Small molecule inhibitor of ribosomal biosynthesis factor NVL2

Abstract

The report describes dibenzothiazepinone-based compounds and dibenzazepinone-based compounds, including small molecule inhibitors of the ribosomal biosynthesis factor NVL2, for treating cancer; related pharmaceutical compositions; methods for inhibiting ribosomal biosynthesis, inducing p53, or inhibiting cancer cells; and methods for screening candidate therapeutic agents for treating cancer.

Description

[Technical Field]

[0001] [Cross-reference of related applications] This application claims priority to U.S. Provisional Patent Application No. 63 / 507,089, filed on 8 June 2023, and this entire disclosure constitutes a part of this specification by reference for all purposes. [Background technology]

[0002] introduction Ribosomes are large macromolecular ribonucleoprotein (RNP) complexes composed of a 40S small subunit and a 60S large subunit, and are involved in the translation of messenger RNA into proteins. Approximately 200 ribosomal biosynthesis factors (RBFs) are required for the synthesis of 40S and 60S. Among these, a large subset, including rRNA processing and modification enzymes, structural proteins that serve as templates in the assembly process, and diverse ATPases that remodel rRNA or actively remove RBFs at critical junctions to lead to ribosome maturation, is involved in hierarchical ribosome assembly (1-3).

[0003] Ribosome abundance and translational activity are closely linked to cell growth rate, and dysregulation of ribosome biosynthesis can directly signal changes in the cell cycle. Accumulation of assembly intermediates resulting from the blockade of ribosome biosynthesis can trigger specific cellular checkpoints (4, 5). This process is initiated by a 5S RNP module that is not incorporated into the 60S precursor intermediate in the nucleolus (6, 7). The unincorporated 5S RNP conforms to bind to and inhibit MDM2, an E3 ubiquitin ligase that constitutively ubiquitinates p53 and causes its proteasomal degradation (5) (8, 9). Consequently, inhibition of MDM2 by 5S RNP leads to an increase in p53 protein levels. This is followed by transcriptional activation of p53 target genes, inducing cell cycle arrest, cellular senescence, or cellular apoptosis (10). Cancer cells are known to actively perform ribosome biosynthesis at significantly enhanced levels to support protein synthesis necessary for unregulated cell growth. Therefore, inhibitors of ribosome biosynthesis have the potential to block cancer growth and trigger checkpoints that lead to p53-dependent cancer cell death (8, 11-13).

[0004] Numerous small molecules exist that block ribosome production, but these molecules have alternative cytotoxic targets, making it difficult to determine the therapeutic potential of targeting ribosome biosynthesis. For example, many cancer chemotherapy drugs that induce DNA damage, including 5-fluorouracil, doxorubicin, and camptothecin, have been reported to also inhibit ribosome biosynthesis (14). Similarly, oxaliplatin uniquely induces nucleolar morphological changes that occur concurrently with the blockade of ribosome biosynthesis (15-18). Furthermore, oxaliplatin, like its related analogs cisplatin and carboplatin, can also produce DNA adducts that trigger DNA damage response pathways. Recent studies provide evidence that oxaliplatin's ability to interfere with ribosome production may be crucial to its anticancer activity (19). However, because oxaliplatin also causes DNA damage, it is difficult to determine the individual contributions of DNA damage and ribosome biosynthesis inhibition to therapeutic benefits and toxic side effects. In attempts to develop more selective inhibitors of ribosome biosynthesis, the focus has been on inhibiting RNA polymerase I, which is involved in ribosomal RNA transcription. Unfortunately, CX-5461, a leading compound in this field, also induces DNA damage by inhibiting topoisomerase TOP2B, thus raising the possibility that its anticancer activity may be mediated through the latter target (20).

[0005] As an alternative to inhibition of POL1, the assembly phase of ribosome biosynthesis involves many enzymes that could hypothetically be targeted by small molecules. The coordinated action of ATP hydrolysis and mechanical removal of specific ribosomal biosynthesis factors is a critical step in the assembly of the ribosome's large subunit (60S). Ribosome assembly and maturation are mediated by several catalytically active AAA+ATPase enzymes, including NVL, MDN1, and SPATA5 (2, 25-28). Small molecules that disrupt AAA+ATPase function during 60S biosynthesis have been characterized with respect to Saccharomyces cerevisiae Drg1 (2, 29, 30) and Schizosaccharomyces pombe Mdn1 (31), but no chemoinhibitors against the corresponding mammalian enzymes have been reported. [Overview of the project]

[0006] This invention provides a small molecule inhibitor of the ribosomal biosynthesis factor NVL2.

[0007] In one embodiment, the present invention relates to formula (I): TIFF2026522300000001.tif25170 (in the formula, R1 is selected from R3;-C(O)R3;-C(S)R3;-C(O)NHR3;-C(S)NHR3;-C(O)NR5R6;-C(S)NR5R6, R2 is selected from C1-C8 alkyl, C2-C8 alkenyl, and C2-C8 alkynyl, encompassing all of their isomers, all of which may be substituted with one or more of D, F, OH, or C(O)NHR4, and all of which may have one or more methylene units substituted with O, S, NH, NR4, or C(O). R3 is a C1-C7 alkyl, a C3-C7 cycloalkyl that may be crosslinked with CH2 or CH2CH2, a C3-C7 cycloalkyl that may be crosslinked with CH2 or CH2CH2, a C3-C7 cycloalkyl linked with CH2 or CHMe, a C2-C7 alkenyl, a C5-C7 cycloalkenyl that may be crosslinked with CH2 or CH2CH2, a C5-C7 cycloalkenyl that may be crosslinked with CH2 or CH2CH2, a C2-C7 alkynyl that is linked with CH2 or CHMe, a crosslinked or condensed C5-C9 cycloalkyl, or a CH2. Linked or CHMe-linked crosslinked or condensed C5-C9 cycloalkyls, C5-C10 spiroalkanes (selected from CH2-linked or CHMe-linked C5-C10 spiroalkanes, all of which encompass all possible isomers thereof, and all of which may be substituted with one or more of D, F, CN, R4, OR4, OH, NHC(O)H, NHC(O)R4, NHSO2R4, CO2H, CO2R4, C(O)NH2, C(O)NHR4, C(O)NR4R4, and all of which may be O, S, SO2, S(O ), NH, NR4, NC(O)H, NC(O)R4, NSO2R4, C(O), C=NOH, C=NOR4 or C=NR4 (which may have one or more methylene units replaced by these), phenyl or naphthyl (which may have one or more of these positions replaced by R7), but not limited to oxazole, isoxazole, thiazole, isothiazole, furan, thiophene, pyrazole, imidazole, triazole, tetrazole, pyridine, pyrimidine, pyrazine, pyridazine, quinoline, isoquinoline, quinazoline, Quinoxaline, cinnoline, phthalazine, naphthyridine, pyridopyrazine, pyrazolopyridine, pyridopyrimidine, pyridopyridazine, benzoxazole, benzoisoxazole, benzothiazole, benzoisothiazole, indole, indazole, benzimidazole, dioxopyridine, dioxolopyridazine, dioxolopyrimidine, dioxolopyrazine, benzofuran, benzothiophene, imidazopyridine, benzodioxol, benzoxazolone, benzoisoxazolone, benzothiazolon, benzoisothiazolon, 1,3-Dihydro-2H-benzimidazole, benzo[d]imidazole-2-one, benzodioxolone, dioxopyridine, dioxopyridazine, dioxopyrimidine, dioxopyrazine, coumarin, isocoumarin, and all possible isomers thereof, all of which may be substituted with R7 at one or more of the positions, selected from 5-membered and 6-membered heteroaryls and condensed heteroaryls, R4 is selected from Me;Et;Pr;iPr;cPr;cBu, which are D, F, CN, OH, OCD3, OCH n F (3-n) It is also acceptable for the substitution to be one or more of the values ​​from (n=0 to 3), NR5R6 forms 4- to 7-membered azacyclic compounds or cross-linked or condensed 6- to 9-membered azacyclic compounds or 5- to 9-membered azaspiroalkanes, encompassing all possible isomers thereof, all of which may be substituted with one or more of D, F, CN, R4, OR4, OH, NHC(O)H, NHC(O)R4, NHSO2R4, CO2H, CO2R4, C(O)NH2, C(O)NHR4, C(O)NR4R4, and all of which may have one or more methylene units that may be substituted with O, S, SO2, NH, NR4, NC(O)H, NC(O)R4, NSO2R4, C(O), C=NOH, C=NR4. R7 is D, F, Cl, Br, CN, N3, OH, OR4, R4, oxetanyl, NHC(O)H, NHC(O)R4, CO2H, CO2R4, C(O)NH2, C(O)NHR4, C(O)NR4R4, SO2NH2, SO2NHR4, SO2NR4R4, C2-C6 alkenyl or C2-C6 alkynyl, encompassing all of their isomers, all of which may be substituted with one or more of D, F, CN, or OH, and all of which may be O, S, S(O), SO 2, C2-C6 alkenyl or C2-C6 alkynyl having one or more methylene units replaced by NH, NR4, NC(O)H, NC(O)R4, NSO2R4, C(O), C=NOH, C=NR4; selected from aryl or 5-membered or 6-membered heteroaryl or heterocyclyl, all of which may be substituted with one or more of D, F, Cl, CN, R4, OH, OR4, Z is selected from S, CH2, CD2, CHR4, CDR4, CR4R4, CHOH, CDOH, CHOR4, CDOR4, CR4OH, CR4OR4, CHCN, CDCN, CHF, CDF, CF2, NH, NR4, NC(O)H, NC(O)R4, NSO2R4. X is selected from CH, CD, CF, CCl, CCN. Y is selected from CH, CD, CF, and CCl. U and W are independently selected from CH, CD, and N. The present invention provides compounds (excluding those in which R1 is C(O)furan-3-yl, X, Y, U, and W are CH, Z is S, and R2 is (CH2)2OMe(MM017)), or salts, hydrates, or stereoisomers thereof.

[0008] In embodiments, the present invention provides the following:

[0009] 2. Furthermore, equation II: The compound described in item 1, which is a compound of TIFF2026522300000002.tif26170.

[0010] 3. Furthermore, Equation III: The compound described in item 1, which is a compound of TIFF2026522300000003.tif27170.

[0011] 4. Furthermore, equation IV: The compound described in item 1, which is a compound of TIFF2026522300000004.tif25170.

[0012] 5. Furthermore, equation V: The compound described in item 1, which is a compound of TIFF2026522300000005.tif25170.

[0013] 6. Furthermore, equation VI: The compound described in item 1, which is a compound of TIFF2026522300000006.tif25170.

[0014] 7. Furthermore, equation VII: The compound described in item 1, which is a compound of TIFF2026522300000007.tif27170.

[0015] 8. Furthermore, equation VIII: The compound described in item 1, which is a compound of TIFF2026522300000008.tif25170.

[0016] 9. The compounds according to items 1 to 8, wherein Z is S, CH2, CD2, CHMe, CHCD3, CDMe, CDCD3, CHCN, CDCN, CMeOH, CCD3OH, preferably S, CH2, CHMe, CHCD3.

[0017] The compounds according to items 1 to 8, wherein 10.X is CH, CD, CF, CCl, CCN, preferably CH, CF, or CCl.

[0018] 11. The compounds according to items 1 to 8, wherein Y is CH, CD, CF, CCl, preferably CH, or CF.

[0019] 12. Compounds listed in items 1-8, wherein W is CH, CD, N.

[0020] 13. The compounds according to items 1 to 8, wherein U is CH, CD, N, preferably CH.

[0021] 14. The compounds described in items 1 to 8, wherein R2 is a C2-C7 alkyl, C3-C7 alkenyl, or C3-C7 alkynyl, encompassing all of these isomers, all of which may be substituted with one or more of D, F, or Cl, and all of which may have one or more methylene units substituted with O.

[0022] 15. Compounds according to items 1 to 8, wherein R2 is CH2C≡CH, CH2C≡CR4, CH2C≡CCl, CH2CH=CH2, CH2CH=CHR4, (CH2)2OR4, (CH2)2OCH2C≡CH, and R2 may contain one or more deuterium atoms.

[0023] 16. R2 is CH2C≡CH, CH2C≡CMe, CH2C≡CCH2F, CH2C≡C c A compound according to items 1 to 8, wherein Pr, CH2C≡CCl, CH2CH=CHMe, and CH2C≡CCF3, and R2 may contain one or more deuterium atoms.

[0024] 17. R2 is CH2C≡CH, CH2C≡CMe, CH2C≡CCH2F, CH2C≡CCl, CH2C≡C c Pr is CH2CH=CHMe, and R2 may contain one or more deuterium atoms. NR5R6 forms a 4- to 7-membered azacyclic compound or a crosslinked or condensed 6- to 9-membered azacyclic compound or a 5- to 9-membered azaspiroalkane, encompassing all possible isomers thereof, all of which may be substituted with one or more of D, F, CN, R4, OR4, OH, NHC(O)H, NHC(O)R4, NHSO2R4, CO2H, CO2R4, C(O)NH2, C(O)NHR4, C(O)NR4R4, and all of which may have one or more methylene units substituted with O, S, SO2, NH, NR4, NC(O)H, NC(O)R4, NSO2R4, C(O), C=NOH, C=NR4. R4 is Me;Et;Pr;iPr;cPr;cBu, and these are D, F, CN, OH, OCD3, OCH n F (3-n) It is also acceptable for the substitution to be one or more of the values ​​from (n=0 to 3), Z is S, CH2, CHMe, CHCD3, CHCN, CMeOH, CCD3OH, preferably S, CH2, CHMe, CHCD3. X is CH, CD, CF, CCl, Y is CH, CD, CF, W is CH, N, U is CH, CD, N, preferably CH. Compounds described in sections 2-3.

[0025] 18. R2 is CH2C≡CH, CH2C≡CMe, CH2C≡CCH2F, CH2C≡CCl, CH2C≡C c Pr, preferably CH2C≡CMe, CH2C≡C c Pr, NR5R6 forms a 4- to 7-membered azacyclic compound, a 6- to 8-membered azabicyclic compound, or a 5- to 7-membered azaspiroalkane, all of which may be substituted with one or more of D, F, CN, R4, OR4, or OH, and all of which may have one or more methylene units substituted with O, S, SO2, NH, NR4, C(O), C=NOH, or C=NR4. R4 is Me; Et; Pr; iPr; cPr; cBu, and these are D, F, CN, OH, OCD3, OCH n F (3-n) and may be substituted with one or more of (n = 0 to 3), Z is S, CH2, CHMe, CHCD3, CHCN, CMeOH, CCD3OH, preferably S, CH2, CHMe, CHCD3, X is CH, CF, CCl, Y is CH, CF, W is CH, N, U is CH, N, preferably CH, The compound according to items 2 to 3.

[0026] 19. R2 is CH2C≡CH, CH2C≡CMe, CH2C≡CCH2F, CH2C≡CCl, CH2C≡C c Pr, CH2CH=CHMe, and R2 may contain one or more deuteriums, R3 may be phenyl (may be substituted with R7 at one or more of its individual positions); however, it is not limited to oxazoles, isoxazoles, thiazoles, isothiazoles, furans, thiophenes, pyrazoles, imidazoles, triazoles, tetrazoles, pyridines, pyridines, pyridazines, quinolines, isoquinolines, quinazolins, quinoxalines, cinnolines, phthalazines, naphthyridines, pyridopyrazines, pyrazolopyridines, pyridopyrimidines, pyridopyridazines, benzoxazoles, benzoisoxazoles, benzothiazoles, benzoisothiazoles, indoles, indazoles, benzimidazoles, dioxopyridines, diox This includes soropyridazine, dioxolopyrimidine, dioxolopyrazine, benzofuran, benzothiophene, imidazopyridine, benzodioxol, benzoxazolone, benzoisoxazolone, benzothiazolon, benzoisothiazolon, 1,3-dihydro-2H-benzimidazole, benzo[d]imidazole-2-one, benzodioxolone, dioxolopyridine, dioxolopyridazine, dioxolopyrimidine, dioxolopyrazine, coumarin, isocoumarin, and other 5-membered and 6-membered heteroaryls and condensed heteroaryls, encompassing all possible isomers thereof, all of which may be substituted with R7 at one or more of their respective positions. R7 is D, F, Cl, Br, CN, N3, OH, R4, OR4, C≡CH, NHC(O)H, C(O)NH2, C(O)NHR4, C(O)NR4R4, R4 consists of Me, Et, Pr, iPr, cPr, and cBu, which are D, F, CN, OH, OCD3, and OCH n F (3-n) It is also acceptable for the substitution to be one or more of the values ​​from (n=0 to 3), Z is S, CH2, CHMe, CHCD3, CHCN, CMeOH, CCD3OH, preferably S, CH2, CHMe, CHCD3. X is CH, CF, CCl, Y is CH, CF, W is CH, N, U is CH, N, preferably CH. Compounds as described in item 4, 5, or 8.

[0027] 20. R2 is CH2C≡CH, CH2C≡CMe, CH2C≡CCH2F, CH2C≡CCl, CH2C≡C c Pr, preferably CH2C≡CMe, CH2C≡C c Pr, R3 is a monosubstituted or disubstituted phenyl ring having a substituent at the ortho position selected from H, D, or F, and substituents at the meta and para positions selected from H, D, F, Cl, R4, OR4, N3, C≡CH; an aromatic heterocycle selected from furan, pyridine, pyrimidine, pyrazine, pyridazine, benzo[d]oxazole-5-yl, benzo[d]thiazole-5-yl, 2-oxo-2,3-dihydrobenzo[d]oxazole-5-yl, benzo[d][1,3]dioxol-5-yl, all of which may be substituted with H, D, F, Cl, CCH, R4, OR4 at one or more of their respective positions. R4 is Me;Et;Pr;iPr;cPr;cBu, and these may be substituted with one or more of D and F. Z is S, CH2, CHMe, CHCD3, CHCN, CMeOH, CCD3OH, preferably S, CH2, CHMe, CHCD3. X is CH, CF, CCl, Y is CH, CF, W is CH, N, U is CH, N, preferably CH. Compounds as described in item 4, 5, or 8.

[0028] twenty one. R2 is CH2C≡CH, CH2C≡CMe, CH2C≡CCH2F, CH2C≡CCl, CH2C≡C c Pr is CH2CH=CHMe, and R2 may contain one or more deuterium atoms. R3 is a C1-C7 alkyl, a C3-C7 cycloalkyl that may be crosslinked with CH2 or CH2CH2, a C3-C6 cycloalkyl that may be crosslinked with CH2 or CH2CH2, linked with CH2 or linked with CHMe, a C2-C7 alkenyl, a C5-C6 cycloalkenyl that may be crosslinked with CH2 or CH2CH2, a C5-C6 cycloalkenyl that may be crosslinked with CH2 or CH2CH2, linked with CH2 or linked with CHMe, a C2-C7 alkynyl, a crosslinked or condensed C5-C9 cycloalkyl, a crosslinked or condensed C5-C9 cycloalkyl linked with CH2 or linked with CHMe, or a C5-C1 0 spiroalkanes, CH2-linked or CHMe-linked C5-C10 spiroalkanes, all of which encompass all possible isomers, and all of which may be substituted with one or more of D, F, CN, R4, OR4, OH, NHC(O)H, NHC(O)R4, NHSO2R4, CO2H, CO2R4, C(O)NH2, C(O)NHR4, C(O)NR4R4, and all of which may have one or more methylene units substituted with O, S, SO2, S(O), NH, NR4, NC(O)H, NC(O)R4, NSO2R4, C(O), C=NOH, C=NOR4, or C=NR4. R4 consists of Me, Et, Pr, iPr, cPr, and cBu, which are D, F, OH, OCD3, and OCH3. n F (3-n) It is also acceptable for the substitution to be one or more of the values ​​from (n=0 to 3), Z is S, CH2, CHMe, CHCD3, CHCN, CMeOH, CCD3OH, preferably S, CH2, CHMe, CHCD3. X is CH, CF, CCl, Y is CH, CF, W is CH, N, U is CH, N, preferably CH. Compounds as described in item 4, 5, or 8.

[0029] twenty two. R2 is CH2C≡CH, CH2C≡CMe, CH2C≡CCH2F, CH2C≡CCl, CH2C≡Cc Pr, CH2CH=CHMe, CH2=CHEt, CH2CH=CHPr, (CH2)2OCH2CCH, where R2 may contain one or more deuterium atoms. R3 may be phenyl (may be substituted with R7 at one or more of its individual positions); however, it is not limited to oxazoles, isoxazoles, thiazoles, isothiazoles, furans, thiophenes, pyrazoles, imidazoles, triazoles, tetrazoles, pyridines, pyridines, pyridazines, quinolines, isoquinolines, quinazolins, quinoxalines, cinnolines, phthalazines, naphthyridines, pyridopyrazines, pyrazolopyridines, pyridopyrimidines, pyridopyridazines, benzoxazoles, benzoisoxazoles, benzothiazoles, benzoisothiazoles, indoles, indazoles, benzimidazoles, dioxopyridines, diox This includes soropyridazine, dioxolopyrimidine, dioxolopyrazine, benzofuran, benzothiophene, imidazopyridine, benzodioxol, benzoxazolone, benzoisoxazolone, benzothiazolon, benzoisothiazolon, 1,3-dihydro-2H-benzimidazole, benzo[d]imidazole-2-one, benzodioxolone, dioxolopyridine, dioxolopyridazine, dioxolopyrimidine, dioxolopyrazine, coumarin, isocoumarin, and other 5-membered and 6-membered heteroaryls and condensed heteroaryls, encompassing all possible isomers thereof, all of which may be substituted with R7 at one or more of their respective positions. R7 is D, F, Cl, Br, CN, N3, OH, R4, OR4, C≡CH, NHC(O)H, C(O)NH2, C(O)NHR4, C(O)NR4R4, R4 consists of Me, Et, Pr, iPr, cPr, and cBu, which are D, F, CN, OH, OCD3, and OCHnF. (3-n) It is also acceptable for the substitution to be one or more of the values ​​from (n=0 to 3), Z is S, CH2, CHMe, CHCD3, CHCN, CMeOH, CCD3OH, preferably S, CH2, CHMe, CHCD3. X is CH, CF, CCl, Y is CH, CF, W is CH, N, U is CH, N, preferably CH. The compounds described in item 6.

[0030] twenty three. R2 is CH2C≡CH, CH2C≡CMe, CH2C≡CCH2F, CH2C≡CCl, CH2C≡C c Pr, CH2CH=CHMe, CH2=CHEt, CH2CH=CHPr, R3 is a 5-membered and 6-membered heteroaryl, including but not limited to pyrazoles, imidazoles, pyridines, pyrimidines, pyrazines, pyridazines, quinolines, isoquinolines, quinazolines, quinoxalines, cinnolines, and phthalazines, encompassing all possible isomers thereof, all of which have D, F, Cl, CN, Me, cPr, CD3, OCD3, OH, or OCH in one or more of their respective positions. n F (3-n) The substitution may also be (n=0~3), Z is S, CH2, CHMe, CHCD3, CHCN, CMeOH, CCD3OH, preferably S, CH2, CHMe, CHCD3. X is CH, CF, CCl, Y is CH, CF, W is CH, N, U is CH, N, preferably CH. The compounds described in item 6.

[0031] twenty four. R2 is CH2C≡CH, CH2C≡CMe, CH2C≡CCH2F, CH2C≡CCl, CH2C≡C c Pr, preferably CH2C≡CMe, CH2C≡C c Pr, R3 is pyrazole, pyridine, pyrimidine, pyrazine, or pyridazine, and all of them have D, F, Cl, CN, Me, cPr, CD3, OCD3, OH, or OCH at one or more of their respective positions. n F(3-n) The substitution may also be (n=0~3), Z is S, CH2, CHMe, CHCN, CMeOH, preferably S, CH2, CHMe. X is CH, CF, CCl, Y is CH, CF, W is CH, N, U is CH, N, preferably CH. The compounds described in item 6.

[0032] twenty five. R2 is CH2C≡CH, CH2C≡CMe, CH2C≡CCH2F, CH2C≡CCl, CH2C≡C c Pr is such that R2 may contain one or more deuterium atoms. R3 is a C2-C4 alkyl, C2-C4 alkenyl, C3-C6 cycloalkyl which may be crosslinked with CH2 or CH2CH2, C3-C6 cycloalkyl which may be crosslinked with CH2 or CH2CH2, linked with CH2 or linked with CHMe, C5-C6 cycloalkenyl which may be crosslinked with CH2 or CH2CH2, C5-C6 cycloalkenyl which may be crosslinked with CH2 or CH2CH2, linked with CH2 or linked with CHMe, C5-C8 spiroalkane, C5-C8 spiroalkane which may be linked with CH2 or linked with CHMe, and all of them are D, F, CN, OH, R4, OCD3, OCH n F (3-n) (n=0~3) may be substituted with one or more of the above, and all of them may have one or more methylene units substituted with O, S, SO2, S(O), NH, NR4, NC(O)H, NC(O)R4, NSO2R4, C(O), C=NOH, C=NOR4, or C=NR4. R4 consists of Me, Et, Pr, iPr, cPr, and cBu, which are D, F, OH, OCD3, and OCH3. n F (3-n) It is also acceptable for the substitution to be one or more of the values ​​from (n=0 to 3), Z is S, CH2, CHMe, CHCD3, CHCN, CMeOH, CCD3OH, preferably S, CH2, CHMe, CHCD3. X is CH, CF, CCl, Y is CH, CF, W is CH, N, U is CH, N, preferably CH. The compounds described in item 6.

[0033] 26. R2 is CH2C≡CMe, CH2C≡CCD3, CH2C≡CCH2F, CH2C≡C c Pr, CH2C≡CCl, CH2C≡CH, preferably CH2C≡CMe, CH2C≡C c Pr, NR5R6 may be substituted with one or more of D, F, CN, R4, OR4, or OH, and may be crosslinked with CH2 or CH2CH2, and all of these may have one or more methylene units substituted with O, NR4, N=OH, NOMe, or N=OCD3. R4 is Me, cPr, and these are D, F, CN, OH, OCD3, OCH n F (3-n) It is also acceptable for the substitution to be one or more of the values ​​from (n=0 to 3), Z is S, CH2, CHMe, preferably S. X is CH, CF, CCl, Y is CH, F, preferably CH. W is CH, N, U is CH. Compounds as described in item 17 or 18.

[0034] 27. R2 is CH2C≡CMe, CH2C≡CCD3, CH2C≡C c Pr, CH2C≡CCH2F, CH2C≡CCl, CH2C≡CH, preferably CH2C≡CMe, CH2C≡C c Pr, R3 is pyridine, pyrimidine, pyrazine, or pyridazine, and all of them have D, F, Cl, CN, Me, Et, iPr, cPr, OH, OCD3, or OCH in one or more of their respective positions. n F (3-n) The substitution may also be (n=0~3), Z is S, CH2, CHMe, preferably S. X is CH, CF, CCl, Y is CH, CF, preferably CH. W is CH, N, U is CH. Compounds described in sections 22-24.

[0035] 28. R2 is CH2C≡CMe, CH2C≡CCD3, CH2C≡C c Pr, CH2C≡CCH2F, CH2C≡CCl, CH2C≡CH, preferably CH2C≡CMe, CH2C≡C c Pr, R3 is a C2-C4 alkyl, C2-C4 alkenyl, C3-C6 cycloalkyl which may be crosslinked with CH2 or CH2CH2, C3-C6 cycloalkyl which may be crosslinked with CH2 or CH2CH2, linked with CH2 or linked with CHMe, C5-C6 cycloalkenyl which may be crosslinked with CH2 or CH2CH2, C5-C6 cycloalkenyl which may be crosslinked with CH2 or CH2CH2, linked with CH2 or linked with CHMe, C5-C8 spiroalkane, C5-C8 spiroalkane linked with CH2 or linked with CHMe, and all of them encompass all of their possible isomers, and all of them are D, F, Me, CD3, cPr, OH, OCD3, OCH n F (3-n) (n=0~3), CH2OH, CHMeOH, CH2OCD3, CH2OCH n F (3-n) (n=0~3), CHMeOCD3, CHMeOCH n F (3-n)(n=0~3) may be substituted with one or more of the above, and all of them may have one or more methylene units substituted with O, S, SO2, NH, NMe, NCD3, CO, N=OH, NOMe, N=OCD3, Z is S, CH2, CHMe, preferably S. X is CH, CF, CCl, Y is CH, CF, preferably CH. W is CH, N, U is CH. The compounds described in item 25.

[0036] 29. R2 is CH2C≡CMe, CH2C≡CCD3, CH2C≡C c Pr, CH2C≡CCH2F, CH2C≡CCl, CH2C≡CH, preferably CH2C≡CMe, CH2C≡C c Pr, R3 is a monosubstituted or disubstituted phenyl ring having a substituent at the ortho position selected from H, D, or F, and substituents at the meta and para positions selected from H, D, F, Cl, R4, OR4, N3, C≡CH; an aromatic heterocycle selected from furan, pyridine, pyrimidine, pyrazine, pyridazine, benzo[d]oxazole-5-yl, benzo[d]thiazole-5-yl, 2-oxo-2,3-dihydrobenzo[d]oxazole-5-yl, benzo[d][1,3]dioxol-5-yl, all of which have H, D, F, Cl, Me, CD3, cPr, CCH, OCD3, OCH at one or more of their respective positions. n F (3-n) The substitution may also be (n=0~3), Z is S, CH2, CHMe, preferably S. X is CH, CF, CCl, Y is CH, CF, preferably CH. W is CH, N, U is CH. The compounds described in item 20.

[0037] 30. R2 is CH2C≡CMe, CH2C≡CCD3, CH2C≡C c Pr, CH2C≡CCH2F, CH2C≡CCl, CH2C≡CH, preferably CH2C≡CMe, CH2C≡C c Pr, R3 is a C2-C4 alkyl, C2-C4 alkenyl, C2-C3 alkynyl, C3-C6 cycloalkyl which may be crosslinked with CH2 or CH2CH2, C3-C6 cycloalkyl which may be crosslinked with CH2 or CH2CH2, linked with CH2 or linked with CHMe, C5-C6 cycloalkenyl which may be crosslinked with CH2 or CH2CH2, C5-C6 cycloalkenyl which may be crosslinked with CH2 or CH2CH2, linked with CH2 or linked with CHMe, C5-C8 spiroalkane, C5-C8 spiroalkane linked with CH2 or linked with CHMe, and all of them encompass all of their possible isomers, and all of them are D, F, CN, Me, CD3, cPr, OH, OCD3, OCH n F (3-n) (n=0~3), CH2OH, CHMeOH, CH2OCD3, CH2OCH n F (3-n) (n=0~3), CHMeOCD3, CHMeOCH n F (3-n) (n=0~3), may be substituted with one or more of CO2Me or CO2CD3, and all of them may have one or more methylene units substituted with O, S, SO2, NH, NMe, NCD3, C(O), N=OH, NOMe, or N=OCD3. Z is S, CH2, CHMe, preferably S. X is CH, CF, CCl, Y is CH, CF, preferably CH. W is CH, N, U is CH. The compounds described in item 21.

[0038] 31. R2 is CH2C≡CMe, CH2C≡CCD3, CH2C≡C cPr, CH2C≡CCH2F, CH2C≡CCl, CH2C≡CH, preferably CH2C≡CMe, CH2C≡C c Pr, R3 is a monosubstituted or disubstituted phenyl ring having a substituent at the ortho position selected from H, D, or F, and substituents at the meta and para positions selected from H, D, F, Cl, R4, OR4, N3, C≡CH; an aromatic heterocycle selected from furan, pyridine, pyrimidine, pyrazine, pyridazine, benzo[d]oxazole-5-yl, benzo[d]thiazole-5-yl, 2-oxo-2,3-dihydrobenzo[d]oxazole-5-yl, benzo[d][1,3]dioxol-5-yl, all of which have H, D, F, Cl, Me, CD3, cPr, CCH, OCD3, OCH at one or more of their respective positions. n F (3-n) The substitution may also be (n=0~3), Z is S, CH2, CHMe, preferably S. X is CH, CF, CCl, Y is CH, CF, preferably CH. W is CH, N, U is CH. The compounds described in item 7.

[0039] 32. R2 is CH2C≡CMe, CH2C≡CCD3, CH2C≡C c Pr, CH2C≡CCH2F, CH2C≡CCl, CH2C≡CH, preferably CH2C≡CMe, CH2C≡C c Pr, R3 is a C2-C4 alkyl, C2-C4 alkenyl, C2-C3 alkynyl, C3-C6 cycloalkyl which may be crosslinked with CH2 or CH2CH2, C3-C6 cycloalkyl which may be crosslinked with CH2 or CH2CH2, linked with CH2 or linked with CHMe, C5-C6 cycloalkenyl which may be crosslinked with CH2 or CH2CH2, C5-C6 cycloalkenyl which may be crosslinked with CH2 or CH2CH2, linked with CH2 or linked with CHMe, C5-C8 spiroalkane, C5-C8 spiroalkane linked with CH2 or linked with CHMe, and all of them encompass all of their possible isomers, and all of them are D, F, CN, Me, CD3, cPr, OH, OCD3, OCH n F (3-n) (n=0~3), CH2OH, CHMeOH, CH2OCD3, CH2OCH n F (3-n) (n=0~3), CHMeOCD3, CHMeOCH n F (3-n) (n=0~3), may be substituted with one or more of CO2Me or CO2CD3, and all of them may have one or more methylene units substituted with O, S, SO2, NH, NMe, NCD3, C(O), N=OH, NOMe, or N=OCD3. Z is S, CH2, CHMe, preferably S. X is CH, CF, CCl, Y is CH, CF, preferably CH. W is CH, N, U is CH. The compounds described in item 7.

[0040] 33. Compounds selected from Tables 1 to 10.

[0041] 34. A compound selected from Table 7.

[0042] 35. Compounds selected from Tables 1 and 2.

[0043] 36. Compounds selected from Tables 3 and 4.

[0044] 37. Compounds selected from Tables 5 and 6.

[0045] 38. Compounds selected from Table 6.

[0046] 39. Compounds selected from Tables 8 to 10.

[0047] 40. A compound selected from Table 10.

[0048] 41. Compounds selected from Tables 8 and 9.

[0049] 42. Compounds selected from Tables 6 and 8.

[0050] 43. A pharmaceutical composition comprising a compound described in items 1 to 42, or a pharmaceutically acceptable salt, hydrate, or stereoisomer thereof, and a pharmaceutically acceptable carrier or excipient, preferably in a pharmaceutically acceptable unit dose.

[0051] 44. A method for inhibiting ribosome biosynthesis, inducing p53, or inhibiting cancer cells, comprising administering a compound described in items 1 to 42 to a person in need thereof.

[0052] 45. A method for treating a disease or condition including cancer, tumor or neoplasia, comprising administering to a person in need thereof one of the compounds described in items 1 to 42, for example, the cancer, tumor or neoplasia including breast cancer, lung cancer, colorectal cancer, ovarian cancer, bladder cancer, kidney cancer, esophageal cancer, gastric cancer, cervical cancer, head and neck cancer, liver cancer, prostate cancer, pancreatic cancer, sarcoma, melanoma, leukemia, lymphoma, brain cancer, skin cancer (melanoma), thyroid cancer, testicular cancer, and multiple myeloma.

[0053] 46. ​​The method of paragraph 44 or 45, further comprising a preceding step of detecting or diagnosing a disease or condition that indicates the need for such detection, and / or a subsequent step of detecting the resulting improvement or delay in the progression of the disease or condition.

[0054] 47. A method for screening candidate therapeutic agents for treating cancer, comprising assaying for NVL2 inhibitors.

[0055] 48. A cell line for which a cancer drug is to be evaluated, which contains a mutant NVL gene sufficient to be MM017 resistant and expresses it, preferably one or more mutations in the D1 AAA+ ATPase domain, e.g., NVL P307T NVL R403W or NVL H304R Cell lines that include this.

[0056] The present invention encompasses all combinations of the specific embodiments described herein, as well as individual combinations described separately. [Modes for carrying out the invention]

[0057] Unless otherwise stated in a contraindication, in these descriptions and throughout this Spec., the terms “a” and “an” mean one or more, and the term “or” means “and / or.” The examples and embodiments described herein are for illustrative purposes only, and it is understood that various modifications or changes thereto are shown to those skilled in the art and are included in the spirit and authority of this application and the appended claims. All publications, patents and patent applications cited herein, including those cited therein, constitute part of this Spec.

[0058] The term "alkyl" refers to a hydrocarbon group selected from linear and branched saturated hydrocarbon groups having 1 to 18, 1 to 12, or 1 to 6 carbon atoms. Examples of alkyl groups include methyl, ethyl, 1-propyl or n-propyl ("n-Pr"), 2-propyl or isopropyl ("i-Pr"), 1-butyl or n-butyl ("n-Bu"), 2-methyl-1-propyl or isobutyl ("i-Bu"), 1-methylpropyl or s-butyl ("s-Bu"), and 1,1-dimethylethyl or t-butyl ("t-Bu"). Other examples of alkyl groups include 1-pentyl group, 2-pentyl group, 3-pentyl group, 2-methyl-2-butyl group, 3-methyl-2-butyl group, 3-methyl-1-butyl group, 2-methyl-1-butyl group, 1-hexyl group, 2-hexyl group, 3-hexyl group, 2-methyl-2-pentyl group, 3-methyl-2-pentyl group, 4-methyl-2-pentyl group, 3-methyl-3-pentyl group, 2-methyl-3-pentyl group, 2,3-dimethyl-2-butyl group, and 3,3-dimethyl-2-butyl group.

[0059] Lower alkyl means having 1 to 8 carbon atoms, preferably 1 to 6, more preferably 1 to 4, while lower alkenyl or alkynyl means having 2 to 8, 2 to 6, or 2 to 4 carbon atoms.

[0060] The term "alkenyl" refers to a hydrocarbon group selected from linear and branched hydrocarbon groups containing 2 to 18, 2 to 12, or 2 to 6 carbon atoms, and containing at least one C=C double bond. Examples of alkenyl groups can be selected from ethenyl or vinyl groups, propa-1-enyl, propa-2-enyl, 2-methylpropa-1-enyl, buta-1-enyl, buta-2-enyl, buta-3-enyl, buta-1,3-dienyl, 2-methylbuta-1,3-diene, hexa-1-enyl, hexa-2-enyl, hexa-3-enyl, hexa-4-enyl, and hexa-1,3-dienyl groups.

[0061] The term "alkynyl" refers to a hydrocarbon group selected from straight-chain and branched hydrocarbon groups containing 2 to 18, 2 to 12, or 2 to 6 carbon atoms, and containing at least one C≡C triple bond. Examples of alkynyl groups include ethynyl, 1-propynyl, 2-propynyl (propargyl), 1-butynyl, 2-butynyl, and 3-butynyl groups.

[0062] The term "cycloalkyl" refers to hydrocarbon groups selected from saturated and partially unsaturated cyclic hydrocarbon groups, including monocyclic and polycyclic (e.g., bicyclic and tricyclic) groups. For example, a cycloalkyl group may have 3 to 12 carbon atoms, or 3 to 8 carbon atoms, or 3 to 6 carbon atoms. Furthermore, for example, a cycloalkyl group may be a monocyclic group with 3 to 12 carbon atoms, or 3 to 8 carbon atoms, or 3 to 6 carbon atoms. Examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopenta-1-enyl, 1-cyclopenta-2-enyl, 1-cyclopenta-3-enyl, cyclohexyl, 1-cyclohexa-1-enyl, 1-cyclohexa-2-enyl, 1-cyclohexa-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, and cyclododecyl groups. Examples of bicyclic cycloalkyl groups include those having 7 to 12 ring atoms arranged as bicyclic rings selected from the [4,4], [4,5], [5,5], [5,6], and [6,6] ring systems, or as bridging bicyclic rings selected from bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, and bicyclo[3.2.2]nonane. The rings may be saturated and may have at least one double bond (i.e., partially unsaturated), but are not fully conjugated and are not aromatic. Aromatic is defined herein.

[0063] The term "aryl" as used herein refers to a group selected from five- and six-membered carbocyclic aromatic rings, e.g., phenyl; seven- to twelve-membered bicyclic ring systems, e.g., where at least one ring is carbocyclic and aromatic, selected from, for example, naphthalene, indan, and 1,2,3,4-tetrahydroquinoline; and tricyclic ring systems, e.g., ten- to fifteen-membered tricyclic ring systems, where at least one ring is carbocyclic and aromatic, e.g., fluorene.

[0064] For example, aryl groups are selected from 5- to 7-membered cycloalkyl groups or 5- and 6-membered carbocyclic aromatic rings fused with heterocyclic rings, which may contain at least one heteroatom selected from N, O, and S. However, when the carbocyclic aromatic ring is fused with a heterocyclic ring, the bond site is located on the carbocyclic aromatic ring, and when the carbocyclic aromatic ring is fused with a cycloalkyl group, the bond site is located on either the carbocyclic aromatic ring or the cycloalkyl group. Divalent radicals formed from substituted benzene derivatives and having free valence on the ring atoms are called substituted phenylene radicals. Divalent radicals obtained from monovalent polycyclic hydrocarbon radicals having a name ending in "-yl" by removing one hydrogen atom from a carbon atom with free valence are named by adding "-idene" to the name of the corresponding monovalent radical. For example, a naphthyl group having two bond sites is called naphthylidene. However, aryl groups do not include, nor overlap with, heteroaryl groups, which are defined separately below. Therefore, when one or more carbocyclic aromatic rings are fused with a heterocyclic aromatic ring, the resulting ring system is heteroaryl, not aryl, as defined herein.

[0065] The term "halogen" refers to F, Cl, Br, or I.

[0066] The term "heteroalkyl" refers to an alkyl group that contains at least one heteroatom.

[0067] The term "heteroaryl" refers to a group selected from the following: A 5- to 7-membered aromatic monocyclic ring containing one, two, three, or four heteroatoms selected from N, O, and S, with the remaining ring atoms being carbon. An 8- to 12-membered bicyclic ring containing one, two, three, or four heteroatoms selected from N, O, and S, with the remaining ring atoms being carbon, at least one ring being aromatic, and at least one heteroatom present in the aromatic ring, and An 11- to 14-membered tricyclic ring containing one, two, three, or four heteroatoms selected from N, O, and S, with the remaining ring atoms being carbon, at least one ring being aromatic, and at least one heteroatom present in the aromatic ring.

[0068] For example, heteroaryl groups include 5- to 7-membered heterocyclic aromatic rings fused with 5- to 7-membered cycloalkyl rings. In the case of such fused bicyclic heteroaryl ring systems in which only one of the rings contains at least one heteroatom, the bonding site can be located on the aromatic heterocyclic ring or the cycloalkyl ring.

[0069] If the total number of S and O atoms in a heteroaryl group exceeds one, those heteroatoms are not adjacent to each other. In some embodiments, the total number of S and O atoms in a heteroaryl group does not exceed two. In some embodiments, the total number of S and O atoms in an aromatic heterocycle does not exceed one.

[0070] Examples of heteroaryl groups are not limited to these, but include (numbered from the linking position assigned priority 1) pyridyl (e.g., 2-pyridyl, 3-pyridyl, or 4-pyridyl), synnolinyl, pyrazinyl, 2,4-pyrimidinyl, 3,5-pyrimidinyl, 2,4-imidazolyl, imidazopyridinyl, isoxazolyl, oxazolyl, thiazoyl, isothiazolyl, thiadiazolyl, tetrazoyl, thienyl, triazinyl, benzothienyl, furyl, benzofuryl, benzimidazolyl, indolyl, isoindolyl, indolinyl, phthalazinyl, pyrazinyl, pyridadinyl, pyrrolyl, triazoyl, quinolinyl, isoquinolinyl, pyrazolyl, pyrrolopyridinyl (e.g., 1H-pyrrolo[2,3-b]pyridinyl-5-yl), pyrazolopyridinyl (e.g., 1H-pyrazolo[3,4-b]pyridine-5-yl), benzoxazolyl (e.g., benzo[d]oxazol-6-yl), pteridinyl, prinyl, 1-oxa-2,3-diazolyl, 1-oxa-2,4-diazolyl, 1-oxa-2,5-diazolyl, 1-oxa-3,4-diazolyl, 1-thia-2,3-diazolyl, 1-thia-2,4-diazolyl, 1-thia-2,5-diazolyl Examples include 1-thia-3,4-diazolyl, flazanil, benzoflazanil, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinil, quinoxalinil, naphthilidinil, phlopyridinil, benzothiazolyl (e.g., benzo[d]thiazole-6-yl), indazolyl (e.g., 1H-indazole-5-yl), and 5,6,7,8-tetrahydroisoquinoline.

[0071] The terms “heterocyclic,” “heterocycle,” or “heterocyclyl” refer to a ring selected from 4- to 12-membered monocyclic, bicyclic, and tricyclic saturated and partially unsaturated rings containing at least one carbon atom in addition to one, two, three, or four heteroatoms selected from oxygen, sulfur, and nitrogen. “Heterocycle” also refers to a 5- to 7-membered heterocycle fused with a 5-, 6-, and / or 7-membered cycloalkyl, carbocyclic aromatic, or aromatic heterocycle, containing at least one heteroatom selected from N, O, and S. However, when the heterocycle is fused with a carbocyclic aromatic or aromatic heterocycle, the bond site is located on the heterocycle, and when the heterocycle is fused with a cycloalkyl, the bond site may be located on the cycloalkyl or heterocycle.

[0072] A "heterocycle" also refers to an aliphatic spirocycle containing at least one heteroatom selected from N, O, and S, provided that the bonding site is located on the heterocycle. The ring may be saturated and may have at least one double bond (i.e., it may be partially unsaturated). The heterocycle may be substituted with an oxo. The bonding site may be a carbon or heteroatom of the heterocycle. The heterocycle is not a heteroaryl as defined herein.

[0073] Examples of heterocycles are not limited to these, but (numbered from the linking position assigned priority 1) include 1-pyrrolidinyl, 2-pyrrolidinyl, 2,4-imidazolidinyl, 2,3-pyrazolidinyl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 2,5-piperazinyl, pyranyl, 2-morpholinyl, 3-morpholinyl, oxylanyl, azilidinyl, and cyanoacrylate. Iranil, azetidinil, oxetanil, thietanil, 1,2-dithietanil, 1,3-dithietanil, dihydropyridinil, tetrahydropyridinil, thiomorpholinil, thioxanil, piperazinil, homopiperazinil, homopiperidinil, azepanil, oxepanil, thiepanil, 1,4-oxathianil, 1,4-dioxepanil, 1,4-oxathiepanil, 1,4-oxazepanil , 1,4-Dithiepanyl, 1,4-Thiazepanyl and 1,4-Diazepanyl, 1,4-Dithianyl, 1,4-Azathianyl, Oxazepinyl, Diazepinyl, Thiazepinyl, Dihydrothienyl, Dihydropyranyl, Dihydrofuranyl, Tetrahydrofuranyl, Tetrahydrothienyl, Tetrahydropyranyl, Tetrahydrothiopyranyl, 1-Pyrrolinyl, 2-Pyrrolinyl, 3-Pyrrolinyl, Indri Examples include nyl, 2H-pyranyl, 4H-pyranyl, 1,4-dioxanyl, 1,3-dioxolanyl, pyrazolinyl, pyrazolidinyl, dithianyl, dithiolanyl, pyrazolidinylimidazolinyl, pyrimidinol, 1,1-dioxo-thiomorpholinyl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, and azabicyclo[2.2.2]hexanyl. As substituted heterocycles, ring systems substituted with one or more oxo moieties include piperidinyl N-oxide, morpholinyl-N-oxide, 1-oxo-1-thiomorpholinyl, and 1,1-dioxo-1-thiomorpholinyl.

[0074] Substituents include halogen, -R', -OR', =O, =NR', =N-OR', -NR'R'', -SR', -SiR'R''R''', -OC(O)R', -C(O)R', -CO2R', -CO NR'R'', -OC(O)NR'R'', -NR''C(O)R', -NR'-C(O)NR''R''', -NR'-SO2NR''', -NR''CO2R', -NH-C(NH2)=NH The groups are selected from -NR'C(NH2)=NH, -NH-C(NH2)=NR', -S(O)R', -SO2R', -SO2NR'R'', -NR''SO2R, -CN and -NO2, -N3, -CH(Ph)2, perfluoro(C1~C4)alkoxy and perfluoro(C1~C4)alkyl, the number of which ranges from 0 to 3, and groups having 0, 1 or 2 substituents are particularly preferred. R', R'' and R''' each independently refer to hydrogen, unsubstituted (C1~C8)alkyl and heteroalkyl, unsubstituted aryl, aryl substituted with 1 to 3 halogens, unsubstituted alkyl, alkoxy or thioalkoxy group, or aryl-(C1~C4)alkyl group. R' and R'' are bonded to the same nitrogen atom and can combine with that nitrogen atom to form a 5-membered, 6-membered or 7-membered ring. Therefore, -NR'R'' encompasses 1-pyrrolidinyl and 4-morpholinyl, and "alkyl" encompasses groups such as trihaloalkyl (e.g., -CF3 and -CH2CF3), and if the aryl group is 1,2,3,4-tetrahydronaphthalene, it may be substituted with a substituted or unsubstituted (C3-C7) spirocycloalkyl group. The (C3-C7) spirocycloalkyl group may be substituted in the same manner as defined herein with respect to "cycloalkyl".

[0075] Preferred substituents are selected from halogens, -R', -OR', =O, -NR'R'', -SR', -SiR'R''R''', -OC(O)R', -C(O)R', -CO2R', -CONR'R'', -OC(O)NR'R'', -NR''C(O)R', -NR''CO2R', -NR'-SO2NR''R''', -S(O)R', -SO2R', -SO2NR'R'', -NR''SO2R, -CN and -NO2, perfluoro(C1-C4)alkoxy and perfluoro(C1-C4)alkyl, where R' and R'' are as defined above.

[0076] The term "fused ring" as used herein refers to a polycyclic ring system, e.g., a bicyclic or tricyclic ring system, in which two rings share only two ring atoms and one bond. Examples of fused rings may include fused bicyclic cycloalkyl rings, e.g., those having 7 to 12 ring atoms arranged as a bicyclic ring selected from the [4,4], [4,5], [5,5] / [5,6] and [6,6] ring systems as described above; fused bicyclic aryl rings, e.g., the 7- to 12-membered bicyclic aryl ring systems described above; fused tricyclic aryl rings, e.g., the 10- to 15-membered tricyclic aryl ring systems described above; fused bicyclic heteroaryl rings, e.g., the 8- to 12-membered bicyclic heteroaryl rings described above; fused tricyclic heteroaryl rings, e.g., the 11- to 14-membered tricyclic heteroaryl rings described above; and fused bicyclic or tricyclic heterocyclyl rings described above.

[0077] Compounds may contain chiral centers and therefore may exist as enantiomers. If a compound has two or more chiral centers, it may also exist as a diastereomer. Enantiomers and diastereomers belong to a broader class of stereoisomers. All such possible stereoisomers are intended to be included as substantially pure, divided enantiomers, as racemic mixtures thereof, and as mixtures of diastereomers. All stereoisomers of a compound and / or its pharmaceutically acceptable salts are intended to be included. Unless otherwise specified, a reference to one isomer applies to any of the possible isomers. If an isomeric composition is not specified, all of those possible isomers are included.

[0078] The compounds of the present invention may contain atomic isotopes in non-natural proportions with respect to one or more of the atoms constituting such compounds. For example, in the case of deuterium, for example, -CD3, CD2H, or CDH2 may be contained instead of methyl. For example, the compound may contain radioactive isotopes, such as tritium. 3 H), Iodine-125 ( 125 I) or carbon-14 ( 14 It may be radiolabeled with C). All isotopic variations of the compounds of the present invention, whether radioactive or not, are intended to be included within the scope of the present invention.

[0079] The term "substantially pure" means that the target stereoisomer contains any other stereoisomer(s) in amounts of 35% by weight or less, for example, 30% by weight or less, more for example, 25% by weight or less, and even more for example, 20% by weight or less. In some embodiments, the term "substantially pure" means that the target stereoisomer contains any other stereoisomer(s) in amounts of 10% by weight or less, for example, 5% by weight or less, for example, 1% by weight or less.

[0080] When a compound contains an olefinic double bond, unless otherwise specified, it is intended that such a double bond encompasses both the E and Z geometric isomers.

[0081] Some compounds may exist with different hydrogen bond sites and are called tautomers. For example, a compound containing a carbonyl-CH2C(O)- group (keto form) can undergo tautomerism to form a hydroxyl-CH=C(OH)- group (enol form). Both the keto and enol forms are intended to be included, individually and as mixtures thereof, where applicable.

[0082] It may be advantageous to separate reaction products from each other and / or from the starting materials. The desired products of each step or series of steps are separated and / or purified (hereinafter, separated) to a desired degree of homogeneity by techniques common in the art. Typically, such separations involve multiphase extraction, crystallization from a solvent or solvent mixture, distillation, sublimation, or chromatography. Chromatography may involve any number of methods, including, for example, reversed-phase and normal-phase; size exclusion; ion exchange; high-pressure, medium-pressure and low-pressure liquid chromatography methods and apparatus; small-scale analytical methods; pseudo-mobile bed ("SMB") and preparative thin-layer or thick-layer chromatography, as well as small-scale thin-layer and flash chromatography techniques. Those skilled in the art will apply the technique that is most likely to achieve the desired separation.

[0083] Diastereomer mixtures can be separated into their individual diastereomers by methods well known to those skilled in the art, based on their physicochemical differences, for example, by chromatography and / or fractional crystallization. Enantiomers can be separated by converting the enantiomer mixture into a diastereomer mixture by reaction with a suitable optically active compound (e.g., a chiral auxiliary such as a chiral alcohol or moscherate), separating the diastereomers, and converting the individual diastereomers back into their corresponding pure enantiomers (e.g., by hydrolysis). Enantiomers can also be separated by using a chiral HPLC column.

[0084] A single stereoisomer, for example, a substantially pure enantiomer, can be obtained by splitting a racemic mixture using methods such as the formation of a diastereomer with an optically active resolving agent. The racemic mixture of the chiral compound of the present invention can be separated and isolated by any suitable method, including (1) the formation of an ionic diastereomer salt with the chiral compound and separation by fractional crystallization or other methods, (2) the formation of a diastereomer compound using a chiral derivatization reagent, separation of the diastereomer, and conversion to a pure stereoisomer, and (3) the direct separation of a substantially pure or enriched stereoisomer under chiral conditions.

