Inducers of KLF2 and methods of using same

Abstract

The present disclosure provides compounds that are inducers of KLF2 and pharmaceutical compositions comprising the same. The present disclosure further provides a method for treating inflammatory disease or endothelial dysfunction, comprising administering a therapeutically effective amount of a compound disclosed herein.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to U.S. Provisional Application No. 63 / 307,416, filed February 7, 2022, the contents of which are hereby incorporated by reference in their entirety.

[0002] Statement of Government Support This invention was made with United States Government support under Grant No. R44HL118826 awarded by the National Institutes of Health National Heart, Lung and Blood Institute. [Background technology]

[0003] The vascular endothelium is a key regulator of vascular integrity and vascular homeostasis. It is a dynamic interface that regulates vasotone, inflammation, hemostasis and vascular remodeling. Endothelial dysfunction, including vasoconstriction, impaired vasoreactivity, inflammation, thrombosis, altered barrier permeability and loss of vascular quiescence, is a critical promoter of many vascular diseases. Thus, the vascular endothelium is important for maintaining vascular and cardiovascular health.

[0004] Kruppel-like factor 2 (KLF2) is a shear stress-inducible transcription factor that may confer anti-inflammatory and / or anti-thrombotic properties to vascular endothelial cells. In endothelial cells, KLF2 may participate in transcriptional processes to regulate inflammation, thrombotic hemostasis, vascular tone, and vascular development. KLF2 is a crucial regulator of activation, differentiation, and migration processes in various immune cell types, including monocytes, macrophages, neutrophils, T lymphocytes, B lymphocytes, and natural killer cells.

[0005] Thus, compounds that induce KLF2 may be useful for maintaining vascular health or for treating vascular or inflammatory conditions. Summary of the Invention [Problem to be solved by the invention]

[0006] [Means for solving the problem]

[0007] In some embodiments, the present invention provides a compound represented by formula I

[0008] [ka] [In the formula, R 1 represents lower alkyl, X is CR 2a or N, R 2a , R 2b , R 2c , and R 2d each independently represents hydrogen, alkyl, alkenyl, alkynyl, halo, aryl, heteroaryl, cycloalkyl, heterocyclyl, cyano, acyl, carboxy, ester, or amido; R 3 represents alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, arylalkyl, heteroaralkyl, (cycloalkyl)alkyl, heterocyclylalkyl, amidoalkyl, alkoxyalkyl, or acylalkyl; Z represents a substituted or unsubstituted aryl or heteroaryl ring, optionally substituted with one or more groups selected from, for example, alkyl, alkenyl, alkynyl, cyano, acyl, carboxy, ester, amide, alkoxy, and halo, or a pharma- ceutically acceptable salt thereof.

[0009] In certain embodiments, the invention is a method for treating an inflammatory disease or endothelial dysfunction comprising administering a therapeutically effective amount of a compound or composition described herein.

[0010] In certain embodiments, the present invention provides a pharmaceutical composition for treating inflammatory diseases or endothelial dysfunction, comprising an effective amount of any of the compounds described herein (e.g., a compound of the present invention, e.g., a compound of Formula (I) or a pharma- ceutical acceptable salt thereof).

[0011] In certain embodiments, the pharmaceutical preparation may be for use in the treatment or prevention of a condition or disease described herein.

[0012] In certain embodiments, the compound of formula (I) is

[0013] [ka]

[0014] [ka]

[0015] [ka]

[0016] [ka]

[0017] [ka]

[0018] [ka]

[0019] [ka]

[0020] [ka]

[0021] [ka]

[0022] [ka]

[0023] [ka]

[0024] [ka] or a pharma- ceutically acceptable salt thereof. [Brief description of the drawings]

[0025] [Figure 1] FIG. 2 is an ellipsoidal representation of the molecular conformation of an exemplary compound of the present invention. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0026] In some embodiments, the present invention provides a compound of formula I

[0027] [ka] [In the formula, R 1 represents lower alkyl, X is CR 2a or N, R 2a , R 2b , R 2c , and R 2deach independently represents hydrogen, alkyl, alkenyl, alkynyl, halo, aryl, heteroaryl, cycloalkyl, heterocyclyl, cyano, acyl, carboxy, ester, or amido; R 3 represents alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, arylalkyl, heteroaralkyl, (cycloalkyl)alkyl, heterocyclylalkyl, amidoalkyl, alkoxyalkyl, or acylalkyl; Z represents a substituted or unsubstituted aryl or heteroaryl ring, optionally substituted with one or more groups selected from, for example, alkyl, alkenyl, alkynyl, cyano, acyl, carboxy, ester, amide, alkoxy, and halo, or a pharma- ceutically acceptable salt thereof.

[0028] In certain embodiments, R 1 is methyl.

[0029] In certain embodiments, X is N. In other embodiments, X is CR 2a It is.

[0030] In certain embodiments, R 2a , R 2b , R 2c , and R 2d are independently hydrogen, methyl, propenyl, chloro, fluoro, haloalkyl (e.g., trifluoromethyl), 5-membered heteroaryl, cyclopropyl, or the structure

[0031] [ka] represents an amide having the formula:

[0032] In certain such embodiments, R a is hydrogen or alkyl, R b and R ctaken together form a cycloalkyl or heterocyclyl, e.g., cyclobutyl. In certain embodiments, R a is hydrogen or methyl, preferably methyl. In certain embodiments, R b and R c together form an oxetane.

[0033] In certain embodiments, R 2a , R 2b , R 2c , and R 2d At least one of is a 5-membered heteroaryl, such as thiazolyl or oxazolyl, optionally substituted with trifluoromethyl, chloro, or cyano. In certain such embodiments, the 5-membered heteroaryl is oxazol-2-yl, such as 4-cyanooxazol-2-yl.

[0034] In certain embodiments, R 2a is hydrogen.

[0035] In certain embodiments, R 2b and R 2d are hydrogen.

[0036] In certain embodiments, R 2c and R 2d are hydrogen.

[0037] In certain embodiments, R 2b , R 2c , and R 2d are hydrogen.

[0038] In certain preferred embodiments, X is CR 2a If R 2a , R 2b , R 2c , and R 2d At least one of is not hydrogen, and thus the benzofuran ring has at least one non-hydrogen substitution. For example, in certain embodiments, when X is CH, preferably R2b , R 2c , and R 2d In certain of these preferred embodiments, one of R 2c is non-hydrogen substituted, preferably an optionally substituted 5-membered heteroaryl, such as oxazolyl.

[0039] In certain embodiments, X is CR 2a If so, then R 2a , R 2b , R 2c , and R 2d are hydrogen.

[0040] In certain preferred embodiments, R 3 is an amidoalkyl, e.g., of the structure

[0041] [ka] [In the formula, R d and R e are independently selected from alkyl or hydroxyalkyl, preferably alkyl (e.g., methyl), or R d and R e and taken together form a heterocyclic ring. In certain such embodiments, R d and R e Each is methyl. In certain embodiments, R d and R e is independently enriched with deuterium at one or more hydrogen-carrying sites. For example, R d and / or R e can contain non-natural abundance deuterium, preferably at least 15%, at least 25%, at least 50%, at least 60%, at least 75%, or at least 80% of the hydrogen positions are deuterium. d is methyl, R e is -(CH2)2OH.

[0042] In certain embodiments, R d and R e taken together with the nitrogen to which they are attached, represent an azetidine which may be substituted with one or more halo, hydroxyl, or hydroxyalkyl, e.g.

[0043] [ka] Form.

[0044] In certain embodiments, R 3 is C3-C6 cycloalkyl, for example,

[0045] [ka] It is.

[0046] In certain embodiments, R 3 is C1-C6 alkyl (including, for example, C1-C2 alkyl or C3-C6 alkyl), C2-C6 alkenyl, or C2-C6 alkynyl, which may be substituted with alkoxy, for example:

[0047] [ka] It is.

[0048] In certain embodiments, R 3 is -CH2-cycloalkyl optionally substituted with halo, alkoxy, or hydroxyl, e.g.

[0049] [ka] It is.

[0050] In certain embodiments, R 3 The structure

[0051] [ka] [In the formula, R f represents alkyl or cycloalkyl, for example ethyl or cyclopropyl.

[0052] In certain embodiments, R 3 may be substituted with alkyl, hydroxyalkyl or alkoxyalkoxyalkyl -(CH2) 1~3 In certain embodiments, R represents a heteroaryl. In certain embodiments, the heteroaryl is tetrazole, 1,2,3-triazole, or 1,2,4-triazole. 3 teeth,

[0053] [ka] It is.

[0054] In certain embodiments, Z is phenyl, pyridinyl, naphthyl, isoquinolinyl, or quinolinyl, preferably pyridyl, each of which may be substituted with one or more groups selected from lower alkyl, lower alkoxy, halo, haloalkoxy, amido, and cyano. In certain embodiments, Z is substituted with one or more groups, or for example at least two groups, selected from methoxy, isopropyloxy, chloro, fluoro, trifluoromethoxy, cyano, and carbamoyl. In certain embodiments, Z is phenyl substituted with methoxy and at least one further substituent. In certain preferred embodiments, Z is pyridyl, which may be substituted with alkoxy (e.g., methoxy). In certain embodiments, Z is mono-, di-, or tri-substituted. In certain embodiments, Z is

[0055] [ka] It is.

[0056] In certain embodiments, the compound of formula (I) is

[0057] [ka] isn't it.

[0058] definition Unless otherwise defined herein, scientific and technical terms used in this application shall have the meanings commonly understood by those of ordinary skill in the art. In general, the nomenclature used in connection with and techniques of chemistry, cell and tissue culture, molecular biology, cell and cancer biology, virology, immunology, microbiology, pharmacology, genetics, and protein and nucleic acid chemistry described herein are those well known and commonly used in the art.

[0059] The methods and techniques of the present disclosure are generally carried out according to conventional methods well known in the art, unless otherwise specified, as described in various general and more specific references cited and discussed throughout this specification.See, for example, Motulsky, "Intuitive Biostatistics", Oxford University Press, Inc. (1995); Lodish et al., "Molecular Cell Biology, 4th ed.", WH Freeman & Co., New York (2000); Griffiths et al., "Introduction to Genetic Analysis, 7th ed.", WH Freeman & Co., NY (1999); and Gilbert et al., "Developmental Biology, 6th ed.", Sinauer Associates, Inc., Sunderland, MA (2000).

[0060] Chemical terms used herein, unless otherwise defined herein, are used according to conventional usage in the art as exemplified in "The McGraw-Hill Dictionary of Chemical Terms", Parker S., Ed., McGraw-Hill, San Francisco, Calif. (1985).

[0061] All of the above and any other publications, patents, and published patent applications mentioned in this application are specifically incorporated herein by reference. In case of conflict, the present specification, including its specific definitions, will control.

[0062] The term "agent" is used herein to denote a chemical compound (e.g., an organic or inorganic compound, a mixture of chemical compounds), a biological macromolecule (e.g., a nucleic acid, an antibody (including portions thereof and humanized, chimeric and human antibodies, and monoclonal antibodies), a protein or portions thereof, such as peptides, lipids, carbohydrates), or an extract made from biological material, such as a bacterial, plant, fungus or animal (particularly mammalian) cell or tissue. Agents include, for example, agents of known structure and agents of unknown structure. The ability of such agents to induce KLF2 and / or vascular protection may make these agents suitable as "therapeutic agents" in the methods and compositions of the present disclosure.

[0063] "Patient," "subject," or "individual" are used interchangeably and refer to either a human or non-human animal. These terms include mammals, such as humans, primates, livestock animals (including cows, pigs, etc.), pets (e.g., dogs, cats, etc.), and rodents (e.g., mice and rats).

[0064] "Treating" a condition or patient refers to taking measures to obtain beneficial or desired results, including clinical results. As used herein, and as is well understood in the art, "treatment" is an approach to obtain beneficial or desired results, including clinical results. Beneficial or desired clinical results may include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions, whether detectable or undetectable, reduction in the extent of disease, stabilization (i.e., not worsening) of a disease state, prevention of disease spread, delay or slowing of disease progression, improvement or alleviation of disease symptoms, and remission (whether partial or complete). "Treatment" can also mean prolonging survival compared to expected survival in the absence of treatment.

[0065] The term "preventing" is art-recognized and, when used in reference to conditions such as local recurrence (e.g., pain), diseases such as cancer, complex syndromes such as heart failure, or any other medical condition, is well understood in the art and includes administration of a composition that reduces the frequency or delays the onset of symptoms of the medical condition in a subject compared to subjects not receiving the composition. Thus, preventing cancer includes, for example, reducing the number of detectable cancer growths in a patient population receiving a prophylactic treatment compared to an untreated control population, e.g., by a statistically and / or clinically significant amount, and / or delaying the appearance of detectable cancer growths in a treated population compared to an untreated control population, e.g., by a statistically and / or clinically significant amount.

[0066] "Administering" or "administration" of a substance, compound or agent to a subject can be performed using one of a variety of methods known to those skilled in the art. For example, the compound or agent can be administered intravenously, intraarterially, intradermally, intramuscularly, intraperitoneally, subcutaneously, intraocularly, sublingually, orally (by ingestion), intranasally (by inhalation), intraspinally, intracerebrally, and transdermally (e.g., by absorption through skin channels). The compound or agent can also be suitably introduced by rechargeable or biodegradable polymeric or other devices, such as patches and pumps, or formulations that provide sustained, delayed or controlled release of the compound or agent. Administering can also be performed, for example, once, multiple times, and / or over one or more extended periods of time.

[0067] Also, the suitable method of administering a substance, compound or agent to a subject depends on, for example, the age and / or physical condition of the subject, and the chemical and biological properties (e.g., solubility, digestibility, bioavailability, stability and toxicity) of the compound or agent.In some embodiments, the compound or agent is orally administered to the subject, for example, by ingestion.In some embodiments, the orally administered compound or agent is an extended release or sustained release formulation, or is administered using a device for such extended release or sustained release.

[0068] As used herein, the phrase "co-administration" refers to any form of administration of two or more different therapeutic agents, such that the second agent is administered while the previously administered therapeutic agent is still effective in the body (e.g., the two agents are effective in the patient at the same time, thereby involving a synergistic effect of the two agents). For example, the different therapeutic compounds can be administered simultaneously or sequentially, either in the same formulation or in separate formulations. Thus, an individual undergoing such treatment can benefit from the combined effects of the different therapeutic agents.

[0069] A "therapeutically effective amount" or "therapeutically effective dose" of a drug or agent is the amount of the drug or agent that exerts the intended therapeutic effect when administered to a subject. The full therapeutic effect does not necessarily occur by administration of one dose, but may occur only after administration of a series of doses. Thus, a therapeutically effective amount can be administered in one or multiple doses. The exact effective amount required for a subject depends, for example, on the size, health and age of the subject, and the nature and extent of the condition to be treated, such as cancer or MDS. Those skilled in the art can easily determine the effective amount for a given situation by routine experimental methods.

[0070] The present disclosure further includes isotopically labeled compounds of the present disclosure. An "isotopically" or "radiolabeled" compound is a compound of the present disclosure in which one or more atoms have been replaced or substituted by an atom having an atomic mass or mass number different from that typically found in nature (i.e., occurring in nature). Suitable radionuclides that can be incorporated into the compounds of the present disclosure include: 2 H (also written as D for deuterium), 3 H (also written as T for tritium), 11 C. 13 C. 14 C. 13 N, 15 N, 15 O. 17 O. 18 O. 18 F, 35 S, 36 Cl, 82 Br, 75 Br, 76 Br, 77 Br, 123 I, 124 I, 125 I and 131 For example, one or more protium (I) in the compounds of the present disclosure may be used. 1 H) atoms may be replaced by deuterium atoms (e.g., C 1~6 One or more hydrogen atoms of the alkyl group may be enriched with deuterium atoms, e.g., the more naturally abundant -C(1 H) -CD3 may be enriched in place of the 3 methyl group).

[0071] In certain embodiments of the compounds disclosed herein, certain atoms may be isotopically enriched (e.g., by isotopically enriching deuterium in hydrogen substituents), for example, for radiolabeling or for metabolically beneficial isotope effects. In such embodiments, the compounds may be isotopically enriched in a desired isotope such that at least 15%, at least 25%, at least 50%, at least 60%, at least 75%, at least 80%, or even more than at least 90% of the molecules of the compound in the composition have the desired isotope at the indicated position.

[0072] In some embodiments, the compound is enriched with 2 or more deuterium atoms. In some embodiments, the compound comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 deuterium atoms. In some embodiments, all of the hydrogen atoms in the compound may be enriched with deuterium atoms instead of protium atoms.

[0073] Synthetic methods for incorporating isotopes into organic compounds are known in the art (Deuterium Labeling in Organic Chemistry by Alan F. Thomas (New York, NY, Appleton-Century-Crofts, 1971; The Renaissance of H / D Exchange by Jens Atzrodt, Volker Derdau, Thorsten Fey and Jochen Zimmermann, Angew. Chem. Int. Ed. 2007, 7744-7765; The Organic Chemistry of Isotopic Labelling by James R. Hanson, Royal Society of Chemistry, 2011). Isotopically labeled compounds can be used in a variety of studies, such as NMR spectroscopy, metabolic experiments, and / or assays.

[0074] Substitution with heavier isotopes, e.g., deuterium for protium, can provide certain therapeutic advantages resulting from higher metabolic stability, e.g., increased in vivo half-life or reduced dosage requirements, and thus may be preferred in some circumstances (see, e.g., A. Kerekes et al., J. Med. Chem. 2011, 54, 201-210; R. Xu et al., J. Label Compd. Radiopharm. 2015, 58, 308-312).

[0075] As used herein, the term "optionally" or "may" means that the subsequently described event or circumstance may or may not occur, and that the description includes cases where the event or circumstance occurs and cases where it does not occur. For example, "optionally substituted alkyl" refers to cases where the alkyl is optionally substituted and cases where the alkyl is not substituted.

[0076] It is understood that the substituents and substitution patterns of the compounds of the present invention can be selected by one skilled in the art to result in chemically stable compounds that can be readily synthesized from readily available starting materials by techniques known in the art and the methods described below. When a substituent is itself substituted with more than one group, it is understood that these multiple groups can be on the same carbon or on different carbons, so long as a stable structure results.

[0077] As used herein, the term "optionally substituted" refers to one to six hydrogen radicals in a given structure being replaced with the radical of a particular substituent, including, but not limited to, hydroxyl, hydroxyalkyl, alkoxy, halogen, alkyl, nitro, silyl, acyl, acyloxy, aryl, heteroaryl, cycloalkyl, heterocyclyl, amino, aminoalkyl, cyano, haloalkyl, haloalkoxy, -OCO-CH2-O-alkyl, -OP(O)(O-alkyl)2, or -CH2-OP(O)(O-alkyl). Preferably, "optionally substituted" refers to one to four hydrogen radicals in a given structure being replaced with the above-mentioned substituents. More preferably, one to three hydrogen radicals are replaced by the aforementioned substituents. It is understood that the substituents may be further substituted.

[0078] As used herein, the term "alkyl" refers to any alkyl group having a C1-C 10 Straight chain alkyl group or C1-C 10It refers to saturated aliphatic groups including but not limited to branched alkyl groups. Preferably, the "alkyl" group refers to a C1-C6 straight chain alkyl group or a C1-C6 branched chain alkyl group. Most preferably, the "alkyl" group refers to a C1-C4 straight chain alkyl group or a C1-C4 branched chain alkyl group. Examples of "alkyl" include, but are not limited to, methyl, ethyl, 1-propyl, 2-propyl, n-butyl, sec-butyl, tert-butyl, 1-pentyl, 2-pentyl, 3-pentyl, neo-pentyl, 1-hexyl, 2-hexyl, 3-hexyl, 1-heptyl, 2-heptyl, 3-heptyl, 4-heptyl, 1-octyl, 2-octyl, 3-octyl, or 4-octyl. Furthermore, the term "alkyl," as used throughout the specification, examples, and claims, is intended to include both unsubstituted and substituted alkyl groups, which refer to alkyl moieties having substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone, including haloalkyl groups, such as trifluoromethyl and 2,2,2-trifluoroethyl.

[0079] The term "acyl" is art-recognized and refers to a group represented by the general formula hydrocarbylC(O)-, preferably alkylC(O)-.

[0080] The term "acylamino" is art-recognized and refers to an amino group substituted with an acyl group and may be represented, for example, by the formula hydrocarbylC(O)NH-.

[0081] The term "acyloxy" is art-recognized and refers to a group represented by the general formula hydrocarbylC(O)O-, preferably alkylC(O)O-.

[0082] The term "alkoxy" refers to an alkyl group having an oxygen attached thereto. Representative alkoxy groups include methoxy, ethoxy, propoxy, tert-butoxy, and the like.

[0083] The term "alkoxyalkyl" refers to an alkyl group substituted with an alkoxy group and may be represented by the general formula alkyl-O-alkyl.

[0084] "C x~y " or "C x~ C y The term " when used with a chemical moiety, such as acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy, is meant to include groups containing x to y carbons in the chain. CO alkyl indicates hydrogen if the group is in a terminal position, and a bond if internal. 1~6 An alkyl group contains, for example, 1 to 6 carbon atoms in the chain.

[0085] The term "alkylamino," as used herein, refers to an amino group substituted with at least one alkyl group.

[0086] The term "alkylthio," as used herein, refers to a thiol group substituted with an alkyl group and may be represented by the general formula alkylS-.

[0087] The term "amide" as used herein means

[0088] [ka] R 9 , R 10 , and R 11 , each independently represent hydrogen or a hydrocarbyl group, or R 9 and R 10 together with the N atom to which they are attached complete a heterocycle having 4 to 8 atoms in the ring structure, or R 10 and R 11 together with the N atom to which they are attached complete a heterocycle having 4 to 8 atoms in the ring structure.

[0089] The term "amidino" as used herein means

[0090] [ka] R 9 , R 10 , and R 11 , each independently represent hydrogen or a hydrocarbyl group, or R 9 and R 10 together with the N atom to which they are attached complete a heterocycle having 4 to 8 atoms in the ring structure, or R 10 and R 11 together with the N atom to which they are attached complete a heterocycle having 4 to 8 atoms in the ring structure.

[0091] The term "amide" as used herein means

[0092] [ka] R 10 represents hydrogen or a hydrocarbyl group.

[0093] The terms "amine" and "amino" are art-recognized and refer to both unsubstituted and substituted amines and their salts, e.g.,

[0094] [ka] wherein R 9 , R 10 , and R 10 Each ' independently represents a hydrogen or a hydrocarbyl group, or R 9 and R 10 together with the N atom to which they are attached complete a heterocycle having 4 to 8 atoms in the ring structure.

[0095] The term "aminoalkyl," as used herein, refers to an alkyl group substituted with an amino group.

[0096] The term "amidoalkyl," as used herein, refers to an alkyl group substituted with an amide group.

[0097] The term "aralkyl," as used herein, refers to an alkyl group substituted with an aryl group.

[0098] The term "aryl" as used herein includes substituted or unsubstituted monocyclic aromatic groups in which each atom of the ring is carbon. Preferably the ring is a 5-7 membered ring, more preferably a 6 membered ring. The term "aryl" also includes polycyclic ring systems having two or more cyclic rings, in which two or more carbons are common to two adjacent rings, at least one of the rings is aromatic, and the other cyclic rings can be, for example, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclyl. Aryl groups include benzene, naphthalene, phenanthrene, phenol, aniline, and the like.

[0099] The term "azido" is art-recognized and refers to the group --N.

[0100] The term "carbamate" is art-recognized and

[0101] [ka] R 9 and R 10 independently represent hydrogen or a hydrocarbyl group.

[0102] The term "carbocyclylalkyl," as used herein, refers to an alkyl group substituted with a carbocycle group.

[0103] The term "carbocycle" includes 5-7 membered monocyclic and 8-12 membered bicyclic rings. Each ring of a bicyclic carbocycle may be selected from saturated, unsaturated and aromatic rings. Carbocycles include bicyclic molecules in which one, two or three or more atoms are shared between the two rings. The term "fused carbocycle" refers to a bicyclic carbocycle in which each of the rings shares two adjacent atoms with the other ring. Each ring of a fused carbocycle may be selected from saturated, unsaturated and aromatic rings. In an exemplary embodiment, an aromatic ring, e.g., phenyl, may be fused to a saturated or unsaturated ring, e.g., cyclohexane, cyclopentane, or cyclohexene. Any combination of saturated, unsaturated and aromatic bicyclic rings, as valences permit, is included in the definition of carbocycle. Exemplary "carbocycles" include cyclopentane, cyclohexane, bicyclo[2.2.1]heptane, 1,5-cyclooctadiene, 1,2,3,4-tetrahydronaphthalene, bicyclo[4.2.0]oct-3-ene, naphthalene, and adamantane. Exemplary fused carbocycles include decalin, naphthalene, 1,2,3,4-tetrahydronaphthalene, bicyclo[4.2.0]octane, 4,5,6,7-tetrahydro-1H-indene, and bicyclo[4.1.0]hept-3-ene. A "carbocycle" may be substituted at any one or more positions capable of carrying a hydrogen atom.

[0104] The term "carbocyclylalkyl," as used herein, refers to an alkyl group substituted with a carbocycle group.

[0105] The term "carbonate" is art-recognized and refers to an --OCO.sub.2-- group.

[0106] The term "carboxy," as used herein, refers to a group represented by the formula -CO2H.

[0107] A "cycloalkyl" group is a cyclic hydrocarbon that is fully saturated. "Cycloalkyl" includes monocyclic and bicyclic rings. Typically, a monocyclic cycloalkyl group has 3 to about 10 carbon atoms, more typically 3 to 8 carbon atoms, unless otherwise defined. The second ring of a bicyclic cycloalkyl may be selected from saturated, unsaturated, and aromatic rings. Cycloalkyl includes bicyclic molecules in which one, two, or three or more atoms are shared between the two rings. The term "fused cycloalkyl" refers to a bicyclic cycloalkyl in which each of the rings shares two adjacent atoms with the other ring. The second ring of a fused bicyclic cycloalkyl may be selected from saturated, unsaturated, and aromatic rings. A "(cycloalkyl)alkyl" group is a cycloalkyl bonded to an alkyl group.

[0108] The term "ester" as used herein means an ester group consisting of -C(O)OR 9 R refers to the 9 represents a hydrocarbyl group.

[0109] The term "ether" as used herein refers to a hydrocarbyl group linked to another hydrocarbyl group through an oxygen. Thus, the ether substituent of a hydrocarbyl group can be hydrocarbyl-O-. Ethers can be either symmetrical or asymmetrical. Examples of ethers include, but are not limited to, heterocycle-O-heterocycle and aryl-O-heterocycle. Ethers include "alkoxyalkyl" groups, which can be represented by the general formula alkyl-O-alkyl.

[0110] The terms "halo" and "halogen" as used herein mean halogen and include chloro, fluoro, bromo, and iodo.

[0111] The term "haloalkyl," as used herein, refers to an alkyl group in which one or more hydrogens have been replaced with a halogen.

[0112] The term "haloalkoxy," as used herein, refers to an alkoxy group in which one or more hydrogen atoms have been replaced with halogen atoms.

[0113] The terms "hetaralkyl" and "heteroaralkyl," as used herein, refer to an alkyl group substituted with a hetaryl group.

[0114] The terms "heteroaryl" and "hetaryl" include substituted or unsubstituted aromatic monocyclic structures, preferably 5-7 membered rings, more preferably 5-6 membered rings, in which the ring structure contains at least one heteroatom, preferably 1-4 heteroatoms, more preferably 1 or 2 heteroatoms. The terms "heteroaryl" and "hetaryl" also include polycyclic ring systems having two or more cyclic rings, in which two or more carbons are common to two adjacent rings, at least one of the rings is heteroaromatic, and the other cyclic rings can be, for example, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclyl. Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, tetrazole, pyridine, pyrazine, pyridazine, and pyrimidine.

