.097 mmol, 8.0 eq). The reaction mixture was stirred at room température for ovemight. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture was neutralized with IN HCl and evaporated under reduced pressure. To this compound acetonitrile (100 ml) was added and concentrated under reduced pressure to obtain the crude desired product (3.0 g) as a white solid. ’HNMR (300 MHz, DMSO-dô): δ ppm 13.34 (brs, 1H), 8.12-8.10 (m, 4H), 2.61 (s, 3H); ESI-MS: m/z 226.87 (M+Na)+.
Intermediate 16: Préparation of 4-(Ll-dioxidothiomorpholino')benzoic acid:
HOOC
Step 1: Synthesis of Methyl 4-(l,l-dioxidothiomorpholino)benzoate:
MeOOC
To a stirred solution of methyl 4-bromobenzoate (1.5 g, 6.975 mmol, 1.0 eq) in toluene (30 ml) was added thiomorpholine 1,1-dioxide (1.13 g, 8.37 mmol, 1.2 eq) and CS2CO3 (6.817 g, 20.92 mmol, 3.0 eq). The reaction mixture was purged with nitrogen for about 10 minutes. Next, palladium acetate (0.015 g, 0.069 mmol, 0.01 eq) and BINAP (0.065 g, 0.104 mmol, 0.015 eq) were added and the reaction mixture was degassed for about 30 minutes and heated to 100 °C for ovemight. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture was allowed to cool to room température, filtered through celite pad and was washed with ethyl acetate (140 ml). The organic layer was separated and was washed with saturated sodium bicarbonate solution, dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified by sihcagel column chromatography by using 90% ethyl acetate in hexane as an eluent to obtain the desired product (1.2 g, yield: 63.8%) as an off-white solid. *H NMR (300 MHz, DMSO-dô): δ ppm 7.82 (d, J = 9.0 Hz, 2H), 7.09 (d, J= 9.0 Hz, 2H), 3.92 (t, J= 4.5 Hz, 4H), 3.78 (s, 3H), 3.14 (t, J= 4.5 Hz, 4H); ESI-MS: m/z 292.0 (M+Na)+.
Step 2: Synthesis of 4-(l,l-dioxidothiomorpholino)benzoic acid:
To a stirred solution of methyl 4-(l,l-dioxidothiomorpholino)benzoate (step 1, 1.6 g, 5.947 mmol, 1.0 eq) in MeOH (20 ml) was added aqueous IN NaOH solution (47.5 ml, 47.5 mmol, 8.0 eq). The reaction mixture was stirred at room température for ovemight. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture was neutralized with IN HCl (47.5 ml) and evaporated under reduced pressure. The crude solid was co-distilled with CH3CN (10 ml) to obtain the desired product (2.0 g) as a white solid.
Intermediate 17: Préparation of 4-((1. l-dioxidothiomorpholino)methvl)benzoic acid:
Step 1: Synthesis of methyl 4-((1, l-dioxidothiomorpholino)methyl)benzoate:
To a stirred solution of methyl 4-(bromomethyl)benzoate (4.0 g, 17.46 mmol, 1.0 eq) in CH3CN (100 ml) was added CS2CO3 (17.0 g, 52.38 mmol, 3.0 eq). The reaction mixture was stirred at room température for about 1 hour then thiomorpholine 1,1-dioxide (2.36 g, 17.46 mmol, 1.0 eq) was added and heated to reflux for ovemight. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture was cooled to room température, filtered through celite pad and was washed with ethyl acetate (100 ml). The filtrate was washed with water (100 ml), dried over Na2SO4, filtered and evaporated under reduced pressure to obtain the desired product (4.0 g) as a yellow oil. *H NMR (300 MHz, DMSO-dô): δ ppm 7.94 (d, J= 8.1 Hz, 2H), 7.50 (d, J= 8.4 Hz, 2H), 3.85 (s, 3H), 3.75 (s, 2H), 3.16-3.09 (m, 4H), 2.92-2.85 (m, 4H); ESI-MS: m/z 306.03 (M+Na)+.
Step 2: Synthesis of 4-((1, l-dioxidothiomorpholino)methyl)benzoic acid:
To a stirred solution of methyl 4-((1,l-dioxidothiomorpholino)methyl)benzoate (step 1,1.0 g, 3.53 mmol, 1.0 eq) in MeOH (10 ml) and THF (10 ml) was added aqueous INNaOH solution (28.2 ml, 28.2 mmol, 8.0 eq). The reaction mixture was stirred at room température for ovemight. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture was neutralized with IN HCl (28 ml) and evaporated under reduced pressure to obtain the desired product (1.5 g crade) as a white solid. ’H NMR (300 MHz, DMSO-dô): δ ppm 7.86 (d, J= 8.1 Hz, 2H), 7.31 (d, J= 7.8 Hz, 2H), 3.68 (s, 2H), 3.123.08 (m, 4H), 2.88-2.84 (m, 4H); ESI-MS: m/z 268.06 (M-H)\
Intermediate 18: Préparation of l-M-chloronhenvDcvclonropane-l-carbaldehvde:
Step 1: Synthesis of (l-(4-chlorophenyl)cyclopropyl)methanol:
To a stirred solution of l-(4-chlorophenyl)cyclopropane-l-carboxylic acid (Intermediate 8, 10 g, 51.02 mmol, 1.0 eq) in THF (150 ml) at 0 °C under nitrogen was added boranedimethyl sulphide (51 ml, 102.04 mmol, 2.0 eq, 2.0 M in THF). The reaction mixture was allowed to stir at room température for ovemight. TLC indicated starting material was consumed and the desired product was observed. The réaction mixture was cooled to 0 °C, quenched with saturated aqueous ammonium chloride solution (50 ml) then diluted with water (100 ml) and extracted with EtOAc (3x200 ml). The combined organic extracts were washed with water (100 ml), brine solution (50 ml), dried over Na2SO4, filtered and evaporated under reduced pressure to obtain the desired product (8.0 g) as colourless oil. *H NMR (300 MHz, CDCh): δ ppm 7.36-7.27 (m, 4H), 3.65 (s, 2H), 0.86 (m, 4H).
Step 2: Synthesis of l-(4-chlorophenyl) cyclopropane-1-carbaldehyde:
To a stirred solution of (l-(4-chlorophenyl)cyclopropyl)methanol (step 1, 6.0 g, 32.84 mmol, 1.0 eq) in DCM (60 ml) was added pyridinium chlorochromate (21.23 g, 98.54 mmol, 3.0 eq) and silicagel (21.23 g). The reaction mixture was stirred at room température for about 1 hour. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture was filtered through celite, filtrate was diluted with water (150 ml) and extracted with DCM (3x50 ml). The combined organic extracts were washed with saturated sodium bicarbonate solution (2x30 ml), dried over Na2SO4, filtered and evaporated under reduced pressure to obtain the desired product (6.0 g) as an oil, which is used as such for next step without further purification.
Intermediate 19: Préparation of 5-isocvanato-2-methylpyridine:
To a stirred solution of 6-methylnicotinic acid (1.0 g, 7.299 mmol, 1.0 eq) in toluene (15 ml) was added triethylamine (0.88 g, 8.759 mmol, 1.2 eq) and DPPA (2.4 g, 8.759 mmol, 1.2 eq). The reaction mixture was stirred at room température for about 4 hours. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture was concentrated to dryness. The residue was purified by silicagel column chromatography by using 2% methanol in dichloromethane as an eluent to obtain the desired product (0.75 g, yield: 77%) as an off-white solid. *H NMR (300 MHz, CDCh): δ ppm 9.09 (d, J- 1.8 Hz, 1H), 8.16 (dd, J= 8.1,2.1 Hz, 1H), 7.27 (d, J= 8.1 Hz, 1H), 2.64 (s, 3H).
Intermediate 20: Préparation of 2-isocvanato-6-methvlpyridine:
To a stirred solution of 6-methylpicolinic acid (1.5 g, 10.937 mmol, 1.0 eq) in toluene (20 ml) was added triethylamine (1.328 g, 13.12 mmol, 1.2 eq) and diphenylphosphonic azide (3.61 g, 13.12 mmol, 1.2 eq). The reaction mixture was stirred at room température for ovemight. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture was evaporated under reduced pressure to obtain the desired product (0.6 g) as a oil, which is used as such for next step without further purification. Intermediate 21: Préparation of sodium 2-(dimethvlamino')-l-hvdroxvethane-l-sulfonate:
SO3Na
I
A stirred solution of 2,2-diethoxy-N,N-dimethylethan-l-amine (15 g, 93.16 mmol. 1.0 eq), conc. hydrochloric acid (15.5 ml) and water (7.5 ml) heated at 40 °C for about 3 hours. Then a solution of sodium pyro sulphite (15.93 g, 83.84 mmol, 0.9 eq) dissolved in water (27 ml) was added dropwise and the mixture was stirred for about 1 hour. Then 90 ml of éthanol was added to reaction mixture and stirred for about 2 hours at 0 °C. The suspension was filtered and washed with éthanol (20 ml), then dried under vacuum at 40 °C for about 30 minutes to afford the desired product (15 g, yield: 84%) as a white solid.
Intermediate 22: Préparation of 4-(carboxvmethvl)thiomorpholin-4-ium 1,1-dioxide 2,2,2trifluoroacetate:
CFjCOO
O
Step 1: Synthesis of tert-butyl 2-(1,1-dioxidothiomorpholino)acetate:
To a stirred solution of thiomorpholine 1,1-dioxide (3.0 g, 17.48 mmol) in DCM (30 ml) at 0 °C, were added TEA (17 ml, 122.37 mmol) and tert-butyl 2-chloroacetate (3.8 ml, 26.22 mmol). The reaction mixture was stirred for ovemight at room température. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with DCM and washed with water, saturated NH4CI solution, brine and dried over Na2SO4. The solvent was evaporated under reduced pressure and purified by silica gel column (elution 1% MeOH in DCM) to afford the title compound (3.0 g, yield: 68.96%) as a thick oil. H1 NMR (DMSOd6, 300 MHz): δ 3.35 (s, 2H), 3.06 (m, 8H), 1.41 (s, 9H).
Step 2: Synthesis of4-(carboxymethyl)thiomorpholin-4-ium 1,1-dioxide 2,2,2-trifluoroacetate:
To a stirred solution of tert-butyl 2-(l,l-dioxidothiomorpholino)acetate (step 1, 1.0 g, 4.01 mmol) in DCM (10 ml), was added TFA (3 ml) and stirred for about 2 hours. After completion of the reaction (monitored by TLC), the reaction mixture was concentrated under reduced pressure to afford the desired compound as a TFA sait (1.2 g, yield: 100%). Next reaction was carried out without any further purification.
EXAMPLES
Example 1: Préparation of (lR,3S)-3-ff((3aR,5aR.5bR.7aR.9S.llaR,llbR,13aS)-3a-f2-(4chlorobenzamido)-2-methvlpropanamido)-l-isopropyl-5a.5b.8.8.11a-pentamethvl-2-oxo-3.
3a,4.5.5a,5b,6,7.7a,8.9.10.11,1 la,l lb,12.13.13a-octadecahvdro-2H-cvclopentaralchrvsen-9vl)oxv)carbonyl)-2.2-dimethvlcvclobutane-l -carboxvlic acid:
HOOC*
Step 1: Synthesis of 1-benzyl 3-((3aR,5aR,5bR,7aR,9S,llaR,llbR,13aS)-3a-(2-(4chlorobenzamido)-2-methylpropanamido)-l-isopropyl-5a,5b,8,8,lla-pentamethyl-2-oxo3,3a,4,5,5a,5b,6,7,7a,8,9,10,ll,lla,llb,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen9-yl) (IR, 3S)-2,2-dimethylcyclobutane-l, 3-dicarboxylate:
BnOOl
To a stirred solution of 4-chlorobenzoic acid (0.304 g, 1.945 mmol, 1.5 eq) in DMF (10 ml) was added HBTU (0.737 g, 1.945 mmol, 1.5 eq) followed by DIPEA (1.55 ml, 9.07 mmol, 7.0 eq). The reaction mixture was stirred at room température for about 30 minutes, then 1 -((3aR,5aR,5bR,7aR,9S, 11 aR, 11 bR, 13aS)-3a-(2-amino-2-methylpropanamîdo)-l-iso propyl-5a,5b,8,8,l la-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,l 1,1 la,l lb,12,13,13aoctadecahydro-2H-cyclopenta[a]chrysen-9-yl) 3-benzyl (1 S,3R)-2,2-dimethylcyclobutane-l,3
-dicarboxylate (Intermediate 1, 1.0 g, 1.296 mmol, 1.0 eq) was added and stirred at same température for ovemight. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture was diluted with water (150 ml) and extracted with 10 ethyl acetate (3x50 ml). The combined organic extracts were washed with water (50 ml), brine solution (50 ml), dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified by silicagel column chromatography by using 0-5% methanol in dichloromethane gradient. The fractions containing the expected product were combined and concentrated under reduced pressure to obtain the desired product (0.700 g, yield: 59.3%) as a 15 white solid. Ή NMR (300 MHz, CDCh): δ ppm 7.71 (d, J= 8.7 Hz, 2H), 7.41 (d, J= 8.4 Hz, 2H), 7.37-7.31 (m, 5H), 7.09 (brs, 1H), 6.82 (brs, 1H), 5.14, 5.08 (ABq, Jab = 12.3 Hz, 2H), 4.43 (dd, J= 11.4,4.8 Hz, 1H), 3.21-3.10 (m, 1H), 2.85-2.72 (m, 3H), 2.70-2.57 (m, 2H), 2.372.23 (m, 2H), 2.08-1.72 (m, 6H), 1.68 (s, 3H), 1.66 (s, 3H), 1.62-1.37 (m, 6H), 1.34 (s, 3H), 1.32-1.28 (m, 2H), 1.28-1.16 (m, 8H), 1.16-1.06 (m, 1H), 1.03 (s, 3H), 0.95 (s, 3H), 0.93 (s, 20 3H), 0.86 (s, 3H), 0.84 (s, 3H), 0.83 (s, 3H), 0.82-0.78 (m, 1 H); ESI-MS: m/z 931.5 (M+Na)+.
Step 2: Synthesis of (lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,llaR,llbR,13aS)-3a-(2-(4-chloro benzamido)-2-methylpropanamido)-l-isopropyl-5a, 5b, 8,8,11 a-pentamethyl-2-oxo-3,3 a, 4,5, 5a,5b,6,7,7a,8,9,10,ll,lla,llb,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy) carbonyl)-2,2-dimethylcyclobutane-l-carboxylic acid:
To a stirred solution of 1-benzyl 3-((3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-3a-(2-(4chlorobenzamido)-2-methylpropanamido)-l-isopropyl-5a,5b,8,8,lla-pentamethyl-2-oxo3,3a,4,5,5a,5b,6,7,7a,8,9,10,l 1,1 la,l lb,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen9-yl) (lR,3S)-2,2-dimethylcyclobutane-l,3-dicarboxylate (step 1,0.700 g, 0.769 mmol, 1.0 eq) in MeOH (15 ml) and THF (15 ml) was added aqueous 2.5N KOH solution (2.15 ml, 5.383 30 mmol, 7.0 eq). The reaction mixture was stirred at room température for ovemight. 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 (15 ml), cooled to 0°C, pH adjusted to 5.0 with IN HCl and extracted with DCM (3x75 ml). The combined organic extracts were washed with water (50 ml), dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by silicagel column chromatography by using 0-5% methanol in dichloromethane gradient. The fractions containing the product were combined and concentrated under reduced pressure to give a solid. To this solid, acetonitrile (10 ml) was added and heated to reflux for about 30 minutes. The mixture was cooled to 0°C, solid was filtered and was washed with n-hexane (10 ml) and dried under vacuum to obtain the desired product (0.4 g, yield: 63.43%) as a white solid. *H NMR (300 MHz, CDCb): δ ppm 7.72 (d, J= 8.4 Hz, 2H), 7.42 (d, J= 8.4 Hz, 2H), 7.09 (s, 1H), 6.77 (s, 1H), 4.46 (dd, J= 11.1, 4.5 Hz, 1H), 3.22-3.11 (m, 1H), 2.86-2.76 (m, 3H), 2.71-2.53 (m, 2H), 2.38-2.25 (m, 2H), 2.10-2.0 (m, 1H), 1.98-1.73 (m, 5H), 1.69 (s, 3H), 1.68 (s, 3H), 1.65-
1.40 (m, 6H), 1.37 (s, 3H), 1.34-1.30 (m, 2H), 1.28-1.18 (m, 8H), 1.16-0.99 (m, 1H), 1.06 (s, 3 H), 1.04 (s, 3H), 0.94 (s, 3H), 0.88 (s, 3H), 0.86 (s, 3H), 0.85 (s, 3H), 0.84-0.78 (m, 1 H); ESIMS: m/z 841.5 (M+Na)+; HPLC: 97.93%.
The below examples 2-21 were prepared by the procedure similar (including reagents and reaction conditions) to the above described in the synthesis of example-1 using with their appropriate intermediates.
Example 2: Préparation of (lR.3S)-3-(((('3aR.5aR.5bR,7aR.9S.l laR,l lbR,13aS)-3a-(2-(l-i4chlorophenvDcvclopropane-l-carboxamido')-2-methvlpronanamido)-l-isopropvl-5a,5b.8.8.
la-pentamethvl-2-oxo-3.3a,4.5.5a.5b.6.7.7a.8.9.10.11.1 la.l lb.l2.13.13a-octadecahydro2H-cyclopentaralchrvsen-9-vl')oxv’)carbonvD-2.2-dimethvlcvclobutane-l-carboxvlic acid:
Intermediate 1 was coupled with l-(4-chlorophenyl)cyclopropane-l-carboxylic acid (Intermediate 8) followed by hydrolysis gave the desired product as a white solid. ’H NMR (300 MHz, CDCb): δ ppm 7.59 (s, 1H), 7.37 (d, J= 8.4 Hz, 2H), 7.31 (d, J= 8.4 Hz, 2H), 5.46 (brs, 1H), 4.48 (dd, J= 11.1,4.5 Hz, 1H), 3.20-3.08 (m, 1H), 2.87-2.75 (m, 3H), 2.67-2.53 (m, 2H), 2.35-2.17 (m, 2H), 2.12-2.01 (m, 1H), 1.97-1.91 (m, 2H), 1.88-1.70 (m, 4H), 1.67-1.48 (m, 6H), 1.44-1.41 (m, 1H), 1.39 (s, 3H), 1.38 (s, 3H), 1.36 (s, 3H), 1.35-1.33 (m, 2H), 1.271.19 (m, 10H), 1.17 (s, 3H), 1.08 (s, 3H), 1.07-1.04 (m, 1H), 0.93 (s, 6H), 0.88 (s, 3H), 0.87 (s, 3H), 0.84-0.80 (m, 1 H); ESI-MS: m/z 881.3 (M+Na)+; HPLC: 97.2%.
Example 3: Préparation of HR.3S)-3-('('(('3aR,5aR.5bR,7aR,9S,l laR.l lbR.13aS~)-3a-(2benzamido-2-methylpropanamidoM -isonropyl-5a.5b,8,8.11 a-pentamethyl-2-oxo-3.3a.4.5.5a.
5b.6,7,7a,8.9,10,11,11 a, 11 b, 12,13,13a-octadecahvdro-2H-cvclopentaralchrysen-9-vl)oxv) carbonvl)-2,2-dimethvlcvclobutane-l -carboxylic acid:
Intermediate 1 was coupled with benzoic acid followed by hydrolysis gave the desired product as a white solid. *H NMR (300 MHz, CDCh): δ ppm 7.77 (d, J= 7.2 Hz, 2H), 7.50-
7.40 (m, 3H), 6.64 (brs, 1H), 4.46 (dd, J= 11.1,4.5 Hz, 1H), 3.22-3.11 (m, 1H), 2.88-2.53 (m, 5H), 2.39-2.24 (m, 2H), 2.10-2.0 (m, 1H), 2.0-1.85 (m, 3H), 1.81-1.72 (m, 2H), 1.69 (s, 3H), 1.67 (s, 3H), 1.65-1.42 (m, 7H), 1.37 (s, 3H), 1.36-1.30 (m, 2H), 1.27-1.21 (m, 7H), 1.20-1.15 (m, 1H), 1.07 (s, 3H), 1.02 (s, 3H), 0.94 (s, 3H), 0.86 (s, 6H), 0.84 (s, 3H), 0.82-0.78 (m, 1H); ESI-MS: m/z 807.53 (M+Na)+; HPLC: 95.3%.
Example 4: Preparation of (lR.3S)-3-i(('(3aR,5aR,5bR,7aR,9S,llaR,llbR,13aS)-3a-(2-(3,4dichlorobenzamido')-2-methvlpropanamido')-l-isopropyl-5a.5b.8.8.1 la-pentamethyl-2-oxo3,3a,4.5.5a.5b.6,7.7a,8, 9,10,11.1 la,l lb.l2,13.13a-octadecahvdro-2H-cvclopentaralchrvsen9-vDoxv)carbonvD-2.2-dimethylcvclobutane-l-carboxvlic acid:
Intermediate 1 was coupled with 3,4-dichlorobenzoic acid followed by hydrolysis gave the desired product as a white solid. *H NMR (300 MHz, CDCI3): δ ppm 7.89 (d, J= 2.1 Hz, 1H), 7.59 (dd, J= 8.4, 1.8 Hz, 1H), 7.52 (d, J= 8.4 Hz, 1H), 6.89 (brs, 1H), 6.85 (brs, 1H), 4.46(dd, J= 11.1,4.5 Hz, 1H), 3.22-3.10 (m, 1H), 2.85-2.75 (m, 3H), 2.70-2.51 (m,2H),2.352.26 (m, 2H), 2.10-2.0 (m, 1H), 1.99-1.74 (m, 5H), 1.69 (s, 6H), 1.67-1.40 (m, 7H), 1.36 (s, 3H), 1.32 (m, 1H), 1.30-1.18 (m, 8H), 1.12-1.03 (m, 7H), 0.94 (s, 3H), 0.89 (s, 3H), 0.86 (s, 3H), 0.85 (s, 3H), 0.79 (m, 1H); ESI-MS: m/z 875.38 (M+Na)+; HPLC: 98.06%.
Example 5: Preparation of (lR,3S)-3-((((3aR,5aR,5bR,7aR,9S.l laR,l lbR,13aS)-l-isopropvl5a,5b,8.8,lla-pentamethvl-3a-(2-methvl-2-(pvrazine-2-carboxamido)propanamido)-2-oxo-3, 3a,4,5,5a,5b.6.7,7a,8,9.10,l 1,11a,! lb,12,13.13a-octadecahvdro-2H-cvclopentaIalchrysen-9vDoxv)carbonvl)-2,2-dimethylcvclobutane-l-carboxvlic acid:
Intermediate 1 was coupled with pyrazine-2-carboxylic acid followed by hydrolysis gave the desired product as a white solid. ’H NMR (300 MHz, CDCh): δ ppm 9.39 (d, J= 1.2 Hz, 1H), 8.80 (d, J=2.1 Hz, 1H), 8.56 (d, J= 1.5 Hz, 1H), 8.19 (s, 1H), 7.46 (s, 1H), 4.45 (dd, J= 11.1,4.5 Hz, 1H), 3.21-3.10 (m, 1H), 2.87-2.53 (m, 5H), 2.38-2.25 (m, 2H), 2.11-1.80 (m, 5H), 1.80-1.62 (m, 3H), 1.70 (s, 3H), 1.68 (s, 3H), 1.60-1.42 (m, 5H), 1.41-1.28 (m, 3H), 1.37 (s, 3H), 1.28-1.12 (m, 8H), 1.07 (s, 3H), 0.94 (s, 3H), 0.93 (s, 3H), 0.90-0.75 (m, 10H); ESIMS: m/z 809.39 (M+Na)+; HPLC: 97.0%.
Example 6: Préparation of (lR.3Sl-3-((((3aR.5aR.5bR,7aR.9S.llaR.llbR.13aS’)-3a-(2-i6aminonicotinamido)-2-methvlpropanamido1-l-isopropvl-5a,5b.8.8.11a-nentamethvl-2-oxo-3. 3 a.4.5.5 a, 5 b, 6.7.7a, 8.9.10.11.1 la.1 lb.l2.13.13a-octadecahvdro-2H-cvclopentaralchrvsen-9yDoxv)carbonvl)-2,2-dimethvlcvclobutane-l -carboxylic acid:
Intermediate 1 was coupled with 6-aminonicotinic acid followed by hydrolysis gave the desired product as a white solid. ’H NMR (300 MHz, DMSO-dô): δ ppm 12.15 (brs, 1H), 8.48 (d, J= 1.8 Hz, 1H), 7.81 (s, 1H), 7.79 (d, J= 1.8 Hz, 1H), 7.30 (s, 1H), 6.47 (brs, 2H), 6.40 (d, J= 6.6 Hz, 1H), 4.38-4.32 (m, 1H), 3.13-3.03 (m, 1H), 2.85-2.73 (m, 3H), 2.43-2.26 (m, 4H), 2.07-2.03 (m, 1H), 1.92-1.80 (m, 3H), 1.78-1.64 (m, 2H), 1.62-1.43 (m, 4H), 1.39 (s, 3H), 1.38 (s, 3H), 1.35-1.17 (m, 4H), 1.26 (s, 3H), 1.15-1.10 (m, 6H), 1.07-0.94 (m, 3H), 0.91 (s, 3H), 0.88 (s, 3H), 0.85 (s, 3H), 0.82 (s, 3H), 0.81 (s, 3H), 0.80 (s, 3H), 0.84-0.77 (m, 1H); ESI-MS: m/z 823.49 (M+Na)+; HPLC: 97.38%.
Example 7: Préparation of (1R.3S)-3-(ï(ï3aR,5aR.5bR,7aR.9S.l laR.l lbR,13aS)-l-isopropyl5a,5b,8.8.11 a-pentamethyl-3a-(2-methvl-2-(5-methylpvrazine-2-carboxamido')propanamido)2-oxo-3.3a.4.5.5a.5b.6.7.7a,8.9.10.11,1 la,l lb.l2.13.13a-octadecahvdro-2H-cvclopentaral chrvsen-9-yl)oxv)carbonyD-2.2-dimethvlcvclobutane-l-carboxylic acid:
Intermediate 1 was coupled with 5-methylpyrazine-2-carboxylic acid followed by hydrolysis gave the desired product as a white solid. ’H NMR (300 MHz, CDCh): δ ppm 9.25 (d, J= 0.9 Hz, 1H), 8.402 (d, J= 0.6 Hz, 1H), 8.10 (s, 1H), 7.54 (s, 1H), 4.46 (dd, J= 8.4, 3.3 Hz, 1H), 3.20-3.11 (m, 1H), 2.85-2.77 (m, 3H), 2.70-2.55 (m, 2H), 2.69 (s, 3H), 2.36-2.25 (m, 2H), 2.08-1.82 (m, 4H), 1.80-1.70 (m, 2H), 1.69 (s, 3H), 1.66 (s, 3H), 1.65-1.57 (m, 2H), 1.55-
1.40 (m, 4H), 1.37 (s, 3H), 1.36-1.25 (m, 3H), 1.25-1.17 (m, 7H), 1.17-1.02 (m, 1H), 1.07 (s, 3H), 0.97 (s, 3H), 0.92 (s, 3H), 0.90-0.82 (m, 9H), 0.81-0.78 (m, 1H); ESI-MS: m/z 823.49 (M+Na)+; HPLC: 96.29%.
Example 8: Préparation of ilR.3S)-3-(((ï3aR.5aR.5bR.7aR.9S.l laR.1 lbR.13aS)-3a-(2-((S)-l(tert-butoxvcarbonvl~)pvrrolidine-2-carboxamido')-2-methvlpropanamido')-l-isopropvl-5a. 5b.8.8.1 la-pentamethyl-2-oxo-3.3a.4.5.5a.5b.6.7.7a.8.9,10.11.1 la.1 lb.l2.13.13a-octadeca hvdro-2H-cvclonentara1chrvsen-9-vDoxv)carbonvD-2,2-dimethvlcvclobutane-l-carboxylic acid:
Intermediate 1 was coupled with (tert-butoxycarbonyl)-L-prolîne followed by hydrolysis gave the desired product as a white solid. ’H NMR (300 MHz, DMSO-dô): δ ppm 12.13 (brs, 1H), 8.18 (s, 1H), 6.75 (s, 1H), 4.39-4.33 (m, 1H), 4.05-3.99 (m, 1H), 3.36 (m, 1H), 3.26 (m, 1H), 3.13-3.06 (m, 1H), 2.84-2.64 (m, 3H), 2.42-2.15 (m, 4H), 2.10-1.83 (m, 5H), 1.80-1.63 (m, 5H), 1.62-1.48 (m, 4H), 1.45-1.23 (m, 22H), 1.22-1.02 (m, 13H), 0.93-0.80 (m, 15H); ESI-MS: m/z 900.53 (M+Na)+; HPLC: 98.3%.
Example 9: Préparation of (lR.3S)-3-((i(3aR.5aR.5bR.7aR,9S,l laR.l lbRJ3aS)-3a-(2-(2-(4ethylpiperazin-l-vl')acetamido,)-2-methvlpropanamido)-l-isopropvl-5a.5b,8.8.11a-nenta methvl-2-oxo-3,3a.4,5.5a,5b.6.7.7a.8.9.10,l 1,11 a,l lb.l2.13,13a-octadecahydro-2H-cvclo nentaralchrysen-g-vDoxvlcarbonvD^^-dimethvlcvclobutane-l-carboxvlic acid:
Intermediate 1 was coupled with 2,2,2-trifluoroacetate sait of 2-(4-ethylpiperazin-l-yl)acetic acid (Intermediate 9) followed by hydrolysis gave the desired product as a white solid. ’HNMR (300 MHz, CDCI3+CD3OD): δ ppm 7.17 (s, 1H), 4.50-4.42 (m, 1H), 3.26-3.22 (m, 2H), 3.203.08 (m, 10H), 3.0-2.90 (m, 2H), 2.86-2.75 (m, 2H), 2.66-2.53 (m, 2H), 2.36-2.20 (m, 2H), 2.10-1.86 (m, 3H), 1.85-1.66 (m,2H), 1.57 (s, 3H), 1.54 (s, 3H), 1.50-1.34 (m, 16H), 1.28-1.18 (m, 11H), 1.13 (s, 3H), 1.05 (s, 3H), 1.0-0.80 (m, 10H); ESI-MS: m/z 835.6 (M+H)+; HPLC: 95.03%.
