Compound

Abstract

A compound of formula (I), or a pharmaceutically acceptable salt thereof:

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 KAT family and is named after the founding members in yeast and mammals: MOZ, Ybf2 / Sas3, Sas2, and TIP60 (Dekker 2014). MYST proteins mediate multiple biological functions, including gene regulation, DNA repair, cell cycle regulation, and development (Avvakumov 2007; Voss 2009). The KAT proteins of the MYST family play a key role in the post-translational modification of histones and thus have a significant impact on chromatin structure in the eukaryotic nucleus (Avvakumov 2007). The family currently contains five mammalian KATs: TIP60 (KAT5; HTATIP; MIM601409), MOZ (KAT6A; MIM 601408; 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 it is known that the malfunction of MYST proteins is associated with cancer (Avvakumov 2007). The most frequently used names for the members of the MYST family are:

[0003] Common Name MYST Name System Name MOF MYST1 KAT8 HBO MYST2 KAT7 MOZ MYST3 KAT6A MORF MYST4 KAT6B TIP60 KAT5

[0004] MYST Functional Domain

[0005] MYST proteins are used in multi-subunit protein complexes, including adaptors that mediate DNA binding, such as ING proteins (Avvakumov 2007). For example, TIP60 belongs to the NuA4 multi-protein complex (which contains more than 16 members) (Zhang 2017). However, there are also some reports of a helix-turn-helix DNA-binding motif within the structure of the MOZ protein itself (Holbert 2007), which indicates the ability to directly bind DNA.

[0006] The acetyltransferase activity of MYST proteins is achieved through the MYST domain (catalytic domain). The MYST domain contains an acetyl-CoA binding motif, which is structurally conserved together with other HATs; and a rare C 2HC-type zinc fingers (Voss 2009). The highly conserved MYST domain, which includes an acetyl-CoA binding motif and zinc fingers, is considered a defining feature of the enzymes in this family (Avvakumov 2007).

[0007] Function of MYST Protein

[0008] 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:

[0009] HBO1 positively regulates the initiation of DNA replication via acetylation of histone substrates (Avvakumov 2007; Aggarwal 2004; Doyon 2006; Iizuka 2006), presumably leading to a more accessible chromatin conformation (Avvakumov 2007, Iizuka 2006). HBO1 is also known to play a role in the pathogenesis of breast cancer by promoting the enrichment of cancer stem-like cells (Duong 2013) and by destabilizing estrogen receptor α (ERα) via ubiquitination, which occurs via the histone acetyltransferase activity of HBO1 (Iizuka 2013). HBO1 has also been implicated in acute myeloid leukemia (AML) (Shi 2015).

[0010] TIP60 (KAT5) is the most studied member of the MYST family. TIP60 plays important roles not only in the regulation of transcription but also in the process of DNA damage repair, particularly 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 is also involved in the regulation of T cell (Treg) biology. FOXP3 is a master regulator in the development and function of Tregs and it has been shown that acetylation of FOXP3 by TIP60 is essential for FOXP3 activity (Li 2007, Xiao 2014). Emphasizing this, conditional deletion of TIP60 in mice leads to a scaly lethal autoimmune disease, thus mimicking the phenotype seen in FOXP3 gene knockout mice (Xiao 2014). In cancer, Treg cells can promote tumor progression by suppressing adaptive immunity against tumors.

[0011] MOF ("males absent on the first") was initially identified in Drosophila as a component of the dosage compensation complex and 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; it contains an acetyl-CoA-binding site, a chromatin domain (which binds histones), and C 2 HC-type zinc fingers (Su 2016). MOF is a key enzyme for acetylating histone H4K16, and the MOF-containing complex is involved in multiple essential cellular functions related to cancer (Su 2016). In addition to a global reduction in histone acetylation, depletion of MOF in mammalian cells can also lead to abnormal gene transcription, particularly causing abnormal expression of certain tumor suppressor genes or oncogenes, indicating a key role of MOF in tumorigenesis (Su 2016). For example, the KAT activity of MOF has been shown to be required for maintaining MLL-AF9 leukemia and may be important for multiple AML subtypes (Valerio 2017).

[0012] KAT6B (Querkopf) was first identified in a mutant screen for genes that regulate the balance between proliferation and differentiation during embryonic development (Thomas 2000). Mice homozygous for a KAT6B mutant allele have severe defects in cerebral cortex development, which are caused by a severe reduction in both proliferation and differentiation of specific cortical progenitor cell populations during embryonic development. KAT6B is required for the maintenance of the adult neural stem cell population and is part of the system that regulates the differentiation of stem cells into neurons (Merson 2006). KAT6B is also mutated in a rare form of leukemia (Vizmanos 2003).

[0013] The MOZ locus ranks as the 12th most common amplified region among all cancer types (Zack 2013). MOZ is within the 8p11-p12 amplicon, which is visible at a frequency of approximately 10 - 15% in multiple cancers, particularly breast and ovarian (Turner-Ivey 2014). MOZ was first identified as a fusion partner of CREB-binding protein (CBP) during the examination of specific chromosomal translocations in acute myeloid leukemia (AML) (Avvakumov 2007; Borrow 1996). The MOZ KAT activity is essential for promoting the expression of MEIS1 and HOXa9, proteins typically seen overexpressed in some lymphomas and leukemias. MOZ is visible in the Eμ-Myc transgenic model of B cell lymphoma + / -Heterozygous mice have increased survival, where loss of a single MOZ allele results in a biologically relevant decrease in Meis1 and Hoxa9 levels in pre-B cells (Sheikh 2015).

[0014] Some inhibitors of MYST are known. For example, the following anacardic acid derivatives (Ghizzoni 2012) have been reported to inhibit TIP60 (IC 50 = 74 μM) and MOF (IC 50 = 47 μM):

[0015]

[0016] Other known inhibitors include (Zhang 2017):

[0017]

[0018] Given the established role of KATs and particularly MYST in diseases such as cancer, new inhibitors of these proteins are needed. SUMMARY OF THE INVENTION

[0019] The present invention provides compounds that inhibit the activity of one or more KATs of the MYST family (i.e., TIP60, KAT6B, MOZ, HBO1, and MOF).

[0020] The first aspect of the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in a method of therapy:

[0021]

[0022] Wherein:

[0023] R 1 、R 2 、R 3 and R 4 are independently selected from:

[0024] (i) H;

[0025] (ii) C 1-3 alkyl, which is optionally substituted with:

[0026] hydroxy,

[0027] C 1-2 alkoxy, which is optionally substituted with one or more fluorine groups,

[0028] NH 2 ,

[0029] phenyl,

[0030] C 5-6 heteroaryl,

[0031] C 1-4 alkylcarbamoyl,

[0032] acylamido, or

[0033] one or more fluoro groups;

[0034] (iii) C 1-3 alkoxy, which is optionally substituted by C 3-6 cycloalkyl or by one or more fluoro groups;

[0035] (iv) C 3-6 cycloalkyl;

[0036] (v) halo;

[0037] (vi) COR C , where R C is selected from NR N1 R N2 , where R N1 and R N2 are independently selected from H and methyl;

[0038] (vii) cyano, NH 2 or NO 2 ; and

[0039] (viii) phenyl or C 5-6 heteroaryl, which is optionally substituted by methyl, cyano, hydroxy or methoxy;

[0040] Ar is phenyl, naphthyl or C 5-10 heteroaryl, said groups being optionally substituted by one or more groups selected from:

[0041] (i) C 1-4 alkyl, which is optionally substituted by hydroxy, C 1-2 alkoxy, NH 2 , C 1-4 alkylcarbamoyl or by one or more fluoro groups;

[0042] (ii) C 3-6 cycloalkyl;

[0043] (iii) hydroxy; cyano; NR N3 R N4 , where R N3 and R N4 are independently selected from H and methyl; or acylamido;

[0044] (iv) halo;

[0045] (v) C 1-3 alkoxy, which is optionally substituted by hydroxy, C(O)NH2 , C 3-6 cycloalkyl, phenyl, C 5-6 heteroaryl or substituted with one or more fluorine groups;

[0046] (vi) phenoxy, which is optionally substituted with fluorine;

[0047] (vii) phenyl or C 5-6 heteroaryl

[0048] (viii) SF 5 or SO 2 CH 3 ;

[0049] (ix) -(CH 2 ) n -Y-, where Y is O or CH 2 , and n is 2 or 3; or

[0050] (x) C 1-4 alkyl ester.

[0051] 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.

[0052] The second aspect of the present invention provides a method for treating cancer, which comprises administering to a patient in need of treatment a compound as defined in the first aspect of the present invention or a pharmaceutically acceptable salt thereof, 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 as defined in the first aspect of the present invention or a pharmaceutically acceptable salt thereof in the manufacture of an agent for treating cancer, and a compound as defined in the first aspect of the present invention or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof for cancer treatment.

[0053] As described below, the compound as defined in the first aspect can be administered simultaneously or sequentially with radiotherapy and / or chemotherapy in cancer treatment.

[0054] The third aspect of the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof:

[0055]

[0056] Wherein:

[0057] R 1 , R 2 , R 3 and R 4 are independently selected from:

[0058] (i) H;

[0059] (ii) C1-3 An alkyl group, optionally substituted with:

[0060] Hydroxy

[0061] C 1-2 An alkoxy group, optionally substituted with one or more fluoro groups

[0062] NH 2 ,

[0063] Phenyl

[0064] C 5-6 Heteroaryl

[0065] C 1-4 Alkylcarbamoyl

[0066] Acylamide, or

[0067] One or more fluoro groups;

[0068] (iii) C 1-3 An alkoxy group, optionally substituted with C 3-6 Cycloalkyl or with one or more fluoro groups;

[0069] (iv) C 3-6 Cycloalkyl;

[0070] (v) Halo;

[0071] (vi) COR C , where R C Is selected from NR N1 R N2 , where R N1 And R N2 Are independently selected from H and methyl;

[0072] (vii) Cyano, NH 2 Or NO 2 ; And

[0073] (viii) Phenyl or C 5-6 Heteroaryl, optionally substituted with methyl, cyano, hydroxy or methoxy;

[0074] Ar is phenyl, naphthyl or C 5-10 Heteroaryl, the group optionally substituted with one or more groups selected from:

[0075] (i) C 1-4 An alkyl group, optionally substituted with hydroxy, C 1-2 Alkoxy, NH 2 , C 1-4 Alkylcarbamoyl or with one or more fluoro groups;

[0076] (ii) C 3-6 Cycloalkyl;

[0077] (iii) Hydroxyl; cyano; NR N3 R N4 , where R N3 and R N4 are independently selected from H and methyl; or acyl amido;

[0078] (iv) Halo;

[0079] (v) C 1-3 alkoxy, which is optionally substituted by hydroxyl, C(O)NH 2 , C 3-6 cycloalkyl, phenyl, C 5-6 heteroaryl or substituted by one or more fluoro groups;

[0080] (vi) Phenoxy, which is optionally substituted by fluoro;

[0081] (vii) Phenyl or C 5-6 heteroaryl;

[0082] (viii) SF 5 or SO 2 CH 3 ;

[0083] (ix) -(CH 2 ) n -Y-, where Y is O or CH 2 , and n is 2 or 3; or

[0084] (x) C 1-4 alkyl ester;

[0085] Provided that:

[0086] (a) At least one of R 1 , R 2 , R 3 and R 4 is not H, and optionally R 3 is not CF 3 ; or

[0087] (b) R 4 is OMe; or

[0088] (c) R 4 is Cl, and R 1 , R 2 and R 3 are H, or R 2 is C 1-3 alkyl or bromine, and R 1 and R 3 are H; or

[0089] (d)R 3 is C 1-3 alkyl and R 1 , R 2 and R 4 are H.

[0090] The fourth aspect of the present invention provides the synthesis of the compounds as defined in the first or third aspect of the present invention, as described below.

[0091] Definition

[0092] Unless otherwise specified, as used herein, the term "substituted" refers to a parent group having one or more substituents. The term "substituent" is used herein in its conventional meaning and refers to a chemical moiety covalently attached to or, where appropriate, fused to the parent group. As used herein, the phrase "optionally substituted" refers to a parent group that may be unsubstituted or substituted.

[0093] C 5-12 Heteroaryl: As used herein, the term "C 5-12 heteroaryl" refers to a monovalent moiety obtained by removing a hydrogen atom from an aromatic structure having 5 to 12 ring atoms, 1 to 3 of which 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.

[0094] 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 (whether carbon atoms or heteroatoms).

[0095] C 5-12 Examples of heteroaryl structures include, but are not limited to, those derived from the following:

[0096] N 1 : pyrrole(azole)(C 5 ), pyridine(azine)(C 6 ); pyridone(C 6 ); indole(C 9 ); quinoline(C 10 );

[0097] O 1 : furan(oxole)(C 5 );

[0098] S 1 : thiophene / thiole(C 5 );

[0099] N1 O 1 : Oxazole (C 5 )、isoxazole (C 5 )、isoxazine (C 6 );

[0100] N 2 O 1 : Oxadiazole (furazan) (C 5 );

[0101] N 1 S 1 : Thiazole (C 5 )、isothiazole (C 5 );

[0102] N 2 S 1 : Thiadiazole (C 5 )

[0103] 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 )

[0104] N 3 : Triazole (C 5 )、triazine (C 6 ).

[0105] Halogen group: As used herein, the term "halogen group" refers to a group selected from fluorine, chlorine, bromine, and iodine.

[0106] Cyano group: As used herein, the term "cyano group" refers to the group -C≡N.

[0107] Hydroxyl group: As used herein, the term "hydroxyl group" refers to the group -OH.

[0108] Phenyl group: As used herein, the term "phenyl group" refers to the monovalent moiety (-C 6 H 5 ) obtained by removing a hydrogen atom from a single aromatic ring structure having 6 carbon ring atoms.

[0109] Phenoxy group: As used herein, the term "phenoxy group" refers to the monovalent moiety (-O-C 6 H 5 ) obtained by removing a hydrogen atom from the oxygen atom of phenol.

[0110] C 1-4 Alkyl: As used herein, the term "C 1-4 alkyl" refers to a monovalent moiety obtained by removing a hydrogen atom from a carbon atom of a saturated hydrocarbon compound having 1 to 4 carbon atoms.

[0111] Examples of saturated alkyls include, but are not limited to, methyl (C 1 ), ethyl (C 2 ), propyl (C 3 ), and butyl (C 4 ).

[0112] Examples of saturated straight-chain alkyls include, but are not limited to, methyl (C 1 ), ethyl (C 2 ), n-propyl (C 3 ), and n-butyl (C 4 ).

[0113] Examples of saturated branched-chain alkyls include isopropyl (C 3 ), isobutyl (C 4 ), sec-butyl (C 4 ), and tert-butyl (C 4 ).

[0114] C 3-6 Cycloalkyl: As used herein, the term "C 3-6 cycloalkyl" refers to a monovalent moiety obtained by removing a hydrogen atom from a carbon atom of a saturated cyclic hydrocarbon compound having 3 to 6 carbon atoms. C 3-6 Examples of cycloalkyls include, but are not limited to, cyclopropyl (C 3 ), cyclobutyl (C 4 ), cyclopentyl (C 5 ), and cyclohexyl (C 6 ).

[0115] C 1-4 Alkoxy: As used herein, the term "C 1-4 alkoxy" refers to a monovalent moiety obtained by removing a hydrogen atom from an oxygen atom of a saturated alcohol compound having 1 to 4 carbon atoms. It can be represented as -O-C 1-4 alkyl. C 1-4 Examples of alkoxys include, but are not limited to, methoxy (C 1 ), ethoxy (C 2 ), propoxy (C 3 ), and butoxy (C 4 ).

[0116] C 1-4 Alkylcarbamoyl: -NHC(=O)OR, where R is C 1-4 alkyl as defined above. C1-4 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 .

[0117] Acylamido: -NR(C=O)R', where R and R' are independently selected from H and C 1-4 alkyl as defined above. R and R' can also be -(CH 2 ) n -, where n is 3 or 4. Examples of acylamido include, but are not limited to, -N(H)C(=O)CF 3 , N(H)C(=O)Me, and:

[0118]

[0119] C 1-4 Alkyl ester: As used herein, the term "C 1-4 alkyl ester" refers to a monovalent moiety obtained by removing a hydrogen atom from the oxygen atom of a saturated carboxylic acid compound having 1 to 5 carbon atoms. It can be represented as -O-C(O)-C 1-4 alkyl. Examples of C 1-4 alkyl ester groups include, but are not limited to, acetoxy (-O-C(O)-CH 3 ), propionyloxy (-O-C(O)-CH 2 CH 3 ), butyryloxy (-O-C(O)-CH 2 CH 2 CH 3 ) and pentyryloxy (-O-C(O)-CH 2 CH 2 CH 2 CH 3 ).

[0120] Including other forms

[0121] Unless otherwise specified, well-known ions, salts, solvates, and protected forms including these substituents are included above. For example, a reference to a carboxylic acid (-COOH) also includes its anionic (carboxylate) form (-COO - ), salt or solvate, as well as conventional protected forms. Similarly, a reference to an amino group includes the protonated form of the amino group (-N + HR 1 R 2) salts or solvates (e.g., hydrochloride), and the conventional protected forms of amino groups. Similarly, the mention of a hydroxyl group also includes its anionic form (-O - ) salts or solvates, and the conventional protected forms.

[0122] Salt

[0123] The preparation, purification and / or handling of the corresponding salts (e.g., pharmaceutically acceptable salts) of the active compound may be convenient or necessary. Examples of pharmaceutically acceptable salts are discussed in Berge 1977.

[0124] For example, if the compound is anionic or has a functional group that can be anionic (e.g., -COOH can be -COO - ), then salts can be formed with suitable cations. Examples of suitable inorganic cations include, but are not limited to, alkali metal ions (such as Na + and K + ), alkaline earth metal cations (such as Ca 2+ and Mg 2+ ), and other cations (such as Al +3 ). Examples of suitable organic cations include, but are not limited to, ammonium ions (i.e., NH 4 + ) and substituted ammonium ions (e.g., NH 3 R + , NH 2 R 2 + , NHR 3 + , NR 4 + ). Some examples of suitable substituted ammonium ions are those derived from: ethylamine, diethylamine, dicyclohexylamine, triethylamine, butylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, benzylamine, phenylbenzylamine, choline, meglumine, and tromethamine, as well as amino acids (such as lysine and arginine). Examples of common quaternary ammonium ions are N(CH 3 ) 4 + .

[0125] If the compound is cationic or has a functional group that can be cationic (e.g., -NH 2 can be -NH 3 + ), then salts can be formed with suitable anions. 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.

[0126] 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, ethylenediaminetetraacetic acid, ethanedisulfonic acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, hydroxymaleic acid, hydroxynaphthoic acid, hydroxyethanesulfonic 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.

[0127] Solvate

[0128] The corresponding solvate of the active compound for preparation, purification, and / or processing may be convenient or required. 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. If the solvent is water, the solvate may conveniently be called a hydrate, such as a monohydrate, dihydrate, trihydrate, etc.

[0129] Isomer

[0130] Certain compounds of the present invention 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; cisoid- and transoid-forms; α- and β-forms; axial and equatorial forms; boat-, chair-, twist-boat-, envelope-, and half-chair-forms; and combinations thereof, collectively referred to hereinafter as "isomers" (or "isomeric forms").

[0131] The term "chiral" refers to a molecule with the property of non-superimposability with its mirror image partner, while the term "achiral" refers to a molecule that is superimposable on its mirror image partner.

[0132] The term "stereoisomer" refers to a compound having the same chemical composition but different arrangements of atoms or groups in space.

[0133] "Diastereomers" refer to stereoisomers that have two or more chiral centers and are not mirror images of each other. Diastereomers have different physical properties, such as melting point, boiling point, spectroscopic properties, and reactivity. Mixtures of diastereomers can be separated according to high-resolution analytical procedures, such as electrophoresis and chromatography.

[0134] "Enantiomers" refer to two stereoisomers of a compound that are non-superimposable mirror images of each other.

[0135] The stereochemical definitions and conventions used herein generally follow S.P. Parker, ed., McGraw-Hill Dictionary of Chemical Terms (1984), McGraw-Hill Book Company, New York; and 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 thus exist in different stereoisomeric forms. All stereoisomeric forms of the compounds of the present invention are expected to form part of the present invention, including but not limited to diastereomers, enantiomers, and atropisomers, as well as mixtures thereof, such as racemic mixtures. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light. When describing optically active compounds, the prefixes D and L or R and S are used to denote the absolute configuration of the molecule around one or more of its chiral centers. The prefixes d and l or (+) and (-) are used to indicate the sign of rotation of plane-polarized light by the compound, where (-) or l means the compound is levorotatory. Compounds with the prefix (+) or d are dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of each other. Specific stereoisomers are also referred to as enantiomers, and mixtures of such isomers are commonly referred to as enantiomeric mixtures. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which may exist in the absence of stereoselectivity or stereospecificity in a chemical reaction or process. The terms "racemic mixture" and "racemate" refer to an equimolar concentration mixture of two enantiomeric substances that lacks optical activity.

[0136] In the present invention, the carbon atom bonded to R 1 and Cy can be a stereochemical center, i.e., when R 1 is not H and R 1 and Cy are different. The compounds of the present invention can be racemic mixtures, or can be enantiomerically enriched or substantially enantiomerically pure.

[0137] Note that, unless otherwise noted with respect to tautomeric forms as discussed below, the term “isomer” as used herein specifically excludes structural (or constitutional) isomers (i.e., isomers in which the connections between atoms are different rather than just the positions of the atoms in space). For example, a reference to methoxy - OCH 3 should not be construed as a reference to its structural isomer hydroxy - methyl - CH 2 OH. Similarly, a reference to o - chlorophenyl should not be construed as a reference to its structural isomer m - chlorophenyl. However, a reference to a class of structures may well include the structural isomeric forms belonging to that class (e.g., C 1-7 alkyl includes n - propyl and isopropyl; butyl includes n - butyl, isobutyl, sec - butyl, and tert - butyl; methoxyphenyl includes o - methoxyphenyl, m - methoxyphenyl, and p - methoxyphenyl).

[0138] The above exclusion does not pertain to tautomeric forms, such as keto -, enol -, and enolate - forms, as in, for example, the following tautomeric pairs: keto / enol (illustrated below), imine / enamine, amide / imino alcohol, amidine / amidine, nitroso / oxime, thioketone / enethiol, N - nitroso / hydroxyazo, and nitro / isonitro.

[0139]

[0140] The term “tautomer” or “tautomeric form” refers to structural isomers of different energies that can interconvert via a low energy barrier. For example, proton tautomers (also called prototropic tautomers) include interconversions that occur via proton migration, such as keto - enol and imine - enamine isomerization. Valence tautomers include interconversions that occur through the reorganization of some of the bonding electrons.

[0141] Note that the term “isomer” specifically includes compounds having one or more isotope substitutions. For example, H can be in any isotopic form, including 1 H, 2 H (D), and 3 H (T); C can be in any isotopic form, including 12 C, 13 C, and 14 C; O can be in any isotopic form, including 16 O and 18 O; and so on.

[0142] Examples of isotopes that can be incorporated into the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as but not limited to 2 H (deuterium, D), 3 H (tritium), 11 C, 13 C, 14 C, 15N, 18 F, 31 P, 32 P, 35 S, 36 Cl and 125 I. The compounds of the invention may be labeled with multiple isotopes, such as those incorporating radioactive isotopes such as 3H, 13C and 14C. The isotopically labeled compounds can be used in metabolic studies, reaction kinetics studies, detection or imaging techniques (such as positron emission tomography (PET) or single photon emission computed tomography (SPECT), including determination of drug or substrate tissue distribution), or can be used for radioactive treatment of patients. Deuterium-labeled or substituted therapeutic compounds of the invention may have improved DMPK (drug metabolism and pharmacokinetics) properties, related to distribution, metabolism and excretion (ADME). Substitution with heavier isotopes such as deuterium can provide certain therapeutic advantages due to greater metabolic stability, such as increased in vivo half-life or reduced dose requirements. 18F-labeled compounds can be used in PET or SPECT studies. The isotopically labeled compounds of the invention and their prodrugs can generally be prepared by carrying out the procedures described in the schemes or examples and preparations below by substituting unlabeled reagents with readily available isotopically labeled reagents. In addition, substitution with heavier isotopes, especially deuterium (i.e., 2H or D), can provide certain therapeutic advantages due to greater metabolic stability, such as increased in vivo half-life or reduced dose requirements or improvement of the therapeutic index. It should be understood that deuterium is considered a substituent in this context. The concentration of such heavier isotopes, especially deuterium, can be defined by the isotope enrichment factor. In the compounds of the invention, any atom not specifically designated as a particular isotope is intended to represent any stable isotope of that atom.

[0143] Unless otherwise specified, reference to a particular compound includes all such isomeric forms, including (fully or partially) its 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 known in the art or can be readily obtained by adapting the methods taught herein or known methods in a known manner.

[0144] Inhibit

[0145] The compounds of the invention inhibit the activity of one or more KATs of the MYST family (i.e., TIP60, KAT6B, MOZ, HBO1 and MOF).

[0146] The inhibitory activity of the compounds of the invention may vary among the KATs of the MYST family.

[0147] Compared with other KATs of the MYST family, the compounds of the present invention can selectively inhibit the activity of one or more KATs of the MYST family, that is, the inhibitory activity of the compounds on one or more KATs of the MYST family can be higher than their inhibitory activity on one or more other KATs of the MYST family.

[0148] The compounds of the present invention can (selectively) inhibit the activity of a single KAT of the MYST family. Therefore, the compounds of the present invention can inhibit the activity of TIP60, MORF, MOZ, HBO1 or MOF.

[0149] The compounds of the present invention can inhibit the activity of two KATs of the MYST family (for example, MOZ and MORF).

[0150] The compounds of the present invention can inhibit the activity of three KATs of the MYST family (for example, MOZ, MORF and HBO1).

[0151] The compounds of the present invention can inhibit the activity of four KATs of the MYST family (for example, MOZ, MORF, HBO1 and TIP60).

[0152] The compounds of the present invention can inhibit the activity of all five KATs of the MYST family. Therefore, the compounds can inhibit the activity of TIP60, MORF, MOZ, HBO1 and MOF.

[0153] The compounds of the present invention can particularly inhibit the activity of MOZ and / or KAT6B and / or HBO1 and / or TIP60.

[0154] Therapeutic indications

[0155] The compounds disclosed herein can provide therapeutic benefits in a variety of conditions, particularly in the treatment or prevention of cancer.

[0156] Cancer

[0157] Inhibitors of post-translational lysine acetylation mediated by KAT of the MYST family are regarded as promising anti-tumor agents and can therefore be useful therapeutic agents, for example, for the treatment of cancer. The agents can also be used as therapeutic agents for the treatment of cancers exhibiting overexpression of MYST proteins.

[0158] "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's lymphoma, Hodgkin's disease, prostate cancer, lung cancer, melanoma, breast cancer, colorectal cancer, colon cancer, squamous cell carcinoma and gastric cancer.

[0159] Alternatively, the cancer may include adrenocortical carcinoma, anal cancer, bladder cancer, blood cancer, bone cancer, brain tumor, female reproductive system cancer, male reproductive system cancer, central nervous system lymphoma, cervical cancer, childhood rhabdomyosarcoma, childhood sarcoma, endometrial cancer, endometrial sarcoma, esophageal cancer, eye cancer, gallbladder cancer, gastrointestinal cancer, hairy cell leukemia, head and neck cancer, hepatocellular carcinoma, hypopharyngeal cancer, Kaposi's sarcoma, kidney cancer, laryngeal cancer, liver cancer, malignant fibrous histiocytoma, malignant thymoma, mesothelioma, multiple myeloma, myeloma, nasal and paranasal sinus 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 tumor, 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.

[0160] The cancer may be of a specific 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).

[0161] The cancer may be a MYST overexpressing cancer. The cancer may overexpress MYST protein relative to non-cancerous tissue. In some cases, the cancer overproduces MYST mRNA relative to non-cancerous tissue. The overexpressed MYST protein or MYST mRNA may be any KAT of the MYST family, i.e., any one of TIP60, KAT6B, MOZ, HBO1, and MOF. In some embodiments, the cancer may overexpress more than one KAT of the MYST family, e.g., two or more selected from the group consisting of TIP60, KAT6B, MOZ, HBO1, and MOF. The cancer may be a cancer that escapes immune recognition, for example, via tumor-associated Treg cells.

[0162] Alternatively or additionally, the cancer can be a bromodomain overexpressing cancer: the cancer cells can overexpress one or more bromodomain-containing proteins (referred to herein as "bromodomain proteins") relative to non-cancerous tissue. As compared to non-cancerous tissue, it can overproduce one or more bromodomain mRNAs. In some cases, the levels of bromodomain protein and / or mRNA in the cells are at levels approximately equal to those of non-cancerous cells. The cancer can 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 referred to as BRM), and SMARC4 (also referred to as BRG1). For example, some colon cancers overexpress BRD8. Some acute myeloid leukemia cells overexpress BRD4.

[0163] Treg Cells as Cancer Targets

[0164] Treg cells are immunosuppressive cells that are used to prevent autoimmunity in the immune system of healthy mammals. However, some cancers use upregulating Treg activity to evade the host immune system. Treg infiltration in multiple tumor types is associated with poor patient prognosis and depletion of Treg cells in tumor models demonstrates increased anti-tumor immune responses (Melero 2015). Tumor-associated Treg suppression of the host immune system has been reported in lung cancer (Joshi 2015), (Tso 2012), breast cancer (Gobert 2009; Yan 2011), prostate cancer (Miller 2006), and pancreatic cancer (Wang X 2016). FOXP3 is regarded as the master regulator of Treg differentiation, development, and function of Treg cells.

[0165] Several studies have demonstrated that acetylation of FOXP3 plays a key role in the stability of the FOXP3 protein and in regulating its ability to access DNA; and FOXP3 acetylation is mediated by KAT (Dhuban 2017). Reduced TIP60-mediated acetylation of FOXP3 has been shown to attenuate Treg development, indicating that inhibition of the acetylation activity of MYST proteins can be used to intervene in additional mechanisms of diseases such as cancer.

[0166] Combination Therapy

[0167] The agents described herein can be used in combination with other anti-cancer therapies. It can act synergistically with chemotherapy or radiotherapy, and / or with targeted therapies (including but not limited to FGFR1 inhibitors and therapies targeting nuclear hormone receptors). For example, the agents described herein can be used 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.

