WO2010135424A1 - Chemical compounds - Google Patents

Abstract

The present invention relates to highly functionalized 1,3-diamino-propan-2-ols and pharmaceutically acceptable salts thereof. More specifically, the invention relates to highly functionalized 1,3-diamino-propan-2-ols that are derivatives of the HIV protease inhibitors brecanavir.

Description

Chemical Compounds

FIELD OF THE INVENTION

[0001] The present invention relates to highly functionalized 1 ,3-diamino-propan-2- ols and pharmaceutically acceptable salts thereof. More specifically, the invention relates to highly functionalized 1 ,3-diamino-propan-2-ols that are derivatives of the HIV protease inhibitor brecanavir.

BACKGROUND ART

[0002] Each element has a unique number of protons in the atoms nucleus. The number of protons is called the atomic number and in a neutral state is equal to the number of electrons that surround the nucleus. The mass number however is defined as the number of protons and neutrons contained within the nucleus of a given atom. The molecular weight of an atom is equal to the number of protons and neutrons contained in that substance. Isotopes are defined as atoms that contain the same number of protons (which define the element) and different numbers of neutrons. Some isotopes are unstable and decay to give off radioactivity, while others are stable and do not decay. Hydrogen (H, ¹H, protio) is the simplest atom containing only a single proton and no neutrons (atomic number 1 , mass number 1 ). Deuterium (D, ²H, deutero) is a stable isotope of hydrogen that contains 1 proton and 1 neutron having an atomic number of 1 and a mass number of 2. Deuterium is present in a natural abundance of 0.015% .

[0003] Any carbon-hydrogen bond has a given energy resulting from vibrations in the molecule at a certain temperature. This energy is defined as the zero point energy. A corresponding carbon-deuterium bond also has a zero point energy under the same conditions, however because of the greater mass of the deuterium (resulting from the extra neutron) the vibrations contribute to give a lower zero point energy relative to the hydrogen counterpart. The difference in the C-H and C-D bond energies result in a different activation energy requirement to reach an identical transition state. This difference in energy gives rise to what is called a kinetic isotope effect. This small but often significant energy difference can lead to retarded reaction rates in the deuterium analog when the bond is being broken in a rate limiting step during a chemical transformation. The approximate 1.2 kcal/mol energy difference that is often found when comparing the two isotope bonds (C-H or C-D) can lead to a several fold reduction in rate depending on the transition state dynamics. In some instances very little effect is noted between the bonds and the rate comparison is at or near 1. In other instances the rate of the hydrogen containing reaction can be up to 7 times faster or even greater in certain circumstances than the deuterium analog.

[0004] It is believed that this retardation of reaction rate can potentially affect the metabolism of drug molecules in an in vitro or in vivo setting thus rendering an altered pharmacokinetic profile of a drug molecule. One potential interest is to alter a drug substance by replacing hydrogen atoms with deuterium atoms. The steric environment is identical and the potency and pharmacologic profile of the compound are expected to be the same when a molecules mechanism of action does not involve a carbon-hydrogen (or carbon-deuterium) bond breaking event.

[0005] Brecanavir (USAN approved name) ((3R,3aS,6aR)-hexahydrofuro[2,3- 6]furan-3-yl {(1 S,2/?)-3-[(1 ,3-benzodioxol-5-ylsulfonyl)(2-methylpropyl)amino]-2-hydroxy-1 - [(4-{[(2-methyl-1 ,3-thiazol-4-yl)methyl]oxy}phenyl)methyl]propyl} carbamate) is an HIV protease inhibitor thought to be useful in the treatment of HIV related conditions such as AIDS. Brecanavir has been in human clinical trials and shown efficacy in HIV infected patients after oral dosing. However, solubility and first pass metabolism were challenges during clinical investigations. To combat the first pass and other metabolism effects it is common to dose HIV protease inhibitors with the pharmacoenhancer ritonavir (RTV). In the presence of RTV, brecanavir exposure after oral dosing is significantly improved. It is however less desirable to dose a drug with RTV than without due to undesirable side effects and drug-drug interactions as a result of the inhibition of metabolic enzymes and other transporters such as Pgp efflux pumps. Considering this situation the alternative is to invent a means to improve the active pharmaceutical ingredient exposure by attenuating its metabolic profile or its removal from circulation. The present invention addresses this issue by employing the deuterium isotope effect by making deuterium analogs of brecanavir. The invention will allow for reduced need for pharmacoenhancers or optionally remove the need altogether for co-dosing with the pharmacoenhancer.

SUMMARY OF THE INVENTION

[0006] The present inventors have now discovered deuterated compounds which are protease inhibitors. Such compounds may be useful in the treatment of conditions related to infection with the human immunodeficiency virus (HIV).

[0007] In a first aspect of the present invention, there is provided a compound of Formula (I):

(I) [0008] wherein:

[0009] each R¹ is independently selected from -D or -H, where at least one R¹ substituent is -D.

[0010] n is 1 , 2, or 3; and

[0011] x is 1 or 2;

[0012] or a salt thereof.

[0013] In a second aspect of the present invention, there is provided a compound of formula (I)

[0014] wherein:

[0015] each R¹ is independently selected from -D or -H, wherein the level of deuterium incorporation in each R¹ group substituted with -D is at least 50%; [0016] n is 1 , 2, or 3; and [0017] x is 1 or 2; [0018] or a salt thereof. [0019] In a third aspect of the present invention, there is provided a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof and one or more of pharmaceutically acceptable carriers, diluents and excipients.

[0020] In a fourth aspect of the present invention, there is provided a method of treating a virus susceptible to HIV protease inhibition in a mammal, comprising administering to said mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0021] In a fifth aspect of the present invention, there is provided a method of inhibiting HIV related aspartyl protease in a mammal, comprising administering to said mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0022] In a sixth aspect of the present invention, there is provided a method of treating protease resistant HIV in a mammal, comprising administering to said mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0023] In a seventh aspect of the present invention, there is provided a method of preventing development of protease resistant HIV in a mammal, comprising administering to said mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0024] In another particular embodiment there is provided a method of treating a virus susceptible to HIV protease inhibition in a mammal comprising administering to said mammal a long-acting parenteral composition, wherein the long-acting parenteral composition comprises a therapeutically effective amount of compound of formula (I), or a pharmaceutically acceptable salt thereof. Related embodiments provide that the long-acting parenteral composition further comprises at least one additional agent useful in treating HIV infection, or further comprises at least one additional agent useful as a pharmacological enhancer.

[0025] In another embodiment there is provided a method of treating protease resistant HIV in a mammal comprising administering to said mammal a long-acting parenteral composition, wherein the long-acting parenteral composition comprises a therapeutically effective amount of compound formula (I), or a pharmaceutically acceptable salt thereof. In related embodiments, the long-acting parenteral composition further comprises at least one additional agent useful in treating HIV infection, or the long-acting parenteral composition further comprises at least one additional agent useful as a pharmacological enhancer. [0026] In another particular embodiment there is provided a method of inhibiting HIV related aspartyl protease in a mammal comprising administering to said mammal a long- acting parenteral composition, wherein the long-acting parenteral composition comprises a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof. Related embodiments provide methods wherein the long-acting parenteral composition further comprises at least one additional agent useful in treating HIV infection, or wherein the long-acting parenteral composition further comprises at least one additional agent useful as a pharmacological enhancer.

[0027] Still another particular embodiment provides a compound selected from the group consisting of:

[0028] Specific examples of compounds of the present invention include the following:

[0029] (3R,3aS,6aR)-Hexahydrofuro[2,3-b]furan-3-yl {(1 S,2R)-3-[(1 ,3-benzodioxol-5- ylsulfonyl)(2-methylpropyl)amino]-2-hydroxy-1-[(4-{[(2-methyl-1 ,3-thiazol-4- yl)methyl]oxy}phenyl)methyl]propyl}- di.carbamate;

[0030]

[0031] (3R,3aS,6aR)-Hexahydrofuro[2,3-b]furan-3-yl {(1 S,2R)-3-[(1 ,3-benzodioxol-5- ylsulfonyl)(2-methylpropyl)amino]-2-hydroxy-d-1-[(4-{[(2-methyl-1 ,3-thiazol-4-yl)methyl-d₂- ]oxy}phenyl)methyl]propyl}carbamate;

[0032] whose structure is

[0033] or a pharmaceutically acceptable salt thereof. [0034] Additional specific examples of compounds of the present invention include the following:

[0035] (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl {(1 S,2R)-3-[(1 ,3-benzodioxol-5- ylsulfonyl)-d₂-(2-methylpropyl)amino]-2-hydroxy-d-1-[(4-{[(2-methyl-1 ,3-thiazol-4- yl)methyl]oxy}phenyl)methyl]propyl}carbamate,

[0036] whose structure is

[0037] (3R,3aS,6aR)-Hexahydrofuro[2,3-b]furan-3-yl-di- {(1 S,2R)-3-[(1 ,3- benzodioxol-5-ylsulfonyl)(2-methylpropyl)amino]-2-hydroxy-1-[(4-{[(2-methyl-1 ,3-thiazol-4- yl)methyl]oxy}phenyl)methyl]propyl}-di-carbamate,

[0038] whose structure is

[0039] (3R,3aS,6aR)-Hexahydrofuro[2,3-b]furan-3-yl-di- {(1 S,2R)-3-[(1 ,3- benzodioxol-5-ylsulfonyl)-d₂-(2-methylpropyl)amino]-2-hydroxy-1-[(4-{[(2-methyl-1 ,3-thiazol- 4-yl)methyl-d₂]oxy}phenyl)methyl]propyl}carbamate

[0041] (3R,3aS,6aR)-Hexahydrofuro[2,3-b]furan-3-yl-di- {(1 S,2R)-3-[(1 ,3- benzodioxol-5-ylsulfonyl)-d₂-(2-methylpropyl)amino]-2-hydroxy-1-[(4-{[(2-methyl-1 ,3-thiazol- 4-yl)methyl]oxy}phenyl)methyl]propyl}carbamate,

[0042] whose structure is

[0043] (3R,3aS,6aR)-Hexahydrofuro[2,3-b]furan-3-yl-di- {(1 S,2R)-3-[(1 ,3- benzodioxol-5-ylsulfonyl)(2-methylpropyl)amino]-2-hydroxy-1-[(4-{[(2-methyl-1 ,3-thiazol-4- yl)methyl-d₂-]oxy}phenyl)methyl]propyl}-d₁-carbamate,

[0044]

[0045] (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl {(1 S,2R)-3-[(1 ,3-benzodioxol -5- ylsulfonyl) -d₂ -(2-methylpropyl)amino]-2-hydroxy-1-[(4-{[(2-methyl-1 ,3-thiazol-4- yl)methyl]oxy}phenyl)methyl]propyl}carbamate,

[0046] whose structure is

[0047] (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl {(1 S,2R)-3-[(1 ,3-benzodioxol-5- ylsulfonyl) -d₂-(2-methylpropyl)amino]-2-hydroxy-1-[(4-{[(2-methyl-1 ,3-thiazol-4-yl) -d₂- methyl]oxy}phenyl)methyl]propyl}carbamate,

[0048] whose structure is

[0049] (3R,3aS,6aR)-Hexahydrofuro[2,3-b]furan-3-yl-di- {(1 S,2R)-3-[(1 ,3- benzodioxol-5-ylsulfonyl)(2-methylpropyl)amino]-2-hydroxy-1-[(4-{[(2-methyl-1 ,3-thiazol-4- yl)methyl]oxy}phenyl)methyl]propyl}carbamate,

[0050] whose

[0051] (3R,3aS,6aR)-Hexahydrofuro[2,3-b]furan-3-yl-di- {(1 S,2R)-3-[(1 ,3- benzodioxol-5-ylsulfonyl)(2-methylpropyl)amino]-2-hydroxy-1-[(4-{[(2-methyl-1 ,3-thiazol-4- yl)methyl-d₃]oxy}phenyl)methyl]propyl}carbamate,

[0052]

[0053] (3R,3aS,6aR)-Hexahydrofuro[2,3-b]furan-3-yl-d₂- {(1 S,2R)-3-[(1 ,3- benzodioxol-5-ylsulfonyl)(2-methylpropyl)amino]-2-hydroxy-1-[(4-{[(2-methyl-1 ,3-thiazol-4- yl)methyl]oxy}phenyl)methyl]propyl-di}carbamate,

[0054] whos

[0055] (3R,3aS,6aR)-Hexahydrofuro[2,3-b]furan-3-yl-d₂- {(1 S,2R)-3-[(1 ,3- benzodioxol-5-ylsulfonyl)(2-methylpropyl)amino]-2-hydroxy-1-[(4-{[(2-methyl-1 ,3-thiazol-4- yl)methyl-d₂]oxy}phenyl)methyl]propyl-di}carbamate,

[0056] whose structure is

[0057] (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl {(1 S,2R)-3-[(1 ,3-benzodioxol-5- ylsulfonyl)(2-methylpropyl) -d₂-amino]-2-hydroxy-1 -[(4-{[(2-methyl-1 ,3-thiazol-4- yl)methyl]oxy}phenyl)methyl]propyl}carbamate,

[0058] whose structure is

[0059] (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl {(1 S,2R)-3-[(1 ,3-benzodioxol-5- ylsulfonyl)(2-methylpropyl) -d₂ -amino]-2-hydroxy-1-[(4-{[(2-methyl-1 ,3-thiazol-4-yl) -d₂ - methyl]oxy}phenyl)methyl]propyl}carbamate,

[0060] whose structure is

[0061] (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-d₂-3-yl {(1 S,2R)-3-[(1 ,3-benzodioxol- d₂-5-ylsulfonyl)(2-methylpropyl)amino]-2-hydroxy-1-[(4-{[(2-methyl-1 ,3-thiazol-4-yl)methyl- d₂]oxy}phenyl)methyl]propyl}carbamate,

[0062] whose structure is

[0063] (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl {(1 S,2R)-3-[(1 ,3-benzodioxol-5- ylsulfonyl)(2-methylpropyl)amino]-2-hydroxy-1-[(4-{[(2-methyl-1 ,3-thiazol-4- yl)methyl]oxy}phenyl)methyl]propyl}-d₆-carbamate,

[0064] whose structure is

[0065] (3R, 3aS, 6aR)-hexahydrofuro[2, 3-b]furan-3-yl {(1 S, 2R)-3-[(1, 3-benzodioxol-5- ylsulfonyl)(2-methylpropyl)amino]-2-hydroxy-1-[(4-{[(2-methyl-1,3-thiazol-4- yl)methyl]oxy}phenyl)methyl]propyl}carbamate-d₈,

[0066] whose structure is

[0067] (3R, 3aS, 6aR)-hexahydrofuro[2, 3-b]furan-3-yl {(1 S, 2R)-3-[(1 ,3-benzodioxol-5- ylsulfonyl)(2-methylpropyl)amino]-2-hydroxy-1-[(4-{[(2-methyl-1,3-thiazol-4- yl)methyl]oxy}phenyl)methyl]propyl}carbamate-di₆,

[0068] whose structure is

[0069] (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl {(1S,2R)-3-[(1,3-benzodioxol-5- ylsulfonyl)(2-methylpropyl)amino]-2-hydroxy-1-[(4-{[(2-methyl-1,3-thiazol-4- yl)methyl]oxy}phenyl)methyl]propyl}carbamate-di9, [0070] whose structure is

[0071] or a pharmaceutically acceptable salt thereof.

Detailed Description of Specific Embodiments

[0072] As used herein, the term "effective amount" means that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal or human that is being sought, for instance, by a researcher or clinician. Furthermore, the term "therapeutically effective amount" means any amount which, as compared to a corresponding subject who has not received such amount, results in improved treatment, healing, prevention, or amelioration of a disease, disorder, or side effect, or a decrease in the rate of advancement of a disease or disorder. The term also includes within its scope amounts effective to enhance normal physiological function.

[0073] As used herein the term "HIV" refers to the human immunodeficiency virus. HIV is the causative agent for AIDS.

[0074] As used herein the term "AIDS" refers to acquired immunodeficiency syndrome. AIDS is a disease characterized by destruction of the immune system, particularly of CD4⁺ T-cells, with attendant susceptibility to opportunistic infections.

[0075] As used herein, the term "D" refers to a deuterium atom. Deuterium (D, ²H, deutero) is a stable isotope of hydrogen that contains 1 proton and 1 neutron having an atomic number of 1 and a mass number of 2. Deuterium is present in a natural abundance of 0.015%.

[0076] Brecanavir is an aspartyl protease inhibitor having the structure of a compound of formula (I) wherein all of the R¹ groups are -H. That is a compound of formula (l^a) following:

(i^a)

[0077] As used herein, the term "deuterated brecanavir" means brecanavir wherein at least one of the brecanavir hydrogens is substituted with deuterium. That is, a compound of formula (I) wherein at least one R¹ is a deuterium.

[0078] As used herein, the term "enriched deuterated brecanavir" means brecanavir wherein in each brecanavir hydrogen substituted with deuterium the deuterium is incorporated at a level of at least 50%. That is, a compound of formula (I) wherein the level of incorporation of deuterium in each hydrogen substituted with deuterium is at least 50%.

[0079] As used herein and known in the art, the term "H" refers to a hydrogen atom. Hydrogen (H, ¹H,) is a stable isotope of hydrogen that contains 1 proton having an atomic number of 1 and a mass number of 1. Also, unless otherwise stated when a particular R¹ is substituted with -H it is understood to have hydrogen and deuterium at their natural abundance isotopic composition.

[0080] It will be apparent to one skilled in the art that due to the natural abundance of deuterium (0.015%) that compounds of formula I will be present at some minor level in compounds previously made wherein all positions were dictated to be 'hydrogens'. However the low percentage of deuterium isotopes in mono deuterium containing analogs and even lower (0.015% x 0.015%) for dual deuterium containing analogs and henceforth higher deuteron analogs is insignificant to the pharmacological effect of previously described drug molecules.

[0081] In the present invention, the compounds of formula I are substantially enriched in deuterium to levels of 50% at the indicated positions. In many cases the preferred level of deuterium incorporation at the indicated position is above 75%, 90%, 95% or 98% and approaching limits of quantitation for determining hydrogen (¹H) content. It will also be understood that compounds with multiple deuterium atoms incorporated will have isotopic mixtures dependent on the level of incorporation at each position. [0082] Accordingly, in one embodiment, the level of deuterium incorporation in each R1 group of the compound of formula (I) indicated as substituted with deuterium is at least 50%. In another embodiment, the level of deuterium incorporation in each R¹ group of the compound of formula (I) indicated as substituted with deuterium is at least 75%. In still another embodiment, the level of deuterium incorporation in each R¹ group of the compound of formula (I) indicated as substituted with deuterium is at least 90%. In a further embodiment, the level of deuterium incorporation in each R¹ group in the compound of formula (I) indicated as substituted with deuterium is at least 95%. In another embodiment, the level of deuterium incorporation in each R¹ group of the compound of formula (I) indicated as substituted with deuterium is at least 98%. In a further embodiment, the level of deuterium incorporation in each R¹ group of the compound of formula (I) indicated as substituted with deuterium approaches 100% and is limited by the limits of quantitation for detecting hydrogen content.

[0083] In one embodiment, the level of deuterium incorporation in each R1 group of the compound of formula (I) indicated as substituted with deuterium is at least 20%. In another embodiment, the level of deuterium incorporation in each R¹ group of the compound of formula (I) indicated as substituted with deuterium is at least 25%. In still another embodiment, the level of deuterium incorporation in each R¹ group of the compound of formula (I) indicated as substituted with deuterium is at least 30%. In a further embodiment, the level of deuterium incorporation in each R¹ group in the compound of formula (I) indicated as substituted with deuterium is at least 35%. In another embodiment, the level of deuterium incorporation in each R¹ group of the compound of formula (I) indicated as substituted with deuterium is at least 40%. In a further embodiment, the level of deuterium incorporation in each R¹ group of the compound of formula (I) indicated as substituted with deuterium is at least 45%.

