JP2021522254A - Tricyclic heterocyclic compounds useful as HIV integrase inhibitors - Google Patents

Abstract

The present invention relates to a tricyclic heterocyclic compound of formula (I) and a pharmaceutically acceptable salt or prodrug thereof, wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R 5, etc. R ⁶ and n are as defined herein. The present invention also relates to a composition comprising at least one tricyclic heterocyclic compound and a method of using the tricyclic heterocyclic compound for the treatment or prevention of HIV infection in a subject.
[Chemical 1]

Description

The present invention relates to a tricyclic heterocyclic compound, a composition comprising at least one tricyclic heterocyclic compound, and a method of using the tricyclic heterocyclic compound to treat or prevent HIV infection in a subject.

Retroviruses called human immunodeficiency virus (HIV), especially strains known as HIV type 1 (HIV-1) virus and type 2 (HIV-2) virus, have progressive disruption of the immune system (acquired immunodeficiency syndrome). AIDS) and the causative agent of complex diseases including degeneration of the central and peripheral nervous systems. A common feature of retrovirus replication is the insertion of + proviral DNA into the host cell genome by virus-encoded integrase, which is required for HIV replication in human T-lymphoid cells and monocytic-like cells. It is the stage to be done. Integration is in three stages: assembling a stable nucleoprotein complex and viral DNA sequence, cleavage of two nucleotides from the 3'end of linear provirus DNA; and staggered cleavage made at the host target site. It is believed to be mediated by integrase in the covalent binding of the 3'recessed end of provirus DNA. The fourth step of this process, the repair synthesis of the resulting gap, may be accomplished by cellular enzymes.

Nucleotide sequencing of HIV indicates the presence of the pol gene in one open reading frame [Ratner, L. et al. Et al., Nature, 313, 277 (1985)]. Amino acid sequence homology provides evidence that the pol sequence encodes reverse transcriptase, integrase, and HIV protease [Toh, H et al., EMBO J. et al. 4,1267 (1985); Power, M. et al. D. Et al., Science, 231, 1567 (1986); Pearl, L. et al. H. Et al., Nature, 329,351 (1987)]. All three enzymes have been shown to be essential for HIV replication.

Some antiviral compounds that act as inhibitors of HIV replication include reverse transcriptase inhibitors such as azidothymidine (AZT) and efavirentz and protease inhibitors such as indinavir and nelfinavir for AIDS and similar diseases. It is known to be an effective drug in treatment. The compounds of the present invention are inhibitors of HIV integrase and inhibitors of HIV replication.

Ratner, L. et al. Et al., Nature, 313, 277 (1985) Toh, H et al., EMBO J. et al. 4,1267 (1985) Power, M.M. D. Et al., Science, 231, 1567 (1986) Pearl, L. et al. H. Et al., Nature, 329,351 (1987)

In one embodiment, the invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof.

During the ceremony
Each appearance of R ¹ is independently halo, hydroxyl, C _1-6 alkyl and -O- (C _1- C ₆ alkyl);
R ² is hydrogen, methyl or ethyl;
R ³ is hydrogen, methyl or ethyl;
R ⁴ is C _1-6 alkyl or (C _1-6 alkyl) OR ⁷ ;
R ⁵ is hydrogen, C _1-6 alkyl or (C _1-6 alkyl) OR ⁷ ;
R ⁶ is hydrogen, C _1-6 alkyl or (C _1-6 alkyl) OR ⁷ ;
R ⁷ _{is a C 1-6} alkyl that is hydrogen or may be substituted with 1-3 halos;
n is an integer of 1-3.

Compounds of formula (I) (also referred to herein as "tricyclic heterocyclic compounds") and pharmaceutically acceptable salts or prodrugs thereof are, for example, inhibition of HIV virus replication or replicon activity, or It can be useful in the treatment or prevention of HIV infection in a subject. Without being bound by any particular theory, it is believed that tricyclic heterocyclic compounds inhibit HIV virus replication by inhibiting HIV integrase.

Accordingly, the present invention provides a method of treating or preventing HIV infection in a subject, comprising administering to the subject an effective amount of at least one tricyclic heterocyclic compound.

The details of the present invention are described in the detailed description below.

Any method and material similar to those described herein can be used in the practice or testing of the present invention, but exemplary methods and materials are described herein. Other embodiments, embodiments and features of the present invention will be further described or will become apparent from the later description, examples and the appended claims.

The present invention includes a tricyclic heterocyclic compound, a composition comprising at least one tricyclic heterocyclic compound, and a method of using the tricyclic heterocyclic compound to treat or prevent HIV infection in a subject.

Definitions and Abbreviations The terms used herein have their usual meanings, and the meanings of such terms are independent at each occurrence. Nevertheless, unless otherwise specified, the following definitions apply throughout the specification and in the claims. Chemical names, generic names and chemical structures may be used interchangeably to indicate the same structure. Unless otherwise noted, these definitions apply regardless of whether the term is used alone or in combination with other terms. Therefore, the definition of "alkyl" applies to "alkyl" as well as "alkyl" moieties such as "hydroxyalkyl", "haloalkyl", "-O-alkyl".

As used herein and throughout the disclosure, the following terms should be understood to have the following meanings, unless otherwise noted.

A "subject" is a human or non-human mammal. In one embodiment, the subject is a human. In another embodiment, the subject is a primate. In another embodiment, the subject is a monkey. In another embodiment, the subject is a chimpanzee. In another embodiment, the subject is a rhesus monkey.

As used herein, the term "effective amount" inhibits HIV replication and, when administered to a subject suffering from HIV infection or AIDS, produces the desired therapeutic, ameliorating, inhibitory or prophylactic effect. The amount of tricyclic heterocyclic compound and / or additional therapeutic agent or composition thereof effective to occur. In the combination therapy agents of the present invention, the effective amount may indicate each individual drug or the entire combination drug, in which case the amounts of all the drugs administered are together effective. Therefore, the individual component drugs of the combination drug may not be present in an effective amount.

As used herein with respect to HIV virus infection or AIDS, the term "treat" or "treatment" refers to inhibiting the severity of HIV infection or AIDS disease, i.e., of HIV infection or AIDS disease or its clinical manifestations. It involves stopping or alleviating the progression; or alleviating HIV infection or AIDS disease, i.e. causing severe regression of HIV infection or AIDS disease or its clinical manifestations.

The term "prevent" or "prevention" as used herein with respect to HIV virus infection or AIDS refers to a reduction in the likelihood or severity of HIV infection or AIDS.

As used herein, the term "alkyl" refers to an aliphatic hydrocarbon group in which one of its hydrogen atoms has been replaced by a bond. The alkyl group may be straight chain or branched chain and contains about 1 to about 20 carbon atoms. In one embodiment, the alkyl group contains from about 1 to about 12 carbon atoms. In different embodiments, the alkyl group comprises 1 to 6 carbon atoms (C _1- C ₆ alkyl) or about 1 to about 4 carbon atoms (C _{1 to about 4} alkyl). Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, neopentyl, isopentyl, n-hexyl, isohexyl and neohexyl. Can be mentioned. In one embodiment, the alkyl group is linear. In another embodiment, the alkyl group is branched. Alkyl groups are not substituted unless otherwise noted.

As used herein, the term "halo" means -F, -Cl, -Br or -I.

As used herein, the term "haloalkyl" refers to an alkyl group in which one or more hydrogen atoms have been replaced with halogen in the alkyl groups defined above. In one embodiment, the haloalkyl group has 1 to 6 carbon atoms. In another embodiment, the haloalkyl group is substituted with 1-3 F atoms. Non-limiting examples of haloalkyl groups include -CH ₂ F, -CHF ₂ , -CF ₃ , -CH ₂ Cl and -C Cl ₃ . The term "C _1- C ₆ haloalkyl" refers to a haloalkyl group having 1 to 6 carbon atoms.

The term "substituted" means that one or more hydrogens on a designated atom have been replaced by a choice from the indicated substituents, but the usual of the designated atom in its current state. The valence shall not be exceeded and the substitution shall result in a stable compound. A combination of substituents and / or variable portions is possible only if such combination results in a stable compound. "Stable compound" or "stable structure" means a compound that is robust enough to remain in isolation from the reaction mixture to a useful degree of purity and formulation into an effective therapeutic agent. ..

As used herein, the term "substantially purified form" refers to the physical state of a compound after it has been isolated from a synthetic process (eg, a reaction mixture), a natural source or a combination thereof. To say. Also, the term "substantially purified form" is derived from the purification process or processes (eg, chromatography, recrystallization, etc.) in which the compound is described herein or well known to those of skill in the art. It also refers to the physical state of the compound after it has been subjected to a purity sufficient to be characterized by standard analytical techniques described herein or known to those of skill in the art.

It should be noted that in the text, diagrams, examples and tables of the present specification, unsatisfied carbon and heteroatoms each have a sufficient number of hydrogen atoms to satisfy their valences. Then it is assumed.

When a functional group of a compound is referred to as "protected," it is modified so that when the compound is subjected to a reaction, the group is modified to eliminate unwanted side reactions at the protected site. It means that it is a form. Suitable protecting groups will be understood by those skilled in the art and are standard reference books such as T.I. W. It is understood by referring to Greene et al., Protective Groups in Organic Synthesis (1991), Wiley, New York, and the like.

If a plurality of substituents or variable elements (eg, R ² and R ³ etc.) are present in any configuration or formula (I), the definition in each case is that in all other cases, unless otherwise noted. It is also independent of the definition.

As used herein, the term "composition" includes products that include a specified component in a specified amount, as well as a product obtained from a combination of a specified amount of the specified component.

Prodrugs and solvates of the compounds of the invention are also envisioned herein. For a description of prodrugs, see T.I. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems (1987) 14 of the A. et al. C. S. Symposium Series, and Bioreversible Carriers in Drug Design, (1987) Edward B. et al. Roche ed. , American Pharmaceutical Association and Pergamon Press. The term "prodrug" means a compound (eg, a drug precursor) that is converted in vivo to produce a tricyclic heterocyclic compound or a pharmaceutically acceptable salt of the compound. This conversion can occur by a variety of mechanisms (eg, by metabolic or chemical processes), such as by hydrolysis in the blood. For example, if the tricyclic heterocyclic compound or a pharmaceutically acceptable salt, hydrate or solvate of the compound contains a carboxylic acid functional group, the prodrug will contain, for example, the hydrogen atom of the acid group. (C _1- C ₈ ) alkyl, (C _2- C ₁₂ ) alkanoyloxymethyl, 1- (alkanoyloxy) ethyl with 4-9 carbon atoms, 1-methyl with 5-10 carbon atoms- 1- (alkanoyloxy) -ethyl, alkoxycarbonyloxymethyl having 3 to 6 carbon atoms, 1- (alkoxycarbonyloxy) ethyl having 4 to 7 carbon atoms, having 5 to 8 carbon atoms 1-Methyl-1- (alkoxycarbonyloxy) ethyl, N- (alkoxycarbonyl) aminomethyl having 3-9 carbon atoms, 1- (N- (alkoxycarbonyl) amino) having 4-10 carbon atoms ) Ethyl, 3-phthalidyl, 4-crotonolactyl, γ-butyrolactone-4-yl, di-N, N- (C _1- C ₂ ) alkylamino (C _2- C ₃ ) alkyl (β-dimethylamino) Ethyl, etc.), carbamoyl- (C _1- C ₂ ) alkyl, N, N-di (C _1- C ₂ ) alkyl carbamoyl- (C _1- C ₂ ) alkyl and piperidino-, pyrrolidino- or morpholino (C _2- C ₃ ) It may contain an ester formed by being replaced with a group such as an alkyl.

Similarly, when the tricyclic heterocyclic compound contains an alcohol functional group, the prodrug has one or more hydrogen atoms of the alcohol group, eg, (C _1- C ₆ ) alkanoyloxymethyl, 1-((C). ₁ -C ₆₎ alkanoyloxy) ethyl, 1-methyl -1 - _((C 1 -C ₆₎ alkanoyloxy) _{ethyl, (C} 1 -C ₆₎ alkoxycarbonyloxymethyl, _N-(C 1 _-C 6) Alkoxycarbonylaminomethyl, succinoyl, (C _1- C ₆ ) alkanoyl, α-amino (C _1- C ₄ ) alkyl, α-amino (C _1- C ₄ ) alkylene-aryl, aryl acyl and α-aminoacyl, or α-Aminoacyl-α-aminoacyl (where each α-aminoacyl group is independently selected from naturally occurring L-amino acids or glycosyls (groups resulting from the removal of hydroxyl groups in the hemiacetal form of carbohydrates). ) Etc. can be formed by being replaced with a group such as.

When an amine functional group is incorporated in the tricyclic heterocyclic compound, the prodrug may add a hydrogen atom of the amine group to, for example, R-carbonyl-, RO-carbonyl-, NRR'-carbonyl-, in the formula. R and R'are independently (C _1- C ₁₀ ) alkyl, (C _3- C ₇ ) cycloalkyl, benzyl, natural α-aminoacyl, -C (OH) C (O) OY ¹ (in the formula). , Y ¹ is H, (C _1- C ₆ ) alkyl or benzyl, -C (OY ² ) Y ³ (in the formula, Y ² is (C _1- C ₄ ) alkyl, Y ³ is (C ₁₎ -C ₆ ) alkyl); carboxy (C _1- C ₆ ) alkyl; amino (C _1- C ₄ ) alkyl or mono-N- or di-N, N- (C _1- C ₆ ) alkyl aminoalkyl -C (Y ⁴ ) Y ⁵ (in the formula, Y ⁴ is H or methyl and Y ⁵ is mono-N- or di-N, N- (C _1- C ₆ ) alkylaminomorpholino); piperidine It can be formed by being replaced with a group such as -1-yl or pyrrolidine-1-yl.

The pharmaceutically acceptable esters of the compounds of the present invention include the following groups: (1) Carboxylic acid esters obtained by esterification of the hydroxy group of hydroxyl compounds [Here, the non-carbonyl portion of the carboxylic acid moiety of the ester group. Is a linear or branched alkyl (eg, methyl, ethyl, n-propyl, isopropyl, t-butyl, sec-butyl or n-butyl), alkoxyalkyl (eg, methoxymethyl), aralkyl (eg, benzyl). , Aryloxyalkyl (eg, phenoxymethyl), aryl (eg, _{phenyls optionally substituted with halogen, C 1-4} alkyl or -OC _1-4 alkyl, amino, etc.). ]; (2) Sulfonic acid esters such as alkyl- or aralkylsulfonyl (eg methanesulfonyl); (3) Amino acid esters such as those corresponding to both natural and unnatural amino acids (eg L-valyl or L). -Isoleucyl); (4) phosphate ester and (5) 1, 2 or 3 phosphate ester. The phosphoric acid ester may be further esterified with, for example, C _1-20 alcohol or a reactive derivative thereof or 2,3-di (C _6-24 ) acylglycerol.

One or more compounds of the present invention may exist in an unsolvated form as well as in a solvated form with a pharmaceutically acceptable solvent (eg, water, ethanol, etc.). , It is intended to include both solvated and unsolvated forms. "Solvate" means a physical association of a compound of the invention with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonds (eg, hydrogen bonds). In some specific cases, the solvate can be isolated, for example, if one or more solvent molecules are incorporated within the crystalline lattice of the crystalline solid. The "solvate" includes both the liquid phase and the isolateable solvate. Non-limiting examples of solvates include etanolate, metanolate and the like. A "hydrate" is a solvate in which the solvent molecule is water.

One or more compounds of the present invention may be converted into solvates. The production of solvates is generally known. Therefore, for example, M.I. Caira et al., J. Mol. Pharmaceutical Sci. , 93 (3) , 601-611 (2004), describe the production of solvates of the antifungal agent fluconazole in ethyl acetate and in water. Similar production of solvates, semi-solvates, hydrates, etc. C. van Tonder et al., AAPS PharmaSciTech. , 5 (1) , article 12 (2004); and A. L. Bingham et al., Chem. Commun. , 603-604 (2001). A typical, non-limiting process is to dissolve the compounds of the invention in a desired amount of a desired solvent (organic or water or a mixture thereof) at temperatures above room temperature, and the solution is crystallized. It involves cooling at a rate sufficient to allow the crystals to be isolated by standard methods. For example, analysis techniques such as IR spectroscopy indicate the presence of a solvent (or water) in the crystal as a solvate (or hydrate).

The tricyclic heterocyclic compound can form a salt, and the salt is also included in the scope of the present invention. It should be understood that references to tricyclic heterocyclic compounds herein also include references to their salts, unless otherwise noted. As used herein, the term "salt (s)" refers to acid salts formed with inorganic and / or organic acids, and basic salts formed with inorganic and / or organic bases. Also, if the tricyclic heterocyclic compound contains both a basic moiety (such as, but not limited to, pyridine or imidazole) and an acidic moiety (such as, but not limited to, a carboxylic acid), a zwitterion (“intramolecular salt””. ) Can be formed and is included in the term "salt (class)" as used herein. In one embodiment, the salt is a pharmaceutically acceptable (ie, non-toxic, physiologically acceptable) salt. In another embodiment, the salt is a salt other than a pharmaceutically acceptable salt. The salt of the compound of formula (I) is, for example, a reaction of a tricyclic heterocyclic compound with a certain amount (for example, an equivalent amount) of an acid or base in a medium (for example, a salt-precipitated one or an aqueous medium). It can be formed by lyophilizing after allowing it to grow.

Examples of acid addition salts include acetate, ascorbate, benzoate, benzenesulfonate, bicarbonate, borate, butyrate, citrate, encephalate, camphor sulfonate, fumal. Acid salt, hydrochloride, hydrobromide, hydroiodide, lactate, maleate, methanesulfonate, naphthalene sulfonate, nitrate, oxalate, phosphate, propionate, salicylic acid Examples include salts, succinates, sulfates, tartrates, thiocyanates, toluene sulfonates (also known as tosylates). In addition, acids generally considered suitable for the formation of pharmaceutically useful salts from basic pharmaceutical compounds are described, for example, in P. et al. Stahl et al., Camille G. et al. (Eds.) Handbook of Physical Salts. Properties, Selection and Use. (2002) Zurich: Wiley-VCH; S.A. Berge et al., Journal of Pharmaceutical Sciences (1977) 66 (1) 1-19; Gold, International J. of Pharmaceutics (1986) 33 201-217; Anderson et al., The Practice of Medical Chemistry (1996), Academic Press, New York; Has been done. These disclosures are incorporated herein by reference.

Exemplary basic salts include ammonium salts, alkali metal salts (sodium, lithium, and potassium salts), alkaline earth metal salts (calcium and magnesium salts), and salts with organic bases (eg, organic amines) (dicyclohexyl). Amin, t-butylamine, choline, etc.), and salts with amino acids (arginine, lysine, etc.) and the like. Basic nitrogen-containing groups include, for example, lower alkyl halides (eg, chloride, bromide and methyl iodide, ethyl and butyl), dialkyl sulfates (eg, dimethyl sulfate, diethyl and dibutyl), long chain halides (eg, eg, dimethyl sulfate, diethyl and dibutyl). It may be quaternized with agents such as chloride, bromide and decyl iodide, lauryl and stearyl), arylalkyl halides (eg, benzyl bromide and phenethyl bromide).

All such acid salts and base salts are intended to be pharmaceutically acceptable salts within the scope of the present invention, and all acids and base salts are the free forms of the corresponding compounds for the purposes of the present invention. Consider equivalent.

The diastereomeric mixture can be separated into its individual diastereomers by methods known to those of skill in the art, such as chromatography and / or fractional crystallization, based on physical and chemical differences. The enantiomers convert the enantiomeric mixture into a diastereomer mixture by reaction with a suitable optically active compound (eg, a chiral auxiliary such as a chiral alcohol or an acidified of Mosher), separating the diastereomers and separating the individual diastereomers. Diastereomers can be separated by conversion (eg, hydrolysis) to the corresponding pure enantiomers. Also, stereochemically pure compounds can be produced by using chiral starting materials or by using salt splitting techniques. In addition, some tricyclic heterocyclic compounds can be atropisomers (eg, substituted biaryls) and are considered part of the present invention. Enantiomers can also be separated directly using chiral chromatography techniques.

Also, tricyclic heterocyclic compounds may exist in different tautomeric forms, all of which are within the scope of the invention. For example, the keto-enol and imine-enamine forms of the compounds are all included in the present invention.

Unless otherwise noted, any stereoisomer (eg, salt of compound, admixture, hydrate, ester and prodrug and salt, admixture and ester of the prodrug) of the present invention (eg, salt, admixture and ester of the compound). Geometric isomers, optical isomers, etc.), eg, those that can be present due to asymmetric carbons on various substituents, eg, enantiomeric forms (which can be present even in the absence of asymmetric carbons). ), Rotational isomer forms, atrop isomers, diastereomeric forms and the like are intended to be within the scope of the present invention. When a double bond or fused ring is incorporated in a tricyclic heterocyclic compound, both cis and trans forms as well as mixtures are included within the scope of the invention.

If the substituents on the chiral carbon atom are drawn without a specific stereochemistry (using a linear bond to the chiral center), it should be understood that the α and β configurations of the substituents are described in this book. It should be considered part of the invention. For example, the compounds of the invention depicted as:

Is understood to include both stereoisomers at the designated chiral center, those with the following structures.

In the Examples section below, the compounds of the invention purified as individual stereoisomers may be depicted in non-stereospecific form, but are described as "diastereomers 1", "diastereomers 2". , "Isomer 1", "Isomer 2", "Enantiomer A" and "Enantiomer B" are identified using one or more of the terms. In this case, the absolute stereochemistry of each isolated diastereomer and enantiomer center has not been determined, and the terms used above refer to each individual purified stereochemically pure compound. Used.

The individual stereoisomers of the compounds of the invention may be, for example, substantially free of other isomers, or, for example, as racemic compounds, or all other or other selections. It may be mixed with a stereoisomer. The chiral center of the present invention can have an S or R configuration as defined by IUPAC 1974 Recommissions. The use of terms such as "salt," "solvent," "ester," and "prodrug" refers to the enantiomers, stereoisomers, rotational isomers, homomorphs, racemic compounds, or prodrugs of the compounds of the invention. It is intended to be equally applied to salts, solvates, esters and prodrugs of.

In the compound of formula (I), the atom may indicate its natural isotopic abundance, and one or more kinds of atoms have the same atomic number but the atomic weight or mass number is mainly found in nature. It may be artificially enriched with a specific isotope different in atomic weight or mass number. The present invention is intended to include any suitable isotopic variant of a compound of general formula I. For example, ^{different isotopic forms of hydrogen (1} H) include protium ( ¹ H) and deuterium ( ² H). Protium is a hydrogen isotope found mainly in nature. Deuterium enrichment can provide certain therapeutic benefits, such as increased in-vivo half-life or reduced dosage requirements, or serves as a standard for characterization of biological samples. Compounds may be provided. Isotope-enriched compounds of formula (I) are similar to those described in the schemes and examples herein, by conventional techniques known to those of skill in the art, without undue experimentation. Depending on the process, it can be prepared with suitable isotope enrichment reagents and / or intermediates. In one embodiment, the compound of formula (I) is one in which one or more hydrogen atoms are replaced with deuterium.

Tricyclic heterocyclic compounds can be useful in human and veterinary drugs for treating or preventing HIV infection in a subject. In one embodiment, the tricyclic heterocyclic compound can be an inhibitor of HIV virus replication. In certain specific embodiments, the tricyclic heterocyclic compound is an inhibitor of HIV-1. Therefore, tricyclic heterocyclic compounds may be useful in the treatment of HIV infection and AIDS. According to the present invention, a tricyclic heterocyclic compound can be administered to a subject in need of treatment or prevention of HIV infection.

Thus, in one embodiment, the invention provides a method of treating HIV infection in a subject, comprising administering to the subject an effective amount of at least one tricyclic heterocyclic compound or a pharmaceutically acceptable salt thereof. do. In certain specific embodiments, the present invention provides a method of treating AIDS in a subject, comprising administering to the subject an effective amount of at least one tricyclic heterocyclic compound or a pharmaceutically acceptable salt thereof. do.

Compounds of Formula (I) The present invention provides tricyclic heterocyclic compounds of formula (I) below and pharmaceutically acceptable salts thereof.

During the ceremony
Each appearance of R ¹ is independently halo, hydroxyl, C _1-6 alkyl and -O- (C _1- C ₆ alkyl);
R ² is hydrogen, methyl or ethyl;
R ³ is hydrogen, methyl or ethyl;
R ⁴ is C _1-6 alkyl or (C _1-6 alkyl) OR ⁷ ;
R ⁵ is hydrogen, C _1-6 alkyl or (C _1-6 alkyl) OR ⁷ ;
R ⁶ is hydrogen, C _1-6 alkyl or (C _1-6 alkyl) OR ⁷ ;
R ⁷ _{is a C 1-6} alkyl optionally substituted with hydrogen or 1-3 halos;
n is an integer of 1-3.

In one embodiment of the invention, R ¹ is halo. In one category of the embodiment, R ¹ is fluoro. In one category of the embodiment, R ¹ is chloro.

In one embodiment of the invention, R ² is hydrogen or methyl. In one category of the present invention, R ² is hydrogen. In another classification of the invention, R ² is methyl.

In one embodiment of the present invention, R ³ is hydrogen or methyl. In one category of the present invention, R ³ is hydrogen. In another class of the present invention, R ³ is methyl.

In one embodiment of the present invention, ^{R 4} is methyl, _{ethyl, CH 2 OCH 3, CH 2 CH} 2 OCH 3 or _{CH 2 CH} 2 OCHF 2. In a class of the invention, R ⁴ is methyl or ethyl. In another class of the invention, R ⁴ is methyl. In another class of the invention, R ⁴ is ethyl. In another class of the invention, ^{R 4} is _CH 2 OCH _3. In another classification of the invention, R ⁴ is CH ₂ CH ₂ OCH ₃ . In another classification of the invention, R ⁴ is CH ₂ CH ₂ OCHF ₂ .

In one embodiment of the present invention, ^{R 5} is _{C 1-6} alkyl. In another embodiment of the present invention, R ⁵ is hydrogen or methyl. In a class of the invention, R ⁵ is methyl. In another class of this invention, R ⁵ is hydrogen.

In one embodiment of the invention, R ⁶ is a C _1-6 alkyl. In a class of the invention, R ⁶ is methyl or ethyl. In another class of the invention, R ⁶ is methyl. In another class of the invention, R ⁶ is ethyl. In another embodiment of the present invention, R ⁶ is hydrogen.

In one embodiment of the present invention, n is 1. In another embodiment of the invention, n is 2. In another embodiment of the invention, n is 3.

In another embodiment, the compound of formula (I) is in substantially purified form.

It should be understood that any of the above embodiments can be combined with one or more other embodiments.

