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NZ625516B2 - Derivatives of betulin - Google Patents
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NZ625516B2 - Derivatives of betulin - Google Patents

Derivatives of betulin Download PDF

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Publication number
NZ625516B2
NZ625516B2 NZ625516A NZ62551612A NZ625516B2 NZ 625516 B2 NZ625516 B2 NZ 625516B2 NZ 625516 A NZ625516 A NZ 625516A NZ 62551612 A NZ62551612 A NZ 62551612A NZ 625516 B2 NZ625516 B2 NZ 625516B2
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NZ
New Zealand
Prior art keywords
mmol
octadecahydro
compound
chrysenyl
cyclopenta
Prior art date
Application number
NZ625516A
Other versions
NZ625516A (en
Inventor
Mark Andrew Hatcher
Brian Alvin Johns
Michael Tolar Martin
Elie Amine Tabet
Jun Tang
Original Assignee
Glaxosmithkline Llcphysical
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Glaxosmithkline Llcphysical filed Critical Glaxosmithkline Llcphysical
Priority claimed from PCT/US2012/069637 external-priority patent/WO2013090664A1/en
Publication of NZ625516A publication Critical patent/NZ625516A/en
Publication of NZ625516B2 publication Critical patent/NZ625516B2/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A61K31/222—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin with compounds having aromatic groups, e.g. dipivefrine, ibopamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A61K31/225—Polycarboxylic acids
    • A—HUMAN NECESSITIES
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/397—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having four-membered rings, e.g. azetidine
    • A—HUMAN NECESSITIES
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    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
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    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
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    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A61K31/568—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone
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    • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
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    • C07D239/26—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/48—Two nitrogen atoms
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    • C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
    • C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
    • C07D243/08—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 not condensed with other rings
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
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    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
    • C07D265/30—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings
    • C07D265/32—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings with oxygen atoms directly attached to ring carbon atoms
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    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
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    • C07J—STEROIDS
    • C07J53/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by condensation with a carbocyclic rings or by formation of an additional ring by means of a direct link between two ring carbon atoms, including carboxyclic rings fused to the cyclopenta(a)hydrophenanthrene skeleton are included in this class
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    • C07J63/008—Expansion of ring D by one atom, e.g. D homo steroids

Abstract

Disclosed herein are derivatives of betulin, or a pharmaceutically acceptable salt thereof. Also disclosed are methods for the synthesis of a wide variety of derivatives of betulin and also their use in the treatment or prevention of HIV.

Description

DERIVATIVES OF BETULIN CROSS NCE TO RELATED PATENTS AND PATENT APPLICATIONS This is a Patent Cooperation Treaty Application and claims the benefit of U.S. Provisional Patent Application No. 61/576,448, filed on December 16, 2011, which is hereby incorporated by reference in its entirety.
FIELD OF THE INVENTION The t ion s to compounds, pharmaceutical compositions, and methods of use thereof for (i) inhibiting HIV replication in a subject infected with HIV, or (ii) treating a subject infected with HIV, by administering such compounds.
BACKGROUND OF THE INVENTION Human immunodeficiency virus type 1 (HIV-1) leads to the contraction of acquired immune deficiency disease (AIDS). The number of cases of HIV continues to rise, and currently over twenty-five million individuals worldwide suffer from the virus. Presently, long-term suppression of viral ation with troviral drugs is the only option for treating HIV-1 infection. Indeed, the U.S. Food and Drug Administration has approved twenty-five drugs over six ent inhibitor classes, which have been shown to greatly increase patient survival and quality of life.
However, additional therapies are still required because of undesirable drug-drug interactions; drug-food interactions; non-adherence to therapy; and drug resistance due to mutation of the enzyme target. tly, almost all HIV positive patients are treated with eutic regimens of antiretroviral drug combinations termed, highly active antiretroviral therapy T"). However, HAART therapies are often complex because a combination of different drugs must be stered often daily to the patient to avoid the rapid emergence of drug-resistant HIV-1 variants. Despite the positive impact of HAART on patient survival, drug resistance can still occur. The emergence of multidrug-resistant HIV-1 isolates has serious clinical consequences and must be suppressed with a new drug regimen, known as e therapy.
Current guidelines recommend that salvage therapy includes at least two, and ably three, fully active drugs. Typically, line ies combine three to four drugs targeting the viral enzymes reverse transcriptase and protease.
One option for salvage therapy is to administer different combinations of drugs from the same mechanistic class that remain active against the resistant isolates.
However, the options for this approach are often limited, as resistant mutations ntly confer broad cross-resistance to different drugs in the same class.
Alternative eutic strategies have recently become ble with the development of fusion, entry, and integrase inhibitors. However, ance to all three new drug s has already been reported both in the lab and in patients.
Sustained successful treatment of HlV—1-infected patients with antiretroviral drugs will ore require the continued development of new and improved drugs with new targets and mechanisms of action.
Presently, long-term suppression of viral replication with antiretroviral drugs is the only option for treating HIV-1 infection. To date, a number of approved drugs have been shown to y increase patient survival. However, therapeutic regimens known as highly active antiretroviral therapy (HAART) are often complex e a combination of different drugs must be administered to the patient to avoid the rapid emergence of drug-resistant HIV-1 variants. Despite the positive impact of HAART on patient survival, drug resistance can still occur.
The HIV Gag polyprotein precursor (Pr55Gag), which is composed of four protein domains — matrix (MA), capsid (CA), nucleocapsid (NC) and p6 — and two spacer peptides, SP1 and SP2, represents a new therapeutic target. Although the cleavage of the Gag polyprotein plays a central role in the progression of ious virus particle production, to date, no antiretroviral drug has been approved for this mechanism.
In most cell types, assembly occurs at the plasma membrane, and the MA domain of Gag mediates membrane binding. Assembly is completed by budding of the immature particle from the cell. Concomitant with le release, the virally encoded PR cleaves Gag into the four mature protein domains, MA, CA, NC and p6, and the two spacer peptides, SP1 and SP2. Gag-Pol is also cleaved by PR, liberating the viral enzymes PR, RT and IN. Gag proteolytic processing induces a morphological rearrangement within the le, known as maturation. Maturation converts the immature, donut-shaped particle to the mature virion, which ns a condensed conical core composed of a CA shell surrounding the viral RNA genome in a complex with NC and the viral enzymes RT and IN. Maturation es the virus for ion of a new cell and is absolutely essential for particle infectivity.
Bevirimat (PA-457) is a maturation inhibitor that inhibits the final step in the processing of Gag, the conversion of capsid-SP1 (p25) to capsid, which is ed for the formation of infectious viral particles. Bevirimat has activity against sistant and wild-type HIV, and has shown synergy with antiretrovirals from all classes. Bevirimat reduced HIV viral load by a mean of 1.3 mL in patients who achieved trough levels of >= 20 ug/mL and who did not have any of the key baseline Gag polymorphisms at Q369, V370 or T371. However, Bevirimat users with Gag polymorphisms at Q369, V370 or T371 demonstrated significantly lower load reductions than patients without Gag rphisms at these sites.
Other examples of maturation tors can be found in PCT Patent Application No. W0201 1/100308, "Derivatives of Betu/in"; PCT Patent Application No. PCT/U82012/024288, "Novel Anti-HIV Compounds and Methods of Use f"; Chinese PCT Application No. , "Carbonyl Derivatives of Betu/in"; Chinese PCT Application No. , "Methylene Derivatives of n"; e PCT Application Nos. and , "Propenoate Derivatives of Betu/in". Maturation inhibitors in the prior art leave open gaps in the areas of polymorphism coverage whereby potency against a broad range of clinically relevant gag sequences is extremely important, along with overall potency including the clinically relevant protein adjusted antiviral activity that will be required for robust efficacy in long term durability trials.
To date, no maturation inhibitor has ed an optimal e of these properties.
It would therefore be an advance in the art to discover alternative compounds that are an ive balance of the aforementioned properties for the prevention and/or treatment of HIV ions.
SUMMARY OF THE INVENTION In accordance with one embodiment of the present invention, there is ed a compound of Formula I: H30 CH3 or a pharmaceutically acceptable salt thereof, wherein: 0 R14 R150 A is R4-OJJ\m< L1 and L2 are independently selected from a bond or [C(R6R6’)]q; each instance of Q is independently selected from —CH2— or —C(=O) —; W is selected from a bond or O; WO 90664 R1 is selected from the group consisting of hydrogen, (C1-C12)alkyl, -C(O)R5, 0 R14 R150 R4-OJJ\ X J\(Q)m (0)" Pi; -CH2-O-(C1-C6)alkyl, 2—tetrahydro-2H-pyran, and R2 is selected from the group consisting of -H, (C1-C12)alkyl, -(C1-C6)alkyl-OR4, -(C1-C6)alkyl-O-(C1-C6)alkyl, -C(O)R5, -(CH2)rNR7R8, and —(CH2)rN+(R4)3, wherein when W is O, R1 and R2 can optionally be taken together with the O and N to which they are respectively joined to form a 4 to 8 membered heterocyclyl ring, wherein the heterocyclyl ring may be ally substituted by one to two R11 ; R3 is selected from the group consisting of hydrogen, (C1-C12)alkyl,—NR1R2, (R13)p -OR5, and wherein: , , , X is a monocyclic or bicyclic (C5-C14)aryl, Y is ed from a monocyclic or bicyclic (C2-C9)heterocyclyl or monocylic or bicyclic (C2-C9)heteroaryl, each having one to three heteroatoms selected from S, N or O, and Z is a clic or bicyclic (C3-C8)cycloalkyl; R2 and R3 can optionally be taken together with the nitrogen and L2 to which they are respectively joined to form a 4 to 8 ed heterocyclyl ring, wherein the heterocyclyl ring may be optionally substituted by one to two R11 groups; R4 is selected from the group consisting of -H and (C1-C6)alkyl; R5 is selected from the group consisting of -H, )alkyl, -R3, -(CH2)rNR7R8, and -(CH2)rOR7.
R6 and R6’ are independently selected from the group consisting of -H, (C1-C- 6)alkyl, (C3-C8)cycloalkyl, (C1-C6)alkoxy, haloalkyl, -Y, -(CH2)rNR7R8, H, and -C(O)NH2, wherein the R6 and R6’ groups can optionally be taken together with the carbon to which they are joined to form a 3 to 8 membered cycloalkyl ring, and wherein the cycloalkyl ring may be optionally substituted by one to three R" groups; R7 and R8 are independently selected from the group consisting of -H, (C1-C- 6)alkyl, (C3-C8)cycloalkyl, -Q-aryl-(R4)n, -NR"R15, -C(O)CH3, wherein R7 and R8 can optionally be taken er with the nitrogen to which they are joined to form a 4 to 8 membered heterocyclyl or heteroaryl ring containing one to three heteroatoms selected from —NR5-, -O-, -S-, -S(O)—, or -SOz-, wherein the heterocyclyl or heteroaryl ring may be optionally substituted by one to three R" groups; R9 is halo; R10 is —N(R16)2; R", R", and R13 are ndently selected from the group consisting of oxo, hydroxyl, halo, )alkoxy, -R6(R9)q, -OR6(R9)q, nitro, —sozR6, (C1-C6)alkyl, -C(O)R10, -R4YR6, -CO(O)R4, and -CO(O)R5, wherein any two R", R12 or R13 groups can optionally join to form a 3 to 8 membered cycloalkyl, aryl, cyclyl or heteroaryl ring, wherein the heterocyclyl or heteroaryl ring may contain one to three atoms selected from —NR5-, -O-, -S-, -S(O)—, or -SOz-, and wherein the cycloalkyl, aryl, heterocyclyl or heteroaryl ring may be optionally substituted by one to three R16 ; R14 and R15 are independently selected from the group consisting of -H, (C1- C6)alkyl, )cycloalkyl, )alkoxy, -[C(R6)2]r-, -O[C(R6)2]r-, oxo, hydroxyl, halo, -C(O)R7, -R10, and -CO(O)R2, wherein R14 and R15 can optionally be taken together with the carbon to which they are joined to form a 3 to 8 membered cycloalkyl ring or 4 to 8 membered heterocyclyl ring containing one to three heteroatoms selected from —NR5-, -O-, -S-, -S(O)—, or -SOz-, wherein the cycloalkyl ring or heterocyclyl ring may be optionally substituted by one to three R16 groups; R16 is independently selected from the group consisting of -H, halo, oxo, yl, (C1-C6)alkyl, (C1-C6)alkoxy, (C3-C8)cycloalkyl, -R6(R9)q, -OR6(R9)q, -N(R4)2, -(CH2),-heterocyclyl, -C(O)OH,-C(O)NH2, -R5(R9)q, -OR5(R9)q, nitro, —sozR5, -C(O)R1°, and —CO(O)R4; m and n in each instance are independently 0, 1, 2, 3, or 4; p is ndently 0, 1, 2, 3, or 4; and r and q in each instance are independently 0, 1, 2, 3, or 4. [0012a] In particular, the compound of formula I according to the present invention is a compound of the a 0 OH N/\©\K, HONO Cl or a pharmaceutically acceptable salt thereof.
In a second aspect, the present invention relates to a pharmaceutical composition comprising a) the compound of Formula | or Formula II or a pharmaceutically acceptable salt the f; and b) a pharmaceutically acceptable excipient.
In a third , the present invention is a method of ng an HIV infection comprising administering to a subject suffering therefrom a compound of Formula | or a II, or a pharmaceutically acceptable salt thereof.
Compounds of the present invention are useful for the treatment of subjects with an HIV infection or for the treatment of subjects at risk of acquiring an HIV infection. 7 (followed by 7A) 7A wed by 8) Figure 5 shows a line graph representing an extrapolation of compound 51 normalized |C50 values to 100% human serum.
DETAILED PTION OF REPRESENTATIVE EMBODIMENTS Throughout this application, references are made to various ments relating to compounds, itions, and methods. The various embodiments described are meant to provide a variety of illustrative examples and should not be construed as descriptions of alternative species. Rather it should be noted that the descriptions of various embodiments provided herein may be of overlapping scope. The embodiments sed herein are merely illustrative and are not meant to limit the scope of the present invention.
It is to be understood that the terminology used herein is for the purpose of describing ular embodiments only and is not intended to limit the scope of the present invention. In this specification and in the claims that follow, reference will be made to a number of terms that shall be defined to have the following meanings.
As used herein unless otherwise specified, "alkyl" refers to to a monovalent ted aliphatic hydrocarbyl group having from 1 to 14 carbon atoms and, in some embodiments, from 1 to 6 carbon atoms. "(CX_Cy)alkyl" refers to alkyl groups having from x to y carbon atoms. The term "alkyl"includes, by way of example, linear and branched hydrocarbyl groups such as methyl (CH3-), ethyl (CH3CH2—), n—propyl (CH3CH2CH2—), isopropyl ((CH3)2CH-), l (CH3CH2CH2CH2-), isobutyl ((CH3)2CHCH2-), tyl ((CH3)(CH3CH2)CH-), t—butyl ((CH3)3C-), n—pentyl (CH3CH2CH2CH2CH2-), and neopentyl ((CH3)3CCH2-).
"Alkylene" or "alkylene" refers to divalent saturated aliphatic hydrocarbyl groups having from 1 to 10 carbon atoms and, in some embodiments, from 1 to 6 carbon atoms. "(CU_CV)alkylene" refers to alkylene groups having from u to v carbon atoms. The alkylene groups include branched and straight chain hydrocarbyl groups. For example, "(C1_C6)alkylene" is meant to e methylene, ethylene, propylene, 2-methypropylene, dimethylethylene, pentylene, and so forth.
As such, the term "propylene" could be exemplified by the following structure: _g E- . Likewise, the term "dimethylbutylene" could be exemplified by any of the X/E- following three structures or more: _§ or €ng— , p , . Furthermore, the term "(C1_C6)alkylene" is meant to e such branched chain hydrocarbyl groups as cyclopropylmethylene, which could be exemplified by the following structure: "Alkenyl" refers to a linear or branched hydrocarbyl group having from 2 to 10 carbon atoms and in some embodiments from 2 to 6 carbon atoms or 2 to 4 carbon atoms and having at least 1 site of vinyl unsaturation (>C=C<). For example, (CX-Cy)alkenyl refers to l groups having from x to y carbon atoms and is meant to include for example, ethenyl, propenyl, isopropylene, tadienyl, and the like.
"Alkynyl" refers to a linear monovalent hydrocarbon l or a branched monovalent hydrocarbon radical containing at least one triple bond. The term "alkynyl" is also meant to include those hydrocarbyl groups having one triple bond and one double bond. For example, (C2-C6)alkynyl is meant to include ethynyl, propynyl, and the like.
"Alkoxy" refers to the group -O-alky| wherein alkyl is defined herein.
Alkoxy includes, by way of example, methoxy, ethoxy, n—propoxy, isopropoxy, n—butoxy, xy, toxy, and n—pentoxy.
"Acyl" refers to the groups H-C(O)—, C(O)—, alkenyl-C(O)—, alkynyl-C(O)—, cycloalkyl-C(O)-, aryl-C(O)-, heteroaryl-C(O)-, and heterocyclic-C(O)-.
Acyl includes the "acetyl" group CH3C(O)-.
"Acylamino" refers to the groups -NR20C(O)alkyl, -NR20C(O)cycloalkyl, -NR20C(O)alkenyl, -NR20C(O)alkynyl, - NR20C(O)aryl, -NR20C(O)heteroaryl, and -NR20C(O)heterocyclic, n R20 is hydrogen or alkyl.
"Acyloxy" refers to the groups alkyl-C(O)O-, alkenyl-C(O)O-, alkynyl-C(O)O-, aryl-C(O)O-, cycloalkyl-C(O)O-, heteroaryl-C(O)O-, and heterocyclic-C(O)O-. " refers to the group 22 where R21 and R22 are independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, heterocyclic, -SOz-alkyl, -SOz-alkenyl, -SOz-cycloalkyl, -SOz-aryl, -SOz-heteroaryl, and -SOz-heterocyclic, and wherein R21 and R22 are optionally joined together with the nitrogen bound thereto to form a heterocyclic group. When R21 is en and R22 is alkyl, the amino group is sometimes referred to herein as alkylamino. When R21 and R22 are alkyl, the amino group is sometimes referred to herein as dialkylamino. When referring to a monosubstituted amino, it is meant that either R21 or R22 is hydrogen but not both. When referring to a disubstituted amino, it is meant that neither R21 nor R22 are hydrogen.
"Hydroxyamino" refers to the group -NHOH.
"Alkoxyamino" refers to the group -NHO-alkyl wherein alkyl is defined "Aminocarbonyl" refers to the group -C(O)NR26R27 where R26 and R27 are independently selected from hydrogen, alkyl, alkenyl, l, aryl, cycloalkyl, heteroaryl, heterocyclic, hydroxy, alkoxy, amino, and acylamino, and where R26 and R27 are ally joined together with the nitrogen bound thereto to form a cyclic group.
"Aryl" refers to an aromatic group of from 6 to 14 carbon atoms and no ring heteroatoms and having a single ring (e.g., phenyl) or multiple condensed (fused) rings (e.g., yl or anthryl). For multiple ring systems, ing fused, bridged, and spiro ring systems having aromatic and omatic rings that have no ring heteroatoms, the term "Aryl" or "Ar" applies when the point of attachment is at an aromatic carbon atom (e.g., 5,6,7,8 tetrahydronaphthaleneyl is an aryl group as its point of attachment is at the 2—position of the aromatic phenyl ring).
"AUC" refers to the area under the plot of plasma concentration of drug (not logarithm of the concentration) against time after drug administration.
"EC50" refers to the concentration of a drug that gives half-maximal response.
"|C50" refers to the half-maximal inhibitory concentration of a drug.
Sometimes, it is also converted to the pleo scale (-log IC50), in which higher values indicate exponentially greater potency.
"Clade" refers to a hypothetical construct based on experimental data.
Clades are found using multiple imes hundreds) of traits from a number of species (or specimens) and analyzing them statistically to find the most likely phylogenetic tree for the group.
"Cyano" or "nitrile" refers to the group -CN. alkyl" refers to a saturated or partially saturated cyclic group of from 3 to 14 carbon atoms and no ring heteroatoms and having a single ring or multiple rings including fused, bridged, and spiro ring systems. For multiple ring systems having aromatic and non-aromatic rings that have no ring heteroatoms, the term "cycloalkyl" applies when the point of attachment is at a non-aromatic carbon atom (e.g. 5,6,7,8,-tetrahydronaphthaleneyl). The term "Cycloalkyl" includes cycloalkenyl groups, such as cyclohexenyl. Examples of cycloalkyl groups e, for instance, adamantyl, cyclopropyl, utyl, cyclohexyl, cyclopentyl, cyclooctyl, cyclopentenyl, and cyclohexenyl. Examples of cycloalkyl groups that e multiple bicycloalkyl ring systems are bicyclohexyl, bicyclopentyl, bicyclooctyl, and the like.
Two such oalkyl multiple ring ures are exemplified and named below: bicyclohexyl, and bicyclohexyl.
"(CU_CV)cycloalkyl" refers to cycloalkyl groups having u to v carbon atoms.
"Spiro lkyl" refers to a 3 to 10 member cyclic substituent formed by replacement of two hydrogen atoms at a common carbon atom in a cyclic ring structure or in an alkylene group having 2 to 9 carbon atoms, as exemplified by the following structure wherein the group shown here attached to bonds marked with wavy lines is substituted with a spiro cycloalkyl group: "Fused lkyl" refers to a 3 to 10 member cyclic substituent formed by the replacement of two hydrogen atoms at different carbon atoms in a cycloalkyl ring structure, as exemplified by the following structure wherein the lkyl group shown here contains bonds marked with wavy lines which are bonded to carbon atoms that are substituted with a fused lkyl group: "Carboxy" or "carboxyl" refers interchangeably to the groups 0H, § "Halo" or "halogen" refers to fluoro, chloro, bromo, and iodo.
"Haloalkyl" refers to substitution of an alkyl group with 1 to 3 halo groups (e.g., bifluoromethyl or trifluoromethyl).
"Haloalkoxy" refers to substitution of alkoxy groups with 1 to 5 (e.g. when the alkoxy group has at least 2 carbon atoms) or in some ments 1 to 3 halo groups (e.g. oromethoxy).
"Human Serum Protein Shift Assay" refers to an HIV assay using a Luciferase Reporter to determine percent inhibition - pIC50. The HIV assay makes use of a two-cell co-culture system. In this assay, an infected cell line J4HxBZ and an indicator cell line HOS (delta LTR + luciferase) are co-cultured in the presence and e of compound. The assay is designed to find inhibitors that prevent the infection of H08 cells by the J4HXBZ cell line. The assay can detect tors of any stage of the HIV infection cycle.
"Hydroxy" or "hydroxyl" refers to the group -OH.
"Heteroaryl" refers to an aromatic group of from 1 to 14 carbon atoms and 1 to 6 heteroatoms selected from oxygen, nitrogen, and sulfur and includes single ring (e.g. imidazolyl) and le ring systems (e.g. benzimidazoIyl and benzimidazolyl). For multiple ring s, including fused, bridged, and spiro ring systems having ic and non-aromatic rings, the term "heteroaryl" applies if there is at least one ring heteroatom and the point of attachment is at an atom of an aromatic ring (e.g. 1,2,3,4-tetrahydroquinolinyl and 5,6,7,8-tetrahydroquinolinyl).
In some embodiments, the nitrogen and/or the sulfur ring atom(s) of the heteroaryl group are optionally oxidized to provide for the N-oxide (N—>O), sulfinyl, or sulfonyl moieties. More specifically the term heteroaryl includes, but is not limited to, pyridyl, furanyl, thienyl, thiazolyl, isothiazolyl, triazolyl, imidazolyl, imidazolinyl, isoxazolyl, pyrrolyl, pyrazolyl, pyridazinyl, dinyl, purinyl, phthalazyl, naphthylpryidyl, benzofuranyl, tetrahydrobenzofuranyl, isobenzofuranyl, benzothiazolyl, benzoisothiazolyl, benzotriazolyl, indolyl, isoindolyl, indolizinyl, dihydroindolyl, indazolyl, indolinyl, azolyl, quinolyl, isoquinolyl, izyl, quianazolyl, quinoxalyl, tetrahydroquinolinyl, isoquinolyl, quinazolinonyl, benzimidazolyl, benzisoxazolyl, hienyl, benzopyridazinyl, pteridinyl, carbazolyl, carbolinyl, phenanthridinyl, acridinyl, phenanthrolinyl, phenazinyl, phenoxazinyl, phenothiazinyl, and phthalimidyl.
"Heterocyclic" or "heterocycle" or "heterocycloalkyl" or "heterocyclyl" refers to a saturated or partially saturated cyclic group having from 1 to 14 carbon atoms and from 1 to 6 heteroatoms selected from en, sulfur, phosphorus or oxygen and includes single ring and multiple ring s including fused, bridged, and spiro ring systems. For multiple ring systems having aromatic and/or non- aromatic rings, the terms "heterocyclic", "heterocycle", "heterocycloalkyl", or "heterocyclyl" apply when there is at least one ring heteroatom and the point of attachment is at an atom of a non-aromatic ring (e.g. 1,2,3,4-tetrahydroquinolineyl, ,6,7,8-tetrahydroquinolineyl, and decahydroquinolinyl). In one embodiment, the nitrogen, phosphorus and/or sulfur atom(s) of the heterocyclic group are optionally oxidized to provide for the N-oxide, phosphinane oxide, sulfinyl, yl moieties. More specifically the heterocyclyl includes, but is not limited to, tetrahydropyranyl, piperidinyl, piperazinyl, olidinyl, 2—pyrrolidonyl, morpholinyl, and pyrrolidinyl. A prefix indicating the number of carbon atoms (e.g., ) refers to the total number of carbon atoms in the portion of the heterocyclyl group exclusive of the number of heteroatoms.
Examples of heterocycle and aryl groups include, but are not limited to, azetidine, e, imidazole, pyrazole, pyridine, pyrazine, dine, pyridazine, pyridone, indolizine, isoindole, indole, dihydroindole, indazole, purine, izine, isoquinoline, quinoline, phthalazine, ylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, indoline, imide, 1,2,3,4-tetrahydroisoquinoline, 4,5,6,7-tetrahydrobenzo[b]thiophene, thiazole, thiazolidine, thiophene, benzo[b]thiophene, line, thiomorpholine (also referred to as thiamorpholine), piperidine, pyrrolidine, and tetrahydrofuranyl.
"Fused heterocyclic" or "fused heterocycle" refer to a 3 to 10 member cyclic substituent formed by the replacement of two hydrogen atoms at ent carbon atoms in a cycloalkyl ring structure, as exemplified by the ing structure wherein the lkyl group shown here ns bonds marked with wavy lines which are bonded to carbon atoms that are substituted with a fused heterocyclic group: "Compound", unds", "chemical entity", and "chemical entities" as used herein refers to a compound encompassed by the generic formulae disclosed herein, any subgenus of those generic formulae, and any forms of the nds within the generic and subgeneric formulae, including the racemates, stereoisomers, and tautomers of the compound or compounds.
The term "heteroatom" means nitrogen, oxygen, or sulfur and includes any oxidized form of nitrogen, such as N(O) {N +—O '} and sulfur such as 8(0) and 8(0) 2, and the quaternized form of any basic nitrogen.
"Oxazolidinone" refers to a 5-membered heterocyclic ring containing one nitrogen and one oxygen as heteroatoms and also contains two s and is substituted at one of the two carbons by a carbonyl group as exemplified by any of the following structures, wherein the oxazolidinone groups shown here are bonded to a parent molecule, which is indicated by a wavy line in the bond to the parent molecule: H O M o H O N‘( N~/( N‘( o K/O Egg/O , ,or "0x0" refers to a (=O) group. orphism" refers to when two or more clearly different phenotypes exist in the same population of a species where the occurrence of more than one form or morph. In order to be fied as such, morphs must occupy the same habitat at the same time and belong to a panmictic population (one with random mating).
"Protein g" refers to the binding of a drug to proteins in blood plasma, tissue membranes, red blood cells and other components of blood. in shift" refers to determining a binding shift by comparing the EC50 values determined in the absence and presence of human serum.
"QVT" refers to the amino acids at positions 369, 370, and 371, respectively in the Sp1 fragment of HIV-1 Gag.
"Racemates" refers to a mixture of enantiomers. In an embodiment of the invention, the compounds of Formula |, or pharmaceutically acceptable salts thereof, are enantiomerically enriched with one enantiomer n all of the chiral carbons referred to are in one configuration. In general, reference to an enantiomerically enriched compound or salt, is meant to indicate that the specified enantiomer will comprise more than 50% by weight of the total weight of all enantiomers of the compound or salt.
"Solvate" or "solvates" of a compound refer to those compounds, as defined above, which are bound to a stoichiometric or non-stoichiometric amount of a t. Solvates of a compound es solvates of all forms of the compound. In n embodiments, solvents are volatile, non-toxic, and/or acceptable for administration to humans in trace amounts. Suitable solvates include water.
"Stereoisomer" or "stereoisomers" refer to compounds that differ in the ity of one or more stereocenters. Stereoisomers include enantiomers and diastereomers.
"Tautomer" refer to ate forms of a compound that differ in the position of a proton, such as enol-keto and imine-enamine tautomers, or the tautomeric forms of heteroaryl groups containing a ring atom attached to both a ring -NH- moiety and a ring =N- moiety such as pyrazoles, imidazoles, benzimidazoles, triazoles, and tetrazoles.
The term ‘atropisomer’ refers to a stereoisomer resulting from an axis of asymmetry. This can result from restricted rotation about a single bond where the rotational barrier is high enough to allow differentiation of the ic species up to and including complete isolation of stable non-interconverting diastereomer or omeric species. One skilled in the art will recognize that upon installing a nonsymmetrical RX to core, the formation of atropisomers is possible. In addition, once a second chiral center is led in a given molecule containing an atropisomer, the two chiral elements taken together can create diastereomeric and enantiomeric stereochemical species. Depending upon the substitution about the Cx axis, interconversion between the somers may or may not be possible and may depend on temperature. In some instances, the atropisomers may interconvert rapidly at room temperature and not resolve under ambient ions. Other ions may allow for resolution and isolation but interconversion can occur over a period of seconds to hours or even days or months such that optical purity is degraded measurably over time. Yet other species may be completely restricted from interconversion under ambient and/or elevated temperatures such that resolution and isolation is possible and yields stable s. When known, the resolved atropisomers were named using the helical lature. For this designation, only the two ligands of highest priority in front and behind the axis are ered. When the turn priority from the front ligand 1 to the rear ligand 1 is clockwise, the configuration is P, if counterclockwise it is M.
"Pharmaceutically acceptable salt" refers to pharmaceutically acceptable salts derived from a variety of organic and inorganic counter ions well known in the art and include, by way of example only, sodium, potassium, calcium, ium, ammonium, and tetraalkylammonium, and when the molecule contains 2012/069637 a basic onality, salts of organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, and oxalate. le salts include those described in P. Heinrich Stahl, Camille G. Wermuth (Eds.), Handbook of Pharmaceutical Salts Properties, Selection, and Use; 2002.
"Patient" or "subject" refers to mammals and includes humans and non-human mammals.
"Treating" or "treatment" of a disease in a patient refers to 1) ting the disease from ing in a patient that is predisposed or does not yet display symptoms of the disease; 2) inhibiting the disease or arresting its development; or 3) ameliorating or causing sion of the disease.
Wherever dashed lines occur adjacent to single bonds denoted by solid lines, then the dashed line represents an optional double bond at that position.
Likewise, wherever dashed circles appear within ring ures denoted by solid lines or solid circles, then the dashed circles represent one to three optional double bonds arranged according to their proper valence taking into account whether the ring has any optional substitutions around the ring as will be known by one of skill in the art. For example, the dashed line in the structure below could either indicate a double bond at that on or a single bond at that position: rly, ring A below could be a cyclohexyl ring without any double bonds or it could also be a phenyl ring having three double bonds arranged in any position that still depicts the proper valence for a phenyl ring. Likewise, in ring B below, any of X1-X5 could be selected from: C, CH, or CH2, N, or NH, and the dashed circle means that ring B could be a cyclohexyl or phenyl ring or a N-containing heterocycle with no double bonds or a N-containing heteroaryl ring with one to three double bonds arranged in any position that still depicts the proper valence: x4flx5 _ x3 ]‘ B I: x2;' X1 Where specific compounds or generic formulas are drawn that have aromatic rings, such as aryl or heteroaryl rings, then it will understood by one of still in the art that the particular aromatic location of any double bonds are a blend of lent positions even if they are drawn in different locations from compound to compound or from a to formula. For example, in the two pyridine rings (A and B) below, the double bonds are drawn in different locations, r, they are known to be the same structure and compound: A B \ / | I / \ N N The present invention includes nds as well as their pharmaceutically acceptable salts. Accordingly, the word "or" in the context of "a compound or a pharmaceutically acceptable salt thereof" is understood to refer to either: 1) a compound alone or a compound and a pharmaceutically acceptable salt thereof (alternative), or 2) a compound and a pharmaceutically acceptable salt thereof (in combination).
Unless indicated otherwise, the nomenclature of substituents that are not explicitly defined herein are arrived at by naming the terminal portion of the functionality followed by the adjacent functionality toward the point of attachment.
For example, the tuent "arylalkyloxycarbonyl" refers to the group (aryl)-(alkyl)-O-C(O)-. In a term such as "-C(RX)2", it should be understood that the two RX groups can be the same, or they can be differentifo is defined as having more than one possible identity. In on, certain tuents are drawn as —RXRy, where the "-" indicates a bond adjacent to the parent molecule and Ry being the terminal portion of the functionality. Similarly, it is tood that the above definitions are not intended to include impermissible substitution patterns (e.g., methyl substituted with 5 fluoro groups). Such impermissible substitution patterns are well known to the d artisan.
As recited above, Bevirimat is a yet unapproved anti-HIV drug derived from a betulinic acid-like compound, first isolated from Syzygium clavif/orum, a Chinese herb. It is ed to inhibit HIV by a novel mechanism, Ied maturation inhibition. Like protease inhibitors, Bevirimat and other maturation inhibitors interfere with protease processing of newly translated HIV polyprotein sor, called gag. Gag is an essential structural protein of the HIV virus. Gag undergoes a chain of interactions both with itself and with other cellular and viral factors to accomplish the assembly of infectious virus particles.
However, naturally occurring polymorphisms in HIV are present in some infected individuals, thus lowering the anti-HIV cy of some currently considered therapies. Indeed, studies have shown that presence of a number of single nucleotide rphisms in the Capsid/SP1 spacer protein 1) ge site has resulted in clinical resistance in HIV patients to Bevirimat.
Likewise, mutations in the glutamine-valine-threonine (QVT) motif of the SP1 peptide are also known to cause Bevirimat ance in HIV infected patients. Mutations in the QVT motif of the SP1 peptide are the primary predictors of failure to respond to Bevirimat and the effect of these mutations has been repeatedly demonstrated.
These ms eventually led to the cessation of clinical development of Bevirimat.
See Knapp, D., et al., J. Clin. Microbiol. 49(1): 201-208 (2011).
Bevirimat: 2012/069637 Bevirimat’s Clinical Problems: - Polymorphism issues & weak potency.
- MT4 antiviral assay NL4-3 strain EC50 = 223 nM.
- MT4 antiviral assay NL4-3 strain with V370A site directed mutant polymorphism EC50 = 6062 nM.
- In assay fold shift with human serum 157 fold. See Table 6.
- Cmin target >20 ug/mL*. ° >40% of clade B patients have QVT polymorphisms*.
*See McCallister, et al., XVII International Drug Resistance Workshop, June 10-14, 2008, Sitges, Spain. Conference poster "HIV-1 Gag Polymorphisms Determine Treatment Response to Bevirimat (PA-457)".
After the above HIV clinical problems with Bevirimat were ed, several new HIV active maturation inhibitor compounds were discovered. For example, certain tion inhibitor compounds (hereinafter, compounds ‘A "B" and ‘C as shown below) have been described in PCT Published Application No.
W02011/100308 and PCT Application Serial No. . In on, the present application also describes compounds 51 and 56, among others, as detailed throughout. The present application describes nds that are novel over the compounds described in PCT Published Application No. W02011/100308 and PCT Application Serial No. . In addition, certain compounds described herein show unexpectedly or properties over the WO 90664 nds ("A", "",B and "C") described in PCT hed ation No.
W02011/100308 and PCT Application Serial No. .
One difference between the compounds described in those two references and the compounds of the present application is that both of those references have compounds requiring a carbonyl group at a position where, instead, the present application application describes compounds that cannot have a carbonyl at the same position. By way of example only, this carbonyl versus rbonyl difference is ghted by the arrows indicated directly below. The generic structures of Formulas (l) and (II) bear this out within the present application e when W is oxygen, there can only be a single bond between the adjacent carbon and the W. In sum, there can be no double bond between W and its adjacent carbon so as to form a carbonyl in the Formulas of the present application.
Indeed, this structural difference has now been discovered to unexpectedly improve many of the properties that are involved with creating an efficacious drug for the prevention and/or treatment of viral diseases, such as HIV.
One or more of such properties of certain compounds described within the t application, include, but are not limited to, improving the HIV virus polymorphism coverage, improving the in vitro potency (EC50), reducing the projected clinical human AUC target, potentially reducing any toxicity window by lowering the required dosage to be cious, and reducing the impact of protein binding and/or serum shift upon the projected clinical AUC target.
Such improvements to the pharmacokinetics and projected clinical use of n compounds described herein are described in more detail within Examples 84-89 below.
Compound A: Compound C: (Example 17-19 from PCT Published Application No. WO/2011/10038) Compound 51: (Example 18 herein) Compound 56: (Example 19 herein) In accordance with one embodiment of the present invention, there is ed a compound having the structure of Formula I: 2012/069637 H3O CH3 or a pharmaceutically acceptable salt thereof, n: 0 R14 R150 R4_ Jk X kO (Qim (on Ais Pei; L1 and L2 are independently selected from a bond or [C(R6R6’)]q; each instance of Q is independently selected from —CH2— or —C(=O) —; W is selected from a bond or O; R1 is selected from the group consisting of -H, (C1-C12)alkyl, -C(O)R5, -CH2-O- 0 R14 R150 R4-OJ\m \ )alkyl, 2—tetrahydro-2H-pyran, and 9d; R2 is selected from the group consisting of -H, (C1-C12)alkyl, -(C1-C6)alkyl-OR4, -(C1-C6)alkyl-O-(C1-C6)alkyl, -C(O)R5, -(CH2)rNR7R8, and —(CH2)rN+(R4)3, wherein when W is O, R1 and R2 can optionally be taken together with the O and N to which they are respectively joined to form a 4 to 8 membered heterocyclyl ring, wherein the heterocyclyl ring may be optionally substituted by one to two R11 groups; R3 is selected from the group consisting of -H, (C1-C12)alkyl,—NR1R2, -OR5, (R13)p and wherein: , , X is a monocyclic or bicyclic (C5-Ci4)aryl, Y is ed from a monocyclic or bicyclic (C2-C9)heterocyclyl or monocylic or bicyclic )heteroaryl, each having one to three heteroatoms selected from S, N or O, and Z is a monocyclic or bicyclic (C3-C8)cycloalkyl; R2 and R3 can optionally be taken er with the nitrogen and L2 to which they are respectively joined to form a 4 to 8 membered heterocyclyl ring, wherein the heterocyclyl ring may be optionally substituted by one to two R" groups; R4 is selected from the group consisting of -H and (C1-C6)alkyl; R5 is ed from the group consisting of -H, (C1-C6)alkyl, -R3, -(CH2)rNR7R8, and -(CH2)rOR7.
R6 and R6’ are independently selected from the group consisting of -H, (C1-C- 6)alkyl, (C3-C8)cycloalkyl, (C1-C6)alkoxy, haloalkyl, -Y, -(CH2)rNR7R8, H, and H2, n the R6 and R6’ groups can optionally be taken together with the carbon to which they are joined to form a 3 to 8 membered cycloalkyl ring, and wherein the cycloalkyl ring may be optionally substituted by one to three R" groups; R7 and R8 are independently selected from the group consisting of -H, (C1-C- 6)alkyl, )cycloalkyl, -Q-aryl-(R4)n, -NR"R15, -C(O)CH3, wherein R7 and R8 can optionally be taken together with the nitrogen to which they are joined to form a 4 to 8 membered heterocyclyl or heteroaryl ring containing one to three heteroatoms selected from —NR5-, -O-, -S-, -S(O)—, or -SOz-, n the heterocyclyl or heteroaryl ring may be optionally substituted by one to three R" groups; R9 is halo; R10 is —N(R16)2; R", R", and R13 are independently selected from the group consisting of 0x0, hydroxyl, halo, (C1-C6)alkoxy, -R6(R9)q, -OR6(R9)q, nitro, —sozR6, (C1-C6)alkyl, - C(O)R10, -R4YR6, -CO(O)R4, and -CO(O)R5, wherein any two R", R12 or R13 groups can optionally join to form a 3 to 8 membered cycloalkyl, aryl, heterocyclyl or heteroaryl ring, wherein the heterocyclyl or heteroaryl ring may contain one to three WO 90664 heteroatoms selected from —NR5-, -O-, -S-, -S(O)—, or -SOz-, and wherein the cycloalkyl, aryl, cyclyl or heteroaryl ring may be optionally substituted by one to three R16 groups; R14 and R15 are ndently selected from the group consisting of -H, (C1- C6)alkyl, (C3-C8)cycloalkyl, (C1-C6)alkoxy, -[C(R6)2]r-, -O[C(R6)2]r-, oxo, hydroxyl, halo, -C(O)R7, -R10, and -CO(O)R2, wherein R14 and R15 can ally be taken together with the carbon to which they are joined to form a 3 to 8 membered cycloalkyl ring or 4 to 8 membered heterocyclyl ring containing one to three heteroatoms selected from —NR5-, -O-, -S-, -S(O)—, or -SOz-, wherein the cycloalkyl ring or heterocyclyl ring may be optionally substituted by one to three R16 groups; R16 is independently selected from the group consisting of -H, halo, oxo, hydroxyl, (C1-Ce)alkyl, (C1-C6)alkoxy, (C3-C8)cycloalkyl, -R6(R9)q, -OR6(R9)q, -N(R4)2, -(CH2)r-heterocycle, -C(O)OH,-C(O)NH2, -R5(R9)q, -OR5(R9)q, nitro, —sozR6, -C(O)R10, and -CO(O)R4; m and n in each instance are independently 0, 1, 2, 3, or 4; p is ndently 0, 1, 2, 3, or 4; and r and q in each instance are independently 0, 1, 2, 3, or 4.
In accordance with r embodiment of the present invention, there is ed a compound having the structure of Formula I: or a pharmaceutically acceptable salt thereof, wherein: 0 R14 R150 A is C>>r"<(QJ"\r"i; L1 and L2 are [C(RBRB’)]q; each Q is independently ed from —CH2— or —C(=O) —; W is ed from a bond or O; R1 is selected from the group consisting of -H, (C1-C6)alkyl, -C(O)R4, and 0 R14 R150 R4‘OJJ\(C})m<(QJ)Jn\gJ{ R2 is selected from the group consisting of -H, (C1-C6)alkyl, -(C1-C6)alkyl-OR4, -(C1-C6)alkyl-O-(C1-C6)alkyl, -C(O)R5, -(CH2)rNR7R8, and —(CH2)rN+(R4)3; R3 is selected from the group consisting of hydrogen, (C1-C12)alkyl,—NR1R2, - (R13)p (R11)m ~\ % ll/'"~/\I/ E I,» ;/ (R12)n ’4 I \ \\"-x‘",' Y Z ' 0R5, "\~__/" \\ I and \ ,’ wherein: ’ , , X is a monocyclic or bicyclic (C5-Ci4)aryl, Y is selected from a clic or bicyclic (C2-C9)heterocyclyl or monocylic or bicyclic (C2-C9)heteroaryl, each having one to three heteroatoms selected from S, N or O, and Z is a monocyclic or bicyclic (C3-C8)cycloalkyl; R4 is selected from the group consisting of -H and (C1-C6)alkyl; R5 is selected from the group consisting of (C1-C6)alkyl, -(CH2)rNR7R8, and -(CH2)rOR7; R6 and R6’ are independently selected from the group consisting of -H, (C1-C- 6)alkyl, )cycloalkyl, )alkoxy, haloalkyl, -(CH2)rNR7R8, -C(O)OH, and -C(O)NH2, wherein the R6 and R6’ groups can optionally be taken together with the carbon to which they are joined to form a 3 to 8 membered cycloalkyl ring, and n the cycloalkyl ring may be optionally substituted by one to three R11 groups; R7 and R8 are independently selected from the group consisting of -H, (C1-C- 6)alkyl, (C3-C8)cycloalkyl, -NR14R15, and -C(O)CH3; R9 is halo; R10 is —N(R16)2; R", R12, and R13 are independently selected from the group ting of oxo, hydroxyl, halo, (C1-C6)alkoxy, -R6(R9)q, -OR6(R9)q, nitro, —sozR6, (C1-C6)alkyl, -C(O)R10, -R4YR6, R4, and -CO(O)R5; R14 and R15 are independently selected from the group consisting of -H, (C1- C6)alkyl, (C3-C8)cycloalkyl, (C1-C6)alkoxy, -[C(R6)2]r-, -O[C(R6)2]r-, oxo, hydroxyl, halo, 7, -R10, and -CO(O)R2; R16 is independently selected from the group consisting of -H, oxo, halo, hydroxyl, (C1-Ce)alkyl, (C1-C6)alkoxy, (C3-C8)cycloalkyl, -R6(R9)q, -OR6(R9)q, -N(R4)2, -(CH2)r-heterocycle, -C(O)OH,-C(O)NH2, -R5(R9)q, -OR5(R9)q, nitro, —sozR6, -C(O)R1O, and -CO(O)R4; m and n in each instance are independently 0, 1, 2, 3, or 4; p is independently 0, 1, 2, 3, or 4; and r and q in each instance are independently 0, 1, 2, 3, or 4.
In accordance with another embodiment of the present invention, there is provided a compound having the ure of Formula I: H3O CH3 or a pharmaceutically acceptable salt thereof, wherein: A is O ; L1 and L2 are both (-CH2-); Q is -C(=O)—; W is O; R1 is -H; R2 is selected from the group consisting of -H, (C1-C6)alkyl, -(C1-C6)alkyl-OR4, -(C1-C6)alkyl-O-(C1-C6)a|kyl, -C(O)R5, and -(CH2)rNR7R8; R3 is ed from the group consisting of -H, (C1-C12)alkyl,—NR1R2, (R13)p ’x"~s\ (R11)m .’ x‘ 12 ,"H/ -OR5, é and wherein: , , , X is a monocyclic or bicyclic (C5-Ci4)aryl, Y is selected from a monocyclic or bicyclic (C2-C9)heterocyclyl or monocylic or ic (C2-C9)heteroaryl, each having one to three heteroatoms selected from S, N or O, and Z is a monocyclic or bicyclic (C3-C8)cycloalkyl; R4 is ed from the group consisting of -H and (C1-C6)alkyl; R5 is selected from the group consisting of (C1-C6)alkyl, -(CH2)rNR7R8, and rOR7; R6 and R6’ are independently ed from the group consisting of -H, (C1-C- 6)alkyl, (C3-C8)cycloalkyl, )alkoxy, haloalkyl, -(CH2)rNR7R8, -C(O)OH, and -C(O)NH2; R7 and R8 are independently selected from the group consisting of -H, (C1-C- 6)alkyl, (C3-C8)cycloalkyl, -NR14R15, and -C(O)CH3; R9 is halo; R10 is —N(R16)2; R", R12, and R13 are independently selected from the group consisting of 0x0, hydroxyl, halo, (C1-C6)alkoxy, -R6(R9)q, -OR6(R9)q, nitro, —SOZR6, (C1-C6)alkyl, , -R4YR6, -CO(O)R4, and -CO(O)R5; R14 and R15 are independently selected from the group consisting of -H, (C1- C6)alkyl, (C3-C8)cycloalkyl, (C1-C6)alkoxy, -[C(R6)2]r-, -O[C(R6)2]r-, oxo, hydroxyl, halo, -C(O)R7, -R10, and -CO(O)R2; R16 is independently selected from the group consisting of -H, oxo, halo, yl, (C1-C6)alkyl, (C1-C6)alkoxy, )cycloalkyl, -R6(R9)q, 9)q, -N(R4)2, -(CH2)r-heterocyclyl, -C(O)OH,-C(O)NH2, -R5(R9)q, -OR5(R9)q, nitro, —sozR6, -C(O)R1O, and -CO(O)R4; m and n in each instance are independently 0, 1, or 2; p is independently 0, 1, or 2; and r and q in each instance are independently 0, 1, 2, or 3.
In ance with another embodiment of the present invention, there is provided a compound having the structure of Formula I: 2012/069637 H3O CH3 or a pharmaceutically acceptable salt thereof, wherein: A is 0 L1 and L2 are both (-CH2-); Q is -C(=O)—; W is O; R1 is -H; R2 is selected from the group consisting of -H, (C1-C6)alkyl, -C(O)R5, and -(CH2)rNR7R8; (R11)m R3 is E ‘~.x’ wherein X is a monocyclic or bicyclic 4)aryl; R4 is selected from the group consisting of —H and (C1-C6)alkyl; R5 is selected from the group consisting of (C1-C6)alkyl, -(CH2)rNR7R8, and -(CH2)rOR7; R6 is selected from the group ting of -H, (C1-C6)alkyl, (C3-C8)cycloalkyl, (C1-C6)alkoxy, haloalkyl, -(CH2)rNR7R8, -C(O)OH, and -C(O)NH2; R7 and R8 are independently selected from the group consisting of -H, (C1-C- 6)aikyi, (C3-C8)cycloalkyl, -NR14R15, and -C(O)CH3; R9 is halo; R10 is —N(R16)2; R", R12, and R13 are independently selected from the group consisting of oxo, hydroxyl, halo, (C1-C6)alkoxy, -R6(R9)q, -OR6(R9)q, nitro, —802R6, (C1-C6)alkyl, -C(O)R10, -CO(O)R4, and -CO(O)R5; R14 and R15 are independently ed from the group consisting of -H, (C1- C6)alkyl, (C3-C8)cycloalkyl, (C1-C6)alkoxy, -[C(R6)2]r-, 6)2]r-, oxo, yl, halo, -C(O)R7, -R10, and -CO(O)R2; R16 is independently ed from the group consisting of -H, oxo, halo, hydroxyl, (C1-Ce)alkyl, (C1-C6)alkoxy, (C3-C8)cycloalkyl, -R6(R9)q, -OR6(R9)q, -N(R4)2, -(CH2)r-heterocyclyl, -C(O)OH,-C(O)NH2, -R5(R9)q, -OR5(R9)q, nitro, —sozR6, -C(O)R10, and -CO(O)R4; m and n in each instance are independently 0, 1, or 2; p is independently 0, 1, or 2; and r and q in each instance are independently 0, 1, 2, or 3.
In accordance with another embodiment of the t invention, there is provided a nd having the structure of Formula I: HaC CH3 or a pharmaceutically acceptable salt thereof, wherein: A is O ; L1 and L2 are both (-CH2-); Q is -C(=O)—; W is O; R1 is -H; R2 is -(CH2)rNR7R8; (R11)m R3 is E x wherein X is phenyl; R7 and R8 are independently selected from the group consisting of -H and methyl; R9 is selected from the group consisting of chloro, bromo, and ; R11 is selected from the group consisting of chloro, bromo, and fluoro; m is 0, 1, or2; and r is 1, 2, or 3.
In accordance with another ment of the present invention, there is provided a compound having the structure of Formula II: (II) or a pharmaceutically acceptable salt thereof, wherein: 0 R14 R150 A is R4-OJJ\m< L1 and L2 are independently selected from a bond or [C(R6R6’)]q; each ce of Q is independently selected from —CH2— or —C(=O) —; W is selected from a bond or O; R1 is ed from the group consisting of -H, (C1-C12)alkyl, -C(O)R5, -CH2-O- 0 R14 R150 R4-OJ\m <0J>Jn\ (C1-C6)alkyl, 2—tetrahydro-2H-pyran, and \ R2 is selected from the group consisting of -H, (C1-C12)alkyl, -(C1-C6)alkyl-OR4, -(C1-C6)alkyl-O-(C1-C6)alkyl, -C(O)R5, -(CH2)rNR7R8, and —(CH2)rN+(R4)3, wherein when W is O, R1 and R2 can optionally be taken er with the O and N to which they are respectively joined to form a 4 to 8 membered heterocyclyl ring, wherein the heterocyclyl ring may be optionally substituted by one to two R11 groups; R3 is selected from the group consisting of hydrogen, (C1-C12)alkyl,—NR1R2, (R13)p % .’ X/\‘/ g ' Y/‘l/(R12)n % z 'ORS, "Nu/I \‘~__r’l and wherein: ’ , , X is a monocyclic or bicyclic (C5-C14)aryl, Y is selected from a monocyclic or bicyclic (C2-C9)heterocyclyl or monocylic or bicyclic (C2-C9)heteroaryl, each having one to three heteroatoms selected from S, N or O, and Z is a monocyclic or bicyclic (C3-C8)cycloalkyl; R2 and R3 can optionally be taken er with the nitrogen and L2 to which they are respectively joined to form a 4 to 8 membered heterocyclyl ring, wherein the heterocyclyl ring may be optionally tuted by one to two R11 groups; R4 is ed from the group consisting of -H and (C1-C6)alkyl; R5 is selected from the group consisting of -H, (C1-C6)alkyl, -R3, rNR7R8, and -(CH2)rOR7.
R6 and R6’ are independently ed from the group ting of -H, (C1-C- 6)alkyl, (C3-C8)cycloalkyl, (C1-C6)alkoxy, haloalkyl, -Y, -(CH2)rNR7R8, -C(O)OH, and -C(O)NH2, wherein the R6 and R6’ groups can optionally be taken together with the carbon to which they are joined to form a 3 to 8 membered cycloalkyl ring, and wherein the cycloalkyl ring may be optionally substituted by one to three R" groups; R7 and R8 are independently selected from the group consisting of -H, (C1-C- 6)alkyl, (C3-C8)cycloalkyl, -Q-aryl-(R4)n, -NR"R15, -C(O)CH3, wherein R7 and R8 can optionally be taken together with the nitrogen to which they are joined to form a 4 to 8 membered cyclyl or heteroaryl ring containing one to three heteroatoms ed from —NR5-, -O-, -S-, -S(O)—, or -SOz-, wherein the heterocyclyl or heteroaryl ring may be optionally substituted by one to three R" groups; R9 is halo; R10 is —N(R16)2; R", R", and R13 are independently selected from the group consisting of oxo, hydroxyl, halo, (C1-C6)alkoxy, -R6(R9)q, -OR6(R9)q, nitro, —sozR6, (C1-C6)alkyl, -C(O)R10, -R4YR6, -CO(O)R4, and -CO(O)R5, n any two R", R12 or R13 groups can optionally join to form a 3 to 8 membered cycloalkyl, aryl, heterocyclyl or aryl ring, wherein the heterocyclyl or aryl ring may contain one to three heteroatoms selected from —NR5-, -O-, -S-, -S(O)—, or -SOz-, and wherein the cycloalkyl, aryl, heterocyclyl or heteroaryl ring may be optionally substituted by one to three R16 groups; R14 and R15 are independently selected from the group consisting of -H, (C1- C6)alkyl, (C3-C8)cycloalkyl, )alkoxy, )2]r-, -O[C(R6)2]r-, oxo, hydroxyl, halo, -C(O)R7, -R10, and -CO(O)R2, wherein R14 and R15 can optionally be taken together with the carbon to which they are joined to form a 3 to 8 ed cycloalkyl ring or 4 to 8 membered heterocyclyl ring containing one to three heteroatoms selected from —NR5-, -O-, -S-, -S(O)—, or -SOz-, n the cycloalkyl ring or heterocyclyl ring may be optionally substituted by one to three R16 groups; R16 is independently selected from the group consisting of -H, halo, oxo, hydroxyl, (C1-C6)alkyl, (C1-C6)alkoxy, )cycloalkyl, -R6(R9)q, -OR6(R9)q, -N(R4)2, -(CH2)r-heterocyc|e, -C(O)OH,-C(O)NH2, -R5(R9)q, -OR5(R9)q, nitro, —sozR6, -C(O)R10, and -CO(O)R4; m and n in each instance are independently 0, 1, 2, 3, or 4; p is ndently 0, 1, 2, 3, or 4; and r and q in each instance are independently 0, 1, 2, 3, or 4.
In accordance with another embodiment of the present invention, there is provided a compound having the structure of Formula II: (II) or a ceutically acceptable salt thereof, wherein: 0 R14 R150 A is R4-OJJ\m< L1 and L2 are [C(RBRB’)]q; each Q is independently selected from —CH2— or —C(=O) —; W is ed from a bond or O; R1 is ed from the group consisting of -H, (C1-C6)a|ky|, -C(O)R4, and 0 R14 R150 R4-Okm< R2 is selected from the group consisting of -H, (C1-C6)alkyl, -(C1-C6)alkyI-OR4, -(C1-C6)a|ky|-O-(C1-C6)a|ky|, -C(O)R5, -(CH2),NR7R8, and —(CH2)rN+(R4)3; WO 90664 R3 is selected from the group consisting of -H, (C1-C12)alkyl, —NR1R2, (R13)p +512?R11"" gJ‘Y‘W/Rhn 7521/ -OR5, and wherein: , , , X is a monocyclic or bicyclic (C5-C14)aryl, Y is selected from a monocyclic or bicyclic (C2-C9)heterocyclyl or monocylic or bicyclic (C2-C9)heteroaryl, each having one to three heteroatoms selected from S, N or O, and Z is a monocyclic or bicyclic (C3-C8)cycloalkyl; R4 is selected from the group consisting of -H and (C1-C6)alkyl; R5 is selected from the group consisting of (C1-C6)alkyl, rNR7R8, and -(CH2)rOR7; R6 and R6’ are independently selected from the group consisting of -H, (C1-C- 6)alkyl, )cycloalkyl, (C1-C6)alkoxy, haloalkyl, -(CH2)rNR7R8, -C(O)OH, and -C(O)NH2, wherein the R6 and R6’ groups can optionally be taken together with the carbon to which they are joined to form a 3 to 8 membered cycloalkyl ring, and wherein the cycloalkyl ring may be optionally tuted by one to three R11 groups; R7 and R8 are independently selected from the group consisting of -H, (C1-C- 6)alkyl, (C3-C8)cycloalkyl, -NR14R15, and H3; R9 is halo; R10 is —N(R16)2; R", R12, and R13 are independently selected from the group consisting of 0x0, hydroxyl, halo, (C1-C6)alkoxy, -R6(R9)q, -OR6(R9)q, nitro, —802R6, (C1-C6)alkyl, -C(O)R10, -R4YR6, R4, and -CO(O)R5; R14 and R15 are ndently selected from the group ting of -H, (C1- C6)alkyl, (C3-C8)cycloalkyl, (C1-C6)alkoxy, -[C(R6)2]r-, -O[C(R6)2]r-, oxo, hydroxyl, halo, -C(O)R7, -R10, and -CO(O)R2; WO 90664 R16 is independently selected from the group consisting of -H, oxo, halo, hydroxyl, (C1-Ce)alkyl, (C1-C6)alkoxy, )cycloalkyl, -R6(R9)q, -OR6(R9)q, -N(R4)2, -(CH2)r-heterocyc|e, -C(O)OH,-C(O)NH2, -R5(R9)q, -OR5(R9)q, nitro, —802R6, -C(O)R10, and -CO(O)R4; m and n in each instance are independently 0, 1, 2, 3, or 4; p is independently 0, 1, 2, 3, or 4; and r and q in each instance are independently 0, 1, 2, 3, or 4.
In ance with another embodiment of the present ion, there is provided a compound having the structure of Formula II: (II) A is L1 and L2 are both (-CH2—); Q is -C(=O)—; W is O; R1 is -H; R2 is selected from the group consisting of -H, (C1-C6)a|ky|, -C(O)R5, and - (CH2),NR7R8; (R11)m 3 4% x ," R is wherein X is a monocyclic or bicyclic (C5-C14)aryl; R4 is selected from the group consisting of -H and (C1-C6)alkyl; R5 is selected from the group consisting of (C1-C6)alkyl, -(CH2)rNR7R8, and -(CH2)rOR7; R6 is selected from the group consisting of -H, (C1-C6)alkyl, (C3-C8)cycloalkyl, (C1-C6)alkoxy, haloalkyl, -(CH2)rNR7R8, -C(O)OH, and -C(O)NH2; R7 and R8 are ndently selected from the group consisting of -H, (C1-C- 6)alkyl, (C3-C8)cycloalkyl, -NR14R15, and -C(O)CH3; R9 is halo; R10 is —N(R16)2; R", R12, and R13 are independently selected from the group consisting of oxo, hydroxyl, halo, (C1-C6)alkoxy, )q, -OR6(R9)q, nitro, —sozR6, (C1-C6)alkyl, , -CO(O)R4, and R5; R14 and R15 are independently selected from the group ting of -H, (C1- C6)alkyl, (C3-C8)cycloalkyl, )alkoxy, -[C(R6)2]r-, -O[C(R6)2]r-, oxo, hydroxyl, halo, -C(O)R7, -R10, and -CO(O)R2; R16 is independently selected from the group consisting of -H, oxo, halo, hydroxyl, (C1-C6)alkyl, (C1-C6)alkoxy, (C3-C8)cycloalkyl, )q, -OR6(R9)q, -N(R4)2, -(CH2)r-heterocycle, -C(O)OH,-C(O)NH2, -R5(R9)q, -OR5(R9)q, nitro, —sozR6, -C(O)R10, and -CO(O)R4; m and n in each instance are independently 0, 1, or 2; p is independently 0, 1, or 2; and r and q in each instance are independently 0, 1, 2, or 3.
In accordance with another embodiment of the present invention, there is provided a compound having the structure of Formula II: (II) A is L1 and L2 are both (-CH2-); Q is -C(=O)-; W is O; R1 is -H; R2 is -(CH2),NR7R8; (Riiim R3 is +x/ wherein X is phenyl; R7 and R8 are independently selected from the group consisting of -H and methyl; R9 is selected from the group consisting of chloro, bromo, and fluoro; R11 is ed from the group consisting of , bromo, and fluoro; m is 0, 1, or2; and r is 1, 2, or 3.
In accordance with another embodiment of the present invention, there is provided a compound of Formula II: (II) a II or a pharmaceutically acceptable salt f, wherein: 0 R14 R150 A is B~\(QJJ\FF.{_n L1 and L2 are independently selected from a bond or [C(R6R6)]q; Q is selected from —CH2- or —C(=O)—; W is selected from a bond or oxygen; R1 is selected from the group consisting of -H, (C1-C12)alkyI,-C(O)R5, -CH2-O- 0 R14 \R150 (C1-C6)alkyl, 2—tetrahydro-2H-pyran and Hokmghokgzn ; R2 is selected from the group consisting of -H, (C1-C12)alkyl, -C1_6 alkyI-OH, -c1_6 alkyI-O-CH; alkyl, ,-C(O)R5, and -(CH2)rNR7R8, -C(O)R5, wherein when Wis oxygen, R1 and R2 can optionally be taken together with the oxygen and nitrogen to which they are respectively joined to form a 4 to 8 membered heterocyclyl ring, wherein the cyclyl ring may be optionally substituted by one to two R11 groups; R3 is selected from the group consisting of hydrogen, (C1-C12)alkyI,—NR1R2, (R13)p x"\ (R11)m §.Y/n,"——"\ 12 I' ~\ Exx/ , I \ Z ' é .
-OR5, I and X x wherein: ’ , , X is a monocyclic or bicyclic (C5-Cr4)aryl, Y is selected from a monocyclic or ic (C2-C9)heterocyclyl or monocylic or bicyclic (C2-C9)heteroaryl, each having one to three heteroatoms selected from S, N or O, and Z is a monocyclic or bicyclic (C3-C8)cycloalkyl; R2 and R3 can optionally be taken together with the en and L2 to which they are respectively joined to form a 4 to 8 membered heterocyclyl ring, n the heterocyclyl ring may be optionally tuted by one to two R" groups; R4 is selected from -H and (C1-C6)alkyl; R5 is selected from (C1-C6)alkyl, -R3, -(CH2)rNR7R8, or -(CH2)rOR7; R6 and R6’ are ndently -H, (C1-C6)alkyl, (C3-C8)cycloalkyl, (C1-C6)alkoxy, haloalkyl, -Y, rNR7R8, H, -C(O)NH2, wherein the R6 and R6’ groups can optionally be taken together with the carbon to which they are joined to form a 3 to 8 membered cycloalkyl ring, n the cycloalkyl ring may be optionally substituted by one to three R" groups; R7 and R8 are independently selected from the group consisting of -H, (C1-C- 6)alkyl, (C3-C8)cycloalkyl, -Q-aryl-(R4)n, 5, -C(O)CH3, wherein R7 and R8 can optionally be taken together with the nitrogen to which they are joined to form a 4 to 8 membered heterocyclyl or aryl ring containing one to three heteroatoms selected from —NR5-, -O-, -S-, -S(O)—, or -SOz-, wherein the heterocyclyl or heteroaryl ring may be optionally substituted by one to three R" groups; R9 is halo; R10 is —N(R16)2; R", R", and R13 are independently selected from the group consisting of 0x0, hydroxyl, halo, (C1-C6)alkoxy, -R6(R9)q, -OR6(R9)q, nitro, —sozR6, (C1-C6)alkyl, -C(O)R1O, -R4YR6, and -CO(O)R5, wherein any two R9, R10 or R" groups can optionally join to form a 3 to 8 membered cycloalkyl, aryl, heterocyclyl or heteroaryl ring, wherein the heterocyclyl or heteroaryl ring may contain one to three heteroatoms selected from —NR5-, -O-, -S-, -S(O)—, or -SOz-, and wherein the cycloalkyl, aryl, heterocyclyl or heteroaryl ring may be optionally substituted by one to three R16 groups; R14 and R15 are independently selected from the group consisting of -H, (C1- C6)alkyl, (C3-C8)cycloalkyl, (C1-C6)alkoxy, )2]r-, -O[C(R6)2]r-, oxo, hydroxyl, halo, -C(O)R7, -R10, and -CO(O)R2, wherein R14 and R15 can optionally be taken together with the carbon to which they are joined to form a 3 to 8 membered cycloalkyl ring or 4 to 8 membered heterocyclyl ring containing one to three heteroatoms selected from —NR5-, -O-, -S-, -S(O)—, or -SOz-, n the cycloalkyl ring or cyclyl ring may be optionally substituted by one to three R16 groups; R16 is independently selected from the group consisting of halo, oxo, hydroxyl, (C1-C6)alkyl, (C1-C6)alkoxy, (C3-C8)cycloalkyl, -R6(R9)q, -OR6(R9)q, -N(R4)2, -(CH2)r- heterocyclyl, -C(O)OH,-C(O)NH2, -R5(R9)q, -OR5(R9)q, nitro, —SOZR6, 1O, and -CO(O)R4; m and n in each ce are independently 0, 1, 2, 3, or 4; p is independently 0, 1, 2, 3, or 4; and r and q in each instance are independently 0, 1, 2, 3, or 4.