[0084] In one embodiment, the level of deuterium incorporation in each R1 group of the compound of formula (I) indicated as substituted with deuterium is greater than 0.015%. In another embodiment, the level of deuterium incorporation in each R¹ group of the compound of formula (I) indicated as substituted with deuterium is at least 1%. In still another embodiment, the level of deuterium incorporation in each R¹ group of the compound of formula (I) indicated as substituted with deuterium is at least 3%. In a further embodiment, the level of deuterium incorporation in each R¹ group in the compound of formula (I) indicated as substituted with deuterium is at least 5%. In another embodiment, the level of deuterium incorporation in each R¹ group of the compound of formula (I) indicated as substituted with deuterium is at least 10%. In a further embodiment, the level of deuterium incorporation in each R¹ group of the compound of formula (I) indicated as substituted with deuterium is at least 15%. [0085] It will be understood by those skilled in the art that the level of deuterium incorporation in each R¹ group indicated as substituted with deuterium may be the same or similar or may be different with the only limitation being the recited lower limit. For instance when the lower limit is at least 50% incorporation of deuterium, each deuterium substituted for hydrogen may be incorporated at any value of 50% or greater. That is, one deuterium substituted R¹ may have 60% deuterium incorporation whereas another deuterium substituted R¹ may have 80% deuterium incorporation and so on for other deuterium substituted R¹ groups..

[0086] Certain of the compounds described herein contain one or more chiral centers, or may otherwise be capable of existing as multiple stereoisomers. The scope of the present invention includes mixtures of stereoisomers as well as purified enantiomers or enantiomerically and/or diastereomerically enriched mixtures. Also included within the scope of the invention are the individual isomers of the compounds of the present invention, as well as any wholly or partially equilibrated mixtures thereof. The present invention also includes the individual isomers of the compounds represented by the formulas above as mixtures with isomers thereof in which one or more chiral centers are inverted. Also, it is understood that any tautomers and mixtures of tautomers of the compounds of formula (I) are included within the scope of the compounds of formula (I).

[0087] Typically, the salts of the present invention are pharmaceutically acceptable salts. Salts encompassed within the term "pharmaceutically acceptable salts" refer to nontoxic salts of the compounds of this invention. Salts of the compounds of the present invention may comprise acid addition salts derived from a nitrogen on a substituent in the compounds of formula (I). Representative salts include the following salts: acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium edetate, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, monopotassium maleate, mucate, napsylate, nitrate, N-methylglucamine, oxalate, pamoate (embonate), palmitate, pantothenate, phosphate/diphosphate, polygalacturonate, potassium, salicylate, sodium, stearate, subacetate, succinate, tannate, tartrate, teoclate, tosylate, triethiodide, trimethylammonium and valerate. Other salts, which are not pharmaceutically acceptable, may be useful in the preparation of compounds of this invention and these form a further aspect of the invention.

[0088] Specific examples of compounds of the present invention include the following: [0089] (3R,3aS,6aR)-Hexahydrofuro[2,3-b]furan-3-yl {(1 S,2R)-3-[(1 ,3-benzodioxol-5- ylsulfonyl)(2-methylpropyl)amino]-2-hydroxy-1-[(4-{[(2-methyl-1 ,3-thiazol-4- yl)methyl]oxy}phenyl)methyl]propyl}- di.carbamate;

[0090]

[0091]

S,2R)-3-[(1 ,3-benzodioxol-5- ylsulfonyl)(2-methylpropyl)amino]-2-hydroxy-d-1-[(4-{[(2-methyl-1 ,3-thiazol-4-yl)methyl-d2- ]oxy}phenyl)methyl]propyl}carbamate;

[0092] whose structure is

[0093] or a pharmaceutically acceptable salt thereof.

[0094] Additional specific examples of compounds of the present invention include the following:

[0095] (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl {(1 S,2R)-3-[(1 ,3-benzodioxol-5- ylsulfonyl)-d₂-(2-methylpropyl)amino]-2-hydroxy-d-1-[(4-{[(2-methyl-1 ,3-thiazol-4- yl)methyl]oxy}phenyl)methyl]propyl}carbamate

[0096] w

[0097] (3R,3aS,6aR)-Hexahydrofuro[2,3-b]furan-3-yl-dr {(1 S,2R)-3-[(1 ,3- benzodioxol-5-ylsulfonyl)(2-methylpropyl)amino]-2-hydroxy-1-[(4-{[(2-methyl-1 ,3-thiazol-4- yl)methyl]oxy}phenyl)methyl]propyl}-di-carbamate,

[0098] whose structure is

[0099] (3R,3aS,6aR)-Hexahydrofuro[2,3-b]furan-3-yl-dr {(1 S,2R)-3-[(1 ,3- benzodioxol-5-ylsulfonyl)-d₂-(2-methylpropyl)amino]-2-hydroxy-1-[(4-{[(2-methyl-1 ,3-thiazol- 4-yl)methyl-d₂]oxy}phenyl)methyl]propyl}carbamate

[00100] whose structure is _s

[00101] (3R,3aS,6aR)-Hexahydrofuro[2,3-b]furan-3-yl-di- {(1 S,2R)-3-[(1 ,3- benzodioxol-5-ylsulfonyl)-d₂-(2-methylpropyl)amino]-2-hydroxy-1-[(4-{[(2-methyl-1 ,3-thiazol- 4-yl)methyl]oxy}phenyl)methyl]propyl}carbamate,

[00103] (3R,3aS,6aR)-Hexahydrofuro[2,3-b]furan-3-yl-di- {(1 S,2R)-3-[(1 ,3- benzodioxol-5-ylsulfonyl)(2-methylpropyl)amino]-2-hydroxy-1-[(4-{[(2-methyl-1 ,3-thiazol-4- yl)methyl-d₂-]oxy}phenyl)methyl]propyl}-d₁-carbamate,

[00105] (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl {(1 S,2R)-3-[(1 ,3- benzodioxol -5-ylsulfonyl) -d₂ -(2-methylpropyl)amino]-2-hydroxy-1 -[(4-{[(2-methyl-1 ,3-thiazol- 4-yl)methyl]oxy}phenyl)methyl]propyl}carbamate,

[00106] whose structure is

[00107] (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl {(1 S,2R)-3-[(1 ,3- benzodioxol-5-ylsulfonyl) <l₂-(2-methylpropyl)amino]-2-hydroxy-1-[(4-{[(2-methyl-1 ,3-thiazol- 4-yl) -d₂-methyl]oxy}phenyl)methyl]propyl}carbamate,

[00108] whose structure is

[00109] (3R,3aS,6aR)-Hexahydrofuro[2,3-b]furan-3-yl-di- {(1 S,2R)-3-[(1 ,3- benzodioxol-5-ylsulfonyl)(2-methylpropyl)amino]-2-hydroxy-1-[(4-{[(2-methyl-1 ,3-thiazol-4- yl)methyl]oxy}phenyl)methyl]propyl}carbamate,

[00110] whose structure is

[00111] (3R,3aS,6aR)-Hexahydrofuro[2,3-b]furan-3-yl-di- {(1S,2R)-3-[(1 ,3- benzodioxol-5-ylsulfonyl)(2-methylpropyl)amino]-2-hydroxy-1-[(4-{[(2-methyl-1 ,3-thiazol-4- yl)methyl-d₂]oxy}phenyl)methyl]propyl}carbamate,

[00112] whose structure is

[00113] (3R,3aS,6aR)-Hexahydrofuro[2,3-b]furan-3-yl-d₂- {(1S,2R)-3-[(1 ,3- benzodioxol-5-ylsulfonyl)(2-methylpropyl)amino]-2-hydroxy-1-[(4-{[(2-methyl-1 ,3-thiazol-4- yOmethyOoxyJphenyOmethyOpropyl-diJcarbamate,

[00114] whose structure is

[00115] (3R,3aS,6aR)-Hexahydrofuro[2,3-b]furan-3-yl-d₂- {(1S,2R)-3-[(1 ,3- benzodioxol-5-ylsulfonyl)(2-methylpropyl)amino]-2-hydroxy-1-[(4-{[(2-methyl-1 ,3-thiazol-4- yl)methyl-d₂]oxy}phenyl)methyl]propyl-d₁}carbamate,

[00116] whose structure is

[00117] (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl {(1S,2R)-3-[(1 ,3- benzodioxol-5-ylsulfonyl)(2-methylpropyl) -d₂-amino]-2-hydroxy-1-[(4-{[(2-methyl-1 ,3-thiazol- 4-yl)methyl]oxy}phenyl)methyl]propyl}carbamate,

[00118]

[00119] (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl {(1 S,2R)-3-[(1 ,3- benzodioxol-5-ylsulfonyl)(2-methylpropyl) -d₂ -amino]-2-hydroxy-1 -[(4-{[(2-methyl-1 ,3- thiazol-4-yl) -d₂ -methyl]oxy}phenyl)methyl]propyl}carbamate,

[00120] whose structure is

[00121] (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-d₂-3-yl {(1 S,2R)-3-[(1 ,3- benzodioxol-d₂-5-ylsulfonyl)(2-methylpropyl)amino]-2-hydroxy-1-[(4-{[(2-methyl-1 ,3-thiazol-4- yl)methyl-d₂]oxy}phenyl)methyl]propyl}carbamate,

[00122] whose structure is

[00123] (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl {(1 S,2R)-3-[(1 ,3- benzodioxol-5-ylsulfonyl)(2-methylpropyl)amino]-2-hydroxy-1-[(4-{[(2-methyl-1 ,3-thiazol-4- yl)methyl]oxy}phenyl)methyl]propyl}-d₆-carbamate,

[00124] whose structure is

[00125] (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl {(1 S,2R)-3-[(1 ,3- benzodioxol-5-ylsulfonyl)(2-methylpropyl)amino]-2-hydroxy-1-[(4-{[(2-methyl-1 ,3-thiazol-4- yl)methyl]oxy}phenyl)methyl]propyl}carbamate-d₈ ,

[00126] whose structure is

[00127] (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl {(1S,2R)-3-[(1 ,3- benzodioxol-5-ylsulfonyl)(2-methylpropyl)amino]-2-hydroxy-1-[(4-{[(2-methyl-1 ,3-thiazol-4- yl)methyl]oxy}phenyl)methyl]propyl}carbamate-di6,

[00128] whose structure is

[00129] (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl {(1 S,2R)-3-[(1 ,3- benzodioxol-5-ylsulfonyl)(2-methylpropyl)amino]-2-hydroxy-1-[(4-{[(2-methyl-1 ,3-thiazol-4- yl)methyl]oxy}phenyl)methyl]propyl}carbamate-di₉,

[00130]

[00131] or a pharmaceutically acceptable salt thereof.

[00132] While it is possible that, for use in therapy, therapeutically effective amounts of a compound of formula (I), as well as salts thereof, may be administered as the raw chemical, it is possible to present the active ingredient as a pharmaceutical composition. Accordingly, the invention further provides pharmaceutical compositions, which include therapeutically effective amounts of the compound of formula (I) or salts thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients. The compounds of the formula (I) or salt thereof, are as described above. The carrier(s), diluent(s) or excipient(s) must be acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. In accordance with another aspect of the invention there is also provided a process for the preparation of a pharmaceutical formulation including admixing a compound of the formula (I), or salt thereof, with one or more pharmaceutically acceptable carriers, diluents or excipients. [00133] Pharmaceutical formulations may be presented in unit dose forms containing a predetermined amount of active ingredient per unit dose. Such a unit may contain, for example, 100mg to 5g, 0.5mg to 1 g, 1 mg to 700mg, or 5mg to 100mg of a compound of the formula (I), depending on the condition being treated, the route of administration and the age, weight and condition of the patient, or pharmaceutical formulations may be presented in unit dose forms containing a predetermined amount of active ingredient per unit dose. Preferred unit dosage formulations are those containing a daily dose or sub-dose, as herein above recited, or an appropriate fraction thereof, of an active ingredient. Furthermore, such pharmaceutical formulations may be prepared by any of the methods well known in the pharmacy art.

[00134] Pharmaceutical formulations may be adapted for administration by any appropriate route, for example by the oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual or transdermal), vaginal or parenteral (including subcutaneous, intramuscular, intravenous or intradermal) route. Such formulations may be prepared by any method known in the art of pharmacy, for example by bringing into association the active ingredient with the carrier(s) or excipient(s).

[00135] Pharmaceutical formulations adapted for oral administration may be presented as discrete units such as capsules or tablets; powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; edible foams or whips; or oil-in-water liquid emulsions or water-in-oil liquid emulsions.

[00136] For instance, for oral administration in the form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like. Powders are prepared by comminuting the compound to a suitable fine size and mixing with a similarly comminuted pharmaceutical carrier such as an edible carbohydrate, as, for example, starch or mannitol. Flavoring, preservative, dispersing and coloring agent can also be present.

[00137] Capsules are made by preparing a powder mixture, as described above, and filling formed gelatin sheaths. Glidants and lubricants such as colloidal silica, talc, magnesium stearate, calcium stearate or solid polyethylene glycol can be added to the powder mixture before the filling operation. A disintegrating or solubilizing agent such as agar-agar, calcium carbonate or sodium carbonate can also be added to improve the availability of the medicament when the capsule is ingested.

[00138] Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents and coloring agents can also be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the like. Tablets are formulated, for example, by preparing a powder mixture, granulating or slugging, adding a lubricant and disintegrant and pressing into tablets. A powder mixture is prepared by mixing the compound, suitably comminuted, with a diluent or base as described above, and optionally, with a binder such as carboxymethylcellulose, an aliginate, gelatin, or polyvinyl pyrrolidone, a solution retardant such as paraffin, a resorption accelerator such as a quaternary salt and/or an absorption agent such as bentonite, kaolin or dicalcium phosphate. The powder mixture can be granulated by wetting with a binder such as syrup, starch paste, acadia mucilage or solutions of cellulosic or polymeric materials and forcing through a screen. As an alternative to granulating, the powder mixture can be run through the tablet machine and the result is imperfectly formed slugs broken into granules. The granules can be lubricated to prevent sticking to the tablet forming dies by means of the addition of stearic acid, a stearate salt, talc or mineral oil. The lubricated mixture is then compressed into tablets. The compounds of the present invention can also be combined with a free flowing inert carrier and compressed into tablets directly without going through the granulating or slugging steps. A clear or opaque protective coating consisting of a sealing coat of shellac, a coating of sugar or polymeric material and a polish coating of wax can be provided. Dyestuffs can be added to these coatings to distinguish different unit dosages.

[00139] Oral fluids such as solutions, syrups and elixirs can be prepared in dosage unit form so that a given quantity contains a predetermined amount of the compound. Syrups can be prepared by dissolving the compound in a suitably flavored aqueous solution, while elixirs are prepared through the use of a non-toxic alcoholic vehicle. Suspensions can be formulated by dispersing the compound in a non-toxic vehicle. Solubilizers and emulsifiers such as ethoxylated isostearyl alcohols and polyoxy ethylene sorbitol ethers, preservatives, flavor additive such as peppermint oil or natural sweeteners or saccharin or other artificial sweeteners, and the like can also be added.

[00140] Where appropriate, dosage unit formulations for oral administration can be microencapsulated. The formulation can also be prepared to prolong or sustain the release as for example by coating or embedding particulate material in polymers, wax or the like.

[00141] The compounds of formula (I) or salts thereof, can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines. [00142] The compounds of formula (I) or salts thereof may also be delivered by the use of monoclonal antibodies as individual carriers to which the compound molecules are coupled. The compounds may also be coupled with soluble polymers as targetable drug carriers. Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide -phenol, polyhydroxyethylaspartamidephenol, or polyethyleneoxidepolylysine substituted with palmitoyl residues. Furthermore, the compounds may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels.

[00143] Pharmaceutical formulations adapted for transdermal administration may be presented as discrete patches intended to remain in intimate contact with the epidermis of the recipient for a prolonged period of time. For example, the active ingredient may be delivered from the patch by iontophoresis as generally described in Pharmaceutical Research, 3(6), 318 (1986).

[00144] Pharmaceutical formulations adapted for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils.

[00145] For treatments of the eye or other external tissues, for example mouth and skin, the formulations are preferably applied as a topical ointment or cream. When formulated in an ointment, the active ingredient may be employed with either a paraffinic or a water-miscible ointment base. Alternatively, the active ingredient may be formulated in a cream with an oil-in-water cream base or a water-in-oil base.

[00146] Pharmaceutical formulations adapted for topical administrations to the eye include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent.

[00147] Pharmaceutical formulations adapted for topical administration in the mouth include lozenges, pastilles and mouth washes.

[00148] Pharmaceutical formulations adapted for rectal administration may be presented as suppositories or as enemas.

[00149] Pharmaceutical formulations adapted for nasal administration wherein the carrier is a solid include a coarse powder having a particle size for example in the range 20 to 500 microns which is administered in the manner in which snuff is taken, i.e. by rapid inhalation through the nasal passage from a container of the powder held close up to the nose. Suitable formulations wherein the carrier is a liquid, for administration as a nasal spray or as nasal drops, include aqueous or oil solutions of the active ingredient. [00150] Pharmaceutical formulations adapted for administration by inhalation include fine particle dusts or mists, which may be generated by means of various types of metered, dose pressurized aerosols, nebulizers or insufflators.

[00151] Pharmaceutical formulations adapted for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations.

[00152] Pharmaceutical formulations adapted for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets.

[00153] It should be understood that in addition to the ingredients particularly mentioned above, the formulations may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavouring agents.

[00154] In one embodiment, the pharmaceutical formulation containing a compound of formula I or a salt thereof is a formulation adapted for parenteral administration. In another embodiment, the formulation is a long-acting parenteral formulation. In a further embodiment, the formulation is a nano-particle formulation.

[00155] A therapeutically effective amount of a compound of the present invention will depend upon a number of factors including, for example, the age and weight of the human or other animal, the precise condition requiring treatment and its severity, the nature of the formulation, and the route of administration, and will ultimately be at the discretion of the attendant physician or veterinarian. An effective amount of a salt thereof, may be determined as a proportion of the effective amount of the compound of formula (I) or salts thereof per se.

[00156] The compounds of formula (I) or salts thereof are believed to have activity in stopping or reducing the effects of HIV as a result of inhibition of aspartyl proteases.

[00157] Accordingly, there is provided a method of treating a virus susceptible to protease inhibition in a mammal, including administering to said mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In one embodiment, the virus is HIV. In another embodiment, the protease is an aspartyl protease. In another embodiment, the protease is an HIV related aspartyl protease. In one embodiment, the mammal is a human.

[00158] In another aspect of the present invention, there is provided a method of inhibiting HIV related aspartyl protease in a mammal, including administering to said mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In one embodiment, the mammal is a human.

[00159] In another aspect of the present invention, there is provided a method of treating protease resistant HIV in a mammal, comprising administering to said mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In one embodiment, the mammal is a human. In one embodiment, the mammal is a human.

[00160] In another aspect of the present invention, there is provided a method of preventing development of protease resistant HIV in a mammal, comprising administering to said mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In one embodiment, the mammal is a human.

[00161] The compounds of the present invention and their salts, solvates, or other pharmaceutically acceptable derivatives thereof, may be employed alone or in combination with other therapeutic agents. The compounds of the present invention and any other pharmaceutically active agent(s) may be administered together or separately and, when administered separately, administration may occur simultaneously or sequentially, in any order. The amounts of the compounds of the present invention 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. The administration in combination of a compound of the present invention and salts, solvates, or other pharmaceutically acceptable 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. Alternatively, the combination may be administered separately 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 (I) 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.

[00162] The present invention may be used in combination with one or more agents useful in the prevention or treatment of HIV. Examples of such agents include: [00163] Nucleotide reverse transcriptase inhibitors such as zidovudine, didanosine, lamivudine, zalcitabine, abacavir, stavidine, adefovir, adefovir dipivoxil, fozivudine, todoxil, emtricitabine, alovudine, amdoxovir, elvucitabine, and similar agents;

[00164] 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, TMC-278, TMC-125, etravirine, and similar agents;

[00165] Protease inhibitors such as saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, fosamprenavir, brecanavir, raltegravir, atazanavir, tipranavir, palinavir, lasinavir, and similar agents;

[00166] Entry inhibitors such as enfuvirtide (T-20), T-1249, PRO-542, PRO¬

MO, TNX-355, BMS-806, 5-Helix and similar agents;

[00167] lntegrase inhibitors such as L-870,810 and similar agents;

[00168] Budding inhibitors such as PA-344 and PA-457, and similar agents; and

[00169] CXCR4 and/or CCR5 inhibitors such as vicriviroc (Sch-C), Sch-D,

TAK779, maraviroc (UK 427,857), TAK449, as well as those disclosed in WO 02/74769, PCT/US03/39644, PCT/US03/39975, PCT/US03/39619, PCT/US03/39618,

PCT/US03/39740, and PCT/US03/39732, and similar agents.