[0085] Examples of "pharmaceutically acceptable salts" include, but are not limited to, salts with inorganic acids selected from hydrochloride, phosphate, diphosphate, hydrobromide, sulfate, sulfinate, and nitrate salts; salts with organic acids selected from alkanates such as malate, maleate, fumarate, tartrate, succinate, citrate, lactate, methanesulfonate, p-toluenesulfonate, 2-hydroxyethylsulfonate, benzoate, salicylate, stearate, and acetate; and salts with HOOC-(CH2)n-COOH (wherein n is selected from 0 to 4). Similarly, examples of pharmaceutically acceptable cations include, but are not limited to, ions of sodium, potassium, calcium, aluminum, lithium, and ammonium.

[0086] Furthermore, if the compound is obtained as an acid addition salt, the free base can be obtained by basicizing the solution of the acidic salt. Conversely, if the product is a free base, the addition salt, such as a pharmaceutically acceptable addition salt, can be produced by dissolving the free base in a suitable organic solvent and treating the solution with acid according to the conventional procedure for preparing acid addition salts from basic compounds. Various systems of synthetic methods that can be used to prepare non-toxic, pharmaceutically acceptable addition salts without excessive experimentation are known to those skilled in the art.

[0087] "To treat," "to treat," or "treatment" means administering at least one compound and / or at least one stereoisomer thereof, and / or at least one pharmaceutically acceptable salt thereof, to a subject for whom such treatment is recognized.

[0088] An "effective dose" refers to the amount of at least one compound and / or at least one stereoisomer thereof and / or at least one pharmaceutically acceptable salt thereof that is effective in "treating" a disease or disorder in a subject and elicits a biological or medical response in the desired tissue, system, animal, or human to some meaningful degree, for example, sufficient to prevent the onset of the condition or disorder being treated, or to alleviate one or more of the symptoms of the condition or disorder being treated to some degree when administered. The therapeutic effective dose varies depending on the compound, the disease and its severity, and the age, weight, etc., of the mammal being treated.

[0089] The term "at least one substituent" includes, for example, one to four substituents, for example, one to three substituents, and even one or two substituents. For example, "at least one substituent R" in this specification includes one to four substituents, for example, one to three substituents, and even one or two substituents selected from the list of Rs described herein.

[0090] The subject compound and its stereoisomers, as well as pharmaceutically acceptable salts thereof, can be used alone or in combination with at least one other therapeutic agent for treatment. In some embodiments, the compound, its stereoisomers, and pharmaceutically acceptable salts thereof can be used in combination with at least one additional therapeutic agent. The compounds and / or one pharmaceutically acceptable salt disclosed herein can be administered in a single dosage form or in separate dosage forms with at least one other therapeutic agent. When administered in separate dosage forms, at least one other therapeutic agent can be administered before, simultaneously with, or after the administration of the compounds and / or one pharmaceutically acceptable salt disclosed herein.

[0091] Compositions comprising the subject compound and its stereoisomers, as well as pharmaceutically acceptable salts thereof, and at least one pharmaceutically acceptable carrier are also provided.

[0092] Compositions comprising the subject compound and its stereoisomers, as well as pharmaceutically acceptable salts thereof, can be administered in various known forms, for example, orally, topically, rectally, parenterally, by inhalation spray, or via an implanted reservoir, but the most appropriate route in any case depends on the specific host and the nature and severity of the condition to which the active ingredient is administered. The term "parenterally," as used herein, includes subcutaneous, intradermal, intravenous, intramuscular, intra-articular, intra-arterial, intra-bursal, intrasternal, intrathecal, intrafocal, and intracranial injection or infusion techniques. The compositions disclosed herein can be conveniently provided as unit dosage forms and can be prepared by any method well known in the art.

[0093] The subject compounds and their stereoisomers, as well as pharmaceutically acceptable salts thereof, may be administered orally in solid dosage forms, such as capsules, tablets, lozenges, sugars, granules, and powders, or in liquid dosage forms, such as elixirs, syrups, emulsions, dispersants, and suspensions. The subject compounds and their stereoisomers, as well as pharmaceutically acceptable salts thereof, disclosed herein may also be administered parenterally in sterile liquid dosage forms, such as dispersants, suspensions, or solutions. Other dosage forms, such as ointments, creams, drops, transdermal patches, or powders for topical administration, ophthalmic solutions or suspensions for ocular administration, i.e., eye drops, aerosol sprays or powder compositions for inhalation or nasal administration, or creams, ointments, sprays, or suppositories for rectal or vaginal administration, may also be used to administer the subject compounds and their stereoisomers, as well as pharmaceutically acceptable salts thereof, disclosed herein.

[0094] Gelatin capsules containing the compounds disclosed herein and / or at least one pharmaceutically acceptable salt thereof, along with a powdered carrier, such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, etc. Compressed tablets can be prepared using similar diluents. Both tablets and capsules can be manufactured as sustained-release products, resulting in a continuous release of the drug over a period of time. Compressed tablets may be sugar-coated or film-coated to mask any unpleasant tastes and protect the tablets from air, or enterically coated to selectively disintegrate in the gastrointestinal tract.

[0095] The liquid dosage form for oral administration may further contain at least one activating agent selected from colorants and flavoring agents to increase patient tolerance.

[0096] Generally, suitable carriers for parenteral solutions may be water, a suitable oil, physiological saline, aqueous dextrose (glucose), and related sugar solutions and glycols, such as propylene glycol or polyethylene glycol. A parenteral solution may contain a water-soluble salt of at least one compound described herein, at least one suitable stabilizer, and, if necessary, at least one buffer. Examples of suitable stabilizers may be antioxidants, either alone or in combination, such as sodium bisulfite, sodium sulfite, or ascorbic acid. Citric acid and its salts, as well as sodium EDTA, can also be used as examples of suitable stabilizers. Furthermore, the parenteral solution may further contain at least one preservative selected from, for example, benzalkonium chloride, methylparaben, propylparaben, and chlorobutanol.

[0097] A pharmaceutically acceptable carrier is selected from carriers that are compatible with the active ingredient of the composition (and in some embodiments, can stabilize the active ingredient) and are not harmful to the object being treated. For example, solubilizers, such as cyclodextrins (which can form specific, more soluble complexes with at least one of the compounds and / or at least one pharmaceutically acceptable salt disclosed herein), can be used as pharmaceutical excipients for delivering the active ingredient. Examples of other carriers include colloidal silicon dioxide, magnesium stearate, cellulose, sodium lauryl sulfate, and dyes. Suitable pharmaceutically acceptable carriers are described in Remington's Pharmaceutical Sciences, A. Osol, and other reference texts in the art.

[0098] With regard to administration by inhalation, the subject compounds and their stereoisomers, as well as pharmaceutically acceptable salts thereof, can be conveniently delivered in a form presented as an aerosol spray from a pressurized pack or nebulizer. The subject compounds and their stereoisomers, as well as pharmaceutically acceptable salts thereof, may also be delivered as powders, which may be formulated, and the powder compositions may be inhaled using a blow-type powder inhalation device. One exemplary inhalation delivery system may be a metered-dose inhalation (MDI) aerosol, which can be formulated, for example, as a suspension or liquid of the subject compounds and their stereoisomers, as well as pharmaceutically acceptable salts thereof, disclosed herein, in at least one suitable propellant selected from fluorocarbons and hydrocarbons.

[0099] With regard to administration to the eye, an ophthalmic preparation can be formulated using a suitable ophthalmic vehicle, containing a suitable weight percentage of the subject compound and its stereoisomers, as well as a solution or suspension of a pharmaceutically acceptable salt thereof, such that the subject compound and its stereoisomers, as well as at least one pharmaceutically acceptable salt thereof, remain in contact with the surface of the eye for a sufficient amount of time to allow the compound to penetrate the corneal and internal regions of the eye.

[0100] Pharmaceutical dosage forms useful for administering the subject compounds and their stereoisomers disclosed herein, as well as pharmaceutically acceptable salts thereof, include, but are not limited to, hard gelatin capsules and soft gelatin capsules, tablets, parenteral injections, and oral suspensions.

[0101] The dosage administered depends on factors such as the recipient's age, health and weight, the severity of the disease, the type and frequency of any concurrent treatments, and the nature of the desired effect. Generally, the daily dose of the active ingredient can vary, for example, from 0.1 milligrams to 2000 milligrams per day. For example, 10 to 500 milligrams per day, once or multiple times, may be effective in achieving the desired results.

[0102] In some embodiments, a large number of unit capsules can be prepared by filling each standard two-piece hard gelatin capsule with, for example, 100 milligrams of powder of the subject compounds disclosed herein and their stereoisomers, as well as pharmaceutically acceptable salts thereof, 150 milligrams of lactose, 50 milligrams of cellulose, and 6 milligrams of magnesium stearate.

[0103] In some embodiments, a compound, its stereoisomer, and a pharmaceutically acceptable salt thereof can be prepared in a mixture with a digestible oil such as soybean oil, cottonseed oil, or olive oil, and injected into gelatin using a volumetric pump to form soft gelatin capsules containing 100 milligrams of the active ingredient. The capsules are washed and dried.

[0104] In some embodiments, a number of tablets can be prepared by conventional procedures, for example, so that each dose unit contains 100 milligrams of the compound, its stereoisomers, and pharmaceutically acceptable salts thereof, 0.2 milligrams of colloidal silicon dioxide, 5 milligrams of magnesium stearate, 275 milligrams of microcrystalline cellulose, 11 milligrams of starch, and 98.8 milligrams of lactose. Appropriate coatings may be applied to increase palatability or delayed absorption.

[0105] In some embodiments, parenteral compositions suitable for administration by injection can be prepared by stirring 1.5% by weight of the compounds disclosed herein and / or at least an enantiomer, diastereomer, or pharmaceutically acceptable salt thereof in 10% by volume of propylene glycol. The solution is brought to the desired volume using sterile water for injection and sterilized.

[0106] In some embodiments, aqueous suspensions can be prepared for oral administration. For example, 5 milliliters each of an aqueous suspension containing 100 milligrams of the finely powdered compound, its stereoisomers, and pharmaceutically acceptable salts thereof, 100 milligrams of sodium carboxymethylcellulose, 5 milligrams of sodium benzoate, 1.0 gram of sorbitol solution (USP), and 0.025 milliliters of vanillin can be used.

[0107] When a compound, its stereoisomers, and pharmaceutically acceptable salts thereof are administered stepwise or in combination with at least one other therapeutic agent, the same dosage form can generally be used. When drugs are administered in physical combinations, the dosage form and route of administration should be selected according to the compatibility of the drugs being combined. Therefore, the term co-administration is understood to encompass the administration of at least two agonists simultaneously or sequentially, or as a combination of fixed doses of at least two active components.

[0108] The compounds disclosed herein, their stereoisomers, and pharmaceutically acceptable salts thereof may be administered as sole active ingredients or in combination with at least one second active ingredient.

[0109] The subject compound is incorporated into a pharmaceutical composition or formulation. The composition contains a pharmaceutically acceptable diluent and / or carrier, i.e., a diluent or carrier that is physiologically compatible and substantially free of pathogenic impurities. Suitable excipients or carriers and methods for preparing an administerable composition are known or obvious to those skilled in the art and are described in more detail in publications such as Remington's Pharmaceutical Science, Mack Publishing Co, NJ. The composition may also be in the form of controlled-release or sustained-release compositions known in the art. For many applications, the subject compound is administered in the morning / daytime with a rest period at night.

[0110] The compound in question can be used in itself or in the form of its pharmaceutically acceptable salts, such as hydrochloride, hydrobromide, acetate, sulfate, citrate, carbonate, trifluoroacetate, etc. If the compound has a relatively acidic functional group, a salt can be obtained by adding the desired base either in its original form or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include salts of sodium, potassium, calcium, ammonium, organic amino acids, or magnesium. If the compound has a relatively basic functional group, a salt can be obtained by adding the desired acid either in its original form or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monocarbonate, phosphoric acid, monohydrogen-phosphoric acid, dihydrogen-phosphoric acid, sulfuric acid, monohydrogen-sulfuric acid, hydroiodic acid, or phosphorous acid, as well as salts derived from relatively non-toxic organic acids such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toylsulfonic acid, citric acid, tartaric acid, and methanesulfonic acid. Salts of amino acids such as alginic acid, and salts of organic acids such as glucuronic acid or galacturonic acid are also included.

[0111] The neutral form of the compound can be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but in other respects, the salt is equivalent to the parent form of the compound for the purposes of the present invention.

[0112] In addition to salt forms, the present invention provides compounds in prodrug form. Prodrugs of the compounds described herein are compounds that readily undergo chemical changes under physiological conditions to yield the compounds of the present invention. Furthermore, prodrugs may be converted to the compounds of the present invention by chemical or biochemical methods in an ex vivo environment. For example, a prodrug can be slowly converted to the compounds of the present invention when placed in a transdermal patch reservoir with appropriate enzymes or chemical reagents. Prodrugs are often useful because they may be easier to administer than the parent drug in some situations. For example, prodrugs may have higher bioavailability by oral administration than the parent drug. Prodrugs may also have improved solubility in pharmacological compositions than the parent drug. A wide variety of prodrug derivatives are known in the art, including those that rely on hydrolysis-induced cleavage or oxidative activation of the prodrug. Without limiting itself thereto, compounds of the present invention that are administered as esters ("prodrugs") but are subsequently metabolically hydrolyzed to the active substance, a carboxylic acid, are also examples of prodrugs.

[0113] Certain compounds of the present invention may exist in solvated forms, including non-solvated and hydrated forms. Generally, solvated forms are equivalent to non-solvated forms and are intended to be included within the scope of the present invention. Certain compounds of the present invention may exist in multiple crystalline or amorphous forms. Generally, all physical forms are equivalent with respect to the intended use in the present invention and are intended to fall within the scope of the present invention.

[0114] Some of the compounds in question have an asymmetric carbon atom (optical center) or a double bond, and racemates, diastereomers, geometric isomers, and individual isomers are all intended to be included within the scope of the present invention.

[0115] Compounds are typically administered in a “therapeutic dose,” that is, the amount of the compound in question that elicits a biological or medical response in a tissue, system, animal, or human as required by the researcher, veterinarian, physician, or other clinician. The term “therapeutic dose” encompasses the amount of the compound that, when administered, is sufficient to prevent the onset of the condition or disorder being treated, or to alleviate one or more of the symptoms of the condition or disorder being treated to some degree. The therapeutic dose varies depending on the compound, the disease and its severity, and the age, weight, etc., of the mammal being treated.

[0116] Contact is typically made by administering an effective amount of one or more compounds having the formulas of this specification, including the various embodiments described above, to the subject. Typically, the administration is adjusted to achieve a therapeutic dose of about 0.1 mg / kg to 50 mg / kg, preferably 0.5 mg / kg to 10 mg / kg, more preferably 1 mg / kg to 10 mg / kg, but the optimal dose is compound-specific and is usually determined empirically for each compound.

[0117] The term "unit dosage form" refers to a physically distinct unit appropriate as a unit dose for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect in conjunction with appropriate pharmaceutical excipients. Typical unit dosage forms include pre-filled and pre-measured ampoules or syringes for liquid compositions, or pills, tablets, capsules, lozenges, etc. for solid compositions. In such compositions, the mimetic is usually a minor component (from about 0.1% to about 50% by weight, or preferably from about 1% to about 40% by weight), with the remainder being various vehicles or carriers and processing aids that help form the desired dosage form. Unit dosage formulations are preferably about 5 mg, 10 mg, 25 mg, 50 mg, 100 mg, 250 mg, 500 mg, or 1000 mg per unit. In certain embodiments, the unit dosage forms are packaged in a multipack adapted for sequential use, for example, a blister pack containing at least six, nine, or twelve sheets of unit dosage forms. [Examples]

[0118] Development of dibenzothiazepinone and dibenzazepinone as anticancer drugs As part of phenotypic screening, we identified a small molecule dibenzothiazepinone, named MM017, that is toxic to colorectal cancer cells. Using forward genetics, we showed that mutations in Nuclear Valosin Like 2 (NVL2) result in 30-fold resistance to MM017. NVL2 is an asymmetric hexameric AAA-ATPase protein that links ATP hydrolysis to the removal of WDR74 and its chaperone complex from nascent 60S ribosomes, a necessary step in 60S biosynthesis. Using photochemistry and structural biology, we demonstrated that these mutations are mapped to compound binding sites and are crucial for compound binding. Since the majority of studies involving NVL2 have been conducted in yeast, we developed an NVL2 degron system to investigate its function in colorectal cancer cells. Degradation of NVL2 leads to a reduction in 60S ribosome biosynthesis (ribogenesis), as measured by polysome profiling, which is consistent with the function of NVL2 reported in yeast. Furthermore, MM017 phenotypicly mimics the effects of NVL2 degradation, which is consistent with the hypothesis that inhibition is mediated by binding. Crucially, cells with mutations in the binding site did not exhibit any of these effects, confirming that these effects are on-target (attributable to NVL2 binding). MM017 was subjected to PRISM analysis, which involved evaluating its potency and efficacy against 902 unique deeply annotated cell lines. The selectivity of MM017 across these cell lines correlated most strongly with oxaliplatin and carmofur (out of 1215 compounds). Carmofur is a 5-fluorouracil prodrug approved in Japan for the treatment of colorectal cancer and has also been shown to block 60S ribosome biosynthesis. These correlations provide independent evidence that oxaliplatin and carmofur are toxic by blocking ribosome biosynthesis. Furthermore, the usefulness of these drugs in CRCs supports the rationale for testing MM017 in a CRC model.From this, we developed an optimized analog of MM017 for in vivo proof-of-concept studies evaluating the tolerability, efficacy, and pharmacodynamic markers of NVL2-targeted ribosome biosynthesis inhibitors. As an on-target pharmacodynamic marker, we developed an optimized screening funnel that includes p53 / p21 upregulation, a known marker of stress induced by impaired ribosome biosynthesis.

[0119] Targeting NVL2 provides a translateable strategy for colorectal cancer chemotherapy via a first-in-class alternative mechanism of ribosome biosynthesis inhibition compared to clinically used molecularly undefined ribotoxic drugs. We disclose (1) the design, synthesis, and evaluation of a collection of benzothiazepine-based NVL2 inhibitors for selecting candidates suitable for in vivo evaluation, and (2) the evaluation of the in vivo drug tolerability, pharmacodynamics, and efficacy of optimized NVL inhibitors in a colorectal cancer xenograft model. As innovations, we present the first and only known small molecule inhibiting NVL2; compound-resistant mutations that delineate on-target and off-target effects in cells; compound-resistant xenografts derived from the above-mentioned resistant cell lines that delineate on-target and off-target pharmacodynamics and efficacy in vivo; and germline compound-resistant NVL2 that delineates on-target and off-target toxicity in mice. R403W / + One example is the knock-in mouse.

[0120] Result I We conducted a high-throughput screening of 99,599 small molecules (UTSW chemical library) for compounds that inhibit the proliferation of HCT116 colorectal cancer cells. The main challenge in phenotypic screening is understanding the mechanism of action, often referred to as target ID. To address this challenge, we developed an isogenic and inducible forward genetic system to elucidate compound resistance mutations.

[0121] As part of this effort, we identified MM017 as a novel small molecule with antiproliferative activity in HCT116 cells. In total, 61 HCT116-resistant clones were isolated, and 11 of them were subjected to whole-exome sequencing, which revealed repeat mutations in nuclear balossin-containing protein-like 2 (NVL2). Follow-up NVL2-focused sequencing revealed that all 61 clones had NVL2 mutations. NVL2 is an AAA-ATPase protein in yeast involved in the removal (or unfolding) of the NSA1 module, a set of chaperones bound to the nascent 60S ribosome subunit in the nucleolus. As a result, NVL2 is essential for 60S ribosome biosynthesis. NVL2 consists only of an N-terminal domain (NTD) important for localization to the nucleolus and two tandem ATPase domains. The concentration of resistance-inducing mutations in specific regions of the first ATPase domain suggests that this domain is involved in the mechanism of action. When the same mutations were conferred to naive cells using CRISPR editing, resistance to the compound was observed.

[0122] To test whether the NVL2 mutation interferes with compound binding, we synthesized MM0514, a crosslinking derivative of MM017. MM0514 contains an aryl azide and is therefore capable of covalently modifying the target protein after exposure to UV light. MM0514 also contains an alkyne group, which provides a "handle" for purifying the bound protein using click chemistry. Crucially, NVL2 R403W Since mutant cells are resistant, MM0514 retains on-target activity against HCT116 cells. (Progenitor HCT116 cells or NVL2) R403WMM0514 was crosslinked into any of the HCT116 cells, and NVL2 binding was analyzed. NVL2 bound to MM0514 in a dose-dependent manner in parental cells, but to a lower degree in NVL2 mutant cells. These findings demonstrate that the NVL2 mutation confers resistance by preventing direct binding of MM017 derivatives. Taken together, these results confirm that the antiproliferative effect of MM017 and its derivatives is due to binding to NVL2. To characterize the binding site, the cryo-EM structure of NVL2 with MM017 was resolved. MM017 binds to a single site near the D subunit in the asymmetric hexamer. Consistent with our binding data, the mutation is mutated to tryptophan in resistant clones and maps to the binding site including R403, which is predicted to prevent binding of MM017 or related analogs. The cryo-EM structure of NVL2 with MM017 provides further evidence for target identification and also offers tools for optimizing bioavailable compounds.

[0123] Since NVL2 is essential for 60S ribosome maturation in yeast, we hypothesized that MM017 may reduce 60S ribosome synthesis. To investigate this hypothesis, parental cells or NVL mutant cells treated with MM017 were subjected to polysome profiling at different time points. In polysome profiling, a sucrose gradient was used to fractionate complete ribosomes (80S) from their constituent large (60S) and small (40S) subunits. In parental cells treated with MM017, a time-dependent decrease in both 60S and 80S ribosome subunits was observed. This is consistent with a reduction in 60S biosynthesis. Since 80S is a complex of 40S and 60S ribosomes, it is expected that fewer 60S ribosomes would lead to an increase in free 40S subunits. All of these changes are attributed to NVL2. R403WSince it is not present in mutant cells, this is a result of binding to NVL2. Taken together, these findings suggest that MM017 inhibits NVL2, which in turn leads to a decrease in 60S ribosomes.

[0124] Inhibition of 60S ribosome biosynthesis is known to induce p53 stability and upregulation; therefore, p53 stability and upregulation may function as a potential pharmacodynamic marker for MM017 in HCT116 cells. Consistently, MM017 upregulates p53 levels in parental HCT116 cells, but NVL2 R403W It did not upregulate p53 levels in mutant cells. The selectivity of MM017 across 902 cancer cell lines was evaluated using PRISM (Brode Institute), and this selectivity was then correlated with 1215 clinical and preclinical compounds in the PRISM database. Carmofur (r=0.53, adjusted p<10) -30 ) and oxaliplatin (r=0.5, adjusted p<10 -30 The selectivity of ) was significantly correlated with that of MM017, suggesting that all three compounds have a similar mode of action. These findings indicate that oxaliplatin and carmofur, like MM017, target ribosome biosynthesis.

[0125] Results II We previously reported that small benzothiazepine molecules dose-dependently bind to the ribosomal biosynthesis factor NVL2, killing colorectal cancer cells, and that this correlates with the upregulation of p53, a downstream effect of ribosomal biosynthesis inhibition. Currently, no known NVL2 inhibitors exist; therefore, this novel class of benzothiazepine-based NVL2 inhibitors provides reagents for optimizing medicinal chemistry toward in vivo active lead compounds for proof-of-concept evaluation in a colorectal cancer xenograft model.

[0126] Medicinal chemistry optimization of dibenzothiazepinone-based and dibenzazepinone-based NVL2 inhibitors Design and synthesis of benzothiazepine-based NVL inhibitors. We demonstrated that the dibenzothiazepinone scaffold is suitable for medicinal chemistry optimization, and therefore, analogues with desirable drug-like properties can be synthesized. Large-scale dibenzothiazepinone and dibenzazepinone analogues were synthesized, and their structure-activity profiles were elucidated. The analogues were evaluated against the colorectal cancer cell line HCT116, and compound-resistant NVL2 inhibitors were identified. R403W A counter-screening was performed on clones. Cytotoxicity in wild-type HCT116 was determined. All active analogs showed on-target cytotoxic activity, and NVL2 R403W The potency against clones was 1 / 10 to 1 / 100. The initial SAR focused on exploring furan ring substitutions for MM017, the first dibenzothiazepinone hit. First, a wide variety of monosubstituted and disubstituted phenyl rings, including those with broad functionalities (F, Cl, alkyl, alkoxy, fluoroalkoxy, CN, formamide, S(O)Me, carboxyl, etc.), were explored. Ortho substituents were not tolerated except for fluorine, and only trisubstituted, tetrasubstituted, or 3,4-disubstituted phenyl analogs retained similar activity to the parent. Five-membered heterocycles other than furan showed significantly reduced potency, but benzoxazoles, benzothiazoles, and 2-oxo-2,3-dihydrobenzoxazoles were equivalent to or somewhat more potent than their corresponding phenyl analogs. It was also found that active analogs could be derived from several amides derived from non-aromatic acyclic, monocyclic, or spirocyclic carboxylic acids. Since amide bonds are potentially subject to protease-mediated cleavage, substitution of the amide linker (C(O)NH) was investigated, and it was found that urea retained similar potency, as did thioamides and thioureas. On the other hand, the use of reversed amides and sulfonamides resulted in inactivity. Moving to the side chain, longer propargyloxy or hexenyl boosted potency by 3 to 10 times, but at the cost of an increased number of lipophilic and rotatable bonds. Shorter rigid 2-butynyl yielded optimal activity and a more than 10 to 20-fold increase.

[0127] SAR data correlated with insights gained from co-cryo-EM NVL2 structures using several dibenzothiazepinones and dibenzazepinones. This led to the design of a series of heteroaromatic analogs in which amide-linked dibenzothiazepinones or dibenzazepinones were replaced with amine-linked dibenzothiazepinones and dibenzazepinones. It was found that linking various aromatic groups, heteroaromatic groups, heterocyclic groups, carbocyclic groups, and acyclic groups to the dibenzothiazepinone or dibenzazepinone skeleton via amine linkage maintained or improved activity.

[0128] Using input from our current SAR data, we designed and synthesized new analogues based on a general scaffold. We explored additional rigidification, metabolic blockade, and shortening while retaining the alkynyl side chain, which has higher potency and lower lipophilicity. We found that oxidation (to SO or SO2) or substitution with an oxygen atom of the central sulfur atom of dibenzothiazepinone is unacceptable, but CH2 substitution reduces activity by only about half. Based on this finding, we also substituted the central sulfur atom with a CHMe unit and found that activity similar to that of the sulfur analogues was retained. Substitution with CHCN or CMe(OH) units resulted in some decrease in activity. Therefore, subsequent designs retained the central sulfur or (optionally substituted) carbon atom. Next, we explored substituents for various available positions on the two benzo rings of the central dibenzothiazepinone skeleton. We found that fluorine, chlorine, and cyano substituents are acceptable on the right-hand benzo ring and retain sufficient potency when introduced at two positions not directly adjacent to the benzo condensation. Such substitutions were not permitted in the left-hand benzo ring. We also investigated analogues (pyrido analogues) in which individual CH units of the two benzo rings were replaced with nitrogen. These were not permitted in the right-hand benzo ring, but were permitted in the left-hand ring at the positions labeled U and W in the general structure of the claims. We further found that replacing the CH with nitrogen at the W position of the general structure significantly increased the metabolic stability of the analogues as measured by microsomal stability assays. All central dibenzothiazepinone and dibenzazepinone scaffoldings can be synthesized from readily available starting materials using the same chemistry as described herein. We focused on substituents that are small, improve physicochemical properties, and reduce metabolism. The final step of synthesis involves conjugation of the amino-substituted central scaffolding to the terminal unit (R3 in the general structure) via Pd-catalyzed CN bond formation (structure of formula VI) or reductive amination, or amide bond formation with a suitable carboxylic acid (structure of formula VII). Thiamide (structure of formula VIII) is formed by aging the amino-dibenzothiazepinone skeleton in an aqueous K2CO3 solution. 3- It is obtained by reacting with an aldehyde and sulfur powder. Urea (the structure of formula II or formula IV) and thiourea (the structure of formula III or formula V) are obtained from the same amino-substituted central skeleton using modern methods of urea / thiourea formation and using triphosgene or thiophosgene. Preferred substitutions incorporate only those groups having drug-like substituents or desirable physicochemical properties and limited predicted metabolic disadvantages. Preferred substituents are small, improve physicochemical properties, and reduce metabolism.

[0129] The next-generation analogs of the present inventors retain or improve CLogP, fit within the druglike space without violating either Lipinski's rule of five or Veber's rule. sp 3 The introduction of a stereocenter can be beneficial for activity and specificity, solubility, and reduction of protein binding.

[0130] Of the NVL2 inhibitors, NVL2 mut Evaluation of the ability to selectively kill wild-type HCT116 compared to HCT116 and block ribosome biogenesis and induce p53. The analogs are evaluated in the colorectal cancer cell line HCT116 and in already available compound-resistant clones. One clone has a mutation in the compound-binding site (NVL2 R403W ), and another clone (NVL2 P307T ) has a mutation away from the binding site, which confers resistance by an unknown effect. Based on the results of the present inventors, analogs that kill HCT116 cells by NVL2 inhibition (on-target) have reduced potency against compound-resistant HCT116 mutant clones. Counter-screening was performed on the NVL2 compound-resistant mutant clones with a resistance fold range of 10-fold to 100-fold (most analogs are 20-fold to 50-fold) for the analogs of the present inventors. This counter-screening provides a strategy for identifying off-target toxins. Progress the analogs that kill wild-type cancer cells in a dose-responsive manner at IC 50 <1000 nM and have at least one-twentieth the potency in the NVL mutant cell line.

[0131] It meets the criteria for efficacy and on-target NVL2 inhibition and is metabolically stable (T in microsomal assays). 1 / 2 (30 min) Further evaluate the analogues for their ability to inhibit ribosome biosynthesis (polysome profiling and induction of p53 and / or p21). Evaluate p53 as a pharmacodynamic marker in in vivo studies using antibodies against p53.

[0132] Profiling of analogues for in vitro metabolism, plasma stability, solubility, and plasma protein binding. The majority of analogues were evaluated for oxidative metabolism using mouse microsomal fractions in the presence of the NADPH regeneration system required for Phase I metabolism. Half-life was determined by substrate depletion. Significant metabolic disadvantages (T 1 / 2 Compounds identified as having <30 mins) showed high in vivo clearance rates and were not further investigated. Since methoxy substituents are potentially unstable to oxidative metabolism, the introduction of fluorine metabolic blockade was also explored. Suspecting that some metabolic clearances might be protease-mediated, selected analogues were evaluated in microsomal fractions in the absence of an NADPH regeneration system to eliminate phase I oxidative metabolism. While some amides were still metabolized at considerable rates, other amides were found to be more stable. Unsurprisingly, amines, ureas, and thioureas were stable under those conditions (T 1 / 2 >120 minutes).

[0133] Compounds with acceptable metabolic clearance rates are evaluated in additional in vitro assays using the gold standard rapid equilibrium dialysis, including solubility in water, stability in plasma, and protein binding. Current SARs have shown that higher activity, solubility, and acceptable metabolic stability can be achieved using more polar compounds (CLogP < 4).

[0134] Pharmacokinetic study of NVL2 inhibitor. For pharmacokinetic evaluation, the exposure levels after intravenous (3 mg / kg or 5 mg / kg), intraperitoneal (10 mg / kg), and oral (20 mg / kg) administrations of the analogs are measured. Drug levels in plasma and liver are measured at eight time points (3 mice per time point) (LC-MS / MS). Total exposure (AUC) and half-life in plasma or tissues are calculated using the non-compartmental analysis tool of WinNonlin. Oral bioavailability is calculated as AUCoral / AUCiv×Doseiv / Doseoral (with the desired criterion of F>30%). For the most promising compounds, the dose is escalated up to the maximum of three dose levels to determine whether an increase in exposure occurs with an increase in dose. The initial PK is performed in female CD1 mice, but dose escalation is evaluated in both females and males.

[0135] For in vivo studies, orally available compounds are preferred, but intraperitoneal (ip) delivery or intravenous (iv) delivery is also considered acceptable as proof-of-concept studies. Select compounds with a terminal-phase half-life exceeding 2 hours and u where [Cmax] 90 exceeds the IC (cytotoxicity in HCT116).

[0136] Tolerance, pharmacodynamics, and efficacy of NVL2 inhibitor in vivo NVL2 ATPase is required for 60S ribosome biosynthesis. Preliminary data, including cryo-EM structures, demonstrate that dibenzothiazepinone and dibenzazepinone directly bind to NVL2, thereby leading to a decrease in 60S and 80S ribosomes, upregulation of p53, and cell death. The cytotoxic effects of dibenzothiazepinone and dibenzazepinone are consistent with the hypothesis that they selectively target cancers that depend on increased ribosome biosynthesis. Oxaliplatin, an effective treatment for colorectal cancer, inhibits ribosome biosynthesis through an unknown mechanism. This suggests that dibenzothiazepinone and dibenzazepinone may have efficacy against colorectal cancer. This hypothesis will be tested by systematically evaluating the antitumor activity of optimized dibenzothiazepinone and dibenzazepinone analogs in preclinical models of colorectal cancer. Furthermore, we will evaluate whether these effects are mediated by inhibition of ribosome biosynthesis and upregulation of p53, and determine whether on-target toxicity exists in healthy, tumor-free tissues due to NVL2 inhibition. We will define the tolerability, pharmacodynamic response, and monotherapy efficacy of bioavailable lead NVL2 inhibitors in wild-type and compound-resistant colorectal cancer xenografts.

[0137] To determine the tolerability of dibenzothiazepinone or dibenzazepinone treatment in mice, and whether the toxicity is caused by association with NVL2. To test the tolerability of long-term, once-daily oral or intravenous treatment (administration route according to PK parameters) using multiple doses of dibenzothiazepinone or dibenzazepinone analogs. Three doses will be selected for evaluation in the tolerability study based on specific PK data and solubility characteristics of each analogue. C57Bl / 6 mice will be randomly assigned to four treatment cohorts for each analogue (n=5 males and 5 females per arm: 1×vehicle, 1×low-dose benzothiazepine, 1×intermediate-dose benzothiazepine, 1×high-dose benzothiazepine). Vehicle and drug treatment will be administered once daily for 14 consecutive days via oral force-feeding (or tail vein injection). The primary endpoints of this study will be body weight change and hematological, nephrotoxic, and hepatotoxicity. The secondary endpoint is the absolute concentration of benzothiazepines in plasma. Exploratory endpoints are other standard parameters measured by complete blood cell count (CBC) and serological chemistry. At the end of the 14-day treatment period, mice are anesthetized, blood samples are collected by cardiac puncture, and the animals are euthanized. Blood samples are evaluated for CBC and serological chemistry.

[0138] Body weight changes provide a baseline for measuring overall toxicity. A toxicity threshold for body weight change was selected as a decrease of 20% or more compared to vehicles-treated mice. Mice reaching this threshold were humanely euthanized. Hematological toxicity was assessed using CBC. Drug-induced thrombocytopenia or anemia was detected using low platelet counts (<772 kJ / μL) or hemoglobin levels (<13 g / dL). Renal and hepatotoxicity were assessed using serological data. Elevated creatinine levels (<1.5 mg / dL) serve as a marker of renal impairment. Elevated alanine aminotransferase (ALT) levels (<346.5 U / L) or elevated aspartate aminotransferase (AST) levels (<690 U / L) indicate liver damage. Thresholds for toxic plasma and serum biomarkers were derived by applying the grade 1 adverse event threshold (Common Terminology Criteria for Adverse Events Version 5.0, published by the NCI) to the 95% confidence interval limits of these biomarkers in naive mice. For each benzothiazepine analog, the MTD was determined as the highest dose that could be administered daily for 14 consecutive days in the cohort without the mean level of toxic biomarkers exceeding the threshold defined above. Bioavailability was confirmed by satellite PK measurements of compound levels in plasma.

[0139] To investigate off-target toxicity relative to on-target toxicity, germline compound-resistant NVL2 R403W We created a knock-in mouse with the mutation. Using C57Bl / 6 as a background, we created a heterozygous knock-in mouse using CRISPR / Cas9, and then mated it to make it homozygous. Next, we used a wild-type mouse and NVL2 R403WMice are treated with a vehicle control or three different doses of dibenzothiazepinone analog or dibenzazepinone analog (n=5 mice / group / genotype). Mice are age-matched and sex-matched (one sex / group unless a difference in toxicity is observed between male and female mice), and analyzed using the same endpoints as above. Doses are selected based on the determination of the MTD, including at least one dose below the MTD and one dose above the MTD. Toxicity in wild-type mice is NVL2. R403W In analogues with high levels of similarity compared to mice, the on-target effect is suggested to be caused by the association of dibenzothiazepinone analog or dibenzazepinone analog with NVL2. To confirm this, wild-type mice and NVL2 R403W In mutant mice, we compare the levels of ribosome biosynthesis and p53 induction in susceptible tissues or cell types. For analogues exhibiting toxicity in germline NVL mutant mice, we conclude that these effects are caused by off-target effects. In cases of on-target mediated toxicity, we define whether there is an available therapeutic range that can maintain antitumor efficacy while minimizing side effects. In cases of off-target effects, we determine the mechanism causing the problem and attempt to identify analogues with reduced off-target toxicity by performing appropriate assays in our medicinal chemistry pipeline.

[0140] The pharmacodynamic effects of dibenzothiazepinone analogs and dibenzazepinone analogs were evaluated, and candidate biomarkers for in vivo target association were identified. Our in vitro data demonstrate that dibenzothiazepinone and dibenzazepinone kill cancer cells by directly inhibiting NVL2. Furthermore, it was demonstrated that NVL2 inhibition using dibenzothiazepinone or dibenzazepinone impairs the biosynthesis of the 60S ribosomal subunit, thereby leading to upregulation of p53. Isogenic dibenzothiazepinone-resistant NVL2 R403WIn similar experiments using knock-in clones, treatment with NVL2-targeting dibenzothiazepinone or dibenzazepinone did not inhibit ribosome biosynthesis, p53 upregulation, or antiproliferative activity. Therefore, p53 upregulation is evaluated as an evaluable PD marker for on-target activity. Furthermore, xenografts are assessed for reduced ribosome biosynthesis and activation of downstream p53 molecules, such as p21.

[0141] To test whether treatment with a dibenzothiazepinone analog or dibenzazepinone analog induces p53 and blocks ribosome biosynthesis in vivo, 5 × 10¹⁶ samples were subcutaneously administered to ICR SCID mice. 6 Individual wild-type HCT116 colorectal cancer cells or NVL2 R403W HCT116 colorectal cancer cells were transplanted. To eliminate potential artifacts that may occur within a single clone with off-target mutations, NVL2 R403W Xenografts are formed from a population of targeted HCT116 cells using knock-in mutation guidance. The tumor is approximately 110 mm. 3 Once the target is reached, mice are randomly assigned to either a vehicle-treated group (arms) or a dibenzothiazepinone or dibenzazepinone-treated group (arm) (n=8 mice per arm; 16 mice / genotype in total). The NVL inhibitor or vehicle control is administered once daily for 3 days via oral force-feeding, intraperitoneal injection, or tail vein injection. On day 3, blood samples are collected, mice are euthanized, and livers and xenografts are collected for assessment of PK (in blood, liver, and tumor) and PD markers (in tumor). To identify candidate biomarkers, tumor tissue collected from control mice or compound-treated mice is compared for p53 by quantitative Western blot analysis and for downstream p21 induction by qPCR.

[0142] To determine the efficacy of dibenzothiazepinone and dibenzazepinone in a xenograft model of colorectal cancer and to validate candidate biomarkers, we will evaluate tolerability and disease progression (PD) in wild-type and NVL2 models. R403W The in vivo antitumor activity of analogs will be assessed using an HCT116 xenograft model. (Wild-type HCT116 cells and NVL) R403W HCT116 cells are transplanted subcutaneously, and treatment is initiated. NVL inhibitor analogs are administered once daily via oral force-feeding, intraperitoneal injection, or intravenously via tail vein injection (frequency and route of administration are determined based on PK). Treatment is continued until the mice exhibit symptoms of tumor burden requiring euthanasia or 50 days after randomization, whichever comes first. Remaining tumor tissue is collected for PD analysis. The primary endpoint is overall survival. Kaplan-Meier curves are constructed for each benzothiazepine analog for each xenograft model. The difference in survival between the drug-treated cohort and the vehicle-treated cohort is statistically assessed using the log-rank test. In addition, tumor volume is measured every 3 days, and tumor growth is graphed over time. This serves as a complementary endpoint.

[0143] Next, wild-type HCT116 xenografts are established, and dose-response efficacy studies are performed by administering NVL inhibitor analogs as described above. The highest dose is designated as the MTD, and two additional lower doses are selected by referring to PK data (n=8 mice per arm × 3 doses and vehicle control; n=32 mice in total). Tumor growth and survival over time are quantified as described, and remaining tumor tissue is collected for PD analysis. The lowest dose with statistically equivalent efficacy to that achieved using the MTD is determined.

[0144] Finally, p53 and p21 levels are reassessed in tumor tissue treated for 3 days with the lowest effective dose in a separate PD cohort (n=5 / arm; vehicle control and one dose, 10 mice in total). For example, the difference between p53 and p21 levels is quantified to determine the magnitude of the biomarker change induced by the therapeutic dose of benzothiazepine.

[0145] The therapeutic range for each dibenzothiazepinone analog or dibenzazepinone analog is defined by identifying the dose that is well-tolerated and induces a robust tumor PD response and efficacy in a colorectal xenograft model. p53 induction observed in benzothiazepine-treated tumors is NVL. R403W The p53 induction level is reduced in xenografts formed from cancer cells, thereby confirming the mechanism of action in vivo. The level of p53 induction is positively correlated in a dose-dependent manner with the degree of antitumor efficacy of dibenzothiazepinone or dibenzazepinone.

[0146] Example: Optimized dibenzothiazepinone and dibenzazepinone chemicals inhibit NVL-mediated ribosome assembly and induce p53-dependent apoptosis in cancer cell xenografts. In these examples, human NVL is identified as a chemical toxin target named MM017. The cryo-EM structure of NVL bound to MM017 reveals the binding site within the hexameric assembly. Mutations in NVL that cause resistance to MM017 are concentrated at the binding site, resulting in reduced compound binding. The NVL-MM017 interaction specifically inhibits the maturation of the 60S ribosomal subunit, leading to an abnormal polysome profile and accumulation of newly synthesized precursor 60S intermediates in the nucleolus. NVL inhibition induces p53-mediated apoptosis without any evidence of DNA damage. Bioavailable analogues of MM017 reduce tumor growth in vivo without apparent toxicity.

[0147] Mutations in NVL confer resistance to the orphan cytotoxic MM017. The inventors recently described an isogeneic forward genetic system for rapidly identifying mutations that confer resistance to compounds with antiproliferative activity (32). This system uses a modified colorectal cancer HCT116 cell line (iHCT116) in which the addition of indoleacetic acid (IAA) initiates ubiquitin-mediated degradation of the DNA mismatch repair protein MLH1, thereby resulting in a mechanism that temporarily increases the mutation rate. This strategy was applied to MM017, a dibenzothiazepinone identified in a high-throughput small molecule screening for HCT116 cytotoxicity. MM017 dose-dependently increased the growth of iHCT116 cells at 0.46 μM IC2. 50 Inhibition was achieved by [method / action]. Pre-cultured barcoded iHCT116 cells with or without IAA (muta-on) were exposed to escalating lethal doses of MM017. The total number of viable clones was dramatically higher under muta-on conditions and increased in a dose-dependent manner, thus suggesting a genetic basis for resistance.

[0148] We identified 59 clones, each possessing a unique barcode sequence indicating that it originated from a specific progenitor event. The IC of MM017 applied to these clones. 50The mutations were 2.45 to 32.89 times greater than those in the parental cell line, providing evidence of resistance. The broad range of resistance suggested that these clones possessed a diverse set of mutations, so whole-exome sequencing was performed on 15 clones spanning the entire range of resistance. Based on the hypothesis that resistance-related genes mutate in multiple clones, whole-exome sequencing identified variants acquired during IAA-induced mutagenesis. At least three of the 15 selected clones contained acquired variants in two genes: TERT, mutated in three of the 15 clones, and NVL, mutated in all 15 clones. These results suggest that the NVL mutation is associated with MM017 resistance. Therefore, PCR-based sequencing of the NVL exon, which was found to mutate in the exome sequencing data, was performed on the remaining clones. In total, 57 out of 59 unique clones possessed the NVL mutation. The majority of mutations were concentrated in the D1 AAA+ ATPase domain and frequently affected the same codon. To test whether these mutations were sufficient for MM017 resistance, CRISPR-Cas9 was used to identify the two most resistant mutations (NVL). P307T NVL R403W ) and mutations with intermediate resistance (NVL) H304R ) was knocked in. By transfecting cells with sgRNAs targeting these NVL residues in addition to the repair template encoding the mutation, the rate of resistance was increased compared to mock treatment. After expansion, cells were knocked in the intended allele (NVL P307T NVL R403W or NVL H304R ) has NVL WT Compared to MM017, it has higher resistance (IC 50 :NVL WT =0.38μM;NVL R403W >50μM;NVL P307T >50μM;NVL H304R(=2.4 μM), and we confirmed that susceptibility to the unrelated toxin, paclitaxel, was equal. Taken together, these findings demonstrate that the NVL mutation is specific and sufficient for MM017 resistance.

[0149] MM017 connects directly to NVL. To assess whether MM017 directly binds to NVL in cells, an MM017 crosslinking agent (probe compound (2), Table A) containing an alkyne that is UV-activatable and can be coupled with biotin for affinity purification was used. Definitively, probe compound 2 inhibited the proliferation of HCT116 cells with the same potency as MM017 (IC). 50 =0.47μM), NVL P307T The cells were relatively resistant to both compounds, suggesting that MM017 and the MM017 probe function similarly. Proteins bound to the MM017 probe were purified from cells treated with various doses of the MM017 probe, either in the presence or absence of UV light. NVL was detected only under conditions containing both the MM017 probe and UV light, indicating that the MM017 probe interacts with NVL non-covalently in the absence of UV light. To assess whether the observed binding of the MM017 probe to NVL is related to its cellular activity, IC50 was used. 50 A probe substitution assay was performed using three chemically related derivatives of MM017 (compounds 3-5, Table A) with concentrations of 0.36 μM (3), 2.1 μM (4), and 13 μM (5). It should be noted that this experiment was performed using a cell line in which the FLAG epitope was knocked into the C-terminus of the NVL. When co-incubated with gradually increasing doses of compound 3, the MM017 probe was effectively substituted compared to compounds 4 and 5, establishing a correlation between NVL binding and cell activity. Next, NVL WT The NVL level of the MM017 probe and UV treatment of the cell line was measured using NVL. R403W cell lines, NVL P307T Cell lines and NVL H304R Compared with that of the cell line. NVL WTIn comparison, mutant cell lines showed a substantially higher amount of MM017 probe required for cross-linking with NVL, thus demonstrating that these mutations affect compound binding. Taken together, these findings establish a correlation between compound binding and cellular activity that is consistent with the hypothesis that NVL is a direct target of MM017.

[0150] [Table 1]

[0151] Cryo-EM Reconstruction of NVL / MM017 Complex To understand the molecular basis of the MM017 / NVL interaction, we attempted to resolve the cryo-EM structure of NVL complexed with MM017. Expression and purification of the D1 / D2 skeleton of wild-type NVL resulted in low yield and protein instability. Cryo-EM analysis showed that wild-type NVL D1 / D2 assembles into a long filamentous spiral rather than the expected hexamer. A double mutation in the Walker B motif of the Chlorachidobacterium thermophilum NVL homolog Rix7 stabilizes the hexameric configuration (33), and mutant human NVL E366Q / E683Q (NVL dEQ Recombinant expression and purification of ) similarly yielded a stable and monodisperse hexamer, and its stoichiometry, determined by mass side spectrometry, showed no effect from the addition of MM017.

[0152] NVL dEQSingle-particle cryo-EM reconstruction of +MM017 yielded a map with an overall resolution of 2.9 Å. Similar to the reconstructions of Chlorachidobacterium thermopyrum Rix7, Homo sapiens (H. sapiens) P97, and Saccharomyces cerevisiae Drg1, the NVL hexamer forms a stepwise configuration, with pore loops from five D1 and D2 AAA+ modules associating with an extended peptide in the central channel (2, 27, 34, 35). By convention, the uppermost stepwise subunit is denoted as A and the lowermost subunit as E. As previously observed, the sixth subunit (F) is in a more dynamic state, transitioning between positions E and A, and therefore its resolution in the cryo-EM map is insufficient. Based on the similarity with the analysis performed using RIX7 (34) and the bulky nature of the side chain density within the peptide, we assumed that the substrate mimetic to which NVL associates represents one of the N-terminal 14×HIS tags in our construct, and therefore modeled the substrate mimetic as a polyhistidine chain, although our tag also includes non-HIS linker residues.

[0153] Initial analysis of the cryo-EM map revealed an additional density corresponding to MM017 at a single location within subunit E. MM017 is wedge-fitted into a predominantly hydrophobic pocket within the core domain of the D1 module. This ligand pocket is surrounded on one side by the central D1 β-sheet (chains 5, 1, and 4) and on the other side by the N-terminal α0 helix and a loop element anterior to chain 1. This helix also associates with the AAA+ lid domain of subunit D, which forms the more peripheral boundary of the MM017 binding pocket. For NVL subunits A-D, the α0 helix is ​​densely packed into the central β-sheet of the domain, preventing MM017 binding, and therefore no ligand-binding sites exist in equivalent regions. To determine whether MM017 also associates with the poorly resolving, mobile F subunit, skip alignment classification was performed by shielding the area around the D1 module of subunit F. Reconstruction of this obtained particle subset revealed a density of MM017 in subunit F at a position similar to that of subunit E. The majority of repressor mutations are concentrated around the ligand-binding pocket, which is consistent with these mutations altering the structure or conformation of the compound docking site. MM017 is an elongated molecule with a distinct 105° twist introduced by a central dibenzothiazepinone skeleton. The furan ring of MM017 is exposed to a central solvent channel separating the D1 and D2 ring stacks, and is in hydrophobic contact with residues M280 and V301, and also forms a hydrogen bond with R428. Adjacent to the furan portion, a planar amide linker forms a hydrogen bond with the main chain carbonyl of amino acid P298. The dibenzothiazepinone ring structure of MM017 is a hydrophobic environment created by residues M280, M284, P297, L324, R403, and L405. Among these, M284, P297, R403, and L405 are located immediately adjacent to mutated or mutated residues in our inhibitory factor dataset. Furthermore, the central carbonyl group is within hydrogen bonding distance of the epsilon-amino group of R403.Finally, the methoxyethyl tail protrudes toward the loop connecting the helix α0 and β1 chains.

[0154] To gain further insight into how substrate binding may affect the inter-subunit dynamics of NVL, ApoNVL dEQ Single-particle cryo-EM reconstructions were obtained at a resolution of 2.6 Å. In the apo structure, the hexamer assembly retains a stepwise conformation, but the ligand-binding pocket of subunit E is closed and in the same configuration as its equivalent position within subunits A-D. Compared to the structure associated with MM017 in NVL, in the apo structure, the D1 domain of subunit E is shifted closer to the adjacent AAA+ module in subunit D, closing the nucleotide-binding site consisting of only two parts at the D / E interface. This suggests that the arginine finger motif of subunit E is closer to the bound ATP, and therefore compound binding allosterically affects the D / E interface within the D1 ring. Consistent with this, P307T, one of the most resistant NVL mutations, maps to the D / E nucleotide interface. The allosteric linkage observed between the ligand-binding pocket and the nucleotide-binding site at the D / E interface suggests that functional assembly of the D1 ring is hindered in the presence of MM017.

[0155] NVL bound to MM017 specifically blocks 60S biosynthesis in the nucleolus. To test the effects of NVL depletion, the C-terminal FLAG-epitope auxin-inducible degron (AID) tag was modified into NVL in cells also expressing the plant E3 ligase TIR1. Treatment with 5-phenyl-indole-3-acetic acid (Ph-IAA) induced dose-dependent depletion of NVL-AID, but untagged NVL was not depleted. AID / AID Regarding cells, their viability decreased in a dose-dependent manner. NVL + / + Cells or NVL AID / +Since cell viability was not affected by Ph-IAA, it is indicated that NVL is essential for HCT116 cell proliferation but is not haploinsufficient.

[0156] Next, the impact of NVL disruption on the distribution of ribosome species was assessed using polysome profiling. AID / AID The addition of Ph-IAA, which induces NVL degradation in cells, resulted in a time-dependent decrease in free 60S and 80S levels (based on absorbance at 260 nm), and simultaneously an increase in 40S levels. Ph-IAA addition also induced half-mer polysomes, which represent a 40S subunit bound to the mRNA start site but not associated, and are characteristic of a 60S biosynthesis defect (36). MM017 is used in NVL WT By adding it to cells, NVL treated with Ph-IAA AID / AID The polysome profile of the cell was phenotypically replicated, but NVL P307T No changes were induced in the polysome profile of the cells. The polysome profile after NVL disruption in HCT116 cells appeared to be similar to the profile reported in yeast with the RIX7 mutation (37) or in human cells overexpressing catalytic mutants of NVL (38).

