Compound

Abstract

To provide compounds which act as Lysine Acetyltransferase (KAT) inhibitors of the MYST family as agents for the treatment of cancer.SOLUTION: The present invention provides a compound of formula (I) or a pharmaceutical salt thereof.SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention relates to compounds that act as inhibitors of lysine acetyltransferases (KATs) of the MYST family.

Background Art

[0002] The MYST family is the largest family of KATs and is named after its founding members in yeast and mammals: MOZ, Ybf2 / Sas3, Sas2, and TIP60 (Dekker 2014). MYST proteins mediate many biological functions including gene regulation, DNA repair, cell cycle regulation, and development (Avvakumov 2007; Voss 2009). KAT proteins of the MYST family play a central role in the post-translational modification of histones and thus have a profound impact on chromatin structure in the nucleus of eukaryotes (Avvakumov 2007). The family currently includes five mammalian KATs: TIP60 (KAT5, HTATIP, MIM601409), MOZ (KAT6A, MIM601408, MYST3), MORF (KAT6b, QKF, MYST4), HBO (KAT8, HBO1, MYST2), and MOF (KAT8, MYST1) (Voss 2009). These five members of the MYST family are present in humans, and dysfunction of MYST proteins is known to be associated with cancer (Avvakumov 2007). The most frequently used names for members of the MYST family are

[0003]

Table 1

[0004] MYST functional domain The MYST protein functions in a multi-subunit protein complex that includes adapters such as the ING protein that mediates DNA binding (Avvakumov 2007). For example, TIP60 belongs to the NuA4 multi-protein complex (encompassing more than 16 members) (Zhang 2017). However, there are also several reports on the helix-turn-helix DNA-binding motif within the structure of the MOZ protein itself (Holbert 2007), which suggests the ability to bind directly to DNA.

[0005] The acetyltransferase activity of the MYST protein is achieved by the MYST domain (catalytic domain). The MYST domain contains an acetyl coenzyme A-binding motif, which is structurally conserved in other HATs and the rare C 2 HC-type zinc finger (Voss 2009). The highly conserved MYST domain, including the acetyl-CoA binding motif and the zinc finger, is considered a characteristic that defines this family of enzymes (Avvakumov 2007).

[0006] The role of the MYST protein Acetylation of histone residues is generally associated with transcriptional activation. However, in some cases, transcriptional repression has also been attributed to MYST proteins (Voss 2009). Individual members of the MYST family are known to be involved in a wide range of important biochemical interactions.

[0007] HBO1 positively regulates the initiation of DNA replication through acetylation of histone substrates (Avvakumov 2007, Aggarwal 2004, Doyon 2006, Iizuka 2006), which likely leads to a more accessible chromatin conformation (Avvakumov 2007, Iizuka 2006). HBO1 is also known to play a role in the etiology of breast cancer by promoting the enrichment of cancer stem-like cells (Duong 2013) and destabilizing estrogen receptor α (ERα) via ubiquitination, which proceeds through the histone acetylation activity of HBO1 (Iizuka 2013). HBO1 has also been implicated in acute myeloid leukemia (AML) (Shi 2015).

[0008] TIP60 (KAT5) is the most studied member of the MYST family. TIP60 plays an important role not only in the regulation of transcription but also, particularly, in the process of DNA damage repair in DNA double-strand breaks (DSBs) (Gil 2017). TIP60 can acetylate p53, ATM, and c-Myc. TIP60 and MOF specifically acetylate lysine 120 (K120) of p53 upon DNA damage (Avvakumov 2007). TIP60 has also been related to being important for regulatory T cell (Treg) biology. FOXP3 is a master regulator in the development and function of Tregs, and acetylation of FOXP3 by TIP60 has been shown to be essential for FOXP3 activity (Li 2007, Xiao 2014). To emphasize this, conditional TIP60 deletion in mice leads to a scurfy-like lethal autoimmune disease that mimics the phenotype seen in FOXP3 knockout mice (Xiao 2014). In cancer, Treg cells can facilitate tumor progression by suppressing adaptive immunity against the tumor.

[0009] MOF ("males absent on the first") was initially identified as one of the components of gene dosage compensation in Drosophila and was classified as a member of the MYST family based on functional studies and sequence analysis (Su 2016). The human ortholog exhibits significant similarity to Drosophila MOF and contains an acetyl-CoA binding site, a chromodomain (which binds histones), and a C 2 HC-type zinc finger (Su 2016). MOF is a central enzyme for acetylating histone H4K16, and MOF-containing complexes are involved in various essential cellular functions associated with cancer (Su 2016). Depletion of MOF in mammalian cells can lead to abnormal gene transcription in addition to an overall reduction in histone acetylation, particularly causing abnormal expression of certain tumor suppressor genes or oncogenes, suggesting a crucial role of MOF in tumorigenesis (Su 2016). For example, the KAT activity of MOF has been shown to be required to sustain MLL-AF9 leukemia and can be important for multiple AML subtypes (Valerio 2017).

[0010] KAT6B (Querkopf) was first identified in a mutagenesis screen for genes that regulate the balance between proliferation and differentiation during embryonic development (Thomas 2000). Mice homozygous for KAT6B mutant alleles have severe defects in cerebral cortex development that result from a severe reduction in both proliferation and differentiation of the cortical progenitor cell population during embryonic development. KAT6B is required for the maintenance of the adult neural stem cell population and is part of a system that regulates the differentiation of stem cells into neurons (Merson 2006). KAT6B is also mutated in a rare form of leukemia (Vizmanos 2003).

[0011] The MOZ locus has been positioned as the 12th most frequently amplified region across all cancer types (Zack 2013). MOZ is within the 8p11-p12 amplicon and is seen at a frequency of around 10 - 15% in various cancers, particularly breast and ovarian cancers (Turner-Ivey 2014). MOZ was first identified as a fusion partner of CREB-binding protein (CBP) during the investigation of specific chromosomal translocations in acute myeloid leukemia (AML) (Avvakumov 2007, Borrow 1996). MOZ KAT activity is required to promote the expression of MEIS1 and HOXa9, proteins that are typically overexpressed in several lymphomas and leukemias. In the Eμ-Myc transgenic model of B-cell lymphoma, MOZ + / - increased survival of heterozygous mice was seen, and loss of a single MOZ allele led to a biologically relevant reduction in Meis1 and Hoxa9 levels in progenitor B cells (Sheikh 2015).

[0012] Several inhibitors of MYST are known. For example, the following anacardic acid derivatives have been reported to inhibit TIP60 (IC 50 = 74 μM) and MOF (IC 50 = 47 μM) (Ghizzoni 2012):

[0013]

Chemical formula

[0014] Other known inhibitors are (Zhang 2017):

[0015]

Chemical formula

Summary of the Invention

Problems to be Solved by the Invention

[0016] Given the generally established role of KATs, particularly MYST, in diseases such as cancer, there is a need for new inhibitors of these proteins.

Means for Solving the Problems

[0017] The present invention provides a compound that inhibits the activity of one or more KATs of the MYST family, namely, TIP60, KAT6B, MOZ, HBO1, and MOF.

[0018] The first aspect of the present invention is a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in a therapeutic method:

[0019]

Chemical formula

[0020] The first aspect also provides a pharmaceutical composition comprising a compound of formula (I) as defined, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0021] The second aspect of the present invention is a method for treating cancer, comprising administering to a patient in need of treatment a compound or a pharmaceutically acceptable salt thereof as defined in the first aspect of the present invention or the pharmaceutical composition of the first aspect of the present invention. The second aspect of the present invention also provides the use of a compound or a pharmaceutically acceptable salt thereof as defined in the first aspect of the present invention in the manufacture of a medicament for treating cancer, and a compound or a pharmaceutically acceptable salt thereof or the pharmaceutical composition thereof as defined in the first aspect of the present invention for use in treating cancer.

[0022] As described below, the compound as defined in the first aspect may be administered simultaneously or sequentially with radiotherapy and / or chemotherapy in the treatment of cancer.

[0023] The third aspect of the present invention is a compound of formula (I), or a pharmaceutically acceptable salt thereof

[0024]

Chemical formula

[0025] The fourth aspect of the present invention provides the synthesis of a compound as defined in the first or third aspect of the present invention, as described below.

Mode for Carrying Out the Invention

[0026] Definition Unless otherwise defined, the term "substituted", as used herein, relates to a parent group bearing one or more substituents. The term "substituent" is used herein in its conventional meaning and refers to a chemical moiety that is covalently bonded to, or, where appropriate, fused to, the parent group. The phrase "optionally substituted", as used herein, relates to a parent group that may be unsubstituted or substituted.

[0027] C 5~12 Heteroaryl: The term "C 5~12 heteroaryl", as used herein, relates to a monovalent moiety obtained by removing a hydrogen atom from an aromatic structure having from 5 to 12 ring atoms, of which from 1 to 3 are ring heteroatoms. The term "aromatic structure" is used to denote a monocyclic or fused ring system having aromatic character, and the term "ring heteroatom" refers to a nitrogen, oxygen or sulfur atom.

[0028] In this context, prefixes (e.g., C 5~12 , C 5~6 etc.) denote the number of atoms, or the range of the number of atoms, that make up the aromatic structure, regardless of whether they are carbon atoms or heteroatoms.

[0029] C 5~12 Examples of heteroaryl structures are N 1 : pyrrole (azole) (C5 )), pyridine (azine) (C 6 ), pyridone (C 6 ), indole (C 9 ), quinoline (C 10 ), O 1 : furan (oxole) (C 5 ), S 1 : thiophene (thiol) (C 5 ), N 1 O 1 : oxazole (C 5 ), isoxazole (C 5 ), isoxazine (C 6 ), N 2 O 1 : oxadiazole (furazan) (C 5 ), N 1 S 1 : thiazole (C 5 ), isothiazole (C 5 ), N 2 S 1 : thiadiazole (C 5 ), N 2 : imidazole (1,3-diazole) (C 5 ), pyrazole (1,2-diazole) (C 5 ), pyridazine (1,2-diazine) (C 6 ), pyrimidine (1,3-diazine) (C 6 )(e.g., cytosine, thymine, uracil), pyrazine (1,4-diazine) (C 6 ), benzimidazole (C 9 ), N 3 : triazole (C 5 ), triazine (C 6 ), including but not limited to those derived from

[0030] Halo: As used herein, the term "halo" refers to a group selected from fluoro, chloro, bromo, and iodo.

[0031] Cyano: The term "cyano," as used herein, refers to the group --C.ident.N.

[0032] Hydroxy: The term "hydroxy," as used herein, refers to the group --OH.

[0033] Phenyl: The term "phenyl," as used herein, refers to a monovalent moiety obtained by removing a hydrogen atom from a single aromatic ring structure having six carbon ring atoms (-C 6 H 5 ) regarding.

[0034] Phenoxy: The term "phenoxy" as used herein refers to a monovalent moiety obtained by removing a hydrogen atom from the oxygen atom of a phenol (-OC 6 H 5 ) regarding.

[0035] C 1~4 Alkyl: The term "C 1~4 "Alkyl," as used herein, pertains to a monovalent moiety obtained by removing a hydrogen atom from a carbon atom of a saturated hydrocarbon compound having from one to four carbon atoms.

[0036] An example of a saturated alkyl group is methyl (C 1 ), ethyl (C 2 ), Propyl (C 3 ) and butyl (C 4 ), but are not limited to:

[0037] An example of a saturated straight-chain alkyl group is methyl (C 1 ), ethyl (C 2 ), n-propyl (C 3 ) and n-butyl (C 4 ), but are not limited to:

[0038] An example of a saturated branched alkyl group is isopropyl (C 3 ), iso-butyl (C4 ), sec-butyl (C 4 ) and tert-butyl (C 4 ).

[0039] C 3~6 Cycloalkyl: The term "C 3~6 cycloalkyl" as used herein relates to a monovalent moiety obtained by removing a hydrogen atom from a carbon atom of a saturated cyclic hydrocarbon compound having from 3 to 6 carbon atoms. C 3~6 Examples of cycloalkyl groups include, but are not limited to, cyclopropyl (C 3 ), cyclobutyl (C 4 ), cyclopentyl (C 5 ) and cyclohexyl (C 6 ).

[0040] C 1~4 Alkoxy: The term "C 1~4 alkoxy" as used herein relates to a monovalent moiety obtained by removing a hydrogen atom from an oxygen atom of a saturated alcohol compound having from 1 to 4 carbon atoms. This can be represented as -O-C 1~4 alkyl. C 1~4 Examples of alkoxy groups include, but are not limited to, methoxy (C 1 ), ethoxy (C 2 ), propyloxy (C 3 ) and butyloxy (C 4 ).

[0041] C 1~4 Alkylcarbamoyl: -NHC(=O)OR, wherein R is a C 1~4 alkyl group as defined above. C 1~4 Examples of alkylcarbamoyl include, but are not limited to, -N(H)C(=O)OCH 3 , -N(H)C(=O)OCH 2 CH 3 and -N(H)C(=O)OC(CH 3 ) 3 .

[0042] Acylamide: -NR(C=O)R' (wherein R and R' are independently selected from H and C 1~4 alkyl as defined above). R and R' may be -(CH 2 ) n - (wherein n is 3 or 4). Examples of acylamide groups are -N(H)C(=O)CF 3 , N(H)C(=O)Me, and

[0043]

Chemical formula

[0044] C 1~4 Alkyl ester: The term "C 1~4 alkyl ester" as used herein relates to a monovalent moiety obtained by removing a hydrogen atom from an oxygen atom of a saturated carboxylic acid compound having from 1 to 5 carbon atoms. This can be represented as -O-C(O)-C 1~4 alkyl. Examples of C 1~4 alkyl ester groups are acetoxy (-O-C(O)-CH 3 ), propanoyloxy (-O-C(O)-CH 2 CH 3 ), butanoyloxy (-O-C(O)-CH 2 CH 2 CH 3 ), and pentanoyloxy (-O-C(O)-CH 2 CH 2 CH 2 CH 3 ), including but not limited to these.

[0045] Including other forms Unless otherwise specified, well-known ionic, salt, solvate, and protected forms of these substituents are included above. For example, a reference to a carboxylic acid (-COOH) includes its anionic (carboxylate) form (-COO -) also includes salts or solvates, and conventional protected forms. Similarly, references to amino groups include the protonated form of the amino group (-N + HR 1 R 2 ), salts or solvates, for example, hydrochloride salts of amino groups and conventional protected forms. Similarly, references to hydroxyl groups also include their anionic form (-O - ), salts or solvates, and conventional protected forms.

[0046] Salt It may be convenient or desirable to prepare, purify, and / or handle the corresponding salts of the active compound, for example, pharmaceutically acceptable salts. Examples of pharmaceutically acceptable salts are discussed in Berge 1977.

[0047] For example, when the compound is anionic or has a functional group that may be anionic (e.g., -COOH may be -COO - ), the salt may be formed with a suitable cation. Examples of suitable inorganic cations include alkali metal ions such as Na + and K + , alkaline earth cations such as Ca 2+ and Mg 2+ , and other cations such as Al +3 . Examples of suitable organic cations include ammonium ions (i.e., NH 4 + ) and substituted ammonium ions (e.g., NH 3 R + , NH 2 R 2 + , NHR 3 + , NR 4 +include, but are not limited to. Examples of some suitable substituted ammonium ions are those derived from ethylamine, diethylamine, dicyclohexylamine, triethylamine, butylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, benzylamine, phenylbenzylamine, choline, meglumine and tromethamine, and amino acids such as lysine and arginine. Examples of common quaternary ammonium ions are N(CH 3 ) 4 + are.

[0048] When the compound is cationic or has a functional group that may be cationic (e.g., -NH 2 may be -NH 3 + ), the salt may be formed with a suitable anion. Examples of suitable inorganic anions include, but are not limited to, those derived from the following inorganic acids: hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfurous acid, nitric acid, nitrous acid, phosphoric acid and phosphorous acid.

[0049] Examples of suitable organic anions include, but are not limited to, those derived from the following organic acids: 2-acetoxybenzoic acid, acetic acid, ascorbic acid, aspartic acid, benzoic acid, camphorsulfonic acid, cinnamic acid, citric acid, edetic acid, ethanedisulfonic acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, hydroxymaleic acid, hydroxynaphthalenecarboxylic acid, isethionic acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, methanesulfonic acid, mucic acid, oleic acid, oxalic acid, palmitic acid, pamoic acid, pantothenic acid, phenylacetic acid, phenylsulfonic acid, propionic acid, pyruvic acid, salicylic acid, stearic acid, succinic acid, sulfanilic acid, tartaric acid, toluenesulfonic acid, trifluoroacetic acid and valeric acid. Examples of suitable polymeric organic anions include, but are not limited to, those derived from the following polymeric acids: tannic acid, carboxymethylcellulose.

[0050] Solvates It may be convenient or desirable to prepare, purify, and / or handle the corresponding solvates of the active compound. The term "solvate" is used herein in its conventional meaning to refer to a complex of a solute (e.g., an active compound, a salt of an active compound) and a solvent. When the solvent is water, the solvate may conveniently be referred to as a hydrate, e.g., a monohydrate, dihydrate, trihydrate, etc.

[0051] Isomer Certain compounds of the invention may hereinafter be collectively referred to as "isomers" (or "isomeric forms") and may exist in one or more specific geometric, optical, enantiomeric, diastereomeric, epimeric, atropisomeric, stereoisomeric, tautomeric, conformational or anomeric forms, including but not limited to cis and trans forms; E and Z forms; c, t and r forms; endo and exo forms; R, S and meso forms; D and L forms; d and l forms; (+) and (-) forms; keto, enol and enolate forms; syn and anti forms; synclinal and anticlinal forms; α and β forms; axial and equatorial forms; boat, chair, twisted, envelope and half chair forms; and combinations thereof.

[0052] The term "chiral" refers to a molecule having the property of not being superimposable on its mirror image partner, while the term "achiral" refers to a molecule that can be superimposed on its mirror image partner.

[0053] The term "stereoisomers" refers to compounds having the same chemical constitution but differing with respect to the arrangement of the atoms or groups in space.

[0054] "Diastereomers" refer to stereoisomers having two or more centers of chirality and whose molecules are not mirror images of each other. Diastereomers have different physical properties, e.g., melting point, boiling point, spectral properties and reactivity. A mixture of diastereomers may be separated under high resolution analytical procedures such as electrophoresis and chromatography.

[0055] "Enantiomers" refer to two stereoisomers of a compound that are mirror images that cannot be superimposed on each other.

[0056] The stereochemical definitions and conventions used herein generally conform to S.P. Parker, ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; as well as Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994. The compounds of the present invention may contain asymmetric or chiral centers and, accordingly, may exist in different stereoisomeric forms. All stereoisomeric forms of the compounds of the present invention, including, but not limited to, diastereomers, enantiomers and atropisomers, and mixtures thereof such as racemic mixtures, are intended to form part of the present invention. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light. When describing an optically active compound, the prefixes D and L, or R and S are used to denote the absolute configuration of the molecules around its chiral center. The prefixes d and l or (+) and (-) are used to designate the sign of rotation of plane-polarized light by the compound, and (-) or l means that the compound is levorotatory. A compound prefixed with (+) or d is dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of each other. Specific stereoisomers may sometimes be referred to as enantiomers, and mixtures of such isomers are often called enantiomeric mixtures. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which can occur when there is no stereoselectivity or stereospecificity in a chemical reaction or process. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomeric species that is not optically active.

[0057] In the present invention, R 1and the carbon atom to which Cy is attached may be a stereochemical center, i.e., when R 1 is not H, R 1 and Cy are different. The compounds of the invention may be racemic mixtures or may have an enantiomeric excess or be substantially enantiomerically pure.

[0058] Except as discussed below for tautomeric forms, it should be noted that specifically excluded from the term "isomer" as used herein are structural (or constitutional) isomers (i.e., isomers that differ not merely in the position of atoms in space but in the connections between atoms). For example, a reference to a methoxy group, -OCH 3 should not be construed as a reference to its structural isomer, the hydroxymethyl group, -CH 2 OH. Similarly, a reference to ortho-chlorophenyl should not be construed as a reference to its structural isomer, meta-chlorophenyl. However, a reference to a class of structures will presumably include the structural isomeric forms that fall within that class (e.g., C 1~7 alkyl includes n-propyl and iso-propyl, butyl includes n-, iso-, sec- and tert-butyl, and methoxyphenyl includes ortho-, meta- and para-methoxyphenyl).

[0059] The above exclusion does not apply to tautomeric forms, for example, pairs of tautomers such as keto / enol (illustrated below), imine / enamine, amide / imino alcohol, amidine / amidine, nitroso / oxime, thioketone / enethiol, N-nitroso / hydroxyazo and nitroso / acy-nitro.

[0060] [Chemical formula]

[0061] The terms "tautomer" or "tautomeric form" refer to structural isomers of different energies that are interconvertible via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) involve interconversion via the movement of a proton, such as keto-enol and imine-enamine isomerization. Valence tautomers involve interconversion by some rearrangement of bonding electrons.

[0062] It should be noted that specifically included within the term "isomer" are compounds having one or more isotope substitutions. For example, H can be 1 H, 2 H (D), and 3 H (T) in any isotopic form, C can be 12 C, 13 C, and 14 C in any isotopic form, O can be 16 O, and 18 O in any isotopic form, etc.

[0063] Examples of isotopes that can be incorporated into the compounds of the present invention are 2 H (deuterium, D), 3 H (tritium), 11 C, 13 C, 14 C, 15 N, 18 F, 31 P, 32 P, 35 S, 36 Cl, and 125It includes isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, but is not limited thereto. Various isotope-labeled compounds of the present invention incorporate radioactive isotopes such as 3H, 13C and 14C. Such isotope-labeled compounds can be useful in metabolic studies, reaction kinetics studies, detection or imaging techniques, including positron emission tomography (PET) or single photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays, or in radioactive treatment of patients. The deuterium-labeled or substituted therapeutic compounds of the present invention may have improved DMPK (drug metabolism and pharmacokinetics) properties with respect to distribution, metabolism and excretion (ADME). Substitution with heavier isotopes such as deuterium may result in certain therapeutic advantages resulting from better metabolic stability, such as an increase in in vivo half-life or a reduction in required dosage. 18F-labeled compounds can be useful in PET or SPECT studies. The isotope-labeled compounds and their prodrugs of the present invention can generally be prepared by substituting readily available non-isotope-labeled reagents with isotope-labeled reagents and performing the procedures disclosed in the schemes or in the examples and the preparations described hereinafter. Furthermore, substitution with heavier isotopes, particularly deuterium (i.e., 2H or D), may result in certain therapeutic advantages resulting from better metabolic stability, such as an increase in in vivo half-life or a reduction in required dosage or an improvement in the therapeutic index. It is understood that deuterium in this context is considered a substituent. The concentration of such heavier isotopes, specifically deuterium, may be defined by the isotope enrichment factor. In the compounds of the present invention, any atom not specifically designated as a particular isotope is intended to represent any suitable isotope of that atom.

[0064] Unless otherwise specified, reference to a particular compound includes all such isomeric forms, including (all or part of) their racemates and other mixtures. Methods for the preparation (e.g., asymmetric synthesis) and separation (e.g., fractional crystallization and chromatographic means) of such isomeric forms are either known in the art or can be readily obtained by adapting known methods, including those taught herein, in a known manner.

[0065] Inhibition The compounds of the present invention inhibit the activity of one or more KATs of the MYST family, namely, TIP60, KAT6B, MOZ, HBO1 and MOF.

[0066] The inhibitory activity of the compounds of the present invention may vary among the KATs of the MYST family.

[0067] The compounds of the present invention may inhibit the activity of one or more KATs of the MYST family more selectively than other KATs of the MYST family, i.e., the inhibitory activity of the compounds may be higher for one or more of the KATs of the MYST family than for one or more of the other KATs of the MYST family.

[0068] The compounds of the present invention may (selectively) inhibit the activity of a single KAT of the MYST family. Thus, the compounds of the present invention may inhibit the activity of TIP60, MORF, MOZ, HBO1 or MOF.

[0069] The compounds of the present invention may inhibit the activity of two KATs of the MYST family, e.g., MOZ and MORF.

[0070] The compounds of the present invention may inhibit the activity of three KATs of the MYST family, e.g., MOZ, MORF and HBO1.

[0071] The compounds of the present invention may inhibit the activity of four KATs of the MYST family, e.g., MOZ, MORF, HBO1 and TIP60.

[0072] The compounds of the present invention may inhibit the activities of all five KATs of the MYST family, and thus, the compounds may inhibit the activities of TIP60, MORF, MOZ, HBO1, and MOF.

[0073] The compounds of the present invention may particularly inhibit the activities of MOZ and / or KAT6B and / or HBO1 and / or TIP60.

[0074] Therapeutic indications The compounds disclosed herein may provide a therapeutic benefit in several disorders, particularly in the treatment or prevention of cancer.

[0075] Cancer Inhibitors of post-translational lysine acetylation mediated by KAT of the MYST family are considered promising anti-neoplastic agents and can thus be useful therapeutic agents for use, for example, in the treatment of cancer. Such agents can also be useful as therapeutic agents for the treatment of cancers that exhibit overexpression of MYST proteins.

[0076] "Cancer" can be any form of cancer. In particular, cancer can include any one or more of the following: leukemia, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), non-Hodgkin lymphoma, Hodgkin's disease, prostate cancer, lung cancer, melanoma, breast cancer, colorectal cancer, colon cancer, squamous cell carcinoma, and gastric cancer.

[0077] Alternatively, the cancer can include adrenocortical cancer, anal cancer, bladder cancer, blood cancer, bone cancer, brain tumor, female genital cancer, male genital cancer, central nervous system lymphoma, cervical cancer, pediatric rhabdomyosarcoma, pediatric sarcoma, endometrial cancer, endometrial sarcoma, esophageal cancer, eye cancer, gallbladder cancer, gastrointestinal cancer, hairy cell leukemia, head and neck cancer, hepatocellular cancer, hypopharyngeal cancer, Kaposi's sarcoma, kidney cancer, laryngeal cancer, liver cancer, malignant fibrous histiocytoma, malignant thymoma, mesothelioma, multiple myeloma, myeloma, nasal and paranasal cavity cancer, nasopharyngeal cancer, nervous system cancer, neuroblastoma, oral cancer, oropharyngeal cancer, osteosarcoma, ovarian cancer, pancreatic cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pituitary tumor, plasma cell neoplasm, primary CNS lymphoma, rectal cancer, respiratory system, retinoblastoma, salivary gland cancer, skin cancer, small intestine cancer, soft tissue sarcoma, stomach cancer, testicular cancer, thyroid cancer, urinary system cancer, uterine sarcoma, vaginal cancer, vascular system, Waldenström's macroglobulinemia and / or Wilms' tumor.

[0078] The cancer can be of a particular type. Examples of cancer types include lymphoma, melanoma, carcinoma (e.g., adenocarcinoma, hepatocellular carcinoma, medullary carcinoma, papillary carcinoma, squamous cell carcinoma), astrocytoma, glioma, medulloblastoma, myeloma, meningioma, neuroblastoma, sarcoma (e.g., angiosarcoma, chondrosarcoma, osteosarcoma).

[0079] The cancer can be a MYST overexpression cancer. The cancer can overexpress MYST protein compared to non-cancerous tissue. In some cases, the cancer overproduces MYST mRNA compared to non-cancerous tissue. The overexpressed MYST protein or MYST mRNA can be any one of the KATs of any one of the MYST family, namely, any one of TIP60, KAT6B, MOZ, HBO1, and MOF. In some embodiments, the cancer can overexpress more than one KAT of the MYST family, for example, two or more selected from the group consisting of TIP60, KAT6B, MOZ, HBO1, and MOF. The cancer can be a cancer that escapes immune recognition, for example, via tumor-associated Treg cells.

[0080] Alternatively or additionally, the cancer may be a bromodomain overexpressing cancer. Cancer cells may overexpress one or more bromodomain-containing proteins (referred to herein as "bromodomain proteins") compared to non-cancerous tissue. This may result in overproduction of one or more bromodomain mRNAs compared to non-cancerous tissue. In some cases, the levels of bromodomain protein and / or mRNA in the cell are approximately equivalent to those of non-cancerous cells. The cancer may overexpress one or more bromodomain proteins selected from the group consisting of bromodomain proteins (i.e., BRD2, BRD3, BRD4, BRD7, BRD8, BRD9 and BRDT), TAF1 / TAF1L, TFIID, SMARC2 (also called BRM) and SMARC4 (also called BRG1). For example, some colon cancers overexpress BRD8. Some acute myeloid leukemia cells overexpress BRD4.

[0081] Treg cells as cancer targets Treg cells are immunosuppressive cells that act to prevent autoimmunity in the immune system of healthy mammals. However, some cancers act to upregulate Treg activity to evade the host immune system. Infiltration of Tregs in many tumor types correlates with poor patient prognosis, and depletion of Treg cells in tumor models demonstrates an increase in anti-tumor immune responses (Melero 2015). Tumor-associated Treg suppression of the host immune system has been reported in lung (Joshi 2015), (Tso 2012), breast (Gobert 2009, Yan 2011), prostate (Miller 2006) and pancreatic (Wang X 2016) cancers. FOXP3 is considered a master regulator of Treg differentiation, development and function in Treg cells.

[0082] Several studies have demonstrated that acetylation of FOXP3 plays a crucial role in the stability of the FOXP3 protein and in regulating its ability to access DNA, and that FOXP3 acetylation is mediated by KAT (Dhuban 2017). A decrease in TIP60-mediated FOXP3 acetylation has been shown to attenuate Treg development, suggesting an additional mechanism by which inhibition of the acetylating activity of MYST proteins could be used to interfere with diseases such as cancer.

[0083] Combination therapy The agents described herein may be useful in combination with other anti-cancer therapies. They may act synergistically with chemotherapy or radiation therapy, and / or with targeted therapies including, but not limited to, FGFR1 inhibitors and therapies targeting nuclear hormone receptors. For example, the agents described herein may be useful in combination with bromodomain-targeted drugs including BET inhibitors. BET inhibitors reversibly bind to the bromodomains of the BET proteins BRD2, BRD3, BRD4, and BRDT.

[0084] Inhibition of MYST family KAT proteins (and other nuclear proteins described herein) to reduce the degree of histone lysine acetylation sensitizes tumor cells to chemotherapy and radiation therapy by attenuating the process of DNA damage repair, e.g., repair of DNA double-strand breaks (DSBs), and may therefore increase the frequency of chemo- and radiotherapy-induced cancer cell death. Thus, inhibition of MYST family KAT proteins will likely synergize well with low-dose chemotherapy or radiation therapy.

[0085] Thus, in some cases, the MYST protein antagonists disclosed herein may be administered in combination with a radiotherapy or chemotherapy regimen. This may be administered concurrently with or sequentially to radiation and / or chemotherapy. Suitable chemotherapeutic agents and radiotherapy protocols will be readily apparent to those skilled in the art. In particular, the compounds described herein may be combined with low-dose chemotherapy or radiotherapy. Appropriate dosages for "low-dose" chemotherapy or radiotherapy will be readily apparent to those skilled in the art.

[0086] In particular, when the compounds of the present application are used to suppress Treg suppression, they may be combined with immune checkpoint inhibitors (Melero 2015, Wang L 2016). Furthermore, the compounds of the present invention that suppress Treg suppression may be used in combination with radiotherapy to reduce the depletion of Treg function in tumors (Persa 2015, Jeong 2016).

[0087] Methods of treatment The compounds of the present invention may be used in a method of treatment. Also provided is a method of treatment comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the present invention. The term "therapeutically effective amount" is an amount sufficient to demonstrate benefit to the patient. Such benefit may be at least an improvement in at least one symptom. The actual amount administered, as well as the rate and time course of administration, will depend on the nature and severity of what is being treated. Prescription of treatment, e.g., determination of dosage, is within the responsibility of general practitioners and other physicians.