[0115] The term "heteroatom" as used herein means an atom of any element other than carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen, and sulfur.

[0116] The term "heterocyclylalkyl," as used herein, refers to an alkyl group substituted with a heterocycle group.

[0117] The terms "heterocyclyl", "heterocycle", and "heterocyclic" refer to a substituted or unsubstituted non-aromatic ring structure, preferably 3-10 membered ring, more preferably 3-7 membered ring, which ring structure contains at least one heteroatom, preferably 1-4 heteroatoms, more preferably 1 or 2 heteroatoms. The terms "heterocyclyl" and "heterocyclic" also include polycyclic ring systems having two or more cyclic rings, where two or more carbons are common to two adjacent rings and at least one of the rings is heterocyclic, e.g., the other cyclic rings can be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclyl. Heterocyclyl groups include, for example, piperidine, piperazine, pyrrolidine, morpholine, lactones, lactams, and the like.

[0118] The term "hydrocarbyl" as used herein refers to a group that does not have =O or =S substituents, typically has at least one carbon-hydrogen bond and a backbone that is primarily carbon, but may contain heteroatoms, and is bonded through carbon atoms. Thus, groups such as methyl, ethoxyethyl, 2-pyridyl, and even trifluoromethyl are considered hydrocarbyl for purposes of this application, while substituents such as acetyl (which has a =O substituent on the linking carbon) and ethoxy (which is linked through an oxygen rather than a carbon) are not. Hydrocarbyl groups include, but are not limited to, aryl, heteroaryl, carbocyclic, heterocyclic, alkyl, alkenyl, alkynyl, and combinations thereof.

[0119] The term "hydroxyalkyl," as used herein, refers to an alkyl group substituted with a hydroxy group.

[0120] The term "imine" is art-recognized and

[0121] [ka] R 9 is hydrogen or a hydrocarbyl group, R 10 represents a hydrocarbyl group, or R 9 and R 10 is R 9 together with the N atom to which it is attached complete a heterocycle having 4 to 8 atoms in the ring structure.

[0122] The term "lower", when used with chemical moieties such as acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy, means to include groups in which there are 10 or fewer atoms, preferably 6 or fewer atoms, excluding hydrogen atoms, in the substituent. "Lower alkyl" refers, for example, to an alkyl group containing 10 or fewer carbon atoms, preferably 6 or fewer carbon atoms. In certain embodiments, the acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy substituents defined herein are lower acyl, lower acyloxy, lower alkyl, lower alkenyl, lower alkynyl, or lower alkoxy, respectively, whether they appear alone or in combination with other substituents, for example in the recitation of hydroxyalkyl and aralkyl (where, for example, atoms in an aryl group are not counted when counting the carbon atoms in the alkyl substituent).

[0123] The term "oxime" is art-recognized and

[0124] [ka] R 9 represents hydrogen or a hydrocarbyl group.

[0125] The terms "polycyclyl", "polycycle", and "polycyclic" refer to two or more rings (e.g., cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclyl) in which two or more atoms are common to two adjacent rings, e.g., the rings are "fused rings". Each of the rings of a polycycle can be substituted or unsubstituted. In certain embodiments, each ring of a polycycle contains 3 to 10, preferably 5 to 7, atoms in the ring.

[0126] The term "sulfate" is art-recognized and refers to the group -OSO3H, or a pharma- ceutically acceptable salt thereof.

[0127] The term "sulfonamide" is art-recognized and can be represented by the general formula

[0128] [ka] In the formula, R 9 and R 10 independently represent hydrogen or hydrocarbyl.

[0129] The term "sulfoxide" is art-recognized and refers to the group --S(O)--.

[0130] The term "sulfonate" is art-recognized and refers to the group SO3H, or a pharma- ceutically acceptable salt thereof.

[0131] The term "sulfone" is art-recognized and refers to a -S(O)2- group.

[0132] The term "substituted" refers to a moiety having a substituent replacing a hydrogen on one or more carbons of the backbone. It is understood that "substituted" or "substituted with" includes the implicit proviso that such substitution is in accordance with the permissible valences of the substituted atom and substituent, and that the substitution results in a stable compound that does not undergo transformation, e.g., naturally, e.g., by rearrangement, cyclization, elimination, and the like. As used herein, the term "substituted" is intended to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. The permissible substituents may be one or more and the same or different for appropriate organic compounds. For purposes of this invention, heteroatoms such as nitrogen may have hydrogen substituents and / or any of the permissible substituents of organic compounds described herein that satisfy the valence of the heteroatom. Substituents may include any of the substituents described herein, such as halogen, hydroxyl, carbonyl (e.g., carboxyl, alkoxycarbonyl, formyl, or acyl), thiocarbonyl (e.g., thioester, thioacetate, or thioformate), alkoxyl, phosphoryl, phosphate, phosphonate, phosphinate, amino, amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, aralkyl, or aromatic or heteroaromatic moieties. It will be understood by those skilled in the art that the moieties substituted on the hydrocarbon chain may themselves be substituted, if appropriate.

[0133] The term "thioalkyl," as used herein, refers to an alkyl group substituted with a thiol group.

[0134] The term "thioester" as used herein means -C(O)SR 9 Or -SC(O)R 9 R refers to the9 represents hydrocarbyl.

[0135] The term "thioether," as used herein, is equivalent to an ether where the oxygen is replaced with a sulfur.

[0136] The term "urea" is art-recognized and has the general formula

[0137] [ka] where R 9 and R 10 independently represent hydrogen or hydrocarbyl.

[0138] The term "modulate," as used herein, includes inhibiting or suppressing a function or activity (eg, cell proliferation), as well as enhancing a function or activity.

[0139] The term "induce" as used herein includes promoting the function, activity, or expression of a particular protein or enzyme. In certain embodiments, the compounds disclosed herein induce KLF2, e.g., increase the expression of KLF2. KLF2 induction can be measured according to techniques known to those skilled in the art, e.g., cell-based assays. For example, KLF2 induction can be measured according to the examples described herein below.

[0140] The phrase "pharmacologically acceptable" is art-recognized. In certain embodiments, the term includes compositions, excipients, adjuvants, polymers and other materials and / or dosage forms that are suitable for use in contact with the tissues of human beings and animals without undue toxicity, irritation, allergic response, or other problem or complication, within the scope of sound medical judgment, commensurate with a reasonable benefit / disadvantage ratio.

[0141] A "pharmacologically acceptable salt" or "salt" is used herein to refer to an acid addition salt or a base addition salt that is suitable or compatible with the treatment of a patient.

[0142] The term "pharmaceutically acceptable acid addition salts" as used herein refers to any non-toxic organic or inorganic salt of any base compound represented by formula I. Exemplary inorganic acids that form suitable salts include hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid, as well as metal salts such as sodium monohydrogen orthophosphate and potassium hydrogen sulfate. Exemplary organic acids that form suitable salts include mono-, di-, and tricarboxylic acids such as glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, benzoic acid, phenylacetic acid, cinnamic acid, and salicylic acid, as well as sulfonic acids such as p-toluenesulfonic acid and methanesulfonic acid. Either mono- or di-acid salts can be formed, and such salts can exist in either hydrated, solvated, or substantially anhydrous form. In general, acid addition salts of compounds of formula I are more soluble in water and various hydrophilic organic solvents, and generally exhibit higher melting points compared to their free base forms. The selection of an appropriate salt is known to those skilled in the art. Other salts that are not pharma-ceutically acceptable, such as oxalates, may be used, for example, for laboratory use or for subsequent conversion to a pharma-ceutically acceptable acid addition salt, in the isolation of compounds of formula I.

[0143] The term "pharmaceutically acceptable base addition salt" as used herein means any non-toxic organic or inorganic base addition salt of any acid compound represented by formula I or its intermediate. Exemplary inorganic bases which form suitable salts include lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, or barium hydroxide. Exemplary organic bases which form suitable salts include aliphatic, alicyclic, or aromatic organic amines, such as methylamine, trimethylamine, and picoline or ammonia. The selection of suitable salts is within the skill of the art.

[0144] Many of the compounds useful in the methods and compositions of the present disclosure have at least one stereocenter in their structure. This stereocenter can exist in the R or S configuration, and the R and S designations are used according to the rules set forth in Pure Appl.Chem.(1976), 45, 11-30. The present disclosure contemplates all stereoisomeric forms, e.g., enantiomeric and diastereomeric forms, of the compounds, salts, prodrugs, or mixtures thereof (including all possible mixtures of stereoisomers). See, e.g., WO01 / 062726.

[0145] Furthermore, certain compounds containing alkenyl groups can exist as Z (zusammen) or E (entgegen) isomers. In each case, the present disclosure includes both mixtures and the individual separate isomers.

[0146] Some of the compounds may also exist in tautomeric forms. Such forms, although not explicitly shown in the formulae written herein, are intended to be included within the scope of the present disclosure.

[0147] "Prodrug" or "Pharmaceutically acceptable prodrug" refers to a compound that undergoes metabolism in the host after administration, e.g., hydrolysis or oxidation, to form a compound of the present disclosure (e.g., a compound of formula I). ​​Typical examples of prodrugs include compounds that have a biologically labile or cleavable (protecting) group on a functional moiety of an active compound. Prodrugs include compounds that can be oxidized, reduced, aminated, deaminated, hydroxylated, dehydroxylated, hydrolyzed, dehydrolyzed, alkylated, dealkylated, acylated, deacylated, phosphorylated, or dephosphorylated to generate an active compound. Examples of prodrugs that use esters or phosphoramidates as biologically labile or cleavable (protecting) groups are disclosed in U.S. Patent Nos. 6,875,751, 7,585,851, and 7,964,580, the disclosures of which are incorporated herein by reference. The prodrugs of the present disclosure are metabolized to generate a compound of formula I. The present disclosure includes within its scope prodrugs of the compounds described herein. Conventional procedures for the selection and preparation of suitable prodrugs are described, for example, in “Design of Prodrugs”, Ed. H. Bundgaard, Elsevier, 1985.

[0148] The phrase "pharmaceutically acceptable carrier" as used herein means a pharma- ceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, useful in formulating a drug for medical or therapeutic use.

[0149] The terms "Log of Solubility", "LogS" or "logS" as used herein are used in the art to quantify the water solubility of a compound. The water solubility of a compound significantly affects its absorption and distribution characteristics. Low solubility often results in poor absorption. The LogS value is the unitless logarithm (base 10) of the solubility measured in mol / liter.

[0150] Pharmaceutical Compositions The compositions and methods of the present invention can be utilized to treat an individual in need thereof. In certain embodiments, the individual is a mammal, such as a human, or a non-human mammal. When the composition or compound is administered to an animal, such as a human, it is preferably administered as a pharmaceutical composition, such as a pharmaceutical composition comprising the compound of the present invention and a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers are well known in the art and include, for example, aqueous solutions, such as water or physiological buffered saline, or other solvents or vehicles, such as glycols, glycerol, oils, such as olive oil, or injectable organic esters. In a preferred embodiment, when such pharmaceutical compositions are for administration to humans, particularly for invasive routes of administration (i.e., routes such as injection or implantation that avoid transport or diffusion through epithelial barriers), the aqueous solution is pyrogen-free or substantially pyrogen-free. The excipient can be selected, for example, to effect delayed release of the drug or to selectively target one or more cells, tissues, or organs. The pharmaceutical composition may be in unit dosage form, such as tablets, capsules (including sprinkle capsules and gelatin capsules), granules, lyophilisates for reconstitution, powders, solutions, syrups, suppositories, injections, etc. The composition may also be in a transdermal delivery system, such as a skin patch. The composition may also be in a solution suitable for topical administration, such as a lotion, cream, or ointment. The pharmaceutically acceptable carrier may contain a physiologically acceptable agent that acts, for example, to stabilize, increase the solubility, or increase the absorption of a compound, such as the compound of the present invention. Such physiologically acceptable agents include, for example, carbohydrates, such as glucose, sucrose, or dextran, antioxidants, such as ascorbic acid or glutathione, chelating agents, low molecular weight proteins, or other stabilizers or excipients. The choice of the pharmaceutically acceptable carrier, including the physiologically acceptable agent, depends, for example, on the route of administration of the composition. The preparation or pharmaceutical composition can be a self-emulsifying drug delivery system or a self-emulsifying micro drug delivery system.The pharmaceutical compositions (preparations) can also be liposomes or other polymer matrices into which, for example, the compounds of the invention may be incorporated. For example, liposomes comprising phospholipids or other lipids are non-toxic, physiologically acceptable, metabolizable carriers that are relatively simple to prepare and administer.

[0151] In some cases, the pharmaceutical composition may be a solid dispersion. The term "solid dispersion" refers to a solid-state system that includes at least two components, one component being dispersed throughout one or more other components. For example, the solid dispersion may be an amorphous solid dispersion. The term "amorphous solid dispersion" as used herein refers to a stable solid dispersion that includes an amorphous drug substance and a polymer. By "amorphous drug substance" is meant that the amorphous solid dispersion contains the drug substance in a substantially amorphous solid state form.

[0152] The phrase "pharmacologically acceptable" is used herein to refer to compounds, materials, compositions, and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without undue toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0153] The phrase "pharmacologically acceptable carrier" as used herein means a pharma- ceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not harmful to the patient. Some examples of materials that can serve as pharma-ceutically acceptable carriers include: (1) sugars, such as lactose, glucose, and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives, such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository wax; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and the like. and soybean oil, (10) glycols, such as propylene glycol, (11) polyols, such as glycerin, sorbitol, mannitol, and polyethylene glycol, (12) esters, such as ethyl oleate and ethyl laurate, (13) agar, (14) buffers, such as magnesium hydroxide and aluminum hydroxide, (15) alginic acid, (16) pyrogen-free water, (17) isotonic saline, (18) Ringer's solution, (19) ethyl alcohol, (20) phosphate buffer solutions, and (21) other compatible non-toxic substances used in pharmaceutical formulations.

[0154] The pharmaceutical compositions (preparations) can be administered to a subject by any of several routes of administration, including, for example, orally (e.g., as drenches, tablets, capsules (including sprinkle capsules and gelatin capsules), boluses, powders, granules, pastes for application to the tongue, such as in aqueous or non-aqueous solutions or suspensions), absorption through the oral mucosa (e.g., sublingually), subcutaneously, transdermally (e.g., as a patch applied to the skin), and topically (e.g., as a cream, ointment, or spray applied to the skin). The compounds can also be formulated for inhalation. In certain embodiments, the compounds can be simply dissolved or suspended in sterile water. Details of suitable routes of administration and compositions suitable therefor can be found, for example, in U.S. Pat. Nos. 6,110,973, 5,763,493, 5,731,000, 5,541,231, 5,427,798, 5,358,970 and 4,172,896, and patents cited therein.

[0155] The formulations can be conveniently presented in unit dosage form and can be prepared by any method well known in the art of pharmacy. The amount of active ingredient that can be combined with carrier materials to produce a single dosage form varies depending on the host treated, the particular mode of administration. The amount of active ingredient that can be combined with carrier materials to produce a single dosage form is generally the amount of compound that produces a therapeutic effect. Generally, this amount ranges from about 1 percent to about 99 percent of one hundred percent of the active ingredient, preferably about 5 percent to about 70 percent, and most preferably about 10 percent to about 30 percent.

[0156] The method of preparing these formulations or compositions includes the step of bringing into association the active compound, e.g., the compound of the present invention, with the carrier and, optionally, one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the compound of the present invention with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.

[0157] Formulations of the present invention suitable for oral administration can be in the form of capsules (including sprinkle capsules and gelatin capsules), cachets, pills, tablets, lozenges (using a flavored base, usually sucrose and acacia or tragacanth), lyophilisates, powders, granules, or as a solution or suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as a lozenge (using an inert base, e.g., gelatin and glycerin, or sucrose and acacia), and / or as a mouthwash, etc., each containing a predetermined amount of a compound of the present invention as an active ingredient. The composition or compound can also be administered as a bolus, lozenge, or paste.

[0158] To prepare solid dosage forms for oral administration (capsules (including sprinkle capsules and gelatin capsules), tablets, pills, dragees, powders, granules, and the like), the active ingredient is mixed with one or more pharma- ceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and / or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and / or silicic acid; (2) binders, such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and / or acacia; (3) humectants, such as glycerol; (4) disintegrants, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) dissolution retarders, such as paraffin; and (6) absorption enhancers, such as quaternary aluminium carbonate. ammonium compounds, (7) wetting agents such as cetyl alcohol and glyceryl monostearate, (8) absorbents such as kaolin and bentonite clay, (9) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof, (10) complexing agents such as modified and unmodified cyclodextrins, (11) biocompatible polymers such as those used to make amporphous solid dispersions, and (12) colorants. In the case of capsules (including sprinkle capsules and gelatin capsules), tablets, and pills, the pharmaceutical compositions may also include buffering agents. Similar types of solid compositions may also be used as fillers in soft and hard-filled gelatin capsules using excipients such as lactose or milk sugar, and high molecular weight polyethylene glycols.

[0159] Tablets can be made by compression or molding, optionally with one or more accessory ingredients.Compressed tablets can be prepared using binders (e.g., gelatin or hydroxypropylmethylcellulose), lubricants, inert diluents, preservatives, disintegrants (e.g., sodium starch glycolate or cross-linked sodium carboxymethylcellulose), surface active agents, or dispersants.Molded tablets can be made by molding a mixture of powdered compound moistened with an inert liquid diluent in a suitable machine.

[0160] Tablets, as well as other solid dosage forms of pharmaceutical compositions, such as dragees, capsules (including sprinkle capsules and gelatin capsules), pills and granules, may be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical formulation art. They may also be formulated to provide sustained or controlled release of the active ingredient therein, for example, using various proportions of hydroxypropylmethylcellulose, other polymer matrices, liposomes and / or microspheres to provide the desired release profile. They may be sterilized, for example, by filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of a sterile solid composition that can be dissolved in sterile water or some other injectable sterile medium immediately before use. These compositions may also contain opacifying agents, and may be of a composition that releases the active ingredient in a delayed manner only, or preferentially, in a certain part of the gastrointestinal tract. Examples of embedding compositions that may be used include polymeric substances and waxes. The active ingredient may also be in microencapsulated form, where appropriate, with one or more of the above-mentioned excipients.

[0161] The liquid dosage form useful for oral administration includes pharma- ceutically acceptable emulsion, lyophilized product for reconstitution, microemulsion, solution, suspension, syrup and elixir.In addition to active ingredient, liquid dosage form may contain inert diluents commonly used in the art, such as water or other solvents, cyclodextrin and its derivatives, solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oil (especially cottonseed, peanut, corn, germ, olive, castor and sesame oil), glycerol, tetrahydrofuryl alcohol, polyethylene glycol and fatty acid ester of sorbitan, and mixtures thereof.

[0162] Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming, and preservative agents.

[0163] Suspensions may contain, in addition to the active compounds, suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth, and mixtures thereof.

[0164] Dosage forms for topical or transdermal administration include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active compound may be mixed under sterile conditions with a pharma- ceutically acceptable carrier, and any preservatives, buffers, or propellants that may be required.

[0165] The ointments, pastes, creams and gels may contain, in addition to the active compound, excipients such as animal and vegetable fats, oils, waxes, paraffins, starches, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonite, silicic acid, talc and zinc oxide, or mixtures thereof.

[0166] Powders and sprays may contain, in addition to the active compound, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate and polyamide powder, or mixtures of these substances. Sprays may further contain customary propellants, such as chlorofluorohydrocarbons, and volatile unsubstituted hydrocarbons, such as butane and propane.

[0167] Transdermal patch has the additional advantage of providing controlled delivery of the compound of the present invention to the body.Such dosage forms can be made by dissolving or dispersing the active compound in a suitable medium.Absorption enhancers can also be used to increase the flux of the compound across the skin.The rate of such flux can be controlled by providing a rate-limiting membrane or dispersing the compound in a polymer matrix or gel.

[0168] The phrases "parenteral administration" and "administered parenterally" as used herein refer to methods of administration other than enteral and topical administration, usually by injection, including, but not limited to, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion. Pharmaceutical compositions suitable for parenteral administration include one or more active compounds in combination with one or more pharma- ceutically acceptable isotonic sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders that can be reconstituted into injectable sterile solutions or dispersions immediately prior to use (which may contain antioxidants, buffers, bacteriostats, solutes that render the formulation isotonic with the blood of the intended recipient, or suspending or thickening agents).

[0169] Examples of suitable aqueous and non-aqueous carriers that can be used in the pharmaceutical compositions of the present invention include water, ethanol, polyols (e.g., glycerol, propylene glycol, polyethylene glycol, etc.) and suitable mixtures thereof, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate.Proper fluidity can be maintained, for example, by using coating materials such as lecithin, by maintaining the required particle size in the case of dispersions, and by using surfactants.

[0170] These compositions may also contain adjuvants, such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of microbial action may be ensured by including various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol sorbic acid, etc. It may be desirable to include isotonic agents, such as sugars, sodium chloride, etc. in the composition. In addition, the inclusion of agents that delay absorption, such as aluminum monostearate and gelatin, may result in prolonged absorption of the injectable pharmaceutical form.

[0171] In some cases, it is desirable to delay the absorption of drug from subcutaneous or intramuscular injection in order to prolong the effect of drug.This can be achieved by using liquid suspension of crystalline or amorphous material with poor water solubility.The absorption rate of drug then depends on its dissolution rate, which in turn depends on crystal size and crystalline form.Alternatively, the delayed absorption of parenterally administered drug form can be achieved by dissolving or suspending drug in oil vehicle.

[0172] Injectable depot forms are prepared by forming microencapsulated matrices of the subject compound in biodegradable polymers, such as polylactide-polyglycolide. The rate of drug release can be controlled depending on the ratio of drug to polymer and the nature of the particular polymer used. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissues.

[0173] For use in the methods of the invention, the active compound may be provided per se or as a pharmaceutical composition containing, for example, 0.1 to 99.5% (more preferably, 0.5 to 90%) of the active ingredient in combination with a pharma- ceutically acceptable carrier.

[0174] The introduction method can also be provided by rechargeable or biodegradable devices.Various delayed release polymeric devices have been developed and tested in vivo in recent years for the controlled delivery of drugs, including proteinaceous biopharmaceuticals.Various biocompatible polymers, including both biodegradable and non-degradable polymers (including hydrogels), can be used to form implants for sustained release of compounds at specific target sites.

[0175] Actual dosage levels of the active ingredients in pharmaceutical compositions may be varied to provide an amount of the active ingredient effective to achieve the desired therapeutic response for a particular patient, composition, and method of administration without being toxic to the patient.

[0176] The selected dosage level will depend on a variety of factors, including the activity of the particular compound or combination of compounds, or esters, salts or amides thereof, used, the route of administration, the timing of administration, the rate of excretion of the particular compound used, the duration of treatment, other drugs, compounds and / or materials used in combination with the particular compound used, the age, sex, weight, condition, overall health and past medical history of the patient being treated, and similar factors well known in the medical arts.

[0177] A physician or veterinarian of ordinary skill in the art can easily determine and prescribe the therapeutically effective amount of the pharmaceutical composition required. For example, a physician or veterinarian can begin dosing the pharmaceutical composition or compound at a level lower than that required to achieve the desired therapeutic effect, and gradually increase the dosage until the desired effect is achieved. By "therapeutically effective amount" is meant the concentration of the compound sufficient to induce the desired therapeutic effect. It is generally understood that the effective amount of the compound will vary according to the subject's weight, sex, age, and medical history. Other factors that affect the effective amount may include, but are not limited to, the severity of the patient's condition, the disorder being treated, the stability of the compound, and, if desired, another type of therapeutic agent administered together with the compound of the present invention. A larger total dose can be delivered by multiple administrations of the agent. Methods for determining efficacy and dosage are known to those skilled in the art (Isselbacher et al. (1996) Harrison's Principles of Internal Medicine 13 ed., 1814-1882, incorporated herein by reference).

[0178] In general, a suitable daily dose of an active compound used in the compositions and methods of the present invention is that amount of the compound that is the minimum dose effective to produce a therapeutic effect. Such an effective dose will generally depend on the factors mentioned above.

[0179] If desired, the effective daily dose of active compound can be administered as 1, 2, 3, 4, 5, 6 or more partial doses administered separately at appropriate intervals throughout the day, optionally in unit dosage form.In certain embodiments of the present invention, active compound can be administered 2 or 3 times a day.In preferred embodiments, active compound is administered once a day.

[0180] The patient to receive this treatment may be any animal in need, including primates, particularly humans, as well as other mammals, such as horses, cows, pigs, sheep, cats and dogs, poultry, and pets in general.

[0181] In certain embodiments, the compounds of the present invention can be used alone or can be administered in combination with another type of therapeutic agent.

[0182] The present disclosure includes the use of pharma- ceutically acceptable salts of the compounds of the present invention in the compositions and methods of the present invention (see Berge et al. (1977) "Pharmaceutical Salts", J. Pharm. Sci. 66:1-19). In certain embodiments, contemplated salts of the present invention include, but are not limited to, alkyl, dialkyl, trialkyl, or tetraalkyl ammonium salts. In certain embodiments, contemplated salts of the present invention include, but are not limited to, L-arginine, benenthamine, benzathine, betaine, calcium hydroxide, choline, deanol, diethanolamine, diethylamine, 2-(diethylamino)ethanol, ethanolamine, ethylenediamine, N-methylglucamine, hydrabamine, 1H-imidazole, lithium, L-lysine, magnesium, 4-(2-hydroxyethyl)morpholine, piperazine, potassium, 1-(2-hydroxyethyl)pyrrolidine, sodium, triethanolamine, tromethamine, and zinc salts. In certain embodiments, contemplated salts of the present invention include, but are not limited to, Na, Ca, K, Mg, Zn or other metal salts.In certain embodiments, contemplated salts of the present invention include 1-hydroxy-2-naphthoic acid, 2,2-dichloroacetic acid, 2-hydroxyethanesulfonic acid, 2-oxoglutaric acid, 4-acetamidobenzoic acid, 4-aminosalicylic acid, acetic acid, adipic acid, l-ascorbic acid, l-aspartic acid, benzenesulfonic acid, benzoic acid, (+)-camphor-10-sulfonic acid, capric acid (decanoic acid), caproic acid (hexanoic acid), caprylic acid (octanoic acid), carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, d-gluconic acid, glyceric ... These include, but are not limited to, heptonate, d-gluconate, d-glucuronic acid, glutamate, glutarate, glycerophosphoric acid, glycolate, hippurate, hydrobromic acid, hydrochloric acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, l-malic acid, malonic acid, mandelic acid, methanesulfonic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid, nitric acid, oleic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, propionic acid, l-pyroglutamic acid, salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, l-tartaric acid, thiocyanate, p-toluenesulfonic acid, trifluoroacetic acid, and undecylenate.

[0183] Pharmaceutically acceptable acid addition salts may also exist as various solvates, such as with water, methanol, ethanol, dimethylformamide, etc. Mixtures of such solvates may also be prepared. The source of such solvates may be from the solvent of crystallization, inherent in the solvent of preparation or crystallization, or adventitious to such solvent.

[0184] Wetting agents, emulsifying agents and lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives, and antioxidants can also be present in the composition.

[0185] Examples of pharma- ceutically acceptable antioxidants include: (1) water-soluble antioxidants, such as ascorbic acid, cysteine ​​hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, α-tocopherol, and the like; and (3) metal-chelating agents, such as citric acid, ethylenediamine.

[0186] Treatment Provided herein is a method of treating inflammatory diseases or endothelial dysfunction comprising administering a therapeutically effective amount of a compound of the invention, e.g., a compound of formula (I), a pharma- ceutically acceptable salt thereof, or a composition comprising a compound of formula (I).

