Compounds and methods for treating cancer

Abstract

Disclosed herein are compounds, compositions, and methods for treating cancer and / or DNA repair.

Description

[Technical Field]

[0001] Government Support Statement This invention was made with government support under Grant No. DE030445 awarded by the National Institutes of Health. The government has certain rights in this invention.

[0002] Related Applications This application claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 436,316, filed December 30, 2022, the entire contents of which are incorporated herein by reference. [Background technology]

[0003] PARP1 and PARP2 are two key enzymes that mediate the DNA damage response (DDR) by functioning as DNA damage sensors and signal transducers. In response to damage such as DNA nick or double-strand break (DSB), PARP1 is rapidly recruited to the damaged DNA site and its catalytic activity increases 10- to 500-fold through an allosteric activation mechanism. This results in the upregulation of NAD + Poly(ADP-ribose) (PAR) chains are synthesized that are linked to proteins that use DDR as an important substrate. The negatively charged PARP functions as a dense protein-binding scaffold and recruits components of the DNA damage repair machinery. Due to their inherently rapid cell division, cancer cells are particularly vulnerable to inhibition of the DDR machinery.

[0004] PARP inhibitors (PARPi) have been effectively used to treat breast and ovarian cancers with BRCA gene mutations using synthetic lethality screening. Furthermore, PARPi has also been used to treat cancer patients with homologous recombination deficiency. However, acquired resistance to PARPi treatment hinders optimal clinical outcomes. PARPi resistance can be acquired through increased expression or activity of replication fork stabilizing factors. For example, in PARPi-resistant cancer cells, the ataxia telangiectasia mutated and Rad3-related kinase (ATR) and checkpoint kinase 1 (CHK1) pathways are often upregulated, which induces phosphorylation of multiple proteins that stabilize replication forks and HR repair. Furthermore, common chemotherapy drugs such as cisplatin induce drug resistance by activating the DNA damage response. To overcome such resistance, patients can be treated with a combination of PARPi and an ATR inhibitor.

[0005] Therefore, dual inhibitors of PARP and ATR are in turn attractive targets for cancer therapy. Summary of the Invention

[0006] In one aspect, the disclosure provides a compound having a structure represented by Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt thereof: [ka] During the ceremony, A is aryl or heteroaryl; n1 is 1, 2, 3, 4, or 5; X 1 is O, S, or NR 7 and X 2 is O, S, or NR 8 and R 2 , R 4 , R 12 , R 13 , R 14 , and R 15are each independently selected from H, fluoro, chloro, bromo, and iodo; R 1 and R 3 are each independently selected from H, fluoro, chloro, bromo, iodo, and —O(alkyl); R 5 , R 7 , and R 8 each is independently selected from H, alkyl, and aralkyl; R A is alkyl, acyl, or amido; R C is H, alkyl, or acyl, R 6 is alkyl, aryl, heteroaryl, or heterocyclyl.

[0007] In another aspect, the present disclosure provides a pharmaceutical composition comprising a compound disclosed herein and a pharmaceutically acceptable excipient.

[0008] In yet another aspect, the present disclosure provides a method of treating cancer in a subject in need thereof, comprising administering to the subject a compound disclosed herein or a pharmaceutically acceptable salt thereof.

[0009] In yet another aspect, the present disclosure provides a method of inhibiting DNA repair in a subject in need thereof, comprising administering to the subject a compound disclosed herein or a pharmaceutically acceptable salt thereof. [Brief explanation of the drawings]

[0010] [Figure 1A] 1 shows that JC081 and JC099 bind to PARP1. The SPR response curve of JC081 is shown. [Figure 1B] Figure 1 shows that JC081 and JC099 bind to PARP1. Figure 2 shows the SPR response curve of JC099. [Figure 2]1 shows that JC099 inhibits PARP1 catalytic activity but not PARP2 catalytic activity. [Figure 3A] JC081 and JC099 capture PARP1, but not PARP2, on chromatin and at sites of DNA damage. Chromatin fractionation assays of PARP1 in breast cancer SUM149PT-BRCA1mut and SUM149PT-BRCA1rev cells were performed in the presence of JC099, olaparib (OLA), or talazoparib (TALA) and 0.01% MMS. Chromatin fractionation assays of PARP1 in breast cancer SUM149PT-BRCA1mut and SUM149PT-BRCA1rev cells were performed in the presence of olaparib (OLA), or talazoparib (TALA), and 0.01% MMS. [Figure 3B] JC081 and JC099 capture PARP1, but not PARP2, on chromatin and at sites of DNA damage. Chromatin fractionation assay of PARP1 in ovarian cancer UWB1.289 and UWB1.289+BRCA1 cells in the presence of JC099 or TALA and 0.01% MMS. [Figure 3C] JC081 and JC099 capture PARP1, but not PARP2, on chromatin and at sites of DNA damage. Chromatin fractionation assays of PARP1 in prostate cancer C4-2B / MR and PC3 cells performed in the presence of JC099, JC081, or OLA and 0.01% MMS. [Figure 3D] JC081 and JC099 capture PARP1, but not PARP2, on chromatin and at sites of DNA damage. Chromatin fractionation assays of PARP2 in breast cancer SUM149PT-BRCA1mut and SUM149PT-BRCA1rev cells were performed in the presence of JC099, OLA, or TALA and 0.01% MMS. [Figure 4A] Figure 1 shows that JC081 and JC099 inhibit HR. Figure 1 shows qPCR data of HR assay when JC081 and JC099 are increased in the prostate cancer cell line PC3. [Figure 4B] Figure 1 shows that JC081 and JC099 inhibit HR. qPCR data of the HR assay at increasing concentrations of JC099 in the breast cancer cell line SUM149PT-BRCA1rev are shown. [Figure 5A] Figure 1 shows that JC099 inhibits ATR activity. Figure 2 shows that JC099 inhibited ATR activity in SUM149PT-BRCA1rev cells. [Figure 5B] 1 shows that JC099 inhibits ATR activity. 1 shows the IC50 of JC099 for inhibiting ATR activity obtained by a cell-independent assay. [Figure 6A] 1 shows that JC081 and JC099 inhibit the ATR-mediated signaling pathway. 2 shows that JC081 and JC099 inhibit the phosphorylation of Rad17 at serine 645 and CHK1 at serine 345 in prostate cancer cell lines C4-2B / MR and PC3. [Figure 6B] 1 shows that JC081 and JC099 inhibit the ATR-mediated signaling pathway. 2 shows that JC081 and JC099 inhibit the phosphorylation of Rad17 at serine 645 and CHK1 at serine 345 in breast cancer SUM149PT-BRCA1rev cells and ovarian cancer UWB1.289+BRCA1 cells, respectively. [Figure 6C] 1 shows that JC081 and JC099 inhibit the ATR-mediated signaling pathway. 2 shows that JC081 and JC099 inhibit the phosphorylation of Rad17 at serine 645 and CHK1 at serine 345 in breast cancer SUM149PT-BRCA1rev cells and ovarian cancer UWB1.289+BRCA1 cells, respectively. [Figure 7A] Figure 1 shows that JC081 and JC099 inhibit cell viability. Figure 1 shows that JC081 and JC099 inhibited cell viability in prostate cancer cell lines PC3, C4-2B / MR, and C4-2B, respectively. [Figure 7B]Figure 1 shows that JC081 and JC099 inhibit cell viability. Figure 1 shows that JC081 and JC099 inhibited cell viability in prostate cancer cell lines PC3, C4-2B / MR, and C4-2B, respectively. [Figure 7C] Figure 1 shows that JC081 and JC099 inhibit cell viability. Figure 1 shows that JC081 and JC099 inhibited cell viability in prostate cancer cell lines PC3, C4-2B / MR, and C4-2B, respectively. [Figure 7D] Figure 1 shows that JC081 and JC099 inhibit cell viability. Figure 1 shows that JC099 inhibited cell viability in breast cancer cell lines SUM149PT-BRCA1mut, SUM149PT-BRCA1rev, MDA-MB-436, and MDA-MB-231, respectively. [Figure 7E] Figure 1 shows that JC081 and JC099 inhibit cell viability. Figure 1 shows that JC099 and JC081 inhibited cell viability in the ovarian cancer cell lines UWB1.289 and UWB1.289+BRCA1, respectively. [Figure 7F] Figure 1 shows that JC081 and JC099 inhibit cell viability. Figure 1 shows that JC099 and JC081 inhibited cell viability in the ovarian cancer cell lines UWB1.289 and UWB1.289+BRCA1, respectively. [Figure 8A] Figure 1 shows that JC081 and JC099 induce cell apoptosis.Figure 1 shows that JC081 and JC099 induced cell apoptosis in prostate cancer PC3 and C4-2B / MR cells. [Figure 8B] Figure 1 shows that JC081 and JC099 induce cell apoptosis. Figure 2 shows that JC099 induced cell apoptosis in ovarian cancer UWB1.289 and UWB1.289+BRCA1 cells. [Figure 8C]Figure 1 shows that JC081 and JC099 induce cell apoptosis. Figure 2 shows that JC099 induced cell apoptosis in breast cancer cell lines SUM149PT-BRCA1mut, SUM149PT-BRCA1rev, MDA-MB-436, and MDA-MB-231. [Figure 9A] 1 shows that JC081 and JC099 suppress the growth of breast cancer MDA-MB-436 xenografts. Images of tumors after treatment with olaparib, JC081, and JC099 are shown. [Figure 9B] Figure 1 shows that JC081 and JC099 inhibit the growth of breast cancer MDA-MB-436 xenografts.Tumor weights after treatment with olaparib, JC081, and JC099 are shown. [Figure 9C] 1 shows that JC081 and JC099 inhibit the growth of breast cancer MDA-MB-436 xenografts. 2 shows tumor volumes after treatment with olaparib, JC081, and JC099. [Figure 9D] Figure 1 shows that JC081 and JC099 inhibit the growth of breast cancer MDA-MB-436 xenografts. Figure 2 shows the body weight of mice after treatment with olaparib, JC081, and JC099. (One-way ANOVA, *P<0.05; **P<0.01) [Figure 10A] 1 shows that JC081 and JC099 suppress the growth of breast cancer MDA-MB-231 xenografts. Images of tumors after treatment with olaparib, JC081, and JC099 are shown. [Figure 10B] Figure 1 shows that JC081 and JC099 inhibit the growth of breast cancer MDA-MB-231 xenografts.Tumor weights after treatment with olaparib, JC081, and JC099 are shown. [Figure 10C] 1 shows that JC081 and JC099 inhibit the growth of breast cancer MDA-MB-231 xenografts. 2 shows tumor volumes after treatment with olaparib, JC081, and JC099. [Figure 10D]JC081 and JC099 inhibit the growth of breast cancer MDA-MB-231 xenografts. Mouse body weights after treatment with olaparib, JC081, and JC099 are shown. (One-way ANOVA, *P<0.05; **P<0.01) [Figure 11A] 1 shows that JC081 and JC099 suppress the growth of PC3 xenografts. Images of tumors after treatment with ENZ, olaparib, JC081, and JC099 are shown. [Figure 11B] 1 shows that JC081 and JC099 inhibit the growth of PC3 xenografts. Tumor weights after treatment with ENZ, olaparib, JC081, and JC099 are shown. [Figure 11C] 1 shows that JC081 and JC099 inhibit the growth of PC3 xenografts. Tumor volumes after treatment with ENZ, olaparib, JC081, and JC099 are shown. [Figure 11D] JC081 and JC099 inhibit the growth of PC3 xenografts. Mouse body weights after treatment with ENZ, olaparib, JC081, and JC099 are shown. (One-way ANOVA, *P<0.05; **P<0.01) [Figure 12A] 1 shows that JC081 and JC099 suppress the growth of C4-2B / MR xenografts. Images of tumors after treatment with ENZ, olaparib, JC081, and JC099 are shown. [Figure 12B] 1 shows that JC081 and JC099 inhibit the growth of C4-2B / MR xenografts. Tumor weights after treatment with ENZ, olaparib, JC081, and JC099 are shown. [Figure 12C] 1 shows that JC081 and JC099 inhibit the growth of C4-2B / MR xenografts. Tumor volumes after treatment with ENZ, olaparib, JC081, and JC099 are shown. [Figure 12D] JC081 and JC099 inhibit the growth of C4-2B / MR xenografts. Mouse body weights after treatment with ENZ, olaparib, JC081, and JC099 are shown. (One-way ANOVA, *P<0.05; **P<0.01) [Figure 13A] We demonstrate that JC099 overcomes cisplatin resistance in head and neck and lung cancers. Unlike OLA, treatment with JC099 significantly suppressed tumor growth of SCC1R cells in vivo. [Figure 13B] We demonstrate that JC099 overcomes cisplatin resistance in head and neck and lung cancers. Unlike OLA, treatment with JC099 significantly suppressed tumor growth of SCC1R cells in vivo. [Figure 13C] These results show that JC099 overcomes cisplatin resistance in head and neck cancer and lung cancer, and that JC099 more potently inhibited tumor growth of H1703R cells than the combination of OLA and VE-822. [Figure 13D] JC099 overcomes cisplatin resistance in head and neck cancer and lung cancer. JC099 inhibited tumor growth of H1703R cells more potently than the combination of OLA and VE-822 (one-way ANOVA, *P<0.05; **P<0.01). [Figure 14A] 1 shows the effect of JCS003 to JCS006 on cell viability. Cell viability is shown for PC3 and C4-2B / MR cells after treatment with 1 μM, 2 μM, and 4 μM JCS003 and JCS006 for 48 hours. [Figure 14B] 1 shows the effect of JCS003 to JCS006 on cell viability. Cell viability after treatment with 1 μM, 2 μM, and 4 μM of JCS004 and JCS005 for 48 hours in PC3 and SUM149PT-BRCA1mut cells is shown. [Figure 15A] 1 shows the effect of JCS007 to JCS019 on cell viability. Cell viability is shown for PC3 and MDA-MB-231 cells after treatment with 0.5 μM, 1 μM, and 2 μM JCS007 and JCS008 for 48 hours. [Figure 15B] 1 shows the effects of JCS007 to JCS019 on cell viability. PC3 cells were treated with 0.5 μM, 1 μM, and 2 μM of JCS009 and JCS010 for 48 hours. [Figure 15C] 1 shows the effect of JCS007 to JCS019 on cell viability. 2 shows the cell viability of PC3 cells after treatment with 0.5 μM, 1 μM, and 2 μM of JCS011 to JCS014 for 48 hours. [Figure 15D] 1 shows the effect of JCS007 to JCS019 on cell viability. Cell viability after treatment with 0.5 μM, 1 μM, and 2 μM of JCS015 to JCS019 for 48 hours in PC3 and SUM149PT-BRCA1mut cells is shown. [Figure 16A] 1 shows the effect of JCS020 to JCS071 on cell viability. Cell viability is shown for PC3 and SUM149PT-BRCA1mut cells after treatment with 1 μM or 2 μM JCS020 to JCS027 for 48 hours. [Figure 16B] 1 shows the effect of JCS020 to JCS071 on cell viability. Cell viability after treatment of PC3 and SUM149PT-BRCA1mut cells with 1 μM or 2 μM of JCS028 to JCS035 for 48 hours is shown. [Figure 16C] 1 shows the effect of JCS020 to JCS071 on cell viability. Cell viability after treatment of PC3 and SUM149PT-BRCA1mut cells with 1 μM or 2 μM of JCS036 to JCS043 for 48 hours is shown. [Figure 16D] 1 shows the effect of JCS020 to JCS071 on cell viability. Cell viability after treatment of PC3 and SUM149PT-BRCA1mut cells with 1 μM or 2 μM of JCS044 to JCS050 for 48 hours is shown. [Figure 16E] 1 shows the effect of JCS020 to JCS071 on cell viability. Cell viability after treatment of PC3 and SUM149PT-BRCA1mut cells with 1 μM or 2 μM of JCS051 to JCS058 for 48 hours is shown. [Figure 16F]1 shows the effect of JCS020 to JCS071 on cell viability. Cell viability after treatment of PC3 and SUM149PT-BRCA1mut cells with 1 μM or 2 μM of JCS059 to JCS063 for 48 hours is shown. [Figure 16G] 1 shows the effect of JCS020 to JCS071 on cell viability. Cell viability is shown for PC3 and SUM149PT-BRCA1mut cells after treatment with 1 μM or 2 μM of JCS064 to JCS071 for 48 hours. [Figure 16H] 1 shows the effect of JCS020 to JCS071 on cell viability. Cell viability is shown for PC3 and SUM149PT-BRCA1mut cells after treatment with 1 μM or 2 μM of JCS072 to JCS076 for 48 hours. [Figure 16I] 1 shows the effect of JCS020 to JCS071 on cell viability. 2 shows the cell viability of PC3 and SUM149PT-BRCA1mut cells after treatment with 1 μM or 2 μM of JCS077 to JCS084 for 48 hours. [Figure 17A] 1 shows that JCS003 to JCS008 inhibit ATR activity. 2 shows that olaparib-induced phosphorylation of CHK1 at serine 345 is suppressed by 0.5 μM, 1 μM, and 2 μM JCS003 in PC3 and SUM149PT-BRCA1rev cells. [Figure 17B] 1 shows that JCS003 to JCS008 inhibit ATR activity. 2 shows that UV-induced phosphorylation of CHK1 at serine 345 is suppressed by 1 μM and 2 μM JCS004 or JCS005 in PC3 and SUM149PT-BRCA1rev cells. [Figure 17C] 1 shows that JCS003 to JCS008 inhibit ATR activity. 2 μM JCS003 or JCS006 suppresses olaparib-induced phosphorylation of Rad17 at serine 645 and CHK1 at serine 345 in PC3 and PC3 cells. [Figure 17D]This shows that JCS003 to JCS008 inhibit ATR activity. This shows that olaparib-induced phosphorylation of Rad17 at serine 645 and CHK1 at serine 345 is suppressed by 1 μM and 2 μM JCS007 or JCS008 in PC3 and MDA-MB-231 cells. [Figure 18A] 1 shows that JCS009 to JCS029 inhibit ATR activity in PC3 cells. 1 μM and 2 μM JCS009 to JCS012 suppress phosphorylation of Rad17 at serine 645 and CHK1 at serine 345 induced by olaparib. [Figure 18B] 1 shows that JCS009 to JCS029 inhibit ATR activity in PC3 cells. 1 μM and 2 μM JCS011 to JCS014 suppress phosphorylation of Rad17 at serine 645 and CHK1 at serine 345 induced by olaparib. [Figure 18C] 1 shows that JCS009 to JCS029 inhibit ATR activity in PC3 cells. 1 μM and 2 μM JCS015 to JCS017 suppress phosphorylation of Rad17 at serine 645 and CHK1 at serine 345 induced by olaparib. [Figure 18D] 1 shows that JCS009 to JCS029 inhibit ATR activity in PC3 cells. 1 μM and 2 μM JCS018 to JCS021 suppress phosphorylation of Rad17 at serine 645 and CHK1 at serine 345 induced by olaparib. [Figure 18E] 1 shows that JCS009 to JCS029 inhibit ATR activity in PC3 cells. 1 μM and 2 μM JCS022 to JCS025 suppress phosphorylation of Rad17 at serine 645 and CHK1 at serine 345 induced by olaparib. [Figure 18F]1 shows that JCS009 to JCS029 inhibit ATR activity in PC3 cells. 1 μM and 2 μM JCS026 to JCS029 suppress phosphorylation of Rad17 at serine 645 and CHK1 at serine 345 induced by olaparib. [Figure 19A] 1 shows that JCS030 to JCS053 inhibit ATR activity in PC3 cells. 1 μM and 2 μM JCS030 to JCS033 suppress phosphorylation of Rad17 at serine 645 and CHK1 at serine 345 induced by olaparib. [Figure 19B] 1 shows that JCS030 to JCS053 inhibit ATR activity in PC3 cells. 1 μM and 2 μM JCS034 to JCS037 suppress phosphorylation of Rad17 at serine 645 and CHK1 at serine 345 induced by olaparib. [Figure 19C] 1 shows that JCS030 to JCS053 inhibit ATR activity in PC3 cells. 1 μM and 2 μM JCS038 to JCS041 suppress phosphorylation of Rad17 at serine 645 and CHK1 at serine 345 induced by olaparib. [Figure 19D] 1 shows that JCS030 to JCS053 inhibit ATR activity in PC3 cells. 1 μM and 2 μM JCS042 to JCS045 suppress phosphorylation of Rad17 at serine 645 and CHK1 at serine 345 induced by olaparib. [Figure 19E] 1 shows that JCS030 to JCS053 inhibit ATR activity in PC3 cells. 1 μM and 2 μM JCS046 to JCS049 suppress phosphorylation of Rad17 at serine 645 and CHK1 at serine 345 induced by olaparib. [Figure 19F]1 shows that JCS030 to JCS053 inhibit ATR activity in PC3 cells. 1 μM and 2 μM JCS050 to JCS053 suppress phosphorylation of Rad17 at serine 645 and CHK1 at serine 345 induced by olaparib. [Figure 20A] 1 shows that JCS054 to JCS071 inhibit ATR activity in PC3 cells. 1 μM and 2 μM JCS054 to JCS057 suppress phosphorylation of Rad17 at serine 645 and CHK1 at serine 345 induced by olaparib. [Figure 20B] 1 shows that JCS054 to JCS071 inhibit ATR activity in PC3 cells. 1 μM and 2 μM JCS058, JCS059, JCS060, and JCS063 suppress phosphorylation of Rad17 at serine 645 and CHK1 at serine 345 induced by olaparib. [Figure 20C] 1 shows that JCS054 to JCS071 inhibit ATR activity in PC3 cells. 1 μM and 2 μM JCS061 or JCS062 suppress phosphorylation of Rad17 at serine 645 and CHK1 at serine 345 induced by olaparib. [Figure 20D] 1 shows that JCS054 to JCS071 inhibit ATR activity in PC3 cells. 1 μM and 2 μM JCS064 to JCS067 suppress phosphorylation of Rad17 at serine 645 and CHK1 at serine 345 induced by olaparib. [Figure 20E] 1 shows that JCS054 to JCS071 inhibit ATR activity in PC3 cells. 1 μM and 2 μM JCS068 to JCS071 suppress phosphorylation of Rad17 at serine 645 and CHK1 at serine 345 induced by olaparib. [Figure 20F]1 shows that JCS054 to JCS071 inhibit ATR activity in PC3 cells. 1 μM and 2 μM JCS072 to JCS075 suppress phosphorylation of Rad17 at serine 645 and CHK1 at serine 345 induced by olaparib. [Figure 20G] 1 shows that JCS054 to JCS071 inhibit ATR activity in PC3 cells. 1 μM and 2 μM JCS076 to JCS079 suppress phosphorylation of Rad17 at serine 645 and CHK1 at serine 345 induced by olaparib. [Figure 20H] 1 shows that JCS054 to JCS071 inhibit ATR activity in PC3 cells. 1 μM and 2 μM JCS080 to JCS083 suppress phosphorylation of Rad17 at serine 645 and CHK1 at serine 345 induced by olaparib. [Figure 20I] 1 shows that JCS054 to JCS071 inhibit ATR activity in PC3 cells. 1 μM and 2 μM JCS084 to JCS087 suppress phosphorylation of Rad17 at serine 645 and CHK1 at serine 345 induced by olaparib. [Figure 21A] 1 shows that JCS003 to JCS028 trap PARP1 at DNA damage sites. This shows that PARP1 was trapped at DNA damage sites by 0.5 μM JCS003 or JCS006 in PC3 and C4-2B / MR cells. [Figure 21B] This shows that JCS003 to JCS028 trap PARP1 at the site of DNA damage. This shows that PARP1 was trapped at the site of DNA damage by 0.5 μM and 2 μM JCS004 or JCS005 in PC3 and C4-2B / MR cells. [Figure 21C]This shows that JCS003 to JCS028 trap PARP1 at DNA damage sites. In PC3 cells, PARP1 was trapped at DNA damage sites by 0.5 μM and 2 μM JCS008, JCS010, JCS011, JCS012, and JCS013. [Figure 21D] This shows that JCS003 to JCS028 trap PARP1 at sites of DNA damage. In PC3 cells, PARP1 was trapped at sites of DNA damage by 0.5 μM and 2 μM JCS016, JCS023, JCS025, JCS027, and JCS028. [Figure 22A] JCS030-JCS072 trap PARP1 at DNA damage sites in PC3 cells. PARP1 was trapped at DNA damage sites by 0.5 μM JCS016, JCS023, JCS025, JCS027, JCS028, JCS030, JCS031, JCS034, JCS036, and JCS037. [Figure 22B] JCS030 to JCS072 trap PARP1 at sites of DNA damage in PC3 cells. PARP1 was trapped at sites of DNA damage by 0.3 μM JCS027, JCS038, JCS041, JCS042, JCS043, JCS044, JCS046, JCS047, JCS048, and JCS050. [Figure 22C] JCS030 to JCS072 trap PARP1 at DNA damage sites in PC3 cells. PARP1 was trapped at DNA damage sites by 0.3 μM JCS053, JCS054, JCS057, JCS058, JCS059, JCS060, JCS061, and JCS062. [Figure 22D] 1 shows that JCS030 to JCS072 trap PARP1 at DNA damage sites in PC3 cells. 1 shows that PARP1 was trapped at DNA damage sites by 0.3 μM JCS063 to JCS072. [Figure 22E]This shows that JCS030 to JCS072 trap PARP1 at the site of DNA damage in PC3 cells. This shows that PARP1 was trapped at the site of DNA damage by 0.3 μM JCS073 to JCS081. [Figure 23A] 1 shows the effect of JC099 analogs on PARP1 trapping. JC064, JC081, JC099, JC103, JC113, JC117, and JC127 trapped PARP1 at sites of DNA damage in SUM149PT-BRCA1rev cells. [Figure 23B] Figure 1 shows the effect of JC099 analogs on PARP1 trapping. JC124, JC125, JC127, and JC128 trapped PARP1 at sites of DNA damage in PC3 and C4-2B / MR cells. [Figure 24A] Figure 1 shows the effect of JC099 analogs on ATR inhibition. Figure 2 shows that JC046, JC048, JC049, JC050, JC052, JC066, and JC070 suppressed OLA-induced Rad17 and CHK1 phosphorylation in PC3 and SUM149PT-BRCA1rev cells, respectively. [Figure 24B] Figure 1 shows the effect of JC099 analogs on ATR inhibition. Figure 2 shows that JC046, JC124, JC125, JC127, and JC128 suppressed OLA-induced Rad17 and CHK1 phosphorylation in PC3 and SUM149PT-BRCA1rev cells, respectively. [Figure 25A] 1 shows the effect of JCS085 to JCS114 on cell viability. Cell viability is shown for PC-3 and SUM149PT-BRCA1mut cells after treatment with 2 μM JCS085 to JCS089 for 48 hours. [Figure 25B] 1 shows the effect of JCS085 to JCS114 on cell viability. Cell viability after treatment of PC-3 and SUM149PT-BRCA1mut cells with 1 μM or 2 μM of JCS090 to JCS093 for 48 hours is shown. [Figure 25C]1 shows the effect of JCS085 to JCS114 on cell viability. Cell viability after treatment of PC-3 and SUM149PT-BRCA1mut cells with 1 μM or 2 μM of JCS093 to JCS100 for 48 hours is shown. [Figure 25D] 1 shows the effect of JCS085 to JCS114 on cell viability. Cell viability is shown for PC-3 and SUM149PT-BRCA1mut cells after treatment with 1 μM or 2 μM of JCS101 to JCS106 for 48 hours. [Figure 25E] 1 shows the effect of JCS085 to JCS114 on cell viability. Cell viability is shown for PC-3 and SUM149PT-BRCA1mut cells after treatment with 1 μM or 2 μM of JCS107 to JCS114 for 48 hours. [Figure 26A] 1 shows the effect of JCS117 to JCS130 on cell viability. Cell viability after treatment with 0.5 μM or 1.5 μM of JCS117 to JCS130 for 48 hours in C4-2B / MR and PC-3 cells. [Figure 26B] 1 shows the effect of JCS117 to JCS130 on cell viability. Cell viability after 48 hours of treatment with 0.5 μM or 1.5 μM of JCS124 to JCS130 is shown for C4-2B / MR and PC-3 cells. [Figure 27A] 1 shows the effect of JCS115, JCS116, and JCS131 to JCS161 on cell viability. Cell viability is shown for PC-3 and SUM149PT-BRCA1mut cells after treatment with 1 μM or 2 μM JCS115, JCS116, and JCS131 to JCS134 for 72 hours. [Figure 27B] This shows the effects of JCS115, JCS116, and JCS131 to JCS161 on cell viability. This shows the cell viability of PC-3 and SUM149PT-BRCA1mut cells after treatment with 1 μM or 2 μM of JCS135 to JCS137 for 72 hours. [Figure 27C]This shows the effects of JCS115, JCS116, and JCS131 to JCS161 on cell viability. This shows the cell viability of PC-3 and SUM149PT-BRCA1mut cells after treatment with 1 μM or 2 μM of JCS138 to JCS140 for 72 hours. [Figure 27D] 1 shows the effects of JCS115, JCS116, and JCS131 to JCS161 on cell viability. Cell viability is shown for PC-3 and SUM149PT-BRCA1mut cells after treatment with 1 μM or 2 μM of JCS141 to JCS145 for 72 hours. [Figure 27E] This shows the effects of JCS115, JCS116, and JCS131 to JCS161 on cell viability. This shows the cell viability of PC-3 and SUM149PT-BRCA1mut cells after treatment with 1 μM or 2 μM of JCS146 to JCS153 for 72 hours. [Figure 27F] 1 shows the effects of JCS115, JCS116, and JCS131 to JCS161 on cell viability. Cell viability is shown for PC-3 and SUM149PT-BRCA1mut cells after treatment with 1 μM or 2 μM of JCS154 to JCS161 for 72 hours. [Figure 28A] 10 shows that JCS088 to JCS114 inhibit ATR activity in PC3 cells. 1 μM and 2 μM JCS088 to JCS089 suppress phosphorylation of Rad17 at serine 645 and CHK1 at serine 345 induced by olaparib or UV. [Figure 28B] This shows that JCS088 to JCS114 inhibit ATR activity in PC3 cells. This shows that olaparib- or UV-induced phosphorylation of Rad17 at serine 645 and CHK1 at serine 345 is suppressed by 1 μM and 2 μM JCS090 to JCS093. [Figure 28C]This shows that JCS088 to JCS114 inhibit ATR activity in PC3 cells. This shows that olaparib- or UV-induced phosphorylation of Rad17 at serine 645 and CHK1 at serine 345 is suppressed by 1 μM and 2 μM JCS094 to JCS097. [Figure 28D] This shows that JCS088 to JCS114 inhibit ATR activity in PC3 cells. This shows that olaparib- or UV-induced phosphorylation of Rad17 at serine 645 and CHK1 at serine 345 is suppressed by 1 μM and 2 μM JCS098 to JCS100. [Figure 28E] 10 shows that JCS088 to JCS114 inhibit ATR activity in PC3 cells. 1 μM and 2 μM JCS101 to JCS104 suppress phosphorylation of Rad17 at serine 645 and CHK1 at serine 345 induced by olaparib or UV. [Figure 28F] This shows that JCS088 to JCS114 inhibit ATR activity in PC3 cells. This shows that olaparib- or UV-induced phosphorylation of Rad17 at serine 645 and CHK1 at serine 345 is suppressed by 1 μM and 2 μM JCS107 to JCS108. [Figure 28G] We show that JCS088 to JCS114 inhibit ATR activity in PC3 cells. We also show that olaparib- or UV-induced phosphorylation of Rad17 at serine 645 and CHK1 at serine 345 is suppressed by 1 μM and 2 μM JCS105, JCS106, JCS109, and JCS110. [Figure 28H] 10 shows that JCS088 to JCS114 inhibit ATR activity in PC3 cells. 1 μM and 2 μM JCS111 to JCS114 suppress phosphorylation of Rad17 at serine 645 and CHK1 at serine 345 induced by olaparib or UV. [Figure 29A]We show that JCS117-JCS130 inhibit ATR / ATM activity in C4-2B / MR cells. We also show that olaparib- or UV-induced phosphorylation of Rad17 at serine 645, CHK1 at serine 345, KAP1 at serine 824, and CHK2 at threonine 68 is suppressed by 0.5 μM and 1.5 μM JCS117-JCS118. [Figure 29B] We show that JCS117-JCS130 inhibit ATR / ATM activity in C4-2B / MR cells. We also show that olaparib- or UV-induced phosphorylation of Rad17 at serine 645, CHK1 at serine 345, KAP1 at serine 824, and CHK2 at threonine 68 is suppressed by 0.5 μM and 1.5 μM JCS119-JCS122. [Figure 29C] We show that JCS117-JCS130 inhibit ATR / ATM activity in C4-2B / MR cells. We also show that olaparib- or UV-induced phosphorylation of Rad17 at serine 645, CHK1 at serine 345, KAP1 at serine 824, and CHK2 at threonine 68 is suppressed by 0.5 μM and 1.5 μM JCS123-JCS126. [Figure 29D] We show that JCS117-JCS130 inhibit ATR / ATM activity in C4-2B / MR cells. We also show that olaparib- or UV-induced phosphorylation of Rad17 at serine 645, CHK1 at serine 345, KAP1 at serine 824, and CHK2 at threonine 68 was suppressed by 0.5 μM and 1.5 μM JCS127-JCS130. [Figure 30A] We show that JCS115, JCS116, and JCS131 to JCS160 inhibit ATR activity in PC3 cells. We also show that olaparib- or UV-induced phosphorylation of Rad17 at serine 645 and CHK1 at serine 345 is suppressed by 1 μM and 2 μM JCS115, JCS116, JCS131, and JCS132. [Figure 30B]We show that JCS115, JCS116, and JCS131 to JCS160 inhibit ATR activity in PC3 cells. We also show that olaparib- or UV-induced phosphorylation of Rad17 at serine 645 and CHK1 at serine 345 is suppressed by 1 μM and 2 μM JCS133 to JCS136. [Figure 30C] We show that JCS115, JCS116, and JCS131 to JCS160 inhibit ATR activity in PC3 cells. We also show that olaparib- or UV-induced phosphorylation of Rad17 at serine 645 and CHK1 at serine 345 is suppressed by 1 μM and 2 μM JCS137 to JCS140. [Figure 30D] We show that JCS115, JCS116, and JCS131 to JCS160 inhibit ATR activity in PC3 cells. We also show that olaparib-induced phosphorylation of Rad17 at serine 645 and CHK1 at serine 345 is suppressed by 1 μM and 2 μM JCS141 to JCS144. [Figure 30E] We show that JCS115, JCS116, and JCS131 to JCS160 inhibit ATR activity in PC3 cells. We also show that olaparib-induced phosphorylation of Rad17 at serine 645 and CHK1 at serine 345 is suppressed by 1 μM and 2 μM JCS145 to JCS148. [Figure 30F] We show that JCS115, JCS116, and JCS131 to JCS160 inhibit ATR activity in PC3 cells. We also show that olaparib-induced phosphorylation of Rad17 at serine 645 and CHK1 at serine 345 is suppressed by 1 μM and 2 μM JCS149 to JCS152. [Figure 30G] We show that JCS115, JCS116, and JCS131 to JCS160 inhibit ATR activity in PC3 cells. We also show that olaparib-induced phosphorylation of Rad17 at serine 645 and CHK1 at serine 345 is suppressed by 1 μM and 2 μM JCS153 to JCS156. [Figure 30H]We show that JCS115, JCS116, and JCS131 to JCS160 inhibit ATR activity in PC3 cells. We also show that olaparib-induced phosphorylation of Rad17 at serine 645 and CHK1 at serine 345 is suppressed by 1 μM and 2 μM JCS157 to JCS160. [Figure 31A] 1 shows that JCS082 to JCS140 trap PARP1 at sites of DNA damage in PC3 cells. 1 shows that PARP1 was trapped at sites of DNA damage by 0.5 μM JCS082 to JCS089. [Figure 31B] 1 shows that JCS090 to JCS100 trap PARP1 at sites of DNA damage in PC3 cells. 1 shows that PARP1 was trapped at sites of DNA damage by 0.5 μM JCS090 to JCS100. [Figure 31C] 1 shows that JCS090 to JCS100 trap PARP1 at DNA damage sites in PC3 cells. 1 shows that PARP1 was trapped at DNA damage sites by 0.5 μM JCS101 to JCS110. [Figure 31D] This shows that JCS090 to JCS100 trap PARP1 at the site of DNA damage in PC3 cells. This shows that PARP1 was trapped at the site of DNA damage by 0.5 μM JCS111 to JCS116. [Figure 31E] This shows that JCS090 to JCS100 trap PARP1 at the site of DNA damage in PC3 cells. This shows that PARP1 was trapped at the site of DNA damage by 0.5 μM JCS131 to JCS140. [Figure 31F] This shows that JCS090 to JCS100 trap PARP1 at the site of DNA damage in PC3 cells. This shows that PARP1 was trapped at the site of DNA damage by 0.3 μM JCS141 to JCS150. [Figure 31G] This shows that JCS090 to JCS100 trap PARP1 at the site of DNA damage in PC3 cells. This shows that PARP1 was trapped at the site of DNA damage by 0.3 μM JCS151 to JCS160. [Figure 32A] Figure 1 shows that JC099 analogs suppress the growth of BRCA2-mutated breast cancer PDXs. Images of tumors after treatment with 50 mg / kg (intragastric administration) of JC099, JCS016, JCS025, JCS027, JCS041, JCS043, JCS063, JCS069, and JCS086 are shown. [Figure 32B] Figure 1 shows that JC099 analogs inhibit the growth of BRCA2-mutated breast cancer PDX. Tumor weights are shown after treatment with 50 mg / kg (intragastric administration) of JC099, JCS016, JCS025, JCS027, JCS041, JCS043, JCS063, JCS069, and JCS086. [Figure 32C] Figure 1 shows that JC099 analogs inhibit the growth of BRCA2-mutated breast cancer PDXs. Tumor volumes are shown after treatment with 50 mg / kg (intragastric administration) of JC099, JCS016, JCS025, JCS027, JCS041, JCS043, JCS063, JCS069, and JCS086. [Figure 32D] JC099 analogs suppress the growth of BRCA2-mutated breast cancer PDXs. Mouse body weights after treatment with 50 mg / kg (intragastric administration) of JC099, JCS016, JCS025, JCS027, JCS041, JCS043, JCS063, JCS069, and JCS086 are shown. (One-way ANOVA, *P<0.05; **P<0.01) [Figure 33A] Figure 1 shows that JC099 analogs inhibit the growth of breast cancer SUM149PT-BRCA1rev xenografts. Images of tumors after treatment with 50 mg / kg (intragastric administration) of JC099, JCS016, JCS025, JCS069, and JCS086 are shown. [Figure 33B] Figure 1 shows that JC099 analogs inhibit the growth of breast cancer SUM149PT-BRCA1rev xenografts. Tumor weights are shown after treatment with 50 mg / kg (intragastric administration) of JC099, JCS016, JCS025, JCS069, and JCS086. [Figure 33C]Figure 1 shows that JC099 analogs inhibit the growth of breast cancer SUM149PT-BRCA1rev xenografts. Figure 2 shows that JC099 analogs inhibit the growth of BRCA2-mutated breast cancer PDXs. Figure 3 shows tumor volumes after treatment with 50 mg / kg (intragastric administration) of JC099, JCS016, JCS025, JCS069, and JCS086. [Figure 33D] Figure 1 shows that JC099 analogs inhibit the growth of breast cancer SUM149PT-BRCA1rev xenografts. Figure 2 shows that JC099 analogs inhibit the growth of BRCA2-mutated breast cancer PDXs. Figure 3 shows mouse body weights after treatment with 50 mg / kg (intragastric administration) of JC099, JCS016, JCS025, JCS069, and JCS086. (One-way ANOVA, *P<0.05; ***P<0.001) [Figure 34A] Figure 1 shows that JC099 analogs inhibit the growth of castration-resistant prostate cancer PDX. Images of tumors after treatment with 50 mg / kg (intragastric administration) of JC099, JCS025, and JCS069 are shown. [Figure 34B] Figure 1 shows that JC099 analogs inhibit the growth of castration-resistant prostate cancer PDX. Tumor weights are shown after treatment with 50 mg / kg (intragastric administration) of JC099, JCS025, and JCS069. [Figure 34C] Figure 1 shows that JC099 analogs inhibit the growth of castration-resistant prostate cancer PDX. Figure 2 shows that JC099 analogs inhibit the growth of BRCA2-mutated breast cancer PDX. Figure 3 shows tumor volumes after treatment with 50 mg / kg (intragastric administration) of JC099, JCS025, and JCS069. [Figure 34D] Figure 1 shows that JC099 analogs inhibit the growth of castration-resistant prostate cancer PDX. Figure 2 shows that JC099 analogs inhibit the growth of BRCA2-mutated breast cancer PDX. Figure 3 shows the body weight of mice after treatment with 50 mg / kg (intragastric administration) of JC099, JCS025, and JCS069. (One-way ANOVA, *P<0.05; **P<0.01; ***P<0.001) [Figure 35A]Figure 1 shows that JC099 analogs suppress the growth of olaparib-resistant breast cancer PDXs. Images of tumors after treatment with 60 mg / kg (intragastric administration) of JC099, JCS090, JCS136, and JCS140 are shown. [Figure 35B] Figure 1 shows that JC099 analogs inhibit the growth of olaparib-resistant breast cancer PDX. Tumor weights are shown after treatment with 50 mg / kg (intragastric administration) of JC099, JCS090, JCS136, and JCS140. [Figure 35C] Figure 1 shows that JC099 analogs inhibit the growth of olaparib-resistant breast cancer PDX. Tumor volumes after treatment with 50 mg / kg (intragastric administration) of JC099, JCS090, JCS136, and JCS140 are shown. [Figure 35D] JC099 analogs inhibit the growth of olaparib-resistant breast cancer PDXs. Mouse body weights after treatment with 50 mg / kg (intragastric administration) of JC099, JCS090, JCS136, and JCS140 are shown. (One-way ANOVA, *P<0.05; **P<0.01; ***P<0.001) DETAILED DESCRIPTION OF THE INVENTION

[0011] In one aspect, the disclosure provides a compound having a structure represented by Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt thereof: [ka] During the ceremony, A is aryl or heteroaryl; n1 is 1, 2, 3, 4, or 5; X 1 is O, S, or NR 7 and X 2 is O, S, or NR 8 and R 2 , R 4 , R 12 , R 13 , R 14 , and R 15are each independently selected from H, fluoro, chloro, bromo, and iodo; R 1 and R 3 are each independently selected from H, fluoro, chloro, bromo, iodo, and —O(alkyl); R 5 , R 7 , and R 8 each is independently selected from H, alkyl, and aralkyl; R A is alkyl, acyl, or amido; R C is H, alkyl, or acyl, R 6 is alkyl, aryl, heteroaryl, or heterocyclyl. In certain embodiments, the compound has the structure of Formula Ia, or a pharmaceutically acceptable salt thereof: [ka] During the ceremony, X 1 is O, S, or NR 7 and X 2 is O, S, or NR 8 and R 1 , R 2 , R 3 , and R 4 are each independently selected from fluoro, chloro, bromo, and iodo; R 5 , R 7 , and R 8 each is independently selected from H, alkyl, and aralkyl; R 6 is alkyl, aryl, heteroaryl, or heterocyclyl.

[0012] In certain embodiments, the compound has the structure of Formula I, or a pharmaceutically acceptable salt thereof. [ka]

[0013] In certain embodiments, the compound has the structure represented by Formula II: or a pharmaceutically acceptable salt thereof. [ka]

[0014] In certain embodiments, the compound has the structure represented by Formula III: or a pharmaceutically acceptable salt thereof. [ka]

[0015] In certain embodiments, the compound is [ka] [ka] or a pharmaceutically acceptable salt thereof.

[0016] In certain embodiments, the compound is [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] or a pharmaceutically acceptable salt thereof.

[0017] In certain embodiments, R 1 is fluoro. In a further embodiment, R 1 is chloro. In yet further embodiments, R 1 is H. In still further embodiments, R 1 is -O(alkyl) (e.g., methoxy).

[0018] In certain embodiments, R 2 is fluoro. In a further embodiment, R 2 is chloro. In yet further embodiments, R 2 is H.

[0019] In certain embodiments, R 3 is fluoro. In a further embodiment, R 3 is chloro. In yet further embodiments, R 3 is H. In still further embodiments, R 3 is -O(alkyl) (e.g., methoxy).

[0020] In certain embodiments, R 4 is fluoro. In a further embodiment, R 4 is chloro. In yet further embodiments, R 4 is H.

[0021] In certain embodiments, R 12 is chloro. In a further embodiment, R 12 is fluoro. In yet further embodiments, R 12 is H.

[0022] In certain embodiments, R 13 is chloro. In a further embodiment, R 13 is fluoro. In yet further embodiments, R13 is H.

[0023] In certain embodiments, R 14 is chloro. In a further embodiment, R 14 is fluoro. In yet further embodiments, R 14 is H.

[0024] In certain embodiments, R 15 is chloro. In a further embodiment, R 15 is fluoro. In certain embodiments, R 15 is H.

[0025] In certain embodiments, X 1 is O.

[0026] In certain embodiments, A is heteroaryl (eg, indazolyl).

[0027] In certain embodiments, n1 is 1.

[0028] In certain embodiments, R A is an alkylamide (e.g., N-diethylamide).

[0029] In certain embodiments, X 2 is O.

[0030] In certain embodiments, R 5 is H.

[0031] In certain embodiments, R 6 is alkyl. In a further embodiment, R 6 is heteroaryl (e.g., pyridinyl, pyrimidinyl, indolyl, or pyrazolopyridinyl). 6 is heteroaryl (e.g., pyridinyl, pyrimidinyl, indolyl, quinazolinyl, phthalazinyl, or pyrazolopyridinyl). 6is pyridinyl or pyrimidinyl. In certain embodiments, R 6 is aryl.

[0032] In certain embodiments, R 6 is substituted with alkyl, alkenyl, alkynyl, halo, hydroxyl, carboxyl, acyl, acetyl, ester, thioester, alkoxy, phosphoryl, amino, amido, cyano, nitro, azido, alkylthio, cycloalkyl, alkylsulfonyl, sulfonamido, cycloalkyl, aryl, heteroaryl, and heterocyclyl. 6 is substituted with heterocyclyl (e.g., pyrrolidinylpyrrolidinyl, piperazinyl, piperidinyl, or (1-ethylpyrrolidin-2-yl)methanamine). 6 is substituted with pyrrolidinyl or (1-ethylpyrrolidin-2-yl)methanamine. 6 is substituted with alkylamino (e.g., —N(CH)N(CH)). In still further embodiments, R 6 is substituted with an alkylamide (e.g., N-diethylamide). In certain embodiments, R 6 is substituted with nitro. In a further embodiment, R 6 is substituted with alkoxy. In yet further embodiments, R 6 is substituted with amino (e.g., —NH). In still further embodiments, R 6 is substituted with heterocyclyl.

[0033] In certain embodiments, the compound has the structure of Formula Ib, or a pharmaceutically acceptable salt thereof: [ka] During the ceremony, Each R 9is independently selected from alkyl, alkenyl, alkynyl, halo, hydroxyl, carboxyl, acyl, acetyl, ester, thioester, alkoxy, phosphoryl, amino, amido, cyano, nitro, azido, alkylthio, cycloalkyl, alkylsulfonyl, sulfonamido, cycloalkyl, aryl, heteroaryl, and heterocyclyl; n is 1, 2, 3, 4, or 5.

[0034] In certain embodiments, the compound has a structure represented by Formula Ic, Formula IIa, or Formula IIIa, or a pharmaceutically acceptable salt thereof: [ka] During the ceremony, X 3 is alkyl or N(R 18 )2, Each R 9 is independently selected from alkyl, alkenyl, alkynyl, halo, hydroxyl, carboxyl, acyl, acetyl, ester, thioester, alkoxy, phosphoryl, amino, amido, cyano, nitro, azido, alkylthio, cycloalkyl, alkylsulfonyl, sulfonamido, cycloalkyl, aryl, heteroaryl, and heterocyclyl; Each R 16 , R 17 , and R 18 are independently H or alkyl; n2 is 1, 2, 3, 4, or 5.

[0035] In certain embodiments, the compound has the structure represented by Formula Ic, or a pharmaceutically acceptable salt thereof. [ka]

[0036] In certain embodiments, the compound has the structure represented by Formula IIa: or a pharmaceutically acceptable salt thereof. [ka]

[0037] In certain embodiments, the compound has the structure of Formula IIIa: [ka]

[0038] In certain embodiments, the compound has the structure represented by Formula Id, Formula IIb, or Formula IIIb, or a pharmaceutically acceptable salt thereof. [ka]

[0039] In certain embodiments, the compound has the structure represented by Formula Id, or a pharmaceutically acceptable salt thereof. [ka]

[0040] In certain embodiments, the compound has the structure represented by Formula IIb: or a pharmaceutically acceptable salt thereof. [ka]

[0041] In certain embodiments, the compound has the structure represented by Formula IIIb: or a pharmaceutically acceptable salt thereof. [ka]

[0042] In certain embodiments, the compound has the structure represented by formula Ie: or a pharmaceutically acceptable salt thereof. [ka] During the ceremony, R 9is selected from alkyl, alkenyl, alkynyl, halo, hydroxyl, carboxyl, acyl, acetyl, ester, thioester, alkoxy, phosphoryl, amino, alkylamino, amido, cyano, nitro, azido, alkylthio, cycloalkyl, alkylsulfonyl, sulfonamido, carbamoylamino, cycloalkyl, aryl, heteroaryl, and heterocyclyl.

[0043] In certain embodiments, the compound has a structure represented by formula If, formula IIc, or formula IIIc, or a pharmaceutically acceptable salt thereof: [ka] During the ceremony, z is 0, 1 or 2; R 9 is selected from alkyl, alkenyl, alkynyl, halo, hydroxyl, carboxyl, acyl, acetyl, ester, thioester, alkoxy, phosphoryl, amino, alkylamino, amido, cyano, nitro, azido, alkylthio, cycloalkyl, alkylsulfonyl, sulfonamido, carbamoylamino, cycloalkyl, aryl, heteroaryl, and heterocyclyl; R 20 is selected from H, cycloalkyl, cycloalkenyl, heterocycloalkyl, and heterocyclyl.

[0044] In certain embodiments, the compound has the structure represented by formula If: or a pharmaceutically acceptable salt thereof. [ka]

[0045] In certain embodiments, the compound has the structure represented by Formula IIc, or a pharmaceutically acceptable salt thereof: [ka]

[0046] In certain embodiments, the compound has the structure of formula IIIc: [ka]

[0047] In certain embodiments, R 1 is fluoro. In certain embodiments, R 2 is fluoro.

[0048] In certain embodiments, R 3 is fluoro. In certain embodiments, R 4 is fluoro.

[0049] In certain embodiments, R 12 is fluoro. In certain embodiments, R 13 is fluoro.

[0050] In certain embodiments, R 14 is fluoro. In certain embodiments, R 15 is fluoro.

[0051] In certain embodiments, R 9 is alkoxy. In a further embodiment, R 9 is amino. In yet further embodiments, R 9 is aryl (e.g., phenyl) or heterocyclyl (e.g., pyrrolidinyl, or N-methylpiperazinyl). In still further embodiments, R 9 is alkylamino.

[0052] In certain embodiments, R 16 is H. In a further embodiment, R 16 is alkyl (e.g., methyl).

[0053] In certain embodiments, R 17 is H. In a further embodiment, R 17is alkyl (e.g., methyl).

[0054] In certain embodiments, z is 1.

[0055] In a further embodiment, z is 2.