[0088] As described above, the anti-cancer treatment defined herein may be applied as a monotherapy or may be accompanied by conventional surgery or radiotherapy or chemotherapy in addition to the compounds of the present invention. Such chemotherapy may include one or more of the following categories of anti-tumor agents: (i) Other anti-proliferative / antineoplastic drugs and combinations thereof as used in medical oncology, including, for example, alkylating agents (e.g., cisplatin, oxaliplatin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulfan, temozolomide and nitrosourea); antimetabolites (e.g., gemcitabine and folic acid antagonists such as fluoropyrimidines like 5-fluorouracil and tegafur, raltitrexed, methotrexate, cytosine arabinoside and hydroxyurea); antitumor antibiotics (e.g., anthracyclines like doxorubicin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin and mitramycin); anti-mitotic agents (e.g., vinca alkaloids like vincristine, vinblastine, vindesine and vinorelbine, and taxoids like paclitaxel and docetaxel (Taxotere), and polo kinase inhibitors); and topoisomerase inhibitors (e.g., epipodophyllotoxins like etoposide and teniposide, amsacrine, topotecan and camptothecin); (ii) Cell growth inhibitors, including, for example, anti-estrogen drugs (e.g., tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene and iodoxyfene), anti-androgen drugs (e.g., bicalutamide, flutamide, nilutamide and cyproterone acetate), LHRH antagonists or LHRH agonists (e.g., goserelin, leuprorelin and buserelin), progestogens (e.g., megestrol acetate), aromatase inhibitors (e.g., anastrozole, letrozole, vorazole and exemestane), and inhibitors of 5 * -reductase such as finasteride; (iii) Anti-invasive agents (e.g., 4-(6-chloro-2,3-methylenedioxyanilino)-7-[2-(4-methylpiperazin-1-yl)ethoxy]-5-tetrahydropyran-4-yloxyquinazoline (AZD0530; International Patent Application No. WO01 / 94341), N-(2-chloro-6-methylphenyl)-2-{6-[4-(2-hydroxyethyl)piperazin-1-yl]-2-methylpyrimidin-4-ylamino}thiazole-5-carboxamide (dasatinib, BMS-354825; J. Med. Chem., 2004, 47, 6658-6661 and 4-((2,4-dichloro-5-methoxyphenyl)amino)-6-methoxy-7-(3-(4-methylpiperazin-1-yl)propoxy)quinoline-3-carbonitrile (bosutinib, SKI-606; Cancer research (2003), 63(2), 375-81) such as c-Src kinase family inhibitors, as well as metalloproteinase inhibitors such as marimastat, inhibitors of urokinase-type plasminogen activator receptor function or antibodies against heparanase); (iv) Inhibitors of growth factor function: For example, such inhibitors include growth factor antibodies and growth factor receptor antibodies (e.g., anti-erbB2 antibody trastuzumab [Herceptin T], anti-EGFR antibody panitumumab, anti-erbB1 antibody cetuximab [Erbitux, C225] and any growth factor or growth factor receptor antibody disclosed by Stern 2005); such inhibitors are tyrosine kinase inhibitors, for example, inhibitors of the epidermal growth factor family (e.g., EGFR family tyrosine kinase inhibitors, such as N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine (gefitinib, ZD1839), N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine (erlotinib, OSI774) and 6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)-quinazolin-4-amine (CI1033), erbB2 tyrosine kinase inhibitors such as lapatinib, inhibitors of the hepatocyte growth factor family, inhibitors of the platelet-derived growth factor family such as imatinib, inhibitors of serine / threonine kinases (e.g., Ras / Raf signal transduction inhibitors, such as farnesyltransferase inhibitors, such as sorafenib (BAY43-9006)), inhibitors of cell signal transduction via MEK and / or AKT kinases, inhibitors of the hepatocyte growth factor family, c-kit inhibitors, abl kinase inhibitors, IGF receptor (insulin-like growth factor) kinase inhibitors; aurora kinase inhibitors (e.g., AZD1152, PH739358, VX-680, MLN8054, R763, MP235, MP529, VX-528 and AX39459) and also cyclin-dependent kinase inhibitors such as CDK2 and / or CDK4 inhibitors; (v) Anti-angiogenic and anti-lymphangiogenic agents, such as those that inhibit the effects of vascular endothelial growth factor, [for example, anti-vascular endothelial growth factor A (VEGFA) antibody bevacizumab (AvastinT), anti-vascular endothelial growth factor A (VEGFA) antibody ranibizumab, anti-VEGF aptamer pegaptanib, anti-vascular endothelial growth factor receptor 3 (VEGFR3) antibody IMC-3C5, anti-vascular endothelial growth factor C (VEGFC) antibody VGX-100, anti-vascular endothelial growth factor D (VEGFD) antibody VGX-200, soluble form of vascular endothelial growth factor receptor 3 (VEGFR3) VGX-300, and VEGF receptor tyrosine kinase inhibitors, such as 4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy) quinazoline (vandetanib; ZD6474; Example 2 in WO01 / 32651), 4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy) quinazoline (cediranib; AZD2171; Example 240 in WO00 / 47212), batatinib (PTK787; WO98 / 35985), pazopanib (GW786034), axitinib (AG013736), sorafenib and sunitinib (SU11248; WO01 / 60814), compounds such as those disclosed in International Patent Applications WO97 / 22596, WO97 / 30035, WO97 / 32856, and WO98 / 13354, and compounds that act through other mechanisms (for example, linomide, inhibitors of integrin avb3 function, and angiostatin)]; (vi) Vascular damaging agents, such as combretastatin A4, and compounds disclosed in International Patent Applications WO99 / 02166, WO00 / 40529, WO00 / 41669, WO01 / 92224, WO02 / 04434, and WO02 / 08213; (vii) Antisense therapies, such as those directed against the targets mentioned above, for example, ISIS2503, anti-ras antisense; (viii) gene therapy approaches, such as approaches for replacing abnormal genes such as abnormal p53, abnormal BRCA1 or BRCA2, GDEPT (gene-directed enzyme prodrug therapy) approaches such as those using cytosine deaminase, thymidine kinase or bacterial nitroreductase enzymes, and approaches for increasing a patient's tolerance to chemotherapy or radiotherapy such as multidrug resistance gene therapy; and (ix) immunotherapy approaches, such as ex vivo and in vivo approaches for increasing the immunogenicity of a patient's tumor cells, including, for example, transfection of cytokines such as interleukin 2, interleukin 4 or granulocyte macrophage colony-stimulating factor, approaches for reducing T cell anergy, approaches using transfected immune cells such as cytokine-transfected dendritic cells, approaches using cytokine-transfected tumor cell lines, and approaches using anti-idiotype antibodies.

[0089] Administration An active compound or a pharmaceutical composition containing the active compound can be administered systemically / peripherally or orally (e.g., by ingestion); topically (e.g., including transdermal, intranasal, intraocular, buccal, and sublingual); via the lungs (e.g., via the mouth or nose, e.g., using an aerosol, e.g., by inhalation or insufflation therapy); rectally; vaginally; parenterally, e.g., by injection including subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subepidermal, intraarticular, subarachnoid, intravitreal, and intrasternal; by depot implants, e.g., subcutaneously, intravitreally, or intramuscularly, but not limited thereto, and can be administered to a subject by any convenient route of administration, regardless of whether it is at the desired site of action. The subject can be a eukaryote, an animal, a vertebrate, a mammal, a rodent (e.g., guinea pig, hamster, rat, mouse), a murine (e.g., mouse), a canine (e.g., dog), a feline (e.g., cat), a equine (e.g., horse), a primate, an anthropoid (e.g., monkey or ape), a monkey (e.g., marmoset, baboon), an ape (e.g., gorilla, chimpanzee, orangutan, langur) or a human.

[0090] Formulation Although it is possible to administer the active compound alone, it is preferred to present at least one active compound as defined above as a pharmaceutical composition (e.g., a formulation) in combination with one or more pharmaceutically acceptable carriers, adjuvants, excipients, diluents, fillers, buffers, stabilizers, preservatives, lubricants, or other materials well known to those skilled in the art, and it may also be included together with other therapeutic or prophylactic agents.

[0091] Accordingly, the present invention further provides a pharmaceutical composition as defined above, and a method of preparing the pharmaceutical composition, the method comprising the step of admixing at least one active compound as defined above with one or more pharmaceutically acceptable carriers, excipients, buffers, adjuvants, stabilizers, or other materials as described herein.

[0092] As used herein, the term “pharmaceutically acceptable” refers to compounds, materials, compositions, and / or dosage forms that, within the scope of sound medical judgment, are suitable for use in contact with the tissues of a subject (e.g., a human) without excessive toxicity, irritation, allergic response, or other problems or complications, and that have a reasonable benefit / risk ratio commensurate with the intended use. Each carrier, excipient, etc. must also be “acceptable” in the sense of being compatible with the other ingredients of the formulation.

[0093] Suitable carriers, excipients, etc. can be found in standard pharmaceutical texts such as Remington’s Pharmaceutical Sciences, 18th Edition, Mack Publishing Company, Easton, Pa., 1990.

[0094] The formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. Such methods include the step of bringing the active compound into association with a carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing the active compound into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product.

[0095] The formulations may be in the form of a liquid preparation, solution, suspension, emulsion, elixir, syrup, tablet, candy, granule, powder, capsule, cachet, pill, ampoule, suppository, pessary, ointment, gel, paste, cream, spray, mist, foam, lotion, oil, bolus, lozenge, or aerosol.

[0096] Formulations suitable for oral administration (e.g., by ingestion) may be presented as discrete units such as capsules, cachets, or tablets each containing a predetermined amount of the active compound; as a powder or granule; as a solution or suspension in an aqueous or non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion; as a bolus; as a lozenge; or as a paste.

[0097] Tablets may be prepared by conventional means, for example, by compression or molding, and one or more auxiliary raw materials may be used. Compressed tablets may be prepared by, within a suitable machine, mixing the active compound with one or more binders (e.g., povidone, gelatin, acacia, sorbitol, tragacanth, hydroxypropylmethylcellulose); fillers or diluents (e.g., lactose, microcrystalline cellulose, calcium hydrogen phosphate); lubricants (e.g., magnesium stearate, talc, silica); disintegrants (e.g., sodium starch glycolate, cross-linked povidone, cross-linked sodium carboxymethylcellulose); surface active or dispersing or wetting agents (e.g., sodium lauryl sulfate); and preservatives (e.g., methyl p-hydroxybenzoate, propyl p-hydroxybenzoate, sorbic acid), and then compressing into a free-flowing form such as a powder or granule. Molded tablets may be prepared by, within a suitable machine, molding a mixture of a powdered compound moistened with an inert liquid diluent. Tablets may be coated or scored and may be formulated, for example, using hydroxypropylmethylcellulose in variable proportions to provide a desired release profile and provide a slow or controlled release of the active compound therein. Tablets may be provided with an enteric coating to provide release in a part of the digestive tract other than the stomach.

[0098] Formulations suitable for topical administration (e.g., transdermal, intranasal, intraocular, buccal, and sublingual) may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols, or oils. Alternatively, the formulation may include patches or dressings such as bandages or plasters that are impregnated with the active compound and may also be impregnated with one or more excipients or diluents.

[0099] Formulations suitable for topical administration to the oral cavity include confectionery preparations that contain the active compound in a flavoring base, usually sucrose and acacia or tragacanth; lozenge preparations that contain the active compound in an inert base such as gelatin and glycerin, or sucrose and acacia; and mouthwashes that contain the active compound in a suitable liquid carrier.

[0100] Formulations suitable for topical administration to the eyes include eye drops in which the active compound is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the active compound.

[0101] Formulations suitable for nasal administration in which the carrier is solid are administered by inhalation through the nose, i.e., by rapid inhalation via the nasal cavity from a container of powder held near the nose, and include, for example, coarse powders having a particle size in the range of from about 20 to about 500 microns. Suitable formulations in which the carrier is a liquid for administration by, for example, nasal spray, as nasal drops, or by aerosol administration using a nebulizer include aqueous or oily solutions of the active compound.

[0102] Formulations suitable for administration by inhalation include those presented as aerosol sprays from pressurized packs, which involve the use of a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichloro-tetrafluoroethane, carbon dioxide, or other suitable gas.

[0103] Formulations suitable for topical administration via the skin include ointments, creams and emulsions. When formulated as an ointment, the active compound may be used with either a paraffinic or a water-miscible ointment base. Alternatively, the active compound may be formulated as a cream using an oil-in-water cream base. If desired, the aqueous phase of the cream base may contain, for example, at least about 30% w / w of a polyhydric alcohol, i.e., an alcohol having two or more hydroxyl groups, such as propylene glycol, butane-1,3-diol, mannitol, sorbitol, glycerol and polyethylene glycol and mixtures thereof. The topical formulation may desirably contain a compound that enhances the absorption or penetration of the active compound through the skin or other affected area. Examples of such skin penetration enhancers include dimethyl sulfoxide and related analogues.

[0104] When formulated as a topical emulsion, the oil phase may contain only an emulsifier (also known otherwise as an emulgent), or may contain at least one emulsifier and a mixture with a fat or an oil, or with both a fat and an oil. Preferably, the hydrophilic emulsifier is included together with a lipophilic emulsifier that acts as a stabilizer. It is also preferred to include both an oil and a fat. The emulsifiers, with or without the addition of a stabilizer, together constitute a so-called emulsifying wax, which together with the oil and / or the fat constitutes a so-called emulsifying ointment base that forms the oily disperse phase of the cream formulation.

[0105] Suitable emulsifiers and emulsion stabilizers include Tween 60, Span 80, cetostearyl alcohol, myristyl alcohol, glyceryl monostearate, and sodium lauryl sulfate. The choice of a suitable oil or fat for the formulation is based on the achievement of the desired cosmetic properties, since the solubility of the active compound in most oils that are likely to be used in pharmaceutical emulsion formulations may be very low. Thus, the cream preparation should preferably be a non-greasy, non-staining, wash-off product with a suitable viscosity to avoid leakage from tubes or other containers. Straight-chain or branched-chain mono- or dibasic acid alkyl esters, such as di-isoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acid, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate, or a blend of branched-chain esters known as Crodamol CAP may be used, with the last three being preferred esters. These may be used alone or in combination depending on the required properties.

[0106] Alternatively, high melting point lipids such as white soft paraffin and / or liquid paraffin or other mineral oils may be used.

[0107] Formulations suitable for rectal administration may be presented, for example, as suppositories using a suitable base containing cocoa butter or salicylate.

[0108] Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing, in addition to the active compound, a carrier as is known in the art to be appropriate.

[0109] Formulations suitable for parenteral administration (e.g., by injection including intradermal, subcutaneous, intramuscular, intravenous, and intradermal) may contain antioxidants, buffers, preservatives, stabilizers, bacteriostatic agents, and solutes that render the formulation isotonic with the blood of the intended recipient, aqueous and non-aqueous isotonic, pyrogen-free, sterile injection solutions; and aqueous and non-aqueous sterile suspensions that may include suspending and thickening agents, and liposomes, or other microparticle systems designed to target the compound to blood components or one or more organs. Examples of suitable isotonic vehicles for use in such formulations include sodium chloride injection, Ringer's solution, or lactated Ringer's solution. Typically, the concentration of the active compound in solution is from about 1 ng / mL to about 10 μg / mL, for example from about 10 ng / ml to about 1 μg / mL. The formulations may be presented in unit-dose or multi-dose sealed containers, for example, ampoules and vials, and may be stored in a freeze-dried (lyophilized) state that requires only the addition of a sterile liquid carrier, for example, water for injection, immediately prior to use. Immediate injection solutions and suspensions may be prepared from sterile powders, granules, and tablets. The formulations may be in the form of liposomes, or other microparticle systems designed to target the active compound to blood components or one or more organs.

[0110] Dosage Those skilled in the art will appreciate that the appropriate dosage of the compounds and compositions containing the compounds can vary from patient to patient. Determining the optimal dosage generally involves a balance of the level of therapeutic benefit against any risks or adverse side effects. The dosage level selected will depend on a variety of factors including, but not limited to, the activity of the particular compound, the route of administration, the time of administration, the rate of excretion of the compound, the duration of treatment, other drugs, compounds and / or materials used in combination, the severity of the condition, and the species, sex, age, weight, condition, general health and medical history of the patient. Generally, the dosage is selected to achieve a local concentration that achieves the desired effect without substantially causing harmful or adverse side effects at the site of action, but the amount of the compound and the route of administration are ultimately at the discretion of the physician, veterinarian or clinician.

[0111] Administration can be achieved in a single dose, continuously or intermittently (e.g., in divided doses at appropriate intervals) throughout the course of treatment. The most effective means of administration and methods for determining dosage will vary with the formulation used in the therapy, the purpose of the therapy, the target cells being treated and the subject being treated. Single or multiple administrations can be carried out at dosage levels and patterns selected by the treating physician, veterinarian or clinician.

[0112] Generally, a suitable dosage of the active compound is in the range of about 100 ng to about 25 mg (more typically about 1 μg to about 10 mg) per kilogram of the subject's body weight per day. When the active compound is a salt, ester, amide, prodrug, etc., the amount administered is calculated based on the parent compound, so the actual weight used will increase proportionally.

[0113] In one embodiment, the active compound is administered to a human patient according to the following dosage regimen: about 100 mg, three times a day.

[0114] In one embodiment, the active compound is administered to a human patient according to the following dosage regimen: about 150 mg, twice a day.

[0115] In one embodiment, the active compound is administered to a human patient according to the following dosage regimen: about 200 mg, twice a day.

[0116] However, in one embodiment, the active compound is administered to a human patient according to the following dosage regimen: about 50 or about 75 mg, three or four times a day.

[0117] In one embodiment, the active compound is administered to a human patient according to the following dosage regimen: about 100 or about 125 mg, twice a day.

[0118] Treatment As used herein in the context of treating a condition, the term "treatment" generally relates to treatment and therapy, whether in a human or an animal (e.g., in veterinary applications), and includes any desired therapeutic effect, such as inhibition of the progression of the condition, reduction in the rate of progression, arrest of the rate of progression, regression of the condition, improvement of the condition, and cure of the condition. Treatment as a prophylactic measure (i.e., prophylaxis, prevention) is also included.

[0119] As used herein, the term "therapeutically effective amount" relates to an amount of an active compound, or a material, composition or dosage form comprising the active compound, that is effective to produce some desired therapeutic effect commensurate with a reasonable benefit / risk ratio when administered according to a desired treatment regimen.

[0120] Similarly, as used herein, the term "prophylactically effective amount" relates to an amount of an active compound, or a material, composition or dosage form comprising the active compound, that is effective to produce some desired prophylactic effect commensurate with a reasonable benefit / risk ratio when administered according to a desired treatment regimen.

[0121] Subject / Patient The subject / patient may be an animal, a mammal, a placental mammal, a marsupial (e.g., kangaroo, wombat), a monotreme (e.g., platypus), a rodent (e.g., guinea pig, hamster, rat, mouse), a murine (e.g., mouse), a lagomorph (e.g., rabbit), a bird (e.g., fowl), a canid (e.g., dog), a felid (e.g., cat), an equid (e.g., horse), a swine (e.g., pig), a sheep (e.g., sheep), a bovine (e.g., female bovine), a primate, an anthropoid (e.g., monkey or ape), a monkey (e.g., marmoset, baboon), an ape (e.g., gorilla, chimpanzee, orangutan, gibbon) or a human.

[0122] Furthermore, the subject / patient may be any of its developmental forms, e.g., a fetus. In one preferred embodiment, the subject / patient is a human.

[0123] General synthesis method The compounds of the present invention can be prepared by using the following general methods and by using the procedures described in detail in the examples. The reaction conditions mentioned are illustrative and non-limiting. For example, those skilled in the art may use various ranges of synthetic methods for synthesizing the desired compounds, such as the methods described in the literature (e.g., March’s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 7th Edition or Larock’s Comprehensive Organic Transformations: Comprehensive Organic Transformations: A Guide to Functional Group Preparations, but not limited thereto).

[0124] The compound of formula (l) as described above can be prepared by the synthetic strategy outlined below, and the above definitions apply.

[0125] General synthesis 1 Scheme 1A illustrates the formation of a sulfonamide bond to form a compound having structure I by coupling a sulfonyl chloride compound of structure G2 with a primary or secondary amine such as benzisoxazole amine G3.

[0126]

Chem.

[0127] Methods for forming such sulfonamides will be apparent to those skilled in the art and include, for example, the use of a suitable base such as, but not limited to, pyridine, LiHMDS, n-BuLi or NaH and the use of an activated form of a sulfonic acid such as a corresponding sulfonyl halide. The formation of the sulfonyl chloride of structure G2 from the corresponding acid of structure G1 can be achieved, for example, by the use of thionyl chloride or cyanuric chloride.

[0128] Alternatively, an activated form of a sulfonic acid such as, but not limited to, a pentafluorophenyl ester or a trichlorophenyl ester of a sulfonic acid having structure G5 can be coupled with a related primary or secondary amine such as benzisoxazole amine G3 (Scheme 1B).

[0129]

Chem.

[0130] The formation of the sulfonic acid ester of G5 from the corresponding sulfonyl chloride G2 and the related phenol (R 5 which may be, for example, pentafluorophenyl or trichlorophenyl) can be achieved using a suitable base such as, but not limited to, pyridine or triethylamine. Methods for forming the sulfonamide of I will be apparent to those skilled in the art and include, for example, the use of a suitable base such as, but not limited to, LiHMDS.

[0131] General synthesis 2 Scheme 2A illustrates the formation of a sulfonyl chloride, such as G2, as a substituent that is part of Ar.

[0132]

Chemical formula

[0133] This can be achieved by reacting a related aryl compound having structure G6 with, for example but not limited to, chlorosulfonic acid. Alternatively, the aryl compound G6 may be sequentially treated with bases such as, but not limited to, n-BuLi and sulfur dioxide to obtain a lithium arylsulfinate, which may then be further oxidized, for example with sulfuryl chloride, to obtain the desired sulfonyl chloride of G2. The product G2 may be isolated by methods known to those skilled in the art or formed in situ and used immediately in a subsequent step.

[0134] In addition, the sulfonyl chloride of G2 may be formed from an aryl thiol of structure G8 as illustrated in Scheme 2B.

[0135]

Chemical formula

[0136] Methods for forming G2 include, for example, the use of suitable oxidizing agents such as, but not limited to, hydrogen peroxide and potassium nitrate in the presence of a chloride source such as, but not limited to, chlorotrimethylsilane or thionyl chloride. The thiol of structure G8 may be synthesized from a compound of structure G7 (wherein (X) may be a halogen) by methods known to those skilled in the art including, but not limited to, nucleophilic substitution in the presence or absence of a transition metal.

[0137] Alternatively, the corresponding sulfonic acid of structure G1 may be obtained by sulfonation of an aryl compound such as G6. This can be achieved with any suitable reagent known to those skilled in the art, such as sulfur trioxide or sulfuric acid.

[0138]

Chem.

[0139] Sulfonic acid G1 may be converted to sulfonyl chloride G2 by the method outlined in General Synthesis 1, Scheme 1A.

[0140] General Synthesis 3 Scheme 3A illustrates the formation of benzisoxazoleamine G3 from aryl nitrile having an ortho substituent X such as structure G9. The group (X) may be a halogen such as a chloro or fluoro group, but is not limited thereto, and is selected to be suitable for the reaction used.

[0141]

Chem.

[0142] For example, starting material G9 may be reacted with an oxime such as acetone oxime, but not limited thereto, or for example acetohydroxamic acid, in the presence of a suitable base such as potassium tert-butoxide, but not limited thereto, to form benzisoxazoleamine G3.

[0143] General Synthesis 4

[0144]

Chem.

[0145] Examples of B 1 that can be used in a Suzuki coupling include, but are not limited to, those shown below.

[0146]

Chemical formula

[0147] Examples of the types of R 7 B 1 compounds that can be used in a Suzuki coupling include, but are not limited to, those shown below.

[0148]

Chemical formula

[0149] In addition to Scheme 4A, the positions of (X) and (B 1 ) can be inverted as shown below in Scheme 4B to obtain the same final compound G11. Similar to Scheme 2A, R 7 X and B 1The group represented by is selected to be suitable for the coupling reaction to be used. For example, in the case of the Suzuki coupling reaction, (X) may be a halogen, triflate or other suitable group, and B 1 represents a suitable boron compound including but not limited to boronic acid or boronic acid ester.

[0150]

Chemical formula

[0151] For example, various coupling reactions other than the Suzuki coupling reaction, such as transition metal-catalyzed coupling reactions or, for example, tin (Stille-type reaction) and zinc (Negishi-type reaction) compounds, etc., may be used to introduce the R 7 group. In addition, when the group (X) is, for example, phenol (O-H) or primary or secondary amine (R’R’’N-H) but not limited thereto, Chan-Lam type coupling may be used.

[0152] The transformation described in Schemes 4A and 4B may be carried out using the substituent R 1 , R 2 , R 3 or R 4 in the benzisoxazole moiety of structure G13, as represented by the following Scheme 4C.

[0153]

Chemical formula

[0154] In addition, before the formation of sulfonamide and benzisoxazole on the general synthesis 3, the nitrile precursor G9 (when R 1 or R 2 or R 3 or R 4 =X or B 1 ), the substituent R 7 may be introduced.

[0155] General synthesis 5 Scheme 5A illustrates the addition of a nitrogen-linked R group as a substituent that is part of Ar or on the benzisoxazole moiety to obtain a compound of structure G16. This can be achieved using any suitable coupling reaction known to those skilled in the art, for example, by SnAr substitution or backward coupling. The group represented by (X) may be, but is not limited to, a halogen and is selected to be suitable for the coupling reaction used. 8 Alternatively, to synthesize an ether-linked compound, a strategy similar to that shown in Scheme 5B can be used. This is achieved using any suitable coupling reaction known to those skilled in the art, for example, by SnAr or Ullmann-type coupling, to obtain a compound having structure G17.

[0156]

Chemical formula

[0157] Both of the above couplings may be reversed such that the group added is R-X.

[0158]

Chemical formula

[0159] The added group is R 8 -X.

[0160] In addition, prior to sulfonamide and benzisoxazole formation on the nitrile precursor G9 (where R 1 or R 2 or R 3 or R 4 =X) in general synthesis 3, Scheme 3D, a substituent OR 8 or NHR 8 may be introduced.

[0161] General synthesis 6

[0162] [Chemical formula]

[0163] Scheme 6A illustrates the addition of an amine (HNR 10 R 11 ) as a substituent that is part of Ar or on the benzisoxazole moiety to form the corresponding amide for obtaining the compound of structure G19. This can be achieved by coupling the relevant carboxylic acid with a primary or secondary amine NHR 10 R 11 . Methods for forming such amides will be apparent to those skilled in the art and include, for example, the use of reagents such as HATU, HBTU, T3P, and EDCI / HOBt, as well as the use of activated forms of carboxylic acids such as the corresponding acyl halides, mixed anhydrides, or N-hydroxysuccinimide esters. Amide G19 may be synthesized directly from an ester compound (when R 12 = Alk such as methyl or ethyl but not limited thereto). The formation of the carboxylic acid from the corresponding ester (when R 12 = H) can be achieved, for example, by hydrolysis with a base such as an alkali metal hydroxide or an acid such as aqueous hydrochloric acid.

[0164] Further conversions may be carried out, such as, but not limited to, the reduction of the amide to form an amine or the dehydration of the amide to form a nitrile, from the amide compound G19. Methods for performing such conversions will be known to those skilled in the art.

[0165] In addition, in general synthesis 3, the nitrile precursor G9 (R 1 or R 2 or R 3 or R 4 = CO 2 R 12 , R 12= When it is Alk or H), before the formation of sulfonamide and benzisoxazole, amide CONR 10 R 11 may be introduced.

[0166] General synthesis 7 The conversion of (X) of structure G20 in Scheme 7A to the ester (R 12 = alkyl such as methyl or ethyl) of structure G18 will be apparent to those skilled in the art. For example, it can be achieved by the use of carbon monoxide in the presence of a transition metal catalyst such as PdCl 2 dppf.DCM etc. but not limited thereto and an alcoholic solvent such as methanol or ethanol etc. but not limited thereto, including a carbonylation reaction. The formation of the carboxylic acid (R = H) of structure G18 can be achieved, for example, by hydrolysis with a base such as an alkali metal hydroxide or an acid such as aqueous hydrochloric acid.

[0167]

Chemical Structure

[0168] The ester or acid G18 in Scheme 7A may be reduced to a hydroxyl compound such as structure G21. Methods for such conversions will be known to those skilled in the art and include, for example, the use of reducing agents such as lithium aluminum hydride (for esters and carboxylic acids) and borane (for carboxylic acids).

[0169] Further conversions may be carried out from the hydroxyl compound G21, such as Mitsunobu or nucleophilic substitution reactions etc. but not limited thereto. Methods for carrying out such conversions will be known to those skilled in the art.

[0170] In addition, in general synthesis 3, the nitrile precursor G9 (R 1 or R 2 or R 3 or R 4When it is =X), an ester group may be introduced before the formation of the sulfonamide and benzisoxazole above.

[0171] General synthesis 8 Scheme 8A illustrates the reduction of the nitro group of structure G22 to form the corresponding amine of structure G23 as a substituent that is part of Ar or on the benzisoxazole moiety.

[0172]

Chemical formula

[0173] The reduction of the nitro group to the primary amine G23 will be apparent to those skilled in the art and includes, but is not limited to, using reduction conditions such as a transition metal (Fe, In, Zn) in the presence of HCl, hydrogenation in the presence of a transition metal or transition metal catalyst.

[0174] Further conversions may be carried out from the amine compound G23, including but not limited to amide bond formation. The methods for carrying out such conversions will be similar to those described in General Synthesis 6.

[0175] In addition, in General Synthesis 3, the nitrile precursor G9 (R 1 or R 2 or R 3 or R 4 =NO 2 When it is), an amine group may be introduced before the formation of the sulfonamide and benzisoxazole above.

[0176] General synthesis 9 Scheme 9A illustrates the introduction of the nitrile group of structure G25 as a substituent that is part of Ar or on the benzisoxazole moiety.

[0177]

Chemical formula

[0178] Methods for such conversions will be apparent to those skilled in the art and include, but are not limited to, SnAr substitution or transition metal-catalyzed coupling using suitable cyanide reagents. The group represented by (X) of structure G24 may be, but is not limited to, halogen, triflate or mesylate, and is selected to be suitable for the reaction used.

[0179] Further preference trends The following preference trends may apply to all aspects of the invention as described above, or may relate to a single aspect. The preference trends may be combined together in any combination.

[0180] R 1 、R 2 、R 3 and R 4 In some embodiments, at least one of R 1 、R 2 、R 3 and R 4 may be H. In some of these embodiments, one of R 1 、R 2 、R 3 and R 4 is H. In other of these embodiments, two of R 1 、R 2 、R 3 and R 4 are H. In other of these embodiments, three of R 1 、R 2 、R 3 and R 4 are H.

[0181] In some embodiments, at least one of R 1 、R 2 、R 3 and R 4 is not H.

[0182] In some embodiments, R 1 、R2 、R 3 and R 4 at least one of which is hydroxy, C which may be substituted by one or more fluoro groups 1~2 alkoxy, NH 2 , phenyl, C 5~6 heteroaryl, C 1~4 alkylcarbamoyl, acylamide, or C which may be substituted by one or more fluoro groups alkyl. 1~3

[0183] In these embodiments, R 1 , R 2 , R 3 and R 4 at least one of which may be C 1~3 alkyl. Further, in these embodiments, the C 1~3 alkyl group may be methyl, ethyl or propyl. These groups may be unsubstituted. These groups may be substituted by one or more fluoro groups and be perfluorinated, for example CF 3 , C 2 F 5 . These groups may be substituted by 1, 2, 3, 4 or 5 fluoro groups. In some embodiments, these groups may be substituted by 1, 1 or 2, or 1, 2 or 3 fluoro groups.

[0184] When the alkyl group is substituted, the substituent is (i) hydroxy, or (ii) unsubstituted C 1~2 alkoxy, i.e., methoxy, ethoxy, or C alkoxy substituted by one or more fluoro groups, for example -OCH 1~2 F, -OCH 2 F, -OCH​2 CF 3 、 or (iii) NH 2 、 or (iv) phenyl, or (v) C 5~6 heteroaryl, such as N - pyrazolyl, or (vi) C 1~4 alkylcarbamoyl, such as NHC(O)Me, or (vii) acylamide, such as NHCO 2 Me may be selected from.

[0185] In some embodiments, R 1 , R 2 , R 3 and R 4 at least one of may be a C 3~6 alkoxy optionally substituted by cycloalkyl or by one or more fluoro groups, which may be a C 1~3 alkoxy. In these embodiments, the C 1~3 alkoxy group may be methoxy, ethoxy or propyloxy. These groups may be unsubstituted. These groups may be substituted by one or more fluoro groups and be perfluorinated, such as OCF 3 , OC 2 F 5 . These groups may be substituted by 1, 2, 3, 4 or 5 fluoro groups. In some embodiments, these groups may be substituted by 1, 1 or 2, or 1, 2 or 3 fluoro groups. The alkoxy group may be substituted by C 3~6 cycloalkyl, such as cyclopropyl. Thus, the whole group may be OCH 2 (cyclopropyl).

[0186] In some embodiments, R 1 , R 2 , R 3 and R 4 at least one of may be a C 3~6It may be cycloalkyl. In these embodiments, C 3~6 The cycloalkyl group may be cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. In particular, C 3~6 The cycloalkyl group may be cyclopropyl.

[0187] In some embodiments, R 1 , R 2 , R 3 and R 4 at least one of may be halo. In these embodiments, the halo group may be fluoro, chloro, bromo or iodo.

[0188] In some embodiments, R 1 , R 2 , R 3 and R 4 at least one of may be COR C (wherein R C is selected from NR N1 R N2 , R N1 and R N2 are independently selected from H and methyl). In these embodiments, the group is C(O)NH 2 , C(O)NHCH 3 and C(O)N(CH 3 ) 2 may be selected from.

[0189] In some embodiments, R 1 , R 2 , R 3 and R 4 at least one of may be cyano, NH 2 , NO 2 . In some of these embodiments, R 1 , R 2 , R 3 and R 4 at least one of may be cyano. In other of these embodiments, R 1 , R 2 , R 3 and R4 At least one of them may be NH 2 In other of these embodiments, R 1 , R 2 , R 3 and R 4 At least one of them may be NO 2 In some embodiments, at least one of R

[0190] , R 1 , R 2 , R 3 and R 4 may be phenyl or C 5~6 heteroaryl, and these groups may be substituted by methyl, cyano, hydroxy or methoxy. In some of these embodiments, at least one of R 1 , R 2 , R 3 and R 4 may be phenyl. In other of these embodiments, at least one of R 1 , R 2 , R 3 and R 4 may be C 5~6 heteroaryl, such as oxazolyl, pyrazolyl, triazolyl, pyridyl and pyrimidinyl. The phenyl or C 5~6 heteroaryl group may be unsubstituted. In certain embodiments, the phenyl group may be substituted by methyl, cyano or methoxy. In certain embodiments, the C 5~6 heteroaryl group may be substituted by one or more methyl groups, so that the whole group is, for example, dimethylpyrazolyl or N-methylpyrazolyl.

[0191] In some embodiments, R 4 is methoxy.

[0192] In some embodiments, R 4 is methoxy and R 2 is CH 2 OCH3 or CH 2 OCH 2 CH 3 and R 1 and R 3 are H.

[0193] In some embodiments, R 4 is methoxy, R 2 is phenyl, optionally substituted by methyl or methoxy, and R 1 and R 3 are H.

[0194] In some embodiments, R 4 is methoxy, R 2 is C 5~6 heteroaryl, optionally substituted by methyl.

[0195] In some embodiments, R 4 is methoxy, and R 1 , R 2 and R 3 are H.

[0196] In some embodiments, R 4 is chloro, R 2 is C 1~3 alkyl or bromo, and R 1 and R 3 are H.

[0197] In some embodiments, R 4 is chloro, and R 1 , R 2 and R 4 are H.

[0198] In some embodiments, R 3 is C 1~3 alkyl, and R 1 , R 2 and R 4 are H.

[0199] Ar Ar is selected from phenyl, naphthyl and C 5~10 heteroaryl groups, which may be unsubstituted or substituted.

[0200] In some embodiments, Ar is phenyl.

[0201] In some embodiments, Ar is naphthyl.