[0187] In certain embodiments, the inflammatory disease or endothelial dysfunction is atherosclerosis, coronary artery disease, stroke, peripheral artery disease, coronary microvascular disease, angina pectoris, systemic hypertension, pulmonary arterial hypertension, heart failure, diabetic microvascular disease, e.g., diabetic nephropathy, diabetic retinopathy, or diabetic neuropathy, or an autoimmune, inflammatory, or infectious disease. EXAMPLES

[0188] [Table 1-1]

[0189] [Table 1-2]

[0190] Intermediate BB-1

[0191] [ka] Methyl bromoacetate (11 g, 7.23 mmol, 1.1 equiv.) was added dropwise over 15 min to a stirred mixture of methyl 2-hydroxybenzoate (10.0 g, 6.57 mmol, 1.0 equiv.) and potassium carbonate (13.6 g, 9.85 mmol, 1.5 equiv.) in dry acetone (100 mL). The mixture was heated and stirred under reflux for 17 h. The reaction was monitored by LCMS. The reaction was cooled and the salts were separated by filtration and washed with acetone. The filtrate was concentrated to give a residue which was diluted with diethyl ether (200 mL) and the solution was washed successively with water, aqueous sodium carbonate, water, and brine. The crude product was distilled under reduced pressure to give methyl 2-(2-methoxy-2-oxoethoxy)benzoate (13.3 g, 90%). LC-MS: 225.1 [M+H]+

[0192] [ka] To a mixture of methyl 2-(2-methoxy-2-oxoethoxy)benzoate (13.2 g, 58.9 mmol, 1.0 equiv) in MeOH (100 mL) was added NaOMe (5N in methanol, 17.7 mL) and the mixture was stirred at 60° C. for 2 h. The reaction was monitored by LCMS. The resulting mixture was cooled, poured into ice water, and acidified to pH 2 with 5% hydrochloric acid. The solid was collected by filtration, washed with water, and recrystallized from methanol to give methyl 3-hydroxybenzofuran-2-carboxylate (9.5 g, 84%) as a white solid. LC-MS: 193.1 [M+H]+

[0193] [ka] To a mixture of methyl 3-hydroxybenzofuran-2-carboxylate (7.2 g, 37.5 mmol, 1.0 equiv.) in acetonitrile (100 mL), K2CO3 (6.21 g, 45 mmol, 1.2 equiv.), chloroacetone (3.82 g, 41.25 mmol, 1.1 equiv.) and 1,4,7,10,13,16-hexaoxacyclooctadecane (99 mg, 3.75 mmol, 0.1 equiv.) were added and the mixture was refluxed for 2 h. The reaction was monitored by LCMS. The resulting mixture was filtered, concentrated and extracted with ethyl acetate to give crude methyl 3-(2-oxopropoxy)benzofuran-2-carboxylate (9.5 g, 100%) as a brown solid. LC-MS: 249.1 [M+H]+

[0194] [ka] A solution of crude methyl 3-(2-oxopropoxy)benzofuran-2-carboxylate (9.5 g, 38.3 mmol, 1.0 equiv) in EtOH (30 mL) and 5% NaOH in water (10 mL) was stirred at room temperature for 2 h. The reaction was monitored by LCMS. The resulting mixture was concentrated, adjusted to pH 2 by adding 1N HCl, and extracted with ethyl acetate. The combined organic layers were washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica (PE:EA=2:1) ​​to give crude 3-(2-oxopropoxy)benzofuran-2-carboxylic acid (2.0 g, 22%) as a red solid. LC-MS: 235.1 [M+H]+

[0195] Example 1

[0196] [ka] A mixture of compound 3-(2-oxopropoxy)benzofuran-2-carboxylic acid (1.0 g, 4.27 mmol, 1.0 equiv.), amine but-3-yn-1-amine (295 mg, 4.27 mmol, 1.0 equiv.), 2-methoxybenzyl isocyanide (628 mg, 4.27 mmol, 1.0 equiv.) in MeOH (3 mL) was stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Hex / EtOAc=1:1) to give Example 1 (1.01 g, 54%) as a light yellow solid. LC-MS: 433.3 [M+1] + 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 8.37 (s, 1H), 7.68 (ddd, J = 7.8, 1.3, 0.7 Hz, 1H), 7.60 (dt, J = 8.4, 0.9 Hz, 1H), 7.52 (ddd, J = 8.4, 7.1, 1.3 Hz, 1H), 7.34 (ddd, J = 7.9, 7.1, 0.9 Hz, 1H), 7.04 (d, J = 7.8 Hz, 1H), 6.84 (d, J = 8.1 Hz, 1H), 6.74 (s, 1H), 6.33 (s, 1H), 4.92 (d, J = 12.6 Hz, 1H), 4.40 (d, J = 12.5 Hz, 1H), 4.18 (d, J = 5.7 Hz, 2H), 3.71 (s, 5H), 3.48 (brs, 1H), 2.90 (s, 1H), 1.70 (s, 4H).

[0197] (1-Fluorocyclobutyl)methanamine

[0198] [ka] To a solution of 1-(aminomethyl)cyclobutan-1-ol (1.0 g, 9.9 mmol, 1.0 equiv.) in toluene (10 mL) was added phthalic anhydride (1.5 g, 10.1 mmol, 1.02 equiv.). The reaction mixture was heated to 120° C. and stirred for 4 h. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (PE / EA, 50:1 to 4:1) to obtain the compound 2-((1-hydroxycyclobutyl)methyl)isoindoline-1,3-dione (2.0 g, 87%) as a white solid. TLC: PE / EA=4:1, UV;R f (Compound 2)=0.40;LC-MS: 254.1 [M+Na] + ; 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 7.96 - 7.81 (m, 4H), 5.09 (s, 1H), 3.68 (s, 2H), 2.21 - 2.11 (m, 2H), 1.96 - 1.85 (m, 2H), 1.75 - 1.62 (m, 1H), 1.58 - 1.43 (m, 1H).

[0199] [ka] To a solution of 2-((1-hydroxycyclobutyl)methyl)isoindoline-1,3-dione (2.0 g, 8.6 mmol, 1.0 equiv) in DMF (20 mL) was added NaH (60%, 520 mg, 12.9 mmol, 1.5 equiv) at 0 °C. The reaction mixture was stirred for 1 h. CS2 (1.3 g, 17.2 mmol, 2.0 equiv) was added to the mixture at 0 °C and the reaction mixture was stirred for 2 h. CH3I (1.8 g, 12.9 mmol, 1.5 equiv) was added to the mixture at 0 °C and stirred at room temperature for 3 h. The mixture was diluted with 1N HCl (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE / EtOAc=50:1 to 10:1) to give O-(1-((1,3-dioxoisoindolin-2-yl)methyl)cyclobutyl)S-methylcarbonodithioate (1.7 g, 60%) as a yellow solid. TLC: PE / EA=10:1, UV; R f (Compound 2)=0.20;R f (Compound 3)=0.60.

[0200] [ka] To a solution of 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione (4.4 g, 15.5 mmol, 5.0 equiv.) in DCM (30 mL) was added HF / Py (65%-70%, 3 mL) in a dry ice-acetone bath. To the reaction mixture was added O-(1-((1,3-dioxoisoindolin-2-yl)methyl)cyclobutyl)S-methylcarbonodithioate (1.0 g, 3.1 mmol, 1.0 equiv.) in DCM (20 mL) at this temperature. The reaction mixture was stirred at 0° C. for 3 h. The reaction mixture was quenched with NaOH (2N aq., 100 mL), extracted with DCM (100 mL×2), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE / EtOAc=50:1 to 10:1) to obtain the compound 2-((1-fluorocyclobutyl)methyl)isoindoline-1,3-dione (600 mg, 82%) as a yellow solid. TLC: PE / EA=20:1, UV; R f (Compound 3)=0.40;R f (Compound 4)=0.60; 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 7.93 - 7.85 (m, 4H), 3.92 (d, J = 21.8 Hz, 2H), 2.34 - 2.09 (m, 4H), 1.85 - 1.72 (m, 1H), 1.66 - 1.53 (m, 1H).

[0201] [ka] To a solution of 2-((1-fluorocyclobutyl)methyl)isoindoline-1,3-dione (600 mg, 2.6 mmol, 1.0 equiv) in MeOH (5 mL) was added methylamine in methanol (10 M, 5 mL). The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (DCM / MeOH, 50:1 to 10:1) to give (1-fluorocyclobutyl)methanamine (30 mg, 11%) as a colorless oil. TLC: DCM / MeOH=10:1, UV, stained with indenhydrin; R f (Compound 4)=0.95;R f (Compound 5)=0.30;LC-MS:104.1[M+H] + .

[0202] Using the procedures and intermediates above, the following compounds were prepared:

[0203] [Table 2-1]

[0204] [Table 2-2]

[0205] [Table 2-3]

[0206] [Table 2-4]

[0207] [Table 2-5]

[0208] Intermediate BB-2

[0209] [ka] A mixture of 3-(2-oxopropoxy)benzofuran-2-carboxylic acid (220 g, 0.94 mol, 1.0 equiv.), 2-methoxyethylamine (90 g, 1.13 mol, 1.2 equiv.), and (S)-(1-isocyanoethyl)benzene (160 g, 1.22 mol, 1.3 equiv.) in MeOH (1 L) was stirred at 60° C. overnight and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (Hex / EtOAc, 100:1 to 50:1) to give 4-(2-methoxyethyl)-3-methyl-5-oxo-N-((S)-1-phenylethyl)-2,3,4,5-tetrahydrobenzofuro[2,3-f][1,4]oxazepine-3-carboxamide (240 g, 60%) as a light yellow solid. LC-MS: 423.1 [M+H] + ;TLC:PE / EA=1:1, UV;R f (Compound 1)=0.70;R f (Compound 4)=0.40.

[0210] [ka] A mixture of 4-(2-methoxyethyl)-3-methyl-5-oxo-N-((S)-1-phenylethyl)-2,3,4,5-tetrahydrobenzofuro[2,3-f][1,4]oxazepine-3-carboxamide (240 g, 0.57 mol, 1.0 equiv.), (Boc)2O (496 g, 2.28 mol, 4.0 equiv.), and DMAP (69 g, 0.57 mol, 1.0 equiv.) in TEA (500 mL) was stirred at 110° C. overnight. The mixture was diluted with EtOAc (500 mL). The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EtOAc=1:1) to give tert-butyl (4-(2-methoxyethyl)-3-methyl-5-oxo-2,3,4,5-tetrahydrobenzofuro[2,3-f][1,4]oxazepine-3-carbonyl)((S)-1-phenylethyl)carbamate (160 g, 54%) as a light yellow solid. LC-MS: 523.1 [M+H] + ;TLC:PE / EA=1:1, UV;R f (Compound 4)=0.40;R f (Compound 5)=0.70.

[0211] [ka] To a solution of tert-butyl (4-(2-methoxyethyl)-3-methyl-5-oxo-2,3,4,5-tetrahydrobenzofuro[2,3-f][1,4]oxazepine-3-carbonyl)((S)-1-phenylethyl)carbamate (160 g, 0.31 mol, 1.0 equiv.) in EtOH (500 mL), THF (250 mL) was added KOH solution (10 w / w% in HO, 500 mL). The reaction mixture was stirred at 70 °C overnight and 6N HCl was added to adjust pH to 1-2. The mixture was filtered and the cake was washed with water (200 mL). The solid was dried under reduced pressure at 25 °C to give the desired product (76 g, 23%). LC-MS: 320.1[M+1]+; 1H NMR (400 MHz, DMSO) δ 13.28 (s, 1H), 7.68 (d, J = 7.6 Hz, 1H), 7.61 (d, J = 8.4 Hz, 1H), 7.51 (ddd, J = 8.4, 7.2, 1.3 Hz, 1H), 7.38 - 7.24 (m, 1H), 4.83 (d, J = 12.3 Hz, 1H), 4.38 (d, J = 12.3 Hz, 1H), 3.83 - 3.72 (m, 1H), 3.64 (dt, J = 14.5, 6.1 Hz, 1H), 3.54 - 3.41 (m, 2H), 3.23 (s, 3H), 1.74 (s, 3H).

[0212] (4-Chloro-5-fluoro-2-methoxyphenyl)methanamine

[0213] [ka] A mixture of NaOH (192 mg, 4.8 mmol, 3.0 equiv) and hydroxylamine hydrochloride (167 mg, 2.4 mmol, 1.5 equiv) was dissolved in 1 mL of water and 5 mL of ethanol at 0° C. for 5 min. To the above mixture, 4-chloro-5-fluoro-2-methoxybenzaldehyde (300 mg, 1.6 mmol, 1.0 equiv) was added. The reaction mixture was warmed to room temperature and stirred for 1 h. At the end of the reaction (confirmed by TLC), the reaction was diluted with water (10 mL) and the aqueous phase was extracted with EA (3×10 mL). The organic phase was washed with brine (10 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the crude product (E)-4-chloro-5-fluoro-2-methoxybenzaldehyde oxime (300 mg, 92%) as a white solid. LC-MS: 204.1 [M+H] + (V1638-085);TLC:PE / EA=10:1,UV;R f (Compound 1)=0.70;R f (Compound 2)=0.50.

[0214] [ka] (E)-4-Chloro-5-fluoro-2-methoxybenzaldehyde oxime (300 mg, 1.5 mmol) was dissolved in EtOH (6 mL) and water (1 mL). Concentrated HCl (2 mL) was added dropwise at 0° C. and the mixture was stirred for 10 min, followed by the addition of Zn powder (780 mg, 12 mmol, 8 equiv.). The mixture was stirred at 80° C. for 1 h. The mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure to give a white solid (4-chloro-5-fluoro-2-methoxyphenyl)methanamine (280 mg, 98%). The crude product was used directly in the next step without further purification. TLC: PE / EA=10:1, UV; R f (Compound 2)=0.50;R f (Compound 3)=0.00;LC-MS:190.1[M+H] + .

[0215] (3-chloro-2-fluoro-6-methoxyphenyl)methanamine

[0216] [ka] To a solution of 3-chloro-2-fluoro-6-methoxybenzaldehyde (2.0 g, 10.61 mmol) in ethanol (20 mL) was added NaOH (1.3 g, 32.50 mmol, 3.0 equiv) and hydroxylamine hydrochloride (2.2 g, 31.66 mmol, 1.5 equiv) at 0° C. The mixture was warmed to room temperature and stirred for 3 h. Water (20 mL) was added and the aqueous phase was extracted with EA (3×20 mL). The combined organic phases were washed with brine (20 mL), dried over NaSO4, filtered and concentrated in vacuo to give the crude product, which was used directly in the next step. LC-MS: 204.1 [M+H] + .

[0217] [ka] To a solution of 3-chloro-2-fluoro-6-methoxybenzaldehyde oxime (200 mg, 0.98 mmol, 1.0 equiv) in ethanol (3 mL) was added concentrated HCl (1 mL) and water (0.5 mL) at 0° C. The mixture was stirred for 15 min. Zn powder (383 mg, 5.89 mmol, 6.0 equiv) was added. The reaction mixture was heated to 80° C. for 1 h, cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure to give the hydrochloride salt of (3-chloro-2-fluoro-6-methoxyphenyl)methanamine (190 mg, 100%) as a yellow solid. LC-MS: 190.1 [M+H] + .

[0218] Using the procedures and intermediates above, the following compounds were prepared:

[0219] [Table 3-1]

[0220] [Table 3-2]

[0221] [Table 3-3]

[0222] [Table 3-4]

[0223] [Table 3-5]

[0224] [Table 3-6]

[0225] [Table 3-7]

[0226]

Table 3-8

[0227]

Table 3-9

[0228]

Table 3-10

[0229]

Table 3-11

[0230] Intermediate BB-3

[0231]

change

[0232]

change

[0233] Peak 1 (front peak) was named 2-P1 (6.644 min, 100% ee). LC-MS: 517.1 [M+1]+; 1H NMR (400 MHz, CDCl3) δ 7.66 (d, J = 1.3 Hz, 1H), 7.56 (d, J = 8.4 Hz, 1H), 7.39 (dd, J = 8.4, 1.5 Hz, 1H), 7.34 - 7.27 (m, 3H), 7.25 - 7.16 (m, 3H), 5.04 - 4.70 (m, 2H), 4.33 - 4.06 (m, 2H), 3.99 - 3.82 (m, 1H), 3.62 - 3.34 (m, 2H), 2.95 (s, 3H), 1.71 (s, 3H), 1.05 (d, J = 6.4 Hz, 3H).

[0234] Peak 2 (the second peak) was designated 2-P2 (7.410 min, 97% ee).

[0235] [ka] To a solution of (R)-8-bromo-4-(2-methoxyethyl)-3-methyl-5-oxo-N-((S)-1-phenylethyl)-2,3,4,5-tetrahydrobenzofuro[2,3-f][1,4]oxazepine-3-carboxamide (570 mg, 1.14 mmol, 1.0 equiv.) in TEA (10 mL) was added (Boc)2O (1 g, 4.54 mmol, 4.0 equiv.), DMAP (277 mg, 2.27 mmol, 2.0 equiv.). The mixture was stirred at 100° C. for 3 h. Water (50 mL) was added. The aqueous phase was extracted with EA (3×50 mL). The combined organic solution was washed with brine (50 mL), dried over anhydrous Na2SO4, and the solution was concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE:EA=3:1) to give tert-butyl ((R)-8-bromo-4-(2-methoxyethyl)-3-methyl-5-oxo-2,3,4,5-tetrahydrobenzofuro[2,3-f][1,4]oxazepine-3-carbonyl)((S)-1-phenylethyl)carbamate (600 mg, 87%) as a brown solid. LC-MS: 603.1[M+1] + .

[0236] tert-Butyl ((S)-8-bromo-4-(2-methoxyethyl)-3-methyl-5-oxo-2,3,4,5-tetrahydrobenzofuro[2,3-f][1,4]oxazepine-3-carbonyl)((S)-1-phenylethyl)carbamate (3-P1) (284 mg, 80%) was prepared in a similar manner as a brown solid. LC-MS: 603.1[M+1] + .

[0237] [ka] To a solution of tert-butyl ((R)-8-bromo-4-(2-methoxyethyl)-3-methyl-5-oxo-2,3,4,5-tetrahydrobenzofuro[2,3-f][1,4]oxazepine-3-carbonyl)((S)-1-phenylethyl)carbamate (600 mg, 0.99 mmol, 1.0 equiv) in THF (5 mL), EtOH (10 mL), and HO (3 mL) was added KOH (560 mg, 10.0 mmol, 10.0 equiv). The mixture was stirred at 70 °C for 3 h. The reaction mixture was concentrated under reduced pressure and then acidified to pH 4-5 with 1 N HCl. The solid was filtered to give (R)-8-bromo-4-(2-methoxyethyl)-3-methyl-5-oxo-2,3,4,5-tetrahydrobenzofuro[2,3-f][1,4]oxazepine-3-carboxylic acid (440 mg, 110%) as a white solid. The crude product was used directly in the next step. LC-MS: 398.1 [M+1] + .

[0238] (S)-8-Bromo-4-(2-methoxyethyl)-3-methyl-5-oxo-2,3,4,5-tetrahydrobenzofuro[2,3-f][1,4]oxazepine-3-carboxylic acid (243 mg, 129%) was prepared in a similar manner as a white solid. LC-MS: 398.1[M+1] + .

[0239] [ka] To a solution of (R)-8-bromo-4-(2-methoxyethyl)-3-methyl-5-oxo-2,3,4,5-tetrahydrobenzofuro[2,3-f][1,4]oxazepine-3-carboxylic acid (440 mg, 1.10 mmol, 1.0 equiv.) in DMF (10 mL) was added HATU (627 mg, 1.65 mmol, 1.5 equiv.), (2-methoxyphenyl)methanamine (226 mg, 1.65 mmol, 1.5 equiv.), DIPEA (284 mg, 2.20 mmol, 2.0 equiv.) at 0° C. After stirring at room temperature for 1 h, the reaction mixture was diluted with water (30 mL). The aqueous phase was extracted with ethyl acetate (3×30 mL). The combined organic phase was washed with brine (20 mL) and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography (EA) to give the title compound as a yellow solid (570 mg, 100%). LCMS: 517.1 [M+1] + .

[0240] (S)-8-Bromo-N-(2-methoxybenzyl)-4-(2-methoxyethyl)-3-methyl-5-oxo-2,3,4,5-tetrahydrobenzofuro[2,3-f][1,4]oxazepine-3-carboxamide (256 mg, 81%) was prepared in a similar manner. LCMS: 517.1[M+1]+.

[0241] [ka] A mixture containing (R)-8-bromo-N-(2-methoxybenzyl)-4-(2-methoxyethyl)-3-methyl-5-oxo-2,3,4,5-tetrahydrobenzofuro[2,3-f][1,4]oxazepine-3-carboxamide (570 mg, 1.10 mmol, 1.0 equiv.), Pd(OAc)2 (25 mg, 0.11 mmol, 0.1 equiv.), DPPF (61 mg, 0.11 mmol, 0.1 equiv.), TEA (559 mg, 5.50 mmol, 5.0 equiv.) in DMSO (10 mL) and MeOH (5 mL) was stirred at 85° C. for 12 h under CO gas atmosphere. The reaction mixture was diluted with water (30 mL). The aqueous phase was extracted with ethyl acetate (3×30 mL). The combined organic phase was washed with brine (20 mL) and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography (EA) to give the title compound as a light brown solid (400 mg, 73%). LCMS: 497.1 [M+1] + .

[0242] (S)-Methyl 3-((2-methoxybenzyl)carbamoyl)-4-(2-methoxyethyl)-3-methyl-5-oxo-2,3,4,5-tetrahydrobenzofuro[2,3-f][1,4]oxazepine-8-carboxylate (130 mg, 52%) was prepared in a similar manner. LCMS: 497.1 [M+1] + .

[0243] [ka] To a solution of (R)-methyl 3-((2-methoxybenzyl)carbamoyl)-4-(2-methoxyethyl)-3-methyl-5-oxo-2,3,4,5-tetrahydrobenzofuro[2,3-f][1,4]oxazepine-8-carboxylate (400 mg, 0.83 mmol, 1.0 equiv.) in THF (6 mL), HO (3 mL) was added LiOH (200 mg, 8.30 mmol, 10.0 equiv.). The mixture was stirred at room temperature for 5 h. The reaction mixture was concentrated under reduced pressure and then acidified to pH 4-5 with 1N HCl. The aqueous phase was extracted with ethyl acetate (3×30 mL). The combined organic phase was washed with brine (20 mL) and dried over anhydrous magnesium sulfate to give the crude product (200 mg, 50%). The crude product was used directly in the next step. LC-MS: 483.1 [M+1] + .

[0244] (Example 49) (S)-N8-Cyclobutyl-N3-(2-methoxybenzyl)-4-(2-methoxyethyl)-3-methyl-5-oxo-2,3,4,5-tetrahydrobenzofuro[2,3-f][1,4]oxazepine-3,8-dicarboxamide (79 mg, 59%). (S)-3-((2-Methoxybenzyl)carbamoyl)-4-(2-methoxyethyl)-3-methyl-5-oxo-2,3,4,5-tetrahydrobenzofuro[2,3-f][1,4]oxazepine-8-carboxylic acid was used to produce the title compound. LC-MS: 536.20[M+1]+; 1H NMR (400 MHz, CDCl3) δ 7.83 (s, 1H), 7.55 (d, J = 8.2 Hz, 1H), 7.54 - 7.49 (m, 1H), 7.49 - 7.40 (m, 1H), 6.93 - 6.78 (m, 2H), 6.57 (d, J = 8.0 Hz, 1H), 6.44 (t, J = 7.2 Hz, 1H), 6.26 (d, J = 7.5 Hz, 1H), 4.89 (d, J = 11.8 Hz, 1H), 4.70 - 4.56 (m, 1H), 4.35 (dd, J = 14.2, 7.0 Hz, 1H), 4.30 - 4.21 (m, 1H), 4.18 - 4.00 (m, 2H), 3.82 - 3.77 (m, 1H), 3.76 (s, 3H), 3.65 - 3.52 (m, 2H), 3.25 (s, 3H), 2.54 - 2.41 (m, 2H), 2.09 - 1.93 (m, 2H), 1.85 - 1.80 (m, 2H), 1.78 (s, 3H).

[0245] (Example 50) (R)-N8-Cyclobutyl-N3-(2-methoxybenzyl)-4-(2-methoxyethyl)-3-methyl-5-oxo-2,3,4,5-tetrahydrobenzofuro[2,3-f][1,4]oxazepine-3,8-dicarboxamide

[0246] [ka] To a solution of (R)-3-((2-methoxybenzyl)carbamoyl)-4-(2-methoxyethyl)-3-methyl-5-oxo-2,3,4,5-tetrahydrobenzofuro[2,3-f][1,4]oxazepine-8-carboxylic acid (200 mg, 0.42 mmol, 1.0 equiv.) in DMF (5 mL) was added HATU (239.5 mg, 0.63 mmol, 1.5 equiv.), cyclobutanamine (44.8 mg, 0.63 mmol, 1.5 equiv.), DIPEA (108.6 mg, 0.84 mmol, 2.0 equiv.) at 0° C. After stirring at room temperature for 30 min, the reaction mixture was diluted with water (20 mL). The aqueous phase was extracted with ethyl acetate (3×20 mL). The combined organic phase was washed with brine (20 mL) and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography (EA) to give (R)-N8-cyclobutyl-N3-(2-methoxybenzyl)-4-(2-methoxyethyl)-3-methyl-5-oxo-2,3,4,5-tetrahydrobenzofuro[2,3-f][1,4]oxazepine-3,8-dicarboxamide as a yellow solid (120 g, 53%). LC-MS: 536.20[M+1]+. 1H NMR (400 MHz, CDCl3) δ 7.82 (s, 1H), 7.59 - 7.49 (m, 2H), 7.45 (t, J = 5.2 Hz, 1H), 6.92-6.80 (m, 2H), 6.57 (d, J = 8.0 Hz, 1H), 6.44 (t, J = 7.2 Hz, 1H), 6.28 (d, J = 7.4 Hz, 1H), 4.89 (d, J = 11.7 Hz, 1H), 4.71 - 4.52 (m, 1H), 4.35 (dd, J = 14.2, 7.0 Hz, 1H), 4.30-4.20 (m, 1H), 4.18 - 4.01 (m, 2H), 3.84 - 3.77 (m, 1H), 3.76 (s, 3H), 3.68 - 3.53 (m, 2H), 3.25 (s, 3H), 2.56 - 2.38 (m, 2H), 2.15 - 1.94 (m, 2H), 1.88 - 1.79 (m, 2H), 1.78 (s, 3H).

[0247] Intermediate BB-4 3-((2-Methoxybenzyl)carbamoyl)-4-(2-methoxyethyl)-3-methyl-5-oxo-2,3,4,5-tetrahydrobenzofuro[2,3-f][1,4]oxazepine-8-carboxylic acid

[0248] [ka] A mixture of 2-hydroxyterephthalic acid (50 g, 274.6 mmol, 1.0 equiv), SOCl2 (300 mL), and DMF (1 mL) in THF (500 mL) was heated at 75 °C and stirred for 4 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in THF (100 mL) and added dropwise to a solution of t-BuOK (123 g, 1.1 mol, 4.0 equiv) in THF (500 mL). The reaction mixture was stirred at room temperature for 16 h and filtered. The filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (Hex / EtOAc, 100:1 to 50:1) to give di-tert-butyl 2-hydroxyterephthalate (30 g, 38%) as a light yellow solid. TLC: PE / EA=10:1, UV; R f (Compound 1)=0.01;R f (Compound 2)=0.80; 1 H NMR (400 MHz, CDCl3) δ (ppm): 11.00 (d, J = 2.1 Hz, 1H), 7.78 (d, J = 8.3 Hz, 1H), 7.53 (d, J = 1.7 Hz, 1H), 7.42 (dd, J = 8.3, 1.7 Hz, 1H), 1.62 (s, 9H), 1.57(s, 9H).