[0056] In certain embodiments, the compound has the structure of formula Ig, or a pharmaceutically acceptable salt thereof: [ka] During the ceremony, R 10 is selected from alkyl, alkenyl, alkynyl, halo, hydroxyl, carboxyl, acyl, acetyl, ester, thioester, alkoxy, phosphoryl, amino, alkylamino, amido, carbamyl, cyano, nitro, azido, alkylthio, cycloalkyl, alkylsulfonyl, sulfonamido, carbamoylamino, cycloalkyl, aryl, heteroaryl, and heterocyclyl; m is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0057] In certain embodiments, the compound has the structure of Formula Ih, Formula IIId, or a pharmaceutically acceptable salt thereof: [ka] During the ceremony, E is heterocyclyl; R B is selected from alkyl, amino, hydroxyl, halo, alkoxy, and sulfonyl; R 10 is selected from alkyl, alkenyl, alkynyl, halo, hydroxyl, carboxyl, acyl, acetyl, ester, thioester, alkoxy, phosphoryl, amino, alkylamino, amido, carbamyl, cyano, nitro, azido, alkylthio, cycloalkyl, alkylsulfonyl, sulfonamido, carbamoylamino, cycloalkyl, aryl, heteroaryl, and heterocyclyl; n3 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; m is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0058] In certain embodiments, the compound has the structure of formula Ih: or a pharmaceutically acceptable salt thereof. [ka]

[0059] In certain embodiments, the compound has the structure represented by formula IIId or a pharmaceutically acceptable salt thereof: [ka]

[0060] In certain embodiments, m is 1. In certain particularly preferred embodiments, m is 2.

[0061] In certain embodiments, R 1 is chloro. In certain preferred embodiments, R 1 is -O(alkyl) (e.g., methoxy). In a further preferred embodiment, R 1 is fluoro. In yet additional preferred embodiments, R 1 is H.

[0062] In certain preferred embodiments, R 2 is fluoro.

[0063] In certain embodiments, R 3 is chloro. In certain preferred embodiments, R 3 is -O(alkyl) (e.g., methoxy). In a further preferred embodiment, R 3 is fluoro. In yet further embodiments, R 3 is H. In certain preferred embodiments, R 3 is H.

[0064] In certain preferred embodiments, R 4 is fluoro.

[0065] In certain embodiments, R 10 is selected from alkyl, alkenyl, alkynyl, halo, hydroxyl, carboxyl, acyl, acetyl, ester, thioester, alkoxy, phosphoryl, amino, alkylamino, amido, carbamyl, cyano, nitro, azido, alkylthio, cycloalkyl, alkylsulfonyl, sulfonamido, carbamoylamino, cycloalkyl, aryl, heteroaryl, and heterocyclyl. In certain preferred embodiments, R 10 is alkylamino (e.g., ethylamino, diethylamino, or —N(CH)O(CH)). In certain preferred embodiments, R 10 is ethylamino. In yet an additional preferred embodiment, R 10 is diethylamino. In certain preferred embodiments, R 10 is heterocyclyl (e.g., 2-oxa-6-azaspiro[3.3]heptyl, piperidinyl, pyrrolidinyl, octahydrocyclopenta[c]pyrrolidinyl, or 3-azabicyclo[3.1.0]hexyl). In certain preferred embodiments, R 10 is piperidinyl. In certain embodiments, R 10 is 2-oxa-6-azaspiro[3.3]heptyl. In certain preferred embodiments, R 10 is pyrrolidinyl. In certain embodiments, R 10 is 3-azabicyclo[3.1.0]hexyl. In a further embodiment, R 10 is octahydrocyclopenta[c]pyrrolidinyl.

[0066] In certain preferred embodiments, R 12 is fluoro. In certain preferred embodiments, R 13 is fluoro. In certain preferred embodiments, R 14 is fluoro. In certain preferred embodiments, R15 is fluoro.

[0067] In certain embodiments, E is heterocyclyl (eg, pyrrolidinyl, azetidinyl, octahydrocyclopenta[c]pyrrolidinyl, octahydropyrrolo[1,2-a]pyrazinyl, or 3-azabicyclo[3.1.0]hexyl).

[0068] In certain embodiments, R B is alkyl (e.g., methyl). In a further embodiment, R B is halo (e.g., fluoro). In still further embodiments, R B is amino (e.g., dimethylamino). In still further embodiments, R B is alkoxy (e.g., methoxy). In certain embodiments, R B is sulfonyl (e.g., —S(O)2CH3).

[0069] In certain embodiments, n3 is 0. In further embodiments, n3 is 1.

[0070] In certain embodiments, the compound has the structure of formula Ii, or a pharmaceutically acceptable salt thereof: [ka] During the ceremony, R 10 is selected from alkyl, alkenyl, alkynyl, halo, hydroxyl, carboxyl, acyl, acetyl, ester, thioester, alkoxy, phosphoryl, amino, alkylamino, amido, carbamyl, cyano, nitro, azido, alkylthio, cycloalkyl, alkylsulfonyl, sulfonamido, carbamoylamino, cycloalkyl, aryl, heteroaryl, and heterocyclyl; R 11 is H, alkyl, or aralkyl, m is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0071] In certain embodiments, the compound has the structure of formula Ij, or a pharmaceutically acceptable salt thereof: [ka] During the ceremony, R 10 is selected from alkyl, alkenyl, alkynyl, halo, hydroxyl, carboxyl, acyl, acetyl, ester, thioester, alkoxy, phosphoryl, amino, alkylamino, amido, carbamyl, cyano, nitro, azido, alkylthio, cycloalkyl, alkylsulfonyl, sulfonamido, carbamoylamino, cycloalkyl, aryl, heteroaryl, and heterocyclyl; R 11 is H, alkyl, or aralkyl, m is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0072] In certain embodiments, m is 1. In further embodiments, m is 2.

[0073] In yet further embodiments, m is 3.

[0074] In certain embodiments, R 10 is amino. In a further embodiment, R 10is NH, alkylamino (e.g., propylamino, pentylamino, or hexylamino), alkyloxyalkylamino (e.g., methoxypropylamino, methoxyethylamino, methoxyethylamino, or ethoxyethylamino), dialkylamino (e.g., diethylamino, dipropylamino, diisopropylamino, dibutylamino, dipentylamino, dihexylamino, or dioctylamino), dialkenylamino (e.g., diallylamino), dialkynylamino (e.g., dibutylamino), dialkyloxy alkylamino (e.g., dimethoxyethylamino), heterocyclylalkylamino (e.g., tetrahydrofuranylmethanamino, N-methylpyrrolidinylmethanamino, or N-ethylpyrrolidinylmethanamino), dialkoxyalkylamino (e.g., diethoxyethylamino), cycloalkylamino (e.g., dicyclohexylamino), aralkylamino (e.g., dibenzylamino), (alkyl)(cycloalkyl)amino (e.g., (methyl)(cyclohexyl)amino or (ethyl)(cyclohexyl)amino). In still further embodiments, R 10 is heterocyclyl (e.g., pyrrolidinyl, piperidinyl, piperazinyl such as N-methylpiperazinyl, azepanyl, azocanyl, morpholinyl, oxazolidinonyl, and phthalimidyl). 10 is heterocyclyl (e.g., pyrrolidinyl such as N-methylpyrrolidinyl, piperidinyl, azetidinyl, octahydrocyclopenta[c]pyrrolidinyl, octahydropyrrolo[1,2-a]pyrazinyl, 3-azabicyclo[3.1.0]hexyl, 2-oxa-6-azaspiro[3.3]heptyl, hexahydro-5H-[1,4]dioxino[2,3-c]pyrrolyl, piperazinyl such as N-methylpiperazinyl, azepanyl, azocanyl, morpholinyl, oxazolidinonyl, phthalimidyl). In certain embodiments, R 10 is carbamyl (e.g., tert-butylcarbamoyl). In a further embodiment, R 10 is heteroaryl (e.g., triazolyl).

[0075] In certain particularly preferred embodiments, R 10 is N-ethylpyrrolidinylmethanamino.

[0076] In certain embodiments, the compound has the structure of formula Ik, or a pharmaceutically acceptable salt thereof: [ka] During the ceremony, R 10 is selected from alkyl, alkenyl, alkynyl, halo, hydroxyl, carboxyl, acyl, acetyl, ester, thioester, alkoxy, phosphoryl, amino, alkylamino, amido, carbamyl, cyano, nitro, azido, alkylthio, cycloalkyl, alkylsulfonyl, sulfonamido, carbamoylamino, cycloalkyl, aryl, heteroaryl, and heterocyclyl; R 11 is H, alkyl, or aralkyl, m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0077] In certain embodiments, the compound has the structure of Formula II, or a pharmaceutically acceptable salt thereof: [ka] During the ceremony, R 10 is selected from alkyl, alkenyl, alkynyl, halo, hydroxyl, carboxyl, acyl, acetyl, ester, thioester, alkoxy, phosphoryl, amino, alkylamino, amido, carbamyl, cyano, nitro, azido, alkylthio, cycloalkyl, alkylsulfonyl, sulfonamido, carbamoylamino, cycloalkyl, aryl, heteroaryl, and heterocyclyl; R 11 is H, alkyl, or aralkyl, m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0078] In certain embodiments, m is 0. In further embodiments, m is 1.

[0079] In certain embodiments, R 10 is heterocyclyl (e.g., azetidine, pyrrolidinyl, pyrrolidinonyl, morpholinyl, piperidinyl, piperazinyl (such as N-methylpiperazinyl), or isoindolinyl). 10 is amino. In a further embodiment, R 10 is alkylamino (e.g., diethylamino or dibutylamino), or alkoxyalkylamino (e.g., dimethoxyethylamino). In certain embodiments, R 10 is heteroaryl (e.g., isoindoline). In a further embodiment, R 10 is substituted with alkyl, alkenyl, alkynyl, aralkyl, halo, hydroxyl, carboxyl, acyl, acetyl, ester, thioester, alkoxy, phosphoryl, amino, alkylamino, amido, carbamyl, cyano, nitro, azido, alkylthio, cycloalkyl, alkylsulfonyl, sulfonamido, carbamoylamino, cycloalkyl, aryl, heteroaryl, and heterocyclyl. 10 is substituted with alkyl (e.g., trifluoromethyl or thiophenylethyl). In still further embodiments, R 10 is substituted with aryl (e.g., phenyl). In certain embodiments, R 10 is substituted with acyl (e.g., cyclopropylmethanonyl). In certain embodiments, R 10 is substituted with amino (e.g., dimethylamino). In certain embodiments, R 10 is substituted with heterocyclyl (e.g., benzopyranyl or pyrrolidinyl). In certain embodiments, R 10 is substituted with an amide (e.g., pyridinylmethylamide). In certain embodiments, R 10is substituted with an ester (e.g., a tert-butyl ester). In certain embodiments, R 10 is substituted with aralkyl.

[0080] In certain embodiments, R 11 is H. In certain embodiments, R 11 is alkyl (e.g., ethyl).

[0081] In certain embodiments, the compound is [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] or a pharmaceutically acceptable salt thereof.

[0082] In certain embodiments, the compound is [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] or a pharmaceutically acceptable salt thereof.

[0083] In another aspect, the present disclosure provides a pharmaceutical composition comprising a compound disclosed herein and a pharmaceutically acceptable excipient.

[0084] In yet another aspect, the present disclosure provides a method of treating cancer in a subject in need thereof, comprising administering to the subject a compound disclosed herein or a pharmaceutically acceptable salt thereof.

[0085] In certain embodiments, the cancer is breast cancer, head and neck cancer, lung cancer, prostate cancer, or ovarian cancer. In further embodiments, the cancer is testicular cancer, cervical cancer, bladder cancer, esophageal cancer, mesothelioma, or brain cancer (e.g., neuroblastoma). In certain embodiments, the cancer is recurrent. In certain embodiments, the cancer is refractory. In certain embodiments, the cancer is resistant to treatment with olaparib. In certain embodiments, the cancer is resistant to treatment with cisplatin.

[0086] In yet another aspect, the present disclosure provides a method of inhibiting DNA repair in a subject in need thereof, comprising administering to the subject a compound disclosed herein or a pharmaceutically acceptable salt thereof.

[0087] Pharmaceutical Composition The compositions and methods of the present invention can be used to treat individuals in need of treatment. In certain embodiments, the individual is a mammal, such as a human, or a non-human mammal. When administered to an animal, such as a human, the composition or compound is preferably administered as a pharmaceutical composition comprising, for example, a compound of the present invention and a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers are well known in the art and include, for example, aqueous solutions such as water or physiologically buffered saline or other solvents, or vehicles such as glycols, glycerol, oils such as olive oil, or injectable organic esters. In preferred embodiments, when such pharmaceutical compositions are intended for human administration, particularly for invasive administration routes (i.e., routes such as injection or implantation that avoid transport or diffusion through epithelial barriers), the aqueous solution is pyrogen-free or substantially pyrogen-free. Excipients can be selected, for example, to provide delayed release of the drug or to selectively target one or more cells, tissues, or organs. The pharmaceutical compositions may be in dosage unit form, such as tablets, capsules (including sprinkle capsules and gelatin capsules), granules, lyophilizates for reconstitution, powders, solutions, syrups, suppositories, injections, etc. The compositions may also be present in transdermal delivery systems, e.g., skin patches. The compositions may also be present in solutions suitable for topical administration, such as lotions, creams, or ointments.

[0088] Pharmaceutically acceptable carriers can include physiologically acceptable agents that act to stabilize, increase the solubility, or enhance the absorption of compounds such as the compounds of the present invention. Such physiologically acceptable agents include, for example, carbohydrates such as glucose, sucrose, or dextran; antioxidants such as ascorbic acid or glutathione; chelating agents; low-molecular-weight proteins; or other stabilizers or excipients. The choice of a pharmaceutically acceptable carrier containing a physiologically acceptable agent depends, for example, on the route of administration of the composition. The preparation or pharmaceutical composition can be a self-emulsifying or self-microemulsifying drug delivery system. The pharmaceutical composition (preparation) can also be a liposome or other polymer matrix, into which, for example, the compounds of the present invention can be incorporated. For example, liposomes containing phospholipids or other lipids are non-toxic, physiologically acceptable, and metabolizable carriers, and are relatively easy to prepare and administer.

[0089] As used herein, the phrase "pharmaceutically acceptable" is used to refer to compounds, materials, compositions, and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0090] As used herein, the phrase "pharmaceutically acceptable carrier" refers to a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not harmful to the patient. Some examples of substances that can function as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose, and sucrose; (2) starches, such as corn starch and potato starch; (3) celluloses and their derivatives, such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository wax; and (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil. (10) glycols such as propylene glycol; (11) polyols such as glycerin, sorbitol, mannitol, and polyethylene glycol; (12) esters such as ethyl oleate and ethyl laurate; (13) agar; (14) buffers such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer; and (21) other non-toxic compatible substances employed in pharmaceutical formulations.

[0091] Pharmaceutical compositions (preparations) can be administered to a subject by any of a number of routes of administration, including, for example, orally (e.g., as a drench such as an aqueous or non-aqueous solution or suspension, a tablet, a capsule (including sprinkle capsules and gelatin capsules), a bolus, a powder, a granule, a paste for application to the tongue), absorption through the oral mucosa (e.g., sublingually), subcutaneously, transdermally (e.g., as a patch applied to the skin), and topically (e.g., as a cream, ointment, or spray applied to the skin). The compounds may also be formulated for inhalation. In certain embodiments, the compounds may simply be dissolved or suspended in sterile water. Details of suitable routes of administration and compositions suitable therefor can be found, for example, in U.S. Pat. Nos. 6,110,973, 5,763,493, 5,731,000, 5,541,231, 5,427,798, 5,358,970, and 4,172,896, and the patents cited therein.

[0092] The formulations can be conveniently presented in unit dosage form and can be prepared by any method well known in the art of pharmacy. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will vary depending on the host being treated and the particular mode of administration. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will generally be that amount of compound that produces a therapeutic effect. Generally, out of 100 percent, this amount will range from about 1 percent to about 99 percent of the active ingredient, preferably from about 5 percent to about 70 percent, and most preferably from about 10 percent to about 30 percent.

[0093] Methods of preparing these formulations or compositions include the step of bringing into association an active compound, such as a compound of the present invention, with the carrier and, optionally, one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association a compound of the present invention with liquid carriers, or finely divided solid carriers, or both, and then, optionally, shaping the product.

[0094] Formulations of the present invention suitable for oral administration may be in the form of capsules (including sprinkle capsules and gelatin capsules), cachets, pills, tablets, lozenges (using a flavored base, usually sucrose and acacia or tragacanth), lyophilized tablets, powders, granules, or solutions or suspensions in aqueous or non-aqueous liquids, or as oil-in-water or water-in-oil emulsions, or as electuaries or syrups, or as pastilles (using an inert base, e.g., gelatin and glycerin, or sucrose and acacia), and / or mouthwashes, each containing a predetermined amount of a compound of the present invention as an active ingredient. The composition or compound may also be administered as a bolus, electuary, or paste.

[0095] To prepare solid dosage forms for oral administration (such as capsules (including sprinkle capsules and gelatin capsules), tablets, pills, dragees, powders, granules, etc.), the active ingredient can be combined with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and / or the following: (1) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol, and / or silicic acid; (2) binders, such as carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and / or acacia; (3) humectants, such as glycerol; and (4) disintegrants, such as agar, calcium carbonate. , potato starch or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarders, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as cetyl alcohol and glycerol monostearate; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof; (10) complexing agents, such as modified and unmodified cyclodextrins; and (11) coloring agents. For capsules (including sprinkle capsules and gelatin capsules), tablets, and pills, the pharmaceutical compositions may also contain buffering agents. Solid compositions of a similar type may also be used as fillers for soft and hard-filled gelatin capsules, using excipients such as lactose or milk sugar, and high molecular weight polyethylene glycols, etc.

[0096] Tablets can be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared using binders (e.g., gelatin or hydroxypropylmethylcellulose), lubricants, inert diluents, preservatives, disintegrants (e.g., sodium starch glycolate or cross-linked sodium carboxymethylcellulose), surface active agents, or dispersing agents. Molded tablets can be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.

[0097] Tablets and other solid dosage forms of pharmaceutical compositions, such as dragees, capsules (including sprinkle capsules and gelatin capsules), pills, and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical formulation art. They may also be formulated to provide sustained or controlled release of the active ingredient therein, for example, using hydroxypropyl methylcellulose in various proportions to provide the desired release profile, using other polymer matrices, using liposomes, and / or using microspheres. They may be sterilized, for example, by filtration through a bacteria-retaining filter or by incorporating a sterilizing agent in the form of a sterile solid composition that can be dissolved in sterile water or some other sterile injectable medium immediately before use. These compositions may also optionally contain opacifying agents and may be composed to release the active ingredient(s) only or preferentially in a certain part of the gastrointestinal tract, optionally in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. The active ingredient can also be in micro-encapsulated form, if appropriate, with one or more of the above-described excipients.

[0098] Liquid dosage forms useful for oral administration include pharmaceutically acceptable emulsions, lyophilized products for reconstitution, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredient, liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, cyclodextrin and its derivatives, solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, sesame oil), glycerol, tetrahydrofuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitan, and mixtures thereof.

[0099] Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.

[0100] Suspensions may contain, in addition to the active compound, suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth, and mixtures thereof.

[0101] Dosage forms for topical or transdermal administration include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants. The active compound may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and any preservatives, buffers, or propellants which may be required.

[0102] The ointments, pastes, creams and gels may contain, in addition to the active compound, excipients such as animal and vegetable fats, oils, waxes, paraffin, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonite, silicic acid, talc and zinc oxide, or mixtures thereof.

[0103] Powders and sprays can contain, in addition to the active compound, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates, and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons, and volatile unsubstituted hydrocarbons, such as butane and propane.

[0104] Transdermal patches have the additional advantage of providing controlled delivery of the compound of the present invention to the body.Such dosage forms can be prepared by dissolving or dispersing the active compound in a suitable medium.Absorption enhancers can also be used to increase the flux of the compound through the skin.The rate of such flux can be controlled by either providing a rate-controlling membrane or dispersing the compound in a polymer matrix or gel.

[0105] As used herein, the phrases "parenteral administration" and "administered parenterally" refer to modes of administration other than enteral and topical administration, usually by injection, and include, but are not limited to, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, and intrasternal injection and infusion. Pharmaceutical compositions suitable for parenteral administration comprise one or more active compounds in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions, or emulsions, or sterile powders that can be reconstituted into sterile injectable solutions or dispersions immediately before use and that may contain antioxidants, buffers, bacteriostats, solutes that render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.

[0106] Examples of suitable aqueous and non-aqueous carriers that can be used in the pharmaceutical compositions of the present invention include water, ethanol, polyols (glycerol, propylene glycol, polyethylene glycol, etc.), and suitable mixtures thereof, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by maintaining the required particle size in the case of dispersions, and by the use of surfactants.

[0107] These compositions may contain adjuvants such as preservatives, wetting agents, emulsifying agents, and dispersing agents. Prevention of the action of microorganisms can be ensured by the inclusion of various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like, in the compositions. Furthermore, prolonged absorption of the injectable pharmaceutical form can be brought about by the inclusion of agents that delay absorption, such as aluminum monostearate and gelatin.

[0108] In some cases, it is desirable to delay the absorption of a drug from subcutaneous or intramuscular injection in order to prolong the effect of the drug. This can be achieved by using a liquid suspension of crystalline or amorphous material that is poorly water-soluble. In this case, the absorption rate of the drug depends on the dissolution rate, which in turn may depend on the crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form can be achieved by dissolving or suspending the drug in an oil vehicle.

[0109] Injectable depot forms are made by forming microencapsulated matrices of the subject compounds in biodegradable polymers such as polylactide-polyglycolide. The rate of drug release can be controlled depending on the ratio of drug to polymer and the nature of the particular polymer used. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations can also be prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissues.

[0110] For use in the methods of the invention, the active compound can be provided per se or as a pharmaceutical composition containing, for example, 0.1 to 99.5% (more preferably 0.5 to 90%) of the active ingredient in combination with a pharmaceutically acceptable carrier.

[0111] The method of introduction can also be provided by a refillable or biodegradable device. For the controlled delivery of drugs, including proteinaceous biopharmaceuticals, various sustained-release polymeric devices have been developed and tested in vivo in recent years. Various biocompatible polymers (including hydrogels), including both biodegradable and non-degradable polymers, can be used to form implants for sustained release of compounds at specific target sites.

[0112] Actual dosage levels of the active ingredients in the pharmaceutical compositions may be varied to obtain an amount of the active ingredient effective to achieve the desired therapeutic response for a particular patient, composition, and method of administration without being toxic to the patient.

[0113] The selected dosage level will depend upon a variety of factors, including the activity of the particular compound or combination of compounds, or esters, salts, or amides thereof, employed, the route of administration, the time of administration, the rate of excretion of the particular compound(s) employed, the duration of treatment, other drugs, compounds, and / or materials used in combination with the particular compound(s) employed, the age, sex, weight, condition, general health, and past medical history of the patient being treated, and similar factors well known in the medical arts.

[0114] A physician or veterinarian of ordinary skill in the art can easily determine and prescribe the therapeutically effective amount of the pharmaceutical composition required. For example, a physician or veterinarian can start by administering a pharmaceutical composition or compound at a level lower than that required to achieve the desired therapeutic effect, and gradually increase the dosage until the desired effect is achieved. A "therapeutically effective amount" refers to the concentration of a compound sufficient to elicit the desired therapeutic effect. It is generally understood that the effective amount of a compound varies depending on the subject's weight, sex, age, and medical history. Other factors that affect the effective amount include, but are not limited to, the severity of the patient's condition, the disorder being treated, the stability of the compound, and, if desired, other types of therapeutic agents administered together with the compound of the present invention. A larger total dose can be delivered by multiple administrations of the drug. Methods for determining efficacy and dosage are known to those skilled in the art (Isselbacher et al. (1996) Harrison's Principles of Internal Medicine 13th ed., 1814-1882, incorporated herein by reference).

[0115] Generally, a suitable daily dose of an active compound used in the compositions and methods of the invention will be that amount of the compound that is the lowest dose effective to produce a therapeutic effect. Such an effective amount will generally depend upon the factors described above.

[0116] If necessary, the effective daily dose of the active compound can be administered as 1, 2, 3, 4, 5, 6 or more subdoses at appropriate intervals throughout the day, optionally administered separately in unit dosage forms. In certain embodiments of the present invention, the active compound can be administered two or three times a day. In a preferred embodiment, the active compound is administered once a day.

[0117] The patient receiving this treatment is any animal in need of treatment, including primates, especially humans; as well as other mammals, such as horses, cows, pigs, sheep, cats, and dogs; poultry; and common pets.

[0118] In certain embodiments, the compounds of the invention can be used alone or co-administered with another type of therapeutic agent.

[0119] The present disclosure includes the use of pharmaceutically acceptable salts of the compounds of the present invention in the compositions and methods of the present invention. In certain embodiments, contemplated salts of the present invention include, but are not limited to, alkyl, dialkyl, trialkyl, or tetraalkylammonium salts. In certain embodiments, contemplated salts of the present invention include, but are not limited to, L-arginine, benentamine, benzathine, betaine, calcium hydroxide, choline, deanol, diethanolamine, diethylamine, 2-(diethylamino)ethanol, ethanolamine, ethylenediamine, N-methylglucamine, hydrabamine, 1H-imidazole, lithium, L-lysine, magnesium, 4-(2-hydroxyethyl)morpholine, piperazine, potassium, 1-(2-hydroxyethyl)pyrrolidine, sodium, triethanolamine, tromethamine, and zinc salts. In certain embodiments, contemplated salts of the present invention include, but are not limited to, Na, Ca, K, Mg, Zn, or other metal salts.In certain embodiments, contemplated salts of the present invention include 1-hydroxy-2-naphthoic acid, 2,2-dichloroacetic acid, 2-hydroxyethanesulfonic acid, 2-oxoglutaric acid, 4-acetamidobenzoic acid, 4-aminosalicylic acid, acetic acid, adipic acid, l-ascorbic acid, l-aspartic acid, benzenesulfonic acid, benzoic acid, (+)-camphoric acid, (+)-camphor-10-sulfonic acid, capric acid (decanoic acid), caproic acid (hexanoic acid), caprylic acid (octanoic acid), carboxylic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, d-glucosamine ... These include, but are not limited to, heptonic acid, d-gluconic acid, d-glucuronic acid, glutamic acid, glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, l-malic acid, malonic acid, mandelic acid, methanesulfonic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid, nitric acid, oleic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, propionic acid, l-pyroglutamic acid, salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, l-tartaric acid, thiocyanic acid, p-toluenesulfonic acid, trifluoroacetic acid, and undecylenate.

[0120] Pharmaceutically acceptable acid addition salts may also exist as various solvates, such as with water, methanol, ethanol, dimethylformamide, etc. Mixtures of such solvates may also be prepared. The source of such solvates may be from the solvent of crystallization, inherent in the solvent of preparation or crystallization, or adventitious to such solvent.

[0121] Wetting agents, emulsifying agents, and lubricating agents such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring, and perfuming agents, preservatives, and antioxidants can also be present in the composition.

[0122] Examples of pharmaceutically acceptable antioxidants include: (1) water-soluble antioxidants such as ascorbic acid, cysteine ​​hydrochloride, sodium bisulfate, sodium disulfite, and sodium sulfite; (2) oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, and alpha-tocopherol; and (3) metal chelating agents such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, and phosphoric acid.

[0123] definition Unless otherwise defined herein, scientific and technical terms used in this application shall have the meanings commonly understood by those of ordinary skill in the art. Generally, the nomenclature used in connection with, and techniques of, chemistry, cell and tissue culture, molecular biology, cell and cancer biology, neurobiology, neurochemistry, virology, immunology, microbiology, pharmacology, genetics, and protein and nucleic acid chemistry described herein are those well known and commonly used in the art.

[0124] The methods and techniques of the present disclosure, unless otherwise indicated, are generally performed according to conventional methods well known in the art and as described in various general and more specific references cited and discussed throughout this specification. See, for example, "Principles of Neural Science," McGraw-Hill Medical, New York, NY (2000); Motulsky, "Intuitive Biostatistics," Oxford University Press, Inc. (1995); Lodish et al., "Molecular Cell Biology, 4th ed.", W.H. Freeman & Co., New York (2000); Griffiths et al., "Introduction to Genetic Analysis, 7th ed.", W.H. Freeman & Co., NY (1999); and Gilbert et al., "Developmental Biology, 6th ed.", Sinauer Associates, Inc., Sunderland, MA (2000).

[0125] As used herein, chemical terms, unless otherwise defined, are used in accordance with conventional usage in the art, as exemplified by "The McGraw-Hill Dictionary of Chemical Terms," ​​Parker S., Ed., McGraw-Hill, San Francisco, CA (1985).

[0126] All of the above, and any other publications, patents, and published patent applications mentioned in this application are specifically incorporated herein by reference. In case of conflict, the present specification, including its specific definitions, will control.

[0127] The term "agent" is used herein to refer to a chemical compound (e.g., an organic or inorganic compound, a mixture of compounds), a biological macromolecule (e.g., nucleic acids, antibodies containing portions thereof, as well as humanized, chimeric, and human antibodies, and monoclonal antibodies, proteins or portions thereof, e.g., peptides, lipids, carbohydrates), or an extract prepared from biological material such as bacterial, plant, fungal, or animal (especially mammalian) cells or tissues. Agents include, for example, agents whose structures are known and agents whose structures are unknown.

[0128] The terms "patient," "subject," or "individual" are used interchangeably and refer to either a human or non-human animal. These terms include mammals, such as humans, primates, livestock animals (including cows, pigs, etc.), companion animals (e.g., dogs, cats, etc.), and rodents (e.g., mice and rats).

[0129] "Treating" a condition or patient refers to taking measures to obtain beneficial or desired results, including clinical results. Beneficial or desired clinical results can include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions, whether detectable or undetectable, diminishment of the extent of the disease, stabilization of the disease state (i.e., not worsening), prevention of disease spread, delay or slowing of disease progression, improvement or palliation of the disease state, and remission (whether partial or total). "Treatment" can also mean prolonging survival as compared to expected survival if not receiving treatment.

[0130] The term "prevention," when used in reference to a condition such as local recurrence (e.g., pain), a disease such as cancer, a complex syndrome such as heart failure, or any other medical condition, is art-recognized and well understood in the art and includes administration of a composition that reduces the frequency of or delays the onset of symptoms of a medical condition in a subject compared to subjects not administered the composition. Thus, cancer prevention, by way of example, includes reducing the number of detectable cancerous growths in a population of patients receiving prophylactic treatment compared to an untreated control population, and / or delaying the appearance of detectable cancerous growths in a treated population relative to an untreated control population, e.g., by a statistically and / or clinically significant amount.

[0131] "Administering" or "administration" of a substance, compound, or agent to a subject can be accomplished using one of a variety of methods known to those skilled in the art. For example, the compound or agent can be administered intravenously, intraarterially, intradermally, intramuscularly, intraperitoneally, subcutaneously, ophthalmically, sublingually, orally (by ingestion), intranasally (by inhalation), intrathecally, intracerebrally, and transdermally (e.g., by absorption through cutaneous channels). The compound or agent can also be suitably introduced via rechargeable or biodegradable polymeric or other devices, e.g., patches and pumps, or formulations that provide extended, gradual, or controlled release of the compound or agent. Administration can also be performed, for example, once, multiple times, and / or over one or more extended periods of time.

[0132] Suitable methods of administering a substance, compound, or agent to a subject also depend, for example, on the age and / or physical condition of the subject, as well as the chemical and biological properties of the compound or agent (e.g., solubility, digestibility, bioavailability, stability, and toxicity). In some embodiments, the compound or agent is administered orally to the subject, for example, by ingestion. In some embodiments, the orally administered compound or agent is in a sustained- or slow-release formulation or is administered using such a slow- or sustained-release device.

[0133] As used herein, the phrase "co-administration" refers to any administration form of two or more different therapeutic agents in which a second agent is administered while a previously administered therapeutic agent is still effective in the body (e.g., the two agents are effective in a patient simultaneously, which may include a synergistic effect of the two agents). For example, the different therapeutic compounds may be administered in the same formulation or in separate formulations, and may be administered simultaneously or sequentially. Thus, an individual receiving such treatment may benefit from the combined effects of the different therapeutic agents.

[0134] A "therapeutically effective amount" or "therapeutically effective dose" of a drug or agent is an amount of the drug or agent that has the intended therapeutic effect when administered to a subject. The full therapeutic effect does not necessarily occur in a single administration, but may occur only after a series of administrations. Thus, a therapeutically effective amount can be administered in one or more administrations. The exact effective amount required for a subject depends, for example, on the subject's size, health, and age, as well as the nature and extent of the condition being treated, e.g., cancer or MDS. Those skilled in the art can easily determine the effective amount for a given situation by routine experimentation.

[0135] As used herein, the term "optionally" or "optionally" means that the subsequently described event or circumstance may or may not occur, and the description includes cases where the event or circumstance occurs and cases where it does not occur. For example, "optionally substituted alkyl" refers to cases where the alkyl can be substituted, as well as cases where the alkyl is not substituted.

[0136] It will be understood that one skilled in the art can select substituents and substitution patterns for the compounds of the present invention to provide chemically stable compounds that can be readily synthesized from readily available starting materials by techniques known in the art and those described below. When a substituent is itself substituted with multiple groups, it will be understood that such multiple groups can be present on the same carbon or on different carbons, so long as a stable structure results.

[0137] As used herein, the term "optionally substituted" refers to the replacement of 1 to 6 hydrogen radicals in a given structure with the radical of a specified substituent, including, but not limited to, hydroxyl, hydroxyalkyl, alkoxy, halogen, alkyl, nitro, silyl, acyl, acyloxy, aryl, cycloalkyl, heterocyclyl, amino, aminoalkyl, cyano, haloalkyl, haloalkoxy, -OCO-CH-O-alkyl, -OP(O)(O-alkyl), or -CH-OP(O)(O-alkyl). Preferably, "optionally substituted" refers to the replacement of 1 to 4 hydrogen radicals in a given structure with the above substituents. More preferably, 1 to 3 hydrogen radicals are replaced with the above substituents. It is understood that a substituent may be further substituted.

[0138] As used herein, the term "alkyl" refers to saturated aliphatic groups, including, but not limited to, C-C 10 Straight chain alkyl groups or C1-C 10 Branched chain alkyl groups are included. Preferably, an "alkyl" group refers to a C1-C6 straight chain alkyl group or a C1-C6 branched chain alkyl group. Most preferably, an "alkyl" group refers to a C1-C4 straight chain alkyl group or a C1-C4 branched chain alkyl group. Examples of "alkyl" include, but are not limited to, methyl, ethyl, 1-propyl, 2-propyl, n-butyl, sec-butyl, tert-butyl, 1-pentyl, 2-pentyl, 3-pentyl, neo-pentyl, 1-hexyl, 2-hexyl, 3-hexyl, 1-heptyl, 2-heptyl, 3-heptyl, 4-heptyl, 1-octyl, 2-octyl, 3-octyl, or 4-octyl, and the like. An "alkyl" group may be optionally substituted.

[0139] The term "acyl" is art-recognized and refers to a group represented by the general formula hydrocarbylC(O)-, preferably alkylC(O)-.

[0140] The term "acylamino" is art-recognized and refers to an amino group substituted with an acyl group and may be represented, for example, by the formula hydrocarbylC(O)NH-.

[0141] The term "acyloxy" is art-recognized and refers to a group represented by the general formula hydrocarbylC(O)O-, preferably alkylC(O)O-.

[0142] The term "alkoxy" refers to an alkyl group having an oxygen attached thereto. Representative alkoxy groups include methoxy, ethoxy, propoxy, tert-butoxy, and the like.

[0143] The term "alkoxyalkyl" refers to an alkyl group substituted with an alkoxy group and may be represented by the general formula alkyl-O-alkyl.

[0144] The term "alkyl" refers to saturated aliphatic groups, including straight-chain alkyl groups, branched-chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl-substituted cycloalkyl groups, and cycloalkyl-substituted alkyl groups. In preferred embodiments, a straight-chain or branched-chain alkyl has 30 or fewer carbon atoms in its backbone, more preferably 20 or fewer carbon atoms (e.g., C for straight chain). 1-30 , C for branched chain 3-30 )

[0145] Furthermore, the term "alkyl," as used throughout the specification, examples, and claims, is intended to include both unsubstituted and substituted alkyl groups, the latter of which refers to alkyl moieties having substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone, including haloalkyl groups (such as trifluoromethyl and 2,2,2-trifluoroethyl).

[0146] "C x~y " or "C x ~C yThe term "C alkyl," when used in conjunction with a chemical moiety such as acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy, is meant to include groups containing x to y carbons in the chain. C alkyl indicates a hydrogen when the group is in a terminal position and a bond when it is internal. 1-6 An alkyl group may, for example, contain 1 to 6 carbon atoms in the chain.

[0147] The term "alkylamino," as used herein, refers to an amino group substituted with at least one alkyl group.

[0148] The term "alkylthio," as used herein, refers to a thiol group substituted with an alkyl group and may be represented by the general formula alkylS-.

[0149] The term "amide" as used herein refers to the group: [ka] In the formula, R 9 and R 10 each independently represents hydrogen or a hydrocarbyl group, or R 9 and R 10 together with the N atom to which they are attached complete a heterocycle having 4 to 8 atoms in the ring structure.

[0150] The terms "amine" and "amino" are art-recognized and refer to both unsubstituted and substituted amines and their salts, e.g., [ka] wherein R 9 , R 10 , and R 10 ' each independently represent hydrogen or a hydrocarbyl group, or R 9 and R 10 together with the N atom to which they are attached complete a heterocycle having 4 to 8 atoms in the ring structure.

[0151] As used herein, the term "aminoalkyl" refers to an alkyl group substituted with an amino group.

[0152] As used herein, the term "aralkyl" refers to an alkyl group substituted with an aryl group.

[0153] As used herein, the term "aryl" includes substituted or unsubstituted monocyclic aromatic groups in which each atom of the ring is carbon. Preferably, the ring is 5- to 7-membered, more preferably 6-membered. The term "aryl" also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjacent rings, at least one of the rings being aromatic, and the other cyclic rings may be, for example, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclyl. Aryl groups include benzene, naphthalene, phenanthrene, phenol, aniline, and the like.

[0154] The term "carbamate" is art-recognized and [ka] In the formula, R 9 and R 10 independently represent hydrogen or a hydrocarbyl group.

[0155] The term "carbocyclylalkyl," as used herein, refers to an alkyl group substituted with a carbocyclic group.

[0156] The term "carbocycle" includes 5- to 7-membered monocyclic rings and 8- to 12-membered bicyclic rings. Each ring in a bicyclic carbocycle may be selected from saturated, unsaturated, and aromatic rings. Carbocycles include bicyclic molecules in which one, two, or more atoms are shared between two rings. The term "fused carbocycle" refers to a bicyclic carbocycle in which each ring shares two adjacent atoms with the other ring. Each ring in a fused carbocycle may be selected from saturated, unsaturated, and aromatic rings. In an exemplary embodiment, an aromatic ring, e.g., phenyl, may be fused to a saturated or unsaturated ring, e.g., cyclohexane, cyclopentane, or cyclohexene. Valence permitting, any combination of saturated, unsaturated, and aromatic bicyclic rings is included in the definition of carbocycle. Exemplary "carbocycles" include cyclopentane, cyclohexane, bicyclo[2.2.1]heptane, 1,5-cyclooctadiene, 1,2,3,4-tetrahydronaphthalene, bicyclo[4.2.0]oct-3-ene, naphthalene, and adamantane. Exemplary fused carbocycles include decalin, naphthalene, 1,2,3,4-tetrahydronaphthalene, bicyclo[4.2.0]octane, 4,5,6,7-tetrahydro-1H-indene, and bicyclo[4.1.0]hept-3-ene. A "carbocycle" may be substituted at any one or more positions capable of bearing a hydrogen atom.

[0157] The term "carbocyclylalkyl," as used herein, refers to an alkyl group substituted with a carbocyclic group.

[0158] The term "carbonate" is art-recognized and refers to an -OCO2- group.

[0159] The term "carboxy," as used herein, refers to a group represented by the formula -CO2H.

[0160] The term "cycloalkyl" includes substituted or unsubstituted non-aromatic monocyclic ring structures, preferably 4-8 membered rings, more preferably 4-6 membered rings. The term "cycloalkyl" also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjacent rings, at least one of which is cycloalkyl, and the cycloalkyl ring may contain substituents (e.g., R 100 ) is added. For example, the other cyclic ring can be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclyl. Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrazine, pyridazine, pyrimidine, denzodioxane, tetrahydroquinoline, and the like.

[0161] The term "ester" as used herein refers to an ester of -C(O)OR 9 refers to a group, wherein R 9 represents a hydrocarbyl group.

[0162] The term "ether," as used herein, refers to a hydrocarbyl group linked to another hydrocarbyl group through an oxygen. Thus, an ether substituent of a hydrocarbyl group can be hydrocarbyl-O-. Ethers can be symmetrical or asymmetrical. Examples of ethers include, but are not limited to, heterocycle-O-heterocycle and aryl-O-heterocycle. Ethers include "alkoxyalkyl" groups, which can be represented by the general formula: alkyl-O-alkyl.

[0163] The terms "halo" and "halogen" as used herein mean halogen and include chloro, fluoro, bromo, and iodo.

[0164] The terms "hetaralkyl" and "heteroaralkyl," as used herein, refer to an alkyl group substituted with a hetaryl group.

[0165] The terms "heteroaryl" and "hetaryl" refer to substituted or unsubstituted aromatic monocyclic ring structures, preferably 5- to 7-membered rings, more preferably 5- or 6-membered rings, in which the ring structure contains at least one heteroatom, preferably 1 to 4 heteroatoms, more preferably 1 or 2 heteroatoms. The terms "heteroaryl" and "hetaryl" also include polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjacent rings, in which at least one of the rings is heteroaromatic, and the other cyclic rings, for example, can be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclyl. Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrazine, pyridazine, pyrimidine, and the like.

[0166] The term "heteroatom" as used herein means an atom of any element other than carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen, and sulfur.

[0167] The term "heterocyclylalkyl," as used herein, refers to an alkyl group substituted with a heterocycle group.

[0168] The terms "heterocyclyl," "heterocycle," and "heterocyclic" refer to a substituted or unsubstituted non-aromatic ring system, preferably a 3- to 10-membered ring, more preferably a 3- to 7-membered ring, which ring system includes at least one heteroatom, preferably 1 to 4 heteroatoms, more preferably 1 or 2 heteroatoms. The terms "heterocyclyl" and "heterocyclic" also include polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjacent rings, and at least one of the rings is heterocyclic, e.g., the other cyclic rings can be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclyl. Heterocyclyl groups include, for example, piperidine, piperazine, pyrrolidine, morpholine, lactones, lactams, and the like.

[0169] As used herein, the term "hydrocarbyl" refers to a group bonded through a carbon atom that does not have an =O or =S substituent, typically has at least one carbon-hydrogen bond and a primary carbon backbone, but may optionally contain heteroatoms. Thus, groups such as methyl, ethoxyethyl, 2-pyridyl, and trifluoromethyl are considered hydrocarbyl for purposes of this application, while substituents such as acetyl (which has an =O substituent on the bonded carbon) and ethoxy (which is bonded through an oxygen rather than a carbon) are not. Hydrocarbyl groups include, but are not limited to, aryl, heteroaryl, carbocycle, heterocycle, alkyl, alkenyl, alkynyl, and combinations thereof.

[0170] As used herein, the term "hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group.

[0171] The term "lower," when used in conjunction with chemical moieties such as acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy, is meant to include groups having 10 or fewer, preferably 6 or fewer atoms in the substituent. For example, "lower alkyl" refers to an alkyl group containing 10 or fewer, preferably 6 or fewer, carbon atoms. In certain embodiments, an acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy substituent as defined herein is a lower acyl, lower acyloxy, lower alkyl, lower alkenyl, lower alkynyl, or lower alkoxy, respectively, whether appearing alone or in combination with other substituents (e.g., when counting the carbon atoms of the alkyl substituent), such as in descriptions of hydroxyalkyl and aralkyl (where the atoms in the aryl group are not counted).

[0172] The terms "polycyclyl," "polycycle," and "polycyclic" refer to two or more rings (e.g., cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclyl) in which two or more atoms are common to two adjacent rings, e.g., the rings are "fused rings." Each ring of a polycycle can be substituted or unsubstituted. In certain embodiments, each ring of a polycycle contains 3 to 10 atoms, preferably 5 to 7 atoms, within the ring.

[0173] The term "sulfate" is art-recognized and refers to the group -OSO3H, or a pharmaceutically acceptable salt thereof.

[0174] The term “sulfonamide” is art-recognized and refers to a group represented by the general formula: [ka] In the formula, R 9 and R 10 independently represent hydrogen or hydrocarbyl.

[0175] The term "sulfoxide" is art-recognized and refers to the group --S(O)--.

[0176] The term "sulfonate" is art-recognized and refers to the group SO3H, or a pharmaceutically acceptable salt thereof.

[0177] The term "sulfone" is art-recognized and refers to the group -S(O)2-.

[0178] The term "substituted" refers to a moiety having substituents replacing a hydrogen on one or more backbone carbons. It will be understood that "substituted" or "substituted with" includes the implicit proviso that such substitution, subject to the permissible valencies of the substituted atom and substituent, results in a stable compound that does not undergo spontaneous transformation, e.g., by rearrangement, cyclization, elimination, and the like. As used herein, the term "substituted" is intended to include all permissible substituents of organic compounds. In a broad aspect, permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this invention, heteroatoms, such as nitrogen, can have any permissible substituents of organic compounds described herein that satisfy hydrogen substitution and / or the valencies of the heteroatoms. Substituents can include any of the substituents described herein, for example, halogen, hydroxyl, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or anacil), thiocarbonyl (such as thioester, thioacetate, or thioformate), alkoxyl, phosphoryl, phosphate, phosphonate, phosphinate, amino, amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, aralkyl, or aromatic or heteroaromatic moieties. It will be understood by those skilled in the art that the moieties substituted on the hydrocarbon chain can themselves be substituted, if appropriate.

[0179] The term "thioalkyl," as used herein, refers to an alkyl group substituted with a thiol group.

[0180] As used herein, the term "thioester" refers to a thioester of -C(O)SR 9 or -SC(O)R 9 This refers to the group In the formula, R 9 represents a hydrocarbyl.

[0181] The term "thioether" as used herein is equivalent to an ether, where the oxygen is replaced by a sulfur.

[0182] The term "urea" is art-recognized and may be represented by the general formula: [ka] In the formula, R 9 and R 10 independently represent hydrogen or hydrocarbyl.

[0183] As used herein, the term "modulate" includes inhibiting or suppressing a function or activity (such as cell proliferation), as well as enhancing a function or activity.

[0184] The phrase "pharmaceutically acceptable" is art-recognized. In certain embodiments, this term includes compositions, excipients, adjuvants, polymers, and other materials and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without undue toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0185] "Pharmaceutically acceptable salt" or "salt" is used herein to refer to an acid addition salt or a base addition salt that is suitable or compatible with the treatment of a patient.

[0186] As used herein, the term "pharmaceutically acceptable acid addition salt" refers to any non-toxic organic or inorganic salt of any base compound represented by Formula I. Exemplary inorganic acids that form suitable salts include hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid, as well as metal salts such as sodium monohydrogen orthophosphate and potassium hydrogen sulfate. Exemplary organic acids that form suitable salts include mono-, di-, and tricarboxylic acids, such as glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, benzoic acid, phenylacetic acid, cinnamic acid, and salicylic acid, and sulfonic acids, such as p-toluenesulfonic acid and methanesulfonic acid. Monobasic and dibasic acid salts may be formed, and such salts may exist in either hydrated, solvated, or substantially anhydrous form. In general, acid addition salts of compounds of Formula I are more soluble in water and various hydrophilic organic solvents and generally demonstrate higher melting points than their free base forms. The selection of an appropriate salt will be known to one skilled in the art. Other non-pharmaceutically acceptable salts, such as oxalates, may be used, for example, in the isolation of compounds of formula I for laboratory use or for subsequent conversion to a pharmaceutically acceptable acid addition salt.

[0187] As used herein, the term "pharmaceutically acceptable base addition salt" refers to any non-toxic organic or inorganic base addition salt of any acid compound represented by Formula 1 or any of its intermediates. Exemplary inorganic bases that form suitable salts include lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, or barium hydroxide. Exemplary organic bases that form suitable salts include aliphatic, alicyclic, or aromatic organic amines such as methylamine, trimethylamine, and picoline or ammonia. The selection of an appropriate salt is within the skill of the art.

[0188] Many of the compounds useful in the methods and compositions of the present disclosure have at least one asymmetric center in their structure. This stereocenter may exist in either the R or S configuration, and the R and S designations are used in accordance with the conventions set forth in Pure Appl. Chem. (1976), 45, 11-30. The present disclosure contemplates all stereoisomeric forms, such as enantiomers and diastereomers, of the compounds, salts, prodrugs, or mixtures thereof, including all possible mixtures of stereoisomers. See, e.g., WO 01 / 062726.

[0189] Furthermore, certain compounds containing alkenyl groups can exist as Z (Zusammen) or E (Entgegen) isomers. In each case, the present disclosure includes both mixtures and the separate individual isomers.

[0190] A "prodrug" or "pharmaceutically acceptable prodrug" refers to a compound that is metabolized (e.g., hydrolyzed or oxidized) in a host after administration to form a compound of the present disclosure (e.g., a compound of Formula I). ​​Representative examples of prodrugs include compounds that have a biologically labile or cleavable (protecting) group on a functional group of the active compound. Prodrugs include compounds that can be oxidized, reduced, aminated, deaminated, hydroxylated, dehydroxylated, hydrolyzed, dehydrolyzed, alkylated, dealkylated, acylated, deacylated, phosphorylated, or dephosphorylated to yield the active compound. Examples of prodrugs that use esters or phosphoramidates as the biologically labile or cleavable (protecting) group are disclosed in U.S. Patent Nos. 6,875,751, 7,585,851, and 7,964,580, the disclosures of which are incorporated herein by reference. The prodrugs of the present disclosure are metabolized to yield a compound of Formula I. The present disclosure includes within its scope prodrugs of the compounds described herein. Conventional procedures for the selection and preparation of suitable prodrugs are described, for example, in "Design of Prodrugs," Ed. H. Bundgaard, Elsevier, 1985.

[0191] As used herein, the phrase "pharmaceutically acceptable carrier" means a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, that is useful in formulating a drug for medicinal or therapeutic use.

[0192] As used herein, the terms "logarithm of solubility," "LogS," or "logS" are used in the art to quantify the water solubility of a compound. The aqueous solubility of a compound significantly affects its absorption and distribution characteristics. Low solubility often results in poor absorption. The LogS value is the unitless logarithm (base 10) of solubility measured in mol / liter. [Example]

[0193] Having now generally described the invention, the same will be more readily understood by reference to the following examples, which are included solely for the purpose of illustrating certain aspects and embodiments of the invention and are not intended to be limiting thereof.

[0194] Example 1: Synthesis of exemplary compounds of the present disclosure General Procedure A: The compound was typically prepared by reacting the corresponding aldehyde, e.g., 3,4-difluorobenzaldehyde, with tert-butyl(4-oxocyclohexyl)carbamate in the presence of 20% aqueous sodium hydroxide to give tert-butyl(3,5-bis((E)-3,4-difluorobenzylidene)-4-oxocyclohexyl)carbamate. The Boc group was deprotected with TFA. Benzoylation with 4-amino-2,6-bis((E)-3,4-difluorobenzylidene)cyclohexane-1-one and 4-(2-(piperidin-1-yl)ethoxy)benzoyl chloride under basic conditions gave N-(3,5-bis((E)-3,4-difluorobenzylidene)-4-oxocyclohexyl)-4-(2-(piperidin-1-yl)ethoxy)benzamide.