[00170] 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, concurrent to, or subsequent to the administration of other agent(s).

[00171] 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 boosters) include, but are not limited to, ritonavir, GS-9350, and SPI-452.

[00172] Ritonavir is 10-hydroxy-2-methyl-5-(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, [5S-(5S^*,8R^*,10R^*,1 1 R^*)] 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 P-gycoprotein (Pgp) cell transport system thereby resulting increased concentrations of active compound within the organism. [00173] GS-9350 is a compound being developed by Gilead Sciences of Foster City California as a pharmacological enhancer.

[00174] SPI-452 is a compound being developed by Sequoia Pharmaceuticals of Gaithersburg, Maryland, as a pharmacological enhancer.

[00175] In one embodiment of the present invention, a compound of formula (I) is used in combination with ritonavir. In one embodiment, the combination is an oral fixed dose combination. In another embodiment, the compound of formula (I) 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 (I) formulated as a long acting parenteral injection and ritonavir formulated as an oral composition. In another embodiment, the compound of formula (I) 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 (I) formulated as a long acting parenteral injection and ritonavir formulated as an injectable composition.

[00176] In another embodiment of the present invention, a compound of formula (I) 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 (I) is formulated as a long acting parenteral injection and GS-9350 is formulated as an oral composition. In one embodiment, is a kit containing the compound of formula (I) formulated as a long acting parenteral injection and GS-9350 formulated as an oral composition. In another embodiment, the compound of formula (I) is formulated as a long acting parenteral injection and GS-9350 is formulated as an injectable composition. In one embodiment, is a kit containing the compound of formula (I) formulated as a long acting parenteral injection and GS-9350 formulated as an injectable composition.

[00177] In one embodiment of the present invention, a compound of formula (I) is used in combination with SPI-452. In one embodiment, the combination is an oral fixed dose combination. In another embodiment, the compound of formula (I) is formulated as a long acting parenteral injection and SPI-452 is formulated as an oral composition. In one embodiment, is a kit containing the compound of formula (I) formulated as a long acting parenteral injection and SPI-452 formulated as an oral composition. In another embodiment, the compound of formula (I) is formulated as a long acting parenteral injection and SPI-452 is formulated as an injectable composition. In one embodiment, is a kit containing the compound of formula (I) formulated as a long acting parenteral injection and SPI-452 formulated as an injectable composition.

[00178] The compounds of this invention may be made by a variety of methods, including standard chemistry. Any previously defined variable will continue to have the previously defined meaning unless otherwise indicated. Illustrative examples are set out below in the Working Examples.

[00179] Certain embodiments of the present invention will now be illustrated by way of example only. The physical data obtained for the compounds exemplified is consistent with the assigned structure of those compounds.

[00180] EXAMPLES

[00181] As used herein the symbols and conventions used in these processes, schemes and examples are consistent with those used in the contemporary scientific literature, for example, the Journal of the American Chemical Society or the Journal of Biological Chemistry. Standard single-letter or three-letter abbreviations are generally used to designate amino acid residues, which are assumed to be in the L-configuration unless otherwise noted. Unless otherwise noted, all starting materials were obtained from commercial suppliers and used without further purification. Specifically, the following abbreviations may be used in the examples and throughout the specification: g (grams); mg (milligrams);

L (liters); ml. (milliliters); μl_ (microliters); psi (pounds per square inch);

M (molar); mM (millimolar); i. v. (intravenous); Hz (Hertz);

MHz (megahertz); mol (moles); mmol (millimoles); rt (room temperature); min (minutes); h (hours); mp (melting point); TLC (thin layer chromatography);

T_r (retention time); RP (reverse phase); eq (equivalents); nM (nanomolar);

[00182] Unless otherwise indicated, all temperatures are expressed in ⁰C

(degrees Centigrade). All reactions are conducted under an inert atmosphere at room temperature unless otherwise noted. All reference to brine refers to a saturated aqueous solution of NaCI.

[00183] ¹H NMR spectra were recorded on a Varian INOVA-400 (400 MHz) or a Bruker Avance 3 (400 or 500 MHz) spectrometer. Chemical shifts are expressed in parts per million (ppm, δ 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), m (multiplet), br (broad). [00184] Several synthetic approaches to preparing brecanavir, deuterated brecanavir, and enriched deuterated brecanavir are illustrated in Schemes 1-17 following. It will be apparent to one skilled in the art that several typical reagents or compounds employed in this synthetic route can be modified to include deuterium atoms and thus this general route can be modified to produce compounds of formula I.

[00185] The synthesis described in Scheme 1 has been demonstrated for the synthesis of brecanavir. It will be apparent to one skilled in the art that replacement of the reagents or conditions described herein with alternative conditions or reagents that contain deuterium wherein that condition installs a hydrogen atom in the current scheme will be a means to compounds of formula I. It has been previously reported that the known O-benzyl tyrosine analog 1 can be treated with iodole chloromethane in the presence of LDA to give the alpha-chloroketone 2. The ketone can be reduced with sodium borohydride in ethanol followed by treatment with base to give the epoxide 3 in a diastereoselective manner. The resultant epoxide can be opened with isobutyl amine and then sulfonylated as shown to provide the amino alcohol derivative 4. Removal of the carbamate protecting group (BOC) followed by re-acylation with the known bis-tetrahydrofuran p-nitrophenol carbonate can result in compound 5. Protection of the compound as an acetonide followed by hydrogenolysis results in compound 6. The phenol group in 6 can be alkylated with the indicated thiazole reagent and subsequently deprotected to give brecanavir 7.

[00186] Scheme 1

1990, 33, 1620.

[00187] It will be apparent to one skilled in the art that a similar sequence to

Scheme 1 can be employed by an earlier installment of the thiazole moiety which is shown in the known compound 8. From this point a similar sequence of epoxide opening, sulfonylation, BOC deprotection and carbamate formation can be employed to give the parent brecanavir.

[00188] Scheme 2

[00189] As mentioned above, the chemistry described in Schemes 1 and 2 can be altered by one skilled in the art to employ deuterium incorporating chemistries to provide compounds of formula I. It will also be apparent to one skilled in the art that the sequences employed in the schemes herein may be re-ordered to facilitate new opportunities to incorporate deuterium into the key intermediates en route to compounds of formula I.

[00190] As shown in Scheme 3, the use of sodium borodeuteride (NaBD₄) may be used to install a deuterium in a stereoselective manner to give a compound such as 11 which in turn may be converted into a compound of formula I using the methods described above.

[00191] Scheme 3

[00192] As shown in Scheme 4, a compound such as 1 may be converted to an intermediate such as 12 through a modification of the methods described in scheme 1 wherein a deutero iodo chloromethane is employed. Optionally, quenching this type of a reaction with a source of D⁺ (CD₃OD or D₂O) may provide the geminal di-deutero intermediate 14 as shown in Scheme 5.

[00193] Scheme 4

[00194] Scheme 5

[00195] Alternatively, the epoxide intermediate 15 may be accessed using the method known to those skilled in the art whereby the anion of DMSO undergoes an addition followed by epoxide ring formation to give an intermediate similar to 15. In the case of the example shown in Scheme 6 the readily available deuteron-DMSO may provide the dideutero epoxide 15, It is possible that both stereoisomers may be used in subsequent sequences wherein the epoxide with the appropriate stereochemistry can be directly used to make a compound of formula I and the diastereomeric epoxide may be inverted after opening with the amine using methods known to one skilled in the art such as a Mitsunobu reaction or through an oxidation/reduction sequence optionally with separation of the undesired isomer.

[00196] Scheme 6

[00197] The method shown in Scheme 7 may be employed wherein a deutero tyrosine derivative is used in place of the protio compound and following similar methods to those shown above could be converted to a compound of formula I.

[00198] Scheme 7

[00199] In a similar manner, if the deutero-tyrosine analog 18 is employed, a compound of formula I as shown in Scheme 8 may be realized.

[00200] Scheme 8

[00201] Likewise, if the deutero analog 19 or 20 is used as a starting tyrosine analog, a compound of formula I as shown in Scheme 9 or 10 respectively may result. It will be apparent to one skilled in the art that these serve as examples and other combinations of the aryl deuterium incorporation are possible using a similar method.

[00202] Scheme 9

[00203] Scheme 10

[00204] As shown in Scheme 11 , catechol may be alkylated with a deuterated dihalomethane derivative to provide the dideuteromethylene dioxy derivative 22. This material may be sulfonylated and subsequently utilized to make a compound of formula I. [00205] Scheme 11

21 22 23

[00206] Alternatively, a deuterated isobutyl amine (27) as shown in Scheme

12 may be employed to give an amino alcohol such as 28 which upon elaboration as shown in the above schemes would provide a compound of formula I.

[00207] Scheme 12

[00208] In a similar manner to the above method, a different deuterated isobutyl amine 29 may be employed to give a compound of formula I (Scheme 13).

[00209] Scheme 13

[00210] Schemes 14 and 15 show a known synthesis of the bis- tetrahydrofuran p-nitrophenyl carbonate shown in Schemes 1 and 2 but the route is modified to incorporate a deuterium in each case using sodium borodeuteride in place of sodium borohydride from the known route. [00211] Scheme 14

37 38

[00212] Scheme 15

[00213] Similarly, Scheme 16 shows a modification of the same known routeporate deuterium as shown. The starting butyrolactone 45 is commercially availablee made by reduction of succinic anhydride with lithium aluminum deuteride (LiAID₄).

[00214] Scheme 16

[00215] A modification of an alternate route to the bis-tetrahydrofuran is shown in Scheme 17. In this case, a deutero propargyl alcohol which can be prepared by known methods is employed. A photochemical cyclization is subsequently employed along with an enzymatic lipase resolution to provide a deutero bis-tetrahydrofuran p-nitrophenyl carbonate for use in the acylation reaction similar to that shown in Schemes 1 and 2.

[00216] Scheme 17

61 60 59 racemic

[00217] A similar method is employed as shown in Scheme 18, however prior to introduction of the propargyl alcohol dihydrofuran 54 is deprotonated and the anion quenched with a deuterium. The 2-deutero-dihydrofuran 64 is subjected to similar methods to those outlined in scheme 17 to provide key intermediate 72 which may be converted to a compound of formula I.

[00218] Scheme 18

[00219] It will be apparent to one skilled in the art that the above methods serve as examples and additional compounds of the formula I may be prepared by combining various steps included in different schemes to incorporate multiple deuterium atoms. Additionally, once skilled in the art will be able to devise other schemes to employ known chemistries wherein a deuterium can be incorporated. The above schemes are meant as examples and the invention is not limited to these methods.

[00220] The following compounds of formula (I) exemplified in Tables 1 , 2, and 3 may be prepared according to methods similar to those disclosed in Schemes 1- 18 recited above.

[00223] Table 3

[00224] Example 1

[00225] Preparation of (3R,3aS,6aR)-Hexahydrofuro[2,3-b]furan-3-yl

{(1S,2R)-3-[(1,3-benzodioxol-5-ylsulfonyl)(2-methylpropyl)amino]-2-hydroxy-1-[(4-{[(2- methyl-1,3-thiazol-4-yl)methyl]oxy}phenyl)methyl]propyl}- di.carbamate

[00226] fa) Preparation of 1,1-Dimethylethyl [(1S)-3-chloro-2-oxo-1-({4

[(phenyl methyl)oxy]phenyl} methyl) propyl] carbamate.

[00227] LDA (169 ml_, 163 mmol) was added drop wise at -78 C through a cannula to a mixture of iodochloromethane (9.45 ml_, 130 mmol) and ethyl Λ/-{[(1 ,1- dimethylethyl)oxy]carbonyl}-O-(phenylmethyl)-L-tyrosinate (prepared as described in J. Med. Chem. 1990, 33, 1620) also at -78 C. The resulting dark solution was stirred for one hour at -78 C, then 50 ml. of a 1 :1 acetic acid: tetrahydrofuran solution was added slowly and the reaction was warmed to ambient temperature, poured onto a mixture of ice water and ethyl acetate, and the aqueous solution was extracted with ethyl acetate, the organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The brown solid was suspended in cold ether and filtered to give the title compound (3.17 g). The filtrate was concentrated under reduced pressure to give an additional 7.4 g of slightly impure title compound (10.57 g, 80% yield). ¹H NMR (400 MHz, CHLOROFORM-d) δ 1.40 (s, 9 H), 2.80 -3.21 (m, 2 H), 3.87 - 4.25 (m, 2 H), 4.42 - 4.72 (m,

1 H), 5.03 (s, 2 H), 6.81 - 7.17 (m, 4H), 7.29 - 7.57 (m, 5 H); LC/MS (m/z) ES⁺ = 427 (M+23).

[00228] (b) Preparation of 1,1-Dimethylethyl f(1S,2S)-3-chloro-2-hvdroxy-

1-({4-f(phenylmethyl)oxyl phenyl}methyl)propyll -di-carbamate.

[00229] Sodium borodeuteride (1.64 g, 39 mmol) was added in portions to a suspension of 1 ,1-dimethylethyl [(1 S)-3-chloro-2-oxo-1-({4 [(phenylmethyl) oxy]phenyl}methyl)propyl] carbamate (3.16 g, 7.82 mmol) in 60 ml. of a 4:1 ethanol: tetrahydrofuran solution at -78 C. The mixture was warmed to O C and stirred 1 hour. The suspension was poured onto ice, placed in a O C bath, acidified with 1 N HCI to a pH~2 and filtered to collect a brown solid. The filtrate was extracted with ethyl acetate, dried over sodium sulfate and combined with the isolated solid. The brown solid was suspended in ethyl acetate (10 vol.), heated to reflux and stirred for 15 minutes. The hot solution was filtered and allowed to cool to ambient temperature and aged overnight. The mixture was filtered and the filter cake was washed with cold ethyl acetate. A second crop was isolated in a similar manner to give the title compound as a white solid in >10:1 d.r. (2 g, 63%). ¹H NMR (400 MHz, CHLOROFORM-d) δ 1.36 (s, 9 H), 2.71 - 3.16 (m, 3 H), 3.43 - 3.71 (m, 2 H), 3.74 - 3.94 (m, 1 H), 4.40 - 4.80 (m, 1 H), 5.03 (s, 2 H), 6.91 (d, J=8.6 Hz, 2 H), 7.12 (d, J=8.5 Hz,

2 H), 7.27 - 7.49 (m, 5 H); LC/MS (m/z) ES⁺ = 429 (M+23).

[00230] (C) Preparation of 1,1-Dimethylethyl ((1S)-1-[(2S)-2-oxiranyl]-2-{4-

[(phenyl methyl)oxy]phenyl}ethyl) -d ^-carbamate.

[00231] 1 N potassium hydroxide (0.82 ml_, 1.5 eq) was added to a suspension of 1 ,1 -dimethylethyl [(1 S,2S)-3-chloro-2-hydroxy-1 -({4-[(phenylmethyl)oxy]phenyl}methyl) propyl] -CZ₁ -carbarn ate (221 mg, 0.543 mmol) in ethanol (8 ml.) and the suspension was stirred for 1 hour at ambient temperature. The yellow solution was concentrated under reduced pressure, diluted with water, the aqueous solution was extracted with dichloromethane and the organics were dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound as a light yellow solid (200 mg, 99%). ¹H NMR (400 MHz, CHLOROFORM-d) δ 1.38 (s, 9H), 2.67 - 2.99 (m, 4 H), 3.39- 3.74 (m, 2 H), 4.41 - 4.59 (m, 1 H), 4.95 - 5.1 1 (m, 2 H), 6.86 - 6.98 (m, 2 H), 7.06 -7.17 (m, 2 H), 7.20 - 7.51 (m, 5 H); LC/MS (m/z) ES⁺ = 393 (M+23).

[00232] (d) Preparation of 1.1 -Dimethylethyl f(1S.2R)-2-hvdroxy-3-f(2- methylpropyl)aminol-1-({4-[(phenylmethyl)oxylphenyl}methyl)propyll -d ^-carbamate.

[00233] 1 , 1 -Dimethylethyl ((1 S)- 1 -[(2S)-2-oxiranyl]-2-{4-[(phenylmethyl)oxy] phenyl} ethy^-c/rcarbamate (91 mg, 0.246 mmol) was suspended in isopropanol (3 mL), isobutylamine (0.17 mL, 1.72 mmol) was added and the mixture was heated to 85 C for 2 hours. The reaction was cooled to 0 C, water was added (66 vol.) and the white precipitate was collected using vacuum filtration and washed with cold water to give the title compound as a white solid (94 mg, 86%). ¹H NMR (400 MHz, CHLOROFORM-d) δ 0.81 - 1.05 (m, 6 H), 1.35 (s, 9 H), 1.60 - 1.79 (m, 2 H), 2.33 - 2.42 (m, 2 H), 2.59 - 2.70 (m, 2 H), 2.77 - 3.03 (m, 2 H), 3.60 - 3.83 (m, 2 H), 4.55- 4.75 (m, 1 H), 5.03 (s, 2 H), 6.89 (d, J=8.6 Hz, 2 H), 7.13 (d, J=8.5 Hz, 2 H), 7.38 (d,J=15.6 Hz, 5 H).

[00234] (e) Preparation of 1,1-Dimethylethyl [(1S,2R)-3-[(1,3-benzodioxol-

5-ylsulfonyl)(2-methylpropyl) amino]-2-hydroxy-1-({4-[(phenylmethyl)oxy]phenyl} methyl)propyl] -drcarbamate.

[00235] 1 ,1-Dimethylethyl [(1 S,2R)-2-hydroxy-3-[(2-methylpropyl)amino]-1-({4-

[(phenylmethyl)oxy]phenyl}methyl)propyl] -c/i-carbamate (168 mg, 0.379 mmol) was dissolved in dichloromethane (5 ml.) and N,N-diisopropylethylamine (0.13 ml_, 0.757 mmol) was added followed by 1 ,3-benzodioxole-5-sulfonyl chloride (100 mg, 0.454 mmol) at ambient temperature. After the reaction was judged complete by LCMS the mixture was diluted with water, the aqueous solution was extracted with dichloromethane, the organics were washed with saturated sodium bicarbonate solution, dried over sodium sulfate, filtered and concentrated under reduced pressure and purified by silica-gel chromatography (0- 100% ethyl acetate/ hexanes gradient elution) to give the title compound as a white solid (200 mg, 84%). ¹H NMR (400 MHz, CHLOROFORM-d) δ 0.83 - 0.92 (m, 6 H), 1.35 (s, 9 H), 1.73 - 1.91 (m, 1 H), 2.69 - 3.13 (m, 6 H), 3.58 - 3.77 (m, 1 H), 3.78 - 3.93 (m, 1 H), 4.52 - 4.68 (m, 1 H), 5.03 (s, 2 H), 6.05 (s, 2 H), 6.83-7.00 (m, 3 H),7.10 - 7.20 (m, 3 H), 7.39 (m, 6 H); LC/MS (m/z) ES⁺ = 651 (M+23).

