HK1248688B - Polycyclic-carbamoylpyridone compounds and their pharmaceutical use - Google Patents

Description

Polycyclic carbamoyl pyridone compounds and their pharmaceutical uses

Technical Field

Disclosed are compounds, compositions, and methods useful for treating human immunodeficiency virus (HIV) infection. In particular, disclosed are novel polycyclic carbamoylpyridone compounds, methods for their preparation, and uses as therapeutic or prophylactic agents.

Background Art

Human immunodeficiency virus infection and related diseases are major public health problems worldwide. Human immunodeficiency virus type 1 (HIV-1) encodes three enzymes required for viral replication: reverse transcriptase, protease, and integrase. Although drugs targeting reverse transcriptase and protease are widely used and have shown effectiveness, especially when used in combination, the development of toxicity and drug-resistant strains limits their usefulness (Palella et al., N. Engl. J Med. (1998) 338: 853–860; Richman, D.D. Nature (2001) 410: 995–1001). Therefore, new agents that inhibit HIV replication are needed.

The goal of antiretroviral therapy is to achieve viral suppression in HIV infected patients. The current treatment guidelines published by the U.S. Department of Health and Human Services stipulate that the realization of viral suppression needs to use combination therapy, i.e., several medicines from at least two or more drug classes. In addition, when patients need to treat other medical conditions, the decision-making about the treatment of HIV infected patients is complicated (ibid., E-12 pages). Because standard treatment needs to use a variety of different drugs to suppress HIV, and other conditions that the treatment patient may experience, the possibility of drug interaction is the standard for selecting a drug regimen. Therefore, it is necessary to have an antiretroviral therapy with reduced drug interaction possibility.

In addition, HIV is known to mutate in infected subjects (Tang et al., Drugs (2012) 72(9)e1-e25). Due to the propensity of HIV to mutate, anti-HIV drugs that are effective against a range of known HIV variants are needed (Hurt et al., HIV/AIDS CID (2014) 58, 423-431).

Summary of the Invention

The present disclosure relates to novel polycyclic carbamoyl pyridone compounds with antiviral activity, including stereoisomers and pharmaceutically acceptable salts thereof. In some embodiments, the compounds can be used to treat HIV infection, inhibit HIV integrase activity and/or reduce HIV replication. In some embodiments, the compounds disclosed herein are effective against a range of known drug-resistant HIV mutants. In some embodiments, when co-administered with other drugs, the compounds disclosed herein can minimize the possibility of drug-drug interactions.

In one embodiment, a compound having the following formula (Ia) is provided:

or a pharmaceutically acceptable salt thereof, wherein:

A is a saturated or partially unsaturated 4- to 7-membered monocyclic heterocyclyl, and is optionally substituted by 1 to 5 R ³ groups;

Each R ³ is independently selected from C _1-4 alkyl, halogen and oxo; or two R ³ attached to the same or adjacent carbon atoms form a spiro or fused C _3-6 cycloalkyl or 4 to 6 membered heterocyclyl ring;

A' is selected from C _3-7 monocyclic cycloalkyl and 4 to 7 membered monocyclic heterocyclyl; wherein each C _3-7 monocyclic cycloalkyl and 4 to 7 membered monocyclic heterocyclyl is optionally substituted by 1 to 5 R ⁴ groups;

Each R ⁴ is independently selected from C _1-4 alkyl, halogen and oxo; or two R ⁴ attached to the same or adjacent carbon atoms form a spiro or fused C _3-6 cycloalkyl or 4 to 6 membered heterocyclyl ring;

R ¹ is phenyl optionally substituted with 1 to 5 R ⁵ groups;

Each R ⁵ is independently selected from halogen and C _1-3 alkyl; and

^R2 is selected from H, _C1-3 haloalkyl and _C1-4 alkyl.

In another embodiment, a pharmaceutical composition is provided, comprising a compound having Formula (Ia) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

In another embodiment, a method of treating HIV infection in a human being having or at risk of HIV infection is provided by administering to the human being a therapeutically effective amount of a compound of formula (Ia) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of a compound of formula (Ia) or a pharmaceutically acceptable salt thereof.

In another embodiment, provided is the use of a compound of formula (Ia) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of a compound of formula (Ia) or a pharmaceutically acceptable salt thereof, for treating HIV infection in a human having or at risk of HIV infection.

In another embodiment, provided is a compound of formula (Ia) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of a compound of formula (Ia) or a pharmaceutically acceptable salt thereof for use in medical therapy.

In another embodiment, provided is a compound of formula (Ia) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of a compound of formula (Ia) or a pharmaceutically acceptable salt thereof for use in the prophylactic or therapeutic treatment of HIV infection.

In another embodiment, methods of using a compound of formula (Ia) in therapy are provided. In particular, methods of treating HIV viral proliferation, treating AIDS, or delaying the onset of AIDS or ARC symptoms in a mammal (e.g., a human) are provided, comprising administering to the mammal a compound of formula (Ia) or a stereoisomer or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

In another embodiment, a composition comprising a compound of formula (Ia) or a stereoisomer or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient is provided for use in a method for treating HIV viral proliferation, treating AIDS, or delaying the onset of AIDS or ARC symptoms in a mammal (e.g., a human).

In another embodiment, disclosed is the use of a compound of formula (Ia) or a pharmaceutically acceptable salt thereof as described herein in the preparation of a medicament for treating HIV infection in a human suffering from or at risk of HIV infection.

In another embodiment, an article of manufacture comprising a composition effective for treating HIV infection is disclosed; and packaging material comprising a label indicating that the composition can be used to treat HIV infection. An exemplary composition comprises a compound of formula (Ia) as disclosed herein, or a pharmaceutically acceptable salt thereof.

In yet another embodiment, a method of inhibiting HIV replication is disclosed, comprising exposing the virus to an effective amount of a compound of formula (Ia) or a salt thereof under conditions that inhibit HIV replication.

In another embodiment, disclosed is the use of a compound of formula (Ia) for inhibiting HIV integrase activity.

In another embodiment, disclosed is the use of a compound of formula (Ia) or a pharmaceutically acceptable salt thereof for inhibiting HIV integrase activity.

In another embodiment, disclosed is the use of a compound of formula (Ia) or a salt thereof for inhibiting HIV replication.

In another embodiment, disclosed is the use of a compound of formula (Ia) or a pharmaceutically acceptable salt thereof as a research tool.

Other embodiments, objects, features, and advantages will be set forth in the detailed description of the embodiments that follow, and in part will be apparent from the description, or may be learned by practicing the claimed embodiments. These objects and advantages may be realized and obtained by the methods and compositions particularly pointed out in the written description and the claims thereof. Having made the foregoing summary, it should be understood that it should be considered as a brief and general summary of some embodiments disclosed herein, provided solely for the benefit and convenience of the reader, and is not intended in any way to limit the scope of the appended claims to which they are legally entitled or the scope of equivalents.

DETAILED DESCRIPTION

In the following description, certain specific details are set forth in order to provide a thorough understanding of the various embodiments disclosed herein. However, it will be understood by those skilled in the art that the embodiments disclosed herein can be implemented without these details. The following description of several embodiments is carried out, and it should be understood that the present disclosure is considered to be an example of the subject matter for which protection is requested, and is not intended to limit the appended claims to the specific embodiments set forth. The headings used throughout this disclosure are provided only for convenience and should not be interpreted as limiting the claims in any way. The embodiments set forth under any heading may be combined with the embodiments set forth under any other heading.

definition

Unless the context requires otherwise, throughout this disclosure and claims, the word "comprise" and variations such as "comprises" and "comprising" should be construed in an open, inclusive sense, that is, to mean "including but not limited to."

Reference throughout this specification to "one embodiment" or "an embodiment" means that a particular feature, structure, or characteristic described with respect to that embodiment is included in at least one embodiment disclosed herein. Thus, the appearance of the phrase "in one embodiment" or "in an embodiment" in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments.

"Amino" refers to a _-NH2 group.

"Hydroxy" or "hydroxyl" refers to an -OH group.

"Oxo" refers to a =0 substituent.

A prefix such as " _Cuv " or ( _Cu - _Cv ) indicates that the following group has u to v carbon atoms. For example, " _C1-6alkyl " indicates that the alkyl group has 1 to 6 carbon atoms.

“Alkyl” refers to a straight or branched saturated hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, having from 1 to 12 carbon atoms (C ₁ -C ₁₂ alkyl), in certain embodiments from 1 to 8 carbon atoms (C ₁ -C ₈ alkyl), or from 1 to 6 carbon atoms (C ₁ -C ₆ alkyl), and which is attached to the rest of the molecule by a single bond, for example, methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl, 1,1-dimethylethyl (tert-butyl), 3-methylhexyl, 2-methylhexyl, and the like.

"Cycloalkyl" or "carbocycle" refers to a stable, non-aromatic, monocyclic hydrocarbon group consisting solely of carbon and hydrogen atoms, having from 3 to 15 carbon atoms, in certain embodiments from 3 to 10 carbon atoms, and which is saturated and attached to the remainder of the molecule by a single bond, or in the case of A', by two single bonds. Cycloalkyl groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

"Fused" refers to any ring structure described herein that is fused to an existing ring structure in the compounds disclosed herein.

"Halo" or "halogen" refers to bromo, chloro, fluoro or iodo.

"Haloalkyl" refers to an alkyl group as defined above substituted with one or more halo groups as defined above, for example, trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like.

"Heterocyclyl" or "heterocycle" refers to a stable monocyclic 3- to 18-membered non-aromatic ring consisting of 2 to 12 carbon atoms and 1 to 6 heteroatoms selected from nitrogen, oxygen, and sulfur, and is attached to the rest of the molecule by a single bond, or in the case of A and A', by two single bonds. The nitrogen, carbon, or sulfur atoms in the heterocyclyl group may optionally be oxidized; the nitrogen atom may optionally be quaternized. As used herein, "heterocyclyl" or "heterocycle" refers to a saturated ring, unless otherwise indicated, for example, in some embodiments, "heterocyclyl" or "heterocycle" refers to a saturated or partially saturated ring where specified. Examples of such heterocyclic groups include, but are not limited to, dioxolanyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, thiazolidinyl, tetrahydrofuranyl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiomorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl.

Embodiments disclosed herein are also intended to include all pharmaceutically acceptable compounds of formula (Ia) that are isotopically labeled by replacing one or more atoms with atoms having different atomic masses or mass numbers. Examples of isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, such as ² H, ³ H, ¹¹ C, ¹³ C, ¹⁴ C, ¹³ N, ¹⁵ N, 15 O, ¹⁷ O, ¹⁸ O, ³¹ P, ³² P, ³⁵ S, ¹⁸ F, ³⁶ Cl, ¹²³ I, and ¹²⁵ I. ^These radiolabeled compounds can be used to help determine or measure the effectiveness of the compound, such as by characterizing the site or mode of action or the binding affinity to a pharmacologically important site of action. Certain isotopically labeled compounds of formula (Ia), (II), and (III), such as those incorporating radioisotopes, can be used for drug and/or substrate tissue distribution studies. The radioactive isotopes tritium, ie, ³ H, and carbon-14, ie, ¹⁴ C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.

Substitution with heavier isotopes such as deuterium (ie, ² H) may afford certain therapeutic advantages resulting from greater metabolic stability. For example, in vivo half-life may be increased or dosage requirements may be reduced. Thus, in some circumstances, heavier isotopes may be preferred.

Substitution with positron emitting isotopes such as ¹¹ C, ¹⁸ F, ¹⁵ O and ¹³ N can be used in positron emission tomography (PET) studies to examine substrate receptor occupancy. Isotopically labeled compounds of formula (Ia) can generally be prepared by conventional techniques known to those skilled in the art or by methods analogous to those described in the Examples described below using an appropriate isotopically labeled reagent in place of the unlabeled reagent previously used.

The methods, compositions, kits and articles of manufacture provided herein use or include a compound (e.g., (Ia)) or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein 1 to n hydrogen atoms attached to a carbon atom can be replaced by a deuterium atom or D, where n is the number of hydrogen atoms in the molecule. As is known in the art, a deuterium atom is a non-radioactive isotope of a hydrogen atom. When administered to a mammal, such compounds can increase resistance to metabolism and thus can be used to increase the half-life of the compound or a pharmaceutically acceptable salt, prodrug or solvate thereof. See, for example, Foster, "Deuterium Isotope Effects in Studies of Drug Metabolism", Trends Pharmacol. Sci., 5(12): 524-527 (1984). Such compounds are synthesized by means well known in the art, for example, by using starting materials in which one or more hydrogen atoms have been replaced by deuterium.

The embodiments disclosed herein are also intended to include in vivo metabolites of the disclosed compounds. Such products can be produced by, for example, oxidation, reduction, hydrolysis, amidation, esterification, etc. of the administered compound, primarily due to enzymatic processes. Therefore, the embodiments disclosed herein include compounds produced by methods including administering a compound according to the embodiments disclosed herein to a mammal for a period of time sufficient to produce its metabolites. Such products are typically administered to animals such as rats, mice, guinea pigs, monkeys, or humans with a detectable dose of a radiolabeled compound according to the embodiments disclosed herein, allowing sufficient time for metabolism to occur, and isolating its conversion products from urine, blood, or other biological samples for identification.

"Stable compound" and "stable structure" are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.

"Mammal" includes humans as well as domestic animals such as laboratory animals and household pets (eg, cats, dogs, pigs, cows, sheep, goats, horses, rabbits) and non-domestic animals such as wild animals and the like.

"Optional" or "optionally" means that the subsequently described event or circumstance can or cannot occur, and that the description includes instances where it occurs and instances where it does not. For example, "optionally substituted heterocyclyl" means that the heterocyclyl group can be substituted or unsubstituted, and that the description includes both substituted heterocyclyl groups and unsubstituted heterocyclyl groups.

"Pharmaceutically acceptable excipients" include, but are not limited to, any adjuvant, carrier, vehicle, glidant, sweetener, diluent, preservative, dye/colorant, flavor enhancer, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier approved by the U.S. Food and Drug Administration for use in humans or veterinary medicine.

Examples of "pharmaceutically acceptable salts" of the compounds disclosed herein include salts derived from suitable bases such as alkali metals (e.g., sodium), alkaline earth metals (e.g., magnesium), ammonium, and NX ₄ ⁺ (wherein X is C ₁ -C ₄ alkyl). Pharmaceutically acceptable salts of nitrogen atoms or amino groups include, for example, organic carboxylic acids such as acetic acid, benzoic acid, lactic acid, fumaric acid, tartaric acid, maleic acid, malonic acid, malic acid, isethionic acid, lactobionic acid, and succinic acid; organic sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid; and inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, and sulfamic acid. Pharmaceutically acceptable salts of hydroxy compounds include combinations of anions of the compounds with suitable cations such as Na ⁺ and NX ₄ ⁺ (wherein X is independently selected from H or C ₁ -C ₄ alkyl).

For therapeutic use, salts of the active ingredients of the compounds disclosed herein are generally pharmaceutically acceptable, i.e., they will be salts derived from physiologically acceptable acids or bases. However, salts of non-pharmaceutically acceptable acids or bases may also be useful, for example, in the preparation or purification of a compound of formula (Ia) or another compound of the embodiments disclosed herein. All salts, whether or not derived from physiologically acceptable acids or bases, are within the scope of the embodiments disclosed herein.

Metal salts are typically prepared by reacting metal hydroxides with compounds according to embodiments disclosed herein. Examples of metal salts prepared in this manner are salts containing Li ⁺ , Na ⁺ , and K ⁺ . Poorly soluble metal salts can be precipitated from solutions of more soluble salts by adding the appropriate metal compound.

In addition, salts can be formed by acid addition of certain organic and inorganic acids (e.g., HCl, HBr, H ₂ SO ₄ , H ₃ PO ₄ or organic sulfonic acids) to basic centers (typically amines). Finally, it should be understood that the compositions herein encompass the compounds disclosed herein in their non-ionized form as well as in zwitterionic form, and in combination with a stoichiometric amount of water in the form of hydrates.

Typically, crystallization produces a solvate of the compound of the embodiments disclosed herein. As used herein, the term "solvate" refers to an aggregate comprising one or more compound molecules of the embodiments disclosed herein and one or more solvent molecules. The solvent can be water, in which case the solvate can be a hydrate. Alternatively, the solvent can be an organic solvent. Thus, the compound of the embodiments disclosed herein can exist as a hydrate, including monohydrates, dihydrates, hemihydrates, sesquihydrates, trihydrates, tetrahydrates, etc., and corresponding solvated forms. The compound of the embodiments disclosed herein can be a true solvate, while in other cases, the compound of the embodiments disclosed herein can retain only added water, or a mixture of water plus some added solvent. In any embodiment disclosed herein, the compound disclosed herein can be in the form of a solvate thereof.

A "pharmaceutical composition" refers to a formulation of a compound of the embodiments disclosed herein and a medium generally accepted in the art for delivering the biologically active compound to a mammal, such as a human. Such a medium includes all pharmaceutically acceptable excipients.

"Effective amount" or "therapeutically effective amount" refers to the amount of a compound according to the embodiments disclosed herein that is sufficient to achieve treatment of the disease state, condition, or disorder disclosed herein when administered to a patient in need thereof. Such an amount will be sufficient to elicit the biological or medical response of the tissue system or patient sought by the researcher or clinician. The amount of a compound according to the embodiments disclosed herein that constitutes a therapeutically effective amount will vary according to factors such as the compound and its biological activity, the composition for administration, the time of administration, the route of administration, the excretion rate of the compound, the duration of treatment, the type of disease state or disorder being treated and its severity, the drugs used in combination or concomitantly with the compound of the embodiments disclosed herein, and the age, weight, general health, sex, and diet of the patient. Such a therapeutically effective amount can be routinely determined by one of ordinary skill in the art, taking into account their own knowledge, the state of the prior art, and this disclosure.

The term "treatment" as used herein is intended to refer to the administration of a compound or composition according to an embodiment of the present invention disclosed herein to alleviate or eliminate the symptoms of HIV infection and/or reduce the viral load in the patient. The term "treatment" also includes administering a compound or composition according to an embodiment of the present invention disclosed herein after an individual is exposed to the virus but before symptoms of the disease appear, and/or before the virus is detected in the blood to prevent the symptoms of the disease from appearing and/or to prevent the virus from reaching a detectable level in the blood, and by administering a compound or composition according to an embodiment of the present invention disclosed herein to the mother before giving birth and to the child within the first few days of life to prevent perinatal transmission of HIV from mother to baby. The term "treatment" also includes administering a compound or composition according to an embodiment of the present invention disclosed herein before an individual is exposed to the virus (also referred to as pre-exposure prophylaxis or PrEP) to prevent HIV infection when the individual is exposed to the virus and/or to prevent the virus from establishing a permanent infection and/or to prevent symptoms of the disease from appearing and/or to prevent the virus from reaching a detectable level in the blood. The term "treatment" also includes administering a compound or composition according to an embodiment of the present invention disclosed herein before and after an individual is exposed to the virus.

As used herein, the term "antiviral agent" is intended to refer to an agent (compound or biological agent) that effectively inhibits the development and/or replication of a virus in a human, including but not limited to agents that interfere with host or viral mechanisms necessary for the development and/or replication of a virus in a human.

As used herein, the term "HIV replication inhibitor" is intended to refer to an agent that is capable of reducing or eliminating the ability of HIV to replicate in a host cell, whether in vitro, ex vivo, or in vivo.

The compounds of the embodiments disclosed herein, or pharmaceutically acceptable salts thereof, may contain one or more asymmetric centers and, therefore, may produce enantiomers, diastereomers, and other stereoisomeric forms, which may be defined in terms of absolute stereochemistry as (R)- or (S)-, or (D)- or (L)- for amino acids. The present invention is intended to include all such possible isomers, as well as their racemic and optically pure forms. (+) and (-), (R)- and (S)-, or (D)- and (L)- optical isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques such as chromatography and fractional crystallization. Conventional techniques for preparing/isolating individual enantiomers include chiral synthesis from suitable optically pure precursors, or resolving racemates (or racemates of salts or derivatives) using, for example, chiral high pressure liquid chromatography (HPLC). When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, unless otherwise indicated, the compounds are intended to include both E and Z geometric isomers. Likewise, all tautomeric forms are also intended to be included.

"Stereoisomers" refer to compounds composed of the same atoms bonded by the same bonds but with different three-dimensional structures, which are not interchangeable. The present disclosure encompasses various stereoisomers and mixtures thereof, and includes "enantiomers," which refer to two stereoisomers whose molecules are non-superimposable mirror images of each other. In any embodiment disclosed herein, the compounds disclosed herein may be in the form of their stereoisomers.

"Tautomer" refers to a proton shift from one atom of a molecule to another atom of the same molecule. The present disclosure includes tautomers of any of the described compounds.

"Partially unsaturated" refers to a cyclic group that contains at least one double bond but is not aromatic.

A "prodrug" is a biologically inactive derivative of a drug that, when administered to the human body, is converted according to some chemical or enzymatic pathway to the biologically active parent drug.

Compound

As described above, in one embodiment, a compound having the following formula (Ia) is provided:

or a pharmaceutically acceptable salt thereof, wherein:

A is a saturated or partially unsaturated 4- to 7-membered monocyclic heterocyclyl, and is optionally substituted by 1 to 5 R ³ groups;

Each R ³ is independently selected from C _1-4 alkyl, halogen and oxo; or two R ³ attached to the same or adjacent carbon atoms form a spiro or fused C _3-6 cycloalkyl or 4 to 6 membered heterocyclyl ring;

A' is selected from C _3-7 monocyclic cycloalkyl and 4 to 7 membered monocyclic heterocyclyl; wherein each C _3-7 monocyclic cycloalkyl and 4 to 7 membered monocyclic heterocyclyl is optionally substituted by 1 to 5 R ⁴ groups;

Each R ⁴ is independently selected from C _1-4 alkyl, halogen and oxo; or two R ⁴ attached to the same or adjacent carbon atoms form a spiro or fused C _3-6 cycloalkyl or 4 to 6 membered heterocyclyl ring;

R ¹ is phenyl optionally substituted with 1 to 5 R ⁵ groups;

Each R ⁵ is independently selected from halogen and C _1-3 alkyl; and

^R2 is selected from H, _C1-3 haloalkyl and _C1-4 alkyl.

In another embodiment, A is a saturated or partially unsaturated 5- or 6-membered monocyclic heterocyclyl, and is optionally substituted with 1 to 5 R ³ groups.

In another embodiment, A is a saturated or partially unsaturated 5-membered monocyclic heterocyclyl, and is optionally substituted with 1 to 5 R ³ groups.

In another embodiment, A is a saturated or partially unsaturated 6-membered monocyclic heterocyclyl, and is optionally substituted with 1 to 5 R ³ groups.

In another embodiment, A is selected from oxazolidinyl, piperidinyl, 3,4-unsaturated piperidinyl, pyrrolidinyl, tetrahydro-1,3-oxazinyl, and thiazolidinyl; each of which is optionally substituted with 1 to 5 R ³ groups.

In another embodiment, A is selected from oxazolidinyl, pyrrolidinyl, and thiazolidinyl; each of which is optionally substituted with 1 to 5 R ³ groups.

In another embodiment, A is selected from piperidinyl, tetrahydro-1,3-oxazinyl, and 3,4-unsaturated piperidinyl; each of which is optionally substituted with 1 to 5 R ³ groups.

In another embodiment, A is piperidinyl optionally substituted with 1 to 5 R ³ groups.

In another embodiment, A is selected from oxazolidinyl, piperidinyl, 3,4-unsaturated piperidinyl, pyrrolidinyl, tetrahydro-1,3-oxazinyl and thiazolidinyl; each of which is optionally substituted with one or two ^R3 groups; wherein ^R3 is _C1-4 alkyl; or two ^R3 attached to the same or adjacent carbon atoms form a spiro or fused _C3-6 cycloalkyl or 4 to 6 membered heterocyclyl ring.

In another embodiment, A is selected from oxazolidinyl, pyrrolidinyl, and thiazolidinyl; each of which is optionally substituted with one or two ^R3 groups; wherein ^R3 is _C1-4 alkyl; or two ^R3 attached to the same or adjacent carbon atoms form a spiro or fused _C3-6 cycloalkyl or 4 to 6 membered heterocyclyl ring.

In another embodiment, A is selected from piperidinyl, tetrahydro-1,3-oxazinyl and 3,4-unsaturated piperidinyl; each of which is optionally substituted with one or two ^R3 groups; wherein ^R3 is _C1-4 alkyl; or two ^R3 attached to the same or adjacent carbon atoms form a spiro or fused _C3-6 cycloalkyl or 4 to 6 membered heterocyclyl ring.

In another embodiment, A is piperidinyl optionally substituted with one or two R ³ groups; wherein R ³ is C _1-4 alkyl; or two R ³ attached to the same or adjacent carbon atoms form a spiro or fused C _3-6 cycloalkyl or 4 to 6 membered heterocyclyl ring.

In another embodiment, A is selected from oxazolidinyl, piperidinyl, 3,4-unsaturated piperidinyl, pyrrolidinyl, tetrahydro-1,3-oxazinyl, and thiazolidinyl; each of which is optionally substituted with methyl.

In another embodiment, A is piperidinyl optionally substituted with methyl.

In another embodiment, A is piperidinyl.

In another embodiment, selected from:

In another embodiment, selected from:

In another embodiment, selected from:

In another embodiment,

In another embodiment, selected from:

In another embodiment, selected from:

In another embodiment,

In another embodiment, selected from:

In another embodiment, A' is selected from _C4-6 monocyclic cycloalkyl and 5 to 6 membered monocyclic heterocyclyl; wherein each _C4-6 monocyclic cycloalkyl and 5 to 6 membered monocyclic heterocyclyl is optionally substituted with 1 to 5 ^R4 groups.

In another embodiment, A' is selected from _C5-6 monocyclic cycloalkyl and 5 to 6 membered monocyclic heterocyclyl; wherein each _C5-6 monocyclic cycloalkyl and 5 to 6 membered monocyclic heterocyclyl is optionally substituted with 1 to 5 ^R4 groups.

In another embodiment, A' is selected from cyclopentyl, tetrahydrofuranyl, cyclohexyl, and tetrahydropyranyl; each of which is optionally substituted with 1 to 5 R ⁴ groups.

In another embodiment, A' is selected from cyclopentyl and cyclohexyl; each of which is optionally substituted with 1 to 5 R ⁴ groups.