[0195] [ka] Example JCS016: To a mixture of tert-butyl (4-oxocyclohexyl)carbamate (213.28 mg, 1 mmol, 1.0 equiv.) and ethanol (1.0 mL) in a round-bottom flask, 20% aqueous sodium hydroxide (1.5 mL) was added dropwise and stirred for 5 minutes. 3,4-Difluorobenzaldehyde (355.3 mg, 2.5 mmol, 2.5 equiv.) was added to the mixture. The reaction mixture was then stirred at room temperature for 5 hours. After 5 hours, the yellow precipitate thus obtained was filtered, washed with water and cold ethanol, and dried to give the pure product (360 mg, 78% yield).

[0196] Trifluoroacetic acid (0.5 ml) was added to a solution of tert-butyl (3,5-bis((E)-3,4-difluorobenzylidene)-4-oxocyclohexyl)carbamate (230.7 mg, 0.5 mmol) in methylene chloride (5.0 ml) at room temperature, and the mixture was stirred at room temperature overnight. The solvent of the reaction solution was then distilled off under reduced pressure, and the resulting residue was poured into a 1N aqueous sodium hydroxide solution and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give 4-amino-2,6-bis((E)-3,4-difluorobenzylidene)cyclohexan-1-one.

[0197] A mixture of 4-amino-2,6-bis((E)-3,4-difluorobenzylidene)cyclohexan-1-one (180.7 mg, 0.5 mmol, 1.0 equiv.) and anhydrous triethylamine (70 μL, 0.5 mmol, 1.0 equiv.) in dichloromethane was maintained at 0 °C (ice bath). To this cooled mixture, 4-(2-(piperidin-1-yl)ethoxy)benzoyl chloride (133.8 mg, 0.5 mmol, 1.0 equiv.) in 2.0 mL of dichloromethane was added dropwise. After the entire amount of 4-(2-(dimethylamino)ethoxy)benzoyl chloride was added, the reaction mixture was allowed to warm slowly to room temperature and stirred overnight. After completion of the reaction, the solvent was evaporated, and the residue was stirred in saturated aqueous KCO solution for 4 h. The mixture was extracted three times with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate. Evaporation of the solvent followed by flash chromatography (gradient elution 10% methanol / EtOAc to 50% methanol / EtOAc) afforded a yellow solid, which was recrystallized by dissolving in pure diethyl ether and placing in a freezer overnight to give pure compound JCS016 (222.2 mg, 75% yield).

[0198] Synthesis method 1 of 4-(2-(piperidin-1-yl)ethoxy)benzoyl chloride Methyl 4-hydroxybenzoate (5.0 g, 32.86 mmol, 10 equiv.) was mixed with 1,2-dibromoethane (35 mL) and potassium carbonate (6.8 g, 49.23 mmol, 1.5 equiv.), and the mixture was then heated to reflux for 18 h. The reaction mixture was then concentrated under reduced pressure, and the residue was partitioned between ethyl ether (300 mL) and water (200 mL). The ether layer was extracted with 2 N sodium hydroxide (5 × 30 mL). The solvent was removed to give the desired product as a white solid (8.5 g, 99% yield).

[0199] A solution of methyl 4-(2-bromoethoxy)benzoate (2.591 g, 10 mmol, 1.0 equiv.), DMF (20 mL), potassium carbonate (4.146 g, 30 mmol, 3.0 equiv.), and piperidine (2.6 g, 30 mmol, 3.0 equiv.) was added to a round-bottom flask equipped with a stir bar. The mixture was heated at 75 °C for 24 h, after which EtOAc (200 mL) and water (200 mL) were added. The organic layer was washed three times with water and then dried over sodium sulfate. Silica gel flash chromatography (gradient elution: 10% methanol / EtOAc to 50% methanol / EtOAc) afforded the pure product, methyl 4-(2-(diethylamino)ethoxy)benzoate (1.97 g, 75% yield), as a pale yellow oil.

[0200] Methyl 4-(2-(piperidin-1-yl)ethoxy)benzoate (1.31 g, 5.0 mmol, 1.0 equiv) was dissolved in 2.5 mL of ethanol and added to a solution of sodium hydroxide (0.4 g) in 2.5 mL of water. The mixture was heated to reflux for 2 hours. The ethanol was removed in vacuo, and the aqueous solution was acidified with concentrated HCl at 5°C. The solid was collected, treated with cold water, filtered, and dried in vacuo at 55°C-60°C to give 4-(2-(piperidin-1-yl)ethoxy)benzoic acid hydrochloride as a white solid (1.28 g, 90% yield).

[0201] To a stirred mixture of 4-(2-(piperidin-1-yl)ethoxy)benzoic acid hydrochloride (285.11 mg, 1.0 mmol) was added thionyl chloride (2.5 mL). The mixture was heated to reflux for 4 hours. The thionyl chloride was removed in vacuo, and the residue was dried to give 4-(2-(piperidin-1-yl)ethoxy)benzoyl chloride, which was sufficiently pure for use in the next step.

[0202] The following compounds JCS008, JCS0009, JCS010, JCS11, JCS12, JCS13, JCS14, JCS015, JCS016, and JCS017 were synthesized by procedure A. [ka] N-(3,5-bis((E)-3,4-difluorobenzylidene)-4-oxocyclohexyl)-4-(2-(piperidin-1-yl)ethoxy)benzamide (JCS016) 1 H NMR (500 MHz, CDCl3) δ 7.76 (s, 2H), 7.63 (d, J = 8.8 Hz, 2H), 7.31 - 7.09 (m, 6H), 6.86 (d, J = 8.8 Hz, 2H), 6.24 (d, J = 7.2 Hz, 1H), 4.50-4.44 (m, 1H), 4.11 (t, J = 6.0 Hz, 2H), 3.24 (bd, J = 15.8 Hz, 2H), 3.04 (dd, J = 15.8, 8.3 Hz, 2H), 2.76 (t, J = 6.0 Hz, 2H), 2.59 - 2.37 (m, 4H), 1.60 (p, J = 5.6 Hz, 4H), 1.43 (m, 2H). 13 C NMR (126 MHz, CDCl3) δ 187.9, 166.6, 161.7, 150.7 (dd, J CF = 254.5 Hz, J C-CF = 13.8 Hz, 2C), 150.3 (dd, J CF = 249.4 Hz, J C-CF = 12.6 Hz, 2C), 137.8 (2C), 132.8 (2C), 132.2 (dd, J C-C-CF = 6.3 Hz, J C-C-CF = 5.0 Hz, 2C), 128.8 (2C), 127.1 (dd, J C-C-CF = 6.3 Hz, J C-C-CF = 3.8 Hz, 2C), 126.2, 119.0 (d, J C-CF = 17.6 Hz, 2C), 117.7 (d, J C-CF = 17.6 Hz, 2C), 114.4 (2C), 66.2, 57.8, 55.1, 44.6, 33.8, 25.9, 24.1. 19 F NMR (376 MHz, CDCl3) δ -135.0 (d, JFF = 18.8 Hz, 2F), -136.5 (d, J FF = 22.5 Hz, 2F). C 34 H 33 HR-APCI m / z calculated for F4N2O3 [M+H] 593.2421, found 593.2444.

[0203] [ka] N-(3,5-bis((E)-3,4-difluorobenzylidene)-4-oxocyclohexyl)-4-(2-(pyrrolidin-1-yl)ethoxy)benzamide (JCS008) 1 H NMR (500 MHz, CDCl3) δ 7.73 (s, 2H), 7.63 (d, J = 8.7 Hz, 2H), 7.23 - 7.06 (m, 6H), 6.86 (d, J = 8.6 Hz, 2H), 6.34 (d, J = 7.2 Hz, 1H), 4.47-4.43 (m, 1H), 4.09 (t, J = 5.9 Hz, 2H), 3.22 (bd, J = 15.7 Hz, 2H), 3.02 (dd, J = 15.7, 8.5 Hz, 2H), 2.87 (t, J = 5.9 Hz, 2H), 2.60-2.58 (m, 4H), 1.89 - 1.69 (m, 4H). 13 C NMR (126 MHz, CDCl3) δ 187.8, 166.7, 161.8, 150.6 (dd, J CF = 253.2 Hz, J C-CF = 12.6 Hz, 2C), 150.2 (dd, J CF = 249.4 Hz, J C-CF = 13.8 Hz, 2C), 137.7 (2C), 132.8 (2C), 132.2 (dd, J C-C-CF = 6.3 Hz, J C-C-CF = 3.7 Hz, 2C), 128.8 (2C), 127.1 (dd, J C-C-CF = 6.3 Hz, JC-C-CF = 3.8 Hz, 2C), 126.1, 118.9 (d, J C-CF = 17.6 Hz, 2C), 117.7 (d, J C-CF = 17.6 Hz, 2C), 114.4 (2C), 67.3, 54.9, 54.8, 44.6, 33.7, 23.5. 19 F NMR (376 MHz, CDCl3) δ -135.0 (d, J FF = 18.8 Hz, 2F), -136.5 (d, J FF = 22.5 Hz, 2F). C 33 H 31 HR-APCI m / z calculated for F4N2O3 [M+H] 579.2265, found 579.2318.

[0204] [ka] N-(3,5-bis((E)-3,4-difluorobenzylidene)-4-oxocyclohexyl)-4-(2-(cyclohexyl(methyl)amino)ethoxy)-benzamide (JCS009) 1 H NMR (500 MHz, CDCl3) δ 7.72 (s, 2H), 7.64 (d, J = 8.8 Hz, 2H), 7.24 - 7.09 (m, 6H), 6.83 (d, J = 8.8 Hz, 2H), 6.52 (d, J = 7.4 Hz, 1H), 4.44-4.40 (m, 1H), 4.07 (t, J = 6.0 Hz, 2H), 3.22 (bd, J = 15.9, 8.8, Hz, 2H), 3.02 (dd, J = 15.9, 8.8, Hz, 2H), 2.90 (t, J = 6.0 Hz, 2H), 2.55 - 2.45 (m, 1H), 2.40 (s, 3H), 1.91 - 1.73 (m, 4H), 1.67 - 1.57 (m, 1H), 1.31 - 1.15 (m, 4H), 1.07 (dtt, J = 12.6, 9.0, 3.7 Hz, 1H), 1.11 - 1.03 (m, 1H).13 C NMR (126 MHz, CDCl3) δ 187.9, 166.7, 161.5, 150.6 (dd, J CF = 253.2 Hz, J C-CF = 12.6 Hz, 2C), 150.2 (dd, J CF = 249.4 Hz, J C-CF = 12.6 Hz, 2C), 137.6 (2C), 132.8 (2C), 132.2 (dd, J C-C-CF = 6.3 Hz, J C-C-CF = 3.7 Hz, 2C), 128.8 (2C), 127.1 (dd, J C-C-CF = 6.3 Hz, J C-C-CF = 2.5 Hz, 2C), 126.3, 118.9 (d, J C-CF = 17.6 Hz, 2C), 117.7 (d, J C-CF = 17.6 Hz, 2C), 114.4 (2C), 66.6, 63.7, 52.1, 44.7, 38.7, 3.8, 28.3, 26.1, 25.8. 19 F NMR (376 MHz, CDCl3) δ -135.1 (d, J FF = 22.5 Hz, 2F), -136.5 (d, J FF = 22.5 Hz, 2F). C 36 H 37 HR-APCI m / z calculated for F4N2O3 [M+H] 621.2760, found 621.2760.

[0205] [ka] N-(3,5-bis((E)-3,4-difluorobenzylidene)-4-oxocyclohexyl)-4-(2-ethoxyethoxy)benzamide (JCS010) 1H NMR (500 MHz, CDCl3) δ 7.81 (s, 2H), 7.62 (d, J = 8.9 Hz, 2H), 7.26 - 7.18 (m, 6H), 6.92 (d, J = 8.5 Hz, 2H), .3 H 6.4 (H - 4.47 (m, 1H), 4.18 - 4.10 (m, 2H), 3.83 - 3.76 (m, 2H), 3.60 (q, J = 7.0 Hz, 2H), 3.26 (bd, J = 16.7 Hz, 3. = 1H), Hz, 2H), 1.24 (t, J = 7.0 Hz, 3H)。 13 C NMR (126 MHz, CDCl3) δ 188.0, 166.7, 161.8, 150.8 (dd, J CF = 254.5 Hz, J C-CF = 12.6 Hz, 2C), 150.3 (dd, J CF = 249.4 Hz, J C-CF = 12.6 Hz, 2C), 138.0 (2C), 132.8 (2C), 132.2 (dd, J C-C-CF = 5.0 Hz, J C-C-CF = 3.7 Hz, 2C), 128.7 (2C), 127.2 (dd, J C-C-CF = 6.3 Hz, J C-C-CF = 3.7 Hz, 2C), 126.38, 119.1 (d, J C-CF = 17.6 Hz, 2C), 117.8 (d, J C-CF = 17.6 Hz, 2C), 114.4 (2C), 68.8, 67.7, 67.0, 44.6, 33.8, 15.2。 19 F NMR (376 MHz, CDCl3) δ −135.0 (d, J FF = 18.8 Hz, 2F), −136.5 (d, J FF = 22.5 Hz, 2F)。C 31 H 28 F4NO4[M+H] is located in HR-APCIm / z

[0206] [ka] N-(3,5-bis((E)-3,4-difluorobenzylidene)-4-oxocyclohexyl)-4-(2-(dipropylamino)ethoxy)benzamide (JCS011) 1 H NMR (500 MHz, CDCl3) δ 7.81 (s, 2H), 7.62 (d, J = 8.8 Hz, 2H), 7.27 - 7.18 (m, 6H), 6.88 (d, J = 8.8 Hz, 2H), 6.03 (d, J = 7.3 Hz, 1H), 4.53 - 4.48 (m, 1H), 4.06 - 4.01 (m, 2H), 3.26 (bd, J = 15.9 Hz, 2H), 3.07 (dd, J = 16.1, 8.9 Hz, 2H), 2.85 (t, J = 6.2 Hz, 2H), 2.51 - 2.41 (m, 4H), 1.50 - 1.44 (m, 4H), 0.88 (t, J = 7.4 Hz, 6H). 13 C NMR (126 MHz, CDCl3) δ 188.0, 166.7, 161.9, 150.8 (dd, J CF = 253.2 Hz, J C-CF = 12.6 Hz, 2C), 150.5 (dd, J CF = 249.4 Hz, J C-CF = 12.6 Hz, 2C), 138.0 (2C), 132.8 (2C), 132.2 (dd, J C-C-CF = 5.0 Hz, J C-C-CF = 3.7 Hz, 2C), 128.7 (2C), 127.2 (dd, J C-C-CF = 7.5 Hz, J C-C-CF = 3.7 Hz, 2C), 126.1, 119.1 (d, J C-CF = 17.6 Hz, 2C), 117.8 (d, J C-CF= 17.6 Hz, 2C), 114.5 (2C), 67.1, 57.2, 52.9, 44.6, 33.9, 20.5, 12.0. 19 F NMR (376 MHz, CDCl3) δ -135.0 (d, J FF = 18.8 Hz, 2F), -136.5 (d, J FF = 22.5 Hz, 2F). C 35 H 37 HR-APCI m / z calculated for F4N2O3 [M+H] 609.2734, found 609.2781.

[0207] [ka] N-(3,5-bis((E)-3,4-difluorobenzylidene)-4-oxocyclohexyl)-4-(2-(dibutylamino)ethoxy)benzamide (JCS012) 1 H NMR (500 MHz, CDCl3) δ 7.81 (s, 2H), 7.62 (d, J = 8.8 Hz, 2H), 7.27 - 7.18 (m, 6H), 6.88 (d, J = 8.8 Hz, 2H), 6.09 - 6.04 (m, 1H), 4.53 - 4.48 (m, 1H), 4.03 (t, J = 6.3 Hz, 2H), 3.24 (bd, J = 16.7 Hz, 2H), 3.06 (dd, J = 16.7, 7.5 Hz, 2H), 2.85 (t, J = 6.3 Hz, 2H), 2.54 - 2.46 (m, 4H), 1.43 (tt, J = 7.6, 6.3 Hz, 4H), 1.30 (dt, J = 14.8, 7.4 Hz, 4H), 0.90 (t, J = 7.4 Hz, 6H). 13 C NMR (126 MHz, CDCl3) δ 187.8, 166.5, 161.8, 150.6 (dd, J CF = 253.2 Hz, J C-CF = 12.6 Hz, 2C), 150.2 (dd, J CF= 249.4 Hz, J C-CF = 12.6 Hz, 2C), 137.8 (2C), 132.7 (2C), 132.1 (dd, J C-C-CF = 6.3 Hz, J C-C-CF = 3.7 Hz, 2C), 128.6 (2C), 127.0 (dd, J C-C-CF = 6.3 Hz, J C-C-CF = 3.7 Hz, 2C), 126.0, 118.9 (d, J C-CF = 17.6 Hz, 2C), 117.6 (d, J C-CF = 17.6 Hz, 2C), 114.5 (2C), 66.9, 54.7, 52.7, 44.5, 33.4, 29.3, 20.6, 14.0. 19 F NMR (376 MHz, CDCl3) δ -135.0 (d, J FF = 18.8 Hz, 2F), -136.5 (d, J FF = 18.8 Hz, 2F). C 37 H 41 HR-APCI m / z calculated for F4N2O3 [M+H] 637.3047, found 637.3096.

[0208] [ka] N-(3,5-bis((E)-3,4-difluorobenzylidene)-4-oxocyclohexyl)-4-(2-(diisopropylamino)ethoxy)benzamide (JCS013) 1H NMR (500 MHz, CDCl3) δ 7.76 (s, 2H), 7.63 (d, J = 8.8 Hz, 2H), 7.24 - 7.13 (m, 6H), 6.84 (d, J = 8.5 Hz, 2H), J.2, 6.4 (29). - 4.44 (m, 1H), 3.90 (t, J = 6.7 Hz, 2H), 3.24 (bd, J = 15.7, Hz, 2H), 3.04 (m, 4H), 2.81 (t, J = 7.1 Hz, 2H (d), J =0 Hz. 13 C NMR (126 MHz, CDCl3) δ 187.9, 166.7, 161.9, 150.7 (dd, J CF = 253.2 Hz, J C-CF = 12.6 Hz, 2C), 150.2 (dd, J CF = 249.4 Hz, J C-CF = 12.6 Hz, 2C), 137.8 (2C), 132.8 (2C), 132.2 (dd, J C-C-CF = 5.0 Hz, J C-C-CF = 3.7 Hz, 2C), 128.6 (2C), 127.1 (dd, J C-C-CF = 7.5 Hz, J C-C-CF = 3.7 Hz, 2C), 126.0, 119.0 (d, J C-CF = 17.6 Hz, 2C), 117.7 (d, J C-CF = 17.6 Hz, 2C), 114.5 (2C), 69.4, 49.8, 44.6, 44.3, 33.8, 20.8。 19 F NMR (376 MHz, CDCl3) δ −135.0 (d, J FF = 22.5 Hz, 2F), −136.5 (d, J FF = 22.5 Hz, 2F)。C 35 H 37 F4N2O3[M+H] is located in HR-APCI m / z contact area 609.2734.

[0209] [ka] N-(3,5-bis((E)-3,4-difluorobenzylidene)-4-oxocyclohexyl)-4-(2-(cyclohexyl(ethyl)amino)ethoxy)-benzamide (JCS014) 1 H NMR (500 MHz, CDCl3) δ 7.80 (s, 2H), 7.62 (d, J = 8.3 Hz, 2H), 7.28 - 7.17 (m, 6H), 6.87 (d, J = 8.3 Hz, 2H), 6.11 (d, J = 6.3 Hz, 1H), 4.55 - 4.45 (m, 1H), 4.01 (t, J = 6.7 Hz, 2H), 3.26 (bd, J = 15.1 Hz, 2H), 3.06 (dd, J = 15.4, 8.1 Hz, 2H), 2.89 (t, J = 6.0 Hz, 2H), 2.75 - 2.62 (m, 1H), 2.59-2.53 (m, 1H), with nearby 1H singlets 1.91 - 1.74 (m, 4H), 1.64-1.62 (m, 1H), 1.27 - 1.18 (m, 4H), 1.12 - 1.04 (m, 1H). 13 C NMR (126 MHz, CDCl3) δ 188.0, 166.7, 161.8, 150.8 (dd, J CF = 253.2 Hz, J C-CF = 12.6 Hz, 2C), 150.3 (dd, J CF = 249.4 Hz, J C-CF = 12.6 Hz, 2C), 137.9 (2C), 132.8 (2C), 132.2 (dd, J C-C-CF = 6.3 Hz, J C-C-CF = 3.7 Hz, 2C), 128.8 (2C), 127.2 (dd, J C-C-CF = 6.3 Hz, J C-C-CF = 2.5 Hz, 2C), 126.1, 119.0 (d, J C-CF = 17.6 Hz, 2C), 117.7 (d, JC-CF = 17.6 Hz, 2C), 114.5 (2C), 68.2, 61.1, 48.9, 46.0, 44.6, 33.9, 29.2, 26.3, 26.2, 14.0. 19 F NMR (376 MHz, CDCl3) δ -135.0 (d, J FF = 22.5 Hz, 2F), -136.5 (d, J FF = 22.5 Hz, 2F). C 37 H 39 HR-APCI m / z calculated for F4N2O3 [M+H] 635.2891, found 635.2950.

[0210] [ka] N-(3,5-bis((E)-3,4-difluorobenzylidene)-4-oxocyclohexyl)-4-(2-(dibenzylamino)ethoxy)benzamide (JCS015) 1 H NMR (500 MHz, CDCl3) δ 7.78 (s, 2H), 7.62 (d, J = 8.7 Hz, 2H), 7.39 (d, J = 7.4 Hz, 4H), 7.32 (t, J = 7.5 Hz, 4H), 7.29 - 7.14 (m, 8H), 6.78 (d, J = 8.6 Hz, 2H), 6.26 (d, J = 7.0 Hz, 1H), 4.52 - 4.46 (m, 1H), 4.01 (t, J = 6.0 Hz, 2H), 3.71 (s, 4H), 3.25 (bd, J = 16.4 Hz, 2H), 3.06 (dd, J = 15.9, 8.3 Hz, 2H), 2.90 (t, J = 6.0 Hz, 2H). 13 C NMR (126 MHz, CDCl3) δ 187.9, 166.7, 161.7, 150.7 (dd, J CF = 253.2 Hz, J C-CF = 12.6 Hz, 2C), 150.2 (dd, J CF = 249.4 Hz, JC-CF = 12.6 Hz, 2C), 139.5 (2C), 137.9 (2C), 132.8 (2C), 132.2 (dd, J C-C-CF = 6.3 Hz, J C-C-CF = 3.7 Hz, 2C), 128.8 (4C), 128.3 (2C), 127.1 (dd, J C-C-CF = 6.3 Hz, J C-C-CF = 3.7 Hz, 2C), 126.1, 119.0 (d, J C-CF = 17.6 Hz, 2C), 117.7 (d, J C-CF = 17.6 Hz, 2C), 114.3 (2C), 66.9, 59.2, 52.0, 44.6, 33.8. 19 F NMR (376 MHz, CDCl3) δ -135.0 (d, J FF = 22.5 Hz, 2F), -136.4 (d, J FF = 22.5 Hz, 2F). C 43 H 38 HR-APCI m / z calculated for F4N2O3 [M+H] 705.2734, found 705.2749.

[0211] [ka] N-(3,5-bis((E)-3,4-difluorobenzylidene)-4-oxocyclohexyl)-4-(2-(dicyclohexylamino)ethoxy)benzamide (JCS017) 1H NMR (500 MHz, CDCl3) δ 7.81 (s, 2H), 7.62 (d, J = 8.7 Hz, 2H), 7.26 - 7.17 (m, 6H), 6.87 (d, J = 8.7 Hz, 2H), 6.3, J 4,05 ( - 4.48 (m, 1H), 3.87 (t, J = 7.3 Hz, 2H), 3.24 (bd, J = 15.7, Hz, 2H), 3.06 (ddd, J = 15.9, 8.3, 2.2 Hz, 27 (H = 2.9), J = 2.9). (t, J = 3.7 Hz, 2H), 1.77 – 1.73 (m, 8H), 1.62–1.59 (m, 2H), 1.26 – 1.21 (m, 8H), 1.10 – 1.03 (m, 2H)。 13 C NMR (126 MHz, CDCl3) 13 C NMR (126 MHz, クロロホルム-d) δ 188.0, 166.7, 162.0, 150.8 (dd, J CF = 253.2 Hz, J C-CF = 12.6 Hz, 2C), 150.3 (dd, J CF = 249.4 Hz, J C-CF = 12.6 Hz, 2C), 137.9 (2C), 132.8 (2C), 132.2 (dd, J C-C-CF = 6.3 Hz, J C-C-CF = 5.0 Hz, 2C), 128.8 (2C), 127.2 (dd, J C-C-CF = 6.3 Hz, J C-C-CF = 2.5 Hz, 2C), 125.9, 119.0 (d, J C-CF = 17.6 Hz, 2C), 117.7 (d, J C-CF = 17.6 Hz, 2C), 114.4 (2C), 69.7, 59.0, 45.5, 44.6, 33.9, 31.9, 26.3 (2C)。 19 F NMR (376 MHz, CDCl3) δ −135.0 (d, J FF= 18.8 Hz, 2F), -136.4 (d, J FF = 22.5 Hz, 2F). C 41 H 45 HR-APCI m / z calculated for F4N2O3 [M+H] 689.3371, found 689.3375.

[0212] General Procedure B: The compound was typically prepared by reacting the corresponding aldehyde, e.g., 3,4-difluorobenzaldehyde, with tert-butyl(4-oxocyclohexyl)carbamate in the presence of 20% aqueous sodium hydroxide to give N-tert-butyl(3,5-bis((E)-3,4-difluorobenzylidene)-4-oxocyclohexyl)carbamate. The Boc group was deprotected by treating the product with trifluoroacetic acid (TFA). 4-Amino-2,6-bis((E)-3,4-difluorobenzylidene)cyclohexan-1-one was benzoylated with 4-(2-(propylamino)-ethoxy)benzoic acid using the standard peptide coupling reagents TBTU or EDC and HOAt to give N-(3,5-bis((E)-3,4-difluorobenzylidene)-4-oxocyclohexyl)-4-(2-(propylamino)ethoxy)benzamide. [ka]

[0213] Example JCS032: To a mixture of N-tert-butyl(4-oxocyclohexyl)carbamate (213.28 mg, 1 mmol, 1.0 equiv.) and ethanol (1.0 mL) in a round-bottom flask, 20% aqueous sodium hydroxide (1.5 mL) was added dropwise and stirred for 5 minutes. 3,4-Difluorobenzaldehyde (355.3 mg, 2.5 mmol, 2.5 equiv.) was added to the mixture. The reaction mixture was then stirred at 21°C for 5 hours. After 5 hours, the yellow precipitate thus obtained was filtered, washed with water and cold ethanol, and dried to give the pure product (360 mg, 78% yield).

[0214] Trifluoroacetic acid (0.5 ml) was added to a solution of N-tert-butyl (3,5-bis((E)-3,4-difluorobenzylidene)-4-oxocyclohexyl)carbamate (230.7 mg, 0.5 mmol) in dichloromethane (5.0 ml) at 21° C., and the mixture was stirred at 21° C. overnight. The solvent of the reaction solution was then distilled off under reduced pressure, and the resulting residue was poured into a 1N aqueous sodium hydroxide solution and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give 4-amino-2,6-bis((E)-3,4-difluorobenzylidene)cyclohexan-1-one.

[0215] A mixture of 4-amino-2,6-bis((E)-3,4-difluorobenzylidene)cyclohexan-1-one (180.7 mg, 0.5 mmol, 1.0 equiv) and anhydrous diisopropylethylamine (261.2 μL, 1.5 mmol, 3.0 equiv) in THF was maintained at 0 °C (ice bath). To this cooled mixture, 4-(2-(propylamino)ethoxy)benzoic acid (111.6 mg, 0.5 mmol, 1.0 equiv) in 2.0 mL of THF was added dropwise, followed by the addition of TBTU (240.8 mg, 0.75 mmol, 1.5 equiv). After the complete addition of 4-(2-(ethylamino)ethoxy)benzoic acid, the reaction mixture was slowly warmed to 21 °C and stirred overnight. After completion of the reaction, the solvent was evaporated, and the residue was stirred in saturated aqueous NaHCO3 solution for 5 min. The mixture was extracted three times with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and then dried over anhydrous sodium sulfate. Evaporation of the solvent, followed by flash chromatography (gradient elution: 10% methanol / ethyl acetate - 75% methanol / ethyl acetate) afforded the desired product JCS032 (222.2 mg, 75% yield) as a yellow solid.

[0216] Synthesis of 4-(2-(propylamino)ethoxy)benzoic acid Methyl 4-hydroxybenzoate (5.0 g, 32.86 mmol, 10 equiv.) was mixed with 1,2-dibromoethane (35 mL) and potassium carbonate (6.8 g, 49.23 mmol, 1.5 equiv.), and the mixture was heated to reflux for 18 h. The reaction mixture was then concentrated under reduced pressure, and the residue was partitioned between ethyl ether (300 mL) and water (200 mL). The ether layer was extracted with 2 N sodium hydroxide (5 × 30 mL). The solvent was removed to give the desired product as a white solid (8.5 g, 99% yield).

[0217] A solution of methyl 4-(2-bromoethoxy)benzoate (2.591 g, 10 mmol, 1.0 equiv.), dimethylformamide (DMF, 20 mL), cesium carbonate (9.7 g, 30 mmol, 3.0 equiv.), and propylamine (1.7 g, 30 mmol, 3.0 equiv.) was added to a round-bottom flask equipped with a stir bar. The mixture was heated at 21 °C for 24 h, after which ethyl acetate (200 mL) and water (200 mL) were added. The organic layer was washed three times with water and then dried over sodium sulfate. Silica gel flash chromatography (gradient elution: 10% methanol / EtOAc to 50% methanol / EtOAc) afforded the pure product, methyl 4-(2-(propylamino)ethoxy)benzoate (1.4 g, 60% yield), as a pale yellow oil.

[0218] Methyl 4-(2-(propylamino)ethoxy)benzoate (1.18 g, 5.0 mmol, 1.0 equiv) was dissolved in 2.5 mL of ethanol and added to a solution of sodium hydroxide (0.4 g) in 2.5 mL of water. The mixture was heated to reflux for 2 h. The ethanol was removed in vacuo, and the aqueous solution was acidified with concentrated HCl at 5 °C. The solid was collected, treated with cold water, filtered, and dried in vacuo at 55 °C–60 °C to give 4-(2-(propylamino)ethoxy)benzoic acid hydrochloride as a white solid (1.16 g, 90% yield) pure enough for use in the next step.

[0219] The following compounds JCS018, JCS019, JCS20, JCS021, JCS022, JCS023, JCS024, JCS025, JCS026, JCS061, JCS062, JCS064, JCS068, JCS029, JCS030, JCS031, JCS032, JCS033, JCS034, JCS035, JCS036, JCS037, JCS0038, JCS039, JCS040, JCS045, JCS049, JCS77, JCS078, JCS079, JCS080, JCS081, JCS083, and JCS084 were synthesized by B.

[0220] [ka] N-(3,5-bis((E)-3,4-difluorobenzylidene)-4-oxocyclohexyl)-4-(2-(propylamino)ethoxy)benzamide (JCS032) 1 H NMR (500 MHz, CDCl3) δ 7.80 (s, 2H), 7.62 (d, J = 8.8 Hz, 2H), 7.26 - 7.16 (m, 6H), 6.88 (d, J = 8.8 Hz, 2H), 6.17 (d, J = 7.3 Hz, 1H), 4.50 - 4.47 (m, 1H), 4.12 (t, J = 5.2 Hz, 2H), 3.26 (bd, J = 15.7 Hz, 2H), 3.11 - 3.02 (m, 4H), 2.68 (t, J = 5.0 Hz, 2H), 2.21 (s, 1H), 1.62-1.54 (m, 2H), 0.93 (t, J = 7.4 Hz, 3H). 13 C NMR (126 MHz, CDCl3) δ 187.9, 166.7, 161.6, 150.8 (dd, J CF = 253.2 Hz, J C-CF = 12.6 Hz, 2C), 150.3 (dd, J CF = 250.7 Hz, J C-CF = 13.8 Hz, 2C), 137.9 (2C), 132.8 (2C), 132.2 (dd, JC-C-CF = 6.3 Hz, J C-C-CF = 3.7 Hz, 2C), 128.8 (2C), 127.2 (dd, J C-C-CF = 7.5 Hz, J C-C-CF = 3.7 Hz, 2C), 126.5, 119.0 (d, J C-CF = 15.1 Hz, 2C), 117.8 (d, J C-CF = 17.6 Hz, 2C), 114.4 (2C), 67.2, 51.6, 48.4, 44.7, 33.8, 22.8, 11.8. 19 F NMR (376 MHz, CDCl3) δ -135.0 (d, J FF = 22.5 Hz, 2F), -136.5 (d, J FF = 22.5 Hz, 2F). C 32 H 31 HR-APCI m / z calculated for F4N2O3 [M+H] 567.2259, found 567.2268.

[0221] [ka] N-(3,5-bis((E)-3,4-difluorobenzylidene)-4-oxocyclohexyl)-4-(2-(hexylamino)ethoxy)benzamide (JCS029) 1H NMR (500 MHz, DMSO-d6) δ 9.33 (bs, 2H), 8.60 (d, J = 6.5 Hz, 1H), 7.87 (d, J = 8.8 Hz, 2H), 7.68 (m, 2H), 7.87 - 7.4. (m, 2H), 7.04 (d, J = 8.8 Hz, 2H), 4.35 (t, J = 5.2 Hz, 2H), 4.10 - 4.05 (m, 1H), 3.31 (t, J = 4.4 Hz, 2H), 3.1 = 3,6 (bd (dd, J = 15.9, 10.9 Hz, 2H), 2.93 (t, J = 8.1 Hz, 2H), 1.70 – 1.63 (m, 2H), 1.36 – 1.19 (m, 6H), 0.86 (t, J = 6.6) 。H. 13 C NMR (126 MHz, DMSO-d6) δ 187.6, 165.4, 160.1, 149.5 (dd, J CF = 249.4 Hz, J C-CF = 12.6 Hz, 2C), 149.2 (dd, J CF = 245.7 Hz, J C-CF = 12.6 Hz, 2C), 135.1 (2C), 134.7 (2C), 132.7 (dd, J C-C-CF = 6.3 Hz, J C-C-CF = 3.7 Hz, 2C), 129.3 (2C), 127.6 (dd, J C-C-CF = 6.3 Hz, J C-C-CF = 3.7 Hz, 2C), 126.9, 119.1 (d, J C-CF = 17.6 Hz, 2C), 117.8 (d, J C-CF = 17.6 Hz, 2C), 114.0 (2C), 63.4, 47.1, 45.6, 45.0, 33.1, 30.7, 25.6, 25.2, 21.8, 13.8。 19 F NMR (376 MHz, DMSO-d6) δ −136.9 (d, J FF= 22.5 Hz, 2F), -137.9 (d, J FF = 22.5 Hz, 2F). C 35 H 37 HR-APCI m / z calculated for F4N2O3 [M+H] 609.2734, found 609.2735.

[0222] [ka] N-(3,5-bis((E)-3,4-difluorobenzylidene)-4-oxocyclohexyl)-4-(2-((3-methoxypropyl)amino)ethoxy)-benzamide (JCS030) 1 H NMR (500 MHz, CDCl3) δ 7.76 (s, 2H), 7.63 (d, J = 8.9 Hz, 2H), 7.25 - 7.14 (m, 6H), 6.85 (d, J = 8.8 Hz, 2H), 6.28 (d, J = 7.3 Hz, 1H), 4.49 - 4.44 (m, 1H), 4.08 (t, J = 5.2 Hz, 2H), 3.45 (t, J = 6.1 Hz, 2H), 3.31 (s, 3H), 3.24 (d, J = 15.0 Hz, 2H), 3.09 - 2.97 (m, 4H), 2.77 (t, J = 7.0 Hz, 2H), 2.53 (bs, 1H), 1.82 - 1.75 (m, 2H). 13 C NMR (126 MHz, CDCl3) δ 187.9, 166.6, 161.7, 150.7 (dd, J CF = 253.2 Hz, J C-CF = 12.6 Hz, 2C), 150.2 (dd, J CF = 250.7 Hz, J C-CF = 13.8 Hz, 2C), 137.8 (2C), 132.8 (2C), 132.2 (dd, J C-C-CF = 6.3 Hz, J C-C-CF = 3.7 Hz, 2C), 128.8 (2C), 127.1 (dd, J C-C-CF= 7.5 Hz, J C-C-CF = 3.7 Hz, 2C), 126.4, 119.0 (d, J C-CF = 17.6 Hz, 2C), 117.7 (d, J C-CF = 17.6 Hz, 2C), 114.3 (2C), 71.3, 67.4, 58.7, 48.62, 47.8, 44.7, 33.8, 29.8. 19 F NMR (376 MHz, CDCl3) δ -131.1 (d, J FF = 30.0 Hz, 2F), -129.7 (d, J FF = 30.0 Hz, 2F). C 33 H 33 HR-APCI m / z calculated for F4N2O3 [M+H] 597.2370, found 597.2366.

[0223] [ka] N-(3,5-bis((E)-3,4-difluorobenzylidene)-4-oxocyclohexyl)-4-(2-((2-methoxyethyl)amino)ethoxy)-benzamide (JCS031) 1 H NMR (500 MHz, CDCl3) δ 7.75 (s, 2H), 7.62 (d, J = 8.8 Hz, 2H), 7.24 - 7.11 (m, 6H), 6.85 (d, J = 8.8 Hz, 2H), 6.32 (d, J = 7.3 Hz, 1H), 4.50 - 4.42 (m, 1H), 4.07 (t, J = 5.2 Hz, 2H), 3.50 (t, J = 5.0 Hz, 2H), 3.34 (s, 3H), 3.23 (bd, J = 15.0 Hz, 2H), 3.09 - 2.98 (m, 4H), 2.85 (t, J = 5.0 Hz, 2H), 2.35 (bs, 1H). 13 C NMR (126 MHz, CDCl3) δ 187.9, 166.7, 161.7, 150.6 (dd, J CF = 253.2 Hz, JC-CF = 12.6 Hz, 2C), 150.2 (dd, J CF = 249.4 Hz, J C-CF = 13.8 Hz, 2C), 137.8 (2C), 132.8 (2C), 132.2 (dd, J C-C-CF = 6.3 Hz, J C-C-CF = 3.7 Hz, 2C), 128.8 (2C), 127.1 (dd, J C-C-CF = 7.5 Hz, J C-C-CF = 3.7 Hz, 2C), 126.3, 118.9 (d, J C-CF = 17.6 Hz, 2C), 117.7 (d, J C-CF = 17.6 Hz, 2C), 114.3 (2C), 71.9, 67.6, 58.9, 49.3, 48.6, 44.7, 33.8. 19 F NMR (376 MHz, CDCl3) δ -135.1 (d, J FF = 22.5 Hz, 2F), -136.5 (d, J FF = 22.5 Hz, 2F). C 32 H 31 HR-APCI m / z calculated for F4N2O3 [M+H] 583.2210, found 583.2212.

[0224] [ka] N-(3,5-bis((E)-3,4-difluorobenzylidene)-4-oxocyclohexyl)-4-(2-(((tetrahydrofuran-2-yl)methyl)-amino)ethoxy)benzamide (JCS033) 1H NMR (500 MHz, CDCl3) δ 7.76 (s, 2H), 7.62 (d, J = 8.8 Hz, 2H), 7.25 - 7.14 (m, 6H), 6.85 (d, J = 8.8 Hz, 2H), 6.30 (d, J = 7.3 Hz, 1H), 4.49 - 4.43 (m, 1H), 4.07 (t, J = 5.2 Hz, 2H), 4.02 - 3.97 (m, 1H), 3.85 - 3.70 (m, 2H), 3.08 - 2.98 (m, 4H), 2.80 - 2.67 (m, 2H), 2.41 (bs, 1H), 2.00 - 1.94 (m, 1H), 1.90 - 1.83 (m, 2H), 1.56 - 1.50 (m, 1H)。 13 C NMR (126 MHz, CDCl3) δ 187.9, 166.7, 161.7, 150.7 (dd, J CF = 254.5 Hz, J C-CF = 12.6 Hz, 2C), 150.2 (dd, J CF = 250.7 Hz, J C-CF = 13.8 Hz, 2C), 137.8 (2C), 132.8 (2C), 132.2 (dd, J C-C-CF = 6.3 Hz, J C-C-CF = 3.7 Hz, 2C), 128.8 (2C), 127.1 (dd, J C-C-CF = 7.5 Hz, J C-C-CF = 3.7 Hz, 2C), 126.3, 119.0 (d, J C-CF = 17.6 Hz, 2C), 117.7 (d, J C-CF = 17.6 Hz, 2C), 114.3 (2C), 78.3, 68.0, 67.7, 54.4, 48.8, 44.6, 33.8, 29.4, 25.8。 19 F NMR (376 MHz, CDCl3) δ -135.1 (d, J FF = 22.5 Hz, 2F), -136.5 (d, J FF = 22.5 Hz, 2F)。C 34 H 33HR-APCI m / z calculated for F4N2O4 [M+H] 609.2371, found 609.2371.

[0225] [ka] N-(3,5-bis((E)-3,4-difluorobenzylidene)-4-oxocyclohexyl)-4-(2-(butylamino)ethoxy)benzamide (JCS034) 1 H NMR (500 MHz, CDCl3) δ 7.78 (s, 2H), 7.62 (d, J = 8.8 Hz, 2H), 7.25 - 7.15 (m, 6H), 6.87 (d, J = 8.8 Hz, 2H), 6.20 (d, J = 7.2 Hz, 1H), 4.52 - 4.45 (m, 1H), 4.10 (t, J = 5.2 Hz, 2H), 3.25 (bd, J = 15.0 Hz, 2H), 3.08 - 3.01 (m, 4H), 2.70 (t, J = 7.3 Hz, 2H), 2.34 (bs, 1H), 1.41 - 1.32 (m, 2H), 1.40 - 1.33 (m, 2H), 0.91 (t, J = 7.3 Hz, 3H). 13 C NMR (126 MHz, CDCl3) δ 187.9, 166.7, 161.7, 150.7 (dd, J CF = 254.5 Hz, J C-CF = 12.6 Hz, 2C), 150.3 (dd, J CF = 249.4 Hz, J C-CF = 13.8 Hz, 2C), 137.9 (2C), 132.8 (2C), 132.2 (dd, J C-C-CF = 6.3 Hz, J C-C-CF = 3.7 Hz, 2C), 128.8 (2C), 127.2 (dd, J C-C-CF = 7.5 Hz, J C-C-CF = 3.7 Hz, 2C), 126.4, 119.0 (d, J C-CF= 17.6 Hz, 2C), 117.7 (d, J C-CF = 17.6 Hz, 2C), 114.4 (2C), 67.4, 49.6, 48.5, 44.7, 33.8, 29.8, 20.5, 14.0. 19 F NMR (376 MHz, CDCl3) δ -135.0 (d, J FF = 18.8 Hz, 2F), -136.5 (d, J FF = 22.5 Hz, 2F). C 33 H 33 HR-APCI m / z calculated for F4N2O3 [M+H] 581.2421, found 581.2429.

[0226] [ka] tert-Butyl (2-(4-((3,5-bis((E)-3,4-difluorobenzylidene)-4-oxocyclohexyl)carbamoyl)phenoxy)ethyl)carbamate (JCS035) 1 H NMR (500 MHz, CDCl3) δ 7.81 (s, 2H), 7.63 (d, J = 8.7 Hz, 2H), 7.26 - 7.17 (m, 6H), 6.87 (d, J = 8.6 Hz, 2H), 6.09 (d, J = 7.0 Hz, 1H), 4.97 (bs, 1H), 4.53 - 4.47 (m, 1H), 4.03 (t, J = 5.2 Hz, 2H), 3.53 (q, J = 5.5 Hz, 2H), 3.26 (bd, J = 15.0 Hz, 2H), 3.07 (dd, J = 15.0, 5.0 Hz, 2H), 1.44 (s, 9H). 13 C NMR (126 MHz, CDCl3) δ 187.9, 166.6, 161.5, 155.9, 150.8 (dd, J CF = 253.6 Hz, J C-CF = 12.6 Hz, 2C), 150.3 (dd, J CF = 249.4 Hz, JC-CF = 13.8 Hz, 2C), 138.0 (2C), 132.8 (2C), 132.2 (dd, J C-C-CF = 5.0 Hz, J C-C-CF = 3.7 Hz, 2C), 128.9 (2C), 127.2 (dd, J C-C-CF = 7.5 Hz, J C-C-CF = 3.7 Hz, 2C), 126.6, 119.1 (d, J C-CF = 17.6 Hz, 2C), 117.8 (d, J C-CF = 17.6 Hz, 2C), 114.4 (2C), 79.8, 67.4, 44.6, 40.0, 33.87, 28. 19 F NMR (376 MHz, CDCl3) δ -131.1 (d, J FF = 30.0 Hz, 2F), -129.7 (d, J FF = 26.3 Hz, 2F). C 34 H 32 HR-APCI m / z calculated for F4N2O5K[M+K] 663.1878, found 663.1884.

[0227] [ka] 4-(2-aminoethoxy)-((E)-3,4-difluorobenzylidene)-4-oxocyclohexyl)benzamide (JCS036) 1 H NMR (500 MHz, CDCl3) δ 7.80 (s, 2H), 7.63 (d, J = 8.8 Hz, 2H), 7.26 - 7.16 (m, 6H), 6.89 (d, J = 8.8 Hz, 2H), 6.12 (d, J = 7.3 Hz, 1H), 4.52 - 4.47 (m, 1H), 4.00 (t, J = 5.2 Hz, 2H), 3.25 (bd, J = 15.0 Hz, 2H), 3.13 - 3.01 (m, 4H), 1.49 (s, 2H). 13C NMR (126 MHz, CDCl3) δ 188.0, 166.6, 161.9, 150.8 (dd, J CF = 254.5 Hz, J C-CF = 12.6 Hz, 2C), 150.3 (dd, J CF = 249.4 Hz, J C-CF = 13.8 Hz, 2C), 138.0 (2C), 132.8 (2C), 132.2 (dd, J C-C-CF = 5.0 Hz, J C-C-CF = 3.7 Hz, 2C), 128.9 (2C), 127.2 (dd, J C-C-CF = 6.3 Hz, J C-C-CF = 2.5 Hz, 2C), 126.4, 119.0 (d, J C-CF = 17.6 Hz, 2C), 117.7 (d, J C-CF = 16.3 Hz, 2C), 114.4 (2C), 70.4, 44.6, 41.5, 33.8. 19 F NMR (376 MHz, CDCl3) δ -135.0 (d, J FF = 22.5 Hz, 2F), -136.5 (d, J FF = 22.5 Hz, 2F). C 39 H 25 HR-APCI m / z calculated for F4N2O3 [M+H] 525.1795, found 525.1799.

[0228] [ka] N-(3,5-bis((E)-3,4-difluorobenzylidene)-4-oxocyclohexyl)-4-(2-(diallylamino)ethoxy)benzamide (JCS037) 1H NMR (500 MHz, CDCl3) δ 7.80 (s, 2H), 7.62 (d, J = 8.4 Hz, 2H), 7.28 - 7.16 (m, 6H), 6.87 (d, J = 8.4 Hz, 2H), 6.3 (d, J = 8, Hz), J - 5.84 (m, 2H), 5.23 - 5.15 (m, 4H), 4.53 - 4.47 (m, 1H), 4.07 (t, J = 6.0 Hz, 2H), 3.35 - 3.15 (m, 6H), 3, J = 6. 2H), 2.89 (t, J = 6.0 Hz, 2H)。 13 C NMR (126 MHz, CDCl3) δ 188.0, 166.6, 161.7, 150.8 (dd, J CF = 254.5 Hz, J C-CF = 12.6 Hz, 2C), 150.3 (dd, J CF = 249.4 Hz, J C-CF = 13.8 Hz, 2C), 137.9 (2C), 135.2 (2C), 132.8 (2C), 132.2 (dd, J C-C-CF = 6.3 Hz, J C-C-CF = 3.7 Hz, 2C), 128.8 (2C), 127.2 (dd, J C-C-CF = 6.3 Hz, J C-C-CF = 2.5 Hz, 2C), 126.2, 119.1 (d, J C-CF = 17.6 Hz, 2C), 118.2 (2C), 117.7 (d, J C-CF = 16.3 Hz, 2C), 114.4 (2C), 66.7, 57.8, 51.8, 44.6, 33.8。 19 F NMR (376 MHz, CDCl3) δ −131.1 (d, J FF = 26.3 Hz, 2F), −129.7 (d, J FF = 26.3 Hz, 2F)。C 33 H 33HR-APCI m / z calculated for F4N2O3 [M+H] 605.2421, found 605.2423.

[0229] [ka] N-(3,5-bis((E)-3,4-difluorobenzylidene)-4-oxocyclohexyl)-4-(2-(4-methylpiperazin-1-yl)ethoxy)benzamide (JCS038) 1 H NMR (500 MHz, CDCl3) δ 7.73 (s, 2H), 7.62 (d, J = 8.8 Hz, 2H), 7.23 - 7.10 (m, 6H), 6.84 (d, J = 8.8 Hz, 2H), 6.30 (d, J = 7.2 Hz, 1H), 4.48 - 4.42 (m, 1H), 4.08 (t, J = 5.8 Hz, 2H), 3.22 (bd, J = 15.3 Hz, 2H), 3.02 (dd, J = 15.8, 8.4 Hz, 2H), 2.78 (t, J = 5.8 Hz, 2H), 2.66 - 2.52 (m, 4H), 2.50 - 2.35 (m, 4H), 2.26 (s, 3H). 13 C NMR (126 MHz, CDCl3) δ 187.8, 166.6, 161.6, 150.6 (dd, J CF = 253.2 Hz, J C-CF = 12.6 Hz, 2C), 150.2 (dd, J CF = 249.4 Hz, J C-CF = 13.8 Hz, 2C), 137.7 (2C), 132.8 (2C), 132.1 (dd, J C-C-CF = 6.3 Hz, J C-C-CF = 3.7 Hz, 2C), 128.8 (2C), 127.1 (dd, J C-C-CF = 6.3 Hz, J C-C-CF = 3.7 Hz, 2C), 126.2, 118.9 (d, J C-CF = 17.6 Hz, 2C), 117.7 (d, JC-CF = 16.3 Hz, 2C), 114.4 (2C), 66.2, 57.0, 55.0, 53.6, 46.1, 44.6, 33.7. 19 F NMR (376 MHz, CDCl3) δ 131.1 (d, J FF = 30.0 Hz, 2F), 129.7 (d, J FF = 26.3 Hz, 2F). C 35 H 34 HR-APCI m / z calculated for F4N3O3 [M+H] 608.2530, found 608.2539.