[0202] In some embodiments, Ar is a C 5~10 heteroaryl group. The C 5~10 heteroaryl group may be selected from quinolinyl, benzothiazolyl, quinoxalinyl, benzoxadiazolyl, benzothiadiazolyl, benzofuran and benzotriazolyl. In certain ones of these embodiments, Ar is quinolinyl or benzothiazolyl.

[0203] In some embodiments, Ar is the group:

[0204]

Chemical formula

[0205] In some embodiments, the substituent for Ar is C 1~2 alkyl which may be substituted by hydroxy, C 2 NH 1~4 , C 1~4 alkylcarbamoyl or one or more fluoro groups. In these embodiments, the C 1~4 alkyl group may be methyl, ethyl, propyl or butyl. These groups may be unsubstituted. These groups may be substituted by one or more fluoro groups and be perfluorinated, for example CF 3 C 2 F 5 as follows. When the alkyl group is substituted, the substituent is (i) Hydroxy, or (ii) C 1~2 alkoxy, i.e., methoxy, ethoxy, or (iii) NH 2 , or (iv) C 1~4 alkylcarbamoyl, e.g., NHC(O)CH 3 may be selected from.

[0206] In some embodiments, the substituent for Ar is C 3~6 cycloalkyl. In these embodiments, the C 3~6 cycloalkyl group may be cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. In particular, the C 3~6 cycloalkyl group may be cyclohexyl.

[0207] In some embodiments, the substituent for Ar is hydroxy, cyano, NR N3 R N4 (wherein R N3 and R N4 are independently selected from H and methyl) or acylamide. In some of these embodiments, the substituent may be hydroxy. In other of these embodiments, the substituent may be cyano. In other of these embodiments, the substituent may be NR N3 R N4 (wherein R N3 and R N4 are independently selected from H and methyl), and thus the substituent may be NH 2 , NHCH 3 or N(CH 3 ) 2 . In other of these embodiments, the substituent may be an acylamide such as NHCO 2 CH 3 etc.

[0208] In some embodiments, the substituent for Ar is halo. In these embodiments, the halo group may be fluoro, chloro, bromo or iodo.

[0209] In some embodiments, the substituent for Ar is hydroxy, C(O)NH 2 , C 3~6 cycloalkyl, phenyl, C 5~6 heteroaryl, or substituted by one or more fluoro groups, C 1~3 alkoxy. In these embodiments, the C 1~3 alkoxy group may be methoxy, ethoxy or propyloxy. These groups may be unsubstituted. These groups may be substituted by one or more fluoro groups and be perfluorinated, for example OCF 3 , OC 2 F 5 . The alkoxy group may be substituted by hydroxyl, so that the whole group is, for example, OC 2 H 4 OH. The alkoxy group may be substituted by C(O)NH 2 , so that the whole group is, for example, OCH 2 C(O)NH 2 . The alkoxy group may be substituted by C 3~6 cycloalkyl, such as cyclopropyl, so that the whole group is, for example, OCH 2 (cyclopropyl). The alkoxy group may be substituted by phenyl, so that the whole group is, for example, benzyloxy. The alkoxy group may be substituted by C 5~6 heteroaryl, such as pyridyl, pyrazolyl, so that the whole group is, for example, OCH 2 (N-methylpyrazolyl) or OCH 2 (methoxypyridyl).

[0210] In some embodiments, the substituent for Ar is phenoxy, which may be substituted by fluoro. In some of these embodiments, the substituent may be phenoxy. In other of these embodiments, the substituent is OC 6 H 4 and may be F.

[0211] In some embodiments, the substituent for Ar is phenyl or C 5~6 heteroaryl. In some of these embodiments, the substituent is phenyl. In other of these embodiments, the substituent may be C 5~6 heteroaryl such as oxazolyl or N - pyrazolyl.

[0212] In some embodiments, the substituent for Ar is SF 5 or SO 2 CH 3 . In some of these embodiments, the substituent is SF 5 . In other of these embodiments, the substituent is SO 2 Me.

[0213] In some embodiments, the substituent for Ar is -(CH 2 ) n -Y- (where Y is O or CH 2 , and n is 2 or 3). This substituent is particularly relevant when Ar is phenyl, and forms a partially unsaturated fused ring with the phenyl. Thus, Ar can be tetralinyl (i.e., fused cyclohexane), indanyl (i.e., fused cyclopentane), chromanyl (i.e., fused tetrahydropyran) or dihydrobenzofuranyl.

[0214] In some embodiments, the substituent for Ar is C 1~4 alkyl ester. In some of these embodiments, the substituent is C(O)OCH 3is. In other of these embodiments, the substituent is C(O)OC(CH 3 ) 3 is.

[0215] A certain embodiment of Ar is of formula (Ar-1):

[0216] [Chemical formula] [wherein Y is either N or C-R A4 and Z is either N or C-R A5 and R A1 , R A2 , R A3 , R A4 (if present) and R A5 (if present) are independently selected from optional substituents for H and Ar] may be represented by.

[0217] In some embodiments, R A2 is ethyl.

[0218] In some embodiments, R A3 is selected from cycloalkyl, phenoxy, phenyl, C 5~6 heteroaryl, SF 5 and SO 2 CH 3 .

[0219] In some embodiments, Ar is 5-ethyl-2-methoxyphenyl.

[0220] In some embodiments, Ar is 5-CF 3 -2-methoxyphenyl.

[0221] In some embodiments, Ar is 2,6-dimethoxyphenyl.

[0222] In some embodiments, Ar is quinolinyl. These compounds may exhibit selective activity against HBO1.

[0223] In some embodiments, R 4 is methoxy, and R 2 is CH 2 OCH 3 、CH 2 OCH 2 CH 3 and optionally substituted phenyl, and Ar is 2,6-dimethoxybenzene. These compounds may exhibit specific activity against MOZ and MORF. R 2 being CH 2 OCH 3 and CH 2 OCH 2 CH 3 selected compounds may exhibit selective activity against MOZ and MORF.

[0224] In some embodiments, for compounds where R 1 , R 2 , R 3 and R 4 are H, Ar is not 4-aminophenyl.

[0225] In some embodiments, for compounds where R 1 , R 2 , R 3 and R 4 are H, Ar is not 2,4,6-trimethylphenyl.

[0226] In some embodiments, for compounds where R 1 , R 2 and R 4 are H and R 3 is CF 3 , Ar is not 2-(difluoromethoxy)phenyl.

[0227] In some embodiments, R 1 , R2 and R 3 and R 4 For compounds where R, R and R are H, Ar is not 4-fluoro-3-methyl-phenyl.

[0228] In some embodiments, for compounds where R 1 , R 2 and R 3 are H and R 4 is methoxy, Ar is not unsubstituted naphthyl.

[0229] Particularly interesting compounds include, for example.

Examples

[0230] The following examples are provided solely to illustrate the invention and are not intended to limit the scope of the invention as described herein.

[0231] Abbreviations For convenience, many chemical moieties are represented using well-known abbreviations including, but not limited to, methyl (Me), ethyl (Et), N-propyl (nPr), isopropyl (iPr), N-butyl (nBu), tert-butyl (tBu), phenyl (Ph), benzyl (Bn), methoxy (MeO), ethoxy (EtO), trimethylsilyl (TMS) and acetyl (Ac).

[0232] For convenience, many chemical compounds are represented using well-known abbreviations including, but not limited to, methanol (MeOH), deuterated methanol (methanol-d 4 ), ethanol (EtOH), isopropanol (i-PrOH), ethyl acetate (EtOAc), acetic acid (AcOH), acetonitrile (MeCN or ACN), dichloromethane (methylene chloride, DCM), trifluoroacetic acid (TFA), N,N-dimethylformamide (DMF), tetrahydrofuran (THF), dimethyl sulfoxide (DMSO), N-methyl-2-pyrrolidone (NMP), deuterated acetone (acetone-d 6 ), deuterated chloroform (CDCl 3) Deuterated dimethyl sulfoxide (DMSO-d 6 )、1,1’-Bis(diphenylphosphino)ferrocene (dppf), triethylamine (Et 3 N or TEA), N,N-diisopropylethylamine (DIPEA or DIEA), 1,1’-Bis(diphenylphosphino)ferrocene dichloropalladium(II) (PdCl 2 (dppf)), trans-Dichlorobis(triphenylphosphine) palladium(II) (PdCl 2 (PPh 3 ) 2 )、Tris(dibenzylideneacetone) dipalladium(0) (Pd 2 (dba) 3 )、Tetrakis(triphenylphosphine) palladium(0) (Pd(PPh 3 ) 4 )、2,4-Dimethoxybenzyl (DMB), petroleum ether (Pet. ether), lithium bis(trimethylsilyl) amide (LHMDS or LiHMDS), potassium bis(trimethylsilyl) amide (KHMDS), sodium bis(trimethylsilyl) amide (NaHMDS), n-butyllithium (n-BuLi), N-bromosuccinimide (NBS), N-chlorosuccinimide (NCS), pyridinium p-toluenesulfonate (PPTS), azobisisobutyronitrile (AIBN), tetramethylethylenediamine (TMEDA), tert-butyldimethylsilyl chloride (TBSCl), tetra-n-butylammonium fluoride (TBAF) and diisopropyl azodicarboxylate (DIAD), and are represented using well-known abbreviations including but not limited to these.

[0233] In addition, TLC refers to thin-layer chromatography.

[0234] Other abbreviations: retention time (rt or R t ), minute (min), hour (h), room temperature (RT), concentrated (conc.), atmosphere (atm), aqueous solution (aq.), saturated (sat.), eq. (equivalent).

[0235] General experimental details Unless otherwise specified, the following generalizations apply. 1 1H NMR spectra were recorded on a Bruker UltraShield Plus (400 MHz) or Bruker Avance III (400 MHz). Signal multiplicities were assigned using the following abbreviations: s, singlet; d, doublet; t, triplet; q, quartet; p, pentet; dd, doublet of doublets; dt, doublet of triplets; tt, triplet of triplets; br, broad; m, multiplet. All observed coupling constants J are reported in Hertz (Hz). Exchangeable protons are not necessarily observed.

[0236] LCMS data were generated using either an Agilent 6100 Series Single Quadrupole (LCMS-A), Agilent 1260 Infinity Series UPLC / MS (LCMS-B), Agilent 1200 (LCMS-C and LCMS-D), Waters 2695 Alliance (LCMS-E), Agilent 6120 Single Quadrupole (LCMS-F), or mass-directed HPLC-MS. Chlorine isotopes are 35 reported as 79 Cl, bromine isotopes are 81 reported as either 79 Br or 81 reported as both

[0237] LCMS method A (LCMS-A): Instrument: Agilent 6100 Series Single Quadrupole LC / MS Agilent 1200 Series HPLC Pump: 1200 Series G1311A Quaternary Pump Autosampler: 1200 Series G1329A Thermostatted Autosampler Detector: 1200 Series G1314B Variable Wavelength Detector

[0238] LC conditions: Reverse-phase HPLC analysis Column: Luna C8(2) 5μm 50×4.6mm 100Å Column temperature: 30 °C Injection volume: 5 μL Solvent A: 0.1% formic acid in water Solvent B: 0.1% formic acid in MeCN Gradient: 5 - 100% Solvent B over 10 minutes Detection: 254 nm or 214 nm

[0239] MS conditions: Ion source: Quadrupole Ion mode: Multiple mode - ES Drying gas temperature: 300 °C Vaporizer temperature: 200 °C Capillary voltage (V): 2000 (positive) Capillary voltage (V): 4000 (negative) Scan range: 100 - 1000 Step width: 0.1 s Acquisition time: 10 minutes

[0240] LCMS method B (LCMS - B): Instrument: Agilent 1260 Infinity series UPLC / MS Pump: 1260 Infinity G1312B binary pump Autosampler: 1260 Infinity G1367E 1260 HiP ALS Detector: 1290 Infinity G4212A 1290 DAD

[0241] LC conditions: Reverse - phase HPLC analysis Column: Poroshell 120 EC - C18 2.7 μm 50×3.0 mm Column temperature: 35 °C Injection volume: 1 μL Solvent A: 0.1% formic acid in water Solvent B: 0.1% formic acid in MeCN Gradient: 5 - 100% Solvent B over 3.8 minutes Detection: Monitored at 254 nm and 214 nm

[0242] MS conditions: Ion source: Quadrupole Ion mode: API-ES Drying gas temperature: 350 °C Capillary voltage (V): 3000 (positive) Capillary voltage (V): 3000 (negative) Scanning range: 100 - 1000 Step width: 0.1 s Acquisition time: 5 min

[0243] LCMS method C (LCMS-C): LC model: Agilent1200 (Pump type: Binary pump, Detector type: DAD) MS model: Agilent G6110A Quadrupole

[0244] LC conditions: Column: CrossBridge-C18, 2.5 μm, 2.1×30 mm Column temperature: 30 °C Wavelength acquisition: 214 nm, 254 nm Mobile phase: A: 0.07% aqueous HCOOH solution, B: MeOH

[0245] MS conditions: MS: Ion source: ES+ (or ES-) MS range: 50 - 900 m / z Fragmentor: 60 Drying gas flow: 10 L / min Nebulizer pressure: 35 psi Drying gas temperature: 350 °C Vcap: 3.5 kV Gradient table:

[0246]

Table 2

[0247] Sample preparation: The sample was dissolved in methanol at a concentration of approximately 0.11 - 1 mg / mL and then filtered through a 0.22 μm syringe filter. (Injection volume: 1 - 10 μL)

[0248] LCMS Method D (LCMS-D): LC Model: Agilent 1200 (Pump type: Binary pump, Detector type: DAD) MS Model: Agilent G6110A Quadrupole

[0249] LCMS Conditions: LC: Column: CrossBridge-C18, 2.5 μm, 2.1×30 mm Column temperature: 30 °C Wavelength acquisition: 214 nm, 254 nm Mobile phase: A: 0.07% Aqueous HCOOH solution, B: MeOH

[0250] MS Conditions: MS: Ion source: ES+ (or ES-) MS range: 50~900 m / z Fragmentor: 60 Dry gas flow: 10 L / min Nebulizer pressure: 35 psi Dry gas temperature: 350 °C Vcap: 3.5 kV

[0251] Gradient table:

[0252]

Table 3

[0253] Sample preparation: The sample was dissolved in methanol at a concentration of approximately 0.11~1 mg / mL, and then filtered through a 0.22 μm syringe filter. (Injection volume: 1~10 μL)

[0254] LCMS Method E (LCMS-E): Equipment information: LC Model: Waters 2695 Alliance (Pump type: Quaternary pump, Detector: 2996 Photodiode array detector) MS Model: Micromass ZQ

[0255] LC Conditions: LC: Column: Crossbridge-C18, 3.5 μm, 2.1×50 mm Column temperature: 30 °C Wavelength acquisition: 214 nm, 254 nm Mobile phase: A: 0.07% aqueous HCOOH solution, B: MeOH

[0256] MS conditions: MS: Ion source: ES+ (or ES-) MS range: 50 - 900 m / z Capillary: 3 kV Cone: 3 V Extractor: 3 V Dry gas flow: 600 L / hour Cone: 50 L / hour Desolvation temperature: 300 °C Source temperature: 100 °C

[0257] Gradient table:

[0258]

Table 4

[0259] Sample preparation: The sample was dissolved in methanol at a concentration of approximately 0.11 - 1 mg / mL and then filtered through a 0.22 μm syringe filter. (Injection volume: 1 - 10 μL)

[0260] LCMS method F (LCMS-F) Equipment: Agilent 6120 series single quadrupole LC / MS Agilent 1200 series HPLC Pump: 1200 series G1311A quaternary pump Autosampler: 1200 series G1329A autosampler with thermostat Detector: 1200 series G1314B variable wavelength detector

[0261] LC conditions: Reverse phase HPLC analysis Column: Luna C8(2) 5 μm 50×4.6 mm 100 Å Column temperature: 30 °C Injection volume: 1 - 10 μL Solvent A: 0.1% formic acid in water Solvent B: 0.1% formic acid in MeCN Gradient: 0 - 95% Solvent B over 10 minutes Detection: 254 nm or 214 nm

[0262] MS conditions: Ion source: Quadrupole Ion mode: Multiple mode - ES and APCI Drying gas temperature: 250 °C Vaporizer temperature: 200 °C Capillary voltage (V): 4000 (positive) Capillary voltage (V): 4000 (negative) Scan range: 100 - 1000 Step width: 0.1 second Acquisition time: 10 minutes

[0263] Preparative mass-directed HPLC Equipment: Waters ZQ3100 - Mass detector Waters 2545 - Pump Waters SFO system fluid organizer Waters 2996 Diode array detector Waters 2767 Sample manager

[0264] LC conditions: Reverse-phase HPLC analysis Column: CrossBridgeTM C18 5 μm 19×50 mm Injection volume 500 μL Solvent A: 0.1% formic acid in water Solvent B: Acetonitrile 0.1% formic acid Gradient: 25 - 100% B over 10 minutes Flow rate: 19 mL / min Detection: 100 - 600 nm

[0265] MS conditions: Ion source: Single quadrupole Ion mode: ES positive Supply source temperature: 150 °C Desolventization temperature: 350 °C Detection: Ion counting Capillary (KV) -3.00 Cone (V): 30 Extractor (V): 3 RF lens (V): 0.1 Scanning range: 100 - 1000 Amu Scanning time: 0.5 seconds Acquisition time: 10 minutes Gas flow rate Desolventization L / h - 650 Cone L / h - 100

[0266] Preparative HPLC (prep.HPLC): Instrument type: Varian 940-LC series Pump type: Quaternary pump Detector type: Diode array detector

[0267] HPLC conditions: Elute at a flow rate of 15 mL / min with a gradient of MeOH in water containing 0.07% TFA using a Waters Sapphire preparative C18 OBD, 5 μm 19×100 mm column. Acquisition wavelengths are 214 nm and 254 nm.

[0268] Analytical thin layer chromatography was performed on Merck silica gel 60F254 aluminum-backed plates and visualized by fluorescence quenching under UV light or by immersion in basic KMnO 4 or ninhydrin immersion.

[0269] Preparative thin layer chromatography (prep.TLC) was performed using Tklst (China), Grand grade: (HPTLC): 8 ± 2 μm > 80%; (TLC): 10 - 40 μm, type: GF254. Compounds were visualized by UV (254 nm).

[0270] Column chromatography was carried out using a Biotage Isolera purification system with Grace or RediSep® silica cartridges, using silica gel of Grand Grade, 100 - 200 mesh, made in Tklst (China).

[0271] Microwave irradiation was achieved using a CEM Explorer SP microwave reactor.

[0272] If necessary, anhydrous solvents were purchased from Sigma - Aldrich and dried using conventional methods.

[0273] Unless otherwise specified, acidification was carried out with concentrated or aqueous HCl.

[0274] Additional cartridges were used as follows: Phase separator: Manufacturer: Biotage Product: ISOLUTE® Phase Separator (3 mL unless otherwise specified)

[0275] Si - amine cartridge: Manufacturer: Biotage Product: Isolute® NH2, 1 g / 6 mL Or Manufacturer: Silicycle Product: Si - amine 500 mg or 1 g

[0276] Synthesis of intermediates i) 6 - (Methoxymethyl) - 5 - methylbenzo[d]isoxazol - 3 - amine I4

[0277]

Chemical formula

[0278] b) 2-Fluoro-4-(hydroxymethyl)-5-methylbenzonitrile I2 N 2 To a solution of methyl 4-cyano-5-fluoro-2-methylbenzoate I1 (2.4 g, 12.4 mmol) in anhydrous THF (20 mL) at room temperature under N 4 (2.0 M solution in THF, 12.4 mL, 24.8 mmol) was added dropwise and the mixture was heated to reflux for 2 h. The reaction was quenched with water (80 mL) and the mixture was extracted with EtOAc (90 mL×3). The combined organic extracts were washed with water (100 mL×3), brine, dried over anhydrous Na 2 SO 4 and filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / EtOAc = 20 / 1 to 10 / 1 to 5 / 1) to give the title compound (1.6 g, 79%) as a yellow solid. LCMS-D: R t 1.43 min; m / z 166.1 [M+H] + , 188.1 [M+Na] + .

[0279] c) 2-Fluoro-4-(methoxymethyl)-5-methylbenzonitrile I3 To a solution of 2-fluoro-4-(hydroxymethyl)-5-methylbenzonitrile I2 (800 mg, 8.8 mmol) and iodomethane (3.4 g, 24.2 mmol) in DMF (12 mL) at 0 °C was added NaH (60% w / w dispersion in oil, 379 mg, 9.7 mmol), and the mixture was stirred at 0 °C for 30 minutes. Water was added and the mixture was extracted with EtOAc (50 mL × 3). The combined organic extracts were washed with brine, dried over anhydrous Na 2 SO 4 and filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / EtOAc = 20 / 1 to 10 / 1 to 5 / 1) to give the title compound (660 mg, 76%) as a yellow solid. LCMS-D: R t 2.44 min; m / z 180.1 [M+H] + , 202.1.1 [M+Na] + .

[0280] d) 6-(Methoxymethyl)-5-methylbenzo[d]isoxazol-3-amine I4 To a solution of acetohydroxamic acid (792 mg, 10.6 mmol) in anhydrous DMF (20 mL) at 0 °C was added potassium tert-butoxide (1.2 g, 10.6 mmol), and the mixture was stirred at room temperature for 2 hours. Then 2-fluoro-4-(methoxymethyl)-5-methylbenzonitrile I3 (630 mg, 3.5 mmol) was added and the mixture was heated at 60 °C overnight. Water was added and the mixture was extracted with EtOAc (80 mL × 3). The combined organic extracts were washed with brine, dried over anhydrous Na 2 SO 4 and filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (DCM / MeOH = 20 / 1 to 10 / 1) to give the title compound (1.0 g, 77%) as a yellow solid. LCMS-D: R t 1.75 min; m / z 193.1 [M+H] + .

[0281] ii) 4-Methoxy-6-(methoxymethyl)benzo[d]isoxazol-3-amine I9

[0282]

Chem.

[0283] b) Methyl 4-cyano-3-fluoro-5-methoxybenzoate I6 A mixture of 4-bromo-2-fluoro-6-methoxybenzonitrile I5 (4.3 g, 18.7 mmol), Pd(dppf)Cl 2 ·DCM (768 mg, 0.94 mmol) and Et 3 N (5.7 g, 56.1 mmol) in MeOH (50 mL) was heated overnight at 100 °C under a CO atmosphere (0.2 MPa). The catalyst was removed by filtration, washed with MeOH, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / EtOAc = 200 / 1 to 50 / 1) to give the title compound (2.9 g, 74%) as a white solid. LCMS-D: R t 2.41 min; m / z 210.0 [M+H] + , 232.0 [M+Na] + .

[0284] c) 2-Fluoro-4-(hydroxymethyl)-6-methoxybenzonitrile I7 N 2 LiBH in anhydrous THF (60 mL) at room temperature 4 To a solution of (2.0 M solution in THF, 13.9 mL, 27.8 mmol) was added dropwise a solution of methyl 4-cyano-3-fluoro-5-methoxybenzoate I6 (2.9 g, 13.9 mmol) in anhydrous THF (10 mL) and the mixture was heated to reflux for 1 h. The reaction was quenched with 1 M aqueous HCl and extracted with EtOAc (100 mL x 3). The combined organic extracts were washed with water (100 mL x 3), brine and anhydrous Na 2 SO 4 Drying at 40° C., filtration and concentration afforded the title compound (2.5 g, 100%) as a white solid. LCMS-D: t 2.31 minutes; m / z 182.1 [M+H] + , 204.1 [M+Na] + .

[0285] d) 2-Fluoro-6-methoxy-4-(methoxymethyl)benzonitrile I8 To a solution of 2-fluoro-4-(hydroxymethyl)-6-methoxybenzonitrile I7 (2.7 g, 14.9 mmol) and iodomethane (10.6 g, 74.5 mmol) in DMF (100 mL) at 0° C., NaH (60% w / w dispersion in oil, 1.2 g, 29.8 mmol) was added in small portions and the mixture was stirred at room temperature for 30 min. Water was added and the mixture was extracted with EtOAc (100 mL×3). The combined organic extracts were washed with brine and anhydrous Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / EtOAc=100 / 1 to 5 / 1) to give the title compound (2.2 g, 76%) as a yellow solid. LCMS-D: t 2.22 min; m / z 218.0 [M+Na] + .

[0286] e) 4-Methoxy-6-(methoxymethyl)benzo[d]isoxazol-3-amine I9 To a solution of acetohydroxamic acid (2.3 g, 30.8 mmol) in anhydrous DMF (1500 mL) at room temperature was added potassium tert-butoxide (3.5 g, 30.8 mmol), and the mixture was stirred at room temperature for 1 hour. Then, 2-fluoro-6-methoxy-4-(methoxymethyl)benzonitrile I8 (2.0 g, 10.3 mmol) was added, and stirring was continued overnight at room temperature. Water was added, and the mixture was extracted with EtOAc. The combined organic extracts were dried over anhydrous Na 2 SO 4 and filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (DCM / MeOH = 20 / 1 to 10 / 1 to 3 / 1) to give the title compound (580 mg, 27%) as a yellow solid. 1 1H NMR (400 MHz, DMSO-d 6 ) δ 6.92 (d, J = 0.8 Hz, 1H), 6.65 (s, 1H), 5.91 (s, 2H), 4.48 (s, 2H), 3.90 (s, 3H), 3.32 (s, 3H, obscured by water peak). LCMS-D: R t t 1.33 min; m / z 209.0 [M+H] + .

[0287] iii) 4-Nitrobenzo[d]isoxazol-3-amine I10

[0288]

Chemical formula

[0289] iv) 4-Methoxy-6-(1-methoxyethyl)benzo[d]isoxazol-3-amine I15

[0290]

Chemical Structure

[0291] b) 4-Acetyl-2-fluoro-6-methoxybenzonitrile I12 To a solution of 4-(1-ethoxyvinyl)-2-fluoro-6-methoxybenzonitrile I11 (1.0 g, 4.5 mmol) in THF (10 mL) was added 2 M aqueous HCl (6.0 mL), and the mixture was stirred at room temperature for 3 h. The mixture was diluted with diethyl ether and washed with saturated NaHCO 3 aqueous solution and water. The organic layer was dried over anhydrous Na 2 SO 4 and filtered, and concentrated under reduced pressure to give the title compound (710 mg, 81%) as a white solid. LCMS-C: R t 1.42 min; m / z 194.0 [M+H] + .

[0292] c) 2-Fluoro-4-(1-hydroxyethyl)-6-methoxybenzonitrile I13 To a solution of 4-acetyl-2-fluoro-6-methoxybenzonitrile I12 (700 mg, 3.6 mmol) in THF (30 mL) was added sodium borohydride (206 mg, 5.4 mmol), and the mixture was stirred at room temperature overnight. Water was added, and the mixture was extracted with EtOAc (30 mL×3). The combined organic extracts were dried over anhydrous Na 2 SO 4 and filtered, and concentrated under reduced pressure to give the title compound (675 mg, 95%) as a colorless oil. LCMS-C: R t 0.98 min; m / z 196.0 [M+H] + .

[0293] d) 2-Fluoro-6-methoxy-4-(1-methoxyethyl)benzonitrile I14 A solution of 2-fluoro-4-(1-hydroxyethyl)-6-methoxybenzonitrile I13 (670 mg, 3.4 mmol) and iodomethane (1.5 g, 10.3 mmol) in DMF (20 mL) at 0 °C was added NaH (60% w / w dispersion in oil, 274 mg, 6.8 mmol) portionwise, and the mixture was stirred at 0 °C for 2 h. Water was added and the mixture was extracted with EtOAc (40 mL × 3). The combined organic extracts were dried over anhydrous Na 2 SO 4 and filtered, concentrated under reduced pressure to give the title compound (650 mg, 90%) as a pale yellow solid. LCMS-C: R t 1.95 min; m / z 210.0 [M+H] + .

[0294] e) 4-Methoxy-6-(1-methoxyethyl)benzo[d]isoxazol-3-amine I15 To a solution of acetohydroxamic acid (698 mg, 9.3 mmol) in anhydrous DMF (20 mL) at 0 °C was added potassium tert-butoxide (1.04 g, 9.3 mmol), and the mixture was stirred at room temperature for 1 h. Then a solution of 2-fluoro-6-methoxy-4-(1-methoxyethyl)benzonitrile I14 (650 mg, 3.1 mmol) in anhydrous DMF (10 mL) was added dropwise, and the mixture was stirred at room temperature overnight. Water was added and the mixture was extracted with EtOAc (50 mL × 3). The combined organic extracts were dried over anhydrous Na 2 SO 4 and filtered, concentrated under reduced pressure. The residue was purified by column chromatography (DCM / MeOH = 300 / 1 to 200 / 1) to give the title compound (130 mg, 19%) as a yellow solid. 1 1H NMR (400 MHz, DMSO-d 6 ) δ 6.90 (s, 1H), 6.64 (s, 1H), 5.92 (s, 2H), 4.39 (q, J = 6.4 Hz, 1H), 3.90 (s, 3H), 3.15 (s, 3H), 1.36 (d, J = 6.4 Hz, 3H). LCMS-C: Rt 0.73 min m / z 223.0 [M+H] + .

[0295] v) 4-Methoxy-6-phenylbenzo[d]isoxazol-3-amine I17

[0296]

Chem.

[0297] b) 4-Methoxy-6-phenylbenzo[d]isoxazol-3-amine I17 A solution of acetohydroxamic acid (8.15 g, 23.98 mmol) in anhydrous DMF (200 mL) at 0 °C was added potassium tert-butoxide (5.5 g, 24.0 mmol), and the mixture was stirred at room temperature for 1 hour. Then, 3-fluoro-5-methoxy-[1,1'-biphenyl]-4-carbonitrile I16 (5.45 g, 7.99 mmol) was added, and the mixture was heated at 60 °C for 4 hours. Water was added, and the mixture was extracted with EtOAc. The combined organic extracts were washed with brine and dried over anhydrous Na 2 SO 4 4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / EtOAc = 10 / 1 to 8 / 1 to 6 / 1) to give the title compound (2.2 g, 38%) as a yellow solid. 1 1H NMR (400 MHz, DMSO-d 6 6) δ 7.79 - 7.74 (m, 2H), 7.52 - 7.46 (m, 2H), 7.45 - 7.39 (m, 1H), 7.26 (d, J = 1.1 Hz, 1H), 6.95 (s, 1H), 5.97 (s, 2H), 4.00 (s, 3H). LCMS-C: R t t 2.15 min; m / z 241.0 [M+H] +

[0298] vi) 3-(3-Amino-4-methoxybenzo[d]isoxazol-6-yl)phenol I19

[0299]

Chemical formula

[0300] b) 3-(3-Amino-4-methoxybenzo[d]isoxazol-6-yl)phenol I19 To a solution of acetohydroxamic acid (636 mg, 8.5 mmol) in anhydrous DMF (60 mL) at 0 °C was added potassium tert-butoxide (952 mg, 8.5 mmol), and the mixture was stirred at room temperature for 1 h. Then 3-fluoro-3'-hydroxy-5-methoxy-[1,1'-biphenyl]-4-carbonitrile I18 (687 mg, 2.8 mmol) was added, and the mixture was heated at 60 °C for 4 h. Water was added, and the mixture was extracted with EtOAc. The combined organic extracts were washed with brine, dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / EtOAc = 1 / 1) to give the title compound (282 mg, 39%) as a yellow solid. LCMS-C: R t 2.3 min; m / z 257.0 [M+H] + .

[0301] vii) 6-(Ethoxymethyl)-4-methoxybenzo[d]isoxazol-3-amine I21

[0302]

Chemical formula

[0303] b) 6-(Ethoxymethyl)-4-methoxybenzo[d]isoxazol-3-amine I21 To a solution of acetohydroxamic acid (1.1 g, 14.3 mmol) in anhydrous DMF (50 mL) at room temperature, potassium tert-butoxide (1.6 g, 14.3 mmol) was added and the mixture was stirred at room temperature for 1 hour. Then 4-(ethoxymethyl)-2-fluoro-6-methoxybenzonitrile I20 (1.0 g, 4.8 mmol) was added and the mixture was stirred at room temperature overnight. Water was added and the mixture was extracted with EtOAc. The organic extract was dried over anhydrous Na 2 SO 4 and filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (DCM / MeOH = 20 / 1 to 10 / 1 to 3 / 1) to give the title compound (650 mg, 61%) as a yellow oil. 1 1H NMR (400 MHz, DMSO-d 6 ) δ 6.92 (s, 1H), 6.65 (s, 1H), 5.91 (s, 2H), 4.53 (s, 2H), 3.89 (s, 3H), 3.51 (q, J = 7.0 Hz, 2H), 1.17 (t, J = 7.0 Hz, 3H). LCMS-C: R t 0.82 min; m / z 223.0 [M+H] + .

[0304] viii) 6-Bromo-4-methoxybenzo[d]isoxazol-3-amine I22

[0305]

Chemical Structure

[0306] ix) 7-Ethoxybenzo[d]isoxazol-3-amine I26

[0307]

Chemical Structure

[0308] b) 2-Fluoro-3-hydroxybenzonitrile I24 To a solution of 2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile I23 (1.9 g, 7.6 mmol) in AcOH (19 mL) under N 2 , H 2 O 2 (30% aqueous solution, 1.9 mL) was added dropwise, and the mixture was stirred at room temperature for 2 h and then poured into a mixture of EtOAc and excess aqueous Na 2 SO 3 . The layers were separated, and the organic layer was washed with water, brine, dried over anhydrous Na 2 SO 4 , filtered, concentrated under reduced pressure to give the title compound (650 mg, 62%) as an off-white waxy solid. LCMS-D: R t 0.93 min; m / z 138.1 [M+H] + .

[0309] c) 3-Ethoxy-2-fluorobenzonitrile I25 To a solution of 2-fluoro-3-hydroxybenzonitrile I24 (360 mg, 2.6 mmol) in DMF (30 mL) was added Cs 2 CO 3 (4.3 g, 13.1 mmol) and iodoethane (1.0 g, 6.6 mmol), and the mixture was stirred at room temperature overnight. The mixture was diluted with EtOAc (80 mL) and washed with water (50 mL × 3). The organic layer was dried over anhydrous Na 2 SO 4 and filtered, and concentrated under reduced pressure to give the title compound (220 mg, 51%) as a yellow solid. LCMS-D: R t 2.31 min; m / z 166.1 [M+H] + .

