HK1239676A1 - Polycyclic-carbamoylpyridone compounds and their pharmaceutical use - Google Patents

Description

Polycyclic carbonyl pyridinone compounds and pharmaceutical use thereof

Background

FIELD

Compounds, compositions and methods useful for treating Human Immunodeficiency Virus (HIV) infection are disclosed. In particular, novel polycyclocarbonylpyridinone compounds, methods for their preparation, and their use as therapeutic or prophylactic agents are disclosed.

Description of the related 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, toxicity and development of resistant strains limit their effectiveness (Palella, et al. N. Engl. J Med. (1998)338: 853-. Thus, there is a need for new drugs that inhibit HIV replication.

The goal of antiretroviral therapy is to achieve viral suppression in HIV-infected patients. Current treatment guidelines promulgated by the U.S. department of health and human service specify that the achievement of viral inhibition requires the use of combination therapy, i.e., several drugs from at least two or more drug classes. (adult and juvenile antiretroviral guidelines groups; guidelines for the use of antiretroviral drugs in HIV-1 infected adults and adolescents; health and human services, http:// aidsinfo. nih. gov/Contentfiles/Adultan DoleScgl. pdf, available on 3/14/2013.) furthermore, decisions regarding treatment of HIV-infected patients are complicated when the patients need to be treated for other medical conditions (supra, see E-12). Because the standard of care requires the use of multiple different drugs to inhibit HIV and treat other conditions that a patient may experience, the possibility of drug interactions is a criterion for the evaluation of drug treatment regimens. Thus, there is a need for antiretroviral therapy with as reduced drug interactions as possible.

Furthermore, HIV viruses are known to mutate in infected subjects (Tang et al, Drugs (2012)72(9) e1-e 25). Due to the propensity of AIDS virus to mutate, there is a need to use anti-HIV drugs to cope with a series of known HIV variants (huret al, HIV/AIDS CID (2014)58, 423-.

Disclosure of Invention

The present invention relates to novel polycyclic carbonylpyridinone compounds having antiviral activity, including stereoisomers thereof and pharmaceutically acceptable salts thereof. The compounds of the invention are useful for treating HIV infection, inhibiting the activity of HIV integrase and/or reducing HIV replication. In some embodiments, the compounds disclosed herein are resistant to a range of known HIV mutants. In some embodiments, the compounds disclosed herein can minimize the likelihood of drug-drug interactions when co-administered with other drugs.

In one embodiment, compounds of the following formula (Ia) are provided:

or a pharmaceutically acceptable salt thereof, wherein:

a' is selected from C_3-7Monocyclic cycloalkyl and 4 to 7 membered monocyclic heterocyclyl; wherein C is_3-7Monocyclic cycloalkyl and 4-7 membered monocyclic heterocyclyl are each optionally substituted with 1 to 5R⁴Substituted by groups;

each R⁴Independently selected from oxo, methyl and ethyl; or two R attached to the same or adjacent carbon atoms⁴Together forming a spiro or fused C_3-6Cycloalkyl or a 4 to 6 membered heterocyclyl ring;

R¹selected from H, C_1-4Alkyl radical, C_1-4Haloalkyl and C_3-6A cycloalkyl group;

R²selected from hydrogen, C_1-3Haloalkyl and C_1-3An alkyl group;

R³selected from the group consisting of at least three R⁵Phenyl substituted with a group;

each R⁵Independently selected from C_1-3Alkyl and halogen.

Another embodiment provides a compound of formula (Ib):

or a pharmaceutically acceptable salt thereof, wherein:

X¹、X²and X³Each independently selected from CHR⁴O, C ═ O and CH₂CHR⁴(ii) a Provided that X¹、X²And X³No more than one of which is O or C ═ O;

each R⁴Independently selected from H and CH₃；

R¹Selected from H, C_1-4Alkyl radical, C_1-4Haloalkyl and C_3-6A cycloalkyl group;

R²selected from hydrogen, C_1-3Haloalkyl and C_1-3An alkyl group;

R³is selected from three R⁵Phenyl substituted with a group;

each R⁵Independently selected from C_1-3Alkyl and halogen.

Another embodiment provides a compound of formula (Ic):

or a pharmaceutically acceptable salt thereof, wherein:

R¹selected from H, C_1-4Alkyl radical, C_1-4Haloalkyl and C_3-6A cycloalkyl group.

Another embodiment provides a compound of formula (Id):

or a pharmaceutically acceptable salt thereof, wherein:

R¹selected from H, C_1-4Alkyl radical, C_1-4Haloalkyl and C_3-6A cycloalkyl group.

Another embodiment provides a compound of formula (Ie):

or a pharmaceutically acceptable salt thereof, wherein:

R¹selected from H, C_1-4Alkyl radical, C_1-4Haloalkyl and C_3-6A cycloalkyl group.

Another embodiment provides a compound of formula (If):

or a pharmaceutically acceptable salt thereof, wherein:

R¹is selected from H, C_1-4Alkyl radical, C_1-4Haloalkyl and C_3-6A cycloalkyl group.

In another embodiment, a pharmaceutical composition is provided comprising a compound having formula (Ia), (Ib), (Ic), (Id), (Ie), or (If), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

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

In another embodiment, there is provided the use of a compound of formula (Ia), (Ib), (Ic), (Id), (Ie) or (If), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (Ia), (Ib), (Ic), (Id), (Ie) or (If), or a pharmaceutically acceptable salt thereof, for the treatment of an HIV infection in a human having or at risk of having the infection.

In another embodiment, there is provided a compound of formula (Ia), (Ib), (Ic), (Id), (Ie) or (If), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (Ia), (Ib), (Ic), (Id), (Ie) or (If), or a pharmaceutically acceptable salt thereof, for use in medical therapy.

In another embodiment, there is provided a compound of formula (Ia), (Ib), (Ic), (Id), (Ie) or (If), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (Ia), (Ib), (Ic), (Id), (Ie) or (If), or a pharmaceutically acceptable salt thereof, for use in prophylactic or therapeutic treatment of HIV infection.

In another embodiment, methods of using compounds having formula (Ia), (Ib), (Ic), (Id), (Ie), or (If) in therapy are provided. In particular, there is provided a method of treating the proliferation of the HIV virus, a method of treating AIDS, or delaying the onset of AIDS or ARC symptoms in a mammal (e.g., a human), comprising administering to the mammal a compound of formula (Ia), (Ib), (Ic), (Id), (Ie), or (If), or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

Another embodiment discloses the use of a compound of formula (Ia), (Ib), (Ic), (Id), (Ie) or (If) described herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of an HIV infection in a human suffering from, or at risk of, the infection.

In another embodiment, an article of manufacture comprising a composition effective to treat HIV infection is disclosed; and packaging materials comprising a label indicating that the composition is useful for treating HIV infection. Exemplary compositions comprise a compound of formula (Ia), (Ib), (Ic), (Id), (Ie), or (If) disclosed herein, or a pharmaceutically acceptable salt thereof.

In another embodiment, a method of inhibiting HIV replication is disclosed. The method comprises exposing the virus to a compound of formula (Ia), (Ib), (Ic), (Id), (Ie) or (If), or a salt thereof, in an amount effective to inhibit HIV replication.

In another embodiment, the use of a compound of formula (Ia), (Ib), (Ic), (Id), (Ie) or (If) to inhibit HIV integrase activity is disclosed.

In another embodiment, the use of a compound of formula (Ia), (Ib), (Ic), (Id), (Ie) or (If), or a pharmaceutically acceptable salt thereof, to inhibit HIV integrase activity is disclosed.

In another embodiment, the use of a compound of formula (Ia), (Ib), (Ic), (Id), (Ie) or (If), or a salt thereof, to inhibit HIV replication is disclosed.

In another embodiment, there is provided the use of a compound of formula (Ia), (Ib), (Ic), (Id), (Ie) or (If), or a pharmaceutically acceptable salt thereof, as a research tool.

The invention also provides a compound of each of the formulae herein, and each of their subgroups and embodiments, including a compound selected from formula (Ia), (Ib), (Ic), (Id), (Ie) or (If) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (Ia), (Ib), (Ic), (Id), (Ie) or (If) or a pharmaceutically acceptable salt thereof, or one of the specific compounds of the examples herein or a pharmaceutically acceptable salt thereof, for use in any of the methods of the invention defined herein.

Other embodiments, objects, features, and advantages may be set forth in the detailed description of the embodiments which follows, and in part will be obvious from the description, or may be learned by practice of the claimed embodiments. The objects and advantages may be realized and attained by means of the instrumentalities and combinations particularly pointed out in the description and claims. It should be noted that the above summary is to be considered a brief and general summary of some embodiments disclosed herein, provided only for the benefit and convenience of the reader, and is not intended to limit in any way the scope or range of equivalents to which the appended claims are legally entitled.

Detailed description of the preferred embodiments

In the following description, certain specific details are set forth in order to provide a thorough understanding of various embodiments disclosed herein. However, it will be understood by those skilled in the art that the embodiments disclosed herein may be practiced without these details. While the following description of several embodiments is provided, it is to be understood that the disclosure is to be considered as an example of the claimed subject matter and is not intended to limit the appended claims to the specific embodiments shown. Headings used in this disclosure are provided for convenience only and are not to be construed as limiting the claims in any way. Embodiments described under any heading may be combined with embodiments shown under any other heading.

Definition of

Unless the context requires otherwise, throughout the present disclosure and claims, the word "comprise" and variations such as "comprises" and "comprising" are to be understood as open, inclusive, i.e., "including but not limited to".

Reference in the specification to "one embodiment" or "an embodiment" means that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment disclosed herein. Thus, appearances of the phrases "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" means-NH₂A group.

"hydroxy" means an-OH group.

"oxo" refers to an ═ O substituent.

Prefixes, e.g. "C_u-v"or (C)_u-C_v) Meaning that the subsequent groups have u to v carbon atoms. E.g. "C_1-6Alkyl "means an alkyl group having 1 to 6 carbon atoms.

"alkyl" refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, which is saturated, having from one to twelve carbon atoms (C)₁-C₁₂Alkyl), in some embodiments, one to eight carbon atoms (C)₁-C₈Alkyl), or one to six carbon atoms (C)₁-C₆Alkyl) and which is attached to the rest of the molecule by a single bond, such as methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl, 1-dimethylethyl (tert-butyl), 3-methylhexyl, 2-methylhexyl, and the like.

"cycloalkyl" or "carbocyclic" refers to a stable, non-aromatic, monocyclic hydrocarbon consisting solely of carbon and hydrogen atoms, having from 3 to 15 carbon atoms, in some 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.

By "fused" is meant any ring structure described herein that is fused to an existing ring structure in a compound disclosed herein.

"halogen" means bromine, chlorine, fluorine or iodine.

"haloalkyl" refers to an alkyl group as defined above substituted with one or more halo groups as defined above, e.g., 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, saturated, 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 attached to the remainder of the molecule by a single bond or, in the case of a', by two single bonds. The nitrogen, carbon or sulfur atom in the heterocyclic group may be optionally oxidized; the nitrogen atoms may optionally be quaternized. Examples of such heterocyclyl groups include, but are not limited to, dioxolanyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidinyl, pyrrolidinyl, pyrazolidinyl, thiazolidinyl, tetrahydrofuranyl, trithianyl, tetrahydropyranyl, thiomorpholinyl, 1-oxo-thiomorpholinyl, and 1, 1-dioxo-thiomorpholinyl.

The embodiments disclosed herein are also intended to include all such pharmaceutically acceptable compounds of formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (II), (IIa), (III), (IIIa), (25-M), (25b), (39-M), and (39) which are isotopically labeled by having one or more atoms replaced by an atom having a different atomic mass or mass number. Examples of isotopes that can be added to the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, e.g., each of²H、³H、¹¹C、¹³C、¹⁴C、¹³N、¹⁵N、¹⁵O、¹⁷O、¹⁸O、³¹P、³²P、³⁵S、¹⁸F、³⁶Cl、¹²³I and¹²⁵I. these radiolabeled compounds may be used to help determine or measure the effectiveness of the compounds, for example by characterizing the site or mode of action or binding affinity to a pharmacologically important site of action. For example, some radiolabeled compounds of the compounds of formulae (Ia), (Ib), (Ic), (Id), (Ie), (If), (II), (IIa), (III), (IIIa), (25-M), (25b), (39-M) and (39), i.e., those incorporating a radioisotope, are useful in drug and/or substrate tissue distribution studies. Radioisotope tritium (i.e. tritium³H) And carbon-14 (i.e.¹⁴C) This is particularly useful because of the ease of incorporation and the ease of detection means.

With heavier isotopes such as deuterium (i.e.²H) Substitution may be made with some therapeutic advantage due to greater metabolic stability. For example, the in vivo half-life may be increased or the dosage requirements may be decreased. Thus, in some cases, heavier isotopes may be preferred.

Using positron emitting isotopes (e.g. of the type¹¹C,¹⁸F,¹⁵O and¹³n) can be used in Positron Emission Tomography (PET) studies to examine substrate receptor occupancy ratios. Formulae (Ia), (Ib), (Ic), (Id), (Ie), (If), (II), (IIa), (III), (IIIa), (25-M), (25b), (39-M) and (39) can generally be by the technicians in this field known conventional techniques or by the method similar to the method described below using the appropriate isotope labeling reagent instead of the previously used unlabelled reagent.

The methods, compositions, kits, and articles of manufacture provided herein use or include compounds (e.g., (Ia), (Ib), (Ic), (Id), (Ie), (If), (II), (IIa), (III), (IIIa), (25-M), (25b), (39-M), and (39)) or pharmaceutically acceptable salts, prodrugs, or solvates thereof, wherein 1 to n hydrogen atoms attached to a carbon atom may be replaced by deuterium atoms or D, wherein n is the number of hydrogen atoms in the molecule. As is known in the art, a deuterium atom is a nonradioactive isotope of a hydrogen atom. Such compounds may increase resistance to metabolism when administered to a mammal, and thus may be useful for increasing the half-life of the compound or a pharmaceutically acceptable salt, prodrug or solvate thereof. See, e.g., Foster, "Deuterium Isotrope Effects in Studies of Drug Metabolism," Trends Pharmacol. Sci.,5(12):524-527 (1984). These compounds are synthesized by methods well known in the art, for example, by using starting materials in which one or more hydrogen atoms are replaced by deuterium.

The embodiments disclosed herein are also intended to include in vivo metabolites of the disclosed compounds. These products can be caused, for example, by oxidation, reduction, hydrolysis, amidation, esterification, etc. of the compounds used, primarily due to enzymatic processes. Accordingly, embodiments disclosed herein include compounds prepared by a method comprising administering a compound according to embodiments disclosed herein to a mammal for a time sufficient for it to produce a metabolite. The identification of such products is generally carried out as follows: a radiolabeled compound according to embodiments disclosed herein is administered to an animal, such as a rat, mouse, guinea pig, monkey, or a human at a detectable dose, allowing sufficient time for metabolism to occur and the transformation products to be isolated from urine, blood, or other biological samples.

"stabilizing compound" and "stable structure" are intended to mean a compound that is sufficiently stable to be able to be isolated from a reaction mixture and formulated into an effective therapeutic agent in a useful purity.

"mammal" includes humans, as well as domestic animals such as laboratory animals and domestic pets (e.g., 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 may or may not occur, and that the description includes instances where said event or event occurs and instances where it does not. For example, "optionally substituted heterocyclyl" means that the heterocyclyl group may or may not be substituted, and the description includes both substituted heterocyclyl groups and unsubstituted heterocyclyl groups.

"pharmaceutically acceptable excipient" includes, but is not limited to, any adjuvant, carrier, excipient, 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 livestock.

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 NX₄ ⁺(wherein X is C₁-C₄Alkyl groups). Pharmaceutically acceptable salts of nitrogen atom or amino group include, for example, salts of organic carboxylic acids such as acetic acid, benzoic acid, lactic acid, fumaric acid, tartaric acid, maleic acid, malonic acid, malic acid, isethionic acid, lactose 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 the anion of the compound with a suitable cation such as Na⁺And NX₄ ⁺(wherein X is independently selected from H or C₁-C₄Alkyl) groups.

For therapeutic use, salts of the active ingredients of the compounds disclosed herein will generally be pharmaceutically acceptable, i.e., they will be salts derived from physiologically acceptable acids or bases. However, salts which are not pharmaceutically acceptable acids or bases may also be useful, for example, in the preparation or purification of compounds of formulas (Ia), (Ib), (Ic), (Id), (Ie), (If), (II), (IIa), (III), (IIIa), (25-M), (25b), (39-M) and (39) or compounds of another embodiment disclosed herein. All salts, whether derived from physiologically acceptable acids or bases, are within the scope of embodiments disclosed herein.

Metal salts are typically prepared by reacting a metal hydroxide with a compound according to embodiments disclosed herein. An example of a metal salt prepared in this way is one containing Li⁺、Na⁺And K⁺A salt. By adding suitable metal compoundsTo precipitate the less soluble metal salt from the more soluble salt solution.

In addition, salts can be prepared by reacting certain organic and inorganic acids such as HCl, HBr, H₂SO₄、H₃PO₄Or addition of organic sulfonic acids to basic centers, usually amine formation. Finally, it is to be understood that the compositions herein include the compounds disclosed herein in their non-ionized form, as well as their zwitterionic form, and in combination with stoichiometric water in the form of a hydrate.

Crystallization typically produces solvates of the compounds of the embodiments disclosed herein. As used herein, the term "solvate" refers to an aggregate of a compound of the embodiments disclosed herein comprising one or more molecules and one or more solvent molecules. The solvent may be water, in which case the solvate may be a hydrate. Alternatively, the solvent may be an organic solvent. Thus, the compounds of the embodiments disclosed herein may exist as hydrates, including monohydrate, dihydrate, hemihydrate, sesquihydrate, trihydrate, tetrahydrate, and the like, as well as the corresponding solvated forms. The compounds of the embodiments disclosed herein may be true solvates, while in other cases, the compounds of the embodiments disclosed herein may retain only extraneous water or a mixture of water plus some extraneous solvent.

"pharmaceutical composition" refers to a formulation of the compounds of the embodiments disclosed herein and a vehicle generally accepted in the art for delivery of biologically active compounds to a mammal, such as a human. Such media include all pharmaceutically acceptable excipients.

An "effective amount" or "therapeutically effective amount" refers to an amount of a compound according to embodiments disclosed herein that, when administered to a patient in need thereof, is sufficient to treat a disease state, condition, or disorder for which the compound is effective. Such an amount is 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 embodiments disclosed herein that constitutes a therapeutically effective amount varies depending upon such factors as the compound and its biological activity, the combination used for administration, the time of administration, the route of administration, the rate of excretion of the compound, the duration of the treatment, the type of disease state or condition to be treated and its severity, the drug used in combination or concurrently with the compound of embodiments disclosed herein, and the age, body weight, general health, sex, and diet. Such therapeutically effective amounts can be determined routinely by those skilled in the art, taking into account their own knowledge, prior art and this disclosure.

The term "treatment" as used herein is intended to mean the administration of a compound or composition according to an embodiment of the invention disclosed herein to reduce or eliminate the symptoms of HIV infection and/or to reduce the viral load of a patient. The term "treating" also includes administering a compound or composition according to embodiments disclosed herein after exposure of an individual to a virus but before symptoms of the disease have not occurred, and/or before the virus is detected in the blood, to prevent the symptoms of the disease from occurring and/or to prevent the virus from reaching detectable levels in the blood, and administration of a compound or composition according to the embodiments disclosed herein can prevent perinatal HIV transmission from the mother to the child by administration to the mother before giving birth, and administration to the child on the first few days after birth.

The term "antiviral agent" as used herein is intended to mean an agent (compound or organism) effective to inhibit the formation and/or replication of a human virus, including, but not limited to, agents that interfere with host or viral mechanisms necessary for the formation and/or replication of the virus in humans.

The term "HIV replication inhibitor" as used herein is intended to mean an agent 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 thus may give rise to enantiomers, diastereomers, and other stereoisomeric forms, which may be defined in terms of absolute stereochemistry as (R) -or (S) -, as (D) -or (L) -of amino acids. The present disclosure is intended to include all such possible isomers, as well as their racemic and optically pure forms. Optically active (+) and (-), (R) -and (S) -or (D) -and (L) -isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques such as chromatography and fractional crystallization. Conventional techniques for the preparation/separation of individual enantiomers include chiral synthesis from suitable optically pure precursors, or resolution of the racemate (or the racemate of a salt or derivative) 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 include both E and Z geometric isomers. Likewise, all tautomeric forms are also included.

"stereoisomers" refers to compounds consisting of the same atoms bonded by the same atoms but having different three-dimensional structures, which are not interchangeable. The present disclosure relates to various stereoisomers and mixtures thereof, and includes "enantiomers," which refers to two stereoisomers whose molecules are mirror images that do not overlap with each other.

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

"doltegravir" (Dolutegravir) or DTG is:

compound (I)

As previously mentioned, in one embodiment there is provided a compound having the following formula (Ia):

or a pharmaceutically acceptable salt thereof, wherein:

a' is selected from C_3-7Monocyclic cycloalkyl and 4 to 7 membered monocyclic heterocyclyl; wherein C is_3-7Monocyclic cycloalkyl and 4-7 membered monocyclic heterocyclyl are each optionally substituted with 1 to 5R⁴Substituted by groups;

each R⁴Independently selected from oxo, methyl and ethyl; or two R attached to the same or adjacent carbon atoms⁴Linked together to form a spiro or fused C_3-6Cycloalkyl or a 4 to 6 membered heterocyclyl ring;

R¹selected from H, C_1-4Alkyl radical, C_1-4Haloalkyl and C_3-6A cycloalkyl group;

R²selected from hydrogen, C_1-3Haloalkyl and C_1-3An alkyl group;

R³selected from the group consisting of at least three R⁵Phenyl substituted with a group;

and is

Each R⁵Independently selected from C_1-3Alkyl and halogen.

In another embodiment, A' is selected from C_5-6Monocyclic cycloalkyl and 5 to 6 membered monocyclic heterocyclyl; wherein each C_5-6Monocyclic cycloalkyl and 5-6 membered monocyclic heterocyclyl are optionally substituted with 1 to 5R⁴Substituted by groups; wherein each R⁴Independently selected from oxo, methyl and ethyl; or two R attached to the same or adjacent carbon atoms⁴Forming spiro or fused C_3-6Cycloalkyl or a 4-6 membered heterocyclyl ring.

In another embodiment, a' is selected from the group consisting of cyclohexyl, cyclopentyl, tetrahydrofuranyl and tetrahydropyranyl; each optionally substituted by one to two R⁴Is substituted by radicals in which each R⁴The groups are independently selected from oxo and methyl; or two R attached to the same or adjacent carbon atoms⁴To form spirodioxanesPentane or a fused cyclopropyl ring.

In another embodiment, A' is substituted with two R⁴Radical substitution in which two R are bound to the same or adjacent carbon atom⁴Forming a spirodioxolane or fused cyclopropyl ring.

In another embodiment, A' is tetrahydrofuranyl (e.g., tetrahydrofuran)Is composed of)。

In another embodiment, A' is tetrahydropyranyl (e.g., aIs composed of)。

In another embodiment, R²Selected from hydrogen, C_1-2Haloalkyl, ethyl and methyl.

In another embodiment, R²Selected from hydrogen, CHF₂And a methyl group.

In another embodiment, R²Is hydrogen.

In another embodiment, R²Is C_1-3A haloalkyl group.

In another embodiment, R²Is CHF₂。

In another embodiment, A' is selected from tetrahydrofuranyl and tetrahydropyranyl, and R is²Is hydrogen. In another embodiment, A' is selected from

In a further embodiment of the process of the present invention,is selected from

In a further embodiment of the process of the present invention,is selected from

In a further embodiment of the process of the present invention,is selected from

In a further embodiment of the process of the present invention,is selected from

In a further embodiment of the process of the present invention,is composed of

In a further embodiment of the process of the present invention,is composed of

In a further embodiment of the process of the present invention,is selected from

In a further embodiment of the process of the present invention,is selected from

In a further embodiment of the process of the present invention,is selected from

In a further embodiment of the process of the present invention,is selected from

In another embodiment, R¹Is selected from C_1-3Alkyl radical, C_1-2Haloalkyl and C_3-4Cycloalkyl radical.

In another embodiment, R¹Selected from hydrogen, methyl, ethyl, propyl, isopropyl, CH₂CF₃、CH₂CHF₂And a cyclopropyl group.

In another embodiment, R¹Is selected from C_1-4Haloalkyl and C_3-6A cycloalkyl group.

In another embodiment, R¹Is selected from CH₂CF₃、CH₂CHF₂And a cyclopropyl group.

In another embodiment, R¹Is ethyl.

In another embodiment, R³Is represented by three R⁵Phenyl substituted by radicals in which each R is⁵Independently selected from methyl, ethyl and halogen.

In another embodiment, R³Selected from:

in another embodiment, R³Selected from:

in another embodiment, R³Is represented by three R⁵Phenyl substituted by radicals in which each R is⁵Independently selected from fluorine and chlorine.

In another embodiment, R³Is phenyl substituted with two fluorines and one chlorine.

In another embodiment, R³Comprises the following steps:

in another embodiment, A' is selected from tetrahydrofuranyl and tetrahydropyranyl, R²Is hydrogen, R¹Is ethyl, and R³Is phenyl substituted with three halogens independently selected from fluorine and chlorine.

In another embodiment, A' is selected from tetrahydrofuranyl and tetrahydropyranyl, R²Is hydrogen, R¹Is ethyl and R³Is phenyl substituted with two fluorines and one chlorine.

In another embodiment, A' is tetrahydrofuranyl, R²Is hydrogen, R¹Is ethyl, and R³Comprises the following steps:

in another embodiment, A' is tetrahydropyranyl, R²Is hydrogen, R¹Is ethyl, and R³Comprises the following steps:

disclosed in one embodiment is a compound of formula (Ia) or a pharmaceutically acceptable salt thereof, wherein:

a' is selected from C_3-7Monocyclic cycloalkyl and 4 to 7 membered monocyclic heterocyclyl; wherein C is_3-7Monocyclic cycloalkyl and 4-to 7-membered monocyclic heterocyclyl are each substituted with two R⁴Substituted by radicals in which two R are bound to the same or to mutually-containing carbon atoms⁴Forming spiro or fused C_3-6Cycloalkyl or a 4 to 6 membered heterocyclyl ring;

R¹selected from H, C_1-4Alkyl radical, C_1-4Haloalkyl and C_3-6A cycloalkyl group;

R²selected from hydrogen, C_1-3Haloalkyl and C_1-3An alkyl group;

R³is selected from one to three R⁵Phenyl substituted with a group;

and is

Each R⁵Independently selected from C_1-3Alkyl and halogen.

Disclosed in one embodiment is a compound of formula (Ia), or a pharmaceutically acceptable salt thereof, wherein:

a' is selected from C_3-7Monocyclic cycloalkyl and 4 to 7 membered monocyclic heterocyclyl; wherein C is_3-7Monocyclic cycloalkyl and 4-7 membered monocyclic heterocyclyl are each optionally substituted with 1 to 5R⁴Substituted by groups;

each R⁴Independently selected from oxo, methyl and ethyl; or two R attached to the same or adjacent carbon atoms⁴Linked together to form a spiro or fused C_3-6Cycloalkyl or a 4 to 6 membered heterocyclyl ring;

R¹is C_3-6A cycloalkyl group;

R²selected from hydrogen, C_1-3Haloalkyl and C_1-3An alkyl group;

R³is selected from one to three R⁵Phenyl substituted with a group;

and is

Each R⁵Independently selected from C_1-3Alkyl and halogen.

Disclosed in one embodiment is a compound of formula (Ia), or a pharmaceutically acceptable salt thereof, wherein:

a' is selected from C_3-7Single ringCycloalkyl and 4 to 7 membered monocyclic heterocyclyl; wherein C is_3-7Monocyclic cycloalkyl and 4-7 membered monocyclic heterocyclyl are each optionally substituted with 1 to 5R⁴Substituted by groups;

each R⁴Independently selected from oxo, methyl and ethyl; or two R attached to the same or adjacent carbon atoms⁴Together forming a spiro or fused C_3-6Cycloalkyl or a 4 to 6 membered heterocyclyl ring;

R¹is C_1-4A haloalkyl group;

R²selected from hydrogen, C_1-3Haloalkyl and C_1-3An alkyl group;

R³is selected from one to three R⁵Phenyl substituted with a group;

and is

Each R⁵Independently selected from C_1-3Alkyl and halogen.

Disclosed in one embodiment is a compound of formula (Ia), or a pharmaceutically acceptable salt thereof, wherein:

a' is selected from C_3-7Monocyclic cycloalkyl and 4 to 7 membered monocyclic heterocyclyl; wherein C is_3-7Monocyclic cycloalkyl and 4-7 membered monocyclic heterocyclyl are each optionally substituted with 1 to 5R⁴Substituted by groups;

each R⁴Independently selected from oxo, methyl and ethyl; or two R attached to the same or adjacent carbon atoms⁴Linked together to form a spiro or fused C_3-6Cycloalkyl or a 4 to 6 membered heterocyclyl ring;

R¹selected from H, C_1-4Alkyl radical, C_1-4Haloalkyl and C_3-6A cycloalkyl group;

R²is C_1-3A haloalkyl group;

R³is selected from one to three R⁵Phenyl substituted with a group;

and is

Each R⁵Independently selected from C_1-3Alkyl and halogen.

Disclosed in one embodiment is a compound of formula (Ia), or a pharmaceutically acceptable salt thereof, wherein:

a' is selected from C_3-7Monocyclic cycloalkyl and 4 to 7 membered monocyclic heterocyclyl; wherein C is_3-7Monocyclic cycloalkyl and 4-to 7-membered monocyclic heterocyclyl are each substituted with two R⁴Radical substitution in which two R are bound to the same or adjacent carbon atom⁴Forming spiro or fused C_3-6Cycloalkyl or a 4 to 6 membered heterocyclyl ring;

R¹selected from H, C_1-4Alkyl radical, C_1-4Haloalkyl and C_3-6A cycloalkyl group;

R²selected from hydrogen, C_1-3Haloalkyl and C_1-3An alkyl group;

R³is selected from one to three R⁵Phenyl substituted with a group;

and is

Each R⁵Independently selected from C_1-3Alkyl and halogen.

Disclosed in one embodiment is a compound of formula (Ia), or a pharmaceutically acceptable salt thereof, wherein:

a' is selected from C_3-7Monocyclic cycloalkyl and 4 to 7 membered monocyclic heterocyclyl; wherein C is_3-7Monocyclic cycloalkyl and 4-to 7-membered monocyclic heterocyclyl are each substituted with two R⁴Radical substitution in which two R are bound to the same or adjacent carbon atom⁴Forming spiro or fused C_3-6Cycloalkyl or a 4 to 6 membered heterocyclyl ring;

R¹selected from H, C_1-4Alkyl radical, C_1-4Haloalkyl and C_3-6A cycloalkyl group;

R²selected from hydrogen,C_1-3Haloalkyl and C_1-3An alkyl group;

R³is selected from three R⁵Phenyl substituted with a group;

and is

Each R⁵Independently selected from C_1-3Alkyl and halogen.

Disclosed in one embodiment is a compound of formula (Ia), or a pharmaceutically acceptable salt thereof, wherein:

a' is selected from C_3-7Monocyclic cycloalkyl and 4 to 7 membered monocyclic heterocyclyl; wherein C is_3-7Monocyclic cycloalkyl and 4-7 membered monocyclic heterocyclyl are each optionally substituted with 1 to 5R⁴Substituted by groups;

each R⁴Independently selected from oxo, methyl and ethyl; or two R attached to the same or adjacent carbon atoms⁴Linked together to form a spiro or fused C_3-6Cycloalkyl or a 4 to 6 membered heterocyclyl ring;

R¹is C_3-6A cycloalkyl group;

R²selected from hydrogen, C_1-3Haloalkyl and C_1-3An alkyl group;

R³is selected from three R⁵Phenyl substituted with a group;

and is

Each R⁵Independently selected from C_1-3Alkyl and halogen.

Disclosed in one embodiment is a compound of formula (Ia), or a pharmaceutically acceptable salt thereof, wherein:

a' is selected from C_3-7Monocyclic cycloalkyl and 4 to 7 membered monocyclic heterocyclyl; wherein C is_3-7Monocyclic cycloalkyl and 4-7 membered monocyclic heterocyclyl are each optionally substituted with 1 to 5R⁴Substituted by groups;

each R⁴Independently selected from oxo, and methylA group and an ethyl group; or two R attached to the same or adjacent carbon atoms⁴Linked together to form a spiro or fused C_3-6Cycloalkyl or a 4 to 6 membered heterocyclyl ring;

R¹is C_1-4A haloalkyl group;

R²selected from hydrogen, C_1-3Haloalkyl and C_1-3An alkyl group;

R³is selected from three R⁵Phenyl substituted with a group;

and is

Each R⁵Independently selected from C_1-3Alkyl and halogen.

Disclosed in one embodiment is a compound of formula (Ia), or a pharmaceutically acceptable salt thereof, wherein:

a' is selected from C_3-7Monocyclic cycloalkyl and 4 to 7 membered monocyclic heterocyclyl; wherein C3-7 monocyclic cycloalkyl and 4-7 membered monocyclic heterocyclyl are each optionally substituted with 1 to 5R⁴Substituted by groups;

each R⁴Independently selected from oxo, methyl and ethyl; or two R attached to the same or adjacent carbon atoms⁴Linked together to form a spiro or fused C_3-6Cycloalkyl or a 4 to 6 membered heterocyclyl ring;

R¹selected from H, C_1-4Alkyl radical, C_1-4Haloalkyl and C_3-6A cycloalkyl group;

R²is C_1-3A haloalkyl group;

R³is selected from 3R⁵Phenyl substituted with a group;

and is

Each R⁵Independently selected from C_1-3Alkyl and halogen.

Disclosed in one embodiment is a compound of formula (Ia), or a pharmaceutically acceptable salt thereof, wherein:

a' is selected from C_3-7Monocyclic cycloalkyl and 4 to 7 membered monocyclic heterocyclyl; wherein C is_3-7Monocyclic cycloalkyl and 4-to 7-membered monocyclic heterocyclyl are each substituted with two R⁴Radical substitution in which two R are bound to the same or adjacent carbon atom⁴Forming spiro or fused C_3-6Cycloalkyl, or a 4 to 6 membered heterocyclyl ring;

R¹selected from H, C_1-4Alkyl radical, C_1-4Haloalkyl and C_3-6A cycloalkyl group;

R²selected from hydrogen, C_1-3Haloalkyl and C_1-3An alkyl group;

R³is selected from three R⁵Phenyl substituted with a group;

and is

Each R⁵Independently selected from C_1-3Alkyl and halogen.

In some embodiments, the compound of formula (Ia) is not:

in another embodiment, compounds of formula (Ib) are provided:

or a pharmaceutically acceptable salt thereof, wherein:

X¹、X²and X³Each independently selected from CHR⁴O, C ═ O and CH₂CHR⁴(ii) a Provided that X¹、X²And X³No more than one of which is O or C ═ O;

each R⁴Independently selected from H and CH₃；

R¹Selected from H, C_1-4Alkyl radical, C_1-4Haloalkyl and C_3-6A cycloalkyl group;

R²selected from hydrogen, C_1-3Haloalkyl and C_1-3An alkyl group;

R³is selected from three R⁵Phenyl substituted with a group;

each R⁵Independently selected from C_1-3Alkyl and halogen.

In another embodiment, X³Is CHR⁴(ii) a And X¹And X²Each independently is O, CHR⁴Or C ═ O.

In another embodiment, X³Is CHR⁴(ii) a And X¹And X²Each independently is O or CHR⁴。

In another embodiment, R⁴Is H.

In another embodiment, -X¹–X²–X³-is selected from-CH₂–CH₂–CH₂–、–CH₂–O–CH₂and-O-CH₂–CH₂–。

In another embodiment, -X¹–X²–X³is-O-CH₂–CH₂–。

In another embodiment, X¹And X³One is CH₂CHR⁴，X¹And X³The other is CHR⁴(ii) a And X²Is O, CHR⁴Or C ═ O.

In another embodiment, X¹Is CH₂CHR⁴，X³Is CHR⁴(ii) a And X²Is O, CHR⁴Or C ═ O。

In another embodiment, X³Is CH₂CHR⁴，X¹Is CHR⁴(ii) a And X²Is O, CHR⁴Or C ═ O.

In another embodiment, R⁴Is H.

In another embodiment, -X¹–X²–X³-is selected from-CH₂–CH₂–CH₂–CH₂、–CH₂–O–CH₂–CH₂–、–CH(CH₃)–O–CH₂–CH₂、–CH₂–CH₂–O–CH₂and-CH₂–C(O)–CH₂–CH₂。

In another embodiment, -X¹–X²–X³is-CH₂–O–CH₂–CH₂–。

In another embodiment, R²Selected from hydrogen, C_1-2Haloalkyl, methyl and ethyl.

In another embodiment, R²Selected from hydrogen, methyl and CHF₂。

In another embodiment, R²Is hydrogen.

In another embodiment, R²Is C_1-3A haloalkyl group.

In another embodiment, R²Is CHF₂。

In another embodiment:selected from:

in a further embodiment of the process of the present invention,is composed of

In a further embodiment of the process of the present invention,selected from:

in a further embodiment of the process of the present invention,selected from:

in another embodiment:

selected from:

in a further embodiment of the process of the present invention,selected from:

in a further embodiment of the process of the present invention,selected from:

in a further embodiment of the process of the present invention,is composed of

In another embodiment:

is composed of

In another embodiment:

is composed of

In another embodiment:

is composed of

In another embodiment:

is composed of

In another embodiment, R¹Selected from H, C_1-3Alkyl radical, C_1-2Haloalkyl, and C_3-5A cycloalkyl group.

In another embodiment, R¹Selected from hydrogen, methyl, ethyl, propyl, isopropyl, CH₂CF₃And CH₂CHF₂And cyclopropyl.

In another embodiment, R¹Is ethyl.

In another embodiment, R¹Is selected from C_1-4Haloalkyl and C_3-6A cycloalkyl group.

In another embodiment, R¹Is selected from CH₂CF₃、CH₂CHF₂And a cyclopropyl group.

In another embodiment:

is composed ofAnd R is¹Is ethyl.

In another embodiment, R³Is represented by three R⁵Phenyl substituted by radicals in which each R is⁵Independently selected from methyl, ethyl and halogen.

In another embodiment, R³Is represented by three R⁵Phenyl substituted by radicals in which each R is⁵Independently selected from methyl, fluoro and chloro.

In another embodiment, R³Selected from:

in another embodiment, R³Selected from:

in another embodiment, R³Is phenyl substituted by 3 halogens.

In another embodiment, R³Is phenyl substituted with 2 fluorines and one chlorine.

In another embodiment, R³Is composed of

In another embodiment:

is composed ofR¹Is ethyl, and R³Is composed of

In another embodiment, compounds having the following formula (Ib), or a pharmaceutically acceptable salt thereof, are disclosed:

X¹、X²and X³Each independently selected from CHR⁴O, C ═ O and CH₂CHR⁴(ii) a Provided that X¹、X²And X³No more than one of which is O or C ═ O;

each R⁴Independently selected from H and CH₃；

R¹Is C_3-6A cycloalkyl group;

R²selected from hydrogen, C_1-3Haloalkyl and C_1-3An alkyl group;

R³is selected from one to three R⁵Phenyl substituted with a group;

each R⁵Independently selected from C_1-3Alkyl and halogen.

In another embodiment, compounds having the following formula (Ib), or a pharmaceutically acceptable salt thereof, are disclosed, wherein:

X¹、X²and X³Each independently selected from CHR⁴O, C ═ O and CH₂CHR⁴(ii) a Provided that X¹、X²And X³No more than one of which is O or C ═ O;

each R⁴Independently selected from H and CH₃；

R¹Is C_1-4A haloalkyl group;

R²selected from hydrogen, C_1-3Haloalkyl and C_1-3An alkyl group;

R³is selected from one to three R⁵Phenyl substituted with a group;

each R⁵Independently selected from C_1-3Alkyl and halogen.

In another embodiment, compounds having the following formula (Ib), or a pharmaceutically acceptable salt thereof, are disclosed, wherein:

X¹、X²and X³Each independently selected from CHR⁴O, C ═ O and CH₂CHR⁴(ii) a Provided that X¹、X²And X³No more than one of which is O or C ═ O;

each R⁴Independently selected from H and CH₃；

R¹Selected from H, C_1-4Alkyl radical, C_1-4Haloalkyl and C_3-6A cycloalkyl group;

R²is C_1-3A haloalkyl group;

R³is selected from one to three R⁵Phenyl substituted with a group;

each R⁵Independently selected from C_1-3Alkyl and halogen.

In another embodiment, compounds having the following formula (Ib), or a pharmaceutically acceptable salt thereof, are disclosed, wherein:

X¹、X²and X³Each independently selected from CHR⁴O, C ═ O and CH₂CHR⁴(ii) a Provided that X¹、X²And X³No more than one of which is O or C ═ O;

each R⁴Independently selected from H and CH₃；

R¹Is C_3-6A cycloalkyl group;

R²selected from hydrogen, C_1-3Haloalkyl and C_1-3An alkyl group;

R³is selected from 3R⁵Phenyl substituted with a group;

each R⁵Independently selected from C_1-3Alkyl and halogen.

