Small molecule inhibitors of ribosome biosynthetic factor NVL2

Abstract

Described are dibenzothiazaone and dibenzoazaone-based compounds, including small molecule inhibitors of ribosomal biosynthesis factor NVL2, related pharmaceutical compositions, methods of inhibiting ribosomal biosynthesis, inducing p53, or inhibiting cancer cells, and methods of screening for candidate therapeutic agents for the treatment of cancer, for use in the treatment of cancer.

Description

[0001] Cross-references to related applications

[0002] This application claims priority to U.S. Provisional Application No. 63 / 507,089, filed June 8, 2023, the disclosure of which is hereby incorporated in its entirety by reference for all purposes.

[0003] introduction

[0004] Ribosomes are large ribonucleoprotein (RNP) complexes composed of a small 40S subunit and a large 60S subunit, responsible for translating proteins from messenger RNA. The synthesis of both 40S and 60S ribosomes requires approximately 200 ribosomal biosynthetic factors (RBFs). A significant portion of these factors are responsible for the hierarchical assembly of ribosomes, including rRNA processing and modification enzymes, structural proteins that serve as templates for assembly steps, and various ATPases that remodel rRNA or actively remove RBFs at key points to guide ribosome maturation (1-3).

[0005] Ribosome abundance and translational activity are closely related to cell growth rate, and dysregulation of ribosome biosynthesis can directly predict changes in the cell cycle. The accumulation of assembly intermediates resulting from ribosome biosynthesis inhibition triggers specific cellular checkpoints (4,5). This process is initiated by 5SRNP modules that are not bound to the pre-60S nucleolar intermediate (6,7). Unbound 5SRNPs adopt a conformation that binds to and inhibits MDM2 (8,9), an E3 ubiquitin ligase that constitutively ubiquitinates p53, leading to its degradation by the proteasome (5). Thus, 5SRNP inhibition of MDM2 leads to increased p53 protein levels. Transcriptional activation of p53 target genes then triggers cell cycle arrest, senescence, or apoptosis (10). Cancer cells have long been known to perform ribosome biosynthesis at significantly enhanced levels to support the synthesis of proteins required for uncontrolled cell growth. Therefore, ribosome biosynthesis inhibitors have the potential to block cancer growth and trigger checkpoints leading to p53-dependent cancer cell death (8,11-13).

[0006] Despite the many small molecules that block ribosome biogenesis, these molecules have other cytotoxic targets, making it difficult to determine the therapeutic potential of targeting ribosome biogenesis. For example, many cancer chemotherapy drugs that trigger DNA damage, including 5-fluorouracil, doxorubicin, and camptothecin, have also been reported to inhibit ribosome biogenesis (14). Similarly, oxaliplatin uniquely induces changes in nucleolar morphology that occur simultaneously with the blockade of ribosome biogenesis (15-18). However, like its related analogs cisplatin and carboplatin, oxaliplatin also causes the formation of DNA adducts that trigger DNA damage response pathways. Recent studies have provided evidence that the ability of oxaliplatin to impede ribosome production can be critical to its anticancer activity (19). However, because oxaliplatin also causes DNA damage, it is difficult to determine the contribution of DNA damage and ribosome biogenesis inhibition to therapeutic benefit and toxic side effects, respectively. Work to develop more selective inhibitors of ribosome biogenesis has focused on inhibiting RNA polymerase I, which is responsible for transcribing ribosomal RNA. Unfortunately, the most advanced of these compounds, CX-5461, also induces DNA damage by inhibiting topoisomerase TOP2B, which raises the possibility that its anticancer activity is achieved through this latter target (20).

[0007] As an alternative to inhibition of POL1, the assembly stage of ribosome biogenesis contains many enzymes that are theoretically targetable by small molecules. ATP hydrolysis coupled to the mechanical removal of specific ribosome biogenesis factors is a critical step in the assembly of the large ribosomal subunit (60S). Ribosome assembly and maturation is mediated by several catalytic AAA+ ATPases, including NVL, MDN1, and SPATA5 (2, 25-28). Small molecules that disrupt AAA+ ATPase function in the 60S biogenesis process have been characterized in the budding yeast (S. cerevisiae) Drg1 (2, 29, 30) and fission yeast (S. pombe) Mdn1 (31), but no chemical inhibitors of the homologous mammalian enzymes have been reported. SUMMARY

[0009] The present invention provides small molecule inhibitors of the ribosome biogenesis factor NVL2.

[0010] In one aspect, the present invention provides a compound of Formula (I) or a salt, hydrate, or stereoisomer thereof:

[0011]

[0012] wherein:

[0013] R1 is selected from: R3; -C(O)R3; -C(S)R3; -C(O)NHR3; -C(S)NHR3; -C(O)NR5R6; -C(S)NR5R6;

[0014] R2 is selected from: C1-C8 alkyl; C2-C8 alkenyl; C2-C8 alkynyl, including all its isomers and all such groups are optionally substituted by one or more of the following groups: D, F, OH, C(O)NHR4, and all such groups are optionally replaced by one or more methylene units replaced by O, S, NH, NR4, C(O);

[0015] R3is selected from the group consisting of: C1-C7alkyl, C3-C7cycloalkyl optionally bridged by CH2or CH2CH2, CH2linked or CHMe linked C3-C7cycloalkyl optionally bridged by CH2or CH2CH2, C2-C7alkenyl, C5-C7cycloalkenyl optionally bridged by CH2or CH2CH2, CH2linked or CHMe linked C5-C7cycloalkenyl optionally bridged by CH2or CH2CH2, C2-C7alkynyl, bridged or fused C5-C9cycloalkyl, CH2linked or CHMe linked bridged or fused C5-C9cycloalkyl, C5-C10spiroalkane, CH2linked or CHMe linked C5-C10spiroalkane, all of which include all possible isomers thereof and all of which are optionally substituted by one or more of the following: D, F, CN, R4, OR4, OH, NHC(O)H, NHC(O)R4, NHSO2R4, CO2H, CO2R4, C(O)NH2, C(O)NHR4, C(O)NR4R4and all of which are optionally have one or more methylene units replaced by O, S, SO2, S(O), NH, NR4, NC(O)H, NC(O)R4, NSO2R4, C(O), C=NOH, C=NOR4or C=NR4, phenyl or naphthyl (optionally substituted at one or more of the positions by R7), 5- and 6-membered heteroaryl and fused heteroaryl, including but not limited to oxazole, isoxazole, thiazole, isothiazole, furan, thiophene, pyrazole, imidazole, triazole, tetrazole, pyridine, pyrimidine, pyrazine, pyridazine, quinoline, isoquinoline, quinazoline, quinoxaline, cinnoline, phthalazine, naphthylidine, pyridopyrazine, pyrazolopyridine, pyridopyrimidine, pyridopyridazine, benzoxazole, benzoisoxazole, benzothiazole, benzoisothiazole, indole, indazole, benzoimidazole, dioxolopyridine, dioxolopyridazine, dioxolopyrimidine, dioxolopyrazine, benzofuran, benzothiophene, imidazopyridine, benzodioxolane, benzoxazolone, benzoisoxazolone, benzothiazolone, benzoisothiazolone, 1,3-dihydro-2H-benzimidazole, benzo[d]imidazol-2-one, benzodioxolone, dioxolopyridine, dioxolopyridazine, dioxolopyrimidine, dioxolopyrazine, coumarin, isocoumarin, and including all possible isomers thereof, and all of which are optionally substituted at one or more of the positions by R7;

[0016] R4is selected from the group consisting of: Me; Et; Pr; iPr; cPr; cBu, optionally substituted by one or more of the following: D, F, CN, OH, OCD3, OCH n F (3-n) (n=0-3);

[0017] NR5R6 constitutes a 4- to 7-membered nitrogen heterocycle, a bridged or fused 6- to 9-membered nitrogen heterocycle, or a 5- to 9-membered azeosylane, including all possible isomers, and all such groups are optionally substituted with one or more of the following groups: 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 such groups optionally have one or more methylene units replaced with O, S, SO2, NH, NR4, NC(O)H, NC(O)R4, NSO2R4, C(O), C=NOH, C=NR4;

[0018] R7 is selected from: D, F, Cl, Br, CN, N3, OH, OR4, R4, oxetane, 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, including all its isomers, and all such groups are optionally substituted by one or more of the following groups: D, F, CN, OH, and all such groups are optionally substituted with one or more methylene units replaced by O, S, S(O), SO2, NH, NR4, NC(O)H, NC(O)R4, NSO2R4, C(O), C=NOH, C=NR4; aryl or 5- or 6-membered heteroaryl or heterocyclic, all such groups are optionally substituted by one or more of the following groups: D, F, Cl, CN, R4, OH, OR4;

[0019] 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;

[0020] X is selected from: CH, CD, CF, CCl, CCN;

[0021] Y is selected from: CH, CD, CF, CCl;

[0022] U and W are independently selected from: CH, CD, N;

[0023] Excluding R1=C(O)furan-3-yl, X, Y, U, W=CH, Z=S, R2=(CH2)2OMe (MM017).

[0024] In the implementation scheme, the present invention provides:

[0025] 2. The compound of claim 1, further comprising a compound of formula II:

[0026] .

[0027] 3. The compound of claim 1, further comprising a compound of formula III:

[0028] .

[0029] 4. The compound of claim 1, further comprising a compound of formula IV:

[0030] .

[0031] 5. The compound of claim 1, further comprising a compound of formula V:

[0032] .

[0033] 6. The compound of claim 1, further comprising a compound of formula VI:

[0034] .

[0035] 7. The compound of claim 1, further comprising a compound of formula VII:

[0036] .

[0037] 8. The compound of claim 1, further comprising a compound of formula VIII:

[0038] .

[0039] 9. The compound according to claims 1-8, wherein Z = S, CH2, CD2, CHMe, CHCD3, CDMe, CDCD3, CHCN, CDCN, CMeOH, CCD3OH, preferably S, CH2, CHMe, CHCD3.

[0040] 10. The compound according to claims 1-8, wherein X = CH, CD, CF, CCl, CCN, preferably CH, CF or CCl.

[0041] 11. The compound according to claims 1-8, wherein Y = CH, CD, CF, CCl, preferably CH or CF.

[0042] 12. The compounds of claims 1-8, wherein W = CH, CD, N.

[0043] 13. The compound according to claims 1-8, wherein U = CH, CD, N, preferably CH.

[0044] 14. The compound of claims 1-8, wherein R2 = C2-C7 alkyl; C3-C7 alkenyl; C3-C7 alkynyl, including all its isomers, and all such groups are optionally substituted by one or more of the following groups: D, F, Cl, and all such groups are optionally replaced by one or more methylene units replaced by O.

[0045] 15. The compounds of claims 1-8, wherein R2=CH2C≡CH, CH2C≡CR4, CH2C≡CCl, CH2CH=CH2, CH2CH=CHR4, (CH2)2OR4, (CH2)2OCH2C≡CH, wherein R2 may contain one or more deuterium.

[0046] 16. The compound according to claims 1-8, wherein R2 = CH2C≡CH, CH2C≡CMe, CH2C≡CCH2F, CH2C≡C c Pr, CH2C≡CCl, CH2CH=CHMe, CH2C≡CCF3, where R2 may contain one or more deuteriums.

[0047] 17. The compound according to claims 2-3, wherein:

[0048] R2=CH2C≡CH, CH2C≡CMe, CH2C≡CCH2F, CH2C≡CCl, CH2C≡C c Pr, CH2CH=CHMe, where R2 may contain one or more deuteriums;

[0049] NR5R6 constitutes a 4- to 7-membered nitrogen heterocycle, a bridged or fused 6- to 9-membered nitrogen heterocycle, or a 5- to 9-membered nitrogen spiroalkane, including all possible isomers thereof, and all such groups are optionally substituted with one or more of the following groups: 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 such groups optionally have one or more methylene units replaced with O, S, SO2, NH, NR4, NC(O)H, NC(O)R4, NSO2R4, C(O), C=NOH, C=NR4;

[0050] R4 = Me; Et; Pr; iPr; cPr; cBu, which may optionally be substituted with one or more of the following groups: D, F, CN, OH, OCD3, OCH n F (3-n) (n=0-3);

[0051] Z = S, CH2, CHMe, CHCD3, CHCN, CMeOH, CCD3OH, with S, CH2, CHMe, and CHCD3 being preferred;

[0052] X = CH, CD, CF, CCl;

[0053] Y = CH, CD, CF;

[0054] W=CH, N; and

[0055] U = CH, CD, N, with CH being the preferred choice.

[0056] 18. The compound according to claims 2-3, wherein:

[0057] R2=CH2C≡CH, CH2C≡CMe, CH2C≡CCH2F, CH2C≡CCl, CH2C≡C c Pr, preferably CH2C≡CHMe, CH2C≡C c Pr;

[0058] NR5R6 constitutes a 4- to 7-membered nitrogen heterocycle, a 6- to 8-membered nitrogen heterocycle, or a 5- to 7-membered azeosylane, all of which are optionally substituted by one or more of the following groups: D, F, CN, R4, OR4, OH, and all of these groups are optionally substituted with one or more methylene units replaced by O, S, SO2, NH, NR4, C(O), C=NOH, C=NR4;

[0059] R4 = Me; Et; Pr; iPr; cPr; cBu, which may optionally be substituted with one or more of the following groups: D, F, CN, OH, OCD3, OCH n F (3-n) (n=0-3);

[0060] Z = S, CH2, CHMe, CHCD3, CHCN, CMeOH, CCD3OH, with S, CH2, CHMe, and CHCD3 being preferred;

[0061] X = CH, CF, CCl;

[0062] Y=CH、CF;

[0063] W=CH, N; and

[0064] U = CH, N, CH is preferred.

[0065] 19. The compound of claim 4, 5 or 8, wherein:

[0066] R2=CH2C≡CH, CH2C≡CMe, CH2C≡CCH2F, CH2C≡CCl, CH2C≡C c Pr, CH2CH=CHMe, where R2 may contain one or more deuteriums;

[0067] R3 = phenyl (optionally substituted with R7 at one or more positions); 5-membered and 6-membered heteroaryl and fused heteroaryl, including but not limited to oxazole, isoxazole, thiazole, isothiazole, furan, thiophene, pyrazole, imidazole, triazole, tetrazolium, pyridine, pyrimidine, pyrazine, pyridazine, quinoline, isoquinoline, quinazoline, quinoxaline, phthaloline, phthalazine, naphthidine, pyridopyrazine, pyrazolopyridine, pyridopyrimidine, pyridopyridazine, benzoxazole, benzoisoxazole, benzothiazole, benzoisothiazole, indole, indazole, benzimidazole, dioxacyclopentenpyridine, dioxacyclopentenpyridazine, Dioxacyclopentenpyrimidine, dioxacyclopentenpyrazine, benzofuran, benzothiophene, imidazopyridine, benzodioxolane, benzoxazolone, benzoisoxazolone, benzothiazolidinone, benzoisothiazolidinone, 1,3-dihydro-2H-benzimidazole, benzo[d]imidazolidin-2-one, benzodioxolane, dioxacyclopentenpyrazine, dioxacyclopentenpyrimidine, dioxacyclopentenpyrazine, coumarin, isocoumarin, and all its possible isomers, wherein all such groups are optionally substituted with R7 at one or more positions in each position;

[0068] R7=D, F, Cl, Br, CN, N3, OH, R4, OR4, C≡CH, NHC(O)H, C(O)NH2, C(O)NHR4, C(O)NR4R4;

[0069] R4 = Me; Et; Pr; iPr; cPr; cBu, which may optionally be substituted with one or more of the following groups: D, F, CN, OH, OCD3, OCH n F (3-n) (n=0-3);

[0070] Z = S, CH2, CHMe, CHCD3, CHCN, CMeOH, CCD3OH, with S, CH2, CHMe, and CHCD3 being preferred;

[0071] X = CH, CF, CCl;

[0072] Y=CH、CF;

[0073] W=CH, N; and

[0074] U = CH, N, CH is preferred.

[0075] 20. The compound of claim 4, 5 or 8, wherein:

[0076] R2=CH2C≡CH, CH2C≡CMe, CH2C≡CCH2F, CH2C≡CCl, CH2C≡C c Pr, preferably CH2C≡CMe, CH2C≡C c Pr;

[0077] R3 = a mono- or di-substituted benzene ring having a substituent selected from H, D, or F at the ortho position and a substituent selected from H, D, F, Cl, R4, OR4, N3, C≡CH at the meta and para positions; a heteroaromatic ring selected from furan, pyridine, pyrimidine, pyrazine, pyridazine, benzo[d]oxazol-5-yl, benzo[d]thiazo-5-yl, 2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl, benzo[d][1,3]dioxopentane-5-yl, and all such groups are optionally substituted at one or more positions in each position by H, D, F, Cl, CCH, R4, OR4;

[0078] R4 = Me; Et; Pr; iPr; cPr; cBu, which may optionally be substituted with one or more of the following groups: D, F;

[0079] Z = S, CH2, CHMe, CHCD3, CHCN, CMeOH, CCD3OH, with S, CH2, CHMe, and CHCD3 being preferred;

[0080] X = CH, CF, CCl;

[0081] Y=CH、CF;

[0082] W=CH, N; and

[0083] U = CH, N, CH is preferred.

[0084] 21. The compound of claim 4, 5 or 8, wherein:

[0085] R2=CH2C≡CH, CH2C≡CMe, CH2C≡CCH2F, CH2C≡CCl, CH2C≡C c Pr, CH2CH=CHMe, where R2 may contain one or more deuteriums;

[0086] R3 = C1-C7 alkyl, C3-C7 cycloalkyl optionally bridged by CH2 or CH2CH2, C3-C6 cycloalkyl optionally bridged by CH2 or CH2CH2, C2-C7 alkenyl, C5-C6 cycloalkenyl optionally bridged by CH2 or CH2CH2, C5-C6 cycloalkenyl optionally bridged by CH2 or CH2CH2, C2-C7 ynyl, bridged or fused C5-C9 cycloalkyl, bridged or fused C5-C9 cycloalkyl via CH2 or CH2CH2, C5-C10 spiroalkyl, CH2-linked or CH2CH2-linked... Me-linked C5-C10 spiroanes, all of which include all their possible isomers, and all of which are optionally substituted with one or more of the following groups: 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 are optionally substituted with one or more methylene units in the form of O, S, SO2, S(O), NH, NR4, NC(O)H, NC(O)R4, NSO2R4, C(O), C=NOH, C=NOR4 or C=NR4;

[0087] R4 = Me; Et; Pr; iPr; cPr; cBu, which may optionally be substituted with one or more of the following groups: D, F, OH, OCD3, OCH n F (3-n) (n=0-3);

[0088] Z = S, CH2, CHMe, CHCD3, CHCN, CMeOH, CCD3OH, with S, CH2, CHMe, and CHCD3 being preferred;

[0089] X = CH, CF, CCl;

[0090] Y=CH、CF;

[0091] W=CH, N; and

[0092] U = CH, N, CH is preferred.

[0093] 22. The compound of claim 6, wherein:

[0094] R2=CH2C≡CH, CH2C≡CMe, CH2C≡CCH2F, CH2C≡CCl, CH2C≡C c Pr, CH2CH=CHMe, CH2=CHEt, CH2CH=CHPr, (CH2)2OCH2CCH, wherein R2 may contain one or more deuteriums;

[0095] R3 = phenyl (optionally substituted with R7 at one or more positions); 5-membered and 6-membered heteroaryl and fused heteroaryl, including but not limited to oxazole, isoxazole, thiazole, isothiazole, furan, thiophene, pyrazole, imidazole, triazole, tetrazolium, pyridine, pyrimidine, pyrazine, pyridazine, quinoline, isoquinoline, quinazoline, quinoxaline, phthaloline, phthalazine, naphthidine, pyridopyrazine, pyrazolopyridine, pyridopyrimidine, pyridopyridazine, benzoxazole, benzoisoxazole, benzothiazole, benzoisothiazole, indole, indazole, benzimidazole, dioxacyclopentenpyridine, dioxacyclopentenpyridazine, Dioxacyclopentenpyrimidine, dioxacyclopentenpyrazine, benzofuran, benzothiophene, imidazopyridine, benzodioxolane, benzoxazolone, benzoisoxazolone, benzothiazolidinone, benzoisothiazolidinone, 1,3-dihydro-2H-benzimidazole, benzo[d]imidazolidin-2-one, benzodioxolane, dioxacyclopentenpyrazine, dioxacyclopentenpyrimidine, dioxacyclopentenpyrazine, coumarin, isocoumarin, and all its possible isomers, wherein all such groups are optionally substituted with R7 at one or more positions in each position;

[0096] R7=D, F, Cl, Br, CN, N3, OH, R4, OR4, C≡CH, NHC(O)H, C(O)NH2, C(O)NHR4, C(O)NR4R4;

[0097] R4 = Me; Et; Pr; iPr; cPr; cBu, which may optionally be substituted with one or more of the following groups: D, F, CN, OH, OCD3, OCH n F (3-n) (n=0-3);

[0098] Z = S, CH2, CHMe, CHCD3, CHCN, CMeOH, CCD3OH, with S, CH2, CHMe, and CHCD3 being preferred;

[0099] X = CH, CF, CCl;

[0100] Y=CH、CF;

[0101] W=CH, N; and

[0102] U = CH, N, CH is preferred.

[0103] 23. The compound of claim 6, wherein:

[0104] R2=CH2C≡CH, CH2C≡CMe, CH2C≡CCH2F, CH2C≡CCl, CH2C≡C cPr, CH2CH=CHMe, CH2=CHEt, CH2CH=CHPr;

[0105] R3 = 5- and 6-membered heteroaryl groups, including but not limited to pyrazole, imidazole, pyridine, pyrimidine, pyrazine, pyridazine, quinoline, isoquinoline, quinazoline, quinoxaline, cyclophosphine, phthalazine, and all their possible isomers, and all these groups are optionally replaced at one or more positions by D, F, Cl, CN, Me, cPr, CD3, OCD3, OH, OCH. n F (3-n) (n=0-3) Replace;

[0106] Z = S, CH2, CHMe, CHCD3, CHCN, CMeOH, CCD3OH, with S, CH2, CHMe, and CHCD3 being preferred;

[0107] X = CH, CF, CCl;

[0108] Y=CH、CF;

[0109] W=CH, N; and

[0110] U = CH, N, CH is preferred.

[0111] 24. The compound of claim 6, wherein:

[0112] R2=CH2C≡CH, CH2C≡CMe, CH2C≡CCH2F, CH2C≡CCl, CH2C≡C c Pr, preferably CH2C≡CHMe, CH2C≡C c Pr;

[0113] R3 = pyrazole, pyridine, pyrimidine, pyrazine, pyridazine, all of which may optionally be replaced by D, F, Cl, CN, Me, cPr, CD3, OCD3, OH, OCH at one or more of the respective positions. n F (3-n) (n=0-3) Replace;

[0114] Z = S, CH2, CHMe, CHCN, CMeOH, with S, CH2, and CHMe being preferred;

[0115] X = CH, CF, CCl;

[0116] Y=CH、CF;

[0117] W=CH, N; and

[0118] U = CH, N, CH is preferred.

[0119] 25. The compound of claim 6, wherein:

[0120] R2=CH2C≡CH, CH2C≡CMe, CH2C≡CCH2F, CH2C≡CCl, CH2C≡C c Pr, where R2 may contain one or more deuteriums;

[0121] R3 = C2-C4 alkyl, C2-C4 alkenyl, C3-C6 cycloalkyl optionally bridged by CH2 or CH2CH2, C3-C6 cycloalkyl optionally bridged by CH2 or CH2CH2 (CH2-linked or CHMe-linked), C5-C6 cycloalkenyl optionally bridged by CH2 or CH2CH2 (CH2-linked or CHMe-linked), C5-C8 spiroalkyl, C5-C8 spiroalkyl optionally bridged by CH2 or CHMe, and all such groups are optionally substituted by one or more of the following groups: D, F, CN, OH, R4, OCD3, OCH n F (3-n) (n=0-3), and all of these groups may optionally have one or more methylene units replaced by O, S, SO2, S(O), NH, NR4, NC(O)H, NC(O)R4, NSO2R4, C(O), C=NOH, C=NOR4 or C=NR4;

[0122] R4 = Me; Et; Pr; iPr; cPr; cBu, which may optionally be substituted with one or more of the following groups: D, F, OH, OCD3, OCH n F (3-n) (n=0-3);

[0123] Z = S, CH2, CHMe, CHCD3, CHCN, CMeOH, CCD3OH, with S, CH2, CHMe, and CHCD3 being preferred;

[0124] X = CH, CF, CCl;

[0125] Y=CH、CF;

[0126] W=CH, N; and

[0127] U = CH, N, CH is preferred.

[0128] 26. The compound according to claims 17-18, wherein:

[0129] R2=CH2C≡CMe, CH2C≡CCD3, CH2C≡CCH2F, CH2C≡C cPr, CH2C≡CCl, CH2C≡CH, preferably CH2C≡CMe, CH2C≡C c Pr;

[0130] NR5R6=N-linked azacyclobutane, pyrrolidine, piperidine, azacyclobutane, which are optionally substituted with one or more of the following groups: D, F, CN, R4, OR4, OH and optionally bridged by CH2 or CH2CH2, and all of these groups optionally have one or more methylene units replaced by O, NR4, N=OH, NOMe, N=OCD3;

[0131] R4 = Me, cPr, which may optionally be substituted with one or more of the following groups: D, F, CN, OH, OCD3, OCH n F (3-n) (n=0-3);

[0132] Z = S, CH2, CHMe, with S being the preferred choice;

[0133] X = CH, CF, CCl;

[0134] Y=CH, F, CH is preferred;

[0135] W=CH, N; and

[0136] U=CH.

[0137] 27. The compound according to claims 22-24, wherein:

[0138] R2=CH2C≡CMe, CH2C≡CCD3, CH2C≡C c Pr, CH2C≡CCH2F, CH2C≡CCl, CH2C≡CH, preferably CH2C≡CMe, CH2C≡C c Pr;

[0139] R3 = pyridine, pyrimidine, pyrazine, pyridazine, all of which may optionally be replaced by D, F, Cl, CN, Me, Et, iPr, cPr, OH, OCD3, OCH at one or more of the respective positions. n F (3-n) (n=0-3) Replace;

[0140] Z = S, CH2, CHMe, with S being the preferred choice;

[0141] X = CH, CF, CCl;

[0142] Y=CH, CF, CH is preferred;

[0143] W=CH, N; and

[0144] U=CH.

[0145] 28. The compound of claim 25, wherein:

[0146] R2=CH2C≡CMe, CH2C≡CCD3, CH2C≡C c Pr, CH2C≡CCH2F, CH2C≡CCl, CH2C≡CH, preferably CH2C≡CMe, CH2C≡C c Pr;

[0147] R3 = C2-C4 alkyl, C2-C4 alkenyl, C3-C6 cycloalkyl optionally bridged by CH2 or CH2CH2, C3-C6 cycloalkyl optionally bridged by CH2 or CH2CH2 (CH2-linked or CHMe-linked), C5-C6 cycloalkenyl optionally bridged by CH2 or CH2CH2 (CH2-linked or CHMe-linked), C5-C8 spiroalkyl, C5-C8 spiroalkyl (CH2-linked or CHMe-linked), all of these groups include all their possible isomers, and all of these groups are optionally substituted by one or more of the following groups: 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), and all of these groups may optionally have one or more methylene units replaced by O, S, SO2NH, NMe, NCD3, CO, N=OH, NOMe, N=OCD3;

[0148] Z = S, CH2, CHMe, with S being the preferred choice;

[0149] X = CH, CF, CCl;

[0150] Y=CH, CF, CH is preferred;

[0151] W=CH, N; and

[0152] U=CH.

[0153] 29. The compound of claim 20, wherein:

[0154] R2=CH2C≡CMe, CH2C≡CCD3, CH2C≡C cPr, CH2C≡CCH2F, CH2C≡CCl, CH2C≡CH, preferably CH2C≡CMe, CH2C≡C c Pr;

[0155] R3 = a mono- or di-substituted benzene ring having a substituent selected from H, D, or F at the ortho position and a substituent selected from H, D, F, Cl, R4, OR4, N3, C≡CH at the meta and para positions; a heteroaromatic ring selected from furan, pyridine, pyrimidine, pyrazine, pyridazine, benzo[d]oxazol-5-yl, benzo[d]thiazo-5-yl, 2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl, benzo[d][1,3]dioxopentane-5-yl, and all these groups are optionally replaced at one or more positions by H, D, F, Cl, Me, CD3, CPr, CCH, OCD3, OCH n F (3-n) (n=0-3) Replace;

[0156] Z = S, CH2, CHMe, with S being the preferred choice;

[0157] X = CH, CF, CCl;

[0158] Y=CH, CF, CH is preferred;

[0159] W=CH, N; and

[0160] U=CH.