In another embodiment, A' is selected from tetrahydropyranyl and tetrahydrofuranyl; each of which is optionally substituted with 1 to 5 R ⁴ groups.

In another embodiment, A' is tetrahydrofuranyl optionally substituted with 1 to 5 R ⁴ groups.

In another embodiment, A' is tetrahydropyranyl optionally substituted with 1 to 5 R ⁴ groups.

In another embodiment, A' is selected from cyclopentyl, tetrahydrofuranyl, cyclohexyl and tetrahydropyranyl; each of which is optionally substituted with one or two ^R4 groups, wherein each ^R4 is independently selected from _C1-4 alkyl, halogen and oxo; or two ^R2 attached to the same or adjacent carbon atoms form a spiro or fused _C3-6 cycloalkyl or 4 to 6 membered heterocyclyl ring.

In another embodiment, A' is selected from cyclopentyl and cyclohexyl; each of which is optionally substituted with one or two ^R4 groups, wherein each ^R4 is independently selected from _C1-4 alkyl, halogen and oxo; or two ^R2 attached to the same or adjacent carbon atoms form a spiro or fused _C3-6 cycloalkyl or 4 to 6 membered heterocyclyl ring.

In another embodiment, A' is selected from tetrahydropyranyl and tetrahydrofuranyl; each of which is optionally substituted with one or two ^R4 groups, wherein each ^R4 is independently selected from _C1-4 alkyl, halogen and oxo; or two ^R2 attached to the same or adjacent carbon atoms form a spiro or fused _C3-6 cycloalkyl or 4 to 6 membered heterocyclyl ring.

In another embodiment, A' is tetrahydropyranyl optionally substituted with one or two R ⁴ groups, wherein each R ⁴ is independently selected from C _1-4 alkyl, halogen and oxo; or two R ² attached to the same or adjacent carbon atoms form a spiro or fused C _3-6 cycloalkyl or 4 to 6 membered heterocyclyl ring.

In another embodiment, A' is tetrahydrofuranyl optionally substituted with one or two R ⁴ groups, wherein each R ⁴ is independently selected from C _1-4 alkyl, halogen and oxo; or two R ² attached to the same or adjacent carbon atoms form a spiro or fused C _3-6 cycloalkyl or 4 to 6 membered heterocyclyl ring.

In another embodiment, A' is selected from cyclopentyl, tetrahydrofuranyl, cyclohexyl, and tetrahydropyranyl; each of which is optionally fused to a _C3-6 cycloalkyl ring.

In another embodiment, A' is cyclopentyl optionally fused to a _C3-6 cycloalkyl ring.

In another embodiment, A' is selected from tetrahydrofuranyl and tetrahydropyranyl; each of which is optionally fused to a _C3-6 cycloalkyl ring.

In another embodiment, A' is tetrahydrofuranyl optionally fused to a _C3-6 cycloalkyl ring.

In another embodiment, A' is tetrahydropyranyl optionally fused to a _C3-6 cycloalkyl ring.

In another embodiment, A' is selected from cyclopentyl, tetrahydrofuranyl, cyclohexyl, and tetrahydropyranyl; each of which is optionally fused with a cyclopropyl group.

In another embodiment, A' is cyclopentyl optionally fused to cyclopropyl.

In another embodiment, A' is selected from tetrahydrofuranyl and tetrahydropyranyl; each of which is optionally fused to a cyclopropyl group.

In another embodiment, A' is tetrahydrofuranyl optionally fused to cyclopropyl.

In another embodiment, A' is tetrahydrofuranyl.

In another embodiment, A' is tetrahydropyranyl optionally fused to cyclopropyl.

In another embodiment, A' is tetrahydropyranyl.

In another embodiment, A' is selected from tetrahydrofuranyl and tetrahydropyranyl, and A is piperidinyl.

In another embodiment, A' is tetrahydrofuranyl and A is piperidinyl.

In another embodiment, A' is tetrahydropyranyl and A is piperidinyl.

In another embodiment, ^R2 is H.

In another embodiment, A' is selected from tetrahydrofuranyl and tetrahydropyranyl, and ^R2 is H.

In another embodiment, A' is selected from tetrahydrofuranyl and tetrahydropyranyl, A is piperidinyl, and ^R2 is H.

In another embodiment, A' is tetrahydrofuranyl, A is piperidinyl, and ^R2 is H.

In another embodiment, A' is tetrahydropyranyl, A is piperidinyl, and ^R2 is H.

In another embodiment, selected from:

In another embodiment, selected from:

In another embodiment, is in another embodiment, is in another embodiment, is selected from:

In another embodiment, selected from:

In another embodiment,

In another embodiment,

In another embodiment, selected from:

In another embodiment, selected from:

In another embodiment,

In another embodiment,

In another embodiment, selected from:

In another embodiment, selected from:

In another embodiment,

In another embodiment,

In another embodiment, R ¹ is phenyl substituted with two or three R ⁵ groups, wherein each R ⁵ is independently selected from halogen and C _1-3 alkyl.

In another embodiment, R ¹ is phenyl substituted with two or three R ⁵ groups, wherein each R ⁵ is independently selected from fluoro and chloro.

In another embodiment, R ¹ is selected from:

In another embodiment, R ¹ is

In another embodiment, a compound having the following formula (Ia) is provided:

or a pharmaceutically acceptable salt thereof, wherein:

A is selected from oxazolidinyl, piperidinyl, 3,4-unsaturated piperidinyl, pyrrolidinyl, tetrahydro-1,3-oxazinyl and thiazolidinyl; each of which is optionally substituted with 1 to 5 R ³ groups;

Each R ³ is independently selected from C _1-4 alkyl, halogen and oxo; or two R ³ attached to the same or adjacent carbon atoms form a spiro or fused C _3-6 cycloalkyl or 4 to 6 membered heterocyclyl ring;

A' is selected from cyclopentyl, tetrahydrofuranyl, cyclohexyl and tetrahydropyranyl; each of which is optionally substituted with 1 to 5 R ⁴ groups;

Each R ⁴ is independently selected from C _1-4 alkyl, halogen and oxo; or two R ⁴ attached to the same or adjacent carbon atoms form a spiro or fused C _3-6 cycloalkyl or 4 to 6 membered heterocyclyl ring;

R ¹ is phenyl substituted with two or three R ⁵ groups, wherein each R ⁵ is independently selected from halogen and C _1-3 alkyl; and

^R2 is selected from H, _C1-3 haloalkyl and _C1-4 alkyl.

In another embodiment, a compound having the following formula (Ia) is provided:

or a pharmaceutically acceptable salt thereof, wherein:

Selected from:

Selected from:

and

R ¹ is phenyl substituted with two or three R ⁵ groups, wherein each R ⁵ is independently selected from fluorine and chlorine.

In another embodiment, a compound having the following structure is provided:

or a pharmaceutically acceptable salt thereof.

In another embodiment, a compound having the following structure is provided:

or a pharmaceutically acceptable salt thereof.

In another embodiment, a compound having the following structure is provided:

or a pharmaceutically acceptable salt thereof.

In another embodiment, a compound having the following structure is provided:

or a pharmaceutically acceptable salt thereof.

In another embodiment, a pharmaceutical composition is provided, comprising a compound having Formula (Ia), (II) or (III) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

In another embodiment, the pharmaceutical composition further comprises one or more additional therapeutic agents.

In another embodiment, the pharmaceutical composition further comprises one or more anti-HIV agents.

In another embodiment, the pharmaceutical composition further comprises one or more additional therapeutic agents selected from HIV protease inhibitors, HIV non-nucleoside reverse transcriptase inhibitors, HIV nucleoside or nucleotide reverse transcriptase inhibitors, HIV non-catalytic site integrase inhibitors, HIV capsid inhibitors, and combinations thereof.

In another embodiment, the pharmaceutical composition further comprises one or more additional therapeutic agents selected from HIV protease inhibitors, HIV non-nucleoside reverse transcriptase inhibitors, HIV nucleoside or nucleotide reverse transcriptase inhibitors, and combinations thereof.

In another embodiment, the pharmaceutical composition further comprises a first additional therapeutic agent selected from the group consisting of abacavir sulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir alafenamide, and tenofovir alafenamide hemifumarate, and a second additional therapeutic agent selected from the group consisting of emtricitabine and lamivudine.

In another embodiment, the pharmaceutical composition further comprises a first additional therapeutic agent selected from the group consisting of tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir alafenamide, and tenofovir alafenamide hemifumarate, and emtricitabine.

In another embodiment, the pharmaceutical composition additionally comprises tenofovir disoproxil fumarate and emtricitabine.

In another embodiment, the pharmaceutical composition further comprises tenofovir alafenamide hemifumarate and emtricitabine.

In another embodiment, a method of treating HIV infection in a human being having or at risk of HIV infection is provided by administering to the human being a therapeutically effective amount of a compound of Formula (Ia), (II) or (III) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of a compound of Formula (Ia), (II) or (III) or a pharmaceutically acceptable salt thereof.

In another embodiment, the method of treating HIV infection in a human having or at risk for HIV infection further comprises administering to the human a therapeutically effective amount of one or more additional therapeutic agents.

In another embodiment, the method of treating HIV infection in a human having or at risk for HIV infection further comprises administering to the human a therapeutically effective amount of one or more additional therapeutic agents selected from the group consisting of HIV protease inhibitors, HIV non-nucleoside reverse transcriptase inhibitors, HIV nucleoside or nucleotide reverse transcriptase inhibitors, HIV non-catalytic site integrase inhibitors, HIV capsid inhibitors, and combinations thereof.

In another embodiment, the method of treating HIV infection in a human having or at risk of HIV infection further comprises administering to the human a therapeutically effective amount of one or more additional therapeutic agents selected from the group consisting of HIV protease inhibitors, HIV non-nucleoside reverse transcriptase inhibitors, HIV nucleoside or nucleotide reverse transcriptase inhibitors, and combinations thereof. In a specific embodiment, the method of treating HIV infection in a human having or at risk of HIV infection further comprises administering to the human a therapeutically effective amount of an HIV non-nucleoside reverse transcriptase inhibitor.

In another embodiment, the method of treating HIV infection in a human having or at risk of HIV infection further comprises administering to the human a therapeutically effective amount of a first additional therapeutic agent selected from the group consisting of abacavir sulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir alafenamide, and tenofovir alafenamide hemifumarate, and a second additional therapeutic agent selected from the group consisting of emtricitabine and lamivudine.

In another embodiment, a method of treating HIV infection in a human having or at risk of HIV infection comprises concurrently administering to the human a compound of Formula (Ia), (II) or (III), or a pharmaceutically acceptable salt thereof, and a first additional therapeutic agent selected from the group consisting of abacavir sulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir alafenamide, and tenofovir alafenamide hemifumarate, and a second additional therapeutic agent selected from the group consisting of emtricitabine and lamivudine.

In another embodiment, a method of treating HIV infection in a human having or at risk of HIV infection comprises administering to the human a fixed-dose combination of a compound of Formula (Ia), (II) or (III), or a pharmaceutically acceptable salt thereof, and a first additional therapeutic agent selected from abacavir sulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir alafenamide, and tenofovir alafenamide hemifumarate, and a second additional therapeutic agent selected from emtricitabine and lamivudine.

In another embodiment, the method of treating HIV infection in a human having or at risk of HIV infection comprises administering to the human a single dosage form, e.g., as a solid dosage form for oral administration, for simultaneous administration to the patient of a compound of Formula (Ia), (II) or (III), or a pharmaceutically acceptable salt thereof, and a first additional therapeutic agent selected from the group consisting of abacavir sulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir alafenamide, and tenofovir alafenamide hemifumarate, and a second additional therapeutic agent selected from the group consisting of emtricitabine and lamivudine.

In another embodiment, the method of treating HIV infection in a human having or at risk of HIV infection further comprises administering to the human a therapeutically effective amount of tenofovir disoproxil and emtricitabine.

In another embodiment, the method of treating HIV infection in a human having or at risk of HIV infection further comprises administering to the human a therapeutically effective amount of tenofovir alafenamide and emtricitabine.

In another embodiment, there is provided a use of a compound of Formula (Ia), (II) or (III) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of a compound of Formula (Ia), (II) or (III) or a pharmaceutically acceptable salt thereof, for treating HIV infection in a human having or at risk of HIV infection.

In another embodiment, a compound of Formula (Ia), (II) or (III) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of a compound of Formula (Ia), (II) or (III) or a pharmaceutically acceptable salt thereof, for use in medical therapy is provided.

In another embodiment, a compound of Formula (Ia), (II) or (III) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of a compound of Formula (Ia), (II) or (III) or a pharmaceutically acceptable salt thereof, for use in the prophylactic or therapeutic treatment of HIV infection is provided.

In another embodiment, a compound of Formula (Ia), (II) or (III) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of a compound of Formula (Ia), (II) or (III) or a pharmaceutically acceptable salt thereof, for use in a method of treating HIV infection in a human having or at risk of HIV infection is provided.

In another embodiment, a compound of Formula (Ia), (II) or (III) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of a compound of Formula (Ia), (II) or (III) or a pharmaceutically acceptable salt thereof, for use in a method of treating HIV infection in a human having or at risk of HIV infection, wherein the method further comprises administering one or more additional therapeutic agents to the human.

In another embodiment, a compound of Formula (Ia), (II) or (III) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of a compound of Formula (Ia), (II) or (III) or a pharmaceutically acceptable salt thereof, for use in a method of treating HIV infection in a person suffering from or at risk of HIV infection is provided, wherein the method further comprises administering to the person one or more additional therapeutic agents selected from the group consisting of HIV protease inhibitors, HIV non-nucleoside reverse transcriptase inhibitors, HIV nucleoside or nucleotide reverse transcriptase inhibitors, HIV non-catalytic site integrase inhibitors, HIV capsid inhibitors, and combinations thereof. In one embodiment, the one or more additional therapeutic agents are selected from the group consisting of HIV protease inhibitors, HIV non-nucleoside reverse transcriptase inhibitors, HIV nucleoside or nucleotide reverse transcriptase inhibitors, and combinations thereof. In one embodiment, the one or more additional therapeutic agents are HIV non-nucleoside reverse transcriptase inhibitors.

In another embodiment, a compound of Formula (Ia), (II) or (III) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of a compound of Formula (Ia), (II) or (III) or a pharmaceutically acceptable salt thereof, for use in a method of treating HIV infection in a human having or at risk of HIV infection is provided, wherein the method further comprises administering to the human a first additional therapeutic agent selected from the group consisting of abacavir sulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir alafenamide, and tenofovir alafenamide hemifumarate, and a second additional therapeutic agent selected from the group consisting of emtricitabine and lamivudine. In one embodiment, the method comprises administering to a human a compound of Formula (Ia), (II) or (III), or a pharmaceutically acceptable salt thereof, simultaneously with a first additional therapeutic agent selected from abacavir sulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir alafenamide, and tenofovir alafenamide hemifumarate, and a second additional therapeutic agent selected from emtricitabine and lamivudine.

In another embodiment, a compound of Formula (Ia), (II) or (III), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of a compound of Formula (Ia), (II) or (III), or a pharmaceutically acceptable salt thereof, for use in a method of treating HIV infection in a human having or at risk of HIV infection is provided, wherein the method comprises administering to the human a fixed-dose combination of a compound of Formula (Ia), (II) or (III), or a pharmaceutically acceptable salt thereof, and a first additional therapeutic agent selected from the group consisting of abacavir sulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir alafenamide, and tenofovir alafenamide hemifumarate, and a second additional therapeutic agent selected from the group consisting of emtricitabine and lamivudine.

In another embodiment, a compound of Formula (Ia), (II) or (III) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of a compound of Formula (Ia), (II) or (III) or a pharmaceutically acceptable salt thereof, for use in a method of treating HIV infection in a human having or at risk of HIV infection is provided, wherein the method comprises administering to the human a single dosage form, e.g., as a solid dosage form for oral administration, for simultaneous administration of a compound of Formula (Ia), (II) or (III) or a pharmaceutically acceptable salt thereof, with a first additional therapeutic agent selected from the group consisting of abacavir sulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir alafenamide, and tenofovir alafenamide hemifumarate, and a second additional therapeutic agent selected from the group consisting of emtricitabine and lamivudine.

In another embodiment, a compound of Formula (Ia), (II) or (III) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of a compound of Formula (Ia), (II) or (III) or a pharmaceutically acceptable salt thereof, for use in a method of treating HIV infection in a human having or at risk of HIV infection is provided, wherein the method further comprises administering to the human a therapeutically effective amount of tenofovir disoproxil and emtricitabine.

In another embodiment, a compound of Formula (Ia), (II) or (III) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of a compound of Formula (Ia), (II) or (III) or a pharmaceutically acceptable salt thereof, for use in a method of treating HIV infection in a human having or at risk of HIV infection is provided, wherein the method further comprises administering to the human a therapeutically effective amount of tenofovir alafenamide and emtricitabine.

In another embodiment, methods of using a compound of Formula (Ia), (II) or (III) in therapy are provided. In particular, methods of treating HIV viral proliferation, treating AIDS, or delaying the onset of AIDS or ARC symptoms in a mammal (e.g., a human) are provided, comprising administering to the mammal a compound of Formula (Ia), (II) or (III) or a stereoisomer or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

In another embodiment, a composition comprising a compound of Formula (Ia), (II) or (III) or a stereoisomer or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient is provided for use in a method of treating HIV viral proliferation, treating AIDS, or delaying the onset of AIDS or ARC symptoms in a mammal (e.g., a human).

In another embodiment, a compound of Formula (Ia), (II) or (III) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of a compound of Formula (Ia), (II) or (III) or a pharmaceutically acceptable salt thereof, is provided for use in pre-exposure prophylaxis (PrEP) before an individual is exposed to HIV virus to prevent HIV infection when the individual is exposed to the virus and/or prevent the virus from establishing permanent infection and/or prevent the onset of disease symptoms and/or prevent the virus from reaching detectable levels in the blood.

In another embodiment, disclosed is the use of a compound of formula (Ia), (II) or (III) as described herein, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating HIV infection in a human having or at risk of HIV infection.

In another embodiment, disclosed is the use of a compound of Formula (Ia), (II) or (III), or a pharmaceutically acceptable salt thereof, as a research tool.

In another embodiment, an article of manufacture is disclosed, comprising a composition effective for treating HIV infection; and packaging material comprising a label indicating that the composition can be used to treat HIV infection. An exemplary composition comprises a compound of Formula (Ia), (II) or (III) according to this embodiment disclosed herein, or a pharmaceutically acceptable salt thereof.

In another embodiment, a method of inhibiting HIV replication is disclosed, comprising exposing the virus to an effective amount of a compound of formula (Ia), (II) or (III) or a salt thereof under conditions that inhibit HIV replication.

In another embodiment, disclosed is the use of a compound of formula (Ia), (II) or (III) for inhibiting HIV integrase activity.

In another embodiment, disclosed is the use of a compound of formula (Ia), (II) or (III) or a salt thereof for inhibiting HIV replication.

The present disclosure also provides compounds of each of the formulae herein and each subgroup and embodiment thereof, for use in any of the methods of the invention as defined herein, including compounds selected from Formula (Ia), (II) and (III), or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising a compound of Formula (Ia), (II) or (III), or pharmaceutically acceptable salts thereof, or a specific compound of the Examples herein, or a salt thereof.

It is understood that any embodiment of the compounds of any of Formula (Ia), (II), or (III) as described above, and any specific substituents A, A', ^R1 , ^R2 , ^R3 , ^R4 , or ^R5 groups described herein in the compounds of Formula (Ia) as described above, can be independently combined with other embodiments and/or substituents of the compounds of any of Formula (Ia) to form embodiments not specifically described above. In addition, where any specific list of substituents for A, A', R1, ^R2 , ^R3 , ^{R4 ,} and ^R5 is listed in the specific embodiments and/or claims, it is understood that each individual substituent can be deleted from the specific embodiments and/or claims, and the remaining list of substituents should be considered to be within the scope of the embodiments disclosed herein.

Pharmaceutical composition

For the purpose of administration, in certain embodiments, the compounds described herein are administered as raw chemicals or formulated as pharmaceutical compositions. Pharmaceutical compositions within the scope of the embodiments disclosed herein comprise a compound of formula (Ia), (II) or (III) and a pharmaceutically acceptable excipient. The compound of formula (Ia), (II) or (III) is present in the composition in an amount effective to treat the specific disease or condition of interest. The activity of the compound of formula (Ia), (II) or (III) can be determined by those skilled in the art, for example, as described in the following examples. Appropriate concentrations and dosages can be easily determined by those skilled in the art.

The compound of the embodiment disclosed herein or its pharmaceutically acceptable salt can be applied in pure form or in an appropriate pharmaceutical composition by any accepted mode of administration of a medicament for similar purposes. The pharmaceutical composition of the embodiment disclosed herein can be prepared by combining the compound of the embodiment disclosed herein with an appropriate pharmaceutically acceptable excipient, and can be formulated into a preparation in solid, semisolid, liquid or gaseous form, such as tablets, capsules, powders, granules, ointments, solutions, suppositories, injections, inhalants, gels, microspheres and aerosols. Typical routes of administration of such pharmaceutical compositions include but are not limited to oral, topical, transdermal, inhalation, parenteral, sublingual, oral, rectal, vaginal and intranasal. The pharmaceutical composition of the embodiment disclosed herein is prepared so that the active ingredient contained therein is bioavailable when the composition is applied to a patient. The composition applied to a subject or patient takes the form of one or more dosage units, wherein, for example, a tablet can be a single dosage unit, and the container of the compound of the embodiment disclosed herein in the form of an aerosol can accommodate multiple dosage units. Actual methods of preparing such dosage forms are known or will be apparent to those skilled in the art; for example, see Remington: The Science and Practice of Pharmacy, 20th edition (Philadelphia College of Pharmacy and Science, 2000). In any case, the composition to be administered will contain a therapeutically effective amount of a compound of the embodiments disclosed herein, or a pharmaceutically acceptable salt thereof, for treating the disease or condition of interest in accordance with the teachings of the present disclosure.

In one embodiment, the pharmaceutical composition is an oral dosage unit. In one embodiment, the pharmaceutical composition is a solid oral dosage unit. In one embodiment, the pharmaceutical composition is a tablet.

The pharmaceutical compositions disclosed herein can be prepared by methods well known in the pharmaceutical field. For example, a pharmaceutical composition intended to be administered by injection can be prepared by combining the compound of the embodiments disclosed herein with sterile distilled water to form a solution. A surfactant can be added to promote the formation of a uniform solution or suspension. A surfactant is a compound that non-covalently interacts with the compound of the embodiments disclosed herein to promote the dissolution or uniform suspension of the compound in an aqueous delivery system.

The compounds of the embodiments disclosed herein, or pharmaceutically acceptable salts thereof, are administered in a therapeutically effective amount, which will vary depending on a variety of factors, including the activity of the particular compound employed; the metabolic stability and length of action of the compound; the age, weight, general health, sex, and diet of the patient; the mode and time of administration; the rate of excretion; the drug combination; the severity of the particular disease or condition; and the treatment the subject is receiving.

Combination therapy

In certain embodiments, methods for treating or preventing HIV infection in a person having HIV infection or at risk of HIV infection are provided, comprising administering to the person a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents. In one embodiment, methods for treating HIV infection in a person having HIV infection or at risk of HIV infection are provided, comprising administering to the person a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents.

In certain embodiments, the present disclosure provides methods for treating HIV infection, comprising administering to a patient in need thereof a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more additional therapeutic agents suitable for treating HIV infection.

The compounds disclosed herein (e.g., any compound of Formula (Ia), (II), or (III)) can be combined with one or more additional therapeutic agents at any dose of the compound of Formula (Ia), (II), or (III) (e.g., 50 mg to 1000 mg of the compound).

In one embodiment, a pharmaceutical composition is provided that comprises a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents, and a pharmaceutically acceptable excipient.

In one embodiment, a kit is provided comprising a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents.

In the above embodiments, the additional therapeutic agent can be an anti-HIV agent. For example, in some embodiments, the additional therapeutic agent is selected from HIV protease inhibitors, HIV non-nucleoside or non-nucleotide reverse transcriptase inhibitors, HIV nucleoside or nucleotide reverse transcriptase inhibitors, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, HIV entry inhibitors (e.g., CCR5 inhibitors, gp41 inhibitors (i.e., fusion inhibitors) and CD4 attachment inhibitors), CXCR4 inhibitors, gp120 inhibitors, G6PD and NADH-oxidase inhibitors, HIV vaccines, HIV maturation inhibitors, latency reversing agents (e.g., histone deacetylase inhibitors, proteasome inhibitors, protein kinase C (PKC) activators and BRD4 inhibitors), compounds targeting HIV capsid ("capsid inhibitors"; e.g., capsid polymerization inhibitors or capsid disrupting compounds, HIV nucleocapsid p7 (NCp7) inhibitors, HIV p24 capsid protein inhibitors), pharmacokinetic enhancers, immune-based therapies (e.g., Pd-1 modulators, Pd-L1 modulators, toll-like receptor modulators, IL-15 agonists), HIV antibodies, bispecific antibodies, and "antibody-like" therapeutic proteins (e.g., Fab derivatives), including those targeting HIV gp120 or gp41, HIV combination drugs, HIV p17 matrix protein inhibitors, IL-13 antagonists, peptidyl-prolyl cis-trans isomerase A modulators, protein disulfide isomerase inhibitors, complement C5a receptor antagonists, DNA methyltransferase inhibitors, HIV vif gene modulators, HIV-1 viral infection factor inhibitors, TAT protein inhibitors, HIV-1 Nef modulators, Hck tyrosine kinase modulators, mixed lineage kinase-3 (MLK-3) inhibitors, HIV-1 splicing inhibitors, Rev protein inhibitors, integrin antagonists, nuclear protein inhibitors, splicing factor modulators, COMM domain-containing protein 1 modulators, HIV ribonuclease H inhibitors, Retrocyclin modulators, CDK-9 inhibitors, dendritic ICAM-3 binding nonintegrin (grabbing nonintegrin) 1 inhibitors, HIV GAG protein inhibitors, HIV POL protein inhibitors, complement factor H modulators, ubiquitin ligase inhibitors, deoxycytidine kinase inhibitors, cyclin-dependent kinase inhibitors, proprotein convertase PC9 stimulators, ATP-dependent RNA helicase DDX3X inhibitors, reverse transcriptase initiation complex (priming complex) inhibitors, HIV gene therapy, PI3K inhibitors, such as WO2013/006738 (Gilead Sciences), US2013/0165489 (University of Pennsylvania), WO2013/091096A1 (Boehringer Ingelheim), WO2009/062285 (Boehringer Ingelheim), US20140221380 (Japan Tobacco), US20140221378 (Japan Tobacco), WO2010/130034 (Boehringer Ingelheim), WO2013/159064 (Gilead Sciences), WO2012/145728 (Gilead Sciences), WO2012/003497 (Gilead Sciences) Sciences), WO2014/100323 (Gilead Sciences), WO2012/145728 (Gilead Sciences), WO2013/159064 (Gilead Sciences) and WO 2012/003498 (Gilead Sciences) and WO 2013/006792 (Pharma Resources) and other drugs for the treatment of HIV, and combinations thereof.