In another embodiment, compounds having the following formula (Ib), or a pharmaceutically acceptable salt thereof, are disclosed, wherein:

X¹、X²and X³Each independently selected from CHR⁴O, C ═ O and CH₂CHR⁴(ii) a Provided that X¹、X²And X³No more than one of which is O or C ═ O;

each R⁴Independently selected from H and CH₃；

R¹Is C_1-4A haloalkyl group;

R²selected from hydrogen, C_1-3Haloalkyl and C_1-3An alkyl group;

R³is selected from 3R⁵Phenyl substituted with a group;

each R⁵Independently selected from C_1-3Alkyl and halogen.

In another embodiment, compounds having the following formula (Ib), or a pharmaceutically acceptable salt thereof, are disclosed, wherein:

X¹、X²and X³Each independently selected from CHR⁴O, C ═ O and CH₂CHR⁴(ii) a Provided that X¹、X²And X³No more than one of which is O or C ═ O;

each R⁴Independently selected from H and CH₃；

R¹Selected from H, C_1-4Alkyl radical, C_1-4Haloalkyl and C_3-6A cycloalkyl group;

R²is C_1-3A haloalkyl group;

R³is selected from 3R⁵Phenyl substituted with a group;

each R⁵Independently selectFrom C_1-3Alkyl and halogen.

In some embodiments, the compound of formula (Ib) is not:

in another embodiment, compounds of formula (Ic) are provided:

or a pharmaceutically acceptable salt thereof, wherein:

R¹selected from H, C_1-4Alkyl radical, C_1-4Haloalkyl and C_3-6A cycloalkyl group.

In another embodiment, compounds of formula (Id) are provided:

or a pharmaceutically acceptable salt thereof, wherein:

R¹selected from H, C_1-4Alkyl radical, C_1-4Haloalkyl and C_3-6A cycloalkyl group.

In another embodiment, compounds of formula (Ie) are provided:

or a pharmaceutically acceptable salt thereof, wherein:

R¹selected from H, C_1-4Alkyl radical, C_1-4Haloalkyl and C_3-6A cycloalkyl group.

In another embodiment, there is provided a compound of formula (If):

or a pharmaceutically acceptable salt thereof, wherein:

R¹selected from H, C_1-4Alkyl radical, C_1-4Haloalkyl and C_3-6A cycloalkyl group.

In another embodiment, R¹Selected from H, C_1-3Alkyl radical, C_1-2Haloalkyl and C_3-5A cycloalkyl group.

In another embodiment, R¹Selected from hydrogen, methyl, ethyl, propyl, isopropyl, CH₂CF₃、CH₂CHF₂And a cyclopropyl group.

In another embodiment, R¹Is ethyl.

In another embodiment, R¹Is selected from C_1-4Haloalkyl and C_3-6A cycloalkyl group.

In another embodiment, R¹Is selected from CH₂CF₃、CH₂CHF₂And a cyclopropyl group.

In another embodiment, compounds of formula (II) are provided:

or a pharmaceutically acceptable salt thereof, wherein:

R¹selected from H, C_1-4Alkyl radical, C_1-4Haloalkyl and C_3-6A cycloalkyl group;

R³is selected from one to three R⁵Phenyl substituted with a group; and is

Each R⁵Independently selected from C_1-3Alkyl and halogen.

In another embodiment, compounds having the following formula (II), or a pharmaceutically acceptable salt thereof, are disclosed, wherein:

R¹selected from H, C_1-4Alkyl radical, C_1-4Haloalkyl and C_3-6A cycloalkyl group;

R³is selected from three R⁵Phenyl substituted with a group; and is

Each R⁵Independently selected from C_1-3Alkyl and halogen.

In another embodiment, the compound of formula (II) is a compound of formula (IIa):

in another embodiment, compounds having the following formula (III) are provided:

or a pharmaceutically acceptable salt thereof, wherein:

R¹selected from H, C_1-4Alkyl radical, C_1-4Haloalkyl and C_3-6A cycloalkyl group;

R³is selected from one to three R⁵Phenyl substituted with a group; and is

Each R⁵Independently selected from C_1-3Alkyl and halogen.

In another embodiment, compounds having the following formula (III), or a pharmaceutically acceptable salt thereof, are disclosed, wherein:

R¹selected from H, C_1-4Alkyl radical, C_1-4Haloalkyl and C_3-6A cycloalkyl group;

R³is selected from three R⁵Phenyl substituted with a group; and is

Each R⁵Independently selected from C_1-3Alkyl and halogen.

In another embodiment, the compound of formula III is a compound of formula (IIIa):

in another embodiment, compounds having the structure:

or a pharmaceutically acceptable salt thereof.

In another embodiment, compounds having the structure:

or a pharmaceutically acceptable salt thereof.

In another embodiment, compounds having the structure:

or a pharmaceutically acceptable salt thereof.

In another embodiment, compounds having the structure:

or a pharmaceutically acceptable salt thereof.

In another embodiment, compounds having the structure:

or a pharmaceutically acceptable salt thereof.

In another embodiment, compounds having the structure:

or a pharmaceutically acceptable salt thereof.

In another embodiment, there is provided a compound of formula (25-M) or a pharmaceutically acceptable salt thereof:

in another embodiment, there is provided a compound of formula (25b) or a pharmaceutically acceptable salt thereof:

in another embodiment, there is provided a compound of formula (39-M) or a pharmaceutically acceptable salt thereof:

in another embodiment, there is provided a compound of formula (39), or a pharmaceutically acceptable salt thereof:

in another embodiment, a pharmaceutical composition is provided comprising a compound having formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (II), (IIa), (III), (IIIa), (25-M), (25b), (39-M), or (39), 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 the group consisting of HIV protease inhibitors, non-nucleoside HIV reverse transcriptase inhibitors, nucleoside or nucleotide HIV reverse transcriptase inhibitors, and combinations thereof.

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

In another embodiment, the pharmaceutical composition further 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 an HIV infection in a human having or at risk of having the infection is provided by administering to the human a therapeutically effective amount of a compound of formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (II), (IIa), (III), (IIIa), (25-M), (25b), (39-M) or (39), or a pharmaceutically acceptable salt thereof, or by administering a pharmaceutical composition of a compound of formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (II), (IIa), (III), (IIIa), (25-M), (25b), (39-M) or (39), or a pharmaceutically acceptable salt thereof.

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

In another embodiment, the method of treating HIV infection in a human having or at risk of 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, non-nucleoside HIV reverse transcriptase inhibitors, nucleoside or nucleotide HIV reverse transcriptase inhibitors, and combinations thereof. In particular embodiments, the method of treating an HIV infection in a human having or at risk of having the infection further comprises administering to the human a therapeutically effective amount of a non-nucleoside HIV reverse transcriptase inhibitor.

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

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

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

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

In another embodiment, there is provided the use of a compound of formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (II), (IIa), (III), (IIIa), (25-M), (25b), (39-M) or (39), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of compound (Ia), (Ib), (Ic), (Id), (Ie), (If), (II), (IIa), (III), (IIIa), (25-M), (25b), (39-M) or (39), or a pharmaceutically acceptable salt thereof, for the treatment of HIV infection in a human having or at risk of infection.

In another embodiment, there is provided the use of a pharmaceutical composition of a compound of formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (II), (IIa), (III), (IIIa), (25-M), (25b), (39-M) or (39), or a pharmaceutically acceptable salt thereof, or a compound of formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (II), (IIa), (III), (IIIa), (25-M), (25b), (39-M) or (39), or a pharmaceutically acceptable salt thereof, for medical therapy.

In another embodiment, there is provided a pharmaceutical composition of a compound of formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (II), (IIa), (III), (IIIa), (25-M), (25b), (39-M) or (39), or a pharmaceutically acceptable salt thereof, or a compound of formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (II), (IIa), (III), (IIIa), (25-M), (25b), (39-M) or (39), or a pharmaceutically acceptable salt thereof, for prophylactic or therapeutic treatment of an HIV infection.

In another embodiment, methods of using a compound having formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (II), (IIa), (III), (IIIa), (25-M), (25b), (39-M), or (39) 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 having formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (II), (IIa), (III), (IIIa), (25-M), (25b), (39-M), or (39), or a stereoisomer or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

In another embodiment, the use of a compound of formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (II), (IIa), (III), (IIIa), (25-M), (25b), (39-M), or (39), described herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating an HIV infection in a human having or at risk of having the infection, is disclosed.

In another embodiment, there is provided the use of a compound of formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (II), (IIa), (III), (IIIa), (25-M), (25b), (39-M), or (39), or a pharmaceutically acceptable salt thereof, as described herein, as a research tool.

In another embodiment, an article of manufacture is disclosed comprising a composition effective for treating HIV infection and a packaging material comprising a label indicating that the composition can be used to treat HIV infection. Exemplary compositions comprise a compound of formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (II), (IIa), (III), (IIIa), (25-M), (25b), (39-M) or (39), or a pharmaceutically acceptable salt thereof, of this embodiment disclosed herein.

In another embodiment, a method of inhibiting HIV replication is disclosed. The method comprises exposing the virus to an effective amount of a compound of formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (II), (IIa), (III), (IIIa), (25-M), (25b), (39-M) or (39) or a salt thereof under conditions in which HIV replication is inhibited.

In another embodiment, the use of a compound of formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (II), (IIa), (III), (IIIa), (25-M), (25b), (39-M) or (39) for inhibiting HIV integrase activity is disclosed.

In another embodiment, the use of formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (II), (IIa), (III), (IIIa), (25-M), (25b), (39-M) or (39), or a salt thereof, for inhibiting HIV replication is disclosed.

The invention also provides a compound of each formula herein, and subgroups and embodiments thereof, for use in any one of the methods of the invention defined herein, including a compound selected from the group consisting of compounds of formulae (Ia), (Ib), (Ic), (Id), (Ie), (If), (II), (IIa), (III), (IIIa), (25-M), (25b), (39-M) and (39), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of a compound of formulae (Ia), (Ib), (Ic), (Id), (Ie), (If), (II), (IIa), (III), (IIIa), (25-M), (25b), (39-M) or (39), or a pharmaceutically acceptable salt thereof, or one of the specific compounds of the embodiments herein, or a salt thereof.

It is understood that any embodiment of the compounds of formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (II), (IIa), (III), (IIIa), (25-M), (25b), (39-M) and (39) as described previously, as well as any particular substituent A ', R' in the compounds of formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (II), (IIa), (III), (IIIa), (25-M), (25b), (39-M) or (39) described herein, is contemplated¹、R²、R³、R⁴、R⁵、X¹、X²Or X³The groups may independently form embodiments not specifically written above with any other embodiment and/or substituent of the compounds of formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (II), (IIa), (III), (IIIa), (25-M), (25b), (39-M) or (39). Furthermore, if any particular A', R is targeted in a particular embodiment and/or claim¹、R²、R³、R⁴、R⁵、X¹、X²Or X³Listing a list of substituents, it is to be understood that each individual substituent may be deleted from the particular embodiment and/or claims, and the remaining list of substituents should be considered to fall within the scope of the embodiments disclosed herein.

Pharmaceutical composition

For administration purposes, in some embodiments, the compounds described herein are administered as the original chemical or are formulated for administration as a pharmaceutical composition. Pharmaceutical compositions within the scope of the embodiments disclosed herein comprise a compound of formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (II), (IIa), (III), (IIIa), (25-M), (25b), (39-M) or (39), and a pharmaceutically acceptable excipient. The compound of formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (II), (IIa), (III), (IIIa), (25-M), (25b), (39-M) or (39) is present in the composition in an amount effective to treat the particular disease or disorder. The activity of a compound of formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (II), (IIa), (III), (IIIa), (25-M), (25b), (39-M) or (39) can be determined by the skilled worker by, for example, the methods described in the examples below. Suitable concentrations and dosages can be readily determined by those skilled in the art.

Administration of a compound of the embodiments disclosed herein, or a pharmaceutically acceptable salt thereof, in pure form or in a suitable pharmaceutical composition may be by any means accepted for administration of agents for similar uses. The pharmaceutical compositions of the embodiments disclosed herein may be prepared by combining the compounds of the embodiments disclosed herein with suitable pharmaceutically acceptable excipients and may be formulated into preparations in solid, semi-solid, 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, buccal, rectal, vaginal and intranasal. The pharmaceutical compositions of the embodiments disclosed herein may be formulated such that the active ingredients contained therein are bioavailable when administered to a patient. The composition to be administered to a subject or patient takes the form of one or more dosage units, where, for example, a tablet may be a single dosage unit and a container in aerosol form of a compound of the embodiments disclosed herein may hold multiple dosage units. The actual methods of making such dosage forms are known or will be apparent to those skilled in the art; see, for example, Remington: the Science and Practice of Pharmacy, 20 th edition (Philadelphia College of Pharmacy and Science, 2000). In any event, the composition to be administered will comprise a therapeutically effective amount of a compound of the embodiments disclosed herein, or a pharmaceutically acceptable salt thereof, for treating a disease or disorder of interest in accordance with the teachings herein.

The pharmaceutical compositions disclosed herein may be prepared by methods well known in the pharmaceutical art. For example, a pharmaceutical composition intended for administration by injection may be prepared by combining a compound of the embodiments disclosed herein with sterile distilled water to form a solution. Surfactants may be added to promote the formation of a homogeneous solution or suspension. A surfactant is a compound that non-covalently interacts with a compound of the embodiments disclosed herein to facilitate 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 therapeutically effective amounts, which will vary depending on a variety of factors, including the activity of the particular compound employed; metabolic stability and length of action of the compound; the age, weight, general health, sex, and eating habits of the patient; mode and time of administration; the rate of excretion; a pharmaceutical composition; the severity of the particular disease or disorder; and the treatment the subject is receiving.

Combination therapy

In some embodiments, there is provided a method for treating or preventing an HBV infection in a human having or at risk of having the infection, comprising administering to the human 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, four, one or two, or one to three, or one to four) additional therapeutic agents. In one embodiment, there is provided a method for treating an HBV infection in a human having or at risk of having the infection, comprising administering to the human 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, four, one or two, or one to three, or one to four) additional therapeutic agents.

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

In some embodiments, a compound disclosed herein (e.g., any compound of formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (II), (IIa), (III), (IIIa), (25-M), (25b), (39-M), or (39)) can be combined with one or more additional therapeutic agents at any dose of the compound of formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (II), (IIa), (III), (IIIa), (25-M), (25b), (39-M), or (39) (e.g., 50mg to 1000mg of the compound).

In one embodiment, a pharmaceutical composition 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, 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 other therapeutic agent may be an anti-HIV agent. For example, in some embodiments, the additional therapeutic agent is selected from HIV protease inhibitors, non-nucleoside or non-nucleotide HIV reverse transcriptase inhibitors, nucleoside or nucleotide HIV reverse transcriptase inhibitors, HIV integrase inhibitors, non-catalytic site (allosteric) integrase inhibitors, HIV entry inhibitors (e.g., CCR5 inhibitors, gp41 inhibitors (i.e., fusion inhibitors), and CD4 ligation inhibitors), CXCR4 inhibitors, gp120 inhibitors, G6PD and NADH-oxidase inhibitors, HIV vaccines, HIV maturation inhibitors, latency reversers (e.g., histone deacetylase inhibitors, proteasome inhibitors, protein kinase c (pkc) activators, and BRD4 inhibitors), HIV capsid targeting compounds ("capsid inhibitors", e.g., capsid polymerization inhibitors or capsid destruction compounds, HIV capsid p7(NCp7) inhibitors, HIV p24 capsid protein inhibitors), pharmacokinetic enhancers, immune-based therapies (e.g., Pd-1 modulators, gamma-gamma,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, combinations for HIV, 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 infectious factor inhibitors, TAT protein inhibitors, HIV-1Nef modulators, Hck tyrosine kinase modulators, mixed lineage kinase-3 (MLK-3) inhibitors, HIV-1 splice inhibitors, Rev protein inhibitors, integrin antagonists, nucleoprotein inhibitors, splice factor modulators, COMM domain containing protein 1 modulators, HIV ribonuclease H inhibitors, reverse transcriptase modulators, CDK-9 inhibitors, Dendic riticaM-3 capture non-integrin 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 priming complex inhibitors, PI3K inhibitors, compounds disclosed in: WO 2013/006738(Gilead Sciences), US 2013/0165489(University of Pennsylvania), WO2013/091096a1(Boehringer Ingelheim), WO2009/062285(Boehringer Ingelheim), US20140221380(Japan tobaco), US20140221378(Japan tobaco), WO 2010/130034(Boehringer Ingelheim), WO2013/159064 (GileadSciences), WO2012/145728(Gilead Sciences), WO2012/003497(Gilead Sciences), WO2014/100323(Gilead Sciences), WO2012/145728 (GileadSciences), WO2013/159064 (GileadSciences) and WO2012/003498 (GileadSciences), and WO 2013/006792(pharma resources) and other HIV treatment drugs, and combinations thereof.

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

In some embodiments, the compounds of formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (II), (IIa), (III), (IIIa), (25-M), (25b), (39-M) or (39) are formulated as tablets, which may optionally contain one or more additional compounds useful in the treatment of HIV. In some embodiments, the tablet may contain another active ingredient for the treatment of HIV, such as HIV protease inhibitors, non-nucleoside or non-nucleotide reverse transcriptase HIV inhibitors, nucleoside or nucleotide reverse transcriptase HIV inhibitors, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, pharmacokinetic enhancers, and combinations thereof.

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

(1) a combination selected from:(efavirenz + tenofovir disoproxil fumarate + emtricitabine),(Rilpivirine + tenofovir disoproxil fumarate + emtricitabine),(elvitegravir + Coxsistal + Tenofovir disoproxil fumarate + emtricitabine), doliravir + Abacavir sulfate + Lamivudine,(Dotiravir + abacavir + lamivudine), lamivudine + Nevirapine + Zidovudine, Dotiravir + Ripivirine, atazanavir sulfate + Coccistane, Darunavir + Coccistane, Efavirenz + Lamivudine + Tenofovir disoproxil fumarate, Tenofovir alafenamide hemifumarate + Emtricitabine + Coccistane + Emviravir, Vacc-4x + Romidepsin, Darunavir + Tenofovir alafenamide hemifumarate + Emtricitabine + Coccistane, APH-0812, Lativir + 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) an HIV protease inhibitor selected from: amprenavir, atazanavir, furinavir calcium, indinavir sulfate, lopinavir, ritonavir, nelfinavir mesylate, saquinavir mesylate, tipranavir, darunavir, DG-17, TMB-657(PPL-100) and TMC-310911;

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

(4) nucleoside or nucleotide reverse transcriptase HIV inhibitors selected fromAndEC (didanosine, ddl), zidovudine, emtricitabine, didanosine, stavudine, zalcitabine, lamivudine, sinxavudine, abacavir sulfate, amdoxvir, elvucitabine, alovudine, phosphazid, fosalvudine tidoxil (fosivudinetoxil), aritabine, amdoxovir, KP-1461, fosalvudine tidoxil (fosalvudine tidoxil), tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, tenofovir alafenamide hemifumarate, adefovir dipivoxil pivoxil and tenofovir;

(5) an HIV integrase inhibitor selected from curcumin, curcumin derivatives, chicoric acid derivatives, 3, 5-dicaffeoylquinic acid derivatives, aurintricarboxylic acid derivatives, caffeic acid phenethyl ester derivatives, tyrphostin: derivatives of inhibitors, quercetin, derivatives of quercetin, latiravir, elvitegravir, dorivavir and cavir;

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

(7) an HIV gp41 inhibitor selected from the group consisting of enfuvirtide, cidivitide and albrevitide;

(8) an HIV entry inhibitor selected from the group consisting of ceniviroc;

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

(10) CCR5 inhibitor selected from the group consisting of Alravirole, Viravirole, Marravirole, Seneviraro, PRO-140, Adaptavir (RAP-101), TBR-220(TAK-220), Nifeviraro (TD-0232), TD-0680, and vMIP (Haimipu);

(11) a CD4 ligation inhibitor selected from ibalizumab;

(12) a CXCR4 inhibitor selected from the group consisting of plerixafor, ALT-1188, vMIP and Haimipu;

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

(14) an immune-based therapy selected from the group consisting of dermaVir, interleukin-7, plaquenil (hydroxychloroquine), proleukin (aldesleukin, IL-2), interferon alpha-2 b, interferon alpha-n 3, pegylated interferon alpha, interferon gamma, hydroxyurea, mycophenolic acid (MPA) and its ester derivative Mycophenolate Mofetil (MMF), WF-10, ribavirin, IL-2, IL-12, polymeric Polyethyleneimine (PEI), Gepon, VGV-1, MOR-22, BMS-936559, toll-like receptor modulators (modulators of TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, TLR10, TLR11, TLR12 and TLR 13), ritodrine, and IR-103;

(15) an HIV vaccine selected from the group consisting of peptide vaccine, recombinant subunit protein vaccine, live vector vaccine, DNA vaccine, virus-like particle vaccine (pseudovirus vaccine), CD 4-derived peptide vaccine, vaccine combination, 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, FIT-3S, multiclade DNA recombinant adenovirus-5 (rAd5), Pennvax-G, VRC-HIV MAB060-00-AB, AVX-101, Tat OYi vaccine, AVX-201, HIV-LAMP-vax, Ad35, 35-GRIN, cGM 3/VSSP-ISA-51, AVLC-06, TatmuI adjuvant, multivalent HIV-GTU-NAMUU-06-Ad-5 (Ad 5, Ad-E-V-, AGS-004, gp140[ ] V2.TV1+ MF-59, rVSVIN HIV-1Gag vaccine, SeV-Gag vaccine, AT-20, DNK-4, Ad35-GRIN/ENV, TBC-M4, 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, CMEN 41-FPA2, PreVaxTat, TL-01, SAV-001, SAV-H, MYM-V101, VbiVvIvax, POL-505, HVETV-355, CMETV-nev, and DNA/Gag/201);

(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 the group consisting of baviximab (bavituximab), UB-421, C2F5, C2G12, C4E10, C2F5+ C2G12+ C4E10, 3-BNC-117, PGT145, PGT121, MDX010 (ipilimumab), VRC01, a32, 7B2, 10E8, and VRC 07;

(17) latency reversal agents selected from histone deacetylation inhibitors such as romidepsin, vorinostat, panobinostat; proteasome inhibitors such as Velcade; protein Kinase C (PKC) activators such as Indolactam, Prostratin, Ingenol B and DAG-lactone, Ionomycin (Ionomycin), GSK-343, PMA, SAHA, BRD4 inhibitors, IL-15, JQ1, disulfram and amphotericin B;

(18) an HIV nucleocapsid p7(NCp7) inhibitor selected from azodicarbonamide;

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

(20) PI3K inhibitor selected from the group consisting of idelite, AZD-8186, buparilite, CLR-457, petilide, neratinib, ligosetide, sodium ligosetide, EN-3342, TGR-1202, apigliflozide, doviside, UCB-5857, taselizide, XL-765, gedarrel, VS-5584, clonilide, CAI orotate, piperacillin, RG-7666, GSK-2636771, DS-7423, panulifloxacin, GSK-2269557, GSK-2126458, CUDC-907, PQR-309, INCB-040093, PILALISE, BAY-1082439, priquintinib mesylate, SAR-245409, AMG-319, RP-6530, ZSTK-474, MLN-1117, SF-1126, RV-1729, sonolifloxacin, LY-3023414, SAR-260301 and CLR-1401;

(21) the compounds disclosed in the following documents: WO 2004/096286(Gilead Sciences), WO 2006/110157(Gilead Sciences), WO 2006/015261(Gilead Sciences), WO 2013/006738(Gilead Sciences), US 2013/0165489(University of Pennsylvania), US20140221380(Japan Tobacco), US20140221378(Japan Tobacco), WO 2013/006792(Pharma Resources), WO2009/062285(Boehringer Ingelheim), WO 2010/130034(Boehringer Ingelheim), WO2013/091096A 25 (Boehringer Ingelheim), WO2013/159064(Gilead Sciences), WO2012/145728(Gilead Sciences), WO2012/003497(Gilead Sciences), WO2014/100323(Gilead Sciences), WO/145728 (Gilead Sciences), WO 2018536 (Gileyderences); and

(22) other agents for the treatment of HIV selected from the group consisting of BanLec, MK-8507, AG-1105, TR-452, MK-8591, REP9, CYT-107, alisporivir, NOV-205, IND-02, Meitengfulin, PGN-007, Acemannan, Gamimone, prolactin, 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, and PA-1050040 (PA-040).

In some embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with one, two, three, four, or more additional therapeutic agents. In some embodiments, a compound disclosed herein or a pharmaceutically acceptable salt thereof is combined with two other therapeutic agents. In other embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts thereof, are combined with three other therapeutic agents. In further embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts thereof, are combined with four other therapeutic agents. The one, two, three, four or more additional therapeutic agents may be different therapeutic agents selected from the same class of therapeutic agents, and/or they may be selected from different classes of therapeutic agents. In a specific embodiment, the compounds disclosed herein, or pharmaceutically acceptable salts thereof, are combined with non-nucleoside reverse transcriptase HIV inhibitors and non-nucleoside reverse transcriptase HIV inhibitors. In a specific embodiment, the compounds disclosed herein, or pharmaceutically acceptable salts thereof, are combined with nucleoside or nucleotide reverse transcriptase HIV inhibitors and non-nucleoside reverse transcriptase HIV inhibitors. In another embodiment, the compounds disclosed herein, or pharmaceutically acceptable salts thereof, are combined with nucleoside or nucleotide reverse transcriptase HIV inhibitors and HIV protease inhibiting compounds. In another embodiment, the compounds disclosed herein, or pharmaceutically acceptable salts thereof, and nucleoside or nucleotide reverse transcriptase HIV inhibitors, non-nucleoside reverse transcriptase HIV inhibitors, and HIV protease inhibiting compounds. In another embodiment, a compound disclosed herein or a pharmaceutically acceptable salt thereof is combined with a nucleoside or nucleotide reverse transcriptase HIV inhibitor, a non-nucleoside reverse transcriptase HIV inhibitor, and a pharmacokinetic enhancer. In some embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with at least one nucleoside reverse transcriptase HIV inhibitor, an integrase inhibitor, and a pharmacokinetic enhancer. In another embodiment, the compounds disclosed herein, or pharmaceutically acceptable salts thereof, are combined with two nucleoside or nucleotide reverse transcriptase HIV inhibitors.

In a specific embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with one, two, three, or four or more additional therapeutic agents, the treatment of which isThe agent is selected from:(Dotiravi + Abacavir + Lamivudine), Dotiravi + Abacavir sulfate + Lamivudine, Latiravi,(tenofovir disoproxil fumarate + emtricitabine, TDF + FTC), Malavirenz, Enfuvirtide,(Abacavir sulfate + lamivudine, ABC +3TC),(abacavir sulfate + zidovudine + lamivudine, ABC + AZT +3TC), adefovir dipivoxil,(avivoravir + Coxstat + Tenofovir disoproxil fumarate + emtricitabine), rilpivirine hydrochloride,(Rilpivirine + tenofovir disoproxil fumarate + emtricitabine), cicletastat,(efavirenz + tenofovir disoproxil fumarate + emtricitabine), atazanavir sulfate, doriravir, elvitegravir, fludarabine, fludarabi,(Lopinavir + ritonavir), ritonavir, emtricitabine, atazanavir sulfate + ritonavir, darunavir, lamivudine, Prolastin, furinavir calcium, efavirenz, fluinavir, flu,(zidovudine + lamivudine, AZT +3TC), etravirin, nelfinavir mesylate, interferon, didanosine, stavudine, indinavir sulfate, tenofovir + lamivudine, zidovudine, nevirapine, saquinavir mesylate, aldesleukin, zalcitabine, tirapavir, amprenavir, delavirdine mesylate, Radha-108(Receptol), Hlviral, lamivudine + tenofovir fumarate, tenofovir dipivoxil, efavirenz + lamivudine + tenofovir fumarate, phosphazid, lamivudine + nevirapine + zidovudine, abacavir sulfate, tenofovir disoproxil, disoproxil, disoproxil fumarate, lenofovir disoproxil, lenofovir fumarate, and tenofovir fumarate.

In a specific embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with abacavir sulfate, tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, tenofovir alafenamide, or tenofovir alafenamide hemifumarate.

In a specific embodiment, a compound disclosed herein or a pharmaceutically acceptable salt thereof is combined with tenofovir, tenofovir disoproxil fumarate, tenofovir alafenamide, or tenofovir alafenamide hemifumarate.

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

In some embodiments, a compound disclosed herein or a pharmaceutically acceptable salt thereof is combined with 5-30mg tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide, and 200mg emtricitabine. In some embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with 5-10; 5-15; 5-20 parts of; 5-25; 25-30; 20-30 parts of; 15-30 or 10-30mg tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate or tenofovir alafenamide, in combination with 200mg emtricitabine. In some embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with 10mg tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide, and 200mg emtricitabine. In some embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with 25mg tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide, and 200mg emtricitabine. The compounds disclosed herein (e.g., compounds of formulas (Ia), (Ib), (Ic), (Id), (Ie), (If), (II), (IIa), (III), (IIIa), (25-M), (25b), (39-M), or (39)) can be combined with the agents set forth herein in any amount of compound administered (e.g., 50mg to 500mg of the compound), as each administered combination is specifically and individually listed.

In some embodiments, a compound disclosed herein or a pharmaceutically acceptable salt thereof is combined with 200 and 400mg tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil fumarate, and 200mg emtricitabine. In some embodiments, a compound disclosed herein or a pharmaceutically acceptable salt thereof is combined with 200-; 200-300; 200-350; 250-350; 250-400;

350-400; 300-400 or 250-400mg tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate or tenofovir disoproxil hemifumarate, and 200mg emtricitabine in combination. In some embodiments, a compound disclosed herein or a pharmaceutically acceptable salt thereof is combined with 300mg tenofovir disoproxil fumarate

A combination of an ester, tenofovir disoproxil hemifumarate or tenofovir disoproxil hemifumarate and 200mg emtricitabine. The compounds disclosed herein (e.g., compounds of formulas (Ia), (Ib), (Ic), (Id), (Ie), (If), (II), (IIa), (III), (IIIa), (25-M), (25b), (39-M), or (39)) can be combined with the agents set forth herein in any amount of compound administered (e.g., 50mg to 500mg of the compound), as each administered combination is specifically and individually listed.

In some embodiments, when a compound disclosed herein is combined with one or more other therapeutic agents as described above, the components of the composition are administered in a simultaneous or sequential regimen. When administered sequentially, the combination may be administered two or more times.

In some embodiments, the compounds disclosed herein are combined with one or more other therapeutic agents in a single dosage form for simultaneous administration to a patient, e.g., in a solid dosage form for oral administration.

In some 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 both the compound disclosed herein and the one or more additional therapeutic agents are present in the patient.

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

General Synthesis procedure

Some embodiments also relate to processes and intermediates useful for preparing the compounds of the invention, or pharmaceutically acceptable salts thereof.

Exemplary chemical entities useful in the methods of the embodiments are now described by reference to exemplary synthetic schemes for general preparation herein and the specific examples that follow. One skilled in the art will recognize that to obtain the various compounds herein, the starting materials may be suitably selected such that the ultimately desired substituent will undergo a reaction scheme by appropriate or unprotected means to yield the desired product. Alternatively, it may be necessary or desirable to replace the final desired substituent with a suitable group that is carried in the reaction scheme and replaced, if desired, with the desired substituent. Furthermore, one skilled in the art will recognize that the transformations shown in the following schemes may be performed in any order that is compatible with the functional groups of the particular pendant groups.

Representative syntheses of the compounds of the present disclosure are described in the schemes below and in the specific examples below. Schemes 1 and 2 are provided as additional embodiments of the present invention and illustrate general methods for preparing compounds having formulas (Ia), (Ib), (II), (IIa), (III) and (IIIa) and which can be used to prepare other compounds having formulas (Ia), (Ib), (II), (IIa), (III) and (IIIa). The method is applicable to a wide range of functional groups.

Route 1

The protected diamine a1 can be combined with the substituted pyrone b1 in a mixture of water and an alcoholic solvent in the presence of a weak base (e.g., sodium bicarbonate). Removal of the protecting group R by strong acids or hydrogenation^dAfter that, heating with a stronger base such as DBU forms a tricyclic c 1. c1 can be treated with an alkylating agent (e.g., MeI or EtI) in the presence of a base, followed by hydrolysis of the ester to yield compound d 1. d1 can be treated with an amine, such as a substituted benzylamine, in the presence of a coupling reagent such as HATU or EDCI to yield e 1. Deprotection of e1 can be carried out under a hydrogen atmosphere on a suitable reagent such as magnesium bromide or lithium bromide or palladium on carbon to give f 1.

Route 2

The protected amino-lactol a2 can be combined with substituted pyrone b2 in a mixture of water and an alcoholic solvent in the presence of a weak base such as sodium bicarbonate to give intermediate c 2. from-O-R^bHydrolysis of the indicated ester can be accomplished with 1 equivalent of an appropriate hydroxide reagent such as lithium hydroxide or sodium hydroxide. In this case, from-O-R^cTransesterification of the indicated esters can be achieved using a suitable alkoxide reagent such as lithium isopropoxide followed by amide coupling with an appropriate benzylamine using a reagent such as HATU or EDCI to yield intermediate d 2. Using strong acids such asDeprotection of the lactol with methanesulfonic acid followed by primary amine (R)¹NH₂) Such as ethylamine or methylamine, to give tricyclic e 2. e2 can be deprotected in the presence of a suitable reagent such as magnesium bromide or lithium bromide or palladium on carbon under a hydrogen atmosphere to give f 2.

The following examples illustrate various methods of making the compounds of the present disclosure, i.e., compounds of formula (Ia):

wherein A' and R¹、R²And R³As defined above. It is understood that one skilled in the art can prepare these compounds by similar methods or by combining other methods known to those skilled in the art. It will also be appreciated that the skilled person will be able to prepare other human compounds of formula (Ia), (Ib), (II), (IIa), (III) and (IIIa) not specifically shown below in a similar manner to that described below using appropriate starting materials and adjusting the parameters of the synthesis method as required. In general, the starting components may be obtained, for example, from Sigma Aldrich, Lancaster Synthesis, Inc., Maybrid, Matrix Scientific, TCI, and Fluorochem USA, or synthesized according to sources known to those skilled in the art (see, e.g., advanced organic chemistry: reactions, mechanisms, and structures, 5 th edition (Wiley, 12 months 2000)), or prepared as described herein. The following examples are provided for illustrative purposes only and are not limiting.

Examples

Example 1

Preparation of Compound 1

Step 1

To a 50mL 1-necked round bottom flask was added reactant 1-A (0.165g, 1.45mmol), 1-B (0.50g, 1.45mmol) and NaHCO in ethanol (10mL) and water (10mL)₃(0.25g,2.9 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated, redissolved in EtOAc (50mL), washed twice with water and Na₂SO₄And (5) drying. After concentration, the crude product was purified by silica gel column chromatography eluting with hexane-EtOAc to afford 1-C. LCMS-ESI⁺(m/z):[M+H]⁺(ii) a Found value is 397.

Step 2

To a 50mL 1-necked round bottom flask was added reactant 1-C (0.11g, 0.27mmol) in THF (5 mL). NaH (0.033g, 60% in mineral oil, 0.81mmol) was added to the reaction mixture. The reaction mixture was stirred at room temperature for 5 minutes. MeI (0.04g, 0.27mmol) was added to the reaction mixture. The reaction mixture was stirred at room temperature for 5 minutes. Water (0.5ml) was added dropwise to the reaction mixture. The reaction mixture was stirred at room temperature for 10 minutes to hydrolyze the ester and form the acid. After acidification with 1N HCl, the solution was concentrated to completely remove the solvent and the crude 1-D was used in the next step without further purification. LCMS-ESI⁺(m/z):[M+H]⁺Found 383 parts.

Step 3

To a 50mL 1-necked round bottom flask was added a solution of reactant 1-D (crude from step 2, 0.27mmol), 2,4, 6-trifluorophenylmethylamine (0.084g, 0.52mmol), DIPEA (0.169g, 1.3mmol), and HATU (0.20g, 0.52mmol) in DCM (10 mL). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated, redissolved in EtOAc (50mL) and treated with saturated NaHCO₃Twice, saturated NH₄Cl washed and Na₂SO₄And (5) drying. After concentration, the crude product was purified by silica gel column chromatography eluting with hexane-EtOAc to afford 1-E. LCMS-ESI⁺(m/z):[M+H]⁺(ii) a Found 526.

Step 4

To a 50mL 1-necked round bottom flask was added reactant 1-E (0.03g, 0.06mmol) in TFA (2 mL). The reaction mixture was stirred at room temperature for 30 minutes. The solution was concentrated and the residue was purified by CombiFlash (12g column, spent column) using 0 to 20% MeOH in EtOAc as eluent to give compound 1.¹H NMR (400MHz, chloroform-d) 10.40(d, J ═ 6.1Hz,1H),8.47(s,1H),6.58(dd, J ═ 8.7,7.5Hz,2H),4.58(d, J ═ 5.7Hz,2H),3.73(td, J ═ 10.6,4.0Hz,1H),3.54-3.25(m,1H),3.03(s,3H),2.83-2.56(m,1H),2.56-2.30(m,1H),2.23-1.78(m,4H),1.76-1.21(m, 3H).¹⁹F NMR (377MHz, chloroform-d) -109.17(t, J ═ 8.3Hz,1F), -112.03(t, J ═ 7.0Hz,2F)⁺(m/z):[M+H]⁺Found 436.

Example 2

Preparation of Compound 2

Step 1

To a 50mL 1-necked round bottom flask was added reactant 2-A (0.33g, 2.9mmol), 1-B (1.0g, 2.9mmol) and NaHCO in ethanol (10mL) and water (10mL)₃(0.5g, 5.8 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated, redissolved in EtOAc (50mL), washed twice with water and Na₂SO₄And (5) drying. After concentration, the crude product was purified by silica gel column chromatography eluting with hexane-EtOAc to afford 2-C. LCMS-ESI⁺(m/z):[M+H]⁺(ii) a Found value is 397.

Step 2

A50 mL 1-necked round bottom flask was charged with a solution of reactant 2-C (0.22g, 0.54mmol) in DMF (5 mL). NaH (0.066g, 60% in mineral oil, 1.62mmol) was added to the reaction mixture. The reaction mixture is placed in a chamberStir at room temperature for 5 minutes. MeI (0.08g, 0.54mmol) was added to the reaction mixture. The reaction mixture was stirred at room temperature for a further 5 minutes. Water (0.5ml) was added dropwise to the reaction mixture. The reaction mixture was stirred at room temperature for 10 minutes to hydrolyze the ester and form the acid. After acidification with 1N HCl, the solution was concentrated to completely remove the solvent and the crude 2-D was used in the next step without further purification. LCMS-ESI⁺(m/z):[M+H]⁺Found 383 parts.

Step 3

To a 50mL 1-necked round bottom flask was added a solution of reactant 2-D (crude from step 2, 0.54mmol), 2,4, 6-trifluorophenylmethylamine (0.168g, 1.04mmol), DIPEA (0.34g, 2.6mmol) and HATU (0.40g, 1.04mmol) in DCM (20 mL). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated, redissolved in EtOAc (50mL) and treated with saturated NaHCO₃Twice washing, saturated NH₄Cl washed and Na₂SO₄And (5) drying. After concentration, the crude product was purified by silica gel column chromatography eluting with hexane-EtOAc to afford 2-E. LCMS-ESI⁺(m/z):[M+H]⁺(ii) a Found 526.

Step 4

A50 mL 1-necked round bottom flask was charged with a solution of reactant 2-E (0.03g, 0.06mmol) in TFA (2 mL). The reaction mixture was stirred at room temperature for 30 minutes. The solution was concentrated and the residue was purified by CombiFlash (12g cartridge with filter cartridge) using EtOAc-20% MeOH in EtOAc as eluent to give compound 2.¹H NMR (400MHz, chloroform-d) 10.48(t, J ═ 5.1Hz,1H),8.55(s,1H),7.26(s,1H),6.65(dd, J ═ 8.8,7.5Hz,2H),4.66(d, J ═ 5.7Hz,2H),3.83(td, J ═ 10.9,4.1Hz,1H),3.65-3.42(m,1H),3.13(s,3H),2.90-2.61(m,1H),2.57-2.40(m,1H),2.07(dd, J ═ 43.2,12.6Hz,2H),1.85-1.26(m,4H).¹⁹F NMR (376MHz, chloroform-d) -109.35(m,1F), -112.49(m,2F). LCMS-ESI⁺(m/z):[M+H]⁺Found 436.