Example 10: Préparation of (lR.3S)-3-((((3aR.5aR.5bR.7aR.9S.llaR.llbR.13aS)-lisonropvl-5a,5b.8.8.11a-pentamethvl-3a-(2-methvl-2-i2-(niperidin-l-vDacetamido’)propan amido)-2-oxo-3.3a,4.5.5a.5b.6.7.7a.8,9.10,11,1 la.l lb.l2.13,13a-octadecahvdro-2H-cyclo nentaralchrvsen-g-vDoxvlcarbonvD^^-dimethvlcvclobutane-l-carboxvlic acid:
Intermediate 1 was coupled with l-(carboxymethyl)piperidin-l-ium 2,2,2trifluoroacetate (Intermediate 10) followed by hydrolysis gave the desired product as a white solid. Ή NMR (300 MHz, pyridine-d5): δ ppm 8.33 (s, 1H), 8.30 (s, 1H), 4.73 (dd, J= 11.1,
4.5 Hz, 1H), 3.25-2.98 (m, 7H), 2.73-2.56 (m, 2H), 2.40-2.35 (m, 4H), 2.25-2.08 (m, 2H), 1.931.75 (m, 2H), 1.85 (s, 3H), 1.78 (s, 3H), 1.75-1.62 (m, 3H), 1.57 (s, 3H), 1.53-1.36 (m, 17H), 1.35-1.22 (m, 9H), 1.21-1.05 (m, 2H), 1.05-0.88 (m, 13H), 0.84-0.76 (m, 1H); ESI-MS: m/z
806.5 (M+H)+; HPLC: 91.5%.
Example 11: Préparation of (lR.3S)-3-fii(3aR.5aR,5bR.7aR,9S.llaR.llbR,13aS)-3a-(2-(2amino-2-methvlpropanamido)-2-methvlpronanamido)-l-isopropvl-5a,5b.8.8.11a-pentamethyl -2-oxo-3.3a.4,5.5a,5b.6.7,7a,8.9.10.1 L1 la,l lb.l2,13,13a-octadecahvdro-2H-cyclopentara1 chrvsen-9-vDoxv)carbonyT)-2.2-dimethvlcvclobutane-l -carboxylic acid hydrochloride:
Step 1: Synthesis of (lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,llaR,llbR,13aS)-3a-(2-(2-((tertbutoxycarbonyl)amino)-2-methylpropanamido)-2-methylpropanamido)-l-isopropyl-5a,5b,8,
8,11 a-pentamethyl-2-oxo-3,3a, 4,5,5 a, 5b, 6,7,7a, 8,9,10,11,1 la,11b,12,13,13a-octadecahydro2H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-l-carboxylic acid:
Intermediate 1 was coupled with 2-((tert-butoxycarbonyl)amino)-2-methylpropanoic acid (Intermediate 1-step 9) followed by hydrolysis gave the desired product as an off-white solid. ‘H NMR (300 MHz, CDCh): δ ppm 7.18 (s, 1H), 6.39 (s, 1H), 4.87 (s, 1H), 4.47 (dd, J = 11.1,4.5 Hz, 1H), 3.22-3.12 (m, 1H), 2.96-2.74 (m, 3H), 2.67-2.48 (m, 3H), 2.20 (d, J= 18.6 Hz, 1H), 2.11-1.90 (m, 4H), 1.83-1.51 (m, 9H), 1.50-1.28 (m, 23H), 1.28-1.20 (m, 8H), 1.15 (s, 3H), 1.07 (s, 3H), 0.99-0.83 (m, 16H).
Step 2: Synthesis of (lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,llaR,llbR,13aS)-3a-(2-(2-amino-2methylpropanamido)-2-methylpropanamido)-l-isopropyl-5a,5b,8,8,lla-pentamethyl-2-oxo3,3a, 4,5,5a, 5 b, 6,7,7a,8,9,10,11,lia,11 b, 12,13,13a-octadecahydro-2H-cyclopenta[ajchrysen -9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-l-carboxylic acid hydrochloride:
To a stirred solution of (lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-3a-(2-(2((tert-butoxy carbonyl)amino)-2-methylpropanamido)-2-methylpropanamido)-1 -isopropyl5a,5b,8,8,l la-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,l 1,1 la,l lb,12,13,13a-octadeca hydro-2H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-l-carboxylic acid (step 1,0.600 g, 0.692 mmol, 1.0 eq) in a round bottomed flask at 0 °C was added 3N HCl in 1,4-dioxane (5 ml). The reaction mixture was allowed to stir at room température for ovemight. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture was evaporated under reduced pressure, the residue was washed with n-hexane (10 ml) and dried under vacuum to obtain the solid. To this solid compound, MTBE (10 ml) was added and heated to reflux for 30 minutes. The mixture was cooled to 0 °C, filtered, solid was washed with MTBE and dried under vacuum to obtain the desired product (0.360 g, yield: 64.75%) as a white solid. *H NMR (300 MHz, CD3OD): δ ppm 7.19 (s, 1H), 4.48-4.41 (m, 1H), 3.21 (m, 1H), 2.95-2.80 (m, 3H), 2.63 (d, J= 18.6 Hz, 1H), 2.57-2.42 (m, 1H), 2.40-2.28 (m, 1H), 2.23-2.14 (m, 1H), 2.10-1.77 (m, 4H), 1.76-1.60 (m, 4H), 1.60-1.50 (m, 15H), 1.50-1.38 (m, 2H), 1.35 (s, 3H), 1.32-1.28 (m, 3H), 1.27-1.18 (m, 9H), 1.18-1.05 (m, 1H), 1.05-0.97 (m, 9H), 0.95-0.87 (m, 7H); ESI-MS: m/z 788.51 (MHCl+Na)+; HPLC: 93.5%, Cl’ ion content by Ion chromatography: 5.2%
Example 12: Préparation 0f(lR.3S)-3-((((3aR.5aR,5bR,7aR.9S.llaR.llbR,13aS)-3a-(2-ilHbenzordlimidazole-5-carboxamido)-2-methvlpropanamido)-l-isopronvl-5a.5b.8.8,lla-penta methvl-2-oxo-3.3a.4.5.5a.5b.6.7,7a,8,9.10,l 1,1 la,l lb.l2.13.13a-octadecahvdro-2H-cvclo nentaralchrvsen-9-vl)oxy)carbonvl)-2.2-dimethvlcvclobutane-l-carboxvlic acid:
Intermediate 1 was coupled with l//-benzo[J]imidazole-5-carboxylic acid followed by hydrolysis gave the desired product as a white solid. Ή NMR (300 MHz, CD3OD): δ ppm 8.29 (d, J= 8.4 Hz, 1H), 8.22 (brs, 1H), 7.84 (dd, J= 8.4, 1.2 Hz, 1H), 7.67 (d, J= 8.4 Hz, 1H), 7.50 (brs, 1H), 4.47-4.38 (m, 1H), 3.28-3.18 (m, 1H), 3.0-2.92 (m, 1H), 2.88-2.77 (m, 2H), 2.67 (d, J= 18.6 Hz, 1H), 2.53-2.42 (m, 1H), 2.38-2.28 (m, 1H), 2.21 (d, J= 18.6 Hz, 1H), 2.02-1.88 (m, 4H), 1.82-1.72 (m, 1H), 1.70-1.62 (m, 2H), 1.58 (brs, 6H), 1.56-1.40 (m, 4H), 1.38-1.27 (m, 8H), 1.27-1.10 (m, 7H), 1.01 (s, 3H), 0.96 (s, 3H), 0.92 (s, 3H), 0.90 (s, 3H), 0.90-0.78 (m, 7H); ESI-MS: m/z 823.62 (M-H)'; HPLC: 96.3%.
Example 13: Préparation of (lR,3S)-3-((((3aR,5aR.5bR.7aR,9S.llaR,llbR,13aS)-l-iso propvl-5a,5b.8.8.11a-pentamethvl-3a-(2-methvl-2-(2-(6-methylpvridin-3-vl)-lH-benzord1 imidazole-5-carboxamido)propanamido)-2-oxo-3.3a.4.5.5a.5b.6.7,7a.8.9.10,l 1.1 la,l 1 b. 12. 13,13a-octadecahvdro-2H-cvclopentara1chrvsen-9-vDoxv)carbonvl)-2.2-dimethvlcvclobutane -1-carboxylic acid:
Intermediate 1 was coupled with 2-(6-methylpyridin-3-yl)-lH-benzo[d]imidazole-5carboxylic acid (Intermediate 11) followed by hydrolysis gave the desired product as an offwhite solid. ’H NMR (300 MHz, DMSO-dô): δ ppm 13.2 (brs, 1H), 12.1 (brs, 1H), 9.23 (d, J=
1.8 Hz, 1H), 8.40 (dd, J= 8.1, 2.1 Hz, 1H), 8.14 (brs, 1H), 7.78 (d, J= 7.8 Hz, 1H), 7.75-7.55 (m, 1H), 7.47 (d, J= 8.1 Hz, 1H), 7.34 (brs, 1H), 4.38-4.30 (m, 1H), 3.15-3.05 (m, 1H), 2.882.70 (m, 4H), 2.56 (s, 3H), 2.35-2.22 (m, 3H), 2.14-2.05 (m, 1H), 1.95-1.80 (m, 4H), 1.80-1.60 (m, 2H), 1.60-1.50 (m, 2H), 1.48 (s, 3H), 1.47 (s, 3H), 1.42-1.20 (m, 5H), 1.32 (s, 3H), 1.201.10 (m, 8H), 1.08-0.93 (m, 2H), 0.90 (s, 3H), 0.87 (s, 3H), 0.86 (s, 3H), 0.79 (s, 3H), 0.77 (s, 3H), 0.76 (s, 3H); ESI-MS: m/z 939.03 (M+Na)+; HPLC: 97.12%.
Example 14: Préparation 0f(lR.3S')-3-iï(i3aR,5aR.5bR.7aR.9S,llaR.llbR.13aS')-3a-(2-(2,4dimethvlthiazole-5-carboxamido)-2-methvlpropanamido’)-l-isopropyl-5a.5b.8.8.11a-penta methyl-2-oxo-3,3a,4.5.5a.5b.6.7.7a.8.9.10.11,1 la,! lb.l2.13.13a-octadecahydro-2H-cvclo pentaralchrvsen-9-vDoxv)carbonvD-2.2-dimethylcvclobutane-l-carboxvlic acid:
Intermediate 1 was coupled with 2,4-dimethylthiazole-5-carboxylic acid followed by hydrolysis gave the desired product as an off-white solid. ’H NMR (300 MHz, CDCI3): δ ppm 7.01 (s, 1H), 6.26 (s, 1H), 4.46 (dd, J= 11.4, 4.8 Hz, 1H), 3.19-3.10 (m, 1H), 2.88-2.75 (m, 3H), 2.67 (s, 3H), 2.64 (s, 3H), 2.63-2.56 (m, 2H), 2.40-2.26 (m, 2H), 2.12-1.82 (m, 5H), 1.821.50 (m, 8H), 1.65 (s, 3H), 1.64 (s, 3H), 1.49-1.30 (m, 2H), 1.37 (s, 3H), 1.28-1.18 (m, 7H), 1.07 (m, 7H), 0.94 (s, 3H), 0.89 (s, 3H), 0.86 (s, 3H), 0.85 (s, 3H), 0.99-0.78 (m, 1H); ESI-MS: m/z 842.51 (M+Na)+; HPLC: 95.6%.
Example 15: Préparation of (lR,3S)-3-((((3aR.5aR,5bR,7aR.9S.l laR,l lbR,13aS)-l-iso propvl-5a,5b.8.8.11a-pentamethvl-3a-(2-methvl-2-(2-(pvrazin-2-vD-lH-benzordiimidazole-5 -carboxamido)propanamido')-2-oxo-3.3a,4.5.5a.5b,6,7.7a.8.9.10.1 Ll la,l lb.l2.13,13a-octa decahvdro-2H-cvclopentaralchrvsen-9-v0oxv)carbonvD-2,2-dimethvlcyclobutane-lcarboxylic acid:
Intermediate 1 was coupled with 2-(pyrazin-2-yl)-lH-benzo[d]imidazole-5-carboxylic acid (Intermediate 12) followed by hydrolysis gave the desired product as an off-white solid. ’HNMR(300 MHz, DMSO-de): δ ppm 13.65 (s, 0.5H), 13.55 (s, 0.5H), 12.1 (s, 1H), 9.52 (s,
1H), 8.85-8.79 (m, 2H), 8.42 (s, 0.5H), 8.22-8.17 (m, 1H), 8.09 (s, 0.5H), 7.86-7.76 (m, 1H), 7.58 (d, J= 8.4 Hz, 1H), 4.38-4.30 (m, 1H), 3.14-3.06 (m, 1H), 2.87-2.72 (m, 3H), 2.35-2.22 (m, 3H), 2.14-2.05 (m, 2H), 1.95-1.72 (m, 4H), 1.70-1.55 (m, 3H), 1.48 (s, 3H), 1.46 (s, 3H), 1.44-1.30 (m, 5H), 1.28-1.20 (m, 3H), 1.26 (s, 3H), 1.16-1.10 (m, 6H), 1.05-0.95 (m, 1H), 0.90 (s, 3H), 0.86 (m, 6H), 0.82-0.75 (m, 10H); ESI-MS: m/z 903.5 (M+H)+; HPLC: 96.6%.
Example 16: Préparation of ilR,3S)-3-((((3aR.5aR.5bR.7aR,9S.llaR.llbR,13aS)-l-iso propyl-5a.5b.8.8,l la-pentamethvl-3a-(2-methvl-2-(l-methvl-lH-imidazole-2-carboxamido) propanamido)-2-oxo-3.3a.4.5.5a.5b.6.7.7a.8.9.10.1 L1 la, 1 lb,12,13.13a-octadecahvdro-2Hcvclopentara1chrvsen-9-vl)oxv)carbonvl)-2.2-dimethvlcvclobutane-l-carboxvlic acid:
Intermediate 1 was coupled with 1-methyl-l/7-imidazole-2-carboxylie acid followed by hydrolysis gave the desired product as an off-white solid. *H NMR (300 MHz, CDCh): δ ppm 7.61 (m, 1H), 7.04 (s, 1H), 7.0 (d, J= 6.6 Hz, 1H), 4.46 (dd, J= 11.1, 4.5 Hz, 1H), 4.02 (s, 3H), 3.20-3.08 (m, 1H), 2.88-2.52 (m, 5H), 2.43-2.22 (m, 2H), 2.10-2.0 (m, 1H), 1.98-1.82 (m, 4H), 1.82-1.40 (m, 14H), 1.37 (s, 3H), 1.36-1.18 (m, 9H), 1.07 (s, 3H), 1.05-1.0 (m, 1H), 0.95 (s, 3H), 0.92 (s, 3H), 0.89-0.83 (m, 9H), 0.78 (m, 1H); ESI-MS: m/z 789.7 (M+H)+; HPLC: 93.5%.
Example 17: Préparation of (lR,3S)-3-(((i3aR.5aR,5bR,7aR,9S,llaR.llbR,13aS)-l-iso propvl-3a-(2-f3-isopropvl-lH-pvrazole-5-carboxamîdo)-2-methvlpropanamidol-5a.5b.8.8.
la-nentamethvl-2-oxo-3.3a,4.5.5a,5b.6.7.7a.8.9.10,l 1.1 la. 1 lb.l2.13,13a-octadecahvdro-2H -cvclopentaralchrvsen-9-vl,)oxv')carbonvl,)-2,2-dimethvlcvclobutane-l-carboxvlic acid:
Intermediate 1 was coupled with 3-isopropyl-l//-pyrazole-5-carboxylic acid followed by hydrolysis gave the desired product as an off-white solid. *H NMR (300 MHz, CDCh): δ ppm 7.79 (s, 1H), 7.14 (s, 1H), 6.58 (s, 1H), 4.46 (dd, J= 11.1,4.5 Hz, 1H), 3.18-3.10 (m, 1H), 3.10-2.90 (m, 1H), 2.90-2.75 (m, 3H), 2.75-2.52 (m, 2H), 2.40-2.20 (m, 2H), 2.10-2.0 (m, 1H), 2.0-1.85 (m, 4H), 1.78-1.69 (m, 2H), 1.65 (s, 3H), 1.60 (s, 3H), 1.58-1.40 (m, 6H), 1.37 (s,
3H), 1.32 (s, 3H), 1.29 (s, 3H), 1.27-1.20 (m, 9H), 1.17-1.10 (m, 1H), 1.07 (s, 3H), 0.99 (s, 3H), 0.92 (s, 3H), 0.88-0.77 (m, 10H); ESI-MS: m/z 817.7 (M+H)+; HPLC: 96.5%.
Example 18: Préparation of (lR.3S)-3-((((3aR.5aR.5bR.7aR,9S.l laR.1 lbR.13aSl-l-iso pronvl-5a.5b.8.8.11 a-nentamethvl-3a-(2-methvl-2-(4-morpholinobenzamido’)propanamido')-2 -oxo-3.3a.4.5.5a.5b.6.7.7a.8.9.10.11,1 la,l lb.l2,13,13a-octadecahydro-2H-cvclopentara1 chrvsen-g-vlloxvlcarbonvll^^-dimethvlcvclobutane-l-carboxvlic acid:
Intermediate 1 was coupled with 4-morpholinobenzoic acid followed by hydrolysis gave the desired product as an off-white solid. ’H NMR (300 MHz, CDCh): δ ppm 7.69 (d, J = 8.4 Hz, 2H), 6.89 (d, J= 9.0 Hz, 2H), 6.43 (s, 1H), 4.46 (dd, J= 11.1,4.5 Hz, 1H), 3.90-3.83 (m, 4H), 3.30-3.23 (m, 4H), 3.20-3.09 (m, 1H), 2.90-2.75 (m, 3H), 2.70-2.52 (m, 2H), 2.382.23 (m, 2H), 2.10-2.0 (m, 1H), 2.0-1.82 (m, 3H), 1.82-1.70 (m, 2H), 1.67 (s, 3H), 1.63 (s, 3H), 1.61-1.54 (m, 2H), 1.54-1.40 (m, 3H), 1.39-1.29 (m, 3H), 1.37 (s, 3H), 1.28-1.17 (m, 9H), 1.06 (s, 3H), 1.02 (s, 3H), 0.93 (s, 3H), 0.89-0.82 (m, 9H), 0.78 (m, 1H); ESI-MS: m/z 892.76 (M+Na)+; HPLC: 98.1%.
Example 19: Préparation of (lR.3S)-3-((((3aR,5aR.5bR.7aR.9S.l laRJ lbR.13aS)-3a-(2-(3.5dimethvlisoxazole-4-carboxamido)-2-methvlpropanamido)-l -isopronvl-5a,5b,8,8,11 a-penta methyl-2-oxo-3.3a.4.5,5a,5b,6,7.7a.8.9.10.11,1 la,l lb.l2.13.13a-octadecahvdro-2H-cyclo pentaralchrvsen-9-vDoxv)carbonvl)-2,2-dimethvlcvclobutane-l-carboxvlic acid:
Intermediate 1 was coupled with 3,5-dimethylisoxazole-4-carboxylic acid followed by hydrolysis gave the desired product as an off-white solid. ’H NMR (300 MHz, CDCh): δ ppm 6.75 (s, 1H), 6.48 (s, 1H), 4.46 (dd, J= 11.1, 4.5 Hz, 1H), 3.20-3.10 (m, 1H), 2.89-2.51 (m, 5H), 2.60 (s, 3H), 2.42 (s, 3H), 2.40-2.27 (m, 2H), 2.10-2.0 (m, 1H), 1.98-1.80 (m, 3H), 1.781.72 (m, 2H), 1.69 (s, 3H), 1.66 (s, 3H), 1.63-1.51 (m, 3H), 1.50-1.39 (m, 3H), 1.36 (s, 3H), 1.35-1.31 (m, 2H), 1.29-1.18 (m, 8H), 1.12 (s, 3H), 1.05 (s, 3H), 1.01 (m, 1H), 0.95 (s, 3H),
0.90 (s, 3H), 0.87 (s, 3H), 0.85 (s, 3H), 0.80 (m, 1H); ESI-MS: m/z 804.52 (M+H)+; HPLC: 97.6%.
Example 20: Préparation of ilR.3S)-3-((((3aR,5aR.5bR.7aR.9S.l laR,llbR.13aS~)-l-iso nropvl-5a.5b.8.8.11a-nentamethvl-3a-(2-methvl-2-(4-(4-methvl-lH-imidazol-l-vDbenz amido)propanamîdo)-2-oxo-3,3a,4,5.5a.5b.6.7.7a.8.9.10,11,11 a,l lb,12,13.13a-octadeca hvdro-2H-cvclonentaralchrvsen-9-vDoxv)carbonvl)-2,2-dimethvlcvclobutane-l-carboxvlîc acid:
Intermediate 1 was coupled with 4-(4-methyl-lJ7-imidazol-l-yl)benzoic acid (Intermediate 13) followed by hydrolysis gave the desired product as an off-white solid. *H NMR (300 MHz, CDCb): δ ppm 7.89 (d, J= 8.4 Hz, 2H), 7.43 (d, J= 8.4 Hz, 2H), 7.08-6.97 (m, 2H), 4.46 (dd, J= 11.1,4.5 Hz, 1H), 3.22-3.11 (m, 1H), 2.90-2.53 (m, 5H), 2.35-2.27 (m, 2H), 2.30 (s, 3H), 2.10-1.84 (m, 4H), 1.78-1.68 (m, 7H), 1.67-1.18 (m, 17H), 1.37 (s, 3H), 1.12-1.05 (m, 7H), 0.95 (s, 3H), 0.87 (s, 3H), 0.85 (s, 3H), 0.84 (s, 3H), 0.79 (m, 1H); ESI-MS: m/z 865.72 (M+H)+; HPLC: 96.8%.
Example 21: Préparation of ilS.3R)-3-i(((3aR.5aR.5bR.7aR.9S.llaR.llbR,13aS)-3a-(2-(4chlorobenzamido)-2-methvlnropanamido)-l -isopropyl-5a,5b.8.8.11 a-pentamethvl-2-oxo-3, 3a,4.5.5a,5b,6.7.7a.8.9.10,l 1.1 la.l lb.l2,13,13a-octadecahvdro-2H-cvclopentara1chrvsen-9vl)oxy)carbonvD-2.2-dimethvlcvclobutane-l -carboxylic acid:
Intermediate 2 was coupled with 4-chlorobenzoic acid followed by hydrolysis gave the desired product as a white solid. *H NMR (300 MHz, CDCb): δ ppm 7.72 (d, J= 8.1 Hz, 2H), 7.42 (d, J= 7.8 Hz, 2H), 7.07 (s, 1H), 6.78 (s, 1H), 4.47 (dd, J= 11.4,4.5 Hz, 1H), 3.23-3.10 (m, 1H), 2.86-2.76 (m, 3H), 2.72-2.50 (m, 2H), 2.40-2.25 (m, 2H), 2.13-2.04 (m, 1H), 2.041.82 (m, 4H), 1.80-1.66 (m, 7H), 1.64-1.45 (m, 6H), 1.44-1.41 (m, 1H), 1.40-1.31 (m, 2H), 1.36 (s, 3H), 1.30-1.20 (m, 7H), 1.20-1.09 (m, 1H), 1.04 (s, 6H), 0.95 (s, 3H), 0.88 (s, 3H), 0.857 (s, 3H), 0.851 (s, 3H), 0.79 (m, 1H); ESI-MS: m/z 841.52 (M+Na)+; HPLC: 94.19%.
Example 22: Préparation 0f(lR.3S)-3-(i(i3aR,5aR.5bR,7aR.9S.llaR.llbR,13aS)-3a-(2-f4fluorobenzamido’)-2-methvlpropanamido)-l-isopropyl-5a.5b.8.8.11a-pentamethvl-2-oxo-3.3a. 4,5.5a.5b,6.7,7a, 8,9,10,11.1 la.l lb.l2.13.13a-octadecahvdro-2H-cvclopenta[a1chrvsen-9-vl') oxv)carbonvl)-2,2-dimethvlcvclobutane-l-carboxvlic acid:
HOOC’
Step 1: Synthesis of l-benzyl 3-((3aR,5aR,5bR,7aR,9S,llaR,llbR,13aS)-3a-(2-(4-fluorobenz amido)-2-methylpropanamido)-l-isopropyl-5a,5b,8,8,lla-pentamethyl-2-oxo-3,3a,4,5,5a,5b, 6,7,7a,8,9,10,ll,lla,llb,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl) (1R,3S)2,2-dimethylcyclobutane-l, 3-dicarboxylate:
BnOOC'
To a stirred solution of 4-fluorobenzoic acid (0.54 g, 3.89 mmol, 1.5 eq) in DMF (20 ml) at 0 °C under nitrogen atmosphère was added EDCI (0.99 g, 5.18 mmol, 2 eq), HOBT (0.52 g, 3.89 mmol, 1.5 eq), DMAP (0.15 g, 1.29 mmol, 0.5eq) and added Triethylamine (1.08 ml, 7.78 mmol, 3 eq) and stirred it for about 30 minutes. Then added l-((3aR,5aR,5bR, 7aR,9S,l laR,l lbR,13aS)-3a-(2-amino-2-methylpropanamido)-l-isopropyl-5a,5b,8,8,l lapentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11 a, 1 lb, 12,13,13a-octadecahydro-2Hcyclopenta[a]chrysen-9-yl) 3-benzyl (1 S,3R)-2,2-dimethylcyclobutane-l,3-dicarboxylate (Intermediate 1,2.0 g, 2.59 mmol, 1 eq). The reaction mixture was stirred at room température for about 14 hours. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture was quenched with ice cold water, filtered through Buchner fiinnel. The solid was separated, was dissolved in DCM, washed with sodium bicarbonate, water, brine solution then dried over sodium sulfate and concentrated under reduced pressure to give a crude compound. The crude compound was purified by flash silica column chromatography (100-200 silica gel) using 2% MeOH in DCM as an eluent gave the desired product (1.5 g, yield: 65.21%) as an off-white solid. *H NMR (300 MHz, CDCh): δ ppm 8.16 (s, 1H), 7.94-7.98 (m, 2H), 7.35 (m, 5H), 7.27-7.34 (m, 3H), 5.15, 5.10 (ABq, Jab= 12.3 Hz, 2H), 4.32-4.36 (t, 1H), 3.07-3.10 (t, 1H), 2.75-2.88 (m, 4H), 2.39-2.43 (m, 1H), 2.27-2.30 (m,
2H), 2.04-2.09 (m, 1H), 1.84-1.90 (m, 3H), 1.48-1.75 (m, 6H), 1.41-1.42 (m, 6H), 1.23-1.32 (m, 9H), 1.11-1.13 (m, 5H), 0.90-1.05 (m, 3H), 0.87 (s, 3H), 0.85 (s, 3H), 0.83 (s, 3H), 0.790.80 (m, 9H); ESI-MS: m/z 915.54 (M+Na)+·
Step 2: Synthesis of (lR,3S)-3-((((3aR,5aR,5bR, 7aR,9S,llaR,llbR,13aS)-3a-(2-(4-fluorobenz 5 amido)-2-methylpropanamido)-l-isopropyl-5a, 5b, 8,8,1 la-pentamethyl-2-oxo-3,3 a, 4,5,5a, 5b,
6,7,7a, 8,9,10,11,1 la,11b,12,13,13a-octadecahydro-2H-cyclopenta[a] chrysen-9-yl)oxy) carbonyl)-2,2-dimethylcyclobutane-l-carboxylic acid:
To a stirred solution of 1-benzyl 3-((3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-3a-(2-(4fluorobenzamido)-2-methylpropanamido)-l-isopropyl-5a,5b,8,8,lla-pentamethyl-2-oxo-3,3a, 10 4,5,5a,5b,6,7,7a, 8,9,10,11,1 la,l lb,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl) (lR,3S)-2,2-dimethylcyclobutane-l,3-dicarboxylate (step 1, 1.5 g, 0.541 mmol, 1.0 eq) in MeOH (15 ml) and THF (15 ml) was added aqueous 2.5 N KOH solution (3.35 ml, 8.39 mmol, 5 eq). The reaction mixture was stirred at room température for ovemight. TLC indicated starting material was consumed and the desired product was observed. The organic phase was 15 evaporated under reduced pressure, the reaction mixture was diluted with water (10 ml), cooled to 0 °C, pH adjusted to 5.0 with IN HCl and extracted with DCM (2x75 ml). The combined organic extracts were washed with water (50 ml), dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by silicagel column chromatography by using 0-5% methanol in dichloromethane gradient. The fractions 20 containing the expected product were combined and concentrated under reduced pressure to obtain the solid. The solid compound was dissolved in MTBE (10 ml) and added Hexane (30 ml) then precipitate was formed, and filtered through Buchner funnel. The solid was washed with MTBE: Hexane (1:3, 10 ml) and dried under vacuum to obtain the desired product (200 mg, yield: 15.38%) as a white solid. ’H NMR (400 MHz, DMSO-d6): δ ppm 12.14 (s, 1H), 25 8.16 (s, 1H), 7.94-7.98 (m, 2H), 7.27-7.34 (m, 3H), 4.32-4.36 (t, 1H), 3.07-3.10 (t, 1H), 2.752.88 (m, 4H), 2.39-2.43 (m, 1H), 2.27-2.30 (m, 2H), 2.04-2.09 (m, 1H), 1.84-1.90 (m, 3H), 1.48-1.75 (m, 6H), 1.41-1.42 (m, 6H), 1.23-1.32 (m, 9H), 1.11-1.13 (m, 5H), 0.90-1.05 (m, 3H), 0.87 (s, 3H), 0.85 (s, 3H), 0.83 (s, 3H), 0.79-0.80 (m, 9H); ESI-MS: m/z 803.47 (M+H)+; HPLC: 92.89 %.