[0161] 30. The compound of claim 21, wherein:

[0162] R2=CH2C≡CMe, CH2C≡CCD3, CH2C≡C c Pr, CH2C≡CCH2F, CH2C≡CCl, CH2C≡CH, preferably CH2C≡CMe, CH2C≡C c Pr;

[0163] R3 = C2-C4 alkyl, C2-C4 alkenyl, C2-C3 alkynyl, C3-C6 cycloalkyl optionally bridged by CH2 or CH2CH2, C3-C6 cycloalkyl optionally bridged by CH2 or CH2CH2 (CH2-linked or CHMe-linked), C5-C6 cycloalkenyl optionally bridged by CH2 or CH2CH2 (CH2-linked or CHMe-linked), C5-C8 spiroalkyl, C5-C8 spiroalkyl (CH2-linked or CHMe-linked), and all these groups include all their possible isomers, and all these groups are optionally substituted by one or more of the following groups: D, F, CN, Me, CD3, cPr, OH, OCD3, OCHn 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), CO2Me, CO2CD3, and all of these groups may optionally have one or more methylene units replaced by O, S, SO2, NH, NMe, NCD3, C(O), N=OH, NOMe, N=OCD3;

[0164] Z = S, CH2, CHMe, with S being the preferred choice;

[0165] X = CH, CF, CCl;

[0166] Y=CH, CF, CH is preferred;

[0167] W=CH, N; and

[0168] U=CH.

[0169] 31. The compound of claim 7, wherein:

[0170] R2=CH2C≡CMe, CH2C≡CCD3, CH2C≡C c Pr, CH2C≡CCH2F, CH2C≡CCl, CH2C≡CH, preferably CH2C≡CMe, CH2C≡C c Pr;

[0171] R3 = a mono- or di-substituted benzene ring having a substituent selected from H, D, or F at the ortho position and a substituent selected from H, D, F, Cl, R4, OR4, N3, C≡CH at the meta and para positions; a heteroaromatic ring selected from furan, pyridine, pyrimidine, pyrazine, pyridazine, benzo[d]oxazol-5-yl, benzo[d]thiazo-5-yl, 2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl, benzo[d][1,3]dioxopentane-5-yl, and all these groups are optionally replaced at one or more positions by H, D, F, Cl, Me, CD3, CPr, CCH, OCD3, OCH n F (3-n) (n=0-3) Replace;

[0172] Z = S, CH2, CHMe, with S being the preferred choice;

[0173] X = CH, CF, CCl;

[0174] Y=CH, CF, CH is preferred;

[0175] W=CH, N; and

[0176] U=CH.

[0177] 32. The compound of claim 7, wherein:

[0178] R2=CH2C≡CMe, CH2C≡CCD3, CH2C≡C c Pr, CH2C≡CCH2F, CH2C≡CCl, CH2C≡CH, preferably CH2C≡CMe, CH2C≡C c Pr;

[0179] R3 = C2-C4 alkyl, C2-C4 alkenyl, C2-C3 alkynyl, C3-C6 cycloalkyl optionally bridged by CH2 or CH2CH2, C3-C6 cycloalkyl optionally bridged by CH2 or CH2CH2 (CH2-linked or CHMe-linked), C5-C6 cycloalkenyl optionally bridged by CH2 or CH2CH2 (CH2-linked or CHMe-linked), C5-C8 spiroalkyl, C5-C8 spiroalkyl (CH2-linked or CHMe-linked), and all these groups include all their possible isomers, and all these groups are optionally substituted by one or more of the following groups: 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), CO2Me, CO2CD3, and all of these groups may optionally have one or more methylene units replaced by O, S, SO2, NH, NMe, NCD3, C(O), N=OH, NOMe, N=OCD3;

[0180] Z = S, CH2, CHMe, with S being the preferred choice;

[0181] X = CH, CF, CCl;

[0182] Y=CH, CF, CH is preferred;

[0183] W=CH, N; and

[0184] U=CH.

[0185] 33. A compound selected from Table 1-10.

[0186] 34. A compound selected from Table 7.

[0187] 35. A compound selected from Table 1-2.

[0188] 36. A compound selected from Table 3-4.

[0189] 37. A compound selected from Table 5-6.

[0190] 38. A compound selected from Table 6.

[0191] 39. A compound selected from Table 8-10.

[0192] 40. A compound selected from Table 10.

[0193] 41. A compound selected from Table 8-9.

[0194] 42. A compound selected from Tables 6 and 8.

[0195] 43. A pharmaceutical composition comprising the compound of claims 1-42 or a pharmaceutically acceptable salt, hydrate or stereoisomer thereof, and a pharmaceutically acceptable carrier or excipient, preferably in a pharmaceutically acceptable unit dose form.

[0196] 44. A method for inhibiting ribosome biosynthesis, inducing p53, or inhibiting cancer cells, comprising administering the compound of claims 1-42 to a person in need.

[0197] 45. A method of treating a disease or condition including cancer, tumor, or tumor formation, comprising administering to a person in need the compound of claims 1-42, such as said cancer, tumor, or tumor formation including breast cancer, lung cancer, colorectal cancer, ovarian cancer, bladder cancer, kidney cancer, esophageal cancer, stomach 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.

[0198] 46. ​​The method of claim 44 or 45, further comprising a preliminary step of detecting or diagnosing a disease or condition indicating its need, and / or a subsequent step of detecting a resultive improvement or delay in the progression of the disease or condition.

[0199] 47. A method for screening candidate therapeutic agents for treating cancer, comprising determining an inhibitor of NVL2.

[0200] 48. A cell line for evaluating cancer therapeutics, comprising and expressing a mutant NVL gene sufficient to induce resistance to MM017, preferably comprising one or more mutations within the D1 AAA+ ATPase domain, such as NVL P307T NVL R403W or NVL H304R .

[0201] This invention covers all combinations of the specific embodiments described herein, as each combination has been exhaustively listed.

[0202] Description of specific embodiments of the present invention

[0203] Unless otherwise prohibited or stated, in these descriptions and throughout this specification, the terms "a" and "an" mean "one or more," and the term "or" means "and / or." It should be understood that the embodiments and implementations described herein are for illustrative purposes only and are intended to inform those skilled in the art of various modifications or changes thereto, and such modifications or changes are included within the spirit and scope of this application and the appended claims. All publications, patents, and patent applications cited herein, including citations therein, are hereby incorporated in their entirety for all purposes.

[0204] The term "alkyl" refers to a hydrocarbon group selected from straight-chain 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 sec-butyl ("s-Bu"), and 1,1-dimethylethyl or tert-butyl ("t-Bu"). Other examples of alkyl groups include 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, and 3,3-dimethyl-2-butyl.

[0205] Lower alkyl groups are defined as having 1-8 carbon atoms, preferably 1-6, and more preferably 1-4 carbon atoms; lower alkenyl or alkynyl groups are defined as having 2-8, 2-6, or 2-4 carbon atoms.

[0206] The term "alkenyl" refers to a hydrocarbon group selected from straight-chain and branched hydrocarbon groups containing at least one C=C double bond and having 2 to 18, 2 to 12, or 2 to 6 carbon atoms. Examples of alkenyl groups may be selected from ethenyl or vinyl, propenyl, propenyl, 2-propenyl, 2-methylpropenyl, butenyl, butenyl, butenyl, 3-propenyl, butenyl, 2-methylbutenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, and 1,3-dienyl groups.

[0207] The term "alkynyl" refers to a hydrocarbon group selected from straight-chain and branched hydrocarbon groups containing at least one C≡C triple bond and having 2 to 18, 2 to 12, or 2 to 6 carbon atoms. Examples of alkynyl groups include ethynyl, 1-propynyl, 2-propynyl (propynyl), 1-butynyl, 2-butynyl, and 3-butynyl groups.

[0208] The term "cycloalkyl" refers to a hydrocarbon group 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 3-12, 3-8, or 3-6 carbon atoms. Even further, for example, a cycloalkyl group may be a monocyclic group with 3-12, 3-8, or 3-6 carbon atoms. Examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, and cyclododecyl groups. Examples of bicyclic cycloalkyl groups include those having 7-12 ring atoms arranged in a bicyclic system selected from [4,4], [4,5], [5,5], [5,6], and [6,6] ring systems, or bridged bicyclic systems arranged in a bicyclic [2.2.1]heptane, bicyclic [2.2.2]octane, and bicyclic [3.2.2]nonane. The ring may be saturated or have at least one double bond (i.e., partially unsaturated), but is not fully conjugated and is not aromatic as defined herein.

[0209] The term "aryl" as used herein refers to a group selected from: 5- and 6-membered carbocyclic aromatic rings, such as phenyl; bicyclic systems, such as 7- to 12-membered bicyclic systems, wherein at least one ring is carbocyclic and aromatic, selected from, for example, naphthalene, indane, and 1,2,3,4-tetrahydroquinoline; and tricyclic systems, such as 10- to 15-membered tricyclic systems, wherein at least one ring is carbocyclic and aromatic, such as fluorene.

[0210] For example, an aryl group is selected from 5- and 6-membered carbocyclic aromatic rings fused to 5- to 7-membered cycloalkyl groups or optionally containing at least one heteroatom selected from N, O, and S, provided that when the carbocyclic aromatic ring is fused to a heterocyclic ring, the connection point is at the carbocyclic aromatic ring, and when the carbocyclic aromatic ring is fused to a cycloalkyl group, the connection point can be at the carbocyclic aromatic ring or at the cycloalkyl group. A divalent group formed from a substituted benzene derivative and having a free valence on a ring atom is called a substituted phenylene group. A divalent group obtained by removing a hydrogen atom from a carbon atom and having a free valence from a monovalent polycyclic hydrocarbon group whose name ends with "-yl" can be named by adding "-yl" to the name of the corresponding monovalent group; for example, a naphthyl group with two connection points is called naphthylene. However, aryl does not encompass or overlap with heteroaryl, which is defined separately below. Therefore, if one or more carbocyclic aromatic rings are fused to a heterocyclic aromatic ring, the resulting ring system is a heteroaryl, not an aryl as defined herein.

[0211] The term "halogen" or "halogenated" refers to F, Cl, Br, or I.

[0212] The term "heteroalkyl" refers to an alkyl group containing at least one heteroatom.

[0213] The term "heteroaryl" refers to a group selected from the following:

[0214] A 5- to 7-membered aromatic monocyclic ring containing 1, 2, 3 or 4 heteroatoms selected from N, O and S, with the remaining ring atoms being carbon;

[0215] An 8- to 12-membered bicyclic ring containing 1, 2, 3, or 4 heteroatoms selected from N, O, and S, with the remaining ring atoms being carbon, wherein at least one ring is aromatic and at least one heteroatom is present in the aromatic ring; and

[0216] It is an 11- to 14-membered tricyclic ring containing 1, 2, 3, or 4 heteroatoms selected from N, O, and S, with the remaining ring atoms being carbon, and at least one of the rings being aromatic and at least one heteroatom present in the aromatic ring.

[0217] For example, heteroaryl groups include 5- to 7-membered heterocyclic aromatic rings fused to 5- to 7-membered cycloalkyl rings. For such fused bicyclic heterocyclic aromatic ring systems in which only one ring contains at least one heteroatom, the connection point can be at the heterocyclic aromatic ring or at the cycloalkyl ring.

[0218] When the total number of S and O atoms in a heteroaryl group exceeds 1, these 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 2. In some embodiments, the total number of S and O atoms in an aromatic heterocycle does not exceed 1.

[0219] Examples of heteroaryl groups include, but are not limited to (numbered from the linking position designated as priority 1), pyridyl (e.g., 2-pyridyl, 3-pyridyl, or 4-pyridyl), cyclolinyl, pyrazinyl, 2,4-pyrimidinyl, 3,5-pyrimidinyl, 2,4-imidazolyl, imidazopyridyl, isoxazolyl, oxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, tetrazolyl, thienyl, triazinyl, benzothiophene, furanyl, benzofuranyl, benzimidazolyl, indoleyl, isoyindolyl, inlinyl, phthalazinyl, pyrazinyl, pyrazinyl, pyrrololyl, triazolyl, quinolinyl, isoquinolinyl, pyrazolyl, pyrrolopyridyl (e.g., 1H-pyrrolo[2,3-b]pyridin-5-yl), pyrazolopyridyl (e.g., 1H-pyrazolopyridyl) [3,4]pyridin-5-yl), benzoxazolyl (e.g., benzo[d]oxazol-6-yl), pteridinyl, purinyl, 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, 1-thia-3,4-diazolyl, furazonyl, benzofurazanyl, benzothiopheneyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxolinyl, naphridinyl, furanpyridinyl, benzothiazolyl (e.g., benzo[d]thiazolyl-6-yl), indazoleyl (e.g., 1H-indazole-5-yl), and 5,6,7,8-tetrahydroisoquinoline.

[0220] 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, which contains 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 containing at least one heteroatom selected from N, O, and S, fused with a 5-, 6-, and / or 7-membered cycloalkyl, carbocyclic aromatic, or heteroaromatic ring, provided that the connection point is at the heterocycle when fused with the carbocyclic aromatic or heteroaromatic ring, and that the connection point can be at the cycloalkyl or heterocycle when fused with the cycloalkyl.

[0221] "Heterocycle" also refers to an aliphatic spirocycle containing at least one heteroatom selected from N, O, and S, provided that the bond site is located at the heterocycle. The ring can be saturated or have at least one double bond (i.e., partially unsaturated). The heterocycle can be substituted with an oxo group. The bond site can be a carbon or a heteroatom in the heterocycle. The heterocycle is not a heteroaryl group as defined herein.

[0222] Examples of heterocycles include, but are not limited to (numbered from the connection position designated as priority 1), 1-pyrrolidinyl, 2-pyrrolidinyl, 2,4-imidazolidinyl, 2,3-pyrazolyl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 2,5-piperazinyl, pyranyl, 2-morpholinyl, 3-morpholinyl, oxetanepropane, azirnepropane, thioheteropropane, azirnebutane, oxetanebutane, and thioheteropropane. Heterocyclic butyl, 1,2-dithiocyclic butyl, 1,3-dithiocyclic butyl, dihydropyridyl, tetrahydropyridyl, thiomorpholinyl, thioxanyl, piperazinyl, homopiperazinyl, homopiperidinyl, azirheptanyl, oxeheptyl, thioheptyl, 1,4-oxothioheptyl, 1,4-dioxeheptyl, 1,4-oxothioheptyl, 1,4-oxazirheptanyl 1,4-Dithioheptanyl, 1,4-thioazaheptanyl and 1,4-diazaheptanane, 1,4-dithiohexyl, 1,4-azathiohexyl, oxazheptenyl, diazaheptenyl, thioazaheptenyl, dihydrothiopheneyl, dihydropyranyl, dihydrofuranyl, tetrahydrofuranyl, tetrahydrothiopheneyl, tetrahydropyranyl, tetrahydrothiopyranyl, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl The substituted heterocycles include 1,4-dioxane-hexyl, 1,3-dioxane-pentyl, pyrazolinyl, pyrazolyl, dithiohexane, dithiohexane, pyrazolylimidazolinyl, pyrimidinone, 1,1-dioxo-thiomorpholinyl, 3-azabicyclo[3.1.0]hexyl, 3-azabicyclo[4.1.0]heptyl, and azabicyclo[2.2.2]hexyl. Substituted heterocycles also include cyclic systems substituted with one or more oxo moieties, such as piperidinyl N-oxide, morpholinyl-N-oxide, 1-oxo-1-thiomorpholinyl, and 1,1-dioxo-1-thiomorpholinyl.

[0223] Substituents are selected from: halogens, -R', -OR', =O, =NR', =N-OR', -NR'R", -SR', -SiR'R"R'", -OC(O)R', -C(O)R', -CO2R', -CONR'R", -OC(O)NR'R", -NR"C(O)R', -NR'-C(O)NR"R'", -NR'-SO2NR'", -NR"CO2R', -NH-C( The groups are NH2)=NH, -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, with the number of substituents ranging from 0 to 3, of which those 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 one to three halogens, unsubstituted alkyl, alkoxy or thioalkoxy group or aryl-(C1-C4)alkyl group. When R' and R'' are attached to the same nitrogen atom, they can combine with the nitrogen atom to form a 5-, 6- or 7-membered ring. Therefore, -NR′R″ includes 1-pyrrolidinyl and 4-morpholinyl, "alkyl" includes groups such as trihaloalkyl (e.g., -CF3 and -CH2CF3), and when the aryl group is 1,2,3,4-tetrahydronaphthalene, it can be substituted or unsubstituted with a (C3-C7) spirocycloalkyl group. The (C3-C7) spirocycloalkyl group can be substituted in the same manner as defined herein as "cycloalkyl".

[0224] 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, wherein R' and R'' are as defined above.

[0225] The term "fused ring" as used herein refers to a polycyclic system, such as a bicyclic or tricyclic system, in which the two rings share only two ring atoms and one common bond. Examples of fused rings may include fused bicyclic cycloalkyl rings, such as those having 7 to 12 ring atoms arranged in a ring system selected from the [4,4], [4,5], [5,5], [5,6], and [6,6] ring systems described above; fused bicyclic aryl rings, such as the 7- to 12-membered bicyclic aryl ring systems described above; fused tricyclic aryl rings, such as the 10- to 15-membered tricyclic aryl ring systems described above; fused bicyclic heteroaryl rings, such as the 8- to 12-membered bicyclic heteroaryl rings described above; fused tricyclic heteroaryl rings, such as the 11- to 14-membered tricyclic heteroaryl rings described above; and fused bicyclic or tricyclic heterocyclic rings described above.

[0226] Compounds may contain asymmetric centers and therefore may exist in enantiomers. When compounds have two or more asymmetric centers, they may also exist in diastereomers. Enantiomers and diastereomers belong to the broader category of stereoisomers. This is intended to include all such possible stereoisomers, such as substantially pure, separated enantiomers, their racemic mixtures, and mixtures of diastereomers. This is intended to include all stereoisomers of the said compound and / or its pharmaceutically acceptable salts. Unless otherwise specifically mentioned, one isomer mentioned applies to all possible isomers. When the isomer composition is not explicitly specified, all possible isomers are included.

[0227] The compounds of the present invention may also contain, at one or more atoms in the atoms constituting such compounds, atomic isotopes in non-natural proportions, such as deuterium, for example -CD3, CD2H, or CDH2, instead of methyl groups. For example, the compounds may use radioactive isotopes such as tritium ( 3 H), Iodine-125 ( 125 I) or carbon-14 ( 14 C) Radioactive labeling. All isotopic variants of the compounds of this invention, whether or not they are radioactive, are intended to be covered within the scope of this invention.

[0228] The term "substantially pure" means that the target stereoisomer contains no more than 35%, such as no more than 30%, further such as no more than 25%, or even further such as no more than 20%, any other (or more) stereoisomers by weight. In some embodiments, the term "substantially pure" means that the target stereoisomer contains no more than 10%, such as no more than 5%, such as no more than 1%, any other (or more) stereoisomers by weight.

[0229] When a compound contains an alkene double bond, unless otherwise specified, such a double bond means that it includes E and Z geometric isomers.

[0230] Some compounds can exist with different hydrogen bonding sites, a phenomenon known as tautomerism. For example, compounds containing a carbonyl group (CH₂C(O)-) (ketone form) may undergo tautomerism to form a hydroxyl group (CH=C(OH)-) (enol form). Where applicable, this is intended to include both ketone and enol forms, whether individually or mixtures thereof.

[0231] It may be advantageous to separate the 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 referred to as separation) to the required degree of homogeneity using techniques commonly used in the art. Typically, such separation involves multiphase extraction, crystallization from a solvent or solvent mixture, distillation, sublimation, or chromatography. Chromatography can involve any number of methods, including, for example: reversed-phase and normal-phase chromatography, size exclusion chromatography, ion exchange chromatography, high, medium, and low-pressure liquid chromatography methods and apparatus, small analytical chromatography, simulated moving bed chromatography (“SMB”), preparative thin-layer or thick-layer chromatography, and small thin-layer chromatography and rapid chromatography techniques. Those skilled in the art will apply the techniques most likely to achieve the desired separation.

[0232] A mixture of diastereomers can be separated into their respective diastereomers based on the physicochemical differences of the diastereomers using methods well known to those skilled in the art, such as chromatography and / or stepwise crystallization. Enantiomers can be separated by reacting the enantiomer mixture with a suitable optically active compound (e.g., a chiral auxiliary agent, such as a chiral alcohol or moselyl chloride), converting the diastereomers, and converting (e.g., hydrolyzing) individual diastereomers to their respective pure enantiomers. Enantiomers can also be separated by using a chiral HPLC column.

[0233] A single stereoisomer, for example, a substantially pure enantiomer, can be obtained by resolving a racemic mixture using methods such as forming diastereomers with an optically active resolving agent. Racemic mixtures of the chiral compounds of the present invention can be separated and isolated by any suitable method, including: (1) forming an ionic diastereomer salt with a chiral compound and separating it by stepwise crystallization or other methods; (2) forming a diastereomer compound with a chiral derivatizing agent, separating the diastereomer, and converting it to a pure stereoisomer; and (3) directly separating substantially pure or enriched stereoisomers under chiral conditions.

[0234] "Pharmaceutically acceptable salts" include, but are not limited to, salts formed with inorganic acids, such as those selected from hydrochlorides, phosphates, diphosphates, hydrobroms, sulfates, sulfites, and nitrates; and salts formed with organic acids, such as those selected from malates, maleates, fumarates, tartrates, succinates, citrates, lactates, methanesulfonates, p-toluenesulfonates, 2-hydroxyethylsulfonates, benzoates, salicylates, stearates, alkylates such as acetates, and salts formed with HOOC-(CH2) salts. n Salts formed from -COOH, where n is selected from 0 to 4. Similarly, pharmaceutically acceptable examples of cations include, but are not limited to, sodium, potassium, calcium, aluminum, lithium, and ammonium.

[0235] Furthermore, if the compound is obtained as an acid addition salt, its free base can be obtained by alkalizing a solution of the acid salt. Conversely, if the product is a free base, the addition salt, such as a pharmaceutically acceptable addition salt, can be prepared according to conventional methods for preparing acid addition salts from base compounds by dissolving the free base in a suitable organic solvent and treating the solution with acid. Those skilled in the art will recognize that non-toxic, pharmaceutically acceptable addition salts can be prepared using various synthetic methods without excessive experimentation.

[0236] "Treating," "treat," or "treatment" refers to administering at least one compound and / or at least one stereoisomer thereof and / or at least one pharmaceutically acceptable salt thereof to a subject who has a clear need for treatment.

[0237] "Effective amount" means the amount of at least one compound and / or at least one stereoisomer thereof, and / or at least one pharmaceutically acceptable salt thereof, which effectively "treats" the disease or condition of the subject and will elicit, to some degree, a biological or medical response in the desired tissue, system, animal, or human, such that, when administered, it is sufficient to prevent the development of one or more symptoms of the treated condition or disorder or to alleviate, to some extent, one or more symptoms of the treated condition or disorder. The therapeutically effective amount will vary depending on the compound, the disease and its severity, and the age, weight, etc., of the mammal to be treated.

[0238] The term "at least one substituent" includes, for example, 1 to 4, such as 1 to 3, and further such as 1 or 2 substituents. For example, "at least one substituent R" as used herein includes 1 to 4, such as 1 to 3, and further such as 1 or 2 substituents selected from the list of R described herein.

[0239] The subject compounds, their stereoisomers, and pharmaceutically acceptable salts can be used alone or in combination with at least one other therapeutic agent for treatment. In some embodiments, the compounds, their stereoisomers, and pharmaceutically acceptable salts can be used in combination with at least one additional therapeutic agent. The compounds and / or a pharmaceutically acceptable salt disclosed herein can be administered in a single dosage form or as separate dosage forms with at least one other therapeutic agent. When administered as separate dosage forms, the at least one other therapeutic agent can be administered before, simultaneously with, or after administration of the compounds and / or a pharmaceutically acceptable salt disclosed herein.

[0240] Compositions comprising the subject compound and its stereoisomers, pharmaceutically acceptable salts thereof, and at least one pharmaceutically acceptable carrier are also provided.

[0241] Compositions comprising the subject compound and its stereoisomers and pharmaceutically acceptable salts can be administered in a variety of known ways, such as orally, topically, rectally, parenterally, by inhalation spray, or via implanted receptacles, although the most appropriate route in any given case will depend on the specific host and the nature and severity of the condition to which the active ingredient is targeted. As used herein, the term “parenterally” includes subcutaneous, intradermal, intravenous, intramuscular, intra-articular, intra-articular, intrasynovial, intrasternal, intrathecal, intralesional, and intracranial injection or infusion techniques. The compositions disclosed herein can be readily available in unit dosage forms and prepared by any method well known in the art.

[0242] The subject compounds, their stereoisomers, and pharmaceutically acceptable salts may be administered orally in solid dosage forms such as capsules, tablets, lozenges, sugar-coated pills, granules, and powders, or in liquid dosage forms such as elixirs, syrups, emulsions, dispersants, and suspensions. The subject compounds, their stereoisomers, and pharmaceutically acceptable salts disclosed herein may also be administered parenterally in sterile liquid dosage forms such as dispersants, suspensions, or solutions. Other dosage forms that may be used to administer the subject compounds, their stereoisomers, and pharmaceutically acceptable salts include ointments, creams, drops, transdermal patches, or powders for topical administration, as well as ophthalmic solutions or suspensions, i.e., eye drops for ocular administration, aerosol sprays or powder compositions for inhalation or intranasal administration, or creams, ointments, sprays, or suppositories for rectal or vaginal administration.

[0243] Gelatin capsules containing compounds disclosed herein and / or at least one pharmaceutically acceptable salt thereof, and powdered carriers such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, etc., can also be used. Similar diluents can be used to manufacture compressed tablets. Both tablets and capsules can be formulated as sustained-release products to achieve sustained drug release over a period of time. Compressed tablets can be sugar-coated or film-coated to mask any unpleasant taste and protect the tablet from atmospheric effects, or enteric-coated for selective disintegration in the gastrointestinal tract.

[0244] Liquid dosage forms for oral administration may further contain at least one agent selected from colorants and flavorings to increase patient acceptance.

[0245] Typically, water, suitable oils, saline solutions, aqueous solutions of dextran (glucose) and related sugar solutions, as well as glycols such as propylene glycol or polyethylene glycol, can be examples of suitable carriers for parenteral solutions. Solutions for parenteral administration may contain a water-soluble salt of at least one of the compounds described herein, at least one suitable stabilizer, and, if necessary, at least one buffering substance. Antioxidants, alone or in combination, such as sodium bisulfite, sodium sulfite, or ascorbic acid, can be examples of suitable stabilizers. Citric acid and its salts, and sodium EDTA, can also be examples of suitable stabilizers. Furthermore, parenteral solutions may further contain at least one preservative, such as those selected from benzalkonium chloride, methylparaben, propylparaben, and chlorobutanol.

[0246] Pharmaceutically acceptable carriers, such as those selected from those compatible with the active ingredient of the composition (and, in some embodiments, capable of stabilizing the active ingredient) and harmless to the subject to be treated, are preferred. For example, solubilizers such as cyclodextrins (which can form specific, more soluble complexes with at least one compound disclosed herein and / or at least one pharmaceutically acceptable salt) can be used as pharmaceutical excipients for delivering the active ingredient. Examples of other carriers include colloidal silica, magnesium stearate, cellulose, sodium dodecyl sulfate, and pigments. Suitable pharmaceutically acceptable carriers are described in Remington's Pharmaceutical Sciences, A. Osol, and other references in the art.

[0247] For inhalation administration, the subject compound, its stereoisomers, and pharmaceutically acceptable salts can be conveniently delivered as aerosol sprays from pressurized packages or nebulizers. The subject compound, its stereoisomers, and pharmaceutically acceptable salts can also be delivered as powders, which can be formulated and inhaled using a dry powder inhaler device. An exemplary delivery system for inhalation may be a metered-dose inhalation (MDI) aerosol, which can be formulated as a suspension or solution of the subject compound, its stereoisomers, and pharmaceutically acceptable salts disclosed herein in at least one suitable propellant selected, for example, from fluorocarbons and hydrocarbons.

[0248] For ocular administration, ophthalmic preparations may be formulated in a solution or suspension of the subject compound and its stereoisomers and pharmaceutically acceptable salts in an appropriate weight percentage of a suitable ophthalmic solvent, such that the subject compound and its stereoisomers and at least one pharmaceutically acceptable salt remain in contact with the ocular surface for a sufficient time to allow the compound to penetrate the cornea and internal regions of the eye.

[0249] Useful pharmaceutical dosage forms for administering the subject compounds disclosed herein, their stereoisomers, and their pharmaceutically acceptable salts include, but are not limited to, hard and soft gelatin capsules, tablets, parenteral injections, and oral suspensions.

[0250] Dosage will depend on factors such as the recipient's age, health condition and weight, disease severity, type of concurrent treatment (if any), treatment frequency, and the nature of the desired effect. Typically, the daily dose of the active ingredient can vary, for example from 0.1 to 2000 mg daily. For example, 10-500 mg once or more daily may effectively achieve the desired results.

[0251] In some implementations, bulk unit capsules can be prepared by filling each standard two-piece hard gelatin capsule with, for example, 100 mg of the subject compound disclosed herein and its stereoisomers and their pharmaceutically acceptable salts in powder form, 150 mg of lactose, 50 mg of cellulose and 6 mg of magnesium stearate.

[0252] In some embodiments, a mixture of the compound, its stereoisomers, and pharmaceutically acceptable salts with a digestible oil such as soybean oil, cottonseed oil, or olive oil can be prepared and injected into gelatin using a positive displacement pump to form a soft gelatin capsule containing 100 mg of the active ingredient. The capsule is then washed and dried.