[0157] The decrease in free 60S observed using polysome profiling may result from reduced 60S synthesis, accelerated 60S degradation, or a combination of both. To distinguish between existing and newly synthesized 60S, HCT116 cells were modified to express a C-terminal SNAP-tag at eL36, a ribosomal protein incorporated into the 60S subunit before NVL binding (39), or to express a control C-terminal SNAP-tag at eS17, a component of the ribosomal small subunit, to monitor 40S biosynthesis (40). First, existing eL36 or eS17 in the cells were labeled with Oregon green benzylguanine (green). Then, the cells were treated with either a vehicle or MM017 for 24 hours, after which 647-SiR benzylguanine was added to label the pool of proteins synthesized over 24 hours, and each polysome profile fraction was evaluated for either existing or new proteins. Existing eL36-SNAP is present in the 60S, 80S, and polysome fractions, demonstrating that SNAP-tagged proteins can be assembled into translating ribosomes. MM017 treatment did not affect the levels or fractionation patterns of existing eL36-SNAP. In contrast, newly synthesized eL36-SNAP decreased in the 60S, 80S, and polysome fractions after MM017 treatment, which is consistent with the hypothesis that MM017 blocks 60S biosynthesis. Existing and newly synthesized eS17-SNAP were detected in the 40S, 80S, and polysome fractions after treatment with either the vehicle or MM017, demonstrating that MM017 does not affect the 40S subunit.

[0158] Next, we investigated the effect of MM017 on the intracellular localization of eL36-SNAP(60S) or eS17-SNAP(40S). As expected for mature ribosomes, the existing eL36-SNAP was almost entirely in the cytoplasm, and treatment with MM017 did not affect its localization. In vehicles-treated cells, the newly synthesized eL36-SNAP was present in both the nucleolus and cytoplasm, reflecting its presence in precursor 60S and mature ribosomes. In contrast, in MM017-treated cells, the novel eL36-SNAP was localized almost exclusively to punctate accumulation sites (foci) within the nucleus. These punctate accumulation sites co-localized with the nucleolar protein fibrillarin, thus suggesting that the arrested eL36-SNAP intermediate resides in the nucleolus. To test whether the observed blockade of 60S biosynthesis is due to binding with NVL, eL36-SNAP and NVL were used. R403W Cells were modified to express MM017. When these cells were treated with MM017, the newly synthesized eL36-SNAP localized in the nucleolus and cytoplasm, in a pattern indistinguishable from that of the vehicle-treated group. These results demonstrate that the arrest of 60S biosynthesis is due to NVL inhibition by MM017. Finally, we investigated whether MM017 affected the degradation or biosynthesis of 40S ribosomes by performing a similar experiment using eS17-SNAP cells. MM017 did not affect the localization of either existing or newly synthesized eS17-SNAP. Taken together, these results demonstrate that MM017 directly inhibits NVL and specifically blocks 60S assembly in the nucleolus.

[0159] Inhibition of NVL leads to p53-dependent apoptosis. To better understand how MM017-mediated inhibition of NVL leads to cell death, a genome-wide pooled CRISPR / Cas9 knockout screening was performed in HCT116 cells using a library of guide RNAs targeting 19,114 genes. Cells were intermittently pulsed with either a vehicle or MM017 for 21 days, at which point cells treated with MM017 had undergone 9.79 fewer population doublings. To infer the relative effect of each gene on compound sensitivity, relative levels of sgRNA sequences were determined using large-scale parallel sequencing of PCR products amplified from genomic DNA. The tumor suppressor TP53 (commonly referred to as p53) and one of its effector genes, CDKN1A (also known as p21), were the most enriched genes in this screening, and therefore, a reduction in p53, and to a lower degree a reduction in p21, indicates that cells were protected from MM017. To determine whether p53 and p21 are required for MM017's antiproliferative activity, growth competition experiments were conducted between ZsGreen-expressing cells with either p53 or p21 knockout (KO) and mCherry-expressing control cells. In the untreated group, the ratio of green to red cells did not change over time. In contrast, MM017 resulted in a dose-dependent enrichment of either p53 or p21 KO cells. Since no competitive advantage was observed in the presence of paclitaxel, the requirement for these two proteins was specific to MM017. Taken together, these results indicate that MM017 reduces HCT116 cell proliferation in a p53-dependent and p21-dependent manner.

[0160] To identify genetic predictors of MM017 susceptibility across different cancer types, PRISM screening was performed across 902 cancer cell lines with known genotypes (31). Correlation analysis revealed that TP53 mutations were most significantly associated with resistance to MM017. These findings are consistent with isogeneic CRISPR screening and indicate that p53 is a critical effector of MM017 in cancer cells originating from multiple lineages and exhibiting different genotypes.

[0161] Since p53 and p21 are essential for MM017 activity, it is hypothesized that these proteins can be upregulated by NVL inhibition. An increase in p53 occurred 6 hours after MM017 treatment, followed immediately by an increase in p21, which is consistent with the role of p21 as a p53 target protein. Importantly, NVL P307T In cells, the abundance of any of the proteins did not change, but NVL AID / AID Since degradation of NVL in cells resulted in a similar increase in p53 levels, the observed increases in p53 and p21 expression are a consequence of NVL inhibition.

[0162] Upregulation of p53 and its effector p21 can lead to cessation of cell growth or induction of apoptosis-induced cell death. To distinguish between these two possibilities, we investigated cell death due to decreased membrane permeability 5 days after treatment of HCT116 control cells and p53 KO cells with MM017, and found a substantially reduced number of dead cells in p53 KO cells. Paclitaxel, an unrelated toxin that stabilizes tubulin polymerization, induced cell death independently of p53, so the protection from MM017-induced cell death due to p53 loss was specific to MM017. Next, we addressed whether cell death was mediated by the apoptotic pathway by assaying cleaved caspase-3, a true marker of apoptosis. Staurosporine, an unrelated compound known to induce apoptosis, induced robust caspase activation in both control cells and p53 KO cells. In contrast, the induction of cleavage caspase-3 by MM017 in control cells was substantially reduced in p53 KO cells. Taken together, these findings demonstrate that inhibition of NVL by MM017 induces p53-dependent apoptosis in HCT116 cells.

[0163] Upregulation of p53 is consistent with the ribosome assembly stress response induced by 5S RNP-mediated inhibition of MDM2 (5). Other ribosome biosynthesis inhibitors, such as oxaliplatin and CX-5461, are similarly thought to activate the same ribosome assembly stress response, but these compounds are also known to induce DNA damage (15, 20). A biochemical marker of activation of the DNA damage response is phosphorylation of serine 15 of p53, which results in an increase in the p53 protein (41). Therefore, MM017, oxaliplatin, and CX-5461 were compared for their effects on both p53 upregulation and p53 serine 15 phosphorylation. All three compounds resulted in a dose-dependent increase in p53 levels, except for phosphorylated p53, where a dose-dependent increase was observed only with oxaliplatin treatment and CX-5461 treatment. Even at a high concentration of 10 μM, no evidence of serine 15 phosphorylation of p53 was observed after MM017 treatment. These findings suggest that the upregulation of p53 by oxaliplatin and CX-5461 is induced, at least in part, by the DNA damage response. Since no evidence of serine 15 p53 phosphorylation was observed after treatment with MM017, it can be concluded that the increased p53 stabilization observed after MM017 treatment is unrelated to the DNA damage response and is entirely initiated by the disruption of the 60S ribosome subunit assembly.

[0164] Biologically available analogues reduce tumor growth in mouse xenografts without apparent toxicity. Next, we investigated whether NVL inhibitors could inhibit the growth of cell line-derived xenograft tumors in mice, and whether systemic inhibition of NVL would result in specific toxicity. Through medicinal chemistry studies, we found that HCT116 proliferation was inhibited by 79 nM IC50. 50 We identified analog MM927 (Table A), which inhibits the compound MM017 and exhibits five times the potency of the parent compound MM017. NVL P307T Cells with the mutation are relatively resistant to MM927 (IC 50(=1.67 μM), therefore, it is suggested that MM927 functions similarly to MM017. To interpret the toxicity of MM927 in mice, we first investigated whether MM927 also inhibits mouse NVL. To test the efficacy of MM927 against mouse NVL within the same cell type, we used either human NVL or mouse NVL. AID / AID Ectopic expression was induced in cells. Treatment with Ph-IAA degrades the endogenous protein, and therefore the cells become dependent only on the ectopically expressed NVL. In mock-infected cells, NVL was expressed by adding Ph-IAA. AID / AID As expected, degradation of NVL reduced cell viability, and ectopic expression of mouse NVL or human NVL completely restored viability. Under these conditions, MM927 produced a 0.051 μM IC50 in cells ectopically expressing human NVL, similar to the potency of endogenous NVL. 50 The inhibition suggested that NVL overexpression does not substantially alter sensitivity. MM927 also inhibited mouse NVL at 0.207 μM IC50. 50 The fact that it inhibited NVL in normal mouse tissue suggests that it is possible to inhibit NVL at sufficient plasma concentrations.

[0165] In pharmacokinetic studies to evaluate MM927 exposure, intraperitoneal (IP) injection of 10 mg / kg of MM927 resulted in a peak plasma level (Cmax) of 2510 ng / mL (5.15 μM) with an elimination half-life of 101.33 minutes. Plasma exposure was dose-dependent up to 35 mg / kg (IP injection), reaching a peak concentration of 17.86 μM. These levels corresponded to the antiproliferative IC50 of MM927 in cells expressing either human or mouse NVL. 99 It exceeds [value]. In subsequent pharmacodynamic (PD) studies, we investigated whether on-target NVL inhibition could be assessed by subsequent p53 and / or p21 induction in tumor xenografts in mice treated with MM927. HCT116 NVL WT Cells and NVL R403WCells were implanted subcutaneously in either flank of a mouse, and p53 and p21 levels in either tumor were evaluated at various time points after intravenous administration of 35 mg / kg of MM927. p53 protein levels increased 3 hours after injection, followed immediately by an increase in p21. Both p53 and p21 remained elevated at 12 hours and decreased to basal levels by 24 hours. This is consistent with the pharmacokinetic properties of MM927. Importantly, the levels of p53 and p21 induction in tumor xenografts were comparable to those obtained from 24 hours of continuous MM017 treatment in cultured cells. Crucially, NVL implanted in the contralateral flank of the same mouse... R403W Regarding tumors, no changes in p53 and p21 were observed. Therefore, the changes observed in NVL wild-type tumors are shown to be a result of NVL inhibition, and p53 and p21 are established as evaluable PD markers.

[0166] Since the kinetics of MM927-mediated NVL inhibition in xenograft tumors have been established, HCT116 NVL wild-type cells or NVL R403W Mice with tumors originating from any of the cells were administered 35 mg / kg of MM927 twice daily as an intracellular therapy (IP) for 21 days. MM927 treatment resulted in NVL WT The rate of tumor growth was significantly reduced, but NVL R403W No significant effect on tumors was observed. Of the 10 samples analyzed, a single NVL was found. WT The tumor growth initially appeared to respond to treatment, but later progressed, suggesting the acquisition of resistance mechanisms. Nevertheless, endpoint tumor measurements performed at either the end of treatment or euthanasia indicated that MM927 was NVL (Nutrient-Vital Lactation). WT It significantly reduced tumor burden, but NVL R403WIt was demonstrated that MM927 had no effect on tumors. MM927 was detected at micromolar levels in plasma and tumors 3 hours after the final treatment dose in all treated mice, thus demonstrating sufficient drug exposure throughout the course of treatment. Importantly, mice treated with MM927 showed no signs of overt toxicity. Furthermore, there were no significant differences between the vehicle-treated and drug-treated groups in body weight, red blood cells, white blood cells, hemoglobin, platelets, levels of the liver enzyme alanine transaminase, and renal clearance of blood urea nitrogen. Taken together, we concluded that MM927, a highly potent and bioavailable analog, reduces tumor growth in mouse xenografts by inhibiting NVL without toxicity.

[0167] Consideration Modern small molecule anticancer drugs are ideally optimized to specifically bind to defined protein targets to maximize on-target efficacy and minimize off-target toxicity. In contrast, older anticancer therapies, which still constitute the majority of small molecule anticancer treatments, often affect multiple protein targets, resulting in polypharmacology and target ambiguity (42). For example, oxaliplatin, the first-line treatment for colorectal cancer, like its related analogs cisplatin and carboplatin, directly targets DNA, resulting in DNA adducts that induce p53 activation in the DNA damage response (15). Oxaliplatin also targets ribosome biosynthesis, causing nucleolar stress, and since neither carboplatin nor cisplatin inhibit ribosome biosynthesis, this activity is mediated through targets other than DNA (16-18, 43). Recent reports suggest that blocking ribosome production is an on-target activity of oxaliplatin, and that patients receiving oxaliplatin may have dose-limiting toxicity due to off-target DNA damage activity (19). If so, small molecules that selectively target ribosome biosynthesis without causing DNA damage may have improved efficacy and reduced toxicity, resulting in a broader therapeutic index. Here, we have discovered that MM017 and its bioavailable derivative MM927 inhibit NVL, thereby blocking ribosome assembly and resulting in p53-dependent apoptosis. Importantly, we have found that MM017 does not induce a DNA damage response, and therefore these molecules now provide tools for specifically targeting ribosome biosynthesis without confounding DNA damage.

[0168] NVL is a member of the type 2 AAA ATPase family of enzymes, which contain two tandem AAA ATPase domains (D1 and D2) and transport peptide substrates through a central channel in a stacked double hexameric ring structure (2, 34, 40). Substrate capture induces the formation of a step-like assembly, followed by sequential ATP binding and hydrolysis events at the AAA+ subunit interfaces of both the D1 and D2 domains (27, 44). Nucleotide hydrolysis at the interface between subunit D and subunit E is an important event in the periodic transport mechanism of this enzyme family, as it frees the "bottom" subunit of the step-like structure, allowing it to move to the top position (45). In a cryo-EM structure with an inactive NVL as a catalyst, we found that MM017 binds to the D1 domain of the substrate-bound NVL at two sites: the D / E interface and the E / F interface. This structure suggests that MM017 blocks substrate movement through the central channel not by inhibiting substrate binding, but by either inhibiting ATP hydrolysis or preventing subunit repositioning within the stepwise arrangement. This mechanism is distinct from that of NMS-873 and UPCDC30245, non-competitive p97 inhibitors that bind in symmetric conformation to all six subunits that promote substrate release (40, 46).

[0169] The discovery of highly potent, selective, and bioavailable NVL inhibitors demonstrates that NVL is a ribosomal biosynthesis enzyme that can be targeted for therapeutic use with small molecules. Developing NVL inhibitors as anticancer drugs requires identifying the tumor and genotypes most likely to respond. Myc is a transcription factor that upregulates rDNA transcription and ribosomal protein expression, which together promote ribosomal biosynthesis and drive cancer (47). Therefore, cancers dependent on Myc protein expression may be susceptible to NVL inhibition. Furthermore, in our study of antiproliferative activity against over 900 cancer cell lines, cell lines with p53 mutations were significantly more likely to be resistant to MM017. Consistent with these findings, genome-wide CRISPR screening in colorectal cancer cell lines identified p53 and its downstream effector p21 as the two most important genes for MM017-induced cell death. Finally, silencing p53 in this colorectal cancer cell line protected the cells from MM017-induced apoptosis. These findings suggest that cancers expressing wild-type p53 protein are more likely to respond to NVL inhibition. Although p53 is frequently mutated in cancer, the frequency of mutations varies among different cancer types, ranging from over 90% in non-small cell lung cancer and small cell lung cancer to less than 20% in leukemia, renal cell carcinoma, and bone cancer (www.cbioportal.com). Our studies also showed that loss of p53 is one possible mechanism of resistance, and therefore, a combination strategy of NVL inhibition with drugs acting via a secondary pathway may be effective.

[0170] Typical synthetic procedure for dibenzothiazepinone analogs

[0171] TIFF2026522300000010.tif24170 Step 1 - General procedure for the synthesis of intermediate ai: To a stirred suspension of each amine (1.0 equivalent) in dry DMF (30 mL / mmol), each carboxylic acid (1.2 equivalents), HATU (1.5 equivalents), and DIPEA (2.0 equivalents) were added. The mixture was stirred at room temperature for 12 hours, and then the reaction mixture was treated with H2O (60 mL / mmol). The organic layer was separated and dried over Na2SO4. The collected filtrate was evaporated under vacuum to obtain the crude disulfide intermediate, which was dissolved in MeOH (7 mL / mmol). The reaction mixture was cooled to 0 degrees Celsius, and then NaBH4 (2.0 equivalents) was slowly added. After stirring at room temperature for 30 minutes, MeOH was removed under reduced pressure, and the residue was diluted with 2N aqueous HCl to pH=4. After lyophilization, intermediate ai was obtained.

[0172] TIFF2026522300000011.tif23170 Step 2 - General procedure for the synthesis of intermediates a-ii: To a solution of compound ai (1.0 equivalent) in anhydrous DMF (5 mL / mmol), 1,2-difluoro-4-nitrobenzene or 3-bromo-2-chloro-5-nitropyridine (1.2 equivalents) and K2CO3 (3.0 equivalents) were added. The mixture was stirred at 75°C for 16 hours, and then the reaction mixture was partitioned between siRNA and H2O. The organic layer was dried over Na2SO4, filtered, concentrated, and purified by column chromatography using silica gel to obtain intermediates a-ii.

[0173] TIFF2026522300000012.tif22170 Step 3 - General procedure for the synthesis of intermediate a-iii: To a solution of a-ii (1.0 equivalent) in MeOH / H2O (4:1 mL) (10 mL / mmol), NH4Cl (18.0 equivalents) and Fe (5.0 equivalents) were added. After refluxing for 2 hours, the reaction mixture was filtered through Celite and washed with MeOH. The collected filtrate was evaporated under vacuum to obtain intermediate a-iii.

[0174] TIFF2026522300000013.tif25170 General procedure for the synthesis of step 4-dibenzothiazepinone analogs a-iv: To a stirred suspension of a-iii (1.0 equivalent) in dry DMF (30 mL / mmol), the respective carboxylic acids (1.2 equivalents), HATU (1.5 equivalents), and DIPEA (2.0 equivalents) were added. Alternatively, intermediate a-iii (1.0 equivalent) and the respective acid chlorides (1.2 equivalents) were dissolved in dry CH2Cl2 (30 mL / mmol). The mixture was stirred at room temperature for 12 hours, and then diluted with H2O. The organic layer was separated, dried over Na2SO4, and evaporated under vacuum to obtain crude intermediate a-iv, which was purified by flash chromatography.

[0175] TIFF2026522300000014.tif22170 Step 5a - Aromatic or Hetero-Aromatic R 3 General procedure for the synthesis of dibenzothiazepinone analogs a-iv having the group: Intermediate a-iii (1.0 equivalent) in toluene (20 mL / mmol), R 3 Cl or R 3 Solutions of Br (2.0 equivalents), Pd2(dba)3 (0.2 equivalents), DPEPhos (0.4 equivalents), and t-BuOK (2.0 equivalents) were stirred at 100°C under an Ar atmosphere. For some substrates, intermediates a-iii (1.0 equivalent) in dioxane (20 mL / mmol), R 3 Cl or R 3 A solution of Br (2.0 equivalents), Pd2(dba)3 (0.2 equivalents), DPEPhos (0.4 equivalents), and Cs2CO3 (2.0 equivalents) was stirred at 100°C under an Ar atmosphere. For some other substrates, intermediates a-iii (1.0 equivalent) in toluene (20 mL / mmol), R 3 Cl or R 3 A solution of Br (2.0 equivalents), Ruphos PdII G1 (0.1 equivalents), and t-BuONa (2.0 equivalents) was stirred at 100°C under an Ar atmosphere. After each reaction was completed as determined by TLC analysis, the mixture was filtered by Celite and the filtrate was concentrated under vacuum. The residue was purified by preparative TLC or HPLC to obtain aromatic or heteroaromatic R 3A dibenzothiazepinone analog av containing the group was obtained. Step 5b - Non-aromatic R 3 General procedure for the synthesis of dibenzothiazepinone analogs a-iv containing the group: To a solution of intermediate a-iii (1.0 equivalent) and the corresponding non-aromatic ketone (2.0 equivalents) in siRNA / TFA (5:1) (20 mL / mmol), NaBH3CN (2.0 equivalents) was slowly added. The resulting mixture was stirred at 25°C under an N2 atmosphere for 2 hours. The reaction mixture was quenched with water and extracted with siRNA. The organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by preparative HPLC to obtain the non-aromatic R 3 A dibenzothiazepinone analog av containing the group was obtained.

[0176] TIFF2026522300000015.tif22170 Process 6 or Step 6 - General procedure for the synthesis of urea-based dibenzothiazepinone analogs a-vi and a-vii: To a solution of a-iii (1.0 equivalent) in dry CH2Cl2 (15 mL / mmol), i-Pr2NEt (6.0 equivalents) and triphosgene (0.4 equivalents) were added at 0°C under an Ar atmosphere. After stirring for 3 hours, the corresponding amine R 3 NH2 or R 5 R 6 NH (2.0 equivalents) was added, and stirring was continued at 25°C for 6 hours. The reaction mixture was partitioned between CH2Cl2 and H2O, the organic layer was dried over anhydrous Na2SO4, filtered, concentrated, and purified by preparative TLC and HPLC to obtain urea-based dibenzothiazepinone analogs a-vi or a-vii.

[0177] TIFF2026522300000016.tif21170 General procedure for the synthesis of thiourea-based dibenzothiazepinone analogs a-viii and a-ix in step 7: The same procedure as in step 6 above was used, except that triphosgene was replaced with thiophosgene.

[0178] TIFF2026522300000017.tif23170 General procedure for the synthesis of 8-thioamide-based dibenzothiazepinone analog ax: Intermediate a-iii (1.0 equivalent), corresponding aldehyde R 3 CHO (1.5 equivalents), sulfur powder (3.0 equivalents), K2CO3 (2.0 equivalents), and water (4 mL / mmol) were placed in a tube sealed with a Teflon septum screw cap. The reaction mixture was stirred at 100°C for 24 hours. After the reaction was complete, the mixture was cooled to room temperature and extracted with ethyl acetate. The organic layer was dried over Na2SO4 and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography to obtain the corresponding thioamide-based dibenzothiazepinone analog ax.

[0179] Typical synthetic procedure for dibenzazepinone analogs

[0180] TIFF2026522300000018.tif24170 Step 1 - Synthesis of intermediate bi: A mixture of concentrated sulfuric acid (1.0 mL / mmol) and CH2Cl2 (0.4 mL / mmol) was cooled to 0°C, and then anthraquinone (1.0 equivalent) and sodium azide (1.2 equivalents, divided) were added. The reaction mixture was stirred overnight at room temperature, and then poured into ice water. The product was filtered off, washed with water until it was no longer acidic, and dried under vacuum to obtain intermediate bi as a white solid.

[0181] TIFF2026522300000019.tif22170 Step 2 - Synthesis of intermediate b-ii: Intermediate bi (1.0 equivalent) and concentrated H2SO4 (1.1 mL / mmol) were added to a round-bottom flask. The mixture was stirred until all the materials were dissolved, then cooled to 0°C, and treated with KNO3 (1.0 equivalent) in portions. The reaction mixture was heated to 25°C and stirred at that temperature for 1 hour. The mixture was basicized to pH 9 with 2N NaOH aqueous solution, thereby producing a precipitate. The solid was collected by filtration, washed with water, and dried to obtain intermediate b-ii as a yellow solid.

[0182] TIFF2026522300000020.tif22170 Step 3 - Synthesis of intermediate b-iii: A suspension of b-ii (1.0 equivalent) and Et3SiH (10 equivalents) in TFA (40 mL / mmol) was stirred at 25°C for 12 hours, and then the mixture was concentrated under vacuum to obtain the residue. The residue was purified by preparative HPLC to obtain intermediate b-iii as a white solid.

[0183] TIFF2026522300000021.tif28170 Step 4 - General procedure for the synthesis of intermediates b-iv: To a solution of b-iii (1.0 equivalent) in DMF (4.0 mL / mmol), NaOH (2.0 equivalents) and 1-bromo-2-butine or propargyl bromide or 1-bromo-4-fluoro-2-butine (1.5 equivalents) were added at room temperature. After stirring at 60°C for 6 hours, the reaction was quenched by adding 1N aqueous HCl. The organic layer was separated, and the aqueous layer was extracted with CH2Cl2. The combined organic layers were washed with brine, dried over Na2SO4, concentrated under vacuum, and purified by flash chromatography on silica gel to obtain intermediate b-iv.

[0184] TIFF2026522300000022.tif30170 Step 5 - General procedure for the synthesis of intermediate bv: To a solution of intermediate b-iv (1.0 equivalent) in MeOH / H2O (4:1; 10 mL / mmol), NH4Cl (18.0 equivalents) and Fe (5.0 equivalents) were added. After refluxing for 2 hours, the reaction mixture was filtered through Celite and washed with MeOH. The collected filtrate was concentrated under vacuum to obtain intermediate bv.

[0185] TIFF2026522300000023.tif27170 Step 6 - General procedure for the synthesis of intermediate b-vi: The synthesis of intermediate b-vi follows the same procedure as the synthesis of intermediate b-iv (step 4) described above.

[0186] TIFF2026522300000024.tif27170 Step 7 - General procedure for the synthesis of intermediate b-vii: The synthesis of intermediate b-vii follows the same procedure as the synthesis of intermediate bv (step 5) described above.

[0187] TIFF2026522300000025.tif27170 Step 8 - General procedure for the synthesis of intermediate b-viii: The synthesis of intermediate b-viii follows the same procedure as the synthesis of dibenzothiazepinone analogs a-iv described above.

[0188] TIFF2026522300000026.tif28170 Step 9 - General procedure for the synthesis of dibenzazepinone analog b-ix: MeMgBr (2.0 equivalents) was added at 0°C to a stirred suspension of b-viii (1.0 equivalent) in dry THF (8.0 mL / mmol). After stirring at 25°C for 6 hours, the reaction mixture was treated with aqueous NH4Cl solution and then extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by flash chromatography on silica gel to obtain dibenzazepinone analog b-ix.

[0189] TIFF2026522300000027.tif29170 Step 10 - General procedure for the synthesis of dibenzazepinone analog bx: A suspension of dibenzazepinone analog b-ix (1.0 equivalent) and Et3SiH (10 equivalents) in TFA (40 mL / mmol) was stirred at 25°C for 12 hours. The mixture was concentrated under vacuum, and the residue was purified by preparative HPLC to obtain dibenzazepinone analog bx.

[0190] TIFF2026522300000028.tif27170 Step 11 General procedure for the synthesis of dibenzazepinone analog b-xi: To a solution of b-viii (1.0 equivalent) in DME (20 mL / mmol), TosMIC (1.5 equivalents) and then EtONa (2.0 equivalents) were added at 0°C under an N2 atmosphere. The reaction mixture was heated to 35°C and stirred for 3 hours, then quenched with water and extracted with siRNA. The combined organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by preparative TLC and HPLC to obtain dibenzazepinone analog b-xi.

[0191] TIFF2026522300000029.tif27170 Step 12 General procedure for the synthesis of dibenzazepinone analog b-xii: NaBH4 (1.5 equivalents) was gradually added to a solution of b-viii (1.0 equivalent) in MeOH (10 mL / mmol) at 0°C. After standing at room temperature for 2 hours, brine was added and the organic layer was separated. The aqueous layer was extracted with CH2Cl2. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by flash chromatography on silica gel to obtain dibenzazepinone analog b-xii.

[0192] TIFF2026522300000030.tif31170 Step 13 - General procedure for the synthesis of dibenzazepinone analogs b-xiii to b-xix: The synthesis of dibenzazepinone analogs b-xiii to b-xix follows the same procedure as the corresponding dibenzothiazepinone analogs a-iv to ax described above.

[0193] Characterization data for representative dibenzothiazepinone analogs and dibenzazepinone analogs

[0194] 4-Azido-N-(11-oxo-10-(2-(propa-2-in-1-yloxy)ethyl)-10,11-dihydrodibenzo[b,f][1,4]thiazepine-7-yl)benzamide(2). Probe(2) was obtained as a yellow solid (yield 82%). 1H NMR (400 MHz, chloroform-d) δ 7.92 (d, J = 2.5 Hz, 1H), 7.84 (d, J = 8.6 Hz, 2H), 7.77 (s, 1H), 7.67 (dd, J = 7.6, 1.7 Hz, 1H), 7.60 (dd, J = 8.8, 2.5 Hz, 1H), 7.50 (d, J = 8.7 Hz, 1H), 7.42 (dd, J = 7.5, 1.5 Hz, 1H), 7.35 - 7.25 (m, 2H), 7.12 (d, J = 8.7 Hz, 2H), 4.57 (qd, J = 8.9, 8.1, 5.1Hz, 1H), 4.16 (d, J = 2.4 Hz, 2H), 3.97 (dq, J = 9.0, 5.0 Hz, 2H), 3.81 (dt, J = 9.5, 4.2 Hz, 1H), 2.41 (t, J = 2.3 Hz, 1H). 13 ¹¹C NMR (10¹ MHz, chloroform-d) δ 169.2, 164.8, 144.0, 139.9, 138.9, 138.2, 137.1, 135.9, 131.1, 131.0, 130.8, 130.7, 129.0, 128.7, 126.7, 124.2, 121.4, 119.2, 79.5, 74.7, 67.6, 58.4, 51.6. 25 H 20 N5O3S[M+H] + The LC-MS (ESI) calculation value for this is 470.1, and the measured value is 470.1.

[0195] N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-7-yl)acetamide. 1H NMR (400 MHz, chloroform-d) δ 8.35 (s, 1H), 7.77 (s, 1H), 7.61 (d, J = 7.2 Hz, 1H), 7.45 (d, J = 8.7 Hz, 1H), 7.36 (d, J = 7.0 Hz, 2H), 7.23 (dd, J = 14.0, 7.0 Hz, 2H), 4.53 (dt, J = 13.1, 6.2 Hz, 1H), 3.93 - 3.83 (m, 1H), 3.76 (dt, J = 11.5, 5.9 Hz, 1H), 3.60 (dt, J = 10.4, 5.4 Hz, 1H), 3.30 (s, 3H), 2.08 (s, 3H). 13 ¹³C NMR (10¹ MHz, chloroform-d) δ 169.4, 169.0, 139.3, 139.0, 138.2, 136.9, 136.3, 131.1, 131.0, 130.8, 128.6, 126.6, 123.7, 121.0, 70.0, 58.9, 51.5, 24.3. 18 H 19 N2O3S[M+H] + The LC-MS (ESI) calculation value for this is 343.11, and the measured value is 343.10.

[0196] N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-7-yl)formamide. 1 H NMR (400 MHz, chloroform-d) δ 8.35 (s, 1H), 7.82 (s, 1H), 7.68 (d, J = 7.2 Hz, 1H), 7.40 - 7.55 (m, 3H), 7.30 - 7.36 (m, 2H), 7.23 (dd, J = 14.0, 7.0 Hz, 2H), 4.53 (dt, J = 13.1, 6.2 Hz, 1H), 3.93 - 3.83 (m, 1H), 3.76 (dt, J = 11.5, 5.9 Hz, 1H), 3.60 (dt, J = 10.4, 5.4 Hz, 1H), 3.30 (s, 3H). C 17 H 17N2O3S[M+H] + The LC-MS (ESI) calculation for this was 329.09, and the measured value was 329.10.

[0197] 4-Fluoro-N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-7-yl)benzamide. 1 H NMR (400 MHz, chloroform-d) δ 8.31 (s, 1H), 7.92 (d, J = 2.5 Hz, 1H), 7.92 - 7.80 (m, 2H), 7.61 (ddd, J = 8.8, 6.1, 2.8 Hz, 2H), 7.46 (d, J = 8.8 Hz, 1H), 7.42 - 7.32 (m, 1H), 7.29 - 7.19 (m, 2H), 7.10 (t, J = 8.6 Hz, 2H), 4.58 - 4.47 (m, 1H), 3.92 (dt, J = 13.8, 5.4 Hz, 1H), 3.84 - 3.74 (m, 1H), 3.67 - 3.57 (m, 1H), 3.33 (s, 3H). 13 ¹C NMR (10¹ MHz, chloroform-d) δ 169.3, 166.3, 164.9, 163.8, 139.9, 138.9, 138.2, 137.0, 135.9, 131.1 (d, J = 3.4 Hz), 130.8, 130.6 (d, J = 3.2 Hz), 129.6, 129.6, 128.6, 126.7, 124.3, 121.5, 116.0, 115.7, 70.1, 58.9, 51.6. 23 H 20 FN2O3S[M+H] + The LC-MS (ESI) calculation value for this is 423.12, and the measured value is 423.10.

[0198] N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-7-yl)benzamide. 1H NMR (400 MHz, chloroform-d) δ 8.27 (s, 1H), 7.94 (d, J = 2.5 Hz, 1H), 7.83 (d, J = 7.6 Hz, 2H), 7.69 - 7.58 (m, 2H), 7.52 (t, J = 7.6 Hz, 1H), 7.47 - 7.32 (m, 4H), 7.31 - 7.19 (m, 2H), 4.53 (dt, J = 13.0, 5.9 Hz, 1H), 3.90 (dt, J = 13.6, 5.4 Hz, 1H), 3.79 (dt, J = 11.5, 5.9 Hz, 1H), 3.62 (dt, J = 10.5, 5.5 Hz, 1H), 3.33 (s, 3H). 13 ¹¹C NMR (10¹ MHz, chloroform-d) δ 169.2, 165.9, 139.9, 139.0, 138.3, 137.0, 136.0, 134.4, 132.1, 131.1, 131.0, 130.7, 129.3, 128.8, 128.6, 127.1, 126.7, 124.2, 121.4, 70.1, 58.9, 51.6. 23 H 21 N2O3S[M+H] + The LC-MS (ESI) calculation value for this is 405.13, and the measured value is 405.10.

[0199] N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-7-yl)-4-(trifluoromethyl)benzamide. 1H NMR (400 MHz, chloroform-d) δ 8.22 (s, 1H), 7.98 - 7.91 (m, 3H), 7.71 (d, J = 8.2 Hz, 2H), 7.68 - 7.59 (m, 2H), 7.51 (d, J = 8.8 Hz, 1H), 7.40 (dd, J = 7.0, 2.0 Hz, 1H), 7.32 - 7.21 (m, 2H), 4.59 - 4.48 (m, 1H), 3.94 (dt, J = 13.8, 5.4 Hz, 1H), 3.86 - 3.76 (m, 1H), 3.64 (dt, J = 10.5, 5.4 Hz, 1H), 3.34 (s, 3H). 13 ¹³C NMR (10¹ MHz, chloroform-d) δ 169.2, 164.5, 140.4, 138.8, 138.2, 137.7, 137.2, 135.5, 133.9, 133.6, 131.1, 131.0, 130.8, 128.7, 127.6, 126.8, 125.9 (t, J = 3.8 Hz), 124.3, 121.4, 70.2, 58.9, 51.7. 24 H 20 F3N2O3S[M+H] + The LC-MS (ESI) calculation value for this is 473.11, and the measured value is 473.10.

[0200] N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-7-yl)cyclohexanecarboxamide. 1H NMR (400 MHz, chloroform-d) δ 7.86 (d, J = 2.4 Hz, 1H), 7.64 (dd, J = 7.0, 2.1 Hz, 1H), 7.58 (s, 1H), 7.47 (dd, J = 8.7, 2.5 Hz, 1H), 7.45 - 7.35 (m, 2H), 7.32 - 7.20 (m, 2H), 4.60 - 4.49 (m, 1H), 3.89 (dt, J = 13.7, 5.5 Hz, 1H), 3.79 (dt, J = 11.9, 6.1 Hz, 1H), 3.62 (dt, J = 10.5, 5.6 Hz, 1H), 3.32 (s, 3H), 2.19 (tt, J = 11.6, 3.3 Hz, 1H), 1.92 - 1.75 (m, 4H), 1.68 (d, J = 6.3 Hz, 1H), 1.50 (q, J = 11.6 Hz, 2H), 1.32 - 1.14 (m, 3H). 13 ¹¹C NMR (10¹ MHz, chloroform-d) δ 174.7, 169.2, 139.4, 139.0, 138.3, 137.0, 136.2, 131.1, 130.7, 128.6, 126.6, 123.7, 120.8, 70.1, 58.9, 51.5, 46.3, 29.6, 25.6. 23 H 27 N2O3S[M+H] + The LC-MS (ESI) calculation value for this is 411.18, and the measured value is 411.10.

[0201] 7-((4-fluorobenzyl)amino)-10-(2-methoxyethyl)dibenzo[b,f][1,4]thiazepine-11(10H)-one. 1H NMR (400 MHz, chloroform-d) δ 7.67 (dd, J = 7.4, 1.8 Hz, 1H), 7.39 (dd, J = 7.4, 1.6 Hz, 1H), 7.34 - 7.20 (m, 5H), 7.02 (t, J = 8.6 Hz, 2H), 6.81 (d, J = 2.8 Hz, 1H), 6.51 (dd, J = 8.7, 2.8 Hz, 1H), 4.54 (dt, J = 15.2, 7.4 Hz, 1H), 4.24 (s, 2H), 3.88 - 3.73 (m, 2H), 3.66 - 3.56 (m, 1H), 3.34 (s, 3H). 13 ¹¹C NMR (10¹ MHz, chloroform-d) δ 169.3, 163.4, 161.0, 145.9, 139.2, 138.7, 137.5, 134.3, 133.8, 131.1, 130.9, 130.4, 129.1, 129.0, 128.4, 127.1, 115.9, 115.7, 115.5, 113.7, 70.0, 58.8, 51.3, 47.6. 23 H 22 FN2O2S[M+H] + The LC-MS (ESI) calculation for this is 409.14, and the measured value is 409.10.

[0202] N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-7-yl)nicotinamide. 1H NMR (400 MHz, chloroform-d) δ 9.07 (d, J = 2.9 Hz, 1H), 8.73 (dd, J = 4.9, 1.7 Hz, 1H), 8.62 (s, 1H), 8.17 (dt, J = 8.1, 2.0 Hz, 1H), 7.94 (d, J = 2.5 Hz, 1H), 7.67 - 7.56 (m, 2H), 7.48 (d, J = 8.8 Hz, 1H), 7.42 - 7.32 (m, 2H), 7.31 - 7.19 (m, 2H), 4.57 - 4.46 (m, 1H), 3.93 (dt, J = 13.8, 5.4 Hz, 1H), 3.85 - 3.75 (m, 1H), 3.71 - 3.58 (m, 1H), 3.33 (s, 3H). 13 ¹¹C NMR (10¹ MHz, chloroform-d) δ 169.3, 164.1, 152.6, 148.1, 140.3, 138.8, 138.2, 137.1, 135.6, 135.4, 131.0, 130.8, 130.3, 128.7, 126.8, 124.4, 123.7, 121.6, 70.1, 58.9, 51.7. 22 H 20 N3O3S[M+H] + The LC-MS (ESI) calculation value for this is 406.12, and the measured value is 406.00.

[0203] N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-7-yl)isonicotinamide. 1H NMR (400 MHz, chloroform-d) δ 8.72 (s, 3H), 7.95 (d, J = 2.4 Hz, 1H), 7.71 - 7.65 (m, 2H), 7.66 - 7.58 (m, 2H), 7.50 (d, J = 8.8 Hz, 1H), 7.42 - 7.33 (m, 1H), 7.28 - 7.19 (m, 2H), 4.57 - 4.46 (m, 1H), 3.93 (dt, J = 13.8, 5.3 Hz, 1H), 3.86 - 3.74 (m, 1H), 3.62 (dt, J = 10.4, 5.4 Hz, 1H), 3.33 (s, 3H). 13 ¹³C NMR (10¹ MHz, chloroform-d) δ 169.3, 164.0, 150.7, 141.6, 140.4, 138.8, 138.1, 137.1, 135.5, 131.1, 131.0, 130.9, 128.7, 126.8, 124.4, 121.6, 121.0, 70.1, 58.9, 51.7. 22 H 20 N3O3S[M+H] + The LC-MS (ESI) calculation value for this is 406.12, and the measured value is 406.00.

[0204] N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-7-yl)-4-methylbenzamide. 1 H NMR (400 MHz, chloroform-d) δ 8.17 (s, 1H), 7.93 (d, J = 2.5 Hz, 1H), 7.73 (d, J = 8.2 Hz, 2H), 7.68 - 7.55 (m, 2H), 7.44 (d, J = 8.8 Hz, 1H), 7.38 (dd, J = 7.2, 1.8 Hz, 1H), 7.31 - 7.19 (m, 4H), 4.60 - 4.49 (m, 1H), 3.96 - 3.85 (m, 1H), 3.84 - 3.74 (m, 1H), 3.67 - 3.57 (m, 1H), 3.33 (s, 3H), 2.40 (s, 3H).13 ¹³C NMR (10¹ MHz, chloroform-d) δ 169.2, 165.8, 142.7, 139.8, 138.9, 138.3, 137.0, 136.1, 131.6, 131.1, 131.0, 130.7, 129.5, 128.6, 127.1, 126.7, 124.1, 121.3, 70.1, 58.9, 51.5, 21.5. 24 H 23 N2O3S[M+H] + The LC-MS (ESI) calculation value for this is 419.14, and the measured value is 419.10.

[0205] 4-Azido-N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-7-yl)benzamide. 1 H NMR (400 MHz, chloroform-d) δ 8.37 (s, 1H), 7.94 (d, J = 2.5 Hz, 1H), 7.84 (d, J = 8.6 Hz, 2H), 7.61 (dd, J = 8.7, 2.4 Hz, 2H), 7.46 (d, J = 8.8 Hz, 1H), 7.41 - 7.32 (m, 1H), 7.29 - 7.18 (m, 2H), 7.03 (d, J = 8.6 Hz, 2H), 4.59 - 4.48 (m, 1H), 3.92 (dt, J = 13.8, 5.4 Hz, 1H), 3.84 - 3.74 (m, 1H), 3.67 - 3.57 (m, 1H), 3.33 (s, 3H). 13 ¹¹C NMR (10¹ MHz, chloroform-d) δ 169.3, 164.9, 144.0, 139.9, 138.9, 138.2, 137.0, 136.0, 131.1, 131.0, 130.8, 129.0, 128.6, 126.7, 124.2, 121.4, 119.1, 70.1, 58.9, 51.6. 23 H 20 N5O3S[M+H] + The LC-MS (ESI) calculation value for this is 446.13, and the measured value is 446.10.

[0206] N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-7-yl)oxazole-4-carboxamide. 1 H NMR (400 MHz, chloroform-d) δ 8.71 (s, 1H), 8.32 (d, J = 1.0 Hz, 1H), 7.95 (d, J = 2.5 Hz, 1H), 7.92 (d, J = 1.0 Hz, 1H), 7.75 - 7.62 (m, 2H), 7.50 (d, J = 8.8 Hz, 1H), 7.42 (dd, J = 7.5, 1.5 Hz, 1H), 7.35 - 7.23 (m, 2H), 4.60 - 4.49 (m, 1H), 3.94 (dt, J = 13.8, 5.5 Hz, 1H), 3.87 - 3.77 (m, 1H), 3.73 - 3.60 (m, 1H), 3.34 (s, 3H). 13 ¹¹C NMR (10¹ MHz, chloroform-d) δ 169.0, 158.1, 150.6, 142.2, 140.2, 138.8, 138.4, 137.2, 135.8, 135.1, 131.2, 131.0, 130.7, 128.7, 126.8, 123.7, 120.9, 70.2, 58.9, 51.6. 20 H 18 N3O4S[M+H] + The LC-MS (ESI) calculation value for this is 396.10, and the measured value is 396.00.

[0207] 4-Azido-N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-7-yl)-2-(propa-2-in-1-yloxy)benzamide. 1H NMR (400 MHz, chloroform-d) δ 9.65 (s, 1H), 8.28 (d, J = 8.5 Hz, 1H), 7.97 (d, J = 2.5 Hz, 1H), 7.71 - 7.59 (m, 2H), 7.53 - 7.39 (m, 2H), 7.35 - 7.22 (m, 2H), 6.89 (dd, J = 8.6, 2.0 Hz, 1H), 6.63 (d, J = 2.0 Hz, 1H), 4.89 (d, J = 2.4 Hz, 2H), 4.62 - 4.50 (m, 1H), 3.93 (dt, J = 13.7, 5.5 Hz, 1H), 3.87 - 3.77 (m, 1H), 3.69 - 3.58 (m, 1H), 3.35 (s, 3H), 2.75 (t, J = 2.4 Hz, 1H). 13 ¹¹C NMR (10¹ MHz, chloroform-d) δ 169.1, 162.1, 156.4, 145.4, 139.8, 138.9, 138.4, 137.0, 136.2, 134.4, 131.2, 131.0, 130.7, 128.6, 126.7, 124.1, 121.3, 118.5, 112.8, 104.0, 77.8, 76.5, 70.2, 58.9, 57.6, 51.5. 26 H 22 N5O4S[M+H] + The LC-MS (ESI) calculation for this is 500.14, and the measured value is 500.10.

[0208] 2-Azido-N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-7-yl)benzamide. 1H NMR (400 MHz, chloroform-d) δ 7.67 (d, J = 2.5 Hz, 1H), 7.39 (d, J = 2.5 Hz, 1H), 7.31 - 7.21 (m, 7H), 6.87 (d, J = 2.0 Hz, 1H), 6.64 - 6.55 (m, 1H), 4.56 (ddd, J = 13.4, 6.7, 2.9 Hz, 1H), 3.79 (tdd, J = 12.6, 6.0, 2.7 Hz, 2H), 3.61 (s, 1H), 3.34 (s, 3H). C 23 H 20 N5O3S[M+H] + The LC-MS (ESI) calculation for this was 446.13, and the measured value was 446.20.

[0209] 3-Azido-N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-7-yl)benzamide. 1 H NMR (400 MHz, chloroform-d) δ 8.21 (s, 1H), 7.92 (d, J = 2.5 Hz, 1H), 7.67 - 7.58 (m, 2H), 7.56 (dt, J = 7.8, 1.4 Hz, 1H), 7.51 (t, J = 2.0 Hz, 1H), 7.50 - 7.41 (m, 2H), 7.41 - 7.36 (m, 1H), 7.30 - 7.22 (m, 2H), 7.18 (dd, J = 7.5, 2.8 Hz, 1H), 4.59 - 4.48 (m, 1H), 3.93 (dt, J = 13.8, 5.4 Hz, 1H), 3.86 - 3.76 (m, 1H), 3.68 - 3.59 (m, 1H), 3.34 (s, 3H). 13¹¹C NMR (10¹ MHz, chloroform-d) δ 169.2, 164.9, 141.1, 140.2, 138.8, 138.2, 137.1, 136.3, 135.7, 131.1, 131.0, 130.8, 130.2, 128.6, 126.8, 124.2, 123.2, 122.4, 121.4, 118.1, 70.2, 58.9, 51.6. 23 H 20 N5O3S[M+H] + The LC-MS (ESI) calculation for this is 446.13, and the measured value is 446.00.

[0210] 4-Azido-N-(11-oxo-10-(2-(propa-2-in-1-yloxy)ethyl)-10,11-dihydrodibenzo[b,f][1,4]thiazepine-7-yl)benzamide. 1 H NMR (400 MHz, chloroform-d) δ 7.92 (d, J = 2.5 Hz, 1H), 7.84 (d, J = 8.6 Hz, 2H), 7.77 (s, 1H), 7.67 (dd, J = 7.6, 1.7 Hz, 1H), 7.60 (dd, J = 8.8, 2.5 Hz, 1H), 7.50 (d, J = 8.7 Hz, 1H), 7.42 (dd, J = 7.5, 1.5 Hz, 1H), 7.35 - 7.25 (m, 2H), 7.12 (d, J = 8.7 Hz, 2H), 4.57 (qd, J = 8.9, 8.1, 5.1Hz, 1H), 4.16 (d, J = 2.4 Hz, 2H), 3.97 (dq, J = 9.0, 5.0 Hz, 2H), 3.81 (dt, J = 9.5, 4.2 Hz, 1H), 2.41 (t, J = 2.3 Hz, 1H). 13¹¹C NMR (10¹ MHz, chloroform-d) δ 169.2, 164.8, 144.0, 139.9, 138.9, 138.2, 137.1, 135.9, 131.1, 131.0, 130.8, 130.7, 129.0, 128.7, 126.7, 124.2, 121.4, 119.2, 79.5, 74.7, 67.6, 58.4, 51.6. 25 H 20 N5O3S[M+H] + The LC-MS (ESI) calculation value for this is 470.13, and the measured value is 470.10.

[0211] 1-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-7-yl)-3-phenylurea. 1 H NMR (400 MHz, chloroform-d) δ 7.87 (s, 1H), 7.76 (s, 1H), 7.63 (d, J = 5.2 Hz, 1H), 7.48 (d, J = 2.3 Hz, 1H), 7.37 (dt, J = 7.5, 3.7 Hz, 1H), 7.33 - 7.17 (m, 6H), 7.01 (t, J = 7.2 Hz, 1H), 4.63 - 4.52 (m, 1H), 3.86 (dt, J = 13.6, 4.8 Hz, 1H), 3.78 - 3.68 (m, 1H), 3.59 (dt, J = 10.3, 5.3 Hz, 1H), 3.28 (s, 3H). 13 ¹¹C NMR (10¹ MHz, chloroform-d) δ 170.0, 153.3, 139.1, 138.2, 138.0, 137.7, 137.3, 136.9, 131.2, 131.0, 130.8, 129.1, 128.8, 126.6, 123.7, 123.1, 120.5, 120.2, 69.9, 58.9, 51.6. 23 H 22 N3O3S[M+H] + The LC-MS (ESI) calculation for this is 420.14, and the measured value is 420.10.

[0212] N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-7-yl)cyclobutancarboxamide. 1 H NMR (400 MHz, chloroform-d) δ 7.83 (d, J = 2.5 Hz, 1H), 7.65 (dd, J = 7.5, 1.7 Hz, 1H), 7.49 (dd, J = 8.7, 2.5 Hz, 1H), 7.45 - 7.36 (m, 3H), 7.33 - 7.20 (m, 2H), 4.60 - 4.49 (m, 1H), 3.95 - 3.84 (m, 1H), 3.79 (dd, J = 16.0, 6.0 Hz, 1H), 3.67 - 3.57 (m, 1H), 3.33 (s, 3H), 3.17 - 3.04 (m, 1H), 2.42 - 2.27 (m, 2H), 2.24 - 2.11 (m, 2H), 2.06 - 1.85 (m, 2H). 13 ¹¹C NMR (10¹ MHz, chloroform-d) δ 173.4, 169.2, 139.5, 138.9, 138.3, 137.0, 136.1, 131.1, 131.0, 130.7, 128.6, 126.6, 123.5, 120.7, 70.1, 58.9, 51.5, 40.7, 25.2, 18.1. 21 H 23 N2O3S[M+H] + The LC-MS (ESI) calculation for this is 383.15, and the measured value is 383.10.

[0213] N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-7-yl)tetrahydro-2H-pyran-4-carboxamide. 1H NMR (400 MHz, chloroform-d) δ 7.86 (d, J = 2.4 Hz, 1H), 7.65 (dd, J = 7.4, 1.9 Hz, 1H), 7.60 (s, 1H), 7.51 - 7.35 (m, 3H), 7.33 - 7.21 (m, 2H), 4.59 - 4.48 (m, 1H), 4.07 - 3.98 (m, 2H), 3.91 (dt, J = 13.7, 5.5 Hz, 1H), 3.84 - 3.74 (m, 1H), 3.67 - 3.57 (m, 1H), 3.40 (td, J = 11.6, 2.3 Hz, 2H), 3.33 (s, 3H), 2.45 (tt, J = 11.3, 4.0 Hz, 1H), 1.86 (td, J = 11.4, 3.4 Hz, 2H), 1.77 (d, J = 13.0 Hz, 2H). 13 ¹¹C NMR (10¹ MHz, chloroform-d) δ 172.7, 169.2, 139.7, 138.9, 138.3, 137.0, 135.8, 131.1, 131.0, 130.7, 128.6, 126.7, 123.7, 120.9, 70.1, 67.1, 58.9, 51.6, 43.1, 29.7. 22 H 25 N2O4S[M+H] + The LC-MS (ESI) calculation for this was 413.16, and the measured value was 413.10.

[0214] N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-7-yl)cycloheptancarboxamide. 1H NMR (400 MHz, chloroform-d) δ 7.84 (d, J = 2.2 Hz, 1H), 7.65 (dd, J = 7.5, 1.8 Hz, 1H), 7.52 - 7.36 (m, 4H), 7.33 - 7.20 (m, 2H), 4.60 - 4.49 (m, 1H), 3.95 - 3.84 (m, 1H), 3.84 - 3.74 (m, 1H), 3.68 - 3.57 (m, 1H), 3.33 (s, 3H), 2.35 (td, J = 9.7, 4.1 Hz, 1H), 1.92 (ddd, J = 14.1, 7.2, 4.2 Hz, 2H), 1.84 - 1.66 (m, 4H), 1.63 - 1.53 (m, 4H), 1.53 - 1.38 (m, 2H). 13 ¹¹C NMR (10¹ MHz, chloroform-d) δ 175.7, 169.1, 139.5, 138.9, 138.3, 137.0, 136.1, 131.1, 131.0, 130.7, 128.6, 126.6, 123.6, 120.7, 70.1, 58.9, 51.5, 48.2, 31.5, 28.2, 26.5. 24 H 29 N2O3S[M+H] + The LC-MS (ESI) calculation value for this is 426.20, and the measured value is 426.20.

[0215] 4-Chloro-N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-7-yl)benzamide. 1H NMR (400 MHz, chloroform-d) δ 8.05 (s, 1H), 7.92 (d, J = 2.5 Hz, 1H), 7.77 (d, J = 8.5 Hz, 2H), 7.69 - 7.57 (m, 2H), 7.49 (d, J = 8.8 Hz, 1H), 7.45 - 7.36 (m, 3H), 7.33 - 7.21 (m, 2H), 4.59 - 4.48 (m, 1H), 3.98 - 3.88 (m, 1H), 3.86 - 3.76 (m, 1H), 3.73 - 3.59 (m, 1H), 3.34 (s, 3H). 13 ¹¹C NMR (10¹ MHz, chloroform-d) δ 169.1, 164.7, 140.2, 138.8, 138.5, 138.3, 137.1, 135.6, 132.8, 131.1, 131.0, 130.8, 129.1, 128.7, 128.5, 126.8, 124.2, 121.3, 70.2, 58.9, 51.6. 23 H 20 ClN2O3S[M+H] + The LC-MS (ESI) calculation value for this is 439.09, and the measured value is 439.1.