In accordance with another embodiment of the present invention, there is provided a compound having the ure of a I or Formula II above, wherein L1 and L2 are both B’)]q.
In accordance with another embodiment of the present invention, there is provided a compound having the structure of Formula I or Formula II above, wherein L1 and L2 are both —CH2—.
In accordance with another embodiment of the present invention, there is provided a compound having the structure of Formula I or Formula II above, wherein q is independently 1, 2, or 3.
In accordance with another embodiment of the present invention, there is provided a compound having the ure of Formula I or Formula II above, wherein q is 1.
In accordance with another embodiment of the present invention, there is provided a compound having the ure of Formula I or a II above, wherein W is O.
In accordance with another embodiment of the present invention, there is provided a compound having the structure of Formula I or Formula II above, wherein W is a bond.
In accordance with another embodiment of the present ion, there is provided a nd having the structure of Formula I or Formula II above, wherein when W is a bond, then R1 is -H.
In accordance with another embodiment of the present invention, there is provided a compound having the ure of Formula I or a II above, wherein when W is 0, then R1 is -H.
In accordance with another embodiment of the present invention, there is provided a compound having the structure of Formula I or Formula II above, wherein Qm in the A group is absent and Qn in the A group is -CH2- and the Q in the Formula I structure is —C(=O) —.
] In accordance with another embodiment of the present invention, there is provided a compound having the structure of Formula I or Formula II above, wherein R1 is -H.
In accordance with another embodiment of the present ion, there is provided a compound having the structure of Formula I or Formula II above, wherein R2 is —(CH2)rNR7R8.
In ance with another embodiment of the present invention, there is provided a compound having the structure of Formula I or Formula II above, wherein R2 is (dimethylamino)ethyl.
In accordance with another embodiment of the present invention, there is provided a compound having the structure of Formula I or Formula II above, wherein r is independently 0, 1, 2, or 3.
In accordance with another embodiment of the present ion, there is provided a compound having the structure of Formula I or Formula II above, wherein r is 2.
In accordance with another embodiment of the present invention, there is provided a compound having the structure of a I or Formula II above, ""x (R11)m _§_" x/‘t/ wherein R3 is .
In accordance with another embodiment of the present ion, there is provided a compound having the ure of Formula I or Formula II above, n X is a monocyclic (C5-C14)aryl.
In ance with another embodiment of the present invention, there is provided a compound having the structure of Formula I or Formula II above, wherein X is phenyl.
In accordance with another embodiment of the present invention, there is provided a compound having the structure of Formula I or Formula II above, wherein R4 is -H.
In accordance with another embodiment of the present invention, there is provided a compound having the structure of Formula I or Formula II above, wherein m is 0 or 1.
In accordance with r embodiment of the present invention, there is provided a nd having the structure of a I or Formula II above, wherein m is 0.
In accordance with another embodiment of the present invention, there is ed a compound having the structure of Formula I or a II above, wherein m is 1.
In accordance with another embodiment of the present invention, there is provided a compound having the structure of Formula I or a II above, wherein n is 1.
In accordance with another ment of the t invention, there is provided a compound having the structure of Formula I or Formula II above, wherein R6 and R6’ are both -H.
In accordance with another embodiment of the present invention, there is provided a compound having the structure of Formula I or Formula II above, wherein R7 and R8 are both (C1-C6)alkyl.
In accordance with another embodiment of the present invention, there is provided a compound having the structure of Formula I or Formula II above, wherein R7 is methyl.
In accordance with another embodiment of the present invention, there is provided a compound having the structure of a I or Formula II above, wherein R8 is .
In accordance with another embodiment of the t invention, there is provided a nd having the structure of a I or Formula II above, wherein R7 and R8 are both methyl.
In accordance with another embodiment of the present invention, there is provided a compound having the structure of Formula I or Formula II above, wherein R" is halo.
In accordance with another ment of the present invention, there is provided a compound having the structure of Formula I or Formula II above, wherein R" is selected from chloro, bromo, orfluoro.
In ance with another embodiment of the present invention, there is provided a compound having the structure of Formula I or Formula II above, wherein R" is chloro.
WO 90664 In accordance with another ment of the present invention, there is provided a compound having the structure of Formula I or Formula II above, wherein R11 is absent.
In accordance with r embodiment of the present invention, there is provided a compound having the structure of Formula I or a II above, wherein R14 and R15 are both (C1-C6)alkyl.
In accordance with another embodiment of the present invention, there is provided a nd having the structure of Formula I or Formula II above, wherein R14 and R15 are both methyl.
In accordance with another embodiment of the present invention, there is provided a compound having the structure of Formula I or Formula II above, +10%)ng wherein A is O In accordance with another embodiment of the present invention, there is provided a compound having the structure of Formula I or Formula II above, 0 O wherein A is Howg‘ In accordance with another ment of the t invention, there is provided a compound having the structure of Formula I or Formula II above, HOWE]: wherein A is O ] In accordance with r embodiment of the present invention, there is provided a compound having the structure of Formula I or Formula II above, : O HON'TE wherein A is O ] In accordance with another embodiment of the present invention, there is provided a compound having the structure: HONO or a pharmaceutically acceptable salt thereof.
In accordance with another embodiment of the present invention, there is provided a compound having the ure: or a pharmaceutically acceptable salt thereof.
In accordance with r embodiment of the present invention, there is provided a compound having the structure: O OH RN/\©\ HONO or a pharmaceutically acceptable salt f.
In accordance with another embodiment of the present invention, there is provided a compound having the structure: or a pharmaceutically acceptable salt thereof.
In a r embodiment of the present invention, there is provided a ceutical composition comprising a compound of Formula I or Formula II, or a pharmaceutically acceptable salt thereof; and a ceutically acceptable excipient.
In a further embodiment of the present invention, there is provided a method of treating HIV comprising stering to a patient ing therefrom an effective amount of a compound of a I or Formula II, or a pharmaceutically able salt thereof.
In a further embodiment of the present invention, there is provided a ceutical composition comprising a compound of Formula I or Formula II, or a pharmaceutically able salt thereof, and a pharmaceutically acceptable excipient.
In a further embodiment of the present invention, there is provided a pharmaceutical composition comprising a compound of Formula I or Formula II, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable ent, wherein the compound is present in an amorphous form.
In a further embodiment of the present invention, there is provided a pharmaceutical composition comprising a compound of Formula I or Formula II, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, wherein the composition is in a tablet form.
In a further embodiment of the present invention, there is provided a pharmaceutical composition comprising a compound of Formula I or Formula II, or a pharmaceutically acceptable salt f, and a pharmaceutically acceptable excipient, wherein the nd is present as a spray dried dispersion.
In a further embodiment of the present invention, there is provided a method of treating an HIV infection in a subject comprising administering to the subject a compound of Formula | or Formula II, or a pharmaceutically acceptable salt thereof. In certain embodiments, the subject is a , and in other embodiments, the subject is a human.
In a further embodiment of the present invention, there is provided a method of treating an HIV infection in a subject comprising administering to the subject a pharmaceutical composition comprising a compound of Formula I or Formula II, or a pharmaceutically able salt thereof, and a ceutically acceptable excipient.
In a further embodiment of the present invention, there is provided a method of preventing an HIV infection in a subject at risk for developing an HIV infection, sing administering to the subject a compound of Formula | or Formula II, or a pharmaceutically acceptable salt thereof.
In a r embodiment of the present invention, there is ed a method of preventing an HIV infection in a subject at risk for developing an HIV infection, comprising administering to the subject a pharmaceutical composition sing a compound of Formula | or a II, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable ent.
In still other embodiments, the present invention also provides the use of a nd or salt as defined in any of Formula I or Formula II in the manufacture of a ment for use in the treatment of an HIV infection in a human.
Furthermore, the compounds of the ion can exist in particular geometric or stereoisomeric forms. The invention contemplates all such compounds, including cis- and trans-isomers, (-)- and (+)-enantiomers, (R)— and (S)—enantiomers, diastereomers, (D)—isomers, (L)-isomers, the racemic es thereof, and other mixtures thereof, such as enantiomerically or diastereomerically enriched es, as falling within the scope of the invention. Additional asymmetric carbon atoms can be present in a substituent such as an alkyl group. All such s, as well as mixtures thereof, are intended to be included in this invention.
Optically active (R)— and (S)—isomers and d and | isomers can be ed using chiral synthons or chiral reagents, or resolved using conventional techniques. If, for instance, a particular enantiomer of a compound of the present invention is desired, it can be prepared by asymmetric synthesis, or by derivatization with a chiral auxiliary, where the resulting reomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomers. Alternatively, where the molecule contains a basic functional group, such as an amino group, or an acidic functional group, such as a carboxyl group, diastereomeric salts can be formed with an appropriate optically active acid or base, followed by tion of the diastereomers thus formed by fractional crystallization or tographic means known in the art, and subsequent recovery of the pure omers. In addition, separation of enantiomers and diastereomers is frequently accomplished using chromatography employing chiral, stationary phases, optionally in combination with chemical tization (e.g., ion of carbamates from ).
In another embodiment of the invention, there is provided a compound of Formula I or Formula II, wherein the compound or salt of the compound is used in the manufacture of a medicament for use in the ent of a viral infection in a human.
In another embodiment of the invention, there is provided a pharmaceutical composition comprising a pharmaceutically acceptable diluent and a therapeutically effective amount of a compound as defined in Formula I.
In one embodiment, the pharmaceutical formulation containing a nd of Formula I or a II or a salt thereof is a formulation adapted for parenteral administration. In another embodiment, the formulation is a long-acting parenteral ation. In a further embodiment, the formulation is a nano-particle ation.
The compounds of the present invention and their salts, solvates, or other pharmaceutically acceptable tives thereof, may be employed alone or in combination with other therapeutic agents. Therefore, in other ments, the methods of treating and/or preventing an HIV infection in a t may in addition to stration of a compound of Formula I or Formula II further comprise administration of one or more additional pharmaceutical agents active against HIV.
In such embodiments, the one or more additional agents active against HIV is selected from the group consisting of zidovudine, didanosine, Iamivudine, zaIcitabine, abacavir, stavudine, adefovir, adefovir dipivoxil, fozivudine, todoxil, emtricitabine, alovudine, amdoxovir, elvucitabine, nevirapine, delavirdine, efavirenz, loviride, immunocal, oltipraz, capravirine, lersivirine, GSK2248761, TMC- 278, TMC-125, etravirine, saquinavir, ritonavir, indinavir, nelfinavir, avir, fosamprenavir, avir, darunavir, atazanavir, tipranavir, palinavir, lasinavir, enfuvirtide, T-20, T-1249, PRO-542, PRO-140, TNX—355, EMS-806, EMS-663068 and BMS-626529, 5-Helix, raltegravir, elvitegravir, GSK1349572, 5744, vicriviroc (Sch-C), Sch-D, TAK779, maraviroc, TAK449, didanosine, tenofovir, vir, and darunavir.
As such, the compounds of the present invention and any other pharmaceutically active agent(s) may be administered together or tely and, when administered tely, administration may occur simultaneously or sequentially, in any order. The amounts of the compounds of the present invention and the other pharmaceutically active s) and the relative timings of administration will be selected in order to achieve the desired combined therapeutic effect. The administration in ation of a nd of the present invention and salts, solvates, or other pharmaceutically able derivatives thereof with other treatment agents may be in combination by administration concomitantly in: (1) a unitary pharmaceutical composition including both compounds; or (2) separate pharmaceutical compositions each including one of the compounds. atively, the combination may be administered tely in a sequential manner wherein one treatment agent is administered first and the other second or vice versa. Such sequential administration may be close in time or remote in time. The amounts of the compound(s) of Formula | or Formula II or salts thereof and the other pharmaceutically active agent(s) and the relative timings of administration will be selected in order to achieve the desired combined therapeutic effect.
In addition, the compounds of the present invention may be used in combination with one or more other agents useful in the prevention or treatment of HIV. es of such agents include: Nucleotide reverse transcriptase inhibitors such as zidovudine, didanosine, dine, zalcitabine, abacavir, stavudine, adefovir, irdipivoxil, fozivudine, todoxil, emtricitabine, alovudine, amdoxovir, tabine, and r agents; Non-nucleotide reverse transcriptase inhibitors (including an agent having anti-oxidation activity such as immunocal, oltipraz, etc.) such as nevirapine, delavirdine, efavirenz, loviride, immunocal, oltipraz, capravirine, lersivirine, GSK2248761, TMC-278, TMC-125, etravirine, and similar agents; Protease inhibitors such as saquinavir, ritonavir, vir, nelfinavir, amprenavir, fosamprenavir, brecanavir, darunavir, avir, tipranavir, palinavir, lasinavir, and similar agents; WO 90664 Entry, attachment and fusion inhibitors such as enfuvirtide (T-20), T- 1249, PRO-542, PRO-140, TNX-355, EMS-806, EMS-663068 and EMS-626529, 5- Helix and r agents; Integrase inhibitors such as raltegravir, elvitegravir, GSK1349572, GSK1265744 and similar agents; Maturation inhibitors such as PA—344 and PA—457, and similar agents; CXCR4 and/or CCR5 tors such as vicriviroc ), Sch-D, TAK779, maraviroc (UK 427,857), TAK449, as well as those disclosed in WO 02/74769, PCT/U803/39644, PCT/U803/39975, PCT/U803/39619, PCT/U803/39618, PCT/U803/39740, and 03/39732, and similar agents.
Further examples where_the compounds of the present invention may be used in combination with one or more agents useful in the prevention or treatment of HIV are found in Table 1.
Table 1: FDA Approval firand Generic Name Manufacturer side Reverse Transcriptase Inhibitors (NRTIs) zidovudine, 1987 Retrovir azidothymidine, GIaxoSmithKline AZT, ZDV didanosine, . 1991 Videx dideoxyinosine, l-Myers SqUIbb zalcntablne, Roche dideoxycytidine, Pharmaceuticals Bristol-Myers stavudine, d4T So uibb 1995 Eoivir lamivudine, 3TC GIaxoSmithKline lamivudine + Combivir GIaxoSmithKline zidovudine abacavir sulfate, Ziagen GIaxoSmithKline abacavir+ Trizivir |amivudine+ GIaxoSmithKline dine enteric coated Bristol-Myers 2000 Videx EC didanosine, dd| Squibb tenofovir Viread disoproxil Gilead Sciences fumarate, TDF Emtriva emtricitabine, FTC Gilead Sciences 2004 Epzicom abacaV!" GIaxoSmithKline lamivudine emtricitabine + 2004 a Sigogfggl Gilead Sciences fumarate Non-Nucleosides Reverse Transcriptase Inhibitors NNRTIs 1996 Viramune. . . Boehnnger nevnraplne, NVP Inelheim Rescriptor delavirdine, DLV Pfizer Bristol-Myers a efavirenz, EFV Squibb Tibotec Intelence rine Theraoeutics Protease Inhibitors saquinavir Roche 1995 se mes late, SQV Pharmaceuticals Abett 1996 Norvir ritonavir, RTV Laboratories.
Crixivan indinavir, IDV Merck Viracept me2::2?:VII\:FV Pfizer avir (no Roche longer marketed) Pharmaceuticals Aenerase amorenavir, APV GIaxoSmithKline lopinavir+ 2000 Kaletra ritonavir, fgggratories LPV/RTV atazanavir sulfate, l-Myers 2003 Reyataz ATV S . uibb fosamprenavir 2003 Lexiva m, FOS- GIaxoSmithKline 2005 Aptivus tripranavir, TPV Boehrin-ger Inoelheim T'bOteC 2006 Prezista darunavir TheraoeutIcs.
Fusion Inhibitors Roche 2003 Fuzeon Enfuvirtide, T-20 Pharmaceuticals & Trimeris Ent Inhibitors 2007 try roc Pfizer Inte o rase Inhibitors 2007 lsentress raltegravir Merck The scope of combinations of compounds of this invention with HIV agents is not limited to those mentioned above, but includes in principle any combination with any pharmaceutical composition useful for the treatment of HIV. As noted, in such combinations the compounds of the present invention and other HIV agents may be administered separately or in conjunction. In addition, one agent may be prior to, rent to, or subsequent to the administration of other agent(s).
The present invention may be used in combination with one or more agents useful as pharmacological enhancers as well as with or without additional compounds for the prevention or treatment of HIV. Examples of such pharmacological enhancers (or pharmakinetic rs) include, but are not limited to, vir, GS-9350, and SPI-452.
Ritonavir is 10-hydroxymethyl(1-methyethyl)—1-1[2-(1- methylethyl)—4-thiazolyl]-3,6-dioxo-8,1 1-bis(phenylmethyl)-2,4,7,12-tetraazatridecan- 13-oic acid, 5-thiazolylmethyl ester, 8*,8R*,10R*,11R*)] and is available from Abbott Laboratories of Abbott park, Illinois, as Norvir. Ritonavir is an HIV protease inhibitor indicated with other antiretroviral agents for the treatment of HIV infection.
Ritonavir also inhibits P450 mediated drug metabolism as well as the protein (ng) cell transport system, thereby resulting in increased concentrations of active compound within the organism.
GS-9350 is a compound being ped by Gilead es of Foster City California as a cological enhancer.
SPl-452 is a compound being developed by Sequoia Pharmaceuticals of Gaithersburg, Maryland, as a pharmacological enhancer.
In one embodiment of the present ion, a compound of Formula | or Formula II is used in combination with ritonavir. In one embodiment, the ation is an oral fixed dose combination. In another embodiment, the nd of Formula | or Formula II is formulated as a long acting parenteral injection and ritonavir is formulated as an oral composition. In one embodiment, is a kit containing the compound of Formula | or Formula II formulated as a long acting parenteral ion and ritonavirformulated as an oral composition. In another embodiment, the compound of a | or Formula II is formulated as a long acting parenteral injection and ritonavir is formulated as an injectable composition. In one embodiment, is a kit containing the compound of Formula | or Formula II formulated as a long acting parenteral injection and ritonavirformulated as an injectable ition.
In another embodiment of the present invention, a compound of Formula I or Formula II is used in combination with GS-9350. In one embodiment, the combination is an oral fixed dose combination. In another embodiment, the compound of Formula | or Formula II is formulated as a long acting parenteral 2012/069637 injection and GS-9350 is formulated as an oral composition. In one embodiment, there is provided a kit ning the nd of Formula | or Formula II formulated as a long acting parenteral injection and GS-9350 formulated as an oral composition.
In r embodiment, the compound of Formula I or Formula II is formulated as a long acting parenteral injection and 0 is formulated as an injectable composition. In one embodiment, is a kit containing the compound of a | or Formula II is formulated as a long acting parenteral injection and GS-9350 formulated as an injectable composition.
In one embodiment of the present invention, a compound of a I or Formula II is used in ation with SPl-452. In one embodiment, the combination is an oral fixed dose combination. In another embodiment, the compound of Formula | or Formula II is formulated as a long acting eral injection and SPl-452 is formulated as an oral composition. In one embodiment, there is provided a kit ning the compound of Formula | or Formula II formulated as a long acting parenteral injection and SPl-452 formulated as an oral composition. In another embodiment, the compound of Formula I or Formula II is formulated as a long acting parenteral injection and SPl-452 is formulated as an injectable composition. In one embodiment, there is provided a kit containing the compound of Formula | or Formula II formulated as a long acting parenteral injection and SPl-452 formulated as an injectable ition.
In one ment of the present invention, a compound of Formula | or Formula II is used in combination with compounds which are found in previously filed , which is herein incorporated by reference.
The above other therapeutic agents, when employed in combination with the chemical entities described herein, may be used, for example, in those amounts indicated in the Physicians' Desk Reference (PDR) or as otherwise determined by one of ordinary skill in the art.
] In another embodiment of the invention, there is provided a method for treating a viral infection in a mammal mediated at least in part by a virus in the retrovirus family of viruses which method comprises administering to a mammal, that has been diagnosed with said viral infection or is at risk of developing said viral infection, a compound of Formula I or Formula II.
In another embodiment of the invention, there is provided a method for treating a viral infection in a mammal mediated at least in part by a virus in the retrovirus family of viruses which method comprises administering to a mammal, that has been diagnosed with said viral infection or is at risk of developing said viral infection, a compound of Formula I or a II, wherein said virus is an HIV virus.
In some embodiments, the HIV virus is the HIV-1 virus.
In another ment of the invention, there is provided a method for ng a viral infection in a mammal mediated at least in part by a virus in the retrovirus family of viruses which method comprises administering to a mammal, that has been diagnosed with said viral infection or is at risk of developing said viral ion, a compound of Formula I or Formula II, further comprising administration of a therapeutically effective amount of one or more agents active against an HIV virus.
In another embodiment of the invention, there is provided a method for treating a viral infection in a mammal mediated at least in part by a virus in the retrovirus family of s which method comprises administering to a mammal, that has been diagnosed with said viral infection or is at risk of developing said viral infection, a nd of Formula I or Formula II, further comprising administration of a therapeutically effective amount of one or more agents active against the HIV virus, wherein said agent active against HIV virus is selected from Nucleotide reverse transcriptase inhibitors; cleotide reverse transcriptase inhibitors; Protease inhibitors; Entry, attachment and fusion inhibitors; Integrase inhibitors; Maturation inhibitors; CXCR4 inhibitors; and CCR5 inhibitors.
In further embodiments, the compound of the present invention, or a pharmaceutically acceptable salt thereof, is chosen from the compounds set forth in Table 2.
Table 2 Example Parent Structure Chemical Name 4-[(1R)—1- [(1R,2R,5R,1OS,13R,14R ,178,19R)—17-[(3- carboxy-3,3- dimethylpropanoyl)oxy]— 1,2,14,18,18- pentamethyloxo—8— (propan-2— y|)pentacyc|o[11.8.0.0"{2 ,10}.0"{5,9}.0"{14,19}]he nicos-8—enyl]—2—{[(4- chlorophenyl)methyl]ami no}ethoxy]—2,2—dimethy|— 4-oxobutanoic acid 4-[(1R)—1- [(1 R,1OS,1 3R, 14R ,178,19R)—17-[(3- carboxy-3,3- dimethylpropanoyl)oxy]— 1,2,14,18,18- pentamethyloxo—8— n-2— y|)pentacyc|o[11.8.0.0"{2 ,10}.0"{5,9}.0"{14,19}]he nicos-8—enyl]—2—{[(4- phenyl)methy|][2— hylamino)ethy|]ami no}ethoxy]—2,2—dimethy|— 4-oxobutanoic acid 4-[(1S)—1- [(1R,2R,5R,1OS,13R,14R ,178,19R)—17-[(3- y-3,3- dimethylpropanoyl)oxy]— 1,2,14,18,18- pentamethyloxo—8— (propan-2— y|)pentacyc|o[11.8.0.0"{2 ,10}.0"{5,9}.0"{14,19}]he nicos-8—enyl]—2—{[(4- HO chlorophenyl)methyl]ami no}ethoxy]—2,2—dimethy|— 4-oxobutanoic acid )—1- [(1 R,2R,5R,1OS,13R,14R ,178,19R)—17-[(3- carboxy-3,3- dimethylpropanoyl)oxy]— 1,2,14,18,18- pentamethyloxo-8— (propan-2— y|)pentacyc|o[11.8.0.0"{2 ,10}.0"{5,9}.0"{14,19}]he nicos—8—enyl]—2—{[(4- chlorophenyl)methy|][2— hylamino)ethy|]ami no}ethoxy]—2,2—dimethy|— 4-oxobutanoic acid {[(1R,2R,5R,1OS,13R,14 R,178,19R)—5-(2—{[(4— chlorophenyl)methyl]ami no}ethy|)—1,2,14,18,18— pentamethyloxo-8— (propan-2— y|)pentacyc|o[11.8.0.0"{2 ,10}.0"{5,9}.0"{14,19}]he nicos—8—enyl]oxy}- 2,2—dimethyl-4— oxobutanoic acid {[(1R,2R,5R,1OS,13R,14 R,17S,19R)—5-[2— lamino)ethy|]— 1,2,14,18,18- pentamethyloxo-8— (propan-2— y|)pentacyc|o[11.8.0.0"{2 ,10}.0"{5,9}.0"{14,19}]he nicos—8—enyl]oxy}- 2,2—dimethyl-4— oxobutanoic acid {[(1R,2R,5R,1OS,13R,14 R,178,19R)—5-(2—{[(3- chlorophenyl)methyl]ami no}ethy|)—1,2,14,18,18— ethyloxo-8— (propan-2— y|)pentacyc|o[11.8.0.0"{2 ,10}.0"{5,9}.0"{14,19}]he nicos—8—enyl]oxy}- 2,2—dimethyl-4— oxobutanoic acid {[(1R,2R,5R,1OS,13R,14 R,178,19R)—5-(2—{[(3- chloro-2— fluorophenyl)methyl]amin o}ethy|)—1,2,14,18,18— pentamethyloxo-8— (propan-2— y|)pentacyc|o[11.8.0.0"{2 ,10}.0"{5,9}.0"{14,19}]he 8—enyl]oxy}- 2,2—dimethyl-4— oxobutanoic acid {[(1R,2R,5R,1OS,13R,14 19R)—5-(2—{[1-(4— chloropheny|)cyc|opropy|] amino}ethy|)— 1,2,14,18,18- pentamethyloxo-8— (propan-2— y|)pentacyc|o[11.8.0.0"{2 ,10}.0"{5,9}.0"{14,19}]he nicos—8—enyl]oxy}- 2,2—dimethyl-4— oxobutanoic acid 2R,5R,1OS,13R,14 R,178,19R)—5-(2—{[(4— chlorophenyl)methy|][2— (dimethylamino)ethy|]ami no}ethy|)—1,2,14,18,18— pentamethyloxo-8— (propan-2— tacyc|o[11.8.0.0"{2 ,10}.0"{5,9}.0"{14,19}]he nicos—8—enyl]oxy}- 2,2—dimethyl-4— oxobutanoic acid {[(1R,2R,5R,1OS,13R,14 R,178,19R)—5-(2—{[1-(4— chloropheny|)cyc|opropy|] (dimethylamino)ethy|]ami no}ethy|)—1,2,14,18,18— pentamethyloxo-8— (propan-2— y|)pentacyc|o[11.8.0.0"{2 ,10}.0"{5,9}.0"{14,19}]he nicos—8—enyl]oxy}- 2,2—dimethyl-4— oxobutanoic acid {[(1R,2R,5R,1OS,13R,14 R,178,19R)—5-(2—{[(4— phenyl)methyl](met hyl)amino}ethy|)— 1,2,14,18,18- pentamethyloxo-8— (propan-2— y|)pentacyc|o[11.8.0.0"{2 ,10}.0"{5,9}.0"{14,19}]he nicos—8—enyl]oxy}- 2,2—dimethyl-4— oxobutanoic acid {[(1R,2R,5R,1OS,13R,14 R,178,19R)—5-(2—{N-[(4- chlorophenyl)methyl]acet amido}ethy|)— 1,2,14,18,18- pentamethyloxo-8— (propan-2— y|)pentacyc|o[11.8.0.0"{2 ,10}.0"{5,9}.0"{14,19}]he nicos—8—enyl]oxy}- 2,2—dimethyl-4— oxobutanoic acid {[(1R,2R,5R,1OS,13R,14 R,17S,19R)—5-[(1R)—2— {[(4- phenyl)methyl]ami no}hydroxyethy|]— 1,2,14,18,18- pentamethyloxo-8— (propan-2— y|)pentacyc|o[11.8.0.0"{2 ,10}.0"{5,9}.0"{14,19}]he nicos—8—enyl]oxy}- 2,2—dimethyl-4— anoic acid 2R,5R,1OS,13R,14 R,17S,19R)—5-[(1S)—2— {[(4- chlorophenyl)methyl]ami no}hydroxyethy|]— 1,2,14,18,18- pentamethyloxo-8— (propan-2— y|)pentacyc|o[11.8.0.0"{2 ,10}.0"{5,9}.0"{14,19}]he nicos—8—enyl]oxy}- 2,2—dimethyl-4— oxobutanoic acid {[(1R,2R,5R,1OS,13R,14 R,17S,19R)—5-[(1S)—2— {[(4- chlorophenyl)methyl]ami no}hydroxyethy|]— 1,2,14,18,18- pentamethyloxo-8— (propan-2— y|)pentacyc|o[11.8.0.0"{2 ,10}.0"{5,9}.0"{14,19}]he nicos—8—enyl]oxy}- 2,2—dimethyl-4— oxobutanoic acid {[(1R,2R,5R,1OS,13R,14 R,17S,19R)—5-[(1R)—1- (acetyloxy)—2—{[(4- chlorophenyl)methyl]ami no}ethy|]—1,2,14,18,18— pentamethyloxo-8— (propan-2— y|)pentacyc|o[11.8.0.0"{2 ,10}.0"{5,9}.0"{14,19}]he nicos—8—enyl]oxy}- 2,2—dimethyl-4— oxobutanoic acid {[(1R,2R,5R,1OS,13R,14 19R)—5-[(1R)—2— {[(4- chlorophenyl)methy|][2— (dimethylamino)ethy|]ami hydroxyethy|]— 1,2,14,18,18- pentamethyloxo-8— (propan-2— tacyc|o[11.8.0.0"{2 ,10}.0"{5,9}.0"{14,19}]he nicos—8—enyl]oxy}- 2,2—dimethyl-4— oxobutanoic acid {[(1R,2R,5R,1OS,13R,14 R,17S,19R)—5-[(1S)—2— {[(4- chlorophenyl)methy|][2— (dimethylamino)ethy|]ami no}hydroxyethy|]— 1,2,14,18,18- pentamethyloxo-8— (propan-2— y|)pentacyc|o[11.8.0.0"{2 ,10}.0"{5,9}.0"{14,19}]he nicos—8—enyl]oxy}- 2,2—dimethyI anoic acid {[(1R,2R,5R,1OS,13R,14 19R)—5-[(1S)—1- (acetyloxy)—2—{[(4- chlorophenyl)methy|][2— (dimethylamino)ethy|]ami no}ethy|]—1,2,14,18,18— pentamethyloxo-8— (propan-2— y|)pentacyc|o[11.8.0.0"{2 ,10}.0"{5,9}.0"{14,19}]he nicos—8—enyl]oxy}- 2,2—dimethyI oxobutanoic acid {[(1R,2R,5R,1OS,13R,14 R,17S,19R)—5-[(1R)—1- (acetyloxy)—2—{[(4- chlorophenyl)methy|][2— (dimethylamino)ethy|]ami no}ethy|]—1,2,14,18,18— pentamethyloxo-8— (propan-2— tacyc|o[11.8.0.0"{2 ,10}.0"{5,9}.0"{14,19}]he nicos—8—enyl]oxy}- methyI oxobutanoic acid WO 90664 2R,5R,1OS,13R,14 R,17S,19R)—5-[(1R)—2— {[(4- chlorophenyl)methy|][2— (dimethylamino)ethy|]ami no}hydroxyethy|]— 1,2,14,18,18- pentamethyloxo-8— (propan-2— y|)pentacyc|o[11.8.0.0"{2 ,10}.0"{5,9}.0"{14,19}]he nicos—8—enyl]oxy}- 3,3-dimethyI oxopentanoic acid {[(1R,2R,5R,1OS,13R,14 R,17S,19R)—5-[(1S)—2— {[(4- chlorophenyl)methy|][2— (dimethylamino)ethy|]ami no}hydroxyethy|]— 1,2,14,18,18- pentamethyloxo-8— (propan-2— y|)pentacyc|o[11.8.0.0"{2 ,10}.0"{5,9}.0"{14,19}]he nicos—8—enyl]oxy}- 3,3-dimethyI oxopentanoic acid {[(1R,2R,5R,1OS,13R,14 R,17S,19R)—5-[(1S)—2— {[(2- chlorophenyl)methyl]ami no}hydroxyethy|]— 1,2,14,18,18- pentamethyloxo-8— (propan-2— tacyc|o[11.8.0.0"{2 ,10}.0"{5,9}.0"{14,19}]he nicos—8—enyl]oxy}- methyI oxobutanoic acid {[(1R,2R,5R,1OS,13R,14 R,17S,19R)—5-[(1R)—2— {[(2- chlorophenyl)methyl]ami no}hydroxyethy|]— 1,2,14,18,18- pentamethyloxo-8— (propan-2— y|)pentacyc|o[11.8.0.0"{2 ,10}.0"{5,9}.0"{14,19}]he nicos—8—enyl]oxy}- 2,2—dimethyl-4— oxobutanoic acid {[(1R,2R,5R,1OS,13R,14 R,17S,19R)—5-[(1S)—1- (acetyloxy)—2—{[(4- fluorophenyl)methyl]amin o}ethy|]—1,2,14,18,18— pentamethyloxo-8— (propan-2— y|)pentacyc|o[11.8.0.0"{2 ,10}.0"{5,9}.0"{14,19}]he nicos—8—enyl]oxy}- methyl-4— oxobutanoic acid {[(1R,2R,5R,1OS,13R,14 R,17S,19R)—5-[(1R)—1- (acetyloxy)—2—{[(4- fluorophenyl)methyl]amin o}ethy|]—1,2,14,18,18— pentamethyloxo-8— n-2— y|)pentacyc|o[11.8.0.0"{2 ,10}.0"{5,9}.0"{14,19}]he nicos—8—enyl]oxy}- methyl-4— oxobutanoic acid PCT/US 12/69637 142013 PR64775WO R,"SaR,5bRMR,98, .1 ‘11aR11bR,13aS)3a ; ((3)1nacetoxy-2((4 1311101013enzlemethyDami no)ekhy1)"1nisopropy1« 513.51)88,118- eihw2-oxo~ 3',3a,4-,_5,5a,5b,6,7,7‘a,8,9 ,‘10,,1111:a’, 11,111 21313 i aoctadecahydro~2H cyc1openta131ch1y31=119- i y1)o1c3'):»2,?_~<11rne:1hy1~ anoicacid » {[(1R.2'R,'5R,1OS,13R,14 _ 1R,17s,19R)-5—{(1s1-2_— 5 :1114~ 1 = 01110erh£111y1)n1et11y11(11'1e1 ' 11y1)amino}—1v hydrax-yethyl} . 1,2,14,18,18- .1 r)’ 116ntar11eti1y1—7«oxo ("s (propan~2~ , A : 31013311139431ch1.80.012 ’ 1;»,1 «£11, N \111'" I’\ ‘ any n "sf on :,1 _/~ F I m’ . ,10}.0"{5,—9}.0"{14,19}}he rm "31),]; nicos—8ieny110xy1— 1 '1 F. \_ 1 2;.2Ld1mathy1-4» ‘ oxobutanoi'c acid (((33R,53R,5bR,'/3R,98. 1'1aR.11bR.13aS)~3a- 4 ((R)1~Aceéoxy-2((4- 3/ C1 benzylxmethyljami I .J.{' *n01e111y111isopr-:>pyl— <<.\\ In certain embodiments, the compound(s) of the present ion, or a pharmaceutically acceptable salt thereof, is chosen from the compounds set forth in Table 2.
Synthetic Methods The methods of synthesis for the provided chemical entities employ readily available ng materials using the ing general methods and procedures. It will be appreciated that where typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given; other process conditions can also be used unless otherwise stated.
Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be ined by one skilled in the art by routine optimization procedures.
Additionally, the methods of this invention may employ ting groups which prevent certain functional groups from undergoing undesired ons.
Suitable protecting groups for various functional groups as well as suitable conditions for ting and deprotecting particular functional groups are well known in the art.
For example, numerous ting groups are bed in T. W. Greene and G. M.
Wuts, Protecting Groups in Organic Synthesis, Third Edition, Wiley, New York, 1999, and references cited therein.
Furthermore, the provided chemical entities may contain one or more chiral s and such compounds can be prepared or isolated as pure stereoisomers, i.e., as individual enantiomers or diastereomers, or as stereoisomer- enriched mixtures. All such stereoisomers (and enriched mixtures) are included within the scope of this specification, unless otherwise indicated. Pure stereoisomers (or ed mixtures) may be prepared using, for example, optically active starting materials or stereoselective reagents well-known in the art. Alternatively, c mixtures of such compounds can be separated using, for example, chiral column chromatography, chiral resolving agents and the like.
The starting materials for the ing reactions are lly known nds or can be prepared by known procedures or obvious modifications thereof. For example, many of the starting materials are ble from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA), Bachem (Torrance, California, USA), Ernka-Chemce or Sigma (St. Louis, Missouri, USA).
Others may be prepared by procedures, or obvious modifications thereof, described in standard reference texts such as Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-15 (John Wiley and Sons, 1991), Rodd's try of Carbon Compounds, Volumes 1-5 and Supplementals (Elsevier Science Publishers, 1989), Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), March's Advanced Organic Chemistry, (John Wiley and Sons, 4th Edition), and Larock's Comprehensive Organic Transformations (VCH Publishers Inc, 1989).
Unless specified to the ry, the reactions described herein take place at atmospheric pressure, generally within a ature range from -78 °C to 200 °C. Further, except as employed in the Examples or as otherwise specified, reaction times and conditions are intended to be approximate, e.g., taking place at about atmospheric pressure within a temperature range of about -78 °C to about 110 °C over a period of about 1 to about 24 hours; reactions left to run overnight e a period of about 16 hours.
The terms "solvent," "organic solvent," and "inert solvent" each mean a solvent inert under the conditions of the reaction being described in conjunction therewith, ing, for e, e, toluene, acetonitrile, tetrahydrofuranyl ("THF"), dimethylformamide ("DMF"), form, methylene chloride (or dichloromethane), l ether, methanol, N-methylpyrrolidone ("NMP"), pyridine and the like.
Isolation and purification of the chemical entities and intermediates described herein can be effected, if desired, by any suitable separation or purification procedure such as, for example, filtration, extraction, crystallization, column chromatography, thin-layer chromatography or thick-layer chromatography, or a combination of these procedures. Specific illustrations of suitable separation and ion procedures can be had by reference to the examples herein below.
However, other equivalent separation or isolation procedures can also be used.
When desired, the (R)— and (S)—isomers may be resolved by methods known to those skilled in the art, for example by formation of diastereoisomeric salts or complexes which may be separated, for example, by crystallization; via formation of diastereoisomeric derivatives which may be separated, for example, by llization, gas-liquid or liquid chromatography; selective reaction of one enantiomer with an omer-specific reagent, for example enzymatic oxidation or reduction, followed by separation of the modified and fied enantiomers; or gas-liquid or liquid chromatography in a chiral environment, for example on a chiral support, such as silica with a bound chiral ligand or in the presence of a chiral t. Alternatively, a specific enantiomer may be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by ting one omer to the other by asymmetric transformation.
EXAMPLES The following examples serve to more fully describe the manner of making and using the above-described invention. It is understood that these examples in no way serve to limit the true scope of the ion, but rather are presented for illustrative purposes. In the examples below and the synthetic schemes above, the following abbreviations have the following meanings. If an abbreviation is not defined, it has its generally ed meaning. aq. = s uL = microliters uM = micromolar NMR = nuclear magnetic resonance boc = utoxycarbonyl br = broad Cbz = benzyloxycarbonyl d = doublet 6 = al shift °C = degrees celcius DCM = dichloromethane dd = doublet of doublets DMEM = Dulbeco’s Modified Eagle’s Medium DMF = N,N-dimethylformamide DMSO = dimethylsulfoxide EtOAc = ethyl acetate g = gram h or hr = hours HCV = hepatitus C virus HPLC = high performance liquid chromatography Hz = hertz lU = International Units |C50 = inhibitory concentration at 50% inhibition J = coupling constant (given in Hz unless otherwise indicated) m = multiplet M = molar M+H+ = parent mass spectrum peak plus H+ mg = milligram min = minutes mL = iter mM = millimolar mmol = ole MS = mass spectrum nm = nanomolar ppm = parts per million q.s. = sufficient amount s = singlet RT = room temperature sat. = ted t = triplet TFA = oroacetic acid Eguipment Description 1H NMR spectra were recorded on a Avance-lll 400 spectrometer. Chemical shifts are expressed in parts per million (ppm, 8 units).
Coupling constants are in units of hertz (Hz). Splitting patterns describe apparent multiplicities and are designated as s (singlet), d (doublet), t (triplet), q (quartet), quint (quintet), m (multiplet), br (broad).
The analytical low-resolution mass spectra (MS) were recorded on Agilent 1200 110 or Agilent 1200 HPLC/6130 using a SunFire C18, 4.6 x 50 mm, 3.5 pm using a gradient elution method.
Solvent A: 0.01 % trifluoroacetic acid (TFA) in water; Solvent B: 0.01% TFA in acetonitrile; Constant A for 1.2 min followed by 5%-95% or 20%-95% B over 4 min.
Schemes and Experimental procedures The ing schemes and ures illustrate how nds of the present invention can be ed. The specific solvents and reaction conditions ed to are also illustrative and are not intended to be limiting. Compounds not described are either commercially available or are readily prepared by one skilled in the art using available starting materials. The Examples disclosed herein are for illustrative purposes only and are not intended to limit the scope of the invention. All examples exhibited LHIV |C50 values n 1 pM and 1 nM using the assay disclosed herein.
For several of the examples the stereochemistry of the C28 secondary alcohol when present was not definitively confirmed as to its te configuration.
Unless stated otherwise, the compounds exemplified in the present ation were isolated as optically pure stereoisomers and initially assigned to a configuration as drawn. There is the possibility that some of these may be listed as the opposite stereochemistry at that single C28 position as shown. This in no way is meant to limit the scope of the ion or utility of the compounds of Formula |. onal examples contained within were determined to have the shown configuration by spectroscopic methods well known to those skilled in the art including, but not limited to, 1D and 2D NMR methods, vibrational circular dichroism and X-ray crystallography. These examples and the methods to make both diastereomers should serve to clearly exemplify the pure stereoisomers of both R and 8 configuration at the C28 position are readily obtained, ted and characterized and any remaining undefined examples could be readily confirmed by similar methods well known to one skilled in the art.
Synthesis of aldehyde intermediate 6.
A020 HBr/AcOH '33") DOM e, AcOH, A020 Step A A00 Step B —> —> - c Toluene, EtOH Step C Step D OH DCM, silica gel Step E Step A: Intermediate 2 ((1 R, 3aS, 5aR, 5bR, 7aR, 98, 1 1aR, 1 1bR, 13aR, 13bR)Acetoxy-5a, 5b, 8, 8, 1 1a- pentamethyl(prop- 1-enyl)icosahydro-1H-cyc/openta[a]chrysen-3a-yl)methyl acetate To a solution of the intermediate 1 (20 g, 45.2 mmol), 4- dimethylaminopyridine (DMAP, 1.66 g, 13.6 mmol), and Et3N (63 mL, 136 mmol) in CH2C|2 (DCM, 100 mL) at room temperature was added acetic anhydride (A020, 17.1 mL, 113 mmol). After it was heated at reflux overnight, and cooled down to room temperature, the reaction was quenched with water (50 mL). The organic phase was then washed with water (50 mL x 2) and dried over sodium sulfate. After removing most of the organic solvent under reduced pressure, anhydrous ethanol (50 mL) was added and the resulting precipitates were collected by filtration as a white solid (intermediate 2, 20 g, 84 %). 1H NMR (400 MHz, CDCI3) 6 ppm 4.69 (1H, m), 4.59 (1H, m), 4.51-4.43 (1H, m), 4.25 (1H, d, J: 11.2 Hz), 3.85 (1H, d, J: 10.8 Hz), 2.49- 2.40 (1H, m), 2.07 (3H, s), 2.04 (3H, s), 1.98-0.77 (42H, m). LC/MS: m/z calculated 526.4, found 527.7 (M + 1)+.
Step B: Intermediate 3 ((3aS, 5aR, 5bR, 7aR, 98, 1 1aR, 1 1bR, 13aS)acetoxy— ropyl—5a, 5b, 8, 8, 1 1a- pentamethyl-3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 10, 1 1, 1 1a, 1 1 b, 12, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysen-3a-yl)methyl acetate HBr in acetic acid (40 mL, 33 %) was added to a suspension of the intermediate 2 (20 g, 38 mmol) in toluene (40 mL), Ac20 (40 mL), and acetic acid (AcOH, 40 mL) previously heated at 105 °C. The reaction mixture was stirred and heated at this temperature for 1.5 h. After cooling down, sodium acetate (24 g) was added and the resulting reaction mixture was evaporated to dryness. The pale brownish e was taken up in DCM (200 mL) and the organic phase was washed with water (100 mL x 3), dried over sodium sulfate, and evaporated to dryness under reduced pressure to provide a residue, which was then recrystallized from ethanol (EtOH, 95 %) and DCM, to afford the intermediate 3 (13.8 g, 69 %) as a white solid. 1H NMR (400 MHz, CDCI3) 6 ppm .46 (1H, m), 4.02 (1H, d, J: 10.8 Hz), 3.98 (1H, d, J =10.8 Hz), 3.18-3.10 (1H, m), 2.43-2.40 (1H, m), 2.26-2.22 (2H, m), 2.04 (3H, 8), 2.05 (3H, s), 2.00-1.95 (1H, m), .85 (1H, m), .83 (39 H, m).
LC/MS: m/z ated 526.4, found 549.2 (M+Na)+.
Step C: Intermediate 4 ((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)Acetoxyisopropyl-5a, 5b, 8, 8, 1 1a- pentamethyloxo-3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0,1 1, 1 1 a, 1 1 b, 1 2, 13, 13a- octadecahydro-2H-cyc/openta[a]chrysen-3a-yl)methyl acetate A mixture of the intermediate 3 (7 g, 13.29 mmol), sodium e , 6.21 g, 76 mmol) and sodium dichromate dihydrate (4.75 g, 15.95 mmol) in ous toluene (90 mL), AcOH (119 mL), and A020 (29 mL) was stirred at 60 °C overnight. After cooling down, the reaction mixture was partitioned between water (150 mL) and ethyl acetate (EtOAc, 250 mL). The organic phase was washed successively with: water (100 mL), a saturated solution of sodium carbonate (100 mL x 2) and brine (100 mL x 2), then dried over sodium e, and concentrated under reduced pressure to afford a sticky oil. The sticky oil was triturated with MeOH (250 mL) and the precipitates were collected to give the intermediate 4 (6 g, 11.1 mmol, 83 %) as a white solid. 1H NMR (400 MHz, CDCI3) 6 ppm 4.52-4.46 (1H, m), 4.33 (1H, d, J = 10.8 Hz), 4.06 (1H, d, J = 11.2 Hz), .16 (1H, m), 2.86 (1H, dd, J = 12.8, 3.2 Hz), 2.42-2.36 (1H, m), 2.05 (3H, s), 2.00 (3H, s), .84 (40H, m).
LC/MS: m/z calculated 540.4, found 563.3 (M + Na)+.
Step D: Intermediate 5 (3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-(Hydroxymethyl)isopropyl- 5a, 5b, 8, 8, 1 1a-pentamethyloxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyclopenta[a]chrysenyl acetate.
A mixture of the intermediate 4 (7 g, 12.94 mmol) and potassium hydroxide (KOH, 0.872 g, 15.5 mmol) in EtOH (200 mL) and toluene (200 mL) was stirred vigorously at room temperature for 1 h. The reaction mixture was neutralized with aqueous HCI (1N) to pH 7 and evaporated to dryness. The obtained residue was taken up in water and a small amount of acetone. The itates were collected and then washed with water and dried in vacuo to obtain the ediate 5 (6.0 g, 93 %) as a white solid. LC/MS: m/z calculated 498.4, found 499.3 (M + 1)+.
Step E: Intermediate 6 (3aR, 5aR, 5bR, 7aR, 98, 1 1aR, 1 1bR, 13aS)-3a-Formyl—1-isopropyl—5a, 5b, 8, 8, 1 1a- pentamethyl0X0-3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a- octadecahydro-2H-cyc/openta[a]chrysenyl acetate To a solution of the intermediate 5 (5.1 g, 10.23 mmol) in DCM (300 mL) at room temperature were added pyridinium chlorochromate (PCC, 6.61 g, 30.7 mmol), and silica gel (6.6 g). The reaction e was stirred at room temperature for 1 h. After the reaction was quenched with water, the organic phase was washed with saturated sodium bicarbonate solution (100 mL), dried over sodium sulfate, and evaporated under reduced pressure to provide a crude product, which was purified by column chromatography on silica gel (EtOAc: PE = 1:10 to 1:5) to provide the ediate 6 (4.2 g, 83 %) as a white solid. LC/MS: m/z calculated 496.4, found 497.2 (M +1)+.
Synthesis of the oxo-butanoate intermediate 10 was accomplished according to the following procedures.
EtOH BuOH H2804 % 0 f’ H0 V —’ 0%" 50 c O StepA 8 Step B Step A: Intermediate 8 4-Ethoxy-2, 2-dimethyloxobutanoic acid A solution of 3,3-dimethyl-dihydrofuran-2,5-dione 7 (25 g, 195 mmol) in anhydrous EtOH (150 mL) was stirred at 50 °C overnight. After cooling down to room temperature, the solvent was d under reduced pressure with a rotary evaporator and the e was triturated with hexane at -50 °C to afford the intermediate 8 (25 g, 133 mmol, 67.9 %) as a white solid. 1H NMR (400 MHz, CDCI3) 6 ppm 4.13-4.18 (2H, q, J = 7.2 Hz), 2.62 (2H, s), 1.28 (6H, s),1.32-1.25 (3H, t, J = 7.6 Hz). LC/MS: m/z calculated 174.1, found 173.1 (M-1)—.
Step B: Intermediate 9 1 butyl 4-ethy/ 2, 2—dimethylsuccinate To a e of the intermediate 8 (20 g, 109 mmol), magnesium sulfate (52.5 g, 436 mmol), and tert—butanol (60 mL) in DCM (480 mL) was added to sulfuric acid (8.72 mL, 164 mmol). After stirring at room temperature overnight, the reaction mixture was poured into saturated sodium bicarbonate solution (300 mL) and water (300 mL). DCM was added to extract the desired product, and the c phase was washed with brine, dried, and concentrated to afford the intermediate 9 (19 g, 83 mmol, 80 %) as a colorless oil. 1H NMR (400 MHz, CDCI3) 6 ppm 4.02-4.08 2012/069637 (2H, q, J = 7.2 Hz), 2.46 (2H, s), 1.07 (9H, s), 1.14-1.20 (9H, m). LC/MS: m/z calculated 230.2, found 253.1 +.
Step C: Intermediate 10 4-(Tert-butoxy)-3, 3-dimethyloxobutanoic acid To a solution of the intermediate 9 (10 g, 41.3 mmol) in EtOH (200 mL) was added to potassium hydroxide (12.86 g, 206 mmol) in water (100 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 h. The pH of the reaction e was adjusted to 3-4 by 1N HCI. The resulting solution was extracted with ether (300 mL), and the ether phase was dried and concentrated to afford a crude product, which was re-crystallized from hexane at -10°C to afford the intermediate 10 (4 g, 19.78 mmol, 47.9 %) as a white solid. 1H NMR (400 MHz, CDCI3) 6 ppm 2.58 (2H, s), 1.43 (9H, s), 1.25 (6H, s). LC/MS: m/z calculated 202.1, found 201.1 (M-1)‘.
Synthesis of diastereomeric intermediates 18 and 19.
Ste A: |ntermediate11 (3aR, 5aR, 5bR, 7aR, 98, 1 1aR, 1 1bR, 13aS)-3a-(1 -Hydroxynitroethyl)— 1 -isopropyl- 5a, 5b, 8, 8, 1 1a-pentamethyloxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyclopenta[a]chrysenyl acetate To a mixture of 1,28-dioxolupenyl acetate (6) (25 g, 50.3 mmo|)and nitromethane (150 ml, 2782 mmol) stirred at room temp was added to triethylamine (75 ml, 538 mmol) in one charge. The reaction mixture was stirred at rt overnight. The reaction e was concentrated and washed with petroleum ether/EtOAc (2:1, 100 mL) to give the product of (24 g, 43.0 mmol, 85 % yield) as a white solid. LC/MS: m/z calculated 557.4, found 558.2 (M+1)+.
Step B: Intermediate 12 (3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-(2-Aminohydroxyethyl)- ropyl- 5a, 5b, 8, 8, 1 1a-pentamethyl-Z-oxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, tadecahydro-2H- cyclopenta[a]chrysenyl acetate To a solution of 11 (15.0 g, 26.9 mmol) in methanol (300 mL) was added NiC|2.6H20 (9.59 g, 40.3 mmol) at -5°C and was slowly added sodium borohydride (10.17 g, 269 mmol) at 5~10°C (internal temp). The reaction mixture was stirred at -5 °C (bath temp) for 30 min. The mixture was then quenched with saturated NH4C| (200 mL), d with EtOAc (1500 mL), then stirred at rt overnight.
And the organic layer was washed with saturated NH4C| (50 mL), water (800 mL), brine (800 mL) and was dried over MgSO4, filtered and concentrated to afford a solid, which was washed with petroleum ether to give the 12 (14 g, 24.40 mmol, 91 % yield) as a white solid. LC/MS: m/z calculated 527.4, found 528.3 (M+1)+.
Step C: ediate 13 (3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-(2-((Tert-butoxycarbony/) (4- chlorobenzyl)amino)- 1-hydroxyethy/)- 1-isopropy/-5a, 5b, 8, 8, 1 1a-pentamethyl—2—oxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyclopenta[a]chrysenyl acetate To a solution of 12 (8g, 14.58 mmol), triethylamine (0.813 ml, 5.83 mmol) and MgSO4 (2.63 g, 21.87 mmol) in methanol (225 ml) stirred at rt was added 4-ch|orobenzaldehyde (2.056 ml, 17.50 mmol). The reaction mixture was stirred at rt for 2 h, then cooled to -5 °C and NaBH4 was added in small portions during 10 min and d for 30 min. Following this, Boc20 (4.06 ml, 17.50 mmol) was added. The reaction was warmed to rt. and stirred for 1 h. The reaction mixture was poured into ice water (300 ml) and the solids were collected and dried to give 13 (7g, 8.56 mmol, 58.7 % yield) as a white foam. LC/MS: m/z calculated 751.5, found 774.3 (M+Na)+.
Step D: ediate 14 (3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-(2-((Tert-butoxycarbony/) (4- ch/orobenzyl)amino)acetyl)- 1-isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyloxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyclopenta[a]chrysenyl acetate To a mixture of 13 (25 g, 29.9 mmol) in dichloromethane (200 mL), was added PCC (50 g, 232 mmol) and silica gel 50 g, This mixture was stirred at rt overnight. The solids were removed by ion to obtain black on, which was concentrated and purified by silica gel column chromatography eluting with hex/EtOAc (10:1) to afford the 14 (20g, 23.99 mmol, 80 % yield) as a white solid.
LC/MS: m/z calculated 749.4, found 772.2 (M+Na)+.
Step E: Intermediate 15 (3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-(2—((4-Chlorobenzyl)amino)acetyl) hydroxy- 1-isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyl- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysen-2—one To a solution of 14 in 1,4-dioxane (200 mL) and methanol (200 mL) stirred at rt was added con HCI (100 mL) in one charge. The on mixture was 2012/069637 stirred ght at 45 °C. The reaction mixture was concentrated and washed with acetone to give 15 (12.5 g, 17.45 mmol, 87 % yield) as a white foam. LC/MS: m/z calculated 607.38, found 608.0 (M+1)+.
Step F: Intermediate 16 Tert-buty/ 4-ch/orobenzy/(2-((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)hydroxy- 1- isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyloxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyclopenta[a]chrysen-3a-yl)oxoethyl)carbamate To a solution of 15 (6g, 9.86 mmol) and Et3N (5.50 mL, 39.5 mmol) in dichloromethane (30 mL) stirred at rt was added Boc20 (2.290 mL, 9.86 mmol) in one charge . The reaction e was stirred at rt for 2 h. From TLC, the reaction was fininshed. The solvent was removed in vacuo. The crude product 16 (6g, 8.47 mmol, 86 % yield) was used without further purification.
Step G: Intermediate 17 4-((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-(2-((Tert-butoxycarbonyl)(4- chlorobenzyl)amino)acetyl)- 1-isopropyl-5a, 5b, 8, 8, 1 tamethyloxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl) 1-tert-buty/ 2, 2-dimethy/succinate To a solution of 10 (5.14 g, 25.4 mmol), DMAP (5.17 g, 42.3 mmol) and 16 (6 g, 8.47 mmol) in dichloromethane (50 mL) stirred at rt was added EDC (8.12 g, 42.3 mmol). The reaction mixture was stirred at rt until starting material disappeared as monitored by TLC. After the on was finished, the mixture was d with CHZCIZ, and washed with aq NH4CI. The oragnic layer was dried with Na2804 and the solvent was removed in vacuo. The material was purified by silica 2012/069637 gel chromatography (hex:EtOAc, 12:1 to 5:1) to give 17 (5.4 g, 6.05 mmol, 71.4 % yield) as a light white solid. The proton NMR consists of a mixture of rotomers. 1H NMR (400 MHz ,CHLOROFORM-d) 6 7.34 - 7.24 (m, 2 H), 7.23 - 7.08 (m, 2 H), 4.63 - 4.29 (m, 3 H), 4.11 - 3.39 (m, 2 H), 3.28 - 3.06 (m, 1 H), 2.69 - 0.69 (m, 68 H).
Step H: Intermediates 18 and 19 4-((3aR, 5aR, 5bR, 7aR, 98, 1 1aR, 1 1bR, 13aS)-3a-((R)(Ttert-butoxycarbony/) (4- chlorobenzyl)amino)- 1-hydroxyethy/)- 1-isopropy/-5a, 5b, 8, 8, 1 1a-pentamethyl—2—oxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 10, 1 1, 1 1 a, 1 1 b, 12, 13, 13a-octadecahydro-2H- cyclopenta[a]chrysenyl) 1-tert-buty/ 2, 2-dimethy/succinate (18) & 4- ((3aR, 5aR, 5bR, 7aR, 98, 1 1aR, 1 1bR, 13aS)-3a-((S)((tert—butoxycarbonyl) (4- chlorobenzyl)amino)- 1-hydroxyethy/)- 1-isopropy/-5a, 5b, 8, 8, 1 1a-pentamethyl—2—oxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 10, 1 1, 1 1 a, 1 1 b, 12, 13, 13a-octadecahydro-2H- cyclopenta[a]chrysenyl) 1 -tert-butyl 2, 2-dimethy/succinate (1 9) To a solution of and 17 (1.5g, 1.680 mmol) in methanol (10 mL)and THF (10.00 mL) stirred at 0 °C was added NaBH4 (0.127 g, 3.36 mmol). The on mixture was d at 0 0C until starting material disappeared (about 2 hours) as monitored by TLC. Upon completion the mixture was diluted with water, extracted with EtOAc and the organic layer was dried with Na2804. The residue was purified by silica gel chromatography (hex:EtOAc, 7:1 to 5:1 ) to give the diastereomer with the 8 configuration R,5aR,5bR,7aR,9S,11aR,11bR,13aS)—3a-((S)—2-((tert— carbony|)(4-ch|orobenzy|)amino)hydroxyethy|)isopropy|-5a,5b,8,8,11a- pentamethyIoxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a- octadecahydro-2H-cyclopenta[a]chrysenyl) 1-tert-butyl 2,2-dimethylsuccinate (18) (700mg, 0.782 mmol, 46.6 % yield) and the diastereomer with the R configuration 4- ((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)—2-((tert-butoxycarbonyl)(4- chlorobenzyl)amino)hydroxyethyl)isopropyl-5a,5b,8,8,11a-pentamethyloxo— 3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H- cyclopenta[a]chrysenyl) 1-tert-butyl 2,2—dimethylsuccinate (19) (500 mg, 0.559 mmol, 33.3 % yield) both as a light white solids. For 18 1H NMR (400MHz ,CHLOROFORM-d) 6 7.40 - 7.24 (m, 2 H), 7.18 (d, J = 8.3 Hz, 2 H), 4.87 - 4.57 (m, 1 H), 4.51 (dd, J = 53,110 Hz, 1 H), 4.42 - 4.13 (m, 2 H), 3.43 - 3.05 (m, 3 H), 2.97 - 2.78 (m, 1 H), 2.62 - 2.47 (m, 2 H), 2.47 - 2.29 (m, 1 H), 2.01 - 0.70 (m, 64 H); LC/MS: m/z calculated 893.6, found 916.5 (M+Na)+. For 19 1H NMR (400MHz OFORM-d) 6 7.36 - 7.23 (m, 2 H), 7.12 (d, J = 8.3 Hz, 2 H), 4.56 - 4.14 (m, 4 H), 3.45-3.18 (m, 1 H), 3.15-2.97 (m, 1 H), .71 (m, 69 H); LC/MS: m/z calculated 893.6, found 916.7 (M+Na)+.
Exam le1: Com ound 21 4-((R)((3aR, 5aR, 5bR, 7aR, 98, 1 1aR, 1 1bR, 13aS)((3-carboxy methy/butanoyl)oxy)- 1-isopropy/-5a, 5b, 8, 8, 1 1a-pentamethyIoxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H— WO 90664 cyclopenta[a]chrysen-3a-yl)((4-chlorobenzyl)amino)ethoxy)-2, 2-dimethyl oxobutanoic acid Ste A: Intermediate 20 4-((R)((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)((4-(tert-butoxy)—3, 3-dimethyl oxobutanoyl)oxy)- 1-isopropyl-5a, 5b, 8, 8, 1 tamethyloxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyclopenta[a]chrysTn-3a-yl)((tert-butoxycarbonyl)(4-ch/orobenzyl)amino)ethyl) 1- tert-buty/ 2, thy/succinate To a solution of 10 (543 mg, 2.68 mmol), DMAP (205 mg, 1.677 mmol) in dichloromethane (5mL) stirred at rt was added EDC (514 mg, 2.68 mmol). The reaction mixture was stirred at rt for 1h. Then 19 (300mg, 0.335 mmol) was added to the reaction mixture. Upon completion, the mixture was washed with 2 M HCI, water and brine. The organic layer was dried over Na2804 and concentrated to give the crude product 20 (400 mg, 0.278 mmol, 83 % yield) as an oil. This material was used in the next step without further purification.
Step B: Compound 21 ((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR,13aS)((3-Carboxy—3— methy/butanoyl)oxy)— 1-isopropy/-5a, 5b, 8, 8, 1 1a-pentamethyIoxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyclopenta[a]chrysen-3a-yl)((4-chlorobenzyl)amino)ethoxy)-2, thyl oxobutanoic acid To a solution of 20 (400mg, 0.371 mmol) in dichloromethane (5 mL) stirred at rt was added TFA (2 mL, 26.0 mmol). The reaction mixture was d at rt for 1 h. The mixture was evaporated to afford the the TFA salt of intermediate 21 (350 mg, 0.343 mmol, 93 % yield) as a light oil. 1H NMR (400MHz ,CHLOROFORM- d) 6 7.33 - 7.12 (m, 4 H), 5.76 - 5.60 (m, 1 H), 4.48 - 4.32 (m, 1 H), 4.26 - 3.98 (m, 2 H), 3.18 - 2.89 (m, 2 H), 2.89 - 2.68 (m, 2 H), 2.69 - 0.60 (m, 58 H); LC/MS: m/z calculated 865.5, found 866.3 (M+1)+.
Examgle 2: Compound 22 4-((R)((3aR, 5aR, 5bR, 7aR, 98, 1 1aR, 1 1bR,13aS)((3-Carboxy—3- butanoyl)oxy)- 1-isopropy/-5a, 5b, 8, 8, 1 1a-pentamethyIoxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysen-3a-yl)((4-chlorobenzyl)(2— (dimethylamino)ethyl)amino)ethoxy)-2, 2—dimethyl—4-oxobutanoic acid To a solution of ethylamino)acetaldehyde, hydrochloride (441 mg, 3.57 mmol) in methanol (12 mL) was added 21, (as it’s trifluoroacetic acid salt) (350 mg, 0.357 mmol). The mixture's pH was adjusted to 7-8 with EN. The reaction mixture was stirred at rt for 2h then NaBH3CN (224 mg, 3.57 mmol) was added and mixture was stirred overnight. The reaction was filtered and evaporated to afford a crude product. The residue was ed by preparative-HPLC to obtain compound 22 as a TFA salt (200 mg, 0.168 mmol, 47.2 % yield) as a white solid. 1H NMR (400MHz ,CHLOROFORM-d) 6 7.33 (d, J = 8.3 Hz, 2 H), 7.22 (d, J = 8.3 Hz, 2 H), 5.83 - 5.67 (m, 1 H), 4.54 - 4.42 (m, 1 H), 3.88 - 3.75 (m, 1 H), 3.65 - 3.49 (m, 1 H), 3.04 - 0.60 (m, 71 H); LC/MS: m/z calculated 936.6, found 937.4 (M+1)+.
Exam le 3: Com ound 25 4-((S)- 1-((3aR,5aR, 5bR, , 1 1aR, 1 1bR,13aS)((3-Carboxy methy/butanoyl)oxy)- 1-isopropy/-5a, 5b, 8, 8, 1 1a-pentamethyIoxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysen-3a-yl)((4-ch/orobenzyl)(2- (dimethylamino)ethyl)amino)ethoxy)-2, 2-dimethyl—4-0X0butan0ic acid Step A: Intermediate 23 - 1-((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)((4-(Tert-butoxy)-3, 3-dimethyl- 4-oxobutanoyl)oxy)- 1-isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyloxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyclopenta[a]chrysen-3a-yl)((tert-butoxycarbonyl)(4-ch/orobenzyl)amino)ethyl) 1- tert-buty/ 2, 2-dimethy/succinate To a solution of 10 (203 mg, 1.006 mmol), DMAP (123 mg, 1.006 mmol) in dichloromethane (10ml) d at rt was added EDC (321 mg, 1.677 mmol).
The reaction mixture was stirred at rt for 1h, then 18 (300 mg, 0.335 mmol) was added to the reaction. Upon completion, silica gel was added, the mixture was concentrated and ed by chromatography leum ether:EtOAc 6:1 to 3:1 )to give the 23 (344 mg, 0.319 mmol, 95 % yield) as a lightwhite solid.