In certain embodiments, the additional therapeutic agent is selected from HIV protease inhibitors, HIV non-nucleoside or non-nucleotide reverse transcriptase inhibitors, HIV nucleoside or nucleotide reverse transcriptase inhibitors, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, pharmacokinetic enhancers, and combinations thereof.

In certain embodiments, the compound of formula (Ia), (II) or (III) is formulated as a tablet, which may optionally contain one or more other compounds useful for treating HIV. In certain embodiments, the tablet may contain another active ingredient useful for treating HIV, such as an HIV protease inhibitor, an HIV non-nucleoside or non-nucleotide reverse transcriptase inhibitor, an HIV nucleoside or nucleotide reverse transcriptase inhibitor, an HIV integrase inhibitor, an HIV non-catalytic site (or allosteric) integrase inhibitor, a pharmacokinetic enhancer, and combinations thereof.

In certain embodiments, such tablets are suitable for once-daily administration. In certain embodiments, the additional therapeutic agent is selected from one or more of the following:

(1) Combination drugs selected from (efavirenz + tenofovir disoproxil fumarate + emtricitabine), (rilpivirine + tenofovir disoproxil fumarate + emtricitabine), (elvitegravir + corbicistat + tenofovir disoproxil fumarate + emtricitabine), dolutegravir + abacavir sulfate + lamivudine, (dolutegravir + abacavir + lamivudine), lamivudine + nevirapine Lapine + Zidovudine, Dolutegravir + Rilpivirine, Atazanavir Sulfate + Corbicistat, Atazanavir + Corbicistat, Darunavir + Corbicistat, Efavirenz + Lamivudine + Tenofovir Disoproxil Fumarate, Tenofovir Alafenamide Hemifumarate + Emtricitabine + Corbicistat + Elvitegravir, Tenofovir Alafenamide Hemifumarate + Emtricitabine, Tenofovir Alafenamide + Emtricitabine Tricitabine, tenofovir alafenamide hemifumarate + emtricitabine + rilpivirine, tenofovir alafenamide + emtricitabine + rilpivirine, Vacc-4x + romidepsin, darunavir + tenofovir alafenamide hemifumarate + emtricitabine + corbicistat, APH-0812, raltegravir + lamivudine, (lopinavir + ritonavir), atazanavir sulfate + ritonavir, (zidovudine + lamivudine, AZT + 3TC), (abacavir sulfate + lamivudine, ABC + 3TC), (abacavir sulfate + zidovudine + lamivudine, ABC + AZT + 3TC), (tenofovir disoproxil fumarate + emtricitabine, TDF + FTC), tenofovir + lamivudine and lamivudine + tenofovir disoproxil fumarate;

(2) HIV protease inhibitors selected from the group consisting of amprenavir, atazanavir, fosamprenavir, fosamprenavir calcium, indinavir, indinavir sulfate, lopinavir, ritonavir, nelfinavir, nelfinavir mesylate, saquinavir, saquinavir mesylate, tipranavir, brenavir, darunavir, DG-17, TMB-657 (PPL-100), and TMC-310911;

(3) HIV non-nucleoside or non-nucleotide reverse transcriptase inhibitors selected from delavirdine, delavirdine mesylate, nevirapine, etravirine, dapivirine, doravirine, rilpivirine, efavirenz, KM-023, VM-1500, lentinan, and AIC-292;

(4) HIV nucleoside or nucleotide reverse transcriptase inhibitors selected from EC (didanosine, ddl), zidovudine, emtricitabine, didanosine, stavudine, zalcitabine, lamivudine, cinxavudine, abacavir, abacavir sulfate, amdosovir, efcitabine, alovudine, phosphazid, fozivudine tidoxil, arithiab, amdosovir, KP-1461, fosalvudinetidoxil, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, tenofovir alafenamide, tenofovir alafenamide hemifumarate, tenofovir alafenamide fumarate, adefovir, adefovir disoproxil and festinavir;

(5) HIV integrase inhibitors selected from the group consisting of curcumin, curcumin derivatives, chicoric acid, chicoric acid derivatives, 3,5-dicaffeoylquinic acid, 3,5-dicaffeoylquinic acid derivatives, aurintricarboxylic acid, aurintricarboxylic acid derivatives, caffeic acid phenethyl ester, caffeic acid phenethyl ester derivatives, tyrosine phosphorylation inhibitors, derivatives of tyrosine phosphorylation inhibitors, quercetin, quercetin derivatives, raltegravir, elvitegravir, dolutegravir and caltegravir;

(6) HIV non-catalytic site, or allosteric integrase inhibitor (NCINI) selected from CX-05168, CX-05045, and CX-14442;

(7) HIV gp41 inhibitors selected from enfuvirtide, sifuvirtide, and albuvirtide;

(8) HIV entry inhibitors selected from cenicriviroc;

(9) HIV gp120 inhibitors selected from Radha-108 (Receptol) and BMS-663068;

(10) CCR5 inhibitors selected from alavir, virivirox, maraviroc, senevirorc, PRO-140, Adaptavir (RAP-101), TBR-220 (TAK-220), nifeviroc (TD-0232), TD-0680 and vMIP (Haimipu);

(11) a CD4 attachment inhibitor selected from ibalizumab;

(12) CXCR4 inhibitors selected from plerixafor, ALT-1188, vMIP and Haimipu;

(13) a pharmacokinetic enhancer selected from the group consisting of cobicistat and ritonavir;

(14) immune-based therapies selected from dermaVir, interleukin-7, hydroxychloroquine (hydroxychloroquine), aldesleukin (aldesleukin, IL-2), interferon alpha, interferon alpha-2b, interferon alpha-n3, pegylated interferon alpha, interferon gamma, hydroxyurea, mycophenolate mofetil (MPA) and its ester derivative mycophenolate mofetil (MMF), WF-10, ribavirin, IL-2, IL-12, polymer polyethyleneimine (PEI), Gepon, VGV-1, MOR-22, BMS-936559, toll-like receptor modulators (tlr1, tlr2, tlr3, tlr4, tlr5, tlr6, tlr7, tlr8, tlr9, tlr10, tlr11, tlr12 and tlr13), rintatolimod and IR-103;

(15) HIV vaccines selected from peptide vaccines, recombinant subunit protein vaccines, live vector vaccines, DNA vaccines, virus-like particle vaccines (pseudovirion vaccines), CD4-derived peptide vaccines, vaccine combinations, rgp120 (AIDSVAX), ALVAC HIV (vCP1521)/AIDSVAX B/E (gp120) (RV144), Remune, ITV-1, Contre Vir, Ad5-ENVA-48, DCVax-001 (CDX-2401), PEP-6409, Vacc-4x, Vacc-C5, VAC-3S, multi-branched DNA recombinant adenovirus-5 (rAd5), Pennvax-G, VRC-HIV MAB060-00-AB, AVX-101, Tat Oyi vaccine, AVX-201, HIV-LAMP-vax, Ad35, Ad35-GRIN, NAcGM3/VSSP ISA-51, poly-ICLC adjuvanted vaccine, TatImmune, GTU-multiHIV (FIT-06), AGS-004, gp140[δ]V2.TV1+MF-59, rVSVIN HIV-1 gag vaccine, SeV-Gag vaccine, AT-20, DNK-4, Ad35-GRIN/ENV, TBC-M4, HIVAX, HIVAX-2, NYVAC-HIV-PT1, NYVAC-HIV-PT4, DNA-HIV-PT123, rAAV1-PG9DP, GOVX-B11, GOVX-B21, ThV-01, TUTI-16, VGX-3300, TVI-HIV-1, Ad-4 (Ad4-envClade C+Ad4-mGag), EN41-UGR7C, EN41-FPA2, PreVaxTat, TL-01, SAV-001, AE-H, MYM-V101, CombiHIVvac, ADVAX, MYM-V201, MVA-CMDR, ETV-01 and DNA-Ad5gag/pol/nef/nev(HVTN505);

(16) HIV antibodies, bispecific antibodies, and “antibody-like” therapeutic proteins (e.g., Fab derivatives), including BMS-936559, TMB-360, and those targeting HIV gp120 or gp41 selected from bavituximab, UB-421, C2F5, C2G12, C4E10, C2F5+C2G12+C4E10, 3-BNC-117, PGT145, PGT121, MDX010 (ipilimumab), VRC01, A32, 7B2, 10E8, and VRC07;

(17) Latency reversing agents selected from histone deacetylase inhibitors such as romidepsin, vorinostat, and panobinostat; proteasome inhibitors such as Velcade; protein kinase C (PKC) activators such as indolactam, prostratin, ingenol B, and DAG-lactone, ionomycin, GSK-343, PMA, SAHA, BRD4 inhibitors, IL-15, JQ1, disulfram, and amphotericin B;

(18) HIV nucleocapsid p7 (NCp7) inhibitors selected from azodicarbonamide;

(19) HIV maturation inhibitors selected from BMS-955176 and GSK-2838232;

(20) PI3K inhibitors selected from idelalisib, AZD-8186, buparlisib, CLR-457, pictilisib, neratinib, rigosertib, rigosertib sodium, EN-3342, TGR-1202, alpelisib, duvelisib, UCB-5857, taselisib, XL-765, gedatolisib, VS-5584, copanlisib, CAI orotate, perifosine ), RG-7666, GSK-2636771, DS-7423, panulisib, GSK-2269557, GSK-2126458, CUDC-907, PQR-309, INCB-040093, pilaralisib, BAY-1082439, puquitinib mesylate, SAR-245409, AMG-319, RP-6530, ZSTK-474, MLN-1117, SF-1126, RV-1729, sonolisib, LY-3023414, SAR-260301, and CLR-1401;

(21) Published in WO2004/096286 (Gilead Sciences), WO2006/110157 (GileadSciences), WO2006/015261 (Gilead Sciences), WO2013/006738 (Gilead Sciences), US2013/0165489 (University of Pennsylvania), US20140221380 (Japan Tobacco), US20140221378 (Japan Tobacco), WO2013/006792 (Pharma Resources), WO2009/062285 (Boehringer Ingelheim), WO2010/130034 (Boehringer Ingelheim), WO2013/091096A1 (Boehringer Ingelheim), WO2013/159064 (Gilead Sciences), WO2012/145728 (Gilead Sciences), WO2012/003497 (Gilead Sciences), WO2014/100323 (Gilead Sciences), WO2012/145728 (Gilead Sciences), WO2013/159064 (Gilead Sciences) and WO2012/003498 (Gilead Sciences) Compounds in Sciences;

and

(22) Other drugs for treating HIV, selected from BanLec, MK-8507, AG-1105, TR-452, MK-8591, REP 9, CYT-107, alisporivir, NOV-205, IND-02, metenkefalin, PGN-007, Acemannan, Gamimune, Prolastin, 1,5-dicaffeoylquinic acid, BIT-225, RPI-MN, VSSP, Hlviral, IMO-3100, SB-728-T, RPI-MN, VIR-576, HGTV-43, MK-1376, rHIV7-shl-TAR-CCR5RZ, MazF gene therapy, BlockAide, ABX-464, SCY-635, naltrexone, AAV-eCD4-Ig gene therapy, and PA-1050040 (PA-040).

In certain embodiments, the compounds disclosed herein or their pharmaceutically acceptable salts are combined with one, two, three, four or more additional therapeutic agents. In certain embodiments, the compounds disclosed herein or their pharmaceutically acceptable salts are combined with two additional therapeutic agents. In other embodiments, the compounds disclosed herein or their pharmaceutically acceptable salts are combined with three additional therapeutic agents. In another embodiment, the compounds disclosed herein or their pharmaceutically acceptable salts are combined with four additional therapeutic agents. The one, two, three, four or more additional therapeutic agents can be different therapeutic agents selected from the same therapeutic agent class, and/or they can be selected from different therapeutic agent classes. In one embodiment, the compounds disclosed herein or their pharmaceutically acceptable salts are combined with HIV non-nucleoside reverse transcriptase inhibitors. In one embodiment, the compounds disclosed herein or their pharmaceutically acceptable salts are combined with HIV nucleoside or nucleotide reverse transcriptase inhibitors and HIV non-nucleoside reverse transcriptase inhibitors. In another embodiment, the compounds disclosed herein or their pharmaceutically acceptable salts are combined with HIV nucleoside or nucleotide reverse transcriptase inhibitors and HIV protease inhibitors. In another embodiment, the compounds disclosed herein or their pharmaceutically acceptable salts are combined with HIV nucleoside or nucleotide reverse transcriptase inhibitors, HIV non-nucleoside reverse transcriptase inhibitors, and HIV protease inhibitory compounds. In another embodiment, the compounds disclosed herein or their pharmaceutically acceptable salts are combined with HIV nucleoside or nucleotide reverse transcriptase inhibitors, HIV non-nucleoside reverse transcriptase inhibitors, and pharmacokinetic enhancers. In certain embodiments, the compounds disclosed herein or their pharmaceutically acceptable salts are combined with at least one HIV nucleoside reverse transcriptase inhibitor, an integrase inhibitor, and a pharmacokinetic enhancer. In another embodiment, the compounds disclosed herein or their pharmaceutically acceptable salts are combined with two HIV nucleoside or nucleotide reverse transcriptase inhibitors.

In one embodiment, the compounds disclosed herein, or pharmaceutically acceptable salts thereof, are combined with one, two, three, four or more additional therapeutic agents selected from the group consisting of: dolutegravir + abacavir + lamivudine), dolutegravir + abacavir sulfate + lamivudine, raltegravir, raltegravir + lamivudine, (tenofovir disoproxil fumarate + emtricitabine, TDF + FTC), maraviroc, enfuvirtide, (abacavir sulfate + lamivudine, ABC + 3TC), (abacavir sulfate + zidovudine + lamivudine, ABC + AZ T+3TC), adefovir, adefovir disoproxil, (elvitegravir + corbicistat + tenofovir disoproxil fumarate + emtricitabine), rilpivirine, rilpivirine hydrochloride, (rilpivirine + tenofovir disoproxil fumarate + emtricitabine), corbicistat, atazanavir sulfate + corbicistat, atazanavir + corbicistat, darunavir + corbicistat, (efavirenz + tenofovir disoproxil fumarate + emtricitabine), atazanavir, atazanavir sulfate, dolutegravir, elvitegravir, (lopinavir + ritonavir), ritonavir, emtricitabine azithromycin, atazanavir sulfate + ritonavir, darunavir, lamivudine, Prolastin, fosamprenavir, fosamprenavir calcium, efavirenz, (zidovudine + lamivudine, AZT + 3TC), etravirine, nelfinavir, nelfinavir mesylate, interferon, didanosine, stavudine, indinavir, indinavir sulfate, tenofovir + lamivudine, zidovudine, nevirapine, saquinavir, saquinavir mesylate, aldesleukin, zalcitabine, tipranavir, amprenavir, delavirdine, delavirdine mesylate, Radha-108 (Receptol), Hlviral, lamivudine + tenofovir disoproxil fumarate, efavirenz + lamivudine + tenofovir disoproxil fumarate, phosphazid, lamivudine + nevirapine + zidovudine, abacavir, abacavir sulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, darunavir + corbicistat, atazanavir sulfate + corbicistat, atazanavir + corbicistat, tenofovir alafenamide, and tenofovir alafenamide hemifumarate.

In one embodiment, the compounds disclosed herein or pharmaceutically acceptable salts thereof are combined with abacavir sulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, tenofovir alafenamide, or tenofovir alafenamide hemifumarate.

In one embodiment, the compounds disclosed herein or pharmaceutically acceptable salts thereof are combined with tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir alafenamide, or tenofovir alafenamide hemifumarate.

In a specific embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with a first additional therapeutic agent selected from abacavir sulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir alafenamide, and tenofovir alafenamide hemifumarate, and a second additional therapeutic agent selected from emtricitabine and lamivudine.

In a specific embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with a first additional therapeutic agent selected from tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir alafenamide, and tenofovir alafenamide hemifumarate, and a second additional therapeutic agent, wherein the second additional therapeutic agent is emtricitabine.

In certain embodiments, a compound disclosed herein or a pharmaceutically acceptable salt thereof is combined with 5-30 mg of tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide and 200 mg of emtricitabine. In certain embodiments, a compound disclosed herein or a pharmaceutically acceptable salt thereof is combined with 5-10; 5-15; 5-20; 5-25; 25-30; 20-30; 15-30; or 10-30 mg of tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide and 200 mg of emtricitabine. In certain embodiments, a compound disclosed herein or a pharmaceutically acceptable salt thereof is combined with 10 mg of tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide and 200 mg of emtricitabine. In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with 25 mg of tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide and 200 mg of emtricitabine. A compound as disclosed herein (e.g., a compound of Formula (Ia)) can be combined with an agent provided herein at any dose of the compound (e.g., 50 mg to 500 mg of the compound), as if each dosage combination were specifically and individually listed.

In certain embodiments, a compound disclosed herein or a pharmaceutically acceptable salt thereof is combined with 200-400 mg of tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil and 200 mg of emtricitabine. In certain embodiments, a compound disclosed herein or a pharmaceutically acceptable salt thereof is combined with 200-250; 200-300; 200-350; 250-350; 250-400; 350-400; 300-400; or 250-400 mg of tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil and 200 mg of emtricitabine. In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with 300 mg of tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil fumarate and 200 mg of emtricitabine. As disclosed herein, a compound (e.g., a compound of formula (Ia)) can be combined with an agent provided herein at any dose of the compound (e.g., 50 mg to 500 mg of the compound), as if each dosage combination were specifically and individually listed.

In certain embodiments, when the compounds disclosed herein are combined with one or more additional therapeutic agents as described above, the components of the composition are administered in a simultaneous or sequential regimen. When administered sequentially, the combination can be administered in the form of two or more administrations.

In certain embodiments, the compounds disclosed herein are combined with one or more additional therapeutic agents in a single dosage form for simultaneous administration to a patient, eg, as a solid dosage form for oral administration.

In certain embodiments, the compounds disclosed herein are administered with one or more additional therapeutic agents. Co-administration of a compound disclosed herein with one or more additional therapeutic agents generally refers to the simultaneous or sequential administration of a compound disclosed herein and one or more additional therapeutic agents such that a therapeutically effective amount of the compound disclosed herein and one or more additional therapeutic agents are present in the patient's body.

Co-administration includes administering a unit dose of a compound disclosed herein before or after administering a unit dose of one or more additional therapeutic agents, for example, administering a compound disclosed herein within seconds, minutes, or hours of administering one or more additional therapeutic agents. For example, in some embodiments, a unit dose of a compound disclosed herein is first administered, and then a unit dose of one or more additional therapeutic agents is administered within seconds or minutes. Alternatively, in other embodiments, a unit dose of one or more additional therapeutic agents is first administered, and then a unit dose of a compound disclosed herein is administered within seconds or minutes. In some embodiments, a unit dose of a compound disclosed herein is first administered, and then a unit dose of one or more additional therapeutic agents is administered after a period of several hours (e.g., 1-12 hours). In other embodiments, a unit dose of one or more additional therapeutic agents is first administered, and then a unit dose of a compound disclosed herein is administered after a period of several hours (e.g., 1-12 hours).

General synthetic procedure

The embodiments also relate to methods and intermediates that are useful for preparing the compounds of the present invention or pharmaceutically acceptable salts thereof.

Exemplary chemical entities useful in the methods of the embodiments will now be described by reference to the illustrative synthetic schemes and subsequent specific examples for the general preparations herein. It will be appreciated by those skilled in the art that, to obtain the various compounds herein, starting materials can be appropriately selected so that the final desired substituent will be carried out to produce the desired product by a suitable reaction scheme with or without protection. Alternatively, it may be necessary or desirable to replace the final desired substituent with a suitable group that allows the reaction scheme to proceed and, when desired, with the desired substituent replacement. Additionally, it will be appreciated by those skilled in the art that the conversions shown in the following schemes can be performed in any order compatible with the functionality of the particular side groups.

Representative syntheses of compounds of the present disclosure are described in the following schemes and in the specific examples that follow. Schemes 1 and 2 are provided as additional embodiments of the present invention and illustrate a general method for preparing compounds of formula (Ia) and for preparing other compounds of formula (Ia). This method is compatible with a wide range of functionalities.

Solution 1

Alcohol a1 is oxidized to form ketone b1, which further reacts to form sulfimide c1. Reaction with an activated vinyl-containing reagent such as allyl or vinyl magnesium bromide forms adduct d1. The amine is then deprotected to form e1, which reacts with f1 to form the bicyclic g1. Allylation of the amide forms h1, which further cyclizes to form i1. The internal olefin can be retained or reduced to form k1. Finally, the methoxy group is converted to a hydroxyl group to form j1.

Option 2

The reaction between amines a2 and f2 forms g2. When ^R1 is H, the hydroxyl group is oxidized to form ketone h2. Cyclization with a hydroxyalkylamine provides tetracyclic i2. Ester hydrolysis followed by amide coupling provides j2. The methoxy group is then converted to a hydroxyl group to provide k2.

In certain embodiments, when ^R1 is a protecting group, the methyl ester of G2 is selectively hydrolyzed and converted to an amide. The alcohol is deprotected and then oxidized to yield H3. At this point, coupling with a hydroxyalkylamine yields the tricyclic J2. Finally, the methoxy group is converted to a hydroxy group to yield K2.

The following examples illustrate various methods for preparing the compounds of the present disclosure, ie, compounds of formula (Ia):

Wherein A, A', R ¹ and R ² are as defined above. It should be understood that those skilled in the art can prepare these compounds by similar methods or by combining other methods known to those skilled in the art. It should also be understood that those skilled in the art can prepare other compounds of formula (Ia) not explicitly described below in a manner similar to the above and below by using appropriate starting components and adjusting the parameters of the synthesis as needed. Typically, starting components can be obtained from sources such as Sigma Aldrich, Lancaster Synthesis, Inc., Maybridge, Matrix Scientific, TCI and Fluorochem USA, or synthesized according to sources known to those skilled in the art (see, for example, Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5th edition (Wiley, December 2000)) or prepared as described herein.

The following examples are offered for purposes of illustration and not limitation.

Example

Example 1

Preparation of compound 14

Step 1

A solution of (3S,4S)-3-aminotetrahydro-2H-pyran-4-ol (1, 2667 mg, 22.77 mmol) and triethylamine (4.76 mL, 34.15 mmol) in water (23 mL) and 1,4-dioxane (23 mL) was stirred at room temperature while 1-[(2-trimethylsilyl)ethoxycarbonyloxy]pyrrolidine-2,5-dione (2, 6498 mg, 25.06 mmol) was added. The resulting mixture was stirred at room temperature. After 71 hours, the reaction mixture was diluted with water (~125 mL) and extracted with ethyl acetate (~125 mLx2). The extracts were washed with water (125 mLx1), combined, dried ( _Na2SO4 ) and concentrated. _The residue was purified by silica gel column chromatography (120 g column) using hexane-ethyl acetate as eluent, and the fractions containing the product were combined and concentrated to give compound 3: ^1H NMR (400 MHz, chloroform-d) δ 4.81 (s, 1H), 4.25-4.09 (m, 2H), 4.09-3.97 (m, 1H), 3.91 (dt, J = 11.6, 4.7 Hz, 1H), 3.69 (s, 1H), 3.52 (d, J = 9.5 Hz, 1H), 3.46 (ddd, J = 11.9, 9. 1H), 3.21 (t, J = 9.4 Hz, 1H), 2.46 (s, 1H), 2.01 (dddd, J = 13.1, 5.4, 4.4, 3.2 Hz, 1H), 1.65 (dtd, J = 13.2, 8.8, _{4.1 Hz} , 1H), 1.07-0.90 (m, 2H), 0.04 (s, 9H). LCMS-ESI ⁺ (m/z): [M+ _{HC2H4 ]} ⁺ _C9H20NO4Si calcd: 234.12; found: 233.94.

Step 2

A mixture of compound 3 (4.994 g, 19.11 mmol) in dichloromethane (98 mL) was stirred at 0 ° C. Dess-Martin periodinane (9724 mg, 22.93 mmol) was added in batches. After 15 minutes, the mixture was stirred at room temperature for 1.5 hours. The reaction mixture was filtered to remove the precipitate, and the solid was washed with dichloromethane. After the filtrate and the washing solution were combined and concentrated, the residue was purified by silica gel column chromatography (120 g column) using hexane-ethyl acetate as eluent to obtain compound ⁴ : NMR (400MHz, chloroform-d) δ5.54 (s, 1H), 4.62 (dd, J=10.3, 6.9Hz, 1H), 4.45 (s, 1H), 4.33 (ddt, J=11.0, 7.4, 1.5Hz, 1H), 4.25-4.05 (m, 2H), 3.62 (ddd, J= 12.4, 11.3, 2.6Hz, 1H), 3.19 (t, J＝10.6Hz, 1H), 2.77 (td, J＝13.1, 7.3Hz, 1H), 2.52 (ddd, J=13.9, 2.5, 1.3Hz, 1H), 1.09-0.89 (m, 2H), 0.04 (s, 9H). LCMS-ESI ⁺ (m/z): [M+HC ₂ H ₄ ] ⁺ C ₉ H ₁₈ NO ₄ Si calcd: 232.10; found: 231.83.