[0216] 3-Chloro-N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-7-yl)benzamide. 1 H NMR (400 MHz, chloroform-d) δ 8.19 (s, 1H), 7.92 (d, J = 2.5 Hz, 1H), 7.82 (s, 1H), 7.70 (d, J = 7.8 Hz, 1H), 7.67 - 7.54 (m, 2H), 7.48 (d, J = 8.8 Hz, 2H), 7.44 - 7.33 (m, 2H), 7.32 - 7.20 (m, 2H), 4.58 - 4.48 (m, 1H), 3.93 (dt, J = 13.8, 5.4 Hz, 1H), 3.86 - 3.76 (m, 1H), 3.64 (dt, J = 10.5, 5.5 Hz, 1H), 3.34 (s, 3H).13 ¹¹C NMR (10¹ MHz, chloroform-d) δ 169.2, 164.5, 140.2, 138.8, 138.2, 137.1, 136.2, 135.6, 135.0, 132.1, 131.1, 131.0, 130.8, 130.1, 128.6, 127.4, 126.8, 125.2, 124.2, 121.4, 70.2, 58.9, 51.6. 23 H 20 ClN2O3S[M+H] + The LC-MS (ESI) calculation value for this is 439.09, and the measured value is 439.00.

[0217] 4-Methoxy-N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-7-yl)benzamide. 1 H NMR (400 MHz, chloroform-d) δ 7.92 (d, J = 2.5 Hz, 1H), 7.87 (s, 1H), 7.81 (d, J = 8.8 Hz, 2H), 7.67 (dd, J = 7.3, 2.0 Hz, 1H), 7.60 (dd, J = 8.8, 2.5 Hz, 1H), 7.47 (d, J = 8.8 Hz, 1H), 7.41 (dd, J = 7.3, 1.7 Hz, 1H), 7.34 - 7.20 (m, 2H), 6.96 (d, J = 8.8 Hz, 2H), 4.61 - 4.50 (m, 1H), 3.98 - 3.88 (m, 1H), 3.87 (s, 3H), 3.85 - 3.74 (m, 1H), 3.65 (dd, J = 10.0, 5.6 Hz, 1H), 3.34 (s, 3H). 13 ¹¹C NMR (10¹ MHz, chloroform-d) δ 169.1, 165.2, 162.7, 139.8, 138.9, 138.4, 137.1, 136.0, 131.1, 131.0, 130.7, 129.0, 128.6, 126.7, 126.5, 124.0, 121.2, 114.1, 70.2, 58.9, 55.5, 51.5. 24H 23 N2O4S[M+H] + The LC-MS (ESI) calculation for this was 435.14, and the measured value was 435.30.

[0218] 4-Cyano-N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-7-yl)benzamide. 1 H NMR (400 MHz, chloroform-d) δ 8.05 (s, 1H), 7.98 - 7.91 (m, 3H), 7.81 - 7.73 (m, 2H), 7.69 - 7.58 (m, 2H), 7.53 (d, J = 8.7 Hz, 1H), 7.41 (dd, J = 7.2, 1.7 Hz, 1H), 7.34 - 7.23 (m, 2H), 4.53 (ddd, J = 13.8, 6.7, 5.3 Hz, 1H), 3.95 (dt, J = 13.8, 5.4 Hz, 1H), 3.82 (ddd, J = 10.1, 6.6, 5.1Hz, 1H), 3.65 (dt, J = 10.5, 5.4 Hz, 1H), 3.35 (s, 3H). 13 ¹¹C NMR (10¹ MHz, chloroform-d) δ 169.1, 163.9, 140.7, 138.7, 138.3, 138.2, 137.2, 135.2, 132.7, 131.2, 131.0, 130.8, 128.7, 127.8, 126.9, 124.3, 121.4, 117.7, 115.7, 70.2, 58.9, 51.7, 29.7. 24 H 20 N3O3S[M+H] + The LC-MS (ESI) calculation for this is 430.12, and the measured value is 430.10.

[0219] 7-(benzylamino)-10-(2-methoxyethyl)dibenzo[b,f][1,4]thiazepine-11(10H)-one. 1H NMR (400 MHz, chloroform-d) δ 7.67 (dd, J = 7.5, 1.8 Hz, 1H), 7.39 (dd, J = 7.3, 1.6 Hz, 1H), 7.37 - 7.27 (m, 4H), 7.26 - 7.21 (m, 2H), 6.82 (d, J = 2.8 Hz, 1H), 6.52 (dd, J = 8.7, 2.8 Hz, 1H), 4.60 - 4.48 (m, 1H), 4.27 (s, 2H), 4.13 (s, 0H), 3.87 - 3.73 (m, 2H), 3.66 - 3.55 (m, 1H), 3.34 (s, 3H). 13 ¹¹C NMR (10¹ MHz, chloroform-d) δ 169.3, 146.1, 139.2, 138.7, 138.6, 137.4, 133.6, 131.1, 130.9, 130.3, 128.7, 128.4, 127.5, 127.0, 115.8, 113.6, 70.0, 58.8, 51.2, 48.2. 23 H 23 N2O2S[M+H] + The LC-MS (ESI) calculation value for this is 391.15, and the measured value is 391.10.

[0220] N-(11-oxo-10-(2-(propa-2-in-1-yloxy)ethyl)-10,11-dihydrodibenzo[b,f][1,4]thiazepine-7-yl)furan-3-carboxamide. 1H NMR (400 MHz, chloroform-d) δ 8.10 (s, 1H), 8.06 (s, 1H), 7.87 (d, J = 2.5 Hz, 1H), 7.64 (dd, J = 7.5, 1.8 Hz, 1H), 7.58 (dd, J = 8.8, 2.5 Hz, 1H), 7.48 - 7.41 (m, 2H), 7.41 - 7.33 (m, 1H), 7.31 - 7.17 (m, 3H), 6.75 (d, J = 1.1 Hz, 1H), 4.63 - 4.51 (m, 1H), 4.15 (d, J = 2.4 Hz, 2H), 4.02 - 3.88 (m, 2H), 3.85 - 3.72 (m, 1H), 2.41 (t, J = 2.3 Hz, 1H). 13 ¹³C NMR (10¹ MHz, chloroform-d) δ 169.3, 160.9, 145.5, 144.7, 139.7, 138.9, 138.2, 137.0, 135.8, 131.1, 131.0, 130.9, 130.7, 130.5, 128.6, 128.4, 127.1, 126.6, 124.2, 122.7, 121.4, 118.4, 116.0, 108.5, 79.5, 74.7, 67.5, 58.4, 51.5. 23 H 19 N2O4S[M+H] + The LC-MS (ESI) calculation value for this is 419.11, and the measured value is 419.30.

[0221] 4-Ethyl-N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-7-yl)benzamide. 1H NMR (400 MHz, chloroform-d) δ 7.96 (s, 1H), 7.93 (d, J = 2.5 Hz, 1H), 7.76 (d, J = 8.3 Hz, 2H), 7.66 (dd, J = 7.4, 1.8 Hz, 1H), 7.60 (dd, J = 8.8, 2.5 Hz, 1H), 7.47 (d, J = 8.8 Hz, 1H), 7.44 - 7.37 (m, 1H), 7.33 - 7.21 (m, 4H), 4.60 - 4.49 (m, 1H), 3.92 (dt, J = 13.8, 5.5 Hz, 1H), 3.86 - 3.76 (m, 1H), 3.71 - 3.59 (m, 1H), 3.34 (s, 3H), 2.71 (q, J = 7.6 Hz, 2H), 1.26 (t, J = 7.6 Hz, 3H). 13 ¹C NMR (10¹ MHz, chloroform-d) δ 169.1, 165.7, 149.0, 139.9, 138.9, 138.3, 137.1, 136.0, 131.8, 131.1, 131.0, 130.7, 128.6, 128.3, 127.2, 126.7, 124.0, 121.2, 70.2, 58.9, 51.5, 28.8, 15.3. 25 H 25 N2O3S[M+H] + The LC-MS (ESI) calculation for this was 433.16, and the measured value was 433.30.

[0222] 4-Ethinyl-N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-7-yl)benzamide. 1H NMR (400 MHz, chloroform-d) δ 8.21 (s, 1H), 7.93 (d, J = 2.5 Hz, 1H), 7.79 (d, J = 8.4 Hz, 2H), 7.67 - 7.58 (m, 2H), 7.55 (d, J = 8.4 Hz, 2H), 7.47 (d, J = 8.8 Hz, 1H), 7.42 - 7.34 (m, 1H), 7.32 - 7.21 (m, 2H), 4.59 - 4.48 (m, 1H), 3.98 - 3.87 (m, 1H), 3.80 (dd, J = 15.3, 6.6 Hz, 1H), 3.68 - 3.58 (m, 1H), 3.34 (s, 3H), 3.24 (s, 1H). 13 ¹¹C NMR (10¹ MHz, chloroform-d) δ 169.2, 165.0, 140.1, 138.8, 138.3, 137.1, 135.8, 134.3, 132.5, 131.1, 131.0, 130.7, 128.6, 127.1, 126.7, 126.0, 124.2, 121.4, 82.6, 80.1, 70.1, 58.9, 51.6. 25 H 21 N2O3S[M+H] + The LC-MS (ESI) calculation for this is 429.13, and the measured value is 429.10.

[0223] N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-7-yl)-2-naphthoamide. 1H NMR (400 MHz, chloroform-d) δ 8.42 (s, 1H), 8.34 (s, 1H), 7.99 (d, J = 2.5 Hz, 1H), 7.89 (d, J = 7.1 Hz, 4H), 7.72 - 7.63 (m, 2H), 7.61 - 7.50 (m, 2H), 7.47 (d, J = 8.8 Hz, 1H), 7.38 (dd, J = 7.0, 2.1 Hz, 1H), 7.31 - 7.17 (m, 2H), 4.60 - 4.49 (m, 1H), 3.98 - 3.87 (m, 1H), 3.86 - 3.75 (m, 1H), 3.68 - 3.57 (m, 1H), 3.34 (s, 3H). 13 ¹¹C NMR (10¹ MHz, chloroform-d) δ 169.2, 166.0, 139.9, 138.9, 138.3, 137.0, 136.1, 134.9, 132.5, 131.7, 131.1, 131.0, 130.7, 129.0, 128.8, 128.6, 128.1, 127.8, 127.7, 127.0, 126.7, 124.1, 123.5, 121.3, 70.1, 58.9, 51.6. 27 H 23 N2O3S[M+H] + The LC-MS (ESI) calculation for this was 455.14, and the measured value was 455.20.

[0224] N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-7-yl)-[1,1'-biphenyl]-4-carboxamide. 1H NMR (400 MHz, chloroform-d) δ 8.09 (s, 1H), 7.97 (d, J = 2.5 Hz, 1H), 7.91 (d, J = 8.3 Hz, 2H), 7.73 - 7.58 (m, 6H), 7.53 - 7.45 (m, 3H), 7.44 - 7.37 (m, 2H), 7.34 - 7.21 (m, 2H), 4.61 - 4.50 (m, 1H), 3.93 (dt, J = 13.7, 5.4 Hz, 1H), 3.87 - 3.77 (m, 1H), 3.65 (dt, J = 10.5, 5.5 Hz, 1H), 3.34 (s, 3H). 13 ¹¹C NMR (10¹ MHz, chloroform-d) δ 169.1, 165.5, 145.0, 140.0, 139.7, 138.9, 138.3, 137.1, 135.9, 133.0, 131.2, 131.0, 130.7, 129.0, 128.6, 128.2, 127.6, 127.5, 127.2, 126.8, 124.1, 121.3, 70.2, 58.9, 51.6. 29 H 25 N2O3S[M+H] + The LC-MS (ESI) calculation for this is 481.16, and the measured value is 481.10.

[0225] 4-Methoxy-N-(11-oxo-10-(2-(propa-2-in-1-yloxy)ethyl)-10,11-dihydrodibenzo[b,f][1,4]thiazepine-7-yl)benzamide. 1H NMR (400 MHz, chloroform-d) δ 7.97 (s, 1H), 7.92 (d, J = 2.5 Hz, 1H), 7.81 (d, J = 8.8 Hz, 2H), 7.65 (dd, J = 7.4, 1.8 Hz, 1H), 7.59 (dd, J = 8.8, 2.6 Hz, 1H), 7.46 (d, J = 8.8 Hz, 1H), 7.40 (dd, J = 7.0, 1.9 Hz, 1H), 7.33 - 7.19 (m, 2H), 6.95 (d, J = 8.8 Hz, 2H), 4.57 (ddd, J = 15.6, 8.7, 5.2Hz, 1H), 4.15 (d, J = 2.5 Hz, 2H), 4.01 - 3.90 (m, 1H), 3.86 (s, 3H), 3.79 (dt, J = 9.5, 4.8 Hz, 1H), 2.41 (t, J = 2.4 Hz, 1H). 13 ¹¹C NMR (10¹ MHz, chloroform-d) δ 169.2, 165.2, 162.7, 139.7, 138.9, 138.3, 137.1, 136.1, 131.1, 131.0, 130.7, 129.0, 128.6, 126.7, 126.5, 124.0, 121.2, 114.0, 79.5, 74.7, 67.6, 58.4, 55.5, 51.5. 26 H 23 N2O4S[M+H] + The LC-MS (ESI) calculation value for this is 459.14, and the measured value is 459.10.

[0226] N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-7-yl)cyclopropanecarboxamide. 1¹H NMR (400 MHz, chloroform-d) δ 7.82 (s, 1H), 7.75 (s, 1H), 7.65 (dd, J = 7.5, 1.7 Hz, 1H), 7.48 - 7.35 (m, 3H), 7.32 - 7.20 (m, 2H), 4.60 - 4.49 (m, 1H), 3.90 (dt, J = 13.7, 5.5 Hz, 1H), 3.84 - 3.74 (m, 1H), 3.68 - 3.57 (m, 1H), 3.33 (s, 3H), 1.48 (tt, J = 8.1, 4.4 Hz, 1H), 1.10 - 1.01 (m, 2H), 0.89 - 0.78 (m, 2H). 13 ¹¹C NMR (10¹ MHz, chloroform-d) δ 172.1, 169.2, 139.4, 138.9, 138.3, 137.0, 136.1, 131.1, 131.0, 130.7, 128.6, 126.6, 123.5, 120.7, 70.1, 58.9, 51.5, 29.7, 15.6, 8.2. 20 H 21 N2O3S[M+H] + The LC-MS (ESI) calculation for this is 369.13, and the measured value is 369.10.

[0227] N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-7-yl)-3-oxocyclobutan-1-carboxamide. 1H NMR (400 MHz, chloroform-d) δ 8.14 (s, 1H), 7.85 (d, J = 2.5 Hz, 1H), 7.69 - 7.60 (m, 1H), 7.52 (dd, J = 8.8, 2.5 Hz, 1H), 7.45 (d, J = 8.8 Hz, 1H), 7.40 (dd, J = 7.2, 1.8 Hz, 1H), 7.33 - 7.21 (m, 2H), 4.60 - 4.49 (m, 1H), 3.92 (dt, J = 13.8, 5.3 Hz, 1H), 3.84 - 3.74 (m, 1H), 3.68 - 3.58 (m, 1H), 3.59 - 3.45 (m, 2H), 3.32 (s, 3H), 3.27 - 3.10 (m, 3H). 13 ¹¹C NMR (10¹ MHz, chloroform-d) δ 203.3, 171.6, 169.3, 139.8, 138.9, 138.2, 137.1, 135.8, 131.1, 131.0, 130.8, 128.7, 126.7, 123.8, 120.9, 70.1, 58.9, 51.7, 38.7, 29.5. 21 H 21 N2O4S[M+H] + The LC-MS (ESI) calculation value for this is 397.12, and the measured value is 397.10.

[0228] N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-7-yl)-4-(trifluoromethoxy)benzamide. 1H NMR (400 MHz, chloroform-d) δ 8.41 (s, 1H), 7.94 (d, J = 2.5 Hz, 1H), 7.89 (d, J = 8.8 Hz, 2H), 7.66 - 7.58 (m, 2H), 7.47 (d, J = 8.8 Hz, 1H), 7.43 - 7.33 (m, 1H), 7.24 (q, J = 2.9, 2.2 Hz, 4H), 4.58 - 4.47 (m, 1H), 3.92 (dt, J = 13.8, 5.4 Hz, 1H), 3.84 - 3.74 (m, 1H), 3.62 (dt, J = 10.4, 5.4 Hz, 1st hour), 3.33 (s, 3rd hour). 13 ¹³C NMR (10¹ MHz, chloroform-d) δ 169.3, 164.6, 151.8, 140.1, 138.8, 138.2, 137.1, 135.8, 132.8, 131.1 (d, J = 3.3 Hz), 130.8, 129.1, 128.6, 126.7, 124.3, 121.5, 120.7, 70.1, 58.9, 51.7. 24 H 20 F3N2O4S[M+H] + The LC-MS (ESI) calculation value for this is 489.11, and the measured value is 489.10.

[0229] 3,4-Dichloro-N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-7-yl)benzamide. 1H NMR (400 MHz, chloroform-d) δ 8.06 (s, 1H), 7.92 (dd, J = 10.4, 2.3 Hz, 2H), 7.70 - 7.58 (m, 3H), 7.52 (dd, J = 12.3, 8.5 Hz, 2H), 7.40 (dd, J = 7.1, 1.8 Hz, 1H), 7.31 - 7.27 (m, 2H), 4.59 - 4.48 (m, 1H), 3.95 (dt, J = 13.8, 5.4 Hz, 1H), 3.87 - 3.77 (m, 1H), 3.65 (dt, J = 10.5, 5.5 Hz, 1H), 3.35 (s, 3H). 13 ¹¹C NMR (10¹ MHz, chloroform-d) δ 169.2, 163.6, 140.4, 138.8, 138.2, 137.2, 136.7, 135.4, 133.4, 131.1, 131.0, 130.9, 130.8, 129.3, 128.7, 126.9, 126.2, 124.2, 121.4, 70.2, 58.9, 51.7. 23 H 19 Cl2N2O3S[M+H] + The LC-MS (ESI) calculation value for this is 473.05, and the measured value is 473.00.

[0230] N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-7-yl)spiro[2,2]pentan-1-carboxamide. 1H NMR (400 MHz, chloroform-d) δ 7.83 (s, 1H), 7.65 (dd, J = 6.6, 2.0 Hz, 2H), 7.48 - 7.42 (m, 1H), 7.41 - 7.35 (m, 2H), 7.32 - 7.20 (m, 2H), 4.60 - 4.49 (m, 1H), 3.94 - 3.84 (m, 1H), 3.84 - 3.74 (m, 1H), 3.66 - 3.57 (m, 1H), 3.32 (s, 3H), 1.91 (dd, J = 7.6, 4.1 Hz, 1H), 1.56 - 1.49 (m, 1H), 1.38 (dd, J = 7.6, 4.0 Hz, 1H), 1.09 - 1.00 (m, 1H), 0.92 (d, J = 4.1 Hz, 3H). 13 ¹¹C NMR (10¹ MHz, chloroform-d) δ 171.4, 169.2, 139.3, 138.9, 138.3, 137.0, 131.1, 131.1, 131.0, 130.7, 128.6, 126.6, 123.4, 120.6, 70.1, 58.8, 51.5, 23.1, 18.3, 15.0, 6.7, 5.1. 22 H 23 N2O3S[M+H] + The LC-MS (ESI) calculation value for this is 395.15, and the measured value is 395.00.

[0231] N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-7-yl)spiro[3,3]heptan-2-carboxamide. 1H NMR (400 MHz, chloroform-d) δ 7.83 (d, J = 2.4 Hz, 1H), 7.64 (dd, J = 7.0, 2.2 Hz, 1H), 7.53 - 7.43 (m, 2H), 7.43 - 7.33 (m, 2H), 7.32 - 7.20 (m, 2H), 4.59 - 4.48 (m, 1H), 3.89 (dt, J = 13.7, 5.5 Hz, 1H), 3.84 - 3.74 (m, 1H), 3.66 - 3.57 (m, 1H), 3.32 (s, 3H), 2.93 (p, J = 8.5Hz, 1H), 2.33 - 2.23 (m, 2H), 2.18 (t, J = 10.3 Hz, 2H), 2.02 (t, J = 7.2 Hz, 2H), 1.92 (t, J = 7.2 Hz, 2H), 1.80 (q, J = 8.5 Hz, 2H). 13 ¹¹C NMR (10¹ MHz, chloroform-d) δ 173.5, 169.2, 139.4, 138.9, 138.3, 137.0, 136.2, 131.1, 131.0, 130.7, 128.6, 126.6, 123.5, 120.7, 70.1, 65.9, 58.9, 51.5, 39.8, 37.8, 35.5, 35.2, 34.3, 16.2. 24 H 27 N2O3S[M+H] + The LC-MS (ESI) calculation for this was 423.18, and the measured value was 423.10.

[0232] N-(10-hexyl-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-7-yl)furan-3-carboxamide. 1H NMR (400 MHz, chloroform-d) δ 8.24 (s, 1H), 8.07 (s, 1H), 7.83 (d, J = 2.5 Hz, 1H), 7.67 - 7.58 (m, 2H), 7.44 (t, J = 1.8 Hz, 1H), 7.33 (dd, J = 7.4, 1.6 Hz, 1H), 7.27 (d, J = 5.3 Hz, 1H), 7.22 (td, J = 7.2, 1.8 Hz, 2H), 6.77 (d, J = 1.1 Hz, 1H), 4.69 (dd, J = 14.5, 6.8 Hz, 1H), 3.59 - 3.47 (m, 1H), 1.61 (p, J = 7.4 Hz, 2H), 1.43 - 1.12 (m, 6H), 0.90 - 0.79 (m, 3H). 13 ¹¹C NMR (10¹ MHz, chloroform-d) δ 169.0, 161.0, 151.9, 150.5, 145.5, 145.0, 144.0, 139.0, 138.9, 138.2, 137.4, 135.8, 131.2, 131.0, 130.6, 129.6, 128.6, 126.1, 124.2, 122.7, 121.3, 121.0, 51.0, 31.4, 28.0, 26.6, 22.5, 14.0. 24 H 25 N2O3S[M+H] + The LC-MS (ESI) calculation for this is 421.16, and the measured value is 421.10.

[0233] 10-(2-methoxyethyl)-7-((1-phenylethyl)amino)dibenzo[b,f][1,4]thiazepine-11(10H)-one. 1H NMR (400 MHz, chloroform-d) δ 7.68 - 7.61 (m, 1H), 7.42 - 7.30 (m, 4H), 7.28 (ddd, J = 5.2, 3.5, 1.7 Hz, 2H), 7.23 (dt, J = 7.4, 1.8 Hz, 2H), 7.15 (d, J = 8.7 Hz, 1H), 6.72 (dd, J = 20.6, 2.8 Hz, 1H), 6.37 (ddd, J = 12.8, 8.7, 2.8 Hz, 1H), 4.54 - 4.46 (m, 1H), 4.45 - 4.35 (m, 1H), 3.84 - 3.70 (m, 2H), 3.62 - 3.52 (m, 1H), 3.31 (d, J = 1.8 Hz, 3H), 1.49 (d, J = 6.7 Hz, 3H). 13 C NMR (101 MHz, chloroform-d) δ 169.3, 145.3, 145.2, 144.4, 139.2, 138.7, 137.2, 133.3, 131.1 (d, J = 4.0 Hz), 130.9 (d, J = 3.2 Hz), 130.3 (d, J = 1.4 Hz), 128.8, 128.4 (d, J = 1.5 Hz), 127.2, 126.9 (d, J = 3.5 Hz), 125.8 (d, J = 3.7 Hz), 116.7, 116.3, 113.9, 113.6, 70.0, 58.8, 53.6, 51.2, 29.7, 24.7. C 24 H 25 N2O2S[M+H] + The LC-MS (ESI) calculation for this is 405.17, and the measured value is 405.10.

[0234] N-(6-(2-methoxyethyl)-5-oxo-5,6-dihydrobenzo[b]pyrido[3,2-f][1,4]thiazepine-9-yl)benzamide. 1H NMR (400 MHz, methanol-d4) δ 8.30 (dd, J = 4.9, 1.8 Hz, 1H), 8.25 (s, 1H), 7.81 (dd, J = 7.6, 1.8 Hz, 1H), 7.78 - 7.71 (m, 1H), 7.63 (s, 1H), 7.48 (d, J = 6.0 Hz, 2H), 7.16 (dd, J = 7.6, 4.8 Hz, 1H), 6.95 (s, 1H), 3.58 (dp, J = 8.5, 4.3, 3.6 Hz, 4H), 3.40 (s, 3H). 13 ¹³C NMR (101 MHz, methanol-d4) δ 168.0, 167.5, 161.9, 157.1, 150.2, 150.0, 138.0, 137.0, 135.5, 135.3, 134.6, 131.8, 129.7, 128.3, 127.3, 119.7, 119.2, 116.1, 107.8, 107.6, 70.4, 57.6, 39.4. 22 H 20 N3O3S[M+Na] + The LC-MS (ESI) calculation value for this is 428.10, and the measured value is 428.00.

[0235] N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-7-yl)azetidine-1-carboxamide. 1 H NMR (400 MHz, methanol-d4) δ 7.78 (d, J = 2.4 Hz, 1H), 7.63 - 7.55 (m, 1H), 7.52 - 7.37 (m, 3H), 7.40 - 7.29 (m, 2H), 4.55 (ddd, J = 14.0, 6.8, 5.3 Hz, 1H), 4.06 (t, J = 7.6 Hz, 4H), 3.90 (dt, J = 14.0, 5.3 Hz, 1H), 3.75 - 3.65 (m, 1H), 3.60 (dt, J = 10.5, 5.4 Hz, 1H), 3.29 (s, 3H), 2.34 - 2.22 (m, 2H). 13¹³C NMR (10¹ MHz, methanol-d4) δ 170.0, 157.3, 139.1, 138.1, 138.0, 137.5, 136.6, 130.7, 130.3, 128.4, 126.2, 122.8, 120.4, 69.6, 57.6, 50.7, 49.2. 20 H 22 N3O3S[M+H] + The LC-MS (ESI) calculation for this is 384.14, and the measured value is 384.10.

[0236] Phenyl(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-7-yl)carbamate. 1 H NMR (400 MHz, chloroform-d) δ 7.73 (s, 1H), 7.68 (dd, J = 7.5, 1.7 Hz, 1H), 7.45 - 7.33 (m, 6H), 7.32 - 7.26 (m, 2H), 7.25 - 7.20 (m, 1H), 7.14 (d, J = 7.4 Hz, 2H), 4.61 - 4.50 (m, 1H), 3.91 (dt, J = 13.7, 5.5 Hz, 1H), 3.86 - 3.76 (m, 1H), 3.70 - 3.60 (m, 1H), 3.33 (s, 3H). 13 ¹¹C NMR (10¹ MHz, chloroform-d) δ 169.2, 151.6, 150.4, 139.4, 138.9, 138.3, 137.2, 135.5, 131.1, 131.0, 130.7, 129.4, 128.6, 126.8, 125.9, 122.6, 121.6, 119.8, 70.2, 58.9, 51.6. 23 H 21 N2O4S[M+H] + The LC-MS (ESI) calculation value for this is 421.12, and the measured value is 421.10.

[0237] 3-Methoxy-N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-7-yl)azetidine-1-carboxamide. 1 H NMR (400 MHz, methanol-d4) δ 7.78 (d, J = 2.4 Hz, 1H), 7.63 - 7.56 (m, 1H), 7.53 - 7.39 (m, 3H), 7.39 - 7.26 (m, 2H), 4.55 (ddd, J = 14.0, 6.8, 5.3 Hz, 1H), 4.21 (d, J = 6.5 Hz, 3H), 3.96 - 3.81 (m, 3H), 3.75 - 3.65 (m, 1H), 3.65 - 3.55 (m, 1H), 3.30 (d, J = 2.0 Hz, 6H). 13 ¹³C NMR (10¹ MHz, methanol-d4) δ 170.0, 157.4, 139.1, 138.1, 137.9, 137.6, 136.7, 130.7, 130.4, 128.4, 126.3, 122.9, 120.4, 69.6, 68.6, 57.6, 56.2, 55.0, 50.8. 21 H 24 N3O4S[M+H] + The LC-MS (ESI) calculation value for this is 414.15, and the measured value is 414.10.

[0238] 1-(11-oxo-10-(2-(propa-2-in-1-yloxy)ethyl)-10,11-dihydrodibenzo[b,f][1,4]thiazepine-7-yl)-3-phenylurea. 1H NMR (400 MHz, chloroform-d) δ 7.84 (s, 1H), 7.71 (s, 1H), 7.65 - 7.59 (m, 1H), 7.47 (d, J = 2.4 Hz, 1H), 7.43 - 7.35 (m, 1H), 7.38 - 7.17 (m, 8H), 7.06 - 6.97 (m, 1H), 4.64 - 4.53 (m, 1H), 4.10 (d, J = 1.5 Hz, 2H), 3.96 - 3.83 (m, 2H), 3.81 - 3.71 (m, 1H), 2.37 (t, J = 2.4Hz, 1H). 13 ¹¹C NMR (10¹ MHz, chloroform-d) δ 170.1, 153.2, 139.1, 138.1, 138.0, 137.6, 137.2, 137.0, 131.2, 131.0, 130.8, 129.1, 128.8, 126.5, 123.7, 123.1, 120.5, 120.3, 79.3, 74.9, 67.2, 58.4, 51.5. 25 H 22 N3O3S[M+H] + The LC-MS (ESI) calculation value for this is 444.14, and the measured value is 444.10.

[0239] 4-(tert-butyl)-N-(11-oxo-10-(2-(propa-2-in-1-yloxy)ethyl)-10,11-dihydrodibenzo[b,f][1,4]thiazepine-7-yl)benzamide. 1H NMR (400 MHz, chloroform-d) δ 7.94 (d, J = 2.5 Hz, 1H), 7.89 (s, 1H), 7.77 (d, J = 8.5 Hz, 2H), 7.67 (dd, J = 7.0, 2.2 Hz, 1H), 7.60 (dd, J = 8.8, 2.5 Hz, 1H), 7.48 (dd, J = 8.6, 6.4 Hz, 3H), 7.41 (dd, J = 7.3, 1.5 Hz, 1H), 7.29 (dd, J = 7.4, 1.9 Hz, 2H), 4.64 - 4.52 (m, 1H), 4.16 (d, J = 2.4 Hz, 2H), 4.02 - 3.89 (m, 2H), 3.81 (dq, J = 10.0, 5.3, 4.8 Hz, 1H), 2.41 (t, J = 2.4 Hz, 1H), 1.35 (s, 9H). 13 ¹¹C NMR (10¹ MHz, chloroform-d) δ 169.1, 165.6, 155.9, 139.9, 138.9, 138.3, 137.1, 136.0, 131.5, 131.2, 131.1, 130.7, 128.6, 126.9, 126.7, 125.8, 124.0, 121.2, 79.5, 74.6, 67.6, 58.4, 51.5, 35.0, 31.1. 29 H 29 N2O3S[M+H] + The LC-MS (ESI) calculation for this was 485.19, and the measured value was 485.10.

[0240] 4-Methoxy-3-methyl-N-(11-oxo-10-(2-(propa-2-in-1-yloxy)ethyl)-10,11-dihydrodibenzo[b,f][1,4]thiazepine-7-yl)benzamide. 1H NMR (400 MHz, chloroform-d) δ 7.91 (d, J = 2.5 Hz, 1H), 7.84 (s, 1H), 7.73 - 7.57 (m, 4H), 7.46 (d, J = 8.8 Hz, 1H), 7.43 - 7.36 (m, 1H), 7.33 - 7.20 (m, 2H), 6.90 - 6.83 (m, 1H), 4.64 - 4.52 (m, 1H), 4.16 (d, J = 2.5 Hz, 2H), 3.96 (h, J = 5.0 Hz, 2H), 3.89 (s, 3H), 3.87 - 3.73 (m, 1H), 2.41 (t, J = 2.4 Hz, 1H), 2.26 (s, 3H). 13 ¹¹C NMR (10¹ MHz, chloroform-d) δ 169.1, 165.4, 160.9, 144.6, 139.7, 138.9, 138.3, 137.1, 136.1, 131.2, 131.1, 131.0, 130.9, 130.7, 130.4, 129.5, 128.6, 128.4, 127.2, 127.1, 126.7, 126.6, 126.0, 123.9, 121.1, 118.4, 116.0, 109.6, 79.5, 74.5, 67.5, 58.4, 55.5, 51.5, 51.2, 29.7, 16.3. C 27 H 25 N2O4S[M+H] + The LC-MS (ESI) calculation for this was 473.16, and the measured value was 473.20.

[0241] 1-Cyclohexyl-3-(11-oxo-10-(2-(propa-2-in-1-yloxy)ethyl)-10,11-dihydrodibenzo[b,f][1,4]thiazepine-7-yl)urea. 1H NMR (400 MHz, chloroform-d) δ 7.66 - 7.59 (m, 1H), 7.55 (d, J = 2.5 Hz, 1H), 7.42 - 7.35 (m, 1H), 7.32 (d, J = 8.8 Hz, 1H), 7.24 (dt, J = 8.6, 2.8 Hz, 3H), 7.09 (s, 1H), 5.10 (d, J = 7.9 Hz, 1H), 4.56 (ddd, J = 16.3, 9.0, 5.3 Hz, 1H), 4.13 (dd, J = 2.4, 1.2 Hz, 2H), 3.96 - 3.85 (m, 2H), 3.82 - 3.70 (m, 1H), 3.60 (tq, J = 11.3, 3.8 Hz, 1H), 2.39 (t, J = 2.4 Hz, 1H), 1.94 - 1.86 (m, 2H), 1.70 - 1.65 (m, 1H), 1.56 (dt, J = 8.0, 3.9 Hz, 1H), 1.41 - 1.21 (m, 3H), 1.21 - 0.96 (m, 3H). 13 ¹¹C NMR (10¹ MHz, chloroform-d) δ 169.6, 154.6, 139.1, 138.2, 137.7, 137.6, 137.0, 131.1, 131.0, 130.8, 128.6, 126.6, 122.9, 120.2, 79.4, 74.7, 67.4, 58.4, 51.4, 48.9, 33.6, 25.5, 24.8. 25 H 28 N3O3S[M+H] + The LC-MS (ESI) calculation for this was 450.19, and the measured value was 450.10.

[0242] N-(11-oxo-10-(2-(propa-2-in-1-yloxy)ethyl)-10,11-dihydrodibenzo[b,f][1,4]thiazepine-7-yl)azetidine-1-carboxamide. 1H NMR (400 MHz, chloroform-d) δ 7.64 (d, J = 9.2 Hz, 2H), 7.37 (d, J = 9.1 Hz, 3H), 7.32 - 7.19 (m, 2H), 6.16 (s, 1H), 4.63 - 4.50 (m, 1H), 4.14 (d, J = 2.4 Hz, 2H), 4.05 (t, J = 7.6 Hz, 4H), 3.98 - 3.86 (m, 2H), 3.82 - 3.71 (m, 1H), 2.40 (t, J = 2.3 Hz, 1H), 2.28 (p, J = 7.5 Hz, 2H). 13 ¹¹C NMR (10¹ MHz, chloroform-d) δ 169.2, 155.8, 139.0, 138.4, 138.3, 136.9, 136.8, 131.1, 131.0, 130.6, 128.5, 126.6, 122.8, 120.1, 79.5, 74.6, 67.5, 58.3, 51.3, 49.2, 15.2. 22 H 22 N3O3S[M+H] + The LC-MS (ESI) calculation value for this is 408.14, and the measured value is 408.10.

[0243] N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-7-yl)pyrrolidine-1-carboxamide. 1 H NMR (400 MHz, chloroform-d) δ 7.70 (d, J = 2.2 Hz, 1H), 7.65 (dd, J = 7.4, 1.8 Hz, 2H), 7.44 - 7.32 (m, 3H), 7.32 - 7.19 (m, 2H), 6.37 (s, 1H), 4.61 - 4.50 (m, 1H), 3.87 (dt, J = 13.5, 5.6 Hz, 1H), 3.78 (dt, J = 10.0, 6.2 Hz, 1H), 3.66 - 3.56 (m, 1H), 3.46 - 3.35 (m, 4H), 3.32 (s, 3H), 2.00 - 1.88 (m, 4H). 13¹³C NMR (10¹ MHz, chloroform-d) δ 169.2, 153.6, 139.1, 138.4, 138.2, 137.3, 136.8, 131.1, 131.0, 130.5, 128.5, 126.4, 123.2, 120.5, 70.0, 58.8, 51.3, 48.0, 45.8, 25.6. 21 H 24 N3O3S[M+H] + The LC-MS (ESI) calculation for this is 398.16, and the measured value is 398.10.

[0244] N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-7-yl)piperidine-1-carboxamide. 1 H NMR (400 MHz, chloroform-d) δ 7.64 (dt, J = 5.1, 2.0 Hz, 2H), 7.43 - 7.33 (m, 2H), 7.31 (d, J = 2.5 Hz, 1H), 7.24 (dd, J = 7.4, 2.0 Hz, 2H), 6.55 (s, 1H), 4.61 - 4.50 (m, 1H), 3.87 (dt, J = 13.5, 5.5 Hz, 1H), 3.82 - 3.73 (m, 1H), 3.65 - 3.56 (m, 1H), 3.41 (t, J = 5.3 Hz, 4H), 3.32 (s, 3H), 1.69 - 1.55 (m, 6H). 13 ¹³C NMR (10¹ MHz, chloroform-d) δ 169.2, 154.5, 139.1, 138.4, 138.3, 137.4, 136.8, 131.1, 131.0, 130.6, 128.5, 126.4, 123.5, 120.8, 70.0, 58.8, 51.3, 45.3, 25.7, 24.3. 22 H 26 N3O3S[M+H] + The LC-MS (ESI) calculation for this was 412.17, and the measured value was 412.10.

[0245] N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-7-yl)azepan-1-carboxamide. 1 H NMR (400 MHz, chloroform-d) δ 7.62 (dd, J = 7.3, 1.9 Hz, 1H), 7.56 (d, J = 2.5 Hz, 1H), 7.44 - 7.29 (m, 2H), 7.29 - 7.18 (m, 3H), 5.29 (t, J = 5.7 Hz, 1H), 4.60 - 4.49 (m, 1H), 3.86 (dt, J = 13.7, 5.3 Hz, 1H), 3.80 - 3.70 (m, 1H), 3.65 - 3.55 (m, 1H), 3.31 (s, 3H), 3.18 (p, J = 7.2 Hz, 3H), 1.66 (s, 1H), 1.50 - 1.37 (m, 3H), 0.86 (q, J = 6.8, 5.2 Hz, 4H). 13 ¹¹C NMR (10¹ MHz, chloroform-d) δ 169.6, 155.5, 139.1, 138.2, 137.8, 137.6, 137.0, 131.1, 130.9, 130.8, 128.6, 126.6, 122.9, 120.3, 70.0, 58.9, 51.4, 40.3, 31.5, 30.0, 26.6, 22.6, 14.0. 23 H 28 N3O3S[M+H] + The LC-MS (ESI) calculation for this was 426.19, and the measured value was 426.10.

[0246] (S)-3-fluoro-N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-7-yl)pyrrolidine-1-carboxamide. 1H NMR (400 MHz, chloroform-d) δ 7.70 - 7.63 (m, 2H), 7.46 - 7.36 (m, 3H), 7.32 - 7.25 (m, 3H), 6.14 (s, 1H), 5.36 (d, J = 3.9 Hz, 0.5H), 5.23 (t, J = 3.6 Hz, 0.5H), 4.55 (dt, J = 13.1, 6.2 Hz, 1H), 3.93 - 3.76 (m, 3H), 3.74 - 3.47 (m, 5H), 3.34 (s, 3H). C 21 H 23 FN3O3S[M+H] + The LC-MS (ESI) calculation value for this is 416.14, and the measured value is 415.10.

[0247] 3-Cyano-N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-7-yl)azetidine-1-carboxamide. 1 H NMR (400 MHz, chloroform-d) δ 7.74 - 7.60 (m, 2H), 7.47 - 7.32 (m, 3H), 7.31 - 7.21 (m, 2H), 6.51 (s, 1H), 4.53 (dt, J = 12.2, 6.4 Hz, 1H), 4.42 - 4.21 (m, 1H), 3.89 (dt, J = 13.7, 5.4 Hz, 1H), 3.83 - 3.73 (m, 1H), 3.62 (dt, J = 10.5, 5.5 Hz, 1H), 3.53 - 3.41 (m, 1H), 3.33 (s, 3H). 13 ¹³C NMR (10¹ MHz, chloroform-d) δ 169.2, 153.6, 139.1, 138.4, 138.2, 137.3, 136.8, 131.1, 131.0, 130.5, 128.5, 126.4, 123.2, 120.5, 70.0, 58.8, 51.3, 48.0, 45.8, 25.6. 21 H 21 N4O3S[M+H] +The LC-MS (ESI) calculation value for this is 409.14, and the measured value is 409.30.

[0248] N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-7-yl)-2-oxa-6-azaspiro[3,3]heptan-6-carboxamide. 1 H NMR (400 MHz, chloroform-d) δ 7.69 - 7.61 (m, 2H), 7.43 - 7.32 (m, 3H), 7.32 - 7.20 (m, 2H), 6.13 (s, 1H), 4.79 (s, 4H), 4.54 (dd, J = 12.9, 6.9 Hz, 1H), 4.18 (s, 4H), 3.89 (dt, J = 13.7, 5.5 Hz, 1H), 3.84 - 3.74 (m, 1H), 3.67 - 3.57 (m, 1H), 3.33 (s, 3H)。 13 ¹¹C NMR (10¹ MHz, chloroform-d) δ 169.1, 155.6, 138.8, 138.4, 136.4, 131.1, 131.0, 130.6, 128.6, 126.7, 123.0, 120.3, 80.8, 70.1, 58.8, 51.5, 37.7, 29.8. 22 H 24 N3O4S[M+H] + The LC-MS (ESI) calculation value for this is 426.15, and the measured value is 426.30.

[0249] 2-Methoxy-N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-7-yl)benzamide. 1H NMR (400 MHz, chloroform-d) δ 8.05 (s, 1H), 7.93 (d, J = 2.5 Hz, 1H), 7.68 - 7.57 (m, 2H), 7.47 (d, J = 8.8 Hz, 1H), 7.42 - 7.37 (m, 2H), 7.37 - 7.33 (m, 2H), 7.31 - 7.22 (m, 2H), 7.12 - 7.03 (m, 1H), 4.54 (ddd, J = 13.8, 6.6, 5.5 Hz, 1H), 3.92 (dt, J = 13.8, 5.5 Hz, 1H), 3.85 (s, 3H), 3.83 - 3.77 (m, 1H), 3.68 - 3.59 (m, 1H), 3.34 (s, 3H). 13 ¹¹C NMR (10¹ MHz, chloroform-d) δ 169.1, 165.6, 160.0, 140.0, 138.9, 138.3, 137.1, 135.9, 135.8, 131.1, 131.0, 130.7, 129.8, 128.6, 126.7, 124.1, 121.2, 118.7, 118.2, 112.6, 70.2, 58.9, 55.5, 51.6. 24 H 23 N2O4S[M+H] + The LC-MS (ESI) calculation for this was 435.14, and the measured value was 435.30.

[0250] N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-7-yl)cyclopropanecarboxamide. 1H NMR (400 MHz, chloroform-d) δ 8.04 (s, 1H), 7.93 (d, J = 2.5 Hz, 1H), 7.71 - 7.57 (m, 2H), 7.47 (d, J = 8.7 Hz, 1H), 7.41 (s, 2H), 7.35 (d, J = 5.3 Hz, 2H), 7.27 (pd, J = 7.4, 1.7 Hz, 2H), 7.12 - 7.03 (m, 1H), 4.60 - 4.49 (m, 1H), 3.92 (dt, J = 13.8, 5.5 Hz, 1H), 3.85 (s, 3H), 3.81 (dd, J = 5.9, 4.1 Hz, 1H), 3.69 - 3.59 (m, 1H), 3.34 (s, 3H). 13 ¹¹C NMR (10¹ MHz, chloroform-d) δ 169.1, 165.6, 160.0, 140.0, 138.9, 138.3, 137.1, 135.9, 135.8, 131.1, 131.0, 130.7, 129.8, 128.6, 126.7, 124.1, 121.2, 118.7, 118.2, 112.6, 70.2, 58.9, 55.5, 51.6. 24 H 23 N2O4S[M+H] + The LC-MS (ESI) calculation for this was 435.14, and the measured value was 435.30.

[0251] 3-Bromo-4-methoxy-N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-7-yl)benzamide. 1H NMR (400 MHz, chloroform-d) δ 8.17 (s, 1H), 8.04 (d, J = 2.3 Hz, 1H), 7.91 (d, J = 2.5 Hz, 1H), 7.81 (dd, J = 8.6, 2.3 Hz, 1H), 7.67 - 7.57 (m, 2H), 7.46 (d, J = 8.8 Hz, 1H), 7.38 (dd, J = 6.7, 2.3 Hz, 1H), 7.33 - 7.19 (m, 2H), 6.91 (d, J = 8.7 Hz, 1H), 4.59 - 4.48 (m, 1H), 3.95 (s, 3H), 3.91 (m, 1H), 3.86 - 3.76 (m, 1H), 3.68 - 3.59 (m, 1H), 3.34 (s, 3H). 13 ¹¹C NMR (10¹ MHz, chloroform-d) δ 169.2, 164.1, 158.8, 139.9, 138.8, 138.3, 137.0, 135.9, 132.3, 131.1, 131.0, 130.7, 128.6, 128.2, 127.8, 126.7, 124.2, 121.4, 111.9, 111.4, 70.1, 58.9, 56.5, 51.6. 24 H 22 BrN2O4S[M+H] + The LC-MS (ESI) calculation value for this is 513.05, and the measured value is 513.30.

[0252] 3-Fluoro-4-methoxy-N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-7-yl)benzamide. 1H NMR 1H NMR (400 MHz, chloroform-d) δ 8.13 (s, 1H), 7.92 (d, J = 2.5 Hz, 1H), 7.68 - 7.56 (m, 4H), 7.47 (d, J = 8.8 Hz, 1H), 7.39 (dd, J = 7.3, 1.6 Hz, 1H), 7.32 - 7.20 (m, 2H), 6.99 (t, J = 8.2 Hz, 1H), 4.60 - 4.49 (m, 1H), 3.95 (s, 3H), 3.95 - 3.87 (m, 1H), 3.86 - 3.76 (m, 1H), 3.69 - 3.59 (m, 1H), 3.34 (s, 3H). 13 ¹¹C NMR (10¹ MHz, chloroform-d) δ 169.2, 164.3, 153.2, 150.7, 140.0, 138.9, 138.3, 137.0, 135.9, 131.1, 131.0, 130.7, 128.6, 126.7, 124.2, 123.8, 121.3, 115.4, 115.2, 112.8, 70.1, 58.9, 56.3, 51.6. 24 H 22 FN2O4S[M+H] + The LC-MS (ESI) calculation for this was 453.13, and the measured value was 453.30.

[0253] 3,4-Dichloro-N-(11-oxo-10-(2-(propa-2-in-1-yloxy)ethyl)-10,11-dihydrodibenzo[b,f][1,4]thiazepine-7-yl)benzamide. 1H NMR (400 MHz, chloroform-d) δ 8.30 (s, 1H), 7.92 (dd, J = 4.9, 2.3 Hz, 2H), 7.72 - 7.57 (m, 3H), 7.50 (dd, J = 10.2, 8.6 Hz, 2H), 7.46 - 7.34 (m, 1H), 7.31 - 7.20 (m, 2H), 4.62 - 4.49 (m, 1H), 4.16 (d, J = 2.4 Hz, 2H), 4.03 - 3.91 (m, 2H), 3.85 - 3.75 (m, 1H), 2.41 (t, J = 2.4Hz, 1H). 13 ¹¹C NMR (10¹ MHz, chloroform-d) δ 169.3, 163.7, 140.2, 138.8, 138.1, 137.1, 136.6, 135.5, 134.2, 133.3, 131.0, 130.8, 129.3, 128.7, 126.8, 126.3, 124.3, 121.5, 79.4, 74.7, 67.6, 58.4, 51.6. 25 H 19 Cl2N2O3S[M+H] + The LC-MS (ESI) calculation value for this is 497.05, and the measured value is 497.10.

[0254] N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-7-yl)-1H-benzo[d][1,2,3]triazole-5-carboxamide. 1H NMR (400 MHz, methanol-d4) δ 8.53 (s, 1H), 8.11 (d, J = 2.5 Hz, 1H), 8.04 (dd, J = 8.7, 1.5 Hz, 1H), 7.93 (d, J = 8.7 Hz, 1H), 7.74 (dd, J = 8.8, 2.5 Hz, 1H), 7.66 - 7.56 (m, 2H), 7.59 - 7.41 (m, 1H), 7.43 - 7.28 (m, 2H), 4.59 (ddd, J = 14.1, 6.8, 5.1 Hz, 1H), 4.02 - 3.91 (m, 1H), 3.78 - 3.69 (m, 1H), 3.65 (dt, J = 10.5, 5.4 Hz, 1H), 3.32 (s, 3H). 13 ¹³C NMR (101 MHz, methanol-d4) δ 169.9, 166.7, 139.3, 139.0, 138.1, 137.0, 136.8, 130.8, 130.7, 130.4, 128.5, 126.5, 124.3, 121.8, 69.7, 57.6, 50.9. 23 H 20 N5O3S[M+H] + The LC-MS (ESI) calculation for this was 446.13, and the measured value was 446.30.

[0255] N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-7-yl)-2-methylfuran-3-carboxamide. 1H NMR (400 MHz, chloroform-d) δ 7.88 (d, J = 2.5 Hz, 1H), 7.65 (dd, J = 7.5, 1.8 Hz, 1H), 7.59 (s, 1H), 7.52 (dd, J = 8.8, 2.5 Hz, 1H), 7.44 (d, J = 8.7 Hz, 1H), 7.39 (dd, J = 7.0, 2.0 Hz, 1H), 7.34 - 7.24 (m, 2H), 6.53 (d, J = 2.1 Hz, 1H), 3.91 (dt, J = 13.7, 5.5 Hz, 1H), 3.85 - 3.75 (m, 1H), 3.69 - 3.58 (m, 1H), 3.33 (s, 3H), 2.62 (s, 3H). 13 ¹¹C NMR (10¹ MHz, chloroform-d) δ 169.1, 162.1, 158.5, 140.7, 139.8, 138.9, 138.3, 137.0, 135.8, 131.1, 131.0, 130.7, 128.6, 126.6, 124.0, 121.2, 115.4, 108.0, 70.1, 58.9, 51.5, 13.7. 22 H 21 N2O4S[M+H] + The LC-MS (ESI) calculation value for this is 409.12, and the measured value is 409.20.

[0256] N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-7-yl)-2,5-dimethylfuran-3-carboxamide. 1H NMR (400 MHz, chloroform-d) δ 7.88 (d, J = 2.5 Hz, 1H), 7.67 (dd, J = 7.6, 1.7 Hz, 1H), 7.50 (dd, J = 8.8, 2.5 Hz, 1H), 7.45 (d, J = 8.7 Hz, 1H), 7.41 (dd, J = 7.1, 1.8 Hz, 1H), 7.34 (s, 1H), 7.33 - 7.27 (m, 2H), 6.07 (s, 1H), 4.61 - 4.50 (m, 1H), 3.91 (dt, J = 13.7, 5.5 Hz, 1H), 3.86 - 3.75 (m, 1H), 3.68 - 3.58 (m, 1H), 3.34 (s, 3H), 2.57 (s, 3H), 2.27 (s, 3H). 13 ¹C NMR (10¹ MHz, chloroform-d) δ 169.1, 162.2, 156.8, 150.5, 139.7, 138.9, 138.4, 137.1, 135.8, 131.2, 131.0, 130.7, 128.6, 126.7, 123.8, 121.0, 115.8, 103.6, 70.1, 58.9, 51.5, 13.6, 13.3. 23 H 23 N2O4S[M+H] + The LC-MS (ESI) calculation for this was 423.14, and the measured value was 423.20.

[0257] N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-7-yl)benzo[d]oxazole-5-carboxamide. 1H NMR (400 MHz, chloroform-d) δ 8.35 (s, 1H), 8.29 (d, J = 1.7 Hz, 1H), 8.19 (s, 1H), 8.03 - 7.94 (m, 3H), 7.65 (ddd, J = 7.8, 5.3, 2.5 Hz, 3H), 7.50 (d, J = 8.8 Hz, 1H), 7.41 (dd, J = 7.4, 1.6 Hz, 1H), 7.28 (qd, J = 7.1, 1.7 Hz, 2H), 4.61 - 4.50 (m, 1H), 3.94 (dt, J = 13.8, 5.4Hz, 1H), 3.87 - 3.77 (m, 1H), 3.70 - 3.60 (m, 1H), 3.35 (s, 3H). 13 ¹¹C NMR (10¹ MHz, chloroform-d) δ 169.1, 165.3, 153.9, 152.2, 140.3, 140.1, 138.9, 138.3, 137.1, 135.9, 131.7, 131.1, 131.0, 130.7, 128.6, 126.8, 125.5, 124.2, 121.4, 119.7, 111.5, 70.2, 58.9, 51.6. 24 H 20 N3O4S[M+H] + The LC-MS (ESI) calculation value for this is 446.12, and the measured value is 446.00.