[0253] In some implementations, large quantities of tablets can be prepared using conventional procedures, such that each dosage unit contains, for example, 100 mg of the compound, its stereoisomers and pharmaceutically acceptable salts, 0.2 mg of colloidal silica, 5 mg of magnesium stearate, 275 mg of microcrystalline cellulose, 11 mg of starch and 98.8 mg of lactose. Appropriate coatings can be applied to improve palatability or delay absorption.

[0254] In some embodiments, parenteral compositions suitable for injection administration can be prepared by stirring 1.5% by weight of the disclosed compound and / or at least its enantiomers, diastereomers, or pharmaceutically acceptable salts in 10% by volume of propylene glycol. The solution is then prepared to the desired volume with water for injection and sterilized.

[0255] In some embodiments, an aqueous suspension can be prepared for oral administration. For example, an aqueous suspension containing 100 mg of finely divided compound, its stereoisomers and pharmaceutically acceptable salts, 100 mg of sodium carboxymethyl cellulose, 5 mg of sodium benzoate, 1.0 g of sorbitol solution (USP), and 0.025 mL of vanillin per 5 mL can be used.

[0256] When a compound, its stereoisomers, and its pharmaceutically acceptable salts are administered in a stepwise manner or in combination with at least one other therapeutic agent, the same dosage form can generally be used. When drugs are administered in a physical combination manner, the dosage form and route of administration should be selected based on the compatibility of the combined drugs. Therefore, the term co-administration should be understood to include the simultaneous or sequential administration of at least two agents, or alternatively, a fixed-dose combination of at least two active components.

[0257] The compounds disclosed herein, their stereoisomers, and pharmaceutically acceptable salts may be administered as the sole active ingredient or in combination with at least one second active ingredient.

[0258] The subject compound is incorporated into a pharmaceutical composition or formulation. The composition contains a pharmaceutically acceptable diluent and / or carrier, i.e., a physiologically compatible diluent or carrier substantially free of pathogenic impurities. Suitable excipients or carriers and methods for preparing the dosedable 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 most applications, the subject compound is administered in the morning / daytime and discontinued at night.

[0259] The subject compound can be used directly or in the form of its pharmaceutically acceptable salts, such as hydrochlorides, hydrobroms, acetates, sulfates, citrates, carbonates, trifluoroacetates, etc. When the compound contains a relatively acidic functional group, the salt can be obtained by adding the desired base, such as sodium carbonate or a base in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium salts, potassium salts, calcium salts, ammonium salts, organic amine salts, or magnesium salts. When the compound contains a relatively basic functional group, the salt can be obtained by adding the desired acid, such as a pure acid or an acid in a suitable inert solvent. Pharmaceutically acceptable examples of acid addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, 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, succinic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and methanesulfonic acid. Also included are amino acid salts such as arginine salts and organic acid salts such as glucuronides or galacturonides.

[0260] The neutral form of the compound can be regenerated by contacting the salt with a base or acid and separating the parent compound in a conventional manner. The parent form of the compound differs from the various salt forms in some physical properties, such as solubility in polar solvents, but otherwise, for the purposes of this invention, the salt is equivalent to the parent form of the compound.

[0261] In addition to salt forms, the present invention also provides compounds in prodrug form. Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to generate the compounds of the present invention. Furthermore, prodrugs can be converted into the compounds of the present invention in an in vitro environment by chemical or biochemical methods. For example, when placed in a transdermal patch reservoir containing suitable enzymes or chemical reagents, prodrugs can be slowly converted into the compounds of the present invention. Prodrugs are generally useful because, in some cases, they may be more readily administered than the parent drug. For example, they may have higher bioavailability than the parent drug when administered orally. The solubility of prodrugs in pharmacological compositions can also be improved compared to the parent drug. Various prodrug derivatives are known in the art, such as prodrug derivatives that depend on the hydrolytic cleavage or oxidative activation of the prodrug. A non-limiting example of a prodrug is a compound of the present invention, which is administered as an ester (“prodrug”) but subsequently metabolized and hydrolyzed into a carboxylic acid, i.e., the active entity.

[0262] Some compounds of the present invention may exist in both non-solventized and solvated forms (including hydrated forms). Generally, solvated forms are equivalent to non-solventized forms and are intended to be included within the scope of the present invention. Some compounds of the present invention may exist in a variety of crystalline or amorphous forms. Generally, all physical forms are equivalent for the intended uses of the present invention and are intended to fall within the scope of the present invention.

[0263] Some of the subject compounds have asymmetric carbon atoms (optical centers) or double bonds; racemates, diastereomers, geometric isomers and monomeric isomers are all intended to be included within the scope of this invention.

[0264] Compounds are typically administered at a “therapeutic effective amount,” which is the amount of the subject compound that elicits a biological or medical response in a tissue, system, animal, or human that is sought by a researcher, veterinarian, physician, or other clinician. The term “therapeutic effective amount” includes the amount of a compound, when administered, sufficient to prevent the development of one or more symptoms of the treated condition or disorder, or to alleviate to some extent one or more symptoms of the treated condition or disorder. Therapeutic effective amounts will vary depending on the compound, the disease and its severity, and the age, weight, etc., of the mammal being treated.

[0265] Contact is typically achieved by administering to the subject an effective amount of one or more compounds having chemical formulas described herein, including the various embodiments described above. Generally, the dosage is adjusted to achieve a therapeutic dose of about 0.1 to 50, preferably 0.5 to 10, more preferably 1 to 10 mg / kg, although the optimal dose varies depending on the compound and is generally determined empirically for each compound.

[0266] The term "unit dosage form" refers to a physically independent unit suitable as a unit dose for human subjects and other mammals, each unit containing a predetermined amount of active substance calculated to produce the desired therapeutic effect, and combined with suitable pharmaceutical excipients. Typical unit dosage forms include pre-filled, pre-quantitative ampoules or syringes of liquid compositions, or, in the case of solid compositions, pills, tablets, capsules, lozenges, etc. In such compositions, the mimic is typically a small amount of the ingredient (about 0.1% to about 50% by weight, or preferably about 1% to about 40% by weight), with the remainder being various solvents or carriers and processing aids that facilitate the formation of the desired dosage form. Unit dosage formulations are preferably about 5, 10, 25, 50, 100, 250, 500, or 1000 mg per unit. In one specific embodiment, the unit dosage form is packaged in multiple packages suitable for continuous use, such as blister packs containing at least 6, 9, or 12 unit dosage forms per sheet.

[0267] Example: Development of dibenzothiazones and dibenzothiazones as anticancer agents.

[0268] As part of phenotypic screening, we discovered a small molecule, a dibenzothiazolone called MM017, which is toxic to colorectal cancer cells. Using forward genetics, we showed that mutations in nucleovaline-like protein 2 (NVL2) lead to 30-fold resistance to MM017. NVL2 is an asymmetric hexameric AAA-ATPase protein that binds 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 localized to the compound-binding region and are crucial for compound binding. Most studies involving NVL2 have been conducted in yeast, so we developed an NVL2 degron system to investigate its function in colorectal cancer cells. Degradation of NVL2 resulted in reduced 60S ribosome production, as measured by polyribosomal profiling, consistent with reported NVL2 function in yeast. Furthermore, MM017 mimicked the phenotypic effects of NVL2 degradation, consistent with the hypothesis that binding leads to inhibition. Crucially, cells carrying binding site mutations did not exhibit any of these effects, confirming their targeting (due to NVL2 binding). We performed a PRISM analysis on MM017, which evaluated the potency and efficacy of 902 unique and deeply annotated cell lines. The selectivity of MM017 in these cell lines correlated most strongly with oxaliplatin and carmoflur (out of 1215 compounds). Carmoflur 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 carmoflur produce toxicity by blocking ribosome biosynthesis. Furthermore, the usefulness of these drugs in CRC supports the fundamental principles for testing MM017 in CRC models. Therefore, we developed an analogue of MM017, which was optimized for in vivo proof-of-concept studies to evaluate the tolerability, efficacy, and pharmacokinetic biomarkers of an inhibitor of NVL2-targeting ribosomal biosynthesis. We developed an optimized screening funnel that includes p53 / p21 upregulation, a known biomarker of stress induced by impaired ribosomal biosynthesis, as a targeted pharmacokinetic biomarker.

[0269] Compared to clinically used ribosomally toxic drugs with undefined molecular targets, targeting NVL2 offers a transformable strategy for colorectal cancer chemotherapy through a novel alternative mechanism of ribosomal biosynthesis inhibition. We disclose (1) the design, synthesis, and evaluation of a series of benzothiazide-based NVL2 inhibitors to screen for candidate compounds suitable for in vivo evaluation, and (2) the evaluation of in vivo drug tolerance, pharmacokinetics, and efficacy of optimized NVL inhibitors in a colorectal cancer xenograft model. Innovations include: the first and only known small molecule to inhibit NVL2; a resistant mutant compound demonstrating intracellular targeting and off-target effects; a resistant xenograft derived from the aforementioned resistant cell lines demonstrating in vivo targeting and off-target pharmacokinetics and efficacy; and a germline resistant NVL2 compound demonstrating targeting and off-target toxicity in mice. R403W / + Gene knock-in mice.

[0270] Result I

[0271] We performed high-throughput screening of 99,599 small molecules (UTSW chemical library) targeting compounds that inhibit the proliferation of HCT116 colorectal cancer cells. A major challenge in phenotypic screening is understanding the mechanism of action, commonly referred to as target ID. To address this challenge, we developed an syngenetic, inducible positive genetic system that revealed drug resistance mutations in the compounds.

[0272] As part of this work, we identified MM017 as a novel small molecule with antiproliferative activity in HCT116 cells. We isolated a total of 61 HCT116 resistant clones and performed whole-exome sequencing on 11 of them, revealing a recurring mutation in nucleovalli-like 2 (NVL2). Subsequent sequencing focusing on NVL2 revealed that all 61 clones carried the NVL2 mutation. NVL2 is an AAA-ATPase protein responsible for removing (or unfolding) the NSA1 module in yeast; the NSA1 module is a set of molecular chaperones that bind to the nascent 60S ribosomal subunits in the nucleolus. Therefore, NVL2 is crucial for the biosynthesis of the 60S ribosome. NVL2 consists of an N-terminal domain (NTD) important for localization to the nucleolus and two tandem ATPase domains. The mutation leading to resistance was concentrated in a discrete region of the first ATPase domain, indicating that this domain is involved in the mechanism of action. We also edited the original cells with this precise mutation using CRISPR and observed compound resistance.

[0273] To test whether the NVL2 mutation prevents compound binding, we synthesized MM0514, a cross-linking agent derivative of MM017. MM0514 contains an aryl azide, thus enabling covalent modification of the target protein upon exposure to UV light. MM0514 also contains an alkyne group, which provides a "handle" for purifying the bound protein using click chemistry. Crucially, MM0514 retained its target activity against HCT116 cells because NVL2... R403W Mutant cells develop drug resistance. We will use parental or NVL2 cells. R403W HCT116 cells were crosslinked with MM0514, and NVL2 binding was analyzed. In parental cells, NVL2 bound to MM0514 in a dose-dependent manner, but binding was lower in NVL2 mutant cells. These observations suggest that mutations in NVL2 confer resistance by preventing direct binding to MM017 derivatives. In summary, these results confirm that MM017 and its derivatives exert their antiproliferative effects by binding to NVL2. To characterize the binding site, we resolved the cryo-electron microscopy (cryo-EM) structures of NVL2 and MM017. MM017 binds to a single site near the D subunit in the asymmetric hexamer. Consistent with our binding data, the mutations are localized near the binding site, including R403, which is mutated to tryptophan in resistant clones and is expected to prevent the binding of MM017 or related analogues. The cryo-EM structures of NVL2 and MM017 provide further evidence for target identification and are also a tool for optimizing bioavailable compounds.

[0274] NVL2 in yeast is crucial for 60S ribosome maturation, and therefore, we hypothesized that MM017 might reduce 60S ribosome synthesis. To test this hypothesis, we performed polyribosome profiling on parental or NVL mutant cells treated with MM017 at different time points. Polyribosome profiling used a sucrose gradient to separate the intact ribosome (80S) from its components, namely the large (60S) and small (40S) subunits. Parental cells treated with MM017 revealed a time-dependent reduction in both the 60S and 80S ribosomal subunits, consistent with reduced 60S biosynthesis. Since the 80S is a complex of the 40S and 60S ribosomes, fewer 60S ribosomes were expected, leading to an increase in free 40S subunits. All these changes were a result of NVL2 binding, as these subunits were absent in NVL2. R403W In mutant cells. In summary, these observations suggest that MM017 inhibits NVL2, leading to a reduction in 60S ribosomes.

[0275] Inhibition of 60S ribosome biosynthesis is known to induce p53 stability and upregulation; therefore, p53 could serve as a potential pharmacokinetic biomarker for MM017 in HCT116 cells. Consistently, MM017 upregulates p53 levels in parental HCT116 cells without upregulating NVL2. R403W p53 levels in mutant cells. We evaluated the selectivity of MM017 in 902 cancer cell lines using PRISM (Broad Institute) and then correlated this selectivity with 1215 clinical and preclinical compounds in the PRISM database. Carmoflu (r=0.53, corrected p<10) -30 ) and oxaliplatin (r=0.5, corrected p<10) -30 The selectivity of oxaliplatin and carmoflurane was significantly correlated with that of MM017, indicating that all three compounds have a similar mode of action. These observations suggest that oxaliplatin and carmoflurane, like MM017, target ribosomal biosynthesis.

[0276] Result II

[0277] We described above a benzothiazazines small molecule that binds to the ribosomal biosynthesis factor NVL2 and kills colorectal cancer cells in a dose-dependent manner, which is associated with the upregulation of p53, a downstream effect of ribosomal biosynthesis inhibition. Currently, there are no known NVL2 inhibitors; therefore, this novel benzothiazazines-based NVL2 inhibitor provides a reagent for the medicinal chemistry optimization of in vivo active lead compounds for proof-of-concept evaluation in a colorectal cancer xenograft model.

[0278] Medicinal chemistry optimization of NVL2 inhibitors based on dibenzothiazide and dibenzothiazide.

[0279] Design and synthesis of NVL inhibitors based on benzothiazepines. 䓬 Evaluation of the ability of the benzothiazepine and benzothiazepinone analogs to inhibit the We demonstrated that the dibenzothiazazone skeleton is suitable for medicinal chemistry optimization, enabling the synthesis of analogs with desired drug-like properties. We synthesized a large number of dibenzothiazazones and their analogs, revealing their structural-active characteristics. Analogs were evaluated against the HCT116 colorectal cancer cell line, and the compound was tested against the drug-resistant NVL2. R403W Clones were reverse-selected. Cytotoxicity in wild-type HCT116 was determined. All active analogs exhibited targeted cytotoxic activity and, relative to NVL2, [the results were as follows]. R403WCloning efficiency was reduced by 10 to 100-fold. Initial SAR focused on exploring substitutions for the furan ring in the initial dibenzothiazide hit compound MM017. We first explored a wide variety of mono- and di-substituted benzene rings, including a broad spectrum of functional groups (F, Cl, alkyl, alkoxy, fluoroalkoxy, CN, formamide, S(O)Me, carboxyl…). Except for fluorine, other ortho-substituents were not feasible, and only 3- or 4-substituted or 3,4-disubstituted phenyl analogs retained similar activity to the parent compound. Five-membered heterocycles other than furan significantly reduced efficiency, while benzoxazole, benzothiazole, and 2-oxo-2,3-dihydrobenzoxazole showed comparable or slightly higher efficiency compared to their respective phenyl analogs. We also found several amides derived from non-aromatic acyclic, monocyclic, or spirocyclic carboxylic acids to produce active analogs. Due to the potential protease-mediated cleavage of the amide bond, we investigated the substitution of the amide linker (C(O)NH) and found that urea retained similar potency, as did thioamides and thioureas. Transamides and sulfonamides, on the other hand, were inactive. Turning to the side chain, we found that longer propargyl or hexenyl groups increased potency by 3 to 10-fold, but at the cost of increased lipophilicity and the number of rotatable bonds. Shorter, rigid 2-butynyl groups proved optimal, with an activity increase of >10 to 20-fold.

[0280] SAR data correlated with insights gained from co-cryo-EM structures of NVL2 with several dibenzothiazide ketones and dibenzothiazide ketones. This guided the design of a series of heteroaromatic analogs in which we replaced amide-linked dibenzothiazide ketones or dibenzothiazide ketones with amine-linked dibenzothiazide ketones and dibenzothiazide ketones. It was found that various aromatic, heteroaromatic, heterocyclic, carbocyclic, and acyclic groups linked to the core of a dibenzothiazide ketone or dibenzothiazide ketone via amine bonds retained or improved activity.

[0281] Using our existing SAR data, we designed and synthesized novel analogs based on a universal skeleton. We retained the more potent and less lipophilic alkynyl side chains, while also exploring additional rigidification, metabolic blocking, and truncation modifications. We found that oxidation (to SO or SO2) or substitution with an oxygen atom of the central dibenzothiazazepine was not tolerated, but CH2 substitution only reduced activity by about 2-fold. Based on this finding, we also substituted the central sulfur atom with CHMe units and found that these retained similar activity to sulfur analogs. Substitution with CHCN or CMe(OH) units reduced activity to some extent. Therefore, our subsequent designs retained the central sulfur or (optionally substituted) carbon atom. Next, we explored substituents at various available positions on the two benzene rings of the central dibenzothiazazepine core. We found that fluorine, chlorine, and cyano substituents on the right-hand benzene ring were acceptable if these substituents were introduced into two positions not directly adjacent to the benzo-fused site, retaining full potency. Such substitutions on the left-hand benzene ring were unacceptable. We also explored replacing a single CH unit on each of the two benzene rings with a nitrogen-containing analog (pyridine analog). These substitutions on the right-hand benzene ring were unacceptable, while those on the left-hand benzene ring at positions U and W in the general structure of the claims were acceptable. We further found that replacing CH with nitrogen at position W in the general structure significantly improved the metabolic stability of the analog when tested in microsomal stability assays. All the central dibenzothiazepines and dibenzothiazepine core skeletons described herein can be synthesized from readily available starting materials using the same chemical approach. We focused on small, physicochemically improved, and metabolically lessening substituents. The final step of the synthesis involved linking the peripheral unit (R3 in the general structure) to the amino-substituted central core via Pd-catalyzed CN bond formation (structure of formula VI), reductive amination, or amide bond formation with a suitable carboxylic acid (structure of formula VII). 3 Aldehydes and sulfur powder are reacted in an aqueous solution of K₂CO₃ to obtain urea (structure of formula II or V) and thiourea (structure of formula III or V) are obtained by contemporary methods of forming urea / thiourea using triphosgene or thiophosgene, with the same amino-substituted central core. Preferred substituents contain only drug-like substituents or groups with desirable physicochemical properties and limited predicted metabolic instability. Preferred substituents are small, improve physicochemical properties, and reduce metabolism.

[0282] Our next-generation analogues maintain or improve upon CLogP and conform to the drug-likeness space, completely complying with Lipinski's 5th rule or Veber's rule. (Introduction of sp...) 3 - Stereocenters can improve activity and specificity, solubility, and reduce protein binding.

[0283] Evaluate the selectivity of NVL2 inhibitors to kill WT vs. NVL2 mut HCT116, block ribosome biogenesis and induce p53 In vitro metabolism, plasma stability, solubility, and plasma protein binding properties of the analogs. We evaluated analogues in the colorectal cancer cell line HCT116 and in existing compound-resistant clones. One clone was found to have resistance at the compound binding site (NVL2). R403W There is a mutation, another clone (NVL2) P307T Mutations at locations far from the binding site confer resistance through unknown effects. Based on our results, analogues that kill HCT116 cells by inhibiting (targeting) NVL2 show reduced potency in compound-resistant HCT116 mutant clones. Our analogues have been back-screened against NVL2-resistant mutant clones, showing resistance folds ranging from 10 to 100 times (most analogues showed 20 to 50 times). This back-screening provides a strategy for identifying off-target toxins. Killing wild-type cancer cells in a dose-responsive manner, IC50... 50 Research has progressed on analogs with a molecular weight <1000 nM and at least 20-fold reduced potency in NVL mutant cell lines.

[0284] Further evaluation was conducted based on efficacy and NVL2 inhibition criteria, and metabolic stability (T in microsomal assays). 1 / 2 The ability of p53 analogues (>30 min) to inhibit ribosome biosynthesis (polyribosome profiling and induction of p53 and / or p21) was evaluated. p53 antibodies were used to assess p53 as a pharmacodynamic biomarker in in vivo studies.

[0285] Pharmacokinetic studies of the NVL2 inhibitors. We evaluated the oxidative metabolism of most analogs using mouse microsomal components in the presence of an NADPH regeneration system essential for phase I metabolism. Half-lives were determined by substrate consumption. Compounds identified as having significant metabolic defects (T...) 1 / 2 The amides exhibited high in vivo clearance rates (<30 minutes), therefore no further investigation was conducted. Methoxy substituents may be susceptible to oxidative metabolism; therefore, the introduction of fluoride metabolism inhibitors was also explored. Since we suspected that some metabolic clearances might be protease-mediated, selected analogs were evaluated in the microsomal fraction to rule out phase I oxidative metabolism in the absence of an NADPH regeneration system. We found that some amides still metabolized at considerable rates, while others were more stable. Unsurprisingly, amines, ureas, and thioureas were stable under these conditions (T0). 1 / 2 >120 minutes).

[0286] For compounds with acceptable metabolic clearance, evaluation was conducted in additional in vitro assays using the gold-standard rapid equilibrium dialysis method, including tests for water solubility, plasma stability, and protein binding. The current structure-activity relationship suggests that high activity, high solubility, and acceptable metabolic stability can be achieved with more polar compounds (CLoP < 4).

[0287] Tolerance of the benzothiazepinones and benzothiazepinones in mice, and determination of whether toxicity is caused by binding to To perform pharmacokinetic assessment, we measured the exposure of the analog after intravenous (3 or 5 mg / kg), intraperitoneal (10 mg / kg), and oral (20 mg / kg) administration. Plasma and liver drug levels were determined (LC-MS / MS) at 8 time points (3 mice / time point). Total plasma or tissue exposure (AUC) and half-life were calculated using WinNonlin's non-compartmental analysis tool. Oral bioavailability was expressed as AUC. 口服 / AUC 静脉内注射 × Dosage 静脉内注射 / dose 口服 Calculations were performed (expected standard F > 30%). For the most promising compounds, dose escalation was conducted at up to three dose levels to determine whether increasing the dose increased exposure. Initial pharmacokinetic studies were performed in female CD1 mice, while dose escalation studies were evaluated in both female and male mice.

[0288] For in vivo studies, we prefer orally administered compounds; however, for proof-of-concept studies, intraperitoneal (ip) or intravenous (iv) delivery is considered acceptable. We selected compounds with a terminal half-life >2 hours and [C 最大 ] u IC 90 (HCT116 cytotoxicity) compounds.

[0289] In vivo tolerability, pharmacokinetics, and efficacy of NVL2 inhibitors.

[0290] NVL2 ATPase is required for 60S ribosome biosynthesis. Preliminary data, including cryo-electron microscopy structures, indicate that dibenzothiazide and dibenzoxazine compounds bind directly to NVL2, leading to a reduction in 60S and 80S ribosomes, upregulation of p53, and cell death. The cytotoxic effects of dibenzothiazide and dibenzoxazine compounds are consistent with the hypothesis that they selectively target cancers dependent on increased ribosome biosynthesis. Oxaliplatin, an effective treatment for colorectal cancer, inhibits ribosome biosynthesis through an unknown mechanism. This suggests that dibenzothiazide and dibenzoxazine compounds may have pharmacodynamic effects against colorectal cancer. We validated this hypothesis by systematically evaluating the antitumor activity of optimized dibenzothiazide and dibenzoxazine analogues in preclinical models of colorectal cancer. We also evaluated whether these effects are mediated by inhibition of ribosome biosynthesis and upregulation of p53, and determined whether inhibition of NVL2 produces targeting toxicity in healthy, tumor-free tissues. We determined the tolerability, pharmacokinetic response, and single-agent efficacy of bioavailable NVL2 lead inhibitors against wild-type and compound-resistant colorectal cancer xenografts.

[0291] NVL2. Evaluation of the pharmacodynamic effects of the benzothiazepinones and benzothiazepinones analogs, and determination of candidate biomarkers of target engagement in vivo. We tested the tolerability of long-term once-daily oral or intravenous treatment with multiple doses of dibenzothiazide or dibenzothiazide analogues (route of administration depending on pharmacokinetic parameters). Three doses were selected for tolerability studies based on specific pharmacokinetic data and solubility characteristics for each analogue. C57B1 / 6 mice were randomly assigned to four treatment groups for each analogue (n=5 males and 5 females per group: 1x solvent, 1x low-dose benzothiazide, 1x intermediate-dose benzothiazide, and 1x high-dose benzothiazide). Solvent and drug treatments were administered orally by gavage (or via tail vein injection) once daily for 14 consecutive days. The primary endpoint of this study was change in body weight and hematological, renal, and hepatic toxicities. Secondary endpoints were the absolute concentrations of benzothiazide in plasma. Exploratory endpoints included other standardized parameters measured by complete blood count (CBC) and serum chemistry analysis. At the end of the 14-day treatment period, we anesthetized the mice, collected blood samples via cardiac puncture, and then euthanized the animals. The blood samples were analyzed and evaluated using CBS and serum chemistry.

[0292] Body weight change provides a measure of overall toxicity. The toxicity threshold for body weight change was selected as a decrease of ≥20% relative to the vector-treated mice. Mice reaching this threshold were euthanized humanely. CBS was used to assess hematologic toxicity. Low platelet count (<772 K / µL) or low hemoglobin level (<13 g / dL) was used to detect drug-induced thrombocytopenia or anemia. Serum chemistry data were used to assess nephrotoxicity and hepatotoxicity. Elevated creatinine levels (>1.5 mg / dL) served as a marker of renal dysfunction. Elevated levels of alanine aminotransferase (ALT) (>346.5 U / L) or aspartate aminotransferase (AST) (>690 U / L) indicated liver injury. Thresholds for plasma and serum toxicity biomarkers were derived by applying the Grade 1 adverse event thresholds (Common Terminology Criteria for Adverse Events Version 5.0, published by the National Cancer Institute (NCI)) to the 95% confidence interval limits of these biomarkers in the original mice. The maximum tolerated dose (MTD) for each benzothiazaza analogue was determined as the highest dose that, when administered daily for 14 consecutive days, did not result in the average level of toxicity biomarkers in the group exceeding the thresholds defined above. Bioavailability was confirmed by satellite pharmacokinetic (SPK) measurements of compound levels in plasma.

[0293] To compare and investigate off-target toxicity and targeted toxicity, we constructed an NVL2 strain carrying a germline compound with drug resistance. R403W Mutant gene knock-in mice. Heterozygous gene knock-in mice were constructed using CRISPR / Cas9 in a C57BI / 6 background and were capable of breeding homozygous. Next, we treated WT and NVL2 mice with a solvent control or three different doses of dibenzothiazide or dibenzothiazide analogues. R403W Mice (n = 5 mice / group / genotype). Mice were age- and sex-matched (1 sex / group unless toxicity differences were observed between male and female mice) and analyzed using the same endpoints described above. Dosage selection was based on MTD determination and included at least one dose below MTD and one dose above MTD. For NVL2 R403W Compared to mice, the analogues were more toxic in WT mice, suggesting that dibenzothiazide or dibenzothiazide analogues exert a targeting effect by binding to NVL2. To confirm this, we compared WT mice and NVL2 mice. R403WWe examined the levels of ribosome biosynthesis and p53 induction in damaged tissues or cell types in mutant mice. Regarding the toxicity of the analogue to germline NVL mutant mice, we concluded that these effects were due to off-target effects. In the case of target-mediated toxicity, we then determined whether there was a usable therapeutic window within which side effects could be minimized while preserving antitumor efficacy. In the case of off-target effects, we will attempt to determine the pathogenic mechanism and implement appropriate assays in our medicinal chemistry pipeline to identify analogues with reduced off-target toxicity.

[0294] Determination of the pharmacodynamics of the benzothiazepinones and benzothiazepinones in a colorectal cancer xenograft model, and Validation of candidate biomarkers. Our in vitro data show that dibenzothiazide and dibenzothiazide kill cancer cells by directly inhibiting NVL2. We also demonstrate that inhibition of NVL2 by dibenzothiazide or dibenzothiazide impairs the biosynthesis of the 60S ribosomal subunit, leading to p53 upregulation. NVL2 resistance was observed with syngeneic dibenzothiazide. R403W Similar experiments conducted with knock-in clones showed that treatment with NVL2-targeting dibenzothiazide or dibenzothiazide did not exhibit inhibition of ribosome biosynthesis, upregulation of p53, or antiproliferative activity. Therefore, we evaluated p53 upregulation as a feasible pharmacodynamic (PD) biomarker for targeting activity. Furthermore, we assessed the reduction in ribosome biosynthesis and the activation of downstream p53 molecules such as p21 in xenografts.