[0230] [ka] N-(3,5-bis((E)-3,4-difluorobenzylidene)-4-oxocyclohexyl)-4-(2-(1,3-dioxoisoindolin-2-yl)ethoxy)benzamide (JCS039) 1 H NMR (500 MHz, CDCl3) δ 7.91 - 7.84 (m, 2H), 7.81 (s, 2H), 7.78 - 7.72 (m, 2H), 7.62 (d, J = 8.3 Hz, 2H), 7.28-7.19 (m, 6H), 6.88 (d, J = 8.4 Hz, 2H), 6.14 (d, J = 7.3 Hz, 1H), 4.52 - 4.48 (m, 1H), 4.26 (t, J = 5.8 Hz, 2H), 4.12 (t, J = 5.8 Hz, 2H), 3.27 (bd, J = 16.0 Hz, 2H), 3.07 (dd, J = 16.0, 8.2 Hz, 2H). 13 C NMR (126 MHz, CDCl3) δ 187.9, 168.2, 166.5, 161.2, 150.7 (dd, J CF = 253.2 Hz, J C-CF = 12.6 Hz, 2C), 150.3 (dd, J CF = 250.7 Hz, J C-CF= 13.8 Hz, 2C), 137.9 (2C), 134.8 (2C), 132.8 (2C), 132.1 (dd, J C-C-CF = 6.3 Hz, J C-C-CF = 3.7 Hz, 2C), 132.0 (2C), 128.8 (2C), 127.2 (dd, J C-C-CF = 6.3 Hz, J C-C-CF = 3.7 Hz, 2C), 126.7, 123.5 (2C), 119.0 (d, J C-CF = 17.6 Hz, 2C), 117.7 (d, J C-CF = 16.3 Hz, 2C), 114.5 (2C), 64.9, 44.6, 37.1, 33.8. 19 F NMR (376 MHz, CDCl3) δ 131.1 (d, J FF = 30.0 Hz, 2F), 129.7 (d, J FF = 30.0 Hz, 2F). C 37 H 27 HR-APCI m / z calculated for F4N2O5 [M+H] 655.1806, found 655.1860.

[0231] [ka] N-(3,5-bis((E)-3,4-difluorobenzylidene)-4-oxocyclohexyl)-4-(2-(di(prop-2-yn-1-yl)amino)ethoxy)-benzamide (JCS040) 1H NMR (500 MHz, CDCl3) δ 7.78 (s, 2H), 7.63 (d, J = 8.7 Hz, 2H), 7.25 - 7.14 (m, 6H), 6.88 (d, J = 8.8 Hz, 2H), 6.3 (d, J = 4,16). - 4.45 (m, 1H), 4.12 (t, J = 5.6 Hz, 2H), 3.55 (d, J = 2.5 Hz, 4H), 3.25 (d, J = 15 Hz, 2H), 3.15 - 2.96 (m, 4 Hz (t, 2. 2). 2H)。 13 C NMR (126 MHz, CDCl3) δ 187.9, 166.6, 161.5, 150.7 (dd, J CF = 254.5 Hz, J C-CF = 12.6 Hz, 2C), 150.3 (dd, J CF = 249.4 Hz, J C-CF = 13.8 Hz, 2C), 137.9 (2C), 132.8 (2C), 132.2 (dd, J C-C-CF = 6.3 Hz, J C-C-CF = 3.7 Hz, 2C), 128.8 (2C), 127.2 (dd, J C-C-CF = 6.3 Hz, J C-C-CF = 3.7 Hz, 2C), 126.4, 119.0 (d, J C-CF = 17.6 Hz, 2C), 117.7 (d, J C-CF = 16.3 Hz, 2C), 114.4 (2C), 78.5, 73.6, 66.7, 51.6, 44.6, 43.1, 33.8。 19 F NMR (376 MHz, CDCl3) δ −135.0 (d, J FF = 22.5 Hz, 2F), −136.5 (d, J FF = 18.8 Hz, 2F)。C 35 H 29 F4N2O3[M+H] is located in HR-APCI m / z contact area 601.2108.

[0232]

change

[0233] [ka] N-(3,5-bis((E)-3,4-difluorobenzylidene)-4-oxocyclohexyl)-4-(pyrrolidin-1-yl)benzamide (JCS019) 1 H NMR (500 MHz, CDCl3) δ 7.77 (s, 2H), 7.57 (d, J = 8.6 Hz, 2H), 7.26 - 7.13 (m, 6H), 6.45 (d, J = 8.5 Hz, 2H), 6.11 (d, J = 7.3 Hz, 1H), 4.52 - 4.46 (m, 1H), 3.33 - 3.27 (m, 4H), 3.23 (bd, J = 15.8 Hz, 2H), 3.04 (dd, J = 15.7, 8.3 Hz, 2H), 2.03 - 1.99 (m, 4H). 13 C NMR (126 MHz, CDCl3) δ 188.2, 167.2, 150.7 (dd, J CF = 253.2 Hz, J C-CF = 12.6 Hz, 2C), 150.3 (dd, J CF = 249.4 Hz, J C-CF = 12.6 Hz, 2C), 150.2, 137.7 (2C), 133.1 (2C), 132.3 (dd, J C-C-CF = 5.0 Hz, J C-C-CF = 2.5 Hz, 2C), 128.7 (2C), 127.1 (dd, J C-C-CF = 6.3 Hz, J C-C-CF = 2.5 Hz, 2C), 119.7, 119.1 (d, J C-CF = 17.6 Hz, 2C), 117.7 (d, J C-CF= 17.6 Hz, 2C), 110.9 (2C), 47.6, 44.4, 34.0, 25.5. 19 F NMR (376 MHz, CDCl3) δ -135.2 (d, J FF = 18.8 Hz, 2F), -136.6 (d, J FF = 18.8 Hz, 2F). C 31 H 27 HR-APCI m / z calculated for F4N2O2 [M+H] 535.2003, found 535.2011.

[0234] [ka] N-(3,5-bis((E)-3,4-difluorobenzylidene)-4-oxocyclohexyl)-4-(diethylamino)benzamide (JCS020) 1 H NMR (500 MHz, CDCl3) δ 7.77 (s, 2H), 7.56 (d, J = 8.4 Hz, 2H), 7.26 - 7.10 (m, 6H), 6.57 (d, J = 8.2 Hz, 2H), 6.10 (d, J = 6.4 Hz, 1H), 4.52 - 4.48 (m, 1H), 3.36 (q, J = 6.9 Hz, 4H), 3.23 (bd, J = 15.3 Hz, 2H), 3.05 (dd, J = 15.6, 7.9 Hz, 2H), 1.15 (t, J = 7.0 Hz, 6H). 13 C NMR (126 MHz, CDCl3) δ 188.1, 167.0, 150.7 (dd, J CF = 253.2 Hz, J C-CF = 12.6 Hz, 2C), 150.3 (dd, J CF = 249.4 Hz, J C-CF = 12.6 Hz, 2C), 150.2, 137.7 (2C), 133.1 (2C), 132.3 (dd, J C-C-CF = 5.0 Hz, J C-C-CF= 2.5 Hz, 2C), 128.7 (2C), 127.1 (dd, J C-C-CF = 5.0 Hz, J C-C-CF = 3.7 Hz, 2C), 119.5, 119.0 (d, J C-CF = 17.6 Hz, 2C), 117.7 (d, J C-CF = 17.6 Hz, 2C), 110.9 (2C), 44.5, 44.3, 33, 12.5. 19 F NMR (376 MHz, CDCl3) δ 130.9 (d, J FF = 26.3 Hz, 2F), 129.6 (d, J FF = 26.3 Hz, 2F). C 31 H 29 HR-APCI m / z calculated for F4N2O2 [M+H] 537.2003, found 537.2011.

[0235] [ka] N-(3,5-bis((E)-3,4-difluorobenzylidene)-4-oxocyclohexyl)-4-(2-(dihexylamino)ethoxy)benzamide (JCS021) 1 H NMR (500 MHz, CDCl3) δ 7.77 (s, 2H), 7.63 (d, J = 8.7 Hz, 2H), 7.26 - 7.13 (m, 6H), 6.86 (d, J = 8.7 Hz, 2H), 6.24 (d, J = 7.3 Hz, 1H), 4.50 - 4.45 (m, 1H), 4.03 (t, J = 6.2 Hz, 2H), 3.24 (bd, J = 15.8 Hz, 2H), 3.05 (dd, J = 15.8, 8.4 Hz, 2H), 2.85 (t, J = 6.2 Hz, 2H), 2.56 - 2.46 (m, 4H), 1.45 (p, J = 7.0 Hz, 4H), 1.31 - 1.25 (m, 12H), 0.87 (t, J = 6.6 Hz, 6H). 13C NMR (126 MHz, CDCl3) δ 187.9, 166.7, 161.8, 150.7 (dd, J CF = 253.2 Hz, J C-CF = 12.6 Hz, 2C), 150.3 (dd, J CF = 249.4 Hz, J C-CF = 12.6 Hz, 2C), 137.8 (2C), 132.8 (2C), 132.2 (dd, J C-C-CF = 6.3 Hz, J C-C-CF = 3.7 Hz, 2C), 128.8 (2C), 127.1 (dd, J C-C-CF = 6.3 Hz, J C-C-CF = 3.7 Hz, 2C), 126.1, 119.0 (d, J C-CF = 17.6 Hz, 2C), 117.7 (d, J C-CF = 17.6 Hz, 2C), 114.4 (2C), 66.9, 55.1, 52.7, 44.6, 33.8, 31.9, 27.2, 27.1, 22.7, 14.1. 19 F NMR (376 MHz, CDCl3) δ -130.9 (d, J FF = 26.3 Hz, 2F), -129.6 (d, J FF = 26.3 Hz, 2F). C 41 H 49 HR-APCI m / z calculated for F4N2O3 [M+H] 693.3673, found 693.3685.

[0236] [ka] 4-(2-(azocan-1-yl)ethoxy)-N-(3,5-bis((E)-3,4-difluorobenzylidene)-4-oxocyclohexyl)benzamide (JCS022) 1H NMR (500 MHz, CDCl3) δ 7.77 (s, 2H), 7.64 (d, J = 8.9 Hz, 2H), 7.25 - 7.14 (m, 6H), 6.87 (d, J = 8.5 Hz, 2H), 6.5 (d, 6.4,26). - 4.46 (m, 1H), 4.05 (t, J = 6.1 Hz, 2H), 3.24 (bd, J = 15.8 Hz, 2H), 3.05 (dd, J = 15.8 (8.4 Hz, 2H), 2.91 (Ht, J = 2, 2H), 4.8 Hz, 4H), 1.64 - 1.53 (m, 10H)。 13 C NMR (126 MHz, CDCl3) δ 187.9, 166.7, 161.9, 150.7 (dd, J CF = 253.2 Hz, J C-CF = 12.6 Hz, 2C), 150.3 (dd, J CF = 249.4 Hz, J C-CF = 12.6 Hz, 2C), 137.8 (2C), 132.8 (2C), 132.2 (dd, J C-C-CF = 6.3 Hz, J C-C-CF = 3.7 Hz, 2C), 128.8 (2C), 127.1 (dd, J C-C-CF = 6.3 Hz, J C-C-CF = 3.7 Hz, 2C), 126.1, 119.0 (d, J C-CF = 17.6 Hz, 2C), 117.7 (d, J C-CF = 17.6 Hz, 2C), 114.4 (2C), 67.0, 57.2, 54.3, 44.6, 33.8, 27.9, 27.3, 26.3。 19 F NMR (376 MHz, CDCl3) δ −135.0 (d, J FF = 18.8 Hz, 2F), −136.5 (d, J FF = 18.8 Hz, 2F)。C 36 H 37HR-APCI m / z calculated for F4N2O3 [M+H] 621.2734, found 621.2739.

[0237] [ka] N-(3,5-bis((E)-3,4-difluorobenzylidene)-4-oxocyclohexyl)-4-(2-(dipentylamino)ethoxy)benzamide (JCS023) 1 H NMR (500 MHz, CDCl3) δ 7.81 (s, 2H), 7.63 (d, J = 8.8 Hz, 2H), 7.30 - 7.26 (m, 1H), 7.25 - 7.16 (m, 5H), 6.87 (d, J = 8.8 Hz, 2H), 6.09 (d, J = 7.3 Hz, 1H), 4.53 - 4.47 (m, 1H), 4.08 (t, J = 6.0 Hz, 2H), 3.26 (bd, J = 15.5 Hz, 2H), 3.07 (dd, J = 15.5, 8.0 Hz, 2H), 2.93 (t, J = 6.0 Hz, 2H), 2.57 - 2.53 (m, 4H), 1.48 (p, J = 7.3 Hz, 4H), 1.35 - 1.21 (m, 8H), 0.88 (t, J = 7.0 Hz, 6H). 13 C NMR (126 MHz, CDCl3) δ 188.0, 166.6, 161.7, 150.8 (dd, J CF = 253.2 Hz, J C-CF = 12.6 Hz, 2C), 150.3 (dd, J CF = 249.4 Hz, J C-CF = 12.6 Hz, 2C), 138.0 (2C), 132.8 (2C), 132.2 (dd, J C-C-CF = 6.3 Hz, J C-C-CF = 3.7 Hz, 2C), 128.8 (2C), 127.1 (dd, J C-C-CF = 6.3 Hz, J C-C-CF= 3.7 Hz, 2C), 126.2, 119.0 (d, J C-CF = 17.6 Hz, 2C), 117.7 (d, J C-CF = 17.6 Hz, 2C), 114.4 (2C), 66.7, 54.9, 52.7, 44.6, 33.8, 29.7, 26.5, 22.7, 14.2. 19 F NMR (376 MHz, CDCl3) δ -135.0 (d, J FF = 22.5 Hz, 2F), -136.5 (d, J FF = 22.5 Hz, 2F). C 39 H 45 HR-APCI m / z calculated for F4N2O3 [M+H] 665.3360, found 665.3377.

[0238] [ka] N-(3,5-bis((E)-3,4-difluorobenzylidene)-4-oxocyclohexyl)-4-(2-(dioctylamino)ethoxy)benzamide (JCS024) 1 H NMR (500 MHz, CDCl3) δ 7.79 (s, 2H), 7.63 (d, J = 8.8 Hz, 2H), 7.26 - 7.16 (m, 6H), 6.87 (d, J = 8.8 Hz, 2H), 6.14 (d, J = 7.3 Hz, 1H), 4.52 - 4.46 (m, 1H), 4.04 (t, J = 6.2 Hz, 2H), 3.25 (bd, J = 15.8 Hz, 2H), 3.06 (dd, J = 15.8, 8.3 Hz, 2H), 2.86 (t, J = 6.2 Hz, 2H), 2.55 - 2.43 (m, 4H), 1.48 - 1.42 (m, 4H), 1.30 - 1.25 (m, 20H), 0.87 (t, J = 6.9 Hz, 6H). 13 C NMR (126 MHz, CDCl3) δ 187.9, 166.7, 161.8, 150.7 (dd, JCF = 253.2 Hz, J C-CF = 12.6 Hz, 2C), 150.3 (dd, J CF = 250.7 Hz, J C-CF = 12.6 Hz, 2C), 137.9 (2C), 132.8 (2C), 132.2 (dd, J C-C-CF = 6.3 Hz, J C-C-CF = 3.7 Hz, 2C), 128.8 (2C), 127.1 (dd, J C-C-CF = 6.3 Hz, J C-C-CF = 3.7 Hz, 2C), 126.1, 119.0 (d, J C-CF = 17.6 Hz, 2C), 117.7 (d, J C-CF = 17.6 Hz, 2C), 114.4 (2C), 66.9, 55.1, 52.8, 44.6, 33.8, 31.9, 29.6, 29.4, 27.6, 27.1, 22.7, 14.2. 19 F NMR (376 MHz, CDCl3) δ -135.0 (d, J FF = 22.5 Hz, 2F), -136.5 (d, J FF = 18.8 Hz, 2F). C 45 H 57 HR-APCI m / z calculated for F4N2O3 [M+H] 749.4299, found 749.4295.

[0239] [ka] 4-(2-(azepan-1-yl)ethoxy)-N-(3,5-bis((E)-3,4-difluorobenzylidene)-4-oxocyclohexyl)benzamide (JCS026) 1H NMR (500 MHz, CDCl3) δ 7.78 (s, 2H), 7.63 (d, J = 8.7 Hz, 2H), 7.27 - 7.09 (m, 6H), 6.87 (d, J = 8.7 Hz, 2H), J.3 , J 6.4,20 ( − 4.45 (m, 1H), 4.08 (t, J = 6.1 Hz, 2H), 3.24 (bd, J = 15.8 Hz, 2H), 3.05 (dd, J = 15.9, 8.2 Hz, 2H), 2.951 (H-81), J = 2, 2.6 (m, 4H), 1.76 - 1.54 (m, 8H)。 13 C NMR (126 MHz, CDCl3) δ 187.9, 166.7, 161.8, 150.7 (dd, J CF = 254.5 Hz, J C-CF = 12.6 Hz, 2C), 150.2 (dd, J CF = 250.7 Hz, J C-CF = 12.6 Hz, 2C), 137.9 (2C), 132.8 (2C), 132.2 (dd, J C-C-CF = 6.3 Hz, J C-C-CF = 3.7 Hz, 2C), 128.8 (2C), 127.1 (dd, J C-C-CF = 6.3 Hz, J C-C-CF = 3.7 Hz, 2C), 126.2, 119.0 (d, J C-CF = 17.6 Hz, 2C), 117.7 (d, J C-CF = 17.6 Hz, 2C), 114.5 (2C), 66.7, 56.1, 55.9, 44.6, 33.8, 27.8, 27.1。 19 F NMR (376 MHz, CDCl3) δ −135.0 (d, J FF = 18.8 Hz, 2F), −136.5 (d, J FF = 22.6 Hz, 2F)。C 35 H 35HR-APCI m / z calculated for F4N2O3 [M+H] 607.2578, found 607.2575.

[0240] [ka] N-(3,5-bis((E)-3,4-difluorobenzylidene)-4-oxocyclohexyl)-4-(2-((S)-2-oxo-4-phenyloxazolidin-3-yl)ethoxy)benzamide (JCS045) 1 H NMR (500 MHz, CDCl3) δ 7.75 (s, 2H), 7.69 (d, J = 8.8 Hz, 2H), 7.43 - 7.34 (m, 3H), 7.34 - 7.28 (m, 2H), 7.27 - 7.20 (m, 2H), 7.18 - 7.15 (m, 4H), 6.78 (d, J = 8.8 Hz, 2H), 6.67 (d, J = 7.2 Hz, 1H), 4.96 (dd, J = 8.9, 7.0 Hz, 1H), 4.61 (t, J = 8.8 Hz, 1H), 4.48 - 4.41 (m, 1H), 4.13 (dd, J = 8.8, 7.0 Hz, 1H), 4.09 - 4.05 (m, 1H), 3.96 - 3.93 (m, 1H), 3.76 - 3.72 (m, 1H), 3.26 (dd, J = 15.1, 3.9 Hz, 2H), 3.20 (m, 1H), 3.08 - 3.01 (m, 2H). 13 C NMR (126 MHz, CDCl3) δ 187.9, 166.5, 160.9, 158.4, 150.6 (dd, J CF = 253.2 Hz, J C-CF = 12.6 Hz, 2C), 150.2 (dd, J CF = 249.4 Hz, J C-CF = 12.6 Hz, 2C), 137.6 (2C), 137.5 (2C), 133.1 (2C), 132.2 (dd, J C-C-CF = 6.3 Hz, J C-C-CF= 3.7 Hz, 2C), 129.5 (2C), 129.4 (2C), 129.0 (2C), 127.3 (dd, J C-C-CF = 6.3 Hz, J C-C-CF = 3.7 Hz, 2C), 127.2, 126.2, 118.9 (d, J C-CF = 17.6 Hz, 2C), 117.7 (d, J C-CF = 17.6 Hz, 2C), 114.1 (2C), 70.2, 65.8, 61.0, 44.9, 41.5, 33.8. 19 F NMR (376 MHz, CDCl3) δ 131.0 (d, J FF = 18.8 Hz, 2F), 129.6 (d, J FF = 22.6 Hz, 2F). C 38 H 31 HR-APCI m / z calculated for F4N2O5 [M+H] 671.2163, found 671.2236.

[0241] [ka] N-(3,5-bis((E)-3,4-difluorobenzylidene)-4-oxocyclohexyl)-4-(2-(bis(2-ethoxyethyl)amino)ethoxy)-benzamide (JCS049) 1 H NMR (500 MHz, CDCl3) δ 7.80 (s, 2H), 7.62 (d, J = 8.8 Hz, 2H), 7.28 - 7.16 (m, 6H), 6.88 (d, J = 8.8 Hz, 2H), 6.09 (d, J = 7.3 Hz, 1H), 4.53 - 4.47 (m, 1H), 4.06 (t, J = 6.1 Hz, 2H), 3.58 - 3.41 (m, 8H), 3.25 (bd, J = 15.2 Hz, 2H), 3.14 - 3.01 (m, 4H), 2.84 (t, J = 6.1 Hz, 4H), 1.17 (t, J = 7.0 Hz, 6H). 13C NMR (126 MHz, CDCl3) δ 188.0, 166.7, 161.9, 150.7 (dd, J CF = 253.2 Hz, J C-CF = 12.6 Hz, 2C), 150.3 (dd, J CF = 249.4 Hz, J C-CF = 12.6 Hz, 2C), 137.9 (2C), 132.8 (2C), 132.2 (dd, J C-C-CF = 6.3 Hz, J C-C-CF = 3.7 Hz, 2C), 128.7 (2C), 127.1 (dd, J C-C-CF = 6.3 Hz, J C-C-CF = 3.7 Hz, 2C), 126.1, 119.0 (d, J C-CF = 17.6 Hz, 2C), 117.7 (d, J C-CF = 17.6 Hz, 2C), 114.4 (2C), 69.2, 67.0, 66.6, 55.0, 54.1, 44.6, 33.8, 15.3. 19 F NMR (376 MHz, CDCl3) δ 131.1 (d, J FF = 11.2 Hz, 2F), 129.7 (d, J FF = 30.0 Hz, 2F). C 37 H 41 HR-APCI m / z calculated for F4N2O5 [M+H] 669.2946, found 669.2922.

[0242] [ka] N-(3,5-bis((E)-3,4-difluorobenzylidene)-4-oxocyclohexyl)-4-(2-(4-(trifluoromethyl)piperidin-1-yl)ethoxy)benzamide (JCS077) 1H NMR (500 MHz, CDCl3) δ 7.79 (s, 2H), 7.63 (d, J = 8.4 Hz, 2H), 7.26 - 7.14 (m, 6H), 6.87 (d, J = 8.5 Hz, 2H), J.3 6.4 (12). - 4.46 (m, 1H), 4.11 (t, J = 5.8 Hz, 2H), 3.25 (bd, J = 15.0 Hz, 2H), 3.08 - 3.03 (m, 4H), 2.81 (t, J = 5.1), J . 2. 21 2H), 2.05 – 2.16 (m, 1H), 1.86 – 1.83 (m, 2H), 1.69 – 1.61 (m, 2H)。 13 C NMR (126 MHz, CDCl3) δ 187.9, 166.6, 161.6, 150.7 (dd, J CF = 253.4 Hz, J C-CF = 13.8 Hz, 2C), 150.3 (dd, J CF = 249.4 Hz, J C-CF = 12.6 Hz, 2C), 137.9 (2C), 132.8 (2C), 132.8, 132.2 (dd, J C-C-CF = 6.3 Hz, J C-C-CF = 5.0 Hz, 2C), 128.8, 127.2 (dd, J C-C-CF = 6.3 Hz, J C-C-CF = 3.8 Hz, 2C), 126.4, 119.0 (d, J C-CF = 17.6 Hz, 2C), 117.7 (d, J C-F = 17.6 Hz, 2C), 114.5 (2C), 66.3, 57.1, 53.0, 44.6, 40.2 (q, J C-F = 27.7 Hz, 1C), 38.7, 33.8, 24.6。 19 F NMR (376 MHz, CDCl3) δ 131.1 (d, J FF = 26.6 Hz, 2F), 129.7 (d, J FF= 26.6 Hz, 2F), -73.6 (s, 3F). C 35 H 32 HR-APCI m / z calculated for F7N2O3 [M+H] 661.2269, found 661.2295.

[0243] [ka] N-(3,5-bis((E)-3,4-difluorobenzylidene)-4-oxocyclohexyl)-4-(2-(6-ethylspiro[chroman-2,4'-piperidin]-1'-yl)ethoxy)benzamide (JCS078) 1 H NMR (500 MHz, CDCl3) δ 7.79 (s, 2H), 7.63 (d, J = 8.2 Hz, 2H), 7.29 - 7.13 (m, 6H), 6.97 - 6.83 (m, 4H), 6.75 (d, J = 8.3 Hz, 1H), 6.15 (d, J = 7.3 Hz, 1H), 4.56 - 4.42 (m, 1H), 4.13 (t, J = 5.8 Hz, 2H), 3.25 (bd, J = 15.1 Hz, 2H), 3.05 (dd, J = 14.9, 7.9 Hz, 2H), 2.85 (t, J = 5.8 Hz, 2H), 2.74 (t, J = 6.9 Hz, 4H), 2.60 - 2.52 (m, 4H), 1.85 - 1.76 (m, 4H), 1.66 (t, J = 10.5 Hz, 2H), 1.19 (t, J = 7.4 Hz, 3H). 13 C NMR (126 MHz, CDCl3) δ 187.8, 166.6, 161.6, 151.1, 150.6 (dd, J CF = 253.2 Hz, J C-CF = 13.8 Hz, 2C), 150.1 (dd, J CF = 248.2 Hz, J C-CF = 12.6 Hz, 2C), 137.7 (2C), 135.6, 132.7 (2C), 132.1 (dd, J C-C-CF= 6.3 Hz, J C-C-CF = 5.0 Hz, 2C), 128.7 (2C), 128.6, 127.1 (dd, J C-C-CF = 6.3 Hz, J C-C-CF = 3.8 Hz, 2C), 126.7, 126.1, 121.0, 118.9 (d, J C-CF = 17.6 Hz, 2C), 117.6 (d, J C-CF = 17.6 Hz, 2C), 117.0, 114.4 (2C), 71.8, 66.3, 57.1, 49.7, 44.6, 34.4, 32.1, 27.9, 21.6, 15.8. 19 F NMR (376 MHz, CDCl3) δ 131.2 (d, J FF = 26.6 Hz, 2F), 129.7 (d, J FF = 26.6 Hz, 2F). C 44 H 43 HR-APCI m / z calculated for F4N2O4 [M+H] 739.3126, found 739.3153.

[0244] [ka] N-(3,5-bis((E)-3,4-difluorobenzylidene)-4-oxocyclohexyl)-4-(2-(2-(2-(thiophen-2-yl)ethyl)piperidin-1-yl)ethoxy)benzamide (JCS079) 1H NMR (500 MHz, CDCl3) δ 7.77 (s, 2H), 7.62 (d, J = 8.8 Hz, 2H), 7.25 - 7.13 (m, 6H), 7.09 (dd, J = 5.1, 1.2 Hz, 1H), 6.89 (dd, J = 5.2, 3.4 Hz, 1H), 6.84 (d, J = 8.8 Hz, 2H), 6.77 (d, J = 3.2 Hz, 1H), 6.24 (d, J = 7.4 Hz, 1H), 4.48 - 4.40 (m, 1H), 4.05 (t, J = 6.0 Hz, 2H), 3.24 (bd, J = 15.0 Hz, 2H), 3.13 - 3.00 (m, 3H), 2.96 - 2.90 (m, 2H), 2.84 - 2.78 (m, 2H), 2.53 - 2.39 (m, 2H), 2.06 - 1.96 (m, 1H), 1.87 - 1.81 (m, 1H), 1.73 - 1.68 (m, 2H), 1.58 - 1.53 (m, 2H), 1.46 - 1.32 (m, 2H)。 13 C NMR (126 MHz, CDCl3) δ 187.9, 166.7, 160.9, 150.6 (dd, J CF = 265.8 Hz, J C-CF = 12.6 Hz, 2C), 150.1 (dd, J CF = 249.4 Hz, J C-CF = 12.6 Hz, 2C), 144.0, 137.5 (2C), 133.1 (2C), 132.3 (dd, J C-C-CF = 6.3 Hz, J C-C-CF = 3.7 Hz, 2C), 129.0, 127.2 (dd, J C-C-CF = 6.3 Hz, J C-C-CF = 3.7 Hz, 2C), 127.0, 126.8, 124.6, 123.5, 119.0 (d, J C-CF = 17.6 Hz, 2C), 117.7 (d, J C-CF= 17.6 Hz, 2C), 114.3, 64.7, 61.1, 52.4, 51.2, 45.0, 33.8, 32.4, 28.0, 26.0, 23.2, 21.9. 19 F NMR (376 MHz, CDCl3) δ -135.2 (d, J FF = 22.6 Hz, 2F), -136.6 (d, J FF = 22.6 Hz, 2F). C 40 H 39 HR-APCI m / z calculated for F4N2O3S [M+H] 703.2617, found 703.2612.

[0245] [ka] N-(3,5-bis((E)-3,4-difluorobenzylidene)-4-oxocyclohexyl)-4-(2-(4-(pyrrolidin-1-yl)piperidin-1-yl)ethoxy)benzamide (JCS080) 1 H NMR (500 MHz, CDCl3) δ 7.78 (s, 2H), 7.63 (d, J = 8.4 Hz, 2H), 7.26 - 7.16 (m, 6H), 6.87 (d, J = 8.4 Hz, 2H), 6.19 (d, J = 7.3 Hz, 1H), 4.51 - 4.45 (m, 1H), 4.09 (t, J = 5.9 Hz, 2H), 3.25 (bd, J = 15.0 Hz, 2H), 3.05 (dd, J = 15.7, 7.9 Hz, 2H), 2.97 - 2.94 (m, 2H), 2.76 (t, J = 5.9 Hz, 2H), 2.60 (t, J = 5.8 Hz, 4H), 2.13 (t, J = 11.4 Hz, 2H), 2.08 - 2.03 (m, 1H), 1.88 - 1.85 (m, 2H), 1.80 - 1.78 (m, 4H), 1.62 - 1.56 (m, 2H). 13 C NMR (126 MHz, CDCl3) δ 187.8, 166.5, 161.6, 150.6 (dd, JCF = 253.2 Hz, J C-CF = 13.8 Hz, 2C), 150.2 (dd, J CF = 249.4 Hz, J C-CF = 12.6 Hz, 2C), 137.7 (2C), 132.7 (2C), 132.1 (dd, J C-C-CF = 6.3 Hz, J C-C-CF = 5.0 Hz, 2C), 128.7 (2C), 127.0 (dd, J C-C-CF = 6.3 Hz, J C-C-CF = 3.8 Hz, 2C), 126.1, 118.9 (d, J C-CF = 17.6 Hz, 2C), 117.6 (d, J C-CF = 17.6 Hz, 2C), 114.4 (2C), 66.4, 61.6, 56.9, 53.0, 51.3, 44.5, 33.7, 29.7, 23.2. 19 F NMR (376 MHz, CDCl3) δ -135.2 (d, J FF = 18.8 Hz, 2F), -136.6 (d, J FF = 22.5 Hz, 2F). C 38 H 40 HR-APCI m / z calculated for F4N3O3 [M+H] 662.2976, found 662.3000.

[0246] [ka] 1-(2-(4-((3,5-bis((E)-3,4-difluorobenzylidene)-4-oxocyclohexyl)carbamoyl)phenoxy)ethyl)-N-(pyridin-2-ylmethyl)piperidine-4-carboxamide (JCS081) 1H NMR (500 MHz, CDCl3) δ 8.51 (d, J = 4.8 Hz, 1H), 7.78 (s, 2H), 7.66 - 7.62 (m, 3H), 7.29 - 7.14 (m, 8H), J. 6.82 ( 6.82 - = 7.3 Hz, 1H), 4.53 (d, J = 4.8 Hz, 2H), 4.52 - 4.41 (m, 1H), 4.12 (t, J = 5.7 Hz, 2H), 3.25 (bd, J = 19.0 Hz, 3. 2H), - 2.81 (t, J = 5.8 Hz, 2H), 2.31 – 2.12 (m, 3H), 2.00 – 1.76 (m, 4H)。 13 C NMR (126 MHz, CDCl3) δ 188.0, 174.8, 166.6, 161.6, 156.2, 150.7 (dd, J CF = 253.2 Hz, J C-CF = 13.8 Hz, 2C), 150.3 (dd, J CF = 243.1 Hz, J C-CF = 12.6 Hz, 2C), 149.0, 137.8 (2C), 136.92, 132.9 (2C), 132.2 (dd, J C-C-CF = 6.3 Hz, J C-C-CF = 5.0 Hz, 2C), 128.8 (2C), 127.2 (dd, J C-C-CF = 6.3 Hz, J C-C-CF = 3.8 Hz, 2C), 126.4, 122.5, 122.2, 119.0 (d, J C-CF = 17.6 Hz, 2C), 117.7 (d, J C-CF = 17.6 Hz, 2C), 114.5 (2C), 66.2, 57.2, 53.7, 44.7, 44.3, 42.9, 33.8, 28.8。 19 F NMR (376 MHz, CDCl3) δ −135.1 (d, J FF = 18.8 Hz, 2F), −136.5 (d, J FF= 22.5 Hz, 2F). C 41 H 39 HR-APCI m / z calculated for F4N4O4 [M+H] 728.2936, found 728.2901.

[0247] [ka] 1-(2-(4-((3,5-bis((E)-3,4-difluorobenzylidene)-4-oxocyclohexyl)carbamoyl)phenoxy)ethyl)piperidine-2-carboxamide (JCS083) 1 H NMR (500 MHz, CDCl3) δ 7.75 (s, 2H), 7.64 (d, J = 8.8 Hz, 2H), 7.25 - 7.15 (m, 6H), 6.81 (d, J = 8.9 Hz, 2H), 6.53 (d, J = 7.3 Hz, 1H), 5.74 (s, 2H), 4.47 - 4.42 (m, 1H), 4.15 - 4.12 (m, 2H), 3.25 (bd, J = 15.0 Hz, 2H), 3.16 (t, J = 5.0 Hz, 1H), 3.05 (dd, J = 15.0, 8.4 Hz, 2H), 2.92 - 2.56 (m, 2H), 2.16 - 1.96 (m, 2H), 1.79 - 1.60 (m, 4H), 1.36 - 1.20 (m, 2H). 13 C NMR (126 MHz, CDCl3) δ 188.0, 166.6, 151.7, 150.6 (dd, J CF = 240.6 Hz, J C-CF = 13.8 Hz, 2C), 150.2 (dd, J CF = 249.4 Hz, J C-CF = 12.6 Hz, 2C), 137.7 (2C), 133.0 (2C), 133.00, 132.2 (dd, J C-C-CF = 6.3 Hz, J C-C-CF = 5.0 Hz, 2C), 129.0 (2C), 127.2 (dd, J C-C-CF= 6.3 Hz, J C-C-CF = 3.8 Hz, 2C), 126.7, 118.9 (d, J C-CF = 17.6 Hz, 2C), 117.7 (d, J C-CF = 17.6 Hz, 2C), 114.2 (2C), 68.0, 65.4, 55.5, 52.6, 44.8, 33.8, 30.4, 24.8, 23.3. 19 F NMR (376 MHz, CDCl3) δ -135.1 (d, J FF = 18.8 Hz, 2F), -136.5 (d, J FF = 22.5 Hz, 2F). C 35 H 34 HR-APCI m / z calculated for F4N3O4 [M+H] 636.2558, found 636.2479.

[0248] [ka] tert-Butyl 3-(4-((3,5-bis((E)-3,4-difluorobenzylidene)-4-oxocyclohexyl)carbamoyl)phenoxy)azetidine-1-carboxylate (JCS084) 1 H NMR (500 MHz, CDCl3) δ 7.78 (s, 2H), 7.63 (d, J = 8.3 Hz, 2H), 7.31 - 7.09 (m, 6H), 6.71 (d, J = 8.3 Hz, 2H), 6.21 (d, J = 7.1 Hz, 1H), 4.88 - 4.86 (m, 1H),4.53 - 4.42 (m, 1H), 4.28 (d, J = 5.2 Hz, 2H), 3.96 (d, J = 5.8 Hz, 2H), 3.24 (bd, J = 15.1 Hz, 2H), 3.05 (dd, J = 14.0, 7.9 Hz, 2H), 1.43 (s, 9H). 13 C NMR (126 MHz, CDCl3) δ 187.9, 166.4, 159.4, 156.1, 150.7 (dd, J CF= 254.5 Hz, J C-CF = 13.8 Hz, 2C), 150.3 (dd, J CF = 249.4 Hz, J C-CF = 12.6 Hz, 2C), 137.9 (2C), 132.7 (2C), 132.2 (dd, J C-C-CF = 6.3 Hz, J C-C-CF = 5.0 Hz, 2C), 129.1 (2C), 127.2 (dd, J C-C-CF = 6.3 Hz, J C-C-CF = 3.8 Hz, 2C), 127.1, 119.0 (d, J C-CF = 17.6 Hz, 2C), 117.7 (d, J C-CF = 17.6 Hz, 2C), 114.5 (2C), 80.1, 66.0, 56.2, 44.7, 33.8, 28.4. 19 F NMR (376 MHz, CDCl3) δ -135.1 (d, J FF = 18.8 Hz, 2F), -136.5 (d, J FF = 22.5 Hz, 2F). C 35 H 33 HR-APCI m / z calculated for F4N2O5 [M+H] 637.2263, found 637.2320.

[0249] [ka] N-(3,5-bis((E)-3,5-dichlorobenzylidene)-4-oxocyclohexyl)-4-(2-(piperidin-1-yl)ethoxy)benzamide (JCS061) 1H NMR (500 MHz, CDCl3) δ 7.68 (s, 2H), 7.64 (d, J = 8.8 Hz, 2H), 7.34 - 7.31 (m, 2H), 7.23 - 7.21 (m, 4H), 6.87 (d, J = 8.8 Hz, 2H), 6.27 (d, J = 7.3 Hz, 1H), 4.54 - 4.46 (m, 1H), 4.10 (t, J = 6.0 Hz, 2H), 3.20 (bd, J = 16.2 Hz, 2H), 3.06 (dd, J = 16.4, 8.4 Hz, 2H), 2.75 (t, J = 6.0 Hz, 2H), 2.48 (t, J = 5.3 Hz, 4H), 1.59 (p, J = 5.6 Hz, 4H), 1.46 - 1.40 (m, 2H). 13 C NMR (126 MHz, CDCl3) δ 187.6, 166.7, 161.8, 137.9 (2C), 137.4 (2C), 135.3, 134.2 (2C), 129.1 (2C), 128.8 (2C), 128.2, 126.1 (2C), 114.5, 66.3, 57.8, 55.2, 44.4, 33.7, 26.0, 24.2. C 34 H 33 HR-APCI m / z calculated for Cl4N2O3 [M+H] 657.1239, found 657.1222.

[0250] [ka] N-(3,5-bis((E)-3,5-dichlorobenzylidene)-4-oxocyclohexyl)-4-(2-(dipropylamino)ethoxy)benzamide (JCS062) 1H NMR (500 MHz, CDCl3) δ 7.68 (s, 2H), 7.64 (d, J = 8.8 Hz, 2H), 7.32 - 7.31 (m, 2H), 7.23 - 7.22 (m, 4H), 6.87 (d, J = 8.8 Hz, 2H), 6.27 (d, J = 7.3 Hz, 1H), 4.54 - 4.47 (m, 1H), 4.02 (t, J = 6.3 Hz, 2H), 3.20 (bd, J = 15.4 Hz, 2H), 3.07 (dd, J = 15.3, 7.4 Hz, 2H), 2.84 (t, J = 6.2 Hz, 2H), 2.52 - 2.40 (m, 4H), 1.54 - 1.40 (m, 4H), 0.87 (t, J = 7.3 Hz, 6H). 13 C NMR (126 MHz, CDCl3) δ 187.6, 166.7, 161.9, 137.9 (2C), 137.4 (2C), 135.3, 134.2 (2C), 129.1(2C), 128.8 (2C), 128.2, 126.0 (2C), 114.47, 67.0, 57.1, 52.8, 44.4, 33.7, 20.5, 11.9. C 35 H 37 HR-APCI m / z calculated for Cl4N2O3 [M+H] 673.1552, found 673.1532.

[0251] [ka] N-(3,5-bis((E)-3,5-dichlorobenzylidene)-4-oxocyclohexyl)-4-(2-(pyrrolidin-1-yl)ethoxy)benzamide (JCS064) 1H NMR (500 MHz, CDCl3) δ 7.73 (s, 2H), 7.63 (d, J = 8.3 Hz, 2H), 7.36 - 7.32 (m, 2H), 7.27 - 7.24 (m, 4H), 6.90 (d, J = 8.6 Hz, 2H), 6.11 (d, J = 7.5 Hz, 1H), 4.53 - 4.48 (m, 1H), 4.11 (t, J = 6.0 Hz, 2H), 3.21 (bd, J = 15.7 Hz, 2H), 3.06 (dd, J = 15.7, 7.9 Hz, 2H), 2.89 (t, J = 5.9 Hz, 2H), 2.60 (t, J = 5.0 Hz, 4H), 1.80 (t, J = 5.0 Hz, 6H). 13 C NMR (126 MHz, CDCl3) δ 187.6, 166.7, 161.9, 138.0 (2C), 137.5 (2C), 135.4, 134.2 (2C), 129.1 (2C), 128.8 (2C), 128.3, 126.2 (2C), 114.5, 67.4, 55.0, 54.9, 44.4, 33.8, 23.6. C 33 H 31 HR-APCI m / z calculated for Cl4N2O3 [M+H] 643.1083, found 643.1065.

[0252] [ka] N-(3,5-bis((E)-3,5-dichlorobenzylidene)-4-oxocyclohexyl)-4-(2-(bis(2-methoxyethyl)amino)ethoxy)-benzamide (JCS068) 1H NMR (500 MHz, CDCl3) δ 7.75 (s, 2H), 7.62 (d, J = 8.3 Hz, 2H), 7.37 - 7.33 (m, 2H), 7.27 - 7.26 (m, 4H), 6.89 (d, J = 8.6 Hz, 2H), 6.03 (d, J = 7.3 Hz, 1H), 4.55 - 4.48 (m, 1H), 4.07 (t, J = 6.1 Hz, 2H), 3.48 (t, J = 5.8 Hz, 4H), 3.33 (s, 6H), 3.22 (bd, J = 15.9 Hz, 2H), 3.10 - 3.00 (m, 4H), 2.83 (t, J = 5.9 Hz, 4H). 13 C NMR (126 MHz, CDCl3) δ 187.5, 166.5, 161.7, 137.8 (2C), 137.4 (2C), 135.2, 134.0 (2C), 129.0 (2C), 128.7 (2C), 128.1, 126.0 (2C), 114.3, 71.2, 66.8, 58.8, 54.7, 53.8, 44.3, 33.7. C 35 H 37 HR-APCI m / z calculated for Cl4N2O5 [M+H] 707.1451, found 707.1435.

[0253] [ka] N-(3,5-bis((E)-3,4-difluorobenzylidene)-4-oxocyclohexyl)-4'-(2-(diethylamino)ethoxy)-[1,1'-biphenyl]-4-carboxamide (JCS095) 1H NMR (500 MHz, CDCl3) δ 7.81 (s, 2H), 7.73 (d, J = 8.3 Hz, 2H), 7.56 (d, J = 8.2 Hz, 2H), 7.50 (d, J = 8.9 Hz, 2H), 7.2H ( m , 7.2). (d, J = 8.7 Hz, 2H), 6.30 (d, J = 7.3 Hz, 1H), 4.56 - 4.50 (m, 1H), 4.17 (t, J = 6.0 Hz, 2H), 3.28 (br d, J = 101 = 15.2 Hz), 8.1 Hz, 2H), 3.02 (t, J = 5.4 Hz, 2H), 2.78 (q, J = 7.0 Hz, 4H), 1.15 (t, J = 7.1 Hz, 6H)。 13 C NMR (126 MHz, CDCl3) δ 187.8, 166.8, 158.8, 150.6 (dd, J CF = 253.2 Hz, J C-CF = 12.6 Hz, 2C), 150.2 (dd, J CF = 249.4 Hz, J C-CF = 12.6 Hz, 2C), 144.2, 137.9 (2C), 132.6 (2C), 132.2, 132.1 (dd, J C-C-CF = 5.0 Hz, J C-C-CF = 3.7 Hz, 2C), 131.8, 128.2 (2C), 127.4 (2C), 127.0 (dd, J C-C-CF = 7.5 Hz, J C-C-CF = 3.7 Hz, 2C), 126.7 (2C), 118.9 (d, J C-CF = 17.6 Hz, 2C), 117.6 (d, J C-CF = 17.6 Hz, 2C), 114.9 (2C), 66.2, 51.5, 47.7, 44.6, 33.7, 11.4。 19 F NMR (376 MHz, CDCl3) δ −135.0 (d, J FF= 18.8 Hz, 2F), -136.4 (d, J FF = 22.5 Hz, 2F). C 39 H 37 HR-APCI m / z calculated for F4N2O3 [M+H] 657.2695, found 657.2734.

[0254] [ka] N-(3,5-bis((E)-3,4-difluorobenzylidene)-4-oxocyclohexyl)-4'-(2-(piperidin-1-yl)ethoxy)-[1,1'-biphenyl]-4-carboxamide (JCS096) 1 H NMR (500 MHz, CDCl3) δ 7.82 (s, 2H), 7.72 (d, J = 8.4 Hz, 2H), 7.57 (d, J = 8.4 Hz, 2H), 7.51 (d, J = 8.7 Hz, 2H), 7.28 - 7.19 (m, 6H), 6.98 (d, J = 8.7 Hz, 2H), 6.21 (d, J = 7.3 Hz, 1H), 4.56 - 4.52 (m, 1H), 4.25 (t, J = 6.0 Hz, 2H), 3.28 (br d, J = 17.5 Hz, 2H), 3.10 (t, J = 5.4 Hz, 2H), 2.74 - 2.59 (m, 4H), 1.72 - 1.70 (m, 4H), 1.55 - 1.46 (m, 2H). 13 C NMR (126 MHz, CDCl3) δ 187.8, 166.8, 158.8, 150.6 (dd, J CF = 253.2 Hz, J C-CF = 12.6 Hz, 2C), 150.2 (dd, J CF = 249.4 Hz, J C-CF = 12.6 Hz, 2C), 144.1, 137.9 (2C), 132.6 (2C), 132.2, 132.0 (dd, J C-C-CF = 5.0 Hz, JC-C-CF = 3.7 Hz, 2C), 131.8, 128.2 (2C), 127.4 (2C), 127.0 (dd, J C-C-CF = 7.5 Hz, J C-C-CF = 3.7 Hz, 2C), 126.7 (2C), 118.9 (d, J C-CF = 17.6 Hz, 2C), 117.6 (d, J C-CF = 17.6 Hz, 2C), 115.0 (2C), 65.6, 57.6, 54.9, 44.6, 33.7, 25.5, 23.8. 19 F NMR (376 MHz, CDCl3) δ -135.0 (d, J FF = 18.8 Hz, 2F), -136.4 (d, J FF = 22.5 Hz, 2F). C 40 H 37 HR-APCI m / z calculated for F4N2O3 [M+H] 669.2670, found 669.2734.

[0255] [ka] N-(3,5-bis((E)-3,4-difluorobenzylidene)-4-oxocyclohexyl)-6-(2-(piperidin-1-yl)ethoxy)-2-naphtha-amide (JCS097) 1H NMR (500 MHz, CDCl3) δ 8.13 (s, 1H), 7.78 (s, 2H), 7.74 (d, J = 9.0 Hz, 1H), 7.69 (s, 2H), 7.28 - 7.13 (m, 7 2H (d), 7. 6.50 (d, J = 7.3 Hz, 1H), 4.57 - 4.49 (m, 1H), 4.26 (t, J = 5.8 Hz, 2H), 3.29 (br d, J = 15.4 Hz, 2H), 3.19 (dd, J = 1 = 1H), 3.9. (t, J = 5.8 Hz, 2H), 2.64 (t, J = 5.2 Hz, 4H), 1.70 – 1.65 (m, 4H), 1.50 – 1.44 (m, 2H)。 13 C NMR (126 MHz, CDCl3) δ 187.9, 167.3, 158.2, 150.7 (dd, J CF = 253.2 Hz, J C-CF = 12.6 Hz, 2C), 150.3 (dd, J CF = 249.4 Hz, J C-CF = 12.6 Hz, 2C), 137.9 (2C), 136.4, 132.9 (2C), 132.2 (dd, J C-C-CF = 5.0 Hz, J C-C-CF = 3.7 Hz, 2C), 130.5, 129.0, 128.0, 127.5, 127.3, 127.2 (dd, J C-C-CF = 7.5 Hz, J C-C-CF = 3.7 Hz, 2C), 124.1, 120.1, 119.1 (d, J C-CF = 17.6 Hz, 2C), 117.7 (d, J C-CF = 17.6 Hz, 2C), 106.6, 77.4, 65.7, 57.7, 55.0, 33.8, 25.5, 23.9。 19 F NMR (376 MHz, CDCl3) δ −135.0 (d, J FF= 18.8 Hz, 2F), -136.5 (d, J FF = 22.5 Hz, 2F). C 38 H 35 HR-APCI m / z calculated for F4N2O3 [M+H] 643.2545, found 643.2578.

[0256] [ka] N-(3,5-bis((E)-3,4-difluorobenzylidene)-4-oxocyclohexyl)-6-(2-(diethylamino)ethoxy)-2-naphthamide (JCS098) 1 H NMR (500 MHz, CDCl3) δ 8.13 (s, 1H), 7.75 (s, 2H), 7.73 - 7.64 (m, 3H), 7.27 - 7.08 (m, 8H), 6.62 (d, J = 7.3 Hz, 1H), 4.55 - 4.48 (m, 1H), 4.18 (t, J = 6.0 Hz, 2H), 3.26 (br d, J = 15.4 Hz, 2H), 3.07 (dd, J = 16.3, 7.8 Hz, 2H), 2.97 (t, J = 6.0 Hz, 2H), 2.71 (q, J = 7.1 Hz, 4H), 1.11 (t, J = 7.2 Hz, 6H). 13 C NMR (126 MHz, CDCl3) δ 187.9, 167.3, 158.3, 150.7 (dd, J CF = 253.2 Hz, J C-CF = 12.6 Hz, 2C), 150.3 (dd, J CF = 249.4 Hz, J C-CF = 12.6 Hz, 2C), 137.8 (2C), 136.3, 132.9 (2C), 132.2 (dd, J C-C-CF = 5.0 Hz, J C-C-CF= 3.7 Hz, 2C), 130.4, 129.0, 127.9, 127.5, 127.2, 127.1 (dd, J C-C-CF = 7.5 Hz, J C-C-CF = 3.7 Hz, 2C), 124.1, 120.1, 118.9 (d, J C-CF = 17.6 Hz, 2C), 117.7 (d, J C-CF = 17.6 Hz, 2C), 106.5, 66.4, 51.5, 47.9, 44.9, 33.8, 11.5. 19 F NMR (376 MHz, CDCl3) δ -135.0 (d, J FF = 18.8 Hz, 2F), -136.5 (d, J FF = 22.5 Hz, 2F). C 37 H 35 HR-APCI m / z calculated for F4N2O3 [M+H] 631.2536, found 631.2573.