Other embodiments of the invention include:
(A) A pharmaceutical composition comprising an effective amount of the compound of formula (I) and a pharmaceutically acceptable carrier.
(B) The pharmaceutical composition of (a), further comprising a second therapeutic agent selected from the group consisting of HIV antiviral agents, immunomodulators and anti-infective agents.
(C) The pharmaceutical composition of (b), wherein the HIV antiviral agent is an antiviral agent selected from the group consisting of an HIV protease inhibitor and an HIV NNRTI inhibitor.
(D) A combination of the compound of formula (I) and a drug which is a second therapeutic agent selected from the group consisting of (ii) HIV antiviral agents, immunomodulators and anti-infective agents. Here, the compound of formula (I) and the second therapeutic agent, respectively, are combined to inhibit HIV replication or treat HIV infection and / or reduce the likelihood or symptom severity of HIV infection. A combination of medicines, used in effective amounts,
(E) The combination of (d), wherein the HIV antiviral agent is an antiviral agent selected from the group consisting of an HIV protease inhibitor and an HIV NNRTI inhibitor.
(F) A method of inhibiting HIV replication in a subject in need, comprising administering to the subject an effective amount of a compound of formula (I).
(G) Methods of treating HIV infection in the subject in need and / or reducing the likelihood or severity of symptoms of HIV infection, including administering to the subject an effective amount of a compound of formula (I).
The compound of formula (I) is administered in combination with an effective amount of at least one second therapeutic agent selected from the group consisting of HIV antiviral agents, immunomodulators and anti-infective agents. Method (g),
(I) The method of (h), wherein the HIV antiviral agent is an antiviral agent selected from the group consisting of an HIV protease inhibitor and an HIV NNRTI inhibitor.
(J) A method of inhibiting HIV replication in a subject in need, comprising administering to the subject the pharmaceutical composition of (a), (b) or (c) or a combination of (d) or (e).
(K) Treatment of HIV infection in the subject in need and / Or a method for reducing the likelihood of HIV infection or the severity of symptoms.

Further embodiments of the invention include:
(L) A pharmaceutical composition comprising an effective amount of a pharmaceutically acceptable salt of the compound of formula (I) and a pharmaceutically acceptable carrier.
(M) The pharmaceutical composition of (l), further comprising a second therapeutic agent selected from the group consisting of HIV antiviral agents, immunomodulators and anti-infective agents.
(N) The pharmaceutical composition of (m), wherein the HIV antiviral agent is an antiviral agent selected from the group consisting of an HIV protease inhibitor and an HIV NNRTI inhibitor.
A second therapeutic agent selected from the group consisting of (o) a pharmaceutically acceptable salt of the compound of formula (I) and (ii) an HIV antiviral agent, an immunomodulatory agent and an anti-infective agent. A pharmaceutically acceptable salt of a compound of formula (I) and a second therapeutic agent, each of which is a combination of drugs that inhibits HIV replication or treats HIV infection and / or HIV. A combination of drugs used in an amount that is effective in reducing the likelihood of infection or the severity of the condition,
(P) The combination of (o), wherein the HIV antiviral agent is an antiviral agent selected from the group consisting of HIV protease inhibitors and HIV NNRTI inhibitors.
(Q) A method of inhibiting HIV replication in a subject in need, comprising administering to the subject an effective amount of a pharmaceutically acceptable salt of the compound of formula (I).
(R) Treatment of HIV infection in the subject in need and / or potential or symptom of HIV infection, including administration of an effective amount of a pharmaceutically acceptable salt of the compound of formula (I) to the subject. How to reduce severity,
The pharmaceutically acceptable salt of the compound of formula (s) (I) is effective for at least one second therapeutic agent selected from the group consisting of HIV antiviral agents, immunomodulators and anti-infective agents. Method (r), administered in combination with the amount,
(T) The method of (s), wherein the HIV antiviral agent is an antiviral agent selected from the group consisting of an HIV protease inhibitor and an HIV NS5B polymerase inhibitor.
(U) A method of inhibiting HIV replication in a subject in need, comprising administering to the subject the pharmaceutical composition of (l), (m) or (n) or a combination of (o) or (p).
(V) Treatment of HIV infection in the subject in need and / Alternatively, a method for reducing the likelihood of HIV infection or the severity of symptoms.

Further embodiments of the invention include:
(W) A pharmaceutical composition comprising an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
(X) The pharmaceutical composition of (w), further comprising a second therapeutic agent selected from the group consisting of HIV antiviral agents, immunomodulators and anti-infective agents.
(Y) The pharmaceutical composition of (x), wherein the HIV antiviral agent is an antiviral agent selected from the group consisting of an HIV protease inhibitor and an HIV NNRTI inhibitor.
(Z) A second therapeutic agent selected from the group consisting of compounds of formula (I) and (ii) or pharmaceutically acceptable salts thereof, HIV antiviral agents, immunomodulators and anti-infective agents. A combination of drugs that is a drug, the compound of formula (I) and the second therapeutic drug, respectively, the combination of which inhibits HIV replication or treats HIV infection and / or the possibility or symptom of HIV infection. A combination of drugs used in an amount that is effective in reducing the severity of the disease,
(Aa) The combination of (z), wherein the HIV antiviral agent is an antiviral agent selected from the group consisting of HIV protease inhibitors and HIV NNRTI inhibitors.
(Bb) A method of inhibiting HIV replication in a subject in need, comprising administering to the subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
(Cc) Treatment of HIV infection in a subject in need and / or potential or symptoms of HIV infection, including administration of an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to the subject. How to reduce the severity of
A compound of formula (I) or a pharmaceutically acceptable salt thereof of at least one second therapeutic agent selected from the group consisting of HIV antiviral agents, immunomodulators and anti-infective agents. Method (cc), administered in combination with an effective amount,
(Ee) The method of (dd), wherein the HIV antiviral agent is an antiviral agent selected from the group consisting of HIV protease inhibitors and HIV NNRTI inhibitors.
(F) A method of inhibiting HIV replication in a subject in need, comprising administering to the subject the pharmaceutical composition of (w), (x) or (y) or a combination of (z) or (aa).
(Gg) Treatment of HIV infection in the subject in need and / Alternatively, a method for reducing the likelihood of HIV infection or the severity of symptoms.

The present invention also relates to (a) pharmaceuticals, (b) inhibition of HIV replication, or (c) treatment of HIV infection and / or reduction of the likelihood or symptom severity of HIV infection, (i) for that purpose. (Ii) Contains the compounds of the invention for use as pharmaceuticals, (iii) for use in the preparation of pharmaceuticals. In such use, the compounds of the present invention may be used in combination with one or more second therapeutic agents selected from HIV antiviral agents, anti-infective agents and immunomodulators.

Further embodiments of the present invention include the pharmaceutical compositions, combinations and methods shown in (a)-(gg) above, as well as the uses shown in the preceding paragraph, wherein the compounds of the invention used in that case are: , A compound that is one of embodiments, embodiments, types, subtypes or characteristics of the above compounds. In all of these embodiments, the compounds may be used in the form of pharmaceutically acceptable salts or hydrates (as appropriate).

It should be further understood that the embodiments of the compositions and methods shown above as (a)-(gg) are all embodiments of the compound (eg, embodiments provided by a combination of embodiments). Is understood to include.

Non-limiting examples of compounds of formula (I) include compounds 1-80 shown in the examples below, as well as pharmaceutically acceptable salts thereof.

Method for Producing Compound of Formula (I) The compound of formula (I) can be produced from a known or easily produced raw material according to a method known to those skilled in the art of organic synthesis. A method useful for producing the compound of the formula (I) is described in the following Examples, and the outline thereof is shown in the following diagram. Separate synthetic routes and related structures will be apparent to those skilled in the art of organic synthesis.

General List of Abbreviations Abbreviations and acronyms used herein include:

General Procedure Raw materials and intermediates are purchased, manufactured using known procedures, or according to methods described in other forms. The general pathways applied to the synthesis of compounds of formula I are illustrated in the diagram below. In some cases, the order in which the reaction steps are carried out in the diagram can be changed to facilitate the reaction or avoid unwanted reaction products.

Reactions sensitive to water or air were carried out under nitrogen or argon using anhydrous solvents and reagents. The progress of the reaction is usually E.I. Confirmed by analytical thin layer chromatography (TLC) or liquid chromatography-mass spectrometry (LC-MS) performed using Merck's pre-coated TLC plate, silica gel 60F-254, layer thickness 0.25 mm.

Typically, the analytical LC-MS system used consisted of a Waters ZQ ™ platform with electrospray ionization in cation detection mode using an Agilent 1100 Series HPLC equipped with an autosampler. The column was generally Waters Xterra MS C18, 3.0 x 50 mm, 5 μm, or Waters Accuracy UPLC® BEH C18 1.0 x 50 mm, 1.7 μm. The flow rate was 1 mL / min and the injection volume was 10 μL. UV detection ranged from 210 to 400 nm. The mobile phase shall consist of solvent A (water + 0.05% TFA) and solvent B (MeCN + 0.05% TFA), 100% solvent A for 0.7 minutes and up to 100% solvent B over 3.75 minutes. A gradient was used which was changed, maintained for 1.1 minutes, and then returned to 100% solvent A over 0.2 minutes. Alternatively, the column was generally Waters Accuracy UPLC® BEH C18 1.0 × 50 mm, 1.7 μm. The flow rate was 0.3 mL / min and the injection volume was 0.5 μL. UV detection was 215 or 254 nm. Each mobile phase is composed of solvent A (water + 0.05% TFA) and solvent B (MeCN + 0.05% TFA), and has a gradient of changing from 90% solvent A to 99% solvent B over 1.6 minutes. It was maintained for 4 minutes and then returned to 90% solvent A over 0.1 minutes, or the moving layer consisted of solvent A (water + 0.05% TFA) and solvent B (MeCN + 0.05% TFA) and was 0. .Slope of 97% solvent A to 4% then 50% solvent B over 5 and 0.9 minutes, 50% to 99% solvent B over 0.2 minutes, maintained for 0.4 minutes, then Was returned to 90% solvent A over 0.1 minutes.

Preparative HPLC purification was usually performed using a mass spectrometry system or a non-mass guide system. Usually it is a Waters ZQ ™ single quadrupole MS system for electrospray ionization, Waters 2525 gradient pump, Waters 2767 injector / collector, Waters 996PDA detector, 150-750amu, positive electrospray, MS-induced collection, And Waters SUNFIRE® C-185 micron, 30 mm (inner diameter) x 100 mm column MS conditions in a WATERS chromatography workstation configured with an LC-MS system. The mobile phase consisted of a mixture of acetonitrile (10% to 100%) in water containing 0.1% TFA. The flow rate was maintained at 50 mL / min, the injection volume was 1800 μL, and the UV detection range was 210-400 nm. Another preparative HPLC system used was Gilson GX-281 injector / collector, Gilson UV / VIS-155 detection phase, Gilson 322, 333 and 334 pumps, and Phenomenex Gemini-NX C-18 5 microns, 50 mm (inner diameter). × 250 mm column, Waters XBridge (trade name) C-18 5 micron OB (trade name), 30 mm (inner diameter) × 250 mm column, or Waters SUNFIRE (trade name) C-18 OBD (trade name) 10 micron, 30 mm (inner diameter) It was a Gilson Workstation consisting of a) × 150 mm column. The mobile phase consisted of a mixture in water containing 0.1% or 0.05% TFA of acetonitrile (0-90%). The flow rate was maintained at 50 mL / min for the Waters Xbridge ™ column, 90 mL / min for the Phenomenex Gemini column, and 30 mL / min for the Waters SUNFIRE ™ column. The injection volume was in the range of 1000 to 8000 μL, and the UV detection range was 210 to 400 nm. The mobile phase gradient was optimized for the individual compounds. Reactions carried out using microwave irradiation were usually carried out using Emrys Optimizer manufactured by Personal Chemistry or Initiator manufactured by Biotage. Reactions performed using photon irradiation were typically performed using a second generation Merck photoreactor or a Kessil 34W blue LED lamp. The solution was concentrated under reduced pressure on a rotary evaporator. Flash chromatography is typically silica gel (32 to 63 microns, 60 Å pore size) in a prepack cartridge of the size described, Biotage® Flash Chromatography Device (Dyax Corp.), ISCO CombiFlash® Rf Device. , Or using ISCO CombiFlash® Companion XL. ^{1 1} H NMR spectra were obtained on a 500 MHz spectrometer in _{CDCl 3 solution unless otherwise noted.} Chemical shifts were reported in parts per million (ppm). Tetramethylsilane (TMS) was used as the internal reference in the CDCl _{3 solution, and residual CH 3} OH peak or TMS was used as the internal reference in the _{CD 3 OD solution.} The coupling constant (J) was reported in Hertz (Hz). Chiral analytical chromatography most often involves the percent ethanol / hexane (% EtOH / Hex), isopropanol / heptan (% IPA / Hep), ethanol / carbon dioxide (% EtOH / CO _{2) described as a constant composition solvent system.} ), Or CHIRALPAK® using isopropanol / carbon dioxide (% IPA / CO ₂ ) AS, CHIRALPAK® AD, CHIRALPCEL® OD, CHIRALCEL® IA, or CHIRALPCEL® One of the OJ columns (250 × 4.6 mm) (Daicel Chemical Industries, Ltd.) was used. Chiral preparative chromatography is CHIRALPAK AS, CHIRALPAK AD, CHIRALCEL® OD, Chiralcel® using a desired constant composition solvent system as confirmed by chiral analytical chromatography or supercritical fluid (SFC) conditions. ) Either IA or CHIRALCEL® OJ column (20 x 250 mm) (Dailel Chemical Industries, Ltd.).

Some methods for producing the compounds of the present invention are also described in Examples. Raw materials and intermediates were purchased commercially from commercial catalog sources or manufactured using known procedures or according to methods described elsewhere.

Example 1
Preparation of intermediate compound Int-1

Step A- Compound Int-1a stirred hydroxy picolinic acid synthesis 15 ℃ of (340 g, 2.44 mol) in a solution medium MeOH (2.8 liters) _of, H ₂ SO 4 to (720g, 7.33mol) added. The reaction solution was heated in an oil bath to 65 ° C. and stirred for 2 hours. After cooling it to room temperature, the reaction contents were neutralized by slowly adding _{a saturated aqueous solution of NaCO 3 to pH = 7.} The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine and dehydrated with _{anhydrous Na 2} SO _4. After filtration, the filtrate was concentrated under reduced pressure to give compound Int-1a. The crude product was used in the next reaction without further purification. ^{1 1} H NMR (400 MHz, CDCl ₃ ) δ10.62 (s, 1H), 6.28 (d, J = 4.4 Hz, 2H), 4.05 (s, 3H).

Step B-Synthesis of Compound Int-1b Bromine (157 g, 979 mmol) was added to a mixture of compound Int-1a (50 g, 327 mmol) in water (5.0 L) stirred at 15 ° C. The mixture was stirred at 15 ° C. for 5 hours. The resulting mixture was filtered, the filter cake was washed with water and vacuum dried to give compound Int-1b. The crude product was used in the next reaction without further purification. ^{1 1} H NMR (400 MHz, CDCl ₃ ) δ11.37 (s, 1H), 7.87 (s, 1H), 4.07 (s, 3H).

Step C-Synthesis of Compound Int-1c _{Cs 2} CO ₃ (377 g, 1.160 mol) was added to a solution of compound Int-1b (200 g, 643 mmol) in acetone (4.0 L) stirred at 15 ° C., and then Iodomethane (274 g, 1930 mmol) was added dropwise. The reaction was heated at 60 ° C. for 2 hours. After cooling it to room temperature, the reaction mixture was filtered. The filter cake was washed with acetone and purified by silica gel chromatography eluting with petroleum ether: EtOAc = 25: 1 to 10: 1 to give compound Int-1c. ^{1 1} H NMR (400 MHz, CDCl ₃ ) δ7.85 (s, 1H), 3.99 (s, 3H), 3.98 (s, 3H).

Step D-Synthesis of Compound Int-1d Water (350 mL) was added to a solution of compound Int-1c (350 g, 1080 mmol) in THF (1.8 liters) stirred at 15 ° C., and then lithium hydroxide, 1 water. Japanese product (54 g, 1300 mmol) was added. The reaction mixture was stirred at 25 ° C. for 2 hours. The solvent was removed under reduced pressure to give compound Int-1d. The crude material was used in the next reaction without further purification. ^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δ7.73 (s, 1H), 3.83 (s, 3H).

Step E-Synthesis of Compound Int-1e Add NaH (115 g, 2.88 mol, 60 wt%) to a solution of Compound Int-1d (240 g, 757 mmol) and DMF (1.50 liters) stirred at 0-5 ° C. Added slowly. It was stirred at 0-5 ° C. for 30 minutes and then a solution of (4-methoxyphenyl) methanol (157 g, 1.14 mol) in DMF (1.50 L) was added. The reaction mixture was stirred at 0-5 ° C. for 30 minutes, then heated to 15 ° C. and stirred for 2 hours. The reaction was stopped by adding 1 liter of saturated NH ₄ Cl aqueous solution, and acidified with 4N HCl aqueous solution up to pH = 4-5. The resulting mixture was extracted with EtOAc. The organic layer was washed with brine, _{dehydrated with anhydrous Na 2} SO ₄ , and then concentrated under reduced pressure to give compound Int-1e. C ₁₅ H ₁₄ NBrO ₅ mass calculated value: 367.0, measured value: 389.8 (M + Na) ⁺ .

Step F- Compound Int-1f Compound Int-1e stirring at synthesis 15 ℃ of (290g, 788mmol) and _{K 2 CO 3 (272g, 1970mmol} ) in DMF (2.5 liters) in a mixture of iodomethane (355g, 2360mmol ) Was added slowly. The reaction was stirred at 15 ° C. for 12 hours. The reaction mixture was diluted with 1.5 liters of water and extracted with EtOAc. The organic layer was washed with brine, _{dehydrated with anhydrous Na 2} SO ₄ , and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting from petroleum ether: EtOAc: dichloromethane = 10: 1 to 2: 1. Products containing fractions were combined and concentrated under reduced pressure. The residue was recrystallized from EtOAc / petroleum ether. The solid was collected by filtration, washed with petroleum ether and dried in vacuo to give compound Int-1. ^{1 1} H NMR (400 MHz, CDCl ₃ ): δ7.35 (d, J = 8.8 Hz, 2H), 7.16 (s, 1H), 6.95 (d, J = 8.8 Hz, 2H), 5 .10 (s, 2H), 3.95 (s, 3H), 3.91 (s, 3H), 3.84 (s, 3H).

Example 2
Production of compound Int-2e

Synthesis of Step A-Compound Int-2a Imidazole (31.6 g, 464 mmol) and TBDPSCl (89 mL, 89 mL) in a solution of 3-methylbut-3-en-1-ol (20 g, 232 mmol) in DCM (300 mL) at 0 ° C. 348 mmol) was added in small portions. The solution was stirred at 25 ° C. for 5 hours, then the reaction was stopped with water (80 mL) and separated. The aqueous layer was extracted with EtOAc (3 times at 60 mL). The combined organic layers were _{dehydrated with anhydrous Na 2} SO ₄ , filtered, and the filtrate concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (200 g) eluting with 100% petroleum ether to give compound Int-2a. ^{1 1} H NMR (400 MHz, CDCl ₃ ): δ7.77 (dd, J = 7.8, 1.7 Hz, 4h); 7.45-7.35 (m, 6H); 4.78-4.64 ( m, 2H); 3.76 (t, J = 6.9Hz, 2H); 2.28 (t, J = 6.8Hz, 2H); 1.68 (s, 3H); 1.04 (s, 9H).

Synthesis of Step B-Compound Int-2b Heptane of 1M dimethylaluminum chloride in a mixture of compound Int-2a (10g, 30.8 mmol) and paraformaldehyde (1.018g, 33.9 mmol) in DCM (150mL) at 0 ° C. The medium solution (40.1 mL, 40.1 mmol) was added dropwise. The mixture was stirred at 0 ° C. for 2 hours and then stopped with water (40 mL). A 1N HCl aqueous solution was added dropwise to dissolve the precipitate. The mixture was filtered and the filtrate was separated. The aqueous layer was extracted with EtOAc (3 times at 40 mL). The combined organic layers were dehydrated over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 10% EtOAc / petroleum ether to give compound Int-2b. ^{1 1} H NMR (400 MHz, CDCl ₃ ): δ7.70-7.64 (m, 4h); 7.44-7.35 (m, 6H); 4.88 (s, 2H); 3.77 (t). , J = 6.7 Hz, 2H); 3.66 (t, J = 6.2 Hz, 2H); 2.31-2.23 (m, 4h); 1.04 (s, 9H).

Synthesis of Step C-Compound Int-2c Compound Int-2b (3 g, 8.46 mmol) and potassium acetate (3.32 g, 33.8 mmol) in DCM (4 mL) and water (4 mL) in a mixture under a nitrogen balloon. (Bromodifluoromethyl) trimethylsilane (3.44 g, 16.92 mmol) was added at 25 ° C. The mixture was stirred at 25 ° C. for 15 hours, then diluted with water (5 mL) and extracted with EtOAc (3 times at 15 mL). The combined organic layers were dehydrated over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (40 g column) eluting with 0% to 5% EtOAc / petroleum ether to give compound Int-2c. ^{1 1} H NMR (400 MHz, CDCl ₃ ): δ7.66 (dd, J = 7.7, 1.5 Hz, 4h); 7.43-7.36 (m, 6H); 6.39-5.94 ( m, 1H); 4.83 (brs, 2H); 3.89 (t, J = 7.0Hz, 2H); 3.75 (t, J = 6.8Hz, 2H); 2.30 (dt, dt, J = 12.5, 6.5Hz, 4h); 1.04 (s, 9H).

Synthesis of Step D-Compound Int-2d To a mixture of compound Int-2c (8 g, 19.77 mmol) in THF (80 mL) was added a solution of 1 M TBAF in THF (23.73 mL, 23.73 mmol). The mixture was stirred at 15 ° C. for 2 hours and then concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (80 g column) eluting with 0% to 15% EtOAc / petroleum ether to give compound Int-2d. ^{1 1} H NMR (400 MHz, CDCl ₃ ): δ6.20 (t, J = 75.0 Hz, 1H); 4.95 (d, J = 6.8 Hz, 2H); 3.96 (t, J = 13. 0Hz, 2H); 3.48 (t, J = 7.2Hz, 2H); 2.61 (t, J = 7.6Hz, 2H); 2.38 (t, J = 6.4Hz, 2H).

Synthesis of Step E-Compound Int-2e Triphenylphosphine (7.96 g, 30.3 mmol) and carbon tetrabromide in a stirred solution of compound Int-2d (4.2 g, 25.3 mmol) in DCM (40 mL). (10.90 g, 32.9 mmol) was added. The mixture was stirred at 20 ° C. for 1 hour and then concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (40 g column) eluting with 0% to 5% EtOAc / petroleum ether to give compound Int-2e. ^{1 1} H NMR (400 MHz, CDCl ₃ ): δ6.21 (t, J = 74.4 Hz, 1H); 4.96 (d, J = 12 Hz, 2H); 3.97 (t, J = 6.8 Hz, 2H); 3.48 (t, J = 6.8Hz, 2H); 2.63 (t, J = 12Hz, 2H); 2.40 (t, J = 6.8Hz, 2H).

Example 3
Preparation of compounds 1-4

Synthesis of Step A-Compound Int-3a Ethanamine (30 mL, 26.2 mmol, THF solvent) was added to a stirred solution of compound Int-1 (10 g, 26.2 mmol) in THF (3 mL). The mixture was stirred at 20 ° C. for 5 hours and then concentrated under reduced pressure to give compound Int-3a. LCMS analysis calculated value of C ₁₇ H ₁₉ BrN ₂ O ₄ : 394.1, 396.1; measured value: 395.0, 397.0 (M + 1) ⁺ .

Synthesis of Step B-Compound Int-3b TFA (10 mL) was added to a stirred solution of compound Int-3a (10 g, 25.3 mmol) in DCM (50 mL). The mixture was stirred at 20 ° C. for 2 hours and then concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 10% MeOH / DCM to give compound Int-3b. LCMS analysis calculated value of C ₉ H ₁₁ BrN ₂ O ₃ : 274.0, 276.0; measured value: 275.0, 277.0 (M + 1) ⁺ .

Synthesis of Step C-Compound Int-3c In a vial (Vial A) containing a magnetic stirring bar, Ir [dF (CF ₃ ) ppy] ₂ (dtbpy) PF ₆ (8.16 mg, 7.27 μmol), Compound Int- 3b (200 mg, 0.727 mmol), sodium carbonate (154 mg, 1.454 mmol), and tris (trimethylsilyl) silane (542 mg, 2.181 mmol) were added. Meanwhile, in another vial (Vial B), nickel (II) chloride ethylene glycol dimethyl ether complex (37 mg, 0.168 mmol), 4,4'-di-tert-butyl-2,2'-bipyridine (45 mg, 0. 168 mmol) and 16 mL of MeCN were added in that order and the mixture was sonicated until homogeneous (about 15 minutes). 7.3 mL of this stock solution in Vial B was added to Vial A containing the other reaction components. The reaction mixture was degassed by blowing nitrogen for 10 minutes. Compound Int-2e (500 mg, 2.181 mmol) was added and the vial was sealed with parafilm. The vial was then placed in front of the Kessil 34W blue LED light. The reaction solution was stirred while irradiating for 4 hours and then filtered. The filtrate was concentrated under reduced pressure and the residue was purified by flash silica gel chromatography (20 g column) eluting with 0% to 10% MeOH / DCM to give compound Int-3c. LCMS analysis calculated value of C ₁₆ H ₂₂ F ₂ N ₂ O ₄ : 344.2; measured value: 345.2 (M + 1) ⁺ .

Synthesis of Step D-Compound Int-3d NBS (393 mg, 2.207 mmol) was added to a stirred solution of compound Int-3c (380 mg, 1.104 mmol) in THF (5 mL). The mixture was stirred at 15 ° C. for 0.5 hours and then concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (12 g column) eluting with 0% to 10% MeOH / DCM to give compound Int-3d. LCMS analysis calculated value of C ₁₆ H ₂₀ Br ₂ F ₂ N ₂ O ₄ : 502.0; measured value: 503.0 (M + 1) ⁺ .

Synthesis of Step E-Compound Int-3e A mixture of compound Int-3d (570 mg, 1.135 mmol) and Cs ₂ CO ₃ (1110 mg, 3.41 mmol) in DMF (10 mL) was stirred at 20 ° C. for 9 hours and then stirred. It was filtered. The filtrate was concentrated under reduced pressure and the residue was purified by flash silica gel chromatography (20 g column) eluting with 0% to 10% MeOH / DCM to give compound Int-3e. LCMS analysis calculated values of C ₁₆ H ₁₉ BrF ₂ N ₂ O ₄ : 420.1, 422.1; measured values: 420.9, 422.9 (M + 1) ⁺ .

Synthesis of Step F-Compound Int-3f To a solution of compound Int-3e (160 mg, 0.380 mmol) in THF (16 mL) was added 1 M LiHMDS / THF (1.140 mL, 1.140 mmol) at −78 ° C. After 20 minutes, a solution of 3-phenyl-2- (phenylsulfonyl) -1,2-oxaziridine (198 mg, 0.760 mmol) in THF (0.5 mL) was added to the mixture at −78 ° C. The mixture was stirred at 16 ° C. for 20 minutes, then the reaction was stopped with MeOH (2 mL) and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (12 g column) eluting with 0% to 10% MeOH / DCM to give compound Int-3f. LCMS analysis calculated value of C ₁₆ H ₁₉ BrF ₂ N ₂ O ₅ : 436.0, 438.0; measured value: 437.1, 439.1 (M + 1) ⁺ .