Step 3

To a solution of compound 4 (997 mg, 3.844 mmol) and (R)-tert-butylsulfinyl imine (5,562 mg, 4.637 mmol) in THF (16 mL, 0.25 M) was added Ti(OEt) ₍ 1.63 mL, 7.775 mmol) at room temperature for 16 hours. The reaction mixture was poured into a stirred mixture of ethyl acetate (-20 mL) and NaHCO _aqueous solution (-15 mL). After adding some diatomaceous earth to the mixture, it was filtered through a pad of diatomaceous earth. The filter cake was washed with ethyl acetate (x2). The filtrate and washings were combined, dried ( _MgSO ), and concentrated. The residue was purified by silica gel column chromatography (40 g column) using dichloromethane-ethyl acetate as eluent to give Compound 6: ^1H NMR (400 MHz, chloroform-d) δ 5.55 (s, 1H), 4.51 (s, 1H), 4.41 (s, 1H), 4.15 (q, J = 7.7 Hz, 3H), 3.77 (d, J = 14.6 Hz, 1H), 3.53 (td, J = 11.8, 2.4 Hz, 1H), 3.22 (t, J = 10.3 Hz, 1H), 2.63 (ddd, J = 14.5, 12.1, 6.5 Hz, 1H), 1.26 (s, 9H), 1.06-0.89 (m, 2H), 0.03 (s, 10H). LCMS-ESI ⁺ (m/z): [M+HC ₂ H ₄ ] ⁺ C ₁₃ H ₂₇ N ₂ O ₄ SSi calcd: 335.15; found: 334.83.

Step 4

To a solution of compound 6 (725 mg, 2.000 mmol) in THF (7.2 mL) stirred in an acetone-dry ice bath was added allylmagnesium bromide (1 M in ether, 6 mL) over ~3 minutes. The bath was warmed to 35°C over 50 minutes, and the reaction mixture was quenched with saturated _NH4Cl . After adding some water to dissolve the solid formed, the mixture was extracted with ethyl acetate (~25 mL _x 2) and the extracts were washed with water (x 2). The combined extracts were dried ( _Na2SO4 ) and concentrated. The residue was purified by silica gel column chromatography (80 g column) using hexane-ethyl acetate to obtain compound 7: ^1H NMR (400 MHz, chloroform-d) δ 5.92 (dt, J = 16.7, 8.6 Hz, 1H), 5.26-5.07 (m, 3H), 4.17 (t, J = 8.5 Hz, 2H), 4.05-3.96 (m, 1H), 3.93 (dd, J = 11.7, 2.4 Hz, 1H), 3.81-3.64 (m, 2H), 3.59 (dd, J = 11.7, 4.2 Hz, 1H), 2.68 (dd, J=14.4, 6.8 Hz, 1H), 2.49-2.38 (m, 1H), 1.81 (ddd, J=14.5, 9.3, 5.2 Hz, 1H), 1.67 (d, J=15.0 Hz, 1H), 1.25 (s, 9H), 0.99 (t, J=8.5 Hz, 2H), 0.04 (d, J ₌ 0.8 Hz, 9H). LCMS-ESI ⁺ (m/z): [M+H] ⁺ calcd _{. for Ci8H37N2O4SSi : 405.22} ; found: 404.82.

Step 5

A mixture of compound 7 (463 mg, 1.144 mmol) and tetrabutylammonium fluoride hydrate (640 mg, 2.290 mmol) in acetonitrile (5 mL) was stirred at 50°C for 8 hours. After adding additional tetrabutylammonium fluoride hydrate (640 mg, 2.290 mmol), the mixture was stirred at 50°C for 8 hours. The reaction mixture was acidified with 2N HCl, and then ~1 mL of saturated _NaHCO₃ was added to neutralize the solution. The resulting mixture was concentrated to a slurry and dried under vacuum. The _{residue was used in the next reaction: LCMS-ESI+ (m/z): [M+H]+ calculated for Ci2H25N2O2S :} ^{261.16 ;} _{found :} 260.91.

To the crude residue were added pyrone 8 (278 mg, 1.148 mmol), NaHCO ₃ (194 mg, 2.309 mmol), water (2 mL), and methanol (2 mL). The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated to remove most of the solvent and the residue was triturated in dichloromethane (-50 mL). The resulting mixture was dried (MgSO ₄ ), filtered, and concentrated.

To the crude concentrated residue in dichloromethane (6 mL) was added 4N HCl in dioxane (6 mL) and the resulting mixture was stirred at room temperature for 1 h. The mixture was concentrated and dried under vacuum for -10 min: LCMS-ESI ⁺ (m/z): [M+H] ⁺ _{Calcd . for Ci8H25N2O7 : 381.17} ; Found: 381.06.

A mixture of the above residue and DBU (0.9 mL, 6.018 mmol) in methanol (10 mL) was stirred in a 50° C. bath for 15 minutes. After concentrating the solution, the residue was purified by silica gel column chromatography (40 g column) using ethyl acetate-20% methanol/ethyl acetate as eluent to give Compound 9: ¹ H NMR (400 MHz, chloroform-d) δ 8.17 (s, 1H), 8.08 (s, 1H), 5.69 (dddd, J=16.8, 10.1, 8.2, 6.5 Hz, 1H), 5.21-5.12 (m, 1H), 5.05 (dd, J=17.0, 1.7 Hz, 1H), 4.14-4.05 (m, 1H), 3.99 (s, 3H), 3.95 (dd, J=11 .5, 5.5 Hz, 1H), 3.87 (s, 3H), 3.83-3.92 (m, 1H), 3.73 (ddt, J=18.3, 6.7, 3.5 Hz, 1H), 3.61 (t, J=11.3 Hz, 1H), 2.43 (dd, J=14.0, 6.5 Hz, 1H), 2.26 (dd, J=14.0, 8.3 Hz, 1H), 1.98-1.85 (m, 2H) _. LCMS-ESI ⁺ (m/z): [M+H] ⁺ _{Calcd. for Ci7H21N2O6} : 349.14; found: 349.09.

Step 6

A mixture of compound 9 (326 mg, 0.936 mmol) and 60% NaH (149 mg, 3.725 mmol) was placed in an ice bath and DMF (4 mL) was added to the mixture. After stirring for 5 minutes, allyl bromide (10, 0.2 mL, 2.311 mmol) was added and the resulting mixture was stirred at room temperature for 1.25 hours: LCMS-ESI ⁺ (m/z): [M+H] ⁺ C ₂₀ H ₂₅ N ₂ O ₆ calculated value: 389.17; found value: 389.13.

To the reaction mixture was added 1N NaOH (1.9 mL) and the mixture was stirred at 0°C for 20 minutes. The reaction mixture was acidified with 4N HCl in dioxane (~1.5 mL) and concentrated using a rotary evaporator with a vacuum pump and _{a 55°C bath to remove all solvents. The residual mixture was co-evaporated with toluene to give the crude acid: LCMS-ESI+ (m/z): [M+H]+ calculated for C19H23N2O6 :} ^{375.16 ;} _{found :} 375.13.

A mixture of the crude acid, 3-chloro-2,4-difluorobenzylamine HCl salt (11, 222 mg, 1.037 mmol), and (dimethylamino)-N,N-dimethyl(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy)methaniminium hexafluorophosphate (HATU, 715 mg, 1.881 mmol) in dichloromethane (10 mL) was stirred at room temperature, and DIPEA (1.75 mL, 10.05 mmol) was added. The mixture was stirred at room temperature for 30 minutes. The reaction mixture was diluted with ethyl acetate and washed with saturated _NH4Cl (x2), saturated _NaHCO3 (x2), and brine (x1). After the aqueous portion was extracted with ethyl acetate (x1), _the two organic portions were combined, dried ( _Na2SO4 ), and concentrated. The residue was purified by silica gel column chromatography (40 g column) using ethyl acetate-20% methanol/ethyl acetate as eluent to give Compound 12: ¹ H NMR (400 MHz, methanol-d ₄ ) δ 8.56 (d, J=2.5 Hz, 1H), 7.37 (td, J=8.4, 6.3 Hz, 1H), 7.08 (td, J=8.7, 1.8 Hz, 1H), 6.10-5.92 (m, 1H), 5.67-5.47 (m, 1H), 5.35 (dd, J=17.3, 1.6 Hz, 1H), 5.24 (dt, J=10.3, 1.3 Hz, 1H), 5.03-4.92 (m, 2H), 4.64 (s, 2H), 4.61 (dd, J=11.0, 5.0 Hz, 1H ), 4.44 (dd, J=15.5, 6.5Hz, 1H), 4.08 (tt, J=11.1, 7.1Hz, 2H), 3.93 (dd, J=11.4, 5.1Hz, 1H), 3.90 (s, 3H), 3.86-3.77 (m, 1 H), 3.57 (dt, J=14.7, 12.0Hz, 2H), 2.49 (dd, J=14.3, 7.4Hz, 1H), 2.44-2.38 (m, 1H), 2.36 (d, J=15.4Hz, 1H), 2.00 (m, 1H). ¹⁹ F NMR (376 MHz, methanol-d ₄ ) δ −117.21 (ddt, J=9.1, 6.0, 2.9 Hz, 1F), −119.79 (d, J=8.8 Hz, 1F). LCMS-ESI ⁺ (m/z): [M+H] ⁺ Calcd. for C ₂₆ H ₂₇ ClF ₂ N ₃ O ₅ : 534.16; Found: 534.17.

Step 7

A solution of compound 12 (63 mg, 0.118 mmol) in dichloromethane (12 mL) was stirred in an ice bath while bubbling with Ar gas. After 30 minutes, 1st generation Grubbs catalyst (3.5 mg, 4.654 μmol) was added and Ar bubbling was continued for 15 minutes. Then, the reaction mixture was refluxed at 47°C. After 2 hours, 1st generation Grubbs catalyst (3 mg, 3.99 μmol) was added and the mixture was refluxed. After another 2.75 hours, 1st generation Grubbs catalyst (5 mg, 6.649 μmol) was added. After refluxing for 45 minutes, the reaction mixture was concentrated and the residue was purified by silica gel column chromatography (24 g column) using hexane-ethyl acetate-20% methanol/ethyl acetate as eluent to obtain compound ¹³ : NMR (400 MHz, chloroform-d) δ 10.43 (t, J = 6.0 Hz, 1H), 8.43 (s, 1H), 7.35-7.21 (m, 1H), 6.92 (td, J = 8.5, 1.8 Hz, 1H), 5.72 (d, J = 3.2 Hz, 2H), 5.20-5.04 (m, 1H), 4.73-4.56 (m, 2H), 4.18-4.09 (m, 1H), 4.03 (d, J = 0.9Hz, 3H), 3.92 (td, J=14.0, 12.9, 4.7Hz, 2H), 3.68 (t, J=11.3Hz, 1H), 3.63-3.53 (m, 1H), 3.47 (d t, J=19.2, 3.7Hz, 1H), 2.57-2.40 (m, 2H), 1.99-1.86 (m, 1H), 1.68 (ddd, J=16.0, 12.4, 4.4Hz, 1H). ¹⁹ F NMR (376MHz, chloroform-d) δ -114.68--115.04 (m, 1F), -117.28 (d, J=7.9Hz, 1F). LCMS-ESI ⁺ (m/z): [M+H] ⁺ calcd. for C ₂₄ H ₂₃ ClF ₂ N ₃ O ₅ : 506.13; found: 506.16.

Step 8

To a solution of compound 13 (11.4 mg, 0.023 mmol) in MeCN (1 mL) was added MgBr ₂ (10.7 mg, 0.058 mmol) at room temperature and the resulting mixture was stirred at 50° C. for 30 minutes. The reaction mixture was stirred at 0° C. and 1N HCl (~6 drops) was added to bring the mixture into solution. The resulting solution was diluted with water and the product was extracted with dichloromethane (x3). The combined extracts were dried (MgSO ₄ ) and concentrated. The residue was purified by silica gel column chromatography (12 g column) using dichloromethane-20% methanol/dichloromethane as eluent to give compound 14: ¹ H NMR (400 MHz, chloroform-d) δ 12.60 (s, 1H), 10.45 (s, 1H), 8.37 (s, 1H), 7.26 (m, 1H), 6.92 (td, J = 8.5, 1.8 Hz, 1H), 5.85-5.61 (m, 2H), 5.19 (d, J = 18.0 Hz, 1H), 4.67 (d, J = 5.8 Hz, 2H) , 4.13 (s, 1H), 4.00-3.85 (m, 2H), 3.72-3.54 (m, 2H), 3.49 (d, J = 18.8 Hz, 1H), 2.57 (dd, J = 20.6, 15.2 Hz, 2H), 1.99 (d, J = 16.7 Hz, 1H), 1.75 (ddd, J = 16.2, 12.4, 4.5 Hz, 1H). ¹⁹ F NMR (376 MHz, CHLOROFORM-d) δ -115.09 (s, 1F), -117.30 (s, 1F). _LCMS -ESI ⁺ (m/z): [M+H] ⁺ _{Calcd. for C23H21ClF2N3O5 :} 492.11; Found: 492.15.

Example 2

Preparation of compound 15

Step 1

A mixture of compound 13 (32 mg, 0.063 mmol) and 10% palladium on carbon (5 mg, 0.174 mmol) in ethanol (2 mL) was stirred under a hydrogen atmosphere. After 2 hours, the reaction mixture was filtered through a pad _of celite and the celite was washed with ethanol. The combined filtrate and washings were concentrated to dryness to give the crude saturated product, which was _used in the next reaction: ^LCMS - ^ESI (m/z): [ _M +H] calculated for _{C₂₄H₂₅ClF₂N₃O₅} : _508.15 ; found: 508.14.

To a solution of the above crude saturated product in MeCN (3 mL) was added magnesium bromide (32 mg, 0.174 mmol) at room temperature and the resulting mixture was stirred in a 50°C bath for 30 minutes. The reaction mixture was stirred at 0°C and 1N HCl (~7 drops) was added to bring the mixture into solution. After diluting the solution with water, the product was extracted with dichloromethane (x3). The combined extracts were dried (MgSO ₄ ) and concentrated. The residue was purified by silica gel column chromatography (12 g column) using dichloromethane-20% methanol/dichloromethane as eluent to give compound 15: ¹ H NMR (400 MHz, chloroform-d) δ 12.60 (s, 1H), 10.45 (s, 1H), 8.37 (s, 1H), 7.26 (m, 1H), 6.92 (td, J = 8.5, 1.8 Hz, 1H), 5.85-5.61 (m, 2H), 5.19 (d, J = 18.0 Hz, 1H), 4.67 (d, J = 5.8 Hz, 2H) , 4.13 (s, 1H), 4.00-3.85 (m, 2H), 3.72-3.54 (m, 2H), 3.49 (d, J = 18.8 Hz, 1H), 2.57 (dd, J = 20.6, 15.2 Hz, 2H), 1.99 (d, J = 16.7 Hz, 1H), 1.75 (ddd, J = 16.2, 12.4, 4.5 Hz, 1H). ¹⁹ F NMR (376 MHz, CHLOROFORM-d) δ -115.09 (s, 1F), -117.30 (s, 1F). _LCMS -ESI ⁺ (m/z): [M+H] ⁺ _{Calcd. for C23H21ClF2N3O5 :} 492.11; Found: 492.15.

Example 3

Preparation of compound 25

Step 1

A solution of compound 16 (4.00 g, 26.04 mmol) and triethylamine (5.44 mL, 39.06 mmol) in water (35 mL) and 1,4-dioxane (35 mL) was stirred at room temperature and compound 2 (7.428 g, 28.64 mmol) was added. The resulting mixture was stirred at room temperature overnight. After 16 hours, the reaction mixture was diluted with water (~125 mL) and extracted with ethyl acetate (~125 mL x 2). The extracts were washed with water (125 mL x 1), combined, dried (Na ₂ SO ₄ ), and concentrated. The residue was purified by silica gel column chromatography (using a 120 g column with a cartridge) using hexane-ethyl acetate as eluent to obtain compound 17: ¹ H NMR (400 MHz, chloroform-d) δ 4.68 (s, 1H), 4.23–4.13 (m, 2H), 4.01 (ddd, J = 11.4, 4.8, 1.1 Hz, 1H), 3.92 (dd, J = 12.0, 4.8 Hz, 1H), 3.56 (ddd, J = 12.3, 9.7, 5.4 Hz, 1H), 3.48 (td, J δ = 1.47 (m, 1H), 1.26 (dtd, J = 13.2, 11.6, 4.8 Hz, 1H), 1.11 (m, 2H), 0.04 (s _, 9H). LCMS-ESI ⁺ (m/z): _[ M+ _HC2H4 ] ⁺ _C9H20NO4Si calcd: 234.12; found _: 233.95.

Step 2

A solution of compound 17 (6.430 g, 24.6 mmol) in dichloromethane (125 mL) was stirred at 0°C (some reactant precipitated) while Dess-Martin periodinane (12.52 g, 29.52 mmol) was added portionwise. After 15 minutes, the mixture was stirred at room temperature for 7 hours. The reaction mixture was filtered to remove the precipitate, and the solid was washed with dichloromethane. The filtrate and washing layer were concentrated. And purified by silica gel column chromatography (120 g column) using hexane-ethyl acetate as eluent to give Compound 18: ^{1 H} NMR (400 MHz, chloroform-d) δ 5.48 (s, 1H), 4.49 (dt, J = 12.8, 6.6 Hz, 1H), 4.22–4.09 (m, 3H), 4.09–3.98 (m, 2H), 3.90 (td, J = 11.7, 3.2 Hz, 1H), 2.84–2.61 (m, 1H), 1.89 (dddd, J = 13.1, 12.1, 10.4, 5.4 Hz, 1H), 1.06–0.93 (m, 2H), 0.04 (s, 9H). LCMS-ESI ⁺ (m/z): [M+HC ₂ H ₄ ] ⁺ C ₉ H ₁₈ NO ₄ Si calcd: 232.10; found: 231.83.

Step 3

To a solution of compound 18 (1.500 g, 5.789 mmol) and (R)-tert-butylsulfenamide (5,841.11 mg, 6.94 mmol) in THF (10 mL) was added titanium tetraethoxide (2.452 mL, 11.7 mmol) at room temperature. The resulting solution was stirred at room temperature overnight. The reaction mixture was poured into a stirred mixture of ethyl acetate (-20 mL) and saturated aqueous _NaHCO₃ (-15 mL). After adding some celite to the mixture, it was filtered through a celite pad and the pad was washed with ethyl acetate. The combined filtrate and washing layers were dried ( _MgSO₄ ) and concentrated. The residue was purified by silica gel column chromatography (40 g column) using ethyl acetate-20% methanol/ethyl acetate as eluent to obtain Compound 19: ^1H NMR (400 MHz, chloroform-d) δ 5.41 (d, J = 14.4 Hz, 1H), 4.53 (d, J = 10.0 Hz, 1H), 4.26-4.07 (m, 3H), 3.97 (d, J = 11.1 Hz, 1H), 3.85-3.67 (m, 1H), 2.58 (d, J = 8.6 Hz, 1H), 1.84 (qd, J = 12.0, 5.4 Hz, 1H), 1.65-1.53 (m, 1H), 1.25 (s, 9H), 0.99 (td, J = 8.9, 8.3, 4.7 Hz, 2H), 0.04 (s, 9H). LCMS-ESI ⁺ (m/z): [M+HC ₂ H ₄ ] ⁺ C ₁₃ H ₂₇ N ₂ O ₄ SSi calcd: 335.15; found: 334.86.

Step 4

A solution of compound 19 (1125 mg, 3.103 mmol) in THF (12 mL) was stirred in a -78°C bath while allylmagnesium bromide (1 M in ether, 9.31 mL) was added over 4 minutes. After 40 minutes, the bath temperature was changed to -60°C, the reaction mixture was removed from the bath and stirred at room temperature for 30 minutes. The reaction mixture was diluted with saturated NH ₄ Cl with some water and extracted with ethyl acetate (~25 mL x 2). After washing the extracts with water (x 2), the combined extracts were dried (Na ₂ SO ₄ ) and concentrated. The residue was purified by silica gel column chromatography (80 g column) using hexane-ethyl acetate as eluent to give compound 20: ¹ H NMR (400 MHz, chloroform-d) δ 6.78 (d, J = 10.2 Hz, 1H), 5.85–5.65 (m, 1H), 5.17–5.01 (m, 2H), 4.17 (ddd, J = 17.5, 10.3, 6.6 Hz, 2H), 3.98 (dd, J = 11.7, 5.0 Hz, 1H), 3.84 (ddd, J = 12.2, 10.2, 4.6 Hz, 1H), 3.74–3.60 (m, 1 3H), 3.55–3.39 (m, 1H), 3.37 (d, J=11.7 Hz, 1H), 2.67 (dd, J=15.0, 7.0 Hz, 1H), 2.45–2.27 (m, 1H), 1.83 (tt, J=12.7, 6.5 Hz, 1H), 1.76–1.53 (m, 2H), 1.28 (s, 9H), 1.01 (dt, J=10.2, 6.4 Hz, 2H), 0.03 (s, 10H). LCMS-ESI ⁺ (m/z): _[ M+H] ⁺ calcd _{. for Ci6H33N2O4SSi} : 377.19; found: 376.98.

Step 5

To a mixture of compound 20 (939 mg, 2.321 mmol) and tetrabutylammonium fluoride hydrate (2594.2 mg, 9.282 mmol) was added acetonitrile (10 mL) and the reaction was stirred at 50° C. overnight. The reaction mixture was acidified with 2N HCl and neutralized with 1 mL of saturated NaHCO _3. The resulting solution was concentrated and dried under vacuum.

To the crude residue were added compound 8 (562 mg, 2.321 mmol), NaHCO ₃ (389.89 mg, 4.641 mmol), water (5 mL) and methanol (8 mL). The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated to remove most of the solvent. After the residue was dissolved in dichloromethane (~50 mL) and dried (MgSO ₄ ), the insoluble material was filtered off and the filtrate was concentrated. The residue was dissolved in dichloromethane (12 mL) and treated with 4N HCl in dioxane (12 mL) at room temperature. After 2 hours, the reaction mixture was concentrated to remove the solvent and the residue was partially purified by silica gel column chromatography (80 g column) using ethyl acetate-20% methanol/ethyl acetate as eluent. The partially purified product was further purified by preparative HPLC (acetonitrile/H ₂ O with 0.1% TFA modifier), and the fractions containing the product were combined and freeze-dried to obtain compound 21: ¹ H NMR (400MHz, chloroform-d) δ8.76 (s, 1H), 6.31 (s, 1H), 5.62 (d, J = 7.8Hz, 1H), 5.19 (d, J = 10.2Hz, 1H), 5.08 (d, J = 17.0Hz, 1H), 4.65 (s, 1 H), 4.13 (s, 4H), 3.98 (s, 3H), 3.86 (d, J = 13.2Hz, 1H), 3.52 (t, J = 11.8Hz, 2H), 2.35 (dd, J = 14.2, 6.6Hz, 1H), 2.30–2.05 (m, 3H). LCMS-ESI ⁺ (m _/ z): [M+H] ⁺ calcd _{. for Ci7H21N2O6} : 349.14; found: 349.13.

Step 6

A mixture of compound 21 (376 mg, 1.079 mmol) and 60% NaH (173 mg, 4.317 mmol) was cooled at 0°C while DMF (5 mL) was added to the mixture. After 5 minutes, allyl bromide (0.231 mL, 2.666 mmol) was added. After 10 minutes, 2N NaOH (0.6 mL) was added and stirred at 0°C for 10 minutes. The reaction mixture was then acidified with 2N HCl (~2.5 mL) and the acidified reaction mixture was concentrated to remove the solvent. The residue was dissolved in water and purified by preparative HPLC (acetonitrile/H ₂ O with 0.1% TFA modifier). The fractions containing the product were combined and freeze-dried to obtain compound 22: ¹ H NMR (400 MHz, chloroform-d) δ 8.33 (s, 1H), 5.93 (dq, J = 14.7, 5.2, 4.5 Hz, 1H), 5.61–5.45 (m, 1H), 5.36 (d, J = 17.2 Hz, 1H), 5.27 (d, J = 10.0 Hz, 1H), 5.14 (d, J = 10.0 Hz, 1H), 4.93 (dd, J = 16.2, 8.2 Hz, 2 5 Hz, 1H), 4.36 (d, J = 13.5 Hz, 1H), 4.13 (s, 5H), 3.99 (dd, J = 15.8, 8.8 Hz, 1H), 3.65-3.49 (m, 1H), 3.42 (d, J = 13.7 Hz, 1H), 2.37 (dd, J = 14.5, 6.7 Hz, 1H), 2.29-2.04 (m, 2H), 1.96 (d, J = 13.5 _Hz , 1H). LCMS-ESI ⁺ (m/z): [M+H] ⁺ _{Calcd. for Ci9H23N2O6 :} 375.16; Found: 375.15.

Step 7

A mixture of compound 22 (141 mg, 0.377 mmol), compound 11 (89 mg, 0.414 mmol) and HATU (286.38 mg, 0.753 mmol) in dichloromethane (5 mL) was stirred at room temperature while N,N-diisopropylethylamine (0.7 mL, 4.011 mmol) was added. After 30 minutes, the reaction mixture was diluted with ethyl acetate and washed with saturated NH ₄ Cl (x2), saturated NaHCO ₃ (x2) and brine (x1). After the aqueous fraction was extracted with ethyl acetate (x1), the organic fractions were combined, dried (Na ₂ SO ₄ ) and concentrated. The residue was purified by silica gel column chromatography (24 g column) using hexane-ethyl acetate-20% methanol/ethyl acetate as eluent to give compound 23: ¹ H NMR (400MHz, chloroform-d) δ10.51 (t, J=6.0Hz, 1H), 8.36 (s, 1H), 7.21 (td, J=8.3, 5. 9Hz, 1H), 6.86 (td, J=8.5, 1.8Hz, 1H), 5.87 (dddd, J=17.3, 10.1, 8.7, 4.3Hz, 1H), 5.45 (dddd, J=17.1, 10.1, 8.3, 7.0Hz, 1H), 5.32–5.21 (m, 1H), 5.17 (d, J ＝10.2Hz, 1H), 5.06–4.98(m, 1H), 4.86(dd, J＝16.8, 1.5Hz, 1H), 4.82–4.74(m , 1H), 4.57 (dd, J=6.1, 2.2Hz, 2H), 4.26 (d, J=13.7Hz, 1H), 4.19 (dd, J=12.0, 4.7Hz, 1H), 4.00 (s, 1H), 3.98 (s, 3H), 3.93 (dd, J=15.8, 8.8Hz, 1H), 3.48 (td , J=12.2, 2.4Hz, 1H), 3.34 (d, J=13.7Hz, 1H), 2.27 (dd, J=14.4, 7.1Hz, 1H), 2 .15(dd, J＝14.4, 8.2Hz, 1H), 2.11–1.98(m, 1H), 1.93–1.82(m, 1H).LCMS-ESI ⁺ (m/z): [M+H] ⁺ Calcd. for C ₂₆ H ₂₇ ClF ₂ N ₃ O ₅ : 534.16; found: 534.19.