Example 3

Preparation of Compound 3

Step 1

To a 50mL 1-necked round bottom flask was added reactant 3-A (0.66g, 5.8mmol), 1-B (2.0g, 5.8mmol) and NaHCO in ethanol (30mL) and water (30mL)₃(0.97g, 11.6 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated, redissolved in EtOAc (100mL), washed twice with water and Na₂SO₄And (5) drying. After concentration, the crude product was purified by silica gel column chromatography, washed with hexane-EtOAc to afford 3-C. LCMS-ESI⁺(m/z):[M+H]⁺(ii) a Measured value: 397.

step 2

To a 50mL 1-necked round bottom flask was added a solution of reactant 3-C (0.11g, 0.27mmol) in DMF (5 mL). NaH (0.033g, 60% in mineral oil, 0.81mmol) was added to the reaction mixture. The reaction mixture was stirred at room temperature for 5 minutes. MeI (0.04g, 0.27mmol) was added to the reaction mixture. The reaction mixture was stirred at room temperature for a further 5 minutes. Water (0.5ml) was added dropwise to the reaction mixture. The reaction mixture was stirred at room temperature for 10 minutes to hydrolyze the ester and form the acid. After acidification with 1N HCl, the solution was concentrated to completely remove the solvent and the crude 3-D was used in the next step without further purification. LCMS-ESI⁺(m/z):[M+H]⁺Found 383 parts.

Step 3

To a 50mL 1-necked round bottom flask was added a solution of reactant 3-D (crude from step 2, 0.27mmol), 2,4, 6-trifluorophenylmethylamine (0.084g, 0.52mmol), DIPEA (0.169g, 1.3mmol), and HATU (0.20g, 0.52mmol) in DCM (10 mL). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated, redissolved in EtOAc (50mL) and treated with saturated NaHCO₃Washing twice, and then washingAnd NH₄Cl washed and Na₂SO₄And (5) drying. After concentration, the crude product was purified by silica gel column chromatography eluting with hexane-EtOAc to afford 3-E. LCMS-ESI⁺(m/z):[M+H]⁺(ii) a Found 526.

Step 4

A50 mL 1-necked round bottom flask was charged with a solution of reactant 3-E (0.10g, 0.19mmol) in TFA (2 mL). The reaction mixture was stirred at room temperature for 30 minutes. The solution was concentrated and the residue was purified by CombiFlash (12g cartridge, cartridge filter) using EtOAc-20% MeOH in EtOAc as eluent to give compound 3 as a mixture of cis enantiomers.¹H NMR(400MHz,DMSO-d6)12.82(s,1H),10.42(t,J＝5.8Hz,1H),8.37(s,1H),7.19(t,J＝8.6Hz,2H),4.80-4.31(m,3H),3.99(d,J＝5.6Hz,1H),3.13(s,3H),1.97(s,1H),1.87-1.62(m,3H),1.43(d,J＝37.9Hz,4H).¹⁹F NMR(376MHz,DMSO-d6)-74.89,-108.61--110.08(m,1F),-112.47(t,J＝7.2Hz,2F).LCMS-ESI⁺(m/z):[M+H]⁺Found 436.

Example 4

Preparation of Compound 4

Step 1

To a 50mL 1-necked round bottom flask was added the reactant 4-A (1.86g, 8.7mmol), 1-B (3.0g, 8.7mmol) and NaHCO in ethanol (30mL) and water (30mL)₃(1.45g, 17.3 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated, redissolved in EtOAc (100mL), washed twice with water and Na₂SO₄And (5) drying. After concentration, the crude product was dissolved in 4N HCl/dioxane (40ml) and stirred at room temperature for 3 hours to remove the Boc protecting group. The reaction mixture was concentrated again. The residue and DBU (6.5g, 43.5mmol) were dissolved in EtOH andheat to 50 ℃ for 20 minutes. After concentration, the crude product was purified by silica gel column chromatography eluting with hexane-EtOAc to afford 4-C. LCMS-ESI⁺(m/z):[M+H]⁺(ii) a Found value is 397.

Step 2

To a 50mL 1-necked round bottom flask was added reactant 4-C (0.4g, 1.0mmol) in THF (10 mL). NaH (0.08g, 60% in mineral oil, 2.0mmol) was added to the reaction mixture. The reaction mixture was stirred at room temperature for 5 minutes. MeI (0.142g, 1.0mmol) was added to the reaction mixture. The reaction mixture was stirred at room temperature for a further 5 minutes. Water (1ml) was added dropwise to the reaction mixture. The reaction mixture was stirred at room temperature for 10 minutes to hydrolyze the ester and form the acid. After acidification with 1n hcl, the solution was concentrated to completely remove the solvent and the crude 4-D was used in the next step without further purification. LCMS-ESI⁺(m/z):[M+H]⁺Found 383 parts.

Step 3

To a 50mL 1-necked round bottom flask was added a solution of reactant 4-D (crude from step 2, 1.0mmol), 2,4, 6-trifluorophenylmethylamine (0.34g, 2.1mmol), DIPEA (0.68g, 5.2mmol) and HATU (0.80g, 2.1mmol) in DCM (10 mL). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated, redissolved in EtOAc (50mL) and treated with saturated NaHCO₃Twice washing, saturated NH₄Washed with Cl and Na₂SO₄And (5) drying. After concentration, the crude product was purified by silica gel column chromatography eluting with hexane-EtOAc to afford 4-E. LCMS-ESI⁺(m/z):[M+H]⁺(ii) a Found 526.

Step 4

A50 mL 1-necked round bottom flask was charged with a solution of reactant 4-E (0.10g, 0.19mmol) in TFA (2 mL). The reaction mixture was stirred at room temperature for 30 minutes. The solution was concentrated and the residue was purified by CombiFlash (12g cartridge, cartridge filter) using EtOAc-20% MeOH in EtOAc as eluent to give compound 4.¹H NMR(400MHz,DMSO-d6)12.82(s,1H),10.42(t,J＝5.8Hz,1H),8.37(s,1H),7.19(t,J＝8.6Hz,2H),4.80-4.31(m,3H),3.99(d,J＝5.6Hz,1H),3.11(s,3H),1.97(s,1H),1.87-1.62(m,3H),1.43(d,J＝37.9Hz,4H).¹⁹F NMR(376MHz,DMSO-d6)-108.61--110.08(m,1F),-112.47(t,J＝7.2Hz,2F).LCMS-ESI⁺(m/z):[M+H]⁺Found 436.

Example 5

Preparation of Compound 5

Step 1

A50 mL 1-necked round bottom flask was charged with a solution of reactant 4-C (0.4g, 1.0mmol) in THF (10 mL). NaH (0.2g, 60% in mineral oil, 5.0mmol) was added to the reaction mixture. The reaction mixture was stirred at room temperature for 5 minutes. To the reaction mixture was added ethyl iodide (0.32g, 2.0 mmol). The reaction mixture was stirred at room temperature for a further 5 minutes. Water (1ml) was added dropwise to the reaction mixture. The reaction mixture was stirred at room temperature for 10 minutes to hydrolyze the ester and form the acid. After acidification with 1n hcl, the solution was concentrated to completely remove the solvent and the crude product 5-B was used in the next step without further purification. LCMS-ESI⁺(m/z):[M+H]⁺Found value is 397.

Step 2

To a 50mL 1-necked round bottom flask was added a solution of reactant 5-B (crude from step 2, 1.0mmol), 2,4, 6-trifluorophenylmethylamine (0.33g, 2.0mmol), DIPEA (0.65g, 5.0mmol) and HATU (0.77g, 2.0mmol) in DCM (10 mL). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated, redissolved in EtOAc (50mL) and treated with saturated NaHCO₃Twice washing, saturated NH₄Cl washed and Na₂SO₄And (5) drying. After concentration, the crude product was purified by silica gel column chromatography eluting with hexane-EtOAc to afford 5-C. LCMS-ESI⁺(m/z):[M+H]⁺(ii) a Found 540.

Step 3

A50 mL 1-necked round bottom flask was charged with a solution of reactant 5-C (0.10g, 0.19mmol) in TFA (2 mL). The reaction mixture was stirred at room temperature for 30 minutes. The solution was concentrated and the residue was purified by CombiFlash (12g cartridge, cartridge filter) using EtOAc-20% MeOH as eluent to give compound 5.¹H NMR(400MHz,DMSO-d6)12.88(s,1H),10.42(t,J＝5.8Hz,1H),8.35(s,1H),7.18(dd,J＝9.3,7.9Hz,2H),4.69-4.43(m,2H),4.29(m,1H),4.06-3.79(m,2H),3.31-3.01(m,1H),2.18(s,1H),1.98-1.58(m,3H),1.61-1.34(m,4H),1.14(t,J＝7.1Hz,3H).¹⁹F NMR(376MHz,DMSO-d6)-109.37(m,1F),-111.01--114.55(m,2F).LCMS-ESI⁺(m/z):[M+H]⁺Found 450.

Example 6

Preparation of Compound 6

Step 1

To a 50mL 1-necked round bottom flask was added the reactant 6-A (0.70g, 4.1mmol), 6-B (1.0g, 4.1mmol) and NaHCO₃(0.69g, 8.3mmol) in methanol (10ml) and water (10 ml). The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated, redissolved in EtOAc (100mL), washed twice with water and Na₂SO₄And (5) drying. After concentration, the crude product was purified by silica gel column chromatography eluting with hexane-EtOAc to afford 6-C. LCMS-ESI⁺(m/z):[M+H]⁺(ii) a Found 293.

Step 2

To a 50mL 1-necked round bottom flask was added a solution of reactant 6-C (0.1g, 0.34mmol) in DMF (10 mL). Reacting NaH with(0.041g, 60% in mineral oil, 1.0mmol) was added to the reaction mixture. The reaction mixture was stirred at room temperature for 5 minutes. MeI (0.1g, 0.68mmol) was added to the reaction mixture. The reaction mixture was stirred at room temperature for a further 5 minutes. Water (0.5ml) was added dropwise to the reaction mixture. The reaction mixture was stirred at room temperature for 10 minutes to hydrolyze the ester and form the acid. After acidification with 1N HCl, the solution was concentrated to completely remove the solvent and the crude product 6-D was used in the next step without further purification. LCMS-ESI⁺(m/z):[M+H]⁺Found 293.

Step 3

To a 50mL 1-necked round bottom flask was added a solution of reactant 6-D (crude from step 2, 0.27mmol), 2,4, 6-trifluorophenylmethylamine (0.088g, 0.55mmol), DIPEA (0.177g, 1.4mmol) and HATU (0.21g, 0.55mmol) in DCM (10 mL). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated, redissolved in EtOAc (50mL) and treated with saturated NaHCO₃Washed twice with saturated NH 4Cl and Na₂SO₄And (5) drying. After concentration, the crude product was purified by silica gel column chromatography eluting with hexane-EtOAc to afford 6-E. LCMS-ESI⁺(m/z):[M+H]⁺(ii) a Found 436.

Step 4

To a 50mL 1-necked round bottom flask was added a solution of reactant 6-E (0.05g, 0.11mmol) and magnesium bromide (0.05g, 0.3mmol) in acetonitrile (5 mL). The reaction mixture was heated to 50 ℃. After 10 min, the reaction mixture was cooled to 0 ℃ and 1N hydrochloric acid (4mL) was added. Some water (about 5mL) was added and the solid formed was filtered and washed with water. The solid was transferred to a vial and lyophilized overnight to give compound 6.¹H NMR (400MHz, chloroform-d) 10.47(s,1H),8.26(s,1H),6.79-6.54(m,2H),4.66(d, J ═ 5.7Hz,2H),4.01(td, J ═ 10.5,7.0Hz,1H),3.72(td, J ═ 11.4,7.0Hz,1H),3.12(s,3H),2.68-2.41(m,1H),2.31(d, J ═ 10.3Hz,1H),2.22-1.95(m,3H),2.02-1.73(m,1H).¹⁹F NMR (376MHz, chloroform-d) -109.17(m,1F), -112.02(t, J ═ 7.0Hz,2F)⁺(m/z):[M+H]⁺Found 422.

Example 7

Preparation of Compound 7

Step 1

To a 50mL 1-necked round bottom flask was added a solution of reactant 7-A (0.1g, 0.33 mmol; 7-A was prepared in a similar manner to 1-C using 6-B instead of 1-B) in DMF (5 mL). NaH (0.06g, 60% in mineral oil, 1.5mmol) was added to the reaction mixture. The reaction mixture was stirred at room temperature for 5 minutes. 2,2, 2-trifluoroethyl triflate (0.23g, 1.0mmol) was added to the reaction mixture. The reaction mixture was stirred at room temperature for a further 5 minutes. Water (1ml) was added dropwise. The reaction mixture was stirred at room temperature for 10 minutes to hydrolyze the ester and form the acid. After acidification with 1N HCl, the solution was concentrated to completely remove the solvent and the crude product 7-B was used in the next step without further purification. LCMS-ESI⁺(m/z):[M+H]⁺Found 375.

Step 2

To a 50mL 1-necked round bottom flask was added a solution of reactant 7-B (crude from step 1, 0.33mmol), 2,4, 6-trifluorophenylmethylamine (0.13g, 0.82mmol), DIPEA (0.53g, 4.0mmol) and HATU (0.37g, 0.98mmol) in DCM (5 mL). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated, redissolved in EtOAc (50mL) and treated with saturated NaHCO₃Twice washing, saturated NH₄Cl washed and Na₂SO₄And (5) drying. After concentration, the crude product was purified by silica gel column chromatography eluting with hexane-EtOAc to afford 7-C. LCMS-ESI⁺(m/z):[M+H]⁺(ii) a Found 518.

Step 3

To a 50mL 1-necked round bottom flask was added the reactant 7-C (0)02g, 0.04mmol) and magnesium bromide (0.02g, 0.1mmol) in acetonitrile (5 mL). The reaction mixture was heated to 50 ℃. After 10 min, the reaction mixture was cooled to 0 ℃ and 1N hydrochloric acid (4mL) was added. Additional water (about 5mL) was added and the solid formed was filtered and washed with water. The solid was transferred to a vial and lyophilized overnight to give compound 7.¹H NMR (400MHz, chloroform-d) 10.32(s,1H),8.52(s,1H),6.58(dd, J ═ 8.7,7.5Hz,2H),4.79(dd, J ═ 15.9,8.8Hz,1H),4.58(d, J ═ 5.6Hz,2H),3.78(ddd, J ═ 15.0,11.7,6.1Hz,2H),3.59(td, J ═ 10.5,4.4, 1H),2.69(d, J ═ 12.2Hz,1H),2.41(s, ddh), 2.03 (J ═ 37.1,9.3Hz,2H),1.64(q, J ═ 10.4,8.3Hz,1H),1.39(q, 7.5H, 9.5Hz, 3H).¹⁹F NMR (377MHz, chloroform-d) -69.01(t, J ═ 8.5Hz,3F), -109.05(t, J ═ 7.7Hz,1F), -112.05(t, J ═ 7.0Hz,2F)⁺(m/z):[M+H]⁺Found 504.

Example 8

Preparation of Compound 8

Step 1

A250 mL 1-necked round bottom flask was charged with a solution of reactant 8-A (2.0g, 17.1mmol) and triethylamine (2.1g, 20.7mmol) in THF (40 mL). The reaction mixture was cooled to 0 ℃. Benzyl chloroformate (3.2g, 19.0mmol) was added dropwise to the reaction mixture. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated, redissolved in EtOAc (100mL), washed twice with water and Na₂SO₄And (5) drying. After concentration, the crude product was purified by silica gel column chromatography eluting with hexane-EtOAc to afford 8-B. LCMS-ESI⁺(m/z):[M+H]⁺(ii) a Found value is 252.

Step 2

To a 250mL 1-necked round bottom flask was added reactant 8-B (1.6g, 6.4mmol), benzoic acid(1.24g, 10.2mmol) and triphenylphosphine (3.67g, 14.0mmol) in THF (40 ml). The reaction mixture was cooled to 0 ℃. DIAD (3.0g, 14.6mmol) was added to the reaction mixture. The reaction mixture was stirred at room temperature overnight. Concentrating the reaction mixture; the crude product was purified by silica gel column chromatography eluting with hexane-EtOAc to afford 8-C. LCMS-ESI⁺(m/z):[M+H]⁺(ii) a Found 356.

Step 3

To a 50mL 1-necked round bottom flask was added a solution of reactant 8-C (0.36g, 1.0mmol) in THF (10mL) and MeOH (5 mL). To the reaction mixture was added 1N KOH (2 mL). The reaction mixture was stirred at room temperature for 30 minutes. After acidification with 1n hcl, the solution was concentrated to completely remove the solvent and the crude product was purified by silica gel column chromatography eluting with hexane-EtOAc to afford 8-D. LCMS-ESI⁺(m/z):[M+H]⁺Found value is 252.

Step 4

A250 mL 1-necked round bottom flask was charged with a solution of reactant 8-D (1.0g, 4.0mmol), phthalimide (0.94g, 6.0mmol) and triphenylphosphine (2.3g, 9.0mmol) in THF (30 mL). The reaction mixture was cooled to 0 ℃. DIAD (1.77g, 9.0mmol) was added to the reaction mixture. The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated and the crude product was purified by silica gel column chromatography eluting with hexane-EtOAc to afford 8-E. LCMS-ESI⁺(m/z):[M+H]⁺(ii) a Found value is 381.

Step 5

To a 100mL 1-necked round bottom flask was added a solution of reactant 8-E (1.2g, 3.0mmol) in ethanol (20 mL). To the reaction mixture was added hydrazine hydrate (0.79g, 16.0 mmol). The reaction mixture was stirred at 70 ℃ for 3 hours. The reaction mixture was cooled to room temperature. After removing the solids by filtration, the filtrate was concentrated and concentrated under high vacuum for 1 hour. The crude 8-F was used in the next step without further purification and characterization. LCMS-ESI⁺(m/z):[M+H]⁺Found 251.

Step 6

A250 mL 1-necked round bottom flask was charged with a solution of reactant 8-F (0.7g, 2.8mmol), DIPEA (1.3g, 10mmol) and di-tert-butyl dicarbonate (1.2g, 5.6mmol) in DCM (20 mL). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated, redissolved in EtOAc (100mL), washed twice with water and Na₂SO₄And (5) drying. After concentration, the crude product was purified by silica gel column chromatography eluting with hexane-EtOAc to afford 8-G. LCMS-ESI⁺(m/z):[M+H]⁺(ii) a Found value is 351.

Step 7

A100 mL 1-necked round bottom flask was charged with a solution of reactant 8-G (0.23G, 0.65mmol) in ethanol (20 mL). Pd (OH) in (1)₂The reaction mixture was charged with/C (0.05 g). The reaction mixture is reacted in H₂Stirred for 1 hour. After removing the solids by filtration, the filtrate was concentrated and concentrated under high vacuum for 1 hour. The crude 8-H was used in the next step without further purification and characterization. LCMS-ESI⁺(m/z):[M+H]⁺Found 217.

Step 8

To a 50mL 1-necked round bottom flask was added the reactants 8-H (0.13g, 0.6mmol), 6-B (0.14g, 0.6mmol) and NaHCO₃(0.11g, 1.3mmol) of ethanol (10ml) and water (10 ml). The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated, redissolved in EtOAc (100mL), washed with water, and Na₂SO₄And (5) drying. After concentration, the crude product was dissolved in 4N HCl/dioxane (3.3ml) and stirred at room temperature for 3 hours to remove the Boc protecting group. The reaction mixture was concentrated again. The residue and DBU (0.49g, 3.0mmol) were dissolved in MeOH (10mL) and heated to 50 deg.C for 20 min. After concentration, the crude product was purified by silica gel column chromatography eluting with hexane-EtOAc to afford 8-J. LCMS-ESI⁺(m/z):[M+H]⁺(ii) a Found 309.

Step 9

To a 50mL 1-necked round bottom flask was added a solution of reactant 8-J (0.01g, 0.16mmol) in DMF (5 mL). NaH (0.032g, 60% in mineral oil, 0.8mmol) was added to the reaction mixture. The reaction mixture was stirred at room temperature for 5 minutes. 2,2, 2-trifluoroethyl trifluoromethanesulfonate (0.075g, 0.32mmol) was added. The reaction mixture was stirred at room temperature for a further 5 minutes. Water (1ml) was added dropwise to the reaction mixture. The reaction mixture was stirred at room temperature for 10 minutes to hydrolyze the ester and form the acid. After acidification with 1N HCl, the solution was concentrated to completely remove the solvent and the crude product 8-K was used in the next step without further purification. LCMS-ESI⁺(m/z):[M+H]⁺The actual measurement value is 377.

Step 10

To a 50mL 1-necked round bottom flask was added a solution of reactant 8-K (crude from step 1, 0.16mmol), 2,4, 6-trifluorophenylmethylamine (0.064g, 0.4mmol), DIPEA (0.26g, 2.0mmol) and HATU (0.18g, 0.48mmol) in DCM (5 mL). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated, redissolved in EtOAc (50mL) and treated with saturated NaHCO₃Washed (twice) with saturated NH₄Cl washing, Na washing₂SO₄And (5) drying. After concentration, the crude product was purified by silica gel column chromatography eluting with hexane-EtOAc to afford 8-L. LCMS-ESI⁺(m/z):[M+H]⁺(ii) a Found 520.

Step 11

To a 50mL 1-necked round bottom flask was added a solution of reactant 8-L (0.02g, 0.04mmol) and magnesium bromide (0.02g, 0.1mmol) in acetonitrile (5 mL). The reaction mixture was heated to 50 ℃. After 10 min, the reaction mixture was cooled to 0 ℃ and 1N hydrochloric acid (4mL) was added. Additional water (about 5mL) was added and the solid formed was filtered and washed with water. The solid was transferred to a vial and lyophilized overnight to give compound 8.¹H NMR (400MHz, chloroform-d) 10.25(s,1H),8.19(s,1H),6.66(t, J ═ 8.2Hz,2H),4.82(d, J ═ 10.7Hz,2H),4.65(d, J ═ 5.6Hz,2H),4.41-4.12(m,1H),3.90(d, J ═ 63.1Hz,1H),3.77-3.48(m,2H),2.53-2.20(m,2H),1.94(d, J ═ 52.4Hz,1H),1.63(s,1H).¹⁹F NMR (376MHz, chloroform-d) -69.01(t,J＝8.3Hz,3F),-109.04(d,J＝8.7Hz,1F),-112.07(d,J＝7.1Hz,2F).LCMS-ESI⁺(m/z):[M+H]⁺Found value is 506.

Example 9

Preparation of Compound 9

Step 1

A250 mL 1-necked round bottom flask was charged with a solution of reactant 9-A (2.0g, 17.1mmol) and triethylamine (2.1g, 20.7mmol) in THF (40 mL). The reaction mixture was cooled to 0 ℃. Benzyl chloroformate (3.2g, 19.0mmol) was added dropwise to the reaction mixture. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated, redissolved in EtOAc (100mL), washed twice with water and Na₂SO₄And (5) drying. After concentration, the crude product was purified by silica gel column chromatography eluting with hexane-EtOAc to afford 9-B. LCMS-ESI⁺(m/z):[M+H]⁺(ii) a Found value is 252.

Step 2

A250 mL 1-necked round bottom flask was charged with a solution of reactant 9-B (2.0g, 8.0mmol) in DCM (34 mL). Desmatin periodinane (4.1g, 9.6mmol) was added to the reaction mixture. The reaction mixture was stirred at room temperature for 2 hours. Concentrating the reaction mixture; the crude product was purified by silica gel column chromatography eluting with hexane-EtOAc to afford 9-C. LCMS-ESI⁺(m/z):[M+H]⁺(ii) a Found 250.

Step 3

A100 mL 1-necked round bottom flask was charged with a solution of reactant 9-C (1.0g, 4.0mmol) and tert-butylsulfinamide (0.58g, 4.8mmol) in THF (20 mL). Titanium ethoxide (1.8g, 8.0mmol) was added to the reaction mixture. The reaction mixture was stirred at room temperature overnight and then with EtOAc (100mL) dilution. Adding saturated NaHCO to the reaction mixture₃Aqueous solution (2 mL). The mixture was filtered through a pad of celite. The filtrate was concentrated to completely remove the solvent, and the crude product was purified by silica gel column chromatography eluting with hexane-EtOAc to give 9-D. LCMS-ESI⁺(m/z):[M+H]⁺Measured value: 353.

Step 4

A250 mL 1-necked round bottom flask was charged with a solution of reactant 9-D (0.5g, 1.4mmol) and difluoromethylbenzenesulfonate (0.28g, 0.14mmol) in THF (10 mL). The reaction mixture was cooled to-78 ℃. LiHMDS (3mL, 1N in THF, 3mmol) was added to the reaction mixture. The reaction mixture was stirred at-78 ℃ for 30 minutes. The reaction mixture was diluted with EtOAc (50mL) and quenched with water (5 mL). After layer separation, the organic layer was washed with Na₂SO₄Drying and concentration, the crude product was purified by silica gel column chromatography eluting with hexane-EtOAc to afford 9-E. LCMS-ESI⁺(m/z):[M+H]⁺(ii) a Found 545.

Step 5

To a 100mL 1-necked round bottom flask was added reactant 9-E (1.7g, 3.1mmol) and Na₂HPO₃(4.4g, 31.0mmol) in methanol (20 mL). The reaction mixture was cooled to-20 ℃. Na/Hg (4.2g, 19.0mmol) was added to the reaction mixture. The reaction mixture was stirred at-20 ℃ for 2 hours. The reaction solution was poured into another flask. After concentration, the crude product was purified by silica gel column chromatography eluting with hexane-EtOAc to afford 9-F. LCMS-ESI⁺(m/z):[M+H]⁺(ii) a Found 405.

Step 6

To a 100mL 1-necked round bottom flask was added a solution of reactant 9-F (0.62g, 1.5mmol) in ethanol (20 mL). Adding Pd (OH) to the reaction mixture₂C (0.12 g). The reaction mixture is reacted in H₂Stirred for 1 hour. After removing the solids by filtration, the filtrate was concentrated and concentrated under high vacuum for 1 hour. The crude 9-G was used in the next step without further purification and characterization. LCMS-ESI⁺(m/z):[M+H]⁺Found 271.

Step 7

To a 50mL 1-necked round bottom flask was added reactants 9-G (0.39G, 1.44mmol), 1-B (0.5G, 1.44mmol) and NaHCO in ethanol (10mL) and water (10mL)₃(0.24g, 2.8 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated, redissolved in EtOAc (100mL), washed twice with water and Na₂SO₄And (5) drying. After concentration, the crude product was dissolved in 4N HCl/dioxane (2ml) and stirred at room temperature for 3 hours to remove the Boc protecting group. The reaction mixture was concentrated again. The residue and DBU (1.1g, 7.0mmol) were dissolved in MeOH (10mL) and heated to 50 deg.C for 20 min. After concentration, the crude product was purified by silica gel column chromatography eluting with hexane-EtOAc to afford 9-I. LCMS-ESI⁺(m/z):[M+H]⁺(ii) a Measured value 449.

Step 8

To a 50mL 1-necked round bottom flask was added a solution of reactant 9-I (0.08g, 0.18mmol) in DMF (10 mL). NaH (0.022g, 60% in mineral oil, 0.54mmol) was added to the reaction mixture. The reaction mixture was stirred at room temperature for 5 minutes. MeI (0.05g, 0.36mmol) was added and the reaction mixture was stirred at room temperature for an additional 5 minutes. Water (0.5ml) was added dropwise and the reaction mixture was stirred at room temperature for 10 minutes to hydrolyze the ester and form an acid. After acidification with 1N HCl, the solution was concentrated to completely remove the solvent and the crude product 9-J was used in the next step without further purification. LCMS-ESI⁺(m/z):[M+H]⁺Found 435.

Step 9

To a 50mL 1-necked round bottom flask was added a solution of reactants 9-J (crude from step 1, 0.18mmol), 2,4, 6-trifluorophenylmethylamine (0.033g, 0.2mmol), DIPEA (0.25g, 1.9mmol) and HATU (0.18g, 0.48mmol) in DCM (3 mL). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated, redissolved in EtOAc (50mL) and treated with saturated NaHCO₃Washed twice with saturated NH₄Cl washing withNa₂SO₄And (5) drying. After concentration, the crude product was purified by silica gel column chromatography eluting with hexane-EtOAc to afford 9-K. LCMS-ESI⁺(m/z):[M+H]⁺(ii) a Found 578 in.

Step 10

A50 mL 1-necked round bottom flask was charged with a solution of reactant 9-K (0.02g, 0.04mmol) in TFA (2 mL). The reaction mixture was stirred at room temperature for 30 minutes. The solution was concentrated and the residue was purified by CombiFlash (12g cartridge, cartridge filter) using EtOAc-20% MeOH in EtOAc as eluent to give compound 9.¹H NMR (400MHz, methanol-d 4)8.48(s,1H),6.98-6.82(m,2H),6.13(t, J ═ 54.3Hz,1H),5.05-4.85(m,1H),4.72-4.55(m,2H),4.15-3.86(m,2H),3.74-3.47(m,2H),3.25(s,3H),2.51(d, J ═ 15.8Hz,1H),2.19-1.97(m,1H).¹⁹F NMR (376MHz, methanol-d 4) -110.68(m,1F), -114.27(t, J ═ 7.3Hz,2F), -128.99(dd, J ═ 288.0,54.2Hz,1F), -132.26(dd, J ═ 288.0,54.5Hz,1F)⁺(m/z):[M+H]⁺Found 488.

Example 10

Preparation of Compound 10

Step 1

A50 mL 1-necked round bottom flask was charged with a solution of reactant 10-A (0.15g, 0.49mmol, synthesis of 10-A described in example 35) in DMF (3 mL). NaH (0.082g, 60% in mineral oil, 2.0mmol) was added to the reaction mixture. The reaction mixture was stirred at room temperature for 5 minutes. MeI (0.1g, 0.68mmol) was added and the reaction mixture was stirred at room temperature for an additional 5 minutes. Water (0.5ml) was added dropwise and the reaction mixture was stirred at room temperature for 10 minutes to hydrolyze the ester and form an acid. After acidification with 1N HCl, the solution was concentrated to completely remove the solvent and the crude product 10-B was used without further purificationIn the next step. LCMS-ESI⁺(m/z):[M+H]⁺Found 309.

Step 2

To a 50mL 1-necked round bottom flask was added a solution of reactant 10-B (crude from step 1, 0.27mmol), 2,4, 6-trifluorophenylmethylamine (0.043g, 0.27mmol), DIPEA (0.33g, 2.5mmol) and HATU (0.18g, 0.49mmol) in DCM (3 mL). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated, redissolved in EtOAc (50mL) and treated with saturated NaHCO₃Washed twice with saturated NH₄Cl washing, Na washing₂SO₄And (5) drying. After concentration, the crude product was purified by silica gel column chromatography eluting with hexane-EtOAc to afford 10-C. LCMS-ESI⁺(m/z):[M+H]⁺(ii) a Found 452.

Step 3

A50 mL 1-necked round bottom flask was charged with a solution of reactant 10-C (0.01g, 0.022mmol) and magnesium bromide (0.01g, 0.058mmol) in acetonitrile (5 mL). The reaction mixture was heated to 50 ℃. After 10 min, the reaction mixture was cooled to 0 ℃ and 1N hydrochloric acid (4mL) was added. Additional water (about 5mL) was added and the solid formed was filtered and washed with water. The solid was transferred to a vial and lyophilized overnight to give compound 10.¹H NMR (400MHz, methanol-d 4)8.43(s,1H),7.05-6.79(m,2H),4.66(s,2H),4.63-4.42(m,1H),4.25(td, J ═ 12.1,5.8Hz,2H),4.10(q, J ═ 7.1Hz,1H),3.76(td, J ═ 10.6,4.6Hz,1H),3.67-3.53(m,1H),3.51(t, J ═ 10.8Hz,1H),3.07(s,3H),2.59(d, J ═ 12.4Hz,1H).¹⁹F NMR (376MHz, methanol-d 4) -110.71(ddd, J ═ 8.9,6.2,2.7Hz,1F), -114.26(t, J ═ 7.1Hz,2F)⁺(m/z):[M+H]⁺Found 438.

Example 11

Preparation of Compound 11

Step 1

To a 50mL 1-necked round bottom flask was added a solution of reactant 10-B (0.075g, 0.24mmol), (3-chloro-2, 4-difluorophenyl) methylamine (0.047g, 0.27mmol), DIPEA (0.33g, 2.5mmol) and HATU (0.18g, 0.49mmol) in DCM (3 mL). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated, redissolved in EtOAc (50mL) and treated with saturated NaHCO₃Twice washing, saturated NH₄Cl washed and Na₂SO₄And (5) drying. After concentration, the crude product was purified by silica gel column chromatography eluting with hexane-EtOAc to afford 11-B. LCMS-ESI⁺(m/z):[M+H]⁺(ii) a Found value is 468.

Step 2

A50 mL 1-necked round bottom flask was charged with a solution of 11-B (0.03g, 0.064mmol) and magnesium bromide (0.03g, 0.167mmol) in acetonitrile (5 mL). The reaction mixture was heated to 50 ℃. After 10 min, the reaction mixture was cooled to 0 ℃ and 1N hydrochloric acid (4mL) was added. Additional water (about 5mL) was added and the solid formed was filtered and washed with water. The solid was transferred to a vial and lyophilized overnight to give compound 11.¹H NMR (400MHz, methanol-d 4)8.43(s,1H),7.38(td, J ═ 8.4,6.0Hz,1H),7.09(td, J ═ 8.7,1.8Hz,1H),4.65(s,2H),4.51(dd, J ═ 10.9,4.6Hz,1H),4.35-4.07(m,2H),3.78(td, J ═ 10.7,4.6Hz,1H),3.60(td, J ═ 12.1,2.2Hz,1H),3.50(d, J ═ 10.8Hz,1H),3.08(s,3H),2.58(ddt, J ═ 14.4,4.2,2.0, 1H),2.03 (q0, 0,5, 0.5H).¹⁹F NMR (376MHz, methanol-d 4) -117.31(s,1F), -119.84(d, J ═ 7.8Hz,1F)⁺(m/z):[M+H]⁺Found 454.

Example 12

Preparation of Compound 12

Step 1

A50 mL 1-necked round bottom flask was charged with a solution of reactant 10-A (0.1g, 0.32mmol) in DMF (3 mL). NaH (0.064g, 60% in mineral oil, 1.6mmol) was added to the reaction mixture. The reaction mixture was stirred at room temperature for 5 minutes. EtI (0.1g, 0.64mmol) was added to the reaction mixture. The reaction mixture was stirred at room temperature for a further 5 minutes. Water (0.5ml) was added dropwise to the reaction mixture. The reaction mixture was stirred at room temperature for 10 minutes to hydrolyze the ester and form the acid. After acidification with 1N HCl, the solution was concentrated to completely remove the solvent and the crude product 12-B was used in the next step without further purification. LCMS-ESI⁺(m/z):[M+H]⁺Found value is 323.

Step 2

To a 50mL 1-necked round bottom flask was added a solution of reactant 12-B (0.075g, 0.23mmol), 2,4, 6-trifluorophenylmethylamine (0.041g, 0.26mmol), DIPEA (0.33g, 2.5mmol) and HATU (0.18g, 0.49mmol) in DCM (3 mL). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated, redissolved in EtOAc (50mL) and treated with saturated NaHCO₃Twice washing, saturated NH₄Cl in combination with Na₂SO₄And (5) drying. After concentration, the crude product was purified by silica gel column chromatography eluting with hexane-EtOAc to afford 12-C. LCMS-ESI⁺(m/z):[M+H]⁺(ii) a Found 466 is.

Step 3

A50 mL 1-necked round bottom flask was charged with a solution of reactant 12-C (0.03g, 0.066mmol) and magnesium bromide (0.03g, 0.174mmol) in acetonitrile (5 mL). The reaction mixture was heated to 50 ℃. After 10 min, the reaction mixture was cooled to 0 ℃ and 1N hydrochloric acid (4mL) was added. Additional water (about 5mL) was added and the solid formed was filtered and washed with water. The solid was then transferred to a vial and lyophilized overnight to give compound 12.¹H NMR (400MHz, methanol-d 4)8.42(s,1H),6.89(dd, J ═ 9.0,7.9Hz,2H),4.66(s,2H),4.49(dd, J ═ 11.1,4.5Hz,1H),4.29-4.17(m,2H),4.09(q, J ═ 7.1Hz,1H),3.97-3.80(m,2H),3.67-3.43(m, 2H)H),2.69-2.53(m,1H),2.18-1.99(m,2H),1.21(dt,J＝17.1,7.2Hz,3H).¹⁹F NMR (377MHz, methanol-d 4) -109.27-111.99 (m,1F), -114.23(t, J ═ 7.1Hz,2F)⁺(m/z):[M+H]⁺Found 452.

Example 13

Preparation of Compound 13

Step 1

To a 50mL 1-necked round bottom flask was added a solution of reactant 12-B (0.04g, 0.12mmol), (3-chloro-2, 4-difluorophenyl) methylamine (0.024g, 0.14mmol), DIPEA (0.17g, 1.28mmol), and HATU (0.094g, 0.25mmol) in DCM (3 mL). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated, redissolved in EtOAc (50mL) and treated with saturated NaHCO₃Twice washing, saturated NH₄Cl washed and Na₂SO₄And (5) drying. After concentration, the crude product was purified by silica gel column chromatography eluting with hexane-EtOAc to afford 13-B. LCMS-ESI⁺(m/z):[M+H]⁺(ii) a Found 483.

Step 2

To a 50mL 1-neck round bottom flask was added a solution of reactant 13-B (0.015g, 0.031mmol) and magnesium bromide (0.015g, 0.081mmol) in acetonitrile (3 mL). The reaction mixture was heated to 50 ℃. After 10 min, the reaction mixture was cooled to 0 ℃ and 1N hydrochloric acid (4mL) was added. Additional water (about 5mL) was added and the solid formed was filtered and washed with water. The solid was then transferred to a vial and lyophilized overnight to give compound 13.¹H NMR (400MHz, methanol-d 4)8.44(s,1H),7.38(td, J ═ 8.4,6.1Hz,1H),7.08(td, J ═ 8.7,1.8Hz,1H),4.66(s,2H),4.50(dd, J ═ 11.0,4.8Hz,1H),4.27(qd, J ═ 11.5,4.6Hz,2H),4.08(d, J ═ 7.1Hz,1H),4.02-3.79(m,3H),3.65-3.48(m,2H),2.60(d, J ═ 14.0Hz,1H),1.21(q, J ═ 7.0Hz,3H).¹⁹F NMR (376MHz, methanol-d 4) -117.31(s,1F), -119.84(d, J ═ 7.8Hz,1F)⁺(m/z):[M+H]⁺Found 469.

Example 14

Preparation of Compound 14

Step 1

A250 mL 1-necked round bottom flask was charged with a solution of reactant 9-D (0.6g, 1.7mmol) in THF (10 mL). The reaction mixture was cooled to-78 ℃. Methyllithium (3.86mL, 1.14M in ether, 4.4mmol) was added to the reaction mixture. The reaction mixture was stirred at-78 ℃ for 2 hours. The reaction mixture was diluted with EtOAc (50mL) and quenched with water (5 mL). After layer separation, the organic layer was washed with Na₂SO₄Drying and concentration, the crude product was purified by silica gel column chromatography eluting with hexane-EtOAc to afford 14-B. LCMS-ESI⁺(m/z):[M+H]⁺(ii) a Found 369.

Step 2

A100 mL 1-necked round bottom flask was charged with a solution of reactant 14-B (0.13g, 0.35mmol) in ethanol (10 mL). Adding Pd (OH) to the reaction mixture₂C (0.03 g). The reaction mixture is reacted in H₂Stirred for 1 hour. After removing the solids by filtration, the filtrate was concentrated and concentrated under high vacuum for 1 hour. The crude product 14-C was used in the next step without further purification and characterization. LCMS-ESI⁺(m/z):[M+H]⁺Found 235.

Step 3

To a 50mL 1-necked round bottom flask was added the reactant 14-C (0.08g, 0.38mmol), 14-D (0.13g, 0.38mmol) and NaHCO₃(0.064g, 0.75mmol) in ethanol (5ml) and water (5 ml). The reaction mixture is added inStir at room temperature overnight. The reaction mixture was concentrated, redissolved in EtOAc (50mL), washed twice with water and Na₂SO₄And (5) drying. After concentration, the crude product was dissolved in 4N HCl/dioxane and stirred for 2 hours. The reaction mixture was concentrated again. The residue and DBU (0.15g, 1.0mmol) were dissolved in EtOH (5mL) and heated to 50 ℃ for 20 min. After concentration, the crude product was purified by silica gel column chromatography eluting with hexane-EtOAc to afford 14-E. LCMS-ESI⁺(m/z):[M+H]⁺(ii) a Found 413.

Step 4

A50 mL 1-necked round bottom flask was charged with a solution of reactant 14-E (0.05g, 0.12mmol) in DMF (5 mL). NaH (0.014g, 60% in mineral oil, 0.36mmol) was added to the reaction mixture. The reaction mixture was stirred at room temperature for 5 minutes. MeI (0.034g, 0.24mmol) was added to the reaction mixture. The reaction mixture was stirred at room temperature for a further 5 minutes. Water (0.5ml) was added dropwise to the reaction mixture. The reaction mixture was stirred at room temperature for 10 minutes to hydrolyze the ester and form the acid. After acidification with 1N HCl, the solution was concentrated to completely remove the solvent and the crude product 14-F was used in the next step without further purification. LCMS-ESI⁺(m/z):[M+H]⁺Measured value is 399.