[0168] Inhibiting KAT proteins of the MYST family to reduce the degree of lysine acetylation of histones (and other nuclear proteins described herein) will likely sensitize tumor cells to chemotherapy and radiotherapy by attenuating the process of DNA damage repair (e.g., repair of DNA double-strand breaks (DSBs)), thus increasing the frequency of chemotherapy- and radiotherapy-induced cancer cell death. Therefore, inhibiting KAT proteins of the MYST family will likely be synergistically enhanced sufficiently with low doses of chemotherapy or radiotherapy.

[0169] Accordingly, in some cases, the MYST protein antagonists disclosed herein can be administered in combination with radiotherapy or chemotherapy regimens. It is administered simultaneously with or sequentially to radiotherapy and / or chemotherapy. Suitable chemotherapy agents and radiotherapy protocols will be readily understood by the skilled person. Specifically, the compounds described herein can be combined with low doses of chemotherapy or radiotherapy. The appropriate doses for "low-dose" chemotherapy or radiotherapy will be readily understood by the skilled practitioner.

[0170] Specifically, in the case where the compounds of the present application are used to eliminate Treg suppression, these compounds can be combined with immune checkpoint inhibitors (Melero 2015, Wang L 2016). In addition, in the case where the compounds of the present invention for eliminating Treg suppression can be used in combination with radiotherapy, to reduce the depletion of Treg function in tumors (Persa 2015, Jeong2016)

[0171] Methods of treatment

[0172] The compounds of the present invention can be used in therapeutic methods. There is also provided a method of treatment, the method 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 a benefit to the patient. The benefit can be at least improvement of at least one symptom. The actual amount administered and the rate and duration of administration will depend on the nature and severity of the disease being treated. Treatment prescriptions (e.g., decisions regarding dosage) are within the purview of general practitioners and other physicians.

[0173] As described above, the anti-cancer treatment defined herein can be applied as a sole therapy or, in addition to the compounds of the present invention, can also involve conventional surgery or radiotherapy or chemotherapy. The chemotherapy can include one or more of the following classifications of anti-tumor agents:

[0174] (i) Other anti-proliferative / anti-tumor drugs and their combinations used in medical oncology, such as alkylating agents (e.g., cisplatin, oxaliplatin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulfan, temozolomide, and nitrosoureas); antimetabolites (e.g., gemcitabine and anti-folates (such as fluoropyrimidines, e.g., 5-fluorouracil) and tegafur, raltitrexed, methotrexate, cytarabine, and hydroxyurea); anti-tumor antibiotics (e.g., anthracyclines, such as doxorubicin, bleomycin, epirubicin, daunorubicin, epirubicin, idarubicin, mitomycin-C, actinomycin D, and mithramycin); anti-mitotic agents (e.g., vinca alkaloids (such as vincristine, vinblastine, vindesine, and vinorelbine) and taxanes (such as paclitaxel and docetaxel (Taxotere)) and polo kinase inhibitors); and topoisomerase inhibitors (e.g., epipodophyllotoxins, such as etoposide and teniposide, amsacrine, topotecan, and camptothecin);

[0175] (ii) Cytostatic agents, such as anti-estrogens (e.g., tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene, and idoxifene), anti-androgens (e.g., bicalutamide, flutamide, nilutamide, and cyproterone acetate), LHRH antagonists or LHRH agonists (e.g., goserelin, leuprorelin, and buserelin), progestins (e.g., megestrol acetate), aromatase inhibitors (e.g., anastrozole, letrozole, vorozole, and exemestane), and 5α-reductase inhibitors (such as finasteride);

[0176] (iii) Anti-invasive agents (such as c-Src kinase family inhibitors, such as 4-(6-chloro-2,3-methylenedioxyanilino)-7-[2-(4-methylpiperazin-1-yl)ethoxy]-5-tetrahydropyran-4-yloxyquinazoline (AZD0530; International Patent Application WO 01 / 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), and metalloproteinase inhibitors (such as marimastat), urokinase plasminogen activator receptor function inhibitors or heparinase antibodies);

[0177] (iv) Growth factor function inhibitors: For example, the inhibitors include growth factor antibodies and growth factor receptor antibodies (e.g., anti-erbB2 antibody trastuzumab [HerceptinT], anti-EGFR antibody panitumumab, anti-erbB1 antibody cetuximab [Erbitux, C225], and any growth factor or growth factor receptor antibody disclosed by Stern 2005; the inhibitors also include tyrosine kinase inhibitors, such as 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 (CI 1033); 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; serine / threonine kinase inhibitors (e.g., Ras / Raf signaling inhibitors, such as farnesyl transferase inhibitors, such as sorafenib (BAY 43-9006)); inhibitors of cell signaling through 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 cyclin-dependent kinase inhibitors, such as CDK2 and / or CDK4 inhibitors;

[0178] (v) Anti-angiogenic and anti-lymphangiogenic agents, such as those that inhibit the effects of vascular endothelial growth factor [e.g., anti-vascular endothelial growth factor A (VEGFA) antibody bevacizumab (Avastin™), 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 WO 01 / 32651), 4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazoline (cediranib; AZD2171; Example 240 in WO 00 / 47212), vatalanib (PTK787; WO 98 / 35985), pazopanib (GW786034), axitinib (AG013736), sorafenib, and sunitinib (SU11248; WO 01 / 60814), compounds such as those disclosed in International Patent Applications WO97 / 22596, WO 97 / 30035, WO97 / 32856, and WO 98 / 13354, and compounds that act through other mechanisms (e.g., linomide, integrin avb3 function inhibitor, and angiostatin)];

[0179] (vi) Vascular damaging agents, such as combretastatin A4 and compounds disclosed in International Patent Applications WO 99 / 02166, WO 00 / 40529, WO 00 / 41669, WO 01 / 92224, WO 02 / 04434, and WO 02 / 08213;

[0180] (vii) Antisense therapies, such as those directed against the targets listed above, such as ISIS 2503 (anti-ras antisense);

[0181] (viii) Gene therapy methods, including, for example, methods of replacing abnormal genes such as abnormal p53 or abnormal BRCA1 or BRCA2, GDEPT (gene-directed enzyme prodrug therapy) methods (such as those using cytosine deaminase, thymidine kinase, or bacterial nitroreductase), and methods of increasing a patient's tolerance to chemotherapy or radiotherapy (such as multi-drug resistance gene therapy); and

[0182] (ix) Immunotherapy methods, including ex vivo and in vivo methods of increasing the immunogenicity of a patient's tumor cells (such as transfection with cytokines such as interleukin 2, interleukin 4 or granulocyte macrophage colony-stimulating factor), methods of reducing T cell anergy, methods of using transfected immune cells such as dendritic cells transfected with cytokines, methods of using tumor cell lines transfected with cytokines, and methods of using anti-idiotype antibodies

[0183] administer

[0184] The active compound or the pharmaceutical composition comprising the active compound can be administered to a subject by any convenient route of administration (systemic / peripheral or at the desired site of action), including but not limited to orally (e.g., by ingestion); topically (including e.g., transdermal, intranasal, ocular, buccal and sublingual); pulmonary (e.g., by inhalation or insufflation therapy using, for example, an aerosol, e.g., orally or nasally); rectal; vaginal; 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 reservoir implantation, e.g., subcutaneously, intravitreally or intramuscularly. 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), an equine (e.g., horse), a primate, a simian (e.g., monkey or ape), a monkey (e.g., marmoset, baboon), an ape (e.g., gorilla, chimpanzee, orangutan, gibbon) or a human.

[0185] formulation

[0186] Although the active compound is potentially administrable alone, it is preferably presented as a pharmaceutical composition (e.g., a formulation) which comprises at least one active compound as defined above, together 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 optionally other therapeutic or prophylactic agents.

[0187] Accordingly, the present invention also provides a pharmaceutical composition as defined above, and a method of manufacturing a pharmaceutical composition, the method comprising mixing at least one active compound as defined above, together with one or more pharmaceutically acceptable carriers, excipients, buffers, adjuvants, stabilizers or other materials as described herein.

[0188] As used herein, the term "pharmaceutically acceptable" means a compound, material, composition, and / or dosage form that, within the scope of sound medical judgment, is 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 is commensurate with a reasonable benefit / risk ratio. Each carrier, excipient, etc. must also be "acceptable" in the sense of being compatible with the other ingredients of the formulation.

[0189] 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.

[0190] The formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the pharmaceutical art. The methods include the step of bringing into association the active compound with a carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the active compound with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product.

[0191] The formulations may be in the form of a liquid, solution, suspension, emulsion, elixir, syrup, tablet, lozenge, granule, powder, capsule, cachet, pill, ampoule, suppository, pessary, ointment, gel, paste, cream, spray, mist, foaming agent, lotion, oil, bolus, electuary, or aerosol.

[0192] 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 an electuary; or as a paste.

[0193] Tablets can be prepared by conventional means, such as by compression or molding, optionally together with one or more auxiliary ingredients. Compressed tablets can be prepared by compressing the active compound in free-flowing form, such as a powder or granules, in a suitable machine, the active compound optionally being mixed with one or more binders (e.g., povidone, gelatin, gum arabic, 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, crospovidone, croscarmellose sodium); surfactants or dispersants or wetting agents (e.g., sodium lauryl sulfate); and preservatives (e.g., methylparaben, propylparaben, sorbic acid). Molded tablets can be prepared by molding a mixture of powdered compounds moistened with an inert liquid diluent in a suitable machine. The tablets can be optionally coated or scored and can be formulated, for example, with hydroxypropylmethylcellulose in varying proportions to provide the desired release characteristics so as to provide slow or controlled release of the active compound therein. The tablets can optionally be provided with an enteric coating to provide release in parts of the intestine other than the stomach.

[0194] Preparations suitable for topical administration (e.g., transdermal, intranasal, ocular, buccal, and sublingual) can be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols, or oils. Alternatively, the preparation can comprise a patch or dressing, such as a bandage or plaster, impregnated with the active compound and optionally one or more excipients or diluents.

[0195] Preparations suitable for topical administration in the mouth include lozenges, which contain the active compound in a flavored matrix, usually sucrose and gum arabic or tragacanth; pills, which contain the active compound in an inert matrix such as gelatin and glycerin or sucrose and gum arabic; and mouthwashes, which contain the active compound in a suitable liquid carrier.

[0196] Preparations suitable for topical administration to the eye also include eye drops, in which the active compound is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the active compound.

[0197] Preparations suitable for nasal administration, where the carrier is a solid, include coarse powders having a specific size, for example, in the range of about 20 microns to about 500 microns, which are administered in a manner where nasal inhalation is taken, i.e., by rapid inhalation through the nasal passage from a powder container held in close proximity to the nose. Suitable preparations for administration as, for example, nasal sprays, nasal drops, or aerosol administration using a nebulizer, where the carrier is a liquid, include aqueous or oily solutions of the active compound.

[0198] Formulations suitable for administration by inhalation include those presented as an aerosol spray from a pressurized pack, using a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichloro - tetrafluoroethane, carbon dioxide or other suitable gases.

[0199] Formulations suitable for topical administration via the skin include ointments, creams and lotions. When formulated in an ointment, the active compound can optionally be used with a paraffin or water - miscible ointment base. Alternatively, the active compound can be formulated in a cream with an oil - in - water cream base. If necessary, the aqueous phase of the cream base can include, for example, at least about 30% w / w of a polyol, 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 skin penetration enhancers include dimethyl sulfoxide and related analogues.

[0200] When formulated as a topical lotion, the oil phase can optionally contain only an emulsifier (otherwise known as an emulgator), or it can contain at least one emulsifier with a fat or an oil or a mixture of both a fat and an oil. Preferably, a 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. Taken together, the emulsifier with or without a stabilizer constitutes a so - called emulsifying wax, and the wax together with the oil and / or fat constitutes a so - called emulsifying ointment base, which forms the oily disperse phase of the cream formulation.

[0201] Suitable emulgators and lotion 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 achieving the desired cosmetic properties, since the solubility of the active compound in most oils that could potentially be used in pharmaceutical lotion formulations can be extremely low. Thus, the cream should preferably be a non - greasy, non - staining and washable product with a suitable consistency to avoid leakage from a tube or other container. Straight - chain or branched, mono - or di - alkyl esters such as di - isoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2 - ethylhexyl palmitate or a blend of branched esters called Crodamol CAP can be used, the latter three being preferred esters. They can be used alone or in combination, depending on the desired properties.

[0202] Alternatively, high - melting - point lipids such as white soft paraffin and / or liquid paraffin or other mineral oils can be used.

[0203] Formulations suitable for rectal administration can be presented as suppositories with a suitable base containing, for example, cocoa butter or salicylate.

[0204] Preparations suitable for vaginal administration can be presented as pessaries, tampons, creams, gels, pastes, foaming agents or spray preparations which, in addition to the active compound, also contain suitable carriers known in the art.

[0205] Preparations suitable for parenteral administration (e.g., by injection, including cutaneous, subcutaneous, intramuscular, intravenous and intradermal) include aqueous and non-aqueous isotonic, pyrogen-free, sterile injection solutions which may contain antioxidants, buffers, preservatives, stabilizers, bacteriostatic agents and solutes rendering the preparation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending and thickening agents and liposomes or other particulate systems designed to target the compound to blood components or one or more organs. Examples of suitable isotonic vehicles for use in such preparations include sodium chloride injection, Ringer's solution or lactated Ringer's injection. Typically, the concentration of the active compound in the 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 preparations may be presented in unit dose or multi-dose sealed containers (e.g., ampoules and vials) and may be stored under lyophilized (freeze-dried) conditions which require only the immediate addition of a sterile liquid carrier (e.g., water for injection) prior to use. Interim injection solutions and suspensions may be prepared from sterile powders, granules and tablets. The preparations may be in the form of liposomes or other particulate systems designed to target the active compound to blood components or one or more organs.

[0206] Dosage

[0207] Those skilled in the art will appreciate that the appropriate dosage of the compound and of the compositions containing the compound may vary between patients. Determining the optimal dosage will generally involve balancing the level of therapeutic benefit against any risk or detrimental side effects. The selected dosage level will depend on a variety of factors including, but not limited to, the activity of the specific compound, the route of administration, the time of administration, the rate of excretion of the compound, the duration of the 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 prior medical history of the patient. The amount of the compound and the route of administration will ultimately be at the discretion of the physician, veterinarian or clinician, but in general, the dosage will be selected to achieve a local concentration at the site of action that achieves the desired effect without causing substantial detrimental side effects.

[0208] Administration can be achieved in one dose, either continuously or intermittently (e.g., in divided doses at appropriate time intervals) during the course of treatment. Methods for determining the most effective means and doses of administration are well known to those skilled in the art and will vary with the formulation used for 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 dose levels and patterns selected by the treating physician, veterinarian, or clinician.

[0209] Generally, suitable doses of the active compound are in the range of about 100 ng to about 25 mg (more typically, about 1 μg to about 10 mg) / per kg of subject body weight / day. In cases where the active compound is a salt, ester, amide, prodrug, etc., the amount administered is calculated based on the parent compound and thus, the actual weight to be used increases proportionally.

[0210] In one embodiment, the active compound is administered to a human patient according to the following dosing regimen: about 100 mg, three times a day.

[0211] In one embodiment, the active compound is administered to a human patient according to the following dosing regimen: about 150 mg, twice a day.

[0212] In one embodiment, the active compound is administered to a human patient according to the following dosing regimen: about 200 mg, twice a day.

[0213] However, in one embodiment, the active compound is administered to a human patient according to the following dosing regimen: about 50 mg or about 75 mg, three or four times a day.

[0214] In one embodiment, the active compound is administered to a human patient according to the following dosing regimen: about 100 mg or about 125 mg, twice a day.

[0215] Treatment

[0216] As used herein in the context of treating a condition, the term "treatment" generally refers to treatment and therapy, whether in humans or animals (e.g., in veterinary applications), where some desired therapeutic effect (e.g., inhibition of the progression of the condition) is achieved, and includes a decrease in the rate of progression, a halt in the rate of progression, regression of the condition, improvement of the condition, and cure of the condition. Also included is treatment as a prophylactic measure (i.e., prophylaxis / prevention).

[0217] As used herein, the term "therapeutically effective amount" refers to the amount of an active compound or a material, composition, or dosage form containing the active compound that, when administered according to the desired treatment regimen, is effective for producing some desired therapeutic effect, commensurate with a reasonable benefit / risk ratio.

[0218] Similarly, as used herein, the term "prophylactically effective amount" refers to the amount of an active compound or a material, composition or dosage form comprising the active compound which, when administered according to a desired treatment regimen, is effective to produce some desired prophylactic effect commensurate with a reasonable benefit / risk ratio.

[0219] Subject / Patient

[0220] The subject / patient can 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., avian), a canine (e.g., dog), a feline (e.g., cat), an equine (e.g., horse), a swine (e.g., pig), a sheep (e.g., sheep), a bovine (e.g., cow), a primate, an ape (e.g., monkey or ape), a monkey (e.g., marmoset, baboon), an ape (e.g., gorilla, chimpanzee, orangutan, gibbon) or a human.

[0221] In addition, the subject / patient can be any of its developmental forms, such as a fetus. In a preferred embodiment, the subject / patient is a human.

[0222] General Synthesis Method

[0223] The compounds of the present invention can be prepared by using the following general methods and the procedures described in detail in the Examples. The reaction conditions mentioned are illustrative and not restrictive. For example, those skilled in the art can use a wide range of synthetic methods to synthesize the desired compounds, such as but not limited to the methods described in the literature (e.g., but not limited to 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).

[0224] The compounds of formula (l) as described above can be prepared by the synthetic strategy outlined below, where the above definitions apply.

[0225] General Synthesis 1

[0226] Scheme 1A illustrates the formation of a sulfonamide bond by coupling a relevant sulfonyl chloride compound of structure G2 with a primary or secondary amine (such as benzisoxazolamine G3) to form a compound having structure I.

[0227]

[0228] Scheme 1A

[0229] The method for forming the sulfonamide will be apparent to those skilled in the art and includes, for example, using a suitable base (such as, but not limited to, pyridine, LiHMDS, n-BuLi, or NaH) and using an activated form of the sulfonic acid (such as the 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 using thionyl chloride or cyanuric chloride.

[0230] Alternatively, an activated form of the sulfonic acid (such as, but not limited to, pentafluorophenyl sulfonate or trichlorophenyl sulfonate having structure G5) can be coupled with the relevant primary or secondary amine (such as benzisoxazolamine G3) (Scheme 1B).

[0231]

[0232] Scheme 1B

[0233] The formation of the sulfonate in G5 from the corresponding sulfonyl chloride G2 and the relevant phenol (R 5 can be, for example, pentafluorophenyl or trichlorophenyl) can be achieved using a suitable base (such as, but not limited to, pyridine or triethylamine). The method for forming the sulfonamide in I will be apparent to those skilled in the art and includes, for example, using a suitable base (such as, but not limited to, LiHMDS).

[0234] General Synthesis 2

[0235] Scheme 2A illustrates the formation of a sulfonyl chloride (such as G2) as a substituent that is part of Ar.

[0236]

[0237] Scheme 2A

[0238] This can be achieved by reacting a relevant aryl compound having structure G6 with, for example, but not limited to, chlorosulfonic acid. Alternatively, the aryl compound G6 can be treated sequentially with a base (such as, but not limited to, n-BuLi) and sulfur dioxide to provide lithium arylsulfinate, which is further oxidized by, for example, sulfonyl chloride to generate the desired sulfonyl chloride in G2. The product G2 can be isolated by methods known to those skilled in the art or can be formed in situ and immediately used in subsequent steps.

[0239] Alternatively, the sulfonyl chloride in G2 can be formed from the aryl mercaptan in structure G8 described in Scheme 2B.

[0240]

[0241] Scheme 2B

[0242] The method for forming G2 includes, for example, using a suitable oxidant (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 mercaptan of structure G8 can be synthesized from the compound of structure G7 (where (X) can 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.

[0243] Alternatively, sulfonation of an aryl compound (such as G6) can produce the corresponding sulfonic acid of structure G1. This can be achieved by any suitable reagent known to those skilled in the art (such as sulfur trioxide or sulfuric acid).

[0244]

[0245] Scheme 2C

[0246] The sulfonic acid G1 can be converted to the sulfonyl chloride G2 by the method outlined in General Synthesis 1, Scheme 1A.

[0247] General Synthesis 3

[0248] Scheme 3A illustrates the formation of benzisoxazolamines (such as G3) from aryl nitriles having an ortho substituent X (such as structure G9). The group (X) can be but not limited to a halogen, such as a chloro or fluoro group, and is selected to suit the reaction used.

[0249]

[0250] Scheme 3A

[0251] For example, the starting material G9 can be reacted with an oxime (such as but not limited to acetone oxime) or with, for example, acetohydroximic acid in the presence of a suitable base (such as but not limited to potassium tert - butoxide) to form the benzisoxazolamine G3.

[0252] General Synthesis 4

[0253]

[0254] Scheme 4A

[0255] Scheme 4A illustrates the addition of the R 7 group to the compound of structure G10, where R 6represents H or a suitable protecting group, including but not limited to 2,4 - dimethoxybenzyl (DMB); the method for removing said protecting group will be known to those skilled in the art (e.g., Greene's Protective Groups in Organic Synthesis, 4th edition), and as a substituent, said substituent is part of Ar. This can be achieved using any suitable coupling reaction known to those skilled in the art (e.g., Suzuki coupling). Select the group R 7 B 1 and X to be suitable for the coupling reaction used. For example, in the case of the Suzuki coupling reaction, (X) can be a halogen, triflate group, or other suitable group and B 1 represents a suitable boron compound, including but not limited to boric acid or borate ester.

[0256] Examples of B 1 that can be used for Suzuki coupling include but are not limited to those shown below.

[0257]

[0258] Examples of R 7 B 1 compounds that can be used for Suzuki coupling include but are not limited to those shown below.

[0259]

[0260] In addition to Scheme 4A, the positions of (X) and (B 1 ) can also be reversed as shown below in Scheme 4B to generate the same final compound G11. Similar to Scheme 2A, select the groups represented by R 7 X and B 1 to be suitable for the coupling reaction used. For example, in the case of the Suzuki coupling reaction, (X) can be a halogen, triflate group, or other suitable group and B 1 represents a suitable boron compound, including but not limited to boric acid or borate ester.

[0261]

[0262] Scheme 4B

[0263] In addition to Suzuki coupling, a variety of coupling reactions can be used to introduce the R 7 group, such as transition metal - catalyzed coupling reactions or compounds of tin (Stille - type reaction) and zinc (Negishi - type reaction) for example. Additionally, when the group (X) is, for example but not limited to, a phenol (O - H) or a primary or secondary amine (R’R”N - H), Chan - Lam type coupling can be used.

[0264] The transformations described in Schemes 4A and 4B can also be carried out with substituents R on the benzisoxazole moiety in structure G13 1 , R 2 , R 3 or R 4 as represented by Scheme 4C below.

[0265]

[0266] Scheme 4C

[0267] Alternatively, in General Synthesis 3 Scheme 3D, the substituent R 1 or R 2 or R 3 or R 4 = X or B 1 can be introduced before the formation of the sulfonamide and benzisoxazole on the nitrile precursor G9 (when R 7 .

[0268] General Synthesis 5

[0269] Scheme 5A illustrates the addition of a nitrogen-linked R 8 group as a substituent that is part of Ar or on the benzisoxazole moiety to produce a compound of structure G16. This can be achieved using any suitable coupling reaction known to those skilled in the art (e.g., by SnAr displacement or Buchwald coupling). The group represented by (X) can be, but is not limited to, a halogen and is selected to suit the coupling reaction used.

[0270]

[0271] Scheme 5A

[0272] Alternatively, for the synthesis of an ether-linked compound, a similar strategy can be used as shown in Scheme 5B. This can be achieved using any suitable coupling reaction known to those skilled in the art (e.g., by SnAr or Ullman-type coupling) to produce a compound having structure G17.

[0273]

[0274] Scheme 5B

[0275] The above couplings can also be reversed such that the added group is R 8 -X.

[0276] Alternatively, in General Synthesis 3 Scheme 3D, the substituent R 1 or R 2 or R 3 or R 4Before = X, a substituent OR 8 or NHR 8 .

[0277] General Synthesis 6

[0278]

[0279] Scheme 6A

[0280] Scheme 6A illustrates that an addition amine (HNR 10 R 11 ) is used to form the corresponding amide as a substituent, which is part of Ar or on the benzisoxazole moiety to generate a compound of structure G19. This can be achieved by coupling the relevant carboxylic acid with a primary or secondary amine NHR 10 R 11 . The method for forming the amide will be obvious to those skilled in the art and includes, for example, using reagents such as HATU, HBTU, T3P, and EDCI / HOBt, and using an activated form of the carboxylic acid, such as the corresponding acyl halide, mixed anhydride, or N-hydroxysuccinimide ester. Amide G19 can also be directly synthesized from an ester compound (when R 12 =Alk, such as but not limited to methyl or ethyl). The formation of the carboxylic acid from the corresponding ester (when R 12 =H) can be achieved by hydrolysis with, for example, a base (such as an alkali metal hydroxide) or an acid (such as aqueous hydrochloric acid).

[0281] Further transformations can be carried out on the amide compound G19, such as but not limited to reducing the amide to form an amine or dehydrating the amide to form a nitrile. The methods for performing these transformations will be known to those skilled in the art.

[0282] In addition, in General Synthesis 3, Scheme 3D, an amide CONR 1 or R 2 or R 3 or R 4 =CO 2 R 12 , R 12 =Alk or H), can be introduced before the formation of the sulfonamide and benzisoxazole on the nitrile precursor G9. 10 R 11 .

[0283] General Synthesis 7

[0284] The conversion of (X) in structure G20 in Scheme 7A to an ester in structure G18 (R 12 =alkyl, such as methyl or ethyl) will be obvious to those skilled in the art and includes, for example, a glycosylation reaction, which can be carried out in, for example, PdCl2 A transition metal catalyst of dppf.DCM; and is achieved by using carbon monoxide in the presence of an alcohol solvent such as, but not limited to, methanol or ethanol. The formation of the carboxylic acid (R = H) in Structure G18 can be achieved, for example, by hydrolysis with a base (such as an alkali metal hydroxide) or an acid (such as an aqueous hydrochloric acid solution).

[0285]

[0286] Scheme 7A

[0287] The ester or acid G18 in Scheme 7A can be reduced to a hydroxy compound such as Structure G21. The methods for such transformation will be known to those skilled in the art and include, for example, using reducing agents such as lithium aluminum hydride (for esters and carboxylic acids) and borane (for carboxylic acids).

[0288] Further transformations can be carried out from the hydroxy compound G21, such as, but not limited to, Mitsunobu or nucleophilic substitution reactions. The methods for performing such transformations will be known to those skilled in the art.

[0289] In addition, in General Synthesis 3 Scheme 3D, an ester group can be introduced before the formation of the sulfonamide and benzisoxazole on the nitrile precursor G9 (when R 1 or R 2 or R 3 or R 4 = X).

[0290] General Synthesis 8

[0291] Scheme 8A illustrates the reduction of the nitro group in Structure G22 to form the corresponding amine in Structure G23, as a substituent that is part of Ar or on the benzisoxazole moiety.

[0292]

[0293] Scheme 8A

[0294] The reduction of the nitro group to the primary amine G23 will be obvious to those skilled in the art and includes, but is not limited to, using reduction conditions such as transition metals (Fe, In, Zn) in the presence of HCl, hydrogenation in the presence of a transition metal or a transition metal catalyst.

[0295] Further transformations can be carried out from the amine compound G23, such as, but not limited to, amide bond formation. The methods for performing such transformations will be similar to those described in General Synthesis 6.

[0296] In addition, in General Synthesis 3 Scheme 3D, on the nitrile precursor G9 (when R 1 or R 2 or R 3 or R4 =NO 2 The amino group is introduced before the sulfonamide and benzisoxazole are formed.

[0297] General Synthesis 9

[0298] Scheme 9A illustrates the introduction of a nitrile group into structure G25 as a substituent either as part of Ar or on the benzisoxazole moiety.

[0299]

[0300] Scheme 9A

[0301] Methods for such transformations will be apparent to those skilled in the art and include, but are not limited to, SnAr displacement or transition metal catalyzed coupling with a suitable cyanide reagent. The group represented by (X) in Structure G24 may be, but is not limited to, a halogen, a triflate or a mesylate and is selected to suit the reaction being used.

[0302] Further Preferred Selection

[0303] The following preferences may apply to all aspects of the invention as described above, or may relate to a single aspect. The preferences may be combined together in any combination.

[0304] R 1 , R 2 , R 3 and R 4

[0305] In some embodiments, R 1 , R 2 , R 3 and R 4 At least one of may be H. In some of these embodiments, R 1 , R 2 , R 3 and R 4 One of the is H. In other of these embodiments, R 1 , R 2 , R 3 and R 4 Two of them are H. In others of these embodiments, R 1 , R 2 , R 3 and R 4 Three of them are H.

[0306] In some embodiments, R 1 , R 2 , R 3 and R 4At least one of them is not H.

[0307] In some embodiments, R 1 , R 2 , R 3 and R 4 at least one of which may be C 1-3 alkyl, optionally substituted with:

[0308] hydroxy,

[0309] C 1-2 alkoxy, optionally substituted with one or more fluorine groups

[0310] NH 2 ,

[0311] phenyl,

[0312] C 5-6 heteroaryl,

[0313] C 1-4 alkylcarbamoyl,

[0314] acylamide, or

[0315] one or more fluorine groups.

[0316] In these embodiments, R 1 , R 2 , R 3 and R 4 at least one of which may be C 1-3 alkyl. Additionally, in these embodiments, the C 1-3 alkyl may be methyl, ethyl or propyl. These groups may be unsubstituted. These groups may be substituted with one or more fluorine groups and may be perfluorinated, such as CF 3 , C 2 F 5 . These groups may be substituted with one, two, three, four or five fluorine groups. In some embodiments, these groups may be substituted with one; one or two; or one, two or three fluorine groups.

[0317] If the alkyl is substituted, the substituent may be selected from:

[0318] (i) hydroxy; or

[0319] (ii) unsubstituted C 1-2 alkoxy, namely methoxy, ethoxy; or C 1-2 alkoxy substituted with one or more fluorine groups, such as -OCH 2 F, -OCH 2 CF 3 ; or

[0320] (iii) NH 2 ; or

[0321] (iv) phenyl; or

[0322] (v) C 5-6 heteroaryl, such as N - pyrazolyl; or

[0323] (vi) C 1-4 alkylcarbamoyl, such as NHC(O)Me; or

[0324] (vii) acylamide group, such as NHCO 2 Me.