The below examples 23-50 were prepared by the procedure similar (including reagents and reaction conditions) to the above described in the synthesis of example-22 using with their appropriate intermediates.
Example 23: Préparation of (lR.3S)-3-((((3aR.5aR,5bR.7aR.9S.llaR,llbR,13aS)-l-iso propyl-5a.5b.8.8.11a-pentamethvl-3a-(2-methvl-2-(4-methvlbenzamido')propanamido,)-2-oxo18389
3.3a.4. 5.5a.5b.6.7.7a,8,9.10.11.1 la,l lb,12,13.13a-octadecahvdro-2H-cvclopentaralchrysen9-vl) oxy)carbonyl)-2,2-dimethvlcvclobutane-l-carboxvlic acid:
Intermediate 1 was coupled with 4-methylbenzoic acid followed by hydrolysis gave the desired product as a white solid. ’H NMR (400 MHz, DMSO-d6): δ ppm 12.13 (s, 1H), 8.03 (s, 1H), 7.78 (d, J= 8.0 Hz, 2H), 7.31 (s, 1H), 7.25 (d, J= 8.0 Hz, 2H),4.32-4.36 (m, 1H), 3.07-
3.10 (m, 1H), 2.73-2.81 (m, 3H), 2.39-2.44 (m, 1H), 2.35 (s, 3H), 2.25-2.30 (m, 2H), 2.04-2.08 (m, 1H), 1.86-1.95 (m, 3H), 1.51-1.75 (m, 6H), 1.425 (d, J= 8.0 Hz, 6H), 1.23-1.29 (m, 8H), 1.11-1.13 (m, 7H), 0.95-1.02 (m, 3H), 0.91 (s, 3H), 0.865 (d, J= 8.0 Hz, 6H), 0.80-0.81 (m, 9H); ESI-MS: m/z 799.42 (M+H)+; HPLC: 91.77%.
Example 24: Préparation of (lR.3S)-3-((ï(3aR.5aR.5bR,7aR.9S.llaR.llbR,13aS)-3a-(2ifuran-3-carboxamidol-2-methvlpropanamîdo,)-l-isopropvl-5a.5b.8.8.11a-pentamethvl-2oxo-3.3a.4.5.5a,5b.6.7.7a,8,9.10.11.1 la.l lb.l2.13.13a-octadecahvdro-2H-cyclopentaral chrvsen-9-vl) oxv')carbonvD-2.2-dimethylcvclobutane-l -carboxvlic acid:
Intermediate 1 was coupled with furan-3-carboxylic acid followed by hydrolysis gave the desired product as a white solid. *H NMR (300 MHz, DMSO-dô): δ ppm 12.15 (s, 1H), 8.215 (d, J= 3 Hz, 1H), 7.83 (s, 1H), 7.715 (d, J= 3 Hz, 1H), 7.35 (s, 1H), 6.835 (d, J= 3 Hz, 1H), 4.33-4.38 (m, 1H), 3.07-3.11 (m, 1H), 2.73-2.83 (m, 3H), 2.28-2.43 (m, 3H), 2.03-2.10 (m, 1H), 1.86-1.90 (m, 3H), 1.40-1.76 (m, 6H), 1.34-1.38 (m, 6H), 1.23-1.30 (m, 8H), 1.111.19 (m, 9H), 1.01 (m, 2H), 0.95 (s, 3H), 0.87-0.91 (s, 3H), 0.81-0.85 (m, 11H); ESI-MS: m/z 797.42 (M+Na)+; HPLC: 92.55%.
Example 25: Préparation of (lR.3S)-3-(ï(ï3aR.5aR.5bR.7aR.9S.llaR.llbR.13aS')-l-iso pronvl-5a,5b.8.8.1 la-pentamethvl-3a-i2-methvl-2-(4-('trifluoromethvnbenzamido}propan amido’)-2-oxo-3.3a.4.5,5a,5b.6.7.7a,8.9,10,l 1.1 la.l lb.l2.13.13a-octadecahydro-2H-cvclo pentaralchrysen-9-vDoxv)carbonvD-2,2-dimethvlcvclobutane-1 -carboxvlic acid:
Intermediate 1 was coupled with 4-(trifluoromethyl)benzoic acid followed by hydrolysis gave the desired product as an off white solid. ’H NMR (300 MHz, DMSO): δ ppm 12.13 (s, 1H), 8.39 (s, 1H), 8.10 (d, J = 8.4 Hz, 2H), 7.85 (d, J = 8.4 Hz, 2H), 7.39 (s, 1H), 4.31-4.36 (t, 1H), 3.07-3.11 (t, 1H), 2.72-2.82 (m, 3H), 2.27-2.31 (m, 3H), 2.05-2.11 (m, 2H), 1.76-1.89 (m, 5H), 1.56-1.63 (m, 4H), 1.43-1.44 (m, 9H), 1.26-1.30 (m, 8H), 1.11-1.13 (m, 6H), 0.98-1.03 (m, 3H), 0.85-0.90 (m, 6H), 0.76-0.80 (m, 9H); ESI-MS: m/z 853.43 (M+H)+. HPLC: 97.60%.
Example 26: Préparation of (lR.3S)-3-(('((3aR.5aR,5bR.7aR.9S.llaR.llbR.13aS)-3a-i2(fiiran-2-carboxamido)-2-methvlpronanamido)-l-isopronvl-5a.5b.8.8.1 la-pentamethvl-2-oxo -3.3a.4.5.5a.5b.6.7.7a.8.9.I0.11.1 Ia,l lb.l2,13,13a-octadecahvdro-2H-cvclonentara1chrysen9-vl) oxv)carbonvl)-2.2-dimethvlcyclobutane-l-carboxvlic acid:
Intermediate 1 was coupled with furan-2-carboxylic acid followed by hydrolysis gave the desired product as a white solid. ’H NMR (300 MHz, DMSO-dô): δ ppm 12.13 (s, 1H), 7.83-7.91 (m, 2H), 7.45 (s, 1H), 7.08-7.10 (m, 1H), 6.61-6.63 (m, 1H), 4.33-4.38 (m, 1H), 3.07-
3.11 (m, 1H), 2.73-2.83 (m, 3H), 2.28-2.43 (m, 3H), 2.03-2.10 (m, 1H), 1.86-1.90 (m, 3H), 1.40-1.76 (m, 6H), 1.34-1.38 (m, 6H), 1.23-1.30 (m, 8H), 1.11-1.19 (m, 9H), 1.01 (m, 2H), 0.95 (s, 3H), 0.87-0.91 (s, 3H), 0.81-0.85 (m, 11H); ESI-MS: m/z 797.42 (M+Na)+; HPLC: 92.65%.
Example 27: Préparation of ilR.3S)-3-((((3aR,5aR,5bR,7aR,9S.llaR,llbR.13aS')-l-iso propyl-5a.5b.8.8.1 la-nentamethvl-3a-(2-methvl-2-il-phenvlcvclonentane-l-carboxamido) nropanamido)-2-oxo-3.3a.4.5.5a,5b.6,7.7a,8.9.10.1 LI la,l lb.l2.13.13a-octadecahvdro-2Hcyclo pentarakhrvsen-g-vnoxvlcarbonvll^^-dimethvlcyclobutane-l -carboxylic acid:
Intermediate 1 was coupled with 1-phenylcyclopentane-l-carboxylic acid followed by hydrolysis gave the desired product as a white solid. ’H NMR (300 MHz, DMSO-dô): δ ppm 12.03 (brs, 1H), 7.20-7.36 (m, 6H), 6.48 (s, 1H), 4.33-4.38 (m, 1H), 3.07-3.09 (m, 1H), 2.702.82 (m, 3H), 2.28-2.31 (m, 2H), 1.50-2.03 (m, 16H), 1.27-1.36 (m, 15H), 1.03-1.10 (m, 14H), 0.81-0.96 (m, 16H); ESI-MS: m/z 853.56 (M+H)+; HPLC: 98.50%.
Example 28: Préparation of (lR.3S)-3-((((3aR.5aR.5bR,7aR.9S.llaR.llbR.13aS')-l-iso pronvl-5a,5b<8.8.11a-pentamethvl-3a-(2-methvl-2-(quinoline-2-carboxamido)propanamido)2-oxo-3.3a,4.5.5a,5b.6.7.7a.8.9.10.11.1 la.1 lb.l2.13.13a-octadecahydro-2H-cvclopentaral chrvsen-9-vl)oxv)carbonyl)-2,2-dimethvlcvclobutane-l-carboxvlic acid:
Intermediate 1 was coupled with quinoline-2-carboxylic acid followed by hydrolysis gave the desired product as a white solid. ’H NMR (300 MHz, DMSO-dô): δ ppm 12.13 (s, 1H), 8.98 (s, 1H), 8.59 (d, J= 8.7 Hz, 1H), 8.16 (d, J= 8.7 Hz, 1H), 8.119-8.092 (m, 2H), 7.907.85 (m, 1H), 7.75-7.70 (m, 2H), 4.37-4.32 (t, 1H), 3.12-3.07 (m, 2H), 2.85-2.73 (m, 3H), 2.40-
2.12 (m, 5H), 1.92-1.79 (m, 5H), 1.60 (m, 9H), 1.31-1.26 (m, 6H), 1.17-1.10 (m, 8H), 0.910.88 (m, 11H), 0.81-0.79 (m, 10H); ESI-MS: m/z 858.55 (M+Na)+. HPLC: 97.06%.
Example 29: Préparation of (lR,3S)-3-fi((3aR.5aR,5bR,7aR,9S.llaR.llbR,13aS)-l-iso propyl-5a.5b.8.8.1 la-pentamethvl-3a-f2-methvl-2-(3-methvlnicolinamido)propanamido)-2oxo-3.3a,4.5,5a,5b.6.7.7a.8.9.10.1 L1 la,l lb.l2.13.13a-octadecahydro-2H-cvclopentaral chrvsen-9-vl') oxv)caibonyl')-2.2-dimethvlcvclobutane-l-carboxvlic acid:
Intermediate 1 was coupled with 3-methylpicolinic acid followed by hydrolysis gave the desired product as a white solid. ’H NMR (300 MHz, DMSO-dô): δ ppm 12.18 (brs, 1H), 8.66 (s, 1H), 8.47-8.45 (m, 1H), 7.76-7.73 (m, 1H), 7.51-7.45 (m, 2H), 4.37-4.32 (m, 1H), 3.123.07 (m, 2H), 2.84-2.73 (m, 4H), 2.53 (brs, 3H), 2.42 (brs, 1H), 2.34-2.23 (m, 2H), 2.15 (brs, 1H), 2.09 (brs, 1H), 1.92-1.83 (m, 3H), 1.52-1.49 (m, 8H), 1.36 (m, 4H), 1.26-1.23 (m, 3H), 1.14-1.10 (m, 9H), 1.03-1.00 (m, 2H), 0.90-0.89 (m, 9H), 0.81-0.79 (m, 10H); ESI-MS: m/z 799.73 (M+H)+; HPLC: 99.31%.
Example 30: Préparation of (lR,3S)-3-i(ïï3aR,5aR,5bR,7aR,9S.llaR.llbR,13aS)-l-iso propyl-5a.5b.8.8.1 la-pentamethvl-3a-(2-methvl-2-(2-methylfiiran-3-carboxamido)nropan amido')-2-oxo-3.3aA5,5a,5b.6.7.7a.8.9J0.11.1 la.1 lb.l2.13.13a-octadecahydro-2H-cyclo pentaralchrvsen-9-vDoxv)carbonyn-2.2-dimethvlcvclobutane-l-carboxvlicacid:
Intermediate 1 was coupled with 2-methylfuran-3-carboxylic acid followed by hydrolysis gave the desired product as a white solid. *H NMR (300 MHz, DMSO-de): δ ppm 12.14 (brs, 1H), 7.64 (s, 1H), 7.519 (d,JAB= 1.5 Hz, 1H), 7.29 (s, 1H), 6.915 (d,JjB= 1.5 Hz, 1H), 4.38-4.33 (m, 1H), 3.11-3.07 (m, 1H), 2.88-2.67 (m, 5H), 2.48-2.46 (m, 4H), 2.40-2.15 (m, 4H), 2.09-2.03 (m, 1H), 1.92-1.58 (m, 10H), 1.40-1.36 (m, 6H), 1.28-1.17 (m, 5H), 1.161.10 (m, 8H), 1.06-0.97 (m, 3H), 0.95-0.80 (m, 15H); ESI-MS: m/z 788.73 (M+H)+; HPLC: 99.08%.
Example 31: Préparation of (lR,3S)-3-(ï((3aR.5aR.5bR,7aR.9S.llaR,llbR,13aS')-l-iso propvl-5a.5b.8.8.11a-pentamethvl-3a-(2-methyl-2-(2-morpholinonicotinamido’)propan amido)-2-oxo-3.3a.4.5.5a.5b.6.7.7a.8.9,10,11.1 la,l lb.l2,13.13a-octadecahvdro-2H-cvclo pentaraIchrysen-9-vDoxv')carbonvD-2.2-dimethvlcvclobutane-l-carboxvlic acid:
Intermediate 1 was coupled with 2-morpholinonicotinic acid followed by hydrolysis gave the desired product as a white solid. ’H NMR (300 MHz, DMSO-de): δ ppm 12.09-12.06 (brs, 1H), 9.06 (s, 1H), 8.31-8.29 (m, 1H), 7.96-7.93 (m, 1H), 7.63 (s, 1H), 7.05-7.01 (m, 1H), 4.36 (m,lH), 3.69 (brs, 4H), 3.13-3.07 (m, 6H), 2.79-2.72 (m, 4H), 2.40-2.12 (m, 6H), 1.961.78 (m, 5H), 1.61-1.55 (m, 11H), 1.39-1.26 (m, 10H), 1.15-1.04 (m, 12H), 0.91-0.81 (m, 9H); ESI-MS: m/z 871.78 (M+H)+; HPLC: 93.74%.
Example 32: Préparation of (lR,3S)-3-((f(3aR.5aR.5bR.7aR.9S.l laR,l lbR.13aS)-l-iso propyL5a^b1818Jlæ£entamethxL3a^2zmethïL2zÎExnmidine=2=çaiboxamido]^roEanamido) -2-oxo-3.3a,4,5,5a.5b.6.7.7a.8,9.10.11,11a,! lb,12,13.13a-octadecahydro-2H-cvclopentaral chrysen-9-vDoxv)carbonvl)-2,2-dimethvlcvclobutane-l-carboxvlic acid:
Intermediate 1 was coupled with pyrimidine-2-carboxylic acid followed by hydrolysis gave the desired product as a white solid. *H NMR (300 MHz, DMSO-dô): δ ppm 12.12 (brs, 1H) 8.98-8.97 (m, 3H), 7.72-7.67 (m, 2H), 4.35 (m, 1H), 3.13-3.07 (m, 1H), 2.82-2.73 (m, 4H), 2.44-2.12 (m, 4H), 1.92-1.85 (m, 3H), 1.83-1.63 (m, 3H), 1.48 (m, 3H), 1.35-1.26 (m, 9H), 1.15-1.10 (m, 8H), 1.03-0.99 (m, 2H), 0.902-0.88 (m, 10H), 0.81-0.80 (m, 12H); ESI-MS: m/z 787.62 (M+H)+; HPLC: 92.90%.
Example 33: Préparation of ilR.3S)-3-f((i3aR,5aR,5bR.7aR.9S.llaR.l lbR.13aS)-3a-i2-i2.5dimethvlfuran-3-carboxamido1-2-methvlpropanamido)-l -isonropyl-5a.5b.8.8.11 a-penta methvl-2-oxo-3,3a.4,5,5a.5b.6.7.7a.8.9.10.11,11a,! lb.l2.13J3a-octadecahvdro-2H-cyclo pentafal chrysen-9-vDoxv)carbonvl)-2.2-dimethvlcvclobutane-l-carboxylic acid:
Intermediate 1 was coupled with 2,5-dimethylfuran-3-carboxylic acid followed by hydrolysis gave the desired product as a white solid. ’H NMR (300 MHz, DMSO-dô): δ ppm 12.17 (brs, 1H), 7.51 (s, 1H), 7.27 (s, 1H), 6.49 (s, 1H), 4.38-4.32 (m, 1H), 3.11-3.07 (m, 1H), 2.87-2.73 (m, 3H), 2.44-2.38 (m, 4H), 2.31-2.22 (m, 5H), 2.09-2.03 (m, 1H), 1.92-1.83 (m, 3H), 1.75-1.58 (m, 5H), 1.38-1.37 (m, 9H), 1.30-1.26 (m, 5H), 1.13-1.10 (m, 9H), 1.02 (m, 2H), 0.95-0.81 (m, 18H); ESI-MS: m/z 803.59 (M+H)+; HPLC: 95.83%.
Example 34: Préparation of (lR.3S)-3-((((3aR.5aR.5bR,7aR.9S,llaR,llbR,13aS)-3a-(2-(2(l.l-dioxidothiomorpholino)acetamido)-2-methvlpropanamido)-l-isopropvl-5a.5b.8,8.11apentamethyl-2-oxo-3.3a,4,5,5a,5b.6.7,7a,8.9.10.11,1 la, 1 lb,12.13.13a-octadecahydro-2Hcvclopentaralchrvsen-9-vDoxv)carbonvl)-2,2-dimethvlcyclobutane-l-carboxvlicacid:
Intermediate 1 was coupled with 4-(carboxymethyl)thiomorpholin-4-ium 1,1-dioxide
2,2,2-trifluoroacetate (Intermediate 22) followed by hydrolysis gave the desired product as a white solid. Ή NMR (300 MHz, DMSO-d6): δ ppm 12.19 (brs, 1H), 7.15 (s, 1H), 6.73 (brs,
1H), 4.38-4.33 (m, 1H), 3.11-3.07 (m, 1H), 2.86-2.73 (m, 3H), 2.39-2.27 (m, 3H), 2.17-1.99 (m, 2H), 1.92-1.87 (m, 3H), 1.69-1.56 (m, 8H), 1.39-1.27 (m, 21H), 1.14-1.09 (m, 12H), 0.910.81 (m, 16H); HPLC: 94.66%.
Example 35: Préparation of ilR,3S)-3-(fii3aR,5aR,5bR.7aR.9S.l laR.l lbR,13aS)-l-iso propyl-5a,5b.8.8.1 la-pentamethvl-3a-(2-methvl-2-(piperidine-4-carboxamido)propanamido')2-oxo-3.3a,4,5.5a.5b.6.7,7a,8,9.10.11.1 la, 1 lb.l2.13.13a-octadecahvdro-2H-cvclopentaral chrvsen-Ç-vDoxvkarbonvD^^-dimethvlcvclobutane-l -carboxylic acid hydrochloride:
Step 1: Synthesis of (lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,llaR,llbR,13aS)-3a-(2-(l-(tertbutoxycarbonyl)piperidine-4-carboxamido)-2-methylpropanamido)-l-isopropyl-5a,5b,8,8, la-pentamethyl-2-oxo-3,3a, 4,5,5a, 5b, 6,7,7a,8,9,10,11,lia,11 b, 12,13,13a-octadecahydro2H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-l-carboxylic acid:
Intermediate 1 was coupled with l-(tert-butoxycarbonyl) piperidine-4-carboxylic acid followed by hydrolysis gave the desired product as a white solid. *H NMR (300 MHz, DMSOd6): δ ppm 12.16 (brs, 1H), 7.14 (s, 1H), 6.09 (s, 1H), 4.47-4.42 (m, 1H), 4.11 (brs, 2H), 3.15 (m, 1H), 3.02-2.57 (m, 8H), 2.28-2.22 (m, 3H), 2.05-1.83 (m, 3H), 1.67-1.62 (m, 4H), 1.561.54 (m, 7H), 1.45-1.40 (m, 13H), 1.36-1.34 (s, 6H), 1.28-1.20 (m, 9H), 1.13 (s, 3H), 0.96-0.91 (m, 11H), 0.85 (m, 7H); ESI-MS: m/z 892.53 (M+H)+.
Step 2: Synthesis of (lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,llaR,llbR,13aS)-l-isopropyl-5a,5b, 8,8,lla-pentamethyl-3a-(2-methyl-2-(piperidine-4-carboxamido)propanamido)-2-oxo-3,3a,4, 5,5a, 5b, 6,7,7a, 8,9,10,11,lia,11b, 12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl) oxy)carbonyl)-2,2-dimethylcyclobutane-l-carboxylic acid hydrochloride:
To a stirred solution of (lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-3a-(2-(l(tert-butoxycarbonyl)piperidine-4-carboxamido)-2-methylpropanamido)-l-isopropyl-5a, 5b,8,8,11 a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11 a, 11 b, 12,13,13a-octadeca hydro-2H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-l-carboxyhc acid (step 1, 0.52 g, 0.58 mmol, 1.0 eq) in DCM (15 ml) then cooled to 0 °C and added 1,4Dioxane.Hcl (10 ml) then the reaction mixture was stirred at room température for about 14 hours. TLC indicated starting material was consumed and the desired product was observed. The organic phase was evaporated under reduced pressure to get the solid compound, that solid compound was stirred in MTBE for about 1 hour and filtered through Buchner tunnel then the solid was washed with n-pentane then the solid compound was filtered through the Buchner tunnel to obtain the desired product (210 mg, yield: 43.75%) as a white solid. ’H NMR (300 MHz, DMSO-de): δ ppm 12.16 (brs, 1H), 8.91-8.88 (m, 1H), 8.43-8.37 (m, 1H), 7.88 (s, 1H), 7.24 (s, 1H), 4.38-4.33 (m, 1H), 3.26-3.22 (m, 2H), 3.07 (s, 2H), 2.85-2.83 (m, 3H), 2.39-2.31 (m, 2H), 2.06-1.58 (m, 14H), 1.48-1.32 (m, 14H), 1.27-1.10 (m, 16H), 1.07-0.81 (m, 15H); ESI-MS: m/z 792.57 (M+H)+; HPLC: 91.08%, Chloride content is 4.2%.
Example 36: Préparation of (lR.3S)-3-((ï(3aR.5aR.5bR.7aR,9S.l laR.l lbR.13aS)-3a-(2-((S)2-amino-3-methvlbutanamido)-2-methvlpropanamido)-l-isonropyl-5a.5b.8.8.1 la-penta methyl-2-oxo-3.3a.4.5.5a.5b,6.7.7a.8.9.10.11,11 a, 11 b, 12,13.13a-octadecahvdro-2H-cvclo nentaralchrvsen-9-vl)oxv)carbonvl)-2,2-dimethvlcvclobutane-l-carboxvlic______________acid hydrochloride:
Step 1: Synthesis of (lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,llaR,llbR,13aS)-3a-(2-((S)-2-((tertbutoxycarbonyl)amino)-3-methylbutanamido)-2-methylpropanamido)-l-isopropyl-5a,5b,8,8, la-pentamethyl-2-oxo-3,3 a, 4,5,5a, 5 b, 6,7,7a,8,9,10,11,lia,11b,12,13,13a-octadecahydro2H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-l-carboxylic acid:
Intermediate 1 was coupled with (tert-butoxycarbonyl)-L-valine followed by hydrolysis gave the desired product as a white solid. ’H NMR (300 MHz, DMSO-de): δ ppm 12.09 (brs, 1H), 7.98-6.91 (m, 3H), 4.38-4.33 (m, 1H), 3.67-3.54 (m, 1H), 3.11-3.07 (m, 2H), 2.83-2.79 (m, 2H), 2.39-2.09 (m, 2H), 2.01-1.86 (m, 6H), 1.75-1.49 (m, 7H), 1.38-1.26 (m, 24H), 1.131.107 (m, 12H), 0.91-0.82 (m, 20H); ESI-MS: m/z 880.48 (M+H)+.
Step 2: Synthesis of (lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,llaR,llbR,13aS)-3a-(2-((S)-2-amino -3-methylbutanamido)-2-methylpropanamido)-l-isopropyl-5a,5b,8,8,lla-pentamethyl-2-oxo3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11 a, 11b, 12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-l-carboxylic acid hydrochloride:
To a stirred solution of (lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,llaR,llbR,13aS)-3a-(2((S)-2-((tert-butoxycarbonyl)amino)-3-methylbutanamido)-2-methylpropanamido)-l-iso propyl-5a,5b,8,8,l la-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,l 1,1 la,l 1 b,12,13,13aoctadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-lcarboxylic acid (step 1,0.52 g, 0.58 mmol, 1.0 eq) in DCM (15 ml) then cool to 0 °C and added 1,4-Dioxane.Hcl (10 ml) then the reaction was stirred at room température for about 14 hours. TLC indicated starting material was consumed and the desired product was observed. The organic phase was evaporated under reduced pressure to get the solid compound, that solid compound was stirred in MTBE for about 1 hour and filtered through Buchner funnel then the solid was washed with n-pentane then the solid compound was filtered through the Buchner funnel to obtain the desired product (55 mg, yield: 14.86%) as a white solid. *H NMR (300 MHz, DMSO-de): δ ppm 12.08 (brs.lH), 8.56-8.40 (m, 3H), 7.32-7.26 (m, 1H), 4.38-4.36 (m, 1H), 3.62 (brs, 1H), 3.17-3.07 (m, 2H), 2.82-2.73 (m, 3H), 2.39-2.03 (m, 5H), 1.92-1.86 (m, 3H), 1.77-1.65 (m, 7H), 1.46-1.34 (m, 12H), 1.26 (s, 4H), 1.13-1.06 (m, 12H), 0.90-0.81 (m, 19H); ESI-MS: m/z 802.68 (M+Na)+; HPLC: 95.54%, Chloride content 4.65%.
Example 37: Préparation of (IR.3S)-3-(if(3aR.5aR.5bR,7aR.9S.llaR.llbR,13aS)-3a-(I-(4chlorobenzamido)cvclopropane-l-carboxamido)-l-isopropyl-5a,5b.8.8.11a-pentamethvl-2oxo-3.3a,4,5.5a,5b.6.7.7a.8.9.10.11,11a,! lb,12,13.13a-octadecahvdro-2H-cvclopentaral chrvsen-9-vl)oxv)carbonvl)-2.2-dimethvlcvclobutane-l-carboxvlic acid:
Intermediate 3 was coupled with 4-chlorobenzoic acid followed by hydrolysis gave the desired product as a white solid. ’H NMR (300 MHz, DMSO-d6): δ ppm 12.14 (s, 1H), 8.85 (s, 1H), 7.93 (d, J= 6.0 Hz, 2H), 7.57 (d, J= 6.0 Hz, 2H), 7.48 (s, 1H), 4.36-4.31 (m, 1H),
3.11-3.07 (m, 2H), 2.83-2.67 (m, 5H), 2.38-2.12 (m, 6H), 1.89-1.83 (m, 3H), 1.71-1.63 (m, 4H), 1.57-1.47 (m, 8H), 1.43-1.39 (m, 11H), 1.29-1.26 (m, 6H), 1.12-0.80 (m, 12H); ESI-MS: m/z 817.45 (M+H)+; HPLC: 97.69%.
Example 38: Préparation of (lR,3S)-3-((((3aR,5aR,5bR,7aR,9S.llaR.llbR.13aS)-lisonropvl-5a,5b.8.8.11a-pentamethvl-3a-(l-(6-methvlnicotinamido,)cvclopronane-l-carbox amido1-2-oxo-3.3a.4.5.5a.5b.6.7,7a.8.9.10.11.11a.llb.l2.13.13a-octadecahvdro-2H-cyclo pentalal chrvsen-9-vl)oxy')carbonvl~)-2.2-dimethylcyclobutane-l-carboxylic acid:
Intermediate 3 was coupled with 6-methylnicotinic acid followed by hydrolysis gave the desired product as a white solid. ’H NMR (300 MHz, DMSO-dô): δ ppm 12.16 (brs,lH), 8.95-8.86 (m,2H), 8.14-8.11 (m, 1H), 7.50-7.36 (m, 2H), 4.37-4.31 (m, 1H), 3.11-3.07 (m, 1H), 2.83-2.76 (m, 2H), 2.45-2.07 (m, 6H), 1.89-1.83 (m, 2H), 1.71-1.47 (m, 9H), 1.44-1.26 (m, 20H), 1.29-1.07 (m, 4H), 1.03.-0.80 (m, 16H); ESI-MS: m/z 820.44 (M+H)+ HPLC: 96.39%.
Example 39: Préparation of (lR.3S')-3-((((3aR,5aR.5bR.7aR.9S.llaR,llbR.13aS')-3a-il-(4fluorobenzamido)cvclopronane-l-carboxamido')-l-isopropvl-5a.5b.8.8.11a-pentamethvl-2oxo-3,3a.4.5.5a.5b.6.7.7a,8.9.10.11,1 la,l lb.l2.13.13a-octadecahvdro-2H-cyclopentara1 chrvsen-9-vBoxv)carbonvD-2,2-dimethvlcvclobutane-l-carboxylic acid:
Intermediate 3 was coupled with 4-fluorobenzoic acid followed by hydrolysis gave the desired product as a white solid. ’H NMR (300 MHz, DMSO-d6): δ ppm 12.14 (s, 1H), 8.818.00 (s, 1H), 7.98-7.96 (m, 2H), 7.49 (s, 1H), 7.36-7.30 (m, 2H), 4.36-4.31 (m, 1H), 3.17-3.07 (m, 2H), 2.83-2.76 (m, 2H), 2.45-2.12 (m, 5H), 1.89-1.83 (m, 2H), 1.73-1.57 (m, 9H), 1.471.43 (m, 11H), 1.26-1.12 (m,9H), 1.10-1.03 (m,5H), 1.00-0.90(m, 12H); ESI-MS: m/z 823.35 (M+Na)+; HPLC: 99.10%.