Step 5

A50 mL 1-necked round bottom flask was charged with a solution of reactant 14-F (0.048,0.112mmol), 2,4, 6-trifluorophenylmethylamine (0.033g, 0.2mmol), DIPEA (0.25g, 1.9mmol) and HATU (0.18g, 0.48mmol) in DCM (3 mL). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated, redissolved in EtOAc (50mL) and treated with saturated NaHCO₃Washed twice with saturated NH₄Cl washing, Na washing₂SO₄And (5) drying. After concentration, the crude product was purified by silica gel column chromatography eluting with hexane-EtOAc to afford 14-G. LCMS-ESI⁺(m/z):[M+H]⁺(ii) a Found 542.

Step 6

To a 50mL 1-necked round bottom flask was added reactant 14-G (0.07G, 0.13mmol) in TFA (2 mL). The reaction mixture was stirred at room temperature for 30 minutes. The solution was concentrated and the residue was purified by CombiFlash (12g cartridge, cartridge filter) using EtOAc-20% MeOH in EtOAc as eluent to give compound 14.¹H NMR (400MHz, methanol-d 4)8.47(s,1H),6.89(dd, J ═ 9.0,7.9Hz,2H),4.66(s,2H),4.55(dd, J ═ 11.1,5.1Hz,1H),3.86(dd, J ═ 11.4,5.4Hz,2H),3.51(dt, J ═ 29.8,11.8Hz,2H),3.11(s,3H),2.40(d, J ═ 15.7Hz,1H),2.05-1.79(m,1H),1.33(s,3H).¹⁹F NMR (376MHz, methanol-d 4) -109.24-112.06 (m,1F), -114.26(t, J ═ 7.2Hz,2F)⁺(m/z):[M+H]⁺Found 452.

Example 15

Preparation of Compound 15

Step 1

To a 50mL 1-necked round bottom flask was added a solution of reactant 15-A (0.015g, 0.047mmol, synthesis of 15-A described in example 41), (5-chloro-2, 4-difluorophenyl) methylamine (0.009g, 0.05mmol), DIPEA (0.06g, 0.47mmol) and HATU (0.035g, 0.09mmol) in DCM (3 mL). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated, redissolved in EtOAc (50mL) and treated with saturated NaHCO₃Washed twice with saturated NH₄Cl washing, Na washing₂SO₄And (5) drying. After concentration, the crude product was purified by silica gel column chromatography eluting with hexane-EtOAc to afford 15-B. LCMS-ESI⁺(m/z):[M+H]⁺(ii) a Found 483.

Step 2

To a 50mL 1-neck round bottom flask was added a solution of reactant 15-B (0.015g, 0.031mmol) and magnesium bromide (0.015g, 0.081mmol) in acetonitrile (3 mL). The reaction mixture was heated to 50 ℃. After 10 minutes, the reaction was carried outThe mixture was cooled to 0 ℃ and 1N hydrochloric acid (4mL) was added. Additional water (about 5mL) was added and the solid formed was filtered and washed with water. The solid was then transferred to a vial and lyophilized overnight to give compound 15.¹H NMR (400MHz, methanol-d 4)8.48(s,1H),7.50(t, J ═ 7.9Hz,1H),7.15(t, J ═ 9.4Hz,1H),4.61(s,2H),4.34(d, J ═ 13.6Hz,1H),4.07(dd, J ═ 14.4,7.4Hz,2H),3.94(d, J ═ 4.0Hz,1H),3.83-3.63(m,2H),3.50(dt, J ═ 14.2,7.0Hz,1H),2.35-2.04(m,1H),2.00-1.84(m,1H),1.25(t, J ═ 7.2Hz,3H).¹⁹F NMR (376MHz, methanol-d 4) -115.23(q, J-8.2 Hz,1F), -117.95(d, J-8.6 Hz,1F). LCMS-ESI⁺(m/z):[M+H]⁺Found 469.

Example 16

Preparation of Compound 16

Step 1

To a 50mL 1-necked round bottom flask was added a solution of reactant 15-A (0.015g, 0.047mmol), (3-chloro-2-fluorophenyl) methylamine (0.008g, 0.05mmol), DIPEA (0.06g, 0.47mmol), and HATU (0.035g, 0.09mmol) in DCM (3 mL). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated, redissolved in EtOAc (50mL) and treated with saturated NaHCO₃Washed twice with saturated NH₄Cl washing, Na washing₂SO₄And (5) drying. After concentration, the crude product was purified by silica gel column chromatography eluting with hexane-EtOAc to afford 16-B. LCMS-ESI⁺(m/z):[M+H]⁺(ii) a Found value is 465.

Step 2

To a 50mL 1-neck round bottom flask was added a solution of reactant 16-B (0.015g, 0.032mmol) and magnesium bromide (0.015g, 0.081mmol) in acetonitrile (3 mL). The reaction mixture was heated to 50 ℃. After 10 min, the reaction mixture was cooled to 0 ℃ and 1N hydrochloric acid (4mL) was added). Additional water (about 5mL) was added and the solid formed was filtered and washed with water. The solid was then transferred to a vial and lyophilized overnight to give compound 16.¹H NMR (400MHz, methanol-d 4)8.49(s,1H),7.46-7.27(m,2H),7.19-7.05(m,1H),4.78(dt, J ═ 11.1,4.2Hz,1H),4.68(s,2H),4.34(d, J ═ 13.7Hz,1H),4.15-3.98(m,2H),4.00-3.86(m,1H),3.78-3.59(m,2H),3.58-3.41(m,1H),2.31-2.05(m,1H),2.00-1.80(m,1H),1.25(t, J ═ 7.2Hz,3H).¹⁹F NMR (376MHz, methanol-d 4) -123.45(s, 1F.) LCMS-ESI⁺(m/z):[M+H]⁺Measured value: 451.

Example 17

Preparation of Compound 17

Step 1

To a 50mL 1-necked round bottom flask was added a solution of reactant 15-A (0.015g, 0.047mmol), (2,4, 5-trifluorophenyl) methylamine (0.008g, 0.05mmol), DIPEA (0.06g, 0.47mmol) and HATU (0.035g, 0.09mmol) in DCM (3 mL). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated, redissolved in EtOAc (50mL) and treated with saturated NaHCO₃Washed twice with saturated NH₄Cl washing, Na washing₂SO₄And (5) drying. After concentration, the crude product was purified by silica gel column chromatography eluting with hexane-EtOAc to afford 17-B. LCMS-ESI⁺(m/z):[M+H]⁺(ii) a Found 466 is.

Step 2

To a 50mL 1-neck round bottom flask was added a solution of reactant 17-B (0.015g, 0.032mmol) and magnesium bromide (0.015g, 0.081mmol) in acetonitrile (3 mL). The reaction mixture was heated to 50 ℃. After 10 min, the reaction mixture was cooled to 0 ℃ and 1N hydrochloric acid (4mL) was added. Additional water (about 5mL) was added and the solid formed was filtered and washed with water. Then transferring the solid toVial and lyophilized overnight to give compound 17.¹H NMR (400MHz, chloroform-d) 10.58(s,1H),8.47(s,1H),7.25-7.09(m,1H),6.92(td, J ═ 9.6,6.4Hz,1H),4.68-4.52(m,2H),4.49-4.33(m,1H),4.24(t, J ═ 14.9Hz,1H),4.15(dt, J ═ 14.6,7.3Hz,1H),4.11-3.89(m,2H),3.77-3.58(m,2H),3.42(dq, J ═ 14.2,6.9Hz,1H),2.29(d, J ═ 10.7Hz,1H),2.11-1.85(m,1H),1.27(t, 7, 3.7Hz, 3H).¹⁹F NMR (376MHz, chloroform-d)

-120.46(dd,J＝10.1,6.3Hz,1F),-134.38--136.34(m,1F),-140.61--145.04(m,1F).LCMS-ESI⁺(m/z):[M+H]⁺Found 452.

Example 18

Preparation of Compound 18

Step 1

To a 50mL 1-necked round bottom flask was added a solution of reactant 15-A (0.015g, 0.047mmol), (2, 3-difluorophenyl) methylamine (0.007g, 0.05mmol), DIPEA (0.06g, 0.47mmol) and HATU (0.035g, 0.09mmol) in DCM (3 mL). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated, redissolved in EtOAc (50mL) and treated with saturated NaHCO₃Washed twice with saturated NH₄Cl washing, Na washing₂SO₄And (5) drying. After concentration, the crude product was purified by silica gel column chromatography eluting with hexane-EtOAc to afford 18-B. LCMS-ESI⁺(m/z):[M+H]⁺(ii) a Found 448.

Step 2

A50 mL 1-necked round bottom flask was charged with a solution of reactant 18-B (0.02g, 0.045mmol) and magnesium bromide (0.015g, 0.081mmol) in acetonitrile (3 mL). The reaction mixture was heated to 50 ℃. After 10 min, the reaction mixture was cooled to 0 ℃ and 1N hydrochloric acid (4mL) was added. Additional water (about 5mL) was addedThe solid formed was filtered and washed with water. The solid was then transferred to a vial and lyophilized overnight to give compound 18.¹H NMR (400MHz, chloroform-d) 10.62(d, J ═ 6.5Hz,1H),8.52(s,1H),7.20-6.97(m,3H),4.86-4.59(m,2H),4.43(dt, J ═ 10.8,4.0Hz,1H),4.34-4.06(m,2H),4.00(d, J ═ 17.8Hz,2H),3.78-3.53(m,2H),3.43(dq, J ═ 14.2,6.8Hz,1H),2.39-2.16(m,1H),1.95(d, J ═ 13.8Hz,1H),1.26(t, J ═ 7.2Hz,3H).¹⁹F NMR (377MHz, chloroform-d) -138.97(ddd, J ═ 20.8,9.7,5.1Hz,1F), -143.93(dt, J ═ 20.7,6.5Hz,1F)⁺(m/z):[M+H]⁺Found 434.

Example 19

Preparation of Compound 19

Step 1

To a 50mL 1-necked round bottom flask was added a solution of reactant 15-A (0.015g, 0.047mmol), (2,3, 4-trifluorophenyl) methylamine (0.008g, 0.05mmol), DIPEA (0.06g, 0.47mmol) and HATU (0.035g, 0.09mmol) in DCM (3 mL). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated, redissolved in EtOAc (50mL) and treated with saturated NaHCO₃Washed twice with saturated NH₄Cl washing, Na washing₂SO₄And (5) drying. After concentration, the crude product was purified by silica gel column chromatography eluting with hexane-EtOAc to afford 19-B. LCMS-ESI⁺(m/z):[M+H]⁺(ii) a Found 466 is.

Step 2

To a 50mL 1-neck round bottom flask was added a solution of reactant 19-B (0.015g, 0.032mmol) and magnesium bromide (0.015g, 0.081mmol) in acetonitrile (3 mL). The reaction mixture was heated to 50 ℃. After 10 min, the reaction mixture was cooled to 0 ℃ and 1N hydrochloric acid (4mL) was added. Additional water (about 5mL) was added, the solid formed was filtered and washed with water. The solid was then transferred to a vial and lyophilized overnight to give compound 19.¹H NMR (400MHz, chloroform-d) 10.59(t, J ═ 5.9Hz,1H),8.48(s,1H),7.08(t, J ═ 6.8Hz,1H),6.91(tdd, J ═ 9.1,6.9,2.1Hz,1H),4.81-4.53(m,2H),4.43(dt, J ═ 10.7,4.1Hz,1H),4.36-4.22(m,1H),4.15(dq, J ═ 14.6,7.3Hz,1H),4.00(d, J ═ 12.3Hz,2H),3.77-3.59(m,2H),3.43(dq, J ═ 14.1,6.8Hz,1H),2.40-2.13(m,1H), 1.95H, 1H), 1H (t, 1H), 1H, J ═ 7.6.6..¹⁹F NMR (376MHz, chloroform-d) -134.81-137.16 (m,1F), -139.27(dt, J ═ 20.1,7.0Hz,1F), -158.56-162.98 (m,1F)⁺(m/z):[M+H]⁺Found 452.

Example 20

Preparation of Compound 20

Step 1

To a 50mL 1-necked round bottom flask was added a solution of reactant 15-A (0.015g, 0.047mmol), (3, 4-difluorophenyl) methylamine (0.007g, 0.05mmol), DIPEA (0.06g, 0.47mmol) and HATU (0.035g, 0.09mmol) in DCM (3 mL). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated, redissolved in EtOAc (50mL) and treated with saturated NaHCO₃Washed twice with saturated NH₄Cl washing, Na washing₂SO₄And (5) drying. After concentration, the crude product was purified by silica gel column chromatography eluting with hexane-EtOAc to afford 20-B. LCMS-ESI⁺(m/z):[M+H]⁺(ii) a Found 448.

Step 2

To a 50mL 1-neck round bottom flask was added a solution of reactant 20-B (0.02g, 0.045mmol) and magnesium bromide (0.015g, 0.081mmol) in acetonitrile (3 mL). The reaction mixture was heated to 50 ℃. After 10 min, the reaction mixture was cooled to 0 ℃ and 1N hydrochloric acid (4mL) was added. Additional water (about 5mL) was added,the solid formed was filtered and washed with water. The solid was then transferred to a vial and lyophilized overnight to give compound 20.¹H NMR (400MHz, chloroform-d) 10.79-10.57(m,1H),8.57(s,1H),7.22-6.96(m,3H),4.58(qd, J ═ 15.2,5.9Hz,2H),4.46(dt, J ═ 10.8,4.1Hz,1H),4.28(d, J ═ 13.8Hz,1H),4.15(dt, J ═ 14.6,7.3Hz,1H),4.07-3.91(m,2H),3.80-3.58(m,2H),3.43(dq, J ═ 14.1,7.0Hz,1H),2.26(dd, J ═ 12.6,8.4Hz,1H),1.97(t, J ═ 13.6, 1H), t, 1H, 27.27 (t, 3H), 1.27 (H, 3H).¹⁹F NMR (376MHz, chloroform-d) -137.90(ddd, J ═ 21.2,11.0,7.5Hz,1F), -139.18-141.35 (m,1F)⁺(m/z):[M+H]⁺Found 434.

Example 21

Preparation of Compound 21

Step 1

Benzyl (R) - (2-oxotetrahydrofuran-3-yl) carbamate (3.29g, 14.0mmol) was azeotropically dried by evaporation from toluene and dissolved in dichloromethane (25 mL). The solution was cooled in a-78 ℃ bath, resulting in precipitation. The mixture was allowed to warm to mostly homogeneous and DIBAL-H (29.4mL, 1.0M in toluene, 29.4mmol) was added while the reaction mixture was cooled again to-78 ℃. Additional dichloromethane (10mL) was added to maintain homogeneity. The reaction mixture was stirred at-78 ℃ for 2 hours and then quenched by the addition of ethyl acetate (2-3 mL). Subsequently, Rochelle's Salt (20mL of saturated aqueous solution) was added and the mixture was warmed to room temperature. After partitioning between ethyl acetate and water, additional rochelle salt solution was added to provide a homogeneous biphasic layer. The layers were separated and the aqueous layer was extracted again with ethyl acetate. The combined organic layers were dried over sodium sulfate (anhydrous), filtered and concentrated to give the crude lactol 21-a as a mixture of diastereomers.

Step 2

Lactol 21-A (3.18g, 13.4mmol) was dissolved in methanol (65mL) and treated with methanesulfonic acid (0.044mL, 0.67 mmol). The reaction mixture was capped and stirred at room temperature. After 16 hours, about half of the solvent was removed in vacuo and the remaining solution was partitioned between ethyl acetate and sodium bicarbonate (saturated aqueous solution). The layers were separated and the organic layer was washed with water and brine and dried over sodium sulfate. After filtration, the solvent was removed in vacuo and the residue was purified by flash chromatography on silica gel (20-60% ethyl acetate: hexanes) to give the desired ketal 21-B.

Step 3

Ketal 21-B (2.14g, 8.52mmol) and 10% palladium on carbon were combined in a round bottom flask, purged with nitrogen and suspended in ethanol (35 mL). The reaction mixture was purged with hydrogen (by balloon) under vacuum three times and stirred at room temperature 1³/₄And (4) hours. After several vacuum purges with nitrogen, the mixture was filtered through celite. The filter cake was washed several times with methanol and the resulting solution was carefully concentrated to a volume of about 20 mL. This solution of crude aminoketal 21-C is taken to the next step.

Step 4

A solution of the amino ketal 21-C (8.5mmol) in ethanol (ca. 20mL) was diluted with water (20mL) and with dimethyl 3-methoxy-4-oxo-4H-pyran-2, 5-dicarboxylate 6-B (2.06g, 8.5mmol) and sodium bicarbonate (1.43g, 17.0 mmol). The mixture was stirred at room temperature for 2 hours and concentrated to an orange solid. The residue was resuspended in methanol and stirred at 50 ℃ for 16 hours. After cooling, most of the solvent was removed in vacuo and the residue was partitioned between ethyl acetate and water. The organic layer was separated and the aqueous layer was extracted again with ethyl acetate. The aqueous solution was treated with sodium chloride (solid) and extracted again with ethyl acetate and 2-butanol. The combined organic layers were dried over sodium sulfate, filtered and concentrated to give the crude diester 21-E.

Step 5

The crude diester 21-E (2.15g, 6.30mmol) was dissolved in THF (8mL) and methanol (4mL) and treated with lithium hydroxide (2.36mL, 2M aq, 4.72mmol) for about 2 min. After stirring for 20 min, the reaction mixture was diluted with ethyl acetate (40mL) and carefully quenched with HCl (12.6mL, 0.5M aqueous solution). After separation of layers, the aqueous layer was treated with brine and extracted again with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated to give the crude carboxylic acid: LCMS-ESI⁺(m/z):[M+H]⁺For C₁₉H₁₈F₃N₃O₅Calculated values: 328.10, respectively; found 328.0.

The crude carboxylic acid intermediate (2.1g, 6.41mmol) and 2,4, 6-trifluorobenzylamine (1.14g, 7.06mmol) were dissolved in acetonitrile (15mL) with N-ethyl-N-isopropylpropan-2-amine (1.24g, 9.6mmol) and HATU (2.68g, 7.05 mmol). After stirring at room temperature for 1 hour, the reaction mixture was diluted with ethyl acetate (100mL) and washed with 0.5M HCl and water. After drying over sodium sulfate, the solution was filtered and concentrated. Flash chromatography (0-40% ethyl acetate: dichloromethane) afforded the desired amide 21-F: LCMS-ESI⁺(m/z):[M+H]⁺C₂₁H₂₂F₃N₂O₇Calculated value 471.14; found 471.1.

Step 6

A solution of amide 21-F (0.476g, 1.01mmol) in a mixture of acetonitrile (3.6mL) and acetic acid (0.4mL) was treated with methanesulfonic acid (0.020mL, 0.30 mmol). The reaction mixture was capped and stirred in the 75 ℃ bath. After 18 hours, water (0.040mL) was added and the mixture was stirred at 75 ℃ for a further 16 hours to give the crude lactol 21-G: LCMS-ESI⁺(m/z):[M+H]⁺C₂₀H₂₀F₃N₂O₇Calculated value 457.12; found 457.1.

Step 7

A portion of the crude lactol solution from step 6 (1mL solution, 0.25mmol) was diluted with acetonitrile (1mL), treated with cyclopropylamine (0.069mL, 1.00mmol), capped and stirred at 75 ℃. After 30 min, the reaction mixture was cooled, diluted with acetonitrile (1mL) and treated with magnesium bromide (0.129g, 0.7 mmol). The mixture was covered and stirred at 50 ℃ for 15 minutes, cooled and partitioned between dichloromethane and 0.5M HCl. The organic layer was separated and dried over sodium sulfate. After filtration and concentration in vacuo, the residue was purified by preparative HPLC (acetonitrile/water gradient with 0.1% TFA) to afford the desired compound 21 as a mixture of enantiomers.

¹H NMR(400MHz,DMSO-d₆)12.59(s,1H),10.34(t,J＝5.9Hz,1H),8.50(s,1H),7.35–7.04(m,2H),5.45(d,J＝5.2Hz,1H),5.09(dt,J＝7.6,5.6Hz,1H),4.64–4.54(m,1H),4.49(dd,J＝14.6,5.7Hz,1H),3.95–3.83(m,2H),2.78–2.70(m,1H),2.64–2.55(m,1H),2.28–2.16(m,1H),1.01–0.88(m,1H),0.87–0.73(m,3H).LCMS-ESI⁺(m/z):[M+H]⁺C₂₁H₁₉F₃N₃O₅Calculated value 450.13; found 450.2.

Example 22

Preparation of Compound 22

Step 1

To a 50mL 1-necked round bottom flask was added reactant 22-A (0.50g, 2.31mmol), 6-B (0.80g, 2.31mmol) and NaHCO in ethanol (10mL) and water (10mL)₃(0.39g, 4.6 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated, redissolved in EtOAc (100mL), washed with water (2X), and Na₂SO₄And (5) drying. After concentration, the crude product was dissolved in 4N HCl/dioxane (11ml) and stirred at room temperature for 3 hours to Boc. The reaction mixture was concentrated again. The residue and DBU (1.58g, 10.4mmol) were dissolved inEtOH (10 mL). Heat to 50 ℃ for 20 minutes. After concentration, the crude product was purified by silica gel column chromatography eluting with hexane-EtOAc to afford 22-C. LCMS-ESI⁺(m/z):[M+H]⁺(ii) a Measured value is 399.

Step 2

To a 50mL 1-necked round bottom flask was added reactant 22-C (0.10g, 0.25mmol) in THF (5mL) and MeOH (5 mL). To the reaction solution was added 1N KOH in water (1.0 mL). The reaction mixture was stirred at room temperature for 1 hour. After acidification with 1N HCl, the solution was concentrated to completely remove the solvent and the crude acid was used in the next step without further purification. The crude acid (0.25mmol), 2,4, 6-trifluorophenylmethylamine (0.08g, 0.5mmol), DIPEA (0.169g, 1.3mmol) and HATU (0.20g, 0.52mmol) in DCM (10ml) were stirred at room temperature for 1 hour. The reaction mixture was concentrated, redissolved in EtOAc (50mL) and treated with saturated NaHCO₃(2x), saturated NH₄Cl washing, Na washing₂SO₄And (5) drying. After concentration, the crude product was purified by silica gel column chromatography eluting with hexane-EtOAc to afford 22-D. LCMS-ESI⁺(m/z):[M+H]⁺(ii) a Found 514.

Step 3

To a 50mL 1-necked round bottom flask was added a solution of reactant 22-D (0.10g, 0.19mmol) in TFA (2 mL). The reaction mixture was stirred at room temperature for 30 minutes. The solution was concentrated and the residue was purified by CombiFlash (12g column, spent column) using EtOAc-20% MeOH in EtOAc as eluent to give compound 22.¹H NMR (400MHz, chloroform-d) 11.70(s,1H),10.65-10.18(m,1H),8.27(s,1H),7.26(m,1H),6.90(td, J ═ 9.7,6.4Hz,1H),4.89(s,1H),4.60(d, J ═ 6.0Hz,2H),4.09(dd, J ═ 11.4,2.6Hz,1H),3.96-3.66(m,2H),2.68(s,1H),2.15-1.43(m,6H).¹⁹F NMR (376MHz, chloroform-d) 120.53-120.85 (m,1F), -134.68-136.79 (m,1F), -142.26-144.11 (m,1F)⁺(m/z):[M+H]⁺Found 424.

Example 23

Preparation of Compound 23

Step 1

A solution of amide 21-F (0.102g, 0.217mmol) in 2-methyl-THF (1mL) was treated with a THF solution of lithium isopropoxide (0.119mL, 2M solution, 0.239mmol) at room temperature. After a few minutes, an additional solution of lithium isopropoxide in THF (0.109mL, 2M solution, 0.217mmol) was added. After 3 hours, the reaction mixture was partitioned between dichloromethane and 0.5M HCl. The layers were separated and the aqueous layer was extracted again with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered and concentrated to give isopropyl ester 23-a, which was used as crude product in the next step: LCMS-ESI⁺(m/z):[M+H]⁺C₂₃H₂₆F₃N₂O₇Calculated value 499.17; found 499.1.

Step 2

Isopropyl 23-A (0.102g, 0.205mmol) was dissolved in acetonitrile (1mL) and treated with methanesulfonic acid (0.004mL, 0.06mmol), acetic acid (0.1mL) and water (0.009mL, 0.51 mmol). The reaction mixture was capped and stirred at 75 ℃ for 16 hours to give a crude solution of lactol 23-B: LCMS-ESI⁺(m/z):[M+H]⁺C₂₂H₂₄F₃N₂O₇Calculated value 485.15; found 485.1.

Step 3

A portion of the crude step 2 lactol solution (0.5mL solution,0.1mmol) was diluted with acetonitrile (0.3mL), treated with methylamine (0.200mL, 2M in THF, 0.40mmol), capped and stirred at 50 ℃. After 2 hours, the reaction mixture was cooled and washed withMagnesium bromide (0.074g, 0.4mmol) was treated. The mixture was covered and stirred at 50 ℃ for 15 minutes, cooled and partitioned between dichloromethane and 0.5M HCl. The organic layer was separated and dried over sodium sulfate. After filtration and concentration in vacuo, the residue was purified by preparative HPLC (acetonitrile/water gradient with 0.1% TFA) to afford the desired compound 23 as a mixture of enantiomers:¹h NMR (400MHz, chloroform-d) 10.34(s,1H),8.40(s,1H),6.66(t, J ═ 8.3Hz,2H),5.39(d, J ═ 5.4Hz,1H), 4.80-4.58 (m,3H), 4.22-3.97 (m,2H),3.13(s,3H), 2.74-2.57 (m,1H), 2.22-2.04 (m,1H), LCMS-ESI⁺(m/z):[M+H]⁺C₁₉H₁₇F₃N₃O₅Calculated value 424.11; found 424.1.

Example 24

Preparation of Compound 24

Compound 24 was prepared in a similar manner to compound 23, except that in the final step, propylamine was used at 75 ℃ instead of methylamine to give 24, a mixture of its enantiomers.¹H NMR (400MHz, chloroform-d) 10.41(s,1H),8.44(s,1H),6.66(t, J ═ 8.2Hz,2H),5.44(d, J ═ 5.2Hz,1H), 4.82-4.52 (m,3H), 4.23-3.99 (m,2H), 3.76-3.58 (m,1H), 3.58-3.40 (m,1H), 2.77-2.57 (m,1H), 2.31-2.12 (m,1H), 1.87-1.56 (m,2H), 1.49-1.35 (m,1H),0.98(t, J ═ 7.4Hz,3H), LCMS-ESI⁺(m/z):[M+H]⁺C₂₀H₁₉F₃N₃O₅Calculated value 452.14; found 452.1.

Example 25

Preparation of Compounds 25a and 25b

Steps 1 and 2

Diester 21-E (3.80g, 11.1mmol) was stirred in THF (14mL) and methanol (11mL) until nearly dissolved. Lithium hydroxide (6.97mL of a 2M aqueous solution, 13.9mmol) was added portionwise over about 2 hours. After stirring for an additional 1 hour, the reaction mixture was treated with 0.5M HCl (35mL) and ethyl acetate (200 mL). The organic layer was separated. The aqueous phase was treated with brine and extracted again with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated to give the crude acid, which was used for further reaction: LCMS-ESI⁺(m/z):[M+H]⁺C₁₄H₁₈NO₈Calculated value 328.10; found 328.1.

The crude acid (0.500g, 1.53mmol) in methyl-THF (6mL) was added to lithium isopropoxide, which was obtained by treating isopropanol (0.351mL) with n-BuLi (1.528mL, 2.5M in hexane) in methyl-THF at 0 deg.C. The reaction mixture was warmed to room temperature, after 16 hours, the mixture was partitioned between 0.5M HCl and ethyl acetate, the layers were separated, the aqueous layer was extracted again with ethyl acetate, the combined organics were dried over sodium sulfate, filtered and concentrated to the desired isopropyl ester 25-J:

LCMS-ESI⁺(m/z):[M+H]⁺C₁₆H₂₂NO₈calculated value 356.13; found 356.1.

Step 3

Isopropyl 25-J (0.543g, 1.53mmol) and (3-chloro-2, 4-difluorophenyl) methylamine (0.326g, 1.83mmol) were suspended in acetonitrile and treated with DIEA (0.546mL, 3.06mmol) and HATU 0.697g, 1.834 mmol). The reaction mixture was capped and stirred at room temperature. After 16 h, the mixture was concentrated and partitioned between ethyl acetate and 0.5M HCl. Separating the layers for reuseThe aqueous layer was extracted with ethyl acetate. The combined organics were dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography on silica gel (10-60% ethyl acetate: hexanes) to afford the desired amide 25-K: LCMS-ESI⁺(m/z):[M+H]⁺C₂₃H₂₆ClF₂N₂O₇Calculated value 515.14; found 515.2.

Steps 4 and 5

Steps 4 and 5 were performed in a similar manner to steps 2 and 3 of compound 23, except that ethylamine was used instead of methylamine in the final step, providing a mixture of enantiomers which were separated by chiral HPLC on a ChiralPak AD-h (etoh) column to afford the individual enantiomers 25a and 25 b. For 25a:¹H NMR(400MHz,DMSO-d6)12.81(s,1H),10.40(t,J＝6.2Hz,1H),8.54(s,1H),7.38(td,J＝8.3,6.2Hz,1H),7.29(td,J＝8.7,1.3Hz,1H),5.57(d,J＝5.5Hz,1H),5.26–5.14(m,1H),4.68–4.48(m,2H),4.01–3.90(m,2H),3.64–3.42(m,2H),2.65–2.53(m,1H),2.21–2.05(m,1H),1.16(t,J＝7.1Hz,3H).

LCMS-ESI⁺(m/z):[M+H]⁺C₂₀H₁₉ClF₂N₃O₅: calculated value 454.2; found 454.1. For 25b:¹H NMR(400MHz,DMSO-d6)12.81(s,1H),10.40(t,J＝6.4Hz,1H),8.54(s,1H),7.44–7.33(m,1H),7.29(td,J＝8.7,1.3Hz,1H),5.57(d,J＝5.6Hz,1H),5.20(td,J＝9.8,9.3,5.7Hz,1H),4.68–4.49(m,2H),3.95(m,2H),3.63–3.44(m,2H),2.65–2.53(m,1H),2.20–2.07(m,1H),1.17(t,J＝7.1Hz,4H).

LCMS-ESI⁺(m/z):[M+H]⁺C₂₀H₁₉ClF₂N₃O₅: calculated value 454.2; found 454.1.

Example 26

Preparation of Compounds 26a and 26b

Compounds 26a and 26b were prepared in a similar manner to compound 23, except ethylamine was used instead of methylamine in the final step to give a mixture of enantiomers which were separated by chiral HPLC on a ChiralPak AD-H column (EtOH) to give the single enantiomers 26a and 26 b.

For 26a:¹H NMR(400MHz,DMSO-d6)12.79(s,1H),10.44–10.25(m,1H),8.52(s,1H),7.33–7.07(m,2H),5.56(d,J＝5.4Hz,1H),5.29–5.09(m,1H),4.59(dd,J＝14.6,5.2Hz,1H),4.50(dd,J＝14.2,5.7Hz,1H),4.01–3.89(m,2H),3.61–3.42(m,2H),2.56(s,1H),2.09(s,1H),1.16(t,J＝7.1Hz,3H).

LCMS-ESI⁺(m/z):[M+H]⁺C₂₀H₁₈F₃N₃O₅calculated value 438.13; found 438.2. For 26b:¹H NMR(400MHz,DMSO-d6)12.79(s,1H),10.35(t,J＝6.0Hz,1H),8.52(s,1H),7.20(t,J＝8.7Hz,2H),5.56(d,J＝5.4Hz,1H),5.19(td,J＝8.5,5.5Hz,1H),4.59(dd,J＝14.8,6.0Hz,1H),4.50(dd,J＝14.6,5.7Hz,1H),4.01–3.87(m,2H),3.63–3.42(m,2H),2.64–2.52(m,1H),2.20–2.04(m,1H),1.16(t,J＝7.1Hz,3H).

LCMS-ESI⁺(m/z):[M+H]⁺C₂₀H₁₈F₃N₃O₅calculated value 438.13; found 438.2.

Example 27

Preparation of Compound 27

Step 1

Isopropyl ester 25-J (0.232g, 0.65mmol) was dissolved in acetonitrile (1.8mL), and methanesulfonic acid was added(0.013mL) and water (0.002mL) in acetic acid (0.2 mL). The mixture was covered and stirred at 75 ℃. After 16 hours, the reaction mixture was cooled to afford the desired lactol 27-N, and the crude product was used in the next step: LCMS-ESI⁺(m/z):[M+H]⁺C₁₅H₂₀NO₈Calculated value 342.12; found 342.1.

Step 2

A solution of crude lactol 27-N (0.119g, 0.35mmol) from the previous step (0.097g, 0.70mmol) was treated with potassium carbonate (0.097g, 0.70mmol) and methylamine (0.467mL, 2M in THF, 0.70g)1mL) was added with a lid and stirred at 50 ℃. After 50 min, the reaction mixture was cooled and treated with TFA (0.134mL, 1.7 mmol). The mixture was concentrated onto silica gel and purified by flash chromatography (5% EtOH: dichloromethane) to give the acid 27-O: LCMS-ESI⁺(m/z):[M+H]⁺C₁₃H₁₅N₂O₆Calculated value 295.09; found 295.1.

Step 3

Acid 27-O (0.044g, 0.150mmol) and (3-chloro-2, 4-difluorophenyl) methylamine (0.053g, 0.30mmol) were suspended in acetonitrile and treated with DIEA (0.053mL, 0.30mmol) and HATU (0.068g, 0.179 mmol). The reaction mixture was stirred at room temperature for a few minutes and stored at 10 ℃. After 3 days, the crude amide was treated with magnesium bromide (0.083g, 0.45mmol) and stirred at 50 ℃ for 10 minutes. An additional portion of acetonitrile (1mL) and magnesium bromide (0.041mg) was added and the mixture was stirred at 50 ℃ for several minutes. After cooling, the reaction mixture was partitioned between dichloromethane and 0.5M HCl. The layers were separated and the organic layer was dried over sodium sulfate, filtered and concentrated. Flash chromatography on silica gel (0-10% ethanol: dichloromethane) afforded the desired product 27 as a mixture of enantiomers: LCMS-ESI⁺(m/z):[M+H]⁺C₁₃H₁₅N₂O₆Calculated value 440.08; found 440.2.

Example 28

Preparation of Compound 28

Step 1

Compound 28-A (501mg, 2.502mmol), pyrone 1-B (865mg, 2.498mmol) and NaHCO₃(424mg, 5.047mmol) in a mixture of water (5mL) and ethanol (5mL) was stirred at room temperature after 1.25 h, the reaction mixture was diluted with water, extracted with ethyl acetate (× 2). after the extracts were washed with water, the organic fractions were combined and dried (Na)₂SO₄) And (4) concentrating. The residue was dried under vacuum for 30 minutes, dissolved in dichloromethane (2mL) and treated with 4N HCl in dioxane (6mL) for 1 hour. The solution was concentrated, co-evaporated with toluene (x1) and dried in vacuo for 30 min. A mixture of the residue and DBU (1.5mL, 10.03mmol) in toluene (15mL) was stirred in the 100 ℃ bath. After the mixture was cooled to room temperature and dissolved with dichloromethane, the solution was concentrated. The residue was purified by silica gel column chromatography (80g column) using ethyl acetate-20% methanol in ethyl acetate as eluent to give compound 28-C.¹H NMR (400MHz, chloroform-d) 8.41(s,1H),7.66-7.53(m,2H),7.37-7.27(m,3H),6.69(s,1H),5.41(d, J ═ 10.0Hz,1H),5.20(d, J ═ 10.0Hz,1H),4.43(q, J ═ 7.2Hz,3H),4.14(m,1H),2.45-2.20(m,2H),2.11-1.80(m,4H),1.42(t, J ═ 7.1Hz,3H), lcm-ESI⁺(m/z):[M+H]⁺C₂₁H₂₃N₂O₅Calculated value 383.16; found 383.24.

Step 2

After stirring a mixture of reactant 28-C (50mg, 0.131mmol) in THF (1mL) and ethanol (1mL) at room temperature and adding 1N KOH (0.26mL) for 30 minutes, the reaction mixture was diluted with water and washed with diethyl ether (× 1). after acidifying the aqueous fraction with 1N HCl (0.3-0.4mL), the product was usedDichloromethane (× 3) extraction the combined extracts were dried (Na)₂SO₄) Concentrated and dried in vacuo to give the crude acid. A mixture of the crude acid, 2,4, 6-trifluorobenzylamine (28mg, 0.174mmol) and HATU (76mg, 0.200mmol) in dichloromethane (5mL) was stirred at room temperature while DIPEA (0.2mL, 1.148mmol) was added. After 30 min, the reaction mixture was diluted with ethyl acetate and saturated NH₄Cl (x 2), water (x1), saturated NaHCO₃(x 2) and brine (x 1). After extraction of the aqueous layer with ethyl acetate (× 1), the two organic fractions were combined and dried (Na)₂SO₄) And concentrated. The residue was purified by column chromatography on silica gel (12g column) using ethyl acetate as eluent to give compound 28-D.¹H NMR (400MHz, chloroform-d) 10.40(s,1H),8.48(s,1H),7.59-7.53(m,2H),7.32(dddd, J ═ 12.2,7.0,4.5,2.3Hz,3H),6.74-6.60(m,2H),6.43(s,1H),5.37(d, J ═ 10.2Hz,1H),5.20(d, J ═ 10.1Hz,1H),4.75-4.58(m,2H),4.35(s,1H),4.07(t, J ═ 4.1Hz,1H),2.31(s,1H),2.11-1.77(m,5H).¹⁹F NMR (376MHz, chloroform-d) -109.05(s,1F), -111.85(s,2F). LCMS-ESI⁺(m/z):[M+H]⁺C₂₆H₂₃F₃N₃O₄Calculated value 498.16; found 498.10.

Step 3

Compound 28-D (35mg, 0.070mmol) was dissolved in trifluoroacetic acid (1mL) at room temperature and stirred at room temperature after 30 min, the solution was concentrated, the residue was dissolved in dichloromethane, after the solution was washed with 0.1N HCl (× 1), the aqueous layer was extracted with dichloromethane (× 2), the organic fractions were combined and dried (Na)₂SO₄) And concentrated.

The residue was purified by column chromatography on silica gel (12g column) using dichloromethane-20% methanol in dichloromethane as eluent to give compound 28.¹H NMR (400MHz, chloroform-d) 12.35(s,1H),10.47(t, J ═ 5.7Hz,1H),8.55(s,1H),7.40(s,1H),6.74-6.52(m,2H),4.70(dd, J ═ 14.5,5.8Hz,1H),4.61(dd, J ═ 14.5,5.6Hz,1H),4.52(td, J ═ 8.7,4.5Hz,1H),4.35-4.18(m,1H),2.32(dq, J ═ 11.8,7.6,6.3Hz,1H),2.22-1.97(m,3H),1.90(dq, J ═ 17.2,10.0,8.1, 2H).¹⁹F NMR(376MHz, chloroform-d) -108.93(ddd, J ═ 15.1,8.6,6.0Hz,1F), -112.07(t, J ═ 6.9Hz,2F)⁺(m/z):[M+H]⁺C₁₉H₁₇F₃N₃O₄Calculated value 408.12; found 408.12.

Example 29

Preparation of Compound 29

Step 1

To a mixture of compound 28-C (129mg, 0.337mmol) in THF (3mL) at room temperature was added 60% NaH (30mg, 0.75mmol) for 5 minutes, then MeI (0.03mL, 0.482mmol) was added, after stirring at room temperature for 1 hour, water (about 3mL) was added to the mixture after about 15 minutes, 1N KOH (0.5mL) was added to complete the hydrolysis, after 10 minutes, the reaction mixture was diluted with water, washed with diethyl ether (× 1), the aqueous layer was 1N HCl (HCl) (3mL)1mL) and the product extracted with dichloromethane (× 3) after washing the extracts with water (x1), the combined extracts were dried (Na)₂SO₄) And concentrating to obtain the crude acid 29-B. A mixture of crude acid 29-B, 2,4, 6-trifluorobenzylamine (75mg, 0.465mmol) and HATU (195mg, 0.513mmol) in dichloromethane (5mL) was stirred at room temperature while DIPEA (0.55mL, 3.158mmol) was added. After 30 min, the reaction mixture was diluted with ethyl acetate and saturated NH₄Cl (x 2), water (x1), saturated NaHCO₃(x 2) and brine (x 1). After extraction of the aqueous layer with ethyl acetate (× 1), the two organic fractions were combined and dried (Na)₂SO₄) And concentrated. The residue was purified by silica gel column chromatography (12g column) using ethyl acetate as eluent to give 126mg of partially purified compound 29-C. LCMS-ESI⁺(m/z):[M+H]⁺C₂₇H₂₅F₃N₃O₄Calculated value 512.18; found 512.16.