[00236] (f) Preparation of N-((2R,3S)-3-Amino-2-hydroxy-4-{4-

[(phenylmethyl)oxy]phenyl}butyl) -di-N-(2-methylpropyl)-1,3-benzodioxole-5- sulfonamide

[00237] Trifluoroacetic acid (0.4 ml_, 5.19 mmol) was added to a solution of

1 , 1 -dimethylethyl [(1 S,2R)-3-[(1 ,3-benzodioxol-5-ylsulfonyl)(2-methylpropyl)amino]-2- hydroxy-1-({4-[(phenylmethyl)oxy]phenyl}methyl)propyl] -c/i-carbamate-c/i (284 mg, 0.452 mmol) in dichloromethane (5 ml.) at ambient temperature. The mixture was stirred 2 hours, concentrated under reduced pressure, diluted with dichloromethane and saturated sodium bicarbonate, extracted with dichloromethane, dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound. This material was used in the next step without further purification (239 mg, 100%). ¹H NMR (400 MHz, CHLOROFORM-d) δ 0.90 (m, 6 H), 1.75 -2.10 (m, 2 H), 2.32 - 2.60 (m, 1 H), 2.76 - 3.42 (m, 6 H), 5.03 (s, 2 H), 6.05 (s, 2 H), 6.73- 7.19 (m, 6 H), 7.24 - 7.64 (m, 6 H); LC/MS (m/z) ES⁺ = 529 (M+1 ). [00238] (g) Preparation of (3R,3aS,6aR)-Hexahydrofuro[2,3-b]furan-3-yl

[(1S,2R)-3-[(1,3-benzodioxol-5-ylsulfonyl)(2-methylpropyl)amino]-2-hydroxy-1-({4- [(phenylmethyl)oxy]phenyl}methyl)propyl] -drcarbamate

[00239] N-((2R,3S)-3-Amino-2-hydroxy-4-{4-[(phenylmethyl)oxy]phenyl}butyl)- c/₁-N-(2-methylpropyl)-1 ,3-benzodioxole-5-sulfonamide (243 mg, 0.461 mmol) was dissolved in acetonitrile (2 ml.) and N,N-diisopropylethylamine (0.32 ml_, 1.84 mmol) was added followed by (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl 4-nitrophenyl carbonate (212 mg, 1.56 mmol) and the mixture was heated at 50 ⁰C for several hours until the reaction was judged complete by LCMS. The mixture was concentrated under reduced pressure, diluted with ethyl acetate, the organics were washed with saturated sodium bicarbonate solution, dried over sodium sulfate, filtered and concentrated under reduced pressure. This material was purified by silica-gel chromatography (0-100% ethyl acetate/hexanes gradient elution) to give the title compound as a white foam (253 mg, 80%). ¹H NMR (400 MHz, CHLOROFORM-d) δ 0.78 - 0.99 (m, 6 H), 1.19 - 1.30 (m, 1 H), 2.66 - 3.21 (m, 7 H), 3.44 - 4.20 (m, 7 H), 4.82 - 4.94 (m, 1 H), 5.01 (s, 2 H), 5.58 - 5.71 (m, 1 H), 6.06 (s, 2 H), 6.84 - 6.96 (m, 3 H), 7.06 -7.19 (m, 3 H), 7.29 - 7.45 (m, 6 H); LC/MS (m/z) ES⁺ = 684 (M+1 ).

[00240] (h) Preparation of (3R,3aS,6aR)-Hexahydrofuro[2,3-b]furan-3-yl

(4S,5R)-5-{[(1,3-benzodioxol-5-ylsulfonyl)(2-methylpropyl)amino]methyl}-2,2-dimethyl- 4-({4-[(phenylmethyl)oxy]phenyl}methyl) -di-1,3-oxazolidine-3-carboxylate

[00241] (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl [(1 S,2R)-3-[(1 ,3- benzodioxol-5-ylsulfonyl)(2-methylpropyl)amino]-2-hydroxy-1-({4-

[(phenylmethyl)oxy]phenyl}methyl) propyls-carbamate (7 mg, 0.001 mmol), was dissolved in dichloromethane (1 ml.) and 2,2-dimethoxypropane (0.02 ml.) followed by p- toluenesulfonic acid (6 mg, 0.032 mmol) were added and the mixture was stirred at reflux for 2 hours. Dichloromethane and saturated sodium bicarbonate were added, the aqueous layer was extracted with dichloromethane, the organics were dried over sodium sulfate, filtered and concentrated under reduced pressure and the material was purified by silica-gel chromatography (0-100% ethyl acetate/hexanes) to give the title compound as a white solid (6 mg, 75%). LC/MS (m/z) ES⁺ = 725 (M+1 ).

[00242] (i) Preparation of (3R,3aS,6aR)-Hexahydrofuro[2,3-b]furan-3-yl

(4S,5R)-5-{[(1,3-benzodioxol-5-ylsulfonyl)(2-methylpropyl)amino]methyl}-4-[(4- hydroxyphenyi)methyi]-di-2,2-dimethyi-1,3-oxazoiidine-3-carboxyiate

[00243] (3R,3aS,6aR)-Hexahydrofuro[2,3-b]furan-3-yl (4S,5R)-5-{[(1 ,3- benzodioxol-5-ylsulfonyl)(2-methylpropyl)amino]methyl}-2,2-dimethyl-4-({4- [(phenylmethyl)oxy]phenyl}methyl)-c/.|-1 ,3-oxazolidine-3-carboxylat.e (218 mg, 0.301 mmol) was dissolved in 4 mL of a 1 :1 ethyl acetate: tetrahydrofuran solution and palladium on carbon (211 mg, degussa type, 50% water, 10 wt%) was added under nitrogen and the reaction was vigorously stirred under 1 atm hydrogen atmosphere until the reaction was judged complete by lcms. The mixture was filtered through a pad of celite, the filter was rinsed with ethyl acetate, and the filtrate was concentrated under reduced pressure to give the title compound as a white solid (200 mg, 100%). LC/MS (m/z) ES⁺ = 635 (M+1 ).

[00244] (j) Preparation of (3R,3aS,6aR)-Hexahydrofuro[2,3-b]furan-3-yl

{(1S,2R)-3-[(1,3-benzodioxol-5-ylsulfonyl)(2-methylpropyl)amino]-2-hydroxy-1-[(4-{[(2- methyl-1,3-thiazol-4-yl)methyl]oxy}phenyl)methyl]propyl}-d₁-carbamate

[00245] (3R,3aS,6aR)-Hexahydrofuro[2,3-b]furan-3-yl (4S,5R)-5-{[(1 ,3- benzodioxol-5-ylsulfonyl)(2-methylpropyl)amino]methyl}-4-[(4-hydroxyphenyl)methyl]-c/₁-2,2- dimethyl-1 ,3-oxazolidine-3-carboxylate (46 mg, 0.073 mmol) was dissolved in N, N- dimethylformamide (2 ml.) and cesium carbonate (95 mg, 0.29 mmol) and 4-(chloromethyl)- 2-methyl-1 ,3-thiazole HCI (36 mg, 0.193 mmol) were added and the mixture was heated to 70 C overnight. The reaction was cooled to ambient temperature, diluted with water, the aqueous layer was extracted with ethyl acetate, the organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. This material was used in the next step without further purification.

[00246] The material prepared as described above was dissolved in dioxane (2 ml.) and treated with 4 N hydrogen chloride in dioxane (2 ml.) and water (0.5 ml_). The mixture was stirred at ambient temperature for several hours. Additional 4 N hydrogen chloride in dioxane (2 ml.) and water (0.5 ml.) were added and the reaction was continued for 16 hours. The mixture was concentrated under reduced pressure, diluted with ethyl acetate, the organics were washed with saturated sodium bicarbonate solution, dried over sodium sulfate, filtered and concentrated under reduced pressure. This material was purified by reverse phase hplc to give the title compound as a white solid (34 mg, 67%). ¹H NMR (400 MHz, CHLOROFORM-d) δ 0.89 (m, 6 H), 1.14 -1.35 (m, 1 H), 1.44 - 1.94 (m, 3 H), 2.61 - 3.33 (m, 9 H), 3.59 - 4.05 (m, 5 H), 4.95 -5.06 (m, 2 H), 5.14 (s, 2 H), 5.56 - 5.70 (m, 1 H), 6.06 (s, 2 H), 6.55-6.75 (br s, 2 H), 6.80-6.95 (m, 3 H), 7.05-7.20 (m, 3 H), 7.34 (m, 1 H); LC/MS (m/z) ES⁺ = 706 (M+1 ).

[00247] Example 2

[00248] (3R,3aS,6aR)-Hexahydrofuro[2,3-b]furan-3-yl {(1S,2R)-3-[(1,3- benzodioxol-5-ylsulfonyl)(2-methylpropyl)amino]-2-hydroxy-d-1-[(4-{[(2-methyl-1,3- thiazol-4-yl)methyl-d₂-]oxy}phenyl)methyl]propyl}carbamate.

[00249] (a) Preparation of (2-Methyl-1,3-thiazol-4-yl)methanol-d₂.

[00250] To a -78 ⁰C solution of lithium aluminum deuteride (33.3 ml, 33.3 mmol) in tetrahydrofuran (39.7 ml) was slowly added ethyl 2-methyl-1 ,3-thiazole-4- carboxylate (10 g, 58.4 mmol) in tetrahydrofuran (43.7 ml). Following the addition, the mixture was allowed to warm to rt over a 2 h period. The reaction mixture was then quenched by the slow addition of 1.2 ml. H₂O followed by 10 min of stirring and then 1.2 ml_ 15% NaOH, followed by 10 min stirring and finally 3.6 ml. of H₂O. The resulting suspension was filtered through a pad of celite and concentrated to afford (2-methyl-1 ,3-thiazol-4- yl)methanol-c/₂ (5.05 g, 38.5 mmol, 65.9 % yield) as a yellow oil: ¹H NMR (400MHz ,CHLOROFORM-d) δ 2.72 (s, 3 H), 7.03 (s, 1 H).

[00251] (b) Preparation of 4-(Chloromethyl) -d^2-methyl-1,3-thiazole hydrochloride.

[00252] A solution of (2-methyl-1 ,3-thiazol-4-yl)methanol-of₂ (6.0 g, 45.7 mmol) in Dichloromethane (229 ml) was treated with thionyl chloride (9.98 ml, 137 mmol). After 30 min, the reaction mixture was concentrated in vacuo to afford 4-(Chloromethyl) -c/₂-2-methyl- 1 ,3-thiazole hydrochloride (8.26 g, 44.4 mmol, 97 % yield) as a brown solid: ¹H NMR (400MHz ,DMSOd₆) δ 2.65 (s, 3 H), 7.57 (s, 1 H).

[00253] (c) Preparation of (3R,3aS,6aR)-Hexahydrofuro[2,3-b]furan-3-yl

{(1S,2R)-3-[(1,3-benzodioxol-5-ylsulfonyl)(2-methylpropyl)amino]-2-hydroxy-1-[(4-{[(2- methyl-1,3-thiazol-4-yl)methyl]oxy}phenyl)methyl]propyl}carbamate-d₃

[00254] The title compound was prepared in a manner similar to that described in example 1 , step 10,from (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl (4S,5R)-5-{[(1 ,3- benzodioxol-5-ylsulfonyl)(2-methylpropyl)amino]methyl}-4-[(4-hydroxyphenyl)methyl]-c/₁-2,2- dimethyl-1 ,3-oxazolidine-3-carboxylate-c/i (52 mg, 0.082 mmol) and 4-(Chloromethyl) -c/₂-2- methyl-1 ,3-thiazole-c/₂.(42 mg, 0.226 mmol) as a white solid after reverse-phase hplc purification (38 mg, 66 %). ¹H NMR (400 MHz, CHLOROFORM-d) δ 0.89 (m, 6 H), 1.41 - 1.98 (m, 3 H), 2.62 - 3.22 (m, 10 H), 3.58 -4.06 (m, 5 H), 5.03 (m, 2 H), 5.64 (m, 1 H), 6.06 (s, 2 H), 6.53 - 6.79 (m, 2 H), 6.87-6.95 (m, 3 H), 7.05 -7.21 (m, 3 H), 7.32 (m, 1 H); LC/MS (m/z) ES⁺ = 708 (M+1 ).

[00255] Example 3 [00256] (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl {(1 S,2R)-3-[(1 ,3- benzodioxol-5-ylsulfonyl)-dr(2-methylpropyl)amino]-2-hydroxy-d-1-[(4-{[(2-methyl-1,3- thiazol-4-yl)methyl]oxy}phenyl)methyl]propyl}carbamate.

[00257] (a) 1,3-benzodioxole-d₂

[00258] A suspension of catechol (5.0 g, 45.4 mmol) and Cs₂CO₃ (22.19 g,

68.1 mmol) in N,N-Dimethylformamide (DMF) (108 ml) was treated with chloroiodomethane- d₂ (4.96 ml, 68.1 mmol). The resulting suspension was heated to 1 10 ⁰C. After 1 h, the reaction mixture was cooled to ambient temperature, filtered through a pad of celite and rinsed with diethyl ether. The filtrate was diluted with water and extracted with diethyl ether. The combined organic layers were washed with water, brine, dried (MgSO₄), filtered and concentrated in vacuo. The residue was then diluted with diethyl ether and the solids were filtered off. The filtrate was concentrated to afford 5.39g (96%) of a brown oil: ¹H NMR (400MHz, CHLOROFORM-d) δ = 6.84 (s, 5 H).

[00259] (b) 1,3-benzodioxole-d₂-5-sulfonyl chloride

[00260] A suspension of SO₃-DMF complex (7.51 g, 49.1 mmol) in 1 ,2-

Dichloroethane (DCE) (43.4 ml) was treated drop wise with a solution of 1 ,3-benzodioxole-d₂ (5.39 g, 43.4 mmol) in 1 ,2-Dichloroethane (43.4 ml) and heated to 75 ⁰C. After 18h, the reaction mixture was cooled to ambient temperature and treated drop wise with oxalyl chloride (4.15 ml, 49.1 mmol) and heated to 65 ⁰C. After 2h, the reaction mixture was quenched by the slow addition of water (5 ml_). The layers were partitioned and the combined organics were washed with water, brine, dried (Na₂SO₄), filtered and concentrated in vacuo. The residue was purified by silica-gel chromatography (0-30% EtOAc-hexanes) to afford 1 ,3-benzodioxole-c/₂-5-sulfonyl chloride- (4.86 g, 21.83 mmol, 50.3% yield) as a white solid: ¹HNMR(400MHz , CHLOROFORM-d) δ = 7.63 (dd, 1 H), 7.42 (d, J = 2.0 Hz, 1 H), 6.96 (d, J = 8.4 Hz, 1 H); LC/MS (m/z) ES⁺ = 203 ((M-CI)+OH).

[00261] (C) (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl {(1 S,2R)-3-[(1 ,3- benzodioxol-5-ylsulfonyl)-d₂-(2-methylpropyl)amino]-2-hydroxy-d-1-[(4-{[(2-methyl-1,3- thiazol-4-yl)methyl]oxy}phenyl)methyl] propyl}carbamate

[00262] The title compound was prepared in a similar manner to that described in example 1 , from 1 ,1-dimethylethyl [(1 S,2/?)-2-hydroxy-d-3-[(2-methylpropyl)amino]-1-({4- [(phenylmethyl)oxy]phenyl}methyl)propyl]carbamate, 1 ,3-benzodioxole-d₂-5-sulfonyl chloride, (3R,3aS,6aR)-hexahydrofuro[2,3-ιb]furan-3-yl 4-nitrophenyl carbonate, and 4-(chloromethyl)- 2-methyl-1 ,3-thiazole and was isolated as a white solid following reverse-phase purification: ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.92 (dd, J=16.58, 6.44 Hz, 6 H), 1.54 - 1.75 (m, 2 H), 1.76 - 1.91 (m, 1 H), 2.74 - 2.86 (m, 5 H), 2.90 - 3.05 (m, 4 H), 3.10 - 3.17 (m, 1 H), 3.69 - 3.77 (m, 2 H), 3.80 - 3.92 (m, 2 H), 3.98 (dd, J=9.37, 6.44 Hz, 1 H), 4.98 - 5.09 (m, 2 H), 5.16 (s, 2 H), 5.66 (d, J=5.27 Hz, 1 H), 6.91 (d, J=8.00 Hz, 3 H), 7.13 - 7.20 (m, 3 H), 7.24 (s, 1 H), 7.34 (dd, J=8.19, 1.37 Hz, 1 H); LC/MS (m/z) ES⁺ = 707 (M+1 ).

[00263] Example 4

[00264] (3R,3aS,6aR)-Hexahydrofuro[2,3-b]furan-3-yl-dr {(1S,2R)-3-[(1,3- benzodioxol-5-ylsulfonyl)(2-methylpropyl)amino]-2-hydroxy-1-[(4-{[(2-methyl-1,3- thiazol-4-yl)methyl]oxy}phenyl)methyl]propyl}-d₁-carbamate.

[00265] (a) 3-Bromo-2-(2-propyn-1-yloxy)tetrahydrofuran. [00266] A mixture of 2,3-dihydrofuran and propargyl alcohol in dichloromethane (20 ml.) was added drop wise to a suspension of N-bromosuccinimide in dichloromethane (50 ml.) at O C. The ice bath was allowed to expire and the reaction was stirred for 1 hour. Water was added, the aqueous layer was extracted with dichloromethane. The combined extracts were washed with saturated sodium thiosulfate solution, saturated sodium bicarbonate solution, dried over sodium sulfate, filtered and concentrated under reduced pressure to give a pale yellow oil contaminated with propargyl alcohol. ¹H NMR (400 MHz, CHLOROFORM-d) δ 2.12 - 2.29 (m, 1 H), 2.43 (m, 1 H), 2.63 (m, 1 H), 3.95-4.10 (m, 2 H), 4.13 - 4.38 (m, 3 H), 5.37 (s, 1 H).

[00267] (b) rac-(3aS, 6aR)-3-methylidenehexahydrofuro[2,3-b]furan.

[00268] AIBN (121 mg, 0.735 mmol) and tributyltin hydride (27 g, 93 mmol) were dissolved in toluene (2OmL) and heated to 104 C. A solution of 3-Bromo-2-(2-propyn- 1-yloxy)tetrahydrofuran (15.07 g, 73.5 mmol) in toluene (20 ml.) was added slowly and the reaction was heated at 108 C for 4 hours. The mixture was concentrated under reduced pressure, diluted with acetonitrile and concentrated again, and the oil was purified by silica- gel chromatography to give a clear oil (7.23 g, 78%). ¹H NMR (400 MHz, CHLOROFORM-d) δ 1.91 (m, 1 H), 2.17 (m, 1 H), 3.27 (m, 1 H), 3.69 - 4.01 (m, 2 H), 4.31 - 4.62 (m, 2H), 5.04 (m, 2 H), 5.79 (m , 1 H).

[00269] (c) rac-(3aR,6aR)-tetrahydrofuro[2,3-b]furan-3(2H)-one.

[00270] rac-(3aS,6aR)-3-methylidenehexahydrofuro[2,3-b]furan (2.21 g, 17.52 mmol) was dissolved in a 1 :1 mixture of methanol and dichloromethane (24 ml.) and cooled to -78 C. A stream of ozone was purged through the reaction mixture until the reaction consumed starting material by TLC (8:2 hexanes: ethyl acetate, KMnO₄ stain). Dimethyl sulfide was added slowly and the reaction was allowed to warm to ambient temperature, stirred for 15 minutes, and the mixture was concentrated under reduced pressure. This material was used in subsequent steps without further purification. ¹H NMR (400 MHz, CHLOROFORM-d) δ 2.10 - 2.31 (m, 1 H), 2.90 -3.02 (m, 1 H), 3.28 - 3.50 (m, 1 H), 3.68 - 3.85 (m, 1 H), 3.91 - 4.08 (m, 1 H), 4.13 (s, 2H), 5.94 - 6.11 (m, 1 H).

[00271] (d) rac-βRJaSrfaRJ-hexahydrofurofoS-blfuranS-ol-d_L

[00272] rac-(3aR,6aR)-Tetrahydrofuro[2,3-b]furan-3(2H)-one (2.97 g, 23.18 mmol) was dissolved in ethanol (20 ml.) and the solution was cooled to 0 C. Sodium borodeuteride (1.18 g, 35 mmol) was added portion wise and stirred until the reaction was complete by TLC (1 :1 hexanes: ethyl acetate, KMnO4 stain). The reaction was quenched with ammonium chloride (6 mL), partially concentrated under reduced pressure, and the aqueous layer was extracted with ethyl acetate (x3), dichloromethane (x3), the combined organics were dried over sodium sulfate and concentrated under reduced pressure. The aqueous layer was evaporated, a 3:1 mixture of acetonitrile: ethanol was added and the resulting suspension was vigorously stirred, filtered through a fritted funnel, and concentrated under reduced pressure. This residue was dissolved in ethyl acetate, dried over sodium sulfate, and combined with the organic extracts to give a colorless oil (2.42 g, 80%). ¹H NMR (400 MHz, CHLOROFORM-d) δ 1.79 (m, 1 H), 2.15 -2.32 (m, 1 H), 2.70 - 2.90 (m, 1 H), 3.52 (m, 1 H), 3.70 - 4.14 (m, 3 H), 5.60 (m, 1 H).