Step B: Compound 24 4-((S)- 1-((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)((4-(Tert-butoxy)-3, 3-dimethyl- 4-oxobutanoyl)oxy)- 1-isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyloxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyclopenta[a]chrysen-3a-yl)((tert-butoxycarbonyl)(4-ch/orobenzyl)amino)ethyl) 1- tert-buty/ 2, 2-dimethy/succinate To a solution of23 (115 mg, 0.107 mmol) in DCM (5 mL) was added TFA (2.5 mL, 0.107 mmol). The reaction mixture was d at rt for 2 h and evaporated in vacuo to afford crude product. This material was then washed with satd. sodium bicarbonate solution, water and brine. The organics were filtered and concentrated to give the 24 (89mg, 0.023 mmol, 21.17 % yield) as a white solid. 1H NMR z ,CHLOROFORM-d) 6 7.40 (s, 4 H), 5.97 - 5.65 (m, 1 H), 4.93 - 3.75 (m, 3 H), 3.59 - 3.27 (m, 1 H), 3.27 - 2.92 (m, 3 H), 2.83 - 2.11 (m, 5 H), 1.98 - 0.59 (m, 52 H) LC/MS: m/z calculated 865.5, found 866.4 (M+1)+.
Example 4: Compound 25 4-((S)((3aR,5aR,5bR, 7aR,98, 1 1aR, 1 1bR,13aS)((3-Carboxy methy/butanoyl)oxy)- ropy/-5a, 5b, 8, 8, 1 1a-pentamethyIoxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysen-3a-yl)((4-chlorobenzyl)(2— (dimethylamino)ethyl)amino)ethoxy)-2, 2—dimethyl—4-0X0butan0ic acid To a solution of 2-(dimethylamino)acetaldehyde (325 mg, 2.63 mmol) in methanol (5 ml) and DOE (50ml) was added 24 (228 mg, 0.263 mmol) and ylamine (0.110 ml, 0.789 mmol). The reaction e was stirred at rt for 3h.
The reaction was cooled to 0°C, and sodium cyanoborohydride (24.80 mg, 0.395 mmol) was added and resultant mixture was stirred overnight. The reaction was ed and the filter cake was washed with DCM. The filtrate was concentrated under reduced pressure and the residue was purified by preparative-HPLC to give the title compound 25 as a TFA salt (76 mg, 0.065 mmol, 24.78 % yield) as a white solid. 1H NMR (400MHz ,CHLOROFORM-d) 6 7.38 - 7.30 (m, 2 H), 7.30 - 7.19 (m, 2 H), 5.82 - 5.69 (m, 1 H), 4.53 - 4.44 (m, 1 H), 4.05 - 3.89 (m, 1 H), 3.70 - 3.54 (m, 1 H), 3.41 - 2.51 (m, 15 H), 2.45 - 2.12 (m, 2 H), 1.97 - 0.65 (m, 54 H); LC/MS: m/z calculated 936.6, found 937.4 (M+1)+.
OAc NaBH4 EtOH, THF Exam le 5: Com ound 32 WO 90664 aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-(2-((4-Chlorobenzy/)amino)ethy/) isopropyl-5a, 5b, 8, 8, 1 tamethyloxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyclopenta[a]chrysenyl)oxy)—2, 2-dimethyloxobutanoic acid Ste A: Intermediate 26 1-((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)Acetoxyisopropyl-5a, 5b, 8, 8, 1 1a- pentamethyloxo-3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0,1 1, 1 1 a, 1 1 b, 1 2, 13, 13a- octadecahydro-2H-cyc/openta[a]chrysen-3a-yl)nitroethyl acetate To a solution of 11 (20 g, 35.9 mmol) in acetic anhydride (100 mL, 1065 mmol) was added 4-methylbenzenesulfonic acid (1.852 g, 10.76 mmol). The reaction mixture was stirred at rt ght. EtOAc (50 ml) and NaHC03 aq. (100 ml) were added. The organic layer was separated, washed with water, brine,and dried(Na2804). Removal of the solvent resulted in the crude product which was used directly in the next step. LC/MS: m/z calculated 599.4, found 600.3 (M+1)+.
Step B: Intermediate 27 (3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)- 1-lsopropyl-5a, 5b, 8, 8, 1 1a-pentamethyl-3a- (2-nitroethy/)oxo-3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a- octadecahydro-2H-cyc/openta[a]chrysenyl acetate To a solution of 26 (21 g, 35.0 mmol) in THF (30 mL) and EtOH (80 mL) in an ice bath was added NaBH4 (5.30 g, 140 mmol). The mixture was then kept at rt for about 1h, diluted with ethyl acetate (200 mL) and extracted with aqueous % citric acid solution (150 mL), saturated aqueous NaHCOs (150 mL), and brine (150 mL). The c layer was dried (Na2804) and evaporated to give the crude product 27 (19 g, 27.2 mmol, 78 % yield). This was used directly for the next step.
LC/MS: m/z calculated 541.4, found 542.3 (M+1)+.
Step C: Intermediate 28 (3aR, 5aR, 5bR, 7aR, 98, 1 1aR, 1 1bR, 13aS)Isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyl oxo-3a-(2-oxoethyl)-3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a- octadecahydro-2H—cyclopenta[a]chryseny/ acetate To a stirred on of 27 (10 g, 18.46 mmol) in acetone (90.00 mL) and methanol (90 mL) at -5 °C was added se a solution of KOH (1.036 g, 18.46 mmol) in 5mL water, then ed by KMnO4 (1.896 g, 12.00 mmol) and MgSO4 (1.666 g, 13.84 mmol) in 90 mL of water. The temperature was held below 0 0C for 1 h and for another 1h at room temperature. The reaction mixture was diluted with DCM (100 mL), then filtered on CeliteT'VI and washed with DCM. The organic phase was concentrated, then extracted with DCM, to give the crude product 28 (5g, 8.12 mmol, 44.0 % yield) which was used directly for the next step without further purification. 1H NMR (400MHz ,CHLOROFORM-d) 6 9.64 (s, 1 H), 4.49 (dd, J= 5.5, 11.0 Hz, 1 H), 3.27 - 3.06 (m, 1 H), 2.87 - 2.76 (m, 1 H), 2.76 - 2.64 (m, 1 H), 2.64 - 2.54 (m, 1 H), 2.45 (d, J: 18.8 Hz, 1 H), 2.20 (d, J: 18.8 Hz, 1 H), 2.05 (s, 3 H), 1.99 - 0.67 (m, 39 H); LC/MS: m/z calculated 510.4, found 533.3 (M+Na)+.
Step D: Intermediate 29 (3aR, 5aR, 5bR, 7aR, 98, 1 1aR, 1 1bR, 13aS)-3a-(2-((Tert-butoxycarbony/) (4- ch/orobenzy/)amino)ethyl)- 1-isopropy/-5a, 5b, 8, 8, 1 1a-pentamethyIoxo- WO 90664 2012/069637 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyclopenta[a]chrysenyl acetate To a solution of28 (1.5 g, 2.94 mmol), TEA (0.164 ml, 1.175 mmol) and MgSO4 (0.530 g, 4.41 mmol) in methanol (15 ml) stirred at rt was added 4- chlorobenzylamine (0.487 ml, 4.11 mmol). The reaction mixture was stirred at 20 °C for 2 h, then cooled to -5 oC and NaBH4 (0.167 g, 4.41 mmol) was added in small portions during 10 min and stirred for 30 min. BOC2O (0.750 ml, 3.23 mmol) was then added. The reaction was warmed to rt and stirred for 1 h. The reaction mixture was poured into ice water (300 ml) and solids were collected and dried to give 29 (1.8g, 2.106 mmol, 72%) as a white foam. This material was used without further purification. LC/MS: m/z calculated 735.5, found 758.3 (M+Na)+.
Step E: Intermediate 30 Tert-buty/ 4-ch/orobenzy/(2—((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)hydroxy- 1- isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyl-Z-oxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysen-3a-yl)ethyl)carbamate To a on of29 (1.6g, 2.173 mmol) in methanol (6 mL) and THF (6 mL), and water (6 mL) was added NaOH (5.21 g, 130 mmol). The reaction mixture was stirred at rt for 1 h. Water and EtOAc were added upon tion and the layers separated. The organic layer was washed with water, brine, and dried (Na2804). Removal of the solvent gave 30 (1.4g, 1.590 mmol, 73%) as a white solid.
LC/MS: m/z calculated 693.5, found 716.3 (M+Na)+.
Step F: Intermediate 31 4-((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-(2-((Tert-butoxycarbonyl)(4- ch/orobenzy/)amino)ethyl)- 1-isopropy/-5a, 5b, 8, 8, 1 1a-pentamethyIoxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl) 1-tert-buty/ 2, 2-dimethy/succinate ] To a on of DMAP (0.862 g, 7.06 mmol), EDC (1.932 g, 10.08 mmol) and 4-tert-butoxy-3,3-dimethyloxobutanoic acid (10) (1.631 g, 8.06 mmol) in DCM (60 mL) stirred at 20 °C for 30 min was added 30 (1.4 g, 2.016 mmol). The reaction mixture was stirred at 20 °C for 1 h. The mixture was washed with saturated um chloride, water, and saturated NaHC03, water, and lastly brine. The organic layer was dried over Na2804, ed and concentrated to give the crude product, which was purified by silica gel column eluting with petrol ether/Ethyl acetate (4:1) to afford the product 4-((3aR,5aR,5bR,7aR,9S,1 1aR,1 1bR,13aS)—3a-(2-((tert— carbonyl)(4-chlorobenzyl)amino)ethyl)—1-isopropyl-5a,5b,8,8,11a-pentamethyl- 2—oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H- cyclopenta[a]chrysenyl) 1-tert-butyl 2,2-dimethylsuccinate (1 .4g, 0.986 mmol, 49%) as a yellow solid.
Step G: Compound 32 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-(2-((4-Ch/orobenzy/)amino)ethy/) isopropyl—5a, 5b, 8, 8, 1 1a-pentamethyloxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyclopenta[a]chrysenyl)oxy)-2, 2-dimethyl—4-oxobutanoic acid To a solution of 31 (1.4g, 1.593 mmol) in DCM (6 mL) was added TFA (3 mL). The reaction mixture was stirred at 20 °C for 2 h and evaporated in vacuo to afford crude product which was purified by preparative-HPLC to give the title compound oroacetic acid salt (1g, 73%) as a white solid. 1H NMR (400MHz ,METHANOL-d4) 6 = 7.57 - 7.42 (m, 4 H), 4.51 (dd, J = 5.1, 11.2 Hz, 1 H), 4.29 - 4.15 (m, 2 H), 3.30 - 3.18 (m, 1 H), 2.98 - 2.69 (m, 3 H), 2.62 (q, J = 16.0 Hz, 2 H), 2.29 (d, J: 19.1 Hz, 1 H), 2.17 - 0.79 (m, 48 H); LC/MS: m/z calculated 721.5, found 722.3 (M+1)+. e 6: Compound 33 4-(((3aR, 5aR, 5bR, 7aR, 98, 1 1aR, 1 1bR, 13aS)-3a-(2-(Benzylamino)ethyl)isopropyl- 5a, 5b, 8, 8, 1 1a-pentamethyl-Z-oxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H— cyclopenta[a]chrysen-9—yl)oxy)-2, 2-dimethyl—4-oxobutanoic acid The title compound was made in a r manner to example 5 as a TFA salt. 1H NMR (400MHz ,METHANOL-d4) 6 = 7.48 (s, 5 H), 4.51 (dd, J = 5.1, 11.2 Hz, 1 H), 4.30 - 4.17 (m, 2 H), 3.31 - 3.19 (m, 1 H), 2.96 - 2.71 (m, 3 H), 2.62 (q, J: 15.9 Hz, 2 H), 2.29 (d, J: 18.8 Hz, 1 H), 2.21 - 0.78 (m, 48 H); LC/MS: m/z calculated 687.5, found 688.4 (M+1)? M9804, NaBH4 Et3N Example 7: Compound 39 4-(((3aR, 5aR, 5bR, 7aR, 98, 1 1aR, 1 1bR, 3a—(2—((3-Chlorobenzy/)amino)ethy/)—1- isopropyl—5a, 5b, 8, 8, 1 1a-pentamethyl-Z-oxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyclopenta[a]chrysenyl)oxy)—2, 2-dimethyl—4-oxobutanoic acid Ste A: Com ound 34 (3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-(2-Aminoethyl)isopropyl- 5a, 5b, 8, 8, 1 tamethyl-Z-oxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyclopenta[a]chrysenyl acetate To a solution of (3aR,5aR,5bR,7aR,98,11aR,11bR,13aS)—1- isopropyl-5a,5b,8,8,11a-pentamethyl-3a-(2-nitroethyl)oxo- 3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H- cyclopenta[a]chrysenyl acetate (27) (10 g, 18.46 mmol) and nickel(ll) chloride (7.18 g, 55.4 mmol) in methanol (100 ml) was added sodium borohydride (6.98 g, 185 mmol) portionwise during 1 hour. The reaction mixture was stirred at 0 °C for 1h.
The mixture was diluted with EtOAc (250 mL). The c phase was washed with sat. NH4CI (50 mL) until the c layer change to ess. The ed organic layers were dried over anhydrous Na2804, and concentrated in vacuo to get the crude product (3aR,5aR,5bR,7aR,98,11aR,11bR,13aS)—3a-(2-aminoethyl)—1- isopropyl-5a,5b,8,8,11a-pentamethyloxo- 3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H- cyclopenta[a]chrysenyl acetate (34) (7g, 12.63 mmol, 68.4 % yield), which was used without further purification. 1H NMR (400MHz ,CHLOROFORM-d) 6 = 9.15 (dd, J: 4.9, 11.4 Hz, 1 H), 8.12 (br. s., 2 H), 7.97 - 7.81 (m, 1 H), 7.63 - 7.49 (m, 1 H), 7.26 - 7.15 (m, 1 H), 7.15 - 7.04 (m, 1 H), 6.98 (d, J: 18.6 Hz, 1 H), 6.81 - 5.38 (m, 47 H); LC/MS: m/z calculated 511.4, found 512.3 (M+1)+.
Step B: Compound 35 (3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-(2-((Tert-butoxycarbonyl)amino)ethyl)- 1-isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyl-Z-oxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyclopenta[a]chrysenyl acetate To a solution of aR,5bR,7aR,9S,11aR,11bR,13aS)—3a-(2- thyl)—1-isopropyl-5a,5b,8,8,11a-pentamethyloxo- 3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H- cyclopenta[a]chrysenyl acetate (34) (5.3 g, 10.36 mmol), TEA (2.165 mL, 15.53 mmol) and TEA (2.165 mL, 15.53 mmol) in dichloromethane (DCM) (100 mL) stirred at room tempwas added BOCZO (2.404 mL, 10.36 mmol). The reaction mixture was stirred at 20 °C for 2 h. The reaction mixture was poured into ice water (300 ml) and the solids were ted and dried to give (3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)— 3a-(2-((tert-butoxycarbonyl)amino)ethyl)—1-isopropyl-5a,5b,8,8,11a-pentamethyl oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H- cyclopenta[a]chrysenyl acetate (35) (5.8 g, 8.34 mmol, 81 % yield) as a white foam. This was ssed crude in next reaction without further purification. 1H NMR (400MHz, CHLOROFORM-d) 6 = 4.58 - 4.37 (m, 2 H), 3.26 - 2.96 (m, 4 H), 2.93 - 2.72 (m, 2 H), 2.28 (d, J: 18.8 Hz, 1 H), 2.11 - 0.71 (m, 53 H); LC/MS: m/z calculated 611.5, found 634.3 (M+Na)+.
Step C: Compound 36 uty/ (2-((3aR, 5aR, 5bR, 7aR, 98, 1 1aR, 1 1bR, 13aS)hydroxy- 1-isopropyl- 5a, 5b, 8, 8, 1 1a-pentamethyl-Z-oxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysen-3a-yl)ethyl)carbamate A solution of (3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)—3a-(2-((tert— butoxycarbonyl)amino)ethyl)—1-isopropyl-5a,5b,8,8,11a-pentamethyloxo- 3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H- cyclopenta[a]chrysenyl acetate (35) (5.8 g, 9.48 mmol) NaOH (11.37 g, 284 mmol) in methanol (4 mL), THF (6mL) and Water (2 mL) was stirred at room temperature for 1 h. EtOAc was added and the reaction mixture was washed with water. The c layer was ted, washed with water and brine,and dried (Na2804). Removal of the solvent provide tert-butyl (2- ((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)—9-hydroxyisopropyl-5a,5b,8,8,11a- pentamethyloxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a- octadecahydro-2H-cyclopenta[a]chrysen-3a-yl)ethyl)carbamate (36) (5.4 g, 7.87 mmol, 83 % yield) as a white solid. 1H NMR (400MHz ,CHLOROFORM-d) 6 = 4.53 - 4.36 (m, 1 H), 3.30 - 2.94 (m, 4 H), 2.94 - 2.67 (m, 2 H), 2.28 (d, J = 18.8 Hz, 1 H), 2.11 - 0.55 (m, 50 H); LC/MS: m/z calculated 569.4, found 592.3 (M+Na)+.
Step D: Compound 37 4-((3aR, 5aR, 5bR, 7aR, 98, 1 1aR, 1 1bR, 13aS)-3a-(2-((Tert- butoxycarbonyl)amino)ethyl)- 1-isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyloxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, tadecahydro-2H- cyc/openta[a]chrysen-9—yl) 1-tert-buty/ 2, 2-dimethy/succinate A on of 4-tert-butoxy-3,3-dimethyloxobutanoic acid (10) (4.79 g, 23.69 mmol), DMAP (3.47 g, 28.4 mmol) and utyl (2- ((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)—9-hydroxyisopropyl-5a,5b,8,8,11a- pentamethyloxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a- octadecahydro-2H-cyclopenta[a]chrysen-3a-yl)ethyl)carbamate (36) (5.4 g, 9.48 mmol) EDC (9.08 g, 47.4 mmol) in dichloromethane (DCM) (25 mL) was stirred at rt overnight. NH4C| was added and the mixture was extracted with DCM, and purified by chromatography with PE:EA (10:1 ) to give the 4- ((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-(2-((tert-butoxycarbonyl)amino)ethy|)- 1-isopropyl-5a,5b,8,8,11a-pentamethyloxo- 3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H- cyclopenta[a]chrysenyl) 1-tert-butyl 2,2-dimethylsuccinate (37) (6.7 g, 8.75 mmol, 9298wad)11NMR(«wwwu,CHLOROFORM8)5=482—439(m,2H)324- 3.10 (m, 1 H), 3.10-2.93 (m, 1 H), .68 (m, 2 H), 2.62-2.49 (m, 1 H), 2.28 (d, J = 18.8 Hz, 1 H), 2.11 - 0.89 (m, 88 H); LC/MS: m/z calculated 753.6, found 778.5 (M+Na)+.
Step E: Compound 38 aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-(2-Aminoethy/)- 1-isopropyl- 5a, 5b, 8, 8, 1 1a-pentamethyloxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H— cyclopenta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid To a solution of 4-((3aR,5aR,5bR,7aR,98,11aR,11bR,13aS)—3a-(2- ((tert—butoxycarbonyl)amino)ethyl)isopropyl-5a,5b,8,8,11a-pentamethyloxo- 3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H- cyclopenta[a]chrysenyl) 1-tert-butyl 2,2-dimethylsuccinate (37) (6.7 g, 8.88 mmol) in DCM (20 mL) stirred at rt was added TFA (4 ml, 51.9 mmol). The on mixture was stirred at rt for 2h. The reaction mixture was washed with sat. NaHC03. A solid was formed and collected by filtration to give 4- (((3aR,5aR,5bR,7aR,98,11aR,11bR,13aS)—3a-(2-aminoethyl)—1-isopropyl- 5a,5b,8,8,11a-pentamethyloxo- 3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H- cyclopenta[a]chrysenyl)oxy)-2,2-dimethyloxobutanoic acid (38) (4 g, 6.55 mmol, 73.7 % yield) as a white solid. 1H NMR z ,DMSO-de) 6 = 4.44 - 4.28 (m, 1 H), 3.20 - 3.05 (m, 1 H), 2.87 - 2.75 (m, 1 H), 2.46 - 2.16 (m, 6 H), 1.97 - 0.66 (m, 47 H); LC/MS: m/z calculated 597.4, found 598.3 (M+1)+.
Step F: Compound 39 WO 90664 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-(2—((3-Chlorobenzy/)amino)ethy/) isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyl-Z-oxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H— cyclopenta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid To a solution of 4-(((3aR,5aR,5bR,7aR,98,11aR,11bR,13aS)-3a-(2- aminoethyl)—1-isopropyl-5a,5b,8,8,11a-pentamethyloxo- 3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H- cyclopenta[a]chrysenyl)oxy)-2,2-dimethyloxobutanoic acid (38) (300 mg, 0.502 mmol), TEA (0.028 ml, 0.201 mmol) and MgSO4 (91 mg, 0.753 mmol) in methanol (15 ml) stirred at room temp was added 3-chlorobenzaldehyde (85 mg, 0.602 mmol).
The reaction mixture was stirred at 20 °C for 2 h. The reaction mixture was then cooled to 0 °C and NaBH4 (1 .541g, 40.7mmol) was added in portions within 30 min, after which the solution was d to d for 1h. The mixture was purified by preparative-TLC eluting with DCM/MeOH (20 :1) to give 39 (108 mg, 0.147 mmol, 29 %).1H NMR (500MHz ,METHANOL-d4) 6 = 7.41 (s, 1 H), 7.38 - 7.24 (m, 3 H), 4.48 (dd, J: 5.7, 10.7 Hz, 1 H), 3.89 - 3.67 (m, 2 H), 3.26 - 3.11 (m, 1 H), 2.84 - 2.73 (m, 1 H), 2.66 - 2.47 (m, 2 H), 2.46 - 2.34 (m, 1 H), 2.34 - 2.21 (m, 2 H), 2.08 - 0.77 (m, 48 H).
Example 8: Compound 40 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-(2-((3-Chloro-2— fluorobenzyl)amino)ethyl)isopropyI-5a, 5b, 8, 8, 1 1a-pentamethyloxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H— enta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid The title compound was made in a similar manner to Example 7, but as a TFA salt. 1H NMR (500MHz ,METHANOL-d4) 6 = 7.46 - 7.38 (m, 1 H), 7.35 (t, J = 6.6 Hz, 1 H), 7.17 (t, J = 7.7 Hz, 1 H), 4.48 (dd, J = 5.5, 10.6 Hz, 1 H), 3.97 - 3.72 (m, 2 H), 3.27 - 3.12 (m, 1 H), 2.85 - 2.73 (m, 1 H), 2.67 - 2.45 (m, 2 H), 2.44 - 2.16 (m, 3 H), 2.09 - 0.73 (m, 48 H).
Example 9: nd 41 4-(((3aR,5aR,5bR, 7aR,98, 1 1aR, 1 1bR,13aS)-3a-(2—((1-(4- chlorophenyl)cyclopropyl)amino)ethy/)- 1-isopropy/-5a, 5b, 8, 8, 1 1a-pentamethyIoxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyclopenta[a]chrysen-9—yl)oxy)-2, 2-dimethyloxobutanoic acid The title compound was made in a r manner to Example 5, but as a TFA salt. The final step was performed ing to the following procedure.
To a solution of 4-(tert-butoxy)-3,3-dimethyIoxobutanoic acid (10) (0.988 g, 4.89 mmol), EDC (1.171 g, 6.11 mmol) and DMAP (0.522 g, 4.28 mmol) in DCM (12 mL) stirred at room temp was added tert-butyl (1-(4-ch|oropheny|)cyc|opropy|)(2- ((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)—9-hydroxyisopropy|-5a,5b,8,8,11a- pentamethyIoxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a- octadecahydro-2H-cyclopenta[a]chrysen-3a-y|)ethy|)carbamate (1.1 g, 1.221 mmol).
The reaction mixture was stirred at rt for 2 h. Next, TFA (6 mL) was added to the reaction mixture. Then, the reaction solution was stirred at rt for another 1.5 h, and the product was extracted with DCM (60 mL*3), and the combined organic phase was washed with brine (100 ml), dried over Na2804, concentrated and the residue was purified by recrystallization from DCM and hexane (1 :6) resulting in 800 mg of the TFA salt of 41 as white solid. 1H NMR (400MHz NOL-d4) 6 = 7.64 - 7.44 (m, 4 H), 4.50 (dd, J: 51,112 Hz, 1 H), 3.26 - 3.10 (m, 1 H), 2.84 - 2.41 (m, 5 H), 2.24 - 2.12 (m, 1 H), 2.12 - 0.78 (m, 52 H); LC/MS: m/z calculated 747.5, found 748.3 \ O I /\If N HO Exam le 10: Com ound 42 4-(((3aR, 5aR, 5bR, 7aR, 98, 1 1aR, 1 1bR, 13aS)-3a-(2-((4-chlorobenzyl) (2- (dimethy/amino)ethy/)amino)ethy/)- 1-isopropy/-5a, 5b, 8, 8, 1 1a-pentamethyI-Z-oxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyclopenta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid To a solution of 2-(dimethylamino)acetaldehyde (244 mg, 1.977 mmol) in methanol (100 ml) was added 4-(((3aR,5aR,5bR,7aR,98,11aR,11bR,13aS)— 3a-(2-((4-chlorobenzyl)amino)ethy|)isopropyl-5a,5b,8,8,11a-pentamethyloxo- 3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H- cyclopenta[a]chrysenyl)oxy)-2,2-dimethyloxobutanoic acid, hloride (32) (300 mg, 0.395 mmol). The reaction mixture was stirred at 40 0C for 2 h. The reaction was cooled to rt and sodium cyanoborohydride (24.84 mg, 0.395 mmol) was added and the resultant solution was stirred overnight. The reaction was diluted with ammonium chloride (40 ml), and extracted with DCM (60 ml x 3). The combined c layers were washed with brine (20 ml), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by preparative-HPLC to afford 42 as a trifluoroacetic acid salt (200 mg, 49 % yield) as a white solid. 1H NMR (400MHz ,METHANOL-d4) 6 = 7.52 - 7.34 (m, 4 H), 4.50 (dd, J = 5.0, 11.0 Hz, 1 H), 4.07 - 3.88 (m, 1 H), 3.83 - 3.62 (m, 1 H), 3.53 - 3.35 (m, 2 H), 3.22 - 2.89 (m, 9 H), 2.71 - 2.54 (m, 2 H), 2.50 - 2.21 (m, 4 H), 2.06 - 0.83 (m, 48 H); LC/MS: m/z ated 792.5, found 793.4 (M+1)+.
Example 11: Compound 43 4-(((3aR,5aR,5bR, 7aR,98, 1 1aR, 1 1bR,13aS)-3a-(2—((1-(4- Chlorophenyl)cyclopropyl) methylamino)ethyl)amino)ethyl)- 1-isopropyl- 5a, 5b, 8, 8, 1 1a-pentamethyl-Z-oxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyclopenta[a]chrysenyl)oxy)-2, 2-dimethyl—4-oxobutanoic acid The title compound was made in a similar manner to Example 10, as a TFA salt. 1H NMR (400MHz ,METHANOL-d4) 6 = 7.35 (s, 4 H), 4.51 (dd, J = 5.1, 11.2 Hz, 1 H), 3.31 - 3.17 (m, 2 H), 3.12 - 2.73 (m, 9 H), 2.73 - 2.51 (m, 2 H), 2.44 - 2.17 (m, 3 H), 2.14 - 0.77 (m, 53 H); LC/MS: m/z calculated 818.4, found 819.4 (M+1)+.
Exam le 12: Com ound 44 4-(((3aR,5aR,5bR, 7aR,98, 1 1aR, 1 1bR,13aS)-3a-(2-((4- Chlorobenzyl)(methyl)amino)ethyl)isopropyI-5a, 5b, 8, 8, 1 1a-pentamethyloxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid ] To a solution of 32 (150 mg, 0.208 mmol) in MeOH (6 mL) at rt was added formaldehyde (33.7 mg, 0.415 mmol). The reaction mixture was stirred at rt for 2 h. NaCNBH4 (104 mg, 1.661 mmol) was added portionwise and the mixture stirred for ght. The t was evaporated, and the mixture was purified by preparative HPLC to provide the TFA salt of 44 (60 mg, 34%). 1H NMR (400MHz ,METHANOL-d4) 6 = 7.60 - 7.44 (m, 4 H), 4.56 - 4.37 (m, 2 H), 4.36 - 4.24 (m, 1 H), 3.28 - 3.14 (m, 1 H), 2.89 (m, 5 H), 2.73 - 2.50 (m, 2 H), 2.28 (d, J: 19.1 Hz, 1 H), 2.20 - 0.83 (m, 49 H); LC/MS: m/z calculated 735.5, found 736.3 (M+1)+.
A020, DMAP Exam le 13: Com ound 45 4-(((3aR, 5aR, 5bR, 7aR, 98, 1 1aR, 1 1bR, 13aS)-3a-(2-(N-(4- Chlorobenzyl)acetamido)ethyl)- 1-isopropyl-5a, 5b, 8, 8, 1 tamethyl-Z-oxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H— cyclopenta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid A mixture of 32 (150 mg, 0.208 mmol), TEA (210 mg, 2.076 mmol) and DMAP (5 mg, 0.042 mmol) in DCM (5ml) was stirred for 3 hours. Next, the mixture was quenched with water (50ml). The organics were then washed with water (2x50ml), dried over Na2804, and evaporated in vacuo to afford crude product. This was then purified by ative HPLC to give 45 (65 mg, 0.085 mmol, 41%) as a white solid. Mixture of rotomers. 1H NMR (400MHz ,METHANOL-d4) 6 = 7.49 - 7.18 (m, 4 H), 4.80 - 4.42 (m, 3 H), 3.27 - 2.81 (m, 4 H), 2.76 - 2.52 (m, 2 H), 2.36 - 2.10 (m, 4 H), 2.08 - 0.82 (m, 48 H); LC/MS: m/z calculated 763.5, found 764.3 (M+1)+. 2012/069637 Exam le 14: Com ound 46 4-(((3aR,5aR,5bR, 7aR,98, 1 1aR, 1 aS)-3a-((R)((4-Chlorobenzyl)amino)- 1- hydroxyethy/)— 1-isopropy/-5a, 5b, 8, 8, 1 1a-pentamethyIoxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyclopenta[a]chrysenyl)oxy)—2, 2-dimethyl—4-oxobutanoic acid To a solution of 4-((3aR,5aR,5bR,7aR,98,11aR,11bR,13aS)—3a-((R)— 2—((tert-butoxycarbony|)(4-ch|orobenzy|)amino)hydroxyethy|)isopropy|- 5a,5b,8,8,11a-pentamethyIoxo- 3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H- cyclopenta[a]chrysenyl) -butyl 2,2—dimethylsuccinate (19) (300 mg, 0.335 mmol) in DCM (30 mL) stirred at rt was was added TFA (15 mL, 195 mmol). The reaction mixture was stirred at rt until LCMS and TLC indicated SM disappeared.
The solvent was removed in vacuo and the residue was purified by preparative HPLC to give 4-(((3aR,5aR,5bR,7aR,98,11aR,11bR,13aS)—3a-((R)—2—((4- Chlorobenzy|)amino)hydroxyethy|)isopropy|-5a,5b,8,8,11a-pentamethyIoxo- 3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H- cyclopenta[a]chrysenyl)oxy)-2,2—dimethyIoxobutanoic acid (46) (100 mg, 0.135 mmol, 40.4 % yield) as a TFA salt. 1H NMR z ,CHLOROFORM-d) 6 = 7.38 - 7.18 (m, 4 H), 4.54 - 4.42 (m, 1 H), 4.28 - 4.14 (m, 1 H), 3.93 - 3.70 (m, 2 H), 3.19 - 3.00 (m, 1 H), 2.75 - 0.69 (m, 52 H); LC/MS: m/z calculated 737.4, found 738.2 (M+1)+.
Example 15: Compound 47 4-(((3aR, 5aR, 5bR, 7aR, 98, 1 1aR, 1 1bR, 13aS)-3a-((S)((4-Chlorobenzy/)amino)- 1- yethy/)- 1-isopropy/-5a, 5b, 8, 8, 1 1a-pentamethyIoxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H— cyclopenta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid ] To a solution of 4-((3aR,5aR,5bR,7aR,98,11aR,11bR,13aS)—3a-((S)— 2—((tert-butoxycarbonyl)(4-chlorobenzyl)amino)hydroxyethyl)isopropy|- 5a,5b,8,8,11a-pentamethyIoxo- 3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H- cyclopenta[a]chrysenyl) 1-tert-butyl 2,2-dimethylsuccinate (18) (130 mg, 0.145 mmol) in DCM (30 mL) stirred at rt was added TFA (15 mL, 195 mmol). The reaction mixture was stirred at rt until LCMS and TLC indicated starting material disappeared. The solvent was ated and then then CH3CN and H20 was added and the material was lyophilized to give 4- (((3aR,5aR,5bR,7aR,98,11aR,11bR,13aS)—3a-((S)((4-Chlorobenzyl)amino) 2012/069637 hydroxyethy|)isopropy|-5a,5b,8,8,11a-pentamethyl-2—oxo- 3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H- cyclopenta[a]chrysen-Q-yl)oxy)-2,2—dimethyIoxobutanoic acid (47), trifluoroacetic acid salt (120 mg, 0.139 mmol, 96 % yield). 1H NMR (400MHz ,CHLOROFORM-d) 6 = 10.30 (br. s., 1 H), 8.08 (br. s., 1 H), 7.38 (s, 4 H), 4.73 - 4.33 (m, 2 H), 4.28 - 4.07 (m, 2 H), 3.34 - 3.08 (m, 2 H), 2.99 - 2.74 (m, 2 H), 2.73 - 2.50 (m, 2 H), 2.48 - 2.29 (m, 1 H), 2.05 - 0.64 (m, 47 H); LC/MS: m/z calculated 737.4, found 738.3 (M+1)+.
Exam le 16: Com ound 49 4-(((3aR, 5aR, 5bR, 7aR, 98, 1 1aR, 1 1bR, 13aS)-3a-((R)Acetoxy((4- chlorobenzy/)amino)ethyl)- 1-isopropy/-5a, 5b, 8, 8, 1 1a-pentamethyIoxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyclopenta[a]chrysenyl)oxy)—2, 2-dimethyl—4-oxobutanoic acid Ste A: Com ound 48 4-((3aR, 5aR, 5bR, 7aR, 98, 1 1aR, 1 1bR, 13aS)-3a-((R)acetoxy((tert— butoxycarbonyl)(4-ch/orobenzyl)amino)ethyl)- 1-isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyl- 2-oxo-3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 10, 1 1, 1 1a, 1 1 b, 12, 13, 13a-octadecahydro-2H— cyc/openta[a]chrysenyl) 1-tert-buty/ 2, thy/succinate To a solution of 19 (500 mg, 0.559 mmol) in dichloromethane (30 mL) stirred at rt was added Ac20 (0.158 mL, 1.677 mmol), triethylamine (0.195 mL, 1.397 mmol) and DMAP (6.83 mg, 0.056 mmol). The on mixture was stirred at rt until TLC indicated SM disappeared. The mixture was worked up and purified by silica gel chromatography =5:1) to give 48 (510mg, 0.517 mmol, 93 % yield). The product consisted of a mixture of rotomers. 1H NMR (400MHz ,CHLOROFORM-d) 6 = 7.39 - 7.20 (m, 2 H), 7.21 - 6.99 (m, 2 H), 5.92 - 5.56 (m, 1 H), 5.00 - 3.88 (m, 2 H), 3.40 - 1.96 (m, 8 H), 1.97 - 0.58 (m, 67 H).
Step B: Compound 49 aR, 5aR, 5bR, 7aR, 98, 1 1aR, 1 1bR, 13aS)-3a-((R)Acetoxy((4- chlorobenzy/)amino)ethyl)- 1-isopropy/-5a, 5b, 8, 8, 1 1a-pentamethyIoxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H— cyclopenta[a]chrysenyl)oxy)-2, 2-dimethyl—4-oxobutanoic acid To a solution of 48 (500 mg, 0.534 mmol) in DCM (30 mL) stirred at rt was added TFA (15 mL, 195 mmol). The reaction mixture was stirred at rt until LCMS and TLC indicated SM had disappeared. The solvent was evaporated and CH3CN and H20 were added and e was lyophilized to give 49 as a trifluoroacetic acid salt (400mg, 0.439 mmol, 82 % . 1H NMR (400MHz, CHLOROFORM-d) 6 = 7.46 - 7.19 (m, 4 H), 5.94 - 5.70 (m, 1 H), 4.58 - 4.36 (m, 1 H), 4.25 - 3.88 (m, 2 H), 3.25 - 3.02 (m, 1 H), 3.01 - 2.41 (m, 5 H), 2.08 (s, 3 H), 2.00 - 0.64 (m, 47 H); LC/MS: m/z calculated 779.5, found 780.4 (M+1)+.
Example 17: Compound 50 4-(((3aR,5aR,5bR, 7aR,98, 1 1aR, 1 1bR,13aS)-3a-((S)— oxy((4- chlorobenzy/)amino)ethyl)- 1-isopropy/-5a, 5b, 8, 8, 1 1a-pentamethyIoxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyclopenta[a]chrysen-9—yl)oxy)-2, 2-dimethyloxobutanoic acid The title compound was made in a similar manner to Example 16 and isolated as a TFA salt. 1H NMR (400MHz ,CHLOROFORM-d) 6 = 7.49 - 7.30 (m, 4 H), 5.85 - 5.71 (m, 1 H), 4.59 - 4.40 (m, 1 H), 4.31 - 4.03 (m, 2 H), 3.41 - 2.79 (m, 4 H), 2.79 - 2.50 (m, 2 H), 2.37 (d, J = 18.1 Hz, 2 H), 2.02 - 0.63 (m, 49 H); LC/MS: m/z calculated 779.5, found 780.3 (M+1)+.
Exam le 18: Com ound 51 4-(((3aR,5aR,5bR, 7aR,98, 1 1aR, 1 1bR,13aS)-3a-((R)((4-Chlorobenzy/)(2- hy/amino)ethy/)amino)- 1-hydroxyethy/)— 1-isopropy/-5a, 5b, 8, 8, 1 1a-pentamethyl- 2-oxo-3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 10, 1 1, 1 1a, 1 1 b, 12, 13, 13a-octadecahydro-2H- cyclopenta[a]chrysenyl)oxy)—2, 2-dimethyloxobutanoic acid To a solution of 2-(dimethylamino)acetaldehyde, hydrochloride (6.75 g, 54.6 mmol) in ol (20 mL) was added 4- (((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)—3a-((R)—2-((4-chlorobenzyl)amino) hydroxyethyl)isopropyl-5a,5b,8,8,11a-pentamethyloxo- 3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H- cyclopenta[a]chrysenyl)oxy)-2,2-dimethyloxobutanoic acid Trifluoroacetic acid salt (46) (9.5 g, 10.92 mmol). The pH was adjusted to 7-8 with EN. The reaction mixture was stirred at rt for 2 h. Sodium orohydride (0.686 g, 10.92 mmol) was then added and the mixture was stirred at rt overnight. After the reaction was complete, water (15 mL) and EtOAc (15 mL) were added, and then the organic phase was removed and concentrated under reduced presure. The product was ted with EtOAc (80 mLx3), the combined organic phase was washed with brine, dried, and trated. The product was purified by flash chromatography (DCM:EtOAc=2:1 to 1:1, then DCM:MeOH=100:1 to 20:1) to give 4- (((3aR,5aR,5bR,7aR,98,11aR,11bR,13aS)—3a-((R)((4-chlorobenzyl)(2- (dimethylamino)ethy|)amino)hydroxyethy|)isopropy|-5a,5b,8,8,11a-pentamethyl- 2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H- cyclopenta[a]chrysenyl)oxy)-2,2-dimethyloxobutanoic acid (51) (6 g, 7.41 mmol, 67.9 % yield) as white solid. Multiple batches of this material (were ed 95 g), dissolved in 600 mL ofdichloromethane and washed with NaHC03 (400 mL*3) and the organic phase was dried over Na2804, filtered and trated. The solids were washed with a mixture of EtOAc: petroleum ether (600 mL), and filtered followed by lyophilization to provide the final title compound 62 g as a white solid. 1H NMR (400MHz ,METHANOL-d4) 6 = 7.47 - 7.29 (m, 4 H), 4.48 (dd, J = 5.8, 10.3 Hz, 1 H), 4.15 - 4.04 (m, 1 H), 3.80 (d, J: 13.8 Hz, 1 H), 3.57 (d, J: 14.1 Hz, 1 H), 3.21 - 2.82 (m, 5 H), 2.72 - 2.41 (m, 9 H), 2.37 - 2.05 (m, 4 H), 2.05 - 0.74 (m, 45 H); LC/MS: m/z calculated 808.5, found 809.5 (M+1)+.
NaBchN Exam le 19: Com ound 56 4-(((3aR, 5aR, 5bR, 7aR, 98, 1 1aR, 1 1bR, 13aS)-3a-((S)((4-Chlorobenzyl) (2- (dimethy/amino)ethy/)amino)- 1-hydroxyethy/)— ropy/-5a, 5b, 8, 8, 1 1a—pentamethyl- 2-oxo-3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 10, 1 1, 1 1a, 1 1 b, 12, 13, 13a-octadecahydro-2H- cyclopenta[a]chrysenyl)oxy)—2, 2-dimethyl—4-oxobutanoic acid Ste A: Com ound 52 (3aR, 5aR, 5bR, 7aR, 98, 1 1aR, 1 1bR, 3a-(2-((4-Chlorobenzy/)(2- (dimethy/amino)ethyl)amino)acetyl)hydroxy— 1-isopropyl-5a, 5b, 8, 8, 1 1a- pentamethyl—3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyclopenta[a]chrysen-2—one To a solution of 2-(dimethylamino)acetaldehyde (4.79 g, 38.8 mmol) in methanol (50 ml) and 1,2-dichloroethane (DCE) (25 ml) was added (3aR,5aR,5bR,7aR,98,11aR,11bR,13aS)—3a-(2-(4-chlorobenzylamino)acetyl)—9- hydroxyisopropyl-5a,5b,8,8,11a-pentamethyl- 3a,4,5,5a,6,7,7a,8,9,10,11,11a,11b,12,13,13a-hexadecahydro—3H- cyclopenta[a]chrysen-2(5bH)-one (15) (5 g, 7.75 mmol) at 0°C. The pH was adjusted to 7 with EN. The reaction mixture was stirred at rt for 1h. Sodium cyanoborohydride (0.487 g, 7.75 mmol) was added and the e was stirred overnight. The reaction was diluted with water (40 ml), and extracted with DCM (60 ml x 3). The combined organic layer was washed with brine (20 ml), dried over sodium sulfate and filtered to afford crude product (3aR,5aR,5bR,7aR,98,11aR,11bR,13aS)—3a-(2-((4-chlorobenzyl)(2- (dimethylamino)ethyl)amino)acetyl)hydroxyisopropyl-5a,5b,8,8,11a- ethyl-3a,4,5,5a,6,7,7a,8,9,10,11,11a,11b,12,13,13a-hexadecahydro-3H- cyclopenta[a]chrysen-2(5bH)-one (52) (5g, 5.89 mmol, 76 % yield) as a light yellow solid, which was used in the next step. LC/MS: m/z calculated 678.5, found 679.3 (M+1)+.
Step B: Compound 53 1-Tert-butyl 4-((3aR, 5aR, 5bR, 7aR, 98, 1 1aR, 1 1bR, 13aS)-3a-(2-((4-ch/orobenzy/) (2- hylamino)ethyl)amino)acetyl)- 1-isopropy/-5a, 5b, 8, 8, 1 1a—pentamethyI-Z-oxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyclopenta[a]chrysenyl) 2, 2-dimethy/succinate To a solution of 4-(tert—butoxy)—3,3-dimethyloxobutanoic acid (11.91 g, 58.9 mmol), N,N-dimethylpyridinamine (4.50 g, 36.8 mmol) in DCM (20 mL) was added EDC (11.29 g, 58.9 mmol). The reaction mixture was stirred at rt for 1h.
Then, (3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-(2-((4-chlorobenzyl)(2- (dimethylamino)ethyl)amino)acetyl)hydroxyisopropy|-5a,5b,8,8,11a- pentamethyl-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H- cyclopenta[a]chrysenone (52) (5 g, 7.36 mmol) was add. Upon completion, the mixture was washed with 2 M HCI, water and brine. The organic layer was dried over Na2804, filtered and concentrated to give the crude product. The product was purified by a silica gel column using romethane/ methanol (20:1) to afford 1- tert-butyl 4-((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-(2-((4-chlorobenzyl)(2- (dimethylamino)ethyl)amino)acetyl)—1-isopropyl-5a,5b,8,8,11a-pentamethyloxo- ,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H- cyclopenta[a]chrysenyl) 2,2-dimethylsuccinate (53) (1.8 g, 1.917 mmol, 26.1 % yield) as an oil. 1H NMR (400MHz, CHLOROFORM-d) 6 = 7.27 (s, 4 H), 4.60 - 4.39 (m, 1 H), 3.82 (d, J: 13.8 Hz, 1 H), 3.59 (d, J: 13.8 Hz, 1 H), 3.50 - 3.05 (m, 3 H), 2.82 - 2.63 (m, 2 H), 2.63 - 0.53 (m, 67 H).
Step C: Compounds 54 and 55 1-tert-buty/ 4-((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((R)((4- chlorobenzyl)(2-(dimethy/amino)ethy/)amino)- 1-hydroxyethyl)- 1-isopropyl- 5a, 5b, 8, 8, 1 1a-pentamethyl-Z-oxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H— cyclopenta[a]chrysenyl) 2, 2-dimethy/succinate (54) and 1-tert-buty/ 4- ((3aR, 5aR, 5bR, 7aR, 98, 1 1aR, 1 1bR, 13aS)-3a-((S)((4-chlorobenzyl) (2- (dimethy/amino)ethy/)amino)- oxyethy/)- 1-isopropy/-5a, 5b, 8, 8, 1 1a-pentamethyl- 2-oxo-3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 10, 1 1, 1 1a, 1 1 b, 12, 13, 13a-octadecahydro-2H— cyclopenta[a]chrysenyl) 2, 2-dimethy/succinate (55) To a solution of 1-tert-butyl 4- ((3aR,5aR,5bR,7aR,98,11aR,11bR,13aS)-3a-(2-((4-chlorobenzyl)(2- (dimethylamino)ethyl)amino)acetyl)—1-isopropyl-5a,5b,8,8,11a-pentamethyloxo- 3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H- enta[a]chrysenyl) 2,2-dimethylsuccinate (53) (1.5g, 1.737 mmol) in methanol (10 mL) was added NaBH4 (0.131 g, 3.47 mmol). The reaction mixture was stirred at rt for 1h. The mixture then was ted with DCM, washed with water and brine. The c layer was dried over Na2804, and concentrated to give the crude product. This was ed by preparative-HPLC then purified by SFC to get 54 (230 mg, 15%) and 55 (360 mg 23%). For 54: 1H NMR (400MHz, CHLOROFORM-d) 6 = 7.45 - 7.18 (m, 4 H), 4.49 (dd, J: 5.6, 10.7 Hz, 1 H), 4.04 (d, J = 9.8 Hz, 1 H), 3.92 - 3.47 (m, 3 H), 3.46 - 0.45 (m, 72 H); LC/MS: m/z calculated 864.6, found 865.4 (M+1)+. For 55: 1H NMR (400MHz ,CHLOROFORM-d) 6 = 7.37 - 7.19 (m, 4 H), 4.50 (dd, J: 5.5, 10.5 Hz, 1 H), 4.18 - 3.98 (m, 1 H), 3.75 (d, J: 13.3 Hz, 1 H), 3.55 (d, J =13.3 Hz, 1 H), 3.29 - 3.10 (m, 1 H), 3.10 - 2.97 (m, 1 H), 2.81 - 0.63 (m, 70 H); LC/MS: m/z calculated 864.6, found 865.9 (M+1)+.
Step D: Compound 56 4-(((3aR, 5aR, 5bR, 7aR, 98, 1 1aR, 1 1bR, 13aS)-3a-((S)((4-Chlorobenzy/) (2- (dimethy/amino)ethy/)amino)- 1-hydroxyethy/)- 1-isopropy/-5a, 5b, 8, 8, 1 1a-pentamethyl- 2-oxo-3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 10, 1 1, 1 1a, 1 1 b, 12, 13, 13a-octadecahydro-2H— cyclopenta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid To a solution of 55 (360mg, 0.416 mmol) in DCM (5 mL) stirred at rt was added TFA (2mL, 26.0 mmol). The reaction mixture was d at rt for 1h. The mixture was evaporated to afford the crude product. This material was purified by preparative-HPLC to provide the title compound 56 as a TFA salt (300 mg, 0.285 mmol, 68.6 % yield) as a white solid. 1H NMR (400MHz ,METHANOL-d4) 6 = 7.58 - 7.34 (m, 4 H), 4.50 (dd, J = 5.0, 11.0 Hz, 1 H), 4.23 - 4.10 (m, 1 H), 4.09 - 3.74 (m, 2 H), 3.58 - 3.12 (m, 3 H), 3.12 - 2.37 (m, 10 H), 2.12 - 0.67 (m, 50 H); LC/MS: m/z ated 808.5, found 809.3 (M+1)+.
NaBHgCN 0 i Exam le 20: Com ound 57 aR,5aR,5bR, 7aR,98, 1 1aR, 1 1bR,13aS)-3a-((S)- 1-Acetoxy((4- chlorobenzyl) (2-(dimethylamino)ethyl)amino)ethyl)- ropyl—5a, 5b, 8, 8, 1 1a- pentamethyl0x0-3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0,1 1, 1 1 a, 1 1 b, 1 2, 13, 13a- octadecahydro-2H-cyclopenta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid To a solution of 2-(dimethylamino)acetaldehyde, hydrochloride (238 mg, 1.922 mmol) in methanol (12 mL) was added 4- (((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)—3a-((S)—1-acetoxy((4- benzyl)amino)ethyl)isopropy|-5a,5b,8,8,11a-pentamethyloxo- 3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H- cyclopenta[a]chrysenyl)oxy)-2,2-dimethyloxobutanoic acid (50) (150 mg, 0.192 mmol). The reaction e was stirred at rt for 2h then sodium cyanoborohydride (121 mg, 1.922 mmol) was added and the mixutre was stirred overnight. Upon completion, the mixture was purified preparative-HPLC to provide the title nd (50 mg, 24%). 1H NMR (400MHz, CHLOROFORM-d) 6 = 7.35 - 7.12 (m, 4 H), 5.65 (d, J = 9.3 Hz, 1 H), 4.49 (dd, J = 5.8, 10.0 Hz, 1 H), 3.83 (d, J: 13.6 Hz, 1 H), 3.55 (d, J =13.6 Hz, 1 H), 3.25 - 2.91 (m, 7 H), 2.91 - 2.73 (m, 7 H), 2.73 - 2.52 (m, 3 H), 2.33 (d, J: 18.1 Hz, 1 H), 1.99 - 0.72 (m, 48 H); LC/MS: m/z calculated 850.5, found 851.4 (M+1)+.
Example 21: Compound 58 4-(((3aR, 5aR, 5bR, 7aR, 98, 1 1aR, 1 1bR, 13aS)-3a-((R)Acetoxy((4- chlorobenzyl) (2-(dimethylamino)ethyl)amino)ethyl)- 1-isopropyl—5a, 5b, 8, 8, 1 1a- pentamethyl0x0-3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0,1 1, 1 1 a, 1 1 b, 1 2, 13, 13a- octadecahydro-2H-cyclopenta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid WO 90664 The title compound was made in a similar manner to example 20. 1 NMR (400MHz ,CHLOROFORM-d) 6 = 7.40 - 7.10 (m, 4 H), 5.68 (d, J = 9.8 Hz, 1 H), 4.55 - 4.39 (m, 1 H), 3.81 (d, J: 13.8 Hz, 1 H), 3.57 (d, J: 13.8 Hz, 1 H), 3.29 - 2.74 (m, 11 H), 2.74 - 2.27 (m, 6 H), 2.14 (s, 3 H), 2.09 - 0.68 (m, 46 H); LC/MS: m/z calculated 850.5, found 851.4 (M+1)+.
Exam le 22 and 23: Com ound 62 and 63 -(((3aR,5aR,5bR, 7aR,9S, 1 1aR, 1 1bR,13aS)-3a-((R)((4-Chlorobenzyl)(2- (dimethy/amino)ethy/)amino)- 1-hydroxyethy/)— 1-isopropy/-5a, 5b, 8, 8, 1 1a-pentamethyl- 2-oxo-3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyclopenta[a]chrysenyl)oxy)-3,3-dimethyloxopentanoic acid (62) and 5- (((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((S)((4-Chlorobenzyl)(2- (dimethy/amino)ethy/)amino)- 1-hydroxyethy/)— 1-isopropy/-5a, 5b, 8, 8, 1 1a-pentamethyl- 2-oxo-3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 10, 1 1, 1 1a, 1 1 b, 12, 13, 13a-octadecahydro-2H- cyclopenta[a]chrysenyl)oxy)-3,3-dimethyloxopentanoic acid (63) Step A: Compound 59 -(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-(2-((Tert-butoxycarbonyl) (4- chlorobenzyl)amino)acetyl)- 1-isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyloxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyclopenta[a]chrysenyl)oxy)—3, thyloxopentanoic acid ] To a on of tert-butyl 4-chlorobenzyl(2- 5aR,5bR,7aR,98,11aR,11bR,13aS)—9-hydroxy—1-isopropyl-5a,5b,8,8,11a- pentamethyloxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a- octadecahydro-2H-cyclopenta[a]chrysen-3a-yl)oxoethyl)carbamate (15) (1 g, 1.412 mmol), DMAP (0.517 g, 4.23 mmol) in pyridine (2ml) stirred at rt was added 4,4-dimethyl-dihydro-3H-pyran-2,6-dione (1.003 g, 7.06 mmol). The reaction mixture was stirred at 50 °C for 5 h. The mixture was diluted with EtOAc and washed with water. The resultant extract was purified by silica gel column to provide 59 (800 mg, 60%). 1H NMR (500MHz ,CHLOROFORM-d) 6 = 8.67 (br. s., 1 H), 7.98 - 7.36 (m, 1 H), 7.33 - 7.27 (m, 2 H), 7.21 - 7.09 (m, 2 H), 4.62 - 4.26 (m, 3 H), 4.07 - 3.42 (m, 2 H), 3.30 - 3.05 (m, 1 H), 2.66 - 0.66 (m, 61 H).
Step B: Compound 60 -(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-(2-((4-Chlorobenzyl)amino)acety/)isopropyl-5a, 5b, 8, 8, 1 tamethyl-Z-oxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyclopenta[a]chrysen-9—yl)oxy)-3, 3-dimethyloxopentanoic acid To a solution of aR,5aR,5bR,7aR,98,11aR,11bR,13aS)—3a-(2- ((tert—butoxycarbonyl)(4-chIorobenzyl)amino)acety|)isopropy|-5a,5b,8,8,11a- pentamethyIoxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a- octadecahydro-2H-cyclopenta[a]chryseny|)oxy)-3,3-dimethyIoxopentanoic acid (59) (800 mg, 0.941 mmol) in romethane (6 mL) stirred at rt was added trifluoroacetic acid (2 mL, 0.941 mmol). The reaction mixture was stirred at rt for 1h.
The mixture was ated to provide the target compound (600 mg, 81%) which was used without further purification. LC/MS: m/z calculated 749.4, found 750.1 (M+1)+.
Step C: Compound 61 -(((3aR,5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-(2-((4-Ch/orobenzy/)(2- (dimethylamino)ethyl)amino)acetyl)- 1-isopropy/-5a, 5b, 8, 8, 1 1a-pentamethyl-Z-oxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyclopenta[a]chrysen-9—yl)oxy)-3, 3-dimethyloxopentanoic acid To a solution of 5-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)—3a-(2- ((4-chlorobenzyl)amino)acetyl)isopropyl-5a,5b,8,8,11a-pentamethyl-2—oxo- 3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H- cyclopenta[a]chrysenyl)oxy)-3,3-dimethyloxopentanoic acid, trifluoroacetic acid salt (60) (700 mg, 0.810 mmol) in methanol (30 ml) was added 2- (dimethylamino)acetaldehyde (353 mg, 4.05 mmol) at 0°C. The pH was adjusted to 7 with Et3N. The reaction mixture was stirred at rt for 1h and sodium orohydride (50.9 mg, 0.810 mmol) was added and the resultant mixture was stirred overnight.
The reaction was diluted with water (40 ml) and extracted with DCM (60 ml x 3). The combined organic layer was washed with brine (20 ml), dried over sodium sulfate and filtered to afford crude product 5-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)—3a—(2- ((4-chlorobenzyl)(2-(dimethylamino)ethyl)amino)acetyl)isopropyl-5a,5b,8,8,11a- ethyloxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a- octadecahydro-2H-cyclopenta[a]chrysenyl)oxy)-3,3-dimethyloxopentanoic acid, trifluoroacetic acid salt (61) (200 mg, 23 % yield) as a light yellow solid. 1H NMR (500MHz ,METHANOL-d4) 5 = 7.39 (s, 4 H), 4.49 (dd, J = 5.7, 10.7 Hz, 1 H), 3.95 (d, J: 13.6 Hz, 1 H), 3.57 (d, J: 13.2 Hz, 1 H), 3.40 - 3.29 (m, 1 H), 3.27 - 3.16 (m, 2 H), 3.05 (s, 6 H), 3.00 - 2.88 (m, 2 H), 2.57 - 2.26 (m, 6 H), 2.09 (d, J = 19.5 Hz, 1 H), 2.04 - 0.75 (m, 47 H); LC/MS: m/z calculated 820.5, found 821.3 (M+1)+.
Step D: Compounds 62 and 63 -(((3aR,5aR,5bR, 7aR,9S, 1 1aR, 1 1bR,13aS)-3a-((R)-2—((4- Chlorobenzyl) ntyl)amino)- 1-hydroxyethyl)- 1-isopropyl-5a, 5b, 8, 8, 1 1a- pentamethyl0x0-3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0,1 1, 1 1 a, 1 1 b, 1 2, 13, 13a- octadecahydro-2H-cyclopenta[a]chrysenyl)oxy)-3, 3-dimethyloxopentanoic acid (62) and 5-(((3aR,5aR,5bR, 7aR,9S, 1 1aR, 1 aS)-3a-((S)-2—((4- benzyl)(isopentyl)amino)hydroxyethyl)- 1-isopropyl-5a, 5b, 8, 8, 1 1a- pentamethyl0x0-3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0,1 1, 1 1 a, 1 1 b, 1 2, 13, 13a- 1 45 octadecahydro-2H-cyclopenta[a]chrysenyl)oxy)-3, 3-dimethyloxopentanoic acid (63) To a solution of 5-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)—3a-(2- ((4-chlorobenzyl)(2-(dimethylamino)ethyl)amino)acetyl)—1-isopropyl-5a,5b,8,8,11a- pentamethyloxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a- octadecahydro-2H-cyclopenta[a]chrysenyl)oxy)-3,3-dimethyloxopentanoic acid, trifluoroacetic acid salt (61) (140mg, 0.133 mmol) in methanol (10 mL) stirred at 0 °C was added NaBH4 (10.09 mg, 0.267 mmol). The reaction mixture was stirred at 0°C for 1h, then more NaBH4 (10.09 mg, 0.267 mmol) was added. After an additional 1h at 0°C, the e was warmed to rt stirred for another 1 h. LCMS indicated the reaction was complete. EtOAc was added and the mixture was washed with water.
The orgnic phase was ated to give the crude which was purified by preparative-HPL to give two diastereomers. 5 mg of isomer A (62) was ed (3.5% yield) and 10 mg of isomer B (63) was ed (7%). The stereochemistry of the newly formed stereocenter in each isomer was assigned by spectral similarity to compounds 51 (analogous to 62) and 56 (analogous to 63). For isomer A (62); 1H NMR (500MHz ,METHANOL-d4) 6 = 7.48 - 7.30 (m, 4 H), 4.57 - 4.43 (m, 1 H), 4.14 (d, J: 10.1 Hz, 1 H), 3.91 -3.74 (m, 1 H), 3.67 (d, J: 13.9 Hz, 1 H), 3.26-3.10 (m, 2 H), 3.10 - 2.93 (m, 2 H), 2.93 - 2.81 (m, 6 H), 2.68 - 2.10 (m, 9 H), 2.06 - 0.65 (m, 46 H); LC/MS: m/z calculated 822.5, found 823.5 (M+1)+. For isomer B (63); 1H NMR (500MHz, METHANOL-d4) 6 = 7.43 (br. s., 4 H), 4.51 (dd, J = 5.8, 9.9 Hz, 1 H), 4.16 (d, J =10.1 Hz, 1 H), 3.98 - 3.75 (m, 2 H), 3.52 - 3.37 (m, 1 H), 3.31 - 3.02 (m, 3 H), 3.02 - 2.71 (m, 9 H), 2.64 - 2.34 (m, 6 H), 2.19 - 0.69 (m, 46 H); LC/MS: m/z calculated 822.5, found 823.4 .
Example 24: Compound 64 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((S)((2-Chlorobenzy/)amino)- 1- hydroxyethy/)- 1-isopropy/-5a, 5b, 8, 8, 1 1a-pentamethyIoxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyclopenta[a]chrysenyl)oxy)—2, 2-dimethyloxobutanoic acid The title compound was made in a similar manner to e 14.
Stereochemistry was ively ed as drawn but not fully confirmed spectroscopically. 1H NMR (400MHz, METHANOL-d4) 6 = 7.73 - 7.38 (m, 4 H), 4.65 - 4.37 (m, 4 H), 3.44 (d, J: 12.3 Hz, 1 H), 3.39 - 3.22 (m, 1 H), 3.11 - 2.96 (m, 2 H), 2.62 (q, J: 16.0 Hz, 2 H), 2.48 (d, J: 18.3 Hz, 1 H), 2.21 - 0.77 (m, 46 H); LC/MS: m/z calculated 737.4, found 738.3 (M+1)+.
Example 25: Compound 65 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((R)((2-ch/orobenzy/)amino) hydroxyethy/)- 1-isopropy/-5a, 5b, 8, 8, 1 1a-pentamethyIoxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyclopenta[a]chrysenyl)oxy)—2, 2-dimethyloxobutanoic acid The title compound was made in a similar manner to example 14.
Stereochemistry was tentatively ed as drawn but not fully confirmed spectroscopically. 1H NMR (400MHz, METHANOL-d4) 6 = 7.63 - 7.37 (m, 4 H), 4.55 - 4.31 (m, 4 H), 3.26 - 3.11 (m, 1 H), 3.01 - 2.46 (m, 6 H), 2.36 - 2.16 (m, 1 H), 2.15 - 0.79 (m, 45 H); LC/MS: m/z calculated 737.4, found 738.0 (M+1)+.
Example 26: Compound 66 4-(((3aR, 5aR, 5bR, 7aR, 98, 1 1aR, 1 1bR, 13aS)-3a-((S)Acetoxy((4- fluorobenzyl)amino)ethy/)isopropyI-5a, 5b, 8, 8, 1 1a-pentamethyloxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyclopenta[a]chrysenyl)oxy)-2, 2-dimethyl—4-oxobutanoic acid The title compound was made as a TFA salt in a similar manner to example 16. Stereochemistry was ively ed as drawn but not fully confirmed spectroscopically. 1H NMR (400MHz ,CHLOROFORM-d) 6 = 10.54 - 8.79 (m, 1 H), 7.50 - 7.34 (m, 2 H), 7.19 - 6.99 (m, 2 H), 5.81 (d, J = 9.8 Hz, 1 H), 4.49 (dd, J: 5.8, 10.3 Hz, 1 H), 4.31 - 3.93 (m, 2 H), 3.26 (d, J = 12.5 Hz, 1 H), 3.20 - 3.05 (m, WO 90664 1 H), 3.05 - 2.82 (m, 2 H), 2.80 - 2.47 (m, 2 H), 2.36 (d, J = 18.1 Hz, 1 H), 2.05 - 0.57 (m, 49 H); LC/MS: m/z calculated 763.5, found 764.3 (M+1)+.
Example 27: Compound 67 4-(((3aR, 5aR, 5bR, 7aR, 98, 1 1aR, 1 1bR, 13aS)-3a-((R)acetoxy((4- fluorobenzyl)amino)ethy/)isopropyI-5a, 5b, 8, 8, 1 1a-pentamethyloxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H— cyclopenta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid The title compound was made as a TFA salt in a r manner to example 16. Stereochemistry was tentatively assigned as drawn but not fully confirmed spectroscopically. 1H NMR (400MHz ,CHLOROFORM-d) 6 = 9.65 (br. s., 1 H), 7.46 - 7.28 (m, 2 H), 7.03 (t, J = 8.2 Hz, 2 H), 5.86 (br. s., 1 H), 4.50 (dd, J = .5, 10.3 Hz, 1 H), 4.29-4.06 (m, 1 H), 4.06- 3.85 (m, 1 H), 3.19-2.99 (m, 1 H), 2.81 - 2.39 (m, 6 H), 2.21 - 0.62 (m, 49 H); LC/MS: m/z calculated 763.5, found 764.3 (M+1)+.
PCT/US 12/69637 142013 PR64?75WO p H s2 "r¢»/‘Y\\ AN/\ ll- /\ ‘ t/J g H I ~ O., 2/5- - ~——a> , ; V A‘xo 3" NaBHscN :0 ° " Ho. k 68 . , x V 0 W JJ4/0 KOH. 5de PhMe La' fl 1‘ OH ..........u.—,'.
H‘OkréOLH 69 Examgle 28: Comgou nd 68 4«(((BaR, 551R, 5M, 7aR, 98, 116R, 11bR,13a8:)-~3a-((S)—T-acetoxy((4- chlorobenzyl)(methyl)amino)ethyl)—1Lisopropyl-5a, 5b, 8, 8, 1 ‘la-pentamethyl-E-oxov 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, -1 0, 11, 1 1 a, 1 7 b, 12,13, 13a-ocfadecahydro-2H- eye/opentafa]chrysen~9—yl)oxy)~2,2-din-rethyl-4~oxobutanoic acid 520 BB: HO\n//r\ To a solution 0)" aR.SaR,5bR,7'aR.QS,11a.R_,1‘1bR',1-SaS)~.Ba‘((S)« 1~acetoxy—2—((4-chlorobenzyl)amino)ethyI)—1—isopr0pyl-53,5b,8,8,11a-pentamethy!~2— oxo~3,3a,4.5,5a.5b.6,7,7a,8.9,10,11 ,11a,11b,12,13,13a-octadecahydro—2H— enta[a]chrysen-9~yl)oxy)—2.2—dimethyl~4--oxobutanoic acid (50) (150 mg, 0.192 AMENDED SHEET - IPEA/US mmol) in MeOH (6 mL) stirred in air at rt was added formaldehyde (31.2 mg, 0.384 mmol). The reaction mixture was stirred at rt for 2 h. Then it was added NaCNBH3 (85 mg, 1.345 mmol) portionwise and stirred for overnight. The solvent was evaporated and the the e diluted with DCM and washed with water and brine.