Step 2

Partially purified compound 29-C (126mg) was dissolved in TFA (1.5mL) at room temperature and stirred at room temperature after 30 minutes, the solution was concentrated, the residue was dissolved in DMF, then filtered (about 2.8 mL.) the solution was poured onto preparative HPLC₂SO₄) And concentrated to give compound 29.¹H NMR (400MHz, chloroform-d) 12.79(s,1H),10.42(t, J ═ 5.7Hz,1H),8.38(s,1H),6.78-6.45(m,2H),4.69(dd, J ═ 14.5,5.8Hz,1H),4.64-4.55(m,1H),4.50(q, J ═ 6.9Hz,1H),4.10(q, J ═ 4.6Hz,1H),3.11(s,3H),2.31(dq, J ═ 14.0,7.3Hz,1H),2.10(dt, J ═ 7.3,4.4Hz,2H),1.99(m,1H),1.91-1.76(m,2H).¹⁹F NMR (376MHz, chloroform-d) -109.22(p, J ═ 7.7Hz,1F), -111.83-112.22 (m,2F)⁺(m/z):[M+H]⁺C₂₀H₁₉F₃N₃O₄Calculated value 422.13; found 422.19.

Example 30

Preparation of Compound 30

Step 1

The mixture of 30-A (553mg, 2.556mmol), pyrone 6-B (619mg, 2.556mmol) and NaHCO₃A mixture of (435mg, 5.178mmol) in water (5mL) and ethanol (5mL) was stirred at room temperature. After 30 minutes, the reaction mixture was concentrated to remove most of the solvent, and the residue was mixed with dichloromethane (about 40mL) and vigorously stirred, then dried (MgSO)₄). The dried solution was concentrated. The residue was dissolved in dichloromethane (2mL),and treated with 4N HCl in dioxane (6 mL). After 40 minutes, the mixture was concentrated and dried under vacuum overnight. A mixture of the residue and DBU (1.9mL, 12.71mmol) in toluene (19mL) was stirred at 100 ℃. After 30 minutes, the reaction mixture was cooled to room temperature, dissolved in dichloromethane and concentrated. The residue was purified by column chromatography on silica gel (40g column) using ethyl acetate-20% methanol in ethyl acetate as eluent to give impure compound 30-C. Impure compound 30-C was dissolved in DMF and purified by preparative HPLC to give compound 30-C as a 1:1 mixture with trifluoroacetic acid.¹H NMR (400MHz, chloroform-d) 9.92(s,1H),8.33(s,1H),7.67(s,1H),4.51(dt, J ═ 12.2,4.1Hz,1H),4.21-4.04(m,3H),3.95(s,3H),3.84(s,3H),3.73(d, J ═ 12.8Hz,1H),3.54(td, J ═ 12.3,2.2Hz,1H),2.24(qd, J ═ 12.6,4.8Hz,1H),1.94(dd, J ═ 13.1,4.9Hz,1H), s-ESI⁺(m/z):[M+H]⁺C₁₄H₁₇N₂O₆Calculated value 309.11; found 309.17.

Step 2

To a mixture of compounds 30-C, TFA (85mg, 0.201mmol) and 60% NaH (40mg, 1mmol) was added THF (3mL) at room temperature. After 5 min, MeI (0.04mL, 0.643mmol) was added. After stirring at room temperature for about 40 minutes, DMF (1mL) was added. After the mixture was stirred at room temperature overnight, 1N HCl (about 1.5mL) was added to the reaction mixture, and the resulting mixture was concentrated to almost dryness to give a crude acid.

A mixture of the crude acid, 2,4, 6-trifluorobenzylamine (96mg, 0.596mmol) and HATU (204mg, 0.537mmol) in dichloromethane (3mL) was stirred at room temperature and DIPEA (0.5mL, 2.871mmol) was added. After 30 min, the reaction mixture was diluted with ethyl acetate and saturated NH₄Cl (x 2), water (x1), saturated NaHCO₃(x 2) and brine (x 1). After extraction of the aqueous layer with ethyl acetate (× 1), the two organic fractions were combined and dried (Na)₂SO₄) And concentrated. The residue was purified by silica gel column chromatography (12g column) using ethyl acetate-20% methanol in ethyl acetate as an eluent to give compound 30-D.¹H NMR(400MHz, chloroform-d) 10.37(d, J ═ 7.3Hz,1H),8.46(s,1H),6.81-6.54(m,2H),4.63(d, J ═ 5.6Hz,2H),4.34(d, J ═ 11.1Hz,1H),4.31-4.22(m,1H),4.02(s,3H),4.01-3.92(m,1H),3.86(d, J ═ 3.2Hz,1H),3.65(dd, J ═ 13.4,1.9Hz,1H),3.62-3.55(m,1H),3.22(s,3H),2.23(qd, J ═ 10.8,4.5Hz,1H),2.01-1.90(m,1H).¹⁹F NMR (377MHz, chloroform-d) -108.92(s,1F), -112.01(s,2F). LCMS-ESI⁺(m/z):[M+H]⁺C₂₁H₂₁F₃N₃O₅Calculated value 452.14; measured value 452.11.

Step 3

To a solution of compound 30-D (48mg, 0.106mmol) in MeCN (3mL) at room temperature was added MgBr₂(60mg, 0.326mmol) and the resulting mixture was stirred at 50 ℃. After 30 minutes, the reaction mixture was stirred at 0 ℃ and 1N HCl (g/l) was added1mL), the mixture was brought into solution, diluted with water and extracted with dichloromethane (× 3) the combined extracts were dried (Na)₂SO₄) And concentrated. The residue was purified by silica gel column chromatography (12g column) using dichloromethane and 20% methanol in dichloromethane as eluent to give compound 30.¹H NMR (400MHz, chloroform-d) 10.37(d, J ═ 7.3Hz,1H),8.46(s,1H),6.81-6.54(m,2H),4.63(d, J ═ 5.6Hz,2H),4.34(d, J ═ 11.1Hz,1H),4.31-4.22(m,1H),4.02(s,3H),4.01-3.92(m,1H),3.86(d, J ═ 3.2Hz,1H),3.65(dd, J ═ 13.4,1.9Hz,1H),3.62-3.55(m,1H),3.22(s,3H),2.23(qd, J ═ 10.8,4.5Hz,1H),2.01-1.90(m,1H).¹⁹F NMR (377MHz, chloroform-d) -108.92(s,1F), -112.01(s,2F). LCMS-ESI⁺(m/z):[M+H]⁺C₂₀H₁₉F₃N₃O₅Calculated value 438.13; measured value 438.29.

Example 31

Preparation of Compound 31

Step 1

To a mixture of compound 30-C (97mg, 0.230mmol) and 60% NaH (46mg, 1.15mmol) was added THF (2mL) and DMF (0.5mL) at room temperature. After 5 minutes, CF was added₃CH₂OTf (0.1mL, 0.694 mmol). After stirring at room temperature for about 40 minutes, additional DMF (1mL) was added. After 2 hours, water (about 2mL) was added to the reaction mixture, and after about 15 minutes at room temperature, the mixture was stirred in an ice bath while 1N KOH (0.5mL) was added. After about 30 minutes, the resulting mixture was acidified with 1N HCl (2mL) and concentrated to near dryness to give the crude acid.

A mixture of the crude acid, 2,4, 6-trifluorobenzylamine (96mg, 0.596mmol) and HATU (272mg, 0.715mmol) in dichloromethane (3mL) was stirred at room temperature while DIPEA (0.5mL, 2.871mmol) was added. After 30 min, the reaction mixture was diluted with ethyl acetate and saturated NH₄Cl (x 2), water (x1), saturated NaHCO₃(x 2) and brine (x 1). After extraction of the aqueous layer with ethyl acetate (× 1), the two organic fractions were combined and dried (Na)₂SO₄) And concentrated. The residue was purified by silica gel column chromatography (12g column) using ethyl acetate-20% methanol in ethyl acetate as eluent to give compound 31-B, which contained 1015% of impurities.¹H NMR (400MHz, chloroform-d) 10.30(s,1H),8.49(s,1H),6.64(t, J ═ 8.1Hz,2H),5.16(dq, J ═ 18.5,9.5Hz,1H),4.71-4.50(m,2H),4.43(dt, J ═ 11.8,3.6Hz,1H),4.34(d, J ═ 14.7Hz,1H),4.06(s,1H),4.02(s,4H),3.79(dq, J ═ 16.3,8.2Hz,1H),3.69(d, J ═ 14.3Hz,1H),3.62(dd, J ═ 11.9,2.6Hz,1H),2.23-2.07(m,1H),1.97(dd, 4.12H, 1H).¹⁹F NMR (377MHz, chloroform-d) -69.91(t, J ═ 8.8Hz,3F), -71.39, -73.29, -108.51(s,1F), -112.21(t, J ═ 7.0Hz,2F)⁺(m/z):[M+H]⁺C₂₂H₂₀F₆N₃O₅Calculated value520.13, respectively; found 520.22.

Step 2

To a solution of reactant 31-B (32mg, 0.062mmol) in MeCN (3mL) at room temperature was added MgBr₂(34mg, 0.185mmol), the resulting mixture was stirred at 50 deg.C after 30 minutes, the reaction mixture was stirred at 0 deg.C and 1N Cl was added to obtain a mixture solution (ca. 1 mL). the resulting solution was further diluted with water and the product was then extracted with dichloromethane (× 3). the combined extracts were dried (Na, 0.185mmol)₂SO₄) And concentrated. The residue was purified by preparative HPLC and lyophilized to give compound 31 as a mixture with CF₃1:1 mixture of COOH.¹H NMR (400MHz, chloroform-d) 10.50(t, J ═ 5.8Hz,1H),8.59(s,1H),6.67(t, J ═ 8.1Hz,2H),5.09(dq, J ═ 18.3,9.2Hz,1H),4.72(dd, J ═ 14.5,5.4Hz,1H),4.63(dd, J ═ 14.5,5.2Hz,1H),4.43(t, J ═ 13.0, 2H),4.13(s,1H),4.06(d, J ═ 11.8Hz,1H),3.80(dq, J ═ 17.1,9.1,8.6Hz,1H),3.75-3.58(m,2H),2.16(s,1H),1.94(d, 13H, 1H).¹⁹FNMR (377MHz, chloroform-d) -69.07(t, J ═ 8.6Hz,3F), -76.38(s,3F), -108.45(m,1F), -112.06(m,2F)⁺(m/z):[M+H]⁺C₂₁H₁₈F₆N₃O₅Calculated value 506.12; found 506.33.

Example 32

Preparation of Compound 32

Step 1

Compound 32-A (2010mg, 17.160mmol) and Boc₂A solution of O (4128mg, 18.910mmol) in methanol (40mL) was stirred at 0 deg.C while adding NEt₃(2.9mL, 20.81 mmol). The resulting mixture was stirred at 0 ℃ for 2 hours and then at room temperature for 17 hours. Concentrating the solution, dissolving the residue in ethyl acetateIn ester, then washed with water (× 2) after extraction of the aqueous fraction with ethyl acetate (× 1), the organic fractions are combined and dried (Na)₂SO₄) And concentrated. The residue was purified by silica gel column chromatography (120g column) using hexane-ethyl acetate as an eluent to give compound 32-B.¹H NMR (400MHz, chloroform-d) 4.67(s,1H),4.01(dd, J ═ 11.3,4.2Hz,1H),3.91(dt, J ═ 11.7,4.5Hz,1H),3.65(q, J ═ 7.1,6.6Hz,1H),3.47(br,1H),3.44(ddd, J ═ 12.0,9.4,3.1Hz,1H),3.24-3.08(m,1H),2.01(dtd, J ═ 13.7,4.7,3.1Hz,1H),1.64(dtd, J ═ 13.4,9.1,4.3Hz,1H),1.45(s,9H), s-ESI⁺(m/z):[M+H-C₄H₈]⁺C₆H₁₂NO₄Calculated value 162.08; found 161.93.

Step 2

A solution of compound 32-B (2493mg, 11.47mmol) and triethylamine (1.95mL, 13.99mmol) in dichloromethane (40mL) was stirred at 0 deg.C and methanesulfonyl chloride (1mL, 12.92mmol) was added dropwise. After 20 minutes at 0 ℃, the mixture was stirred at room temperature for 30 minutes. The reaction mixture was diluted with ethyl acetate and washed with water. After extraction of the aqueous layer with ethyl acetate (× 1), the organic fractions were combined and dried (Na)₂SO₄) Concentrating, and vacuum drying to obtain compound 32-C.¹H NMR (400MHz, chloroform-d) 4.96(s,1H),4.74(td, J ═ 6.7,4.0Hz,1H),4.00(dd, J ═ 11.9,3.6Hz,1H),3.86(ddd, J ═ 11.5,7.7,3.5Hz,1H),3.66(s,1H),3.60(ddd, J ═ 11.4,6.6,3.9Hz,1H),3.45(dd, J ═ 11.9,5.9Hz,1H),3.09(s,3H),2.19(ddd, J ═ 12.2,8.0,4.0Hz,1H),1.93(d, J ═ 13.3Hz,1H),1.45(s,9H), ESI-s-ESI)⁺(m/z):[M+H-C₄H₈]⁺C₇H₁₄NO₆S, calculating value 240.05; found 239.73.

Step 3

A mixture of compound 32-C (3389mg, 11.47mmol), sodium acetate (1890mg, 23.04mmol) and sodium azide (1496mg, 23.01mmol) in DMF (20mL) was stirred at a bath temperature of 95 ℃ for 6.5 hours, the mixture was diluted with water, the product was extracted with ethyl acetate (× 2), the extracts were washed with water (× 1), combined, dried (Na)₂SO₄) And (4) concentrating. The residue was purified by silica gel column chromatography (120g column) using hexane-ethyl acetate as an eluent to give compound 32-D.¹H NMR (400MHz, chloroform-d) 4.82(s,1H),3.89(m,2H),3.74m,1H),3.62(dt, J ═ 9.6,4.9Hz,2H),3.51(dd, J ═ 11.4,7.5Hz,1H),2.01-1.82(m,2H),1.46(s, 9H).

Step 4

The compound 32-D (2.066g, 8.528mmol) and PtO₂A mixture of (201mg, 0.885mmol) in ethanol (30mL) in H₂Stirring under an atmosphere. After 2.5 hours, the mixture was filtered through celite. Washed with ethanol (about 10mL), and the filtrate and washings were concentrated to give crude amine.

A mixture of crude amine, compound 6-B (2070mg, 8.547mmol) and sodium bicarbonate (1432mg, 17.05mmol) in water (ca. 15mL) and ethanol (ca. 20mL) was stirred at room temperature. After 30 minutes, the reaction mixture was concentrated to remove most of the solvent and the residue was dissolved in dichloromethane (about 100 mL). The resulting mixture was dried (MgSO)₄) And after concentration, the residue was dissolved in dichloromethane (8mL) and treated with 4N HCl in dioxane (24 mL). After stirring at room temperature for 2.5 hours, the mixture was concentrated and dried in vacuo.

The residue and DBU (6.4mL, 42.64mmol) were dissolved in MeOH (50mL) and stirred at room temperature for 20 min. After dilution with toluene (ca. 20mL), the solution was concentrated and purified by silica gel column chromatography (120g column) using ethyl acetate-20% MeOH in ethyl acetate as eluent to give compound 32-E.¹H NMR (400MHz, chloroform-d) 8.27(d, J ═ 1.3Hz,1H),6.98(s,1H),4.43-4.29(m,1H),4.17-4.08(m,2H),4.08-4.05(m,2H),4.03(s,3H),3.90(s,3H),3.72(dd, J ═ 13.1,1.6Hz,1H),3.53(td, J ═ 12.4,2.2Hz,1H),2.26(qd, J ═ 12.7,4.9Hz,1H),1.93 (lcm, J ═ 13.3,4.8Hz,1H), s-ESI⁺(m/z):[M+H]⁺C₁₄H₁₇N₂O₆Calculated value 309.11; found 309.06.

Step 5

To a mixture of compound 32-E (251mg, 814mmol) and 60% NaH (132mg, 3.300mmol) was added THF (4mL) and DMF (2mL) at room temperature. After 5 minutes, CF was added₃CH₂OTf (0.35mL, 2.429 mmol). After stirring at room temperature for about 30 minutes, the reaction mixture was stirred at 0 ℃ while 1N KOH (2mL) was added. After 10 minutes, the resulting mixture was acidified with concentrated HCl (about 0.45mL) and concentrated to near dryness to give the crude acid.

A mixture of the crude acid, 2,4, 6-trifluorobenzylamine (153mg, 0.950mmol) and HATU (626mg, 1.647mmol) in dichloromethane (7mL) was stirred at room temperature while DIPEA (1mL, 5.741mmol) was added. After 30 min, the reaction mixture was diluted with ethyl acetate and saturated NH₄Cl (x 2), water (x1), saturated NaHCO₃(x 2), water (x1) and brine (x 1). After extraction of the aqueous layer with ethyl acetate (× 1), the two organic fractions were combined and dried (Na)₂SO₄) And concentrated. The residue was purified by column chromatography on silica gel (40g column) using hexane-ethyl acetate-20% MeOH in ethyl acetate as eluent to give compound 32-F.¹H NMR (400MHz, chloroform-d) 10.29(t, J ═ 5.3Hz,1H),8.44(s,1H),6.77-6.50(m,2H),5.15(dq, J ═ 18.4,9.5Hz,1H),4.72-4.56(m,2H),4.33(d, J ═ 14.4Hz,2H),4.09-3.98(m,2H),4.02(s,3H),3.79(dq, J ═ 16.3,8.3Hz,1H),3.72-3.65(m,1H),3.65-3.59(m,1H),2.28-2.09(m,1H),2.02-1.92(m,1H).¹⁹F NMR (376MHz, chloroform-d) -69.87(t, J ═ 8.8Hz,3F), -108.85(p, J ═ 7.5Hz,1F), -112.05(t, J ═ 6.9Hz,2F)⁺(m/z):[M+H]⁺C₂₂H₂₀F₆N₃O₅Calculated value 520.13; found 520.34.

Step 6

To a solution of compound 32-F (139mg, 0.268mmol) in MeCN (3mL) at room temperature was added MgBr₂(129mg, 0.701mmol), the resulting mixture stirred in a 50 ℃ bath for 30 minutes, the reaction mixture stirred at 0 ℃ and 1N HCl (ca. 1mL) was added to bring the mixture into solution, the resulting solution was further diluted with water and the product was extracted with dichloromethane (× 3). the combined extracts were dried (Na. RTM.)₂SO₄) And concentrated. The residue was purified by column chromatography on silica gel (24g column) using dichloromethane-20% MeOH in dichloromethane as eluent to give compound 32.¹H NMR (400MHz, chloroform-d) 11.84(s,1H),10.27(t, J ═ 5.9Hz,1H),8.41(s,1H),6.83-6.49(m,2H),5.08(dq, J ═ 15.6,9.2Hz,1H),4.76-4.54(m,2H),4.45(s,1H),4.39(d, J ═ 14.0Hz,1H),4.21-4.12(m,1H),4.08-4.00(m,1H),3.80(dt, J ═ 15.9,8.0Hz,1H),3.75-3.60(m,2H),2.17(d, J ═ 12.8Hz,1H),1.93(d, J ═ 13.0, 1H).¹⁹F NMR (376MHz, chloroform-d) -69.10(t, J ═ 8.5Hz,3F), -108.95(s,1F), -111.36-112.46 (m,2F)⁺(m/z):[M+H]⁺C₂₁H₁₈F₆N₃O₅Calculated value 506.12; found 506.31.

Example 33

Preparation of Compound 33

Step 1

To a mixture of compound 32-E (132mg, 428mmol) and 60% NaH (75mg, 1.875mmol) was added THF (2mL) and DMF (1mL) at room temperature. After 5 min, EtOTf (0.17mL, 1.311mmol) was added. After 1 hour, an additional 60% NaH (35mg, 0.875mmol) and EtOTf (0.08mL, 0.617mmol) were added. After 30 minutes, water (0.5mL) was added to the reaction mixture. After 30 min, the reaction mixture was concentrated and the residue was co-evaporated with toluene (× 1) to give the crude acid.

A mixture of the crude acid, 2,4, 6-trifluorobenzylamine (833mg, 0.515mmol) and HATU (327mg, 0.860mmol) in dichloromethane (4mL) was stirred at room temperature while DIPEA (0.55mL, 3.158mmol) was added. After 30 min, the reaction mixture was diluted with ethyl acetate and saturated NH₄Cl (x 2), water (x1), saturated NaHCO₃(x 2) and brine (x 1). After extraction with ethyl acetate (x1)After taking the aqueous layer, the two organic fractions were combined and dried (Na)₂SO₄) The residue was purified by preparative HPLC and the fractions containing the product were combined and concentrated to remove mecn the remaining aqueous mixture was neutralized with sodium bicarbonate, diluted with brine, the product was extracted with dichloromethane (× 3) after the extracts were washed with water (x1), the organic fractions were combined and dried (Na)₂SO₄) And concentrating to obtain a compound 33-B.

¹H NMR (400MHz, chloroform-d) 10.51-10.17(m,1H),8.44(s,1H),6.66(t, J ═ 8.1Hz,2H),4.74-4.54(m,2H),4.33(dt, J ═ 8.2,3.6Hz,1H),4.11(dt, J ═ 15.3,7.6Hz,1H),4.03(s,3H),4.01(m,1H),3.84(dq, J ═ 8.2,5.0,3.8Hz,2H),3.67(dtd, J ═ 11.9,8.9,7.7,4.1Hz,2H),3.37(dq, J ═ 14.2,7.1Hz,1H),2.37(dtd, J ═ 13.9, 3.7, 4.1Hz,2H),3.37 (ddq, J ═ 14.2,7.1Hz,1H),2.37 (ddd, 13.9, 3.0, 3.9, 1H), 3.1H, 1H.¹⁹F19F NMR (376MHz, chloroform-d) -108.99(p, J ═ 7.5Hz,1F), -111.82-112.20 (m,2F)⁺(m/z):[M+H]⁺C₂₂H₂₃F₃N₃O₅Calculated value 466.16; found 466.24.

Step 2

To a solution of compound 33-B (32mg, 0.062mmol) in MeCN (3mL) at room temperature was added MgBr₂(34mg, 0.185mmol), the resulting mixture was stirred in a 50 ℃ bath after 30 minutes, the reaction mixture was stirred at 0 ℃ and 1N Cl (ca. 1mL) was added to bring the mixture into solution, the resulting solution was further diluted with water and the product was extracted with dichloromethane (× 3)₂SO₄) And concentrated. The residue was purified by preparative HPLC and freeze dried to give compound 33, which is a mixture with CF₃1:1 mixture of COOH.¹H NMR (400MHz, chloroform-d) 10.57(d, J ═ 6.5Hz,1H),8.56(s,1H),6.67(dd, J ═ 8.8,7.5Hz,2H),4.76-4.57(m,2H),4.43(dt, J ═ 10.7,4.0Hz,1H),4.26(d, J ═ 13.6Hz,1H),4.15(dq, J ═ 14.6,7.3Hz,1H),4.05-3.92(m,2H),3.76-3.61(m,2H),3.42(dq, J ═ 14.2,7.0Hz,1H),2.40-2.16(m,1H),1.99-1.88(m,1H),1.26(t, J ═ 14.2,7.0Hz, 1H).¹⁹F NMR (376MHz, chloroform-d) -76.38(s,3F), -108.50(ddd, J ═ F)15.2,8.8,6.5Hz,1F),-112.04(t,J＝7.1Hz,2F).LCMS-ESI⁺(m/z):[M+H]⁺C₂₁H₂₁F₃N₃O₅Calculated value 452.14; found 452.43.

Example 34

Preparation of Compound 34

Step 1

To a mixture of compound 32-E (162mg, 0.525mmol) and 60% NaH (90mg, 2.25mmol) was added DMF (4mL) at 0 ℃. After 20 minutes, CHF was added₂CH₂OTf (about 0.22mL, 360mg, 1.681 mmol). After stirring at room temperature for about 15 minutes, the reaction mixture was stirred at 0 ℃ and 1N KOH (1mL) was added. After 10 min, the mixture was acidified with concentrated HCl (0.35mL) and concentrated to almost dryness to give the crude acid.

A mixture of the crude acid, 2,4, 6-trifluorobenzylamine (95mg, 0.590mmol) and HATU (400mg, 1.052mmol) in dichloromethane (5mL) was stirred at room temperature while adding DIPEA (0.65mL, 3.732 mmol). After 20 min, the reaction mixture was diluted with ethyl acetate and saturated NH₄Cl (x 2), water (x1, + some brine), saturated NaHCO₃(x 2) and brine (x 1). After extraction of the aqueous layer with ethyl acetate (× 1), the two organic fractions were combined and dried (Na)₂SO₄) And concentrated. The residue was purified by column chromatography on silica gel (40g column) using hexane-ethyl acetate-20% MeOH in ethyl acetate as eluent to give compound 34-B.¹H NMR (400MHz, chloroform-d) 10.30(t, J ═ 5.9Hz,1H),8.44(s,1H),6.73-6.56(m,2H),6.03(dddd, J ═ 57.1,54.5,6.4,2.2Hz,1H),4.73-4.50(m,3H),4.42-4.23(m,2H),4.03(s,3H),3.98(m,2H),3.65(ddt, J ═ 21.7,14.4,4.9Hz,3H),2.31-2.15(m,1H),1.99(dd, J ═ 14.0,3.8Hz,1H).¹⁹F NMR (376MHz, chloroform-d) -108.79(dq,J＝14.7,7.2,6.5Hz,1F),-112.08(t,J＝7.0Hz,2F),-120.33(ddt,J＝291.1,54.4,8.1Hz,1F),-123.23(dddd,J＝290.8,57.2,26.6,13.6Hz,1F).LCMS-ESI⁺(m/z):[M+H]⁺C₂₂H₂₁F₅N₃O₅Calculated value 502.14; found 502.19.

Step 2

To a solution of compound 34-B (86mg, 0.172mmol) in MeCN (3mL) at room temperature was added MgBr₂(84mg, 0.456mmol), the resulting mixture was stirred in a 50 ℃ bath for 30 minutes, after which the reaction mixture was stirred at 0 ℃ and 1N Cl was added to bring the mixture into solution, the resulting solution was further diluted with water, then the product was extracted with dichloromethane (× 3), the combined extracts were dried (Na. RTM.) and the solvent was evaporated to dryness₂SO₄) And concentrated. The residue was purified by column chromatography on silica gel (12g column) using dichloromethane-20% MeOH in dichloromethane, and the product containing fractions were combined and lyophilized to give compound 34.¹H NMR (400MHz, chloroform-d) 12.02(s,1H),10.27(t, J ═ 5.8Hz,1H),8.39(s,1H),6.78-6.49(m,2H),6.07(dddd, J ═ 56.8,54.3,6.3,2.2Hz,1H),4.69(dd, J ═ 14.5,5.9Hz,1H),4.59(dd, J ═ 14.5,5.6Hz,1H),4.52(ddd, J ═ 15.3,9.9,2.3Hz,1H),4.47-4.34(m,2H),4.02(dt, J ═ 12.0,3.7Hz,1H),3.75-3.59(m,3H),2.21 tq (m, 7, 1H), 11.86H, 1H),1.97 (m,1H).¹⁹F NMR (376MHz, chloroform-d) -108.99(ddd, J ═ 15.0,8.9,6.4Hz,1F), -112.11(t, J ═ 7.0Hz,2F), -119.30-120.56 (ddt, J ═ 293.0,52.7,9.4Hz,1F), -122.96(dddd, J ═ 293.0,57.3,25.9,13.9Hz,1F), -LCMS-ESI⁺(m/z):[M+H]⁺C₂₁H₁₉F₅N₃O₅Calculated value 488.12; found 488.34.

Example 35

Preparation of Compound 35

Step 1

A mixture of compound 32-B (2086mg, 9.601mmol), benzoic acid (2006mg, 16.43mmol), and triphenylphosphine (5560mg, 21.2mmol) in THF (40mL) was stirred in a 0 deg.C bath while DIAD (4.35mL, 22.09mmol) was added. After 5 minutes at 0 ℃, the mixture was stirred at room temperature for 22 hours. The solution was concentrated, and the residual syrup was partially purified by silica gel column chromatography (120g column) using ethyl acetate-hexane as an eluent to give a main fraction (5.324 g).

The main fraction was dissolved in THF (20mL) and MeOH (20mL) and stirred at 0 deg.C, 1N KOH (10mL) was added, after stirring at 0 deg.C for 1.25 h, the solution was stirred at room temperature for 1h, the solution was concentrated to about 1/2 volume, diluted with water (about 100mL) and then extracted with dichloromethane (2 × 100mL), after the extracts were washed with water (x1), the combined organic fractions were dried (Na)₂SO₄) And concentrated. The residue was purified by silica gel column chromatography (120g column) using hexane-ethyl acetate as an eluent to give compound 35-B.¹H NMR (400MHz, chloroform-d) 5.12(s,1H),3.96(dt, J ═ 8.1,3.8Hz,1H),3.84(dt, J ═ 10.6,5.0Hz,2H),3.70(dd, J ═ 11.9,5.2Hz,1H),3.57(dd, J ═ 11.5,3.1Hz,1H),3.47(ddd, J ═ 11.8,8.3,3.6Hz,1H),2.71(s,1H),1.94-1.78(m,1H),1.72(dtd, J ═ 13.7,8.4,4.1Hz,1H),1.44(s,9H), s-ESI⁺(m/z):[M+H-C₄H₈]⁺C₆H₁₂NO₄Calculated value 162.08; found 161.90.

Step 2

Compound 35-B (1824mg, 8.395mmol), phthalimide (2017mg, 13.71mmol) and PPh₃A mixture of (4872mg, 18.58mmol) in THF (50mL) was stirred in a 0 deg.C bath while DIAD (3.75mL, 19.05mmol) was added dropwise. After the addition, the mixture was stirred at 0 ℃ for 30 minutes and then at room temperature overnight. The mixture was concentrated to a syrup, dissolved in diethyl ether (about 200mL) and the insoluble material filtered. The filtrate was concentrated. The residue was purified by column chromatography on silica gel (120g column) using hexane-ethyl acetate as eluentTo obtain an impure phthalimide product. LCMS-ESI⁺(m/z):[M+H-C₄H₈]⁺C₁₄H₁₅N₂O₅Calculated value 291.10; found 291.08.

To a solution of the impure phthalimide product (3.309g) in ethanol (50mL) was added hydrazine hydrate (1.65mL, 33.92mmol) at room temperature, the resulting solution was stirred in a 70 ℃ bath for 3 hours, the mixture was diluted with ether, stirred at room temperature, and the insolubles were filtered off, the filtrate was concentrated, the residue was dissolved in water with about 1N HCl, washed with ethyl acetate (× 1), and washed with NaHCO₃The aqueous portion was neutralized with aqueous solution, then extracted with dichloromethane (× 3) and discarded the aqueous portion was saturated with NaCl, extracted again with dichloromethane (× 6), combined, and dried (Na)₂SO₄) And concentrating to obtain the compound 35-C. LCMS-ESI⁺(m/z):[M+H-C₄H₈]⁺C₆H₁₃N₂O₃Calculated value 161.09; found 161.00.

Step 3

Mixing compound 6-B (810mg, 3.345mmol), compound 35-C (724mg, 3.348mmol) and NaHCO₃A mixture of (566mg, 6.738mmol) in water (6mL) and EtOH (8mL) was stirred at room temperature. After 30 min, the reaction mixture was concentrated to remove most of the solvent and the residue was dissolved in dichloromethane (100 mL). The resulting mixture was dried (MgSO)₄) And concentrated. The concentrated residue was dissolved in dichloromethane (3mL) and treated with 4N HCl in dioxane (10 mL). After 2 hours, the mixture was concentrated and dried in vacuo.

The concentrated residue and DBU (2.5mL, 42.64mmol) were dissolved in MeOH (20mL) and stirred in a 50 deg.C bath. After 15 min, the solution was concentrated and the residue triturated with dichloromethane (20mL) with heating. The mixture was filtered and the insoluble compound 10-A was collected. The filtrate was purified by silica gel column chromatography (80g column) using ethyl acetate-20% MeOH in ethyl acetate as eluent to give compound 10-a. Two portions of compound 10-A were combined and triturated with methanol (25mL) at room temperature1.5 hours, then 30 minutes at 0 ℃, followed by filtration. The solid was washed with methanol and dried under vacuum overnight to give compound 10-A.¹H NMR (400MHz, chloroform-d) 8.23(s,1H),6.01(d, J ═ 4.5Hz,1H),4.38-4.27(m,1H),4.21-4.13(m,1H),4.10(d, J ═ 1.2Hz,3H),3.97-3.90(m,1H),3.92(s,3H),3.69-3.57(m,2H),3.36(t, J ═ 10.7Hz,1H),2.48(d, J ═ 12.7Hz,1H),2.04(dd, J ═ 11.5,5.2Hz,1H), lcm s-ESI⁺(m/z):[M+H]⁺C₁₄H₁₇N₂O₆Calculated value 309.11; found 309.06.

Step 4

To a mixture of compound 10-A (133mg, 0.431mmol) and 60% NaH (92mg, 2.300mmol) was added DMF (3mL) at 0 ℃. After 15 minutes, CF was added₃CH₂OTf (0.25mL, 1.735 mmol). After stirring at room temperature for 2 hours, the reaction mixture was stirred at 0 ℃ and 1N KOH (0.9mL) was added. After 30 minutes, the resulting mixture was acidified with concentrated HCl (0.35mL) and the mixture was concentrated to near dryness.

A mixture of the above residue, 2,4, 6-trifluorobenzylamine (182mg, 0.509mmol) and HATU (343mg, 0.902mmol) in dichloromethane (4mL) was stirred at room temperature while DIPEA (0.55mL, 3.158mmol) was added. After 20 min, the reaction mixture was diluted with ethyl acetate and saturated NH₄Cl (x 2), water (x1), saturated NaHCO₃(x 2) and brine (x 1). After extraction of the aqueous layer with ethyl acetate (× 1), the two organic fractions were combined and dried (Na)₂SO₄) And concentrated. The residue was purified by preparative HPLC. The product containing fractions were combined and concentrated to remove acetonitrile, with saturated NaHCO₃Neutralization, organic products were extracted with dichloromethane (× 3), combined, and dried (Na)₂SO₄) And concentrated to give compound 35-E.¹H NMR (400MHz, chloroform-d) 10.29(d, J ═ 6.8Hz,1H),8.66-8.42(m,1H),6.78-6.53(m,2H),4.85(dq, J ═ 17.8,9.1Hz,1H),4.64(qd, J ═ 14.5,5.4Hz,2H),4.51-4.41(m,1H),4.35-4.24(m,1H),4.06(td, J ═ 11.0,4.7Hz,1H),4.01(s,3H),3.77(td, J ═ 10.3,4.6Hz,1H),3.63-3.45(m,2H),3.38(t, J ═ 10.7, 1H),2.57(d, 12.12 Hz,1H), 3.06 (qd, 3.06 Hz,3H).¹⁹F NMR (376MHz, chloroform-d) -69.94(t, J ═ 8.6Hz,3F), -109.00(t, J ═ 8.2Hz,1F), -111.70-112.47 (m,2F)⁺(m/z):[M+H]⁺C₂₂H₂₀F₆N₃O₅Calculated value 520.13; found 520.18.

Step 5

To a solution of compound 35-E (42mg, 0.081mmol) in MeCN (3mL) at room temperature was added MgBr₂(42mg, 0.228mmol), the resulting mixture was stirred in a 50 ℃ bath for 15 minutes, after which the reaction mixture was stirred at 0 ℃, 1N Cl (ca. 0.6mL) was added to bring the mixture into solution, the resulting solution was further diluted with water and the product was extracted with dichloromethane (× 3). the combined extracts were dried (Na. RTM.) and dried₂SO₄) And concentrated. The residue was purified by column chromatography on silica gel (12g column) eluting with dichloromethane-20% MeOH in dichloromethane to afford compound 35.¹H NMR (400MHz, chloroform-d) 10.32(s,1H),8.54(s,1H),6.77-6.49(m,2H),4.72-4.55(m,3H),4.48(dd, J ═ 10.9,4.3Hz,1H),4.32(dt, J ═ 12.1,3.0Hz,1H),4.14(td, J ═ 11.5,11.0,4.1Hz,1H),3.83(td, J ═ 10.3,4.3Hz,1H),3.72(dq, J ═ 16.8,8.9,8.5Hz,1H),3.66-3.54(m,1H),3.43(t, J ═ 10.7Hz,1H),2.65(d, J ═ 12.5, 1H),2.5 (q, 12.09, 12H).¹⁹F NMR (376MHz, chloroform-d) -69.17(t, J ═ 8.4Hz,3F), -108.90(h, J ═ 7.9,6.9Hz,1F), -111.77-112.55 (m,2F)⁺(m/z):[M+H]⁺C₂₁H₁₈F₆N₃O₅Calculated value 506.12; found 506.25.

Example 36

Preparation of Compound 36

Step 1

At 0 ℃ to the compoundDMF (3mL) was added to a mixture of 32-E (148mg, 0.480mmol) and 60% NaH (77mg, 1.92 mmol). After 20 minutes, CHF was added₂CH₂OTf (360mg, 1.681 mmol). After stirring at room temperature for about 30 minutes, the reaction mixture was stirred at 0 ℃ and 1N KOH (0.5mL) was added to the mixture. After 10 min, the reaction mixture was acidified with concentrated HCl (0.35mL) and concentrated to almost dryness.

A mixture of the above residue, 3-chloro-2, 4-difluorobenzylamine (103mg, 0.580mmol) and HATU (385mg, 1.013mmol) in dichloromethane (5mL) was stirred at room temperature while DIPEA (0.7mL, 4.019mmol) was added. After 30 min, the reaction mixture was diluted with ethyl acetate and saturated NH₄Cl (x 2), water (x1, + some brine), saturated NaHCO₃(x 2) and brine (x 1). After extraction of the aqueous layer with ethyl acetate (× 1), the two organic fractions were combined and dried (Na)₂SO₄) And concentrated. The residue was purified by column chromatography on silica gel (40g column) using hexane-ethyl acetate-20% MeOH in ethyl acetate as eluent to give compound 36-B.¹H NMR (400MHz, chloroform-d) 10.42(t, J ═ 6.1Hz,1H),8.49(s,1H),7.36-7.18(m,1H),6.92(td, J ═ 8.5,1.9Hz,1H),6.04(dddd, J ═ 57.1,54.4,6.4,2.2Hz,1H),4.78-4.50(m,3H),4.43-4.20(m,2H),4.05(s,3H),4.04-3.91(m,2H),3.65(dddd, J ═ 15.1,13.8,7.3,4.4Hz,3H),2.35-2.13(m,1H),2.13-1.93(m,1H).¹⁹F NMR (377MHz, chloroform-d) -114.75(q, J ═ 5.3,3.8Hz,1F), -117.28(d, J ═ 7.7Hz,1F), -120.31(ddt, J ═ 291.4,54.6,8.1Hz,1F), -123.21(dddd, J ═ 290.8,57.4,26.5,13.9Hz,1F), -LCMS-ESI⁺(m/z):[M+H]⁺C₂₂H₂₁ClF₄N₃O₅Calculated value 518.11; found 518.30.

Step 2

To a solution of compound 36-B (85mg, 0.164mmol) in MeCN (3mL) at room temperature was added MgBr₂(83mg, 0.451mmol) and the resulting mixture was stirred in a 50 ℃ bath. After 30 minutes, the reaction mixture was stirred at 0 ℃ and 1N Cl (about 1mL) was added to bring the mixture into solution. The resulting solution was further diluted with water and then dichloromethaneThe product was extracted with alkane (× 3) the combined extracts were dried (Na)₂SO₄) And concentrated. The residue was purified by preparative HPLC and the product containing fractions were combined and freeze dried to give compound 36.¹H NMR (400MHz, chloroform-d) 10.59(t, J ═ 6.1Hz,1H),11-9(br,1H),8.70(s,1H),7.42-7.15(m,1H),6.94(td, J ═ 8.5,1.8Hz,1H),6.30-5.82(m,1H),4.77-4.41(m,6H),4.15(d, J ═ 3.5Hz,1H),4.06(dd, J ═ 11.3,4.3Hz,1H),3.70(td, J ═ 12.5,6.0Hz,3H),2.31-2.08(m,1H),1.96(dd, J ═ 13.3,3.8, 1H).¹⁹F NMR (376MHz, chloroform-d) -76.41(s,3F), -114.13(d, J ═ 7.7Hz,1F), -117.04(s,1F), -119.86(ddt, J ═ 293.4,54.4,8.6Hz,1F), -122.96(dddd, J ═ 293.0,56.7,24.7,14.3Hz,1F)⁺(m/z):[M+H]⁺C₂₁H₁₉ClF₄N₃O₅Calculated value 504.09; found 504.30.

Example 37

Preparation of Compound 37

Step 1

A solution of n-PrOH (0.667mL, 8.964mmol) and pyridine (0.72mL, 8.918mmol) in dichloromethane (12mL) was stirred in a-40 ℃ bath while triflic anhydride (1.5mL, 8.918mmol) was added dropwise. The bath temperature was raised to 0 ℃ in 30 minutes. After that, the resulting mixture was stirred at room temperature for 30 minutes. The mixture was cooled to 0 ℃ and the mixture was diluted with dry pentane (12 mL). After 20 minutes, the mixture was filtered through a pad of celite. The filtrate was stored in a freezer until use. (assuming 100% yield, the concentration of the solution was 0.3716 mM).