[0295] To test whether treatment with dibenzothiazide or dibenzothiazide analogues can induce p53 and block ribosome biosynthesis in vivo, 5 × 10⁻⁶ μg / mL of dibenzothiazide or dibenzothiazide analogues were used. 6 WT or NVL2 R403W HCT116 colorectal cancer cells were subcutaneously transplanted into ICR SCID mice. The xenograft was formed from a population of HCT116 cells, which were then transfected via NVL2. R403W The knock-in mutation wizard targets the target to eliminate potential artifacts that may occur in individual clones that have already undergone off-target mutations. Once the tumor reaches ~110mm... 3Mice were randomly assigned to either a solvent group or a dibenzothiazide or dibenzothiazide treatment group (n=8 mice per group; 16 mice / genotype in total). The NVL inhibitor or solvent control was administered once daily at the maximum tolerated dose via oral gavage, intraperitoneal injection, or tail vein injection for 3 days. On day 3, blood samples were collected and mice were euthanized to harvest livers and xenografts for evaluation of PK (in blood, liver, and tumor) and PD biomarkers (in tumor). To identify candidate biomarkers, tumor tissues collected from control mice or compound-treated mice were compared by quantitative Western blot analysis of p53 and by downstream induction of p21 via qPCR.

[0296] Pharmacokinetic studies Pharmacodynamic studies: After evaluating tolerability and PD, we used wild-type and NVL2. R403W We used the HCT116 xenograft model to evaluate the in vivo antitumor activity of the analogue. We compared wild-type and NVL... R403W HCT116 cells were subcutaneously transplanted and treatment began. NVL inhibitor analogs were administered once daily via oral gavage, intraperitoneal injection, or intravenous injection via tail vein according to the MTD (frequency and route of administration to be determined based on PK). Treatment continued until mice exhibited tumor burden symptoms necessitating euthanasia, or until 50 days after randomization, whichever occurred first. Remaining available tumor tissue was collected for PD analysis. The primary endpoint was overall survival. Kaplan-Meier curves were constructed for each benzothiazide analog in each xenograft model. The difference in survival between the drug-treated and solvent-treated groups was statistically evaluated using the log-rank test. Additionally, tumor volume was measured every 3 days, and tumor growth curves were plotted over time, which served as a supplementary endpoint.

[0297] Next, we conducted a dose-response efficacy study by establishing wild-type HCT116 xenografts and administering the aforementioned NVL inhibitor analogue. The highest dose was the MTD, and two other lower doses were selected based on reference PK data (n = 8 mice per group × 3 dose groups and a solvent control group; total n = 32 mice). Tumor growth and survival over time were quantified as described above, and usable residual tumor tissue was collected for PD analysis. The lowest dose that was statistically equivalent to the efficacy achieved using the MTD was determined.

[0298] Finally, in a separate PD group, the levels of p53 and p21 in tumor tissue treated with the lowest effective dose for 3 days were reassessed (n=5 / group; solvent control group and 1 dose group, totaling 10 mice). For example, we quantified the differences in p53 and p21 levels to determine the magnitude of changes in biomarkers induced by the treatment dose of benzothiazide.

[0299] We defined the therapeutic window of each dibenzothiazide or dibenzothiazide analogue by determining the dose that was well-tolerated and induced a strong tumor PD response and efficacy in a colorectal xenograft model. (The last sentence appears to be incomplete and possibly refers to a separate topic: "In NVL...") R403W The reduced p53 induction observed in tumors treated with benzo[a]thiazide in xenografts of cancer cells confirms its mechanism of action in vivo. The p53 induction level was dose-dependently positively correlated with the antitumor potency of benzo[a]thiazide or dibenzo[a]thiazide.

[0300] Example: Optimized dibenzothiazone and dibenzothiazone chemicals inhibit NVL-mediated ribosome assembly and induce p53-dependent apoptosis in cancer cell xenografts.

[0301] In these embodiments, we identified human NVL as a target for a chemical toxin named MM017. Cryo-electron microscopy of the NVL-MM017 binding structure revealed the binding site during hexamer assembly. Mutations in NVL leading to resistance to MM017 were concentrated at the binding site, resulting in reduced compound binding. The NVL-MM017 interaction specifically inhibited the maturation of the 60S ribosomal subunit, leading to an aberrant polyribosomal pattern and the accumulation of newly synthesized pre-60S intermediates in the nucleolus. NVL inhibited p53-mediated apoptosis without any indication of DNA damage. Bioavailable analogues of MM017 reduced tumor growth in vivo without significant toxicity.

[0302] Mutations in NVL confer resistance to the orphan cytotoxin MM017.

[0303] We recently described an isogenetic forward genetic system for the rapid discovery of mutations conferring resistance to compounds with antiproliferative activity (32). This system utilizes an engineered colorectal cancer HCT116 cell line (iHCT116) with the addition of indoleacetic acid (IAA) to initiate the degradation of the ubiquitin-mediated DNA mismatch repair protein MLH1, thereby providing a mechanism for temporarily increasing the mutation rate. We applied this strategy to MM017, a dibenzothiazide ketone discovered in high-throughput small molecule screening for HCT116 cytotoxicity. MM017 inhibited the growth of iHCT116 cells in a dose-dependent manner, with an IC50 concentration of 100 mg / dL. 50The concentration was 0.46 µM. We exposed barcoded iHCT116 cells to increased lethal doses of MM017, cells that had previously been cultured either under IAA-containing conditions (mutagenic on) or under IAA-free conditions (mutagenic off). Under mutagenic on conditions, the total number of surviving clones was significantly higher and increased in a dose-dependent manner, suggesting a genetic basis for resistance.

[0304] We identified 59 clones with unique barcode sequences, indicating that each clone originated from a unique initiation event. MM017's IC of these clones... 50 The proportion of NVL mutations was 2.45 to 32.89 times that of the parental cell lines, providing evidence for drug resistance. The breadth of resistance indicated that these clones carried a variety of different mutations; therefore, we performed whole-exome sequencing on 15 clones covering the entire range of resistance. Through whole-exome sequencing, we identified variants acquired during IAA-induced mutagenesis and hypothesized that genes associated with drug resistance would be mutated in multiple clones. Two genes contained acquired variants in at least three of the 15 selected clones: TERT, mutated in three of the 15 clones, and NVL, mutated in all 15 clones. These results suggest that NVL mutations are associated with MM017 resistance. Therefore, for the remaining clones, we performed PCR-based sequencing on the mutated NVL exons identified in the genome sequencing data. In summary, 57 of the 59 unique clones carried NVL mutations. Most mutations were concentrated within the D1 AAA+ ATPase domain and frequently affected the same codons. To verify whether these mutations are sufficient to cause MM017 resistance, we used CRISPR-Cas9 to knock in the two most resistant mutations (NVL). P307T NVL R403W ) and a moderately resistant mutation (NVL) H304R Compared to the simulated treatment, transfecting cells with sgRNAs targeting these NVL residues, in addition to encoding the repair template for mutations, improved the drug resistance rate. After amplification, we confirmed that the cells carried the expected alleles (NVLs). P307T NVL R403W or NVL H304R ), and with NVL WT Compared to MM017, it exhibits stronger resistance (IC). 50 NVL WT =0.38 µM; NVL R403W >50 µM; NVL P307T >50 µM; NVL H304R =2.4 µM), but the sensitivity to the irrelevant toxin paclitaxel was the same. In summary, these observations suggest that the NVL mutation is a specific and sufficient cause of MM017 resistance.

[0305] MM017 is directly combined with NVL.

[0306] To assess whether MM017 directly binds to NVL in cells, we used an MM017 cross-linking agent (probe compound (2), Table A), which is UV-activated and contains an alkyne group that can be conjugated to biotin for affinity purification. Crucially, probe compound 2 inhibited the proliferation of HCT116 cells (IC50). 50 =0.47 μM), its potency is comparable to MM017, while NVL P307T Cells exhibited comparable resistance to both compounds, suggesting functional similarities between MM017 and the MM017 probe. We purified the MM017 probe-bound protein from cells treated with different doses of the MM017 probe, with or without 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 cellular activity, we performed probe displacement assays using three chemically related derivatives of MM017 (compounds 3-5, Table A), and their IC50 values... 50 The concentrations were 0.36 μM (3), 2.1 μM (4), and 13 μM (5). It is important to note that in the cell lines used in this experiment, we knocked the FLAG epitope into the C-terminus of NVL. Compared to compounds 4 and 5, increasing the dose of compound 3 during co-incubation more effectively replaced the MM017 probe, establishing the relationship between NVL binding and cell viability. Next, we compared NVL... WT Compared to NVL R403W NVL R307T With NVL H304R NVL levels in cell lines after treatment with the MM017 probe and ultraviolet light. (Compared to NVL) WT Compared to other cell lines, the amount of MM017 probe required to crosslink NVL was significantly higher in mutant cell lines, indicating that these mutations affect compound binding. In summary, these observations establish a relationship between compound binding and cell activity, consistent with the hypothesis that NVL is a direct target of MM017.

[0307] Table A. Structures of MM017, MM927, probe compound 2, and analogs 3-5.

[0308]

[0309] Cryo-electron microscopy reconstruction of the NVL / MM017 complex.

[0310] To understand the molecular basis of the interaction between MM017 and NVL, we set out the cryo-electron microscopy structure of the NVL-MM017 complex. Expression and purification of the D1 / D2 core of wild-type NVL resulted in low yield and protein instability. Cryo-electron microscopy analysis revealed that wild-type NVL D1 / D2 assembles into a long, filamentous helical structure, rather than the expected hexamer. The stable hexamer conformation of the Walker B motif in the thermophilic NVL homolog Rix7 (33) was found in the human NVL mutant. E366Q / E683Q Recombinant expression and purification (NVT) dEQ Stable monodisperse hexamers were also produced, as determined by mass spectrometry, and their stoichiometry was not affected by the addition of MM017.

[0311] NVL dEQ Single-particle cryo-electron microscopy reconstruction of +MM017 yielded an overall resolution of 2.9 Å. Similar to the reconstructions of *C. thermophilum* Rix7, *H. sapiens* P97, and *S. cerevisiae* Drg1, the NVL hexamer forms a ladder-like configuration, with loops from five D1 and D2 AAA+ modules bound to an extended peptide (2, 27, 34, 35) within the central channel. By convention, we designate the topmost ladder subunit as A and the bottommost as E. As previously observed, the sixth subunit (F) is in a more dynamic state, switching between positions E and A, and therefore exhibits low resolution in the cryo-electron microscopy image. By analogy with the analysis done with RIX7 (34) and the bulky nature of the side chain density in the peptide, we hypothesize that the substrate mimicry bound by NVL represents one of the 14x-HIS tags at the N-terminus of our construct, and thus model it as a multihistidine chain, although our tag also contains nonhistidine linking residues.

[0312] Preliminary analysis of cryo-electron microscopy revealed additional density consistent with MM017 at a single location within subunit E. MM017 is embedded in a predominantly hydrophobic pocket within the core structural domain of the D1 module. The ligand pocket is surrounded on one side by the central D1 β-sheet (chains 5, 1, and 4) and on the other side by an N-terminal α0 helix and a loop element preceding chain 1. This helix also binds to the AAA+ cap domain of subunit D, which forms a more peripheral boundary of the MM017 binding pocket. No ligand binding sites are found in the equivalent region of the NVL subunit AD because the α0 helix is ​​tightly packed with the central β-sheet of this domain, hindering MM017 binding. To determine whether MM017 also binds to the low-resolution and mobile F subunit, we performed a skip-align classification around the D1 module of the F subunit using a mask. Reconstruction of this subset of particles showed that the density location of MM017 in the F subunit is similar to that in the E subunit. Most repressive mutations are concentrated around the ligand-binding pocket, consistent with the alterations to the structure or conformation of the docking site. MM017 is an elongated molecule, introducing a pronounced 105° bend through a central dibenzothiazide ketone core. The furan ring of MM017 is exposed to a central solvent channel separating the D1 and D2 ring stacks, forming hydrophobic contacts with residues M280 and V301, and forming a hydrogen bond with R428. The planar amide linker adjacent to the furan moiety forms a hydrogen bond with the skeletal carbonyl group of amino acid P298. The dibenzothiazide ketone ring structure of MM017 is situated in a hydrophobic environment formed by residues M280, M284, P297, L324, R403, and L405. Among these, M284, P297, R403, and L405 are either mutated or adjacent to mutated residues in our inhibitor dataset. Furthermore, the central carbonyl group is within hydrogen-bonding distance of the ε-amino group of R403. Finally, the tail of the methoxyethyl chain extends into a loop adjacent to the α0 helix and the β1 chain.

[0313] To further understand how substrate binding can affect the inter-subunit dynamics of NVL, we obtained apo-NVL. dEOSingle-particle cryo-electron microscopy reconstructions were performed at a resolution of 2.6 Å. In the apo structure, the hexameric assembly retained a ladder conformation, but the ligand-binding pocket in subunit E was closed, occupying the same conformation as the equivalent position in subunit AD. In the apo structure, the D1 domain of subunit E moved closer to the adjacent AAA+ module in subunit D, closing the dinucleotide binding site at the D / E interface, and compared to the MM017-bound structure of NVL, the arginine finger motif of subunit E was closer to the bound ATP, indicating that compound binding affects the D / E interface within the D1 ring through an allosteric effect. Consistent with this, one of the most resistant NVL mutations, P307T, is located at the D / E nucleotide interface. We infer that, in the presence of MM017, the allosteric association observed between the ligand-binding pocket and the nucleotide binding site at the D / E interface hinders the assembly of the functional D1 ring.

[0314] NVL, which binds to MM017, specifically blocks the biosynthesis of 60S in the nucleolus.

[0315] To investigate the effects of NVL loss, we constructed a C-terminal FLAG epitope auxin-induced degradation (AID) tag into NVL cells that also expressed the plant E3 ligase TIR1. Treatment with 5-phenylindole-3-acetic acid (Ph-IAA) resulted in dose-dependent loss of NVL-AID, but unlabeled NVL cells were unaffected. AID / AID In cells, viability decreases in a dose-dependent manner. NVL + / + or NVL AID / + Cell viability was not affected by Ph-IAA, indicating that although NVL is crucial for HCT116 cell proliferation, it is not haploid deficient.

[0316] Next, we used multiribosome profiling to assess the effect of disrupting NVL on ribosomal material distribution. Ph-IAA was added to induce NVL. AID / AID NVL degradation in cells leads to a time-dependent decrease in free 60S and 80S levels (based on absorbance at 260 nm), accompanied by a corresponding increase in 40S levels. The addition of Ph-IAA also generates hemimeric polyribosomes representing the unadded 40S subunit bound to the mRNA initiation site, a characteristic of 60S biosynthesis defects (36). WT The addition of MM017 to cells resulted in NVL cells that were treated with Ph-IAA. AID / AID The cells exhibited similar phenotypes to the polyribosome profile, but did not elicit NVL. P3071 Changes in the polyribosome profile of cells. The polyribosome profile of HCT116 cells after NVL disruption is similar to that reported in yeast cells with RIX7 mutation (37) or human cells overexpressing NVL catalytic mutant (38).

[0317] The observed reduction in free 60S using polyribosomal profiling could be a result of reduced 60S synthesis, accelerated 60S degradation, or both. To differentiate between pre-existing and newly synthesized 60S, we engineered HCT116 cells to express a C-terminal SNAP tag on eL36 (a ribosomal protein that binds to the 60S subunit prior to NVL binding) (39), or a control C-terminal SNAP tag on eS17, a fraction of the small ribosomal subunit, to monitor 40S biosynthesis (40). We first labeled pre-existing eL36 or eS17 in cells with Oregon green benzylguanine (green). Then, we treated cells with solvent or MM017 for 24 hours, followed by the addition of 647-SiR benzylguanine to label pools of synthesized proteins over the 24-hour period and evaluated pre-existing or new proteins in each polyribosomal profiling fraction. Existing eL36-SNAP was present in the 60S, 80S, and polysome fractions, indicating that SNAP-tagged proteins can assemble into ribosomes undergoing translation. MM017 treatment had no effect on the level or segregation pattern of existing eL36-SNAP. In contrast, MM017 treatment reduced newly synthesized eL36-SNAP in the 60S, 80S, and polysome fractions, 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 the solvent or MM017, indicating that MM017 has no effect on the 40S subunit.

[0318] Next, we investigated the effect of MM017 on the subcellular localization of eL36-SNAP (60S) or eS17-SNAP (40S). As expected of mature ribosomes, the existing eL36-SNAP was almost entirely located in the cytoplasm, and MM017 treatment had no effect on its localization. In solvent-treated cells, newly synthesized eL36-SNAP was present in both the nucleolus and cytoplasm, reflecting its presence in both pre-60S and mature ribosomes. In contrast, in MM017-treated cells, the new eL36-SNAP was localized only in the foci within the nucleus. These foci co-localized with nucleolar fibrin, indicating that the arrested eL36-SNAP intermediate is located in the nucleolus. To verify whether the observed arrest in 60S biosynthesis was caused by binding to NVL, we constructed a system expressing eL36-SNAP and NVL. R403WCells treated with MM017 showed that newly synthesized eL36-SNAP was localized in the nucleolus and cytoplasm, a pattern indistinguishable from that in the solvent-treated group. These results indicate that the arrest of 60S biosynthesis is due to the inhibition of NVL by MM017. Finally, we conducted similar experiments using eS17-SNAP cells to investigate whether MM017 affects the degradation or biosynthesis of 40S ribosomes. MM017 had no effect on the localization of existing or newly synthesized eS17-SNAP. In summary, these results indicate that MM017 directly inhibits NVL, thereby specifically blocking 60S assembly in the nucleolus.

[0319] Inhibition of NVL leads to p53-dependent apoptosis.

[0320] To better understand how MM017 inhibition of NVL leads to cell death, we performed genome-wide mixed CRISPR / Cas9 knockout screening in HCT116 cells using a guide RNA library targeting 19,114 genes. Cells were intermittently pulsed with either solvent or MM017 over 21 days; the population doubling time was 9.79 times less for cells treated with MM017. Massive parallel sequencing of PCR products amplified from genomic DNA was used to determine the relative levels of sgRNA sequences, thus inferring the relative impact of each gene on compound sensitivity. 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, indicating that the loss of p53 and, to a lesser extent, the loss of p21 protects cells from the effects of MM017. To confirm whether p53 and p21 are required for the antiproliferative activity of MM017, we performed a growth competition assay between ZsGreen-expressing p53 or p21 gene knockout (KO) cells and control cells expressing mCherry. In the untreated case, the ratio of green to red cells did not change over time. In contrast, MM017 resulted in a dose-dependent enrichment of p53 or p21 gene knockout cells. The demand for these two proteins is specific to MM017, as no competitive advantage was observed in the presence of paclitaxel. In summary, these results indicate that MM017 reduces the proliferation of HCT116 cells in a p53- and p21-dependent manner.

[0321] To identify genetic predictors of MM017 sensitivity in different cancer types, we performed PRISM screening on 902 cancer cell lines with known genotypes (31). Correlation analysis revealed that TP53 mutation was most significantly associated with resistance to MM017. These findings are consistent with the results of syngeneic CRISPR screening, indicating that p53 is a key effector of MM017 in cancer cells with diverse lineages and genotypes.

[0322] The importance of p53 and p21 to MM017 activity leads to the hypothesis that these proteins may be upregulated by inhibiting NVL. MM017 treatment resulted in an increase in p53 at 6 hours post-treatment, followed shortly thereafter by an increase in p21, consistent with its role as a target protein of p53. Importantly, the observed increases in p53 and p21 expression were a consequence of NVL inhibition, as NVL... P307T The cells did not show any changes in the abundance of any protein, while in NVL AID / AID Degradation of NVL in cells leads to a similar increase in p53 levels.

[0323] Upregulation of p53 and its effector p21 can either arrest cell growth or induce cell death through apoptosis. To differentiate between these two possibilities, we examined cell death by measuring membrane permeability loss in HCT116 control cells and p53 KO cells after five days of MM017 treatment, finding significantly fewer dead cells in p53 KO cells. The protective effect of p53 deficiency against MM017-induced cell death is specific to MM017, as paclitaxel-induced cell death (an unrelated toxin that stabilizes microtubule polymerization) is unrelated to p53. Next, we determined whether cell death was mediated by the apoptotic pathway by detecting cleaved caspase-3 (a confirmed apoptosis marker). Astrocytocin (a known unrelated compound that induces apoptosis) caused strong activation of caspase in both control and p53 KO cells. In contrast, MM017-induced cleaved caspase-3 was significantly reduced in p53 KO cells. In summary, these findings suggest that MM017 inhibition of NVL leads to p53-dependent apoptosis in HCT116 cells.

[0324] Upregulation of p53 is consistent with the ribosome assembly stress response triggered by 5SRNP-mediated MDM2 inhibition (5). Other ribosome biosynthesis inhibitors, such as oxaliplatin and CX-5461, are also 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 DNA damage response activation is phosphorylation of serine 15 of p53, which leads to an increase in p53 protein (41). Therefore, we compared the effects of MM017, oxaliplatin, and CX-5461 on p53 upregulation and phosphorylation of serine 15 of p53. All three compounds resulted in a dose-dependent increase in p53 levels, but only oxaliplatin and CX-5461 treatments resulted in a dose-dependent increase in phosphorylated p53. Even at concentrations up to 10 μM, no evidence of serine 15 phosphorylation of p53 was found after MM017 treatment. These observations suggest that the upregulation of p53 by oxaliplatin and CX-5461 is at least partially triggered by a DNA damage response. Since there was no evidence of serine 15 phosphorylation of p53 after treatment with MM017, we conclude that the increased p53 stability observed after MM017 treatment is independent of a DNA damage response and is entirely induced by disruption of 60S ribosomal subunit assembly.

[0325] A bioavailable analogue reduced tumor growth in mouse xenografts without significant toxicity.

[0326] Next, we investigated whether NVL inhibitors inhibited the growth of xenograft tumors derived from cell lines in mice, and whether systemic inhibition of NVL led to specific toxicities. Through medicinal chemistry studies, we identified the analog MM927 (Table A), which exhibited an IC50 of 79 nM for inhibiting HCT116 proliferation, five times more potent than the parent compound MM017. [NVL-carrying...] P307T The mutant cells were relatively resistant to MM927 (IC50 = 1.67 μM), indicating that MM927 functions similarly to MM017. To understand the toxicity of MM927 in mice, we first investigated whether MM927 also inhibited mouse NVL. To test the potency of MM927 on mouse NVL in the same cell type, we... AID / AID Human or mouse NVL was ectopically expressed in the cells. Treatment with Ph-IAA degraded the endogenous protein, forcing the cells to rely solely on the ectopically expressed NVL. In cells simulating infection, NVL was degraded as expected by adding Ph-IAA. AID / AIDCell viability was reduced, but cell viability was completely restored by ectopic expression of mouse NVL or human NVL. Under these conditions, MM927 inhibited cells ectopically expressing human NVL with an IC50 of 0.051 µM, similar to its potency against endogenous NVL, indicating that NVL overexpression does not significantly alter sensitivity. MM927 also inhibited mouse NVL with an IC50 of 0.207 μM, indicating that sufficient plasma concentrations can inhibit NVL in normal mouse tissues.

[0327] In pharmacokinetic studies evaluating MM927 exposure, the peak plasma level (C) resulting from intraperitoneal (IP) injection of 10 mg / kg MM927 was [data missing]. 最大 The concentration was 2510 ng / mL (5.15 μM), with an elimination half-life of 101.33 minutes. Plasma exposure was dose-dependent at doses up to 35 mg / kg (IP injection), reaching a maximum concentration at 17.86 µM. These levels exceeded the antiproliferative IC99 of MM927 in cells expressing human or mouse NVL. In subsequent pharmacodynamic (PD) studies, we investigated whether we could assess the targeted inhibitory effect on NVL by inducing p53 and / or p21 in tumor xenografts in mice subsequently treated with MM927. We used HCT116 NVL... WT and NVL R403W Cells were subcutaneously implanted into both sides of the body of mice, and the levels of p53 and p21 in each tumor were evaluated at different time points after intraperitoneal administration of 35 mg / kg MM927. Three hours post-injection, p53 protein levels increased, followed by a rapid increase in p21. Both p53 and p21 remained elevated over 12 hours and decreased to baseline levels within 24 hours, consistent with the pharmacokinetic characteristics of MM927. Importantly, the induced levels of p53 and p21 in the tumor xenografts were comparable to those induced by continuous 24-hour treatment with MM017 in cultured cells. Crucially, NVLs implanted on opposite sides of the same mouse body... R403W The tumors did not show changes in p53 and p21, suggesting that the changes observed in NVL wild-type tumors were a result of NVL suppression, and establishing p53 and p21 as viable biomarkers for PD.

[0328] After determining the kinetics of MM927-mediated NVL inhibition in xenograft tumors, we introduced NVL-derived HCT116 wild-type or NVL-derived tumors into the tumor. R403W Mice with tumor-bearing cells were administered 35 mg / kg MM927 intraperitoneally twice daily for 21 days. MM927 treatment significantly reduced NVL. WT The growth rate of the tumor, but for NVL R403W Tumors had no significant impact. (This was observed in the 10 NVLs analyzed.)WT One tumor initially appeared to respond to treatment but subsequently continued to develop, indicating the presence of acquired resistance. Nevertheless, endpoint tumor measurements performed at the end of treatment or at euthanasia confirmed that MM927 significantly reduced NVL. WT Tumor burden, but for NVL R403W No effect on tumors. Micromolar levels of MM927 were detected in the plasma and tumors of all treated mice 3 hours after the last treatment, indicating adequate drug exposure during treatment. Importantly, no obvious signs of toxicity were observed in mice treated with MM927. Furthermore, there were no significant differences between the solvent-treated group and the drug-treated group in terms of body weight, erythrocyte and leukocyte levels, hemoglobin, platelets, liver enzyme alanine aminotransferase, and renal clearance of blood urea nitrogen. In conclusion, we find that the potent and bioavailable analogue MM927 reduces the growth of xenograft tumors in mice by inhibiting NVL without toxicity.

[0329] discuss

[0330] Modern small-molecule anticancer drug managers aim to optimize specific binding to particular protein targets to maximize targeted efficacy and minimize off-target toxicity. In contrast, older cancer therapies, which still constitute the majority of small-molecule cancer treatments, often affect multiple protein targets, leading to multipharmacological effects and target ambiguity (42). For example, oxaliplatin, a first-line treatment for colorectal cancer, like its analogues cisplatin and carboplatin, directly targets DNA, causing DNA adducts to trigger p53 activation via DNA damage responses (15). Oxaliplatin also targets ribosome biosynthesis and causes nucleolar stress, and this activity is achieved through targets other than DNA, since neither carboplatin nor cisplatin inhibits ribosome biosynthesis (16-18, 43). Recent reports suggest that blocking ribosome production is a targeted activity of oxaliplatin, which increases the likelihood that patients receiving oxaliplatin may experience dose-limiting toxicity due to off-target DNA damage activity (19). If this is indeed the case, small molecules that selectively target ribosome biosynthesis without causing DNA damage may offer enhanced efficacy and reduced toxicity, leading to a broader therapeutic index. Here, we found that MM017 and its bioavailable derivative MM927 inhibit NVL to block ribosome assembly, thereby leading to p53-dependent apoptosis. Importantly, we found that MM017 does not trigger a DNA damage response; therefore, these molecules now provide a tool for specifically targeting ribosome biosynthesis without DNA damage as a confounding factor.

[0331] NVL is a member of the type 2 AAA ATPase family, containing two tandem AAA ATPase domains (D1 and D2) that transport peptide substrates through a central channel in a stacked dihexameric ring structure (2, 34, 40). Substrate capture triggers the formation of a ladder-like assembly, followed by a series of ATP binding and hydrolysis events at the AAA+ subunit interface of the D1 and D2 domains (27, 44). Nucleotide hydrolysis at the interface between the D and E subunits is a key event in the cyclic transport mechanism of this enzyme family, as it allows the subunit at the “bottom” of the ladder to detach and move to the top position (45). In the cryo-electron microscopy structure of NVL with catalytically inactivated NVL, we found that MM017 binds to the D1 domain of the substrate-bound NVL at two sites at the D / E and E / F interfaces. This structure suggests that MM017 does not inhibit substrate binding but rather blocks substrate transport through the central channel by inhibiting ATP hydrolysis or by preventing the subunits from repositioning within the ladder structure. This mechanism differs from that of the non-competitive p97 inhibitors NMS-873 and UPCDC30245, which bind to all six subunits in a symmetrical conformation, thereby promoting substrate detachment (40, 46).

[0332] The discovery of potent, selective, and bioavailable NVL inhibitors suggests that NVL, a ribosomal biosynthesizer, can serve as a therapeutic target for small molecules. Developing NVL inhibitors as anticancer drugs requires identifying which tumor types and genotypes are most likely to respond. Myc is a transcription factor that upregulates rDNA transcription and ribosomal protein expression, both of which contribute to ribosome biosynthesis, thereby driving cancer (47). Therefore, cancers dependent on Myc protein expression may be more sensitive to NVL inhibition. Furthermore, in our investigation of antiproliferative activity in over 900 cancer cell lines, cell lines with p53 mutations were significantly more likely to develop resistance to MM017. Consistent with these findings, genome-wide CRISPR screening in colorectal cancer cell lines revealed that p53 and its downstream effector p21 are two of the most critical genes for MM017-induced cell death. Finally, silencing p53 in this colorectal cancer cell line protected 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 mutation frequency varies across 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 study also suggests that p53 deficiency may be a possible mechanism of drug resistance; therefore, a combined strategy of integrating NVL inhibition with drugs that act through alternative pathways may be effective.

[0333] Representative synthetic steps for the synthesis of dibenzothiazide ketone analogs.