Step H-Compound Int-3g Synthetic Compound Int-3f (40 mg, 0.091 mmol) in DMSO (1.5 mL) and MeOH (0.5 mL) solution to (2,4-difluorophenyl) methaneamine (39. 3 mg, 0.274 mmol), N-ethyl-N-isopropylpropan-2-amine (59.1 mg, 0.457 mmol), and Pd (Ph ₃ P) ₄ (52.9 mg, 0.046 mmol) were added. The mixture was degassed and purged with CO 3 times. The resulting mixture was stirred under CO (about 0.103 MPa (15 psi)) at 120 ° C. After 2 hours, the mixture was diluted with EtOAc (20 mL) and washed with water (5 mL) and brine (5 mL). The organic layer was dehydrated over sodium sulfate, filtered and concentrated under reduced pressure. Residues are purified by preparative TLC plates eluting with 100% EtOAc to give the product and preparative SFC (DAICEL CHIRALPAKAD-H, 5 μm, 30 × 250 mm column, 60 mL / min, 40% ( was further purified by _{EtOH + 0.1% NH 3 H 2} O) / CO 2), isomer a (first eluted component compound Int-3 g), isomer B (second component eluted compound Int-3 g ), Compound C (third elution component) of compound Int-3g, and isomer D (fourth elution component) of compound Int-3g were obtained. Isomer C compound Int-3 g, preparative SFC (DAICEL CHIRALCEL OJ-H, 5μm, 30 × 250mm column, 60 mL / _{min, 30% (EtOH + 0.1%} NH 3 H 2 O) / CO 2) further by Purification gave the isomer C of compound Int-3g. Isomer D compound Int-3 g, preparative SFC (DAICEL CHIRALCEL OJ-H, 5μm, 30 × 250mm column, 60 mL / _{min, 30% (EtOH + 0.1%} NH 3 H 2 O) / CO 2) further by Purification gave the isomer D of compound Int-3g. LCMS analysis calculated value of C ₂₄ H ₂₅ F ₄ N ₃ O ₆ : 527.2; measured value: 528.1 (M + 1) ⁺ .

Step H-Synthesis of Compound 1, Compound 2, Compound 3 and Compound 4 Magnesium bromide (12.22 mg, 0.066 mmol) was added. The mixture is stirred at 30 ° C. for 2 hours and then purified by preparative reverse phase HPLC (Boston Green ODS, 5 μm, 30 × 150 mm column) eluting with 30% to 60% ACN / (water + 0.1% TFA). bottom. After lyophilization, the product was co-distilled with toluene (twice at 10 mL) to give compound 1. ^{1 1} H NMR (400 MHz, CD ₃ OD) δ: 7.48-7.37 (m, 1H); 7.00-6.86 (m, 2H); 6.49-6.06 (m, 1H) 5.69 (t, J = 7.9Hz, 1H); 4.63 (brs, 2H); 3.99-3.83 (m, 4h); 3.73 (brdd, J = 13.4, 6.8Hz, 1H); 3.50-3.61 (m, 1H); 3.02 (dd, J = 13.1, 7.7Hz, 1H); 2.23-1.97 (m, 3H) ); 1.24 (t, J = 7.2Hz, 3H). LCMS analysis of calculated values C ₂₃ H ₂₃ F ₄ N ₃ O ₆ : 513.2; measured values: 514.0 (M + 1) ⁺ .

Compound 2 was prepared from isomer B of compound Int-3g, essentially according to the method used to prepare compound 1 in step H of Example 3. ^{1 1} H NMR (400 MHz, CD ₃ OD) δ: 7.48-7.39 (m, 1H); 6.99-6.89 (m, 2H); 6.55-6.12 (m, 1H) 5.73 (d, J = 7.6Hz, 1H); 4.62 (s, 2H); 4.02-4.15 (m, 2H); 3.94-3.87 (m, 1H) 3.84-3.72 (m, 2H); 3.50 (dq, J = 13.8, 7.1Hz, 1H); 2.55-2.48 (m, 1H); 2.43- 2.28 (m, 3H); 1.24 (t, J = 12Hz, 3H). LCMS analysis calculated value of C ₂₃ H ₂₃ F ₄ N ₃ O ₆ : 513.2; measured value: 514.0 (M + 1) ⁺ .

Compound 3 was prepared from isomer C of compound Int-3g, essentially according to the method used to produce compound 1 in step H of Example 3. ^{1 1} H NMR (400 MHz, CD ₃ OD) δ: 7.43 (brd, J = 6.8 Hz, 1H); 7.00-6.87 (m, 2H); 6.57-6.12 (m, 1H); 5.73 (brd, J = 7.3Hz, 1H); 4.62 (brs, 2H); 4.09 (brd, J = 5.1Hz, 2H); 3.94-3.87 ( m, 1H); 3.86-3.75 (m, 2H); 3.53-3.46 (m, 1H); 2.56-2.47 (m, 1H); 2.44-2. 30 (m, 3H); 1.24 (brt, J = 12Hz, 3H). LCMS analysis calculated value of C ₂₃ H ₂₃ F ₄ N ₃ O ₆ : 513.2; measured value: 514.0 (M + 1) ⁺ .

Compound 4 was prepared from isomer D of compound Int-3g, essentially according to the method used to prepare compound 1 in step H of Example 3. ^{1 1} H NMR (400 MHz, CD ₃ OD) δ: 7.42 (brd, J = 8.3 Hz, 1H); 6.94 (brd, J = 11.2 Hz, 2H); 6.49-6.06 ( m, 1H); 5.75-5.62 (m, 1H); 4.63 (brs, 2H); 3.91 (brd, J = 12.5Hz, 4h); 3.72 (brs, 1H) 3.61-3.52 (m, 1H); 3.09-2.97 (m, 1H); 2.24-2.04 (m, 3H); 1.24 (brt, J = 13Hz, 3H). LCMS analysis calculated value of C ₂₃ H ₂₃ F ₄ N ₃ O ₆ : 513.2; measured value: 514.0 (M + 1) ⁺ .

Example 4
Preparation of compounds 5-8

Synthesis of Step A-Compound Int-4a Tributyl (1-ethoxyvinyl) stannane (5.13 mL, 15.18 mmol) and bis (tri) in a solution of compound Int-3a (5 g, 12.65 mmol) in acetonitrile (100 mL). Phenylphosphine) palladium (II) dichloride (0.888 g, 1.265 mmol) was added. The mixture was blown with nitrogen for 5 minutes and then heated at 75 ° C. overnight. The reaction mixture was cooled to room temperature, and then phosphoric acid (12.65 mL, 12.65 mmol) was added. The reaction mixture was stirred for 1 hour, and then a saturated aqueous sodium bicarbonate solution (150 mL) was added. The mixture was extracted with EtOAc (3 times at 100 mL). The combined organic layers were washed with brine, dehydrated with magnesium sulfate, filtered and concentrated. The residue was purified by flash silica gel chromatography (220 g column) eluting with 0% to 100% EtOAc / Hexanes to give compound Int-4a. LCMS analysis calculated value of C ₁₉ H ₂₂ N ₂ O ₅ : 358.15; measured value: 359.12 (M + 1) ⁺ .

Step B- Compound Int-4b Compound Int-4a (2.0g, 5.58mmol) of in tetrahydrofuran (50 mL), and under a _{N 2} atmosphere 3-bromo-2-methylprop-1-ene (1. 507 g, 11.16 mmol), sodium iodide (1.673 g, 11.16 mmol), and indium (1.281 g, 11.16 mmol) were added. The mixture was stirred at room temperature for 30 minutes and then heated to 70 ° C. for 1 hour. The reaction solution was cooled to room temperature and filtered. The filtrate was concentrated and the residue was purified by flash silica gel chromatography (80 g column) eluting with 10% MeOH / DCM to give compound Int-4b. LCMS analysis calculated value of C ₂₃ H ₃₀ N ₂ O ₅ : 414.22; measured value: 415.30 (M + 1) ⁺ .

Synthesis of Step C-Compound Int-4c Trifluoroacetic acid (2 mL, 26.1 mmol) was added to a solution of compound Int-4b (2.0 g, 4.83 mmol) in dichloromethane (20 mL). The mixture was stirred at room temperature for 1 hour and then concentrated. Imidazole (0.657 g, 9.65 mmol) was added to a solution of the obtained residue in N, N-dimethylformamide (10 mL), and then chlorotriethylsilane (1.09 g, 7.24 mmol) was added. The resulting mixture was stirred at 50 ° C. for 2 hours and then concentrated. The obtained residue was purified by silica gel column chromatography (80 g column) in which elution was performed with 0% to 10% MeOH / DCM to obtain compound Int-4c. LCMS analysis calculated value of C ₂₁ H ₃₆ N ₂ O ₄ Si: 408.24; measured value: 409.34 (M + 1) ⁺ .

Synthesis of Step D-Compound Int-4d To a stirred solution of compound Int-4c (1.0 g, 2.447 mmol) in acetonitrile (25 mL), 1-bromopyrrolidine-2,5-dione (1.089 g, 6. 12 mmol) was added. The mixture was stirred at room temperature for 1.5 hours and then concentrated. The residue was taken in 50% EtOAc / Hexanes (3 mL) and filtered. The filtrate is concentrated and the resulting residue is purified by C18 reverse phase chromatography (80 g column) eluting with 10% to 100% (ACN / water) + 0.05% TFA to give compound Int-4d. Obtained. LCMS analysis calculated value of C ₂₁ H ₃₄ Br ₂ N ₂ O ₄ Si: 566.06; measured value: 567.06 (M + 1) ⁺ .

Synthesis of Step E-Compound Int-4e Cesium carbonate (621 mg, 1.907 mmol) was added to a solution of the stirred compound Int-4d (720 mg, 1.271 mmol) in dimethyl sulfoxide (12 mL). The mixture was stirred at room temperature for 1.5 hours and then purified directly on a C18 reverse phase column eluting with 0% to 100% (ACN / water) + 0.05% TFA to give compound Int-4e. LCMS analysis calculated value of C ₂₁ H ₃₃ BrN ₂ O ₄ Si: 484.14; measured value: 485.13 (M + 1) ⁺ .

Step F-Synthesis of Compound Int-4f Add a solution of 4M hydrochloric acid in dioxane (0.520 mL, 2.080 mmol) to a stirred solution of compound Int-4e (0.5 g, 1.04 mmol) in methanol (15 mL). rice field. The reaction mixture was stirred at room temperature for 2 hours and then concentrated under reduced pressure. The resulting residue was redissolved in methanol (15 mL), palladium / carbon (10 wt%) (0.111 g, 0.104 mmol) after adding, the mixture was placed under _{H 2} balloon. After 2 hours, the reaction was filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (40 g column) eluting with 0% to 30% MeOH / DCM to give compound Int-4f. LCMS analysis calculated value of C ₁₅ H ₂₀ N ₂ O ₄ : 292.14; measured value: 293.12 (M + 1) ⁺ .

Synthesis of Step G-Compound Int-4g N-iodosuccinate imide (142 mg, 0.631 mmol) and 3-chloroperbenzoic acid (136 mg, 0.631 mmol) were added to the methanol of Compound Int-4f (123 mg, 0.421 mmol). It was added to the stirred solution in (5 mL). The reaction mixture was heated at 70 ° C. for 2 hours, then cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified by preparative TLC plate elution with 10% MeOH / DCM to give compound Int-4g. LCMS analysis calculated value of C ₁₅ H ₁₉ IN ₂ O ₄ : 418.04; measured value: 419.00 (M + 1) ⁺ .

Synthesis of Step H-Compound Int-4h Tetrakis (triphenylphosphine) palladium (0) (61 mg, 0.053 mmol), N, N-diisopropylethylamine (184 μL, 1.052 mmol), and 2,4-difluorobenzylamine ( 75 mg, 0.526 mmol) was added to the stirred solution of compound Int-4 g (110 mg, 0.263 mmol) in dimethyl sulfoxide (2 mL). The reaction mixture was degassed and placed in a carbon monoxide atmosphere. The resulting reaction mixture is stirred at 90 ° C. for 1 hour, then cooled to room temperature, filtered through a 0.45 μm syringe filter, diluted with methanol and 10% to 100% (ACN / water) + 0.05%. Purification by reverse phase HPLC (RediSep Rf C18, 100 g column) elution with TFA to obtain the product, which was subjected to chiral preparative SFC (ChirarPak AD-H, 21 × 250 mm column, 70 g / min, 12 MPa (12 MPa). 120 bar), 25% EtOH / CO ₂ , 40 ° C.) to further purify compound Int-4h isomer A (first elution component), compound Int-4h isomer B (second elution component). ), The isomer C of compound Int-4h (third elution component), and the isomer D of compound Int-4h (fourth elution component) were obtained. LCMS analysis calculated value of C ₂₃ H ₂₅ F ₂ N ₃ O ₅ : 461.18; measured value: 462.41 (M + 1) ⁺ .

Step I-Synthesis of Compound 5, Compound 6, Compound 7, and Compound 8 Int-4h isomer A (19.0 mg, 0.041 mmol), magnesium bromide (114 mg, 0.618 mmol) and acetonitrile (1. 0 mL) was combined and stirred at room temperature. After 30 minutes, the reaction mixture was diluted with MeOH, filtered through a 0.45 μm syringe filter and then purified by reverse phase HPLC (Waters Sunfire C18 OBD, 10 μm, 30 × 150 mm column). The product fractions were combined, frozen and lyophilized to give compound 5. ^{1 1} H NMR (500 MHz, CDCl ₃ ): δ11.48 (s, 1H); 8.20 (brs, 1H); 7.35-7.25 (m, 1H); 6.82-6.78 (m). , 2H); 4.66-4.65 (m, 2H); 3.83-3.79 (d, J = 20Hz, 1H); 3.74 (m, 1H); 3.69 (m, 1H) ); 3.50-3.47 (m, 1H); 2.46 (m, 2H); 1.86 (s, 3H); 1.54 (s, 3H); 1.26 (t, J = 5.0Hz, 3H). LCMS analysis calculated value of C ₂₂ H ₂₃ F ₂ N ₃ O ₅ : 447.16; measured value: 448.13 (M + 1) ⁺ .

Compound 6 was prepared from isomer B of compound Int-4h, essentially according to the method used to prepare compound 5 in step I of Example 4. ^{1 1} H NMR (500 MHz, CDCl ₃ ): δ10.75 (s, 1H); 7.40-7.26 (m, 1H); 6.84-6.81 (m, 2H); 4.72-4 .68 (m, 2H); 4.60-4.56 (m, 2H); 3.76-3.71 (m, 2H); 3.58-3.50 (m, 2H); 2.59 -2.56 (d, J = 15Hz, 1H); 2.13-2.10 (s, J = 15Hz, 1H); 1.73 (s, 3H); 1.65 (s, 3H); 1 .27 (t, J = 10Hz, 3H). LCMS analysis calculated value of C ₂₂ H ₂₃ F ₂ N ₃ O ₅ : 447.16; measured value: 448.40 (M + 1) ⁺ .

Compound 7 was prepared from isomer C of compound Int-4h, essentially according to the method used to prepare compound 5 in step I of Example 4. ^{1 1} H NMR (500 MHz, CDCl ₃ ): δ10.75 (s, 1H); 7.41-7.35 (m, 1H); 6.86-6.78 (m, 2H); 4.73-4 .68 (m, 2H); 4.60-4.56 (m, 2H); 3.77-3.70 (m, 2H); 3.57-3.50 (m, 2H); 2.59 -2.56 (d, J = 15Hz, 1H); 2.13-2.10 (s, J = 15Hz, 1H); 1.72 (s, 3H); 1.65 (s, 3H); 1 .27 (t, J = 10Hz, 3H). LCMS analysis calculated value of C ₂₂ H ₂₃ F ₂ N ₃ O ₅ : 447.16; measured value: 448.42 (M + 1) ⁺ .

Compound 8 was prepared from isomer D of compound Int-4h, essentially according to the method used to prepare compound 5 in step I of Example 4. ^{1 1} H NMR (500 MHz, CDCl ₃ ): δ11.48 (s, 1H); 8.22 (wide, 1H); 7.36-7.33 (m, 1H); 6.82-6.80 (m) , 2H); 4.65 (m, 2H); 3.83-3.79 (d, J = 20Hz, 1H); 3.74 (m, 1H); 3.71 (m, 1H); 3. 50-3.47 (m, 1H); 2.46 (m, 2H); 1.86 (s, 3H); 1.54 (s, 3H); 1.26 (t, J = 5.0Hz, 3H). LCMS analysis calculated value of C ₂₂ H ₂₃ F ₂ N ₃ O ₅ : 447.16; measured value: 448.13 (M + 1) ⁺ .

Example 5
Preparation of compounds 9-12

Step A-Synthesis of Compound Int-5a In a 40 mL vial containing a magnetic stirring bar, Ir [dF (CF ₃ ) ppy] ₂ (dtbpy) PF ₆ (12.23 mg, 10.91 μmol), Compound Int-3b (300 mg). , 1.091 mmol), sodium carbonate (231 mg, 2.181 mmol), and 1,1,1,3,3,3-hexamethyl-2- (trimethylsilyl) trisilane (1.009 mL, 3.27 mmol). Meanwhile, another 40 mL vial was filled with nickel (II) chloride grime (50.3 mg) and 4.4'-di-tert-butyl-2,2'-bipyridine (61.5 mg). 1,2-Dimethoxyethane (22.9 mL) was added and the mixture was sonicated until homogeneous (about 15 minutes). 10.9 mL of this solution was added to a vial containing the other reaction components. The reaction mixture was degassed by bubbling N ₂ 10 minutes. 4-Bromo-2-methylbuta-1-ene (0.390 mL, 3.27 mmol) was added and the vial was sealed with parafilm. The vial was then placed in a second generation Merck photoreactor (50% LED power, 1000 rpm stirring, 10200 rpm fan cooling). After 1 hour, the vial was opened and the mixture was stirred under air. The mixture was filtered and washed with dichloromethane. The filtrate was concentrated under reduced pressure and the residue was chromatographed on silica gel (80 g column) eluting with 0% to 90% (25% EtOH / EtOAc) / hexanes to give compound Int-5a. .. LCMS analysis calculated value of C ₁₄ H ₂₀ N ₂ O ₃ : 264.15; measured value: 265.24 (M + 1) ⁺ .

Step B-Synthesis of Compound Int-5b Compound Int-5a (406 mg, 1.536 mmol) was placed in a 100 mL round bottom flask containing a magnetic stirring bar. THF (15.4 mL) and imide N-bromosuccinate (547 mg, 3.07 mmol) were added and the mixture was stirred at room temperature. After 15 minutes, the mixture was concentrated under reduced pressure to give compound Int-5b, which was used in step C of Example 5 without further purification. LCMS analysis calculated value of C ₁₄ H ₁₈ Br ₂ N ₂ O ₃ : 421.97; measured value: 423.07 (M + 1) ⁺ .

A magnetic stirring bar was placed in a 40 mL vial containing synthetic compound Int-5b of step C-compound Int-5c. Cesium carbonate (1501 mg, 4.61 mmol) and DMSO (30.7 mL) were added and the mixture was stirred at room temperature. After 16.5 hours, the reaction mixture was diluted with dichloromethane, water, and brine. The aqueous layer was extracted 3 times with dichloromethane. The combined organic layers were _{dehydrated with NaSO 4} , filtered and concentrated. The residue was purified by flash chromatography (80 g column) on silica gel eluting with 0% to 100% (25% EtOH / EtOAc) / hexane. Since the residue was found to contain DMSO, it was dissolved in DCM and washed with LiCl. The LiCl layer was back-extracted once with DCM. The combined organic layers were _{dehydrated with Na 2} SO ₄ , filtered and concentrated to give compound Int-5c. LCMS analysis calculated value of C ₁₄ H ₁₇ BrN ₂ O ₃ : 340.04; measured value: 341.10 (M + 1) ⁺ .

The Compound Int-5c stage D- Compound Int-5d placed under _{N 2} atmosphere. THF (21.2 mL) and DMF (4.25 mL) were added and the mixture was cooled with stirring to -78 ° C. A solution of lithium bis (trimethylsilyl) amide 1.0 M in THF (3.825 mL, 3.82 mmol) was added dropwise and the mixture was stirred at −78 ° C. for 10 minutes. 3-Phenyl-2- (phenylsulfonyl) -1,2-oxaziridine (733 mg, 2.80 mmol) was added dropwise as the smallest volume of solution in THF. The temperature of the mixture was raised to room temperature. After raising the temperature of the reaction solution to room temperature (about 20 minutes), the mixture was diluted with MeOH and concentrated. The mixture was partitioned between EtOAc and water and the layers were separated. The EtOAc layer was extracted with an additional amount of water. The combined aqueous layers were filtered and purified directly by reverse phase HPLC eluting with 0% to 50% (MeCN / H ₂ O) + 0.1% TFA to give compound Int-5d. LCMS analysis calculated value of C ₁₄ H ₁₇ BrN ₂ O ₄ : 356.04; measured value: 357.13 (M + 1) ⁺ .

A magnetic stirring bar was placed in a 100 mL round bottom flask containing the synthetic compound Int-5d (320 mg, 0.896 mmol) of step E-compound Int-5e. DMSO (17.9 mL) was added. The flask is evacuated _{and refilled with N 2} , then (2,4-difluorophenyl) methaneamine (319 μL, 2.69 mmol), N, N-diisopropylethylamine (782 μL, 4.48 mmol), and Pd (dppf). Cl ₂ (131 mg, 0.179 mmol) was added. The flask was evacuated, CO was refilled from the balloon three times, and then heated to 100 ° C. and stirred for 24 hours. The mixture was cooled, diluted with a small amount of methanol and filtered. The resulting solution was purified by reverse-phase HPLC eluting from 20% _{90% (MeCN / H 2 O} ) + 0.1% TFA. The product obtained from the product fraction was further purified by chromatography on silica gel (40 g column) elution with 0% to 70% (25% EtOH / EtOAc) / hexane to give the product. , Further purified by chiral preparative SFC (ChiralPakAD-H, 20 × 250 mm column, 50 mL / min, 10 MPa (100 bar), 50% MeOH / CO ₂ ) to isomer A of compound Int-5e (first). Elution component), isomer B of compound Int-5e (second elution component), isomer C of compound Int-5e (third elution component), and isomer D of compound Int-5e (fourth elution component). Ingredient) was obtained. Isomer B was further purified under the same SFC conditions to obtain a sufficiently pure product. LCMS analysis calculated value of C ₂₂ H ₂₃ F ₂ N ₃ O ₅ : 447.16; measured value: 448.26 (M + 1) ⁺ .

Step F-The isomer A of compound Int-5e and DMF (223 μL) were placed in a 4 mL vial containing a synthetic magnetic stirring bar of compound 9, compound 10, compound 11 and compound 12. Lithium chloride (9.47 mg, 0.223 mmol) was added and the mixture was heated with stirring to 100 ° C. After 2 hours, the mixture was diluted with DMF and purified directly by reverse phase HPLC eluting with _{5% to 95% (MeCN / H 2 O) + 0.1% TFA.} The pure fraction was lyophilized to give compound 9. ^{1 1} H NMR (500 MHz, CDCl ₃ ): δ11.29 (s, 1H); 7.35 (q, J = 8.4 Hz, 1H); 6.87-6.78 (m, 2H); 5.73 (T, J = 7.9Hz, 1H); 4.69 (dd, J = 15.2, 5.7Hz, 1H); 4.62 (dd, J = 15.0, 5.3Hz, 1H); 3.88 (d, J = 12.9Hz, 1H); 3.73 (dq, J = 14.4, 7.4Hz, 1H); 3.64-3.49 (m, 2H); 2.81 (Dd, J = 12.6, 7.4Hz, 1H); 2.20 (dd, J = 12.5, 8.7Hz, 1H); 1.45 (s, 3H); 1.28 (t, J = 7.2Hz, 3H). LCMS analysis calculated value of C ₂₁ H ₂₁ F ₂ N ₃ O ₅ : 433.14; measured value: 434.26 (M + 1) ⁺ .

Compound 10 was prepared from isomer B of compound Int-5e, essentially according to the method used to produce compound 9 in step F of Example 5. ^{1 1} H NMR (500 MHz, CDCl ₃ ): δ10.86 (s, 1H); 7.36 (q, J = 8.2 Hz, 1H); 6.89-6.76 (m, 2H); 5.72 (D, J = 7.5Hz, 1H); 4.67 (dd, J = 15.2, 5.8Hz, 1H); 4.60 (dd, J = 15.3, 5.5Hz, 1H); 3.81-3.70 (m, 2H); 3.61-3.49 (m, 2H); 2.43 (d, J = 13.5Hz, 1H); 2.34 (dd, J = 13) .6, 7.7Hz, 1H); 1.69 (s, 3H); 1.28 (t, J = 7.2Hz, 3H). LCMS analysis calculated value of C ₂₁ H ₂₁ F ₂ N ₃ O ₅ : 433.14; measured value: 434.24 (M + 1) ⁺ .

Compound 11 was prepared from isomer C of compound Int-5e, essentially according to the method used to prepare compound 9 in step F of Example 5. ^{1 1} H NMR (600 MHz, CDCl ₃ ): δ10.92 (s, 1H); 7.40-7.33 (m, 1H); 6.87-6.78 (m, 2H); 5.68 (d). , J = 7.5Hz, 1H); 5.26 (s, 1H); 4.67 (dd, J = 15.2, 6.3Hz, 1H); 4.60 (dd, J = 15.4, 5.5Hz, 1H); 3.81-3.67 (m, 2H); 3.60-3.46 (m, 2H); 2.40 (d, J = 13.5Hz, 1H); 2. 33 (dd, J = 13.5, 7.8Hz, 1H); 1.67 (s, 3H); 1.27 (t, J = 7.2Hz, 3H). LCMS analysis calculated value of C ₂₁ H ₂₁ F ₂ N ₃ O ₅ : 433.14; measured value: 434.24 (M + 1) ⁺ .

Compound 12 was prepared from isomer D of compound Int-5e, essentially according to the method used to produce compound 9 in step F of Example 5. ^{1 1} H NMR (500 MHz, CDCl ₃ ): δ11.31 (t, J = 5.1 Hz, 1H); 7.36 (q, J = 8.2 Hz, 1H); 6.87-6.78 (m, 2H); 5.72 (t, J = 8.0Hz, 1H); 4.69 (dd, J = 15.3, 5.7Hz, 1H); 4.62 (dd, J = 15.2, 5) .6Hz, 1H); 3.88 (d, J = 12.8Hz, 1H); 3.73 (dq, J = 14.3, 7.2Hz, 1H); 3.63-3.52 (m, 2H); 2.80 (dd, J = 12.6, 7.4Hz, 1H); 2.20 (dd, J = 12.5, 8.7Hz, 1H); 1.45 (s, 3H); 1.28 (t, J = 7.2Hz, 3H). LCMS analysis calculated value of C ₂₁ H ₂₁ F ₂ N ₃ O ₅ : 433.14; measured value: 434.24 (M + 1) ⁺ .

Example 6
Preparation of compound Int-6c

Synthesis of Step A-Compound Int-6a TBDPSCl (100 g, 0.365 mmol) was added to a mixture of 3-methylbut-3-en-1-ol (21 g, 244 mmol) and imidazole (33 g, 487 mmol) in DCM (200 mL). Added little by little. The mixture was stirred at 25 ° C. for 10 hours and then washed with brine (100 mL). The aqueous layer was extracted with EtOAc (twice at 100 mL). The combined organic layers were dehydrated over sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography eluting with 100% PE to obtain compound Int-6a. ^{1 1} H NMR (400 MHz, CDCl ₃ ): δ7.68-7.66 (m, 4h); 7.42-7.36 (m, 6H); 4.74-4.67 (d, J = 24. 8Hz, 2H); 3.77-3.74 (t, J = 7.2Hz, 2H); 2.29-2.25 (t, J = 6.8Hz, 2H); 1.67 (s, 3H) ); 1.04 (s, 9H).