To a mixture of compound 32-E (103mg, 0.334mmol) and 60% NaH (58mg, 1.45mmol) was added DMF (2mL) at 0 ℃. After 15 minutes, the above n-PrOTf solution (2.7mL, about 1.003mmol) was added. After stirring at 0 ℃ for 30 minutes, 1N KOH (0.5mL) was added to the mixture. After 1 hour, the reaction mixture was acidified with concentrated HCl (0.35mL) and concentrated to almost dryness.

A mixture of the above residue, 2,4, 6-trifluorobenzylamine (64mg, 0.397mmol) and HATU (280mg, 0.736mmol) in dichloromethane (3mL) was stirred at room temperature while adding DIPEA (0.6mL, 3.445 mmol). After 20 min, the reaction mixture was diluted with ethyl acetate and saturated NH₄Cl (x 2), saturated NaHCO₃(x 2) and brine (x 1). After extraction of the aqueous layer with ethyl acetate (× 1), the two organic fractions were combined and dried (Na)₂SO₄) And concentrated. The residue was purified by preparative HPLC. The product containing fractions were combined and concentrated to remove acetonitrile, with saturated NaHCO₃Neutralized (ca. 2mL), diluted with brine (20mL), the organic product extracted with dichloromethane (× 3), combined and dried (Na)₂SO₄) And concentrated to give compound 37-A.¹H NMR (400MHz, chloroform-d) 10.39(s,1H),8.48(s,1H),6.78-6.54(m,2H),4.77-4.51(m,2H),4.37(d, J ═ 8.8Hz,1H),4.02(s,5H),3.84(s,2H),3.75-3.60(m,2H),3.22(ddd, J ═ 14.5,9.5,5.5Hz,1H),2.36(d, J ═ 12.0Hz,1H),2.03(dd, J ═ 11.6,7.6Hz,1H),1.75-1.51(m,2H),0.95(t, J ═ 7.4Hz,3H).¹⁹F NMR (376MHz, chloroform-d) -108.95(s,1F), -111.96(d, J ═ 10.7Hz,2F)⁺(m/z):[M+H]⁺C₂₃H₂₅F₃N₃O₅Calculated value 480.17; measured value 480.45

Step 2

To a solution of compound 37-A (26mg, 0.054mmol) in MeCN (2mL) at room temperature was added MgBr₂(28mg, 0.152mmol), the resulting mixture was stirred in a 50 ℃ bath after 30 minutes, the reaction mixture was stirred at 0 ℃ and 1N Cl (ca. 1mL) was added to bring the mixture into solution, the resulting solution was further diluted with water and the product was extracted with dichloromethane (× 3)₂SO₄) And concentrated. The residue was purified by preparative HPLC and the product containing fractions were combined and freeze dried to give compound 37.¹H NMR(400MHz, chloroform-d) 10.52(t, J ═ 5.5Hz,1H),8.55(s,1H),6.66(t, J ═ 8.2Hz,2H),4.79-4.65(m,1H),4.65-4.55(m,1H),4.48(s,1H),4.20(d, J ═ 12.0Hz,1H),4.05(dt, J ═ 15.5,8.2Hz,1H),3.97(d, J ═ 11.1Hz,2H),3.80-3.55(m,2H),3.36-3.19(m,1H),2.27(s,1H),1.94(d, J ═ 13.0Hz,1H),1.66(q, J ═ 7.7, 2H), 0.7 (t, 2H), 3.98 (t, 3H).¹⁹F NMR (376MHz, chloroform-d) -76.43(s,3F), -108.54(p, J ═ 7.2Hz,1F), -111.64-112.56 (m,2F)⁺(m/z):[M+H]⁺C₂₂H₂₃F₃N₃O₅Calculated value 466.16; found 466.19.

Example 38

Preparation of Compound 38

Step 1

A solution of i-PrOH (0.685mL, 8.948mmol) and pyridine (0.72mL, 8.929mmol) in dichloromethane (12mL) was stirred at-40 deg.C and trifluoromethanesulfonic anhydride (1.5mL, 8.918mmol) was added dropwise. The bath temperature was raised to 0 ℃ in 30 minutes. The resulting mixture was then stirred at room temperature for 30 minutes. The mixture was cooled to 0 ℃ and the mixture was diluted with dry pentane (12 mL). After 20 minutes, the mixture was filtered through a pad of celite. The filtrate was stored in a freezer until use. (assuming 100% yield, 0.3716mM concentration in solution)

To a mixture of compound 32-E (101mg, 0.328mmol) and 60% NaH (58mg, 1.45mmol) was added DMF (2mL) at 0 ℃. After 10 minutes, the above i-PrOTf solution (2.7mL, about 1.003mmol) was added. After stirring at 0 ℃ for 1.75 hours, 1N KOH (0.5mL) was added to the mixture. After 1.25 h, the reaction mixture was acidified with concentrated HCl (0.35mL) and concentrated to almost dryness.

The above residue, 2,4, 6-trifluorobenzylamine (64mg, 0.397mmol) and HATU (280 m)g, 0.736mmol) in dichloromethane (3mL) was stirred at room temperature while DIPEA (0.6mL, 3.445mmol) was added. After 30 min, the reaction mixture was diluted with ethyl acetate and saturated NH₄Cl (x 2), saturated NaHCO₃(x 2) and brine (x 1). After extraction of the aqueous layer with ethyl acetate (× 1), the two organic fractions were combined and dried (Na)₂SO₄) And concentrated. The residue was purified by preparative HPLC to give compound 38-a.¹H NMR (400MHz, chloroform-d) 10.67(s,1H),8.65(s,1H),6.80-6.56(m,2H),4.94-4.80(m,1H),4.79-4.69(m,1H),4.62(dd, J ═ 15.0,4.6Hz,1H),4.47(d, J ═ 3.6Hz,1H),4.04(s,3H),3.92-3.65(m,3H),3.26(td, J ═ 11.5,10.9,6.0Hz,2H),2.77(d, J ═ 15.6Hz,1H),2.37(t, J ═ 14.1Hz,1H),1.27(d, J ═ 6.7Hz,6H).¹⁹F NMR (376MHz, chloroform-d) -76.30(s,3F), -108.39(ddd, J ═ 15.1,8.6,6.1Hz,1F), -112.00(t, J ═ 6.9Hz,2F)⁺(m/z):[M+H]⁺C₂₃H₂₅F₃N₃O₅Calculated value 480.17; found 480.23.

Step 2

To a solution of compound 38-A (3mg, about 0.006mmol) in MeCN (1mL) at room temperature was added MgBr₂(5mg, 0.027mmol) and the resulting mixture was stirred in a bath at 50 ℃. After 30 minutes, the reaction mixture was stirred at 0 ℃ and 1N Cl (about 0.1mL) was added to bring the mixture into solution. The resulting solution was further diluted with water (0.3mL) and DMF (1mL), filtered and purified by preparative HPLC, and the product-containing fractions were lyophilized to give compound 38.¹H NMR (400MHz, chloroform-d) 10.57(d, J ═ 6.1Hz,1H),8.58(s,1H),6.80-6.54(m,2H),4.79-4.56(m,3H),4.48(s,1H),3.87(q, J ═ 8.6,7.0Hz,3H),3.49(t, J ═ 11.9Hz,1H),3.44-3.31(m,1H),2.79(d, J ═ 15.9Hz,1H),2.34(t, J ═ 14.0Hz,1H),1.35(d, J ═ 6.8Hz,3H),1.34(d, J ═ 6.8Hz,3H).¹⁹FNMR (376MHz, chloroform-d) -76.38(s,3F), -108.68(d, J ═ 10.1Hz,1F), -112.01(s,2F)⁺(m/z):[M+H]⁺C₂₂H₂₃F₃N₃O₅Calculated value 466.16; found 466.21.

Example 39

Preparation of Compound 39

Step 1

To a mixture of compound 32-E (120mg, 0.389mmol) and 60% NaH (69mg, 1.725mmol) was added DMF (2mL) at 0 ℃. After 5 min, EtOTf (0.17mL, 1.311mmol) was added. After 20 min, 2N NaOH (0.8mL) was added to the mixture. After 20 minutes, the reaction mixture was acidified with 2N HCl (about 2mL) and the acidified reaction mixture was concentrated to almost dryness. A mixture of the above residue, 3-chloro-2, 4-difluorobenzylamine (79mg, 0.445mmol) and HATU (315mg, 0.829mmol) in dichloromethane (4mL) was stirred at room temperature while DIPEA (0.7mL, 4.019mmol) was added. After 1 hour, the reaction mixture was diluted with ethyl acetate and saturated NH₄Cl (x 2), saturated NaHCO₃(x 2) and brine (x 1). After extraction of the aqueous layer with ethyl acetate (× 1), the two organic fractions were combined and dried (Na)₂SO₄) And concentrated. The residue was purified by column chromatography on silica gel (12g column) using hexane-ethyl acetate-20% MeOH in ethyl acetate as eluent to give impure compound 39-a. LCMS-ESI⁺(m/z):[M+H]⁺C₂₂H₂₃ClF₂N₃O₅Calculated value 482.13; found 482.41.

Step 2

To a solution of compound 39-A (43mg, ca. 0.089mmol) in MeCN (3mL) at room temperature was added MgBr₂(44mg, 0.239mmol), stirring the resulting mixture in a 50 ℃ bath after 30 minutes, stirring the reaction mixture at 0 ℃, adding 1N HCl (ca. 0.2mL) to bring the mixture into solution, further diluting the resulting solution with water, then extracting the product with dichloromethane (× 3), drying the combined extracts (Na) (×)₂SO₄) And concentrated. The residue was purified by preparative HPLC and the product containing fractions were combined and freeze dried to give compound 39.¹H NMR (400MHz, chloroform-d) 10.68-10.40(m,1H),8.52(s,1H),7.36-7.20(m,1H),6.93(td, J ═ 8.6,1.9Hz,1H),4.65(qd, J ═ 15.2,5.4Hz,2H),4.48(s,1H),4.36-4.21(m,1H),4.13(dq, J ═ 14.5,7.3Hz,1H),4.05(s,1H),4.00(d, J ═ 12.2Hz,1H),3.86-3.55(m,2H),3.43(dq, J ═ 14.0,6.9Hz,1H),2.38-2.14(m,1H),2.03-1.82(m,1H), 7.27.27 (t ═ 1H, 1H).¹⁹F NMR (376MHz, chloroform-d) -76.43(s,3F), -114.60(s,1F), -117.24(d, J ═ 7.7Hz,1F)⁺(m/z):[M+H]⁺C₂₁H₂₁ClF₂N₃O₅Calculated value 468.11; found 468.20.

Example 40

Preparation of Compounds 40a and 40b

Step 1

Compound 40-A (9.999g, 24.07mmol) is dissolved in dichloromethane (100mL) and saturated NaHCO₃In solution (200mL), after separation of the two layers, the aqueous layer was extracted with dichloromethane (100mL), the organic fractions were washed twice with water (× 1), combined, and dried (MgSO 4)₄) Concentrating, and vacuum drying.

The dried residue was dissolved in ethanol containing 10% Pd/C (2.11g) and the resulting mixture was washed with 40-50psi H₂Shaken under atmosphere for 20 hours. The mixture was filtered through a pad of celite and the filtrate was concentrated to almost dryness.

Mixing the residue with Na₂CO₃A solution of (3830mg, 36.14mmol) in water (200mL) was stirred at 0 deg.C while benzyl chloroformate (4.35mL, 95% purity, 28.95mmol) was added. The resulting mixture was stirred at room temperature for 67 hours and the product was taken up in dichloromethane(100mL × 3) the extracts were washed with water (× 1), then combined and dried (Na)₂SO₄) And concentrated.

The residue was purified by silica gel column chromatography (120g column) using hexane-ethyl acetate as an eluent to give compound 40-B.¹H NMR (400MHz, chloroform-d) 7.44-7.28(m,5H),5.45(d, J ═ 8.2Hz,1H),5.10(d, J ═ 4.3Hz,2H),3.94(m,4H),3.87-3.74(m,1H),3.65(m,1H),2.14(ddd, J ═ 13.2,4.6,1.8Hz,1H),1.93(dq, J ═ 12.5,4.0Hz,1H),1.87-1.75(m,1H),1.68(ddd, J ═ 12.4,10.1,5.7Hz,1H),1.62-1.47(m,2H), s-ESI⁺(m/z):[M+H]⁺C₁₆H₂₂NO₅Calculated value 308.15; found 307.89.

Step 2

A solution of compound 40-B (1066mg, 3.468mmol) and triethylamine (0.59mL, 4.233mmol) in dichloromethane (12mL) was stirred at 0 deg.C while methanesulfonyl chloride (0.3mL, 3.876mmol) was added dropwise, after 20 minutes at 0 deg.C, the mixture was stirred at room temperature for 30 minutes, the reaction mixture was diluted with ethyl acetate, washed with water (× 2), after extraction of the aqueous fraction with ethyl acetate (x1), the organic fractions were combined, dried (Na)₂SO₄) And concentrated. The residue was purified by column chromatography on silica gel (40g column) using hexane-ethyl acetate as eluent to give compound 40-C.¹H NMR (400MHz, chloroform-d) 7.46-7.29(m,5H),5.86(s,1H),5.10(q, J ═ 12.2Hz,2H),4.68(s,1H),4.06(s,1H),4.00-3.85(m,4H),3.07(s,3H),2.24-2.10(m,1H),2.06(q, J ═ 6.5,4.3Hz,2H),1.86(d, J ═ 11.9Hz,1H),1.75-1.57(m,2H), LCMS-ESI⁺(m/z):[M+H]⁺C₁₇H₂₄NO₇S, calculating value 386.13; found 386.04.

Step 3

A mixture of compound 40-C (1282mg, 3.326mmol), NaOAc (547mg, 6.668mmol) and sodium azide (441mg, 6.784mmol) in DMF (6mL) was stirred in a 95 deg.C bath for 9 hours, the mixture was diluted with water, the product was extracted with ethyl acetate (× 2), the extracts were washed with water (x1), combined, dried (Na 1)₂SO₄) And concentrated, and the residue was purified by silica gel column chromatography (80g column) using hexane-ethyl acetate as an eluent to give 40-D.¹H NMR (400MHz, chloroform-d) 7.43-7.28(m,5H),5.22(d, J ═ 9.2Hz,1H),5.11(s,2H),4.08(t, J ═ 7.0Hz,1H),3.93(dd, J ═ 4.6,2.7Hz,4H),3.83(s,1H),2.01-1.83(m,2H),1.83-1.67(m,3H),1.64-1.56(m,1H) LCMS-ESI⁺(m/z):[M+H]⁺C₁₆H₂₁N₄O₄Calculated value 333.16; found 332.83.

Step 4

A solution of compound 40-D (680mg, 2.046mmol) and triphenylphosphine (600mg, 2.288mmol) in THF (10mL) was stirred at room temperature for 18h, and water (2mL) was added. The mixture was refluxed in a 70 ℃ bath for 4 hours, concentrated and dried under vacuum for 30 minutes. The residue was dissolved in dichloromethane (about 50mL) and dried (MgSO)₄) Then, insoluble matter was filtered off, and the filtrate was concentrated.

The concentrated residue, Compound 6-B (496mg, 2.048mmol) and NaHCO₃A mixture of (345mg, 4.107mmol) in water (3mL) and MeOH (6mL) was stirred at room temperature for 5 h. The mixture was concentrated and dried in vacuo for 30 min. The residue was triturated with methanol (about 20mL) and stirred in a 50 ℃ bath for 5.5 hours. The resulting mixture was concentrated, the residue dissolved in dichloromethane and dried (MgSO₄). After insoluble matter was filtered off, the filtrate was concentrated.

The concentrated residue and a solution of 10% Pd/C (140mg) in ethanol (30mL) in H₂Stirring under an atmosphere. After 2 hours, more Pd/C (400mg) was added. Over another hour, more Pd/C (700mg) was added. After an additional 1.25 hours, more Pd/C (580mg) was added. Mixing the mixture in H₂Stir under atmosphere overnight. The mixture was filtered and concentrated. The residue was purified by column chromatography on silica gel (40g column) using ethyl acetate-20% MeOH in ethyl acetate as eluent to give compound 40-E.¹H NMR (400MHz, methanol-d 4)8.56(s,1H),4.54-4.42(m,1H),4.22(m,1H),4.12-4.02(m,1H),4.00-3.88(m,3H),3.92(s,3H),3.86(s,3H),2.15(td, J ═ 12.7,4.1Hz,1H),2.05(m,2H), 2.03H-1.94(m,1H),1.86(d,J＝13.9Hz,1H),1.78(td,J＝13.4,4.0Hz,1H).LCMS-ESI⁺(m/z):[M+H]⁺C₁₇H₂₁N₂O₇Calculated value 365.13; found 365.17.

Step 5

To a mixture of compound 40-E (49mg, 0.134mmol) and 60% NaH (25mg, 0.625mmol) was added DMF (2mL) at 0 ℃. After 15 min EtOTf (0.06mL, 0.463mmol) was added. After 20 min, 1NKOH (0.2mL) was added to the reaction mixture. After 20 minutes, the reaction mixture was acidified with 2N HCl (about 2mL) and the acidified reaction mixture was concentrated to remove all solvents. The residue was purified by preparative HPLC to give 28mg (55%) of the acid.

A mixture of the acid, 2,4, 6-trifluorobenzylamine (25mg, 0.155mmol) and HATU (90mg, 0.237mmol) in dichloromethane (3mL) was stirred at room temperature while DIPEA (0.3mL, 1.722mmol) was added. After 30 min, the reaction mixture was diluted with ethyl acetate and saturated NH₄Cl (x 2), saturated NaHCO₃(x 2) and brine (x 1). After extraction of the aqueous layer with ethyl acetate (× 1), the two organic fractions were combined and dried (Na)₂SO₄) And concentrated.

The residue was purified by preparative HPLC to give compound 40-F.¹H NMR (400MHz, chloroform-d) 10.75-10.48(m,1H),8.58(s,1H),6.80-6.45(m,2H),5.25(s,1H),4.73(dd, J ═ 14.5,5.7Hz,1H),4.60(dd, J ═ 14.7,5.3Hz,1H),4.36(d, J ═ 3.3Hz,1H),4.02(s,3H),3.95(ddd, J ═ 7.0,5.4,3.9Hz,3H),3.86(dq, J ═ 14.2,7.2Hz,1H),3.75(dt, J ═ 12.5,3.8Hz,1H),3.29(dq, J ═ 14.2,7.1H, 1H),3.75 (t, J ═ 12.5,3.8Hz,1H),3.29(dq, J ═ 14.2, 1.2, 1H), 1.5H, 1H, 13.5 (1H, 13.5H, 1H, 13.5H, 1H, 13H, 1H, 13H, 1H, 3H) in that respect¹⁹F NMR (376MHz, chloroform-d) -76.37(s,3F), -108.71(ddd, J ═ 15.0,8.8,6.3Hz,1F), -111.97(t, J ═ 6.9Hz,2F)⁺(m/z):[M+H]⁺C₂₅H₂₇F₃N₃O₆Calculated value 522.19; found 522.25.

Step 6

To a solution of compound 40-F (10mg, 0.01574mmol) in MeCN (1mL) at room temperature was added MgBr₂(10mg, 0.054mmol) and the resulting mixture stirred at 50 ℃. After about 25 minutes, the reaction mixture was stirred at 0 ℃ and 0.1N HCl (about 3-4 drops) was added to the mixture to bring the mixture into solution. The resulting solution was diluted with DMF, filtered, and the filtrate was purified by preparative HPLC, and the two fractions containing the product were lyophilized to give compound 40a and compound 40b, respectively. Compound 40a:¹h NMR (400MHz, chloroform-d) 10.50(s,1H),8.68(s,1H),6.67(t, J ═ 8.1Hz,2H),4.67(q, J ═ 15.6,15.1Hz,3H),4.32(s,2H),4.11(s,1H),3.39-3.07(m,1H),2.97-2.40(m,4H),2.30(s,1H),1.25(dd, J ═ 8.7,6.8Hz,3H).¹⁹F NMR (376MHz, chloroform-d) -76.36(s,3F), -108.47(s,1F), -112.01(s,2F). LCMS-ESI⁺(m/z):[M+H]⁺C₂₂H₂₃F₃N₃O₅Calculated value 464.14; found 464.17.

Compound 40b:¹h NMR (400MHz, chloroform-d) 10.56(s,1H),8.57(s,1H),6.66(dd, J ═ 8.7,7.5Hz,2H),4.67(d, J ═ 5.2Hz,2H),4.37(s,1H),4.07-3.90(m,5H),3.86(d, J ═ 11.7Hz,1H),3.21(dd, J ═ 13.9,7.0Hz,1H),2.76(d, J ═ 15.7Hz,1H),2.20(t, J ═ 14.4Hz,1H),1.98(d, J ═ 13.1Hz,1H),1.75(d, J ═ 14.3Hz,1H),1.64(q, J ═ 12.2, 2H), 29.7H, 1H).¹⁹F NMR (376MHz, chloroform-d) -76.36(s,3F), -108.92(s,1F), -111.96(s,2F). LCMS-ESI⁺(m/z):[M+H]⁺C₂₄H₂₅F₃N₃O₆Calculated value 508.17; found 508.19.

EXAMPLE 41

Preparation of Compound 41

Step 1

Intermediate 41-B was prepared in a similar manner to 39-a, except 2, 4-difluorobenzylamine was used instead of 3-chloro-2, 4-difluorobenzylamine:¹h NMR (400MHz, chloroform-d) 10.46(s,1H),8.48(s,1H),7.44-7.29(m,1H),6.90-6.68(m,2H),4.62(dt, J ═ 4.9,1.9Hz,2H),4.36(s,1H),4.28(q, J ═ 7.1Hz,1H),4.13(dq, J ═ 9.9,7.1Hz,1H),4.05(s,3H),3.85(t, J ═ 6.4Hz,2H),3.76-3.59(m,2H),3.38(dqd, J ═ 14.1,7.0,2.7Hz,1H),2.39(dd, J ═ 14.6,7.9, 1H),2.04(s,1H), 3.25H, td ═ 3H, 3H.¹⁹F NMR (376MHz, chloroform-d) -112.03(s,1F), -114.69(s,1F). LCMS-ESI⁺(m/z):[M+H]⁺C₂₂H₂₄F₂N₃O₅Calculated value 448.17; found 448.18.

Step 2

To a solution of compound 41-B (16mg, 0.036mmol) in MeCN (1mL) at room temperature was added MgBr₂(17mg, 0.093mmol) and the resulting mixture was stirred in a 50 ℃ bath. After 30 minutes, the reaction mixture was stirred at 0 ℃ and 1N Cl (about 0.1mL) was added to bring the mixture into solution. The resulting solution was further diluted with water (about 0.3mL) and DMF (1mL), filtered, and purified by preparative HPLC. The product-containing fractions were freeze-dried to give compound 41.¹H NMR (400MHz, chloroform-d) 10.60(s,1H),8.64(s,1H),7.35(q, J ═ 7.9Hz,1H),6.83(q, J ═ 9.2,8.7Hz,2H),4.65(qd, J ═ 15.3,5.3Hz,2H),4.50(s,1H),4.29(d, J ═ 13.5Hz,1H),4.16(dq, J ═ 14.6,7.3Hz,1H),4.02(d, J ═ 10.0Hz,2H),3.79-3.61(m,2H),3.44(dq, J ═ 14.1,7.0Hz,1H),2.26(q, J ═ 11.8,10.7, 1H),1.95 (J ═ 1H), 1.13.13H, 1H, 7.27H), and t ═ 1H.¹⁹F NMR (376MHz, chloroform-d) -76.40(s,3F), -111.08-111.68 (m,1F)), -114.43(q, J ═ 8.6,8.0Hz,1F)⁺(m/z):[M+H]⁺C₂₁H₂₁ClF₂N₃O₅Calculated value 434.15; found 434.19.

Example 42

Preparation of Compound 42

Step 1

A solution of (3S,4R) -4-aminotetrahydrofuran-3-ol (1.99g, 19.3mmol) in dichloromethane (100mL) was cooled to 0 ℃ under nitrogen, treated with N, N-diisopropylethylamine (5mL, 29mmol), and then benzyl chloroformate (3mL, 21mmol) was added. The reaction mixture was gradually warmed to room temperature and stirred for 18 hours. The reaction mixture was then washed with water, saturated NaHCO in sequence₃(aqueous solution) and brine, washed with Na₂SO₄Drying, filtration and concentration gave benzyl ((3R,4S) -4-hydroxytetrahydrofuran-3-yl) carbamate, which was used further without further purification.

Step 2 to 3

To a solution of benzyl ((3R,4S) -4-hydroxytetrahydrofuran-3-yl) carbamate (1.00g, 4.2mmol) and triphenylphosphine (1.32g, 5.2mmol) in tetrahydrofuran (20ml) was added N, N-diisopropylethylamine (0.75ml, 4.3 mmol). The mixture was then cooled to 0 ℃ and diisopropyl azodicarboxylate (1ml, 5.1mmol) was added dropwise. The reaction mixture was stirred for 10 min, at which time diphenylphosphoryl azide (1.1ml, 5.1mmol) was added dropwise and the reaction mixture was gradually warmed and stirred for 3 h.

The reaction mixture was then cooled again to 0 ℃ and a solution of triphenylphosphine (1.44g, 5.5mmol) in tetrahydrofuran (2mL) was added dropwise. The reaction solution was warmed to room temperature and stirred for 2 hours, at which time water (1mL) was added and the reaction stirred at 50 ℃ for 18 hours. An additional 1mL of water was added, the reaction temperature was raised to 70 ℃ and stirring was continued for 6 hours to complete the reaction, at which time the reaction solution was cooled, washed with basified brine, washed with Na₂SO₄Dried, filtered and concentrated. Purification by silica gel chromatography (0-10% MeOH/DCM) gave benzyl ((3S,4R) -4-aminotetrahydrofuran-3-yl) carbamate.

Step 4

Intermediate 42-a (356mg, 1.47mmol), ((3S,4R) -4-aminotetrahydrofuran-3-yl) carbamic acid benzyl ester (346mg, 1.46mmol) and sodium bicarbonate (260mg, 3.09mmol) in 1:1 water: the mixture in ethanol (10mL) was stirred at room temperature for 18 hours. The reaction mixture was concentrated, dissolved in methanol (10mL) and stirred at 50 ℃ for 3 hours to afford complete conversion. The reaction mixture was concentrated, partitioned between brine and ethyl acetate, and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were washed with Na₂SO₄Dried, filtered and concentrated to give intermediate 42-B, which was used without further purification.

Step 5 to step 6

A solution of intermediate 42-B (151mg, 0.33mmol) in N, N-dimethylformamide (1mL) was cooled to 0 deg.C and treated dropwise with a solution of 1M KHMDS in tetrahydrofuran (0.5mL, 0.5 mmol). The reaction solution was then warmed to room temperature, stirred for 15 minutes, treated by dropwise addition of a solution of methyl iodide (60 μ L, 0.96mmol) in N, N-dimethylformamide (1mL), and stirred for an additional 18 hours. The reaction solution was then saturated with NH₄Partition between Cl (aq) and ethyl acetate. The aqueous phase was extracted three times with ethyl acetate and the combined organic phases were washed with brine, over Na₂SO₄Dried, filtered and concentrated.

To the crude residue were added 10 wt% palladium on carbon (84mg, 0.08mmol) and ethanol (5 mL). The reaction was stirred under 1 atmosphere of hydrogen for 18 hours at which time LCMS showed complete conversion to intermediate 42-C. The reaction solution was filtered through celite and concentrated to give crude intermediate 42-C, which was used without further purification.

Steps 7 to 9

To a solution of intermediate 42-C (0.33mmol max.) in 1:1 tetrahydrofuran ethanol (6mL) was added a 1M solution of KOH (aq) (0.65 mL). The reaction solution was stirred for 2 hours, diluted with ethyl acetate, acidified with 10% HCl (aq) and partitioned between ethyl acetate and brine. The aqueous phase was extracted three times with ethyl acetate and furtherExtracted to 2-butanol. The combined organic phases were washed with Na₂SO₄Dried, filtered, concentrated and carried on to the next step in crude form.

The residue from the previous step was dissolved in dichloromethane (5mL) and washed sequentially with (dimethylamino) -N, N-dimethyl (3H- [1,2, 3)]Triazolo [4,5-b]Pyridin-3-yloxy) formamidine hexafluorophosphate (HATU, 0.16g, 0.41mmol), (2,4, 6-trifluorophenyl) methylamine (50 μ L, 0.41mmol) and N, N-diisopropylethylamine (240 μ L, 1.34mmol) were treated. The reaction mixture was stirred for 30 minutes and then at NH₄Partition between Cl (aq) and ethyl acetate. The aqueous phase was extracted three times with ethyl acetate and the combined organics were taken up with Na₂SO₄Dried, concentrated and taken on to the next step as crude.

The residue from the previous step was dissolved in acetonitrile (2mL), treated with magnesium bromide (133mg, 0.72mmol), and heated at 50 ℃ for 1 hour. The reaction was quenched by addition of 0.5M HCl (aq), extracted three times with dichloromethane, Na₂SO₄Drying, filtration, concentration and purification by silica gel chromatography (0-10% MeOH/DCM) afforded compound 42.¹H NMR(400MHz,CDCl₃)12.78(br s,1H),10.28(t,J＝5.6Hz,1H),8.34(s,1H),6.64(t,J＝8.1Hz,2H),4.96(q,J＝7.1Hz,1H),4.67(dd,J＝14.4,5.9Hz,1H),4.56(dd,J＝14.4,5.5Hz,1H),4.42–4.36(m,1H),4.32(dd,J＝9.3,7.8Hz,1H),4.20(dd,J＝10.4,2.7Hz,1),4.13(dd,J＝10.4,4.3Hz,1H),3.84(dd,J＝9.4,7.2Hz,1H),3.16(s,3H).LCMS-ESI⁺(m/z):[M+H]⁺C₁₉H₁₇F₃N₃O₅Calculated value 424.11; found 424.2.

Example 43

Preparation of Compound 43

Step 1

A solution of (3R,4S) -4-aminotetrahydrofuran-3-ol (2.02g, 19.5mmol) in dichloromethane (100mL) was cooled to 0 ℃ under nitrogen, treated with N, N-diisopropylethylamine (5mL, 29mmol) and then with benzyl chloroformate (3mL, 21 mmol). The reaction mixture was gradually warmed to room temperature and stirred for 18 hours. The reaction mixture was then washed with water, saturated NaHCO in sequence₃(aqueous solution) and brine, washed with Na₂SO₄Dried, filtered and concentrated to give benzyl ((3S,4R) -4-hydroxytetrahydrofuran-3-yl) carbamate, which is used without further purification.

Step 2 to 3

To a solution of benzyl ((3S,4R) -4-hydroxytetrahydrofuran-3-yl) carbamate (1.0g, 4.2mmol) and triphenylphosphine (1.31g, 5.0mmol) in tetrahydrofuran (20ml) was added N, N-diisopropylethylamine (0.75ml, 4.3 mmol). The mixture was then cooled to 0 ℃ and diisopropyl azodicarboxylate (1ml, 5.1mmol) was added dropwise. The reaction mixture was stirred for 10 min, at which time diphenylphosphoryl azide (1.1ml, 5.1mmol) was added dropwise and the reaction mixture was gradually warmed and stirred for 3 h.

The reaction mixture was then cooled again to 0 ℃ and a solution of triphenylphosphine (1.43g, 5.4mmol) in tetrahydrofuran (2mL) was added dropwise. The reaction solution was warmed to room temperature and stirred for 2 hours, at which time water (1mL) was added and the reaction stirred at 50 ℃ for 18 hours. An additional 1mL of water was added, the reaction temperature was raised to 70 ℃ and stirring was continued for 6 hours to complete the reaction, at which time the reaction solution was cooled, washed with basified brine, washed with Na₂SO₄Dried, filtered and concentrated. Purification by silica gel chromatography (0-10% MeOH/DCM) gave benzyl ((3R,4S) -4-aminotetrahydrofuran-3-yl) carbamate.

Step 4

Intermediate 42-a (325mg, 1.34mmol), ((3R,4S) -4-aminotetrahydrofuran-3-yl) carbamic acid benzyl ester (316mg, 1.34mmol) and sodium bicarbonate (226mg, 2.69mmol) in 1:1 water: the solution in ethanol (10mL) was stirred at room temperature 18And (4) hours. The reaction mixture was concentrated, dissolved in methanol (10mL) and stirred at 50 ℃ for 3 hours to afford complete conversion. The reaction mixture was concentrated, partitioned between brine and ethyl acetate, and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were washed with Na₂SO₄Dried, filtered and concentrated to give intermediate 43-B, which was used without further purification.

Step 5 to step 6

A solution of intermediate 43-B (149mg, 0.32mmol) in N, N-dimethylformamide (1mL) was cooled to 0 deg.C and treated dropwise with a solution of 1M KHMDS in tetrahydrofuran (0.5mL, 0.5 mmol). The reaction solution was then warmed to room temperature, stirred for 15 minutes, added dropwise with a solution of iodomethane (60 μ L, 0.96mmol) in N, N-dimethylformamide (1mL) and stirred for a further 18 hours. The reaction solution was then saturated with NH₄Partition between Cl (aq) and ethyl acetate. The aqueous phase was extracted three times with ethyl acetate and the combined organic phases were washed with brine, over Na₂SO₄Dried, filtered and concentrated.

To the crude residue were added 10 wt% palladium on carbon (72mg, 0.07mmol) and ethanol (5 mL). The reaction was stirred under 1 atm hydrogen for 18 hours at which time LCMS showed complete conversion to intermediate 43-C. The reaction solution was filtered through celite and concentrated to give intermediate 43-C, which was used without further purification.

Steps 7 to 9

To intermediate 43-C (0.32mmol max) in 1:1 tetrahydrofuran: to a solution in ethanol (6mL) was added a 1M solution of KOH (aq) (0.65 mL). The reaction solution was stirred for 2 hours, neutralized with HCl (aq) and concentrated to near dryness under vacuum. The residue obtained is taken on to the next step in the form of a crude product.

The residue from the previous step was dissolved in dichloromethane (5mL) and washed sequentially with (dimethylamino) -N, N-dimethyl (3H- [1,2, 3)]Triazolo [4,5-b]Pyridin-3-yloxy) formamidine hexafluorophosphate (HATU, 0.16g, 0.42mmol), (2,4, 6-trifluorophenyl) methylamine (50 μ L, 0).41mmol) and N, N-diisopropylethylamine (240. mu.L, 1.34 mmol). The reaction mixture was stirred for 45 minutes and then at NH₄Partition between Cl (aq) and ethyl acetate. The aqueous phase was extracted three times with ethyl acetate and the combined organics were taken up with Na₂SO₄Dried, concentrated and taken to the next step as crude.

The residue from the previous step was dissolved in acetonitrile (2mL), treated with magnesium bromide (119mg, 0.65mmol), and heated at 50 ℃ for 1 hour. The reaction was quenched by addition of 0.5M HCl (aq), extracted three times with dichloromethane, Na₂SO₄Drying, filtration, concentration, and purification by silica gel chromatography (0-10% MeOH/DCM) afforded compound 43:¹H NMR(400MHz,CDCl₃)12.73(br s,1H),10.28(t,J＝5.6Hz,1H),8.34(s,1H),6.64(t,J＝8.1Hz,2H),4.99(q,J＝7.1Hz,1H),4.67(dd,J＝14.5,5.9Hz,1H),4.55(dd,J＝14.5,5.4Hz,1H),4.43–4.37(m,1H),4.32(dd,J＝9.4,7.8Hz,1H),4.20(dd,J＝10.4,2.7Hz,1H),4.13(dd,J＝10.4,4.3Hz,1H),3.83(dd,J＝9.4,7.1Hz,1H),3.16(s,3H).LCMS-ESI⁺(m/z):[M+H]⁺C₁₉H₁₇F₃N₃O₅calculated value 424.11; found 424.2.

Example 44

Preparation of Compound 44

Step 1-2

A solution of intermediate 42-B (236mg, 0.51mmol) in N, N-dimethylformamide (2mL) was cooled to 0 deg.C and treated dropwise with a solution of 1M KHMDS in tetrahydrofuran (0.8mL, 0.8 mmol). The reaction solution was then warmed to room temperature, stirred for 15 minutes, treated by dropwise addition of a solution of ethyl iodide (130. mu.L, 1.62mmol) in N, N-dimethylformamide (1mL), and stirred for an additional 18 hours. Then the reaction solution is saturatedAnd NH₄Partition between Cl (aq) and ethyl acetate. The aqueous phase was extracted three times with ethyl acetate and the combined organic phases were washed with brine, over Na₂SO₄Dried, filtered and concentrated.

To the crude residue were added 10 wt% palladium on carbon (160mg, 0.15mmol) and ethanol (4 mL). The reaction was stirred under 1 atmosphere of hydrogen for 18 hours at which time LCMS showed complete conversion. The reaction solution was filtered through celite and concentrated to give crude intermediate 44-B, which was used without further purification.

Step 3 to step 5

To intermediate 44-B (max 0.64mmol) in 1:1 tetrahydrofuran: to a solution in ethanol (6mL) was added a 1M solution of KOH (aq) (1.3 mL). The reaction solution was stirred for 1 hour, neutralized with HCl (aq) and concentrated to near dryness in vacuo. The residue obtained is taken on to the next step in the form of a crude product.

The residue from the previous step was dissolved in dichloromethane (10mL) and washed sequentially with (dimethylamino) -N, N-dimethyl (3H- [1,2, 3)]Triazolo [4,5-b]Pyridin-3-yloxy) formamidine hexafluorophosphate (HATU, 300mg, 0.79mmol), (2,4, 6-trifluorophenyl) methylamine (100. mu.L, 0.82mmol) and N, N-diisopropylethylamine (470. mu.L, 2.63mmol) were treated. The reaction mixture was stirred for 30 minutes and then at NH₄Partition between Cl (aq) and ethyl acetate. The aqueous phase was extracted three times with ethyl acetate and the combined organics were taken up with Na₂SO₄Dried, concentrated and taken to the next step as crude product. The residue from the previous step was dissolved in acetonitrile (3mL), treated with magnesium bromide (225mg, 1.2mmol), and heated at 50 ℃ for 3 hours. The reaction was quenched by addition of 0.5MHCl (aq), extracted three times with dichloromethane, and Na₂SO₄Drying, filtration, concentration, and purification by silica gel chromatography (0-10% MeOH/DCM) afforded compound 44:¹H NMR(400MHz,CDCl₃)12.99(br s,1H),10.28(t,J＝5.6Hz,1H),8.34(s,1H),6.65(t,J＝8.4Hz,2H),4.94(q,J＝6.4Hz,1H),4.67(dd,J＝14.3,6.0Hz,1H),4.57(dd,J＝14.5,5.5Hz,1H),4.48–4.40(m,1H),4.33(dd,J＝9.8,7.0Hz,1H),4.19(dd,J＝10.1,4.9Hz,1H),4.07(dd,J＝10.1,3.9Hz,1H),3.99(dd,J＝9.8,6.1Hz,1H),3.78–3.66(m,3H),1.29(t,J＝7.2Hz,3H).LCMS-ESI⁺(m/z):[M+H]⁺C₂₀H₁₉F₃N₃O₅calculated value 438.13; found 438.1.

Example 45

Preparation of Compound 45

Step 1-2

A solution of intermediate 43-B (240mg, 0.52mmol) in N, N-dimethylformamide (2mL) was cooled to 0 deg.C and treated dropwise with a 1M solution of KHMDS in tetrahydrofuran (0.8mL, 0.8 mmol). The reaction solution was then warmed to room temperature, stirred for 15 minutes, treated by dropwise addition of a solution of ethyl iodide (130. mu.L, 1.62mmol) in N, N-dimethylformamide (1mL) and stirred for a further 18 hours. The reaction solution was then saturated with NH₄Partition between Cl (aq) and ethyl acetate. The aqueous phase was extracted three times with ethyl acetate and the combined organic phases were washed with brine, over Na₂SO₄Dried, filtered and concentrated. To the crude residue were added 10 wt% palladium on carbon (145mg, 0.13mmol) and ethanol (4 mL). The reaction was stirred under 1 atmosphere of hydrogen for 18 hours at which time LCMS showed complete conversion. The reaction solution was filtered through celite and concentrated to give crude intermediate 45-B, which was used without further purification.

Step 3 to step 5

To intermediate 45-B (0.52mmol max) in 1:1 tetrahydrofuran: to a solution in ethanol (6mL) was added a 1M solution of KOH (aq) (0.75 mL). The reaction solution was stirred for 1 hour, neutralized with HCl (aq) and concentrated to near dryness in vacuo. The residue obtained was taken as crude product to the next step.