[0249] [ka] To a solution of di-tert-butyl 2-hydroxyterephthalate (30 g, 96.6 mmol, 1.0 equiv.) and K2CO3 (26.7 g, 193.3 mmol, 2.0 equiv.) in acetone (300 mL) was added methyl bromoacetate (29.5 g, 193.3 mmol, 2.0 equiv.). The reaction mixture was heated to reflux for 16 h, cooled to room temperature, and filtered. The filtrate was concentrated under reduced pressure to give crude di-tert-butyl 2-(2-methoxy-2-oxoethoxy)terephthalate (39.9 g) as a yellow solid. TLC: PE / EA=10:1, UV; R f (Compound 2)=0.80;R f (Compound 3)=0.30; 1 H NMR (400 MHz, CDCl3) δ (ppm): 7.72 - 7.68 (m, 1H), 7.59 (dd, J = 7.9, 1.5 Hz, 1H), 7.45 (d, J = 1.4 Hz, 1H), 4.72 (s, 2H), 3.78 (s, 3H), 1.59 (s, 9H), 1.55 (s, 9H).

[0250] [ka] To a solution of di-tert-butyl 2-(2-methoxy-2-oxoethoxy)terephthalate (39.9 g, 108.9 mmol, 1.0 equiv) in MeOH (100 mL) was added t-BuOK (18.3 g, 163.4 mmol, 1.5 equiv) in THF (200 mL) dropwise at 0° C. The reaction mixture was stirred at room temperature for 1.5 h. The mixture was quenched with aqueous NH4Cl and extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give crude 6-tert-butyl 2-methyl 3-hydroxybenzofuran-2,6-dicarboxylate (27 g) as a light yellow solid. 1 H NMR (400 MHz, CD3OD): δ (ppm) 7.99 (d, J = 1.1 Hz, 1H), 7.86 (dd, J = 8.3, 1.4 Hz, 1H), 7.78 (dd, J = 8.4, 0.9 Hz, 1H), 3.93 (s, 3H), 1.60 (s, 9H).

[0251] [ka] A mixture of 6-tert-butyl 2-methyl 3-hydroxybenzofuran-2,6-dicarboxylate (27 g, 92.4 mmol, 1.0 equiv), K2CO3 (25.5 g, 184.7 mmol, 2.0 equiv), chloroacetone (12.8 g, 138.6 mmol, 1.5 equiv), and 18-crown-6 (2.4 g, 9.2 mmol, 0.1 equiv) in CH3CN (300 mL) was heated to 80 °C and stirred for 16 h. The reaction mixture was cooled to room temperature and filtered. The cake was diluted with EtOAc (3 x 300 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Hex / EtOAc=10:1 to 3:1) to give 6-tert-butyl 2-methyl 3-(2-oxopropoxy)benzofuran-2,6-dicarboxylate (5.3 g, 33%) as a light yellow solid. TLC: DCM / MeOH=20:1, UV; R f (Compound 4)=0.55;R f (Compound 5)=0.65;LC-MS: 349.15 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ (ppm): 8.13 - 8.08 (m, 1H), 7.91 (dt, J = 8.3, 1.0 Hz, 1H), 7.74 (dt, J = 8.3, 0.7 Hz, 1H), 5.05 (s, 2H), 3.97 - 3.91 (m, 3H), 2.32 - 2.25 (m, 3H), 1.65 - 1.55 (m, 9H).

[0252] [ka] To a solution of 6-tert-butyl 2-methyl 3-(2-oxopropoxy)benzofuran-2,6-dicarboxylate (18.8 g, 53.96 mmol, 1.0 equiv.) in THF (100 mL) and MeOH (100 mL) was added LiOH solution (5 w / w% in H2O, 50 mL). The reaction mixture was stirred at room temperature for 2 h, adjusted to pH 2-3 by adding 1N HCl, and extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give crude 6-(tert-butoxycarbonyl)-3-(2-oxopropoxy)benzofuran-2-carboxylic acid (12 g) as a yellow solid, which was used directly in the next step. LC-MS: 335.05 [M+H] + .

[0253] [ka] A mixture of 6-(tert-butoxycarbonyl)-3-(2-oxopropoxy)benzofuran-2-carboxylic acid (12.0 g, 35.9 mmol, 1.0 equiv.), 2-methoxyethylamine (2.7 g, 35.9 mmol, 1.0 equiv.), and 2-methoxybenzyl isocyanide (5.81 g, 39.5 mmol, 1.1 equiv.) in MeOH (120 mL) was stirred at room temperature for 16 h and concentrated under reduced pressure. The crude product was recrystallized from MeOH to give tert-butyl 3-((2-methoxybenzyl)carbamoyl)-4-(2-methoxyethyl)-3-methyl-5-oxo-2,3,4,5-tetrahydrobenzofuro[2,3-f][1,4]oxazepine-8-carboxylate (6.5 g, 34%) as a white solid. LC-MS: 539.3 [M+H] + ; 1 H NMR (400 MHz, CDCl3) δ (ppm): 7.99 (q, J = 1.2 Hz, 1H), 7.79 (dt, J = 8.3, 1.2 Hz, 1H), 7.56 - 7.49 (m, 1H), 7.41 (s, 1H), 6.91 - 6.76 (m, 2H), 6.55 (d, J = 8.1 Hz, 1H), 6.42 (s, 1H), 4.86 (d, J = 12.0 Hz, 1H), 4.32 (dt, J = 23.5, 11.7 Hz, 2H), 4.15 - 4.02 (m, 2H), 3.81 - 3.70 (m, 4H), 3.61 - 3.50 (m, 2H), 3.23 (s, 3H), 1.76 (s, 3H), 1.61 (s, 9H).

[0254] 3-((2-Methoxybenzyl)carbamoyl)-4-(2-methoxyethyl)-3-methyl-5-oxo-2,3,4,5-tetrahydrobenzofuro[2,3-f][1,4]oxazepine-8-carboxylic acid

[0255] [ka] A mixture of tert-butyl 3-((2-methoxybenzyl)carbamoyl)-4-(2-methoxyethyl)-3-methyl-5-oxo-2,3,4,5-tetrahydrobenzofuro[2,3-f][1,4]oxazepine-8-carboxylate (4.0 g, 7.43 mmol, 1.0 equiv.) and TFA (40 mL) in CHCl (40 mL) was stirred at room temperature for 2 h and concentrated under reduced pressure. The crude product was triturated with MeOH to give the compound 3-((2-methoxybenzyl)carbamoyl)-4-(2-methoxyethyl)-3-methyl-5-oxo-2,3,4,5-tetrahydrobenzofuro[2,3-f][1,4]oxazepine-8-carboxylic acid (2.8 g, 78%) as a white solid. LC-MS: 483.2 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 8.27 (s, 1H), 8.05 (d, J = 1.1 Hz, 1H), 7.91 (d, J = 8.0 Hz, 1H), 7.78 (d, J = 8.0 Hz, 1H), 7.04 (t, J = 7.0 Hz, 1H), 6.84 (d, J = 8.0 Hz, 1H), 6.71 (brs, 1H), 6.32 (brs, 1H), 4.93 (d, J = 12.5 Hz, 1H), 4.36 (d, J = 12.5 Hz, 1H), 4.14 (d, J = 5.7 Hz, 2H), 3.95 - 3.60 (m, 5H), 3.50 (brs, 2H), 3.23 (s, 3H), 1.70 (s, 3H). Two isomers were obtained by chiral HPLC. Chiral IC-H column (0.46 cm ID x 15 cm), heptane:ethanol (60:40); flow rate 0.5 mL / min, monitored at 254 nm. Peak 1: (2.72 min, 100% ee). LC-MS: 483.2 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 8.32 (brs, 1H), 8.05 (s, 1H), 7.90 (d, J = 8.0 Hz, 1H),7.74 (d, J = 9.7 Hz, 1H), 7.04 (t, J = 7.0 Hz, 1H), 6.84 (d, J = 8.0 Hz, 1H), 6.73 (brs, 1H), 6.35 (brs, 1H), 4.96 (d, J = 12.5 Hz, 1H), 4.38 (d, J = 12.5 Hz, 1H), 4.16 (d, J = 5.7 Hz, 2H), 3.95 - 3.60 (m, 5H), 3.50 (brs, 2H), 3.22 (s, 3H), 1.72 (s, 3H).Peak 2 (3.29 min, 99.2% ee).

[0256] General Procedure for Amide Formation

[0257] [ka] To a solution of carboxylic acid (100 mg, 0.21 mmol, 1.0 equiv) in DMF (2 mL) was added HATU (118 mg, 0.31 mmol, 1.5 equiv). The mixture was stirred at room temperature for 10 min. Amine RNH2 and DIPEA (54 mg, 0.41 mmol, 2.0 equiv) were added. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was poured into H2O (30 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude products were purified by preparative HPLC to give the respective final products after lyophilization.

[0258] (Example 51)

[0259] [ka] LC-MS: 510.45 [M+H] + ; 1 H NMR (400 MHz, CDCl3) δ (ppm): 7.78 (s, 1H), 7.50 (d, J = 19.0 Hz, 3H), 6.85 (d, J = 6.9 Hz, 2H), 6.56 (s, 1H), 6.41 (s, 1H), 6.23 (s, 1H), 4.94 - 4.80 (m, 1H), 4.32 (s, 2H), 4.06 (s, 2H), 3.74 (s, 4H), 3.53 (s, 4H), 3.23 (s, 3H), 1.76 (s, 3H), 1.28 (t, J = 7.2 Hz, 3H).

[0260] (1r,3r)-3-Methoxycyclobutanamine hydrochloride

[0261] [ka] To a mixture of 2-(3-hydroxycyclobutyl)isoindoline-1,3-dione (5.3 g, 24.4 mmol, 1.0 equiv) in DCM (50 mL) was added HBF4 (2.4 mL, 48% in water, 24.4 mmol, 1.0 equiv), TMSCHN2 (2M in hexanes, 24.4 mL, 48.8 mmol, 2.0 equiv) at 0 °C. The mixture was slowly warmed to room temperature and stirred for 2 h. Water (50 mL) was added. The aqueous phase was extracted with EA (3 x 50 mL). The combined organic solution was washed with brine (50 mL), dried over anhydrous Na2SO4 and the solution was concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE:EA=9:1) to give 2-((1s,3s)-3-methoxycyclobutyl)isoindoline-1,3-dione (2-P1) (300 mg, 5%) as a white solid and 2-((1r,3r)-3-methoxycyclobutyl)isoindoline-1,3-dione (2-P2) (1.8 g, 31%) as a white solid. LC-MS of 2-P1: 232.1 [M+1] + ; 2-P1 1H NMR (400 MHz, CDCl3) δ 7.89 - 7.76 (m, 2H), 7.78 - 7.61 (m, 2H), 5.11 - 4.93 (m, 1H), 4.39 - 4.23 (m, 1H), 3.31 (s, 3H), 3.09 - 2.90 (m, 2H), 2.55 - 2.33 (m, 2H). LC-MS of 2-P2: 232.1 [M+1] +; 1H NMR of 2-P2 (400 MHz, CDCl3) δ 7.86 - 7.80 (m, 2H), 7.73 - 7.68 (m, 2H), 4.39 - 4.22 (m, 1H), 3.80 - 3.67 (m, 1H), 3.31 (s, 3H), 2.98 - 2.81 (m, 2H), 2.72 - 2.59 (m, 2H).

[0262] [ka] To a solution of 2-((1r,3r)-3-methoxycyclobutyl)isoindoline-1,3-dione (2-P2) (280 mg, 1.21 mmol, 1.0 equiv) in MeOH (3 mL) was added MeNH2 (33% in EtOH, 3 mL). The mixture was stirred at room temperature overnight. The insoluble material was filtered off and the mother liquor was concentrated to a small volume and filtered again. The remainder of the volatile material was evaporated and the residue was purified by silica gel chromatography (DCM:MeOH=10:1) and subsequently acidified to pH 3-4 with HCl (8%) in EA. After concentration under reduced pressure, 110 mg (66%) of (1r,3r)-3-methoxycyclobutanamine hydrochloride was obtained as a white solid. 1H NMR (400 MHz, DMSO) δ 8.36 (s, 3H), 4.15 - 4.04 (m, 1H), 3.73 - 3.61 (m, 1H), 3.18 - 3.11 (s, 3H), 2.39 - 2.27 (m, 2H), 2.27 - 2.17 (m, 2H).

[0263] Using the procedures and intermediates above, the following compounds were prepared:

[0264] [Table 4-1]

[0265] [Table 4-2]

[0266] [Table 4-3]

[0267] [Table 4-4]

[0268] [Table 4-5]

[0269]

Table 4-6

[0270]

Table 4-7

[0271]

Table 4-8

[0272]

Table 4-9

[0273]

Table 4-10

[0274]

Table 4-11

[0275]

Table 4-12

[0276]

Table 4-13

[0277]

Table 4-14

[0278]

Table 4-15

[0279] [Table 4-16]

[0280] Intermediate BB-6

[0281] [ka] A mixture of compound 4-bromo-2-hydroxybenzoic acid (200 g, 0.92 mol, 1.0 equiv.), SOCl2 (550 g, 4.60 mol, 5.0 equiv.), and DMF (15 mL) in MeOH (500 mL) was heated at 65° C. and stirred for 10 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was washed with saturated NaOH, extracted with EA, and the combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain crude compound methyl 4-bromo-2-hydroxybenzoate (205 g, 96%) as a light yellow solid. TLC: PE / EA=3:1, UV; R f (Compound 1)=0.01;R f (Compound 2)=0.80;LC-MS: 231.0 [M+1] +; 1H NMR (400 MHz, CDCl3) δ 10.82 (s, 1H), 7.67 (d, J = 8.5 Hz, 1H), 7.17 (d, J = 1.9 Hz, 1H), 7.01 (dd, J = 8.5, 1.9 Hz, 1H), 3.94 (s, 3H).

[0282] [ka] Methyl bromoacetate (164 g, 1.07 mol, 1.2 equiv.) was added dropwise over 30 min to a stirred mixture of compound methyl 4-bromo-2-hydroxybenzoate (205 g, 0.89 mol, 1.0 equiv.) and potassium carbonate (192 g, 1.33 mol, 1.5 equiv.) in MeCN (2 L). The mixture was heated and stirred under reflux for 4 h. The reaction was monitored by LCMS. The reaction was cooled and the salts were separated by filtration and washed with acetone. The filtrate was concentrated to give a residue which was diluted with EA (2 L) and the solution was washed successively with water, aqueous sodium carbonate, water, and brine. The crude product was distilled under reduced pressure to give compound methyl 4-bromo-2-(2-methoxy-2-oxoethoxy)benzoate (255 g, 95%) as a brown solid. TLC: PE / EA=3:1, UV; R f (Compound 2)=0.80;R f (Compound 3)=0.50;LC-MS: 303.0 [M+1] + .1H NMR (400 MHz, DMSO) δ 7.61 (d, J = 8.3 Hz, 1H), 7.34 (d, J = 1.7 Hz, 1H), 7.27 (dd, J = 8.3, 1.7 Hz, 1H), 4.97 (s, 2H), 3.80 (s, 3H), 3.71 (s, 3H).

[0283] [ka] To a mixture of compound methyl 4-bromo-2-(2-methoxy-2-oxoethoxy)benzoate (255 g, 0.84 mol, 1.0 equiv.) in MeOH (1 L), NaOMe (30% in methanol, 182 mL, 1.01 mol, 1.2 equiv.) was added and the mixture was stirred at 60° C. for 4 h. The reaction was monitored by LCMS. The resulting mixture was cooled, poured into ice water, and acidified to pH 2 with 5% hydrochloric acid. The solid was collected by filtration, washed with water, and recrystallized from methanol to obtain compound methyl 6-bromo-3-hydroxybenzofuran-2-carboxylate (220 g, 96%) as a yellow solid. TLC: PE / EA=3:1, UV; Rf (Compound 3)=0.50;R f (Compound 4)=0.45;LC-MS: 271.1 [M+1] + .1H NMR (400 MHz, DMSO) δ 11.04 (s, 1H), 7.92 (d, J = 1.5 Hz, 1H), 7.85 (d, J = 8.5 Hz, 1H), 7.49 (dd, J = 8.5, 1.6 Hz, 1H), 3.84 (s, 3H).

[0284] [ka] To a mixture of compound methyl 6-bromo-3-hydroxybenzofuran-2-carboxylate (200 g, 0.74 mol, 1.0 eq.) in acetonitrile (1 L), TEA (89 g, 0.89 mol, 1.2 eq.), chloroacetone (75 g, 0.81 mmol, 1.1 eq.) were added and the mixture was refluxed for 4 h. The reaction was monitored by LCMS. The resulting mixture was filtered, concentrated and extracted with ethyl acetate to obtain crude compound methyl 6-bromo-3-(2-oxopropoxy)benzofuran-2-carboxylate (23 g, 95%) as a brown solid. TLC: PE / EA=3:1, UV; R f (Compound 4)=0.45;R f (Compound 5)=0.6;LC-MS:327.1[M+1] + .

[0285] [ka] A solution of crude compound methyl 6-bromo-3-(2-oxopropoxy)benzofuran-2-carboxylate (100 g, 0.31 mol, 1.0 equiv.) in MeOH (1 L) and 20% NaOH in water (400 mL) was stirred at room temperature for 4 h. The reaction was monitored by LCMS. The resulting mixture was concentrated, adjusted to pH 2 by adding 1N HCl, and extracted with ethyl acetate. The combined organic layers were washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica (DCM:MeOH=10:1) to give crude compound 6-bromo-3-(2-oxopropoxy)benzofuran-2-carboxylic acid (60 g, 63%) as a yellow solid. TLC: DCM:MeOH=10:1, UV;R f (Compound 5)=0.9;R f (Compound 6)=0.2;LC-MS: 313.0 [M+1] + .1H NMR (400 MHz, DMSO) δ 13.49 (s, 1H), 7.98 (d, J = 1.4 Hz, 1H), 7.77 (d, J = 8.5 Hz, 1H), 7.52 (dd, J = 8.5, 1.5 Hz, 1H), 5.20 (s, 2H), 2.16 (s, 3H).

[0286] [ka] A solution of acid 6-bromo-3-(2-oxopropoxy)benzofuran-2-carboxylic acid (50 g, 0.16 mmol, 1.0 equiv.), 2-methoxyethylamine (18 g, 2.4 mmol, 1.5 equiv.) and isonitrile (30 g, 0.21 mmol, 1.3 equiv.) in methanol (500 mL) was stirred at room temperature for 16 h. The conversion of the reagents was followed by TLC. Upon completion, the reaction mixture was cooled to room temperature and the residue was purified by flash column chromatography on silica gel (PE:EA=3:1), triturated with ethyl acetate and filtered to give 8-bromo-N-(2-methoxybenzyl)-4-(2-methoxyethyl)-3-methyl-5-oxo-2,3,4,5-tetrahydrobenzofuro[2,3-f][1,4]oxazepine-3-carboxamide (40 g, 48%) as a light yellow solid. TLC:PE:EA=1:3, UV;R f (Compound 6)=0.01;R f (Compound BB-6)=0.2;LC-MS: 517.2 [M+1] + ; 1H NMR (400 MHz, DMSO) δ 8.30 (s, 1H), 7.97 (s, 1H), 7.63 (d, J = 8.4 Hz, 1H), 7.50 (d, J = 8.3 Hz, 1H), 7.07 (t, J = 7.3 Hz, 1H), 6.85 (d, J = 8.1 Hz, 1H), 6.74 (s, 1H), 6.40 (s, 1H), 4.95 (d, J = 11.8 Hz, 1H), 4.37 (d, J = 12.3 Hz, 1H), 4.18 (d, J = 3.8 Hz, 2H), 3.78-3.74 (m, 2H), 3.72 (s, 3H), 3.50 (t, J = 5.6 Hz, 2H), 3.23 (s, 3H), 1.72 (s, 3H).

[0287] (Example 95) N-(2-Methoxybenzyl)-4-(2-methoxyethyl)-3,8-dimethyl-5-oxo-2,3,4,5-tetrahydrobenzofuro[2,3-f][1,4]oxazepine-3-carboxamide

[0288] [ka] A mixture of Pd(PPh3)4 (134 mg, 0.011 mmol, 0.12 equiv), K3PO4 (308 mg, 1.45 mmol), intermediate 8-bromo-N-(2-methoxybenzyl)-4-(2-methoxyethyl)-3-methyl-5-oxo-2,3,4,5-tetrahydrobenzofuro[2,3-f][1,4]oxazepine-3-carboxamide (500 mg, 0.10 mmol, 1.0 equiv) and 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (182 mg, 1.45 mmol, 1.5 equiv) in dioxane (3 ml) and H2O (0.3 ml) was degassed with argon for 2 min and the resulting mixture was stirred at 90 °C under argon for 3 h. The reaction mixture was cooled and diluted with ethyl acetate. The solution was washed with water. The organic layer was separated, dried over sodium sulfate, evaporated under reduced pressure, and the residue was purified by flash column chromatography on silica gel (PE:EA=3:1), triturated with ethyl acetate, and filtered to give N-(2-methoxybenzyl)-4-(2-methoxyethyl)-3,8-dimethyl-5-oxo-2,3,4,5-tetrahydrobenzofuro[2,3-f][1,4]oxazepine-3-carboxamide (150 mg, 34%) as a pale yellow solid. TLC: PE:EA=1:1, UV;R f (Compound BB-6)=0.2;R f (Compound 3)=0.5;LC-MS: 453.2 [M+1] + ; 1H NMR (400 MHz, CDCl3) δ 7.41 (d, J = 8.1 Hz, 1H), 7.36 (s, 1H), 7.20 (s, 1H), 7.02 (d, J = 8.1 Hz, 1H), 6.92 (dd, J = 13.3, 7.1 Hz, 2H), 6.59 (d, J = 8.1 Hz, 1H), 6.50 (t, J = 7.1 Hz, 1H), 4.84 (d, J = 12.0 Hz, 1H), 4.36 (dd, J = 14.4, 6.7 Hz, 1H), 4.27 - 4.00 (m, 3H), 3.84 - 3.76 (m, 1H), 3.75 (s, 3H), 3.65 - 3.53 (m, 2H), 3.23 (s, 3H), 2.48 (s, 3H), 1.76 (s, 3H).

[0289] Using the procedures and intermediates above, the following compounds were prepared:

[0290] [Table 5]

[0291] Intermediate BB-7

[0292] [ka] A mixture of (1,1'-bis(diphenylphosphino)ferrocene)palladium(ll) chloride (200 mg, 0.27 mmol, 0.03 equiv.), potassium acetate (2.64 g, 26.9 mmol), intermediate 8-bromo-N-(2-methoxybenzyl)-4-(2-methoxyethyl)-3-methyl-5-oxo-2,3,4,5-tetrahydrobenzofuro[2,3-f][1,4]oxazepine-3-carboxamide (4.2 g, 8.2 mmol, 1.1 equiv.) and bis(pinacolato)diboron (2.3 g, 9.1 mmol, 1.1 equiv.) in dioxane (60 ml) was degassed with argon for 5 min and the resulting mixture was stirred at 100° C. under argon for 3 h. The reaction mixture was cooled and diluted with ethyl acetate. The solution was washed with water. The organic layer was separated, dried over sodium sulfate, evaporated under reduced pressure, and the residue was purified by flash column chromatography on silica gel (PE:EA=3:1), triturated with ethyl acetate, and filtered to give N-(2-methoxybenzyl)-4-(2-methoxyethyl)-3-methyl-5-oxo-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3,4,5-tetrahydrobenzofuro[2,3-f][1,4]oxazepine-3-carboxamide (2.8 g, 61%) as a light yellow solid. LC-MS: 565.2[M+1] + ;TLC:PE:EA=3:1, UV;R f (Compound BB-6)=0.4;R f (Compound BB-7)=0.8.

[0293] Using the procedures and intermediates above, the following compounds were prepared:

[0294] [Table 6]

[0295] Intermediate BB-8 5-Chloro-3-(2-oxopropoxy)benzofuran-2-carboxylic acid

[0296] [ka]

[0297] Methyl 5-chloro-2-(2-methoxy-2-oxoethoxy)benzoate Methyl bromoacetate (90 g, 0.589 mol, 1.1 equiv.) was added dropwise over 30 min to a stirred mixture of compound methyl 5-chloro-2-hydroxybenzoate (100 g, 0.536 mol, 1.0 equiv.), 18-crown-6 (3 g, 0.011 mol, 0.02 equiv.) and potassium carbonate (111 g, 0.804 mol, 1.5 equiv.) in MeCN (2 L). The mixture was heated and stirred under reflux for 4 h. The reaction was monitored by LCMS. The reaction was cooled and the salts were separated by filtration and washed with acetone. The filtrate was concentrated to give a residue which was diluted with EA (2 L) and the solution was washed successively with water, aqueous sodium carbonate, water, and brine. The crude product was distilled under reduced pressure to give the product (138.7 g) as a brown solid. The crude product was used directly in the next step. TLC:PE / EA=5:1, UV;R f Starting material = 0.8, product = 0.5. LC-MS: calculated exact mass = 258.0, observed [M+H] + =259.0.

[0298] Methyl 5-chloro-3-hydroxybenzofuran-2-carboxylate To a mixture of compound methyl 5-chloro-2-(2-methoxy-2-oxoethoxy)benzoate (138.7 g, 0.537 mol, 1.0 equiv.) in MeOH (1 L), NaOMe (30% in methanol, 5M, 128.8 mL, 0.644 mol, 1.2 equiv.) was added and the mixture was stirred at 60° C. for 4 h. The reaction was monitored by LCMS. The resulting mixture was cooled, poured into ice water, and acidified to pH 2 with 5% hydrochloric acid. The solid was collected by filtration, washed with water, and recrystallized from methanol to give the product (116 g, 96%) as a yellow solid. TLC: PE / EA=1:1, UV; R f Starting material = 0.5, product = 0.4. LC-MS: calculated exact mass = 226.0, observed [M+H] +=227.1.

[0299] Methyl 5-chloro-3-(2-oxopropoxy)benzofuran-2-carboxylate To a mixture of compound methyl 5-chloro-3-hydroxybenzofuran-2-carboxylate (115 g, 0.508 mol, 1.0 eq.) in acetonitrile (1 L), TEA (103 g, 1.017 mol, 2 eq.), chloroacetone (47 g, 0.508 mmol, 1.0 eq.) were added and the mixture was refluxed for 4 h. The reaction was monitored by LCMS. The resulting mixture was filtered, concentrated and extracted with ethyl acetate to give the product (108 g, 75%) as a brown solid. TLC: PE / EA=1:1, UV; R f Starting material = 0.4, product = 0.8. LC-MS: calculated exact mass = 282.0, observed [M+H] + =283.0.

[0300] 5-Chloro-3-(2-oxopropoxy)benzofuran-2-carboxylic acid A solution of crude compound methyl 5-chloro-3-(2-oxopropoxy)benzofuran-2-carboxylate (90 g, 0.318 mol, 1.0 equiv.) in MeOH (1 L) and 10% NaOH in water (400 mL) was stirred at room temperature for 4 h. The reaction was monitored by LCMS. The resulting mixture was concentrated, adjusted to pH 2 by adding 1N HCl, and extracted with ethyl acetate. The combined organic layers were washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography on silica (DCM:MeOH=10:1) to give the product (26 g, 50%) as a yellow solid. TLC: DCM:MeOH=10:1, UV;R f Starting material = 0.9, product = 0.2. LC-MS: calculated exact mass = 268.0, observed [M+H] + = 269.1. 1 H NMR (400 MHz, DMSO) δ 13.55 (s, 1H), 7.88 (d, J = 2.1 Hz, 1H), 7.68 (d, J = 8.9 Hz, 1H), 7.56 (dd, J = 8.9, 2.2 Hz, 1H), 5.17 (s, 2H), 2.15 (s, 3H).