[0334]

[0335] Step 1—General procedure for the synthesis of intermediate ai: Under stirring, the corresponding carboxylic acid (1.2 equivalents), HATU (1.5 equivalents), and DIPEA (2.0 equivalents) were added to a suspension of the corresponding amine (1.0 equivalent) in anhydrous DMF (30 mL / mmol). The mixture was stirred at room temperature for 12 hours, followed by treatment of the reaction mixture with H2O (60 mL / mmol). The organic layer was separated and dried with Na2SO4. The collected filtrate was evaporated under vacuum to obtain a crude disulfide intermediate, which was dissolved in MeOH (7 mL / mmol). The reaction mixture was cooled to 0°C, followed by slow addition of NaBH4 (2.0 equivalents). After stirring at room temperature for 30 minutes, the MeOH was removed under reduced pressure, and the residue was diluted with 2N HCl aqueous solution to pH=4. After freeze-drying, intermediate ai was obtained.

[0336]

[0337] Step 2—General procedure for the synthesis of intermediate a-ii: 1,2-Difluoro-4-nitrobenzene or 3-bromo-2-chloro-5-nitropyridine (1.2 equivalents) and K₂CO₃ (3.0 equivalents) were added to an anhydrous DMF (5 mL / mmol) solution of compound ai (1.0 equivalents). The mixture was stirred at 75°C for 16 hours, after which the reaction mixture was partitioned between EtOAc and H₂O. The organic layer was dried over Na₂SO₄, filtered, concentrated, and purified by silica gel column chromatography to obtain intermediate a-ii.

[0338]

[0339] Step 3—General procedure for the synthesis of intermediate a-iii: NH4Cl (18.0 equivalents) and iron (5.0 equivalents) were added to a MeOH / H2O (4:1 mL) solution (10 mL / mmol) of a-ii (1.0 equivalents). After reflux for 2 hours, the reaction mixture was filtered through diatomaceous earth and washed with MeOH. The collected filtrate was evaporated under vacuum to give intermediate a-iii.

[0340]

[0341] Step 4—General procedure for the synthesis of dibenzothiazide ketone analogs a-iv: Add the corresponding carboxylic acid (1.2 equivalents), HATU (1.5 equivalents), and DIPEA (2.0 equivalents) to a suspension of a-iii (1.0 equivalents) in anhydrous DMF (30 mL / mmol) under stirring. Alternatively, dissolve intermediate a-iii (1.0 equivalents) and the corresponding acyl chloride (1.2 equivalents) in anhydrous CH2Cl2 (30 mL / mmol). Stir the mixture at room temperature for 12 hours, then dilute with H2O. Separate the organic layer, dry with Na2SO4, and evaporate under vacuum to obtain crude intermediate a-iv, which is purified by rapid chromatography.

[0342]

[0343] Step 5a—Having aromatic or heteroaromatic R 3 The general steps for the synthesis of dibenzothiazide ketone analogs a-iv are as follows: intermediate a-iii (1.0 equivalent), R 3 Cl or R 3 A solution of Br (2.0 equivalents), Pd2(dha)3 (0.2 equivalents), DPEPhos (0.4 equivalents), and t-BuOK (2.0 equivalents) in toluene (20 mL / mmol) was stirred at 100°C under an Ar atmosphere. For some substrates, intermediate a-iii (1.0 equivalents), R 3 Cl or R 3 A dioxane solution (20 mL / mmol) of Br (2.0 equivalents), Pd2(dha)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, intermediate a-iii (1.0 equivalents), R 3 Cl or R 3 A solution of Br (2.0 equivalent), Ruphos PdIIG1 (0.1 equivalent), and t-BuONa (2.0 equivalent) in toluene (20 mL / mmol) was stirred at 100°C under an Ar atmosphere. After each reaction was determined by TLC analysis, the mixture was filtered through diatomaceous earth, and the filtrate was concentrated under vacuum. The residue was purified by preparative TLC or HPLC to obtain aromatic or heteroaromatic R compounds. 3 dibenzothiazide ketone analogues av.

[0344] Step 5b—Having non-aromatic R 3The general procedure for the synthesis of dibenzothiazide ketone analogs a-iv is as follows: NaBH3CN (2.0 equivalents) is slowly added to an EtOAc / TFA (5:1) (20 mL / mmol) solution of intermediate a-iii (1.0 equivalent) and the corresponding non-aromatic ketone (2.0 equivalent). The resulting mixture is stirred at 25°C for 2 hours under a N2 atmosphere. The reaction mixture is quenched with water and extracted with EtOAc. The organic phase is washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The residue is purified by preparative high-performance liquid chromatography (HPLC) to obtain the non-aromatic ketone analogs a-iv. 3 Dibenzothiazone analogs with a group.

[0345]

[0346] Step 6—General procedure for the synthesis of urea-based dibenzothiazide ketone analogs a-vi and a-vii: i-Pr2NFt (6.0 equivalents) and triphosgene (0.4 equivalents) were added to an anhydrous CH2Cl2 solution (15 mL / mmol) of a-iii (1.0 equivalents) at 0°C under an Ar atmosphere. After stirring for 3 hours, the corresponding amine R was added. 3 NH2 or R 5 R 6 NH (2.0 equivalents) was added, and stirring continued at 25°C for 6 hours. The reaction mixture was partitioned between CH2Cl2 and H2O, the organic layer was dried with anhydrous Na2SO4, filtered, concentrated, and purified by preparative TLC and HPLC to obtain urea-based dibenzothiazide ketone analogs a-vi or a-vii.

[0347]

[0348] Step 7—General steps for the synthesis of thiourea-based dibenzothiazide ketone analogs a-viii and a-ix: Use the same steps as in Step 6 above, except that triphosgene is replaced with thiophosgene.

[0349]

[0350] Step 8—General steps for the synthesis of thioamide-based dibenzothiazide ketone analogs ax: intermediate a-iii (1.0 equivalent), the corresponding aldehyde R 3CHO (1.5 equivalents), sulfur powder (3.0 equivalents), K2CO3 (2.0 equivalents), and water (4 mL / mmol) were placed in a sealed test tube with a Teflon-sealed 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 give the corresponding thioamide-based dibenzothiazide ketone analog ax.

[0351] Representative synthetic methods for the synthesis of dibenzozazepine ketone analogs.

[0352]

[0353] 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, followed by the addition of anthraquinone (1.0 equivalent) and sodium azide (1.2 equivalent, in portions). The reaction mixture was stirred overnight at room temperature and then poured into ice water. The product was filtered, washed with water until acid-free, and dried under vacuum to give intermediate bi as a white solid.

[0354]

[0355] 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 substances dissolved, then cooled to 0°C and treated in batches with KNO₃ (1.0 equivalent). The reaction mixture was heated to 25°C and stirred at this temperature for 1 hour. The mixture was alkalized to pH 9 with a 2N NaOH aqueous solution, resulting in a precipitate. The solid was collected by filtration, washed with water, and dried to obtain a yellow solid intermediate b-ii.

[0356]

[0357] Step 3—Synthesis of intermediate b-iii: A suspension of b-ii (1.0 equivalent) and Et3SiH (10 equivalent) in TFA (40 mL / mmol) was stirred at 25 °C for 12 hours, and then the mixture was concentrated under vacuum to obtain a residue. The residue was purified by preparative HPLC to obtain a white solid intermediate b-iii.

[0358]

[0359] Step 4—General procedure for the synthesis of intermediate b-iv: At room temperature, add NaOH (2.0 equivalents) and 1-bromo-2-butyne or propargyl bromide or 1-bromo-4-fluoro-2-butyne (1.5 equivalents) to a DMF (4.0 mL / mmol) solution of b-iii (1.0 equivalents). After stirring at 60 °C for 6 hours, add 1N HCl aqueous solution to quench the reaction. Separate the organic layer and extract the aqueous layer with CH2Cl2. Wash the combined organic layers with brine, dry with Na2SO4, concentrate under vacuum, and then purify by rapid silica gel chromatography to obtain intermediate b-iv.

[0360]

[0361] Step 5—General procedure for the synthesis of intermediate bv: NH4Cl (18.0 equivalents) and iron (5.0 equivalents) were added to a MeOH / H2O (4:1; 10 mL / mmol) solution of intermediate b-iv (1.0 equivalents). After reflux for 2 hours, the reaction mixture was filtered through diatomaceous earth and washed with MeOH. The collected filtrate was concentrated under vacuum to obtain intermediate bv.

[0362]

[0363] Step 6—General steps for the synthesis of intermediate b-vi: The synthesis of intermediate b-vi follows the same steps as the synthesis of intermediate b-iv (step 4) described above.

[0364]

[0365] Step 7—General steps for the synthesis of intermediate b-vii: The synthesis of intermediate b-vii follows the same steps as the synthesis of intermediate bv (step 5) described above.

[0366]

[0367] Step 8—General steps for the synthesis of intermediate b-viii: The synthesis of intermediate b-viii follows the same steps as the synthesis of dibenzothiazide ketone analogs a-iv described above.

[0368]

[0369] Step 9—General procedure for the synthesis of the dibenzozazepine analog b-ix: At 0°C, with stirring, MeMgBr (2.0 equivalents) was added to a suspension of b-viii (1.0 equivalents) in anhydrous tetrahydrofuran (THF) (8.0 mL / mmol). After stirring at 25°C for 6 hours, the reaction mixture was treated with aqueous NH4Cl solution, followed by extraction with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography to give the dibenzozazepine analog b-ix.

[0370]

[0371] Step 10—General procedure for the synthesis of dibenzozazone analogue bx: A suspension of dibenzozazone analogue b-ix (1.0 equivalent) and Et3SiH (10 equivalent) 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 dibenzozazone analogue bx.

[0372]

[0373] Step 11—General procedure for the synthesis of dibenzozazone analogue b-xi: TosMIC (1.5 equivalents) was added to a DME (20 mL / mmol) solution of b-viii (1.0 equivalents) at 0°C under a N2 atmosphere, followed by the addition of EtONa (2.0 equivalents). The reaction mixture was heated to 35°C and stirred for 3 hours, then quenched with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by preparative TLC and HPLC to obtain the dibenzozazone analogue b-xi.

[0374]

[0375] Step 12—General procedure for the synthesis of dibenzozazone analogue b-xii: NaBH4 (1.5 equivalents) was added fractionally to a MeOH (10 mL / mmol) solution of b-viii (1.0 equivalent) at 0°C. After reacting for 2 hours at room temperature, 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 rapid silica gel column chromatography to obtain dibenzozazone analogue b-xii.

[0376]

[0377] Step 13—General steps for the synthesis of dibenzozazaone analogs b-xiii to b-xix: The synthesis of dibenzozazaone analogs b-xiii to b-xix follows the same steps as the corresponding dibenzothiazazaone analogs a-iv to ax described above.

[0378] Characterization data of representative dibenzothiazones and dibenzothiazone analogs.

[0379] 4-Azide-N-(11-oxo-10-(2-(prop-2-yn-1-yloxy)ethyl)-10,11-dihydrodibenzo[b,f][1,4]thiaza-7-yl)benzamide (2). The probe compound (2) obtained was a yellow solid (yield 82%). 1 HNMR (400MHz, chloroform-d) δ 7.92 (d, J=2.5Hz, 1H), 7.84 (d, J=8.6Hz, 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=8.7Hz, 1H), 7.42 (dd, J=7.5, 1.5 Hz, 1H), 7.35-7.25 (m, 2H), 7.12 (d, J=8.7Hz, 2H), 4.57 (qd, J=8.9, 8.1, 5.1 Hz, 1H), 4.16 (d, J=2.4Hz, 2H), 3.97 (dq, J=9.0, 5.0Hz, 2H), 3.81 (dt, J=9.5, 4.2 Hz, 1H), 2.41 (t, J=2.3Hz, 1H). 13 C10 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. LC-MS (ESI): C10 25 H 20 [M+H] of N5O3S + The calculated value is 470.1, and the measured value is 470.1.

[0380] N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazo-7-yl)acetamide. 1H NMR (400MHz, 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 C10 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. LC-MS (ESI): C10 18 H 19 [M+H] of N2O3S + The calculated value is 343.11, and the measured value is 343.10.

[0381] N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazo-7-yl)formamide. 1 ¹H 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, 5.4Hz, 1H), 3.30 (s, 3H). LC-MS (ESI): C 17 H 17 [M+H] of N2O3S + The calculated value is 329.09, and the measured value is 329.10.

[0382] 4-Fluoro-N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiaza-7-yl)benzamide. 1 H NMR (400MHz, 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 C10 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. LC-MS (ESI): C10 23 H 20 [M+H] of FN2O3S + The calculated value is 423.12, and the measured value is 423.10.

[0383] N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiaza-7-yl)benzamide. 1 H NMR (400MHz, 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). 13C10 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. LC-MS (ESI): C10 23 H 21 [M+H] of N2O3S + The calculated value is 405.13, and the measured value is 405.10.

[0384] N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiaza-7-yl)-4-(trifluoromethyl)benzamide. 1 H NMR (400MHz, 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, 2.0Hz, 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 C10 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. LC-MS (ESI): C10 24 H 20 [M+H] of F3N2O3S + The calculated value is 473.11, and the measured value is 473.10.

[0385] N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiaza-7-yl)cyclohexaneformamide. 1H NMR (400MHz, chloroform-d) δ 7.86 (d, J=2.4 Hz, 1H), 7.64 (dd, J=7.0, 2.1Hz, 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 C10 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. LC-MS (ESI): C10 23 H 27 [M+H] of N2O3S + The calculated value is 411.18, and the measured value is 411.10.

[0386] 7-((4-fluorobenzyl)amino)-10-(2-methoxyethyl)dibenzo[b,f][1,4]thiazazon-11(10H)-one. 1 H NMR (400MHz, 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). 13C10 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. LC-MS (ESI): C10 23 H 22 [M+H] of FN2O2S + The calculated value is 409.14, and the measured value is 409.10.

[0387] N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazo-7-yl)nicotinamide. 1 H NMR (400MHz, 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 C10 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. LC-MS (ESI): C10 22 H 20 [M+H] of N3O3S + The calculated value is 406.12, and the measured value is 406.00.

[0388] N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazolidin-7-yl)isonicotinamide. 1¹H NMR (400MHz, 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 C10 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. LC-MS (ESI): C10 22 H 20 [M+H] of N3O3S + The calculated value is 406.12, and the measured value is 406.00.

[0389] N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiaza-7-yl)-4-methylbenzamide. 1 H NMR (400MHz, 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, 1.8Hz, 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 C10 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. LC-MS (ESI): C1024 H 23 [M+H] of N2O3S + The calculated value is 419.14, and the measured value is 419.10.

[0390] 4-Azide-N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiaza-7-yl)benzamide. 1 H NMR (400MHz, 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 C10 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. LC-MS (ESI): C10 23 H 20 [M+H] of N5O3S + The calculated value is 446.13, and the measured value is 446.10.

[0391] N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazolidin-7-yl)oxazol-4-carboxamide. 1H NMR (400MHz, 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 C10 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. LC-MS (ESI): C10 20 H 18 [M+H] of N3O4S + The calculated value is 396.10, and the measured value is 396.00.

[0392] 4-Azide-N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiaza-7-yl)-2-(prop-2-yn-1-yloxy)benzamide. 1 H NMR (400MHz, 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=2.4Hz, 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). 13C10 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. LC-MS (ESI): C10 26 H 22 [M+H] of N5O4S + The calculated value is 500.14, and the measured value is 500.10.

[0393] 2-Azide-N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiaza-7-yl)benzamide. 1 ¹H NMR (400MHz, 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). LC-MS (ESI): C 23 H 20 [M+H] of N5O3S + The calculated value is 446.13, and the measured value is 446.20.

[0394] 3-Azide-N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiaza-7-yl)benzamide. 1H NMR (400MHz, 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). 13 C10 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. LC-MS (ESI): C10 23 H 20 [M+H] of N5O3S + The calculated value is 446.13, and the measured value is 446.00.

[0395] 4-Azide-N-(11-oxo-10-(2-(prop-2-yn-1-yloxy)ethyl)-10,11-dihydrodibenzo[b,f][1,4]thiaza-7-yl)benzamide. 1 H NMR (400MHz, 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, 2.5Hz, 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, 5.1 Hz, 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). 13C10 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. LC-MS (ESI): C10 25 H 20 [M+H] of N5O3S + The calculated value is 470.13, and the measured value is 470.10.

[0396] 1-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiaza-7-yl)-3-phenylurea. 1 H NMR (400MHz, 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 C10 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. LC-MS (ESI): C10 23 H 22 [M+H] of N3O3S + The calculated value is 420.14, and the measured value is 420.10.

[0397] N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiaza-7-yl)cyclobutaneformamide. 1H NMR (400MHz, chloroform-d) δ 7.83 (d, J=2.5 Hz, 1H), 7.65 (dd, J=7.5, 1.7Hz, 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 CNMR (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. LC-MS (ESI): C 21 H 23 [M+H] of N2O3S + The calculated value is 383.15, and the measured value is 383.10.

[0398] N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiaza-7-yl)tetrahydro-2H-pyran-4-carboxamide. 1 H NMR (400MHz, 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). 13C10 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. LC-MS (ESI): C10 22 H 25 [M+H] of N2O4S + The calculated value is 413.16, and the measured value is 413.10.

[0399] N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiaza-7-yl)cycloheptaneformamide. 1 H NMR (400MHz, chloroform-d) δ7.84 (d, J=2.2 Hz, 1H), 7.65 (dd, J=7.5, 1.8Hz, 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 C10 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. LC-MS (ESI): C10 24 H 29 [M+H] of N2O3S + The calculated value is 426.20, and the measured value is 426.20.

[0400] 4-Chloro-N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiaza-7-yl)benzamide. 1¹H NMR (400MHz, 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 C10 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. LC-MS (ESI): C10 23 H 20 [M+H] of ClN2O3S + The calculated value is 439.09, and the measured value is 439.1.

[0401] 3-Chloro-N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiaza-7-yl)benzamide. 1 H NMR (400MHz, 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). 13C10 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. LC-MS (ESI): C10 23 H 20 [M+H] of ClN2O3S + The calculated value is 439.09, and the measured value is 439.00.

[0402] 4-Methoxy-N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiaza-7-yl)benzamide. 1 H NMR (400MHz, 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 C10 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. LC-MS (ESI): C10 24 H 23 [M+H] of N2O4S + The calculated value is 435.14, and the measured value is 435.30.

[0403] 4-Cyano-N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiaza-7-yl)benzamide.1 ¹H NMR (400MHz, 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, 5.1 Hz, 1H), 3.65 (dt, J = 10.5, 5.4 Hz, 1H), 3.35 (s, 3H). 13 C10 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. LC-MS (ESI): C10 24 H 20 [M+H] of N3O3S + The calculated value is 430.12, and the measured value is 430.10.

[0404] 7-(benzylamino)-10-(2-methoxyethyl)dibenzo[b,f][1,4]thiaza-11(10H)-one. 1 HNMR (400MHz, 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). 13C10 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. LC-MS (ESI): C10 23 H 23 [M+H] of N2O2S + The calculated value is 391.15, and the measured value is 391.10.

[0405] N-(11-oxo-10-(2-(prop-2-yn-1-yloxy)ethyl)-10,11-dihydrodibenzo[b,f][1,4]thiaza-7-yl)furan-3-carboxamide. 1 H NMR (400MHz, 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 C10 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. LC-MS (ESI): C10 23 H 19 [M+H] of N2O4S + The calculated value is 419.11, and the measured value is 419.30.

[0406] 4-Ethyl-N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiaza-7-yl)benzamide. 1H NMR (400MHz, chloroform-d) δ7.96 (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=7.6Hz, 2H), 1.26 (t, J=7.6Hz, 3H). 13 C10 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. LC-MS (ESI): C10 25 H 25 [M+H] of N2O3S + The calculated value is 433.16, and the measured value is 433.30.

[0407] 4-ethynyl-N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiaza-7-yl)benzamide. 1 H NMR (400MHz, chloroform-d) δ8.21 (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). 13C10 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. LC-MS (ESI): C10 25 H 21 [M+H] of N2O3S + The calculated value is 429.13, and the measured value is 429.10.

[0408] N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazo-7-yl)2-naphthamide. 1 H NMR (400MHz, 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 C10 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. LC-MS (ESI): C10 27 H 23 [M+H] of N2O3S + The calculated value is 455.14, and the measured value is 455.20.

[0409] N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiaza-7-yl)-[1,1'-biphenyl]-4-carboxamide. 1H NMR (400MHz, chloroform-d) δ 8.09 (s, 1H), 7.97 (d, J=2.5Hz, 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 C10 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. LC-MS (ESI): C10 29 H 25 [M+H] of N2O3S + The calculated value is 481.16, and the measured value is 481.10.

[0410] 4-Methoxy-N-(11-oxo-10-(2-(prop-2-yn-1-yloxy)ethyl)-10,11-dihydrodibenzo[b,f][1,4]thiaza-7-yl)benzamide. 1 H NMR (400MHz, 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, 2.6Hz, 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, 5.2 Hz, 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). 13C10 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. LC-MS (ESI): C10 26 H 23 [M+H] of N2O4S + The calculated value is 459.14, and the measured value is 459.10.

[0411] N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiaza-7-yl)cyclopropaneformamide. 1 ¹H NMR (400MHz, chloroform-d) δ 7.82 (s, 1H), 7.75 (s, 1H), 7.65 (dd, J=7.5, 1.7Hz, 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, 5.5Hz, 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 C10 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. LC-MS (ESI): C10 20 H 21 [M+H] of N2O3S + The calculated value is 369.13, and the measured value is 369.10.

[0412] N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiaza-7-yl)-3-oxocyclobutane-1-carboxamide. 1H NMR (400MHz, chloroform-d) δ 8.14 (s, 1H), 7.85 (d, J=2.5Hz, 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, 5.3Hz, 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 C10 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. LC-MS (ESI): C10 21 H 21 [M+H] of N2O4S + The calculated value is 397.12, and the measured value is 397.10.

[0413] N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiaza-7-yl)-4-(trifluoromethoxy)benzamide. 1 H NMR (400MHz, chloroform-d) δ 8.41 (s, 1H), 7.94 (d, J=2.5Hz, 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, 1H), 3.33 (s, 3H). 13C10 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. LC-MS (ESI): C10 24 H 20 [M+H] of F3N2O4S + The calculated value is 489.11, and the measured value is 489.10.

[0414] 3,4-Dichloro-N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiaza-7-yl)benzamide. 1 H NMR (400MHz, 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 C10 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. LC-MS (ESI): C10 23 H 19 [M+H] of Cl2N2O3S + The calculated value is 473.05, and the measured value is 473.00.

[0415] N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiaza-7-yl)spiro[2,2]pentane-1-carboxamide. 1H NMR (400MHz, chloroform-d) δ 7.83 (s, 1H), 7.65 (dd, J=6.6, 2.0Hz, 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 C10 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. LC-MS (ESI): C10 22 H 23 [M+H] of N2O3S + The calculated value is 395.15, and the measured value is 395.00.

[0416] N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiaza-7-yl)spiro[3.3]-heptane-2-carboxamide. 1 H NMR (400MHz, 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=8.5 Hz, 1H), 2.33-2.23 (m, 2H), 2.18 (t, J=10.3 Hz, 2H), 2.02 (t, J=7.2Hz, 2H), 1.92 (t, J=7.2 Hz, 2H), 1.80 (q, J=8.5 Hz, 2H). 13C10 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. LC-MS (ESI): C10 24 H 27 [M+H] of N2O3S + The calculated value is 423.18, and the measured value is 423.10.

[0417] N-(10-hexyl-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiaza-7-yl)furan-3-carboxamide. 1 H NMR (400MHz, chloroform-d) δ8.24 (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 C10 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. LC-MS (ESI): C10 24 H 25 [M+H] of N2O3S + The calculated value is 421.16, and the measured value is 421.10.

[0418] 10-(2-methoxyethyl)-7-((1-phenylethyl)amino)dibenzo[b,f][1,4]thiaza-11(10H)-one. 1H NMR (400MHz, 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=6.7Hz, 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. LC-MS (ESI): C 24 H 25 [M+H] of N2O2S + The calculated value is 405.17, and the measured value is 405.10.

[0419] N-(6-(2-methoxyethyl)-5-oxo-5,6-dihydrobenzo[b]pyrido[3,2-f][1,4]thiaza-9-yl)benzamide. 1 H NMR (400MHz, 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). 13C10 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. LC-MS (ESI): C10 22 H 20 [M+Na] of N3O3S + The calculated value is 428.10, and the measured value is 428.00.

[0420] N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazazon-7-yl)azacyclobutane-1-carboxamide. 1 H NMR (400MHz, 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). 13 C10 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. LC-MS (ESI): C10 20 H 22 [M+H] of N3O3S + The calculated value is 384.14, and the measured value is 384.10.

[0421] Phenyl(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiaza-7-yl)carbamate. 1¹H NMR (400MHz, 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 C10 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. LC-MS (ESI): C10 23 H 21 [M+H] of N2O4S + The calculated value is 421.12, and the measured value is 421.10.

[0422] 3-Methoxy-N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazazon-7-yl)azacyclobutane-1-carboxamide. 1 ¹H NMR (400MHz, 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, 5.3Hz, 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 C10 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. LC-MS (ESI): C10 21 H 24 [M+H] of N3O4S +The calculated value is 414.15, and the measured value is 414.10.

[0423] 1-(11-oxo-10-(2-(prop-2-yn-1-yloxy)ethyl)-10,11-dihydrodibenzo[b,f][1,4]thiaza-7-yl)-3-phenylurea. 1 H NMR (400MHz, 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=2.4 Hz, 1H). 13 C10 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. LC-MS (ESI): C10 25 H 22 [M+H] of N3O3S + The calculated value is 444.14, and the measured value is 444.10.

[0424] 4-(tert-butyl)-N-(11-oxo-10-(2-(prop-2-yn-1-yloxy)ethyl)-10,11-dihydrodibenzo[b,f][1,4]thiaza-7-yl)benzamide. 1H NMR (400MHz, 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, 2.5Hz, 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, 1.9Hz, 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 C10 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. LC-MS (ESI): C10 29 H 29 [M+H] of N2O3S + The calculated value is 485.19, and the measured value is 485.10.

[0425] 4-Methoxy-3-methyl-N-(11-oxo-10-(2-(prop-2-yn-1-yloxy)ethyl)-10,11-dihydrodibenzo[b,f][1,4]thiaza-7-yl)benzamide. 1 H NMR (400MHz, 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). 13CNMR (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. LC-MS (ESI): C 27 H 25 [M+H] of N2O4S + The calculated value is 473.16, and the measured value is 473.20.

[0426] 1-Cyclohexyl-3-(11-oxo-10-(2-(prop-2-yn-1-yloxy)ethyl)-10,11-dihydrodibenzo[b,f][1,4]thiazolidin-7-yl)urea. 1 H NMR (400MHz, chloroform-d) δ 7.66-7.59 (m, 1H), 7.55 (d, J=2.5Hz, 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 C10 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. LC-MS (ESI): C10 25H 28 [M+H] of N3O3S + The calculated value is 450.19, and the measured value is 450.10.

[0427] N-(11-oxo-10-(2-(prop-2-yn-1-yloxy)ethyl)-10,11-dihydrodibenzo[b,f][1,4]thiazazon-7-yl)azacyclobutane-1-carboxamide. 1 H NMR (400MHz, 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 C10 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. LC-MS (ESI): C10 22 H 22 [M+H] of N3O3S + The calculated value is 408.14, and the measured value is 408.10.

[0428] N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiaza-7-yl)pyrrolidine-1-carboxamide. 1H NMR (400MHz, chloroform-d) δ7.70 (d, J=2.2 Hz, 1H), 7.65 (dd, J=7.4, 1.8Hz, 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). 13C10 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. LC-MS (ESI): C10 21 H 24 [M+H] of N3O3S + The calculated value is 398.16, and the measured value is 398.10.

[0429] N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiaza-7-yl)piperidine-1-carboxamide. 1 H NMR (400MHz, 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 C10 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. LC-MS (ESI): C10 22 H 26 [M+H] of N3O3S + The calculated value is 412.17, and the measured value is 412.10.

[0430] N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazazon-7-yl)azacycloheptane-1-carboxamide. 1H NMR (400MHz, 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 C10 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. LC-MS (ESI): C10 23 H 28 [M+H] of N3O3S + The calculated value is 426.19, and the measured value is 426.10.

[0431] (S)-3-fluoro-N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiaza-7-yl)pyrrolidine-1-carboxamide. 1 ¹H NMR (400MHz, 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). LC-MS (ESI): C 21 H 23 [M+H] of FN3O3S + The calculated value is 416.14, and the measured value is 415.10.

[0432] 3-Cyano-N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazazon-7-yl)azacyclobutane-1-carboxamide. 1 ¹H NMR (400MHz, 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 C10 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. LC-MS (ESI): C10 21 H 21 [M+H] of N4O3S + The calculated value is 409.14, and the measured value is 409.30.

[0433] N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiaza-7-yl)-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide. 1 H NMR (400MHz, 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). 13C10 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. LC-MS (ESI): C10 22 H 24 [M+H] of N3O4S + The calculated value is 426.15, and the measured value is 426.30.