[0257] [ka] N-(3,5-bis((E)-3,4-difluorobenzylidene)-4-oxocyclohexyl)-3-(2-(diethylamino)ethoxy)benzamide (JCS099) 1 H NMR (500 MHz, CDCl3) δ 7.78 (s, 2H), 7.33 - 7.16 (m, 9H), 7.04 - 6.97 (m, 1H), 6.41 (d, J = 7.4 Hz, 1H), 4.51 - 4.44 (m, 1H), 4.10 (t, J = 6.1 Hz, 2H), 3.26 (br d, J = 15.2 Hz, 2H), 3.06 (dd, J = 15.8, 8.6 Hz, 2H), 2.89 (t, J = 6.1 Hz, 2H), 2.67 (q, J = 7.2 Hz, 4H), 1.08 (t, J = 7.2 Hz, 7H). 13C NMR (126 MHz, CDCl3) δ 187.7, 166.8, 158.9, 150.6 (dd, J CF = 253.2 Hz, J C-CF = 12.6 Hz, 2C), 150.2 (dd, J CF = 249.4 Hz, J C-CF = 12.6 Hz, 2C), 137.7 (2C), 135.3, 132.7 (2C), 132.1 (dd, J C-C-CF = 5.0 Hz, J C-C-CF = 3.7 Hz, 2C), 129.6, 127.0 (dd, J C-C-CF = 7.5 Hz, J C-C-CF = 3.7 Hz, 2C), 119.0, 118.9 (d, J C-CF = 17.6 Hz, 2C), 118.3, 117.6 (d, J C-CF = 17.6 Hz, 2C), 113.0, 66.3, 51.5, 47.7, 44.7, 33.7, 11.4. 19 F NMR (376 MHz, CDCl3) δ -135.1 (d, J FF = 18.8 Hz, 2F), -136.5 (d, J FF = 22.5 Hz, 2F). C 33 H 33 HR-APCI m / z calculated for F4N2O3 [M+H] 581.2422, found 581.2421.

[0258] [ka] N-(3,5-bis((E)-3,4-difluorobenzylidene)-4-oxocyclohexyl)-3-(2-(piperidin-1-yl)ethoxy)benzamide (JCS100) 1H NMR (500 MHz, CDCl3) δ 7.78 (s, 2H), 7.33 - 7.17 (m, 9H), 7.02 - 7.00 (m, 1H), 6.40 (d, J = 7.4 Hz, 1H), J 4.41 ( , 4.164), ( m = 6.0 Hz, 2H), 3.26 (br d, J = 14.6 Hz, 2H), 3.06 (dd, J = 15.8, 8.7 Hz, 2H), 2.81 (t, J = 6.1 Hz, 2H), 2.56 (H1-9), J = 1.4. (m, 4H), 1.49 - 1.43 (m, 2H)。 13 C NMR (126 MHz, CDCl3) δ 187.7, 166.7, 158.8, 150.6 (dd, J CF = 253.2 Hz, J C-CF = 12.6 Hz, 2C), 150.2 (dd, J CF = 249.4 Hz, J C-CF = 12.6 Hz, 2C), 137.7 (2C), 135.3, 132.7 (2C), 132.1 (dd, J C-C-CF = 5.0 Hz, J C-C-CF = 3.7 Hz, 2C), 129.6, 127.0 (dd, J C-C-CF = 7.5 Hz, J C-C-CF = 3.7 Hz, 2C), 119.0, 118.9 (d, J C-CF = 17.6 Hz, 2C), 118.3, 117.6 (d, J C-CF = 17.6 Hz, 2C), 113.1, 65.7, 57.6, 55.0, 44.8, 33.7, 25.5, 23.9。 19 F NMR (376 MHz, CDCl3) δ −135.1 (d, J FF = 18.8 Hz, 2F), −136.5 (d, J FF = 22.5 Hz, 2F)。 C 34 H 33HR-APCI m / z calculated for F4N2O3 [M+H] 593.2455, found 593.2421.

[0259] [ka] 3-(Benzyloxy)-N-(3,5-bis((E)-3,4-difluorobenzylidene)-4-oxocyclohexyl)-4-(2-(diethylamino)ethoxy)-benzamide (JCS101) 1 H NMR (500 MHz, CDCl3) δ 7.78 (s, 2H), 7.41 - 7.14 (m, 13H), 6.84 (d, J = 8.4 Hz, 1H), 6.19 (d, J = 7.3 Hz, 1H), 5.13 (s, 2H), 4.51 - 4.44 (m, 1H), 4.11 (t, J = 6.3 Hz, 2H), 3.25 (br d, J = 14.1 Hz, 2H), 3.04 (dd, J = 15.8, 8.3 Hz, 2H), 2.91 (t, J = 6.2 Hz, 2H), 2.62 (q, J = 7.2 Hz, 4H), 1.03 (t, J = 7.1 Hz, 6H). 13 C NMR (126 MHz, CDCl3) δ 187.7, 166.6, 151.6, 150.7 (dd, J CF = 211.6 Hz, J C-CF = 11.3 Hz, 2C), 150.2 (dd, J CF = 219.2 Hz, J C-CF = 10.0 Hz, 2C), 137.9 (2C), 136.5, 132.8 (2C), 132.2 (dd, J C-C-CF = 5.0 Hz, J C-C-CF = 3.7 Hz, 2C), 128.6 (2C), 128.1, 127.3 (2C), 127.1 (dd, J C-C-CF = 7.5 Hz, J C-C-CF = 3.7 Hz, 2C), 119.7, 119.0 (d, J C-CF= 17.6 Hz, 2C), 117.7 (d, J C-CF = 17.6 Hz, 2C), 113.2, 112.7, 70.9, 66.3, 51.5, 47.7, 44.7, 33.7, 11.4. 19 F NMR (376 MHz, CDCl3) δ -135.0 (d, J FF = 18.8 Hz, 2F), -136.5 (d, J FF = 22.5 Hz, 2F). C 40 H 39 HR-APCI m / z calculated for F4N2O4 [M+H] 687.2863, found 687.2840.

[0260] [ka] 3-(benzyloxy)-N-(3,5-bis((E)-3,4-difluorobenzylidene)-4-oxocyclohexyl)-4-(2-(piperidin-1-yl)ethoxy)benzamide (JCS102) 1 H NMR (500 MHz, CDCl3) δ 7.78 (s, 2H), 7.42 - 7.15 (m, 13H), 6.84 (d, J = 8.4 Hz, 1H), 6.20 (d, J = 7.3 Hz, 1H), 5.14 (s, 2H), 4.51 - 4.44 (m, 1H), 4.18 (t, J = 6.1 Hz, 2H), 3.25 (br d, J = 15.3 Hz, 2H), 3.04 (dd, J = 15.5, 8.4 Hz, 2H), 2.11 (t, J = 6.2 Hz, 2H), 2.59 - 2.47 (m, 4H), 1.60 - 1.56 (m, 4H), 1.45 - 1.40 (m, 2H). 13 C NMR (126 MHz, CDCl3) δ 187.9, 166.6, 151.7, 150.7 (dd, J CF = 211.6 Hz, J C-CF= 11.3 Hz, 2C), 150.2 (dd, J CF = 219.2 Hz, J C-CF = 10.0 Hz, 2C), 149.0, 137.8 (2C), 136.6, 132.8 (2C), 132.2 (dd, J C-C-CF = 5.0 Hz, J C-C-CF = 3.7 Hz, 2C), 128.6 (2C), 128.1, 127.3 (2C), 127.2 (dd, J C-C-CF = 7.5 Hz, J C-C-CF = 3.7 Hz, 2C), 127.1, 119.9, 119.0 (d, J C-CF = 17.6 Hz, 2C), 117.7 (d, J C-CF = 17.6 Hz, 2C), 113.4, 113.1, 70.9, 67.5, 57.8, 55.1, 44.8, 33.8, 26.0, 24.2. 19 F NMR (376 MHz, CDCl3) δ -135.0 (d, J FF = 18.8 Hz, 2F), -136.5 (d, J FF = 22.5 Hz, 2F). C 41 H 39 HR-APCI m / z calculated for F4N2O4 [M+H] 699.2863, found 699.2840.

[0261] [ka] 3-Acetyl-N-(3,5-bis((E)-3,4-difluorobenzylidene)-4-oxocyclohexyl)-4-(2-(piperidin-1-yl)ethoxy)-benzamide (JCS103) 1H NMR (500 MHz, CDCl3) δ 8.16 − 8.04 (m, 2H), 7.85 (s, 2H), 7.37 − 7.20 (m, 6H), 7.08 (d, J = 8.1 Hz, 1H), − 4.5 = 1.7 (d 4.44 (m, 1H), 4.30 (t, J = 6.0 Hz, 2H), 3.38 (br d, J = 15.7 Hz, 2H), 3.08 (dd, J = 16.4, 9.4 Hz, 2H), 2.89 (Hs, J = 2.3, 6.2). 2.62 – 2.48 (m, 4H), 1.69 – 1.64 (m, 4H), 1.55 – 1.50 (m, 2H)。 13 C NMR (126 MHz, CDCl3) δ 199.2, 187.8, 165.7, 160.9, 150.7 (dd, J CF = 211.6 Hz, J C-CF = 11.3 Hz, 2C), 150.2 (dd, J CF = 219.2 Hz, J C-CF = 10.0 Hz, 2C), 137.6 (2C), 134.0, 133.0 (2C), 132.2 (dd, J C-C-CF = 5.0 Hz, J C-C-CF = 3.7 Hz, 2C), 128.3, 127.5, 127.1 (dd, J C-C-CF = 7.5 Hz, J C-C-CF = 3.7 Hz, 2C), 126.1, 119.0 (d, J C-CF = 17.6 Hz, 2C), 117.7 (d, J C-CF = 17.6 Hz, 2C), 112.9, 67.1, 57.6, 55.1, 45.1, 34.0, 32.1, 26.0, 24.2。 19 F NMR (376 MHz, CDCl3) δ −135.1 (d, J FF = 18.8 Hz, 2F), −136.4 (d, J FF= 22.5 Hz, 2F). C 36 H 35 HR-APCI m / z calculated for F4N2O4 [M+H] 635.2540, found 635.2527.

[0262] [ka] 3-Acetyl-N-(3,5-bis((E)-3,4-difluorobenzylidene)-4-oxocyclohexyl)-4-(2-(diethylamino)ethoxy)-benzamide (JCS104) 1 H NMR (500 MHz, CDCl3) δ 8.03 - 7.93 (m, 2H), 7.73 (s, 2H), 7.26 - 7.13 (m, 6H), 6.96 (d, J = 8.8 Hz, 1H), 6.71 (d, J = 7.3 Hz, 1H), 4.51 - 4.39 (m, 1H), 4.17 (t, J = 6.3 Hz, 2H), 3.27 (br d, J = 15.5 Hz, 2H), 3.03 - 2.96 (m, 2H), 2.93 (t, J = 6.2 Hz, 2H), 2.64 (q, J = 7.2 Hz, 4H), 2.59 (s, 3H), 1.04 (t, J = 7.1 Hz, 6H). 13 C NMR (126 MHz, CDCl3) δ 199.0, 187.7, 165.6, 160.6, 150.7 (dd, J CF = 211.6 Hz, J C-CF = 11.3 Hz, 2C), 150.2 (dd, J CF = 219.2 Hz, J C-CF = 10.0 Hz, 2C), 137.4 (2C), 133.8, 133.0 (2C), 132.1 (dd, J C-C-CF = 5.0 Hz, J C-C-CF = 3.7 Hz, 2C), 128.4, 127.4, 127.0 (dd, J C-C-CF = 7.5 Hz, JC-C-CF = 3.7 Hz, 2C), 126.1, 118.9 (d, J C-CF = 17.6 Hz, 2C), 117.6 (d, J C-CF = 17.6 Hz, 2C), 112.8, 67.4, 51.7, 47.6, 45.0, 33.8, 31.9, 11.6. 19 F NMR (376 MHz, CDCl3) δ -135.2 (d, J FF = 18.8 Hz, 2F), -136.5 (d, J FF = 22.5 Hz, 2F). C 35 H 35 HR-APCI m / z calculated for F4N2O4 [M+H] 623.2545, found 623.2527.

[0263] [ka] N-(3,5-bis((E)-3,4-difluorobenzylidene)-4-oxocyclohexyl)-3-nitro-4-(2-(piperidin-1-yl)ethoxy)benzamide (JCS105) 1 H NMR (500 MHz, CDCl3) δ 8.19 (s, 1H), 7.96 (d, J = 8.8 Hz, 1H), 7.75 (s, 2H), 7.29 - 7.15 (m, 6H), 7.08 (d, J = 8.9 Hz, 1H), 6.72 (d, J = 7.3 Hz, 1H), 4.51 - 4.44 (m, 1H), 4.27 (t, J = 5.8 Hz, 2H), 3.29 (br d, J = 15.1 Hz, 2H), 3.05 (dd, J = 16.3, 8.4 Hz, 2H), 2.85 (t, J = 5.8 Hz, 2H), 2.55 (t, J = 5.4 Hz, 4H), 1.61 - 1.56 (m, 4H), 1.55 - 1.50 (m, 2H). 13C NMR (126 MHz, CDCl3) δ 187.8, 164.5, 154.7, 150.7 (dd, J CF = 254.5 Hz, J C-CF = 12.6 Hz, 2C), 150.2 (dd, J CF = 249.4 Hz, J C-CF = 12.6 Hz, 2C), 139.0, 137.9 (2C), 133.6, 132.7 (2C), 132.1 (dd, J C-C-CF = 5.0 Hz, J C-C-CF = 3.7 Hz, 2C), 127.2 (dd, J C-C-CF = 7.5 Hz, J C-C-CF = 3.7 Hz, 2C), 126.1, 124.4, 118.9 (d, J C-CF = 17.6 Hz, 2C), 117.7 (d, J C-CF = 17.6 Hz, 2C), 114.6, 68.5, 57.2, 55.2, 45.2, 33.7, 25.8, 23.9. 19 F NMR (376 MHz, CDCl3) δ -134.9 (d, J FF = 18.8 Hz, 2F), -136.4 (d, J FF = 22.5 Hz, 2F). C 34 H 32 HR-APCI m / z calculated for F4N3O5 [M+H] 638.2268, found 638.2272.

[0264] [ka] N-(3,5-bis((E)-3,4-difluorobenzylidene)-4-oxocyclohexyl)-4-(2-(diethylamino)ethoxy)-3-nitrobenzamide (JCS106) 1H NMR (500 MHz, CDCl3) δ 8.18 (s, 1H), 7.95 (d, J = 8.0 Hz, 1H), 7.76 (s, 2H), 7.29 - 7.15 (m, 6H), 7.08 (d, J 6, = 81.7), Hz, 1H), 4.49 - 4.43 (m, 1H), 4.21 (t, J = 5.8 Hz, 2H), 3.29 (br d, J = 16.0 Hz, 2H), 3.05 (dd, J = 15.5, 7.7 (J, 2. Hz), 9 2H), 2.66 (q, J = 7.2 Hz, 4H), 1.04 (t, J = 7.1 Hz, 6H)。 13 C NMR (126 MHz, CDCl3) δ 187.8, 164.5, 154.8, 150.7 (dd, J CF = 254.5 Hz, J C-CF = 12.6 Hz, 2C), 150.2 (dd, J CF = 249.4 Hz, J C-CF = 12.6 Hz, 2C), 139.0, 137.9 (2C), 133.6, 132.7 (2C), 132.2 (dd, J C-C-CF = 5.0 Hz, J C-C-CF = 3.7 Hz, 2C), 127.2 (dd, J C-C-CF = 7.5 Hz, J C-C-CF = 3.7 Hz, 2C), 126.1, 124.4, 119.0 (d, J C-CF = 17.6 Hz, 2C), 117.8 (d, J C-CF = 17.6 Hz, 2C), 114.5, 69.1, 51.3, 48.1, 45.3, 33.8, 11.7。 19 F NMR (376 MHz, CDCl3) δ −134.9 (d, J FF = 18.8 Hz, 2F), −136.4 (d, J FF = 22.5 Hz, 2F)。 C33 H 32 HR-APCI m / z calculated for F4N3O5 [M+H] 626.2270, found 626.2272.

[0265] [ka] N-(3,5-bis((E)-3,4-difluorobenzylidene)-4-oxocyclohexyl)-4-(2-(bis(2-hydroxyethyl)amino)ethoxy)-benzamide (JCS107) 1 H NMR (500 MHz, CDCl3) δ 7.74 (s, 2H), 7.61 (d, J = 8.9 Hz, 2H), 7.23 - 7.11 (m, 6H), 6.82 (d, J = 8.8 Hz, 2H), 6.51 (d, J = 7.3 Hz, 1H), 4.46 - 4.39 (m, 1H), 4.02 (t, J = 5.4 Hz, 2H), 3.59 (t, J = 5.2 Hz, 4H), 3.23 (br d, J = 15.2 Hz, 2H), 3.01 (dd, J = 16.5, 8.0 Hz, 2H), 2.96 (t, J = 5.4 Hz, 2H), 2.75 (t, J = 5.2 Hz, 4H). 13 C NMR (126 MHz, CDCl3) δ 188.0, 166.7, 161.3, 150.6 (dd, J CF = 240.6 Hz, J C-CF = 12.6 Hz, 2C), 150.2 (dd, J CF = 236.8 Hz, J C-CF = 12.6 Hz, 2C), 137.7 (2C), 132.9 (2C), 132.2 (dd, J C-C-CF = 5.0 Hz, J C-C-CF = 3.7 Hz, 2C), 128.9 (2C), 127.2 (dd, J C-C-CF = 7.5 Hz, J C-C-CF = 3.7 Hz, 2C), 126.6, 118.9 (d, JC-CF = 17.6 Hz, 2C), 117.7 (d, J C-CF = 17.6 Hz, 2C), 114.3 (2C), 66.6, 59.7, 57.0, 53.5, 44.8, 33.8. 19 F NMR (376 MHz, CDCl3) δ -135.0 (d, J FF = 18.8 Hz, 2F), -136.5 (d, J FF = 22.5 Hz, 2F). C 33 H 33 HR-APCI m / z calculated for F4N2O5 [M+H] 613.2318, found 613.2320.

[0266] [ka] N-(3,5-bis((E)-3,4-difluorobenzylidene)-4-oxocyclohexyl)-4-(2-((2-methoxyethyl)(2-phenoxyethyl)amino)ethoxy)benzamide (JCS108) 1 H NMR (500 MHz, CDCl3) δ 7.82 (s, 2H), 7.64 (d, J = 8.7 Hz, 2H), 7.30 - 7.19 (m, 8H), 6.97 - 6.88 (m, 5H), 6.16 (d, J = 7.3 Hz, 1H), 4.54 - 4.49 (m, 1H), 4.10 - 4.08 (m, 4H), 3.53 (t, J = 5.7 Hz, 2H), 3.36 (s, 3H), 3.28 (br d, J = 14.0 Hz, 2H), 3.10 - 3.06 (m, 6H), 2.93 (t, J = 5.7 Hz, 2H). 13 C NMR (126 MHz, CDCl3) δ 187.9, 166.6, 161.8, 158.8, 150.7 (dd, J CF = 211.6 Hz, J C-CF = 12.6 Hz, 2C), 150.2 (dd, J CF = 219.8 Hz, J C-CF= 12.6 Hz, 2C), 137.9 (2C), 132.8 (2C), 132.2 (dd, J C-C-CF = 5.0 Hz, J C-C-CF = 3.7 Hz, 2C), 129.5 (2C), 128.8 (2C), 127.1 (dd, J C-C-CF = 7.5 Hz, J C-C-CF = 3.7 Hz, 2C), 126.2, 120.8, 119.0 (d, J C-CF = 17.6 Hz, 2C), 117.7 (d, J C-CF = 17.6 Hz, 2C), 114.6 (2C), 114.4 (2C), 71.4, 67.1, 66.6, 59.0, 55.0, 54.3, 54.1, 44.6, 33.8. 19 F NMR (376 MHz, CDCl3) δ -131.2 (d, J FF = 18.8 Hz, 2F), -132.6 (d, J FF = 22.5 Hz, 2F). C 40 H 39 HR-APCI m / z calculated for F4N2O5 [M+H] 703.2819, found 703.2789.

[0267] [ka] N-(3,5-bis((E)-3,4-difluorobenzylidene)-4-oxocyclohexyl)-4-(2-(ethyl(2-methoxyethyl)amino)ethoxy)benzamide (JCS109) 1H NMR (500 MHz, CDCl3) δ 7.79 (s, 2H), 7.65 (d, J = 8.5 Hz, 2H), 7.32 - 7.14 (m, 6H), 6.89 (d, J = 8.5 Hz, 2H), 6.3 H 6.4 (23). - 4.49 (m, 1H), 4.07 (t, J = 6.1 Hz, 2H), 3.49 (t, J = 5.8 Hz, 2H), 3.35 (s, 3H), 3.26 (d, J = 14.5 Hz, 2H, 5, J = 8). 2.94 (t, J = 6.1 Hz, 2H), 2.77 (t, J = 5.8 Hz, 2H), 2.69 (q, J = 7.1 Hz, 2H), 1.07 (t, J = 7.1 Hz, 3H)。 13 C NMR (126 MHz, CDCl3) δ 187.9, 166.7, 161.8, 150.7 (dd, J CF = 211.6 Hz, J C-CF = 12.6 Hz, 2C), 150.2 (dd, J CF = 219.8 Hz, J C-CF = 12.6 Hz, 2C), 137.8 (2C), 132.8 (2C), 132.2 (dd, J C-C-CF = 5.0 Hz, J C-C-CF = 3.7 Hz, 2C), 128.8 (2C), 127.1 (dd, J C-C-CF = 7.5 Hz, J C-C-CF = 3.7 Hz, 2C), 126.1, 119.0 (d, J C-CF = 17.6 Hz, 2C), 117.7 (d, J C-CF = 17.6 Hz, 2C), 114.4 (2C), 71.2, 66.9, 58.9, 53.7, 52.7, 49.2, 44.6, 33.8, 11.8。 19 F NMR (376 MHz, CDCl3) δ −135.0 (d, J FF= 18.8 Hz, 2F), -136.5 (d, J FF = 22.5 Hz, 2F). C 34 H 35 HR-APCI m / z calculated for F4N2O4 [M+H] 611.2557, found 611.2527.

[0268] [ka] N-(3,5-bis((E)-3,4-difluorobenzylidene)-4-oxocyclohexyl)-4-(2-((2-methoxyethyl)((tetrahydrofuran-2-yl)methyl)amino)ethoxy)benzamide (JCS110) 1 H NMR (500 MHz, CDCl3) δ 7.69 (s, 2H), 7.62 (d, J = 8.8 Hz, 2H), 7.23 - 7.03 (m, 6H), 6.82 (d, J = 8.7 Hz, 2H), 6.48 (d, J = 7.3 Hz, 1H), 4.46 - 4.38 (m, 1H), 4.03 (t, J = 5.4 Hz, 2H), 3.98 - 3.92 (m, 1H), 3.80 (td, J = 7.0, 7.0 Hz, 1H), 3.68 (td, J = 7.5, 7.5 Hz, 1H), 3.45 (t, J = 5.5 Hz, 2H), 3.29 (s, 3H), 3.20 (br d, J = 13.8 Hz, 2H), 3.03 - 2.97 (m, 4H), 2.84 - 2.79 (m, 2H), 2.70 - 2.64 (m, 2H), 1.95 - 1.88 (m, 1H), 1.87 - 1.74 (m, 2H), 1.49 - 1.42 (m, 1H). 13 C NMR (126 MHz, CDCl3) δ 187.8, 166.6, 161.7, 150.5 (dd, J CF = 253.3 Hz, J C-CF = 12.6 Hz, 2C), 150.1 (dd, J CF = 249.4 Hz, J C-CF= 12.6 Hz, 2C), 137.5 (2C), 132.8 (2C), 132.1 (dd, J C-C-CF = 5.0 Hz, J C-C-CF = 3.7 Hz, 2C), 128.7 (2C), 127.1 (dd, J C-C-CF = 7.5 Hz, J C-C-CF = 3.7 Hz, 2C), 126.0, 118.9 (d, J C-CF = 17.6 Hz, 2C), 117.6 (d, J C-CF = 17.6 Hz, 2C), 114.3 (2C), 77.9, 71.3, 67.9, 66.9, 59.9, 58.8, 54.9, 53.9, 44.6, 33.7, 30.0, 25.4. 19 F NMR (376 MHz, CDCl3) δ -135.1 (d, J FF = 18.8 Hz, 2F), -136.5 (d, J FF = 22.5 Hz, 2F). C 37 H 39 HR-APCI m / z calculated for F4N2O5 [M+H] 667.2817, found 667.2789.

[0269] [ka] N-(3,5-bis((E)-3,4-difluorobenzylidene)-4-oxocyclohexyl)-4-(2-(diethylamino)ethoxy)-3-methoxy-benzamide (JCS111) 1H NMR (500 MHz, CDCl3) δ 7.78 (s, 2H), 7.33 (d, J = 2.1 Hz, 1H), 7.27 - 7.12 (m, 7H), 6.82 (d, J = 8.3 Hz, 1H), 6.3 H 6.4 (20). - 4.43 (m, 1H), 4.10 (t, J = 6.7 Hz, 2H), 3.85 (s, 3H), 3.25 (br d, J = 14.2 Hz, 2H), 3.06 (dd, J = 15.6, 8.7 (J, 2, Hz), 2H 2H), 2.64 (q, J = 7.1 Hz, 4H), 1.05 (t, J = 7.1 Hz, 6H)。 13 C NMR (126 MHz, CDCl3) δ 187.9, 166.7, 150.7 (dd, J CF = 211.6 Hz, J C-CF = 12.6 Hz, 2C), 151.5, 150.2 (dd, J CF = 207.9 Hz, J C-CF = 12.6 Hz, 2C), 149.4, 137.9 (2C), 132.8 (2C), 132.2 (dd, J C-C-CF = 5.0 Hz, J C-C-CF = 3.7 Hz, 2C), 127.2 (dd, J C-C-CF = 7.5 Hz, J C-C-CF = 3.7 Hz, 2C), 126.7, 119.2, 119.0 (d, J C-CF = 17.6 Hz, 2C), 117.7 (d, J C-CF = 17.6 Hz, 2C), 111.7, 111.1, 67.5, 56.1, 51.5, 48.0, 44.7, 33.8, 11.8。 19 F NMR (376 MHz, CDCl3) δ −135.0 (d, J FF = 18.8 Hz, 2F), −136.5 (d, J FF = 22.5 Hz, 2F)。 C34 H 35 HR-APCI m / z calculated for F4N2O4 [M+H] 611.2557, found 611.2527.

[0270] [ka] N-(3,5-bis((E)-3,4-difluorobenzylidene)-4-oxocyclohexyl)-4-(2-(diethylamino)ethoxy)-2-methyl-benzamide (JCS112) 1 H NMR (500 MHz, CDCl3) δ 7.81 (s, 2H), 7.28 - 7.20 (m, 7H), 6.69 (s, 1H), 6.67 (d, J = 8.5 Hz, 1H), 5.86 (d, J = 7.2 Hz, 1H), 4.53 - 4.49 (m, 1H), 4.04 (t, J = 6.2 Hz, 2H), 3.22 (br d, J = 15.0 Hz, 2H), 3.15 (dd, J = 15.9, 6.9 Hz, 2H), 2.88 (t, J = 6.2 Hz, 2H), 2.66 (q, J = 7.2 Hz, 4H), 2.30 (s, 3H), 1.08 (t, J = 7.2 Hz, 6H). 13 C NMR (126 MHz, CDCl3) δ 187.9, 169.4, 160.2, 150.7 (dd, J CF = 211.6 Hz, J C-CF = 12.6 Hz, 2C), 150.2 (dd, J CF = 207.9 Hz, J C-CF = 12.6 Hz, 2C), 138.8, 138.1 (2C), 132.7 (2C), 132.2 (dd, J C-C-CF = 5.0 Hz, J C-C-CF = 3.7 Hz, 2C), 128.6, 128.0, 127.1 (dd, J C-C-CF = 7.5 Hz, J C-C-CF = 3.7 Hz, 2C), 119.0 (d, JC-CF = 17.6 Hz, 2C), 117.7 (d, J C-CF = 17.6 Hz, 2C), 117.3, 111.5, 66.6, 51.6, 47.9, 44.4, 33.4, 20.3, 11.8. 19 F NMR (376 MHz, CDCl3) δ -135.0 (d, J FF = 18.8 Hz, 2F), -136.4 (d, J FF = 22.5 Hz, 2F). C 34 H 35 HR-APCI m / z calculated for F4N2O3 [M+H] 595.2602, found 595.2578.

[0271] [ka] N-(3,5-bis((E)-3,4-difluorobenzylidene)-4-oxocyclohexyl)-2-methyl-4-(2-(piperidin-1-yl)ethoxy)-benzamide (JCS113) 1 H NMR (500 MHz, CDCl3) δ 7.83 (s, 2H), 7.31 - 7.20 (m, 7H), 6.71 (s, 1H), 6.68 (d, J = 8.3 Hz, 1H), 5.77 (d, J = 7.2 Hz, 1H), 4.55 - 4.51 (m, 1H), 4.10 (t, J = 6.0 Hz, 2H), 3.23 (br d, J = 14.1 Hz, 2H), 3.16 (dd, J = 16.0, 6.9 Hz, 2H), 2.78 (t, J = 6.0 Hz, 2H), 2.58 - 2.49 (m, 4H), 2.31 (s, 3H), 1.66 - 1.59 (m, 4H), 1.50 - 1.44 (m, 2H). 13 C NMR (126 MHz, CDCl3) δ 187.9, 169.4, 160.2, 150.8 (dd, J CF = 211.6 Hz, JC-CF = 12.6 Hz, 2C), 150.3 (dd, J CF = 207.9 Hz, J C-CF = 12.6 Hz, 2C), 138.7, 138.2 (2C), 132.6 (2C), 132.2 (dd, J C-C-CF = 5.0 Hz, J C-C-CF = 3.7 Hz, 2C), 128.6, 128.0, 127.1 (dd, J C-C-CF = 7.5 Hz, J C-C-CF = 3.7 Hz, 2C), 119.0 (d, J C-CF = 17.6 Hz, 2C), 117.7 (d, J C-CF = 17.6 Hz, 2C), 117.4, 111.6, 66.0, 57.8, 55.1, 44.4, 33.4, 25.9, 24.2, 20.3. 19 F NMR (376 MHz, CDCl3) δ -131.3 (d, J FF = 18.8 Hz, 2F), -132.7 (d, J FF = 22.5 Hz, 2F). C 35 H 35 HR-APCI m / z calculated for F4N2O3 [M+H] 607.2607, found 607.2578.

[0272] [ka] N-(3,5-bis((E)-3,4-difluorobenzylidene)-4-oxocyclohexyl)-5-(2-(piperidin-1-yl)ethoxy)pyrazine-2-carboxamide (JCS114) 1H NMR (500 MHz, CDCl3) δ 8.12 (s, 1H), 7.97 (s, 1H), 7.83 (s, 2H), 7.53 (d, J = 7.9 Hz, 1H), 7.31 − 7.18 (m, 41 H), − 4. 4.00 (t, J = 6.0 Hz, 2H), 3.29 (br d, J = 16.0 Hz, 2H), 3.04 (dd, J = 16.8, 10.0 Hz, 2H), 2.61 (t, J = 6.0 Hz, 2.43 H), m 1. - 1.50 (m, 4H), 1.42 - 1.38 (m, 2H)。 13 C NMR (126 MHz, CDCl3) δ 187.7, 162.5, 156.2, 150.7 (dd, J CF = 211.6 Hz, J C-CF = 12.6 Hz, 2C), 150.2 (dd, J CF = 207.9 Hz, J C-CF = 12.6 Hz, 2C), 145.9, 137.8 (2C), 133.1, 132.8 (2C), 132.3 (dd, J C-C-CF = 5.0 Hz, J C-C-CF = 3.7 Hz, 2C), 127.2 (dd, J C-C-CF = 7.5 Hz, J C-C-CF = 3.7 Hz, 2C), 125.6, 119.0 (d, J C-CF = 17.6 Hz, 2C), 117.7 (d, J C-CF = 17.6 Hz, 2C), 56.4, 54.6, 46.7, 44.3, 34.0, 26.0, 24.2。 19 F NMR (376 MHz, CDCl3) δ −131.1 (d, J FF = 18.8 Hz, 2F), −132.5 (d, J FF = 22.5 Hz, 2F)。 C 32 H 31HR-APCI m / z calculated for F4N4O3 [M+H] 595.2353, found 595.2353.

[0273] [ka] N-(3,5-bis((E)-3,4-difluorobenzylidene)-4-oxocyclohexyl)-6-(2-(diethylamino)ethoxy)nicotinamide (JCS115) 1 H NMR (500 MHz, CDCl3) δ 8.10 (d, J = 2.6 Hz, 1H), 7.84 (s, 2H), 7.55 (dd, J = 9.5, 2.7 Hz, 1H), 7.33 - 7.20 (m, 6H), 6.50 (d, J = 9.5 Hz, 1H), 6.16 (d, J = 7.2 Hz, 1H), 4.53 - 4.44 (m, 1H), 4.00 (t, J = 5.9 Hz, 2H), 3.30 (br d, J = 14.8 Hz, 2H), 3.07 (dd, J = 16.9, 8.2 Hz, 2H), 2.75 (t, J = 5.9 Hz, 2H), 2.53 (q, J = 7.1 Hz, 4H), 0.94 (t, J = 7.1 Hz, 6H). 13 C NMR (126 MHz, CDCl3) δ 187.7, 163.9, 162.3, 150.8 (dd, J CF = 211.6 Hz, J C-CF = 12.6 Hz, 2C), 150.3 (dd, J CF = 207.9 Hz, J C-CF = 12.6 Hz, 2C), 142.5, 138.0 (2C), 136.2, 132.6 (2C), 132.2 (dd, J C-C-CF = 5.0 Hz, J C-C-CF = 3.7 Hz, 2C), 127.3 (dd, J C-C-CF = 7.5 Hz, J C-C-CF = 3.7 Hz, 2C), 119.2, 119.1 (d, JC-CF = 17.6 Hz, 2C), 117.8 (d, J C-CF = 17.6 Hz, 2C), 111.7, 51.4, 49.0, 47.5, 44.7, 33.8, 12.2. 19 F NMR (376 MHz, CDCl3) δ -131.4 (d, J FF = 18.8 Hz, 2F), -133.0 (d, J FF = 22.5 Hz, 2F). C 32 H 32 HR-APCI m / z calculated for F4N3O3 [M+H] 582.2402, found 582.2374.

[0274] [ka] N-(3,5-bis((E)-3,4-difluorobenzylidene)-4-oxocyclohexyl)-6-(2-(piperidin-1-yl)ethoxy)nicotinamide (JCS116) 1 H NMR (500 MHz, CDCl3) δ 8.08 (s, 1H), 7.75 (s, 2H), 7.55 (d, J = 9.5 Hz, 1H), 7.25 - 7.13 (m, 6H), 6.42 - 6.40 (m, 2H), 4.47 - 4.42 (m, 1H), 3.99 (t, J = 6.1 Hz, 2H), 3.25 (br d, J = 13.8 Hz, 2H), 3.00 (dd, J = 14.7, 8.9 Hz, 2H), 2.55 (t, J = 6.1 Hz, 2H), 2.36 (t, J = 5.3 Hz, 4H), 1.48 - 1.44 (m, 4H), 1.37 - 1.34 (m, 2H). 13 C NMR (126 MHz, CDCl3) δ 187.6, 163.9, 162.2, 150.7 (dd, J CF = 254.5 Hz, J C-CF= 12.6 Hz, 2C), 150.2 (dd, J CF = 249.8 Hz, J C-CF = 12.6 Hz, 2C), 142.2, 137.8 (2C), 136.4, 132.7 (2C), 132.2 (dd, J C-C-CF = 5.0 Hz, J C-C-CF = 3.7 Hz, 2C), 127.3 (dd, J C-C-CF = 7.5 Hz, J C-C-CF = 3.7 Hz, 2C), 119.0, 118.9 (d, J C-CF = 17.6 Hz, 2C), 117.7 (d, J C-CF = 17.6 Hz, 2C), 112.1, 57.1, 54.6, 47.1, 44.8, 33.8, 26.1, 24.2. 19 F NMR (376 MHz, CDCl3) δ -134.8 (d, J FF = 18.8 Hz, 2F), -136.4 (d, J FF = 22.5 Hz, 2F). C 33 H 32 HR-APCI m / z calculated for F4N3O3 [M+H] 594.2405, found 594.2374.

[0275] [ka] N-(3,5-bis((E)-3,4-difluorobenzylidene)-4-oxocyclohexyl)-5-(2-(diethylamino)ethoxy)picolinamide (JCS131) 1H NMR (500 MHz, CDCl3) δ 8.17 (d, J = 2.8 Hz, 1H), 8.05 (d, J = 8.7 Hz, 1H), 7.97 (d, J = 8.0 Hz, 1H), 7.79 (s. 79 , 2H - 7.2). - 4.39 (m, 1H), 4.12 (t, J = 6.0 Hz, 2H), 3.28 (br d, J = 15.7 Hz, 2H), 3.02 (dd, J = 16.9, 10.2 Hz, 2H), 2.89 (H = Hz), J = 7.1 Hz, 4H), 1.07 (t, J = 7.1 Hz, 6H)。 13 C NMR (126 MHz, CDCl3) δ 188.0, 163.9, 157.5, 150.7 (dd, J CF = 254.5 Hz, J C-CF = 12.6 Hz, 2C), 150.2 (dd, J CF = 249.8 Hz, J C-CF = 12.6 Hz, 2C), 142.0, 137.6 (2C), 136.9, 133.1 (2C), 132.2 (dd, J C-C-CF = 5.0 Hz, J C-C-CF = 3.7 Hz, 2C), 127.3 (dd, J C-C-CF = 7.5 Hz, J C-C-CF = 3.7 Hz, 2C), 123.5, 120.9, 118.9 (d, J C-CF = 17.6 Hz, 2C), 117.7 (d, J C-CF = 17.6 Hz, 2C), 67.5, 51.6, 48.0, 44.4, 34.1, 11.8。 19 F NMR (376 MHz, CDCl3) δ −135.4 (d, J FF = 18.8 Hz, 2F), −136.6 (d, J FF = 22.5 Hz, 2F)。 C 32 H 32HR-APCI m / z calculated for F4N3O3 [M+H] 582.2454, found 582.2374.

[0276] [ka] N-(3,5-bis((E)-3,4-difluorobenzylidene)-4-oxocyclohexyl)-5-(2-(piperidin-1-yl)ethoxy)picolinamide (JCS132) 1 H NMR (500 MHz, CDCl3) δ 8.17 (d, J = 2.8 Hz, 1H), 8.04 (d, J = 8.7 Hz, 1H), 7.97 (d, J = 8.0 Hz, 1H), 7.78 (s, 2H), 7.28 - 7.14 (m, 7H), 4.45 - 4.40 (m, 1H), 4.16 (t, J = 5.9 Hz, 2H), 3.27 (br d, J = 15.8 Hz, 2H), 3.02 (dd, J = 15.7, 11.0 Hz, 2H), 2.78 (t, J = 5.9 Hz, 2H), 2.49 (t, J = 5.4 Hz, 4H), 1.62 - 1.56 (m, 4H), 1.46 - 1.40 (m, 2H). 13 C NMR (126 MHz, CDCl3) δ 187.9, 163.9, 157.5, 150.7 (dd, J CF = 254.5 Hz, J C-CF = 12.6 Hz, 2C), 150.2 (dd, J CF = 249.8 Hz, J C-CF = 12.6 Hz, 2C), 142.0, 137.6 (2C), 136.9, 133.1 (2C), 132.3 (dd, J C-C-CF = 5.0 Hz, J C-C-CF = 3.7 Hz, 2C), 127.1 (dd, J C-C-CF = 7.5 Hz, J C-C-CF = 3.7 Hz, 2C), 123.5, 121.0, 119.0 (d, JC-CF = 17.6 Hz, 2C), 117.7 (d, J C-CF = 17.6 Hz, 2C), 66.8, 57.7, 55.2, 44.3, 34.1, 25.9, 24.1. 19 F NMR (376 MHz, CDCl3) δ -135.4 (d, J FF = 18.8 Hz, 2F), -136.6 (d, J FF = 22.5 Hz, 2F). C 33 H 32 HR-APCI m / z calculated for F4N3O3 [M+H] 594.2453, found 594.2374.

[0277] [ka] N-(3,5-bis((E)-3,4-difluorobenzylidene)-4-oxocyclohexyl)-1-(2-(diethylamino)ethoxy)phthalazine-6-carboxamide (JCS133) 1 H NMR (500 MHz, CDCl3) δ 8.28 (d, J = 8.5 Hz, 1H), 8.06 (s, 1H), 7.90 (s, 1H), 7.80 (s, 2H), 7.77 (d, J = 8.1 Hz, 1H), 7.26 - 7.16 (m, 6H), 6.49 (d, J = 7.2 Hz, 1H), 4.56 - 4.51 (m, 1H), 3.98 (t, J = 5.7 Hz, 2H), 3.29 (br d, J = 14.5 Hz, 2H), 3.10 (dd, J = 15.7, 7.9 Hz, 2H), 2.72 (t, J = 5.8 Hz, 2H), 2.50 (q, J = 7.1 Hz, 4H), 0.88 (t, J = 7.1 Hz, 6H). 13 C NMR (126 MHz, CDCl3) δ 187.6, 166.1, 160.5, 150.7 (dd, J CF = 254.5 Hz, JC-CF = 12.6 Hz, 2C), 150.2 (dd, J CF = 249.8 Hz, J C-CF = 12.6 Hz, 2C), 148.7, 148.2, 139.3, 138.2 (2C), 132.4 (2C), 132.2 (dd, J C-C-CF = 5.0 Hz, J C-C-CF = 3.7 Hz, 2C), 127.5, 127.2 (dd, J C-C-CF = 7.5 Hz, J C-C-CF = 3.7 Hz, 2C), 125.8, 125.3, 124.1, 119.0 (d, J C-CF = 17.6 Hz, 2C), 117.7 (d, J C-CF = 17.6 Hz, 2C), 51.3, 47.6, 45.7, 45.1, 33.6, 12.2. 19 F NMR (376 MHz, CDCl3) δ -134.9 (d, J FF = 18.8 Hz, 2F), -136.4 (d, J FF = 22.5 Hz, 2F). C 35 H 33 HR-APCI m / z calculated for F4N4O3 [M+H] 633.2575, found 633.2483.

[0278] [ka] N-(3,5-bis((E)-3,4-difluorobenzylidene)-4-oxocyclohexyl)-5-(2-(bis(2-methoxyethyl)amino)ethoxy)-pyrazine-2-carboxamide (JCS134) 1H NMR (500 MHz, CDCl3) δ 8.36 (s, 1H), 7.93 (s, 1H), 7.80 (s, 2H), 7.52 (d, J = 7.9 Hz, 1H), 7.30 − 7.16 (m, 48H), − 4. 3.94 (t, J = 5.6 Hz, 2H), 3.32 - 3.24 (m, 6H), 3.22 (s, 6H), 3.01 (dd, J = 15.8, 9.1 Hz, 2H), 2.89 (t, J = 5.6. Hz), J = 2. Hz, 4H)。 13 C NMR (126 MHz, CDCl3) δ 187.7, 162.5, 156.3, 150.7 (dd, J CF = 254.5 Hz, J C-CF = 12.6 Hz, 2C), 150.2 (dd, J CF = 249.8 Hz, J C-CF = 12.6 Hz, 2C), 145.2, 137.7 (2C), 134.0, 132.8 (2C), 132.2 (dd, J C-C-CF = 5.0 Hz, J C-C-CF = 3.7 Hz, 2C), 127.1 (dd, J C-C-CF = 7.5 Hz, J C-C-CF = 3.7 Hz, 2C), 125.4, 118.8 (d, J C-CF = 17.6 Hz, 2C), 117.6 (d, J C-CF = 17.6 Hz, 2C), 71.5, 58.6, 55.0, 53.4, 48.5, 44.1, 33.9。 19 F NMR (376 MHz, CDCl3) δ −135.2 (d, J FF = 18.8 Hz, 2F), −136.6 (d, J FF = 22.5 Hz, 2F)。 C 33 H 35HR-APCI m / z calculated for F4N4O5 [M+H] 643.2587, found 643.2538.

[0279] [ka] N-(3,5-bis((E)-3,4-difluorobenzylidene)-4-oxocyclohexyl)-4-(2-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)benzamide (JCS135) 1 H NMR (500 MHz, CDCl3) δ 7.80 (s, 2H), 7.62 (d, J = 8.7 Hz, 2H), 7.29 - 7.16 (m, 6H), 6.89 (d, J = 8.7 Hz, 2H), 6.05 (d, J = 7.3 Hz, 1H), 4.53 - 4.46 (m, 1H), 4.10 (t, J = 6.0 Hz, 2H), 3.25 (br d, J = 14.2 Hz, 2H), 3.06 (dd, J = 16.1, 8.0 Hz, 2H), 2.93 (t, J = 6.0 Hz, 2H), 2.81 (t, J = 6.0 Hz, 2H), 2.68 - 2.58 (m, 2H), 2.08 - 2.05 (m, 2H), 1.80 - 1.35 (m, 7H). 13 C NMR (126 MHz, CDCl3) δ 188.0, 166.6, 161.8, 150.7 (dd, J CF = 254.5 Hz, J C-CF = 12.6 Hz, 2C), 150.2 (dd, J CF = 249.8 Hz, J C-CF = 12.6 Hz, 2C), 137.7 (2C), 132.8 (2C), 132.2 (dd, J C-C-CF = 5.0 Hz, J C-C-CF = 3.7 Hz, 2C), 128.8 (2C), 127.1 (dd, J C-C-CF = 7.5 Hz, J C-C-CF= 3.7 Hz, 2C), 126.2, 119.0 (d, J C-CF = 17.6 Hz, 2C), 117.7 (d, J C-CF = 17.6 Hz, 2C), 114.5 (2C), 67.3, 62.3 (2C), 54.6, 44.6, 42.5 (2C), 33.8, 32.5 (2C's), 25.7, multiple carbon signals overlapping upfield. 19 F NMR (376 MHz, CDCl3) δ -135.0 (d, J FF = 18.8 Hz, 2F), -136.5 (d, J FF = 22.5 Hz, 2F). C 36 H 35 HR-APCI m / z calculated for F4N3O3K[M+K] 672.2124, found 672.2246.

[0280] [ka] N-(3,5-bis((E)-3,4-difluorobenzylidene)-4-oxocyclohexyl)-4-(2-(hexahydro-6H-[1,4]dioxino[2,3-c]pyrrol-6-yl)ethoxy)benzamide (JCS137) 1 H NMR (500 MHz, CDCl3) δ 7.80 (s, 2H), 7.62 (d, J = 8.8 Hz, 2H), 7.27 - 7.17 (m, 6H), 6.87 (d, J = 8.8 Hz, 2H), 6.10 (d, J = 7.3 Hz, 1H), 4.52 - 4.46 (m, 1H), 4.10 (t, J = 5.1 Hz, 4H), 3.84 - 3.80 (m, 2H), 3.60 - 3.55 (m, 2H), 3.25 (br d, J = 15.2 Hz, 2H), 3.05 (dd, J = 15.9, 8.2 Hz, 2H), 3.01 - 2.95 (m, 6H). 13C NMR (126 MHz, CDCl3) δ 187.9, 166.6, 161.6, 150.7 (dd, J CF = 254.5 Hz, J C-CF = 12.6 Hz, 2C), 150.2 (dd, J CF = 249.8 Hz, J C-CF = 12.6 Hz, 2C), 137.9 (2C), 132.8 (2C), 132.2 (dd, J C-C-CF = 5.0 Hz, J C-C-CF = 3.7 Hz, 2C), 128.8 (2C), 127.1 (dd, J C-C-CF = 7.5 Hz, J C-C-CF = 3.7 Hz, 2C), 126.3, 119.0 (d, J C-CF = 17.6 Hz, 2C), 117.7 (d, J C-CF = 17.6 Hz, 2C), 114.4 (2C), 73.5, 67.3, 62.6, 55.8, 55.4, 44.6, 33.8. 19 F NMR (376 MHz, CDCl3) δ -135.1 (d, J FF = 18.8 Hz, 2F), -136.5 (d, J FF = 22.5 Hz, 2F). C 35 H 33 HR-APCI m / z calculated for F4N2O5 [M+H] 637.2332, found 637.2320.

[0281] [ka] N-(3,5-bis((E)-3,4-difluorobenzylidene)-4-oxocyclohexyl)-4-(2-(hexahydrocyclopenta[c]pyrrol-2(1H)-yl)ethoxy)benzamide (JCS138) 1H NMR (500 MHz, CDCl3) δ 7.82 (s, 2H), 7.66 (d, J = 8.4 Hz, 2H), 7.34 - 7.16 (m, 6H), 6.91 (d, J = 8.4 Hz, 2H), 6.3 (d 6.4, Hz). - 4.46 (m, 1H), 4.15 (t, J = 5.8 Hz, 2H), 3.28 (br d, J = 12.8 Hz, 2H), 3.13 - 3.03 (m, 4H), 2.95 - 2.87 (m, 2, 3H), 2.21 – 2.02 (m, 3H), 1.91 – 1.70 (m, 3H), 1.49 – 1.36 (m, 1H)。 13 C NMR (126 MHz, CDCl3) δ 187.9, 166.6, 161.6, 150.7 (dd, J CF = 254.5 Hz, J C-CF = 12.6 Hz, 2C), 150.2 (dd, J CF = 249.8 Hz, J C-CF = 12.6 Hz, 2C), 137.9 (2C), 132.8 (2C), 132.2 (dd, J C-C-CF = 5.0 Hz, J C-C-CF = 3.7 Hz, 2C), 128.8 (2C), 127.1 (dd, J C-C-CF = 7.5 Hz, J C-C-CF = 3.7 Hz, 2C), 126.2, 119.0 (d, J C-CF = 17.6 Hz, 2C), 117.7 (d, J C-CF = 17.6 Hz, 2C), 114.5 (2C), 66.2, 62.6, 58.5, 53.4, 51.6, 44.6, 33.8, 27.7。 19 F NMR (376 MHz, CDCl3) δ −135.1 (d, J FF = 18.8 Hz, 2F), −136.5 (d, J FF = 22.5 Hz, 2F)。 C 36 H 34 HR-APCI m / z calculated for F4N2O3[M+] 618.2512, found 618.2500.

[0282] [ka] N-(3,5-bis((E)-3,4-difluorobenzylidene)-4-oxocyclohexyl)-4-(2-(ethylamino)ethoxy)benzamide (JCS140) 1 H NMR (500 MHz, CDCl3) δ 7.77 (s, 2H), 7.61 (d, J = 8.4 Hz, 2H), 7.26 - 7.16 (m, 6H), 6.85 (d, J = 8.5 Hz, 2H), 6.33 (m, 1H), 4.49 - 4.42 (m, 1H), 4.10 (t, J = 5.2 Hz, 2H), 3.24 (br d, J = 15.2 Hz, 2H), 3.09 - 2.99 (m, 4H), 2.75 (q, J = 7.2 Hz, 2H), 1.14 (t, J = 7.1 Hz, 3H). 13 C NMR (126 MHz, CDCl3) δ 187.8, 166.6, 161.5, 150.7 (dd, J CF = 254.5 Hz, J C-CF = 12.6 Hz, 2C), 150.2 (dd, J CF = 249.8 Hz, J C-CF = 12.6 Hz, 2C), 137.7 (2C), 132.7 (2C), 132.1 (dd, J C-C-CF = 5.0 Hz, J C-C-CF = 3.7 Hz, 2C), 128.7 (2C), 127.1 (dd, J C-C-CF = 7.5 Hz, J C-C-CF = 3.7 Hz, 2C), 126.3, 118.9 (d, J C-CF = 17.6 Hz, 2C), 117.6 (d, J C-CF= 17.6 Hz, 2C), 114.2 (2C), 67.0, 47.9, 44.6, 43.8, 33.7, 14.6. 19 F NMR (376 MHz, CDCl3) δ -131.2 (d, J FF = 18.8 Hz, 2F), -132.6 (d, J FF = 22.5 Hz, 2F). C 31 H 29 HR-APCI m / z calculated for F4N2O3 [M+H] 553.2103, found 553.2108.