[0310] d) 7-Ethoxybenzo[d]isoxazol-3-amine I26 N 2 Under N, to a solution of acetohydroxamic acid (300 mg, 4.0 mmol) in DMF (15 mL) at 0 °C was added potassium tert-butoxide (450 mg, 4.0 mmol), and the mixture was heated at 30 °C for 1 h. A solution of 3-ethoxy-2-fluorobenzonitrile I25 (220 mg, 1.3 mmol) in DMF (10 mL) was added, and the mixture was heated at 30 °C overnight. EtOAc (80 mL) was added, and the mixture was washed with water (50 mL × 3). The organic layer was dried over anhydrous Na 2 SO 4 and filtered, and concentrated under reduced pressure to give the title compound (170 mg, 70%) as a yellow solid. LCMS-D: R t 1.68 min; m / z 179.1 [M+H] + .

[0311] x) 7-(Cyclopropylmethoxy)benzo[d]isoxazol-3-amine I28

[0312]

Chemical formula

[0313] b) 7-(Cyclopropylmethoxy)benzo[d]isoxazol-3-amine I28 7-Ethoxybenzo[d]isoxazol-3-amine I26, prepared from 3-(cyclopropylmethoxy)-2-fluorobenzonitrile I27 according to the procedure described for step d. LCMS-D: R t 2.23 min; m / z 205.1 [M+H] + .

[0314] xi) 6-Ethoxybenzo[d]isoxazol-3-amine I32

[0315]

Chemical formula

[0316] b) 6-((Tetrahydro-2H-pyran-2-yl)oxy)benzo[d]isoxazol-3-amine I30 N 2 To a solution of acetohydroxamic acid (13.7 g, 182.3 mmol) in DMF (60 mL) at 0 °C was added potassium tert-butoxide (20.4 g, 182.3 mmol), and the mixture was stirred at room temperature for 1 h. Then 2-fluoro-4-((tetrahydro-2H-pyran-2-yl)oxy)benzonitrile I29 (13.4 g, 60.8 mmol) was added, and the mixture was stirred at room temperature overnight. EtOAc (500 mL) was added, and the mixture was washed with water (100 mL × 5). The organic layer was dried over anhydrous Na 2 SO 4 and filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / EtOAc = 100 / 1 to 5 / 1) to give the title compound (12.1 g, 85%) as a white solid. LCMS-D: R t 2.31 min; m / z 235.1 [M+H] + .

[0317] c) 3-aminobenzod]isoxazol-6-ol I31 A solution of 6-((tetrahydro-2H-pyran-2-yl)oxy)benzo[d]isoxazol-3-amine I30 (3.5 g, 15 mmol) in THF (50 mL) was added with 2M aqueous HCl solution (20 mL), and the mixture was stirred at room temperature for 3 hours. The mixture was diluted with EtOAc (300 mL) and washed with water (×2). The organic layer was dried over anhydrous Na 2 SO 4 and filtered, and concentrated under reduced pressure to obtain the title compound (2.1 g, 94%) as a white solid, which was used directly in the next step.

[0318] d) 6-Ethoxybenzo[d]isoxazol-3-amine I32 A mixture of 3-aminobenzo[d]isoxazol-6-ol I31 (300 mg, 2 mmol), Cs 2 CO 3 (2.0 g, 6 mmol), KI (66 mg, 0.4 mmol) and bromoethane (436 mg, 4 mmol) in DMF (30 mL) was heated at 50 °C overnight under N 2 . The mixture was diluted with EtOAc (300 mL) and washed with water (100 mL×5). The organic layer was dried over anhydrous Na 2 SO 4 and filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / EtOAc = 100 / 1 to 5 / 1) to obtain the title compound (270 mg, 76%) as a white solid. LCMS-D: R t 0.37 min; m / z 179.0 [M+H] + .

[0319] xii) 6-(Cyclopropylmethoxy)benzo[d]isoxazol-3-amine I33

[0320]

Chemical formula

[0321] xiii) 6-(1H-1,2,3-Triazol-1-yl)benzo[d]isoxazol-3-amine I36

[0322]

Chemical formula

[0323] b) 2-Fluoro-4-(1H-1,2,3-triazol-1-yl)benzonitrile I35 A mixture of 4-azido-2-fluorobenzonitrile I34 (500 mg, 3.1 mmol), ethynyltrimethylsilane (454 mg, 4.6 mmol) and CuI (704 mg, 3.7 mmol) in THF (50 mL) was heated at 50 °C for 24 h under N 2 2. Then additional ethynyltrimethylsilane (454 mg, 4.6 mmol) was added and the mixture was heated at 50 °C for a further 24 h and then concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / EtOAc = 100 / 1 to 10 / 1) to give 2-fluoro-4-(5-(trimethylsilyl)-1H-1,2,3-triazol-1-yl)benzonitrile (410 mg), which was dissolved in a 1 M solution of TBAF in THF (50 mL) and heated at 45 °C overnight under N 2 2. The solvent was removed under reduced pressure and the residue was purified by column chromatography (petroleum ether / EtOAc = 50 / 1 to 2 / 1) to give the title compound (200 mg, 34%) as a white solid, which was used directly in the next step.

[0324] c) 6-(1H-1,2,3-Triazol-1-yl)benzo[d]isoxazol-3-amine I36 N 2 2. To a solution of acetohydroxamic acid (239 mg, 3.16 mmol) in DMF (25 mL) at 0 °C was added potassium tert-butoxide (357 mg, 3.18 mmol) and the mixture was stirred at room temperature for 2 h. Then a solution of 2-fluoro-4-(1H-1,2,3-triazol-1-yl)benzonitrile I35 (200 mg, 1.06 mmol) in DMF (15 mL) was added and stirring was continued at room temperature overnight. EtOAc (100 mL) was added and the mixture was washed with water (×5). The organic layer was dried over anhydrous Na 2 SO 4 4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / EtOAc = 100 / 1 to 2 / 1) to give the title compound (150 mg, 70%) as a white solid. LCMS-D: R t t 0.47 min; m / z 202.1 [M+H]+ .

[0325] xiv) 6-(Pyrimidin-2-yl)benzo[d]isoxazol-3-amine I39

[0326]

Chemical Structure

[0327] b) 2-Fluoro-4-(pyrimidin-2-yl)benzonitrile I38 N 2 2. A solution of 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile I37 (464 mg, 2 mmol) and 2-bromopyrimidine (736 mg, 4 mmol) in water (40 mL), toluene (40 mL) and i-PrOH (10 mL) was treated with Pd(dppf)Cl 2 (146 mg, 0.2 mmol) and K 3 3PO 4 ·3H 2O (1.33 g, 5.0 mmol) was added, and the mixture was heated at 85 °C for 4 h. The mixture was diluted with EtOAc (200 mL) and washed with water (50 mL). The organic layer was dried over anhydrous Na 2 SO 4 and filtered, concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether / EtOAc = 50 / 1 to 2 / 1) to afford the title compound (270 mg, 68%) as a white solid. LCMS-D: R t 2.38 min; m / z 200.1 [M+H] + .

[0328] c) 6-(Pyrimidin-2-yl)benzo[d]isoxazol-3-amine I39 N 2 To a solution of acetohydroxamic acid (306 mg, 4.07 mmol) in DMF (20 mL) at 0 °C was added potassium tert-butoxide (457 mg, 4.07 mmol), and the mixture was heated at 30 °C for 1 h. Then, a solution of 2-fluoro-4-(pyrimidin-2-yl)benzonitrile I38 (270 mg, 1.36 mmol) in DMF (10 mL) was added, and heating was continued at 30 °C overnight. The mixture was diluted with EtOAc (100 mL) and washed with water (50 mL × 3). The organic layer was dried over anhydrous Na 2 SO 4 and filtered, concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether / EtOAc = 50 / 1 to 2 / 1) to afford the title compound (200 mg, 69%) as a white solid. LCMS-D: R t 0.38 min; m / z 213.1 [M+H] + , 235.1 [M+Na] + .

[0329] xv) 5-Bromobenzo[d]isoxazol-3-amine I40

[0330]

Chemical Structure

[0331] xvi) 4-Bromobenzo[d]isoxazol-3-amine I41

[0332]

Chemical Structure

[0333] xvii) 4-(Trifluoromethyl)benzo[d]isoxazol-3-amine I42

[0334]

Chem.

[0335] xviii) 5-Bromo-4-chlorobenzo[d]isoxazol-3-amine I44

[0336]

Chem.

[0337] b) 5-Bromo-4-chlorobenzo[d]isoxazol-3-amine I44 N 2 To a solution of acetohydroxamic acid (5.1 g, 67.8 mmol) in DMF (150 mL) at 0 °C was added t-BuOK (7.6 g, 6.4 mmol), and the mixture was stirred at room temperature for 2 h. Then 3-bromo-2-chloro-6-fluorobenzonitrile I43 (5.3 g, 22.6 mmol) was added, and the mixture was stirred at room temperature overnight. The mixture was diluted with EtOAc (500 mL), washed with water (×3), brine, dried over anhydrous Na 2 SO 4 It was dried, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / EtOAc = 50 / 1 to 2 / 1) to obtain the title compound (3.1 g, 52%) as a white solid, which was used directly in the next step.

[0338] xix) 5-Bromo-4-methoxybenzo[d]isoxazol-3-amine I48

[0339]

Chemical formula

[0340] b) 3-Bromo-6-fluoro-2-methoxybenzamide I46 A mixture of 3-bromo-6-fluoro-2-methoxybenzoic acid I45 (8.0 g, 32.1 mmol) and SOCl 2 (30 mL) was heated at 85 °C for 3 hours. The mixture was concentrated under reduced pressure, the residue was dissolved in DCM (5 mL), and added dropwise to concentrated NH 4 OH (20 mL) at 0 °C. The mixture was warmed to room temperature, stirred for 20 minutes, then extracted with DCM (50 mL × 3). The combined organic extracts were washed with water and brine, dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / EtOAc = 50 / 1 to 1 / 1) to give the title compound (6.8 g, 80%) as a white solid. LCMS-E: R t2.24 min; m / z 247.8 / 249.8 [M+H] +

[0341] c) 3-Bromo-6-fluoro-2-methoxybenzonitrile I47 A mixture of 3-bromo-6-fluoro-2-methoxybenzamide I46 (6.8 g, 25.6 mmol) and SOCl 2 (30 mL) was heated at 80 °C overnight and then concentrated under reduced pressure. The residue was partitioned between water and EtOAc, the phases were separated, the organic layer was washed with water and brine, dried over anhydrous Na 2 SO 4 and filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / EtOAc = 100 / 1 to 20 / 1) to give the title compound (3.5 g, 55%) as a colorless oil, which was used directly in the next step.

[0342] d) 5-Bromo-4-methoxybenzo[d]isoxazol-3-amine I48 N 2 To a solution of acetohydroxamic acid (3.4 g, 45.7 mmol) in DMF (150 mL) at 0 °C was added t-BuOK (5.1 g, 45.7 mmol), and the mixture was stirred at room temperature for 90 minutes. Then a solution of 3-bromo-6-fluoro-2-methoxybenzonitrile I47 (3.5 g, 15.2 mmol) in DMF (30 mL) was added, and the mixture was heated at 70 °C overnight. The mixture was diluted with EtOAc (1000 mL), washed with water (×3) and brine, dried over anhydrous Na 2 SO 4 and filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / EtOAc = 50 / 1 to 3 / 1) to give the title compound (3.2 g, 86%) as a white solid. LCMS-D: R t 2.24 min; m / z 243.0 / 244.9 [M+H] + .

[0343] xx) 4-(Methoxymethyl)benzo[d]isoxazol-3-amine I51

[0344] [Chemical] a) 2-(Bromomethyl)-6-chlorobenzonitrile I49 CCl 4 A mixture of 2-chloro-6-methylbenzonitrile (2.0 g, 13.2 mmol), NBS (2.5 g, 13.8 mmol) and AIBN (660 mg, 4.0 mmol) in N 2 was heated at 85 °C overnight under N. The mixture was concentrated under reduced pressure and the residue was purified by column chromatography (petroleum ether / EtOAc = 100 / 1 to 50 / 1) to give the title compound (1.7 g, 37%) as a white solid, which was used directly in the next step.

[0345] b) 2-Chloro-6-(methoxymethyl)benzonitrile I50 Sodium metal (115 mg, 4.8 mmol) was dissolved in MeOH (5 mL) and THF (5 mL), and the mixture was stirred at room temperature for 20 minutes. Then, 2-(bromomethyl)-6-chlorobenzonitrile I49 (560 mg, 2.4 mmol) was added and the mixture was stirred at room temperature for 5 hours. The solvent was removed under reduced pressure and the residue was purified by column chromatography (petroleum ether / EtOAc = 50 / 1) to give the title compound (340 mg, 77%) as a colorless oil. 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.75 - 7.70 (m, 3H), 4.82 (s, 2H), 3.35 (s, 3H).

[0346] c) 4-(Methoxymethyl)benzo[d]isoxazol-3-amine I51 N 2To a solution of acetohydroxamic acid (422 mg, 5.6 mmol) in DMF (25 mL) at -78 °C was added t-BuOK (630 mg, 5.6 mmol), and the mixture was stirred at 0 °C for 1 hour. Then, 2-chloro-6-(methoxymethyl)benzonitrile I50 (340 mg, 1.9 mmol) was added, and the mixture was stirred at room temperature overnight and then heated at 85 °C overnight. The mixture was diluted with water (70 mL) and extracted with EtOAc (100 mL × 2). The combined organic extracts were washed with water (200 mL × 3) and dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / EtOA = 5 / 1 to 3 / 1) to give the title compound (105 mg, 31%) as a pale yellow oil. LCMS-D: R t 1.57 min; m / z 179.1 [M+H] + .

[0347] xxi) 4-Ethoxybenzo[d]isoxazol-3-amine I53

[0348]

Chemical formula

[0349] b) 4-Ethoxybenzo[d]isoxazol-3-amine I53 N 2 Under N₂, to a solution of acetohydroxamic acid (2.18 g, 29 mmol) in DMF (40 mL) at 0 °C was added t-BuOK (3.26 g, 29 mmol), and the mixture was stirred at room temperature for 1 hour. Then, 2-Ethoxy-6-fluorobenzonitrile I52 (1.6 g, 9.7 mmol) was added, and the mixture was stirred at room temperature overnight. The mixture was diluted with DCM (80 mL) and washed with water (60 mL × 4), dried over Na 2 SO 4 and filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / EtOAc = 5 / 1) to give the title compound (240 mg, 15%) as a white solid. LCMS-E: R t 5.05 min; m / z 179.0 [M+H] + .

[0350] xxii) 5-Methoxybenzo[d]isoxazol-3-amine I54

[0351]

Chemical Structure

[0352] xxiii) 5-Ethoxybenzo[d]isoxazol-3-amine I57

[0353] [Chemical formula] a) 2-Fluoro-5-hydroxybenzonitrile I55 A mixture of 2-fluoro-5-methoxybenzonitrile (1.7 g, 1.2 mmol) and pyridine·HCl (17 g) was heated at 80 °C for 5 h under N 2 and then diluted with DCM (40 mL), washed with 2 M aqueous HCl (8 mL) and water (2 × 40 mL). The organic layer was extracted with K 2 CO 3 aqueous solution (50 mL × 2), the combined aqueous extracts were washed with DCM (70 mL × 2), then adjusted to pH 3 - 4 with 2 M aqueous HCl and extracted with DCM (80 mL × 3). The combined organic extracts were dried over anhydrous Na 2 SO 4 and filtered, concentrated under reduced pressure to give the title compound (430 mg, 28%) as an off-white solid, which was used directly in the next step.

[0354] b) 5-Ethoxy-2-fluorobenzonitrile I56 To a solution of 2-fluoro-5-hydroxybenzonitrile I55 (430 mg, 3.1 mmol) in DMF (15 mL) was added K 2 CO 3 (1.3 g, 9.4 mmol), and the mixture was stirred at room temperature for 30 min under N 2 . Then bromoethane (512 mg, 4.7 mmol) was added and stirring was continued overnight at room temperature. The mixture was diluted with water (70 mL) and extracted with EtOAc (100 mL × 2). The combined organic extracts were washed with water (200 mL × 3), dried over anhydrous Na 2 SO 4It was dried, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether / EtOAc = 30 / 1 to 20 / 1) to obtain the title compound (480 mg, 92%) as a white solid. LCMS-D: R t 2.44 min; m / z 166.0 [M+H] + 188.0 [M+Na] + .

[0355] c) 5-Ethoxybenzo[d]isoxazol-3-amine I57 N 2 Under N2, potassium tert-butoxide (978 mg, 8.7 mmol) was added to a solution of acetohydroxamic acid (645 mg, 8.7 mmol) in DMF (35 mL) at 0 °C, and the mixture was heated at 30 °C for 1 hour. Then, a solution of 5-ethoxy-2-fluorobenzonitrile I56 (480 mg, 2.9 mmol) in DMF (5 mL) was added, and the mixture was heated at 30 °C overnight. The mixture was diluted with water (60 mL) and extracted with EtOAc (80 mL × 2). The combined organic extracts were washed with water (150 mL × 2) and dried over anhydrous Na 2 SO 4 and filtered, and concentrated under reduced pressure to obtain the title compound (400 mg, 77%) as a pale yellow solid. LCMS-D: R t 2.02 min; m / z 179.1 [M+H] + .

[0356] xxiv) 6-(3,5-Dimethyl-1H-pyrazol-1-yl)benzo[d]isoxazol-3-amine I59

[0357]

Chemical formula

[0358] b) 6-(3,5-Dimethyl-1H-pyrazol-1-yl)benzo[d]isoxazol-3-amine I59 N 2 To a solution of acetohydroxamic acid (972 mg, 12.9 mmol) in DMF (20 mL) at 0 °C was added t-BuOK (1.45 g, 12.9 mmol) and the mixture was heated at 30 °C for 1 hour. Then, 2-chloro-4-(3,5-dimethyl-1H-pyrazol-1-yl)benzonitrile I58 (1 g, 4.3 mmol) was added and the mixture was heated at 60 °C for 5 hours. The mixture was diluted with water and extracted with EtOAc. The organic extract was dried over anhydrous Na 2 SO 4 and filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (MeOH / DCM = 1 / 20) to give the title compound (150 mg, 15%) as a white solid. LCMS-D: R t 2.22 min; m / z 229.1 [M+H] + .

[0359] xxv) 5-Methylbenzo[d]isoxazol-3-amine I60

[0360]

Chemical Structure

[0361] xxvi) 6-(Methoxymethyl)benzo[d]isoxazol-3-amine I62

[0362]

Chemical Structure

[0363] b) 6-(Methoxymethyl)benzo[d]isoxazol-3-amine I62 To a solution of acetohydroxamic acid (1.5 g, 9.1 mmol) in DMF (50 mL) was added t-BuOK (3.06 g, 27.2 mmol), and the mixture was stirred at room temperature for 1 hour. Then, 2-fluoro-4-(methoxymethyl)benzonitrile I61 (1.5 g, 9.1 mmol) was added, and the mixture was heated at 40 °C overnight. The mixture was diluted with water and extracted with EtOAc. The organic extract was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (petroleum ether / EtOAc = 100 / 1 to 10 / 1) to give the title compound (1 g, 62%) as a yellow solid. LCMS-D: R t 0.95 min, m / z 179.0 [M+H] + .

[0364] xxvii) 5-(Trifluoromethoxy)benzo[d]isoxazol-3-amine I63

[0365]

Chemical Structure

[0366] xxviii) 5-Methyl-6-(oxazol-2-yl)benzo[d]isoxazol-3-amine I65

[0367]

Chemical Structure

[0368] b) 5-Methyl-6-(oxazol-2-yl)benzo[d]isoxazol-3-amine I65 N 2 To a solution of acetohydroxamic acid (189 mg, 2.52 mmol) in DMF (10 mL) at 0 °C was added t-BuOK (377 mg, 3.26 mmol), and the mixture was stirred at 0 °C for 1 hour. Then, 2-Fluoro-5-methyl-4-(oxazol-2-yl)benzonitrile I64 (170 mg, 0.84 mmol) was added, and the mixture was heated at 50 °C overnight. The mixture was diluted with water and extracted with EtOAc. The organic extract was dried over anhydrous Na 2 SO 4 and filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (DCM / MeOH = 10 / 1) to give the title compound (90 mg, 50%) as a white solid. LCMS-D: R t 2.10 min; m / z 216.0 [M+H] + .

[0369] xxix) 7-Bromobenzo[d]isoxazol-3-amine I66

[0370]

Chemical Structure

[0371] xxx) 7-(Pyrimidin-2-yl)benzo[d]isoxazol-3-amine I68

[0372]

Chemical formula

[0373] b) 7-(Pyrimidin-2-yl)benzo[d]isoxazol-3-amine I68 N 2 Under N, a solution of acetohydroxamic acid (243 mg, 3.2 mmol) in DMF (15 mL) at 0 °C was added with t-BuOK (363 mg, 3.2 mmol), and the mixture was stirred for 1 hour. Then, a solution of 2-fluoro-3-(pyrimidin-2-yl)benzonitrile I67 (400 mg, 1.6 mmol) in DMF (5 mL) was added dropwise, and the mixture was stirred at room temperature overnight. The mixture was diluted with EtOAc (80 mL) and washed with water (60 mL × 3). The organic layer was dried over anhydrous Na 2 SO 4 It was dried, filtered, concentrated under reduced pressure to obtain the title compound (230 mg, 67%) as a yellow solid. LCMS-D: R t 0.80 min, m / z 213.1 [M+H] + .

[0374] xxxi) 6-(1H-Pyrazol-1-yl)benzo[d]isoxazol-3-amine I70

[0375]

Chemical Structure

[0376] b) 6-(1H-Pyrazol-1-yl)benzo[d]isoxazol-3-amine I70 To a solution of acetohydroxamic acid (215 mg, 2.9 mmol) in DMF (25 mL) at 0 °C was added t-BuOK (322 mg, 2.9 mmol), and the mixture was heated at 30 °C for 2 hours. Then 2-fluoro-4-(1H-pyrazol-1-yl)benzonitrile I69 (120 mg, 0.64 mmol) was added, and the mixture was heated at 30 °C overnight. The mixture was partitioned between EtOAc (100 mL) and water (50 mL), the layers were separated, the organic layer was washed with water (×3), brine, dried over anhydrous Na 2 SO 4 4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / EtOAc = 50 / 1 to 2 / 1) to give the title compound (72 mg, 57%) as a white solid, which was used directly in the next step.

[0377] xxxii) 6-(2H-1,2,3-Triazol-2-yl)benzo[d]isoxazol-3-amine I72

[0378]

Chemical Structure

[0379] b) 6-(2H-1,2,3-triazol-2-yl)benzo[d]isoxazol-3-amine I72 To a solution of acetohydroxamic acid (221 mg, 2.9 mmol) in DMF (25 mL) at 0 °C was added t-BuOK (330 mg, 2.9 mmol), and the mixture was heated at 30 °C for 2 hours. Then 2-chloro-4-(2H-1,2,3-triazol-2-yl)benzonitrile I71 (200 mg, 0.98 mmol) was added, and the mixture was heated at 30 °C overnight. The mixture was partitioned between EtOAc (100 mL) and water (50 mL), the layers were separated, the organic layer was washed with water (×3), brine, dried over anhydrous Na 2 SO 4 and filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / EtOAc = 50 / 1 to 2 / 1) to give the title compound (90 mg, 46%) as a white solid. LCMS-D: Rt 1.93 min, m / z 202.1 [M+H] + .

[0380] xxxiii) 6-(Pyridin-2-yl)benzo[d]isoxazol-3-amine I74

[0381]

Chem.

[0382] b) 6-(Pyridin-2-yl)benzo[d]isoxazol-3-amine I74 To a solution of acetohydroxamic acid (216 mg, 2.88 mmol) in DMF (50 mL) at 0 °C was added t-BuOK (323 mg, 2.88 mmol), and the mixture was stirred at room temperature for 1 hour. Then, a solution of 2-fluoro-4-(pyridin-2-yl)benzonitrile I73 (190 mg, 0.96 mmol) in DMF (10 mL) was added, and the mixture was stirred at room temperature overnight. The mixture was partitioned between EtOAc (200 mL) and water (50 mL), the layers were separated, and the organic layer was washed with water (50 mL × 3), brine, dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (DCM / MeOH = 100 / 0 to 100 / 1) to afford the title compound (105 mg, 52%) as a white solid. LCMS-D: R t 0.83 min, m / z 212.1 [M+H] + .

[0383] xxxiv) 6-Bromobenzo[d]isoxazol-3-amine I75

[0384]

Chemical Structure

[0385] xxxv) 4-Methoxy-6-(pyridin-2-yl)benzo[d]isoxazol-3-amine I77

[0386]

Chem.

[0387] b) 4-Methoxy-6-(pyridin-2-yl)benzo[d]isoxazol-3-amine I77 A solution of acetohydroxamic acid (178 mg, 2.37 mmol) in anhydrous DMF (20 mL) at 0 °C was added potassium tert-butoxide (266 mg, 2.37 mmol), and the mixture was stirred at 0 °C for 1 hour. Then, 2-fluoro-6-methoxy-4-(pyridin-2-yl)benzonitrile I76 (180 mg, 0.79 mmol) was added, and the mixture was heated at 40 °C overnight. Water was added, and the mixture was extracted with EtOAc. The combined organic extracts were dried over anhydrous Na 2 SO 4 4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (DCM / MeOH = 200 / 1 to 100 / 1 to 60 / 1) to give the title compound (70 mg, 37%) as a yellow solid. LCMS-C: R t 0.52 min; m / z 242.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.73 - 8.68 (m, 1H), 8.14 - 8.09 (m, 1H), 7.95 - 7.88 (m, 1H), 7.70 (d, J = 1.0 Hz, 1H), 7.46 (s, 1H), 7.44 - 7.38 (m, 1H), 6.01 (s, 2H), 4.01 (s, 3H).

[0388] xxxvi) 4-Methoxy-7-phenylbenzo[d]isoxazol-3-amine I80

[0389]

Chemical Structure

[0390] b) 2-Fluoro-4-methoxy-[1,1'-biphenyl]-3-carbonitrile I79 N 2 under, to a solution of 3-bromo-2-fluoro-6-methoxybenzonitrile I78 (600 mg, 2.6 mmol), phenylboronic acid (636 mg, 5.2 mmol) and Na 2 CO 3 (829 mg, 7.8 mmol) in 1,4-dioxane (40 mL) and water (10 mL), Pd(PPh 3 ) 4 (300 mg, 0.26 mmol) was added and the mixture was heated at 100 °C overnight. The mixture was partitioned between water and EtOAc, the layers were separated, and the organic layer was washed with water, brine, dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / EtOAc = 10 / 1 to 3 / 1) to give the title compound (538 mg, 90%) as a white solid. LCMS-C: R t 2.43 min; m / z 228.0 [M+H] + .

[0391] c) 4-Methoxy-7-phenylbenzo[d]isoxazol-3-amine I80 A solution of acetohydroxamic acid (533 mg, 7.11 mmol) in anhydrous DMF (30 mL) at room temperature was added potassium tert-butoxide (797 mg, 7.11 mmol), and the mixture was stirred at room temperature for 1 hour. Then, 2-fluoro-4-methoxy-[1,1'-biphenyl]-3-carbonitrile I79 (538 mg, 2.37 mmol) was added, and the mixture was heated at 60 °C overnight. Water was added, and the mixture was extracted with EtOAc (30 mL × 3). The combined organic extracts were dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / EtOAc = 10 / 1 to 5 / 1) to give the title compound (413 mg, 72%) as an orange solid. LCMS-C: R t 1.33 min; m / z 209.0 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ) δ 7.84 - 7.79 (m, 2H), 7.61 (d, J = 8.1 Hz, 1H), 7.46 (t, J = 7.7 Hz, 2H), 7.38 - 7.32 (m, 1H), 6.67 (d, J = 8.2 Hz, 1H), 4.00 (s, 3H).

[0392] xxxvii) 4-Methoxy-7-(1-methyl-1H-pyrazol-4-yl)benzo[d]isoxazol-3-amine I82

[0393]

Chemical Structure

[0394] b) 4-Methoxy-7-(1-methyl-1H-pyrazol-4-yl)benzo[d]isoxazol-3-amine I82 To a solution of acetohydroxamic acid (474 mg, 6.24 mmol) in anhydrous DMF (20 mL) at room temperature, potassium tert-butoxide (700 mg, 6.24 mmol) was added and the mixture was stirred at room temperature for 1 hour. Then, 2-fluoro-6-methoxy-3-(1-methyl-1H-pyrazol-4-yl)benzonitrile I81 (485 mg, 2.04 mmol) was added and the mixture was heated at 60 °C overnight. Water was added and the mixture was extracted with EtOAc (30 mL×3). The combined organic extracts were dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by column chromatography (DCM / MeOH = 50 / 1) to give the title compound (225 mg, 45%) as a yellow solid. LCMS-C: R t 0.46 min; m / z 245.0 [M+H] + .1 H NMR (400 MHz, DMSO-d 6 ) δ 8.19 (s, 1H), 7.95 (s, 1H), 7.69 (d, J = 8.2 Hz, 1H), 6.74 (d, J = 8.2 Hz, 1H), 6.00 (s, 2H), 3.91 (s, 3H), 3.90 (s, 3H).

[0395] xxxviii) 5-Chloro-4-methoxy-6-(methoxymethyl)benzo[d]isoxazol-3-amine I83

[0396]

Chemical Structure

[0397] xxxix) 4-Methoxy-6-(oxazol-2-yl)benzo[d]isoxazol-3-amine I86

[0398]

Chem.

[0399] b) 2-Fluoro-6-methoxy-4-(oxazol-2-yl)benzonitrile I85 To a solution of 4-bromo-2-fluoro-6-methoxybenzonitrile I5 (305 mg, 1.33 mmol) in 1,4-dioxane (25 mL) were added 2-(tributylstannyl)oxazole I84 (1.43 g, 3.98 mmol) and Pd(PPh 3 ) 4 (154 mg, 0.133 mmol), and the mixture was heated at 90 °C overnight. The mixture was diluted with water and extracted with EtOAc. The combined organic extracts were washed with water, brine, and dried over anhydrous Na 2 SO 4It was dried, filtered, and concentrated. The residue was purified by column chromatography (petroleum ether / EtOAc = 8 / 1) to obtain the title compound (370 mg, 96%) as a white solid. LCMS-C: R t 1.86 min; m / z 218.9 [M+H] + .

[0400] c) 4-Methoxy-6-(oxazol-2-yl)benzo[d]isoxazol-3-amine I86 To a solution of acetohydroxamic acid (382 mg, 5.09 mmol) in DMF (25 mL) at 0 °C was added potassium tert-butoxide (570 mg, 5.09 mmol), and the mixture was stirred at room temperature for 1 h. Then, 2-fluoro-6-methoxy-4-(oxazol-2-yl)benzonitrile I85 (370 mg, 1.7 mmol) was added, and the mixture was heated at 60 °C for 2 h. The mixture was diluted with EtOAc, washed with water and brine, and dried over anhydrous Na 2 SO 4 and filtered and concentrated to obtain the title compound (100 mg, 26%) as a yellow solid. LCMS-C: R t 0.57 min; m / z 232.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.29 (s, 1H), 7.56 (s, 1H), 7.47 - 7.42 (m, 1H), 7.27 (s, 1H), 6.09 (s, 2H), 4.00 (s, 3H).

[0401] xl) 6-(Oxazol-2-yl)benzo[d]isoxazol-3-amine I90

[0402]

Chemical Structure

[0403] b) 4-Cyano-N-(2,2-dimethoxyethyl)-3-fluorobenzamide I88 To a solution of 4-cyano-3-fluorobenzoyl chloride I87 (1.1 g, 6.06 mmol) and Et 3 N (1.84 g, 18 mmol) in DCM (20 mL) at 0 °C, 2,2-dimethoxyethanamine (955 mg, 9.1 mmol) was added, and the mixture was stirred for 2 hours. The mixture was poured into water and extracted with EtOAc. The organic extract was washed with water and brine, dried over anhydrous Na 2 SO 4 and filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / EtOAc = 1 / 1, v / v) to obtain the title compound (1.2 g, 78%) as a white solid. LCMS-D: R t 1.55 min, m / z 274.9 [M+Na] + .

[0404] c) 3-Amino-N-(2,2-dimethoxyethyl)benzo[d]isoxazole-6-carboxamide I89 To a solution of acetohydroxamic acid (448 mg, 5.95 mmol) in DMF (30 mL) at 0 °C, t-BuOK (889 mg, 7.92 mmol) was added portionwise, and the mixture was stirred for 1 hour. Then, 4-cyano-N-(2,2-dimethoxyethyl)-3-fluorobenzamide I88 (500 mg, 1.98 mmol) was added, and the mixture was heated at 40 °C overnight. The mixture was poured into water and extracted with EtOAc. The organic layer was washed with water and brine, dried over anhydrous Na 2 SO 4It was dried, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / EtOAc = 1 / 1, v / v) to obtain the title compound (380 mg, 72%) as a yellow solid. LCMS-D: R t 0.59 min, m / z 287.9 [M+Na] + .

[0405] d) 6-(Oxazol-2-yl)benzo[d]isoxazol-3-amine I90 3-Amino-N-(2,2-dimethoxyethyl)benzo[d]isoxazole-6-carboxamide I89 (240 mg, 0.9 mmol) and P 2 O 5 (193 mg, 1.36 mmol) in methanesulfonic acid (10 mL) were heated under microwave irradiation at 150 °C for 30 minutes. The mixture was poured into water, made basic with aqueous KOH, and extracted with EtOAc. The organic extract was washed with brine and dried over anhydrous Na 2 SO 4 then filtered and concentrated under reduced pressure. The residue was purified by preparative TLC (DCM / MeOH = 10 / 1, v / v) to obtain the title compound (50 mg, 28%) as a solid. LCMS-D: R t 1.57 min, m / z 201.9 [M+H] + .