[0258] N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-7-yl)-4-propoxybenzamide. 1H NMR (400 MHz, chloroform-d) δ 8.00 (s, 1H), 7.92 (d, J = 2.5 Hz, 1H), 7.80 (d, J = 8.8 Hz, 2H), 7.65 (dd, J = 7.4, 1.8 Hz, 1H), 7.59 (dd, J = 8.8, 2.5 Hz, 1H), 7.45 (d, J = 8.8 Hz, 1H), 7.39 (dd, J = 7.4, 1.6 Hz, 1H), 7.34 - 7.12 (m, 2H), 6.93 (d, J = 8.8 Hz, 2H), 4.61 - 4.50 (m, 1H), 3.97 (t, J = 6.6 Hz, 2H), 3.91 (dd, J = 13.8, 5.5 Hz, 1H), 3.85 - 3.75 (m, 1H), 3.68 - 3.58 (m, 1H), 3.33 (s, 3H), 1.83 (q, J = 7.6, 7.2 Hz, 2H), 1.05 (t, J = 7.4 Hz, 3H). 13 ¹¹C NMR (10¹ MHz, chloroform-d) δ 169.2, 165.3, 162.3, 139.7, 138.9, 138.3, 137.0, 136.1, 131.1, 131.0, 129.0, 128.6, 126.7, 126.2, 124.0, 121.2, 114.5, 70.1, 69.8, 58.9, 51.5, 22.5, 10.5. 26 H 27 N2O4S[M+H] + The LC-MS (ESI) calculation for this was 463.17, and the measured value was 463.30.

[0259] N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-7-yl)cyclopropanecarboxamide. 1H NMR (400 MHz, chloroform-d) δ 7.93 (s, 1H), 7.90 (d, J = 2.5 Hz, 1H), 7.65 (dd, J = 7.1, 2.1 Hz, 1H), 7.57 (dd, J = 8.8, 2.5 Hz, 1H), 7.46 (d, J = 8.7 Hz, 1H), 7.38 (ddd, J = 13.8, 7.5, 1.8 Hz, 2H), 7.32 (d, J = 1.8 Hz, 1H), 7.30 - 7.22 (m, 2H), 6.84 (d, J = 8.1 Hz, 1H), 6.05 (s, 2H), 4.60 - 4.49 (m, 1H), 3.97 - 3.87 (m, 1H), 3.87 - 3.76 (m, 1H), 3.63 (dt, J = 10.4, 5.4 Hz, 1H), 3.34 (s, 3H). 13 ¹C NMR (10¹ MHz, chloroform-d) δ 169.1, 165.0, 150.9, 148.3, 139.9, 138.9, 138.3, 137.1, 135.9, 131.1, 131.0, 130.7, 128.6, 128.5, 126.7, 124.0, 121.8, 121.2, 108.2, 107.7, 101.9, 70.1, 58.9, 51.6. 24 H 21 N2O5S[M+H] + The LC-MS (ESI) calculation value for this is 449.12, and the measured value is 449.20.

[0260] 2-(7-(furan-3-carboxamide)-11-oxodibenzo[b,f][1,4]thiazepine-10(11H)-yl)ethylpenta-4-enoate. 1H NMR (400 MHz, chloroform-d) δ 8.07 - 8.02 (m, 1H), 7.85 (d, J = 2.5 Hz, 1H), 7.72 (s, 1H), 7.69 - 7.61 (m, 2H), 7.48 (t, J = 1.7 Hz, 1H), 7.40 (dd, J = 7.0, 1.9 Hz, 1H), 7.36 - 7.22 (m, 3H), 6.72 (d, J = 1.1 Hz, 1H), 5.04 - 4.93 (m, 2H), 4.91 - 4.84 (m, 1H), 4.36 (td, J = 5.9, 1.9 Hz, 2H), 3.87 (dt, J = 14.1, 6.1 Hz, 1H), 2.39 - 2.18 (m, 4H). 13 ¹C NMR (10¹ MHz, chloroform-d) δ 172.8, 169.1, 160.7, 145.4, 144.2, 139.4, 138.8, 137.9, 137.5, 136.6, 135.8, 131.3, 131.1, 130.9, 128.8, 126.3, 124.1, 122.6, 121.3, 115.5, 108.3, 61.9, 49.8, 33.4, 28.6. 25 H 23 N2O5S[M+H] + The LC-MS (ESI) calculation for this was 463.13, and the measured value was 463.20.

[0261] 4-Methoxy-N-(11-oxo-10-(2-propoxyethyl)-10,11-dihydrodibenzo[b,f][1,4]thiazepine-7-yl)benzamide. 1H NMR (400 MHz, chloroform-d) δ 7.89 (d, J = 2.5 Hz, 1H), 7.85 - 7.76 (m, 2H), 7.72 (s, 1H), 7.67 (dd, J = 7.5, 1.7 Hz, 1H), 7.61 (dd, J = 8.8, 2.5 Hz, 1H), 7.54 (d, J = 8.8 Hz, 1H), 7.42 (dd, J = 7.5, 1.5 Hz, 1H), 7.35 - 7.27 (m, 2H), 7.01 - 6.93 (m, 2H), 4.51 (dt, J = 13.6, 5.8Hz, 1H), 4.02 - 3.92 (m, 1H), 3.92 - 3.83 (m, 4H), 3.73 - 3.63 (m, 1H), 3.45 - 3.38 (m, 2H), 1.55 (q, J = 7.1 Hz, 2H), 0.87 (t, J = 7.4 Hz, 3H). C 26 H 27 N2O4S[M+H] + The LC-MS (ESI) calculation for this was 463.17, and the measured value was 463.30.

[0262] (E)-N-(10-(hexa-2-en-1-yl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-7-yl)furan-3-carboxamide. 1H NMR (400 MHz, chloroform-d) δ 8.06 (s, 1H), 7.98 (s, 1H), 7.80 (d, J = 2.5 Hz, 1H), 7.66 (dd, J = 7.4, 1.8 Hz, 1H), 7.60 (dd, J = 8.7, 2.5 Hz, 1H), 7.45 (t, J = 1.7 Hz, 1H), 7.36 (td, J = 5.8, 5.0, 3.1 Hz, 2H), 7.26 - 7.19 (m, 2H), 6.75 (s, 1H), 5.64 (q, J = 5.2 Hz, 2H), 4.77 (dd, J = 14.9, 4.3 Hz, 1H), 4.47 (dd, J = 14.7, 4.6 Hz, 1H), 2.03 - 1.93 (m, 2H), 1.34 (h, J = 6.9 Hz, 2H), 0.83 (t, J = 7.4 Hz, 3H). 13 ¹C NMR (10¹ MHz, chloroform-d) δ 168.9, 160.8, 145.4, 144.1, 139.5, 138.8, 138.2, 136.7, 135.7, 134.5, 131.3, 131.0, 130.7, 130.6, 128.6, 126.2, 125.9, 124.9, 124.2, 124.0, 122.7, 121.3, 121.1, 108.4, 53.4, 34.3, 22.2, 13.6. 24 H 23 N2O3S[M+H] + The LC-MS (ESI) calculation value for this is 419.15, and the measured value is 419.30.

[0263] N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-7-yl)-2-methylfuran-3-carboxamide. 1H NMR (400 MHz, chloroform-d) δ 7.88 (d, J = 2.5 Hz, 1H), 7.65 (dd, J = 7.5, 1.8 Hz, 1H), 7.59 (s, 1H), 7.52 (dd, J = 8.8, 2.5 Hz, 1H), 7.44 (d, J = 8.7 Hz, 1H), 7.39 (dd, J = 7.0, 2.0 Hz, 1H), 7.34 - 7.24 (m, 2H), 6.53 (d, J = 2.1 Hz, 1H), 3.91 (dt, J = 13.7, 5.5 Hz, 1H), 3.85 - 3.75 (m, 1H), 3.69 - 3.58 (m, 1H), 3.33 (s, 3H), 2.62 (s, 3H). 13 ¹¹C NMR (10¹ MHz, chloroform-d) δ 169.1, 162.1, 158.5, 140.7, 139.8, 138.9, 138.3, 137.0, 135.8, 131.1, 131.0, 130.7, 128.6, 126.6, 124.0, 121.2, 115.4, 108.0, 70.1, 58.9, 51.5, 13.7. 22 H 21 N2O4S[M+H] + The LC-MS (ESI) calculation value for this is 409.12, and the measured value is 409.20.

[0264] N-(10-(2-methoxypropyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-7-yl)furan-3-carboxamide (reported as a racemic rotational isomer). 1H NMR (400 MHz, chloroform-d) δ 8.02 (dt, J = 2.6, 1.2 Hz, 1H), 7.87 (dd, J = 11.1, 2.4 Hz, 1H), 7.68 (ddd, J = 7.3, 3.3, 1.8 Hz, 1H), 7.62 - 7.52 (m, 2H), 7.49 (q, J = 1.3, 0.8 Hz, 1H), 7.45 - 7.38 (m, 2H), 7.36 - 7.27 (m, 2H), 6.72 - 6.66 (m, 1H), 4.76 (dd, J = 13.5, 4.5 Hz, 0.5H), 4.40 (dd, J = 13.6, 6.5 Hz, 0.5H), 3.90 (h, J = 6.2 Hz, 0.5H), 3.70 (ddd, J = 23.8, 12.6, 5.7 Hz, 1H), 3.49 (dd, J = 13.5, 7.4 Hz, 0.5H), 3.38 (s, 1.5H), 3.23 (s, 1.5H), 1.22 (d, J = 6.2 Hz, 1.5H), 1.18 (d, J = 6.2 Hz, 1.5H). C 22 H 21 N2O4S[M+H] + The LC-MS (ESI) calculation value for this is 409.12, and the measured value is 409.30.

[0265] N-(11-oxo-10-(2-(penta-4-en-1-yloxy)ethyl)-10,11-dihydrodibenzo[b,f][1,4]thiazepine-7-yl)furan-3-carboxamide. 1H NMR (600 MHz, chloroform-d) δ 8.04 (s, 1H), 7.84 (d, J = 2.5 Hz, 1H), 7.71 (s, 1H), 7.65 (dd, J = 7.4, 1.9 Hz, 1H), 7.59 (dd, J = 8.7, 2.5 Hz, 1H), 7.50 (d, J = 8.8 Hz, 1H), 7.47 (t, J = 1.7 Hz, 1H), 7.39 (dd, J = 7.4, 1.6 Hz, 1H), 7.33 - 7.21 (m, 2H), 6.71 (dd, J = 1.9, 0.9 Hz, 1H), 5.82 - 5.73 (m, 1H), 5.00 - 4.86 (m, 2H), 4.57 - 4.49 (m, 1H), 3.95 (dt, J = 13.8, 5.5 Hz, 1H), 3.85 (ddd, J = 10.1, 6.6, 5.3 Hz, 1H), 3.71 - 3.63 (m, 1H), 3.48 - 3.39 (m, 2H), 2.08 - 2.01 (m, 2H), 1.61 (dt, J = 13.7, 6.7 Hz, 2H). 13 ¹³C NMR (151 MHz, chloroform-d) δ 169.1, 160.7, 145.4, 144.2, 140.1, 138.8, 138.3, 138.3, 137.0, 135.5, 131.1, 131.0, 130.7, 128.6, 126.8, 124.0, 122.7, 121.2, 114.7, 108.3, 70.6, 68.3, 51.8, 30.3, 28.9. 25 H 25 N2O4S[M+H] + The LC-MS (ESI) calculation value for this is 449.15, and the measured value is 449.10.

[0266] 3,4-Difluoro-N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-7-yl)benzamide. 1¹H NMR (600 MHz, chloroform-d) δ 8.24 (s, 1H), 7.91 (d, J = 2.5 Hz, 1H), 7.76 - 7.69 (m, 1H), 7.66 - 7.56 (m, 3H), 7.49 (d, J = 8.7 Hz, 1H), 7.39 (dd, J = 6.9, 2.2 Hz, 1H), 7.30 - 7.19 (m, 3H), 4.53 (ddd, J = 13.9, 6.7, 5.3 Hz, 1H), 3.94 (dt, J = 13.9, 5.4 Hz, 1H), 3.81 (ddd, J = 10.1, 6.7, 5.2 Hz, 1H), 3.67 - 3.60 (m, 1H), 3.34 (s, 3H). 13 ¹C NMR (151 MHz, chloroform-d) δ 169.2, 163.6, 153.7, 151.9, 151.1, 149.5, 140.2, 138.8, 138.2, 137.1, 135.6, 131.4, 131.0 (d, J = 6.9 Hz), 130.8, 128.7, 126.8, 124.3, 123.7 (d, J = 3.6 Hz), 121.5, 117.8, 117.6, 117.1, 117.0, 70.1, 58.9, 51.7. 23 H 19 F2N2O3S[M+H] + The LC-MS (ESI) calculation value for this is 441.11, and the measured value is 441.20.

[0267] 4-Chloro-3-fluoro-N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-7-yl)benzamide. 1H NMR (600 MHz, chloroform-d) δ 8.19 (s, 1H), 7.93 (dd, J = 6.8, 2.3 Hz, 1H), 7.90 (d, J = 2.5 Hz, 1H), 7.74 (ddd, J = 8.6, 4.4, 2.3 Hz, 1H), 7.65 - 7.56 (m, 2H), 7.49 (d, J = 8.7 Hz, 1H), 7.39 (dd, J = 6.9, 2.2 Hz, 1H), 7.28 - 7.23 (m, 2H), 7.21 (t, J = 8.5 Hz, 1H), 4.53 (ddd, J = 13.9, 6.7, 5.4 Hz, 1H), 3.94 (dt, J = 13.9, 5.4 Hz, 1H), 3.81 (ddd, J = 10.1, 6.7, 5.2 Hz, 1H), 3.69 - 3.61 (m, 1H), 3.34 (s, 3H). 13 ¹C NMR (151 MHz, chloroform-d) δ 169.2, 163.6, 161.2, 159.5, 140.3, 138.8, 138.2, 137.1, 135.5, 131.6 (d, J = 3.6 Hz), 131.1, 131.0, 130.8, 130.1, 128.7, 127.4 (d, J = 8.2 Hz), 126.8, 124.3, 121.4, 117.1, 116.9, 70.1, 58.9, 51.7. 23 H 19 FClN2O3S[M+H] + The LC-MS (ESI) calculation for this was 457.08, and the measured value was 457.10.

[0268] N-(10-(2-cyanoethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-7-yl)furan-3-carboxamide. 1H NMR (400 MHz, chloroform-d) δ 8.10 - 8.01 (m, 1H), 7.85 (d, J = 2.5 Hz, 1H), 7.72 - 7.63 (m, 2H), 7.50 (dd, J = 4.1, 2.3 Hz, 2H), 7.42 (td, J = 7.3, 1.7 Hz, 1H), 7.35 - 7.28 (m, 3H), 7.10 (d, J = 8.6 Hz, 1H), 5.01 - 4.78 (m, 1H), 3.91 - 3.70 (m, 1H), 2.96 - 2.86 (m, 2H). C 21 H 16 N3O3S[M+H] + The LC-MS (ESI) calculation for this was 390.08, and the measured value was 390.20.

[0269] 4-Chloro-3-methoxy-N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-7-yl)benzamide. 1 H NMR (600 MHz, chloroform-d) δ 8.36 (s, 1H), 7.93 (d, J = 2.5 Hz, 1H), 7.89 (d, J = 2.3 Hz, 1H), 7.77 (dd, J = 8.6, 2.3 Hz, 1H), 7.66 - 7.57 (m, 2H), 7.46 (d, J = 8.7 Hz, 1H), 7.38 (dd, J = 7.4, 1.5 Hz, 1H), 7.26 - 7.21 (m, 2H), 6.94 (d, J = 8.7 Hz, 1H), 4.58 - 4.50 (m, 1H), 3.95 (s, 3H), 3.92 (dt, J = 13.8, 5.5 Hz, 1H), 3.84 - 3.77 (m, 1H), 3.67 - 3.60 (m, 1H), 3.34 (s, 3H). 13¹³C NMR (151 MHz, chloroform-d) δ 169.2, 157.9, 139.8, 138.9, 138.2, 137.0, 136.0, 131.1, 131.0, 130.7, 129.3, 128.6, 127.5, 127.4, 126.7, 124.2, 122.8, 121.4, 111.5, 70.1, 58.9, 56.4, 51.6. 24 H 22 ClN2O4S[M+H] + The LC-MS (ESI) calculation for this was 469.10, and the measured value was 469.30.

[0270] 4-Cyano-3-methoxy-N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-7-yl)benzamide. 1 H NMR (600 MHz, chloroform-d) δ 8.66 (s, 1H), 8.17 - 8.11 (m, 2H), 7.97 (d, J = 2.5 Hz, 1H), 7.60 (dd, J = 8.8, 2.5 Hz, 2H), 7.47 (d, J = 8.8 Hz, 1H), 7.39 - 7.33 (m, 1H), 7.27 - 7.19 (m, 2H), 7.03 (d, J = 8.9 Hz, 1H), 4.57 - 4.50 (m, 1H), 4.00 (s, 3H), 3.93 (dt, J = 13.9, 5.4 Hz, 1H), 3.80 (dt, J = 10.5, 6.0 Hz, 1H), 3.63 (dt, J = 10.5, 5.4 Hz, 1H), 3.33 (s, 3H). 13 ¹¹C NMR (151 MHz, chloroform-d) δ 169.3, 163.5, 139.9, 138.8, 138.1, 137.0, 135.9, 134.5, 132.9, 131.0, 131.0, 130.8, 128.6, 127.2, 126.7, 124.4, 121.6, 115.8, 111.5, 101.7, 70.1, 58.9, 56.6, 51.6. 25 H 22N3O4S[M+H] + The LC-MS (ESI) calculation for this was 460.13, and the measured value was 460.30.

[0271] 3,5-difluoro-4-methoxy-N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-7-yl)benzamide. 1 H NMR (600 MHz, chloroform-d) δ 8.25 (s, 1H), 7.90 (d, J = 2.5 Hz, 1H), 7.62 (dd, J = 6.7, 2.5 Hz, 1H), 7.58 (dd, J = 8.8, 2.6 Hz, 1H), 7.48 (d, J = 8.7 Hz, 1H), 7.44 (d, J = 8.1 Hz, 2H), 7.38 (dd, J = 7.3, 1.8 Hz, 1H), 7.26 - 7.19 (m, 2H), 4.52 (ddd, J = 13.9, 6.7, 5.3 Hz, 1H), 4.09 (s, 3H), 3.94 (dt, J = 13.9, 5.4 Hz, 1H), 3.84 - 3.78 (m, 1H), 3.64 (dt, J = 10.5, 5.5 Hz, 1H), 3.34 (s, 3H). 13 ¹³C NMR (151 MHz, chloroform-d) δ 169.3, 163.2, 155.8, 154.1, 140.2, 138.8, 138.1, 137.1, 135.5, 131.0, 130.8, 128.6, 126.8, 124.3, 121.5, 111.7 (d, J = 6.1 Hz), 111.6 (d, J = 6.0 Hz), 70.1, 58.9, 51.7. 24 H 21 F2N2O4S[M+H] + The LC-MS (ESI) calculation value for this is 471.12, and the measured value is 471.30.

[0272] 4-Formamide-N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-7-yl)benzamide.1 H NMR (600 MHz, chloroform-d) δ 8.44 (d, J = 1.6 Hz, 1H), 7.93 (dd, J = 4.8, 2.6 Hz, 1H), 7.89 - 7.79 (m, 2H), 7.71 - 7.65 (m, 2H), 7.61 (ddd, J = 7.3, 5.0, 2.5 Hz, 1H), 7.51 (dd, J = 9.0, 5.7 Hz, 1H), 7.26 (s, 3H), 7.19 - 7.14 (m, 1H), 4.56 (ddd, J = 13.6, 6.6, 5.3 Hz, 1H), 3.94 (dtd, J = 13.9, 5.5, 3.5 Hz, 1H), 3.83 (tdd, J = 6.7, 5.1, 3.2 Hz, 1H), 3.66 (dtd, J = 10.4, 5.5, 3.0 Hz, 1H), 3.35 (s, 3H). C 24 H 22 N3O4S[M+H] + The LC-MS (ESI) calculation for this was 448.13, and the measured value was 448.30.

[0273] N-(10-(2-(cyanomethoxy)ethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-7-yl)furan-3-carboxamide. 1 H NMR (600 MHz, chloroform-d) δ 8.05 (d, J = 9.3 Hz, 1H), 8.02 (s, 1H), 7.72 (d, J = 8.7 Hz, 1H), 7.55 (s, 1H), 7.47 (s, 1H), 7.43 (s, 1H), 7.37 - 7.30 (m, 1H), 7.21 - 7.14 (m, 1H), 6.82 (d, J = 8.3 Hz, 1H), 6.78 (d, J = 7.6 Hz, 1H), 6.70 (s, 1H), 5.02 (s, 2H), 3.72 (t, J = 5.3 Hz, 2H), 3.32 (t, J = 5.3 Hz, 2H). 13¹³C NMR (151 MHz, chloroform-d) δ 167.8, 164.5, 145.1, 144.0, 142.6, 133.8, 132.0, 130.6, 126.2, 125.9, 124.8, 124.1, 114.5, 113.5, 111.3, 108.2, 60.9, 48.9, 45.8. 22 H 17 N3O4SNa[M+Na] + The LC-MS (ESI) calculation for this was 442.08, and the measured value was 442.10.

[0274] N-(10-(2-hydroxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-7-yl)furan-3-carboxamide. 1 ¹H NMR (400 MHz, chloroform-d) δ 8.50 (d, J = 2.6 Hz, 1H), 8.19 (dd, J = 8.9, 2.6 Hz, 1H), 7.76 - 7.69 (m, 1H), 7.62 (d, J = 8.9 Hz, 1H), 7.54 - 7.46 (m, 1H), 7.43 - 7.32 (m, 2H), 4.65 - 4.55 (m, 1H), 4.16 - 3.74 (m, 3H). C 20 H 17 N2O4S[M+Na] + The LC-MS (ESI) calculation for this was 381.08, and the measured value was 381.10.

[0275] N-(10-(1-methoxypropan-2-yl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-7-yl)furan-3-carboxamide. 1H NMR (400 MHz, chloroform-d) δ 8.02 (dt, J = 2.6, 1.2 Hz, 1H), 7.87 (dd, J = 11.1, 2.4 Hz, 1H), 7.68 (ddd, J = 7.3, 3.3, 1.8 Hz, 1H), 7.62 - 7.52 (m, 2H), 7.49 (q, J = 1.3, 0.8 Hz, 1H), 7.45 - 7.38 (m, 2H), 7.36 - 7.27 (m, 2H), 6.72 - 6.66 (m, 1H), 4.76 (dd, J = 13.5, 4.5 Hz, 0.5H), 4.40 (dd, J = 13.6, 6.5 Hz, 0.5H), 3.90 (h, J = 6.2 Hz, 0.5H), 3.70 (ddd, J = 23.8, 12.6, 5.7 Hz, 1H), 3.49 (dd, J = 13.5, 7.4 Hz, 0.5H), 3.38 (s, 1.5H), 3.23 (s, 1.5H), 1.22 (d, J = 6.2 Hz, 1.5H), 1.18 (d, J = 6.2 Hz, 1.5H). C 22 H 21 N2O4S[M+H] + The LC-MS (ESI) calculation value for this is 409.12, and the measured value is 409.20.

[0276] N-(10-allyl-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-7-yl)furan-3-carboxamide. 1H NMR (600 MHz, chloroform-d) δ 8.08 - 8.03 (m, 2H), 7.81 (d, J = 2.5 Hz, 1H), 7.65 (dd, J = 7.6, 1.7 Hz, 1H), 7.59 (dd, J = 8.8, 2.5 Hz, 1H), 7.45 (t, J = 1.8 Hz, 1H), 7.40 - 7.31 (m, 2H), 7.29 - 7.21 (m, 2H), 6.75 (s, 1H), 6.05 - 5.95 (m, 1H), 5.30 (dd, J = 17.2, 1.5 Hz, 1H), 5.20 (dd, J = 10.3, 1.4 Hz, 1H), 4.80 (dd, J = 15.6, 5.4 Hz, 1H), 4.56 (dd, J = 15.6, 5.8 Hz, 1H). 13 ¹³C NMR (151 MHz, chloroform-d) δ 168.9, 160.9, 145.5, 144.1, 139.4, 138.7, 138.0, 136.5, 135.8, 133.2, 131.3, 131.0, 130.9, 128.7, 125.6, 124.2, 122.7, 121.3, 117.5, 108.4, 54.0. 21 H 17 N2O3S[M+H] + The LC-MS (ESI) calculation value for this is 377.10, and the measured value is 377.10.

[0277] (E)-N-(10-(5-hydroxypenta-2-en-1-yl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-7-yl)furan-3-carboxamide. 1¹H NMR (400 MHz, chloroform-d) δ 9.73 (t, J = 1.7 Hz, 1H), 8.06 - 8.01 (m, 1H), 7.84 (d, J = 2.6 Hz, 1H), 7.69 (dd, J = 7.5, 1.8 Hz, 1H), 7.66 - 7.57 (m, 1H), 7.53 - 7.47 (m, 2H), 7.46 - 7.38 (m, 2H), 7.36 - 7.28 (m, 1H), 6.69 (dd, J = 2.0, 0.9 Hz, 1H). 5.83 - 5.65 (m, 1H), 5.58 - 5.47 (m, 1H), 4.85 (d, J = 5.2 Hz, 1H), 4.48 (dd, J = 15.1, 6.0 Hz, 1H), 2.42 - 2.34 (m, 4H). C 23 H 21 N2O4S[M+H] + The LC-MS (ESI) calculation value for this is 421.11, and the measured value is 421.30.

[0278] (E)-6-(7-(furan-3-carboxamide)-11-oxodibenzo[b,f][1,4]thiazepine-10(11H)-yl)hexa-4-enoic acid. 1 H NMR (400 MHz, methanol-d4) δ 8.23 ​​(dd, J = 1.6, 0.9 Hz, 1H), 8.04 (d, J = 2.5 Hz, 1H), 7.73 - 7.60 (m, 3H), 7.58 - 7.45 (m, 2H), 7.45 - 7.34 (m, 2H), 6.94 (dd, J = 2.0, 0.9 Hz, 1H), 5.83 - 5.65 (m, 1H), 5.58 - 5.47 (m, 1H), 4.85 (d, J = 5.2 Hz, 1H), 4.48 (dd, J = 15.1, 6.0 Hz, 1H), 2.42 - 2.34 (m, 4H). C 24 H 21 N2O5S[M+H] + The LC-MS (ESI) calculation value for this is 449.11, and the measured value is 449.30.

[0279] 4-Methoxy-N-(11-oxo-10-(2-(propa-2-in-1-yloxy)ethyl)-10,11-dihydrodibenzo[b,f][1,4]oxazepine-7-yl)benzamide. 1 H NMR (600 MHz, chloroform-d) δ 7.91 (s, 1H), 7.90 - 7.84 (m, 2H), 7.78 (dd, J = 7.9, 1.7 Hz, 1H), 7.74 (s, 1H), 7.21 (ddd, J = 8.7, 7.1, 1.8 Hz, 1H), 7.11 (d, J = 1.3 Hz, 2H), 7.02 - 6.96 (m, 2H), 6.88 (td, J = 8.0, 7.5, 1.1 Hz, 1H), 6.48 (d, J = 8.5 Hz, 1H), 4.63 (d, J = 2.4 Hz, 2H), 4.61 - 4.56 (m, 2H), 3.95 - 3.90 (m, 2H), 3.88 (s, 3H), 2.47 (t, J = 2.4 Hz, 1H). 13 ¹³C NMR (151 MHz, chloroform-d) δ 172.0, 165.3, 162.7, 153.3, 146.4, 137.2, 133.6, 133.4, 131.9, 129.0, 127.8, 126.7, 120.5, 120.0, 119.7, 114.1, 113.8, 107.1, 77.9, 75.8, 65.5, 56.3, 55.4, 54.5. 26 H 23 N2O5[M+H] + The LC-MS (ESI) calculation for this was 443.16, and the measured value was 443.20.

[0280] N-(5-(2-methoxyethyl)-6-oxo-6,11-dihydro-5H-dibenzo[b,e]azepine-2-yl)furan-3-carboxamide. 1H NMR (600 MHz, chloroform-d) δ 8.03 (s, 1H), 7.76 (dd, J = 7.7, 1.5 Hz, 1H), 7.65 (d, J = 2.1 Hz, 1H), 7.59 (s, 1H), 7.48 (t, J = 1.8 Hz, 1H), 7.35 - 7.28 (m, 3H), 7.23 (t, J = 6.9 Hz, 1H), 7.13 (d, J = 7.0 Hz, 1H), 6.71 (s, 1H), 4.72 (ddd, J = 14.1, 7.0, 4.8 Hz, 1H), 4.23 (d, J = 13.1 Hz, 1H), 3.94 - 3.87 (m, 1H), 3.68 (qt, J = 10.3, 5.3 Hz, 2H), 3.49 (d, J = 13.2 Hz, 1H), 3.31 (s, 3H). 13 ¹³C NMR (151 MHz, chloroform-d) δ 168.9, 160.6, 145.2, 144.1, 142.5, 139.7, 136.4, 135.4, 132.9, 131.5, 130.6, 126.9, 126.0, 124.6, 122.8, 118.8, 118.7, 108.2, 69.9, 58.6, 49.7, 38.7. 22 H 21 N2O4[M+H] + The LC-MS (ESI) calculation for this was 377.15, and the measured value was 377.20.

[0281] N-(11-oxo-10-(2-(propa-2-in-1-yloxy)ethyl)-10,11-dihydrodibenzo[b,f][1,4]thiazepine-7-yl)benzo[d]thiazole-5-carboxamide. 1H NMR (400 MHz, chloroform-d) δ 9.08 (s, 1H), 8.58 (s, 1H), 8.51 (s, 1H), 7.98 (dd, J = 17.5, 7.0 Hz, 3H), 7.65 (d, J = 7.7 Hz, 2H), 7.48 (d, J = 8.7 Hz, 1H), 7.38 (d, J = 8.7 Hz, 1H), 7.26 (d, J = 6.1 Hz, 2H), 4.62 - 4.51 (m, 1H), 4.16 (s, 2H), 4.03 - 3.92 (m, 2H), 3.81 (q, J = 6.5, 5.0Hz, 1H), 2.42 (d, J = 2.3 Hz, 1H). 13 ¹¹C NMR (151 MHz, chloroform-d) δ 169.2, 165.44, 155.8, 153.0, 140.0, 138.9, 138.2, 137.4, 137.1, 136.0, 133.0, 131.1, 131.0, 130.8, 128.6, 126.7, 124.6, 124.2, 122.5, 122.1, 121.4, 79.5, 74.7, 67.6, 58.4, 51.6, 38.6. 26 H 20 N3O3S2[M+H] + The LC-MS (ESI) calculation value for this is 486.10, and the measured value is 486.10.

[0282] N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-7-yl)isoxazole-4-carboxamide. 1H NMR (400 MHz, chloroform-d) δ 9.07 (s, 1H) 7.73 (d, J =10 Hz, 1H), 7.78 (d, J =2.0 Hz, 1H), 7.58-7.60 (m, 2H), 7.48 (d, J =8.8 Hz, 1H), 7.33-7.35 (m, 1H), 7.19-7.26 (m, 2H), 4.52-4.57 (m, 1H), 3.92-3.96 (m, 1H), 3.75-3.78 (m, 1H), 3.60-3.65 (m, 1H), 3.34 (s, 3H). 13 ¹¹C NMR (151 MHz, chloroform-d) δ 169.6, 159.4, 158.0, 148.0, 139.9, 138.8, 138.0, 137.1, 135.4, 131.1, 130.9, 128.7, 126.8, 124.3, 121.5, 118.0, 70.1, 58.9, 51.8. 20 H 18 N3O4S[M+H] + The LC-MS (ESI) calculation value for this is 396.10, and the measured value is 396.10.

[0283] N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-7-yl)thiazole-4-carboxamide. 1 H NMR (400 MHz, chloroform-d) δ 9.25 (s, 1H) 8.80 (d, J =1.6 Hz, 1H), 8.28 (d, J =2.0 Hz, 1H), 8.00 (d, J =2.4 Hz, 1H), 7.67-7.70 (m, 2H), 7.50 (d, J =8.8 Hz, 1H), 7.42-7.44 (m, 1H), 7.27-7.31 (m, 2H), 4.54-4.57 (m, 1H), 3.92-3.96 (m, 1H), 3.81-3.84 (m, 1H), 3.64-3.66 (m, 1H), 3.35 (s, 3H). 13¹³C NMR (151 MHz, chloroform-d) δ 169.1, 158.7, 152.9, 150.7, 140.0, 138.8, 138.4, 137.2, 135.5, 131.2, 131.0, 130.7, 128.6, 126.8, 124.4, 123.6, 120.7, 70.2, 58.9, 51.6. 20 H 18 N3O3S2[M+H] + The LC-MS (ESI) calculation value for this is 412.08, and the measured value is 412.00.

[0284] N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-7-yl)benzo[d]thiazole-5-carboxamide. 1 H NMR (400 MHz, chloroform-d) δ 9.11 (s, 1H), 8.58 (s, 1H), 8.26 (s, 1H), 8.06 (d, J =8.4 Hz, 1H), 7.98 (d, J =9.2 Hz, 2H), 7.63-7.67 (m, 2H), 7.51 (d, J =4.8 Hz, 1H), 7.40-7.42 (m, 1H), 7.26-7.29 (m, 2H), 4.52-4.57 (m, 1H), 3.92-3.96 (m, 1H), 3.80-3.85 (m, 1H), 3.64-3.67 (m, 1H), 3.35 (s, 3H). 13 ¹¹C NMR (151 MHz, chloroform-d) δ 169.1, 165.3, 155.9, 153.0, 140.2, 138.8, 138.3, 137.2, 135.7, 133.0, 131.1, 131.0, 130.7, 128.7, 126.8, 124.5, 124.1, 122.6, 121.9, 121.3, 70.2, 58.9, 51.6. 24 H 20 N3O3S2[M+H] + The LC-MS (ESI) calculation value for this is 462.10, and the measured value is 462.10.

[0285] N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-7-yl)imidazo[1,2-a]pyridine-6-carboxamide. 1 ¹H NMR (400 MHz, chloroform-d): δ 8.82 (s, 1H), 8.23 ​​(s, 1H), 7.94 (s, 1H), 7.73 (s, 1H), 7.61-7.68 (m, 4H), 7.48-7.53 (m, 2H), 7.46-7.47 (d, J = 1.6 Hz, 1H), 7.23-7.40 (m, 2H), 4.50-4.57 (m, 1H), 3.92-3.98 (m, 1H), 3.80-3.85 (m, 1H), 3.35-3.68 (m, 1H), 3.25 (s, 3H). 13 ¹³C NMR (151 MHz, chloroform-d) δ 169.2, 163.2, 145.0, 140.3, 138.7, 138.2, 137.1, 135.7, 134.6, 131.1, 131.0, 130.8, 128.7, 128.4, 126.8, 124.4, 122.4, 121.6, 120.7, 117.0, 113.9, 70.2, 58.9, 51.7. 24 H 21 N4O3S[M+H] + The LC-MS (ESI) calculation value for this is 445.14, and the measured value is 445.10.

[0286] N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-7-yl)imidazo[1,2-a]pyridine-6-carboxamide. 1¹H NMR (400 MHz, chloroform-d): δ 9.62 (s, 1H), 8.34 (s, 1H), 8.18-8.20 (d, J = 8.0 Hz, 1H), 8.11 (s, 1H), 7.73-7.74 (d, J = 4.0 Hz, 1H), 7.65-7.72 (m, 3H), 7.49-7.52 (d, J = 12.0 Hz, 1H), 7.41-7.42 (m, 1H), 7.25-7.40 (m, 4H), 4.53-4.57 (m, 1H), 3.93-3.97 (m, 1H), 3.82-3.84 (m, 1H), 3.64-3.67 (m, 1H), 3.35(s, 3H). 13 ¹¹C NMR (151 MHz, chloroform-d) δ 169.1, 164.3, 143.8, 140.1, 138.9, 138.3, 137.1, 136.4, 135.0, 131.3, 131.2, 131.0, 130.7, 128.6, 126.7, 126.0, 124.2, 121.3, 116.4, 113.7, 111.8, 70.2, 58.9, 51.6. 24 H 21 N4O3S[M+H] + The LC-MS (ESI) calculation value for this is 445.14, and the measured value is 445.10.

[0287] N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-7-yl)pyrimidine-2-carboxamide. 1H NMR (400 MHz, chloroform-d) δ 9.95 (s, 1H), 8.94 (d, J =4.8 Hz, 2H), 7.98 (d, J =2.4 Hz, 1H), 7.85 (dd, J =2.8, 2.4 Hz, 1H), 7.69 (dd, J =2.0, 1.4 Hz, 1H), 7.50-7.55 (m, 2H), 7.44 (dd, J =1.2, 1.6 Hz, 1H), 7.26-7.33 (m, 2H), 4.54-4.57 (m, 1H), 3.94-3.97 (m, 1H), 3.81-3.84 (m, 1H), 3.64-3.67 (m, 1H), 3.35 (s, 3H). 13 ¹³C NMR (151 MHz, chloroform-d) δ 169.0, 159.7, 157.7, 157.2, 140.4, 138.8, 138.4, 137.2, 135.1, 131.2, 131.0, 130.7, 128.7, 127.0, 123.7, 122.9, 120.9, 70.2, 58.9, 51.6. 21 H 19 N4O3S[M+H] + The LC-MS (ESI) calculation value for this is 407.12, and the measured value is 407.10.

[0288] N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-7-yl)pyrimidine-4-carboxamide. 1H NMR (400 MHz, chloroform-d) δ 9.87 (s, 1H), 9.30 (d, J =0.8 Hz, 1H), 9.05 (d, J =3.2 Hz, 1H), 8.20 (dd, J =1.2, 1.2 Hz, 1H), 8.05 (d, J =2.8 Hz, 1H), 7.75 (d, J =2.4 Hz, 1H), 7.73 (d, J =2.4 Hz, 1H), 7.70 (d, J =2.0 Hz, 1H), 7.55 (d, J =8.8 Hz, 1H), 7.26-7.45 (m, 2H), 4.53-4.56 (m, 1H), 3.94-3.98 (m, 1H), 3.82-3.85 (m, 1H), 3.65-3.69 (m, 1H), 3.35 (s, 3H). 13 ¹³C NMR (151 MHz, chloroform-d) δ 169.0, 160.3, 159.8, 157.7, 155.7, 140.7, 138.7, 138.3, 137.3, 134.7, 131.2, 131.0, 130.8, 128.7, 127.0, 123.8, 120.9, 118.6, 70.2, 58.9, 51.7. 21 H 19 N4O3S[M+H] + The LC-MS (ESI) calculation value for this is 407.12, and the measured value is 407.10.

[0289] N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-7-yl)pyrazine-2-carboxamide. 1H NMR (400 MHz, chloroform-d) δ 9.67 (s, 1H), 9.50 (s, 1H), 8.82 (d, J =2.0 Hz, 1H), 8.59 (s, 1H), 8.05 (d, J =2.4 Hz, 1H), 7.67-7.75 (m, 2H), 7.54 (d, J =8.8 Hz, 1H), 7.44 (dd, J =1.2, 1.2 Hz, 1H), 7.27-7.34 (m, 2H), 4.52-4.58 (m, 1H), 3.93-3.99 (m, 1H), 3.81-3.86 (m, 1H), 3.64-3.69 (m, 1H), 3.35 (s, 3H). 13 ¹³C NMR (151 MHz, chloroform-d) δ 169.1, 160.7, 147.8, 144.7, 143.9, 142.4, 140.4, 138.8, 138.3, 137.3, 135.0, 131.2, 131.0, 130.8, 128.7, 126.9, 123.7, 120.8, 70.2, 58.9, 51.7. 21 H 19 N4O3S[M+H] + The LC-MS (ESI) calculation value for this is 407.12, and the measured value is 407.10.

[0290] 3-Fluoro-4-formamide-N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-7-yl)benzamide. 1 H NMR (400 MHz, chloroform-d) δ 8.47-8.52 (m, 2H), 8.13 (s, 1H), 7.92 (d, J =2.8 Hz, 1H), 7.58-7.75 (m, 5H), 7.49 (d, J =8.8 Hz, 1H), 7.40 (dd, J =1.2, 1.4 Hz, 1H), 7.26-7.31 (m, 2H), 4.53-4.56 (m, 1H), 3.92-3.95 (m, 1H), 3.80-3.88 (m, 1H), 3.64-3.66 (m, 1H), 3.35 (s, 3H). 13¹³C NMR (151 MHz, chloroform-d) δ 169.1, 158.9, 152.6, 151.0, 140.1, 138.8, 138.2, 137.0, 131.1 (d, J = 15.2 Hz), 130.8, 128.7, 126.8, 124.2, 123.0, 121.4, 114.8 (d, J = 21.0 Hz), 70.2, 58.9, 51.6. 24 H 21 FN3O4S[M+H] + The LC-MS (ESI) calculation for this is 466.13, and the measured value is 466.10.

[0291] 3-Fluoro-N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-7-yl)-4-(trifluoromethoxy)benzamide. 1 ¹H NMR (400 MHz, chloroform-d): δ7.91 (d, J=2.0 Hz, 1H), 7.87 (br, 1H), 7.72-7.75 (m, 1H), 7.62-7.68 (m, 2H), 7.57-7.60 (m, 1H), 7.51-7.54 (m, 1H), 7.41-7.44 (m, 2H), 7.26-7.32 (m, 2H), 4.49-4.56 (m, 1H), 3.92-3.98 (m, 1H), 3.80-3.86 (m, 1H), 3.62-3.68 (m, 1H), 3.35 (s, 3H). 13 ¹³C NMR (151 MHz, chloroform-d) δ 169.1, 163.3, 155.2, 153.5, 140.6, 138.7, 138.2, 137.2, 135.2, 134.7, 131.1, 131.0, 130.8, 128.7, 126.9, 124.3, 123.7, 123.2, 121.4, 116.9, 116.7, 70.2, 58.9, 51.7. 24 H 19 F4N2O4S[MH] + The LC-MS (ESI) calculation value for this is 507.10, and the measured value is 505.20.

[0292] N-(4-fluoro-10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-7-yl)furan-3-carboxamide. 1 H NMR (400 MHz, MeOD): δ 8.21 (s, 1H), 8.03 (d, J =2.4 Hz, 1H), 7.75 (dd, J =2.4, 2.4 Hz, 1H), 7.59-7.61 (m, 2H), 7.35-7.43 (m, 2H), 7.20-7.24 (m, 1H), 6.91 (d, J =1.2 Hz, 1H), 4.54-4.60 (m, 1H), 3.92-3.97 (m, 1H), 3.69-3.72 (m, 1H), 3.63-3.67 (m, 1H), 3.33 (s, 3H). 13 ¹³C NMR (151 MHz, chloroform-d) δ 160.7, 158.5, 145.4, 144.3, 140.5, 140.3, 136.0, 135.6, 129.9 (d, J = 8.1 Hz), 127.0, 126.5, 124.4, 122.6, 121.7, 117.5, 117.4, 108.2, 70.1, 58.9, 51.6. 21 H 18 FN2O4S[M+H] + The LC-MS (ESI) calculation value for this is 413.10, and the measured value is 413.10.

[0293] N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-7-yl)isoxazole-5-carboxamide. 1H NMR (400 MHz, chloroform-d): δ 8.39 (s, 1H), 8.28 (m, 1H), 7.95 (s, 1H), 7.68(d, J=7.6 Hz, 1H), 7.62 (d, J=8.8 Hz, 1H), 7.54 (d, J=8.8 Hz, 1H), 7.43 (d, J=7.2 Hz, 1H), 7.28-7.33 (m, 2H), 7.04 (s, 1H), 4.48-4.55 (m, 1H), 3.93-3.99 (m, 1H), 3.81-3.86 (m, 1H), 3.63-3.68 (m, 1H), 3.35 (s, 3H). 13 ¹³C NMR (151 MHz, chloroform-d) δ 169.0, 162.3, 153.3, 151.4, 141.1, 138.6, 138.3, 137.3, 134.2, 131.2, 131.0, 130.8, 128.7, 127.0, 124.1, 121.2, 107.5, 70.2, 58.9, 51.8. 20 H 18 N3O4S[MH] + The LC-MS (ESI) calculation value for this is 394.08, and the measured value is 394.20.

[0294] N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-7-yl)pyrimidine-5-carboxamide. 1 H NMR (400 MHz, chloroform-d) δ 9.36 (s, 1H), 9.19 (s, 2H), 8.39 (s, 1H),7.90-7.91 (d, J = 4.0 Hz, 1H), 7.60-7.62 (m, 2H), 7.52-7.54 (d, J = 8.0 Hz, 1H), 7.38-7.41 (m, 1H), 7.25-7.27 (m, 2H), 4.47-4.54 (m, 1H), 3.93-3.99 (m, 1H), 3.78-3.84 (m, 1H), 3.62-3.67 (m, 1H), 3.34 (s, 3H). 13¹³C NMR (151 MHz, chloroform-d) δ 169.5, 162.1, 160.7, 155.9, 140.3, 138.8, 138.0, 137.1, 135.3, 131.1, 130.9 (d, J = 5.4 Hz), 128.7, 128.1, 126.8, 124.5, 121.7, 70.1, 58.9, 51.8. 21 H 19 N4O3S[M+H] + The LC-MS (ESI) calculation value for this is 407.12, and the measured value is 407.10.

[0295] 3-Chloro-4-formamide-N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-7-yl)benzamide. 1 ¹H NMR (400 MHz, chloroform-d): δ 8.58 (s, 1H), 7.88-7.96 (m, 4H), 7.61-7.76 (m, 3H), 7.42-7.43 (d, J = 4.0 Hz, 1H), 7.40-7.41 (d, J = 4.0 Hz, 1H), 7.25-7.30 (m, 2H), 4.50-4.57 (m, 1H), 3.85-3.97 (m, 1H), 3.79-3.84 (m, 1H), 3.62-3.67 (m, 1H), 3.34 (s, 3H). 13 ¹³C NMR (151 MHz, chloroform-d) δ 169.2, 163.7, 159.0, 140.2, 138.8, 138.2, 137.1, 136.7, 135.7, 131.1, 131.0, 130.8 (d, J = 11.3 Hz), 128.8, 128.7, 126.8, 126.2, 124.2, 122.9, 121.4, 121.2, 70.2, 58.9, 51.6. 24 H 21 ClN3O4S[M+H] + The LC-MS (ESI) calculation value for this is 482.10, and the measured value is 482.10.

[0296] 4-(difluoromethoxy)-3-fluoro-N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-7-yl)benzamide. 1 ¹H NMR (400 MHz, chloroform-d): δ 7.91-7.92 (d, J = 4.0 Hz, 2H), 7.60-7.72 (m, 4H), 7.50-7.52 (d, J = 8.0 Hz, 1H), 7.26-7.42 (m, 3H), 6.45-6.81 (m, 1H), 4.50-4.57 (m, 1H), 3.85-3.97 (m, 1H), 3.79-3.84 (m, 1H), 3.62-3.67 (m, 1H), 3.34 (s, 3H). 13 C NMR (151 MHz, chloroform-d) δ 169.2, 163.6, 154.6, 152.9, 140.3, 138.8, 138.2, 137.1, 135.5, 133.0 (d, J = 5.9 Hz), 131.0 (d, J = 4.1 Hz), 130.8, 128.7, 126.8, 124.3, 123.4 (d, J = 3.7 Hz), 122.6, 121.5, 117.0, 116.6, 116.5, 115.2, 113.4, 70.1, 58.9, 51.7, 29.7. C 24 H 20 F3N2O4S[M+H] + The LC-MS (ESI) calculation value for this is 489.11, and the measured value is 489.10.

[0297] 3-Fluoro-N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-7-yl)-4-(methylsulfonyl)benzamide. 11H NMR (400 MHz, chloroform-d): δ 9.04 (s, 1H), 7.99 (d, J = 2.4 Hz, 1H), 7.87 (d, J = 6.8 Hz, 1H), 7.71-7.74 (m, 2H), 7.65 (dd, J = 2.0, 2.4 Hz, 1H), 7.57-7.59 (m, 1H), 7.50 (d, J = 4.8 Hz, 1H), 7.37-7.39 (m, 1H), 7.22-7.25 (m, 2H), 4.53-4.55 (m, 1H), 3.91-3.96 (m, 1H), 3.76-3.80 (m, 1H), 3.62-3.66 (m, 1H), 3.35 (s, 3H), 325 (s, 3H). 13 ¹³C NMR (151 MHz, chloroform-d) δ 169.4, 163.1, 160.1, 158.4, 142.5, 140.3, 138.8, 138.1, 137.1, 135.5, 131.1, 131.0, 130.9, 130.6, 130.5, 130.1, 128.7, 126.8, 124.4, 123.3, 121.6, 116.8, 116.7, 70.1, 58.9, 51.7, 43.9. 24 H 22 FN2O5S2[M+H] + The LC-MS (ESI) calculation value for this is 501.10, and the measured value is 501.10.

[0298] 3-Fluoro-N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-7-yl)-4-(methylsulfinyl)benzamide. 1¹H NMR (400 MHz, chloroform-d): δ 8.91 (s, 1H), 8.00 (d, J=2.4 Hz, 1H), 7.75-7.82 (m, 2H), 7.62-7.69 (m, 3H), 7.49-7.51 (m, 1H), 7.38-7.41 (m, 1H), 7.27-7.30 (m, 1H), 7.22-7.25 (m, 1H), 4.50-4.57 (m, 1H), 3.91-3.97 (m, 1H), 3.78-3.84 (m, 1H), 3.62-3.67 (m, 1H), 3.34 (s, 3H), 2.87 (s, 3H). 13 ¹C NMR (151 MHz, chloroform-d) δ 169.2, 163.8, 158.2, 156.5, 140.2, 139.9 (d, J = 6.5 Hz), 138.8, 138.2, 137.0, 136.1, 136.0, 135.8, 131.1 (d, J = 7.5 Hz), 130.8, 128.7, 126.8, 125.9, 124.3, 123.7, 121.5, 115.7, 115.5, 70.1, 58.9, 51.7, 41.9. 24 H 22 FN2O4S2[M+H] + The LC-MS (ESI) calculation value for this is 485.10, and the measured value is 485.10.

[0299] N-(2-fluoro-10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-7-yl)furan-3-carboxamide. 1¹H NMR (400 MHz, chloroform-d): δ 8.04 (s, 1H), 7.98 (s, 1H), 7.88 (d, J=2.4 Hz, 1H), 7.55-7.58 (m, 1H), 7.43-7.46 (m, 2H), 7.31-7.35 (m, 2H), 6.90-6.95 (m, 1H), 6.73 (s, 1H), 4.47-4.54 (m, 1H), 3.88-3.95 (m, 1H), 3.74-3.80 (m, 1H), 3.58-3.64 (m, 1H), 3.32 (s, 3H). 13 ¹³C NMR (151 MHz, chloroform-d) δ 168.0, 163.4, 161.8, 160.8, 145.4, 144.2, 140.1, 139.6, 137.0, 135.8, 134.3 (d, J = 3.4 Hz), 132.9 (d, J = 7.8 Hz), 126.9, 124.0, 122.6, 121.4, 118.2, 108.4, 70.0, 58.9, 51.5. 21 H 18 FN2O4S[M+H] + The LC-MS (ESI) calculation value for this is 413.10, and the measured value is 413.10.

[0300] N-(3-fluoro-10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-7-yl)furan-3-carboxamide. 1 ¹H NMR (400 MHz, chloroform-d): δ 8.04 (s, 1H), 7.87 (s, 1H), 7.86 (s, 1H), 7.59-7.74 (m, 2H), 7.49-7.48 (m, 2H), 7.11 (dd, J = 2.4, 2.4 Hz, 1H), 6.96-7.00 (m, H), 6.72 (d, J = 0.8 Hz, 1H), 4.53-4.56 (m, 1H), 3.98-4.04 (m, 1H), 3.77-3.80 (m, 1H), 3.62-3.66 (m, 1H), 3.33 (s, 3H). 13C NMR (151 MHz, chloroform-d) δ 168.3, 163.8, 162.1, 160.8, 145.4 (d, J = 6.6 Hz), 144.2 (d, J = 4.4 Hz), 140.9 (d, J = 8.3 Hz), 139.8, 136.2, 135.8, 134.4, 126.8, 124.1, 122.6, 118.0, 117.9, 116.1, 115.9, 108.3, 108.3, 70.1, 58.9, 51.6. C 21 H 18 FN2O4S[M+H] + The LC-MS (ESI) calculation value for this is 413.10, and the measured value is 413.10.

[0301] (E)-10-(hexa-2-en-1-yl)-7-(pyridine-2-ylamino)dibenzo[b,f][1,4]thiazepine-11(10H)-one. 1 H NMR (400 MHz, chloroform-d): δ 8.21 (s, 1H), 7.71 (d, J=7.2 Hz, 1H), 7.61 (s, 1H), 7.53 (t, J=7.2 Hz, 1H), 7.41 (d, J=7.2 Hz, 1H), 7.26-7.33 (m, 3H), 6.73-6.80 (m, 3H), 5.60-5.72 (m, 2H), 4.78 (d, J=13.6 Hz, 1H), 4.44 (d, J=13.6 Hz, 1H), 1.98-2.02 (m, 2H), 1.31-1.40 (m, 2H), 0.84 (t, J=7.2 Hz, 3H). 13 C NMR (151 MHz, Chloroform-d) δ 168.7, 154.9, 147.9, 138.9, 138.5, 138.4, 138.0, 137.7, 137.0, 131.0, 130.6, 128.6, 126.2, 122.9 (d, J = 16.8 Hz), 120.2, 115.7 (d, J = 12.4 Hz), 109.4 (d, J = 11.4 Hz), 53.3, 34.3, 22.3, 13.6. C 24 H 24N3OS[M+H] + The LC-MS (ESI) calculation value for this is 402.17, and the measured value is 402.20.