[0301] (Example 102) (R)-4-(2-(bis(methyl-d3)amino)-2-oxoethyl)-9-chloro-N-(2-fluoro-6-methoxybenzyl)-3-methyl-5-oxo-2,3,4,5-tetrahydrobenzofuro[2,3-f][1,4]oxazepine-3-carboxamide

[0302] [ka] Methyl 2-((R)-9-chloro-3-methyl-5-oxo-3-(((S)-1-phenylethyl)carbamoyl)-2,3-dihydrobenzofuro[2,3-f][1,4]oxazepin-4(5H)-yl)acetate A mixture of 5-chloro-3-(2-oxopropoxy)benzofuran-2-carboxylic acid (4 g, 14.89 mmol, 1.0 equiv), methyl glycinate hydrochloride (2.8 g, 22.34 mmol, 1.5 equiv), TEA (4.5 g, 44.68 mmol, 3.0 equiv) and (S)-(1-isocyanoethyl)benzene (2.15 g, 16.38 mmol, 1.1 equiv) in MeOH (20 mL) was stirred at 50° C. for 16 h. The mixture was concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel (PE:EA=1:1) to give the product (2 g, 28.6%) as a yellow solid. TLC: PE / EA=1:1, UV; R f Starting material = 0.0, product = 0.4, isomer = 0.6; LC-MS: calculated exact mass = 470.1, observed [M+H] + =471.1.

[0303] 2-((R)-9-Chloro-3-methyl-5-oxo-3-(((S)-1-phenylethyl)carbamoyl)-2,3-dihydrobenzofuro[2,3-f][1,4]oxazepin-4(5H)-yl)acetic acid A mixture of methyl 2-((R)-9-chloro-3-methyl-5-oxo-3-(((S)-1-phenylethyl)carbamoyl)-2,3-dihydrobenzofuro[2,3-f][1,4]oxazepin-4(5H)-yl)acetate (2 g, 4.2 mmol, 1.0 equiv.), 6M HCl (40 mL) in dioxane (80 mL) was stirred at 80° C. for 16 h. The mixture was concentrated under reduced pressure. The solution was extracted with EA and the solvent was removed under reduced pressure to give the product (1. g, 92.8%) as a yellow solid. TLC: PE / EA=1:1, UV; R f Starting material = 0.4, product = 0.0. LC-MS: calculated exact mass = 456.1, observed [M+H] + =457.1.

[0304] (R)-4-(2-(bis(methyl-d3)amino)-2-oxoethyl)-9-chloro-3-methyl-5-oxo-N-((S)-1-phenylethyl)-2,3,4,5-tetrahydrobenzofuro[2,3-f][1,4]oxazepine-3-carboxamide To a solution of 2-((R)-9-chloro-3-methyl-5-oxo-3-(((S)-1-phenylethyl)carbamoyl)-2,3-dihydrobenzofuro[2,3-f][1,4]oxazepin-4(5H)-yl)acetic acid (1 g, 2.19 mmol, 1.0 equiv.) in DMF (30 mL) was added HATU (1.25 g, 3.29 mmol, 1.5 equiv.), bis(methyl-d3)amine hydrochloride (383 mg, 4.38 mmol, 2.0 equiv.) and DIPEA (1.4 g, 10.95 mmol, 5.0 equiv.). The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was poured into H2O (30 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel (DCM:MeOH=5:1) to give the product (800 mg, 74.7%) as a white solid. TLC: DCM / MeOH=5:1, UV; f Starting material = 0.15, product = 0.6. LC-MS: calculated exact mass = 565.2, observed [M+H] +=566.2.

[0305] tert-Butyl ((R)-4-(2-(bis(methyl-d3)amino)-2-oxoethyl)-9-chloro-3-methyl-5-oxo-2,3,4,5-tetrahydrobenzofuro[2,3-f][1,4]oxazepine-3-carbonyl)((S)-1-phenylethyl)carbamate To a solution of (R)-4-(2-(bis(methyl-d3)amino)-2-oxoethyl)-9-chloro-3-methyl-5-oxo-N-((S)-1-phenylethyl)-2,3,4,5-tetrahydrobenzofuro[2,3-f][1,4]oxazepine-3-carboxamide (750 mg, 1.53 mmol, 1.0 equiv.) in TEA (20 mL) and DMA (2 mL) was added (Boc)2O (6.5 g, 30.6 mmol, 20.0 equiv.), DMAP (238 mg, 1.95 mmol, 1.5 equiv.). The mixture was stirred at 100° C. for 3 h. Water (50 mL) was added. The aqueous phase was extracted with EA (3×50 mL). The combined organic solution was washed with brine (50 mL), dried over anhydrous Na2SO4, and the solution was concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE:EA=1:2) to give the product (750 mg, 83%) as a brown solid. TLC: PE / EA=1:2, UV; f Starting material = 0.15, product = 0.6. LC-MS: calculated exact mass = 589.2, observed [M+H] + =590.2

[0306] (R)-4-(2-(bis(methyl-d3)amino)-2-oxoethyl)-9-chloro-3-methyl-5-oxo-2,3,4,5-tetrahydrobenzofuro[2,3-f][1,4]oxazepine-3-carboxylic acid To a solution of tert-butyl ((R)-4-(2-(bis(methyl-d3)amino)-2-oxoethyl)-9-chloro-3-methyl-5-oxo-2,3,4,5-tetrahydrobenzofuro[2,3-f][1,4]oxazepine-3-carbonyl)((S)-1-phenylethyl)carbamate (750 mg, 1.27 mmol, 1.0 equiv) in THF (5 mL), MeOH (6 mL), HO (3 mL) was added KOH (1.4 g, 25.4 mmol, 20.0 equiv). The mixture was stirred at 70 °C for 3 h. The reaction mixture was concentrated under reduced pressure and then acidified to pH 4-5 with 1 N HCl. The solid was filtered to give the product (410 mg, 83.6%) as a white solid. The crude product was used directly in the next step. LC-MS: calculated exact mass = 386.1, observed [M+H] + =387.1

[0307] (R)-4-(2-(bis(methyl-d3)amino)-2-oxoethyl)-9-chloro-N-(2-fluoro-6-methoxybenzyl)-3-methyl-5-oxo-2,3,4,5-tetrahydrobenzofuro[2,3-f][1,4]oxazepine-3-carboxamide To a solution of (R)-4-(2-(bis(methyl-d3)amino)-2-oxoethyl)-9-chloro-3-methyl-5-oxo-2,3,4,5-tetrahydrobenzofuro[2,3-f][1,4]oxazepine-3-carboxylic acid (150 mg, 0.389 mmol, 1.0 equiv.) in DMF (2 mL) was added HATU (222 mg, 0.584 mmol, 1.5 equiv.). The mixture was stirred at room temperature for 10 min. (2-Fluoro-6-methoxyphenyl)methanamine (72.3 mg, 0.466 mmol, 1.2 equiv.) and DIPEA (251 mg, 1.95 mmol, 5.0 equiv.) were added. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was poured into HO (30 mL) and extracted with EtOAc (3×30 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by preparative HPLC to give the product (85 mg, 41.8%) as a white solid. LC-MS: Calculated exact mass = 523.2, found [M+H]+ = 524.2. 1 H NMR (400 MHz, DMSO) δ 9.55 (s, 1H), 7.58 (d, J = 13.5 Hz, 1H), 7.55 (d, J = 8.9 Hz, 1H), 7.49 (dd, J = 8.9, 2.1 Hz, 1H), 7.04 (dd, J = 15.2, 7.8 Hz, 1H), 6.61 (d, J = 8.3 Hz, 1H), 6.38 (s, 1H), 4.84 (d, J = 11.8 Hz, 1H), 4.49 (s, 1H), 4.38 - 4.22 (m, 3H), 3.92 (s, 1H), 3.63 (s, 3H), 1.53 (s, 3H).

[0308] The following examples were prepared using procedures similar to those described above.

[0309] [Table 7]

[0310] (Examples 106 and 107) 9-Chloro-4-(2-(dimethylamino)-2-oxoethyl)-N-(2-fluoro-6-methoxybenzyl)-3-methyl-5-oxo-2,3,4,5-tetrahydrobenzofuro[2,3-f][1,4]oxazepine-3-carboxamide and (S)-9-Chloro-4-(2-(dimethylamino)-2-oxoethyl)-N-(2-fluoro-6-methoxybenzyl)-3-methyl-5-oxo-2,3,4,5-tetrahydrobenzofuro[2,3-f][1,4]oxazepine-3-carboxamide

[0311] [ka] 9-Chloro-4-(2-(dimethylamino)-2-oxoethyl)-N-(2-fluoro-6-methoxybenzyl)-3-methyl-5-oxo-2,3,4,5-tetrahydrobenzofuro[2,3-f][1,4]oxazepine-3-carboxamide A mixture of 5-chloro-3-(2-oxopropoxy)benzofuran-2-carboxylic acid (7 g, 26.1 mmol, 1.0 equiv.), 2-amino-N,N-dimethylacetamide (3.2 g, 31.32 mmol, 1.2 equiv.), and 1-fluoro-2-(isocyanomethyl)-3-methoxybenzene (4.3 g, 26.1 mmol, 1.0 equiv.) in MeOH (20 mL) was stirred at 50° C. for 16 h. The mixture was concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel (PE:EA=1:1) to give the product (7 g, 51.8%) as a yellow solid. TLC:PE / EA=1:1, UV;R f Starting material = 0.0, product = 0.4. LC-MS: calculated exact mass = 517.2, observed [M+H] + = 518.2. 1 H NMR (400 MHz, DMSO) δ 9.54 (s, 1H), 7.60 (s, 1H), 7.55 (d, J = 8.9 Hz, 1H), 7.49 (dd, J = 8.9, 2.1 Hz, 1H), 7.04 (dd, J = 15.0, 7.7 Hz, 1H), 6.61 (d, J = 8.2 Hz, 1H), 6.38 (s, 1H), 4.84 (d, J = 11.8 Hz, 1H), 4.49-4.47 (m, 1H), 4.38 - 4.20 (m, 3H),4.01- 3.92 (m, 1H), 3.63 (s, 3H), 3.03 (s, 3H), 2.86 (s, 3H), 1.53 (s, 3H).

[0312] (S)-9-Chloro-4-(2-(dimethylamino)-2-oxoethyl)-N-(2-fluoro-6-methoxybenzyl)-3-methyl-5-oxo-2,3,4,5-tetrahydrobenzofuro[2,3-f][1,4]oxazepine-3-carboxamide Chiral HPLC: Chiral AS-H column (0.46 cm ID x 15 cm L), CO2:ethanol (0.1% DEA) (70:30); flow rate 2.5 mL / min, monitored at 254 nm. Peak 1 = 3.397 min, 100% ee, 3.2 g. LC-MS: calculated exact mass = 517.2, observed [M+H] + = 518.2. 1 H NMR (400 MHz, DMSO) δ 9.57 (s, 1H), 7.60 (s, 1H), 7.56 (d, J = 8.9 Hz, 1H), 7.49 (dd, J = 8.9, 2.2 Hz, 1H), 7.15 - 6.93 (m, 1H), 6.61 (d, J = 8.2 Hz, 1H), 6.38 (s, 1H), 4.84 (d, J = 11.8 Hz, 1H), 4.50 (m, 1H), 4.38 - 4.18 (m, 3H), 4.01-3.92 (m, 1H), 3.63 (s, 3H), 3.03 (s, 3H), 2.87 (s, 3H), 1.53 (s, 3H).

[0313] (R)-9-Chloro-4-(2-(dimethylamino)-2-oxoethyl)-N-(2-fluoro-6-methoxybenzyl)-3-methyl-5-oxo-2,3,4,5-tetrahydrobenzofuro[2,3-f][1,4]oxazepine-3-carboxamide Chiral HPLC: Chiral AS-H column (0.46 cm ID x 15 cm L), CO2:ethanol (0.1% DEA) (70:30); flow rate 2.5 mL / min, monitored at 254 nm. Peak 2 = 3.661 min, 98.05% ee, 3.1 g. LC-MS: calculated exact mass = 517.2, observed [M+H] + = 518.2.1 H NMR (400 MHz, DMSO) δ 9.57 (s, 1H), 7.60 (s, 1H), 7.56 (d, J = 8.9 Hz, 1H), 7.49 (dd, J = 8.9, 2.2 Hz, 1H), 7.15 - 6.93 (m, 1H), 6.61 (d, J = 8.2 Hz, 1H), 6.38 (s, 1H), 4.84 (d, J = 11.8 Hz, 1H), 4.50 (m, 1H), 4.38 - 4.18 (m, 3H), 4.01-3.92 (m, 1H), 3.63 (s, 3H), 3.03 (s, 3H), 2.87 (s, 3H), 1.53 (s, 3H).

[0314] (Example 108) 9-Chloro-N-(2-fluoro-6-methoxybenzyl)-3-methyl-4-((1-methyl-1H-1,2,4-triazol-5-yl)methyl)-5-oxo-2,3,4,5-tetrahydrobenzofuro[2,3-f][1,4]oxazepine-3-carboxamide

[0315] [ka] 9-Chloro-N-(2-fluoro-6-methoxybenzyl)-3-methyl-4-((1-methyl-1H-1,2,4-triazol-5-yl)methyl)-5-oxo-2,3,4,5-tetrahydrobenzofuro[2,3-f][1,4]oxazepine-3-carboxamide A mixture of 5-chloro-3-(2-oxopropoxy)benzofuran-2-carboxylic acid (80 mg, 0.298 mmol, 1.0 equiv), (1-methyl-1H-1,2,4-triazol-5-yl)methanamine (40 mg, 0.358 mmol, 1.2 equiv), and 1-fluoro-2-(isocyanomethyl)-3-methoxybenzene (59 mg, 0.358 mmol, 1.02 equiv) in MeOH (20 mL) was stirred at 50° C. for 16 h. The mixture was concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel (PE:EA=1:1) to give the product (70 mg, 44.5%) as a white solid. TLC: DCM / MeOH=10:1, UV; R f Starting material = 0.1, product = 0.4. LC-MS: calculated exact mass = 527.2, observed [M+H] + = 528.2. 1 H NMR (400 MHz, DMSO) δ 9.30 (s, 1H), 7.66 (d, J = 2.0 Hz, 1H), 7.60 (d, J = 8.9 Hz, 1H), 7.52 (dd, J = 8.9, 2.2 Hz, 1H), 7.50 (s, 1H), 7.16 (dd, J = 15.3, 8.3 Hz, 1H), 6.70 (d, J = 8.4 Hz, 1H), 6.54 (t, J = 8.7 Hz, 1H), 4.93 (d, J = 12.1 Hz, 1H), 4.87 (s, 2H), 4.40 (d, J = 12.1 Hz, 1H), 4.20 (dd, J = 13.7, 5.1 Hz, 1H), 4.13 - 4.03 (m, 1H), 3.86 (s, 3H), 3.60 (s, 3H), 1.66 (s, 3H).

[0316] (Example 109) 4-(2-(bis(methyl-d3)amino)-2-oxoethyl)-9-chloro-N-((3-ethoxypyridin-2-yl)methyl)-3-methyl-5-oxo-2,3,4,5-tetrahydrobenzofuro[2,3-f][1,4]oxazepine-3-carboxamide

[0317] [ka] Methyl 2-(9-chloro-3-((2-methoxybenzyl)carbamoyl)-3-methyl-5-oxo-2,3-dihydrobenzofuro[2,3-f][1,4]oxazepin-4(5H)-yl)acetate A mixture of 5-chloro-3-(2-oxopropoxy)benzofuran-2-carboxylic acid (2.4 g, 8.9 mmol, 1.0 equiv.), methyl glycinate hydrochloride (1.68 g, 13.4 mmol, 1.5 equiv.), TEA (2.71 g, 26.8 mmol, 3.0 equiv.) and 1-(isocyanomethyl)-2-methoxybenzene (2.63 g, 16.38 mmol, 1.2 equiv.) in MeOH (20 mL) was stirred at 50° C. for 16 h. The mixture was concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel (PE:EA=1:1) to give the product (2.6 g, 59.7%) as a yellow solid. TLC: PE / EA=1:1, UV; R f Starting material = 0.0, product = 0.4. LC-MS: calculated exact mass = 486.1, observed [M+H] + =487.1.

[0318] 2-(9-chloro-3-((2-methoxybenzyl)carbamoyl)-3-methyl-5-oxo-2,3-dihydrobenzofuro[2,3-f][1,4]oxazepin-4(5H)-yl)acetic acid A mixture of methyl 2-(9-chloro-3-((2-methoxybenzyl)carbamoyl)-3-methyl-5-oxo-2,3-dihydrobenzofuro[2,3-f][1,4]oxazepin-4(5H)-yl)acetate (2.5 g, 5.13 mmol, 1.0 equiv), 6M HCl (40 mL) in dioxane (80 mL) was stirred at 70° C. for 16 h. The mixture was concentrated under reduced pressure. The solution was extracted with EA and the solvent was removed under reduced pressure to give the product (2.3 g, 95%) as a yellow solid. LC-MS: calculated exact mass=472.0, found [M+H] + =473.1.

[0319] 4-(2-(bis(methyl-d3)amino)-2-oxoethyl)-9-chloro-N-(2-methoxybenzyl)-3-methyl-5-oxo-2,3,4,5-tetrahydrobenzofuro[2,3-f][1,4]oxazepine-3-carboxamide To a solution of 2-(9-chloro-3-((2-methoxybenzyl)carbamoyl)-3-methyl-5-oxo-2,3-dihydrobenzofuro[2,3-f][1,4]oxazepin-4(5H)-yl)acetic acid (1 g, 2.1 mmol, 1.0 equiv.) in DMF (30 mL) was added HATU (1.2 g, 3.1 mmol, 1.5 equiv.), bis(methyl-d3)amine hydrochloride (370 mg, 4.2 mmol, 2.0 equiv.) and DIPEA (1.36 g, 10.5 mmol, 5.0 equiv.). The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was poured into H2O (30 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel (DCM:MeOH=5:1) to give the product (900 mg, 85%) as a white solid. TLC: DCM / MeOH=5:1, UV; f Starting material = 0.15, product = 0.6. LC-MS: calculated exact mass = 505.1, observed [M+H] + =506.2.

[0320] tert-Butyl (4-(2-(bis(methyl-d3)amino)-2-oxoethyl)-9-chloro-3-methyl-5-oxo-2,3,4,5-tetrahydrobenzofuro[2,3-f][1,4]oxazepine-3-carbonyl)(2-methoxybenzyl)carbamate To a solution of 4-(2-(bis(methyl-d3)amino)-2-oxoethyl)-9-chloro-N-(2-methoxybenzyl)-3-methyl-5-oxo-2,3,4,5-tetrahydrobenzofuro[2,3-f][1,4]oxazepine-3-carboxamide (900 mg, 1.78 mmol, 1.0 equiv.) in TEA (20 mL) and DMA (2 mL) was added (Boc)2O (7.7 g, 35.6 mmol, 20.0 equiv.), DMAP (238 mg, 1.95 mmol, 1.5 equiv.). The mixture was stirred at 100° C. for 3 h. Water (50 mL) was added. The aqueous phase was extracted with EA (3×50 mL). The combined organic solution was washed with brine (50 mL), dried over anhydrous Na2SO4, and the solution was concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE:EA=1:2) to give the product (650 mg, 60%) as a brown solid. TLC: PE / EA=2:1, UV; f Starting material = 0.15, product = 0.6. LC-MS: calculated exact mass = 605.1, observed [M+H] + =606.1.

[0321] 4-(2-(bis(methyl-d3)amino)-2-oxoethyl)-9-chloro-3-methyl-5-oxo-2,3,4,5-tetrahydrobenzofuro[2,3-f][1,4]oxazepine-3-carboxylic acid To a solution of tert-butyl (4-(2-(bis(methyl-d3)amino)-2-oxoethyl)-9-chloro-3-methyl-5-oxo-2,3,4,5-tetrahydrobenzofuro[2,3-f][1,4]oxazepine-3-carbonyl)(2-methoxybenzyl)carbamate (500 mg, 0.826 mmol, 1.0 equiv) in THF (5 mL), MeOH (6 mL), HO (3 mL) was added KOH (0.925 g, 16.5 mmol, 20.0 equiv). The mixture was stirred at 70 °C for 3 h. The reaction mixture was concentrated under reduced pressure and then acidified to pH 4-5 with 1 N HCl. The solid was filtered to give the product (300 mg, 94%) as a white solid. The crude product was used directly in the next step. LC-MS: calculated exact mass = 386.1, observed [M+H] + =387.1

[0322] 4-(2-(bis(methyl-d3)amino)-2-oxoethyl)-9-chloro-N-((3-ethoxypyridin-2-yl)methyl)-3-methyl-5-oxo-2,3,4,5-tetrahydrobenzofuro[2,3-f][1,4]oxazepine-3-carboxamide To a solution of 4-(2-(bis(methyl-d3)amino)-2-oxoethyl)-9-chloro-3-methyl-5-oxo-2,3,4,5-tetrahydrobenzofuro[2,3-f][1,4]oxazepine-3-carboxylic acid (100 mg, 0.077 mmol, 1.0 equiv.) in DMF (2 mL) was added HATU (141 mg, 0.116 mmol, 1.5 equiv.). (3-Ethoxypyridin-2-yl)methanamine (43.3 mg, 0.085 mmol, 1.1 equiv.) and DIPEA (167 mg, 0.388 mmol, 5.0 equiv.) were added. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was poured into H2O (30 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by preparative HPLC to give the product (80 mg, 59.7%) as a white solid. LC-MS: calculated exact mass = 521.2, found [M+H] + = 522.2. 1H NMR (400 MHz, DMSO) δ 9.42 (s, 1H), 7.63-7.61 (m, 2H), 7.52 (dd, J = 8.9, 2.2 Hz, 2H), 7.18 (d, J = 7.6 Hz, 1H), 7.02 (s, 1H), 4.85 (d, J = 11.2 Hz, 1H), 4.48 (s, 2H), 4.40 - 4.23 (m, 2H), 4.21 - 3.80 (m, 3H), 1.58 (s, 3H), 1.27 (t, J = 6.9 Hz, 3H).

[0323] The following examples were prepared using procedures similar to those described above.

[0324] [Table 8]

[0325] Intermediate BB-9 5-Fluoro-3-(2-oxopropoxy)benzofuran-2-carboxylic acid

[0326] [ka] Methyl 5-fluoro-2-hydroxybenzoate To a solution of 5-fluoro-2-hydroxybenzoic acid (190 g, 1.218 mol, 1.0 equiv) in MeOH (2 L) was added H2SO4 (98%, 100 mL) and the mixture was heated and stirred under reflux for 1 h. The reaction was monitored by LCMS. The crude product was distilled under reduced pressure, washed with H2O, extracted with ethyl acetate and the organic phase was distilled under reduced pressure to give the product (192 g, 94%) as a brown solid. TLC: PE / EA=5:1, UV; R f Starting material = 0.0, product = 0.5. LC-MS: calculated exact mass = 170.0, observed [M+H] - =169.0.

[0327] Methyl 5-fluoro-2-(2-methoxy-2-oxoethoxy)benzoate Methyl bromoacetate (205 g, 1.34 mol, 1.2 eq.) was added dropwise over 30 min to a stirred mixture of compound methyl 5-fluoro-2-hydroxybenzoate (190 g, 1.12 mol, 1.0 eq.), 18-crown-6 (3 g, 0.011 mol, 0.02 eq.) and potassium carbonate (232 g, 1.68 mol, 1.5 eq.) in MeCN (1 L). The mixture was heated and stirred under reflux for 4 h. The reaction was monitored by LCMS. The reaction was cooled and the salts were separated by filtration and washed with acetone. The filtrate was concentrated to give a residue which was diluted with EA (2 L) and the solution was washed successively with water, aqueous sodium carbonate, water, and brine. The crude product was distilled under reduced pressure to give the product (270 g, 87%) as a brown solid. The crude product was used directly in the next step. TLC:PE / EA=4:1, UV;R f Starting material = 0.7, product = 0.4. LC-MS: calculated exact mass = 242.0, observed [M+H] + =243.0.

[0328] Methyl 6-bromo-3-hydroxyfuro[3,2-b]pyridine-2-carboxylate To a mixture of compound methyl 5-fluoro-2-(2-methoxy-2-oxoethoxy)benzoate (250 g, 1.1 mol, 1.0 equiv.) in MeOH (3 L), NaOMe (30% in methanol, 5M, 264 mL, 1.32 mol, 1.2 equiv.) was added and the mixture was stirred at 60° C. for 4 h. The reaction was monitored by LCMS. The resulting mixture was cooled, poured into ice water, and acidified to pH 2 with 5% hydrochloric acid. The solid was collected by filtration, washed with water, and recrystallized from methanol to give the product (190 g, 80%) as a yellow solid. TLC: PE / EA=1:1, UV; R f Starting material = 0.5, product = 0.4. LC-MS: calculated exact mass = 210.0, observed [M+H] + =211.1.

[0329] Methyl 5-fluoro-3-(2-oxopropoxy)benzofuran-2-carboxylate To a mixture of compound methyl 5-fluoro-3-hydroxybenzofuran-2-carboxylate (190 g, 0.905 mol, 1.0 eq.) in acetonitrile (1 L), TEA (110 g, 1.086 mol, 1.2 eq.), chloroacetone (92 g, 0.995 mmol, 1.1 eq.) were added and the mixture was refluxed for 4 h. The reaction was monitored by LCMS. The resulting mixture was filtered, concentrated and extracted with ethyl acetate to give the product (132 g, 73%) as a brown solid. TLC: PE / EA=1:1, UV; R f Starting material = 0.4, product = 0.8. LC-MS: calculated exact mass = 266.0, observed [M+H] + =267.0

[0330] 5-Fluoro-3-(2-oxopropoxy)benzofuran-2-carboxylic acid (BB-9) A solution of crude compound methyl 5-fluoro-3-(2-oxopropoxy)benzofuran-2-carboxylate (55 g, 0.207 mol, 1.0 equiv.) in MeOH (1.2 L) and 10% NaOH in water (600 mL) was stirred at room temperature for 4 h. The reaction was monitored by LCMS. The resulting mixture was concentrated, adjusted to pH 2 by adding 1N HCl, and extracted with ethyl acetate. The combined organic layers were washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography on silica (DCM:MeOH=10:1) to give the product (27 g, 31%) as a yellow solid. TLC: DCM:MeOH=5:1, UV;R f Starting material=0.9, product=0.2. LC-MS: Calculated exact mass = 252.0, Measured value [M+H] + = 253.0. 1 H NMR (400 MHz, DMSO) δ 13.51 (s, 1H), 7.69 (dd, J = 9.2, 4.0 Hz, 1H), 7.63 (dd, J = 8.5, 2.6 Hz, 1H), 7.41 (td, J = 9.2, 2.7 Hz, 1H), 2.17 (s, 3H).