[0325] In some embodiments, at least one of R 1 , R 2 , R 3 and R 4 may be C 1-3 alkoxy, which is optionally substituted by C 3-6 cycloalkyl or by one or more fluoro groups. In these embodiments, the C 1-3 alkoxy may be methoxy, ethoxy or propoxy. These groups may be unsubstituted. These groups may be substituted by one or more fluoro groups and may be perfluorinated, such as OCF 3 , OCF 2 F 5 . These groups may be substituted by one, two, three, four or five fluoro groups. In some embodiments, these groups may be substituted by one; one or two; or one, two or three fluoro groups. The alkoxy may be substituted by C 3-6 cycloalkyl (e.g., cyclopropyl). Thus, the overall group may be OCH 2 (cyclopropyl).

[0326] In some embodiments, at least one of R 1 , R 2 , R 3 and R 4 may be C 3-6 cycloalkyl. In these embodiments, the C 3-6 cycloalkyl may be cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. Specifically, the C 3-6 cycloalkyl may be cyclopropyl.

[0327] In some embodiments, at least one of R 1 , R 2 , R 3 and R 4 may be a halogen group. In these embodiments, the halogen group may be fluorine, chlorine, bromine or iodine.

[0328] In some embodiments, R 1 , R 2 , R 3 and R 4 may be COR C , where R C is selected from NR N1 R N2 , where R N1 and R N2 are independently selected from H and methyl. In these embodiments, the group may be selected from C(O)NH 2 , C(O)NHCH 3 and C(O)N(CH 3 ) 2 .

[0329] In some embodiments, R 1 , R 2 , R 3 and R 4 may be cyano, NH 2 , NO 2 . In some of these embodiments, R 1 , R 2 , R 3 and R 4 may be cyano. In other of these embodiments, R 1 , R 2 , R 3 and R 4 may be NH 2 . In other of these embodiments, R 1 , R 2 , R 3 and R 4 may be NO 2 .

[0330] In some embodiments, R 1 , R 2 , R 3 and R 4 may be phenyl or C 5-6 heteroaryl, the group being optionally substituted by methyl, cyano, hydroxy or methoxy. In some of these embodiments, R 1 , R 2 , R 3 and R 4 may be phenyl. In other of these embodiments, R 1 , R 2 , R 3 and R 4 may be C5-6 Heteroaryl, such as oxazolyl, pyrazolyl, triazolyl, pyridyl and pyrimidinyl. The phenyl or C 5-6 heteroaryl may be unsubstituted. In certain embodiments, the phenyl may be substituted with methyl, cyano or methoxy. In certain embodiments, the C 5-6 heteroaryl may be substituted with one or more methyl groups such that the overall group is, for example, dimethylpyrazolyl or N-methylpyrazolyl.

[0331] In some embodiments, R 4 is methoxy.

[0332] In some embodiments, R 4 is methoxy, R 2 is CH 2 OCH 3 or CH 2 OCH 2 CH 3 and R 1 and R 3 are H.

[0333] In some embodiments, R 4 is methoxy, R 2 is a phenyl optionally substituted with methyl or methoxy, and R 1 and R 3 are H.

[0334] In some embodiments, R 4 is methoxy, R 2 is a C 5-6 heteroaryl optionally substituted with methyl.

[0335] In some embodiments, R 4 is methoxy and R 1 、R 2 and R 3 are H.

[0336] In some embodiments, R 4 is chlorine, R 2 is C 1-3 alkyl or bromine, and R 1 and R 3 are H.

[0337] In some embodiments, R 4 is chlorine and R 1 、R 2 and R 4 are H.

[0338] In some embodiments, R 3 is C 1-3 alkyl and R 1, R 2 and R 4 is H.

[0339] Ar

[0340] Ar is selected from phenyl, naphthyl and C 5-10 heteroaryl, which may be unsubstituted or substituted.

[0341] In some embodiments, Ar is phenyl.

[0342] In some embodiments, Ar is naphthyl.

[0343] In some embodiments, Ar is C 5-10 heteroaryl. The C 5-10 heteroaryl may be selected from: quinolinyl, benzothiazolyl, quinoxalinyl, benzoxadiazolyl, benzothiadiazolyl, benzofuran and benzotriazolyl. In some of these embodiments, Ar is quinolinyl or benzothiazolyl.

[0344] In some embodiments, Ar is the group:

[0345]

[0346] In some embodiments, the substituent on Ar is C 1-4 alkyl, which is optionally substituted by hydroxy, C 1-2 alkoxy, NH 2 , C 1-4 alkylcarbamoyl or one or more fluoro groups. In these embodiments, the C 1-4 alkyl may be methyl, ethyl, propyl or butyl. These groups may be unsubstituted. These groups may be substituted by one or more fluoro groups and may be perfluorinated, such as CF 3 , C 2 F 5 . If the alkyl is substituted, the substituents may be selected from:

[0347] (i) hydroxy; or

[0348] (ii) C 1-2 alkoxy, i.e., methoxy, ethoxy; or

[0349] (iii) NH 2 ; or

[0350] (iv) C 1-4 alkylcarbamoyl, such as NHC(O)CH 3 .

[0351] In some embodiments, the substituent on Ar is C 3-6 cycloalkyl. In these embodiments, the C3-6 The cycloalkyl group can be cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. Specifically, the C 3-6 cycloalkyl group can be cyclohexyl.

[0352] In some embodiments, the substituent on Ar is a hydroxyl group; a cyano group; NR N3 R N4 , where R N3 and R N4 are independently selected from H and methyl; or an acyl amide group. In some of these embodiments, the substituent can be a hydroxyl group. In other of these embodiments, the substituent can be a cyano group. In other of these embodiments, the substituent can be NR N3 R N4 , where R N3 and R N4 are independently selected from H and methyl, thus, the substituent can be NH 2 , NHCH 3 or N(CH 3 ) 2 . In other of these embodiments, the substituent can be an acyl amide group, such as NHCO 2 CH 3 .

[0353] In some embodiments, the substituent on Ar is a halogen group. In these embodiments, the halogen group can be fluorine, chlorine, bromine or iodine.

[0354] In some embodiments, the substituent on Ar is a C 1-3 alkoxy group, which is optionally substituted by a hydroxyl group, C(O)NH 2 , C 3-6 cycloalkyl, phenyl, C 5-6 heteroaryl or substituted by one or more fluorine groups. In these embodiments, the C 1-3 alkoxy group can be methoxy, ethoxy or propoxy. These groups can be unsubstituted. These groups can be substituted by one or more fluorine groups and can be perfluorinated, for example OCF 3 , OCF 2 F 5 . The alkoxy group can be substituted by a hydroxyl group such that the overall group is for example OCH 2 H 4 OH. The alkoxy group can be substituted by C(O)NH 2 such that the overall group is for example OCH 2 C(O)NH 2 . The alkoxy group can be substituted by C 3-6 cycloalkyl (e.g., cyclopropyl) such that the overall group can be for example OCH 2(Cyclopropyl). The alkoxy group may be substituted by a phenyl group such that the overall group is, for example, benzyloxy. The alkoxy group may be substituted by a C 5-6 heteroaryl (e.g., pyridyl, pyrazolyl) such that the overall group is, for example, OCH 2 (N-methylpyrazolyl) or OCH 2 (methoxypyridyl).

[0355] In some embodiments, the substituent on Ar is phenoxy, which is optionally substituted by fluorine. In some of these embodiments, the substituent may be phenoxy. In other of these embodiments, the substituent may be OC 6 H 4 F.

[0356] In some embodiments, the substituent on 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.

[0357] In some embodiments, the substituent on 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.

[0358] In some embodiments, the substituent on Ar is -(CH 2 ) n -Y-, where Y is O or CH 2 , and n is 2 or 3. The substituent is particularly relevant when Ar is phenyl and forms a partially unsaturated fused ring with the phenyl. Thus, Ar can be tetrahydronaphthyl (i.e., fused cyclohexane), indanyl (i.e., fused cyclopentane), chromanyl (i.e., fused tetrahydropyran), or dihydrobenzofuranyl.

[0359] In some embodiments, the substituent on Ar is C 1-4 alkyl ester. In some of these embodiments, the substituent is C(O)OCH 3 . In other of these embodiments, the substituent is C(O)OC(CH 3 ) 3 .

[0360] Certain embodiments of Ar can be represented by formula (Ar-1):

[0361]

[0362] wherein Y is N or C-R A4 , and Z is N or C-R A5 ; and

[0363] R A1 、R A2 、R A3 、R A4 (if present) and R A5 (if present) are independently selected from H and optional substituents on Ar.

[0364] In some embodiments, R A2 is ethyl.

[0365] In some embodiments, R A3 is selected from cycloalkyl; phenoxy; phenyl; C 5-6 heteroaryl; SF 5 ; and SO 2 CH 3 .

[0366] In some embodiments, Ar is 5-ethyl-2-methoxyphenyl.

[0367] In some embodiments, Ar is 5-CF 3 -2-methoxyphenyl.

[0368] In some embodiments, Ar is 2,6-dimethoxyphenyl.

[0369] In some embodiments, Ar is quinolinyl. These compounds may exhibit selective activity against HBO1.

[0370] In some embodiments, R 4 is methoxy, R 2 is selected from CH 2 O CH 3 、CH 2 O CH 2 CH 3 and optionally substituted phenyl, and Ar is 2,6-dimethoxybenzene. These compounds may exhibit specific activity against MOZ and MORF. Wherein R 2 is selected from CH 2 OCH 3 and CH 2 OCH 2 CH 3 of the compound may exhibit selective activity against MOZ and MORF.

[0371] In some embodiments, regarding wherein R 1 、R 2 、R3 and R 4 is a compound of H, then Ar is not 4-aminophenyl.

[0372] In some embodiments, regarding those in which R 1 , R 2 , R 3 and R 4 is a compound of H, then Ar is not 2,4,6-trimethylphenyl.

[0373] In some embodiments, regarding those in which R 1 , R 2 and R 4 is H and R 3 is CF 3 of the compound, then Ar is not 2-(difluoromethoxy)phenyl.

[0374] In some embodiments, regarding those in which R 1 , R 2 , R 3 and R 4 is a compound of H, then Ar is not 4-fluoro-3-methyl-phenyl.

[0375] In some embodiments, regarding those in which R 1 , R 2 and R 3 is H and R 4 is methoxy of the compound, then Ar is not unsubstituted naphthyl.

[0376] Compounds of particular interest include those of the examples. Detailed Description

[0377] Examples

[0378] The following examples are provided to illustrate only the invention and are not intended to limit the scope of the invention as described herein.

[0379] Acronyms

[0380] For convenience, various 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).

[0381] For convenience, various 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 (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), dichlorobis(1,1'-bis(diphenylphosphino)ferrocene)palladium(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).

[0382] In addition, TLC refers to thin layer chromatography.

[0383] Other abbreviations: retention time (rt or R t ) minutes (min), hours (h), room temperature (RT), concentrated (conc.), atmospheric pressure (atm), aqueous (aq.), saturated (sat.), equivalents (eq.).

[0384] General experimental details

[0385] Unless otherwise specified, the following generalizations apply. 11H NMR spectra were recorded on a Bruker UltrashieldPlus (400 MHz) or Bruker AVANCE III (400 MHz). The multiplicity of signals was designated by the following abbreviations: s, singlet; d, doublet; t, triplet; q, quartet; p, pentuplet; dd, doublet of doublets; dt, doublet of triplets; tt, triplet of triplets; br, broad; m, multiplet. All observed coupling constants J were reported in Hertz (Hz). Exchangeable protons were never observed.

[0386] LCMS data were generated using an Agilent 6100 Series Single Quadrupole (LCMS-A), an Agilent 1260 Infinity Series UPLC / MS (LCMS-B), an Agilent 1200 (LCMS-C and LCMS-D), a Waters 2695 alliance (LCMS-E), an Agilent 6120 Single Quadrupole (LCMS-F), or mass-directed HPLC-MS. Chlorine isotopes were reported as 35 Cl, bromine isotopes were reported as 79 Br or 81 Br or 79 Br / 81 Br both.

[0387] LCMS Method A (LCMS-A) :

[0388] Instrument: Agilent 6100 Series Single Quadrupole LC / MS

[0389] Agilent 1200 Series HPLC

[0390] Pump: 1200 Series G1311A Quaternary Pump

[0391] Autosampler: 1200 Series G1329A Thermostatted Autosampler

[0392] Detector: 1200 Series G1314B Variable Wavelength Detector

[0393] LC Conditions:

[0394] Reverse-phase HPLC analysis

[0395] Column: Luna C8(2) 5μm 50×4.6 mm

[0396] Column temperature: 30 °C

[0397] Injection volume: 5 μL

[0398] Solvent A: water 0.1% formic acid

[0399] Solvent B: 0.1% formic acid in MeCN

[0400] Gradient: 5 - 100% Solvent B over 10 minutes

[0401] Detection: 254 nm or 214 nm

[0402] MS conditions:

[0403] Ion source: Quadrupole

[0404] Ion mode: Multimode - ES

[0405] Drying gas temperature: 300 °C

[0406] Vaporizer temperature: 200 °C

[0407] Capillary voltage (V): 2000 (positive)

[0408] Capillary voltage (V): 4000 (negative)

[0409] Scan range: 100 - 1000

[0410] Step size: 0.1 s

[0411] Acquisition time: 10 minutes

[0412] LCMS Method B (LCMS-B) :

[0413] Instrument: Agilent 1260 Infinity series UPLC / MS

[0414] Pump: 1260 Infinity G1312B binary pump

[0415] Autosampler: 1260 Infinity G1367E 1260 HiP ALS

[0416] Detector: 1290 Infinity G4212A 1290 DAD

[0417] LC conditions:

[0418] Reverse phase HPLC analysis

[0419] Column: Poroshell 120 EC - C18 2.7 μm 50×3.0 mm

[0420] Column temperature: 35 °C

[0421] Injection volume: 1 μL

[0422] Solvent A: 0.1% formic acid in water

[0423] Solvent B: 0.1% formic acid in MeCN

[0424] Gradient: 5 - 100% Solvent B over 3.8 minutes

[0425] Detection: Monitor at 254 nm and 214 nm

[0426] MS conditions:

[0427] Ion source: Quadrupole

[0428] Ion mode: API - ES

[0429] Drying gas temperature: 350 °C

[0430] Capillary voltage (V): 3000 (positive)

[0431] Capillary voltage (V): 3000 (negative)

[0432] Scan range: 100 - 1000

[0433] Step size: 0.1 s

[0434] Acquisition time: 5 minutes

[0435] LCMS Method C (LCMS-C) :

[0436] LC model: Agilent 1200

[0437] (Pump type: Binary pump, Detector type: DAD)

[0438] MS model: Agilent G6110A Quadrupole

[0439] LC conditions:

[0440] Column: Xbridge - C18, 2.5 μm, 2.1×30 mm

[0441] Column temperature: 30 °C

[0442] Wavelength acquisition: 214 nm, 254 nm

[0443] Mobile phase: A: 0.07% aqueous HCOOH solution, B: MeOH

[0444] MS conditions:

[0445] MS: Ion source: ES+(or ES -) MS range: 50 - 900 m / z

[0446] Fragmentation voltage: 60 Drying gas flow: 10 L / min

[0447] Sprayer pressure: 35 psi, Dry gas temperature: 350 °C

[0448] Vcap: 3.5 kV

[0449] Gradient table:

[0450]

[0451] Sample preparation:

[0452] The sample was dissolved in methanol at a concentration of approximately 0.11 - 1 mg / mL and then filtered through a syringe filter with 0.22 μm. (Injection volume: 1 - 10 μL)

[0453] LCMS Method D (LCMS-D) :

[0454] LC model: Agilent 1200

[0455] (Pump type: Binary pump, Detector type: DAD)

[0456] MS model: Agilent G6110A Quadrupole

[0457] LCMS conditions:

[0458] LC: Column: Xbridge-C18, 2.5 μm, 2.1×30 mm

[0459] Column temperature: 30 °C

[0460] Wavelength collection: 214 nm, 254 nm

[0461] Mobile phase: A: 0.07% aqueous HCOOH solution, B: MeOH

[0462] MS conditions:

[0463] MS: Ion source: ES+(or ES-), MS range: 50 - 900 m / z

[0464] Fragmentation voltage: 60, Dry gas flow: 10 L / min

[0465] Sprayer pressure: 35 psi, Dry gas temperature: 350 °C

[0466] Vcap: 3.5 kV

[0467] Gradient table:

[0468]

[0469] Sample preparation:

[0470] The sample was dissolved in methanol at a concentration of approximately 0.11 - 1 mg / mL and then filtered through a syringe filter with 0.22 μm. (Injection volume: 1 - 10 μL)

[0471] LCMS Method E (LCMS-E) :

[0472] Equipment information:

[0473] LC model: Waters 2695 alliance

[0474] (Pump type: quaternary pump, detector: 2996 photodiode array detector)

[0475] MS model: Micromass ZQ

[0476] LC conditions:

[0477] LC: Column: Xbridge-C18, 3.5 μm, 2.1×50 mm

[0478] Column temperature: 30 °C

[0479] Wavelength acquisition: 214 nm, 254 nm

[0480] Mobile phase: A: 0.07% aqueous HCOOH solution, B: MeOH

[0481] MS conditions:

[0482] MS: Ion source: ES+(or ES-) MS range: 50 - 900 m / z

[0483] Capillary: 3 kV Cone: 3 V Extractor: 3 V

[0484] Drying gas flow: 600 L / hour Cone: 50 L / hour

[0485] Desolvation temperature: 300 °C

[0486] Source temperature: 100 °C

[0487] Gradient table:

[0488]

[0489] Sample preparation:

[0490] The sample was dissolved in methanol at a concentration of approximately 0.11 - 1 mg / mL and then filtered through a syringe filter with 0.22 μm. (Injection volume: 1 - 10 μL)

[0491] LCMS Method F (LCMS-F)

[0492] Instrument: Agilent 6120 Series Single Quadrupole LC / MS

[0493] Agilent 1200 Series HPLC

[0494] Pump: 1200 Series G1311A Quaternary Pump

[0495] Autosampler: 1200 Series G1329A Thermostatic Autosampler

[0496] Detector: 1200 Series G1314B Variable Wavelength Detector

[0497] LC Conditions:

[0498] Reverse-phase HPLC analysis

[0499] Column: Luna C8(2) 5μm 50×4.6mm

[0500] Column temperature: 30°C

[0501] Injection volume: 1 - 10 μL

[0502] Solvent A: Water 0.1% formic acid

[0503] Solvent B: MeCN 0.1% formic acid

[0504] Gradient: 0 - 95% Solvent B over 10 minutes

[0505] Detection: 254 nm or 214 nm

[0506] MS Conditions:

[0507] Ion source: Quadrupole

[0508] Ion mode: Multi-mode - ES and APCI

[0509] Drying gas temperature: 250°C

[0510] Vaporizer temperature: 200°C

[0511] Capillary voltage (V): 4000 (positive)

[0512] Capillary voltage (V): 4000 (negative)

[0513] Scan range: 100 - 1000

[0514] Step size: 0.1 second

[0515] Acquisition time: 10 minutes

[0516] Preparative Mass-Directed HPLC

[0517] Instrument:

[0518] Waters ZQ 3100 - Mass Detector

[0519] Waters 2545 - Pump

[0520] Waters SFO System Fluid Organizer

[0521] Waters 2996 Diode Array Detector

[0522] Waters 2767 Sample Manager

[0523] LC Conditions:

[0524] Reverse - phase HPLC analysis

[0525] Column: XBridge TM C18 5μm 19×50mm

[0526] Injection volume 500 μL

[0527] Solvent A: Water 0.1% formic acid

[0528] Solvent B: Acetonitrile 0.1% formic acid

[0529] Gradient: 25 - 100% B over 10 minutes

[0530] Flow rate: 19 mL / min

[0531] Detection: 100 - 600 nm

[0532] MS Conditions:

[0533] Ion source: Single - quadrupole

[0534] Ion mode: ES positive

[0535] Source temperature: 150 °C

[0536] Desolvation temperature: 350 °C

[0537] Detection: Ion counting

[0538] Capillary (KV) - 3.00

[0539] Cone voltage (V): 30

[0540] Extractor voltage (V): 3

[0541] RF lens voltage (V): 0.1

[0542] Scan range: 100 - 1000 Amu

[0543] Scanning time: 0.5 seconds

[0544] Collection time: 10 minutes

[0545] Airflow

[0546] Desolvation rate (L / h): -650

[0547] Cone voltage rate (L / h): -100

[0548] Preparative HPLC (prep.HPLC):

[0549] Instrument type: Varian 940-LC series;

[0550] Pump type: Quaternary pump;

[0551] Detector type: Diode array detector

[0552] HPLC conditions:

[0553] Waters Sunfire prep C18 OBD, 5μm 19×100mm column, eluted with a gradient of MeOH in water containing 0.07% TFA at a flow rate of 15 mL / min. Collection wavelengths are 214 nm and 254 nm.

[0554] Analytical thin-layer chromatography is performed on Merck silica gel 60F254 pre-coated aluminum plates, and the plates are observed visually using fluorescence quenching under UV light or basic KMnO 4 dipping solution or Ninhydrin dipping solution.

[0555] Preparative thin-layer chromatography (Prep TLC) is performed using Tklst (China), main grade: (HPTLC): 8±2μm >80%; (TLC): 10 - 40μm. Type: GF254. Compounds are observed visually by UV (254 nm).

[0556] Column chromatography is performed using a Biotage Isolera purification system, which uses Grace or silica cartridges or silica gel with Tklst (China), main grade, 100 - 200 mesh.

[0557] Microwave irradiation is achieved using a CEM Explorer SP microwave reactor.

[0558] When necessary, anhydrous solvents are purchased from Sigma-Aldrich or dried using conventional methods.

[0559] Unless otherwise specified, acidification is carried out with concentrated HCl or aqueous HCl solution.

[0560] The additional cylinders used are as follows:

[0561] Phase Separator:

[0562] Manufacturer: Biotage

[0563] Product: Phase separator (3 mL, unless otherwise specified)

[0564] Si-Amine Cartridge :

[0565] Manufacturer: Biotage

[0566] Product: NH2, 1 g / 6 mL

[0567] Or

[0568] Manufacturer: Silicycle

[0569] Product: Si-amine 500 mg or 1 g

[0570] Synthetic Intermediate

[0571] i) 6-(Methoxymethyl)-5-methyl-1,2-benzisoxazol-3-amine I4

[0572]

[0573] a) Methyl 4-cyano-5-fluoro-2-methylbenzoate I1

[0574] A mixture of 4-bromo-2-fluoro-5-methylbenzonitrile (3.5 g, 16.4 mmol), Pd(dppf)Cl 2 ·DCM (668 mg, 0.82 mmol) and Et 3 N (5.0 g, 49.1 mmol) in MeOH (80 mL) was heated overnight at 100 °C under a CO atmosphere (0.2 MPa). Additional Pd(dppf)Cl 2 ·DCM (340 mg, 0.4 mmol) was added and heating was continued under a CO atmosphere (0.2 MPa) overnight. 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 = 20 / 1 to 10 / 1 to 5 / 1) to give the title compound as a yellow solid (2.4 g, 74%). LCMS-D: R t 2.48 min; m / z 216.1 [M+Na] + .

[0575] b) 2-Fluoro-4-(hydroxymethyl)-5-methylbenzonitrile I2

[0576] At room temperature in 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) was added dropwise LiBH 4 (2.0 M solution in THF, 12.4 mL, 24.8 mmol) and the mixture was heated under 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 afford the title compound as a yellow solid (1.6 g, 79%). LCMS-D: R t 1.43 min; m / z 166.1 [M+H] + , 188.1 [M+Na] + .

[0577] c) 2-Fluoro-4-(methoxymethyl)-5-methylbenzonitrile I3

[0578] At 0 °C to a solution of 2-fluoro-4-(hydroxymethyl)-5-methylbenzonitrile I2 (800 mg, 8.8 mmol) and methyl iodide (3.4 g, 24.2 mmol) in DMF (12 mL) was added NaH (60% w / w dispersion in oil, 379 mg, 9.7 mmol) and the mixture was stirred at 0 °C for 30 min. 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 afford the title compound as a yellow solid (660 mg, 76%). LCMS-D: R t 2.44 min; m / z 180.1 [M+H] + , 202.1.1 [M+Na] + .

[0579] d) 6-(Methoxymethyl)-5-methylbenzo[d]isoxazol-3-amine I4

[0580] 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 h. 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 dried, 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 as a yellow solid (1.0 g, 77%). LCMS-D: R t 1.75 min; m / z 193.1 [M+H] + .

[0581] ii) 4-Methoxy-6-(methoxymethyl)benzo[d]isoxazol-3-amine I9

[0582]

[0583] a) 4-Bromo-2-fluoro-6-methoxybenzonitrile I5

[0584] To a solution of 4-bromo-2,6-difluorobenzonitrile (6.0 g, 27.5 mmol) in THF (100 mL) was added sodium methoxide (1.5 g, 55.0 mmol) and the mixture was stirred at room temperature for 48 h. Water was added and the mixture was extracted with EtOAc (150 mL × 3). The combined organic extracts were washed with brine, dried over anhydrous Na 2 SO 4 dried, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / EtOAc = 300 / 1 to 200 / 1) to give the title compound as a white solid (4.3 g, 68%). LCMS-D: R t 2.53 min; m / z251.8 / 253.8 [M+Na] + .

[0585] b) Methyl 4-cyano-3-fluoro-5-methoxybenzoate I6

[0586] 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 3A mixture of 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 as a white solid (2.9 g, 74%). LCMS-D: R t 2.41 min; m / z 210.0 [M+H] + , 232.0 [M+Na] + .

[0587] c) 2-Fluoro-4-(hydroxymethyl)-6-methoxybenzonitrile I7

[0588] At room temperature under N 2 To a solution of LiBH 4 (2.0 M solution in THF, 13.9 mL, 27.8 mmol) in anhydrous THF (60 mL) 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 under reflux for 1 h. The reaction was quenched with 1 M aqueous HCl and extracted with EtOAc (100 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 to give the title compound as a white solid (2.5 g, 100%). LCMS-D: R t 2.31 min; m / z182.1 [M+H] + , 204.1 [M+Na] + .

[0589] d) 2-Fluoro-6-methoxy-4-(methoxymethyl)benzonitrile I8

[0590] Portions were added at 0 °C to a solution of 2-fluoro-4-(hydroxymethyl)-6-methoxybenzonitrile I7 (2.7 g, 14.9 mmol) and methyl iodide (10.6 g, 74.5 mmol) in DMF (100 mL) and NaH (60% w / w dispersion in oil, 1.2 g, 29.8 mmol) 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, dried over anhydrous Na 2 SO 4Dry, filter and concentrate under reduced pressure. The residue was purified by column chromatography (petroleum ether / EtOAc = 100 / 1 to 5 / 1) to afford the title compound as a yellow solid (2.2 g, 76%). LCMS-D: R t 2.22 min; m / z 218.0 [M+Na] + .

[0591] e) 4-Methoxy-6-(methoxymethyl)benzo[d]isoxazol-3-amine I9

[0592] 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 h. Then 2-fluoro-6-methoxy-4-(methoxymethyl)benzonitrile I8 (2.0 g, 10.3 mmol) was added and stirring was continued at room temperature overnight. Water was added and the mixture was extracted with EtOAc. The combined organic extracts were dried over anhydrous Na 2 SO 4 dried, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (DCM / MeOH = 20 / 1 to 10 / 1 to 3 / 1) to afford the title compound as a yellow solid (580 mg, 27%). 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 1.33 min; m / z 209.0 [M+H] + .

[0593] iii) 4-Nitrobenzo[d]isoxazol-3-amine I10

[0594]

[0595] To a solution of 2-fluoro-6-nitrobenzonitrile (1.0 g, 6.17 mmol) in DMF / H 2 2O (32 mL / 32 mL) was added acetohydroxamic acid (2.78 g, 37.0 mmol) and K 2 2CO 3 3 (10.23 g, 74.0 mmol) and the mixture was heated at 70 °C for 19 h. Water (200 mL) was added and the mixture was extracted with EtOAc (100 mL × 3). The combined organic extracts were washed with water, brine, dried over anhydrous Na 2SO 4 Dry, filter and concentrate under reduced pressure. The residue is purified by column chromatography (petroleum ether / EtOAc = 30 / 1 to 1 / 1) to afford the title compound as a yellow solid (380 mg, 35%). LCMS-D: R t 2.82 min; m / z 180.1 [M+H] + .

[0596] iv) 4-Methoxy-6-(1-methoxyethyl)benzo[d]isoxazol-3-amine I15

[0597]

[0598] a) 4-(1-Ethoxyvinyl)-2-fluoro-6-methoxybenzonitrile I11

[0599] To a solution of 4-bromo-2-fluoro-6-methoxybenzonitrile I5 (2.0 g, 8.7 mmol) in THF (40 mL) was added tributyl(1-ethoxyvinyl)stannane (3.4 g, 9.6 mmol), Pd(PPh 3 )(201 mg, 0.174 mmol) and LiCl (1.15 g, 27.0 mmol) and the mixture was heated under reflux in N 4 for 48 h. The mixture was diluted with EtOAc and washed successively with water, 5% aqueous ammonium hydroxide and brine. The organic layer was dried over anhydrous Na 2 SO 2 SO 4 dry, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / EtOAc = 200 / 1) to afford the title compound as a pale yellow solid (1.6 g, 84%). LCMS-C: R t 2.41 min; m / z 222.0 [M+H] + .

[0600] b) 4-Acetyl-2-fluoro-6-methoxybenzonitrile I12

[0601] To a solution of 4-(1-ethoxyvinyl)-2-fluoro-6-methoxybenzonitrile I11 (1.0 g, 4.5 mmol) in THF (10 mL) was added 2M aqueous HCl (6.0 mL) and the mixture was stirred at room temperature for 3 h. The mixture was diluted with ether and washed with saturated NaHCO 3 aqueous solution and water. The organic layer was dried over anhydrous Na 2 SO 4Dry, filter and concentrate under reduced pressure to give the title compound as a white solid (710 mg, 81%). LCMS-C: R t 1.42 min; m / z 194.0 [M+H] + 。

[0602] c) 2-Fluoro-4-(1-hydroxyethyl)-6-methoxybenzonitrile I13

[0603] 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 overnight at room temperature. 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 Dry, filter and concentrate under reduced pressure to give the title compound as a colorless oil (675 mg, 95%). LCMS-C: R t 0.98 min; m / z 196.0 [M+H] + 。

[0604] d) 2-Fluoro-6-methoxy-4-(1-methoxyethyl)benzonitrile I14

[0605] Portions were added at 0 °C to a solution of 2-fluoro-4-(1-hydroxyethyl)-6-methoxybenzonitrile I13 (670 mg, 3.4 mmol) and methyl iodide (1.5 g, 10.3 mmol) in DMF (20 mL) and NaH (60% w / w dispersion in oil, 274 mg, 6.8 mmol) 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 Dry, filter and concentrate under reduced pressure to give the title compound as a pale yellow solid (650 mg, 90%). LCMS-C: R t 1.95 min; m / z 210.0 [M+H] + 。

[0606] e) 4-Methoxy-6-(1-methoxyethyl)benzo[d]isoxazol-3-amine I15

[0607] At 0 °C, potassium tert-butoxide (1.04 g, 9.3 mmol) was added to a solution of acetohydroxamic acid (698 mg, 9.3 mmol) in anhydrous DMF (20 mL), and the mixture was stirred at room temperature for 1 hour. 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 , filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (DCM / MeOH = 300 / 1 to 200 / 1) to give the title compound as a yellow solid (130 mg, 19%). 1 H 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: R t 0.73 min; m / z 223.0 [M+H] + .