[0302] 4-Methoxy-N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-7-yl)-2-methylbenzamide. 1 H NMR (400 MHz, chloroform-d) δ 7.90 (d, J =2.4 Hz, 1H), 7.66 (dd, J =2.0, 1.2 Hz, 1H), 7.53-7.56 (m, 2H), 7.46 (d, J =8.8 Hz, 1H), 7.40-7.43 (m, 2H), 7.27-7.32 (m, 2H), 6.73-6.77 (m, 2H), 4.52-4.58 (m, 1H), 3.87-3.94 (m, 1H), 3.78-3.83 (m, 4H), 3.61-3.66 (m, 1H), 3.34 (s, 3H), 2.48 (s, 3H). 13 ¹C NMR (151 MHz, chloroform-d) δ 169.07, 167.66, 161.17, 139.82, 139.46, 138.87, 138.31, 137.14, 136.07, 131.06, 130.69, 128.62, 128.52, 128.03, 126.73, 123.64, 120.83, 116.91 (d, J = 13.7 Hz), 111.04 (d, J = 13.5 Hz), 70.15, 58.89, 55.31, 20.41. 25 H 25 N2O4S[M+H] + The LC-MS (ESI) calculation for this was 449.16, and the measured value was 449.20.

[0303] 2-Fluoro-4-methoxy-N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-7-yl)benzamide. 1H NMR (400 MHz, chloroform-d) δ 8.37 (d, J =16.8 Hz, 1H), 8.10 (t, J =9.2, Hz, 1H), 7.94 (d, J =2.4 Hz, 1H), 7.67 (dd, J =2.0, 1.6 Hz, 1H), 7.61 (dd, J =2.4, 2.4 Hz, 1H), 7.48 (d, J =8.8 Hz, 1H), 7.43 (dd, J =1.2, 1.6 Hz, 1H), 7.25-7.33 (m, 2H), 6.84 (dd, J =2.4, 2.4 Hz, 1H), 6.67 (dd, J =0.64, 0.2 Hz, 1H), 4.53-4.59 (m, 1H), 3.90-3.96 (m, 1H), 3.80-3.87 (m, 4H), 3.61-3.67 (m, 1H), 3.34 (s, 3H). 13 ¹C NMR (151 MHz, chloroform-d) δ 169.05, 164.14, 162.30, 161.22, 160.67, 140.03, 138.85, 138.36, 137.06, 135.72, 133.49, 131.04, 130.69, 128.63, 126.72, 124.28, 121.54, 113.00 (d, J = 11.4 Hz), 111.15 (d, J = 11.5 Hz), 101.69, 70.15, 58.86, 55.89, 51.26. 24 H 22 FN2O4S[M+H] + The LC-MS (ESI) calculation value for this is 453.13, and the measured value is 453.10.

[0304] 3-((10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-7-yl)carbamoyl)benzoic acid. 1H NMR (400 MHz, DMSO-d6) δ 10.58 (s, 1H), 8.52 (s, 1H), 8.13-8.17 (m, 3H), 7.79 (dd, J =2.4, 2.4 Hz, 1H), 7.64-7.69 (m, 2H), 7.59-7.61 (m, 1H), 7.53 (dd, J =2.4, 4.0 Hz, 1H), 7.39-7.41 (m, 2H), 4.51-4.57 (m, 1H), 3.84-3.89 (m, 1H), 3.56-3.61 (m, 1H), 3.50-3.57 (m, 1H), 3.21 (s, 3H). 13 C NMR (151 MHz, DMSO-d6) δ 167.1, 166.2, 164.3, 137.9, 137.5, 136.3, 135.1, 134.2, 131.8, 131.4, 130.6, 130.5 - 130.2 (m), 128.3 (d, J = 9.1 Hz), 127.8, 126.1, 123.1, 120.9, 68.7, 57.5, 49.3. C 24 H 21 N2O5S[M+H] + The LC-MS (ESI) calculation value for this is 449.12, and the measured value is 449.10.

[0305] N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-7-yl)isophthalamide. 1 H NMR (400 MHz, methanol-d4) δ 8.43 (s, 1H), 8.06-8.09 (m, 3H), 7.71-7.73 (m, H), 7.58-7.62 (m, 3H), 7.48 (dd, J =2.0, 4.0 Hz, 1H), 7.36 (d, J =4.0, Hz, 2H), 4.56-4.61 (m, 1H), 3.94-3.98 (m, 1H), 3.71-3.75 (m, 1H), 3.63-3.66 (m, 1H), 3.31 (s, 3H). 13¹³C NMR (151 MHz, methanol-d4) δ 169.9, 166.6, 139.3, 139.0, 138.1, 136.9, 136.8, 135.0, 134.2, 130.8, 130.8, 130.6, 130.5, 130.4, 128.6, 128.5, 126.6, 126.5, 124.2, 121.7, 69.7, 57.7, 50.9. 24 H 22 N3O4S[M+H] + The LC-MS (ESI) calculation for this is 448.14, and the measured value is 448.10.

[0306] N1-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-7-yl)-N4-methylterephthalamide. 1 H NMR (400 MHz, chloroform-d) δ 9.02 (s, 1H), 8.17 (s, 1H), 7.99 (d, J =2.4, Hz, 1H), 7.92 (d, J =7.6, Hz, 1H), 7.78 (d, J =2.0, Hz, 1H), 7.62-7.66 (m, 2H), 7.36-7.45 (m, 3H), 7.23-7.26 (m, 2H), 6.80 (d, J =4.4, Hz, 1H), 4.50-4.55 (m, 1H), 3.87-3.93 (m, 1H), 3.76-3.81 (m, 1H), 3.62-3.66 (m, 1H), 3.33 (s, 3H), 2.92 (d, J =4.8, Hz, 3H). 13 ¹³C NMR (151 MHz, chloroform-d) δ 169.3, 167.9, 165.4, 139.9, 138.9, 138.1, 137.0, 136.0, 134.5, 131.1 (d, J = 5.1 Hz), 130.8, 130.7, 130.1, 129.2, 128.7, 126.7, 125.4, 124.2, 121.4, 70.1, 58.9, 51.6, 27.0. 25 H 24 N3O4S[M+H] +The LC-MS (ESI) calculation value for this is 462.15, and the measured value is 462.20.

[0307] 4-((10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-7-yl)carbamoyl)benzoic acid. 1 H NMR (400 MHz, DMSO-d6) δ10.55 (s, 1H), 8.17 (d, J =2.4, Hz, 1H), 8.06 (d, J =7.6, Hz, 2H), 8.01 (d, J =8.8, Hz, 2H), 7.77 (dd, J =2.4, 2.4 Hz, 2H), 7.65 (d, J =8.8, Hz, 2H), 7.59-7.61 (m, 1H), 7.52-7.54 (m, 1H), 7.39-7.41 (m, 2H), 4.52-4.54 (m, 1H), 3.84-3.87 (m, 1H), 3.50-3.54 (m, 1H), 3.56-3.60 (m, 1H), 3.21 (s, 3H). 13 C NMR (151 MHz, DMSO-d6) δ 167.1, 166.3, 164.5, 137.9, 137.5, 137.2, 136.3, 135.1, 130.3, 128.7, 128.3, 127.2, 126.1, 123.0, 120.9, 68.7, 57.5, 49.3. C 24 H 20 N2O5S[M+H] + The LC-MS (ESI) calculation value for this is 449.12, and the measured value is 449.10.

[0308] N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-7-yl)terephthalamide. 1H NMR (400 MHz, DMSO-d6) δ10.51 (s, 1H), 8.16 (d, J =16.4, Hz, 2H), 8.00 (s, 4H), 7.79 (d, J =8.8, Hz, 1H), 7.51-7.66 (m, 4H), 7.41 (d, J =3.6, Hz, 2H), 4.53-4.56 (m, 1H), 3.83-3.88 (m, 1H), 3.50-3.60 (m, 2H), 3.21 (s, 3H). 13 C NMR (151 MHz, DMSO-d6) δ 167.1, 166.5, 164.4, 137.8, 137.5, 136.4, 136.3, 136.1, 135.1, 130.3 (d, J = 6.6 Hz), 128.3, 127.0, 126.9, 126.1, 123.0, 120.9, 68.7, 57.5, 49.3. C 24 H 22 N3O4S[M+H] + The LC-MS (ESI) calculation for this was 448.14, and the measured value was 448.20.

[0309] N1-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-7-yl)-N4-methylterephthalamide. 1 H NMR (400 MHz, DMSO-d6) δ10.5 (s, 1H), 8.61 (d, J =4.8, Hz, 1H), 8.17 (d, J =2.4, Hz, 1H), 7.97 (dd, J =8.4, 8.4 Hz, 4H), 7.97 (dd, J =2.0, 2.0 Hz, 1H), 7.59-7.66 (m, 2H),7.52-7.54 (m, 1H), 7.40 (t, J =4.4, Hz, 2H), 4.52-4.56 (m, 1H), 3.84-3.87 (m, 1H), 3.50-3.60 (m, 2H), 3.21 (s, 3H), 2.82 (t, J = 4.4, Hz, 3H). 13C NMR (151 MHz, DMSO-d6) δ 167.1, 165.2, 164.4, 137.9, 137.5, 136.6, 136.3, 136.0, 135.1, 130.4, 128.3, 127.1, 126.5, 126.1, 120.9, 68.7, 57.5, 49.3, 25.7. C 25 H 24 N3O4S[M+H] + The LC-MS (ESI) calculation value for this is 462.15, and the measured value is 462.20.

[0310] N1-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-7-yl)-N4,N4-dimethylterephthalamide. 1 H NMR (400 MHz, chloroform-d) δ 9.04 (s, 1H), 8.08 (d, J =2.4, Hz, 1H), 7.77-7.82 (m, 3H), 7.68 (dd, J =1.6, 1.6 Hz, 4H), 7.49 (d, J =8.8, Hz, 1H), 7.42 (dd, J =1.2, 1.6 Hz, 1H), 7.25-7.31 (m, 4H), 4.54-4.59 (m, 1H), 3.90-3.95 (m, 1H), 3.79-3.85 (m, 1H), 3.64-3.68 (m, 1H), 3.35 (s, 3H), 3.16 (s, 3H), 2.94 (s, 3H). 13 ¹¹C NMR (151 MHz, chloroform-d) δ 171.0, 169.1, 165.6, 139.7, 139.0, 138.6, 138.4, 136.8, 136.5, 135.9, 131.2, 131.0, 130.7, 128.6, 127.7, 126.8, 126.5, 124.3, 121.4, 70.1, 58.9, 51.5, 39.5, 35.6. 26 H 26 N3O4S[M+H] + The LC-MS (ESI) calculation value for this is 476.17, and the measured value is 476.20.

[0311] 3-(1-cyanoethyl)-N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-7-yl)benzamide. 1 H NMR (400 MHz, chloroform-d): δ 8.00 (s, 1H), 7.93 (s, 1H),7.84 (s, 1H),7.76-7.78 (d, J = 8.0 Hz, 1H), 7.61-7.67 (m, 2H), 7.50-7.51 (d, J = 4.0 Hz, 1H), 7.42-7.48 (m, 2H), 7.39-7.40 (d, J = 4.0 Hz, 1H), 7.26-7.31 (m, 2H), 4.52-4.56 (m, 1H), 3.91-3.98 (m, 2H), 3.71-3.83 (m, 1H), 3.62-3.68 (m, 1H), 3.34 (s, 3H), 1.67-1.68(d, J = 4.0 Hz, 3H). 13 ¹³C NMR (151 MHz, chloroform-d) δ 169.1, 165.1, 140.2, 138.8, 138.2, 138.0, 137.1, 135.6, 135.5, 131.1, 131.0, 130.8, 130.3, 129.7, 128.7, 126.8, 126.6, 125.8, 124.2, 121.4, 121.1, 70.13, 58.9, 51.6, 31.2, 21.3. 26 H 24 N3O3S[M+H] + The LC-MS (ESI) calculation for this was 458.16, and the measured value was 458.20.

[0312] 3-(cyanomethyl)-N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-7-yl)benzamide. 1¹H NMR (400 MHz, chloroform-d): δ 7.92 (s, 2H), 7.77-7.92 (m, 2H), 7.61-7.67 (m, 2H), 7.49-7.53 (m, 3H), 7.40-7.43 (m, 1H), 7.26-7.30 (m, 2H), 4.51-4.57 (m, 1H), 3.91-3.97 (m, 1H), 3.81-3.85 (m, 1H), 3.79 (s, 2H), 3.62-3.67 (m, 1H), 3.32 (s, 3H). 13 ¹³C NMR (151 MHz, chloroform-d) δ 169.1, 165.0, 140.2, 138.8, 138.2, 137.1, 135.6, 135.5, 131.5, 131.1, 131.0, 130.9, 130.8, 129.7, 128.7, 126.9, 126.8, 126.7, 124.2, 121.4, 117.3, 70.1, 58.9, 51.6, 23.5. 25 H 22 N3O3S[M+H] + The LC-MS (ESI) calculation value for this is 444.14, and the measured value is 444.10.

[0313] tert-butyl-4-(aminomethyl)-N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-7-yl)benzamide hydrochloride. 1 H NMR (400 MHz, d4-MeOD) δ8.50 (br, 1H), 8.08 (d, J=2.4 Hz, 1H), 8.01 (d, J=8.0 Hz, 2H), 7.71-7.74 (m, 1H), 7.59-7.63 (m, 4H), 7.48-7.51 (m, 1H), 7.34-7.41 (m, 2H), 4.55-4.62 (m, 1H), 4.20 (s, 2H), 3.93-4.00 (m, 1H), 3.71-3.76 (m, 1H), 3.62-3.68 (m, 1H), 3.32 (s, 3H). 13¹³C NMR (151 MHz, methanol-d4) δ 169.9, 166.5, 139.4, 138.9, 138.1, 137.3, 136.8 (d, J = 2.8 Hz), 135.1, 130.8, 130.8, 130.4, 128.7, 128.5, 128.1, 126.5, 124.3, 121.8, 69.7, 57.6, 50.9, 42.5. 24 H 24 N3O3S[M+H] + The LC-MS (ESI) calculation for this was 434.16, and the measured value was 434.20.

[0314] (E)-4-((10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-7-yl)amino)-4-oxobuta-2-enoic acid. 1 H NMR (400 MHz, methanol-d4) δ 8.03 (d, J =2.0, Hz, 1H), 7.56-7.62 (m, 3H), 7.47 (s, 1H), 7.35-7.37 (m, 2H), 7.10 (d, J =15.6, Hz, 1H), 6.81 (d, J =15.6, Hz, 1H), 4.53-4.60 (m, 1H), 3.90-3.97 (m, 1H), 3.68-3.72 (m, 1H), 3.62-3.65 (m, 1H), 3.61 (s, 3H). 13 ¹³C NMR (151 MHz, methanol-d4) δ 169.9, 162.9, 139.4, 138.8, 138.0, 137.0, 136.6, 136.0, 131.7, 130.9, 130.8, 130.4, 128.6, 126.6, 123.3, 120.9, 69.7, 57.6, 50.9. 20 H 19 N2O5S[M+H] + LC-MS (ESI) calculation value for this: 399.10, measured value: 399.10.

[0315] 2-Cyano-N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-7-yl)acetamide. 1 H NMR (400 MHz, chloroform-d): δ 8.19 (s, 1H), 7.75-7.77 (d, J =8.0 Hz, 1H), 7.63-7.64 (d, J =4.0 Hz, 1H), 7.41-7.42 (d, J =4.0 Hz, 2H), 7.29-7.30 (d, J =4.0 Hz, 1H), 7.25-7.29 (m, 2H), 4.48-4.54 (m, 1H), 3.90-3.96 (m, 1H), 3.76-3.81 (m, 1H), 3.53-3.66 (m, 1H), 3.33 (s, 3H). 13 ¹³C NMR (151 MHz, chloroform-d) δ 169.5, 159.5, 140.3, 138.7, 138.0, 137.2, 134.9, 131.2, 131.0, 131.0, 128.8, 126.8, 124.2, 121.4, 114.3, 70.0, 58.9, 51.7, 26.8. 19 H 18 N3O3S[M+H] + The LC-MS (ESI) calculation value for this is 468.11, and the measured value is 368.10.

[0316] 2-((10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-7-yl)amino)-2-oxoacetic acid. 1 ¹H NMR (400 MHz, chloroform-d) δ 8.96 (s, 1H), 7.91 (s, 1H), 7.67-7.69 (m, 1H), 7.54-7.56 (m, 2H), 7.42-7.44 (d, J = 8.0 Hz, 1H), 7.29-7.34 (m, 2H), 4.48-4.54 (m, 1H), 3.94-3.99 (m, 1H), 3.82-3.87 (m, 1H), 3.66-3.71 (m, 1H), 3.35 (s, 3H). 13¹³C NMR (151 MHz, methanol-d4) δ 169.8, 139.9, 138.8, 138.0, 136.9, 135.6, 130.9, 130.8, 130.4, 128.6, 126.6, 123.9, 121.4, 69.7, 57.6, 50.9. 18 H 17 N2O5S[M+H] + The LC-MS (ESI) calculation for this was 373.09, and the measured value was 373.10.

[0317] (E)-10-(hexa-2-en-1-yl)-7-(isoquinoline-1-ylamino)dibenzo[b,f][1,4]thiazepine-11(10H)-one. 1 H NMR (400 MHz, chloroform-d): δ7.86 (d, J=4.0 Hz, 2H), 7.80 (t, J=8.4 Hz, 1H), 7.72 (d, J=7.6 Hz, 1H), 7.67 (t, J=6.8 Hz, 1H), 7.42-7.44 (m, 2H), 7.28-7.38 (m, 5H), 7.21-7.24 (m, 1H), 5.63-5.75 (m, 2H), 4.72-4.76 (m, 1H), 4.52-4.57 (m, 1H), 2.01-2.09 (m, 2H), 1.35-1.44 (m, 2H), 0.88 (t, J = 7.6 Hz, 3H). 13 ¹³C NMR (151 MHz, chloroform-d) δ 168.8, 162.5, 162.2, 151.9, 142.3, 138.9, 138.0, 137.9, 137.4, 135.6, 134.9, 134.6, 131.4, 131.1, 131.1, 128.9, 128.5, 128.1, 128.0, 127.1, 127.0, 126.6, 124.8, 124.2, 118.7, 116.8, 114.8, 53.7, 34.3, 22.2, 13.6. 28 H 26 N3OS[M+H] + The LC-MS (ESI) calculation for this was 452.18, and the measured value was 452.30.

[0318] 2-Cyano-4-methoxy-N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-7-yl)benzamide. 1 ¹H NMR (400 MHz, chloroform-d): δ 10.22 (s, 1H), 7.92 (s, 1H), 7.74-7.80 (m, 3H), 7.62-7.64 (m, 1H), 7.51-7.54 (m, 2H), 7.41-7.43 (m, 2H), 7.26-7.29 (m, 1H), 4.52-4.57 (m, 1H), 3.89-3.95 (m, 1H), 3.92 (s, 3H), 3.60-3.64 (m, 1H), 3.54-3.58 (m, 1H), 3.21 (s, 3H). 13 ¹³C NMR (151 MHz, chloroform-d) δ 168.9, 166.4, 164.7, 156.6, 144.6, 138.2, 137.6, 132.1, 131.3, 131.1, 129.0, 127.7, 126.6, 125.7, 125.3, 120.0, 118.7, 106.4, 106.2, 70.2, 59.0, 56.1, 52.3. 25 H 22 N3O4S[M+H] + The LC-MS (ESI) calculation for this was 460.14, and the measured value was 460.20.

[0319] N1-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-7-yl)-N4,N4-dimethylterephthalamide. 1¹H NMR (400 MHz, chloroform-d) δ9.24 (s, 1H), 8.07 (d, J =2.4, Hz, 1H), 7.82 (d, J =7.6, Hz, 1H), 7.79 (s, 1H), 7.71 (dd, J =2.4, 2.4 Hz, 1H), 7.66 (dd, J =1.6, 1.6 Hz, 1H), 7.45 (dd, J =6.4, 7.2 Hz, 1H), 7.34-7.38 (m, 3H), 7.25-7.29 (m, 2H), 4.53-4.58 (m, 1H), 3.90-3.94 (m, 1H), 3.78-3.84 (m, 1H), 3.63-3.67 (m, 1H), 3.35 (s, 3H), 3.13 (s, 3H), 2.96 (s, 3H). 13 ¹³C NMR (151 MHz, chloroform-d) δ 171.2, 169.2, 165.4, 139.8, 139.0, 138.3, 137.0, 136.3, 135.6, 135.1, 131.1, 131.1, 130.7, 129.9, 129.2, 129.0, 128.6, 126.6, 125.7, 124.1, 121.3, 70.1, 58.9, 51.5, 39.7, 35.6. 26 H 26 N3O4S[M+H] + The LC-MS (ESI) calculation value for this is 476.17, and the measured value is 476.20.

[0320] N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-7-yl)-4-sulfamoylbenzamide. 1HNMR (400 MHz, DMSO-d6) δ 10.55 (s, 1H), 8.16 (d, J =2.4 Hz, 1H), 8.08 (d, J =8.4, Hz, 2H), 7.96 (d, J =8.1 Hz, 2H), 7.76 (d, J =2.4, Hz, 1H), 7.66 (d, J =8.8, Hz, 1H), 7.59 (d, J =4.8 Hz, 1H), 7.52 (t, J =4.0, Hz, 3H), 7.39-7.42 (m, 2H), 4.53-4.56 (m, 1H), 3.83-3.89 (m, 1H), 3.49-3.61 (m, 2H), 3.21 (s, 3H). 13 C NMR (151 MHz, DMSO-d6) δ 167.1, 164.1, 146.1, 138.0, 137.5, 136.8, 136.1, 135.1, 130.4, 130.3, 128.3, 127.8, 126.1, 125.1, 123.0, 120.9, 68.7, 57.5, 49.3. C 23 H 22 N3O5S2[M+H] + The LC-MS (ESI) calculation value for this is 484.10, and the measured value is 484.10.

[0321] 4-(difluoromethoxy)-N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-7-yl)benzamide. 1H NMR (400 MHz, chloroform-d): δ 8.02 (s, 1H), 7.87 (s, 1H), 7.65-7.66 (d, J = 4.0 Hz, 2H), 7.60-7.61 (d, J = 4.0 Hz, 1H), 7.58-7.59 (d, J = 4.0 Hz, 1H), 7.47-7.48 (d, J = 4.0 Hz, 1H), 7.41-7.42 (d, J = 4.0 Hz, 1H), 7.20-7.30 (m, 2H), 7.18-7.20 (d, J = 8.0 Hz, 1H), 6.40-6.77 (m, 1H), 4.50-4.57 (m, 1H), 3.91-3.96 (m, 1H), 3.82-3.90 (m, 1H), 3.62-3.80 (m, 1H), 3.34 (s, 3H). 13 ¹³C NMR (151 MHz, chloroform-d) δ 169.2, 164.7, 153.9, 140.0, 138.8, 138.2, 137.1, 135.8, 131.3, 131.1, 131.0, 130.8, 129.1, 128.6, 126.8, 124.2, 121.4, 119.2, 117.1, 115.3, 113.6, 70.1, 58.9, 51.6. 24 H 21 F2N2O4S[M+H] + The LC-MS (ESI) calculation value for this is 471.12, and the measured value is 471.10.

[0322] 4-(formamidomethyl)-N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-7-yl)benzamide. 1H NMR (600 MHz, chloroform-d) δ 8.32 (s, 1H), 8.00 (s, 1H), 7.95 (d, J = 2.5 Hz, 1H), 7.80 (d, J = 8.3 Hz, 2H), 7.67 (dd, J = 7.6, 1.6 Hz, 1H), 7.62 (dt, J = 8.7, 2.3 Hz, 1H), 7.50 (d, J = 8.7 Hz, 1H), 7.41 (dd, J = 7.6, 1.4 Hz, 1H), 7.38 (d, J = 8.1 Hz, 2H), 7.29 (ddd, J = 15.1, 7.5, 5.9 Hz, 2H), 4.58 - 4.48 (m, 3H), 3.93 (dt, J = 13.8, 5.5 Hz, 1H), 3.86 - 3.79 (m, 1H), 3.68 - 3.61 (m, 1H), 3.35 (s, 3H). 13 ¹³C NMR (151 MHz, chloroform-d) δ 169.1, 161.1, 161.0, 142.0, 140.1, 138.8, 138.3, 135.7, 133.8, 131.2, 131.0, 130.7, 128.7, 128.0, 127.5, 126.8, 124.1, 121.2, 70.2, 58.9, 51.6, 41.7. 25 H 24 N3O4S[M+H] + The LC-MS (ESI) calculation value for this is 462.15, and the measured value is 462.10.

[0323] 4-(acetamidomethyl)-N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-7-yl)benzamide. 1H NMR (400 MHz, chloroform-d) δ8.69 (s, 1H), 7.99 (s, 1H), 7.74 (d, J=8.0 Hz, 2H), 7.62-7.67 (m, 2H), 7.44 (d, J=8.8 Hz, 1H), 7.37 (d, J=7.2 Hz, 1H), 7.21-7.26 (m, 4H), 6.39 (br, 1H), 4.50-4.56 (m, 1H), 4.40 (d, J=4.2 Hz, 2H), 3.86-3.93 (m, 1H), 3.76-3.81 (m, 1H), 3.59-3.65 (m, 1H), 3.32 (s, 3H), 2.03 (s, 3H). 13 ¹¹C NMR (151 MHz, chloroform-d) δ 170.3, 169.1, 165.6, 142.6, 140.0, 138.8, 138.3, 137.0, 136.0, 133.6, 131.2, 131.0, 130.7, 128.6, 127.8, 127.5, 126.7, 124.1, 121.3, 70.1, 58.9, 51.5, 43.2, 29.7, 23.3. 26 H 26 N3O4S[M+H] + The LC-MS (ESI) calculation value for this is 476.17, and the measured value is 476.20.

[0324] 6-Ethinyl-N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-7-yl)nicotinamide. 1H NMR (400 MHz, DMSO-d6) δ 9.05 (s, 1H), 8.28-8.30 (d, J=8.0 Hz, 2H), 8.14 (s, 1H), 7.73-7.76 (m, 2H), 7.60-7.61 (d, J=4.0 Hz, 1H), 7.58-7.59 (m, 1H). 7.51-7.53 (m, 1H), 7.39-7.41(m, 1H), 4.57(s, 1H), 4.50-4.55 (m, 1H), 3.82-3.88 (m, 1H), 3.50-3.52 (m, 1H), 3.53-3.61 (m, 1H), 3.20(s, 3H). 13 C NMR (151 MHz, DMSO-d6) δ 167.1, 162.8, 148.6, 143.5, 138.1, 137.5, 136.0, 135.5, 135.1, 130.4, 130.3, 129.0, 128.3, 126.4, 126.2, 123.0, 120.9, 82.0, 68.7, 57.5, 49.3. C 24 H 20 N3O3S[M+H] + The LC-MS (ESI) calculation for this is 430.12, and the measured value is 430.10.

[0325] 2-Ethinyl-N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-7-yl)isonicotinamide. 1 ¹H NMR (400 MHz, chloroform-d) δ 8.68-8.69 (d, J = 4.0 Hz, 1H), 8.52 (s, 1H), 7.92-7.93 (d, J = 4.0 Hz, 1H), 7.85 (s, 1H), 7.60-7.65 (m, 3H), 7.50-7.52 (d, J = 8.0 Hz, 1H), 7.37-7.39 (m, 1H), 7.25-7.26 (m, 1H), 4.47-4.54 (m, 1H), 3.91-3.97 (m, 1H), 3.66-3.83 (m, 1H), 3.61-3.65 (m, 1H), 3.33(s, 3H), 3.18 (s, 1H).13 ¹³C NMR (151 MHz, chloroform-d) δ 169.3, 163.2, 150.8, 143.3, 142.1, 140.5, 138.7, 138.1, 137.1, 135.3, 131.1, 131.0, 130.9, 128.7, 126.8, 124.8, 124.5, 121.6, 120.8, 82.0, 78.8, 70.1, 58.9, 51.8. 24 H 20 N3O3S[M+H] + The LC-MS (ESI) calculation for this is 430.12, and the measured value is 430.10.

[0326] 6-Methoxy-N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-7-yl)nicotinamide. 1 HNMR (400 MHz, chloroform-d) δ 8.67 (d, J =2.4 Hz, 1H), 8.19 (s, 1H), 8.06 (dd, J =2.4, 2.0 Hz, 1H), 7.92 (d, J =2.4 Hz, 1H), 7.62-7.64 (m, 1H), 7.58 (d, J =2.4, 2.4 Hz, 1H), 7.47 (d, J =8.8, Hz, 1H), 7.37-7.39 (m, 1H), 7.23-7.27 (m, 2H), 6.79 (d, J =4.4 Hz, 1H), 4.51-4.57 (m, 1H), 4.00 (s, 3H), 3.89-3.96 (m, 1H), 3.77-3.83 (m, H), 3.61-3.66 (m, H), 3.33 (s, 3H). 13 ¹³C NMR (151 MHz, chloroform-d) δ 169.3, 166.2, 164.0, 146.6, 139.9, 138.8, 138.2, 138.1, 137.0, 135.8, 131.0, 130.8, 128.6, 126.7, 124.3, 123.6, 121.4, 111.0, 70.1, 58.9, 54.2, 51.6. 23 H 22N3O4S[M+H] + The LC-MS (ESI) calculation for this is 436.14, and the measured value is 436.10.

[0327] 2-Methoxy-N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-7-yl)isonicotinamide. 1 ¹H NMR (400 MHz, chloroform-d): δ 8.27-8.28 (d, J = 4.0 Hz, 1H), 8.16 (s, 1H), 7.92-7.93 (d, J = 4.0 Hz, 1H), 7.60-7.64 (m, 2H), 7.48-7.50 (d, J = 8.0 Hz, 1H), 7.38-7.39 (d, J = 4.0 Hz, 1H), 7.22-7.28 (m, 3H), 7.10 (s, 1H), 4.50-4.53 (m, 1H), 3.97 (s, 3H), 3.91-3.95 (m, 1H), 3.79-3.82 (m, 1H), 3.62-3.65(s, 3H), 3.34 (s, 3H). 13 ¹³C NMR (151 MHz, chloroform-d) δ 169.2, 164.8, 163.9, 148.1, 144.4, 140.4, 138.7, 138.2, 137.1, 135.3, 131.1, 131.0, 130.8, 128.7, 126.8, 124.3, 121.4, 113.9, 108.8, 70.2, 58.9, 53.9, 51.7. 23 H 22 N3O4S[M+H] + The LC-MS (ESI) calculation for this was 436.14, and the measured value was 436.20.

[0328] 4-Fluoro-3-methoxy-N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-7-yl)benzamide. 1H NMR (400 MHz, chloroform-d): δ 7.96 (s, 1H), 7.90-7.91 (d, J =4.0 Hz, 1H), 7.48-7.66 (m, 4H), 7.39-7.40 (d, J =4.0 Hz, 1H), 7.25-7.38 (m, 3H), 7.10-7.14 (m, 1H), 4.52-4.55 (m, 1H), 3.90-3.96 (m, 4H), 3.80-3.84 (m, 1H), 3.63-3.67 (m, 1H), 3.34 (s, 3H). 13 ¹C NMR (151 MHz, chloroform-d) δ 169.2, 164.9, 155.6, 153.9, 148.2, 140.0, 138.8, 138.2, 137.1, 135.8, 131.1, 131.0, 130.8, 128.6, 126.8, 124.2, 121.3, 119.2, 116.1, 115.9, 113.1 (d, J = 2.9 Hz), 70.1, 58.9, 56.3, 51.6. 24 H 22 FN2O4S[M+H] + The LC-MS (ESI) calculation for this was 453.13, and the measured value was 453.20.

[0329] N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-7-yl)benzo[d]oxazole-6-carboxamide. 1 H NMR (400 MHz, chloroform-d) δ 8.24 (s, 1H), 8.15 (d, J =0.8 Hz, 1H), 7.95 (t, J =4.4 Hz, 2H), 7.82-7.89 (m, 2H), 7.61-7.68 (m, 2H), 7.52 (d, J =8.8, Hz, 1H), 7.42 (dd, J =1.6, 1.6 Hz, 1H), 7.26-7.32 (m, 2H), 4.51-4.56 (m, 1H), 3.92-3.97 (m, 1H), 3.80-3.86 (m, 1H), 3.64-3.68(m, 1H), 3.35(s, 3H).13 ¹³C NMR (151 MHz, chloroform-d) δ 169.2, 165.1, 154.7, 149.9, 143.1, 140.1, 138.8, 138.2, 137.1, 135.8, 132.3, 131.1, 131.0, 130.8, 128.6, 126.8, 124.2, 123.5, 121.4, 120.8, 110.9, 70.1, 58.9, 51.6. 24 H 20 N3O4S[M+H] + The LC-MS (ESI) calculation value for this is 446.12, and the measured value is 446.10.

[0330] N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-7-yl)-2-methylbenzo[d]oxazole-5-carboxamide. 1 H NMR (400 MHz, chloroform-d) δ 8.11 (s, 1H), 7.94-7.95 (d, J =4.0 Hz, 2H), 7.84-7.86 (d, J =8.0 Hz, 1H), 7.60-7.68 (m, 2H), 7.43-7.56 (m, 2H), 7.41-7.42 (d, J =4.0 Hz, 1H), 7.26-7.30 (m, 2H), 4.52-4.58 (m, 1H), 3.85-3.97 (m, 1H), 3.79-3.81 (m, 1H), 3.63-3.67 (m, 1H), 3.35 (s, 3H), 2.68 (s, 3H). 13 ¹³C NMR (151 MHz, chloroform-d) δ 169.1, 165.6, 165.5, 153.2, 141.8, 140.0, 138.8, 138.3, 137.1, 135.9, 131.1, 131.1, 131.0, 130.7, 128.6, 126.8, 124.4, 124.1, 121.3, 118.4, 110.6, 70.1, 58.9, 51.6, 14.6. 25 H 22 N3O4S[M+H] +The LC-MS (ESI) calculation for this was 460.14, and the measured value was 460.20.

[0331] 1-(benzo[d]oxazol-5-yl)-3-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-7-yl)urea. 1 H NMR (400 MHz, MeOH-d4) δ 8.03 (s, 1H), 7.83 (d, J =20.5, Hz, 2H), 7.72 (s, 1H), 7.63 (d, J =9.2, Hz, 1H), 7.51 (d, J =2.0, Hz, 1H), 7.36-7.40 (m, 2H), 7.26-7.30 (m, 3H), 7.22 (t, J =3.6, Hz, 2H), 4.56-4.61 (m, 1H), 3..84-3.88 (m, 1H), 3.71-3.76 (m, 1H), 3.59-3.63 (m, 1H), 3.29 (s, 3H). 13 ¹³C NMR (151 MHz, chloroform-d) δ 169.9, 153.4, 146.6, 140.5, 139.1, 138.0, 137.9, 137.1, 137.0, 135.2, 131.2, 130.9, 130.8, 128.7, 126.6, 123.1, 120.5, 119.5, 112.5, 111.0, 69.9, 58.9, 51.5. 24 H 21 N4O4S[M+H] + The LC-MS (ESI) calculation value for this is 461.13, and the measured value is 461.10.

[0332] (E)-10-(hexa-2-en-1-yl)-7-((4-methylpyridine-2-yl)amino)dibenzo[b,f][1,4]thiazepine-11(10H)-one. 1H NMR (400 MHz, chloroform-d): δ 7.71-7.76 (m, 2H), 7.54-7.55 (d, J =4.0 Hz, 1H), 7.41-7.46 (m 2H), 7.31-7.37 (m, 2H), 7.20-7.26 (m, 2H), 6.71-6.72 (d, J =4.0 Hz, 1H), 5.64-5.68 (m, 2H), 4.77-4.82 (m, 1H), 4.47-4.52 (m, 1H), 2.38 (s, 3H), 1.99-2.03 (m, 2H), 1.33-1.40 (m, 2H), 0.83-0.86 (t, J = 8.0 Hz, 3H). 13 ¹¹C NMR (151 MHz, chloroform-d) δ 168.5, 157.4, 152.6, 141.9, 138.2, 138.0, 137.8, 136.5, 134.7, 134.1, 131.6, 131.1, 131.0, 128.9, 126.8, 125.0, 124.8, 115.6, 110.0, 53.3, 34.3, 22.5, 22.2, 13.6. 25 H 26 N3OS[M+H] + The LC-MS (ESI) calculation for this was 416.18, and the measured value was 416.30.

[0333] (E)-2-((10-(hexa-2-en-1-yl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-7-yl)amino)isonicotinonitrile. 1H NMR (400 MHz, chloroform-d): δ 8.32-8.33 (d, J =4.0 Hz, 1H), 7.72-7.73 (d, J =4.0 Hz, 1H), 7.26-7.43 (m, 5H), 6.92-6.93 (d, J =4.0 Hz, 1H), 6.87 (s, 1H), 5.61-5.71 (m, 2H), 4.77-4.82 (m, 1H), 4.46-4.50 (m, 1H), 2.38 (s, 3H), 1.99-2.03 (m, 2H), 1.31-1.40 (m, 2H), 0.82-0.86 (t, J =8.0 Hz, 3H). 13 ¹¹C NMR (151 MHz, chloroform-d) δ 168.8, 155.6, 149.6, 138.8, 138.7, 138.3, 137.2, 137.1, 134.5, 131.4, 131.1, 130.8, 128.7, 126.2, 125.0, 124.0, 121.6, 121.0, 116.8, 115.9, 111.3, 53.4, 34.3, 22.2, 13.6. 25 H 23 N4OS[M+H] + The LC-MS (ESI) calculation for this was 427.16, and the measured value was 427.20.

[0334] N-(6-(2-methoxyethyl)-5-oxo-5,6-dihydrobenzo[b]pyrido[4,3-f][1,4]thiazepine-9-yl)furan-3-carboxamide. 1¹H NMR (400 MHz, chloroform-d): δ 8.69 (s, 1H), 8.56 (s, 1H), 8.06 (s, 1H), 7.90 (s, 1H), 7.83 (d, J = 2.4 Hz, 1H), 7.71-7.74 (m, 1H), 7.65 (d, J = 4.4 Hz, 1H), 7.47-7.52 (m, 2H), 6.74 (d, J = 0.8 Hz, 1H), 4.50-4.56 (m, 1H), 3.91-3.98 (m, 1H), 3.76-3.81 (m, 1H), 3.62-3.67 (m, 1H), 3.33 (s, 3H). 13 ¹³C NMR (151 MHz, chloroform-d) δ 166.5, 160.9, 149.1, 147.9, 147.1, 145.6, 144.3, 138.9, 136.3, 135.7, 127.4, 125.3, 124.3, 122.5, 121.9, 108.3, 69.8, 58.9, 51.8. 20 H 18 N3O4S[M+H] + The LC-MS (ESI) calculation for this was 396.10, and the measured value was 396.30.

[0335] N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrobenzo[b]pyrido[3,4-f][1,4]thiazepine-7-yl)furan-3-carboxamide. 1 ¹H NMR (400 MHz, methanol-d4): δ 8.77 (s, 1H), 8.49-8.51 (d, J = 8.0 Hz, 1H), 8.21 (s, 1H), 8.10-8.11 (d, J = 4.0 Hz, 1H), 7.71-7.74 (m, 1H), 7.61-7.66 (m, 3H), 6.91 (m, 1H), 4.62-4.68 (m, 1H), 3.92-3.98 (m, 1H), 3.62-3.71 (m, 2H), 3.30 (s, 3H). 13¹³C NMR (151 MHz, methanol-d4) δ 166.7, 162.1, 151.6, 149.7, 149.0, 145.9, 144.1, 138.4, 137.2, 134.1, 127.0, 125.6, 124.4, 122.5, 122.1, 108.4, 69.6, 57.6, 50.6. 20 H 18 N3O4S[M+H] + The LC-MS (ESI) calculation value for this is 396.10, and the measured value is 396.20.

[0336] (E)-10-(hexa-2-en-1-yl)-7-(pyrazine-2-ylamino)dibenzo[b,f][1,4]thiazepine-11(10H)-one. 1 H NMR (400 MHz, chloroform-d): δ8.18 (s, 1H), 8.13-8.14 (d, J=4.0 Hz, 1H), 8.02 (s, 1H), 7.70-7.75 (m, 3H), 7.41-7.44 (m, 2H), 7.25-7.37 (m, 3H), 6.58 (s, 1H), 5.64-5.67 (m, 2H), 4.77-4.82 (m, 1H), 4.44-4.48 (m, 1H), 1.97-2.02 (m, 2H), 1.32-1.38 (m, 2H), 0.82-0.85 (t, J=12.0 Hz, 3H). 13 ¹³C NMR (151 MHz, chloroform-d) δ 168.8, 151.5, 141.7, 138.8, 138.4, 138.2, 137.4, 137.1, 135.4, 134.4, 133.8, 131.4, 131.0, 130.7, 128.6, 126.1, 125.1, 122.9, 120.1, 53.3, 34.3, 22.2, 13.6. 23 H 23 N4OS[M+H] + The LC-MS (ESI) calculation for this is 403.16, and the measured value is 403.10.

[0337] (E)-10-(hexa-2-en-1-yl)-7-(pyrimidine-2-ylamino)dibenzo[b,f][1,4]thiazepine-11(10H)-one. 1 H NMR (400 MHz, chloroform-d): δ 9.43 (s, 1H), 8.47 (d, J =3.2 Hz, 2H), 7.97 (d, J =2.4 Hz, 1H), 7.71 (dd, J =2.0, 1.6 Hz, 1H), 7.55 (dd, J =2.4, 2.4 Hz, 1H), 7.44 (dd, J =1.2, 1.2 Hz, 1H), 7.38 (d, J =8.8 Hz, 1H), 7.25-7.33 (m, 2H), 6.85 (t, J =4.8 Hz, 1H), 5.64-5.67 (m, 1H), 4.75-4.80 (m, 1H), 4.46-4.50 (m, 1H), 1.97-2.02 (m, 2H), 1.35 (q, J =7.2 Hz, 2H), 0.84 (t, J =7.6 Hz, 3H). 13 ¹³C NMR (151 MHz, chloroform-d) δ 168.7, 157.5, 157.2, 139.1, 138.7, 138.4, 136.8, 136.0, 134.4, 131.4, 131.0, 130.7, 128.6, 125.9, 125.1, 123.7, 121.0, 112.2, 53.3, 34.3, 22.2, 13.6. 23 H 23 N4OS[M+H] + The LC-MS (ESI) calculation for this is 403.16, and the measured value is 403.10.

[0338] N-(10-(6-(methylamino)-6-oxohexyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-7-yl)furan-3-carboxamide. 1H NMR (400 MHz, chloroform-d):δ8.75 (s, 1H), 8.13 (s, 1H), 7.81 (d, J =2.4, Hz, 1H), 7.61-7.62 (m, 2H), 7.44 (t, J =1.6, Hz, 1H), 7.31-7.33 (m, 1H), 7.21-7.28 (m, 3H), 6.84 (d, J =1.2, Hz, 1H), 6.38 (d, J =4.4, Hz, 1H), 4.69-7.76 (m, 1H), 3.47-3.54 (m, 1H), 2.71 (d, J =4.8, Hz, 3H), 2.15(t, J =7.2, Hz, 2H), 1.50-1.64 (m, 4H), 1.34-1.48 (m, 2H). 13 ¹³C NMR (151 MHz, chloroform-d) δ 174.9, 169.5, 161.4, 145.8, 144.0, 138.8, 138.4, 138.0, 137.2, 136.2, 131.1, 131.0, 130.9, 128.7, 126.1, 124.6, 122.6, 121.8, 108.7, 50.4, 36.1, 27.5, 26.5, 26.2, 25.2. 25 H 26 N3O4S[M+H] + The LC-MS (ESI) calculation for this was 464.17, and the measured value was 464.20.

[0339] (E)-10-(hexa-2-en-1-yl)-7-((3-methylpyridine-2-yl)amino)dibenzo[b,f][1,4]thiazepine-11(10H)-one. 1H NMR (400 MHz, chloroform-d): δ 7.93-7.94 (d, J =4.0 Hz, 1H), 7.79-7.81 (d, J =8.0 Hz, 1H), 7.69-7.72 (m 1H), 7.33-7.39 (m, 4H), 7.33-7.34 (d, J =4.0 Hz, 1H), 7.04-7.32 (m, 2H), 5.62-5.66 (m, 2H), 4.76-4.81 (m, 1H), 4.45-4.50 (m, 1H), 1.97-2.01 (m, 2H), 1.93 (s, 3H), 1.32-1.38 (m, 2H), 0.83-0.86 (t, J =8.0 Hz, 3H). 13 ¹¹C NMR (151 MHz, chloroform-d) δ 168.6, 163.8, 163.5, 151.1, 146.4, 140.7, 138.2, 138.1, 137.0, 136.2, 136.1, 134.6, 131.5, 131.0, 130.9, 128.9, 126.4, 125.9, 125.6, 125.0, 123.1, 116.3, 53.3, 34.3, 22.2, 19.5, 13.6. 25 H 26 N3OS[M+H] + The LC-MS (ESI) calculation for this was 416.18, and the measured value was 416.30.

[0340] (E)-2-((10-(hexa-2-en-1-yl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-7-yl)amino)nicotinonitrile. 11H NMR (400 MHz, chloroform-d): δ 8.39 - 8.41 (m, 1H), 7.88 - 7.89 (d, J = 4.0 Hz, 1H), 7.79 - 7.81 (m, 1H), 7.69 - 7.72 (m, 1H), 7.53 - 7.56 (m, 1H), 7.31 - 7.44 (m, 2H), 7.26 - 7.30 (m, 2H), 5.65 - 5.68 (m, 2H), 4.75 - 4.79 (m, 1H), 4.50 - 4.51 (m, 1H), 1.99 - 2.01 (m, 2H), 1.33 - 1.39 (m, 2H), 0.83 - 0.87 (t, J = 8.0 Hz, 3H). 13 13C NMR (151 MHz, chloroform-d) δ 168.6, 155.4, 152.3, 141.7, 139.1, 138.7, 138.4, 136.8, 136.3, 134.3, 131.4, 131.0, 130.7, 128.6, 125.9, 125.1, 124.2, 121.3, 116.0, 114.7, 93.6, 53.3, 34.3, 22.2, 13.6.C 25 H 23 N4OS[M+H] + LC-MS for: (ESI) calculated value 427.16, measured value 427.20.

[0341] N-(3-Fluoro-11-oxo-10-(2-(prop-2-yn-1-yloxy)ethyl)-10,11-dihydrodibenzo[b,f][1,4]thiazepin-7-yl)benzo[d]thiazole-5-carboxamide. 11H NMR (400 MHz, chloroform-d): δ 9.11 (s, 1H), 8.57 (s, 1H), 8.15 (s, 1H), 8.07 (d, J = 8.4 Hz, 1H), 7.97 - 8.01 (m, 2H), 7.65 - 7.69 (m, 2H), 7.51 (d, J = 8.8 Hz, 1H), 7.13 - 7.16 (m, 1H), 6.97 - 7.02 (m, 1H), 4.55 - 4.61 (m, 1H), 4.16 (d, J = 2.4 Hz, 2H), 3.93 - 4.00 (m, 2H), 3.78 - 3.84 (m, 1H), 2.42 (t, J = 2.0 Hz, 1H). 13 13C NMR (151 MHz, chloroform-d) δ 168.3, 165.3, 163.8, 162.1, 155.9, 140.9 (d, J = 8.2 Hz), 140.1, 137.6, 136.4, 136.0, 134.4 (d, J = 3.5 Hz), 133.3 (d, J = 9.2 Hz), 132.9, 126.9, 124.5, 124.2, 122.6, 121.9, 121.5, 118.0, 117.9, 115.9, 79.4, 74.7, 67.6, 58.4, 51.5.C 26 H 19 FN3O3S2[M+H] + LC-MS for: (ESI) calculated value 504.09, measured value 504.10.

[0342] N-(10-(2-Methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepin-7-yl)-2-(4-methoxyphenyl)acetamide. 1¹H NMR (400 MHz, chloroform-d): δ 7.63-7.65 (m, 1H), 7.36-7.41 (m, 3H), 7.15-7.28 (m, 5H), 6.92 (d, J=8.0 Hz, 2H), 4.48-4.54 (m, 1H), 3.84-3.90 (m, 1H), 3.82 (s, 3H), 3.74-3.78 (m, 1H), 3.64 (s, 2H), 3.57-3.62 (m, 1H), 3.31 (s, 3H). 13 ¹¹C NMR (151 MHz, chloroform-d) δ 169.7, 169.1, 159.2, 139.8, 138.8, 138.3, 136.9, 135.6, 131.1, 131.0, 130.7, 130.6, 128.6, 126.6, 125.9, 123.5, 120.8, 114.7, 70.1, 58.8, 55.3, 51.5, 43.8. 25 H 25 N2O4S[M+H] + The LC-MS (ESI) calculation for this is 449.16, and the measured value is 449.10.

[0343] N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-7-yl)benzothioamide. 1 H NMR (600 MHz, chloroform-d) δ 8.97 (s, 1H), 8.05 (s, 1H), 7.91 (s, 1H), 7.80 (s, 1H), 7.68 (dd, J = 7.6, 1.7 Hz, 1H), 7.60 (d, J = 8.7 Hz, 1H), 7.51 (t, J = 7.3 Hz, 1H), 7.42 (d, J = 8.2 Hz, 2H), 7.36 - 7.27 (m, 3H), 4.49 (dt, J = 13.3, 6.0 Hz, 1H), 4.01 (dt, J = 13.9, 5.3 Hz, 1H), 3.86 (ddd, J = 10.2, 6.8, 5.0 Hz, 1H), 3.67 (dt, J = 10.4, 5.4 Hz, 1H), 3.36 (s, 3H). C23 H 21 N2O2S2[M+H] + LC-MS (ESI) calculation value for this is 421.10, and the measured value is 421.10.

[0344] N-(10-(buta-2-in-1-yl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-7-yl)benzo[d]thiazole-5-carboxamide. 1 ¹H NMR (400 MHz, chloroform-d) δ 9.08 (s, 1H), 8.59 (d, J = 1.7 Hz, 1H), 8.46 (s, 1H), 8.06 - 7.94 (m, 3H), 7.77 - 7.65 (m, 3H), 7.43 - 7.34 (m, 1H), 7.32 - 7.22 (m, 2H), 4.94 (dd, J = 17.0, 2.4 Hz, 1H), 4.44 (dd, J = 17.0, 2.4 Hz, 1H), 1.85 (t, J = 2.4 Hz, 3H). 13 ¹³C NMR (151 MHz, chloroform-d) δ 168.5, 165.4, 155.8, 153.0, 139.9, 138.5, 137.5, 137.5, 136.1, 135.8, 131.8, 131.1, 131.1, 128.6, 125.1, 124.6, 124.1, 122.5, 122.0, 121.2, 80.2, 74.7, 41.2, 3.9. 25 H 18 N3O2S2[M+H] + The LC-MS (ESI) calculation for this was 456.09, and the measured value was 456.10.

[0345] N-(10-(buta-2-in-1-yl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-7-yl)-3-methoxybenzamide. 1H NMR (400 MHz, chloroform-d) δ 8.12 (s, 1H), 7.95 (d, J = 2.4 Hz, 1H), 7.78 - 7.61 (m, 3H), 7.45 - 7.33 (m, 4H), 7.32 - 7.27 (m, 2H), 7.07 (dt, J = 7.4, 2.6 Hz, 1H), 4.93 (dd, J = 17.0, 2.4 Hz, 1H), 4.43 (dd, J = 17.0, 2.4 Hz, 1H), 3.85 (s, 3H), 1.85 (s, 3H). 13 ¹¹C NMR (151 MHz, chloroform-d) δ 168.5, 165.7, 160.0, 144.8, 139.7, 138.6, 137.6, 136.1, 135.9, 135.8, 131.8, 131.7, 131.1, 131.1, 131.0, 130.8, 129.8, 128.6, 128.4, 125.6, 125.1, 124.1, 121.2, 118.8, 118.3, 118.2, 115.8, 112.5, 80.2, 74.7, 55.5, 41.2, 3.8. 25 H 21 N2O3S[M+H] + The LC-MS (ESI) calculation for this was 429.13, and the measured value was 429.20.

[0346] (E)-10-(hexa-2-en-1-yl)-7-((3-methoxypyridine-2-yl)amino)dibenzo[b,f][1,4]thiazepine-11(10H)-one. 1H NMR (400 MHz, chloroform-d): δ 7.91-7.92 (d, J=4.0 Hz, 1H), 7.82-7.84 (m, 1H), 7.68-7.72 (m, 2H), 7.40-7.42 (m, 1H), 7.24-7.33 (m, 2H), 6.96-7.01 (m, 1H), 6.72-6.75 (m, 1H), 5.65-5.67 (m, 2H), 4.75-4.78 (m, 1H), 4.46-4.47 (m, 1H), 3.89 (s, 3H), 1.98-2.00 (m, 2H), 1.33-1.38 (m, 2H), 0.83-0.86 (t, J=8.0 Hz, 3H). 13 ¹³C NMR (151 MHz, chloroform-d) δ 168.8, 145.8, 142.3, 139.1, 138.6, 138.5, 138.3, 136.8, 136.6, 134.1, 131.3, 131.0, 130.4, 128.4, 125.9, 125.3, 121.9, 119.2, 114.9, 114.7, 55.4, 53.3, 34.3, 22.3, 13.6. 25 H 26 N3O2S[M+H] + The LC-MS (ESI) calculation for this was 432.18, and the measured value was 432.30.

[0347] (E)-10-(hexa-2-en-1-yl)-7-((3-(trifluoromethyl)pyridine-2-yl)amino)dibenzo[b,f][1,4]thiazepine-11(10H)-one. 1H NMR (400 MHz, chloroform-d): δ 8.36 (d, J=4.0 Hz, 1H), 7.76-7.82 (m, 2H), 7.71 (d, J=4.0 Hz, 1H), 7.51-7.54 (m, 1H), 7.30-7.43 (m, 2H), 7.26-7.29 (m, 2H), 6.85-6.88 (m, 1H), 6.69(s, 1H), 5.66-5.68 (m, 2H), 4.73-4.77 (m, 1H), 4.47-4.51 (m, 1H), 1.98-2.02 (m, 2H), 1.34-1.39 (m, 2H), 0.85 (t, J=8.0 Hz, 3H). 13 ¹³C NMR (151 MHz, chloroform-d) δ 168.7, 151.5, 151.3, 138.8, 138.7, 138.5, 137.0, 136.6, 135.7 (q, J = 5.2 Hz), 134.2, 131.4, 131.0, 130.6, 128.6, 125.8, 125.2, 124.3, 121.6, 114.6, 53.3, 34.3, 22.3, 13.6. 25 H 23 F3N3OS[M+H] + The LC-MS (ESI) calculation value for this is 470.15, and the measured value is 470.20.