Example 40: Préparation of (lR,3S)-3-((((3aR.5aR,5bR,7aR,9S,llaR.llbR,13aS)-lisopropyl-5a,5b.8.8,11 a-pentamethyl-3a-( 1 -(4-methylbenzamido)cvclopropane-1 carboxamido)-2-oxo-3.3a,4.5.5a.5b,6,7.7a,8.9.10.11,1 la,l lb,12,13,13a-octadecahvdro-2Hcvclopentaralchrvsen-9-vDoxv)carbonvD-2.2-dimethylcvclobutane-l-carboxvlic acid:
HOOC
Intermediate 3 was coupled with 4-methylbenzoic acid followed by hydrolysis gave the desired product as a white solid. ’H NMR (300 MHz, DMSO-de): δ ppm 12.03 (brs, 1H), 8.74 (s, 1H), 7.80 (d, J= 6.0 Hz, 2H), 7.43 (s, 1H), 7.28 (d, J= 6.0 Hz, 2H ), 4.36-4.31 (m, 1H),
3.11-3.07 (m, 1H), 2.82-2.73 (m, 3H), 2.45 (m, 1H), 2.39-2.12 (m, 8H), 1.92-1.83 (m, 2H), 1.71-1.40 (m, 9H), 1.26 (m, 8H), 1.12-1.10 (m, 9H), 1.02-1.00 (m, 4H), 0.90-0.87 (m, 5H), 0.84-0.80 (m, 10H); ESI-MS: m/z 819.16 (M+Na)+; HPLC: 98.11%.
Example 41: Préparation oft'lS.SRWiïGaR.SaR.SbRJaR.ÇS.llaR.llbR.lSaSl-Sa-H-f^chlorobenzamidokvclopropane-l-carboxamido)-l-isopropyl-5a.5b.8.8.1 la-pentamethyl-2oxo-3.3a.4.5.5a,5b.6.7.7a.8.9.10.11.1 la.l lb.l2.13.13a-octadecahvdro-2H-cvclopentaral chrvsen-9-vl')oxv)carbonvl,)-2.2-dimethvlcvclobutane-l-carboxvlic acid:
HOOC'
Intermediate 4 was coupled with 4-chlorobenzoic acid followed by hydrolysis gave the desired product as a white solid. ’HNMR(300 MHz, DMSO-d6): δ ppm 12.14 (s,lH), 8.85 (s, 1H), 7.93 (d, J= 6.0 Hz, 2H), 7.57 (d, J=6.0 Hz, 2H), 7.48 (s, 1H), 4.36-4.31 (m, 1H), 3.113.07 (m, 1H), 2.87-2.73 (m, 3H), 2.45-2.38 (m, 1H), 2.33-2.22 (m, 2H), 2.18-2.12 (m, 1H), 1.98-1.82 (m, 2H), 1.73-1.40 (m, 8H), 1.29-1.26 (m, 10H), 1.17-1.10 (m, 7H), 1.01-0.93 (m, 4H), 0.89 (s, 3H) 0.84 (s, 3H) 0.79 (s, 12H); ESI-MS: m/z 817.50 (M+H)+; HPLC: 93.55%. Example 42: Préparation of (lR,3S)-3-((((3aR.5aR,5bR.7aR.9S.llaR,llbR.13aS)-3a-(l-(4chlorobenzamido)cvclobutane-l-carboxamido)-l-isopropyl-5a.5b.8.8Jla-pentamethvl-2oxo-3,3a.4.5.5a,5b,6,7.7a,8.9.10.1 Ll la,l lb.l2,13.13a-octadecahydro-2H-cvclopentaral chrysen-9-vl~)oxy) carbonyl~)-2.2-dimethvlcvclobutane-l -carboxvlic acid:
HOOC1
Intermediate 5 was coupled with 4-chlorobenzoic acid followed by hydrolysis gave the desired product as a white solid. *H NMR (300 MHz, DMSO-d6): δ ppm 12.14 (brs, 1H), 8.79 (s, 1H), 7.955 (d, J= 9.0 Hz, 2H), 7.565 (d, J= 9.0 Hz, 2H), 7.44 (s, 1H), 4.35-4.30 (m, 1H),
3.11-3.04 (m, 1H), 2.82-2.66 (m, 3H), 2.44-2.38 (m, 1H), 2.30-2.19 (m, 6H), 1.92-1.38 (m, 12H), 1.26 (brs, 8H), 1.15-1.10 (m, 7H), 0.98 (s, 3H), 0.90 (s, 3H), 0.83 (s, 3H), 0.79-0.77 (m, 6H), 0.72 (s, 3H), 0.58 (s, 3H); ESI-MS: m/z 853.62 (M+Na)+; HPLC: 98.95%.
Example 43: Préparation of (lR.3S)-3-((((3aR.5aR,5bR.7aR.9S.llaR.llbR.13aS)-lisopropyl-5a,5b.8.8.11a-pentamethvl-3a-(l-(6-methvlnicotinamido)cvclobutane-lcarboxamido)-2-oxo-3.3a.4.5.5a.5b.6.7.7a.8.9.10.11.1 la.1 lb.l2.13.13a-octadecahydro-2Hcvclonentaralchrvsen-9-vl)oxv)carbonvl)-2.2-dimethvlcvclobutane-l-carboxvlic acid:
Intermediate 5 was coupled with 6-methylnicotinic acid followed by hydrolysis gave the desired product as a white solid. 'H NMR (300 MHz, DMSO-de): δ ppm 12.09 (brs, 1H), 8.98-8.83 (m, 2H), 8.17-8.13 (m, 1H), 7.46-7.36 (m, 2H), 4.35-4.30 (m, 1H), 3.11-3.07 (m, 1H), 2.94-2.68 (m, 4H), 2.59-2.56 (m, 2H), 2.44-2.13 (m, 6H), 1.89-1.76 (m, 13H), 1.26-1.23 (m, 8H), 1.15-1.11 (m, 7H), 0.97 (m, 3H), 0.90-0.71 (m, 15H), 0.58 (s, 3H); ESI-MS: m/z 812.52 (M+H)+; HPLC: 94.64%.
Example 44: Préparation of (lR,3S)-3-((((3aR,5aR,5bR.7aR.9S.llaR.llbR.13aS)-lisopronvl-5a.5b.8.8.11a-pentamethvl-2-oxo-3a-(l-(pvrimidine-2-carboxamido)cvclobutanel-carboxamido)-3.3a.4.5.5a.5b.6.7.7a.8.9.10.11.1 la. 1 lb.l2.13.13a-octadecahvdro-2Hcvclopentalal chrvsen-9-vDoxv)carbonvD-2,2-dimethvlcvclobutane-l-carboxylic acid:
Intermediate 5 was coupled with pyrimidine-2-carboxylic acid followed by hydrolysis gave the desired product as a white solid. ’H NMR (300 MHz, DMSO-dô): δ ppm 12.12 (brs, 1H), 9.31 (s, 1H), 9.00-8.99 (m, 2H), 7.74-7.70 (m, 1H), 7.51 (s,lH), 4.35-4.29 (m, 1H), 3.103.06 (m, 1H), 2.82-2.75 (m, 2H), 2.72-2.63 (m, 3H), 2.34-2.18 (m, 6H), 1.92-1.36 (m, 12H),
1.26-1.11 (m, 15H), 1.01-0.97 (m, 2H), 0.90 (brs, 3H), 0.82-0.68 (m, 12H), 0.42 (brs, 3H); ESIMS: m/z 799.79 (M+H)+; HPLC: 98.35%.
Example 45: Préparation of (lR.3S)-3-((((3aR.5aR.5bR.7aR,9S.llaR.llbR.13aS)-lisonropyl-5a.5b,8.8.11a-pentamethvl-3a-(l-(2-morpholinonicotinamido')cvclobutane-lcarboxamido’)-2-oxo-3.3a.4.5.5a.5b.6.7.7a.8.9.10.11.1 la, 1 lb.l2.13.13a-octadecahvdro-2Hcyclopentaral chrvsen-9-vl~)oxvkarbonvI~)-2,2-dimethvlcvclobutane-l-carboxylic acid:
Intermediate 5 was coupled with 2-morpholinonicotinic acid followed by hydrolysis gave the desired product as a white solid. *H NMR (300 MHz, DMSO-de): δ ppm 12.15 (brs, 1H), 8.94 (s, 1H), 8.27-8.25 (m, 1H), 7.86-7.83 (m, 1H), 7.48 (s,lH), 6.95-6.91 (m, 1H), 4.374.32 (m, 1H), 3.67 (brs, 4H), 3.25 (bs, 2H), 3.11-3.07 (m, 2H), 2.79-2.73 (m, 3H), 2.50 (m, 2H), 2.41-2.14 (m, 6H), 1.914.78 (m, 7H), 1.57-1.46 (m, 6H), 1.31-1.26 (m, 6H), 1.14-1.10 (m, 9H), 0.90-0.88 (m, 10H), 0.81-0.80 (m, 10H); ESI-MS: m/z 905.84 (M+Na)+; HPLC: 97.06%.
Example 46: Préparation of (lR.3S)-3-((((3aR.5aR.5bR.7aR.9S.l laR.1 lbR.13aS)-3a-(l-(4chlorobenzamido-) cvclopentane-l-carboxamido)-l-isoproovl-5a.5b.8.8.1 la-pentamethvl-2oxo-3,3a.4.5, 5a,5b, 6,7.7a, 8.9.10.11.1 la, 11 b, 12,13.13a-octadecahydro-2H-cyclopentaral chrvsen-9-v0oxv)carbonvD-2.2-dimethylcvclobutane-l-carboxylic acid:
Intermediate 6 was coupled with 4-chlorobenzoic acid followed by hydrolysis gave the desired product as a white solid. ’HNMR (300 MHz, DMSO-dô): δ ppm 12.08 (brs, 1H), 8.31 (s, 1H), 7.93 (d, J= 9.0 Hz, 2H), 7.54 (d, J = 9.0 Hz, 2H), 7.43 (s, 1H), 4.36-4.30 (m, 1H), 3.10-3.07 (m, 1H), 2.79 (m, 3H), 2.38-2.23 (m, 3H), 2.16-2.08 (m, 3H), 1.95-1.82 (m, 4H), 1.76-1.57 (m, 8H), 1.43-1.39 (m, 2H), 1.26 (brs, 8H), 1.03-1.10 (m, 8H), 1.04-0.96 (m, 2H), 0.90 (brs, 3H), 0.83-0.76 (m, 12H), 0.69 (brs, 3H); ESI-MS: m/z 845.21 (M+H)+; HPLC: 95.88%.
100
Example 47: Preparation of (lR.3S)-3-(i((3aR,5aR,5bR.7aR.9S.llaR.llbR.13aS)-lisopropyl-5a,5b.8.8.1 la-nentamethvl-3a-(l-(6-methvlnicotinamido)cvclopentane-lcarboxamido)-2-oxo-3.3a,4.5.5a,5b.6.7.7a,8.9.10.11.1 la.1 lb.l2,13.13a-octadecahydro-2Hcyclopentaral chrvsen-9-vl)oxv)carbonvl)-2,2-dimethvlcyclobutane-l-carboxvlic acid:
Intermediate 6 was coupled with 6-methylnicotinic acid followed by hydrolysis gave the desired product as a white solid. ’H NMR (300 MHz, DMSO-de): δ ppm 12.16 (brs, 1H), 8.95 (s, 1H), 8.34 (s, 1H), 8.15-8.11 (m, 1H), 7.43 (s, 1H), 7.37-7.34 (m, 1H), 4.36-4.31 (m, 1H), 3.11-3.06 (m, 1H), 2.79-2.76 (m, 1H), 2.39 (m, 1H), 2.16-2.07 (m, 4H), 1.95-1.43 (m, 16H), 1.39-1.25 (m, 11H), 1.14-1.12 (m, 7H), 1.04-0.99 (m, 2H), 0.96-0.86 (m, 18H), 0.84 (brs, 3H); ESI-MS: m/z 848.44 (M+Na)+; HPLC: 99.78%.
Example 48: Preparation of (lR,3S)-3-iii(3aR.5aR.5bR.7aR,9S.l laR.1 lbR,13aS)-3a-(l-(4chlorobenzamido) cvclohexane-l-carboxamido,)-l-isopropvl-5a.5b.8.8.11a-nentamethvl-2oxo-3,3a,4.5, 5a,5b.6,7.7a.8.9.10.11,1 la,l lb.l2.13.13a-octadecahvdro-2H-cyclopentaral chrysen-9-vl)oxy,)carbonvn-2.2-dimethvlcvclobutane-l-carboxvlic acid:
Intermediate 7 was coupled with 4-chlorobenzoic acid followed by hydrolysis gave the desired product as a white solid. ’H NMR (300 MHz, DMSO-de): δ ppm 12.17 (brs, 1H), 7.90 (d, J= 8.4 Hz, 2H), 7.87 (s, 1H), 7.55 (d, J = 8.4 Hz, 2H), 7.30 (s, 1H), 4.37-4.31 (m, 1H),
3.11-3.07 (m, 1H), 2.82-2.76 (m, 3H), 2.31-2.06 (m, 6H), 1.89-1.71 (m, 8H), 1.63-1.39 (s, 10H), 1.31 (m, 10H), 1.26-1.10 (m, 9H), 1.01-0.90 (m, 2H), 0.85-0.80 (m, 14H); ESI-MS: m/z 859.30 (M+H)+; HPLC: 98.57%.
Example 49: Preparation of ('lR.3S)-3-((((3aR,5aR.5bR,7aR,9S.llaR.llbR.13aS)-lisopropyl-5a,5b,8.8,11 a-pentamethyl-3a-( 1 -(6-methylnicotinamido)cyclohexane-1 carboxamido)-2-oxo-3.3a.4.5,5a.5b.6.7.7a.8,9,10,11.11 a. 11 b, 12,13.13a-octadecahvdro-2Hcvclopentalal chrvsen-9-vDoxv)carbonvl~)-2.2-dimethvlcyclobutane-l -carboxylic acid:
101
Intermediate 7 was coupled with 6-methylnicotinic acid followed by hydrolysis gave the desired product as a white solid. ’H NMR (300 MHz, DMSO-dô): δ ppm 12.16 (brs, 1H), 8.926-8.920 (m, 1H), 8.12-8.09 (m, 1H), 7.93 (s, 1H), 7.37-7.31 (m, 2H), 4.37-4.31 (m, 1H), 3.07-2.75 (brs, 3H), 2.41-2.35 (m, 2H), 2.21-2.06 (m, 2H), 1.89-1.75 (m, 5H), 1.52 (brs, 10H), 1.42-1.26 (m, 8H), 1.13-1.10 (m, 10H), 1.06-0.96 (m, 4H), 0.90-0.79 (m, 22H); ESI-MS: m/z 840.52 (M+H)+; HPLC: 99.89%.
Example 50: Préparation of /lR.3S~)-3-iii(3aR.5aR.5bR.7aR,9S.llaR.llbR.13aS)-lisopropvl-5a,5b.8.8.11a-pentamethvl-3a-il-(4-methvlbenzamido)cvclohexane-lcarboxamido)-2-oxo-3.3a.4.5,5a,5b.6.7.7a.8.9.10.11,1 la.1 lb.l2,13.13a-octadecahydro-2Hcvcl opentaf al chrysen 9-yl)oxvkarbonvn-2,2-di methyl cyclobutane-1 -carboxyl ic acid :
Intermediate 7 was coupled with 4-methylbenzoic acid followed by hydrolysis gave the desired product as a white solid. *H NMR (300 MHz, DMSO-dô): δ ppm 12.18 (brs, 1H), 8.74 (s, 1H), 7.757 (d, J= 13.2 Hz, 2H), 7.34 (s, 1H), 7.291 (d, J= 13.2, Hz, 2H), 4.37-4.32 (m, 1H), 3.11-3.06 (m, 1H), 2.82-2.76 (m, 1H), 2.43-2.36 (m, 6H), 2.16-2.06 (m, 6H), 1.89-1.64 (m, 7H), 1.51 (brs, 9H), 1.32-1.26 (m, 10H), 1.13-1.11 (m, 8H), 1.06-1.02 (m, 4H), 0.90-0.86 (m, 14H); ESI-MS: m/z 839.46 (M+H)+; HPLC: 92.98%.
Example 51: Préparation of (lR,3S’)-3-((((3aR,5aR.5bR.7aR.9S,llaR,llbR,13aS)-lisopropyl-5a,5b,8.8.11 a-pentamethyl-3a-(2-methvl-2-(4-(methvlsulfonyDbenzamido) propanamido)-2-oxo-3,3a,4.5.5a,5b.6,7,7a,8.9,10,11,1 la,l lb,12,13.13a-octadecahydro-2Hcvclopentalal chrvsen-9-vl)oxv)carbonvl)-2,2-dimethylcvclobutane-l-carboxylic acid:
102
Step 1: Synthesis of 1-benzyl 3-((3aR,5aR,5bR7aR,9S,llaR,llbR,13aS)-l-isopropyl-5a,5b,8, 8,lla-pentamethyl-3a-(2-methyl-2-(4-(methylsulfonyl)benzamido)propanamido)-2-oxo-3,3a, 4,5,5a, 5b, 6,7,7a, 8,9,10,11,11 a, 11b, 12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl) (IR, 3S)-2,2 -dimethylcyclobutane-1,3-dicarboxylate:
BnO<
To a stirred solution of 4-(methylsulfonyl)benzoic acid (0.778 g, 3.889 mmol, 3.0 eq) in DMF (10 ml) was added HBTU (1.475 g, 3.889 mmol, 3.0 eq) followed by triethylamine (1.08 ml, 7.776 mmol, 6.0 eq). The reaction mixture was stirred at room température for about 30 minutes then l-((3aÆ,5aÆ,5bR,7aÆ,9S,llaÆ,llbR,13aS)-3a-(2-amino-2-methyl propanamido)-l-isopropyl-5a,5b,8,8,lla-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,ll, 1 la,l lb,12,13,13a-octadecahydro-2H-cyclopenta[cr]chrysen-9-yl) 3-benzyl (lS,3JÎ)-2,2-di methylcyclobutane-1,3-dicarboxylate (Intermediate 1, 1.0 g, 1.296 mmol, 1.0 eq) was added and stirred at room température for ovemight. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture was diluted with water (120 ml) and extracted with ethyl acetate (2x50 ml). The combined organic extracts were washed with water (70 ml), dried overNaîSCh, filtered and evaporated under reduced pressure. The residue was purified by silicagel column chromatography by using 0-2% methanol in dichloromethane gradient. The fractions containing the expected product were combined and concentrated under reduced pressure to obtain the desired product (0.75 g, yield: 60.97%) as a white solid. ’H NMR (300 MHz, CDC13): δ ppm 8.0 (d, J= 6.9 Hz, 2H), 7.96 (d, J = 6.9 Hz, 2H), 7.34 (m, 5H), 7.18 (s, 1H), 6.70 (s, 1H), 5.15, 5.09 (ABq, Jab = 12.3 Hz, 2H), 4.45 (dd, J = 11.1, 4.5 Hz, 1H), 3.22-3.11 (m, 1H), 3.06 (s, 3H), 2.84-2.72 (m, 3H), 2.70-2.60 (m, 2H), 2.38-2.26 (m, 2H), 2.09-1.98 (m, 1H), 1.97-1.83 (m, 3H), 1.72 (brs, 6H), 1.71-1.40 (m, 9H), 1.40-1.29 (m, 2H), 1.34 (s, 3H), 1.27-1.17 (m, 8H), 1.08 (s, 3H), 0.96 (s, 3H), 0.95 (s, 3H), 0.89 (s, 3H), 0.85 (s, 3H), 0.84 (s, 3H), 0.79 (m, 1H); ESI-MS: m/z 976.15 (M+Na)+.
Step 2: Synthesis of (lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,llaRllbR,13aS)-l-isopropyl-5a,5b,
8,8,1 la-pentamethyl-3a-(2-methyl-2-(4-(methylsulfonyl)benzamido)propanamido)-2-oxo-3, 3a,4,5,5a,5b, 6,7,7a, 8,9,10,11,lia,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9yl)oxy)carbonyl)-2,2-dimethylcyclobutane-l-carboxylic acid:
To a stirred solution of 1-benzyl 3-((3aÆ,5aÆ,5bÆ,7aÆ,91S',llaÆ,llbÆ,13aS)-lisopropyl-5a,5b,8,8,lla-pentamethyl-3a-(2-methyl-2-(4-(methylsulfonyl)benzamido)propan
103 amido)-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,l 1,1 la,l lb,12,13,13a-octadecahydro-277-cyclo penta[a]chrysen-9-yl) (17?,35)-2,2-dimethylcyclobutane-l,3-dicarboxylate (step 1, 0.750 g, 0.786 mmol, 1.0 eq) in MeOH (7.5 ml) and THF (7.5 ml) was added aqueous 2.5N KOH solution (2.36 ml, 5.89 mmol, 7.5 eq). The reaction mixture was stirred at room température for ovemight. TLC indicated starting material was consumed and the desired product was observed. The organic phase was evaporated under reduced pressure, the reaction mixture was diluted with water (10 ml), cooled to 0 °C, pH adjusted to 5.0 with IN HCl and extracted with DCM (2x50 ml). The combined organic extracts were washed with water (30 ml), dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by silicagel column chromatography by using 0-5% methanol in dichloromethane gradient. The fractions containing the expected product were combined and concentrated under reduced pressure to obtain the solid. To this solid compound, CH3CN: EtOAc (4:1, 10 ml) was added and heated to reflux for about 30 minutes. The mixture was cooled to 0 °C, solid was filtered and dried under vacuum to obtain the desired product (0.275 g, yield: 40.48%) as a white solid. *H NMR (300 MHz, CDCh): δ ppm 8.02 (d, J= 8.4 Hz, 2H), 7.96 (d, J= 8.4 Hz, 2H), 7.10 (s, 1H), 6.63 (s, 1H), 4.46 (dd, J= 11.1, 4.5 Hz, 1H), 3.22-3.11 (m, 1H), 3.06 (s, 3H), 2.86-2.75 (m, 3H), 2.71-2.52 (m, 2H), 2.40-2.26 (m, 2H), 2.10-2.01 (m, 1H), 2.0-1.78 (m, 3H), 1.72 (brs, 6H), 1.69-1.40 (m, 9H), 1.40-1.32 (m, 2H), 1.37 (s, 3H), 1.26-1.20 (m, 8H), 1.08 (s, 3H), 1.06 (s, 3H), 0.96 (s, 3H), 0.89 (s, 3H), 0.86 (s, 3H), 0.85 (s, 3H), 0.79 (m, 1H); ESI-MS: m/z 863.6 (M+H)+; HPLC: 97.9%.
The below examples 52-58 were prepared by the procedure similar (including reagents and reaction conditions) to the above described in the synthesis of example-51 using with their appropriate intermediates.
Example 52: Préparation of (lR,3S)-3-((((3aR,5aR,5bR.7aR.9S.llaR,llbR,13aS)-lisopropyl-5a,5b.8.8.1 la-pentamethyl-3a-(2-methvl-2-((S)-piperidine-3-carboxamido)propan amido)-2-oxo-3.3a.4.5.5a.5b.6,7.7a.8.9.10.11.1 la.1 lb,12.13.13a-octadecahvdro-2H-cvclo oentaralchrvsen-9-vl)oxv)carbonvD-2.2-dimethvlcvclobutane-l-carboxvlic______________acid hydrochloride:
104
Step 1: Synthesis of (lR,3S)-3-((((3aR5aR,5bR,7aR,9S,llaR,llbR,13aS)-3a-(2-((S)-l-(tertbutoxycarbonyl)piperidine-3-carboxamido)-2-methylpropanamido)-l-isopropyl-5a,5b,8,8, a-pentamethyl-2-oxo-3,3 a,4,5,5a, 5 b, 6,7,7a, 8,9,10,11,1 la, 11 b, 12,13,13a-octadecahydro2H-cyclopenta[a] chrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-l-carboxylic acid:
Intermediate 1 was coupled with (S)-l-(tert-butoxycarbonyl)piperidine-3-carboxylic acid followed by hydrolysis gave the desired product as a white solid. ’H NMR (300 MHz,
CDCb): δ ppm 4.47 (dd, J= 11.1,4.5 Hz, 1H), 3.83-3.50 (m, 2H), 3.40-3.02 (m, 3H), 3.0-2.73 (m, 4H), 2.68-2.53 (m, 2H), 2.38-2.20 (m, 4H), 2.10-1.65 (m, 15H), 1.58-1.53 (m, 4H), 1.53 (s, 3H), 1.46 (s, 9H), 1.37 (m, 4H), 1.35-1.32 (m, 2H), 1.25-1.18 (m, 7H), 1.14 (s, 3H), 1.07 (s,
3H), 0.93 (s, 3H), 0.92 (s, 3H), 0.87 (s, 3H), 0.85 (s, 3H), 0.83 (m, 1H); ESI-MS: m/z 914.71 (M+Na)+.
Step 2: Synthesis of (lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,llaR,llbR,13aS)-l-isopropyl-5a,5b,
8,8,1 la-pentamethyl-3a-(2-methyl-2-((S)-piperidine-3-carboxamido)propanamido)-2-oxo-3,
3a,4,5,5a,5b,6,7,7a,8,9,10,l 1,1 la,l lb,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9yl)oxy)carbonyl)-2,2-dimethylcyclobutane-l-carboxylic acid hydrochloride:
A solution of (lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-3a-(2-((S)-l-(tertbutoxycarbonyl)piperidine-3-carboxamido)-2-methylpropanamido)-l-isopropyl-5a,5b,8,8,lla -pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11 a, 11 b, 12,13,13a-octadecahydro-2H20 cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-l-carboxylic acid (step 1, 0.500 g, 0.560 mmol, 1.0 eq) and 3N HCl in 1,4-dioxane (10 ml) was stirred at room température for ovemight. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture was evaporated under reduced pressure, MTBE (10 ml) was added and heated to reflux for about 30 minutes. The reaction mixture was cooled to 0 °C, filtered, solid was washed with MTBE (10 ml) and dried under vacuum to obtain the desired product (0.220 g, yield: 47.4%) as a white solid. *H NMR (300 MHz, CD3OD): δ ppm 8.02 (s, 1H), 7.15 (s, 1H), 4.32-4.23 (m, 1H), 3.07-2.85 (m, 6H), 2.80-2.55 (m, 4H), 2.50-2.21 (m, 3H), 2.21-1.93 (m, 2H), 1.93-1.76 (m, 4H), 1.76-1.58 (m, 5H), 1.58-1.40 (m, 4H), 1.401.36 (m, 2H), 1.36-1.21 (m, 11H), 1.17 (s, 3H), 1.15-1.10 (m, 1H), 1.08-1.0 (m, 9H), 0.96-0.89 (m, 1H), 0.87-0.78 (m, 7H), 0.72 (brs, 6H); ESI-MS: m/z 792.58 (M-HC1+H/; HPLC: 90.7%;
chloride content by Ion chromatography: 6.8%.
105
Example 53: Préparation 0f(lR.3S)-3-O3aR.5aR.5bR.7aR.9S.llaR.llbR.13aS)-3a-(2-(2(4-chlorophenvl)acetamido,)-2-methvlpropanamido)-l-Îsopropvl-5a.5b.8.8.11a-pentamethvl2-oxo-3.3a.4.5.5a.5b.6.7.7a.8,9.10.11,1 la.Hb,12,13,13a-octadecahvdro-2H-cyclopentaral chrvsen-g-vlloxvIcarbonvD^^-dimethvlcyclobutane-l-carboxvlic acid:
Intermediate 1 was coupled with 2-(4-chlorophenyl)acetic acid followed by hydrolysis gave the desired product as a white solid. *H NMR (300 MHz, CDCI3): δ ppm 7.33 (d, J= 8.1 Hz, 2H), 7.19 (d, J= 8.4 Hz, 2H), 7.11 (brs, 1H), 5.84 (brs, 1H), 4.47 (dd, J= 11.1, 4.5 Hz, 1H), 3.50 (s, 2H), 3.20-3.08 (m, 1H), 2.87-2.70 (m, 3H), 2.67-2.53 (m, 2H), 2.29-2.02 (m, 3H), 1.98-1.65 (m, 6H), 1.55-1.47 (m, 4H), 1.51 (s, 3H), 1.49 (s, 3H), 1.42-1.35 (m, 2H), 1.37 (s, 3H), 1.28-1.18 (m, 9H), 1.13-1.03 (m, 1H), 1.10 (s, 3H), 1.07 (s, 3H), 0.93 (s, 3H), 0.91 (s, 3H), 0.89-0.78 (m, 7H); ESI-MS: m/z 855.6 (M+Na)+; HPLC: 89.2% + 9% isomer.
Example 54: Préparation of (lR.3S')-3-((((3aR,5aR,5bR.7aR.9S.llaR.llbR.13aS')-lisopropvl-5a,5b.8.8.11a-pentamethvl-3a-(2-methvl-2-(pvrazolori.5-alpvrimidine-3carboxamido')propanamido)-2-oxo-3.3a,4.5.5a.5b.6.7.7a.8.9.10.11.1 la.llb.12.13.13aoctadecahvdro-2H-cvclopentara1chrvsen-9-vl~)oxv')carbonvl)-2.2-dimethvlcyclobutane-lcarboxylic acid:
Intermediate 1 was coupled with pyrazolo[l,5-a]pyrimidine-3-carboxylic acid followed by hydrolysis gave the desired product as an off-white solid. *H NMR (300 MHz, CDCb): δ ppm 11.74(brs, 1H), 9.02(dd,J= 7.2,1.5 Hz, 1H), 8.75 (dd, J= 4.2,1.5 Hz, 1H), 8.57(s, 1H), 8.27 (s, 1H), 7.66 (m, 1H), 7.16 (dd, J= 6.9,4.2 Hz, 1H), 4.40 (dd, J= 10.5,4.5 Hz, 1H), 3.203.10 (m, 1H), 2.97-2.83 (m, 1H), 2.81-2.70 (m, 2H), 2.62-2.58 (m, 2H), 2.42-2.12 (m, 2H), 2.07-1.87 (m, 4H), 1.80-1.50 (m, 6H), 1.66 (s, 3H), 1.62 (s, 3H), 1.47-1.31 (m, 4H), 1.34 (s, 3H), 1.23-1.15 (m, 8H), 1.05-0.97 (m, 1H), 1.02 (s, 3H), 0.99 (s, 3H), 0.92 (s, 3H), 0.88-0.78 (m, 10H); ESI-MS: m/z 826.7 (M+H)+; HPLC: 91%.