[0608] v) 4-Methoxy-6-phenylbenzo[d]isoxazol-3-amine I17

[0609]

[0610] a) 3-Fluoro-5-methoxy-[1,1'-biphenyl]-4-carbonitrile I16

[0611] Under N 2 to a solution of 4-bromo-2-fluoro-6-methoxybenzonitrile I5 (6.0 g, 26.1 mmol) and phenylboronic acid (6.36 g, 52.2 mmol) in 1,4-dioxane (200 mL) and water (50 mL) was added Pd(PPh 3 ) 4 (2.99 g, 2.66 mmol) and Na 2 CO 3 (8.29 g, 78.2 mmol), and the mixture was heated at 100 °C overnight. Water was added, and the mixture was extracted with EtOAc. The combined organic extracts were washed with brine, dried over anhydrous Na 2 SO 4Dry, filter and concentrate under reduced pressure. The residue was purified by column chromatography (petroleum ether / EtOAc = 100 / 1 to 50 / 1) to give the title compound as a yellow solid (5.45 g, 93%). LCMS-C: R t 2.48 min; m / z 228.0 [M+H] + .

[0612] b) 4-Methoxy-6-phenylbenzo[d]isoxazol-3-amine I17

[0613] To 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 h. 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 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 dry, 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 as a yellow solid (2.2 g, 38%). 1 H NMR (400 MHz, DMSO-d 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 2.15 min; m / z 241.0 [M+H] +

[0614] vi) 3-(3-Amino-4-methoxybenzo[d]isoxazol-6-yl)phenol I19

[0615]

[0616] a) 3-Fluoro-3'-hydroxy-5-methoxy-[1,1'-biphenyl]-4-carbonitrile I18

[0617] Under N 2 2 to a solution of 4-bromo-2-fluoro-6-methoxybenzonitrile I5 (650 mg, 2.8 mmol) and (3-hydroxyphenyl)boronic acid (1.2 g, 5.6 mmol) in 1,4-dioxane (40 mL) and water (10 mL) was added Pd(PPh3 ) 4 (327 mg, 0.28 mmol) and Na 2 CO 3 (899 mg, 8.5 mmol), and the mixture was heated at 100 °C overnight. 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 = 3 / 1) to give the title compound as a yellow solid (687 mg, 94%). LCMS-C: R t 2.07 min; m / z 244.0 [M+H] + .

[0618] b) 3-(3-Amino-4-methoxybenzo[d]isoxazol-6-yl)phenol I19

[0619] 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 as a yellow solid (282 mg, 39%). LCMS-C: R t 2.3 min; m / z 257.0 [M+H] + .

[0620] vii) 6-(Ethoxymethyl)-4-methoxybenzo[d]isoxazol-3-amine I21

[0621]

[0622] a) 4-(Ethoxymethyl)-2-fluoro-6-methoxybenzonitrile I20

[0623] Portions were added to a solution of 2-fluoro-4-(hydroxymethyl)-6-methoxybenzonitrile I7 (1.15 g, 6.4 mmol) and iodoethane (5.0 g, 31.7 mmol) in DMF (40 mL) at 0 °C and NaH (60% w / w dispersion in oil, 508 mg, 12.7 mmol) was added and the mixture was stirred at room temperature for 30 minutes. Water was added and the mixture was extracted with EtOAc (100 mL × 3). The combined organic extracts were washed with brine, dried over anhydrous Na 2 SO 4 dried, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / EtOAc = 2 / 1) to give the title compound as a yellow solid (1.0 g, 79%). LCMS-C: R t 2.15 min; m / z 210.0 [M+H] + .

[0624] b) 6-(Ethoxymethyl)-4-methoxybenzo[d]isoxazol-3-amine I21

[0625] Potassium tert-butoxide (1.6 g, 14.3 mmol) was added to a solution of acetohydroxamic acid (1.1 g, 14.3 mmol) in anhydrous DMF (50 mL) at room temperature 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 overnight at room temperature. Water was added and the mixture was extracted with EtOAc. The organic extract was dried over anhydrous Na 2 SO 4 dried, 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 as a yellow oil (650 mg, 61%). 1 HNMR (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] + .

[0626] viii) 6-Bromo-4-methoxybenzo[d]isoxazol-3-amine I22

[0627]

[0628] To a solution of acetohydroxamic acid (2.0 g, 26.1 mmol) in anhydrous DMF (100 mL) at room temperature was added potassium tert-butoxide (2.9 g, 26.1 mmol) and the mixture was stirred at room temperature for 1 h. Then 4-bromo-2-fluoro-6-methoxybenzonitrile I5 (2.0 g, 8.7 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 , filtered and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / EtOAc = 2 / 1) to afford the title compound as a white solid (296 mg, 14%). 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.32 (d, J = 1.2 Hz, 1H), 6.90 (d, J = 1.2 Hz, 1H), 6.04 (s, 2H), 3.92 (s, 3H). LCMS-C: R t 1.4 min; m / z 244.0 [M+H] + .

[0629] ix) 7-Ethoxybenzo[d]isoxazol-3-amine I26

[0630]

[0631] a) 2-Fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile I23

[0632] A mixture of 3-bromo-2-fluorobenzonitrile (3.0 g, 15.0 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-di(1,3,2-dioxaborolane) (11.4 g, 45 mmol), potassium acetate (5.9 g, 60.0 mmol) and Pd(dppf)Cl 2 (2.2 g, 3.0 mmol) in DMSO (45 mL) and 1,4-dioxane (15 mL) was heated at 105 °C under N 2 for 3 h. The mixture was diluted with EtOAc (30 mL) and washed with water (30 mL × 3). The organic layer was dried over anhydrous Na 2 SO 4 , filtered, concentrated under reduced pressure and the residue was purified by column chromatography (petroleum ether / EtOAc = 20 / 1) to afford the title compound as a white solid (3.9 g, >100%), which was used directly in the next step.

[0633] b) 2-Fluoro-3-hydroxybenzonitrile I24

[0634] In N 2 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) was added dropwise H 2 O 2 (30% aqueous solution, 1.9 mL) and the mixture was stirred at room temperature for 2 h, then poured into a mixture of EtOAc and excess Na 2 SO 3 aqueous solution. Then the layers were separated and the organic layer was washed with water, brine, dried over anhydrous Na 2 SO 4 and filtered, concentrated under reduced pressure to give the title compound as an off-white waxy solid (650 mg, 62%). LCMS-D: R t 0.93 min; m / z 138.1 [M+H] + .

[0635] c) 3-Ethoxy-2-fluorobenzonitrile I25

[0636] 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, concentrated under reduced pressure to give the title compound as a yellow solid (220 mg, 51%). LCMS-D: R t 2.31 min; m / z 166.1 [M+H] + .

[0637] d) 7-Ethoxybenzo[d]isoxazol-3-amine I26

[0638] At 0 °C in N 2To a solution of acetohydroxamic acid (300 mg, 4.0 mmol) in DMF (15 mL) 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 , filtered and concentrated under reduced pressure to give the title compound as a yellow solid (170 mg, 70%). LCMS-D: R t 1.68 min; m / z 179.1 [M+H] + .

[0639] x) 7-(Cyclopropylmethoxy)benzo[d]isoxazol-3-amine I28

[0640]

[0641] a) 3-(Cyclopropylmethoxy)-2-fluorobenzonitrile I27

[0642] To a solution of 2-fluoro-3-hydroxybenzonitrile I24 (360 mg, 2.6 mmol) in DMF (30 mL) were added Cs 2 CO 3 (4.3 g, 13.1 mmol), KI (87 mg, 0.5 mmol) and (bromomethyl)cyclopropane (880 mg, 6.6 mmol) and the mixture was stirred at room temperature 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 , filtered and concentrated under reduced pressure to give the title compound as a red solid (150 mg, 30%). LCMS-D: R t 2.54 min; m / z 192.1 [M+H] + .

[0643] b) 7-(Cyclopropylmethoxy)benzo[d]isoxazol-3-amine I28

[0644] Prepared from 3-(cyclopropylmethoxy)-2-fluorobenzonitrile I27 according to the procedure described in step d for 7-ethoxybenzo[d]isoxazol-3-amine I26. LCMS-D: R t 2.23 min; m / z 205.1 [M+H] + .

[0645] xi) 6-Ethoxybenzo[d]isoxazol-3-amine I32

[0646]

[0647] a) 2-Fluoro-4-((tetrahydro-2H-pyran-2-yl)oxy)benzonitrile I29

[0648] Under N 2 To a solution of 2-fluoro-4-hydroxybenzonitrile (20 g, 145.9 mmol) and PPTS (733 mg, 2.9 mmol) in DCM (500 mL) was added 3,4-dihydro-2H-pyran (24.5 g, 292 mmol) and the mixture was stirred overnight at room temperature. The solvent was removed under reduced pressure and the residue was purified by column chromatography (petroleum ether / EtOAc = 100 / 0 to 100 / 2) to give the title compound as a white solid (27 g, 83%), which was used directly in the next step.

[0649] b) 6-((Tetrahydro-2H-pyran-2-yl)oxy)benzo[d]isoxazol-3-amine I30

[0650] At 0 °C under N 2 To a solution of acetohydroxamic acid (13.7 g, 182.3 mmol) in DMF (60 mL) 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 overnight at room temperature. 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 dried, 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 as a white solid (12.1 g, 85%). LCMS-D: R t 2.31 min; m / z 235.1 [M+H] + .

[0651] c) 3-Aminobenzo[d]isoxazol-6-ol I31

[0652] To 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 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 , filtered, and concentrated under reduced pressure to give the title compound as a white solid (2.1 g, 94%), which was used directly in the next step.

[0653] d) 6-Ethoxybenzo[d]isoxazol-3-amine I32

[0654] 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 under N 2 overnight. 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 , 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 as a white solid (270 mg, 76%). LCMS-D: R t 0.37 min; m / z 179.0 [M+H] + .

[0655] xii) 6-(Cyclopropylmethoxy)benzo[d]isoxazol-3-amine I33

[0656]

[0657] Prepared from 3-aminobenzo[d]isoxazol-6-ol I31 (395 mg, 97%) according to the procedure described for step d of 6-ethoxybenzo[d]isoxazol-3-amine I32. LCMS-D: R t 2.27 min; m / z 205.1 [M+H] + .

[0658] xiii) 6-(1H-1,2,3-Triazol-1-yl)benzo[d]isoxazol-3-amine I36

[0659]

[0660] a) 4 - Azido - 2 - fluorobenzonitrile I34

[0661] A mixture of 4 - amino - 2 - fluorobenzonitrile (2.0 g, 14.7 mmol) in water (4 mL), ACN (32 mL), and concentrated HCl (10 mL) was stirred overnight at room temperature under N 2 ₂. Then NaNO 2 (2.0 g, 29.4 mmol) was added portionwise and stirring was continued at room temperature for 2 h. The mixture was cooled to 0 °C, and NaN 3 (1.9 g, 29.4 mmol) was added portionwise and stirring was continued at room temperature for 2 h. Water (50 mL) was added and most of the organic solvents were removed under reduced pressure. Then the remaining aqueous mixture was extracted with DCM (50 mL × 4) and the combined organic extracts were washed with water and brine, dried over anhydrous Na 2 ₂SO 4 ₄, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / EtOAc = 100 / 0 to 20 / 1) to give the title compound as a yellow solid (1.5 g, 62%), which was used directly in the next step.

[0662] b) 2 - Fluoro - 4-(1H - 1,2,3 - triazol - 1 - yl)benzonitrile I35

[0663] 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 under N 2 ₂ for 24 h. Additional ethynyltrimethylsilane (454 mg, 4.6 mmol) was added and the mixture was heated at 50 °C for an additional 24 h, 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 under N 2 ₂ overnight. 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 as a white solid (200 mg, 34%), which was used directly in the next step.

[0664] c) 6-(1H - 1,2,3 - triazol - 1 - yl)benzo[d]isoxazol - 3 - amine I36

[0665] At 0 °C in N 2 To a solution of acetohydroxamic acid (239 mg, 3.16 mmol) in DMF (25 mL) 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 dried, 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 as a white solid (150 mg, 70%). LCMS-D: R t 0.47 min; m / z 202.1 [M+H] + .

[0666] xiv) 6-(Pyrimidin-2-yl)benzo[d]isoxazol-3-amine I39

[0667]

[0668] a) 2-Fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile I37

[0669] 4-Bromo-2-fluorobenzonitrile (1.0 g, 5.0 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-di(1,3,2-dioxaborolane) (1.3 g, 5.0 mmol), potassium acetate (5.9 g, 20.0 mmol) and Pd(dppf)Cl 2 (2.0 g, 1.0 mmol) in a mixture of DMSO (50 mL) and 1,4-dioxane (10 mL) was heated at 105 °C in N 2 for 3 h. The mixture was diluted with EtOAc (200 mL) and washed with water (100 mL × 3). The organic layer was dried over anhydrous Na 2 SO 4 dried, filtered, concentrated under reduced pressure and the residue was purified by column chromatography (petroleum ether / EtOAc = 100 / 0 to 50 / 1) to give the title compound as a white solid (1.1 g, 89%), which was used directly in the next step.

[0670] b) 2-Fluoro-4-(pyrimidin-2-yl)benzonitrile I38

[0671] In N 2 To 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 added Pd(dppf)Cl 2 (146 mg, 0.2 mmol) and K 3 PO 4 ·3H 2 O (1.33 g, 5.0 mmol) 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 give the title compound as a white solid (270 mg, 68%). LCMS-D: R t 2.38 min; m / z 200.1 [M+H] + .

[0672] c) 6-(Pyrimidin-2-yl)benzo[d]isoxazol-3-amine I39

[0673] At 0 °C under N 2 To a solution of acetohydroxamic acid (306 mg, 4.07 mmol) in DMF (20 mL) 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 give the title compound as a white solid (200 mg, 69%). LCMS-D: R t 0.38 min; m / z 213.1 [M+H] + , 235.1 [M+Na] + .

[0674] xv) 5-Bromobenzo[d]isoxazol-3-amine I40

[0675]

[0676] At 0 °C under N 2 To a solution of acetohydroxamic acid (23.7 g, 0.315 mol) in DMF (800 mL) was added t-BuOK (35.4 g, 0.315 mol) at 0 °C and the mixture was stirred at 15 °C for 2 h. Then 5-bromo-2-fluorobenzonitrile (21.0 g, 0.105 mol) was added and the mixture was stirred at room temperature overnight. The mixture was diluted with EtOAc (1.5 L) and washed with water (400 mL × 4). The organic layer was washed with brine, dried over anhydrous Na 2 SO 4 dried, 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 as a white solid (19 g, 86%). LCMS-D: R t 2.13 min; m / z 212.9 / 214.9 [M+H] + .

[0677] xvi) 4-Bromobenzo[d]isoxazol-3-amine I41

[0678]

[0679] At 0 °C under N 2 To a solution of acetohydroxamic acid (11.25 g, 0.15 mol) in DMF (220 mL) was added t-BuOK (16.8 g, 0.15 mol) at 0 °C and the mixture was stirred at 25 °C for 1 h. Then a solution of 2-bromo-6-fluorobenzonitrile (10.0 g, 0.05 mol) in DMF (80 mL) was added dropwise and stirring was continued at 25 °C overnight. The mixture was diluted with water (200 mL) and extracted with EtOAc (400 mL). The organic extract was washed with water (400 mL × 3), dried over anhydrous Na 2 SO 4 dried, filtered and concentrated under reduced pressure to give the title compound as a light red solid (7.0 g, 66%). LCMS-D: R t 2.05 min; m / z 212.9 / 214.9 [M+H] + .

[0680] xvii) 4-(Trifluoromethyl)benzo[d]isoxazol-3-amine I42

[0681]

[0682] At 0 °C under N 2To a solution of acetohydroxamic acid (2.25 g, 30 mmol) in DMF (80 mL) was added t-BuOK (3.37 g, 30 mmol) and the mixture was heated at 30 °C for 1 h. Then a solution of 2-fluoro-6-(trifluoromethyl)benzonitrile (1.89 g, 10 mmol) in DMF (20 mL) was added and heating was continued at 30 °C overnight. The mixture was partitioned between EtOAc (300 mL) and water (100 mL), the layers were separated and the organic layer was 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 = 50 / 1 to 1 / 1) to give the title compound as a white solid (1.3 g, 64%) LCMS-D: R t 2.19 min; m / z 203.0 [M+H] + .

[0683] xviii) 5-Bromo-4-chlorobenzo[d]isoxazol-3-amine I44

[0684]

[0685] a) 3-Bromo-2-chloro-6-fluorobenzonitrile I43

[0686] At 0 °C under N 2 To a solution of 2-chloro-6-fluorobenzonitrile (1.0 g, 6.4 mmol) in trifluoromethanesulfonic acid (10 mL) was added NBS (1.1 g, 6.4 mmol) and the mixture was stirred at room temperature overnight. The mixture was poured onto ice and extracted with EtOAc (30 mL × 2). 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 (petroleum ether / EtOAc = 200 / 1 to 100 / 1) to give the title compound as a white solid (705 mg, 47%), which was used directly in the next step.

[0687] b) 5-Bromo-4-chlorobenzo[d]isoxazol-3-amine I44

[0688] At 0 °C under N 2To a solution of hydroxamic acid (5.1 g, 67.8 mmol) in DMF (150 mL) 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) and washed with water (×3), brine, dried over anhydrous Na 2 SO 4 dried, 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 as a white solid (3.1 g, 52%), which was used directly in the next step.

[0689] xix) 5-Bromo-4-methoxybenzo[d]isoxazol-3-amine I48

[0690]

[0691] a) 3-Bromo-6-fluoro-2-methoxybenzoic acid I45

[0692] To a solution of diisopropylamine (5.4 g, 53.7 mmol) in THF (150 mL) at -78 °C was added dropwise n-BuLi (2.5 M solution in hexanes, 23.4 mL, 58.5 mmol) and the mixture was stirred at -78 °C for 1 h. The resulting mixture was added dropwise at -78 °C to a solution of 1-bromo-4-fluoro-2-methoxybenzene (10.0 g, 48.8 mmol) in THF (50 mL) and stirring was continued for 90 min. CO 2 was bubbled through the mixture with stirring at -78 °C for 20 min, then it was warmed to room temperature and stirred for 15 min. The mixture was adjusted to pH = 1 with HCl and the mixture was diluted with water and extracted with DCM (500 mL). The combined organic extracts were washed with brine, dried over anhydrous Na 2 SO 2 SO 4 dried, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (DCM / MeOH = 100 / 1 to 30 / 1) to give the title compound as a colorless oil (8.0 g, 66%). LCMS-D: R t 2.12 min; m / z 248.9 / 250.9 [M+H] + .

[0693] b) 3-Bromo-6-fluoro-2-methoxybenzamide I46

[0694] 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 h. The mixture was concentrated under reduced pressure and 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 min, and 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 as a white solid (6.8 g, 80%). LCMS-E: R t 2.24 min; m / z 247.8 / 249.8 [M+H] +

[0695] c) 3-Bromo-6-fluoro-2-methoxybenzonitrile I47

[0696] 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 and the organic layer was 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 = 100 / 1 to 20 / 1) to give the title compound as a colorless oil (3.5 g, 55%), which was used directly in the next step.

[0697] d) 5-Bromo-4-methoxybenzo[d]isoxazol-3-amine I48

[0698] At 0 °C under N 2 , t-BuOK (5.1 g, 45.7 mmol) was added to a solution of acetohydroxamic acid (3.4 g, 45.7 mmol) in DMF (150 mL) and the mixture was stirred at room temperature for 90 min. 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) and washed with water (×3) and brine, dried over anhydrous Na 2 SO 4Dry, filter and concentrate under reduced pressure. The residue was purified by column chromatography (petroleum ether / EtOAc = 50 / 1 to 3 / 1) to afford the title compound as a white solid (3.2 g, 86%). LCMS-D: R t 2.24 min; m / z 243.0 / 244.9 [M+H] + .

[0699] xx) 4-(Methoxymethyl)benzo[d]isoxazol-3-amine I51

[0700]

[0701] a) 2-(Bromomethyl)-6-chlorobenzonitrile I49

[0702] 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 CCl 4 (60 mL) was heated at 85 °C under N 2 for overnight. The mixture was concentrated under reduced pressure and the residue was purified by column chromatography (petroleum ether / EtOAc = 100 / 1 to 50 / 1) to afford the title compound as a white solid (1.7 g, 37%), which was used directly in the next step.

[0703] b) 2-Chloro-6-(methoxymethyl)benzonitrile I50

[0704] 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 min. Then 2-(bromomethyl)-6-chlorobenzonitrile I49 (560 mg, 2.4 mmol) was added and the mixture was stirred at room temperature for 5 h. The solvent was removed under reduced pressure and the residue was purified by column chromatography (petroleum ether / EtOAc = 50 / 1) to afford the title compound as a colorless oil (340 mg, 77%). 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.75–7.70 (m, 3H), 4.82 (s, 2H), 3.35 (s, 3H).

[0705] c) 4-(Methoxymethyl)benzo[d]isoxazol-3-amine I51

[0706] At -78 °C under N 2To a solution of acetohydroxamic acid (422 mg, 5.6 mmol) in DMF (25 mL) was added t-BuOK (630 mg, 5.6 mmol) and the mixture was stirred at 0 °C for 1 h. 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), dried over Na 2 SO 4 dried, 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 as a pale yellow oil (105 mg, 31%). LCMS-D: R t 1.57 min; m / z 179.1 [M+H] + .

[0707] xxi) 4-Ethoxybenzo[d]isoxazol-3-amine I53

[0708]

[0709] a) 2-Ethoxy-6-fluorobenzonitrile I52

[0710] A mixture of 2-chloro-6-hydroxybenzonitrile (2.0 g, 14.6 mmol), K 2 CO 3 (6.04 g, 43.8 mmol) and bromoethane (2.38 g, 21.9 mmol) in DMF (4 mL) was stirred at room temperature under N 2 2 overnight. The mixture was diluted with EtOAc (300 mL), washed with water (100 mL × 5), brine, dried over Na 2 SO 4 dried, 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 as a white solid (1.6 g, 67%). LCMS-E: R t 5.24 min; m / z 166.1 [M+H] + .

[0711] b) 4-Ethoxybenzo[d]isoxazol-3-amine I53

[0712] At 0 °C under N 2To a solution of hydroxamic acid (2.18 g, 29 mmol) in DMF (40 mL) was added t-BuOK (3.26 g, 29 mmol) and the mixture was stirred at room temperature for 1 h. 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), washed with water (60 mL×4), dried over Na 2 SO 4 dried, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / EtOAc = 5 / 1) to afford the title compound as a white solid (240 mg, 15%). LCMS-E: R t 5.05 min; m / z 179.0 [M+H] + .

[0713] xxii) 5-Methoxybenzo[d]isoxazol-3-amine I54

[0714]

[0715] At 0 °C under N 2 To a solution of hydroxamic acid (1.49 mg, 19.8 mmol) in DMF (35 mL) was added t-BuOK (2.23 mg, 19.8 mmol) and the mixture was heated at 30 °C for 1 h. Then a solution of 2-fluoro-5-methoxybenzonitrile (1.0 g, 6.6 mmol) in DMF (5 mL) was added and the mixture was heated at 30 °C overnight. The mixture was diluted with water (70 mL) and extracted with EtOAc (100 mL×3). The combined organic extracts were washed with water (200 mL×3), then dried over anhydrous Na 2 SO 4 dried, filtered, concentrated under reduced pressure to afford the title compound as a yellow solid (110 mg, 11%), which was used directly in the next step.

[0716] xxiii) 5-Ethoxybenzo[d]isoxazol-3-amine I57

[0717]

[0718] a) 2-Fluoro-5-hydroxybenzonitrile I55

[0719] A mixture of 2-fluoro-5-methoxybenzonitrile (1.7 g, 1.2 mmol) and pyridine·HCl (17 g) was heated at 80 °C under N 2The lower heating was continued for 5 h, then diluted with DCM (40 mL) and 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), and 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 , filtered and concentrated under reduced pressure to give the title compound as an off - white solid (430 mg, 28%), which was used directly in the next step.

[0720] b) 5 - Ethoxy - 2 - fluorobenzonitrile I56

[0721] 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 under N 2 for 30 min. Then bromoethane (512 mg, 4.7 mmol) was added and stirring was continued at room temperature 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), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether / EtOAc = 30 / 1 to 20 / 1) to give the title compound as a white solid (480 mg, 92%). LCMS - D: R t 2.44 min; m / z 166.0 [M + H] + 188.0 [M + Na] + .

[0722] c) 5 - Ethoxybenzo[d]isoxazol - 3 - amine I57

[0723] At 0 °C under N 2A solution of acetohydroxamic acid (645 mg, 8.7 mmol) in DMF (35 mL) was added with t-BuOK (978 mg, 8.7 mmol) and the mixture was heated at 30 °C for 1 h. 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), dried over anhydrous Na 2 SO 4 dried, filtered and concentrated under reduced pressure to give the title compound as a pale yellow solid (400 mg, 77%). LCMS-D: R t 2.02 min; m / z 179.1 [M+H] + .

[0724] xxiv) 6-(3,5-Dimethyl-1H-pyrazol-1-yl)benzo[d]isoxazol-3-amine I59

[0725]

[0726] a) 2-Chloro-4-(3,5-dimethyl-1H-pyrazol-1-yl)benzonitrile I58

[0727] A mixture of 3,5-dimethyl-1H-pyrazole (5 g, 0.052 mol), NaH (60% dispersion in oil, 2.6 g, 0.065 mol) in DMF (50 mL) was stirred at room temperature for 1 h. Then a solution of 2-chloro-4-fluorobenzonitrile (6.74 g, 0.043 mol) in DMF (50 mL) was added and stirring was continued at room temperature for 1 h. The reaction was quenched with water and the mixture was extracted with EtOAc. The organic extract was concentrated under reduced pressure to give the title compound as a yellow solid (11.0 g, 92%). LCMS-D: R t 2.58 min; m / z 232.1 [M+H] + .

[0728] b) 6-(3,5-Dimethyl-1H-pyrazol-1-yl)benzo[d]isoxazol-3-amine I59

[0729] At 0 °C under N 2A solution of acetohydroxamic acid (972 mg, 12.9 mmol) in DMF (20 mL) was added to t-BuOK (1.45 g, 12.9 mmol) and the mixture was heated at 30 °C for 1 h. 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 h. The mixture was diluted with water and extracted with EtOAc. The organic extract was dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by preparative TLC (MeOH / DCM = 1 / 20) to afford the title compound as a white solid (150 mg, 15%). LCMS-D: R t 2.22 min; m / z 229.1 [M+H] + .

[0730] xxv) 5-Methylbenzo[d]isoxazol-3-amine I60

[0731]

[0732] To a solution of acetohydroxamic acid (8.33 g, 0.11 mol) in DMF (200 mL) was added t-BuOK (12.5 g, 0.11 mol) and the mixture was stirred at room temperature for 1 h. Then 2-fluoro-5-methylbenzonitrile (5 g, 0.37 mol) was added and the mixture was heated at 60 °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 (DCM / MeOH = 200 / 1 to 50 / 1) to afford the title compound as a white solid (3.0 g, 55%). LCMS-D: R t 1.75 min, m / z 149.0 [M+H] + .

[0733] xxvi) 6-(Methoxymethyl)benzo[d]isoxazol-3-amine I62

[0734]

[0735] a) 2-Fluoro-4-(methoxymethyl)benzonitrile I61

[0736] A mixture of MeI (2.0 g, 13.2 mmol) and NaH (60% dispersion in oil, 790 mg, 19.8 mmol) in THF (50 mL) was stirred at 0 °C for 10 minutes, then 2-fluoro-4-(hydroxymethyl)benzonitrile (2.0 g, 13.2 mmol) was added and the mixture was stirred at room temperature for 2 hours. The reaction was quenched with water and the mixture was 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 20 / 1) to give the title compound as a white solid (1.7 g, 78%). LCMS-D: R t 2.01 min; m / z 166.0 [M+H] + 187.9 [M+Na] + 。

[0737] b) 6-(Methoxymethyl)benzo[d]isoxazol-3-amine I62

[0738] 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 as a yellow solid (1 g, 62%). LCMS-D: R t 0.95 min, m / z 179.0 [M+H] + 。

[0739] xxvii) 5-(Trifluoromethoxy)benzo[d]isoxazol-3-amine I63

[0740]

[0741] To a solution of acetohydroxamic acid (2.2 g, 0.029 mol) in DMF (50 mL) was added t-BuOK (3.28 g, 0.029 mol) and the mixture was stirred at room temperature for 1 hour. Then 2-fluoro-5-(trifluoromethoxy)benzonitrile (2 g, 9.75 mmol) was added and the mixture was heated at 60 °C overnight. The mixture was diluted with water and extracted with EtOAc. The organic extract was concentrated under reduced pressure to give the title compound as a yellow solid (1.6 g, 75%). LCMS-D: R t2.43 min; m / z 219.0 [M+H] + 。

[0742] xxviii) 5-Methyl-6-(oxazol-2-yl)benzo[d]isoxazol-3-amine I65

[0743]

[0744] a) 2-Fluoro-5-methyl-4-(oxazol-2-yl)benzonitrile I64

[0745] At -70 °C under N 2 to a solution of oxazole (90 mg, 1.31 mmol) in THF (10 mL) was added n-BuLi (2.5 M solution in hexanes, 1.1 mL, 2.66 mmol) and the mixture was stirred for 10 minutes. Solid ZnCl 2 (380 mg, 2.79 mmol) was added and the mixture was warmed to room temperature. 4-Bromo-2-fluoro-5-methylbenzonitrile (200 mg, 0.93 mmol) was added and the mixture was heated at 60 °C overnight. The solvent was removed under reduced pressure and the residue was purified by silica gel chromatography (petroleum ether / EtOAc 10 / 1) to give the title compound as a white solid (50 mg, 27%). LCMS-D: R t 2.51 min; m / z 203.0 [M+H] + 。

[0746] b) 5-Methyl-6-(oxazol-2-yl)benzo[d]isoxazol-3-amine I65

[0747] At 0 °C under N 2 to a solution of acetohydroxamic acid (189 mg, 2.52 mmol) in DMF (10 mL) 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 filtered and concentrated under reduced pressure. The residue was purified by preparative TLC (DCM / MeOH = 10 / 1) to give the title compound as a white solid (90 mg, 50%). LCMS-D: R t 2.10 min; m / z 216.0 [M+H] + 。

[0748] xxix) 7-Bromobenzo[d]isoxazol-3-amine I66

[0749]

[0750] To a solution of acetohydroxamic acid (3.75 g, 0.05 mol) in DMF (60 mL) was added t-BuOK (5.6 g, 0.05 mol) at 0 °C and the mixture was stirred at room temperature for 1 h. Then a solution of 3-bromo-2-fluorobenzonitrile (5.0 g, 0.025 mol) in DMF (90 mL) was added dropwise and stirring was continued at room temperature overnight. The mixture was diluted with DCM (300 mL), washed with water (250 mL × 4), brine, dried over anhydrous Na 2 SO 4 dried, filtered and concentrated under reduced pressure to afford the title compound as a white solid (4.0 g, 63%). LCMS-D: R t 2.09 min, m / z 213.0 / 215.0 [M+H] + .