[0348] (E)-7-((3-fluoropyridine-2-yl)amino)-10-(hexa-2-en-1-yl)dibenzo[b,f][1,4]thiazepine-11(10H)-one. 1H NMR (400 MHz, chloroform-d): δ 8.02-8.03 (d, J=4.0 Hz, 1H), 7.89-7.90 (d, J=4.0 Hz, 1H), 7.63-7.71 (m, 1H), 7.61-7.62 (m, 1H), 7.41-7.43 (m, 1H), 7.25-7.35 (m, 4H), 6.74-6.78 (m, 1H), 6.60-6.61 (m, 1H), 5.65-5.67 (m, 1H), 4.76-4.79 (m, 1H), 4.47-4.48 (m, 1H), 1.98-2.01 (m, 2H), 1.33-1.38 (m, 2H), 0.82-0.86 (t, J=8.0 Hz, 3H). 13 ¹C NMR (151 MHz, chloroform-d) δ 168.8, 147.8, 146.1, 144.7 (d, J = 9.2 Hz), 142.6 (d, J = 6.1 Hz), 138.9, 138.5, 137.6, 136.7, 134.2, 131.4, 131.0, 130.5, 128.5, 125.9, 125.2, 122.4, 121.3, 121.2, 119.6, 115.2, 53.3, 34.3, 22.2, 13.6. 24 H 23 FN3OS[M+H] + The LC-MS (ESI) calculation for this is 420.16, and the measured value is 420.10.

[0349] N-(10-allyl-3-fluoro-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-7-yl)benzo[d]thiazole-5-carboxamide. 1¹H NMR (400 MHz, chloroform-d):δ 9.08 (s, 1H), 8.57 (s, 1H), 8.49 (s, 1H), 8.02 (d, J =8.4Hz, 1H), 7.95-7.99 (m, 2H), 7.66-7.70 (m, 2H), 7.39 (d, J =8.4 Hz, 1H), 7.09-7.12 (m, 1H), 6.94-6.99 (m, 1H), 5.95-6.04 (m, 1H), 5.29 (d, J =17.2 Hz, 1H), 5.20 (d, J =10.4Hz, 1H), 4.81-4.86 (m, 1H), 4.51-4.56 (m, 1H). 13 C NMR (151 MHz, chloroform-d) δ 167.9, 165.4, 163.9, 162.2, 155.8, 153.1, 140.7 (d, J = 8.2 Hz), 139.7, 137.6, 136.0, 135.9, 134.3 (d, J = 3.3 Hz), 133.6 (d, J = 8.9 Hz), 133.2, 132.9, 125.9, 124.5, 124.2, 122.6, 122.0, 121.4, 118.0, 117.9, 117.7, 116.1, 116.0, 53.9. C 24 H 17 FN3O2S2[M+H] + The LC-MS (ESI) calculation for this was 462.08, and the measured value was 462.10.

[0350] N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-7-yl)-2-(3-methoxyphenyl)acetamide. 1¹H NMR (400 MHz, chloroform-d): δ 7.64-7.65 (m, 1H), 7.36-7.41 (m, 3H), 7.24-7.33 (m, 3H), 7.17 (s, 1H), 6.83-6.89 (m, 2H), 6.80 (s, 1H), 4.48-4.54 (m, 1H), 3.84-3.90 (m, 1H), 3.82 (s, 3H), 3.74-3.78 (m, 1H), 3.68 (s, 2H), 3.57-3.63 (m, 1H), 3.31 (s, 3H). 13 ¹³C NMR (151 MHz, chloroform-d) δ 169.0, 160.2, 139.9, 138.8, 138.3, 136.9, 135.5, 135.4, 131.1, 131.0, 130.7, 130.4, 128.6, 126.7, 123.6, 121.6, 120.9, 115.2, 113.2, 70.1, 58.8, 55.3, 51.5, 44.8. 25 H 25 N2O4S[M+H] + The LC-MS (ESI) calculation for this is 449.16, and the measured value is 449.10.

[0351] N-(10-(buta-2-in-1-yl)-3-fluoro-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-7-yl)-6-methoxynicotinamide. 1 ¹H NMR (400 MHz, chloroform-d): δ 8.68 (s, 1H), 8.12 (s, 1H), 8.05-8.08 (m, 1H), 7.94 (d, J = 2.0 Hz, 1H), 7.64-7.75 (m, 3H), 7.10-7.13 (m, 1H), 6.96-7.00 (m, 1H), 6.80 (d, J = 8.4 Hz, 1H), 4.89-4.93 (m, 1H), 4.40-4.44 (m, 1H), 4.00 (s, 3H), 1.85 (s, 3H). 13C NMR (151 MHz, chloroform-d) δ 167.5, 166.5, 164.1, 163.9, 162.4, 146.5, 140.6 (d, J = 11.0 Hz), 139.9, 137.8, 135.9, 135.0, 134.1 (d, J = 9.2 Hz), 133.7 (d, J = 15.9 Hz), 125.3, 124.1, 123.4, 121.4, 118.1, 117.9, 116.1, 116.0, 111.3, 80.3, 74.6, 54.1, 41.2, 3.8. C 24 H 19 FN3O3S[M+H] + The LC-MS (ESI) calculation value for this is 448.12, and the measured value is 448.10.

[0352] N-(10-(buta-2-in-1-yl)-3-fluoro-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-7-yl)-4-(trifluoromethoxy)benzamide. 1 ¹H NMR (400 MHz, chloroform-d): δ 7.83-7.94 (m, 3H), 7.79 (s, 1H), 7.69-7.78 (m, 2H), 7.62-7.65 (m, 1H), 7.33 (d, J=8.0Hz, 2H), 7.14-7.26 (m, 1H), 7.00-7.04 (m, 1H), 4.89-4.94 (m, 1H), 4.41-4.46 (m, 1H), 1.85 (s, 3H). 13 C NMR (151 MHz, chloroform-d) δ 167.7, 164.5, 164.1, 162.4, 151.9, 140.6 (d, J = 8.3 Hz), 139.9, 136.1, 135.0, 134.0 (d, J = 9.1 Hz), 133.7 (d, J = 3.3 Hz), 132.7, 129.1, 125.2, 124.2, 121.6, 120.8, 118.1, 118.0, 116.1, 116.0, 80.4, 74.6, 41.3, 3.8. C 25 H 17F4N2O3S[M+H] + The LC-MS (ESI) calculation value for this is 501.09, and the measured value is 501.10.

[0353] N-(10-(buta-2-in-1-yl)-3-fluoro-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-7-yl)-4-(difluoromethoxy)benzamide. 1 ¹H NMR (400 MHz, chloroform-d): δ 7.94 (s, 1H), 7.79-7.89 (m, 3H), 7.72-7.77 (m, 2H), 7.63-7.66 (m, 1H), 7.21-7.26 (m, 2H), 7.13-7.16 (m, 1H), 6.99-7.03 (m, 1H), 6.41-6.78 (m, 1H), 4.89-4.94 (m, 1H), 4.41-4.46 (m, 1H), 1.85 (s, 3H). 13 ¹³C NMR (151 MHz, chloroform-d) δ values: 167.6, 164.7, 164.0, 162.4, 153.9, 140.6 (d, J = 8.2 Hz), 139.8, 136.1, 135.0, 134.0 (d, J = 8.9 Hz), 133.7 (d, J = 3.4 Hz), 131.2, 129.1, 125.2, 124.2, 121.5, 119.3, 118.1, 117.9, 117.0, 116.1, 115.9, 115.3, 113.6, 80.4, 74.6, 41.2, 3.8. 13C NMR (151 MHz, DMSO-d6) δ 162.9, 162.6, 161.0, 148.6, 143.5, 139.6 (d, J = 8.6 Hz), 137.5, 136.4, 135.5, 133.6, 133.3 (d, J = 9.8 Hz), 128.9, 126.5, 125.1, 123.2, 121.1, 117.3 (d, J = 22.8 Hz), 115.8 (d, J = 21.5 Hz), 82.1, 79.3, 74.3, 2.6. C 25 H 18 F3N2O3S[M+H]+ LC-MS for it: (ESI) calculated value 483.10, measured value 483.00.

[0354] N-(10-(Buta-2-yn-1-yl)-3-fluoro-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepin-7-yl)benzo[d]thiazole-5-carboxamide. 1 H NMR (400 MHz, chloroform-d): δ 9.11 (s, 1H), 8.58 (d, J = 1.2 Hz, 1H), 8.21 (s, 1H), 8.05 - 8.08 (m, 1H), 7.98 - 8.01 (m, 2H), 7.74 - 7.79 (m, 2H), 7.68 - 7.71 (m, 1H), 7.13 - 7.16 (m, 1H), 6.98 - 7.03 (m, 1H), 4.90 - 4.95 (m, 1H), 4.42 - 4.47 (m, 1H), 1.86 (t, J = 2.0 Hz, 3H). 13 C NMR (151 MHz, chloroform-d) δ 167.6, 165.3, 164.0, 162.4, 155.9, 153.1, 140.6 (d, J = 8.4 Hz), 139.9, 137.6, 136.1, 135.1, 134.0 (d, J = 9.2 Hz), 133.76 (d, J = 3.4 Hz), 132.9, 125.3, 124.5, 124.1, 122.6, 121.9, 121.4, 118.1, 117.9, 116.1, 115.9, 80.3, 74.6, 41.2, 3.8. C 25 H 17 FN3O2S2[M+H] + LC-MS for it: (ESI) calculated value 474.08, measured value 474.10.

[0355] N-(10-(Buta-2-yn-1-yl)-3-fluoro-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepin-7-yl)-3-(1-cyanoethyl)benzamide. 1H NMR (400 MHz, chloroform-d): δ 8.08 (s, 1H), 7.95 (d, J =2.4 Hz, 1H), 7.86 (s, 1H), 7.81 (s, 1H), 7.00-7.79 (m, 3H), 7.68 (d, J =2.4 Hz, 1H), 7.50-7.58 (m, 1H), 7.12-7.15 (m, 1H), 6.97-7.02 (m, 1H), 4..89-4.94 (m, 1H), 4.41-4.46 (m, 1H), 3.96-4.02 (m, 1H), 1.86 (t, J =2.0 Hz, 3H), 1.68 (t, J (=7.2 Hz, 3H). 13 ¹³C NMR (151 MHz, chloroform-d) δ 167.6, 165.1, 164.0, 162.3, 140.6 (d, J = 8.4 Hz), 139.9, 138.0, 136.0, 135.4, 134.9, 134.0 (d, J = 9.2 Hz), 133.7 (d, J = 3.3 Hz), 130.4, 129.8, 126.7, 125.8, 125.2, 124.3, 121.6, 121.1, 118.1, 117.9, 116.1, 115.9, 80.4, 74.6, 41.2, 31.2, 21.3, 3.8. C 27 H 21 FN3O2S[M+H] + The LC-MS (ESI) calculation for this is 470.14, and the measured value is 470.10.

[0356] 10-(buta-2-in-1-yl)-3-fluoro-7-((3-methylpyrazine-2-yl)amino)dibenzo[b,f][1,4]thiazepine-11(10H)-one. 1H NMR (400 MHz, chloroform-d): δ 8.03 (d, J =2.4, Hz, 1H), 7.96 (d, J =2.4, Hz, 1H), 7.86 (d, J =2.4, Hz, 1H), 7.77-7.80 (m, 1H), 7.71 (d, J =8.8, Hz, 1H), 7.61-7.64 (m, 1H), 7.14-7.17 (m, 1H), 6.99-7.04 (m, 1H), 6.64 (s, 1H), 4.90-4.95 (m, 1H), 4.37-4.43 (m, 1H), 2.54 (s, 3H), 1.86 (t, J =2.4 Hz, 3H). 13 ¹C NMR (151 MHz, chloroform-d) δ 167.6, 164.0, 162.3, 149.7, 141.0, 140.7, 139.3, 138.2, 137.9, 134.9, 134.0 (d, J = 9.4 Hz), 125.2, 123.2, 120.9, 118.0, 117.9, 116.0, 115.9, 80.1, 74.8, 41.2, 20.4, 3.9. 22 H 18 FN4OS[M+H] + The LC-MS (ESI) calculation value for this is 405.12, and the measured value is 405.20.

[0357] 10-(buta-2-in-1-yl)-3-fluoro-7-((3-methoxypyrazine-2-yl)amino)dibenzo[b,f][1,4]thiazepine-11(10H)-one. 1 ¹H NMR (400 MHz, chloroform-d): δ 8.02 (s, 1H), 7.77-7.80 (m, 1H), 7.67-7.74 (m, 3H), 7.53 (d, J = 2.8, Hz, 1H), 7.15-7.18 (m, 1H), 7.11 (s, 1H), 6.99-7.04 (m, 1H), 4.89-4.94 (m, 1H), 4.39-4.44 (m, 1H), 4.05 (s, 3H), 1.85 (d, J = 2.4 Hz, 3H). 13¹C NMR (151 MHz, chloroform-d) δ 167.6, 164.0, 162.3, 148.4, 141.6, 140.8 (d, J = 8.3 Hz), 137.8, 137.7, 134.9, 134.0 (d, J = 9.2 Hz), 133.1, 129.9, 129.0, 128.4, 125.2, 122.3, 119.9, 118.0, 117.9, 116.0, 115.8, 80.0, 74.8, 53.9, 41.2, 3.8. 22 H 18 FN4O2S[M+H] + The LC-MS (ESI) calculation value for this is 421.12, and the measured value is 421.10.

[0358] N-(10-(buta-2-in-1-yl)-3-fluoro-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-7-yl)benzo[d]oxazole-5-carboxamide. 1 ¹H NMR (400 MHz, chloroform-d): δ 8.29 (s, 1H), 8.21 (s, 1H), 7.95-7.99 (m, 3H), 7.65-7.80 (m, 4H), 7.15-7.17 (m, 1H), 6.99-7.04 (m, 1H), 4.90-4.95 (m, 1H), 4.43-4.48 (m, 1H), 1.86 (t, J = 4.4 Hz, 3H). 13 C NMR (151 MHz, chloroform-d) δ 167.6, 165.3, 164.0, 162.4, 154.0, 152.2, 140.6 (d, J = 8.6 Hz), 140.3, 139.9, 136.1, 135.0, 134.0 (d, J = 9.1 Hz), 133.8 (d, J = 3.4 Hz), 131.6, 125.5, 125.3, 124.2, 121.5, 119.6, 118.1, 117.9, 116.1, 115.9, 111.6, 80.4, 74.6, 41.2, 3.8. C 25 H 17 FN3O3S[M+H] +The LC-MS (ESI) calculation value for this is 458.10, and the measured value is 458.10.

[0359] N-(10-(3-cyclopropylpropane-2-in-1-yl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-7-yl)benzo[d]thiazole-5-carboxamide. 1 H NMR (600 MHz, chloroform-d) δ 9.13 (s, 1H), 8.62 (d, J = 1.7 Hz, 1H), 8.21 (d, J = 2.6 Hz, 1H), 8.07 (d, J = 8.4 Hz, 1H), 8.03 - 7.98 (m, 2H), 7.78 - 7.72 (m, 1H), 7.72 - 7.66 (m, 2H), 7.46 - 7.40 (m, 1H), 7.30 (td, J = 7.1, 1.8 Hz, 2H), 4.89 (dd, J = 17.2, 1.9 Hz, 1H), 4.54 (dd, J = 17.2, 2.0 Hz, 1H), 1.25 (td, J = 5.1, 2.5 Hz, 1H), 0.78 - 0.72 (m, 2H), 0.71 - 0.61 (m, 2H). 13 ¹¹C NMR (151 MHz, chloroform-d) δ 168.4, 165.2, 156.3, 156.0, 153.0, 151.9, 139.8, 138.6, 137.6, 136.2, 135.9, 133.0, 131.8, 131.1, 131.1, 128.7, 125.4, 124.6, 124.0, 122.6, 121.9, 121.0, 87.9, 70.7, 41.0, 8.2, 8.1. 27 H 20 N3O2S2[M+H] + The LC-MS (ESI) calculation value for this is 482.10, and the measured value is 482.10.

[0360] N-(10-(buta-2-in-1-yl)-3-fluoro-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-7-yl)-6-ethynylnicotinamide.1 H NMR (400 MHz, DMSO-d6): δ 10.67 (s, 1H), 9.07(s, 1H), 8.29-8.32 (m, 1H), 8.18 (s, 1H), 7.69-7.81 (m, 4H), 7.46-7.48 (m, 1H), 7.27-7.31 (m, 1H), 4.83-4.88 (m, 1H), 4.66-4.71 (m, 1H), 4.58 (s, 1H), 1.77 (s, 3H). 13 C NMR (151 MHz, DMSO-d6) δ 165.7, 162.9, 162.6, 161.0, 148.6, 143.5, 139.6 (d, J = 8.6 Hz), 137.5, 136.4, 135.5, 133.6, 133.3 (d, J = 9.8 Hz), 128.9, 126.5, 125.1, 123.2, 121.1, 117.3, 117.2, 115.8, 115.7, 82.1, 79.3, 74.3, 2.6. C 25 H 17 FN3O2S[M+H] + The LC-MS (ESI) calculation value for this is 442.10, and the measured value is 442.10.

[0361] 1-(benzo[d]thiazole-5-yl)-3-(10-(buta-2-in-1-yl)-3-fluoro-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-7-yl)urea. 1 H NMR (400 MHz, DMSO-d6): δ 9.35 (s, 1H), 9.26 (s, 2H), 8.33 (s, 1H), 8.04 (d, J=8.8 Hz, 1H), 7.95-7.96 (m, 1H), 7.70-7.72 (m, 1H), 7.41-7.50 (m, 3H), 7.26-7.30 (m, 1H), 4.78-4.83 (m, 1H), 4.64-4.69 (m, 1H), 1.77 (t, J=2.4 Hz, 3H). 13C NMR (151 MHz, DMSO-d6) δ 165.8, 162.6, 160.9, 156.2, 153.2, 152.0, 139.7 (d, J = 8.4 Hz), 137.6 (d, J = 7.2 Hz), 135.6, 133.7, 133.4 (d, J = 3.1 Hz), 133.2 (d, J = 9.4 Hz), 126.1, 125.1, 121.7, 120.9, 119.2, 117.2 (d, J = 23.0 Hz), 117.1, 115.7, 115.6, 111.2, 79.1, 74.4, 2.6. C 25 H 18 FN4O2S2[M+H] + The LC-MS (ESI) calculation value for this is 489.09, and the measured value is 489.00.

[0362] 10-(buta-2-in-1-yl)-3-fluoro-7-((3-methylpyridine-2-yl)amino)dibenzo[b,f][1,4]thiazepine-11(10H)-one. 1 ¹H NMR (400 MHz, chloroform-d): δ 7.98 (d, J = 4.0 Hz, 1H), 7.69-7.81 (m, 3H), 7.33 (s, 1H), 7.18-7.21 (m, 1H), 7.12-7.15 (m, 1H), 7.02-7.06 (m, 2H), 4.88-4.93 (m, 1H), 4.41-4.46 (m, 1H), 2.01 (s, 3H), 1.84 (t, J = 4.4 Hz, 3H). 13 C NMR (151 MHz, chloroform-d) δ 167.4, 164.2, 162.5, 151.1, 146.4, 140.7, 140.1 (d, J = 8.4 Hz), 136.5, 136.3, 135.2, 134.2 (d, J = 9.3 Hz), 133.6 (d, J = 3.5 Hz), 125.9, 125.7, 125.6, 123.5, 118.1, 117.9, 116.4, 116.3, 116.2, 80.5, 74.5, 41.2, 19.5, 3.8. C 23 H19 FN3OS[M+H] + The LC-MS (ESI) calculation for this was 404.13, and the measured value was 404.20.

[0363] 2-((10-(buta-2-in-1-yl)-3-fluoro-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-7-yl)amino)nicotinonitrile. 1 ¹H NMR (400 MHz, chloroform-d): δ 7.94 (d, J = 4.0 Hz, 1H), 7.81-7.83 (m, 1H), 7.77-7.80 (m, 2H), 7.72-7.74 (m, 1H), 7.57-7.60 (m, 1H), 7.15-7.18 (m, 1H), 6.99-7.05 (m, 2H), 6.85-6.88 (m, 1H), 4.90-4.95 (m, 1H), 4.39-4.44 (m, 1H), 1.86 (t, J = 4.4 Hz, 3H). 13 C NMR (151 MHz, chloroform-d) δ 167.5, 164.0, 162.3, 155.4, 152.3, 141.8, 140.6 (d, J = 8.2 Hz), 139.1, 136.7, 134.8, 134.1 (d, J = 9.1 Hz), 133.9 (d, J = 3.5 Hz), 125.1, 124.1, 121.7, 118.1, 117.9, 116.0 (d, J = 7.1 Hz), 115.9, 114.9, 93.7, 80.2, 74.7, 41.2, 3.9. C 23 H 16 FN4OS[M+H] + The LC-MS (ESI) calculation value for this is 415.11, and the measured value is 415.10.

[0364] 10-(buta-2-in-1-yl)-3-fluoro-7-((3-fluoropyridine-2-yl)amino)dibenzo[b,f][1,4]thiazepine-11(10H)-one. 1¹H NMR (400 MHz, chloroform-d): δ 8.04 (d, J = 3.2, Hz, 1H), 7.97 (d, J = 3.2, Hz, 1H), 7.77-7.81 (m, 1H), 7.64-7.71 (m, 2H), 7.26-7.33 (m, 1H), 6.99-7.04 (m, 1H), 6.76-6.80 (m, 1H), 6.64 (s, 1H), 4.89-4.93 (m, 1H), 4.40-4.44 (m, 1H), 1.86 (t, J = 2.4 Hz, 3H). 13 C NMR (151 MHz, chloroform-d) δ 167.7, 164.0, 162.3, 147.8, 146.1, 144.6 (d, J = 8.5 Hz), 142.6 (d, J = 6.2 Hz), 140.9 (d, J = 8.3 Hz), 138.0, 137.6, 134.9, 134.0 (d, J = 9.3 Hz), 125.2, 122.3, 121.4, 121.3, 120.0, 118.0, 117.9, 115.9, 115.8, 115.4 (d, J = 2.1 Hz), 80.0, 74.8, 41.2, 3.9. C 22 H 16 F2N3OS[M+H] + The LC-MS (ESI) calculation value for this is 408.10, and the measured value is 408.10.

[0365] 10-(buta-2-in-1-yl)-3-fluoro-7-((3-methoxypyridine-2-yl)amino)dibenzo[b,f][1,4]thiazepine-11(10H)-one. 1 ¹H NMR (400 MHz, chloroform-d): δ 7.99 (d, J = 2.8 Hz, 1H), 7.83-7.85 (m, 1H), 7.71-7.80 (m, 2H), 7.65 (d, J = 8.8 Hz, 1H), 7.15-7.17 (m, 3H), 6.74-6.77 (m, 1H), 4.87-4.92 (m, 1H), 4.39-4.44 (m, 1H), 3.90 (s, 3H), 1.85 (t, J = 4.8 Hz, 3H).13 C NMR (151 MHz, chloroform-d) δ 167.8, 163.9, 162.2, 145.7, 142.3, 141.1 (d, J = 8.2 Hz), 138.9, 138.3, 136.8, 134.7, 134.1 (d, J = 3.5 Hz), 133.9 (d, J = 9.1 Hz), 125.1, 121.9, 119.6, 118.0, 117.9, 115.8, 115.7, 115.0, 114.9, 79.9, 74.9, 55.5, 41.2, 3.9. C 23 H 19 FN3O2S[M+H] + The LC-MS (ESI) calculation for this was 420.12, and the measured value was 420.20.

[0366] 10-(buta-2-in-1-yl)-7-((3-cyclopropylpyridine-2-yl)amino)-3-fluorodibenzo[b,f][1,4]thiazepine-11(10H)-one. 1 H NMR (400 MHz, methanol-d4): δ 7.92 (d, J =8.4, Hz, 1H), 7.85 (d, J =7.2, Hz, 1H), 7.80 (d, J =2.4, Hz, 1H), 7.30-7.36 (m, 1H), 7.67 (d, J =5.6, Hz, 1H), 7.53-7.56 (m, 1H), 7.31-7.33 (m, 1H), 7.17-7.22 (m, 1H), 7.02 (d, J =6.4, Hz, 1H), 4.72(d, J =2.4, Hz, 1H), 4.68 (d, J =2.4, Hz, 1H), 1.87-1.90 (m, 1H), 1.81 (t, J =2.4, Hz, 3H), 1.13-1.17 (m, 2H), 0.78-0.83 (m, 2H). 13 ¹³C NMR (151 MHz, methanol-d4) δ 167.5, 163.9, 139.8, 134.7, 133.5, 133.1, 126.0, 117.5, 117.3, 115.7, 115.6, 114.2, 39.9, 9.7, 5.2.25 H 21 FN3OS[M+H] + The LC-MS (ESI) calculation for this was 430.14, and the measured value was 430.30.

[0367] 3-Cyano-N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-7-yl)benzamide. 1 ¹H NMR (400 MHz, chloroform-d): δ 8.15 (s, 1H), 8.07-8.11 (m, 2H), 7.93 (s 1H), 7.84 (d, J = 8.0 Hz, 1H), 7.59-7.66 (m, 3H), 7.53 (d, J = 8.8 Hz, 1H), 7.40-7.42 (m, 1H), 7.26-7.30 (m, 2H), 4.49-4.56 (m, 1H), 3.92-3.98 (m, 1H), 3.80-3.85 (m, 1H), 3.62-3.68 (m, 1H), 3.35 (s, 3H). 13 ¹³C NMR (151 MHz, chloroform-d) δ 169.2, 163.6, 140.4, 138.7, 138.2, 137.1, 135.7, 135.4, 135.1, 131.7, 131.0, 130.9, 130.8, 129.8, 128.7, 126.8, 124.4, 121.5, 118.0, 113.0, 70.1, 58.9, 51.7. 24 H 20 N3O3S[M+H] + The LC-MS (ESI) calculation for this is 430.12, and the measured value is 430.10.

[0368] 3-Fluoro-N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-7-yl)benzamide. 1¹H NMR (400 MHz, chloroform-d): δ 7.98 (s, 1H), 7.92 (d, J = 2.4 Hz, 1H), 7.66 (d, J = 2.0 Hz, 1H), 7.51-7.65 (m, 3H), 7.40-7.49 (m, 3H), 7.23-7.31 (m, 3H), 4.50-4.57 (m, 1H), 3.91-3.97 (m, 1H), 3.79-3.84 (m, 1H), 3.62-0.367 (m, 1H), 3.34 (s, 3H). 13 C NMR (151 MHz, chloroform-d) δ 169.1, 164.4, 163.6, 162.0, 140.3, 138.8, 138.2, 137.1, 136.6, 135.5, 131.1 (d, J = 12.4 Hz), 130.8, 130.6 (d, J = 7.9 Hz), 128.7, 126.8, 124.2, 122.5 (d, J = 3.0 Hz), 121.3, 119.3, 119.1, 114.7, 114.5, 70.2, 58.9, 51.6. C 23 H 20 FN2O3S[M+H] + The LC-MS (ESI) calculation value for this is 423.12, and the measured value is 423.10.

[0369] N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-7-yl)-3-(trifluoromethoxy)benzamide. 1 H NMR (400 MHz, chloroform-d): δ 8.19 (s, 1H), 7.92 (d, J =2.4 Hz, 1H), 7.72-7.76 (m, 2H), 7.50-7.60 (m, 2H), 7.48-7.52 (m, 2H), 7.38-7.41 (m, 2H), 7.24-7.28 (m, 2H), 4.49-4.56 (m, 1H), 3.90-3.96 (m, 1H), 3.78-3.83 (m, 1H), 3.61-366 (m, 1H), 3.34 (s, 3H). 13¹³C NMR (151 MHz, chloroform-d) δ 169.2, 164.2, 149.5, 140.3, 138.8, 138.2, 137.1, 136.5, 135.5, 131.1, 131.0, 130.8, 130.4, 128.7, 126.8, 125.1, 124.4, 124.3, 121.4, 120.1, 70.2, 58.9, 51.7. 24 H 20 F3N2O4S[M+H] + The LC-MS (ESI) calculation value for this is 489.11, and the measured value is 489.10.

[0370] 3-(difluoromethoxy)-N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-7-yl)benzamide. 1 ¹H NMR (400 MHz, chloroform-d): δ 7.91 (d, J = 2.4 Hz, 1H), 7.86 (s, 1H), 7.59-7.68 (m, 4H), 7.47-7.52 (m, 2H), 7.40-7.43 (m, 1H), 7.26-7.33 (m, 3H), 6.39-6.76 (m, 1H), 4.50-4.57 (m, 1H), 3.91-3.96 (m, 1H), 3.79-3.85 (m, 1H), 3.63-3.67 (m, 1H), 3.35 (s, 3H). 13 ¹³C NMR (151 MHz, chloroform-d) δ 169.1, 164.6, 151.3 (t, J = 2.8 Hz), 140.3, 138.8, 138.2, 137.1, 136.4, 135.5, 131.1, 131.0, 130.8, 130.3, 128.7, 126.8, 124.2, 123.7, 123.3, 121.4, 118.6, 117.3, 115.5, 113.8, 70.2, 58.9, 51.6. 24 H 21 F2N2O4S[M+H] + The LC-MS (ESI) calculation value for this is 471.12, and the measured value is 471.10.

[0371] N-(10-(buta-2-in-1-yl)-3-fluoro-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-7-yl)-3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazole-5-carboxamide. 1 H NMR (400 MHz, chloroform-d): δ 7.93 (d, J=2.8 Hz, 1H), 7.80-7.88 (m, 1H), 7.68-7.74 (m, 2H), 7.66-7.67 (m, 1H), 7.56-7.58 (m, 2H), 7.26-7.29 (m, 1H), 7.14-7.16 (m, 1H), 7.00-7.05 (m, 1H), 4.90-4.95 (m, 1H), 4.42-4.47 (m, 1H), 3.47 (s, 3H), 1.86 (t, J=4.4 Hz, 3H). 13 ¹³C NMR (151 MHz, chloroform-d) δ 167.6, 164.8, 164.0, 162.3, 154.4, 145.2, 140.6 (d, J = 8.2 Hz), 139.9, 136.1, 134.9, 134.0 (d, J = 9.1 Hz), 133.7 (d, J = 3.3 Hz), 132.5, 130.7, 125.3, 124.2, 121.5, 121.3, 118.0, 117.9, 116.1, 116.0, 109.7, 108.1, 80.4, 74.6, 41.3, 28.4, 3.8. C 26 H 19 FN3O4S[M+H] + The LC-MS (ESI) calculation value for this is 488.11, and the measured value is 488.10.

[0372] 1-(benzo[d]oxazol-5-yl)-3-(10-(buta-2-in-1-yl)-3-fluoro-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-7-yl)urea. 1H NMR (400 MHz, methanol-d4): δ 8.29 (s, 1H), 8.03 (d, J =2.4, Hz, 1H), 7.80 (d, J =2.0, Hz, 1H), 7.67-7.71 (m, 1H), 7.61-7.63 (m, 1H), 7.39-7.42 (m, 1H), 7.32 (d, J =2.0, Hz, 1H), 7.11-7.16 (m, 2H), 6.81 (t, J =8.8, Hz, 1H), 4.71-4.76 (m, 1H), 4.63-4.67 (m, 1H), 1.79 (s, 3H). 13 C NMR (151 MHz, methanol-d4) δ 167.9, 163.8, 162.1, 160.2, 153.7, 143.0, 138.1, 134.8, 133.6, 132.9 (d, J = 9.3 Hz), 130.0, 125.3, 124.9, 121.8, 119.6, 117.3, 116.9, 115.4 (d, J = 21.9 Hz), 114.4, 113.7, 79.3, 73.5, 39.8, 1.4. C 25 H 18 FN4O3S[M+H] + The LC-MS (ESI) calculation value for this is 473.11, and the measured value is 473.10.

[0373] (E)-3-((10-(hexa-2-en-1-yl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-7-yl)amino)pyrazine-2-carbonitrile. 1H NMR (400 MHz, chloroform-d): δ 8.33 (d, J =2.4 Hz, 1H), 8.12 (d, J =2.4 Hz, 1H), 7.88 (d, J =2.4 Hz, 1H), 7.70-7.73 (m, 1H), 7.50-7.53 (m, 1H), 7.40-7.44 (m, 2H), 7.26-7.34 (m, 2H), 7.15 (s, 1H), 5.61-5.70 (m, 2H), 4.76-4.81 (m, 1H), 4.47-4.51 (m, 1H), 2.00-2.03 (m, 2H), 1.31-1.39(m, 2H), 1.85 (d, J = 7.2 Hz, 3H). 13C NMR (151 MHz, chloroform-d) δ 168.6, 153.0, 145.4, 139.9, 138.5, 138.3, 137.0, 136.0, 135.1, 134.5, 131.5, 131.0, 130.8, 128.7, 126.0, 125.1, 124.5, 121.5, 115.9, 114.6, 53.3, 34.3, 22.2, 13.6. C 24 H 22 N5OS[M+H] + The LC-MS (ESI) calculation for this is 428.16, and the measured value is 428.10.

[0374] 10-(buta-2-in-1-yl)-7-((3-(trifluoromethyl)pyridine-2-yl)amino)dibenzo[b,f][1,4]thiazepine-11(10H)-one. 1 ¹H NMR (400 MHz, chloroform-d): δ 8.37 (d, J = 4.8 Hz, 1H), 7.76-7.82 (m, 3H), 7.70 (d, J = 4.8 Hz, 1H), 7.56-7.59 (m, 1H), 7.42-7.44 (m, 1H), 7.26-7.34 (m, 2H), 6.86-6.89 (m, 1H), 6.72 (s, 1H), 4.93-7.98 (m, 1H), 4.39-4.44 (m, 1H), 1.87 (d, J = 2.0 Hz, 3H). 13¹³C NMR (151 MHz, chloroform-d) δ 168.5, 151.5, 151.3, 138.8, 138.6, 137.8, 137.2, 135.7 (q, J = 5.2 Hz), 135.6, 131.9, 131.1, 131.0, 128.6, 125.0, 124.3, 121.8, 114.6, 79.9, 74.9, 41.2, 3.9. 23 H 17 F3N3OS[M+H] + The LC-MS (ESI) calculation value for this is 440.11, and the measured value is 440.10.

[0375] Methyl 2-((10-(buta-2-in-1-yl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-7-yl)aminonicotinate. 1 ¹H NMR (400 MHz, chloroform-d): δ 10.23 (s, 1H), 8.38-8.40 (m, 1H), 8.23-8.25 (m, 1H), 7.98-7.99 (m, 1H), 7.66-7.78 (m, 4H), 7.43 (d, J=8.8 Hz, 1H), 7.26-7.33 (m, 2H), 6.75-6.78 (m, 1H), 4.92-4.97 (m, 1H), 4.43-4.44 (m, 1H), 3.93 (s, 3H), 1.86 (t, J =4.4 Hz, 3H). 13 ¹C NMR (151 MHz, chloroform-d) δ 168.6, 167.9, 155.6, 153.1, 140.3, 138.8, 138.1, 137.9 (d, J = 2.0 Hz), 135.4, 131.8, 131.1, 130.9, 128.5, 124.9, 124.1, 121.5, 114.0, 107.4, 79.8, 75.0, 52.4, 41.2, 3.9. 24 H 20 N3O3S[M+H] + The LC-MS (ESI) calculation for this is 430.12, and the measured value is 430.10.

[0376] 4-Azido-N-(11-oxo-10-(propa-2-in-1-yl)-10,11-dihydrodibenzo[b,f][1,4]thiazepine-7-yl)benzamide. 1 H NMR (400 MHz, chloroform-d) δ 8.02 (s, 1H), 7.95 (d, J = 2.2 Hz, 1H), 7.85 (d, J = 8.6 Hz, 2H), 7.82 - 7.71 (m, 1H), 7.71 - 7.60 (m, 2H), 7.41 (dt, J = 7.8, 3.0 Hz, 1H), 7.35 - 7.25 (m, 2H), 7.09 (d, J = 8.6 Hz, 2H), 4.94 (dd, J = 17.3, 2.5 Hz, 1H), 4.55 (dd, J = 17.3, 2.5 Hz, 1H), 2.36 (t, J = 2.4 Hz, 1H). 13 ¹¹C NMR (10¹ MHz, chloroform-d) δ 168.5, 164.7, 144.1, 139.5, 138.6, 137.3, 136.2, 136.1, 131.9, 131.3, 131.2, 130.7, 128.9, 128.7, 125.1, 124.2, 121.3, 119.3, 79.4, 72.5, 40.6. 23 H 16 N5O2S[M+H] + The LC-MS (ESI) calculation value for this is 426.10, and the measured value is 426.10.

[0377] N-(10-(buta-2-in-1-yl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-7-yl)-2-(7-(dimethylamino)-2-oxo-2H-chromen-4-yl)acetamide. 1H NMR (400 MHz, chloroform-d) δ 7.78 - 7.70 (m, 1H), 7.63 (d, J = 8.8 Hz, 1H), 7.55 - 7.48 (m, 1H), 7.47 - 7.42 (m, 2H), 7.39 (dd, J = 7.5, 1.6 Hz, 1H), 7.29 (dd, J = 6.9, 1.9 Hz, 3H), 6.62 (dd, J = 9.0, 2.6 Hz, 1H), 6.51 (d, J = 2.5 Hz, 1H), 6.12 (s, 1H), 4.90 (dd, J = 16.8, 2.7 Hz, 1H), 4.39 (dd, J = 16.9, 2.6 Hz, 1H), 3.78 (s, 2H), 3.05 (s, 6H), 1.83 (t, J = 2.3 Hz, 3H). C 30 H 26 N3O4S[M+H] + The LC-MS (ESI) calculation for this was 524.16, and the measured value was 524.30.

[0378] N-(11-oxo-10-(propa-2-in-1-yl)-10,11-dihydrodibenzo[b,f][1,4]thiazepine-7-yl)benzo[d]thiazole-5-carboxamide. 1 H NMR (600 MHz, chloroform-d) δ 9.11 (s, 1H), 8.59 (d, J = 2.4 Hz, 1H), 8.31 (s, 1H), 8.08 - 8.01 (m, 2H), 7.99 (dd, J = 8.4, 1.7 Hz, 1H), 7.80 - 7.74 (m, 1H), 7.69 (d, J = 1.4 Hz, 2H), 7.46 - 7.40 (m, 1H), 7.35 - 7.27 (m, 2H), 4.96 (dd, J = 17.3, 2.5 Hz, 1H), 4.56 (dd, J = 17.3, 2.5 Hz, 1H), 2.37 (t, J (= 2.5 Hz, 1H). 13¹¹C NMR (151 MHz, chloroform-d) δ 168.5, 165.3, 155.9, 153.0, 139.6, 138.6, 137.3, 136.2, 136.1, 132.9, 131.9, 131.3, 131.2, 128.7, 125.1, 124.5, 124.2, 122.6, 122.0, 121.3, 79.4, 72.5, 40.6. 24 H 16 N3O2S2[M+H] + The LC-MS (ESI) calculation for this was 442.07, and the measured value was 442.20.

[0379] N-(5-(buta-2-in-1-yl)-6-oxo-6,11-dihydro-5H-dibenzo[b,e]azepine-2-yl)-4-methoxybenzamide. 1 H NMR (600 MHz, chloroform-d) δ 7.86 - 7.80 (m, 4H), 7.75 (d, J = 2.5 Hz, 1H), 7.58 (d, J = 8.7 Hz, 1H), 7.42 - 7.32 (m, 2H), 7.25 (d, J = 6.2 Hz, 1H), 7.16 (d, J = 7.4 Hz, 1H), 6.99 - 6.93 (m, 2H), 4.89 (dd, J = 16.9, 2.4 Hz, 1H), 4.58 (dd, J = 17.0, 2.4 Hz, 1H), 4.18 (d, J = 13.3 Hz, 1H), 3.87 (s, 3H), 3.54 (d, J = 13.3 Hz, 1H), 1.84 (t, J = 2.3 Hz, 3H). 13 ¹¹C NMR (151 MHz, chloroform-d) δ 168.2, 165.2, 162.6, 142.1, 138.2, 136.3, 136.0, 132.3, 131.7, 131.1, 128.9, 127.0, 126.8, 126.1, 123.1, 118.8, 118.6, 114.0, 79.8, 75.1, 55.5, 40.1, 38.6, 3.8. 26 H 23 N2O3[M+H] +The LC-MS (ESI) calculation value for this is 411.17, and the measured value is 411.20.

[0380] (E)-10-(hexa-2-en-1-yl)-7-(isoquinoline-3-ylamino)dibenzo[b,f][1,4]thiazepine-11(10H)-one. 1 H NMR (400 MHz, chloroform-d): δ 8.95 (s, 1H), 7.82-7.84(d, J=8.0 Hz, 1H), 7.72-7.73 (d, J=4.0 Hz, 1H), 7.56-7.71 (m, 3H), 7.41-7.43 (m, 1H), 7.26-7.37 (m, 5H), 7.13(s, 1H), 6.64 (s, 1H), 5.66-5.69 (m, 2H), 4.80-4.84 (m, 1H), 4.48-4.49 (m, 1H), 2.00-2.02 (m, 2H), 1.34-1.40 (m, 2H), 0.83-0.87 (t, J=8.0 Hz, 3H). 13 ¹¹C NMR (151 MHz, chloroform-d) δ 168.8, 152.0, 150.8, 139.1, 138.9, 138.5, 138.4, 137.4, 137.3, 134.3, 131.4, 131.0, 130.8, 130.6, 128.6, 127.8, 126.4, 125.3, 125.2, 124.8, 124.2, 122.4, 119.6, 100.4, 53.2, 34.3, 22.3, 13.6. 28 H 26 N3OS[M+H] + The LC-MS (ESI) calculation for this was 452.18, and the measured value was 452.30.

[0381] 2-(benzo[d]oxazol-5-yl)-N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-7-yl)acetamide. 1¹H NMR (400 MHz, chloroform-d): δ 8.26 (s, 1H), 8.15 (s, 1H), 7.95-7.96 (d, J = 4.0 Hz, 1H), 7.82-7.89 (m, 1H), 7.61-7.68 (m, 1H), 7.51-7.53 (d, J = 8.0 Hz, 1H), 7.40-7.42 (d, J = 8.0 Hz, 1H), 7.25-7.32 (m, 2H), 4.51-4.58 (m, 1H), 3.92-3.98 (m, 1H), 3.80-3.85 (m, 1H), 3.63-3.68 (m, 1H), 3.35 (s, 3H). 13 ¹¹C NMR (151 MHz, chloroform-d) δ 169.1, 169.0, 153.3, 149.5, 140.7, 139.9, 138.8, 138.2, 137.0, 135.5, 131.1, 131.0, 130.9, 130.7, 128.6, 127.0, 126.6, 123.6, 121.4, 120.9, 111.6, 70.1, 58.8, 51.5, 44.4. 25 H 22 N3O4S[M+H] + The LC-MS (ESI) calculation for this is 460.14, and the measured value is 446.10.

[0382] N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-7-yl)-2-oxo-2,3-dihydrobenzo[d]oxazole-5-carboxamide. 1H NMR (600 MHz, DMSO-d6) δ 10.40 (s, 1H), 8.16 (d, J = 2.4 Hz, 1H), 7.80 - 7.71 (m, 2H), 7.64 (dd, J = 5.3, 3.5 Hz, 2H), 7.63 - 7.57 (m, 1H), 7.56 - 7.49 (m, 1H), 7.44 (d, J = 8.4 Hz, 1H), 7.40 (td, J = 6.8, 6.1, 3.4 Hz, 2H), 4.58 - 4.50 (m, 1H), 3.85 (dt, J = 14.0, 5.6 Hz, 1H), 3.58 (dt, J = 10.1, 6.0 Hz, 1H), 3.52 (dd, J = 10.1, 5.7 Hz, 1H), 3.21 (s, 3H). 13 C NMR (151 MHz, DMSO-d6) δ 167.1, 164.3, 153.8, 145.2, 137.7, 137.5, 136.4, 135.0, 130.4, 130.3, 130.3, 130.0, 129.5, 128.3, 126.0, 123.0, 121.6, 120.9, 108.6, 108.5, 68.7, 57.5, 49.3. C 24 H 20 N3O5S[M+H] + The LC-MS (ESI) calculation value for this is 462.11, and the measured value is 462.10.

[0383] N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-7-yl)-3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazole-5-carboxamide. 1H NMR (400 MHz, methanol-d4) δ 8.07 (s, 1H), 7.69-7.78 (m, 3H), 7.59-7.62 (m, 2H), 7.48-7.50 (m, 1H), 7.33-7.37 (m, 3H), 4.55-4.61 (m, 1H), 3.92-3.98 (m, 1H), 3.65-3.75 (m, 1H), 3.51-3.64 (m, 1H), 3.44 (s, 3H), 3.30 (s, 3H). 13 ¹³C NMR (151 MHz, methanol-d4) δ 169.9, 166.3, 154.9, 145.2, 139.3, 139.0, 138.1, 137.0, 136.8, 132.2, 130.8, 130.8, 130.7, 130.4, 128.5, 126.5, 124.2, 122.5, 121.7, 109.0, 107.9, 69.7, 57.6, 50.9, 27.2. 25 H 22 N3O5S[M+H] + The LC-MS (ESI) calculation value for this is 476.13, and the measured value is 476.10.

[0384] 2-(2-(7-(furan-3-carboxamide)-11-oxodibenzo[b,f][1,4]thiazepine-10(11H)-yl)ethoxy)acetic acid. 1 ¹H NMR (400 MHz, methanol-d4): δ 8.20 (s, 1H), 8.03 (s, 1H), 7.60-7.66 (m, 4H), 7.47-7.49 (d, J = 8.0 Hz, 2H), 7.35-7.37 (m, 2H), 6.91 (s, 1H), 4.52 (m, 1H), 3.96-4.08 (m, 4H), 3.82-3.85 (m, 1H). 13¹³C NMR (151 MHz, methanol-d4) δ 172.8, 170.0, 162.1, 145.8, 144.0, 139.2, 138.9, 138.1, 136.7, 136.6, 130.8, 130.7, 130.4, 128.5, 126.6, 124.0, 122.6, 121.6, 108.5, 68.4, 67.8, 51.1. 22 H 19 N2O6S[M+H] + The LC-MS (ESI) calculation value for this is 439.10, and the measured value is 439.10.

[0385] 6-(7-(furan-3-carboxamide)-11-oxodibenzo[b,f][1,4]thiazepine-10(11H)-yl)hexanoic acid. 1 H NMR (400 MHz, chloroform-d): δ 8.49 (s, 1H), 8.08 (s, 1H), 7.78 (d, J =2.4, Hz, 1H), 7.61 (t, J =6.8, Hz, 2H), 7.41 (s, 1H), 7.29 (d, J =1.6, Hz, 1H), 7.20-7.26 (m, 3H), 6.78 (d, J =1.2, Hz, 1H), 4.71-4.74 (m, 1H), 3.50-3.53 (m, 1H), 2.27 (t, J =6.8, Hz, 2H), 1.54-1.65 (m, 4H), 1.36-1.43 (m, 2H). 13 ¹³C NMR (151 MHz, chloroform-d) δ 178.3, 169.2, 161.3, 145.7, 144.0, 138.9, 138.0, 137.4, 131.2, 131.0, 130.7, 128.6, 126.2, 124.6, 122.6, 121.7, 108.5, 50.5, 33.8, 27.6, 26.2, 24.3. 24 H 23 N2O5S[M+H] + The LC-MS (ESI) calculation value for this is 451.13, and the measured value is 451.10.

[0386] (E)-10-(hexa-2-en-1-yl)-7-((4-methoxypyridine-2-yl)amino)dibenzo[b,f][1,4]thiazepine-11(10H)-one. 1 H NMR (400 MHz, chloroform-d): δ 8.00 (d, J=6.0 Hz, 1H), 7.71 (t, J=7.6 Hz, 1H), 7.57 (s, 1H), 7.41 (d, J=7.6 Hz, 1H), 7.29-7.35 (m, 3H), 7.19-7.25 (m, 1H), 6.39 (d, J=5.6 Hz, 1H), 6.29 (s, 1H), 5.60-5.71 (m, 2H), 4.76-4.81 (m, 1H), 4.43-4.48 (m, 1H), 3.81 (s, 3H), 1.96-2.06 (m, 2H), 1.33-1.38 (m, 2H), 0.84 (t, J=7.2 Hz, 3H). 13 ¹¹C NMR (151 MHz, chloroform-d) δ 170.0, 168.7, 167.7, 156.5, 148.2, 138.8, 138.4, 138.2, 138.1, 137.1, 134.3, 131.4, 131.0, 130.6, 128.6, 126.3, 125.2, 123.5, 120.7, 103.6, 93.4, 55.3, 53.2, 34.3, 22.3, 13.6. 25 H 26 N3O2S[M+H] + The LC-MS (ESI) calculation value for this is 432.18, and the measured value is 432.10.

[0387] (E)-10-(hexa-2-en-1-yl)-7-((4-(trifluoromethyl)pyridine-2-yl)amino)dibenzo[b,f][1,4]thiazepine-11(10H)-one. 1H NMR (400 MHz, chloroform-d): δ 8.14-8.16 (d, J=8.0 Hz, 1H), 7.71-7.73 (d, J=8.0 Hz, 1H), 7.59 (s, 1H), 7.41-7.46 (m, 2H), 7.11 (s, 1H), 6.99-7.00 (m, 1H), 5.30-5.68 (m, 2H), 4.79-4.84 (m, 1H), 4.46-4.82 (m, 1H), 2.00-2.04 (m, 2H), 1.33-1.39 (m, 2H), 0.82-0.85 (t, J=8.0 Hz, 3H). 13 ¹³C NMR (151 MHz, chloroform-d) δ 168.5, 154.7, 138.3, 138.1, 137.9, 134.7, 131.6, 131.1, 131.0, 128.9, 126.8, 126.3, 125.0, 123.1, 109.8, 106.7, 53.3, 34.3, 22.2, 13.5. 25 H 23 F3N3OS[M+H] + The LC-MS (ESI) calculation value for this is 470.15, and the measured value is 470.20.

[0388] (E)-10-(hexa-2-en-1-yl)-7-((4-isopropylpyridine-2-yl)amino)dibenzo[b,f][1,4]thiazepine-11(10H)-one. 1H NMR (400 MHz, chloroform-d): δ 12.03 (s, 1H), 7.77 (d, J =6.4, Hz, 1H), 7.35 (m, 1H), 7.55 (d, J =2.4 Hz, 1H), 7.41-7.46 (m, 2H), 7.31-7.35 (m, 2H), 7.22-7.26 (m, 1H), 6.90 (s, 1H), 6.76-6.77 (m, 1H), 5.64-5.68 (m, 2H), 4.79-4.82 (m, 1H), 4.46-4.51 (m, 1H), 2.85-2.90 (m, 1H), 2.01-2.03 (m, 2H), 1.36-1.43 (m, 2H), 1.21-1.25 (m, 6H), 0.85 (t, J =7.2, Hz, 3H). 13 ¹¹C NMR (151 MHz, chloroform-d) δ 168.4, 167.3, 152.8, 141.7, 138.3, 138.1, 137.8, 137.0, 134.6, 134.4, 131.6, 131.0, 131.0, 128.9, 127.3, 126.8, 125.0, 124.3, 113.0, 107.6, 53.3, 34.7, 34.3, 22.4, 22.3, 22.2, 13.6. 27 H 30 N3OS[M+H] + The LC-MS (ESI) calculation value for this is 444.21, and the measured value is 444.40.

[0389] (E)-7-((4-cyclopropylpyridine-2-yl)amino)-10-(hexa-2-en-1-yl)dibenzo[b,f][1,4]thiazepine-11(10H)-one. 1H NMR (400 MHz, methanol-d4): δ 7.71 (d, J =6.4, Hz, 1H), 7.63-7.67 (m, 3H), 7.49-7.51 (m, 1H), 7.37-7.40 (m, 3H), 6.88 (s, 1H), 6.70-6.72 (m, 1H), 5.71 (s, 1H), 5.62 (s, 1H), 4.91-4.97 (m, 2H), 4.44-4.48 (m, 1H), 1.99-2.04 (m, 3H), 1.30-1.39 (m, 2H), 1.26-1.29 (m, 2H), 0.97-1.00 (m, 2H), 0.84 (t, J = 7.2 Hz, 3H). 13 ¹³C NMR (151 MHz, methanol-d4) δ 169.2, 165.2, 151.0, 141.4, 138.3, 138.0, 137.9, 136.0, 134.6, 134.3, 131.1, 130.9, 130.7, 128.8, 127.6, 127.3, 124.7, 124.5, 111.8, 108.8, 52.6, 34.0, 21.9, 15.7, 12.5, 11.4. 27 H 28 N3OS[M+H] + The LC-MS (ESI) calculation for this was 442.20, and the measured value was 442.30.

[0390] (E)-7-((4-fluoropyridine-2-yl)amino)-10-(hexa-2-en-1-yl)dibenzo[b,f][1,4]thiazepine-11(10H)-one. 1H NMR (400 MHz, methanol-d4): δ 8.15 (dd, J =14.8, 6.0 Hz, 1H), 7.70-7.72 (m, 1H), 7.58 (d, J =2.4 Hz, 1H), 7.26-7.43 (m, 5H), 6.74 (s, 1H), 6.54 (dd, J =3.6, 2.4 Hz, 1H), 6.45-6.48 (m, 1H), 5.64-5.67 (m, 2H), 4.87 (d, J =14 Hz, 1H), 4.48 (d, J =4.8 Hz, 1H), 1.99-2.01 (m, 2H), 1.32-1.39 (m, 2H), 0.84 (t, J = 7.6 Hz, 3H). 13 C NMR (151 MHz, chloroform-d) δ 170.9, 169.2, 168.7, 157.5 (d, J = 10.4 Hz), 150.6, 138.7, 138.5, 138.4, 137.7, 137.2, 134.4, 131.5, 131.0, 130.7, 128.6, 126.3, 125.1, 123.8, 121.0, 104.3 (d, J = 18.0 Hz), 95.5 (d, J = 21.2 Hz), 53.3, 34.3, 22.3, 13.6. C 24 H 23 FN3OS[M+H] + The LC-MS (ESI) calculation for this was 420.16, and the measured value was 420.30.