[00273] (e) rac-(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl acetate-di.

[00274] rac-(3R,3aS,6aR)-Hexahydrofuro[2,3-b]furan-3-ol-di (1.71 g, 13.04 mmol), sodium carbonate (3.45 g, 32.6 mmol), and DMAP (16 mg, 0.13 mmol) were combined in tetrahydrofuran (25 mL) and this mixture was cooled to 0 C. Acetic anhydride (1.85 mL, 19.56 mmol) was added drop wise and the reaction was allowed to warm to ambient temperature and stirred until complete by TLC (1 :1 ethyl acetate: hexanes, KMnO4 stain). Dichloromethane was added and the mixture was filtered, the filter was washed with dichloromethane, and the filtrate was collected and washed with 1 N HCI, dried over sodium sulfate and concentrated under reduced pressure to give a colorless oil (2.26 g, 100%). ¹H NMR (400 MHz, CHLOROFORM-d) δ 1.80-2.07 (m, 5 H), 2.93 - 3.12 (m, 1 H), 3.57 -4.15 (m, 4 H), 5.69 (m, 1 H). [00275] (f) (3R,3aS,6aR)-Hexahydrofuro[2,3-b]furan-3-yl acetate-d^

[00276] rac-(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl acetate-c/i (0.821 g,

4.74 mmol) was dissolved in a 0.1 N NaH₂PO₄ solution (2.5 ml.) and this mixture is adjusted to pH -5.0 by the addition of 1 N NaOH. Altus Biologies ChiroClec-PC (2 drops, 0.05 g/mL dry weight suspension) was added and the reaction was heated to 40 C. The pH of the mixture was kept between 4 and 5 with periodic addition of 1 N NaOH. The reaction was stirred for 24 hours at 40 C and then allowed to cool to ambient temperature, filtered through a fritted funnel, the filter was rinsed with water and dichloromethane, and the filtrate was extracted with dichloromethane. The combined organics were washed with water until no undesired alcohol was present by TLC (1 :1 hexanes: ethyl acetate, KMnO4 stain), dried over sodium sulfate and concentrated under reduced pressure and purified by silica-gel chromatography (0-100 % ethyl acetate/ hexanes gradient elution) to give a colorless oil (0.322 g, 39 %). ¹H NMR (400 MHz, CHLOROFORM-d) δ 1.78 - 2.19 (m, 5 H), 2.93 - 3.15 (m, 1 H), 3.64 - 4.28 (m, 4 H), 5.71 (m, 1 H).

[00277] (g) (SRJaSJaRj-HexahydrofurofrS-blfuranS-ol-d_L

[00278] (3R,3aS,6aR)-Hexahydrofuro[2,3-b]furan-3-yl acetate-c/i (307 mg, 1.77 mmol) was dissolved in methanol (2 ml.) and potassium carbonate (245 mg, 1.77 mmol) was added and this suspension was stirred for 2 hours at ambient temperature, filtered, the filter was rinsed with ethyl acetate, and the filtrate was concentrated under reduced pressure to give the title compound as a colorless oil (230 mg, 99%). ¹H NMR (400 MHz, CHLOROFORM-d) δ 1.79 (m, 1 H), 2.20 -2.32 (m, 1 H), 2.75 - 2.90 (m, 1 H), 3.52 (m, 1 H), 3.70 - 4.14 (m, 3 H), 5.60 (m, 1 H).

[00279] (h) (βRJaS^aRJ-HexahydrofurofoS-blfuranS-yl-di- 4-nitrophenyl carbonate.

[00280] 4-Nitrophenylchloroformate (725 mg, 3.60 mmol) was added to a O C solution of (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol-c/i (236 mg, 1.80 mmol) and pyridine (0.29 ml_, 3.60 mmol) in dichloromethane (2 ml.) and the resulting mixture was stirred 1 hour at ambient temperature. The reaction was cooled to O C and additional pyridine (0.03 ml.) and 4 nitrophenylchloroformate (73 mg) were added and stirring was continued at ambient temperature for 12 hours. The reaction was diluted with water, the organic layer was washed with 1 N HCI, saturated sodium bicarbonate solution, and dried over sodium sulfate. Purification by silica-gel chromatography (0-100 % ethyl acetate/ hexanes) gave the title compound as a white solid (533 mg, 92%). ¹H NMR (400 MHz, CHLOROFORM-d) δ 1.82 - 2.48 (m, 2 H), 2.97 - 3.29 (m, 1 H), 3.79 - 4.46 (m, 4 H), 5.75 (m, 1 H), 7.30 - 7.52 (m, 2 H), 8.17 - 8.36 (m, 2H). [00281] (I) (βRJaSJaRj-HexahydrofurofrS-blfuranS-yl-di- {(1S,2R)-

3-[(1,3-benzodioxol-5-ylsulfonyl)(2-methylpropyl)amino]-2-hydroxy-1-[(4-{[(2-methyl- 1,3-thiazol-4-yl)methyl]oxy}phenyl)methyl]propyl}-d₁-carbamate.

[00282] The title compound was prepared in a manner similar to that described in example 1 from (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl-c/i- 4-nitrophenyl carbonate and 1 ,1-dimethylethyl [(1 S,2R)-2-hydroxy-3-[(2-methylpropyl)amino]-1-({4[(phenylmethyl)oxy] phenyl}methyl)propyl]-c/i-carbamate after purification by reverse-phase hplc. ¹H NMR (400 MHz, CHLOROFORM-d) δ 0.80-1.00 (m, 6 H), 1.42 -2.1 1 (m, 3 H), 2.60 - 3.23 (m, 9 H), 3.50-4.00 (m., 5 H), 4.89 - 5.03 (m, 1 H), 5.14 (s, 2 H), 5.64 (m, 1 H), 6.07 (s, 2 H), 6.81 - 6.95 (m, 3 H), 7.07 - 7.18 (m, 3 H), 7.22 (s, 1 H), 7.28 - 7.36 (m, 1 H); HRMS cacld for 706.2437 (M+H); found 706.2440.

[00283] Example 5

[00284] (βRJaSJaRt-HexahydrofuroPJ-blfuranS-yl-di- {(1 S,2R)-3-[(1 ,3- benzodioxol-5-ylsulfonyl)-d₂-(2-methylpropyl)amino]-2-hydroxy-1-[(4-{[(2-methyl-1,3- thiazol-4-yl)methyl-d₂]oxy}phenyl)methyl]propyl}carbamate.

[00285] The title compound was prepared in a manner similar to that described in example 1 as a white solid from (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl-c/i- 4- nitrophenyl carbonate, 4-(chloromethyl) -c/₂-2-methyl-1 ,3-thiazole hydrochloride, 1 ,3- benzodioxole-c/₂-5-sulfonyl chloride, and 1 ,1-dimethylethyl[(1S,2R)-2-hydroxy-3-[(2- methylpropyl)amino]-1-({4-[(phenylmethyl)oxy]phenyl}methyl)propyl]carbamate after purification by reverse-phase hplc. ¹H NMR (400 MHz, CHLOROFORM-d) δ 0.80-1.00 (m, 6 H), 1.42 -2.1 1 (m, 3 H), 2.60 - 3.23 (m, 10 H), 3.50-4.00 (m., 5 H), 4.89 - 5.03 (m, 1 H), 5.64 (m, 1 H), 6.81 - 6.95 (m, 3 H), 7.07 - 7.18 (m, 3 H), 7.22 (s, 1 H), 7.28 - 7.36 (m, 1 H); HRMS cacld for 709.2625 (M+H); found 709.2624.

[00286] Example 6

[00287] (SRJaSrfaRj-HexahydrofuroPJ-bJfuranS-yl-dr {(1S,2R)-3-[(1,3- benzodioxol-5-ylsulfonyl)-d₂-(2-methylpropyl)amino]-2-hydroxy-1-[(4-{[(2-methyl-1,3- thiazol-4-yl)methyl]oxy}phenyl)methyl]propyl}carbamate.

[00288] The title compound was prepared in a manner similar to that described in example 1 as a white solid from (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl-c/₁- 4- nitrophenyl carbonate), 1 ,3-benzodioxole-c/₂-5-sulfonyl chloride, and 1 ,1-dimethylethyl [(1S,2R)-2-hydroxy-3-[(2-methylpropyl)amino]-1-({4-[(phenylmethyl)oxy] phenyl}methyl)propyl] carbamate after purification by reverse-phase hplc. ¹H NMR (400 MHz, CHLOROFORM-d) δ 0.80-1.00 (m, 6 H), 1.42 -2.11 (m, 3 H), 2.60 - 3.23 (m, 10 H), 3.50-4.00 (m., 5 H), 4.89 - 5.03 (m, 1 H), 5.13 (s, 2 H), 5.64 (m, 1 H), 6.81 - 6.95 (m, 3 H), 7.07 - 7.18 (m, 3 H), 7.22 (s, 1 H), 7.28 - 7.36 (m, 1 H); HRMS cacld for 707.2500 (M+H); found 707.2494.

[00289] Example 7

[00290] (3R,3aS,6aR)-Hexahydrofuro[2,3-b]furan-3-yl-dr {(1S,2R)-3-[(1,3- benzodioxol-5-ylsulfonyl)(2-methylpropyl)amino]-2-hydroxy-1-[(4-{[(2-methyl-1,3- thiazol-4-yl)methyl-d₂-]oxy}phenyl)methyl]propyl}-d₁-carbamate.

[00291] The title compound was prepared in a manner similar to that described in example 1 as a white solid from (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl-c/i- 4- nitrophenyl carbonate, 4-(chloromethyl)-c/₂-2-methyl-1 ,3-thiazole hydrochloride, and 1 ,1- dimethylethyl [(1S,2R)-2-hydroxy-3-[(2-methylpropyl)amino]-1-({4[(phenylmethyl) oxy] phenyl}methyl)propyl]-c/i-carbamate after purification by reverse-phase hplc. ¹H NMR (400 MHz, CHLOROFORM-d) δ 0.80-1.00 (m, 6 H), 1.42 -2.1 1 (m, 3 H), 2.60 - 3.23 (m, 9 H), 3.50-4.00 (m., 5 H), 4.89 - 5.03 (m, 1 H), 5.64 (m, 1 H), 6.07 (s, 2 H), 6.81 - 6.95 (m, 3 H), 7.07 - 7.18 (m, 3 H), 7.22 (s, 1 H), 7.28 - 7.36 (m, 1 H); HRMS cacld for 708.2563 (M+H); found 708.2560. [00292] Example 8

[00293] (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl {(1S,2R)-3-[(1,3- benzodioxol -5-ylsulfonyl) -d₂ -(2-methylpropyl)amino]-2-hydroxy-1-[(4-{[(2-methyl-1,3- thiazol-4-yl)methyl]oxy}phenyl)methyl]propyl}carbamate.

[00294] The title compound was prepared in a manner similar to that described in example 1 from 1 ,1-dimethylethyl [(1 S,2R)-2-hydroxy-3-[(2-methylpropyl)amino]-1-({4- [(phenylmethyl)oxy]phenyl}methyl)propyl]carbamate, 1 ,3-benzodioxole-5-sulfonyl chloride-c/₂, (3R,3aS,6aR)-hexahydrofuro[2,3-6]furan-3-yl 4-nitrophenyl carbonate and 4-(chloromethyl)- 2-methyl-1 ,3-thiazole and was isolated as a white solid after reverse-phase hplc purification. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.90 (d, J=6.6 Hz, 3 H), 0.95 (d, J=6.5 Hz, 3 H), 1.50 - 1.93 (m, 3 H), 2.67 - 2.88 (m, 5 H), 2.91 - 3.03 (m, 4 H), 3.09 - 3.24 (m, 1 H), 3.61 - 3.80 (m, 2 H), 3.80 - 3.94 (m, 3 H), 3.97 - 4.01 (m, 1 H), 4.94 - 4.96 (m, 1 H), 5.00 - 5.09 (m, 1 H), 5.17 (s, 2 H), 5.67 (d, J=5.1 Hz, 1 H), 6.91 (d, J=8.4 Hz, 3 H), 7.09 - 7.22 (m, 3 H), 7.24 (s, 1 H), 7.31 - 7.39 (m, 1 H); LC/MS (m/z) ES⁺ = 706 (M + 1 ).

[00295] Example 9

[00296] (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl {(1S,2R)-3-[(1,3- benzodioxol-5-ylsulfonyl) -d₂-(2-methylpropyl)amino]-2-hydroxy-1 -[(4-{[(2-methyl-1 ,3- thiazol-4-yl) -d₂-methyl]oxy}phenyl)methyl]propyl}carbamate.

[00297] The title compound was prepared in a manner similar to that described in example 1 from 1 ,1-dimethylethyl [(1 S,2R)-2-hydroxy-3-[(2-methylpropyl)amino]-1-({4- [(phenylmethyl)oxy]phenyl}methyl)propyl]carbamate, 1 ,3-benzodioxole-5-sulfonyl chloride-c/₂, (3R,3aS,6aR)-hexahydrofuro[2,3-6]furan-3-yl 4-nitrophenyl carbonate and 4-(chloromethyl)- 2-methyl-1 ,3-thiazole-c/₂ and was isolated as a white solid after reverse-phase hplc purification. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.90 (d, J=6.6 Hz, 3 H), 0.95 (d, J=6.4 Hz, 3 H), 1.56 - 1.88 (m, 3 H), 2.76 - 2.83 (m, 5 H), 2.91 - 3.03 (m, 4 H), 3.12 - 3.18 (m, 1 H), 3.63 - 3.79 (m, 2 H), 3.79 - 3.92 (m, 3 H), 3.94 - 4.05 (m, 1 H), 4.92 (d, J=9.0 Hz, 1 H), 5.02 - 5.07 (m, 1 H), 5.67 (d, J=5.1 Hz, 1 H), 6.90 - 6.93 (m, 3 H), 7.10 - 7.23 (m, 4 H), 7.33 - 7.36 (m, 1 H); LC/MS (m/z) ES⁺ = 708 (M + 1 ).

[00298] Example 10

[00299] (βRJaSJaRt-HexahydrofuroPJ-blfuranS-yl-di- {(1 S,2R)-3-[(1 ,3- benzodioxol-5-ylsulfonyl)(2-methylpropyl)amino]-2-hydroxy-1-[(4-{[(2-methyl-1,3- thiazol-4-yl)methyl]oxy}phenyl)methyl]propyl}carbamate.

[00300] The title compound was prepared in a manner similar to that described in example 1 as a white solid from (SR^aS^aR^hexahydrofuro^S-bJfuran-S-yl-c/_!- 4- nitrophenyl carbonate and 1 ,1-dimethylethyl [(1S,2R)-2-hydroxy-3-[(2-methylpropyl)amino]-1- ({4-[(phenylmethyl)oxy]phenyl}methyl)propyl] carbamate after purification by reverse-phase hplc. ¹H NMR (400 MHz, CHLOROFORM-d) δ 0.80-1.00 (m, 6 H), 1.42 -2.1 1 (m, 3 H), 2.60 - 3.23 (m, 10 H), 3.50-4.00 (m., 5 H), 4.89 - 5.03 (m, 1 H), 5.12 (s, 2 H), 5.64 (m, 1 H), 6.07 (s, 2 H), 6.81 - 6.95 (m, 3 H), 7.07 - 7.20 (m, 4 H), 7.28 - 7.36 (m, 1 H); HRMS cacld for 705.2374 (M+H); found 705.2370.

[00301] Example 11

[00302] (SRJaSrfaRj-HexahydrofuroPJ-bJfuranS-yl-dr {(1S,2R)-3-[(1,3- benzodioxol-5-ylsulfonyl)(2-methylpropyl)amino]-2-hydroxy-1-[(4-{[(2-methyl-1,3- thiazol-4-yl)methyl-dJoxy}phenyl)methyl]propyl}carbamate.

[00303] The title compound was prepared in a manner similar to that described in example 1 as a white solid from (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl-c/"r 4- nitrophenyl carbonate, 4-(chloromethyl)-d₂-2-methyl-1 ,3-thiazole hydrochloride, and 1 ,1- dimethylethyl[(1 S,2R)-2-hydroxy-3-[(2-methylpropyl)amino]-1-({4-

[(phenylmethyl)oxy]phenyl}methyl)propyl] carbamate after purification by reverse-phase hplc. ¹H NMR (400 MHz, CHLOROFORM-d) δ 0.80-1.00 (m, 6 H), 1.42 -2.11 (m, 3 H), 2.60 - 3.23 (m, 10 H), 3.50-4.00 (m., 5 H), 4.89 - 5.03 (m, 1 H), 5.64 (m, 1 H), 6.07 (s, 2 H), 6.81 - 6.95 (m, 3 H), 7.07 - 7.20 (m, 4 H), 7.28 - 7.36 (m, 1 H); HRMS cacld for 707.2500 (M+H); found 707.2495.

[00304] Example 12

[00305] (3R,3aS,6aR)-Hexahydrofuro[2,3-b]furan-3-yl-d₂- {(1 S,2R)-3-[(1 ,3- benzodioxol-5-ylsulfonyl)(2-methylpropyl)amino]-2-hydroxy-1-[(4-{[(2-methyl-1,3- thiazol-4-yl)methyl]oxy}phenyl)methyl]propyl-d₁}carbamate.

[00306] (a) 2-Propyn-1-ol-d₂.

[00307] Lithium aluminum deuteride (64.2 ml_, 1 M in diethyl ether) was suspended in tetrahydrofuran (150 ml.) and cooled to -78 C. A solution of methylpropiolate (10.58 ml_, 1 19 mmol) in tetrahydrofuran (20 ml.) was added drop wise using a syringe pump over 1 Vi hours. After the addition was complete, the mixture was stirred 30 minutes at -78 C, then allowed to warm to ambient temperature and stirred 10 minutes. The reaction was cooled to 0 C and water (2.7 ml_), 1 N NaOH (2.7 ml_), and water (2.7 ml.) were added successively and the suspension was stirred for 30 minutes at ambient temperature, filtered through a pad of celite, the filter pad was rinsed with diethyl ether, and the filtrate was concentrated under reduced pressure in the absence of a heating bath to give a yellow oil (3.76 g, 54%). ¹H NMR (400 MHz, CHLOROFORM-d) δ 2.43 (s, 1 H).

[00308] (b) 3-Bromo-2-(2-propyn-1-yloxy) -d₂-tetrahydrofuran.

[00309] N-Bromosuccinimide (2.80 g, 15.75 mmol) was dissolved in dichloromethane and cooled to O C. A mixture of 2,3 dihydrofuran (1.135 ml, 15 mmol) and 2-propyn-1-ol-c/₂ (1.474 ml, 23.76 mmol) was added drop wise. The reaction was stirred over 1 hour letting ice bath expire. The mixture was diluted with water and dichloromethane, the organic layer was washed with water, sodium thiosulfate solution, sodium bicarbonate solution, dried over sodium sulfate, and concentrated under reduced pressure to give a yellow oil (3.2 g) that was used in subsequent steps without further purification. ¹H NMR (400 MHz, CHLOROFORM-d) δ 2.12 - 2.29 (m, 1 H), 2.43 (m, 1 H), 2.63 (m, 1 H), 4.13 - 4.38 (m, 3 H), 5.37 (s, 1 H).

[00310] (c) rac-(3aS,6aR)-3-Methylidenehexahydrofuro[2,3-b]furan-d₂.

[00311] Tributyltin hydride (15.74 ml_, 59.4 mmol) and AIBN (0.077 g, 0.471 mmol) were combined in toluene (20 ml.) and heated to 104 C. A solution of 3-bromo-2-(2- propyn-1-yloxy) -c/₂-tetrahydrofuran in toluene (1 OmL) and the reaction was heated at 104 C for 4 hours. The solution was concentrated under reduced pressure, diluted with acetonitrile, concentrated again, and purified by silica-gel chromatography (0-100% EtOAc/hexanes) to give a clear oil (3.03 g, 50%). ¹H NMR (400 MHz, CHLOROFORM-d) δ 1.8-2.2 (m, 2 H), 3.3 (br s, 1 H), 4.9-5.1 (m, 2 H), 5.77 (m, 1 H).