[0406] xli) 5-Ethyl-1-methyl-2-oxo-1,2-dihydropyridine-3-sulfonyl chloride I94

[0407]

Chemical Structure

[0408] b) 5-Ethylpyridin-2(1H)-one I92 A solution of 5-ethyl-2-methoxypyridine I91 (1.6 g, 11.66 mmol) in concentrated HCl (30 mL) was heated at 100 °C overnight. The mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (DCM / MeOH = 20 / 1) to afford the title compound (800 mg, 56%) as a white solid, which was used directly in the next step.

[0409] c) 5-Ethyl-1-methylpyridin-2(1H)-one I93 A mixture of 5-ethylpyridin-2(1H)-one I92 (800 mg, 6.5 mmol), K 2 CO 3 (1.8 g, 13 mmol), and iodomethane (1.85 g, 13 mmol) in MeOH (20 mL) was heated at 50 °C overnight under N 2 . The solvent was removed under reduced pressure, and the residue was dissolved in DCM (100 mL), washed with water, brine, dried over anhydrous Na 2 SO 4It was dried, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (DCM / MeOH = 40 / 1) to obtain the title compound (500 mg, 56%) as a colorless oil. LCMS-D: R t 0.68 min; m / z 138.1 [M+H] + .

[0410] d) 5-Ethyl-1-methyl-2-oxo-1,2-dihydropyridine-3-sulfonyl chloride I94 A mixture of chlorosulfonic acid (6 mL) and 5-ethyl-1-methylpyridin-2(1H)-one I93 (0.6 g, 4.37 mmol) was heated at 150 °C for 3 h under N 2 and then cooled to room temperature and poured onto ice (100 g). The mixture was extracted with DCM (50 mL × 3), and the combined organic extracts were washed twice with ice-cold water and dried over anhydrous Na 2 SO 4 and filtered and concentrated under reduced pressure. The residue was purified by column chromatography (DCM / MeOH = 100 / 1 to 20 / 1) to obtain the title compound (200 mg, 12%) as a yellow solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.87 - 7.84 (m, 1H), 7.71 (s, 1H), 3.47 (s, 3H), 2.39 (q, J = 7.6 Hz, 2H), 1.09 (t, J = 7.5 Hz, 3H). LCMS-D: R t 1.58 min; m / z 236.0 [M+H] + .

[0411] xlii) 5-Bromo-2,3-dihydrobenzofuran-7-sulfonyl chloride I95

[0412]

Chemical formula

[0413] xliii) 4,6-Dimethoxy-2,3-dihydro-1H-inden-5-sulfonyl chloride I98

[0414]

Chemical formula

[0415] b) 4,6 - Dimethoxy - 2,3 - dihydro - 1H - indene I97 A mixture of 5,7 - dimethoxy - 2,3 - dihydro - 1H - inden - 1 - one I96 (3.0 g, 15.6 mmol) and triethylsilane (7.3 g, 62.4 mmol) in TFA (20 mL) was stirred at room temperature for 11 h under N 2 The mixture was concentrated under reduced pressure and the residue was purified by column chromatography (petroleum ether / EtOAc = 20 / 1) to afford the title compound (2.0 g, 72%) as a white solid. 1 H NMR (400 MHz, CDCl 3 ) δ 6.42 (s, 1H), 6.29 (d, J = 2.0 Hz, 1H), 3.81 (s, 3H), 3.80 (s, 3H), 2.89 (t, J = 7.5 Hz, 2H), 2.80 (t, J = 7.3 Hz, 2H), 2.13 - 2.02 (m, 2H).

[0416] c) 4,6 - Dimethoxy - 2,3 - dihydro - 1H - indene - 5 - sulfonyl chloride I98 To a solution of 4,6 - dimethoxy - 2,3 - dihydro - 1H - indene I97 (1 g, 5.6 mmol) and TMEDA (0.72 g, 6.17 mmol) in n - hexane (20 mL) at - 70 °C was added dropwise n - BuLi (2.5 M in hexane, 2.5 mL, 6.17 mmol). The mixture was warmed to 0 °C and stirred for 2 h. Then the mixture was recooled to - 65 °C and bubbled with SO 2 gas for 20 min and then slowly warmed to 10 °C. The resulting precipitate was collected by filtration and washed with dry diethyl ether. The solid was suspended in n - hexane (20 mL), cooled to 0 °C, and SO 2 Cl 2 (0.83 g, 6.2 mmol) was added dropwise. The mixture was stirred at 0 °C for 1 h under N 2 and then filtered. The filter cake was dissolved in diethyl ether, washed with water, brine, and anhydrous Na2 SO 4 It was dried with SO, filtered, and concentrated under reduced pressure to obtain the title compound (550 mg, 35%) as a white solid. 1 H NMR (400 MHz, CDCl 3 ) δ 6.72 (s, 1H), 3.95 (s, 3H), 3.94 (s, 3H), 2.96 (q, J = 7.6 Hz, 4H), 2.18 - 2.08 (m, 2H).

[0417] xliv) 2-Methoxy-5-phenoxybenzenesulfonyl chloride I100

[0418]

Chemical formula

[0419] b) 2-Methoxy-5-phenoxybenzenesulfonyl chloride I100 POCl 3 (3 mL) of a mixture of 2-methoxy-5-phenoxybenzenesulfonic acid I99 (250 mg, 0.9 mmol) and PCl 5 (284 mg, 1.3 mmol) was heated under N 2 at 90 °C for 1 hour. Then, the mixture was slowly added to ice-cold water (20 mL) and extracted with DCM (15 mL × 2). The combined organic extracts were washed with brine and anhydrous Na 2 SO4 It was dried, filtered, and concentrated under reduced pressure to obtain the title compound (51 mg, 18%) as a yellow oil. LCMS-D: R t 2.72 min; m / z 295.0 [M-Cl+OCH 3 + , 317.0 [M-Cl+OCH 3 +Na] + .

[0420] xlv) 2,6-Dimethoxy-3-(trifluoromethyl)benzenesulfonyl chloride I102

[0421]

Chemical Structure

[0422] ​b) 2,6-Dimethoxy-3-(trifluoromethyl)benzenesulfonyl chloride I102 N 2 Under nitrogen, a solution of 2,4-dimethoxy-1-(trifluoromethyl)benzene I101 (1.5 g, 7.3 mmol) and TMEDA (0.93 g, 8.0 mmol) in n-hexane (30 mL) at -78 °C was added dropwise with n-BuLi (2.5 M in hexane, 3.2 mL, 8.0 mmol), and the mixture was stirred at 0 °C for 1 hour. Then, SO 2 gas was bubbled through the mixture at -78 °C for 20 minutes, then warmed to 0 °C and stirred for 1 hour. The resulting precipitate was collected by filtration and washed with hexane. The filter cake was suspended in n-hexane (30 mL), cooled to 0 °C, and SO 2 Cl 2 (1.1 g, 8.0 mmol) was added dropwise. The mixture was stirred at 0 °C for 1 hour, the solid was collected by filtration, and washed with cold n-hexane. The filter cake was dissolved in ether and washed with water. The aqueous phase was extracted with ether, the combined organic layers were dried over anhydrous Na 2 SO 4 4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / EtOAc = 5 / 1) to give the title compound (1.5 g, 68%) as a yellow solid. 1 H NMR (400 MHz, CDCl 3 ) δ 7.90 - 7.84 (m, 1H), 6.98 - 6.92 (m, 1H), 4.09 (s, 3H), 4.04 (s, 3H).

[0423] xlvi) 3-Ethyl-2,6-dimethoxybenzenesulfonyl chloride I106

[0424]

Chemical Structure

[0425] b) Ethyl-2,4-dimethoxybenzene I104 To a solution of 2,4-dimethoxy-1-vinylbenzene I103 (2.6 g, 15.8 mmol) in EtOAc (50 mL) was added 10% Pd / C (300 mg), and the mixture was stirred overnight at room temperature under an H 2 2 atmosphere. The catalyst was removed by filtration through Celite and rinsed with EtOAc. The filtrate was concentrated under reduced pressure to afford the title compound (2.0 g, 83%) as a yellow oil. LCMS-D: R t t 2.39 min; m / z 167.1 [M+H] + .

[0426] c) 3-Ethyl-2,6-dimethoxybenzenesulfonic acid I105 Prepared from ethyl-2,4-dimethoxybenzene I104 according to the procedure described for 2,6-dimethoxybenzenesulfonyl chloride I111. The product obtained was found to be mostly 3-ethyl-2,6-dimethoxybenzenesulfonic acid. LCMS-D: R t 2.36 min; m / z 247.0 [M+H] + .

[0427] d) 3-Ethyl-2,6-dimethoxybenzenesulfonyl chloride I106 A mixture of 3-ethyl-2,6-dimethoxybenzenesulfonic acid I105 (300 mg, 1.22 mmol) and thionyl chloride (6 mL) was heated at 95 °C for 3 h and then concentrated under reduced pressure to give the title compound (322 mg, 100%) as a brown oil, which was used directly in the next step.

[0428] xlvii) 7-Methoxyquinoline-8-sulfonyl chloride I107

[0429]

Chemical Structure

[0430] xlviii) 6-Methoxy-2,3-dihydro-1H-inden-5-sulfonyl chloride I108

[0431]

Chem.

[0432] xlix) 3-Methoxy-5,6,7,8-tetrahydronaphthalene-2-sulfonyl chloride I109

[0433]

Chem.

[0434] l) 4-Bromo-2-methoxybenzenesulfonyl chloride I110

[0435]

Chem.

[0436] li) 2,6-Dimethoxybenzenesulfonyl chloride I111

[0437]

Chem.

[0438] lii) 5-Ethyl-2-methoxybenzenesulfonyl chloride I112

[0439]

Chemical formula

[0440] liii) 2,4-Dimethoxy-[1,1'-biphenyl]-3-sulfonyl chloride I114

[0441]

Chemical formula

[0442] b) 2,4-Dimethoxy-[1,1'-biphenyl]-3-sulfonyl chloride I114 N 2 To a solution of 2,4-dimethoxy-1,1'-biphenyl I113 (1.0 g, 4.70 mmol) and TMEDA (601 mg, 5.20 mmol) in n-hexane (40 mL) at 0 °C was added dropwise n-BuLi (2.5 M solution in hexane, 2.1 mL, 5.20 mmol) while maintaining the internal reaction temperature below 5 °C. The mixture was stirred at 0 °C for 20 min and then cooled to -70 °C and bubbled with SO 2 gas for 20 min. The mixture was then slowly warmed to 10 °C and the resulting precipitate was collected by filtration and washed with dry diethyl ether. The solid was suspended in n-hexane (40 mL), cooled to 0 °C and SO 2 Cl 2A solution of (634 mg, 4.7 mmol) was added dropwise. The mixture was then stirred at 0 °C for 1 hour, and the solid was collected by filtration and washed with cold n-hexane. The solid was then partitioned between diethyl ether and water, the layers were separated, and the aqueous layer was further extracted with diethyl ether. The combined organic extracts were dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure to give the title compound (590 mg, 40%) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.48 - 7.35 (m, 4H), 7.34 - 7.21 (m, 2H), 6.87 (m, 1H), 3.76 (s, 3H), 3.29 (s, 3H).

[0443] liv) 3,5-Dimethoxy-[1,1'-biphenyl]-4-sulfonyl chloride I116

[0444]

Chemical Structure

[0445] b) 3,5 - Dimethoxy - [1,1'-biphenyl] - 4 - sulfonyl chloride I116 It was prepared from 3,5 - dimethoxy - 1,1'-biphenyl I115 according to the procedure described for 2,4 - dimethoxy - [1,1'-biphenyl] - 3 - sulfonyl chloride I114. 1 H NMR (400 MHz, CDCl 3 ) δ 7.62 - 7.55 (m, 2H), 7.54 - 7.44 (m, 3H), 6.81 (s, 2H), 4.04 (s, 6H).

[0446] lv) 4 - Methoxy - 6 - ((2,2,2 - trifluoroethoxy)methyl)benzo[d]isoxazol - 3 - amine I118

[0447]

Chemical Structure

[0448] b) 4-Methoxy-6-((2,2,2-trifluoroethoxy)methyl)benzo[d]isoxazol-3-amine I118 A suspension of acetohydroxamic acid (86 mg, 1.14 mmol) and t-BuOK (128 mg, 1.14 mmol) in anhydrous DMF (10 mL) was stirred at room temperature for 1 hour. Then, 2-fluoro-6-methoxy-4-((2,2,2-trifluoroethoxy)methyl)benzonitrile I117 (100 mg, 0.38 mmol) was added, and the mixture was stirred at room temperature overnight. The mixture was diluted with water and extracted with EtOAc. The organic extract was washed with brine and dried over Na 2 SO 4 and filtered, and concentrated under reduced pressure. The reaction was appropriately scaled up using 2-fluoro-6-methoxy-4-((2,2,2-trifluoroethoxy)methyl)benzonitrile I117 (400 mg, 1.52 mmol). The two batches were combined and purified by column chromatography (petroleum ether / EtOAc = 20 / 1 to 5 / 1) to obtain the title product (350 mg, 67%) as a yellow solid. LCMS-C: R t 2.08 min; m / z 277.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 6.96 (s, 1H), 6.68 (s, 1H), 5.94 (s, 2H), 4.74 (s, 2H), 4.13 (q, J = 9.4 Hz, 2H), 3.90 (s, 3H).

[0449] lvi) 6-(Difluoromethoxy)-4-methoxybenzo[d]isoxazol-3-amine I121

[0450]

Chem.

[0451] b) 4-(Difluoromethoxy)-2-fluoro-6-methoxybenzonitrile I120 To a solution of 4-(difluoromethoxy)-2,6-difluorobenzonitrile I119 (2.52 g, 12.3 mmol) in dry THF (30 mL) was added NaOMe (1.32 g, 24.57 mmol) portionwise and the mixture was heated at 40 °C overnight. Water was added and the mixture was extracted with EtOAc (30 mL × 3). The combined organic extracts were washed with brine and dried over Na 2 SO 4 and filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / EtOAc = 10 / 1 to 5 / 1) to give the title compound (663 mg, 25%) as a white solid. LCMS-C: R t 2.11 min; m / z 217.9 [M+H]+ .

[0452] c) 6-(Difluoromethoxy)-4-methoxybenzo[d]isoxazol-3-amine I121 A suspension of acetohydroxamic acid (680 mg, 9.15 mmol) and t-BuOK (1.03 g, 9.15 mmol) in anhydrous DMF (50 mL) was stirred at room temperature for 1 hour. Then, 5-(difluoromethoxy)-1-fluoro-2-isocyano-3-methoxybenzene I120 (663 mg, 3.05 mmol) was added and the mixture was stirred at room temperature overnight. The mixture was diluted with water and extracted with EtOAc (30 mL × 3). The combined organic extracts were washed with brine and dried over Na 2 SO 4 and filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / EtOAc = 10 / 1 to 8 / 1) to give the title compound (186 mg, 26%) as a pale orange solid. LCMS-C: R t 1.14 min; m / z 231.0 [M+H] + .

[0453] lviii) 5-Methyl-6-(pyridin-2-yl)benzo[d]isoxazol-3-amine I124

[0454]

Chemical formula

[0455] b) 2-Fluoro-5-methyl-4-(pyridin-2-yl)benzonitrile I123 N 2 Below, to a solution of 2-fluoro-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile I122 (1.32 g, 5.1 mmol) and 2-bromopyridine (1.69 g, 7.65 mmol) in 1,4-dioxane (50 mL) and water (10 mL), Pd(PPh 3 ) 4 (589 mg, 0.5 mmol) and Na 2 CO 3 (2.16 g, 20.4 mmol) were added and the mixture was heated at 100 °C for 3 hours. Water was added and the mixture was extracted with EtOAc. The combined organic extracts were washed with brine and dried over anhydrous Na 2 SO 4 . It was filtered and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / EtOAc = 8 / 1 to 3 / 1) to obtain the title compound (440 mg, 88%) as a red solid. LCMS-C: R t 1.09 min; m / z 213.0 [M+H] + .

[0456] c) 5-Methyl-6-(pyridin-2-yl)benzo[d]isoxazol-3-amine I124 A suspension of acetohydroxamic acid (255 mg, 3.39 mmol) and t-BuOK (381 mg, 3.39 mmol) in anhydrous DMF (30 mL) was stirred at 0 °C for 1 hour. Then, 2-fluoro-5-methyl-4-(pyridin-2-yl)benzonitrile I123 (240 mg, 1.13 mmol) was added, and the mixture was warmed to room temperature and stirred overnight. Water was added, and the mixture was extracted with EtOAc (50 mL × 3). The combined organic extracts were washed with brine and dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / EtOAc = 8 / 1 to 3 / 1) to afford the title compound (180 mg, 73%) as a white solid. LCMS-C: R t 0.50 min; m / z 226.0 [M+H] + .

[0457] lix) 7-Bromo-5-methylbenzo[d]isoxazol-3-amine I129

[0458]

Chemical formula

[0459] b) 3-Bromo-2-fluoro-5-methylbenzoyl chloride I126 N 2 To a solution of 3-bromo-2-fluoro-5-methylbenzoic acid I125 (12.3 g, 53 mmol) and DMF (4 drops) in DCM (100 mL) at room temperature, oxalyl chloride (13.0 g, 106 mmol) was added dropwise, and the mixture was stirred for 2 hours. The mixture was concentrated under reduced pressure to give the title compound (14.0 g, 100%) as a brown solid, which was used in the next step without further purification.

[0460] c) 3-Bromo-2-fluoro-5-methylbenzamide I127 A solution of 3-bromo-2-fluoro-5-methylbenzoyl chloride I126 (14.0 g, 53 mmol) in DCM (100 mL) was added dropwise to 30% aqueous ammonium hydroxide (100 mL), and the mixture was stirred for 2 hours. The mixture was diluted with EtOAc (200 mL), washed with water (200 mL × 3), brine, and the organic layer was dried over Na 2 SO 4 and filtered, concentrated under reduced pressure to give the title compound (12.0 g, 97%) as a brown solid, which was used in the next step without further purification. LCMS-C: R t 1.01 min; m / z 231.9 [M+H] + .

[0461] d) 3-Bromo-2-fluoro-5-methylbenzonitrile I128 A solution of 3-bromo-2-fluoro-5-methylbenzamide I127 (10.0 g, 43.0 mmol) and thionyl chloride (15.4 g, 129 mmol) in DMF (100 mL) was heated at 100 °C for 3 hours. The mixture was diluted with EtOAc (200 mL), washed with water (400 mL × 5), brine, and the organic layer was dried over Na 2 SO 4It was dried, filtered, and concentrated under reduced pressure to obtain the title compound (5.0 g, 54%) as a brown solid, which was used in the next step without further purification. LCMS-C: R t 2.50 min; m / z 213.9 [M+H] + .

[0462] e) 7-Bromo-5-methylbenzo[d]isoxazol-3-amine I129 A suspension of acetohydroxamic acid (5.27 g, 70.2 mmol) and t-BuOK (7.88 g, 70.2 mmol) in anhydrous DMF (200 mL) was stirred at 0 °C for 1 hour. Then, 3-bromo-2-fluoro-5-methylbenzonitrile I128 (5.0 g, 23.4 mmol) was added, the mixture was warmed to room temperature, and stirred overnight. The mixture was diluted with EtOAc (300 mL), washed with water (600 mL × 4), brine, and the organic layer was dried over Na 2 SO 4 dried, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / EtOAc = 10 / 1) to obtain the title compound (2.8 g, 52%) as a yellow solid. LCMS-C: R t 0.50 min; m / z 226.9 [M+H] + .

[0463] Synthesis of Examples (Examples 1 - 45) (Table A):

[0464]

Chemical Structure

[0465] Method AB LiHMDS (1 M in THF, 445 μL, 0.445 mmol) was added to a solution of 4-chlorobenzo[d]isoxazol-3-amine (50 mg, 0.297 mmol) in THF (3 mL) and stirred at room temperature for 10 minutes. Sulfonyl chloride (0.445 mmol) was added and the reaction was stirred at room temperature for 16 hours. After reducing the volatiles to approximately 1 mL, DCM (3 mL) and water (3 mL) were added and the mixture was stirred for 10 minutes. The mixture was passed through a phase separator, then the organic fraction was loaded onto a 1 g Si-amine cartridge (Biotage), the cartridge was washed with MeOH (6 mL), and then the product was eluted with HCl solution (2 M, 1:1 methanol:1,4-dioxane 6 mL). The HCl wash was then evaporated in vacuo to yield the crude product, which was loaded onto silica gel and purified by silica gel column chromatography (Biotage Isolera, SiO 2 cartridge, petroleum benzine 40 - 60 °C, 0 - 100% EtOAc) to yield the desired product.

[0466] Method AC LiHMDS (1 M in THF, 445 μL, 0.445 mmol) was added to a solution of 4-chlorobenzo[d]isoxazol-3-amine (50 mg, 0.297 mmol) in THF (3 mL), and the mixture was stirred at room temperature for 10 minutes. The sulfonyl chloride (0.445 mmol) was added, and the reaction was stirred at room temperature for 16 hours. After reducing the volatiles to approximately 1 mL, DCM (3 mL) and water (3 mL) were added, and the mixture was stirred for 10 minutes. The mixture was passed through a phase separator, and then the organic fraction was loaded onto a 1 g Si-amine cartridge (Biotage). The cartridge was washed with MeOH (10 mL), and then the product was eluted with methanolic HCl solution (ca. 1.25 M, 10 mL). The HCl wash was then evaporated in vacuo to yield the desired product.

[0467] Method AD A solution of 4-chlorobenzo[d]isoxazol-3-amine (50 mg, 0.298 mmol) and sulfonyl chloride (2 equiv, 0.595 mmol) in pyridine (1.5 mL) was irradiated in a microwave at 100 °C for 2 hours. Upon cooling, the reaction mixture was loaded onto silica gel and purified using silica gel column chromatography (Biotage Isolera, 24 g of SiO 2 cartridge, 0 - 100% EtOAc in petroleum benzine 40 - 60 °C) to yield the desired product.

[0468] Method AE A suspension of sulfonyl chloride (2 equiv, 1.19 mmol) and 4-chlorobenzo[d]isoxazol-3-amine (100 mg, 0.593 mmol) in pyridine (1.5 mL) was irradiated in a microwave at 100 °C for 2 hours. Upon cooling, the mixture was loaded onto silica gel and purified using silica gel column chromatography (Biotage Isolera, 24 g of SiO 2 cartridge, 0 - 100% EtOAc in petroleum benzine 40 - 60 °C, then 0 - 40% MeOH in EtOAc) to yield the desired product.

[0469] Method AF A suspension of sulfonyl chloride (2 equivalents, 1.19 mmol) and 4-chlorobenzo[d]isoxazol-3-amine (100 mg, 0.593 mmol) in pyridine (1 mL) was irradiated in a microwave at 80 °C for 1 hour. Upon cooling, the mixture was loaded onto silica gel and purified using silica gel column chromatography (Biotage Isolera, 24 g of SiO 2 cartridge, petroleum benzine 40 - 60 °C with 0 - 100% EtOAc) to yield the desired product.

[0470] [Table 5-1]

[0471] [Table 5-2]

[0472] [Table 5-3]

[0473] [Table 5-4]

[0474] [Table 5-5]

[0475] [Table 5-6]

[0476] [Table 5-7]

[0477] (Examples 46 - 71) (Table D):

[0478]

Chem.

[0479] Method BB A mixture of benzo[d]isoxazol-3-amine and sulfonyl chloride in pyridine (0.5 mL) was stirred at room temperature for 64 h. The reaction mixture was concentrated, diluted with 5% aqueous HCl solution (1 mL), and sonicated for at least 30 min. The resulting precipitate was collected by filtration, and a portion of the crude material (less than 50 mg) was purified by preparative mass-directed HPLC to obtain the desired product. See Table B for the reaction components and amounts used.

[0480] Method BC A mixture of benzo[d]isoxazol-3-amine and sulfonyl chloride in pyridine (0.5 mL) was stirred at room temperature for 16 h. The reaction mixture was concentrated, diluted with 5% aqueous HCl solution (1 mL), and sonicated for at least 30 min. The resulting precipitate was collected by filtration, and a portion of the crude material (less than 50 mg) was purified by mass-directed preparative HPLC to obtain the desired product. See Table B for the reaction components and amounts used.

[0481]

Table 6-1

[0482]

Table 6-2

[0483]

Table 6-3

[0484] Method CA A mixture of benzod[d]isoxazol-3-amine and sulfonyl chloride in pyridine (1 mL) was stirred at room temperature for 16 h, at which time a second portion of benzenesulfonyl chloride was added and stirring was continued for an additional 64 h. The reaction mixture was concentrated, diluted with 5% aqueous HCl (1 mL), and sonicated for at least 30 min. The resulting precipitate was collected by filtration and purified either by preparative mass-directed HPLC (up to 50 mg of crude material) or by silica gel column chromatography (0-40% EtOAc / petroleum benzine 40-60 °C) to afford the desired product. See Table C for reaction components and amounts used and purification conditions.

[0485]

Table 7

[0486]

Table 8-1

[0487]

Table 8-2

[0488]

Table 8-3

[0489]

Table 8-4

[0490]

Table 8-5

[0491]

Table 8-6

[0492]

Table 8-7

[0493]

Table 8-8

[0494] (Examples 72 - 88) (Table E):

[0495]

Chem.

[0496] Method EB NaH (60% in mineral oil, 61 mg, 1.52 mmol) was added to a solution of 4-methoxybenzo[d]isoxazol-3-amine (50 mg, 0.305 mmol) in DMF (3.0 mL), and the mixture was stirred at room temperature for 10 minutes. Sulfonyl chloride (1 equiv, 0.305 mmol) was added, and the reaction was stirred for 16 hours. The resulting mixture was loaded onto silica gel and purified by column chromatography (0 - 100% petroleum benzine 40 - 60 °C, then 0 - 60% MeOH in EtOAc) to yield the desired product.

[0497] Method EC NaH (60% in mineral oil, 22 mg, 0.914 mmol) was added to a solution of 4-methoxybenzo[d]isoxazol-3-amine (50 mg, 0.305 mmol) in DMF (5 mL), and the mixture was stirred at room temperature for 10 minutes. Sulfonyl chloride (1 equiv, 0.305 mmol) was added, and the reaction was stirred for 16 hours. The resulting mixture was quenched with water (3 mL), stirred at room temperature for 10 minutes, then loaded onto silica gel and purified by column chromatography (0 - 100% petroleum benzine 40 - 60 °C, then 0 - 60% MeOH in EtOAc) to yield the desired product.

[0498] Method ED NaH (60% in mineral oil, 5 or 10 equiv) was added to a solution of 4-methoxybenzo[d]isoxazol-3-amine (100 mg, 0.609 mmol) in THF (5.0 mL), and the mixture was stirred at room temperature for 10 minutes. Sulfonyl chloride (1 equiv, 0.609 mmol) was added, and the reaction was stirred for 16 hours. The resulting mixture was loaded onto silica gel and purified by column chromatography (0 - 100% petroleum benzine 40 - 60 °C, then 0 - 60% MeOH in EtOAc) to yield the desired product.

[0499] Method EF NaH (60% in mineral oil, 122 mg, 3.05 mmol) was added to a solution of 4-methoxybenzo[d]isoxazol-3-amine (100 mg, 0.609 mmol) in THF (5.0 mL) and stirred at room temperature for 10 minutes. Sulfonyl chloride (1 equiv, 0.609 mmol) was added and the reaction was stirred for 16 h. The resulting mixture was loaded onto silica gel and purified by column chromatography (0 - 100% petroleum benzine 40 - 60 °C, then 0 - 60% MeOH in EtOAc), and the isolated solid was sonicated in MeOH (1 mL) and collected by filtration to yield the desired product.

[0500] Method EG NaH (60% in mineral oil, 122 mg, 3.05 mmol) was added to a solution of 4-methoxybenzo[d]isoxazol-3-amine (100 mg, 0.609 mmol) in THF (5.0 mL) and stirred at room temperature for 10 minutes. Sulfonyl chloride (1 equiv, 0.609 mmol) was added and the reaction was stirred at room temperature for 16 h. After reducing the volatiles to approximately 1 mL, DCM (3 mL) and water (3 mL) were carefully added and stirred for 10 minutes. The mixture was passed through a phase separator, then the organic fraction was loaded onto a 1 g Si-amine cartridge (Biotage), the cartridge was washed with MeOH (6 mL), and then the product was eluted with HCl solution (2 M, 1:1 methanol:1,4-dioxane, 6 mL). The HCl wash was then evaporated in vacuo to yield the desired product.

[0501] Method EH A suspension of 4-methoxybenzo[d]isoxazol-3-amine (48 mg, 0.29 mmol) and NaH (60% in mineral oil, 0.117 mg, 2.93 mmol) in DMF (10 mL) was stirred at room temperature for 10 minutes and then cooled to -78 °C. To this cooled mixture was added sulfonyl chloride (1.5 equiv, 0.439 mmol), and the mixture was stirred at -78 °C for 1 hour and then warmed to room temperature and stirred for 16 hours. The reaction mixture was loaded onto silica gel and purified by column chromatography (Biotage Isolera, 24 g of SiO 2 cartridge, 0 - 100% EtOAc in petroleum benzine 40 - 60 °C, then 0 - 40% MeOH in EtOAc) to give a solid, which was suspended in diethyl ether (25 mL) and sonicated for 5 minutes. The solid was collected by filtration and air-dried to give the desired product.

[0502] Method EI A mixture of 4-methoxybenzo[d]isoxazol-3-amine (0.035 g, 0.21 mmol) and sulfonyl chloride (1.05 equiv, 0.22 mmol) in pyridine (1 mL) was stirred at room temperature for 16 hours. The reaction was concentrated, diluted with 5% aqueous HCl (1 mL), and sonicated for at least 30 minutes. Purification by extraction with DCM (2 × 1 mL) and silica gel column chromatography (0 - 100% EtOAc in petroleum benzine 40 - 60 °C) gave the desired product.

[0503] Method EJ A solution of 4-methoxybenzo[d]isoxazol-3-amine (1 equiv) in THF (3 mL) was treated with LiHMDS (1 M in THF, 1.5 equiv). After stirring for 10 minutes, the sulfonyl chloride (1.5 equiv) was added and the reaction was left open to the atmosphere and stirred for 17 h. The THF was removed in vacuo, then DCM (3 mL) and water (3 mL) were added and the mixture was stirred for 10 minutes. After separation of the layers, the organic fraction was loaded onto a 1 g Si-amine cartridge (Biotage). The cartridge was washed with MeOH (6 mL) and then eluted with 1.25 M HCl in MeOH (6 mL). The HCl washings were then evaporated in vacuo to afford the desired product.

[0504] [Table 9-1]

[0505] [Table 9-2]

[0506] [Table 9-3]

[0507] [Table 9-4]

[0508] [Table 9-5]

[0509] (Examples 89 - 147) (Table F) Method FA

[0510] [Chemical Formula] N 2To a solution of the amine (0.5 mmol, 1.0 equiv) in anhydrous THF (10 mL) at -78 °C was added dropwise LiHMDS (1 M solution in THF, 3 equiv), and the mixture was stirred at -78 °C for 30 minutes. Then, a solution of the sulfonyl chloride (1.5 equiv) in anhydrous THF (2.0 mL) was added dropwise, the mixture was warmed to room temperature, and stirred overnight. Water was added and the mixture was extracted with EtOAc. The combined organic extracts were washed with brine and dried over anhydrous Na 2 SO 4 and filtered, and concentrated under reduced pressure. The residue was purified by column chromatography or preparative TLC to give the title compound. Variations of the above conditions are noted in Table F.

[0511] Method FB

[0512]

Chemical formula

[0513] Method FC

[0514]

Chemical formula

[0515] Method FD

[0516]

Chemical formula

[0517]

Table 10-1

[0518]

Table 10-2

[0519]

Table 10-3

[0520]

Table 10-4

[0521]

Table 10-5

[0522]

Table 10-6

[0523]

Table 10-7

[0524]

Table 10-8

[0525]

Table 10-9

[0526]

Table 10-10

[0527]

Table 10-11

[0528]

Table 10-12

[0529]

Table 10-13

[0530]

Table 10-14

[0531]

Table 10-15

[0532]

Table 10-16

[0533]

Table 10-17

[0534]

Table 10-18

[0535]

Table 10-19

[0536]

Table 10-20

[0537]

Table 10-21

[0538]

Table 10-22

[0539]

Table 10-23

[0540]

Table 10-24

[0541]

Table 10-25

[0542]

Table 10-26

[0543]

Table 10-27

[0544]

Table 10-28

[0545]

Table 10-29

[0546]

Table 10-30

[0547]

Table 10-31

[0548] (Example 148) N-(Benzo[d]isoxazol-3-yl)-2,4-dimethoxybenzenesulfonamide 148

[0549] [Chemical] A solution of 2,4-dimethoxybenzenesulfonyl chloride (0.18 g, 0.75 mmol) and benzo[d]isoxazol-3-amine (0.10 g, 0.75 mmol) in pyridine (1 mL) was irradiated in a microwave at 110 °C for 2 hours. The resulting mixture was loaded onto silica gel, and the product was purified twice by column chromatography (4 g of SiO 2 cartridge, 0 - 45% EtOAc in petroleum benzine 40 - 60 °C, then 4 g of SiO 2 cartridge, 0 - 35% EtOAc in petroleum benzine 40 - 60 °C) to yield two batches (78 mg and 5 mg) of the title compound (total mass 83 mg, 33% yield) as a white solid. 1 H NMR (400 MHz, CDCl 3 ) δ 8.11 (d, J = 8.05 Hz, 1H), 7.79 (s, 1H), 7.70 (d, J = 8.81 Hz, 1H), 7.57 - 7.50 (m, 1H), 7.47 - 7.40 (m, 1H), 7.37 - 7.29 (m, 1H), 6.50 (d, J = 2.27 Hz, 1H), 6.42 (dd, J = 2.25, 8.81 Hz, 1H), 3.98 (s, 3H), 3.81 (s, 3H). LCMS - B: rt 3.20 min, m / z = 356.8 [M+Na] + , 334.8 [M+H] + .