Step 8

A solution of compound 23 (142 mg, 0.266 mmol) in dichloromethane (26 mL) was stirred in an ice bath while bubbling with Ar gas. After 20 minutes, 1st generation Grubbs catalyst (20 mg, 26.59 μmol) was added and Ar bubbling was continued for 15 minutes. The reaction mixture was then refluxed at 50°C. After 2 hours, the reaction mixture was concentrated and purified by silica gel column chromatography (24 g column) using hexane-ethyl acetate-20% methanol/ethyl acetate as eluent to obtain compound ²⁴ : NMR (400 MHz, chloroform-d) δ 10.43 (t, J = 6.0 Hz, 1H), 8.43 (s, 1H), 7.35-7.21 (m, 1H), 6.92 (td, J = 8.5, 1.8 Hz, 1H), 5.72 (d, J = 3.2 Hz, 2H), 5.20-5.04 (m, 1H), 4.73-4.56 (m, 2H), 4.18-4.09 (m, 1H), 4.03 (d, J = 0.9Hz, 3H), 3.92 (td, J=14.0, 12.9, 4.7Hz, 2H), 3.68 (t, J=11.3Hz, 1H), 3.63-3.53 (m, 1H), 3.47 (d t, J=19.2, 3.7Hz, 1H), 2.57-2.40 (m, 2H), 1.99-1.86 (m, 1H), 1.68 (ddd, J=16.0, 12.4, 4.4Hz, 1H). ¹⁹ F NMR (377MHz, chloroform-d) δ -114.68--115.04 (m, 1F), -117.28 (d, J=7.9Hz, 1F). LCMS-ESI ⁺ (m/z): [M+H] ⁺ calcd. for C ₂₄ H ₂₃ ClF ₂ N ₃ O ₅ : 506.13; found: 506.16.

Step 9

To a solution of compound 24 (15 mg, 0.03 mmol) in MeCN (1.4 mL) was added magnesium bromide (14.19 mg, 0.077 mmol) at room temperature and the resulting mixture was stirred at 50°C. After 30 minutes, the reaction mixture was stirred at 0°C and 1N HCl was added to make the mixture a solution, diluted with water, and then extracted with _CH2Cl2 ( _x3 ). The combined extracts were dried ( _MgSO4 ) and concentrated. The residue was purified by silica gel column chromatography (12 g column) using dichloromethane-20% methanol/dichloromethane as eluent. The sample was dissolved in dioxane and freeze-dried to give compound 25: ^1H NMR (400 MHz, chloroform-d) δ 12.85 (s, 1H), 10.48 (t, J = 6.1 Hz, 1H), 8.39 (s, 1H), 7.40-7.14 (m, 1H), 6.91 (td, J = 8.5, 1.8 Hz, 1H), 4.64 (dd, J = 17.4, 5.7 Hz, 3H), 4.08-3.98 (m, 1H), 3.87 (ddd, J = 16. 9, 11.7, 6.9Hz, 2H), 3.65 (t, J=11.2Hz, 1H), 3.61-3.52 (m, 1H), 3.03 (td, J=13.4, 3.1Hz, 1H) , 2.70 (d, J=15.7Hz, 1H), 1.92 (ddd, J=19.2, 9.3, 4.7Hz, 1H), 1.83-1.67 (m, 4H), 1.58 (m, 2H). ¹⁹ FNMR (376MHz, chloroform-d) δ -115.18 (q, J=6.5, 5.4Hz, 1F), -117.36 (dd, J=8.0, 3.3Hz, 1F). LCMS-ESI ⁺ (m/z): [M+H] ⁺ calcd. for C ₂₃ H ₂₁ ClF ₂ N ₃ O ₅ : 492.11; found: 492.15.

Example 4

Preparation of compound 26

Step 1

To a solution of compound 24 (105 mg, 0.208 mmol) in ethanol (5 mL) was added 10% palladium on carbon (18.2 mg) and the resulting mixture was stirred under a hydrogen atmosphere. After 2 hours, the reaction mixture was filtered through a pad of celite and washed with ethanol. The filtrate was concentrated and dried in vacuo. The residue was dissolved in acetonitrile (10 mL) and magnesium bromide (98.96 mg, 0.573 mmol) was added to the solution at room temperature. The resulting mixture was stirred at 50° C. for 30 minutes. The reaction mixture was stirred at 0° C. and 1N HCl was added to make the mixture a solution. The resulting solution was further diluted with water and the product was extracted with dichloromethane (x3). The combined extracts were dried (MgSO ₄ ) and concentrated. The residue was purified by silica gel column chromatography (12 g column) using dichloromethane-20% methanol/dichloromethane as eluent to obtain compound 26: ¹ H NMR (400 MHz, chloroform-d) δ 12.85 (s, 1H), 10.48 (t, J = 6.1 Hz, 1H), 8.39 (s, 1H), 7.40-7.14 (m, 1H), 6.91 (td, J = 8.5, 1.8 Hz, 1H), 4.64 (dd, J = 17.4, 5.7 Hz, 3H), 4.08-3.98 (m, 1H), 3.87 (ddd, J = 16. 9, 11.7, 6.9Hz, 2H), 3.65 (t, J=11.2Hz, 1H), 3.61-3.52 (m, 1H), 3.03 (td, J=13.4, 3.1Hz, 1H) , 2.70 (d, J=15.7Hz, 1H), 1.92 (ddd, J=19.2, 9.3, 4.7Hz, 1H), 1.83-1.67 (m, 4H), 1.58 (m, 2H). ¹⁹ F NMR (376MHz, chloroform-d) δ -115.18 (q, J=6.5, 5.4Hz, 1F), -117.36 (dd, J=8.0, 3.3Hz, 1F). LCMS-ESI ⁺ (m/z): [M+H] ⁺ Calcd. for C ₂₃ H ₂₃ ClF ₂ N ₃ O ₅ : 494.13; Found: 494.17

Example 5

Preparation of compound 30

Step 1

A mixture of 22 (144 mg, 0.385 mmol), 2,4,6-trifluorobenzylamine (27, 68.17 mg, 0.423 mmol) and HATU (292.47 mg, 0.769 mmol) in dichloromethane (5 mL) was stirred at room temperature while N,N-diisopropylethylamine (0.713 mL, 4.096 mmol) was added. After 30 minutes, the reaction mixture was diluted with ethyl acetate and washed with saturated _NH4Cl (x2), saturated _NaHCO3 (x2) and brine (x1). After the aqueous portion was extracted with ethyl acetate (x1), _the organic portions were combined, dried ( _Na2SO4 ), and concentrated. The residue was purified by silica gel column chromatography (24 g column) using hexane-ethyl acetate-20% methanol/ethyl acetate as eluent to obtain compound 28: ^1H NMR (400 MHz, chloroform-d) δ 10.36 (s, 1H), 8.31 (s, 1H), 6.66 (dd, J = 8.8, 7.4 Hz, 2H), 5.93 (dddd, J = 17.3, 10.2, 8.8, 4.2 Hz, 1H), 5.50 (dddd, J = 16.9, 10.1, 8.4, 6.8 Hz, 1H), 5.39–5.27 (m, 1H), 5.24 (d, J = 10.1 Hz, 1H), 5.12 (dd, J = 9.9, 1.4 Hz, 1H), 4.97–4.84 (m, 2H), 4.66 (dd, J = 5.5, 2.0Hz, 2H), 4.33 (d, J=13.6Hz, 1H), 4.11 (dt, J=14.9, 7.4Hz, 3H), 4.05 (s, 3H), 3.98 (dd, J=15.8, 8.8Hz, 1H), 3.53 (td, J=12.3, 2 .4Hz, 1H), 3.39 (d, J=13.6Hz, 1H), 2.33 (dd, J=14.4, 6.9Hz, 1H), 2.19 (dd, J=14.4, 8.5Hz, 1H), 2.16–2.05 (m, 1H), 1.97–1.85 (m, 1H). LCMS-ESI ⁺ (m _{/ z): [M+H]+ calcd. for C26H27F3N3O5 : 518.19 ;} found: 518.20.

Step 2

A solution of compound 28 (164 mg, 0.317 mmol) in dichloromethane (32 mL, 10 mM) was stirred in an ice bath while bubbling with Ar gas. After 30 minutes, 1st generation Grubbs catalyst (23.83 mg, 31.69 μmol) was added and Ar bubbling was continued for 15 minutes. The reaction mixture was then refluxed under a 50°C bath. After 1 hour, the reaction mixture was concentrated and purified by silica gel column chromatography (24 g column) using hexane-ethyl acetate-20% methanol/ethyl acetate as eluent to obtain compound 29 ^. NMR (400 MHz, chloroform-d) δ 10.32 (s, 1H), 8.38 (s, 1H), 6.80-6.54 (m, 2H), 5.71 (dddd, J = 41.1, 10.1, 4.6, 2.2 Hz, 2H), 5.30 (s, 1H), 5.11 (d, J = 18.5 Hz, 1H), 4.66 (dd, J = 5.7, 3.3 Hz, 2H), 4.48 (dd, J = 13.4, 1.3 Hz, 1H), 4.2 4-4.04 (m, 3H), 3.77-3.64 (m, 1H), 3.66-3.52 (m, 1H), 3.16 (d, J=13.4 Hz, 1H), 2.51-2.34 (m, 1H), 2.25 (qd, J=12.5, 5.4 Hz, 1H), 2.04 (s, 2H), 1.93 (d, J=13.6 Hz, 1H), 1.79 (d, J=17.5 Hz, 1H), 1.26 ( _t , J=7.1 _Hz , 2H). LCMS-ESI ⁺ (m/z): [M+H] ⁺ _{Calcd .} for _C24H23F3N3O5 : 490.16; found: 490.18.

Step 3

To a solution of compound 29 (18 mg, 0.037 mmol) in acetonitrile (1.4 mL) was added magnesium bromide (17.6 mg, 0.096 mmol) at room temperature and the resulting mixture was stirred under a 50°C bath. After 30 minutes, the reaction mixture was stirred at 0°C and 1N HCl was added to allow the mixture to become a solution. The resulting solution was further diluted with water and the product was then extracted with dichloromethane (x3). The combined extracts were dried (MgSO ₄ ) and concentrated. The residue was purified by silica gel column chromatography (12 g column) using dichloromethane-20% methanol/dichloromethane as eluent. The sample was dissolved in dioxane and freeze-dried to give compound 30: ¹ HNMR (400 MHz, chloroform-d) δ 12.64 (s, 1H), 10.36 (t, J = 5.7 Hz, 1H), 8.35 (s, 1H), 6.74-6.52 (m, 2H), 5.87-5.61 (m, 2H), 5.25-5.02 (m, 1H), 4.66 (dd, J = 5.8, 2.8 Hz, 2H), 4.50 (d, J = 13. 5 Hz, 1H), 4.09 (ddt, J = 16.4, 11.1, 4.9 Hz, 2H), 3.81-3.50 (m, 2H), 3.21 (d, J = 13.6 Hz, 1H), 2.50 (ddd, J = 17.6, 4.3, 2.2 Hz, 1H), 2.19 (qd, J = 12.4 _{, 5.3 Hz, 1H), 1.97-1.79 (m, 2H). LCMS-ESI+ (m/z): [M+H]+ Calcd. for C23H21F3N3O5 :} ^{476.14 ;} _{found : 476.16} .

Example 6

Preparation of compound 31

Step 1

To a solution of compound 29 (111 mg, 0.227 mmol) in ethanol (5 mL) was added 10% palladium on carbon (19.88 mg) at room temperature and the resulting mixture was stirred under a hydrogen atmosphere. After 2.5 hours, the reaction mixture was filtered through a celite pad and washed with ethanol. After concentrating the filtrate, acetonitrile (10 mL) and magnesium bromide (108.12 mg, 0.587 mmol) were added to the residue at room temperature and stirred under a 50°C bath. After 30 minutes, the reaction mixture was stirred at 0°C and 1N HCl was added to make the mixture a solution. The resulting solution was further diluted with water and the product was then extracted with dichloromethane (x3). The combined extracts were dried (MgSO ₄ ) and concentrated. The residue was purified by silica gel column chromatography (24 g column) using dichloromethane-20% methanol/dichloromethane as eluent to give Compound 31: ^1H NMR (400 MHz, CHLOROFORM-d) δ 10.58 (s, 1H), 8.56 (s, 1H), 6.67 (dd, J = 8.6, 7.6 Hz, 2H), 4.88–4.49 (m, 4H), 4.21–3.90 (m, 2H), 3.62 (t, J = 11.4 Hz, 1H), 3.25 (dd, J = 39.5, 13.4 Hz, 2H), 2.19 (d, J = 12.7 Hz, 1H), 1.91 (d, J = 13.6 Hz, 1H), 1.87–1.47 (m, 5H). LCMS-ESI ⁺ (m/z): [M+H] ⁺ calcd. for C ₂₃ H ₂₃ F ₃ N ₃ O ₅ : 478.16; found: 478.22.

Example 7

Preparation of compound 41

Step 1

A solution of compound 32 (2.000 g, 19.39 mmol) and triethylamine (4.055 mL, 29.09 mmol) in water (15 mL) and 1,4-dioxane (15 mL) was stirred at room temperature, and compound 2 (5.533 g, 21.33 mmol) was added. The resulting mixture was stirred at room temperature overnight. After 16 hours, the reaction mixture was diluted with water (~125 mL) and extracted with ethyl acetate (~125 mL x 2). The extracts were washed with water (125 mL x 1), combined, dried (Na ₂ SO ₄ ), and concentrated. The residue was purified by silica gel column chromatography (120 g column) using hexane-ethyl acetate as eluent to give Compound 33: ^1H NMR (400 MHz, chloroform-d) δ 4.86 (d, J = 6.3 Hz, 1H), 4.30 (dt, J = 5.1, 2.5 Hz, 1H), 4.16 (dd, J = 12.3, 4.9 Hz, 2H), 4.07-4.03 (m, 2H), 3.99 (tt, J = 5.3, 2.2 Hz, 1H), 3.67 (ddd, J = 20.4, 9.7, 2.9 Hz, 2H), 2.71 (s, 1H), 1.05-0.91 (m, 2H), 0.04 (s, 9H).

Step 2

A solution of compound 33 (4.191 g, 16.94 mmol) in dichloromethane (80 mL) was stirred at 0°C (some reactant precipitated) while Dess-Martin periodinane (8.623 g, 20.33 mmol) was added portionwise. After 15 minutes, the mixture was stirred at room temperature (almost in solution). After 7.5 hours, the reaction mixture was filtered to remove the precipitate, and the solid was washed with dichloromethane. The filtrate and washings were concentrated. And purified by silica gel column chromatography (120 g column) using ethyl acetate-20% methanol/ethyl acetate as eluent to give ketone 34: ^1H NMR (400 MHz, chloroform-d) δ 5.07 (s, 1H), 4.67 (t, J = 8.9 Hz, 1H), 4.22-4.13 (m, 4H), 3.93 (d, J = 17.5 Hz, 1H), 3.80 (t, J = 9.7 Hz, 1H), 1.07-0.91 (m, 2H), 0.04 (s, 9H).

Step 3

To a solution of compound 34 (1.812 g, 7.385 mmol) and compound 5 (1.074 g, 8.863 mmol) in THF (15 mL) was added titanium tetraethoxide (3.132 mL, 14.94 mmol) at room temperature. The resulting solution was stirred at room temperature overnight. The reaction mixture was poured into a stirred mixture of ethyl acetate (-20 mL) and saturated NaHCO ₃ (-15 mL). After adding some celite to the mixture, it was filtered through a celite pad and the celite pad was washed with ethyl acetate. After the combined filtrate and washings were dried ( _MgSO4 ) and concentrated, the residue was purified by silica gel column chromatography (80 g column) using dichloromethane-ethyl acetate as eluent to afford Compound 35: ^1H NMR (400 MHz, chloroform-d) δ 5.07 (s, 1H), 5.01 (d, J=18.2 Hz, 1H), 4.54 (s, 1H), 4.46 (d, J=18.1 Hz, 1H), 4.22-4.14 (m, 2H), 3.44-3.29 (m, 1H), 1.30-1.23 (m, 9H), 1.06-0.94 (m, 2H), 0.04 (s, 9H). LCMS-ESI ⁺ (m/z): [M+HC ₂ H ₄ ] ⁺ C ₁₂ H ₂₅ N ₂ O ₄ SSi calcd: 321.13; found: 320.82.

Step 4

A solution of compound 35 (1.604 g, 4.602 mmol) in THF (15 mL) was stirred in an acetone-dry ice bath and allylmagnesium bromide (1 M in ether, 13.81 mL) was added over ~4 minutes. After 40 minutes, the bath temperature was changed to ~-55°C and the reaction mixture was removed from the bath. After 30 minutes, saturated _NH4Cl was added to the reaction mixture with some water. The mixture was extracted with ethyl acetate (~25 mL x 2) and the extracts were washed with water (x2). The combined extracts were dried ( _Na2SO4 ) and concentrated. _The residue was purified by silica gel column chromatography (80 g column) using hexane-ethyl acetate as eluent to give compound 36: ^1H NMR (400 MHz, CHLOROFORM-d) δ 6.36 (s, 1H), 5.92–5.68 (m, 1H), 5.26–5.11 (m, 2H), 4.31 (t, J = 8.7 Hz, 1H), 4.22–4.12 (m, 3H), 3.85 (d, J = 9.5 Hz, 1H), 3.82–3.74 (m, 2H), 3.53 (t, J = 8.6 Hz, 1H), 2.70 (dd, J = 14.8, 7.2 Hz, 1H), 2.56–2.38 (m, 1H), 1.49–1.33 (m, 1H), 1.25 (s, 9H), 0.03 (s, 9H). LCMS-ESI ⁺ (m/z): [M+HC ₂ H ₄ ] ⁺ C ₁₆ H ₃₁ N ₂ O ₄ SSi calcd: 363.18; found: 362.95.

Step 5

To a mixture of compound 36 (906 mg, 2.319 mmol) and tetrabutylammonium fluoride hydrate (2592.9 mg, 9.278 mmol) was added acetonitrile (10 mL) and stirred at 50°C overnight. The reaction mixture was acidified with 2N HCl and neutralized with 1 _mL of saturated NaHCO₃. The resulting solution was concentrated and dried under vacuum. A mixture of the crude residue, compound 8 (540 mg, 2.231 mmol) and _NaHCO₃ (389.7 mg, 4.639 mmol) in water (5 mL) and MeOH (8 mL) was stirred at room temperature for 1 hour. The reaction mixture was concentrated to remove most of the solvent. The residue was dissolved in dichloromethane (~50 mL) and dried ( _MgSO₄ ), then the insoluble material was filtered off and the filtrate was concentrated. The residue was dissolved in dichloromethane (12 mL) and treated with 4N HCl in dioxane (12 mL) for 2 hours at room temperature. After the reaction mixture was concentrated, the residue was dissolved in methanol (20 mL) and DBU (1.734 mL, 11.6 mmol) was added to the solution. After stirring the resulting mixture at 50 ° C for 15 minutes, the reaction mixture was concentrated and the solvent was co-evaporated with toluene. The residue was purified by silica gel column chromatography (80 g column) using ethyl acetate-methanol/ethyl acetate as eluent to obtain compound 37: ¹ H NMR (400 MHz, chloroform-d) δ 8.09 (s, 1H), 5.99 (s, 1H), 5.28–5.15 (m, 2H), 4.56–4.32 (m, 2H), 4.11 (s, 3H), 4.06–3.95 (m, 4H), 3.93 (s, 3H), 2.48 (dd, J = 15.3, 7.4 Hz, 2H). LCMS-ESI ⁺ (m/z): [M+H] ⁺ calcd. for C ₁₆ H ₁₉ N ₂ O ₆ : 335.12; found: 335.06.

Step 6

A mixture of compound 37 (488 mg, 1.46 mmol) and 60% NaH (58.38 mg, 1.46 mmol) was placed in a 0°C bath and DMF (5 mL) was added to the mixture. After 5 minutes, allyl bromide (0.126 mL, 1.46 mmol) was added. After 45 minutes, 2N NaOH (2.6 mL) was added and stirred at 0°C for 2 hours. The reaction mixture was then acidified with 2N HCl (~4 mL) and the acidified reaction mixture was concentrated to remove the solvent. The residue was dissolved in water and purified by HPLC to obtain compound 38. LCMS-ESI ⁺ (m/z): [M+H] ⁺ C ₁₈ H ₂₁ N ₂ O ₆ calculated value: 361.14; found value: 361.11.

Step 7

A mixture of compound 38 (223 mg, 0.619 mmol), compound 11 (145.7 mg, 0.681 mmol) and HATU (470.55 mg, 1.238 mmol) in dichloromethane (8 mL) was stirred at room temperature while N,N-diisopropylethylamine (1.148 mL, 6.59 mmol) was added. After 30 minutes, the reaction mixture was diluted with ethyl acetate and washed with saturated NH ₄ Cl (x2), saturated NaHCO ₃ (x2) and brine (x1). After the aqueous portion was extracted with ethyl acetate (x1), the organic portions were combined, dried (Na ₂ SO ₄ ) and concentrated. The residue was purified by silica gel column chromatography (24 g column) using hexane-ethyl acetate-20% methanol/ethyl acetate as eluent to give compound 39: ¹ H NMR (400 MHz, chloroform-d) δ 8.36 (s, 1H), 7.37–7.26 (m, 1H), 6.94 (td, J = 8.5, 1.9 Hz, 1H), 6.11–5.85 (m, 1H), 5.48 (dt, J = 17.1, 8.6 Hz, 1H), 5.41–5.22 (m, 2H), 5.20–4. 99 (m, 2H), 4.65 (t, J = 6.1 Hz, 2H), 4.56-4.32 (m, 3H), 4.06 (s, 3H), 4.04-3.76 (m, 3H), 2.81 (s, 1H), 2.57 ₍ dd, J = 14.5, 7.6 Hz, 1H), 2.41 (dd, J = 14.4 _{, 7.5 Hz, 1H). LCMS-ESI+ (m/z): [M+H]+ Calcd. for C25H25ClF2N3O5 :} ^{520.15 ;} _{Found :} 520.11.

Step 8

A solution of compound 39 (220 mg, 0.423 mmol) in dichloromethane (42 mL) was stirred in a 0°C bath while bubbling with Ar gas. After 20 minutes, 1st generation Grubbs catalyst (31.82 mg, 42.31 μmol) was added and Ar bubbling was continued for 15 minutes. The reaction mixture was then refluxed at 50°C. After 2 hours, the reaction mixture was concentrated and purified by silica gel column chromatography (24 g column) using hexane-ethyl acetate-20% methanol/ethyl acetate as eluent to obtain compound ⁴⁰ : NMR (400MHz, chloroform-d) δ10.40 (s, 1H), 8.37 (s, 1H), 7.35-7.27 (m, 1H), 6.93 (td, J=8.6, 1.8Hz, 1H), 5.81 (dd, J=23.9, 8.4Hz, 2H), 5.01 (d, J=19.2Hz, 1H ), 4.65 (d, J=6.1Hz, 2H), 4.52 (s, 1H), 4.39 (dd, J=22.2, 9.6Hz, 2H), 4.06 ( s, 3H), 3.92-3.74 (m, 3H), 2.67 (d, J=16.8Hz, 1H), 2.16 (d, J=17.3Hz, 1H). LCMS-ESI ⁺ (m/z): [M+H] ⁺ calcd. for C ₂₃ H ₂₁ ClF ₂ N ₃ O ₅ : 492.11; found: 492.15.

Step 9

To a solution of compound 40 (16 mg, 0.033 mmol) in acetonitrile (1.4 mL) was added magnesium bromide (15.57 mg, 0.085 mmol) at room temperature and the resulting mixture was stirred at 50°C. After 30 minutes, the reaction mixture was stirred at 0°C and 1N HCl was added to bring the mixture into solution. The resulting solution was further diluted with water and then extracted with dichloromethane (×3). The combined extracts were dried (MgSO ₄ ) and concentrated. The residue was purified by silica gel column chromatography (12 g column) using dichloromethane-20% methanol/dichloromethane as eluent to give compound 41: ¹ H NMR (400 MHz, chloroform-d) δ 12.72 (s, 1H), 10.43 (t, J = 6.0 Hz, 1H), 8.36 (s, 1H), 7.33-7.19 (m, 1H), 6.91 (td, J = 8.5, 1.8 Hz, 1H), 5.88 (ddt, J = 9.8, 5.9, 1.9 Hz, 1H), 5.84-5.76 (m, 1H) ), 5.12 (dq, J = 20.4, 3.1, 2.6 Hz, 1H), 4.64 (dd, J = 10.9, 7.0 Hz, 3H), 4.40-4.34 (m, 2H), 3.86-3.74 (m, 3H), 2.75 (dd, J = 16.9, 4.0 Hz, 1H), 2.22 (ddd, J = 17.5, 6.2 _, 2.1 Hz, _1H ). LCMS-ESI ⁺ (m/z): [M+H] ⁺ Calcd _{. for C22H19ClF2N3O5} : 478.10; found: 478.12.

Example 8

Preparation of compound 42

Step 1

To a solution of compound 40 (171 mg, 0.348 mmol) in ethanol (8 mL) was added 10% palladium on carbon (30.48 mg) and the resulting mixture was stirred under a hydrogen atmosphere. After 2.5 hours, the reaction mixture was filtered through a pad of celite and washed with ethanol. After concentrating the filtrate, the residue was dissolved in acetonitrile (15 mL) and magnesium bromide (166.42 mg, 0.904 mmol) was added at room temperature, and the resulting mixture was stirred under a 50°C bath for 30 minutes. After stirring the reaction mixture at 0°C, 1N HCl was added to make the mixture a solution. The resulting solution was further diluted with water, and the product was then extracted with dichloromethane (x3). The combined extracts were dried (MgSO ₄ ) and concentrated. The residue was purified by silica gel column chromatography (24 g column) using dichloromethane-20% methanol/dichloromethane as eluent to obtain compound 42: ¹ H NMR (400MHz, chloroform-d) δ12.97 (s, 1H), 10.45 (s, 1H), 8.27 (s, 1H), 7.27 (s, 3H), 7.00-6.85 (m, 1H), 4.83 (d, J=14.1Hz, 1H), 4.67 (d, J= 5.6Hz, 2H), 4.52-4.40 (m, 1H), 4.38 (s, 2H), 4.03 (d, J=10.3Hz, 1H), 3.80 (s, 1H), 2.96 (d, J=13.3Hz, 1H), 1.93 (d, J=35.7Hz, 3H). LCMS-ESI ⁺ (m/z): [M+H] ⁺ calcd. for C ₂₂ H ₂₁ ClF ₂ N ₃ O ₅ : 480.11; found: 480.15.