The dried organics were filtered and concentrated to give 4- (((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)—3a-((S)—1-acetoxy((4- chlorobenzyl)(methyl)amino)ethyl)—1-isopropyl-5a,5b,8,8,11a-pentamethyloxo- 3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H- cyclopenta[a]chrysenyl)oxy)-2,2-dimethyloxobutanoic acid (68) (120 mg, 65% yield) as a white solid. This material was used without further purification. 1H NMR z ,CHLOROFORM-d) 6 = 7.31 - 7.26 (m, 2 H), 7.24 - 7.16 (m, 2 H), 5.65 (d, J = 8.5 Hz, 1 H), 4.50 (br. s., 1 H), 3.66 - 3.51 (m, 1 H), 3.49 - 3.36 (m, 1 H), 3.27 - 3.06 (m, 2 H), 2.73 - 2.32 (m, 5 H), 2.26 (s, 3 H), 2.08 - 0.73 (m, 49 H); LC/MS: m/z calculated 793.5, found 794.3 .
Example 29: Compound 69 4-(((3aR, 5aR, 5bR, 7aR, 98, 1 1aR, 1 1bR,13aS)—3a-((S)—2—((4- Chlorobenzyl)(methyl)amino)hydroxyethyl)- 1-isopropyl—5a, 5b, 8, 8, 1 1a- pentamethyl0X0-3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0,1 1, 1 1 a, 1 1 b, 1 2, 13, 13a- octadecahydro-2H-cyclopenta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid To a solution of 4-(((3aR,5aR,5bR,7aR,98,11aR,11bR,13aS)—3a-((S)— 1-acetoxy((4-chlorobenzyl)(methyl)amino)ethyl)isopropyl-5a,5b,8,8,11a- ethyloxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a- octadecahydro-2H-cyclopenta[a]chrysenyl)oxy)-2,2-dimethyloxobutanoic acid (68) (120 mg, 0.151 mmol) in ethanol (2 mL) and toluene (2 mL) was added potassium hydroxide (15.25 mg, 0.272 mmol). The reaction mixture was stirred at rt for 30 min. The reaction mixture was neutralized with s 1N HCI to pH=7 and evaporated to obtain the e. This was extracted with DCM, washed with water and dried to yield the crude product which was purified by preparative-HPLC to afford 4-(((3aR,5aR,5bR,7aR,98,11aR,11bR,13aS)—3a-((S)—2-((4- chlorobenzyl)(methyl)amino)hydroxyethyl)isopropyl-5a,5b,8,8,11a-pentamethyl- 2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H- cyclopenta[a]chrysenyl)oxy)-2,2-dimethyloxobutanoic acid as a trifluoroacetate salt (95 mg, 72 % yield) as a white solid. 1H NMR (400MHz ,METHANOL-d4) 6 = 7.55 (s, 4 H), 4.60 - 4.12 (m, 3 H), 3.32 - 3.19 (m, 1 H), 3.18 - 2.84 (m, 5 H), 2.71 - 2.52 (m, 2 H), 2.11 - 0.78 (m, 49 H); LC/MS: m/z calculated 751.5, found 752.4 (M+1)+.
Example 30: Compound 70 4-(((3aR, 5aR, 5bR, 7aR, 98, 1 1aR, 1 1bR, 3a-((R)Acetoxy((4- chlorobenzyl) (methy/)amino)ethy/)isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyl—2—oxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyclopenta[a]chrysenyl)oxy)-2, 2-dimethyl—4-oxobutanoic acid The title compound was made in similar manner to example 28. 1H NMR (400MHz ,CHLOROFORM-d) 6 = 7.31 - 7.23 (m, 2 H), 7.22 - 7.13 (m, 2 H), .66 (dd, J: 2.4, 8.7 Hz, 1 H), 4.55 - 4.43 (m, 1 H), 3.51 - 3.35 (m, 2 H), 3.19 - 3.05 (m, 1 H), 2.74 - 2.42 (m, 5 H), 2.42 - 0.66 (m, 53 H); LC/MS: m/z calculated 793.5, found 794.5 (M+1)+.
Example 31: Compound 71 4-(((3aR,5aR,5bR, 7aR,98, 1 1aR, 1 1bR,13aS)-3a-((R)-2—((4- Chlorobenzyl)(methyl)amino)hydroxyethyl)- ropyl—5a, 5b, 8, 8, 1 1a- pentamethyl0x0-3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0,1 1, 1 1 a, 1 1 b, 1 2, 13, 13a- cahydro-2H-cyclopenta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid The title compound was made in similar manner to example 29. 1H NMR (500MHz ,METHANOL-d4) 6 = 7.63 - 7.38 (m, 4 H), 4.56 - 4.25 (m, 4 H), 3.25 - 3.14 (m, 1 H), 2.99 (s, 3 H), 2.82 - 2.52 (m, 4 H), 2.52 - 2.32 (m, 2 H), 2.24 (d, J: 12.9 Hz, 1 H), 2.09 - 0.77 (m, 45 H); LC/MS: m/z calculated 751.5, found 752.3 (M+1)+.
KOH, EtOH PhMe Examgle 32: Coonund 72 4-(((3aR, 5aR, 5bR, 7aR, 98, 1 1aR, 1 1bR, 13aS)-3a-((S)- 1-Acetoxy(N-(4- chlorobenzyl)acetamido)ethyl)- 1-isopropyl-5a, 5b, 8, 8, 1 1a—pentamethyl-Z-oxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyclopenta[a]chrysenyl)oxy)—2, 2-dimethyl—4-oxobutanoic acid ] A mixture of aR,5aR,5bR,7aR,98,1 1aR,1 1bR,13aS)—3a-((S)—1- acetoxy((4-chlorobenzyl)amino)ethyl)—1-isopropy|—5a,5b,8,8,11a-pentamethyI oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H- cyclopenta[a]chrysen-Q-yl)oxy)-2,2—dimethyIoxobutanoic acid (50) (200 mg, 0.256 mmol), TEA (0.332 mL, 2.56 mmol), DMAP (6.3 mg, 0.05 mmol) and in DCM ( 5ml) was stirred for 3 h. The e was quenched with water (50ml), washed with water ( 2x50ml), dried over Na2804, filtered and concentrated in vacuo to afford 4- (((3aR,5aR,5bR,7aR,98,11aR,11bR,13aS)—3a-((S)—1-acetoxy(N-(4- chlorobenzyl)acetamido)ethyl)—1-isopropyl-5a,5b,8,8,11a-pentamethyloxo- 3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H- cyclopenta[a]chrysenyl)oxy)-2,2-dimethyloxobutanoic acid (72) (160 mg, 0.182 mmol, 71.0 % yield) as a white solid. 1H NMR (400MHz ,CHLOROFORM-d) 6 = 7.42 - 7.24 (m, 2 H), 7.24 - 6.90 (m, 2 H), 5.98 - 5.68 (m, 1 H), 5.15 - 4.56 (m, 1 H), 4.56 - 4.45 (m, 1 H), 4.40 - 3.98 (m, 2 H), 2.29 - 0.68 (m, 66 H), 3.48 - 0.58 (m, 58 H); LC/MS: m/z calculated 821.5, found 822.3 (M+1)+.
Example 33: Compound 73 4-(((3aR,5aR,5bR, 7aR,98, 1 1aR, 1 1bR,13aS)-3a-((S)(N-(4- Chlorobenzyl)acetamido)- 1-hydroxyethyl)— 1-isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyl-Z- oxo-3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyclopenta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid To a solution of aR,5aR,5bR,7aR,98,11aR,11bR,13aS)—3a-((S)— 1-acetoxy(N-(4-chlorobenzyl)acetamido)ethyl)—1-isopropyl-5a,5b,8,8,11a- pentamethyloxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a- octadecahydro-2H-cyclopenta[a]chrysenyl)oxy)-2,2-dimethyloxobutanoic acid (72) (150 mg, 0.182 mmol) in ethanol (2 mL) and toluene (2 mL) was added potassium hydroxide (40.9 mg, 0.729 mmol). The reaction mixture was stirred at rt for min. The reaction mixture was neutralized with aqueous 1 N HCI to pH=7 and concentrated to obtain a residue. The residue was ted with DCM, washed with water and dried to yield the crude product which was purified by preparative-HPLC to afford 4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)—3a-((S)—2-(N-(4- chlorobenzyl)acetamido)hydroxyethyl)isopropyl-5a,5b,8,8,11a-pentamethyl oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H- cyclopenta[a]chrysenyl)oxy)-2,2—dimethyloxobutanoic acid (73) (40 mg, 28%) as a white solid. Compound exists as a mixture of rotomers; 1H NMR (400MHz ,DMSO-ds) 6 = 12.18 (br. s., 1 H), 7.52 - 7.14 (m, 4 H), 5.03 - 3.77 (m, 5 H), 3.39 - 2.80 (m, 3 H), 2.62 - 2.54 (m, 1 H), 2.27 (t, J = 17.2 Hz, 1 H), 2.20 - 0.58 (m, 51 H); LC/MS: m/z ated 779.5, found 802.3 (M+Na)+.
Example 34: Compound 74 4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)—3a-((R)(N-(4- Chlorobenzyl)acetamido)hydroxyethyl)isopropyl-5a,5b,8,8,11a-pentamethyl 3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H- cyclopenta[a]chrysenyl)oxy)-2,2-dimethyloxobutanoic acid A mixture of 4-(((3aR,5aR,5bR,7aR,98,1 1aR,1 1bR,13aS)—3a-((R)—1- acetoxy((4-chlorobenzyl)amino)ethy|)isopropy|—5a,5b,8,8,11a-pentamethyI oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H- cyclopenta[a]chrysenyl)oxy)-2,2-dimethyIoxobutanoic acid (49) (150 mg, 0.192 mmol), Na2C03 (20.37 mg, 0.192 mmol), in ol (3 mL) was stirred for 3 h, then purified by ative-HPLC to afford 4-(((3aR,5aR,5bR,7aR,98,11aR,11bR,13aS)— 3a-((R)—2-(N-(4-ch|orobenzy|)acetamido)—1-hydroxyethy|)isopropyI-5a,5b,8,8,1 1a- pentamethyIoxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a- octadecahydro-2H-cyclopenta[a]chryseny|)oxy)-2,2-dimethyIoxobutanoic acid (74) (45 mg, 30%) as a white solid. Compound exists as a mixture of rotomers; 1H NMR (500MHz ,METHANOL-d4) 5 = 7.43 - 7.27 (m, 2 H), 7.28 - 7.11 (m, 2 H), 5.30 - 4.09 (m, 6 H), 3.55 - 2.09 (m, 11 H), 2.09 - 0.78 (m, 44 H); LC/MS: m/z calculated 779.5, found 780.4 (M+1)+.
Example 35: Compound 76 4-(((3aR,5aR,5bR, 7aR,98, 1 1aR, 1 aS)-3a-((S)(N-(2— Chlorobenzyl)acetamido)- 1-hydroxyethyl)- 1-isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyl-Z- oxo-3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H— cyclopenta[a]chrysenyl)oxy)-2, 2-dimethyl—4-oxobutanoic acid To a solution of 4-((3aR,5aR,5bR,7aR,98,11aR,11bR,13aS)—3a-((S)— 1-acetoxy—2—((tert-butoxycarbonyl)(2—chlorobenzyl)amino)ethyl)isopropyl- 5a,5b,8,8,11a-pentamethyloxo- 3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H- cyclopenta[a]chrysenyl) 1-tert-butyl 2,2—dimethylsuccinate (75, made in a similar manner to compound 48) (100 mg, 0.107 mmol) in DCM (30 mL) stirred at rt was added TFA (15 mL, 195 mmol). The reaction mixture was d at rt until LCMS and TLC indicated SM disappeared. The solvent was removed to give the crude product purified by preparative HPLC to give 4- (((3aR,5aR,5bR,7aR,98,11aR,11bR,13aS)-3a-((S)(N-(2—chlorobenzyl)acetamido)- oxyethyl)isopropyl-5a,5b,8,8,11a-pentamethyl-2—oxo- 3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H- cyclopenta[a]chrysenyl)oxy)—2,2—dimethyloxobutanoic acid (40 mg, 48%).
Stereochemistry was tentatively assigned as drawn, but not fully med spectroscopically. The compound exists as a mixture of rotomers. 1H NMR (400MHz ,METHANOL-d4) 6 = 7.55 - 7.14 (m, 4 H), 5.10 - 4.72 (m, 2 H), 4.72 - 3.97 (m, 3 H), 3.54- 3.39 (m, 1 H), 3.30—3.21 (m, 1 H), 3.13-2.97 (m, 1 H), 2.84-0.69 (m, 53 H); LC/MS: m/z calculated 779.5, found 780.3 (M+1)+.
Example 36: Compound 77 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((S)- 1-Acetoxy((2- chlorobenzyl) (2-(dimethylamino)ethyl)amino)ethyl)- 1-isopropyl—5a, 5b, 8, 8, 1 1a- pentamethyl0X0-3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0,1 1, 1 1 a, 1 1 b, 1 2, 13, 13a- cahydro-2H-cyclopenta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid The title compound was made in a similar manner to e 20.
Stereochemistry was tentatively assigned as drawn but not fully confirmed spectroscopically. 1H NMR (400MHz ,CHLOROFORM-d) 6 = 7.64 - 7.06 (m, 4 H), .61 (d, J: 8.8 Hz, 1 H), 4.50 (dd, J: 5.4, 10.7 Hz, 1 H), 3.82 (d, J = 13.8 Hz, 1 H), 3.65 (d, J: 13.6 Hz, 1 H), 3.26 - 2.92 (m, 7 H), 2.89 - 2.74 (m, 7 H), 2.74 - 2.53 (m, 3 H), 2.26 (d, J = 18.3 Hz, 1 H), 1.93 - 0.67 (m, 48 H); LC/MS: m/z ated 850.5, found 851.4 (M+1)+.
Example 37: Compound 78 4-(((3aR, 5aR, 5bR, 7aR, 98, 1 1aR, 1 1bR, 13aS)-3a-((S)((3-Chlorobenzy/)amino)- 1- hydroxyethyl) - 1-isopropy/-5a, 5b, 8, 8, 1 1a-pentamethyIoxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H— cyclopenta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid The title compound was made in a similar manner to e 20 as a TFA salt. Stereochemistry was tentatively ed as drawn but not fully confirmed spectroscopically. 1H NMR (400MHz ,METHANOL-d4) 5 = 7.61 (s, 1 H), 7.56 - 7.43 (m, 3 H), 4.57 - 4.44 (m, 2 H), 4.35 - 4.21 (m, 2 H), 3.38 (dd, J = 2.5, 12.5 Hz, 1 H), 3.31 - 3.23 (m, 1 H), 3.09-3.01 (m, 1 H), 2.96 (t, J: 11.8 Hz, 1 H), 2.71 -2.51 (m, 1 H), 2.46 (d, J = 18.3 Hz, 1 H), 2.15 - 0.79 (m, 48 H); LC/MS: m/z calculated 737.4, found 738.3 (M+1)+.
Example 38: Compound 79 4-(((3aR,5aR,5bR, 7aR,9S, 1 1aR, 1 aS)-3a-((R)((3-Ch/orobenzyl)amino)- 1- hydroxyethy/)- 1-isopropy/-5a, 5b, 8, 8, 1 1a-pentamethyIoxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H— cyclopenta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid The title compound was made in a similar manner to example 20 as a TFA salt. chemistry was tentatively assigned as drawn but not fully confirmed spectroscopically. 1H NMR (400MHz ,METHANOL-d4) 6 = 7.77 - 7.28 (m, 4 H), 4.68 - 4.15 (m, 4 H), 3.27 - 3.11 (m, 1 H), 2.73 - 2.48 (m, 5 H), 2.38 - 2.17 (m, 1 H), 2.16 - 0.71 (m, 4 H); LC/MS: m/z calculated 737.4, found 738.4 .
Example 39: Compound 80 4-(((3aR, 5aR, 5bR, 7aR, 98, 1 1aR, 1 1bR, 13aS)-3a-((S)- 1-Acetoxy-2—((3— chlorobenzy/)amino)ethyl)- 1-isopropy/-5a, 5b, 8, 8, 1 1a-pentamethyIoxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H— cyclopenta[a]chrysen-9—yl)oxy)-2, 2-dimethyl—4-oxobutanoic acid The title compound was made in a similar manner to e 16 as a TFA salt. Stereochemistry was tentatively assigned as drawn, but not fully confirmed oscopically. 1H NMR (500MHz ,CHLOROFORM-d) 6 = 7.43 (s, 1 H), 7.42 - 7.32 (m, 3 H), 5.81 (d, J = 10.1 Hz, 1 H), 4.49 (dd, J = 5.5, 10.2 Hz, 1 H), 4.24 (d, J = 13.2 Hz, 1 H), 4.13 - 3.96 (m, 1 H), 3.34 - 3.04 (m, 2 H), 3.05 - 2.82 (m, 2 H), 2.75 - 2.62 (m, 1 H), 2.62 - 2.52 (m, 1 H), 2.37 (d, J: 18.0 Hz, 1 H), 1.93 (s, 3 H), 1.90 - 0.65 (m, 47 H); LC/MS: m/z calculated 779.5, found 780.3 (M+1)+.
Example 40: Compound 81 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((R)Acetoxy((3- chlorobenzyl)amino)ethyl)- 1-isopropy/-5a, 5b, 8, 8, 1 1a-pentamethyIoxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyclopenta[a]chrysenyl)oxy)—2, thyloxobutanoic acid The title compound was made in a similar manner to Example 16 as a TFA salt. Stereochemistry was ively assigned as drawn but not fully confirmed spectroscopically. 1H NMR (500MHz ,CHLOROFORM-d) 6 = 9.77 (br. s., 1 H), 7.50 - 7.09 (m, 4 H), 5.87 (br. s., 1 H), 4.57 - 4.44 (m, 1 H), 4.12 (d, J: 1.6 Hz, 1 H), 3.96 (d, J = 13.2 Hz, 1 H), 3.23 - 3.00 (m, 1 H), 2.86 - 2.37 (m, 5 H), 2.20 - 0.66 (m, 50 H); LC/MS: m/z calculated 779.5, found 780.2 .
Example 41: Compound 82 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((S)acetoxy—2-((3- chlorobenzyl) (2-(dimethylamino)ethyl)amino)ethyl)- 1-isopropyl—5a, 5b, 8, 8, 1 1a- pentamethyloxo-3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0,1 1, 1 1 a, 1 1 b, 1 2, 13, 13a- octadecahydro-2H-cyclopenta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid WO 90664 The title nd was made in a similar manner to Example 18 as a TFA salt. To a solution of 2-(dimethylamino)acetaldehyde (553 mg, 4.47 mmol) in methanol (10 ml), was added 4—(((3aR,5aR,5bR,7aR,98,11aR,11bR,13aS)—3a-((S)—1- acetoxy((3-ch|orobenzy|)amino)ethy|)isopropy|—5a,5b,8,8,11a-pentamethyI oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H- cyclopenta[a]chryseny|)oxy)-2,2-dimethyIoxobutanoic acid, trifluoroacetic acid salt (80) (400 mg, 0.447 mmol). The reaction mixture was stirred at 40 0C for 2h. The reaction was cooled to rt and NaBH3CN (281 mg, 4.47 mmol) was added. The mixture and stirred overnight. Then concentrated in vacuo and purified by ative-HPLC to afford 4-(((3aR,5aR,5bR,7aR,98,11aR,11bR,13aS)—3a-((S)—1- acetoxy((3-chlorobenzyl)(2-(dimethylamino)ethyl)amino)ethyl)—1-isopropyl- 5a,5b,8,8,11a-pentamethyIoxo- 3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H- cyclopenta[a]chrysenyl)oxy)-2,2—dimethyIoxobutanoic acid (82) (80mg, 20%) as a light yellow solid. Stereochemistry was tentatively assigned as drawn but not fully confirmed spectroscopically. LC/MS: m/z calculated 850.5, found 851.5 (M+1)+.
Exam le 42 and 43: Com ound 83 and 84 aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((R)acetoxy—2-((3- chlorobenzyl) (2-(dimethylamino)ethyl)amino)ethyl)— 1-isopropyl—5a, 5b, 8, 8, 1 1a- pentamethyl0X0-3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0,1 1, 1 1 a, 1 1 b, 1 2, 13, 13a- octadecahydro-2H-cyclopenta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid (83) and 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR,13aS)-3a-((R)((3- chlorobenzyl)(ethy/)amino)hydroxyethyl)isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyl oxo-3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyclopenta[a]chrysenyl)oxy)-2,2—dimethyl—4-oxobutanoic acid (84) To a solution of 2-(dimethylamino)acetaldehyde, hydrochloride (553 mg, 4.47 mmol) in methanol (10 ml) was added (3aR,5aR,5bR,7aR,98,11aR,11bR,13aS)—3a-(2-(4-chlorobenzylamino)acetyl)—9- hydroxyisopropyl-5a,5b,8,8,11a-pentamethyl- ,5a,6,7,7a,8,9,10,11,11a,11b,12,13,13a-hexadecahydro—3H- cyclopenta[a]chrysen-2(5bH)-one (81) (15g, 24.66 mmol). The reaction mixture was stirred at 40 0C for 2h. The reaction was cooled to rt and sodium orohydride (7.75 g, 123 mmol) was added and the resultant mixture was stirred ght. The reaction was diluted with ammonium chloride solution (40 ml), and extracted with DCM (60 ml x 3). The combined organic layer was washed with brine (20 ml), dried over sodium sulfate, filtered and concentrated in vacuo to afford crude product which was purified by preparative-HPLC to give 4- (((3aR,5aR,5bR,7aR,98,11aR,11bR,13aS)—3a-((R)—1-acetoxy((3-chlorobenzyl)(2- (dimethylamino)ethy|)amino)ethy|)isopropy|-5a,5b,8,8,11a-pentamethyloxo- 3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H- cyclopenta[a]chrysenyl)oxy)-2,2-dimethyloxobutanoic acid (83) (80 mg, 20%) and 4-(((3aR,5aR,5bR,7aR,98,11aR,11bR,13aS)—3a-((R)—2-((3- chlorobenzyl)(ethyl)amino)hydroxyethy|)isopropy|-5a,5b,8,8,11a-pentamethyl oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H- enta[a]chrysenyl)oxy)-2,2-dimethyloxobutanoic acid (84) (14 mg, 3%) as their respective TFA salts. chemistry was tentatively assigned as drawn but not fully confirmed spectroscopically. For 83; 1H NMR (500MHz ,CHLOROFORM-d) 6 = 7.25 - 7.10 (m, 3 H), 7.04 (d, J = 3.8 Hz, 1 H), 5.57 (d, J = 9.1 Hz, 1 H), 4.42 (dd, J: 5.0,10.7 Hz, 1 H), 3.72 (d, J: 13.9 Hz, 1 H), 3.42 (d, J = 14.2 Hz, 1 H), 3.16 - 2.90 (m, 8 H), 2.90 - 2.79 (m, 1 H), 2.79 - 2.85 (m, 7 H), 2.85 - 2.41 (m, 3 H), 2.22 (d, J = 18.3 Hz, 1 H), 1.89 (s, 3 H), 1.84 - 0.82 (m, 45 H); LC/MS: m/z calculated 850.5, found 851.4 (M+1)+. For 84; 1H NMR (400MHz ,METHANOL-d4) = 7.85 (s, 1 H), 7.82 - 7.48 (m, 3 H), 4.58 - 4.28 (m, 4 H), 3.49 - 3.38 (m, 1 H), 3.31 - 3.23 (m, 2 H), 3.13 - 2.91 (m, 2 H), 2.62 (q, J: 15.9 Hz, 2 H), 2.10 - 0.76 (m, 51 H); LC/MS: m/z calculated 765.5, found 766.5 (M+1)+.
Example 44: Compound 85 4-(((3aR, 5aR, 5bR, 7aR, 98, 1 1aR, 1 1bR, 13aS)-3a-((S)((3-Chlorobenzyl) (2- (dimethy/amino)ethy/)amino)- 1-hydroxyethy/)- 1-isopropy/-5a, 5b, 8, 8, 1 1a-pentamethyl- 2-oxo-3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 10, 1 1, 1 1a, 1 1 b, 12, 13, 13a-octadecahydro-2H- cyclopenta[a]chrysenyl)oxy)-2, 2-dimethyl—4-oxobutanoic acid The title compound was made in a similar manner to Example 33.
Stereochemistry was ively assigned as drawn but not fully confirmed spectroscopically. 1H NMR (400MHz ,METHANOL-d4) 6 = 7.57 - 7.31 (m, 4 H), 4.50 (dd, J: 5.0, 11.0 Hz, 1 H), 4.28 (br. s., 1 H), 4.02 - 3.69 (m, 2 H), 3.53 - 3.36 (m, 1 H), 3.32 - 3.07 (m, 4 H), 3.08 - 2.85 (m, 2 H), 2.78 (s, 6 H), 2.73 - 2.51 (m, 3 H), 2.45 (d, J = 18.3 Hz, 1 H), 2.13 - 0.75 (m, 46 H); LC/MS: m/z calculated 808.5, found 809.5 (M+1)+.
Example 45: Compound 86 aR, 5aR, 5bR, 7aR, 98, 1 1aR, 1 1bR, 3a-((R)((3-Chlorobenzyl)(2- (dimethy/amino)ethy/)amino)- 1-hydroxyethyl) - 1-isopropy/-5a, 5b, 8, 8, 1 1a-pentamethyl- 2-oxo-3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 10, 1 1, 1 1a, 1 1 b, 12, 13, 13a-octadecahydro-2H— cyclopenta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid The title nd was made in a similar manner to example 33.
Stereochemistry was tentatively assigned as drawn but not fully confirmed spectroscopically. 1H NMR z ,METHANOL-d4) 6 = 7.46 - 7.23 (m, 4 H), 4.49 (dd, J: 51,109 Hz, 1 H), 4.19 (d, J: 10.0 Hz, 1 H), 3.95 - 3.78 (m, 1 H), 3.78 - 3.66 (m, 1 H), 3.41 - 3.33 (m, 1 H), 3.27 - 3.00 (m, 3 H), 2.87 (s, 6 H), 2.70 - 2.50 (m, 3 H), 2.37 (br. s., 1 H), 2.34 - 2.16 (m, 3 H), 2.08 - 0.82 (m, 46 H); LC/MS: m/z ated 808.5, found 809.5 (M+1)+.
Example 46: Compound 87 4-(((3aR,5aR,5bR, 7aR,9S, 1 1aR, 1 1bR,13aS)-3a-((R)(N-(3— chlorobenzyl)acetamido)- 1-hydroxyethy/)- 1-isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyl-Z- oxo-3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H— cyclopenta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid The title compound was made in a similar manner to example 33 from compound 81. Stereochemistry was tentatively assigned as drawn but not fully confirmed spectroscopically. The compound exists as a mixture of rotomers. 1H NMR (400MHz ,METHANOL-d4) 6 = 7.42 - 7.04 (m, 4 H), 5.42 - 3.97 (m, 3 H), 3.55 - 3.00 (m, 3 H), 2.82 - 0.79 (m, 53 H); LC/MS: m/z calculated 779.5, found 780.3 (M+1)+.
Example 47: Compound 88 aR,5aR,5bR, 7aR,98, 1 1aR, 1 1bR,13aS)-3a-((S)—2—(N-(3- benzyl)acetamido)- 1-hydroxyethyl)- 1-isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyl-Z- oxo-3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyclopenta[a]chrysenyl)oxy)-2, 2-dimethyl—4-oxobutanoic acid The title compound was made in a similar manner to e 33 from compound 80. Stereochemistry was tentatively assigned as drawn but not fully confirmed oscopically. 1H NMR (400MHz ,METHANOL-d4) 6 = 7.36 - 6.99 (m, 4 H), 4.89 - 3.88 (m, 4 H), 3.39 - 2.83 (m, 3 H), 2.73 - 0.66 (m, 53 H); LC/MS: m/z calculated 779.5, found 780.3 (M+1)? Example 48 and 49 Compounds 89 and 90 aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((R)acetoxy((2- chlorobenzyl) (2-(dimethylamino)ethyl)amino)ethyl)- 1-isopropyl—5a, 5b, 8, 8, 1 1a- pentamethyl0X0-3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0,1 1, 1 1 a, 1 1 b, 1 2, 13, 13a- octadecahydro-2H-cyclopenta[a]chrysenyl)oxy)-2, 2—dimethyloxobutanoic acid (89) and 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 aS)-3a-((R)((2- chlorobenzyl)(ethy/)amino)hydroxyethyl)isopropyI-5a, 5b, 8, 8, 1 1a-pentamethyI oxo-3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H— cyclopenta[a]chrysenyl)oxy)-2,2—dimethyloxobutanoic acid (90) The title compounds were made in a similar manner to examples 42 and 43. Stereochemistry was tentatively assigned as drawn but not fully confirmed spectroscopically. For 89; 1H NMR (400MHz ,CHLOROFORM-d) 6 = 7.42 - 7.18 (m, 4 H), 5.70-5.56 (m, 1 H), 4.57-4.42 (m, 1 H), 3.83-3.51 (m, 2 H), 3.21 -2.85 (m, 3 H), 2.79 (s, 6 H), 2.74 - 2.54 (m, 3 H), 2.54 - 2.23 (m, 4 H), 2.15 - 0.65 (m, 50 H); LC/MS: m/z ated 850.5, found 851.4 (M+1)+. For 90; 1H NMR (400MHz ,METHANOL-d4) 5 = 7.77 - 7.43 (m, 4 H), 4.69 - 4.27 (m, 4 H), 3.62 - 3.37 (m, 2 H), 3.26 - 3.10 (m, 1 H), 2.97 - 2.82 (m, 1 H), 2.61 (q, J: 16.0 Hz, 2 H), 2.27 - 2.10 (m, 1 H), 2.10 - 0.77 (m, 51 H); LC/MS: m/z calculated 765.5, found 766.3 (M+1)+.
Example 50: Compound 91 4-(((3aR, 5aR, 5bR, 7aR, 9s, 1 1aR, 1 1bR, 13aS)-3a-((R)((2-chlorobenzyl)(2- (dimethy/amino)ethy/)amino)- 1-hydroxyethyl) - 1-isopropy/-5a, 5b, 8, 8, 1 1a-pentamethyl- 1 69 2-oxo-3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 10, 1 1, 1 1a, 1 1 b, 12, 13, tadecahydro-2H— cyclopenta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid The title compound was made in a similar manner to Example 33.
Stereochemistry was tentatively assigned as drawn but not fully med spectroscopically. 1H NMR (400MHz 6 = 7.55 - 7.42 (m, 2 H), 7.42 , METHANOL-d4) - 7.32 (m, 2 H), 4.49 (dd, J = 5.5, 11.0 Hz, 1 H), 4.43 - 4.30 (m, 1 H), 4.00 - 3.89 (m, 1 H), 3.87 - 3.76 (m, 1 H), 3.42 - 3.34 (m, 1 H), 3.24 - 2.91 (m, 3 H), 2.91 - 2.51 (m, H), 2.52 - 2.17 (m, 4 H), 2.11 - 1.84 (m, 2 H), 1.84 - 0.78 (m, 44 H); LC/MS: m/z calculated 808.5, found 809.4 (M+1)+.
Example 51: Compound 92 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 3a-((S)((2-chlorobenzy/) (2- (dimethy/amino)ethy/)amino)- 1-hydroxyethy/)- 1-isopropy/-5a, 5b, 8, 8, 1 1a-pentamethyl- 2-oxo-3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 10, 1 1, 1 1a, 1 1 b, 12, 13, 13a-octadecahydro-2H— cyclopenta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid WO 90664 The title compound was made in a similar manner to Example 33.
Stereochemistry was tentatively assigned as drawn but not fully confirmed spectroscopically. 1H NMR (400MHz ,METHANOL-d4) 6 = 7.57 - 7.45 (m, 2 H), 7.39 (dd, J: 3.6, 5.6 Hz, 2 H), 4.56 - 4.40 (m, 2 H), 4.02 (d, J: 12.8 Hz, 1 H), 3.81 (d, J: 12.8 Hz, 1 H), 3.46 - 3.23 (m, 2 H), 3.13 - 2.89 (m, 4 H), 2.81 - 2.41 (m, 10 H), 2.15 - 1.91 (m, 3 H), 1.89 - 0.82 (m, 44 H); LC/MS: m/z calculated 808.5, found 809.5 (M+1)+.
Example 52: Compound 93 4-(((3aR, 5aR, 5bR, 7aR, 98, 1 1aR, 1 1bR, 3a-((R)Acetoxy (benzy/amino)ethyl)- 1-isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyloxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyclopenta[a]chrysenyl)oxy)-2, 2-dimethyl—4-oxobutanoic acid The title compound was made as a TFA salt in a similar manner to e 16. Stereochemistry was tentatively assigned as drawn but not fully confirmed spectroscopically. 1H NMR (500MHz ,DMSO-de) 6 = 12.17 (br. s., 1 H), 9.49 (br. s., 1 H), 9.19 (br. s., 1 H), 7.66 - 7.28 (m, 5 H), 5.86 - 5.53 (m, 1 H), 4.49 - 3.97 (m, 3 H), 3.16 - 2.84 (m, 2 H), 2.68 - 2.55 (m, 1 H), 2.55 - 2.47 (m, 2 H), 2.41 (d, J: 19.5 Hz, 1 H), 2.11 (s, 3 H), 2.04 - 0.67 (m, 47 H); LC/MS: m/z calculated 745.5, found 746.5 (M+1)+.
Example 53: Compound 94 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((S)Acetoxy (benzy/amino)ethyl)- 1-isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyloxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H— cyclopenta[a]chrysenyl)oxy)-2, 2-dimethyl—4-oxobutanoic acid The title compound was made as a TFA salt in a similar manner to Example 16. Stereochemistry was tentatively assigned as drawn but not fully confirmed spectroscopically. 1H NMR (500MHz OFORM-d) 6 = 7.41 (br. s., 5 H), 5.81 (d, J: 10.1 Hz, 1 H), 4.48 (dd, J: 5.5, 10.2 Hz, 1 H), 4.25 (d, J: 13.2 Hz, 1 H), 4.06 (d, J = 13.2 Hz, 1 H), 3.27 (d, J = 12.3 Hz, 1 H), 3.14 (dt, J = 6.8, 13.6 Hz, 1 H), 3.08 - 2.85 (m, 2 H), 2.74 - 2.62 (m, 1 H), 2.62 - 2.54 (m, 1 H), 2.36 (d, J = 18.0 Hz, 1 H), 1.99 - 0.63 (m, 49 H); LC/MS: m/z calculated 745.5, found 746.5 .
Example 54: Compound 95 aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((R)((3-Chloro fluorobenzy/)amino)- 1-hydroxyethy/)- 1-isopropy/-5a, 5b, 8, 8, 1 1a-pentamethyIoxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H— cyclopenta[a]chrysenyl)oxy)-2, 2-dimethyl—4-oxobutanoic acid The title compound was made as a TFA salt in a similar manner to Example 14. Stereochemistry was tentatively assigned as drawn but not fully confirmed spectroscopically. LC/MS: m/z calculated 755.4, found 756.3 (M+1)+.
Example 55: Compound 96 4-(((3aR, 5aR, 5bR, 7aR, 98, 1 1aR, 1 1bR, 13aS)-3a-((S)((3-ch/oro-2— fluorobenzyl)amino)hydroxyethyl)isopropyl-5a, 5b, 8, 8, 1 tamethyl—2—oxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyclopenta[a]chrysenyl)oxy)-2, 2-dimethyl—4-oxobutanoic acid The title compound was made as a TFA salt in a similar manner to Example 14. Stereochemistry was tentatively assigned as drawn but not fully med oscopically. LC/MS: m/z calculated 755.4, found 756.2 (M+1)+.
Example 56: Compound 97 4-(((3aR, 5aR, 5bR, 7aR, 98, 1 1aR, 1 1bR, 13aS)-3a-((R)((3-Chloro-2—f/uorobenzyl)(2- hy/amino)ethy/)amino)- 1-hydroxyethy/)- 1-isopropy/-5a, 5b, 8, 8, 1 1a-pentamethyl- 2-oxo-3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 10, 1 1, 1 1a, 1 1 b, 12, 13, 13a-octadecahydro-2H— cyclopenta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid The title compound was made as a TFA salt in a similar manner to e 18. Stereochemistry was tentatively assigned as drawn but not fully confirmed spectroscopically. 1H NMR (500MHz ,CHLOROFORM-d) 6 = 7.49 - 7.35 (m, 2 H), 7.15 (t, J: 7.7 Hz, 1 H), 4.46 (dd, J: 6.1, 9.9 Hz, 1 H), 4.22 (d, J = 10.4 Hz, 1 H), 4.05 (d, J: 13.9 Hz, 1 H), 3.90 (d, J: 13.6 Hz, 1 H), 3.48 (br. s., 1 H), 3.32 - 3.02 (m, 4 H), 2.85 (br. s., 6 H), 2.74 - 2.40 (m, 4 H), 2.40 - 2.15 (m, 3 H), 1.99 - 0.58 (m, 43 H); LC/MS: m/z calculated 826.5, found 827.3 (M+1)+.
Example 57: Compound 98 4-(((3aR, 5aR, 5bR, 7aR, 98, 1 1aR, 1 1bR, 13aS)-3a-((S)((3-Chlorof/uorobenzyl)(2- (dimethy/amino)ethy/)amino)- 1-hydroxyethy/)- ropy/-5a, 5b, 8, 8, 1 1a-pentamethyl- 2-oxo-3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 10, 1 1, 1 1a, 1 1 b, 12, 13, 13a-octadecahydro-2H— cyclopenta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid ] The title compound was made as a TFA salt in a similar manner to Example 18. Stereochemistry was tentatively assigned as drawn but not fully confirmed spectroscopically. 1H NMR (500MHz ,CHLOROFORM-d) 6 = 7.56 - 7.32 (m, 2 H), 7.16 (t, J: 7.7 Hz, 1 H), 4.53 - 4.38 (m, 1 H), 4.28 (d, J = 9.1 Hz, 1 H), 4.13 - 3.87 (m, 2 H), 3.44 (br. s., 1 H), 3.33 - 2.91 (m, 5 H), 2.93 - 2.21 (m, 11 H), 2.09 - 1.95 (m, 1 H), 1.95 - 0.65 (m, 45 H); LC/MS: m/z calculated 826.5, found 827.3 (M+1)+.
Example 58: Compound 99 aR, 5aR, 5bR, 7aR, 98, 1 1aR, 1 1bR, 13aS)-3a-((R)Hydroxy (isopropy/amino)ethy/)- 1-isopropy/-5a, 5b, 8, 8, 1 1a-pentamethyIoxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyclopenta[a]chrysenyl)oxy)-2, 2-dimethyl—4-oxobutanoic acid The title compound was made as a TFA salt in a similar manner to e 18. Stereochemistry was tentatively assigned as drawn but not fully confirmed spectroscopically. 1H NMR (400MHz, CHLOROFORM-d) 6 = 10.30 (br. s., 1 H), 4.71 - 4.26 (m, 2 H), 3.49 - 2.98 (m, 2 H), 2.87 - 2.42 (m, 6 H), 2.42 - 2.21 (m, 1 H), 2.07 — 0.68 (m, 53 H); LC/MS: m/z ated 655.5, found 656.5 (M+1)+. e 59: Compound 100 4-(((3aR, 5aR, 5bR, 7aR, 98, 1 1aR, 1 1bR, 13aS)-3a-((R)(cyclohexy/amino) hydroxyethy/)- 1-isopropy/-5a, 5b, 8, 8, 1 1a-pentamethyIoxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H— cyclopenta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid O 100 The title compound was made as a TFA salt in a similar manner to Example 18. chemistry was tentatively assigned as drawn but not fully confirmed spectroscopically. 1H NMR (400MHz ,CHLOROFORM-d) 6 = 10.25 (br. s., 1 H), 7.12 (br. s., 1 H), 4.67-4.34 (m, 2 H), 3.29-3.03 (m, 1 H), 2.92 (br. s., 1 H), 2.83 - 2.42 (m, 6 H), 2.42 - 2.26 (m, 1 H), 2.11 - 0.72 (m, 55 H); LC/MS: m/z calculated 695.5, found 696.4 (M+1)+.
\«N:% 0 02H 1) DMAP, EDCI 2) Separate Exam le 60 and 61: Com ound 111 and 112 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((S)(1-(5-chloropyrimidin-2— yl) cyclopropyl)oxooxazolidinyl)- 1-isopropy/-5a, 5b, 8, 8, 1 1a-pentamethyIoxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, tadecahydro-2H- cyclopenta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid (1 1 1) and 4- (((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((R)(1-(5-chloropyrimidin-2— yl) cyclopropyl)oxooxazolidinyl)- 1-isopropy/-5a, 5b, 8, 8, 1 1a-pentamethyIoxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyclopenta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid (1 12) WO 90664 Ste A: |ntermediate101 (3aR, 5aR, 5bR, 7aR, 98, 1 1aR, 1 1bR, 13aS)-3a-((1, 3-Dithianyl)(hydroxy)methy/) hydroxy- 1-isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyl- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysen-2—one ] To a solution of 1, 3-dithiane (5.7 g, 47.4 mmol) in anhydrous tetrahydrofuran (THF, 60 mL) under an atmosphere of nitrogen at -40 °C was slowly added a solution of n—BuLi (27 mL, 67.5 mmol). After the reaction mixture was stirred at -20 °C for another 2 h, a solution of the intermediate 6 (4.2 g, 8.46 mmol) in anhydrous THF (40 mL) was slowly added under an atmosphere of nitrogen at -70 °C. The reaction was then stirred at -78 °C for 1 h before it was quenched with a saturated solution of NaHC03. Extraction was conducted with EtOAc and the organic phase was washed with water (50 mL), saturated brine (50 mL), dried over sodium sulfate, and evaporated under reduced pressure to provide a crude product, which was purified by column chromatography on silica gel (PE:EtOAc = 8:1 to 4:1) to afford the intermediate 101 (3.0 g, 5.22 mmol, 61.7 %). LC/MS: m/z ated 574.4, found 575.0 (M + 1)+.
Step B: Intermediate 102 (3aR, 5aR, 5bR, 7aR, 98, 1 1aR, 1 1bR, 3a-(Acetoxy(1,3-dithian-2—yl)methyl) isopropyl—5a, 5b, 8, 8, 1 1a-pentamethyl-Z-oxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyclopenta[a]chrysenyl acetate To a solution of the intermediate 101 (3.5 g, 6.09 mmol), Et3N (2.55 mL, 18.26 mmol), and DMAP (0.149 g, 1.218 mmol) in DCM (40 mL) was added A020 (3.45 mL, 36.5 mmol) at room temperature. After stirring at 50 °C for 2 h, the reaction mixture was quenched with water. The organic phase was washed with water (100 mL), dried over sodium e, and evaporated under reduced pressure to provide the intermediate 102 (3.41 g, 85 %). LC/MS: m/z calculated 658.4, found 659.1 (M +1)+.
Step C: Intermediate 103 (3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((1, 3-Dithianyl)(hydroxy)methyl)- 1- isopropyl-5a, 5b, 8, 8, 1 tamethyl-Z-oxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyclopenta[a]chrysenyl acetate ] A solution of 102 (6.7 g, 10.17 mmol) and potassium hydroxide (1.141 g, 20.33 mmol) in a mixture 1:1 of toluene and ethanol (100ml) was stirred vigorously at rt for 1 hr. The reaction mixture was neutralized with aqueous 1N HCI to pH 7 and reduced to s. The residue was purified on a silica gel using Petroleum ether/EtOAc (5:1) to yield (3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)—3a-((1,3-dithian- 2-yl)(hydroxy)methyl)isopropyl-5a,5b,8,8,11a-pentamethyloxo- 3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H- enta[a]chrysenyl acetate (103) (3.4g, 5.01 mmol, 49%) as a light yellow compound. LC/MS: m/z calculated 616.4, found 617.3 (M + 1)+.
Step D: ediate 104 (3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-(1-hydroxyoxoethy/)— 1-isopropyl- 5a, 5b, 8, 8, 1 1a-pentamethyloxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyclopenta[a]chrysenyl acetate To a solution of 103 (1.2g, 1.945 mmol) in acetonitrile (20 ml) and water (5.00 ml) stirred in air at rt was added NBS (1.385 g, 7.78 mmol) in one charge . The reaction mixture was stirred at rt for 0.5 h, then quenched with Na2803 (solid), concentrated and the residue was extracted with EtOAc. The organic phase was washed with water and saturated brine dried over sodium sulphate and concentrated in vacuo to give (3aR,5aR,5bR,7aR,98,11aR,11bR,13aS)—3a-(1- yoxoethyl)—1-isopropyl-5a,5b,8,8,1 tamethyloxo- 3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H- cyclopenta[a]chrysenyl acetate (104) (1 .09g, 1.083 mmol, 55.7 % yield) as a light yellow solid which was used without further purification.
Step E: Intermediate 106 (3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-(2-((1-(5-Chloropyrimidin-2— lopropy/)amino)— 1-hydroxyethy/)- 1-isopropy/-5a, 5b, 8, 8, 1 1a-pentamethyIoxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyclopenta[a]chrysenyl acetate To a solution of (3aR,5aR,5bR,7aR,98,11aR,11bR,13aS)—3a-(1- hydroxyoxoethyl)isopropyl-5a,5b,8,8,1 1a-pentamethyloxo- 3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H- cyclopenta[a]chrysenyl acetate (104) (545 mg, 1.035 mmol) and 1-(5- chloropyrimidinyl)cyclopropanamine, hloride (105) (213 mg, 1.035 mmol) in methanol (5 ml) and chloroethane (5 ml) was added zinc chloride (141 mg, 1.035 mmol). The reaction e was stirred at room temperature overnight. and then sodium cyanoborohydride (65.0 mg, 1.035 mmol) was added. The reaction mixture was allowed to stir for 1h then silica gel was added to the mixture and the solvents removed in vacuo to give the residue-silica gel powder which was purified on a silica gel column using petroleum ether/EtOAc (5:1 to 3:1) to afford (3aR,5aR,5bR,7aR,98,11aR,11bR,13aS)—3a-(2-((1-(5-chloropyrimidin yl)cyclopropyl)amino)hydroxyethyl)isopropy|-5a,5b,8,8,11a-pentamethyloxo- 3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H- cyclopenta[a]chrysenyl acetate (105) as a e of diastereomers (200mg, 0.166 mmol, 16.04 % yield) as a yellow foam. LC/MS: m/z calculated 679.4, found 680.3 (M +1)+.
Step F: Intermediate 107 (3aR, 5aR, 5bR, 7aR, 98, 1 1aR, 1 1bR, 13aS)-3a-(3-(1-(5-Chloropyrimidin-2— yl) cyclopropyl)-2—oxooxazo/idin-5—yl)- 1-isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyIoxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyclopenta[a]chrysenyl acetate ] To a solution of (3aR,5aR,5bR,7aR,98,11aR,11bR,13aS)—3a-(2-((1- (5-chloropyrimidinyl)cyclopropyl)amino)hydroxyethyl)isopropyl- WO 90664 5a,5b,8,8,11a-pentamethyloxo- 3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H- cyclopenta[a]chrysenyl e (106) (400 mg, 0.588 mmol) in dichloromethane (15 ml) stirred at rt was added BOCZO (1.365 ml, 5.88 mmol). The reaction mixture was stirred at rt overnight then ated under reduced re and the residue was subjected to a silica gel chromatography with petroleum ether/EtOAc (6:1 to 3:1) to give aR,5bR,7aR,9S,11aR,11bR,13aS)—3a-(3-(1-(5-ch|oropyrimidin yl)cyclopropyl)oxooxazolidiny|)isopropy|-5a,5b,8,8,11a-pentamethyloxo- 3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H- cyclopenta[a]chrysenyl acetate (107) (350 mg, 0.496 mmol, 84 % yield) as a white solid.
Step G: Intermediate 108 3-(1-(5-Ch/oropyrimidinyl)cyc/opropyl) ((3aR, 5aR, 5bR, 7aR, 98, 1 1aR, 1 1bR, 13aS)hydroxy— 1-isopropyl-5a, 5b, 8, 8, 1 1a- pentamethyl0X0-3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0,1 1, 1 1 a, 1 1 b, 1 2, 13, 13a- octadecahydro-2H-cyclopenta[a]chrysen—3a-yl)oxazo/idin-Z-one To a solution of (3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)—3a-(3-(1-(5- chloropyrimidinyl)cyclopropyl)oxooxazolidiny|)isopropyl-5a,5b,8,8,11a- pentamethyloxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a- octadecahydro-2H-cyclopenta[a]chrysenyl acetate (107) (350 mg, 0.496 mmol) in 1,4-dioxane (10 mL) and methanol (5 mL) was added hydrochloric acid (5 mL, 165 mmol). The reaction mixture was stirred at 40 °C overnight. The solvents were removed under reduced pressure and taken up in DCM (100 ml), washed with sat.
NaHC03 (20 ml), water (20 ml) and brine (20 ml), dried over sodium sulfate, filtered and concentrated to give residue, which was subjected to a silica gel column eluting WO 90664 with petroleum ether/EtOAc (6:1 to 3:1) to give 3-(1-(5-chloropyrimidin yI)cyclopropy|)((3aR,5aR,5bR,7aR,98,11aR,11bR,13aS)—9-hydroxyisopropy|— 5a,5b,8,8,11a-pentamethyIoxo- 3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H- cyclopenta[a]chrysen-3a-yl)oxazolidinone (130 mg, 0.087 mmol, 17%) as a white solid. LC/MS: m/z calculated 663.4, found 664.3 (M + 1)+.
Step H: Intermediates 109 and 110 1-tert-buty/ 4-((3aR, 5aR, 5bR, 7aR, 98, 1 1aR, 1 1bR, 13aS)-3a-((S)(1-(5- chloropyrimidinyl)cyc/opropyl)oxooxazo/idin-5—yl)- 1-isopropyl-5a, 5b, 8, 8, 1 1a- pentamethyloxo-3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0,1 1, 1 1 a, 1 1 b, 1 2, 13, 13a- octadecahydro-2H-cyclopenta[a]chrysenyl) 2, 2-dimethy/succinate (1 09) and 1 -tert- buty/ R, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((R)(1-(5-chloropyrimidin-2— yl) cyclopropyl)oxooxazo/idin-5—yl)- 1-isopropy/-5a, 5b, 8, 8, 1 1a-pentamethyIoxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyclopenta[a]chrysenyl) 2, 2-dimethy/succinate (1 10) A mixture of 4-tert-butoxy-3,3-dimethyIoxobutanoic acid 10 (119 mg, 0.587 mmol), 3-(1-(5-chloropyrimidinyl)cyclopropyl) ((3aR,5aR,5bR,7aR,98,11aR,11bR,13aS)—9-hydroxy—1-isopropy|-5a,5b,8,8,11a- pentamethyIoxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a- octadecahydro-2H-cyclopenta[a]chrysen-3a-y|)oxazoIidinone (108) (130 mg, 0.196 mmol), EDC (188 mg, 0.978 mmol) and DMAP (71.7 mg, 0.587 mmol) in DCM (5 mL) was stirred at rt overnight. After the reaction finished, the e was diluted with DCM (25ml), washed with water (2x15ml) and brine (20ml), dried over sodium sulfate, ed and concentrated under reduced pressure. The residue was purified by silica gel chromatography using petroleum ether/EtOAc (6:1 to 3:1 ) as eluent to give the two diastereomeric products 1-tert-butyl 4- ((3aR,5aR,5bR,7aR,98,11aR,11bR,13aS)—3a-((S)—3-(1-(5-chloropyrimidin-2— yl)cyclopropyl)—2—oxooxazolidinyl)—1-isopropyl-5a,5b,8,8,11a-pentamethyloxo- 3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H- cyclopenta[a]chrysenyl) 2,2—dimethylsuccinate (109) and 1-tert-butyl 4- ((3aR,5aR,5bR,7aR,98,11aR,11bR,13aS)—3a-((R)—3-(1-(5-chloropyrimidin-2— yl)cyclopropyl)oxooxazolidinyl)—1-isopropyl-5a,5b,8,8,11a-pentamethyl-2—oxo- 3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H- cyclopenta[a]chrysenyl) 2,2—dimethylsuccinate (110) in the amounts of (80 mg, 45%) and (50 mg, 22%) as white solids. The chemical assignments for each diastereomer were not made. Compound A (tentatively designated as 109): LC/MS: m/z calculated 847.5, found 848.3 (M + 1)+. nd B tively designated as 110): LC/MS: m/z calculated 847.5, found 848 (M + 1)+.
Step I: nd 111 4-(((3aR, 5aR, 5bR, 7aR, 98, 1 1aR, 1 1bR, 13aS)-3a-((S)(1-(5-chloropyrimidin—2— yl) cyclopropyl)oxooxazo/idinyl)— 1-isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyIoxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyclopenta[a]chrysenyl)oxy)—2, 2-dimethyloxobutanoic acid To a solution of 1-tert-butyl 4- ((3aR,5aR,5bR,7aR,98,11aR,11bR,13aS)—3a-((S)—3-(1-(5-chloropyrimidin-2— yl)cyclopropyl)—2—oxooxazolidinyl)—1-isopropyl-5a,5b,8,8,11a-pentamethyloxo- 3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H- cyclopenta[a]chrysenyl) 2,2—dimethylsuccinate (109) (80 mg, 0.094 mmol) in DCM (10 mL) was added TFA (1 mL, 0.094 mmol). The reaction e was stirred at rt overnight, then diluted with DCM (20ml) and washed with water (2x15ml), saturated sodium bicarbonate solution (20ml) and brine (20ml), dried over sodium sulfate, filtered and concentrated to get a residue. The residue was purified on silica gel using petroleum ether/EtOAc ( 4:1 to 1:1 ) as eluent to give the product 4- (((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)—3a-((S)—3-(1-(5-chloropyrimidin yl)cyclopropyl)oxooxazolidinyl)—1-isopropyl-5a,5b,8,8,11a-pentamethyloxo- ,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H- cyclopenta[a]chrysenyl)oxy)-2,2—dimethyloxobutanoic acid (111) (50mg, 67%) as a white solid. This material was lyophilized to give a white powder.
Stereochemistry was tentatively assigned as drawn but not fully confirmed spectroscopically. 1H NMR (400MHz OFORM-d) 6 = 8.58 (s, 2 H), 5.04 (t, J = 8.5 Hz, 1 H), 4.51 (dd, J = 4.6, 10.9 Hz, 1 H), 3.41 - 3.04 (m, 4 H), 2.75 - 2.44 (m, 3 H), 2.36 (d, J = 13.3 Hz, 1 H), 2.12 - 0.72 (m, 49 H); LC/MS: m/z calculated 791.4, found 792.3 (M + 1)+.
Step J: Compound 112 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((R)(1-(5-chloropyrimidin-2— yl) cyclopropyl)-2—oxooxazo/idin-5—yl)- ropyl-5a, 5b, 8, 8, 1 1a-pentamethyIoxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyclopenta[a]chrysen-9—yl)oxy)-2, 2-dimethyl—4-oxobutanoic acid The title compound was made in a similar manner to that described for compound 111. Stereochemistry was ively assigned as drawn but not fully confirmed spectroscopically. 1H NMR (400MHz ,CHLOROFORM-d) 6 = 8.59 (s, 2 H), .10 (t, J: 8.8 Hz, 1 H), 4.52 (dd, J: 5.3, 10.8 Hz, 1 H), 3.70 - 3.54 (m, 2 H), 3.28 - 3.10 (m, 2 H), 3.08 - 2.92 (m, 2 H), 2.77 - 2.53 (m, 2 H), 2.14 - 0.58 (m, 49 H); LC/MS: m/z calculated 791.4, found 792.3 (M + 1)+.
Exam le 62: Com ound 124 4-(((3aS,5aR,5bR, 7aR,98, 1 1aR, 1 1bR,13aS)-3a-((S)((4-Chlorobenzyl)amino)- 1- hydroxyethy/)— 1-isopropy/-5a, 5b, 8, 8, 1 1a—pentamethyl- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, tadecahydro-2H- cyclopenta[a]chrysenyl)oxy)—2, 2-dimethyl—4-oxobutanoic acid 1 86 Ste A: Intermediate 113 (3aS, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-(Hydroxymethyl)— ropyl- 5a, 5b, 8, 8, 1 1a-pentamethyl-3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 10, 1 1, 1 1a, 1 1 b, 12, 13, 13a- octadecahydro-2H-cyclopenta[a]chrysenyl acetate To a solution of the intermediate 3 (5 g, 7.59 mmol) in EtOH (100 mL) and e (100 mL) was added KOH (0.51 g, 9.11 mmol). After stirring at room temperature for 4 h, the reaction mixture was then partitioned between water (500 mL) and EtOAc (500 mL). The organic phase was washed with water (200 mL x 3), brine (100 mL), and dried over sodium sulfate. Removal of the solvent provided a residue, which was purified by column chromatography on silica gel (Hex:EtOAc = 6:1 to 4:1) to afford the intermediate 113 (2.5 g, 67.9 %) as a white solid. 1H NMR (400 Hz, CDCI3) 6 ppm 4.50-4.67 (1H, m), 3.68 (1H, d, J = 10.4Hz), 3.32 (1H, d, J = .4Hz), 3.23-3.15 (1H, m), 2.42-2.28 (3H, m), 2.05 (3H, s), 2.02-1.89 (2H, m), 1.77- 0.83 (40H, m).
Step B: Intermediate 114 (3aS, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-Formyl—1-isopropyl-5a, 5b, 8, 8, 1 1a- pentamethyl-3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyclopenta[a]chrysenyl acetate To a solution of the intermediate 113 (3 g, 6.19 mmol) in DCM (75 mL) at room temperature were added PCC (4 g, 18.57 mmol) and silica gel (3.0 g). After WO 90664 stirring at room temperature for 2 h, the reaction was quenched with water (100 mL).
The organic phase was separated, washed with saturated sodium bicarbonate (50 mL), dried over sodium e and concentrated in vacuo to provide a residue, which was ed by column chromatography on silica gel tOAc = 10:1) to afford the intermediate 114 (3 g, 100 %) as a white solid. 1H NMR (400 Hz, CDCI3) 6 ppm 9.43 (1H, s), 4.50-4.46 (1H, m), 3.25-3.21 (1H, m), 2.43-2.02 (5H, m), 2.04 (3H, m), 2.00- 1.93 (1H, m), 1.75-0.81 (38H, m).
Step C: Intermediate 115 (3aS, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-(1 -Hydroxynitroethyl)- 1-isopropyl- 5a, 5b, 8, 8, 1 1a-pentamethyl—3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 10, 1 1, 1 1a, 1 1 b, 12, 13, 13a- octadecahydro-2H-cyc/openta[a]chrysenyl acetate To a solution of the intermediate 114 (5 g, 10.36 mmol) in MeN02 (128 mL, 2382 mmol) was added Et3N (10.11 mL, 72.5 mmol). After it was stirred at 60 °C overnight, the reaction mixture was partitioned between water and EtOAc (100 mL each). The organic phase was washed with water (20 mL x 3), brine (20 mL), and dried over sodium sulfate. Removal of the solvent ed a residue, which was purified by column chromatography on silica gel (Hex:EtOAc = 10:1 to 6:1) to afford the intermediate 115 (2.8 g, 49.7 %) as a white powder. LC/MS: m/z calculated 543.4, found 566.3 (M + Na+)+.
Step D: Intermediate 116 (3aS, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-(2-Aminohydroxyethy/)- 1-isopropyl- 5a, 5b, 8, 8, 1 1a-pentamethyl—3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 10, 1 1, 1 1a, 1 1 b, 12, 13, 13a- octadecahydro-2H-cyc/openta[a]chrysenyl acetate WO 90664 To a solution of the intermediate 115 (2.8 g, 5.15 mmol) in MeOH (166 mL) were added nickel(ll) chloride (1.67 g, 12.87 mmol) and sodium borohydride (4.87 g, 129 mmol) at 0 °C. After stirring at 0 °C for 10 min, the on mixture was partitioned between water and EtOAc (200 mL each), and the organic phase was washed with water (100 mL x 3), brine (50 mL), and dried over sodium sulfate.
Removal of the solvent provided the intermediate 116 (2.65 g, 100 %) as a solid.
LC/MS: m/z calculated 513.4, found 514.3 (M + 1)+.
Step E: ediate 118 (3aS, 5aR, 5bR, 7aR, 98, 1 1aR, 1 1bR, 3a-(2-((tert-Butoxycarbonyl) (4- ch/orobenzyl)amino)- 1-hydroxyethyl)isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyl- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyclopenta[a]chrysenyl acetate To a solution of the intermediate 116 (350 mg, 0.613 mmol) and 4- benzaldehyde (86 mg, 0.613 mmol) in MeOH (15 mL) and roethane (DCE, 15 mL) was added zinc chloride (50.1 mg, 0.368 mmol). After the reaction mixture was stirred at 80 °C for 1 h and cooled down to room temperature, sodium cyanoborohydride (57.8 mg, 0.92 mmol) was added. The resulting mixture was stirred at room temperature for another 1 h to provide the intermediate 117.
To the reaction mixture obtained above were added Et3N (0.18 mL, 1.38 mmol) and di-tert—butyl dicarbonate (0.157 mL, 0.674 mmol). After stirring at room temperature for 30 min, the reaction mixture was partitioned between water (20 mL) and EtOAc (100 mL). The organic phase was washed with water (30 mL X 3), brine (20 mL), and dried over sodium sulfate. Removal of the solvent provided a residue, which was purified by column chromatography on silica gel (Hex:EtOAc = :1) to afford the intermediate 118 (125 mg, 27.6 %) as a white solid.
Step F: Intermediate 119 (3aS, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-(2-((tert-Butoxycarbonyl) (4- chlorobenzyl)amino)acetyl)- 1-isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyl- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyclopenta[a]chrysenyl acetate To a solution of the intermediate 118 (120 mg, 0.162 mmol) in DCM (10 mL) were added PCC (35 mg, 0.162 mmol) and silica gel (100 mg). After stirring at room temperature for 2 h, the insoluble material was removed by filtration and the filtrate was concentrated to afford the ediate 119 (110 mg, 92 %) as a white solid.
Step G: Intermediate 120 uty/ 4-Ch/orobenzy/(2—((3aS, 5aR, 5bR, 7aR, 98, 1 1aR, 1 1bR, 13aS)hydroxy isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyl- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- enta[a]chrysen-3a-yl)oxoethyl)carbamate To a solution of NaOH (597 mg, 14.94 mmol) in MeOH (1 mL), THF (1 mL), and water (0.5 mL) was added the intermediate 119 (110 mg, 0.149 mmol).
After stirring at room temperature for 1 h, the reaction was diluted with water (20 mL), and extracted with EtOAc (50 mL). The organic phase was washed with brine (20 mL), dried over sodium sulfate, and evaporated in vacuo to afford the intermediate 120 (100 mg, 96 %) as a white solid.
Step H: Intermediate 121 4-((3aS, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 3a-(2-((tert-butoxycarbonyl) (4- chlorobenzyl)amino)acetyl)- 1-isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyl- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl) 1-tert-buty/ 2, 2-dimethy/succinate To a solution of 4-tert-butoxy-3,3-dimethyloxobutanoic acid 10 (1.648 g, 8.15 mmol), DMAP (0.995 g, 8.15 mmol) in DCM (15ml) stirred at rt was added EDCI (2.60 g, 13.58 mmol). The reaction mixture was stirred at rt. for 2h.
Then tert-butyl 4-chlorobenzyl(2-((3aS,5aR,5bR,7aR,98,11aR,11bR,13aS)—9- hydroxyisopropyl-5a,5b,8,8,11a-pentamethyl- 3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H- cyclopenta[a]chrysen-3a-yl)oxoethyl)carbamate 120 (1 .886g, 2.72 mmol) was added to the reaction. The reaction e was stirred at rt overnight. Upon completion, the mixtuere was washed with water (25 mLx 2) and brine, dried over sodium sulfate filtered through a short silica gel column and evaporated in vacuo to give the crude product which was futher purified on a silica gel column using eum ether/EtOAc (50:1 to 10:1) to give ediate 121 (2.37g, 99%) as white foam.
Step I: Intermediates 122 and 123 4-((3aS,5aR,5bR, 7aR,9S, 1 1aR, 1 1bR,13aS)-3a-((S)((tert—Butoxvcarbon[0(4- ch/orobenz lamino h drox eth liso r0 l-5a 5b 8 8 11a- entameth /- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 10, 1 1,1 1 a, 1 1b,12,13,13a-octadecahvdro-2H- czclopentalalchczsenz/2 1-tert-butv/ 2, 2-dimethv/succinate (122) and 4- ((3aS,5aR,5bR, 7aR,9S, 1 1aR, 1 1bR,13aS)-3a-((R2((tert—butoxvcarbon[0(4- ch/orobenz lamino h drox eth liso r0 l-5a 5b 8 8 11a- entameth /- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 10, 1 1,1 1 a, 1 1b,12,13,13a-octadecahvdro-2H- entalalchrvsenv/l 1 -tert-butvl 2, 2-dimethv/succinate (1 23) To a solution of and 4-((3aS,5aR,5bR,7aR,9S,11aR,11bR,13aS)—3a- (2-((tert-butoxycarbonyl)(4-chlorobenzyl)amino)acetyl)isopropyl-5a,5b,8,8,11a- pentamethyl-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H- cyclopenta[a]chrysenyl) 1-tert-butyl 2,2-dimethylsuccinate (121) (791 mg, 0.90 mmol) in MeOH (10 mL) and THF (10.00 mL) stirred at 0°C was added NaBH4 (170 mg, 4.50 mmol). The reaction mixture was stirred at rt for 2h until starting material had disappeared. Upon completion, silica gel was added and the mixture ated to dryness and purified by silica gel tography (petroleum ether/EtOAc, 40:1 to :1 ) to give the two diastereomeric products: 4- ((3aS,5aR,5bR,7aR,9S,11aR,11bR,13aS)—3a-((S)((tert-butoxycarbonyl)(4- chlorobenzyl)amino)hydroxyethyl)isopropyl-5a,5b,8,8,11a-pentamethyl- ,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H- cyclopenta[a]chrysenyl) 1-tert-butyl 2,2-dimethylsuccinate and 4- ((3aS,5aR,5bR,7aR,9S,11aR,11bR,13aS)—3a-((R)—2-((tert-butoxycarbonyl)(4- chlorobenzyl)amino)hydroxyethyl)isopropyl-5a,5b,8,8,11a-pentamethyl- ,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H- cyclopenta[a]chrysenyl) 1-tert-butyl 2,2-dimethylsuccinate. Stereochemistry was not confirmed but the diastereomers were produced in the amount of (410 mg, 52%, tentatively assigned as compound 122) and (77 mg, 10%, tentatively assigned as compound 123) as white foams.