[00312] (d) rac-(3aR, 6aR)- Tetrahydrofuro[2,3-b]furan-3(2H)-one-d₂.

[00313] rac-(3aS,6aR)-3- Methylidenehexahydrofuro[2,3-b]furan-c/₂ (2.52 g,

19.66 mmol) was dissolved in methanol (10 ml.) and dichloromethane (10 ml.) and cooled to -78 C. Ozone was bubbled through the reaction mixture until a blue color persisted and TLC (8:2 hexanes: ethyl acetate) showed consumption of starting material. Dimethylsulfide was added slowly at -78 C and the mixture was allowed to warm to ambient temperature and concentrated under reduced pressure to give a colorless oil (3.16 g). This material was carried on without further purification. ¹H NMR (400 MHz, CHLOROFORM-d) δ 2.10 - 2.31 (m, 1 H), 2.90 -3.02 (m, 1 H), 3.28 - 3.50 (m, 1 H), 3.68 - 3.85 (m, 1 H), 3.91 - 4.08 (m, 1 H), 5.94 - 6.1 1 (m, 1 H).

[00314] (e) rac-(3R,3aS,6aR)-Hexahydrofuro[2,3-b]furan-3-yl acetate-d₂.

[00315] Lithium aluminum hydride (2.25mL, 1 M in tetrahydrofuran) was added drop wise to a solution of rac-(3aR,6aR)-tetrahydrofuro[2,3-b]furan-3(2H)-one-c/₂-(0.650 g, 4.99 mmol) in dichloromethane (3 mL) at 0 C. After the addition was complete, the mixture was stirred 20 minutes and then quenched slowly with water (0.37 mL). 1 N Sodium hydroxide (0.37 mL) and water (0.37 mL) were added successively and the suspension was stirred 10 minutes and filtered through a pad of celite. The filter pad was washed with ethyl acetate and the filtrate was concentrated under reduced pressure to give a colorless oil.

[00316] The oil obtained above was dissolved in tetrahydrofuran and cooled to

0 C. Sodium carbonate (1.32 g, 12.49 mmol) and DMAP (6 mg, 0.05 mmol) were added, followed by the drop wise addition of acetic anhydride (0.71 mL, 7.49 mmol). This mixture was stirred 2 hours at ambient temperature and filtered. The filtrate was diluted with dichloromethane and the organics were washed with 1 N HCI and dried over sodium sulfate. Purification by silica-gel chromatography (0-100% ethyl acetate/hexanes) gave the title compound as a colorless oil (0.331 g, 38 % 2 steps). ¹H NMR (400 MHz, CHLOROFORM-d) δ 1.80 - 2.04 (m, 2 H), 2.06 - 2.12 (m, 3 H), 2.96 - 3.17 (m,1 H), 3.74 - 4.15 (m, 2 H), 5.04 - 5.33 (m, 1 H), 5.62 - 5.84 (m, 1 H). [00317] (f) (3R,3aS,6aR)-Hexahydrofuro[2,3-b]furan-3-yl acetate-d₂.

[00318] rac-(3R,3aS,6aR)-Hexahydrofuro[2,3-b]furan-3-yl acetate-c/₂ (330 mg,

1.89 mmol) was dissolved in a 0.1 N NaH₂PO₄ solution (1 ml.) and this mixture was adjusted to pH -5.0 by the addition of 1 N NaOH. Altus Biologies ChiroClec-PC (2 drops, 0.05 g/mL dry weight suspension) was added and the reaction was heated to 40 C. The pH of the mixture was kept between 4 and 5 with periodic addition of 1 N NaOH. The reaction was stirred for 24 hours at 40 C and then allowed to cool to ambient temperature, filtered through a fritted funnel, the filter was rinsed with water and dichloromethane, and the filtrate was extracted with dichloromethane. The combined organics were washed with water until no undesired alcohol was present by TLC (1 :1 hexanes: ethyl acetate, KMnO4 stain), dried over sodium sulfate and concentrated under reduced pressure and purified by silica-gel chromatography (0-100 % ethyl acetate/ hexanes gradient elution) to give a colorless oil (1 11 mg, 33 %). ¹H NMR (400 MHz, CHLOROFORM-d) δ 1.80 - 2.04 (m, 2 H), 2.06 - 2.12 (m, 3 H), 2.96 - 3.17 (m,1 H), 3.74 - 4.15 (m, 2 H), 5.04 - 5.33 (m, 1 H), 5.62 - 5.84 (m, 1 H).

[00319] (g) (3R,3aS,6aR)-Hexahydrofuro[2,3-b]furan-3-ol-d₂.

[00320] (3R,3aS,6aR)-Hexahydrofuro[2,3-b]furan-3-yl acetate-c/₂ (111 mg,

0.637 mmol) was dissolved in methanol (5 ml.) and potassium carbonate (100 mg, 0.724 mmol) was added and this suspension was stirred at ambient temperature for 12 hours. The reaction was filtered, and the filtrate was concentrated under reduced pressure to give a colorless oil (84 mg, 100%). ¹H NMR (400 MHz, CHLOROFORM-d) δ 1.75-2.01 (m, 2 H), 2.19-2.38 (m, 1 H), 2.73-2.99 (m, 1 H), 3.80-4.09 (m, 2 H), 5.60-5.72 (m, 1 H).

[00321] (h) (3R,3aS,6aR)-Hexahydrofuro[2,3-b]furan-3-yl-d₂- 4-nitrophenyl carbonate.

[00322] (3R,3aS,6aR)-Hexahydrofuro[2,3-b]furan-3-ol-c/₂ was dissolved in dichloromethane and cooled to 0 C and pyridine was added followed by 4- nitrophenylchloroformate. The reaction was allowed to stir at ambient temperature overnight. Water was added and the organic layer was washed in 1 N HCI, sodium bicarbonate solution and dried over sodium sulfate. Purification by silica-gel chromatography (0-100 % ethyl acetate/ hexanes) gave the title compound as a white solid (133 mg, 71%). ¹H NMR (400 MHz, CHLOROFORM-d) δ 1.88 - 2.32 (m, 2 H), 2.99 -3.27 (m, 1 H), 3.85 - 4.32 (m, 2 H), 5.18 - 5.29 (m, 1 H), 5.76 (m, 1 H), 7.38 (m, 2 H), 8.18 - 8.37 (m, 2 H).

[00323] (i) (3R,3aS,6aR)-Hexahydrofuro[2,3-b]furan-3-yl-d2- {(1S,2R)-3-

[(1,3-benzodioxol-5-ylsulfonyl)(2-methylpropyl)amino]-2-hydroxy-1-[(4-{[(2-methyl-1,3- thiazol-4-yl)methyl]oxy}phenyl)methyl]propyl-d₁}carbamate.

[00324] The title compound was prepared in a manner similar to that described in example 1 as a white solid from (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl-c/₂- 4- nitrophenyl carbonate and 1 ,1-dimethylethyl[(1S,2R)-2-hydroxy-3-[(2-methylpropyl)amino]-1- ^[(phenylmethyOoxylphenylJmethyOpropyO-c/i-carbamate after purification by reverse-phase hplc. ¹H NMR (400 MHz, CHLOROFORM-d) δ 0.80-1.00 (m, 6 H), 1.42 -2.1 1 (m, 3 H), 2.60 - 3.23 (m, 9H), 3.63-4.02 (m., 3 H), 4.89 - 5.07 (m, 2 H), 5.14 (s, 2 H), 5.64 (m, 1 H), 6.07 (s, 2 H), 6.81 - 6.95 (m, 3 H), 7.07 - 7.18 (m, 3H), 7.22 (s, 1 H), 7.28 - 7.36 (m, 1 H); HRMS cacld for 707.2500 (M+H); found 707.2499.

[00325] Example 13

[00326] (3R,3aS,6aR)-Hexahydrofuro[2,3-b]furan-3-yl-d₂- {(1 S,2R)-3-[(1 ,3- benzodioxol-5-ylsulfonyl)(2-methylpropyl)amino]-2-hydroxy-1-[(4-{[(2-methyl-1,3- thiazol-4-yl)methyl-d₂]oxy}phenyl) me thyljpropyl-dj carbarn a te.

[00327] The title compound was prepared in a manner similar to that described in example 1 as a white solid from 4-(chloromethyl)-c/₂-2-methyl-1 ,3-thiazole hydrochloride, (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl-c/₂- 4-nitrophenyl carbonate, and 1 ,1- dimethylethyl[(1 S,2R)-2-hydroxy-3-[(2-methylpropyl)amino]-1 -

(^[(phenylmethyOoxyJphenylJmethyOpropylJ-c/i-carbamate after purification by reverse-phase hplc. ¹H NMR (400 MHz, CHLOROFORM-d) δ 0.80-1.00 (m, 6 H), 1.42 -2.1 1 (m, 3 H), 2.60 - 3.23 (m, 9H), 3.63-4.02 (m., 3 H), 4.89 - 5.07 (m, 2 H), 5.64 (m, 1 H), 6.07 (s, 2 H), 6.81 - 6.95 (m, 3 H), 7.07 - 7.18 (m, 3H), 7.22 (s, 1 H), 7.28 - 7.36 (m, 1 H); HRMS cacld for 709.2625 (M+H); found 709.2625.

[00328] Example 14

[00329] (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl {(1S,2R)-3-[(1,3- benzodioxol-5-ylsulfonyl)(2-methylpropyl) -d₂-amino]-2-hydroxy-1-[(4-{[(2-methyl-1,3- thiazol-4-yl)methyl]oxy}phenyl)methyl]propyl}carbamate.

[00330] (a) 1,1-dimethylethyl [(1 S)-2-hydroxy-1 -({4-

[(phenylmethyl)oxyjphenyl} methyl)ethyl]carbamate.

[00331] To a solution of lithium aluminum hydride (7.51 ml_, 7.51 mmol, 1 M solution in tetrahydrofuran) in tetrahydrofuran (7.5 ml.) was slowly added a solution of ethyl N-{[(1 ,1-dimethylethyl)oxy]carbonyl}-O-(phenylmethyl)-L-tyrosinate (2.00 g, 5.01 mmol) in tetrahydrofuran (10 ml_). After the addition, the mixture was warmed to ambient temperature and judged complete by TLC after 40 minutes (3:7 EtOAc/hexanes). The mixture was cooled to 0° C, water (285 μl_) was slowly added and the resultant was stirred for 5 minutes. Then 15% aq. NaOH (285 μl_) was slowly added and the mixture was stirred for 5 minutes. Lastly, water (885 μL) was added and the suspension was diluted with ether (15 mL) and tetrahydrofuran (5 mL) and the cooling bath was removed. After vigorous stirring (10 minutes) the mixture was filtered over Celite and the filtrate was concentrated to give the title compound as a white solid (1.75 g, 98% yield). ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.43 (s, 9 H), 2.26 (m, 1 H), 2.79 (d, J=7.2 Hz, 2 H), 3.53 - 3.59 (m, 1 H), 3.63 - 3.72 (m, 1 H), 3.83 (m, 1 H), 4.70 (br. s., 1 H), 5.06 (s, 2 H), 6.85 - 6.97 (d, J=8.6 Hz, 2 H), 7.13 (d, J=8.6 Hz, 2 H), 7.30 - 7.48 (m, 5 H); LC/MS (m/z) ES⁺ = 380 (M + 23).

[00332] (b) 1,1-dimethylethyl ((1S)-1-formyl-2-{4-

[(phenylmethyl)oxy]phenyl} ethyl)carbamate.

[00333] To a solution of oxalyl chloride (0.367 mL, 4.20 mmol) in dichloromethane (20 mL) at -78° C was added drop wise Dimethyl sulfoxide (0.596 mL, 8.39 mmol) and the mixture was stirred at -78° C for 10 minutes. Next, a solution of 1 ,1- dimethylethyl [(1 S)-2-hydroxy-1 -({4-[(phenylmethyl)oxy]phenyl}methyl)ethyl]carbamate (1.000 g, 2.80 mmol) in dichloromethane (7 mL) was added slowly and the resultant was stirred for 20 minutes at -78° C before slow addition of triethylamine (1.170 mL, 8.39 mmol). The mixture was stirred for 30 minutes at -78° C (a clear solution) and then warmed to ambient temperature for 30 minutes after which time the mixture became a suspension. Saturated NaHCO₃ and brine were added and the layers were separated. The organic layer was washed with saturated NaHCO₃, then brine, dried over MgSO₄, filtered and concentrated to give the crude aldehyde as a white solid (0.92 g, 92% yield. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.45 (s, 9 H), 3.07 (d, J=6.4 Hz, 2 H), 4.38 - 4.43 (m, 1 H), 5.03 - 5.07 (m, 3 H), 6.93 (d, J=8.6 Hz, 2 H), 7.09 (d, J=8.6 Hz, 2 H), 7.30 - 7.46 (m, 5 H), 9.63 (s, 1 H).

[00334] (c) 1,1-dimethylethyl [(1S)-1-({4-

[(phenylmethyl)oxy]phenyl}methyl)-2-propen-1-yl]carbamate-d₂.

[00335] A suspension of potassium terf-butoxide (628 mg, 5.60 mmol) in diethyl ether (30 mL) was treated with methyl-c/₃-triphenylphosphonium bromide (2017 mg, 5.60 mmol) and heated to reflux for 2 hours to give a yellow solution. The mixture was cooled to ambient temperature and a solution of 1 , 1 -dimethylethyl ((1S)-1-formyl-2-{4- [(phenylmethyl)oxy]phenyl}ethyl)carbamate (995 mg, 2.8 mmol) in diethyl ether (15 ml.) and tetrahydrofuran (5 ml.) (for solubility) was added. TLC after additions end indicated consumption of starting material and a new less polar spot was observed (1 :9 EA/hexanes). The mixture was stirred over 3 days, filtered over Celite to remove precipitate and the filtrate was concentrated. The residue was purified by silica gel chromatography (0-40% EtOAc/hexanes) to give the title compound as a white solid. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.42 (s, 9 H), 2.79 (d, J=6.2 Hz, 2 H), 4.33 - 4.50 (m, 2 H), 5.05 (s, 2 H), 5.78 (br. s., 1 H), 6.91 (d, J=8.6 Hz, 2 H), 7.10 (d, J=8.6 Hz, 2 H), 7.29 - 7.47 (m, 5 H).

[00336] (d) 1,1 -dimethylethyl [(1S,2S)-2-hydroxy-3-[(2- methylpropyl)amino]-1-({4-[(phenylmethyl)oxy]phenyl}methyl)propyl]carbamate-d₂.

[00337] A solution of 1 ,1 -dimethylethyl [(1S)-1-({4-

[(phenylmethyl)oxy]phenyl}methyl)-2-propen-1-yl]carbamate-c/2 (764 mg, 2.149 mmol) in dichloromethane (25 ml.) was treated with 3-chloroperoxybenzoic acid (2967 mg, 8.60 mmol) and stirred at ambient temperature. After 2 hours additional 3-chloroperoxybenzoic acid (500 mg) was added and the mixture was stirred overnight. The starting material was consumed by TLC (15:85 EtOAc/hexanes). The mixture was diluted with dichloromethane and then washed subsequently with cold 10% Na₂SO₃, saturated NaHCO₃ and brine, dried over Na₂SO₄, filtered and concentrated to give a pale yellow residue. 1 H NMR indicated this to be a mixture of desired product and 3-chloroperoxybenzoic acid. The crude epoxide containing mixture was suspended in isopropanol (12 mL), treated with isobutylamine (1.0 mL, 10.06 mmol) and heated to 65° C for one hour. The mixture was concentrated and purified by silica gel chromatography (0-50% dichloromethane/(80:19:1 , dichloromethane/methanol/ammonium hydroxide)) to give the title compound as a pale yellow oil (474 mg, 50% yield). LC/MS (m/z) ES⁺ = 445 (M + 1 ).

[00338] (e) 1,1-dimethylethyl [(1S,2S)-3-[(1,3-benzodioxol-5-ylsulfonyl)(2- methylpropyl)amino]-2-hydroxy-1-({4-[(phenylmethyl)oxy]phenyl}methyl) propyljcarbama te-d₂.

[00339] A solution of 1 ,1-dimethylethyl [(1S,2S)-2-hydroxy-3-[(2- methylpropyl)amino]-1-({4-[(phenylmethyl)oxy]phenyl}methyl)propyl]carbamate-d2 (474 mg, 1.066 mmol) and Hunig's base (0.372 mL, 2.132 mmol) in dichloromethane (10 mL) was treated with 1 ,3-benzodioxole-5-sulfonyl chloride (306 mg, 1.386 mmol). After 90 minutes, additional sulfonyl chloride (100 mg) was added. After 1 hour water was added and the mixture was extracted with dichloromethane. The extracts were washed with saturated NaHCO₃, dried over Na₂SO₄, filtered and concentrated. The residue was purified on silica gel (0-50% ethyl acetate/hexanes) to give the title compound as a white foam (358 mg, 53% yield). ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.80 - 0.84 (m, 6 H), 1.41 (s, 9 H), 1.55 - 1.66 (m, 1 H, coincidental with water), 2.59 - 2.73 (m, 1 H), 2.80 - 2.93 (m, 2 H), 2.94 - 3.00 (m, 1 H), 3.48 (m, 1 H), 3.56 - 3.68 (m, 1 H), 3.73 (m, 1 H), 4.91 - 5.00 (m, 1 H), 5.05 (s, 2 H), 6.08 (d, J=2.5 Hz, 2 H), 6.81 - 6.95 (m, 3 H), 7.09 - 7.20 (m, 3 H), 7.28 - 7.48 (m, 6 H); LC/MS {m/z) ES⁺ = 630 (M + 1 ).

[00340] (f) 1,1-dimethylethyl [(1S)-3-[(1,3-benzodioxol-5-ylsulfonyl)(2- methylpropyl)amino]-2-oxo-1-({4-[(phenylmethyl)oxy]phenyl}methyl) propyljcarbama te-d₂.

[00341] An ice cold mixture of 1 ,1-dimethylethyl [(1S,2S)-3-[(1 ,3-benzodioxol-

5-ylsulfonyl)(2-methylpropyl)amino]-2-hydroxy-1-({4-[(phenylmethyl)oxy]phenyl}methyl) propyl]carbamate-d2 (350 mg, 0.557 mmol) and sodium bicarbonate (234 mg, 2.78 mmol) in dichloromethane (15 ml.) was treated with Dess-Martin periodinane (354 mg, 0.835 mmol). The mixture was stirred for 2 hours until complete by TLC (3:7 ethyl acetate/hexanes). To the mixture was added 2M Na₂CO₃ (10 ml.) and saturated Na₂S₂O₃ (10 ml.) followed by solid Na₂S₂O₃ (1 g) and ethyl acetate (5 ml.) and the mixture was stirred until clear. The mixture was diluted with ethyl acetate and the organic layer was washed with saturated Na₂S₂O₃ and saturated NaHCO₃, dried over Na₂SO₄, filtered and concentrated to a white foam. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.82 - 0.84 (m, 6 H), 1.42 (m, 9 H), 2.73 - 3.02 (m, 3 H), 4.37 - 4.42 (m, 1 H), 4.95 (m, 1 H), 5.05 (s, 2 H), 6.07 (s, 2 H), 6.84 (d, J=8.2 Hz, 1 H), 6.94 (d, J=8.6 Hz, 2 H), 7.09 (d, J=8.6 Hz, 2 H), 7.19 (d, J=1.8 Hz, 1 H), 7.30 - 7.47 (m, 6 H); LC/MS (m/z) ES⁺ = 649 (M + 23).