[0283] [ka] N-(4-oxo-3,5-bis((E)-3,4,5-trifluorobenzylidene)cyclohexyl)-4-(2-(piperidin-1-yl)ethoxy)benzamide (JCS141) 1 H NMR (500 MHz, CDCl3) δ 7.71 (s, 2H), 7.68 (d, J = 8.9 Hz, 2H), 7.14 - 6.98 (m, 4H), 6.89 (d, J = 8.9 Hz, 2H), 6.45 (d, J = 7.2 Hz, 1H), 4.52 - 4.42 (m, 1H), 4.18 (t, J = 5.9 Hz, 2H), 3.27 (br d, J = 13.1 Hz, 2H), 3.06 (dd, J = 17.2, 9.6 Hz, 2H), 2.87 (t, J = 5.9 Hz, 2H), 2.62 (t, J = 5.3 Hz, 4H), 1.71 - 1.63 (m, 4H), 1.53 - 1.45 (m, 2H). 13 C NMR (126 MHz, CDCl3) δ 187.4, 166.7, 161.6, 151.2 (dd, J C-F = 210.4, 3.7 Hz, 2C), 151.1 (dd, J C-F= 209.1, 3.7 Hz, 2C), 140.0 (dt, J C-F = 214.2, 3.7 Hz, 2C), 136.8 (2C), 133.9 (2C), 128.9 (2C), 126.2, 114.5 (dd, J C-F = 13.8, 3.7 Hz, 2C), 114.4 (2C), 65.8, 57.6, 55.1, 44.7, 33.7, 25.6, 23.9. 19 F NMR (376 MHz, CDCl3) δ -133.3 (d, J FF = 26.3 Hz, 3F). C 34 H 31 HR-APCI m / z calculated for F6N2O3 [M+H] 629.2234, found 629.2233.

[0284] [ka] 4-((((S)-1-ethylpyrrolidin-2-yl)methyl)amino)-N-(4-oxo-3,5-bis((E)-3,4,5-trifluorobenzylidene)-cyclohexyl)benzamide (JCS142) 1 H NMR (500 MHz, CDCl3) δ 7.73 (s, 2H), 7.57 (d, J = 8.7 Hz, 2H), 7.11 - 7.06 (m, 4H), 6.58 (d, J = 8.7 Hz, 2H), 6.09 (d, J = 7.3 Hz, 1H), 4.97 (m, 1H), 4.52 - 4.42 (m, 1H), 3.36 - 3.16 (m, 5H), 3.06 (dd, J = 15.0, 7.6 Hz, 2H), 3.00 - 2.73 (m, 2H), 2.38 - 2.26 (m, 2H), 2.02 - 1.71 (m, 4H), 1.14 (t, J = 7.2 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 187.5, 166.9, 151.6, 151.2 (dd, J C-F = 210.4, 3.7 Hz, 2C), 151.1 (dd, J C-F = 209.1, 3.7 Hz, 2C), 140.0 (dt, J C-F = 214.2, 3.7 Hz, 2C), 136.8 (2C), 133.9 (2C), 128.6 (2C), 121.2, 114.3 (dd, J C-F = 13.8, 3.7 Hz, 2C), 111.7 (2C), 62.8, 53.6, 48.4, 44.3, 44.2, 33.7, 28.5, 22.7, 13.5. 19 F NMR (376 MHz, CDCl3) δ -133.2 (d, J FF = 26.3 Hz, 3F). C 34 H 32 HR-APCI m / z calculated for F6N3O2 [M+H] 628.2391, found 628.2393.

[0285] [ka] 4-(2-(bis(2-methoxyethyl)amino)ethoxy)-N-(4-oxo-3,5-bis((E)-3,4,5-trifluorobenzylidene)cyclohexyl)benzamide (JCS143) 11H NMR (500 MHz, CDCl3) δ 7.74 (s, 2H), 7.67 (d, J = 8.8 Hz, 2H), 7.14 - 7.04 (m, 4H), 6.92 (d, J = 8.8 Hz, 2H), 6.18 (d, J = 7.2 Hz, 1H), 4.52 - 4.42 (m, 1H), 4.12 (t, J = 6.1 Hz, 2H), 3.52 (t, J = 5.8 Hz, 4H), 3.37 (s, 6H), 3.29 (br d, J = 15.6 Hz, 2H), 3.14 - 3.02 (m, 4H), 2.88 (t, J = 5.8 Hz, 4H). 13 13C NMR (126 MHz, CDCl3) δ 187.4, 166.7, 161.8, 151.2 (dd, J C-F = 210.4, 3.7 Hz, 2C), 151.1 (dd, J C-F = 209.1, 3.7 Hz, 2C), 140.0 (dt, J C-F = 214.2, 3.7 Hz, 2C), 137.0 (2C), 133.7 (2C), 128.8 (2C), 126.0, 114.5 (2C), 114.4 (dd, J C-F = 13.8, 3.7 Hz, 2C), 71.2, 66.8, 58.9, 54.8, 53.9, 44.6, 33.7. 19 19F NMR (376 MHz, CDCl3) δ -133.3 (d, J FF = 26.3 Hz, 3F). C 35 H 35 Calculated HR-APCI m / z for C18H6F6N2O5[M+H] 677.2445, found 677.2444.

[0286]

Chemical Structure

[0287] [ka] N-(3,5-bis((E)-2,4-difluorobenzylidene)-4-oxocyclohexyl)-4-((((S)-1-ethylpyrrolidin-2-yl)methyl)-amino)benzamide (JCS145) 1 H NMR (500 MHz, CDCl3) δ 7.88 (s, 2H), 7.50 (d, J = 8.7 Hz, 2H), 7.37 - 7.31 (m, 2H), 6.95 - 6.80 (m, 4H), 6.53 (d, J = 8.8 Hz, 2H), 6.01 (d, J = 7.5 Hz, 1H), 4.97 (br s, 1H), 4.52 - 4.42 (m, 1H), 3.28 - 3.07 (m, 5H), 2.96 (dd, J = 15.9, 7.6 Hz, 2H), 2.88 - 2.69 (m, 2H), 2.32 - 2.18 (m, 2H), 1.96 - 1.68 (m, 4H), 1.10 (t, J = 7.2 Hz, 3H). 13 C NMR (126 MHz, CDCl3) δ 187.9, 166.9, 163.4 (dd, J C-F = 277.2, 10.4 Hz, 2C), 161.5 (dd, J C-F = 278.4, 11.3 Hz, 2C), 151.6, 134.5 (2C), 131.9 (2C), 131.6 (dd, J C-F = 7.5, 3.7 Hz, 2C), 128.7 (2C), 121.5, 119.6 (dd, J C-F = 11.3, 2.5 Hz, 2C), 111.7 (2C), 111.6 (dd, J C-F = 17.6, 6.3 Hz, 2C), 104.5 (t, J C-F = 21.4 Hz, 2C), 62.9, 53.6, 48.5, 44.4, 44.4, 34.2, 28.6, 22.8, 13.5. 19F NMR (376 MHz, CDCl3) δ -106.8 (d, J FF = 7.5 Hz, 2F), -107.1 (d, J FF = 7.5 Hz, 2F). C 34 H 34 HR-APCI m / z calculated for F4N3O2 [M+H] 592.2583, found 592.2581.

[0288] [ka] N-(3,5-bis((E)-2,4-difluorobenzylidene)-4-oxocyclohexyl)-4-(2-(bis(2-methoxyethyl)amino)ethoxy)-benzamide (JCS146) 1 H NMR (500 MHz, CDCl3) δ 7.80 (s, 2H), 7.60 (d, J = 8.8 Hz, 2H), 7.30 - 7.24 (m, 2H), 6.86 - 6.44 (m, 6H), 6.45 (d, J = 7.5 Hz, 1H), 4.46 - 4.38 (m, 1H), 4.02 (t, J = 6.1 Hz, 2H), 3.44 (t, J = 5.8 Hz, 4H), 3.29 (s, 6H), 3.07 (br d, J = 14.6 Hz, 2H), 2.98 (t, J = 6.1 Hz, 2H), 2.92 (dd, J = 15.6, 8.6 Hz, 2H), 2.80 (t, J = 5.8 Hz, 4H). 13 C NMR (126 MHz, CDCl3) δ 187.5, 166.5, 163.0 (dd, J C-F = 277.2, 10.4 Hz, 2C), 161.5, 161.3 (dd, J C-F = 278.4, 11.3 Hz, 2C), 134.3 (2C), 131.6 (2C), 131.5 (dd, J C-F= 7.5, 3.7 Hz, 2C), 128.7 (2C), 126.2, 119.4 (dd, J C-F = 11.3, 2.5 Hz, 2C), 114.2 (2C), 111.5 (dd, J C-F = 17.6, 6.3 Hz, 2C), 104.4 (t, J C-F = 21.4 Hz, 2C), 71.1, 66.7, 58.8, 54.6, 53.7, 44.6, 33.9. 19 F NMR (376 MHz, CDCl3) δ -106.8 (d, J FF = 11.2 Hz, 2F), -106.9 (d, J FF = 11.2 Hz, 2F). C 35 H 37 HR-APCI m / z calculated for F4N2O5 [M+H] 641.2635, found 641.2633.

[0289] [ka] N-(3,5-bis((E)-2,4-difluorobenzylidene)-4-oxocyclohexyl)-4-(2-(diethylamino)ethoxy)benzamide (JCS147) 1 H NMR (500 MHz, CDCl3) δ 7.88 (s, 2H), 7.61 (d, J = 8.8 Hz, 2H), 7.34 - 7.30 (m, 2H), 6.96 - 6.81 (m, 6H), 6.15 (d, J = 7.4 Hz, 1H), 4.52 - 4.45 (m, 1H), 4.09 (t, J = 6.1 Hz, 2H), 3.11 (br d, J = 14.1 Hz, 2H), 2.97 (dd, J = 15.6, 8.3 Hz, 2H), 2.91 (t, J = 6.1 Hz, 2H), 2.68 (q, J = 7.1 Hz, 4H), 1.09 (t, J = 7.2 Hz, 6H). 13C NMR (126 MHz, CDCl3) δ 187.6, 166.4, 163.0 (dd, J C-F = 277.2, 10.4 Hz, 2C), 161.5, 161.3 (dd, J C-F = 278.4, 11.3 Hz, 2C), 134.2 (2C), 132.0 (2C), 131.5 (dd, J C-F = 7.5, 3.7 Hz, 2C), 128.6 (2C), 126.3, 119.4 (dd, J C-F = 11.3, 2.5 Hz, 2C), 114.3 (2C), 111.5 (dd, J C-F = 17.6, 6.3 Hz, 2C), 104.4 (t, J C-F = 21.4 Hz, 2C), 66.3, 51.4, 47.7, 44.5, 33.9, 11.4. 19 F NMR (376 MHz, CDCl3) δ -106.8 (d, J FF = 11.2 Hz, 2F), -106.9 (d, J FF = 11.2 Hz, 2F). C 33 H 33 HR-APCI m / z calculated for F4N2O3 [M+H] 581.2426, found 581.2421.

[0290] [ka] N-(3,5-bis((E)-4-fluorobenzylidene)-4-oxocyclohexyl)-4-(2-(bis(2-methoxyethyl)amino)ethoxy)-benzamide (JCS148) 11H NMR (500 MHz, CDCl3) δ 7.85 (s, 2H), 7.61 (d, J = 8.8 Hz, 2H), 7.40 (dd, J = 8.7, 5.5 Hz, 4H), 7.06 (dd, J = 8.7, 5.5 Hz, 4H), 6.85 (d, J = 8.8 Hz, 2H), 6.24 (d, J = 7.4 Hz, 1H), 4.52 - 4.47 (m, 1H), 4.05 (t, J = 6.1 Hz, 2H), 3.47 (t, J = 5.8 Hz, 4H), 3.32 (s, 6H), 3.24 (br d, J = 13.9 Hz, 2H), 3.07 (dd, J = 16.5, 7.5 Hz, 2H), 3.00 (t, J = 6.1 Hz, 2H), 2.82 (t, J = 5.8 Hz, 4H). 13 13C NMR (126 MHz, CDCl3) δ 188.4, 166.6, 162.9 (d, J C-F = 250.7 Hz, 2C), 161.7, 138.8 (2C), 132.4 (d, J C-F = 7.5 Hz, 4C), 131.9 (2C), 131.4 (d, J C-F = 3.7 Hz, 2C), 128.7 (2C), 126.3, 115.8 (d, J C-F = 21.4 Hz, 4C), 114.3 (2C), 71.2, 66.8, 58.9, 54.7, 53.8, 44.6, 33.8. 19 19F NMR (376 MHz, CDCl3) δ -110.5 (s, 2F) C 35 H 39 Calculated HR-APCI m / z for C18H20F2N2O5[M+H]: 605.2824, found: 605.2821.

[0291]

Chemical Structure

[0292] [ka] N-(3,5-bis((E)-3,4-difluorobenzylidene)-4-oxocyclohexyl)-4-(2-(piperidin-1-ylamino)ethoxy)-benzamide (JCS150) 1 H NMR (500 MHz, CDCl3) δ 7.81 (s, 2H), 7.62 (d, J = 8.8 Hz, 2H), 7.26 - 7.16 (m, 6H), 6.86 (d, J = 8.8 Hz, 2H), 6.10 (d, J = 7.3 Hz, 1H), 4.53 - 4.46 (m, 1H), 4.19 (t, J = 5.8 Hz, 2H), 3.26 (br d, J = 13.9 Hz, 2H), 3.06 (dd, J = 16.8, 9.0 Hz, 2H), 2.90 (t, J = 5.7 Hz, 2H), 2.64 (t, J = 6.0 Hz, 4H), 1.71 - 1.63 (m, 4H), 1.51 - 1.44 (m, 2H). 13 C NMR (126 MHz, CDCl3) δ 188.0, 166.6, 161.4, 150.7 (dd, J CF = 254.5 Hz, J C-CF = 12.6 Hz, 2C), 150.2 (dd, J CF = 249.8 Hz, J C-CF = 12.6 Hz, 2C), 138.0 (2C), 132.8 (2C), 132.2 (dd, J C-C-CF = 5.0 Hz, J C-C-CF = 3.7 Hz, 2C), 128.8 (2C), 127.1 (dd, J C-C-CF = 7.5 Hz, J C-C-CF = 3.7 Hz, 2C), 126.5, 119.1 (d, J C-CF = 17.6 Hz, 2C), 117.7 (d, J C-CF= 17.6 Hz, 2C), 114.5 (2C), 65.7, 57.5, 55.0, 44.6, 33.9, 25.4, 23.8. 19 F NMR (376 MHz, CDCl3) δ -131.1 (d, J FF = 18.8 Hz, 2F), -132.6 (d, J FF = 22.5 Hz, 2F). C 34 H 34 HR-APCI m / z calculated for F4N3O3 [M+H] 608.2558, found 608.2530.

[0293] [ka] 4-(2-(2-oxa-6-azaspiro[3.3]heptan-6-yl)ethoxy)-N-(3,5-bis((E)-3,4-difluorobenzylidene)-4-oxocyclohexyl)benzamide (JCS151) 1 H NMR (500 MHz, CDCl3) δ 7.83 (s, 2H), 7.66 (d, J = 8.8 Hz, 2H), 7.30 - 7.20 (m, 6H), 6.89 (d, J = 8.8 Hz, 2H), 6.25 (d, J = 7.3 Hz, 1H), 4.56 - 4.48 (m, 1H), 4.07 (t, J = 5.3 Hz, 2H), 3.87 (s, 2H), 3.81 (s, 2H), 3.46 (br d, J = 15.8 Hz, 2H), 3.38 - 3.26 (m, 4H), 3.10 (dd, J = 16.6, 7.1 Hz, 2H), 2.99 (t, J = 5.3 Hz, 2H). 13 C NMR (126 MHz, CDCl3) δ 187.8, 166.5, 161.3, 150.7 (dd, J CF = 254.5 Hz, J C-CF = 12.6 Hz, 2C), 150.2 (dd, J CF= 249.8 Hz, J C-CF = 12.6 Hz, 2C), 137.8 (2C), 132.7 (2C), 132.1 (dd, J C-C-CF = 5.0 Hz, J C-C-CF = 3.7 Hz, 2C), 128.7 (2C), 127.1 (dd, J C-C-CF = 7.5 Hz, J C-C-CF = 3.7 Hz, 2C), 126.4, 118.9 (d, J C-CF = 17.6 Hz, 2C), 117.6 (d, J C-CF = 17.6 Hz, 2C), 114.2 (2C), 66.5, 64.5, 56.7, 48.0, 44.6, 38.6, 33.7. 19 F NMR (376 MHz, CDCl3) δ -131.2 (d, J FF = 18.8 Hz, 2F), -132.6 (d, J FF = 22.5 Hz, 2F). C 34 H 31 HR-APCI m / z calculated for F4N2O4 [M+H] 607.2218, found 607.2214.

[0294] [ka] N-(3,5-bis((E)-3,4-difluoro-5-methoxybenzylidene)-4-oxocyclohexyl)-4-(2-(diethylamino)-ethoxy)benzamide (JCS152) 1H NMR (500 MHz, CDCl3) δ 7.77 (s, 2H), 7.63 (d, J = 8.8 Hz, 2H), 6.89 - 6.85 (m, 4H), 6.81 (d, J = 7.2 Hz, 2H), J.2, J 6.4, Hz ( - 4.48 (m, 1H), 4.14 (t, J = 5.7 Hz, 2H), 3.91 (s, 6H), 3.25 (br d, J = 14.1 Hz, 2H), 3.09 (dd, J = 14.1, 7.2 Hz, 2. 2H), 2H), 2.75 (q, J = 7.1 Hz, 4H), 1.12 (t, J = 7.1 Hz, 6H)。 13 C NMR (126 MHz, CDCl3) δ 187.8, 166.5, 161.4, 150.9 (dd, J C-F = 248.2, 11.3 Hz, 2C), 149.1 (dd, J C-F = 8.8, 3.7 Hz, 2C), 141.4 (dd, J C-F = 254.5, 15.1 Hz, 2C), 138.4 (2C), 132.2 (2C), 130.6 (dd, J C-F = 8.8, 5.0 Hz, 2C), 128.7 (2C), 126.3, 114.3 (2C), 111.1 (d, J C-F = 2.5 Hz, 2C), 110.6 (dd, J C-F = 18.9 Hz, 2C), 56.8, 51.4, 47.7, 44.5, 33.6, 11.7。 19 F NMR (376 MHz, CDCl3) δ −136.2 (d, J FF = 18.8 Hz, 2F), −156.7 (d, J FF = 22.5 Hz, 2F)。 C 35 H 37 F4N2O5[M+H] is located at HR-APCI m / z.

[0295] [ka] N-(3,5-bis((E)-3,4-difluoro-5-methoxybenzylidene)-4-oxocyclohexyl)-4-(2-(bis(2-methoxyethyl)amino)ethoxy)benzamide (JCS153) 1 H NMR (500 MHz, CDCl3) δ 7.75 (s, 2H), 7.62 (d, J = 8.9 Hz, 2H), 6.92 - 6.84 (m, 4H), 6.79 (d, J = 7.0 Hz, 2H), 6.19 (d, J = 7.3 Hz, 1H), 4.52 - 4.48 (m, 1H), 4.08 (t, J = 6.0 Hz, 2H), 3.90 (s, 6H), 3.49 (t, J = 5.8 Hz, 4H), 3.32 (s, 6H), 3.25 (br d, J = 15.6 Hz, 2H), 3.13 - 2.99 (m, 4H), 2.86 (t, J = 5.7 Hz, 4H). 13 C NMR (126 MHz, CDCl3) δ 187.9, 166.7, 161.7, 150.9 (dd, J C-F = 248.2, 11.3 Hz, 2C), 149.2 (dd, J C-F = 8.8, 3.7 Hz, 2C), 141.4 (dd, J C-F = 254.5, 15.1 Hz, 2C), 138.4 (2C), 132.9 (2C), 130.7 (dd, J C-F = 8.8, 5.0 Hz, 2C), 128.7 (2C), 126.2, 114.4 (2C), 111.1 (d, J C-F = 2.5 Hz, 2C), 110.6 (dd, J C-F = 18.9 Hz, 2C), 71.0, 66.7, 58.9, 56.9, 54.8, 53.9, 44.7, 33.7. 19F NMR (376 MHz, CDCl3) δ -136.2 (d, J FF = 18.8 Hz, 2F), -156.7 (d, J FF = 22.5 Hz, 2F). C 37 H 41 HR-APCI m / z calculated for F4N2O7 [M+H] 701.2840, found 701.2844.

[0296] [ka] 4-((((S)-1-ethylpyrrolidin-2-yl)methyl)amino)-N-(4-oxo-3,5-bis((E)-2,4,5-trifluorobenzylidene)-cyclohexyl)benzamide (JCS154) 1 H NMR (500 MHz, CDCl3) δ 7.81 (s, 2H), 7.51 (d, J = 8.7 Hz, 2H), 7.22 - 7.13 (m, 2H), 7.02 - 6.94 (m, 2H), 6.54 (d, J = 8.7 Hz, 2H), 5.98 (d, J = 8.7 Hz, 1H), 4.87 (br s, 1H), 4.52 - 4.42 (m, 1H), 3.32 - 3.07 (m, 5H), 3.02 - 2.67 (m, 4H), 2.30 - 2.19 (m, 2H), 1.99 - 1.64 (m, 4H), 1.09 (t, J = 7.2 Hz, 3H). 13 C NMR (126 MHz, CDCl3) δ 166.9, 157.3, 156.3 (dd, J C-F = 252.0, 8.8 Hz, 2C), 151.8, 150.6 (dt, J C-F = 254.5, 12.6 Hz, 2C), 146.7 (dd, J C-F = 243.1, 11.3 Hz, 2C), 135.2 (2C), 131.0 (2C), 128.7 (2C), 121.3, 119.6 (dd, J C-F= 15.1, 5.0 Hz, 2C), 118.2 (dd, J C-F = 20.1, 3.7 Hz, 2C), 111.8 (2C), 106.2 (dd, J C-F = 27.7, 3.7 Hz, 2C), 62.8, 53.7, 44.4, 44.3, 34.2, 34.2, 28.6, 22.8, 13.7. 19 F NMR (376 MHz, CDCl3) δ -112.4 (d, J FF = 18.8, 11.2 Hz, 2F), -130.3 (d, J FF = 30.0, 7.5 Hz, 2F), -141.5 (d, J FF = 30.0, 18.8 Hz, 2F). C 34 H 32 HR-APCI m / z calculated for F6N3O2 [M+H] 628.2391, found 628.2393.

[0297] [ka] 4-(2-(bis(2-methoxyethyl)amino)ethoxy)-N-(4-oxo-3,5-bis((E)-2,4,5-trifluorobenzylidene)cyclohexyl)benzamide (JCS155) 1 H NMR (500 MHz, CDCl3) δ 7.81 (s, 2H), 7.65 (d, J = 8.8 Hz, 2H), 7.22 - 7.13 (m, 2H), 7.02 - 6.94 (m, 2H), 6.89 (d, J = 8.8 Hz, 2H), 6.32 (d, J = 7.3 Hz, 1H), ), 4.52 - 4.42 (m, 1H), 4.11 (t, J = 6.0 Hz, 2H), 3.52 (t, J = 5.8 Hz, 4H), 3.36 (s, 6H), 3.20 - 2.92 (m, 6H), 2.88 (t, J = 5.8 Hz, 4H). 13C NMR (126 MHz, CDCl3) δ 187.1, 166.6, 161.7, 156.3 (dd, J C-F = 252.0, 8.8 Hz, 2C), 150.6 (dt, J C-F = 254.5, 12.6 Hz, 2C), 146.7 (dd, J C-F = 243.1, 11.3 Hz, 2C), 135.0 (2C), 130.9 (2C), 128.7 (2C), 126.1, 119.6 (dd, J C-F = 15.1, 5.0 Hz, 2C), 118.1 (dd, J C-F = 20.1, 3.7 Hz, 2C), 114.3 (2C), 106.2 (dd, J C-F = 27.7, 3.7 Hz, 2C), 71.1, 66.7, 58.9, 54.7, 53.8, 44.6, 34.0. 19 F NMR (376 MHz, CDCl3) δ -112.4 (d, J FF = 18.8, 11.2 Hz, 2F), -130.3 (d, J FF = 30.0, 7.5 Hz, 2F), -141.5 (d, J FF = 30.0, 18.8 Hz, 2F). C 35 H 35 HR-APCI m / z calculated for F6N2O5 [M+H] 677.2442, found 677.2442.

[0298] [ka] 4-(2-(diethylamino)ethoxy)-N-(4-oxo-3,5-bis((E)-2,4,5-trifluorobenzylidene)cyclohexyl)benzamide (JCS156) 1H NMR (500 MHz, CDCl3) δ 7.79 (s, 2H), 7.64 (d, J = 8.8 Hz, 2H), 7.22 − 7.13 (m, 2H), 7.02 − 6.94 (m, 2H), J, 3 = 86 (d). (d, J = 7.4 Hz, 1H), 4.52 - 4.42 (m, 1H), 4.15 (t, J = 5.9 Hz, 2H), 3.12 (br d, J = 15.6 Hz, 2H), 3.05 - 2.70.2, (J = 4q). 4H), 1.13 (t, J = 7.2 Hz, 6H)。 13 C NMR (126 MHz, CDCl3) δ 187.1, 166.6, 161.4, 156.3 (dd, J C-F = 252.0, 8.8 Hz, 2C), 150.6 (dt, J C-F = 254.5, 12.6 Hz, 2C), 146.7 (dd, J C-F = 243.1, 11.3 Hz, 2C), 135.1 (2C), 130.9 (2C), 128.9 (2C), 126.4, 119.5 (dd, J C-F = 15.1, 5.0 Hz, 2C), 118.2 (dd, J C-F = 20.1, 3.7 Hz, 2C), 114.4 (2C), 106.2 (dd, J C-F = 27.7, 3.7 Hz, 2C), 66.1, 51.5, 47.8, 44.6, 34.0, 11.2。 19 F NMR (376 MHz, CDCl3) δ −112.4 (d, J FF = 18.8, 11.2 Hz, 2F), −130.3 (d, J FF = 30.0, 7.5 Hz, 2F), −141.5 (d, J FF = 30.0, 18.8 Hz, 2F)。 C 33 H 31HR-APCI m / z calculated for F6N2O3 [M+H] 617.2231, found 617.2233.

[0299] [ka] 4-((((S)-1-ethylpyrrolidin-2-yl)methyl)amino)-N-(4-oxo-3,5-bis((E)-2,3,4-trifluorobenzylidene)-cyclohexyl)benzamide (JCS157) 1 H NMR (500 MHz, CDCl3) δ 7.83 (s, 2H), 7.50 (d, J = 8.7 Hz, 2H), 7.10 - 6.95 (m, 4H), 6.53 (d, J = 8.7 Hz, 2H), 5.99 (d, J = 7.4 Hz, 1H), 4.81 (br s, 1H), 4.52 - 4.42 (m, 1H), 3.26 - 3.13 (m, 3H), 3.09 (br d, J = 14.3 Hz, 2H), 2.95 (dd, J = 15.6, 8.1 Hz, 2H), 2.83 - 2.77 (m, 1H), 2.26 - 2.18 (m, 1H), 2.26 - 2.15 (m, 2H), 1.95 - 1.65 (m, 4H), 1.09 (t, J = 7.2 Hz, 3H). 13 C NMR (126 MHz, CDCl3) δ 187.4, 166.9, 151.9, 151.6 (dd, J C-F = 254.5, 3.7 Hz, 2C), 149.9 (dd, J C-F = 254.5, 3.7 Hz, 2C), 140.6 (dt, J C-F = 253.2, 15.5 Hz, 2C), 135.5 (2C), 131.1 (2C), 128.6 (2C), 124.49 - 124.37 (m, 2C), 121.3, 121.0 (dd, J C-F = 11.3, 3.7 Hz, 2C), 112.4 (dd, J C-F= 17.6, 3.7 Hz, 2C), 111.8 (2C), 62.6, 53.6, 48.2, 44.4, 44.3, 34.2, 28.6, 22.8, 13.9. 19 F NMR (376 MHz, CDCl3) δ -131.6 (dd, J FF = 26.3, 11.2 Hz, 2F), -131.8 (dd, J FF = 30.0, 15.0 Hz, 2F), -159.3 (t, J FF = 26.3 Hz, 2F). C 34 H 32 HR-APCI m / z calculated for F6N3O2 [M+H] 628.2395, found 628.2393.

[0300] [ka] 4-(2-(bis(2-methoxyethyl)amino)ethoxy)-N-(4-oxo-3,5-bis((E)-2,3,4-trifluorobenzylidene)cyclohexyl)benzamide (JCS158) 1 H NMR (500 MHz, CDCl3) δ 7.79 (s, 2H), 7.59 (d, J = 8.9 Hz, 2H), 7.07 - 6.96 (m, 4H), 6.84 (d, J = 8.9 Hz, 2H), 6.23 (d, J = 7.4 Hz, 1H), 4.47 - 4.40 (m, 1H), 4.06 (t, J = 6.0 Hz, 2H), 3.47 (t, J = 5.8 Hz, 4H), 3.31 (s, 6H), 3.09 (br d, J = 13.8 Hz, 2H), 3.01 (t, J = 6.0 Hz, 2H), 2.94 (dd, J = 15.5, 8.4 Hz, 2H), 2.83 (t, J = 5.8 Hz, 4H). 13 C NMR (126 MHz, CDCl3) δ 187.1, 166.5, 161.6, 151.6 (dd, JC-F = 254.5, 3.7 Hz, 2C), 149.9 (dd, J C-F = 254.5, 3.7 Hz, 2C), 140.6 (dt, J C-F = 253.2, 15.5 Hz, 2C), 135.2 (2C), 131.0 (2C), 128.6 (2C), 126.0, 124.37 - 124.24 (m, 2C), 120.8 (dd, J C-F = 11.3, 3.7 Hz, 2C), 114.3 (2C), 112.3 (dd, J C-F = 17.6, 3.7 Hz, 2C), 71.0, 66.7, 58.8, 54.7, 53.7, 44.5, 33.9. 19 F NMR (376 MHz, CDCl3) δ -131.6 (dd, J FF = 26.3, 11.2 Hz, 2F), -131.8 (dd, J FF = 30.0, 15.0 Hz, 2F), -159.3 (t, J FF = 26.3 Hz, 2F). C 35 H 35 HR-APCI m / z calculated for F6N2O5 [M+H] 677.2446, found 677.2444.

[0301] [ka] 4-(2-(diethylamino)ethoxy)-N-(4-oxo-3,5-bis((E)-2,3,4-trifluorobenzylidene)cyclohexyl)benzamide (JCS159) 1H NMR (500 MHz, CDCl3) δ 7.82 (s, 2H), 7.60 (d, J = 8.8 Hz, 2H), 7.10 - 6.97 (m, 4H), 6.86 (d, J = 8.8 Hz, 2H), 6.8, J .4 (4,5). - 4.42 (m, 1H), 4.09 (t, J = 6.0 Hz, 2H), 3.10 (br d, J = 15.7 Hz, 2H), 3.03 - 2.89 (m, 4H), 2.69 (q, J = 7.2. Hz), J = 4. 6H)。 13 C NMR (126 MHz, CDCl3) δ 187.2, 166.6, 161.6, 151.6 (dd, J C-F = 254.5, 3.7 Hz, 2C), 149.9 (dd, J C-F = 254.5, 3.7 Hz, 2C), 140.6 (dt, J C-F = 253.2, 15.5 Hz, 2C), 135.3 (2C), 131.2 (2C), 128.7 (2C), 126.2, 124.46 - 124.36 (m, 2C), 120.9 (dd, J C-F = 11.3, 3.7 Hz, 2C), 114.4 (2C), 112.4 (dd, J C-F = 17.6, 3.7 Hz, 2C), 66.5, 51.5, 47.8, 44.6, 34.1, 11.4。 19 F NMR (376 MHz, CDCl3) δ −131.4 (dd, J FF = 26.3, 11.2 Hz, 2F), −131.8 (dd, J FF = 30.0, 15.0 Hz, 2F), −159.3 (t, J FF = 26.3 Hz, 2F)。 C 33 H 31 F6N2O3[M+H] is located in the HR-APCI m / z range.

[0302] [ka] N-(3,5-bis((E)-3,4-difluorobenzylidene)-4-oxocyclohexyl)-4-((2-(pyrrolidin-1-yl)ethyl)amino)benzamide (JCS027) To a mixture of N-tert-butyl(4-oxocyclohexyl)carbamate (213.28 mg, 1 mmol, 1.0 equiv.) and ethanol (1.0 mL) in a round-bottom flask, 20% aqueous sodium hydroxide (1.5 mL) was added dropwise and stirred for 5 minutes. 3,4-Difluorobenzaldehyde (355.3 mg, 2.5 mmol, 2.5 equiv.) was added to the mixture. The reaction mixture was then stirred at 21°C for 5 hours. After 5 hours, the yellow precipitate thus obtained was filtered, washed with water and cold ethanol, and dried to give the pure product (360 mg, 78% yield).

[0303] Trifluoroacetic acid (0.5 ml) was added to a solution of N-tert-butyl (3,5-bis((E)-3,4-difluorobenzylidene)-4-oxocyclohexyl)carbamate (230.7 mg, 0.5 mmol) in dichloromethane (5.0 ml) at 21° C., and the mixture was stirred at 21° C. overnight. The solvent of the reaction solution was then distilled off under reduced pressure, and the resulting residue was poured into a 1N aqueous sodium hydroxide solution and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give 4-amino-2,6-bis((E)-3,4-difluorobenzylidene)cyclohexan-1-one.

[0304] A mixture of 4-amino-2,6-bis((E)-3,4-difluorobenzylidene)cyclohexan-1-one (180.7 mg, 0.5 mmol, 1.0 equiv.) and anhydrous diisopropylethylamine (261.2 μL, 1.5 mmol, 3.0 equiv.) in THF was maintained at 0 °C (ice bath). To this cooled mixture, 4-((2-(pyrrolidin-1-yl)ethyl)amino)benzoic acid (117.0 mg, 0.5 mmol, 1.0 equiv.) in 2.0 mL of THF was added dropwise, followed by the addition of TBTU (240.8 mg, 0.75 mmol, 1.5 equiv.). After the complete addition of 4-((2-(pyrrolidin-1-yl)ethyl)amino)benzoic acid, the reaction mixture was allowed to warm slowly to room temperature and stirred overnight. After completion of the reaction, the solvent was evaporated, and the residue was stirred in saturated aqueous NaHCO3 solution for 5 min. The mixture was extracted three times with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate. Evaporation of the solvent, followed by flash chromatography (gradient elution: 50% methanol / ethyl acetate-100% methanol) afforded the desired product, JCS027 (0.172 mg, 60% yield), as a yellow solid.

[0305] Synthesis of 4-((2-(pyrrolidin-1-yl)ethyl)amino)benzoic acid To a microwave vial equipped with a stir bar was added tert-butyl 4-fluorobenzoate (0.502 g, 2.55 mmol, 1.0 equiv.) and 2-(pyrrolidin-1-yl)ethan-1-amine (1.16 g, 10.2 mmol, 4.0 equiv.). The mixture was heated in a microwave at 120 °C for 24 h, then diluted with ethyl acetate (15 mL), washed with saturated aqueous sodium bicarbonate (10 mL) and brine (10 mL), dried over sodium sulfate, and evaporated to give the crude product. Silica gel flash chromatography (gradient elution 10% methanol / EtOAc to 100% methanol) afforded the pure product, tert-butyl 4-((2-(pyrrolidin-1-yl)ethyl)amino)benzoate (0.44 g, 60% yield), as a pale yellow oil. tert-Butyl 4-((2-(pyrrolidin-1-yl)ethyl)amino)benzoate (0.29 g, 1.0 mmol, 1.0 equiv) was dissolved in 6 mL of dichloromethane and trifluoroacetic acid (2 mL) was added dropwise. The mixture was stirred at 21 °C for 5 h. The dichloromethane was removed in vacuo, and the crude residue was washed with dichloromethane and evaporated several times to remove excess trifluoroacetic acid to give 4-((2-(pyrrolidin-1-yl)ethyl)amino)benzoic acid (0.22 g, 90% yield) as a brown solid, sufficiently pure for use in the next step.

[0306] N-(3,5-bis((E)-3,4-difluorobenzylidene)-4-oxocyclohexyl)-4-((2-(pyrrolidin-1-yl)ethyl)amino)benzamide (JCS027) 11H NMR (500 MHz, CDCl3) δ 7.78 (s, 2H), 7.53 (d, J = 8.7 Hz, 2H), 7.27 - 7.15 (m, 6H), 6.54 (d, J = 8.7 Hz, 2H), 6.07 (d, J = 7.3 Hz, 1H), 4.85 (t, J = 5.2 Hz, 1H), 4.53 - 4.45 (m, 1H), 3.30 - 3.18 (m, 4H), 3.04 (dd, J = 17.0, 8.1 Hz, 2H), 2.77 (t, J = 6.0 Hz, 2H), 2.59 (t, J = 6.3 Hz, 4H), 1.83 - 1.80 (m, 4H). 13 13C NMR (126 MHz, CDCl3) δ 188.1, 167.0, 151.3, 150.7 (dd, J CF = 253.2 Hz, J C-CF = 12.6 Hz, 2C), 150.3 (dd, J CF = 249.4 Hz, J C-CF ​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​ N-(3,5-bis((E)-3,4-difluorobenzylidene)-4-oxocyclohexyl)-4-((2-(piperidin-1-yl)ethyl)amino)-benzamide (JCS028) 1 H NMR (500 MHz, CDCl3) δ 7.76 (s, 2H), 7.53 (d, J = 8.6 Hz, 2H), 7.26 - 7.12 (m, 6H), 6.52 (d, J = 8.7 Hz, 2H), 6.15 (d, J = 7.3 Hz, 1H), 4.82 (t, J = 4.9 Hz, 1H), 4.52-4.44 (m, 1H), 3.22 (bd, J = 15.3 Hz, 2H), 3.03 (dd, J = 15.5, 8.0 Hz, 2H), 2.56 (t, J = 6.0 Hz, 2H), 2.39 (t, J = 6.3 Hz, 4H), 1.60-1.54 (m, 4H), 1.47-1.42 (m, 2H). 13 C NMR (126 MHz, CDCl3) δ 188.13, 167.03, 151.2, 150.6 (dd, J CF = 211.6 Hz, J C-CF = 7.5 Hz, 2C), 150.3 (dd, J CF = 207.9 Hz, J C-CF = 10.0 Hz, 2C), 137.7 (2C), 133.1 (2C), 132.3 (dd, J C-C-CF = 5.0 Hz, J C-C-CF = 2.5 Hz, 2C), 128.7 (2C), 127.1 (dd, J C-C-CF = 6.3 Hz, J C-C-CF = 3.7 Hz, 2C), 121.5, 119.0 (d, J C-CF = 15.1 Hz, 2C), 117.6 (d, J C-CF = 15.1 Hz, 2C), 111.8 (2C), 57.0, 54.3, 44.4, 39.8, 33.9, 26.0, 24.4. 19F NMR (376 MHz, CDCl3) δ -135.2 (d, J FF = 22.5 Hz, 2F), -136.6 (d, J FF = 18.8 Hz, 2F). C 34 H 34 HR-APCI m / z calculated for F4N3O2 [M+H] 592.2581, found 592.2578.

[0308] [ka] N-(3,5-bis((E)-3,4-difluorobenzylidene)-4-oxocyclohexyl)-4-((2-(1-methylpyrrolidin-2-yl)ethyl)-amino)benzamide (JCS041) 1 H NMR (500 MHz, CDCl3) δ 7.78 (s, 2H), 7.52 (d, J = 8.3 Hz, 2H), 7.27 - 7.14 (m, 6H), 6.49 (d, J = 8.3 Hz, 2H), 6.04 (d, J = 7.4 Hz, 1H), 4.86 (bs, 1H), 4.52-4.47 (m, 1H), 3.32 - 3.12 (m, 4H), 3.12 - 2.99 (m, 3H), 2.32 (s, 3H), 2.25-2.21 (m, 1H), 2.18 - 2.12 (m, 1H), 1.99 - 1.82 (m, 2H), 1.77 - 1.63 (m, 3H), 1.60 - 1.53 (m, 1H). 13 C NMR (126 MHz, CDCl3) δ 188.16, 167.02, 151.5, 150.7 (dd, J CF = 253.2 Hz, J C-CF = 12.6 Hz, 2C), 150.3 (dd, J CF = 249.4 Hz, J C-CF = 12.6 Hz, 2C), 137.8 (2C), 133.0 (2C), 132.3 (dd, J C-C-CF = 6.3 Hz, J C-C-CF= 3.7 Hz, 2C), 128.7 (2C), 127.1 (dd, J C-C-CF = 6.3 Hz, J C-C-CF = 3.7 Hz, 2C), 121.5, 119.0 (d, J C-CF = 15.1 Hz, 2C), 117.7 (d, J C-CF = 17.6 Hz, 2C), 111.6 (2C), 64.6, 57.2, 44.4, 40.9, 40.8, 33.9, 31.6, 29.9, 22.4. 19 F NMR (376 MHz, CDCl3) δ 135.2 (d, J FF = 22.5 Hz, 2F), 129.6 (d, J FF = 30.0 Hz, 2F). C 34 H 34 HR-APCI m / z calculated for F4N3O2 [M+H] 592.2581, found 592.2578.

[0309] [ka] N-(3,5-bis((E)-3,4-difluorobenzylidene)-4-oxocyclohexyl)-4-((2-morpholinoethyl)amino)benzamide (JCS042) 1 H NMR (500 MHz, CDCl3) δ 7.79 (s, 2H), 7.53 (d, J = 8.7 Hz, 2H), 7.27 - 7.14 (m, 6H), 6.54 (d, J = 8.7 Hz, 2H), 6.02 (d, J = 7.3 Hz, 1H), 4.72 (bs, 1H), 4.53-4.47 (m, 1H), 3.72 (t, J = 4.7 Hz, 4H), 3.24 (bd, J = 15.0 Hz, 2H), 3.18 (t, J = 6.0 Hz, 2H), 3.05 (dd, J = 15.3, 8.1 Hz, 2H), 2.63 (t, J = 5.9 Hz, 2H), 2.47 (t, J = 4.7 Hz, 4H). 13C NMR (126 MHz, CDCl3) δ 188.17, 166.98, 151.6, 150.7 (dd, J CF = 211.6 Hz, J C-CF = 11.3 Hz, 2C), 150.3 (dd, J CF = 209.1 Hz, J C-CF = 11.3 Hz, 2C), 137.8 (2C), 133.0 (2C), 132.3 (dd, J C-C-CF = 6.3 Hz, J C-C-CF = 3.7 Hz, 2C), 128.7 (2C), 127.1 (dd, J C-C-CF = 6.3 Hz, J C-C-CF = 3.7 Hz, 2C), 121.9, 119.0 (d, J C-CF = 13.8 Hz, 2C), 117.7 (d, J C-CF = 15.1 Hz, 2C), 111.9 (2C), 67.0, 56.8, 53.4, 44.4, 39.3, 33.9. 19 F NMR (376 MHz, CDCl3) δ -135.1 (d, J FF = 18.8 Hz, 2F), -136.5 (d, J FF = 18.8 Hz, 2F). C 34 H 32 HR-APCI m / z calculated for F4N3O3 [M+H] 594.2374, found 594.2366.

[0310] [ka] N-(3,5-bis((E)-3,4-difluorobenzylidene)-4-oxocyclohexyl)-4-((2-(4-methylpiperazin-1-yl)ethyl)amino)benzamide (JCS043) 1H NMR (500 MHz, CDCl3) δ 7.81 (s, 2H), 7.52 (d, J = 8.7 Hz, 2H), 7.29 - 7.18 (m, 1H), 6.55 (d, J = 8.7 Hz, 2H), J.3 , J 5.4 ( Hz (t, J = 5.0 Hz, 1H), 4.54–4.48 (m, 1H), 3.25 (bd, J = 15.0 Hz, 2H), 3.17 (q, J = 5.3 Hz, 2H), 3.06 (dd, J = 15.3 Hz, J, =620). Hz, 2H), 2.58–2.41 (m, 8H), 2.30 (s, 3H)。 13 C NMR (126 MHz, CDCl3) δ 188.2, 166.9, 151.4, 150.8 (dd, J CF = 254.5 Hz, J C-CF = 11.3 Hz, 2C), 150.3 (dd, J CF = 249.4 Hz, J C-CF = 11.3 Hz, 2C), 137.9 (2C), 133.0 (2C), 132.3 (dd, J C-C-CF = 6.3 Hz, J C-C-CF = 3.7 Hz, 2C), 128.7 (2C), 127.1 (dd, J C-C-CF = 6.3 Hz, J C-C-CF = 3.7 Hz, 2C), 121.8, 119.1 (d, J C-CF = 17.6Hz, 2C), 117.8 (d, J C-CF = 17.6 Hz, 2C), 111.9 (2C), 56.3, 55.2, 52.8, 46.1, 44.4, 39.7, 34.0。 19 F NMR (376 MHz, CDCl3) at δ 131.0 (d, J FF = 30.0 Hz, 2F), 129.6 (d, J FF = 30.0 Hz, 2F)。C 34 H 35HR-APCI m / z calculated for F4N4O2 [M+H] 607.2690, found 607.2671.

[0311] [ka] N-(3,5-bis((E)-3,4-difluorobenzylidene)-4-oxocyclohexyl)-4-((3-(pyrrolidin-1-yl)propyl)amino)benzamide (JCS044) 1 H NMR (500 MHz, CDCl3) δ 7.80 (s, 2H), 7.52 (d, J = 8.3 Hz, 2H), 7.25 - 7.15 (m, 6H), 6.55 (d, J = 8.3 Hz, 2H), 5.95 (d, J = 7.4 Hz, 1H), 4.70 (bs, 1H), 4.54-4.47 (m, 1H), 3.71 (t, J = 4.6 Hz, 4H), 3.24 (bd, J = 15.0 Hz, 2H), 3.18 (t, J = 5.7 Hz, 2H), 3.05 (dd, J = 15.6, 7.8 Hz, 2H), 2.63 (t, J = 5.7 Hz, 2H), 2.46 (t, J = 4.5 Hz, 4H), 1.64-1.54 (m, 1H). 13 C NMR (126 MHz, CDCl3) δ 188.1, 166.9, 151.3, 150.8 (dd, J CF = 254.5 Hz, J C-CF = 11.3 Hz, 2C), 150.3 (dd, J CF = 249.4 Hz, J C-CF = 11.3 Hz, 2C), 137.9 (2C), 133.0 (2C), 132.3 (dd, J C-C-CF = 6.3 Hz, J C-C-CF = 3.7 Hz, 2C), 128.7 (2C), 127.2 (dd, J C-C-CF = 6.3 Hz, J C-C-CF = 3.7 Hz, 2C), 121.9, 119.1 (d, J C-CF= 17.6Hz, 2C), 117.7 (d, J C-CF = 17.6 Hz, 2C), 111.9 (2C), 67.0, 56.8, 53.4 (2C), 44.4, 39.3, 33.9. 19 F NMR (376 MHz, CDCl3) δ 131.0 (d, J FF = 30.0 Hz, 2F), 129.6 (d, J FF = 30.0 Hz, 2F). C 34 H 34 HR-APCI m / z calculated for F4N3O2 [M+H] 592.2581, found 592.2566.

[0312] [ka] N-(3,5-bis((E)-3,5-dichlorobenzylidene)-4-oxocyclohexyl)-4-((2-(pyrrolidin-1-yl)ethyl)amino)-benzamide (JCS063) 1 H NMR (500 MHz, CDCl3) δ 7.73 (s, 2H), 7.56 (d, J = 8.3 Hz, 2H), 7.36 - 7.34 (m, 2H), 7.28 - 7.26 (m, 4H), 6.56 (d, J = 8.4 Hz, 2H), 6.12 (d, J = 7.5 Hz, 1H), 4.73 (t, J = 5.1 Hz, 1H), 4.56 - 4.51 (m, 1H), 3.27 - 3.16 (m, 4H), 3.08 (dd, J = 15.2, 7.9 Hz, 2H), 2.74 (t, J = 6.0 Hz, 2H), 2.53 (t, J = 5.6 Hz, 4H), 1.80 (t, J = 6.6 Hz, 4H). 13C NMR (126 MHz, CDCl3) δ 187.8, 167.0, 151.5, 138.0 (2C), 137.3 (2C), 135.3, 134.4 (2C), 129.0 (2C), 128.7 (2C), 128.3, 121.5 (2C), 111.8, 54.5, 53.9, 44.2, 41.9, 33.9, 23.6. C 33 H 32 HR-APCI m / z calculated for Cl4N3O2 [M+H] 642.1243, found 642.1222.

[0313] [ka] N-(3,5-bis((E)-3,4-difluorobenzylidene)-4-oxocyclohexyl)-4-((2-(dipropylamino)ethyl)amino)benzamide (JCS065) 1 H NMR (500 MHz, CDCl3) δ 7.80 (s, 2H), 7.51 (d, J = 8.3 Hz, 2H), 7.28 - 7.18 (m, 6H), 6.52 (d, J = 8.3 Hz, 2H), 5.98 (d, J = 7.3 Hz, 1H), 4.94 (bs, 1H), 4.54 - 4.45 (m, 1H), 3.30 - 3.01 (m, 6H), 2.71 (t, J = 5.0 Hz, 2H), 2.43 (t, J = 7.6 Hz, 4H), 1.45 (q, J = 7.5 Hz, 4H), 0.87 (t, J = 7.4 Hz, 6H). 13 C NMR (126 MHz, CDCl3) δ 188.2, 167.0, 151.6, 150.7 (dd, J CF = 253.2 Hz, J C-CF = 12.6 Hz, 2C), 150.3 (dd, J CF = 250.7 Hz, J C-CF = 12.6 Hz, 2C), 137.8 (2C), 133.0 (2C), 132.3 (dd, J C-C-CF= 6.3 Hz, J C-C-CF = 3.7 Hz, 2C), 128.7 (2C), 127.1 (dd, J C-C-CF = 6.3 Hz, J C-C-CF = 3.7 Hz, 2C), 121.6, 119.0 (d, J C-CF = 17.6 Hz, 2C), 117.7 (d, J C-CF = 17.6 Hz, 2C), 112.0 (2C), 55.7, 52.4, 44.4, 40.6, 34.0, 20.1, 12.0. 19 F NMR (376 MHz, CDCl3) δ -135.2 (d, J FF = 18.8 Hz, 2F), -136.6 (d, J FF = 22.5 Hz, 2F). C 35 H 38 HR-APCI m / z calculated for F4N3O2 [M+H] 608.2894, found 608.2891.