106
Example 55: Préparation of (lR,3S)-3-((((3aR.5aR.5bR.7aR.9S.llaR.llbR,13aS)-3a-(2-(2aminothiazole-4-carboxamido)-2-methvlpropanamido)-l-isopropyl-5a.5b.8.8.1 la-penta methyl-2-oxo-3,3a.4.5.5a,5b,6.7.7a,8.9.10.11.1 la.1 lb.l2.13,13a-octadecahvdro-2H-cyclo pentaralchrysen-9-v0oxy')carbonvl')-2.2-dimethylcyclobutane-l-carboxvlic acid:
Intermediate 1 was coupled with 2-aminothiazole-4-carboxylic acid (Intermediate 14) followed by hydrolysis gave the desired product as an off-white solid. *H NMR (300 MHz, DMSO-de): δ ppm 12.18 (brs, 1H), 7.95 (s, 1H), 7.66 (s, 1H), 7.20 (brs, 2H), 7.13 (s, 1H), 4.404.32 (m, 1H), 3.18-3.07 (m, 1H), 2.85-2.72 (m, 3H), 2.40-2.22 (m, 3H), 2.13 (d, J= 18.3 Hz, 1H), 2.0-1.82 (m, 3H), 1.80-1.61 (m, 3H), 1.60-1.44 (m, 2H), 1.52 (brs, 6H), 1.43-1.30 (m, 5H), 1.30-1.23 (m, 2H), 1.26 (s, 3H), 1.18-1.10 (m, 7H), 1.08-0.98 (m, 1H), 1.0 (s, 3H), 0.91 (s, 3H), 0.89 (s, 3H), 0.88-0.72 (m, 10H); ESI-MS: m/z 829.54 (M+Na)+; HPLC: 91.3%. Examnle 56: Préparation of ilR.3S~)-3-(ï((3aR.5aR,5bR.7aR.9S.llaR.llbR.13aS)-lisopropyl-5a,5b.8.8.1 la-pentamethvl-3a-(2-methvl-2-i4-i5-methyl-1.3.4-oxadiazol-2-vl~) benzamido)propanamido)-2-oxo-3.3a.4.5.5a,5b.6.7,7a,8.9.10.11.1 la.1 lb.l2,13.13a-octa decahvdro-2H-cvclonentaralchrysen-9-vl)oxy)carbonvl)-2.2-dimethvlcvclobutane-lcarboxylic acid:
Intermediate 1 was coupled with 4-(5-methyl-l,3,4-oxadiazol-2-yl)benzoic acid (Intermediate 15) followed by hydrolysis gave the desired product as a white solid. *H NMR (300 MHz, CDCh): δ ppm 8.11 (d, J= 8.4 Hz, 2H), 7.91 (d, J= 8.4 Hz, 2H), 6.98 (s, 1H), 6.92 (s, 1H), 4.46 (dd, J= 11.1, 4.5 Hz, 1H), 3.22-3.10 (m, 1H), 2.88-2.70 (m, 4H), 2.65 (s, 3H), 2.61-2.52 (m, 1H), 2.38-2.27 (m, 2H), 2.10-1.83 (m, 5H), 1.80-1.67 (m, 1H), 1.72 (s, 3H), 1.71 (s, 3H), 1.65-1.42 (m, 7H), 1.40-1.31 (m, 2H), 1.36 (s, 3H), 1.28-1.20 (m, 7H), 1.08-1.04 (m, 7H), 0.95 (s, 3H), 0.90-0.78 (m, 10H); ESI-MS: m/z 889.67 (M+Na)+; HPLC: 93.3%. Example 57: Préparation of (lR,3S)-3-((((3aR.5aR,5bR.7aR.9S.llaR.llbR.13aS)-3a-(2-(4(1.1 -dioxidothiomorpholino)benzamido)-2-methvlpropanamido’)-l-isopropyl-5a.5b.8.8.11a18389
107 penta methvl-2-oxo-3.3a,4,5,5a,5b.6.7.7a.8.9.10.11.11 a, 11 b, 12,13,13a-octadecahvdro-2Hcvclo pentaralchrvsen-9-vboxy)carbonvD-2.2-dimethvlcvclobutane-l-carboxylic acid:
HOOC*
Intermediate 1 was coupled with 4-(l,l-dioxidothiomorpholino)benzoic acid (Intermediate 16) followed by hydrolysis gave the desired product as an off-white solid. *H NMR (300 MHz, DMSO-d6): δ ppm 12.10 (s, 1H), 7.92 (s, 1H), 7.80 (d, J= 8.4 Hz, 2H), 7.31 (s, 1H), 7.07 (d, J= 8.7 Hz, 2H), 4.40-4.30 (m, 1H), 3.90 (m, 4H), 3.09 (m, 5H), 2.87-2.70 (m, 3H), 2.48-2.18 (m, 4H), 2.06 (d, J= 18.3 Hz, 1H), 1.98-1.80 (m, 3H), 1.80-1.48 (m, 6H), 1.42 (s, 3H), 1.40 (s, 3H), 1.38-1.20 (m, 6H), 1.26 (s, 3H), 1.18-1.10 (m, 6H), 0.93-0.75 (m, 20H); ESI-MS: m/z 940.72 (M+Na)+; HPLC: 92.4%.
Example 58: Préparation of ilR,3S)-3-i(((3aR.5aR,5bR,7aR.9S.llaR.llbR.13aS)-3a-f2-(4i(l.l-dioxidothiomornholino’)methvDbenzamidoy2-methvlpropanamido)-l-isopropvl-5a,5b.
8,8,1 la-pentamethyl-2-oxo-3.3a.4.5.5a,5b.6.7.7a,8.9.10,11.11 a.l lb.l2.13.13a-octadecahydro -2H-cvc1onentaralchrvsen-9-vDoxv)carbonvD-2.2-dimethvlcvclobutane-l-carboxvlic acid:
HOOC*
Intermediate 1 was coupled with 4-((1,l-dioxidothiomorpholino)methyl)benzoic acid (Intermediate 17) followed by hydrolysis gave the desired product as a white solid. ’H NMR (300 MHz, DMSO-dô): δ ppm 11.8 (brs, 1H), 8.13 (s, 1H), 7.86 (d, J= 7.8 Hz, 2H), 7.42 (d, J = 7.8 Hz, 2H), 7.36 (s, 1H), 4.38-4.31 (m, 1H), 3.73 (s, 2H), 3.11 (m, 5H), 2.92-2.70 (m, 7H), 2.48-2.18 (m, 3H), 2.12-1.98 (m, 2H), 1.96-1.80 (m, 3H), 1.80-1.51 (m, 5H), 1.50-1.38 (m, 1H), 1.43 (s, 3H), 1.41 (s, 3H), 1.38-1.24 (m, 4H), 1.26 (s, 3H), 1.20-1.06 (m, 8H), 1.05-0.96 (m, 2H), 0.90 (s, 3H), 0.86 (m, 6H), 0.79 (m, 9H); ESI-MS: m/z 954.75 (M+Na)+; HPLC: 92.9%.
Example 59: Préparation of (lR.3S)-3-((((3aR,5aR.5bR,7aR,9S.llaR.llbR,13aS)-3a-(2-(2(dimethylamino')acetamido')-2-methvlnropanamido)-l-isopropvl-5a.5b,8,8.1 la-pentamethyl2-oxo-3.3a,4.5.5a,5b,6.7.7a,8.9,10.11,11a,! lb,12,13.13a-octadecahvdro-2H-cyclopentaral chrvsen-9-vDoxv')carbonvl)-2,2-dimethvlcvclobutane-l-carboxvlic acid:
108
Step 1: Synthesis of 1-benzyl 3-((3aR,5aR,5bR,7aR,9S,llaR,llbR,13aS)-3a-(2-(2-(dimethyl amino)acetamido)-2-methylpropanamido)-l-isopropyl-5a,5b,8,8,lla-pentamethyl-2-oxo-3, 3a, 4,5,5a,5b, 6,7,7a, 8,9,10,11,1 la, 11b, 12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9yl) (IR, 3S)-2,2-dimethylcyclobutane-l, 3-dicarboxylate:
To a stirred solution of dimethyl glycine hydrochloride (0.543 g, 3.893 mmol, 3.0 eq) in DMF (10 ml) was added HATU (0.980 g, 2.59 mmol, 2.0 eq) followed by DIPEA (1.34 ml, 7.78 mmol, 6.0 eq). The reaction mixture was stirred at room température for about 30 minutes then l-((3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-3a-(2-amino-2-methylpropan amido)-lisopropyl-5a,5b,8,8,l la-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,l 1,1 la, lb,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl) 3-benzyl (lS,3R)-2,2-dimethyl cyclobutane-1,3-dicarboxylate (Intermediate 1, 1.0 g, 1.297 mmol, 1.0 eq) was added and stirred at the same température for ovemight. TLC indicated starting material was consumed and the desired product was observed. The réaction mixture was diluted with water (150 ml) and extracted with DCM (3x20 ml). The combined organic extracts were washed with water (20 ml), dried over Na2SÜ4, filtered and evaporated under reduced pressure. The residue was purified by silicagel column chromatography by using 0-3% MeOH in DCM gradient. The fractions containing the product were combined and concentrated under reduced pressure to give the desired product (0.5 g, yield: 45.4%) as a white solid. ’H NMR (300 MHz, CDCh): δ ppm 7.99 (s, 1H), 7.46 (s, 1H), 7.35 (m, 5H), 5.15, 5.09 (ABq, Jab = 12.3 Hz, 2H), 4.45 (dd, J = 11.4, 4.8 Hz, 1H), 3.20-3.10 (m, 1H), 2.97 (s, 2H), 2.87-2.73 (m, 3H), 2.70-2.60 (m, 2H), 2.33 (s, 6H), 2.30-2.22 (m, 2H), 2.08-1.99 (m, 2H), 1.98-1.83 (m, 2H), 1.80-1.72 (m, 2H), 1.601.53 (m, 2H), 1.56 (s, 3H), 1.51 (s, 3H), 1.49-1.38 (m, 4H), 1.38-1.30 (m, 2H), 1.34 (s, 3H), 1.27-1.18 (m, 8H), 1.13 (s, 3H), 1.10-0.98 (m, 1H), 0.96 (s, 3H), 0.93 (s, 3H), 0.92 (s, 3H), 0.85 (s, 3H), 0.84 (s, 3H), 0.78 (m, 1H); ESI-MS: m/z 856.4 (M+H)+.
Step 2: Synthesis of (lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,llaR,llbR,13aS)-3a-(2-(2-(dimethyl amino)acetamido)-2-methylpropanamido)-l-isopropyl-5a,5b,8,8,lla-pentamethyl-2-oxo-3,
109
3a, 4,5,5a, 5b, 6,7,7a,8,9,10,11,11a, 11b, 12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9yl)oxy)carbonyl)-2,2-dimethylcyclobutane-l-carboxylic acid:
To a stirred solution of 1-benzyl 3-((3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-3a-(2-(2(dimethylamino)acetamido)-2-methylpropanamido)-l-isopropyl-5a,5b,8,8,lla-pentamethyl5 2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,l 1,1 la,l lb,12,13,13a-octadecahydro-2H-cyclopenta[a] chrysen-9-yl) (lR,3S)-2,2-dimethylcyclobutane-l,3-dicarboxylate (step 1, 0.5 g, 0.584 mmol, 1.0 eq) in MeOH (10 ml) and THF (10 ml) was added aqueous 2.5N KOH solution (1.85 ml). The reaction mixture was stirred at room température for ovemight. TLC indicated starting material was consumed and the desired product was observed. The organic phase was 10 evaporated under reduced pressure, the reaction mixture was diluted with water ( 15 ml), cooled to 0°C, acidified with IN HCl to pH 5.0 and extracted with DCM (3x25 ml). The combined organic extracts were washed with water (10 ml), dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by silicagel column chromatography by using 0-10% MeOH in DCM gradient. The fractions containing the product 15 were combined and concentrated under reduced pressure to give a solid. To this solid compound, acetonitrile (15 ml) was added and heated to reflux for about 30 minutes. The mixture was cooled to 0°C, the solids formed were collected by filtration and were washed with n-hexane (10 ml) and dried under vacuum to obtain the desired product (0.266 g, yield: 59.5%) as a white solid. *H NMR (300 MHz, CDCh): δ ppm 8.01 (s, 1H), 7.53 (s, 1H), 4.47 (dd, J= 20 11.1,4.5 Hz, 1 H), 3.20-3.10 (m, 1H), 2.96 (s, 2H), 2.86-2.75 (m, 3H), 2.68-2.40 (m, 2H), 2.32 (s, 6H), 2.30-2.22 (m, 2H), 2.12-2.0 (m, 1H), 1.99-1.83 (m, 3H), 1.82-1.67 (m, 2H), 1.65-1.58 (m, 2H), 1.56 (s, 3H), 1.51 (s, 3H), 1.49-1.40 (m, 3H), 1.40-1.30 (m, 3H), 1.37 (s, 3H), 1.301.15 (m, 8H), 1.13 (s, 3H), 1.07 (s, 3H), 1.01 (m, 1H), 0.93 (s, 3H), 0.91 (s, 3H), 0.86 (s, 3H), 0.85 (s, 3H), 0.80 (m, 1H); ESI-MS: m/z 766.49 (M+H)+; HPLC: 97.5%.
The below examples 60-61 were prepared by the procedure similar (including reagents and reaction conditions) to the above described in the synthesis of example-59 using with their appropriate intermediates.
Example 60: Préparation of flR.3S)-3-((((3aR.5aR.5bR.7aR.9S.llaR.llbR.13aS)-lisonropvl-5a.5b.8.8,lla-pentamethvl-3a-(2-methvl-2-(6-methylpicolinamido)propanamido)30 2-oxo-3,3a.4,5,5a,5b.6.7.7a.8.9.10.11.1 la.1 lb.l2,13,13a-octadecahydro-2H-cvclopentaral chrysen-9-vl) oxv)carbonvl)-2.2-dimethvlcvclobutane-1 -carboxylic acid:
110
Intermediate 1 was coupled with 6-methylpicolinic acid followed by hydrolysis gave the desired product as a white solid. *H NMR (300 MHz, DMSO-dô): δ ppm 12.13 (brs, 1H), 8.76 (s, 1H), 7.90-7.80 (m, 2H), 7.62 (s, 1H), 7.47 (d, J= 6.9 Hz, 1H), 4.39-4.31 (m, 1H), 3.183.06 (m, 1H), 2.88-2.70 (m, 3H), 2.55 (s, 3H), 2.48-2.38 (m, 2H), 2.27-2.22 (m, 2H), 2.14 (d, J= 18.3 Hz, 1H), 2.0-1.62 (m, 6H), 1.55 (brs, 6H), 1.62-1.50 (m, 3H), 1.50-1.38 (m,2H), 1.381.20 (m, 2H), 1.33 (s, 3H), 1.20-0.99 (m, 9H), 0.98-0.80 (m, 19H); ESI-MS: m/z 800.79 (M+H)+; HPLC: 96.27%.
Example 61: Préparation of (lR.3S)-3-((i(3aR.5aR.5bR.7aR.9S.llaR.llbR.13aS)-lisopropvl-5a.5b.8<8.11a-pentamethvl-3a-(2-methvl-2-i6-methvlnicotinamido)propanamido')2-oxo-3.3a.4.5.5a.5b,6.7.7a.8.9.10.11.1 la, 1 lb.l2.13,13a-octadecahvdro-2H-cvclopentalal chrysen-9-vD oxv)carbonvD-2.2-dimethvlcvclobutane-l -carboxylic acid:
Intermediate 1 was coupled with 6-methylnicotinic acid followed by hydrolysis gave the desired product as a white solid. ’H NMR (300 MHz, CDCh): δ ppm 8.90 (d, J= 1.8 Hz, 1H), 7.99 (dd, J= 8.1, 2.4 Hz, 1H), 7.26 (d, 1H), 6.98 (brs, 1H), 6.80 (brs, 1H), 4.48 (dd, J=
11.1,4.5 Hz, 1H), 3.23-3.12 (m, 1H), 2.88-2.70 (m, 4H), 2.64 (s, 3H), 2.63-2.57 (m, 1H), 2.382.27 (m, 2H), 2.13-2.02 (m, 1H), 2.01-1.76 (m, 5H), 1.71 (brs, 6H), 1.66-1.43 (m, 8H), 1.39 (s, 3H), 1.37-1.20 (m, 8H), 1.20-1.15 (m, 1H), 1.08 (s, 3H), 1.07 (s, 3H), 0.96 (s, 3H), 0.90 (s, 3H), 0.88 (s, 3H), 0.86 (s, 3H), 0.80 (m, 1H); ESI-MS: m/z 800.6 (M+H)+; HPLC: 95.4%. Example 62: Préparation of (lR,3S)-3-(((('3aR.5aR,5bR,7aR,9S,llaR,llbR.13aS)-lisopropvl-5a,5b.8.8.11a-pentamethvl-3a-(2-methvl-2-pivalamidopropanamido')-2-oxo3,3a,4.5,5a,5b,6, 7,7a,8,9,10.11,1 la,l lb,12,13.13a-octadecahvdro-2H-cyclopentala1chrvsen9-vDoxv) carbonvD-2,2-dimethvlcyclobutane-l-carboxvlic acid:
111
Step 1: Synthesis of 1-benzyl 3-((3aR,5aR,5bR,7aR,9S,llaR,llbR,13aS)-l-isopropyl-5a,5b,
8,8, lla-pentamethyl-3a-(2-methyl-2-pivalamidopropanamido)-2-oxo-3,3a, 4,5,5a, 5b, 6,7,7a, 8,
9,10,11, lia, 1 lb, 12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl) (lR,3S)-2,2-di methylcyclobutane-l,3-dicarboxylate:
To a stirred solution of l-((3aR,5aR,5bR,7aR,9S,llaR,llbR,13aS)-3a-(2-amino-2methylpropanamido)-l-isopropyl-5a,5b,8,8,lla-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,
10,11,1 la,l lb,12,13,13a-octadecahydro-277-cyclopenta[a]chrysen-9-yl) 3-benzyl (15,35)-2,2 -dimethylcyclobutane-l,3-dicarboxylate (Intermediate 1, 0.800 g, 1.037 mmol, 1.0 eq) in DCM (10 ml) at 0 °C was added triethyl amine (0.72 ml, 5.187 mmol, 5.0 eq) followed by pivaloyl chloride (0.192 ml, 1.556 mmol, 1.5 eq). The reaction mixture was allowed to stir at room température for ovemight. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture was diluted with water (50 ml) and extracted with DCM (3x30 ml). The combined organic extracts were washed with 0.5N HCl (10 ml), water (20 ml), dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by silicagel column chromatography by using 0-3% methanol in dichloromethane gradient. The fractions containing the expected product were combined and concentrated under reduced pressure to obtain the desired product (0.800 g, yield: 90.19%) as a white solid. ’H NMR (300 MHz, CDCh): δ ppm 7.35 (m, 5H), 5.97 (s, 1H), 5.15, 5.09 (ABq, Jab = 12.3 Hz, 2H), 4.45 (dd, J= 11.4,4.8 Hz, 1H), 3.20-3.10 (m, 1H), 2.87-2.73 (m, 3H), 2.71-2.57 (m, 2H), 2.36-2.22 (m, 2H), 2.09-2.0 (m, 1H), 1.98-1.82 (m, 3H), 1.78-1.60 (m, 5H), 1.55 (s, 3H), 1.53 (s, 3H), 1.50-1.38 (m, 4H), 1.37-1.30 (m, 3H), 1.34 (s, 3H), 1.26-1.20 (m, 6H), 1.18 (s, 9H), 1.14 (s, 3H), 1.10-1.0 (m, 1H), 0.96 (s, 3H), 0.95-0.89 (m, 1H), 0.93 (s, 3H), 0.91 (s, 3H), 0.85 (s, 3H), 0.84 (s, 3H), 0.81-0.77 (m, 1H); ESI-MS: m/z 855.56 (M+H)+.
Step 2: Synthesis of (lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,llaR,llbR,13aS)-l-isopropyl-5a,5b, 8,8, lla-pentamethyl-3a-(2-methyl-2-pivalamidopropanamido)-2-oxo-3,3 a, 4,5,5a, 5b, 6,7,7a, 8, 9,10,11,lia,11b, 12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2dimethylcyclobutane-l-carboxylic acid:
To a stirred solution of 1-benzyl 3-((3aR,5aR,5b5,7aR,95,llaR,llb5,13aS)-l-iso propyl-5a,5b,8,8,11 a-pentamethyl-3a-(2-methyl-2-pivalamidopropanamido)-2-oxo-3,3a,4,5,
112
5a,5b,6,7,7a,8,9,10,l 1,1 la,l lb,12,13,13a-octadecahydro-27f-cyclopenta[a]chrysen-9-yl) (IR,3S)-2,2-dimethylcyclobutane-l,3-dicarboxylate (step 1, 0.800 g, 0.935 mmol, 1.0 eq) in MeOH (8 ml) and THF (8 ml) was added aqueous 2.5N KOH solution (2.8 ml, 7.015 mmol,
7.5 eq). The reaction mixture was stirred at room température for ovemight. TLC indicated starting material was consumed and the desired product was observed. The organic phase was evaporated under reduced pressure, the reaction mixture was diluted with water (10 ml), cooled to 0 °C, pH adjusted to 5.0 with IN HCl and extracted with DCM (3x40 ml). The combined organic extracts were washed with water (40 ml), dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by silicagel column chromatography by using 0-4% methanol in dichloromethane gradient. The fractions containing the expected product were combined and concentrated under reduced pressure to obtain the desired product (0.320 g, yield: 44.71%) as a white solid. *H NMR (300 MHz, CDCb): δ ppm 7.36 (s, 1H), 5.97 (s, 1H), 4.47 (dd, J= 8.7, 3.3 Hz, 1H), 3.20-3.11 (m, 1H), 2.87-2.76 (m, 3H), 2.65-2.57 (m, 2H), 2.34-2.23 (m, 2H), 2.10-2.02 (m, 1H), 1.97-1.82 (m, 3H), 1.80-1.68 (m, 2H), 1.64-1.47 (m, 6H), 1.56 (s, 3H), 1.53 (s, 3H), 1.46-1.30 (m, 4H), 1.37 (s, 3H), 1.22 (s, 3H), 1.21 (s, 3H), 1.18 (s, 9H), 1.15 (s, 3H), 1.07 (s, 3H), 1.06-1.0 (m, 1H), 0.93 (s, 3H), 0.92 (s, 3H), 0.87 (s, 3H), 0.86 (s, 3H), 0.84-0.79 (m, 1H); ESI-MS: m/z 765.63 (M+H)+; HPLC: 95.2%.
The below examples 63-66 were prepared by the procedure similar (including reagents and reaction conditions) to the above described in the synthesis of example-62 using with their appropriate intermediates.
Example 63: Préparation of sodium (lR,3S')-3-((i(3aR,5aR,5bR.7aR.9S.llaRJlbR,13aS')-liso propyl-5a.5b.8.8.11 a-pentamethvl-3a-i2-methvl-2-imethvlsulfonamido)proDanamido)-2oxo-3.3a.4.5.5a,5b.6.7.7a,8.9,10.11.1 la,l lb.l2.13.13a-octadecahvdro-2H-cyclopentaral chrvsen-9-vl)oxv~)carbonvl)-2.2-dimethvlcvclobutane-l-carboxvlate:
Step 1: Synthesis of (lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,llaR,llbR,13aS)-l-isopropyl-5a,5b, 8,8,lla-pentamethyl-3a-(2-methyl-2-(methylsulfonamido)propanamido)-2-oxo-3,3a,4,5,5a, 5b, 6,7,7a,8,9,10,11,lia,11 b, 12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy) carbonyl)-2,2-dimethylcyclobutane-l-carboxylic acid:
Intermediate 1 was coupled with methanesulfonyl chloride followed by hydrolysis gave the desired product as an off-white solid. ’H NMR (300 MHz, CDCh): δ ppm 6.50 (s, 1H), 4.96 (s, 1H), 4.46 (dd, J= 11.1, 4.5 Hz, 1H), 3.22-3.10 (m, 1H), 3.07 (s, 3H), 2.87-2.75 (m, 5 3H), 2.69-2.53 (m, 2H), 2.35-2.24 (m, 2H), 2.11-2.0 (m, 1H), 1.97-1.82 (m, 3H), 1.79-1.65 (m,
2H), 1.65-1.53 (m, 2H), 1.60 (s, 3H), 1.58 (s, 3H), 1.52-1.43 (m, 3H), 1.42-1.30 (m, 3H), 1.37 (s, 3H), 1.29-1.18 (m, 8H), 1.14 (s, 3H), 1.07 (s, 3H), 1.03-0.97 (m, 1H), 0.94 (s, 3H), 0.92 (s, 3H), 0.86 (s, 3H), 0.85 (s, 3H), 0.79 (m, 1H); ESI-MS: m/z 759.51 (M+H)+.
Step 2: Synthesis of sodium (lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,llaR,llbR,13aS)-l-isopropyï
-5a,5b,8,8,lla-pentamethyl-3a-(2-methyl-2-(methylsulfonamido)propanamido)-2-oxo-3,3a,4, 5,5a, 5b, 6,7,7a, 8,9,10,11,1 la,11b, 12,13,13a-octadecahydro-2H-cyclopenta[a] chrysen-9-yl) oxy)carbonyl)-2,2-dimethylcyclobutane-l-carboxylate:
To a stirred solution of (U?,3S)-3-((((3aJÎ,5aJÎ,5bl?,7aJÎ,9S',llaJÎ,llbl?,13aS)-lisopropyl-5a,5b,8,8,11 a-pentamethyl-3a-(2-methyl-2-(methylsulfonamido)propanamido)-215 oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11 a,l lb,12,13,13a-octadecahydro-2//-cyclopenta[a] chrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-l-carboxyllc acid (step 1,0.320 g, 0.421 mmol, 1.0 eq) in MeOH (3.2 ml) and water (0.15 ml) was added sodium hydroxide (0.0168 g, 0.421 mmol, 1.0 eq). The reaction mixture was stirred at room température for about 2 hours and then distilled out 90% of methanol under reduced pressure. Ethyl acetate (5 ml) was added and the reaction mixture was stirred at room température for ovemight. The reaction mixture was filtered, solid was washed ethyl acetate (5 ml) and then dried under vacuum to obtain the desired product (0.185 g, yield: 56.19%) as an off-white solid. ’H NMR (300 MHz, CD3OD): δ ppm 4.47-4.40 (m, 1H), 3.28-3.20 (m, 1H), 3.03 (s, 3H), 2.98-2.92 (m, 1H), 2.72-2.43 (m, 4H), 2.36-2.17 (m, 2H), 2.12-1.85 (m, 5H), 1.83-1.76 (m, 1H), 1.73-1.55 (m, 4H), 1.51 (s, 3H),
1.55-1.38 (m, 3H), 1.49 (s, 3H), 1.38-1.26 (m, 2H), 1.33 (s, 3H), 1.24-1.05 (m, 8H), 1.03 (s,
3H), 1.0 (s, 3H), 0.96 (s, 3H), 0.95-0.85 (m, 10H); ESI-MS: m/z 781.46 (M+H)+; HPLC: 97.84%; sodium content by Ion chromatography: 3.7%.
Example 64: Préparation of (!R.3S)-3-((((3aR,5aR,5bR.7aR.9S.l laR.llbR, 13aS)-3a-(2i(ethoxycarbonyl)amino)-2-methvlpropanamido)-l -isopropyl-5a.5b.8.8.11 a-pentamethyl-218389
114 oxo-3.3a.4.5.5a.5b.6.7.7a.8.9.10.11.1 la,l lb.l2,13.13a-octadecahvdro-2H-cvclopentaral chrysen-9-vDoxv)carbonvD-2,2-dimethvlcvclobutane-l-carboxvlic acid:
Intermediate 1 was coupled with ethyl carbonochloridate followed by hydrolysis gave the desired product as a white solid. *H NMR (300 MHz, CDCh): δ ppm 5.48 (s, 1H), 4.504.40 (m, 1H), 3.23-3.12 (m, 1H), 2.88-2.76 (m, 2H), 2.67-2.32 (m, 4H), 2.11-1.92 (m, 3H), 1.80-1.50 (m, 11H), 1.50-1.31 (m, 15H), 1.30-1.18 (m, 8H), 1.12-0.98 (m, 1H), 1.07 (s, 3H), 1.03 (s, 3H), 0.99 (s, 3H), 0.89 (s, 3H), 0.86 (s, 3H), 0.85 (s, 3H), 0.79 (m, 1H); ESI-MS: m/z 775.47 (M+Na)+; HPLC: 93.5%.
Example 65: Préparation of (lR,3S)-3-((((3aR,5aR.5bR.7aR.9S.llaR.llbR13aS)-3a-(2-((4chlorophenv0sulfonamido)-2-methvlpropanamido)-l-isopropvl-5a,5b.8.8.1 la-pentamethvl-2oxo-3.3a.4.5.5a.5b,6.7.7a.8.9J0.1 L1 la,l lb.12.13 J3a-octadecahvdro-2H-cvclopentara1 chrysen-9-vl)oxv)carbonvD-2.2-dimethvlcvclobutane-l-carboxvlic acid:
Intermediate 1 was coupled with 4-chlorobenzenesulfonyl chloride followed by hydrolysis gave the desired product as an off-white solid. ’H NMR (300 MHz, CDCI3): δ ppm 7.81 (d, J= 8.7 Hz, 2H), 7.49 (d, J= 8.7 Hz, 2H), 6.58 (brs, 1H), 5.40 (s, 1H), 4.47 (dd, J=
11.1,4.5 Hz, 1H), 3.22-3.10 (m, 1H), 2.88-2.75 (m, 3H), 2.67-2.53 (m, 2H), 2.40-2.26 (m, 2H), 2.11-2.0 (m, 1H), 2.0-1.82 (m, 3H), 1.80-1.68 (m, 3H), 1.68-1.48 (m, 6H), 1.47-1.30 (m, 11H), 1.27-1.20 (m, 7H), 1.15 (s, 3H), 1.07 (s, 3H), 0.97 (s, 3H), 1.05-0.98 (m, 1H), 0.97 (s, 3H), 0.95 (s, 3H), 0.87 (s, 3H), 0.86 (s, 3H), 0.83-0.80 (m, 1H); ESI-MS: m/z 855.6 (M+H)+; HPLC: 99.6%.