[0434] 2-Methoxy-N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiaza-7-yl)benzamide. 1 ¹H NMR (400MHz, 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 C10 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. LC-MS (ESI): C10 24 H 23 [M+H] of N2O4S + The calculated value is 435.14, and the measured value is 435.30.

[0435] N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiaza-7-yl)cyclopropaneformamide. 1H NMR (400MHz, 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 C10 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. LC-MS (ESI): C10 24 H 23 [M+H] of N2O4S + The calculated value is 435.14, and the measured value is 435.30.

[0436] 3-Bromo-4-methoxy-N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiaza-7-yl)benzamide. 1 H NMR (400MHz, 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). 13C10 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. LC-MS (ESI): C10 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 [M+H] of BrN2O4S + The calculated value is 513.05, and the measured value is 513.30.

[0437] 3-Fluoro-4-methoxy-N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiaza-7-yl)benzamide. 1 H NMRNMR (400MHz, chloroform-d) δ 8.13 (s, 1H), 7.92 (d, J=2.5Hz, 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 C10 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. LC-MS (ESI): C10 24 H 22 [M+H] of FN2O4S + The calculated value is 453.13, and the measured value is 453.30.

[0438] 3,4-Dichloro-N-(11-oxo-10-(2-(prop-2-yn-1-yloxy)ethyl)-10,11-dihydrodibenzo[b,f][1,4]thiaza-7-yl)benzamide. 1H NMR (400MHz, 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=2.4 Hz, 1H). 13 C10 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. LC-MS (ESI): C10 25 H 19 [M+H] of Cl2N2O3S + The calculated value is 497.05, and the measured value is 497.10.

[0439] N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiaza-7-yl)-1H-benzo[d][1,2,3]triazole-5-carboxamide. 1 H NMR (400MHz, methanol-d4) δ8.53 (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, 5.4Hz, 1H), 3.32 (s, 3H). 13C10 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. LC-MS (ESI): C10 23 H 20 [M+H] of N5O3S + The calculated value is 446.13, and the measured value is 446.30.

[0440] N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiaza-7-yl)-2-methylfuran-3-carboxamide. 1 H NMR (400MHz, 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 CNMR (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. LC-MS (ESI): C 22 H 21 [M+H] of N2O4S + The calculated value is 409.12, and the measured value is 409.20.

[0441] N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiaza-7-yl)-2,5-dimethylfuran-3-carboxamide. 1H NMR (400MHz, chloroform-d) δ7.88 (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 C10 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. LC-MS (ESI): C10 23 H 23 [M+H] of N2O4S + The calculated value is 423.14, and the measured value is 423.20.

[0442] N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiaza-7-yl)benzo[d]oxazol-5-carboxamide. 1 H NMR (400MHz, 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, 5.4 Hz, 1H), 3.87-3.77 (m, 1H), 3.70-3.60 (m, 1H), 3.35 (s, 3H). 13C10 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. LC-MS (ESI): C10 24 H 20 [M+H] of N3O4S + The calculated value is 446.12, and the measured value is 446.00.

[0443] N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiaza-7-yl)-4-propoxybenzamide. 1 H NMR (400MHz, chloroform-d) δ8.00 (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 C10 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. LC-MS (ESI): C10 26 H 27 [M+H] of N2O4S + The calculated value is 463.17, and the measured value is 463.30.

[0444] N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiaza-7-yl)cyclopropaneformamide. 1 H NMR (400MHz, chloroform-d) δ7.93 (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 C10 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. LC-MS (ESI): C10 24 H 21 [M+H] of N2O5S + The calculated value is 449.12, and the measured value is 449.20.

[0445] 2-(7-(furan-3-carbamoyl)-11-oxodibenzo[b,f][1,4]thiazazonyl-10(11H)-yl)ethyl pent-4-enoic acid. 1H NMR (400MHz, 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 C10 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. LC-MS (ESI): C10 25 H 23 [M+H] of N2O5S + The calculated value is 463.13, and the measured value is 463.20.

[0446] 4-Methoxy-N-(11-oxo-10-(2-propoxyethyl)-10,11-dihydrodibenzo[b,f][1,4]thiaza-7-yl)benzamide. 1 H NMR (400MHz, 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, 5.8 Hz, 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). LC-MS (ESI): C26 H 27 [M+H] of N2O4S + The calculated value is 463.17, and the measured value is 463.30.

[0447] (E)-N-(hex-2-en-1-yl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiaza-7-yl)furan-3-carboxamide. 1 H NMR (400MHz, chloroform-d) δ 8.06 (s, 1H), 7.98 (s, 1H), 7.80 (d, J=2.5Hz, 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=5.2Hz, 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 C10 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. LC-MS (ESI): C10 24 H 23 [M+H] of N2O3S + The calculated value is 419.15, and the measured value is 419.30.

[0448] N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiaza-7-yl)-2-methylfuran-3-carboxamide. 1H NMR (400MHz, 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 CNMR (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. LC-MS (ESI): C 22 H 21 [M+H] of N2O4S + The calculated value is 409.12, and the measured value is 409.20.

[0449] N-(10-(2-methoxypropyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiaza-7-yl)furan-3-carboxamide (reported as a racemic rotational isomer). 1H NMR (400MHz, 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). LC-MS (ESI): C 22 H 21 [M+H] of N2O4S + The calculated value is 409.12, and the measured value is 409.30.

[0450] N-(11-oxo-10-(2-(pent-4-en-1-yloxy)ethyl)-10,11-dihydrodibenzo[b,f][1,4]thiaza-7-yl)furan-3-carboxamide. 1H NMR (600MHz, chloroform-d) δ 8.04 (s, 1H), 7.84 (d, J=2.5Hz, 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 C10 NMR (151MHz, 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. LC-MS (ESI): C10 25 H 25 [M+H] of N2O4S + The calculated value is 449.15, and the measured value is 449.10.

[0451] 3,4-Difluoro-N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiaza-7-yl)benzamide. 1H NMR (600MHz, 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 C10 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. LC-MS (ESI): C10 23 H 19 [M+H] of F2N2O3S + The calculated value is 441.11, and the measured value is 441.20.

[0452] 4-Chloro-3-fluoro-N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiaza-7-yl)benzamide. 1H NMR (600MHz, 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 C10 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. LC-MS (ESI): C10 23 H 19 [M+H] of FClN2O3S + The calculated value is 457.08, and the measured value is 457.10.

[0453] N-(10-(2-cyanoethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazo-7-yl)furan-3-carboxamide. 1 ¹H NMR (400MHz, 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). LC-MS (ESI): C 21 H 16 [M+H] of N3O3S +The calculated value is 390.08, and the measured value is 390.20.

[0454] 4-Chloro-3-methoxy-N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiaza-7-yl)benzamide. 1 H NMR (600MHz, 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). 13 C10 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. LC-MS (ESI): C10 24 H 22 [M+H] of ClN2O4S + The calculated value is 469.10, and the measured value is 469.30.

[0455] 4-Cyano-3-methoxy-N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiaza-7-yl)benzamide. 1H NMR (600MHz, 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 C10 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. LC-MS (ESI): C10 25 H 22 [M+H] of N3O4S + The calculated value is 460.13, and the measured value is 460.30.

[0456] 3,5-Difluoro-4-methoxy-N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiaza-7-yl)benzamide. 1 H NMR (600MHz, chloroform-d) δ 8.25 (s, 1H), 7.90 (d, J=2.5Hz, 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). 13C10 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. LC-MS (ESI): C10 24 H 21 [M+H] of F2N2O4S + The calculated value is 471.12, and the measured value is 471.30.

[0457] 4-Formamido-N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiaza-7-yl)benzamide. 1 ¹H NMR (600MHz, 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). Hz, 1H), 3.66 (dtd, J=10.4, 5.5, 3.0 Hz, 1H), 3.35 (s, 3H). LC-MS (ESI): C 24 H 22 [M+H] of N3O4S + The calculated value is 448.13, and the measured value is 448.30.

[0458] N-(10-(2-(cyanomethoxy)ethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiaza-7-yl)furan-3-carboxamide. 1H NMR (600MHz, chloroform-d) δ8.05 (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). 13 C10 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. LC-MS (ESI): C10 22 H 17 [M+Na] of N3O4SNa + The calculated value is 442.08, and the measured value is 442.10.

[0459] N-(10-(2-hydroxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazo-7-yl)furan-3-carboxamide. 1 ¹H NMR (400MHz, chloroform-d) δ 8.50 (d, J=2.6 Hz, 1H), 8.19 (dd, J=8.9, 2.6Hz, 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). LC-MS (ESI): C 20 H 17 [M+Na] of N2O4S + The calculated value is 381.08, and the measured value is 381.10.

[0460] N-(10-(1-methoxypropyl-2-yl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiaza-7-yl)furan-3-carboxamide. 1H NMR (400MHz, 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). LC-MS (ESI): C 22 H 21 [M+H] of N2O4S + The calculated value is 409.12, and the measured value is 409.20.

[0461] N-(10-allyl-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiaza-7-yl)furan-3-carboxamide. 1 H NMR (600MHz, 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). 13C10 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. LC-MS (ESI): C10 21 H 17 [M+H] of N2O3S + The calculated value is 377.10, and the measured value is 377.10.

[0462] (E)-N-(5-hydroxypent-2-en-1-yl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiaza-7-yl)furan-3-carboxamide. 1 H NMR (400MHz, 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). LC-MS (ESI): C 23 H 21 [M+H] of N2O4S + The calculated value is 421.11, and the measured value is 421.30.

[0463] (E)-6-(7-(furan-3-carbamoyl)-11-oxodibenzo[b,f][1,4]thiazo-10(11H)-yl)hex-4-enoic acid. 1H NMR (400MHz, methanol-d4) δ8.23 (dd, J=1.6, 0.9 Hz, 1H), 8.04 (d, J=2.5Hz, 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, 0.9Hz, 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). LC-MS (ESI): C 24 H 21 [M+H] of N2O5S + The calculated value is 449.11, and the measured value is 449.30.

[0464] 4-Methoxy-N-(11-oxo-10-(2-(prop-2-yn-1-yloxy)ethyl)-10,11-dihydrodibenzo[b,f][1,4]oxazine-7-yl)benzamide. 1 H NMR (600MHz, 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 C10 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. LC-MS (ESI): C10 26 H 23 [M+H] of N2O5 + The calculated value is 443.16, and the measured value is 443.20.

[0465] N-(5-(2-methoxyethyl)-6-oxo-6,11-dihydro-5H-dibenzo[b,e]aza-2-yl)furan-3-carboxamide. 1 H NMR (600MHz, 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 C10 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. LC-MS (ESI): C10 22 H 21 [M+H] of N2O4 + The calculated value is 377.15, and the measured value is 377.20.

[0466] N-(11-oxo-10-(2-(prop-2-yn-1-yloxy)ethyl)-10,11-dihydrodibenzo[b,f][1,4]thiazo-7-yl)benzo[d]thiazo-5-carboxamide. 1H NMR (400MHz, 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=8.7Hz, 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, 5.0 Hz, 1H), 2.42 (d, J=2.3 Hz, 1H). 13 C10 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. LC-MS (ESI): C10 26 H 20 [M+H] of N3O3S2 + The calculated value is 486.10, and the measured value is 486.10.

[0467] N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazolidin-7-yl)isoxazole-4-carboxamide. 1 ¹H NMR (400MHz, 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). 13C10 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. LC-MS (ESI): C10 20 H 18 [M+H] of N3O4S + The calculated value is 396.10, and the measured value is 396.10.

[0468] N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazolidin-7-yl)thiazolidin-4-carboxamide. 1 H NMR (400MHz, 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). 13 C10 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. LC-MS (ESI): C10 20 H 18 [M+H] of N3O3S2 + The calculated value is 412.08, and the measured value is 412.00.

[0469] N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazo-7-yl)benzo[d]thiazo-5-carboxamide. 1H NMR (400MHz, 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 C10 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. LC-MS (ESI): C10 24 H 20 [M+H] of N3O3S2 + The calculated value is 462.10, and the measured value is 462.10.

[0470] N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazolidin-7-yl)imidazolium[1,2-a]pyridine-6-carboxamide. 1 H NMR (400MHz, 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). 13C10 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. LC-MS (ESI): C10 24 H 21 [M+H] of N4O3S + The calculated value is 445.14, and the measured value is 445.10.

[0471] N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazolidin-7-yl)imidazolium[1,2-a]pyridine-6-carboxamide. 1 H NMR (400MHz, 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 C10 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. LC-MS (ESI): C10 24 H 21 [M+H] of N4O3S + The calculated value is 445.14, and the measured value is 445.10.

[0472] N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiaza-7-yl)pyrimidine-2-carboxamide. 1H NMR (400MHz, 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 C10 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. LC-MS (ESI): C10 21 H 19 [M+H] of N4O3S + The calculated value is 407.12, and the measured value is 407.10.

[0473] N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiaza-7-yl)pyrimidine-4-carboxamide. 1 H NMR (400MHz, 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). 13C10 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. LC-MS (ESI): C10 21 H 19 [M+H] of N4O3S + The calculated value is 407.12, and the measured value is 407.10.

[0474] N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazo-7-yl)pyrazine-2-carboxamide. 1 H NMR (400MHz, chloroform-d) δ 9.67 (s, 1H), 9.50 (s, 1H), 8.82 (d, J =2.0Hz, 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 C10 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. LC-MS (ESI): C10 21 H 19 [M+H] of N4O3S + The calculated value is 407.12, and the measured value is 407.10.

[0475] 3-Fluoro-4-carbamate-N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiaza-7-yl)benzamide. 1¹H NMR (400MHz, 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). 13 C10 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. LC-MS (ESI): C10 24 H 21 [M+H] of FN3O4S + The calculated value is 466.13, and the measured value is 466.10.

[0476] 3-Fluoro-N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiaza-7-yl)-4-(trifluoromethoxy)benzamide. 1 ¹H NMR (400MHz, chloroform-d): δ 7.91 (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). 13C10 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. LC-MS (ESI): C10 24 H 19 [M+H] of F4N2O4S + The calculated value is 507.10, and the measured value is 505.20.

[0477] N-(4-fluoro-10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiaza-7-yl)furan-3-carboxamide. 1 H NMR (400MHz, 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 C10 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. LC-MS (ESI): C10 21 H 18 [M+H] of FN2O4S + The calculated value is 413.10, and the measured value is 413.10.

[0478] N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazolidin-7-yl)isoxazole-5-carboxamide. 1H NMR (400MHz, 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=7.2Hz, 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 C10 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. LC-MS (ESI): C10 20 H 18 [MH] of N3O4S + The calculated value is 394.08, and the measured value is 394.20.

[0479] N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiaza-7-yl)pyrimidine-5-carboxamide. 1 ¹H NMR (400MHz, 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). 13 C10 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. LC-MS (ESI): C1021 H 19 [M+H] of N4O3S + The calculated value is 407.12, and the measured value is 407.10.

[0480] 3-Chloro-4-carbamate-N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiaza-7-yl)benzamide. 1 H NMR (400MHz, 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 C10 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. LC-MS (ESI): C10 24 H 21 [M+H] of ClN3O4S + The calculated value is 482.10, and the measured value is 482.10.

[0481] 4-(difluoromethoxy)-3-fluoro-N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiaza-7-yl)benzamide. 1 ¹H NMR (400MHz, 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). 13C10 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. LC-MS (ESI): C10 24 H 20 [M+H] of F3N2O4S + The calculated value is 489.11, and the measured value is 489.10.

[0482] 3-Fluoro-N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiaza-7-yl)-4-(methanesulfonyl)benzamide. 1 H HNMR (400MHz, chloroform-d): δ9.04 (s, 1H), 7.99 (d, J =2.4Hz, 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 C10 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. LC-MS (ESI): C10 24 H 22 [M+H] of FN2O5S2 + The calculated value is 501.10, and the measured value is 501.10.

[0483] 3-Fluoro-N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiaza-7-yl)-4-(methylsulfinyl)benzamide. 1 ¹H NMR (400MHz, 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 C10 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. LC-MS (ESI): C10 24 H 22 [M+H] of FN2O4S2 + The calculated value is 485.10, and the measured value is 485.10.

[0484] N-(2-fluoro-10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiaza-7-yl)furan-3-carboxamide. 1 ¹H NMR (400MHz, 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). 13C10 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. LC-MS (ESI): for C10 21 H 18 [M+H] of FN2O4S + The calculated value is 413.10, and the measured value is 413.10.

[0485] N-(3-fluoro-10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiaza-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). 13 C10 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. LC-MS (ESI): C10 21 H 18 [M+H] of FN2O4S + The calculated value is 413.10, and the measured value is 413.10.

[0486] (E)-10-(hex-2-en-1-yl)-7-(pyridin-2-ylamino)dibenzo[b,f][1,4]thiazazon-11(10H)-one. 1H NMR (400MHz / 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 C10 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. LC-MS (ESI): C10 24 H 24 N3OS's [M+H] + The calculated value is 402.17, and the measured value is 402.20.

[0487] 4-Methoxy-N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiaza-7-yl)-2-methylbenzamide. 1 H NMR (400MHz, 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). 13C10 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. LC-MS (ESI): C10 25 H 25 [M+H] of N2O4S + The calculated value is 449.16, and the measured value is 449.20.

[0488] 2-Fluoro-4-methoxy-N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiaza-7-yl)benzamide. 1 H NMR (400MHz, 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 C10 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. LC-MS (ESI): C10 24 H 22[M+H] of FN2O4S + The calculated value is 453.13, and the measured value is 453.10.

[0489] 3-((10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiaza-7-yl)carbamoyl)benzoic acid. 1 H NMR (400MHz, 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) δ167.1, 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. LC-MS (ESI): C 24 H 21 [M+H] of N2O5S + The calculated value is 449.12, and the measured value is 449.10.

[0490] N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazo-7-yl)isophthalamide. 1 ¹H 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). 13CNMR (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. LC-MS (ESI): C 24 H 22 [M+H] of N3O4S + The calculated value is 448.14, and the measured value is 448.10.

[0491] N1-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiaza-7-yl)-N4-methylterephthalamide. 1 H NMR (400MHz, 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 C10 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. LC-MS (ESI): C10 25 H 24 [M+H] of N3O4S + The calculated value is 462.15, and the measured value is 462.20.

[0492] 4-((10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiaza-7-yl)carbamoyl)benzoic acid. 1H NMR (400MHz, 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. LC-MS (ESI): C 24 H 20 [M+H] of N2O5S + The calculated value is 449.12, and the measured value is 449.10.

[0493] N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiaza-7-yl)terephthalamide. 1 H NMR (400MHz, 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. LC-MS (ESI): C 24 H 22[M+H] of N3O4S + The calculated value is 448.14, and the measured value is 448.20.

[0494] N1-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiaza-7-yl)-N4-methylterephthalamide. 1 H NMR (400MHz, 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). 13 C 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. LC-MS (ESI): C 25 H 24 [M+H] of N3O4S + The calculated value is 462.15, and the measured value is 462.20.

[0495] N1-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiaza-7-yl)-N4,N4-dimethylterephthalamide. 1H NMR (400MHz, 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 CNMR (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. LC-MS (ESI): C 26 H 26 [M+H] of N3O4S + The calculated value is 476.17, and the measured value is 476.20.

[0496] 3-(1-Cyanoethyl-N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiaza-7-yl)benzamide. 1 H NMR (400MHz, 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). 13C10 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. LC-MS (ESI): C10 26 H 24 [M+H] of N3O3S + The calculated value is 458.16, and the measured value is 458.20.

[0497] 3-(1-cyanomethyl-N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiaza-7-yl)benzamide. 1 ¹H NMR (400MHz, 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 C10 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. LC-MS (ESI): C10 25 H 22 [M+H] of N3O3S + The calculated value is 444.14, and the measured value is 444.10.

[0498] tert-Butyl-4-(aminomethyl)-N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiaza-7-yl)benzamide hydrochloride. 1H NMR (400MHz, 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). 13 C10 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. LC-MS (ESI): C10 24 H 24 [M+H] of N3O3S + The calculated value is 434.16, and the measured value is 434.20.

[0499] (E)-4-((10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiaza-7-yl)amino)-4-oxobut-2-enoic acid. 1 H NMR (400MHz, 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 C10 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. LC-MS (ESI): C10 20 H 19[M+H] of N2O5S + The calculated value is 399.10, and the measured value is 399.10.

[0500] 2-Cyano-N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiaza-7-yl)acetamide. 1 ¹H NMR (400MHz, 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 C10 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. LC-MS (ESI): C10 19 H 18 [M+H] of N3O3S + The calculated value is 468.11, and the measured value is 368.10.

[0501] 2-((10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiaza-7-yl)amino)-2-oxoacetic acid. 1 ¹H NMR (400MHz, 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). 13C10 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. LC-MS (ESI): C10 18 H 17 [M+H] of N2O5S + The calculated value is 373.09, and the measured value is 373.10.

[0502] (E)-10-(hex-2-en-1-yl)-7-(isoquinoline-1-ylamino)dibenzo[b,f][1,4]thiazazon-11(10H)-one. 1 H NMR (400MHz, 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 C10 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. LC-MS (ESI): C10 28 H 26 N3OS's [M+H] + The calculated value is 452.18, and the measured value is 452.30.

[0503] 2-Cyano-4-methoxy-N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiaza-7-yl)benzamide. 1¹H NMR (400MHz, 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 C10 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. LC-MS (ESI): C10 25 H 22 [M+H] of N3O4S + The calculated value is 460.14, and the measured value is 460.20.

[0504] N1-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiaza-7-yl)-N4,N4-dimethylterephthalamide. 1 H NMR (400MHz, 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). 13C10 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. LC-MS (ESI): C10 26 H 26 [M+H] of N3O4S + The calculated value is 476.17, and the measured value is 476.20.

[0505] N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazo-7-yl)-4-sulfamoylbenzamide. 1 HNMR (400MHz, 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. LC-MS (ESI): C 23 H 22 [M+H] of N3O5S2 + The calculated value is 484.10, and the measured value is 484.10.

[0506] 4-(difluoromethoxy)-N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiaza-7-yl)benzamide. 1H NMR (400MHz, 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 C10 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. LC-MS (ESI): C10 24 H 21 [M+H] of F2N2O4S + The calculated value is 471.12, and the measured value is 471.10.

[0507] 4-(formamidomethyl)-N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiaza-7-yl)benzamide. 1H NMR (600MHz, 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=8.1Hz, 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, 5.5Hz, 1H), 3.86-3.79 (m, 1H), 3.68-3.61 (m, 1H), 3.35 (s, 3H). 13 C10 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. LC-MS (ESI): C10 25 H 24 [M+H] of N3O4S + The calculated value is 462.15, and the measured value is 462.10.

[0508] 4-(acetamidomethyl)-N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiaza-7-yl)benzamide. 1 H NMR (400MHz, 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). 13C10 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. LC-MS (ESI): C10 26 H 26 [M+H] of N3O4S + The calculated value is 476.17, and the measured value is 476.20.

[0509] 6-ethynyl-N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiaza-7-yl)nicotinamide. 1 H 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) δ167.1, 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. LC-MS (ESI): C 24 H 20 [M+H] of N3O3S + The calculated value is 430.12, and the measured value is 430.10.

[0510] 2-Ethynyl-N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiaza-7-yl)isonicotinamide. 1H NMR (400MHz, 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 C10 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. LC-MS (ESI): C10 24 H 20 [M+H] of N3O3S + The calculated value is 430.12, and the measured value is 430.10.

[0511] 6-Methoxy-N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiaza-7-yl)nicotinamide. 1 H NMR (400MHz, 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). 13C10 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. LC-MS (ESI): C10 23 H 22 [M+H] of N3O4S + The calculated value is 436.14, and the measured value is 436.10.

[0512] 2-Methoxy-N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiaza-7-yl)isonicotinamide. 1 H NMR (400MHz, 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 CNMR (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. LC-MS (ESI): C 23 H 22 [M+H] of N3O4S + The calculated value is 436.14, and the measured value is 436.20.

[0513] 4-Fluoro-3-methoxy-N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiaza-7-yl)benzamide. 1H NMR (400MHz, 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 C10 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. LC-MS (ESI): C10 24 H 22 [M+H] of FN2O4S + The calculated value is 453.13, and the measured value is 453.20.

[0514] N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazo-7-yl)benzo[d]oxazol-6-carboxamide. 1 H NMR (400MHz, 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). 13C10 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. LC-MS (ESI): C10 24 H 20 [M+H] of N3O4S + The calculated value is 446.12, and the measured value is 446.10.

[0515] N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiaza-7-yl)-2-methylbenzo[d]oxazol-5-carboxamide. 1 ¹H NMR (400MHz, 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 C10 NMR (151MHz, 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. LC-MS (ESI): C10 25 H 22 [M+H] of N3O4S + The calculated value is 460.14, and the measured value is 460.20.

[0516] 1-(benzo[d]oxazol-5-yl)-3-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazolidin-7-yl)urea. 1H NMR (400MHz, methanol-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 C10 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. LC-MS (ESI): C10 24 H 21 [M+H] of N4O4S + The calculated value is 461.13, and the measured value is 461.10.

[0517] (E)-10-(hex-2-en-1-yl)-7-((4-methylpyridin-2-yl)amino)dibenzo[b,f][1,4]thiazazon-11(10H)-one. 1 ¹H NMR (400MHz, chloroform-d): δ 7.71-7.76 (m, 2H), 7.54-7.55 (d, J = 4.0Hz, 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 = 4.0Hz, 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). 13C10 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. LC-MS (ESI): C10 25 H 26 N3OS's [M+H] + The calculated value is 416.18, and the measured value is 416.30.

[0518] (E)-2-((10-(hex-2-en-1-yl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiaza-7-yl)amino)isonicotinonitrile. 1 ¹H NMR (400MHz, 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 C10 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. LC-MS (ESI): C10 25 H 23 N4OS's [M+H] + The calculated value is 427.16, and the measured value is 427.20.

[0519] N-(6-(2-methoxyethyl)-5-oxo-5,6-dihydrodibenzo[b]pyrido[4,3-f][1,4]thiaza-9-yl)furan-3-carboxamide. 1H NMR (400MHz, 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 C10 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. LC-MS (ESI): C10 20 H 18 [M+H] of N3O4S + The calculated value is 396.10, and the measured value is 396.30.

[0520] N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrobenzo[b]pyrido[3,4-f][1,4]thiaza-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). 13 C10 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. LC-MS (ESI): C10 20 H 18 [M+H] of N3O4S +The calculated value is 396.10, and the measured value is 396.20.

[0521] (E)-10-(hex-2-en-1-yl)-7-(pyrazin-2-ylamino)dibenzo[b,f][1,4]thiazazide-11(10H)-one. 1 ¹H NMR (400MHz, chloroform-d): δ 8.18 (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 C10 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. LC-MS (ESI): C10 23 H 23 N4OS's [M+H] + The calculated value is 403.16, and the measured value is 403.10.

[0522] (E)-10-(hex-2-en-1-yl)-7-(pyrimidin-2-ylamino)dibenzo[b,f][1,4]thiazazon-11(10H)-one. 1H NMR (400MHz, 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 C10 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. LC-MS (ESI): C10 23 H 23 N4OS's [M+H] + The calculated value is 403.16, and the measured value is 403.10.

[0523] N-(10-(6-methylamino)-6-oxohexyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiaza-7-yl)furan-3-carboxamide. 1 H NMR (400MHz, 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). 13C10 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. LC-MS (ESI): C10 25 H 26 [M+H] of N3O4S + The calculated value is 464.17, and the measured value is 464.20.

[0524] (E)-10-(hex-2-en-1-yl)-7-((3-methylpyridin-2-yl)amino)dibenzo[b,f][1,4]thiazazon-11(10H)-one. 1 H NMR (400MHz, 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 C10 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. LC-MS (ESI): C10 25 H 26 N3OS's [M+H] + The calculated value is 416.18, and the measured value is 416.30.

[0525] (E)-2-((10-(hex-2-en-1-yl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazo-7-yl)amino)nicotinonitrile.1 ¹H NMR (400MHz, 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 C10 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. LC-MS (ESI): C10 25 H 23 N4OS's [M+H] + The calculated value is 427.16, and the measured value is 427.20.

[0526] N-(3-fluoro-11-oxo-10-(2-(prop-2-yn-1-yloxy)ethyl)-10,11-dihydrodibenzo[b,f][1,4]thiazo-7-yl)benzo[d]thiazo-5-carboxamide. 1 H NMR (400MHz, 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). 13C10 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. LC-MS (ESI): C10 26 H 19 [M+H] of FN3O3S2 + The calculated value is 504.09, and the measured value is 504.10.

[0527] N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiaza-7-yl)-2-(4-methoxyphenyl)acetamide. 1 ¹H NMR (400MHz, 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 CNMR (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. LC-MS (ESI): C 25 H 25 [M+H] of N2O4S + The calculated value is 449.16, and the measured value is 449.10.

[0528] N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazo-7-yl)benzothioamide. 1H NMR (600MHz, 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). LC-MS (ESI): C 23 H 21 [M+H] of N2O2S2 + The calculated value is 421.10, and the measured value is 421.10.

[0529] N-(10-(but-2-yn-1-yl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazo-7-yl)benzo[d]thiazo-5-carboxamide. 1 ¹H NMR (400MHz, 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 C10 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. LC-MS (ESI): C10 25 H 18 [M+H] of N3O2S2 + The calculated value is 456.09, and the measured value is 456.10.