Synthesis of Step B-Compound Int-6b Hexanes of dimethylaluminum chloride 1M at 0 ° C. in a mixture of compound Int-6a (10 g, 30.8 mmol) and paraformaldehyde (1.018 g, 33.9 mmol) in DCM (150 mL). The medium solution (40.1 mL, 40.1 mmol) was added dropwise. The mixture was stirred at 0 ° C. for 2 hours and then stopped with water (40 mL). 1N HCl was added dropwise to dissolve the precipitate. The mixture was extracted with DCM (3 times at 40 mL), the combined organic layers were dehydrated over sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography eluting with 10% EtOAc / PE to give compound Int-6b. ^{1 1} H NMR (400 MHz, CDCl ₃ ): δ7.68 (dd, J = 7.7, 1.5 Hz, 4h); 7.44-7.37 (m, 6H); 4.89 (s, 2H) 3.78 (t, J = 6.8Hz, 2H); 3.67 (t, J = 6.4Hz, 2H); 2.30-2.22 (m, 4h); 1.06-1. 05 (m, 9H).

Step C-Synthesis of Compound Int-6c Triphenylphosphine (10.65 g, 40.6 mmol) and CBr ₄ (14. 59 g, 44.0 mmol) was added. The mixture was stirred at 20 ° C. for 2.5 hours and then concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography eluting with 2% EtOAc / PE to give compound Int-6c. ^{1 1} H NMR (400 MHz, CDCl ₃ ): δ7.77 (dd, J = 7.9, 1.3 Hz, 4h); 7.45-7.37 (m, 6H); 4.89-4.81 ( m, 2H); 3.79-3.71 (m, 2H); 3.39 (t, J = 7.5Hz, 2H); 2.54 (t, J = 7.5Hz, 2H); 2. 28 (t, J = 6.8 Hz, 2H); 1.07 to 1.05 (m, 9H).

Example 7
Preparation of compounds 13-16

Synthesis of Step A-Compound Int-7a TFA (10 mL, 130 mmol) was added dropwise to a stirred solution of compound Int-1 (3 g, 7.85 mmol) in DCM (30 mL). The mixture was stirred at 25 ° C. for 3 hours and then concentrated under reduced pressure. The obtained residue was purified by flash silica gel chromatography (24 g column) eluting with 5% MeOH / DCM to give compound Int-7a. LCMS analysis calculated value of C ₈ H ₈ BrNO ₄ : 263.0; measured value: 263.9 (M + 1) ⁺ .

Synthesis of Step B-Compound Int-7b In a vial (Vial A) containing a magnetic stirring bar, Ir [dF (CF ₃ ) ppy] ₂ (dtbpy) PF ₆ (4.28 mg, 3.82 μmol), Compound Int-7a (100 mg, 0.382 mmol), sodium carbonate (81 mg, 0.763 mmol), and tris (trimethylsilyl) silane (285 mg, 1.145 mmol) were added. Meanwhile, in another vial (Vial B), nickel (II) chloride ethylene glycol dimethyl ether complex (37 mg, 0.168 mmol) and 4,4'-di-tert-butyl-2,2'-bipyridine (45 mg, 0.168 mmol) ) Was put in. DME (16 mL) was added and the mixture was sonicated until homogeneous (about 15 minutes). 3.6 mL of this stock solution was added to Vial A containing the other reaction components. The reaction mixture was degassed by blowing _{N 2 for 10 minutes.} Compound Int-6c (319 mg, 0.763 mmol) was added and the vial was sealed with parafilm. The vial was then placed in front of the Kessil 34W blue LED light. The reaction was stirred with irradiation and cooling with a fan. After 16 hours, the reaction mixture was diluted with EtOAc (20 mL) and washed with water (10 mL). The aqueous layer was extracted with EtOAc (3 times at 20 mL). The combined organic layers were dehydrated over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative TLC plate elution with 9% MeOH / DCM to give compound Int-7b. LCMS analysis calculated value of C ₃₀ H ₃₇ NO ₅ Si: 519.2; measured value: 520.2 (M + 1) ⁺ .

Synthesis of Step C-Compound Int-7c Compound Int-7b (1.1 g, 2.117 mmol), O- (2,4-dinitrophenyl) hydroxylamine (0.843 g, 4.23 mmol), and bis [rodium ( α, α, α', α'-tetramethyl-1,3-benzenedipropionic acid)] (0.032 g, 0.042 mmol) in CF ₃ CH ₂ OH (15 mL) was degassed and hydrated with nitrogen. It was purged. The resulting mixture was stirred at 50 ° C. for 10 hours, concentrated under reduced pressure and purified by silica gel chromatography eluting with 7% MeOH / DCM to give compound Int-7c. LCMS analysis calculated value of C ₂₉ H ₃₄ N ₂ O ₄ Si: 502.2; measured value: 503.0 (M + 1) ⁺ .

Synthesis of Step D-Compound Int-7d Sodium hydride (0.175 g, 0.175 g,) in a mixture of compound Int-7c (1.1 g, 2.188 mmol) and iodoethane (1.024 g, 6.56 mmol) in DMF (15 mL). 4.38 mmol, 60% by weight) was added. The mixture was stirred at 0 ° C. for 1 hour, then the reaction was stopped with 1 M aqueous HCl solution (3 mL, 3 mmol) and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 9% MeOH / DCM to give compound Int-7d. LCMS analysis calculated value of C ₃₁ H ₃₈ N ₂ O ₄ Si: 530.3; measured value: 531.1 (M + 1) ⁺ .

Synthesis of Step E-Compound Int-7e To a mixture of Int-7d (0.9 g, 1.696 mmol) in THF (5 mL) is added a solution of TBAF 1.0 M in THF (2.035 mL, 2.035 mmol). rice field. The mixture was stirred at 15 ° C. for 2 hours and then concentrated under reduced pressure. The resulting residue was purified by preparative TLC elution with 30% MeOH / THF to give compound Int-7e. LCMS analysis calculated value of C ₁₅ H ₂₀ N ₂ O ₄ : 292.1; measured value: 293.0 (M + 1) ⁺ .

Synthesis of Step F-Compound Int-7f Sodium hydride (41.0 mg, 1.026 mmol, 60 wt%) at 0 ° C. in a stirred mixture of compound Int-7e (150 mg, 0.513 mmol) in DMF (5 mL). And iodomethane (87 mg, 0.616 mmol) was added. The mixture was stirred for 1 hour at 20 ° C., quenched with saturated aqueous _NH 4 Cl (5 mL), and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography eluting with 9% MeOH / DCM to give compound Int-7f. LCMS analysis calculated value of C ₁₆ H ₂₂ N ₂ O ₄ : 306.2; measured value: 307.0 (M + 1) ⁺ .

Step G-Compound Int-7g Synthetic Compound Int-7f (100 mg, 0.326 mmol) in THF (8 mL) and DMF (1.5 mL) in THF (0.979 mL) in THF (0.979 mL) of LiHMDS 1M at −78 ° C. , 0.979 mmol) was added. After 20 minutes, 3-phenyl-2- (phenylsulfonyl) -1,2-oxaziridine (171 mg, 0.653 mmol) in THF (1 mL) was added to the above mixture at −78 ° C. The obtained mixture was stirred at 16 ° C. for 20 minutes, the reaction was stopped with MeOH, and the mixture was concentrated under reduced pressure. The crude product was purified by preparative TLC eluting with 10% methanol / dichloromethane to give compound Int-7g. LCMS analysis calculated value of C ₁₆ H ₂₂ N ₂ O ₅ : 322.2; measured value: 323.2 (M + 1) ⁺ .

Synthesis of Step H-Compound Int-7h In 7 g (40 mg, 0.124 mmol) of compound Int-7 g (40 mg, 0.124 mmol) in a stirred solution in MeOH (1 mL), m-CPBA (26.8 mg, 0.124 mmol) and NIS (55.8 mg, 55.8 mg, 0.248 mmol) was added. The mixture was stirred at 60 ° C. for 1 hour _{, then the reaction was stopped with saturated aqueous Na 2} SO ₃ solution (2 mL) and concentrated under reduced pressure. The resulting residue was purified by preparative TLC plate elution with 6% MeOH / DCM to give compound Int-7h. LCMS analysis calculated value of C ₁₆ H ₂₁ IN ₂ O ₅ : 448.1; measured value: 449.1 (M + 1) ⁺ .

Step I- Compound Int-7i of compound Int-7h (45 mg, 0.100 mmol) to a stirred solution of DMSO (2 mL) of, _{N 2} under, (2,4-difluorophenyl) methanamine (28.7 mg, 0.201 mmol), N-ethyl-N-isopropylpropane-amine (64.9 mg, 0.502 mmol), and Pd (PPh ₃ ) ₄ (116 mg, 0.100 mmol) were added. The reaction mixture was stirred under CO (about 0.103 MPa (15 psi)) at 75 ° C. for 1.5 hours and then treated with water (5 mL) and EtOAc (5 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (twice at 5 mL). The combined organic extracts were washed with water and brine _{, dehydrated with Na 2} SO ₄ , and concentrated under reduced pressure. The crude product was _{purified using preparative TLC (SiO 2} , petroleum ether / EtOAc = 1: 2) and it was subjected to SFC (DAICEL CHIRALPAK AD, 10 μm, 30 × 250 mm column, 60 mL / min, 40% ( was further purified by _{EtOH + 0.1% NH 3 H 2} O) / CO 2), isomer a (first eluted component compound Int-7i), isomer B of the compound Int-7i (second component eluted ), Isomer C of compound Int-7i (third elution component), and isomer D of compound Int-7i (fourth elution component). LCMS analysis calculated value of C ₂₄ H ₂₇ F ₂ N ₃ O ₆ : 491.2; measured value: 492.2 (M + 1) ⁺ .

Step J-Synthesis of Compound 13, Compound 14, Compound 15, and Compound 16 Magnesium bromide (18.73 mg, 0) in a solution of isomer A (10 mg, 0.020 mmol) of compound Int-7i in acetonitrile (1 mL). .102 mmol) was added. The mixture is stirred at room temperature 20 ° C. for 1 hour, then filtered and eluted with 40% to 70% ACN / (water + 0.1% TFA) reverse phase HPLC (Boston Green ODS, 5 μm, 30 × 150 mm column). Purified with to give compound 13. ^{1 1} H NMR (400 MHz, CDCl ₃ ): δ7.46-7.43 (m, 1H); 6.98-6.91 (m, 2H); 5.66-5.62 (t, J = 2. 4, 1H); 4.64 (s, 2H); 3.90 (s, 2H); 3.72-3.34 (m, 4h); 3.17 (s, 3H); 3.04-2 .99 (m, 1H); 2.08-1.93 (m, 3H); 1.28-1.20 (t, J = 7.2Hz, 3H). LCMS analysis calculated value of C ₂₃ H ₂₅ F ₂ N ₃ O ₆ : 477.2; measured value: 478.0 (M + 1) ⁺ .

Compound 14 was prepared from isomer B of compound Int-7i, essentially according to the method used to produce compound 13 in step J of Example 7. ^{1 1} H NMR (400 MHz, CDCl ₃ ): δ7.44 (s, 1H); 6.95-6.93 (m, 2H); 5.71-5.69 (m, 1H); 4.62 (s) , 2H); 3.98-3.58 (m, 6H); 3.27 (s, 3H); 2.55-2.15 (m, 4h); 1.26-1.20 (t, J) = 7.2Hz, 3H). LCMS analysis calculated value of C ₂₃ H ₂₅ F ₂ N ₃ O ₆ : 477.2; measured value: 478.0 (M + 1) ⁺ .

Compound 15 was prepared from isomer C of compound Int-7i, essentially according to the method used to produce compound 13 in step J of Example 7. ^{1 1} H NMR (400 MHz, CDCl ₃ ): δ7.48-7.44 (m, 1H); 6.99-6.91 (m, 2H); 5.70-5.68 (m, 1H); 4 .62 (m, 2H); 3.98-3.49 (m, 6H); 3.27 (s, 3H); 2.54-2.13 (m, 4h); 1.26-1.22 (T, J = 12Hz, 3H). LCMS analysis calculated value of C ₂₃ H ₂₅ F ₂ N ₃ O ₆ : 477.2; measured value: 478.0 (M + 1) ⁺ .

Compound 16 was prepared from isomer D of compound Int-7i, essentially according to the method used to produce compound 13 in step J of Example 7. ^{1 1} H NMR (400 MHz, CDCl ₃ ): δ7.43 (s, 1H); 6.93 (s, 2H); 5.66-5.62 (t, J = 2.4, 1H); 4.64 (S, 2H); 3.90 (s, 2H); 3.70-3.34 (m, 4h); 3.17 (s, 3H); 3.04-2.99 (m, 1H); 2.08-1.93 (m, 3H); 1.28-1.22 (t, J = 7.2Hz, 3H). LCMS analysis calculated value of C ₂₃ H ₂₅ F ₂ N ₃ O ₆ : 477.2; measured value: 478.0 (M + 1) ⁺ .

Example 8
Production of compounds 17-20

Step A-Synthesis of Compound Int-8a In a 40 mL vial containing a magnetic stirring bar, Ir [dF (CF ₃ ) ppy] ₂ (dtbpy) PF ₆ (12.84 mg, 0.011 mmol), Compound Int-7a (300 mg). , 1.145 mmol), 1,1,1,3,3,3-hexamethyl-2- (trimethylsilyl) trisilane (1.060 mL, 3.43 mmol), and 2,6-lutidine (0.265 mL, 2.290 mmol). ) Was put in. Meanwhile, another 40 mL vial was filled with nickel (II) chloride grime (37.0 mg) and 4,4'-di-tert-butyl-2,2'-bipyridine (45.0 mg). 1,2-Dimethoxyethane (16.7 mL) was added and the mixture was sonicated until homogeneous (about 15 minutes). 11.4 mL of this stock solution was added to a vial containing other reaction components. The reaction mixture was degassed by blowing nitrogen for 10 minutes. 4-Bromo-2-methylbuta-1-ene (0.409 mL, 3.43 mmol) was added and the vial was sealed with parafilm. The vial was then placed in a second generation Merck photoreactor (50% LED power, 700 rpm stirring, 10200 rpm fan cooling). After 2 hours, the reaction solution was removed from the light and concentrated. The residue was purified by flash chromatography (120 g column) on silica gel eluting with 0% to 100% (25% EtOH / EtOAc) / hexanes to give a non-pure product. The obtained product is further purified by reverse phase HPLC (Sunfire Prep C18 OBD, 10 μm, 50 × 250 mm column) elution with 0% to 80% (MeCN / H _{2 O) + 0.1% TFA to compound Int.} -8a was obtained. LCMS analysis calculated value of C ₁₃ H ₁₇ NO ₄ : 251.12; measured value: 252.15 (M + 1) ⁺ .

Step B-Synthesis of Compound Int-8b A solution of Compound Int-8a (505 mg, 2.010 mmol) in methanol (10.0 mL) was placed in a 40 mL vial containing a magnetic stirring bar. A solution of methylamine 2.0 M in THF (10.05 mL, 20.10 mmol) was added and the mixture was stirred at room temperature. After 6 hours, the mixture was concentrated under reduced pressure to give compound Int-8b, which was used in step C of Example 8 without further purification. LCMS analysis calculated value of C ₁₃ H ₁₈ N ₂ O ₃ : 250.13; measured value: 251.16 (M + 1) ⁺ .

A magnetic stir bar was placed in a 40 mL vial containing synthetic compound Int-8b (503 mg, 2.01 mmol) of step C-compound Int-8c. THF (20.1 mL) and imide N-bromosuccinate (787 mg, 4.42 mmol) were added and the mixture was stirred at room temperature. After 15 minutes, the mixture was diluted with MeOH and concentrated to give compound Int-8c, which was used in step D of Example 8 without further purification. LCMS analysis calculated value of C ₁₃ H ₁₆ Br ₂ N ₂ O ₃ : 407.95; measured value: 409.04 (M + 1) ⁺ .

Synthetic of Step D-Compound Int-8d Compound Int-8c (820 mg, 2.01 mmol) was placed in a 40 mL vial containing a magnetic stirring bar. DMSO (20.1 mL) and cesium carbonate (2619 mg, 8.04 mmol) were added and the mixture was stirred at room temperature. After 1 hour, the mixture is filtered, washed with DMSO _{and eluted with 0% to 60% (MeCN / H 2} O) + 0.1% TFA Reverse Phase HPLC (Sunfire Prep C18 OBD, 10 μm, 50 × 250 mm). Purified by. The solid from the filtration was dissolved in MeOH and filtered again. The filtrate was concentrated and dissolved in DMSO / MeOH. The mixture was purified by reverse phase HPLC using the same conditions as described above. The product fraction was concentrated under reduced pressure to give compound Int-8d. LCMS analysis calculated value of C ₁₃ H ₁₅ BrN ₂ O ₃ : 326.03; measured value: 327.08 (M + 1) ⁺ .

Step E- Compound Int-8e of the synthesized magnetic stirring bar was charged with flame-dried 200mL round-bottom flask was charged with compound Int-8d (608mg, 1.858mmol) were charged, and placed under _{N 2} atmosphere. THF (24.8 mL) and DMF (12.4 mL) were added and the mixture was cooled with stirring to -78 ° C. A solution of lithium bis (trimethylsilyl) amide 1.0 M in THF (5.575 mL, 5.58 mmol) was added dropwise and the mixture was stirred at −78 ° C. for 10 minutes. 3-Phenyl-2- (phenylsulfonyl) -1,2-oxaziridine (1068 mg, 4.09 mmol) was added dropwise as a minimum amount of solution in THF. The temperature of the mixture was raised to room temperature. The mixture was partitioned between water and EtOAc. A small amount of brine was added to facilitate layer separation. The EtOAc layer was washed twice with additional small amounts of water. The combined aqueous layer is filtered and first _{fixed at 100% H 2} O + 0.1% TFA constant composition, then _{eluted with 0% to 50% (MeCN / H 2} O) + 0.1% TFA reverse phase HPLC ( Purified directly by Sunfire Prep C18 OBD (10 μm, 50 × 250 mm column). Reverse-phase HPLC (Phenomenex Luna) in which the product is recovered, first _{fixed at 100% H 2} O + 0.1% TFA constant composition, then _{eluted with 0% to 50% (MeCN / H 2 O) + 0.1% TFA.} Further purified by Prep C18, 5 μm, 50 × 250 mm column). The product fraction was concentrated to give compound Int-8e. LCMS analysis calculated value of C ₁₃ H ₁₅ BrN ₂ O ₄ : 342.02; measured value: 343.07 (M + 1) ⁺ .

Step F-Compound Int-8e (140 mg, 0.408 mmol) was placed in a 50 mL round bottom flask containing a synthetic magnetic stirring bar of Compound Int-8f. DMSO (8.16 mL), (2,4-difluorophenyl) methaneamine (0.145 mL, 1.224 mmol), N, N-diisopropylethylamine (0.356 mL, 2.040 mmol), and Pd (dppf) Cl ₂ ( 59.7 mg (0.082 mmol) was added. The flask was evacuated, refilled with CO from the balloon three times, heated to 100 ° C., and stirred for 7.5 hours. The reaction is cooled to room temperature, filtered and purified by reverse phase HPLC (Sunfire Prep C18 OBD, 10 μm, 50 × 250 mm column) elution with _{5% to 85% (MeCN / H 2 O) + 0.1% TFA.} Then, a pale yellow foam / solid was obtained. This material was further purified by chiral preparative SFC (ChiralPak IA, 20 × 150 mm column, 65 mL / min, 10 MPa (100 bar), 20% to 35% ethanol / CO ₂ ) to isomerize compound Int-8f. A (first elution component), isomer B of compound Int-8f (second elution component), isomer C of compound Int-8f (third elution component), and isomer D of compound Int-8f. (Fourth eluted component) was obtained. LCMS analysis calculated value of C ₂₁ H ₂₁ F ₂ N ₃ O ₅ : 433.14; measured value: 434.21 (M + 1) ⁺ .

A magnetic stirring bar was placed in a 20 mL vial containing isomer A (21 mg, 0.048 mmol) of the synthetic compound Int-8f of Step G-Compound 17, Compound 18, Compound 19, and Compound 20. DMF (0.500 mL) was added, then lithium chloride (20.54 mg, 0.485 mmol) was added and the mixture was heated with stirring to 100 ° C. After 3 hours, the reaction solution was cooled to room temperature. The mixture was diluted with DMSO and purified by reverse phase HPLC (Sunfire Prep C18 OBD, 5 μm, 30 × 150 mm column) eluting with 5% to 95% (MeCN / H _{2 O) + 0.1% TFA.} The product fraction was concentrated, co-distilled with DCM / MeOH / toluene and lyophilized to give compound 17. ^{1 1} H NMR (500 MHz, SO (CD ₃ ) ₂ ): δ11.66 (s, 1H); 11.45 (t, J = 5.5 Hz, 1H); 7.44 (q, J = 7.9, 7.4Hz, 1H); 7.30-7.21 (m, 1H); 7.13-7.04 (m, 1H); 6.89 (s, 1H); 5.63 (t, J = 7.9Hz, 1H); 4.58 (qd, = 14.9, 6.1Hz, 2H); 3.95 (d, = 12.9Hz, 1H); 3.73 (d, J = 12.8Hz) , 1H); 3.09 (s, 3H); 2.71 (dd, J = 11.9, 7.6Hz, 1H); 2.03-1.96 (m, 1H); 1.36 (s) 3, 3H). LCMS analysis calculated value of C ₂₀ H ₁₉ F ₂ N ₃ O ₅ : 419.13; measured value: 420.23 (M + 1) ⁺ .

Compound 18 was prepared from isomer B of compound Int-8f, essentially according to the method used to produce compound 17 in step G of Example 8. ^{1 1} H NMR (500 MHz, CDCl ₃ ): δ11.41 (brs, 1H); 10.89 (t, J = 5.0 Hz, 1H); 7.37 (q, J = 8.2 Hz, 1H); 6 .88-6.77 (m, 2H); 5.66 (d, = 7.4Hz, 1H); 5.24 (s, 1H); 4.70-4.56 (m, 2H); 3. 84 (d, = 12.7Hz, 1H); 3.51 (d, J = 12.7Hz, 1H); 3.21 (s, 3H); 2.39 (d, J = 13.4Hz, 1H) 2.32 (dd, J = 13.4, 7.5Hz, 1H); 1.68 (s, 3H). LCMS analysis calculated value of C ₂₀ H ₁₉ F ₂ N ₃ O ₅ : 419.13; measured value: 420.23 (M + 1) ⁺ .

Compound 19 was prepared from isomer C of compound Int-8f, essentially according to the method used to produce compound 17 in step G of Example 8. ^{1 1} H NMR (500 MHz, SO (CD ₃ ) ₂ ): δ11.66 (s, 1H); 11.45 (t, J = 5.8 Hz, 1H); 7.44 (q, J = 8.5 Hz, 1H); 7.26 (td, J = 10.6, 2.4Hz, 1H); 7.08 (td, J = 8.8, 2.2Hz, 1H); 6.89 (s, 1H); 5.62 (t, J = 8.0Hz, 1H); 4.58 (qd, J = 15.1, 5.9Hz, 2H); 3.95 (d, J = 12.8Hz, 1H); 3 .73 (d, J = 12.8Hz, 1H); 3.08 (s, 3H); 2.71 (dd, J = 12.2, 7.4Hz, 1H); 1.99 (dd, J = 12.1, 8.9Hz, 1H); 1.36 (s, 3H). LCMS analysis calculated value of C ₂₀ H ₁₉ F ₂ N ₃ O ₅ : 419.13; measured value: 420.22 (M + 1) ⁺ .

Compound 20 was prepared from isomer D of compound Int-8f, essentially according to the method used to produce compound 17 in step G of Example 8. ^{1 1} H NMR (500 MHz, SO (CD ₃ ) ₂ ): δ11.47 (s, 1H); 10.85 (t, J = 5.3 Hz, 1H); 7.42 (q, J = 8.4 Hz, 1H); 7.24 (td, J = 10.5, 10.0, 2.2Hz, 1H); 7.07 (td, J = 8.6, 1.9Hz, 1H); 5.68 (d) , J = 7.1Hz, 1H); 5.45 (s, 1H); 4.56 (d, J = 5.4Hz, 2H); 3.79 (d, J = 12.7Hz, 1H); 3 .72 (d, J = 12.8Hz, 1H); 3.09 (s, 3H); 2.32 (dd, J = 13.2, 7.3Hz, 1H); 2.15 (d, J = 13.4Hz, 1H); 1.56 (s, 3H). LCMS analysis calculated value of C ₂₀ H ₁₉ F ₂ N ₃ O ₅ : 419.13; measured value: 420.22 (M + 1) ⁺ .

Example 9
Preparation of Compounds 21-24 Starting from Int-8e and substituting 4-fluorobenzylamine in step F, chiral preparative SFC (CiralPak AD-H, 20 × 250 mm column, 60 mL / min, 100 bar, 35%. Purification with MeOH / CO ₂ ) to obtain a mixture of isomer A and isomer B, isomer C and isomer D, and a mixture of isomer A and isomer B was prepared by chiral preparative SFC (ChiralPak AD-H). Essentially described in Steps F and G in Example 8 except that further purification with a 20 × 250 mm column, 70 mL / min, 100 bar, 25% MeOH / CO _{2) gave isomers A and B.} The following compounds were prepared using the same method of.

Example 10
Preparation of Compounds 25-28 Using Int-8e as a raw material and substituting 2,4,6-trifluorobenzylamine in step F, chiral preparative SFC (ChiralPak AD-H, 20 × 150 mm column, 60 mL / min, Purification with 100 bar, 20% MeOH / CO ₂ ) to give isomer A, isomer B, isomer C, and isomer D, and further purify isomer C and isomer D under the same SFC conditions. The following compounds were prepared essentially using the same methods described in Step F and Step G in Example 8 except that the obtained product of sufficient purity was obtained.

Example 11
Preparation of Compounds 29-32 Using Int-8e as a raw material and substituting 3-chloro-2,6-difluorobenzylamine in step F, chiral preparative SFC (CiralPak IA, 20 × 150 mm column, 65 mL / min, 100). Purification with VAL, 25% EtOH / CO ₂ ) to give isomer A, isomer B, isomer C, and isomer D to further purify isomer B, isomer C, and isomer D. The following compounds were prepared essentially using the same methods described in Step F and Step G in Example 8, except that the obtained product of sufficient purity was obtained in.

Example 12
Preparation of Compounds 33-36 Using Int-8e as a raw material and substituting 3-chloro-2-fluorobenzylamine in step F, chiral preparative SFC (ChiralPak IA, 20 × 150 mm column, 65 mL / min, 100 bar, Essentially described in Steps F and G in Example 8 except that purification with 25% to 35% MeOH / CO _{2) gave isomer A, isomer B, isomer C, and isomer D.} The following compounds were prepared using the same method of.