Example 9

Preparation of compound 48

Step 1

A solution of compound 19 (1192 mg, 3.288 mmol) in THF (15 mL) was stirred in a -78°C bath while vinylmagnesium bromide (1 M in THF, 13.5 mL) was added over ~2 minutes. The reaction mixture was slowly warmed to -10°C over 1.25 hours and saturated _NH4Cl was added to the reaction mixture with some water. The mixture was extracted with ethyl acetate (x2) and _the extracts were washed with water (x1). The combined extracts were dried ( _Na2SO4 ) and concentrated. The residue was purified by silica gel column chromatography (120 g column) using hexane-ethyl acetate as eluent to give Compound 43: ^1H NMR (400 MHz, chloroform-d) δ 6.00-5.88 (m, 1H), 5.61-5.49 (m, 2H), 4.59 (d, J=9.6 Hz, 1H), 4.39-4.28 (m, 1H), 4.23-4.06 (m, 3H), 4.04-3.93 (m, 1H), 3.82 (q, J=9.1 Hz, 1H), 3.56-3.43 (m, 2H), 1.66 (tt, J=12.9, 5.7 Hz, 2H), 1.20 (s, 9H), 1.04-0.88 (m, 2H), 0.04 (s, 9H). LCMS-ESI ⁺ (m/z): [M+H] ⁺ calcd. for C ₁₇ H ₃₅ N ₂ O ₄ SSi: 391.21; found: 390.88.

Step 2

To a mixture of compound 43 (791 mg, 2.025 mmol) and tetrabutylammonium fluoride hydrate (2282 mg, 8.165 mmol) was added acetonitrile (10 mL) and stirred at 50° C. for 17 hours. The reaction mixture was acidified with 2N HCl and neutralized with ~1 mL of saturated NaHCO _3. The resulting solution was concentrated and dried under vacuum. A mixture of the residue, compound 8 (490.42 mg, 2.025 mmol) and NaHCO ₃ (340.23 mg, 4.050 mmol) in water (2 mL) and MeOH (8 mL) was stirred at room temperature for 1 hour. The reaction mixture was concentrated to remove most of the solvent. The residue was dissolved in dichloromethane (12 mL) and treated with 4N HCl in dioxane (12 mL) at room temperature for 2 hours. After concentrating the reaction mixture, the residue was dissolved in methanol (20 mL) and DBU (1.591 mL, 10.64 mmol) was added to the solution. After stirring the resulting mixture at 50° C. for 15 minutes, the reaction mixture was concentrated and the solvent was co-evaporated with toluene. The residue was purified by silica gel column chromatography (80 g column) using ethyl acetate-methanol/ethyl acetate as eluent to obtain compound 44: ¹ H NMR (400 MHz, chloroform-d) δ 8.10 (s, 1H), 6.61 (s, 1H), 6.11 (dd, J=17.2, 10.7 Hz, 1H), 5.37 (d, J=5.3 Hz, 1H), 5.34 (d, J=1.2 Hz, 1H), 4.41 (dt, J=12.1, 3.1 Hz, 1H), 4. 3H), 3.29 (dd, J = 12.2, 4.3 Hz, 1H), 4.08 (s, 3H), 3.91 (s, 4H), 3.74 (td, J = 12.0, 2.4 Hz, 1H), 3.63-3.52 (m, 1H), 2.33 (d, J = 12.4 Hz, 1H), 2.17 (qd, J = 12.2 _{, 5.1 Hz, 1H). LCMS-ESI+ (m/z): [M+H]+ Calcd. for Ci6Hi8N2O6 :} ^{335.12 ;} _{found :} 335.09.

Step 3

A mixture of compound 44 (360 mg, 1.077 mmol) and 60% NaH (172.27 mg, 4.307 mmol) was cooled at 0°C and DMF (5 mL) was added to the mixture. After 5 minutes, compound 10 (0.051 mL, 0.589 mmol) was added. After 20 minutes, 2N NaOH (0.6 mL) was added and stirred at 0°C for 10 minutes. The reaction mixture was then acidified with 2N HCl (~2.5 mL) and the acidified reaction mixture was concentrated to remove the solvent. The residue was dissolved in water and purified by preparative HPLC (acetonitrile/H ₂ O with 0.1% TFA modifier). The fractions containing the product were combined and freeze-dried to obtain compound 45: ¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.31 (s, 1H), 6.00 (dd, J = 17.3, 10.7 Hz, 1H), 5.90 (dddd, J = 15.1, 11.6, 6.1, 3.4 Hz, 1H), 5.36 (d, J = 10.7 Hz, 1H), 5.32–5.18 (m, 2H), 5.10 (d, J = 17.2 Hz, 1H), 4.51–4.34 (m, 3H), 4.18 (d, J = 11.1 Hz, 1H), 4.06 (s, 3H), 3.76–3.62 (m, 3H), 2.52–2.36 (m, 1H), 2.16 (dd, J = 12.2, 5.1 Hz, 1H). LCMS-ESI ⁺ (m/ _z ): [M+H] ⁺ calcd. _{for Ci8H20N2O6} : _361.14 ; found: 361.14.

Step 4

A mixture of compound 45 (360.36 mg, 0.658 mmol), compound 11 (154.85 mg, 0.723 mmol) and HATU (500.09 mg, 1.315 mmol) in dichloromethane (15 mL) was stirred at room temperature while N,N-diisopropylethylamine (1.220 mL, 7.004 mmol) was added. After 30 minutes, the reaction mixture was diluted with ethyl acetate and washed with saturated NH ₄ Cl (x2), saturated NaHCO ₃ (x2) and brine (x1). After the aqueous portion was extracted with ethyl acetate (x1), the organic portions were combined, dried (Na ₂ SO ₄ ) and concentrated. The residue was purified by silica gel column chromatography (24 g column) using hexane-ethyl acetate-20% methanol/ethyl acetate as eluent to give compound 46: ¹ H NMR (400 MHz, DMSO-d ₆ )δ10.42 (t, J=6.0Hz, 1H), 8.24 (s, 1H), 7.40 (td, J=8.5, 6.3Hz, 1H), 7.29 (td, J=8.8, 1.6Hz, 1H), 6.05 (dd, J=17.2, 10.7Hz, 1H), 5.87 (dddd, J=16.8, 10.6, 6.2, 4.6Hz, 1H), 5.40–5.18 (m, 2H), 5.21–5.09 (m, 1H), 5.0 4-4.89 (m, 1H), 4.67 (dd, J = 11.8, 4.4 Hz, 1H), 4.56 (qd, J = 15.1, 6.0 Hz, 2H), 4.33-4.13 (m, 3H), 3.82 (s, 3H), 3.70-3.51 (m, 2H), 3.35 (s, 2H), 2.69 (s, 1H), 2.40 (dd, J = 12.1, 4.4 Hz, 1H), 2.09 (tt, J = 12.2, 6.1 Hz, 1H) _. LCMS-ESI ⁺ (m/z): [M+H] ⁺ _{calcd. for C25H24ClF2N3O5 :} 520.14; found: 520.18.

Step 5

A solution of compound 46 (29 mg, 0.056 mmol) in dichloromethane (6 mL) was stirred in an ice bath while bubbling with Ar gas. After 30 minutes, 2nd generation Grubbs catalyst (4.735 mg, 0.006 mmol) was added and Ar bubbling was continued for 15 minutes. The reaction mixture was then refluxed at 80°C. After 24 hours, the reaction mixture was concentrated and purified by silica gel column chromatography (12 g column) using hexane-ethyl acetate-20% methanol/ethyl acetate as eluent to obtain compound 47: ¹ H NMR (400 MHz, chloroform-d) δ 10.59 (t, J = 5.9 Hz, 1H), 8.49 (s, 1H), 7.26 (m, 1H), 6.93 (td, J = 8.5, 1.9 Hz, 1H), 6.42-6.21 (m, 2H), 4.79-4.55 (m, 3H), 4.40 (ddd, J = 21. 5, 12.0, 4.6 Hz, 2H), 4.15-4.03 (m, 1H), 4.02 (s, 3H), 3.87 (dd, J=10.8, 1.1 Hz, 1H), 3.72 (td, J=11.8, 3.0 Hz, 1H), 3.45 (d, J=10.7 Hz, 1H), 2.62-2.35 (m, 2H). _LCMS -ESI ⁺ (m/z): [M+H] ⁺ _{Calcd . for C23H20ClF2N3O5 :} 492.11; found: 492.09.

Step 6

To a solution of compound 47 (3.8 mg) in ethanol (1 mL) was added 10% palladium on carbon (1.6 mg) at room temperature and the resulting mixture was stirred under a hydrogen atmosphere. After 40 minutes, the mixture was filtered through celite and the celite pad was washed with ethanol. The combined filtrate and washings were concentrated and the residue was used in the next reaction.

To the above residue in acetonitrile (1 mL) was added magnesium bromide (4.7 mg, 0.026 mmol) at room temperature and the resulting mixture was stirred at 50°C. After 30 minutes, the reaction mixture was stirred at 0°C and 1N HCl was added to make the mixture into solution, diluted with water, and then extracted with _CH2Cl2 ( _x3 ). The combined extracts were dried ( _MgSO4 ) and concentrated. The residue was purified by silica gel column chromatography (12 g column) using dichloromethane-20% methanol/dichloromethane as eluent. The sample was dissolved in dioxane and freeze-dried to give compound 48: ^1H NMR (400 MHz, chloroform-d) δ 12.85 (s, 1H), 10.48 (t, J = 6.1 Hz, 1H), 8.39 (s, 1H), 7.40-7.14 (m, 1H), 6.91 (td, J = 8.5, 1.8 Hz, 1H), 4.64 (dd, J = 17.4, 5.7 Hz, 3H), 4.08-3.98 (m, 1H), 3.87 (ddd, J = 16. 9, 11.7, 6.9Hz, 2H), 3.65 (t, J=11.2Hz, 1H), 3.61-3.52 (m, 1H), 3.03 (td, J=13.4, 3.1Hz, 1H) , 2.70 (d, J=15.7Hz, 1H), 1.92 (ddd, J=19.2, 9.3, 4.7Hz, 1H), 1.83-1.67 (m, 4H), 1.58 (m, 2H). ¹⁹ F NMR (376MHz, chloroform-d) δ -115.18 (q, J=6.5, 5.4Hz, 1F), -117.36 (dd, J=8.0, 3.3Hz, 1F). LCMS-ESI ⁺ (m/z): [M+H] ⁺ calcd. for C ₂₃ H ₂₁ ClF ₂ N ₃ O ₅ : 492.11; found: 492.15.

Example 10

Preparation of compounds 56 and 57

Step 1

A mixture of compound 8 (6.4 g, 26.4 mmol), compound 49 (4.9 g, 25.7 mmol) and sodium bicarbonate (8.64 g, 103 mmol) in a 7:2 mixture (90 mL) of MeOH: water was stirred at room temperature for 24 hours. After the solution was concentrated, the residue was dissolved in methanol (80 mL) and stirred at 50 ° C for another 2 hours. After the solution was concentrated, the residue was distributed between water and ethyl acetate. The separated aqueous phase was extracted into ethyl acetate (x3), all organic portions were combined, dried (MgSO ₄ ), and concentrated to give crude compound 50, which was carried out to the next step as a crude material: LCMS-ESI ⁺ (m / z): [M + H] ⁺ C ₂₂ H ₂₆ NO ₇ calculated value: 416.17; found value: 416.2.

Step 2

The crude compound 50 and 20% palladium hydroxide on carbon (4.37 g, 3.11 mmol) were suspended in ethanol (100 mL) and stirred at 40° C. under hydrogen atmosphere for 2 hours. After filtering the suspension through a pad of celite (rinsed with ethanol), the filtrate was concentrated to give compound 51, which was carried into the next step as a crude material: ^1H NMR (400 MHz, DMSO- _d6 ) δ 8.30 (s, 1H), 5.31 (d, J = 5.4 Hz, 1H), 4.35-4.19 (m, 1H), 3.93 (s, 3H), 3.81 (q, J = 8.1 Hz, 1H), 3.75 (s, 3H), 3.74 (s, 3H), 2.16-2.03 (m, 1H), 1.99-1.85 (m, 1H), 1.84-1.63 (m, 3H), 1.56-1.44 (m, 1H).

Step 3

A solution of crude compound 51 in dichloromethane (100 mL) was treated with Dess-Martin periodinane (5.75 g, 13.6 mmol) at room temperature for 1 hour. After quenching the reaction mixture with saturated _NaHCO₃ (50 mL) and some solid _{Na₂SO₃ ,} the separated aqueous portion was extracted into dichloromethane (x1), and the combined organic portions were dried ( _MgSO₄ ) and concentrated. _The resulting residue was purified by silica gel column chromatography using dichloromethane-10% methanol/dichloromethane as eluent to afford compound 52: LCMS-ESI ⁺ (m/z): _[ M+H] ⁺ _{C₁₅H₁₈NO₇} calculated: 324.11; found: 324.1.

Step 4

To a solution of compound 52 (740 mg, 2.3 mmol) in acetonitrile (13.5 mL) were added acetic acid (1.5 mL, 26.2 mmol), potassium carbonate (1.27 g, 9.2 mmol) and (S)-1-aminopropan-2-ol (0.75 mL, 9.6 mmol), and the mixture was stirred at 70° C. for 4 hours. After the reaction mixture was concentrated with silica gel, the resulting adsorption mixture was purified by silica gel flash column chromatography using dichloromethane-6% methanol/dichloromethane as the eluent to give compound 53 as a mixture of diastereomers.

Step 5

A solution of compound 53 (242 mg, 0.69 mmol) in a 2:1 mixture of THF:MeOH (5 mL) was treated with 2.0 M lithium hydroxide (0.7 mL, 1.4 mmol). After 3 hours, the reaction mixture was acidified with 0.5 M HCl and the product was extracted with ethyl acetate (x3). The combined extracts were dried (MgSO ₄ ) and concentrated. The residue was purified by silica gel column chromatography using dichloromethane-4% methanol/dichloromethane as eluent to obtain compound 54, which is a mixture of diastereomers.

Steps 6-7

To a solution of compound 54 (40 mg, 0.12 mmol), HATU (58 mg, 0.15 mmol) and compound 11 (40 mg, 0.18 mmol) in dichloromethane (2 mL) was added N,N-diisopropylethylamine (0.11 mL, 0.62 mmol). After 1.5 h, the reaction mixture was diluted with ethyl acetate, washed with 5% aqueous NaHCO ₃ (x2), dried (MgSO ₄ ), and concentrated under reduced pressure to give compound 55, which was carried forward crude.

To a solution of compound 55 in acetonitrile (2 mL) was added magnesium bromide (48 mg, 0.26 mmol) and the resulting mixture was stirred at 50° C. for 2 hours. After the mixture was cooled and dissolved by the addition of 0.5 M HCl, the product was extracted with dichloromethane (×3), and the combined extracts were dried (MgSO ₄ ) and concentrated. The residue was purified by preparative HPLC (acetonitrile/H ₂ O with 0.1% TFA modifier) to afford compounds 56 and 57 as different diastereomers.

Compound 56 (earlier eluting diastereomer): ¹ H NMR (400 MHz, chloroform-d) δ 10.49 (s, 1H), 8.57 (s, 1H), 7.33–7.23 (m, 1H), 6.92 (td, J = 8.5, 1.6 Hz, 1H), 4.66 (d, J = 5.6 Hz, 2H), 4.51 (dt, J = 12.7, 6.4 Hz, 1H), 4.15 (d, J = 4.8 Hz, 2H). z, 1H), 3.87 (dd, J = 11.5, 6.8 Hz, 1H), 3.51 (dd, J = 11.4, 8.1 Hz, 1H), 2.67-2.46 (m, 2H), 2.18 (ddd, J = 13.1, 8.8, 3.7 Hz, 1H), 2.06-1.63 (m, 3H), 1.44 (d, J = 6.1 Hz, 3H) _{. LCMS-ESI+ (m/z): [M+H]+ Calcd. for C22H21ClF2N3O5 :} ^{480.10 ;} _{found : 480.2} .

Compound 57 (late eluting diastereomer): ¹ H NMR (400 MHz, chloroform-d) δ 10.52 (s, 1H), 8.60 (s, 1H), 7.33-7.22 (m, 1H), 6.93 (t, J = 8.3 Hz, 1H), 4.66 (s, 2H), 4.47 (dd, J = 11.5, 5.5 Hz, 1H), 4.25 (dt, J = 9.7, 5.8 Hz , 1H), 4.07 (d, J = 4.3 Hz, 1H), 3.18 (t, J = 10.4 Hz, 1H), 2.72–2.41 (m, 2H), 2.16 (t, J = 10.1 Hz, 1H), 2.08–1.91 (m, 1H), 1.91–1.72 ( _m , 1H), 1.45 (d, J = 6.0 Hz, 3H). LCMS-ESI ⁺ (m/z): [M+H] ⁺ _{Calcd . for C22H21ClF2N3O5 :} 480.10; found: 480.2.

Example 11

Preparation of compounds 60 and 61

Step 1

A mixture of compound 52 (1.33 g, 4.12 mmol), acetic acid (3 mL, 52.40 mmol), potassium carbonate (2.31 g, 16.5 mmol) and 2-aminoethanol (0.99 mL, 16.5 mmol) in acetonitrile (27 mL) was stirred at 60 ° C for 2.5 hours. The reaction mixture was cooled, treated with methanol, and concentrated on silica gel. The adsorption mixture was purified by silica gel column chromatography using ethyl acetate-ethanol as eluent to give compound 58 as a racemic mixture: LCMS-ESI ⁺ (m / z): [M + H] ⁺ C ₁₅ H ₁₈ NO ₇ calculated value: 335.12; found value: 335.1.

Step 2

Compound 58 (0.415 g, 1.24 mmol) in THF (4 mL) and methanol (2 mL) was treated with 2M lithium hydroxide (1.24 mL) and stirred at room temperature for 20 minutes. After acidification of the reaction mixture with 0.5 M HCl (5-10 mL) and dilution with water, the product was extracted with ethyl acetate ( _x2 ), and the combined organic extracts were dried ( _Na2SO4 ) and concentrated to give compound 59: ^1H NMR (400 MHz, DMSO- _d6 ) 8.62 (s, 1H), 4.52 (d, J = 5.0 Hz, 1H), 4.20-4.02 (m, 2H), 3.90 (m, 4H), 3.57 (ddd, J = 11.1, 6.7, 5.0 Hz, 1H), 2.60-2.51 (m, 1H), 2.41-2.27 (m, 1H), 2.09-1.95 (m, 1H), 1.82-1.56 (m, 3H).

Step 3

A solution of compound 59 (0.085 g, 0.27 mmol), compound 11 (0.098 g, 0.552 mmol), and HATU (0.111 g, 0.29 mmol) in acetonitrile (3 mL) was treated with N,N-diisopropylethylamine (0.094 mL, 0.53 mmol). The reaction mixture was stirred for 2 h and additional compound 11 (0.050 g, 0.28 mmol) and HATU (0.050 g, 0.13 mmol) were added. After 10 min, the reaction mixture was diluted with ethyl acetate, washed with 0.5 M HCl (x 1) and 5% aqueous NaHCO ₃ solution (x 1), dried (Na ₂ SO ₄ ) and concentrated to give the crude amide, which was used in the next step: LCMS-ESI ⁺ (m/z): [M+H] ⁺ calculated for C ₂₀ H ₂₀ F ₃ N ₂ O ₇ : 457.12; found: 457.1.

The crude amide (0.127 g, 0.265 mmol) was suspended in acetonitrile and treated with magnesium bromide (0.146 g, 0.795 mmol). The mixture was placed in a 50 ° C bath and stirred for 10 minutes. After cooling, the reaction mixture was acidified with 0.5 M HCl and the product was extracted with ethyl acetate. The organic extract was dried (Na ₂ SO ₄ ), concentrated, and purified by silica gel column chromatography using dichloromethane-ethanol as eluent to obtain the racemic product. The substance was separated into its enantiomers by HPLC using a ChiralPak AD-H column (eluent: methanol-acetonitrile) to obtain the desired two enantiomers 60 and 61.

Compound 60 (earlier eluting enantiomer): ¹ H NMR (400 MHz, DMSO-d ₆ )δ12.34 (s, 1H), 10.41 (t, J=5.8Hz, 1H), 8.43 (s, 1H), 7.40 (td, J=8.7, 6.6Hz, 1H), 7.35–7.21 (m, 1H), 4.65–4.52 (m, 2H), 4.42 (d, J=4.9Hz, 1H), 4.22–4.07(m, 2H), 3.98–3.87(m, 1H), 3.75–3.62(m, 1H), 2.47–2 .41(m,1H), 2.42–2.29(m,1H), 2.13–1.99(m,1H), 1.81–1.66(m,3H). LCMS-ESI ⁺ (m/z): [M+H] ⁺ calcd. for C ₂₁ H ₁₉ ClF ₂ N ₃ O ₅ : 466.10; found: 466.2.

Compound 61 (late eluting enantiomer): ¹ H NMR (400 MHz, DMSO-d ₆ )δ12.34 (s, 1H), 10.41 (t, J=6.2Hz, 1H), 8.43 (s, 1H), 7.40 (td, J=8.5, 6.8Hz, 1H), 7.35–7.25 (m, 1H), 4.64–4.54 (m, 2H), 4.43 (d, J=5 .2Hz, 1H), 4.24–4.07(m, 2H), 4.00–3.88(m, 1H), 3.73–3.62(m, 1H), 2.45(m, 1H), 2.42–2.29(m, 1H), 2.06(m, 1H), 1.80–1.64(m, 3H). LCMS-ESI ⁺ (m/z): [M+H] ⁺ calcd. for C ₂₁ H ₁₉ ClF ₂ N ₃ O ₅ : 466.10; found: 466.2.

Example 12

Preparation of compound 65

Step 1

A mixture of compound 52 (430 mg, 1.3 mmol), acetic acid (1 mL, 17.47 mmol), potassium carbonate (0.78 g, 5.6 mmol) and (R)-2-aminopropan-1-ol (0.43 mL, 5.5 mmol) in acetonitrile (9 mL) was stirred at 70° C. for 5 hours. The reaction mixture was diluted with methanol and then concentrated on silica gel. The adsorption mixture was purified by silica gel column chromatography using ethyl acetate-15% ethanol/dichloromethane as eluent to obtain compound 62 as a single diastereomer.

Step 2

A mixture of compound 62 (161 mg, 0.43 mmol) in a 2:1 mixture of THF: MeOH (3 mL) was treated with 2.0 M lithium hydroxide (0.5 mL) and stirred at room temperature for 1 hour. After acidifying the reaction mixture with 0.5 M HCl and diluting with water, the product was extracted with ethyl acetate (x3), and the combined organic extracts were dried (Na ₂ SO ₄ ) and concentrated. The residue was purified by silica gel column chromatography using dichloromethane-10% ethanol/dichloromethane as eluent to obtain compound 63.

Step 3

To a solution of compound 63 (32 mg, 0.1 mmol), HATU (54 mg, 0.14 mmol) and compound 11 (32 mg, 0.15 mmol) in dichloromethane (2 mL) was added N,N-diisopropylethylamine (0.1 mL, 0.56 mmol). The reaction mixture was stirred for 1.5 hours, diluted with ethyl acetate, washed with 5% aqueous NaHCO ₃ solution (x2), dried (MgSO ₄ ), and concentrated to give compound 64, which was carried forward crude.

Step 4

To a solution of the above-mentioned compound 64 in acetonitrile (2 mL) was added magnesium bromide (41 mg, 0.22 mmol) and the resulting mixture was stirred at 50 ° C for 30 minutes. After cooling the mixture, it was acidified with 0.5 M HCl, extracted into dichloromethane (x3), dried (MgSO ₄ ), and concentrated. The resulting residue was purified by silica gel column chromatography using dichloromethane-10% ethanol/dichloromethane as eluent to obtain compound 65. ¹ H NMR (400 MHz, chloroform-d) δ 10.50–10.37 (m, 1H), 8.53 (s, 1H), 7.33–7.23 (m, 1H), 6.91 (t, J=9.3 Hz, 1H), 4.64 (d, J=6.0 Hz, 2H), 4.47 (q, J=6.6 Hz, 1H), 4.33 (dd, J=8.9, 7 .3 Hz, 1H), 4.06 (d, J = 4.8 Hz, 1H), 3.75 (dd, J = 8.9, 6.6 Hz, 1H), 2.66–2.57 (m, 1H), 2.52–2.39 (m, 1H), 2.22–2.08 (m, 1H), 2.03–1.69 (m, 3H), 1.46 (d, J = 6.4 Hz, 3H) _. LCMS-ESI ⁺ (m/z): [M+H] ⁺ _{Calcd . for C22H21ClF2N3O5} : 480.10; found: 480.2.

Example 13

Preparation of compound 66

Step 1

To a solution of compound 63 (32 mg, 0.1 mmol), HATU (46 mg, 0.12 mmol) and compound 27 (0.02 mL, 0.17 mmol) in dichloromethane (2 mL) was added N,N-diisopropylethylamine (0.07 mL, 0.39 mmol). The reaction mixture was stirred for 1.5 hours, diluted with ethyl acetate, washed with 5% aqueous NaHCO ₃ solution (x2), dried (MgSO ₄ ) and concentrated under reduced pressure to give the crude amide, which was carried forward as crude material.