[0751] xxx) 7-(Pyrimidin-2-yl)benzo[d]isoxazol-3-amine I68

[0752]

[0753] a) 2-Fluoro-3-(pyrimidin-2-yl)benzonitrile I67

[0754] 2-Fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile I23 (1.5 g, 6.1 mmol), 2-bromopyrimidine (1.9 g, 12.0 mmol), Pd(dppf)Cl 2 (1.3 g, 1.8 mmol) and K 3 PO 4 (6.5 g, 24.2 mmol) in a mixture of water (60 mL), toluene (60 mL) and i-PrOH (15 mL) were heated at 85 °C under N 2 for 4 h. The mixture was diluted with EtOAc (50 mL) and washed with water (80 mL × 3). The organic layer was dried over anhydrous Na 2 SO 4 dried, filtered, concentrated under reduced pressure and the residue was purified by column chromatography (petroleum ether / EtOAc = 4 / 1) to afford the title compound as a pale yellow solid (450 mg, 38%). LCMS-E: R t 4.82 min; m / z 199.9 [M+H] + .

[0755] b) 7-(Pyrimidin-2-yl)benzo[d]isoxazol-3-amine I68

[0756] At 0 °C under N 2 To a solution of acetohydroxamic acid (243 mg, 3.2 mmol) in DMF (15 mL) was added t-BuOK (363 mg, 3.2 mmol) and the mixture was stirred for 1 h. 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 dried, filtered and concentrated under reduced pressure to give the title compound as a yellow solid (230 mg, 67%). LCMS-D: R t 0.80 min, m / z 213.1 [M+H] + .

[0757] xxxi) 6-(1H-Pyrazol-1-yl)benzo[d]isoxazol-3-amine I70

[0758]

[0759] a) 2-Fluoro-4-(1H-pyrazol-1-yl)benzonitrile I69

[0760] A mixture of 4-bromo-2-fluorobenzonitrile (400 mg, 2.0 mmol), 1H-pyrazole (177 mg, 2.6 mmol), CuI (381 mg, 2.0 mmol), K 3 PO 4 (849 mg, 4.0 mmol) and (1S,2S)-N 1 ,N 2 -dimethylcyclohexane-1,2-diamine (28 mg, 0.2 mmol) in DMF (20 mL) was heated in a microwave at 100 °C for 1 h. The mixture was partitioned between EtOAc (200 mL) and water (100 mL), the layers were separated and the organic layer was washed with water (×3), brine, dried over anhydrous Na 2 SO 4 dried, 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 as a white solid (120 mg, 32%). LCMS-D: R t 2.20 min, m / z 188.1 [M+H] + .

[0761] b) 6-(1H-pyrazol-1-yl)benzo[d]isoxazol-3-amine I70

[0762] 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 h. 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 and the organic layer was washed with water (×3), brine, dried over anhydrous Na 2 SO 4 dried, 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 as a white solid (72 mg, 57%), which was used directly in the next step.

[0763] xxxii) 6-(2H-1,2,3-triazol-2-yl)benzo[d]isoxazol-3-amine I72

[0764]

[0765] a) 2-chloro-4-(2H-1,2,3-triazol-2-yl)benzonitrile I71

[0766] A mixture of 2H-1,2,3-triazole (553 mg, 8.0 mmol) and NaH (60% dispersion in oil, 192 mg, 4.8 mmol) in DMF (20 mL) was stirred at 0 °C for 30 min, then a solution of 2-chloro-4-fluorobenzonitrile (622 mg, 4.0 mmol) in DMF (10 mL) was added. The mixture was stirred at 0 °C for 2 h, then warmed to room temperature and stirred for 2 h. The mixture was partitioned between EtOAc (300 mL) and water (100 mL), the layers were separated and the organic layer was washed with water (×3), brine, dried over anhydrous Na 2 SO 4 dried, 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 as a white solid (200 mg, 24%). 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.31–8.28 (m, 3H), 8.19–8.14 (m 2H).

[0767] b) 6-(2H-1,2,3-triazol-2-yl)benzo[d]isoxazol-3-amine I72

[0768] At 0 °C, t-BuOK (330 mg, 2.9 mmol) was added to a solution of acetohydroxamic acid (221 mg, 2.9 mmol) in DMF (25 mL) and the mixture was heated at 30 °C for 2 h. 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 and the organic layer was washed with water (×3), brine, dried over anhydrous Na 2 SO 4 dried, 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 as a white solid (90 mg, 46%). LCMS-D: R t 1.93 min, m / z 202.1 [M+H] + .

[0769] xxxiii) 6-(pyridin-2-yl)benzo[d]isoxazol-3-amine I74

[0770]

[0771] a) 2-fluoro-4-(pyridin-2-yl)benzonitrile I73

[0772] A mixture of 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile I37 (494 mg, 2.0 mmol), 2-bromopyridine (948 mg, 6.0 mmol), Pd(dppf)Cl 2 (293 mg, 0.4 mmol) and K 3 PO 4 ·3H 2 O (2.66 g, 10.0 mmol) in H 2 O (40 mL), toluene (40 mL) and i-PrOH (10 mL) was heated at 85 °C under N 2 for 4 h. The mixture was partitioned between EtOAc (200 mL) and water (30 mL), the layers were separated and the organic layer was washed with water, brine, dried over anhydrous Na 2 SO 4Dry, filter and concentrate under reduced pressure. The residue was purified by column chromatography (petroleum ether / EtOAc = 30 / 1 to 10 / 1) to give the title compound as a white solid (190 mg, 48%). LCMS-D: R t 2.32 min, m / z 199.1 [M+H] + .

[0773] b) 6-(Pyridin-2-yl)benzo[d]isoxazol-3-amine I74

[0774] 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 h. 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 overnight at room temperature. 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 Dry, filter and concentrate under reduced pressure. The residue was purified by column chromatography (DCM / MeOH = 100 / 0 to 100 / 1) to give the title compound as a white solid (105 mg, 52%). LCMS-D: R t 0.83 min, m / z 212.1 [M+H] + .

[0775] xxxiv) 6-Bromobenzo[d]isoxazol-3-amine I75

[0776]

[0777] To a solution of acetohydroxamic acid (13.7 g, 182 mmol) in DMF (60 mL) at 0 °C was added t-BuOK (20.5 g, 182 mmol) and the mixture was stirred at 0 °C for 1 h. Then a solution of 4-bromo-2-fluorobenzonitrile (12.2 g, 60.8 mmol) in DMF (30 mL) was added and the mixture was stirred overnight at room temperature. The mixture was partitioned between EtOAc (500 mL) and water (200 mL), the layers were separated and the organic layer was washed with water (×2), brine, dried over anhydrous Na 2 SO 4 Dry, filter and concentrate under reduced pressure. The residue was purified by column chromatography (petroleum ether / EtOAc = 100 / 1 to 30 / 1) to give the title compound as a white solid (8.1 g, 63%). LCMS-D: Rt 2.34 min; m / z 213.0 / 215.0 [M+H] + 。

[0778] xxxv) 4-Methoxy-6-(pyridin-2-yl)benzo[d]isoxazol-3-amine I77

[0779]

[0780] a) 2-Fluoro-6-methoxy-4-(pyridin-2-yl)benzonitrile I76

[0781] A mixture of 4-bromo-2-fluoro-6-methoxybenzonitrile I5 (244 mg, 1.06 mmol), pyridin-2-ylboronic acid (195 mg, 1.59 mmol), CuCl (105 mg, 1.06 mmol), Pd(OAc) 2 (24 mg, 0.106 mmol), XPhos (100 mg, 0.212 mmol) and Cs 2 CO 3 (1.38 g, 4.24 mmol) in DMF (10.6 mL) was heated at 100 °C in a 20 mL sealed tube under a nitrogen atmosphere for 16 h. The reaction was repeated three more times on the same scale and the four reactions were quenched with saturated aqueous NH 4 Cl, combined and extracted with EtOAc (80 mL × 3). The combined organic extracts were washed with water, dried over anhydrous Na 2 SO 4 dried, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / EtOAc = 10 / 1 to 5 / 1) to afford the title compound as a yellow solid (190 mg, 20%). LCMS-C: R t 2.13 min; m / z 229.0 [M+H] + 。

[0782] b) 4-Methoxy-6-(pyridin-2-yl)benzo[d]isoxazol-3-amine I77

[0783] To 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 h. 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 4Dry, filter and concentrate 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 as a yellow solid (70 mg, 37%). 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).

[0784] xxxvi) 4-Methoxy-7-phenylbenzo[d]isoxazol-3-amine I80

[0785]

[0786] a) 3-Bromo-2-fluoro-6-methoxybenzonitrile I78

[0787] Add a solution of Br 2 (507 mg, 3.2 mmol) in CCl 4 (4.0 mL) to a solution of 2-fluoro-6-methoxybenzonitrile (480 mg, 3.2 mmol) and Fe (8.0 mg, 0.1 mmol) in CCl 4 (4.0 mL) at -10 °C over a period of 30 minutes, then warm the mixture to room temperature and stir overnight. Partition the mixture between water and EtOAc, separate the layers and wash the organic layer with saturated Na 2 SO 3 aqueous solution (×2), brine, dry over anhydrous Na 2 SO 4 dry, filter and concentrate to give the title compound as a white solid (580 mg, 80%). LCMS-C: R t 2.12 min; m / z 229.9 [M+H] + .

[0788] b) 2-Fluoro-4-methoxy-[1,1'-biphenyl]-3-carbonitrile I79

[0789] Under N 2 to 3-bromo-2-fluoro-6-methoxybenzonitrile I78 (600 mg, 2.6 mmol), phenylboronic acid (636 mg, 5.2 mmol) and Na 2CO 3 (829 mg, 7.8 mmol) was added to a solution of Pd(PPh 3 ) 4 (300 mg, 0.26 mmol) in 1,4 - dioxane (40 mL) and water (10 mL), 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 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 = 10 / 1 to 3 / 1) to give the title compound as a white solid (538 mg, 90%). LCMS - C: R t 2.43 min; m / z 228.0 [M + H] + .

[0790] c) 4 - Methoxy - 7 - phenylbenzo[d]isoxazol - 3 - amine I80

[0791] To 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 h. 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 as an orange solid (413 mg, 72%). 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).

[0792] xxxvii) 4 - Methoxy - 7-(1 - methyl - 1H - pyrazol - 4 - yl)benzo[d]isoxazol - 3 - amine I82

[0793]

[0794] a) 2-Fluoro-6-methoxy-3-(1-methyl-1H-pyrazol-4-yl)benzonitrile I81

[0795] In N 2 To a solution of 3-bromo-2-fluoro-6-methoxybenzonitrile I78 (720 mg, 3.31 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.30 g, 6.26 mmol) and Na 2 CO 3 (995 mg, 9.39 mmol) in 1,4-dioxane (50 mL) and water (10 mL) was added Pd(PPh 3 ) 4 (358 mg, 0.30 mmol) and the mixture was heated at 100 °C overnight. 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 and filtered and concentrated under reduced pressure. The residue was purified by column chromatography (DCM / MeOH = 100 / 1) to give the title compound as a white solid (485 mg, 63%). LCMS-C: R t 1.26 min; m / z 232.0 [M+H] + .

[0796] b) 4-Methoxy-7-(1-methyl-1H-pyrazol-4-yl)benzo[d]isoxazol-3-amine I82

[0797] To a solution of acetohydroxamic acid (474 mg, 6.24 mmol) in anhydrous DMF (20 mL) at room temperature was added potassium tert-butoxide (700 mg, 6.24 mmol) and the mixture was stirred at room temperature for 1 h. 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 and filtered and concentrated under reduced pressure. The residue was purified by column chromatography (DCM / MeOH = 50 / 1) to give the title compound as a yellow solid (225 mg, 45%). LCMS-C: R t 0.46 min; m / z 245.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6 ) 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).

[0798] xxxviii) 5-Chloro-4-methoxy-6-(methoxymethyl)benzo[d]isoxazol-3-amine I83

[0799]

[0800] To a solution of 4-methoxy-6-(methoxymethyl)benzo[d]isoxazol-3-amine I9 (300 mg, 1.4 mmol) in DMF (10 mL) was added NCS (192 mg, 1.4 mmol) and the mixture was heated at 50 °C for 2 h. The mixture was diluted with EtOAc (100 mL) and washed with H 2 O (40 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 = 7 / 1 to 5 / 1) to give the title compound as a white solid (190 mg, 54%). LCMS-C: R t 1.21 min; m / z 242.9 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.32 (s, 1H), 6.19 (s, 2H), 4.55 (s, 2H), 3.93 (s, 3H), 3.41 (s, 3H).

[0801] xxxix) 4-Methoxy-6-(oxazol-2-yl)benzo[d]isoxazol-3-amine I86

[0802]

[0803] a) 2-(Tributylstannyl)oxazole I84

[0804] At -78 °C in N 2A solution of 2 - (tributylstannyl)oxazole (500 mg, 7.25 mmol) in THF (15 mL) was added dropwise with n - BuLi (2.5 M solution in hexanes, 2.9 mL, 7.32 mmol), and the mixture was stirred at -78 °C for 30 minutes. Then tributylchlorostannane (1.96 mL, 7.25 mmol) was added, and the mixture was warmed to room temperature and stirred for 1 hour. The solvent was removed under reduced pressure, and the residue was dissolved in hexanes (50 mL). The resulting precipitate was removed by filtration, and the filtrate was concentrated under reduced pressure to afford the title compound as a colorless oil (2.0 g, 77%). 1 H NMR (400 MHz, DMSO - d 6 ) δ 8.20 (s, 1H), 7.20 (s, 1H), 1.59–1.49 (m, 6H), 1.31–1.26 (m, 6H), 1.16–1.10 (m, 6H), 0.83 (t, J = 7.3 Hz, 9H).

[0805] b) 2 - Fluoro - 6 - methoxy - 4 - (oxazol - 2 - yl)benzonitrile I85

[0806] To a solution of 4 - bromo - 2 - fluoro - 6 - methoxybenzonitrile I5 (305 mg, 1.33 mmol) in 1,4 - dioxane (25 mL) was 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, dried over anhydrous Na 2 SO 4 4, filtered, and concentrated. The residue was purified by column chromatography (petroleum ether / EtOAc = 8 / 1) to afford the title compound as a white solid (370 mg, 96%). LCMS - C: R t 1.86 min; m / z 218.9 [M + H] + .

[0807] c) 4 - Methoxy - 6 - (oxazol - 2 - yl)benzo[d]isoxazol - 3 - amine I86

[0808] 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 and washed with water, brine, dried over anhydrous Na 2 SO 4 dried, filtered and concentrated to give the title compound as a yellow solid (100 mg, 26%). 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).

[0809] xl) 6-(oxazol-2-yl)benzo[d]isoxazol-3-amine I90

[0810]

[0811] a) 4-cyano-3-fluorobenzoyl chloride I87

[0812] To a solution of 4-cyano-3-fluorobenzoic acid (1.0 g, 6.1 mmol) in DCM (20 mL) at 0 °C was added dropwise DMF (0.1 mL) and oxalyl chloride (1.86 g, 12.1 mmol) and the mixture was stirred overnight at room temperature. The solvent was removed under reduced pressure to give the title compound as a white solid (1.2 g), which was used directly in the next step without further purification.

[0813] b) 4-cyano-N-(2,2-dimethoxyethyl)-3-fluorobenzamide I88

[0814] 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 was added 2,2-dimethoxyethylamine (955 mg, 9.1 mmol) and the mixture was stirred for 2 h. 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 4Dry, filter and concentrate under reduced pressure. The residue was purified by column chromatography (petroleum ether / EtOAc = 1 / 1, v / v) to give the title compound as a white solid (1.2 g, 78%). LCMS-D: R t 1.55 min, m / z 274.9 [M+Na] + .

[0815] c) 3-Amino-N-(2,2-dimethoxyethyl)benzo[d]isoxazole-6-carboxamide I89

[0816] To a solution of acetohydroxamic acid (448 mg, 5.95 mmol) in DMF (30 mL) at 0 °C was added t-BuOK (889 mg, 7.92 mmol) portionwise and the mixture was stirred for 1 h. 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 4 dry, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / EtOAc = 1 / 1, v / v) to give the title compound as a yellow solid (380 mg, 72%). LCMS-D: R t 0.59 min, m / z 287.9 [M+Na] + .

[0817] d) 6-(Oxazol-2-yl)benzo[d]isoxazol-3-amine I90

[0818] A mixture of 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) was heated at 150 °C for 30 min under microwave irradiation. The mixture was poured into water, made basic with aqueous KOH and extracted with EtOAc. The organic extract was washed with brine, dried over anhydrous Na 2 SO 4 dry, filtered and concentrated under reduced pressure. The residue was purified by preparative TLC (DCM / MeOH = 10 / 1, v / v) to give the title compound as a solid (50 mg, 28%). LCMS-D: R t 1.57 min, m / z 201.9 [M+H] + .

[0819] xli) 5-Ethyl-1-methyl-2-oxo-1,2-dihydropyridine-3-sulfonyl chloride I94

[0820]

[0821] a) 5-Ethyl-2-methoxypyridine I91

[0822] At -78 °C under N 2 To a solution of 5-bromo-2-methoxypyridine (10.2 g, 54.25 mmol) in THF (200 mL) was added dropwise n-BuLi (2.5 M solution in hexanes, 24.0 mL, 60.0 mmol) and the mixture was stirred at -78 °C for 1.5 h. Then ethyl iodide (12.7 g, 81.4 mmol) was added dropwise and the mixture was stirred at -78 °C for 20 min, then warmed to room temperature and stirred for 30 min. The reaction was quenched with water (5 mL) and the solvent was removed under reduced pressure. The residue was dissolved in DCM, washed with water, brine, dried over anhydrous Na 2 SO 4 dried, 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 as a colorless oil (2.8 g, 38%). LCMS-D: R t 1.80 min; m / z 138.1 [M+H] + .

[0823] b) 5-Ethylpyridin-2(1H)-one I92

[0824] 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 give the title compound as a white solid (800 mg, 56%), which was used directly in the next step.

[0825] c) 5-Ethyl-1-methylpyridin-2(1H)-one I93

[0826] A mixture of 5-ethylpyridin-2(1H)-one I92 (800 mg, 6.5 mmol), K 2 CO 3 (1.8 g, 13 mmol) and ethyl iodide (1.85 g, 13 mmol) in MeOH (20 mL) was heated at 50 °C under N 2 overnight. The solvent was removed under reduced pressure and the residue was dissolved in DCM (100 mL), washed with water, brine, dried over anhydrous Na2 SO 4 Dry, filter and concentrate under reduced pressure. The residue was purified by column chromatography (DCM / MeOH = 40 / 1) to give the title compound as a colorless oil (500 mg, 56%). LCMS-D: R t 0.68 min; m / z 138.1 [M+H] + .

[0827] d) 5-Ethyl-1-methyl-2-oxo-1,2-dihydropyridine-3-sulfonyl chloride I94

[0828] 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 under N 2 for 3 h, 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, dried over anhydrous Na 2 SO 4 dry, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (DCM / MeOH = 100 / 1 to 20 / 1) to give the title compound as a yellow solid (200 mg, 12%). 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] + .

[0829] xlii) 5-Bromo-2,3-dihydrobenzofuran-7-sulfonyl chloride I95

[0830]

[0831] 5-Bromo-2,3-dihydrobenzofuran (2.0 g, 10 mmol) was slowly added to chlorosulfonic acid (6 mL) at -5 °C and the mixture was stirred at -5 °C for 30 min. The mixture was poured into ice-cold water (100 mL) and extracted with EtOAc (180 mL × 2). The combined organic extracts were washed with water (250 mL × 3), dried over anhydrous Na 2 SO 4Dry, filter and concentrate under reduced pressure. The residue was purified by column chromatography (petroleum ether / EtOAc = 15 / 1) to give the title compound as a white solid (1.45 g, 48%). 1 H NMR (400 MHz, CDCl 3 ) δ 7.80–7.76 (m, 1H), 7.63–7.58 (m, 1H), 4.91 (m, 2H), 3.35 (m, 2H). LCMS-D: R t 2.74 min; m / z 318.8 / 320.8 [M+Na] + 。

[0832] xliii) 4,6-Dimethoxy-2,3-dihydro-1H-indene-5-sulfonyl chloride I98

[0833]

[0834] a) 5,7-Dimethoxy-2,3-dihydro-1H-inden-1-one I96

[0835] A mixture of 3-(3,5-dimethoxyphenyl)propionic acid (5 g, 23.8 mmol) and methanesulfonic acid (24 mL) was heated at 90 °C for 10 min, then cooled to room temperature and poured into water. The mixture was adjusted to pH 9 with 10 M aqueous KOH and extracted with EtOAc (×5). The combined organic extracts were washed with water, brine, dried over anhydrous Na 2 SO 4 dried, filtered and concentrated under reduced pressure to give the title compound as a white solid (3.5 g, 76%). LCMS-D: R t 1.76 min; m / z193.1 [M+H] + 。

[0836] b) 4,6-Dimethoxy-2,3-dihydro-1H-indene I97

[0837] 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 under N 2 for 11 h. The mixture was concentrated under reduced pressure and the residue was purified by column chromatography (petroleum ether / EtOAc = 20 / 1) to give the title compound as a white solid (2.0 g, 72%). 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).

[0838] c) 4,6 - Dimethoxy - 2,3 - dihydro - 1H - indene - 5 - sulfonyl chloride I98

[0839] At - 70 °C, n - BuLi (2.5 M in hexanes, 2.5 mL, 6.17 mmol) was added dropwise 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), and the mixture was warmed to 0 °C and stirred for 2 h. Then the mixture was cooled again to - 65 °C, 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 anhydrous 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 under N 2 for 1 h, and then filtered. The filter cake was dissolved in diethyl ether and washed with water, brine, dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure to give the title compound as a white solid (550 mg, 35%). 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).

[0840] xliv) 2 - Methoxy - 5 - phenoxybenzenesulfonyl chloride I100

[0841]

[0842] a) 2 - Methoxy - 5 - phenoxybenzenesulfonic acid I99

[0843] To a solution of 1-methoxy-4-phenoxybenzene (2 g, 10 mmol) in DCM (15 mL) at 0 °C was added dropwise a solution of chlorosulfonic acid (0.35 mL) in DCM (10 mL) and the mixture was stirred at 0 °C for 15 minutes. The mixture was slowly poured into ice-cold water (100 mL), then concentrated under reduced pressure. The residue was washed with DCM (100 mL × 2) and dried to give the title compound as an off-white solid (560 mg, 40%). LCMS-D: R t 0.62 min; m / z 281.0 [M+H] + .

[0844] b) 2-Methoxy-5-phenoxybenzenesulfonyl chloride I100

[0845] A mixture of 2-methoxy-5-phenoxybenzenesulfonic acid I99 (250 mg, 0.9 mmol) and PCl 5 (284 mg, 1.3 mmol) in POCl 3 (3 mL) was heated at 90 °C under N 2 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, dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure to give the title compound as a yellow oil (51 mg, 18%). LCMS-D: R t 2.72 min; m / z 295.0 [M-Cl+OCH 3 + , 317.0 [M-Cl+OCH 3 +Na] + .

[0846] xlv) 2,6-Dimethoxy-3-(trifluoromethyl)benzenesulfonyl chloride I102

[0847]

[0848] a) 2,4-Dimethoxy-1-(trifluoromethyl)benzene I101

[0849] To (2,4-dimethoxyphenyl)boronic acid (3.0 g, 16.5 mmol), CF 3 SO 2 Na (18.0 g, 115.4 mmol), Cu(OAc) 2 ​(748 mg, 4.1 mmol), imidazole (281 mg, 4.1 mmol), 2,4,6-trimethylpyridine (3.0 g, 33.0 mmol) and NH 4 Cl (11.3 g, 206.0 mmol) were added dropwise to a mixture of water (16.5 mL) and DCM (100 mL), and t-BuOOH (3.6 mL, 4.1 mmol) was added dropwise while the mixture was stirred at room temperature for 16 hours. Then the layers were separated and the aqueous layer was extracted with DCM. 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) to give the title compound as an oil (900 mg, 27%). 1 H NMR (400 MHz, CDCl 3 ) δ 7.42–7.36 (m, 1H), 6.45–6.37 (m, 2H), 3.79 (s, 3H), 3.76 (s, 3H).

[0850] b) 2,6-Dimethoxy-3-(trifluoromethyl)benzenesulfonyl chloride I102

[0851] At -78 °C under N 2 , n-BuLi (2.5 M in hexanes, 3.2 mL, 8.0 mmol) was added dropwise to 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), 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 allowed to warm 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 and 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 and 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 as a yellow solid (1.5 g, 68%). 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).

[0852] xlvi) 3-Ethyl-2,6-dimethoxybenzenesulfonyl chloride I106

[0853]

[0854] a) 2,4-Dimethoxy-1-vinylbenzene I103

[0855] A suspension of 1-bromo-2,4-dimethoxybenzene (4.0 g, 18.4 mmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (3.4 g, 22.1 mmol), Pd(dppf)Cl 2 ·DCM (753 mg, 0.92 mmol) and K 2 CO 3 (7.6 g, 55.2 mmol) in 1,4-dioxane (40 mL) and water (10 mL) was heated at 90 °C overnight under N 2 atmosphere. The mixture was filtered through a Celite pad and rinsed with EtOAc. The filtrate was diluted with water and extracted with EtOAc (60 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) to give the title compound as a yellow oil (2.6 g, 86%). LCMS-D: R t 2.28 min; m / z 165.0 [M+H] + .

[0856] b) Ethyl-2,4-dimethoxybenzene I104

[0857] 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 H 2 atmosphere. The catalyst was removed by filtration through Celite and rinsed with EtOAc. The filtrate was concentrated under reduced pressure to give the title compound as a yellow oil (2.0 g, 83%). LCMS-D: R t 2.39 min; m / z 167.1 [M+H] + .

[0858] c) 3-Ethyl-2,6-dimethoxybenzenesulfonic acid I105

[0859] Prepared according to the procedure described for 2,6-dimethoxybenzenesulfonyl chloride I111 from ethyl-2,4-dimethoxybenzene I104. The product obtained was found to be mainly 3-ethyl-2,6-dimethoxybenzenesulfonic acid. LCMS-D: R t 2.36 min; m / z 247.0 [M+H] + .

[0860] d) 3-Ethyl-2,6-dimethoxybenzenesulfonyl chloride I106

[0861] 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 as a brown oil (322 mg, 100%), which was used directly in the next step.

[0862] xlvii) 7-Methoxyquinoline-8-sulfonyl chloride I107

[0863]

[0864] Chlorosulfonic acid (1.8 g, 15.7 mmol) was added dropwise to 7-methoxyquinoline (500 mg, 3.14 mmol) at 0 °C and the mixture was heated at 100 °C for 1 h. The mixture was cooled to room temperature, poured onto ice and then neutralized with saturated NaHCO 3 aqueous solution. The mixture was extracted with EtOAc (30 mL × 3) and the combined organic extracts were washed with brine, dried over anhydrous Na 2 SO 4 and filtered and concentrated under reduced pressure to give the title compound as a yellow solid (280 mg, 34%). LCMS-D: R t 0.27 min; m / z 239.9 [M-Cl+H 2 O] +

[0865] xlviii) 6-Methoxy-2,3-dihydro-1H-inden-5-sulfonyl chloride I108

[0866]

[0867] At -5 °C in N 2A solution of 5-methoxy-2,3-dihydro-1H-indene (3.1 g, 20.9 mmol) in DCM (40 mL) was added dropwise with chlorosulfonic acid (6.5 g, 62.8 mmol) and the mixture was stirred at -5 °C for 40 minutes. The reaction was quenched with ice water (20 mL) and the mixture was extracted with EtOAc (30 mL × 2). The combined organic extracts were washed with water (50 mL × 3), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / EtOAc = 20 / 1) to give the title compound as a white solid (3.1 g, 60%), which was used directly in the next step. 1 H NMR (400 MHz, CDCl 3 ) δ 7.77 (d, J = 1.1 Hz, 1H), 6.98 (s, 1H), 4.02 (s, 3H), 2.99 (t, J = 7.5 Hz, 2H), 2.91 (t, J = 7.4 Hz, 2H), 2.19–2.10 (m, 2H).

[0868] xlix) 3-Methoxy-5,6,7,8-tetrahydronaphthalene-2-sulfonyl chloride I109

[0869]

[0870] Prepared from 6-methoxy-1,2,3,4-tetrahydronaphthalene and chlorosulfonic acid according to the procedure described for 6-methoxy-2,3-dihydro-1H-indene-5-sulfonyl chloride I108 and used directly in the next step without purification.

[0871] l) 4-Bromo-2-methoxybenzenesulfonyl chloride I110

[0872]

[0873] 1-Bromo-3-methoxybenzene (15.0 g, 80 mmol) was slowly added to chlorosulfonic acid (16 mL) at -5 °C and the mixture was stirred at -5 °C for 5 minutes. The mixture was poured into ice-cold water (50 mL) and extracted with EtOAc (80 mL × 2). The combined organic extracts were washed with water (150 mL × 3), 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 give the title compound as a yellow solid (2.6 g, 17%), which was used directly in the next step.