Example 13
Preparation of compound Int-13b

Synthesis of Step A-Compound Int-13a _{NaBH 4} (9.45 g, 250 mmol) was added in small portions to a solution of 2-methylenebutanal (20 g, 238 mmol) in MeOH (120 mL). The mixture was stirred at 0 ° C. for 1 hour. The mixture was quenched with saturated aqueous _NH 4 Cl (40 mL), was diluted with water (80 mL), and extracted with EtOAc (3 x 100 mL). The combined organic layer was _{dehydrated with Na 2} SO ₄ , filtered, and the solvent was evaporated. The residue obtained was purified by flash silica gel chromatography (80 g column) eluting with 0% to 10% EtOAc / petroleum ether to give compound Int-13a. ^{1 1} H NMR (400 MHz, CDCl ₃ ) δ: 4.99 (s, 1H); 4.98 (s, 1H); 4.07 (s, 2H); 2.08-2.02 (m, 2H) 1.22-1.02 (m, 3H).

Synthesis of Step B-Compound Int-13b _{PBr 3} (1.095 mL, 11.61 mmol) was added to a solution of compound Int-13a (2 g, 23.22 mmol) in DCM (40 mL) at 0 ° C. The temperature of the mixture was raised to 20 ° C., and the mixture was stirred for 12 hours. The mixture was cooled to 0 ° C., the reaction was stopped with _5% K 2 CO ₃ aq (15 mL), and diluted with water (20 mL). The organic layer was isolated, washed with brine (20 mL), _{dehydrated with Na 2} SO ₄ , filtered and concentrated under reduced pressure to give compound Int-13b. This obtained product was used in step D of Example 14 without further purification. ^{1 1} H NMR (400 MHz, CDCl ₃ ): δ5.23 (s, 1H); 4.99 (s, 1H); 3.83 (s, 2H); 2.20-1.14 (m, 2H); 1.03-1.00 (m, 3H).

Example 14
Production of compounds 37-40

Step A-Synthesis of Compound Int-14a 1,1'-Bis (diphenylphosphino) ferrocene-palladium (II) dichloride-dichloromethane complex (590.9 mg, 0.724 mmol) was added to Compound Int-1 (5.04 g, 5.04 g, 13.19 mmol), potassium vinyl trifluoroborate (3.52 g, 26.3 mmol), and potassium carbonate (3.65 g, 26.4 mmol) in dioxane (53.0 mL) and water (13.0 mL) with stirring solution. In addition to. The reaction mixture was degassed (3 times), placed under nitrogen, and then heated to 80 ° C. for 3 hours. The reaction mixture was cooled to room temperature and then partitioned between EtOAc (200 mL) and water (200 mL). The aqueous layer was extracted with EtOAc (twice at 100 mL). The organic layers were combined, washed with brine (once at 30 mL), _{dehydrated with sulfonyl 4} , filtered and solvent evaporated under reduced pressure. The resulting solid was purified by silica gel column (220 g) chromatography eluting with 0% to 40% (25% EtOH / EtOAc) / hexanes to give compound Int-14a. LCMS analysis calculated value of C ₁₈ H ₁₉ NO ₅ : 329.13; measured value: 330.21 (M + 1) ⁺ .

Synthesis of Step B-Compound Int-14b Osmium tetroxide 2.5 wt% t-butanol solution (3.4 mL, 0.271 mmol) and NMO (1.4025 g, 11.97 mmol) were added to Compound Int-14a (1). .7072 g, 5.18 mmol) was added to the stirred solution in THF (24.0 mL), t-butanol (21.0 mL), and water (4.0 mL). The reaction mixture was stirred at room temperature for 2.5 hours and then diluted with THF (52.0 mL). Sodium metabisulfite (24.60 g, 129.4 mmol) was added to the reaction mixture, which was stirred for an additional hour and then filtered through the Celite layer. The filtrate was _{dehydrated with Na 2} SO ₄ , filtered, and the solvent was evaporated under reduced pressure. The resulting oil was purified by silica gel column (120 g) chromatography eluting with 0% to 8% MeOH / DCM to give compound Int-14b. LCMS analysis calculated value of C ₁₈ H ₂₁ NO ₇ : 363.13; measured value: 364.25 (M + 1) ⁺ .

Synthesis of Step C-Compound Int-14c Sodium periodate (2.1 g, 9.82 mmol), THF (38.0 mL) and water (10.0 mL) of Compound Int-14b (1.7344 g, 4.77 mmol) ) Was added to the stirred solution. The reaction mixture was stirred at room temperature for 3.5 hours, then filtered through a layer of Celite and washed with EtOAc (twice at 30 mL). The filtrate was partitioned between EtOAc (40 mL), water (50 mL), and saturated aqueous sodium thiosulfate solution (50 mL). The aqueous layer was extracted with EtOAc (twice at 50 mL). The organic layers were combined, washed with brine (once at 30 mL), _{dehydrated with sulfonyl 4} , filtered and solvent evaporated under reduced pressure. The resulting solid was purified by silica gel column (40 g) chromatography eluting with 0% to 40% EtOAc / Hexanes to give compound Int-14c. LCMS analysis calculated value of C ₁₇ H ₁₇ NO ₆ : 331.11; measured value: 332.22 (M + 1) ⁺ .

Synthesis of Step D-Compound Int-14d Compound Int-14c (106.7 mg, 0.322 mmol), sodium iodide (142.6 mg, 0.951 mmol), Int-13b (73.4 mg, 0.493 mmol), THF (1.5 mL) and water (1.5 mL) were combined and stirred at room temperature. After 10 minutes, indium (76.7 mg, 0.668 mmol) was added to the reaction mixture. After 17.5 hours, the reaction mixture was diluted with EtOAc (30 mL), sonicated, then filtered through a layer of Celite and washed with additional EtOAc (twice at 10 mL). The combined filtrate was _{dehydrated with sulfonyl 4} , filtered, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column (12 g) chromatography eluting with 0% to 30% (25% EtOH / EtOAc) / hexanes to give compound Int-14d. LCMS analysis calculated value of C ₂₂ H ₂₇ NO ₆ : 401.18; measured value: 402.24 (M + 1) ⁺ .

Synthesis of Step E-Compound Int-14e Int-14d (63.3 mg, 0.158 mmol) and a solution of methylamine 2.0 M in THF (1.6 mL, 3.20 mmol) were combined and stirred at room temperature. Two days later, a solution of methylamine 2.0 M in THF (1.6 mL, 3.20 mmol) was added to the reaction mixture. After a further 3 days, the reaction mixture was evaporated under reduced pressure and the resulting residue was dissolved in a solution of methylamine 2.0 M in THF (1.6 mL, 3.20 mmol). The obtained solution was stirred at room temperature for 3 days and then heated to 40 ° C. for an additional 19.5 hours. The reaction mixture was cooled to room temperature and the solvent was distilled off under reduced pressure. The resulting residue was dissolved in ACN / water, frozen and lyophilized to give compound Int-14e. LCMS analysis calculated value of C ₂₂ H ₂₈ N ₂ O ₅ : 400.20; measured value: 401.31 (M + 1) ⁺ .

Synthesis of Step F-Compound Int-14f p-Toluenesulfonic Acid Monohydrate (604.8 mg, 3.18 mmol) was added to MeOH (10.0 mL) of Compound Int-14e (391.2 mg, 0.977 mmol). Added to the stirred solution inside. The reaction mixture was stirred at room temperature for 24 hours before additional p-toluenesulfonic acid monohydrate (315.8 mg, 1.66 mmol) was added. After an additional 17 hours, additional p-toluenesulfonic acid monohydrate (213.8 mg, 1.12 mmol) was added to the reaction mixture. After an additional 4 days, the reaction mixture is concentrated under reduced pressure to about 4 mL, followed by reverse phase chromatography (50 gC18 RediSep ™ gold column) elution with 0% to 60% (ACN / water) + 0.05% TFA. ). Clean product fractions were combined, frozen and lyophilized. Product fractions heavily contaminated with tosylate were combined and extracted with EtOAc (3 times at 50 mL). Two spoons of NaCl were added to the aqueous layer and extracted with EtOAc (50 mL) and DCM (50 mL). 3 tablespoons of NaCl was added to the aqueous layer and extracted with DCM (50 mL) and 10% MeOH / DCM (50 mL). An additional 3 spoons of NaCl was added to the aqueous layer and extracted with 10% MeOH / DCM (twice at 50 mL). The organic layers were combined, _{dehydrated with butadiene 4} , filtered, and the solvent was evaporated under reduced pressure. The residue obtained was purified by reverse phase HPLC (Waters Sunfire C18 OBD, 10 μm, 30 × 150 mm column) eluting with 10% to 60% (ACN / water) + 0.05% TFA. The product fractions were combined and the solvent was evaporated under reduced pressure. The obtained residue was dissolved in MeOH / EtOAc, combined with the lyophilized product from ISCO purification, and the solvent was evaporated under reduced pressure to give compound Int-14f. LCMS analysis calculated value of C ₁₄ H ₂₀ N ₂ O ₄ : 280.14; measured value: 281.23 (M + 1) ⁺ .

Synthesis of Step G-Compound Int-14g tert-butyldimethylsilyl chloride (475.0 mg, 3.15 mmol), compound Int-14f (371.6 mg, 1.326 mmol), imidazole (381.1 mg, 5.60 mmol). And DMAP (28.0 mg, 0.229 mmol) were added to the stirred solution in DMF (6.6 mL). The reaction mixture was stirred at room temperature for 15 hours and then partitioned between EtOAc (150 mL) and water (40 mL). The organic layer was washed with water (twice at 40 mL) and brine (once at 20 mL) _{, dehydrated with sulfonyl 4} , filtered, and the solvent was evaporated under reduced pressure. The resulting oil was purified by silica gel column (24 g) chromatography eluting with 0% to 40% (25% EtOH / EtOAc) / hexanes to give compound Int-14 g. LCMS analysis calculated value of C ₂₀ H ₃₄ N ₂ O ₄ Si: 394.23; measured value: 395.42 (M + 1) ⁺ .

Synthesis of Step H-Compound Int-14h NBS (277.1 mg, 1.557 mmol) was added to a stirred solution of Compound Int-14 g (306.9 mg, 0.778 mmol) in THF (7.8 mL). The reaction mixture was stirred at room temperature for 2 hours, then additional NBS (69.3 mg, 0.389 mmol) was added. After an additional 1.5 hours, additional NBS (86.9 mg, 0.488 mmol) was added to the reaction mixture. After an additional hour, additional NBS (91.1 mg, 0.512 mmol) was added to the reaction mixture. After 15 minutes, the reaction mixture was partitioned between EtOAc (125 mL) and 0.1 M NaOH (50 mL). The organic layer was washed with 0.1 M NaOH (1 time at 50 mL) and brine (1 time at 20 mL). The organic layer was diluted with DCM (about 75 mL). The combined aqueous layer was extracted with DCM (once at 50 mL). The organic layers were combined, _{dehydrated with butadiene 4} , filtered, and the solvent was evaporated under reduced pressure. The resulting residue was purified by column (24 g) chromatography eluting with 0% to 80% (25% EtOH / EtOAc) / hexane and then with 10% MeOH / DCM to give compound Int-14h. rice field. LCMS analysis calculated value of C ₂₀ H ₃₂ Br ₂ N ₂ O ₄ Si: 552.05; measured value: 553.23 (M + 1) ⁺ .

Synthesis of Step I-Compound Int-14i Cesium carbonate (1.1225 g, 3.45 mmol) is added to a stirred suspension of compound Int-14h (411.5 mg, 0.745 mmol) in DMSO (7.5 mL). rice field. The reaction mixture was stirred at room temperature for 17.5 hours and then partitioned between EtOAc (175 mL) and water (50 mL). The organic layer was washed with water (twice at 50 mL) and brine (once at 20 mL). The combined aqueous layers were extracted with EtOAc (once at 50 mL). The organic layers were combined, _{dehydrated with butadiene 4} , filtered, and the solvent was evaporated under reduced pressure. The resulting solid was purified by silica gel column (24 g) chromatography eluting with 0% to 50% (25% EtOH / EtOAc) / hexanes to give compound Int-14i. LCMS analysis calculated value of C ₂₀ H ₃₁ BrN ₂ O ₄ Si: 470.12, 472.12; measured value: 471.27, 473.27 (M + 1) ⁺ .

Step J-Compound Int-14j Synthesis Compound Int-14i (300.8 mg, 0.638 mmol) and HCl 1.25 M solution in MeOH (6.5 mL, 8.13 mmol) are combined, stirred and heated to 40. The temperature was adjusted to ° C. Three days later, it was discovered that the cap had blown off and all the solvent had evaporated. The obtained residue was purified by silica gel column (24 g) chromatography eluting with 0% to 10% MeOH / DCM to give compound Int-14j. LCMS analysis calculated value of C ₁₄ H ₁₇ BrN ₂ O ₄ : 356.04, 358.04; measured value: 357.16, 359.16 (M + 1) ⁺ .

Synthesis of Step K-Compound Int-14k N, N-diisopropylethylamine (0.2 mL, 1.145 mmol), 2,4-difluorobenzylamine (0.08 mL, 0.673 mmol), and 1,1'-bis ( Diphenylphosphino) ferrocene-palladium (II) dichloride-dichloromethane complex (35.2 mg, 0.043 mmol) in a stirred solution of compound Int-14j (80.3 mg, 0.225 mmol) in DMSO (2.3 mL). added. The reaction mixture was degassed (3 times) and placed under nitrogen, then degassed and placed under a carbon monoxide balloon. The reaction mixture was stirred at 100 ° C. for 16.5 hours. Reverse phase chromatography (50 gC18 RediSep) where the reaction mixture is cooled to room temperature, diluted with MeOH, filtered (0.45 μm syringe filter) and eluted with 0% to 100% (ACN / water) + 0.05% TFA. Purified by (trade name) gold column). The product fractions were combined, frozen and lyophilized to give an amber solid, which was subjected to chiral preparative SFC (CiralPakAD-H, 21 250 mm column, 50 g / min, 12 MPa (120 bar), 35%. Further purified by (1: 1 ACN / MeOH + 0.2% DIPA) / CO ₂ , 40 ° C.), isomer A of compound Int-14k (first elution component), isomer B of compound Int-14k (first elution component). 2 elution component), isomer C of compound Int-14k (third elution component), and isomer D of compound Int-14k (fourth elution component) were obtained. Isomer C and isomer D were separated from each other in the second time using the above chiral preparative SFC conditions to obtain sufficient purity. LCMS analysis calculated value of C ₂₂ H ₂₃ F ₂ N ₃ O ₅ : 447.16; measured value: 448.30 (M + 1) ⁺ .

Step L-Compound 37, Compound 38, Compound 39 and Compound 40 Synthesis of Compound Int-14k Isomer A (37.5 mg, 0.084 mmol), Magnesium Bromide (160.2 mg, 0.870 mmol), and acetonitrile ( 1.8 mL) was combined and stirred at room temperature for 3 hours. The reaction mixture is diluted with MeOH, filtered (0.45 μm syringe filter) and eluted with 10% to 90% (ACN / water) + 0.05% TFA Reverse Phase HPLC (Waters Sunfire C18 OBD, 10 μm, 30 × Purified by 150 mm column). The product fractions were combined and concentrated under reduced pressure until most of the acetonitrile was removed. The remaining aqueous solution was extracted with DCM (about 5 mL 4 times). The organic layers were sequentially dehydrated with sodium sulfate, filtered, combined, and the solvent was distilled off under reduced pressure. The resulting residue was dissolved in ACN / water, frozen and lyophilized to give compound 37. ^{1 1} H NMR (500 MHz, CD ₃ OD): δ7.49-7.42 (m, 1H); 7.02-6.91 (m, 2H); 5.68 (t, J = 7.9 Hz, 1H) ); 4.70-4.61 (m, 2H); 3.91 (d, J = 13.3Hz, 1H); 3.84 (d, J = 13.3Hz, 1H); 3.18 (s) , 3H); 2.91 (dd, J = 13.1, 7.7Hz, 1H); 2.03 (dd, J = 12.9, 8.1Hz, 1H); 1.84 (dq, J = 14.8, 7.4Hz, 1H); 1.74 (dq, J = 14.7, 7.5Hz, 1H); 0.85 (t, J = 7.5Hz, 3H). LCMS analysis calculated value of C ₂₁ H ₂₁ F ₂ N ₃ O ₅ : 433.14; measured value: 434.20 (M + 1) ⁺ .

Compound 38 was prepared from isomer B of compound Int-14k, essentially according to the method used to produce compound 37 in step L of Example 14. ^{1 1} H NMR (500 MHz, CD ₃ OD): δ7.5-7.42 (m, 1H); 7.01-6.91 (m, 2H); 5.72 (d, J = 7.7 Hz, 1H) ); 4.69-4.60 (m, 2H); 3.87 (d, J = 13.4Hz, 1H); 3.75 (d, J = 13.4Hz, 1H); 3.18 (s) , 3H); 2.42 (d, J = 13.9Hz, 1H); 2.29 (dd, J = 13.9, 7.8Hz, 1H); 1.99 (q, J = 7.4Hz, 2H); 1.03 (t, = 7.5Hz, 3H). LCMS analysis calculated value of C ₂₁ H ₂₁ F ₂ N ₃ O ₅ : 433.14; measured value: 434.22 (M + 1) ⁺ .

Compound 39 was prepared from isomer C of compound Int-14k, essentially according to the method used to produce compound 37 in step L of Example 14. ^{1 1} H NMR (500 MHz, CD ₃ OD): δ7.5-7.42 (m, 1H); 7.01-6.91 (m, 2H); 5.72 (d, J = 7.8 Hz, 1H) ); 4.69-4.60 (m, 2H); 3.87 (d, J = 13.4Hz, 1H); 3.75 (d, J = 13.4Hz, 1H); 3.18 (s) , 3H); 2.42 (d, J = 13.9Hz, 1H); 2.29 (dd, J = 13.9, 7.8Hz, 1H); 1.99 (q, J = 7.4Hz, 2H); 1.03 (t, J = 7.5Hz, 3H). LCMS analysis calculated value of C ₂₁ H ₂₁ F ₂ N ₃ O ₅ : 433.14; measured value: 434.23 (M + 1) ⁺ .

Compound 40 was prepared from isomer D of compound Int-14k, essentially according to the method used to produce compound 40 in step L of Example 14. ^{1 1} H NMR (500 MHz, CD ₃ OD): δ7.5-7.42 (m, 1H); 7.02-6.91 (m, 2H); 5.68 (t, J = 7.9 Hz, 1H) ); 4.70-4.60 (m, 2H); 3.92 (d, J = 13.2Hz, 1H); 3.84 (d, J = 13.3Hz, 1H); 3.18 (s) , 3H); 2.91 (dd, J = 13.1, 7.7Hz, 1H); 2.04 (dd, J = 12.9, 8.1Hz, 1H); 1.84 (dq, J = 14.8, 7.5Hz, 1H); 1.74 (dq, J = 14.7, 7.4Hz, 1H); 0.85 (t, J = 7.5Hz, 3H). LCMS analysis calculated value of C ₂₁ H ₂₁ F ₂ N ₃ O ₅ : 433.14; measured value: 434.27 (M + 1) ⁺ .

Example 15
Production of compounds 41-44

Synthesis of Step A-Compound Int-15a DMAP (2.389 g, 19.55 mmol), 2,6-dimethyl, in a solution of compound Int-14d (15.7 g, 39.1 mmol) in DCM (200 mL) at 0 ° C. Pyridine (12.57 g, 117 mmol) and tert-butyldimethylsilyltrifluoromethanesulfonate (20.68 g, 78 mmol) were added. The reaction mixture was stirred at 20 ° C. for 2 hours, then the reaction was stopped with water (50 mL) and extracted with DCM (100 mL). The combined organic layers were _{dehydrated with Na 2} SO ₄ , filtered and concentrated under reduced pressure. The crude product was purified by flash silica gel chromatography eluting with 0% to 20% EtOAc / petroleum ether to give compound Int-15a. LCMS analysis calculated value of C ₂₈ H ₄₁ NO ₆ Si: 515.3; measured value: 516.9 (M + 1) ⁺ .

Synthesis of Step B-Compound Int-15b To a solution of compound Int-15a (8.4 g, 16.29 mmol) in DCM (85 mL) was added TFA (8.5 mL) at 0 ° C. The reaction mixture was stirred at 20 ° C. for 2 hours _{, then the reaction was stopped with saturated aqueous NaHCO 3} solution (50 mL) and diluted with water (50 mL). The aqueous phase was extracted with DCM (100 mL) and the combined organic layers were _{dehydrated with Na 2} SO ₄ , filtered and concentrated under reduced pressure. The crude product was purified by flash silica gel chromatography (120 g column) eluting with 0% to 50% EtOAc / petroleum ether to give compound Int-15b. LCMS analysis calculated value of C ₂₀ H ₃₃ NO ₅ Si: 395.2; measured value: 396.5 (M + 1) ⁺ .

Synthesis of Step C-Compound Int-15c _{CF 3} CH ₂ OH of Compound Int-15b (5.3 g, 13.40 mmol) and O- (2,4-dinitrophenyl) hydroxylamine (8.00 g, 40.2 mmol) To the mixture in (80 mL) was added bis [lodium (α, α, α', α'-tetramethyl-1,3-benzenedipropionic acid)] (0.204 g, 0.268 mmol). The reaction mixture was stirred under nitrogen at 65 ° C. for 6 hours and then concentrated under reduced pressure. The resulting residue was purified by flash silica gel chromatography (40 g column) eluting with 0% to 10% MeOH / DCM to give compound Int-15c. LCMS analysis calculated value of C ₁₉ H ₃₀ N ₂ O ₄ Si: 378.2; measured value: 379.0 (M + 1) ⁺ .

Synthesis of Step D-Compound Int-15d To a mixture of compound Int-15d (1.35 g, 3.57 mmol) in DMF (25 mL) at 0 ° C., NaH (0.428 g, 10.70 mmol) and iodomethane (0.666 mL). 10.70 mmol) was added. The reaction mixture was stirred at 20 ° C. for 2 hours, the reaction was stopped with 1N HCl (0.5 mL), and the mixture was concentrated under reduced pressure. The crude product was purified by preparative TLC plate elution with 10% MeOH / DCM to give compound Int-15d. LCMS analysis calculated value of C ₂₀ H ₃₂ N ₂ O ₄ Si: 392.2; measured value: 393.3 (M + 1) ⁺ .

Synthesis of Step E-Compound Int-15e TBAF (12.74 mL, 12.74 mmol) was added to a mixture of compound Int-15d (2.5 g, 6.37 mmol) in THF (40 mL) at 0 ° C. The reaction mixture was stirred at 20 ° C. for 2 hours and then concentrated under reduced pressure. The crude product was purified by preparative TLC plate elution with 12% MeOH / DCM to give compound Int-15e. LCMS analysis of calculated value C ₁₄ H ₁₈ N ₂ O ₄ : 278.1; measured value: 279.1 (M + 1) ⁺ .

Synthesis of Step F-Compound Int-15f In a solution of compound Int-15e (1.7 g, 6.11 mmol) in MeOH (30 mL), m-CPBA (5.27 g, 24.43 mmol) and NIS (5.50 g, 24.43 mmol) was added. The reaction mixture was stirred at 80 ° C. for 1.5 hours and then _{stopped with saturated aqueous Na 2} SO ₃ solution (15 mL). The reaction mixture is filtered and purified by preparative reverse phase HPLC (Phenomenex Synergi Max-RP, 10 μm, 50 × 250 mm column) eluting with 0% to 20% ACN / (water + 0.1% TFA) to compound. Int-15f was obtained. LCMS analysis calculated value of C ₁₄ H ₁₇ IN ₂ O ₄ : 404.0; measured value: 404.8 (M + 1) ⁺ .

Step G-Compound Int-15g Synthetic Compound Int-15f (300 mg, 0.742 mmol) in DMSO (5 mL) with (3-chloro-2-fluorophenyl) methaneamine (237 mg, 1.484 mmol), Pd ( Ph ₃ P) ₄ (429 mg, 0.371 mmol) and DIEA (0.648 mL, 3.71 mmol) were added. The reaction mixture was degassed, purged with CO (3 times) and then stirred under a CO balloon at 80 ° C. for 1.5 hours. The reaction mixture was filtered and purified by preparative reverse phase HPLC (Boston Green ODS, 5 μm, 30 × 150 mm column) elution with 40% to 60% ACN / (water + 0.1% TFA). This material, chiral preparative SFC (DAICEL CHIRALPAK AS-H, 5μm, 30 × 250mm column, 60 mL / _{min, 40% (EtOH + 0.1%} NH 3 H 2 O) / CO 2, 220nm) was further purified by , A mixture of isomer A and isomer B of compound Int-15g (first elution component), isomer C of compound Int-15g (second elution component), and isomer D of compound Int-15g (first elution component). 3 elution component) was obtained. Compound Int-15 g mixture of isomer A and isomer B of preparative chiral SFC (DAICEL CHIRALPAK IC, 10μm, 30 × 250mm column, 50 mL / _{min, 50% (EtOH + 0.1%} NH 3 H 2 O) / Further purification with CO ₂ , 220 nm) gave isomer A (first elution component) of compound Int-15g and isomer B (second elution component) of compound Int-15g. Isomer A compound Int-15 g, chiral preparative SFC (DAICEL CHIRALPAK AD, 10μm, 30 × 250mm, 70mL / _{min, 50% (MeOH + 0.1%} NH 3 H 2 O) / CO 2, 220nm) by further Purification gave Int-15 g of isomer A. LCMS analysis calculated value of C ₂₂ H ₂₃ ClFN ₃ O ₅ : 463.1; measured value: 464.1 (M + 1) ⁺ .

Step H-Compound 41, Compound 42, Compound 43, and Synthesis of Compound 44 Magnesium bromide (99 mg, 0.539 mmol) in a solution of isomer B (50 mg, 0.108 mmol) of compound Int-15 g in acetonitrile (3 mL). ) Was added. The mixture is stirred at 10 ° C. for 12 hours, then diluted with MeOH (0.5 mL) and eluted with 33% to 63% ACN / (water + 0.1% TFA) preparative reverse phase HPLC (Boston Green ODS). Purified by a 5 μm, 30 × 150 mm column). The product fraction was co-distilled with toluene twice to give compound 42. ^{1 1} H NMR (400 MHz, CDCl ₃ ): δ10.99 (brs, 1H); 7.30 (q, J = 6.6 Hz, 2H); 7.11-6.98 (m, 1H); 5.67 (D, J = 7.9Hz, 1H); 4.86-4.63 (m, 2H); 3.69 (s, 2H); 3.20 (s, 3H); 2.46 (d, J) = 14.0 Hz, 1H); 2.20-2.14 (m, 1H); 2.04-1.88 (m, 2H); 1.09-1.00 (m, 3H). LCMS analysis calculated value of C ₂₁ H ₂₁ ClFN ₃ O ₅ : 449.1; measured value: 450.2 (M + 1) ⁺ .

Compound 41 was prepared from isomer A of compound Int-15g, essentially according to the method used to produce compound 42 in step H of Example 15. ^{1 1} H NMR (400 MHz, CDCl ₃ ): δ11.43 (brs, 1H); 7.33-7.26 (m, 2H); 7.04 (t, J = 7.9 Hz, 1H); 5.66 (T, J = 7.9Hz, 1H); 4.72 (brd, J = 5.7Hz, 2H); 3.87 (d, J = 13.2Hz, 1H); 3.63 (d, J = 12.7Hz, 1H); 3.20 (s, 3H); 2.82 (dd, J = 13.2, 7.9Hz, 1H); 2.35 (s, 1H); 2.07 (dd, dd, J = 13.2, 7.9Hz, 1H); 1.86-1.67 (m, 2H); 0.85 (t, J = 7.5Hz, 3H). LCMS analysis calculated value of C ₂₁ H ₂₁ ClFN ₃ O ₅ : 449.1; measured value: 450.2 (M + 1) ⁺ .