[0550] (Example 149) N-(Benzo[d]isoxazol-3-yl)-2,6-dimethoxybenzenesulfonamide 149

[0551] [Chemical] A solution of 2,6-dimethoxybenzene-1-sulfonyl chloride I111 (0.088 g, 0.37 mmol) and benzo[d]isoxazol-3-amine (0.050 g, 0.37 mmol) in pyridine (1 mL) was irradiated in a microwave at 110 °C for 2 h and then at 120 °C for 2 h. The reaction mixture was loaded onto silica and purified by column chromatography (12 g of SiO 2 cartridge, 0 - 35% EtOAc in petroleum benzine 40 - 60 °C) to afford the title compound (3.9 mg, 3.1% yield) as a white solid. 1 H NMR (400 MHz, CDCl 3 ) δ 8.30 (s, 1H), 8.17 (dt, J = 1.04, 8.15 Hz, 1H), 7.55 - 7.47 (m, 1H), 7.47 - 7.34 (m, 2H), 7.34 - 7.28 (m, 1H), 6.60 (d, J = 8.52 Hz, 2H), 3.91 (s, 6H). LCMS-B: rt 3.13 min, m / z = 334.8 [M+H] + .

[0552] (Example 150) N-(5-Chlorobenzo[d]isoxazol-3-yl)-5-ethyl-2-methoxybenzenesulfonamide 150

[0553] [Chemical formula] a) 5-Chlorobenzo[d]isoxazol-3-amine A1 Potassium tert-butoxide (793 mg, 7.07 mmol) was added to a suspension of acetohydroxamic acid (531 mg, 7.07 mmol) in DMF (10 mL), and the mixture was stirred at room temperature for 30 minutes. 5-Chloro-2-fluorobenzonitrile (1.00 g, 6.43 mmol) was added, and the reaction was heated to 50 °C for 1 hour. Upon cooling, the reaction mixture was diluted with a saturated aqueous solution of NaCl (15 mL), the aqueous layer was extracted with EtOAc (3 × 100 mL), the organics were combined, dried (Na 2 SO 4 ), filtered, and the volatiles were removed in vacuo. The residue was loaded onto silica gel, and the product was purified by column chromatography (Biotage Isolera, 40 g of SiO 2 cartridge, 0 - 40% EtOAc in petroleum benzine 40 - 60 °C) to afford the title compound as a white solid (507 mg, 47%). 1 1H NMR (400 MHz, DMSO-d 6 ) δ = 7.94 (dd, J = 2.1, 0.6, 1H), 7.59 - 7.48 (m, 1H), 6.51 (s, 1H).

[0554] b) N-(5-Chlorobenzo[d]isoxazol-3-yl)-5-ethyl-2-methoxybenzenesulfonamide 150 A suspension of 5-ethyl-2-methoxybenzene-1-sulfonyl chloride (150 mg, 0.639 mmol) and 5-chlorobenzo[d]isoxazol-3-amine A1 (108 mg, 0.639 mmol) in pyridine (1.5 mL) was irradiated in a microwave at 110 °C for 2 hours. 10 M aqueous solution of KOH (1 mL) was added, and the resulting mixture was stirred at room temperature for 4 hours. The reaction mixture was loaded onto silica gel, and the product was purified by column chromatography (0 - 100% EtOAc in petroleum benzine 40 - 60 °C) to afford the title compound as a white solid (53 mg, 23%). 1 1H NMR (400 MHz, DMSO-d 6) δ = 8.11 (t, J = 1.4, 1H), 7.71 (d, J = 2.3, 1H), 7.68 (d, J = 1.4, 2H), 7.48 (dd, J = 8.5, 2.3, 1H), 7.10 (d, J = 8.6, 1H), 3.72 (s, 3H), 2.62 (q, J = 7.6, 2H), 1.16 (t, J = 7.6, 3H). LCMS-A: rt 6.637 min; m / z 367.0 [M+H] + .

[0555] (Example 151) N-(4-Chlorobenzo[d]isoxazol-3-yl)benzenesulfonamide 151

[0556] [Chemical formula] a) N-(4-Chlorobenzo[d]isoxazol-3-yl)-N-(phenylsulfonyl)benzenesulfonamide A2 A solution of 4-chlorobenzo[d]isoxazol-3-amine (50 mg, 0.298 mmol) and benzenesulfonyl chloride (2 equiv, 0.595 mmol) in pyridine (1.5 mL) was irradiated in a microwave at 100 °C for 2 h. Upon cooling, the reaction mixture was loaded onto silica gel and purified using silica gel column chromatography (Biotage Isolera, 24 g of SiO 2 cartridge, 0 - 100% EtOAc in petroleum benzine 40 - 60 °C) to afford the title compound. 1 H NMR (400 MHz, DMSO-d 6 ) δ = 7.97 (d, J = 8.6, 1H), 7.90 - 7.77 (m, 6H), 7.71 - 7.64 (m, 7H), 7.57 (d, J = 7.7, 1H).

[0557] b) N-(4-Chlorobenzo[d]isoxazol-3-yl)benzenesulfonamide 151 A suspension of N-(4-chlorobenzo[d]isoxazol-3-yl)-N-(phenylsulfonyl)benzenesulfonamide A2 (50 mg, 0.11 mmol) in THF (10 mL) and 10 M aqueous KOH (1 mL) was stirred at room temperature for 16 h. The reaction mixture was diluted with water (25 mL), and the aqueous layer was extracted with EtOAc (3 × 50 mL). The combined organics were washed with brine (25 mL), dried (Na 2 SO 4 ), filtered, and concentrated under reduced pressure. The resulting gum was dissolved in the minimum amount of acetone, then petroleum benzine 40 - 60 °C (50 mL) was added. The precipitate was filtered off and air-dried to give the title compound as a tan solid (10 mg, 29%). 1 H NMR (400 MHz, DMSO-d 6 ) δ = 7.89 - 7.80 (m, 2H), 7.41 - 7.30 (m, 4H), 7.26 (dd, J = 8.3, 0.8, 1H), 7.10 (dd, J = 7.5, 0.8, 1H). LCMS-A: rt 6.334 min, m / z 307.0 [M-H] - .

[0558] (Example 152) 5-Ethyl-N-(7-fluorobenzo[d]isoxazol-3-yl)-2-methoxybenzenesulfonamide 152

[0559] [Chemical formula] a) 7-Fluorobenzo[d]isoxazol-3-amine A3 Potassium tert-butoxide (887 mg, 7.91 mmol) was added to a suspension of acetohydroxamic acid (594 mg, 7.91 mmol) in DMF (10 mL), and the reaction mixture was stirred at room temperature for 30 minutes. 2,3-Difluorobenzonitrile (1.00 g, 7.19 mmol) was added, and the reaction mixture was heated to 50 °C for 1 hour. Upon cooling, the reaction mixture was diluted with a saturated aqueous solution of NaCl (15 mL), the aqueous layer was extracted with EtOAc (3 × 100 mL), the organics were combined, dried (Na 2 SO 4 ), filtered, and the volatiles were removed in vacuo. The resulting gum was loaded onto silica gel and purified by column chromatography (Biotage Isolera, 24 g SiO 2 cartridge, 0 - 100% EtOAc in petroleum benzine 40 - 60 °C) to afford the title compound as a white solid (303 mg, 27%). 1 H NMR (400 MHz, CDCl 3 ) δ = 7.33 (dd, J = 7.6, 1.3, 1H), 7.30 - 7.26 (m, 1H), 7.26 - 7.19 (m, 1H), 4.45 (s, 2H). LCMS - B: rt 3.371 min, m / z 153.2 [M + H] + .

[0560] b) 5 - Ethyl - N-(7 - fluorobenzo[d]isoxazol - 3 - yl)-2 - methoxybenzenesulfonamide 152 A solution of 7 - fluorobenzo[d]isoxazol - 3 - amine A3 (100 mg, 0.657 mmol) and 2 - methoxy - 5 - ethylsulfonyl chloride I112 (154 mg, 0.657 mmol) in pyridine (2 mL) was irradiated in a microwave at 100 °C for 2 hours. Upon cooling, the reaction mixture was loaded onto silica gel and purified by column chromatography (Biotage Isolera, 24 g SiO 2 cartridge, 0 - 100% EtOAc in petroleum benzine 40 - 60 °C) to afford the title compound as a white solid (127 mg, 55%). 11H NMR (400 MHz, DMSO-d 6 ) δ = 7.91 (dd, J=8.1, 0.8, 1H), 7.73 (d, J=2.3, 1H), 7.57 (dd, J=11.9, 8.0, 1H), 7.48 (dd, J=8.5, 2.3, 1H), 7.38 (td, J=8.0, 4.1, 1H), 7.10 (d, J=8.6, 1H), 3.73 (s, 3H), 2.63 (q, J=7.6, 2H), 1.16 (t, J=7.6, 3H). LCMS-A: rt 6.429 min, m / z 351.1 [M+H] + .

[0561] (Example 153) N-(4-Chloro-5-methylbenzo[d]isoxazol-3-yl)-5-ethyl-2-methoxybenzenesulfonamide 153

[0562] [Chemical formula] a) 4-Chloro-5-methylbenzo[d]isoxazol-3-amine A4 Potassium tert-butoxide (728 mg, 6.49 mmol) was added to a suspension of acetohydroxamic acid (487 mg, 6.49 mmol) in DMF (10 mL), and the mixture was stirred at room temperature for 30 minutes. 2-Chloro-6-fluoro-3-methylbenzonitrile (1.00 g, 5.90 mmol) was added, and the reaction was heated to 50 °C for 1 hour. Upon cooling, the reaction mixture was diluted with a saturated aqueous solution of NaCl (15 mL), the aqueous layer was extracted with EtOAc (3 × 100 mL), the organics were combined, dried (Na 2 SO 4 )), filtered, and the volatiles were removed in vacuo. The resulting solid was sonicated in acetone (10 mL), then petroleum benzine 40 - 60 °C (50 mL) was added, and the precipitate was collected by filtration and air-dried to yield the product as a white solid (524 mg, 49%). 11H NMR (400 MHz, DMSO-d 6 ) δ = 7.51 (d, J=8.5, 1H), 7.38 (d, J=8.5, 1H), 6.15 (s, 2H), 2.38 (s, 3H). LCMS-B: rt 3.562 min, m / z 183.1 [M+H] + .

[0563] b) N-(4-Chloro-5-methylbenzo[d]isoxazol-3-yl)-5-ethyl-2-methoxybenzenesulfonamide 153 A solution of 4-chloro-5-methylbenzo[d]isoxazol-3-amine A4 (100 mg, 0.548 mmol) and 2-methoxy-5-ethylsulfonyl chloride I112 (129 mg, 0.548 mmol) in pyridine (2 mL) was irradiated in a microwave at 100 °C for 2 h. Upon cooling, the reaction mixture was added to water, the precipitate was removed by filtration, the filtrate was loaded onto silica gel, and purified by column chromatography (Biotage Isolera, 24 g of SiO 2 cartridge, 0 - 100% EtOAc in petroleum benzine 40 - 60 °C) to give the title compound as a white solid (33 mg, 16%). 1 1H NMR (400 MHz, DMSO-d 6 ) δ = 10.48 (s, 1H), 7.69 - 7.57 (m, 3H), 7.48 (dd, J=8.5, 2.3, 1H), 7.15 (d, J=8.5, 1H), 3.68 (s, 3H), 2.60 (q, J=7.5, 2H), 2.42 (s, 3H), 1.15 (t, J=7.6, 3H). LCMS-A: rt 6.665 min, m / z 381.1 [M+H] + .

[0564] (Example 154) N-(4-Chlorobenzo[d]isoxazol-3-yl)-5-ethyl-2-methoxybenzenesulfonamide 154

[0565] [Chemical formula] A mixture of 5-ethyl-2-methoxybenzenesulfonyl chloride I112 (0.414 g, 1.77 mmol) and 4-chlorobenzo[d]isoxazol-3-amine (0.225 g, 1.34 mmol) in pyridine (2.0 mL) was stirred at 30 °C for 40 h under a nitrogen atmosphere. The reaction mixture was concentrated and then sonicated with aqueous HCl (5%) for 2 h, and the resulting precipitate was collected. The precipitate was purified using silica gel column chromatography (0 - 100% ethyl acetate / petroleum benzine 40 - 60 °C) to give the title compound as two fractions (A and B) with a combined yield of 0.060 g and a 12% yield. Fraction A: Yield 0.038 g. 1 H NMR (400 MHz, acetone-d 6 ) δ 8.88 (br s, 1H), 7.75 (d, J = 2.3 Hz, 1H), 7.66 (dd, J = 8.5, 7.6 Hz, 1H), 7.57 (dd, J = 8.5, 0.6 Hz, 1H), 7.49 (dd, J = 8.5, 2.3 Hz, 1H), 7.42 (dd, J = 7.6, 0.6 Hz, 1H), 7.14 (d, J = 8.5 Hz, 1H), 3.91 (s, 3H), 2.66 (q, J = 7.6 Hz, 2H), 1.21 (t, J = 7.6 Hz, 3H). LCMS-B: rt 3.766 min; m / z 367.1 / 369.1 [M+H] + . Fraction B: Yield 0.021 g. 1 H NMR (400 MHz, acetone-d 6 ) δ 8.88 (br s, 1H), 7.75 (d, J = 2.3 Hz, 1H), 7.65 (dd, J = 8.5, 7.6 Hz, 1H), 7.59 - 7.55 (m, 1H), 7.49 (dd, J = 8.5, 2.3 Hz, 1H), 7.44 - 7.40 (m, 1H), 7.14 (d, J = 8.5 Hz, 1H), 3.90 (s, 3H), 2.66 (q, J = 7.6 Hz, 2H), 1.21 (t, J = 7.6 Hz, 3H). LCMS-B: rt 3.755 min; m / z 367.1 / 369.1 [M+H] +

[0566] (Example 155) N-(4-Chlorobenzo[d]isoxazol-3-yl)-2-methoxybenzenesulfonamide 155

[0567] [Chemical Structure] A mixture of 4-chlorobenzo[d]isoxazol-3-amine (0.034 g, 0.200 mmol) and 2-methoxybenzenesulfonyl chloride (0.092 g, 0.450 mmol) in pyridine (1.0 mL) and triethylamine (0.1 mL) was stirred at room temperature for 16 h. The reaction mixture was concentrated, diluted with 5% aqueous HCl (1 mL), and sonicated for at least 30 min. The resulting precipitate was collected by filtration and purified using preparative mass-directed HPLC to give the title compound. 1 H NMR (400 MHz, acetone-d 6 ) δ 7.94 - 7.91 (dd, J = 7.8, 1.7 Hz, 1H), 7.69 - 7.63 (m, 2H), 7.60 - 7.57 (dd, J = 8.5, 0.7 Hz, 1H), 7.44 - 7.42 (dd, J = 7.6, 0.7 Hz, 1H), 7.25 - 7.22 (m, 1H), 7.16 - 7.11 (m, 1H), 3.94 - 3.94 (s, 3H). HPLC-MS: rt 6.02 min; m / z 339.16 / 341.18 [M+H] + .

[0568] (Example 156) N-(4-Fluorobenzo[d]isoxazol-3-yl)-2-methoxybenzenesulfonamide 156

[0569] [Chemical Structure] A mixture of 4-fluorobenzo[d]isoxazol-3-amine (0.032 g, 0.21 mmol) and 2-methoxybenzenesulfonyl chloride (0.109 g, 0.529 mmol) in pyridine (1.0 mL) and triethylamine (0.1 mL) was stirred at room temperature for 16 h. The reaction mixture was concentrated, diluted with 5% aqueous HCl (1 mL), and sonicated for at least 30 min. The resulting precipitate was collected by filtration and purified using preparative mass-directed HPLC to give the title compound. 1 H NMR (400 MHz, acetone-d 6 ) δ 9.73 - 9.45 (br s, 1H), 7.92 - 7.88 (dd, J = 7.9, 1.7 Hz, 1H), 7.70 - 7.61 (m, 2H), 7.44 - 7.40 (d, J = 8.5 Hz, 1H), 7.25 - 7.21 (d, J = 8.3 Hz, 1H), 7.13 - 7.07 (m, 2H), 3.95 - 3.91 (s, 3H). HPLC-MS: rt 5.72 min; m / z 323.16 [M+H] + .

[0570] (Example 157) N-(6-Bromobenzo[d]isoxazol-3-yl)-2-methoxybenzenesulfonamide 157

[0571] [Chemical formula] A mixture of 6-bromobenzo[d]isoxazol-3-amine I75 (0.039 g, 0.180 mmol) and 2-methoxybenzenesulfonyl chloride (0.101 g, 0.490 mmol) in pyridine (1.0 mL) and triethylamine (0.1 mL) was stirred at room temperature for 16 h. The reaction mixture was concentrated, diluted with 5% aqueous HCl (1 mL), and sonicated for at least 30 min. The resulting precipitate was collected by filtration and purified using preparative mass-directed HPLC to give the title compound. 1 H NMR (400 MHz, acetone-d 6 ) δ 8.06 - 8.02 (dd, J = 8.6, 0.5 Hz, 1H), 7.90 - 7.87 (dd, J = 7.9, 1.7 Hz, 1H), 7.85 - 7.83 (dd, J = 1.6, 0.5 Hz, 1H), 7.64 - 7.59 (ddd, J = 8.4, 7.4, 1.8 Hz, 1H), 7.58 - 7.54 (dd, J = 8.6, 1.6 Hz, 1H), 7.21 - 7.18 (dd, J = 8.4, 0.8 Hz, 1H), 7.10 - 7.05 (m, 1H), 3.88 - 3.85 (s, 3H). HPLC-MS: rt 6.32 min; m / z 383.1 / 385.2 [M+H] + .

[0572] (Example 158) N-(6-Chlorobenzo[d]isoxazol-3-yl)-2-methoxybenzenesulfonamide 158

[0573] [Chemical formula] A mixture of 6-chlorobenzo[d]isoxazol-3-amine (0.033 g, 0.200 mmol) and 2-methoxybenzenesulfonyl chloride (0.095 g, 0.460 mmol) was stirred in pyridine (1.0 mL) and triethylamine (0.1 mL) at room temperature for 16 h. The reaction mixture was concentrated, diluted with 5% aqueous HCl (1 mL), and sonicated for at least 30 min. The resulting precipitate was collected by filtration and purified using mass-directed preparative HPLC to afford the title compound. 1 H NMR (400 MHz, acetone-d 6 ) δ 8.12 - 8.07 (dd, J = 8.6, 0.5 Hz, 1H), 7.91 - 7.87 (dd, J = 7.9, 1.7 Hz, 1H), 7.68 - 7.65 (dd, J = 1.7, 0.5 Hz, 1H), 7.64 - 7.58 (ddd, J = 8.4, 7.4, 1.8 Hz, 1H), 7.44 - 7.39 (dd, J = 8.6, 1.7 Hz, 1H), 7.21 - 7.17 (m, 1H), 7.10 - 7.05 (m, 1H), 3.88 - 3.86 (s, 3H). HPLC-MS: rt 6.26 min; m / z 339.16 / 341.18 [M+H]+.

[0574] (Example 159) N-(4-Chlorobenzo[d]isoxazol-3-yl)isoquinoline-8-sulfonamide 159

[0575]

Chemical Structure

[0576] (Example 160) N-(7-Iodo-4-methoxy-6-(methoxymethyl)benzo[d]isoxazol-3-yl)-2,6-dimethoxybenzenesulfonamide 160

[0577]

Chem.

[0578] b) N-(7-Iodo-4-methoxy-6-(methoxymethyl)benzo[d]isoxazol-3-yl)-2,6-dimethoxybenzenesulfonamide 160 A solution of 7-iodo-4-methoxy-6-(methoxymethyl)benzo[d]isoxazol-3-amine A5 (0.024 g, 0.099 mmol) and 2,6-dimethoxybenzenesulfonyl chloride I111 (0.023 g, 0.099 mmol) in pyridine (0.5 mL) was irradiated in a microwave at 110 °C for 2 h. The reaction mixture was cooled to room temperature and wet-loaded onto a silica cartridge. The residue was purified by column chromatography (12 g of SiO 2 cartridge, 0 - 70% EtOAc in petroleum benzine 40 - 60 °C) to give the title compound (0.032 g, 53% yield) as a white solid. 1 H NMR (400 MHz, CDCl 3 ) δ 7.38 (t, J = 8.5 Hz, 1H), 6.86 (s, 1H), 6.58 (d, J = 8.5 Hz, 2H), 4.52 (s, 2H), 4.04 (s, 3H), 3.88 (s, 6H), 3.51 (s, 3H). LCMS-A: rt 5.86 min, m / z 534.6 [M+H] + .

[0579] (Example 161) N-(7-Chloro-4-methoxy-6-(methoxymethyl)benzo[d]isoxazol-3-yl)-2,6-dimethoxybenzenesulfonamide 161

[0580] [Chemical formula] a) 7-Chloro-4-methoxy-6-(methoxymethyl)benzo[d]isoxazol-3-amine A6 4-Methoxy-6-(methoxymethyl)benzo[d]isoxazol-3-amine I9 (0.150 g, 0.720 mmol) was dissolved in N,N-dimethylformamide (2 mL), and then N-chlorosuccinimide (96 mg, 0.72 mmol) was added. Upon completion of the addition, the reaction mixture was heated at 50 °C for 2 h. At the end of this period, the reaction mixture was poured onto ice and then diluted with EtOAc (15 mL). The resulting mixture was washed with H 2 O (3 × 8 mL) and brine (8 mL), dried over Na 2 SO 4 , filtered. The volatiles were removed under reduced pressure and the residue was purified by column chromatography (12 g SiO 2 cartridge, 0 - 40% EtOAc in petroleum benzine 40 - 60 °C) to afford the title compound (0.0240 g, 14% yield) as a white solid. 1 H NMR (400 MHz, CDCl 3 ) δ 6.77 (s, 1H), 4.63 (d, J = 0.6 Hz, 2H), 3.97 (s, 3H), 3.49 (s, 3H).

[0581] b) N-(7-Chloro-4-methoxy-6-(methoxymethyl)benzo[d]isoxazol-3-yl)-2,6-dimethoxybenzenesulfonamide 161 A solution of 7-chloro-4-methoxy-6-(methoxymethyl)benzo[d]isoxazol-3-amine A6 (0.024 g, 0.099 mmol) and 2,6-dimethoxybenzenesulfonyl chloride I111 (0.023 g, 0.099 mmol) in pyridine (0.5 mL) was irradiated in a microwave at 110 °C for 2 h. The reaction mixture was cooled to room temperature and wet loaded onto a silica cartridge. The residue was purified by column chromatography (12 g SiO 2 cartridge, 0 - 100% EtOAc in petroleum benzine 40 - 60 °C) to afford the title compound (0.0094 g, 21% yield) as a white solid. 1 H NMR (400 MHz, CDCl 3) δ 8.20 (s, 1H), 7.39 (t, J = 8.5 Hz, 1H), 6.85 (s, 1H), 6.59 (d, J = 8.5 Hz, 2H), 4.61 (d, J = 0.6 Hz, 2H), 4.04 (s, 3H), 3.88 (s, 6H), 3.49 (s, 3H). LCMS-F: rt 6.39 min, m / z 442.8 [M+H] + .

[0582] (Example 162) 5-Methoxy-N-(4-methoxy-6-(methoxymethyl)benzo[d]isoxazol-3-yl)quinoline-8-sulfonamide 162

[0583] [Chemical formula] A solution of 4-methoxy-6-(methoxymethyl)benzo[d]isoxazol-3-amine I9 (0.0500 g, 0.240 mmol) and 5-methoxyquinoline-8-sulfonyl chloride (0.0619 g, 0.240 mmol) in pyridine (0.500 mL) was irradiated in a microwave at 110 °C for 2 hours. The reaction was cooled to room temperature and added to DCM (10 mL). The organic layer was washed with 0.5 M HCl (10 mL), and the layers were separated by a phase separation cartridge. The collected organic layer was dried in vacuo, and the residue was purified by column chromatography (12 g of SiO 2 cartridge, 0 - 80% EtOAc in petroleum benzine 40 - 60 °C) to give the title compound (0.0110 g, 11% yield) as an off-white solid. 1 H NMR (400 MHz, CDCl 3 ) δ 8.98 (dd, J = 4.3, 1.8 Hz, 1H), 8.64 - 8.53 (m, 2H), 7.45 (dd, J = 8.5, 4.3 Hz, 1H), 6.91 (d, J = 8.4 Hz, 1H), 6.87 (d, J = 0.9 Hz, 1H), 6.54 (s, 1H), 4.44 (s, 2H), 4.05 (s, 3H), 4.03 (s, 3H), 3.36 (s, 3H). LCMS-B: rt 3.49 min, m / z = 429.8 [M+H] + .

[0584] (Example 163) 2-Hydroxy-6-methoxy-N-(4-methoxy-6-(methoxymethyl)benzo[d]isoxazol-3-yl)benzenesulfonamide 163

[0585] [Chemical formula] A solution of 4-methoxy-6-(methoxymethyl)benzo[d]isoxazol-3-amine I9 (0.0440 g, 0.211 mmol) and 2,6-dimethoxybenzenesulfonyl chloride I111 (0.0500 g, 0.211 mmol) in pyridine (0.500 mL) was irradiated in a microwave at 120 °C for 2 hours and then at 120 °C for 1 hour. The reaction was cooled to room temperature and added to DCM (10 mL). The organic matter was washed with 1M HCl (2 × 10 mL) and then dried over MgSO 4 . The crude material was purified twice by silica gel chromatography (24 g of SiO 2 cartridge, 0 - 85% EtOAc in petroleum benzene 40 - 60 °C, then 12 g of SiO 2 cartridge, 0 - 75% EtOAc in petroleum benzene 40 - 60 °C) to obtain the title compound (1.5 mg). 1 H NMR (400 MHz, CDCl 3 ) δ 9.62 (s, 1H), 8.14 (s, 1H), 7.33 (t, J = 8.4 Hz, 1H), 6.99 (q, J = 0.9 Hz, 1H), 6.70 - 6.61 (m, 2H), 6.37 (dd, J = 8.3, 1.0 Hz, 1H), 4.51 (s, 1H), 4.03 (s, 3H), 3.87 (s, 3H), 3.42 (s, 3H). LCMS-A: rt 3.54 min, m / z 394.8 [M+H] +

[0586] (Example 164) 6-Methoxy-N-(6-(methoxymethyl)-5-methylbenzo[d]isoxazol-3-yl)pyridine-3-sulfonamide 164

[0587] [Chemical formula] A solution of 6-methoxypyridine-3-sulfonyl chloride (0.0540 g, 0.260 mmol) and 6-(methoxymethyl)-5-methylbenzo[d]isoxazol-3-amine I4 (0.050 g, 0.26 mmol) in pyridine (0.500 mL) was irradiated in a microwave at 120 °C for 2 hours. The reaction was cooled to room temperature and then dissolved in DCM and washed with 1M HCl (×2). The organic layer was dried in vacuo and then wet loaded onto silica gel, and the product was purified by column chromatography (24 g of SiO 2 cartridge, 0 - 80% EtOAc in petroleum benzine 40 - 60 °C) to give the title compound (15.6 mg, 17% yield) as a colorless oil. 1 H NMR (400 MHz, CDCl 3 ) δ 8.63 (dd, J = 0.71, 2.62 Hz, 1H), 7.99 - 7.89 (m, 2H), 7.72 (s, 1H), 7.55 (s, 1H), 6.75 (dd, J = 0.71, 8.94 Hz, 1H), 4.54 (s, 2H), 3.95 (s, 3H), 3.50 (s, 3H), 2.39 (s, 3H). LCMS-F: rt 6.39 min, m / z 348.1 [M+H] + .

[0588] (Example 165) N-(6-(Methoxymethyl)-5-methylbenzo[d]isoxazol-3-yl)pyridine-3-sulfonamide 165

[0589] [Chemical Structure Diagram] A solution of pyridine-3-sulfonyl chloride (0.0462 g, 0.260 mmol) and 6-(methoxymethyl)-5-methylbenzo[d]isoxazol-3-amine I4 (0.050 g, 0.26 mmol) in pyridine (0.500 mL) was irradiated in a microwave at 120 °C for 2 hours. The reaction mixture was cooled to room temperature and then wet-loaded onto silica gel, and the product was purified by column chromatography (24 g of SiO 2 cartridge, 0 - 80% EtOAc in petroleum benzine 40 - 60 °C) to give the title compound (0.0220 g, 25% yield) as a yellow solid. 1 H NMR (400 MHz, CDCl 3 ) δ 9.09 (s, 1H), 8.83 (s, 1H), 8.18 (d, J = 8.09 Hz, 1H), 7.70 (s, 1H), 7.57 (s, 1H), 7.46 (s, 1H), 4.54 (s, 2H), 3.50 (s, 3H), 2.40 (s, 3H). LCMS-F: rt 6.12 min m / z 334.1 [M+H] + , 332.0 [M-H] - .

[0590] (Example 166) 2,4-Dimethoxy-N-(6-(methoxymethyl)-5-methylbenzo[d]isoxazol-3-yl)benzenesulfonamide 166

[0591] [Chemical Structure Diagram] A solution of 2,4-dimethoxybenzenesulfonyl chloride (0.052 g, 0.22 mmol) and 6-(methoxymethyl)-5-methylbenzo[d]isoxazol-3-amine I4 (0.042 g, 0.22 mmol) in pyridine (0.500 mL) was irradiated in a microwave at 110 °C for 2 h. The resulting mixture was loaded onto silica gel and the product was purified by column chromatography (4 g of SiO 2 cartridge, 0 - 45% EtOAc in petroleum benzine 40 - 60 °C) to yield the title compound (0.0413 g, 48% yield) as a white solid. 1 H NMR (400 MHz, CDCl 3 ) δ 7.96 (s, 1H), 7.83 (s, 1H), 7.71 (d, J = 8.33 Hz, 1H), 7.47 (s, 1H), 6.48 (d, J = 1.82 Hz, 1H), 6.42 (d, J = 8.36 Hz, 1H), 4.50 (s, 2H), 3.95 (s, 3H), 3.80 (s, 3H), 3.47 (s, 3H), 2.37 (s, 3H). LCMS-A: rt 5.78 min, m / z = 392.8 [M+H] + , 414.7 [M+Na] + .

[0592] (Example 167) N-(6-(Hydroxymethyl)benzo[d]isoxazol-3-yl)-2,4-dimethoxybenzenesulfonamide 167

[0593]

Chemical Structure

[0594] b) Methyl 3-((2,4-dimethoxyphenyl)sulfonamido)benzo[d]isoxazole-6-carboxylate A10 A solution of 2,4-dimethoxybenzene-1-sulfonyl chloride (0.67 g, 2.8 mmol) and methyl 3-aminobenzo[d]isoxazole-6-carboxylate A9 (0.55 g, 2.8 mmol) in pyridine (4 mL) was irradiated in a microwave at 130 °C for 3 hours. The reaction mixture was cooled to room temperature and then diluted with DCM (40 mL). The organic layer was washed with 1 M HCl (40 mL), and the aqueous layer was back-extracted with DCM (2 × 40 mL). The combined organic layers were dried in vacuo, and the residue was purified by column chromatography (24 g of SiO 2The cartridge was purified twice with petroleum benzene (40 - 60 °C, 0 - 35% EtOAc) to obtain two batches of the title compound (0.369 g, impure and 0.0310 g, 2.8% yield, purity > 95%) as a white solid. 1 H NMR (400 MHz, methanol-d 4 ) δ 8.13 - 8.06 (m, 2H), 7.97 (dd, J = 1.25, 8.47 Hz, 1H), 7.86 - 7.80 (m, 1H), 6.58 (dq, J = 2.29, 4.60 Hz, 2H), 3.95 (s, 3H), 3.83 (s, 3H), 3.79 (s, 3H). LCMS: rt 3.26 min, m / z 392.8 [M+H] + , 415.8 [M+Na] + .

[0595] c) N-(6-(Hydroxymethyl)benzo[d]isoxazol-3-yl)-2,4-dimethoxybenzenesulfonamide 167 Under nitrogen, a solution of methyl 3-((2,4-dimethoxyphenyl)sulfonamido)benzo[d]isoxazole-6-carboxylate A10 (impure, 0.392 g, 0.500 mmol) in THF (8 mL) was added to a suspension of lithium aluminum hydride powder (0.0758 g, 2.00 mmol) in anhydrous THF (4 mL). The mixture was stirred overnight at room temperature. The reaction was quenched with wet THF under nitrogen, followed by the dropwise addition of 1 mL of water. After the evolution of gas ceased, 0.5 M aqueous HCl was added, and the aqueous layer was extracted with ethyl acetate (3 × 20 mL). The combined organic layers were washed with water and brine, dried over MgSO 4 and the solvent was removed in vacuo. The crude residue was purified by column chromatography (24 g of SiO 2 cartridge, petroleum benzene (40 - 60 °C, 0 - 100% EtOAc)) to obtain the title compound (0.191 g, 100% yield) as a white solid. 1 H NMR (400 MHz, CDCl 3) δ 8.08 (dd, J = 0.78, 8.30 Hz, 1H), 7.77 (s, 1H), 7.69 (d, J = 8.82 Hz, 1H), 7.47 (t, J = 1.03 Hz, 1H), 7.30 (dd, J = 1.34, 8.29 Hz, 1H), 6.49 (d, J = 2.26 Hz, 1H), 6.42 (dd, J = 2.30, 8.79 Hz, 1H), 4.84 (s, 2H), 3.98 (s, 3H), 3.80 (s, 3H). LCMS-B: rt 3.02 min, m / z 364.8 [M+H] + , 386.8 [M+Na] + .