[0530] N-(10-(but-2-yn-1-yl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiaza-7-yl)-3-methoxybenzamide. 1 H NMR (400MHz, 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 C10 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. LC-MS (ESI): C10 25 H 21 [M+H] of N2O3S + The calculated value is 429.13, and the measured value is 429.20.

[0531] (E)-10-(hex-2-en-1-yl)-7-((3-methoxypyridin-2-yl)amino)dibenzo[b,f][1,4]thiazazon-11(10H)-one. 1 ¹H NMR (400MHz, 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). 13C10 NMR (151MHz, 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. LC-MS (ESI): C10 25 H 26 [M+H] of N3O2S + The calculated value is 432.18, and the measured value is 432.30.

[0532] (E)-10-(hex-2-en-1-yl)-7-((3-(trifluoromethyl)pyridin-2-yl)amino)dibenzo[b,f][1,4]thiazazon-11(10H)-one. 1 H 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 C10 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. LC-MS (ESI): C10 25 H 23 F3N3OS's [M+H] + The calculated value is 470.15, and the measured value is 470.20.

[0533] (E)-7-((3-fluoropyridin-2-yl)amino)-10-(hex-2-en-1-yl)dibenzo[b,f][1,4]thiazazon-11(10H)-one. 1H NMR (400MHz, 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 CNMR (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. LC-MS (ESI): C 24 H 23 FN3OS's [M+H] + The calculated value is 420.16, and the measured value is 420.10.

[0534] N-(10-allyl-3-fluoro-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazolidin-7-yl)benzo[d]thiazolidin-5-carboxamide. 1 H NMR (400MHz, 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). 13C10 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. LC-MS (ESI): C10 24 H 17 [M+H] of FN3O2S2 + The calculated value is 462.08, and the measured value is 462.10.

[0535] N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiaza-7-yl)-2-(3-methoxyphenyl)acetamide. 1 ¹H NMR (400MHz, 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 C10 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. LC-MS (ESI): C10 25 H 25 [M+H] of N2O4S + The calculated value is 449.16, and the measured value is 449.10.

[0536] N-(10-(but-2-yn-1-yl)-3-fluoro-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiaza-7-yl)-6-methoxynicotinamide. 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). 13 C10 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. LC-MS (ESI): C10 24 H 19 [M+H] of FN3O3S + The calculated value is 448.12, and the measured value is 448.10.

[0537] N-(10-(but-2-yn-1-yl)-3-fluoro-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiaza-7-yl)-4-(trifluoromethoxy)benzamide. 1 ¹H NMR (400MHz, 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). 13C10 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. LC-MS (ESI): C10 25 H 17 [M+H] of F4N2O3S + The calculated value is 501.09, and the measured value is 501.10.

[0538] N-(10-(but-2-yn-1-yl)-3-fluoro-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiaza-7-yl)-4-(difluoromethoxy)benzamide. 1 ¹H NMR (400MHz, 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). 13CNMR (151 MHz, chloroform-d) δ 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 (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. LC-MS (ESI): C 25 H 18 [M+H] of F3N2O3S + The calculated value is 483.10, and the measured value is 483.00.

[0539] N-(10-(but-2-yn-1-yl)-3-fluoro-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazo-7-yl)benzo[d]thiazo-5-carboxamide. 1 H NMR (400 MHz, chloroform-d): δ 9.11 (s, 1H), 8.58 (d, J =1.2Hz, 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). 13C10 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. LC-MS (ESI): C10 25 H 17 [M+H] of FN3O2S2 + The calculated value is 474.08, and the measured value is 474.10.

[0540] N-(10-(but-2-yn-1-yl)-3-fluoro-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiaza-7-yl)-3-(1-cyanoethyl)benzamide. 1 H 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 CNMR (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. LC-MS (ESI): C 27 H 21 [M+H] of FN3O2S +The calculated value is 470.14, and the measured value is 470.10.

[0541] 10-(but-2-yn-1-yl)-3-fluoro-7-((3-methylpyrazin-2-yl)amino)dibenzo[b,f][1,4]thiazazide-11(10H)-one. 1 H NMR (400MHz, 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 C10 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. LC-MS (ESI): C10 22 H 18 FN4OS's [M+H] + The calculated value is 405.12, and the measured value is 405.20.

[0542] 10-(but-2-yn-1-yl)-3-fluoro-7-((3-methoxypyrazin-2-yl)amino)dibenzo[b,f][1,4]thiazazon-11(10H)-one. 1 ¹H NMR (400MHz, 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). 13CNMR (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. LC-MS (ESI): C 22 H 18 [M+H] of FN4O2S + The calculated value is 421.12, and the measured value is 421.10.

[0543] N-(10-(but-2-yn-1-yl)-3-fluoro-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiaza-7-yl)benzo[d]oxazol-5-carboxamide. 1 H 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 C10 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. LC-MS (ESI): C10 25 H 17 [M+H] of FN3O3S + The calculated value is 458.10, and the measured value is 458.10.

[0544] N-(10-(3-cyclopropylprop-2-yn-1-yl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazo-7-yl)benzo[d]thiazo-5-carboxamide. 1H NMR (600MHz, chloroform-d) δ 9.13 (s, 1H), 8.62 (d, J=1.7Hz, 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 C10 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. LC-MS (ESI): C10 27 H 20 [M+H] of N3O2S2 + The calculated value is 482.10, and the measured value is 482.10.

[0545] N-(10-(but-2-yn-1-yl)-3-fluoro-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiaza-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). 13C 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. LC-MS (ESI): C 25 H 17 [M+H] of FN3O2S + The calculated value is 442.10, and the measured value is 442.10.

[0546] 1-(benzo[d]thiazo-5-yl)-3-(10-(but-2-yn-1-yl)-3-fluoro-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazo-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=2.4Hz, 3H). 13 C 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=9.4Hz), 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. LC-MS (ESI): C 25 H 18 [M+H] of FN4O2S2 + The calculated value is 489.09, and the measured value is 489.00.

[0547] 10-(but-2-yn-1-yl)-3-fluoro-7-((3-methylpyridin-2-yl)amino)dibenzo[b,f][1,4]thiazazon-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 C10 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. LC-MS (ESI): C10 23 H 19 FN3OS's [M+H] + The calculated value is 404.13, and the measured value is 404.20.

[0548] 2-((10-(but-2-yn-1-yl)-3-fluoro-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazo-7-yl)amino)nicotinonitrile. 1 H 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). 13C10 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. LC-MS (ESI): C10 23 H 16 FN4OS's [M+H] + The calculated value is 415.11, and the measured value is 415.10.

[0549] 10-(but-2-yn-1-yl)-3-fluoro-7-((3-fluoropyridin-2-yl)amino)dibenzo[b,f][1,4]thiazazon-11(10H)-one. 1 H NMR (400MHz, 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 =2.4Hz, 3H). 13 C NMR (151 Mhz, chloroform-d) δ 167.7, 164.0, 162.3, 147.8, 146.1, 144.6 (d, J=8.5Hz), 142.6 (d, J=6.2 Hz), 140.9 (d, J=8.3 Hz), 138.0, 137.6, 134.9, 134.0 (d, J=9.3Hz), 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. LC-MS (ESI): C 22 H 16 F2N3OS's [M+H] + The calculated value is 408.10, and the measured value is 408.10.

[0550] 10-(but-2-yn-1-yl)-3-fluoro-7-((3-methoxypyridin-2-yl)amino)dibenzo[b,f][1,4]thiazazon-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 CNMR (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. LC-MS (ESI): C 23 H 19 [M+H] of FN3O2S + The calculated value is 420.12, and the measured value is 420.20.

[0551] 10-(but-2-yn-1-yl)-7-((3-cyclopropylpyridin-2-yl)amino)-3-fluorodibenzo[b,f][1,4]thiazazet-11(10H)-one. 1H NMR (400MHz, 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 C10 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. LC-MS (ESI): C10 25 H 21 FN3OS's [M+H] + The calculated value is 430.14, and the measured value is 430.30.

[0552] 3-Cyano-N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiaza-7-yl)benzamide. 1 ¹H NMR (400MHz, 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). 13C10 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. LC-MS (ESI): C10 24 H 20 [M+H] of N3O3S + The calculated value is 430.12, and the measured value is 430.10.

[0553] 3-Fluoro-N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiaza-7-yl)benzamide. 1 ¹H NMR (400MHz, 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), 3.62–3.367 (m, ¹H), 3.34 (s, ³H). 13 C10 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. LC-MS (ESI): C10 23 H 20 [M+H] of FN2O3S + The calculated value is 423.12, and the measured value is 423.10.

[0554] N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiaza-7-yl)-3-(trifluoromethoxy)benzamide. 1¹H 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). 13 C10 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. LC-MS (ESI): C10 24 H 20 [M+H] of F3N2O4S + The calculated value is 489.11, and the measured value is 489.10.

[0555] 3-(difluoromethoxy)-N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiaza-7-yl)benzamide. 1 H NMR (400MHz, 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). 13C10 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. LC-MS (ESI): C10 24 H 21 [M+H] of F2N2O4S + The calculated value is 471.12, and the measured value is 471.10.

[0556] N-(10-(but-2-yn-1-yl)-3-fluoro-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiaza-7-yl)-3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-carboxamide. 1 ¹H 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 C10 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. LC-MS (ESI): C10 26 H 19 [M+H] of FN3O4S + The calculated value is 488.11, and the measured value is 488.10.

[0557] 1-(benzo[d]oxazol-5-yl)-3-(10-(but-2-yn-1-yl)-3-fluoro-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazolidin-7-yl)urea. 1 H NMR (400MHz, 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 C10 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. LC-MS (ESI): C10 25 H 18 [M+H] of FN4O3S + The calculated value is 473.11, and the measured value is 473.10.

[0558] (E)-3-((10-(hex-2-en-1-yl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiaza-7-yl)amino)pyrazine-2-carboxynitrile. 1H NMR (400MHz, 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. LC-MS (ESI): C 24 H 22 N5OS's [M+H] + The calculated value is 428.16, and the measured value is 428.10.

[0559] 10-(but-2-yn-1-yl)-7-((3-(trifluoromethyl)pyridin-2-yl)amino)dibenzo[b,f][1,4]thiazazon-11(10H)-one. 1 ¹H NMR (400MHz, 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 = 2.0Hz, 3H). 13C10 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. LC-MS (ESI): C10 23 H 17 F3N3OS's [M+H] + The calculated value is 440.11, and the measured value is 440.10.

[0560] 2-((10-(but-2-yn-1-yl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiaza-7-yl)amino)nicotinic acid methyl ester. 1 H NMR (400MHz, 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 C10 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. LC-MS (ESI): C10 24 H 20 [M+H] of N3O3S + The calculated value is 430.12, and the measured value is 430.10.

[0561] 4-Azide-N-(11-oxo-10-(prop-2-yn-1-yl)-10,11-dihydrodibenzo[b,f][1,4]thiaza-7-yl)benzamide. 1H NMR (400MHz, 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 C10 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. LC-MS (ESI): C10 23 H 16 [M+H] of N5O2S + The calculated value is 426.10, and the measured value is 426.10.

[0562] N-(10-(but-2-yn-1-yl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiaza-7-yl)-2-(7-(dimethylamino)-2-oxo-2H-chromene-4-yl)acetamide. 1 H NMR (400MHz, 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). LC-MS (ESI): C 30 H 26 [M+H] of N3O4S + The calculated value is 524.16, and the measured value is 524.30.

[0563] N-(11-oxo-10-(prop-2-yn-1-yl)-10,11-dihydrodibenzo[b,f][1,4]thiazo-7-yl)benzo[d]thiazo-5-carboxamide. 1 H NMR (600MHz, 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). 13 C10 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. LC-MS (ESI): C10 24 H 16 [M+H] of N3O2S2 + The calculated value is 442.07, and the measured value is 442.20.

[0564] N-(5-(but-2-yn-1-yl)-6-oxo-6,11-dihydro-5H-dibenzo[b,e]aza-2-yl)-4-methoxybenzamide. 1 H NMR (600MHz, 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 C10 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. LC-MS (ESI): C10 26 H 23 [M+H] of N2O3 + The calculated value is 411.17, and the measured value is 411.20.

[0565] (E)-10-(hex-2-en-1-yl)-7-(isoquinoline-3-ylamino)dibenzo[b,f][1,4]thiazazon-11(10H)-one. 1 ¹H NMR (400MHz, 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 C10 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. LC-MS (ESI): C10 28 H 26 N3OS's [M+H] + The calculated value is 452.18, and the measured value is 452.30.

[0566] 2-(benzo[d]oxazol-5-yl)-N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiaza-7-yl)acetamide.1 H NMR (400MHz, 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 C10 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. LC-MS (ESI): C10 25 H 22 [M+H] of N3O4S + The calculated value is 460.14, and the measured value is 446.10.

[0567] N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiaza-7-yl)-2-oxo-2,3-dihydrobenzo[d]oxazol-5-carboxamide. 1 H NMR (600MHz, 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). 13C 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, 1 30.0, 129.5, 128.3, 126.0, 123.0, 121.6, 120.9, 108.6, 108.5, 68.7, 57.5, 49.3. LC-MS (ESI): C 24 H 20 [M+H] of N3O5S + The calculated value is 462.11, and the measured value is 462.10.

[0568] N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiaza-7-yl)-3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-carboxamide. 1 ¹H NMR (400MHz, 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 C10 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. LC-MS (ESI): C10 25 H 22 [M+H] of N3O5S + The calculated value is 476.13, and the measured value is 476.10.

[0569] 2-(2-(7-(furan-3-carbamoyl)-11-oxodibenzo[b,f][1,4]thiazo-10(11H)-yl)ethoxyacetic acid. 1¹H 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). 13 C10 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. LC-MS (ESI): C10 22 H 19 [M+H] of N2O6S + The calculated value is 439.10, and the measured value is 439.10.

[0570] 6-(7-(furan-3-carbamate)-11-oxodibenzo[b,f][1,4]thiazo-10(11H)-yl)hexanoic acid. 1 H NMR (400MHz, 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 C10 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. LC-MS (ESI): C10 24 H 23 [M+H] of N2O5S + The calculated value is 451.13, and the measured value is 451.10.

[0571] (E)-10-(hex-2-en-1-yl)-7-((4-methoxypyridin-2-yl)amino)dibenzo[b,f][1,4]thiazazon-11(10H)-one. 1 H NMR (400MHz, chloroform-d): δ 8.00 (d, J=6.0 Hz, 1H), 7.71 (t, J=7.6Hz, 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 CNMR (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. LC-MS (ESI): C 25 H 26 [M+H] of N3O2S + The calculated value is 432.18, and the measured value is 432.10.

[0572] (E)-10-(hex-2-en-1-yl)-7-((4-(trifluoromethyl)pyridin-2-yl)amino)dibenzo[b,f][1,4]thiazazon-11(10H)-one. 1 ¹H NMR (400MHz, 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 C10 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. LC-MS (ESI): C10 25 H 23 F3N3OS's [M+H] + The calculated value is 470.15, and the measured value is 470.20.

[0573] (E)-10-(hex-2-en-1-yl)-7-((4-isopropylpyridin-2-yl)amino)dibenzo[b,f][1,4]thiazazon-11(10H)-one. 1 H NMR (400MHz, 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 C10 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. LC-MS (ESI): C10 27 H 30 N3OS's [M+H] + The calculated value is 444.21, and the measured value is 444.40.

[0574] (E)-7-((4-cyclopropylpyridin-2-yl)amino)-10-(hex-2-en-1-yl)dibenzo[b,f][1,4]thiazazon-11(10H)-one. 1 H NMR (400MHz, 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 C10 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. LC-MS (ESI): C10 27 H 28 N3OS's [M+H] + The calculated value is 442.20, and the measured value is 442.30.

[0575] (E)-7-((4-fluoropyridin-2-yl)amino)-10-(hex-2-en-1-yl)dibenzo[b,f][1,4]thiazazon-11(10H)-one. 1 H NMR (400MHz, 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, 2.4Hz, 1H), 6.45-6.48 (m, 1H), 5.64-5.67 (m, 2H), 4.87 (d, J =14 Hz, 1H), 4.48 (d, J =4.8Hz, 1H), 1.99-2.01 (m, 2H), 1.32-1.39 (m, 2H), 0.84 (t, J =7.6 Hz, 3H).13 C10 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. LC-MS (ESI): C10 24 H 23 FN3OS's [M+H] + The calculated value is 420.16, and the measured value is 420.30.

[0576] 3-(1-Cyanoethyl)-N-(11-oxo-10-(2-(prop-2-yn-1-yloxy)ethyl)-10,11-dihydrodibenzo[b,f][1,4]thiaza-7-yl)benzamide. 1 H 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 =2.4Hz, 1H), 1.66 (d, J =7.6 Hz, 3H). 13 C10 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. LC-MS (ESI): C10 28 H 24 [M+H] of N3O3S + The calculated value is 482.16, and the measured value is 482.10.

[0577] N-(10-allyl-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazolidin-7-yl)benzo[d]thiazolidin-5-carboxamide. 1 H NMR (400MHz, 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 C10 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. LC-MS (ESI): C10 24 H 18 [M+H] of N3O2S2 + The calculated value is 444.09, and the measured value is 444.00.

[0578] N-(10-(but-2-yn-1-yl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiaza-7-yl)furan-3-carboxamide. 1H NMR (400MHz, 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 C10 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. LC-MS (ESI): C10 22 H 17 [M+H] of N2O3S + The calculated value is 389.10, and the measured value is 389.10.

[0579] 4-Methoxy-N-(6-oxo-5-(2-(prop-2-yn-1-yloxy)ethyl)-6,11-dihydro-5H-dibenzo[b,e]aza-2-yl)benzamide. 1 H NMR (600MHz, 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, 4.3Hz, 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 C10 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. LC-MS (ESI): C10 27 H 25 [M+H] of N2O4 + The calculated value is 441.18, and the measured value is 441.10.

[0580] 3-(fluoromethoxy)-N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiaza-7-yl)benzamide. 1 H NMR (400MHz, 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 C10 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. LC-MS (ESI): C10 24 H 22 [M+H] of FN2O4S + The calculated value is 452.50, and the measured value is 452.12.

[0581] 2,2-Difluoro-N-(10-(2-methoxyethyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiaza-7-yl)benzo[d][1,3]dioxolane-5-carboxamide. 1¹H NMR (400MHz, 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). 13 C10 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. LC-MS (ESI): C10 24 H 19 [M+H] of F2N2O5S + The calculated value is 484.47, and the measured value is 484.09.

[0582] (E)-10-(hex-2-en-1-yl)-7-((3-methylpyrazin-2-yl)amino)dibenzo[b,f][1,4]thiazazide-11(10H)-one. 1 ¹H NMR (400MHz, chloroform-d): δ 7.71-7.76 (m, 2H), 7.54-7.55 (d, J = 4.0Hz, 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 = 4.0Hz, 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). 13C10 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. LC-MS (ESI): C10 24 H 25 N4OS's [M+H] + The calculated value is 417.54, and the measured value is 417.20.

[0583] (E)-10-(hex-2-en-1-yl)-7-((3-methoxypyrazin-2-yl)amino)dibenzo[b,f][1,4]thiazazide-11(10H)-one. 1 ¹H NMR (400MHz, chloroform-d): δ 7.71-7.76 (m, 2H), 7.54-7.55 (d, J = 4.0Hz, 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 = 4.0Hz, 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 C10 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. LC-MS (ESI): C10 24 H 25 [M+H] of N4O2S + The calculated value is 433.54, and the measured value is 433.20.

[0584] (E)-7-((3,5-dimethylpyridin-2-yl)amino)-10-(hex-2-en-1-yl)dibenzo[b,f][1,4]thiazazon-11(10H)-one. 1¹H NMR (400 MHz, chloroform-d): δ 10.22 (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 = 7.2 Hz, 3H). 13 C10 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. LC-MS (ESI): C10 26 H 28 N3OS's [M+H] + The calculated value is 430.59, and the measured value is 430.20.

[0585] 10-(but-2-yn-1-yl)-7-((3-ethynylpyridin-2-yl)amino)dibenzo[b,f][1,4]thiazazon-11(10H)-one. 1 H NMR (400MHz, chloroform-d): δ 8.21 (s, 1H), 7.88 (s, 1H), 7.77 (d, J=7.2Hz, 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). 13 C10 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. LC-MS (ESI): C10 24 H18 N3OS's [M+H] + The calculated value is 496.48, and the measured value is 396.10.

[0586] 10-(but-2-yn-1-yl)-7-((3-fluoro-4-methylpyridin-2-yl)amino)dibenzo[b,f][1,4]thiazazon-11(10H)-one. 1 ¹H NMR (400MHz, chloroform-d): δ 7.88 (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 C10 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. LC-MS (ESI): C10 23 H 19 FN3OS's [M+H] + The calculated value is 403.47, and the measured value is 403.12.

[0587] 10-(but-2-yn-1-yl)-7-((3-fluoro-5-methylpyridin-2-yl)amino)dibenzo[b,f][1,4]thiazazon-11(10H)-one. 1 ¹H NMR (400MHz, 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). 13C10 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. LC-MS (ESI): C10 23 H 19 FN3OS's [M+H] + The calculated value is 404.47, and the measured value is 404.20.

[0588] 10-(but-2-yn-1-yl)-7-((3-fluoro-6-methylpyridin-2-yl)amino)dibenzo[b,f][1,4]thiazazon-11(10H)-one. 1 ¹H 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 C10 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. LC-MS (ESI): C10 23 H 19 FN3OS's [M+H] + The calculated value is 404.47, and the measured value is 404.20.

[0589] 2-((10-(but-2-yn-1-yl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiaza-7-yl)amino)-3-methylisonicotinonitrile. 1H 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). LC-MS (ESI): C 24 H 19 N4OS's [M+H] + The calculated value is 411.49, and the measured value is 411.20.

[0590] 10-(but-2-yn-1-yl)-7-(pyridazin-3-ylamino)dibenzo[b,f][1,4]thiazazide-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 C10 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. LC-MS (ESI): C10 21 H 17 N4OS's [M+H] + The calculated value is 373.44, and the measured value is 373.10.

[0591] N-(10-(but-2-yn-1-yl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiaza-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 C10 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. LC-MS (ESI): C10 25 H 19 [M+H] of F2N2O3S + The calculated value is 464.48, and the measured value is 464.10.

[0592] N-(10-(but-2-yn-1-yl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiaza-7-yl)-4-(fluoromethoxy)benzamide. 1 ¹H NMR (400MHz, chloroform-d): δ 7.84–7.86 (m, 4H), 7.62–7.76 (m, 3H), 7.40–7.743 (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). 13 C10 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. LC-MS (ESI): C10 25 H 20 [M+H] of FN2O3S+ The calculated value is 447.49, and the measured value is 447.10.

[0593] N-(10-(but-2-yn-1-yl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiaza-7-yl)-6-methoxynicotinamide. 1 H NMR (400 MHz, chloroform-d) δ 8.49 (s, 1H), 8.18 (s, 1H), 8.05-8.08 (m, 1H), 7.93 (d, J =2.4 Hz, 1H), 7.68-7.73 (m, 2H), 7.62-7.64 (m, 1H), 7.38-7.40 (m, 1H), 7.28-7.30 (m, 2H), 6.78 (d, J =8.8 Hz, 1H), 4.91-495 (m, 1H), 4.40-4.45 (m, 1H), 3.99 (s, 3H), 1.85 (s, 3H). 13 C10 NMR (151 MHz, chloroform-d) δ 168.5, 166.3, 164.0, 146.7, 139.8, 138.5, 137.8, 137.5, 135.9, 135.8, 131.8, 131.1, 128.6, 125.1, 124.2, 123.5, 121.3, 111.1, 80.2, 74.7, 54.1, 41.2, 3.8. LC-MS (ESI): C10 24 H 20 [M+H] of N3O3S + The calculated value is 430.49, and the measured value is 430.10.

[0594] (E)-N-(10-(but-2-en-1-yl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiaza-7-yl)-4-methoxybenzamide. 1 ¹H NMR (400MHz, chloroform-d) δ 7.87 (d, J=2.5 Hz, 1H), 7.83-7.77 (m, 2H), 7.73 (d, J=6.1 Hz, 1H), 7.72-7.68 (m, 1H), 7.62 (ddd, J=8.9, 6.8, 2.6 Hz, 1H), 7.44-7.35 (m, 2H), 7.33-7.26 (m, 2H), 7.01-6.93 (m, 2H), 5.77-5.57 (m, 2H), 4.80-4.70 (m, 1H), 4.58-4.43 (m, 1H), 3.87 (s, 3H), 1.76-1.64 (m, 3H). LC-MS (ESI): C25 H 23 [M+H] of N2O3S + The calculated value is 431.14, and the measured value is 431.20.

[0595] N-(5-(but-2-yn-1-yl)-6,11-dioxo-6,11-dihydro-5H-dibenzo[b,e]aza-2-yl)-4-methoxybenzamide. ¹H NMR (400 MHz, chloroform-d) δ 8.21 (d, J=7.6 Hz, 1H), 8.09 (dd, J=8.9, 2.7 Hz, 1H), 7.95 (s, 1H), 7.83 (dd, J=8.7, 5.5 Hz, 3H), 7.77–7.48 (m, 4H), 6.97 (d, J=8.7 Hz, 2H), 4.69 (p, J=2.6 Hz, 2H), 3.87 (s, 3H), 1.89 (q, J=4.5, 3.4 Hz, 3H). LC-MS (ESI): C 26 H 21 [M+H] of N2O4 + The calculated value is 425.14, and the measured value is 425.20.

[0596] N-(5-(but-2-yn-1-yl)-11-hydroxy-6-oxo-6,11-dihydro-5H-dibenzo[b,e]aza-2-yl)-4-methoxybenzamide. 1 ¹H NMR (400MHz, chloroform-d): δ 7.93–7.74 (m, 5H), 7.61–7.50 (m, 3H), 7.42 (td, J=7.6, 1.4 Hz, 1H), 7.00–6.92 (m, 2H), 5.31 (s, 1H), 4.81 (dt, J=17.0, 2.4 Hz, 1H), 4.52 (dq, J=17.0, 2.3 Hz, 1H), 3.87 (s, 3H), 1.83 (t, J=2.4 Hz, 3H). LC-MS (ESI): C 26 H 23 [M+H] of N2O4 + The calculated value is 427.16, and the measured value is 427.20.

[0597] 5-(but-2-yn-1-yl)-2-((3-methylpyridin-2-yl)amino)-5H-dibenzo[b,e]aza-6(11H)-one. 1H NMR (400MHz, chloroform-d): δ 7.91 (d, J=5.6 Hz, 1H), 7.86 (d, J=7.6 Hz, 1H), 7.74 (d, J=7.2 Hz, 1H), 7.59 (d, J=8.8 Hz, 1H), 7.35-7.39 (m, 1H), 7.26-7.31 (m, 1H), 7.15 (d, J=7.2 Hz, 1H), 6.93-7.03 (m, 2H), 6.91 (d, J=2.4 Hz, 1H), 4.88-4.93 (m, 1H), 4.53-4.58 (m, 1H), 4.16-4.20 (m, 1H), 3.48-3.52 (m, 1H), 1.92 (s, 3H), 1.83 (t, J = 2.0 Hz, 3 H). 13 C10 NMR (151 MHz, chloroform-d) δ 168.1, 151.5, 145.9, 141.7, 138.5, 137.8, 136.0, 135.8, 132.1, 131.9, 131.2, 127.1, 126.1, 125.5, 123.2, 121.4, 121.2, 115.6, 80.0, 74.9, 40.1, 38.6, 19.5, 3.8. LC-MS (ESI): C10 24 H 22 [M+H] of N3O + The calculated value is 368.44, and the measured value is 368.20.

[0598] 2-((5-(but-2-yn-1-yl)-6-oxo-6,11-dihydro-5H-dibenzo[b,e]aza-2-yl)amino)nicotinonitrile. 1 H NMR (400 MHz, chloroform-d): δ 8.38 (d, J=1.6 Hz, 1H), 7.85 (d, J=6.8 Hz, 1H), 7.78-7.80 (m, 1H), 7.62 (d, J=8.4 Hz, 1H), 7.48-7.51 (m, 2H), 7.33-7.35 (m, 1H), 7.26-7.29 (m, 1H), 7.17-7.18 (m, 1H), 6.95 (s, 1H), 6.80-6.83 (m, 1H), 4.89-4.94 (m, 1H), 4.54-4.59 (m, 1H), 4.20-4.23 (m, 1H), 3.52-3.56 (m, 1H), 1.85 (t, J=2.0 Hz, 3H). 13C10 NMR (151 MHz, chloroform-d) δ 168.2, 155.8, 152.3, 142.0, 141.7, 138.1, 136.2, 132.4, 131.7, 131.1, 127.0, 126.1, 123.1, 119.6, 119.4, 116.2, 114.4, 93.3, 79.7, 75.1, 40.1, 38.9, 3.8. LC-MS (ESI): C10 24 H 19 [M+H] of N4O + The calculated value is 379.43, and the measured value is 379.00.