Step J: Compound 124 4-(((3aS, 5aR, 5bR, 7aR, 98, 1 1aR, 1 1bR, 13aS)-3a-((S)((4-chlorobenzyl)amino)- 1- hydroxyethy/)- 1-isopropy/-5a, 5b, 8, 8, 1 1a-pentamethyl- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyclopenta[a]chrysenyl)oxy)-2, 2-dimethyl—4-oxobutanoic acid ] To a solution of 122 (410 mg, 0.466 mmol) in DCM (10 mL) was added TFA (2 mL, 26.0 mmol). The reaction mixture was stirred at rt for 2 h. The reaction mixture was concentrated to dryness and purified by preparative-HPLC to afford 4-(((3aS,5aR,5bR,7aR,98,11aR,11bR,13aS)—3a-((S)—2-((4- chlorobenzy|)amino)hydroxyethy|)isopropyI-5a,5b,8,8,11a-pentamethyl- 3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H- cyclopenta[a]chryseny|)oxy)-2,2-dimethyIoxobutanoic acid, trifluoroacetic acid salt (124) (185 mg, 0.221 mmol, 47.4 % yield) as white solid. 1H NMR (500MHz ,CHLOROFORM-d) 5 = 7.36 (q, J = 8.5 Hz, 4 H), 4.58 - 4.41 (m, 1 H), 4.41 - 4.31 (m, 1 H), 4.20 - 3.97 (m, 2 H), 3.23 - 3.05 (m, 2 H), 2.85 - 2.66 (m, 2 H), 2.56 (d, J: 16.1 Hz, 1 H), 2.51 -2.38 (m, 1 H), 2.34-2.19 (m, 2 H), 1.93- 1.82 (m, 1 H), .67 (m, 46 H); LC/MS: m/z calculated 723.5, found 724.3 (M + 1)+.
Exam le 63: Com ound 132 2012/069637 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 3a-((R)(3, 4-dihydroisoquinolin- 2(1H)-yl)hydroxyethyl)isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyl—2-oxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyclopenta[a]chrysenyl)oxy)—2, 2-dimethyloxobutanoic acid Ste A: Intermediate 125 (3aS, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)- 1-isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyl oxo-3a-vinyl-3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyclopenta[a]chrysenyl e To a cold (-78 oC) solution of methyltriphenylphosphonium bromide (8.63 g, 24.16 mmol) in THF (30 mL) was added lithium bis(trimethy|si|y|)amide (4.4 g, 24.1 mmol) in THF dropwise. The reaction was stirred at -78°C for 1h, then 6 (10.09, 20.1 mmol) in THF (60ml) was added. The mixture was allowed to warm to rt and stirred for 1h. TLC indicated the reaction was complete. 2N HCI was added to the mixture and it was extracted with ethyl acete and washed with water and brine.
The organic phase was dried with Na2804 followed by filtration and concentration followed by precipitation of the desired product (109 of 85% purity, 85% chemical yield) with 5% EtOAc/petroleum ether.
Step B: Intermediate 126 (3aS, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)hydroxyisopropyl-5a, 5b, 8, 8, 1 1a- pentamethyI-3a-vinyl-3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 10, 1 1, 1 1a, 1 1 b, 12,13, 13a- octadecahydro-2H-cyc/openta[a]chrysenone ] To a solution of 125 (16g, 32.3 mmol) in 1,4-dioxane (300 mL) and MeOH (30ml) stirred at rt was added HCI (37%) (150 mL, 32.3 mmol). The reaction mixture was stirred at 60 °C for 3h. TLC and LCMS indicated the starting material was consumed completely. Water was added and the volatiles were concentrated, a resultant precipitate was d and washed with water. The cake was dried to give 126 (14g, 81%).
Step C: ediate 127 1 butyl 4-((3aS, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)- 1-isopropyl-5a, 5b, 8, 8, 1 1a- pentamethyloxo-3a-vinyl-3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a- octadecahydro-2H-cyclopenta[a]chrysenyl) 2, 2-dimethy/succinate To a solution of 10 (14.52 g, 71.8 mmol), DMAP (10.52 g, 86 mmol) and 126 (13 g, 28.7 mmol) in dichloromethane (150 mL) was added EDC (27.5 g, 144 mmol). The mixture was stirred at rt for 2h, at which time TLC indicated the reaction was complete. The reaction was washed with 2N HCI, and brine. The organics were dried with Na2804, filtered and concentrated. The residue was purified by silica gel chromatogrpahy to give 127 (9.5 g, 49%) alogn with an additional 4 g impure product requiring repurification prior to further use.
Step D: Intermediates 128 and 129 1-tert-buty/ 4-((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)isopropyl—5a, 5b, 8, 8, 1 1a- pentamethy/—3a-((S)-oxiranyl)oxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyclopenta[a]chrysenyl) 2, 2-dimethy/succinate (128) and 1-tert-buty/ 4- ((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)isopropyl—5a, 5b, 8, 8, 1 1a-pentamethyl- 3a-((R)-oxiranyl)oxo-3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a- octadecahydro-2H-cyclopenta[a]chrysenyl) 2, 2-dimethy/succinate (1 29) To a solution of 127 (8.5 g, 13.34 mmol) in DCM (90 mL) at rt was added m—CPBA (5.42 g, 26.7 mmol). The reaction mixture was stirred at rt ght.
The mixture was r diluted with DCM 150ml then washed with saturated NaHC03, water and brine (note for safety reasons this the excess peroxide should be neutralized but was not in this ic procedure). The organic phase was concentrated and purified by silica gel chromatogrpahy (EtOAc/PE 5% to 15%) to give 128 (2.0 g, 21%) and 129 (800 mg, 8%) along with 2.4 g of recovered starting material. For 128: 1H NMR (500MHz ,CHLOROFORM-d) = 4.51 (dd, J = 5.4, 11.3 Hz, 1 H), 3.26 - 3.12 (m, 3 H), 2.66 (t, J = 4.4 Hz, 1 H), 2.54 (s, 2 H), 2.35 (dd, J = 2.7, 4.6 Hz, 1 H), 2.18 (d, J: 18.3 Hz, 1 H), 2.12 - 1.93 (m, 3 H), 1.91 - 0.74 (m, 52 H); LC/MS: m/z ated 652.5, found 653.3 (M + 1)+. For 129 : 1H NMR (500MHz ,CHLOROFORM-d) 6 = 4.51 (dd, J = 5.0, 11.3 Hz, 1 H), 3.26 - 3.07 (m, 2 H), 3.00 (dd, J: 3.2, 12.6 Hz, 1 H), 2.69 (t, J: 4.3 Hz, 1 H), 2.59 - 2.41 (m, 3 H), 2.21 - 0.76 (m, 56 H); LC/MS: m/z calculated 652.5, found 653.3 (M + 1)+.
Step E: Intermediate 131 -buty/ 4-((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((R)(3,4- dihydroisoquino/in-2(1H)-yl)- 1-hydroxyethyl)- 1-isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyl- 2-oxo-3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 10, 1 1, 1 1a, 1 1 b, 12, 13, 13a-octadecahydro-2H— cyclopenta[a]chrysenyl) 2, 2-dimethy/succinate To a solution of 1-tert-butyl 4- ((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)—1-isopropy|-5a,5b,8,8,11a-pentamethyl- WO 90664 3a-((R)—oxiranyl)oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a- octadecahydro-2H-cyclopenta[a]chrysenyl) 2,2-dimethylsuccinate (0.2 g, 0.306 mmol) in tert—butanol (3 mL) was added 1,2,3,4-tetrahydroisoquinoline (0.408 g, 3.06 mmol). The reaction e was stirred at 100 °C for 5 h. Upon completion and g, EtOAc was added and the mixture was washed with 4N HCI, and brine, then dried with Na2804, filtered and concentrated to give 132 (200 mg, 66%) which was used without further cation. LC/MS: m/z calculated 785.6, found 786.5 (M + 1)+.
Step F: Compound 132 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((R)-2—(3, 4-dihydroisoquino/in- 2(1H)-yl)hydroxyethyl)isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyl0X0- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyclopenta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid To a solution of 131 (0.2 g, 0.254 mmol) in DCM (2 mL) was added TFA (1 mL, 12.98 mmol) . The reaction mixture was stirred at rt for 1h then concentrated. The residue was purified by preparative-HPLC to give the title compound (106 mg, 48%) as a TFA salt as white solid. 1H NMR (500MHz ,METHANOL-d4) 6 = 7.43 - 7.15 (m, 4 H), 4.66 - 4.41 (m, 4 H), 3.28 - 3.05 (m, 3 H), 3.05 - 2.83 (m, 2 H), 2.73 - 2.52 (m, 3 H), 2.30 (d, J: 13.9 Hz, 1 H), 2.16 - 2.03 (m, 1 H), 2.00 - 0.72 (m, 48 H); LC/MS: m/z ated 729.5, found 730.5 (M + 1)+.
The Examples below were made in a similar manner to the above examples or via combinations or re-ordering of the methods descibed and/or usage of other methods well known to those skilled in the art.
Example 64: Compound 133 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((S)(3, 4-dihydroisoquino/in-2(1H)- y/)hydroxyethy/)— 1-isopropy/-5a, 5b, 8, 8, 1 1a-pentamethyl0X0- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- enta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid 00., ] Stereochemistry was tentatively assigned as drawn but not fully med spectroscopically. LC/MS: m/z calculated 729.5, found 730.5 (M + 1)+.
Example 65: Compound 134 4-(((3aS,5aR,5bR, 7aR,9S, 1 1aR, 1 1bR,13aS)-3a-((R)hydroxy(4- methy/piperazin- 1-yl)ethy/)- 1-isopropy/-5a, 5b, 8, 8, 1 1a-pentamethyl- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyclopenta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid Isolated as a mixture of diastereomers. LC/MS: m/z calculated , found 683.5 (M + 1)+.
Example 66: Compound 135 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-(2-((4-chlorobenzyl)amino)ethyl) isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyl- 1 98 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyclopenta[a]chrysenyl)oxy)—2, 2-dimethyloxobutanoic acid 0 O ‘3 W" H LC/MS: m/Z calculated 707.5, found 708.3 (M + 1)+.
Example 67: Compound 136 4-(((3aS,5aR,5bR, 7aR,9S, 1 1aR, 1 1bR,13aS)-3a-((S)((cyclohexylmethyl)amino)- 1- hydroxyethy/)— 1-isopropy/-5a, 5b, 8, 8, 1 tamethyl- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- enta[a]chrysenyl)oxy)—2, 2-dimethyloxobutanoic acid Stereochemistry was tentatively assigned as drawn but not fully confirmed spectroscopically. LC/MS: m/z calculated 695.6, found 696.5 (M + 1)+.
Example 68: Compound 137 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 3a-((S)(cyclohexylamino)—1- hydroxyethyl) - 1-isopropy/-5a, 5b, 8, 8, 1 1a-pentamethyIoxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyclopenta[a]chrysenyl)oxy)-2, thyloxobutanoic acid Stereochemistry was tentatively assigned as drawn but not fully confirmed spectroscopically. LC/MS: m/z calculated 695.5, found 696.5 (M + 1)+.
Example 69: Compound 138 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((S)(benzyl(2- (dimethy/amino)ethy/)amino)- 1-hydroxyethy/)— 1-isopropy/-5a, 5b, 8, 8, 1 1a-pentamethyl- 2-oxo-3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- enta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid chemistry was tentatively assigned as drawn but not fully confirmed spectroscopically. LC/MS: m/z calculated 774.6, found 775.5 (M + 1)+.
Example 70: Compound 139 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((S)acetoxy—2-((2- (dimethylamino)ethyl) (4-f/uorobenzyl)amino)ethy/)—1-isopropyl—5a, 5b, 8, 8, 1 1a- pentamethyloxo-3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0,1 1, 1 1 a, 1 1 b, 1 2, 13, 13a- octadecahydro-2H-cyclopenta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid Stereochemistry was tentatively assigned as drawn but not fully confirmed spectroscopically. LC/MS: m/z calculated 834.6, found 835 (M + 1)+.
Example 71: Compound 140 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((R)acetoxy((2- (dimethylamino)ethyl) (4-f/uorobenzyl)amino)ethy/)isopropyl—5a, 5b, 8, 8, 1 1a- pentamethyl0X0-3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0,1 1, 1 1 a, 1 1 b, 1 2, 13, 13a- octadecahydro-2H-cyclopenta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid Stereochemistry was tentatively assigned as drawn but not fully confirmed spectroscopically. LC/MS: m/z ated 834.6, found 835 (M + 1)+.
Example 72: Compound 141 -(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((R)((4-ch/orobenzy/)amino) hydroxyethy/)— 1-isopropy/-5a, 5b, 8, 8, 1 1a-pentamethyIoxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, tadecahydro-2H- cyclopenta[a]chrysenyl)oxy)-3, 3-dimethyloxopentanoic acid Stereochemistry was ively ed as drawn but not fully confirmed spectroscopically. LC/MS: m/z calculated 751.5, found 752.3 (M + 1)+.
Example 73: Compound 142 -(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((S)((4-chlorobenzyl)amino)- 1- hydroxyethy/)— 1-isopropy/-5a, 5b, 8, 8, 1 1a-pentamethyIoxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyclopenta[a]chrysenyl)oxy)-3, 3-dimethyloxopentanoic acid Stereochemistry was tentatively ed as drawn but not fully confirmed spectroscopically. LC/MS: m/z calculated 751.5, found 752.3 (M + 1)+.
Example 74: Compound 143 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((S)((2, 4-dich/orobenzy/)(2- (dimethy/amino)ethy/)amino)- 1-hydroxyethy/)— 1-isopropy/-5a, 5b, 8, 8, 1 1a-pentamethyl- 2-oxo-3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyclopenta[a]chrysenyl)oxy)-2, 2-dimethyl—4-oxobutanoic acid Stereochemistry was tentatively assigned as drawn but not fully confirmed spectroscopically. LC/MS: m/z ated 842.5, found 843.3 (M + 1)+.
Example 75: Compound 144 aR,5aR,5bR, 7aR,9S, 1 1aR, 1 1bR,13aS)-3a-((R)(benzyl(2— (dimethy/amino)ethy/)amino)- 1-hydroxyethy/)— 1-isopropy/-5a, 5b, 8, 8, 1 1a-pentamethyl- 2-oxo-3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 10, 1 1, 1 1a, 1 1 b, 12, 13, 13a-octadecahydro-2H- cyclopenta[a]chrysenyl)oxy)-2, 2-dimethyl—4-oxobutanoic acid Stereochemistry was ively assigned as drawn but not fully confirmed spectroscopically. LC/MS: m/z calculated 774.6, found 775.4 (M + 1)+.
Example 76: Compound 145 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 3a-((R)((2-(dimethy/amino)ethyl)(4- f/uorobenzy/)amino)— 1-hydroxyethy/)— 1-isopropy/-5a, 5b, 8, 8, 1 1a-pentamethyIoxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyclopenta[a]chrysenyl)oxy)-2, 2-dimethyl—4-oxobutanoic acid Stereochemistry was tentatively assigned as drawn but not fully confirmed spectroscopically. LC/MS: m/z calculated 792.5, found 793.5 (M + 1)+.
Example 77: nd 146 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((R)((4-fluorobenzyl)amino) hydroxyethy/)— 1-isopropy/-5a, 5b, 8, 8, 1 1a-pentamethyIoxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyclopenta[a]chrysenyl)oxy)-2, 2-dimethyl—4-oxobutanoic acid Stereochemistry was tentatively assigned as drawn but not fully confirmed spectroscopically. LC/MS: m/z calculated 721.5, found 722.3 (M + 1)+.
Example 78: nd 147 aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((S)((2-(dimethy/amino)ethyl)(4- f/uorobenzy/)amino)— 1-hydroxyethy/)— 1-isopropy/-5a, 5b, 8, 8, 1 1a-pentamethyIoxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyclopenta[a]chrysenyl)oxy)-2, 2-dimethyl—4-oxobutanoic acid Stereochemistry was tentatively assigned as drawn but not fully confirmed oscopically. LC/MS: m/z calculated 792.5, found 793.5 (M + 1)+.
Example 79: Compound 148 aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((S)-2—((4-f/uorobenzyl)amino) hydroxyethy/)— 1-isopropy/-5a, 5b, 8, 8, 1 1a-pentamethyIoxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyclopenta[a]chrysenyl)oxy)-2, 2-dimethyl—4-oxobutanoic acid Stereochemistry was tentatively assigned as drawn but not fully confirmed spectroscopically. LC/MS: m/z calculated 721.5, found 722.3 (M + 1)+.
Example 80: Compound 149 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((R)-2—((2, 4-dich/orobenzyl) (2- (dimethy/amino)ethy/)amino)- 1-hydroxyethy/)— 1-isopropy/-5a, 5b, 8, 8, 1 tamethyl- 2-oxo-3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 10, 1 1, 1 1a, 1 1 b, 12, 13, 13a-octadecahydro-2H- cyclopenta[a]chrysenyl)oxy)-2, 2-dimethyl—4-oxobutanoic acid Stereochemistry was tentatively assigned as drawn but not fully confirmed spectroscopically. LC/MS: m/z ated 842.5, found 843.5 (M + 1)+.
Example 81: Compound 150 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((R)(4-chloro-N-(2- (dimethy/amino)ethyl)benzamido)— 1-hydroxyethyl)— 1-isopropyl-5a, 5b, 8, 8, 1 1a- pentamethyloxo-3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0,1 1, 1 1 a, 1 1 b, 1 2, 13, 13a- octadecahydro-2H-cyclopenta[a]chrysenyl)oxy)-2, thyloxobutanoic acid Stereochemistry was tentatively assigned as drawn but not fully confirmed spectroscopically. LC/MS: m/z calculated 822.5, found 823.4 (M + 1)+.
Example 82: Compound 151 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-(2-((2-chlorobenzyl)amino)ethyl) isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyloxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- enta[a]chrysenyl)oxy)-2, 2-dimethyl—4-oxobutanoic acid LC/MS: m/z calculated 721.5, found 722.3 (M + 1)+.
Example 83: Compound 152 4-(((3aR, 5aR, 5bR, 7aR, 98, 1 1aR, 1 1bR, 13aS)-3a-(2-benzamidoethyl)isopropyl- 5a, 5b, 8, 8, 1 1a-pentamethyl-Z-oxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyclopenta[a]chrysenyl)oxy)—2, 2-dimethyloxobutanoic acid ] LC/MS: m/Z calculated 701.5, found 702.5 (M + 1)+.
Example 84: Compound 153 4-(((3aR, 5aR, 5bR, 7aR,9S, IIaR, IIbR, I3aS)-3a-((((R)-I—(4- Chlorophenyl)ethyDamin0)methyl)-I-is0pr0pyl—5a, 5b, 8, 8, I tamethyl—Z—oxo- 3,361, 4, 5, 5a,5b, 6, 7, 7a, 8, 9, 10, 11, 11a, 11b, 12, I3, I3a-octadecahydr0-2H- cyclopenta[a]chrysenyl)0xy)-2,2-dimethyl—4-0x0butan0ic acid.
LC/MS: m/z calculated 721.5, found 722.3 (M + 1)+. e 85: Compound 154 4-(((3aR, 5aR, 56R, 7aR,9S, IIaR, IIbR, I3aS)-3a-((N-(4- chlorobenzyl)acetamid0)methyl)-I—isopropyl—5a, 5b, 8, 8, I Ia-pentamethyl—Z—oxo- 3,361, 4, 5, 5a,5b, 6, 7, 7a, 8, 9, 10, 11, 11a, 11b, 12, I3, I3a-octadecahydr0-2H- cyclopenta[a]chrysenyl)0xy)-2,2-dimethyl—4-0x0butan0ic acid LC/MS: m/z calculated 749.4, found 750.3 (M + 1)+.
Exam le 86: Com ound 155 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 MR, 1MR, I3aS)-3a-(((4-chlor0benzy0amin0)methyl)-I- isopropyl—5a, 5b, 8, 8, I tamethyl—Z—oxo- 3,361, 4, 5,561, 5b, 6, 7, 7a, 8, 9, 10, 11, 11a, 11b, 12, I3, I3a-octadecahydr0-2H- cyclopenta[a]chrysenyl)0xy)-2,2-dimethyl—4-0x0butan0ic acid.
LC/MS: m/z calculated 707.4, found 708.3 (M + 1)+.
Example 87: nd 156 4-(((3aR, 5aR, 56R, 7aR,9S, IIaR, IIbR, I3aS)-3a-((N-(4- chlorophenethybacetamido)methyD-I-is0pr0pyl—5a, 5b, 8, 8, I Ia-pentamethyl—Z—oxo- 3,361, 4, 5, 5a,5b, 6, 7, 7a, 8, 9, 10, 11, 11a, 11b, 12, I3, I3a-octadecahydr0-2H- cyclopenta[a]chrysenyl)0xy)-2,2-dimethyl—4-0x0butan0ic acid.
LC/MS: m/z calculated 763.5, found 764.3 (M + 1)+.
Example 88: nd 157 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-(((4-chlorophenethyl)amino)methyl)- 1-isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyl-Z-oxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 721.5, found 722.3 (M + 1)+ Example 89: Compound 158 4-(((3aR, 5aR, 5bR, 7aR, 98, 1 1aR, 1 1bR, 13aS)-3a-((R)((4-chlorobenzy/) (3- ypropy/)amino)— 1 -hydroxyethy/)— 1-isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyI-Z-oxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 809.50, found 810.7 (M + 1)+ e 90: Compound 159 4-(((3aR, 5aR, 5bR, 7aR, 98, 1 1aR, 1 1bR, 13aS)-3a-((S)((4-chlorobenzyl) (3- methoxypropy/)amino)— 1 xyethy/)— 1-isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyl-Z-oxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
] LC/MS: m/z calculated 809.5, found 810.4 (M + 1)+ Example 91: Compound 160 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((R)((4-chlorobenzyl) (2- methoxyethyl)amino)- 1-hydroxyethy/)— 1-isopropy/-5a, 5b, 8, 8, 1 1a-pentamethyI-Z-oxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 795.5, found 796.3 (M + 1)+ Example 92: Compound 161 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((S)((4-chlorobenzyl) (2- methoxyethyl)amino)- 1-hydroxyethy/)— 1-isopropy/-5a, 5b, 8, 8, 1 1a-pentamethyI-Z-oxo- 2012/069637 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyclopenta[a]chrysenyl)oxy)—2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 795.5, found 796.3 (M + 1)+ Example 93: Compound 162 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((S)(4-chloro-N-(2- (dimethy/amino)ethyl)benzamido)— oxyethyl)— 1-isopropyl-5a, 5b, 8, 8, 1 1apentamethyloxo-3 , 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0,1 1, 1 1 a, 1 1 b, 1 2, 13, 13a- octadecahydro-2H-cyclopenta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 822.5, found 823.5 (M + 1)+ Example 94: Compound 163 4-(((3aS, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((R)((4-chlorobenzyl) (2- (dimethy/amino)ethy/)amino)- 1-hydroxyethy/)— 1-isopropy/-5a, 5b, 8, 8, 1 1a-pentamethyl- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, tadecahydro-2H- cyclopenta[a]chrysenyl)oxy)—2, 2-dimethyloxobutanoic acid. 2012/069637 LC/MS: m/z calculated 794.5, found 795.5 (M + 1)+ Example 95: Compound 164 aR,5aR,5bR, 7aR,9S, 1 1aR, 1 1bR,13aS)-3a-((R)-2—((4-ch/orobenzyl)((R)- pyrro/idiny/methyl)amino)- 1-hydroxyethy/)— 1-isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyl- 2-oxo-3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
] LC/MS: m/z calculated 820.5, found 821.5 (M + 1)+ Example 96: Compound 165 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((S)((4-chlorobenzyl) ((R)- pyrro/idiny/methyl)amino)- 1-hydroxyethy/)— 1-isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyl- 2-oxo-3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 10, 1 1, 1 1a, 1 1 b, 12, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 820.5, found 821.5 (M + 1)+ Example 97: Compound 166 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((R)((4-chlorobenzyl) (2- hydroxyethy/)amino)- 1-hydroxyethy/)— 1-isopropy/-5a, 5b, 8, 8, 1 1a-pentamethyl0X0- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- enta[a]chrysenyl)oxy)—2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 781.5, found 782.5 (M + 1)+ Example 98: Compound 167 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((R)(4-chlorobenzyl)-5, 6- dioxomorpho/in-2—y/)— 1-isopropyl-5a, 5b, 8, 8, 1 tamethyIoxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)—2, thyloxobutanoic acid.
LC/MS: m/z calculated 791.4, found 792.5 (M + 1)+ Example 99: Compound 168 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((S)(((5-chloropyridin-2— yl)methy/)amino)hydroxyethy/)—1-isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyl—2-0X0- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)—2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 738.4, found 739.5 (M + 1)+ Example 100: Compound 169 aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((R)(4-chlorobenzyl) oxomorpho/in-2—yl)isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyloxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 777.4, found 778.6 (M + 1)+ Exam le 101: Com ound 170 4-(((3aR, 5aR, 5bR, 7aR, 98, 1 1aR, 1 1bR, 13aS)-3a-((R)(4-chlorobenzyl) oxomorpho/in-2—yl)isopropyl-5a, 5b, 8, 8, 1 tamethyloxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 777.4, found 777.9 (M + 1)+ Example 102: Compound 171 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((S)(4-chlorobenzyl) oxomorpho/inyl)isopropyl-5a, 5b, 8, 8, 1 tamethyloxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 777.4, found 777.9 (M + 1)+ Example 103: Compound 172 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((R)(((5-chloropyridin yl)methy/)amino)hydroxyethy/)—1-isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyl0X0- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)—2, thyloxobutanoic acid.
LC/MS: m/z calculated 737.4, found 739.4 (M + 1)+ Example 104: Compound 173 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((S)((4-chlorobenzy/) (2- yethy/)amino)- 1-hydroxyethy/)— 1-isopropy/-5a, 5b, 8, 8, 1 1a-pentamethyl0X0- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)—2, 2-dimethyloxobutanoic acid. 21 5 WO 90664 LC/MS: m/z calculated 781.5, found 782.3 (M + 1)+ Examgle 105: Compound 174 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-(((4-chlorobenzyl) (2- (dimethylamino)ethyl)amino)methy/)— 1-isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyl0X0- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 778.5, found 779.5 (M + 1)+ Example 106: Compound 175 aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-(((4-ch/orophenethyl)(2- (dimethylamino)ethyl)amino)methy/)— 1-isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyl0X0- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/Z calculated 792.5, found 793.5 (M + 1)+ Examgle 107: Compound 176 4-(((3aR, 5aR, 5bR, 7aR, 98, 1 1aR, 1 1bR, 13aS)-3a-((S)(N-(4-ch/orobenzyl) (dimethy/amino)acetamido)- 1-hydroxyethyl)— 1-isopropy/-5a, 5b, 8, 8, 1 1a-pentamethyl- 2-oxo-3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/Z calculated 822.5, found 823.5 (M + 1)+ Examgle 108: Coonund 177 aR, 5aR, 5bR, 7aR, 98, 1 1aR, 1 1bR, 13aS)-3a-((R)(N-(4-chlorobenzyl) (dimethy/amino)acetamido)- 1-hydroxyethy/)— 1-isopropy/-5a, 5b, 8, 8, 1 1a-pentamethyl- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 10, 1 1, 1 1a, 1 1 b, 12, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 822.5, found 823.5 (M + 1)+ Exam le 109: Com ound 178 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((R)((4-ch/orobenzyl) (2- (pyrro/idiny/)ethyl)amino)— oxyethy/)— 1-isopropy/-5a, 5b, 8, 8, 1 1a-pentamethyl- 2-oxo-3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 10, 1 1, 1 1a, 1 1 b, 12, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 834.5, found 835.5 (M + 1)+ Examgle 110: nd 179 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((S)((4-chlorobenzyl) (2- /idiny/)ethyl)amino)— 1-hydroxyethy/)— 1-isopropy/-5a, 5b, 8, 8, 1 1a-pentamethyl- 2-oxo-3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 10, 1 1, 1 1a, 1 1 b, 12, 13, 13a-octadecahydro-2H- enta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 834.5, found 835.5 (M + 1)+ Example 111: Compound 180 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((R)((4-chlorobenzyl) (2- (methy/amino)ethyl)amino)- 1-hydroxyethyl)—1-isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyl oxo-3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid. 2012/069637 LC/MS: m/z calculated 794.5, found 795.4 (M + 1)+ Example 112: Compound 181 4-(((3aR, 5aR, 5bR, 7aR, 98, 1 1aR, 1 1bR, 13aS)-3a-((S)((2-aminoethyl) (4- chlorobenzyl)amino)— 1-hydroxyethy/)— 1-isopropy/-5a, 5b, 8, 8, 1 1a-pentamethyl—2—oxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/Z calculated 780.5, found 781.4 (M + 1)+ Example 113: Compound 182 4-(((3aR, 5aR, 5bR, 7aR, 98, 1 1aR, 1 1bR, 13aS)-3a-((R)((2-aminoethyl)(4- chlorobenzyl)amino)— 1-hydroxyethy/)— 1-isopropy/-5a, 5b, 8, 8, 1 1a-pentamethyl—2—oxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, tadecahydro-2H- enta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/Z calculated 780.5, found 781.4 (M + 1)+ Example 114: Compound 183 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((S)((4-chlorobenzyl) (2- (methy/amino)ethyl)amino)- 1-hydroxyethyl)—1-isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyl oxo-3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
] LC/MS: m/Z calculated 794.5, found 795.5 (M + 1)+ Example 115: Compound 184 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((R)((4-chlorobenzyl) (2-(N- methy/acetamido)ethyl)amino)- 1-hydroxyethyl)- ropyl-5a, 5b, 8, 8, 1 1a- ethyl0X0-3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a- octadecahydro-2H-cyclopenta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 836.5, found 837.5 (M + 1)+ Example 116: Compound 185 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((S)((4-ch/orobenzy/) (2-(N- methy/acetamido)ethyl)amino)- 1-hydroxyethyl)- 1-isopropyl-5a, 5b, 8, 8, 1 1a- pentamethyloxo-3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0,1 1, 1 1 a, 1 1 b, 1 2, 13, 13a- octadecahydro-2H-cyclopenta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 836.5, found 837.5 (M + 1)+ Example 117: Compound 186 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((S)(((S)- 1-(5-ch/oropyridin yl)ethyl)amino)hydroxyethy/)—1-isopropyl-5a, 5b, 8, 8, 1 tamethyl0X0- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)—2, 2-dimethyloxobutanoic acid.
LC/MS: m/z ated 752.5, found 753.4 (M + 1)+ Example 118: Compound 187 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((R)(((S)(5-ch/oropyridin-2— yl)ethyl)amino)hydroxyethy/)—1-isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyl0X0- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)—2, 2-dimethyloxobutanoic acid.
] LC/MS: m/Z calculated 752.5, found 753.4 (M + 1)+ Example 119: Compound 188 4-(((3aR,5aR,5bR, 7aR,9S, 1 1aR, 1 1bR,13aS)-3a-((R)—2—((2— (dimethy/amino)ethyl)(phenethyl)amino)hydroxyethy/)— 1-isopropyl—5a, 5b, 8, 8, 1 amethyl0X0-3 , 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0,1 1, 1 1 a, 1 1 b, 1 2, 13, 13a- octadecahydro-2H-cyclopenta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 788.6, found 789.5 (M + 1)+ Example 120: Compound 189 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((S)(cyclohexyl(2— (dimethy/amino)ethy/)amino)- 1-hydroxyethy/)— 1-isopropy/-5a, 5b, 8, 8, 1 1a-pentamethyl- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 10, 1 1, 1 1a, 1 1 b, 12, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 766.6, found 767.6 (M + 1)+ e 121: Compound 190 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 3a-((R)(cyclohexyl(2- (dimethy/amino)ethy/)amino)- 1-hydroxyethy/)— 1-isopropy/-5a, 5b, 8, 8, 1 tamethyl- 2-oxo-3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 10, 1 1, 1 1a, 1 1 b, 12, 13, 13a-octadecahydro-2H- cyclopenta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 766.6, found 767.6 (M + 1)+ Example 122: Compound 191 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((S)(((5-chloropyridin yl)methyl) (2-(dimethylamino)ethy/)amino)- 1-hydroxyethy/)— 1-isopropy/—5a, 5b, 8, 8, 1 1a- pentamethyl0X0-3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0,1 1, 1 1 a, 1 1 b, 1 2, 13, 13a- octadecahydro-2H-cyclopenta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 809.5, found 810.5 (M + 1)+ Example 123: Compound 192 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-(2-(N-(4-ch/orobenzyl) (dimethylamino)acetamido)ethy/)- 1-isopropy/-5a, 5b, 8, 8, 1 1a-pentamethyI-Z-oxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyclopenta[a]chrysenyl)oxy)—2, 2-dimethyloxobutanoic acid.
] LC/MS: m/z calculated 806.5, found 807.4 (M + 1)+ Example 124: nd 193 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-(2-(2-amino-N-(4- chlorobenzyl)acetamido)ethyl)- 1-isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyloxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)—2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 778.5, found 779.4 (M + 1)+ Example 125: Compound 194 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-(2-(N-(4-ch/orobenzyl) (methy/amino)acetamido)ethyl)isopropyI-5a, 5b, 8, 8, 1 1a-pentamethyl—2-0X0- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)—2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 792.5, found 793.4 (M + 1)+ WO 90664 Example 126: Compound 195 4-(((3aR,5aR,5bR, 7aR,9S, 1 1aR, 1 1bR,13aS)-3a-((S)(((S)(dimethylamino) pheny/ethyl)amino)- 1-hydroxyethy/)— 1-isopropy/-5a, 5b, 8, 8, 1 1a-pentamethyl0X0- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)—2, 2-dimethyloxobutanoic acid.
LC/MS: m/Z calculated 760.5, found 761.5 (M + 1)+ Example 127: Compound 196 4-(((3aR,5aR,5bR, 7aR,9S, 1 1aR, 1 1bR,13aS)-3a-((R)(((R)(dimethy/amino) pheny/ethyl)amino)- 1-hydroxyethy/)— 1-isopropy/-5a, 5b, 8, 8, 1 1a-pentamethyl0X0- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)—2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 760.5, found 761.5 (M + 1)+ Example 128: Compound 197 4-(((3aR,5aR,5bR, 7aR,9S, 1 1aR, 1 1bR,13aS)-3a-((R)(((R)(dimethy/amino) pheny/ethyl)amino)- oxyethy/)— 1-isopropy/-5a, 5b, 8, 8, 1 1a-pentamethyl0X0- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- enta[a]chrysenyl)oxy)—2, 2-dimethyloxobutanoic acid.
LC/MS: m/Z calculated 760.5, found 761.5 (M + 1)+ Example 129: Compound 198 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((R)((4-chlorobenzyl) (3- (dimethy/amino)propyl)amino)- 1-hydroxyethyl)— 1-isopropyl-5a, 5b, 8, 8, 1 1apentamethyl0X0-3 , 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0,1 1, 1 1 a, 1 1 b, 1 2, 13, 13a- octadecahydro-2H-cyclopenta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 822.5, found 823.5 (M + 1)+ Example 130: Compound 199 aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((S)((4-ch/orobenzy/) (3- (dimethy/amino)propyl)amino)- 1-hydroxyethyl)— 1-isopropyl-5a, 5b, 8, 8, 1 1apentamethyl0X0-3 , 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0,1 1, 1 1 a, 1 1 b, 1 2, 13, 13a- octadecahydro-2H-cyclopenta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 822.5, found 823.5 (M + 1)+ WO 90664 Example 131: nd 200 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)- 1-isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyl- 2-0X0-3a-(2-(phenethy/amino)ethyl)- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)—2, thyloxobutanoic acid.
LC/MS: m/z calculated 701.5, found 702.5 (M + 1)+ Example 132: Compound 201 4-(((3aR,5aR,5bR, 7aR,9S, 1 1aR, 1 1bR,13aS)-3a-((R)((2- (dimethylamino)ethyl)(isopropy/)amino)— 1 -hydroxyethy/)— 1-isopropy/—5a, 5b, 8, 8, 1 1a- pentamethyloxo-3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0,1 1, 1 1 a, 1 1 b, 1 2, 13, 13a- octadecahydro-2H-cyclopenta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 726.5, found 727.5 (M + 1)+ Example 133: Compound 202 2-(((R)((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)((3-carboxy—3- methy/butanoyl)oxy)— 1-isopropy/-5a, 5b, 8, 8, 1 1a-pentamethyIoxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysen-3a-yl)hydroxyethyl) (4-ch/orobenzyl)amino)-N, N, N- trimethy/ethanaminium trifluoroacetate.
] LC/MS: m/z calculated 823.5, found 823.5 (M)+ e 134: Compound 203 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 3a-((S)(4-chlorobenzyl) oxomorpho/in-2—yl)isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyloxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 777.4, found 778.4 (M + 1)+ Example 135: Compound 204 4-(((3aR,5aR,5bR, 7aR,9S, 1 1aR, 1 1bR,13aS)-3a-((R)(((S)(dimethylamino) pheny/ethyl)amino)- 1-hydroxyethy/)— 1-isopropy/-5a, 5b, 8, 8, 1 1a-pentamethyl0X0- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)—2, 2-dimethyloxobutanoic acid.
WO 90664 LC/MS: m/Z calculated 760.5, found 761.4 (M + 1)+ Exam le 136: Com ound 205 4-(((3aR, 5aR, 5bR, 7aR, 98, 1 1aR, 1 1bR,13aS)-3a-((S)—2—((2— (dimethylamino)ethyl)(isopropy/)amino)— 1 -hydroxyethy/)— 1-isopropy/—5a, 5b, 8, 8, 1 1a- pentamethyloxo-3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0,1 1, 1 1 a, 1 1 b, 1 2, 13, 13a- octadecahydro-2H-cyclopenta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 726.6, found 727.5 (M + 1)+ Example 137: Compound 206 4-(((3aR, 5aR, 5bR, 7aR, 98, 1 1aR, 1 1bR, 13aS)-3a-((R)(((5-chloropyridin-2— yl)methyl) (2-(dimethylamino)ethy/)amino)- 1-hydroxyethy/)— 1-isopropy/—5a, 5b, 8, 8, 1 1apentamethyloxo-3 , 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0,1 1, 1 1 a, 1 1 b, 1 2, 13, 13a- octadecahydro-2H-cyclopenta[a]chrysenyl)oxy)-2, thyloxobutanoic acid.
LC/MS: m/z calculated 809.5, found 810.5 (M + 1)+ Example 138: Compound 207 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((S)hydroxy (isopropy/amino)ethy/)— 1-isopropy/-5a, 5b, 8, 8, 1 tamethyIoxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyclopenta[a]chrysenyl)oxy)—2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 655.5, found 656.4 (M + 1)+ Example 139: Compound 208 4-(((3aR,5aR,5bR, 7aR,9S, 1 1aR, 1 1bR,13aS)-3a-(2-(((R)(dimethylamino) pheny/ethyl)amino)ethyl)- 1-isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyl0X0- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyclopenta[a]chrysenyl)oxy)—2, thyloxobutanoic acid.
LC/MS: m/Z calculated 744.5, found 745.5 (M + 1)+ Example 140: Compound 209 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-(2-(((S)(dimethylamino) pheny/ethyl)amino)ethyl)- 1-isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyl—2-0X0- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, tadecahydro-2H- cyc/openta[a]chrysenyl)oxy)—2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 744.5, found 745.5 (M + 1)+ Examgle 141: Compound 210 )((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)((3-carboxy—3- methy/butanoyl)oxy)— 1-isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyIoxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyclopenta[a]chrysen-3a-yl)hydroxyethyl) (4-ch/orobenzyl)amino)-N, N, N- hy/ethanaminium trifluoroacetate.
LC/MS: m/z calculated 823.5, found 823.5 (M)+ Example 142: Compound 211 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((R)(4-chlorobenzyl) oxopiperazinyl)- 1-isopropy/-5a, 5b, 8, 8, 1 1a-pentamethyloxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)—2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 776.5, found 777.4 (M + 1)+ Example 143: Compound 212 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((S)(4-ch/orobenzyl)methyl erazin-2—yl)- 1-isopropy/-5a, 5b, 8, 8, 1 1a-pentamethyloxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/Z calculated 790.5, found 791.4 (M + 1)+ Example 144: Compound 213 4-(((3aR, 5aR, 5bR, 7aR, 98, 1 1aR, 1 1bR, 13aS)-3a-((R)((4-chlorobenzyl) (2- hy/amino)ethy/)amino)- 1-methoxyethy/)—1-isopropyI-5a, 5b, 8, 8, 1 1apentamethyl0X0-3 , 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0,1 1, 1 1 a, 1 1 b, 1 2, 13, 13aoctadecahydro-2H-cyclopenta [a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
] LC/MS: m/z calculated 822.5, found 823.5 (M + 1)+ e 145: Compound 214 4-(((3aR, 5aR, 5bR, 7aR, 98, 1 1aR, 1 1bR, 13aS)-3a-((S)hydroxy(piperidin yl) ethyl)isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyl—2—oxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)—2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 681.5, found 682.5 (M + 1)+ Examgle 146: Compound 215 4-(((3aR, 5aR, 5bR, 7aR, 98, 1 1aR, 1 1bR, 13aS)-3a-((R)hydroxy(piperidin- 1- yl)isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyl—2—oxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)—2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 681.5, found 682.5 (M + 1)+ Examgle 147: Compound 216 4-(((3aS, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((R)((4-chlorobenzy/)amino) hydroxyethy/)— 1-isopropy/-5a, 5b, 8, 8, 1 1a-pentamethyl- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyclopenta[a]chrysenyl)oxy)—2, 2-dimethyloxobutanoic acid.
"ON0 Ii LC/MS: m/z calculated 723.5, found 724.4 (M + 1)+ Examgle 148: Compound 217 4-(((3aS, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((R)((4-chlorobenzy/)amino) hydroxyethy/)— 1-isopropy/-5a, 5b, 8, 8, 1 1a—pentamethyl- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyclopenta[a]chrysenyl)oxy)—2, 2-dimethyloxobutanoic acid.
] LC/MS: m/z calculated 653.5, found 654.4 (M + 1)+ Examgle 149: Compound 218 4-(((3aS, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((S)((4-chlorobenzyl)amino)- 1- hydroxyethy/)— ropy/-5a, 5b, 8, 8, 1 1a—pentamethyl- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyclopenta[a]chrysenyl)oxy)—2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 653.5, found 654.4 (M + 1)+ Example 150: Compound 219 4-(((3aR, 5aR, 5bR, 7aR, 98, 1 1aR, 1 1bR, 13aS)-3a-((S)((4-chlorobenzy/) (2- hy/amino)ethy/)amino)- 1-methoxyethy/)—1-isopropyI-5a, 5b, 8, 8, 1 1a- pentamethyloxo-3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0,1 1, 1 1 a, 1 1 b, 1 2, 13, 13a- octadecahydro-2H-cyclopenta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 822.5, found 823.5 (M + 1)+ Examgle 151: Compound 220 -(((3aR,5aR,5bR, 7aR,9S, 1 1aR, 1 aS)-3a-((R)(benzy/amino)- 1- hydroxyethy/)— 1-isopropy/-5a, 5b, 8, 8, 1 1a-pentamethyIoxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)—3, 3-dimethyloxopentanoic acid.
LC/MS: m/Z calculated 717.5, found 718.5 (M + 1)+ Exam le 152: Com ound 221 4-(((3aR,5aR,5bR, , 1 1aR, 1 1bR,13aS)-3a-((R)((4-ch/orobenzyl)amino) methoxyethy/)— 1-isopropy/-5a, 5b, 8, 8, 1 1a-pentamethyI-Z-oxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)—2, 2-dimethyloxobutanoic acid.
LC/MS: m/Z calculated 751.5, found 752.5 (M + 1)+ Example 153: Compound 222 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((S)((4-chlorobenzyl)amino)- 1- methoxyethy/)— 1-isopropy/-5a, 5b, 8, 8, 1 1a-pentamethyI-Z-oxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/Z calculated 751.5, found 752.5 (M + 1)+ Example 154: nd 223 -(((3aR, 5aR, 5bR, 7aR, 98, 1 1aR, 1 1bR, 13aS)-3a-((R)(2-(dimethylamino)-N-(4- fluorobenzyl)acetamido)- 1-hydroxyethyl)— 1-isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyl-Z- oxo-3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyclopenta[a]chrysenyl)oxy)—3, 3-dimethyloxopentanoic acid.
] LC/MS: m/z calculated 820.5, found 821.5 (M + 1)+ Example 155: Compound 224 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((R)((cyc/ohexy/methyl)amino)- 1- hydroxyethy/)— 1-isopropy/-5a, 5b, 8, 8, 1 1a-pentamethyIoxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyclopenta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 709.5, found 710.6 (M + 1)+ Example 156: Compound 225 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((S)(4-ch/orobenzyl)methyl oxopiperazinyl)- 1-isopropy/-5a, 5b, 8, 8, 1 1a-pentamethyloxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyclopenta[a]chrysenyl)oxy)—2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 790.5, found 791.5 (M + 1)+ Example 157: nd 226 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((R)((cyclohexylmethyl) (2- hy/amino)ethy/)amino)- 1-hydroxyethy/)— 1-isopropy/-5a, 5b, 8, 8, 1 1a-pentamethyl- 2-oxo-3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 10, 1 1, 1 1a, 1 1 b, 12, 13, 13a-octadecahydro-2H- enta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 780.6, found 781.5 (M + 1)+ Example 158: nd 227 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((R)((cyclopropy/methy/) (2- (dimethy/amino)ethy/)amino)- 1-hydroxyethy/)— 1-isopropy/-5a, 5b, 8, 8, 1 1a-pentamethyl- 2-oxo-3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 10, 1 1, 1 1a, 1 1 b, 12, 13, 13a-octadecahydro-2H- enta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 738.6, found 739.8 (M + 1)+ Example 159: nd 228 2-(2-(((3aR,5aR,5bR, 7aR,98, 1 1aR, 1 1bR,13aS)-3a-((R)(benzylamino) hydroxyethy/)— 1-isopropy/-5a, 5b, 8, 8, 1 1a-pentamethyIoxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)—2—oxoethoxy)acetic acid.
LC/MS: m/z calculated 691.4, found 692.5 (M + 1)+ Example 160: Compound 229 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-(2-((4-chloro ((dimethylamino)methy/)benzyl)amino)ethyl)isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyl- 2-oxo-3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyclopenta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 778.5, found 779.5 (M + 1)+ Example 161: Compound 230 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-(2-(N-(4-chloro ((dimethy/amino)methyl)benzyl)acetamido)ethyl)isopropyl-5a, 5b, 8, 8, 1 1a- ethyloxo-3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0,1 1, 1 1 a, 1 1 b, 1 2, 13, 13a- octadecahydro-2H-cyclopenta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/Z calculated 820.5, found 821.7 (M + 1)+ Exam le 162: Com ound 231 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-(2-(N-(4-chloro ((dimethy/amino)methyl)benzyl)acetamido)ethyl)isopropyl-5a, 5b, 8, 8, 1 1a- pentamethyloxo-3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0,1 1, 1 1 a, 1 1 b, 1 2, 13, 13aoctadecahydro-2H-cyclopenta ysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 717.5, found 718.5 (M + 1)+ Example 163: Compound 232 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((S)benzamidohydroxyethy/)— 1 -isopropyl-5a, 5b, 8, 8, 1 tamethyl-Z-oxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 717.5, found 718.5 (M + 1)+ Example 164: Compound 233 4-(((3aR,5aR,5bR, 7aR,9S, 1 1aR, 1 1bR,13aS)-3a-((R)hydroxy(N- methylbenzamido)ethyl)— 1-isopropy/-5a, 5b, 8, 8, 1 1a-pentamethyl—2-0X0- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)—2, 2-dimethyloxobutanoic acid.
] LC/MS: m/z calculated 731.5, found 732.3 (M + 1)+ Example 165: Compound 234 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((S)hydroxy(N- methy/benzamido)ethyl)- 1-isopropy/-5a, 5b, 8, 8, 1 1a-pentamethyl0X0- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 731.5, found 732.5 (M + 1)+ Example 166: Compound 235 aS, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((S)((4-chlorobenzyl)(2- (dimethy/amino)ethy/)amino)- 1-hydroxyethy/)— 1-isopropy/-5a, 5b, 8, 8, 1 1a-pentamethyl- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 794.5, found 795.7 (M + 1)+ e 167: Compound 236 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((R)(2-(dimethy/amino)-N- (pyridin-2—y/methyl)acetamido)- 1-hydroxyethyl)— 1-isopropyl-5a, 5b, 8, 8, 1 1a- pentamethyloxo-3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a- octadecahydro-2H-cyclopenta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 789.5, found 790.5 (M + 1)+ Example 168: Compound 237 aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((R)hydroxy(2-(methy/amino)- N-(pyridinylmethyl)acetamido)ethy/)— 1-isopropy/-5a, 5b, 8, 8, 1 1a-pentamethyl0X0- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)—2, 2-dimethyloxobutanoic acid.
] LC/MS: m/z calculated 775.5, found 776.5 (M + 1)+ Example 169: Compound 238 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-(2-((4-chloro ((dimethylamino)methyl)benzy/)(methyl)amino)ethyl)— 1-isopropyl—5a, 5b, 8, 8, 1 amethyloxo-3 , 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0,1 1, 1 1 a, 1 1 b, 1 2, 13, 13a- octadecahydro-2H-cyclopenta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 792.5, found 793.5 (M + 1)+ Example 170: Compound 239 4-(((3aR, 5aR, 5bR, 7aR, 98, 1 1aR, 1 1bR, 13aS)-3a-((R)acetoxy((2— chlorobenzyl) (2-(dimethylamino)ethyl)amino)ethyl)— 1-isopropyl—5a, 5b, 8, 8, 1 1apentamethyl0X0-3 , 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0,1 1, 1 1 a, 1 1 b, 1 2, 13, 13a- cahydro-2H-cyclopenta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
] LC/MS: m/z calculated 850.5, found 851.5 (M + 1)+ Example 171: Compound 240 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((R)(2-amino-N- benzy/acetamido)— 1-hydroxyethyl)- 1-isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyl-Z-oxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 760.5, found 761.5 (M + 1)+ Examgle 172: Compound 241 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((R)(N-benzyl (methylamino)acetamido)—1-hydroxyethy/)—1-isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyI oxo-3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 774.5, found 775.5 (M + 1)+ Examgle 173: Compound 242 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((R)(N-benzyl (dimethy/amino)acetamido)- 1-hydroxyethy/)— 1-isopropy/-5a, 5b, 8, 8, 1 1a-pentamethyl- 2-oxo-3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 10, 1 1, 1 1a, 1 1 b, 12, 13, 13a-octadecahydro-2H- enta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 788.5, found 789.5 (M + 1)+ e 174: Coonund 243 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((R)(2-amino-N-(pyridin y/)acetamido)— 1-hydroxyethy/)— 1-isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyI0X0- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)—2, 2-dimethyloxobutanoic acid. 2012/069637 LC/MS: m/z ated 761.5, found 762.5 (M + 1)+ Example 175: Compound 244 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((S)(((R)- 1-(5-ch/oropyridin yl)ethyl)amino)hydroxyethy/)—1-isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyl—2-0X0- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 752.5, found 753.5 (M + 1)+ Example 176: Compound 245 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((R)(((R)(5-ch/oropyridin-2— yl)ethyl)amino)hydroxyethy/)—1-isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyl—2-0X0- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 752.5, found 753.4 (M + 1)+ Example 177: Compound 246 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((R)(N-((R)- 1-(5-ch/oropyridin-2— yl)ethyl)(dimethylamino)acetamido)- 1-hydroxyethyl)— 1-isopropyl-5a, 5b, 8, 8, 1 1apentamethyloxo-3 , 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0,1 1, 1 1 a, 1 1 b, 1 2, 13, 13aoctadecahydro-2H-cyclopenta [a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 837.5, found 838.5 (M + 1)+ Example 178: Compound 247 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR,13aS)-3a-((S)—2—((2- (dimethy/amino)ethyl)(phenethyl)amino)hydroxyethy/)— 1-isopropyl—5a, 5b, 8, 8, 1 1a- pentamethyloxo-3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0,1 1, 1 1 a, 1 1 b, 1 2, 13, 13a- octadecahydro-2H-cyclopenta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 788.6, found 789.5 (M + 1)+ Example 179: Compound 248 aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((R)(N-benzyl (dimethy/amino)acetamido)- 1-hydroxyethy/)— 1-isopropy/-5a, 5b, 8, 8, 1 1a-pentamethyl- 2-oxo-3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 10, 1 1, 1 1a, 1 1 b, 12, 13, tadecahydro-2H- enta[a]chrysenyl)oxy)—3, 3-dimethyloxopentanoic acid.
LC/MS: m/z calculated 802.6, found 803.5 (M + 1)+ Exam le 180: Com ound 249 4-(((3aR,5aR,5bR, 7aR,9S, 1 1aR, 1 1bR,13aS)-3a-((R)(N-(2- (dimethy/amino)ethyl)cyclohexanecarboxamido)— 1-hydroxyethyl)— 1-isopropyl- 5a, 5b, 8, 8, 1 tamethyl-Z-oxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)—2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 794.6, found 795.5 (M + 1)+ Exam le 181: Com ound 250 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((R)(cyc/ohexanecarboxamido) hydroxyethy/)— ropy/-5a, 5b, 8, 8, 1 1a-pentamethyIoxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 723.5, found 724.5 (M + 1)+ Example 182: nd 251 4-(((3aR,5aR,5bR, , 1 1aR, 1 1bR,13aS)-3a-((R)(2-amino-N-((S)(5- chloropyridinyl)ethyl)acetamido)- 1-hydroxyethyl)— 1-isopropyl-5a, 5b, 8, 8, 1 1apentamethyloxo-3 , 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0,1 1, 1 1 a, 1 1 b, 1 2, 13, 13aoctadecahydro-2H-cyclopenta [a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 809.5, found 810.4 (M + 1)+ Example 183: Compound 252 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((R)(N-((S)(5-chloropyridin-2— yl)ethyl)(methy/amino)acetamido)- 1-hydroxyethyl)— 1-isopropyl-5a, 5b, 8, 8, 1 1a- pentamethyloxo-3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0,1 1, 1 1 a, 1 1 b, 1 2, 13, 13a- octadecahydro-2H-cyclopenta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 823.5, found 824.5 (M + 1)+ Example 184: Compound 253 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((R)(N-((S)(5-chloropyridin-2— yl)ethyl)(dimethylamino)acetamido)- 1-hydroxyethyl)— 1-isopropyl-5a, 5b, 8, 8, 1 1a- pentamethyloxo-3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0,1 1, 1 1 a, 1 1 b, 1 2, 13, adecahydro-2H-cyclopenta [a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 837.5, found 838.5 (M + 1)+ Example 185: Compound 254 4-(((3aR,5aR,5bR, 7aR,9S, 1 1aR, 1 1bR,13aS)-3a-((R)—2-((2- aminoethyl) (benzyl)amino)—1-hydroxyethy/)—1-isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyI oxo-3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
] LC/MS: m/z calculated 746.5, found 747.5 (M + 1)+ Example 186: Compound 255 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((R)((cyc/obuty/methyl)amino) hydroxyethy/)— 1-isopropy/-5a, 5b, 8, 8, 1 1a-pentamethyIoxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- enta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 681.5, found 682.5 (M + 1)+ e 187: Compound 256 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((R)acetoxy-2—(benzy/(2— (dimethy/amino)ethy/)amino)ethy/)— 1-isopropy/-5a, 5b, 8, 8, 1 1a-pentamethyI-Z-oxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)-2, thyloxobutanoic acid.
LC/MS: m/z calculated 816.6, found 817.5 (M + 1)+ Exam le 188: Com ound 257 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((S)acetoxy(benzy/(2— (dimethy/amino)ethy/)amino)ethy/)— 1-isopropy/-5a, 5b, 8, 8, 1 1a-pentamethyI-Z-oxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 816.6, found 817.5 (M + 1)+ Example 189: Compound 258 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((S)(cyclohexanecarboxamido) hydroxyethy/)— 1-isopropy/-5a, 5b, 8, 8, 1 1a-pentamethyIoxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z ated 723.5, found 724.5 (M + 1)+ Example 190: nd 259 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((S)((cyc/obuty/methyl)amino) hydroxyethy/)— 1-isopropy/-5a, 5b, 8, 8, 1 1a-pentamethyIoxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 681.5, found 682.5 (M + 1)+ Example 191: Compound 260 4-(((3aR,5aR,5bR, , 1 1aR, 1 1bR,13aS)-3a-((S)(N-(2- (dimethylamino)ethyl)cyclohexanecarboxamido) - 1-hydroxyethy/)— 1-isopropyl- 5a, 5b, 8, 8, 1 1a-pentamethyloxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, tadecahydro-2H- cyclopenta[a]chrysenyl)oxy)—2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 794.6, found 795.6 (M + 1)+ Exam le 192: Com ound 261 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((S)((cyclobutylmethyl) (2- (dimethy/amino)ethy/)amino)- 1-hydroxyethy/)— 1-isopropy/-5a, 5b, 8, 8, 1 1a—pentamethyl- 2-oxo-3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- enta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 752.6, found 753.6 (M + 1)+ e 193: Compound 262 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((R)(((1H-pyrazolyl)methyl)(2- (dimethy/amino)ethy/)amino)- 1-hydroxyethy/)— 1-isopropy/-5a, 5b, 8, 8, 1 1a—pentamethyl- 2-oxo-3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 10, 1 1, 1 1a, 1 1 b, 12, 13, 13a-octadecahydro-2H- cyclopenta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 764.6, found 765.5 (M + 1)+ Example 194: Compound 263 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((R)((cyclopropy/methyl)amino)- 1-hydroxyethyl)- 1-isopropy/-5a, 5b, 8, 8, 1 1a-pentamethyl-Z-oxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, tadecahydro-2H- cyc/openta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 667.5, found 668.5 (M + 1)+ Example 195: nd 264 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((1S)hydroxy((2-hydroxy-2— pheny/ethyl)(methyl)amino)ethyl)—1-isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyl—2-0X0- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 747.5, found 748.5 (M + 1)+ Example 196: Compound 265 WO 90664 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((S)- 1-hydroxy((2-(pyridin yl)ethy/)amino)ethyl)— 1-isopropyl—5a, 5b, 8, 8, 1 1a-pentamethyl—2-0X0- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyclopenta[a]chrysenyl)oxy)—2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 718.5, found 719.5 (M + 1)+ Example 197: Compound 266 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 3a-((S)hydroxy((R) ypiperidin- 1-yl)ethy/)- 1-isopropy/-5a, 5b, 8, 8, 1 1a-pentamethyI0X0- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyclopenta[a]chrysenyl)oxy)—2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 697.5, found 698.5 (M + 1)+ Example 198: Compound 267 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((S)hydroxy((3-(2- oxopyrrolidin- 1-yl)propyl)amino)ethyl)— 1-isopropy/-5a, 5b, 8, 8, 1 1a-pentamethyl—2-0X0- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyclopenta[a]chrysenyl)oxy)—2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 738.5, found 739.5 (M + 1)+ Example 199: Compound 268 aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((S)- 1-hydroxy((2- phenoxyethyl)amino)ethyl)isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyl0X0- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 733.5, found 734.5 (M + 1)+ Example 200: Compound 269 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((S)hydroxy(4-(2— hydroxyethyl)piperazin- 1-yl)ethyl)- 1-isopropy/-5a, 5b, 8, 8, 1 1a-pentamethyI-Z-oxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 726.5, found 727.5 (M + 1)+ Examgle 201: Compound 270 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((1S)(2, 6-dimethy/morpho/ino)— 1- yethy/)— 1-isopropy/-5a, 5b, 8, 8, 1 tamethyIoxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyclopenta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 711.5, found 712.5 (M + 1)+ Examgle 202: Coonund 271 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((S)hydroxy thiomorpho/inoethyl)isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyl—2-0X0- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyclopenta[a]chrysenyl)oxy)—2, 2-dimethyloxobutanoic acid.
] LC/MS: m/z calculated 699.5, found 700.4 (M + 1)+ Examgle 203: Compound 272 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((S)- 1-hydroxy—2-((3- morpho/inopropyl)amino)ethyl)- 1-isopropyl—5a, 5b, 8, 8, 1 1a-pentamethyl—2-0X0- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyclopenta[a]chrysenyl)oxy)—2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 740.5, found 741.5 (M + 1)+ Example 204: Compound 273 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((S)((3-(1H-imidazol yl)propyl)amino)— 1-hydroxyethy/)— 1-isopropy/-5a, 5b, 8, 8, 1 1a-pentamethyI-Z-oxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, tadecahydro-2H- cyc/openta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 721.5, found 722.5 (M + 1)+ Example 205: Compound 274 4-(((3aR,5aR,5bR, 7aR,9S, 1 1aR, 1 aS)-3a-((S)— 1-hydroxy((4- hydroxyphenethyl)amino)ethy/)- 1-isopropyl—5a, 5b, 8, 8, 1 1a-pentamethyl0X0- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- enta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/Z calculated 733.5, found 734.5 (M + 1)+ Example 206: Compound 275 4-(((3aR,5aR,5bR, 7aR,9S, 1 1aR, 1 aS)-3a-((R)(cyclopentylamino)—1- hydroxyethy/)— 1-isopropy/-5a, 5b, 8, 8, 1 1a-pentamethyIoxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyclopenta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 681.5, found 682.5 (M + 1)+ Example 207: Compound 276 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((S)((cyclohexy/methyl)amino)- 1- hydroxyethy/)— 1-isopropy/-5a, 5b, 8, 8, 1 1a-pentamethyIoxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, tadecahydro-2H- cyclopenta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
] LC/MS: m/Z calculated 709.5, found 710.5 (M + 1)+ Example 208: Compound 277 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((R)((cyclobutylmethyl) (2- (dimethy/amino)ethy/)amino)- 1-hydroxyethy/)— 1-isopropy/-5a, 5b, 8, 8, 1 1a—pentamethyl- 2-oxo-3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyclopenta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
O 277 LC/MS: m/Z calculated 752.6, found 753.6 (M + 1)+ Example 209: Compound 278 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((R)(((1H-pyrazolyl)methyl)(2- (dimethy/amino)ethy/)amino)- 1-hydroxyethy/)— 1-isopropy/-5a, 5b, 8, 8, 1 1a-pentamethyl- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 10, 1 1, 1 1a, 1 1 b, 12, 13, 13a-octadecahydro-2H- enta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 764.6, found 765.5 (M + 1)+ Examgle 210: Compound 279 4-(((3aR, 5aR, 5bR, 7aR, 98, 1 1aR, 1 1bR, 3a-((S)((cyclopropy/methy/)amino) hydroxyethy/)— 1-isopropy/-5a, 5b, 8, 8, 1 1a-pentamethyIoxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 667.5, found 668.5 (M + 1)+ Example 211: Compound 280 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((S)(cyc/obutylamino)—1- hydroxyethy/)— 1-isopropy/-5a, 5b, 8, 8, 1 1a-pentamethyIoxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z ated 667.5, found 668.5 (M + 1)+ Example 212: Compound 281 4-(((3aR,5aR,5bR, 7aR,9S, 1 1aR, 1 1bR,13aS)-3a-((R)(cyclobuty/amino) hydroxyethy/)— 1-isopropy/-5a, 5b, 8, 8, 1 1a-pentamethyIoxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z ated 667.5, found 668.5 (M + 1)+ Exam le 213: Com ound 282 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 3a-((S)- 1-hydroxy((3-(pyrrolidin yl)propyl)amino)ethyl)— 1-isopropy/-5a, 5b, 8, 8, 1 1a-pentamethyl0X0- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)—2, 2-dimethyloxobutanoic acid.
LC/MS: m/z ated 724.5, found 725.5 (M + 1)+ Example 214: Compound 283 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((S)- 1-hydroxy(4-(pyridin yl)piperazin- 1-yl)ethyl)- 1-isopropyl—5a, 5b, 8, 8, 1 1a-pentamethyl—2-0X0- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)-2, thyloxobutanoic acid.
LC/MS: m/z calculated 759.5, found 760.5 (M + 1)+ Example 215: Compound 284 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((S)hydroxy(4-methyI-1, 4- diazepanyl)ethyl)isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyloxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)—2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 710.5, found 711.5 (M + 1)+ Example 216: Compound 285 4-(((3aR,5aR,5bR, 7aR,9S, 1 1aR, 1 1bR,13aS)-3a-((S)- 1-hydroxy((4- sulfamoy/phenethyl)amino)ethy/)isopropyI-5a, 5b, 8, 8, 1 1a-pentamethyIoxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)—2, 2-dimethyloxobutanoic acid.
] LC/MS: m/Z calculated 796.5, found 797.5 (M + 1)+ Example 217: Compound 286 aR,5aR,5bR, 7aR,9S, 1 1aR, 1 1bR, 13aS)-3a-((S)(4-carbamoy/piperidin- 1-yl)- 1- hydroxyethy/)— 1-isopropy/-5a, 5b, 8, 8, 1 1a-pentamethyIoxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, tadecahydro-2H- cyc/openta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 724.5, found 725.5 (M + 1)+ Example 218: Compound 287 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((S)hydroxy(4-(2- methoxyethyl)piperazin- 1-yl)ethy/)isopropy/-5a, 5b, 8, 8, 1 1a-pentamethyl0X0- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)—2, 2-dimethyloxobutanoic acid.