[0596] (Example 168) 3 - ((5 - Methoxyquinoline) - 8 - sulfonamido) - 5 - methylbenzo[d]isoxazole - 6 - carboxamide 168

[0597] [Chemical formula] a) Methyl 3 - amino - 5 - methylbenzo[d]isoxazole - 6 - carboxylate A11 To a solution of ethanehydroxamic acid (0.126 g, 1.69 mmol) in DMF (2 mL) was added potassium 2 - methylpropane - 2 - olate (0.19 g, 1.7 mmol), and the reaction mixture was stirred for 30 minutes. Methyl 4 - cyano - 5 - fluoro - 2 - methylbenzoate (0.22 g, 1.1 mmol) was then added, followed by DMF (3 mL), and the reaction mixture was stirred at 40 °C for an additional 2 hours. The reaction mixture was diluted with ethyl acetate (50 mL) and water (50 mL). The aqueous layer was extracted with ethyl acetate, and the combined organic layers were washed with water, dried, filtered, and concentrated. The crude material was purified by silica gel chromatography (12 g of SiO 2 cartridge, 0 - 50% EtOAc in petroleum benzine 40 - 60 °C) to afford the title compound (0.11 g, 48% yield) as a white solid. 11H NMR (400 MHz, methanol-d 4 ) δ 7.85 (s, 1H), 7.64 (t, J = 0.79 Hz, 1H), 3.92 (s, 3H), 2.62 (d, J = 0.85 Hz, 3H). LCMS: rt 3.02 min, m / z 207.0 [M+H] + .

[0598] b) Methyl 3-((5-methoxyquinoline)-8-sulfonamido)-5-methylbenzo[d]isoxazole-6-carboxylate hydrochloride A12 A solution of 5-methoxyquinoline-8-sulfonyl chloride (0.12 g, 0.48 mmol) and methyl 3-amino-5-methylbenzo[d]isoxazole-6-carboxylate A11 (0.10 g, 0.48 mmol) in pyridine (3 mL) was irradiated in a microwave at 110 °C for 2 h. The reaction was irradiated in a microwave at 110 °C for an additional 1.5 h. The resulting mixture was loaded onto silica gel and the product was purified by column chromatography (4 g of SiO 2 cartridge, 0 - 45% EtOAc in petroleum benzine 40 - 60 °C). The product was further purified by solid phase extraction (1 g of Si-amine, 3 void volumes of MeOH, followed by 4 void volumes of methanolic HCl). The acidic eluate was collected and dried in vacuo to afford the title compound (17.7 mg, 7.9% yield) as a pale yellow solid. 1 1H NMR (400 MHz, methanol-d 4 ) δ 9.40 - 9.33 (m, 2H), 8.77 (d, J = 8.66 Hz, 1H), 8.14 - 8.05 (m, 1H), 7.91 (s, 1H), 7.80 - 7.73 (m, 1H), 7.47 (d, J = 8.73 Hz, 1H), 4.23 (s, 3H), 3.91 (s, 3H), 2.62 (s, 3H). LCMS: rt 3.35 min, m / z 427.8 [M+H] + .

[0599] c) 3 - ((5 - Methoxyquinoline) - 8 - sulfonamido) - 5 - methylbenzo[d]isoxazole - 6 - carboxamide 168 Under nitrogen, to a 15 mL thick - walled pressure tube equipped with a magnetic stir bar, methyl 3 - ((5 - methoxyquinoline) - 8 - sulfonamido) - 5 - methylbenzo[d]isoxazole - 6 - carboxylate hydrochloride A12 (15.0 mg, 0.0323 mmol), ammonia solution (2.0 M in methanol, 0.50 mL, 1.0 mmol) and calcium dichloride (3.59 mg, 0.0323 mmol) were added. The reaction vessel was sealed and heated at 80 °C for 3 days. The solvent was removed under a stream of gas, and ammonia solution (7.0 M in methanol, 0.50 mL, 3.5 mmol) and calcium dichloride (3.6 mg, 0.032 mmol) were added. The reactor was sealed and heated at 80 °C for 24 hours. The reaction was cooled to room temperature and the solvent was removed in vacuo. The compound was purified by column chromatography (4 g of SiO 2 cartridge, 0 - 100% EtOAc in petroleum benzine 40 - 60 °C) to give the title compound (0.00180 g, 13% yield) as a white solid. 1 H NMR (400 MHz, methanol - d 4 ) δ 9.01 (dd, J = 1.78, 4.24 Hz, 1H), 8.65 (dd, J = 1.78, 8.52 Hz, 1H), 8.43 (d, J = 8.47 Hz, 1H), 7.73 (d, J = 12.46 Hz, 2H), 7.57 (dd, J = 4.28, 8.54 Hz, 1H), 7.08 (d, J = 8.50 Hz, 1H), 4.09 (s, 3H), 2.57 (s, 3H). LCMS - B: rt 3.15 min, m / z 413.8 [M + H] + .

[0600] (Example 169) N-(6-Cyano-5-methylbenzo[d]isoxazol-3-yl)-2,4-dimethoxybenzenesulfonamide 169

[0601]

Chem.

[0602] b) N-(6-Cyano-5-methylbenzo[d]isoxazol-3-yl)-2,4-dimethoxybenzenesulfonamide 169 A solution of 2,4-dimethoxybenzene-1-sulfonyl chloride (0.22 g, 0.92 mmol) and 3-amino-5-methyl-1,2-benzoxazole-6-carbonitrile A13 (0.16 g, 0.92 mmol) in pyridine (2.5 mL) was irradiated in a microwave at 130 °C for 2 h. The reaction mixture was allowed to stand at room temperature for 50 min and then irradiated in a microwave at 130 °C for an additional 2 h. The reaction mixture was cooled to room temperature and then diluted with DCM (40 mL). The organic layer was washed with 1 M HCl (40 mL), and the aqueous layer was back-extracted twice with DCM (2 × 40 mL). The combined organic layers were dried in vacuo, and the residue was loaded onto silica gel, and the product was purified by column chromatography (24 g of SiO 2 cartridge, 0 - 45% EtOAc in petroleum benzine 40 - 60 °C) to give a yellow solid. The solid was dissolved in warm MeOH and DCM and purified by solid-phase extraction (1 g of Si-amine, 3 void volumes of MeOH, followed by 3 void volumes of approximately 1.25 M methanolic ammonia). The acidic eluate was dried in vacuo to give a white solid. The solid was dissolved in MeOH, and MeOH was removed in vacuo (repeated × 3). The residue was purified by column chromatography (24 g of SiO 2 cartridge, 45% EtOAc in petroleum benzine 40 - 60 °C) again to give two batches of the title compound (22 and 78 mg, total mass 100 mg, 29% yield) as an off-white solid. 1 H NMR (400 MHz, CDCl 3 ) δ 8.09 (s, 1H), 7.82 (s, 1H), 7.72 (s, 1H), 7.66 (d, J = 8.80 Hz, 1H), 6.52 (d, J = 2.25 Hz, 1H), 6.44 (dd, J = 2.24, 8.85 Hz, 1H), 3.98 (s, 3H), 3.82 (s, 3H), 2.67 (s, 3H). LCMS-B: rt 3.30 min, m / z = 373.8 [M+H] + , 371.9 [M-H] - .

[0603] (Example 170) 2,4-Dimethoxy-N-(5-methylbenzo[d]isoxazol-3-yl)benzenesulfonamide 170

[0604] [Chemical formula] A solution of 2,4-dimethoxybenzene-1-sulfonyl chloride (0.0799 g, 0.337 mmol) and 5-methylbenzo[d]isoxazol-3-amine I60 (0.050 g, 0.34 mmol) in pyridine (1 mL) was irradiated in a microwave at 110 °C for 2 hours. The resulting mixture was loaded onto silica gel, and the product was purified by column chromatography (12 g of SiO 2 cartridge, 0 - 45% EtOAc in petroleum benzene 40 - 60 °C) to yield the title compound (55.0 mg, 42% yield) as a white solid. 1 H NMR (400 MHz, CDCl 3 ) δ 7.86 - 7.82 (m, 1H), 7.72 (d, J = 8.81 Hz, 1H), 7.37 - 7.28 (m, 2H), 6.49 (d, J = 2.26 Hz, 1H), 6.43 (dd, J = 2.29, 8.82 Hz, 1H), 3.96 (s, 3H), 3.80 (s, 3H), 2.47 (s, 3H). LCMS-A: rt 5.66 min, m / z 348.8 [M+H] + , 347.1 [M-H] - .

[0605] (Example 171) N-(6-Bromo-5-methylbenzo[d]isoxazol-3-yl)-2,4-dimethoxybenzenesulfonamide 171

[0606] [Chemical formula] a) 6-Bromo-5-methylbenzo[d]isoxazol-3-amine A14 To a solution of ethanohydroxamic acid (0.263 g, 3.50 mmol) in N,N-dimethylformamide (5 mL) was added t-BuOK (393 mg, 3.50 mmol), and the reaction was stirred for 30 minutes. 4-Bromo-2-fluoro-5-methylbenzonitrile (0.50 g, 2.3 mmol) was added to the reaction, and this was stirred at room temperature for a further 2 hours. The reaction was diluted with ethyl acetate (50 mL) and water (50 mL), the aqueous layer was extracted with ethyl acetate, the combined organic layers were washed with water, dried, filtered, and concentrated. The crude material was purified by silica gel chromatography (12 g of SiO 2 cartridge, 0 - 50% EtOAc in petroleum benzine 40 - 60 °C) to give the title compound (0.30 g, 56% yield) as a white solid. 1 H NMR (400 MHz, CDCl 3 ) δ 7.68 (s, 1H), 7.37 (s, 1H), 4.35 (br s, 2H), 2.49 (s, 3H). LCMS - B: rt 3.18 min, m / z 229.8 [M + H] + .

[0607] b) N-(6-Bromo-5-methylbenzo[d]isoxazol-3-yl)-2,4-dimethoxybenzenesulfonamide 171 A solution of 2,4-dimethoxybenzenesulfonyl chloride (0.052 g, 0.22 mmol) and 6-bromo-5-methylbenzo[d]isoxazol-3-amine A14 (0.050 g, 0.22 mmol) in pyridine (1 mL) was irradiated twice in a microwave at 110 °C for 2 hours and then at 130 °C for 2 hours. The resulting mixture was loaded onto silica gel, and the product was purified by column chromatography (4 g of SiO 2 cartridge, 0 - 45% EtOAc in petroleum benzine 40 - 60 °C) to give the title compound (102 mg, quantitative yield) as a white solid. 1 H NMR (400 MHz, CDCl3 ) δ 7.98 - 7.94 (m, 1H), 7.70 - 7.65 (m, 2H), 6.50 (d, J = 2.24 Hz, 1H), 6.43 (dd, J = 2.26, 8.82 Hz, 1H), 3.97 (s, 3H), 3.81 (s, 3H), 2.51 (d, J = 0.87 Hz, 4H). LCMS-A: rt 6.08 min, m / z 426.9 [M+H] + .

[0608] (Example 172) N-(6-(Ethoxymethyl)-4-methoxybenzo[d]isoxazol-3-yl)-2,6-dimethoxybenzenesulfonamide 172

[0609] [Chemical Structure] N 2 Under nitrogen, a solution of 6-(ethoxymethyl)-4-methoxybenzo[d]isoxazol-3-amine I21 (250 mg, 1.13 mmol) in anhydrous THF (25 mL) at -78 °C was added dropwise with LiHMDS (1 M solution in THF, 4.5 mL, 4.5 mmol), and the mixture was stirred at -78 °C for 2 hours. Then, a solution of 2,6-dimethoxybenzenesulfonyl chloride I111 (400 mg, 1.69 mmol) in anhydrous THF (2 mL) was added dropwise, and the mixture was warmed to room temperature and stirred overnight. The mixture was acidified to pH 4 - 5 with 2 M aqueous HCl and extracted with EtOAc. The combined organic extracts were washed with water and brine, dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by preparative TLC (DCM / MeOH = 100 / 1) to give the title compound (170 mg, purity 96%) as a white solid. Further purification by preparative HPLC gave the title compound (60 mg, purity 100%, 13% yield). LCMS-C: R t 2.08 min; m / z 423.0 [M+H] + ; 11H NMR (400 MHz, DMSO-d 6 ) δ 9.53 (s, 1H), 7.51 (t, J = 8.4 Hz, 1H), 7.09 (s, 1H), 6.78 - 6.76 (m, 3H), 4.55 (s, 2H), 3.91 (s, 3H), 3.77 (s, 6H), 3.54 (q, J = 6.8 Hz, 2H), 1.19 (t, J = 6.8 Hz, 3H).

[0610] (Example 173) 2,6 - Dimethoxy - N - (4 - methoxy - 6 - (methoxymethyl)benzo[d]isoxazol - 3 - yl)benzenesulfonamide 173

[0611] [Chemical Structure] N 2 Under nitrogen, a solution of 4 - methoxy - 6 - (methoxymethyl)benzo[d]isoxazol - 3 - amine I9 (3.0 g, 14.4 mmol) in anhydrous THF (200 mL) at - 78 °C was added dropwise with LiHMDS (1 M solution in THF, 43.2 mL, 43.2 mmol), and the mixture was stirred at - 78 °C for 2 hours. Then, a solution of 2,6 - dimethoxybenzenesulfonyl chloride I111 (5.1 g, 21.6 mmol) in anhydrous THF (10 mL) was added dropwise, the mixture was warmed to room temperature, and stirred overnight. The mixture was acidified to pH 4 - 5 with 2 M aqueous HCl and extracted with EtOAc. The combined organic extracts were washed with water and brine, dried over anhydrous Na 2 SO 4 4, filtered, and concentrated under reduced pressure. The reaction was repeated using 4 - methoxy - 6 - (methoxymethyl)benzo[d]isoxazol - 3 - amine I9 (2.0 g, 9.6 mmol) in 150 mL of THF, the two batches were combined, and purified by column chromatography (petroleum ether / EtOAc = 8 / 1 to 2 / 1) to obtain the title compound (4.1 g, 42%) as a white solid. LCMS - C: R t1.96 min; m / z 409.0 [M+H] + ; 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.58 (s, 1H), 7.52 (t, J = 8.4 Hz, 1H), 7.09 (s, 1H), 6.78 (d, J = 8.4 Hz, 2H), 6.76 (s, 1H), 4.51 (s, 2H), 3.91 (s, 3H), 3.77 (s, 6H), 3.33 (s, 3H).

[0612] (Example 174) 2,6-Dimethoxy-N-(4-methoxy-6-phenylbenzo[d]isoxazol-3-yl)benzenesulfonamide 174

[0613]

Chemical Structure

[0614] (Example 175) 3-Chloro-2,6-dimethoxy-N-(4-methoxy-6-(methoxymethyl)benzo[d]isoxazol-3-yl)benzenesulfonamide 175

[0615] [Chemical Structure] To a solution of 2,6-dimethoxy-N-(4-methoxy-6-(methoxymethyl)benzo[d]isoxazol-3-yl)benzenesulfonamide 173 (50 mg, 0.123 mmol) in DMF (10 mL) was added NCS (14 mg, 0.123 mmol), and the mixture was heated at 50 °C for 2 h. The mixture was then diluted with EtOAc (150 mL), washed with water and brine, dried over anhydrous Na 2 SO 4 and filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (DCM / MeOH = 120 / 1) to give the title compound (15 mg, 27%) as a white solid. LCMS-C: R t 2.21 min; m / z 441.0 [M+H] + . 1 1H NMR (400 MHz, methanol-d 4 ) δ 7.56 (d, J = 9.1 Hz, 1H), 7.01 (s, 1H), 6.91 (d, J = 9.1 Hz, 1H), 6.76 (s, 1H), 4.55 (s, 2H), 3.99 (s, 6H), 3.76 (s, 3H), 3.41 (s, 3H).

[0616] (Example 176) 2,6-Dimethoxy-N-(4-methoxy-6-(2-methoxyphenyl)benzo[d]isoxazol-3-yl)benzenesulfonamide 176

[0617] [Chemical Structure Diagram] A mixture of N-(6-bromo-4-methoxybenzo[d]isoxazol-3-yl)-2,6-dimethoxybenzenesulfonamide 89 (30 mg, 0.068 mmol), (2-methoxyphenyl)boronic acid (21 mg, 0.135 mmol), Pd(PPh 3 ) 4 (9 mg, 0.007 mmol) and Na 2 CO 3 (22 mg, 0.203 mmol) in 1,4-dioxane (4 mL) and water (1 mL) was heated at 100 °C overnight under N 2 2. The mixture was diluted with water and extracted with EtOAc. The combined organic extracts were washed with brine, dried over anhydrous Na 2 SO 4 4, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (petroleum ether / EtOAc = 1 / 2) to give the title compound (10 mg, 31%) as a white solid. LCMS-C: R t t 2.36 min, m / z 471.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.60 (s, 1H), 7.51 (t, J = 8.5 Hz, 1H), 7.44 - 7.37 (m, 2H), 7.22 (s, 1H), 7.16 (d, J = 8.8 Hz, 1H), 7.05 (t, J = 7.4 Hz, 1H), 6.90 (s, 1H), 6.79 (d, J = 8.6 Hz, 2H), 3.94 (s, 3H), 3.81 (s, 6H), 3.79 (s, 3H).

[0618] (Example 177) 2,6-Dimethoxy-N-(4-methoxy-6-(3-methoxyphenyl)benzod]isoxazol-3-yl)benzenesulfonamide 177

[0619] [Chemical Structure Diagram] A mixture of N-(6-bromo-4-methoxybenzod]isoxazol-3-yl)-2,6-dimethoxybenzenesulfonamide 89 (50 mg, 0.113 mmol), (3-methoxyphenyl)boronic acid (35 mg, 0.226 mmol), Pd(PPh 3 ) 4 (14 mg, 0.011 mmol) and Na 2 CO 3 (36 mg, 0.339 mmol) in 1,4-dioxane (8 mL) and water (2 mL) was heated at 100 °C overnight under N 2 . The mixture was cooled to room temperature, adjusted to pH 4 - 5, then diluted with water and extracted with EtOAc. The combined organic extracts were washed with brine, dried over anhydrous Na 2 SO 4 and filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (DCM / MeOH = 50 / 1) to give the title compound (8 mg, 15%) as a white solid. LCMS - C: R t 2.35 min; m / z 471.0 [M + H] + . 1 H NMR (400 MHz, DMSO - d 6 ) δ 9.63 (s, 1H), 7.51 (t, J = 8.5 Hz, 1H), 7.46 (d, J = 1.0 Hz, 1H), 7.41 (t, J = 7.9 Hz, 1H), 7.37 - 7.29 (m, 2H), 7.07 (s, 1H), 7.03 - 6.98 (m, 1H), 6.79 (d, J = 8.5 Hz, 2H), 4.02 (s, 3H), 3.84 (s, 3H), 3.79 (s, 6H).

[0620] (Example 178) 5-Ethyl-2-methoxy-N-(7-phenylbenzo[d]isoxazol-3-yl)benzenesulfonamide 178

[0621] [Chemical formula] A suspension of N-(7-bromobenzo[d]isoxazol-3-yl)-5-ethyl-2-methoxybenzenesulfonamide 137 (100 mg, 0.24 mmol), phenylboronic acid (60 mg, 0.48 mmol), Pd(dppf)Cl 2 (18 mg, 0.024 mmol) and K 3 PO 4 ·3H 2 O (260 mg, 0.97 mmol) in toluene (5 mL), isopropanol (2 mL) and water (5 mL) was heated at 100 °C for 2 hours under N 2 2. The mixture was cooled to room temperature, diluted with EtOAc and washed with water (25 mL × 3). The organic layer was dried over anhydrous Na 2 SO 4 4, filtered and concentrated under reduced pressure. The residue was purified by preparative TLC (petroleum ether / EtOAc = 2 / 1) to give the title compound (55 mg, 55%) as a white solid. LCMS-D: R t 3.06 min; m / z 409.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.8 (s, 1H), 8.08 - 8.02 (m, 1H), 7.89 - 7.78 (m, 3H), 7.72 (d, J = 2.3 Hz, 1H), 7.55 - 7.40 (m, 5H), 7.13 - 7.08 (m, 1H), 3.75 (s, 3H), 2.61 (q, J = 7.5 Hz, 2H), 1.15 (t, J = 7.5 Hz, 3H).

[0622] (Example 179) 5-Ethyl-2-methoxy-N-(6-phenylbenzo[d]isoxazol-3-yl)benzenesulfonamide 179

[0623] [Chemical formula] A mixture of N-(6-bromobenzo[d]isoxazol-3-yl)-5-ethyl-2-methoxybenzenesulfonamide 138 (120 mg, 0.3 mmol), Pd(dppf)Cl 2 (45 mg, 0.06 mmol), phenylboronic acid (150 mg, 1.2 mmol) and K 3 PO 4 ·3H 2 O (399 mg, 1.5 mmol) in water (10 mL), toluene (10 mL) and isopropanol (5 mL) was heated at 85 °C for 4 hours under N 2 . The mixture was cooled to room temperature, diluted with water (200 mL) and extracted with diethyl ether (200 mL × 3). The combined organic extracts were washed with water and brine, dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / EtOAc = 100 / 1 to 5 / 1) to give the title compound (60 mg, 50%) as a white solid. LCMS-D: R t 3.10 min; m / z 409.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6) δ 11.7 (s, 1H), 8.14 - 8.08 (m, 1H), 7.87 (s, 1H), 7.79 - 7.74 (m, 2H), 7.73 - 7.67 (m, 2H), 7.54 - 7.39 (m, 4H), 7.12 - 7.07 (m, 1H), 3.74 (s, 3H), 2.61 (q, J = 7.5 Hz, 2H), 1.15 (t, J = 7.6 Hz, 3H).

[0624] (Example 180) N-(4-Chlorobenzo[d]isoxazol-3-yl)-2,3-dihydrobenzofuran-7-sulfonamide 180

[0625] [Chemical Structure] To a solution of 5-bromo-N-(4-chlorobenzo[d]isoxazol-3-yl)-2,3-dihydrobenzofuran-7-sulfonamide 127 (100 mg, 0.23 mmol) in THF (10 mL) were added 10% Pd / C (20 mg) and KOAc (20 mg, 0.28 mmol), and the mixture was stirred at 40 °C for 2 h under H 2 atmosphere, then at room temperature overnight. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (DCM / MeOH = 30 / 1) to give the title compound (22 mg, 27%) as a pale yellow solid. LCMS-D: R t t = 2.32 min; m / z 351.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.9 (s, 1H), 7.76 - 7.62 (m, 2H), 7.53 - 7.43 (m, 3H), 6.96 (t, J = 7.7 Hz, 1H), 4.50 (t, J = 8.8 Hz, 2H), 3.22 (t, J = 8.8 Hz, 2H).

[0626] (Example 181) N-(4-Chlorobenzo[d]isoxazol-3-yl)-5-ethyl-2,3-dihydrobenzofuran-7-sulfonamide 181

[0627] [Chemical Structure] a) N-(4-Chlorobenzo[d]isoxazol-3-yl)-5-vinyl-2,3-dihydrobenzofuran-7-sulfonamide A15 In 1,4-dioxane (20 mL), EtOH (10 mL) and H 2 O (10 mL), to a solution of 5-bromo-N-(4-chlorobenzo[d]isoxazol-3-yl)-2,3-dihydrobenzofuran-7-sulfonamide 127 (200 mg, 0.47 mmol), K 2 CO 3 (206 mg, 1.86 mmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (140 mg, 0.93 mmol) and Pd(PPh 3 ) 4 (54 mg, 0.047 mmol) were added and the mixture was heated at 90 °C overnight under N 2 atmosphere. The solvent was removed under reduced pressure and the residue was partitioned between DCM (50 mL), water (45 mL) and 2 M aqueous HCl solution (5 mL). The layers were separated, the organic layer was washed with brine, dried over anhydrous Na 2 SO 4 and filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / EtOAc = 3 / 1) to give the title compound (120 mg, 70%) as a yellow solid. LCMS-D: R t 0.40 min; m / z 377.0 [M+H] + .

[0628] b) N-(4-Chlorobenzo[d]isoxazol-3-yl)-5-ethyl-2,3-dihydrobenzofuran-7-sulfonamide 181 To a solution of N-(4-chlorobenzo[d]isoxazol-3-yl)-5-vinyl-2,3-dihydrobenzofuran-7-sulfonamide A15 (120 mg, 0.32 mmol) in MeOH (15 mL) was added 10% Pd / C (24 mg), and the mixture was stirred 2 under H atmosphere at room temperature overnight. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (DCM / MeOH = 30 / 1) to afford the title compound (33 mg, 27%) as a white solid. LCMS-D: R t 2.59 min; m / z 379.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.8 (s, 1H), 7.75 - 7.70 (m, 1H), 7.69 - 7.63 (m, 1H), 7.47 - 7.43 (m, 1H), 7.37 (s, 1H), 7.29 (s, 1H), 4.46 (t, J = 8.7 Hz, 2H), 3.18 (t, J = 8.7 Hz, 2H), 2.56 (q, J = 7.6 Hz, 2H), 1.13 (t, J = 7.6 Hz, 3H).

[0629] (Example 182) N-(Benzo[d]isoxazol-3-yl)-4-ethyl-2-methoxybenzenesulfonamide 182

[0630] [Chemical Structure] a) N-(Benzo[d]isoxazol-3-yl)-2-methoxy-4-vinylbenzenesulfonamide A16 A solution of N-(benzo[d]isoxazol-3-yl)-4-bromo-2-methoxybenzenesulfonamide 141 (200 mg, 0.52 mmol) in toluene (16 mL), water (8 mL) and isopropanol (8 mL) was added with K 2 CO 3 (288 mg, 2.09 mmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (160 mg, 1.04 mmol) and Pd(PPh 3 ) 4 (60 mg, 0.052 mmol). The mixture was heated at 90 °C for 2 h under N 2 atmosphere. The mixture was diluted with water (50 mL) and 2 M aqueous HCl (20 mL), and extracted with EtOAc (80 mL × 2). The combined organic extracts were washed with brine, dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether / EtOAc = 5 / 1) to give the title compound (150 mg, 76%) as a pale yellow solid. LCMS-D: R t 2.47 min; m / z 331.0 [M+H] + , 353.0 [M+Na] + .

[0631] b) N-(benzo[d]isoxazol-3-yl)-4-ethyl-2-methoxybenzenesulfonamide 182 To a solution of N-(benzo[d]isoxazol-3-yl)-2-methoxy-4-vinylbenzenesulfonamide A16 (80 mg, 0.24 mmol) in MeOH (10 mL) was added 10% Pd / C (16 mg). The mixture was stirred at 25 °C overnight under H 2 atmosphere. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (petroleum ether / EtOAc = 5 / 1) to give the title compound (20 mg, 25%) as a pale yellow solid. LCMS-D: R t 2.55 min; m / z 333.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6 ) δ 11.7 (s, 1H), 8.07 (d, J = 8.0 Hz, 1H), 7.79 (d, J = 8.0 Hz, 1H), 7.66 - 7.55 (m, 2H), 7.44 - 7.31 (m, 1H), 7.01 (s, 1H), 6.96 (d, J = 8.4 Hz, 1H), 3.76 (s, 3H), 2.63 (q, J = 7.6 Hz, 2H), 1.17 (t, J = 7.6 Hz, 3H).

[0632] (Example 183) N-(Benzo[d]isoxazol-3-yl)-3-methoxy-[1,1'-biphenyl]-4-sulfonamide 183

[0633] [Chemical formula] To a solution of N-(benzo[d]isoxazol-3-yl)-4-bromo-2-methoxybenzenesulfonamide 141 (100 mg, 0.26 mmol) in toluene (7 mL), water (7 mL) and isopropanol (2.5 mL), K 2 CO 3 (144 mg, 10 mmol), phenylboronic acid (64 mg, 0.52 mmol) and Pd(PPh 3 ) 4 (30 mg, 0.026 mmol) were added and the mixture was heated at 90 °C for 2 h under N 2 atmosphere. The mixture was diluted with water (50 mL) and 2 M aqueous HCl solution (10 mL), and extracted with EtOAc (70 mL × 2). The combined organic extracts were washed with brine, dried over anhydrous Na 2 SO 4 and filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether / EtOAc = 100 / 1 to 5 / 1) to give the title compound (55 mg, 46%) as a pale yellow solid. LCMS-D: R t2.79 min; m / z 381.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.9 (s, 1H), 8.10 (d, J = 8.0 Hz, 1H), 7.98 (d, J = 8.0 Hz, 1H), 7.79 - 7.72 (m, 2H), 7.66 - 7.58 (m, 2H), 7.54 - 7.35 (m, 6H), 3.89 (s, 3H).

[0634] (Example 184) 3-(5-Ethyl-2-methoxyphenylsulfonamido)-N-methylbenzo[d]isoxazole-7-carboxamide 184

[0635] [Chemical formula] a) N-(7-Bromobenzo[d]isoxazol-3-yl)-N-((2,4-dimethoxybenzyl)oxy)-5-ethyl-2-methoxybenzenesulfonamide A17 N 2 Under N, a solution of N-(7-bromobenzo[d]isoxazol-3-yl)-5-ethyl-2-methoxybenzenesulfonamide 137 (2.3 g, 5.5 mmol), (2,4-dimethoxyphenyl)methanol (1.4 g, 8.4 mmol) and PPh 3 (3.6 g, 14.2 mmol) in THF (400 mL) at 0 °C was added DIAD (3.3 g, 16.4 mmol), and the mixture was stirred at room temperature over the weekend. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (petroleum ether / EtOAc = 5 / 1) to give the title compound (1.0 g, 32%) as a pale blue solid. LCMS-D: R t 3.35 min; m / z 583.1 / 585.1 [M+Na] + .

[0636] b) Methyl 3-(N-((2,4-dimethoxybenzyl)oxy)-5-ethyl-2-methoxyphenylsulfonamido)benzo[d]isoxazole-7-carboxylate A18 To a solution of N-(7-bromobenzo[d]isoxazol-3-yl)-N-((2,4-dimethoxybenzyl)oxy)-5-ethyl-2-methoxybenzenesulfonamide A17 (250 mg, 1.34 mmol) in MeOH (5 mL) and DMF (45 mL) was added Et 3 N (675 mg, 6.68 mmol) and Pd(dppf)Cl 2 (98 mg, 0.13 mmol), and the mixture was heated at 80 °C overnight under a CO atmosphere. The solvent was removed under reduced pressure, and the residue was diluted with EtOAc (50 mL), washed with water (50 mL × 3), brine, dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether / EtOAc = 4 / 1) to give the title compound (210 mg, 31%) as a white solid. LCMS-D: R t 3.10 min; m / z 541.2 [M+H] + .

[0637] c) 3-(N-((2,4-Dimethoxybenzyl)oxy)-5-ethyl-2-methoxyphenylsulfonamido)-N-methylbenzo[d]isoxazole-7-carboxamide A19 A mixture of methyl 3-(N-((2,4-dimethoxybenzyl)oxy)-5-ethyl-2-methoxyphenylsulfonamido)benzo[d]isoxazole-7-carboxylate A18 (20 mg, 0.037 mmol) and CH 3 NH 2 (33% solution in EtOH, 4 mL) was heated in a sealed tube at 100 °C for 30 min. The solvent was removed under reduced pressure to give the title compound (20 mg, 100%), which was used in the next step without further purification. LCMS-D: R t 2.86 min; m / z 540.2 [M+H] + .

[0638] d) 3-(5-Ethyl-2-methoxyphenylsulfonamido)-N-methylbenzo[d]isoxazole-7-carboxamide 184 A mixture of 3-(N-((2,4-dimethoxybenzyl)oxy)-5-ethyl-2-methoxyphenylsulfonamido)-N-methylbenzo[d]isoxazole-7-carboxamide A19 (40 mg, 0.07 mmol) and TFA (2 mL) was stirred at room temperature for 3 hours and then concentrated under reduced pressure. The residue was purified by preparative TLC to give the title compound (18 mg, 64%) as a white solid. LCMS-D: R t 2.35 min; m / z 390.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.9 (s, 1H), 8.31 - 8.11 (m, 2H), 8.00 - 7.90 (m, 1H), 7.72 (s, 1H), 7.52 - 7.41 (m, 2H), 7.14 - 7.04 (m, 1H), 3.73 (s, 3H), 2.81 (s, 3H), 2.62 (q, J = 8.0, 7.6 Hz, 2H), 1.15 (t, J = 7.9 Hz, 3H).

[0639] (Example 185) 3-(5-Ethyl-2-methoxyphenylsulfonamido)-N,N-dimethylbenzo[d]isoxazole-7-carboxamide 185

[0640]

Chemical Structure

[0641] b) 3-((5-Ethyl-2-methoxyphenyl)sulfonamido)benzo[d]isoxazole-7-carboxylic acid A21 To a suspension of methyl 3-(5-ethyl-2-methoxyphenylsulfonamido)benzo[d]isoxazole-7-carboxylate A20 (200 mg, 0.5 mmol) in MeOH (10 mL) and THF (10 mL) was added 2M aqueous NaOH solution (1.28 mL), and the mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure, the residue was diluted with water and adjusted to pH 2 - 3. The resulting precipitate was collected by filtration to give the title compound (144 mg, 75%) as an off-white solid. LCMS-D: R t 2.43 min; m / z 377.1 [M+H] + . 11H NMR (400 MHz, DMSO-d 6 ) δ 13.5 (s, 1H), 11.8 (s, 1H), 8.35 - 8.29 (m, 1H), 8.15 - 8.09 (m, 1H), 7.72 (d, J = 2.3 Hz, 1H), 7.53 - 7.44 (m, 2H), 7.12 - 7.05 (m, 1H), 3.71 (s, 3H), 2.62 (q, J = 7.6 Hz, 2H), 1.16 (t, J = 7.6 Hz, 3H).

[0642] c) 3-(5-Ethyl-2-methoxyphenylsulfonamido)benzo[d]isoxazole-7-carbonyl chloride A22 A mixture of 3-((5-ethyl-2-methoxyphenyl)sulfonamido)benzo[d]isoxazole-7-carboxylic acid A21 (30 mg, 0.08 mmol) and SOCl 2 (5 mL) was heated at 85 °C for 3 h under N 2 atmosphere and then concentrated under reduced pressure to give the title compound (31 mg, 100%), which was used directly in the next step without further purification.