[0599] 5-(but-2-yn-1-yl)-2-((3-fluoropyridin-2-yl)amino)-5H-dibenzo[b,e]aza-6(11H)-one. 1 H NMR (400 MHz, chloroform-d): δ 8.02 (d, J=5.6 Hz, 1H), 7.84 (d, J=2.4 Hz, 1H), 7.51-7.58 (m, 2H), 7.49-7.50 (m, 1H), 7.24-7.35 (m, 3H), 7.16-7.18 (m, 1H), 6.72-6.77 (m, 1H), 6.58 (s, 1H), 4.86-4.91 (m, 1H), 4.56-4.60 (m, 1H), 4.19-4.22 (m, 1H), 3.52-3.55 (m, 1H), 1.84 (t, J=2.0 Hz, 3H). 13 C10 NMR (151 MHz, chloroform-d) δ 168.3, 147.8, 145.0 (d, J=9.1 Hz), 142.6 (d, J=6.1 Hz), 142.2, 138.1, 137.5, 134.8, 132.5, 131.6, 131.1, 126.9, 126.1, 123.1, 121.1 (d, J=15.5 Hz), 117.8, 117.5, 114.7, 79.6, 75.3, 40.1, 38.9, 3.8. LC-MS (ESI): C10 23 H 19 FN3O's [M+H] + The calculated value is 372.41, and the measured value is 372.00.

[0600] 6-((10-(but-2-yn-1-yl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiaza-7-yl)amino)-5-methylnicotinonitrile. 1¹H NMR (400 MHz, chloroform-d): δ 8.40 (d, J = 5.2 Hz, 1H), 7.72–7.79 (m, 3H), 7.63–7.66 (m, 1H), 7.55 (d, J = 1.2 Hz, 1H), 7.42–7.44 (m, 1H), 7.28–7.35 (m, 2H), 6.46 (s, 1H), 4.94–4.99 (m, 1H), 4.39–4.44 (m, 1H), 2.28 (s, 3H), 1.86 (t, J = 4.4 Hz, 3H). 13 C10 NMR (151 MHz, chloroform-d) δ 168.4, 158.9, 155.4, 150.2, 149.9, 143.1, 139.5, 139.2, 138.5, 137.7, 136.8, 135.6, 131.9, 131.0, 128.7, 128.0, 125.1, 124.4, 121.8, 118.0 (d, J=11.3 Hz), 106.5, 100.1, 80.0, 74.8, 41.2, 16.9, 3.9. LC-MS (ESI): C10 24 H 19 N4OS's [M+H] + The calculated value is 411.49, and the measured value is 411.20.

[0601] 6-((10-(but-2-yn-1-yl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiaza-7-yl)amino)-5-methylpicolinonitrile. 1 ¹H NMR (400 MHz, chloroform-d): δ 7.80–7.85 (m, 2H), 7.7...

Claims

1. A compound of formula (I) or its salts, hydrates or stereoisomers: （Ⅰ）， in: 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; C2-C8 alkynyl, including all its isomers and all such groups are optionally substituted by one or more of the following groups: D, F, OH, C(O)NHR4, and all such groups are optionally replaced by one or more methylene units replaced by O, S, NH, NR4, C(O); R3 is selected from: C1-C7 alkyl, C3-C7 cycloalkyl optionally bridged by CH2 or CH2CH2, C3-C7 cycloalkyl optionally bridged by CH2 or CH2CH2, C2-C7 alkenyl, C5-C7 cycloalkenyl optionally bridged by CH2 or CH2CH2, C5-C7 cycloalkenyl optionally bridged by CH2 or CH2CH2, C2-C7 alkynyl, bridged or fused C5-C9 cycloalkyl, bridged or fused C5-C9 cycloalkyl, C 5-C10 spiroanes, CH2-linked or CHMe-linked C5-C10 spiroanes, all of which include all possible isomers and all of which are optionally substituted with one or more of the following groups: 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 optionally have one or more methylene units replaced by O, S, SO2, S(O), NH, NR4, NC(O)H, NC(O)R4 NSO2R4, C(O), C=NOH, C=NOR4 or C=NR4, phenyl or naphthyl (optionally substituted with R7 at one or more positions), 5-membered and 6-membered heteroaryl and fused heteroaryl, including but not limited to oxazole, isoxazole, thiazole, isothiazole, furan, thiophene, pyrazole, imidazole, triazole, tetrazolium, pyridine, pyrimidine, pyrazine, pyridazine, quinoline, isoquinoline, quinazoline, quinoxaline, phthalazine, naphthidine, pyridopyrazine, pyrazolopyridine, pyridopyrimidine, pyridopyridazine, benzoxazole, benzoisoxazole, benzothiazole, benzoisothiazole, indole, indazole, benzimidazole, dioxane En-pyridine, dioxacyclopenten-pyridazine, dioxacyclopenten-pyrimidine, dioxacyclopenten-pyridazine, benzofuran, benzothiophene, imidazopyridine, benzodioxolane, benzoxazolone, benzoisoxazolone, benzothiazolidinone, benzoisothiazolidinone, 1,3-dihydro-2H-benzimidazole, benzo[d]imidazol-2-one, benzodioxolane, dioxacyclopenten-pyridazine, dioxacyclopenten-pyrimidine, dioxacyclopenten-pyridazine, coumarin, isocumarin, and all their possible isomers, wherein all such groups are optionally substituted with R7 at one or more of the positions. R4 is selected from: Me; Et; Pr; iPr; cPr; cBu, and is optionally substituted by one or more of the following groups: D, F, CN, OH, OCD3, OCH n F (3-n) (n=0-3); NR5R6 constitutes a 4- to 7-membered nitrogen heterocycle, a bridged or fused 6- to 9-membered nitrogen heterocycle, or a 5- to 9-membered azeosylane, including all possible isomers, and all such groups are optionally substituted with one or more of the following groups: 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 such groups optionally have one or more methylene units replaced with O, S, SO2, NH, NR4, NC(O)H, NC(O)R4, NSO2R4, C(O), C=NOH, C=NR4; R7 is selected from: D, F, Cl, Br, CN, N3, OH, OR4, R4, oxetane, 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, including all its isomers, and all such groups are optionally substituted by one or more of the following groups: D, F, CN, OH, and all such groups are optionally substituted with one or more methylene units replaced by O, S, S(O), SO2, NH, NR4, NC(O)H, NC(O)R4, NSO2R4, C(O), C=NOH, C=NR4; aryl or 5- or 6-membered heteroaryl or heterocyclic, all such groups are optionally substituted by one or more of the following groups: 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, CCl; U and W are independently selected from: CH, CD, N; Excluding R1=C(O)furan-3-yl, X, Y, U, W=CH, Z=S, R2=(CH2)2OMe (MM017).

2. The compound of claim 1, further comprising a compound of formula II: (II)。 3. The compound of claim 1, further comprising a compound of formula III: (III)。 4. The compound of claim 1, further comprising a compound of formula IV: (IV)。 5. The compound of claim 1, further comprising a compound of formula V: （V）。 6. The compound of claim 1, further comprising a compound of formula VI: (WE).

7. The compound of claim 1, further comprising a compound of formula VII: (VII)。 8. The compound of claim 1, further comprising a compound of formula VIII: (VIII)。 9. The compound according to claims 1-8, wherein Z = S, CH2, CD2, CHMe, CHCD3, CDMe, CDCD3, CHCN, CDCN, CMeOH, CCD3OH, preferably S, CH2, CHMe, CHCD3.

10. The compound according to claims 1-8, wherein X = CH, CD, CF, CCl, CCN, preferably CH, CF or CCl.

11. The compound according to claims 1-8, wherein Y = CH, CD, CF, CCl, preferably CH or CF.

12. The compound according to claims 1-8, wherein W = CH, CD, N.

13. The compound according to claims 1-8, wherein U = CH, CD, N, preferably CH.

14. The compound of claims 1-8, wherein R2 = C2-C7 alkyl; C3-C7 alkenyl; C3-C7 alkynyl, including all its isomers, and all such groups are optionally substituted by one or more of the following groups: D, F, Cl, and all such groups are optionally replaced by one or more methylene units replaced by O.

15. The compounds of claims 1-8, wherein R2=CH2C≡CH, CH2C≡CR4, CH2C≡CCl, CH2CH=CH2, CH2CH=CHR4, (CH2)2OR4, (CH2)2OCH2C≡CH, wherein R2 may contain one or more deuterium.

16. The compound according to claims 1-8, wherein R2 = CH2C≡CH, CH2C≡CMe, CH2C≡CCH2F, CH2C≡C c Pr, CH2C≡CCl, CH2CH=CHMe, CH2C≡CCF3, where R2 may contain one or more deuteriums.

17. The compound according to claims 2-3, wherein: R2=CH2C≡CH, CH2C≡CMe, CH2C≡CCH2F, CH2C≡CCl, CH2C≡C c Pr, CH2CH=CHMe, where R2 may contain one or more deuteriums; NR5R6 constitutes a 4- to 7-membered nitrogen heterocycle, a bridged or fused 6- to 9-membered nitrogen heterocycle, or a 5- to 9-membered azeosylane, including all possible isomers, and all such groups are optionally substituted with one or more of the following groups: 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 such groups optionally have one or more methylene units replaced with O, S, SO2, NH, NR4, NC(O)H, NC(O)R4, NSO2R4, C(O), C=NOH, C=NR4; R4 = Me; Et; Pr; iPr; cPr; cBu, which may optionally be substituted with one or more of the following groups: D, F, CN, OH, OCD3, OCH n F (3-n) (n=0-3); Z = S, CH2, CHMe, CHCD3, CHCN, CMeOH, CCD3OH, with S, CH2, CHMe, and CHCD3 being preferred; X = CH, CD, CF, CCl; Y = CH, CD, CF; W=CH, N; and U = CH, CD, N, with CH being the preferred choice.

18. The compound according to claims 2-3, wherein: R2=CH2C≡CH, CH2C≡CMe, CH2C≡CCH2F, CH2C≡CCl, CH2C≡C c Pr, preferably CH2C≡CHMe, CH2C≡C c Pr; NR5R6 constitutes a 4- to 7-membered nitrogen heterocycle, a 6- to 8-membered nitrogen heterocycle, or a 5- to 7-membered azeosylane, all of which are optionally substituted by one or more of the following groups: D, F, CN, R4, OR4, OH, and all of which optionally have one or more methylene units replaced by O, S, SO2, NH, NR4, C(O), C=NOH, C=NR4; R4 = Me; Et; Pr; iPr; cPr; cBu, which may optionally be substituted with one or more of the following groups: D, F, CN, OH, OCD3, OCH n F (3-n) (n=0-3); Z = S, CH2, CHMe, CHCD3, CHCN, CMeOH, CCD3OH, with S, CH2, CHMe, and CHCD3 being preferred; X = CH, CF, CCl; Y=CH、CF; W=CH, N; and U = CH, N, CH is preferred.

19. The compound of claim 4, 5 or 8, wherein: R2=CH2C≡CH, CH2C≡CMe, CH2C≡CCH2F, CH2C≡CCl, CH2C≡C c Pr, CH2CH=CHMe, where R2 may contain one or more deuteriums; R3 = phenyl (optionally substituted with R7 at one or more of the various positions); 5-membered and 6-membered heteroaryl and fused heteroaryl, including but not limited to oxazole, isoxazole, thiazole, isothiazole, furan, thiophene, pyrazole, imidazole, triazole, tetrazolium, pyridine, pyrimidine, pyrazine, pyridazine, quinoline, isoquinoline, quinazoline, quinoxaline, phthalazine, naphthidine, pyridopyrazine, pyrazolopyridine, pyridopyrimidine, pyridopyridazine, benzoxazole, benzoisoxazole, benzothiazole, benzoisothiazole, indole, indazole, benzimidazole, dioxacyclopentenpyridine, dioxacyclopentenpyridazine ... Oxacyclopentenopyrimidine, dioxacyclopentenopyrazine, benzofuran, benzothiophene, imidazopyridine, benzodioxolane, benzoxazolone, benzoisoxazolone, benzothiazolidinone, benzoisothiazolidinone, 1,3-dihydro-2H-benzimidazole, benzo[d]imidazol-2-one, benzodioxolane, dioxacyclopentenopyrimidine, dioxacyclopentenopyrimidine, dioxacyclopentenopyrazine, coumarin, isocumarin, and all its possible isomers, wherein all such groups are optionally substituted with R7 at one or more of the respective positions; R4 = Me; Et; Pr; iPr; cPr; cBu, which may optionally be substituted with one or more of the following groups: D, F, CN, OH, OCD3, OCH n F (3-n) (n=0-3); R7=D, F, Cl, Br, CN, N3, OH, R4, OR4, C≡CH, NHC(O)H, C(O)NH2, C(O)NHR4, C(O)NR4R4; Z = S, CH2, CHMe, CHCD3, CHCN, CMeOH, CCD3OH, with S, CH2, CHMe, and CHCD3 being preferred; X = CH, CF, CCl; Y=CH、CF; W=CH, N; and U = CH, N, CH is preferred.

20. The compound of claim 4, 5 or 8, wherein: R2=CH2C≡CH, CH2C≡CMe, CH2C≡CCH2F, CH2C≡CCl, CH2C≡C c Pr, preferably CH2C≡CMe, CH2C≡C c Pr; R3 = a mono- or di-substituted benzene ring having a substituent selected from H, D, or F at the ortho position and a substituent selected from H, D, F, Cl, R4, OR4, N3, C≡CH at the meta and para positions; a heteroaromatic ring selected from furan, pyridine, pyrimidine, pyrazine, pyridazine, benzo[d]oxazol-5-yl, benzo[d]thiazo-5-yl, 2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl, benzo[d][1,3]dioxopentane-5-yl, and all such groups are optionally substituted at one or more positions in each position by H, D, F, Cl, CCH, R4, OR4; R4 = Me; Et; Pr; iPr; cPr; cBu, which may optionally be substituted with one or more of the following groups: D, F; Z = S, CH2, CHMe, CHCD3, CHCN, CMeOH, CCD3OH, with S, CH2, CHMe, and CHCD3 being preferred; X = CH, CF, CCl; Y=CH、CF; W=CH, N; and U = CH, N, CH is preferred.

21. The compound of claim 4, 5 or 8, wherein: R2=CH2C≡CH, CH2C≡CMe, CH2C≡CCH2F, CH2C≡CCl, CH2C≡C c Pr, CH2CH=CHMe, where R2 may contain one or more deuteriums; R3 = C1-C7 alkyl, C3-C7 cycloalkyl optionally bridged by CH2 or CH2CH2, C3-C6 cycloalkyl optionally bridged by CH2 or CH2CH2, C2-C7 alkenyl, C5-C6 cycloalkenyl optionally bridged by CH2 or CH2CH2, C5-C6 cycloalkenyl optionally bridged by CH2 or CH2CH2, C2-C7 ynyl, bridged or fused C5-C9 cycloalkyl, bridged or fused C5-C9 cycloalkyl via CH2 or CH2CH2, C5-C10 spiroalkyl, CH2-linked or CH2CH2-linked... Me-linked C5-C10 spirolones, all of which include all possible isomers and all of which are optionally substituted with one or more of the following groups: 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 optionally have one or more methylene units replaced by O, S, SO2, S(O), NH, NR4, NC(O)H, NC(O)R4, NSO2R4, C(O), C=NOH, C=NOR4 or C=NR4; R4 = Me; Et; Pr; iPr; cPr; cBu, which may optionally be substituted with one or more of the following groups: D, F, OH, OCD3, OCH n F (3-n) (n=0-3); Z = S, CH2, CHMe, CHCD3, CHCN, CMeOH, CCD3OH, with S, CH2, CHMe, and CHCD3 being preferred; X = CH, CF, CCl; Y=CH、CF; W=CH, N; and U = CH, N, CH is preferred.

22. The compound of claim 6, wherein: R2=CH2C≡CH, CH2C≡CMe, CH2C≡CCH2F, CH2C≡CCl, CH2C≡C c Pr, CH2CH=CHMe, CH2=CHEt, CH2CH=CHPr, (CH2)2OCH2CCH, wherein R2 may contain one or more deuteriums; R3 = phenyl (optionally substituted with R7 at one or more positions); 5-membered and 6-membered heteroaryl and fused heteroaryl, including but not limited to oxazole, isoxazole, thiazole, isothiazole, furan, thiophene, pyrazole, imidazole, triazole, tetrazolium, pyridine, pyrimidine, pyrazine, pyridazine, quinoline, isoquinoline, quinazoline, quinoxaline, phthaloline, phthalazine, naphthidine, pyridopyrazine, pyrazolopyridine, pyridopyrimidine, pyridopyridazine, benzoxazole, benzoisoxazole, benzothiazole, benzoisothiazole, indole, indazole, benzimidazole, dioxacyclopentenpyridine, dioxacyclopentenpyridazine, Dioxacyclopentenpyrimidine, dioxacyclopentenpyrazine, benzofuran, benzothiophene, imidazopyridine, benzodioxolane, benzoxazolone, benzoisoxazolone, benzothiazolidinone, benzoisothiazolidinone, 1,3-dihydro-2H-benzimidazole, benzo[d]imidazolidin-2-one, benzodioxolane, dioxacyclopentenpyrazine, dioxacyclopentenpyrimidine, dioxacyclopentenpyrazine, coumarin, isocoumarin, and all its possible isomers, wherein all such groups are optionally substituted with R7 at one or more positions in each position; R7=D, F, Cl, Br, CN, N3, OH, R4, OR4, C≡CH, NHC(O)H, C(O)NH2, C(O)NHR4, C(O)NR4R4; R4 = Me; Et; Pr; iPr; cPr; cBu, which may optionally be substituted with one or more of the following groups: D, F, CN, OH, OCD3, OCH n F (3-n) (n=0-3); Z = S, CH2, CHMe, CHCD3, CHCN, CMeOH, CCD3OH, with S, CH2, CHMe, and CHCD3 being preferred; X = CH, CF, CCl; Y=CH、CF; W=CH, N; and U = CH, N, CH is preferred.

23. The compound of claim 6, wherein: R2=CH2C≡CH、CH2C≡CMe,CH2C≡CCH2F,CH2C≡CCl,CH2C≡C c Pr、CH2CH=CHMe、CH2=CHEt、CH2CH=CHPr; R3 = 5- and 6-membered heteroaryl groups, including but not limited to pyrazole, imidazole, pyridine, pyrimidine, pyrazine, pyridazine, quinoline, isoquinoline, quinazoline, quinoxaline, cyclophosphine, phthalazine, and all their possible isomers, and all these groups are optionally replaced at one or more positions by D, F, Cl, CN, Me, cPr, CD3, OCD3, OH, OCH n F (3-n) (n=0-3) Replace; Z = S, CH2, CHMe, CHCD3, CHCN, CMeOH, CCD3OH, with S, CH2, CHMe, and CHCD3 being preferred; X = CH, CF, CCl; Y=CH、CF; W=CH, N; and U = CH, N, CH is preferred.

24. The compound of claim 6, wherein: R2=CH2C≡CH, CH2C≡CMe, CH2C≡CCH2F, CH2C≡CCl, CH2C≡C c Pr, preferably CH2C≡CHMe, CH2C≡C c Pr; R3 = pyrazole, pyridine, pyrimidine, pyrazine, pyridazine, all of which may optionally be replaced by D, F, Cl, CN, Me, cPr, CD3, OCD3, OH, OCH at one or more of the respective positions. n F (3-n) (n=0-3) Replace; Z = S, CH2, CHMe, CHCN, CMeOH, with S, CH2, and CHMe being preferred; X = CH, CF, CCl; Y=CH、CF; W=CH, N; and U = CH, N, CH is preferred.

25. The compound of claim 6, wherein: R2=CH2C≡CH, CH2C≡CMe, CH2C≡CCH2F, CH2C≡CCl, CH2C≡C c Pr, where R2 may contain one or more deuteriums; R3 = C2-C4 alkyl, C2-C4 alkenyl, C3-C6 cycloalkyl optionally bridged by CH2 or CH2CH2, C3-C6 cycloalkyl optionally bridged by CH2 or CH2CH2 (CH2-linked or CHMe-linked), C5-C6 cycloalkenyl optionally bridged by CH2 or CH2CH2 (CH2-linked or CHMe-linked), C5-C8 spiroalkyl, C5-C8 spiroalkyl optionally bridged by CH2 or CHMe, and all such groups are optionally substituted by one or more of the following groups: D, F, CN, OH, R4, OCD3, OCH n F (3-n) (n=0-3), and all of these groups may optionally have one or more methylene units replaced by O, S, SO2, S(O), NH, NR4, NC(O)H, NC(O)R4, NSO2R4, C(O), C=NOH, C=NOR4 or C=NR4; R4 = Me; Et; Pr; iPr; cPr; cBu, which may optionally be substituted with one or more of the following groups: D, F, OH, OCD3, OCH n F (3-n) (n=0-3); Z = S, CH2, CHMe, CHCD3, CHCN, CMeOH, CCD3OH, with S, CH2, CHMe, and CHCD3 being preferred; X = CH, CF, CCl; Y=CH、CF; W=CH, N; and U = CH, N, CH is preferred.

26. The compound according to claims 17-18, wherein: R2=CH2C≡CMe, CH2C≡CCD3, CH2C≡CCH2F, CH2C≡C c Pr, CH2C≡CCl, CH2C≡CH, preferably CH2C≡CMe, CH2C≡C c Pr; The NR5R6=N-linked azacyclobutane, pyrrolidine, piperidine, azacyclobutane, optionally substituted with one or more of the following groups: D, F, CN, R4, OR4, OH and optionally bridged by CH2 or CH2CH2, and all of these groups optionally have one or more methylene units replaced by O, NR4, N=OH, N=OMe, N=OCD3; R4 = Me, cPr, which may optionally be substituted with one or more of the following groups: D, F, CN, OH, OCD3, OCH n F (3-n) (n=0-3); Z = S, CH2, CHMe, with S being the preferred choice; X = CH, CF, CCl; Y=CH, F, CH is preferred; W=CH, N; and U=CH.

27. The compound according to claims 22-24, wherein: R2 = CH2C≡CMe, CH2C≡CCD3, CH2C≡CcPr, CH2C≡CCH2F, CH2C≡CCl, CH2C≡CH, with CH2C≡CMe and CH2C≡C being preferred. c Pr; R3 = pyridine, pyrimidine, pyrazine, pyridazine, all of which may optionally be replaced by D, F, Cl, CN, Me, Et, iPr, cPr, OH, OCD3, OCH at one or more of the respective positions. n F (3-n) (n=0-3) Replace; Z = S, CH2, CHMe, with S being the preferred choice; X = CH, CF, CCl; Y=CH, CF, CH is preferred; W=CH, N; and U=CH.

28. The compound of claim 25, wherein: R2=CH2C≡CMe, CH2C≡CCD3, CH2C≡C c Pr, CH2C≡CCH2F, CH2C≡CCl, CH2C≡CH, preferably CH2C≡CMe, CH2C≡C c Pr; R3 = C2-C4 alkyl, C2-C4 alkenyl, C3-C6 cycloalkyl optionally bridged by CH2 or CH2CH2, C3-C6 cycloalkyl optionally bridged by CH2 or CH2CH2 (CH2-linked or CHMe-linked), C5-C6 cycloalkenyl optionally bridged by CH2 or CH2CH2 (CH2-linked or CHMe-linked), C5-C8 spiroalkyl, C5-C8 spiroalkyl (CH2-linked or CHMe-linked), all of these groups include all their possible isomers, and all of these groups are optionally substituted by one or more of the following groups: 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), and all of these groups may optionally have one or more methylene units replaced by O, S, SO2NH, NMe, NCD3, CO, N=OH, N=OMe, N=OCD3; Z = S, CH2, CHMe, with S being the preferred choice; X = CH, CF, CCl; Y=CH, CF, CH is preferred; W=CH, N; and U=CH.

29. The compound of claim 20, wherein: R2=CH2C≡CMe, CH2C≡CCD3, CH2C≡C c Pr, CH2C≡CCH2F, CH2C≡CCl, CH2C≡CH, preferably CH2C≡CMe, CH2C≡C c Pr; R3 = a mono- or di-substituted benzene ring having a substituent selected from H, D, or F at the ortho position and a substituent selected from H, D, F, Cl, R4, OR4, N3, C≡CH at the meta and para positions; a heteroaromatic ring selected from furan, pyridine, pyrimidine, pyrazine, pyridazine, benzo[d]oxazol-5-yl, benzo[d]thiazo-5-yl, 2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl, benzo[d][1,3]dioxopentane-5-yl, and all these groups are optionally replaced at one or more of the respective positions by H, D, F, Cl, Me, CD3, cPr, CCH, OCD3, OCH n F (3-n) (n=0-3) Replace; Z = S, CH2, CHMe, with S being the preferred choice; X = CH, CF, CCl; Y=CH, CF, CH is preferred; W=CH, N; and U=CH.

30. The compound of claim 21, wherein: R2=CH2C≡CMe, CH2C≡CCD3, CH2C≡C c Pr, CH2C≡CCH2F, CH2C≡CCl, CH2C≡CH, preferably CH2C≡CMe, CH2C≡C c Pr; R3 = C2-C4 alkyl, C2-C4 alkenyl, C2-C3 alkynyl, C3-C6 cycloalkyl optionally bridged by CH2 or CH2CH2, C3-C6 cycloalkyl optionally bridged by CH2 or CH2CH2 (CH2-linked or CHMe-linked), C5-C6 cycloalkenyl optionally bridged by CH2 or CH2CH2 (CH2-linked or CHMe-linked), C5-C8 spiroalkyl, C5-C8 spiroalkyl (CH2-linked or CHMe-linked), and all these groups include all their possible isomers, and all these groups are optionally substituted by one or more of the following groups: 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), CO2Me, CO2CD3, and all of these groups may optionally have one or more methylene units replaced by O, S, SO2, NH, NMe, NCD3, C(O), N=OH, N=OMe, N=OCD3; Z = S, CH2, CHMe, with S being the preferred choice; X = CH, CF, CCl; Y=CH, CF, CH is preferred; W=CH, N; and U=CH.

31. The compound of claim 7, wherein: R2=CH2C≡CMe, CH2C≡CCD3, CH2C≡C c Pr, CH2C≡CCH2F, CH2C≡CCl, CH2C≡CH, preferably CH2C≡CMe, CH2C≡C c Pr; R3 = a mono- or di-substituted benzene ring having a substituent selected from H, D, or F at the ortho position and a substituent selected from H, D, F, Cl, R4, OR4, N3, C≡CH at the meta and para positions; a heteroaromatic ring selected from furan, pyridine, pyrimidine, pyrazine, pyridazine, benzo[d]oxazol-5-yl, benzo[d]thiazo-5-yl, 2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl, benzo[d][1,3]dioxopentane-5-yl, and all these groups are optionally replaced at one or more of the respective positions by H, D, F, Cl, Me, CD3, cPr, CCH, OCD3, OCH n F (3-n) (n=0-3) Replace; Z = S, CH2, CHMe, with S being the preferred choice; X = CH, CF, CCl; Y=CH, CF, CH is preferred; W=CH, N; and U=CH.

32. The compound of claim 7, wherein: R2=CH2C≡CMe, CH2C≡CCD3, CH2C≡C c Pr, CH2C≡CCH2F, CH2C≡CCl, CH2C≡CH, preferably CH2C≡CMe, CH2C≡C c Pr; R3 = C2-C4 alkyl, C2-C4 alkenyl, C2-C3 alkynyl, C3-C6 cycloalkyl optionally bridged by CH2 or CH2CH2, C3-C6 cycloalkyl optionally bridged by CH2 or CH2CH2 (CH2-linked or CHMe-linked), C5-C6 cycloalkenyl optionally bridged by CH2 or CH2CH2 (CH2-linked or CHMe-linked), C5-C8 spiroalkyl, C5-C8 spiroalkyl (CH2-linked or CHMe-linked), and all these groups include all their possible isomers, and all these groups are optionally substituted by one or more of the following groups: 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), CO2Me, CO2CD3, and all of these groups may optionally have one or more methylene units replaced by O, S, SO2, NH, NMe, NCD3, C(O), N=OH, N=OMe, N=OCD3; Z = S, CH2, CHMe, with S being the preferred choice; X = CH, CF, CCl; Y=CH, CF, CH is preferred; W=CH, N; and U=CH.

33. A compound selected from Table 1-10.

34. A compound selected from Table 7.

35. A compound selected from Table 1-2.

36. A compound selected from Table 3-4.

37. A compound selected from Table 5-6.

38. A compound selected from Table 6.

39. A compound selected from Table 8-10.

40. A compound selected from Table 10.

41. A compound selected from Table 8-9.

42. A compound selected from Tables 6 and 8.

43. A pharmaceutical composition comprising the compound of claims 1-42 or a pharmaceutically acceptable salt, hydrate or stereoisomer thereof, and a pharmaceutically acceptable carrier or excipient, preferably in a pharmaceutically acceptable unit dose form.

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

45. A method of treating a disease or condition including cancer, tumor, or tumor formation, comprising administering to a person in need the compound of claims 1-42, such as said cancer, tumor, or tumor formation including breast cancer, lung cancer, colorectal cancer, ovarian cancer, bladder cancer, kidney cancer, esophageal cancer, stomach 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 of claim 44 or 45, further comprising a preliminary step of detecting or diagnosing a disease or condition indicating its need, and / or a subsequent step of detecting a resultive improvement or delay in the progression of the disease or condition.

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

48. A cell line for evaluating cancer therapeutics, comprising and expressing a mutant NVL gene sufficient to induce resistance to MM017, preferably comprising one or more mutations within the D1 AAA+ ATPase domain, such as NVL P307T NVL R403W or NVL H304R .

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