Compound 43 was prepared from isomer C of compound Int-15g, essentially according to the method used to produce compound 42 in step H of Example 15. ^{1 1} H NMR (400 MHz, CDCl ₃ ): δ11.42 (brs, 1H); 7.33-7.27 (m, 2H); 7.08-7.00 (m, 1H); 5.66 (t). , J = 7.9Hz, 1H); 4.72 (brd, J = 5.7Hz, 2H); 3.87 (d, J = 13.2Hz, 1H); 3.63 (d, J = 13. 2Hz, 1H); 3.20 (s, 3H); 2.82 (dd, J = 13.2, 7.9Hz, 1H); 2.07 (dd, J = 13.2, 8.3Hz, 1H) ); 1.86-1.68 (m, 2H); 0.85 (t, J = 7.5Hz, 3H). LCMS analysis calculated value of C ₂₁ H ₂₁ ClFN ₃ O ₅ : 449.1; measured value: 450.2 (M + 1) ⁺ .

Compound 44 was prepared from isomer D of compound Int-15g, essentially according to the method used to produce compound 42 in step H of Example 15. ^{1 1} H NMR (400 MHz, CDCl ₃ ): δ10.99 (brs, 1H); 7.34-7.27 (m, 2H); 7.04 (t, J = 7.9 Hz, 1H); 5.65 (D, J = 7.9Hz, 1H); 4.78-4.58 (m, 2H); 3.76-3.64 (m, 2H); 3.20 (s, 3H); 2.45 (D, J = 14.0Hz, 1H); 2.18 (dd, J = 14.0, 8.3Hz, 1H); 2.06-1.90 (m, 2H), 1.27 (brd, brd, J = 7.0Hz, 1H), 1.01 (t, J = 7.5Hz, 3H). LCMS analysis calculated value of C ₂₁ H ₂₁ ClFN ₃ O ₅ : 449.1; measured value: 450.2 (M + 1) ⁺ .

Example 16
Preparation of Compounds 45-48 Using Int-15f as a raw material and substituting 2,4,6-trifluorobenzylamine in step G, chiral preparative SFC (DAICEL CHIRALPAK AS-H, 5 μm, 30 × 250 mm column, 65 mL / min to give 35% mixture of _{(EtOH + 0.1% NH 3 H} 2 O) / CO 2, 220nm) isomer a and isomer B to give the isomer C, and the isomers D, isomerization body a and a mixture of isomers B preparative chiral component SFC (DAICEL CHIRALPAK AD, 10μm, 30 × 250mm column, 70 mL / _{min, 40% (EtOH + 0.1%} NH 3 H 2 O) / CO 2, 220nm) by further dried to give isomer a and isomer B, the chiral preparative SFC (DAICEL CHIRALPAK AD, 10μm, 30 × 250mm column, 50 mL / _{min, 50% (MeOH + 0.1%} NH 3 H 2 O) / CO 2 , 220 nm) to produce the following compounds essentially using the same methods described in Step G and Step H in Example 15, except that isomer A was further purified.

Example 17
Preparation of Compounds 49-52 Using Int-15f as a raw material and substituting 2,3,6-trifluorobenzylamine in step G, chiral preparative SFC (DAICEL CHIRALPAK AD, 10 μm, 30 × 250 mm column, 50 mL / min, 35% yield _{(EtOH + 0.1% NH 3 H} 2 O) / CO 2, 220nm) and purified by isomer a, isomer B, and a mixture of isomers C and isomer D, isomer C and mixtures of preparative chiral component SFC of D (DAICEL CHIRALPAK AD, 10μm, 30 × 250mm column, 50 mL / _{min, 25% (EtOH + 0.1%} NH 3 H 2 O) / CO 2, 220nm) isomer was further purified by The following compounds were prepared essentially using the same methods described in Step G and Step H in Example 15, except that body C and isomer D were obtained.

Example 18
Preparation of Compounds 53-56 Using Int-15f as a raw material and using (3-chloro-2,6-difluorophenyl) methaneamine instead in step G, chiral preparative SFC (DAICEL CHIRALPAK AD, 10 μm, 30 × 250 mm column) , 70 mL / min, to give a mixture of _{40% (EtOH + 0.1% NH} 3 H 2 O) / CO 2, 220nm) isomer a to give the isomer B and isomer C, and the isomers D, SFC chiral preparative min a mixture of isomers B and C (DAICEL CHIRALPAK OJ-H, 5μm, 30 × 250mm column, 50 mL / _{min, 30% (EtOH + 0.1%} NH 3 H 2 O) / CO 2, 220nm) by further to obtain isomer B and isomer C and purified by chiral preparative SFC (DAICEL CHIRALPAK OJ-H, 5μm, 30 × 250mm column, 50 mL / _{min, 30% (EtOH + 0.1%} NH 3 H 2 O) The following compounds were prepared essentially using the same methods described in Step G and Step H in Example 15, except that isomer B was further purified by (/ CO _{2, 220 nm).}

Example 19
Preparation of compound Int-19b

Synthesis of Step A-Compound Int-19a DCM of TBDPSC1 (9.0 mL, 35.0 mmol) with 2-methylenepropane-1,3-diol (3 g, 34.1 mmol) and imidazole (4.70 g, 69.0 mmol) It was added dropwise to the stirred turbid solution in (340 mL). The reaction mixture was stirred at room temperature overnight. The next morning, the reaction mixture was concentrated under reduced pressure (about 80 mL), filtered through a layer of Celite and washed with additional DCM / MeOH. The filtrate was evaporated under reduced pressure. The resulting oil was purified by silica gel column (220 g) chromatography eluting with 0% to 20% EtOAc / Hexanes to give compound Int-19a. ^{1 1} H NMR (500 MHz, CDCl ₃ ): δ7.69 (d, J = 7.4 Hz, 4h); 7.49-7.37 (m, 6H); 5.16 (apparent s, 1H); 5 .13 (apparent s, 1H); 4.27 (s, 2H); 4.19 (d, J = 6.2Hz, 2H); 1.80 (t, J = 6.1Hz, 1H); 1 .08 (s, 9H).

Synthesis of Step B-Compound Int-19b Triphenylphosphine (3.87 g, 14.75 mmol) and carbon tetrabromide (5.12 g, 15.44 mmol) were added to Int-19a (3.8542 g, 11.80 mmol). It was added to the stirred solution in DCM (118.0 mL). The reaction mixture was stirred at room temperature for 1.5 hours and then concentrated under reduced pressure to 15-20 mL. The concentrated reaction mixture was purified by silica gel column (120 g) chromatography eluting with 0% to 10% DCM / hexane to give compound Int-19b. ^{1 1} H NMR (400 MHz, CDCl ₃ ): δ7.69 (d, J = 7.0 Hz, 4h); 7.49-7.37 (m, 6H); 5.32 (apparent s, 1H); 5 .30 (apparent s, 1H); 4.31 (s, 2H); 4.04 (s, 2H); 1.08 (s, 9H).

Example 20
Production of compounds 57-60

Synthesis of Step A-Compound Int-20a Compound Int-14c (503.2 mg, 1.519 mmol), sodium iodide (762.5 mg, 5.09 mmol), compound Int-19b (1.1612 g, 2.98 mmol), THF (6.0 mL) and water (6.0 mL) were combined. The reaction mixture was stirred at room temperature for 10 minutes, then indium (392.5 mg, 3.42 mmol) was added. After 16.5 hours, the reaction mixture was diluted with EtOAc (75 mL), filtered through a layer of Celite and washed with additional EtOAc (twice at 50 mL). The combined filtrate was placed in a 250 mL separatory funnel and the layers were separated. The organic layer was _{dehydrated with director 4} and filtered, and the solvent was distilled off under reduced pressure. The resulting foam was purified by silica gel column (40 g) chromatography eluting with 0% to 80% (25% EtOH / EtOAc) / hexanes to give compound Int-20a. LCMS analysis calculated value of C ₃₇ H ₄₃ NO ₇ Si: 641.28; measured value: 642.42 (M + 1) ⁺ .

Synthesis of Step B-Compound Int-20b A stirred solution of compound Int-20a (886.0 mg, 1.380 mmol) in DCM (14.0 mL) was cooled in an ice bath to 0 ° C. N, N-diisopropylethylamine (1.2 mL, 6.87 mmol), MOMCl (0.52 mL, 6.85 mmol) (dripping) and DMAP (37.2 mg, 0.304 mmol) were added to the reaction mixture. After 50 minutes, the reaction mixture was removed from the bath and warmed to room temperature. After 1.5 days, the reaction mixture is concentrated under reduced pressure (approximately 6 mL residual) and then purified by silica gel column (40 g) chromatography eluting with 0% to 20% (25% EtOH / EtOAc) / hexane. , Compound Int-20b was obtained. LCMS analysis calculated value of C ₃₉ H ₄₇ NO ₈ Si: 685.31; measured value: 686.51 (M + 1) ⁺ .

Synthesis of Step C-Compound Int-20c TBAF 1.0 M solution in THF (1.7 mL, 1.700 mmol) in THF (11.0 mL) of Compound Int-20b (866.6 mg, 1.263 mmol). Added to stirring solution. The reaction mixture was stirred at room temperature. After 4.5 hours, the reaction mixture was distilled off under reduced pressure. The resulting product was purified by silica gel column (40 g) chromatography eluting with 0% to 50% (25% EtOH / EtOAc) / hexanes to give compound Int-20c. LCMS analysis calculated value of C ₂₃ H ₂₉ NO ₈ : 447.19; measured value: 448.23 (M + 1) ⁺ .

Synthetic iodomethane (0.21 mL, 3.36 mmol) of step D-compound Int-20d and dispersion in 60% sodium hydride oil (107.1 mg, 2.68 mmol) are cooled in an ice bath to 0 ° C. The compound Int-20c (498.1 mg, 1.113 mmol) was added to a stirred solution in THF (11.0 mL) in that order. After 50 minutes, the reaction mixture was removed from the ice bath and warmed to room temperature. After an additional 20 minutes, the reaction mixture was cooled in an ice bath to 0 ° C. and then diluted with EtOAc (50 mL). 1.0 M HCl (3 mL, 3 mmol) was diluted with 50 mL of additional water. About 10 to 15 mL of this HCl solution was slowly added to the reaction. The reaction mixture was removed from the ice bath and immediately partitioned between EtOAc (50 mL) and the remaining dilute HCl solution. The aqueous layer was extracted with EtOAc (twice at 50 mL). The organic layers were combined, _{dehydrated with butadiene 4} , filtered, and the solvent was evaporated under reduced pressure. The obtained oil was dissolved in MeOH (10.0 mL), and a solution of TMS-diazomethane 2.0 M in diethyl ether (2.0 mL, 4.00 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 2 hours and then the solvent was evaporated under reduced pressure. The resulting product was purified by silica gel column (40 g) chromatography eluting with 0% to 30% (25% EtOH / EtOAc) / hexanes to give compound Int-20d. LCMS analysis calculated value of C ₂₄ H ₃₁ NO ₈ : 461.20; measured value: 462.33 (M + 1) ⁺ .

Synthesis of Step E-Compound Int-20e 4-Methylbenzenesulfonic acid hydrate (281.3 mg, 1.479 mmol) in MeOH (11.0 mL) of Compound Int-20d (502.8 mg, 1.089 mmol). Was added to the stirred solution of. The reaction mixture was stirred at room temperature for 20 hours. Sodium bicarbonate (123.9 mg, 1.475 mmol) and triethylamine (0.21 mL, 1.507 mmol) were added to the reaction mixture and placed in the freezer over the weekend. The reaction mixture is removed from the freezer, warmed to room temperature, filtered (0.45 μm syringe filter), diluted with MeOH, and then eluted with 0% to 60% (ACN / water) + 0.05% TFA. Purified by reverse phase HPLC (Waters Sunfire C18 OBD, 10 μm, 30 × 150 mm column). The product fractions were combined and concentrated under reduced pressure until the water began to evaporate. The remaining aqueous solution (about 100 mL) was extracted with DCM (4 times at 50 mL). The organic layers were combined, _{dehydrated with Na 2} SO ₄ , filtered, and the solvent was evaporated under reduced pressure to give compound Int-20e. LCMS analysis calculated value of C ₁₆ H ₂₃ NO ₇ : 341.15; measured value: 342.32 (M + 1) ⁺ .

Synthetic Bis of Step F-Compound Int-20f [Rodium (α, α, α', α'-Tetramethyl-1,3-benzenedipropionic Acid)] (21.6 mg, 0.028 mmol) and O- (2) , 4-Dinitrophenyl) Hydroxylamine (290.7 mg, 1.460 mmol) in 2,2,2-trifluoroethanol (9.5 mL) of compound Int-20e (318.9 mg, 0.934 mmol). Added to the solution. The reaction mixture was stirred at room temperature for 3 hours. Additional bis [rhodium (α, α, α', α'-tetramethyl-1,3-benzenedipropionic acid)] (25.8 mg, 0.034 mmol) and O- (2,4-dinitrophenyl) hydroxylamine Amine (286.5 mg, 1.44 mmol) was added to the reaction mixture. After an additional 21 hours, the reaction mixture was distilled off under reduced pressure. The resulting residue was purified by silica gel column (40 g) chromatography eluting with 0% to 100% (90: 9: 1 DCM / MeOH / NH _{4 OH) / DCM to give compound Int-20f.} .. LCMS analysis calculated value of C ₁₅ H ₂₀ N ₂ O ₆ : 324.13; measured value: 325.21 (M + 1) ⁺ .

Step G-Compound Int-20g Synthetic Cesium Carbonate (615.0 mg, 1.888 mmol) and iodoethane (65 μL, 0.804 mmol) in DMSO (6.0 mL) of Compound Int-20f (199.5 mg, 0.615 mmol) ) Was added to the stirred solution. The reaction mixture is stirred at room temperature for 3.5 hours, then filtered (0.45 μm syringe filter) and eluted with 0% to 70% (ACN / water) + 0.05% TFA reverse phase HPLC (Waters Sunfire C18). Purified by OBD, 10 μm, 30 × 150 mm column). The product fractions were combined, partially concentrated under reduced pressure, frozen and lyophilized to give compound Int-20g. LCMS analysis calculated value of C ₁₇ H ₂₄ N ₂ O ₆ : 352.16; measured value: 353.28 (M + 1) ⁺ .

Synthesis of Step H-Compound Int-20h NIS (237.5 mg, 1.056 mmol) and m-CPBA (217.1 mg, 0.969 mmol) were combined with MeOH (199.7 mg, 0.567 mmol) of Compound Int-20 g (199.7 mg, 0.567 mmol). 5.6 mL) was added to the stirred solution. The reaction mixture was heated to 70 ° C. for 2 hours, then cooled to room temperature, and the solvent was distilled off under reduced pressure. The obtained solid was purified by silica gel column (24 g) chromatography eluting with 0% to 4% MeOH / DCM to give compound Int-20h. LCMS analysis calculated value of C ₁₇ H ₂₃ IN ₂ O ₆ : 478.06; measured value: 479.09 (M + 1) ⁺ .

Synthesis of Step I-Compound Int-20i Int-20h (271 mg, 0.567 mmol) was dissolved in a solution of HCl 1.25 M in MeOH (6.0 mL, 7.50 mmol) and heated to 40 ° C. After 18.5 hours, the reaction mixture was cooled to room temperature and the solvent was evaporated under reduced pressure. The obtained solid was purified by silica gel column (24 g) chromatography eluting with 0% to 10% MeOH / DCM to give compound Int-20i. LCMS analysis calculated value of C ₁₅ H ₁₉ IN ₂ O ₅ : 434.03; measured value: 435.05 (M + 1) ⁺ .

Synthesis of Step J-Compound Int-20i Bis (2-diphenylphosphinophenyl) ether (8.9 mg, 0.017 mmol), N, N-diisopropylethylamine (62 μL, 0.355 mmol), 2,4-difluorobenzylamine (25 μL, 0.210 _{mmol) and Pd (OAc) 2} (9.5 mg, 0.042 mmol) in a stirred solution of compound Int-20i (30.1 mg, 0.069 mmol) in DMSO (1.0 mL). added. The reaction mixture was degassed (3 times) and placed under nitrogen, then degassed and placed under a carbon monoxide balloon. The reaction mixture is stirred at 100 ° C. for 16 hours, then cooled to room temperature, filtered (0.45 μm syringe filter), diluted with MeOH and 10% to 90% (ACN / water) + 0.05% TFA. Purification was performed by elution reverse phase HPLC (Waters Sunfire C18 OBD, 10 μm, 30 × 150 mm column). The product fractions were combined, frozen, lyophilized and subjected to chiral preparative SFC (ChiralPak AD-H, 21 x 250 mm column, 70 g / min, 12 MPa (120 bar), 25% IPA / CO ₂ , 40. Further purified by (° C.), isomer A of compound Int-20j (first elution component), isomer B of compound Int-20j (second elution component), isomer C of compound Int-20j (first elution component). 3 elution component) and isomer D (fourth elution component) of compound Int-20j were obtained. Isomer A, isomer C, and isomer D were each further purified using the above chiral preparative SFC conditions to obtain sufficient purity. LCMS analysis calculated value of C ₂₃ H ₂₅ F ₂ N ₃ O ₆ : 477.17; measured value: 478.17 (M + 1) ⁺ .

Step K-Isomer A (11.0 mg, 0.023 mmol) of compound Int-20j, a synthetic compound of compound 57, compound 58, compound 59, and compound 60, magnesium bromide (45.9 mg, 0.249 mmol), and acetonitrile. (0.5 mL) was combined and stirred at room temperature. After 2 hours, the reaction mixture is diluted with MeOH, filtered (0.45 μm syringe filter) and then eluted with 10% to 90% (ACN / water) + 0.05% TFA reverse phase HPLC (Waters Sunfire C18). Purified by OBD, 10 μm, 30 × 150 mm column). The product fractions were combined and concentrated under reduced pressure until most of the ACN was removed. The remaining aqueous solution was extracted with DCM (about 5 mL 3 times). The organic layer was _{sequentially dehydrated with Na 2} SO ₄ , filtered, combined, and the solvent was evaporated under reduced pressure. The resulting residue was dissolved in ACN (about 5 mL), diluted with water (about 5 mL), frozen and lyophilized to give compound 57. ^{1 1} H NMR (500 MHz, CD ₃ OD): δ7.5-7.43 (m, 1H); 7.02-6.92 (m, 2H); 5.66 (t, J = 7.8 Hz, 1H) ); 4.69-4.61 (m, 2H); 3.96 (d, J = 13.4Hz, 1H); 3.89 (d, J = 13.3Hz, 1H); 3.71 (dq) , J = 14.4, 7.1Hz, 1H); 3.61-3.49 (m, 3H); 3.26 (s, 3H); 2.93 (dd, J = 12.8, 7. 8Hz, 1H); 2.07 (dd, J = 12.8, 7.9Hz, 1H); 1.24 (t, J = 7.2Hz, 3H). LCMS analysis calculated value of C ₂₂ H ₂₃ F ₂ N ₃ O ₆ : 463.16; measured value: 464.35 (M + 1) ⁺ .

Compound 58 was prepared from isomer B of compound Int-20j, essentially according to the method used to produce compound 57 in step K of Example 20. ^{1 1} H NMR (500 MHz, CD ₃ OD): δ7.5-7.43 (m, 1H); 7.01-6.91 (m, 2H); 5.74 (d, J = 7.5 Hz, 1H) ); 4.69-4.60 (m, 2H); 4.00 (d, J = 13.0Hz, 1H); 3.84-3.72 (m, 2H); 3.69 (d, J) = 9.1Hz, 1H); 3.64 (d, J = 9.1Hz, 1H); 3.44 (dq, J = 14.1, 7.1Hz, 1H); 3.38 (s, 3H) 2.49 (d, J = 13.9Hz, 1H); 2.32 (dd, J = 13.5, 7.7Hz, 1H); 1.25 (t, J = 7.2Hz, 3H). LCMS analysis calculated value of C ₂₂ H ₂₃ F ₂ N ₃ O ₆ : 463.16; measured value: 464.13 (M + 1) ⁺ .

Compound 59 was prepared from isomer C of compound Int-20j, essentially according to the method used to prepare compound 57 in step K of Example 20. ^{1 1} H NMR (500 MHz, CD ₃ OD): δ7.5-7.43 (m, 1H); 7.02-6.92 (m, 2H); 5.66 (t, J = 7.8 Hz, 1H) ); 4.69-4.61 (m, 2H); 3.96 (d, J = 13.4Hz, 1H); 3.89 (d, J = 13.3Hz, 1H); 3.71 (dq) , J = 14.3, 7.2Hz, 1H); 3.61-3.49 (m, 3H); 3.26 (s, 3H); 2.93 (dd, J = 12.8, 7. 7Hz, 1H); 2.07 (dd, J = 12.8, 7.8Hz, 1H); 1.24 (t, J = 7.2Hz, 3H). LCMS analysis calculated value of C ₂₂ H ₂₃ F ₂ N ₃ O ₆ : 463.16; measured value: 464.18 (M + 1) ⁺ .

Compound 60 was prepared from isomer D of compound Int-20j, essentially according to the method used to produce compound 57 in step K of Example 20. ^{1 1} H NMR (500 MHz, CD ₃ OD): δ7.49-7.42 (m, 1H); 7.01-6.91 (m, 2H); 5.74 (d, J = 7.5 Hz, 1H) ); 4.68-4.60 (m, 2H); 4.00 (d, J = 13.0Hz, 1H); 3.84-3.72 (m, 2H); 3.69 (d, J) = 9.0Hz, 1H); 3.64 (d, J = 9.1Hz, 1H); 3.44 (dq, J = 14.3, 7.3Hz, 1H); 3.38 (s, 3H) 2.48 (d, J = 13.9Hz, 1H); 2.32 (dd, J = 13.5, 7.8Hz, 1H); 1.25 (t, J = 7.2Hz, 3H). LCMS analysis calculated value of C ₂₂ H ₂₃ F ₂ N ₃ O ₆ : 463.16; measured value: 464.19 (M + 1) ⁺ .

Example 21
Preparation of Compounds 61-64 Using Int-20i as a raw material and using 2,4,6-trifluorobenzylamine instead in step J, chiral preparative SFC (ChiralPak AS-H, 21 × 250 mm column, 50 g / min). , 120 bar, 30% EtOH / CO ₂ , 40 ° C.) to obtain a mixture of isomer A and isomer B, isomer C, and isomer D to obtain a mixture of isomer A and isomer B. Further purification by chiral preparative SFC (ChiralPak OJ-H, 21 × 250 mm column twice, 50 g / min, 120 bar, 15% EtOH / CO ₂ , 40 ° C.) to give isomer A and isomer B. Essential except that isomer B was further purified by chiral preparative SFC (ChiralPak OJ-H, 21 x 250 mm column twice, 50 g / min, 12 MPa (120 bar), 15% EtOH / CO _{2, 40 ° C.).} The following compounds were prepared using the same methods described in Step J and Step K in Example 20.

Example 22
Preparation of compounds 65-72

Synthesis of Step A-Compound Int-22a A mixture of compound Int-14c (50 mg, 0.151 mmol) and K ₂ CO ₃ (83 mg, 0.604 mmol) in dehydrated acetone (5 mL) was stirred at 70 ° C. After 14 hours, the reaction mixture was filtered and the filtrate was evaporated to give compound Int-22a. This material was used in step B of Example 22 without further purification. LCMS analysis calculated value of C ₂₀ H ₂₃ NO ₇ : 389.2; measured value: 390.1 (M + 1) ⁺ .

Synthesis of Step B-Compound Int-22b Compound Int-22a (60 mg, 0.154 mmol), DMAP (9.41 mg, 0.077 mmol), and DCM (5 mL) of 2,6-dimethylpyridine (165 mg, 1.541 mmol). ) was added, 0 ° C. under _{N 2} under tert- butyldimethylsilyl trifluoromethanesulfonate (244 mg, 0.925 mmol) was added dropwise. The mixture was stirred at 25 ° C. for 1 hour and then stopped with water (10 mL). The separated aqueous phase was extracted with DCM (twice at 10 m). The combined organic layers were _{dehydrated with Na 2} SO ₄ , filtered and concentrated. The residue was purified by flash silica gel chromatography (4 g column) eluting with 0% to 25% EtOAc / petroleum ether to give compound Int-22b. LCMS analysis calculated value of C ₂₆ H ₃₇ NO ₇ Si: 503.2; measured value: 504.4 (M + 1) ⁺ .

Synthesis of Step C-Compound Int-22c THF (120 mL) of the compounds Int-22b (6.2 g, 12.31 mmol) and 5- (ethylsulfonyl) -1-phenyl-1H-tetrazole (5.87 g, 24.62 mmol). ) was added dropwise a THF solution of LiHMDS 1M under _{N 2} at -78 ℃ (49.2mL, 49.2mmol). The reaction mixture was stirred for 1 hour at -78 ° C., and quenched with aqueous _NH 4 Cl (200 mL) at -78 ° C.. The aqueous layer was extracted with EtOAc (3 times at 100 mL). The combined organic layers were _{dehydrated with Na 2} SO ₄ , filtered and concentrated. The residue was purified by flash silica gel chromatography (120 g column) eluting with 0% to 8% EtOAc / petroleum ether to give compound Int-22c. LCMS analysis calculated value of C ₂₈ H ₄₁ NO ₆ Si: 515.3; measured value: 516.3 (M + 1) ⁺ .

Synthesis of Step D-Compound Int-22d A mixture of Compound Int-22c (2.45 g, 4.75 mmol) in DCM (50 mL) and TFA (5 mL) was stirred at 25 ° C. After 1 hour, the solvent was evaporated and the residue was purified by flash silica gel chromatography (40 g column) eluting with 0% to 50% EtOAc / petroleum ether to give compound Int-22d. LCMS analysis calculated value of C ₂₀ H ₃₃ NO ₅ Si: 395.2; measured value: 396.2 (M + 1) ⁺ .

Synthesis of Step E-Compound Int-22e _{CF 3} CH ₂ OH of Compound Int-22d (1.7 g, 4.30 mmol) and O- (2,4-dinitrophenyl) hydroxylamine (2.57 g, 12.89 mmol) To the mixture in (20 mL) was added bis [lodium (α, α, α', α'-tetramethyl-1,3-benzenedipropionic acid)] (0.164 g, 0.215 mmol). The mixture was stirred under _{N 2} at 60 ° C. After 36 hours, the solvent was evaporated and the residue was purified by flash silica gel chromatography (40 g column) eluting with 0% to 5% MeOH / DCM to give compound Int-22e. LCMS analysis calculated value of C ₁₉ H ₃₀ N ₂ O ₄ Si: 378.2; measured value: 379.1 (M + 1) ⁺ .