[0314] [ka] N-(3,5-bis((E)-3,4-difluorobenzylidene)-4-oxocyclohexyl)-4-((((R)-1-ethylpyrrolidin-2-yl)methyl)-amino)benzamide (JCS066) 1H NMR (500 MHz, CDCl3) δ 7.78 (s, 2H), 7.52 (d, J = 8.7 Hz, 2H), 7.26 - 7.16 (m, 6H), 6.53 (d, J = 8.7 Hz, 2H), 6.04 (d, J = 7.3 Hz, 1H), 4.75 (bs, 1H), 4.52- 4.46 (m, 1H), 3.27 - 3.10 (m, 5H), 3.04 (dd, J = 15.7, 9.0 Hz, 2H), 2.82 - 2.75 (m, 1H), 2.67 - 2.63 (m, 1H), 2.24 - 2.15 (m, 2H), 1.93 - 1.85 (m, 1H), 1.77 - 1.66 (m, 3H), 1.08 (t, J = 7.2 Hz, 3H)。 13 C NMR (126 MHz, CDCl3) δ 188.1, 167.0, 151.7, 150.7 (dd, J CF = 253.2 Hz, J C-CF = 12.6 Hz, 2C), 150.3 (dd, J CF = 249.4 Hz, J C-CF = 12.6 Hz, 2C), 137.8 (2C), 133.1 (2C), 132.3 (dd, J C-C-CF = 6.3 Hz, J C-C-CF = 3.7 Hz, 2C), 128.7 (2C), 127.1 (dd, J C-C-CF = 6.3 Hz, J C-C-CF = 3.7 Hz, 2C), 121.4, 119.0 (d, J C-CF = 17.6 Hz, 2C), 117.7 (d, J C-CF = 17.6 Hz, 2C), 111.8 (2C), 62.9, 53.7, 48.5, 44.4 (2C), 33.9, 28.6, 22.8, 13.6。 19 F NMR (376 MHz, CDCl3) δ 130.9 (d, J FF = 30.0 Hz, 2F), 129.6 (d, J FF = 22.5 Hz, 2F)。C 34 H35 HR-APCI m / z calculated for F4N3O2 [M+H] 592.2581, found 592.2576.

[0315] [ka] N-(3,5-bis((E)-3,4-difluorobenzylidene)-4-oxocyclohexyl)-4-((2-(dibutylamino)ethyl)amino)-benzamide (JCS067) 1 H NMR (500 MHz, CDCl3) δ 7.74 (s, 2H), 7.54 (d, J = 8.7 Hz, 2H), 7.27 - 7.13 (m, 6H), 6.53 (d, J = 8.6 Hz, 2H), 6.49 (d, J = 7.4 Hz, 1H), 4.44 - 4.37 (m, 1H), 3.50 (t, J = 5.7 Hz, 2H), 3.29 - 3.16 (m, 4H), 3.12 - 2.91 (m, 6H), 1.67 - 1.55 (m, 4H), 1.35 - 1.28 (m, 4H), 0.89 (t, J = 7.3 Hz, 6H). 13 C NMR (126 MHz, CDCl3) δ 188.0, 167.0, 150.6 (dd, J CF = 253.2 Hz, J C-CF = 12.6 Hz, 2C), 150.2 (dd, J CF = 249.4 Hz, J C-CF = 12.6 Hz, 2C), 150.0, 137.4 (2C), 133.2 (2C), 132.3 (dd, J C-C-CF = 6.3 Hz, J C-C-CF = 3.7 Hz, 2C), 129.0 (2C), 127.2 (dd, J C-C-CF = 6.3 Hz, J C-C-CF = 3.7 Hz, 2C), 122.7, 119.0 (d, J C-CF = 17.6 Hz, 2C), 117.7 (d, J C-CF= 17.6 Hz, 2C), 111.9 (2C), 53.3, 52.1, 44.8, 38.7, 34.0, 25.5, 20.0, 13.6. 19 F NMR (376 MHz, CDCl3) δ 130.8 (d, J FF = 30.0 Hz, 2F), 129.5 (d, J FF = 30.0 Hz, 2F). C 37 H 42 HR-APCI calculated m / z for F4N3O2 [M+H] = 636.3207, found 636.3208.

[0316] [ka] N-(3,5-bis((E)-3,4-difluorobenzylidene)-4-oxocyclohexyl)-4-((((S)-1-ethylpyrrolidin-2-yl)methyl)-amino)benzamide (JCS069) 1 H NMR (500 MHz, CDCl3) δ 7.78 (s, 2H), 7.51 (d, J = 8.5 Hz, 2H), 7.25 - 7.15 (m, 6H), 6.52 (d, J = 8.5 Hz, 2H), 6.04 (d, J = 7.3 Hz, 1H), 4.69 (bs, 1H), 4.52 - 4.46 (m, 1H), 3.26 - 3.09 (m, 5H), 3.03 (dd, J = 15.2, 8.2 Hz, 2H), 2.81 - 2.74 (m, 1H), 2.65 - 2.60 (m, 2H), 2.24 - 2.12 (m, 2H), 1.92 - 1.86 (m, 1H), 1.76 - 1.65 (m, 3H), 1.08 (t, J = 7.2 Hz, 3H). 13 C NMR (126 MHz, CDCl3) δ 188.1, 167.0, 151.9, 150.7 (dd, J CF = 253.2 Hz, J C-CF = 12.6 Hz, 2C), 150.3 (dd, J CF= 249.4 Hz, J C-CF = 12.6 Hz, 2C), 137.8 (2C), 133.0 (2C), 132.3 (dd, J C-C-CF = 6.3 Hz, J C-C-CF = 3.7 Hz, 2C), 128.7 (2C), 127.1 (dd, J C-C-CF = 6.3 Hz, J C-C-CF = 3.7 Hz, 2C), 121.3, 119.0 (d, J C-CF = 17.6 Hz, 2C), 117.7 (d, J C-CF = 17.6 Hz, 2C), 62.5, 53.6, 48.1, 44.5, 44.3, 33.9, 28.7, 22.7, 14.0. 19 F NMR (376 MHz, CDCl3) δ 131.1 (d, J FF = 26.3 Hz, 2F), 129.6 (d, J FF = 26.3 Hz, 2F). C 34 H 35 HR-APCI m / z calculated for F4N3O2 [M+H] 592.2581, found 592.2585.

[0317] [ka] N-(3,5-bis((E)-3,4-difluorobenzylidene)-4-oxocyclohexyl)-4-((2-(diethylamino)ethyl)amino)benzamide (JCS070) 1H NMR (500 MHz, CDCl3) δ 7.78 (s, 2H), 7.52 (d, J = 8.7 Hz, 2H), 7.26 - 7.16 (m, 6H), 6.53 (d, J = 8.1 Hz, 2H), J.3 , J 4, Hz (8.3). (bs, 1H), 4.52- 4.46 (m, 1H), 3.23 (bd, J = 15.1 Hz, 2H), 3.12 (t, J = 6.0 Hz, 2H), 3.04 (dd, J = 16.5, 8.4 H, J, 6. 2H), 2.54 (q, J = 7.2 Hz, 4H), 1.01 (t, J = 5.0 Hz, 6H)。 13 C NMR (126 MHz, CDCl3) δ 188.18, 167.03, 151.6, 150.7 (dd, J CF = 253.2 Hz, J C-CF = 12.6 Hz, 2C), 150.2 (dd, J CF = 249.4 Hz, J C-CF = 12.6 Hz, 2C), 137.8 (2C), 133.0 (2C), 132.3 (dd, J C-C-CF = 6.3 Hz, J C-C-CF = 3.7 Hz, 2C), 128.7 (2C), 127.1 (dd, J C-C-CF = 6.3 Hz, J C-C-CF = 3.7 Hz, 2C), 121.6, 119.0 (d, J C-CF = 17.6 Hz, 2C), 117.7 (d, J C-CF = 17.6 Hz, 2C), 111.9 (2C), 51.2, 46.6, 44.4, 40.6, 33.9, 11.7。 19 F NMR (376 MHz, CDCl3) δ 131.1 (d, J FF = 30.0 Hz, 2F), 129.6 (d, J FF = 30.0 Hz, 2F)。C 33 H 34HR-APCI m / z calculated for F4N3O2 [M+H] 580.2581, found 580.2530.

[0318] [ka] N-(3,5-bis((E)-3,4-difluorobenzylidene)-4-oxocyclohexyl)-4-(4-methylpiperazin-1-yl)benzamide (JCS071) 1 H NMR (500 MHz, CDCl3) δ 7.76 (s, 2H), 7.59 (d, J = 8.5 Hz, 2H), 7.26 - 7.10 (m, 6H), 6.82 (d, J = 8.6 Hz, 2H), 6.19 (d, J = 7.4 Hz, 1H), 4.52- 4.44 (m, 1H), 3.35 - 3.16 (m, 6H), 3.04 (dd, J = 15.4, 8.2 Hz, 2H), 2.52 (t, J = 5.1 Hz, 4H), 2.33 (s, 3H). 13 C NMR (126 MHz, CDCl3) δ 188.0, 166.7, 153.5, 150.7 (dd, J CF = 316.2 Hz, J C-CF = 15.1 Hz, 2C), 150.3 (dd, J CF = 312.4 Hz, J C-CF = 15.1 Hz, 2C), 137.7 (2C), 132.9 (2C), 132.2 (dd, J C-C-CF = 6.3 Hz, J C-C-CF = 3.7 Hz, 2C), 128.4 (2C), 127.1 (dd, J C-C-CF = 6.3 Hz, J C-C-CF = 3.7 Hz, 2C), 123.4, 119.0 (d, J C-CF = 17.6 Hz, 2C), 117.7 (d, J C-CF = 17.6 Hz, 2C), 114.2 (2C), 54.8, 47.8, 46.2, 44.5, 33.8. 19F NMR (376 MHz, CDCl3) δ -131.1 (d, J FF = 30.0 Hz, 2F), -129.6 (d, J FF = 30.0 Hz, 2F). C 32 H 30 HR-APCI m / z calculated for F4N3O2 [M+H] 564.2268, found 564.2272.

[0319] [ka] N-(3,5-bis((E)-3,4-difluorobenzylidene)-4-oxocyclohexyl)-3-nitro-4-((pyridin-3-ylmethyl)amino)benzamide (JCS082) 1 H NMR (500 MHz, CDCl3) δ 8.63 - 8.49 (m, 4H), 7.87 (d, J = 8.9 Hz, 1H), 7.70 - 7.67 (m, 2H), 7.66 (d, J = 5.0 Hz, 1H), 7.30 - 7.09 (m, 7H), 6.76 (d, J = 9.1 Hz, 1H), 4.59 (d, J = 5.7 Hz, 2H), 4.46- 4.39 (m, 1H), 3.27 (bd, J = 15.0 Hz, 2H), 3.03 (dd, J = 15.0, 9.8 Hz, 2H). 13 C NMR (126 MHz, CDCl3) δ 187.8, 165.0, 150.5 (dd, J CF = 253.2 Hz, J C-CF = 12.6 Hz, 2C), 150.1 (dd, J CF = 250.7 Hz, J C-CF = 12.6 Hz, 2C), 149.0, 148.3, 146.5, 137.4 (2C), 135.6, 135.3, 133.0 (2C), 132.2 (dd, J C-C-CF = 6.3 Hz, J C-C-CF = 3.7 Hz, 2C), 131.3, 127.2 (dd, J C-C-CF= 6.3 Hz, J C-C-CF = 3.7 Hz, 2C), 125.7, 124.1, 121.9, 118.8 (d, J C-CF = 17.6 Hz, 2C), 117.6 (d, J C-CF = 17.6 Hz, 2C), 114.1 (2C), 45.2, 44.7, 33.7. 19 F NMR (376 MHz, CDCl3) δ -135.0 (d, J FF = 26.6 Hz, 2F), -136.5 (d, J FF = 26.6 Hz, 2F). C 33 H 25 HR-APCI m / z calculated for F4N4O4 [M+H] = 617.1779, found 617.1806.

[0320] [ka] N-(3,5-bis((E)-3,4-difluorobenzylidene)-4-oxocyclohexyl)-6-((2-(pyrrolidin-1-yl)ethyl)amino)nicotinamide (JCS086) 1 H NMR (500 MHz, CDCl3) δ 8.40 (s, 1H), 7.76 (s, 2H), 7.73 (d, J = 8.9 Hz, 1H), 7.26 - 7.14 (m, 6H), 6.32 (d, J = 8.8 Hz, 1H), 6.20 (d, J = 7.2 Hz, 1H), 5.56 (t, J = 5.1 Hz, 1H), 4.52- 4.44 (m, 1H), 3.37 (t, J = 6.0 Hz, 2H), 3.22 (bd, J = 15.0 Hz, 2H), 3.06 (dd, J = 15.0, 8.0 Hz, 2H), 2.69 (t, J = 6.0 Hz, 2H), 2.51 (d, J = 6.0 Hz, 4H), 1.85 - 1.67 (m, 4H). 13 C NMR (126 MHz, CDCl3) δ 187.8, 165.8, 160.3, 150.6 (dd, JCF = 316.2 Hz, J C-CF = 12.6 Hz, 2C), 150.2 (dd, J CF = 312.4 Hz, J C-CF = 12.6 Hz, 2C), 147.8, 137.8 (2C), 136.3, 132.7 (2C), 132.1 (dd, J C-C-CF = 6.3 Hz, J C-C-CF = 3.7 Hz, 2C), 127.0 (dd, J C-C-CF = 6.3 Hz, J C-C-CF = 3.7 Hz, 2C), 118.9 (d, J C-CF = 17.6 Hz, 2C), 118.2, 117.6 (d, J C-CF = 17.6 Hz, 2C), 106.5, 54.4, 53.8, 44.3, 40.3, 33.7, 23.5. 19 F NMR (376 MHz, CDCl3) δ -135.0 (d, J FF = 26.6 Hz, 2F), -136.5 (d, J FF = 26.6 Hz, 2F). C 32 H 31 HR-APCI m / z calculated for F4N4O4 [M+H] 579.2389, found 579.2377.

[0321] [ka] 4-((2-(4-benzylpiperazin-1-yl)ethyl)amino)-N-(3,5-bis((E)-3,4-difluorobenzylidene)-4-oxocyclohexyl)benzamide (JCS087) 1H NMR (500 MHz, CDCl3) δ 7.77 (s, 2H), 7.53 (d, J = 8.4 Hz, 2H), 7.34 - 7.15 (m, 11H), 6.53 (d, J = 8.4 Hz, 2H (d)), J = 6.1. 4.76 (s, 1H), 4.51- 4.45 (m, 1H), 3.54 (s, 2H), 3.23 (bd, J = 15.0 Hz, 2H), 3.17 (t, J = 5.9 Hz, 2H), 3.04, 1.04 (dd, J = Hz), (t, J = 5.9 Hz, 2H), 2.52 (m, 8H)。 13 C NMR (126 MHz, CDCl3) δ 188.0, 166.8, 151.2, 150.6 (dd, J CF = 253.2 Hz, J C-CF = 12.6 Hz, 2C), 150.1 (dd, J CF = 250.7 Hz, J C-CF = 12.6 Hz, 2C), 137.6 (2C), 137.4, 132.9 (2C), 132.2 (dd, J C-C-CF = 6.3 Hz, J C-C-CF = 3.7 Hz, 2C), 129.2 (2C), 128.6, 128.3, 127.2, 127.0 (dd, J C-C-CF = 6.3 Hz, J C-C-CF = 3.7 Hz, 2C), 121.6, 118.9 (d, J C-CF = 17.6 Hz, 2C), 117.6 (d, J C-CF = 17.6 Hz, 2C), 111.7 (2C), 62.9, 56.1, 52.7, 52.6, 44.3, 39.5, 33.8。 19 F NMR (376 MHz, CDCl3) at δ 131.0 (d, J FF = 26.6 Hz, 2F), 129.6 (d, J FF = 26.6 Hz, 2F)。C 40 H 39HR-APCI m / z calculated for F4N4O2 [M+H] 683.3018, found 683.3003.

[0322] [ka] N-(3,5-bis((E)-3,4-difluorobenzylidene)-4-oxocyclohexyl)-4-(ethyl(2-(pyrrolidin-1-yl)ethyl)amino)benzamide (JCS073) 1 H NMR (500 MHz, CDCl3) δ 7.75 (s, 2H), 7.59 (d, J = 8.5 Hz, 2H), 7.26 - 7.15 (m, 6H), 6.65 (d, J = 8.5 Hz, 2H), 6.29 (d, J = 7.1 Hz, 1H), 4.53 - 4.38 (m, 1H), 3.65 (t, J = 5.0 Hz, 2H), 3.40 (q, J = 7.2 Hz, 2H), 3.23 (bd, J = 15.3 Hz, 2H), 3.05 (dd, J = 17.0, 8.1 Hz, 2H), 2.96 - 2.80 (m, 6H), 2.02 - 1.88 (m, 4H), 1.13 (t, J = 7.1 Hz, 3H). 13 C NMR (126 MHz, CDCl3) δ 188.1, 166.8, 150.6 (dd, J CF = 254.5 Hz, J C-CF = 12.6 Hz, 2C), 150.2 (dd, J CF = 249.4 Hz, J C-CF = 12.6 Hz, 2C), 149.8, 137.6 (2C), 133.2 (2C), 132.3 (dd, J C-C-CF = 6.3 Hz, J C-C-CF = 3.7 Hz, 2C), 128.9 (2C), 127.2 (dd, J C-C-CF = 6.3 Hz, J C-C-CF = 3.7 Hz, 2C), 120.9, 119.0 (d, J C-CF= 17.6 Hz, 2C), 117.7 (d, J C-CF = 17.6 Hz, 2C), 111.0 (2C), 54.4, 52.6, 48.0, 45.5, 44.5, 34.0, 23.5, 12.2. 19 F NMR (376 MHz, CDCl3) δ 130.9 (d, J FF = 22.5 Hz, 2F), 129.5 (d, J FF = 22.5 Hz, 2F). C 35 H 36 HR-APCI m / z calculated for F4N3O2 [M+H] 606.2738, found 578.2748.

[0323] [ka] N-(3,5-bis((E)-3,4-difluorobenzylidene)-4-oxocyclohexyl)-1-(2-(pyrrolidin-1-yl)ethyl)-1H-indole-5-carboxamide (JCS075) 1 H NMR (500 MHz, CDCl3) δ 7.97 (d, J = 1.5 Hz, 1H), 7.79 (s, 2H), 7.56 (dd, J = 8.6, 1.6 Hz, 1H), 7.34 (d, J = 8.6 Hz, 1H), 7.27 - 7.17 (m, 6H), 6.52 (d, J = 3.1 Hz, 1H), 6.28 (d, J = 7.3 Hz, 1H), 4.57 - 4.53 (m, 1H), 4.30 (t, J = 7.1 Hz, 2H), 3.26 (bd, J = 15.0 Hz, 2H), 3.09 (dd, J = 15.0, 8.0 Hz, 2H), 2.90 (t, J = 7.2 Hz, 2H), 2.56 (t, J = 5.0 Hz, 4H), 1.85 - 1.67 (m, 4H). 13 C NMR (126 MHz, CDCl3) δ 188.1, 168.2, 150.7 (dd, J CF = 253.2 Hz, J C-CF= 12.6 Hz, 2C), 150.3 (dd, J CF = 250.7 Hz, J C-CF = 12.6 Hz, 2C), 137.9, 137.8, 133.0 (2C), 132.3 (dd, J C-C-CF = 6.3 Hz, J C-C-CF = 3.7 Hz, 2C), 129.7, 128.7 (2C), 127.1 (dd, J C-C-CF = 6.3 Hz, J C-C-CF = 3.7 Hz, 2C), 125.4, 120.6, 120.5, 119.1 (d, J C-CF = 17.6 Hz, 2C), 117.7 (d, J C-CF = 17.6 Hz, 2C), 109.4 (2C), 102.7, 55.7, 54.5, 45.8, 44.6, 33.9, 23.6. 19 F NMR (376 MHz, CDCl3) δ 131.0 (d, J FF = 30.0 Hz, 2F), 129.6 (d, J FF = 30.0 Hz, 2F). C 35 H 32 HR-APCI m / z calculated for F4N3O2 [M+H] 602.2425, found 602.2418.

[0324] [ka] N-(3,5-bis((E)-3,4-difluorobenzylidene)-4-oxocyclohexyl)-4-chloro-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide (JCS086) 1 H NMR (500 MHz, CDCl3) δ 8.61 (s, 1H), 7.84 (s, 2H), 7.35 - 7.11 (m, 6H), 6.43 (d, J = 7.1 Hz, 1H), 4.65 - 4.61 (m, 1H), 4.01 (s, 3H), 3.24 (bd, J = 15.6 Hz, 4H), 2.67 (s, 3H).13 C NMR (126 MHz, CDCl3) δ 187.6, 164.4, 151.8, 150.7 (dd, J CF = 254.5 Hz, J C-CF = 12.6 Hz, 2C), 150.3, 150.2 (dd, J CF = 249.4 Hz, J C-CF = 12.6 Hz, 2C), 141.8, 138.4 (2C), 135.6 (2C), 132.1, 132.0 (dd, J C-C-CF = 6.3 Hz, J C-C-CF = 3.7 Hz, 2C), 127.0 (dd, J C-C-CF = 6.3 Hz, J C-C-CF = 3.7 Hz, 2C), 122.2, 118.9 (d, J C-CF = 22.6 Hz, 2C), 117.7 (d, J C-CF = 22.6 Hz, 2C), 112.4, 44.9, 33.8, 33.1, 14.7. 19 F NMR (376 MHz, CDCl3) δ 131.4 (d, J FF = 26.3 Hz, 2F), 129.9 (d, J FF = 26.3 Hz, 2F). HR-APCI m / z calculated for C29H22ClF4N4O2 [M+H] 569.1439, found 569.2319.

[0325] [ka] tert-Butyl (3-((3,5-bis((E)-3,4-difluorobenzylidene)-4-oxocyclohexyl)carbamoyl)-6-(4-(isopropylsulfonyl)phenyl)pyrazin-2-yl)carbamate (JCS088) 11H NMR (500 MHz, DMSO-d6) δ 11.05 (s, 1H), 9.25 (s, 1H), 9.16 (d, J = 7.9 Hz, 1H), 8.52 (d, J = 8.6 Hz, 2H), 8.00 (d, J = 8.6 Hz, 2H), 7.71 - 7.42 (m, 8H), 4.31 - 4.18 (m, 1H), 3.56 - 3.48 (m, 1H), 3.28 - 3.14 (m, 4H), 1.41 (s, 9H), 1.20 (d, J = 6.8 Hz, 6H). 13 13C NMR (126 MHz, DMSO-d6) δ 187.4, 164.8, 149.7, 149.6 (dd, J CF = 250.7 Hz, J C-CF = 12.6 Hz, 2C), 149.3 (dd, J CF = 245.7 Hz, J C-CF = 12.6 Hz, 2C), 147.8, 143.5, 141.6, 139.8, 137.2, 135.4 (2C), 134.4 (2C), 132.6 (dd, J C-C-CF = 6.3 Hz, J C-C-CF = 3.7 Hz, 2C), 129.7, 129.0 (2C), 127.6 (dd, J C-C-CF = 6.3 Hz, J C-C-CF = 3.7 Hz, 2C), 127.2 (2C), 119.2 (d, J C-CF = 17.6 Hz, 2C), 118.4 (2C), 117.8 (d, J C-CF = 17.6 Hz, 2C), 80.3, 54.1, 45.0, 32.7, 27.7, 15.1. 19 19F NMR (376 MHz, DMSO-d6) δ -134.6 (d, J FF = 18.8 Hz, 2F), -136.2 (d, J FF = 22.5 Hz, 2F). C 39 H 37 Calculated HR-APCI m / z for C19H14F4N4O6S [M+H]+: 765.2397, found: 765.2364.

[0326] [ka] 3-Amino-N-(3,5-bis((E)-3,4-difluorobenzylidene)-4-oxocyclohexyl)-5-(4-(isopropylsulfonyl)phenyl)pyrazine-2-carboxamide (JCS089) 1 H NMR (500 MHz, DMSO-d6) δ 8.97 (s, 1H), 8.77 (d, J = 7.8 Hz, 1H), 8.39 (d, J = 8.2 Hz, 2H), 7.92 (d, J = 8.2 Hz, 2H), 7.74 - 7.44 (m, 8H), 4.29 - 4.17 (m, 1H), 3.53 - 3.41 (m, 1H), 3.27 - 3.14 (m, 4H), 1.19 (d, J = 6.9 Hz, 6H). 13 C NMR (126 MHz, DMSO-d6) δ 188.0, 165.8, 154.9, 150.1 (dd, J CF = 252.0 Hz, J C-CF = 12.6 Hz, 2C), 149.7 (dd, J CF = 245.7 Hz, J C-CF = 12.6 Hz, 2C), 145.6, 141.3, 136.5, 136.1, 135.9 (2C), 134.9 (2C), 133.0 (dd, J C-C-CF = 6.3 Hz, J C-C-CF = 3.7 Hz, 2C), 129.4 (2C), 128.0 (dd, J C-C-CF = 6.3 Hz, J C-C-CF = 3.7 Hz, 2C), 126.3 (2C), 124.7, 119.7 (d, J C-CF = 17.6 Hz, 2C), 118.2 (d, J C-CF = 17.6 Hz, 2C), 54.6, 45.0, 33.3, 15.6. 19F NMR (376 MHz, DMSO-d6) δ -136.7 (d, J FF = 22.5 Hz, 2F), -137.8 (d, J FF = 22.5 Hz, 2F). C 34 H 29 HR-APCI m / z calculated for F4N4O4S [M+H] 665.1874, found 665.1840.

[0327] [ka] N-(3,5-bis((E)-3,4-difluorobenzylidene)-4-oxocyclohexyl)-2-((2-(pyrrolidin-1-yl)ethyl)amino)pyrimidine-5-carboxamide (JCS090) 1 H NMR (500 MHz, DMSO-d6) δ 8.70 (s, 2H), 8.49 (d, J = 6.2 Hz, 1H), 7.69 - 7.40 (m, 9H), 4.10 - 4.02 (m, 1H), 3.41 (t, J = 7.1 Hz, 2H), 3.18 (br d, J = 13.3 Hz, 2H), 3.01 (dd, J = 15.0, 8.0 Hz, 2H), 2.57 (t, J = 6.8 Hz, 2H), 2.47 (t, J = 6.4 Hz, 4H), 1.69 - 1.64 (m, 4H). 13 C NMR (126 MHz, DMSO-d6) δ 188.0, 164.1, 163.2, 158.3 (2C), 150.5 (dd, J CF = 249.4 Hz, J C-CF = 12.6 Hz, 2C), 149.7 (dd, J CF = 249.4 Hz, J C-CF = 12.6 Hz, 2C), 135.6 (2C), 135.0 (2C), 132.1 (dd, J C-C-CF = 6.3 Hz, J C-C-CF = 3.7 Hz, 2C), 128.0 (dd, JC-C-CF = 6.3 Hz, J C-C-CF = 3.7 Hz, 2C), 119.5 (d, J C-CF = 17.6 Hz, 2C), 118.2 (d, J C-CF = 17.6 Hz, 2C), 116.3, 54.9, 54.0, 45.2, 40.3, 33.5, 23.5. 19 F NMR (376 MHz, DMSO-d6) δ -136.9 (d, J FF = 22.5 Hz, 2F), -137.9 (d, J FF = 22.5 Hz, 2F). C 31 H 30 HR-APCI m / z calculated for F4N5O2 [M+H] 580.2330, found 580.2306.

[0328] [ka] N-(3,5-bis((E)-3,4-difluorobenzylidene)-4-oxocyclohexyl)-2-cyano-4-((2-(pyrrolidin-1-yl)ethyl)amino)benzamide (JCS091) 1 H NMR (500 MHz, CDCl3) δ 7.80 (s, 2H), 7.60 (d, J = 8.7 Hz, 1H), 7.30 - 7.15 (m, 6H), 6.78 (s, 1H), 6.75 (d, J = 7.2 Hz, 1H), 6.43 (d, J = 7.2 Hz, 1H), 5.32 (br s, 1H), 4.53 - 4.47 (m, 1H), 3.28 - 3.21 (m, 4H), 3.09 (dd, J = 16.1, 8.4 Hz, 2H), 2.83 (t, J = 6.0 Hz, 2H), 2.65 (t, J = 6.3 Hz, 4H), 1.87 - 1.84 (m, 4H). 13 C NMR (126 MHz, CDCl3) δ 187.9, 164.7, 150.7 (dd, JCF = 253.2 Hz, J C-CF = 12.6 Hz, 2C), 150.5 (dd, J CF = 249.4 Hz, J C-CF = 12.6 Hz, 2C), 150.3, 138.1(2C), 132.8 (2C), 132.3 (dd, J C-C-CF = 6.3 Hz, J C-C-CF = 3.7 Hz, 2C), 131.0, 127.1 (dd, J C-C-CF = 6.3 Hz, J C-C-CF = 3.7 Hz, 2C), 124.3, 119.1 (d, J C-CF = 17.6 Hz, 2C), 118.7, 117.7 (d, J C-CF = 17.6 Hz, 2C), 116.3, 116.1, 111.3, 54.1, 53.9, 45.2, 41.2, 33.7, 23.6. 19 F NMR (376 MHz, CDCl3) δ -135.2 (d, J FF = 18.8 Hz, 2F), -136.6 (d, J FF = 22.5 Hz, 2F). C 34 H 31 HR-APCI m / z calculated for F4N4O2 [M+H] 603.2377, found 603.2395.

[0329] [ka] N-(3,5-bis((E)-3,4-difluorobenzylidene)-4-oxocyclohexyl)-5-nitro-6-((2-(pyrrolidin-1-yl)ethyl)amino)nicotinamide (JCS092) 1H NMR (500 MHz, CDCl3) δ 8.82 (d, J = 2.5 Hz, 1H), 8.80 (br s, 1H)8.72 (d, J = 2.3 Hz, 1H), 7.76 (s, 2H), 7.27 ( d , J . 7.65), 7.3 Hz, 1H), 4.53 - 4.45 (m, 1H), 3.78 - 3.74 (m, 2H), 3.29 (br d, J = 15.8 Hz, 2H), 3.08 (dd, J = 17.0, 8.5 Hz), J = 8.5 Hz, 2. 2H), 2.62 (t, J = 5.9 Hz, 4H), 1.89 − 1.71 (m, 4H)。 13 C NMR (126 MHz, CDCl3) δ 187.7, 163.7, 155.3, 153.2, 150.6 (dd, J CF = 253.2 Hz, J C-CF = 12.6 Hz, 2C), 150.2 (dd, J CF = 249.4 Hz, J C-CF = 12.6 Hz, 2C), 137.7, 133.6 (2C), 132.6 (2C), 132.0 (dd, J C-C-CF = 6.3 Hz, J C-C-CF = 3.7 Hz, 2C), 127.1 (dd, J C-C-CF = 6.3 Hz, J C-C-CF = 3.7 Hz, 2C), 126.6, 118.8 (d, J C-CF = 17.6 Hz, 2C), 117.6 (d, J C-CF = 17.6 Hz, 2C), 117.4, 54.0, 53.9, 44.9, 40.2, 33.7, 23.5。 19 F NMR (376 MHz, CDCl3) δ −134.8 (d, J FF = 18.8 Hz, 2F), −136.3 (d, J FF = 18.8 Hz, 2F)。 C 32 H30 HR-APCI m / z calculated for F4N5O4 [M+H] 624.2202, found 624.2228.

[0330] [ka] N-(3,5-bis((E)-3,4-difluorobenzylidene)-4-oxocyclohexyl)-5-((2-(pyrrolidin-1-yl)ethyl)amino)pyrazine-2-carboxamide (JCS093) 1 H NMR (500 MHz, CDCl3) δ 8.70 (s, 1H), 7.78 (s, 2H), 7.70 (s, 1H), 7.56 (d, J = 8.2 Hz, 1H), 7.32 - 7.14 (m, 6H), 5.94 (d, J = 7.3 Hz, 1H), 4.46 - 4.40 (m, 1H), 3.50 - 3.47 (m, 2H), 3.25 (br d, J = 14.4 Hz, 2H), 3.01 (dd, J = 14.4, 9.1 Hz, 2H), 2.75 (t, J = 5.9 Hz, 2H), 2.57 (t, J = 5.9 Hz, 4H), 1.89 - 1.71 (m, 4H). 13 C NMR (126 MHz, CDCl3) δ 187.8, 163.7, 155.6, 150.4 (dd, J CF = 253.2 Hz, J C-CF = 12.6 Hz, 2C), 150.0 (dd, J CF = 249.4 Hz, J C-CF = 12.6 Hz, 2C), 142.9, 137.4 (2C), 132.8 (2C), 132.4, 132.1 (dd, J C-C-CF = 6.3 Hz, J C-C-CF = 3.7 Hz, 2C), 129.8, 126.8 (dd, J C-C-CF = 6.3 Hz, J C-C-CF = 3.7 Hz, 2C), 118.8 (d, J C-CF= 16.3 Hz, 2C), 117.6 (d, J C-CF = 16.3 Hz, 2C), 54.0, 53.6, 43.8, 39.4, 33.8, 23.3. 19 F NMR (376 MHz, CDCl3) δ -135.3 (d, J FF = 18.8 Hz, 2F), -136.6 (d, J FF = 18.8 Hz, 2F). C 31 H 30 HR-APCI m / z calculated for F4N5O2 [M+H] 580.2306, found 580.2330.

[0331] [ka] N-(3,5-bis((E)-3,4-difluorobenzylidene)-4-oxocyclohexyl)-6-((2-(pyrrolidin-1-yl)ethyl)amino)-4-(trifluoromethyl)nicotinamide (JCS094) 1 H NMR (500 MHz, CDCl3) δ 8.18 (s, 1H), 7.81 (s, 2H), 7.29 - 7.18 (m, 6H), 6.58 (s, 1H), 6.32 (s, 1H), 6.02 (d, J = 7.2 Hz, 1H), 4.51 - 4.47 (m, 1H), 3.55 - 3.49 (m, 2H), 3.22 (br d, J = 15.2 Hz, 2H), 3.12 (dd, J = 15.7, 7.0 Hz, 2H), 2.85 (t, J = 5.7 Hz, 2H), 2.72 (t, J = 5.9 Hz, 4H), 1.96 - 1.81 (m, 4H). 13 C NMR (126 MHz, CDCl3) δ 187.6, 165.9, 159.2, 150.6 (dd, J CF = 254.5 Hz, J C-CF = 12.6 Hz, 2C), 150.2 (dd, J CF= 249.4 Hz, J C-CF = 12.6 Hz, 2C), 149.5, 138.1 (2C), 136.1 (q, J C-F = 32.7 Hz, C), 132.3 (2C), 132.0 (dd, J C-C-CF = 6.3 Hz, J C-C-CF = 3.7 Hz, 2C), 127.0 (dd, J C-C-CF = 6.3 Hz, J C-C-CF = 3.7 Hz, 2C), 123.5, 121.3, 118.8 (d, J C-CF = 16.3 Hz, 2C), 117.6 (d, J C-CF = 16.3 Hz, 2C), 117.4, 54.4, 53.8, 44.7, 39.5, 33.0, 23.4. 19 F NMR (376 MHz, CDCl3) δ -61.4 (s, 3F), -135.0 (d, J FF = 18.8 Hz, 2F), -136.5 (d, J FF = 18.8 Hz, 2F). C 33 H 30 HR-APCI m / z calculated for F7N4O2 [M+H] 647.2230, found 647.2251.

[0332] [ka] N-(3,5-bis((E)-3,4-difluorobenzylidene)-4-oxocyclohexyl)-2-((((S)-1-ethylpyrrolidin-2-yl)methyl)-amino)pyrimidine-5-carboxamide (JCS136) 1H NMR (500 MHz, CDCl3) δ 8.71 (s, 2H), 7.73 (s, 2H), 7.30 - 7.16 (m, 6H), 6.70 (br s, 2H), 4.44 - 4.40 (m, 1H), 3.78 - 3.65 (m, 1H), 3.55 - 3.34 (m, 2H), 3.26 (br d, J = 12.6 Hz, 2H), 3.09 - 2.98 (m, 4H), 2.62 - 2.42 (m, 2H), 2.10 - 1.94 (m, 1H), 1.91 - 1.66 (m, 3H), 1.19 (t, J = 7.2 Hz, 3H)。 13 C NMR (126 MHz, CDCl3) δ 187.8, 164.0, 163.4, 158.3 (2C), 150.7 (dd, J CF = 253.2 Hz, J C-CF = 12.6 Hz, 2C), 150.3 (dd, J CF = 249.4 Hz, J C-CF = 12.6 Hz, 2C), 137.5 (2C), 133.0 (2C), 132.3 (dd, J C-C-CF = 6.3 Hz, J C-C-CF = 3.7 Hz, 2C), 127.3 (dd, J C-C-CF = 6.3 Hz, J C-C-CF = 3.7 Hz, 2C), 119.0 (d, J C-CF = 17.6 Hz, 2C), 117.7 (d, J C-CF = 17.6 Hz, 2C), 117.2, 64.4, 53.9, 49.2, 44.9, 43.0, 33.8, 28.1, 23.0, 12.9。 19 F NMR (376 MHz, CDCl3) δ -135.2 (d, J FF = 26.3 Hz, 2F), -136.6 (d, J FF = 26.3 Hz, 2F)。 C 32 H 32HR-APCI m / z calculated for F4N5O2 [M+H] 594.2534, found 594.2486.

[0333] [ka] N-(3,5-bis((E)-3,4-difluorobenzylidene)-4-oxocyclohexyl)-2-cyano-4-((((S)-1-ethylpyrrolidin-2-yl)methyl)amino)benzamide (JCS139) 1 H NMR (500 MHz, CDCl3) δ 7.81 (s, 2H), 7.61 (d, J = 8.2 Hz, 1H), 7.32 - 7.19 (m, 7H), 6.99 (s, 1H), 6.79 (d, J = 8.3 Hz, 1H), 5.41 (br s, 1H), 4.61 - 4.41 (m, 1H), 3.78 (t, J = 14.1 Hz, 2H), 3.29 - 3.07 (m, 5H), 2.85 - 2.72 (m, 2H), 2.33 - 2.20 (m, 2H), 2.02 - 1.93 (m, 1H), 1.85 - 1.69 (m, 3H), 1.15 (t, J = 7.0 Hz, 3H). 13 C NMR (126 MHz, CDCl3) δ 188.1, 167.0, 154.2, 150.7 (dd, J CF = 253.2 Hz, J C-CF = 12.6 Hz, 2C), 150.3 (dd, J CF = 249.4 Hz, J C-CF = 12.6 Hz, 2C), 136.8 (2C), 134.8, 134.0 (2C), 132.7, 132.3 (dd, J C-C-CF = 6.3 Hz, J C-C-CF = 3.7 Hz, 2C), 127.1 (dd, J C-C-CF = 6.3 Hz, J C-C-CF = 3.7 Hz, 2C), 125.3, 119.0 (d, J C-CF= 17.6 Hz, 2C), 118.1, 117.6 (d, J C-CF = 17.6 Hz, 2C), 116.4, 106.1, 62.2, 53.6, 48.0, 46.1, 44.1, 31.5, 28.7, 22.8, 13.9. 19 F NMR (376 MHz, CDCl3) δ -135.5 (d, J FF = 26.3 Hz, 2F), -136.7 (d, J FF = 26.3 Hz, 2F). C 35 H 31 HR-APCI m / z calculated for F4N4O2 [M+H] 615.2397, found 615.2388.

[0334] [ka] N-(3,5-bis((E)-3,4-difluorobenzylidene)-4-oxocyclohexyl)-4-(2-(pyrrolidin-1-yl)acetamido)benzamide (JCS046) To a mixture of tert-butyl (4-oxocyclohexyl)carbamate (213.28 mg, 1 mmol, 1.0 equiv.) and ethanol (1.0 mL) in a round-bottom flask, 20% aqueous sodium hydroxide (1.5 mL) was added dropwise and stirred for 5 minutes. 3,4-Difluorobenzaldehyde (355.3 mg, 2.5 mmol, 2.5 equiv.) was added to the mixture. The reaction mixture was then stirred at room temperature for 5 hours. After 5 hours, the yellow precipitate thus obtained was filtered, washed with water and cold ethanol, and dried to give the pure product (360 mg, 78% yield).

[0335] Trifluoroacetic acid (0.5 ml) was added to a solution of tert-butyl (3,5-bis((E)-3,4-difluorobenzylidene)-4-oxocyclohexyl)carbamate (230.7 mg, 0.5 mmol) in methylene chloride (5.0 ml) at room temperature, and the mixture was stirred at room temperature overnight. The solvent of the reaction solution was then distilled off under reduced pressure, and the resulting residue was poured into a 1N aqueous sodium hydroxide solution and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give 4-amino-2,6-bis((E)-3,4-difluorobenzylidene)cyclohexan-1-one.

[0336] A mixture of 4-amino-2,6-bis((E)-3,4-difluorobenzylidene)cyclohexan-1-one (180.7 mg, 0.5 mmol, 1.0 equiv.) and anhydrous diisopropylethylamine (261.2 μL, 1.5 mmol, 3.0 equiv.) in THF was maintained at 0 °C (ice bath). To this cooled mixture, 4-(2-(pyrrolidin-1-yl)acetamido)benzoic acid hydrochloride (142.0 mg, 0.5 mmol, 1.0 equiv.) in 2.0 mL of THF was added dropwise, followed by the addition of TBTU (240.8 mg, 0.75 mmol, 1.5 equiv.). After the complete addition of 4-(2-(pyrrolidin-1-yl)acetamido)benzoic acid hydrochloride, the reaction mixture was allowed to warm slowly to room temperature and stirred overnight. After completion of the reaction, the solvent was evaporated, and the residue was stirred in saturated aqueous NaHCO3 solution for 5 min. The mixture was extracted three times with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate. Evaporation of the solvent, followed by flash chromatography (gradient elution 20% methanol / EtOAc to 75% methanol / EtOAc) afforded the desired product JCS046 (147.7 mg, 60% yield) as a yellow solid. 1H NMR (500 MHz, CDCl3) δ 9.29 (s, 1H), 7.82 (s, 2H), 7.67 - 7.63 (m, 6H), 7.26 - 7.17 (m, 6H), 6.11 (d, J = 7.3 - Hz), 1H), 3.29 - 3.25 (m, 4H), 3.07 (dd, J = 17.0, 8.1 Hz, 2H), 2.70 (t, J = 6.3 Hz, 4H), 1.87 (t, J = 6.3 Hz, 4H)。 13 C NMR (126 MHz, CDCl3) δ 188.0, 169.6, 166.5, 150.8 (dd, J CF = 253.2 Hz, J C-CF = 12.6 Hz, 2C), 150.3 (dd, J CF = 249.4 Hz, J C-CF = 12.6 Hz, 2C), 141.0, 137.9 (2C), 132.8 (2C), 132.2 (dd, J C-C-CF = 6.3 Hz, J C-C-CF = 3.7 Hz, 2C), 129.2 (2C), 127.2, 127.1 (dd, J C-C-CF = 6.3 Hz, J C-C-CF = 3.7 Hz, 2C), 119.1 (d, J C-CF = 17.6 Hz, 2C), 119.0 (2C), 117.8 (d, J C-CF = 17.6 Hz, 2C), 59.8, 54.8, 44.8, 33.8, 24.2。 19 F NMR (376 MHz, CDCl3) δ −135.0 (d, J FF = 22.5 Hz, 2F), −136.5 (d, J FF = 18.8 Hz, 2F)。 C 33 H 30 F4N3O3[M+H] is located at HR-APCI m / z located at

[0337] Synthesis of 4-(2-(pyrrolidin-1-yl)acetamido)benzoic acid A round-bottom flask equipped with a stir bar was charged with a solution of ethyl 4-aminobenzoate (0.33 g, 2.0 mmol, 1.0 equiv.), dimethylformamide (DMF, 10 mL), 2-(pyrrolidin-1-yl)acetic acid (0.25 g, 2.0 mmol, 1.0 equiv.), HATU (0.83 g, 2.2 mmol, 1.1 equiv.), and diisopropylethylamine (0.69 mL, 4.0 mmol, 2.0 equiv.). The mixture was heated at 21 °C for 16 h, after which ethyl acetate (20 mL) and water (30 mL) were added. The organic layer was washed three times with water and then dried over sodium sulfate. The pure product was obtained by silica gel flash chromatography (gradient elution 10% methanol / EtOAc to 50% methanol / EtOAc) to give the desired product, ethyl 4-(2-(pyrrolidin-1-yl)acetamido)benzoate (0.38 g, 70% yield) as a yellow solid.

[0338] Ethyl 4-(2-(pyrrolidin-1-yl)acetamido)benzoate (0.290 g, 1.0 mmol, 1.0 equiv) was dissolved in 2.5 mL of ethanol and added to a solution of sodium hydroxide (0.2 g) in 2.5 mL of water. The mixture was heated to reflux for 2 h. The ethanol was removed in vacuo, and the aqueous solution was acidified with concentrated HCl at 5 °C. The solid was collected, treated with cold water, filtered, and dried in vacuo at 55 °C-60 °C to give 4-(2-(propylamino)ethoxy)benzoic acid hydrochloride as a white solid (0.25 g, 90% yield) sufficiently pure for use in the next step.

[0339] [ka] N-(3,5-bis((E)-3,4-difluorobenzylidene)-4-oxocyclohexyl)-4-(2-morpholinoacetamido)benzamide (JCS047) 1H NMR (500 MHz, CDCl3) δ 9.21 (s, 1H), 7.80 (s, 2H), 7.73 - 7.55 (m, 4H), 7.27 - 7.16 (m, 6H), 6.22 (d, J = 7.3 - Hz), 1H), 3.78 (t, J = 4.6 Hz, 4H), 3.26 (bd, J = 15.6 Hz, 2H), 3.14 (s, 2H), 3.12 - 3.01 (m, 2H), 2.62 (t, J = 4.6) 。 13 C NMR (126 MHz, CDCl3) δ 187.9, 168.4, 166.4, 150.8 (dd, J CF = 253.2 Hz, J C-CF = 12.6 Hz, 2C), 150.3 (dd, J CF = 249.4 Hz, J C-CF = 12.6 Hz, 2C), 140.7, 138.0 (2C), 132.8 (2C), 132.2 (dd, J C-C-CF = 6.3 Hz, J C-C-CF = 3.7 Hz, 2C), 129.5 (2C), 128.2, 127.2 (dd, J C-C-CF = 6.3 Hz, J C-C-CF = 3.7 Hz, 2C), 119.1 (d, J C-CF = 17.6 Hz, 2C), 119.0 (2C), 117.8 (d, J C-CF = 17.6 Hz, 2C), 67.1, 62.5, 53.9, 44.8, 33.8。 19 F NMR (376 MHz, CDCl3) δ −135.0 (d, J FF = 22.5 Hz, 2F), −136.4 (d, J FF = 22.5 Hz, 2F)。 C 33 H 30 F4N3O4[M+H] is located at HR-APCI m / z location 608.2166.

[0340] [ka] N-(3,5-bis((E)-3,4-difluorobenzylidene)-4-oxocyclohexyl)-4-(2-(2-oxopyrrolidin-1-yl)acetamido)benzamide (JCS048) 1 H NMR (500 MHz, CDCl3) δ 8.83 (s, 1H), 7.81 (s, 2H), 7.60 - 7.48 (m, 4H), 7.28 - 7.18 (m, 6H), 6.19 (d, J = 7.3 Hz, 1H), 4.53 - 4.46 (m, 1H), 4.05 (s, 2H), 3.61 (t, J = 7.1 Hz, 2H), 3.27 (bd, J = 15.2 Hz, 2H), 3.06 (dd, J = 15.9, 8.5 Hz, 2H), 2.49 (t, J = 8.1 Hz, 2H), 2.18 - 2.12 (m, 2H). 13 C NMR (126 MHz, CDCl3) δ 187.9, 177.0, 166.8, 166.6, 150.8 (dd, J CF = 253.2 Hz, J C-CF = 12.6 Hz, 2C), 150.3 (dd, J CF = 249.4 Hz, J C-CF = 12.6 Hz, 2C), 141.0, 138.0 (2C), 132.8 (2C), 132.2 (dd, J C-C-CF = 6.3 Hz, J C-C-CF = 3.7 Hz, 2C), 129.5 (2C), 128.0, 127.2 (dd, J C-C-CF = 6.3 Hz, J C-C-CF = 3.7 Hz, 2C), 119.3 (2C), 119.0 (d, J C-CF = 17.6 Hz, 2C), 117.8 (d, J C-CF = 17.6 Hz, 2C), 49.3, 49.2, 44.8, 33.8, 30.5, 18.2. 19 F NMR (376 MHz, CDCl3) δ -135.0 (d, J FF = 18.8 Hz, 2F), -136.4 (d, J FF = 22.5 Hz, 2F). C 33 H 28 HR-APCI m / z calculated for F4N3O4 [M+H] 606.2010, found 606.1991.

[0341] [ka] N-(3,5-bis((E)-3,4-difluorobenzylidene)-4-oxocyclohexyl)-4-(2-(4-methylpiperazin-1-yl)acetamido)benzamide (JCS050) 1 H NMR (500 MHz, CDCl3) δ 9.29 (s, 1H), 7.76 (d, J = 2.0 Hz, 2H), 7.67 (d, J = 8.8 Hz, 2H), 7.58 (d, J = 8.7 Hz, 2H), 7.25 - 7.13 (m, 6H), 6.45 (d, J = 7.3 Hz, 1H), 4.49 - 4.43 (m, 1H), 3.25 (bd, J = 15.3 Hz, 2H), 3.11 (s, 2H), 3.05 (dd, J = 15.9, 8.7 Hz, 2H), 2.63 (t, J = 5.1 Hz, 2H), 2.49 (t, J = 5.1 Hz, 2H), 2.31 (s, 3H). 13 C NMR (126 MHz, CDCl3) δ 187.9, 168.8, 166.4, 150.7 (dd, J CF = 253.2 Hz, J C-CF = 12.6 Hz, 2C), 150.2 (dd, J CF = 249.4 Hz, J C-CF= 12.6 Hz, 2C), 140.7, 137.8 (2C), 132.9 (2C), 132.2 (dd, J C-C-CF = 6.3 Hz, J C-C-CF = 3.7 Hz, 2C), 129.3 (2C), 128.2, 127.1 (dd, J C-C-CF = 6.3 Hz, J C-C-CF = 3.7 Hz, 2C), 119.0 (d, J C-CF = 17.6 Hz, 2C), 118.9 (2C), 117.8 (d, J C-CF = 17.6 Hz, 2C), 61.9, 55.3, 53.5, 46.0, 44.8, 33.7. 19 F NMR (376 MHz, CDCl3) δ 131.1 (d, J FF = 30.0 Hz, 2F), 129.7 (d, J FF = 30.0 Hz, 2F). C 34 H 33 HR-APCI m / z calculated for F4N4O3 [M+H] 621.2483, found 621.2464.

[0342] [ka] N1-(3,5-bis((E)-3,4-difluorobenzylidene)-4-oxocyclohexyl)-N4-(2-(pyrrolidin-1-yl)ethyl)terephthalamide (JCS076) 1H NMR (500 MHz, CDCl3) δ 9.01 (t, J = 5.7 Hz, 1H), 8.17 (d, J = 8.1 Hz, 2H), 7.90 (s, 2H), 7.86 (d, J = 8.2 Hz, 2H), 7.31 ( 7.41 ). (d, J = 7.2 Hz, 1H), 4.59 - 4.52 (m, 1H), 4.04 - 3.96 (m, 4H), 3.48 - 3.43 (m, 2H), 3.42 (bd, J = 19.8 Hz, 2. 2H), Hz, 2H), 3.02 (t, J = 8.9 Hz, 2H), 2.41 − 2.18 (m, 4H)。 13 C NMR (126 MHz, CDCl3) δ 187.8, 166.8, 166.5, 150.7 (dd, J CF = 254.5 Hz, J C-CF = 12.6 Hz, 2C), 150.3 (dd, J CF = 249.4 Hz, J C-CF = 12.6 Hz, 2C), 137.8, 136.8, 136.5, 132.9 (2C), 132.2 (dd, J C-C-CF = 6.3 Hz, J C-C-CF = 3.7 Hz, 2C), 127.8 (2C), 127.3 (2C), 127.2 (dd, J C-C-CF = 6.3 Hz, J C-C-CF = 3.7 Hz, 2C), 119.0 (d, J C-CF = 17.6 Hz, 2C), 117.8 (d, J C-CF = 17.6 Hz, 2C), 55.7, 54.5, 45.2, 37.0, 33.8, 23.5。 19 F NMR (376 MHz, CDCl3) at δ 131.0 (d, J FF = 30.0 Hz, 2F), −129.6 (d, J FF = 30.0 Hz, 2F)。 C 34 H32 HR-APCI m / z calculated for F4N3O3 [M+H] 606.2374, found 606.2386.