[0643] d) 3-(5-Ethyl-2-methoxyphenylsulfonamido)-N,N-dimethylbenzo[d]isoxazole-7-carboxamide 185 To a solution of 3-(5-ethyl-2-methoxyphenylsulfonamido)benzo[d]isoxazole-7-carbonyl chloride A22 (31 mg, 0.08 mmol) in THF (1 mL) was added dropwise dimethylamine (40% solution in water, 2 mL), and the mixture was stirred at room temperature for 1 h. The mixture was concentrated under reduced pressure, the residue was diluted with water, adjusted to pH 2 - 3, and extracted with DCM (30 mL × 3). The combined organic extracts were washed with brine and dried over anhydrous Na 2 SO 4It was dried, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC to obtain the title compound (18 mg, 56%) as a white solid. LCMS-D: R t 2.36 min; m / z 404.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.9 (s, 1H), 8.21 - 8.06 (m, 1H), 7.78 - 7.56 (m, 2H), 7.45 (s, 2H), 7.17 - 6.97 (m, 1H), 3.71 (s, 3H), 3.01 (s, 3H), 2.80 (s, 3H), 2.61 (m, 2H), 1.15 (m, 3H).

[0644] (Example 186) 5-Ethyl-N-(7-(hydroxymethyl)benzo[d]isoxazol-3-yl)-2-methoxybenzenesulfonamide 186

[0645]

Chemical Structure

[0646] (Example 187) 5-Ethyl-2-methoxy-N-(7-methylbenzo[d]isoxazol-3-yl)benzenesulfonamide 187

[0647] [Chemical formula] To a suspension of N-(7-bromobenzo[d]isoxazol-3-yl)-5-ethyl-2-methoxybenzenesulfonamide 137 (150 mg, 0.36 mmol) in 1,4-dioxane (18 mL) and water (4.5 mL) were added K 2 CO 3 (150 mg, 1.09 mmol), methylboronic acid (45 mg, 0.73 mmol), and Pd(dppf)Cl 2 (27 mg, 0.036 mmol), and the mixture was heated at 90 °C for 4 h under a N 2 atmosphere. The mixture was concentrated under reduced pressure, and the residue was partitioned between EtOAc (50 mL), water (40 mL), and 1 M aqueous HCl solution (15 mL). The layers were separated, and the organic layer was washed with 0.5 M aqueous HCl solution (40 mL × 2) and brine, and dried over anhydrous Na 2 SO 4It was dried, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC to obtain the title compound (20 mg, 16%) as a white solid. LCMS-D: R t 2.25 min; m / z 347.1 [M+H] + , 369.1 [M+Na] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.7 (s, 1H), 7.89 - 7.82 (m, 1H), 7.70 (d, J = 2.3 Hz, 1H), 7.50 - 7.38 (m, 2H), 7.25 (t, J = 7.6 Hz, 1H), 7.12 - 7.04 (m, 1H), 3.73 (s, 3H), 2.60 (q, J = 7.6 Hz, 2H), 2.39 (s, 3H), 1.15 (t, J = 7.6 Hz, 3H).

[0648] (Example 188) 5-Ethyl-N-(7-ethylbenzo[d]isoxazol-3-yl)-2-methoxybenzenesulfonamide 188

[0649]

Chemical formula

[0650] b) 5-Ethyl-2-methoxy-N-(7-vinylbenzo[d]isoxazol-3-yl)benzenesulfonamide A24 A mixture of N-((2,4-dimethoxybenzyl)oxy)-5-ethyl-2-methoxy-N-(7-vinylbenzo[d]isoxazol-3-yl)benzenesulfonamide A23 (95 mg, 0.18 mmol) and TFA (4 mL) was stirred at room temperature for 3 h and then concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether / EtOAc = 2 / 1) to give the title compound (40 mg, 61%) as a white solid. LCMS-D: R t 2.78 min; m / z 359.1 [M+H] +

[0651] c) 5-Ethyl-N-(7-ethylbenzo[d]isoxazol-3-yl)-2-methoxybenzenesulfonamide 188 To a solution of 5-ethyl-2-methoxy-N-(7-vinylbenzo[d]isoxazol-3-yl)benzenesulfonamide A24 (35 mg, 0.098 mmol) in EtOAc (5 mL) was added 10% Pd / C (7 mg) and the mixture was placed under H 2Under an atmosphere, it was stirred at room temperature overnight. The mixture was filtered, the filtrate was concentrated, and the residue was purified by silica gel chromatography (petroleum ether / EtOAc = 4 / 1) to obtain the title compound (30 mg, 85%) as a white solid. LCMS-D: R t 2.83 min; m / z 361.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.7 (s, 1H), 7.90 - 7.83 (m, 1H), 7.70 (d, J = 2.3 Hz, 1H), 7.50 - 7.40 (m, 2H), 7.28 (t, J = 7.6 Hz, 1H), 7.12 - 7.05 (m, 1H), 3.73 (s, 3H), 2.80 (q, J = 7.5 Hz, 2H), 2.61 (q, J = 7.6 Hz, 2H), 1.22 (t, J = 7.5 Hz, 3H), 1.15 (t, J = 7.6 Hz, 3H).

[0652] (Example 189) N-(7-Cyclopropylbenzo[d]isoxazol-3-yl)-5-ethyl-2-methoxybenzenesulfonamide 189

[0653]

Chemical Structure

[0654] b) N-(7-Cyclopropylbenzo[d]isoxazol-3-yl)-5-ethyl-2-methoxybenzenesulfonamide 189 A mixture of N-(7-cyclopropylbenzo[d]isoxazol-3-yl)-N-((2,4-dimethoxybenzyl)oxy)-5-ethyl-2-methoxybenzenesulfonamide A25 (140 mg, 0.27 mmol) and TFA (6 mL) was stirred at room temperature for 3 h and then concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether / EtOAc = 2 / 1) to give the title compound (80 mg, 81%) as a white solid. LCMS-D: R t 2.86 min; m / z 373.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.7 (s, 1H), 7.81 (dd, J = 7.0, 2.1 Hz, 1H), 7.70 (d, J = 2.3 Hz, 1H), 7.50 - 7.43 (m, 1H), 7.27 - 7.19 (m, 2H), 7.12 - 7.06 (m, 1H), 3.73 (s, 3H), 2.61 (q, J = 7.6 Hz, 2H), 2.17 - 2.10 (m, 1H), 1.15 (t, J = 7.5 Hz, 3H), 1.04 - 0.97 (m, 2H), 0.90 - 0.84 (m, 2H).

[0655] (Example 190) N-(7-Cyclohexylbenzo[d]isoxazol-3-yl)-5-ethyl-2-methoxybenzenesulfonamide 190

[0656] [Chemical formula] a) N-(7-(Cyclohex-1-en-1-yl)benzo[d]isoxazol-3-yl)-N-(2,4-dimethoxybenzyl)-5-ethyl-2-methoxybenzenesulfonamide A26 To a suspension of N-(7-bromobenzo[d]isoxazol-3-yl)-N-(2,4-dimethoxybenzyl)-5-ethyl-2-methoxybenzenesulfonamide A17 (200 mg, 0.36 mmol) in 1,4-dioxane (15 mL) and water (3 mL) were added cyclohex-1-en-1-ylboronic acid (90 mg, 0.71 mmol), Pd(dppf)Cl 2 (26 mg, 0.036 mmol) and K 2 CO 3 (148 mg, 1.07 mmol), and the mixture was heated at 90 °C for 4 h under N 2 . The mixture was concentrated under reduced pressure, the residue was diluted with EtOAc (30 mL), and washed with water (25 mL × 3). The organic layer was dried over anhydrous Na 2 SO 4 and filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / EtOAc = 3 / 1) to give the title compound (150 mg, 75%) as a white solid, which was used directly in the next step.

[0657] b) N-(7-(Cyclohex-1-en-1-yl)benzo[d]isoxazol-3-yl)-5-ethyl-2-methoxybenzenesulfonamide A27 A mixture of N-(7-(Cyclohex-1-en-1-yl)benzo[d]isoxazol-3-yl)-N-(2,4-dimethoxybenzyl)-5-ethyl-2-methoxybenzenesulfonamide A26 (150 mg, 0.26 mmol) and TFA (7 mL) was stirred at room temperature for 3 hours and then concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether / EtOAc = 2 / 1) to give the title compound (65 mg, 60%) as a white solid. LCMS-D: R t 3.64 min; m / z 413 [M+H] + .

[0658] c) N-(7-Cyclohexylbenzo[d]isoxazol-3-yl)-5-ethyl-2-methoxybenzenesulfonamide 190 A mixture of N-(7-(Cyclohex-1-en-1-yl)benzo[d]isoxazol-3-yl)-5-ethyl-2-methoxybenzenesulfonamide A27 (65 mg, 0.15 mmol) and 10% Pd / C (13 mg) in EtOAc (10 mL) was stirred under H 2 atmosphere at room temperature for 3 hours. The mixture was filtered and the filtrate was concentrated under reduced pressure to give the title compound (40 mg, 61%) as a white solid. LCMS-D: R t 3.34 min; m / z 415.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.7 (s, 1H), 7.87 - 7.82 (m, 1H), 7.70 (d, J = 2.3 Hz, 1H), 7.49 - 7.41 (m, 2H), 7.28 (t, J = 7.6 Hz, 1H), 7.12 - 7.06 (m, 1H), 3.72 (s, 3H), 2.62 (q, J = 7.6 Hz, 2H), 1.85 - 1.75 (m, 4H), 1.75 - 1.67 (m, 1H), 1.61 - 1.48 (m, 2H), 1.44 - 1.20 (m, 4H), 1.15 (t, J = 7.6 Hz, 3H).

[0659] (Example 191) 5-Ethyl-2-methoxy-N-(7-(1-methyl-1H-pyrazol-4-yl)benzo[d]isoxazol-3-yl)benzenesulfonamide 191

[0660] [Chemical formula] a) N-((2,4-Dimethoxybenzyl)oxy)-5-ethyl-2-methoxy-N-(7-(1-methyl-1H-pyrazol-4-yl)benzo[d]isoxazol-3-yl)benzenesulfonamide A29 A mixture of N-(7-bromobenzo[d]isoxazol-3-yl)-N-((2,4-dimethoxybenzyl)oxy)-5-ethyl-2-methoxybenzenesulfonamide A17 (150 mg, 0.27 mmol) in 1,4-dioxane (15 mL) and H 2 O (3 mL) was added with K 2 CO 3 (110 mg, 0.80 mmol), (1-methyl-1H-pyrazol-4-yl)boronic acid (67 mg, 0.33 mmol) and Pd(dppf)Cl 2 (20 mg, 0.027 mmol), and the mixture was heated at 90 °C overnight under a N 2 atmosphere. The mixture was diluted with 0.5 M aqueous HCl (30 mL) and the organic solvents were almost removed under reduced pressure. The remaining aqueous mixture was extracted with DCM (40 mL × 3), and the combined organic extracts were dried over anhydrous Na 2 SO 4It was dried, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (DCM / MeOH = 100 / 1) to obtain the title compound (80 mg, 53%) as a pale yellow solid, which was used directly in the next step.

[0661] b) 5-Ethyl-2-methoxy-N-(7-(1-methyl-1H-pyrazol-4-yl)benzo[d]isoxazol-3-yl)benzenesulfonamide 191 A mixture of N-((2,4-dimethoxybenzyl)oxy)-5-ethyl-2-methoxy-N-(7-(1-methyl-1H-pyrazol-4-yl)benzo[d]isoxazol-3-yl)benzenesulfonamide A29 (80 mg, 0.14 mmol) and TFA (3 mL) was stirred at room temperature for 3 hours and then concentrated under reduced pressure. The residue was purified by silica gel chromatography (DCM / MeOH = 80 / 1) to obtain the title compound (50 mg, 86%) as a pale yellow solid. LCMS-D: R t 2.59 min; m / z 413.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.8 (s, 1H), 8.34 (s, 1H), 8.06 (s, 1H), 7.91 - 7.84 (m, 2H), 7.72 (d, J = 2.3 Hz, 1H), 7.50 - 7.43 (m, 1H), 7.41 - 7.32 (m, 1H), 7.13 - 7.06 (m, 1H), 3.90 (s, 3H), 3.74 (s, 3H), 2.62 (q, J = 7.6 Hz, 2H), 1.16 (t, J = 7.5 Hz, 3H).

[0662] (Example 192) 5-Ethyl-2-methoxy-N-(7-(pyrimidin-5-yl)benzo[d]isoxazol-3-yl)benzenesulfonamide 192

[0663] [Chem.] To a suspension of N-(7-bromobenzo[d]isoxazol-3-yl)-5-ethyl-2-methoxybenzenesulfonamide 137 (200 mg, 0.49 mmol) in toluene (16 mL), water (8 mL) and isopropanol (8 mL), pyrimidin-5-ylboronic acid (181 mg, 1.46 mmol), K 3 PO 4 (518 mg, 1.95 mmol) and Pd(dppf)Cl 2 (36 mg, 0.049 mmol) were added and the mixture was heated at 90 °C overnight under N 2 atmosphere. The mixture was adjusted to pH 5 - 6 and extracted with EtOAc (20 mL × 3). The combined organic extracts were dried over anhydrous Na 2 SO 4 and filtered, then concentrated under reduced pressure. The residue was purified by silica gel chromatography (DCM / MeOH = 40 / 1) to give the title compound (18 mg, 9%) as a brown solid. LCMS-D: R t 2.49 min; m / z 411.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.9 (s, 1H), 9.34 - 9.18 (m, 2H), 8.17 (d, J = 8.1 Hz, 1H), 8.06 (d, J = 7.4 Hz, 1H), 7.73 (s, 1H), 7.62 - 7.42 (m, 3H), 7.17 - 7.06 (m, 1H), 3.75 (s, 3H), 2.62 (q, J = 7.6 Hz, 2H), 1.16 (t, J = 7.6 Hz, 3H).

[0664] (Example 193) 5-Ethyl-2-methoxy-N-(6-methylbenzo[d]isoxazol-3-yl)benzenesulfonamide 193

[0665]

Chem.

[0666] b) N-(2,4-Dimethoxybenzyl)-5-ethyl-2-methoxy-N-(6-methyl-1,2-benzisoxazol-3-yl)benzenesulfonamide A31 To a mixture of N-(6-bromo-1,2-benzisoxazol-3-yl)-N-(2,4-dimethoxybenzyl)-5-ethyl-2-methoxybenzenesulfonamide A30 (120 mg, 0.214 mmol), CH 3 B(OH) 2 (64 mg, 1.07 mmol), Pd(dppf)Cl 2 (31 mg, 0.428 mmol) and K 2 ₂CO 3 (148 mg, 1.07 mmol) in 1,4-dioxane (10 mL) and water (2 mL) was added N 2Below, it was heated overnight at 90 °C. The solvent was removed under reduced pressure, and the residue was purified by column chromatography (petroleum ether / EtOAc = 50 / 1 to 5 / 1) to obtain the title compound (72 mg, 68%) as a white solid, which was used directly in the next step.

[0667] c) 5-Ethyl-2-methoxy-N-(6-methylbenzo[d]isoxazol-3-yl)benzenesulfonamide 193 A mixture of N-(2,4-dimethoxybenzyl)-5-ethyl-2-methoxy-N-(6-methylbenzo[d]isoxazol-3-yl)benzenesulfonamide A31 (72 mg, 0.145 mmol) and TFA (3 mL) was stirred at room temperature for 3 hours and then concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / EtOAc = 50 / 1 to 3 / 1) to obtain the title compound (45 mg, 90%) as a white solid. LCMS-D: R t 2.76 min; m / z 347.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.6 (s, 1H), 7.94 - 7.87 (m, 1H), 7.68 (d, J = 2.3 Hz, 1H), 7.49 - 7.42 (m, 1H), 7.39 (s, 1H), 7.23 - 7.16 (m, 1H), 7.13 - 7.05 (m, 1H), 3.72 (s, 3H), 2.60 (q, J = 7.5 Hz, 2H), 2.43 (s, 3H), 1.14 (t, J = 7.5 Hz, 3H).

[0668] (Example 194) 5-Ethyl-N-(6-ethylbenzo[d]isoxazol-3-yl)-2-methoxybenzenesulfonamide 194

[0669]

Chemical Structure

[0670] b) 5-Ethyl-N-(6-ethylbenzo[d]isoxazol-3-yl)-2-methoxybenzenesulfonamide 194 A mixture of N-(2,4-dimethoxybenzyl)-5-ethyl-N-(6-ethylbenzo[d]isoxazol-3-yl)-2-methoxybenzenesulfonamide A32 (120 mg, 0.24 mmol) and TFA (5 mL) was stirred overnight at room temperature and then concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / EtOAc = 50 / 1 to 3 / 1) to give the title compound (80 mg, 94%) as a white solid. LCMS-D: R t 2.84 min; m / z 361.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6 ) δ 11.6 (s, 1H), 7.97 - 7.90 (m, 1H), 7.69 (d, J = 2.3 Hz, 1H), 7.49 - 7.37 (m, 2H), 7.26 - 7.19 (m, 1H), 7.11 - 7.04 (m, 1H), 3.72 (s, 3H), 2.73 (q, J = 7.6 Hz, 2H), 2.60 (q, J = 7.6 Hz, 2H), 1.20 (t, J = 7.6 Hz, 3H), 1.14 (t, J = 7.6 Hz, 3H).

[0671] (Example 195) N-(6-Cyclopropylbenzo[d]isoxazol-3-yl)-5-ethyl-2-methoxybenzenesulfonamide 195

[0672] [Chemical Structure] A mixture of N-(6-bromobenzo[d]isoxazol-3-yl)-5-ethyl-2-methoxybenzenesulfonamide 138 (206 mg, 0.5 mmol), cyclopropylboronic acid (215 mg, 2.5 mmol), Pd(dppf)Cl 2 (73 mg, 0.1 mmol), and K 2 CO 3 (345 mg, 2.5 mmol) in 1,4-dioxane (20 mL) and water (4 mL) was heated at 90 °C overnight under N 2 . The solvent was removed under reduced pressure, and the residue was purified by column chromatography (petroleum ether / EtOAc = 50 / 1 to 3 / 1) to give the title compound (80 mg, 43%) as a white solid. LCMS-D: R t 2.86 min; m / z 373.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.6 (s, 1H), 7.91 - 7.85 (m, 1H), 7.68 (d, J = 2.3 Hz, 1H), 7.48 - 7.42 (m, 1H), 7.27 (s, 1H), 7.12 - 7.04 (m, 2H), 3.72 (s, 3H), 2.60 (q, J = 7.6 Hz, 2H), 2.10 - 2.00 (m, 1H), 1.14 (t, J = 7.5 Hz, 3H), 1.07 - 0.99 (m, 2H), 0.83 - 0.75 (m, 2H).

[0673] (Example 196) 5-Ethyl-2-methoxy-N-(6-(1-methyl-1H-pyrazol-4-yl)benzo[d]isoxazol-3-yl)benzenesulfonamide 196

[0674]

Chemical formula

[0675] b) 5-Ethyl-2-methoxy-N-(6-(1-methyl-1H-pyrazol-4-yl)benzo[d]isoxazol-3-yl)benzenesulfonamide 196 A mixture of N-(2,4-dimethoxybenzyl)-5-ethyl-2-methoxy-N-(6-(1-methyl-1H-pyrazol-4-yl)benzo[d]isoxazol-3-yl)benzenesulfonamide A33 (90 mg, 0.16 mmol) and TFA (5 mL) was stirred overnight at room temperature and then concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / EtOAc = 50 / 1 to 5 / 1) to obtain the title compound (30 mg, 46%) as a brown solid. LCMS-D: R t 2.57 min; m / z 413.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.6 (s, 1H), 8.29 (s, 1H), 8.06 - 7.95 (m, 2H), 7.78 (s, 1H), 7.70 (d, J = 2.3 Hz, 1H), 7.64 - 7.56 (m, 1H), 7.50 - 7.42 (m, 1H), 7.13 - 7.05 (m, 1H), 3.87 (s, 3H), 3.71 (s, 3H), 2.61 (q, J = 7.6 Hz, 2H), 1.15 (t, J = 7.5 Hz, 3H).

[0676] (Example 197) 5-Ethyl-2-methoxy-N-(6-(pyrimidin-5-yl)benzo[d]isoxazol-3-yl)benzenesulfonamide 197

[0677] [Chemical Structure] A mixture of N-(6-bromobenzo[d]isoxazol-3-yl)-5-ethyl-2-methoxybenzenesulfonamide 138 (100 mg, 0.24 mmol), pyrimidin-5-ylboronic acid (45 mg, 0.36 mmol), Pd(PPh 3 ) 4 (28 mg, 0.024 mmol) and K 2 CO 3 (166 mg, 1.2 mmol) in toluene (8 mL), water (8 mL) and isopropanol (2 mL) was heated at 90 °C for 4 h under N 2 . 2M aqueous NaOH solution (15 mL) was added and the mixture was stirred at room temperature for 20 min. The mixture was washed with EtOAc (20 mL × 2), then adjusted to pH 2 with concentrated HCl and extracted with DCM (50 mL × 2). The combined organic extracts were washed with water and brine, dried over anhydrous Na 2 SO 4 and filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (DCM / MeOH = 30 / 1) to give the title compound (15 mg, 15%) as a white solid. LCMS-D: R t 2.97 min; m / z 411.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.8 (s, 1H), 9.24 (s, 3H), 8.21 - 8.15 (m, 1H), 8.11 (s, 1H), 7.85 - 7.78 (m, 1H), 7.72 (d, J = 2.3 Hz, 1H), 7.49 - 7.42 (m, 1H), 7.13 - 7.05 (m, 1H), 3.73 (s, 3H), 2.61 (q, J = 7.6 Hz, 2H), 1.15 (t, J = 7.6 Hz, 3H).

[0678] (Example 198) 5-Ethyl-2-methoxy-N-(4-methylbenzo[d]isoxazol-3-yl)benzenesulfonamide 198

[0679] [Chemical formula] a) N-(4-Bromobenzo[d]isoxazol-3-yl)-N-((2,4-dimethoxybenzyl)oxy)-5-ethyl-2-methoxybenzenesulfonamide A34 N 2 Under N, in THF (200 mL) at 0 °C, N-(4-bromobenzo[d]isoxazol-3-yl)-5-ethyl-2-methoxybenzenesulfonamide 129 (2.1 g, 5.1 mmol), (2,4-dimethoxyphenyl)methanol (1.3 g, 7.7 mmol) and PPh 3 (3.35 g, 12.8 mmol) of the solution, DIAD (3.1 g, 15.3 mmol) was added, the mixture was stirred at 0 °C for 1 hour, then warmed to room temperature and stirred overnight. The mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether / EtOAc = 5 / 1) to obtain the title compound (1.2 g, 42%) as a white solid. LCMS-D: R t 3.40 minutes; m / z 583.0 [M+H] + .

[0680] b) N((2,4-Dimethoxybenzyl)oxy)-5-ethyl-2-methoxy-N-(4-methylbenzo[d]isoxazol-3-yl)benzenesulfonamide A35 In 1,4-dioxane (15 mL) and water (3 mL), N-(4-bromobenzo[d]isoxazol-3-yl)-N-((2,4-dimethoxybenzyl)oxy)-5-ethyl-2-methoxybenzenesulfonamide A34 (200 mg, 0.36 mmol), methylboronic acid (43 mg, 0.71 mmol), K2 CO 3 (148 mg, 1.07 mmol) and Pd(dppf)Cl 2 (26 mg, 0.036 mmol) were heated under N 2 at 90 °C for 4 h. The mixture was adjusted to pH 2 - 3 and most of the solvent was removed under reduced pressure. The residue was diluted with water (10 mL) and extracted with DCM (25 mL × 3). The combined organic layers were dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / EA = 5 / 1) to give the title compound (125 mg, 71%) as a white solid, which was used directly in the next step.

[0681] c) 5 - Ethyl - 2 - methoxy - N-(4 - methylbenzo[d]isoxazol - 3 - yl)benzenesulfonamide 198 A mixture of N - ((2,4 - dimethoxybenzyl)oxy)-5 - ethyl - 2 - methoxy - N-(4 - methylbenzo[d]isoxazol - 3 - yl)benzenesulfonamide A35 (125 mg, 0.26 mmol) and TFA (3 mL) was stirred at room temperature for 3 h, then diluted with DCM (100 mL), washed with water, dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / EtOAc = 3 / 1) to give the title compound (85 mg, 92%) as a white solid. LCMS - D: R t 2.69 min m / z 347.1 [M + H] + . 1 H NMR (400 MHz, DMSO - d 6 ) δ 10.6 (s, 1H), 7.58 - 7.56 (m, 1H), 7.52 - 7.46 (m, 3H), 7.18 - 7.14 (m, 2H), 3.73 (s, 3H), 2.62 - 2.56 (m, 5H), 1.14 (t, J = 7.6 Hz, 3H)

[0682] (Example 199) 5-Ethyl-N-(4-ethylbenzo[d]isoxazol-3-yl)-2-methoxybenzenesulfonamide 199

[0683] [Chemical formula] a) N-(2,4-Dimethoxybenzyl)-5-ethyl-N-(4-ethylbenzo[d]isoxazol-3-yl)-2-methoxybenzenesulfonamide A36 A mixture of N-(4-bromobenzo[d]isoxazol-3-yl)-N-((2,4-dimethoxybenzyl)oxy)-5-ethyl-2-methoxybenzenesulfonamide A34 (200 mg, 0.36 mmol), ethylboronic acid (53 mg, 0.71 mmol), K 2 CO 2 (148 mg, 1.07 mmol) and Pd(dppf)Cl 3 (26 mg, 0.036 mmol) in 1,4-dioxane (15 mL) and H 2 O (3 mL) was heated at 90 °C for 4 h under N 2 . The mixture was adjusted to pH 2 - 3 and most of the solvent was removed under reduced pressure. The residue was diluted with water (15 mL) and extracted with DCM (20 mL × 3). The combined organic layers were dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / EtOAc = 5 / 1) to give the title compound (120 mg, 66%) as a white solid, which was used directly in the next step.

[0684] b) 5-Ethyl-N-(4-ethylbenzo[d]isoxazol-3-yl)-2-methoxybenzenesulfonamide 199 A mixture of N-(2,4-dimethoxybenzyl)-5-ethyl-N-(4-ethylbenzo[d]isoxazol-3-yl)-2-methoxybenzenesulfonamide A36 (120 mg, 0.23 mmol) and TFA (3 mL) was stirred at N2 It was stirred at room temperature for 3 hours, then diluted with DCM (100 mL), washed with water, dried over anhydrous Na 2 SO 4 and filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / EtOAc = 3 / 1) to obtain the title compound (75 mg, 89%) as a white solid. LCMS-D: R t 2.80 min 361.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.5 (s, 1H), 7.60 - 7.49 (m, 4H), 7.22 - 7.18 (m, 2H), 3.81 (s, 3H), 8.09 (q, J = 7.6 Hz, 2H), 2.59 (q, J = 7.6 Hz, 2H), 1.25 (t, J = 7.6 Hz, 3H), 1.14 (t, J = 7.6 Hz, 3H).

[0685] (Example 200) N-(4-Cyclopropylbenzo[d]isoxazol-3-yl)-5-ethyl-2-methoxybenzenesulfonamide 200

[0686]

Chemical Structure

[0687] b) N-(4-Cyclopropylbenzo[d]isoxazol-3-yl)-5-ethyl-2-methoxybenzenesulfonamide 200 A mixture of N-(4-cyclopropylbenzo[d]isoxazol-3-yl)-N-(2,4-dimethoxybenzyl)-5-ethyl-2-methoxybenzenesulfonamide A37 (130 mg, 0.25 mmol) and TFA (3 mL) was stirred at room temperature for 3 h under N 2 . It was then concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / EtOAc = 3 / 1) to give the title compound (85 mg, 92%) as a yellow solid. LCMS-D: R t t 2.81 min, 373.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.6 (s, 1H), 7.58 - 7.57 (d, J = 2.0 Hz, 1H), 7.53 - 7.42 (m, 3H), 7.18 - 7.16 (m, 1H), 6.86 - 6.84 (m, 1H), 3.74 (s, 3H), 2.72 (m, 1H), 2.60 (q, J = 7.6 Hz, 2H), 1.14 (t, J = 7.6 Hz, 3H), 1.02 - 0.98 (m, 2H), 0.82 - 0.78 (m, 2H).

[0688] (Example 201) N-(4-Cyclohexylbenzo[d]isoxazol-3-yl)-5-ethyl-2-methoxybenzenesulfonamide 201

[0689] [Chemical formula] a) N-(4-(Cyclohex-1-en-1-yl)benzo[d]isoxazol-3-yl)-N-(2,4-dimethoxybenzyl)-5-ethyl-2-methoxybenzenesulfonamide A38 In 1,4-dioxane (15 mL) and H 2 O (3 mL), a mixture of N-(4-bromobenzo[d]isoxazol-3-yl)-N-((2,4-dimethoxybenzyl)oxy)-5-ethyl-2-methoxybenzenesulfonamide A34 (200 mg, 0.36 mmol), cyclohex-1-en-1-ylboronic acid (90 mg, 0.71 mmol), K 2 CO 3 (148 mg, 1.07 mmol) and Pd(dppf)Cl 2 (26 mg, 0.036 mmol) was heated at 90 °...

Claims

1. A compound of formula (I) or a pharma- ceutically acceptable salt thereof 【Chemistry 1】 [In the formula, R １ , R ２ , R ３ and R ４ teeth, (i) H, (ii) Hydroxy, C １～２ Alkoxy, NH ２ 、 Phenyl, C ５～６ Heteroaryl, C １～４ alkylcarbamoyl, or Acyl amide C may be substituted １～３ Alkyl, (iii) C ３～６ C, optionally substituted by cycloalkyl or by one or more fluoro groups; １～３ Alkoxy, (iv) C ３～６ Cycloalkyl, (v) halo, (vi) COR Ｃ (In the formula, R Ｃ is N.R. Ｎ１ R Ｎ２ is selected from R Ｎ１ and R Ｎ２ is independently selected from H and methyl; (vii) cyano, NH ２ Or NO ２ , and (viii) phenyl or C optionally substituted by methyl, hydroxy or methoxy ５～６ Heteroaryl are independently selected from Ar is a phenyl group, which is (i) Hydroxy, C １～２ Alkoxy, NH ２ , C １～４ C may be substituted by alkylcarbamoyl or by one or more fluoro groups; １～４ Alkyl, (ii) C ３～６ Cycloalkyl, (iii) hydroxy, cyano, NR Ｎ３ R Ｎ４ (In the formula, R Ｎ３ and R Ｎ４ is independently selected from H and methyl) or acylamide, (iv) halo, (v) Hydroxy, C(O)NH ２ , C ３～６ Cycloalkyl, phenyl, C ５～６ C, optionally substituted by heteroaryl or by one or more fluoro groups; １～３ Alkoxy, (vi) phenoxy optionally substituted by fluoro; (vii) phenyl or C ５～６ Heteroaryl, (viii) Science Fiction ５ or S.O. ２ CH ３ , and optionally substituted with one or more groups selected from However, R １ , R ２ , R ３ and R ４ at least one of which is not H.

2. R １ , R ２ , R ３ and R ４ At least one of Hydroxy, C １～２ Alkoxy, NH ２ 、 Phenyl, C ５～６ Heteroaryl, C １～４ alkylcarbamoyl, or Acylamide, C may be substituted １～３ 2. The compound or salt of claim 1, wherein the aryl group is alkyl.

3. R １ , R ２ , R ３ and R ４ At least one of ３～６ C, optionally substituted by cycloalkyl or one or more fluoro groups; １～３ 2. The compound or salt of claim 1 which is alkoxy.

4. R １ , R ２ , R ３ and R ４ At least one of (a) C ３～６ Cycloalkyl, (b) COR Ｃ (In the formula, R Ｃ is N.R. Ｎ１ R Ｎ２ is selected from R Ｎ１ and R Ｎ２ is independently selected from H and methyl; (c) Cyano, NH ２ Or NO ２ ,or (d) phenyl or C optionally substituted by methyl, hydroxy or methoxy ５～６ Heteroaryl, 2. The compound or salt of claim 1,

5. (a) R ４ is methoxy, and R ２ But, CH ２ OCH ３ or CH ２ OCH ２ CH ３ and R １ and R ３ is H, (b) R ４ is methoxy, and R ２ is phenyl optionally substituted by methyl or methoxy; R １ and R ３ is H, (c) R ４ is methoxy, and R ２ is optionally substituted by methyl; ５～６ is heteroaryl, (d) R ４ is methoxy, and R １ , R ２ and R ３ is H, (e) R ４ is chloro, R ２ But, C １～３ alkyl or bromo; R １ and R ３ is H, (f) R ３ But, C １～３ alkyl, R １ , R ２ and R ４ is H, 2. A compound or salt according to claim 1.

6. Ar is hydroxy, C １～２ Alkoxy, NH ２ , C １～４ C may be substituted by alkylcarbamoyl or one or more fluoro groups; １～４ 2. The compound or salt of claim 1 which is substituted by alkyl.

7. Ar is hydroxy, C(O)NH ２ , C ３～６ Cycloalkyl, phenyl, C ５～６ C, optionally substituted by heteroaryl or one or more fluoro groups; １～３ 2. The compound or salt of claim 1 which is substituted by alkoxy.

8. Ar is (a) C ３～６ Cycloalkyl, (b) hydroxy, (c) cyano, (d) NR Ｎ３ R Ｎ４ (In the formula, R Ｎ３ and R Ｎ４ is independently selected from H and methyl) or acylamide, (e) phenoxy optionally substituted by fluoro; (f) phenyl or C ５～６ Heteroaryl, (g) Science Fiction ５ or S.O. ２ CH ３ 2. The compound or salt of claim 1 , substituted by:

9. Ar is (a) 5-ethyl-2-methoxyphenyl, (b) 5-CF ３ -2-methoxyphenyl, or (c) 2,6-dimethoxyphenyl 2. The compound or salt of claim 1,

10. 10. A pharmaceutical composition comprising a compound according to any one of claims 1 to 9, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient.

11. 11. The pharmaceutical composition of claim 10 for use in the treatment of cancer.

12. 12. The pharmaceutical composition of claim 11, wherein the cancer is selected from leukemia, acute lymphocytic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, non-Hodgkin's lymphoma, Hodgkin's disease, prostate cancer, lung cancer, melanoma, breast cancer, colon and rectal cancer, colon cancer, squamous cell carcinoma and gastric cancer.

13. 12. The pharmaceutical composition according to claim 11 for use simultaneously or sequentially with radiation therapy or chemotherapy.

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