Example 66: Preparation of (ÎR.3S)-3-((((3aR.5aR.5bR,7aR.9SJlaR.llbR,13aS)-3a-(2(cyclo hexanecarboxamido)-2-methvlnropanamido)-l-isopropyl-5a.5b.8.8.11a-nentamethvl2-oxo-3.3a,4,5,5a,5b.6.7,7a,8,9.10.1L11 a, 11 b, 12,13.13a-octadecahvdro-2H-cvclopentar al chrvsen-9-vl’)oxv)carbonvl')-2.2-dimethylcvclobutane-l-carboxylic acid:
115
HOO
Intermediate 1 was coupled with cyclohexane carbonyl chloride followed by hydrolysis gave the desired product as a white solid. ’H NMR (300 MHz, CDCh): δ ppm 7.51 (s, 1H), 5.78 (s, 1H), 4.47 (dd, J= 11.1,4.8 Hz, 1H), 3.20-3.09 (m, 1H), 2.87-2.77 (m, 3H), 2.65-2.53 (m, 2H), 2.32-2.20 (m, 2H), 2.12-2.0 (m, 2H), 2.0-1.90 (m, 2H), 1.88-1.75 (m, 5H), 1.75-1.65 (m, 4H), 1.56 (s, 3H), 1.52 (s, 3H), 1.55-1.50 (m, 1H), 1.50-1.40 (m, 4H), 1.40-1.37 (m, 2H), 1.37 (s, 3H), 1.36-1.28 (m, 4H), 1.27-1.18 (m, 9H), 1.14 (s, 3H), 1.07 (m, 4H), 0.93 (s, 3H), 0.91 (s, 3H), 0.87 (s, 3H), 0.85 (s, 3H), 0.80 (m, 1H); ESI-MS: m/z 813.48 (M+Na)+; HPLC: 96.4%
Example 67: Préparation of (lR.3S)-3-((((3aR,5aR,5bR,7aR.9S.llaR,llbR.13aS)-lisopropvl-5a.5b.8.8.11a-pentametbvl-3a-(2-methvl-2-((nvridin-2-vlmethvDamino)propan amido)-2-oxo-3.3a,4.5.5a.5b.6,7.7a,8.9,10.11.1 la.l lb.l2.13.13a-octadecahydro-2H-cvclo pentaralchrvsen-9-vl)oxv)carbonvl)-2,2-dimethvlcyclobutane-l-carboxvlic acid:
HOOC'
Step 1: Synthesis of 1-benzyï 3-((3aR,5aR,5bR,7aR,9S,llaR,llbR,13aS)-l-isopropyl-5a,5b,
8,8,1 la-pentamethyl-3a-(2-methyl-2-((pyridin-2-ylmethyl)amino)propanamido)-2-oxo-3,3a,4, 5,5a,5b,6,7,7a,8,9,10,11,lia, 11b, 12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl) (lR,3S)-2,2-dimethylcycïobutane-l,3-dicarboxylate:
BnOOC’
To a stirred solution of l-((3aR,5aR,5bR,7aR,9S,llaR,llbR,13aS)-3a-(2-amino-2methylpropanamido)-l-isopropyl-5a,5b,8,8,lla-pentametbyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,
9,10,11,1 la,l lb,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl) 3-benzyl (1S,3R)2,2-dimethylcyclobutane-l,3-dicarboxylate (Intermediate 1,1.0 g, 1.29 mmol, 1.0 eq) in THF (10 ml) was added picolinaldehyde (0.153 g, 1.42 mmol, 1.1 eq). The reaction mixture was stirred at room température for about 30 minutes, then sodiumtriacetoxyborohydride (0.60 g,
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2.83 mmol, 2.2 eq) was added and stirred at same température for ovemight. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture was cooled to 0 °C, pH adjusted to 7.0 with IN HCl, diluted with water (20 ml) and extracted with CH2CI2 (3x50 ml). The combined organic extracts were dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified by silicagel column chromatography by using 5% MeOH in DCM as an eluent to obtain the desired product (0.5 g, yield: 44.7%) as a white solid. ’H NMR (300 MHz, DMSO-de): δ ppm 8.49 (d, J = 4.2 Hz,
1H), 8.20 (brs, 1H), 7.75 (td, .7=7.5,1.5 Hz, 1H), 7.43-7.31 (m, 6H), 7.25 (dd, .7=6.9,5.1 Hz,
1H), 5.12, 5.05 (ABq, Jab= 12.6 Hz, 2H), 4.38-4.31 (m, 1H), 3.76-3.61 (m, 2H), 3.18-3.05 (m, 10 1H), 2.98-2.72 (m, 3H), 2.43-2.25 (m, 3H), 2.18 (d, J= 18.3 Hz, 1H), 2.0-1.72 (m, 5H), 1.701.42 (m, 5H), 1.40-1.20 (m, 13H), 1.18-1.0 (m, 9H), 0.90 (s, 3H), 0.89 (s, 3H), 0.86-0.77 (m, 13H); ESI-MS: m/z 862.7 (M+H)+.
Step 2: Synthesis of (lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,llaR,llbR,13aS)-l-isopropyl-5a,5b, 8,8,lla-pentamethyl-3a-(2-methyl-2-((pyridin-2-ylmethyl)amino)propanamido)-2-oxo-3,3a,4,
5,5a,5b,6,7,7a,8,9,10,ll,lla,llb,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl) oxy)carbonyl)-2,2-dimethylcyclobutane-l-carboxylic acid:
To a stirred solution of 1-benzyl 3-((3aR,5aR,5bR,7aR,9S,llaR,llbR,13aS)-lisopropyl-5a,5b,8,8,11 a-pentamethyl-3a-(2-methyl-2-((pyridin-2-ylmethyl)amino)propan amido)-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,l 1,1 la,l lb,12,13,13a-octadecahydro-2H-cyclo penta[a]chrysen-9-yl) (lR,3S)-2,2-dimethylcyclobutane-l,3-dicarboxylate (step 1, 0.5 g, 0.58 mmol, 1.0 eq) in MeOH (10 ml), THF (10 ml) and water (1.6 ml) was added KOH (0.227 g,
4.06 mmol, 7.0 eq). The reaction mixture was stirred at room température for about 16 hours. TLC indicated starting material was consumed and the desired product was observed. The organic phase was evaporated under reduced pressure, the reaction mixture was diluted with 25 water (20 ml), cooled to 0°C, pH adjusted to 7.0 with IN HCl and extracted with DCM (2x25 ml). The combined organic extracts were dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by silicagel column chromatography by using 8% MeOH in DCM as an eluent to obtain the desired product (350 mg, yield: 78.1%) as a white solid. ’H NMR (300 MHz, DMSO-de): δ ppm 8.49 (d, J= 4.2 Hz, 1H), 8.20 (brs, 1H), 7.7930 7.71 (m, 1H), 7.41 (d, J= 7.5 Hz, 1H), 7.29-7.22 (m, 1H), 4.38-4.31 (m, 1H), 3.75-3.62 (m,
2H), 3.16-3.06 (m, 1H), 2.83-2.72 (m, 3H), 2.42-2.14 (m, 5H), 1.95-1.70 (m, 5H), 1.69-1.31 (m, 8H), 1.29-1.21 (m, 9H), 1.17-1.02 (m, 9H), 0.94-0.88 (m, 9H), 0.86-0.76 (m, 10H); ESIMS: m/z 772.6 (M+H)+; HPLC: 94.9%.
117
The below example 68 was prepared by the procedure similar (including reagents and reaction conditions) to the above described in the synthesis of example-67 using with their appropriate intermediates.
Example 68: Préparation of (lR.3S)-3-((((3aR.5aR.5bR.7aR.9S.llaR.l lbR.13aS)-3a-(2-((4chlorobenzvl)amino)-2-methvlpropanamido)-l-isopropyl-5a.5b.8.8.11a-pentamethvl-2-oxo3.3a.4.5.5a.5b.6.7.7a.8.9.10.11.11 a. 1 lb.l2.13.13a-octadecahvdro-2H-cvclopenta[alchrysen9-vl)oxv)carbonyl)-2.2-dimethvlcvclobutane-l -carboxvlic acid:
Intermediate 1 was coupled with 4-chlorobenzaldehyde followed by hydrolysis gave the desired product as a white solid. ’H NMR (300 MHz, CDCb): δ ppm 7.62 (s, 1H), 7.25 (d, J= 8.4 Hz, 2H), 7.17 (d, J= 8.7 Hz, 2H), 4.38 (dd, J= 11.1,4.5 Hz, 1H), 4.17-4.12 (m, 1H), 3.65,3.58 (ABq, Jab= 13.5 Hz, 2H), 3.12-3.02 (m, 1H), 2.92-2.68 (m, 2H), 2.63-2.45 (m, 3H), 2.41-2.23 (m, 2H), 2.04-1.92 (m, 2H), 1.75-1.59 (m, 4H), 1.58-1.40 (m, 4H), 1.40-1.23 (m, 14H), 1.23-1.10 (m, 7H), 1.09-0.93 (m, 1H), 1.0 (s, 3H), 0.93-0.75 (m, 15H), 0.75-0.68 (m, 1H); ESI-MS: m/z 805.4 (M+H)+; HPLC: 92.56%.
Example 69: Préparation 0f(lR.3S)-3-((((3aR,5aR,5bR,7aR,9S.llaR.llbR,13aS)-3a-(2-(((l(4-chlorophenvl)cvclopropvl)methvl)amino)-2-methvlpropanamido)-l-isopropyl-5a.5b.8.8.
la-pentamethvl-2-oxo-3.3a.4.5.5a.5b.6.7.7a.8.9.10.11.1 la. 1 lb.l2.13.13a-octadecahvdro2H-cvclopentaralchrvsen-9-vl)oxv)carbonvl)-2.2-dimethvlcvclobutane-l-carboxvlic acid:
Step 1: Synthesis of 1-benzyl 3-((3aR,5aR,5bR,7aR,9S,llaR,llbR,13aS)-3a-(2-(((l-(4-chloro phenyl)cyclopropyl)methyl)amino)-2-methylpropanamido)-l-isopropyl-5a,5b,8,8,lla-penta methyl-2-oxo-3,3 a, 4,5,5 a, 5b, 6,7,7a, 8,9,10,11,1 la,1 lb,12,13,13a-octadecahydro-2H-cyclo penta[a]chrysen-9-yl) (lR,3S)-2,2-dimethylcyclobutane-l,3-dicarboxylate:
118
To a stirred solution of l-((3a/?,5a7?,5bR,7a7?,95,lla7?,llbR,13a5)-3a-(2-amino-2methylpropanamido)-l-isopropyl-5a,5b,8,8,11 a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,
10.11.1 la,l lb,12,13,13a-octadecahydro-27/-cyclopenta[a]chrysen-9-yI) 3-benzyl (15,37?)-2,2 -dimethylcyclobutane-l,3-dicarboxylate (Intermediate 1, 1.0 g, 1.297 mmol, 1.0 eq) in 1,2DCE (10 ml) at 0 °C was added l-(4-chlorophenyl)cyclopropane-l-carbaldehyde (Intermediate 18, 0.468 g, 2.595 mmol, 2.0 eq), followed by acetic acid (0.116 g, 1.945 mmol, 1.5 eq). The reaction mixture was stirred at 0 °C for about 30 minutes then sodiumtriacetoxy borohydride (1.09 g, 5.18 mmol, 4.0 eq) was added and allowed to stir at room température for ovemight. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture was cooled to 0 °C, quenched with saturated ammonium chloride solution (10 ml), diluted with water (30 ml) and extracted with DCM (3x30 ml). The combined organic extracts were washed with water (30 ml), dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by silicagel column chromatography by using 0-5% methanol in dichloromethane gradient. The fractions containing the expected product were combined and concentrated under reduced pressure to obtain the desired product (600 mg, yield: 49.4%) as a white solid. Ή NMR (300 MHz, CDCb): δ ppm 7.37-7.23 (m, 9H), 5.15, 5.09 (ABq, Jab= 12.3 Hz, 2H), 4.45 (dd, J= 11.1,4.5 Hz, 1H), 3.16-3.05 (m, 1H), 2.862.73 (m, 2H), 2.70-2.44 (m, 5H), 2.12-1.99 (m, 2H), 1.96-1.82 (m, 2H), 1.80-1.65 (m, 3H), 1.57-1.44 (m, 4H), 1.44-1.37 (m, 2H), 1.37-1.32 (m, 2H), 1.34 (s, 3H), 1.31-1.16 (m, 14H), 1.16-1.03 (m, 2H), 0.99 (s, 3H), 0.96 (s, 3H), 0.93-0.84 (m, 12H), 0.83-0.64 (m, 5H); ESI-MS: m/z 935.52 (M+H)+.
Step 2: Synthesis of (lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,llaR,llbR,13aS)-3a-(2-(((l-(4chlorophenyl)cyclopropyl)methyl)amino)-2-methylpropanamido)-l-isopropyl-5a,5b,8,8,llapentamethyl-2-oxo-3,3a, 4,5,5a, 5b, 6,7,7a, 8,9,10,11,lia,11b, 12,13,13a-octadecahydro-2Hcyclopenta[a] chrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-l-carboxylic acid'.
To a stirred solution of 1-benzyl 3-((3a7?, 5a7?,5b??,7a7?,95,l la/?,l lbR,13a5)-3a-(2-(((l(4-chlorophenyl)cyclopropyl)methyl)amino)-2-methylpropanamido)-l-isopropyl-5a,5b,
8.8.1 la-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,l 1,1 la,l lb,12,13,13a-octadecahydro -2//-cyclopenta[a]chrysen-9-yl) (17?,35)-2,2-dimethylcyclobutane-l,3-dicarboxylate (step 1, 0.6 g, 0.641 mmol, 1.0 eq) in MeOH (10 ml) and THF (10 ml) was added aqueous 2.5N KOH solution (1.78 ml, 4.49 mmol, 7.0 eq). The reaction mixture was stirred at room température for ovemight. TLC indicated starting material was consumed and the desired product was observed. The organic phase was evaporated under reduced pressure, the reaction mixture was diluted with water (30 ml), cooled to 0 °C, pH adjusted to 5.0 with IN HCl and extracted with
119
DCM (3x30 ml). The combined organic extracts were washed with water (20 ml), dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by silicagel column chromatography by using 0-10% methanol in dichloromethane gradient. The fractions containing the expected product were combined and concentrated under reduced pressure to obtain the solid. To this solid compound, MTBE (5 ml) and hexane (5 ml) was added and heated to reflux for about 20 minutes. The mixture was filtered and dried under vacuum to obtain the desired product (90 mg, yield: 16.6%) as a white solid. ’H NMR (300 MHz, CDC13): δ ppm 7.36-7.20 (m, 4H), 4.47 (dd, J= 11.1, 4.5 Hz, 1H), 3.18-3.05 (m, 1H), 2.88-2.76 (m, 2H), 2.68-2.60 (m, 1H), 2.60-2.52 (m, 2H), 2.50-2.44 (m, 2H), 2.13-2.0 (m, 2H), 1.92-1.83 (m,2H), 1.77-1.63 (m,3H), 1.63-1.41 (m,6H), 1.38 (s, 3H), 1.37-1.29 (m,3H), 1.261.10 (m, 14H), 1.08 (s, 3H), 1.05 (m, 1H), 1.0 (s, 3H), 0.93-0.84 (m, 12H), 0.83-0.73 (m, 4H), 0.72-0.65 (m, 1H); ESI-MS: m/z 845.44 (M+H)+; HPLC: 91.5%.
Example 70: Préparation of (HR.3S')-3-(ï(ï3aR.5aR,5bR.7aR.9S.llaR.llbR.13aS')-3a-('2-(5chloronicolinamido)-2-methylpropanamido')-l-isopronvl-5a.5b.8.8.11a-pentamethvl-2-oxo3.3a.4.5.5a.5b.6.7.7a.8.9.10.11.1 la,l lb,12,13.13a-octadecahydro-2H-cvclonentaralchrvseng-vDoxvkarbonvD^^-d imethvl cvclobutane-1 -carboxvli c acid :
Step 1: Synthesis of l-benzyl 3-((3aR,5aR,5bR,7aR,9S,llaR,llbR,13aS)-3a-(2-(5-chloro picolinamido)-2-methylpropanamido)-l-isopropyl-5a, 5 b, 8,8,1 la-pentamethyl-2-oxo-3,3a, 4,5, 5a,5b, 6,7,7a,8,9,10,11,lia,11b, 12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl) (IR, 3S)-2,2-dimethylcyclobutane-l, 3-dicarboxylate:
To a stirred solution of 5-chloropicolinic acid (0.286 g, 1.815 mmol, 2.0 eq) in DMF (7 ml) was added HATU (1.034 g, 2.721 mmol, 3.0 eq) followed by triethylamine (0.89 ml, 6.35 mmol, 7.0 eq). The reaction mixture was stirred at room température for about 30 minutes then 1 -((3aR,5aR,5bR,7aR,9S, 11 aR, 1 IbR, 13aS)-3a-(2-amino-2-methylpropan amido)-1 isopropyl-5a,5b,8,8,l la-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,l 1,11a, lb,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl) 3-benzyl (lS,3R)-2,2-dimethyl
120 cyclobutane-l,3-dicarboxylate (Intermediate 1, 0.700 g, 0.907 mmol, 1.0 eq) was added and heated at 60 °C for ovemight. TLC indicated starting material was consumed and the desired product was observed. The réaction mixture was diluted with water (100 ml) and stirred at room température for about 30 minutes. The précipitâtes formed were collected by filtration, 5 washed with water (100 ml), and dried under vacuum to obtain the solid. The resulting solid was purified by silicagel column chromatography by using 0-2% methanol in dichloromethane gradient. The fractions containing the expected product were combined and concentrated under reduced pressure to obtain the desired product (0.800 g, yield: 96.85%) as a white solid. ’H NMR (300 MHz, CDCh): δ ppm 8.52 (d, 7= 2.1 Hz, 1H), 8.25 (brs, 1H), 8.13 (d, J= 8.4 Hz, 10 1H), 7.85 (dd, J= 8.4, 2.4 Hz, 1H), 7.56 (brs, 1H), 7.35 (m, 5H), 5.15, 5.09 (ABq, 7ab = 12.3
Hz, 2H), 4.44 (dd, 7=11.1,4.5 Hz, 1H), 3.22-3.10 (m, 1H), 2.87-2.57 (m, 5H), 2.40-2.22 (m, 2H), 2.09-2.0 (m, 1H), 1.98-1.80 (m, 3H), 1.78-1.70 (m, 2H), 1.68 (s, 3H), 1.65 (s, 3H), 1.531.40 (m, 4H), 1.37-1.33 (m, 4H), 1.31-1.0 (m, 12H), 0.96 (s, 3H), 0.93 (s, 3H), 0.92 (s, 3H), 0.87-0.76 (m, 10H).
Step 2: Synthesis of (lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,llaR,llbR,13aS)-3a-(2-(5-chloro picolinamido)-2-methylpropanamido)-l-isopropyl-5a, 5 b, 8,8,1 la-pentamethyl-2-oxo-3,3a, 4,5, 5 a,5b, 6,7,7a, 8,9,10,11,lia,11b, 12,13,13a-octadecahydro-2H-cyclopenta[a] chrysen-9-yl)oxy) carbonyl)-2,2-dimethylcyclobutane-l-carboxylic acid:
To a stirred solution of 1-benzyl 3-((3aR,5aR,5bR,7aR,9S,llaR,l lbR,13aS)-3a-(2-(520 chloropicolinamido)-2-methylpropanamido)-l-isopropyl-5a,5b,8,8,lla-pentamethyl-2-oxo-3,
3a,4,5,5a,5b,6,7,7a,8,9,10,l 1,1 la, 1 lb,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9yl) (lR,3S)-2,2-dimethylcyclobutane-l,3-dicarboxylate (step 1, 0.800 g, 0.878 mmol, 1.0 eq) in MeOH (8 ml) and THF (8 ml) was added aqueous 2.5N KOH solution (2.63 ml, 6.585 mmol,
7.5 eq). The reaction mixture was stirred at room température for ovemight. TLC indicated 25 starting material was consumed and the desired product was observed. The organic phase was evaporated under reduced pressure, the reaction mixture was diluted with water (10 ml), cooled to 0 °C, pH adjusted to 5.0 with IN HCl and extracted with DCM (2x50 ml). The combined organic extracts were washed with water (30 ml), dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by silicagel column 30 chromatography by using 0-5% methanol in dichloromethane gradient. The fractions containing the expected product were combined and concentrated under reduced pressure to obtain the solid. To this solid compound, MTBE (10 ml) was added and heated to reflux for about 30 minutes. The mixture was cooled to 0 °C, solid was filtered and dried under vacuum to obtain the desired product (0.048 g, yield: 6.6%) as an off-white solid. ’H NMR (300 MHz,
121
CDCb): δ ppm 8.52 (d, J= 2.1 Hz, 1H), 8.24 (brs, 1H), 8.13 (d, J= 8.4 Hz, 1H), 7.85 (dd, J= 8.4, 2.1 Hz, 1H), 7.56 (s, 1H), 4.46 (dd, J= 11.4, 4.8 Hz, 1H), 3.20-3.07 (m, 1H), 2.87-2.75 (m, 3 H), 2.72-2.53 (m, 2H), 2.37-2.24 (m, 2H), 2.11-2.0 (m, 1H), 1.98-1.80 (m, 5H), 1.70-1.63 (m, 4H), 1.68 (s, 3H), 1.64 (s, 3H), 1.44-1.36 (m, 5H), 1.37 (s, 3H), 1.25-1.18 (m, 7H), 1.07 (m, 4H), 0.94 (s, 3H), 0.92 (s, 3H), 0.89-0.82 (m, 10H); ESI-MS: m/z 820.78 (M+H)+; HPLC: 90.8%.
Example 71: Préparation of (lR,3S)-3-((((3aR,5aR.5bR.7aR.9S.llaR.llbR.13aS)-lisopropvl-5a.5b.8.8.11a-nentamethvl-3a-(2-methvl-2-(3-(6-methvlpyridin-3-vl)ureido) propanamido)-2-oxo-3.3a.4.5.5a.5b.6.7.7a,8.9,10.1 L1 la,l lb.l2,13.13a-octadecahvdro-2Hcvclopentaralchrvsen-9-vl)oxv)carbonvl)-2.2-dimethvIcvclobutane-l-carboxvIic acid:
Step 1: Synthesis of 1-benzyl 3-((3aR,5aR,5bR,7aR,9S,llaR,llbR,13aS)-l-isopropyl-5a,5b,
8,8,1 la-pentamethyl-3a-(2-methyl-2-(3-(6-methylpyridin-3-yl)ureido)propanamido)-2-oxo-3, 3 a, 4,5,5a, 5b, 6,7,7a, 8,9,10,11,1 la, 11 b, 12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9yl) (lR,3S)-2,2-dimethylcyclobutane-l,3-dicarboxylate:
To a stirred solution of l-((3a/î,5a7î,5b7?,7a7î,95,lla7î,llb7?,13a5)-3a-(2-amino-2methylpropanamido)-l-isopropyl-5a,5b,8,8,lla-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,
10,11,1 la,l lb, 12,13,13a-octadecahydro-27/-cycIopenta[a]chrysen-9-yl) 3-benzyl (15,377)-2,2 -dimethylcyclobutane-l,3-dicarboxylate (Intermediate 1, 0.800 g, 1.037 mmol, 1.0 eq) in THF (20 ml) was added DIPEA (0.73 ml, 4.148 mmol, 4.0 eq) and 5-isocyanato-2-methylpyridine (Intermediate 19,0.139 g, 1.037 mmol, 1.0 eq). The reaction mixture was heated at 60 °C for about 16 hours. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture was diluted with water (15 ml) and extracted with ethyl acetate (3x25 ml). The combined organic extracts were washed with water (25 ml), dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by silicagel column chromatography by using 3% methanol in dichloromethane as an eluent to obtain the desired product (560 mg, yield: 59.7%) as a white solid. *H NMR (300 MHz, CDCb): δ ppm
122
8.30 (d, J= 1.8 Hz, 1H), 7.94 (brs, 1H), 7.86 (dd, J= 8.4, 2.1 Hz, 1H), 7.54 (s, 1H), 7.35 (m, 5H), 7.03 (d, J= 8.4 Hz, 1H), 5.96 (s, 1H), 5.15, 5.09 (ABq, Jab = 12.3 Hz, 2H), 4.43 (dd, J= 10.8,4.2 Hz, 1H), 3.20-3.08 (m, 1H), 2.98-2.90 (m, 1H), 2.88-2.72 (m, 2H), 2.70-2.58 (m, 2H), 2.49 (s, 3H), 2.35-2.20 (m, 2H), 2.20-1.83 (m, 8H), 1.63-1.40 (m, 2H), 1.49 (s, 3H), 1.47 (s,
3H), 1.40-1.10 (m, 12H), 1.34 (s, 3H), 1.10-0.75 (m, 20H); ESI MS: m/z 905.58 (M+H)+.
Step 2: Synthesis of (lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,llaR,llbR,13aS)-l-isopropyl-5a,5b,
8,8,1 la-pentamethyl-3a-(2-methyl-2-(3-(6-methylpyridin-3-yl)ureido)propanamido)-2-oxo-3, 3a, 4,5,5a,5 b, 6,7,7a, 8,9,10,11,lia,11b, 12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9yl)oxy) carbonyl)-2,2-dimethylcyclobutane-l-carboxylic acid:
To a stirred solution of 1-benzyl 3-((3aJ?,5aJ?,5bTÎ,7aJÎ,9S,lla/?, 1 lb/?, 13aS)-l-iso propyl-5a,5b,8,8,lla-pentamethyl-3a-(2-methyl-2-(3-(6-methylpyridin-3-yl)ureido)propan amido)-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11 a, 11 b, 12,13,13a-octadecahydro-2//-cyclo penta[a]chrysen-9-yl) (17?,3S)-2,2-dimethylcyclobutane-l,3-dicarboxylate (step 1, 0.700 g, 0.773 mmol, 1.0 eq) in MeOH (14 ml) and THF (14 ml) was added aqueous 2.5 N KOH solution (2.32 ml, 5.80 mmol, 7.5 eq). The reaction mixture was stirred at room température for ovemight. 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 (20 ml), cooled to 0 °C, pH adjusted to 5.0 with IN HCl and extracted with
DCM (3x40 ml). The combined organic extracts were washed with water (40 ml), dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by silicagel column chromatography by using 0-6% methanol in dichloromethane gradient. The fractions containing the expected product were combined and concentrated under reduced pressure to give a solid. To this solid compound, acetonitrile (15 ml) was added and heated to reflux for about 30 minutes. The mixture was cooled to 0 °C, filtered and dried under vacuum to obtain the desired product (310 mg, yield: 49.1%) as a white solid. *H NMR (300 MHz, DMSO-de): δ ppm 12.1 (brs, 1H), 8.72 (s, 1H), 8.35 (d, J= 2.4 Hz, 1H), 7.74 (dd, J= 8.4,2.4
Hz, 1H), 7.50 (s, 1H), 7.08 (d, J= 8.7 Hz, 1H), 6.48 (s, 1H), 4.34 (m, 1H), 3.09 (m, 1H), 2.882.72 (m, 3H), 2.45-2.20 (m, 4H), 2.43 (s, 3H), 2.10 (d, J= 17.7 Hz, 1H), 2.0-1.80 (m, 3H), 1.80-1.50 (m, 4H), 1.50-1.40 (m, 2H), 1.42 (s, 3H), 1.40 (s, 3H), 1.38-1.18 (m, 5H), 1.26 (s,
3H), 1.18-0.98 (m, 8H), 0.91 (s, 3H), 0.87 (s, 3H), 0.84 (s, 3H), 0.80 (s, 3H), 0.78 (s, 3H), 0.750.63 (m, 1H), 0.72 (s, 3H); ESI MS: m/z 815.45 (M+H)+; HPLC: 95.0%.
Example 72: Préparation of (lR,3S’)-3-(i('i3aR.5aR.5bR,7aR.9S.llaR.llbR.13aS,)-lisoEroEYl=5a^b1818Jla=EentainetliYlz3azi2^nethxF2=(3=£6=methylExridin=2^1)ureidp)
123 propanamido)-2-oxo-3.3a.4.5.5a.5b.6.7.7a.8.9.10.11.1 la.1 lb.l2.13.13a-octadecahydro-2Hcvclopentaralchrvsen-9-vDoxv)carbonvD-2.2-dimethvlcyclobutane-l-carboxylic acid:
Step 1: Synthesis of 1-benzyl3-((3aR5aR,5bR,7aR,9S,llaR,llbR,13aS)-l-isopropyl-5a,5b,8,
8,1 la-pentamethyl-3a-(2-methyl-2-(3-(6-methylpyridin-2-yl)ureido)propanamido)-2-oxo-3,
3a, 4,5,5 a, 5b, 6,7,7a, 8,9,10,11,11a, 11b, 12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-
To a stirred solution of l-((3aÆ,5aÆ,5bR,7aÆ,9S,llaÆ,llbR,13aS)-3a-(2-amino-2methylpropanamido)-l-isopropyl-5a,5b,8,8,lla-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,
10,11,1 la,l lb,12,13,13a-octadecahydro-277-cyclopenta[a]chrysen-9-yl) 3-benzyl (1S,3R)2,2-dimethylcyclobutane-l,3-dicarboxylate (Intermediate 1,0.6 g, 0.778 mmol, 1.0 eq) in THF (6 ml) was added triethylamine (0.54 ml, 3.89 mmol, 5.0 eq) and 2-isocyanato-6methylpyridine (Intermediate 20, 0.208 g, 1.556 mmol, 2.0 eq). The reaction mixture was stirred at room température for ovemight. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture was evaporated under reduced pressure, diluted with water (15 ml) and extracted with DCM (2x25 ml). The combined organic extracts were washed with water (25 ml), dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by silicagel column chromatography by using 0-5% MeOH in DCM gradient. The fractions containing the expected product were combined and concentrated under reduced pressure to obtain the desired product (0.400 g, yield: 57.14%) as a white solid. Ή NMR (300 MHz, CDCh): δ ppm 10.39 (s, 1H), 7.94 (s, 1H), 7.56-7.48 (m, 1H), 7.35 (m, 5H), 6.79 (d, J= 7.5 Hz, 1H), 6.48 (d, J= 8.1 Hz, 1H), 5.15, 5.09 (ABq, Jab = 12.3 Hz, 2H), 4.44 (dd, J= 11.4, 4.5 Hz, 1H), 3.20-3.08 (m, 1H), 2.90-2.58 (m, 5H), 2.46 (s, 3H), 2.35-2.23 (m, 2H), 2.09-1.98 (m, 1H), 1.97-1.86 (m, 3H), 1.80-1.67 (m, 2H), 1.64 (s, 3H), 1.61 (s, 3H), 1.55-1.10 (m, 17H), 1.34 (s, 3H), 1.08 (s, 3H), 0.96 (s, 3H), 0.92 (s, 3H), 0.860.80 (m, 10H); ESI-MS: m/z 905.76 (M+H)+.