] LC/MS: m/z calculated 740.5, found 741.5 (M + 1)+ Example 219: Compound 288 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((S)hydroxy(((R)hydroxy- 1- ethyl)amino)ethyl)- 1-isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyl0X0- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)—2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 733.5, found 734.5 (M + 1)+ Example 220: Compound 289 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((1S)hydroxy (octahydroisoquinolin-2(1H)-yl)ethyl)isopropyI-5a, 5b, 8, 8, 1 1a-pentamethyloxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)—2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 735.5, found 736.5 (M + 1)+ Example 221: Compound 290 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((S)- 1-hydroxy((3-(piperidin yl)propyl)amino)ethyl)— 1-isopropy/-5a, 5b, 8, 8, 1 1a-pentamethyl—2-0X0- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyclopenta[a]chrysenyl)oxy)—2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 738.5, found 739.5 (M + 1)+ Example 222: Compound 291 4-(((3aR,5aR,5bR, 7aR,9S, 1 1aR, 1 1bR,13aS)-3a-((R)(2-(dimethy/amino)-N-((S)- 1- inyl)ethyl)acetamido)— 1-hydroxyethyl)— 1-isopropyl-5a, 5b, 8, 8, 1 1a- pentamethyloxo-3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0,1 1, 1 1 a, 1 1 b, 1 2, 13, 13a- octadecahydro-2H-cyclopenta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 803.5, found 804.5 (M + 1)+ Example 223: nd 292 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((S)(cyclopentylamino)—1- hydroxyethy/)— ropy/-5a, 5b, 8, 8, 1 1a-pentamethyIoxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyclopenta[a]chrysenyl)oxy)—2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 681.5, found 682.5 (M + 1)+ Example 224: Compound 293 4-(((3aR, 5aR, 5bR, 7aR, 98, 1 1aR, 1 1bR, 13aS)-3a-((S)(benzo[d][1, 3]dioxol y/amino)- 1-hydroxyethy/)— 1-isopropy/-5a, 5b, 8, 8, 1 1a-pentamethyI-Z-oxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/Z calculated 733.5, found 734.5 (M + 1)+ e 225: Compound 294 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((S)- oxy((2-(thiophen yl)ethy/)amino)ethy/)— 1-isopropyl—5a, 5b, 8, 8, 1 tamethyl0X0- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)—2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 723.5, found 724.4 (M + 1)+ Example 226: Compound 295 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((S)hydroxy(4-(4- methy/benzy/)piperazinyl)ethyl)- 1-isopropyl—5a, 5b, 8, 8, 1 1a-pentamethyl0X0- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, tadecahydro-2H- enta[a]chrysenyl)oxy)—2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 786.5, found 787.5 (M + 1)+ Example 227: Compound 296 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((S)(bis(2-methoxyethyl)amino)- 1-hydroxyethyl)- 1-isopropy/-5a, 5b, 8, 8, 1 1a-pentamethyl0X0- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)—2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 729.5, found 730.5 (M + 1)+ Example 228: Compound 297 4-(((3aR,5aR,5bR, , 1 1aR, 1 1bR,13aS)-3a-((1S)- 1-hydroxy((2- methy/cyc/ohexyl)amino)ethyl)- 1-isopropy/-5a, 5b, 8, 8, 1 1a-pentamethyI0X0- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)—2, 2-dimethyloxobutanoic acid.
LC/MS: m/Z calculated 709.5, found 710.5 (M + 1)+ Example 229: Compound 298 aR,5aR,5bR, 7aR,9S, 1 1aR, 1 aS)-3a-((1S)hydroxy((2-(1- methy/pyrro/idinyl)ethy/)amino)ethyl)- 1-isopropy/-5a, 5b, 8, 8, 1 1a-pentamethyI oxo-3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 724.5, found 725.5 (M + 1)+ Example 230: Compound 299 4-(((3aR,5aR,5bR, 7aR,9S, 1 1aR, 1 1bR,13aS)-3a-((S)- 1-hydroxy(((1 r, 4S) hydroxycyc/ohexyl)amino)ethyl)- 1-isopropy/-5a, 5b, 8, 8, 1 tamethyIoxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)—2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 711.5, found 712.4 (M + 1)+ Example 231: Compound 300 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 3a-((S)(4-ethy/piperazin- 1-y/)- 1- hydroxyethy/)— 1-isopropy/-5a, 5b, 8, 8, 1 1a-pentamethyIoxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- enta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 710.5, found 711.5 (M + 1)+ e 232: Compound 301 4-(((3aR,5aR,5bR, 7aR,9S, 1 1aR, 1 1bR,13aS)-3a-((S)hydroxy(((S) hydroxypropyl)amino)ethyl)- 1-isopropy/-5a, 5b, 8, 8, 1 1a-pentamethyI0X0- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)—2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 671.5, found 672.4 (M + 1)+ Example 233: Compound 302 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((S)((4-ch/orophenyl)amino) hydroxyethy/)— 1-isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyIoxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)—2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 723.4, found 724.4 (M + 1)+ e 234: Compound 303 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((S)hydroxy(isoindolin-2— yl) ethyl)isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyloxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)—2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 715.5, found 716.5 (M + 1)+ Example 235: Compound 304 4-(((3aR, 5aR, 5bR, 7aR, 98, 1 1aR, 1 1bR, 13aS)-3a-((R)(((S)(5-ch/oropyridin-2— y/)ethyl) (2-(dimethy/amino)ethy/)amino)hydroxyethy/)—1-isopropyl-5a, 5b, 8, 8, 1 1apentamethyl0X0-3 , 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0,1 1, 1 1 a, 1 1 b, 1 2, 13, 13a- octadecahydro-2H-cyclopenta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
] LC/MS: m/z calculated 823.5, found 824.5 (M + 1)+ Example 236: Compound 305 aR, 5aR, 5bR, 7aR, 98, 1 1aR, 1 1bR, 13aS)-3a-((S)(((S)- 1-(5-chloropyridin-2— yl) (2-(dimethy/amino)ethy/)amino)hydroxyethy/)—1-isopropyl-5a, 5b, 8, 8, 1 1apentamethyloxo-3 , 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0,1 1, 1 1 a, 1 1 b, 1 2, 13, 13aoctadecahydro-2H-cyclopenta [a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 823.5, found 824.5 (M + 1)+ Example 237: Compound 306 4-(((3aR, 5aR, 5bR, 7aR, 98, 1 1aR, 1 1bR, 13aS)-3a-((R)hydroxy(isoindo/in yl) ethyl)isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyloxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)—2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 715.5, found 716.5 (M + 1)+ Example 238: Compound 307 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((S)((2-(5-chloropyridin yl)propany/)amino)—1-hydroxyethy/)—1-isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyl0X0- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- enta[a]chrysenyl)oxy)—2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 766.5, found 767.5 (M + 1)+ Exam le 239: Com ound 308 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((R)((2-(5-chloropyridin y/)propan-2—y/)amino)—1-hydroxyethy/)—1-isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyl0X0- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 766.5, found 767.6 (M + 1)+ Exam le 240: Com ound 309 4-(((3aR,5aR,5bR, 7aR,9S, 1 1aR, 1 1bR,13aS)-3a-((R)hydroxy(((S)(pyridin yl)ethy/)amino)ethy/)— 1-isopropyl—5a, 5b, 8, 8, 1 1a-pentamethyl0X0- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, tadecahydro-2H- cyc/openta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
] LC/MS: m/z calculated 718.5, found 719.5 (M + 1)+ Example 241: Compound 310 WO 90664 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((S)hydroxy((pyridin y/methyl)amino)ethyl)- 1-isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyl0X0- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 704.5, found 705.5 (M + 1)+ Examgle 242: Compound 311 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((R)hydroxy((pyridin-2— yl)amino)ethyl)— 1-isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyl0X0- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 704.5, found 705.5 (M + 1)+ Examgle 243: Compound 312 4-(((3aR,5aR,5bR, 7aR,9S, 1 1aR, 1 1bR,13aS)-3a-((R)-2—((2— (dimethylamino)ethyl)(pyridiny/methyl)amino)hydroxyethy/)— 1-isopropyl- 5a, 5b, 8, 8, 1 1a-pentamethyl-Z-oxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- enta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/Z calculated 775.5, found 776.5 (M + 1)+ Example 244: Compound 313 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((S)hydroxy lamino)ethyl)— 1-isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyl0X0- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)—2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 689.5, found 690.5 (M + 1)+ Examgle 245: Compound 314 4-(((3aR,5aR,5bR, , 1 1aR, 1 aS)-3a-((S)- 1-hydroxy((4- methoxyphenyl)amino)ethyl)- 1-isopropyl—5a, 5b, 8, 8, 1 1a-pentamethyl0X0- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)—2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 719.5, found 720.5 (M + 1)+ Example 246: Compound 315 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((S)hydroxy((S) (hydroxymethyl)pyrro/idin- 1-yl)ethy/)- 1-isopropyl—5a, 5b, 8, 8, 1 1a-pentamethyl0X0- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- enta[a]chrysenyl)oxy)—2, thyloxobutanoic acid.
LC/MS: m/z calculated 697.5, found 698.5 (M + 1)+ Example 247: Compound 316 aR,5aR,5bR, 7aR,9S, 1 1aR, 1 1bR,13aS)-3a-((S)((R)—3- (ethoxycarbonyl)piperidinyl)- 1-hydroxyethy/)— 1-isopropyl—5a, 5b, 8, 8, 1 1a- pentamethyloxo-3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0,1 1, 1 1 a, 1 1 b, 1 2, 13, 13a- octadecahydro-2H-cyclopenta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 753.5, found 754.5 (M + 1)+ Example 248: Compound 317 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((S)(4-formylpiperazin- 1-yl)- 1- hydroxyethy/)— 1-isopropy/-5a, 5b, 8, 8, 1 1a-pentamethyIoxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 710.5, found 711.5 (M + 1)+ Example 249: Compound 318 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((S)-2—(4-benzy/piperidin- 1-y/) hydroxyethy/)— 1-isopropy/-5a, 5b, 8, 8, 1 1a-pentamethyIoxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, tadecahydro-2H- cyc/openta[a]chrysenyl)oxy)-2, thyloxobutanoic acid.
LC/MS: m/z calculated 771.5, found 772.5 (M + 1)+ Example 250: Compound 319 4-(((3aR, 5aR, 5bR, 7aR, 98, 1 1aR, 1 1bR, 13aS)-3a-((S)(4-acetylpiperaziny/) hydroxyethy/)— 1-isopropy/-5a, 5b, 8, 8, 1 1a-pentamethyIoxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 724.5, found 725.5 (M + 1)+ Example 251: nd 320 4-(((3aR, 5aR, 5bR, 7aR, 98, 1 1aR, 1 1bR, 13aS)-3a-((S)hydroxy(4-(2- morpholinoethy/)piperazin- 1-yl)ethyl)isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyl—2-0X0- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyclopenta[a]chrysenyl)oxy)—2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 795.6, found 796.5 (M + 1)+ Example 252: Compound 321 4-(((3aR,5aR,5bR, , 1 1aR, 1 1bR,13aS)-3a-((R) (benzy/(carboxymethyl)amino)hydroxyethyl)- 1-isopropyl—5a, 5b, 8, 8, 1 1a- pentamethyloxo-3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0,1 1, 1 1 a, 1 1 b, 1 2, 13, 13a- octadecahydro-2H-cyclopenta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/Z calculated 761.5, found 762.5 (M + 1)+ Example 253: Compound 322 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((S)hydroxy(((S)- 1-(pyridin yl)ethy/)amino)ethyl)— 1-isopropyl—5a, 5b, 8, 8, 1 1a-pentamethyl—2-0X0- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, tadecahydro-2H- cyclopenta[a]chrysenyl)oxy)—2, 2-dimethyloxobutanoic acid.
LC/MS: m/Z calculated 718.5, found 719.5 (M + 1)+ Example 254: Compound 323 4-(((3aR,5aR,5bR, , 1 1aR, 1 1bR,13aS)-3a-((R)(2-(dimethy/amino)-N-((R) (pyridiny/)ethyl)acetamido)— 1-hydroxyethyl)— 1-isopropyl-5a, 5b, 8, 8, 1 1apentamethyl0X0-3 , 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0,1 1, 1 1 a, 1 1 b, 1 2, 13, 13a- octadecahydro-2H-cyclopenta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 803.5, found 804.5 (M + 1)+ Example 255: Compound 324 4-(((3aR, 5aR, 5bR, 7aR, 98, 1 1aR, 1 1bR, 13aS)-3a-((R)— 1-hydroxy((2- lamino)ethyl)(pyridiny/methyl)amino)ethyl)isopropyl-5a, 5b, 8, 8, 1 1apentamethyl0X0-3 , 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0,1 1, 1 1 a, 1 1 b, 1 2, 13, 13a- octadecahydro-2H-cyclopenta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 761.5, found 762.5 (M + 1)+ Example 256: Compound 325 4-((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((R)(bis(4-ch/orobenzyl)amino)- 1- yethy/)— 1-isopropy/-5a, 5b, 8, 8, 1 1a-pentamethyIoxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, tadecahydro-2H- cyclopenta[a]chrysenyl) 1-tert-buty/ 2, 2-dimethy/succinate.
LC/MS: m/Z calculated 917.5, found 918.5 (M + 1)+ Example 257: Compound 326 4-(((3aR,5aR,5bR, 7aR,9S, 1 1aR, 1 1bR, 13aS)-3a-((R)(bis(4-chlorobenzyl)amino) hydroxyethy/)— 1-isopropy/-5a, 5b, 8, 8, 1 1a-pentamethyIoxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 861.4, found 862.4 (M + 1)+ Example 258: Compound 327 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((R)- 1-hydroxy((2-(pyridin yl)ethy/)amino)ethyl)— ropyl—5a, 5b, 8, 8, 1 1a-pentamethyl0X0- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)—2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 718.5, found 719.5 (M + 1)+ Example 259: Compound 328 4-(((3aR,5aR,5bR, 7aR,9S, 1 1aR, 1 1bR, 13aS)-3a-((R)hydroxy((R)—3- ypiperidin- 1-yl)ethy/)- 1-isopropy/-5a, 5b, 8, 8, 1 1a-pentamethyI-Z-oxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)-2, thyloxobutanoic acid.
LC/MS: m/z calculated 697.5, found 698.5 (M + 1)+ Example 260: Compound 329 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((R)- 1-hydroxy((4- hydroxyphenethyl)amino)ethy/)- 1-isopropyl—5a, 5b, 8, 8, 1 1a-pentamethyl0X0- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- enta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 733.5, found 734.4 (M + 1)+ Example 261: Compound 330 aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR,13aS)-3a-((R)- 1-hydroxy(4-(2- hydroxyethyl)piperazin- 1-yl)ethyl)- 1-isopropy/-5a, 5b, 8, 8, 1 tamethyl0X0- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyclopenta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z ated 726.5, found 727.5 (M + 1)+ Example 262: Compound 331 4-(((3aR,5aR,5bR, 7aR,9S, 1 1aR, 1 1bR,13aS)-3a-((R)hydroxy thiomorpho/inoethyl)isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyl0X0- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyclopenta[a]chrysenyl)oxy)—2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 699.4, found 700.4 (M + 1)+ Example 263: Compound 332 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((R)hydroxy(4-(pyridin yl)piperazin- 1-yl)ethyl)- 1-isopropyl—5a, 5b, 8, 8, 1 1a-pentamethyl0X0- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyclopenta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 759.5, found 760.5 (M + 1)+ Example 264: Compound 333 aR, 5aR, 5bR, 7aR, 98, 1 1aR, 1 1bR, 13aS)-3a-((R)- 1-hydroxy(4-methyl-1, 4- diazepanyl)ethyl)isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyloxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 710.5, found 711.5 (M + 1)+ Example 265: Compound 334 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((R)(4-carbamoy/piperidinyl)- 1- hydroxyethy/)— 1-isopropy/-5a, 5b, 8, 8, 1 1a-pentamethyIoxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, tadecahydro-2H- cyc/openta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 724.5, found 725.5 (M + 1)+ e 266: Compound 335 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR,13aS)-3a-((R)- 1-hydroxy(4-(2- yethyl)piperazin- 1-yl)ethy/)isopropy/-5a, 5b, 8, 8, 1 1a-pentamethyI0X0- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)—2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 740.5, found 741.5 (M + 1)+ e 267: Compound 336 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((R)hydroxy(((R)hydroxy pheny/ethyl)amino)ethyl)- 1-isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyl0X0- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)—2, 2-dimethyloxobutanoic acid.
LC/MS: m/Z calculated 733.5, found 734.5 (M + 1)+ Example 268: Compound 337 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((S)hydroxy((pyrimidin y/methyl)amino)ethyl)— 1-isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyl0X0- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)—2, 2-dimethyloxobutanoic acid.
] LC/MS: m/z calculated 705.5, found 706.4 (M + 1)+ Example 269: Compound 338 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((R)hydroxy((pyrimidin y/methyl)amino)ethyl)— ropyl-5a, 5b, 8, 8, 1 1a-pentamethyl—2-0X0- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/Z calculated 705.5, found 706.4 (M + 1)+ Example 270: Compound 339 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((R)(N-benzyl(dimethy/amino)— 2-oxoacetamido)- 1-hydroxyethyl)— 1-isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyl-Z-oxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 802.5, found 803.5 (M + 1)+ Example 271: Compound 340 4-(((3aR, 5aR, 5bR, 7aR, 98, 1 1aR, 1 1bR, 3a-((S)((4-chloro ((dimethy/amino)methyl)benzyl)amino)—1-hydroxyethy/)—1-isopropyl-5a, 5b, 8, 8, 1 1apentamethyloxo-3 , 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0,1 1, 1 1 a, 1 1 b, 1 2, 13, 13aoctadecahydro-2H-cyclopenta [a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
] LC/MS: m/Z calculated 794.5, found 795.5 (M + 1)+ Example 272: Compound 341 4-(((3aR,5aR,5bR, 7aR,9S, 1 1aR, 1 1bR, 3a-((R)((4-ch/oro ((dimethy/amino)methyl)benzyl)amino)—1-hydroxyethy/)—1-isopropyl-5a, 5b, 8, 8, 1 1a- pentamethyloxo-3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0,1 1, 1 1 a, 1 1 b, 1 2, 13, 13a- octadecahydro-2H-cyclopenta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/Z calculated 794.5, found 795.5 (M + 1)+ Example 273: Compound 342 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((S)((4-chloro ((dimethy/amino)methyl)benzyl)(methyl)amino)hydroxyethyl)— 1-isopropyl- 5a, 5b, 8, 8, 1 1a-pentamethyloxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)—2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 808.5, found 809.5 (M + 1)+ Examgle 274: Comgound 343 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((R)(N-(4-chloro ((dimethy/amino)methy/)benzyl)acetamido)- 1-hydroxyethy/)— 1-isopropyl- 5a, 5b, 8, 8, 1 1a-pentamethyloxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 836.5, found 837.5 (M + 1)+ Exam le 275: Com ound 344 4-(((3aR,5aR,5bR, 7aR,9S, 1 1aR, 1 1bR, 3a-((R)((4-chloro ((dimethy/amino)methyl)benzyl)(methyl)amino)hydroxyethyl)— 1-isopropyl- 5a, 5b, 8, 8, 1 tamethyloxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z ated 808.5, found 809.5 (M + 1)+ Example 276: Compound 345 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((R)(N-(cyclopropy/methyl) (dimethy/amino)acetamido)- 1-hydroxyethy/)— 1-isopropy/-5a, 5b, 8, 8, 1 1a-pentamethyl- 2-oxo-3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 10, 1 1, 1 1a, 1 1 b, 12, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
HOWo :, LC/MS: m/Z calculated 752.5, found 753.5 (M + 1)+ e 277: Compound 346 4-(((3aR,5aR,5bR, 7aR,9S, 1 1aR, 1 1bR,13aS)-3a-((R)(benzyl(2- (methylamino)ethyl)amino)- 1-hydroxyethyl)—1-isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyl oxo-3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- enta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 760.5, found 761.5 (M + 1)+ Example 278: Compound 347 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 3a-((R)((cyclopropy/methy/) (2- (dimethy/amino)oxoethyl)amino)— 1 -hydroxyethy/)— 1-isopropy/—5a, 5b, 8, 8, 1 1a- pentamethyloxo-3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0,1 1, 1 1 a, 1 1 b, 1 2, 13, 13a- octadecahydro-2H-cyclopenta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
] LC/MS: m/Z calculated 752.5, found 753.5 (M + 1)+ Example 279: Compound 348 4-(((3aR,5aR,5bR, 7aR,9S, 1 1aR, 1 1bR,13aS)-3a-((R)—2—((2— acetamidoethyl)(cyclopropy/methyl)amino)- 1-hydroxyethy/)— 1-isopropyl- 5a, 5b, 8, 8, 1 1a-pentamethyl-Z-oxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, tadecahydro-2H- cyc/openta[a]chrysenyl)oxy)—2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 752.5, found 753.5 (M + 1)+ Example 280: Compound 349 aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((R)((cyclopropy/methyl)(2-(N- methy/acetamido)ethyl)amino)- 1-hydroxyethyl)- 1-isopropyl-5a, 5b, 8, 8, 1 1a- pentamethyl0X0-3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a- octadecahydro-2H-cyclopenta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/Z calculated 766.5, found 767.5 (M + 1)+ Example 281: Compound 350 4-(((3aR,5aR,5bR, 7aR,9S, 1 1aR, 1 1bR,13aS)-3a-((R)((2-amino oxoethy/)(benzyl)amino)—1-hydroxyethyl)—1-isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyI oxo-3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)-2, thyloxobutanoic acid.
LC/MS: m/Z calculated 760.5, found 761.5 (M + 1)+ Example 282: Compound 351 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((R)(benzy/(2-(dimethy/amino)—2— oxoethyl)amino)— 1-hydroxyethy/)— 1-isopropy/-5a, 5b, 8, 8, 1 1a-pentamethyIoxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- enta[a]chrysenyl)oxy)—2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 788.5, found 789.5 (M + 1)+ Example 283: Compound 352 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((S)hydroxy (isobuty/amino)ethyl)— 1-isopropy/-5a, 5b, 8, 8, 1 1a-pentamethyloxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- enta[a]chrysenyl)oxy)—2, 2-dimethyloxobutanoic acid.
LC/MS: m/z ated 669.5, found 670.5 (M + 1)+ Exam le 284: Com ound 353 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((R)(2-amino-N-(pyridin y/methy/)acetamido)— 1-hydroxyethy/)— 1-isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyI-Z-oxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 761.5, found 762.5 (M + 1)+ Example 285: Compound 354 4-(((3aR, 5aR, 5bR, 7aR, 98, 1 1aR, 1 1bR, 13aS)-3a-((R)(2-(dimethy/amino)—N- (pyridiny/methyl)acetamido)- 1-hydroxyethyl)— ropyl-5a, 5b, 8, 8, 1 1apentamethyl0X0-3 , 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13aoctadecahydro-2H-cyclopenta [a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 789.5, found 790.5 (M + 1)+ Example 286: Compound 355 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((R)hydroxy(2-(methy/amino)- N-(pyridinylmethyl)acetamido)ethy/)— ropy/-5a, 5b, 8, 8, 1 1a-pentamethyl0X0- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)—2, 2-dimethyloxobutanoic acid.
LC/MS: m/z ated 775.5, found 776.5 (M + 1)+ Example 287: Compound 356 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((R)- 1-hydroxy((3- (trif/uoromethyl)benzyl)amino)ethyl)- 1-isopropy/-5a, 5b, 8, 8, 1 1a-pentamethyI0X0- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)—2, 2-dimethyloxobutanoic acid.
] LC/MS: m/z calculated 771.5, found 772.4 (M + 1)+ Example 288: Compound 357 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((R)hydroxy((pyridin y/methyl)amino)ethyl)— 1-isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyl—2-0X0- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)—2, 2-dimethyloxobutanoic acid.
LC/MS: m/Z calculated 704.5, found 705.5 (M + 1)+ Example 289: Compound 358 4-(((3aR,5aR,5bR, , 1 1aR, 1 1bR,13aS)-3a-((1R)hydroxy (((tetrahydrofuran-2—yl)methyl)amino)ethy/)isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyI oxo-3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 697.5, found 698.5 (M + 1)+ e 290: Compound 359 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((R)(cyclohexyl(methy/)amino) hydroxyethy/)— 1-isopropy/-5a, 5b, 8, 8, 1 1a-pentamethyIoxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/Z calculated 709.5, found 710.5 (M + 1)+ Example 291: Compound 360 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((R)hydroxy(((S)- oxy methy/pentany/)amino)ethyl)isopropyl—5a, 5b, 8, 8, 1 1a-pentamethyl0X0- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)—2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 713.5, found 714.5 (M + 1)+ Example 292: Compound 361 4-(((3aR,5aR,5bR, 7aR,9S, 1 1aR, 1 1bR,13aS)-3a-((R)- 1-hydroxy((1- methylpiperidinyl)amino)ethy/)- 1-isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyl0X0- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)—2, thyloxobutanoic acid.
LC/MS: m/z calculated 710.5, found 711.5 (M + 1)+ Example 293: Compound 362 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((R)(N-benzyl- 1- carboxyformamido)- 1-hydroxyethyl)— 1-isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyloxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)—2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 775.5, found 776.5 (M + 1)+ Example 294: Compound 363 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((R)(2-amino-N-benzy/ oxoacetamido)— 1-hydroxyethyl)— 1-isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyloxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 774.5, found 775.5 (M + 1)+ Example 295: Compound 364 4-(((3aR,5aR,5bR, 7aR,9S, 1 1aR, 1 1bR,13aS)-3a-((R)hydroxy (isobuty/amino)ethyl)— ropy/-5a, 5b, 8, 8, 1 1a-pentamethyloxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, tadecahydro-2H- cyc/openta[a]chrysenyl)oxy)—2, 2-dimethyloxobutanoic acid. 2012/069637 LC/MS: m/z calculated 669.5, found 670.5 (M + 1)+ e 296: nd 365 4-(((3aR,5aR,5bR, 7aR,9S, 1 1aR, 1 1bR,13aS)-3a-((R)hydroxy (phenethy/amino)ethyl)—1-isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyl0X0- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 717.5, found 718.5 (M + 1)+ Exam le 297: Com ound 366 4-(((3aR,5aR,5bR, 7aR,9S, 1 1aR, 1 1bR,13aS)-3a-((R)-2—((2— (dimethylamino)ethyl)(pyridiny/methyl)amino)hydroxyethy/)— 1-isopropyl- 5a, 5b, 8, 8, 1 1a-pentamethyl-Z-oxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 775.5, found 776.5 (M + 1)+ Example 298: Compound 367 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((R)((2-aminoethyl)(pyridin y/methy/)amino)—1-hydroxyethyl)isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyl0X0- WO 90664 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)—2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 747.5, found 748.5 (M + 1)+ Example 299: nd 368 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((R)((1-(5-chloropyrimidin-2— yl)cyclopropy/)amino)— 1-hydroxyethy/)— ropy/-5a, 5b, 8, 8, 1 1a-pentamethyIoxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)—2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 765.5, found 766.5 (M + 1)+ Example 300: Compound 369 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((R)(2-amino-N-(pyridin ylmethy/)acetamido)— 1-hydroxyethy/)— 1-isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyI0X0- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)—2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 761.5, found 762.5 (M + 1)+ Example 301: Compound 370 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((R)hydroxy(2-(methy/amino)- N-(pyridinylmethyl)acetamido)ethy/)— 1-isopropy/-5a, 5b, 8, 8, 1 1a-pentamethyl-Z-oxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, tadecahydro-2H- cyc/openta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 775.5, found 776.5 (M + 1)+ Example 302: Compound 371 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((R)(2-(dimethy/amino)—N- (pyridiny/methyl)acetamido)- 1-hydroxyethyl)— 1-isopropyl-5a, 5b, 8, 8, 1 1apentamethyl0X0-3 , 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a- octadecahydro-2H-cyclopenta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 789.5, found 790.5 (M + 1)+ e 303: Compound 372 4-(((3aR,5aR,5bR, 7aR,9S, 1 1aR, 1 1bR,13aS)-3a-((R)—2-((2- (dimethylamino)ethyl)(pyridiny/methyl)amino)- 1 xyethy/)— 1-isopropyl- 5a, 5b, 8, 8, 1 1a-pentamethyloxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)—2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 775.5, found 776.5 (M + 1)+ Example 304: Compound 373 4-(((3aR, 5aR, 5bR, 7aR, 98, 1 1aR, 1 1bR, 13aS)-3a-((R)- 1-hydroxy((2- (methylamino)ethyl)(pyridiny/methyl)amino)ethyl)isopropyl-5a, 5b, 8, 8, 1 1a- ethyloxo-3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0,1 1, 1 1 a, 1 1 b, 1 2, 13, 13a- octadecahydro-2H-cyclopenta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
O \ ] LC/MS: m/z calculated 761.5, found 762.5 (M + 1)+ Example 305: Compound 374 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-(2-(cyclohexanecarboxamido)ethyl)- 1-isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyloxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
WO 90664 LC/MS: m/z calculated 707.5, found 708.5 (M + 1)+ Example 306: Compound 375 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((R)((2-aminoethyl)(pyridin y/methy/)amino)—1-hydroxyethyl)isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyl—2-0X0- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- enta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 747.5, found 748.5 (M + 1)+ Example 307: Compound 376 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((R)((2-aminoethyl)(pyridin y/methy/)amino)—1-hydroxyethyl)isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyl—2-0X0- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 747.5, found 748.5 (M + 1)+ Example 308: Compound 377 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((R)hydroxy((2-(N- acetamido)ethyl)(pyridiny/methyl)amino)ethyl)—1-isopropyI-5a, 5b, 8, 8, 1 1apentamethyloxo-3 , 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0,1 1, 1 1 a, 1 1 b, 1 2, 13, 13aoctadecahydro-2H-cyclopenta [a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 803.5, found 804.5 (M + 1)+ e 309: nd 378 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((R)((1-(5-chloropyrimidin-2— yl) cyclopropyl) (2-(dimethylamino)ethyl)amino)- 1-hydroxyethy/)— 1-isopropyl- 5a, 5b, 8, 8, 1 1a-pentamethyloxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyclopenta[a]chrysenyl)oxy)—2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 836.5, found 837.5 (M + 1)+ Example 310: Compound 379 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((R)(benzy/(2-(methy/amino) oxoethyl)amino)— 1-hydroxyethy/)— 1-isopropy/-5a, 5b, 8, 8, 1 1a-pentamethyIoxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyclopenta[a]chrysenyl)oxy)—2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 774.5, found 775.5 (M + 1)+ Example 311: Compound 380 4-(((3aR, 5aR, 5bR, 7aR, 98, 1 1aR, 1 1bR, 13aS)-3a-((R)((2-(dimethy/amino) yl)(pyridiny/methyl)amino)hydroxyethy/)— 1-isopropy/—5a, 5b, 8, 8, 1 1a- pentamethyl0X0-3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0,1 1, 1 1 a, 1 1 b, 1 2, 13, 13a- octadecahydro-2H-cyclopenta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 789.5, found 790.5 (M + 1)+ Example 312: Compound 381 aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((R)(benzy/(2-(N- methy/acetamido)ethyl)amino)- 1-hydroxyethyl)- 1-isopropyl-5a, 5b, 8, 8, 1 1a- pentamethyl0X0-3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a- octadecahydro-2H-cyclopenta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 802.5, found 803.5 (M + 1)+ Example 313: nd 382 4-(((3aR, 5aR, 5bR, 7aR, 98, 1 1aR, 1 1bR, 13a8)-3a-((R)(benzy/(2-(2-oxopyrro/idin- 1- yl)ethyl)amino)hydroxyethy/)— 1-isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyl0X0- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)-2, 2-dimethyl—4-oxobutanoic acid.
LC/MS: m/z calculated 814.5, found 815.5 (M + 1)+ Example 314: nd 383 4-(((3aR, 5aR, 5bR, 7aR, 98, 1 1aR, 1 1bR, 13a8)-3a-((R)(((1H-benzo[d]imidazol—2— yl)methy/)amino)hydroxyethy/)—1-isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyl0X0- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)-2, 2-dimethyl—4-oxobutanoic acid.
LC/MS: m/z calculated 743.5, found 744.5 (M + 1)+ Example 315: nd 384 4-(((3aR,5aR,5bR, 7aR,98, 1 1aR, 1 1bR,13a8)-3a-((R)(2-(aminomethyl)-1H- benzo[d]imidazol— 1 -yl)- 1-hydroxyethy/)— 1-isopropy/-5a, 5b, 8, 8, 1 1a-pentamethyl—2—oxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)—2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 743.5, found 744.5 (M + 1)+ Example 316: Compound 385 4-(((3aR,5aR,5bR, 7aR,9S, 1 1aR, 1 1bR,13aS)-3a-((S)((1-(4- chlorophenyl)cyclopropyl)amino)- 1-hydroxyethy/)— 1-isopropy/—5a, 5b, 8, 8, 1 1apentamethyloxo-3 , 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a- cahydro-2H-cyclopenta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 763.5, found 764.5 (M + 1)+ Example 317: Compound 386 4-(((3aR,5aR,5bR, , 1 1aR, 1 1bR,13aS)-3a-((R)((1-(4- chlorophenyl)cyclopropyl)amino)- 1-hydroxyethy/)— 1-isopropy/—5a, 5b, 8, 8, 1 1a- pentamethyloxo-3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13aoctadecahydro-2H-cyclopenta [a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid. 2012/069637 ] LC/MS: m/z calculated 763.5, found 764.5 (M + 1)+ Example 318: Compound 387 4-(((3aR, 5aR, 5bR, 7aR, 98, 1 1aR, 1 1bR, 13aS)-3a-((R)- 1-hydroxy((2- morpho/inoethyl) (pyridiny/methyl)amino)ethyl)- 1-isopropyl—5a, 5b, 8, 8, 1 1apentamethyl0X0-3 , 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0,1 1, 1 1 a, 1 1 b, 1 2, 13, 13aoctadecahydro-2H-cyclopenta [a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/Z calculated 817.6, found 818.5 (M + 1)+ Example 319: Compound 388 aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((R)- 1-hydroxy((2-(2- oxopyrrolidin- 1-yl)ethyl)(pyridiny/methy/)amino)ethyl)- 1-isopropyl—5a, 5b, 8, 8, 1 1a- pentamethyl0X0-3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0,1 1, 1 1 a, 1 1 b, 1 2, 13, 13a- octadecahydro-2H-cyclopenta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 815.5, found 816.5 (M + 1)+ Example 320: Compound 389 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((S)—1-hydroxy (phenethy/amino)ethyl)—1-isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyl0X0- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- enta[a]chrysenyl)oxy)—2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 717.5, found 718.5 (M + 1)+ Exam le 321: Com ound 390 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((R)hydroxy((thiazol—5— yl)amino)ethyl)— 1-isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyl—2-0X0- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)—2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 710.4, found 711.4 (M + 1)+ Exam le 322: Com ound 391 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-(2-(cyclopenty/amino)ethyl)- 1- isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyloxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)—2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 665.5, found 666.5 (M + 1)+ Example 323: Compound 392 4-(((3aR, 5aR, 5bR, 7aR, 98, 1 1aR, 1 1bR, 13aS)-3a-((R)((2-(dimethy/amino) oxoethyl)(pyridiny/methyl)amino)hydroxyethy/)— 1-isopropy/—5a, 5b, 8, 8, 1 1a- pentamethyloxo-3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0,1 1, 1 1 a, 1 1 b, 1 2, 13, 13aoctadecahydro-2H-cyclopenta [a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z ated 789.5, found 790.5 (M + 1)+ Example 324: Compound 393 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((R)((2-aminooxoethyl)(pyridin- thyl)amino)- 1-hydroxyethy/)— 1-isopropy/-5a, 5b, 8, 8, 1 1a-pentamethyl-Z-oxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)—2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 761.5, found 762.5 (M + 1)+ Example 325: Compound 394 4-(((3aR,5aR,5bR, , 1 1aR, 1 1bR,13aS)-3a-((R)- 1-hydroxy((2-((2- hydroxyethy/)amino)ethyl) (pyridiny/methyl)amino)ethy/)- 1-isopropy/—5a, 5b, 8, 8, 1 1a- pentamethyloxo-3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0,1 1, 1 1 a, 1 1 b, 1 2, 13, 13a- cahydro-2H-cyclopenta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z ated 791.5, found 792.5 (M + 1)+ Example 326: Compound 395 4-(((3aR,5aR,5bR, 7aR,98, 1 1aR, 1 1bR,13aS)-3a-((R)- 1-hydroxy((2-((2- methoxyethyl)amino)ethyl) (pyridin-2—y/methyl)amino)ethyl)isopropyl-5a, 5b, 8, 8, 1 1a- pentamethyl0X0-3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0,1 1, 1 1 a, 1 1 b, 1 2, 13, 13aoctadecahydro-2H-cyclopenta [a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 805.6, found 806.5 (M + 1)+ Exam le 327: Com ound 396 aR,5aR,5bR, 7aR,98, 1 1aR, 1 1bR,13aS)-3a-((R)((2-((tert- butoxycarbony/)amino)ethyl)(cyclopropy/methyl)amino)- 1-hydroxyethy/)— 1-isopropyl- 5a, 5b, 8, 8, 1 1a-pentamethyl-Z-oxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 810.6, found 811.5 (M + 1)+ Example 328: Compound 397 4-(((3aR,5aR,5bR, 7aR,9S, 1 1aR, 1 aS)-3a-((R)((2-((tert— butoxycarbonyl) (methy/)amino)ethy/) (cyc/opropy/methyl)amino)- 1-hydroxyethy/)—1- pyl-5a, 5b, 8, 8, 1 1a-pentamethyl-Z-oxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z ated 824.6, found 825.5 (M + 1)+ Exam le 329: Com ound 398 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-(2-(N-benzyl carboxyformamido)ethyl)— 1-isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyl-Z-oxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 759.5, found 760.5 (M + 1)+ Example 330: Compound 399 4-(((3aR,5aR,5bR, 7aR,9S, 1 1aR, 1 1bR,13aS)-3a-((R)—2-((2- aminoethyl)(cyclopropy/methyl)amino)- 1-hydroxyethy/)— 1-isopropy/—5a, 5b, 8, 8, 1 1a- pentamethyloxo-3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0,1 1, 1 1 a, 1 1 b, 1 2, 13, 13a- octadecahydro-2H-cyclopenta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 710.5, found 711.5 (M + 1)+ Example 331: Compound 400 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((R)((2-acetamidoethyl) (pyridin y/methy/)amino)—1-hydroxyethyl)isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyl0X0- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)—2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 789.5, found 790.5 (M + 1)+ Example 332: Compound 401 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((R)hydroxy((thiazol—4— y/methyl)amino)ethyl)— 1-isopropyl-5a, 5b, 8, 8, 1 tamethyl—2-0X0- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- enta[a]chrysenyl)oxy)—2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 710.4, found 711.4 (M + 1)+ Example 333: Compound 402 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 3a-((R)hydroxy((thiazol—2- y/methyl)amino)ethyl)— 1-isopropyl-5a, 5b, 8, 8, 1 tamethyl—2-0X0- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 710.4, found 711.4 (M + 1)+ Exam le 334: Com ound 403 4-(((3aR,5aR,5bR, , 1 1aR, 1 1bR,13aS)-3a-((R)—2—((2- (dimethylamino)ethyl) (thiazoly/methyl)amino)- 1-hydroxyethy/)— 1-isopropyl- 5a, 5b, 8, 8, 1 1a-pentamethyl-Z-oxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 781.5, found 782.5 (M + 1)+ Example 335: Compound 404 4-(((3aR,5aR,5bR, 7aR,9S, 1 1aR, 1 1bR,13aS)—3a-(2— (benzy/(carboxymethyl)amino)ethy/)- 1-isopropyl-5a, 5b, 8, 8, 1 tamethyloxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
] LC/MS: m/z calculated 745.5, found 746.5 (M + 1)+ Example 336: Compound 405 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)- 1-isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyl- 3a-(2-(N-methy/benzamido)ethyl)oxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 715.5, found 716.5 (M + 1)+ Example 337: Compound 406 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-(2-(N-benzyl(dimethy/amino)—2— oxoacetamido)ethyl)— 1-isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyI-Z-oxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, tadecahydro-2H- cyc/openta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/Z calculated 786.5, found 787.5 (M + 1)+ Example 338: Compound 407 4-(((3aR,5aR,5bR, 7aR,9S, 1 1aR, 1 1bR,13aS)-3a-((R)((2- acetamidoethyl)(benzyl)amino)hydroxyethyl)- 1-isopropyl-5a, 5b, 8, 8, 1 1apentamethyl0X0-3 , 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0,1 1, 1 1 a, 1 1 b, 1 2, 13, 13aoctadecahydro-2H-cyclopenta [a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 788.5, found 789.5 (M + 1)+ Example 339: Compound 408 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-(2-(2-amino-N-benzyl oxoacetamido)ethyl)— 1-isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyI-Z-oxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, tadecahydro-2H- cyc/openta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 758.5, found 759.5 (M + 1)+ Example 340: nd 409 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((R)((2-acetamidoethyl) (pyridin-2— y/)amino)—1-hydroxyethyl)isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyl0X0- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 789.5, found 790.5 (M + 1)+ Example 341: Compound 410 4-(((3aR,5aR,5bR, 7aR,9S, 1 1aR, 1 1bR,13aS)-3a-((R)—2—((2— hylamino)ethyl) (thiazoly/methyl)amino)- 1-hydroxyethy/)— ropyl- 5a, 5b, 8, 8, 1 1a-pentamethyloxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)—2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 781.5, found 782.5 (M + 1)+ Example 342: Compound 411 4-(((3aR,5aR,5bR, , 1 1aR, 1 1bR,13aS)-3a-((R)—2—((2— (dimethylamino)ethyl) (thiazoly/methyl)amino)- 1-hydroxyethy/)— 1-isopropyl- 5a, 5b, 8, 8, 1 1a-pentamethyloxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)—2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 781.5, found 782.5 (M + 1)+ Example 343: Compound 412 aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 3a-((R)((cyclopropylmethy/) (2- (methy/amino)ethyl)amino)- 1-hydroxyethyl)—1-isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyl oxo-3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 724.5, found 725.5 (M + 1)+ Example 344: Compound 413 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((R)((2-acetamidoethyl) (pyridin y/methy/)amino)—1-hydroxyethyl)isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyl—2-0X0- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)—2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 789.5, found 790.5 (M + 1)+ Example 345: Compound 414 aR,5aR,5bR, 7aR,9S, 1 1aR, 1 1bR,13aS)-3a-((R)((2- acetamidoethyl)(cyclopropy/methyl)amino)- 1-acetoxyethyl)— 1-isopropyl- 5a, 5b, 8, 8, 1 1a-pentamethyloxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)—2, 2-dimethyloxobutanoic acid.
; NW 0 5 HON .5 = — A S 0 g o HN o 0 414 \f LC/MS: m/z calculated 794.5, found 795.5 (M + 1)+ Example 346: Compound 415 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((R)- 1-acetoxy ((cyc/opropylmethyl)(2-(N-methy/acetamido)ethyl)amino)ethyl)isopropyl- 5a, 5b, 8, 8, 1 1a-pentamethyloxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)—2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 808.6, found 809.5 (M + 1)+ Exam le 347: Com ound 416 aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((R)(((5-ch/oropyrimidin-2— hy/)amino)hydroxyethy/)—1-isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyl0X0- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)—2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 739.4, found 740.4 (M + 1)+ Example 348: Compound 417 4-(((3aR,5aR,5bR, 7aR,9S, 1 1aR, 1 1bR,13aS)-3a-((R)((2- hy/amino)ethyl) (pyrimidiny/methyl)amino)— 1-hydroxyethy/)— 1-isopropyl- 5a, 5b, 8, 8, 1 tamethyloxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyclopenta[a]chrysenyl)oxy)—2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 776.5, found 777.5 (M + 1)+ Example 349: Compound 418 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((S)(((5-ch/oropyrimidin yl)methy/)amino)hydroxyethy/)—1-isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyl—2-0X0- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyclopenta[a]chrysenyl)oxy)—2, 2-dimethyloxobutanoic acid.
LC/MS: m/Z ated 739.4, found 740.4 (M + 1)+ Exam le 350: Com ound 419 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((R)- 1-hydroxy((2- (methylamino)ethyl)(pyridiny/methyl)amino)ethyl)isopropyl—5a, 5b, 8, 8, 1 1apentamethyloxo-3 , 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0,1 1, 1 1 a, 1 1 b, 1 2, 13, 13a- octadecahydro-2H-cyclopenta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 761.5, found 762.5 (M + 1)+ Example 351: Compound 420 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)- 1-isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyl- 2-0X0-3a-((R)-2—oxo(pyridinylmethyl)oxazo/idinyl)- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)-2, thyloxobutanoic acid.
LC/MS: m/z calculated 730.5, found 731.4 (M + 1)+ Exam le 352: Com ound 421 aR, 5aR, 5bR, 7aR, 98, 1 1aR, 1 1bR, 13aS)-3a-((S)((1-(5-chloropyrimidin-2— yl)cyclopropy/)amino)— 1-hydroxyethy/)— 1-isopropy/-5a, 5b, 8, 8, 1 1a-pentamethyIoxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 765.4, found 766.4 (M + 1)+ e 353: Compound 422 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((R)-2, 1 1-dimethyl-3, 10-dioxo (pyridiny/methyl)oxa-2, 5, 1 1-triazadodecan-7—yl)isopropyl-5a, 5b, 8, 8, 1 1apentamethyl0X0-3 , 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0,1 1, 1 1 a, 1 1 b, 1 2, 13, 13aoctadecahydro-2H-cyclopenta [a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 874.6, found 875.6 (M + 1)+ e 354: Compound 423 4-(((3aR,5aR,5bR, 7aR,9S, 1 1aR, 1 1bR,13aS)-3a-((R)hydroxy-2—((2-(methylamino)- 2—oxoethyl)(pyridinylmethyl)amino)ethy/)- 1-isopropy/-5a, 5b, 8, 8, 1 1a-pentamethyl oxo-3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- enta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/Z calculated 775.5, found 776.5 (M + 1)+ e 355: Compound 424 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((R)((2-(dimethy/amino) oxoethyl)(pyridiny/methyl)amino)hydroxyethy/)— 1-isopropy/—5a, 5b, 8, 8, 1 1a- pentamethyl0X0-3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0,1 1, 1 1 a, 1 1 b, 1 2, 13, 13aoctadecahydro-2H-cyclopenta [a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 789.5, found 790.5 (M + 1)+ Example 356: Compound 425 aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((R)(2-(dimethy/amino)—N- (pyrimidin-Z-y/methyl)acetamido)- 1-hydroxyethyl)— 1-isopropyl-5a, 5b, 8, 8, 1 1apentamethyl0X0-3 , 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0,1 1, 1 1 a, 1 1 b, 1 2, 13, 13a- octadecahydro-2H-cyclopenta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/Z calculated 790.5, found 791.5 (M + 1)+ Example 357: Compound 426 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)- 1-isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyl- 2—oxo-3a-(2-(picolinamido)ethyl)-3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13aoctadecahydro-2H-cyclopenta [a]chrysenyl)oxy)-2, thyloxobutanoic acid.
LC/MS: m/Z calculated 702.5, found 703.4 (M + 1)+ e 358: Compound 427 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((R)((2-(1H-imidazol- 1- y/)ethyl) (benzyl)amino)—1-hydroxyethy/)—1-isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyl oxo-3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/Z calculated 797.5, found 798.5 (M + 1)+ Example 359: Compound 428 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((R)—2—((3-(1H-imidazol- 1- yl)propy/)(benzy/)amino)hydroxyethyl)—1-isopropyl-5a, 5b, 8, 8, 1 tamethyl oxo-3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)-2, thyloxobutanoic acid.
LC/MS: m/Z calculated 811.5, found 812.5 (M + 1)+ Example 360: Compound 429 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((S)-2—((3-(1H-imidazol yl)propy/)(benzy/)amino)—1-hydroxyethyl)—1-isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyl oxo-3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/Z calculated 811.5, found 812.5 (M + 1)+ Example 361: Compound 430 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 3a-(2-(N-benzyl—2— (dimethylamino)acetamido)ethy/)- 1-isopropy/-5a, 5b, 8, 8, 1 1a-pentamethyI0X0- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)—2, 2-dimethyloxobutanoic acid.
LC/MS: m/z ated 772.5, found 773.5 (M + 1)+ Example 362: Compound 431 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((R)(2-(dimethy/amino)—N- isopropy/acetamido)- 1-hydroxyethyl)— 1-isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyloxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)—2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 740.5, found 741.5 (M + 1)+ e 363: Compound 432 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((R)hydroxy(N-isopropyl (methy/amino)acetamido)ethyl)—1-isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyl0X0- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)—2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 726.5, found 727.5 (M + 1)+ Example 364: nd 433 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((R)(2-amino-N- isopropy/acetamido)- 1-hydroxyethyl)— 1-isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyloxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, tadecahydro-2H- cyc/openta[a]chrysenyl)oxy)—2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 712.5, found 713.5 (M + 1)+ Example 365: Compound 434 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((R)((2-(dimethylamino)ethyl)(3- (trif/uoromethoxy)benzyl)amino)- 1-hydroxyethyl)— 1-isopropyl-5a, 5b, 8, 8, 1 1a- pentamethyloxo-3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0,1 1, 1 1 a, 1 1 b, 1 2, 13, 13a- octadecahydro-2H-cyclopenta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid. 32 1 LC/MS: m/z calculated 858.5, found 859.5 (M + 1)+ Examgle 366: Comgound 435 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((R)((2-(dimethylamino)ethyl)(4- (trif/uoromethoxy)benzyl)amino)- 1-hydroxyethyl)— 1-isopropyl-5a, 5b, 8, 8, 1 amethyloxo-3 , 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0,1 1, 1 1 a, 1 1 b, 1 2, 13, adecahydro-2H-cyclopenta [a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 858.5, found 859.5 (M + 1)+ Example 367: Compound 436 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-(2-(2-(dimethy/amino)-N-(pyridin ylmethy/)acetamido)ethyl)- 1-isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyl0X0- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)—2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 773.5, found 774.5 (M + 1)+ e 368: nd 437 4-(((3aR,5aR,5bR, 7aR,9S, 1 1aR, 1 1bR,13aS)-3a-((R)—2—((2— aminoethyl) (isopropyl)amino)- 1-hydroxyethyl)— 1-isopropyl-5a, 5b, 8, 8, 1 1apentamethyl0X0-3 , 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0,1 1, 1 1 a, 1 1 b, 1 2, 13, 13aoctadecahydro-2H-cyclopenta [a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 698.5, found 699.5 (M + 1)+ Example 369: Compound 438 4-(((3aR,5aR,5bR, 7aR,9S, 1 1aR, 1 1bR,13aS)-3a-((R)—2—((2— acetamidoethyl)(isopropyl)amino)- 1-hydroxyethyl)— 1-isopropyl-5a, 5b, 8, 8, 1 1a- ethyl0X0-3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0,1 1, 1 1 a, 1 1 b, 1 2, 13, 13a- octadecahydro-2H-cyclopenta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 740.5, found 741.5 (M + 1)+ Example 370: Compound 439 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((R)((2-(dimethy/amino) oxoethyl) (thiazoly/methyl)amino)- 1-hydroxyethy/)— 1-isopropy/—5a, 5b, 8, 8, 1 1a- ethyl0X0-3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1a, 1 1 b, 1 2, 13, 13a- octadecahydro-2H-cyclopenta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/Z calculated 795.5, found 796.4 (M + 1)+ Exam le 371: Com ound 440 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)- 1-isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyl- 3a-((R)methyl(pyridiny/methyl)-8, 1 1-dioxa-2, 5-diazadodecanyl)0X0- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)—2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 833.6, found 834.5 (M + 1)+ Examgle 372: Compound 441 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 3a-((R)((S)-N-benzyl-3, 4- dihydroxybutanamido)— oxyethy/)— 1-isopropy/-5a, 5b, 8, 8, 1 1a-pentamethyIoxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)—2, 2-dimethyloxobutanoic acid.
O fi LC/MS: m/z calculated 805.5, found 806.5 (M + 1)+ Example 373: Compound 442 4-(((3aR,5aR,5bR, 7aR,9S, 1 1aR, 1 1bR,13aS)-3a-((R)((2-amino oxoethyl)(isopropy/)amino)— 1-hydroxyethy/)— 1-isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyI oxo-3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, tadecahydro-2H- cyc/openta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid. o I: LC/MS: m/z calculated 712.5, found 713.5 (M + 1)+ Example 374: Compound 443 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((R)((2-(dimethy/amino) oxoethyl)(isopropy/)amino)— 1-hydroxyethy/)— 1-isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyI oxo-3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- enta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 740.5, found 741.5 (M + 1)+ Example 375: Compound 444 aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((R)hydroxy(isopropyl(2— (methylamino)oxoethyl)amino)ethyl)isopropy/-5a, 5b, 8, 8, 1 1a-pentamethyI0X0- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)—2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 726.5, found 727.5 (M + 1)+ Example 376: Compound 445 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((R)—2—((S)—3, droxy-N-(pyridin- 2—ylmethyl)butanamido)—1-hydroxyethy/)—1-isopropyI-5a, 5b, 8, 8, 1 1a-pentamethyI oxo-3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 806.5, found 807.5 (M + 1)+ e 377: Compound 446 4-(((3aR,5aR,5bR, 7aR,9S, 1 1aR, 1 1bR, 13aS)-3a-((R)((2-(ethylamino) oxoethyl)(isopropy/)amino)hydroxyethyl)- 1-isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyI oxo-3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid. o a LC/MS: m/z calculated 740.5, found 741.5 (M + 1)+ Example 378: Compound 447 4-(((3aR,5aR,5bR, 7aR,9S, 1 1aR, 1 aS)-3a-((R)—2- ((carboxymethyl)(isopropy/)amino)— 1-hydroxyethy/)— 1-isopropy/—5a, 5b, 8, 8, 1 1apentamethyl0X0-3 , 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0,1 1, 1 1 a, 1 1 b, 1 2, 13, 13aoctadecahydro-2H-cyclopenta [a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid. 0 447 LC/MS: m/z calculated 713.5, found 714.5 (M + 1)+ Example 379: nd 448 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((R)-2—((2-(cyc/opropylamino) oxoethyl)(isopropy/)amino)— 1-hydroxyethy/)— 1-isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyl—2— oxo-3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyclopenta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
HONO ._eF, E LC/MS: m/z calculated 752.5, found 753.5 (M + 1)+ Example 380: nd 449 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((R)(((5-ch/oropyrimidin-2— hyl) (2-(dimethylamino)ethy/)amino)- 1-hydroxyethy/)— 1-isopropy/—5a, 5b, 8, 8, 1 1a- pentamethyl0X0-3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0,1 1, 1 1 a, 1 1 b, 1 2, 13, 13a- octadecahydro-2H-cyclopenta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 810.5, found 811.5 (M + 1)+ Examgle 381: nd 450 4-(((3aR,5aR,5bR, , 1 1aR, 1 1bR,13aS)-3a-((R)—2—(N- (cyc/opropy/methyl)acetamido)- 1-hydroxyethyl)— 1-isopropyl-5a, 5b, 8, 8, 1 1apentamethyloxo-3 , 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0,1 1, 1 1 a, 1 1 b, 1 2, 13, 13aoctadecahydro-2H-cyclopenta [a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/Z calculated 709.5, found 710.5 (M + 1)+ Example 382: Compound 451 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)- 1-isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyl- 2-oxo-3a-(2-((pyridiny/methyl)amino)ethyl)- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)—2, 2-dimethyloxobutanoic acid.
] LC/MS: m/z calculated 688.5, found 689.5 (M + 1)+ Example 383: Compound 452 4-(((3aR,5aR,5bR, 7aR,9S, 1 1aR, 1 1bR,13aS)-3a-((R)—2— ((cyclopropy/methyl)(methyl)amino)—1-hydroxyethyl)—1-isopropyl-5a, 5b, 8, 8, 1 1a- ethyl0X0-3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0,1 1, 1 1 a, 1 1 b, 1 2, 13, 13a- octadecahydro-2H-cyclopenta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 681.5, found 682.5 (M + 1)+ Example 384: Compound 453 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((R)(N-(cyclopropy/methyl) (methylamino)acetamido)—1-hydroxyethy/)—1-isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyI oxo-3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 738.5, found 739.5 (M + 1)+ Example 385: Compound 454 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((R)(N-benzylisobutyramido)- 1- hydroxyethy/)— ropy/-5a, 5b, 8, 8, 1 1a-pentamethyIoxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, tadecahydro-2H- enta[a]chrysenyl)oxy)—2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 773.5, found 774.5 (M + 1)+ Exam le 386: Com ound 455 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((R)(N-benzyl methy/butanamido)- 1-hydroxyethy/)— 1-isopropy/-5a, 5b, 8, 8, 1 1a-pentamethyIoxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)—2, 2-dimethyloxobutanoic acid.
LC/MS: m/Z calculated 787.5, found 788.5 (M + 1)+ Example 387: Compound 456 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((R)(N-benzy/propionamido) hydroxyethy/)— 1-isopropy/-5a, 5b, 8, 8, 1 1a-pentamethyIoxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, tadecahydro-2H- cyc/openta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 759.5, found 760.5 (M + 1)+ e 388: nd 457 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)- 1-isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyl- 2-0X0-3a-(2-((pyridiny/methyl)amino)ethyl)- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 688.5, found 689.5 (M + 1)+ Example 389: Compound 458 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)- 1-isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyl- 2-oxo-3a-(2-((pyridiny/methyl)amino)ethyl)- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 688.5, found 689.5 (M + 1)+ Example 390: Compound 459 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((R)((cyclopropy/methy/)(2- (pyrro/idiny/)ethyl)amino)— 1-hydroxyethy/)— 1-isopropy/-5a, 5b, 8, 8, 1 1a-pentamethyl- 2-oxo-3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid. 2012/069637 LC/MS: m/z calculated 764.6, found 765.5 (M + 1)+ Example 391: Compound 460 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((R)(N-benzylacetamido) hydroxyethy/)— 1-isopropy/-5a, 5b, 8, 8, 1 1a-pentamethyIoxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 745.5, found 746.5 (M + 1)+ Example 392: Compound 461 4-(((3aR,5aR,5bR, 7aR,9S, 1 1aR, 1 1bR,13aS)-3a-((R)(benzyl(2— morpholinoethyl)amino)hydroxyethyl)— 1-isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyI oxo-3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, tadecahydro-2H- cyc/openta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 816.6, found 817.5 (M + 1)+ Example 393: Compound 462 4-(((3aR, 5aR, 5bR, 7aR, 98, 1 1aR, 1 1bR, 13a8)-3a-((R)(N,3-dimethy/butanamido) hydroxyethy/)— 1-isopropy/-5a, 5b, 8, 8, 1 1a-pentamethyIoxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 711.5, found 712.5 (M + 1)+ Example 394: nd 463 aR, 5aR, 5bR, 7aR, 98, 1 1aR, 1 1bR, 13a8)-3a-((R)(N-(cyc/opropy/methyl)(2- oxopyrro/idin- 1-y/)acetamido)- 1-hydroxyethyl)— 1-isopropyl-5a, 5b, 8, 8, 1 1a- pentamethyl0X0-3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0,1 1, 1 1 a, 1 1 b, 1 2, 13, 13a- octadecahydro-2H-cyclopenta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 792.5, found 793.5 (M + 1)+ Example 395: Compound 464 4-(((3aR, 5aR, 5bR, 7aR, 98, 1 1aR, 1 1bR, 13a8)-3a-((R)- 1-(isobutyry/oxy)-2— (methylamino)ethyl)— 1-isopropy/-5a, 5b, 8, 8, 1 1a-pentamethyl-Z-oxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- enta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
WO 90664 LC/MS: m/z calculated 697.5, found 698.5 (M + 1)+ Example 396: Compound 465 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-(2-((cyclobuty/methy/)amino)ethyl)- 1-isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyl-Z-oxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- enta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 665.5, found 666.5 (M + 1)+ Example 397: Compound 466 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-(2-((cyc/opropylmethy/)amino)ethy/)— 1 -isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyl-Z-oxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
HONO ._6g E 0 466 LC/MS: m/z calculated 651.5, found 652.5 (M + 1)+ WO 90664 Example 398: Compound 467 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((R)(N-(cyc/obuty/methyl) (dimethy/amino)acetamido)- 1-hydroxyethy/)— ropy/-5a, 5b, 8, 8, 1 1a-pentamethyl— 2-oxo-3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 10, 1 1, 1 1a, 1 1 b, 12, 13, 13a-octadecahydro-2H- cyclopenta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/Z calculated 766.5, found 767.5 (M + 1)+ Exam le 399: Com ound 468 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-(2-((cyclobuty/methyl) (2- (dimethy/amino)ethy/)amino)ethy/)- 1-isopropy/-5a, 5b, 8, 8, 1 1a-pentamethyI-Z-oxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, tadecahydro-2H- cyclopenta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/Z calculated 736.6, found 737.5 (M + 1)+ Example 400: Compound 469 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((R)hydroxy((pyrimidin y/methyl)amino)ethyl)— 1-isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyl—2-0X0- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyclopenta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
WO 90664 LC/MS: m/z calculated 705.5, found 706.5 (M + 1)+ Example 401: nd 470 4-(((3aR,5aR,5bR, 7aR,9S, 1 1aR, 1 1bR,13aS)-3a-((R)(N- (cyc/obuty/methyl)acetamido)— 1-hydroxyethyl)- 1-isopropyl-5a, 5b, 8, 8, 1 1apentamethyl0X0-3 , 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0,1 1, 1 1 a, 1 1 b, 1 2, 13, 13a- octadecahydro-2H-cyclopenta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 723.5, found 724.5 (M + 1)+ Example 402: Compound 471 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((R)((4-chlorobenzoy/)oxy) (methylamino)ethyl)— 1-isopropy/-5a, 5b, 8, 8, 1 1a-pentamethyl-Z-oxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/Z calculated 765.4, found 766.4 (M + 1)+ e 403: Compound 472 4-(((3aR,5aR,5bR, 7aR,9S, 1 1aR, 1 1bR,13aS)-3a-((R)(benzoy/oxy)((2— yethyl)amino)ethyl)- 1-isopropy/-5a, 5b, 8, 8, 1 1a-pentamethyI-Z-oxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 761.5, found 762.4 (M + 1)+ Exam le 404: Com ound 473 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)- 1-isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyl- 3a-((R)(methy/amino)—1-(2-phenylacetoxy)ethyl)oxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/Z calculated 745.5, found 746.5 (M + 1)+ Examgle 405: Compound 474 4-(((3aR,5aR,5bR, , 1 1aR, 1 1bR,13aS)-3a-((R)hydroxy(N- methylacetamido)ethyl)— 1-isopropy/-5a, 5b, 8, 8, 1 1a-pentamethyIoxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 669.5, found 670.4 (M + 1)+ Example 406: Compound 475 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((R)(4-chloro-N- methy/benzamido)- 1-hydroxyethy/)— ropyl-5a, 5b, 8, 8, 1 1a-pentamethyl0X0- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z ated 765.4, found 766.4 (M + 1)+ e 407: Compound 476 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((R)- 1-hydroxy(N-methyl phenylacetamido)ethyl)- 1-isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyloxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/Z calculated 745.5, found 746.5 (M + 1)+ e 408: Compound 477 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((R)hydroxy(N-(2- hydroxyethyl)benzamido)ethy/)- 1-isopropy/-5a, 5b, 8, 8, 1 1a-pentamethyloxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)-2, thyloxobutanoic acid.
LC/MS: m/z calculated 761.5, found 762.4 (M + 1)+ Example 409: nd 478 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((R)hydroxy((pyrimidin y/methyl)amino)ethyl)— 1-isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyl—2-oxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 705.5, found 706.5 (M + 1)+ Example 410: Compound 479 4-(((3aR,5aR,5bR, 7aR,9S, 1 1aR, 1 1bR,13aS)-3a-((R)((2- ((cyc/obuty/methyl)amino)oxoethyl)(isopropyl)amino)— 1-hydroxyethy/)— 1-isopropyl- 5a, 5b, 8, 8, 1 1a-pentamethyl-Z-oxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)—2, 2-dimethyloxobutanoic acid.
LC/MS: m/Z calculated 780.6, found 781.6 (M + 1)+ Exam le 411: Com ound 480 4-(((3aR,5aR,5bR, 7aR,9S, 1 1aR, 1 1bR,13aS)-3a-((R)hydroxy(N- methylisobutyramido)ethy/)- 1-isopropy/-5a, 5b, 8, 8, 1 tamethyloxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)—2, thyloxobutanoic acid.
LC/MS: m/z calculated 697.5, found 698.5 (M + 1)+ Examgle 412: Compound 481 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR,13aS)-3a-((R)hydroxy(N- methy/cyclopentanecarboxamido)ethyl)- 1-isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyl oxo-3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 723.5, found 724.5 (M + 1)+ Example 413: Compound 482 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR,13aS)-3a-((R)hydroxy(N- methy/cyc/ohexanecarboxamido)ethyl)- 1-isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyI-Z-oxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)—2, 2-dimethyloxobutanoic acid.
LC/MS: m/Z calculated 737.5, found 738.5 (M + 1)+ Example 414: Compound 483 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-(2-((cyclopropylmethyl) (2- (dimethy/amino)ethy/)amino)ethy/)- ropy/-5a, 5b, 8, 8, 1 1a-pentamethyI-Z-oxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)—2, 2-dimethyloxobutanoic acid.
O a O 483 ] LC/MS: m/Z calculated 722.6, found 723.6 (M + 1)+ Example 415: Compound 484 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-(2-(cyclopentyl(2- (dimethy/amino)ethy/)amino)ethy/)— 1-isopropy/-5a, 5b, 8, 8, 1 1a-pentamethyI-Z-oxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)-2, 2-dimethyl—4-oxobutanoic acid. 0 WMtog 2 LC/MS: m/Z calculated 736.6, found 737.5 (M + 1)+ Example 416: Compound 485 4-(((3aR,5aR,5bR, , 1 1aR, 1 1bR,13aS)-3a-((R)—2—((2— (dimethy/amino)ethyl) (pyrimidiny/methyl)amino)— oxyethy/)— 1-isopropyl- 5a, 5b, 8, 8, 1 1a-pentamethyl-Z-oxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, tadecahydro-2H- cyc/openta[a]chrysenyl)oxy)-2, 2-dimethyl—4-oxobutanoic acid.
LC/MS: m/z calculated 776.5, found 777.5 (M + 1)+ Example 417: Compound 486 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((S)(benzy/(2-(2-oxopyrrolidin yl)ethyl)amino)hydroxyethy/)—1-isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyl0X0- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyclopenta[a]chrysenyl)oxy)—2, 2-dimethyloxobutanoic acid.
LC/MS: m/z ated 814.5, found 815.5 (M + 1)+ Examgle 418: Compound 487 aR,5aR,5bR, 7aR,9S, 1 1aR, 1 1bR,13aS)-3a-((R)hydroxy(N- methy/picolinamido)ethyl)- 1-isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyI0X0- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyclopenta[a]chrysenyl)oxy)—2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 732.5, found 733.5 (M + 1)+ Exam le 419: Com ound 488 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((R)(N-(4-ch/orobenzyl) hydroxyacetamido)— 1-hydroxyethy/)— 1-isopropy/-5a, 5b, 8, 8, 1 1a-pentamethyl—2—oxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyclopenta[a]chrysenyl)oxy)—2, 2-dimethyloxobutanoic acid.
LC/MS: m/Z ated 795.4, found 796.3 (M + 1)+ Example 420: Compound 489 4-(((3aR,5aR,5bR, 7aR,9S, 1 1aR, 1 1bR,13aS)-3a-((R)hydroxy(N- methylisonicotinamido)ethy/)- 1-isopropy/-5a, 5b, 8, 8, 1 1a-pentamethyI-Z-oxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)-2, thyloxobutanoic acid.