[0331] (Example 111) 9-Fluoro-N-(2-fluoro-6-methoxybenzyl)-4-(2-((2-hydroxyethyl)(methyl)amino)-2-oxoethyl)-3-methyl-5-oxo-2,3,4,5-tetrahydrobenzofuro[2,3-f][1,4]oxazepine-3-carboxamide

[0332] [ka] Methyl 2-(9-fluoro-3-((2-fluoro-6-methoxybenzyl)carbamoyl)-3-methyl-5-oxo-2,3-dihydrobenzofuro[2,3-f][1,4]oxazepin-4(5H)-yl)acetate A mixture of 5-fluoro-3-(2-oxopropoxy)benzofuran-2-carboxylic acid (900 mg, 3.57 mmol, 1.0 equiv), methyl glycinate hydrochloride (669 mg, 5.36 mmol, 1.5 equiv), and 1-fluoro-2-(isocyanomethyl)-3-methoxybenzene (707 mg, 4.285 mmol, 1.2 equiv) in MeOH (20 mL) was stirred at 50° C. for 16 h. The mixture was concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel (PE:EA=1:1) to give the product (1 g, 57.4%) as a yellow solid. TLC: PE / EA=1:1, UV; R f Starting material = 0.0, product = 0.4. LC-MS: calculated exact mass = 488.1, observed [M+H] + =489.1.

[0333] 2-(9-Fluoro-3-((2-fluoro-6-methoxybenzyl)carbamoyl)-3-methyl-5-oxo-2,3-dihydrobenzofuro[2,3-f][1,4]oxazepin-4(5H)-yl)acetic acid A mixture of methyl 2-(9-fluoro-3-((2-fluoro-6-methoxybenzyl)carbamoyl)-3-methyl-5-oxo-2,3-dihydrobenzofuro[2,3-f][1,4]oxazepin-4(5H)-yl)acetate (820 mg, 1.68 mmol, 1.0 equiv), 6M HCl (40 mL) in dioxane (80 mL) was stirred at 70° C. for 16 h. The mixture was concentrated under reduced pressure. The solution was extracted with EA and the solvent was removed under reduced pressure to give the product (750 mg, 94%) as a yellow solid. LC-MS: calculated exact mass=474.1, found [M+H] + =475.1

[0334] 9-Fluoro-N-(2-fluoro-6-methoxybenzyl)-4-(2-((2-hydroxyethyl)(methyl)amino)-2-oxoethyl)-3-methyl-5-oxo-2,3,4,5-tetrahydrobenzofuro[2,3-f][1,4]oxazepine-3-carboxamide To a solution of 2-(9-fluoro-3-((2-fluoro-6-methoxybenzyl)carbamoyl)-3-methyl-5-oxo-2,3-dihydrobenzofuro[2,3-f][1,4]oxazepin-4(5H)-yl)acetic acid (100 mg, 0.21 mmol, 1.0 equiv.) in DMF (2 mL) was added HATU (120 mg, 0.420 mmol, 1.5 equiv.). 2-(Methylamino)ethan-1-ol (31 mg, 0.42 mmol, 2.0 equiv.) and DIPEA (136 mg, 1.05 mmol, 5.0 equiv.) were added. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was poured into H2O (30 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by preparative HPLC to give the product (70 mg, 62.5%) as a white solid. LC-MS: calculated exact mass = 531.2, found [M+H] + = 532.2. 1H NMR (400 MHz, DMSO) δ 9.54 (s, 1H), 7.54 (dt, J = 7.6, 3.7 Hz, 1H), 7.45 - 7.21 (m, 2H), 7.02 (dd, J = 15.2, 7.7 Hz, 1H), 6.61 (d, J = 8.3 Hz, 1H), 6.38 (s, 1H), 4.99 (s, 1H), 4.82 (d, J = 11.6 Hz, 1H), 4.36 (ddd, J = 80.0, 54.0, 18.7 Hz, 5H), 3.89 (d, J = 10.8 Hz, 1H), 3.63 (s, 3H), 3.61 - 3.43 (m, 3H), 3.08 (s, 1H), 2.88 (s, 2H), 1.53 (s, 1H), 1.50 (s, 2H).

[0335] (Example 112) 4-(2-(dimethylamino)-2-oxoethyl)-9-fluoro-N-(2-fluoro-6-methoxybenzyl)-3-methyl-5-oxo-2,3,4,5-tetrahydrobenzofuro[2,3-f][1,4]oxazepine-3-carboxamide

[0336] [ka] 4-(2-(dimethylamino)-2-oxoethyl)-9-fluoro-N-(2-fluoro-6-methoxybenzyl)-3-methyl-5-oxo-2,3,4,5-tetrahydrobenzofuro[2,3-f][1,4]oxazepine-3-carboxamide A mixture of 5-fluoro-3-(2-oxopropoxy)benzofuran-2-carboxylic acid (100 mg, 0.59 mmol, 1.0 equiv), 2-amino-N,N-dimethylacetamide (91 mg, 1.5 mmol, 1.5 equiv), and 1-fluoro-2-(isocyanomethyl)-3-methoxybenzene (147 mg, 0.89 mmol, 1.5 equiv) in MeOH (20 mL) was stirred at 50° C. for 16 h. The mixture was concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel (PE:EA=1:1) to give the product (58 mg, 29%) as a yellow solid. LC-MS: Calculated exact mass = 502.2, found [M+H] + = 501.2. 1 H NMR (400 MHz, DMSO) δ 9.54 (s, 1H), 7.55 (dd, J = 9.0, 3.9 Hz, 1H), 7.41 - 7.27 (m, 2H), 7.03 (dd, J = 15.2, 7.8 Hz, 1H), 6.61 (d, J = 8.3 Hz, 1H), 6.40 (s, 1H), 4.83 (d, J = 11.7 Hz, 1H), 4.64 - 4.21 (m, 4H), 3.93-3.91 (m, 1H), 3.63 (s, 3H), 3.03 (s, 3H), 2.86 (s, 3H), 1.53 (s, 3H).

[0337] (Example 113) 4-(2-cyclopropyl-2-oxoethyl)-9-fluoro-N-(2-methoxybenzyl)-3-methyl-5-oxo-2,3,4,5-tetrahydrobenzofuro[2,3-f][1,4]oxazepine-3-carboxamide

[0338] [ka] 4-(2-Cyclopropyl-2-hydroxyethyl)-9-fluoro-N-(2-methoxybenzyl)-3-methyl-5-oxo-2,3,4,5-tetrahydrobenzofuro[2,3-f][1,4]oxazepine-3-carboxamide A mixture of 5-fluoro-3-(2-oxopropoxy)benzofuran-2-carboxylic acid (998 mg, 3.96 mmol, 1.0 equiv), 2-amino-1-cyclopropylethan-1-ol (600 mg, 5.94 mmol, 1.5 equiv), and 1-fluoro-2-(isocyanomethyl)-3-methoxybenzene (698 mg, 4.75 mmol, 1.2 equiv) in MeOH (20 mL) was stirred at 50° C. for 16 h. The mixture was concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel (PE:EA=1:1) to give the product (1.1 g, 58%) as a yellow solid. TLC: PE / EA=1:1, UV; R f Starting material = 0.0, product = 0.4. LC-MS: calculated exact mass = 482.2, observed [M+H] + =483.2.

[0339] 4-(2-cyclopropyl-2-oxoethyl)-9-fluoro-N-(2-methoxybenzyl)-3-methyl-5-oxo-2,3,4,5-tetrahydrobenzofuro[2,3-f][1,4]oxazepine-3-carboxamide A mixture of 4-(2-cyclopropyl-2-hydroxyethyl)-9-fluoro-N-(2-methoxybenzyl)-3-methyl-5-oxo-2,3,4,5-tetrahydrobenzofuro[2,3-f][1,4]oxazepine-3-carboxamide (100 mg, 0.207 mmol, 1.0 equiv.) and Dess-Martin periodinane (131 mg, 0.31 mmol, 1.5 equiv.) in DCM (20 mL) was stirred at 25° C. for 16 h. The mixture was washed with water, extracted with DCM and the organic phase was concentrated under reduced pressure. The crude product was purified by preparative HPLC to give the product (25 mg, 25%) as a yellow solid. LC-MS: calculated exact mass = 480.2, found [M+H] + = 481.2. 1H NMR (400 MHz, DMSO) δ 8.75 (s, 1H), 7.67 (dd, J = 9.1, 3.9 Hz, 1H), 7.49 (dd, J = 8.1, 2.6 Hz, 1H), 7.41 (td, J = 9.3, 2.7 Hz, 1H), 7.03 (t, J = 7.4 Hz, 1H), 6.82 (d, J = 8.2 Hz, 1H), 6.53 (s, 1H), 6.23 (s, 1H), 4.94 (d, J = 12.2 Hz, 1H), 4.84 (d, J = 18.3 Hz, 1H), 4.55-4.51 (m, 1H), 4.41 (d, J = 12.3 Hz, 1H), 4.25 (dd, J = 15.9, 6.4 Hz, 1H), 4.12 - 3.95 (m, 1H), 3.70 (s, 3H), 2.19-2.17 (m, 1H), 1.56 (s, 3H), 1.06 - 0.73 (m, 4H).

[0340] (Example 114) (R)-4-(2-(bis(methyl-d3)amino)-2-oxoethyl)-9-fluoro-N-(2-fluoro-6-methoxybenzyl)-3-methyl-5-oxo-2,3,4,5-tetrahydrobenzofuro[2,3-f][1,4]oxazepine-3-carboxamide

[0341] [ka] Methyl 2-((R)-9-fluoro-3-methyl-5-oxo-3-(((S)-1-phenylethyl)carbamoyl)-2,3-dihydrobenzofuro[2,3-f][1,4]oxazepin-4(5H)-yl)acetate A mixture of 5-fluoro-3-(2-oxopropoxy)benzofuran-2-carboxylic acid (1.3 g, 5.155 mmol, 1.0 equiv.), methyl glycinate hydrochloride (1.4 g, 10.31 mmol, 2.0 equiv.), TEA (1.03 g, 10.31 mmol, 2.0 equiv.) and (S)-(1-isocyanoethyl)benzene (0.9 g, 10.31 mmol, 2.0 equiv.) in MeOH (20 mL) was stirred at 50° C. for 16 h. The mixture was concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel (PE:EA=1:1) to give the product (550 mg, 23.5%) as a yellow solid. TLC: PE / EA=1:1, UV; R f Starting material = 0.0, product = 0.4, isomer = 0.6; LC-MS: calculated exact mass = 454.1, observed [M+H] + =455.1.

[0342] 2-((R)-9-Fluoro-3-methyl-5-oxo-3-(((S)-1-phenylethyl)carbamoyl)-2,3-dihydrobenzofuro[2,3-f][1,4]oxazepin-4(5H)-yl)acetic acid A mixture of methyl 2-((R)-9-fluoro-3-methyl-5-oxo-3-(((S)-1-phenylethyl)carbamoyl)-2,3-dihydrobenzofuro[2,3-f][1,4]oxazepin-4(5H)-yl)acetate (500 mg, 1.1 mmol, 1.0 equiv.), 6M HCl (8 mL) in dioxane (6 mL) was stirred at 70° C. for 16 h. The mixture was concentrated under reduced pressure. The solution was extracted with EA and the solvent was removed under reduced pressure to give the product (436 mg, 90%) as a yellow solid. TLC: PE / EA=1:1, UV; R f Starting material = 0.4, product = 0.0. LC-MS: calculated exact mass = 440.1, observed [M+H] + =441.1.

[0343] (R)-4-(2-(bis(methyl-d3)amino)-2-oxoethyl)-9-fluoro-3-methyl-5-oxo-N-((S)-1-phenylethyl)-2,3,4,5-tetrahydrobenzofuro[2,3-f][1,4]oxazepine-3-carboxamide To a solution of 2-((R)-9-fluoro-3-methyl-5-oxo-3-(((S)-1-phenylethyl)carbamoyl)-2,3-dihydrobenzofuro[2,3-f][1,4]oxazepin-4(5H)-yl)acetic acid (400 mg, 0.908 mmol, 1.0 equiv.) in DMF (30 mL) was added HATU (690 mg, 1.816 mmol, 2.0 equiv.), bis(methyl-d3)amine hydrochloride (92 mg, 1.816 mmol, 2.0 equiv.) and DIPEA (234 mg, 1.816 mmol, 2.0 equiv.). The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was poured into H2O (30 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel (DCM:MeOH=5:1) to give the product (200 mg, 46.7%) as a white solid. LC-MS: calculated exact mass=473.2, found [M+H] + =474.2.

[0344] tert-Butyl ((R)-4-(2-(bis(methyl-d3)amino)-2-oxoethyl)-9-fluoro-3-methyl-5-oxo-2,3,4,5-tetrahydrobenzofuro[2,3-f][1,4]oxazepine-3-carbonyl)((S)-1-phenylethyl)carbamate To a solution of (R)-4-(2-(bis(methyl-d3)amino)-2-oxoethyl)-9-fluoro-3-methyl-5-oxo-N-((S)-1-phenylethyl)-2,3,4,5-tetrahydrobenzofuro[2,3-f][1,4]oxazepine-3-carboxamide (150 mg, 0.317 mmol, 1.0 equiv.) in TEA (50 mL) was added (Boc)2O (10 g, 45.8 mmol, 144.0 equiv.), DMAP (18 mg, 0.158 mmol, 0.5 equiv.). The mixture was stirred at 100° C. for 3 h. Water (50 mL) was added. The aqueous phase was extracted with EA (3×50 mL). The combined organic solution was washed with brine (50 mL), dried over anhydrous Na2SO4 and the solution was concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE:EA=1:2) to give the product (210 mg, 100%) as a brown solid. TLC: PE / EA=1:2, UV; f Starting material = 0.15, product = 0.6. LC-MS: calculated exact mass = 589.2, observed [M+H] + =590.2.

[0345] (R)-4-(2-(bis(methyl-d3)amino)-2-oxoethyl)-9-fluoro-3-methyl-5-oxo-2,3,4,5-tetrahydrobenzofuro[2,3-f][1,4]oxazepine-3-carboxylic acid To a solution of tert-butyl ((R)-4-(2-(bis(methyl-d3)amino)-2-oxoethyl)-9-fluoro-3-methyl-5-oxo-2,3,4,5-tetrahydrobenzofuro[2,3-f][1,4]oxazepine-3-carbonyl)((S)-1-phenylethyl)carbamate (150 mg, 0.261 mmol, 1.0 equiv) in THF (5 mL) and MeOH (10 mL) was added KOH (10%, 10 mL). The mixture was stirred at 70° C. for 3 h. The reaction mixture was concentrated under reduced pressure and then acidified to pH 4-5 with 1N HCl. The solid was filtered to give the product (120 mg, 89%) as a white solid. The crude product was used directly in the next step. LC-MS: calculated exact mass=370.1, found [M+H] + =371.1

[0346] (R)-4-(2-(bis(methyl-d3)amino)-2-oxoethyl)-9-fluoro-N-((3-methoxypyridin-2-yl)methyl)-3-methyl-5-oxo-2,3,4,5-tetrahydrobenzofuro[2,3-f][1,4]oxazepine-3-carboxamide To a solution of (R)-4-(2-(bis(methyl-d3)amino)-2-oxoethyl)-9-fluoro-3-methyl-5-oxo-2,3,4,5-tetrahydrobenzofuro[2,3-f][1,4]oxazepine-3-carboxylic acid (100 mg, 0.27 mmol, 1.0 equiv.) in DMF (2 mL) was added HATU (205 mg, 0.54 mmol, 2.0 equiv.). The mixture was stirred at room temperature for 10 min. (3-Methoxypyridin-2-yl)methanamine (75 mg, 0.54 mmol, 2.0 equiv.) and DIPEA (70 mg, 0.54 mmol, 2.0 equiv.) were added. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was poured into HO (30 mL) and extracted with EtOAc (3×30 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by preparative HPLC to give the product (20 mg, 15%) as a white solid. LC-MS: Calculated exact mass = 579 found [M+H] + = 580.2; 1 H NMR (400 MHz, DMSO) δ 9.41 (s, 1H), 7.62 (dd, J = 9.1, 3.9 Hz, 1H), 7.56 (s, 1H), 7.41 (d, J = 7.5 Hz, 1H), 7.35 (dt, J = 9.2, 4.6 Hz, 1H), 7.22 (d, J = 8.2 Hz, 1H), 7.06 (s, 1H), 4.84 (d, J = 11.4 Hz, 1H), 4.47 (s, 2H), 4.41 - 4.25 (m, 2H), 4.15 (s, 1H), 3.69 (s, 3H), 1.57 (s, 3H).

[0347] The following examples were prepared using procedures similar to those described above.

[0348] [Table 9-1]

[0349] [Table 9-2]

[0350] (Example 120) (R)-9-Fluoro-4-((1-(2-hydroxyethyl)-1H-1,2,3-triazol-4-yl)methyl)-N-((3-methoxypyridin-2-yl)methyl)-3-methyl-5-oxo-2,3,4,5-tetrahydrobenzofuro[2,3-f][1,4]oxazepine-3-carboxamide

[0351] [ka] (R)-9-Fluoro-3-methyl-5-oxo-N-((S)-1-phenylethyl)-4-(prop-2-yn-1-yl)-2,3,4,5-tetrahydrobenzofuro[2,3-f][1,4]oxazepine-3-carboxamide A mixture of 5-fluoro-3-(2-oxopropoxy)benzofuran-2-carboxylic acid (4 g, 15.86 mmol, 1.0 equiv.), prop-2-yn-1-amine (1.3 g, 23.79 mmol, 1.5 equiv.) and 1-(isocyanomethyl)-2-methoxybenzene (2.3 g, 17.45 mmol, 1.1 equiv.) in MeOH (20 mL) was stirred at 50° C. for 16 h. The mixture was concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel (PE:EA=1:1) to give the product (2.7 g, contained 30% isomers) as a yellow solid. TLC: PE / EA=1:1, UV; R fStarting material = 0.0, product = 0.4. Isomer = 0.5; LC-MS: calculated exact mass = 420.1, found [M+H] + =421.1.

[0352] tert-Butyl ((R)-9-fluoro-3-methyl-5-oxo-4-(prop-2-yn-1-yl)-2,3,4,5-tetrahydrobenzofuro[2,3-f][1,4]oxazepine-3-carbonyl)((S)-1-phenylethyl)carbamate To a solution of (R)-9-fluoro-3-methyl-5-oxo-N-((S)-1-phenylethyl)-4-(prop-2-yn-1-yl)-2,3,4,5-tetrahydrobenzofuro[2,3-f][1,4]oxazepine-3-carboxamide (2.7 g, 6.43 mmol, 1.0 equiv.) in TEA (20 mL) was added (Boc)2O (20 mL), DMAP (1.18 g, 9.64 mmol, 1.5 equiv.). The mixture was stirred at 100° C. for 3 h. Water (50 mL) was added. The aqueous phase was extracted with EA (3×50 mL). The combined organic solution was washed with brine (50 mL), dried over anhydrous Na2SO4, and the solution was concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE:EA=5:1) to give the product (1.05 g) as a brown solid. TLC: PE / EA=5:1, UV; f Starting material = 0.15, product = 0.5.; LC-MS: calculated exact mass = 520.1, observed [M+H] + =521.1

[0353] (R)-9-Fluoro-3-methyl-5-oxo-4-(prop-2-yn-1-yl)-2,3,4,5-tetrahydrobenzofuro[2,3-f][1,4]oxazepine-3-carboxylic acid To a solution of tert-butyl ((R)-9-fluoro-3-methyl-5-oxo-4-(prop-2-yn-1-yl)-2,3,4,5-tetrahydrobenzofuro[2,3-f][1,4]oxazepine-3-carbonyl)((S)-1-phenylethyl)carbamate (1.05 g, 2.0 mmol, 1.0 equiv) in THF (10 mL) and MeOH (20 mL) was added KOH (10%, 20 mL). The mixture was stirred at 70° C. for 3 h. The reaction mixture was concentrated under reduced pressure and then acidified to pH 4-5 with 1N HCl. The solid was filtered to give the product (640 mg, 100%) as a white solid. The crude product was used directly in the next step. LC-MS: calculated exact mass=317.1, found [M+H] + =318.1

[0354] (R)-9-Fluoro-N-((3-methoxypyridin-2-yl)methyl)-3-methyl-5-oxo-4-(prop-2-yn-1-yl)-2,3,4,5-tetrahydrobenzofuro[2,3-f][1,4]oxazepine-3-carboxamide To a solution of (R)-9-fluoro-3-methyl-5-oxo-4-(prop-2-yn-1-yl)-2,3,4,5-tetrahydrobenzofuro[2,3-f][1,4]oxazepine-3-carboxylic acid (600 mg, 1.89 mmol, 1.0 equiv.) in DMF (15 mL) was added HATU (1.07 g, 2.83 mmol, 1.5 equiv.). The mixture was stirred at room temperature for 10 min. (3-Methoxypyridin-2-yl)methanamine (522 mg, 3.78 mmol, 2.0 equiv.) and DIPEA (1.5 g, 11.34 mmol, 6.0 equiv.) were added. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was poured into H2O (30 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by preparative HPLC to give the product (650 mg, 78.6%) as a white solid. LC-MS: calculated exact mass = 437.1, observed [M+H] + =438.1.

[0355] (R)-9-Fluoro-4-((1-(2-hydroxyethyl)-1H-1,2,3-triazol-4-yl)methyl)-N-((3-methoxypyridin-2-yl)methyl)-3-methyl-5-oxo-2,3,4,5-tetrahydrobenzofuro[2,3-f][1,4]oxazepine-3-carboxamide To a solution of 4-(2-(dimethylamino)-2-oxoethyl)-3-((2-methoxybenzyl)carbamoyl)-3-methyl-5-oxo-2,3,4,5-tetrahydropyrido[2',3':4,5]furo[2,3-f][1,4]oxazepine-8-carboxylic acid (150 mg, 0.34 mmol, 1.0 equiv.) in t-BuOH (3 mL) and HO (3 mL), 2-azidoethan-1-ol (33 mg, 0.34 mmol, 1.0 equiv.), CuSO4·5HO (21 mg, 0.085 mmol, 0.25 equiv.), TEA (34 mg, 0.34 mmol, 1.0 equiv.) and sodium ascorbate (34 mg, 0.17 mmol, 0.5 equiv.) were added. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was poured into H2O (30 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by preparative HPLC to give the product (22 mg, 12%) as a white solid. LC-MS: Calculated exact mass = 524.2, found [M+H] + = 525.3. 1 H NMR (400 MHz, DMSO) δ 8.34 (s, 1H), 7.94 (s, 1H), 7.77 (s, 1H), 7.66 (dd, J = 9.1, 3.9 Hz, 1H), 7.46 (dd, J = 8.1, 2.5 Hz, 1H), 7.37 (td, J = 9.3, 2.7 Hz, 1H), 7.30 (d, J = 7.7 Hz, 1H), 7.17 (dd, J = 8.2, 4.7 Hz, 1H), 5.05 (d, J = 16.1 Hz, 1H), 4.99 (t, J = 5.3 Hz, 1H), 4.87 (d, J = 12.4 Hz, 1H), 4.56 (d, J = 16.1 Hz, 1H), 4.41 (d, J = 12.6 Hz, 1H), 4.37 - 4.14 (m, 4H), 3.75 (s, 3H), 3.75 - 3.71 (m, 2H), 1.65 (s, 3H).

[0356] Intermediate BB-10 6-Bromo-3-(2-oxopropoxy)furo[3,2-b]pyridine-2-carboxylic acid

[0357] [ka]

[0358] 5-Bromo-3-fluoropicolinic acid 5-Bromo-3-fluoropicolinonitrile (45 g, 0.223 mol, 1.0 equiv) in concentrated HCl (36%) (500 mL) was stirred at 60° C. for 16 h. The reaction was monitored by LCMS. The resulting mixture was cooled and poured into ice water. The solid was collected by filtration, washed with water, and recrystallized from methanol to give the product (49 g, 99.4%) as a yellow solid. TLC: DCM / MeOH=1:1, UV; R f Starting material=0.9, product=0.15.

[0359] Methyl 5-bromo-3-fluoropicolinate To a solution of 5-bromo-3-fluoropicolinic acid (49 g, 0.222 mol, 1.0 equiv) in MeOH (0.7 L) was added H2SO4 (98%, 50 mL) and the mixture was heated and stirred under reflux for 1 h. The reaction was monitored by LCMS. The crude product was distilled under reduced pressure, washed with H2O, extracted with ethyl acetate and the organic phase was distilled under reduced pressure to give the product (48.3 g, 92.7%) as a brown solid. TLC: PE / EA=1:1, UV; R f Starting material=0.0, product=0.5.

[0360] Methyl 5-bromo-3-fluoropicolinate To a solution of methyl 5-bromo-3-fluoropicolinate (48.3 g, 0.208 mol, 1.0 equiv.) in THF (1.5 L) was added NaH (25 g, 0.619 mol, 3.0 equiv.) at 0° C., the mixture was stirred for 30 min, and then methyl 2-hydroxyacetate (28 g, 0.309 mol, 1.5 equiv.). The reaction was monitored by LCMS. The resulting mixture was cooled, poured into ice water, and acidified to pH 2 with 5% hydrochloric acid. The solid was collected by filtration, washed with water, and recrystallized from methanol to give the product (49 g, 87.2%) as a brown solid. TLC: PE / EA=1:1, UV; R f Starting material = 0.5, product = 0.1. LC-MS: calculated exact mass = 270.9, observed [M+H] + =271.9.

[0361] Methyl 6-bromo-3-(2-oxopropoxy)furo[3,2-b]pyridine-2-carboxylate To a mixture of compound methyl 6-bromo-3-hydroxyfuro[3,2-b]pyridine-2-carboxylate (49 g, 0.18 mol, 1.0 eq.) in acetonitrile (1 L), TEA (54 g, 0.54 mol, 3.0 eq.), chloroacetone (33.3 g, 0.36 mmol, 2.0 eq.) were added and the mixture was refluxed for 4 h. The reaction was monitored by LCMS. The resulting mixture was filtered, concentrated and extracted with ethyl acetate to give the product (42 g, 87%) as a brown solid. TLC: PE / EA=2:1, UV; R f Starting material = 0.2, product = 0.5. LC-MS: calculated exact mass = 326.9, observed [M+H] + =327.9

[0362] 6-Bromo-3-(2-oxopropoxy)furo[3,2-b]pyridine-2-carboxylic acid (BB-3, V2616-041) A solution of methyl 6-bromo-3-(2-oxopropoxy)furo[3,2-b]pyridine-2-carboxylate (42 g, 0.128 mol, 1.0 equiv.) in MeOH (300 L) and 10% NaOH in water (100 mL) was stirred at room temperature for 4 h. The reaction was monitored by LCMS. The resulting mixture was concentrated, adjusted to pH 5 by adding 1N HCl, and extracted with ethyl acetate. The combined organic layers were washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography on silica (DCM:MeOH=10:1) to give the product (28 g, 69.7%) as a yellow solid. TLC: DCM:MeOH=10:1, UV;R f Starting material = 0.9, product = 0.1. LC-MS: calculated exact mass = 312.9, observed [M+H] + =313.9.

[0363] (Example 121) 4-(2-(dimethylamino)-2-oxoethyl)-N3-(2-methoxybenzyl)-3-methyl-N8-(3-methyloxetan-3-yl)-5-oxo-2,3,4,5-tetrahydropyrido[2',3':4,5]furo[2,3-f][1,4]oxazepine-3,8-dicarboxamide

[0364] [ka] 8-Bromo-4-(2-(dimethylamino)-2-oxoethyl)-N-(2-methoxybenzyl)-3-methyl-5-oxo-2,3,4,5-tetrahydropyrido[2',3':4,5]furo[2,3-f][1,4]oxazepine-3-carboxamide A mixture of 6-bromo-3-(2-oxopropoxy)furo[3,2-b]pyridine-2-carboxylic acid (3 g, 9.55 mmol, 1.0 equiv.), 2-amino-N,N-dimethylacetamide (1.4 g, 14.33 mmol, 1.5 equiv.), and 1-(isocyanomethyl)-2-methoxybenzene (1.3 g, 12.42 mmol, 1.3 equiv.) in MeOH (20 mL) was stirred at 50° C. for 16 h. The mixture was concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel (DCM:MeOH=20:1) to give the product (2.4 g, 46%) as a yellow solid. TLC: DCM / MeOH=20:1, UV; R f Starting material=0.0, product=0.4.