124
Step 2: Synthesis of (lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,llaR,llbR,13aS)-l-isopropyl-5a,5b,
8,8,1 la-pentamethyl-3a-(2-methyl-2-(3-(6-methylpyridin-2-yl)ureido)propanamido)-2-oxo-3, 3 a, 4,5,5a,5b, 6,7,7a, 8,9,10,11,1 la, llb,12,13,13a-octadecahydro-2H-cycïopenta[a]chrysen-9yl)oxy)carbonyl)-2,2-dimethylcyclobutane-l-carboxylic acid:
To a stirred solution of 1-benzyl 3-((3a/?,5a/?,5b/?,7aÆ,95,llaÆ,llb/?,13a5)-l-iso propyl-5a,5b,8,8,11 a-pentamethyl-3a-(2-methyl-2-(3-(6-methylpyridin-2-yl)ureido)propan amido)-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,l 1,1 la,l lb,12,13,13a-octadecahydro-2//-cyclo penta[a]chrysen-9-yl) (17?,35)-2,2-dimethylcyclobutane-l,3-dicarboxylate (step 1,0.4 g, 0.441 mmol, 1.0 eq) in MeOH (4 ml) and THF (4 ml) was added aqueous 2.5N KOH solution (1.23 ml, 3.093 mmol, 7.0 eq). The reaction mixture was stirred at room température for ovemight. TLC indicated starting material was consumed and the desired product was observed. The organic phase was evaporated under reduced pressure, the reaction mixture was diluted with water (10 ml), cooled to 0 °C, pH adjusted to 5.0 with IN HCl and extracted with DCM (2x30 ml). The combined organic extracts were washed with water, dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purifîed by silicagel column chromatography by using 0-6% methanol in dichloromethane gradient. The fractions containing the expected product were combined and concentrated under reduced pressure to obtain the solid. To this solid compound, acetonitrile (20 ml) was added and heated to reflux for about 30 minutes. The mixture was cooled to 0 °C, filtered, was washed with acetonitrile (10 ml) and dried under vacuum to obtain the desired product (0.060 g, yield: 16%) as an offwhite solid. ’HNMR(300MHz, CDCb): δ ppm 10.5 (brs, 1H), 9.12 (s, 1H), 8.06 (s, 1H), 7.53 (t,J=7.8Hz, 1H), 6.80 (d,J=7.2Hz, 1H), 6.62 (d,J=7.8Hz, 1H), 4.54-4.47 (m, 1H),3.213.09 (m, 1H), 2.97-2.88 (m, 1H), 2.87-2.77 (m, 2H), 2.73-2.50 (m, 2H), 2.47 (s, 3H), 2.40-2.30 (m, 2H), 2.17-2.05 (m, 1H), 2.0-1.80 (m, 3H), 1.72-1.57 (m, 4H), 1.64 (s, 3H), 1.60 (s, 3H),
1.57-1.48 (m, 3H), 1.45-1.35 (m, 2H), 1.39 (s, 3H), 1.34-1.10 (m, 10H), 1.12 (s, 3H), 1.06 (s,
3H), 0.92 (s, 3H), 0.88 (s, 3H), 0.87-0.80 (m, 7H); ESI-MS: m/z 815.70 (M+H)+; HPLC: 93.1%.
Example 73: Préparation of (lR.3S)-3-ii((3aR.5aR.5bR.7aR.9S.llaR.llbR.13aS)-3a-(2-((2(dimethvlamino)ethvl)amino)-2-methvlpropanamido)-l-isonronvl-5a.5b.8,8.11a-pentam ethyl
-2-oxo-3.3a.4.5.5a.5b.6.7.7a.8.9.10.11.11 a. 11 b, 12,13.13a-octadecahvdro-2H-cvclopentara1 chrvsen-9-vl)oxv)carbonvl)-2,2-dimethvlcvclobutane-l-carboxylic acid:
125
Step 1: Synthesis of 1-benzyl 3-((3aR,5aR,5bR,7aR,9S,l laR,llbR,13aS)-3a-(2-((2-(dimethyl amino)ethyl)amino)-2-methylpropanamido)-l-isopropyl-5a, 5b, 8,8,1 la-pentamethyl-2-oxo-3, 3a, 4,5,5 a, 5b, 6,7,7a,8,9,10,11,lia,11 b, 12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9yl) (lR,3S)-2,2-dimethylcyclobutane-l ,3-dicarboxylate:
To a stirred solution of l-((3aR,5aR,5bR,7aR,9S,llaR,llbR,13aS)-3a-(2-amino-2methylpropanamido)-l-isopropyl-5a,5b,8,8,lla-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,
10,11,1 la,l lb,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl) 3-benzyl (lS,3R)-2,2 -dimethylcyclobutane-l,3-dicarboxylate (Intermediate 1, 1.0 g, 1.298 mmol, 1.0 eq) and sodium 2-(dimethylamino)-l-hydroxyethane-l-sulfonate (Intermediate 21, 1.241 g, 6.49 mmol, 5.0 eq) in methanol (10 ml) at 0 °C under nitrogen was added TEA (1 ml, 7.139 mmol,
5.5 eq). The reaction mixture was stirred at 0 °C for about 30 minutes then sodium cyanoborohydride (0.163 g, 2.596 mmol, 2.0 eq) was added and stirred at room température for ovemight. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture cooled to 0 °C, pH adjusted to 7.0 with IN HCl, and evaporated under reduced pressure. The reaction mixture was diluted with DCM (75 ml), washed with water (30 ml) and brine solution (20 ml). The combined organic extracts were dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified by silicagel column chromatography by using 0-10% methanol in dichloromethane gradient. The fractions containing the expected product were combined and concentrated under reduced pressure to obtain the desired product (0.3 g, yield: 27.7%) as a white solid. *H NMR (300 MHz, CDCb): δ ppm 7.65 (brs, 1H), 7.38-7.33 (m, 5H), 5.15, 5.09 (ABq, Jab= 12.3 Hz, 2H), 4.45 (dd, J=
11.1.4.5 Hz, 1 H), 3.23-3.08 (m, 1H), 2.89-2.58 (m, 8H), 2.56-2.41 (m, 7H), 2.36-2.28 (m, 2H), 2.09-1.83 (m, 5H), 1.80-1.44 (m, 7H), 1.42-1.29 (m, 12H), 1.27-1.18 (m, 8H), 1.12 (s, 3H), 1.1-1.0 (m, 1H), 0.96 (s, 3H), 0.94 (s, 3H), 0.91 (s, 3H), 0.85 (s, 3H), 0.84 (s, 3H), 0.79 (m, 1H); ESI-MS: m/z 862.7 (M+H)+(100%).
126
Step 2: Synthesis of (lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,llaR,llbR,13aS)-3a-(2-((2-(dimethyl amino)ethyl)amino)-2-methylpropanamido)-l-isopropyl-5a,5b,8,8,lla-pentamethyl-2-oxo-3, 3a, 4,5,5a, 5b, 6,7,7a,8,9,10,11,lia,11b, 12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9yl)oxy)carbonyl)-2,2-dimethylcyclobutane-l-carboxylic acid:
To a stirred solution of 1-benzyl 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,lla-penta methyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,l 1,1 la, 1 lb,12,13,13a-octadecahydro-2H-cyclo penta[a]chrysen-9-yl) (lR,3S)-2,2-dimethylcyclobutane-l,3-dicarboxylate (step 1,0.3 g, 0.356 mmol, 1.0 eq) in MeOH (5 ml) and THF (5 ml) was added aqueous 2.5N KOH solution (1.0 ml, 2.492 mmol, 7.0 eq). The reaction mixture was stirred at room température for ovemight. 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 (15 ml), cooled to 0 °C, pH adjusted to 5.0 with IN HCl and extracted with DCM (3x15 ml). The combined organic extracts were washed with water (10 ml), dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by silicagel column chromatography by using 0-10% methanol in dichloromethane gradient. The fractions containing the expected product were combined and concentrated under reduced pressure to give a solid. To this solid, acetonitrile (15 ml) was added and heated to reflux for about 30 minutes. The mixture was filtered through a Buchner fùnnel and was washed with acetonitrile (10 ml) and dried under vacuum to obtain the desired product (60 mg, yield: 22.3%) as a white solid. ’H NMR (300 MHz, Pyridine-d5): δ ppm 8.43 (s, 1H), 4.82 (dd, J= 11.1, 4.2 Hz, 1H), 3.44-3.33 (m, 1H), 3.22-3.04 (m, 5H), 2.80-2.68 (m, 2H), 2.66-2.57 (m, 2H), 2.57-2.47 (m, 3H), 2.29 (s, 6H), 2.22-1.90 (m, 5H), 1.90-1.70 (m, 3H), 1.65 (s, 3H), 1.61-1.50 (m, 18H), 1.48-1.39 (m, 5H), 1.30 (s, 3H), 1.27-1.18 (m, 1H), 1.09 (s, 3H), 1.06 (s, 3H), 1.03 (s, 3H), 0.98 (s, 3H), 0.94-0.88 (m, 1H); ESI-MS: m/z 752.66 (M+H)+; HPLC: 95.77%.
Example 74: Préparation of (lR.3S)-3-(((i3aR.5aR.5bR.7aR.9S,llaR,llbR,13aS)-3a-(2amino-2-methvlpropanamido)-l-isopronvl-5a,5b<8.8,lla-pentamethvl-2-oxo-3.3a.4.5,5a,5b. 6.7.7a.8.9.10.1 L1 la.1 lb.l2.13.13a-octadecahydro-2H-cvclopentaialchrvsen-9-vboxy) carbonvl)-2,2-dimethvlcvclobutane-l-carboxylic acid hydrochloride:
127
To a stirred solution of l-((3aR,5aR,5bR,7aR,9S,llaR,llbR,13aS)-3a-(2-amino-2methylpropanamido)-l-isopropyl-5a,5b,8,8,lla-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,
10,11,1 la,l lb,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl) 3-benzyl (lS,3R)-2,2 -dimethylcyclobutane-1,3-dicarboxylate (Intermediate 1,0.6 g, 0.778 mmol, 1.0 eq) in MeOH (10 ml) and THF (10 ml) was added aqueous 2.5N KOH solution (2.18 ml, 5.44 mmol, 7.0 eq). The reaction mixture was stirred at room température for ovemight. 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 (20 ml), cooled to 0 °C, pH adjusted to 5 with IN HCl and extracted with DCM (3x15 ml). The combined organic extracts were washed with water (15 ml), dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by silicagel column chromatography by using 0-10% methanol in dichloromethane gradient, followed by recrystallization over acetonitrile provided the solid. To this solid, 2N HCl in dioxane (5 ml) was added and stirred at room température for ovemight. The mixture was evaporated under reduced pressure and recrystallization over MTBE gave the desired product (0.44 g, yield: 80%) as a white solid. *H NMR (300 MHz, DMSO-de): δ ppm 12.16 (s, 1H), 8.17-8.08 (m, 4H), 4.40-4.32 (m, 1H), 3.16-3.06 (m, 1H), 2.84-2.67 (m, 3H), 2.32-2.22 (m, 4H), 2.02-1.83 (m, 3H), 1.80-1.55 (m, 5H), 1.53 (s, 3H), 1.49 (s, 3H), 1.47-1.32 (m, 6H), 1.27 (s, 3H), 1.311.23 (m, 1H), 1.22-1.10 (m, 9H), 1.06 (s, 3H), 0.92 (s, 3H), 0.91 (s, 3H), 0.87 (s, 3H), 0.83 (s, 3H), 0.82 (s, 3H); ESI-MS: m/z 681.5 (M-HC1+H)+; HPLC: 97.9%; chloride content by Ion chromatography: 4.4%.
Example 75: Préparation of ilR.3S)-3-((((3aR.5aR,5bR,7aR,9S.llaR,llbR.13aS)-3a-(2((tert-butoxvcarbonvl)amino)-2-methylpropanamido)-l-isopropvl-5a.5b.8.8.1 la-pentamethvl2-oxo-3,3a,4.5.5a.5b.6.7,7a.8.9.10.11.1 la.1 lb.l2.13,13a-octadecahvdro-2H-cvclopentaral chrvsen-9-vl)oxv)carbonvl)-2,2-dimethvlcvclobutane-l-carboxvlic acid:
To a stirred solution of 1-benzyl 3-((3aÆ,5aÆ,5bR,7aÆ,95',llaÆ,llbR,13aS)-3a-(2((tert-butoxycarbonyl)amino)-2-methylpropanamido)-l-isopropyl-5a,5b,8,8,lla-pentamethyl2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,l 1,1 la,l lb,12,13,13a-octadecahydro-277-cyclopenta[a] chrysen-9-yl) (1 R,35)-2,2-dimethylcyclobutane-l,3-dicarboxylate (Intermediate 1-step 12,
128
0.700 g, 0.803 mmol, 1.0 eq) in MeOH (7 ml) and THF (7 ml) was added aqueous 2.5N KOH solution (2.41 ml, 6.026 mmol, 7.5 eq). The reaction mixture was stirred at room température for ovemight. TLC indicated starting material was consumed and the desired product was observed. The organic phase was evaporated under reduced pressure, the reaction mixture was diluted with water (10 ml), cooled to 0 °C, pH adjusted to 5.0 with IN HCl and extracted with DCM (3x40 ml). The combined organic extracts were washed with water (40 ml), dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by silicagel column chromatography by using 0-4% methanol in dichloromethane gradient. The fractions contaîning the expected product were combined and concentrated under reduced pressure to obtain the desired product (0.245 g, yield: 39%) as a white solid. ’H NMR (300 MHz, CDCh): δ ppm 4.88 (s, 1H), 4.47 (dd, J= 11.1, 4.8 Hz, 1H), 3.20-3.09 (m, 1H), 2.902.70 (m, 3H), 2.67-2.50 (m, 2H), 2.40-2.22 (m, 2H), 2.10-2.0 (m, 1H), 1.98-1.85 (m, 3H), 1.801.66 (m, 4H), 1.65-1.55 (m, 3H), 1.49 (s, 3H), 1.47 (s, 3H), 1.42 (s, 9H), 1.40-1.35 (m, 4H), 1.35-1.27 (m, 3H), 1.26-1.18 (m, 7H), 1.14 (s, 3H), 1.07 (s, 3H), 1.0-0.98 (m, 1H), 0.93 (s, 3H), 0.92 (s, 3H), 0.87 (s, 3H), 0.86 (s, 3H), 0.83-0.78 (m, 1H); ESI-MS: m/z 803.51 (M+Na)+. Example 76: Préparation of (lR.3S)-3-((((3aR.5aR.5bR.7aR,9S.llaR.llbR.13aS)-lisopropvl-5a.5b.8.8.11a-pentamethvl-3a-(2-methvl-2-((S')-pvrrolidine-2-carboxamido') propanamido)-2-oxo-3.3a.4.5.5a,5b.6.7.7a.8.9.10.11,1 la,l lb.l2.13.13a-octadecahydro-2Hcvclopentaralchrvsen-9-vDoxv)carbonvD-2.2-dimethvlcvclobutane-l-carboxvlic________acid hydrochloride:
A solution of (lR,3S)-3-((((3a/?,5a/?,5b/î,7a7?,95,lla/?,llbR,13aS)-3a-(2-((S)-l-(tertbutoxycarbonyl)pyrrolidine-2-carboxamido)-2-methylpropanamido)-l-isopropyl-5a,5b,8,8, la-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,l 1,1 la,l lb,12,13,13a-octadecahydro-2H -cyclopenta[q/chrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-1 -carboxylic acid (Example 8, 0.400 g, 0.455 mmol, 1.0 eq) and 3N HCl in 1,4-dioxane (5 ml) was stirred at room température for ovemight. TLC indicated starting material was consumed and the desired product was observed. The mixture was evaporated under reduced pressure, the residue was washed with n-hexane (10 ml), MTBE (10 ml) was added and heated to reflux for about 30 minutes. The reaction mixture was cooled to 0 °C, filtered, solid was washed with MTBE (10
129 ml) and dried under vacuum to obtain the desired product (0.340 g, yield: 91.64%) as a white solid. Ή NMR (300 MHz, DMSO-dô): δ ppm 12.16 (brs, 1H), 9.65 (brs, 1H), 8.52 (s, 1H), 8.46 (brs, 1H), 7.32 (s, 1H), 4.39-4.33 (m, 1H), 4.24-4.17 (m, 1H), 3.22-3.06 (m, 3H), 2.822.73 (m, 3H), 2.45-2.23 (m, 4H), 2.10 (d, J= 13.8 Hz, 1H), 1.98-1.64 (m, 9H), 1.62-1.47 (m, 4H), 1.46-1.41 (m, 1H), 1.43 (s, 3H), 1.40-1.32 (m, 3H), 1.37 (s, 3H), 1.26 (s, 3H), 1.25-1.17 (m, 2H), 1.15-1.10 (m, 6H), 1.09-1.01 (m, 2H), 1.03 (s, 3H), 0.91 (s, 3H), 0.90 (s, 3H), 0.87 (s, 3H), 0.82 (s, 3H), 0.81 (s, 3H); ESI-MS: m/z 778.46 (M-HC1+H)+; HPLC: 99.6%; chloride content by Ion chromatography: 4.46%.
BIOLOGICAL ACTIVITY
The compounds described herein can be tested for their antiviral activity following procedures known to a person of ordinary skill in the art. For example, the following protocols can be employed for testing the compounds. These protocols are illustrative and do not limit to the scope of the invention.
Example 77: Evaluation of compounds antiviral activity aeainst HTV-1 strain 92HT599 in MT2 cells:
MT2 cells were infected with HIV-1 strain 92HT599 (10 TCID 50/ 30000 cells). The infected cells were plated at the concentration of ~30,000 cells per well in 96 well plate. Test compound was added to the micro plate in defined format with the final concentration of DMSO (vehicle) is not more than 1%. Incubation was carried out in CO2 incubator for ~ 96 hours for viral infection. At the end of incubation period an aliquot from each well was taken for p24 estimation. The quantitation of p24 is an index for antiviral activity of the compound. Percent inhibition was calculated with reference to control values (vehicle controls). p24 estimation was carried out using Advance biosciences kit as per the procedure detailed by supplier.
For 0% sérum binding assay, wherein “A” refers to an IC50 value of less than 3 nM, “B” refers to IC50 value in range of 3.01-10 nM, and “C” refers to IC50 values greater than 10 nM.
For 40% sérum binding assay, wherein “A” refers to an IC50 value of less than 50 nM, “B” refers to IC50 value in range of50.01-200 nM, and “C” refers to IC50 values greater than 200 nM. The IC50 (nM) values are set forth in Table-1.
Table-1
Example no | IC50 0% sérum | IC50 40% sérum | Example no | IC50 0% sérum | IC50 40% sérum |
1 | A | A | 39 | A | A |
130
Example no | IC50 0% sérum | IC50 40% sérum | Example no | IC50 0% sérum | IC50 40% sérum |
2 | B | A | 40 | A | A |
3 | A | A | 41 | A | A |
4 | A | A | 42 | A | A |
5 | A | B | 43 | A | A |
6 | A | B | 44 | A | B |
7 | A | A | 45 | B | A |
8 | A | A | 46 | A | A |
9 | A | C | 47 | A | A |
10 | A | A | 48 | A | A |
11 | A | B | 49 | A | A |
12 | A | B | 50 | A | A |
13 | A | A | 51 | A | A |
14 | A | A | 53 | A | A |
15 | A | A | 54 | A | A |
16 | A | B | 55 | B | B |
17 | A | A | 56 | A | A |
18 | A | A | 57 | A | A |
19 | A | A | 58 | A | A |
20 | A | A | 59 | A | B |
21 | B | A | 60 | A | A |
22 | A | A | 61 | A | A |
23 | A | A | 63 | A | A |
24 | A | B | 64 | A | A |
25 | A | A | 65 | A | A |
26 | A | B | 67 | A | A |
27 | B | B | 68 | B | A |
28 | A | A | 69 | C | B |
30 | A | A | 70 | A | A |
31 | A | A | 71 | A | B |
32 | B | C | 72 | A | A |
33 | A | A | 73 | A | A |
34 | A | A | 74 | A | A |
35 | C | C | 75 | A | A |
36 | A | B | 76 | A | B |
37 | A | A | - | - | - |
38 | A | A | - | - | - |
Example 78: Evaluation of compounds antiviral activitv against pNL4-3/WT & V7A strains in MT4 cells:
MT4 cells were Transfected with HIV-1 Plasmid (pNL4-3-WT & V7A) (Cells were 5 incubating with required number of TCID50 of HIV-1 for 1.5h at 37°C). After infection, the infected cells were plated at the concentration of 3 x 104 cells per well in 96 well plate. Test compound was added to the test plate in defined format with the final concentration of DMSO is not more than 1%. Incubation was carried out in CO2 incubator for 4 days for viral infection.
131
At the end of incubation period an aliquot from each well was taken for p24 estimation. p24 estimation was carried out using Advance biosciences kit as per the procedure detailed by supplier.
For pNL4-3 WT assay, IC50 wherein “A” refers to an IC50 value of less than 5 nM, “B” 5 refers to IC50 value in range of 5.01 -10 nM, and “C” refers to IC50 values greater than 10 nM;
For pNL4-3 V7A assay, wherein “A” refers to an IC50 value of less than 10 nM, “B” refers to IC50 value in range of 10.01-50 nM, and “C” refers to IC50 values greater than 50 nM. The IC50 (nM) values are set forth in Table-2.
Table-2
Example no | pNL4-3 WT IC50 | pNL4-3 V7A IC50 | Example no | pNL4-3 WT IC50 | pNL4-3 V7A IC50 |
1 | A | A | 39 | B | B |
5 | A | A | 40 | A | A |
7 | A | A | 41 | C | B |
14 | A | B | 42 | B | A |
15 | A | C | 44 | C | C |
16 | B | C | 45 | A | B |
17 | A | A | 47 | A | A |
18 | A | A | 51 | B | C |
19 | A | A | 53 | A | A |
20 | C | C | 54 | A | B |
25 | A | A | 55 | C | C |
28 | B | B | 56 | B | B |
29 | A | B | 57 | B | B |
30 | B | C | 58 | B | C |
31 | A | C | 61 | A | B |
32 | C | C | 63 | C | C |
33 | A | A | 64 | B | C |
34 | A | B | 65 | C | C |
37 | A | A | 70 | A | A |
38 | A | A | 72 | A | C |
Example 79: Evaluation of compounds cvto-toxicitv (MTT Assay):
On day 1 calculate the number of cells required for the assay and seed 3 x 104 cells in
200 μΐ per well. Weigh the compound and dissolve it in DMSO to get 10 mM stock which is further diluted to 3 mM and 1 mM. The drugs from these stocks were added to plate to get final 15 concentration of 100 μΜ, 30 μΜ and 10 μΜ. Add DMSO to controls in a way to obtain final concentration of solvent that is not greater than 1%. Incubate for 4 days in 5% CO2 incubator at 37°C. On day 4,100 μΐ of medium was removed from each well without disturbing the cells.
Add 10 μΐ of MTT reagent and incubate for 4 hours at 5% CO2 incubator at 37°C for formation
132 of crystals. Add 200 μΐ of 0.1N acidic isopropanol to dissolve the crystals and read the plate at 590nm. The values are mentioned in below Table-3 and Table-3A.
Table-3
Example No. | Cytotoxicity % viability | Example No. | Cytotoxicity % viability | ||||
1 μΜ | 0.1 μΜ | 0.01 μΜ | 1 μΜ | 0.1 μΜ | 0.01 μΜ | ||
1 | 4 | 10 | 57 | 35 | 77 | 92 | 84 |
2 | 8 | 9 | 42 | 36 | 8 | 15 | 56 |
3 | 7 | 13 | 32 | 37 | 1 | 4 | 26 |
4 | 9 | 12 | 20 | 38 | 2 | 9 | 20 |
5 | 4 | 35 | 74 | 39 | 0 | 2 | 29 |
6 | 4 | 19 | 60 | 40 | 1 | 2 | 26 |
7 | 0 | 9 | 28 | 42 | 4 | 5 | 27 |
8 | 3 | 5 | 28 | 43 | 3 | 26 | 76 |
9 | 14 | 53 | 100 | 46 | 4 | 12 | 52 |
10 | 0 | 1 | 67 | 47 | 4 | 14 | 75 |
11 | 1 | 3 | 41 | 48 | 4 | 12 | 44 |
12 | 3 | 7 | 42 | 49 | 4 | 12 | 56 |
13 | 4 | 10 | 45 | 50 | 0 | 0 | 21 |
14 | 2 | 8 | 44 | 59 | 8 | 15 | 94 |
15 | 2 | 8 | 44 | 60 | 2 | 27 | 77 |
16 | 2 | 11 | 37 | 61 | 2 | 42 | 88 |
21 | 6 | 7 | 36 | 63 | 0 | 16 | 51 |
22 | 3 | 3 | 21 | 64 | 1 | 2 | 26 |
23 | 4 | 8 | 34 | 65 | 2 | 3 | 27 |
24 | 6 | 21 | 69 | 67 | 3 | 21 | 59 |
25 | 2 | 6 | 31 | 69 | 8 | 8 | 42 |
26 | 0 | 20 | 55 | 71 | 3 | 5 | 41 |
27 | 0 | 2 | 52 | 73 | 9 | 11 | 52 |
28 | 6 | 10 | 21 | 74 | 19 | 14 | 61 |
29 | 2 | 3 | 29 | 75 | 2 | 17 | 63 |
30 | 2 | 3 | 30 | 76 | 6 | 6 | 59 |
34 | 1 | 10 | 26 | - | - | - | - |
Table-3A
Example No. | Cytotoxicity % viability | ||
0.01 μΜ | 0.003 μΜ | 0.001 μΜ | |
17 | 26 | 62 | 81 |
18 | 29 | 61 | 78 |
19 | 40 | 65 | 79 |
20 | 40 | 85 | 91 |
31 | 54 | 86 | 81 |
44 | 58 | 80 | 84 |
51 | 37 | 85 | 86 |
133
52 | 59 | 89 | 83 |
72 | 27 | 84 | 98 |
Example 80: Evaluation of compounds Single dose oral Pharmacokinetic study:
The test item was administered through oral route to animais (rat/mice) at 30mg/kg dose in a suitable vehicle (10% SolutoH- 20%PEG) at 10 ml/kg dose volume. Blood samples 5 (~50pL at each time point) were collected from retro-orbital plexus using K3 EDTA as anticoagulant in eppendorf tubes at defined time intervals 30 minutes, 1 hour, 2 hour, 4 hour, 8 hour, 24 hour & 48 hour under light ether anaesthesia. The samples were centrifuged at 3500xg to separate plasma and stored at -80 °C until analysis. Plasma 25μ1 for Mice were processed as per described in sample préparation.
Standard solutions of the test compound lmg/mL solutions were prepared in DMSO and further dilutions were made in methanol. The calibration curve samples for LCMSMS analysis were prepared by spiking 25μ1 of Mice plasma with 2.5μ1 and of the appropriate working standard solution to obtain final concentrations 0.078, 0.156, 0.312, 0.625, 1.25, 2.5, 5,10,20 & 40pg/ml. To the test compound plasma extraction was carried out using Acetonitrile précipitation. After reconstitution with solvent (50% Acetonitrile in Buffer) samples were analyzed by LCMSMS to get the concentrations to calculate PK Parameters. The values are set forth in Table-4.
Table-4
Example no | Mice oral PK @30 mg/kg | Example no | Mice oral PK @30 mg/kg | ||
Cmax (pg/ml) | AUCo-t (pg.hr/ml) | Cmax (pg/ml) | AUCo-t (pg.hr/ml) | ||
2 | 13.153 | 165.708 | 37 | 38.844 | 874.12 |
3 | 29.61 | 544.857 | 38 | 10.069 | 113.719 |
4 | 8.845 | 184.919 | 40 | 20.255 | 343.317 |
5 | 26.008 | 289.239 | 42 | 22.873 | 480.991 |
6 | 11.099 | 100.412 | 43 | 31.344 | 320.392 |
7 | 41.921 | 517.02 | 44 | 19.807 | 153.713 |
10 | 9.794 | 69.762 | 45 | 21.17 | 214.252 |
12 | 8.54 | 61.312 | 46 | 29.49 | 835.997 |
13 | 2.716 | 18.218 | 47 | 23.578 | 537.72 |
14 | 26.752 | 377.338 | 48 | 20.301 | 477.13 |
15 | 12.843 | 141.167 | 50 | 23.295 | 454.291 |
17 | 28.565 | 332.923 | 51 | 32.327 | 277.12 |
18 | 15.925 | 235.704 | 53 | 9.746 | 57.84 |
19 | 13.875 | 93.04 | 54 | 29.226 | 402.064 |
20 | 18.992 | 236.062 | 59 | 13.92 | 185.948 |
21 | 16.034 | 191.391 | 60 | 20.228 | 216.625 |
134
Example no | Mice oral PK @30 mg/kg | Example no | Mice oral PK @30 mg/kg | ||
Cmax (pg/ml) | AUCo-t (pg.hr/ml) | Cmax (pg/ml) | AUCo-t (pg.hr/ml) | ||
22 | 23.6 | 489.844 | 61 | 45.721 | 615.349 |
23 | 29.736 | 589.886 | 64 | 27.378 | 335.569 |
24 | 29.618 | 427.527 | 65 | 7.383 | 145.21 |
25 | 23.997 | 336.08 | 67 | 24.254 | 86.58 |
28 | 16.239 | 344.768 | 68 | 20.045 | 271.842 |
30 | 22.971 | 477.469 | 70 | 36.636 | 880.717 |
31 | 18.68 | 254.609 | 71 | 19.304 | 129.737 |
33 | 11.391 | 231.111 | 72 | 15.266 | 191.83 |
References:
L Antîvîral methods and protocols (Eds: D Kînchington and R. F. Schinazi) Humana Press Inc., 2000.