The residue from the previous step was dissolved in dichloromethane (5mL) and washed sequentially with (dimethylamino) -N, N-dimethyl (3H- [1,2, 3)]Triazolo [4,5-b]Pyridin-3-yloxy) formamidine hexafluorophosphate (HATU, 160mg, 0.42mmol), (2,4, 6-trifluorophenyl) methylamine (100 μ L, 0.45mmol) and N, N-diisopropylethylamine (260 μ L, 1.46mmol) were treated. The reaction mixture was stirred for 45 minutes and then at NH₄Partition between Cl (aq) and ethyl acetate. The aqueous phase was extracted 3 times with ethyl acetate and the combined organics were taken over Na₂SO₄Dried, concentrated and continued as a crude product.

The residue from the previous step was dissolved in acetonitrile (2mL), treated with magnesium bromide (145mg, 0.8mmol), and heated at 50 ℃ for 2 hours. The reaction was quenched by addition of 0.5M HCl (aq), extracted three times with dichloromethane, Na₂SO₄Drying, filtration, concentration, and purification by silica gel chromatography (0-10% MeOH/DCM) afforded compound 45:¹H NMR(400MHz,CDCl₃)13.04(br s,1H),10.28(t,J＝5.5Hz,1H),8.34(s,1H),6.65(t,J＝7.2Hz,2H),4.95(q,J＝6.4Hz,1H),4.67(dd,J＝14.4,5.9Hz,1H),4.61–4.53(m,1H),4.45(ddd,J＝6.2,4.8,3.7Hz,1H),4.33(dd,J＝9.8,7.0Hz,1H),4.18(dd,J＝10.2,4.9Hz,1H),4.07(dd,J＝10.2,3.9Hz,1H),3.99(dd,J＝9.8,6.0Hz,1H),3.77–3.66(m,2H),1.29(t,J＝7.2Hz,3H).LCMS-ESI⁺(m/z):[M+H]⁺C₂₀H₁₉F₃N₃O₅calculated value 438.13; found 438.2.

Example 46

Preparation of Compound 46

Step 1-2

To a solution of tert-butyl ((3R,4R) -4-hydroxytetrahydrofuran-3-yl) carbamate (0.52g, 2.55mmol) and triphenylphosphine (0.8g, 3.1mmol) in tetrahydrofuran (12ml) was added N, N-diisopropylethylamine (0.45ml, 2.6 mmol). The mixture was then cooled to 0 ℃ and diisopropyl azodicarboxylate (0.6ml, 3.1mmol) was added dropwise. The reaction mixture was stirred for 10 minutes at which time diphenylphosphorylazide (0.65ml, 3.0mmol) was added dropwise and the reaction mixture was allowed to gradually warm and stir for 2 hours.

The reaction mixture was then cooled again to 0 ℃ and a solution of triphenylphosphine (0.88g, 3.35mmol) in tetrahydrofuran (3mL) was added dropwise. The reaction solution was warmed to room temperature and stirred for 2 hours, at which time water (2mL) was added and the reaction stirred at 60 ℃ for 18 hours. The reaction solution was then cooled, washed with alkalised brine, washed with Na₂SO₄Dried, filtered and concentrated. Purification by silica gel chromatography (0-10% MeOH/DCM) gave tert-butyl ((3S,4S) -4-aminotetrahydrofuran-3-yl) carbamate.

Step 3

Intermediate 42-A (537mg, 2.22mmol), ((3S,4S) -4-aminotetrahydrofuran-3-yl) carbamic acid tert-butyl ester (444mg, 2.2mmol) and sodium bicarbonate (386mg, 4.59mmol) in 1:1 water: the mixture in methanol (15mL) was stirred at room temperature for 2 hours. The reaction mixture was concentrated, dissolved in methanol (10mL) and stirred at 50 ℃ for 1.5 hours to afford complete conversion. The reaction mixture was concentrated, partitioned between brine and ethyl acetate, and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were washed with Na₂SO₄Drying, filtration and concentration gave 577mg (62% yield) of intermediate 46-B, which was used further without further purification.

Step 4 to step 5

A solution of intermediate 46-B (95mg, 0.22mmol) in N, N-dimethylformamide (1mL) was cooled to 0 deg.C and treated dropwise with a 1M solution of KHMDS in tetrahydrofuran (0.4mL, 0.4 mmol). The reaction solution was then warmed to room temperature, stirred for 15 minutes, treated by dropwise addition of a solution of methyl iodide (45. mu.L, 0.72mmol) in N, N-dimethylformamide (0.5mL), and stirred for an additional 18 hours. The reaction solution was then saturated with NH₄Partition between Cl (aq) and ethyl acetate. The aqueous phase was extracted 3 times with ethyl acetate and the combined organic phases were washed with brine, over Na₂SO₄Drying, filtration, concentration and purification by silica gel chromatography (0-10% MeOH/DCM) gave the methylated product.

This material (38.2mg, 0.09mmol) was dissolved in 2:1THF: MeOH (1.5mL) and 0.5M LiOH (aq) (162 μ L) was carefully titrated to give monoester hydrolysate 46-C. After completion of the reaction, the solution was quenched by addition of 0.5M HCl (aq) (180. mu.L). The aqueous phase was extracted 3 times with ethyl acetate and the combined organic phases were extracted with Na₂SO₄Dried, filtered, concentrated and taken to the next step as crude.

Step 6

To a solution of crude intermediate 46-C (0.09mmol) in dichloromethane (2mL) was added sequentially (dimethylamino) -N, N-dimethyl (3H- [1,2,3] triazolo [4,5-b ] -3-yloxy) formamidine hexafluorophosphate (HATU, 0.40g, 0.11mmol), (2,4, 6-trifluorophenyl) methylamine (40. mu.L, 0.32mmol) and N, N-diisopropylethylamine (60. mu.L, 0.34 mmol). The reaction mixture was stirred for 45 min, concentrated on silica gel, and purified by silica gel chromatography (0-100% EtOAc/hexanes) to give intermediate 46-D.

Steps 7 to 9

A solution of intermediate 46-D (36.4mg, 0.06mmol) in 4M HCl/dioxane (0.8mL) was stirred at room temperature for 1 hour. After completing the Boc deprotection, the reaction mixture was concentrated, azeotroped three times from toluene and used further as crude product.

The residue from the above step was dissolved in 2:1THF: MeOH (1.5mL), treated with 0.5M LiOH (aq) (0.5mL) and stirred for 2h until completion. The reaction was neutralized with 0.5M HCl (aq), extracted into dichloromethane, and Na₂SO₄Dried, filtered, concentrated, and taken as crude.

The residue of the previous step was dissolved in acetonitrile (1mL), treated with magnesium bromide (29mg, 0.16mmol), and heated at 50 deg.CFor 30 minutes. Quench the reaction by adding 0.5M HCl (aq), extract 3 times with dichloromethane, Na₂SO₄Drying, filtration, concentration, and purification by silica gel chromatography (0-10% MeOH/DCM) afforded compound 46:¹H NMR(400MHz,CDCl₃)12.22(s,1H),10.33–10.18(m,1H),7.95(s,1H),6.65(t,J＝8Hz,2H),4.64(d,J＝5.7Hz,2H),4.59(t,J＝7.4Hz,1H),4.49–4.35(m,2H),4.24–4.13(m,2H),4.00(dd,J＝10.5,7.6Hz,1H),3.08(s,3H).LCMS-ESI⁺(m/z):[M+H]⁺C₁₉H₁₇F₃N₃O₅calculated value 424.11; found 424.2.

Example 47

Preparation of Compound 47

Step 1

A solution of intermediate 15-A (20.7mg, 0.06mmol) in dichloromethane (1.5mL) was sequentially treated with (dimethylamino) -N, N-dimethyl (3H- [1,2, 3)]Triazolo [4,5-b]-3-yloxy) formamidine hexafluorophosphate (HATU, 32mg, 0.08mmol), (2, 4-difluoro-3-methylphenyl) methylamine (20 μ L, 0.15mmol) and N, N-diisopropylethylamine (45 μ L, 0.25 mmol). The reaction mixture was stirred for 45 minutes and then at NH₄Partition between Cl (aq) and ethyl acetate. The aqueous phase was extracted 3 times with ethyl acetate and the combined organic layers were extracted with 5% NaHCO₃(aqueous solution) washing with Na₂SO₄Drying and filtration gave intermediate 47-B which was taken on to the next step as crude product.

Step 2

Crude intermediate 47-B (max. 0.06mmol) was dissolved in acetonitrile (1mL), treated with magnesium bromide (26mg, 0.14mmol), and heated at 50 ℃ for 1 hour. Quench the reaction by adding 0.5M HCl (aq) and extract 3 with dichloromethaneSecondly, use Na₂SO₄Drying, filtration, concentration, and purification by silica gel chromatography (0-10% MeOH/DCM) afforded compound 47:¹H NMR(400MHz,CDCl₃)12.71(s,1H),10.40(t,J＝5.4Hz,1H),8.36(s,1H),7.15(q,J＝8.2Hz,1H),6.76(t,J＝8.8Hz,1H),4.58(qd,J＝15.3,5.8Hz,2H),4.46–4.38(m,1H),4.23(d,J＝15.5Hz,1H),4.12(dt,J＝14.4,7.2Hz,1H),4.01–3.92(m,2H),3.73–3.62(m,2H),3.41(dd,J＝14.2,7.1Hz,1H),2.31–2.19(m,1H),2.17(s,3H),1.96–1.87(m,1H),1.26(t,J＝7.2Hz,3H).LCMS-ESI⁺(m/z):[M+H]⁺C₂₂H₂₄F₂N₃O₅calculated value 448.17; found 448.2.

Example 48

Preparation of Compound 48

Step 1

Intermediate 32-E (0.10g, 0.32mmol) was dissolved in a 1:1 mixture of DMF: THF (2mL) and sodium hydride (60%, 0.026g, 0.65mmol) was added. The solution was stirred at room temperature for 5 minutes, then methyl iodide (0.05mL, 0.8mmol) was added. After stirring for 1.5 h, aqueous potassium hydroxide (1M, 0.5mL, 0.5mmol) was added. The solution was stirred for an additional 45 minutes, then aqueous hydrochloric acid (6M, 0.22mL, 1.3mmol) was added and the solution was concentrated to dryness. The crude product obtained was used in the subsequent step.

LCMS-ESI⁺(m/z):[M+H]⁺C₁₄H₁₆N₂O₆Calculated value 309.11; found 309.09.

Step 2

To intermediate 48-B (0.1g, 0.32mmol) in CH₂Cl₂(4mL) to the slurry was added (2,4, 6-trifluorophenyl) methylamine (0.078g, 0.48mmol), HATU (0.15g, 0.41mmol), and N, N-diisopropylethylamine (0.2mL, 1.15 mmol). The resulting solution was stirred at room temperature for 1 hour, then CH was used₂Cl₂And (6) diluting. The solution was then washed with HCl (aq, 1M). CH for aqueous layer₂Cl₂Back-extracted (2 times), and the combined organic layers were dried over magnesium sulfate and concentrated to dryness. The crude material is then purified by column chromatography (SiO)₂2 → 10% MeOH in CH₂Cl₂Solution) to yield intermediate 48-C.

LCMS-ESI⁺(m/z):[M+H]⁺C₂₁H₂₀F₃N₃O₅Calculated value 452.14; found 452.23.

Step 3

To a solution of intermediate 48-C (0.15g, 0.34mmol) in acetonitrile (5mL) was added MgBr₂(0.12g, 0.68 mmol). The reaction mixture was stirred at 45 ℃ for 1.5 h with CH₂Cl₂And (6) diluting. The solution was washed with aqueous hydrochloric acid (1N) and aqueous NaCl (saturated). The combined aqueous layers are treated with CH₂Cl₂And (2) back extraction. The combined organic layers were concentrated and the resulting crude material was purified by preparative HPLC (10 → 60% ACN/H)₂O with 0.1% TFA modifier) to give compound 48:

¹H NMR(400MHz,DMSO-d6)12.67(s,1H),10.39(t,1H),8.44(s,1H),7.19(t,2H),4.85(dt,1H),4.53(qd 2H),4.38-4.26(m,1H),4.08-4.00(m,1H),3.90-3.82(m,1H),3.50(ddd,2H),3.09(s,3H),1.98-1.76(m,2H).

LCMS-ESI⁺(m/z):[M+H]⁺C₂₀H₁₈F₃N₃O₅calculated value 438.13; found 438.74.

Example 49

Preparation of Compound 49

Step 1

To intermediate 48-B (0.1g, 0.32mmol) in CH₂Cl₂(4mL) to the slurry was added (3-chloro-2, 4-difluorophenyl) methylamine (0.075g, 0.42mmol), HATU (0.15g, 0.41mmol) and N, N-diisopropylethylamine (0.2mL, 1.15 mmol). The resulting solution was stirred at room temperature for 1 hour, then CH was used₂Cl₂And (6) diluting. The solution was then washed with HCl (aq, 1M). CH for aqueous layer₂Cl₂Back-extracted (2 times), and the combined organic layers were dried over magnesium sulfate and concentrated to dryness. The crude material is then purified by column chromatography (SiO)₂2 → 10% MeOH in CH₂Cl₂Solution) to yield intermediate 49-B.

LCMS-ESI⁺(m/z):[M+H]⁺C₂₁H₂₀ClF₂N₃O₅Calculated value 468.11; found 468.44.

Step 2

To a solution of intermediate 49-B (0.11g, 0.23mmol) in acetonitrile (4mL) was added MgBr₂(0.1g, 0.54 mmol). The reaction mixture was stirred at 45 ℃ for 45 minutes and CH₂Cl₂And (6) diluting. The solution was washed with aqueous hydrochloric acid (1N) and aqueous NaCl (saturated). The combined aqueous layers are treated with CH₂Cl₂And (2) back extraction. The combined organic layers were concentrated and the resulting crude material was purified by preparative HPLC (10 → 65% ACN/H)₂O with 0.1% TFA modifier) to afford compound 49:

¹H NMR(400MHz,DMSO-d6)12.70(s,1H),10.44(t,1H),8.46(s,1H),7.37(td,1H),7.28(td,1H),4.87(dt,1H),4.62-4.52(m,2H),4.34(dd,1H),4.04(d,1H),3.94-3.79(m,1H),3.50(ddd,2H),3.10(s,3H),1.99-1.73(m,2H).

LCMS-ESI⁺(m/z):[M+H]⁺C₂₀H₁₈ClF₂N₃O₅calculated value 454.10; found 455.17.

Example 50

Preparation of Compound 50

Step 1

Intermediate 32-E (0.25g, 0.81mmol) was dissolved in a 1:1 mixture of DMF: THF (2mL) and sodium hydride (60%, 0.065g, 1.63mmol) was added. The solution was stirred at room temperature for 5 minutes, then 2,2, 2-trifluoroethyl triflate (0.25ml, 1.74mmol) was added. After stirring for 1.5 hours, add MeOH to quench. The solution was diluted with EtOAc and washed with NH₄Aqueous Cl (50%) wash. The aqueous layer was back-extracted with EtOAc (2x), and the combined organic layers were dried over sodium sulfate and concentrated to dryness. Subjecting the crude material to column chromatography (SiO)₂2 → 10% MeOH in CH₂Cl₂Solution) to yield intermediate 50-a.

Step 2

To intermediate 50-A (0.22g, 0.56mmol) in 3:1: 1THF: MeOH: H₂To a solution in the O (5mL) mixture was added lithium hydroxide (0.05g, 1.19 mmol). The solution was stirred for an additional 2 hours, then aqueous hydrochloric acid (6M, 0.25mL2mmol) was added and the solution was concentrated to dryness. The resulting crude 50-B was used in the subsequent step.

Step 3

To intermediate 50-B (0.21g, 0.56mmol) in CH₂Cl₂(4mL) to the slurry was added (3-chloro-2, 4-difluorophenyl) methylamine (0.12g, 0.69mmol), HATU (0.25g, 0.67mmol) and N, N-diisopropylethylamine (0.3mL, 1.67 mmol). The resulting solution was stirred at room temperature for 1 hour, and additional HATU (0.25g, 0.67mmol) and N, N-diisopropylethylamine (0.3mL, 1.67mmol) were added. After stirring at room temperature for 18 hours, with CH₂Cl₂The solution is diluted. The solution was then washed with HCl (aq, 1M). CH for aqueous layer₂Cl₂Back-extracted (2 times), and the combined organic layers were dried over magnesium sulfate and concentrated to dryness. The crude material is then purified by column chromatography (SiO)₂2 → 10% MeOH in CH₂Cl₂Solution) to yield intermediate 50-C.

Step 4

To a solution of intermediate 50-C (0.06g, 0.12mmol) in acetonitrile (5mL) was added MgBr₂(0.05g, 0.26 mmol). The reaction mixture was stirred at 45 ℃ for 1.5 h with CH₂Cl₂And (6) diluting. The solution was washed with aqueous hydrochloric acid (1N) and aqueous NaCl (saturated). The combined aqueous layers are treated with CH₂Cl₂And (2) back extraction. The combined organic layers were concentrated and the resulting crude material was purified by preparative HPLC (10 → 75% ACN/H with 0.1% TFA modifier₂O) purification to give compound 50:¹H NMR(400MHz,DMSO-d6)11.80(s,1H),10.35(t,1H),8.50(s,1H),7.32(dt,2H),4.89(dt,2H),4.67-4.51(m,2H),4.32-4.02(m,3H),3.84(d,1H),3.64(d,1H),2.09-1.81(m,2H).LCMS-ESI⁺(m/z):[M+H]⁺C₂₁H₁₇ClF₅N₃O₅calculated value 522.09; found 522.64.

Example 51

Preparation of Compound 51

Step 1

Reactant 51-A, i.e. (1S,2S,3S,5S) -2- ((tert-butyldimethylsilyl) oxy) bicyclo [3.1.0]A solution of hex-3-amine (2.06g, 9.06mmol) in dichloromethane (100ml) was stirred at room temperature and N, N-diisopropylethylamine (6.31ml, 36.23mmol) and 97% (3.95g, 18.12mmol) of di-tert-butyl dicarbonate were added. After 16 hours, the reaction mixture was concentrated. The residue was purified by flash chromatography using 0-50% ethyl acetate/hexane as eluent to give (1S,2S,3S,5S) -2- ((tert-butyldimethylsilyl) oxy) bicyclo [3.1.0]Hexane-3 amine 51-B:¹h NMR (400MHz, chloroform-d) 4.23(s,1H),4.11(dd, J ═ 7.7,4.8Hz,1H),3.32(s,1H),2.05(dd, J ═ 12.6,7.6Hz,1H),1.68-1.47(m,1H),1.46(s,9H),1.35(s,9H),1.31-1.20(m,1H),1.20-1.10(m,1H),0.83(s,9H),0.56(q, J ═ 4.3Hz,1H),0.30(td, J ═ 8.0,5.5Hz,1H),0.01(d, J ═ 7.0Hz,6H), s-ESI⁺(m/z):[M+H]⁺Chemical formula C₂₂H₄₁NO₅Si, calculated molecular weight 427.65; found 327.73(M +1-100).

Step 2

To a cold (0 ℃) solution of silyl ether 51-B (6.93mmol) in dry tetrahydrofuran (70mL) was added tetra-n-butylammonium fluoride (TBAF) (13.9mL of a 1M solution in tetrahydrofuran, 13.9mmol), and the resulting solution was stirred and warmed to 60 ℃ for 3 hours. The reaction mixture was cooled to room temperature, diluted with EtOAc (100mL), and saturated NaHCO₃And brine (50mL), then dried over magnesium sulfate, followed by solvent reduction in vacuo. The crude product was purified by flash chromatography (0-100% ethyl acetate/hexane) to give ((1S,2S,3S,5S) -2-hydroxybicyclo [ 3.1.0)]Hex-3-yl) carbamic acid tert-butyl ester 51-C.¹H NMR (400MHz, chloroform-d) 4.54(s,1H),4.28-4.20(m,1H),3.35(q, J ═ 7.9Hz,1H),2.55(br,1H),2.19(dd, J ═ 12.4,7.7Hz,1H),1.71-1.51(m,2H),1.43(s,9H),1.37-1.23(m,1H),0.65(q, J ═ 4.0Hz,1H),0.47(td, J ═ 7.8,5.5Hz,1H).

Step 3

To ((1S,2S,3S,5S) -2-hydroxybicyclo [ 3.1.0)]Hex-3-yl) carbamic acid tert-butyl ester 51-C (1.63g, 7.64mmol) and triphenylphosphine (2.6g, 9.9mmol) in 76ml THF was added N, N-diisopropylethylamine (1.5ml, 8.6mmol) and cooled in an ice bath. Diisopropyl azodicarboxylate, 95% (1.8ml, 9.17mmol) was added slowly and the mixture was stirred for 10 min. Diphenylphosphoryl azide (2.0ml, 9.28mmol) was added dropwise and the reaction was gradually warmed to room temperature over 2 hours and held at room temperature for an additional 3 hours. Dilute with ether and filter off the white solid. Saturated NH for organic matter₄Cl, saturated NaHCO₃And a brine wash. After drying over sodium sulfate and concentration, the residue was purified by flash chromatography (0-50% ethyl acetate/hexane) to give ((1S,2R,3S,5S) -2-azidobicyclo [ 3.1.0)]Hex-3-yl) carbamic acid tert-butyl ester 51-D: 1HNMR (400MHz, chloroform-d) 4.30(s,1H),3.56(d, J ═ 5.3Hz,1H),3.40(t, J ═ 8.4Hz,1H),1.68(dd, J ═ 12.4,7.3Hz,1H),1.28-1.07(m,3H),1.06(s,9H),0.19(td, J ═ 8.2,6.0Hz,1H),0.02(q, J ═ 4.1Hz,1H).

Step 4

1g of ((1S,2R,3S,5S) -2-azidobicyclo [3.1.0] is reacted at room temperature]Hex-3-yl) carbamic acid tert-butyl ester 51-D was dissolved in dichloromethane (10 mL). A solution of 4N HCl in dioxane (4mL) was added. The mixture was stirred at room temperature for 60 minutes, concentrated by evaporation from toluene and azeotropically dried twice to give (1S,2R,3S,5S) -2-azidobicyclo [3.1.0]Hexane-3-amine hydrochloride 51-E: LCMS-ESI⁺(m/z):[M+H]⁺The chemical formula is as follows: c₆H₁₀N₄Calculated molecular weight 138.17; found 138.98.

Step 5,6, 7

A mixture of pyrone 42-A (1017mg, 4.2mmol), (1S,2R,3S,5S) -2-azidobicyclo [3.1.0] hexane-3-amine hydrochloride 51-E (733mg, 4.2mmol) and sodium bicarbonate (2.12g, 25.19mmol) in water (50mL) and methanol (20mL) was stirred at room temperature for 4 hours. The mixture was concentrated and the water was removed by co-evaporation with acetonitrile. Ethanol (150mL) was added and insoluble material was filtered off through celite. The filtrate was treated with 4mL 4N HCl/dioxane, stirred for 1 hour, and used directly for the next reaction.

To the crude mixture was added 0.5g of 10% Pd/C catalyst. Purged three times with hydrogen and stirred under hydrogen atmosphere for 18 hours. After filtering off the catalyst, the mixture was concentrated to dryness. After purification (6aR,6bS,7aS,8aS) -4-methoxy-3, 5-dioxo-5, 6,6a,6b,7,7a,8,8 a-octahydro-3H-cyclopropyl [4,5 ] is obtained]Cyclopenta [1,2-e ] s]Pyrido [1,2-a ]]Pyrazine-2-carboxylic acid ethyl ester 51-G: LCMS-ESI⁺(m/z):[M+H]⁺Chemical formula C₁₅H₁₆N₂O₅Calculated molecular weight is 304.30; measured value of LCMS [ m +1 ]]＝305.16.

Step 8, 9

To (6aR,6bS,7aS,8aS) -4-methoxy-3, 5-dioxo-5, 6,6a,6b,7,7a,8,8 a-octahydro-3H-cyclopropyl [4,5 ] at room temperature]Cyclopenta [1,2-e ] s]Pyrido [1,2-a ]]To a solution of pyrazine-2-carboxylic acid ethyl ester (422mg,1.387mmol) in THF (20mL) and DMF (8mL) was added sodium hydride (60%, 222mg,5.55 mmol). After 5 min sulfomethane (345. mu.l, 5.55mmol) was added. After stirring at room temperature for 120 minutes, 1N NaOH (5mL) was added. Stir at room temperature for about 5 minutes. The resulting mixture was acidified with 3N HCl and concentrated to give (6aR,6bS,7aS,8aS) -4-methoxy-6-methyl-3, 5-dioxo-5, 6,6a,6b,7,7a,8,8 a-octahydro-3H-cyclopropylo [4,5]Cyclopenta [1,2-e ] s]Pyrido [1,2-a ]]Pyrazine-2-carboxylic acid 51-H, which was used in the next step: LCMS-ESI⁺(m/z):[M+H]⁺The chemical formula is C15H16N2O5, the molecular weight is 304.30; found 305.18.

Steps 10, 11

Steps 10 and 11 were performed in analogy to Steps 2 and 3 of Compound 48 to give 51(6aR,6bS,7aS,8aS) -4-hydroxy-6-methyl-3, 5-dioxo-N- (2,4, 6-trifluorobenzyl) -5,6,6a,6b,7,7a,8,8 a-octahydro 3H-cyclopropylo [4,5 a ] -octahydro-3H-cyclopropylo [4,5]Cyclopenta [1,2-e ] s]Pyrido [1,2-a ]]Pyrazine-2-carboxamide:¹h NMR (400MHz, chloroform-d) 12.75(s,1H),10.36(t, J ═ 5.6Hz,1H),8.23(s,1H),6.82-6.51(m,2H),5.29(s,1H),4.76-4.47(m,2H),4.31-4.00(m,2H),3.23(s,3H),2.32(dd,J＝12.7,7.4Hz,1H),2.14-1.95(m,1H),1.90(ddd,J＝9.1,6.0,3.6Hz,1H),1.59(ddd,J＝10.2,8.2,4.2Hz,1H),1.34-1.19(m,1H),0.78(q,J＝7.7Hz,1H),0.56(dt,J＝7.0,3.8Hz,1H).¹⁹F NMR (377MHz, chloroform-d) -109.19(p, J ═ 7.4Hz), -111.98(t, J ═ 6.9Hz)⁺(m/z):[M+H]⁺Chemical formula C₂₁H₁₈F₃N₃O₄433.38 as molecular weight; found 434.61.

Example 52

Preparation of Compound 52

Compound 52 was prepared in a similar manner to compound 51 using (3-chloro-2, 4-difluorophenyl) methylamine in place of 2,4, 6-trifluorobenzylamine to give 52(6aR,6bS,7aS,8aS) -N- (3-chloro-2, 4-difluorobenzyl) -4-hydroxy-6-methyl-3, 5-dioxo-5, 6,6a,6b,7,7a,8,8 a-octahydro-3H-cyclopropa [4, 5-d]Cyclopenta [1,2-E]Pyrido [1,2-a ]]Pyrazine-2-carboxamide:¹h NMR (400MHz, chloroform-d) 12.82(s,1H),10.49(t, J ═ 5.9Hz,1H),8.24(s,1H),7.41-7.11(m,1H),6.90(td, J ═ 8.5,1.8Hz,1H),4.74-4.46(m,2H),4.25-4.15(m,2H),3.23(s,3H),2.44-2.27(m,1H),2.10-2.04(m,1H),1.91(ddd, J ═ 8.6,6.0,3.6Hz,1H),1.60(d, J ═ 8.0,4.3,1.3Hz,1H),0.77(q, J ═ 7.9Hz,1H),0.57 (J ═ 8.0,4.3, 1H),0.77(q, J ═ 7.9Hz,1H), 1H, 6, 1H, 8.8, 1H.¹⁹F NMR (376MHz, chloroform-d) -72.01, -73.90, -113.53-116.27 (m), -117.43(dd, J ═ 8.6,3.0Hz).

LCMS-ESI⁺(m/z):[M+H]⁺Chemical formula C₂₁H₁₈ClF₂N₃O₄449.84 as molecular weight;

found 450.47.

Example 53

Preparation of Compound 53

Step 1

Reacting 53-A (1R,2R,3R,5R) -2- ((tert-butyldimethylsilyl) oxy) bicyclo [3.1.0]A solution of hex-3-amine (2.3g, 10.11mmol) in dichloromethane (100ml) was stirred at room temperature and N, N-diisopropylethylamine (3.5ml, 20.22mmol) and 97% (2.65g, 12.14mmol) of di-tert-butyl dicarbonate were added. After 16 hours, the reaction mixture was concentrated. The residue was purified by flash evaporation using 0-50% ethyl acetate/hexane as eluent to give (1R,2R,3R,5R) -2- ((tert-butyldimethylsilyl) oxy) bicyclo [3.1.0]Hexane-3-amine 53-B:¹h (400MHz, chloroform-d) 4.34-4.01(m,2H),3.33(d, J ═ 11.0Hz,1H),2.05(dd, J ═ 12.6,7.6Hz,1H),1.53(d, J ═ 11.9Hz,1H),1.46(s,2H),1.35(s,9H),1.31-1.22(m,1H),1.21-1.09(m,1H),0.83(s,9H),0.61-0.52(m,1H),0.30(td, J ═ 7.7,5.3Hz,1H),0.01(d, J ═ 7.1Hz,6H), s-ESI⁺(m/z):[M+H]⁺Chemical formula C₁₇H₃₃NO₃Si, calculated molecular weight 327.53; found 227.73(M +1-100).

Step 2

To a cold (0 ℃) solution of silyl ether 53-B (3.23g, 9.86mmol) in dry tetrahydrofuran (70mL) was added tetra-n-butylammonium fluoride (TBAF) (23mL of a 1M solution in tetrahydrofuran, 23mmol) and the resulting solution was warmed to 60 ℃ for 2 hours. The reaction mixture was cooled to room temperature, diluted with EtOAc (100mL), and saturated NaHCO₃And brine (50mL) and then dried over magnesium sulfate, then the solvent was removed in vacuo. The crude product was purified by flash column chromatography (0-100% ethyl acetate/hexane) to give ((1R,2R,3R,5R) -2-hydroxybicyclo [ 3.1.0)]Hexane-3-yl) carbamic acidTert-butyl ester 53-C:¹h NMR (400MHz, chloroform-d) 4.53(s,1H),4.24(dd, J ═ 6.7,5.0Hz,1H),3.35(dt, J ═ 11.4,5.9Hz,1H),2.19(dd, J ═ 12.4,7.6Hz,1H),1.73-1.51(m,2H),1.43(s,9H),1.37-1.27(m,1H),0.65(q, J ═ 4.3Hz,1H),0.47(td, J ═ 7.8,5.4Hz,1H).

Step 3

To ((1R,2R,3R,5R) -2-hydroxybicyclo [ 3.1.0)]Hexane-3-yl) carbamic acid tert-butyl ester 53-C (1.7g, 7.97mmol) and triphenylphosphine (2.7g, 10.36mmol) in 80ml THF was added N, N-diisopropylethylamine (1.67ml, 9.57mmol) and cooled in an ice bath. Diisopropyl azodicarboxylate 95% (1.88ml, 9.57mmol) was added slowly and the mixture was stirred for about 10 minutes. Diphenylphosphoryl azide (2.06ml, 9.57mmol) was then added dropwise and the reaction was gradually warmed to room temperature over 2 hours and held at room temperature for an additional 3 hours. Dilute with ether and filter off the white solid. Saturated NH for organic matter₄Cl, saturated NaHCO₃And a brine wash. After drying over sodium sulfate and concentration, the residue was purified by flash chromatography (0-50% ethyl acetate/hexane) to give ((1R,2S,3R,5R) -2-azidobicyclo [ 3.1.0)]Hex-3-yl) carbamate 53-D: LCMS-ESI⁺(m/z):[M+H]⁺The chemical formula is as follows: c₁₁H₁₈N₄O₂Molecular weight: calculated value 238.29; found 238.98.

Step 4

To ((1R,2S,3R,5R) -2-azidobicyclo [3.1.0] at 0 DEG C]Hexane-3-yl) carbamic acid tert-butyl ester 53-D (1.2g, 5.036mmol) in THF was added triphenylphosphine (3g, 11.44 mmol). The reaction solution was stirred at 0 ℃ for 20 minutes and then at room temperature for 20 hours. To this mixture was added 20mL of H₂O and stirred at room temperature for 1 hour, then warmed to 80 ℃ and stirred for 30 hours. After cooling to room temperature, the reaction mixture was diluted with EtOAc and saturated NaHCO₃And a brine wash. Drying (Na)₂SO₄) And after concentration, the residue was purified by flash column chromatography (0-20% methanol/dichloromethane) to give ((1R,2S,3R,5R) -2-aminobicyclo [3.1.0]]Hex-3-yl) carbamic acid tert-butyl ester53-E：¹H NMR (400MHz, methanol-d 4)3.22(dt, J ═ 12.0,6.4Hz,1H),3.05-2.92(m,2H),2.85(d, J ═ 5.5Hz,1H),1.57(dd, J ═ 12.4,7.5Hz,1H),1.36(td, J ═ 11.7,4.2Hz,1H),1.11(s,9H),1.00(dt, J ═ 8.6,4.1Hz,2H),0.15(td, J ═ 8.2,5.7Hz,1H),0.01(q, J ═ 4.3Hz,1H), s-ESI⁺(m/z):[M+H]⁺The chemical formula is as follows: c₁₁H₂₀N₂O₂Molecular weight: calculated value 212.29; found 212.83.

Step 5 to step 11

Steps 5 to 11 were carried out in a similar manner to steps 5 to 11 of Compound 51 to give Compound 53(6aR,7aR,8aR,8bS) -4-hydroxy-6-methyl-3, 5-dioxo-N- (2,4, 6-trifluorobenzyl) -5,6,6a,7,7a,8,8a,8 b-octahydro-3H-cyclopropa [3, 4H ] -a]Cyclopenta [1,2-E]Pyrido [1,2- α]Pyrazine-2-carboxamide:¹H NMR(400MHz,DMSO-d6)13.22(d,J＝19.1Hz,1H),10.42(t,J＝5.8Hz,1H),8.59(s,1H),7.28-6.97(m,2H),4.64(d,J＝5.7Hz,1H),4.54(dd,J＝5.9,2.8Hz,2H),3.95-3.87(m,1H),3.03(s,3H),2.29(dd,J＝12.3,6.9Hz,1H),2.07(ddd,J＝9.0,5.8,3.4Hz,1H),1.68(td,J＝11.6,4.4Hz,1H),1.47(dt,J＝5.8,3.7Hz,1H),0.79-0.58(m,2H).19F NMR(377MHz,DMSO-d6)-75.52,-108.85--110.57(m),-112.47(t,J＝7.2Hz).LCMS-ESI⁺(m/z):[M+H]⁺the chemical formula is as follows: C21H18F3N3O4, molecular weight: 433.38, respectively; found 434.51.

Example 54

Preparation of Compound 54

Step 1

Tert-butyl ((2S,3R,4S) -3, 6-dihydroxy-2-methyltetrahydro-2H-pyran-4-yl) carbamate 54-A (3g, 12.13mmol) was dissolved in 50ml of a 30% TFA in dichloromethane solution. A solution of triethylsilane (2.91ml, 0.02mol) in dichloromethane (35ml) was added. It was stirred at room temperature for 1 hour. The solution was diluted with 10mL of toluene and concentrated. Trituration with hexanes afforded the TFA salt of (2S,3R,4S) -4-amino-2-methyltetrahydro-2H-pyran-3-ol. It is used directly in the next step.

Step 2

The TFA salt of (2S,3R,4S) -4-amino-2-methyltetrahydro-2H-pyran-3-ol was dissolved in ethyl acetate (50mL) and saturated NaHCO at room temperature₃(50mL) of (to pH)>7). Di-tert-butyl dicarbonate (97 g, 60mmol) was added. It was stirred at room temperature overnight.

Brine was added and the layers were separated. The organic layer was dried (Na)₂SO₄) And concentrated. The residue was purified by flash column chromatography using 0-100% ethyl acetate/hexane as eluent to give tert-butyl ((2S,3R,4S) -3-hydroxy-2-methyltetrahydro-2H-pyran-4-yl) carbamate 54-B.¹H NMR (400MHz, chloroform-d) 4.60(s,1H),3.92(ddd, J ═ 11.9,4.9,1.6Hz,1H),3.55(d, J ═ 12.7Hz,1H),3.50-3.39(m,1H),3.22(dq, J ═ 9.1,6.2Hz,1H),3.00(t, J ═ 9.1Hz,1H),1.95-1.84(m,1H),1.64-1.49(m,1H),1.45(s,8H),1.30(d, J ═ 6.1Hz,3H), no LCMS mass.

Step 3

To a solution of tert-butyl ((2S,3R,4S) -3-hydroxy-2-methyltetrahydro-2H-pyran-4-yl) carbamate (1.09g, 4.713mmol) and triphenylphosphine (1.358g, 5.184mmol) in 100mL THF was added N, N-diisopropylethylamine (0.985mL, 5.655mmol) and then cooled in an ice bath.

Diisopropyl azodicarboxylate 95% (1.113ml, 5.655mmol) was added slowly and the mixture was stirred for about 10 minutes. Diphenylphosphoryl azide (1.22ml, 5.655mmol) was then added dropwise and the reaction was gradually warmed to room temperature over 2 hours and held at room temperature for an additional 3 hours. Dilute with ether and filter. Saturated NH for filtrate₄Cl, saturated NaHCO₃Saline water washingWashing with Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated and purified by flash column chromatography (0-100% ethyl acetate/hexane) to give tert-butyl ((2S,3S,4S) -3-azido-2-methyltetrahydro-2H-pyran-4-yl) carbamate 54-C.¹HNMR (400MHz, chloroform-d) 4.78(d, J ═ 8.0Hz,2H),3.97(ddd, J ═ 11.8,4.9,1.6Hz,3H),3.90-3.69(m,5H),3.66(d, J ═ 3.3Hz,2H),3.58(qd, J ═ 6.4,1.4Hz,3H),3.46(td, J ═ 12.1,2.5Hz,3H),3.26(ddd, J ═ 11.8,10.9,4.7Hz,1H),2.84(td, J ═ 6.6,1.3Hz,1H),2.46(dd, J ═ 6.5,2.1Hz,1H),2.07-1.91(m,1H), 1.74H, 1.5 (td, 1.5H), 1H, 13.5H, 33.5H, 33.7H, 1H, 13H, 33.5 (dd, 13H, 1.

Step 4

Tert-butyl ((2S,3R,4S) -3-hydroxy-2-methyltetrahydro-2H-pyran-4-yl) carbamate 54-C (830mg, 3.24mmol) was dissolved in dichloromethane at room temperature and treated with 4N HCl in dioxane. Evaporation to dryness followed by twice azeotropy with toluene gave the HCl salt of (2S,3S,4S) -3-azido-2-methyltetrahydro-2H-pyran-4-amine 54-D.

Step 5 to step 11

Steps 5 to 11 were carried out in a similar manner to steps 5 to 11 of the compound 51 to give the compound 54(4S,4aS,11aS) -7-hydroxy-4, 5-dimethyl-6, 8-dioxo-N- (2,4, 6-trifluorobenzyl) -1,2,4,4a, 5,6,8,11 a-octahydropyrano [3,4-e ]]Pyrido [1,2-a ]]Pyrazine-9-carboxamide:¹h NMR (400MHz, methanol-d 4)8.45(s,1H),6.97-6.74(m,2H),4.74-4.53(m,3H),4.13-3.86(m,3H),3.71(ddd, J ═ 12.3,9.0,3.5Hz,1H),3.26(s,3H),2.28(ddt, J ═ 13.7,9.0,4.5Hz,1H),2.00(dt, J ═ 14.4,4.5Hz,1H),1.36(d, J ═ 7.0Hz,3H), 19F NMR (377MHz, methanol-d 4) -78.26, -110.66(ddd, J ═ 15.3,9.0,6.1Hz), -114.22(t, J ═ 7.1Hz, s-H), -ESI (t, J ═ 7.1)⁺(m/z):[M+H]⁺The chemical formula is as follows: C21H20F3N3O5, molecular weight: 451.40, respectively; found 452.17.

Example 55

Preparation of Compound 55

Compound 55 is prepared in a similar manner aS compound 54, substituting (3-chloro-2, 4-difluorophenyl) methylamine for 2,4, 6-trifluorobenzylamine to give (4S,4aS,11aS) -N- (3-chloro-2, 4-difluorobenzyl) -7-hydroxy-4, 5-dimethyl-6, 8-dioxo-1, 2,4,4a,5,6,8,11 a-octahydropyrano [3,4-e ]]Pyrido [1,2-a ]]Pyrazine-9-carboxamide:¹h NMR (400MHz, methanol-d 4)8.47(s,1H),7.37(td, J ═ 8.1,5.8Hz,1H),7.20-6.93(m,1H),4.68(d, J ═ 31.9Hz,3H),4.14-3.87(m,3H),3.71(ddd, J ═ 12.2,9.1,3.4Hz,1H),3.27(s,3H),2.39-2.18(m,1H),2.05-1.88(m,1H),1.38(d, J ═ 7.0Hz,3H), 19F NMR (377MHz, methanol-d 4) -78.25, -116.52-118.01 (m), -119.84(d, J ═ 7.7Hz), lcm-ESI⁺(m/z):[M+H]⁺The chemical formula is as follows: c₂₁H₂₀ClF₂N₃O₅Molecular weight: 467.85; found 448.15.