[0874] li) 2,6-Dimethoxybenzenesulfonyl chloride I111

[0875]

[0876] At 0 °C in N 2 To a solution of 1,3-dimethoxybenzene (5.0 g, 36 mmol) and TMEDA (4.6 g, 39.8 mmol) in n-hexane (100 mL) was added dropwise n-BuLi (2.5 M solution in hexanes, 16.0 mL, 39.8 mmol) at 0 °C while maintaining the internal reaction temperature below 5 °C. The mixture was stirred at 0 °C for 20 minutes, then cooled to -78 °C and bubbled with SO 2 gas for 20 minutes. Then the mixture was slowly warmed to 10 °C and the resulting precipitate was collected by filtration and washed with anhydrous diethyl ether. The solid was suspended in n-hexane (100 mL), cooled to 0 °C and a solution of SO 2 Cl 2 (4.9 g, 36 mmol) in n-hexane (20 mL) was added dropwise while maintaining the internal temperature below 3 °C. The mixture was then stirred at 0 °C for 1 hour and the solid was collected by filtration and washed with cold n-hexane. Then the solid was 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 anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure to give the title compound as a white solid (4.0 g, 47%). 1 1H NMR (400 MHz, CDCl 3 ) δ 7.54 (t, J = 8.4 Hz, 1H), 6.66 (d, J = 8.4 Hz, 2H), 3.97 (s, 6H).

[0877] lii) 5-Ethyl-2-methoxybenzenesulfonyl chloride I112

[0878]

[0879] 1-Ethyl-4-methoxybenzene (5.0 g, 37 mmol) was added dropwise to chlorosulfonic acid (20 mL) at 0 °C and the mixture was stirred at room temperature for 2 hours, then poured onto ice and extracted with EtOAc (50 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 = 100 / 1 to 30 / 1) to give the title compound as a white solid (4.6 g, 53%). LCMS-D: R t 2.70 min; m / z 256.9 [M+Na] + .

[0880] liii) 2,4-Dimethoxy-[1,1'-biphenyl]-3-sulfonyl chloride I114

[0881]

[0882] a) 2,4-Dimethoxy-1,1'-biphenyl I113

[0883] A suspension of 1-bromo-2,4-dimethoxybenzene (5.0 g, 23.0 mmol), phenylboronic acid (3.4 g, 27.6 mmol), Pd(PPh 3 ) 4 (1.3 g, 1.15 mmol) and potassium carbonate (7.3 g, 69.0 mmol) in 1,4-dioxane (30 mL) and water (6 mL) was heated at 90 °C under N 2 for 16 h. The mixture was filtered through a Celite pad and washed with EtOAc. The filtrate was diluted with water and extracted with EtOAc (30 mL × 3). The combined organic extracts were dried over Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / EtOAc = 100 / 1 to 10 / 1) to give the title compound as a yellow oil (2.8 g, 57%). LCMS-D: R t 2.46 min; m / z 215.0 [M+H] + .

[0884] b) 2,4-Dimethoxy-[1,1'-biphenyl]-3-sulfonyl chloride I114

[0885] n-BuLi (2.5 M solution in hexanes, 2.1 mL, 5.20 mmol) was added dropwise 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 under N 2 , while maintaining the internal reaction temperature below 5 °C. The mixture was stirred at 0 °C for 20 min, 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 anhydrous diethyl ether. The solid was suspended in n-hexane (40 mL), cooled to 0 °C and SO 2 Cl 2A solution of 2 SO 4 (634 mg, 4.7 mmol) in n-hexane (5 mL) was added while maintaining the internal temperature below 3 °C. The mixture was then stirred at 0 °C for 1 h and the solid was collected by filtration and washed with cold n-hexane. The solid was then partitioned between ether and water, the layers were separated and the aqueous layer was further extracted with ether. The combined organic extracts were dried over Na 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).

[0886] liv) 3,5-Dimethoxy-[1,1'-biphenyl]-4-sulfonyl chloride I116

[0887]

[0888] a) 3,5-Dimethoxy-1,1'-biphenyl I115

[0889] A suspension of 1-bromo-3,5-dimethoxybenzene (5.0 g, 23.0 mmol), phenylboronic acid (2.8 g, 23.0 mmol), Pd(dppf)Cl 2 (0.57 g, 0.69 mmol) and potassium carbonate (4.8 g, 34.6 mmol) in 1,4-dioxane (80 mL) and water (20 mL) was heated at 90 °C under N 2 for 4 h. The mixture was diluted with water, extracted with EtOAc and the combined organic extracts were dried over Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / EtOAc = 500 / 1 to 200 / 1 to 100 / 1) to give the title compound as a white solid (5.2 g, 100%). LCMS-C: R t 2.47 min; m / z 215.0 [M+H] + .

[0890] b) 3,5-Dimethoxy-[1,1'-biphenyl]-4-sulfonyl chloride I116

[0891] 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. 1¹H 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).

[0892] lv) 4-Methoxy-6-((2,2,2-trifluoroethoxy)methyl)-1,2-benzisoxazol-3-amine I118

[0893]

[0894] a) 2-Fluoro-6-methoxy-4-((2,2,2-trifluoroethoxy)methyl)benzonitrile I117

[0895] At 0 °C under N 2 ₂, to a solution of 2-fluoro-4-(hydroxymethyl)-6-methoxybenzonitrile I7 (500 mg, 2.76 mmol) in anhydrous THF (50 mL) were successively added NaH (60% w / w dispersion in oil, 331 mg, 8.28 mmol), 2,2,2-trifluoroethyl trifluoromethanesulfonate (1.9 g, 8.28 mmol) and the mixture was stirred at 0 °C for 1 h, then allowed to warm to room temperature and stirred overnight. The mixture was diluted with water and extracted with EtOAc. The organic extract was washed with brine, dried over Na 2 ₂SO 4 ₄, filtered and concentrated under reduced pressure. The reaction was repeated twice with 2-fluoro-4-(hydroxymethyl)-6-methoxybenzonitrile I7 (100 mg, 0.55 mmol) and the three batches were combined and purified by column chromatography (petroleum ether / EtOAc = 5 / 1 to 2 / 1) to afford the title compound as a white solid (577 mg, 57%). LCMS - C: R t t 2.43 min; m / z 263.9 [M + H] + .

[0896] b) 4-Methoxy-6-((2,2,2-trifluoroethoxy)methyl)-1,2-benzisoxazol-3-amine I118

[0897] 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 h. 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, dried over Na 2 ₂SO4 Dry, filter and concentrate under reduced pressure. The reaction was scaled up accordingly using 2-fluoro-6-methoxy-4-((2,2,2-trifluoroethoxy)methyl)benzonitrile I117 (400 mg, 1.52 mmol), and the two batches were combined and purified by column chromatography (petroleum ether / EtOAc = 20 / 1 to 5 / 1) to give the title product as a yellow solid (350 mg, 67%). 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).

[0898] lvi) 6-(Difluoromethoxy)-4-methoxybenzo[d]isoxazol-3-amine I121

[0899]

[0900] a) 4-(Difluoromethoxy)-2,6-difluorobenzonitrile I119

[0901] To a suspension of KOH (22.0 g, 392 mmol) in acetonitrile (30 mL) and water (30 mL) at -20 °C was added portionwise 2,6-difluoro-4-hydroxybenzonitrile (3.1 g, 20.0 mmol), followed by diethyl (bromodifluoromethyl)phosphonate (10.0 g, 37.4 mmol) and the mixture was stirred overnight at room temperature. Water was added and the mixture was extracted with EtOAc (50 mL×3). The combined organic extracts were washed with brine, dried over Na 2 SO 4 dried, filtered and concentrated under reduced pressure to give the title compound as a colorless oil (4.0 g, 97%). LCMS-C: R t 2.11 min; m / z 205.9 [M+H] + .

[0902] b) 4-(Difluoromethoxy)-2-fluoro-6-methoxybenzonitrile I120

[0903] To a solution of 4-(difluoromethoxy)-2,6-difluorobenzonitrile I119 (2.52 g, 12.3 mmol) in anhydrous THF (30 mL) was added portionwise NaOMe (1.32 g, 24.57 mmol) and the mixture was warmed 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, 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 5 / 1) to afford the title compound as a white solid (663 mg, 25%). LCMS-C: R t 2.11 min; m / z 217.9 [M+H] + .

[0904] c) 6-(Difluoromethoxy)-4-methoxybenzo[d]isoxazol-3-amine I121

[0905] 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 h. Then 5-(difluoromethoxy)-1-fluoro-2-isocyanato-3-methoxybenzene I120 (663 mg, 3.05 mmol) was added and the mixture was stirred overnight at room temperature. The mixture was diluted with water and extracted with EtOAc (30 mL × 3). The combined organic extracts were washed with brine, 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 8 / 1) to afford the title compound as a pale orange solid (186 mg, 26%). LCMS-C: R t 1.14 min; m / z 231.0 [M+H] + .

[0906] lviii) 5-Methyl-6-(pyridin-2-yl)benzo[d]isoxazol-3-amine I124

[0907]

[0908] a) 2-Fluoro-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile I122

[0909] A mixture of 4-bromo-2-fluoro-5-methylbenzonitrile (500 mg, 2.34 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (1.78 g, 2.34 mmol), potassium acetate (918 mg, 9.36 mmol) and Pd(dppf)Cl 2 (188 mg, 0.23 mmol) in 1,4-dioxane (20 mL) was heated under reflux in N 2 for 3 h. The mixture was washed with water, extracted with EtOAc (300 mL) and the organic layer was washed with water (50 mL×3), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give the title compound (1.56 g, 88%), which was used in the next step without further purification. LCMS-C: R t 2.75 min; m / z 262.0 [M+H] + .

[0910] b) 2-Fluoro-5-methyl-4-(pyridin-2-yl)benzonitrile I123

[0911] Under N 2 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) was added Pd(PPh 3 ) 4 (589 mg, 0.5 mmol) and Na 2 CO 3 (2.16 g, 20.4 mmol) and the mixture was heated at 100 °C for 3 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 = 8 / 1 to 3 / 1) to give the title compound as a red solid (440 mg, 88%). LCMS-C: R t 1.09 min; m / z 213.0 [M+H] + .

[0912] c) 5-Methyl-6-(pyridin-2-yl)benzo[d]isoxazol-3-amine I124

[0913] 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 h. 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, dried over Na 2 SO 4 dried, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / EtOAc = 8 / 1 to 3 / 1) to give the title compound as a white solid (180 mg, 73%). LCMS-C: R t 0.50 min; m / z 226.0 [M+H] + .

[0914] lix) 7-Bromo-5-methylbenzo[d]isoxazol-3-amine I129

[0915]

[0916] a) 3-Bromo-2-fluoro-5-methylbenzoic acid I125

[0917] At -78 °C under N 2 2, n-BuLi (2.5 M solution in hexanes, 25.6 mL, 64.0 mmol) was added dropwise to a solution of 2-bromo-1-fluoro-4-methylbenzene (10.0 g, 53 mmol) and diisopropylamine (5.9 g, 58 mmol) in anhydrous THF (200 mL) and the mixture was stirred at -78 °C for 1 h. Excess solid CO 2 (dry ice) was added and stirring was continued at -78 °C for 3 h. The mixture was diluted with water (500 mL) and extracted with EtOAc (500 mL). The organic layer was washed with brine, dried over Na 2 SO 4 dried, filtered and concentrated under reduced pressure to give the title compound as a brown solid (12.3 g, 100%), which was used in the next step without further purification. LCMS-C: R t 2.03 min; m / z 232.8 [M+H] + .

[0918] b) 3-Bromo-2-fluoro-5-methylbenzoyl chloride I126

[0919] At room temperature under N 2To a solution of 3-bromo-2-fluoro-5-methylbenzoic acid I125 (12.3 g, 53 mmol) and DMF (4 drops) in DCM (100 mL) was added oxalyl chloride (13.0 g, 106 mmol) dropwise and the mixture was stirred for 2 h. The mixture was concentrated under reduced pressure to give the title compound as a brown solid (14.0 g, 100%), which was used in the next step without further purification.

[0920] c) 3-Bromo-2-fluoro-5-methylbenzamide I127

[0921] 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 h. 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 2SO4, filtered and concentrated under reduced pressure to give the title compound as a brown solid (12.0 g, 97%), which was used in the next step without further purification. LCMS-C: R t 1.01 min; m / z 231.9 [M+H] + .

[0922] d) 3-Bromo-2-fluoro-5-methylbenzonitrile I128

[0923] 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 h. The mixture was diluted with EtOAc (200 mL) and washed with water (400 mL × 5), brine and the organic layer was dried over Na 2 SO 4 2SO4, filtered and concentrated under reduced pressure to give the title compound as a brown solid (5.0 g, 54%), which was used in the next step without further purification. LCMS-C: R t 2.50 min; m / z 213.9 [M+H] + .

[0924] e) 7-Bromo-5-methylbenzo[d]isoxazol-3-amine I129

[0925] 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 h. Then 3-bromo-2-fluoro-5-methylbenzonitrile I128 (5.0 g, 23.4 mmol) was added and 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 , filtered and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / EtOAc = 10 / 1) to give the title compound as a yellow solid (2.8 g, 52%). LCMS-C: R t 0.50 min; m / z 226.9 [M+H] + .

[0926] Synthesis Example

[0927] Examples 1-45 (Table A):

[0928]

[0929] Method AA

[0930] 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 min. Sulfonyl chloride (0.445 mmol) was added and the reaction mixture was stirred at room temperature for 16 h. The volatiles were reduced to approximately 1 mL, then DCM (3 mL) and water (3 mL) were added and the mixture was stirred for 10 min. The mixture was passed through a phase separator, then the organic portion was loaded onto a 1 g Si-amine cartridge (Biotage) and the cartridge was washed with MeOH (6 mL), 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 give the desired product.

[0931] Method AB

[0932] 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. Sulfonyl chloride (0.445 mmol) was added and the reaction mixture was stirred at room temperature for 16 hours. The volatiles were reduced to approximately 1 mL, then 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 portion was loaded onto a 1 g Si-amine cartridge (Biotage) and the cartridge was washed with MeOH (6 mL), 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 give the crude product, which was loaded onto silica gel and purified by silica gel column chromatography (Biotage Isolera, SiO 2 cartridge, 0 - 100% EtOAc / petroleum spirit 40 - 60 °C) to give the desired product.

[0933] Method AC

[0934] 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. Sulfonyl chloride (0.445 mmol) was added and the reaction mixture was stirred at room temperature for 16 hours. The volatiles were reduced to approximately 1 mL, then 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 portion was loaded onto a 1 g Si-amine cartridge (Biotage) and the cartridge was washed with MeOH (10 mL), then the product was eluted with methanolic HCl solution (ca. 1.25 M, 10 mL). The HCl wash was then evaporated in vacuo to give the desired product.

[0935] Method AD

[0936] 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. After cooling, the reaction mixture was loaded onto silica gel and purified using silica gel column chromatography (Biotage Isolera, 24 g SiO 2 cartridge, 0 - 100% EtOAc / petroleum spirit 40 - 60 °C) to give the desired product.

[0937] Method AE

[0938] 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 h. After cooling, the mixture was loaded onto silica gel and purified using silica column chromatography (Biotage Isolera, 24 g SiO 2 cartridge, 0-100% EtOAc / petroleum spirit 40-60 °C, then 0-40% MeOH / EtOAc) to afford the desired product.

[0939] Method AF

[0940] 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 mL) was irradiated in a microwave at 80 °C for 1 h. After cooling, the mixture was loaded onto silica gel and purified using silica column chromatography (Biotage Isolera, 24 g SiO 2 cartridge, 0-100% EtOAc / petroleum spirit 40-60 °C) to afford the desired product.

[0941] Table A

[0942]

[0943]

[0944]

[0945]

[0946]

[0947]

[0948]

[0949] Examples 46-71 (Table D):

[0950]

[0951] Method BA

[0952] A mixture of benzo[d]isoxazol-3-amine and sulfonyl chloride in pyridine (1 mL) was stirred at room temperature for 16 h. The reaction mixture was concentrated and diluted with 5% aqueous HCl (1 mL) and sonicated for at least 30 min. The resulting precipitate was collected by filtration or DCM extraction (2×1 mL) and purified by silica gel column chromatography (EtOAc / petroleum spirit 40 - 60 °C gradient) or preparative mass-directed HPLC to give the desired product. For reaction components and amounts used and purification conditions, see Table B.

[0953] Method BB

[0954] 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 and diluted with 5% aqueous HCl (1 mL) and sonicated for at least 30 min. The resulting precipitate was collected by filtration and a portion of the crude material (50 mg or less) was purified by preparative mass-directed HPLC to give the desired product. For reaction components and amounts used, see Table B.

[0955] Method BC

[0956] 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 and diluted with 5% aqueous HCl (1 mL) and sonicated for at least 30 min. The resulting precipitate was collected by filtration and a portion of the crude material (50 mg or less) was purified by mass-directed preparative HPLC to give the desired product. For reaction components and amounts used, see Table B.

[0957] Table B

[0958]

[0959]

[0960]

[0961]

[0962] Method CA

[0963] A mixture of benz[d]isoxazol-3-amine and sulfonyl chloride in pyridine (1 mL) was stirred at room temperature for 16 h, at which point a second portion of benzenesulfonyl chloride was added and stirring continued for 64 h. The reaction mixture was concentrated and diluted with 5% aqueous HCl (1 mL) and sonicated for at least 30 min. The resulting precipitate was collected by filtration and purified by preparative mass-directed HPLC (up to 50 mg of crude material) or by silica gel column chromatography (0 - 40% EtOAc / petroleum spirit 40 - 60 °C) to give the desired product. For reaction components and amounts used and purification conditions, see Table C.

[0964] Table C

[0965]

[0966] Table D

[0967]

[0968]

[0969]

[0970]

[0971]

[0972]

[0973]

[0974]

[0975] Examples 72 - 88 (Table E):

[0976]

[0977] Method EA

[0978] NaH (60% in mineral oil, 49 mg, 1.22 mmol) was added to a solution of 4-methoxybenzo[d]isoxazol-3-amine (50 mg, 0.305 mmol) in THF (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 mixture was stirred for 16 h. The volatiles were reduced to approximately 1 mL, then 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 portion was loaded onto a 1 g Si-amine cartridge (Biotage) and the cartridge was washed with MeOH (6 mL), then the product was eluted with HCl solution (1.25 M in MeOH, 6 mL). The HCl wash was evaporated in vacuo to afford the desired product.

[0979] Method EB

[0980] 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 mixture was stirred for 16 h. The resulting mixture was loaded onto silica gel and purified by column chromatography (0 - 100% petroleum spirit 40 - 60 °C, then 0 - 60% MeOH / EtOAc) to afford the desired product.

[0981] Method EC

[0982] 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 mixture was stirred for 16 h. 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 spirit 40 - 60 °C, then 0 - 60% MeOH / EtOAc) to afford the desired product.

[0983] Method ED

[0984] 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 min. Sulfonyl chloride (1 equiv, 0.609 mmol) was added and the reaction mixture was stirred for 16 h. The resulting mixture was loaded onto silica gel and purified by column chromatography (0 - 100% petroleum spirit 40 - 60 °C, then 0 - 60% MeOH / EtOAc) to afford the desired product.

[0985] Method EF

[0986] 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 the mixture was stirred at room temperature for 10 min. Sulfonyl chloride (1 equiv, 0.609 mmol) was added and the reaction mixture was stirred for 16 h. The resulting mixture was loaded onto silica gel and purified by column chromatography (0 - 100% petroleum spirit 40 - 60 °C, then 0 - 60% MeOH / EtOAc) and the isolated solid was sonicated in MeOH (1 mL) and collected by filtration to afford the desired product.

[0987] Method EG

[0988] 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 the mixture was stirred at room temperature for 10 min. Sulfonyl chloride (1 equiv, 0.609 mmol) was added and the reaction mixture was stirred at room temperature for 16 h. The volatiles were reduced to ca. 1 mL, then DCM (3 mL) and water (3 mL) were carefully added and the mixture was stirred for 10 min. The mixture was passed through a phase separator, then the organic portion was loaded onto a 1 g Si-amine cartridge (Biotage) and the cartridge was washed with MeOH (6 mL), 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 afford the desired product.

[0989] Method EH

[0990] 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. Sulfonyl chloride (1.5 equiv, 0.439 mmol) was added to the cooled mixture and the mixture was stirred at -78 °C for 1 hour, 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 SiO 2 cartridge, 0 - 100% EtOAc / petroleum spirit 40 - 60 °C, then 0 - 40% MeOH / 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.

[0991] Method EI

[0992] 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 and diluted with 5% aqueous HCl (1 mL) and sonicated for at least 30 minutes. It was extracted with DCM (2 × 1 mL) and purified using silica column chromatography (0 - 100% EtOAc / petroleum spirit 40 - 60 °C) to give the desired product.

[0993] Method EJ

[0994] To a solution of 4-methoxybenzo[d]isoxazol-3-amine (1 equiv) in THF (3 mL) was added LiHMDS (1 M in THF, 1.5 equiv). After stirring for 10 minutes, sulfonyl chloride (1.5 equiv) was added and the reaction was stirred for 17 hours, open to air. THF was removed in vacuo, then DCM (3 mL) and water (3 mL) were added and stirred for 10 minutes. After separating the layers, the organic portion was loaded onto a 1 g Si-amine cartridge (Biotage). The cartridge was washed with MeOH (6 mL), then eluted with 1.25 M HCl in MeOH (6 mL). The HCl wash was then evaporated in vacuo to give the desired product.

[0995] Table E

[0996]

[0997]

[0998]

[0999]

[1000] Examples 89 - 147 (Table F)

[1001] Method FA

[1002]

[1003] At - 78 °C under N 2 To a solution of amine (0.5 mmol, 1.0 equiv) in anhydrous THF (10 mL) 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 sulfonyl chloride (1.5 equiv) in anhydrous THF (2.0 mL) was added dropwise and 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, dried over anhydrous Na 2 SO 4 2SO4, 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.

[1004] Method FB

[1005]

[1006] Under N 2 To a solution of amine (0.3 mmol, 1.0 equiv) in pyridine (5 mL) was added sulfonyl chloride (2.0 equiv) and the mixture was heated at 100 °C overnight. The reaction was quenched with 1 M aqueous HCl, then 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 2SO4, 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.

[1007] Method FC

[1008]

[1009] At - 20 °C under N 2A solution of the downward amine (0.5 mmol, 1.0 equivalent) in anhydrous THF (10 mL) was added dropwise with n-BuLi (2.5 M in hexanes, 1.5 equivalents), and the mixture was stirred at -20 °C for 1 hour. Then a solution of the sulfonyl chloride (1.5 equivalents) in anhydrous THF (2.0 mL) was added dropwise, and 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, dried over anhydrous Na 2 SO 4 dried, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (DCM / MeOH = 20 / 1) to give the title compound.

[1010] Method FD

[1011]

[1012] At -78 °C under N 2 A solution of the downward amine (0.5 mmol, 1.0 equivalent) in anhydrous THF (10 mL) was added dropwise with KHMDS (1 M solution in THF, the equivalent specified in Table F), and the mixture was stirred at -78 °C or 0 °C for 30 minutes to 1 hour (as specified in Table F). Then a solution of the sulfonyl chloride (the equivalent specified in Table F) in anhydrous THF (2.0 mL) was added dropwise, and 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, dried over anhydrous Na 2 SO 4 dried, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography or preparative TLC to give the title compound.

[1013] Table F

[1014]

[1015]

[1016]

[1017]

[1018]

[1019]

[1020]

[1021]

[1022]

[1023]

[1024]

[1025]

[1026]

[1027]

[1028]

[1029]

[1030]

[1031]

[1032]

[1033]

[1034]

[1035]

[1036] Example 148: N-(Benzo[d]isoxazol-3-yl)-2,4-dimethoxybenzenesulfonamide 148

[1037]

[1038] 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 h. The resulting mixture was loaded onto silica gel and the product was purified by column chromatography (4 g SiO 2 cartridge, 0 - 45% EtOAc / petroleum spirit 40 - 60 °C, then 4 g SiO 2 cartridge, 0 - 35% EtOAc / petroleum spirit 40 - 60 °C) to give two batches (78 mg and 5 mg) of the title compound as a white solid (total mass 83 mg, 33% yield). 1 1H NMR (400 MHz, CDCl 3)δ8.11(d,J=8.05Hz,1H),7.79(s,1H),7.70(d,J=8.81Hz,1H),7.57–7.50(m,1H),7.47–7.40(m,1H),7.37–7.29(m,1H),6.50(d,J=2.27Hz,1H),6.42(dd,J=2.25,8.81Hz,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] + .

[1039] Example 149: N-(Benzo[d]isoxazol-3-yl)-2,6-dimethoxybenzenesulfonamide 149

[1040]

[1041] 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 SiO 2 cartridge, 0 - 35% EtOAc / petroleum spirit 40 - 60 °C) to give the title compound as a white solid (3.9 mg, 3.1% yield). 1 H NMR (400 MHz, CDCl 3 )δ8.30(s,1H),8.17(dt,J=1.04,8.15Hz,1H),7.55–7.47(m,1H),7.47–7.34(m,2H),7.34–7.28(m,1H),6.60(d,J=8.52Hz,2H),3.91(s,6H). LCMS-B: rt 3.13 min, m / z 334.8[M+H] + .

[1042] Example 150: N-(5-Chlorobenzo[d]isoxazol-3-yl)-5-ethyl-2-methoxybenzenesulfonamide 150

[1043]

[1044] a) 5-Chlorobenzo[d]isoxazol-3-amine A1

[1045] 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 stirred at room temperature for 30 minutes. 5-Chloro-2-fluorobenzonitrile (1.00 g, 6.43 mmol) was added and the reaction mixture was heated to 50 °C for 1 hour. After cooling, the reaction mixture was diluted with saturated aqueous NaCl solution (15 mL), the aqueous layer was extracted with EtOAc (3 × 100 mL), the organic layers 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 SiO 2 cartridge, 0 - 40% EtOAc / petroleum spirit 40 - 60 °C) to give 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).

[1046] b) N-(5-Chlorobenzo[d]isoxazol-3-yl)-5-ethyl-2-methoxybenzenesulfonamide 150

[1047] 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 KOH solution (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 / petroleum spirit 40 - 60 °C) to give 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] + .

[1048] Example 151: N-(4-chlorobenzo[d]isoxazol-3-yl)benzenesulfonamide 151

[1049]

[1050] a) N-(4-chlorobenzo[d]isoxazol-3-yl)-N-(benzenesulfonyl)benzenesulfonamide A2

[1051] 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. After cooling, the reaction mixture was loaded onto silica gel and purified using silica gel column chromatography (Biotage Isolera, 24 g SiO 2 cartridge, 0 - 100% EtOAc / petroleum spirit 40 - 60 °C) to give the title compound. 1 1H 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).

[1052] b) N-(4-chlorobenzo[d]isoxazol-3-yl)benzenesulfonamide 151

[1053] A suspension of N-(4-chlorobenzo[d]isoxazol-3-yl)-N-(benzenesulfonyl)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 organic layers were washed with brine (25 mL), dried (Na 2 2 4 SO 1 4), filtered and concentrated under reduced pressure. The resulting gum was dissolved in the minimum amount of acetone, then petroleum spirit 40 - 60 °C (50 mL) was added and the precipitate was filtered off and air-dried to give the title compound as a brown solid (10 mg, 29%). 6 1H NMR (400 MHz, DMSO-d - ) 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]

[1054] Example 152: 5-Ethyl-N-(7-fluorobenzo[d]isoxazol-3-yl)-2-methoxybenzenesulfonamide 152

[1055]

[1056] a) 7-Fluorobenzo[d]isoxazol-3-amine A3

[1057] 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 reactants were stirred at room temperature for 30 minutes. 2,3-Difluorobenzonitrile (1.00 g, 7.19 mmol) was added and the reactants were heated to 50 °C for 1 hour. After cooling, the reaction mixture was diluted with saturated aqueous NaCl solution (15 mL), the aqueous layer was extracted with EtOAc (3 × 100 mL), the organic layers 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 / petroleum spirit 40 - 60 °C) to afford the title compound as a white solid (303 mg, 27%). 1 1H 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] + .

[1058] b) 5-Ethyl-N-(7-fluorobenzo[d]isoxazol-3-yl)-2-methoxybenzenesulfonamide 152

[1059] 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. After cooling, the reaction mixture was loaded onto silica gel and purified by column chromatography (Biotage Isolera, 24 g SiO 2 cartridge, 0 - 100% EtOAc / petroleum spirit 40 - 60 °C) to afford the title compound as a white solid (127 mg, 55%). 1 1H 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] + 。

[1060] Example 153: N-(4-chloro-5-methylbenzo[d]isoxazol-3-yl)-5-ethyl-2-methoxybenzenesulfonamide 153

[1061]

[1062] a) 4-chloro-5-methylbenzo[d]isoxazol-3-amine A4

[1063] 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 stirred at room temperature for 30 minutes. 2-Chloro-6-fluoro-3-methylbenzonitrile (1.00 g, 5.90 mmol) was added and the reaction mixture was heated to 50 °C for 1 hour. After cooling, the reaction mixture was diluted with saturated NaCl aqueous solution (15 mL), the aqueous layer was extracted with EtOAc (3 × 100 mL), the organic layers 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 ether 40 - 60 °C (50 mL) was added, the precipitate was collected by filtration and air-dried to give the product as a white solid (524 mg, 49%). 1 1H 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] + 。

[1064] b) N-(4-chloro-5-methylbenzo[d]isoxazol-3-yl)-5-ethyl-2-methoxybenzenesulfonamide 153

[1065] A solution of 4-chloro-5-methyl-1,2-benzisoxazol-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. After cooling, the reaction mixture was added to water, the precipitate was removed by filtration and the filtrate was loaded onto silica gel and purified by column chromatography (Biotage Isolera, 24 g SiO 2 cartridge, 0-100% EtOAc / petroleum spirit 40-60 °C) to afford the title compound as a white solid (33 mg, 16%). 1 H 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] + .

[1066] Example 154: N-(4-chlorobenzo[d]isoxazol-3-yl)-5-ethyl-2-methoxybenzenesulfonamide 154

[1067]

[1068] 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 under a nitrogen atmosphere at 30 °C for 40 h. The reaction was concentrated, 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 spirit 40-60 °C) to afford the title compound in two fractions (A and B) with a combined yield of 0.060 g, 12% yield.