2. HIV protocols (Eds: N. L. Michael and J. H. Kim) Humana Press Inc, 1999.
3. DAIDS Virology manual from HIV laboratories, Publication NIH-97-3838,1997.
4. HIV-1 p24 antigen capture assay, enzyme immunoassay for détection of Human immunodeficiency Virus Type 1 (HIV-1) p24 in tissue culture media - Advanced bio science laboratories, Inc kit procedure.
Although the invention herein has been described with reference to particular embodiments, it is to be understood that these embodiments are merely illustrative of the principles and applications of the présent invention. It is therefore to be understood that numerous modifications may be made to the illustrative embodiments and that other arrangements may be devised without departing from the spirit and scope of the présent 15 invention as described above.
Ail publications and patent applications cited in this application are herein incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated herein by reference.
Claims (15)
135
We Claim:
1. A compound ofthe formula ( 1 ):
wherein,
Ri is substituted or unsubstituted Ci-Cô alkyl, ο l , ο , o ozC
9 9 9 9 9 9 9 9 λ-~ν-^° »œ· H00Ya- hoocZ\ rrv o f,c-^cfSj fjo^cf, °**r. ho^x/^-, CT , \Z or hooc (wherein Ra is selected from hydrogen, substituted or unsubstituted Ci-Cô alkyl, or substituted or unsubstituted C3-C8 cycloalkyl);
R2 is selected from hydrogen, substituted or unsubstituted Ci-Cô alkyl;
R3 and R» are independently selected from substituted or unsubstituted Ci-Cô alkyl, substituted or unsubstituted amine, substituted or unsubstituted C3-C8 cycloalkyl and R3 and R4 are taken together with the carbon atom to which they are attached to form substituted or unsubstituted C3-C8 cycloalkyl, epoxide, oxetane or azetidine;
R5 and Rô are independently selected from hydrogen, substituted or unsubstituted CiCô alkyl and R5 and Rô are taken together with the carbon atom to which they are attached form substituted or unsubstituted C3-C8 cycloalkyl or R5 and Rô together represent oxo;
R7 is selected from hydrogen, substituted or unsubstituted Ci-Cô alkyl, substituted or unsubstituted Ci-Cô alkoxy, substituted or unsubstituted amino, substituted or unsubstituted CiCô amino alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted CôC12 aryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaryl, or S(O)2Rb; wherein the substituents are independently selected from one or more Rm;
Rm is selected from halo, Ci-Cô alkyl, haloalkyl, amino, -C(O)ORc, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted heteroaryl or -S(O)2Rb;
136
Rb and Rc are independently selected from substituted or unsubstituted Ci-Cô alkyl or substituted or unsubstituted Cô-Cnaryl;
‘n’ is an integer selected from 0, lor 2;
pharmaceutically acceptable salts, pharmaceutically acceptable solvatés, pharmaceutically acceptable hydrates, tautomers, stereoisomers, ester prodrugs, or combination thereof.
2. Thecompoundofclaim 1, whereinRi is H0 .
3. The compound according to claim 1, which is a compound ofthe formula (IA):
wherein,
R2, Rs, Re, R7 and ‘n’ are same as defined in claim 1.
4. The compound according to claim 1, which is a compound of the formula (IB):
OH wherein,
R2, R5, Re, R7 and ‘n’ are same as defined in claim 1;
X is selected from -O-, -CH2O-, -CH2N-, -or (-CH2-)m;
‘m’is an integer selected from 1,2, 3 or 4.
5. A compound selected from the group consisting of:
(lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,llaR,llbR,13aS)-3a-(2-(4-chlorobenzamido)-2methylpropanamido)-l-isopropyl-5a,5b,8,8,lla-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,
9,10,11,1 la,l lb,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2dimethylcyclobutane-1 -carboxylic acid, (lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,llaR,llbR,13aS)-3a-(2-(l-(4-chlorophenyl) cyclopropane-l-carboxamido)-2-methylpropanamido)-l-isopropyl-5a,5b,8,8,lla-pentamethyl
-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,l 1,1 la,l lb,12,13,13a-octadecahydro-2H-cyclopenta[a] chrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-l -carboxylic acid, ( 1 R,3 S)-3-((((3aR,5aR,5bR,7aR,9S, 11 aR, 11 bR, 13aS)-3a-(2-benzamido-2-methyl propanamido)-l -isopropyl-5a,5b,8,8,11 a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,
5 11 a, 11 b, 12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2-dimethyl cyclobutane-1-carboxylic acid, (lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,llaR,llbR,13aS)-3a-(2-(3,4-dichlorobenzamido) -2-methylpropanamido)-l-isopropyl-5a,5b,8,8,lla-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a, 8,9,10,11,11 a, 11 b, 12,13,13 a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)10 2,2-dimethylcyclobutane-l-carboxylic acid, (lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,llaR,llbR,13aS)-l-isopropyl-5a,5b,8,8,llapentamethyl-3a-(2-methyl-2-(pyrazine-2-carboxamido)propanamido)-2-oxo-3,3a,4,5,5a,5b, 6,7,7a,8,9,10,l 1,1 la,l lb,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy) carbonyl)-2,2-dimethylcyclobutane-l-carboxylic acid,
15 (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,lla-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,
8,9,10,11,1 la,l lb,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-
2,2-dimethylcyclobutane-l -carboxylic acid, (lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-l-isopropyl-5a,5b,8,8,l la20 pentamethyl-3a-(2-methyl-2-(5-methylpyrazine-2-carboxamido)propanamido)-2-oxo-3,3a, 4,5,5a,5b,6,7,7a,8,9,10,l 1,1 la,1 lb,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9yl)oxy)carbonyl)-2,2-dimethylcyclobutane-l-carboxylicacid, (lR,3S)-3-((((3aR,5aR,5bR,7aR,9S, 1 laR,l lbR,13aS)-3a-(2-((S)-l-(tert-butoxy carbonyl)pyrrolidine-2-carboxamido)-2-methylpropanamido)-l-isopropyl-5a,5b,8,8,lla25 pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,l 1,1 la,l lb,12,13,13a-octadecahydro-2Hcyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-l-carboxylic acid, (lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,llaR,llbR,13aS)-3a-(2-(2-(4-ethylpiperazin-lyl)acetamido)-2-methylpropanamido)-l-isopropyl-5a,5b,8,8,lla-pentamethyl-2-oxo-3,3a,4,5, 5a,5b,6,7,7a,8,9,10,l 1,1 la,l lb,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)
30 carbonyl)-2,2-dimethylcyclobutane-l -carboxylic acid, (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,l 1,1 la,l lb,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy) carbonyl)-2,2-dimethylcyclobutane-l-carboxylic acid, <lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,llaR,llbR,13aS)-3a-(2-(2-amino-2-methyl propanamido)-2-methylpropanamido)-l-isopropyl-5a,5b,8,8,lla-pentamethyl-2-oxo-3,3a,4,5, 5a,5b,6,7,7a,8,9,10,l 1,11 a, 1 lb,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy) carbonyl)-2,2-dimethylcyclobutane-l-carboxylic acid hydrochloride,
5 (lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-3a-(2-(lH-benzo[d]imidazole5-carboxamido)-2-methylpropanamido)-l-isopropyl-5a,5b,8,8,lla-pentamethyl-2-oxo-3,3a,4, 5,5a,5b,6,7,7a,8,9,10,l 1,1 la,l lb,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl) oxy)carbonyl)-2,2-dimethylcyclobutane-l-carboxylic acid, (lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-l-isopropyl-5a,5b, 8,8,1 la10 pentamethyl-3a-(2-methyl-2-(2-(6-methylpyridin-3-yl)-lH-benzo[d]imidazole-5carboxamido)propanamido)-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,l 1,11 a,l 1 b, 12,13,13aoctadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-lcarboxylic acid, (lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,llaR,llbR,13aS)-3a-(2-(2,4-dimethylthiazole-515 carboxamido)-2-methylpropanamido)-l-isopropyl-5a,5b,8,8,lla-pentamethyl-2-oxo-3,3a,4, 5,5a,5b,6,7,7a,8,9,10,l 1,1 la, 1 lb,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl) oxy)carbonyl)-2,2-dimethylcyclobutane-l-carboxylic acid, (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)-1 H-benzo[d] imidazole-5-carboxamido)propan 20 amido)-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,l 1,11 a, 1 lb,12,13,13a-octadecahydro-2H-cyclo penta[a]chrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-1 -carboxylic acid, (lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-l-isopropyl-5a,5b, 8,8,1 lapentamethyl-3a-(2-methy 1-2-( 1 -methyl-1 H-imidazole-2-carboxamido)propanamido)-2-oxo3,3a,4,5,5a,5b,6,7,7a,8,9,10,l 1,1 la, 1 lb,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen25 9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-l-carboxylicacid, (lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,llaR,llbR,13aS)-l-isopropyl-3a-(2-(3-isopropyl1 H-pyrazole-5-carboxamido)-2-methylpropanamido)-5a,5b,8,8,11 a-pentamethyl-2-oxo-3,3a, 4,5,5a,5b,6,7,7a,8,9,10,l 1,11 a,l lb,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl) oxy)carbonyl)-2,2-dimethylcyclobutane-l-carboxylic acid,
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-(4-morpholinobenzamido)propanamido)-2-oxo-3,3a,4,5,5a,5b,
6,7,7a, 8,9,10,11,1 la, 1 lb,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy) carbonyl)-2,2-dimethylcyclobutane-l -carboxylic acid, (lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,llaR,llbR,13aS)-3a-(2-(3,5-dimethylisoxazole4-carboxamido)-2-methylpropanamido)-1 -isopropyl-5a,5b,8,8,11 a-pentamethyl-2-oxo-3,3a, 4,5,5a,5b,6,7,7a,8,9,10,l 1,1 la,l lb,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl) oxy)carbonyl)-2,2-dimethylcyclobutane-l-carboxylic acid,
5 (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-1 H-imidazol-1 -yl)benzamido)propanamido)-2oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,l 1,1 la»l lb,12,13,13a-octadecahydro-2H-cyclopenta[a] chrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-l-carboxylic acid, (lS,3R)-3-((((3aR,5aR,5bR,7aR,9S,llaR,llbR,13aS)-3a-(2-(4-chlorobenzamido)-210 methylpropanamido)-l-isopropyl-5a,5b,8,8,lla-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,
9,10,11,1 la,l lb,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2dimethylcyclobutane-1 -carboxylic acid, (lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,llaR,llbR,13aS)-3a-(2-(4-fluorobenzamido)-2methylpropanamido)-l-isopropyl-5a,5b,8,8,lla-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,
15 9,10,11,1 la,l lb,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl) oxy)carbonyl)-2,2dimethylcyclobutane-1 -carboxylic acid, (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,l 1,1 la,l lb,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)
20 -2,2-dimethylcyclobutane-l -carboxylic acid, ( 1 R,3S)-3-((((3aR,5aR,5bR,7aR,9S, 11 aR, 11 bR, 13aS)-3a-(2-(furan-3-carboxamido)2-methylpropanamido)-l-isopropyl-5a,5b,8,8,lla-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,
9,10,11,1 la,l lb,12,13,13a-octadecahydro-2H-cyclopenta[a] chrysen-9-yl) oxy)carbonyl)-2,2dimethylcyclobutane-1 -carboxylic acid,
25 (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,l 1,1 la»l lb,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy) carbonyl)-2,2-dimethylcyclobutane-l -carboxylic acid, ( 1 R,3S)-3-((((3aR,5aR,5bR,7aR,9S, 11 aR, 11 bR, 13aS)-3a-(2-(furan-2-carboxamido)30 2-methylpropanamido)-l -isopropyl-5a,5b,8,8,11 a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,
8,9,10,11,11 a, 11 b, 12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-
2,2-dimethylcyclobutane-1 -carboxylic acid, (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-( 1 -phenylcyclopentane-1 -carboxamido)propanamido)-2-oxo18389
3,3a,4,5,5a,5b,6,7,7a,8,9,10,l 1,1 la,l lb,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-l-carboxylic acid, (lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-l-isopropyl-5a,5b,8,8,1 lapentamethyl-3a-(2-methyl-2-(quinoline-2-carboxamido)propanamido)-2-oxo-3,3a,4,5,5a,5b,
5 6,7,7a,8,9,10,l 1,1 la,l lb,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy) carbonyl)-2,2-dimethylcyclobutane-l-carboxylic acid, (lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-l-isopropyl-5a,5b, 8,8,1 lapentamethyl-3a-(2-methyl-2-(3-methylpicolinamido)propanamido)-2-oxo-3,3a,4,5,5a,5b, 6,7,7a,8,9,10,l 1,1 la,l lb,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy) 10 carbonyl)-2,2-dimethylcyclobutane-l-carboxylic acid, (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-methylfùran-3-carboxamido)propanamido)-2-oxo-3,3a,4,5, 5a,5b,6,7,7a,8,9,10,l 1,1 la»l lb,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy) carbonyl)-2,2-dimethylcyclobutane-l-carboxylic acid,
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-(2-morpholinonicotinamido)propanamido)-2-oxo-3,3a,4,5,5a,5b, 6,7,7a,8,9,10,l 1,1 la,l lb,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy) carbonyl)-2,2-dimethylcyclobutane-l-carboxylic acid, (lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-l-isopropyl-5a,5b,8,8,l la20 pentamethyl-3a-(2-methyl-2-(pyrimidine-2-carboxamido)propanamido)-2-oxo-3,3a,4,5,5a,5b,
6,7,7a,8,9,10,l 1,1 la,l lb,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy) carbonyl)-2,2-dimethylcyclobutane-l -carboxylic acid, (lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,llaR,llbR,13aS)-3a-(2-(2,5-dimethylfùran-3carboxamido)-2-methylpropanamido)-l-isopropyl-5a,5b,8,8,lla-pentamethyl-2-oxo-3,3a,4,5, 25 5a,5b,6,7,7a,8,9,10,l 1,1 la,l lb,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy) carbonyl)-2,2-dimethylcyclobutane-l-carboxylic acid, (lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,llaR,llbR,13aS)-3a-(2-(2-(l,l-dioxidothio morpholino)acetamido)-2-methylpropanamido)-l-isopropyl-5a,5b,8,8,11 a-pentamethyl-2oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,l 1,1 la,l lb,12,13,13a-octadecahydro-2H-cyclopenta[a]
30 chrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-1 -carboxylic acid, (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, 8,9,10,11,1 la,l lb,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy) carbonyl)-2,2-dimethylcyclobutane-1 -carboxylic acid hydrochloride, (lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,llaR,llbR,13aS)-3a-(2-((S)-2-amino-3-methyl butanamido)-2-methylpropanamido)-l-isopropyl-5a,5b,8,8,lla-pentamethyl-2-oxo-3,3a,4,5, 5a,5b,6,7,7a,8,9,10,11,11 a, 1 lb, 12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy) carbonyl)-2,2-dimethylcyclobutane-l-carboxylic acid hydrochloride,
5 (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,l 1,1 la,l lb,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy) carbonyl)-2,2-dimethylcyclobutane-l -carboxylic acid, (lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-l-isopropyl-5a,5b,8,8,l la10 pentamethyl-3a-(2-methyl-2-((S)-piperidine-3-carboxamido)propanamido)-2-oxo-3,3a,4,5,5a, 5b,6,7,7a,8,9,10,l 1,1 la,l lb,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy) carbonyl)-2,2-dimethylcyclobutane-l-carboxylic acid hydrochloride, (1 R,3S)-3-((((3aR,5aR,5bR,7aR,9S, 1 laR, 1 IbR, 13aS)-3a-(2-(2-(4-chlorophenyl) acetamido)-2-methylpropanamido)-l-isopropyl-5a,5b,8,8,lla-pentamethyl-2-oxo-3,3a,4,5,
15 5a,5b,6,7,7a,8,9,10,l 1,1 la,1 lb,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy) carbonyl)-2,2-dimethylcyclobutane-l -carboxylic acid, (!R,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]pyrimidÎne-3-carboxamido)propanamido)-2oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,l 1,1 la,l lb,12,13,13a-octadecahydro-2H-cyclopenta[a]
20 chrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-l-carboxylic acid, (lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,llaR,llbR,13aS)-3a-(2-(2-aminothiazole-4carboxamido)-2-methylpropanamido)-l-isopropyl-5a,5b,8,8,lla-pentamethyl-2-oxo-3,3a,4,5, 5a,5b,6,7,7a,8,9,10,l 1,11 a, 1 lb,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy) carbonyl)-2,2-dimethylcyclobutane-l -carboxylic acid,
25 (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)-2oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,l 1,1 la,l lb,12,13,13a-octadecahydro-2H-cyclopenta[a] chrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-l-carboxylicacid, (1 R,3S)-3-((((3aR,5aR,5bR,7aR,9S, 11 aR, 11 bR, 13aS)-3a-(2-(4-( 1,1 -dioxidothio
30 morpholino)benzamido)-2-methylpropanamido)-l -isopropyl-5a,5b,8,8,11 a-pentamethyl-2oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,l 1,1 la,l lb,12,13,13a-octadecahydro-2H-cyclopenta[a] chrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-l-carboxylic acid, (lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-3a-(2-(4-((l,l-dioxidothio morpholino)methyl)benzamido)-2-methylpropanamido)-l-isopropyl-5a,5b,8,8,11 a-penta methyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,l 1,1 la,l lb,12,13,13a-octadecahydro-2H-cyclo penta[a]chrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-1 -carboxylic acid, (1 R,3S)-3-((((3aR,5aR,5bR,7aR,9S, 11 aR, 1 IbR, 13aS)-3a-(2-(2-(dimethylamino) acetamido)-2-methylpropanamido)-l-isopropyl-5a,5b,8,8,lla-pentamethyl-2-oxo-3,3a,4,5,5a,
5 5b,6,7,7a,8,9,10,11,11 a, 11 b, 12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy) carbonyl)-2,2-dimethylcyclobutane-l -carboxylic acid, (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,8,9,10,11,11 a, 11 b, 12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)
10 carbonyl)-2,2-dimethylcyclobutane-l-carboxylic acid, (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, 8,9,10,11,1 la,l lb,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy) carbonyl)-2,2-dimethylcyclobutane-l -carboxylic acid,
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-pivalamidopropanamido)-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,
11 a, 11 b, 12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2-dimethy 1 cyclobutane-1-carboxylic acid, sodium (lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-l-isopropyl-5a,5b,8,8,
20 11 a-pentamethyl-3a-(2-methyl-2-(methylsulfonamido)propanamido)-2-oxo-3,3a,4,5,5a,5b,
6,7,7a,8,9,10,l 1,1 la,l lb,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy) carbonyl)-2,2-dimethylcyclobutane-l-carboxylate, (lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,llaR,llbR,13aS)-3a-(2-((ethoxycarbonyl)amino) -2-methylpropanamido)-1 -isopropyl-5a,5b,8,8,11 a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,
25 8,9,10,11,1 la,l lb,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-
2,2-dimethylcyclobutane-l -carboxylic acid, (lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,llaR,llbR,13aS)-3a-(2-((4-chlorophenyl) sulfonamido)-2-methylpropanamido)-l-isopropyl-5a,5b,8,8,lla-pentamethyl-2-oxo-3,3a,4,5, 5a,5b,6,7,7a,8,9,10,11,11 a, 11 b, 12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy) 30 carbonyl)-2,2-dimethylcyclobutane-l-carboxylic acid, ( 1 R,3S)-3-((((3aR,5aR,5bR,7aR,9S, 11 aR, 11 bR, 13aS)-3a-(2-(cyclohexanecarbox amido)-2-methylpropanamido)-l-isopropyl-5a,5b,8,8,11 a-pentamethyl-2-oxo-3,3a,4,5,5a,5b, 6,7,7a,8,9,10,l 1,1 la,l lb,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy) carbonyl)-2,2-dimethylcyclobutane-l -carboxylic acid, (lR3S)-3-((((3aR,5aR,5bR,7aR,9S,llaR,llbR,13aS)-l-isopropyl-5a,5b,8,8,llapentamethyl-3a-(2-methyl-2-((pyridin-2-ylmethyl)amino)propanamido)-2-oxo-3,3a,4,5,5a, 5b,6,7,7a,8,9,10,l 1,1 la,l lb,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy) carbonyl)-2,2-dimethylcyclobutane-l-carboxylic acid,
5 (lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,llaR,llbR,13aS)-3a-(2-((4-chlorobenzyl)amino)2-methylpropanamido)-l-isopropyl-5a,5b,8,8,lla-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,
8,9,10,11,1 la,l lb,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-
2.2- dimethylcyclobutane-l-carboxylic acid, (1 R,3S)-3-((((3aR,5aR,5bR,7aR,9S, 11 aR, 11 bR, 13aS)-3a-(2-((( 1 -(4-chlorophenyl)
10 cyclopropyl)methyl)amino)-2-methylpropanamido)-l-isopropyl-5a,5b,8,8,lla-pentamethyl2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,l 1,1 la,l lb,12,13,13a-octadecahydro-2H-cyclopenta[a] chrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-l-carboxylic acid, (lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,llaR,llbR,13aS)-3a-(2-(5-chloropicolinamido)2-methylpropanamido)-l-isopropyl-5a,5b,8,8,lla-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,
15 8,9,10,11,1 la,1 lb,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-
2.2- dimethylcyclobutane-1 -carboxylic acid, (lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-l-isopropyl-5a,5b,8,8,1 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,l 1,1 la,l lb,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy) 20 carbonyl)-2,2-dimethylcyclobutane-l-carboxylic acid, (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,l 1,1 la,l lb,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy) carbonyl)-2,2-dimethylcyclobutane-l -carboxylic acid,
25 (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,lla-pentamethyl-2-oxo-3,3a,4,5, 5a,5b,6,7,7a,8,9,10,l 1,1 la,l lb,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy) carbonyl)-2,2-dimethylcyclobutane-l -carboxylic acid, (1 R,3S)-3-((((3aR,5aR,5bR,7aR,9S, 11 aR, 11 bR, 13aS)-3a-(2-amino-2-methylpropan
30 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 1,11a,
11 b, 12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2-dimethyl cyclobutane-1-carboxylic acid hydrochloride, (lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,llaR,llbR,13aS)-3a-(2-((tert-butoxycarbonyl) amino)-2-methylpropanamido)-l-isopropyl-5a,5b,8,8,lla-pentamethyl-2-oxo-3,3a,4,5,5a,5b,
6,7,7a,8,9,10,l 1,1 la,l lb,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy) carbonyl)-2,2-dimethylcyclobutane-1 -carboxylic acid, (lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-l-isopropyl-5a,5b,8,8,1 lapentamethyl-3a-(2-methyl-2-((S)-pyrrolidine-2-carboxamido)propanamido)-2-oxo-3,3a,4,5,
5 5a,5b,6,7,7a,8,9,10,l 1,1 la,l lb,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy) carbonyl)-2,2-dimethylcyclobutane-1 -carboxylic acid hydrochloride, or pharmaceutically acceptable salts, solvatés, including hydrates and prodrugs of compounds are also contemplated.
6. A compound selected from the group consisting of:
10 (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,lla-pentamethyl-2-oxo-3,3a,4,5,5a,5b, 6,7,7a,8,9,10,l 1,1 la,l lb,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy) carbonyl)-2,2-dimethylcyclobutane-1 -carboxylic acid, (lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-l-isopropyl-5a,5b,8,8,1 la15 pentamethyl-3a-(l-(6-methylnicotinamido)cyclobutane-l-carboxamido)-2-oxo-3,3a,4,5,5a, 5b,6,7,7a,8,9,10,l 1,1 la,l lb,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy) carbonyl)-2,2-dimethylcyclobutane-l-carboxylic acid, (lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,llaR,llbR,13aS)-3a-(l-(4-chlorobenzamido) cyclohexane-1 -carboxamido)-1 -isopropyl-5a,5b,8,8,11 a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,
20 6,7,7a,8,9,10,11,11 a, 11 b, 12,13,13 a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy) carbonyl)-2,2-dimethylcyclobutane-l -carboxylic acid, (lR,3S)-3-((((3aR,5aR,5bR,7aR,9S, 11 aR, 11 bR, 13aS)-3a-(l -(4-chlorobenzamido) cyclopentane-l-carboxamido)-l-isopropyl-5a,5b,8,8,lla-pentamethyl-2-oxo-3,3a,4,5,5a,5b, 6,7,7a,8,9,10,l 1,1 la,l lb,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)
25 carbonyl)-2,2-dimethylcyclobutane-l-carboxylic acid, (lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,llaR,llbR,13aS)-l-isopropyl-5a,5b,8,8,llapentamethyl-3a-(l-(6-methylnicotinamido)cyclohexane-l-carboxamido)-2-oxo-3,3a,4,5,5a, 5b,6,7,7a,8,9,10,l 1,1 la,l lb,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy) carbonyl)-2,2-dimethylcyclobutane-l-carboxylic acid,
30 (lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-l-isopropyl-5a,5b,8,8,llapentamethyl-3a-(l-(6-methylnicotinamido)cyclopentane-l-carboxamido)-2-oxo-3,3a,4,5,5a, 5b,6,7,7a,8,9,10,l 1,1 la,l lb,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy) carbonyl)-2,2-dimethylcyclobutane-l -carboxylic acid,
145 (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,8,9,10,11,11 a, 11 b, 12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy) carbonyl)-2,2-dîmethyl cyclobutane-1 -carboxylic acid, (lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,llaR,llbR,13aS)-3a-(l-(4-chlorobenzamido) cyclopropane-1 -carboxamido)-l -isopropyl-5a,5b,8,8,11 a-pentamethyl-2-oxo-3,3a,4,5,5a,5b, 6,7,7a,8,9,10,11,11 a, 11 b, 12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy) carbonyl)-2,2-dimethylcyclobutane-l -carboxylic acid, (lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-l-isopropyl-5a,5b,8,8,1 lapentamethyl-3a-(l-(6-methylnicotinamido)cyclopropane-l-carboxamido)-2-oxo-3,3a,4,5,5a, 5b,6,7,7a,8,9,10,l 1,1 la,l lb,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy) carbonyl)-2,2-dimethyl cyclobutane-1 -carboxylic acid, ( 1 R,3 S)-3-((((3aR,5aR,5bR,7aR,9S, 11 aR, 11 bR, 13aS)-3a-(l -(4-fluorobenzamido) cyclopropane-l-carboxamido)-l-isopropyl-5a,5b,8,8,lla-pentamethyl-2-oxo-3,3a,4,5,5a,5b, 6,7,7a,8,9,10,l 1,1 la,l lb,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy) carbonyl)-2,2-dimethyl cyclobutane-1 -carboxylic acid, (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,8,9,10,11,11 a, 11 b, 12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy) carbonyl)-2,2-dimethyl cyclobutane-1 -carboxylic acid, (lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-l-isopropyl-5a,5b,8,8,1 lapentamethyl-2-oxo-3a-(l-(pyrimidine-2-carboxamido)cyclobutane-l-carboxamido)-3,3a,4,5, 5a,5b,6,7,7a,8,9,10,11,11 a, 11 b, 12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy) carbonyl)-2,2-dimethyl cyclobutane-1 -carboxylic acid, (lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-l-isopropyl-5a,5b,8,8,l lapentamethyl-3a-(l-(2-morpholinonicotinamido)cyclobutane-l-carboxamido)-2-oxo-3,3a,4,5, 5a,5b,6,7,7a,8,9,10,11,11 a, 11 b, 12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy) carbonyl)-2,2-dimethylcyclobutane-l-carboxylic acid, ( 1 S,3R)-3-((((3aR,5aR,5bR,7aR,9S, 11 aR, 11 bR, 13aS)-3a-(l -(4-chlorobenzamido) cyclopropane-l-carboxamido)-l-isopropyl-5a,5b,8,8,lla-pentamethyl-2-oxo-3,3a,4,5,5a,5b, 6,7,7a, 8,9,10,11,1 la,l lb,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy) carbonyl)-2,2-dimethylcyclobutane-1 -carboxylic acid, or pharmaceutically acceptable salts, solvatés, including hydrates and prodrugs of compounds are also contemplated.
146
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.
5
9. A compound according to any one of claims 1-6 for use in a method for preventing, ameliorating or treating a viral mediated disease, disorder or syndrome in a subject in need thereof.
10. The compound for use according to claim 9, wherein the viral mediated disease, disorder or syndrome is HTV infection, HBV infection , HCV infection , a retroviral infection
10 genetically related to AIDS, respiratory disorders (including adult respiratory distress syndrome (ARDS)), inflammatory disease, or a combination thereof.
11. A compound according to any one of claims 1- 6 for use in a method of treating HIV in a subject in need thereof.
12. A pharmaceutical composition according to claim 7 for use in a method for 15 preventing, ameliorating or treating a viral mediated disease, disorder or syndrome in a subject in need thereof.
13. The pharmaceutical composition for use 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
20 respiratory distress syndrome (ARDS)), inflammatory disease, or a combination thereof.
14. Use of a compound according to any one of claims 1-6 in the manufacture of a médicament for preventing, ameliorating or treating a viral mediated disease, disorder or syndrome.
15. Use of a compound according to any one of claims 1- 6 in the manufacture of a
25 médicament for treating HIV.
147
The invention relates to C-3 novel triterpenone with C-17 reverse amide dérivatives, related compounds, and pharmaceutical compositions useful for the therapeutic treatment of 5 viral diseases and particularly HIV mediated diseases.
The invention relates to C-3 novel triterpenone with C-17 reverse amide dérivatives, related compounds, and pharmaceutical compositions useful for the therapeutic treatment of 5 viral diseases and particularly HIV mediated diseases.
Figure accompanving Abstract
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IN623/CHR/2015 | 2015-02-09 |
Publications (1)
Publication Number | Publication Date |
---|---|
OA18389A true OA18389A (en) | 2018-11-02 |
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