Example 56

Preparation of Compound 56

Step 1

To a solution of tert-butyl ((3S,4S) -4-hydroxytetrahydro-2H-pyran-3-yl) carbamate 56-A (3.0g, 13.81mmol) and triphenylphosphine (4.0g, 15.25mmol) in THF (100ml) was added N, N-diisopropylethylamine (3.0ml, 17.20mmol), and the mixture was cooled in an ice bath. Diisopropyl 95% azodicarboxylate (3.3ml, 16.76mmol) was added slowly and the mixture was stirred for about 10 minutes. Then diphenyl is added dropwisePhosphoryl azide (3.6ml, 16.76mmol), the reaction was gradually warmed to room temperature over 2 hours and held at room temperature for an additional 3 hours. The mixture was diluted with ether, filtered and the filtrate was diluted with saturated NH₄Cl saturated NaHCO₃And brine, then dried (Na)₂SO₄) And concentrated. The residue was purified by flash column chromatography (0-100% ethyl acetate/hexane) to give tert-butyl ((3R,4R) -4-azidotetrahydro-2H-pyran-3-yl) carbamate 56-B.¹H NMR (400MHz, chloroform-d) 4.87(d, J ═ 8.9Hz,1H),3.87(dq, J ═ 9.8,4.4,4.0Hz,2H),3.71(ddd, J ═ 11.8,7.8,3.9Hz,1H),3.59(dd, J ═ 11.7,4.3Hz,2H),3.48(dd, J ═ 11.4,7.5Hz,1H),1.87(dtd, J ═ 8.7,5.5,3.7Hz,2H),1.42(s,9H).

Step 2

Tert-butyl ((3R,4R) -4-azidotetrahydro-2H-pyran-3-yl) carbamate (1.72g, 7.1mmol) was dissolved in DCM at room temperature and treated with 4N HCl in dioxane. It was evaporated to dryness and then azeotroped twice with toluene to give the HCl salt 56-C of (3R,4R) -4-azidotetrahydro-2H-pyran-3-amine.

Steps 3 to 9

Steps 3-9 were carried out in a similar manner to steps 5-11 of Compound 51, substituting ethyl iodide for methyl iodide to give compound 56(4aR,11aR) -5-ethyl-7-hydroxy-6, 8-dioxo-N- (2,4, 6-trifluorobenzyl) -1,3,4,4a,5,6,8,11 a-octahydropyrano [4,3-e ]]Pyrido [1,2-a ]]Pyrazine-9-carboxamide:¹HNMR (400MHz, methanol-d 4)8.60(s,1H),6.88(t, J ═ 8.4Hz,2H),4.74(dt, J ═ 15.2,2.0Hz,1H),4.65(s,2H),4.44(d, J ═ 2.8Hz,1H),4.14(dt, J ═ 11.3,3.9Hz,1H),4.03-3.80(m,3H),3.64(td, J ═ 11.5,2.5Hz,1H),3.39-3.32(m,1H),1.99(dd, J ═ 14.0,3.6Hz,1H),1.71(ddt, J ═ 14.1,11.0,5.7, 1H),1.28(t, J ═ 7, 1H),3.7, 3H).¹⁹F NMR 19F NMR (377MHz, methanol-d 4) -78.20, -110.71(ddd, J ═ 15.3,9.0,6.2Hz), -114.19(t, J ═ 7.1Hz)⁺(m/z):[M+H]⁺The chemical formula is as follows: c₂₁H₂₀F₃N₃O₅Molecular weight: 451.40, respectively; found 452.19.

Example 57

Preparation of Compound 57

Compound 57 was prepared in a similar manner as compound 56, substituting (3-chloro-2, 4-difluorophenyl) methylamine for (2,4, 6-trifluorophenyl) methylamine to give compound 57(4aR,11aR) -N- (3-chloro-2, 4-difluorobenzyl) -5-ethyl-7-hydroxy-6, 8-dioxo-1, 3,4,4a,5,6,8,11 a-octahydropyrano [4,3-e ] -a]Pyrido [1,2-a ]]Pyrazine-9-carboxamide:¹h NMR (400MHz, methanol-d 4)8.62(s,1H),7.38(td, J ═ 8.4,6.0Hz,1H),7.08(td, J ═ 8.7,1.9Hz,1H),4.79-4.68(m,1H),4.66(s,2H),4.44(d, J ═ 3.4Hz,1H),4.14(dt, J ═ 11.6,4.1Hz,1H),4.03-3.81(m,3H),3.64(td, J ═ 11.5,2.5Hz,1H),3.40-3.32(m,1H),2.10-1.91(m,1H),1.81-1.59(m,1H),1.29(t, J ═ 7.2, 3H).¹⁹F NMR 19F NMR (377MHz, methanol-d 4) -115.45-118.97 (m), -119.92(d, J ═ 7.9Hz)⁺(M/z) [ M + H formula: c₂₁H₂₀ClF₂N₃O₅Molecular weight: 467.85; found 468.15.

Example 58

Preparation of Compound 58

Compound 58 was prepared in analogy to the synthetic sequence described previously for compound 29, using N-Boc protected (1R,2S) -cyclopentane-1, 2-diamine as the reaction partner with the pyrone 1-B described previously. Final purification was performed on a 4g silica gel column eluting from 100% EtOAc to 9:1EtOAc/MeOH according to the reference procedure (see above) to give final product 58.

¹H NMR(400MHz,CD3OD)8.43(s,1H),6.88(m,2H),4.67(m,1H),4.64-4.55(m,1H),4.44(s,1H),4.11(m,1H),3.12(s,3H),2.34(dq,J＝14.0,7.3Hz,1H),2.14(dt,J＝7.3,4.4Hz,2H),1.96(m,1H),1.91-1.76(m,2H).

LCMS-ESI+(m/z):[M+H]+C₂₀H₁₉F₃N₃O₄Calculated value 422.13; found 422.2.

Example 59

Preparation of Compound 59

Compound 59 was prepared in analogy to the synthetic sequence described hereinbefore for compound 4, using tert-butyl ((1R,2S) -2-aminocyclohexyl) carbamate as reaction partner with the aforementioned pyrone 1-B. The final purification was performed on a 4g silica gel column in a similar sequence to that described previously (see above), eluting with 100% EtOAc to 9:1EtOAc/MeOH, to give final product 59.

¹H NMR (400MHz, chloroform-d) 12.62(s,1H),10.44(s,1H),8.41(s,1H),6.66-6.61(m,2H),4.65-4.60(dd, m,1H),4.59(m,1H),4.24(m,1H),4.10(m,1H),3.76(s,3H),2.27(s,1H),2.10(m,2H),1.99(m,1H),1.85(m,2H),1.60-1.76(bm,4H),1.22(m,1H).

LCMS-ESI+(m/z):[M+H]+C₂₀H₁₉F₃N₃O₄Calculated value 436.2; found 436.1.

Example 60

Preparation of Compound 60

Step 1,2,3

A mixture of pyrone 1-B (500mg, 1.44mmol) and tert-butyl ((1R,2S) -2-aminocyclohexyl) carbamate (60-A) (310mg, 1.44mmol) with sodium bicarbonate (242mg, 2.88mmol) in water (10mL) and ethanol (10mL) was stirred at room temperature for 16 h. It was concentrated and co-evaporated with acetonitrile to remove water. The crude residue was used directly for the next reaction.

The crude residue was dissolved in dichloromethane (10mL) and treated with 4N HCl in dioxane (6 mL). It was stirred at room temperature for 2 hours and concentrated to dryness.

To the above residue were added 20mL of anhydrous ethanol and 1, 8-diazabicyclo [5.4.0 ]]Undec-7-ene (2.0ml, 13.5 mmol). The mixture was warmed to 60 ℃ for 120 minutes. The mixture was concentrated. The residue was purified by flash chromatography on silica gel to give (4aR,11aS) -7-methoxy-6, 8-dioxo-2, 3,4,4a,5,6,8,11 a-octahydro-1H-pyrido [1,2-a ]]Quinoxaline-9-carboxylic acid methyl ester 60-C. LCMS-ESI + (M/z) [ M + H ]]+ formula (II): c₂₂H₂₄N₂O₅Molecular weight: calculated value 396.44; found 397.34.

Step 4

To a mixture of reaction 60-C (528mg, 1.33mmol) in THF (10mL) and methanol (2mL) was added 1N NaOH (5 mL). The mixture was stirred at room temperature for about 60 minutes, then acidified with 2mL 3N HCl and concentrated to dryness. The crude acid 60-D was used directly in the next reaction. LCMS-ESI + (M/z) [ M + H ]]+ formula (II): c₂₀H₂0N₂O₅Molecular weight: calculated value 368.38; found 369.23.

Step 5, step 6

Intermediate 60-D (1.33mmol) and (2,4, 6-trifluorophenyl) methylamine (429mg, 2.66mmol) were suspended in dichloromethane (70mL) and treated with diisopropylethylamine (1mL, 6.2mmol) at room temperature. (dimethylamino) -N, N-dimethyl (3H- [1,2, 3) is added to the suspension]Triazolo [4,5-b]-3-yloxy) formamidine hexafluorophosphate (HATU, 0.76g, 2.0mmol). After 0.5 h, the reaction mixture was diluted with dichloromethane and saturated NH with 3% aqueous LiCl₄Cl and 0.5 NHCl. The organic layer was dried (Na)₂SO₄) And concentrating. Purification by flash chromatography gave the desired amide.

The residue from the previous step was dissolved in TFA (2mL) at room temperature and stirred for 30 min. The mixture was concentrated and the residue was purified by flash chromatography to give 60.¹H NMR(400MHz,DMSO-d6)12.64(s,1H),10.41(t,J＝5.8Hz,1H),9.18(s,1H),8.44(s,1H),7.31-6.94(m,2H),4.71-4.28(m,3H),4.22-3.88(m,1H),2.15-1.81(m,1H),1.78-1.48(m,4H),1.38(dt,J＝27.0,8.4Hz,3H).¹⁹F NMR(376MHz,DMSO-d6)-109.35(tt,J＝9.1,6.3Hz),-112.48(p,J＝7.5Hz).LCMS-ESI+(m/z):[M+H]+ formula (II):

C₂₀H₁₈F₃N₃O₄molecular weight: 421.32, respectively; found 422.31.

Example 61

Preparation of Compound 61

Step 1

To a 50mL 1-necked round bottom flask was added reactant 2-A (0.165g, 1.45mmol), 1-B (0.50g, 1.45mmol) and NaHCO in ethanol (10mL) and water (10mL)₃(0.25g, 2.9 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated, redissolved in EtOAc (50mL), washed with water (2 ×), and Na₂SO₄And (5) drying. After concentration, the crude product was purified by silica gel column chromatography eluting with hexane-EtOAc to afford 2-C. LCMS-ESI + (M/z) [ M + H ]]+; found value is 397.

Step 2

Firing into 50mL of 1-necked round bottomThe flask was charged with reactant 2-C (0.17g, 0.43mmol) in THF (5mL) and MeOH (5 mL). To the reaction solution was added 1N KOH in water (1.3 mL). The reaction mixture was stirred at room temperature for 1 hour. After acidification with 1N HCl, the solution was concentrated to completely remove the solvent and the crude acid was used in the next step without further purification. The crude acid (0.27mmol), 2,4, 6-trifluorophenylmethylamine (0.084g, 0.52mmol), DIPEA (0.169g, 1.3mmol) and HATU (0.20g, 0.52mmol) were stirred in DCM (10ml) at room temperature for 1 hour. The reaction mixture was concentrated, redissolved in EtOAc (50mL) and treated with saturated NaHCO₃(2x), saturated NH₄Cl washing with NH₄And drying the Cl. After concentration, the crude product was purified by silica gel column chromatography eluting with hexane-EtOAc to afford 61-A. LCMS-ESI + (M/z) [ M + H ]]+; found 512.

Step 3

A50 mL 1-necked round bottom flask was charged with a solution of reactant 61-A (0.03g, 0.06mmol) in TFA (2 mL). The reaction mixture was stirred at room temperature for 30 minutes. The solution was concentrated and the residue was purified by flash chromatography eluting with 0-20% MeOH in EtOAc to afford compound 61.¹H NMR(400MHz,DMSO-d6)12.84(s,1H),10.42(t,J＝5.6Hz,1H),9.37(s,1H),8.28(s,1H),7.18(t,J＝8.7Hz,2H),4.53(d,J＝5.7Hz,2H),3.88(d,J＝11.3Hz,1H),3.51(d,J＝10.9Hz,1H),2.10-1.78(m,2H),1.71(d,J＝11.4Hz,1H),1.64-1.08(m,4H).¹⁹F NMR(376MHz,DMSO-d6)-109.41(m,1F),-112.48(d,J＝7.8Hz,2F).LCMS-ESI+(m/z):[M+H]+ measured value 422.

Example 62

Preparation of Compound 62

Step 1

To a 50mL 1-necked round bottom flask was added reactant 1 in ethanol (10mL) and water (10mL)A (0.165g, 1.45mmol), 1-B (0.50g, 1.45mmol) and NaHCO₃(0.25g, 2.9 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated, redissolved in EtOAc (50mL), washed with water (2 ×), and Na₂SO₄And (5) drying. After concentration, the crude product was purified by silica gel column chromatography eluting with hexane-EtOAc to afford 1-C. LCMS-ESI⁺(m/z):[M+H]⁺(ii) a Found value is 397.

Step 2

To a 50mL 1-necked round bottom flask was added reactant 1-C (0.17g, 0.43mmol) in THF (5mL) and MeOH (5 mL). To the reaction solution was added 1N KOH in water (1.3 mL). The reaction mixture was stirred at room temperature for 1 hour. After acidification with 1N HCl, the solution was concentrated to completely remove the solvent and the crude acid was used in the next step without further purification. A solution of the crude acid (0.27mmol), 2,4, 6-trifluorophenylmethylamine (0.084g, 0.52mmol), DIPEA (0.169g, 1.3mmol) and HATU (0.20g, 0.52mmol) in DCM (10ml) was stirred at room temperature for 1 hour. The reaction mixture was concentrated, redissolved in EtOAc (50mL) and treated with saturated NaHCO₃(2x), saturated NH₄Cl washing, Na washing₂SO₄And (5) drying. After concentration, the crude product was purified by silica gel column chromatography eluting with hexane-EtOAc to give 62-A. LCMS-ESI⁺(m/z):[M+H]⁺(ii) a Found 512.

Step 3

A50 mL 1-necked round bottom flask was charged with a solution of reactant 62-A (0.03g, 0.06mmol) in TFA (2 mL). The reaction mixture was stirred at room temperature for 30 minutes. The solution was concentrated and the residue was purified by flash chromatography using 0-20% MeOH in EtOAc to afford compound 62.¹H NMR(400MHz,DMSO-d6)10.41(t,J＝5.9Hz,1H),9.38(s,1H),8.28(s,1H),7.18(t,J＝8.6Hz,2H),4.53(d,J＝5.7Hz,2H),3.88(d,J＝10.4Hz,1H),3.48(d,J＝11.1Hz,1H),1.95(dd,J＝33.6,17.4Hz,2H),1.70(d,J＝11.9Hz,1H),1.60-1.14(m,5H).¹⁹F NMR(376MHz,DMSO-d6)-109.41(m,1F),-112.48(d,J＝7.8Hz,2F).

LCMS-ESI⁺(m/z):[M+H]⁺Found 422.

Example 63

Preparation of Compound 63

Step 1

To a 50mL 1-necked round bottom flask was added the reactant 4-A (0.165g, 1.45mmol), 1-B (0.50g, 1.45mmol) and NaHCO in ethanol (10mL) and water (10mL)₃(0.25g, 2.9 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated, redissolved in EtOAc (50mL), washed with water (2 ×), and Na₂SO₄And (5) drying. After concentration, the crude product was purified by silica gel column chromatography eluting with hexane-EtOAc to afford 4-C. LCMS-ESI⁺(m/z):[M+H]⁺(ii) a Found value is 397.

Step 2

To a 50mL 1-necked round bottom flask was added reactant 4-C (0.17g, 0.43mmol) in THF (5mL) and MeOH (5 mL). To the reaction solution was added 1N KOH in water (1.3 mL). The reaction mixture was stirred at room temperature for 1 hour. After acidification with 1N HCl, the solution was concentrated to completely remove the solvent and the crude acid was used in the next step without further purification. A solution of the crude acid (0.27mmol), 2,4, 6-trifluorophenylmethylamine (0.084g, 0.52mmol), DIPEA (0.169g, 1.3mmol) and HATU (0.20g, 0.52mmol) in DCM (10ml) was stirred at room temperature for 1 hour. The reaction mixture was concentrated, redissolved in EtOAc (50mL) and treated with saturated NaHCO₃(2x), saturated NH₄Cl washing, Na washing₂SO₄And (5) drying. After concentration, the crude product was purified by silica gel column chromatography eluting with hexane-EtOAc to afford 63-A.

LCMS-ESI⁺(m/z):[M+H]⁺(ii) a Found 512.

Step 3

A50 mL 1-necked round bottom flask was charged with a solution of reactant 63-A (0.03g, 0.06mmol) in TFA (2 mL). The reaction mixture was stirred at room temperature for 30 minutes. The solution was concentrated and the residue was purified by flash chromatography using 0-20% MeOH in EtOAc to afford compound 63.¹H NMR (400MHz, chloroform-d) 11.70(s,1H),10.65-10.18(m,1H),8.27(s,1H),7.26(m,1H),6.90(td, J ═ 9.7,6.4Hz,1H),4.89(s,1H),4.60(d, J ═ 6.0Hz,2H),4.09(dd, J ═ 11.4,2.6Hz,1H),3.96-3.66(m,2H),2.68(s,1H),2.15-1.43(m,6H).¹⁹FNMR (376MHz, chloroform-d) 120.53-120.85 (m,1F), -134.68-136.79 (m,1F), -142.26-144.11 (m,1F)⁺(m/z):[M+H]⁺Found 422.

Example 64

Antiviral assays in MT4 cells

To perform an antiviral assay using MT4 cells, 0.4 μ L of a 3-fold serial dilution of compound in DMSO at 189X assay concentration was added in quadruplicate to 40 μ L of cell growth medium (RPMI1640, 10% FBS, 1% penicillin/streptomycin, 1% L-glutamine, 1% HEPES) in each well of a 384-well assay plate (10 concentrations).

2×10⁶A1 mL aliquot of MT4 cells was preinfected with 25 μ L (MT4) of cell growth medium (mock infection) or 1:250 freshly diluted ABI stock of concentrated HIV-IIIb for 1 and 3 hours, respectively, at 37 deg.C (0.004 m.o.i. for MT4 cells). Infected and uninfected cells were diluted in cell growth medium and 35 μ L of 2000(MT4) cells were added to each well of the assay plate.

The assay plates were then incubated in a 37 ℃ incubator. After 5 days of incubation, 25 μ L of 2X concentrated CellTiter-GloTM reagent (catalog No. G7573, Promega Biosciences, inc., Madison, WI) was added to each well of the assay plate. Cell lysis was performed by incubation at room temperature for 2-3 minutes, followed by chemiluminescence reading using an Envision reader (PerkinElmer).

The compounds of the present disclosure showed antiviral activity in this assay, as shown in table 1 below. Thus, the compounds of the embodiments disclosed herein are useful for treating the proliferation of the HIV virus, treating AIDS, or delaying the onset of AIDS or ARC symptoms.

Example 65

Human PXR activation assay

Luciferase reporter gene assay.Stably transformed tumor cell lines (DPX2) were placed in 96-well microtiter plates. DPX2 cells contained the human PXR gene (NR1I2) and a luciferase reporter gene linked to two promoters identified in the human CYP3a4 gene (i.e., XREM and PXRE). Cells were treated with six concentrations of each compound (0.15-50 μ M) and incubated for 24 hours. The number of viable cells is determined and reporter activity is assessed. Positive control: 6 concentrations (0.1)20 μ M) of rifampicin. Maximum fold induction% E relative to 10 or 20. mu.M RIF_maxCalculated for the tested compounds according to the following equation, the DMSO background has been adjusted: % E_max(fold induction-1)/(maximum fold induction of RIF-1) x 100%.

Example 66

OCT2 inhibition assay

Study of test Compounds on OCT 2-mediated model substrates in wild-type and OCT 2-transfected MDCKII cells at 7 concentrations from 0.014. mu.M to 10. mu.M¹⁴Dose-dependent inhibition of the absorption of C-Tetraethylammonium (TEA).

At 37 deg.C, 90% humidity and 5% CO₂In an incubator containing 1% Pen/Strep, 10% fetal bovine serum and 0.25mg/mL hygromycin B, MDCKII cells were maintained in minimal essential medium (M)EM) medium containing 5mM sodium butyrate was added to MDCKII cells in flasks 24 hours prior to assay and the cells were grown to 80-90% confluence, on assay day, cells were trypsinized and treated with 5 × 10⁶Million cells/mL were resuspended in Krebs-Henseleit buffer (KHB), pH 7.4. Cells were preincubated in assay plates for 15 minutes prior to addition of test compound or substrate.

Test compounds were serially diluted in DMSO and then added (2 μ Ι _) to 0.4mL KHB buffer containing wild type or OCT2 transfected cells and incubated for 10 minutes. By adding 0.1mL of 100. mu.M KHB buffer solution¹⁴C-TEA was initially assayed (final concentration 20. mu.M after mixing). The concentration of TEA is based on K_m. After incubation for 10 min, the mixture was quenched by the addition of 0.5mL ice-cold 1 × PBS buffer. The sample was then centrifuged at 1000rpm for 5 minutes and the supernatant removed. The washing step was repeated four times with ice-cold PBS. Finally, the cell pellet was lysed with 0.2N NaOH and left at room temperature for at least 30 minutes to ensure complete lysis. The samples were then counted on a liquid scintillation counter and the following calculations were performed using dpm counts. The% inhibition was calculated as follows: inhibition [% 1- { [ OCT2]_i-[WT]_ni}/{[OCT2]_ni-[WT]_ni}]100, wherein [ OCT2]_iRepresenting dpm counts of an OCT2 cell in the presence of test compound, [ OCT2]_niRepresenting dpm counts of OCT2 cells in the absence of test compound, and [ WT]_niRepresenting dpm counts of wild type cells in the absence of test compound.

TABLE 1

The data in table 1 represent the average over time for each assay for each compound. For some compounds, multiple assays were performed throughout the life cycle of the project.

Example 67

Pharmacokinetic analysis of Male SD rats after oral or intravenous administration

Pharmacokinetic analysis was performed after intravenous or oral administration of compounds 25b and 39 to rats.

Test compounds were formulated in 5% ethanol, 55% PEG 300 and 40% water at 0.1mg/mL for IV infusion and oral administration.

Each dosing group consisted of 3 male Sprague-Dawley rats. At the time of administration, the average weight of the animals was 0.25 kg. Animals were fasted overnight prior to dosing until 4 hours post-dosing.

For the IV infusion group, the test article was administered by intravenous infusion over 30 minutes. The infusion rate was adjusted to deliver a dose of 0.5mg/kg depending on the body weight of each animal. For the oral administration group, 0.5mg/kg of the test article was administered at a dose of 5mL/kg by oral gavage.

For pharmacokinetic analysis of intravenously administered compounds, venous blood samples (approximately 0.3mL each) were taken continuously from each animal at 0, 0.250, 0.483, 0.583, 0.750, 1.50, 3.00, 6.00, 8.00, 12.0, 24.0, 48, and 72 hours post-dose. Blood samples were collected into Vacutainer containing EDTA-K2 as an anticoagulant^TMTubes, and immediately placed on wet ice, await centrifugation of plasma. The concentration of the test compound in plasma was determined using the LC/MS method. Aliquots of 50 μ L of each plasma sample were added to a clean 96-well plate and 200 μ L of cold acetonitrile/internal standard solution (ACN)/(ISTD) was added. After protein precipitation, an aliquot of 110. mu.L of supernatant was transferredMoving to a clean 96-well plate, diluting with 300 μ L of water, injecting 10 μ L aliquots of the above solutions into an abciex API-4000 triple quadrupole LC/MS system using a HyPurity C18HPLC column (30 × 2.1.1 mm, 3 μ) from Thermo-Hypersil (Part #22103 032130), Agilent 1200 series binary Pump (P/N G1312A Bin Pump) for elution and separation, using HTS Pal auto-injector (apap technologies, Carrboro, NC) for sample injection, using API-4000 triple quadrupole mass spectrometer multiplex reaction monitoring mode (Applied Biosystems, fost, CA), using two mobile phases for liquid chromatography, mobile phase a containing 0.1% formic acid and 1% isopropylamine in aqueous solution, mobile phase B containing 0.1% formic acid and 1% isopropylamine in aqueous solution, the mean time of plasma concentration-5 μ L for removal of the compounds is shown in the low-5.5-5-three-column pharmacokinetic profiles, the in-5-three column time profiles of the following the sample removal rate of the sample is shown as the low-5-three column curve of the in-three column time curve, the sample removal rate, the low-5-three column curve of the sample removal rate of the sample is shown in the low-5-three column curve.

TABLE 2 rat pharmacokinetics

Compound (I)	Cl(L/h/kg)	Vss(L/kg)	MRT(h)	% F (solution)
					25b	0.0013	0.141	119	39
39	0.0023	0.212	105	15
					Dolabrasvir	0.01	0.17	12.4	84

Some reference compounds were also tested in pharmacokinetic analysis in dogs.

Example 68

Resistance test

To perform an antiviral assay for MT-2 cells, compounds serially diluted 3-fold of the assay concentration of 50 μ Ι _ 2X in medium with 10% FBS were added to each well of a 96-well plate (9 concentrations) in triplicate. Disease of MT-2 cells by using one volumeThe virulent inoculum (which has been determined to produce 90% cell kill) was infected with the wild-type or mutant variant of HIV-1 for 3 hours. Then 50. mu.l of a solution containing 10% FBS (Beckman-biosystems) (Beckman, Ltd.) was added to each well containing 50. mu.l of the serially diluted compound1.5 × 104 cells) was added to the culture medium, then the plates with the HIV-infected culture were incubated at 37 ℃ for 5 days in the presence of the test compound, after 5 days of incubation, 100 μ L CelTiter-Glo was added to each well^TMReagents (catalog No. G7571, Promega Biosciences, inc., Madison, WI). Cell lysis was performed by incubation at room temperature for 10 minutes, followed by a readout of chemiluminescence.

Data analysis

Direct analysis of chemiluminescence readings from 10-point antiviral dose response by curve fitting with equation (I) to determine EC₅₀。

Where y is cell survival, M is maximum cell survival achieved by drug protection, H is baseline cell survival without drug protection, n is the Hill coefficient of antiviral dose response, M is the Hill coefficient of cytotoxic dose response, and [ I ] is inhibitory concentration.

EC₅₀Values (mean ± standard deviation) were calculated from at least three independent experiments (three each). Fold change in antiviral Activity of test Compounds to average EC per mutant Virus₅₀Divided by the mean EC of control WT virus₅₀The ratio of (a) to (b) is calculated. Lower fold change indicates lower resistance of the mutant virus to the compound.

Example 69

Plasma protein binding

Apparatus and reagents for dialysis

Plasma protein binding was determined using HTD96b equilibrium dialysis machine with base plate, stainless steel compression plate and teflon block. The 9 teflon rods are labeled in sequence from a to I and assembled with two stainless steel connecting rods. The membrane was placed between two teflon rods, the membrane was positioned at about 2mm from the top edge of the rod, and the lower membrane edge overlapped the bottom of all holes. The membrane was soaked in water for about 20 minutes, in ethanol (30/70v/v) for about 20 minutes, and rinsed three times with water to remove the ethanol. Soak in PBS for at least 30 minutes. Plasma in sodium EDTA (bioreclaimation or similar) was used. Plasma (without pH adjustment) was stored at-80 ℃ and thawed at room temperature prior to use.

Storage solution and quenching

Stock solutions of the compounds tested were 200 μ M in DMSO. The quenching solution used was 50nM of internal standard in 100% CAN.

Test article solutions in plasma and CCM

To prepare a 2 μ M solution of the test compound in plasma, 5 μ L of 200 μ M stock solution was added to 495 μ L of blank plasma.

Balanced dialysis procedure-HTD 96b dialysis machine

To one side of the well was added 100 μ L of plasma containing 2 μ M of test compound. 100 μ L buffer (for plasma vs. buffer) was added to the other side of the well.

The 96-well plate was covered with an adhesive sealing film and incubated at 37 ℃ with slow rotation for 24 hours.

This procedure was repeated for each compound.

Sample preparation for analysis

50 μ L of plasma sample was placed in a 96-well plate and 50 μ L of buffer was added.

50 microliters of buffer was placed in a 96-well plate. 50L of plasma was added.

Add 300 μ L of quench solution, seal the plate and shake for 15 minutes.

The material was centrifuged at 3000RPM for 30 minutes and approximately 250 μ Ι _ was transferred to a short plate. Samples were analyzed by LC/MS.

The resulting data, shown in the last row of table 3, "% Free" corresponds to the percentage of compounds that do not bind protein.

Table 3-resistance (fold change in MT2 cells, mutant vs. wild type (wt)) and% Free in plasma protein binding Compound (I)

All U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applications and non-patent publications referred to in this specification are herein incorporated by reference in their entirety for all purposes to the extent not inconsistent with this disclosure.

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 deviating from the spirit and scope of the disclosure. Accordingly, the disclosure is not to be restricted except in light of the attached claims.

Claims (72)

1. A compound of formula (Ia):

or a pharmaceutically acceptable salt thereof, wherein:

a' is selected from C_3-7Monocyclic cycloalkyl and 4 to 7 membered monocyclic heterocyclyl; wherein C is_3-7Monocyclic cycloalkyl and 4-7 membered monocyclic heterocyclyl are each optionally substituted with 1 to 5R⁴Substituted by groups;

each R⁴Independently selected from oxo, methyl and ethyl; or two R attached to the same or adjacent carbon atoms⁴Linked together to form a spiro or fused C_3-6Cycloalkyl or a 4 to 6 membered heterocyclyl ring;

R¹selected from H, C_1-4Alkyl radical, C_1-4Haloalkyl and C_3-6A cycloalkyl group;

R²selected from hydrogen, C_1-3Haloalkyl and C_1-3An alkyl group;

R³selected from the group consisting of at least three R⁵Phenyl substituted with a group;

and is

Each R⁵Independently selected from C_1-3Alkyl and halogen.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein a' is selected from the group consisting of cyclohexyl, cyclopentyl, tetrahydrofuranyl and tetrahydropyranyl; each optionally substituted by one or two R⁴Is substituted by radicals in which each R⁴Independently selected from oxo and methyl; or two R attached to the same or adjacent carbon atoms⁴Independently selected from spirodioxolanes or fused cyclopropyl rings.

3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein a' is substituted with two R⁴Radical substitution in which two R are bound to the same or adjacent carbon atom⁴Independently selected from spirodioxolanes or fused cyclopropyl rings.

4. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein a' is selected from tetrahydrofuranyl and tetrahydropyranyl.

5. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R¹Selected from hydrogen, methyl, ethyl, propyl, isopropyl, CH₂CF₃、CH₂CHF₂And a cyclopropyl group.

6. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt thereof, wherein R¹Is selected from C_1-4Haloalkyl and C_3-6A cycloalkyl group.

7. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R¹Is selected from CH₂CF₃、CH₂CHF₂And a cyclopropyl group.

8. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt thereof, wherein R¹Is ethyl.

9. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R²Selected from hydrogen, CHF₂And a methyl group.

10. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R²Is hydrogen.

11. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt thereof, wherein R²Is C_1-3A haloalkyl group.

12. The compound of claim 11, or a pharmaceutically acceptable salt thereof, wherein R²Is CHF₂。

13. The compound of any one of claims 1-10, or a pharmaceutically acceptable salt thereof, wherein a' is selected from tetrahydrofuranyl andtetrahydropyranyl, and R²Is hydrogen.

14. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein a' is selected from

15. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R³Is represented by three R⁵Phenyl substituted by radicals in which each R is⁵Independently selected from methyl, ethyl and halogen.

16. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R³Is represented by three R⁵Phenyl substituted by radicals in which each R is⁵Independently selected from fluorine and chlorine.

17. A compound of formula (Ib):

or a pharmaceutically acceptable salt thereof, wherein:

X¹、X²and X³Each independently selected from CHR⁴O, C ═ O and CH₂CHR⁴(ii) a Provided that X¹、X²And X³No more than one of which is O or C ═ O;

each R⁴Independently selected from H and CH₃；

R¹Selected from H, C_1-4Alkyl radical, C_1-4Haloalkyl and C_3-6A cycloalkyl group;

R²selected from hydrogen, C_1-3Haloalkyl and C_1-3An alkyl group;

R³is selected from three R⁵Phenyl substituted by radicals；

Each R⁵Independently selected from C_1-3Alkyl and halogen.

18. The compound of claim 17 or a pharmaceutically acceptable salt thereof, wherein X³Is CHR⁴(ii) a And X¹And X²Each independently is O, CHR⁴Or C ═ O.

19. The compound of claim 17 or 18, or a pharmaceutically acceptable salt thereof, wherein R⁴Is H.

20. The compound of claim 17 or 18, or a pharmaceutically acceptable salt thereof, wherein-X¹–X²–X³-is selected from-CH₂–CH₂–CH₂–、–CH₂–O–CH₂and-O-CH₂–CH₂–。

21. The compound of claim 17 or a pharmaceutically acceptable salt thereof, wherein X¹And X³One is CH₂CHR⁴And X¹And X³The other is CHR⁴(ii) a And X²Is O, CHR⁴Or C ═ O.

22. The compound of claim 17 or 21, or a pharmaceutically acceptable salt thereof, wherein R⁴Is H.

23. The compound of claim 17 or 21, or a pharmaceutically acceptable salt thereof, wherein-X¹–X²–X³-is selected from-CH₂–CH₂–CH₂–CH₂–、–CH₂–O–CH₂–CH₂–、–CH(CH₃)–O–CH₂–CH₂–、–CH₂–CH₂–O–CH₂-and-CH₂–C(O)–CH₂–CH₂–。

24. The compound of any one of claims 17-23, or a pharmaceutically acceptable salt thereof, wherein R²Selected from hydrogen, methyl and CHF₂。

25. The compound of any one of claims 17-24, or a pharmaceutically acceptable salt thereof, wherein R²Is hydrogen.

26. The compound of any one of claims 17-23, or a pharmaceutically acceptable salt thereof, wherein R²Is C_1-3A haloalkyl group.

27. The compound of claim 26, or a pharmaceutically acceptable salt thereof, wherein R²Is CHF₂。

28. The compound of any one of claims 17-27, or a pharmaceutically acceptable salt thereof, whereinSelected from:

29. the compound of any one of claims 17-27, or a pharmaceutically acceptable salt thereof, whereinIs composed of

30. The compound of any one of claims 17-27, or a pharmaceutically acceptable salt thereof, whereinSelected from:

31. the compound of any one of claims 17-27, or a pharmaceutically acceptable salt thereof, whereinIs composed of

32. The compound of any one of claims 17-27, or a pharmaceutically acceptable salt thereof, whereinIs selected from

33. The compound of any one of claims 17-27, or a pharmaceutically acceptable salt thereof, whereinIs selected from

34. The compound of any one of claims 17-33, or a pharmaceutically acceptable salt thereof, wherein R¹Selected from H, C_1-3Alkyl radical, C_1-2Haloalkyl and C_3-5A cycloalkyl group.

35. The compound of any one of claims 17-34, or a pharmaceutically acceptable salt thereof, wherein R¹Selected from hydrogen, methyl, ethyl, propyl, isopropyl, CH₂CF₃、CH₂CHF₂And a cyclopropyl group.

36. The compound of any one of claims 17-35, or a pharmaceutically acceptable salt thereof, wherein R¹Is ethyl.

37. The compound of any one of claims 17-34, or a pharmaceutically acceptable salt thereof, wherein R¹Is selected from C_1-4Haloalkyl and C_3-6A cycloalkyl group.

38. The compound of any one of claims 17-33, 35, or 37, or a pharmaceutically acceptable salt thereof, wherein R¹Is selected from CH₂CF₃、CH₂CHF₂And a cyclopropyl group.

39. The compound of any one of claims 17-38, or a pharmaceutically acceptable salt thereof, wherein R³Is represented by three R⁵Phenyl substituted by radicals in which each R is⁵Independently selected from methyl, ethyl and halogen.

40. The compound of any one of claims 17-39, or a pharmaceutically acceptable salt thereof, wherein R³Is represented by three R⁵Phenyl substituted by radicals in which each R is⁵Independently selected from methyl, fluoro and chloro.

41. The compound of any one of claims 17-40, or a pharmaceutically acceptable salt thereof, wherein R³Selected from:

42. the compound of any one of claims 17-41, or a pharmaceutically acceptable salt thereof, wherein R³Is composed of

43. A compound of the formula (Ic),

or a pharmaceutically acceptable salt thereof, wherein:

R¹selected from H, C_1-4Alkyl radical, C_1-4Haloalkyl and C_3-6A cycloalkyl group.

44. The compound of claim 43, having formula (Id):

45. a compound of formula (Ie):

or a pharmaceutically acceptable salt thereof, wherein:

R¹selected from H, C_1-4Alkyl radical, C_1-4Haloalkyl and C_3-6A cycloalkyl group.

46. The compound of claim 45, having formula (If):

47. the compound of any one of claims 43-46, or a pharmaceutically acceptable salt thereof, wherein R¹Selected from H, C_1-3Alkyl radical, C_1-2Haloalkyl and C_3-5A cycloalkyl group.

48. The compound of any one of claims 43-47, or a pharmaceutically acceptable salt thereof, wherein R¹Selected from hydrogen, methyl, ethyl, propyl, isopropyl, CH₂CF₃、CH₂CHF₂And a cyclopropyl group.

49. The compound of any one of claims 43-48, or a pharmaceutically acceptable salt thereof, wherein R¹Is ethyl.

50. The compound of any one of claims 43-46, or a pharmaceutically acceptable salt thereof, wherein R¹Is selected from C_1-4Haloalkyl and C_3-6A cycloalkyl group.

51. The compound of claim 50, or a pharmaceutically acceptable salt thereof, wherein R¹Is selected from CH₂CF₃、CH₂CHF₂And a cyclopropyl group.

52. A compound selected from:

or a pharmaceutically acceptable salt thereof.

53. A compound selected from:

or a pharmaceutically acceptable salt thereof.

54. A compound selected from:

or a pharmaceutically acceptable salt thereof.

55. A compound selected from:

or a pharmaceutically acceptable salt thereof.

56. A compound selected from:

or a pharmaceutically acceptable salt thereof.

57. A compound selected from:

or a pharmaceutically acceptable salt thereof.

58. A compound of formula (25 b):

or a pharmaceutically acceptable salt thereof.

59. A compound of formula (39):

or a pharmaceutically acceptable salt thereof.

60. A pharmaceutical composition comprising a compound of any one of claims 1-59, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

61. The pharmaceutical composition of claim 60, further comprising one or more additional therapeutic agents.

62. The pharmaceutical composition of claim 61, wherein the one or more additional therapeutic agents is an anti-HIV agent.

63. The pharmaceutical composition of claim 61 or 62, wherein the one or more additional therapeutic agents are selected from the group consisting of HIV protease inhibitors, non-nucleoside HIV reverse transcriptase inhibitors, nucleoside or nucleotide HIV reverse transcriptase inhibitors, and combinations thereof.

64. The pharmaceutical composition of claim 60, further comprising a first additional therapeutic agent selected from the group consisting of: abacavir sulfate, tenofovir disoproxil fumarate, tenofovir alafenamide or tenofovir alafenamide hemifumarate, and a second additional therapeutic agent selected from emtricitabine and lamivudine.

65. A method of treating an HIV infection in a human having or at risk of having the infection by administering to the human a therapeutically effective amount of a compound of any one of claims 1-59 or a pharmaceutical composition of any one of claims 60-64.

66. The method of claim 65, further comprising administering to the human a therapeutically effective amount of one or more additional therapeutic agents.

67. The method of claim 66, wherein the one or more additional therapeutic agents is an anti-HIV agent.

68. The method of claim 66 or 67, wherein the one or more additional therapeutic agents are selected from the group consisting of HIV protease inhibitors, non-nucleoside HIV reverse transcriptase inhibitors, nucleoside or nucleotide HIV reverse transcriptase inhibitors, and combinations thereof.

69. The method of claim 65, further comprising administering to the human a first additional therapeutic agent selected from the group consisting of: abacavir sulfate, tenofovir disoproxil fumarate, tenofovir alafenamide or tenofovir alafenamide hemifumarate, and a second additional therapeutic agent selected from emtricitabine and lamivudine.

70. Use of the compound of any one of claims 1-59 or the pharmaceutical composition of any one of claims 60-64 for treating an HIV infection in a human having or at risk of having the infection.

71. Use of a compound of any one of claims 1-59, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of any one of claims 60-64 for medical therapy.

72. The compound of any one of claims 1-59, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of any one of claims 60-64, for use in the prevention or treatment of HIV infection.