Step F- Compound Int-22f of compound Int-22e (1g, 2.64mmol) and MeI (0.496mL, 7.93mmol) in DMF (10 mL) in a mixture of, NaH (0 under _{N 2} at 0 ℃ .211 g, 5.28 mmol) was added. The mixture was stirred for 1 hour at 0 ° C., then quenched with aqueous _NH 4 Cl (2 mL). The mixture is purified by preparative reverse phase HPLC (Phenomenex Synergi C18, 4 μm, 30 × 150 mm column) eluting with 34% to 44% ACN / (water + 0.1% TFA) to the isomer of compound Int-22f. A mixture of body A, isomer B, isomer C, and isomer D (first elution component), a mixture of isomer E and isomer F of compound Int-22f (second elution component), and compound Int. A mixture of -22f isomer G and isomer H (third elution component) was obtained. LCMS analysis calculated value of C ₂₀ H ₃₂ N ₂ O ₄ Si: 392.2; measured value: 393.2 (M + 1) ⁺ .

Synthesis of Step G-Compound Int-22g in THF (5 mL) A mixture of isomers A, B, C and D of compound Int-22f (270 mg, 0.688 mmol) and TBAF 1M in THF. The solution (0.344 mL, 0.344 mmol) was stirred at 25 ° C. After 14 hours, the solvent was evaporated to dryness and the residue was purified by flash silica gel chromatography (12 g column) elution with 0% to 12% MeOH / DCM to isomer A of compound Int-22 g. , A mixture of isomer B, isomer C, and isomer D was obtained. LCMS analysis calculated value of C ₁₄ H ₁₈ N ₂ O ₄ : 278.1; measured value: 279.1 (M + 1) ⁺ .

A solution of 1M TBAF in THF (0.611 mL, 0.611 mmol) was added to a solution of compound Int-22f in THF (5 mL) of isomer E and isomer F (120 mg, 0.306 mmol). The reaction was stirred at 25 ° C. for 1 hour. The solvent is evaporated to dryness and the residue is purified by flash silica gel chromatography (4 g column) eluting with 0% to 10% MeOH / DCM to isomer E and isomer F of compound Int-22g. A mixture of LCMS analysis calculated value of C ₁₄ H ₁₈ N ₂ O ₄ : 278.1; measured value: 279.1 (M + 1) ⁺ .

A mixture of isomer G and isomer H of compound Int-22f in THF (5 mL) (400 mg, 1.019 mmol) and a solution of TBAF 1M in THF (3.06 mL, 3.06 mmol) was stirred at 25 ° C. After 14 hours, the solvent was distilled off to dryness, and the residue was purified by flash silica gel chromatography (12 g column) eluting with 0% to 10% MeOH / DCM, and the isomer G of compound Int-22 g. And a mixture of isomer H was obtained. LCMS analysis calculated value of C ₁₄ H ₁₈ N ₂ O ₄ : 278.1; measured value: 279.1 (M + 1) ⁺ .

Synthesis of Step H-Compound Int-22h A mixture of isomer A, isomer B, isomer C and isomer D (0.25 g, 0.898 mmol) of compound Int-22 g in MeOH (10 mL), m-CPBA. (0.620 g, 3.59 mmol) and NIS (0.808 g, 3.59 mmol) were stirred at 90 ° C. After 1 _h, the reaction was quenched with Na ₂ S _{2 O} 5 2g and water 0.5 mL. The mixture is stirred at 25 ° C. for 10 minutes, the solvent is distilled off and the residue is purified by flash silica gel chromatography (12 g column) eluting with 0% to 10% MeOH / DCM to compound Int-22h. A mixture of isomer A, isomer B, isomer C and isomer D was obtained. LCMS analysis calculated value of C ₁₄ H ₁₇ IN ₂ O ₄ : 404.0; measured value: 405.0 (M + 1) ⁺ .

90 mixtures of isomer E and isomer F of compound Int-22g in MeOH (10 mL) (70 mg, 0.252 mmol), m-CPBA (130 mg, 0.755 mmol), and NIS (170 mg, 0.755 mmol). Stirred at ° C. After 1 hour, the reaction was stopped with 300 mg of _{Na 2} S ₂ O _{5 and 1 mL of water.} The mixture is stirred at 25 ° C. for 10 minutes, the solvent is distilled off and the residue is purified by flash silica gel chromatography (4 g column) eluting with 0% to 12% MeOH / DCM to compound Int-22h. A mixture of isomer E and isomer F was obtained. LCMS analysis calculated value of C ₁₄ H ₁₇ IN ₂ O ₄ : 404.0; measured value: 405.1 (M + 1) ⁺ .

90 of a mixture of isomer G and isomer H (160 mg, 0.575 mmol), m-CPBA (298 mg, 1.725 mmol), and NIS (388 mg, 1.725 mmol) of compound Int-22 g in MeOH (10 mL). Stirred at ° C. After 2 hours, the reaction was stopped with 700 mg of _{Na 2} S ₂ O _{5 and 1 mL of water.} The mixture is stirred at 25 ° C. for 10 minutes, the solvent is distilled off and the residue is purified by flash silica gel chromatography (12 g column) eluting with 0% to 10% MeOH / DCM to compound Int-22h. A mixture of isomer G and isomer H was obtained. LCMS analysis calculated value of C ₁₄ H ₁₇ IN ₂ O ₄ : 404.0; measured value: 405.1 (M + 1) ⁺ .

Synthesis of Step I-Compound Int-22i In a solution of a mixture of isomer A, isomer B, isomer C, and isomer D (370 mg, 0.915 mmol) of compound Int-22h in DMSO (3 mL) (2). , 4-Difluorophenyl) methaneamine (393 mg, 2.75 mmol), DIEA (0.959 mL, 5.49 mmol) and Pd (Ph ₃ P) ₄ (529 mg, 0.458 mmol) were added. The mixture was degassed and purged with CO 3 times. The resulting mixture was stirred under CO (about 15 psi) at 90 ° C. After 3 hours, the mixture is filtered and purified by preparative reverse phase HPLC (Boston Green ODS, 5 μm, 30 × 150 mm column) eluting with 29% to 49% ACN / (water + 0.1% TFA). by preparative SFC (DAICEL CHIRALPAK AD-H, 5μm, 30 × 250mm column, 50 mL / _{min, 35% (IPA + 0.1%} NH 3 H 2 O) / CO 2) was further purified by, compound Int-22i A (first elution component), isomer B of compound Int-22i (second elution component), isomer C of compound Int-22i (third elution component), and compound Int-22i. The isomer D (fourth elution component) was obtained. LCMS analysis calculated value of C ₂₂ H ₂₃ F ₂ N ₃ O ₅ : 447.2; measured value: 448.2 (M + 1) ⁺ .

A mixture of isomer E and isomer F of compound Int-22h (110 mg, 0.272 mmol) in DMSO (10 mL) with (2,4-difluorophenyl) methaneamine (117 mg, 0.816 mmol), DIEA (0). .285 mL, 1.633 mmol), and Pd (Ph ₃ P) ₄ (157 mg, 0.136 mmol) were added. The mixture was degassed and purged with CO 3 times. The resulting mixture was stirred under CO (about 15 psi) at 90 ° C. After 2 hours, the mixture is filtered and purified by preparative reverse phase HPLC (Boston Green ODS, 5 μm, 30 × 150 mm column) eluting with 29% to 49% ACN / (water + 0.1% TFA). by preparative SFC (DAICEL CHIRALPAK AD, 10μm, 50 × 250mm column, 70 mL / _{min, 40% (IPA + 0.1%} NH 3 H 2 O) / CO 2) was further purified by, isomeric compounds Int-22i Body E (first elution component) and isomer F (second elution component) of compound Int-22i were obtained. LCMS analysis calculated value of C ₂₂ H ₂₃ F ₂ N ₃ O ₅ : 447.2; measured value: 448.2 (M + 1) ⁺ .

A mixture of isomer G and isomer H of compound Int-22h (320 mg, 0.792 mmol) in DMSO (10 mL) with (2,4-difluorophenyl) methaneamine (340 mg, 2.375 mmol), DIEA (0). .830 mL, 4.75 mmol), and Pd (Ph ₃ P) ₄ (457 mg, 0.396 mmol) were added. The mixture was degassed and purged with CO 3 times. The resulting mixture was stirred under CO (about 15 psi) at 90 ° C. After 3 hours, the mixture is filtered and purified by preparative reverse phase HPLC (Boston Green ODS, 5 μm, 30 × 150 mm column) eluting with 29% to 49% ACN / (water + 0.1% TFA). by preparative SFC (DAICEL CHIRALPAK AD, 10μm, 50 × 250mm column, 70 mL / _{min, 50% (IPA + 0.1%} NH 3 H 2 O) / CO 2) was further purified by, isomeric compounds Int-22i Body G (first elution component) and isomer H of compound Int-22i (second elution component) were obtained. LCMS analysis calculated value of C ₂₂ H ₂₃ F ₂ N ₃ O ₅ : 447.2; measured value: 448.2 (M + 1) ⁺ .

Step J-Compound 65 of compound 65, compound 66, compound 67, compound 68, compound 69, compound 70, compound 71 and compound 72 , isomer A (7 mg, 0.016 mmol) of compound Int-22i and magnesium bromide (28. The mixture in 8 mg, 0.156 mmol) acetonitrile (3 mL) was stirred at 25 ° C. After 2 hours, MeOH (1 mL) was added and the mixture was purified by preparative HPLC (Boston Green ODS, 5 μm, 30 × 150 mm column) eluting with 30% to 60% ACN / (water + 0.1% TFA). Then, compound 65 was obtained. ^{1 1} H NMR (400 MHz, CD ₃ OD): δ11.34 (brs, 1H); 7.60-7.25 (m, 1H); 7.06-6.75 (m, 2H); 5.67 ( t, J = 7.9Hz, 1H); 4.72-4.53 (m, 2H); 3.91 (q, J = 6.6Hz, 1H); 3.23-3.11 (m, 3H) ); 2.67 (dd, J = 13.0, 7.8Hz, 1H); 2.26 (dd, J = 13.0, 8.1Hz, 1H); 1.59-1.37 (m, 3H); 1.26 (d, J = 6.6Hz, 3H). LCMS analysis calculated value of C ₂₁ H ₂₁ F ₂ N ₃ O ₅ : 433.1; measured value: 434.2 (M + 1) ⁺ .

Compound 66 was prepared from isomer B of compound Int-22i, essentially according to the method used to prepare compound 65 in step J of Example 22. ^{1 1} H NMR (400 MHz, CD ₃ OD): δ7.52-7.34 (m, 1H); 7.02-6.83 (m, 2H); 5.64 (t, = 8.1 Hz, 1H) 4.73-4.53 (m, 2H); 4.06 (q, J = 7.0Hz, 1H); 3.14 (s, 3H); 2.80 (dd, J = 12.5, 7.3Hz, 1H); 2.13-1.98 (m, 1H); 1.45 (d, J = 7.1Hz, 3H); 1.28 (s, 3H). LCMS analysis calculated value of C ₂₁ H ₂₁ F ₂ N ₃ O ₅ : 433.1; measured value: 434.2 (M + 1) ⁺ .

Compound 67 was prepared from isomer C of compound Int-22i, essentially according to the method used to prepare compound 65 in step J of Example 22. ^{1 1} H NMR (400 MHz, CD ₃ OD): δ11.34 (brs, 1H); 7.53-7.31 (m, 1H); 7.06-6.78 (m, 2H); 5.67 ( t, J = 7.9Hz, 1H); 4.72-4.53 (m, 2H); 3.96-3.78 (m, 1H); 3.23-3.12 (m, 3H); 2.67 (dd, J = 13.0, 7.8Hz, 1H); 2.32-2.19 (m, 1H); 1.51-1.41 (m, 3H); 1.26 (brd) , J = 6.6Hz, 3H). LCMS analysis calculated value of C ₂₁ H ₂₁ F ₂ N ₃ O ₅ : 433.1; measured value: 434.2 (M + 1) ⁺ .

Compound 68 was prepared from isomer D of compound Int-22i, essentially according to the method used to prepare compound 65 in step J of Example 22. ^{1 1} H NMR (400 MHz, CD ₃ OD): δ7.55-7.33 (m, 1H); 7.00-6.79 (m, 2H); 5.63 (t, J = 8.1 Hz, 1H) ); 4.75-4.45 (m, 2H); 4.07 (q, J = 6.8Hz, 1H); 3.13 (s, 3H); 2.79 (dd, J = 12.5) , 7.6Hz, 1H); 2.06 (brdd, J = 12.1, 8.9Hz, 1H); 1.44 (d, J = 6.8Hz, 3H); 1.27 (s, 3H) .. LCMS analysis calculated value of C ₂₁ H ₂₁ F ₂ N ₃ O ₅ : 433.1; measured value: 434.2 (M + 1) ⁺ .

Compound 69 was prepared from isomer E of compound Int-22i, essentially according to the method used to prepare compound 65 in step J of Example 22. ^{1 1} H NMR (400 MHz, CD ₃ OD): δ10.90 (brs, 1H); 7.53-7.28 (m, 1H); 7.03-6.75 (m, 2H); 5.75 ( d, J = 7.8Hz, 1H); 4.63 (s, 2H); 3.92 (m, 1H); 3.18 (s, 3H); 2.61 (dd, J = 13.8, 7.5Hz, 1H); 2.16 (d, J = 14.2Hz, 1H); 1.70 (s, 3H); 1.17 (d, J = 6.6Hz, 3H). LCMS analysis calculated value of C ₂₁ H ₂₁ F ₂ N ₃ O ₅ : 433.1; measured value: 434.2 (M + 1) ⁺ .

Compound 70 was prepared from the isomer F of compound Int-22i, essentially according to the method used to produce compound 65 in step J of Example 22. ^{1 1} H NMR (400 MHz, CD ₃ OD): δ10.90 (brs, 1H); 7.57-7.31 (m, 1H); 7.06-6.78 (m, 2H); 5.75 ( d, J = 7.8Hz, 1H); 4.62 (s, 2H); 3.92 (q, J = 6.6Hz, 1H); 3.18 (s, 3H); 2.61 (dd, dd, J = 14.1, 7.7Hz, 1H); 2.16 (d, J = 13.9Hz, 1H); 1.70 (s, 3H); 1.17 (d, J = 6.6Hz, 3H) ). LCMS analysis calculated value of C ₂₁ H ₂₁ F ₂ N ₃ O ₅ : 433.1; measured value: 434.2 (M + 1) ⁺ .

Compound 71 was prepared from the isomer G of compound Int-22i, essentially according to the method used to prepare compound 65 in step J of Example 22. ^{1 1} H NMR (400 MHz, CD ₃ OD): δ7.5-7.34 (m, 1H); 7.04-6.83 (m, 2H); 5.66 (d, J = 7.3 Hz, 1H) ); 4.68-4.54 (m, 2H); 3.96 (m, 1H); 3.13 (s, 3H); 2.40-2.24 (m, 2H); 1.48 ( s, 3H); 1.45 (d, J = 6.8Hz, 3H). LCMS analysis calculated value of C ₂₁ H ₂₁ F ₂ N ₃ O ₅ : 433.1; measured value: 434.2 (M + 1) ⁺ .

Compound 72 was prepared from the isomer H of compound Int-22i, essentially according to the method used to prepare compound 65 in step J of Example 22. ^{1 1} H NMR (400 MHz, CD ₃ OD): δ7.52-7.36 (m, 1H); 7.03-6.82 (m, 2H); 5.66 (d, J = 7.1 Hz, 1H) ); 4.71-4.49 (m, 2H); 3.96 (q, J = 6.8Hz, 1H); 3.13 (s, 3H); 2.46-2.18 (m, 2H) ); 1.48 (s, 3H); 1.45 (d, J = 6.8Hz, 3H). LCMS analysis calculated value of C ₂₁ H ₂₁ F ₂ N ₃ O ₅ : 433.1; measured value: 434.2 (M + 1) ⁺ .

Example 23
Preparation of compound Int-23b

Step A- Compound Int-23a Synthesis 0 of methyl magnesium bromide 3M stirring at ° C. Et ₂ O solution of (71.1mL, 213mmol) in, methacryl aldehyde over _{N 2} 45 minutes under (13.6 g, 194 mmol) The _{solution in Et 2} O (130 mL) was added dropwise. After the addition, the solution was stirred at 0 ° C. for 30 minutes and then charged into 200 mL of 2N HCl at 0 ° C. The layers were separated and the aqueous layer was _{extracted with Et 2} O (twice at 200 mL). The combined organic extracts were washed with NaHCO ₃ (150 mL) and brine (150 mL), dehydrated with _{Na 2} SO _{4 and filtered.} The filtrate was concentrated at room temperature to give a residue, which was distilled under reduced pressure (water pump, 55-70 ° C.) to give compound Int-23a. ^{1 1} H NMR (400 MHz, CDCl ₃ ): δ4.93 (s, 1H); 4.77 (s, 1H); 4.22 (q, J = 6.3 Hz, 1H); 1.73 (s, 3H) ); 1.26 (d, J = 6.6Hz, 3H).

Step B-Synthesis of Compound Int-23b Phosphorus tribromide (1.314 mL) in a solution of compound Int-23a (3 g, 34.8 mmol) at 0 ° C. in Et _{2 O (50 mL) under high stirring under N 2.} , 13.93 mmol) was added dropwise. After 1 hour at 0 ° C., the reaction was stopped with 20 mL of water. The layers were separated and the organic extract was washed with _{aqueous NaHCO 3} solution (30 mL) and water (30 mL), dehydrated with _{Na 2} SO _{4 and filtered.} The filtrate was concentrated at room temperature to give compound Int-23b, which was used in step C of Example 14 without further purification. ^{1 1} H NMR (400 MHz, CDCl ₃ ): δ5.06 (s, 1H); 4.86 (t, J = 1.3 Hz, 1H); 4.72 (q, = 6.8 Hz, 1H); 1. 88 (s, 3H); 1.62 (d, J = 6.8Hz, 3H).

Example 24
Production of compounds 73-80

Synthesis of Step A-Compound Int-24a In compound Int-14c (1 g, 3.02 mmol), sodium iodide (0.905 g, 6.04 mmol) and indium (1.733 g, 15.09 mmol) in DMF (15 mL). The mixture was stirred at 25 ° C. for 10 minutes and then Int-23b (1.349 g, 9.05 mmol) was added. The mixture was stirred at 25 ° C. for 14 hours and then diluted with EtOAc (50 mL). After filtration, the organic layer was washed with water (twice at 20 mL) and brine (20 mL) and then dehydrated with _{Na 2} SO _4. After filtration, the organic solvent was removed under reduced pressure and the residue was purified by flash silica gel chromatography (20 g column) eluting with 0% to 35% EtOAc / petroleum ether to give compound Int-24a. LCMS analysis calculated value of C ₂₂ H ₂₇ NO ₆ : 401.2; measured value: 402.2 (M + 1) ⁺ .

Step B-Synthesis of Compound Int-24b DCM (10 mL) of compound Int-24a (800 mg, 1.993 mmol) at 0 ° C., DMAP (122 mg, 0.996 mmol) and 2,6-dimethylpyridine (2135 mg, 19.93 mmol). ), Tert-butyldimethylsilyltrifluoromethanesulfonate (3161 mg, 11.96 mmol) was added dropwise to the solution. The mixture was stirred at 25 ° C. for 1 hour and then stopped with water (20 mL). The separated aqueous phase was extracted with DCM (twice at 20 mL) and the combined organic layers were _{dehydrated with Na 2} SO ₄ , filtered and concentrated to dryness. The residue obtained was purified by flash silica gel chromatography (40 g column) eluting with 0% to 25% EtOAc / petroleum ether to give compound Int-24b. LCMS analysis calculated value of C ₂₈ H ₄₁ NO ₆ Si: 515.3; measured value: 516.3 (M + 1) ⁺ .

Synthesis of Step C-Compound Int-24c A mixture of compound Int-24b (750 mg, 1.454 mmol) in DCM (10 mL) and TFA (1 mL) was stirred at 25 ° C. After 2 hours, the mixture was concentrated under reduced pressure and the residue was purified by flash silica gel chromatography (12 g column) eluting with 0% to 50% EtOAc / petroleum ether to give compound Int-24c. LCMS analysis calculated value of C ₂₀ H ₃₃ NO ₅ Si: 395.2; measured value: 396.2 (M + 1) ⁺ .

Synthesis of Step D-Compound Int-24d In compound Int-24c (640 mg, 1.618 mmol) and CF ₃ CH ₂ OH (10 mL) of O- (2,4-dinitrophenyl) hydroxylamine (966 mg, 4.85 mmol). Bis [lodium (α, α, α', α'-tetramethyl-1,3-benzenedipropionic acid)] (24.67 mg, 0.032 mmol) was added to the mixture. The mixture _{was stirred under N 2} at 60 ° C. After 36 hours, the solvent was evaporated and the residue was purified by flash silica gel chromatography (24g column) eluting with 0% to 3% MeOH / DCM to give compound Int-24d. LCMS analysis calculated value of C ₁₉ H ₃₀ N ₂ O ₄ Si: 378.2; measured value: 379.2 (M + 1) ⁺ .

Synthesis of Step E-Compound Int-24e To a mixture of compound Int-24d (340 mg, 0.898 mmol) at 0 ° C. and MeI (0.168 mL, 2.69 mmol) in DMF (5 mL) _{under N 2} NaH (71). 8.8 mg (1.796 mmol) was added. The mixture was stirred for 1 hour at 0 ° C., then quenched with aqueous _NH 4 Cl (20 mL). The aqueous layer was extracted with EtOAc (3 times at 20 mL). The combined organic layers were washed with brine (3 times at 10 mL), _{dehydrated with Na 2} SO ₄ , filtered, solvent distilled off and dried. The obtained residue was purified by flash silica gel chromatography (4 g column) eluting with 0% to 8% MeOH / DCM to give compound Int-24e. LCMS analysis calculated value of C ₂₀ H ₃₂ N ₂ O ₄ Si: 392.2; measured value: 393.2 (M + 1) ⁺ .

Step F-Compound Int-24f Synthesis Compound Int-24e (270 mg, 0.688 mmol) and TBAF 1M solution in THF (1.376 mL, 1.376 mmol) in THF (5 mL) is stirred at 25 ° C. bottom. After 1 hour, the solvent was evaporated to dryness and the residue was purified by flash silica gel chromatography (12 g column) elution with 0% to 15% MeOH / DCM to give compound Int-24f. LCMS analysis calculated value of C ₁₄ H ₁₈ N ₂ O ₄ : 278.1; measured value: 279.1 (M + 1) ⁺ .

Step G-Compound Int-24g Synthetic Compound Int-24f (210 mg, 0.755 mmol), m-CPBA (521 mg, 3.02 mmol), and NIS (679 mg, 3.02 mmol) in MeOH (5 mL) 90. Stirred at ° C. After 1 hour, the reaction was stopped with 1 g of _{Na 2} S ₂ O _{5 and 5 mL of water.} The mixture is stirred at 25 ° C. for 10 minutes, the solvent is evaporated and the residue is purified by flash silica gel chromatography (20 g column) eluting with 0% to 10% MeOH / DCM, compound Int-24g. Got LCMS analysis calculated value of C ₁₄ H ₁₇ IN ₂ O ₄ : 404.0; measured value: 405.0 (M + 1) ⁺ .

Synthesis of Step H-Compound Int-24h In a solution of Int-24 g (580 mg, 1.435 mmol) in DMSO (10 mL), (2,4-difluorophenyl) methaneamine (616 mg, 4.30 mmol), DIEA (1. 504 mL, 8.61 mmol), and Pd (Ph ₃ P) ₄ (829 mg, 0.717 mmol) were added. The mixture was degassed and purged with CO 3 times. The resulting mixture was stirred under CO (about 0.103 MPa (15 psi)) at 90 ° C. After 6 hours, the reaction mixture was diluted with EtOAc (30 mL) and washed with water (twice at 10 mL) and brine (once at 10 mL). The organic layer was dehydrated over sodium sulfate, filtered and concentrated under reduced pressure. The residue is purified by flash silica gel chromatography (12 g column) eluting with 50% to 100% EtOAc / petroleum ether to give the crude product, which is 26% to 41% ACN / (water + 0. Further purified by preparative reverse phase HPLC (Phenomenex Synergi C18, 4 μm, 30 × 150 mm column) eluting with 1% TFA), a mixture of isomer A and isomer B of compound Int-24h (first elution). A mixture (second elution component) of isomer C, isomer D, isomer E, isomer F, isomer G, and isomer H of compound Int-24h was obtained.

Compound Int-24h mixture of isomer A and isomer B of preparative SFC (Phenomenex- cellulose -2,10μm, 30 × 250mm column, 80 mL / _{min, 50% (EtOH + 0.1%} NH 3 H 2 O) Further purification with / CO ₂ ) gave isomer A of compound Int-24h (first elution component) and isomer B of compound Int-24h (second elution component).

A mixture of isomer C, isomer D, isomer E, isomer F, isomer G and isomer H of compound Int-24h was prepared by preparative SFC (Phenomenex-cellulose-2, 5 μm, 30 × 250 mm column, 50 mL). / min, and further purified by _{40% (EtOH + 0.1% NH} 3 H 2 O) / CO 2), isomer C compound Int-24h, mixture of isomers D, and isomer E (first elution Component), isomer F of compound Int-24h (second elution component), isomer G of compound Int-24h (third elution component), and isomer H of compound Int-24h (fourth elution component). ) Was obtained. A mixture of isomer C, isomer D, and isomer E of compound Int-24h was mixed with a preparative SFC (YMC CHIRAL Amylose-C, 10 μm, 30 × 250 mm column, 70 mL / min, 55% (EtOH + 0.1% NH). _{3 H 2 O) / CO 2} ) was further purified by, isomer C (first component eluted compound Int-24h), isomer D (second component eluted compound Int-24h), and compound Int The -24h isomer E (third elution component) was obtained. Isomer G of Compound Int-24h, preparative SFC (DAICEL CHIRALPAK IC, 5μm, 30 × 250mm column, 50 mL / _{min, 50% (EtOH + 0.1%} NH 3 H 2 O) / CO 2) was further purified by The isomer G of compound Int-24h was obtained. LCMS analysis calculated value of C ₂₂ H ₂₃ F ₂ N ₃ O ₅ : 447.2; measured value: 448.1 (M + 1) ⁺ .

Step I-Synthetic compound of compound 73, compound 74, compound 75, compound 76, compound 77, compound 78, compound 79 and compound 80 Int-24h isomer A (33 mg, 0.074 mmol) and magnesium bromide (136 mg, The mixture in acetonitrile (3 mL) of 0.738 mmol) was stirred at 25 ° C. After 2 hours, MeOH (1 mL) is added and the mixture is eluted with 30% to 60% ACN / (water + 0.1% TFA) preparative reverse phase HPLC (Boston Green ODS, 5 μm, 30 × 150 mm column). Purified by. The product fraction was co-distilled with toluene (twice) to give compound 73. ^{1 1} H NMR (400 MHz, CDCl ₃ ): δ10.95 (br, 1H); 7.46-7.30 (m, 1H); 6.93-6.68 (m, 2H); 5.26 (s) , 1H); 4.74-4.52 (m, 2H); 3.91 (d, J = 12.7Hz, 1H); 3.30 (d, J = 12.7Hz, 1H); 3.22 (S, 3H); 2.64 (q, J = 7.7Hz, 1H); 1.70 (s, 3H); 1.11 (d, J = 7.9Hz, 3H). LCMS analysis calculated value of C ₂₁ H ₂₁ F ₂ N ₃ O ₅ : 433.1; measured value: 434.2 (M + 1) ⁺ .