[0365] Methyl 4-(2-(dimethylamino)-2-oxoethyl)-3-((2-methoxybenzyl)carbamoyl)-3-methyl-5-oxo-2,3,4,5-tetrahydropyrido[2',3':4,5]furo[2,3-f][1,4]oxazepine-8-carboxylate A mixture of 8-bromo-4-(2-(dimethylamino)-2-oxoethyl)-N-(2-methoxybenzyl)-3-methyl-5-oxo-2,3,4,5-tetrahydropyrido[2',3':4,5]furo[2,3-f][1,4]oxazepine-3-carboxamide (500 mg, 0.92 mmol, 1.0 equiv.), TEA (464 mg, 4.58 mmol, 5 equiv.), and Pd(dppf)Cl2 (67 mg, 0.092 mmol, 0.1 equiv.) in MeOH (20 mL) and DMSO (5 mL) was stirred at 80 °C under CO for 16 h. The mixture was concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel (PE:EA=1:1) to give the product (330 mg, 60%) as a yellow solid. TLC: DCM / MeOH=20:1, UV; f Starting material=0.4, product=0.5.

[0366] 4-(2-(Dimethylamino)-2-oxoethyl)-3-((2-methoxybenzyl)carbamoyl)-3-methyl-5-oxo-2,3,4,5-tetrahydropyrido[2',3':4,5]furo[2,3-f][1,4]oxazepine-8-carboxylic acid To a solution of methyl 4-(2-(dimethylamino)-2-oxoethyl)-3-((2-methoxybenzyl)carbamoyl)-3-methyl-5-oxo-2,3,4,5-tetrahydropyrido[2',3':4,5]furo[2,3-f][1,4]oxazepine-8-carboxylate (330 mg, 0.629 mmol, 1.0 equiv) in THF (10 mL) and MeOH (20 mL) was added KOH (10%, 20 mL). The mixture was stirred at 25 °C for 3 h. The reaction mixture was concentrated under reduced pressure and then acidified to pH 4-5 with 1N HCl. The solid was filtered to give the product (310 mg, 96.5%) as a white solid. The crude product was used directly in the next step.

[0367] 4-(2-(dimethylamino)-2-oxoethyl)-N3-(2-methoxybenzyl)-3-methyl-N8-(3-methyloxetan-3-yl)-5-oxo-2,3,4,5-tetrahydropyrido[2',3':4,5]furo[2,3-f][1,4]oxazepine-3,8-dicarboxamide To a solution of (R)-9-fluoro-N-((3-methoxypyridin-2-yl)methyl)-3-methyl-5-oxo-4-(prop-2-yn-1-yl)-2,3,4,5-tetrahydrobenzofuro[2,3-f][1,4]oxazepine-3-carboxamide (380 mg, 0.744 mmol, 1.0 equiv.) in DMF (2 mL) was added HATU (425 mg, 1.17 mmol, 1.5 equiv.), 3-methyloxetan-3-amine (92 mg, 1.17 mmol, 1.5 equiv.) and DIPEA (141 mg, 1.17 mmol, 1.5 equiv.). The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was poured into HO (30 mL) and extracted with EtOAc (3×30 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by preparative HPLC to give the product (150 mg, 42%) as a white solid. LC-MS: Calculated exact mass = 490.2, found [M+H] + = 491.3. 1 H NMR (400 MHz, DMSO) δ 9.71 (s, 1H), 9.20 (s, 1H), 9.04 (d, J = 1.7 Hz, 1H), 8.43 (d, J = 1.7 Hz, 1H), 6.97 (t, J = 7.6 Hz, 1H), 6.81 (d, J = 8.1 Hz, 1H), 6.47 (s, 1H), 6.19 (s, 1H), 4.99 (d, J = 11.9 Hz, 1H), 4.78 (d, J = 6.3 Hz, 2H), 4.54-4.42 (m, 5H), 4.22 (dd, J = 15.7, 6.6 Hz, 1H), 3.95 (dd, J = 15.4, 4.8 Hz, 1H), 3.69 (s, 3H), 3.07 (s, 3H), 2.89 (s, 3H), 1.67 (s, 3H), 1.64 (s, 2H).

[0368] The following examples were prepared using procedures similar to those described above.

[0369] [Table 10]

[0370] (Example 124) 4-(2-(dimethylamino)-2-oxoethyl)-N-(2-fluoro-6-methoxybenzyl)-3-methyl-8-(oxazol-2-yl)-5-oxo-2,3,4,5-tetrahydropyrido[2',3':4,5]furo[2,3-f][1,4]oxazepine-3-carboxamide

[0371] [ka] 8-Bromo-4-(2-(dimethylamino)-2-oxoethyl)-N-(2-methoxybenzyl)-3-methyl-5-oxo-2,3,4,5-tetrahydropyrido[2',3':4,5]furo[2,3-f][1,4]oxazepine-3-carboxamide A mixture of 6-bromo-3-(2-oxopropoxy)furo[3,2-b]pyridine-2-carboxylic acid (500 mg, 1.59 mmol, 1.0 equiv), 2-amino-N,N-dimethylacetamide (146 mg, 1.43 mmol, 0.9 equiv), and 1-fluoro-2-(isocyanomethyl)-3-methoxybenzene (289 mg, 1.75 mmol, 1.1 equiv) in MeOH (20 mL) was stirred at 50° C. for 16 h. The mixture was concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel (DCM:MeOH=20:1) to give the product (320 mg, 35%) as a yellow solid. TLC: DCM / MeOH=20:1, UV; R f Starting material=0.0, product=0.4.

[0372] 4-(2-(Dimethylamino)-2-oxoethyl)-N-(2-fluoro-6-methoxybenzyl)-3-methyl-5-oxo-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3,4,5-tetrahydropyrido[2',3':4,5]furo[2,3-f][1,4]oxazepine-3-carboxamide 8-Bromo-4-(2-(dimethylamino)-2-oxoethyl)-N-(2-fluoro-6-methoxybenzyl)-3-methyl-5-oxo-2,3,4,5-tetrahydropyrido[2',3':4,5]furo[2,3-f][1,4]oxazepine-3-carboxamide (300 mg, 0.53 mmol, 1.0 equiv.), 4,4,4',4',5,5, A mixture of 5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (2700 mg, 10.6 mmol, 20 equiv), KOAc (156 mg, 1.6 mmol, 3.0 equiv), Pd2(dba)3 (48 mg, 0.053 mmol, 0.1 equiv) and tricyclohexylphosphane (29 mg, 0.106 mmol, 0.2 equiv) was stirred at 50° C. for 16 h. The mixture was concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel (PE:EA=1:1) to give the product (200 mg, 61%) as a yellow solid.

[0373] 4-(2-(dimethylamino)-2-oxoethyl)-N-(2-fluoro-6-methoxybenzyl)-3-methyl-8-(oxazol-2-yl)-5-oxo-2,3,4,5-tetrahydropyrido[2',3':4,5]furo[2,3-f][1,4]oxazepine-3-carboxamide In dioxane (3 ml) and H2O (0.3 ml), Pd(PPh3)4 (34 mg, 0.029 mmol, 0.1 equiv.), Cs2CO3 (288 mg, 0.88 mmol, 3.0 equiv.), the intermediate 4-(2-(dimethylamino)-2-oxoethyl)-N-(2-fluoro-6-methoxybenzyl)-3-methyl-5-oxo-8-(4,4,5,5-tetramethyl-1,3,2-dioxo)- A mixture of saborolan-2-yl)-2,3,4,5-tetrahydropyrido[2',3':4,5]furo[2,3-f][1,4]oxazepine-3-carboxamide (180 mg, 0.294 mmol, 1.0 equiv.) and 2-bromooxazole (87 mg, 0.589 mmol, 2.0 equiv.) was degassed with argon for 2 min and the resulting mixture was stirred at 100° C. under argon for 3 h. The reaction mixture was cooled and diluted with ethyl acetate. The solution was washed with water. The organic layer was separated, dried over sodium sulfate, evaporated under reduced pressure and the residue was purified by flash column chromatography on silica gel (DCM:MeOH=20:1) to give the product (28 mg, 17%) as a white solid. LC-MS: Calculated exact mass = 551.2, found [M+H] + = 552.2. 1 H NMR (400 MHz, DMSO) δ 9.62 (s, 1H), 9.12 (d, J = 1.6 Hz, 1H), 8.46 (d, J = 1.5 Hz, 1H), 8.39 (d, J = 0.7 Hz, 1H), 7.52 (d, J = 0.7 Hz, 1H), 6.93-6.91 (m, 1H), 6.64 (d, J = 8.1 Hz, 1H), 6.33-6.31 (m, 1H), 4.90 (d, J = 11.9 Hz, 1H), 4.55-4.51 (m, 1H), 4.43 - 4.26 (m, 3H), 3.89-3.84 (m, 1H), 3.66 (s, 3H), 3.05 (s, 3H), 2.89 (s, 3H), 1.57 (s, 3H).

[0374] Intermediate BB-11 6-Bromo-3-(2-oxopropoxy)benzofuran-2-carboxylic acid

[0375] [ka] Methyl 4-bromo-2-hydroxybenzoate A mixture of compound 4-bromo-2-hydroxybenzoic acid (200 g, 0.92 mol, 1.0 equiv.), SOCl2 (550 g, 4.60 mol, 5.0 equiv.), and DMF (15 mL) in MeOH (500 mL) was heated at 65° C. and stirred for 10 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was washed with saturated NaOH, extracted with EA, and the combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the crude product (205 g, 96%) as a light yellow solid. TLC: PE / EA=3:1, UV; R f Starting material = 0.0, product = 0.8. LC-MS: calculated exact mass = 230.0, observed [M+H] + = 231.0. 1 H NMR (400 MHz, CDCl3) δ (ppm): 10.82 (s, 1H), 7.67 (d, J = 8.5 Hz, 1H), 7.17 (d, J = 1.9 Hz, 1H), 7.01 (dd, J = 8.5, 1.9 Hz, 1H), 3.94 (s, 3H).

[0376] Methyl 4-bromo-2-(2-methoxy-2-oxoethoxy)benzoate Methyl bromoacetate (164 g, 1.07 mol, 1.2 equiv.) was added dropwise over 30 min to a stirred mixture of compound methyl 4-bromo-2-hydroxybenzoate (205 g, 0.89 mol, 1.0 equiv.) and potassium carbonate (192 g, 1.33 mol, 1.5 equiv.) in MeCN (2 L). The mixture was heated and stirred under reflux for 4 h. The reaction was monitored by LCMS. The reaction was cooled and the salts were separated by filtration and washed with acetone. The filtrate was concentrated to give a residue which was diluted with EA (2 L) and the solution was washed successively with water, aqueous sodium carbonate, water, and brine. The crude product was distilled under reduced pressure to give the product (255 g, 95%) as a brown solid. TLC: PE / EA=3:1, UV; R f Starting material = 0.8, product = 0.5. LC-MS: calculated exact mass = 302.0, observed [M+H] + = 303.0. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 7.61 (d, J = 8.3 Hz, 1H), 7.34 (d, J = 1.7 Hz, 1H), 7.27 (dd, J = 8.3, 1.7 Hz, 1H), 4.97 (s, 2H), 3.80 (s, 3H), 3.71 (s, 3H).

[0377] Methyl 6-bromo-3-hydroxybenzofuran-2-carboxylate To a mixture of compound methyl 4-bromo-2-(2-methoxy-2-oxoethoxy)benzoate (255 g, 0.84 mol, 1.0 equiv.) in MeOH (1 L), NaOMe (30% in methanol, 182 mL, 1.01 mol, 1.2 equiv.) was added and the mixture was stirred at 60° C. for 4 h. The reaction was monitored by LCMS. The resulting mixture was cooled, poured into ice water, and acidified to pH 2 with 5% hydrochloric acid. The solid was collected by filtration, washed with water, and recrystallized from methanol to give the product (220 g, 96%) as a yellow solid. TLC: PE / EA=3:1, UV; R fStarting material = 0.5, product = 0.4. LC-MS: calculated exact mass = 270.0, observed [M+H] + = 271.1. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 11.04 (s, 1H), 7.92 (d, J = 1.5 Hz, 1H), 7.85 (d, J = 8.5 Hz, 1H), 7.49 (dd, J = 8.5, 1.6 Hz, 1H), 3.84 (s, 3H).

[0378] Methyl 6-bromo-3-(2-oxopropoxy)benzofuran-2-carboxylate To a mixture of compound methyl 6-bromo-3-hydroxybenzofuran-2-carboxylate (200 g, 0.74 mol, 1.0 eq.) in acetonitrile (1 L), TEA (89 g, 0.89 mol, 1.2 eq.), chloroacetone (75 g, 0.81 mmol, 1.1 eq.) were added and the mixture was refluxed for 4 h. The reaction was monitored by LCMS. The resulting mixture was filtered, concentrated and extracted with ethyl acetate to give the product (23 g, 95%) as a brown solid. TLC: PE / EA=3:1, UV; R f Starting material = 0.4, product = 0.6. LC-MS: calculated exact mass = 326.0, observed [M+H] + =327.1.

[0379] 6-Bromo-3-(2-oxopropoxy)benzofuran-2-carboxylic acid A solution of crude compound methyl 6-bromo-3-(2-oxopropoxy)benzofuran-2-carboxylate (100 g, 0.31 mol, 1.0 equiv.) in MeOH (1 L) and 20% NaOH in water (400 mL) was stirred at room temperature for 4 h. The reaction was monitored by LCMS. The resulting mixture was concentrated, adjusted to pH 2 by adding 1N HCl, and extracted with ethyl acetate. The combined organic layers were washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography on silica (DCM:MeOH=10:1) to give the product (60 g, 63%) as a yellow solid. TLC: DCM:MeOH=10:1, UV;R f Starting material = 0.9, product = 0.2. LC-MS: calculated exact mass = 312.0, observed [M+H] + = 313.0. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 13.49 (s, 1H), 7.98 (d, J = 1.4 Hz, 1H), 7.77 (d, J = 8.5 Hz, 1H), 7.52 (dd, J = 8.5, 1.5 Hz, 1H), 5.20 (s, 2H), 2.16 (s, 3H).

[0380] (Example 125) (R)-4-(2-(dimethylamino)-2-oxoethyl)-N-((3-methoxypyridin-2-yl)methyl)-3-methyl-8-(oxazol-2-yl)-5-oxo-2,3,4,5-tetrahydrobenzofuro[2,3-f][1,4]oxazepine-3-carboxamide

[0381] [ka] Methyl 2-((R)-8-bromo-3-methyl-5-oxo-3-(((S)-1-phenylethyl)carbamoyl)-2,3-dihydrobenzofuro[2,3-f][1,4]oxazepin-4(5H)-yl)acetate A mixture of 6-bromo-3-(2-oxopropoxy)benzofuran-2-carboxylic acid (55 g, 0.176 mol, 1.0 equiv.), methyl glycinate (24 g, 0.263 mol, 1.5 equiv.) and (S)-(1-isocyanoethyl)benzene (24 g, 0.263 mol, 1.5 equiv.) in MeOH (20 mL) was stirred at 50° C. for 16 h. The mixture was concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel (PE:EA=1:1) to give the product (40 g, 43.9%) as a yellow solid. TLC: PE / EA=1:1, UV; R f Starting material = 0.0, product = 0.4, isomer = 0.6.

[0382] 2-((R)-8-Bromo-3-methyl-5-oxo-3-(((S)-1-phenylethyl)carbamoyl)-2,3-dihydrobenzofuro[2,3-f][1,4]oxazepin-4(5H)-yl)acetic acid A mixture of methyl 2-((R)-8-bromo-3-methyl-5-oxo-3-(((S)-1-phenylethyl)carbamoyl)-2,3-dihydrobenzofuro[2,3-f][1,4]oxazepin-4(5H)-yl)acetate (40 g, 77.62 mmol, 1.0 equiv), 6 M HCl (600 mL) in dioxane (800 mL) was stirred at 80° C. for 16 h. The mixture was concentrated under reduced pressure. The solution was extracted with EA and the solvent was removed under reduced pressure to give the product (35 g, 92%) as a yellow solid.

[0383] (R)-8-Bromo-4-(2-(dimethylamino)-2-oxoethyl)-3-methyl-5-oxo-N-((S)-1-phenylethyl)-2,3,4,5-tetrahydrobenzofuro[2,3-f][1,4]oxazepine-3-carboxamide To a solution of 2-((R)-8-bromo-3-methyl-5-oxo-3-(((S)-1-phenylethyl)carbamoyl)-2,3-dihydrobenzofuro[2,3-f][1,4]oxazepin-4(5H)-yl)acetic acid (27 g, 53.86 mmol, 1.0 equiv.) in DMF (30 mL) was added HATU (41 g, 107.7 mmol, 2.0 equiv.), dimethylamine (50 mL, 2 M, 107.7 mmol, 2.0 equiv.) and DIPEA (45 mL, 269.3 mmol, 5.0 equiv.). The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was poured into H2O (30 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel (DCM:MeOH=5:1) to give the product (25 g, 89%) as a white solid.

[0384] (R)-4-(2-(dimethylamino)-2-oxoethyl)-3-methyl-5-oxo-N-((S)-1-phenylethyl)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3,4,5-tetrahydrobenzofuro[2,3-f][1,4]oxazepine-3-carboxamide A mixture of (1,1'-bis(diphenylphosphino)ferrocene)palladium(ll) chloride (3.5 g, 4.73 mmol, 0.1 equiv.), potassium acetate (23 g, 236.6 mmol, 5.0 equiv.), (R)-8-bromo-4-(2-(dimethylamino)-2-oxoethyl)-3-methyl-5-oxo-N-((S)-1-phenylethyl)-2,3,4,5-tetrahydrobenzofuro[2,3-f][1,4]oxazepine-3-carboxamide (25 g, 47.31 mmol, 1.0 equiv.) and bis(pinacolato)diboron (60 g, 236.6 mmol, 5.0 equiv.) in dioxane (600 ml) was degassed with argon for 5 minutes and the resulting mixture was stirred at 100° C. under argon for 3 hours. The reaction mixture was cooled and diluted with ethyl acetate. The solution was washed with water. The organic layer was separated, dried over sodium sulfate, evaporated under reduced pressure, and the residue was purified by flash column chromatography on silica gel (PE:EA=3:1) to give the product (12 g, 45%) as a pale yellow solid.

[0385] (R)-4-(2-(dimethylamino)-2-oxoethyl)-3-methyl-8-(oxazol-2-yl)-5-oxo-N-((S)-1-phenylethyl)-2,3,4,5-tetrahydrobenzofuro[2,3-f][1,4]oxazepine-3-carboxamide In dioxane (100 ml) and H2O (10 ml), Pd(PPh3)4 (1.2 g, 1.04 mmol, 0.1 equiv.), Cs2CO3 (6.8 g, 20.86 mmol, 2.0 equiv.), the intermediate (R)-4-(2-(dimethylamino)-2-oxoethyl)-3-methyl-5-oxo-N-((S)-1-phenylethyl)-8-(4,4,5,5-tetramethyl-1-phenylethyl)- A mixture of ,3,2-dioxaborolan-2-yl)-2,3,4,5-tetrahydrobenzofuro[2,3-f][1,4]oxazepine-3-carboxamide (6 g, 10.43 mmol, 2.0 equiv.) and 2-bromooxazole (3 g, 20.86 mmol, 2.0 equiv.) was degassed with argon for 2 min and the resulting mixture was stirred at 100° C. under argon for 16 h. The reaction mixture was cooled and diluted with ethyl acetate. The solution was washed with water. The organic layer was separated, dried over sodium sulfate, evaporated under reduced pressure and the residue was purified by flash column chromatography on silica gel (DCM:MeOH=20:1) to give the product (3.8 g, 72%) as a pale yellow solid.

[0386] tert-Butyl ((R)-4-(2-(dimethylamino)-2-oxoethyl)-3-methyl-8-(oxazol-2-yl)-5-oxo-2,3,4,5-tetrahydrobenzofuro[2,3-f][1,4]oxazepine-3-carbonyl)((S)-1-phenylethyl)carbamate To a solution of ((R)-4-(2-(dimethylamino)-2-oxoethyl)-3-methyl-8-(oxazol-2-yl)-5-oxo-N-((S)-1-phenylethyl)-2,3,4,5-tetrahydrobenzofuro[2,3-f][1,4]oxazepine-3-carboxamide (4 g, 7.74 mmol, 1.0 equiv.) in TEA (100 mL) was added (Boc)O (17 g, 77.44 mmol, 10.0 equiv.), DMA (1.0 g, 77.44 mmol, 10.0 equiv.). P (0.95 g, 7.74 mmol, 1.0 equiv) was added. The mixture was stirred at 100° C. for 16 h. Water (150 mL) was added. The aqueous phase was extracted with EA (3×50 mL). The combined organic solution was washed with brine (50 mL), dried over anhydrous Na2SO4, and the solution was concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE:EA=1:2) to give the product (4 g, 75%) as a brown solid.

[0387] (R)-4-(2-(dimethylamino)-2-oxoethyl)-3-methyl-8-(oxazol-2-yl)-5-oxo-2,3,4,5-tetrahydrobenzofuro[2,3-f][1,4]oxazepine-3-carboxylic acid To a solution of tert-butyl ((R)-4-(2-(dimethylamino)-2-oxoethyl)-3-methyl-8-(oxazol-2-yl)-5-oxo-2,3,4,5-tetrahydrobenzofuro[2,3-f][1,4]oxazepine-3-carbonyl)((S)-1-phenylethyl)carbamate (3.5 g, 5.676 mmol, 1.0 equiv) in THF (25 mL), MeOH (50 mL) was added KOH (10%, 50 mL) and the mixture was stirred at 70 °C for 3 h. The reaction mixture was concentrated under reduced pressure and then acidified to pH 4-5 with 1N HCl. The solid was filtered to give the product (2.3 g, 82%) as a white solid. The crude product was used directly in the next step.

[0388] (R)-4-(2-(dimethylamino)-2-oxoethyl)-N-((3-methoxypyridin-2-yl)methyl)-3-methyl-8-(oxazol-2-yl)-5-oxo-2,3,4,5-tetrahydrobenzofuro[2,3-f][1,4]oxazepine-3-carboxamide To a solution of (R)-4-(2-(dimethylamino)-2-oxoethyl)-3-methyl-8-(oxazol-2-yl)-5-oxo-2,3,4,5-tetrahydrobenzofuro[2,3-f][1,4]oxazepine-3-carboxylic acid (2.3 g, 5.564 mmol, 1.0 equiv.) in DMF (20 mL) was added HATU (4.2 g, 11.14 mmol, 2.0 equiv.), (3-methoxypyridin-2-yl)methanamine (1.5 g, 11.13 mmol, 2.0 equiv.) and DIPEA (3.6 g, 27.82 mmol, 5.0 equiv.). The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was poured into HO (130 mL) and extracted with EtOAc (3×130 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by preparative HPLC to give the product (2 g, 70%) as a white solid. LC-MS: Calculated exact mass = 533.2, found [M+H] + = 534.2. 1 H NMR (400 MHz, DMSO) δ 9.45 (s, 1H), 8.30 (d, J = 0.6 Hz, 1H), 8.09 (s, 1H), 7.92 (dd, J = 8.3, 1.0 Hz, 1H), 7.76 (d, J = 8.2 Hz, 1H), 7.55 (s, 1H), 7.46 (d, J = 0.7 Hz, 1H), 7.22 (d, J = 8.1 Hz, 1H), 7.02 (s, 1H), 4.88 (d, J = 11.9 Hz, 1H), 4.50 (s, 2H), 4.38 (d, J = 11.4 Hz, 1H), 4.31 (dd, J = 15.6, 6.2 Hz, 1H), 4.14 (s, 1H), 3.69 (s, 3H), 3.06 (s, 3H), 2.86 (s, 3H), 1.59 (s, 3H).

[0389] The following examples were prepared using procedures similar to those described above.

[0390] [Table 11]

[0391] (Example 129) (R)-8-(4-cyanooxazol-2-yl)-4-(2-(dimethylamino)-2-oxoethyl)-N-((3-methoxypyridin-2-yl)methyl)-3-methyl-5-oxo-2,3,4,5-tetrahydrobenzofuro[2,3-f][1,4]oxazepine-3-carboxamide

[0392] [ka] Methyl 2-((R)-8-bromo-3-methyl-5-oxo-3-(((S)-1-phenylethyl)carbamoyl)-2,3-dihydrobenzofuro[2,3-f][1,4]oxazepin-4(5H)-yl)acetate A mixture of 6-bromo-3-(2-oxopropoxy)benzofuran-2-carboxylic acid (55 g, 0.176 mol, 1.0 equiv.), methyl glycinate (24 g, 0.263 mol, 1.5 equiv.) and (S)-(1-isocyanoethyl)benzene (24 g, 0.263 mol, 1.5 equiv.) in MeOH (20 mL) was stirred at 50° C. for 16 h. The mixture was concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel (PE:EA=1:1) to give the product (40 g, 43.9%) as a yellow solid. TLC: PE / EA=1:1, UV; R f Starting material = 0.0, product = 0.4, isomer = 0.6

[0393] 2-((R)-8-Bromo-3-methyl-5-oxo-3-(((S)-1-phenylethyl)carbamoyl)-2,3-dihydrobenzofuro[2,3-f][1,4]oxazepin-4(5H)-yl)acetic acid A mixture of methyl 2-((R)-8-bromo-3-methyl-5-oxo-3-(((S)-1-phenylethyl)carbamoyl)-2,3-dihydrobenzofuro[2,3-f][1,4]oxazepin-4(5H)-yl)acetate (40 g, 77.62 mmol, 1.0 equiv), 6 M HCl (600 mL) in dioxane (800 mL) was stirred at 80° C. for 16 h. The mixture was concentrated under reduced pressure. The solution was extracted with EA and the solvent was removed under reduced pressure to give the product (35 g, 92%) as a yellow solid.

[0394] (R)-8-Bromo-4-(2-(dimethylamino)-2-oxoethyl)-3-methyl-5-oxo-N-((S)-1-phenylethyl)-2,3,4,5-tetrahydrobenzofuro[2,3-f][1,4]oxazepine-3-carboxamide To a solution of 2-((R)-8-bromo-3-methyl-5-oxo-3-(((S)-1-phenylethyl)carbamoyl)-2,3-dihydrobenzofuro[2,3-f][1,4]oxazepin-4(5H)-yl)acetic acid (27 g, 53.86 mmol, 1.0 equiv.) in DMF (30 mL) was added HATU (41 g, 107.7 mmol, 2.0 equiv.), dimethylamine (50 mL, 2 M, 107.7 mmol, 2.0 equiv.) and DIPEA (45 mL, 269.3 mmol, 5.0 equiv.). The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was poured into H2O (30 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel (DCM:MeOH=5:1) to give the product (25 g, 89%) as a white solid.