LC/MS: m/z calculated 732.5, found 733.5 (M + 1)+ Exam le 421: Com ound 490 4-(((3aR,5aR,5bR, 7aR,9S, 1 1aR, 1 1bR,13aS)-3a-((R)hydroxy(N- methylnicotinamido)ethyl)- 1-isopropy/-5a, 5b, 8, 8, 1 1a-pentamethyI-Z-oxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 732.5, found 733.4 (M + 1)+ Example 422: Compound 491 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((R)(N-(4-ch/orobenzyl) yacetamido)— 1-hydroxyethy/)— 1-isopropy/-5a, 5b, 8, 8, 1 1a-pentamethyloxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 809.5, found 810.3 (M + 1)+ Exam le 423: Com ound 492 4-(((3aR,5aR,5bR, 7aR,9S, 1 1aR, 1 1bR,13aS)-3a-((R)(N-(4- chlorobenzyl)isobutyramido)- 1-hydroxyethy/)— 1-isopropy/-5a, 5b, 8, 8, 1 1a-pentamethyl- 2-oxo-3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 807.5, found 808.5 (M + 1)+ Exam le 424: Com ound 493 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((R)(N-(2-(dimethy/amino)ethyl)- yl- 1, 3, 4-oxadiazo/ecarboxamido)- 1-hydroxyethyl)— 1-isopropyl- 5a, 5b, 8, 8, 1 1a-pentamethyl-Z-oxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)—2, 2-dimethyloxobutanoic acid.
] LC/MS: m/Z calculated 794.5, found 795.5 (M + 1)+ Exam le 425: Com ound 494 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)- 1-isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyl- 2—oxo-3a-(2-((pyrimidin-2—y/methyl)amino)ethyl)- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)—2, 2-dimethyloxobutanoic acid.
] LC/MS: m/z calculated 689.5, found 690.4 (M + 1)+ Example 427: Compound 496 4-(((3aR,5aR,5bR, 7aR,9S, 1 1aR, 1 1bR,13aS)-3a-((R)((4-ch/orobenzyl)amino) su/foethyl)- 1-isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyl-Z-oxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)—2, 2-dimethyloxobutanoic acid.
LC/MS: m/Z calculated 801.4, found 802.2 (M + 1)+ Example 428: Compound 497 aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)- 1-isopropyl-5a, 5b, 8, 8, 1 tamethyl- 2—oxo-3a-(2-((pyrimidiny/methyl)amino)ethyl)- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)—2, 2-dimethyloxobutanoic acid.
] LC/MS: m/z calculated 689.5, found 690.4 (M + 1)+ Example 429: Compound 498 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-(2-((2-(dimethylamino) oxoethyl)(pyridiny/methy/)amino)ethy/)- 1-isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyl oxo-3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, tadecahydro-2H- cyc/openta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 773.5, found 774.5 (M + 1)+ Example 430: Compound 499 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-(2-((2-(dimethylamino) oxoethyl)(pyridiny/methy/)amino)ethy/)- 1-isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyl oxo-3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 773.5, found 774.5 (M + 1)+ Example 431: Compound 500 aR,5aR,5bR, 7aR,9S, 1 1aR, 1 1bR,13aS)-3a-((R)((2- (dimethy/amino)ethyl) (pyrimidiny/methyl)amino)— 1-hydroxyethy/)— 1-isopropyl- 5a, 5b, 8, 8, 1 1a-pentamethyloxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)—2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 776.5, found 777.4 (M + 1)+ Example 433: Compound 502 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)- 1-isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyl- 2-oxo-3a-(2-(((R)- 1-(pyridiny/)ethy/)amino)ethy/)— 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)—2, thyloxobutanoic acid.
LC/MS: m/z calculated 702.5, found 703.3 (M + 1)+ Example 434: Compound 503 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((R)(N-(cyclobuty/methy/)—2—(2— oxopyrro/idin- 1-y/)acetamido)- 1-hydroxyethyl)— 1-isopropyl-5a, 5b, 8, 8, 1 1a- ethyloxo-3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0,1 1, 1 1 a, 1 1 b, 1 2, 13, 13a- cahydro-2H-cyclopenta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 806.5, found 806.9 (M + 1)+ Exam le 435: Com ound 504 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((R)((cyc/obutylmethyl) (2- (methy/amino)ethyl)amino)- 1-hydroxyethyl)—1-isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyl oxo-3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 738.5, found 739.5 (M + 1)+ Exam le 436: Com ound 505 4-(((3aR,5aR,5bR, 7aR,9S, 1 1aR, 1 1bR,13aS)-3a-((R)-2—((2— (dimethylamino)ethyl) (oxazol—2—y/methyl)amino)- 1-hydroxyethy/)— 1-isopropyl- 5a, 5b, 8, 8, 1 1a-pentamethyl-Z-oxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)-2, thyloxobutanoic acid.
LC/MS: m/z calculated 765.5, found 765.9 (M + 1)+ Example 437: Compound 506 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((R)hydroxy(1-oxoisoindolin yl) ethyl)isopropyl-5a, 5b, 8, 8, 1 tamethyloxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)—2, 2-dimethyloxobutanoic acid.
LC/MS: m/Z calculated 729.5, found 729.9 (M + 1)+ Example 438: Compound 507 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-(2-(cyclobuty/amino)ethyl)— 1- isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyloxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, tadecahydro-2H- cyc/openta[a]chrysenyl)oxy)—2, 2-dimethyloxobutanoic acid.
HOWO a LC/MS: m/z calculated 651.5, found 652.0 (M + 1)+ Example 439: Compound 508 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 3a-(2-(cyclobutyl(2- (dimethy/amino)ethy/)amino)ethy/)— 1-isopropy/-5a, 5b, 8, 8, 1 1a-pentamethyI0X0- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)—2, 2-dimethyloxobutanoic acid.
LC/MS: m/Z calculated 722.6, found 723.0 (M + 1)+ Example 440: Compound 509 aR,5aR,5bR, 7aR,9S, 1 1aR, 1 1bR,13aS)-3a-((R)-2—((2— acetamidoethyl)(cyc/obuty/methyl)amino)— 1 -hydroxyethy/)— 1-isopropy/—5a, 5b, 8, 8, 1 1apentamethyl0X0-3 , 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0,1 1, 1 1 a, 1 1 b, 1 2, 13, 13a- cahydro-2H-cyclopenta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 766.5, found 766.9 (M + 1)+ Example 441: Compound 510 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-(2-(2-(dimethy/amino)-N-(pyridin y/methy/)acetamido)ethyl)- 1-isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyl-Z-oxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)—2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 773.5, found 774.5 (M + 1)+ 2012/069637 Examgle 442: Compound 511 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-(2-((2-(dimethy/amino)ethyl) (pyridin- 2-y/methy/)amino)ethyl)— 1-isopropy/-5a, 5b, 8, 8, 1 1a-pentamethyI0X0- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyclopenta[a]chrysenyl)oxy)—2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 759.6, found 760.5 (M + 1)+ e 443: nd 512 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((R)((cyclobutylmethyl) (2- (dimethy/amino)oxoethyl)amino)— 1 -hydroxyethy/)— 1-isopropy/—5a, 5b, 8, 8, 1 1a- pentamethyloxo-3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0,1 1, 1 1 a, 1 1 b, 1 2, 13, 13a- octadecahydro-2H-cyclopenta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/Z calculated 766.5, found 767.5 (M + 1)+ Exam le 444: Com ound 513 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-(2-((2-(dimethy/amino)ethyl) (pyridin- 3-ylmethyl)amino)ethyl)- 1-isopropy/-5a, 5b, 8, 8, 1 1a-pentamethyI0X0- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyclopenta[a]chrysenyl)oxy)—2, 2-dimethyloxobutanoic acid.
] LC/MS: m/z calculated 759.6, found 760.5 (M + 1)+ Example 445: Compound 514 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-(2-((2-(dimethy/amino)ethyl) (pyridin- 4-y/methyl)amino)ethyl)isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyl—2-0X0- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 759.6, found 760.5 (M + 1)+ e 446: Compound 515 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-(2-(2-(dimethy/amino)-N-(pyridin y/methy/)acetamido)ethyl)- 1-isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyl-Z-oxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 773.5, found 774.5 (M + 1)+ e 447: Compound 516 aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((R)((cyclobuty/methyl)(2-(N- methy/acetamido)ethyl)amino)- 1-hydroxyethyl)- 1-isopropyl-5a, 5b, 8, 8, 1 1a- pentamethyloxo-3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a- octadecahydro-2H-cyclopenta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/Z calculated 780.6, found 781.4 (M + 1)+ Example 448: Compound 517 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((R)hydroxy(((R)(pyrimidin- 4-yl)ethy/)amino)ethy/)isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyl0X0- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)—2, 2-dimethyloxobutanoic acid.
HOWo a LC/MS: m/z calculated 719.5, found 720.4 (M + 1)+ e 449: Compound 518 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-(2-((azetidin y/methyl)amino)ethyl)— 1-isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyl0X0- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)—2, 2-dimethyloxobutanoic acid. 2012/069637 LC/MS: m/z calculated 666.5, found 667.4 (M + 1)+ Examgle 450: Comgound 519 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((R)(N-(cyclopropy/methyl) (pyrrolidin- 1-yl)acetamido)- 1-hydroxyethy/)— 1-isopropy/-5a, 5b, 8, 8, 1 1a-pentamethyI oxo-3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/Z ated 778.5, found 779.5 (M + 1)+ Example 451: Compound 520 4-(((3aR, 5aR, 5bR, 7aR, 98, 1 1aR, 1 1bR, 13aS)- 1-isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyl- 3a-(2-(((R)- 1-(pyridiny/)ethy/)amino)ethy/)— 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/Z calculated 702.5, found 703.5 (M + 1)+ Example 452: Compound 521 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-(2-((azetidiny/methyl)(2- (dimethy/amino)ethy/)amino)ethy/)— 1-isopropy/-5a, 5b, 8, 8, 1 1a-pentamethyI0X0- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyclopenta[a]chrysenyl)oxy)—2, thyloxobutanoic acid.
LC/MS: m/Z calculated 737.6, found 738.7 (M + 1)+ Example 454: Compound 523 4-(((3aR, 5aR, 5bR, 7aR, 98, 1 1aR, 1 1bR, 13aS)-3a-((R)- 1-hydroxy((2- morpholinoethyl) (pyridiny/methy/)amino)ethy/)- 1-isopropy/—5a, 5b, 8, 8, 1 1a- pentamethyloxo-3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0,1 1, 1 1 a, 1 1 b, 1 2, 13, 13a- octadecahydro-2H-cyclopenta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z ated 817.6, found 818.5 (M + 1)+ Example 455: Compound 524 aR,5aR,5bR, 7aR,9S, 1 1aR, 1 1bR,13aS)-3a-(2-((2-(dimethylamino)ethyl)((R) (pyridinyl)ethy/)amino)ethy/)- 1-isopropy/-5a, 5b, 8, 8, 1 1a-pentamethyl—2-0X0- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyclopenta[a]chrysenyl)oxy)—2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 773.6, found 774.5 (M + 1)+ Example 456: Compound 525 4-(((3aR,5aR,5bR, 7aR,9S, 1 1aR, 1 1bR,13aS)-3a-((R)((2-(dimethylamino)ethyl)((5- methyl- 1, 3, iazolyl)methyl)amino)— 1-hydroxyethyl)— 1-isopropyl- 5a, 5b, 8, 8, 1 1a-pentamethyl-Z-oxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)-2, thyloxobutanoic acid.
LC/MS: m/z calculated 780.6, found 781.5 (M + 1)+ Example 457: nd 526 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)- 1-isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyl- 2—oxo-3a-(2-(((R)- 1-(pyridiny/)ethy/)amino)ethy/)- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 702.5, found 703.5 (M + 1)+ Example 458: Compound 527 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-(2-(((1-acety/azetidinyl)methyl)(2- hy/amino)ethy/)amino)ethy/)— 1-isopropy/-5a, 5b, 8, 8, 1 1a-pentamethyI0X0- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)—2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 779.6, found 780.7 (M + 1)+ Example 459: Compound 528 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR,13aS)-3a-(2-((2- (dimethylamino)ethyl) (pyrimidiny/methyl)amino)ethy/)- 1-isopropy/—5a, 5b, 8, 8, 1 1a- pentamethyloxo-3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0,1 1, 1 1 a, 1 1 b, 1 2, 13, 13a- cahydro-2H-cyclopenta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 760.5, found 761.7 (M + 1)+ Example 460: Compound 529 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((R)- oxy(((S)- 1-(pyrimidin- -yl)ethy/)amino)ethy/)isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyl0X0- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)—2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 719.5, found 720.5 (M + 1)+ Exam le 461: Com ound 530 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((R)hydroxy-2—((2-morpholino-2— oxoethyl)(pyridiny/methy/)amino)ethyl)- 1-isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyl oxo-3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 831.5, found 832.7 (M + 1)+ Example 462: Compound 531 4-(((3aR,5aR,5bR, 7aR,9S, 1 1aR, 1 aS)-3a-(2-((2-(dimethylamino)ethyl)((R) (pyridinyl)ethy/)amino)ethy/)- 1-isopropy/-5a, 5b, 8, 8, 1 tamethyl-Z-oxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 773.6, found 774.7 (M + 1)+ Example 463: Compound 532 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((R)(benzy/(2-morpholino oxoethyl)amino)— 1-hydroxyethy/)— 1-isopropy/-5a, 5b, 8, 8, 1 1a-pentamethyIoxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)—2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 830.5, found 831.5 (M + 1)+ Example 464: Compound 533 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-(2-((cyclopenty/methy/)amino)ethyl)- 1-isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyloxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)-2, thyloxobutanoic acid.
O fi LC/MS: m/z calculated 679.5, found 680.7 (M + 1)+ Example 465: Compound 534 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 3a-(2-(((1-acety/azetidin yl)methy/)amino)ethy/)isopropyI-5a, 5b, 8, 8, 1 1a-pentamethyl0X0- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- enta[a]chrysenyl)oxy)—2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 708.5, found 709.7 (M + 1)+ Example 466: Compound 535 4-(((3aR,5aR,5bR, , 1 1aR, 1 1bR,13aS)-3a-((R)- 1-hydroxy((2-((2- methoxyethyl) (methyl)amino)ethyl)(pyridiny/methy/)amino)ethyl)- 1-isopropyl- 5a, 5b, 8, 8, 1 tamethyl-Z-oxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 819.6, found 820.5 (M + 1)+ Example 467: Compound 536 aR,5aR,5bR, 7aR,9S, 1 1aR, 1 1bR,13aS)-3a-(2-(N-(2— (dimethy/amino)ethyl)benzamido)ethyl)—1-isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyI oxo-3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 772.5, found 773.5 (M + 1)+ Example 468: Compound 537 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((R)- oxy(((S)- 1-(pyrimidin- 4-yl)ethy/)amino)ethy/)isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyl0X0- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 719.5, found 720.5 (M + 1)+ Example 469: Compound 538 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)- 1-isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyl- 3a-(2-((1-(pyridinyl)cyclopropyl)amino)ethyl)- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
IZ / \ HONO LC/MS: m/z calculated 714.5, found 715.5 (M + 1)+ Example 471: Compound 540 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)- 1-isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyl- 2-oxo-3a-(2-(piperidiny/)ethyl)-3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 10, 1 1, 1 1a, 1 1 b, 12, 13, adecahydro-2H-cyclopenta [a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 665.5, found 666.5 (M + 1)+ Examgle 472: Comgound 541 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)- 1-isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyl- 2-0X0-3a-(2-(((S)(pyridinyl)ethy/)amino)ethy/)- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)-2, 2-dimethyl—4-oxobutanoic acid.
LC/MS: m/z calculated 702.5, found 703.4 (M + 1)+ Examgle 473: Compound 542 4-(((3aR,5aR,5bR, 7aR,9S, 1 1aR, 1 1bR,13aS)-3a-(2-((2-(dimethy/amino)ethyl)((S) (pyridinyl)ethy/)amino)ethy/)- 1-isopropy/-5a, 5b, 8, 8, 1 1a-pentamethyl-Z-oxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, tadecahydro-2H- enta[a]chrysenyl)oxy)-2, 2-dimethyl—4-oxobutanoic acid.
LC/MS: m/z calculated 773.6, found 774.7 (M + 1)+ Example 474: Compound 543 4-(((3aR,5aR,5bR, 7aR,9S, 1 1aR, 1 1bR,13aS)-3a-(2-((2-(dimethylamino)ethyl)((R) (pyridinyl)ethy/)amino)ethy/)- 1-isopropy/-5a, 5b, 8, 8, 1 1a-pentamethyl-Z-oxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- enta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 773.6, found 774.7 (M + 1)+ Example 475: Compound 544 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((R)hydroxy(((R)(pyrimidin- -yl)ethy/)amino)ethy/)isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyl0X0- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 719.5, found 719.8 (M + 1)+ Example 476: Compound 545 4-(((3aR,5aR,5bR, , 1 1aR, 1 1bR,13aS)-3a-((R)(N-(2- chlorobenzyl)acetamido)- oxyethyl)- 1-isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyl-Z- oxo-3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 779.4, found 780.3 (M + 1)+ Examgle 477: Comgound 546 4-(((3aR, 5aR, 5bR, 7aR, 98, 1 1aR, 1 1bR, 13aS)-3a-((R)((4-chlorobenzyl) (2-(2- oxopyrro/idin- 1-yl)ethyl)amino)- 1-hydroxyethy/)— 1-isopropyl—5a, 5b, 8, 8, 1 amethyl0X0-3 , 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0,1 1, 1 1 a, 1 1 b, 1 2, 13, 13aoctadecahydro-2H-cyclopenta [a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 848.5, found 849.5 (M + 1)+ Examgle 478: Compound 547 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)- 1-isopropyl-5a, 5b, 8, 8, 1 tamethyl- 3a-(2-((oxetany/methyl)amino)ethyl)oxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 667.5, found 668.4 (M + 1)+ e 479: Compound 548 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)- 1-isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyl- 2-0X0-3a-(2-(((S)(pyridiny/)ethy/)amino)ethy/)— 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyclopenta[a]chrysenyl)oxy)—2, 2-dimethyloxobutanoic acid.
G N N ‘ O | HON ._fi 2 / 0 a LC/MS: m/z calculated 702.5, found 703.5 (M + 1)+ Example 480: nd 549 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)- 1-isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyl- 2-0X0-3a-(2-(((S)(pyridinyl)ethy/)amino)ethy/)- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyclopenta[a]chrysenyl)oxy)—2, thyloxobutanoic acid. 0 ~ \ HON 06O a 549 LC/MS: m/z calculated 702.5, found 703.4 (M + 1)+ Example 481: Compound 550 4-(((3aR,5aR,5bR, 7aR,9S, 1 1aR, 1 1bR,13aS)-3a-((R)((2-(dimethy/amino)ethy/)((R)- 1-(pyrimidinyl)ethyl)amino)hydroxyethyl)isopropyl-5a, 5b, 8, 8, 1 1a- pentamethyloxo-3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0,1 1, 1 1 a, 1 1 b, 1 2, 13, 13a- octadecahydro-2H-cyclopenta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 790.6, found 791.5 (M + 1)+ e 482: Comgound 551 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-(2-((2-(dimethylamino)ethyl)(1- (pyridin-2—yl)cyc/opropyl)amino)ethyl)- 1-isopropy/-5a, 5b, 8, 8, 1 1a-pentamethyl-Z-oxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 785.6, found 786.5 (M + 1)+ Example 483: nd 552 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)- 1-isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyl- 2-oxo-3a-(2-((2-(pyridinyl)propanyl)amino)ethyl)— 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 716.5, found 717.5 (M + 1)+ Example 484: Compound 553 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-(2-((2-(dimethylamino)ethyl) (oxetan- 3-y/methyl)amino)ethyl)isopropyI-5a, 5b, 8, 8, 1 1a-pentamethyl0X0- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)—2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 738.5, found 739.5 (M + 1)+ Example 485: Compound 554 4-(((3aR,5aR,5bR, 7aR,9S, 1 1aR, 1 aS)-3a-(2-((2-(dimethy/amino)ethyl)((S) (pyridinyl)ethy/)amino)ethy/)- 1-isopropy/-5a, 5b, 8, 8, 1 1a-pentamethyl0X0- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- enta[a]chrysenyl)oxy)—2, thyloxobutanoic acid.
LC/MS: m/z calculated 773.6, found 774.5 (M + 1)+ Example 486: Compound 555 4-(((3aR,5aR,5bR, 7aR,9S, 1 1aR, 1 1bR,13aS)-3a-(2-((2-(dimethy/amino)ethy/)((S) (pyridinyl)ethy/)amino)ethy/)- 1-isopropy/-5a, 5b, 8, 8, 1 1a-pentamethyl0X0- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)—2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 773.6, found 774.5 (M + 1)+ Example 487: nd 556 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)- 1-isopropyl-5a, 5b, 8, 8, 1 tamethyl- 2—oxo-3a-(2-((1-(pyrimidinyl)cyc/opropy/)amino)ethyl)- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 715.5, found 716.5 (M + 1)+ Example 488: Compound 557 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-(2-((2-(dimethylamino)ethyl)(1- (pyrimidin-2—yl)cyclopropy/)amino)ethy/)- 1-isopropy/-5a, 5b, 8, 8, 1 1a-pentamethyI-Z- oxo-3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/Z calculated 786.6, found 787.5 (M + 1)+ Example 489: Compound 558 4-(((3aR,5aR,5bR, 7aR,9S, 1 1aR, 1 1bR,13aS)-3a-(2-(N-(2- (dimethylamino)ethyl)pico/inamido)ethyl)isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyI oxo-3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
] LC/MS: m/z calculated 773.5, found 774.5 (M + 1)+ Example 490: Compound 559 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)- 1-isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyl- 2-oxo-3a-(2-((2-(pyridinyl)propanyl)amino)ethyl)— 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)—2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 716.5, found 717.5 (M + 1)+ Example 491: Compound 560 aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)- ropyl-5a, 5b, 8, 8, 1 1a-pentamethyl- 2-oxo-3a-(2-((2-(pyridinyl)propanyl)amino)ethyl)— 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)—2, 2-dimethyloxobutanoic acid.
WO 90664 LC/MS: m/z calculated 716.5, found 717.5 (M + 1)+ Example 492: Compound 561 aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((R)(benzy/(2-(4-methy/piperazin- 1-yl)oxoethy/)amino)— 1-hydroxyethyl)— 1-isopropyl—5a, 5b, 8, 8, 1 1a—pentamethyl oxo-3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyclopenta[a]chrysenyl)oxy)-2, 2-dimethyl—4-oxobutanoic acid.
LC/MS: m/z calculated 843.6, found 844.5 (M + 1)+ Example 493: Compound 562 4-(((3aR,5aR,5bR, 7aR,9S, 1 1aR, 1 1bR,13aS)-3a-((R)-2—((2— (dimethylamino)ethyl) (oxazoly/methyl)amino)- 1-hydroxyethy/)— 1-isopropyl- 5a, 5b, 8, 8, 1 tamethyl-Z-oxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyclopenta[a]chrysenyl)oxy)-2, 2-dimethyl—4-oxobutanoic acid.
LC/MS: m/z calculated 765.5, found 766.5 (M + 1)+ Example 494: Compound 563 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-(2-((2-(dimethylamino)ethyl)(2- (pyridin-2—yl)propan-2—y/)amino)ethy/)- 1-isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyl—2-0X0- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, tadecahydro-2H- cyc/openta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 787.6, found 788.5 (M + 1)+ e 495: Compound 564 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 3a-(2-((2-(dimethylamino) oxoethyl)(pyridiny/methy/)amino)ethy/)- 1-isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyl oxo-3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 773.6, found 774.5 (M + 1)+ Example 496: Compound 565 4-(((3aR,5aR,5bR, 7aR,9S, 1 1aR, 1 1bR,13aS)-3a-((R)—2-((2- (dimethylamino)ethyl) (oxazoly/methyl)amino)- 1-hydroxyethy/)— 1-isopropyl- 5a, 5b, 8, 8, 1 1a-pentamethyl-Z-oxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, tadecahydro-2H- cyclopenta[a]chrysenyl)oxy)-2, 2-dimethyl—4-oxobutanoic acid.
LC/MS: m/z calculated 765.5, found 766.5 (M + 1)+ Example 497: Compound 46 mphor Ligand 568 * Cu(0Ac)2 02 ’ MeNo2 THF / HOAc DIEPA 0 MeOH / MgSO4/ Et3N Step C 0 Step D 569 570 Step E _>100 _>rgo DCM / TFA 1)N /—\ —> NH HN 2) H2 (s)— camphor (S)—camphor Ligand 568 Ste A: Intermediate 566 (3aR, 5aR, 5bR, 7aR, 98, 1 1aR, 1 1bR, 13aS)hydroxy—1-isopropyl-5a, 5b, 8, 8, 1 1a- pentamethyl0X0-3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 10,1 1, 1 1a, 1 1 b, 12, 13, 13aoctadecahydro-2H-cyclopenta [a]chrysene-3a-carbaldehyde. (3aR,5aR,5bR,7aR,98,11aR,11bR,13aS)—3a-Formy|—1-isopropy|— 5a,5b,8,8,11a-pentamethyIoxo- 3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H- cyclopenta[a]chrysenyl acetate (50 g) placed in a round bottomed flask with methanol (500 ml, 10 vol) and DCM ("dichloromethane" - 200 ml, 4 vol) and stirred at ambient temp while adding solid ZrCl4 (23.4 g, 1 equiv.) in portions.
The reaction was warmed to approximately 60 °C and maintained for a total of 16 hours. The on was monitored for tion on HPLC (starting material and product formed an acetal derivative during the reaction). Once complete, the on was treated with water (5 equiv.) and maintained at 60 s for approximately 30 minutes.
Next, the reaction was cooled and evaporated under vacuum at a bath temp of approximately 40 °C to 200 ml (4 volumes). Ethyl acetate (500 ml, 10 vol) was added and reaction was then treated with 1N HCI (250 ml, 5 vol). The reaction was then mixed thoroughly and the layers were allowed to separate. The lower s layer was drained off and back-washed with fresh ethyl e (100 ml, 2 vol).
The combined organic layer was washed with 1N HCI (250ml, 5 vol) and evaporated under vacuum at a bath temp of 40 °C to 200 ml (4 vol) and then treated with acetonitrile (500 ml, 10 vol). The reaction was then evaporated to a final volume of approximately 150ml (3 vol). Acetonitrile (500 ml, 10 vol) was then added and the reaction was warmed to a 60 °C forming solution. Next, was slowly added 3N HCI (100 ml, 2 vol), which resulted in precipitate formation. (see note 2). The reaction was then allowed to cool to ambient temperature and then it was filtered.
The ted solid was next rinsed with acetonitrile (2 vol) and dried in vacuo to give a weight of 33.0 g, 72% yield of (3aR,5aR,5bR,7aR,98,11aR,11bR,13aS)—9—hydroxy isopropyl-5a,5b,8,8,11a-pentamethyloxo- 3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H- cyclopenta[a]chrysene-3a-carbaldehyde.
Note 1: The isolated solids were contaminated with a small amount of dimethyl acetal of product, which required reslurry in hot acetonitrile / 3N HCI to complete the hydrolysis and resulted in loss of t (27 g recovered on re- treatment). It was determined that in process monitoring of reaction es during final hydrolysis require filtration of on aliquot in order to observe remaining dimethyl acetal. Dissolution of crude acetonitrile/aqueous HCI reaction solution for HPLC monitoring results in cially low observed levels of dimethyl acetal due to hydrolysis in sample prep.
Note 2: Preferred ure would be to add a portion of the 3N HCI (0.5 vol) and maintain reaction in solution at approximately 60 °C until dimethyl acetal hydrolysis is te followed by addition of remainder (1.5 vol) of the 3N HCI and cooling to ambient ature for filtration. Expected yield is 72%.
Step B: Intermediate 567 1-terf-buty/ 4-((3aR,5aR,5bR,7aR,98,11aR,11bR,13aS)-3a-formyl—1-isopropyl- 5a, 5b, 8, 8, 1 1a-pentamethyl-Z-oxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 10, 1 1, 1 1 a, 1 1 b, 12, 13, 13a-octadecahydro-2H- cyclopenta[a]chrysen—9-yl) 2, 2-dimethy/succinate. (3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)—9-Hydroxy—1-isopropyl- 5a,5b,8,8,11a-pentamethyloxo- 3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H- cyclopenta[a]chrysene-3a-carbaldehyde (26.9 g, 1 equiv), 4-(tert—butoxy)—3,3- dimethyloxobutanoic acid (14.96 g, 1.25 equiv) and THF (538 ml, 20 vol) were charged to a flask. Benzoyl chloride (10.4 g, 1.25 equiv) was added ed by slow addition of triethylamine (14.97 g, 2.5 equiv) forming a thick slurry. DMAP (0.1 .81g, 0.25 equiv) was added and the reaction was allowed to stir at ambient temperature for approximately 18 hours until te by HPLC. Reaction was then charged with ethyl acetate (538 mL, 20 vol) and water (269 ml, 10 vol), stirred well and allowed to settle. Aqueous phase was removed and the organic phase washed with saturated sodium bicarbonate solution (2x 10 vol) followed by water (269 mL, 10 vol).
The reaction solution evaporated under vacuum to approximately 4 volumes to produce solids. Additional s (269 ml, 10 vol) was added and reaction heated back to reflux to nearly form solution and slowly cooled to ambient temperature (seeding with desired product) and let stir for 15 minutes then cooled to 0 °C for approximately two hours and filtered solid. Washed solid with hexanes (2x10 vol) and dried at 50 °C under vacuum to a weight of 32.15g, 85% yield of -butyl 4- ((3aR,5aR,5bR,7aR,98,11aR,11bR,13aS)—3a-formylisopropyl-5a,5b,8,8,11a- pentamethyloxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a- octadecahydro-2H-cyclopenta[a]chrysenyl) 2,2-dimethylsuccinate.
Step C: Intermediate 569 1-tert-buty/ 4-((3aR, 5aR, 5bR, 7aR, 98, 1 1aR, 1 1bR, 13aS)-3a-((R)hydroxy thy/)- 1-isopropy/-5a, 5b, 8, 8, 1 1a-pentamethyl-Z-oxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 10, 1 1, 1 1 a, 1 1 b, 12, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl) 2, 2-dimethy/succinate.
The reaction was charged with -butyl 4- ((3aR,5aR,5bR,7aR,98,11aR,11bR,13aS)—3a-formylisopropyl-5a,5b,8,8,11a- pentamethyloxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a- octadecahydro-2H-cyclopenta[a]chrysenyl) 2,2-dimethylsuccinate (15.75 g, 1 equiv), tert-butanol (157 ml, 10 vol) and toluene (47 ml, 3 vol) and stirred at ambient temperature. The ligand (N1,N2-bis(1,7,7-trimethylbicyclo[2.2.1]heptanyl)ethane- 1,2-diamine, d from (S)—camphor, 0.492 g, 0.06 equiv) and copper (ll) acetate mono hydrate (0.246 g, 0.05 equiv) were added in a single portion and reaction allowed to stir at ambient temperature for at least 2.5 hours (see note 1). The reaction is charged with nitromethane (7.52 g, 5 equiv) and Hunig’s base ("N,N- diisopropylethylamine" - 3.82 g, 1.2 equiv) and allowed to stir at ambient temperature for approximately 5 days. (See note 2). Reaction concentrated under vacuum at bath temp of no more than 35 °C to imately 2 vols. (See note 3). on charged with toluene (236 ml, 15 vols) and concentrated under vacuum again to approx 3 vols. Additional toluene (95 ml, 3 vol) was added to achieve a final reaction volume of approx 6 vols. Heptane (158 ml, 10 vols) was added slowly of to solution. Product began to crystallize out of solution upon seeding. Reaction was allowed to stir at ambient ature for one to two hours and solids collected by filtration and washed with 10 vols of e. Solids were dried to a weight of 14.3 g (83% yield).
Purity of isolated solid is typically ~90-95% with a 98/2 reomeric ratio ng 1-tert-butyl R,5aR,5bR,7aR,98,11aR,11bR,13aS)—3a-((R)—1-hydroxy nitroethyl)isopropyl-5a,5b,8,8,11a-pentamethyloxo- 3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H- cyclopenta[a]chrysenyl) 2,2-dimethylsuccinate as the major diastereomer.
Step D: Intermediate 570 R, 5aR, 5bR, 7aR, 98, 1 1aR, 1 1bR, 13aS)-3a-((R)-2—aminohydroxyethy/)- 1- isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyl-Z-oxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl) 1-tert-buty/ 2, 2-dimethy/succinate 1-tert-butyl 4-((3aR,5aR,5bR,7aR,98,11aR,11bR,13aS)—3a-((R)—1- hydroxynitroethyl)isopropyl-5a,5b,8,8,1 1a-pentamethyloxo- 3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H- cyclopenta[a]chrysenyl) 2,2-dimethylsuccinate (12.9 g, 18.4 mmol) was placed in 1-L retreat curve impellor reactor and then added 22 vol of 90% THF-HOAc and stirred to dissolve at ambient temp. The reactor was purged 3x with nitrogen and then a slurry of water was added and then washed (pH ~8-9) RaNi catalyst (50% water, added 2.6 ml catalyst slurry, 1.3g RaNi calculated) and then placed under hydrogen at 0.3 bar pressure for 3 hours and then raised the pressure to 2 bar and allowed to stir for 18 hours. Reaction was approximately 20% complete at this time. The temperature was raised to 35 deg C and then the reaction was stirred for another 7 hours and sampled. The reaction was approximately 31% complete at this time. Reaction pressure was increased to 4 bar hydrogen and was allow to continue stirring at 35 deg for 20 hours. Reaction is 75% complete at this time and no change in impurity profile. Added another 0.15 wt of RaNi (3.0 ml of 50% slurry) to bring total RaNi loading up to 25 wt % and the reaction was d to stir at 35 deg under 4 bar Hydrogen for another 24 hours. The reaction was then determined to be te by HPLC.
The reaction was then filtered through a 4 micron in-line filter, rinsing with THF (50ml). Evaporated to approximately 3 vol and added ethyl acetate (195ml, vol) and washed with 1N NaOH solution (3x 10 vol) and verified final wash to be basic pH. (Note: addition of 0.5 vol saturated NaCl solution was required on second and third washes to obtain efficient separation). Washed with saturated sodium chloride solution (5 vol) and evaporated to a solid foam that was azeotroped with 2x vol romethane in order to obtain a solid foam. Dried on high vacuum pump to weight of 11.1g (90% yield).
Recrystallized above sample (10.5 g) by dissolving in ol (147 ml, 14 volumes) at reflux and then cooling with seeding to ambient temperature and d to stir 30 minutes). Mixture was further cooled to 15 degrees and filtered. Solids collected by filtration and washed with methanol (1 volume) and dried at 50 degrees in vacuo to a weight of 7.5 g (71% yield on recrystallization) of 4- ((3aR,5aR,5bR,7aR,98,11aR,11bR,13aS)—3a-((R)—2—aminohydroxyethyl)—1- isopropyl-5a,5b,8,8,11a-pentamethyloxo- 3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H- cyclopenta[a]chrysenyl) 1-tert-butyl 2,2—dimethylsuccinate..
Step E and F: Compound 46 1-tert-buty/ 4-((3aR,5aR,5bR, 7aR,98, 1 1aR, 1 1bR,13aS)-3a-((R)—2—((4- chlorobenzyl)amino)- 1-hydroxyethy/)- ropy/-5a, 5b, 8, 8, 1 tamethyl—2—oxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyclopenta[a]chrysen—9-yl) 2, 2-dimethy/succinate. 4-((3aR,5aR,5bR,7aR,98,11aR,11bR,13aS)—3a-((R)—2-Amino yethy|)isopropy|-5a,5b,8,8,11a-pentamethyloxo- 3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H- cyclopenta[a]chrysenyl) 1-tert-butyl 2,2-dimethylsuccinate and p-Cl-benzaldehyde (1.1 equiv) were placed in a round bottomed flask with EtOH (10 vol) and added Na2C03 powder (2.5 equiv) and allowed to stir overnight (16 hrs). The next day, the on slurry was cooled to approximately 10 degrees and added NaBH4 to the reaction in a single portion and d reaction to stir while slowly warming to ambient temperature. ed HPLC after 45 minutes showing essentially complete conversion to desired product. p-Cl-benzyl alcohol present as well (using 220 nm wavelength). The reaction was then diluted with methylene chloride (30 ml, 10 vol) and water (30 ml, 10 vol) and the layers were allowed to separate. The DCM layer was then washed with onal water (10 vol) and evaporated to minimum volume on rotovap and added back DCM (10 vol) and treated with trifluoroacetic acid (6 ml, 2 vol) and the reaction was allowed to stir at ambient temperature. The reaction was almost complete after one hour, but it was left to stir overnight. After 18 hours reaction complete by HPLC and was evaporated to an oil.
Dissolved with warming to approximately 45 degrees in ethyl acetate (60 ml, 20 vol) and washed with NaHC03 solution (2x10 vol) to remove al TFA.
Then, washed with ethyl e and with half-saturated NaCl solution and evaporated to dryness and azeotroped dry with isopropanol (2x5 vol). Dissolved in panol (5 vol) and d with acetonitrile to cloud point (10 vol) and then allowed to crystallize overnight. Cloudy mixture, but no filterable solids present.
Meanwhile the test crystallization from ethyl e-heptane of the original isolated TFA salt solution had produced nice solids.
The entire reaction was then evaporated to dryness and azeotroped several portions of ethyl acetate on rotovap (3x10 vol) to remove all isopropanol and acetonitrile. Reaction disolved with warming to reflux in ethyl acetate (30 ml, 10 vol).
Added one equivalent oroacetic acid (0.51 g) and slowly diluted with e to cloud point (15 ml, 3 volumes). Seeded with test crystallization seeds from above.
Nice solids resulted almost immediately. Stirred with cooling to ambient temperature.
Filtered solids and washed with heptane (15 ml, 3 vol). Dried on funnel to weight of 2.55 g, 67% yield of 4-(((3aR,5aR,5bR,7aR,98,1 1aR,11bR,13aS)—3a-((R)—2-((4- chlorobenzyl)amino)hydroxyethyl)isopropyl-5a,5b,8,8,11a-pentamethyloxo— 3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H- cyclopenta[a]chrysenyl)oxy)-2,2-dimethyIoxobutanoic acid..
Alternatve Procedure 4-((3aR,5aR,5bR,7aR,98,11aR,11bR,13aS)—3a-((R)Amino hydroxyethyl)isopropy|-5a,5b,8,8,11a-pentamethyloxo- 3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H- cyclopenta[a]chrysenyl) -butyl 2,2-dimethylsuccinate (7 g, 1 equiv.) was placed in a round bottom flask and added MgSO4 powder (2.5 equiv) and Et3N (0.8 equiv) and p-Chlorobenzaldehyde and added MeOH (10 vol) and allowed to stir overnight (16 hrs). After this time an aliquot (0.5ml) of the white slurry was removed and treated with approximately 25mg NaBH4 and allowed to stir for 5 minutes.
Obtained HPLC of this aliquot ting complete consumption of the amine ng material. The reaction mixture was cooled to 0 degrees on ice-brine bath and treated with solid NaBH4 in a single portion (475 mg, 1.2 equiv) and allowed to stir at 0 degrees for approximately 45 minutes. HPLC after this time shows reaction is complete. The on was warmed to ambient temperature briefly and filtered through a celite bed. The solid was rinsed with additional methanol (35 ml, 5 vol) and then dichloromethane (70 ml, 10 vol). The filtrate/rinse was then treated with water (70 ml, 10 vol) and shaken in separatory funnel. The upper s was washed well with additional dichloromethane (3x 5 vol) and then the combined organic layers 2012/069637 were washed with brine (10 vol). The c phase was ated to a solid foam and azeotroped with dichloromethane. Dissolved in dichloromethane (70 ml, 10 vol) and treated with trifluoroacetic acid (14 ml, 2 vol) and allowed to stir at ambient temperature. The reaction almost complete in approximately 2 hours.
The reaction was allowed to sit over a weekend at which point the reaction was complete. The reaction was allowed to evaporate to a minimum volume and then ethyl acetate (10 vol) was added and evaporated to a m volume again. Repeated this evaporating to minimum volume and then dissolved in total of volume ethyl acetate. Heated to near reflux and diluted with heptane (5 vol) and stirred while cooling to ambient temperature while solids were formed. Stirred for 30 s and filtered. Rinsed with heptane (3 vol) and dried to a weight of 4.85 g, 63% yield of 4-(((3aR,5aR,5bR,7aR,98,1 1aR,1 1bR,13aS)—3a-((R)—2—((4- chlorobenzyl)amino)hydroxyethyl)isopropyl-5a,5b,8,8,11a-pentamethyloxo- 3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H- cyclopenta[a]chrysenyl)oxy)-2,2—dimethyloxobutanoic acid over two steps.
Example 498: Compound 51 Benzoyl chloride, Zrc14 / MeOH, Et3N,THF, EtOAc EtOAc o CHZCIZ, MeCN, aq HCl Raney Nickel, . (S)—Camphor Ligand 568 * Hz, THF Cu(OAc), MeNOZ AcOH, EtOAc Cl N02 —> _ —> iPrZNEt, t-BuOH NaBH(OAc)3 toluene, heptane THF utyl methyl ether Step D Step C O 569 O 570 Step E >(0 0 >(0 0 \T/YSO3NEOH N —> NaBHacN MeOH, Et3N /N\ >r0 571 Step F 70 1) /—\ o HZN NH2 , NH HN 2) H2 (s)— camphor (S)—cam phor Ligand 568 Step A: Intermediate 566 (3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)hydroxy— 1-isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyl- 2-oxo-3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 10, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysene-3a-carba/dehyde The compound (3aR,5aR,5bR,7aR,98,11aR,11bR,13aS)—3a-formyl isopropyl-5a,5b,8,8,11a-pentamethyloxo- 3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H- cyclopenta[a]chrysenyl acetate (400 g, 0.81 mol) was placed in a flask with ol (4 L) and DCM (1.6 L) and stirred at ambient temp while adding solid ZrCl4 (225.2 g, 0.97 mol) in portions. The reaction was warmed to approximately 45~55 °C and maintained for a total of ~36 hours. The reaction was monitored for completion by HPLC.
Once complete, the reaction was then treated with water (120 mL) and maintained at 45~55 °C for approximately 30~60 minutes. The reaction was then cooled and evaporated under vacuum (at bath temp approximately 40 °C) to 1200 mL. Dichloromethane (4 L) was added and reaction was treated with 1N HCI (2 L), mixed thoroughly and the layers were allowed to separate. ards, the upper s layer was washed with fresh dichloromethane (800 mL). Next, the combined organic layer was washed with 1N HCI (2 L) and evaporated under vacuum (at bath temp of 40 °C) to 800 mL and treated with itrile (4 L).
The reaction was then evaporated (at bath temp of 40 °C) to a final volume of approximately 800 mL. Acetonitrile (3.2 L) was added and the reaction was warmed to 50~60 °C, thus forming a solution. Next was slowly added, 3N HCI (100 mL), which resulted in precipitate formation and which was maintained as a reaction in solution at approximately 50~60 °C until yl acetal hydrolysis was complete followed by addition of water (4.8 L).
The on was allowed to cool to 0-10°C and then the e was filtered and the resultant solid was rinsed with acetonitrile/water (1/1,800 mL). The solid was then slurryed in 10 volumes of heptane at 85~100 °C for 1~3 hours. The slurry was then cooled to ambient temperature and filtered. Washed the cake with 800 mL heptane then dried in vacuo at 40~50 °C to the 4-((3aR,5aR,5bR, 7aR,9S, 1 1aR, 1 1bR,13aS)-3a-formyl—1-isopropyl- 5a, 5b, 8, 8, 1 1a-pentamethyloxo-3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 10, 1 1, 1 1a, 1 1b, 12, 13, 13a- cahydro-2H-cyc/openta[a]chrysenyl) 2, 2—dimethy/succinate 286 9. Yield is 72.6% corrected by assay. 1H NMR (400MHz ,CDCI3) 6 = 9.33 (s, 1 H), 3.20-3.28 (m, 2 H), 2.57 (d, J =1 H), 2.36-2.42 (m, 2 H), 2.04-2.08 (m, 2 H), 1.86 -1.90 (m, 2 H), 1.75 — 1.78 (m, 1 H), 1.23 — 1.66 (m, 35 H); LC/MS: m/z calculated 454.3, found 455.4 (M+1)+ Step B: Intermediate 567 1-tert-butyl 4-((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-formyl—1-isopropyl- 5a, 5b, 8, 8, 1 1 a-pentamethyl0x0-3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a- octadecahydro-2H-cyclopenta[a]chrysenyl) 2, 2-dimethy/succinate The starting material (3aR,5aR,5bR, , 1 1aR, 1 aS)hydroxy—1- isopropyl—5a, 5b, 8, 8, 1 1a-pentamethyl-Z-oxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 10, 1 1, 1 1a, 1 1 b, 12, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysene-3a-carbaldehyde (32.4 g, 71 mmol), 4-(tert-butoxy)-3,3-dimethyl oxobutanoic acid (18 g, 89 mmol) and THF (648 mL) were charged to a flask. Benzoyl chloride (12.5 g, 89 mmol) was added followed by slow addition of triethyl amine (18 g, 178 mmol) forming a thick slurry. DMAP (2.17 g, 18 mmol) was added and the reaction was d to stir at ambient temperature for approximately 24~30 hours until complete by HPLC. The reaction was then charged with ethyl acetate (648 mL) and water (324 mL), stirred well and allowed to settle. The s phase was removed and the organic phase washed with saturated sodium bicarbonate solution (2x 324 mL) ed by water (324 mL).
The reaction solution was then evaporated under vacuum to approximately 129 mL in order to produce solids. Additional heptane (324 mL) was added and the reaction heated back to reflux to a nearly formed solution and slowly cooled to ambient temperature and was d for 15 minutes then cooled to 0 °C for approximately two hours and the solids were filtered. The solids were then washed with heptane (2x324 mL) and dried at 50 °C under vacuum to give the desired compound as an off-white solid 1-tert-buty/ 4- ((3aR, 5aR, 5bR, 7aR, 98, 1 1aR, 1 1bR, 13aS)-3a-formyl—1-isopropyl-5a, 5b, 8, 8, 1 1a- pentamethyl0x0-3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 10,1 1, 1 1a, 1 1 b, 12, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysen-9—yl) 2, 2—dimethy/succinate 36.8 g. yield is 80%. 1H NMR (400MHz, CDCI3) 6 = 9.24 (s, 1 H), 4.41-4.45 (m, 1 H), 3.19-3.20 (m, 1 H), 2.33-2.48 (m, 5 H), 0.96- 1.60 (m, 37 H), 0.77-0.87 (m, 17 H); LC/MS: m/z calculated 638.4, found 639.4 (M+1)+.
Step C: Intermediate 569 1-tert-buty/ 4-((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((R)hydroxynitroethy/) isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyl-Z-oxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 10, 1 1, 1 1a, 1 1 b, 12, 13, 13a-octadecahydro-2H- cyclopenta[a]chrysenyl) 2, 2—dimethy/succinate The reaction was d with of 4- ((3aR,5aR,5bR,7aR,98,11aR,11bR,13aS)—3a-formylisopropyl-5a,5b,8,8,11a-pentamethyl- 2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H- cyclopenta[a]chrysenyl) 2,2-dimethylsuccinate (50 g, 78 mmol), tert—butanol (500 mL) and toluene (150 mL) and the temperature was ed to 20-25°C. The ligand (N1,N2— bis(1,7,7-trimethylbicyclo ] heptanyl)ethane-1,2-diamine (1.56 g, 4.7 mmol) and Copper(l) acetate (0.48 g, 3.9 mmol) were added in a single portion and the reaction was then stirred at 20-25 °C for 3-5 hrs.
The on was next d to cool to 7-13 °C. The reaction was then charged with nitromethane (33 g, 0.55 mmol) and N,N-diisopropyl ethylamine (12.1 g, 94 mmol) and allowed to stir at 7-13 °C for approximately 30 hrs. The reaction was again charged with ethane (17 g, 0.3 mmol) and allowed to stir at 7-13 °C for approximately 40 hrs. The reaction was yet again charged with nitromethane (17 g, 0.3 mmol) and allowed to stir at 7-13 °C for approximately 20 hrs.
Next, the reaction was charged with MTBE (750 mL) and a 15% ammonium chloride solution (300 mL), allowed to stirfor 30 min, and then separated into two phases.
The organic phase was washed with water (250 mL) followed by brine (200 mL). The organic phase was then trated to 100 mL and MTBE (25 mL) was added. Next, nheptane (500 mL) was slowly added and then stirred at 10-20 °C for 2 hrs. The reaction was then filtered and washed with n-heptane, and then dried under vaccum at 50-55 °C to give 4- ((3aR,5aR,5bR,7aR,98,11aR,11bR,13aS)—3a-((R)—1-hydroxynitroethyl)—1-isopropyl- 5a,5b,8,8,11a-pentamethyloxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a- octadecahydro-2H-cyclopenta[a]chrysenyl) 2,2-dimethylsuccinate as off-white solid 41.6 WO 90664 g. Yield is 75.9%,1H NMR (400MHz, CDCI3) 5 = 4.85 (bd, 1 H), 4.51-4.55 (dd, 1 H), 4.08- 4.20 (m, 2 H), 3.15-3.22 (m, 1 H), 2.35 -2.83 (m, 6 H), 0.80 — 2.03 (m, 54 H); LC/MS: m/z calculated 699.4, found 700.4 .
Step D: Intermediate 570 4-((3aR, 5aR, 5bR, 7aR, 98, 1 1aR, 1 1bR, 13aS)-3a-((R)-2—amino- 1-hydroxyethyl)- 1-isopropyl- 5a, 5b, 8, 8, 1 1a-pentamethyloxo-3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 10, 1 1, 1 1a, 1 1 b, 12, 13, 13a- octadecahydro-2H-cyclopenta[a]chrysenyl) 1 -tert-butyl 2, 2-dimethy/succinate To 4-((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)—3a-((R)—1-hydroxy nitroethyl)isopropyl-5a,5b,8,8,11a-pentamethyloxo- ,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H- cyclopenta[a]chrysenyl) 2,2-dimethylsuccinate (30 g, 42.6 mmol) in THF (600 mL) and AcOH (30 mL) was added Raney Ni (30 g, 5%) under N2 at room ature. The reaction was stirred at 45-550C under hydrogen gas (0.30-0.40MPa) for 10-12 hours. The reaction mixture was filtered through a filter aid, washing with THF [2 x 90 mL] and the filtrate was adjusted to a pH of 7-8 with 5% K2C03 aqueous.
Next, ethyl acetate (450 mL) was added to the reaction mixture and the two phases were separated. The s layer was ted with ethyl acetate (150 mL). The combined c phase was washed two times with 7.5% NaCl aqueous (300 mL) and then washed with 17% NaCl aqueous (300 mL). The organic phase was concentrated under vacuum to give 25.7 g of 4-((3aR,5aR,5bR,7aR,9S,1 1aR,1 1bR,13aS)—3a-((R)—2-amino hydroxyethyl)isopropyl-5a,5b,8,8,1 1a-pentamethyloxo- 3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H- cyclopenta[a]chrysenyl) 1-tert—butyl 2,2-dimethylsuccinate. Yield is 92%. 1H NMR (400MHz 6 = 4.40-4.44 (dd, 1 H), 3.79-3.80 (bd, 1 , DMSO-da) H), 3.59-3.62 (M, 2 H), 3.12- 3.17 (m, 2 H), 2.60-2.75 (m, 1 H), 2.22-2.34 (m, 2 H), 2.19 — 2.22 (m, 2 H), 1.37 — 1.84 (m, H), 1.08-1.11 (m, 17H), 0.81-0.91 (m, 13H); LC/MS: m/z calculated 669.5, found 670.4 (lV|+1)+ Step E: Intermediate 571 -buty/ 4-((3aR, 5aR, 5bR, 7aR, 98, 1 1aR, 1 1bR, 13aS)-3a-((R)((4-ch/orobenzyl)amino)- 1-hydroxyethyl)— ropy/-5a, 5b, 8, 8, 1 1a-pentamethyI-Z-oxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 10, 1 1, 1 1a, 1 1 b, 12, 13, 13a-octadecahydro-2H- cyclopenta[a]chrysenyl) 2, 2—dimethy/succinate To a solution of 4-((3aR,5aR,5bR,7aR,9S,1 1aR,1 1bR,13aS)—3a-((R)—2—amino- oxyethyl)isopropyl-5a,5b,8,8,11a-pentamethyloxo- 3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H- cyclopenta[a]chrysenyl) 1-tert-butyl 2,2—dimethylsuccinate in THF (5 g, 7.6 mmol in 100 mL THF )was added robenzaldehyde (0.96 g, 6.84 mmol) and then stirred at 2°C for 0.5 hours. Next, NaHB(OAc)3 (3.53 g, 16.7 mmol) was added to the reaction and stirred at 2°C for 0.5 hours. The reaction was then warmed to 3-7°C and again stirred at 3-7°C for -15 hours and then stirred at 8-12°C for 5-8 hours.
The reaction was quenched by saturated NH4C| (aqueous) (50 mL) and water (20 mL) and then stirred at 10~20°C for 0.5 hours. The reaction was then extracted with MTBE (75 mL) and the aqueous layer was extracted with MTBE (25 mL). The ed organic phase was washed with water (25 mL) and the pH adjusted to 7-8 with 5% K2C03 aqueous. The organic phase was separated and washed two times with 7.5% NaCl aqueous (50 mL) and then washed with 20% NaCl aqueous (50 mL). The organic phase was concentrated under vacuum again to approx 20 mL. Additional DCM (60 mL) was added and concentrated under vacuum to approx 20 mL. Additional DCM (60 mL) was again added and concentrated under vacuum to approx 20 mL. onal DCM (60 mL) was again added and concentrated under vacuum to approx 20 mL. Then, 50 mL MeOH was charged and concentrated under vacuum again to approx 20 mL. An additional 50 mL MeOH was charged to give a solution of 4-((3aR,5aR,5bR,7aR,9S,11aR,1 1bR,13aS)—3a- ((R)—2—((4-chlorobenzyl)amino)hydroxyethyl)isopropyl-5a,5b,8,8,11a-pentamethyl oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H- cyclopenta[a]chrysenyl) 2,2—dimethylsuccinate in MeOH. This mixture was used in the next step directly. 1HNMR (400MHz, DMSO-d6) 6 = 0.81—1.78(m,49H),1.91(s,6H), 2.18— 2.20(m,2H) 2.32—2.37 (m,3H), 3.02-3.08 (M, 2H?] 3.56—3.62(m,4H) 4.00—4.04 (d,1H) 4.12— 4.15(d,1H) .40 (m,1H) 4.39-4.43(m,1H), 7.43-7.45 (d, 2H) ,7.52—7.54 (d,2H); LC/MS: m/z calculated 793.5, found 794.4 (M+1)+.
Step F: Intermediate 54 1-tert-buty/ 4-((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 3a-((R)((4-chlorobenzyl)(2— (dimethy/amino)ethyl)amino)hydroxyethyl)isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyl—2-0X0- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 10, 1 1, 1 1a, 1 1 b, 12, 13, 13a-octadecahydro-2H- enta[a]chrysenyl) 2, 2—dimethy/succinate Added a solution of R,5aR,5bR,7aR,98,1 1aR,1 1bR,13aS)—3a-((R)—2— ((4-chlorobenzyl)amino)—1-hydroxyethyl)isopropyl-5a,5b,8,8,11a-pentamethyl-2—oxo- 3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H- cyclopenta[a]chrysenyl) 2,2—dimethylsuccinatee (55 g, 69.3 mmol) dissolved in methanol (825 mL), dimethyl amino acetaldehyde hydrogen sulfite sodium salt (66.8 g, 0.35 mol) and Et3N(38.7 g, 0.38 mol) into a r. The reaction was stirred for 2—3 hrs at 30-40°C under nitrogen tion. NaBH3CN (8.8 g, 0.14 mol) was added and stirred at 30-40°C under nitrogen protection for 13-15 hrs. Next, the reaction temperature was adjusted to 50-60°C and stirred for 3-5 hrs. The on mixture was then concentrated to 275 mL and then DCM (550 mL) was added, followed by water (440 mL). The two phases were separated and the water phase was extracted with DCM (twice with 385 mLs each time). The organic phase was washed with water (twice with 358 mLs each time). Next, the organic phase was concentrated to give 1-tert—butyl 4-((3aR,5aR,5bR,7aR,98,11aR,11bR,13aS)—3a-((R)—2—((4- chlorobenzyl)(2—(dimethylamino)ethyl)amino)—1-hydroxyethyl)—1-isopropyl-5a,5b,8,8,1 1a- pentamethyl-2—oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H- cyclopenta[a]chrysenyl) 2,2—dimethylsuccinate 43 g oil. Yield is 71%. 1HNMR (400MHz,CDCl3) 6 = 7.27-7.29 (m, 4H),4.46—4.50 (m,1H), 4.08-4.13 (m,2 H), .02 (m, 1H), 3.59-3.60 (m, 1H), 3.09 (m, 1H), 2.03-2.67 (m, 14H), 0.62-1.42 (m, 57 H); LC/MS: m/z calculated 864.5, found 865.6 (M+1)+.
Step G: Compound 51 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((R)((4-ch/orobenzyl)(2- (dimethy/amino)ethyl)amino)hydroxyethyl)isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyl—2-0X0- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 10, 1 1, 1 1a, 1 1 b, 12, 13, 13a-octadecahydro-2H- cyclopenta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid From the last step, dissolved the 1-tert-butyl 4- 5aR,5bR,7aR,98,11aR,11bR,13aS)-3a-((R)((4-chlorobenzyl)(2- (dimethylamino)ethyl)amino)—1-hydroxyethy|)isopropy|-5a,5b,8,8,11a-pentamethyloxo- 3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H- cyclopenta[a]chrysenyl) 2,2-dimethylsuccinate (0.8 g, 0.92 mmol) in 3.2 mL DCM, then charged 1.6 mL TFA into the solution.
The reaction mixture was then stirred at 15-25°C for 1~3 hrs. Next, the reaction was charged with 4 mL DCM and 4 mL water, stirred well and then allowed to .
The aqueous phase was then removed and the organic phase washed two times with water (4 mLs each). The aqueous phase was then extracted with DCM (1.6 mL). The ed organic phase was then washed with ted sodium bicarbonate until the pH was between 7-8, followed by two more washes with water (4 mLs each).
Next, the organic phase was evaporated under vacuum to give 0.69 g crude product. The crude product was then dissolved in 4.8 mL isopropanol and heated to reflux to dissolve all material. Acetonitrile (19 mL) was added and brought to a gentle reflux and allowed to start cooling while seeded with 2 mg seed al at 45 °C. The mixture was then stirred at 45 °C for 2 hours. Solids began form and they were cooled to 10~20 °C and stirred for 3 hours. The solution solids were filtered and then rinsed twice with 1 g acetonitrile each time.
The solids were then dried in a vacuum oven at 45 deg C for 18 hours to give the desired product: aR,5aR,5bR,7aR,98,11aR,11bR,13aS)-3a-((R)((4- chlorobenzyl)(2-(dimethylamino)ethyl)amino)- 1-hydroxyethy/)- 1-isopropy/-5a, 5b, 8, 8, 1 1apentamethyloxo-3 , 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 10,1 1, 1 1a, 1 1 b, 12, 13, 13a-octadecahydro-2H- cyclopenta[a]chrysenyl)oxy)-2,2-dimethyloxobutanoic acid (0.59 g, yield was 78%).
Example 499: Compound 51 4-methoxybenzoyl chloride, Czfio'éll "fig/KL Et3N,THF, EtOAc O 2 2‘ C heptane _, o MeCN, aq HCI Raney Nickel, (S)—Camphor Ligand 568 * H2, THF CuOAc, MeN02 AcOH, EtOAc N02 ’ t-BuOH Mgso4 e, heptane NaBH4 tert-butyl methyl ether 1 MeOH Step 0 o Step D 569 o 570 Et3N X0 0 Step E CI CI DCM / TFA Step F O 571 HO \N/YsosNaI 1) /—\ o H2N NH2 /_\ —> NH HN NaBH3CN 2) H2 MeOH (s)- camphor (S)—camphor o Ligand 568 Step G HO Procedures for steps A and D below are not ed and are similar to those reported in previous examples and will be understood by one skilled in the art.
Step B: Intermediate 567 1-tert-butyl 4-((3aR, 5aR, 5bR, 7aR, 98, 1 1aR, 1 1bR, 13aS)-3a-formyl—1-isopropyl- 5a, 5b, 8, 8, 1 1 a-pentamethyloxo-3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a- octadecahydro-2H-cyclopenta[a]chrysenyl) 2, 2-dimethy/succinate ] The starting material aR,5bR,7aR,98,11aR,11bR,13aS)—9-hydroxy—1- isopropyl-5a,5b,8,8,11a-pentamethyloxo- 3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H- cyclopenta[a]chrysene-3a-carbaldehyde (5 g, 11 mmol), 4-(tert—butoxy)—3,3-dimethyl anoic acid (3.4 g, 16.5 mmol) THF ("tetrahydrofuran" - 100 mL) and triethylamine (3.4 g, 33 mmol) were charged to a flask.
The mixture was then stirred for 20~30 mins at 0~5 °C. Then, 4- ybenzoyl chloride (2.8 g, 16.5 mmol) was added through a dropping funnel while the reaction temperature was maintained at 0~5 °C. The reaction was then stirred for an additional 1 hour, then DMAP ("dimethylaminopyridine" - 0.2 g, 1.65 mmol) was added and the reaction allowed to stir at ambient temperature for approximately 24~30 hours until complete by HPLC.
Next, the on was charged with ethyl acetate (100 mL) and water (50 mL), stirred well and allowed to settle. The aqueous phase was removed and the organic phase washed with saturated sodium bicarbonate solution (2x 50 mL) followed by water (50 mL). The reaction solution was evaporated under vacuum to approximately 5-10 mL to produce solids. An additional amount of heptane (50 mL) was added and the reaction heated back to reflux to nearly form solution and slowly cooled to ambient temperature and let stir for 15 minutes then cooled to 0 °C for approximately two hours and the solids were filtered out. Next, the solids were washed with heptane (2x50 mL) and dried at 50 °C under vacuum to give the desired compound as off-white solid -buty/ 4- ((3aR,5aR,5bR,7aR,98,11aR,11bR,13aS)—3a-formylisopropyl-5a,5b,8,8,11a-pentamethyl- 3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H- cyclopenta[a]chrysenyl) 2,2-dimethylsuccinate. (4.7 g, yield is 67%).
Step C: Intermediate 569 1-tert-buty/ 4-((3aR, 5aR, 5bR, 7aR, 98, 1 1aR, 1 1bR, 13aS)-3a-((R)hydroxynitroethy/)—1- isopropyl—5a, 5b, 8, 8, 1 1a-pentamethyloxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 10, 1 1, 1 1a, 1 1 b, 12, 13, 13a-octadecahydro-2H- cyclopenta[a]chrysenyl) 2, 2-dimethy/succinate A reaction was charged with R,5aR,5bR,7aR,98,11aR,11bR,13aS)—3a- isopropyl-5a,5b,8,8,11a-pentamethyloxo- ,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H- cyclopenta[a]chrysenyl) 2,2-dimethylsuccinate (6 g, 9.4 mmol ), tert-butanol (60 mL) and e (18 mL) and temperature was adjusted to 20-25°C. The ligand (N1,N2-bis(1,7,7— trimethylbicyclo [2.2.1] heptanyl)ethane-1,2-diamine (0.2 g, 0.57 mmol)) and (l) acetate (0.06 g, 0.47 mmol) were added in a single n and the reaction allowed to stir at -25 °C for 3-5 hrs.
] The reaction was then cooled to a temperature of 7-13 °C. Afterwards, the reaction was charged with nitromethane (3.9 g, 63 mmol) and allowed to stir at 7-13 °C for approximately 30 hrs. The reaction was charged with additional nitromethane (2.2 g, 35.7 mmol) and allowed to stir at 7-13 °C for approximately 40 hrs. The reaction was charged again with additional nitromethane (2.2 g, 35.7 mmol) and allowed to stir at 7-13 °C for approximately 20 hrs.
Next, the reaction was charged with MTBE ("methyl tertiary butyl ether" - 90 mL) and a 15% ammonium chloride solution (36 mL), and allowed to stirfor 30 min and then allowed to separate out into two phases. The organic phase was washed with water (30 mL) followed by brine (24 mL). The organic phase was then concentrated to 12 mL and MTBE (3 mL) was added. Next, n-heptane (60 mL) was slowly added and then stirred at 10-20 °C for 2 hrs. The solution was then filtered and washed with n-heptane, the cake was then dried under vaccum at 50-55 °C to give 4-((3aR,5aR,5bR,7aR,98,11aR,11bR,13aS)—3a-((R)—1- hydroxynitroethyl)—1-isopropyl-5a,5b,8,8,1 1a-pentamethyloxo- ,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H- cyclopenta[a]chrysenyl) 2,2-dimethylsuccinate as off-white solid 4.27 g. (65% yield) Step E: Intermediate 571 1-tert-buty/ R, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 3a-((R)((4-ch/orobenzyl)amino)- 1-hydroxyethyl)— 1-isopropy/-5a, 5b, 8, 8, 1 1a-pentamethyIoxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 10, 1 1, 1 1a, 1 1 b, 12, 13, 13a-octadecahydro-2H- cyclopenta[a]chrysenyl) 2, thy/succinate 4-((3aR,5aR,5bR,7aR,98,11aR,11bR,13aS)—3a-((R)aminohydroxyethy|)- 1-isopropyI-5a,5b,8,8,11a-pentamethyIoxo- ,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H- cyc|openta[a]chrysenyl) 1-tert-butyl 2,2-dimethylsuccinate (15 g, 22.4 mmol) was placed in a round bottomed flask and then the following were also added: MgSO4 powder (8.1 g, 56 mmol) and Et3N (3.6 g,35.8 mmol) and p-Chlorobenzaldehyde (5.05 g, 29.1 mmol) and added MeOH (300mL). The reaction was then allowed to stirfor 2 hrs.
The reaction mixture was then cooled to 0 degrees C on ice-brine bath and treated with solid NaBH4 (1 .61g, 42.56mmol) under 10 degrees C and allowed to stir at 20 s for approximately 45 minutes. HPLC after this time showed the reaction was complete. The reaction was then filtered h a CeliteT'VI bed. The solids were rinsed with additional methanol (75 mL) and then dichloromethane (150 mL). The filtrate/rinse was treated with water (150 mL) and shaken in a separation funnel. The organic layers were then washed with water (150 mL). Next, the organic phase was evaporated to give 15 g of 1-tert- butyl 4-((3aR,5aR,5bR,7aR,98,11aR,11bR,13aS)-3a-((R)((4-chlorobenzyl)amino) hydroxyethyl)isopropyl-5a,5b,8,8,1 1a-pentamethyloxo- 3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H- cyclopenta[a]chrysenyl) 2,2-dimethylsuccinate as a foamy solid, 84% yield. The crude product was used for the next step directly.