[0391] 3-(1-cyanoethyl)-N-(11-oxo-10-(2-(propa-2-in-1-yloxy)ethyl)-10,11-dihydrodibenzo[b,f][1,4]thiazepine-7-yl)benzamide. 1H NMR (400 MHz, chloroform-d): δ 8.17 (s, 1H), 7.93 (d, J =2.4 Hz, 1H), 7.84 (s, 1H), 7.78 (d, J =2.4 Hz, 1H), 7.61-7.65 (m, 2H), 7.55(d, J =2.0 Hz, 1H), 7.47-7.51 (m, 2H), 7.38-7.41 (m, 1H), 7.23-7.30 (m, 2H), 4.53-4.59 (m, 1H), 4.15 (d, J =2.4 Hz, 2H), 3.94-4.00 (m, 3H), 3.79-3.83 (m, 1H), 2.42 (t, J =2.4 Hz, 1H), 1.66 (d, J =7.6 Hz, 3H). 13 ¹³C NMR (151 MHz, chloroform-d) δ 169.2, 165.1, 140.1, 138.8, 138.2, 138.0, 137.1, 135.7, 135.5, 131.1, 131.0, 130.8, 130.3, 129.7, 128.7, 126.8, 126.7, 125.8, 124.3, 121.4, 121.1, 79.4, 74.7, 67.6, 58.4, 51.5, 31.2, 21.3. 28 H 24 N3O3S[M+H] + The LC-MS (ESI) calculation for this is 482.16, and the measured value is 482.10.

[0392] N-(10-allyl-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-7-yl)benzo[d]thiazole-5-carboxamide. 1H NMR (400 MHz, chloroform-d) δ 9.10 (s, 1H), 8.60 (s, 1H), 8.45 (s, 1H), 8.09 - 7.94 (m, 3H), 7.72 - 7.63 (m, 2H), 7.42 - 7.33 (m, 2H), 7.29 (s, 1H), 6.08 - 5.94 (m, 1H), 5.30 (d, J = 17.2 Hz, 1H), 5.20 (d, J = 10.3 Hz, 1H), 4.83 (dd, J = 15.6, 5.4 Hz, 1H), 4.56 (dd, J = 15.6, 5.9 Hz, 1H). 13 ¹¹C NMR (151 MHz, chloroform-d) δ 168.8, 165.4, 156.0, 155.5, 152.8, 139.7, 138.6, 138.1, 137.4, 136.7, 135.9, 133.3, 133.0, 131.4, 131.1, 130.9, 128.7, 126.5, 125.8, 125.8, 124.6, 124.2, 122.5, 121.9, 121.2, 117.5, 54.0. 24 H 18 N3O2S2[M+H] + The LC-MS (ESI) calculation value for this is 444.09, and the measured value is 444.00.

[0393] N-(10-(buta-2-in-1-yl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-7-yl)furan-3-carboxamide. 1H NMR (400 MHz, chloroform-d) δ 8.07 - 8.02 (m, 1H), 7.86 (d, J = 2.5 Hz, 1H), 7.79 - 7.73 (m, 1H), 7.69 (d, J = 8.7 Hz, 1H), 7.61 (dd, J = 8.7, 2.5 Hz, 1H), 7.55 (s, 1H), 7.49 (d, J = 1.8 Hz, 1H), 7.40 (td, J = 6.3, 5.7, 1.9 Hz, 1H), 7.34 - 7.28 (m, 2H), 6.71 (d, J = 2.0 Hz, 1H), 4.94 (dd, J = 17.0, 2.4 Hz, 1H), 4.43 (dd, J = 17.0, 2.4 Hz, 1H), 1.85 (t, J = 2.4 Hz, 3H). 13 ¹³C NMR (151 MHz, chloroform-d) δ 168.6, 160.8, 145.5, 144.1, 139.6, 138.6, 137.5, 135.9, 135.7, 131.7, 131.0, 128.6, 125.1, 124.0, 122.7, 121.2, 108.4, 80.2, 74.7, 41.3, 3.8. 22 H 17 N2O3S[M+H] + The LC-MS (ESI) calculation value for this is 389.10, and the measured value is 389.10.

[0394] 4-Methoxy-N-(6-oxo-5-(2-(propa-2-in-1-yloxy)ethyl)-6,11-dihydro-5H-dibenzo[b,e]azepine-2-yl)benzamide. 1H NMR (600 MHz, chloroform-d) δ 7.87 (s, 1H), 7.86 - 7.79 (m, 2H), 7.76 (dd, J = 7.8, 1.4 Hz, 1H), 7.71 (d, J = 2.4 Hz, 1H), 7.37 - 7.27 (m, 3H), 7.23 (t, J = 6.9 Hz, 1H), 7.14 (d, J = 6.1 Hz, 1H), 6.98 - 6.93 (m, 2H), 4.77 (ddd, J = 13.8, 7.1, 4.3 Hz, 1H), 4.27 (d, J = 13.1 Hz, 1H), 4.12 (t, J = 2.5 Hz, 2H), 3.96 - 3.88 (m, 2H), 3.86 (s, 3H), 3.79 (ddd, J = 10.0, 7.1, 4.2 Hz, 1H), 3.50 (d, J = 13.2 Hz, 1H), 2.39 (t, J = 2.4 Hz, 1H). 13 ¹³C NMR (151 MHz, chloroform-d) δ 168.9, 165.2, 162.6, 142.6, 139.8, 136.0, 132.9, 131.5, 130.6, 128.9, 126.9, 126.8, 126.0, 124.5, 118.8, 118.6, 114.0, 79.4, 74.7, 67.1, 58.0, 55.5, 49.6. 27 H 25 N2O4[M+H] + The LC-MS (ESI) calculation for this was 441.18, and the measured value was 441.10.

[0395] 3-(fluoromethoxy)-N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-7-yl)benzamide. 1H NMR (400 MHz, DMSO-d6): δ 7.91 (d, J = 8.0 Hz, 1H), 7.86 (s, 1H), 7.67 (d, J = 1.6 Hz, 1H), 7.40-7.62 (m, 7H), 7.26-7.30 (m, 3H), 5.82 (s, 1H), 5.69 (s, 1H), 4.51-4.57 (m, 1H), 3.90-3.96 (m, 1H), 3.79-3.84 (m, 1H), 3.62-3.67 (m, 1H), 3.34 (s, 3H). 13 ¹³C NMR (151 MHz, chloroform-d) δ 169.1, 165.1, 157.0, 140.1, 138.8, 138.2, 137.1, 136.2, 135.7, 131.1, 131.0, 130.7, 130.2, 128.6, 126.8, 124.1, 121.7, 121.3, 120.3, 115.5, 70.1, 58.9, 51.6. 24 H 22 FN2O4S[M+H] + The LC-MS (ESI) calculation for this was 452.50, and the measured value was 452.12.

[0396] 2,2-difluoro-N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-7-yl)benzo[d][1,3]dioxol-5-carboxamide. 1 H NMR (400 MHz, chloroform-d): δ 7.91 (d, J =7.2 Hz, 2H), 7.64-7.66 (m, 1H), 7.57-7.61 (m, 3H), 7.50 (d, J =8.4 Hz, 1H), 7.39-7.42 (m, 2H), 7.13 (d, J =8.8 Hz, 1H), 4.50-4.56 (m, 1H), 3.91-3.97 (m, 1H), 3.79-3.84 (m, 1H), 3.62-3.67 (m, 1H), 3.45 (s, 3H). 13¹³C NMR (151 MHz, chloroform-d) δ 169.2, 164.1, 146.3, 144.1, 140.2, 138.8, 138.2, 137.1, 135.6, 131.7, 131.1, 131.0, 130.8, 128.7, 126.8, 124.2, 123.3, 121.4, 109.4, 109.1, 70.1, 58.9, 51.7. 24 H 19 F2N2O5S[M+H] + The LC-MS (ESI) calculation value for this is 484.47, and the measured value is 484.09.

[0397] (E)-10-(hexa-2-en-1-yl)-7-((3-methylpyrazine-2-yl)amino)dibenzo[b,f][1,4]thiazepine-11(10H)-one. 1 H NMR (400 MHz, chloroform-d): δ 7.71-7.76 (m, 2H), 7.54-7.55 (d, J =4.0 Hz, 1H), 7.41-7.46 (m 2H), 7.31-7.37 (m, 2H), 7.20-7.26 (m, 2H), 6.71-6.72 (d, J =4.0 Hz, 1H), 5.64-5.68 (m, 2H), 4.77-4.82 (m, 1H), 4.47-4.52 (m, 1H), 2.38 (s, 3H), 1.99-2.03 (m, 2H), 1.33-1.40 (m, 2H), 0.83-0.86 (t, J = 8.0 Hz, 3H). 13 ¹¹C NMR (151 MHz, chloroform-d) δ 168.7, 149.8, 140.9, 139.3, 138.8, 138.5, 138.1, 137.4, 136.7, 134.7, 134.2, 131.4, 131.0, 130.6, 128.6, 125.9, 125.2, 123.3, 120.5, 53.3, 34.3, 22.3, 20.4, 13.6. 24 H 25 N4OS[M+H] + The LC-MS (ESI) calculation for this was 417.54, and the measured value was 417.20.

[0398] (E)-10-(hexa-2-en-1-yl)-7-((3-methoxypyrazine-2-yl)amino)dibenzo[b,f][1,4]thiazepine-11(10H)-one. 1 H NMR (400 MHz, chloroform-d): δ 7.71-7.76 (m, 2H), 7.54-7.55 (d, J =4.0 Hz, 1H), 7.41-7.46 (m 2H), 7.31-7.37 (m, 2H), 7.20-7.26 (m, 2H), 6.71-6.72 (d, J =4.0 Hz, 1H), 5.64-5.68 (m, 2H), 4.77-4.82 (m, 1H), 4.47-4.52 (m, 1H), 2.38 (s, 3H), 1.99-2.03 (m, 2H), 1.33-1.40 (m, 2H), 0.83-0.86 (t, J = 8.0 Hz, 3H). 13 ¹³C NMR (151 MHz, chloroform-d) δ 168.7, 148.4, 141.7, 138.9, 138.5, 137.7, 137.4, 136.8, 134.2, 133.1, 131.4, 131.0, 130.6, 129.7, 128.5, 126.0, 125.2, 122.3, 119.5, 53.8, 53.3, 34.3, 22.2, 13.6. 24 H 25 N4O2S[M+H] + The LC-MS (ESI) calculation for this was 433.54, and the measured value was 433.20.

[0399] (E)-7-((3,5-dimethylpyridine-2-yl)amino)-10-(hexa-2-en-1-yl)dibenzo[b,f][1,4]thiazepine-11(10H)-one. 1H NMR (400 MHz, chloroform-d): δ10.22 (s, 1H), 7.66-7.75 (m, 3H), 7.26-7.39 (m, 4H),7.14 (d, J =2.4 Hz, 1H), 7.00-7.02 (m, 1H), 5.62-5.65 (m, 2H), 4.75-4.80 (m, 1H), 4.44-4.50 (m, 1H), 2.34 (s, 3H), 1.97-2.02 (m, 2H), 1.95 (s, 3H), 1.32-1.37 (m, 2H), 1.85 (d, J =7.2Hz, 3H). 13 ¹¹C NMR (151 MHz, chloroform-d) δ 168.5, 149.3, 147.8, 139.9, 138.3, 138.2, 137.0, 136.9, 135.2, 134.5, 131.5, 131.0, 130.8, 128.8, 127.0, 126.4, 125.1, 124.5, 122.2, 53.2, 34.3, 22.2, 19.2, 17.4, 13.6. 26 H 28 N3OS[M+H] + The LC-MS (ESI) calculation for this was 430.59, and the measured value was 430.20.

[0400] 10-(buta-2-in-1-yl)-7-((3-ethinylpyridine-2-yl)amino)dibenzo[b,f][1,4]thiazepine-11(10H)-one. 1 ¹H NMR (400 MHz, chloroform-d): δ 8.21 (s, 1H), 7.88 (s, 1H), 7.77 (d, J = 7.2 Hz, 1H), 7.65-7.72 (m, 3H), 7.43 (d, J = 7.2 Hz, 1H), 7.24-7.33 (m, 3H), 6.73-6.76 (m, 1H), 4.94 (d, J = 17.2 Hz, 1H), 4.42 (d, J = 17.2 Hz, 1H), 3.57 (s, 1H), 1.86 (s, 3H). 13¹³C NMR (151 MHz, chloroform-d) δ 168.5, 155.3, 147.9, 140.7, 138.7, 138.0, 137.9, 137.8, 135.6, 131.8, 131.1, 130.9, 128.5, 125.1, 122.9, 120.4, 114.7, 103.7, 85.4, 79.9, 78.6, 75.0, 41.1, 3.9. 24 H 18 N3OS[M+H] + The LC-MS (ESI) calculation for this was 496.48, and the measured value was 396.10.

[0401] 10-(buta-2-in-1-yl)-7-((3-fluoro-4-methylpyridine-2-yl)amino)dibenzo[b,f][1,4]thiazepine-11(10H)-one. 1 H NMR (400 MHz, chloroform-d): δ7.88 (d, J =6.0 Hz, 2H), 7.77 (d, J =7.2 Hz, 1H), 7.63-7.68 (m, 2H), 7.43 (d, J =7.2 Hz, 1H), 7.26-7.33 (m, 2H), 6.58-6.64 (m, 2H), 4.91-4.96 (m, 1H), 4.39-4.43 (m, 1H), 2.28 (s, 3H), 1.86 (s, 3H). 13 ¹C NMR (151 MHz, chloroform-d) δ 168.6, 146.7, 145.0, 144.2, 141.7 (d, J = 7.5 Hz), 138.8, 138.1, 137.9, 137.5, 135.7, 132.1 (d, J = 13.0 Hz), 131.8, 131.1, 130.9, 128.5, 125.1, 122.3, 119.7, 117.9, 79.8, 75.0, 41.1, 13.9, 3.9. 23 H 19 FN3OS[M+H] + The LC-MS (ESI) calculation for this was 403.47, and the measured value was 403.12.

[0402] 10-(buta-2-in-1-yl)-7-((3-fluoro-5-methylpyridine-2-yl)amino)dibenzo[b,f][1,4]thiazepine-11(10H)-one. 1 ¹H NMR (400 MHz, chloroform-d): δ 7.86-7.90 (m, 2H), 7.76-7.78 (m, 1H), 7.62-7.67 (m, 1H), 7.59-7.60 (m, 1H), 7.42 (d, J = 7.6 Hz, 1H), 7.26-7.33 (m, 2H), 7.14 (d, J = 11.6 Hz, 1H), 6.51 (d, J = 2.0 Hz, 1H), 4.91-4.96 (m, 1H), 4.39-4.44 (m, 1H), 2.27 (s, 3H), 1.86 (s, 3H). 13 ¹C NMR (151 MHz, chloroform-d) δ 168.6, 147.7, 146.0, 142.3 (d, J = 9.9 Hz), 142.0 (d, J = 5.5 Hz), 138.8, 138.3, 137.9, 137.3, 135.7, 131.8, 131.1, 130.9, 128.5, 125.4, 125.1, 122.5, 122.4, 121.8, 119.3, 79.8, 75.0, 41.1, 17.5, 3.9. 23 H 19 FN3OS[M+H] + The LC-MS (ESI) calculation for this was 404.47, and the measured value was 404.20.

[0403] 10-(buta-2-in-1-yl)-7-((3-fluoro-6-methylpyridine-2-yl)amino)dibenzo[b,f][1,4]thiazepine-11(10H)-one. 1¹H NMR (400 MHz, chloroform-d): δ 7.86 (d, J = 8.0, 1H), 7.73-7.77 (m, 2H), 7.65 (d, J = 8.0, 1H), 7.43 (d, J = 8.0, 1H), 7.15-7.20 (m, 2H), 6.55-6.60 (m, 2H), 4.91-4.96 (m, 1H), 4.39-4.45 (m, 1H), 2.46 (s, 3H), 1.86 (t, J = 2.4 Hz, 3H). 13 ¹C NMR (151 MHz, chloroform-d) δ 168.6, 151.6, 146.1, 144.4, 143.3 (d, J = 9.5 Hz), 138.8, 138.2, 137.9, 137.3, 135.6, 131.8, 131.1, 130.9, 128.5, 125.1, 121.9, 121.7, 121.5, 119.3, 114.2, 79.9, 75.0, 41.2, 23.7, 3.9. 23 H 19 FN3OS[M+H] + The LC-MS (ESI) calculation for this was 404.47, and the measured value was 404.20.

[0404] 2-((10-(buta-2-in-1-yl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-7-yl)amino)-3-methylisonicotinonitrile. 1 H NMR (400 MHz, chloroform-d): δ 8.50 (s, 1H), 8.18 (d, J = 5.2 Hz, 1H), 7.97 (d, J = 2.4 Hz, 1H), 7.75 (d, J = 2.4 Hz, 1H), 7.61-7.64 (m, 2H), 7.50-7.52 (m, 1H), 7.40-7.43 (m, 2H), 7.16 (d, J = 5.2 Hz, 1H), 4.80-4.85(m, 1H), 4.65-4.70 (m, 1H), 2.44 (s, 3H), 1.78(s, 3H). C 24 H 19 N4OS[M+H] +The LC-MS (ESI) calculation for this was 411.49, and the measured value was 411.20.

[0405] 10-(buta-2-in-1-yl)-7-(pyridazine-3-ylamino)dibenzo[b,f][1,4]thiazepine-11(10H)-one. 1 ¹H NMR (400 MHz, chloroform-d): δ 8.73 (d, J = 4.4 Hz, 1H), 7.71-7.79 (m, 1H), 7.68-7.70 (m, 2H), 7.40-7.44 (m, 2H), 7.26-7.35 (m, 3H), 7.03-7.06 (m, 1H), 4.93-4.98 (m, 1H), 4.40-4.45 (m, 1H), 1.86 (t, J = 4.4 Hz, 3H). 13 ¹³C NMR (151 MHz, chloroform-d) δ 168.4, 157.4, 145.4, 138.9, 138.5, 137.7, 137.6, 136.2, 131.1, 131.0, 128.7, 127.9, 125.5, 123.7, 121.2, 114.2, 80.1, 74.8, 41.2, 3.9. 21 H 17 N4OS[M+H] + The LC-MS (ESI) calculation for this was 373.44, and the measured value was 373.10.

[0406] N-(10-(buta-2-in-1-yl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-7-yl)-4-(difluoromethoxy)benzamide. 1¹H NMR (400 MHz, chloroform-d): δ 9.11 (s, 1H), 8.58 (d, J = 1.2 Hz, 1H), 8.21 (s, 1H), 8.05-8.08 (m, 1H), 7.98-8.01 (m, 2H), 7.74-7.79 (m, 2H), 7.68-7.71 (m, 1H), 7.13-7.16 (m, 1H), 6.98-7.03 (m, 1H), 4.90-4.95 (m, 1H), 4.42-4.47 (m, 1H), 1.86 (t, J = 2.0 Hz, 3H). 13 ¹³C NMR (151 MHz, chloroform-d) δ 168.5, 164.7, 153.9, 139.9, 138.5, 137.6, 135.9, 131.8, 131.3, 131.1, 129.1, 128.7, 125.2, 124.1, 121.2, 119.3, 117.1, 115.3, 113.6, 80.2, 74.7, 41.2, 3.8. 25 H 19 F2N2O3S[M+H] + The LC-MS (ESI) calculation for this was 464.48, and the measured value was 464.10.

[0407] N-(10-(buta-2-in-1-yl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-7-yl)-4-(fluoromethoxy)benzamide. 1 ¹H NMR (400 MHz, chloroform-d): δ 7.84-7.86 (m, 4H), 7.62-7.76 (m, 3H), 7.40-7.7.43 (m, 1H), 7.26-7.33 (m, 2H), 7.15 (d, J = 8.8 Hz, 1H), 5.84 (s, 1H), 5.70 (s, 1H), 4.91-4.96 (m, 1H), 4.41-4.46 (m, 1H), 1.86 (t, J = 4.4 Hz, 3H). 13¹³C NMR (151 MHz, chloroform-d) δ 168.5, 164.9, 159.5, 139.8, 138.5, 137.6, 136.0, 135.8, 131.8, 131.1, 129.3, 129.1, 128.6, 125.1, 124.0, 121.1, 116.4, 100.7, 99.2, 80.2, 74.7, 41.2, 3.8. 25 H 20 FN2O3S[M+H] + The LC-MS (ESI) calculation for this was 447.49, and the measured value was 447.10.

[0408] N-(10-(buta-2-in-1-yl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-7-yl)-6-methoxyni...

Claims

1. Equation (I): (In the formula, R1 is selected from R3; -C(O)R3; -C(S)R3; -C(O)NHR3; -C(S)NHR3; -C(O)NR5R6; -C(S)NR5R6, R2 is selected from C1-C8 alkyl, C2-C8 alkenyl, and C2-C8 alkynyl, encompassing all of their isomers, all of which may be substituted with one or more of D, F, OH, or C(O)NHR4, and all of which may have one or more methylene units substituted with O, S, NH, NR4, or C(O). R3 is C1-C7 alkyl, CH ２ or CH ２ CH ２ C3-C7 cycloalkyl which may be crosslinked by, CH ２ or CH ２ CH ２ C3-C7 cycloalkyl which may be crosslinked by, CH ２ linked by or linked by CHMe, C2-C7 alkenyl, CH ２ or CH ２ CH ２ C5-C7 cycloalkenyl which may be crosslinked by, CH ２ or CH ２ CH ２ C5-C7 cycloalkenyl which may be crosslinked by, CH ２ linked by or linked by CHMe, C2-C7 alkynyl, crosslinked or fused C5-C9 cycloalkyl, CH ２ linked by or linked by CHMe, crosslinked or fused C5-C9 cycloalkyl, C5-C10 spiroalkane, CH ２ linked by or linked by CHMe, C5-C10 spiroalkane (all of which include all possible isomers thereof, all of which are D, F, CN, R4, OR4, OH, NHC(O)H, NHC(O)R4, NHS ２ R4, CO ２ H, CO ２ R4, C(O)NH ２ , C(O)NHR4, C(O)NR4R4, and may be substituted by one or more of them, all of which are O, S, SO ２ , S(O), NH, NR4, NC(O)H, NC(O)R4, NSO ２ (May have one or more methylene units replaced by R4, C(O), C=NOH, C=NOR4 or C=NR4), phenyl or naphthyl (may be substituted with R7 at one or more of the positions), but not limited to oxazole, isoxazole, thiazole, isothiazole, furan, thiophene, pyrazole, imidazole, triazole, tetrazole, pyridine, pyrimidine, pyrazine, pyridazine, quinoline, isoquinoline, quinazoline, quinoxaline, cinnoline, phthalazine, naphthyridine, pyridopyrazine, pyrazolopyridine, pyridopyrimidine, pyridopyridazine, benzoxazole, benzoisoxazole, benzothiazole, benzoisothiazole, indole, The following are selected from 5-membered and 6-membered heteroaryls and condensed heteroaryls, including dazole, benzimidazole, dioxopyridine, dioxopyridazine, dioxopyrimidine, dioxopyrazine, benzofuran, benzothiophene, imidazopyridine, benzodioxol, benzoxazolone, benzoisoxazolone, benzothiazolon, benzoisothiazolon, 1,3-dihydro-2H-benzimidazole, benzo[d]imidazole-2-one, benzodioxolone, dioxopyridine, dioxopyridazine, dioxopyrimidine, dioxopyrazine, coumarin, isocoumarin, and all possible isomers thereof, all of which may be substituted with R7 at one or more of the positions: R4 is selected from Me; Et; Pr; iPr; cPr; cBu, which are D, F, CN, OH, OCD. ３ , OCH ｎ F （３－ｎ） It is also possible that one or more of (n = 0 to 3) are used as substitutions. NR5R6 forms 4- to 7-membered azacyclic compounds, cross-linked or condensed 6- to 9-membered azacyclic compounds, or 5- to 9-membered azaspiroalkanes, encompassing all possible isomers thereof, all of which are D, F, CN, R4, OR4, OH, NHC(O)H, NHC(O)R4, NHSO ２ R4, CO ２ H, CO ２ R4, C(O)NH ２ , may be substituted with one or more of C(O)NHR4, C(O)NR4R4, and all of them may be O, S, SO ２ , NH, NR4, NC(O)H, NC(O)R4, NSO ２ It may have one or more methylene units that may be replaced by R4, C(O), C=NOH, or C=NR4. R7 is D, F, Cl, Br, CN, N ３ OH, OR4, R4, oxetanyl, NHC(O)H, NHC(O)R4, CO ２ H, CO ２ R4, C(O)NH ２ , C(O)NHR4, C(O)NR4R4, SO ２ NH ２ SO ２ NHR4, SO ２ NR4R4, C2-C6 alkenyl or C2-C6 alkynyl, encompassing all isomers thereof, all of which may be substituted with one or more of D, F, CN, or OH, and all of which are O, S, S(O), SO ２ , NH, NR4, NC(O)H, NC(O)R4, NSO ２ C2-C6 alkenyls or C2-C6 alkynyls that may have one or more methylene units replaced by R4, C(O), C=NOH, or C=NR4; selected from aryls or 5-membered or 6-membered heteroaryls or heterocyclies, all of which may be substituted with one or more of D, F, Cl, CN, R4, OH, or OR4, Z is S, CH ２ CD ２ , CHR4, CDR4, CR4R4, CHOH, CDOH, CHOR4, CDOR4, CR4OH, CR4OR4, CHCN, CDCN, CHF, CDF, CF ２ , NH, NR4, NC(O)H, NC(O)R4, NSO ２ Selected from R4, X is selected from CH, CD, CF, CCl, CCN, Y is selected from CH, CD, CF, and CCl. U and W are independently selected from CH, CD, and N. R1 is C(O)furan-3-yl, X, Y, U, W are CH, Z is S, and R2 is (CH ２ ) ２ Compounds of OMe (excluding those that are MM017), or their salts, hydrates, or stereoisomers.

2. Furthermore, equation II: The compound according to claim 1, which is a compound of the above.

3. Furthermore, formula III: The compound according to claim 1, which is a compound of the above.

4. Furthermore, formula IV: The compound according to claim 1, which is a compound of the above.

5. Furthermore, formula V: The compound according to claim 1, which is a compound of the above.

6. Furthermore, formula VI: The compound according to claim 1, which is a compound of the above.

7. Furthermore, formula VII: The compound according to claim 1, which is a compound of the above.

8. Furthermore, formula VIII: The compound according to claim 1, which is a compound of the above.

9. Z is S, CH ２ CD ２ , CHMe, CHCD ３ , CDMe, CDCD ３ , CHCN, CDCN, CMeOH, CCD ３ OH, preferably S, CH ２ , CHMe, CHCD ３ The compound according to any one of claims 1 to 8.

10. The compound according to any one of claims 1 to 8, wherein X is CH, CD, CF, CCl, CCN, preferably CH, CF, or CCl.

11. The compound according to any one of claims 1 to 8, wherein Y is CH, CD, CF, CCl, preferably CH, or CF.

12. The compound according to any one of claims 1 to 8, wherein W is CH, CD, or N.

13. The compound according to any one of claims 1 to 8, wherein U is CH, CD, N, preferably CH.

14. The compound according to any one of claims 1 to 8, wherein R2 is a C2-C7 alkyl, C3-C7 alkenyl, or C3-C7 alkynyl compound, encompassing all of these isomers, all of which may be substituted with one or more of D, F, or Cl, and all of which may have one or more methylene units substituted with O.

15. R2 is CH ２ C≡CH, CH ２ C≡CR4, CH ２ C≡CCl, CH ２ CH=CH ２ ,CH ２ CH=CHR4, (CH ２ ) ２ OR4, (CH ２ ) ２ OCH ２ The compound according to any one of claims 1 to 8, wherein C≡CH and R2 may contain one or more deuterium atoms.

16. R2 is CH ２ C≡CH, CH ２ C≡CMe, CH ２ C≡CCH ２ F, CH ２ C≡C ｃ Pr, CH ２ C≡CCl, CH ２ CH=CHMe, CH ２ C≡CCF ３ The compound according to any one of claims 1 to 8, wherein R2 may contain one or more deuterium atoms.

17. R2 is CH ２ C≡CH, CH ２ C≡CMe, CH ２ C≡CCH ２ F, CH ２ C≡CCl, CH ２ C≡C ｃ Pr, CH ２ CH=CHMe, and R2 may contain one or more deuterium atoms. NR5R6 forms 4- to 7-membered aza-cyclic compounds, cross-linked or condensed 6- to 9-membered aza-cyclic compounds, or 5- to 9-membered aza-spiroalkanes, encompassing all possible isomers thereof, all of which are D, F, CN, R4, OR4, OH, NHC(O)H, NHC(O)R4, NHSO ２ R4, CO ２ H, CO ２ R4, C(O)NH ２ , may be substituted with one or more of C(O)NHR4, C(O)NR4R4, and all of them may be O, S, SO ２ , NH, NR4, NC(O)H, NC(O)R4, NSO ２ It may have one or more methylene units that are replaced by R4, C(O), C=NOH, or C=NR4. R4 is Me; Et; Pr; iPr; cPr; cBu, and these may be substituted with one or more of D, F, CN, OH, OCD ３ , OCH ｎ F （３－ｎ） (n = 0 to 3). Z is S, CH ２ , CHMe, CHCD ３ , CHCN, CMeOH, CCD ３ OH, preferably S, CH ２ , CHMe, CHCD ３ and is X is CH, CD, CF, CCl, Y is CH, CD, CF, W is CH, N, U is CH, CD, N, preferably CH. The compound according to claim 2 or 3.

18. R2 is CH ２ C≡CH, CH ２ C≡CMe, CH ２ C≡CCH ２ F, CH ２ C≡CCl, CH ２ C≡C ｃ Pr, preferably CH ２ C≡CMe, CH ２ C≡C ｃ It is Pr, NR5R6 forms a 4- to 7-membered azacyclic compound, a 6- to 8-membered azabicyclic compound, or a 5- to 7-membered azaspiroalkane, all of which may be substituted with one or more of D, F, CN, R4, OR4, or OH, and all of which may be O, S, or SO ２ It may have one or more methylene units replaced by NH, NR4, C(O), C=NOH, or C=NR4. R4 is Me;Et;Pr;iPr;cPr;cBu, which are D, F, CN, OH, and OCD. ３ , OCH ｎ F （３－ｎ） It is also possible that one or more of (n = 0 to 3) are used as substitutions. Z is S, CH ２ , CHMe, CHCD ３ , CHCN, CMeOH, CCD ３ OH, preferably S, CH ２ , CHMe, CHCD ３ And, X is CH, CF, CCl, Y is CH, CF, W is CH, N, U is CH, N, preferably CH. The compound according to claim 2 or 3.

19. R2 is CH ２ C≡CH, CH ２ C≡CMe, CH ２ C≡CCH ２ F, CH ２ C≡CCl, CH ２ C≡C ｃ Pr, CH ２ CH=CHMe, and R2 may contain one or more deuterium atoms. R3 is phenyl (may be substituted with R7 in one or more of its individual positions); however, it is not limited to oxazoles, isoxazoles, thiazoles, isothiazoles, furans, thiophenes, pyrazoles, imidazoles, triazoles, tetrazoles, pyridines, pyrimidines, pyrazines, pyridazines, quinolines, isoquinolines, quinazolins, quinoxalines, cinnolines, phthalazines, naphthyridines, pyridopyrazines, pyrazolopyridines, pyridopyrimidines, pyridopyridazines, benzoxazoles, benzoisoxazoles, benzothiazoles, benzoisothiazoles, indoles, indazoles, benzimidazoles, dioxopyridines, diox This includes soropyridazine, dioxolopyrimidine, dioxolopyrazine, benzofuran, benzothiophene, imidazopyridine, benzodioxol, benzoxazolone, benzoisoxazolone, benzothiazolon, benzoisothiazolon, 1,3-dihydro-2H-benzimidazole, benzo[d]imidazole-2-one, benzodioxolone, dioxolopyridine, dioxolopyridazine, dioxolopyrimidine, dioxolopyrazine, coumarin, isocoumarin, and other five-membered and six-membered heteroaryls and condensed heteroaryls, encompassing all possible isomers thereof, all of which may be substituted with R7 at one or more of their respective positions. R4 consists of Me, Et, Pr, iPr, cPr, and cBu, which are D, F, CN, OH, and OCD. ３ , OCH ｎ F （３－ｎ） It is also possible that one or more of (n = 0 to 3) are used as substitutions. 27が、4、0、33、33、38、8 ３ 、OH、R4、OR4、C≡CH、883(9)2、3(9)88 ２ 、3(9)82244444444 Z is S, CH ２ , CHMe, CHCD ３ , CHCN, CMeOH, CCD ３ OH, preferably S, CH ２ , CHMe, CHCD ３ And, X is CH, CF, CCl, Y is CH, CF, W is CH, N, U is CH, N, preferably CH. The compound according to claim 4, 5, or 8.

20. R2 is CH ２ C≡CH, CH ２ C≡CMe, CH ２ C≡CCH ２ F, CH ２ C≡CCl, CH ２ C≡C ｃ Pr, preferably CH ２ C≡CMe, CH ２ C≡C ｃ It is Pr, R3 is a substituent in the ortho position selected from H, D, or F, and H, D, F, Cl, R4, OR4, N ３ , a monosubstituted or disubstituted phenyl ring having substituents at the meta and para positions selected from C≡CH; an aromatic heterocycle selected from furan, pyridine, pyrimidine, pyrazine, pyridazine, benzo[d]oxazole-5-yl, benzo[d]thiazole-5-yl, 2-oxo-2,3-dihydrobenzo[d]oxazole-5-yl, benzo[d][1,3]dioxol-5-yl, all of which may be substituted with H, D, F, Cl, CCH, R4, OR4 at one or more of their respective positions. R4 is Me;Et;Pr;iPr;cPr;cBu, and these may be substituted with one or more of D and F. Z is S, CH ２ , CHMe, CHCD ３ , CHCN, CMeOH, CCD ３ OH, preferably S, CH ２ , CHMe, CHCD ３ And, X is CH, CF, CCl, Y is CH, CF, W is CH, N, U is CH, N, preferably CH. The compound according to claim 4, 5, or 8.

21. R2 is CH ２ C≡CH, CH ２ C≡CMe, CH ２ C≡CCH ２ F, CH ２ C≡CCl, CH ２ C≡C ｃ Pr, CH ２ CH=CHMe, and R2 may contain one or more deuterium atoms. R3 is C1-C7 alkyl, CH ２ or CH ２ CH ２ C3-C7 cycloalkyl groups, CH3, CH4 ２ or CH ２ CH ２ CH may be crosslinked ２ C3-C6 cycloalkyl, C2-C7 alkenyl, CH linked by or linked by CHMe ２ or CH ２ CH ２ C5-C6 cycloalkenyls, CH2, which may be crosslinked. ２ or CH ２ CH ２ CH may be crosslinked ２ C5-C6 cycloalkenyls linked with or linked with CHMe, C2-C7 alkynyls, crosslinked or condensed C5-C9 cycloalkyls, CH ２ Linked or CHMe-linked cross-linked or condensed C5-C9 cycloalkyl, C5-C10 spiroalkane, CH ２ These are C5-C10 spiroalkanes linked by or CHMe, all of which encompass all possible isomers, and all of which are D, F, CN, R4, OR4, OH, NHC(O)H, NHC(O)R4, NHSO4 ２ R4, CO ２ H, CO ２ R4, C(O)NH ２ , may be substituted with one or more of C(O)NHR4, C(O)NR4R4, and all of them may be O, S, SO ２ , S(O), NH, NR4, NC(O)H, NC(O)R4, NSO ２ It may have one or more methylene units replaced by R4, C(O), C=NOH, C=NOR4, or C=NR4. R4 consists of Me, Et, Pr, iPr, cPr, and cBu, which are D, F, OH, and OCD. ３ , OCH ｎ F （３－ｎ） It is also possible that one or more of (n = 0 to 3) are used as substitutions. Z is S, CH ２ , CHMe, CHCD ３ , CHCN, CMeOH, CCD ３ OH, preferably S, CH ２ , CHMe, CHCD ３ And, X is CH, CF, CCl, Y is CH, CF, W is CH, N, U is CH, N, preferably CH. The compound according to claim 4, 5, or 8.

22. R2 is CH ２ C≡CH, CH ２ C≡CMe, CH ２ C≡CCH ２ F, CH ２ C≡CCl, CH ２ C≡C ｃ Pr, CH ２ CH=CHMe, CH ２ =CHEt, CH ２ CH=CHPr, (CH ２ ) ２ OCH ２ It is CCH, and R2 may contain one or more deuterium atoms. R3 is phenyl (may be substituted with R7 in one or more of its individual positions); however, it is not limited to oxazoles, isoxazoles, thiazoles, isothiazoles, furans, thiophenes, pyrazoles, imidazoles, triazoles, tetrazoles, pyridines, pyrimidines, pyrazines, pyridazines, quinolines, isoquinolines, quinazolins, quinoxalines, cinnolines, phthalazines, naphthyridines, pyridopyrazines, pyrazolopyridines, pyridopyrimidines, pyridopyridazines, benzoxazoles, benzoisoxazoles, benzothiazoles, benzoisothiazoles, indoles, indazoles, benzimidazoles, dioxopyridines, diox This includes soropyridazine, dioxolopyrimidine, dioxolopyrazine, benzofuran, benzothiophene, imidazopyridine, benzodioxol, benzoxazolone, benzoisoxazolone, benzothiazolon, benzoisothiazolon, 1,3-dihydro-2H-benzimidazole, benzo[d]imidazole-2-one, benzodioxolone, dioxolopyridine, dioxolopyridazine, dioxolopyrimidine, dioxolopyrazine, coumarin, isocoumarin, and other five-membered and six-membered heteroaryls and condensed heteroaryls, encompassing all possible isomers thereof, all of which may be substituted with R7 at one or more of their respective positions. 27が、4、0、33、33、38、8 ３ 、OH、R4、OR4、C≡CH、883(9)2、3(9)88 ２ 、3(9)82244444444 R4 consists of Me, Et, Pr, iPr, cPr, and cBu, which are D, F, CN, OH, and OCD. ３ , OCHnF （３－ｎ） It is also possible that one or more of (n = 0 to 3) are used as substitutions. Z is S, CH ２ , CHMe, CHCD ３ , CHCN, CMeOH, CCD ３ OH, preferably S, CH ２ , CHMe, CHCD ３ And, X is CH, CF, CCl, Y is CH, CF, W is CH, N, U is CH, N, preferably CH. The compound according to claim 6.

23. R2 is CH ２ C≡CH, CH ２ C≡CMe, CH ２ C≡CCH ２ F, CH ２ C≡CCl, CH ２ C≡C ｃ Pr, CH ２ CH=CHMe, CH ２ =CHEt, CH ２ CH=CHPr, R3 is a five- and six-membered heteroaryl compound, including, but not limited to, pyrazoles, imidazoles, pyridines, pyrimidines, pyrazines, pyridazines, quinolines, isoquinolines, quinazolines, quinoxalines, cinnolines, and phthalazines, encompassing all possible isomers thereof, all of which have D, F, Cl, CN, Me, cPr, or CD in one or more of their respective positions. ３ OCD ３ OH, OCH ｎ F （３－ｎ） The substitution may also be (n = 0 to 3), Z is S, CH ２ , CHMe, CHCD ３ , CHCN, CMeOH, CCD ３ OH, preferably S, CH ２ , CHMe, CHCD ３ And, X is CH, CF, CCl, Y is CH, CF, W is CH, N, U is CH, N, preferably CH. The compound according to claim 6.

24. R2 is CH ２ C≡CH, CH ２ C≡CMe, CH ２ C≡CCH ２ F, CH ２ C≡CCl, CH ２ C≡C ｃ Pr, preferably CH ２ C≡CMe, CH ２ C≡C ｃ It is Pr, R3 is pyrazole, pyridine, pyrimidine, pyrazine, or pyridazine, and all of them have D, F, Cl, CN, Me, cPr, or CD at one or more of their respective positions. ３ OCD ３ OH, OCH ｎ F （３－ｎ） The substitution may also be (n = 0 to 3), Z is S, CH ２ CHMe, CHCN, CMeOH, preferably S, CH ２ , CHMe, X is CH, CF, CCl, Y is CH, CF, W is CH, N, U is CH, N, preferably CH. The compound according to claim 6.

25. R2 is CH ２ C≡CH, CH ２ C≡CMe, CH ２ C≡CCH ２ F, CH ２ C≡CCl, CH ２ C≡C ｃ It is Pr, and R2 may contain one or more deuterium atoms. R3 is C2-C4 alkyl, C2-C4 alkenyl, CH ２ or CH ２ CH ２ C3-C6 cycloalkyl groups, CH3, CH4, CH4, CH3 may be crosslinked. ２ or CH ２ CH ２ CH may be crosslinked ２ C3-C6 cycloalkyl groups linked by or CHMe, CH ２ or CH ２ CH ２ C5-C6 cycloalkenyls, CH2, which may be crosslinked. ２ or CH ２ CH ２ CH may be crosslinked ２ C5-C6 cycloalkenyls, C5-C8 spiroalkanes, CH5-C8 spiroalkanes linked by or CHMe, CH ２ These are C5-C8 spiroalkanes linked by or CHMe, and all of them are D, F, CN, OH, R4, OCD. ３ , OCH ｎ F （３－ｎ） (n = 0 to 3) may be substituted with one or more of the following: O, S, SO ２ , S(O), NH, NR4, NC(O)H, NC(O)R4, NSO ２ It may have one or more methylene units replaced by R4, C(O), C=NOH, C=NOR4, or C=NR4. R4 consists of Me, Et, Pr, iPr, cPr, and cBu, which are D, F, OH, and OCD. ３ , OCH ｎ F （３－ｎ） It is also possible that one or more of (n = 0 to 3) are used as substitutions. Z is S, CH ２ , CHMe, CHCD ３ , CHCN, CMeOH, CCD ３ OH, preferably S, CH ２ , CHMe, CHCD ３ And, X is CH, CF, CCl, Y is CH, CF, W is CH, N, U is CH, N, preferably CH. The compound according to claim 6.

26. R2 is CH ２ C≡CMe, CH ２ C≡CCD ３ ,CH ２ C≡CCH ２ F, CH ２ C≡C ｃ Pr, CH ２ C≡CCl, CH ２ C≡CH, preferably CH ２ C≡CMe, CH ２ C≡C ｃ It is Pr, NR5R6 may be substituted with one or more of D, F, CN, R4, OR4, or OH, CH ２ or CH ２ CH ２ N-linked azetidine, pyrrolidine, piperidine, and azepine, which may be crosslinked, all of which are O, NR4, N=OH, N=OMe, and N=OCD. ３ It may have one or more methylene units that are replaced by R4 is Me, cPr, and these are D, F, CN, OH, OCD ３ , OCH ｎ F （３－n） It is also possible that one or more of (n = 0 to 3) are used as substitutions. Z is S, CH ２ , CHMe, preferably S, X is CH, CF, CCl, Y is CH, F, preferably CH. W is CH, N, U is CH. The compound according to claim 17 or 18.

27. R2 is CH ２ C≡CMe, CH ２ C≡CCD ３ ,CH ２ C≡C ｃ Pr, CH ２ C≡CCH ２ F, CH ２ C≡CCl, CH ２ C≡CH, preferably CH ２ C≡CMe, CH ２ C≡C ｃ It is Pr, R3 is pyridine, pyrimidine, pyrazine, or pyridazine, and all of them have D, F, Cl, CN, Me, Et, iPr, cPr, OH, or OCD in one or more of their respective positions. ３ , OCH ｎ F （３－ｎ） The substitution may also be (n = 0 to 3), Z is S, CH ２ , CHMe, preferably S, X is CH, CF, CCl, Y is CH, CF, preferably CH. W is CH, N, U is CH. The compound according to any one of claims 22 to 24.

28. R2 is CH ２ C≡CMe, CH ２ C≡CCD ３ ,CH ２ C≡C ｃ Pr, CH ２ C≡CCH ２ F, CH ２ C≡CCl, CH ２ C≡CH, preferably CH ２ C≡CMe, CH ２ C≡C ｃ It is Pr, R3 is C2-C4 alkyl, C2-C4 alkenyl, CH ２ or CH ２ CH ２ C3-C6 cycloalkyl groups, CH3, CH4, CH4, CH3 may be crosslinked. ２ or CH ２ CH ２ CH may be crosslinked ２ C3-C6 cycloalkyl groups linked by or CHMe, CH ２ or CH ２ CH ２ C5-C6 cycloalkenyls, CH2, which may be crosslinked. ２ or CH ２ CH ２ CH may be crosslinked ２ C5-C6 cycloalkenyls, C5-C8 spiroalkanes, CH5-C8 spiroalkanes linked by or CHMe, CH ２ These are C5-C8 spiroalkanes linked by or CHMe, all of which encompass all possible isomers, and all of which are D, F, Me, CD. ３ ,cPr,OH,OCD ３ , OCH ｎ F （３－ｎ） (n=0-3), CH ２ OH, CHMeOH, CH ２ OCD ３ ,CH ２ OCH ｎ F （３－ｎ） (n=0-3), CHMeOCD ３ CHMeOCH ｎ F （３－ｎ） (n = 0 to 3) may be substituted with one or more of the following: O, S, SO ２ , NH, NMe, NCD ３ , CO, N=OH, N=OMe, N=OCD ３ It may have one or more methylene units that are replaced by Z is S, CH ２ , CHMe, preferably S, X is CH, CF, CCl, Y is CH, CF, preferably CH. W is CH, N, U is CH. The compound according to claim 25.

29. R2 is CH ２ C≡CMe, CH ２ C≡CCD ３ ,CH ２ C≡C ｃ Pr, CH ２ C≡CCH ２ F, CH ２ C≡CCl, CH ２ C≡CH, preferably CH ２ C≡CMe, CH ２ C≡C ｃ It is Pr, R3 is a substituent in the ortho position selected from H, D, or F, and H, D, F, Cl, R4, OR4, N ３ , a monosubstituted or disubstituted phenyl ring having substituents at the meta and para positions selected from C≡CH; an aromatic heterocycle selected from furan, pyridine, pyrimidine, pyrazine, pyridazine, benzo[d]oxazole-5-yl, benzo[d]thiazole-5-yl, 2-oxo-2,3-dihydrobenzo[d]oxazole-5-yl, benzo[d][1,3]dioxol-5-yl, all of which have H, D, F, Cl, Me, CD at one or more of their respective positions. ３ ,cPr,CCH,OCD ３ , OCH ｎ F （３－ｎ） The substitution may also be (n = 0 to 3), Z is S, CH ２ , CHMe, preferably S, X is CH, CF, CCl, Y is CH, CF, preferably CH. W is CH, N, U is CH. The compound according to claim 20.

30. R2 is CH ２ C≡CMe, CH ２ C≡CCD ３ ,CH ２ C≡C ｃ Pr, CH ２ C≡CCH ２ F, CH ２ C≡CCl, CH ２ C≡CH, preferably CH ２ C≡CMe, CH ２ C≡C ｃ It is Pr, R3 is C2-C4 alkyl, C2-C4 alkenyl, C2-C3 alkynyl, CH ２ or CH ２ CH ２ C3-C6 cycloalkyl groups, CH3, CH4, CH4, CH3 may be crosslinked. ２ or CH ２ CH ２ CH may be crosslinked ２ C3-C6 cycloalkyl groups linked by or CHMe, CH ２ or CH ２ CH ２ C5-C6 cycloalkenyls, CH2, which may be crosslinked. ２ or CH ２ CH ２ CH may be crosslinked ２ C5-C6 cycloalkenyls, C5-C8 spiroalkanes, CH5-C8 spiroalkanes linked by or CHMe, CH ２ These are C5-C8 spiroalkanes linked by or CHMe, all of which encompass all possible isomers, and all of which are D, F, CN, Me, CD. ３ ,cPr,OH,OCD ３ , OCH ｎ F （３－ｎ） (n=0-3), CH ２ OH, CHMeOH, CH ２ OCD ３ ,CH ２ OCH ｎ F （３－ｎ） (n=0-3), CHMeOCD ３ CHMeOCH ｎ F （３－ｎ） (n=0-3), CO ２ Me, CO ２ CD ３ It is also possible that one or more of these are substituted, and all of them are O, S, SO ２ , NH, NMe, NCD ３ , C(O), N=OH, N=OMe, N=OCD ３ It may have one or more methylene units that are replaced by Z is S, CH ２ , CHMe, preferably S, X is CH, CF, CCl, Y is CH, CF, preferably CH. W is CH, N, U is CH. The compound according to claim 21.

31. R2 is CH ２ C≡CMe, CH ２ C≡CCD ３ ,CH ２ C≡C ｃ Pr, CH ２ C≡CCH ２ F, CH ２ C≡CCl, CH ２ C≡CH, preferably CH ２ C≡CMe, CH ２ C≡C ｃ It is Pr, R3 is a substituent in the ortho position selected from H, D, or F, and H, D, F, Cl, R4, OR4, N ３ , a monosubstituted or disubstituted phenyl ring having substituents at the meta and para positions selected from C≡CH; an aromatic heterocycle selected from furan, pyridine, pyrimidine, pyrazine, pyridazine, benzo[d]oxazole-5-yl, benzo[d]thiazole-5-yl, 2-oxo-2,3-dihydrobenzo[d]oxazole-5-yl, benzo[d][1,3]dioxol-5-yl, all of which have H, D, F, Cl, Me, CD at one or more of their respective positions. ３ ,cPr,CCH,OCD ３ , OCH ｎ F （３－ｎ） The substitution may also be (n = 0 to 3), Z is S, CH ２ , CHMe, preferably S, X is CH, CF, CCl, Y is CH, CF, preferably CH. W is CH, N, U is CH. The compound according to claim 7.

32. R2 is CH ２ C≡CMe, CH ２ C≡CCD ３ ,CH ２ C≡C ｃ Pr, CH ２ C≡CCH ２ F, CH ２ C≡CCl, CH ２ C≡CH, preferably CH ２ C≡CMe, CH ２ C≡C ｃ It is Pr, R3 is C2-C4 alkyl, C2-C4 alkenyl, C2-C3 alkynyl, CH ２ or CH ２ CH ２ C3-C6 cycloalkyl groups, CH3, CH4, CH4, CH3 may be crosslinked. ２ or CH ２ CH ２ CH may be crosslinked ２ C3-C6 cycloalkyl groups linked by or CHMe, CH ２ or CH ２ CH ２ C5-C6 cycloalkenyls, CH2, which may be crosslinked. ２ or CH ２ CH ２ CH may be crosslinked ２ C5-C6 cycloalkenyls, C5-C8 spiroalkanes, CH5-C8 spiroalkanes linked by or CHMe, CH ２ These are C5-C8 spiroalkanes linked by or CHMe, all of which encompass all possible isomers, and all of which are D, F, CN, Me, CD. ３ ,cPr,OH,OCD ３ , OCH ｎ F （３－ｎ） (n=0-3), CH ２ OH, CHMeOH, CH ２ OCD ３ ,CH ２ OCH ｎ F （３－ｎ） (n=0-3), CHMeOCD ３ CHMeOCH ｎ F （３－ｎ） (n=0-3), CO ２ Me, CO ２ CD ３ It is also possible that one or more of these are substituted, and all of them are O, S, SO ２ , NH, NMe, NCD ３ , C(O), N=OH, N=OMe, N=OCD ３ It may have one or more methylene units that are replaced by Z is S, CH ２ , CHMe, preferably S, X is CH, CF, CCl, Y is CH, CF, preferably CH. W is CH, N, U is CH. The compound according to claim 7.

33. A compound selected from Tables 1 to 10.

34. A compound selected from Table 7.

35. Compounds selected from Table 1 and Table 2.

36. Compounds selected from Table 3 and Table 4.

37. Compounds selected from Table 5 and Table 6.

38. A compound selected from Table 6.

39. A compound selected from Tables 8 to 10.

40. A compound selected from Table 10.

41. Compounds selected from Table 8 and Table 9.

42. Compounds selected from Table 6 and Table 8.

43. A pharmaceutical composition comprising, preferably in a pharmaceutically acceptable unit dose, a compound according to any one of claims 1 to 42, or a pharmaceutically acceptable salt, hydrate, or stereoisomer thereof, and a pharmaceutically acceptable carrier or excipient.

44. A method for inhibiting ribosome biosynthesis, inducing p53, or inhibiting cancer cells, comprising administering a compound according to any one of claims 1 to 42 to a person in need thereof.

45. A method for treating a disease or condition including cancer, tumor or neoplasia, comprising administering to a person in need thereof a compound according to any one of claims 1 to 42, for example, the cancer, tumor or neoplasia including breast cancer, lung cancer, colorectal cancer, ovarian cancer, bladder cancer, kidney cancer, esophageal cancer, gastric cancer, cervical cancer, head and neck cancer, liver cancer, prostate cancer, pancreatic cancer, sarcoma, melanoma, leukemia, lymphoma, brain cancer, skin cancer (melanoma), thyroid cancer, testicular cancer, and multiple myeloma.

46. The method according to claim 44 or 45, further comprising a preceding step of detecting or diagnosing a disease or condition that indicates such need, and / or a subsequent step of detecting the resulting improvement or delay in the progression of the disease or condition.

47. A method for screening candidate therapeutic agents for treating cancer, comprising assaying for an inhibitor or NVL2.

48. A cell line for which cancer therapeutics are being evaluated contains a mutant NVL gene sufficient to provide MM017 resistance and expresses it, preferably one or more mutations within the D1 AAA+ ATPase domain, for example, NVL Ｐ３０７Ｔ NVL Ｒ４０３Ｗ or NVL Ｈ３０４Ｒ Cell lines that include this.

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