[0395] tert-Butyl ((R)-8-bromo-4-(2-(dimethylamino)-2-oxoethyl)-3-methyl-5-oxo-2,3,4,5-tetrahydrobenzofuro[2,3-f][1,4]oxazepine-3-carbonyl)((S)-1-phenylethyl)carbamate To a solution of (R)-8-bromo-4-(2-(dimethylamino)-2-oxoethyl)-3-methyl-5-oxo-N-((S)-1-phenylethyl)-2,3,4,5-tetrahydrobenzofuro[2,3-f][1,4]oxazepine-3-carboxamide (22 g, 41.7 mmol, 1.0 equiv.) in TEA (200 mL) and DMA (90 mL) was added (Boc)2O (150 mL), DMAP (2.8 g, 22.7 mmol, 1.0 equiv.). The mixture was stirred at 100° C. for 16 h. Water (150 mL) was added. The aqueous phase was extracted with EA (3×250 mL). The combined organic solution was washed with brine (250 mL), dried over anhydrous Na2SO4 and the solution was concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE:EA=1:2) to give the product (15 g, 57.6%) as a brown solid.

[0396] (R)-8-Bromo-4-(2-(dimethylamino)-2-oxoethyl)-3-methyl-5-oxo-2,3,4,5-tetrahydrobenzofuro[2,3-f][1,4]oxazepine-3-carboxylic acid To a solution of tert-butyl ((R)-8-bromo-4-(2-(dimethylamino)-2-oxoethyl)-3-methyl-5-oxo-2,3,4,5-tetrahydrobenzofuro[2,3-f][1,4]oxazepine-3-carbonyl)((S)-1-phenylethyl)carbamate (15 g, 23.9 mmol, 1.0 equiv.) in THF (170 mL), MeOH (170 mL) and HO (100 mL), KOH (26.7 g, 478 mmol, 20 equiv.) was added and the mixture was stirred at 70 °C for 3 h. The reaction mixture was concentrated under reduced pressure and then acidified to pH 4-5 with 1N HCl. The solid was filtered to give the product (8 g, 80%) as a white solid. The crude product was used directly in the next step.

[0397] (R)-8-Bromo-4-(2-(dimethylamino)-2-oxoethyl)-N-((3-methoxypyridin-2-yl)methyl)-3-methyl-5-oxo-2,3,4,5-tetrahydrobenzofuro[2,3-f][1,4]oxazepine-3-carboxamide To a solution of ((R)-8-bromo-4-(2-(dimethylamino)-2-oxoethyl)-3-methyl-5-oxo-2,3,4,5-tetrahydrobenzofuro[2,3-f][1,4]oxazepine-3-carboxylic acid (8 g, 18.86 mmol, 1.0 equiv.) in DMF (20 mL) was added HATU (37.7 g, 18.86 mmol, 1.0 equiv.), (3-methoxypyridin-2-yl)methanamine (3.8 g, 27.82 mmol, 1.0 equiv.), 1,2-dimethylpyridine (1.0 ... (3.6 g, 27.82 mmol, 2.0 equiv.) and DIPEA (3.6 g, 27.82 mmol, 2.0 equiv.) were added. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was poured into H2O (130 mL) and extracted with EtOAc (3 x 130 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by preparative HPLC to give the product (8 g, 77.9%) as a white solid.

[0398] (R)-4-(2-(dimethylamino)-2-oxoethyl)-N-((3-methoxypyridin-2-yl)methyl)-3-methyl-5-oxo-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3,4,5-tetrahydrobenzofuro[2,3-f][1,4]oxazepine-3-carboxamide (1,1'-bis(diphenylphosphino)ferrocene)palladium(ll) chloride (670 mg, 0.917 mmol, 0.1 equiv.), potassium acetate (4.5 g, 45.85 mmol, 5.0 equiv.), (R)-8-bromo-4-(2-(dimethylamino)-2-oxoethyl)-N-((3-methoxypyridin-2-yl)methyl) in dioxane (100 ml). A mixture of -3-methyl-5-oxo-2,3,4,5-tetrahydrobenzofuro[2,3-f][1,4]oxazepine-3-carboxamide (25 g, 9.17 mmol, 1.0 equiv.) and bis(pinacolato)diboron (11.6 g, 45.85 mmol, 5.0 equiv.) was degassed with argon for 5 min and the resulting mixture was stirred at 100° C. under argon for 3 h. The reaction mixture was cooled and diluted with ethyl acetate. The solution was washed with water. The organic layer was separated, dried over sodium sulfate, evaporated under reduced pressure and the residue was purified by flash column chromatography on silica gel (PE:EA=3:1) to give the product (3.3 g, 60.5%) as a pale yellow solid.

[0399] Ethyl (R)-2-(4-(2-(dimethylamino)-2-oxoethyl)-3-(((3-methoxypyridin-2-yl)methyl)carbamoyl)-3-methyl-5-oxo-2,3,4,5-tetrahydrobenzofuro[2,3-f][1,4]oxazepin-8-yl)oxazole-4-carboxylate In dioxane (100 ml) and H2O (10 ml), Pd(PPh3)4 (643 mg, 0.557 mmol, 0.1 equiv.), Cs2CO3 (3.6 g, 11.18 mmol, 2.0 equiv.), the intermediate (R)-4-(2-(dimethylamino)-2-oxoethyl)-N-((3-methoxypyridin-2-yl)methyl)-3-methyl-5-oxo-8-(4,4,5,5-tetramethyl-1,3, A mixture of 2-dioxaborolan-2-yl)-2,3,4,5-tetrahydrobenzofuro[2,3-f][1,4]oxazepine-3-carboxamide (3.3 g, 5.57 mmol, 1.0 equiv.) and ethyl 2-bromooxazole-4-carboxylate (1.6 g, 7.2 mmol, 1.3 equiv.) was degassed with argon for 2 min and the resulting mixture was stirred at 100° C. under argon for 16 h. The reaction mixture was cooled and diluted with ethyl acetate. The solution was washed with water. The organic layer was separated, dried over sodium sulfate, evaporated under reduced pressure and the residue was purified by flash column chromatography on silica gel (DCM:MeOH=20:1) to give the product (2.6 g, 77%) as a pale yellow solid.

[0400] (R)-8-(4-carbamoyloxazol-2-yl)-4-(2-(dimethylamino)-2-oxoethyl)-N-((3-methoxypyridin-2-yl)methyl)-3-methyl-5-oxo-2,3,4,5-tetrahydrobenzofuro[2,3-f][1,4]oxazepine-3-carboxamide A mixture of ethyl (R)-2-(4-(2-(dimethylamino)-2-oxoethyl)-3-(((3-methoxypyridin-2-yl)methyl)carbamoyl)-3-methyl-5-oxo-2,3,4,5-tetrahydrobenzofuro[2,3-f][1,4]oxazepin-8-yl)oxazole-4-carboxylate (2.6 g, 4.29 mmol, 1.0 equiv) in NH MeOH (10 mL, 7N) was stirred in MW at 80 °C for 2 h. The solvent was removed under reduced pressure to give the product (2.2 g, 89%) as a yellow solid.

[0401] (R)-8-(4-cyanooxazol-2-yl)-4-(2-(dimethylamino)-2-oxoethyl)-N-((3-methoxypyridin-2-yl)methyl)-3-methyl-5-oxo-2,3,4,5-tetrahydrobenzofuro[2,3-f][1,4]oxazepine-3-carboxamide A mixture of (R)-8-(4-carbamoyloxazol-2-yl)-4-(2-(dimethylamino)-2-oxoethyl)-N-((3-methoxypyridin-2-yl)methyl)-3-methyl-5-oxo-2,3,4,5-tetrahydrobenzofuro[2,3-f][1,4]oxazepine-3-carboxamide (2.2 g, 3.81 mol, 1.0 equiv.), TEA (1.54 g, 15.24 mol, 4.0 equiv.) and TFAA (1.6 g, 7.6 mol, 2 equiv.) in DCM (50 mL) was stirred at 0° C. for 2 h. The mixture was concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel (PE:EA=1:1) to give the product (1.15 g, 52%) as a white solid. LC-MS: Calculated exact mass = 558.2, Measured value [M+H] + = 559.2. 1 H NMR (400 MHz, DMSO) δ 9.47 (s, 1H), 9.28 (s, 1H), 8.18 (s, 1H), 7.92 (dd, J = 8.3, 1.0 Hz, 1H), 7.80 (d, J = 8.2 Hz, 1H), 7.51 (s, 1H), 7.21 (d, J = 8.1 Hz, 1H), 7.01 (s, 1H), 4.89 (d, J = 11.8 Hz, 1H), 4.50 (s, 2H), 4.39 (d, J = 11.7 Hz, 1H), 4.32 (dd, J = 15.5, 6.3 Hz, 1H), 4.19 - 4.06 (m, 1H), 3.68 (s, 3H), 3.07 (s, 3H), 2.86 (s, 3H), 1.60 (s, 3H).

[0402] The following examples were prepared in racemic form using procedures similar to those described above.

[0403] [Table 12]

[0404] Intermediate BB-12 5-Trifluoromethyl-3-(2-oxopropoxy)benzofuran-2-carboxylic acid

[0405] [ka] 2-Hydroxy-5-(trifluoromethyl)benzoic acid BBr3 (1M in DCM) (89 mL, 89 mmol, 2.0 equiv.) was added dropwise to a stirred mixture of compound 2-methoxy-5-(trifluoromethyl)benzoic acid (9.8 g, 44.5 mmol, 1.0 equiv.) in DCM (100 mL) over 30 min at -20°C, and the mixture was stirred at -20°C for 4 h. The reaction was monitored by LCMS. The reaction was cooled, poured into ice water, extracted with DCM, and the solution was washed successively with water, aqueous sodium carbonate, water, and brine. The crude product was purified by flash chromatography on silica gel (PE:EA=1:1) to give the product (9 g, 98%) as a yellow solid. TLC: PE / EA=5:1, UV;R f Starting material=0.7, product=0.5.

[0406] Methyl 2-hydroxy-5-(trifluoromethyl)benzoate SOCl2 (10 mL) was added dropwise over 5 min to a stirred mixture of compound 2-hydroxy-5-(trifluoromethyl)benzoic acid (8.5 g, 41.24 mol, 1.0 equiv.) in MeOH (85 mL). The mixture was heated and stirred under reflux for 4 h. The reaction was monitored by LCMS. The crude product was distilled under reduced pressure, washed with H2O, extracted with ethyl acetate, and the organic phase was distilled under reduced pressure to give the product (8 g, 95%) as a brown solid. The crude product was used directly in the next step. TLC: PE / EA=5:1, UV; R f Starting material=0.3, product=0.8.

[0407] Methyl 2-(2-methoxy-2-oxoethoxy)-5-(trifluoromethyl)benzoate Methyl bromoacetate (6.11 g, 39.97 mol, 1.1 equiv.) was added dropwise over 5 min to a stirred mixture of compound methyl 2-hydroxy-5-(trifluoromethyl)benzoate (8 g, 36.34 mol, 1.0 equiv.) and potassium carbonate (15.07 g, 109 mol, 3.0 equiv.) in MeCN (80 mL). The mixture was heated and stirred under reflux for 4 h. The reaction was monitored by LCMS. The reaction was cooled and the salts were separated by filtration and washed with acetone. The filtrate was concentrated to give a residue which was diluted with EA (0.25 L) and the solution was washed successively with water, aqueous sodium carbonate, water, and brine. The crude product was distilled under reduced pressure to give the product (10 g, 94%) as a brown solid. The crude product was used directly in the next step.

[0408] Methyl 3-hydroxy-5-(trifluoromethyl)benzofuran-2-carboxylate To a mixture of compound methyl 2-(2-methoxy-2-oxoethoxy)-5-(trifluoromethyl)benzoate (10 g, 34.22 mmol, 1.0 equiv.) in MeOH (100 mL), NaOMe (30% in methanol, 5 M, 13.6 mL, 68.44 mmol, 1.2 equiv.) was added and the mixture was stirred at 60° C. for 4 h. The reaction was monitored by LCMS. The resulting mixture was cooled, poured into ice water, and acidified to pH 2 with 5% hydrochloric acid. The solid was collected by filtration, washed with water, and recrystallized from methanol to give the product (8.7 g, 97%) as a yellow solid. LC-MS: calculated exact mass=260.0, found [M+H] + =261.0.

[0409] Methyl 3-(2-oxopropoxy)-5-(trifluoromethyl)benzofuran-2-carboxylate To a mixture of compound methyl 3-hydroxy-5-(trifluoromethyl)benzofuran-2-carboxylate (8.7 g, 33.44 mmol, 1.0 equiv.) in acetonitrile (90 mL), TEA (9.32 mL, 66.88 mol, 2 equiv.), chloroacetone (3.7 g, 40.13 mmol, 1.2 equiv.) were added and the mixture was refluxed for 4 h. The reaction was monitored by LCMS. The resulting mixture was filtered, concentrated and extracted with ethyl acetate to give the product (9 g, 85%) as a brown solid. LC-MS: Calculated exact mass = 316.0, Found [M+H] + =317.0.

[0410] 5-Trifluoromethyl-3-(2-oxopropoxy)benzofuran-2-carboxylic acid (BB-5) A solution of crude compound methyl 3-(2-oxopropoxy)-5-(trifluoromethyl)benzofuran-2-carboxylate (8 g, 25.3 mmol, 1.0 equiv.) in MeOH (100 mL) and 5% NaOH in water (40 mL) was stirred at room temperature for 4 h. The reaction was monitored by LCMS. The resulting mixture was concentrated, adjusted to pH 2 by adding 1N HCl, and extracted with ethyl acetate. The combined organic layers were washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography on silica (DCM:MeOH=10:1) to give the product (3.8 g, 49%) as a yellow solid. LC-MS: calculated exact mass=302.0, found [M+H] + =303.0.

[0411] (Example 131) 4-(2-(Dimethylamino)-2-oxoethyl)-N-(2-fluoro-6-methoxybenzyl)-3-methyl-5-oxo-9-(trifluoromethyl)-2,3,4,5-tetrahydrobenzofuro[2,3-f][1,4]oxazepine-3-carboxamide

[0412] [ka] 4-(2-(Dimethylamino)-2-oxoethyl)-N-(2-fluoro-6-methoxybenzyl)-3-methyl-5-oxo-9-(trifluoromethyl)-2,3,4,5-tetrahydrobenzofuro[2,3-f][1,4]oxazepine-3-carboxamide 3-(2-oxopropoxy)-5-(trifluoromethyl)benzofuran-2-carboxylic acid (100 mg, 0.33 mmol, 1.0 equiv), 2-amino-N,N-dimethylacetamide (40.5 mg, 0.397 mmol, 1.2 equiv), and 1-fluoro-2-(isocyanomethyl)-3-methoxybenzene (65 mg, 0.397 mmol, 1.2 equiv) in MeOH (10 mL) were stirred at 50° C. for 16 h. The mixture was concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel (PE:EA=1:1) to give the product (90 mg, 30%) as a white solid. LC-MS: Calculated exact mass = 551.2, found [M+H] + = 552.2. 1 H NMR (400 MHz, DMSO) δ 9.59 (s, 1H), 7.90 (s, 1H), 7.80 (dd, J = 8.9, 1.6 Hz, 1H), 7.74 (d, J = 8.8 Hz, 1H), 6.97 (d, J = 7.7 Hz, 1H), 6.57 (d, J = 8.3 Hz, 1H), 6.29 (s, 1H), 4.87 (d, J = 12.0 Hz, 1H), 4.52 (s, 1H), 4.31 (dt, J = 13.7, 11.3 Hz, 3H), 3.89 (s, 1H), 3.62 (s, 3H), 3.04 (s, 3H), 2.88 (s, 3H), 1.55 (s, 3H).

[0413] Using similar procedures, the following examples were prepared:

[0414] [Table 13]

[0415] (Example 133) 4-(2-(Dimethylamino)-2-oxoethyl)-N-(2-fluoro-6-methoxybenzyl)-3,9-dimethyl-5-oxo-2,3,4,5-tetrahydrobenzofuro[2,3-f][1,4]oxazepine-3-carboxamide

[0416] [ka] 5-Methyl-3-(2-oxopropoxy)benzofuran-2-carboxylic acid was prepared using a procedure similar to that described above.

[0417] [Table 14]

[0418] (Example 134) (R)-4-(2-(dimethylamino)-2-oxoethyl)-N-(2-fluoro-6-methoxybenzyl)-3-methyl-5-oxo-8-(trifluoromethyl)-2,3,4,5-tetrahydropyrido[2',3':4,5]furo[2,3-f][1,4]oxazepine-3-carboxamide

[0419] [ka] 3-(2-oxopropoxy)-6-(trifluoromethyl)furo[3,2-b]pyridine-2-carboxylic acid was prepared using a procedure similar to that described above.

[0420] [Table 15]

[0421] (Examples 135 to 138)

[0422] [Table 16]

[0423] Conditions for cell-based bioassay of KLF2 induction The highest working concentration stock was made in endothelial cell medium with DMSO vehicle at 1% or less. The working stock was then serially diluted 1:2 to generate an 11-point concentration response curve. The 96-well plate contained two reference compounds with known potency. A DMSO row was included in the 96-well plate with the highest percent vehicle of the working stock. A 96-well cell culture plate of primary human endothelial cells expressing luciferase under the control of the KLF2 promoter was dosed with 200 μL of the dilution series and the DMSO control row per well. The assay plate was incubated at 37° C. for 24 hours. Supernatants were collected at 24 hours.

[0424] 20 μL of the supernatant was then placed into a 384-well plate containing optical replicates. A corner of the plate contained 20 μL of Gaussia luciferase enzyme, a positive control, and 20 μL of 50 μM Coelenterizine substrate. Plate readings were then calibrated using the controls and read using a Molecular Devices SpectraMax iD5 to provide luminescence in relative light units (RLU). 20 μL of 50 μM Coelenterizine substrate was injected into the plate reader immediately prior to taking the RLU measurements per well.

[0425] The sample signals were then normalized to the average signal of the DMSO column and the maximum signal of one of the reference compounds, as shown in the following equation:

[0426]

number

[0427] The EC50 for each compound is then defined as the concentration at which the concentration-response curve passes through 0.5.

[0428] The active range is defined as follows:

[0429] [Table 17]

[0430] Using these activity definitions, the biological activities of the examples are shown below.

[0431] [Table 18-1]

[0432] [Table 18-2]

[0433] Confirmation of stereochemistry of Example 129 Crystals were obtained from a 1:1:1:1 ratio of dichloromethane / methanol / ethyl acetate / n-hexane after 8 days at room temperature (15-23 °C).

[0434] Instrument parameters (Bruker D8 Venture): Light source: Cu target X-ray: Cu-Kα (=1.54178Å) Detector: CMOS surface detector Resolution: 0.88 Å Current and voltage: 50kV, 1.2mA Exposure time: 3 seconds Distance from surface detector to sample: 40 mm Test temperature: 170(2)K

[0435] Structure analysis and refinement process After integral reduction of the diffraction data by the SAINT program, empirical absorption correction of the data is performed by using the SADABS program, and the single crystal structure is analyzed by direct methods using SHEXLT2014, and the structure is refined by the least squares method. The refinement process of hydrogen atoms is obtained by isotropic calculation, hydrogen atoms on O and N are obtained by residual electron density, and hydrogen atoms on CH are obtained by calculating hydrogenation and refined by adopting the riding model. The Flack constant is -0.03(10) throughout the structure diagram, and the absolute configuration can be determined. The C10 configuration of the structure is S.

[0436] Crystal data

[0437] [Table 19]

[0438] Data collection

[0439] [Table 20]

[0440] Precision

[0441] [Table 21]

[0442] Special details Geometry. All ESDs (except the ESD at the dihedral angle between two ls faces) are estimated using the full covariance matrix. For the estimation of distance, angle and torsion angle ESDs, the cell ESDs are taken into account individually, and correlations between the ESDs of cell parameters are used only if they are defined by the crystal symmetry. To estimate ESDs involving ls faces, an approximate (isotropic) treatment of the cell ESDs is used.

[0443] Refinement. Refined as a two-component twin.

[0444] Fractional atomic coordinates and isotropic or equivalent isotropic dislocation parameters (Å) for (cu_20221392_0m) 2 )

[0445] [Table 22-1]

[0446] [Table 22-2] Atomic displacement parameters (Å) for (cu_20221392_0m) 2 )

[0447] [Table 23-1]

[0448] [Table 23-2] Geometric parameters for (cu_20221392_0m) (Å, °)

[0449] [Table 24-1]

[0450] [Table 24-2]

[0451] [Table 24-3]

[0452] Biological activity of steroisomers

[0453] [Table 25]

[0454] Incorporation by Reference All publications and patents mentioned herein are hereby incorporated by reference in their entirety as if each individual publication or patent was specifically and individually indicated to be incorporated by reference. In case of conflict, the present application, including any definitions herein, will control.

[0455] Doctrine of Equivalents While specific embodiments of the subject invention have been discussed, the above specification is illustrative and not restrictive. Many variations of the invention will become apparent to those skilled in the art upon review of this specification and the following claims. The full scope of the invention should be determined by reference to the claims, along with their full scope of equivalents, and the specification, along with such variations.

Claims

1. Compounds represented by formula I 【Chemistry 1】 [In the formula, R １ represents lower alkyl, X is C-R ２ａ or N, R ２ａ , R ２ｂ , R ２ｃ , and R ２ｄ each independently represents hydrogen, alkyl, alkenyl, alkynyl, halo, aryl, heteroaryl, cycloalkyl, heterocyclyl, cyano, acyl, carboxy, ester, or amido; R ３ represents alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, arylalkyl, heteroaralkyl, (cycloalkyl)alkyl, heterocyclylalkyl, amidoalkyl, alkoxyalkyl, or acylalkyl; Z represents a substituted or unsubstituted aryl or heteroaryl ring, which may be substituted, for example, with one or more groups selected from alkyl, alkenyl, alkynyl, cyano, acyl, carboxy, ester, amide, alkoxy, and halo, with the proviso that 【Chemistry 2】 or a pharma- ceutically acceptable salt thereof.

2. R １ The compound of claim 1 , wherein is methyl.

3. 3. The compound of claim 1 or 2, wherein X is N.

4. X is C-R ２ａ 3. The compound according to claim 1 or 2,

5. R ２ａ , R ２ｂ , R ２ｃ , and R ２ｄ are independently hydrogen, methyl, propenyl, chloro, fluoro, haloalkyl (e.g., trifluoromethyl), a 5-membered heteroaryl, cyclopropyl, or the structure 【Chemistry 3】 [In the formula, R ａ is hydrogen or alkyl; R ｂ and R ｃ and R 1 and R 2 are taken together to form a cycloalkyl or heterocyclyl.

6. R ｂ and R ｃ The compound of claim 5 , wherein taken together, forms a cyclobutyl.

7. R ａ The compound according to claim 5 or 6, wherein is hydrogen or methyl.

8. R ｂ and R ｃ taken together to form an oxetane.

9. R ａ The compound of claim 8 , wherein is methyl.

10. R ２ａ , R ２ｂ , R ２ｃ , and R ２ｄ The compound of claim 5 , wherein at least one of is a 5-membered heteroaryl.

11. 11. The compound of claim 10, wherein the 5-membered heteroaryl is thiazolyl or oxazolyl optionally substituted with trifluoromethyl, chloro, or cyano.

12. The compound of claim 10, wherein the 5-membered heteroaryl is oxazol-2-yl.

13. The compound of claim 10, wherein the 5-membered heteroaryl is 4-cyanooxazol-2-yl.

14. R ２ａ 14. The compound according to any one of claims 1 to 13, wherein is hydrogen.

15. R ２ｂ and R ２ｄ 15. The compound of claim 1, wherein each is hydrogen.

16. R ２ｃ and R ２ｄ 15. The compound of claim 1, wherein each is hydrogen.

17. R ２ｂ , R ２ｃ , and R ２ｄ 15. The compound of claim 1, wherein each is hydrogen.

18. R ２ａ , R ２ｂ , R ２ｃ , and R ２ｄ 5. The compound of claim 1 , wherein each is hydrogen.

19. R ３ The compound of any one of claims 1 to 18, wherein is amidoalkyl.

20. The amidoalkyl has the structure 【Chemistry 4】 [In the formula, R ｄ and R ｅ is independently selected from alkyl or hydroxyalkyl, or R ｄ and R ｅ taken together form a heterocyclic ring.

21. R ｄ and R ｅ 21. The compound of claim 20, wherein each is methyl.

22. R ｄ and R ｅ is independently substituted with one or more deuterium atoms.

23. R ｄ is methyl, R ｅ - (CH ２ ) ２ 23. The compound of claim 22, wherein:

24. R ｄ and R ｅ and the nitrogen to which they are attached form an azetidine optionally substituted with one or more halo, hydroxyl, or hydroxyalkyl.

25. Azetidine is 【Chemistry 5】 25. The compound of claim 24, wherein

26. R ３ C ３ ~C ６ 19. The compound of any one of claims 1 to 18, which is cycloalkyl.

27. R ３ but, 【Chemistry 6】 27. The compound of claim 26,

28. R ３ C optionally substituted with alkoxy １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl, or C ２ ~C ６ 19. A compound according to any one of claims 1 to 18, which represents alkynyl.

29. R ３ but, 【Chemistry 7】 29. The compound of claim 28,

30. R ３ is -CH, optionally substituted with halo, alkoxy, or hydroxyl; ２ -cycloalkyl.

31. R ３ but, 【Chemistry 8】 31. The compound of claim 30,

32. R ３ But the structure 【Chemistry 9】 [In the formula, R ｆ 19. The compound according to any one of claims 1 to 18, wherein R is an acylalkyl group having the formula:

33. R ｆ 33. The compound of claim 32, wherein is ethyl or cyclopropyl.

34. R ３ may be substituted with alkyl, hydroxyalkyl or alkoxyalkoxyalkyl -(CH ２ ) １～３ 19. A compound according to any one of claims 1 to 18, which represents -heteroaryl.

35. The compound of claim 34, wherein the heteroaryl is tetrazole, 1,2,3-triazole, or 1,2,4-triazole.

36. R ３ but, 【Chemistry 10】 36. The compound of claim 35,

37. 37. The compound of any one of claims 1 to 36, wherein Z represents phenyl, pyridinyl, naphthyl, isoquinolinyl, or quinolinyl, each of which is optionally substituted with one or more groups selected from lower alkyl, lower alkoxy, halo, haloalkoxy, amido, and cyano.

38. 38. The compound of claim 37, wherein Z is substituted with one or more groups selected from methoxy, isopropyloxy, chloro, fluoro, trifluoromethoxy, cyano, and carbamoyl.

39. 39. The compound of claim 37 or 38, wherein Z is mono-, di-, or tri-substituted.

40. 39. The compound of claim 37 or 38, wherein Z is phenyl substituted with methoxy and at least one further substitutent.

41. Z, 【Chemistry 11】 41. The compound according to any one of claims 1 to 40, wherein

42. 【Chemical 12-1】 【Chemistry 12-2】 【Chemistry 12-3】 【Chemistry 12-4】 【Chemistry 12-5】 【Chemistry 12-6】 【Chemistry 12-7】 【Chemistry 12-8】 【Chemistry 12-9】 【Chemistry 12-10】 【Chemistry 12-11】 【Chemistry 12-12】 or a pharma- ceutically acceptable salt thereof.

43. 43. A pharmaceutical composition comprising a compound according to any one of claims 1 to 42, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier.

44. A method for treating an inflammatory disease or endothelial dysfunction, comprising administering to a subject in need thereof a therapeutically effective amount of a compound described in any one of claims 1 to 42 or a pharma- ceutically acceptable salt thereof, or a composition described in claim 43.

45. 45. The method of claim 44, wherein the inflammatory disease or endothelial dysfunction is selected from atherosclerosis, coronary artery disease, stroke, peripheral artery disease, coronary microvascular disease, angina pectoris, systemic hypertension, pulmonary arterial hypertension, heart failure, and diabetic microvascular disease, such as diabetic nephropathy, diabetic retinopathy or diabetic neuropathy, or an autoimmune, inflammatory or infectious disease.

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