Compound 74 was prepared from isomer B of compound Int-24h, essentially according to the method used to produce compound 73 in step I of Example 24. ^{1 1} H NMR (400 MHz, CDCl ₃ ): δ10.95 (br, 1H); 7.45-7.29 (m, 1H), 6.88-6.68 (m, 2H); 5.26 (s) , 1H); 4.73-4.48 (m, 2H); 3.91 (d, J = 12.7Hz, 1H); 3.30 (d, J = 12.7Hz, 1H); 3.22 (S, 3H); 2.64 (q, J = 7.7Hz, 1H); 1.70 (s, 3H); 1.11 (d, J = 7.5Hz, 3H). LCMS analysis calculated value of C ₂₁ H ₂₁ F ₂ N ₃ O ₅ : 433.1; measured value: 434.2 (M + 1) ⁺ .

Compound 75 was prepared from isomer C of compound Int-24h, essentially according to the method used to prepare compound 73 in step I of Example 24. ^{1 1} H NMR (400 MHz, CDCl ₃ ): δ11.35 (br, 1H); 7.38-7.22 (m, 1H); 7.02 (s, 1H); 6.82-6.63 (m) , 2H); 5.06 (d, J = 9.0Hz, 1H); 4.71-4.38 (m, 2H); 3.76-3.63 (m, 1H); 3.39 (s) , 1H); 3.15 (s, 3H); 2.37-2.27 (m, 1H); 1.32-1.24 (m, 6H). LCMS analysis calculated value of C ₂₁ H ₂₁ F ₂ N ₃ O ₅ : 433.1; measured value: 434.2 (M + 1) ⁺ .

Compound 76 was prepared from isomer D of compound Int-24h, essentially according to the method used to prepare compound 73 in step I of Example 24. ^{1 1} H NMR (400 MHz, CDCl ₃ ): δ11.62-11.34 (m, 2H); 7.48-7.39 (m, 1H); 7.37-7.24 (m, 1H); 6 .80-6.64 (m, 2H); 5.61 (d, J = 7.1Hz, 1H); 4.64-4.47 (m, 2H); 3.92 (d, J = 13. 0Hz, 1H); 3.22 (d, J = 13.0Hz, 1H); 3.16 (s, 3H); 2.88 (m, 1H); 1.40 (s, 3H); 1.02 (D, J = 7.3Hz, 3H). LCMS analysis calculated value of C ₂₁ H ₂₁ F ₂ N ₃ O ₅ : 433.1; measured value: 434.1 (M + 1) ⁺ .

Compound 77 was prepared from isomer E of compound Int-24h, essentially according to the method used to prepare compound 73 in step I of Example 24. ^{1 1} H NMR (400 MHz, CDCl ₃ ): δ11.34 (br, 1H); 7.34-7.23 (m, 1H); 7.08-6.91 (m, 1H); 6.83-6 .57 (m, 2H); 5.05 (d, J = 8.8Hz, 1H); 4.72-4.47 (m, 2H); 3.73 (d, J = 13.0Hz, 1H) 3.41 (d, J = 12.7Hz, 1H); 3.15 (s, 3H); 2.39-2.23 (m, 1H); 1.37-1.20 (m, 6H) .. LCMS analysis calculated value of C ₂₁ H ₂₁ F ₂ N ₃ O ₅ : 433.1; measured value: 434.2 (M + 1) ⁺ .

Compound 78 was prepared from the isomer F of compound Int-24h, essentially according to the method used to produce compound 73 in step I of Example 24. ^{1 1} H NMR (400 MHz, CDCl ₃ ): δ11.36 (br, 1H); 10.80 (br, 1H); 7.34-7.23 (m, 1H); 6.87-6.65 (m). , 2H); 5.38 (d, J = 6.6Hz, 1H); 4.90 (brs, 1H); 4.62-4.51 (m, 2H); 3.66 (d, J = 12) .5Hz, 1H); 3.40 (d, J = 12.7Hz,
1H); 3.14 (s, 3H); 2.37-2.24 (m, 1H); 1.46 (s, 3H); 1.21 (d, J = 7.1Hz, 3H). LCMS analysis calculated value of C ₂₁ H ₂₁ F ₂ N ₃ O ₅ : 433.1; measured value: 434.2 (M + 1) ⁺ .

Compound 79 was prepared from the isomer G of compound Int-24h, essentially according to the method used to prepare compound 73 in step I of Example 24. ^{1 1} H NMR (400 MHz, CDCl ₃ ): δ11.47 (br, 2H); 7.47-7.40 (m, 1H); 7.34-7.26 (m, 1H); 6.82-6 .67 (m, 2H); 5.61 (d, J = 6.8Hz, 1H); 4.66-4.48 (m, 2H); 3.92 (d, J = 13.0Hz, 1H) 3.22 (d, J = 12.7Hz, 1H); 3.16 (s, 3H); 2.92-2.84 (m, 1H); 1.40 (s, 3H); 1.03 (Brd, J = 3.4Hz, 3H). LCMS analysis calculated value of C ₂₁ H ₂₁ F ₂ N ₃ O ₅ : 433.1; measured value: 434.1 (M + 1) ⁺ .

Compound 80 was prepared from the isomer H of compound Int-24h, essentially according to the method used to produce compound 73 in step I of Example 24. ^{1 1} H NMR (400 MHz, CDCl ₃ ): δ11.35 (br, 1H); 10.79 (br, 1H); 7.39-7.26 (m, 1H); 6.86-6.65 (m) , 2H); 5.38 (d, J = 6.8Hz, 1H); 4.90 (brs, 1H); 4.64-4.44 (m, 2H); 3.67 (d, J = 12) .7Hz, 1H); 3.40 (d, J = 12.7Hz, 1H); 3.23-3.04 (m, 3H), 2.34-2.22 (m, 1H); 1.46 (S, 3H); 1.20 (d, J = 7.1Hz, 3H). LCMS analysis calculated value of C ₂₁ H ₂₁ F ₂ N ₃ O ₅ : 433.1; measured value: 434.2 (M + 1) ⁺ .

Evaluation of Antiviral Capability in Multi-Round HIV-1 Infection Assay The antiviral activity of the examples herein was evaluated in an assay that measures the rate of HIV replication in cell culture and was performed in the following manner. HIV-1 replication was monitored using MT4-gag-GFP clone D3 (hereinafter referred to as MT4-GFP), which is an MT-4 cell modified to carry the GFP reporter gene. Expression depends on the HIV-1-expressing proteins tat and rev. Proliferative infection of MT4-GFP cells with HIV-1 results in GFP expression approximately 24 hours after infection. _{Maintain MT4-GFP cells at 37 ° C / 5% CO 2} /90% relative humidity in RPMI 1640 supplemented with 10% bovine fetal serum, 100 U / mL penicillin / streptomycin and 400 μg / mL G418 to maintain the reporter gene. bottom. For infection, MT4-GFP cells were placed in the same medium lacking G418 and infected overnight with approximately 0.01 multiplicity of infection HIV-1 (H9 / IIIB strain) virus under the same incubation conditions. The cells were then washed and ^{resuspended in either 1.6 × 10 5} cells / mL (0% NHS condition) or 2 × 10 ⁵ cells / mL in 100% normal human serum (NHS). Compound plates were prepared by dispensing (0.2 μL / well) the compounds dissolved in DMSO into the wells of a 384-well polyD lysine coated plate using an ECHO ultrasonic dispenser. Each compound was tested at 10 consecutive 3-fold dilutions (typical final concentration: 1050 nM to 0.05 nM under 0% NHS conditions, or 42 μM to 2.13 nM under 100% NHS conditions). Controls included a combination of no inhibitors (DMSO only) and three antiviral agents (each final concentration of 4 μM, efavirenz, indinavir, and in-house integrase chain transfer inhibitor). Cells were added to compound plates (50 μL / well) and infected cells were _{maintained at 37 ° C./5% CO 2} /90% relative humidity.

Infected cells were quantified at two time points, about 48 hours and about 72 hours after infection, by counting the number of green cells in each well using an Acumen eX3 scanner. Reproduction rate R0 is obtained from the increase in the number of green cells over about 24 hours, which is typically 5 to 15 and has been experimentally shown to be in the logarithmic phase (data not shown). .). Inhibition of R0 was calculated for each well, IC ₅₀ values were determined by nonlinear 4-parameter curve fit. The results of the assay IC ₅₀ are shown in the table below.

Treatment or Prevention of HIV Infection Tricyclic heterocyclic compounds inhibit HIV, inhibit HIV integrase, treat HIV infection and / or reduce the likelihood or severity of HIV infection, and in cell-based systems. It may be useful in inhibiting HIV virus replication and / or HIV virus production. For example, the tricyclic heterocyclic compound is HIV when past exposure to HIV is suspected, such as by blood transfusion, fluid exchange, biting, accidental needle stick, or exposure to the target blood during surgery or other medical procedure. Can be useful in treating infections caused by HIV / AIDS.

Thus, in one embodiment, the invention comprises administering to a subject an effective amount of at least one tricyclic heterocyclic compound or a pharmaceutically acceptable salt or prodrug thereof for HIV infection in the subject. Provide a treatment method. In certain specific embodiments, the doses administered are effective in treating or preventing HIV infection in the subject. In another specific embodiment, the dose administered is effective in inhibiting HIV virus replication and / or virus production in the subject. In one embodiment, HIV infection has progressed to AIDS.

The tricyclic heterocyclic compound is also useful in the preparation and implementation of screening assays for antiviral compounds. For example, the tricyclic heterocyclic compound may be useful in identifying resistant HIV cell lines with mutations, which is an excellent screening tool for more potent antiviral compounds. Furthermore, the tricyclic heterocyclic compound is useful in establishing or determining the binding site of another antiviral agent to HIV integrase.

The compositions and combinations of the present invention may be useful in treating a subject suffering from an infection associated with any HIV genotype.

Combination Therapy In another embodiment, the invention for treating or preventing HIV infection can further comprise administration of an additional therapeutic agent that is not one or more tricyclic heterocyclic compounds.

In one embodiment, the additional therapeutic agent is an antiviral agent.

In another embodiment, the additional therapeutic agent is an immunomodulator, such as an immunosuppressant.

Thus, in one embodiment, the invention is subject to (i) at least one tricyclic heterocyclic compound (which may also include two or more different tricyclic heterocyclic compounds) or is pharmaceutically acceptable. These salts or prodrugs, and (ii) additional therapeutic agents other than at least one tricyclic heterocyclic compound, are administered in the same amounts and are effective in treating or preventing viral infections. It provides a method for treating viral infections in a subject.

When the combination therapy of the present invention is targeted, the therapeutic agent to be combined or the pharmaceutical composition or composition containing the therapeutic agent can be administered in any order such as sequential, simultaneous point, together, and simultaneous. The amounts of the various active agents in such combination therapies may be different amounts (different doses) or the same amount (same dose). Thus, for non-limiting exemplary purposes, the tricyclic heterocyclic compound and additional therapeutic agent can be present in a fixed amount (dose) in a single dose unit (eg, capsule, tablet, etc.). ..

In one embodiment, at least one tricyclic heterocyclic compound is administered, or vice versa, while the additional therapeutic agent exerts its prophylactic or therapeutic effect.

In another embodiment, the at least one tricyclic heterocyclic compound and the additional therapeutic agent are administered at the doses commonly used when such agents are used as monotherapy for the treatment of viral infections.

In another embodiment, the at least one tricyclic heterocyclic compound and the additional therapeutic agent are administered at a lower dose than commonly used when such agents are used as monotherapy for the treatment of viral infections. ..

In yet another embodiment, the at least one tricyclic heterocyclic compound and the additional therapeutic agent act synergistically from the doses commonly used when such agents are used as monotherapy in the treatment of viral infections. Administered at low doses.

In one embodiment, the at least one tricyclic heterocyclic compound and the additional therapeutic agent are present in the same composition. In one embodiment, the composition is suitable for oral administration. In another embodiment, the composition is suitable for intravenous administration. In another embodiment, the composition is suitable for subcutaneous administration. In yet another embodiment, the composition is suitable for parenteral administration.

Virus infections and virus-related disorders that can be treated or prevented using the combination therapy of the present invention include, but are not limited to, those listed above.

In one embodiment, the viral infection is an HIV infection.

In another embodiment, the viral infection is AIDS.

The at least one tricyclic heterocyclic compound and the additional therapeutic agent may act additively or synergistically. Synergistic combinations can lower the dose of one or more agents and / or reduce the number of doses of one or more agents in combination therapy. By reducing the dose or frequency of administration of one or more agents, the toxicity of the treatment can be reduced without reducing the efficacy of the treatment.

In one embodiment, administration of at least one tricyclic heterocyclic compound and the additional therapeutic agent can inhibit resistance to viral infection to these agents.

As mentioned above, the present invention also relates to the use of compounds of formula I with one or more anti-HIV agents. "Anti-HIV agents" are direct or indirect to the inhibition of HIV reverse transcription enzyme or another enzyme required for HIV replication or infection, the treatment or prevention of HIV infection, and / or the treatment, prevention or onset or delay of progression of AIDS. It is a drug that is effective against HIV / AIDS. It is clear that antiretroviral agents are effective in treating, preventing or delaying the onset or progression of HIV infection or AIDS and / or the diseases or symptoms that result from or are associated with it. For example, the compounds of the invention are selected from HIV antivirals, immunomodulators, anti-infectives or vaccines useful for the treatment of HIV infection or AIDS, pre-exposure and / or post-exposure. It can be effectively administered in combination with an effective amount of one or more anti-HIV agents. Suitable HIV antiviral agents used in combination with the compounds of the present invention include, for example, those listed in Table A below.

Table A

In one embodiment, one or more anti-HIV agents are selected from lamivudine, abacavir, ritonavir, darunavir, atazanavir, emtricitabine, tenofovir, rilpivirine and lopinavir.

In another embodiment, the compound of formula (I) is used in combination with lamivudine.

In yet another embodiment, the compound of formula (I) is used in combination with atazanavir.

In another embodiment, the compound of formula (I) is used in combination with darunavir.

In another embodiment, the compound of formula (I) is used in combination with rilpivirine.

In one embodiment, the compound of formula (I) is used in combination with lamivudine and abacavir.

In another embodiment, the compound of formula (I) is used in combination with darunavir.

In another embodiment, the compound of formula (I) is used in combination with emtricitabine and tenofovir.

In yet another embodiment, the compound of formula (I) is used in combination with atazanavir.

In another embodiment, the compound of formula (I) is used in combination with ritonavir and lopinavir.

In one embodiment, the compound of formula (I) is used in combination with abacavir and lamivudine.

In another embodiment, the compound of formula (I) is used in combination with lopinavir and ritonavir.

In one embodiment, the invention comprises (i) a compound of formula (I) or a pharmaceutically acceptable salt or prodrug thereof; (ii) a pharmaceutically acceptable carrier; and (iii) lamivudine, abacavir. A pharmaceutical composition comprising ritonavir and lopinavir or one or more additional anti-HIV agents selected from their pharmaceutically acceptable salts or prodrugs, wherein the abundance of ingredients (i) and (iii) is Together, they provide pharmaceutical compositions that are effective in treating or preventing HIV infection in subjects in need of treatment or in treating, preventing or delaying the onset or progression of AIDS.

In another embodiment, the invention is a method for the treatment or prevention of HIV infection in a subject in need of treatment or for the treatment, prevention or onset or delay of progression of AIDS. i) selected from compounds of formula (I) or pharmaceutically acceptable salts or prodrugs thereof, and (ii) lamivudine, abacavir, ritonavir and lopinavir or pharmaceutically acceptable salts or prodrugs thereof 1 Having administered the above additional anti-HIV agents, the doses of components (i) and (ii) together may be the treatment or prevention of HIV infection in subjects in need of treatment or AIDS. Provide effective methods for treatment, prevention or delay of onset or progression.

The range of combinations of the compounds of the present invention and anti-HIV agents is not limited to the HIV antiviral agents listed in Table A, and in principle any combination with any pharmaceutical composition useful for the treatment or prevention of AIDS. Is understood to include. HIV antivirals and other agents are typically used in these combinations according to the usual dose ranges and regimens reported in the art, eg, Physicians' Desk Reference , Thomason PDR, Thomason PDR, 57. The doses described in Editions (2003), 58th Editions (2004), 59th Editions (2005) and the like are included. In these combinations, the dose ranges of the compounds of the invention are the same as those described above.

The doses and methods of administration of other agents used in the concomitant therapies of the invention for the treatment or prevention of HIV infection are the doses and methods approved in the package insert by the attending physician; the subject's age, gender and method of administration. General health; as well as the type and severity of viral infections or related diseases or disorders may be considered. When administered in combination, the tricyclic heterocyclic compounds (classes) and other agents (classes) may be administered simultaneously (ie, in the same composition or in separate compositions immediately after one). On the other hand), it may be administered sequentially. This can be the case if the components of the concomitant drug are administered on different dosing schedules (eg, one component is administered once daily and another is administered every 6 hours), or the pharmaceutical composition is different (for example). For example, some ingredients are tablets and some ingredients are capsules), which is particularly useful. Therefore, a kit containing separate formulations is convenient.

When administered to the composition and subject, the tricyclic heterocyclic compound may be administered as a component of a composition comprising a pharmaceutically acceptable carrier or vehicle. The present invention provides a pharmaceutical composition comprising an effective amount of at least one tricyclic heterocyclic compound and a pharmaceutically acceptable carrier. In the pharmaceutical compositions and methods of the invention, the active ingredient is typically the intended dosage form, i.e. either an oral tablet, a capsule (solid-filled, semi-solid-filled or liquid-filled). ), Constructive powders, oral gels, elixirs, dispersible granules, syrups, suspensions, etc., and administered in admixture with carrier materials consistent with conventional pharmaceutical practices. NS. For example, for oral administration in the form of tablets or capsules, the active agent component is any non-toxic, pharmaceutically acceptable inert carrier for oral use, such as lactose, starch, sucrose, cellulose, stearate. It can be combined with magnesium, dicalcium phosphate, calcium sulfate, starch, mannitol, ethyl alcohol (in liquid form) and the like. The solid preparation includes powders, tablets, dispersible granules, capsules, cashiers and suppositories. Powders and tablets can make up about 0.5 to about 95 percent of the compositions of the invention. Tablets, powders, cachets and capsules can be used as solid formulations suitable for oral administration.

In addition, suitable binders, lubricants, disintegrants and colorants may be incorporated into the mixture if desired or required. Suitable binders include starch, gelatin, natural sugars, corn sweeteners, natural and synthetic rubbers such as acacia, sodium alginate, carboxymethyl cellulose, polyethylene glycol and wax. Among the lubricants, boric acid, sodium benzoate, sodium acetate, sodium chloride and the like can be mentioned for use in such a preparation. Disintegrants include starch, methylcellulose, guar gum and the like. Also, where appropriate, sweeteners and flavors as well as preservatives may be included.

Liquid formulations include liquids, suspensions and emulsions and may include water or water-propylene glycol solutions for parenteral injection.

The liquid preparation includes a liquid preparation for intranasal administration.

It also includes a solid formulation intended to be converted into a liquid formulation for either oral or parenteral administration immediately prior to use. Such liquid forms include liquids, suspensions and emulsions.

To prepare a suppository, first, a low melting point wax (such as a mixture of fatty acid glycerides or cocoa butter) is melted and the active ingredient is uniformly dispersed inside by stirring. The melted homogeneous mixture is then poured into a mold of convenient size and allowed to cool, thereby solidifying.

In addition, the compositions of the present invention may be formulated in sustained release form to result in a rate controlled release of any one or more ingredients or active ingredients to optimize therapeutic effects (ie, antiviral activity, etc.). Suitable formulations for sustained release include layers of various disintegration rates or controlled release polymer matrices impregnated with the active ingredient, and laminated tablets molded into tablet forms or capsules comprising such impregnated or encapsulated porous polymer matrices. including.

In one embodiment, the one or more tricyclic heterocyclic compounds are orally administered.

In another embodiment, the one or more tricyclic heterocyclic compounds are administered intravenously.

In one embodiment, the pharmaceutical preparation containing at least one tricyclic heterocyclic compound is a unit preparation. In such a form, the pharmaceutical product is subdivided into unit doses containing an effective amount of the active ingredient.

The compositions can be prepared according to each of the conventional mixing, granulation or coating methods, and the compositions of the present invention, in one embodiment, are about 0.1% to about 99% by weight or volume. It may contain a tricyclic heterocyclic compound (class). In various embodiments, the compositions of the invention comprise, in one embodiment, about 1% to about 70% or about 5% to about 60% tricyclic heterocyclic compounds (s) on a weight or volume basis. It can be a thing.

The compounds of formula I can be administered orally in a single dose or divided dose range of 0.001 to 1000 mg / kg body weight of a mammal (eg, human) per day. One dose range is 0.01-500 mg / kg body weight orally per day in single or divided doses. Another dose range is 0.1 to 100 mg / kg body weight orally per day in single or divided doses. For oral administration, the composition comprises 1.0-500 milligrams of active ingredient, particularly active ingredients 1, 5, 10, 15, 20, 25, 50 to adjust the dose according to the condition of the subject to be treated. , 75, 100, 150, 200, 250, 300, 400, and 500 milligrams can be provided in the form of tablets or capsules. Specific dose levels and frequency of administration for a particular subject may vary, including the activity of the particular compound used, the metabolic stability and duration of action of the compound, age, weight, general health, gender, diet, It depends on a variety of factors, including mode and time of administration, rate of excretion, concomitant medications, specific severity of symptoms, and host to be treated.

For convenience, if desired, the total daily dose may be divided and administered in divided doses within a day. In one embodiment, the daily dose is administered in a single dose. In another embodiment, the total daily dose is administered in two divided doses over a 24-hour period. In another embodiment, the total daily dose is administered in 3 divided doses over a 24-hour period. In yet another embodiment, the total daily dose is administered in 4 divided doses over a 24-hour period.

The unit dose of the tricyclic heterocyclic compound can be administered at various times. In one embodiment, a unit dose of the tricyclic heterocyclic compound can be administered once daily. In another embodiment, a unit dose of the tricyclic heterocyclic compound can be administered twice a week. In another embodiment, a unit dose of the tricyclic heterocyclic compound can be administered once a week. In yet another embodiment, a unit dose of the tricyclic heterocyclic compound can be administered once every two weeks. In another embodiment, a unit dose of the tricyclic heterocyclic compound can be administered once a month. In yet another embodiment, a unit dose of the tricyclic heterocyclic compound can be administered once every two months. In another embodiment, a unit dose of the tricyclic heterocyclic compound can be administered once every three months. In yet another embodiment, a unit dose of the tricyclic heterocyclic compound can be administered once every 6 months. In another embodiment, a unit dose of the tricyclic heterocyclic compound can be administered annually.

The amount and frequency of administration of the tricyclic heterocyclic compound will be adjusted according to the discretion of the attending physician, taking into account factors such as the subject's age, physical condition and physique, and the severity of the symptoms being treated. The compositions of the present invention may further comprise one or more additional therapeutic agents selected from those described above herein.

In one aspect of the kit, the invention comprises a therapeutically effective amount of at least one tricyclic heterocyclic compound or a pharmaceutically acceptable salt or prodrug of said compound and a pharmaceutically acceptable carrier, vehicle or dilution. A kit containing the agent is provided.

In another aspect, the invention comprises an amount of at least one tricyclic heterocyclic compound or a pharmaceutically acceptable salt or prodrug of said compound and an amount of at least one additional therapeutic agent described above. In a kit containing, the amount of the two or more active ingredients provides the desired therapeutic effect. In one embodiment, one or more tricyclic heterocyclic compounds and one or more additional therapeutic agents are provided in the same container. In one embodiment, one or more tricyclic heterocyclic compounds and one or more additional therapeutic agents are provided in separate containers.

The present invention is not limited by the specific embodiments disclosed in the examples of some embodiments of the present invention, and any functionally equivalent embodiment is included in the scope of the present invention. Will be done. In fact, various modifications of the invention other than those shown or described herein will be apparent to those skilled in the art and are included in the appended claims.

Although many references are cited herein, all of these disclosures are incorporated herein by reference.

Claims (16)

A compound of the formula below or a pharmaceutically acceptable salt thereof.

[During the ceremony,
Each appearance of R ¹ is independently halo, hydroxyl, C _1-6 alkyl and -O- (C _1- C ₆ alkyl);
R ² is hydrogen, methyl or ethyl;
R ³ is hydrogen, methyl or ethyl;
R ⁴ is C _1-6 alkyl or (C _1-6 alkyl) OR ⁷ ;
R ⁵ is hydrogen, C _1-6 alkyl or (C _1-6 alkyl) OR ⁷ ;
R ⁶ is hydrogen, C _1-6 alkyl or (C _1-6 alkyl) OR ⁷ ;
R ⁷ _{is a C 1-6} alkyl optionally substituted with hydrogen or 1-3 halos;
n is an integer of 1-3. ] The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein each R ^{1 is halo.} R ² is hydrogen or methyl, the compound or a pharmaceutically acceptable salt thereof according to claim 1 or 2. The compound according to any one of claims 1 to 3, wherein R ^{3 is hydrogen or methyl, or a pharmaceutically acceptable salt thereof.} The compound according to any one of claims 1 to 4, wherein R ⁴ is methyl, ethyl, CH ₂ OCH ₃ , CH ₂ CH ₂ OCH ₃ , CH ₂ CH ₂ OCHF _{2, or a pharmaceutically acceptable compound thereof.} salt. The compound according to any one of claims 1 to 5, wherein R ^{4 is methyl or ethyl, or a pharmaceutically acceptable salt thereof.} The compound according to any one of claims 1 to 6, wherein R ^{5 is hydrogen or methyl, or a pharmaceutically acceptable salt thereof.} The compound according to any one of claims 1 to 7, wherein R ^{6 is methyl or ethyl, or a pharmaceutically acceptable salt thereof.} The compound according to claim 1 or a pharmaceutically acceptable salt thereof selected from the following.

A pharmaceutical composition comprising an effective amount of the compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. Inhibition of HIV integrase in a subject in need of treatment, comprising administering to the subject an effective amount of the compound according to any one of claims 1-9 or a pharmaceutically acceptable salt thereof. Method. Treatment of HIV infection in a subject in need of treatment, comprising administering to the subject an effective amount of the compound according to any one of claims 1-9 or a pharmaceutically acceptable salt thereof. Or a method of treating AIDS. The pharmaceutical composition according to claim 10, further comprising one or more additional therapeutic agents selected from raltegravir, lamivudine, abacavir, ritonavir, dolutegravir, arunavir, atazanavir, emtricitabine, tenofovir, elvitegravir, rilpivirine and lopinavir. .. Subject further includes and claims to administer one or more additional therapeutic agents selected from raltegravir, lamivudine, abacavir, ritonavir, dolutegravir, arunavir, atazanavir, emtricitabine, tenofovir, elvitegravir, lylpivirin and lopinavir. The dose of the compound according to any one of Items 1 to 9 and the dose of one or more additional therapeutic agents are combined to treat HIV infection or treat, prevent or develop AIDS. The method of claim 12, which is effective in delaying the progress. Claims 1 to for use in the manufacture of a medicament for the inhibition of HIV integrase, the treatment or prevention of HIV infection, or the treatment, prevention or delay of onset or progression of AIDS in subjects in need of treatment. 9. The compound according to any one of paragraphs 9 or a pharmaceutically acceptable salt thereof. The compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof, which is used in a therapeutic method.