[00342] (g) 1,1-dimethylethyl [(1S,2R)-3-[(1,3-benzodioxol-5-ylsulfonyl)(2- methylpropyl)amino]-2-hydroxy-1-({4-[(phenylmethyl)oxy]phenyl}methyl) propyljcarbama te-d₂-

[00343] A -78° C mixture of 1 ,1-dimethylethyl [(1S)-3-[(1 ,3-benzodioxol-5- ylsulfonyl)(2-methylpropyl)amino]-2-oxo-1-({4-[(phenylmethyl)oxy]phenyl}methyl)propyl] carbamate-d2 (305 mg, 0.487 mmol) in dichloromethane (10 mL) was treated by drop wise addition of L-selectride (1.217 mL, 1.217 mmol, 1 M solution in tetrahydrofuran). The mixture was stirred at -78° C for 10 minutes and then warmed to ambient temperature. The mixture was poured over ice, acidified to pH 2 with 1 N HCI and then extracted with ethyl acetate. The extracts were washed with brine, dried over Na₂SO₄, filtered and concentrated. The crude residue was purified by silica gel chromatography (0-50% ethyl acetate/hexanes) to give the title compound as a colorless residue in >10:1 d.r. (235 mg, 77% yield). ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.87 - 0.96 (m, 36 H), 1.37 (s, 9 H), 1.82 - 1.89 (m, 1 H), 2.80 - 3.09 (m, 4 H), 3.68 - 3.91 (m, 2 H), 4.6 (m, 1 H), 5.05 (s, 2 H), 6.08 (s, 2 H), 6.76 - 6.96 (m, 3 H), 7.12 - 7.22 (m, 3 H), 7.29 - 7.48 (m, 6 H); LC/MS (m/z) ES⁺ = 629 (M + 1 ). [00344] (h) (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl {(1 S,2R)-3-[(1 ,3- benzodioxol-5-ylsulfonyl)(2-methylpropyl) -d₂-amino]-2-hydroxy-1-[(4-{[(2-methyl-1,3- thiazol-4-yl)methyl]oxy}phenyl)methyl]propyl}carbamate.

[00345] The title compound was prepared in a manner similar to that described in example 1 from 1 ,1 -dimethylethyl [(1 S,2R)-3-[(1 ,3-benzodioxol-5-ylsulfonyl)(2- methylpropyl)amino]-2-hydroxy-1-({4-[(phenylmethyl)oxy]phenyl}methyl)propyl] carbamate- d₂, (3R,3aS,6aR)-hexahydrofuro[2,3-6]furan-3-yl 4-nitrophenyl carbonate and 4- (chloromethyl)-2-methyl-1 ,3-thiazole and was isolated as a white solid after reverse phase HPLC purification. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.90 (d, J=6.4 Hz, 3 H), 0.94 (d, J=6.4 Hz, 3 H), 1.44 - 1.90 (m, 3 H), 2.73 - 2.88 (m, 5 H), 2.88 - 3.07 (m, 3 H), 3.59 - 3.78 (m, 2 H), 3.79 - 3.93 (m, 3 H), 3.97 - 4.01 (m, 1 H), 4.87 - 5.10 (m, 2 H), 5.16 (s, 2 H), 5.67 (d, J=5.1 Hz, 1 H), 6.10 (s, 2 H), 6.87 - 6.95 (m, 3 H), 7.10 - 7.20 (m, 3 H), 7.23 (s, 1 H), 7.33 - 7.36 (m, 1 H); LC/MS (m/z) ES⁺ = 706 (M + 1 ).

[00346] Example 15

[00347] (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl {(1 S,2R)-3-[(1 ,3- benzodioxol-5-ylsulfonyl)(2-methylpropyl) -d₂ -amino]-2-hydroxy-1-[(4-{[(2-methyl-1,3- thiazol-4-yl) -d₂ -methyl]oxy}phenyl)methyl]propyl}carbamate.

[00348] The title compound was prepared in a manner similar to that described in example 1 from 1 ,1 -dimethylethyl [(1 S,2R)-3-[(1 ,3-benzodioxol-5-ylsulfonyl)(2- methylpropyl)amino]-2-hydroxy-1-({4-[(phenylmethyl)oxy]phenyl}methyl)propyl] carbamate- d₂, (3R,3aS,6aR)-hexahydrofuro[2,3-6]furan-3-yl 4-nitrophenyl carbonate and 4- (chloromethyl)-2-methyl-1 ,3-thiazole-c/₂ and was isolated as a white solid after RP-HPLC purification. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.90 (d, J=6.6 Hz, 3 H), 0.94 (d, J=6.6 Hz, 3 H), 1.47 - 1.91 (m, 3 H), 2.75 - 2.87 (m, 5 H), 2.89 - 3.07 (m, 3 H), 3.64 - 3.78 (m, 2 H), 3.81 - 3.92 (m, 3 H), 3.97 - 4.01 (m, 1 H), 4.87 - 5.11 (m, 2 H), 5.67 (d, J=5.1 Hz, 1 H), 6.10 (s, 2 H), 6.91 (m, 3 H), 7.1 1 - 7.21 (m, 3 H), 7.25 (s, 1 H), 7.33 - 7.36 (m, 1 H); LC/MS (m/z) ES⁺ = 708 (M + 1 ).

[00349] Example 16

[00350] (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-d₂-3-yl {(1 S,2R)-3-[(1 ,3- benzodioxol-d₂-5-ylsulfonyl)(2-methylpropyl)amino]-2-hydroxy-1-[(4-{[(2-methyl-1,3- thiazol-4-yl)methyl-d₂]oxy}phenyl)methyl]propyl}carbamate

[00351] The title compound was prepared in a manner similar to that described in example 1 from 1 ,1-dimethylethyl [(1S,2R)-2-hydroxy-3-[(2-methylpropyl)amino]-1-({4- [(phenylmethyl)oxy]phenyl}methyl)propyl]carbamate (prepared as reported in WO 2000076961 ), 1 ,3-benzodioxole-d₂-5-sulfonyl chloride, (3R,3aS,6aR)-hexahydrofuro[2,3- b]furan-d₂-3-yl 4-nitrophenyl carbonate, and 4-(chloromethyl-d₂)-2-methyl-1 ,3-thiazole and was isolated as a white solid after reverse-phase HPLC purification: ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.90 (d, J=6.44 Hz, 3 H), 0.94 (d, J=6.63 Hz, 3 H), 1.53 - 1.63 (m, 1 H), 1.68 (d, J=9.17 Hz, 1 H), 1.78 - 1.89 (m, 1 H), 2.84 (s, 5 H), 2.98 (dd, J=13.76, 9.27 Hz, 4 H), 3.11 - 3.19 (m, 1 H), 3.69 - 3.77 (m, 1 H), 3.86 (d, J=8.00 Hz, 3 H), 5.01 (dd, J=15.71 , 8.29 Hz, 2 H), 5.67 (d, J=5.07 Hz, 1 H), 6.91 (d, J=7.80 Hz, 3 H), 7.13 - 7.20 (m, 3 H), 7.27 (s, 1 H), 7.34 (dd, J=8.19, 1.37 Hz, 1 H); LC/MS (m/z) ES⁺ = 710 (M+1 ).

[00352] Example 17

[00353] Preparation of (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl

{(1S,2R)-3-[(1,3-benzodioxol-5-ylsulfonyl)(2-methylpropyl)amino]-2-hydroxy-1-[(4-{[(2- methyl-1,3-thiazol-4-yl)methyl]oxy}phenyl)methyl]propyl}-d₆-carbamate

[00354] (a) (3R,3aS,6aR)-Hexahydrofuro [2,3-b] furan-3-yl 4-nitrophenyl carbonate-</₃-

[00355] The title compound was prepared in a manner similar to that described in example 12e-h from rac-(3aR,6aR)-tetrahydrofuro[2,3-b]furan-3(2H)-one-d₂ (example 12d) using lithium aluminum deuteride in placed of lithium aluminum hydride. ¹H NMR (400 MHz, CHLOROFORM-d) δ 1.85 - 2.05 (m, 1 H), 2.06 - 2.28 (m, 1 H),2.97 - 3.30 (m, 1 H), 3.77 - 4.13 (m, 2 H), 5.72 (m, 1 H), 5.86 - 6.01 (m, 1 H),7.30 - 7.42 (m, 2 H), 8.16 - 8.31 (m, 2 H). [00356] (b) (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl {(1 S,2R)-3-[(1 ,3- benzodioxol-5-ylsulfonyl)(2-methylpropyl)amino]-2-hydroxy-1-[(4-{[(2-methyl-1,3- thiazol-4-yl)methyl]oxy}phenyl)methyl]propyl}-d₆-carbamate

[00357] The title compound was prepared in a manner similar to that described in example 1 from (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl - 4-nitrophenyl carbonate-d3 , 3-benzodioxole-d₂-5-sulfonyl chloride , 4-(chloromethyl)-2-methyl-1 ,3-thiazole and 1 ,1- dimethylethyl [(1S,2R)-2-hydroxy-3-[(2-methylpropyl)amino]-1-({4[(phenylmethyl)oxy] phenyl}methyl)propyl]-c/i-carbamate after purification by reverse-phase hplc. ¹H NMR (400 MHz, CHLOROFORM-d) δ 0.80-1.00 (m, 6 H), 1.42 -2.11 (m, 3 H), 2.60 - 3.23 (m, 10 H), 3.50-4.00 (m., 3 H), 4.89 - 5.03 (m, 1 H), 5.13 (s, 2 H), 5.64 (m, 1 H), 6.81 - 6.95 (m, 3 H), 7.07 - 7.18 (m, 3 H), 7.22 (s, 1 H), 7.28 - 7.36 (m, 1 H); HRMS cacld for 710.2688 (M+H); found 710.2687.

[00358] Example 18

[00359] Preparation of (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl

{(1S,2R)-3-[(1,3-benzodioxol-5-ylsulfonyl)(2-methylpropyl)amino]-2-hydroxy-1-[(4-{[(2- methyl-1,3-thiazol-4-yl)methyl]oxy}phenyl)methyl]propyl}carbamate-d₈

[00360] The title compound was prepared in a manner similar to that described in example 1 from (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl - 4-nitrophenyl carbonate-d₃ , 3-benzodioxole-d2-5-sulfonyl chloride , 4-(chloromethyl)-2-methyl-1 ,3-thiazole-d2 and 1 ,1- dimethylethyl [(1S,2R)-2-hydroxy-3-[(2-methylpropyl)amino]-1-({4[(phenylmethyl)oxy] phenyl}methyl)propyl]-c/₁-carbamate after purification by reverse-phase hplc. ¹H NMR (400 MHz, CHLOROFORM-d) δ 0.80-1.00 (m, 6 H), 1.42 -2.11 (m, 3 H), 2.60 - 3.23 (m, 10 H), 3.50-4.00 (m., 3 H), 4.89 - 5.03 (m, 1 H), 5.64 (m, 1 H), 6.81 - 6.95 (m, 3 H), 7.07 - 7.18 (m, 3 H), 7.22 (s, 1 H), 7.28 - 7.36 (m, 1 H); HRMS cacld for 712.2814 (M+H); found 712.2811.

[00361] Example 19

[00362] (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl {(1S,2R)-3-[(1,3- benzodioxol-5-ylsulfonyl)(2-methylpropyl)amino]-2-hydroxy-1-[(4-{[(2-methyl- 1,3-thiazol-4-yl)methyl]oxy}phenyl)methyl]propyl}carbamate-d₁₆

[00363] (a) d-methylidenehexahydrofuroβj-bjfuran-di.

[00364] An ice cold solution of 2,3-dihydrofuran (5.0 ml_, 66.1 mmol) in

TMEDA (2.0 ml_, 13.25 mmol) was treated by dropwise addition of n-butyllithium (30.9 ml_, 77 mmol, 2.5 M solution in hexanes). The mixture was stirred for 2 hours, then cooled to - 78° C and treated slowly with deuterium oxide (3 ml_, 166 mmol). The cooling bath was allowed to expire and the mixture was stirred overnight. The pale yellow solution was filtered over Celite to remove the precipitates, dried over sodium sulfate, filtered and used crude in the next step. A mixture of n-bromosuccinimide (12.95 g, 72.7 mmol) in dichloromethane (4OmL) was cooled to 0° C and treated with the crude solution of 2,3-dihydrofuran-c/-ι and propargyl alcohol (5.76 ml_, 98.9 mmol). The ice bath was allowed to expire and the mixture was stirred for two hours at RT. The mixture was diluted with dichloromethane and then washed with saturated sodium thiosulfate and saturated sodium bicarbonate. The extracts were dried over sodium sulfate, filtered and concentrated to give a pale yellow oil that was used with no further purification. A mixture of tributyltin hydride (21.91 ml_, 83 mmol) and AIBN (0.109 g, 0.661 mmol) in toluene (10 ml.) was heated to 105° C and a solution of the crude 3-bromo-2-(2-propyn-1-yloxy)tetrahydrofuran-c/₁ in toluene (10 ml.) was slowly added. The mixture was heated at 105° C for four hours and then stirred at room temperature overnight. The mixture was concentrated and then azeotroped with acetonitrile. The resultant yellow oil was purified on silica gel (0-30% ethyl acetate/hexanes gradient) to give the desired product as a pale yellow oil (2.17 g, 26%). ¹H NMR (400 MHz, CHLOROFORM- d) δ ppm 1.94 (m, J=12.3, 5.3, 1.6, 1.6 Hz, 1 H), 2.19 (tt, J=1 1.8, 8.2 Hz, 1 H), 3.30 (d, J=8.4 Hz, 1 H), 3.81 (ddd, J=11.1 , 8.6, 5.3 Hz, 1 H), 3.96 (td, J=8.2, 1.6 Hz, 1 H), 4.35 - 4.46 (m, 1 H), 4.46 - 4.57 (m, 1 H), 5.06 (dq, J=12.4, 2.2 Hz, 2 H).

[00365] (b) (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl 4-nitrophenyl carbonate-d₂.

[00366] (3R,3aS,6aR)-Hexahydrofuro[2,3-b]furan-3-yl 4-nitrophenyl carbonate-

0₂ was prepared in a manner similar to that described in example 4, steps c-h, from 3- methylidenehexahydrofuro[2,3-b]furan-di and isolated as a white solid. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.01 (m, J=13.2, 9.9, 9.9, 8.2 Hz, 1 H), 2.13 - 2.25 (m, 1 H), 3.15 (d, J=9.6 Hz, 1 H), 3.85 - 4.1 1 (m, 3 H), 4.17 (d, J=10.0 Hz, 1 H), 7.35 - 7.45 (m, 2 H), 8.26 - 8.35 (m, 2 H).

[00367] (c) 2-methyl-1-propanamine-d₉-hydrochloride.

[00368] 2-Methyl-1-propanamine-c/9-hydrochloride was prepared using a modified procedure to that reported in WO2009055006. An ice cold solution of 2- methylpropanoic ac\ύ-d₇ (1.0 ml_, 9.96 mmol) and triethylamine (1.666 ml_, 1 1.96 mmol) in dichloromethane (50 ml.) was treated with ethyl chloroformate (1.053 ml_, 10.96 mmol). After 1 hour, a white suspension had formed and ammonia gas was bubbled through the mixture for 45 minutes to give a very thick suspension. The mixture was poured into water and the layers were partitioned and separated. Solid sodium chloride was added to the aqueous layer and the mixture was extracted with chloroform/isopropanol (3:1 ). The combined extracts were dried over sodium sulfate, filtered and concentrated to a white solid. The crude primary amide product was dissolved in tetrahydrofuran (20 ml.) and cooled to 0° C. Lithium aluminum deuteride (14.95 ml_, 14.95 mmol, 1 M solution in THF) was slowly added and the mixture was heated at 50° C for 2 hours. The mixture was cooled to ambient temperature and then to 0° C. The solution was slowly treated with water (630 μl_) and the mixture was stirred for 5 minutes. Next was added 15% sodium hydroxide (630 μl_) and the mixture was stirred for 5 minutes. Lastly, water (1.9 mL) was added, the mixture was diluted with ether and then stirred at ambient temperature for 30 minutes. The suspension was filtered over Celite. The filtrate was treated with hydrogen chloride gas for 5 minutes and then the mixture was concentrated. The resultant was azeotroped with toluene and methanol to give the desired product as a white solid. ²H NMR (61 MHz, CHLOROFORM-d) δ ppm 0.69 - 1.15 (m, 6 D), 1.88 - 2.19 (m, 1 D), 2.66 - 3.00 (m, 2 D).

[00369] (d) 1,1-dimethylethyl [(1S,2R)-3-[(1,3-benzodioxol-5-ylsulfonyl)(2- methylpropyl)amino]-2-hydroxy-1-({4- [(phenylmethyl)oxy]phenyl}methyl)propyl]carbamate-d₁₂-

[00370] 1 , 1 -Dimethylethyl [(1 S,2R)-3-[(1 ,3-benzodioxol-5-ylsulfonyl)(2- methylpropyl)amino]-2-hydroxy-1-({4-[(phenylmethyl)oxy]phenyl}methyl)propyl]carbamate-c/v2 was prepared in a manner similar to that described in example 1 , steps d and e, from 1 ,1- dimethylethyl ((1 S)-1-[(2S)-2-oxiranyl]-2-{4-[(phenylmethyl)oxy]phenyl}ethyl)carbamate-c/v, 2- methyl-1-propanamine-c/g hydrochloride and 1 ,3-benzodioxole-5-sulfonyl chloride-c/₂ and was isolated as a white solid. LC/MS (m/z) ES⁺ = 639 (M+1 ).

[00371] (e) (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl {(1S,2R)-3-

[(1,3-benzodioxol-5-ylsulfonyl)(2-methylpropyl)amino]-2-hydroxy-1-[(4-{[(2- methyl-1,3-thiazol-4-yl)methyl]oxy}phenyl)methyl]propyl}carbamate-d₁₆. [00372] The title compound was prepared in a manner similar to that described in example 1 from (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl 4-nitrophenyl carbon ate-c/₂, 1 , 1 -Dimethylethyl [(1 S,2R)-3-[(1 ,3-benzodioxol-5-ylsulfonyl)(2-methylpropyl)amino]-2- hydroxy-1-({4-[(phenylmethyl)oxy]phenyl}methyl)propyl]carbamate-c/v2 and 4-(chloromethyl)- 2-methyl-1 ,3-thiazole-c/₂ and was isolated as a white solid after RP-HPLC purification. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.55 - 1.75 (m, 2 H), 2.76 - 2.82 (m, 4 H), 2.92 - 3.03 (m, 3 H), 3.12 - 3.15 (m, 1 H), 3.70 - 3.77 (m, 2 H), 3.81 - 3.91 (m, 2 H), 3.99 (d, J=9.6 Hz, 1 H), 4.94 (d, J=9.2 Hz, 1 H), 6.90 - 6.93 (m, 3 H), 7.14 - 7.18 (m, 3 H), 7.23 (s, 1 H), 7.33 - 7.36 (m, 1 H); ES+ MS: 720 (M + 1 ).

[00373] Example 20

[00374] Preparation of (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl

{(1S,2R)-3-[(1,3-benzodioxol-5-ylsulfonyl)(2-methylpropyl)amino]-2-hydroxy-1-[(4-{[(2- methyl-1,3-thiazol-4-yl)methyl]oxy}phenyl)methyl]propyl}carbamate-d₁₉

[00375] (a) 4-[(Phenylmethyl)oxy]-1-butanol-d₂.

[00376] Ethyl 4-[(phenylmethyl)oxy]butanoate (6.45g, 29mmol) was dissolved in THF, cooled to 0 °C and a solution of lithium aluminium deuteride (1 M diethyl ether, 29 ml.) was added dropwise. After stirring 20 minutes water (1 mL), 1 N sodium hydroxide (1 mL), and water (4 mL) were successively added and the mixture was vigorously stirred for 10 minutes, then filtered through a pad of celite. The filtrate was concentrated under reduced pressure to give a colorless oil. ¹H NMR (400 MHz, CHLOROFORM-d) δ 1.67 (m, 6 H), 2.1 1 (s, 1 H), 3.50 (m, 2 H), 4.50 (s, 2 H), 7.00-7.50 (s, 5 H).

[00377] (b) (1,1-Dimethylethyl)(dimethyl)({4-

[(phenylmethyl)oxy]butyl}oxy)silane-d₂.