To a solution of the crude amide in acetonitrile (2 mL) was added magnesium bromide (39 mg, 0.21 mmol) and the resulting mixture was stirred at 50° C. for 30 minutes. After the mixture was cooled and acidified with 0.5 M HCl, the product was extracted with dichloromethane (×3), and the combined extracts were dried (MgSO ₄ ) and concentrated. The residue was purified by silica gel column chromatography using dichloromethane-10% ethanol/dichloromethane as eluent to give compound 66. ¹ H NMR (400 MHz, CHLOROFORM-d) δ 10.35 (t, J = 5.5 Hz, 1H), 8.53 (s, 1H), 6.69–6.58 (m, 2H), 4.69–4.58 (m, 2H), 4.46 (q, J = 6.6 Hz, 1H), 4.35–4.29 (m, 1H), 4.06–4.01 (m, 1H), 3.77–3.72 (m, 1H), 2.66–2.56 (m, 1H), 2.50–2.37 (m, 1H), 2.19–2.09 (m, 1H), 2.00–1.68 (m, 3H), 1.45 (d, J = 6.4 Hz, 3H). LCMS-ESI ⁺ (m/z): [M+H] ⁺ calcd. for C ₂₂ H ₂₁ F ₃ N ₃ O ₅ : 464.14; found: 464.3.

Example 14

Preparation of compound 69

Step 1

A mixture of compound 52 (481 mg, 1.5 mmol), acetic acid (1 mL, 17.5 mmol), potassium carbonate (0.82 g, 5.9 mmol) and (S)-2-aminopropan-1-ol (0.5 mL, 6.4 mmol) in acetonitrile (9 mL) was stirred at 70° C. for 6 hours, then diluted with methanol and concentrated over silica gel. The resulting adsorption mixture was purified by silica gel column chromatography using dichloromethane-15% ethanol/dichloromethane as eluent to give compound 67 as a single diastereomer.

Step 2

To a mixture of compound 67 (142 mg, 0.41 mmol) in a 2:1 mixture of THF: MeOH (3 mL) was added 2.0 M lithium hydroxide (0.5 mL, 1.0 mmol) and the reaction mixture was stirred at room temperature for 1 hour. After acidifying the mixture with 0.5 M HCl, the product was extracted with ethyl acetate (x3), dried (MgSO ₄ ) and the combined organic extracts were concentrated. Residues were purified by silica gel column chromatography using dichloromethane-10% methanol/dichloromethane as eluent to obtain compound 68.

Step 3

To a solution of compound 68 (25 mg, 0.07 mmol), HATU (40 mg, 0.11 mmol) and compound 11 (20 mg, 0.09 mmol) in dichloromethane (2 mL) was added N,N-diisopropylethylamine (0.06 mL, 0.34 mmol). The reaction mixture was stirred for 1.5 hours, diluted with ethyl acetate, washed with 5% aqueous NaHCO ₃ solution (x2), dried (MgSO ₄ ) and concentrated to give the crude amide, which was carried forward as crude material.

To a solution of the crude amide in acetonitrile (2 mL) was added magnesium bromide (32 mg, 0.17 mmol) and the reaction mixture was stirred at 50° C. for 30 minutes. After acidifying the mixture with 0.5 M HCl, the product was extracted into dichloromethane (×3), the combined extracts were dried (MgSO ₄ ) and concentrated. The residue was purified by silica gel column chromatography using dichloromethane-10% methanol/dichloromethane as eluent to give compound 69. ¹ H NMR (400MHz, chloroform-d) δ10.43 (t, J=5.9Hz, 1H), 8.52 (s, 1H), 7.27 (q, J=7.0, 5 .9Hz, 1H), 6.91(tt, J＝8.5, 2.3Hz, 1H), 4.64(d, J＝6.0Hz, 1H), 4.51–4.29(m , 2H), 4.06 (d, J=4.8Hz, 1H), 3.75 (dd, J=8.9, 6.6Hz, 1H), 3.46 (s, 1H), 2.71 –2.39 (m, 2H), 2.23–2.08 (m, 1H), 2.06–1.68 (m, 3H), 1.47 (d, J=6.4Hz, 3H). LCMS-ESI ⁺ (m/z): [M+H] ⁺ calcd. for C ₂₂ H ₂₁ ClF ₂ N ₃ O ₅ : 480.10; found: 480.3.

Example 15

Preparation of Compound 70

Step 1

To a solution of compound 68 (25 mg, 0.07 mmol), HATU (38 mg, 0.1 mmol) and compound 27 (0.03 mL, 0.25 mmol) in dichloromethane (2 mL) was added N,N-diisopropylethylamine (0.06 mL, 0.34 mmol). The reaction mixture was stirred for 1.5 hours, diluted with ethyl acetate, washed with 5% aqueous NaHCO ₃ solution (x2), dried (MgSO ₄ ) and concentrated to give the crude amide, which was carried forward as crude material.

To a solution of the crude amide in acetonitrile (2 mL) was added magnesium bromide (36 mg, 0.2 mmol) and the reaction mixture was stirred at 50° C. for 30 minutes. After acidifying the mixture with 0.5 M HCl, the product was extracted into dichloromethane (×3), and the combined extracts were dried (MgSO ₄ ) and concentrated. The residue was purified by silica gel column chromatography using dichloromethane-10% methanol/dichloromethane as eluent to give compound 70. ¹ H NMR (400MHz, chloroform-d) δ10.34 (t, J=5.5Hz, 1H), 8.53 (s, 1H), 6.68–6.59 (m, 2H ), 4.72–4.59(m, 2H), 4.47(q, J＝6.7Hz, 1H), 4.33(dd, J＝8.9, 7.2Hz, 1H), 4 .04(d, J＝4.9Hz, 1H), 3.75(dd, J＝9.0, 6.6Hz, 1H), 2.67–2.57(m, 1H), 2.52 –2.39 (m, 1H), 2.21–2.10 (m, 1H), 1.95–1.67 (m, 3H), 1.47 (d, J=6.4Hz, 3H). LCMS-ESI ⁺ (m/z): [M+H] ⁺ calcd. for C ₂₂ H ₂₁ F ₃ N ₃ O ₅ : 464.14; found: 464.2.

Example 16

Preparation of compounds 73 and 74

Step 1

To compound 52 (950 mg, 2.94 mmol) in acetonitrile (20 mL) was added acetic acid (1.5 mL, 26.20 mmol), potassium carbonate (1.624 g, 11.75 mmol) and (R)-1-aminopropan-2-ol (0.92 mL, 11.75 mmol). After stirring at 70 ° C for 16 hours, the mixture was dissolved in MeOH and concentrated on silica gel. The resulting adsorption mixture was purified by silica gel column chromatography using dichloromethane-20% methanol/dichloromethane as eluent to obtain 71 as a mixture of two diastereomers. LCMS-ESI ⁺ (m / z): [M + H] ⁺ C ₁₇ H ₂₁ N ₂ O ₆ calculated value: 349.14; found value: 349.12.

Step 2

A solution of 71 (423 mg, 1.214 mmol) in THF (20 mL), MeOH (2 mL), and 1N NaOH (5 mL) was stirred at room temperature for 1 hour. After acidification with 3N HCl, the mixture was concentrated to dryness and _the residue was purified by silica gel column chromatography using dichloromethane-10% ethanol/dichloromethane as eluent to give the acid. _LCMS -ESI ⁺ (m/z): [M+H] ⁺ calculated _{for Ci6H19N2O6} : 335.12; found: 335.11.

To a mixture of the crude acid (94 mg, 0.281 mmol), compound 11 (120 mg, 0.562 mmol), and HATU (160 mg, 0.422 mmol) in DMF (3 mL) was added N,N-diisopropylethylamine (0.3 mL, 1.7 mmol) at room temperature. After 0.5 h, the reaction mixture was diluted with dichloromethane and washed with 3% LiCl, saturated _NH4Cl , and 0.5 _N HCl. The organic portion was dried ( _Na2SO4 ) and concentrated. The residue was purified by silica _{gel column} chromatography using dichloromethane-20% methanol/dichloromethane as eluent to afford a mixture of two isomers, 72. LCMS-ESI ⁺ (m/z): [M+H] ⁺ calculated _{for C23H23ClF2N3O5} : _494.13 ; found: 494.15.

Step 3

To a solution of compound 72 (138 mg, 0.281 mmol) in acetonitrile (5 mL) was added magnesium bromide (155 mg, 0.843 mmol) and the mixture was stirred at 50°C for 30 minutes. After the mixture was cooled and acidified with 10% HCl, the product was extracted with ethyl acetate (x2). The combined organic extracts were dried ( _MgSO4 ), concentrated, and purified by preparative HPLC (acetonitrile/ _H2O with 0.1% TFA modifier) to give compounds 73 and 74.

Compound 73 (earlier eluting diastereomer): 35 mg (26%), ¹ H NMR (400 MHz, chloroform-d) δ 10.52 (t, J = 6.1 Hz, 1H), 8.58 (s, 1H), 7.32-7.23 (m, 1H), 6.93 (td, J = 8.5, 1.8 Hz, 1H), 4.67 (d, J = 6.0 Hz, 2H), 4.52 (dt, J = 8.0, 6.3 Hz, 1H), 4.15 (d, J = 4.9 Hz, 1H), 3.87 (d d, J=11.5, 6.8Hz, 1H), 3.52 (dd, J=11.4, 8.1Hz, 1H), 2.68-2.40 (m, 2H), 2.19 (ddd, J=14.8, 8. 6, 3.9Hz, 1H), 2.07-1.77 (m, 2H), 1.69 (ddd, J=13.9, 10.5, 7.5Hz, 1H), 1.44 (d, J=6.1Hz, 3H). ¹⁹ F NMR (377MHz, chloroform-d) δ -76.42, -114.87 (p, J=4.1Hz), -117.24 (dd, J=8.3, 3.3Hz). LCMS-ESI ⁺ (m/z): [M+H] ⁺ calcd. for C ₂₂ H ₂₁ ClF ₂ N ₃ O ₅ : 480.11; found: 480.16.

Compound 74 (late eluting diastereomer): 9 mg (7%), ¹ H NMR (400 MHz, chloroform-d) δ 10.48 (t, J = 5.9 Hz, 1H), 8.56 (s, 1H), 7.43-7.15 (m, 1H), 6.92 (td, J = 8.7, 1.6 Hz, 1H), 4.66 (d, J = 4.5 Hz, 2H), 4.48 (dd, J = 11.5, 5.5 Hz, 1H), 4.24 (dt , J=9.4, 5.8Hz, 1H), 4.02 (d, J=4.5Hz, 1H), 3.17 (dd, J=11.5, 9.5Hz, 1H), 2.67-2.4 0 (m, 2H), 2.25-2.09 (m, 1H), 2.00 (s, 2H), 1.92-1.73 (m, 2H), 1.45 (d, J=6.0Hz, 3H). ¹⁹ F NMR (377MHz, chloroform-d) δ -76.46, -115.00 (dq, J=8.4, 3.8Hz), -117.32 (d, J=7.6Hz). LCMS-ESI ⁺ (m/z): [M+H] ⁺ calcd. for C ₂₂ H ₂₁ ClF ₂ N ₃ O ₅ : 480.11; found: 480.11.

Example 17

Preparation of compound 77

Step 1

To a solution of compound 52 (460 mg, 1.42 mmol) in acetonitrile (20 mL) was added acetic acid (1.0 mL, 17.47 mmol), potassium carbonate (0.8 g, 5.7 mmol) and (R)-3-aminobutan-1-ol (0.39 mL, 4.27 mmol). The mixture was stirred at 70°C for 24 hours, then concentrated and the residue was used in the next reaction.

A solution of the above residue in THF (2 mL), methanol (2 mL), and 1N NaOH (5 mL) was stirred at room temperature for 1 h. The resulting mixture was acidified with 3N HCl and concentrated to dryness. The residue was purified by silica gel _column chromatography using dichloromethane-20% methanol/dichloromethane as eluent to provide compound 75. _LCMS -ESI ⁺ (m/z): [M+H] ⁺ calculated _{for Ci7H21N2O6} : 349.14; found: 349.13.

Step 2

To a mixture of compound 75 (62 mg, 0.178 mmol), compound 11 (95 mg, 0.445 mmol), and HATU (135 mg, 0.356 mmol) in dichloromethane (3 mL) was added N,N-diisopropylethylamine (0.186 mL, 1.07 mmol) at room temperature. After 0.5 h, the reaction mixture was diluted with dichloromethane and washed with 3% LiCl, saturated _NH4Cl , and 0.5 _N HCl. The organic portion was dried ( _Na2SO4 ) and concentrated. The residue was purified by silica gel _{column chromatography using dichloromethane-20% methanol/dichloromethane as the eluent to provide compound 76. LCMS-ESI+ (m/z): [M+H]+ calculated for C24H25ClF2N3O5 :} ^508.15 _{; found} ^: _508.17 .

Step 3

To a solution of compound 76 (60 mg, 0.118 mmol) in acetonitrile (5 mL) was added magnesium bromide (65 mg, 0.354 mmol) and the mixture was stirred for 30 minutes at 50° C. After the mixture was cooled and acidified with 10% HCl, the product was extracted with ethyl acetate (×2). The combined organic extracts were dried ( _MgSO4 ), concentrated, and purified by preparative HPLC (acetonitrile/ _H2O with 0.1% TFA modifier) to give compound 77: ^1H NMR (400 MHz, CHLOROFORM-d) δ 8.45 (s, 1H), 7.29 (d, J = 7.6 Hz, 1H), 6.95 (t, J = 8.2 Hz, 1H), 4.71 (s, 2H), 4.51 (s, 1H), 4.30 (s, 1H), 4.14 (q, J = 7.3 Hz, 0H), 3.17-2.87 (m, 5H), 2.30 (d, J = 9.5 Hz, 3H), 1.64 (s, 3H), 1.26 (d, J = 4.3 Hz, 1H). LCMS-ESI ⁺ (m/z): [M+H] ⁺ calcd. for C ₂₃ H ₂₃ ClF ₂ N ₃ O ₅ : 494.13; found: 494.18.

Example 18

Preparation of Compound 80

Step 1

To compound 52 (460 mg, 1.42 mmol) in acetonitrile (20 mL) were added acetic acid (1.0 mL, 17.47 mmol), potassium carbonate (0.8 g, 5.7 mmol) and (S)-3-aminobutan-1-ol (0.39 mL, 4.27 mmol). After stirring at 70°C for 24 hours, the mixture was concentrated and the residue was used in the next reaction.

A solution of the above residue in THF (20 mL), MeOH (2 mL), and 1N NaOH (5 mL) was stirred at room temperature for 1 hour. The resulting mixture was acidified with 3N HCl and concentrated to dryness. The residue was purified by silica gel _column chromatography using dichloromethane-20% methanol/dichloromethane as eluent to provide compound 78. _LCMS -ESI ⁺ (m/z): [M+H] ⁺ calculated _{for Ci7H21N2O6} : 349.14; found: 349.15.

Step 2

To a mixture of compound 78 (63 mg, 0.18 mmol), compound 11 (95 mg, 0.445 mmol), and HATU (135 mg, 0.356 mmol) in dichloromethane (3 mL) was added N,N-diisopropylethylamine (0.186 mL, 1.07 mmol) at room temperature. After 0.5 h, the reaction mixture was diluted with dichloromethane and washed with 3% LiCl, saturated _NH4Cl , and 0.5 _N HCl. The organic portion was dried ( _Na2SO4 ) and concentrated. The residue was purified by silica gel _{column chromatography using dichloromethane-20% methanol/dichloromethane as the eluent to provide compound 79. LCMS-ESI+ (m/z): [M+H]+ calculated for C24H25ClF2N3O5 :} ^508.15 _{; found} ^: _508.18 .

Step 3

To a solution of compound 76 (78 mg, 0.154 mmol) in acetonitrile (5 mL) was added magnesium bromide (85 mg, 0.461 mmol) and the mixture was stirred for 30 minutes at 50° C. After the mixture was cooled and acidified with 10% HCl, the product was extracted with ethyl acetate (×2). The combined organic extracts were dried ( _MgSO4 ), concentrated, and purified by preparative HPLC (acetonitrile/ _H2O with 0.1% TFA modifier) to give Compound 80: ^1H NMR (400 MHz, Acetonitrile- _d3 ) δ 8.26 (s, 1H), 7.39 (td, J = 8.4, 6.1 Hz, 1H), 7.09 (td, J = 8.8, 1.9 Hz, 1H), 4.65 (d, J = 6.1 Hz, 2H), 3.68-3.38 (m, 2H), 3.21-2.58 (m, 5H), 1.96 (p, J = 2.5 Hz, 12H), 1.55 (d, J = 6.8 Hz, 3H), 1.29 (s, 1H). ¹⁹ F NMR (377 MHz, acetonitrile-d ₃ ) δ −117.55 (d, J=7.3 Hz), −119.63 (d, J=8.1 Hz). LCMS-ESI ⁺ (m/z): [M+H] ⁺ Calcd. for C ₂₃ H ₂₃ ClF ₂ N ₃ O ₅ : 494.13; Found: 494.19.

Example 19

Preparation of Compounds (88a and 88b)

Step 1

(1R,2R)-2-(Benzyloxy)cyclohexylamine (81, 760 mg, 3.70 mmol), pyrone 82 (1.00 g, 3.7 mmol), and sodium bicarbonate (1.24 g, 15 mmol) in methanol (30 mL) and water (10 mL) were stirred at room temperature for 16 hours. The mixture was evaporated to remove most of the methanol, _diluted with water _, and the product was extracted with ethyl acetate. The organic extract was dried ( _Na2SO4 ) and concentrated. The residue was used as is in the next reaction. LCMS-ESI ⁺ (m/z): [ _M + _HC25H31NO7 calcd: 457.52; found: 458.16.

A solution of the above residue in THF (20 mL), MeOH (2 mL), and 1 M LiOH (3.28 mL) was stirred at room temperature for 1.5 hours. The resulting mixture was acidified with 3N HCl and concentrated to dryness. The residue was purified by preparative HPLC (acetonitrile/ _H₂O with 0.1% TFA modifier) to provide compound 83. LCMS- ^ESI⁺ (m/z): [M+H] ^⁺ calcd _{for C₂₄H₂₆NO⁷ :} 443.49; found: 444.16.

Step 2

To a mixture of compound 83 (406 mg, 0.92 mmol), compound 11 (587.84 mg, 2.75 mmol), and HATU (696 mg, 1.83 mmol) in dichloromethane (3 mL) was added N,N-diisopropylethylamine (0.96 mL, 5.49 mmol) at room temperature. After 0.5 h, the reaction mixture was diluted with dichloromethane and washed with 3% LiCl, saturated _NH4Cl , and 0.5 _N HCl. The organic portion was dried ( _Na2SO4 ) and concentrated. The residue was purified by silica gel _{column chromatography using dichloromethane-20% methanol/dichloromethane as the eluent to provide compound 84. LCMS-ESI+ (m/z): [M+H]+ calculated for C31H33ClF2N2O6 :} ^603.05 _{; found} ^: _603.19 .

Step 3

A mixture of compound 84 (34 mg, 0.056 mmol) and 20% palladium hydroxide on carbon (15 mg) in ethanol (4 mL) was stirred at room temperature under a hydrogen atmosphere for 0.5 h. After filtering the mixture through a pad _{of celite} , the filtrate was concentrated to dryness and then co-evaporated with dichloromethane (x2) to give a mixture of _{compounds 85a} and _85b . LCMS- ^ESI (m/z): [M+H] calculated for ^{C₂₄H₂₈ClF₂N₂O₆} : _513.16 and _{calculated for C₂₄H₂F₂N₂O₆} : _479.20 ; found: 513.13 and 479.16.

Step 4

To a solution of the crude mixture of 85a and 85b in dichloromethane (5 mL ₎ was added Dess-Martin periodinane (92.6 mg, _0.218 mmol). The mixture was stirred at room temperature for 20 minutes. The reaction mixture was diluted with a mixture of saturated _Na2S2O3 /saturated _NaHCO3 (7: ₁ ) and stirred for 10 minutes before extraction with dichloromethane. The organic extracts were dried ( _Na2SO4 ) and concentrated, and the residue was purified by _{silica gel} column chromatography using hexane-ethyl acetate to afford a mixture _of ketones 86a and 87b. LCMS-ESI ⁺ (m/z): [M+H _] ⁺ calculated for _{C24H26ClF2N2O6} : _511.14 , and calculated for _C24H27F2N2O6 : _477.18 ; found _: 511.12 and _477.16 .

Step 5

To the above mixture of ketones 86a and 86b (46 mg) in acetonitrile (20 mL) was added acetic acid (0.1 mL, 1.75 mmol), potassium carbonate (50 mg, 0.36 mmol), and (R)-2-aminopropan-1-ol (27 mg, 0.36 mmol). The reaction mixture was stirred at 70°C for 27 hours and concentrated. The residue was then dissolved in methanol and concentrated on silica gel. The resulting adsorption mixture was purified by silica gel column chromatography using dichloromethane-20% methanol/dichloromethane as the eluent _to afford a mixture _{of compounds} 87a and 87b. LCMS-ESI ⁺ (m/z ₎ : [M+H _] ⁺ calculated for _{C24H24ClF2N3O5 and C24H25F2N3O5} : 508.15 and _474.18 ; found _: 508.17 and 474.27.

Step 6

To a solution of a mixture of compounds 87a and 87b (30 mg) in acetonitrile (5 mL) was added magnesium bromide (33 mg, 0.177 mmol) and the mixture was stirred at 50°C for 30 minutes. After the mixture was cooled and acidified with 10% HCl, the product was extracted with ethyl acetate (x2). The combined organic extracts were dried ( _MgSO4 ), concentrated, and purified by preparative HPLC (acetonitrile/ _H2O with 0.1% TFA modifier) to give compounds 88a and 88b.

Compound 88a: 5 mg (17%), ¹ H NMR (400MHz, chloroform-d) δ8.50 (s, 1H), 7.36-7.27 (m, 1H), 6.95 (t, J=8.3Hz, 1H), 4.66 (d, J=47.2Hz, 2H), 4.42 (s, 1H), 4.08 (d, J=13.9Hz, 1H), 3.72 (dd, J=14.1, 9.8Hz, 1H), 3.10 (d, J=16.4Hz, 1H), 2.69 (s, 0H), 2.48 (d, J=19.6 Hz, 3H), 1.80 (d, J=43.0Hz, 4H), 1.33 (d, J=6.2Hz, 3H), 1.31-1.22 (m, 1H). ¹⁹ F NMR (377 MHz, chloroform-d) δ -76.43, -114.57, -117.38. LCMS-ESI ⁺ (m/z): [M+H] ⁺ Calcd. for C ₂₃ H ₂₃ ClF ₂ N ₃ O ₅ : 494.13; Found: 494.19.

Compound 88b: 5 mg (17%), ¹ H NMR (400 MHz, chloroform-d) δ 8.54 (s, 1H), 7.39 (d, J = 7.0 Hz, 1H), 6.90-6.68 (m, 2H), 4.78-4.26 (m, 4H), 4.12-3.96 (m, 1H), 3.81-3.58 (m, 1H), 2.53 (m, 2H), 1.80 (d, J = 39.1 Hz, 5H), 1.32 (d, J = 6.3 Hz, 3H), 1.23 (d, J = 16.1 Hz, 3H). ¹⁹ F NMR (377 MHz, chloroform-d) δ -76.45, -111.84, -114.77. LCMS-ESI ⁺ (m/z): [M+H] ⁺ calcd. for C ₂₃ H ₂₄ F ₂ N ₃ O ₅ : 460.17; found: 460.22.

Example 20

Preparation of Compound 94

Step 1

To a mixture of compound 1 (43 mg, 0.367 mmol), compound 82 (97 mg, 0.359 mmol), and sodium bicarbonate (65 mg, 0.774 mmol) was added water (0.5 mL) and methanol (1 mL). The resulting mixture was stirred at room temperature for 16 hours. The mixture was diluted with water and extracted with dichloromethane (x3). The organic fractions were washed with water (x1), combined, and dried ( _MgSO4 ) to give a solution of crude compound 89 (~40 mL). This solution was used in the next reaction. LCMS-ESI ⁺ (m/z): _[ M+ _H2O +H] ⁺ _C17H24NO8 calculated value: _370.15 ; found value: 370.07.

Step 2

A solution of crude compound 89 in dichloromethane was stirred at 0°C and Dess-Martin periodinane (180 mg, 0.424 mmol) was added. After 5 minutes at 0°C, the mixture was stirred at room temperature. After 1.25 hours, Dess-Martin periodinane (185 mg, 0.436 mmol) was further added at room temperature. After another 1.75 hours at room temperature, Dess-Martin periodinane (360 mg, 0.849 mmol) was further added at room temperature. After 1.5 hours, Dess-Martin periodinane (360 mg, 0.849 mmol) was further added at room temperature. After 1.5 hours, the reaction mixture was filtered through a pad of celite and the filtrate was concentrated. The residue was purified by silica gel column chromatography (12 g column) using hexane-ethyl acetate-20% methanol/ethyl acetate as eluent, and the fractions containing the product were combined and concentrated. The residue was further purified by preparative HPLC (acetonitrile/H ₂ O with 0.1% TFA modifier) to obtain compound 90. ^1H NMR (400 MHz, CHLOROFORM-d) δ 7.97 (s, 1H), 5.40 (s, 1H), 5.28 (p, J=6.3 Hz, 1H), 4.69 (dd, J=10.5, 6.8 Hz, 1H), 4.61-4.47 (m, 1H), 4.43-4.28 (m, 1H), 4.00 (d, J=10.6 Hz, 1H), 3.96 (s, 3H), 3.88 (s, 3H), 2.81 (ddd, J=15.2, 12.2, 7.4 Hz, 1H), 2.66 (ddd, J=15.1, 2.9, 1.4 Hz, 1H), 1.38 (dd, J=10.8, 6.3 Hz, 6H). LCMS-ESI ⁺ (m/z): [M+H] ⁺ _{calcd . for Ci7H22NO8 :} 368.13; found: 368.03.