[1069] 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] + 。

[1070] Part 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] +

[1071] Example 155: N-(4 - Chlorobenzo[d]isoxazol - 3 - yl)-2 - methoxybenzenesulfonamide 155

[1072]

[1073] 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 and diluted with 5% aqueous HCl (1 mL) and sonicated for at least 30 min. The resulting precipitate was collected by filtration and purified by 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] + 。

[1074] Example 156: N-(4-Fluorobenzo[d]isoxazol-3-yl)-2-methoxybenzenesulfonamide 156

[1075]

[1076] 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 and diluted with 5% aqueous HCl (1 mL) and sonicated for at least 30 min. The resulting precipitate was collected by filtration and purified by preparative mass-directed HPLC to give the title compound. 1 1H 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] + 。

[1077] Example 157: N-(6-Bromobenzo[d]isoxazol-3-yl)-2-methoxybenzenesulfonamide 157

[1078]

[1079] 6-Bromo-1,2-benzisoxazol-3-amine I75 (0.039 g, 0.180 mmol) and 2-methoxybenzenesulfonyl chloride (0.101 g, 0.490 mmol) in a mixture of pyridine (1.0 mL) and triethylamine (0.1 mL) were stirred at room temperature for 16 h. The reaction mixture was concentrated and diluted with 5% aqueous HCl (1 mL) and sonicated for at least 30 min. The resulting precipitate was collected by filtration and purified by 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] + .

[1080] Example 158: N-(6-Chloro-1,2-benzisoxazol-3-yl)-2-methoxybenzenesulfonamide 158

[1081]

[1082] 6-Chloro-1,2-benzisoxazol-3-amine (0.033 g, 0.200 mmol) and 2-methoxybenzenesulfonyl chloride (0.095 g, 0.460 mmol) in a mixture of pyridine (1.0 mL) and triethylamine (0.1 mL) were stirred at room temperature for 16 h. The reaction mixture was concentrated and diluted with 5% aqueous HCl (1 mL) and sonicated for at least 30 min. The resulting precipitate was collected by filtration and purified by mass-directed preparative HPLC to give the title compound. 1 H NMR (400 MHz, acetone-d 6)δ8.12–8.07(dd, J = 8.6, 0.5Hz, 1H), 7.91–7.87(dd, J = 7.9, 1.7Hz, 1H), 7.68–7.65(dd, J = 1.7, 0.5Hz, 1H), 7.64–7.58(ddd, J = 8.4, 7.4, 1.8Hz, 1H), 7.44–7.39(dd, J = 8.6, 1.7Hz, 1H), 7.21–7.17(m, 1H), 7.10–7.05(m, 1H), 3.88–3.86(s, 3H). HPLC-MS: rt 6.26min; m / z339.16 / 341.18[M+H]+.

[1083] Example 159: N-(4-chlorobenzo[d]isoxazol-3-yl)isoquinoline-8-sulfonamide 159

[1084]

[1085] A solution of 4-chlorobenzo[d]isoxazol-3-amine (0.050 g, 0.30 mmol) in anhydrous THF (2 mL) was cooled to -78 °C under a nitrogen atmosphere. Lithium bis(trimethylsilyl)amide (1.0 M in THF, 0.59 mL, 0.59 mmol) was carefully added, and then the mixture was stirred at 0 °C for 1 h. The mixture was cooled to -78 °C, a solution of 8-isoquinolinesulfonyl chloride (0.068 g, 0.30 mmol) in anhydrous THF (1 mL) was added and the mixture was warmed to room temperature. After stirring for 3 h, TLC indicated the presence of only starting material. The mixture was cooled to -78 °C, sodium hydride (60% dispersion in mineral oil, 0.059 g, 1.5 mmol) was added and the mixture was returned to room temperature and stirred overnight. Water (10 mL) was added and the pH was adjusted to about 3 with aqueous HCl (2 M). The aqueous phase was extracted with DCM (3 × 20 mL), the organic layers were combined, dried (MgSO 4 ) and the solvent was removed in vacuo. The solid residue was purified by column chromatography (Biotage Isolera, 12 g SiO 2 cartridge, 0 - 100% EtOAc / petroleum spirit 40 - 60 °C, then 0 - 40% MeOH / EtOAc) to give the title compound as a white solid (0.026 g, 24%). 1 1H NMR (400 MHz, DMSO-d 6)δ10.31(s,1H),8.53(d,J=5.8Hz,1H),8.28–8.21(m,1H),8.09(d,J=8.2Hz,1H),7.92(d,J=5.7Hz,1H),7.89–7.82(m,1H),7.39(t,J=7.9Hz,1H),7.31(d,J=8.3Hz,1H),7.17(d,J=7.5Hz,1H). LCMS-A: rt 5.43min; m / z 360.1[M+H] + 。

[1086] Example 160: N-(7-Iodo-4-methoxy-6-(methoxymethyl)benzo[d]isoxazol-3-yl)-2,6-dimethoxybenzenesulfonamide 160

[1087]

[1088] a) 7-Iodo-4-methoxy-6-(methoxymethyl)benzo[d]isoxazol-3-amine A5

[1089] A portion of 4-methoxy-6-(methoxymethyl)benzo[d]isoxazol-3-amine I9 (0.121 g, 0.581 mmol) was dissolved in N,N-dimethylformamide (2 mL), and then N-iodosuccinimide (0.131 g, 0.581 mmol) was added. At the end 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 and filtered. The volatiles were removed under reduced pressure and the residue was purified by column chromatography (12 g SiO 2 cartridge, 0 - 35% EtOAc / petroleum spirit 40 - 60 °C, then 12 g SiO 2 cartridge, 0 - 25% EtOAc / petroleum spirit 40 - 60 °C) twice to give the title compound as an off-white solid (0.038 g, 20% yield). 1 H NMR (400 MHz, CDCl 3 )δ6.78(s,1H),4.73(s,2H),4.54(s,2H),3.96(s,3H),3.50(s,3H). LCMS-A: rt 3.26min, m / z334.7[M+H] + 。

[1090] b) N-(7-Iodo-4-methoxy-6-(methoxymethyl)benzo[d]isoxazol-3-yl)-2,6-dimethoxybenzenesulfonamide 160

[1091] 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 column. The residue was purified by column chromatography (12 g SiO 2 column, 0 - 70% EtOAc / petroleum spirit 40 - 60 °C) to afford the title compound as a white solid (0.032 g, 53% yield). 1 1H NMR (400 MHz, CDCl 3 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] + .

[1092] Example 161: N-(7-Chloro-4-methoxy-6-(methoxymethyl)benzo[d]isoxazol-3-yl)-2,6-dimethoxybenzenesulfonamide 161

[1093]

[1094] a) 7-Chloro-4-methoxy-6-(methoxymethyl)benzo[d]isoxazol-3-amine A6

[1095] 4-Methoxy-6-(methoxymethyl)benzo[d]isoxazol-3-amine I9 (0.150 g, 0.720 mmol) was dissolved in N,N-dimethylformamide (2 mL), then N-chlorosuccinimide (96 mg, 0.72 mmol) was added. At the end 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 2O (3 × 8 mL) and brine (8 mL), dried over Na 2 2SO 4 4 and filtered. The volatiles were removed under reduced pressure and the residue was purified by column chromatography (12 g SiO 2The tube was purified with 0 - 40% EtOAc / petroleum spirit at 40 - 60 °C to give the title compound as a white solid (0.0240 g, 14% yield). 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).

[1096] b) N-(7-chloro-4-methoxy-6-(methoxymethyl)benzo[d]isoxazol-3-yl)-2,6-dimethoxybenzenesulfonamide 161

[1097] 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 tube. The residue was purified by column chromatography (12 g SiO 2 tube, 0 - 100% EtOAc / petroleum spirit at 40 - 60 °C) to give the title compound as a white solid (0.0094 g, 21% yield). 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] + .

[1098] Example 162: 5-Methoxy-N-(4-methoxy-6-(methoxymethyl)benzo[d]isoxazol-3-yl)quinoline-8-sulfonamide 162

[1099]

[1100] A solution of 4-methoxy-6-(methoxymethyl)-1,2-benzisoxazol-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 h. The reaction mixture 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 separator. The collected organic layer was dried in vacuo and the residue was purified by column chromatography (12 g SiO 2 cartridge, 0 - 80% EtOAc / petroleum spirit 40 - 60 °C) to give the title compound as an off-white solid (0.0110 g, 11% yield). 1 1H 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] + .

[1101] Example 163: 2-Hydroxy-6-methoxy-N-(4-methoxy-6-(methoxymethyl)-1,2-benzisoxazol-3-yl)benzenesulfonamide 163

[1102]

[1103] A solution of 4-methoxy-6-(methoxymethyl)-1,2-benzisoxazol-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 h, then at 120 °C for 1 h. The reaction mixture was cooled to room temperature and added to DCM (10 mL). The organic matter was washed with 1 M HCl (2×10 mL) and then dried over MgSO 4 4. The crude material was purified by silica gel chromatography (24 g SiO 2 cartridge, 0 - 85% EtOAc / petroleum spirit 40 - 60 °C, then 12 g SiO 2 cartridge, 0 - 75% EtOAc / petroleum spirit 40 - 60 °C) twice to give the title compound (1.5 mg). 11H 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] +

[1104] Example 164: 6-Methoxy-N-(6-(methoxymethyl)-5-methylbenzo[d]isoxazol-3-yl)pyridine-3-sulfonamide 164

[1105]

[1106] 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 h. The reaction mixture was cooled to room temperature, then dissolved in DCM and washed with 1 M HCl (×2). The organic layer was dried in vacuo, then wet loaded onto silica gel and the product was purified by column chromatography (24 g SiO 2 cartridge, 0 - 80% EtOAc / petroleum spirit 40 - 60 °C) to give the title compound as a colorless oil (15.6 mg, 17% yield). 1 1H 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] + .

[1107] Example 165: N-(6-(methoxymethyl)-5-methylbenzo[d]isoxazol-3-yl)pyridine-3-sulfonamide 165

[1108]

[1109] A solution of pyridine-3-sulfonyl chloride (0.0462 g, 0.260 mmol) and 6-(methoxymethyl)-5-methyl-1,2-benzisoxazol-3-amine I4 (0.050 g, 0.26 mmol) in pyridine (0.500 mL) was irradiated in a microwave at 120 °C for 2 h. 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 SiO 2 cartridge, 0 - 80% EtOAc / petroleum spirit 40 - 60 °C) to afford the title compound as a yellow solid (0.0220 g, 25% yield). 1 1H 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] - .

[1110] Example 166: 2,4-Dimethoxy-N-(6-(methoxymethyl)-5-methyl-1,2-benzisoxazol-3-yl)benzenesulfonamide 166

[1111]

[1112] A solution of 2,4-dimethoxybenzenesulfonyl chloride (0.052 g, 0.22 mmol) and 6-(methoxymethyl)-5-methyl-1,2-benzisoxazol-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 SiO 2 cartridge, 0 - 45% EtOAc / petroleum spirit 40 - 60 °C) to afford the title compound as a white solid (0.0413 g, 48% yield). 1 1H 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] + 。

[1113] Example 167: N-(6-(Hydroxymethyl)benzo[d]isoxazol-3-yl)-2,4-dimethoxybenzenesulfonamide 167

[1114]

[1115] a) Methyl 3-aminobenzo[d]isoxazole-6-carboxylate A9

[1116] To a solution of ethanehydroxamic acid (0.629 g, 8.37 mmol) in DMF (5 mL) was added potassium 2-methyl-2-propanolate (0.94 g, 8.4 mmol) and the reaction mixture was stirred for 30 minutes. Methyl 4-cyano-3-fluorobenzoate (1.0 g, 5.6 mmol) and DMF (2 mL) were added successively and the reaction mixture was stirred at room temperature for another 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 SiO 2 column, 0 - 50% EtOAc / petroleum spirit 40 - 60 °C) to give the title compound as a white solid (0.55 g, 51% yield). 1 H NMR (400 MHz, CDCl 3 ) δ 8.12 (d, J = 1.02 Hz, 1H), 7.96 (dd, J = 1.24, 8.29 Hz, 1H), 7.59 (dd, J = 0.77, 8.25 Hz, 1H), 3.98 (s, 3H). LCMS: rt 2.97 min, m / z 193.0 [M + H] + 。

[1117] b) Methyl 3-((2,4-dimethoxyphenyl)sulfonamido)benzo[d]isoxazole-6-carboxylate A10

[1118] 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 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 with DCM (2 × 40 mL). The combined organic layers were dried in vacuo and the residue was purified by column chromatography (24 g SiO 2 cartridge, 0 - 35% EtOAc / petroleum spirit 40 - 60 °C) twice to give two batches of the title compound as a white solid (0.369 g, impure and 0.0310 g, 2.8% yield, >95% purity). 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] + .

[1119] c) N-(6-(Hydroxymethyl)benzo[d]isoxazol-3-yl)-2,4-dimethoxybenzenesulfonamide 167

[1120] Under nitrogen, a solution of methyl 3-((2,4-dimethoxyphenyl)sulfamoyl)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 at room temperature overnight. The reaction mixture was quenched under nitrogen by dropwise addition of wet THF followed by 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, brine, dried over MgSO 4 and the solvent was removed in vacuo. The crude residue was purified by column chromatography (24 g SiO 2 cartridge, 0 - 100% EtOAc / petroleum spirit 40 - 60 °C) to give the title compound as a white solid (0.191 g, 100% yield). 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] + .

[1121] Example 168: 3 - ((5 - methoxyquinolinyl)-8 - sulfamoyl)-5 - methyl - 1,2 - benzisoxazole - 6 - carboxamide 168

[1122]

[1123] a) Methyl 3 - amino - 5 - methyl - 1,2 - benzisoxazole - 6 - carboxylate A11

[1124] To a solution of ethanehydroxamic acid (0.126 g, 1.69 mmol) in DMF (2 mL) was added potassium 2 - methyl - 2 - propoxide (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) and DMF (3 mL) were added successively 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 SiO 2 column, 0 - 50% EtOAc / petroleum spirit 40 - 60 °C) to give the title compound as a white solid (0.11 g, 48% yield). 1 H 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] + .

[1125] b) Methyl 3 - ((5 - methoxyquinolinyl)-8 - sulfamoyl)-5 - methyl - 1,2 - benzisoxazole - 6 - carboxylate hydrochloride A12

[1126] 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 mixture was irradiated in the 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 SiO 2 cartridge, 0 - 45% EtOAc / petroleum spirit 40 - 60 °C). The product was further purified by solid phase extraction (1 g, Si-amine, 3 void volumes of MeOH, followed by 4 void volumes of MeOH / HCl). The acidic eluate was collected and dried in vacuo to afford the title compound as a pale yellow solid (17.7 mg, 7.9% yield). 1 H 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] + .

[1127] c) 3-((5-Methoxyquinolin-8-yl)sulfamoyl)-5-methylbenzo[d]isoxazole-6-carboxamide 168

[1128] Under nitrogen, methyl 3-((5-methoxyquinolin-8-yl)sulfamoyl)-5-methylbenzo[d]isoxazole-6-carboxylate hydrochloride A12 (15.0 mg, 0.0323 mmol), aqueous ammonia solution (2.0 M in MeOH, 0.50 mL, 1.0 mmol) and calcium dichloride (3.59 mg, 0.0323 mmol) were added to a 15 mL thick-walled pressure tube equipped with a magnetic stir bar. The reaction vessel was sealed and heated at 80 °C for 3 days. The solvent was removed under a stream of air and aqueous ammonia solution (7.0 M in MeOH, 0.50 mL, 3.5 mmol) and calcium dichloride (3.6 mg, 0.032 mmol) were added. The reaction vessel was sealed and heated at 80 °C for 24 h. The reaction mixture was cooled to room temperature and the solvent was removed in vacuo. The compound was purified by column chromatography (4 g SiO 2 cartridge, 0 - 100% EtOAc / petroleum spirit 40 - 60 °C) to afford the title compound as a white solid (0.00180 g, 13% yield). 1 H NMR (400 MHz, methanol-d4 ) 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] + 。

[1129] Example 169: N-(6-Cyano-5-methylbenzo[d]isoxazol-3-yl)-2,4-dimethoxybenzenesulfonamide 169

[1130]

[1131] a) 3-Amino-5-methylbenzo[d]isoxazole-6-carbonitrile A13

[1132] To a solution of ethanehydroxamic acid (0.176 g, 2.34 mmol) in DMF (5 mL) was added potassium 2-methylpropan-2-olate (0.26 g, 2.3 mmol) and the reaction mixture was stirred for 30 minutes. 2-Fluoro-5-methyl-terephthalonitrile (0.25 g, 1.6 mmol) and DMF (3 mL) were added successively and the reaction mixture was stirred at room temperature overnight. 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 SiO 2 column, 0 - 50% EtOAc / petroleum spirit 40 - 60 °C) to give the title compound as an off-white solid (0.16 g, 59% yield). 1 1H NMR (400 MHz, CDCl 3 ) δ 7.72 (s, 1H), 7.47 (t, J = 0.86 Hz, 1H), 2.65 (d, J = 0.86 Hz, 3H). LCMS-B: rt 2.90 min, m / z 174.0 [M+H] + 。

[1133] b) N-(6-Cyano-5-methylbenzo[d]isoxazol-3-yl)-2,4-dimethoxybenzenesulfonamide 169

[1134] 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 left at room temperature for 50 min and then irradiated in the microwave at 130 °C for another 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 SiO 2 cartridge, 0 - 45% EtOAc / petroleum spirit 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 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 times). The residue was re-purified by column chromatography (24 g SiO 2 cartridge, 45% EtOAc / petroleum spirit 40 - 60 °C) to give two batches of the title compound as an off-white solid (22 mg and 78 mg, total mass 100 mg, 29% yield). 1 1H NMR (400 MHz, CDCl 3 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] - .

[1135] Example 170: 2,4 - Dimethoxy - N-(5 - methylbenzo[d]isoxazol - 3 - yl)benzenesulfonamide 170

[1136]

[1137] 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 h. The resulting mixture was loaded onto silica gel and the product was purified by column chromatography (12 g SiO 2 cartridge, 0-45% EtOAc / petroleum spirit 40-60 °C) to give the title compound as a white solid (55.0 mg, 42% yield). 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] - .

[1138] Example 171: N-(6-Bromo-5-methylbenzo[d]isoxazol-3-yl)-2,4-dimethoxybenzenesulfonamide 171

[1139]

[1140] a) 6-Bromo-5-methylbenzo[d]isoxazol-3-amine A14

[1141] To a solution of ethanehydroxamic 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 mixture was stirred for 30 min. 4-Bromo-2-fluoro-5-methylbenzonitrile (0.50 g, 2.3 mmol) was added to the reaction mixture and the reaction mixture was stirred at room temperature for a further 2 h. 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 SiO 2 cartridge, 0-50% EtOAc / petroleum spirit 40-60 °C) to give the title compound as a white solid (0.30 g, 56% yield). 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] + 。

[1142] b) N-(6-Bromo-5-methyl-1,2-benzisoxazol-3-yl)-2,4-dimethoxybenzenesulfonamide 171

[1143] A solution of 2,4-dimethoxybenzenesulfonyl chloride (0.052 g, 0.22 mmol) and 6-bromo-5-methyl-1,2-benzisoxazol-3-amine A14 (0.050 g, 0.22 mmol) in pyridine (1 mL) was irradiated twice in a microwave at 110 °C for 2 h, then irradiated at 130 °C for 2 h. The resulting mixture was loaded onto silica gel and the product was purified by column chromatography (4 g SiO 2 cartridge, 0 - 45% EtOAc / petroleum spirit 40 - 60 °C) to give the title compound as a white solid (102 mg, quantitative yield). 1 H NMR (400 MHz, CDCl 3 )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] + 。

[1144] Example 172: N-(6-(Ethoxymethyl)-4-methoxy-1,2-benzisoxazol-3-yl)-2,6-dimethoxybenzenesulfonamide 172

[1145]

[1146] At -78 °C in N 2A solution of downward 6-(ethoxymethyl)-4-methoxybenzo[d]isoxazol-3-amine I21 (250 mg, 1.13 mmol) in anhydrous THF (25 mL) was added dropwise with LiHMDS (1 M in THF, 4.5 mL, 4.5 mmol), and the mixture was stirred at -78 °C for 2 h. 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 adjusted 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 , filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (DCM / MeOH = 100 / 1) to give the title compound as a white solid (170 mg, 96% purity). Further purification by preparative HPLC gave the title compound (60 mg, 100% purity, 13% yield). LCMS-C: R t 2.08 min; m / z 423.0 [M+H] + ; 1 H 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).

[1147] Example 173: 2,6-Dimethoxy-N-(4-methoxy-6-(methoxymethyl)benzo[d]isoxazol-3-yl)benzenesulfonamide 173

[1148]

[1149] At -78 °C in N 2A solution of downward 4-methoxy-6-(methoxymethyl)benzo[d]isoxazol-3-amine I9 (3.0 g, 14.4 mmol) in anhydrous THF (200 mL) 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, and the mixture was warmed to room temperature and stirred overnight. The mixture was adjusted 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 dried, filtered, and concentrated under reduced pressure. The reaction was repeated with 4-methoxy-6-(methoxymethyl)benzo[d]isoxazol-3-amine I9 (2.0 g, 9.6 mmol) in 150 mL of THF, and the two batches were combined and purified by column chromatography (petroleum ether / EtOAc = 8 / 1 to 2 / 1) to give the title compound as a white solid (4.1 g, 42%). LCMS-C: R t 1.96 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).

[1150] Example 174: 2,6-Dimethoxy-N-(4-methoxy-6-phenylbenzo[d]isoxazol-3-yl)benzenesulfonamide 174

[1151]

[1152] At -78 °C in N 2A solution of downward 4-methoxy-6-phenylbenzo[d]isoxazol-3-amine I17 (2.5 g, 10.4 mmol) in anhydrous THF (60 mL) was added dropwise with LiHMDS (1 M solution in THF, 31.0 mL, 31.0 mmol), and the mixture was stirred at -78 °C for 2 hours. Then a solution of 2,6-dimethoxybenzenesulfonyl chloride I111 (3.7 g, 15.6 mmol) in anhydrous THF (20 mL) was added dropwise, and the mixture was warmed to 0 °C and stirred overnight. Water was added, and the mixture was washed with EtOAc (50 mL × 2). The aqueous layer was acidified to pH 3 with 1 M aqueous HCl and extracted with EtOAc (50 mL × 3). 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 (DCM / MeOH = 300 / 1) and further purified by column chromatography (DCM / MeOH = 200 / 1) to give the title compound as a white solid (1.5 g, 33%). 1 1H NMR (400 MHz, DMSO-d 6 ) δ 9.61 (s, 1H), 7.80 (d, J = 7.2 Hz, 2H), 7.50–7.44 (m, 5H), 7.09 (s, 1H), 6.80 (d, J = 8.8 Hz, 2H), 4.02 (s, 3H), 3.79 (s, 6H); LCMS-C: R t 2.46 min; m / z 441.0 [M+H] + .

[1153] Example 175: 3-Chloro-2,6-dimethoxy-N-(4-methoxy-6-(methoxymethyl)benzo[d]isoxazol-3-yl)benzenesulfonamide 175

[1154]

[1155] 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 hours. Then the mixture was diluted with EtOAc (150 mL) and washed with water and brine, dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (DCM / MeOH = 120 / 1) to give the title compound as a white solid (15 mg, 27%). LCMS-C: Rt 2.21 min; m / z 441.0 [M+H] + 。 1 H 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).

[1156] Example 176: 2,6-Dimethoxy-N-(4-methoxy-6-(2-methoxyphenyl)benzo[d]isoxazol-3-yl)benzenesulfonamide 176

[1157]

[1158] 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 a mixture of 1,4-dioxane (4 mL) and water (1 mL) were heated overnight at 100 °C under N 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 and filtered and concentrated under reduced pressure. The residue was purified by preparative TLC (petroleum ether / EtOAc = 1 / 2) to give the title compound as a white solid (10 mg, 31%). LCMS-C: R 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).

[1159] Example 177: 2,6-Dimethoxy-N-(4-methoxy-6-(3-methoxyphenyl)benzo[d]isoxazol-3-yl)benzenesulfonamide 177

[1160]

[1161] A mixture of N-(6-bromo-4-methoxybenzo[d]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 a mixture of 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 , filtered and concentrated under reduced pressure. The residue was purified by preparative TLC (DCM / MeOH = 50 / 1) to give the title compound as a white solid (8 mg, 15%). 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).

[1162] Example 178: 5 - Ethyl - 2 - methoxy - N-(7 - phenylbenzo[d]isoxazol - 3 - yl)benzenesulfonamide 178

[1163]

[1164] A mixture 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)Cl2 (18 mg, 0.024 mmol) and K 3 PO 4 ·3H 2 O (260 mg, 0.97 mmol) in a suspension of toluene (5 mL), isopropanol (2 mL) and water (5 mL) was heated at 100 °C under N 2 for 2 h. 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 , filtered and concentrated under reduced pressure. The residue was purified by preparative TLC (petroleum ether / EtOAc = 2 / 1) to give the title compound as a white solid (55 mg, 55%). 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).

[1165] Example 179: 5-Ethyl-2-methoxy-N-(6-phenylbenzo[d]isoxazol-3-yl)benzenesulfonamide 179

[1166]

[1167] 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 a mixture of water (10 mL), toluene (10 mL) and isopropanol (5 mL) was heated at 85 °C under N 2 for 4 h. The mixture was cooled to room temperature, diluted with water (200 mL) and extracted with ether (200 mL × 3). The combined organic extracts were washed with water, brine, dried over anhydrous Na 2 SO 4Dry, filter and concentrate under reduced pressure. The residue was purified by column chromatography (petroleum ether / EtOAc = 100 / 1 to 5 / 1) to give the title compound as a white solid (60 mg, 50%). 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).

[1168] Example 180: N-(4-chlorobenzo[d]isoxazol-3-yl)-2,3-dihydrobenzofuran-7-sulfonamide 180

[1169]

[1170] 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) was added 10% Pd / C (20 mg) and KOAc (20 mg, 0.28 mmol) and the mixture was stirred at 40 °C under H 2 atmosphere for 2 h, then stirred overnight at room temperature. 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 as a pale yellow solid (22 mg, 27%). LCMS-D: R 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).

[1171] Example 181: N-(4-chlorobenzo[d]isoxazol-3-yl)-5-ethyl-2,3-dihydrobenzofuran-7-benzenesulfonamide 181

[1172]

[1173] a) N-(4-chlorobenzo[d]isoxazol-3-yl)-5-vinyl-2,3-dihydrobenzofuran-7-benzenesulfonamide A15

[1174] To a solution of 5-bromo-N-(4-chlorobenzo[d]isoxazol-3-yl)-2,3-dihydrobenzofuran-7-sulfonamide 127 (200 mg, 0.47 mmol) in 1,4-dioxane (20 mL), EtOH (10 mL) and H 2 O (10 mL) was added 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) and the mixture was heated overnight at 90 °C under a 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 and 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 as a yellow solid (120 mg, 70%). LCMS-D: R t 0.40 min; m / z 377.0 [M+H] + .

[1175] b) N-(4-chlorobenzo[d]isoxazol-3-yl)-5-ethyl-2,3-dihydrobenzofuran-7-sulfonamide 181

[1176] 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 overnight at room temperature under a H 2 atmosphere. 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 as a white solid (33 mg, 27%). LCMS-D: R t 2.59 min; m / z 379.1 [M+H] + . 11H 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).

[1177] Example 182: N-(Benzo[d]isoxazol-3-yl)-4-ethyl-2-methoxybenzenesulfonamide 182

[1178]

[1179] a) N-(Benzo[d]isoxazol-3-yl)-2-methoxy-4-vinylbenzenesulfonamide A16

[1180] To a solution of N-(benzo[d]isoxazol-3-yl)-4-bromo-2-methylbenzenesulfonamide 141 (200 mg, 0.52 mmol) in toluene (16 mL), water (8 mL) and isopropanol (8 mL) was added 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) and the mixture was heated at 90 °C under N 2 atmosphere for 2 h. The mixture was diluted with water (50 mL) and 2 M aqueous HCl solution (20 mL) and extracted with EtOAc (80 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 = 5 / 1) to give the title compound as a pale yellow solid (150 mg, 76%). LCMS-D: R t 2.47 min; m / z 331.0 [M+H] + , 353.0 [M+Na] + .

[1181] b) N-(Benzo[d]isoxazol-3-yl)-4-ethyl-2-methoxybenzenesulfonamide 182

[1182] 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) and the mixture was stirred overnight at 25 °C 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 afford the title compound as a pale yellow solid (20 mg, 25%). LCMS-D: R t 2.55 min; m / z 333.1 [M+H] + . 1 HNMR (400 MHz, DMSO-d 6 ) 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).

[1183] Example 183: N-(benzo[d]isoxazol-3-yl)-3-methoxy-[1,1'-biphenyl]-4-sulfonamide 183

[1184]

[1185] To a solution of N-(benzo[d]isoxazol-3-yl)-4-bromo-2-methylbenzenesulfonamide 141 (100 mg, 0.26 mmol) in toluene (7 mL), water (7 mL) and isopropanol (2.5 mL) was added 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) and the mixture was heated at 90 °C under N 2 atmosphere for 2 h. The mixture was diluted with water (50 mL) and 2 M aqueous HCl (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 afford the title compound as a pale yellow solid (55 mg, 46%). LCMS-D: Rt 2.79 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)。

[1186] Example 184: 3-(5-Ethyl-2-methoxyphenylsulfonamido)-N-methylbenzo[d]isoxazole-7-carboxamide 184

[1187]

[1188] a) N-(7-Bromobenzo[d]isoxazol-3-yl)-N-((2,4-dimethoxybenzyl)oxy)-5-ethyl-2-methoxybenzenesulfonamide A17

[1189] At 0 °C under N 2 to 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) 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 as a pale blue solid (1.0 g, 32%). LCMS-D: R t 3.35 min; m / z 583.1 / 585.1 [M+Na] + 。

[1190] b) Methyl 3-(N-((2,4-dimethoxybenzyl)oxy)-5-ethyl-2-methoxyphenylsulfonamido)benzo[d]isoxazole-7-carboxylate A18

[1191] 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)Cl2 (98 mg, 0.13 mmol) and the mixture was heated overnight at 80 °C 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 dried, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether / EtOAc = 4 / 1) to afford the title compound as a white solid (210 mg, 31%). LCMS-D: R t 3.10 min; m / z 541.2 [M+H] + .

[1192] c) 3-(N-((2,4-Dimethoxybenzyl)oxy)-5-ethyl-2-methoxyphenylsulfonamido)-N-methylbenzo[d]isoxazole-7-carboxamide A19

[1193] 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 minutes. The solvent was removed under reduced pressure to afford 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] + .