Step F: Compound 46 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 3a-((R)((4-chlorobenzyl)amino)- 1- hydroxyethyl)- 1-isopropy/-5a, 5b, 8, 8, 1 1a-pentamethyIoxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 10, 1 1, 1 1a, 1 1 b, 12, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)-2, 2-dimethyl—4-oxobutanoic acid, 2, 2, 2-trif/uoroacetic acid salt (1: 1) Dissolved 1-tert-butyl 4-((3aR,5aR,5bR,7aR,98,11aR,11bR,13aS)—3a-((R)—2— ((4-chlorobenzyl)amino)hydroxyethyl)isopropyl-5a,5b,8,8,11a-pentamethyloxo- 3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H- cyclopenta[a]chrysenyl) methylsuccinate (15 g,18.9 mmol ) in dichloromethane (150mL) and treated with trifluoroacetic acid (30 mL) and allowed to stir at ambient temperature. The on was complete in approximately 10 hours. Next, the reaction washed with water mL) and the organic phase was evaporated to a minimum volume and ethyl acetate (150mL vol) was added and then evaporated again to a minimum volume.
Evaporated again to a minimum volume and then ved in a total of 150 mL volume ethyl acetate.
Next, the resultant solution was heated to near reflux and then diluted with heptane (90mL) and stirred while cooling to ambient temperature, at which point, solids were formed. The solution was then stirred for 30 minutes and filtered. The filtered solids were rinsed with heptane (30mL) and dried to give 13 g 4- (((3aR,5aR,5bR,7aR,98,11aR,11bR,13aS)—3a-((R)—2—((4—chlorobenzyl)amino) hydroxyethyl)isopropyl-5a,5b,8,8,1 1a-pentamethyloxo- ,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H- cyclopenta[a]chrysenyl)oxy)-2,2—dimethyloxobutanoic acid, 2, 2, 2-trif/uoroacetic acid salt (1:1), 81% yield. 1HNMR (400MHz, DMSO-d6) 6 = 0.60—1.89(m, 46H) 2.16—2.19(d,1H) 2.32—2.68 (m, 4H) 3.02—3.11 (m,1H) 4.10—4.26 (m, 3H) , 4.38—4.42(dd,1H) 5.93(s,1H) 7.51(s,4H), 8.80-8.98(d, 2H); LC-MS: m/z calculated (free base) 737.4, found 738.1 (M+1)+.
Step G: Compound 51 4-(((3aR, 5aR, 5bR, 7aR, 98, 1 1aR, 1 1bR, 13aS)-3a-((R)((4-ch/orobenzyl)(2— (dimethy/amino)ethyl)amino)hydroxyethyl)isopropyl-5a, 5b, 8, 8, 1 tamethyl—2-oxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 10, 1 1, 1 1a, 1 1 b, 12, 13, 13a-octadecahydro-2H- enta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid 2012/069637 ] From Step F above, the 4-(((3aR,5aR,5bR,7aR,98,11aR,11bR,13aS)—3a-((R)— 2-((4-chlorobenzyl)amino)hydroxyethyl)- 1isopropyl-5a,5b,8,8,11a-pentamethyl-2 -oxo- 3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H- cyclopenta[a]chrysenyl)oxy)-2,2-dimethyloxobutanoicacid trifluoroacetic acid salt (9.0 g, 10.56 mmol) was placed in a round bottomed flask and added dimethylamino acetaldehyde hydrogen sulfite salt (5.05 g, 26.4 mmol) and CH3COONa (3.46 g, 42.23 mmol) and added MeOH (180mL) and allowed to stir for 1 hour.
To the reaction mixture was added NaBH3CN (2.65 g, 42.23 mmol) and allowed to stir at 25 degrees C for approximately 36 hrs. HPLC after this time showed reaction was complete. Next, the reaction was filtered through a CeliteT'VI bed. The solids were then rinsed with additional methanol (45 mL) and then dichloromethane (90 mL). The te/rinse was treated with water (45 mL) and shaken in tory funnel. The organic layers were then washed with NaHC03 (4 times - 45 mL each) and water (two times - 45 mL each).
The organic phase was then evaporated to a minimum volume and i-PrOH (36 mL) was added and heated to 75 degrees C for 2 hours. The resulting solution was then diluted with CH3CN (45 mL) at 75 degrees C. The solution was then cooled to 5 degrees C over 4 hours. The on was then stirred at 5 degrees C for 2 hours and filtered. The filtrate was then rinsed with CH3CN (9 mL) and dried to give crude 4- (((3aR, 5aR, 5bR, 7aR, 98, 1 1aR, 1 1bR, 13aS)-3a-((R)((4-ch/orobenzyl) (2- (dimethy/amino)ethyl)amino)- 1-hydroxyethy/)- 1-isopropy/-5a, 5b, 8, 8, 1 1a-pentamethyl—Z-oxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 10, 1 1, 1 1a, 1 1 b, 12, 13, 13a-octadecahydro-2H- cyclopenta[a]chrysenyl)oxy)-2,2—dimethyloxobutanoic acid (5.6 g, 65% yield).
Re-crystallization From Step G above, the crude 4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)- 3a-((R)((4-ch/orobenzyl)(2—(dimethy/amino)ethyl)amino)hydroxyethyl)isopropyl- 5a, 5b, 8, 8, 1 1a-pentamethyl-2—oxo-3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 10, 1 1, 1 1a, 1 1b, 12, 13, 13a- cahydro-2H—cyclopenta[a]chrysenyl)oxy)-2,2—dimethyloxobutanoic acid (5.6 g) was placed in a round bottomed flask and added i-PrOH (36 mL) and heated to 75 s C for 2 hours. Next, the reaction was diluted with CH3CN (45 mL) at 75 degrees C. The reaction was then cooled to 5 degrees C over 4 hours.
The reaction was then stirred at 5 degrees C for 2 hours and filtered. The filtrate was then rinsed with CH3CN (9 mL) and dried to give 4.8 g 4- (((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)((4-chlorobenzyl)(2- (dimethylamino)ethyl)amino)hydroxyethyl) isopropyl-5a,5b,8,8,11a-pentamethyloxo- 3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H- cyclopenta[a]chrysenyl)oxy)-2,2-dimethyloxobutanoic acid, 84% yield. 1HNMR (400MHz,DMSO-d6) 6 = 0.80—0.29 (m,14H),0.97—1.17 (m, 21H),1.32-1.91 (m, 13), 2.08—2.23 (m,12H) 2.27—2.38 (m, 3H) 2.40-2.46 (m, 1H) 2.51-2.20 (m,1H) 2.66—2.70 (m,1H) 3.00—3.04 H) 3.71—3.78(m, 1H) 3.89-3.91(d, 1H) 4.37-4.41(dd, 1H), 7.31-7.37 (m,4H); LC-MS: m/z calculated 808.5, found 809.1 (M+1)+.
S nthesis of Intermediate 118 DIPEA Cu(OAc)2 MeNo2 Emma (R)— capmphor Ligand 572 (3aR, 5aR, 5bR, 7aR, 98, 1 1aR, 1 1bR, 13aS)-3a-((S)—1-hydroxynitroethyl)isopropyl- 5a, 5b, 8, 8, 1 1 amethyloxo-3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a- octadecahydro-2H-cyc/openta[a]chryseny/ e aR,5bR,7aR,9S,11aR,11bR,13aS)—3a-formylisopropyl- 5a,5b,8,8,11a-pentamethyloxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13aoctadecahydro-2H-cyclopenta [a]chrysenyl acetate (2.0 g, 4.03 mmol) was placed in a flask with n-BuOH (10ml) and diamine catalyst derived from (R)—camphor (N1,N2-bis(1,7,7- hylbicyclo[2.2.1]heptanyl)ethane-1,2-diamine, 0.08 g, 0.242 mmol) diamine catalyst 2012/069637 and Cu(OAc)2 (0.037 g, 0.201 mmol) and stirred approximately 16 hours at ambient temperature.
The reaction was then cooled to approximately 0 °C and treated with nitromethane (1.23 g, 20.1 mmol) and Hunig’s base (("N,N-diisopropylethylamine" - 0.053 g, 0.40 mmol) and allowed to held at 5 °C for 24 hours. Additional BuOH (25ml) and s base ("N,N-diisopropylethylamine") were added and the on held at -10 °C for 24 hours and then at ambient temperature for 24 hours. Solids t in the reaction were filtered to provide the title compound as an off white solid (1.1 g, 49% as ~ 95:5 mixture of diastereomers). 1H NMR (500MHz, CDCI3) 6 = 4.89 (bd, 1 H), 4.57 (d, 1 H), 4.49 (dd, 1 H), 4.34 (dd, 1 H), 3.21 (m, 1H)2.94 (dd, 1H) 2.38 (m, 2H)2.08 to 0.8 (m, 54H) *Note: Integration of the 2.4 to 0.8 region of the spectrum is higher due to the presence of impurities in the sample.
S nthesis of Intermediate 128 (3aR, 5aR, 5bR, 7aR, 98, 1 1aR, 1 1bR, 13aS)-3a-((S)-2—aminohydroxyethy/)- 1-isopropyl- 5a, 5b, 8, 8, 1 1 a-pentamethyl0X0-3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a- octadecahydro-2H-cyc/openta[a]chryseny/ acetate To a flask containing (3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)—3a-((S)—1- hydroxynitroethyl)isopropyl-5a,5b,8,8,1 1a-pentamethyloxo- 3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H- cyclopenta[a]chrysenyl acetate (~95% single diastereomer from the previous Intermediate 118 stage, 0.5 g, 0.89 mmol) in methanol and cooled to -5 °C was added NiClz (0.232 g, 1.79 mmol). The ts were stirred and treated with NaBH4 (0.475 g, 12.5 mmol), which was added slowly in portions over a 30 minute period while maintaining at approximately -5 An extremely exothermic reaction resulted in some al loss. The eeaction was warmed to ambient temperature slowly over a 30 minute period and allowed to stir for approximately 2 hours. The reaction was then quenched with NH4C| soln and diluted with methylene chloride. The liquid layers were separated and the organic layer was washed several times with NH4CI soln. Next, the organic layer was evaporated to s and the residue was chromatographed on silica gel column and eluted with 10% methanol- dichloromethane. The product containing fractions were evaporated to give title compound as grey solid (250 mg, 53% yield). Sample was d on to next stage without further terization. sis of Intermediate 138 (3aR, 5aR, 5bR, 7aR, 98, 1 1aR, 1 1bR, 13aS)-3a-((S)((4-ch/orobenzyl)amino)- 1-hydroxyethyl)— 1 -isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyl-Z-oxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyclopenta[a]chrysenyl acetate To a flask ning (3aR,5aR,5bR,7aR,98,11aR,11bR,13aS)—3a-((S)—2— aminohydroxyethyl)isopropyl-5a,5b,8,8,11a-pentamethyloxo- 3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H- cyclopenta[a]chrysenyl acetate (200 mg, 379 mmol) and methanol (15 ml) was added triethylamine (15 mg, 0.152 mmol), magnesium sulfate (68 mg, 0.168 mmol) and 4- chlorobenzaldehyde (64 mg, 0.455 mmol). The contents were allowed to stir at ambient 2012/069637 temperature for approximately 2 hours. To the resulting mixture was added sodium borohydride (17mg, 455 mmol) in a single portion and the reaction was allowed to stir at ambient ature for two and a half days. The reaction was then charged with an additional 20% excess of the p-Cl-benzaldehyde and sodium borohydride and allowed to stir an additional 2 hours. Finally, the on was quenched with water, allowed to stir 15 minutes and solids filtered to provide title compound contaminated with impurities. LC/MS: m/z calculated 651.4, found 652 (M+1)+. sis of (S) camphor d chiral diamine ligand 568 :E Ti(OiPr)4 E H2 5% Pt/C 0 fl fl H2N\/\NH2 £8"? heptane 4bar EJNH g Step A: N,N’-bis(isobornyl)ethylenediimine (573).
Titanium (IV) isopropoxide (235.4 g, 830 mmol, 1.04 eq) was added to a flask containing (1S)—(-)-camphor 3 g, 798 mmol, 1 eq) at ambient temperature. The reaction was then heated to ~ 50 OC. Next, ethylenediamine (31.2 g, 518 mmol, 0.65 eq) was charged to the on. The temperature was then kept above 45 0C during the addition. The reaction was then heated to ~ 91 0C for 17 hours. Next, the reaction was cooled to 20-25 0C and heptane (1.2 L) was added. Water (29.9 g, 1659 mmol, 2.08 eq) was added over at least 15 minutes. The slurry was then d for 20 minutes at ambient temperature, cooled to ~ 0 °C, and stirred for 30 minutes at ~ 0 OC. The slurry was then filtered and the solids washed with heptane (607 mL). The diimine solution was stored ~ 5 oC overnight. The solution was then warmed to ambient temperature and filtered to remove additional salts. Next, the solution was partially concentrated and filtered through CeliteT'V'.
Finally, the solution was concentrated to ~ 608 mL and used as is in the next reaction.
Step B: N,N’-bis(isobornyl)ethylenediamine ligand (568).
To a 1L Jacketed Lab Reactor (JLR) was added the above diimine solution followed by 5% Pt/C (Johnson-Matthey, B501018-5, 6.6 g). The reaction was hydrogenated for ~ 15 hours at 4 par at ambient ature. The reaction was filtered and washed with heptane (300 mL). The solution was concentrated to e a white solid (115.07 g). This two step procedure was repeated. Both s were ed. Attempts to crystallize the material from i-PrOH and water . The product was extracted with heptane. The heptane layer was then washed with water, brine, dried over sodium sulfate, filtered and concentrated on rotovapor and then high vaccum. The product 568 8 g) was obtained as a white solid and used as is in the asymmetric Henry reaction during the camphor ligand addition step. 1H NMR (500MHz, CDCI3) 5 2.69-2.61 (m, 1 H), 2.53-2.47 (m, 2 H), 1.71-1.63 (m, 2 H), 1.6-1.43 (m, 3 H), 1.1-1.01 (m, 2H), 1.01-0.98 (m, 3H), 0.89-0.83 (m, 3H), 0.81- 0.78 (m, 3H) Synthesis of (R) camphor derived chiral diamine ligand 572 i) ethylenediamine((0.65 eq) i) 5%Pt/C 100 psi H2 Ti((OiPr)4, reflux heptane N/ \N NH HN \0 ii) hep ane,t H O2 II) IPFOH/HZO (1 —Camphor 572 This material was prepared with modifications to methods shown in Tetrahedron: Asymmetry 14 (2003) 1451—1454.
Step A: is(isoborny|)ethylenediimine (574).
Titanium isopropoxide (100 mL, 341 mmol, 1.04 eq) was charged to a roundbottom flask containing (1 R)—(+)—camphor (50 g, 328 mmol) at 20-25 °C. The reaction mixture was then heated to 50 °C, at which time ethylenediamine (14.3 mL, 213 mmol, 0.65 eq) was charged to the reaction. Note: The ethylenediamine addition was exothermic, but it is important to conduct the charge above 45 °C to prevent solidification of the reaction mixture as titanium/ethylenediamine complexes are formed. The solution was then heated to reflux (~90-92 °C) for 20-24 hours. At that time, the reaction is cooled to 20-25 °C and diluted with heptane (500 mL), followed by slow on of H20 (12.3 mL, 2.08 eq) over ~15 minutes to initiate the formation (and subsequent precipitation) of Ti02 from the reaction.
The slurry was stirred for 20 minutes at 20-25 °C, cooled to 0 °C, and stirred for 20 minutes at 0 °C. Finally, the precipitate was filtered and washed with e (250 mL) to obtain a solution of diimine (573) in heptane, which was trated to 250 mL of heptane (~4.6 vol) prior to use in the subsequent hydrogenation stage.
Step B: N,N’-bis(isobornyl)ethylenediamine ligand (572). n-Matthey Yellow Kit #28 [5% Pt/C, B501018—5] catalyst (2.7 g, 5 wt% wrt 6) was charged to a Parr vessel, followed by a solution of diimine (6) in heptane (~54 g in 250 mL heptane). The reaction was hydrogenated for 15 h at 100 psi H2, 20 °C, at which time the only product was observed by LCMS. The mixture was then filtered through a celite pad and washed with heptane (130 mL). The filtrate solvent was d from heptanes to panol (270 mL, 5 vol), after which water (86 mL, 1.5 vol) was d and the reaction was heated to reflux to dissolve all material. Slow cooling of the solution to 20 °C resulted in crystallization of the product. Additional water (200 mL, 3.7 vol) was charged over 15 minutes and the reaction was held for an additional 20 minutes. The slurry was then cooled to 0 °C and held for 30 s, at which time the product was ed and washed with a 0 °C mixture of 1:1 water/isopropanol (130 mL) to yield 46.05g (572) (84.3%) after drying overnight.
The above intermediates 118, 128, and 13S serve to demonstrate application of the asymmetric Henry reaction in the r ligand step to produce the 8 alcohol on a useful intermediate in consistent yield and selectivity with the earlier examples that provide the R diastereomeric alcohol. It will be apparent to one skilled in the art that this methodology can be employed in combination with the appropriate triterpene derived scaffolds to give either the R or S diastereomer upon chosing the appropriate camphor derived diamine chiral ligand under the conditions outlined herein. Furthermore, it is shown that the above nitroalcohol intermediates, whether a e of diastereomeric alcohols or in optically enriched form, are useful to provide compounds of Formula I or Formula II. e 500: Compound 575 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((R)(((5-ch/oropyrimidin-Z-yl)methyl)(2- (2-oxopyrro/idin- thyl)amino)— 1-hydroxyethy/)— 1-isopropyl-5a, 5b, 8, 8, 1 tamethyl—2— oxo-3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyclopenta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 850.5, found 851.5 (M + 1)+ Examgle 501: Compound 576 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((R)(((5-ch/oropyrimidin-Z-yl)methyl)(2- (dimethylamino)oxoethyl)amino)hydroxyethy/)—1-isopropyI-5a, 5b, 8, 8, 1 1a-pentamethyl— 2—oxo-3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 10, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyclopenta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z ated 824.5, found 825.5 (M + 1)+ Exam le 502: Com ound 577 (R)(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((R)((cyclopropylmethyl) (2- (dimethy/amino)ethy/)amino)- 1-hydroxyethyl)—1-isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyl—2-0X0- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 10, 1 1, 1 1a, 1 1 b, 12, 13, 13a-octadecahydro-2H- cyclopenta[a]chrysenyl)oxy)methyloxobutanoic acid.
HO:NO LC/MS: m/z calculated 724.5, found 725.5 (M + 1)+ Exam le 503: Com ound 578 (R)(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((R)((4-chlorobenzyl) (2- (dimethy/amino)ethyl)amino)hydroxyethyl)isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyl0X0- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 10, 1 1, 1 1a, 1 1 b, 12, 13, tadecahydro-2H- cyc/openta[a]chrysenyl)oxy)—2—methyl—4-oxobutanoic acid.
LC/MS: m/Z calculated 794.5, found 795.5 (M + 1)+ Exam le 504: Com ound 579 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((R)((2-(dimethylamino)ethyl)(pyridazin- thyl)amino)- 1-hydroxyethy/)— 1-isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyI-Z-oxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 10, 1 1, 1 1a, 1 1 b, 12, 13, 13a-octadecahydro-2H- cyclopenta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 776.5, found 777.6 (M + 1)+ Examgle 505: Compound 580 4-(((3aR,5aR,5bR, 7aR,9S, 1 1aR, 1 1bR,13aS)-3a-((R)((cyclobuty/methyl)(2-(2- oxopyrrolidin- 1-yl)ethyl)amino)- 1-hydroxyethy/)— 1-isopropy/-5a, 5b, 8, 8, 1 1a-pentamethyI oxo-3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyclopenta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 792.6, found 793.6 (M + 1)+ Exam le 506: Com ound 581 4-(((3aR, 5aR, 5bR, 7aR, 98, 1 1aR, 1 1bR, 13aS)-3a-((R)(((S)— 1-(5-ch/oropyrimidin yl)ethyl)(2-(dimethy/amino)ethyl)amino)- 1-hydroxyethyl)- 1-isopropyl—5a, 5b, 8, 8, 1 1a- ethyl0X0-3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyclopenta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
] LC/MS: m/z ated 824.5, found 825.5 (M + 1)+ Exam le 507: Com ound 582 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((R)—2—(((R)—1-(5-chloropyrimidin yl)ethyl)(2-(dimethy/amino)ethyl)amino)- 1-hydroxyethyl)- 1-isopropyl—5a, 5b, 8, 8, 1 1a- pentamethyloxo-3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyclopenta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/z calculated 824.5, found 825.5 (M + 1)+ Exam le 508: Com ound 583 (R)(((3aR,5aR,5bR, , 1 1aR, 1 1bR,13aS)-3a-((R)((2- (dimethylamino)ethyl)(isopropy/)amino)— 1-hydroxyethyl)— 1-isopropyl—5a, 5b, 8, 8, 1 1apentamethyloxo-3 , 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- enta[a]chrysenyl)oxy)—2—methyl—4-oxobutanoic acid.
Exact Mass: 712.54 LC/MS: m/z calculated 712.5, found 713.7 (M + 1)+ Exam le 509: Com ound 584 4-(((3aR, 5aR, 5bR, 7aR, 9S, 1 1aR, 1 1bR, 13aS)-3a-((R)((cyclopropylmethyl)(2-(2- oxopyrrolidin- 1-yl)ethyl)amino)- 1-hydroxyethy/)— 1-isopropy/-5a, 5b, 8, 8, 1 1a-pentamethyl—2— oxo-3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 1 0, 1 1, 1 1 a, 1 1 b, 1 2, 13, 13a-octadecahydro-2H- cyclopenta[a]chrysenyl)oxy)-2, 2-dimethyloxobutanoic acid.
LC/MS: m/Z calculated 778.6, found 779.6 (M + 1)+ Exam le 510: Com ound 585 (S)(((3aR, 5aR, 5bR, 7aR, 98, 1 1aR, 1 1bR, 13aS)-3a-((R)((4-chlorobenzyl)(2- (dimethy/amino)ethyl)amino)hydroxyethyl)isopropyl-5a, 5b, 8, 8, 1 1a-pentamethyl—2-0X0- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 10, 1 1, 1 1a, 1 1 b, 12, 13, 13a-octadecahydro-2H- cyc/openta[a]chrysenyl)oxy)—2—methyl—4-oxobutanoic acid.
LC/MS: m/z calculated 794.5, found 795.5 (M + 1)+ After the above description of synthesis procedures for the compounds described , there is provided in ance with other embodiments of the present invention, a process for preparing a nd of Formula (I) having the structure: comprising the steps of: (1) fying a compound having the structure: (2) reacting the compound product of Step (1), with a compound having the structure: 0 in the presence of an acid chloride and a tertiary amine in order to provide a compound having the structure: (3) ng nitromethane with the compound product of Step (2) in the presence of a chiral ligand, an optional base, and a second metal catalyst in order to provide a compound having the structure: (4) reducing the compound product of Step (3), in the presence of a third metal catalyst and hydrogen gas in order to provide a compound having the structure: (5) reacting p-chlorobenzaldehyde with the compound product of Step (4), in the ce of a metal hydride, to provide a compound having the structure: WO 90664 (6) acidifying the compound product of Step (5), in the presence of an acid in order to provide the compound having the structure: (7) reacting the compound product of Step (6) with a compound having the (III) structure according to Formula III: A1 wherein A1 is either optionally absent or is selected from the group consisting —H, , and ethyl; and A2 is selected from the group consisting of —H, methoxy, ethoxy, hydroxyl, and —SOg'Na+; while in the ce of a metal hydride in order to provide the compound having the structure: As will be known to one of skill in the art after reading the synthetic procedures bed here and the process steps described above and below, several suitable chemical components can be used to carry out the process steps. Such suitable chemical ents can be used interchangeably with any process step description described herein according to dge in the art.
In accordance with other embodiments of the present invention, there is provided a process for preparing a compound of Formula (I), n one or more of Steps (1) — (7) are conducted in the presence of a solvent.
] In accordance with other embodiments of the present invention, there is provided a process for preparing a compound of Formula (I), wherein one or more of Steps (1) — (7) are conducted in the presence of an organic solvent.
In accordance with other embodiments of the present invention, there is provided a process for preparing a compound of Formula (I), wherein one or more of Steps (1) — (7) are ted in the presence of a solvent that is selected from the group consisting of water, dichloromethyl, methanol, tetrahydrofuran, ydrofuran acetate, ethanol, ethyl acetate, heptane, isopropanoI, tert—butanol, toluene, acetonitrile, and tert—butyl methyl ether.
In ance with other embodiments of the present ion, there is provided a process for preparing a compound of Formula (I), wherein the first metal catalyst of Step (1) is a metal halide.
In accordance with other embodiments of the present invention, there is ed a process for preparing a compound of Formula (I), wherein the first metal catalyst of Step (1) is zirconium tetrachloride.
In accordance with other embodiments of the present invention, there is provided a process for preparing a compound of Formula (I), wherein the acid chloride of Step (2) is selected from the group consisting of benzoyl chloride and methoxybenzoyl chloride.
In accordance with other embodiments of the present invention, there is provided a process for preparing a compound of Formula (I), wherein the acid chloride of Step (2) is methoxybenzoyl chloride.
In accordance with other embodiments of the present invention, there is provided a process for preparing a compound of Formula (I), wherein the tertiary amine of Step (2) is a tertiary amine coupling agent.
In accordance with other embodiments of the present invention, there is provided a process for preparing a compound of Formula (I), wherein the tertiary amine of Step (2) is selected from the group consisting of ylamine, N,N-diisopropylethylamine, and 1-ethyI[3-dimethylaminopropyl]carbodiimide hloride.
In accordance with other embodiments of the t invention, there is provided a process for preparing a compound of Formula (I), wherein the tertiary amine of Step (2) is 1-ethyI[3-dimethylaminopropyl]carbodiimide hloride.
In ance with other embodiments of the present invention, there is provided a process for ing a compound of Formula (I), wherein the tertiary amine of Step (2) is ylamine.
In accordance with other embodiments of the present invention, there is ed a process for preparing a nd of Formula (I), n the second metal st of Step (3) is a compound comprising a metal selected from the group consisting of Zn, Co, Cu, Mg, and Cr.
In accordance with other embodiments of the present invention, there is provided a process for preparing a compound of Formula (I), wherein the second metal WO 90664 catalyst of Step (3) is a compound comprising a metal selected from the group consisting of Cu(l) and Cu(ll).
In accordance with other embodiments of the present invention, there is provided a process for preparing a compound of Formula (I), wherein the second metal st of Step (3) is a compound sing Cu(l).
In accordance with other embodiments of the present invention, there is provided a process for preparing a compound of Formula (I), wherein the second metal st of Step (3) is selected from the group consisting of Copper(l) acetate and Cu(ll) acetate.
In accordance with other embodiments of the present invention, there is provided a process for preparing a compound of Formula (I), wherein the second metal catalyst of Step (3) is Copper(l) acetate.
In accordance with other embodiments of the present invention, there is provided a process for preparing a compound of Formula (I), wherein the second metal catalyst of Step (3) is Copper(ll) acetate.
In accordance with other embodiments of the present invention, there is provided a process for preparing a compound of Formula (I), wherein the optional base of Step (3) is selected from the group consisting of alkali metal hydroxides, alkoxides, carbonates, fluoride , and nonionic organic amine bases.
] In accordance with other embodiments of the present invention, there is provided a process for preparing a nd of Formula (I), wherein the optional base of Step (3) is iPeret.
In accordance with other embodiments of the present invention, there is provided a process for preparing a compound of Formula (I), wherein the chiral ligand of Step (3) is a tive of S-Camphor.
In accordance with other embodiments of the t invention, there is provided a s for preparing a compound of Formula (I), wherein the chiral ligand of Step (3) is a nd having the structure: ENHHN In ance with other embodiments of the present ion, there is provided a process for preparing a compound of Formula (I), wherein the third metal catalyst of Step (4) is selected from the group consisting of Raney Nickel, nickel, nickel chloride, aluminum, palladium, copper, zinc, chromium, iridium, rhodium, platinum, and combinations thereof.
In accordance with other embodiments of the t invention, there is ed a process for ing a compound of Formula (I), wherein the third metal catalyst of Step (4) is Raney Nickel.
In accordance with other embodiments of the present invention, there is provided a process for preparing a compound of Formula (I), wherein the hydrogen of Step (4) is hydrogen gas.
In accordance with other embodiments of the present invention, there is provided a process for preparing a compound of Formula (I), wherein the metal e of Step (5) is a borohydride.
] In accordance with other embodiments of the present invention, there is provided a process for preparing a compound of Formula (I), n the metal hydride of Step (5) is selected from the group ting of NaBH4 and NaBH(OAc)3.
] In accordance with other embodiments of the present invention, there is provided a process for preparing a compound of Formula (I), n the metal hydride of Step (5) is NaBH4.
In accordance with other embodiments of the present ion, there is provided a process for preparing a compound of Formula (I), wherein the metal e of Step (5) is NaBH(OAc)3.
In accordance with other embodiments of the present invention, there is provided a process for preparing a compound of Formula (I), wherein the acid of Step (6) is selected from the group ting of trifluoroacetic acid, HCI, and trichloroacetic acid, In accordance with other embodiments of the present invention, there is provided a process for preparing a compound of Formula (I), wherein the acid of Step (6) is trifluoroacetic acid.
In accordance with other embodiments of the present invention, there is provided a process for preparing a compound of Formula (I), wherein the A2 of Step (7) is -SOgNa.
In accordance with other embodiments of the present invention, there is ed a s for preparing a compound of Formula (I), wherein the A2 of Step (7) is -H.
In accordance with other embodiments of the present ion, there is provided a process for preparing a compound of Formula (I), wherein the A1 of Step (7) is absent.
In accordance with other embodiments of the t ion, there is provided a process for preparing a compound of Formula (I), wherein the A1 of Step (7) is -H.
In accordance with other embodiments of the present invention, there is provided a process for preparing a nd of Formula (I), wherein the compound of Formula III of Step (7) has the following structure: In accordance with other ments of the t invention, there is provided a process for preparing a compound of Formula (I), wherein the compound of 803Na Formula III of Step (7) has the following structure: OH In ance with other embodiments of the present invention, there is provided a process for preparing a nd of Formula (I), wherein the compound of \N/YOHI Formula III of Step (7) has the following structure: OH In accordance with other embodiments of the present invention, there is provided a process for preparing a compound of Formula (I), wherein the compound of \N/YO-CHSI Formula III of Step (7) has the following structure: O-CH3 In accordance with other embodiments of the present invention, there is provided a s for preparing a compound of Formula (I), wherein the compound of O-CHZCH3 Formula III of Step (7) has the following structure: O-CHZCH3 In accordance with other embodiments of the present invention, there is provided a s for preparing a compound of Formula (I), n the metal hydride of Step (7) is a borohydride.
In accordance with other embodiments of the t invention, there is provided a process for preparing a compound of Formula (I), n the metal hydride of Step (7) is NaBH3CN.
In accordance with other embodiments of the present invention, there is provided a process for preparing a compound of Formula (I) having the structure: comprising the steps of: (1) saponifying a compound having the structure: (2) reacting the compound product of Step (1), with a compound having the ure: 0 in the presence of an acid chloride and a tertiary amine in order to provide a compound having the structure: (3) reacting nitromethane with the compound product of Step (2) in the presence of a chiral ligand and a base and a second metal catalyst in order to provide a compound having the structure: (4) reducing the nd product of Step (3), in the presence of a third metal catalyst and hydrogen gas in order to e a compound having the structure: (5) reacting p-chlorobenzaldehyde with the compound product of Step (4), in the ce of a metal e and a tertiary amine, to provide a compound having the structure: (6) reacting the compound product of Step (5) with a compound having the A2 (Ill) structure according to a lll: \A1 wherein A1 is either optionally absent or is selected from the group consisting —H, methyl, and ethyl; and A2 is selected from the group consisting of —H, methoxy, ethoxy, hydroxyl, and —803'Na+; while in the presence of a metal hydride in order to provide the compound having the structure: (7) acidifying the compound product of Step (6), in the presence of an acid in order to provide the compound having the structure: With regards to the synthesis procedures herein, and in accordance with other embodiments of the present invention, there is also provided a process for preparing a compound of Formula (I), wherein one or more of Steps (1 ) — (7) are conducted in the presence of a t.
] In ance with other embodiments of the present invention, there is provided a process for preparing a compound of Formula (I), wherein one or more of Steps (1) — (7) are conducted in the presence of an organic solvent.
In ance with other embodiments of the present ion, there is provided a process for preparing a compound of Formula (I), wherein one or more of Steps (1) — (7) are conducted in the ce of a solvent that is selected from the group consisting of water, dichloromethyl, methanol, tetrahydrofuran, tetrahydrofuran acetate, ethanol, ethyl acetate, heptane, isopropanol, tert-butanol, toluene, acetonitrile, and tert-butyl methyl ether.
In accordance with other embodiments of the t invention, there is provided a process for preparing a compound of Formula (I), wherein the base of Step (3) is selected from the group consisting of alkali metal ides, alkoxides, carbonates, de anions, and nonionic organic amine bases.
In accordance with other embodiments of the present invention, there is provided a s for preparing a compound of Formula (I), wherein the base of Step (3) is iPr2Net.
In accordance with other embodiments of the present invention, there is provided a process for preparing a compound of Formula (I), wherein the tertiary amine of Step (5) is selected from the group consisting of triethylamine and 1-ethyl[3- dimethylaminopropyl]carbodiimide hydrochloride.
In accordance with other embodiments of the present invention, there is provided a process for preparing a compound of Formula (I), wherein the tertiary amine of Step (5) is triethylamine.
In accordance with other embodiments of the present ion, there is provided a process for preparing a compound of Formula (I), wherein the metal hydride of Step (5) is a borohydride.
In accordance with other embodiments of the present invention, there is provided a process for preparing a nd of Formula (I), n the metal e of Step (5) is selected from the group consisting of NaBH4 and NaBH(OAc)3.
In accordance with other embodiments of the t invention, there is provided a process for ing a compound of Formula (I), wherein the metal hydride of Step (5) is NaBH4.
In ance with other embodiments of the present invention, there is provided a process for preparing a compound of Formula (I), wherein the tertiary amine of Step (6) is triethylamine.
In accordance with other embodiments of the present invention, there is provided a process for preparing a compound of Formula (I), having the structure: sing the steps of: (1) reacting a compound having the structure: with a compound having the structure according to Formula lll: A2 (III) A1 n A1 is either optionally absent or is selected from the group consisting —H, methyl, and ethyl; and A2 is selected from the group consisting of —H, methoxy, ethoxy, hydroxyl, and —803'Na+; while in the presence of a metal hydride in order to provide the compound having the structure: WO 90664 In accordance with other embodiments of the present invention and the suitable process step components recited above, there is ed a process for preparing a compound of Formula (I), having the structure: comprising the steps of: (1) acidifying a compound having the structure: in the presence of an acid in order to provide the compound having the structure: In accordance with other embodiments of the present invention and the suitable process step ents recited above, there is provided a process for preparing a compound of Formula (I), having the ure: comprising the steps of: (1) reacting p-ch|orobenza|dehyde with a compound having the structure: in the ce of a metal hydride to e the compound having the structure: In accordance with other embodiments of the present invention and the suitable process step components recited above, there is provided a process for preparing a compound of Formula (I), having the structure: comprising the steps of: (1) reducing a compound having the structure: in the presence of a metal catalyst and hydrogen gas in order to provide the compound having the structure: In ance with other embodiments of the present invention and the suitable process step components d above, there is provided a process for preparing a compound of Formula (I), having the structure: comprising the steps of: (1) reacting nitromethane with a compound having the structure: in the presence of a chiral ligand and a metal catalyst in order to provide a compound having the structure: In accordance with other embodiments of the present invention and the suitable process step components recited above, there is provided a s for preparing a compound of Formula (I), having the ure: comprising the steps of: 2012/069637 (1) reacting a compound having the structure: XOWOH with a compound having the structure: 0 , , in the presence of an acid chloride and a tertiary amine in order to e the nd having the structure: In accordance with other embodiments of the present invention and the suitable process step components recited above, there is provided a process for preparing a compound of Formula (I), having the structure: comprising the steps of: (1) saponifying a compound having the structure: ] In accordance with other embodiments of the present invention and the le process step components recited above, there is provided a process for preparing a compound of Formula (I), having the structure: comprising the steps according to the following synthesis scheme. As will be known to one of skill in the art, the above reagents recited in still other synthesis schemes may be substituted within the synthesis scheme below as described above. 2012/069637 NaBH4,NiC|2 MeOH 1) M9504, NaBHA, MeOH 2)B0020,TEA O Pcc —> —> dioxane\MeOH Administration and Formulation In another embodiment, there is provided a pharmaceutical composition comprising a pharmaceutically acceptable diluent and a therapeutically effective amount of a compound of Formula | or Formula II or a pharmaceutically acceptable salt thereof.
The compounds of the present invention can be supplied in the form of a pharmaceutically acceptable salt. The terms "pharmaceutically acceptable salt" refer to salts prepared from pharmaceutically acceptable nic and organic acids and bases.
Accordingly, the word "or" in the context of "a nd or a pharmaceutically acceptable salt thereof" is tood to refer to either a compound or a pharmaceutically acceptable salt thereof (alternative), or a compound and a pharmaceutically acceptable salt thereof (in combination).
As used herein, the term "pharmaceutically acceptable" refers to those compounds, materials, compositions, and dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals t excessive toxicity, tion, or other problem or complication. The d artisan will appreciate that pharmaceutically acceptable salts of compounds according to Formula I or Formula II may be prepared. These ceutically acceptable salts may be prepared in situ during the final ion and purification of the compound, or by separately reacting the purified compound in its free acid or free base form with a suitable base or acid, tively.
Illustrative pharmaceutically acceptable acid salts of the nds of the present invention can be prepared from the following acids, including, without tion formic, acetic, propionic, c, succinic, glycolic, gluconic, lactic, maleic, malic, tartaric, citric, nitic, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, hydrochloric, hydrobromic, odic, isocitric, trifluoroacetic, pamoic, propionic, anthranilic, mesylic, oxalacetic, oleic, stearic, lic, p-hydroxybenzoic, nicotinic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, phosphoric, phosphonic, ethanesulfonic, benzenesulfonic, pantothenic, toluenesulfonic, 2—hydroxyethanesulfonic, sulfanilic, sulfuric, salicylic, cyclohexylaminosulfonic, algenic, B-hydroxybutyric, galactaric and galacturonic acids. red pharmaceutically acceptable salts include the salts of hloric acid and trifluoroacetic acid.
Illustrative pharmaceutically acceptable inorganic base salts of the compounds of the present invention e metallic ions. More preferred ic ions include, but are not d to, appropriate alkali metal salts, alkaline earth metal salts and other physiological acceptable metal ions. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc, and the like and in their usual valences. ary base salts include aluminum, calcium, lithium, magnesium, potassium, sodium and zinc.
Other exemplary base salts include the ammonium, calcium, ium, potassium, and sodium salts. Still other exemplary base salts include, for example, hydroxides, carbonates, hydrides, and alkoxides including NaOH, KOH, Na2C03, K2C03, NaH, and potassium-t- butoxide.
Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary , including in part, trimethylamine, diethylamine, N, N'-dibenzylethylenediamine, procaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine; substituted amines ing naturally occurring substituted amines; cyclic amines; quaternary ammonium cations; and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,N- dibenzylethylenediamine, diethylamine, 2—diethylaminoethanol, 2—dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, ine, hydrabamine, isopropylamine, lysine, glucamine, morpholine, piperazine, piperidine, ine resins, procaine, purines, theobromine, ylamine, trimethylamine, tripropylamine, tromethamine and the like.
All of the above salts can be ed by those skilled in the art by conventional means from the corresponding compound of the present invention. For example, the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. lly, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. The salt may itate from solution and be collected by filtration or may be red by evaporation of the solvent. The degree of ionisation in the salt may vary from completely ionised to almost non-ionised. Lists of le salts are found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing y, , Pa., 1985, p.1418, the disclosure of which is hereby incorporated by nce only with regards to the lists of suitable salts.
] The nds of the invention may exist in both unsolvated and solvated forms. The term ‘solvate’ is used herein to describe a molecular complex comprising the compound of the invention and one or more pharmaceutically acceptable solvent molecules, for e, ethanol. The term ‘hydrate’ is ed when said solvent is water.
Pharmaceutically able solvates e hydrates and other solvates wherein the solvent of crystallization may be ically substituted, e.g. D20, de-acetone, de-DMSO.
] Compounds of Formula | or Formula II containing one or more asymmetric carbon atoms can exist as two or more stereoisomers. Where a compound of Formula I or a II contains an alkenyl or alkenylene group or a cycloalkyl group, geometric cis/trans (or Z/E) isomers are possible. Where the compound contains, for example, a keto or oxime group or an aromatic moiety, tautomeric isomerism (‘tautomerism’) can occur. It follows that a single compound may exhibit more than one type of isomerism.
Included within the scope of the claimed compounds present invention are all stereoisomers, geometric isomers and tautomeric forms of the compounds of Formula I or a II, including compounds exhibiting more than one type of isomerism, and mixtures of one or more thereof. Also included are acid addition or base salts wherein the counterion is optically active, for example, D-lactate or L-lysine, or racemic, for example, DL-tartrate or DL-arginine.
Cis/trans isomers may be separated by conventional techniques well known to those skilled in the art, for example, chromatography and fractional crystallisation.
Conventional techniques for the preparation/isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC).
Alternatively, the racemate (or a racemic precursor) may be reacted with a suitable optically active compound, for e, an alcohol, or, in the case where the compound of Formula I or Formula II contains an acidic or basic moiety, an acid or base such as tartaric acid or 1-phenylethylamine. The resulting diastereomeric mixture may be separated by chromatography and/or fractional crystallization and one or both of the diastereoisomers converted to the corresponding pure enantiomer(s) by means well known to a skilled person.
Chiral compounds of the invention (and chiral precursors thereof) may be obtained in enantiomerically—enriched form using chromatography, typically HPLC, on a resin with an asymmetric stationary phase and with a mobile phase consisting of a arbon, typically heptane or hexane, containing from 0 to 50% isopropanol, typically from 2 to 20%, and from 0 to 5% of an alkylamine, typically 0.1% diethylamine. Concentration of the eluate affords the ed mixture.
Mixtures of stereoisomers may be separated by conventional techniques known to those skilled in the art. [see, for example, "Stereochemistry of Organic Compounds" by E L Eliel (Wiley, New York, ] The present invention includes all pharmaceutically acceptable isotopically- labelled compounds of Formula | or Formula II wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number y found in nature.
Examples of isotopes suitable for ion in the compounds of the invention include es of hydrogen, such as 2H and 3H, carbon, such as "C, 13C and 14C, chlorine, such as 36Cl, fluorine, such as 18F, iodine, such as 123| and 125l, nitrogen, such as 13N and 15N, oxygen, such as 15O, 17O and 18O, phosphorus, such as 32P, and sulphur, such as 35S.
Certain isotopically-labelled compounds of Formula I or a II, for example, those orating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies. The radioactive isotopes tritium, i.e. 3H, and carbon-14, i.e. 14C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection. tution with r isotopes such as deuterium, i.e. 2H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances. lsotopically-labelled nds of Formula | or Formula II can generally be prepared by tional techniques known to those skilled in the art or by processes ous to those described in the accompanying Examples and Preparations using an appropriate isotopically-labelled ts in place of the non-labelled reagent previously employed.
The compounds of the present invention may be administered as gs.
Thus, certain derivatives of compounds of Formula | or Formula II, which may have little or no pharmacological activity themselves can, when administered into or onto the body, be converted into compounds of Formula | or Formula II as ‘prodrugs’.
] Administration of the chemical entities described herein can be via any of the ed modes of administration for agents that serve similar utilities including, but not limited to, orally, sublingually, subcutaneously, intravenously, intranasally, topically, transdermally, eritoneally, intramuscularly, intrapulmonarilly, vaginally, rectally, or intraocularly. In some embodiments, oral or parenteral administration is used.
Pharmaceutical compositions or formulations include solid, semi-solid, liquid and aerosol dosage forms, such as, e.g., tablets, capsules, s, s, sions, suppositories, ls or the like. The chemical entities can also be administered in sustained or controlled release dosage forms, including depot injections, osmotic pumps, pills, transdermal (including electrotransport) patches, and the like, for prolonged and/or timed, pulsed administration at a predetermined rate. In certain embodiments, the compositions are provided in unit dosage forms suitable for single administration of a precise dose.
The chemical entities described herein can be administered either alone or more typically in combination with a conventional pharmaceutical carrier, excipient or the like (e.g., mannitol, lactose, starch, magnesium stearate, sodium rine, talcum, ose, sodium crosscarmellose, glucose, gelatin, sucrose, magnesium carbonate, and the like). If desired, the pharmaceutical composition can also contain minor amounts of nontoxic auxiliary substances such as wetting agents, fying agents, solubilizing agents, pH buffering agents and the like (e.g., sodium acetate, sodium citrate, cyclodextrine derivatives, sorbitan monolaurate, triethanolamine acetate, triethanolamine , and the like). lly, depending on the ed mode of administration, the pharmaceutical composition will contain about 0.005% to 95%; in certain embodiments, about 0.5% to 50% by weight of a chemical entity. Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art; for example, see Remington's Pharmaceutical es, Mack Publishing Company, Easton, Pennsylvania.
WO 90664 In certain embodiments, the compositions will take the form of a pill or tablet and thus the composition will contain, along with the active ingredient, a diluent such as lactose, sucrose, dicalcium phosphate, or the like; a lubricant such as magnesium stearate or the like; and a binder such as , gum acacia, polyvinylpyrrolidine, gelatin, cellulose, cellulose derivatives or the like. In another solid dosage form, a powder, , solution or suspension (e.g., in propylene carbonate, vegetable oils or triglycerides) is encapsulated in a gelatin capsule.
Liquid pharmaceutically administrable compositions can, for e, be prepared by dissolving, dispersing, etc. at least one chemical entity and al pharmaceutical adjuvants in a carrier (e.g., water, saline, s dextrose, glycerol, glycols, ethanol or the like) to form a solution or sion. lnjectables can be prepared in conventional forms, either as liquid solutions or suspensions, as emulsions, or in solid forms suitable for dissolution or suspension in liquid prior to injection. The tage of chemical entities contained in such parenteral compositions is highly dependent on the specific nature thereof, as well as the activity of the al entities and the needs of the subject.
However, percentages of active ingredient of 0.01% to 10% in solution are employable, and will be higher if the composition is a solid which will be subsequently diluted to the above tages. In certain embodiments, the composition will se from about 0.2 to 2% of the active agent in solution.
Pharmaceutical compositions of the chemical entities described herein may also be administered to the respiratory tract as an aerosol or solution for a nebulizer, or as a microfine powder for insufflation, alone or in combination with an inert carrier such as lactose. In such a case, the particles of the pharmaceutical composition have diameters of less than 50 microns, in certain embodiments, less than 10 microns.
In general, the chemical entities provided will be administered in a therapeutically effective amount by any of the accepted modes of stration for agents that serve r utilities. The actual amount of the chemical entity, i.e., the active ingredient, will depend upon numerous factors such as the severity of the disease to be treated, the age and relative health of the t, the potency of the chemical entity used the route and form of administration, and other factors. The drug can be administered more than once a day, such as once or twice a day. eutically effective s of the chemical entities bed herein may range from approximately 0.01 to 200 mg per kilogram body weight of the recipient per day; such as about 0.01-100 mg/kg/day, for example, from about 0.1 to 50 mg/kg/day. Thus, for administration to a 70 kg person, the dosage range may be about 7-3500 mg per day.
In general, the chemical entities will be administered as pharmaceutical compositions by any one of the ing : oral, systemic (e.g., transdermal, intranasal or by suppository), or parenteral (e.g., intramuscular, intravenous or subcutaneous) administration. In certain ments, oral administration with a convenient daily dosage regimen that can be adjusted according to the degree of affliction may be used.
Compositions can take the form of tablets, pills, capsules, semisolids, powders, sustained release formulations, solutions, suspensions, elixirs, aerosols, or any other appropriate compositions. Another manner for administering the provided chemical entities is inhalation.
The choice of formulation depends on various factors such as the mode of drug administration and bioavailability of the drug substance. For delivery via inhalation the chemical entity can be formulated as liquid solution, suspensions, aerosol lants or dry powder and loaded into a suitable dispenser for administration. There are several types of pharmaceutical inhalation s-nebulizer inhalers, metered dose inhalers (MDI) and dry powder inhalers (DPI). Nebulizer devices produce a stream of high velocity air that causes the therapeutic agents (which are formulated in a liquid form) to spray as a mist that is carried into the patient's respiratory tract. MDls typically are formulation packaged with a compressed gas. Upon actuation, the device discharges a measured amount of therapeutic agent by ssed gas, thus affording a reliable method of administering a set amount of agent. DPI dispenses therapeutic agents in the form of a free flowing powder that can be dispersed in the patient's inspiratory ream during ing by the device. In order to achieve a free flowing powder, the therapeutic agent is formulated with an excipient such as lactose. A measured amount of the therapeutic agent is stored in a e form and is dispensed with each actuation.
Recently, pharmaceutical compositions have been developed for drugs that show poor bioavailability based upon the principle that bioavailability can be increased by increasing the e area i.e., decreasing particle size. For example, US. Patent No. 4,107,288 describes a pharmaceutical formulation having particles in the size range from 10 to 1,000 nm in which the active al is supported on a cross-linked matrix of macromolecules. US. Patent No. 5,145,684 describes the production of a pharmaceutical formulation in which the drug substance is pulverized to nanoparticles (average particle size of 400 nm) in the presence of a surface modifier and then dispersed in a liquid medium to give a pharmaceutical formulation that exhibits remarkably high bioavailability.
The compositions are comprised of, in general, at least one chemical entity described herein in combination with at least one pharmaceutically acceptable ent.
Acceptable excipients are non-toxic, aid administration, and do not adversely affect the therapeutic benefit of the at least one chemical entity described herein. Such excipient may be any solid, liquid, semi-solid or, in the case of an aerosol composition, gaseous ent that is generally available to one of skill in the art.
Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, e, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk and the like. Liquid and semisolid excipients may be selected from ol, ene glycol, water, l and various oils, including those of eum, animal, vegetable or synthetic , e.g., peanut oil, soybean oil, mineral oil, sesame oil, etc. Liquid carriers, for injectable solutions, include water, saline, s dextrose, and glycols.
Compressed gases may be used to disperse a chemical entity described herein in aerosol form. Inert gases suitable for this purpose are nitrogen, carbon dioxide, etc.
Other suitable pharmaceutical excipients and their formulations are described in Remington's Pharmaceutical Sciences, edited by E. W. Martin (Mack Publishing y, 18th ed., 1990).
The amount of the chemical entity in a composition can vary within the full range employed by those skilled in the art. Typically, the composition will n, on a weight percent (wt%) basis, from about 0.01-99.99 wt% of at least one al entity described herein based on the total composition, with the balance being one or more suitable pharmaceutical excipients. In certain embodiments, the at least one chemical entity described herein is present at a level of about 1-80 wt%.
Example 84 MT4 Cell Antiviral Assay ] Experimental Procedure: Antiviral HIV activity and compound-induced cytotoxicity were measured in parallel by means of a propidium iodide based procedure in the human T-cell lymphotropic virus transformed cell line MT4. Aliquots of the test compounds were serially diluted in medium (RPMI 1640, 10% fetal calf serum (FCS), and gentamycin) in 96-well plates (Costar 3598) using a Cetus Pro/Pette. Exponentially growing MT4 cells were harvested and centrifuged at 1000 rpm for 10 min in a Jouan centrifuge (model CR 4 12). Cell pellets were resuspended in fresh medium (RPMI 1640, 20% FCS, 20% |L-2, and gentamycin) to a density of 5 x 105 cells/ml. Cell aliquots were infected by the addition of HIV-1 n lllB) diluted to give a viral multiplicity of infection of 100 x TClD50. A similar cell t was diluted with medium to provide a mock-infected control. Cell infection was allowed to proceed for 1 hr at 37°C in a tissue culture incubator with humidified 5% C02 here.
After the 1 hr incubation the virus/cell suspensions were diluted 6-fold with fresh medium, and 125 pl of the cell suspension was added to each well of the plate ning luted compound. Plates were then placed in a tissue culture incubator with humidified 5% C02 for days. At the end of the incubation period, cell number and hence HIV-induced cytopathy was estimated by either (A) propidium iodide staining, or by an (B) MTS tetrazolium staining method.
For propidium iodide readout, 27 ul of 5% Nonidet—40 was added to each well of the incubation plate. After thorough mixing with a Costar multitip pipetter, 60 ul of the mixture was transferred to filter-bottomed l plates. The plates were analyzed in an automated assay ment (Screen Machine, Idexx Laboratories). The control and standard used was 3'-azido-3'-deoxythymidine tested over a concentration range of 0.01 to 1 [M in every assay. The expected range of |C50 values for 3'-azido-3'-deoxythymidine is 0.04 to 0.12 uM. The assay makes use of a propidium iodide dye to estimate the DNA content of each well.
For MTS readout, 20 ul CeIITiter 96 AQ One on reagent (Promega #G3582) was added to each well. At 75 minutes following the addition of MTS reagent, nce was read at 492 nM using a Tecan Sunrise l plate reader.
Analysis: The antiviral effect of a test nd is reported as an EC50, i.e. the inhibitory concentration that would produce a 50% decrease in the HIV-induced cytopathic effect. This effect is measured by the amount of test compound required to restore 50% of the cell growth of HIV-infected MT4 cells, compared to uninfected MT4 cell controls. |C50 was calculated by RoboSage, Automated Curve Fitting Program, version 5.00, -1995.
For each assay plate, the results (relative scence units, rfU, or OD values) of wells containing uninfected cells or infected cells with no compound were averaged, respectively. For measurements of compound-induced cytotoxicty, results from wells containing various compound concentrations and uninfected cells were compared to the average of uninfected cells without compound ent. Percent of cells remaining is determined by the following formula: Percent of cells remaining = (compound-treated cted cells, rfU, or OD values/ untreated uninfected cells) x 100.
A level of percent of cells remaining of 79% or less indicates a icant level of direct compound-induced cytotoxicity for the compound at that concentration. When this condition occurs the results from the compound-treated infected wells at this concentration are not ed in the calculation of EC50.
For measurements of compound antiviral ty, results from wells ning various compound concentrations and infected cells are compared to the average of uninfected and infected cells without compound treatment. Percent inhibition of virus is determined by the following formula: Percent inhibition of virus = (1-((ave. untreated uninfected cells - treated infected cells) / (ave. ted uninfected cells - ave. untreated infected cells)))x 100.
Results: Compounds of the t invention have anti-HIV activity in the range EC50 = 1-1000 nM.
Table 3 Table 3 shows EC50 values for representative compounds of Table 2 after the HIV MT4 Antiviral Cell Assay of e 84.
Example number EC50 NL4-3 wt (nM) EC50V370A (nM) 6.9 31.1 16 11.0 7.6 WO 90664 WO 90664 379.0 17.2 8409.0 10000.0 213.2 WO 90664 83 7.3 143.5 Example 86 This example shows the EC50 potencies of Bevirimat, compound 51, compound A, and compound B against wild type HIV, site directed HIV mutants, and clinical HIV isolates. As can be seen in Table 5, compound 51 demostrates higher potency than the other compounds when measured t HIV among wildtype, n site directed mutants, and against several al HIV isolates. Surprisingly, nd 51 ues to have excellent potency against HIV relative to the other compounds, when protein binding is taken into account as can be seen in Table 6.
The results in Tables 5 and 6 for compound 51 demostrate an unexpected result taken in light of mat and compounds A and B. The results in the above tables are indicative of the unpredictability in developing anti-HIV compounds where a subtle change in the chemical structure can have a large impact on the clinical result. Where compounds A and B show alternating efficacy in their both their EC50 values for polymorphism and protein binding, compound 51 shows none of this variability and is therefor unexpectedly superior when viewed in terms of potential clinical applicability. A direct comparison between compound 51 and compounds A and B, rate how subtle chemical substitutions can have a dramatic effect on the in vitro efficacy of a putative anti- HIV compound.
] A similar advantage for compound 51 can be seen in Table 6 where protein binding and serum shift for the above compounds are compared. This table shows both a significant se in the EC50 and a reduced serum effect for compound 51 relative to the other compounds tested.
Table 5 Wild-type, Polymorphisms, & PBLs - EC50 (nM) HIV-1 B HIV-1 B HIV-1 c MT4 NL. wt* MT4 NL. V370A CC1/85 ASJM108 972A009 ) (V370A+) (V370A+) —"———-m- —————— "nu—mm- ————-at-- *Consensus Clade B Sp1 Genotype.
Table 6 n Binding s on Potency LHIV Fold shift IC5o (nM) with 40%HuS with 40% HuS Compound A CompoundB Com ound51 * Definitive protein shifi value determined in PBL’s by titration at SR1 is 1X Example 87 It is ted that many anti-HIV compounds might potentially be less effective in the treatment of ts who have failed a previous protease inhibitor-containing n and whose viruses have developed drug resistance mutations within the protease gene.
A major obstacle to their long-term efficacy of anti-HIV therapies has been the emergence of resistance to current antiretroviral drugs. One method for comparing the effectiveness of anti-HIV compounds is the characterization of such compounds’ polymorphism at drug resistant sites.
A comparison of compound 51 versus Bevirimet ("BVM") against a broad panel of HIV isolates is shown in Figure 1. From Figure 1, it can be seen that compound 51 shows superior rphism coverage across this panel of HIV isolates to Bevirimat.
Likewise, compound 51 shows superior polymorphism coverage as compared to compound C as shown in Figure 2.
This example was performed as follows. Crude human primary blood mononuclear cells (PBMCs) were collected from healthy donors via leukapheresis and determined to be negative for HIV exposure, among a variety of additional infectious diseases. PBMCs were isolated via Ficoll-Hypaque density gradient separation followed by aspiration of the banded leukocytes from the gradient. ed PBMCs from 10 individual donors were combined and cryopreserved in liquid en as a PBMC pool. Various PBMC pools were utilized.
] Various HIV-1 isolates were obtained from different sources. A stock of the virus was generated in a pool of CD4+ PBMCs and frozen. Viral replication for each virus stock was measured on PHA-blasted PBMC pools to determine the appropriate virus input for anti-viral . HIV gag sequences were determined for each isolate by the Sanger di- deoxy sequencing method.
Cryo-preserved PBMC pools were thawed and stimulated with 2ug/mL PHA in media (RPMI1640, 20%FBS, 10% T cell growth factor, antibiotics) for 3 days. Blasts were then washed, counted, and cultured in media at 2 x 106 cells/mL in media with 10U/mL recombinant lL-2 for an additional 24 hours. Stimulated PBMCs were counted for trypan blue exclusion ity and seeded in 96-well round bottom plates at a final density of 1 x 106 cells/well. A volume of the drug dose titration was added to the cells followed by a pre- determined amount of virus. The plates were incubated for 7 days at 37°C, 5% C02.to allow for viral replication and inhibition by compound to assess iral potency.
In order to determine anti-viral potency, HIV reverse transcriptase activity in cell culture supernatants was measured as a measure of viral replication in the presence or e of compound. At the end of the tion period, fifty (50) [L of PBMC culture supernatants were transferred to a new 96-well plate; 10 uL of RT extraction buffer was added followed by the addition of 40 uL of RT assay buffer. The RT plates were thoroughly mixed and placed in a fied tor at 37°C, 5% C02 for 2h. DE-81 96-well plates were placed on a vacuum manifold and 100uL of the RT on transferred to the ion- exchange chromatography plates. After applying the solution phase of the RT reaction to the DE-81 plate, the plate was then washed once with prepared 5% 4, ed by a wash of dH20. Plates were then allowed to dry overnight at room temperature. The plates were sealed and 50uL scintillation fluid added prior to reading on a Topcount (Packard) luminometer at 10s/well.
Below are the particular HIV-1 isolates tested as shown in Figure 1: 1 - HIV-1 A_UG275 2 - HIV-1 AE_42368 3— HIV-1 C_97/ZA/009 4— HIV-1 C_ETH2220 - HIV-1 C_ZAM18 6 - HIV-1 16 7 - HIV-1 B_CC1/85 8 - HIV-1 B_ASJM108 9 - HIV-1 B_SF162 - HIV-1 B_92U8657 11 - HIV-1 B_BR92030 12 - HIV-1 B_ASM42 13 - HIV-1 B_BR92023 14 - HIV-1 B_ASM44 - HIV-1 B_92U8660 16 - HIV-1 B_THA92014 17 - HIV-1B_lllB 18 - HIV-1 B_301596 19 - HIV-1 B_ASM34 - HIV-1 B_BK132 21 - HIV-1 7 22 - HIV-1 B_ASM54 23 - HIV-1 B_92HT599 24 - HIV-1 B_CM237 - HIV-1 B_92HT593 26 - HIV-1 B_BZ167 27 - HIV-1 B_92US723 Below are the particular HIV isolates tested as shown in Figure 2: 1 - HIV-1 A_UG275 2 - HIV-1 AE_42368 3 - HIV-1 B_301596 4 - HIV-1 B_92HT593 - HIV-1 599 6 - HIV-1 657 7 - HIV-1 B_92U8660 8 - HIV-1 B_92US723 9 - HIV-1 B_ASJM108 - HIV-1 B_ASM34 11 - HIV-1 B_ASM42 12 - HIV-1 B_ASM44 13 - HIV-1 B_ASM54 14 - HIV-1 B_BK132 - HIV-1 B_BZ167 16 - HIV-1 B_CC1/85 17 - HIV-1 B_CM237 18 - HIV-1B_|||B 19 - _SF162 - HIV-1 C_97/ZA/009 21 - HIV-1 C_ETH2220 22 - HIV-1 C_ZAM18 e 88 This example shows in Table 7 a direct comparison between compound 51, compound 56, and compound C. Intrinsic HIV wild type potency for compound 51 relative to compound C is about 10X better (0.8 nM vs. 6 nM). In the HIV polymorphic strain, V370, the potency for compound 51 relative to compound C is even more ic (0.7 nM vs. 19 nM).
In terms of human protein shift listed as human serum (HS) in this e, is another factor of 10 fold better for compound 51 relative to compound C (5.5 fold shift vs. a 48.9 fold shift).
All taken together, as can be seen in Table 7 there is a factor of 238 fold improvement for compound 51 over nd C for the Ctrough target, which is the PAEC50 (or PAECgO which is the same factorjust higher for each by a factor of 3-4 fold). In fact, the reported 5.5 fold shift in Table 7 for 40% human serum in a multicell HIV full life cycle reporter based assay.
Table 7 also depicts the protein adjusted EC50 for the V370A polymorphic virus (which represents up to 40% of patients in clade B and maybe more e clade B) you can see that compound 51 potency is unexpectedly greater at 3.9 nM, while compound C y is lower at 929 nM.
Table 7 Compound Identity HIV w/t mEcso V370A mEcso Human Serum V370A Fold Shift** PAEC50*** nd 51 (‘232) Compound 56 (‘233) **Human Serum fold shift values determined using 40% human serum in a HIV multicell full life cycle assay.
***V370A PAEc50 is determined by the t of V370A MT4Ec50 and human serum fold shift.
Example 89 The PBL assay in this example was performed as follows in order to study the effect of human serum on the HIV antiviral ty of certain compounds. In particular, the effect of the presence of human serum on the antiviral activity of compound 51 and Bevirimat ("BVM") was ted in a modified PMBC assay.
In the standard assay, -2 stimulated PBMCs (5 x 104 cells/well) were incubated with virus and compound 51 or BVM (both compounds tested at range of 0.06 nM to 25 mM) for 7 days.
In the modified PBMC assay, PHA/IL-2 stimulated PBMCs were pre- incubated with HIV-1 strain JR-CSF prior to addition of compound 51 or BVM and human serum. In this assay, 8 x 106 cells from pooled donors were incubated with virus for 1 hour, followed by centrifugation for 1 hour. Cells were then gently re-suspended and incubated an additional 2 hours. During this second incubation period, 2.5 x 104 uninfected PBMCs from pooled donors were added to the interior 60 wells of a 96 well plate, followed by the addition of nd 51 or BVM (both compounds tested at range of 0.06 nM to 25 mM) and human serum (10%, 20%, 30% and 40%) to the appropriate weIIs. At the end of the second incubation period, infected cells were diluted in media (5 x 105 ceIIs/mL) (without washout of virus) and 50 mL (2.5 x 104 cells) were added to each well of the plate and incubated for 7 days.
Following incubation in both the standard and modified assays, supernatants were assayed for reverse transcriptase (RT) activity and p24 antigen t by ELISA and spectrophotometric analysis at 450 nM.
Compound 51 maintained antiviral activity in the presence of human serum at all serum concentrations tested, with no nt shift in IC50 values (range: 0.52 to 3.07 nM) compared to the |C50 value (0.69 nM) in the standard assay (0% serum). These results indicate that the tory activity of compound 51 is minimally or not at all impacted by serum proteins. Extrapolating from the ized |C50 values observed in the presence of the various human serum concentrations gave an estimated |C50 value of 0.33 nM for 100% human serum (assuming a linear relationship). BVM also ined antiviral activity in the presence of human serum at all concentrations, however, there was a large increase in the IC50 values (range: 1.38 mM to 13 mM) associated with increasing human serum concentrations compared to the standard assay (9.76 nM). Extrapolating from the normalized |C50 values observed in the presence of the various concentrations of human serum there is a 2,310-fold change in the |C50 value in the presence of 100% serum (compared to the control ment, suggesting that BVM is highly bound by serum proteins).
The effect of human serum on antiviral activity of compound 51 and BVM was also evaluated in the LHIV assay. Using the same format as the standard LHIV assay, the addition of 40% human serum caused a 5.6-fold shift in the IC50 value (10.6 nM) for compound 51 and a 174.9-fold shift in IC50 value (3.88 mM) for BVM.
However, when determined in a PBL assay containing a titration n 0 and 40% human serum the extrapolated value is 1 fold or less. Therefore, the improvement of compound 51 over compound C, in terms of potency while in the ce of human serum, is likely >1300 fold better when a more typical baseline is taken into account. See Figures 3, 4, and 5.

Claims (8)

What we claim is:
1. A compound having the structure: HONO or a pharmaceutically acceptable salt thereof.
2. A compound of claim 1, which has the structure: or a pharmaceutically acceptable salt thereof.
3. A compound according to claim 1 or 2.
4. A pharmaceutically able salt of claim 1 or 2.
5. A pharmaceutical composition comprising a compound or pharmaceutically acceptable salt according to any one of claims 1 to 4.
6. A pharmaceutical composition according to claim 5, comprising at least one pharmaceutically able excipient.
7. A compound or pharmaceutically acceptable salt according to claim 1, substantially as herein described or exemplified.
8. A pharmaceutical composition according to claim 5, substantially as herein bed or exemplified.
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