Step 3

A mixture of compound 90 (15 mg, 0.041 mmol), (-)-(R)-2-aminopropanol (17 mg, 0.226 mmol) and potassium carbonate (26 mg, 0.188 mmol) in acetonitrile (1 mL) was stirred at room temperature while acetic acid (0.1 mL, 0.175 mmol) was added. The flask was sealed and stirred at 60° C. for 2 hours and in a 70° C. bath for 19 hours. The reaction mixture was concentrated and the residue was dissolved in DMF, filtered, and the filtrate was purified by preparative HPLC (acetonitrile/H ₂ O with 0.1% TFA modifier) to give compound 91. ¹ H NMR (400MHz, chloroform-d) δ8.48 (s, 1H), 4.66 (d, J=14.5Hz, 1H), 4.54 (h, J=6.7Hz, 1H), 4.36 (dd, J=9.0, 7.0Hz, 1H), 4.19 (dd, J=14.5, 1.6Hz, 1H), 4.06 (s, 3H), 3.89 (s, 4H), 3.81 (dd, J=9.0, 6.9Hz, 1H), 3.79-3.70 (m, 2H), 1.94-1.66 (m, 2H), 1.43 (d, J=6.4Hz, 3H). LCMS-ESI ⁺ (m _/ z): [M+H] ⁺ calcd _{. for Ci7H21N2O7} : 365.13; found: 365.11.

Step 4

To a mixture of compound 91 (8 mg, 0.022 mmol) in methanol (1 mL) and THF (1 mL) was added 1 N LiOH (0.1 mL) at room temperature and the resulting mixture was stirred at room temperature for 16.5 hours. The resulting solution was concentrated to remove methanol and THF and the residue was dissolved in water, acidified with 1 N HCl, and further diluted with DMF. The solution was purified by preparative HPLC (acetonitrile/H ₂ O with 0.1% TFA modifier) and the acid-containing fractions were concentrated to dryness, co-evaporated with toluene (×2), and dried under vacuum for ~30 minutes to give compound 92. LCMS-ESI ⁺ (m/z): [M+H] ⁺ C ₁₆ H ₁₉ N ₂ O ₇ calculated value: 351.12; found value: 351.08.

Step 5

To a solution of compound 92 (7 mg, 0.020 mmol), compound 11 (12 mg, 0.056 mmol), and HATU (27 mg, 0.071 mmol) in dichloromethane (2 mL) was added N,N-diisopropylethylamine (0.07 mL, 0.402 mmol) at room temperature. After 30 minutes, the mixture was diluted with ethyl acetate (~15 mL) and washed with saturated _NH4Cl (x2), saturated _NaHCO3 (x2), and brine (x1). After the aqueous portion was extracted with ethyl acetate (x1), the organic portions were combined, dried ( _MgSO4 ), and concentrated. The residue was purified by silica gel column chromatography (12 g column) using hexane-ethyl acetate-20% methanol/ethyl acetate as eluent to give compound 93. ¹ H NMR (400 MHz, chloroform-d) δ 10.42 (s, 1H), 8.74 (s, 1H), 7.31 (td, J = 8.3, 6.1 Hz, 1H), 6.93 (td, J = 8.5, 1.8 Hz, 1H), 4.76-4.68 (m, 1H), 4.63 (td, J = 15.5, 14.4, 6.1 Hz, 2H), 4.54 (q, J = 6.6 Hz, 1H), 4.35 (dd, J=9.0, 7.0Hz, 1H), 4.20-4.13 (m, 1H), 4.08 (s, 3H), 3.91-3.84 (m, 1H), 3.81 (dd, J=9.0, 6.9Hz, 1H ), 3.75 (dd, J=11.4, 3.6Hz, 1H), 3.70 (d, J=2.8Hz, 1H), 1.84-1.70 (m, 2H), 1.45 (d, J=6.3Hz, 3H). ¹⁹ F NMR (376MHz, chloroform-d) δ -114.98 (s, 1F), -117.38 (s, 1F). LCMS-ESI ⁺ (m/z): [M+H] ⁺ calcd. for C ₂₃ H ₂₃ ClF ₂ N ₃ O ₆ : 510.12; found: 510.11.

Step 6

To a solution of compound 93 (4.7 mg, 0.009 mmol) in MeCN (1 mL) was added MgBr ₂ (7.8 mg, 0.042 mmol) at room temperature and the resulting mixture was stirred in a 50°C bath. After 30 minutes, the reaction mixture was stirred at 0°C and 1N HCl was added to make the mixture a solution, which was then diluted with water and the product was extracted with dichloromethane (x3). The combined extracts were dried (MgSO ₄ ) and concentrated, and the residue was purified by silica gel column chromatography (12 g column) using dichloromethane-20% methanol/dichloromethane as the eluent to give compound 94. ¹ H NMR (400 MHz, chloroform-d) δ 11.62 (s, 1H), 10.37 (s, 1H), 8.71 (s, 1H), 7.35-7.27 (m, 1H), 6.92 (td, J = 8.5, 1.9 Hz, 1H), 4.76 (d, J = 14.4 Hz, 1H), 4.70-4.61 (m, 2H), 4.51 (p, J = 6.4 Hz, 1H), 4.44 (dd, J = 8.9, 7.3 Hz, 1H), 4.19-4. 11 (m, 1H), 3.97-3.90 (m, 1H), 3.87 (dd, J=8.8, 6.5Hz, 1H), 6.89-6.87 (m, 0H), 3.76 (td, J=11.9, 2.7Hz, 1H) , 3.71 (d, J=2.1Hz, 1H), 1.88 (td, J=13.1, 12.2, 5.2Hz, 1H), 1.80 (d, J=14.3Hz, 1H), 1.51 (d, J=6.3Hz, 3H). ¹⁹ F NMR (376MHz, chloroform-d) δ -115.17 (d, J=7.1Hz, 1F), -117.41 (d, J=7.7Hz, 1F). LCMS-ESI ⁺ (m/z): [M+H] ⁺ calcd. for C ₂₂ H ₂₁ ClF ₂ N ₃ O ₆ : 496.11; found: 496.08.

Example 21

Preparation of Compound 96

Step 1

To compound 86a (95 mg, 0.186 mmol, containing a small amount of 86b) in acetonitrile (10 mL) was added acetic acid (0.5 mL, 8.73 mmol), potassium carbonate (114 mg, 0.825 mmol), and 2-aminoethanol (62 mg, 1.02 mmol). After stirring at 70°C for 24 hours, the mixture was dissolved in methanol and concentrated on silica _{gel. The resulting adsorption mixture was purified by silica gel column chromatography using dichloromethane-20% methanol/dichloromethane as the eluent to afford racemic compound 95. LCMS-ESI+ (m/z): [M+H]+ calculated for C23H23ClF2N3O5 :} ^{494.13 ;} _{found : 494.21} .

Step 2

To a solution of compound 95 (59 mg, 0.119 mmol) in acetonitrile (5 mL) was added magnesium bromide (66 mg, 0.358 mmol) and the mixture was stirred at 50°C for 30 minutes. After the mixture was cooled and acidified with 10% HCl, the product was extracted with ethyl acetate (x2). The combined organic extracts were dried ( _MgSO4 ), concentrated, and purified by preparative HPLC (acetonitrile/ _H2O with 0.1% TFA modifier) to give racemic compound 96. ¹ H NMR (400 MHz, chloroform-d) δ 10.58 (d, J = 7.2 Hz, 1H), 8.57 (s, 1H), 7.30 (t, J = 7.7 Hz, 1H), 7.00-6.85 (m, 1H), 4.66 (d, J = 5.2 Hz, 2H), 4.20-3.88 (m, 2H), 2.91-2.50 (m, 2H), 2.36 (t, J = 7.5 Hz, 1H), 1.88 (d, J = 13.1 Hz, 2H), 1.62 (q, J = 7.4 Hz, 1H), 1.25, 0.95-0.63 (m, 3H). ¹⁹ F NMR (377 MHz, CHLOROFORM-d) δ -76.43, -114.27, -117.28. LCMS-ESI ⁺ (m/z): [M+H] ⁺ Calcd. for C ₂₂ H ₂₁ ClF ₂ N ₃ O ₅ : 480.11; Found: 480.17.

Example 22

Preparation of Compound 100

Step 1

To compound 97 (0.05 g, 0.14 mmol) in acetonitrile (3 mL), which was prepared by the same procedure as compound 90, was added acetic acid (0.3 mL, 5.24 mmol), potassium carbonate (0.08 g, 0.58 mmol), and (R)-2-aminopropan-1-ol (0.04 g, 0.54 mmol). After stirring at 70° C. for 17 hours, the reaction mixture was cooled to room temperature and filtered. The crude solution was purified by preparative HPLC (acetonitrile/H ₂ O with 0.1% TFA modifier) to afford compound 98. LCMS-ESI ⁺ (m / z): [M + H] ⁺ C ₁₇ H ₂₁ N ₂ O ₇ calculated value: 365.13; found value: 365.

Step 2

A mixture of compound 98 (5 mg, 0.014 mmol) in THF (0.5 mL), methanol (0.5 mL) and 1N KOH (0.1 mL) was stirred at room temperature for 1 hour. After acidifying the resulting mixture with 1N HCl, it was concentrated to dryness and co-evaporated with toluene (x3). The resulting crude acid was used in the next reaction as it was.

To a mixture of the above crude acid, compound 11 (6 mg, 0.028 mmol) and HATU (10 mg, 0.028 mmol) in dichloromethane (1 mL) was added N,N-diisopropylethylamine (0.009 g, 0.07 mmol) at room temperature. After 2 hours, the reaction mixture was concentrated and the crude residue was purified by preparative HPLC (acetonitrile/H ₂ O with 0.1% TFA modifier) to afford compound 99. LCMS-ESI ⁺ (m / z): [M+H] ⁺ calculated for C ₂₃ H ₂₃ ClF ₂ N ₃ O ₆ : 510.12; found: 510.

Step 3

To a solution of compound 99 (3 mg, 0.006 mmol) in acetonitrile (2 mL) was added magnesium bromide (0.01 g, 0.054 mmol) and the mixture was stirred at 50° C. for 30 minutes. After the mixture was cooled to 0° C. and acidified with 1N HCl, the resulting solution was purified by preparative HPLC (acetonitrile/H ₂ O with 0.1% TFA modifier) to give compound 100. ¹ H NMR (400 MHz, chloroform-d) δ 10.38 (d, J=6.2 Hz, 1H), 8.54 (s, 1H), 7.45-7.19 (m, 1H), 6.94 (td, J=8.7, 1.8 Hz, 1H), 4.81-4.60 (m, 1H), 4.61-4.39 (m, 1H), 4.29-4.05 (m, 2H), 4.0 5-3.83 (m, 2H), 3.79-3.66 (m, 1H), 3.62-3.37 (m, 1H), 3.29 (d, J=12.8 Hz, 1H), 3.20-3.07 (m, 1H), 2.70 (d, J=10.5 Hz, 2H), 2.36 (d, J=7.4 Hz, 1H), 1.44 (d, J=6.2 Hz, _3H ). ¹⁹ _F NMR (376 MHz, CHLOROFORM-d) δ -113.81 - -116.52 (m, 1F), -117.29 (m, 1F). LCMS-ESI ⁺ (m/z): [M+H] ⁺ _{Calcd .} for _{C22H21ClF2N3O6} : 496.11; found: 496.

Example 23

Preparation of Compound 103

Step 1

To compound 90 (0.05 g, 0.14 mmol) in acetonitrile (3 mL) was added 2-aminoethanethiol HCl salt (0.06 g, 0.54 mmol), potassium carbonate (0.08 g, 0.58 mmol), and acetic acid (0.3 mL, 5.24 mmol). After stirring at 70°C for 17 hours, the mixture was cooled to room temperature and filtered. The filtrate was purified by preparative HPLC (acetonitrile/ _H2O with 0.1% TFA modifier) to afford racemic mixture 101. LCMS-ESI ⁺ (m/ _{z )} : [M+H] ⁺ calculated for _Ci6H19N2O6S : _367.10 ; found: 367.

Step 2

A mixture of compound 101 (0.01 g, 0.028 mmol) in THF (0.5 mL), methanol (0.5 mL) and 1N KOH (0.1 mL) was stirred at room temperature for 1 hour. After acidifying the resulting mixture with 3N HCl, it was concentrated to dryness and co-evaporated with toluene (x3). The resulting crude acid was used in the next reaction as it was.

To a mixture of the above crude acid, compound 11 (0.01 g, 0.056 mmol) and HATU (0.02 g, 0.056 mmol) in dichloromethane (1 mL) was added N,N-diisopropylethylamine (0.02 g, 0.15 mmol) at room temperature. After 2 hours, the reaction mixture was concentrated and the crude residue was purified by preparative HPLC (acetonitrile/H ₂ O with 0.1% TFA modifier) to afford racemic compound 102. LCMS-ESI ⁺ (m / z): [M + H] ⁺ calculated for C ₂₂ H ₂₁ ClF ₂ N ₃ O ₅ S: 512.09; found: 512.

Step 3

To a solution of compound 102 (0.005 g, 0.01 mmol) in acetonitrile (2 mL) was added magnesium bromide (0.01 g, 0.054 mmol) and the mixture was stirred at 50° C. for 30 minutes. After the mixture was cooled to 0° C. and acidified with 1N HCl, the resulting solution was purified by preparative HPLC (acetonitrile/H ₂ O with 0.1% TFA modifier) to give racemic compound 103. ¹ H NMR (400MHz, chloroform-d) δ 10.57 (m, 1H), 8.60 (s, 1H), 7.26 (m, 1H), 7.12-6.92 (m, 1H), 4.77 (ddd, J=12.5, 6.3, 4.0Hz, 1H), 4.67 (d, J=5.4Hz, 2H), 4.49 ( s, 1H), 4.14-3.93 (m, 1H), 3.86-3.72 (m, 2H), 3.66-3.43 (m, 2H), 3.33-3 .00 (m, 2H), 2.83 (d, J=16.5Hz, 1H), 2.56 (d, J=14.3Hz, 1H), 2.01 (m, 1H). ¹⁹ F NMR (376 MHz, CHLOROFORM-d) δ -114.36 (m, 1F), -117.06 (m, 1F). LCMS-ESI ⁺ (m/z): [M+H] ⁺ Calcd. for C ₂₁ H ₁₉ ClF ₂ N ₃ O ₅ S: 498.07; Found: 498.

Example 24

Preparation of compounds 110a and 110b

Step 1

A mixture of (1S,2S,3S,5S)-2-((tert-butyldimethylsilyl)oxy)bicyclo[3.1.0]hexan-3-amine (104, 795.27 mg, 3.5 mmol), pyrone 82 (0.9 g, 3.33 mmol), and sodium bicarbonate (1.12 g, 13.3 mmol) in methanol (80 mL) and water (20 mL) was stirred _at room temperature for 16 hours. After evaporation of the mixture to remove most of the methanol, the aqueous residue was diluted with water and the product _was extracted with EtOAc. The organic extracts were dried ( _Na2SO4 ) and concentrated to give the crude adduct, which was used as is in the next reaction. _LCMS -ESI ⁺ (m/z): [M+H] ⁺ calculated for _C24H38NO7Si : 480.24; found: 480.19.

To the above adduct (1.40 g, 2.92 mmol) in THF (20 mL) and methanol (5 mL) was added 1 M LiOH (3 mL), and the mixture was stirred at room temperature for 1.5 hours. The mixture was acidified with 3 N HCl and concentrated to dryness. The residue was purified by silica gel column chromatography using hexane-ethyl acetate as eluent to give compound 105. LCMS-ESI ⁺ (m / z): [M + H] ⁺ C ₂₃ H ₃₆ NO ₇ Si calculated value: 466.23; found value: 466.19.

Step 2

To a mixture of compound 105 (515 mg, 1.106 mmol), compound 11 (473 mg, 2.21 mmol), and HATU (841 mg, 2.21 _mmol ) in dichloromethane (13 mL) was added N,N-diisopropylethylamine (1.12 mL, 6.63 mmol). After 0.5 h, the mixture was diluted with dichloromethane and washed with 3% LiCl, saturated _NH4Cl , and 0.5N HCl. The organic portion was dried ( _Na2SO4 ) and concentrated. The residue was purified by silica gel column chromatography using dichloromethane-20% methanol _/ dichloromethane as eluent to provide compound 106. LCMS-ESI ⁺ (m/z): [M+H _] ⁺ calculated _{for C30H40ClF2N2O6Si} : _625.23 ; found: 625.21.

Step 3

To a solution of compound 106 (452 mg, 0.72 mmol) in THF (20 mL) was added 1 M tetrabutylammonium fluoride hydrate in THF (0.8 mL, 0.80 mmol) at room temperature under a nitrogen atmosphere. After 20 minutes, the mixture was quenched with saturated _NH₄Cl solution and acidified to pH <3 with 10% HCl, and the product was extracted with ethyl acetate. The extract was dried ( _Mg₂SO₄ ) and concentrated, and the residue was purified by silica gel column chromatography using _hexane -ethyl acetate as the eluent to provide compound 107. LCMS- ^ESI⁺ (m/z): [M+H] ^⁺ _{Calcd . for C₂₄H₂ClF₂N₂O₆} : _511.14 ; Found: 511.13.

Step 4

To a solution of compound 107 (100 mg, 0.196 mmol) in dichloromethane (5 mL) was added _Dess - _Martin periodinane (332.06 mg, 0.78 mmol). After the mixture was stirred at room temperature for 20 minutes, a mixture of saturated _{Na₂S₂O₃} /saturated _NaHCO₃ (7:1) was added to the mixture, which was stirred for 10 minutes. The product was extracted with _{dichloromethane} , and the extract _was dried ( _Na₂SO₄ ) and concentrated to give crude compound 108. LCMS- ^ESI⁺ (m/ _z ): [M+H] ^⁺ _{Calcd .} for _{C₂₄H₂ClF₂N₂O₆} : 509.13; Found: 509.12.

Step 5

To a solution of the above crude 108 in acetonitrile (10 mL) was added 3-aminopropan-1-ol (0.06 mL, 0.78 mmol), acetic acid (0.5 mL, 8.73 mmol), and potassium carbonate (108 mg, 0.784 mmol). After stirring at 70°C for 24 hours, the reaction mixture was diluted with methanol and concentrated on silica gel. The resulting adsorption mixture was purified by silica _gel column chromatography using dichloromethane- ₂₀ % methanol/dichloromethane as eluent to afford 109 ( _a mixture of two diastereomers, 109a and 109b). LCMS-ESI ⁺ (m/z): [M+H _] ⁺ calculated for _{C24H23ClF2N3O5} : 506.13; found: 506.18.

Step 6

To a solution of 109 (10 mg, 0.020 mmol) in acetonitrile (5 mL) was added magnesium bromide (11 mg, 0.060 mmol). The reaction mixture was stirred at 50° C. for 30 minutes, acidified with 10% HCl, and extracted with ethyl acetate (×2). The combined organic fractions were dried (MgSO ₄ ) and concentrated, and the residue was purified by preparative HPLC (acetonitrile/H ₂ O with 0.1% TFA modifier) to afford 110 (a 4:1 mixture of 110a and 110b). ¹ H NMR (400MHz, methanol-d4) δ8.22 (s, 1H), 7.39 (q, J = 7.5Hz, 1H), 7.08 (t, J = 8.5Hz, 1H), 4.67 (s, 2H), 4.58-3.56 (m, 4H), 3.23 (d, J = 17.2Hz, 1H) , 3.14-2.93 (m, 1H), 2.45 (d, J=25.2Hz, 1H), 2.34-1.87 (m, 3H), 1.46-1.13 (m, 3H), 0.82 (dd, J=55.8, 6.7Hz, 1H), 0.61 (q, J=3.9Hz, 1H). ¹⁹ F NMR (376 MHz, Methanol-d4) δ -77.72 (d, J = 256.2 Hz), -116.59--117.81 (m), -119.77. LCMS-ESI ⁺ (m/z): [M+H] ⁺ Calcd. for C ₂₃ H ₂₁ ClF ₂ N ₃ O ₅ : 492.11; found: 492.14.

Example 25

Antiviral assay in MT4 cells

For antiviral assays using MT4 cells, 0.4 μL of 189X test concentration of compound serially diluted 3-fold in DMSO was added to 40 μL of cell growth medium (RPMI 1640, 10% FBS, 1% penicillin/streptomycin, 1% L-glutamine, 1% HEPES) in quadruplicate to each well of a 384-well assay plate (10 concentrations).

A 1 mL aliquot of 2 × 10 ⁶ MT4 cells was pre-infected with 25 μL (MT4) or cell growth medium (mock infection) or fresh 1:250 dilution of HIV-IIIb concentrated ABI stock (0.004 moi for MT4 cells) for 1 hour and 3 hours at 37°C. Infected and uninfected cells were diluted in cell growth medium and 35 μL of 2000 (for MT4) cells were added to each well of the assay plate.

The assay plate was then incubated in a 37°C incubator. After 5 days of incubation, 25 μL of 2X concentrated CellTiter-Glo ^™ reagent (Cat. No. G7573, Promega Biosciences, Inc., Madison, WI) was added to each well of the assay plate. Cells were lysed by incubation at room temperature for 2-3 minutes, and chemiluminescence was then read using an Envision reader (PerkinElmer).

The compounds of the present disclosure exhibited antiviral activity in this assay, as shown below in Table 1. Therefore, the compounds of the embodiments disclosed herein can be used to treat HIV viral proliferation, treat AIDS, or delay the onset of AIDS or ARC symptoms.

Table 1

The data in Table 1 represent the time-averaged values for each determination for each compound. For some compounds, multiple determinations were made over the entire duration of the project.

The entire contents of all U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applications, and non-patent publications mentioned in this specification are incorporated herein by reference in their entirety to the extent not inconsistent with this specification.

From the foregoing it will be appreciated that although specific embodiments have been described herein for purposes of illustration, various modifications may be made without departing from the spirit and scope of the present disclosure. Accordingly, the present disclosure is not to be restricted, except as in the appended claims.

Claims (24)

1. Compounds of formula (Ia) Or its pharmaceutically acceptable salt, wherein: A is a saturated or partially unsaturated 4- to 7-membered monocyclic heterocyclic group, and is optionally substituted by 1 to 5 ^R3 groups; Each ^R3 is independently selected from _C1-4 alkyl, halogen, and oxo; or two ^R3s attached to the same or adjacent carbon atoms form a spiro or fused _C3-6 cycloalkyl or 4- to 6-membered heterocyclic ring; A' is selected from _C3-7 monocyclic cycloalkyl groups and 4- to 7-membered monocyclic heterocyclic groups; wherein each _C3-7 monocyclic cycloalkyl group and 4- to 7-membered monocyclic heterocyclic group is optionally substituted by 1 to 5 ^R4 groups; Each ^R4 is independently selected from _C1-4 alkyl, halogen, and oxo; or two ^R4s attached to the same or adjacent carbon atoms form a spiro or fused _C3-6 cycloalkyl or 4- to 6-membered heterocyclic ring; ^R1 is a phenyl group optionally substituted with 1 to 5 ^R5 groups; Each ^R5 is independently selected from halogens and _C1-3 alkyl groups; and ^R2 is selected from H, _C1-3 haloalkyl and _C1-4 alkyl. 2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein A is a saturated or partially unsaturated 5- or 6-membered monocyclic heterocyclic group, and optionally substituted with 1 to 5 ^R3 groups. 3. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein A is selected from oxazolidinyl, piperidinyl, 3,4-unsaturated piperidinyl, pyrrolidinyl, tetrahydro-1,3-oxazinyl, and thiazolyl; each of which is optionally substituted with 1 to 5 ^R3 groups. 4. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein A is selected from oxazolidinyl, piperidinyl, 3,4-unsaturated piperidinyl, pyrrolidinyl, tetrahydro-1,3-oxazinyl, and thiazolyl; each of which is optionally substituted by one or two ^R3 groups; wherein ^R3 is a _C1-4 alkyl; or two ^R3s attached to the same or adjacent carbon atoms form a spiro or fused _C3-6 cycloalkyl or a 4- to 6-membered heterocyclic ring. 5. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein A is selected from oxazolidinyl, piperidinyl, 3,4-unsaturated piperidinyl, pyrrolyl, tetrahydro-1,3-oxazinyl, and thiazolyl; each of which is optionally substituted with a methyl group. 6. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from: 7. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from: 8. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein A' is selected from _C5-6 monocyclic cycloalkyl groups and 5- to 6-membered monocyclic heterocyclic groups; wherein each _C5-6 monocyclic cycloalkyl group and 5- to 6-membered monocyclic heterocyclic group is optionally substituted with 1 to 5 ^R4 groups. 9. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein A' is selected from cyclopentyl, tetrahydrofuranyl, cyclohexyl and tetrahydropyranyl; each of which is optionally substituted by 1 to 5 ^R4 groups. 10. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein A' is selected from cyclopentyl, tetrahydrofuranyl, cyclohexyl, and tetrahydropyranyl; each of which is optionally substituted by one or two ^R4 groups, wherein each ^R4 is independently selected from _C1-4 alkyl, halogen, and oxo; or two ^R4s attached to the same or adjacent carbon atoms form a spiro or fused _C3-6 cycloalkyl or 4- to 6-membered heterocyclic ring. 11. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein A' is selected from cyclopentyl, tetrahydrofuranyl, cyclohexyl and tetrahydropyranyl; each optionally fused with a _C3-6 cycloalkyl ring. 12. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein A’ is selected from cyclopentyl, tetrahydrofuranyl, cyclohexyl and tetrahydropyranyl; each optionally fused with cyclopropyl. 13. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein ^R2 is H. 14. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from: 15. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from: 16. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from: 17. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein ^R1 is a phenyl group substituted with two or three ^R5 groups, wherein each ^R5 is independently selected from halogens and _C1-3 alkyl groups. 18. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein ^R1 is a phenyl group substituted with two or three ^R5 groups, wherein each ^R5 is independently selected from fluorine and chlorine. 19. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein ^R1 is selected from: 20. The compound of claim 1, wherein the compound is selected from the group consisting of: Or its pharmaceutically acceptable salt. 21. A pharmaceutical composition comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. 22. The pharmaceutical composition of claim 21, further comprising a first additional therapeutic agent selected from: abacavir sulfate, tenofovir, tenofovir disoproxil fumarate, tenofovir alafenamide and tenofovir alafenamide hemifumarate, and a second additional therapeutic agent selected from emtricitabine and lamivudine. 23. Use of a therapeutically effective amount of the compound of claim 1 or the pharmaceutical composition of claim 21 in the preparation of a medicament for treating HIV infection in humans. 24. The use of claim 23, wherein the medicament further comprises a first additional therapeutic agent selected from: abacavir sulfate, tenofovir, tenofovir disoproxil fumarate, tenofovir alafenamide and tenofovir alafenamide hemifumarate, and a second additional therapeutic agent selected from emtricitabine and lamivudine.