[00378] TBDMSCI (5.39 g, 35.7 mmol) was added to a mixture of 4-

[(phenylmethyl)oxy]-1-butanol-c/₂ (5 g, 27.5 mmol), imidazole (2.43 g, 35.7 mmol), and N, N- dimethylformamide (20 mL) and the mixture was stirred 2 hours at room temperature. Water was added, the aqueous layer was extracted with diethyl ether, and the combined organics were washed with brine, dried over sodium sulfate and concentrated under reduced pressure to give a colorless oil. ¹H NMR (400 MHz, CHLOROFORM-d) δ 0.03 (s, 6H), 0.88 (s, 9 H), 1.50 - 1.80 (m, 4 H), 3.40 - 3.54 (m, 2 H), 4.49 (s, 2 H), 7.00-7.50 (m, 5 H).

[00379] (c) 4-{[(1, 1-Dimethylethyl)(dimethyl)silyl]oxy}-1-butanol-d₂.

[00380] A mixture of (1 ,1-dimethylethyl)(dimethyl)({4-

[(phenylmethyl)oxy]butyl}oxy)silane-c/2 (7.94 g, 26.8 mmol), Pd/C (812 mg) and methanol (10 ml.) was stirred at 40 psi for 12 hours. Acetic acid (4 ml.) was added and the mixture was stirred at 50 psi for 12 hours. The suspension was filtered through celite and the filtrate was concentrated under reduced pressure to give a colorless oil. ¹H NMR (400 MHz, CHLOROFORM-d) δ 0.05 (s, 6 H), 0.88 (s, 9 H), 1.51 - 1.73 (m, 4 H), 3.63 (s, 2 H).

[00381] (d) 4-{[(1, 1-Dimethylethyl)(dimethyl)silyl]oxy}butanal-d₂.

[00382] A -78 °C solution of oxalyl chloride (0.222 ml_, 2.53 mmol) in dichloromethane (10 ml.) was treated slowly with DMSO (0.359 ml_, 5.06 mmol) and stirred for 10 min. A solution of 4-{[(1 ,1-dimethylethyl)(dimethyl)silyl]oxy}-1-butanol-c/2 (345 mg, 1.688 mmol) in dichloromethane (5 ml.) was added slowly and the mix was stirred 15 minutes at - 78 °C. Triethylamine (0.706 ml_, 5.06 mmol) was added slowly and the mix was stirred 10 minutes at -78 °C and allowed to warm to room temperature and stirred 30 minutes. Saturated sodium bicarbonate solution and brine were added, the aqueous layer was extracted with dichloromethane, the organics were washed with brine, dried over sodium sulfate and concentrated under reduced pressure to give yellow oil. ¹H NMR (400 MHz, CHLOROFORM-d) δ 0.01 (s, 6 H), 0.85 (s, 9 H), 1.76 - 1.87 (m, 2 H), 2.41 - 2.53 (m, 2 H), 9.68 - 9.85 (m, 1 H).

[00383] (e) (3R,3aS)-Hexahydrofuro[2,3-b]furan-3-ol-d₄.

[00384] Dissolved 4-{[(1 , 1 -dimethylethyl)(dimethyl)silyl]oxy}butanal-c/2 (795 mg,

3.89 mmol) in Tetrahydrofuran (THF) (5 ml) and placed in ice water bath. Added L-proline (0.089 g, 0.776 mmol) and stirred in an ice bath for 10 hours and then overnight letting the ice bath expire. The reaction was stirred at room temperature for 12 additional hours. Added 1 N hydrochloric acid (0.11 ml.) and stirred the mixture for 48 hours. Pyridine (0.15 ml.) toluene (6.4 vol.) and water (1 ml.) were added and the mixture was stirred 10 minutes and then filtered through a pad of celite. The organic layer was extracted with water, the aqueous layer was washed with toluene, and the aqueous layer was concentrated under reduce pressure to give a yellow oil. Purification by silica gel chromatography (20-100% ethyl acetate/ hexanes) gave a colorless oil. ¹H NMR (400 MHz, CHLOROFORM-d) δ 1.71 - 1.80 (m, 1 H), 1.81 -1.91 (m, 1 H), 2.28 (m, 1 H), 2.83 (m,, 1 H), 4.43 (m, 1 H), 5.68 (m, 1 H).

[00385] (f) (3aR)-Tetrahydrofuro[2,3-b]furan-3(2H)-one-d₄.

[00386] TPAP (36.3 mg, 0.103 mmol), (3R,3aS)-hexahydrofuro[2,3-b]furan-3- ol-c/₄ (146 mg, 1.088 mmol), and NMO (195 mg, 1.662 mmol) were added sequentially to a suspension of activated molecular sieves in dichloromethane (2 mL) and the reaction was warmed to room temperature for 40 minutes. Celite was added and the product was purified by silca gel chromatography (0-100% ethyl acetate/hexanes) to give a colorless oil. ¹H NMR (400 MHz, CHLOROFORM-d) δ 2.09 - 2.34 (m, 2 H), 2.82 - 3.14 (m, 1 H), 6.05 (m, 1 H).

[00387] (g) (3R,3aS,6aR)-Hexahydrofuro [2,3-b] furan-3-yl 4-nitrophenyl carbonate-^.

[00388] The title compound was prepared in a manner similar to that described in example 17a. ¹H NMR (400 MHz, CHLOROFORM-d) δ 1.90 - 2.26 (m, 2 H), 3.07 - 3.25 (m, 1 H), 5.68 - 5.95 (m, 1 H), 7.39 (m, 2 H), 8.30 (m, 2 H).

[00389] (h) (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl {(1 S,2R)-3-[(1 ,3- benzodioxol-5-ylsulfonyl)(2-methylpropyl)amino]-2-hydroxy-1-[(4-{[(2-methyl-1,3- thiazol-4-yl)methyl]oxy}phenyl)methyl]propyl}carbamate-d₁₉

[00390] The title compound was prepared in a manner similar to that described in example 1 from (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl - 4-nitrophenyl carbonate-c/₄ , 3-benzodioxole-d₂-5-sulfonyl chloride , 4-(chloromethyl)-2-methyl-1 ,3-thiazole-d₂ and 1 ,1- dimethylethyl [(1S,2R)-2-hydroxy-3-[(2-methylpropyl)amino]-1-({4[(phenylmethyl)oxy] phenyl}methyl)propyl]-c/io-carbamate after purification by reverse-phase hplc. ¹H NMR (400 MHz, CHLOROFORM-d) δ 1.25-1.75 (m, 3 H), 2.60 - 3.23 (m, 7 H), 3.50-4.00 (m., 1 H), 4.89 - 5.03 (m, 1 H), 5.64 (m, 1 H), 6.81 - 6.95 (m, 3 H), 7.07 - 7.18 (m, 3 H), 7.22 (s, 1 H), 7.28 - 7.36 (m, 1 H); HRMS cacld for 723.3504 (M+H); found 723.3506.

[00391] Biological Data:

[00392] For the purpose of evaluating the novel compounds of formula I it will be apparent to one skilled in the art that common methods of determining metabolic rates and metabolic profile can be used. These include but are not limited to the use of in vitro systems such as liver microsomes, liver S9 fractions and fresh and cryopreserved hepatocytes. The above mentioned assays could be of interest when using liver cells, cell fractions, purified enzymes or other preparations from various species including mouse, rat, dog, monkey and human. In addition in vitro systems that assess permeability and gut metabolism are also of particular interest. These may include but are not limited to MDCK and CACO-2 assays. Additionally in vivo studies can also be of use to evaluate the compounds of formula I including orally administered pharmacokinetic studies originating from a solution, suspension or solid dosage form and bolus solution injection IV pharmacokinetic studies commonly employed to evaluate pharmaceutical agents. These include several common species such as mouse, rat, dog, monkey and mini-pigs. In addition to the above routes of administration, parenteral injection of suspension or solution dosages are of particular interest. These studies may include particle size reduced drug substance in a sterile formulation suitable for injection into the species ultimately being human. Particle size reduction may include D50 values in the range of 10 micron to 0.1 micron.

[00393] The embodiments of the invention described above are intended to be merely exemplary; numerous variations and modifications will be apparent to those skilled in the art. All such variations and modifications are intended to be within the scope of the present invention as defined in any appended claims.

Claims

What is claimed is:

1. A compound of Formula (I):

(I) wherein: each R¹ is independently selected from -D or -H, where at least one R¹ substituent is -D. n is 1 , 2, or 3; and x is 1 or 2; or a salt thereof.

2. A compound of formula (I)

(I) wherein: each R¹ is independently selected from -D or -H, where the level of deuterium incorporation in each R¹ group substituted with -D is least 50%; n is 1 , 2, or 3; and x is 1 or 2; or a salt thereof.

3. A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof and one or more of pharmaceutically acceptable carriers, diluents and excipients.

4. A method of treating a virus susceptible to HIV protease inhibition in a mammal, comprising administering to said mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

5. A method of inhibiting HIV related aspartyl protease in a mammal, comprising administering to said mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

6. A method of treating protease resistant HIV in a mammal, comprising administering to said mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

7. A method of preventing development of protease resistant HIV in a mammal, comprising administering to said mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

8. A method of treating a virus susceptible to HIV protease inhibition in a mammal comprising: administering to said mammal a long-acting parenteral composition, wherein the long-acting parenteral composition comprises a therapeutically effective amount of compound or composition as claimed in any of claims 1-3, or a pharmaceutically acceptable salt thereof.

9. A method according to claim 8, wherein the long-acting parenteral composition further comprises at least one additional agent useful in treating HIV infection.

10. A method according to claim 8, wherein the long-acting parenteral composition further comprises at least one additional agent useful as a pharmacological enhancer.

11. A method of treating protease resistant HIV in a mammal comprising: administering to said mammal a long-acting parenteral composition, wherein the long- acting parenteral composition comprises a therapeutically effective amount of compound or composition as claimed in any of claims 1-3, or a pharmaceutically acceptable salt thereof.

12. A method according to claim 10, wherein the long-acting parenteral composition further comprises at least one additional agent useful in treating HIV infection.

13. A method according to claim 10, wherein the long-acting parenteral composition further comprises at least one additional agent useful as a pharmacological enhancer.

14. A method of inhibiting HIV related aspartyl protease in a mammal comprising: administering to said mammal a long-acting parenteral composition, wherein the long- acting parenteral composition comprises a therapeutically effective amount of a compound or composition as claimed in any of claims 1-3, or a pharmaceutically acceptable salt thereof.

15. A method according to claim 14, wherein the long-acting parenteral composition further comprises at least one additional agent useful in treating HIV infection.

16. A method according to claim 14, wherein the long-acting parenteral composition further comprises at least one additional agent useful as a pharmacological enhancer.

17. A method as claimed in claim 6, comprising further administering at least one additional agent useful in treating HIV infection.

18. A method as claimed in claim 6, comprising further administering at least one additional agent useful as a pharmacological enhancer.

19. A method as claimed in claim 17, comprising further administering at least one additional agent useful as a pharmacological enhancer.

20. A method as claimed in claim 5, comprising further administering at least one additional agent useful in treating HIV infection.

21. A method as claimed in claim 5, comprising further administering at least one additional agent useful as a pharmacological enhancer in treating HIV infection.

22. A method as claimed in claim 20, comprising further administering at least one additional agent useful as a pharmacological enhancer.

23. A method as claimed in claim 6, comprising further administering at least one additional agent useful in treating HIV infection.

24. A method as claimed in claim 6, comprising further administering at least one additional agent useful as a pharmacological enhancer in treating HIV infection.

25. A method as claimed in claim 23, comprising further administering at least one additional agent useful as a pharmacological enhancer.

26. A method as claimed in claim 9, comprising further administering at least one additional agent useful in treating HIV infection.

27. A method as claimed in claim 11 , comprising further administering at least one additional agent useful as a pharmacological enhancer in treating HIV infection.

28. A method as claimed in claim 26, comprising further administering at least one additional agent useful as a pharmacological enhancer.

29. A compound: (3R,3aS,6aR)-Hexahydrofuro[2,3-b]furan-3-yl {(1 S,2R)-3-[(1 ,3- benzodioxol-5-ylsulfonyl)(2-methylpropyl)amino]-2-hydroxy-1-[(4-{[(2-methyl-1 ,3-thiazol- 4-yl)methyl]oxy}phenyl)methyl]propyl}- di.carbamate, whose structure is

or a salt thereof.

30. A compound: (3R,3aS,6aR)-Hexahydrofuro[2,3-b]furan-3-yl {(1 S,2R)-3-[(1 ,3- benzodioxol-5-ylsulfonyl)(2-methylpropyl)amino]-2-hydroxy-d-1-[(4-{[(2-methyl-1 ,3- thiazol-4-yl)methyl-d₂-]oxy}phenyl)methyl]propyl}carbamate, whose structure is

or a salt thereof.

31. A method as claimed in claim 4, comprising further administering at least one additional agent useful in treating HIV infection.

32. A method as claimed in claim 4, comprising further administering at least one additional agent useful as a pharmacological enhancer.

33. A method as claimed in claim 31 , comprising further administering at least one additional agent useful as a pharmacological enhancer.

34. A method as claimed in claim 5, comprising further administering at least one additional agent useful in treating HIV infection.

35. A method as claimed in claim 5, comprising further administering at least one additional agent useful as a pharmacological enhancer in treating HIV infection.

36. (A method as claimed in claim 34, comprising further administering at least one additional agent useful as a pharmacological enhancer.

37. (A method as claimed in claim 6, comprising further administering at least one additional agent useful in treating HIV infection.

38. (A method as claimed in claim 6, comprising further administering at least one additional agent useful as a pharmacological enhancer in treating HIV infection.

39. (A method as claimed in claim 37, comprising further administering at least one additional agent useful as a pharmacological enhancer.

40. (A method as claimed in claim 7, comprising further administering at least one additional agent useful in treating HIV infection.

41. A method as claimed in claim 7, comprising further administering at least one additional agent useful as a pharmacological enhancer in treating HIV infection.

42. A method as claimed in claim 40, comprising further administering at least one additional agent useful as a pharmacological enhancer .

43. A compound selected from:

(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl {(1 S,2R)-3-[(1 ,3-benzodioxol-5-ylsulfonyl)- d₂-(2-methylpropyl)amino]-2-hydroxy-d-1-[(4-{[(2-methyl-1 ,3-thiazol-4- yl)methyl]oxy}phenyl)methyl]propyl}carbamate, whose structure is

(3R,3aS,6aR)-Hexahydrofuro[2,3-b]furan-3-yl-dr {(1 S,2R)-3-[(1 ,3-benzodioxol-5- ylsulfonyl)(2-methylpropyl)amino]-2-hydroxy-1-[(4-{[(2-methyl-1 ,3-thiazol-4- yOmethylJoxyJphenyOmethylJpropylJ-drcarbamate, whose structure is

(3R,3aS,6aR)-Hexahydrofuro[2,3-b]furan-3-yl-dr {(1 S,2R)-3-[(1 ,3-benzodioxol-5- ylsulfonyl)-d₂-(2-methylpropyl)amino]-2-hydroxy-1-[(4-{[(2-methyl-1 ,3-thiazol-4-yl)methyl- d₂]oxy}phenyl)methyl]propyl}carbamate, whose structure is

(3R,3aS,6aR)-Hexahydrofuro[2,3-b]furan-3-yl-di- {(1 S,2R)-3-[(1 ,3-benzodioxol-5- ylsulfonyl)-d₂-(2-methylpropyl)amino]-2-hydroxy-1-[(4-{[(2-methyl-1 ,3-thiazol-4- yl)methyl]oxy}phenyl)methyl]propyl}carbamate, whose structure is

(3R,3aS,6aR)-Hexahydrofuro[2,3-b]furan-3-yl-di- {(1 S,2R)-3-[(1 ,3-benzodioxol-5- ylsulfonyl)(2-methylpropyl)amino]-2-hydroxy-1-[(4-{[(2-methyl-1 ,3-thiazol-4-yl)methyl-d2- ]oxy}phenyl)methyl]propyl}-di-carbamate, whose structure is

(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl {(1 S,2R)-3-[(1 ,3-benzodioxol -5-ylsulfonyl) -d₂ -(2-methylpropyl)amino]-2-hydroxy-1-[(4-{[(2-methyl-1 ,3-thiazol-4- yl)methyl]oxy}phenyl)methyl]propyl}carbamate, whose structure is

(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl {(1 S,2R)-3-[(1 ,3-benzodioxol-5-ylsulfonyl) d₂-(2-methylpropyl)amino]-2-hydroxy-1-[(4-{[(2-methyl-1 ,3-thiazol-4-yl) -6₂- methyl]oxy}phenyl)methyl]propyl}carbamate, whose structure is

(3R,3aS,6aR)-Hexahydrofuro[2,3-b]furan-3-yl-di- {(1 S,2R)-3-[(1 ,3-benzodioxol-5- ylsulfonyl)(2-methylpropyl)amino]-2-hydroxy-1-[(4-{[(2-methyl-1 ,3-thiazol-4- yl)methyl]oxy}phenyl)methyl]propyl}carbamate, whose structure is

(3R,3aS,6aR)-Hexahydrofuro[2,3-b]furan-3-yl-di- {(1 S,2R)-3-[(1 ,3-benzodioxol-5- ylsulfonyl)(2-methylpropyl)amino]-2-hydroxy-1-[(4-{[(2-methyl-1 ,3-thiazol-4-yl)methyl- d₂]oxy}phenyl)methyl]propyl}carbamate, whose structure is

(3R,3aS,6aR)-Hexahydrofuro[2,3-b]furan-3-yl-d₂- {(1 S,2R)-3-[(1 ,3-benzodioxol-5- ylsulfonyl)(2-methylpropyl)amino]-2-hydroxy-1-[(4-{[(2-methyl-1 ,3-thiazol-4- yl)methyl]oxy}phenyl)methyl]propyl-di}carbamate, whose structure is

(3R,3aS,6aR)-Hexahydrofuro[2,3-b]furan-3-yl-d₂- {(1 S,2R)-3-[(1 ,3-benzodioxol-5- ylsulfonyl)(2-methylpropyl)amino]-2-hydroxy-1-[(4-{[(2-methyl-1 ,3-thiazol-4-yl)methyl- d₂]oxy}phenyl)methyl]propyl-di}carbamate, whose structure is

(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl {(1 S,2R)-3-[(1 ,3-benzodioxol-5- ylsulfonyl)(2-methylpropyl) -d₂-amino]-2-hydroxy-1 -[(4-{[(2-methyl-1 ,3-thiazol-4- yl)methyl]oxy}phenyl)methyl]propyl}carbamate, whose structure is

(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl {(1 S,2R)-3-[(1 ,3-benzodioxol-5- ylsulfonyl)(2-methylpropyl) -d₂ -amino]-2-hydroxy-1-[(4-{[(2-methyl-1 ,3-thiazol-4-yl) -d₂ -methyl]oxy}phenyl)methyl]propyl}carbamate, whose structure is

(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-d₂-3-yl {(1 S,2R)-3-[(1 ,3-benzodioxol-d₂-5- ylsulfonyl)(2-methylpropyl)amino]-2-hydroxy-1-[(4-{[(2-methyl-1 ,3-thiazol-4-yl)methyl- d₂]oxy}phenyl)methyl]propyl}carbamate, whose structure is

(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl {(1 S,2R)-3-[(1 ,3-benzodioxol-5- ylsulfonyl)(2-methylpropyl)amino]-2-hydroxy-1-[(4-{[(2-methyl-1 ,3-thiazol-4- yl)methyl]oxy}phenyl)methyl]propyl}-d₆-carbamate, whose structure is

(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl {(1 S,2R)-3-[(1 ,3-benzodioxol-5- ylsulfonyl)(2-methylpropyl)amino]-2-hydroxy-1-[(4-{[(2-methyl-1 ,3-thiazol-4- yl)methyl]oxy}phenyl)methyl]propyl}carbamate-d₈ , whose structure is

(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl {(1 S,2R)-3-[(1 ,3-benzodioxol-5- ylsulfonyl)(2-methylpropyl)amino]-2-hydroxy-1-[(4-{[(2-methyl-1 ,3-thiazol-4- yl)methyl]oxy}phenyl)methyl]propyl}carbamate-di6, whose structure is

(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl {(1 S,2R)-3-[(1 ,3-benzodioxol-5- ylsulfonyl)(2-methylpropyl)amino]-2-hydroxy-1-[(4-{[(2-methyl-1 ,3-thiazol-4- yl)methyl]oxy}phenyl)methyl]propyl}carbamate-di9, whose structure is

a pharmaceutically acceptable salt thereof.