[1194] d) 3-(5-Ethyl-2-methoxyphenylsulfonamido)-N-methylbenzo[d]isoxazole-7-carboxamide 184

[1195] 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 afford the title compound as a white solid (18 mg, 64%). LCMS-D: R t 2.35 min; m / z 390.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6)δ11.9(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=8.0,7.6Hz,2H),1.15(t,J=7.9Hz,3H).

[1196] Example 185: 3-(5-Ethyl-2-methoxyphenylsulfonamido)-N,N-dimethylbenzo[d]isoxazole-7-carboxamide 185

[1197]

[1198] a) Methyl 3-(5-ethyl-2-methoxyphenylsulfonamido)benzo[d]isoxazole-7-carboxylate A20

[1199] A mixture of methyl 3-(N-((2,4-dimethoxybenzyl)oxy)-5-ethyl-2-methoxyphenylsulfonamido)benzo[d]isoxazole-7-carboxylate A18 (150 mg, 0.28 mmol) and TFA (5 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 = 3 / 1) to give the title compound as a white solid (80 mg, 74%). LCMS-D: R t 2.63 min; m / z 391.1 [M+H] + , 413.1 [M+Na] + . 1 1H NMR (400 MHz, DMSO-d 6 )δ11.9(s,1H),8.39–8.32(m,1H),8.19–8.12(m,1H),7.72(d,J = 2.2Hz,1H),7.56–7.44(m,2H),7.12–7.05(m,1H),3.89(s,3H),3.71(s,3H),2.62(q,J = 7.5Hz,2H),1.16(t,J = 7.6Hz,3H).

[1200] b) 3-((5-Ethyl-2-methoxyphenyl)sulfonamido)benzo[d]isoxazole-7-carboxylic acid A21

[1201] 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 2 M aqueous NaOH solution (1.28 mL) and the mixture was stirred overnight at room temperature. The solvent was removed under reduced pressure and the residue was diluted with water and adjusted to pH 2 - 3. The resulting precipitate was collected by filtration to give the title compound as an off-white solid (144 mg, 75%). LCMS-D: R t 2.43 min; m / z 377.1 [M+H] + . 1 H 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).

[1202] c) 3-(5-Ethyl-2-methoxyphenylsulfonamido)benzo[d]isoxazole-7-carbonyl chloride A22

[1203] 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 under N 2 atmosphere for 3 h 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.

[1204] d) 3-(5-Ethyl-2-methoxyphenylsulfonamido)-N,N-dimethylbenzo[d]isoxazole-7-carboxamide 185

[1205] 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 and 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, dried over anhydrous Na 2 SO 4Dry, filter and concentrate under reduced pressure. The residue was purified by preparative TLC to give the title compound as a white solid (18 mg, 56%). 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).

[1206] Example 186: 5-Ethyl-N-(7-(hydroxymethyl)-1,2-benzisoxazol-3-yl)-2-methoxybenzenesulfonamide 186

[1207]

[1208] A mixture of 3-(5-ethyl-2-methoxyphenylsulfonamido)-1,2-benzisoxazole-7-carboxylic acid A21 (30 mg, 0.08 mmol) and BH 3 ·THF (1 M solution in THF, 3 mL, 3 mmol) was stirred at room temperature under N 2 atmosphere for 5 h. The reaction was quenched with water and most of the THF was removed under reduced pressure. The residue was adjusted to pH 2-3 and extracted with DCM (15 mL × 3). The combined organic extracts were dried over anhydrous Na 2 SO 4 dried, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (DCM / MeOH = 30 / 1) to give the title compound as a light red solid (20 mg, 71%). LCMS-D: R t 2.35 min; m / z 363.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6)δ 11.7 (s, 1H), 7.96–7.89 (m, 1H), 7.70 (d, J = 2.3 Hz, 1H), 7.61–7.55 (m, 1H), 7.46 (dd, J = 8.5, 2.3 Hz, 1H), 7.34 (t, J = 7.6 Hz, 1H), 7.12–7.05 (m, 1H), 5.39 (t, J = 5.7 Hz, 1H), 4.70 (d, J = 5.4 Hz, 2H), 3.73 (s, 3H), 2.61 (q, J = 7.2 Hz, 2H), 1.16 (t, J = 7.6 Hz, 3H).

[1209] Example 187: 5-Ethyl-2-methoxy-N-(7-methylbenzo[d]isoxazol-3-yl)benzenesulfonamide 187

[1210]

[1211] 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) was 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 under N 2 atmosphere for 4 h. 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), brine, dried over anhydrous Na 2 SO 4 and filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC to give the title compound as a white solid (20 mg, 16%). 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).

[1212] Example 188: 5-Ethyl-N-(7-ethyl-1,2-benzisoxazol-3-yl)-2-methoxybenzenesulfonamide 188

[1213]

[1214] a) N-((2,4-Dimethoxybenzyl)oxy)-5-ethyl-2-methoxy-N-(7-ethenyl-1,2-benzisoxazol-3-yl)benzenesulfonamide A23

[1215] To a suspension of N-(7-bromo-1,2-benzisoxazol-3-yl)-N-((2,4-dimethoxybenzyl)oxy)-5-ethyl-2-methoxybenzenesulfonamide A17 (200 mg, 0.36 mmol) in 1,4-dioxane (15 mL) and water (3 mL) was added 4,4,5,5-tetramethyl-2-ethenyl-1,3,2-dioxaborolane (110 mg, 0.71 mmol), K 2 CO 3 (148 mg, 1.07 mmol) and Pd(dppf)Cl 2 (26 mg, 0.036 mmol) and the mixture was heated at 90 °C under N 2 atmosphere for 4 h. The mixture was concentrated under reduced pressure and 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 , filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether / EtOAc = 2 / 1) to give the title compound as a white solid (95 mg, 52%). LCMS-D: R t 3.28 min; m / z 509.0 [M+H] + .

[1216] b) 5-Ethyl-2-methoxy-N-(7-ethenyl-1,2-benzisoxazol-3-yl)benzenesulfonamide A24

[1217] 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 as a white solid (40 mg, 61%). LCMS-D: R t 2.78 min; m / z 359.1 [M+H] +

[1218] c) 5-Ethyl-N-(7-ethylbenzo[d]isoxazol-3-yl)-2-methoxybenzenesulfonamide 188

[1219] 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 stirred at room temperature under H 2 atmosphere overnight. The mixture was filtered, the filtrate was concentrated and the residue was purified by silica gel chromatography (petroleum ether / EtOAc 4 / 1) to give the title compound as a white solid (30 mg, 85%). LCMS-D: R t 2.83 min; m / z 361.1 [M+H] + . 1 HNMR (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).

[1220] Example 189: 5-Ethyl-N-(7-cyclopropylbenzo[d]isoxazol-3-yl)-2-methoxybenzenesulfonamide 189

[1221]

[1222] a) N-(7-Cyclopropylbenzo[d]isoxazol-3-yl)-N-((2,4-dimethoxybenzyl)oxy)-5-ethyl-2-methoxybenzenesulfonamide A25

[1223] To a suspension of N-(7-bromobenzo[d]isoxazol-3-yl)-N-((2,4-diethylbenzyl)oxy)-5-ethyl-2-methoxybenzenesulfonamide A17 (200 mg, 0.36 mmol) in 1,4-dioxane (15 mL) and H 2 O (3 mL) was added cyclopropylboronic acid (61 mg, 0.71 mmol), K 2 CO 3 (148 mg, 1.07 mmol) and Pd(dppf)Cl 2 (26 mg, 0.036 mmol), and the mixture was heated at 90 °C under N 2 atmosphere for 4 h. The mixture was concentrated under reduced pressure and 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 , filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether / EtOAc = 3 / 1) to give the title compound as a white solid (140 mg, 75%). LCMS-D: R t 3.34 min; m / z 523.2 [M+H] + .

[1224] b) N-(7-Cyclopropylbenzo[d]isoxazol-3-yl)-5-ethyl-2-methoxybenzenesulfonamide 189

[1225] 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 as a white solid (80 mg, 81%). 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).

[1226] Example 190: N-(7-Cyclohexylbenzo[d]isoxazol-3-yl)-5-ethyl-2-methoxybenzenesulfonamide 190

[1227]

[1228] a) N-(7-(Cyclohex-1-en-1-yl)benzo[d]isoxazol-3-yl)-N-(2,4-dimethoxybenzyl)-5-ethyl-2-methoxybenzenesulfonamide A26

[1229] 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) was 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 under N 2 for 4 h. The mixture was concentrated under reduced pressure and 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 , filtered and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / EtOAc = 3 / 1) to give the title compound as a white solid (150 mg, 75%), which was used directly in the next step.

[1230] b) N-(7-(Cyclohex-1-en-1-yl)benzo[d]isoxazol-3-yl)-5-ethyl-2-methoxybenzenesulfonamide A27

[1231] A mixture of N-(7-(cyclohex-1-en-1-yl)-1,2-benzisoxazol-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 h and then concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether / EtOAc = 2 / 1) to afford the title compound as a white solid (65 mg, 60%). LCMS-D: R t 3.64 min; m / z 413 [M+H] + .

[1232] c) N-(7-Cyclohexyl-1,2-benzisoxazol-3-yl)-5-ethyl-2-methoxybenzenesulfonamide 190

[1233] A mixture of N-(7-(cyclohex-1-en-1-yl)-1,2-benzisoxazol-3-yl)-5-ethyl-2-methoxybenzenesulfonamide A27 (65 mg, 0.15 mmol) and 10% Pd / C (13 mg) in EtOAc (10 mL) was stirred at room temperature under H 2 atmosphere for 3 h. The mixture was filtered and the filtrate was concentrated under reduced pressure to afford the title compound as a white solid (40 mg, 61%). 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).

[1234] Example 191: 5-Ethyl-2-methoxy-N-(7-(1-methyl-1H-pyrazol-4-yl)-1,2-benzisoxazol-3-yl)benzenesulfonamide 191

[1235]

[1236] 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

[1237] To 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 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 under N 2 atmosphere overnight. The mixture was diluted with 0.5 M aqueous HCl (30 mL) and most of the organic solvents were 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 4 and filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (DCM / MeOH = 100 / 1) to afford the title compound as a pale yellow solid (80 mg, 53%), which was used directly in the next step.

[1238] b) 5-Ethyl-2-methoxy-N-(7-(1-methyl-1H-pyrazol-4-yl)benzo[d]isoxazol-3-yl)benzenesulfonamide 191

[1239] 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 h and then concentrated under reduced pressure. The residue was purified by silica gel chromatography (DCM / MeOH = 80 / 1) to afford the title compound as a pale yellow solid (50 mg, 86%). LCMS-D: R t 2.59 min; m / z 413.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6)δ11.8(s,1H),8.34(s,1H),8.06(s,1H),7.91–7.84(m,2H),7.72(d,J=2.3Hz,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=7.6Hz,2H),1.16(t,J=7.5Hz,3H).

[1240] Example 192: 5-Ethyl-2-methoxy-N-(7-(pyrimidin-5-yl)benzo[d]isoxazol-3-yl)benzenesulfonamide 192

[1241]

[1242] 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) was added 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), and the mixture was heated overnight at 90 °C 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 , filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (DCM / MeOH = 40 / 1) to afford the title compound as a brown solid (18 mg, 9%). LCMS-D: R t 2.49 min; m / z 411.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ11.9(s,1H),9.34–9.18(m,2H),8.17(d,J=8.1Hz,1H),8.06(d,J=7.4Hz,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=7.6Hz,2H),1.16(t,J=7.6Hz,3H).

[1243] Example 193: 5-Ethyl-2-methoxy-N-(6-methylbenzo[d]isoxazol-3-yl)benzenesulfonamide 193

[1244]

[1245] a) N-(6-Bromobenzo[d]isoxazol-3-yl)-N-(2,4-dimethoxybenzyl)-5-ethyl-2-methoxybenzenesulfonamide A30

[1246] At 0 °C in N 2 To a solution of N-(6-bromobenzo[d]isoxazol-3-yl)-5-ethyl-2-methoxybenzenesulfonamide 138 (4.1 g, 10.0 mmol), (2,4-dimethoxyphenyl)methanol (2.5 g, 15.0 mmol) and PPh 3 (6.6 g, 25.0 mmol) in THF (100 mL) was added DIAD (4.0 g, 20.0 mmol) and the mixture was stirred overnight at room temperature. The mixture was concentrated under reduced pressure and the residue was purified by silica gel chromatography (petroleum ether / EtOAc = 50 / 1 to 5 / 1) to give the title compound as a white solid (4.0 g, 71%), which was used directly in the next step.

[1247] b) N-(2,4-Dimethoxybenzyl)-5-ethyl-2-methoxy-N-(6-methylbenzo[d]isoxazol-3-yl)benzenesulfonamide A31

[1248] N-(6-Bromobenzo[d]isoxazol-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 CO 3 (148 mg, 1.07 mmol) in a mixture of 1,4-dioxane (10 mL) and water (2 mL) was heated at 90 °C in N 2 overnight. The solvent was removed under reduced pressure and the residue was purified by column chromatography (petroleum ether / EtOAc = 50 / 1 to 5 / 1) to give the title compound as a white solid (72 mg, 68%), which was used directly in the next step.

[1249] c) 5-Ethyl- -2-methoxy-N-(6-methylbenzo[d]isoxazol-3-yl)benzenesulfonamide 193

[1250] 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 h and then concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / EtOAc = 50 / 1 to 3 / 1) to afford the title compound as a white solid (45 mg, 90%). 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).

[1251] Example 194: 5-Ethyl-N-(6-ethylbenzo[d]isoxazol-3-yl)-2-methoxybenzenesulfonamide 194

[1252]

[1253] a) N-(2,4-Dimethoxybenzyl)-5-ethyl-N-(6-ethylbenzo[d]isoxazol-3-yl)-2-methoxybenzenesulfonamide A32

[1254] A mixture of N-(6-bromobenzo[d]isoxazol-3-yl)-N-(2,4-dimethoxybenzyl)-5-ethyl-2-methoxybenzenesulfonamide A30 (200 mg, 0.356 mmol), ethylboronic acid (132 mg, 1.78 mmol), Pd(dppf)Cl 2 (52 mg, 0.071 mmol) and K 2 CO 3 (246 mg, 1.78 mmol) in a mixture of 1,4-dioxane (20 mL) and water (4 mL) was heated at 90 °C under N 2 overnight. The solvent was removed under reduced pressure and the residue was partitioned between DCM (200 mL) and water (50 mL). The layers were separated and the organic layer was washed with water, brine, dried over anhydrous Na 2 SO 4Dry, filter and concentrate under reduced pressure. The residue was purified by column chromatography (petroleum ether / EtOAc = 100 / 1 to 5 / 1) to give the title compound as a white solid (120 mg, 67%), which was used directly in the next step.

[1255] b) 5-Ethyl-N-(6-ethylbenzo[d]isoxazol-3-yl)-2-methoxybenzenesulfonamide 194

[1256] 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 as a white solid (80 mg, 94%). LCMS-D: R t 2.84 min; m / z 361.1 [M+H] + 。 1 H NMR (400 MHz, DMSO-d 6 ) 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).

[1257] Example 195: N-(6-Cyclopropylbenzo[d]isoxazol-3-yl)-5-ethyl-2-methoxybenzenesulfonamide 195

[1258]

[1259] 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 a mixture of 1,4-dioxane (20 mL) and water (4 mL) was heated at 90 °C under N 2Heat under reflux overnight. Remove the solvent under reduced pressure and purify the residue by column chromatography (petroleum ether / EtOAc = 50 / 1 to 3 / 1) to give the title compound as a white solid (80 mg, 43%). 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).

[1260] Example 196: 5-Ethyl-2-methoxy-N-(6-(1-methyl-1H-pyrazol-4-yl)benzo[d]isoxazol-3-yl)benzenesulfonamide 196

[1261]

[1262] a) N-(2,4-Dimethoxybenzyl)-5-ethyl-2-methoxy-N-(6-(1-methyl-1H-pyrazol-4-yl)benzo[d]isoxazol-3-yl)benzenesulfonamide A33

[1263] To a mixture of N-(6-bromobenzo[d]isoxazol-3-yl)-N-(2,4-dimethoxybenzyl)-5-ethyl-2-methoxybenzenesulfonamide A30 (120 mg, 0.214 mmol), (1-methyl-1H-pyrazol-4-yl)boronic acid (54 mg, 0.428 mmol), Pd(dppf)Cl 2 (31 mg, 0.043 mmol) and K 2 CO 3 (148 mg, 1.07 mmol) in 1,4-dioxane (10 mL) and water (2 mL) was heated at 90 °C under N 2 overnight. Remove the solvent under reduced pressure and partition the residue between DCM (150 mL) and water (50 mL). Separate the layers and wash the organic layer with water, brine, dried over anhydrous Na 2 SO 4Dry, filter and concentrate under reduced pressure. The residue was purified by column chromatography (petroleum ether / EtOAc = 50 / 1 to 5 / 1) to give the title compound as a brown solid (90 mg, 75%). LCMS-D: R t 3.05 min; m / z 563.0 [M+H] + .

[1264] b) 5-Ethyl-2-methoxy-N-(6-(1-methyl-1H-pyrazol-4-yl)benzo[d]isoxazol-3-yl)benzenesulfonamide 196

[1265] 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 give the title compound as a brown solid (30 mg, 46%). 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).

[1266] Example 197: 5-Ethyl-2-methoxy-N-(6-(pyrimidin-5-yl)benzo[d]isoxazol-3-yl)benzenesulfonamide 197

[1267]

[1268] 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 a mixture of toluene (8 mL), water (8 mL) and isopropanol (2 mL) was heated at 90 °C under N 2 for 4 h. 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 concentrated under reduced pressure. The residue was purified by silica gel chromatography (DCM / MeOH = 30 / 1) to give the title compound as a white solid (15 mg, 15%). 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).

[1269] Example 198: 5-Ethyl-2-methoxy-N-(4-methylbenzo[d]isoxazol-3-yl)benzenesulfonamide 198

[1270]

[1271] a) N-(4-Bromobenzo[d]isoxazol-3-yl)-N-((2,4-dimethoxybenzyl)oxy)-5-ethyl-2-methoxybenzenesulfonamide A34

[1272] At 0 °C under N 2 to 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 3A solution of [[ID=]], t 3.40 min; m / z 583.0 [M+H] + .

[1273] b) N-((2,4-Dimethoxybenzyl)oxy)-5-ethyl-2-methoxy-N-(4-methylbenzo[d]isoxazol-3-yl)benzenesulfonamide A35

[1274] 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), methylboronic acid (43 mg, 0.71 mmol), K 2 CO 3 (148 mg, 1.07 mmol) and Pd(dppf)Cl 2 (26 mg, 0.036 mmol) in 1,4-dioxane (15 mL) and water (3 mL) was heated at 90 °C under N 2 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 as a white solid (125 mg, 71%), which was used directly in the next step.

[1275] c) 5-Ethyl-2-methoxy-N-(4-methylbenzo[d]isoxazol-3-yl)benzenesulfonamide 198

[1276] 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 4Dry, filter and concentrate under reduced pressure. The residue was purified by column chromatography (petroleum ether / EtOAc = 3 / 1) to give the title compound as a white solid (85 mg, 92%). 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)

[1277] Example 199: 5-Ethyl-N-(4-ethylbenzo[d]isoxazol-3-yl)-2-methoxybenzenesulfonamide 199

[1278]

[1279] a) N-(2,4-Dimethoxybenzyl)-5-ethyl-N-(4-ethylbenzo[d]isoxazol-3-yl)-2-methoxybenzenesulfonamide A36

[1280] 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 3 (148 mg, 1.07 mmol) and Pd(dppf)Cl 2 (26 mg, 0.036 mmol) in 1,4-dioxane (15 mL) and H 2 O (3 mL) was heated at 90 °C under N 2 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 (15 mL) and extracted with DCM (20 mL × 3). The combined organic layers were dried over anhydrous 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 as a white solid (120 mg, 66%), which was used directly in the next step.

[1281] b) 5-Ethyl-N-(4-ethylbenzo[d]isoxazol-3-yl)-2-methoxybenzenesulfonamide 199

[1282] 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 room temperature under N 2 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 afford the title compound as a white solid (75 mg, 89%). 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).

[1283] Example 200: N-(4-Cyclopropylbenzo[d]isoxazol-3-yl)-5-ethyl-2-methoxybenzenesulfonamide 200

[1284]

[1285] a) N-(4-Cyclopropylbenzo[d]isoxazol-3-yl)-N-(2,4-dimethoxybenzyl)-5-ethyl-2-methoxybenzenesulfonamide A37

[1286] 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), cyclopropylboronic acid (61 mg, 0.71 mmol), K 2 CO 3 (148 mg, 1.07 mmol) and Pd(dppf)Cl 2 (26 mg, 0.036 mmol) in 1,4-dioxane (15 mL) and H 2 O (3 mL) was stirred at 90 °C under N 2The lower heating is continued for 4 h. The mixture is adjusted to pH 2 - 3 and most of the solvent is removed under reduced pressure. The residue is diluted with water (15 mL) and extracted with DCM (20 mL×3). The combined organic extracts are dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue is purified by column chromatography (petroleum ether / EtOAc = 5 / 1) to give the title compound as a yellow solid (120 mg, 66%), which is used directly in the next step.

[1287] b) N-(4-Cyclopropylbenzo[d]isoxazol-3-yl)-5-ethyl-2-methoxybenzenesulfonamide 200

[1288] 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) is stirred at room temperature under N 2 for 3 h and then concentrated under reduced pressure. The residue is purified by column chromatography (petroleum ether / EtOAc = 3 / 1) to give the title compound as a yellow solid (85 mg, 92%). LCMS-D: R 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).

[1289] Example 201: N-(4-Cyclohexylbenzo[d]isoxazol-3-yl)-5-ethyl-2-methoxybenzenesulfonamide 201

[1290]

[1291] a) N-(4-(Cyclohex-1-en-1-yl)benzo[d]isoxazol-3-yl)-N-(2,4-dimethoxybenzyl)-5-ethyl-2-methoxybenzenesulfonamide A38

[1292] 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) in a mixture of 1,4-dioxane (15 mL) and H 2 O (3 mL) was heated at 90 °C under N 2 for 4 h. Most of the solvent was removed under reduced pressure, the residue was diluted with water (30 mL), adjusted to pH 1 - 2 and extracted with DCM (35 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 = 100 / 1) to give the title compound as a white solid (150 mg, 75%), which was used directly in the next step.

[1293] b) N-(4-(cyclohex-1-en-1-yl)benzo[d]isoxazol-3-yl)-5-ethyl-2-methoxybenzenesulfonamide A39

[1294] A mixture of N-(4-(cyclohex-1-en-1-yl)benzo[d]isoxazol-3-yl)-N-(2,4-dimethoxybenzyl)-5-ethyl-2-methoxybenzenesulfonamide A38 (150 mg, 0.27 mmol) and TFA (3 mL) was stirred at room temperature under N 2 for 3 h and then concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / EtOAc = 2 / 1) to give the title compound as a white solid (80 mg, 73%), which was used directly in the next step.

[1295] c) N-(4-cyclohexylbenzo[d]isoxazol-3-yl)-5-ethyl-2-methoxybenzenesulfonamide 201

[1296] A mixture of N-(4-(cyclohex-1-en-1-yl)benzo[d]isoxazol-3-yl)-5-ethyl-2-methoxybenzenesulfonamide A39 (80 mg, 0.19 mmol) and 10% Pd / C (16 mg) in EtOAc (10 mL) was stirred at room temperature under H 2Stirring was continued for 3 h under an atmosphere. The mixture was filtered and the filtrate was concentrated under reduced pressure to give the title compound as a white solid (75 mg, 94%). LCMS-D: R t 3.24 min, 415.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.5 (s, 1H), 7.58 - 7.48 (m, 4H), 7.26 (d, J = 7.2 Hz, 1H), 7.19 (d, J = 8.8 Hz, 1H), 3.80 (s, 3H), 3.62 - 3.56 (m, 1H), 2.59 (q, J = 7.6 Hz, 2H), 1.91 - 1.71 (m, 5H), 1.45 - 1.23 (m, 5H), 1.15 (t, J = 7.6 Hz, 3H).

[1297] Example 202: 5-Ethyl-2-methoxy-N-(4-(1-methyl-1H-pyrazol-4-yl)benzo[d]isoxazol-3-yl)benzenesulfonamide 202

[1298]

[1299] a) N-(2,4-Dimethoxybenzyl)-5-ethyl-2-methoxy-N-(4-(1-methyl-1H-pyrazol-4-yl)benzo[d]isoxazol-3-yl)benzenesulfonamide A40

[1300] 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), (1-methyl-1H-pyrazol-4-yl)boronic 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) in 1,4-dioxane (15 mL) and H 2 O (3 mL) was heated at 90 °C under N 2 for 4 h. Most of the solvent was removed under reduced pressure, the residue was diluted with water (30 mL), adjusted to pH 1 - 2 and extracted with DCM (35 mL×3). The combined organic extracts were dried over anhydrous Na 2 SO 4Dry, filter and concentrate under reduced pressure. The residue was purified by column chromatography (DCM / MeOH = 100 / 1) to give the title compound as a yellow solid (105 mg, 53%), which was used directly in the next step.

[1301] b) 5-Ethyl-2-methoxy-N-(4-(1-methyl-1...

Claims

1. A compound of formula (I): or a pharmaceutically acceptable salt thereof, wherein: R 1 , R 2 , R 3 and R 4 Independently selected from: (i) H; (ii)C 1-3 alkyl, optionally substituted with: hydroxy; C 1-2 alkoxy NH 2 , phenyl; C 5-6 heteroaryl C 1-4 alkylcarbamoyl, or acylamido; (iii) C 1-3 an alkoxy group, which is optionally substituted by C 3-6 cycloalkyl or by one or more fluorine groups; (iv) C 3-6 Naphthenyl; (v) halo; (vi) COR C , wherein R C is selected from NR N1 R N2 , wherein R N1 and R N2 are independently selected from H and methyl; (vii) Cyano, NH 2 or NO 2 ; and (viii) phenyl or C 5-6 heteroaryl, which is optionally substituted by methyl, hydroxy or methoxy; Ar is phenyl, optionally substituted by one or more groups selected from: (i) C 1-4 alkyl, optionally substituted by hydroxy, C 1-2 alkoxy, NH 2 、C 1-4 alkylcarbamoyl or substituted by one or more fluoro groups; (ii)C 3-6 Naphthenyl; (iii) Hydroxy; cyano; NR N3 R N4 , where R N3 and R N4 are independently selected from H and methyl; or acylamide group; (iv) halo; (v)C 1-3 an alkoxy group, which is optionally substituted by a hydroxyl group, C(O)NH 2 , C 3-6 cycloalkyl, phenyl, C 5-6 heteroaryl or substituted by one or more fluoro groups; (vi) phenoxy, optionally substituted by fluorine; (vii) phenyl or C 5-6 heteroaryl; or (viii) SF 5 or SO 2 CH 3 ; and wherein at least one of R 1 , R 2 , R 3 and R 4 is not H.

2. The compound or salt according to claim 1, wherein R 1 , R 2 , R 3 and R 4 at least one of which is C 1-3 alkyl, which is optionally substituted with the following: hydroxy; C 1-2 alkoxy NH 2 , phenyl; C 5-6 heteroaryl C 1-4 alkylcarbamoyl, or acylamido.

3. The compound or salt according to claim 1, wherein at least one of R 1 , R 2 , R 3 and R 4 is a C 1-3 alkoxy group, which is optionally substituted with a C 3-6 cycloalkyl group or one or more fluorine groups.

4. The compound or salt according to claim 1, wherein at least one of R 1 , R 2 , R 3 and R 4 is (a) C 3-6 Naphthenyl; (b) COR C , wherein R C is selected from NR N1 R N2 , wherein R N1 and R N2 are independently selected from H and methyl; (c) Cyano, NH 2 or NO 2 ; or (d) phenyl or C 5-6 heteroaryl, which is optionally substituted by methyl, hydroxy or methoxy.

5. The compound or salt according to claim 1, wherein: (a)R 4 is methoxy, R 2 is CH 2 OCH 3 or CH 2 OCH 2 CH 3 , and R 1 and R 3 are H; (b)R 4 is methoxy, R 2 is phenyl optionally substituted with methyl or methoxy, and R 1 and R 3 is H; (c)R 4 is methoxy, R 2 is a C 5-6 heteroaryl optionally substituted with methyl; (d)R 4 is methoxy and R 1 , R 2 and R 3 are H; (e)R 4 is chlorine, R 2 is C 1-3 alkyl or bromine, and R 1 and R 3 are H; or (f)R 3 is C 1-3 alkyl and R 1 , R 2 and R 4 is H.

6. The compound or salt according to any one of claims 1 to 5, wherein Ar is substituted by C 1-4 alkyl, and the C 1-4 alkyl is optionally substituted by hydroxyl, C 1-2 alkoxy, NH 2 , C 1-4 alkylcarbamoyl or one or more fluoro groups.

7. The compound or salt according to any one of claims 1 to 5, wherein Ar is substituted by C 1-3 alkoxy, and the C 1-3 alkoxy is optionally substituted by hydroxy, C(O)NH 2 , C 3-6 cycloalkyl, phenyl, C 5-6 heteroaryl or one or more fluoro groups.

8. The compound or salt according to any one of claims 1 to 5, wherein Ar is substituted by: (a)C 3-6 Naphthenyl; (b) hydroxy; (c) cyano; (d)NR N3 R N4 , where R N3 and R N4 are independently selected from H and methyl; or acylamide group; (e) phenoxy optionally substituted by fluorine; (f) phenyl or C 5-6 heteroaryl; or (g) SF 5 or SO 2 CH 3 。 9. The compound or salt according to any one of claims 1 to 5, wherein Ar is: (a) 5-ethyl-2-methoxyphenyl; (b) 5-CF 3 -2-methoxyphenyl; or (c) 2,6-dimethoxyphenyl.

10. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is:

11. A pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 10 and a pharmaceutically acceptable excipient.

12. Use of the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 10 as an inhibitor of lysine acetyltransferase (KAT) of the MYST family in the manufacture of a medicament for the treatment of cancer.

13. The use according to claim 12, wherein the cancer is selected from leukemia, acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, non-Hodgkin's lymphoma, Hodgkin's disease, prostate cancer, lung cancer, melanoma, breast cancer, colorectal cancer, colon cancer, squamous cell carcinoma and gastric cancer.

14. The use according to claim 12, wherein the compound or a pharmaceutically acceptable salt thereof is administered simultaneously or sequentially with radiotherapy and / or chemotherapy.

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