[0343] [ka] N-(3,5-bis((E)-3,4-difluorobenzylidene)-4-oxocyclohexyl)-4-(3,3-dipropylureido)benzamide (JCS051) To a mixture of tert-butyl (4-oxocyclohexyl)carbamate (213.28 mg, 1 mmol, 1.0 equiv.) and ethanol (1.0 mL) in a round-bottom flask, 20% aqueous sodium hydroxide (1.5 mL) was added dropwise and stirred for 5 minutes. 3,4-Difluorobenzaldehyde (355.3 mg, 2.5 mmol, 2.5 equiv.) was added to the mixture. The reaction mixture was then stirred at room temperature for 5 hours. After 5 hours, the yellow precipitate thus obtained was filtered, washed with water and cold ethanol, and dried to give the pure product (360 mg, 78% yield).

[0344] Trifluoroacetic acid (0.5 ml) was added to a solution of tert-butyl (3,5-bis((E)-3,4-difluorobenzylidene)-4-oxocyclohexyl)carbamate (230.7 mg, 0.5 mmol) in methylene chloride (5.0 ml) at room temperature, and the mixture was stirred at room temperature overnight. The solvent of the reaction solution was then distilled off under reduced pressure, and the resulting residue was poured into a 1N aqueous sodium hydroxide solution and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give 4-amino-2,6-bis((E)-3,4-difluorobenzylidene)cyclohexan-1-one.

[0345] A mixture of 4-amino-2,6-bis((E)-3,4-difluorobenzylidene)cyclohexan-1-one (180.7 mg, 0.5 mmol, 1.0 equiv.) and anhydrous diisopropylethylamine (261.2 μL, 1.5 mmol, 3.0 equiv.) in THF was maintained at 0 °C (ice bath). To this cooled mixture, 4-(3,3-dipropylureido)benzoic acid hydrochloride (150.3 mg, 0.5 mmol, 1.0 equiv.) in 2.0 mL of THF was added dropwise, followed by the addition of TBTU (240.8 mg, 0.75 mmol, 1.5 equiv.). After the complete addition of 4-(3,3-dipropylureido)benzoic acid hydrochloride, the reaction mixture was allowed to warm slowly to room temperature and stirred overnight. After completion of the reaction, the solvent was evaporated, and the residue was stirred in saturated aqueous NaHCO3 solution for 5 min. The mixture was extracted three times with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and then dried over anhydrous sodium sulfate. Evaporation of the solvent, followed by flash chromatography (gradient elution 20% methanol / EtOAc to 75% methanol / EtOAc) afforded the desired product JCS051 (182 mg, 60% yield) as a yellow solid. 1 H NMR (500 MHz, DMSO-d6) δ 8.40 (d, J = 6.6 Hz, 1H), 8.36 (s, 1H), 7.78 - 7.70 (br d, J = 8.2 Hz, 2H), 7.70 - 7.60 (m, 4H), 7.59 - 7.49 (m, 4H), 7.46 - 7.39 (m, 2H), 4.11 - 4.04 (m, 1H), 3.25 (t, J = 7.0 Hz, 4H), 3.19 (br d, J = 15.0 Hz, 2H), 3.01 (dd, J = 15.0, 8.1 Hz, 2H), 1.51 (sextet, J = 7.4 Hz, 4H), 0.85 (t, J = 7.4 Hz, 6H). 13 C NMR (126 MHz, DMSO-d6) δ 187.6, 165.7, 154.4, 149.6 (dd, J CF = 250.7 Hz, J C-CF= 12.6 Hz, 2C), 149.3 (dd, J CF = 246.9 Hz, J C-CF = 12.6 Hz, 2C), 143.7, 135.1 (2C), 134.7 (2C), 132.7 (dd, J C-C-CF = 6.3 Hz, J C-C-CF = 3.7 Hz, 2C), 127.7 (2C), 127.6 (dd, J C-C-CF = 6.3 Hz, J C-C-CF = 3.7 Hz, 2C),126.7, 119.1 (d, J C-CF = 17.6 Hz, 2C), 118.4 (2C), 117.8 (d, J C-CF = 17.6 Hz, 2C), 48.0, 45.0, 33.1, 21.2, 11.1. 19 F NMR (376 MHz, DMSO-d6) δ -136.9 (d, J FF = 22.5 Hz, 2F), -137.9 (d, J FF = 18.8 Hz, 2F). C 34 H 34 HR-APCI m / z calculated for F4N3O3 [M+H] 608.2530, found 608.2517.

[0346] Synthesis of 4-(3,3-dipropylureido)benzoic acid To a round-bottom flask equipped with a stir bar was added a solution of methyl 4-isocyanatobenzoate (0.35 g, 2.0 mmol, 1.0 equiv) in THF (5 mL). Dipropylamine (0.22 g, 2.2 mmol, 1.1 equiv) was then added in one portion, and the reaction mixture was stirred at 21 °C overnight. The solution was concentrated to a slurry, diluted with ether, and filtered to give methyl 4-(3,3-dipropylureido)benzoate as a white solid (0.50 g, 90%), sufficiently pure for use in the next step.

[0347] Methyl 4-(3,3-dipropylureido)benzoate (0.27 g, 1.0 mmol, 1.0 equiv) was dissolved in 2.5 mL of ethanol and added to a solution of sodium hydroxide (0.2 g) in 2.5 mL of water. The mixture was heated to reflux for 2 h. The ethanol was removed in vacuo, and the aqueous solution was acidified with concentrated HCl at 5 °C. The solid was collected, treated with cold water, filtered, and dried in vacuo at 55 °C–60 °C to give 4-(3,3-dipropylureido)benzoic acid hydrochloride as a white solid (0.27 g, 90% yield) sufficiently pure for use in the next step.

[0348] [ka] N-(3,5-bis((E)-3,4-difluorobenzylidene)-4-oxocyclohexyl)-4-(3,3-bis(2-methoxyethyl)ureido)benzamide (JCS052) 1 H NMR (500 MHz, DMSO-d6) δ 8.57 (s, 1H), 8.41 (d, J = 6.6 Hz, 1H), 7.74 (d, J = 8.7 Hz, 2H), 7.69 - 7.60 (m, 4H), 7.56 - 7.38 (m, 6H), 4.12 - 4.04 (m, 1H), 3.53 - 3.48 (m, 8H), 3.29 (s, 6H), 3.19 (bd, J = 15.7 Hz, 2H), 3.01 (dd, J = 15.0, 8.1 Hz, 2H). 13 C NMR (126 MHz, DMSO-d6) δ 187.6, 165.7, 154.9, 149.6 (dd, J CF = 250.7 Hz, J C-CF = 12.6 Hz, 2C), 149.3 (dd, J CF = 246.9 Hz, J C-CF = 12.6 Hz, 2C), 143.4, 135.1 (2C), 134.7 (2C), 132.7 (dd, J C-C-CF = 6.3 Hz, J C-C-CF= 3.7 Hz, 2C), 128.0 (2C), 127.6 (dd, J C-C-CF = 6.3 Hz, J C-C-CF = 3.7 Hz, 2C),126.9, 119.1 (d, J C-CF = 17.6 Hz, 2C), 118.0 (2C), 117.8 (d, J C-CF = 17.6 Hz, 2C), 70.9, 58.2, 47.1, 45.0, 33.1. 19 F NMR (376 MHz, DMSO-d6) δ -136.9 (d, J FF = 22.5 Hz, 2F), -137.9 (d, J FF = 22.5 Hz, 2F). C 34 H 34 HR-APCI m / z calculated for F4N3O5 [M+H] 640.2429, found 640.2407.

[0349] [ka] N-(4-((3,5-bis((E)-3,4-difluorobenzylidene)-4-oxocyclohexyl)carbamoyl)phenyl)piperidine-1-carboxamide (JCS053) 1 H NMR (500 MHz, DMSO-d6) δ 8.68 (s, 1H), 8.39 (d, J = 6.5 Hz, 1H), 7.73 (d, J = 8.5 Hz, 2H), 7.69 - 7.61 (m, 4H), 7.55 - 7.51 (m, 4H), 7.49 - 7.40 (m, 2H), 4.10 - 4.05 (m, 1H), 3.42 (t, J = 5.4 Hz, 4H), 3.19 (bd, J = 15.0 Hz, 2H), 3.01 (dd, J = 15.0, 8.1 Hz, 2H), 1.59 - 1.55 (m, 2H), 1.50 - 1.46 (m, 4H). 13 C NMR (126 MHz, DMSO-d6) δ 187.6, 165.7, 154.4, 149.6 (dd, JCF = 250.7 Hz, J C-CF = 12.6 Hz, 2C), 149.3 (dd, J CF = 246.9 Hz, J C-CF = 12.6 Hz, 2C), 143.8, 135.1 (2C), 134.7 (2C), 132.7 (dd, J C-C-CF = 6.3 Hz, J C-C-CF = 3.7 Hz, 2C), 127.8 (2C), 127.6 (dd, J C-C-CF = 6.3 Hz, J C-C-CF = 3.7 Hz, 2C),126.6, 119.1 (d, J C-CF = 17.6 Hz, 2C), 118.0 (2C), 117.8 (d, J C-CF = 17.6 Hz, 2C), 45.0, 44.6, 33.1, 25.5, 24.0. 19 F NMR (376 MHz, DMSO-d6) δ -136.9 (d, J FF = 22.5 Hz, 2F), -137.9 (d, J FF = 22.5 Hz, 2F). C 33 H 30 HR-APCI m / z calculated for F4N3O3 [M+H] 592.2217, found 592.2202.

[0350] [ka] N-(4-((3,5-bis((E)-3,4-difluorobenzylidene)-4-oxocyclohexyl)carbamoyl)phenyl)pyrrolidine-1-carboxamide (JCS054) 1H NMR (500 MHz, DMSO-d6) δ 8.39 (d, J = 6.6 Hz, 1H), 8.35 (s, 1H), 7.73 (d, J = 8.5 Hz, 2H), 7.70 - 7.58 (m. 74 H), - m , 7.5. - 7.38 (m, 2H), 4.13 - 4.04 (m, 1H), 3.37 (t, J = 5.0 Hz, 4H), 3.19 (bd, J = 15.5 Hz, 2H), 3.01 (dd, J = 1.0 Hz), 1.0 Hz, 8.8. (m, 4H)。 13 C NMR (126 MHz, DMSO-d6) δ 187.5, 165.7, 153.5, 149.6 (dd, J CF = 250.7 Hz, J C-CF = 12.6 Hz, 2C), 149.3 (dd, J CF = 246.9 Hz, J C-CF = 12.6 Hz, 2C), 143.6, 135.1 (2C), 134.6 (2C), 132.7 (dd, J C-C-CF = 6.3 Hz, J C-C-CF = 3.7 Hz, 2C), 127.8 (2C), 127.6 (dd, J C-C-CF = 6.3 Hz, J C-C-CF = 3.7 Hz, 2C), 126.6, 119.1 (d, J C-CF = 17.6 Hz, 2C), 117.9 (2C), 117.8 (d, J C-CF = 17.6 Hz, 2C), 45.7, 45.0, 33.1, 25.0。 19 F NMR (376 MHz, DMSO-d6) δ −136.9 (d, J FF = 22.5 Hz, 2F), −137.9 (d, J FF = 22.5 Hz, 2F)。C 32 H 28 F4N3O3[M+H] is located in HR-APCI m / z contact area 578.2061.

[0351] [ka] N-(4-((3,5-bis((E)-3,4-difluorobenzylidene)-4-oxocyclohexyl)carbamoyl)phenyl)azetidine-1-carboxamide (JCS055) 1 H NMR (500 MHz, DMSO-d6) δ 8.59 (s, 1H), 8.39 (d, J = 6.5 Hz, 1H), 7.73 (d, J = 8.4 Hz, 2H), 7.70 - 7.48 (m, 8H), 7.49 - 7.40 (m, 2H), 4.13 - 4.04 (m, 1H), 3.96 (t, J = 7.6 Hz, 4H), 3.18 (bd, J = 15.6 Hz, 2H), 3.01 (dd, J = 15.0, 8.1 Hz, 2H), 2.20 - 2.14 (m, 4H). 13 C NMR (126 MHz, DMSO-d6) δ 187.5, 165.7, 156.2, 149.6 (dd, J CF = 250.7 Hz, J C-CF = 12.6 Hz, 2C), 149.3 (dd, J CF = 246.9 Hz, J C-CF = 12.6 Hz, 2C), 143.2, 135.1 (2C), 134.6 (2C), 132.7 (dd, J C-C-CF = 6.3 Hz, J C-C-CF = 3.7 Hz, 2C), 128.0 (2C), 127.6 (dd, J C-C-CF = 6.3 Hz, J C-C-CF = 3.7 Hz, 2C),127.6, 119.1 (d, J C-CF = 17.6 Hz, 2C), 117.7 (d, J C-CF = 17.6 Hz, 2C), 117.3 (2C), 49.3, 45.0, 33.1, 14.7. 19 F NMR (376 MHz, DMSO-d6) δ 129.3 (d, J FF= 30.8 Hz, 2F), 128.3 (d, J FF = 30.8 Hz, 2F). C 31 H 26 HR-APCI m / z calculated for F4N3O3 [M+H] 564.1904, found 564.1892.

[0352] [ka] N-(4-((3,5-bis((E)-3,4-difluorobenzylidene)-4-oxocyclohexyl)carbamoyl)phenyl)isoindoline-2-carboxamide (JCS056) 1 H NMR (500 MHz, acetone-d6) δ 8.00 (s, 1H), 7.77 (d, J = 5.0 Hz, 2H), 7.71 - 7.69 (m, 3H), 7.58 - 7.53 (m, 2H), 7.46 - 7.29 (m, 8H), 4.84 (s, 4H), 4.37 - 4.29 (m, 1H), 3.41 (bd, J = 15.1 Hz, 2H), 3.15 (dd, J = 15.2, 12.1 Hz, 2H). 13 C NMR (126 MHz, acetone-d6) δ 188.1, 166.8, 154.4, 151.0 (dd, J CF = 250.7 Hz, J C-CF = 12.6 Hz, 2C), 150.8 (dd, J CF = 246.9 Hz, J C-CF = 12.6 Hz, 2C), 144.5, 137.8 (2C), 136.3, 135.6 (2C), 134.0 (dd, J C-C-CF = 6.3 Hz, J C-C-CF = 3.7 Hz, 2C), 128.7 (2C), 128.6, 128.3 (dd, J C-C-CF = 6.3 Hz, J C-C-CF = 3.7 Hz, 2C),128.2, 123.6, 118.4 (d, J C-CF= 17.6 Hz, 2C), 118.9 (2C), 118.7 (d, J C-CF = 17.6 Hz, 2C), 52.7, 46.3, 34.4. 19 F NMR (376 MHz, acetone-d6) δ -129.3 (d, J FF = 30.8 Hz, 2F), -128.3 (d, J FF = 30.8 Hz, 2F). C 36 H 28 HR-APCI m / z calculated for F4N3O3 [M+H] 626.2061, found 626.2044.

[0353] [ka] N-(4-((3,5-bis((E)-3,4-difluorobenzylidene)-4-oxocyclohexyl)carbamoyl)phenyl)-4-(cyclopropanecarbonyl)piperazine-1-carboxamide (JCS057) 1 H NMR (500 MHz, CDCl3) δ 7.70 (s, 2H), 7.54 (s, 1H), 7.52 (d, J = 8.4 Hz, 2H), 7.33 (d, J = 8.4 Hz, 2H), 7.22 - 7.11 (m, 6H), 6.89 (d, J = 7.3 Hz, 1H), 4.40 - 4.33 (m, 1H), 3.65 - 3.40 (m, 8H), 3.23 (bd, J = 15.2 Hz, 2H), 3.01 (dd, J = 15.2, 9.9 Hz, 2H), 0.95 - 0.92 (m, 1H), 1.72 - 1.67 (m, 2H), 0.83 - 0.70 (m, 2H). 13 C NMR (126 MHz, CDCl3) δ 188.0, 172.6, 167.1, 154.9, 150.6 (dd, J CF = 253.2 Hz, J C-CF = 12.6 Hz, 2C), 150.2 (dd, J CF = 249.4 Hz, JC-CF = 12.6 Hz, 2C), 142.6, 137.5 (2C), 133.1 (2C), 132.2 (dd, J C-C-CF = 6.3 Hz, J C-C-CF = 3.7 Hz, 2C), 128.3 (2C), 127.9, 127.2 (dd, J C-C-CF = 6.3 Hz, J C-C-CF = 3.7 Hz, 2C), 119.5 (2C), 118.8 (d, J C-CF = 17.6 Hz, 2C), 117.7 (d, J C-CF = 17.6 Hz, 2C), 45.2, 45.1, 44.1, 43.5, 41.5, 33.82, 11.1, 7.9. 19 F NMR (376 MHz, CDCl3) δ 131.1 (d, J FF = 26.3 Hz, 2F), 129.6 (d, J FF = 26.3 Hz, 2F). C 36 H 33 HR-APCI m / z calculated for F4N4O4 [M+H] 661.2432, found 661.2411.

[0354] [ka] N-(3,5-bis((E)-3,4-difluorobenzylidene)-4-oxocyclohexyl)-4-(3,3-bis(3-(dimethylamino)propyl)ureido)benzamide (JCS058) 11H NMR (500 MHz, acetone-d6) δ 10.40 (s, 1H), 7.77 (d, J = 8.5 Hz, 3H), 7.70 (s, 2H), 7.59 - 7.51 (m, 4H), 7.42 (dd, J = 8.9, 6.6 Hz, 4H), 4.35 - 4.27 (m, 1H), 3.55 (t, J = 6.2 Hz, 4H), 3.39 (bd, J = 15.8 Hz, 2H), 3.15 (dd, J = 15.2, 12.1 Hz, 2H), 2.97 - 2.88 (m, 4H), 2.80 - 2.67 (m, 12H). 13 13C NMR (126 MHz, acetone-d6) δ 188.1, 166.7, 158.9, 151.0 (dd, J CF = 250.7 Hz, J C-CF = 12.6 Hz, 2C), 150.8 (dd, J CF = 246.9 Hz, J C-CF [[ID=X]] = 12.6 Hz, 2C), 144.6, 136.3 (2C), 135.6 (2C), 134.0 (dd, J C-C-CF = 6.3 Hz, J C-C-CF = 3.7 Hz, 2C), 128.7 (2C), 128.9, 128.4 (dd, J C-C-CF = 6.3 Hz, J C-C-CF = 3.7 Hz, 2C), 119.7 (d, J C-CF = 17.6 Hz, 2C), 119.0 (2C), 118.4 (d, J C-CF = 17.6 Hz, 2C), 55.1, 46.3, 43.9, 42.7, 34.3, 23.9. 19 19F NMR (376 MHz, acetone-d6) δ -138.5 (d, J FF = 22.5 Hz, 2F), -139.3 (d, J FF = 18.8 Hz, 2F). C 38 H 44 Calculated HR-APCI m / z for C14H15F4N5O3[M+H] 694.3374, found 694.3348.

[0355] [ka] N-(3,5-bis((E)-3,4-difluorobenzylidene)-4-oxocyclohexyl)-4-(3,3-diethylureido)benzamide (JCS059) 1 H NMR (500 MHz, CDCl3) δ 7.79 (s, 2H), 7.59 (dd, J = 8.7, 3.2 Hz, 2H), 7.42 (dd, J = 8.7, 3.1 Hz, 2H), 7.27 - 7.16 (m, 6H), 6.47 (s, 1H), 6.28 - 6.19 (m, 1H), 4.50 - 4.43 (m, 1H), 3.40 - 3.34 (m, 4H), 3.26 (bd, J = 15.7 Hz, 2H), 3.04 (dd, J = 15.8, 8.3 Hz, 2H), 1.22 (t, J = 7.1 Hz, 6H). 13 C NMR (126 MHz, CDCl3) δ 188.0, 166.7, 154.1, 150.7 (dd, J CF = 253.2 Hz, J C-CF = 12.6 Hz, 2C), 150.3 (dd, J CF = 249.4 Hz, J C-CF = 12.6 Hz, 2C), 142.8, 137.8 (2C), 132.9 (2C), 132.2 (dd, J C-C-CF = 6.3 Hz, J C-C-CF = 3.7 Hz, 2C), 128.0 (2C), 127.8, 127.1 (dd, J C-C-CF = 6.3 Hz, J C-C-CF = 3.7 Hz, 2C), 119.0 (d, J C-CF = 17.6 Hz, 2C), 118.9 (2C), 117.7 (d, J C-CF = 17.6 Hz, 2C), 44.8, 41.8, 33.9, 14.0. 19F NMR (376 MHz, CDCl3) δ -135.1 (d, J FF = 22.5 Hz, 2F), -136.5 (d, J FF = 22.5 Hz, 2F). C 32 H 30 HR-APCI m / z calculated for F4N3O3 [M+H] 580.2217, found 580.2198.

[0356] [ka] N-(3,5-bis((E)-3,4-difluorobenzylidene)-4-oxocyclohexyl)-4-(3,3-dibutylureido)benzamide (JCS060) 1 H NMR (500 MHz, CDCl3) δ 7.78 (s, 2H), 7.59 (d, J = 8.3 Hz, 2H), 7.40 (d, J = 8.3 Hz, 2H), 7.26 - 7.14 (m, 6H), 6.49 (s, 1H), 6.31 (d, J = 7.3 Hz, 1H), 4.50 - 4.42 (m, 1H), 3.30 - 3.23 (m, 6H), 3.03 (dd, J = 15.5, 8.6 Hz, 2H), 1.62 - 1.55 (m, 4H), 1.40 - 1.31 (m, 4H), 0.95 (t, J = 7.3 Hz, 6H). 13 C NMR (126 MHz, CDCl3) δ 188.0, 166.7, 154.4, 150.7 (dd, J CF = 253.2 Hz, J C-CF = 12.6 Hz, 2C), 150.3 (dd, J CF = 249.4 Hz, J C-CF = 12.6 Hz, 2C), 142.8, 137.8 (2C), 133.0 (2C), 132.2 (dd, J C-C-CF = 6.3 Hz, J C-C-CF = 3.7 Hz, 2C), 128.0 (2C), 127.7, 127.1 (dd, JC-C-CF = 6.3 Hz, J C-C-CF = 3.7 Hz, 2C), 119.0 (d, J C-CF = 17.6 Hz, 2C), 118.8 (2C), 117.7 (d, J C-CF = 17.6 Hz, 2C), ￥ 47.6, 44.8, 33.9, 30.8, 20.3, 14.0. 19 F NMR (376 MHz, CDCl3) δ -135.1 (d, J FF = 22.5 Hz, 2F), -136.5 (d, J FF = 22.5 Hz, 2F). C 36 H 38 HR-APCI m / z calculated for F4N3O3 [M+H] 636.2843, found 636.2805.

[0357] General Procedure C: The compounds were typically prepared by reacting the corresponding aldehyde, e.g., 3,4-difluorobenzaldehyde, with tert-butyl(4-oxocyclohexyl)carbamate in the presence of 20% aqueous sodium hydroxide to give N-tert-butyl(3,5-bis((E)-3,4-difluorobenzylidene)-4-oxocyclohexyl)carbamate. The Boc group was deprotected by treating the product with trifluoroacetic acid (TFA). The BOC-deprotected amine was subjected to hydrogenation to give 4-amino-2,6-bis(3,4-difluorobenzyl)cyclohexan-1-one. 4-Amino-2,6-bis(3,4-difluorobenzyl)cyclohexan-1-one was benzoylated with 4-((2-(pyrrolidin-1-yl)ethyl)amino)benzoic acid using standard peptide coupling reagents TBTU or EDC and HOAt to give N-(3,5-bis(3,4-difluorobenzyl)-4-oxocyclohexyl)-4-((2-(pyrrolidin-1-yl)ethyl)amino)benzamide.

[0358] [ka] Example JCS072: To a mixture of N-tert-butyl(4-oxocyclohexyl)carbamate (213.28 mg, 1 mmol, 1.0 equiv.) and ethanol (1.0 mL) in a round-bottom flask, 20% aqueous sodium hydroxide (1.5 mL) was added dropwise and stirred for 5 minutes. 3,4-Difluorobenzaldehyde (355.3 mg, 2.5 mmol, 2.5 equiv.) was added to the mixture. The reaction mixture was then stirred at 21°C for 5 hours. After 5 hours, the yellow precipitate thus obtained was filtered, washed with water and cold ethanol, and dried to give the pure product (360 mg, 78% yield).

[0359] Trifluoroacetic acid (1.0 ml) was added to a solution of N-tert-butyl (3,5-bis((E)-3,4-difluorobenzylidene)-4-oxocyclohexyl)carbamate (461.4 mg, 1.0 mmol) in dichloromethane (5.0 ml) at 21° C., and the mixture was stirred at 21° C. overnight. The solvent of the reaction solution was then distilled off under reduced pressure, and the resulting residue was poured into a 1N aqueous sodium hydroxide solution and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give 4-amino-2,6-bis((E)-3,4-difluorobenzylidene)cyclohexan-1-one.

[0360] A mixture of 4-amino-2,6-bis((E)-3,4-difluorobenzylidene)cyclohexan-1-one (361.3 mg, 1.0 mmol, 1.0 equiv) and 5 wt% Pd / C (212.8 mg, 2.0 mmol, 2.0 equiv) in MeOH was stirred under a hydrogen atmosphere at 21° C. for 24 hours. The resulting solution was then filtered through a Celite pad and concentrated to give 4-amino-2,6-bis(3,4-difluorobenzyl)cyclohexan-1-one, which was used in the next step without further purification.

[0361] A mixture of 4-amino-2,6-bis(3,4-difluorobenzyl)cyclohexan-1-one (182.6 mg, 0.5 mmol, 1.0 equiv.) and anhydrous diisopropylethylamine (261.2 μL, 1.5 mmol, 3.0 equiv.) in THF was maintained at 0 °C (ice bath). To this cooled mixture, 4-((2-(pyrrolidin-1-yl)ethyl)amino)benzoic acid (117.0 mg, 0.5 mmol, 1.0 equiv.) in 2.0 mL of THF was added dropwise, followed by the addition of TBTU (240.8 mg, 0.75 mmol, 1.5 equiv.). After the complete addition of 4-((2-(pyrrolidin-1-yl)ethyl)amino)benzoic acid, the reaction mixture was allowed to warm slowly to room temperature and stirred overnight. After completion of the reaction, the solvent was evaporated, and the residue was stirred in saturated aqueous NaHCO3 solution for 5 min. The mixture was extracted three times with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate. Evaporation of the solvent, followed by flash chromatography (gradient elution: 50% methanol / ethyl acetate-100% methanol) afforded the desired product, JCS072 (87 mg, 30% yield), as a white solid.

[0362] [ka] N-(3,5-bis(3,4-difluorobenzyl)-4-oxocyclohexyl)-4-((2-(pyrrolidin-1-yl)ethyl)amino)benzamide (JCS072) 1H NMR (500 MHz, CDCl3) δ 7.55 (d, J = 8.4 Hz, 2H), 7.09 - 6.78 (m, 6H), 6.54 (d, J = 8.4 Hz, 2H), 5.85 (d, J = 8.2 Hz), (H. 4. Hz), 4. Hz - 4.42 (m, 1H), 3.20 (t, J = 6.3 Hz, 2H), 3.10 (bd, J = 15.0 Hz, 2H), 2.73 (t, J = 6.2 Hz, 4H), 2.56 - 2.52, 3.3 (J, 3 = 4 H). Hz, 2H), 2.28 (t, J = 6.3 Hz, 2H), 1.80 − 1.76 (m, 4H), 1.35 (q, J = 12.5 Hz, 2H)。 13 C NMR (126 MHz, CDCl3) δ 210.3, 166.7, 151.4, 150.2 (dd, J CF = 249.4 Hz, J C-CF = 12.6 Hz, 2C), 149.1 (dd, J CF = 246.9 Hz, J C-CF = 12.6 Hz, 2C), 136.5 (dd, J C-C-CF = 6.3 Hz, J C-C-CF = 3.7 Hz, 2C), 128.7 (2C), 125.0 (dd, J C-C-CF = 6.3 Hz, J C-C-CF = 3.7 Hz, 2C), 121.7, 118.1 (d, J C-CF = 17.6 Hz, 2C), 117.1 (d, J C-CF = 17.6 Hz, 2C), 111.8 (2C), 54.5, 53.9, 49.8, 46.8, 41.8, 39.8, 34.4, 23.5。 19 F NMR (376 MHz, CDCl3) δ −137.9 (d, J FF = 22.5 Hz, 2F), −141.5 (d, J FF = 18.8 Hz, 2F)。C 33 H 36HR-APCI m / z calculated for F4N3O2 [M+H] 582.2738, found 582.2738.

[0363] [ka] N-(3,5-bis(3,4-difluorobenzyl)-4-oxocyclohexyl)-4-(2-(diethylamino)ethoxy)benzamide (JCS074) 1 H NMR (500 MHz, CDCl3) δ 7.64 (d, J = 8.3 Hz, 2H), 7.09 - 6.92 (m, 4H), 6.91 - 6.82 (m, 4H), 5.92 (d, J = 8.0 Hz, 1H), 4.51 - 4.42 (m, 1H), 4.12 (t, J = 5.9 Hz, 2H), 3.12 (dd, J = 14.1, 5.8 Hz, 2H), 2.95 (t, J = 5.9 Hz, 2H), 2.77 - 2.68 (m, 4H), 2.45 (dd, J = 14.2, 7.4 Hz, 2H), 2.32 - 2.29 (m, 2H), 1.38 (q, J = 12.6 Hz, 2H), 1.10 (t, J = 7.1 Hz, 6H). 13 C NMR (126 MHz, CDCl3) δ 210.1, 166.3, 161.5, 150.2 (dd, J CF = 248.2 Hz, J C-CF = 12.6 Hz, 2C), 149.1 (dd, J CF = 246.9 Hz, J C-CF = 12.6 Hz, 2C), 136.5 (dd, J C-C-CF = 6.3 Hz, J C-C-CF = 3.7 Hz, 2C), 128.8 (2C), 126.4 (2C), 125.0 (dd, J C-C-CF = 6.3 Hz, J C-C-CF = 3.7 Hz, 2C), 121.7, 118.0 (d, J C-CF = 17.6 Hz, 2C), 117.2 (d, JC-CF = 17.6 Hz, 2C), 114.4 (2C), 66.4, 51.5, 49.8, 47.8, 47.0, 39.6, 34.4, 11.4. 19 F NMR (376 MHz, CDCl3) δ 131.1 (d, J FF = 26.3 Hz, 2F), 128.3 (d, J FF = 30.0 Hz, 2F). C 33 H 37 HR-APCI m / z calculated for F4N3O2 [M+H] 585.2734, found 585.2725.

[0364] General Procedure D: Compound JCS007 and its analogs were typically prepared by reacting 3,4-difluorobenzaldehyde with tert-butyl(4-oxocyclohexyl)carbamate in the presence of 20% aqueous sodium hydroxide to give tert-butyl(3,5-bis((E)-3,4-difluorobenzylidene)-4-oxocyclohexyl)carbamate. The Boc protecting group was deprotected with TFA. tert-butyl(3,5-bis((E)-3,4-difluorobenzylidene)-4-oxocyclohexyl)carbamate was acylated with acryloyl chloride under basic conditions to give N-(3,5-bis((E)-3,4-difluorobenzylidene)-4-oxocyclohexyl)acrylamide. Michael addition of an amine, such as pyrrolidine, gave N-(3,5-bis((E)-3,4-difluorobenzylidene)-4-oxocyclohexyl)-3-(pyrrolidin-1-yl)propenamide.

[0365] [ka] Preparation of JCS007: To a mixture of tert-butyl (4-oxocyclohexyl)carbamate (213.28 mg, 1 mmol, 1.0 equiv.) and ethanol (1.0 mL) in a round-bottom flask, 20% aqueous sodium hydroxide (1.0 mL) was added dropwise, and the reaction mixture was stirred for 5 minutes. 3,4-Difluorobenzaldehyde (355.3 mg, 2.5 mmol, 2.5 equiv.) was then added to the mixture. The reaction mixture was then stirred at 21 °C for 5 hours, at which point a yellow solid precipitated. The precipitate thus obtained was filtered, washed with water and cold ethanol, and dried to give the pure product, bis(arylmethylidene)cyclohexanone (360 mg, 78% yield).

[0366] Trifluoroacetic acid (0.5 ml) was added to a solution of tert-butyl (3,5-bis((E)-3,4-difluorobenzylidene)-4-oxocyclohexyl)carbamate (230.7 mg, 0.5 mmol) in methylene chloride (5.0 ml) at 21° C., and the reaction mixture was stirred at 21° C. overnight. The reaction solvent was evaporated under reduced pressure, and the resulting residue was poured into a 1N aqueous solution of sodium hydroxide and extracted with ethyl acetate and chloroform. The organic layer was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give 4-amino-2,6-bis((E)-3,4-difluorobenzylidene)cyclohexan-1-one.

[0367] A mixture of 4-amino-2,6-bis((E)-3,4-difluorobenzylidene)cyclohexan-1-one (180.7 mg, 0.5 mmol, 1.0 equiv.) and anhydrous triethylamine (70 μL, 0.5 mmol, 1.0 equiv.) in dichloromethane was maintained at 0 °C (ice bath). To this cooled mixture, acryloyl chloride (40 μL, 0.5 mmol, 1.0 equiv.) was added dropwise. After the complete addition of acryloyl chloride, the reaction mixture was slowly warmed to 21 °C and stirred overnight. After completion of the reaction, the solvent was evaporated, and the residue thus obtained was washed with water, filtered, and dried. The crude amide product was sufficiently pure to be used in the next step.

[0368] A mixture of crude N-(3,5-bis((E)-3,4-difluorobenzylidene)-4-oxocyclohexyl)acrylamide (207.7 mg, 0.5 mmol, 1.0 equiv.), 2,6-bis(1,1-dimethylethyl)-4-methylphenol (1.1 mg, 0.005 mmol, 1%), and pyrrolidine (0.375 mL, 0.75 mmol, 1.5 equiv.) in 1.0 mL of anhydrous THF was heated to 65° C. for 12 h under argon. The solvent was evaporated, and the residue was subjected to flash chromatography (gradient elution 20% methanol / EtOAc to 100% methanol) to give the desired compound JCS007 (170.2 mg, 70% yield) as a yellow solid.

[0369] [ka] N-(3,5-bis((E)-3,4-difluorobenzylidene)-4-oxocyclohexyl)-3-(pyrrolidin-1-yl)propanamide (JCS007) 1 H NMR (500 MHz, CDCl3) δ 9.32 (d, J = 6.4 Hz, 1H), 7.80 (s, 2H), 7.26 - 7.16 (m, 6H), 4.50 - 4.38 (m, 1H), 3.13 (bd, J = 15.9 Hz, 2H), 3.02 (dd, J = 16.0, 5.7 Hz, 2H), 2.59 (t, J = 5.3 Hz, 2H), 2.44 - 2.41 (m, 4H), 2.27 (t, J = 5.3 Hz, 2H), 1.72 - 1.69 (m, 4H). 13 C NMR (126 MHz, CDCl3) δ 187.9, 172.6, 150.7 (dd, J CF = 253.2 Hz, J C-CF = 12.6 Hz, 2C), 150.3 (dd, J CF = 249.4 Hz, J C-CF = 12.6 Hz, 2C), 137.7 (2C), 132.8 (2C), 132.3 (dd, J C-C-CF= 6.3 Hz, J C-C-CF = 3.7 Hz, 2C), 127.1 (dd, J C-C-CF = 6.3 Hz, J C-C-CF = 3.7 Hz, 2C), 118.9 (d, J C-CF = 17.6 Hz, 2C), (2C), 117.7 (d, J C-CF = 17.6 Hz, 2C), 53.2, 51.5, 42.7, 33.7, 33.3, 23.6. 19 F NMR (376 MHz, CDCl3) δ -135.1 (d, J FF = 22.5 Hz, 2F), -136.5 (d, J FF = 22.5 Hz, 2F). C 27 H 27 HR-APCI m / z calculated for F4N2O2 [M+H] 487.2003, observed 487.2018.

[0370] [ka] 3,5-Bis((E)-3,4-difluorobenzylidene)-1-(3-(dipropylamino)propanoyl)piperidin-4-one (JCS117) 1 H NMR (500 MHz, CDCl3) δ 7.71 (br s, 2H), 7.31 - 7.08 (m, 6H), 4.82 (s, 2H), 4.70 (s, 2H), 2.64 (t, J = 7.4 Hz, 2H), 2.31 (t, J = 7.4 Hz, 2H), 2.24 - 2.13 (m, 4H), 1.34 - 1.22 (m, 4H), 0.73 (t, J = 7.4 Hz, 6H). 13 C NMR (126 MHz, CDCl3) δ 185.9, 171.0, 151.0 (dd, J CF = 254.5 Hz, J C-CF = 12.6 Hz, 2C), 150.4 (dd, J CF= 250.7 Hz, J C-CF = 12.6 Hz, 2C), 136.2, 135.2, 132.3, 132.2, 131.4 (d, J C-CF = 22.6 Hz, 2C), 127.1 (d, J C-CF = 45.3 Hz, 2C), 119.1 (dd, J C-C-CF = 39.0 Hz, J C-C-CF = 17.6 Hz, 2C), 117.9 (dd, J C-C-CF = 30.2 Hz, J C-C-CF = 17.6 Hz, 2C), 56.1, 49.8, 46.4, 43.1, 31.2, 20.1, 11.7. Due to the slow rotation of the amide bond, double absorption is observed at some carbons. 19 F NMR (376 MHz, CDCl3) δ -132.0 (dd, J FF = 154.1, 30.0 Hz, 2F), -130.3 (dd, J FF = 244.4, 26.3 Hz, 2F). C 28 H 31 HR-APCI m / z calculated for F4N2O2 [M+H] 503.2339, found 503.2316.

[0371] [ka] 1-(3-(bis(2-methoxyethyl)amino)propanoyl)-3,5-bis((E)-3,4-difluorobenzylidene)piperidin-4-one (JCS118) 1 H NMR (500 MHz, CDCl3) δ 7.70 (br s, 2H), 7.29 - 7.11 (m, 6H), 4.82 (s, 2H), 4.70 (s, 2H), 3.33 (t, J = 5.7 Hz, 4H), 3.23 (s, 6H), 2.79 (t, J = 5.8 Hz, 2H), 2.55 (t, J = 5.8 Hz, 4H), 2.36 (t, J = 5.8 Hz, 2H). 13 C NMR (126 MHz, CDCl3) δ 185.9, 170.7, 151.0 (dd, J CF = 254.5 Hz, J C-CF = 12.6 Hz, 2C), 150.4 (dd, J CF = 250.7 Hz, J C-CF = 12.6 Hz, 2C), 136.1, 135.2, 132.1 (2C), 131.4 (d, J C-CF = 34.0 Hz, 2C), 127.1 (d, J C-CF = 45.3 Hz, 2C), 119.1 (dd, J C-C-CF = 39.0 Hz, J C-C-CF = 17.6 Hz, 2C), 117.9 (dd, J C-C-CF = 30.2 Hz, J C-C-CF = 17.6 Hz, 2C), 70.7, 58.7, 53.8, 50.7, 46.3, 42.9, 30.8. Due to the slow rotation of the amide bond, double absorption is observed at some carbons. 19 F NMR (376 MHz, CDCl3) δ -134.2 (dd, J FF = 154.1, 30.0 Hz, 2F), -135.9 (dd, J FF = 244.4, 26.3 Hz, 2F). C 28 H 31 HR-APCI m / z calculated for F4N2O2 [M+H] 535.2334, found 535.2214.

[0372] [ka] 3,5-Bis((E)-3,4-difluorobenzylidene)-1-(3-(2,5-dihydro-1H-pyrrol-1-yl)propanoyl)piperidin-4-one (JCS119) 1H NMR (500 MHz, CDCl3) δ 7.73 (br s, 2H), 7.26 - 7.13 (m, 6H), 5.69 (s, 2H), 4.85 (s, 2H), 4.72 (s, 2H), 3.33 (s, 4H), 2.85 (t, J = 5.8 Hz, 2H), 2.39 (t, J = 5.8 Hz, 2H). 13 C NMR (126 MHz, CDCl3) δ 185.8, 170.2, 151.0 (dd, J CF = 254.5 Hz, J C-CF = 12.6 Hz, 2C), 150.4 (dd, J CF = 250.7 Hz, J C-CF = 12.6 Hz, 2C), 136.3, 135.3, 132.1 (2C), 131.4 (d, J C-CF = 34.0 Hz, 2C), 127.2 (2C), 127.1 (d, J C-CF = 45.3 Hz, 2C), 119.1 (dd, J C-C-CF = 39.0 Hz, J C-C-CF = 17.6 Hz, 2C), 117.9 (dd, J C-C-CF = 30.2 Hz, J C-C-CF = 17.6 Hz, 2C), 59.7, 51.4, 46.2, 43.0, 32.7. Due to the slow rotation of the amide bond, double absorption is observed at some carbons. 19 F NMR (376 MHz, CDCl3) δ -134.0 (dd, J FF = 154.1, 30.0 Hz, 2F), -135.8 (dd, J FF = 244.4, 26.3 Hz, 2F). C 26 H 23 HR-APCI m / z calculated for F4N2O2 [M+H] 471.1712, found 471.1690.

[0373] [ka] 1-(3-(3-azabicyclo[3.1.0]hexan-3-yl)propanoyl)-3,5-bis((E)-3,4-difluorobenzylidene)piperidin-4-one (JCS120) 1 H NMR (500 MHz, CDCl3) δ 7.76 (br s, 2H), 7.44 - 7.06 (m, 6H), 4.87 (s, 2H), 4.74 (s, 2H), 2.86 (d, J = 8.6 Hz, 2H), 2.70 (t, J = 5.8 Hz, 2H), 2.39 (t, J = 5.8 Hz, 2H), 2.28 (d, J = 8.7 Hz, 2H), 1.36 - 1.31 (m, 2H), 0.62 - 0.58 (m, 1H), 0.41 - 0.34 (m, 1H). 13 C NMR (126 MHz, CDCl3) δ 185.9, 170.7, 151.0 (dd, J CF = 254.5 Hz, J C-CF = 12.6 Hz, 2C), 150.4 (dd, J CF = 250.7 Hz, J C-CF = 12.6 Hz, 2C), 136.2, 135.3, 132.1 (2C), 131.4 (d, J C-CF = 34.0 Hz, 2C), 127.1 (d, J C-CF = 45.3 Hz, 2C), 119.1 (dd, J C-C-CF = 39.0 Hz, J C-C-CF = 17.6 Hz, 2C), 118.0 (dd, J C-C-CF = 30.2 Hz, J C-C-CF = 17.6 Hz, 2C), 55.0, 50.8, 46.4, 43.2, 32.4, 15.2, 6.9. Due to the slow rotation of the amide bond, double absorption is observed at some carbons. 19 F NMR (376 MHz, CDCl3) δ -132.0 (dd, J FF = 154.1, 30.0 Hz, 2F), -130.4 (dd, JFF = 244.4, 26.3 Hz, 2F). C 27 H 25 HR-APCI m / z calculated for F4N2O2 [M+H] 485.1866, found 485.1846.

[0374] [ka] 1-(3-(azetidin-1-yl)propanoyl)-3,5-bis((E)-3,4-difluorobenzylidene)piperidin-4-one (JCS121) 1 H NMR (500 MHz, CDCl3) δ 7.74 (br s, 2H), 7.31 - 7.13 (m, 6H), 4.84 (s, 2H), 4.69 (s, 2H), 3.08 (t, J = 7.1 Hz, 4H), 2.61 (t, J = 7.4 Hz, 2H), 2.22 (t, J = 7.4 Hz, 2H), 2.01 - 1.97 (m, 2H). 13 C NMR (126 MHz, CDCl3) δ 186.0, 170.2, 151.0 (dd, J CF = 254.5 Hz, J C-CF = 12.6 Hz, 2C), 150.4 (dd, J CF = 250.7 Hz, J C-CF = 12.6 Hz, 2C), 136.4, 135.5, 132.2 (2C), 131.5 (d, J C-CF = 34.0 Hz, 2C), 127.1 (d, J C-CF = 45.3 Hz, 2C), 119.1 (dd, J C-C-CF = 39.0 Hz, J C-C-CF = 17.6 Hz, 2C), 118.1 (dd, J C-C-CF = 30.2 Hz, J C-C-CF= 17.6 Hz, 2C), 55.1, 54.8, 46.4, 43.1, 31.2, 17.5. Due to the slow rotation of the amide bond, double absorption is observed at some carbons. 19 F NMR (376 MHz, CDCl3) δ -134.0 (dd, J FF = 154.1, 30.0 Hz, 2F), -135.8 (dd, J FF = 244.4, 26.3 Hz, 2F). C 25 H 23 HR-APCI m / z calculated for F4N2O2 [M+H] 459.1711, found 459.1690.

[0375] [ka] 3,5-Bis((E)-3,4-difluorobenzylidene)-1-(3-(3-methoxypyrrolidin-1-yl)propanoyl)piperidin-4-one (JCS122) 1 H NMR (500 MHz, CDCl3) δ 7.73 (br s, 2H), 7.26 - 7.15 (m, 6H), 4.84 (s, 2H), 4.72 (s, 2H), 3.88 - 3.84 (m, 1H), 3.24 (s, 3H), 2.81 (t, J = 7.5 Hz, 2H), 2.73 - 2.47 (m, 6H), 2.07 - 1.95 (m, 1H), 1.85 - 1.77 (m, 1H). 13 C NMR (126 MHz, CDCl3) δ 186.0, 170.0, 151.0 (dd, J CF = 254.5 Hz, J C-CF = 12.6 Hz, 2C), 150.4 (dd, J CF = 250.7 Hz, J C-CF = 12.6 Hz, 2C), 136.4, 135.7, 132.1 (2C), 131.5 (d, J C-CF= 34.0 Hz, 2C), 127.1 (d, J C-CF = 45.3 Hz, 2C), 119.1 (dd, J C-C-CF = 39.0 Hz, J C-C-CF = 17.6 Hz, 2C), 118.1 (dd, J C-C-CF = 30.2 Hz, J C-C-CF = 17.6 Hz, 2C), 79.9, 59.8, 56.6, 52.8, 51.6, 46.4, 43.1, 31.7, 31.1. Due to the slow rotation of the amide bond, double absorption is observed at some carbons. 19 F NMR (376 MHz, CDCl3) δ -134.0 (dd, J FF = 154.1, 30.0 Hz, 2F), -135.8 (dd, J FF = 244.4, 26.3 Hz, 2F). C 27 H 27 HR-APCI m / z calculated for F4N2O3 [M+H] 503.1971, found 503.1952.

[0376] [ka] 3,5-Bis((E)-3,4-difluorobenzylidene)-1-(3-((S)-3-fluoropyrrolidin-1-yl)propanoyl)piperidin-4-one (JCS123) 1 H NMR (500 MHz, CDCl3) δ 7.72 (br s, 2H), 7.29 - 7.12 (m, 6H), 5.08 (dt, J = 55.3, 5.7 Hz, 1H), 4.84 (br s, 2H), 4.70 (br s, 2H), 2.82 - 2.67 (m, 4H), 2.29 - 2.25 (m, 1H), 2.40 (t, J = 7.5 Hz, 2H), 1.85 - 1.77 (m, 1H), 2.13 - 1.90 (m, 2H). 13C NMR (126 MHz, CDCl3) δ 185.9, 170.3, 151.0 (dd, J CF = 254.5 Hz, J C-CF = 12.6 Hz, 2C), 150.4 (dd, J CF = 250.7 Hz, J C-CF = 12.6 Hz, 2C), 136.4, 135.4, 132.1 (2C), 131.4 (d, J C-CF = 34.0 Hz, 2C), 127.1 (d, J C-CF = 45.3 Hz, 2C), 119.1 (dd, J C-C-CF = 39.0 Hz, J C-C-CF = 17.6 Hz, 2C), 118.1 (dd, J C-C-CF = 30.2 Hz, J C-C-CF = 17.6 Hz, 2C), 93.3 (d, J CF = 176.4 Hz, 1C), 60.7 (d, J C-CF = 22.6 Hz, 2C), 56.6, 52.3, 51.2, 46.3, 43.2, 32.7 (d, J C-CF = 22.6 Hz, 2C), 32.2. Due to the slow rotation of the amide bond, double absorption is observed at some carbons. 19 F NMR (376 MHz, CDCl3) δ -134.0 (dd, J FF = 154.1, 30.0 Hz, 2F), -135.8 (dd, J FF = 244.4, 26.3 Hz, 2F), -167.8 (s, 1F) C 26 H 24 HR-APCI m / z calculated for F5N2O2 [M+H] 491.1775, found 491.1752.

[0377] [ka] 3,5-Bis((E)-3,4-difluorobenzylidene)-1-(3-((R)-2-methylpyrrolidin-1-yl)propanoyl)piperidin-4-one (JCS124) 1 H NMR (500 MHz, CDCl3) δ 7.73 (br s, 2H), 7.32 - 7.15 (m, 6H), 4.93 - 4.67 (m, 4H), 3.21 - 2.98 (m, 2H), 2.67 - 2.41 (m, 4H), 2.22 - 2.14 (m, 1H), 1.99 - 1.90 (m, 1H), 1.88 - 1.65 (m, 2H), 1.52 - 1.44 (m, 1H), 1.12 (d, J = 6.1 Hz, 3H). 13 C NMR (126 MHz, CDCl3) δ 185.9, 169.9, 151.0 (dd, J CF = 254.5 Hz, J C-CF = 12.6 Hz, 2C), 150.4 (dd, J CF = 250.7 Hz, J C-CF = 12.6 Hz, 2C), 136.2, 135.6, 131.9 (2C), 131.4 (d, J C-CF = 34.0 Hz, 2C), 127.1 (d, J C-CF = 45.3 Hz, 2C), 119.1 (dd, J C-C-CF = 39.0 Hz, J C-C-CF = 17.6 Hz, 2C), 118.1 (dd, J C-C-CF = 30.2 Hz, J C-C-CF = 17.6 Hz, 2C), 61.1, 53.7, 49.2, 46.4, 42.9, 32.1, 31.5, 21.4, 17.9. Due to the slow rotation of the amide bond, double absorption is observed at some carbons. 19 F NMR (376 MHz, CDCl3) δ -134.0 (dd, J FF = 154.1, 30.0 Hz, 2F), -135.8 (dd, J FF= 244.4, 26.3 Hz, 2F). C 27 H 27 HR-APCI m / z calculated for F4N2O2 [M+H] 487.2025, found 487.2003.

[0378] [ka] 3,5-Bis((E)-3,4-difluorobenzylidene)-1-(3-(hexahydrocyclopenta[c]pyrrol-2(1H)-yl)propanoyl)-piperidin-4-one (JCS125) 1 H NMR (500 MHz, CDCl3) δ 7.73 (br s, 2H), 7.27 - 7.13 (m, 6H), 4.84 (s, 2H), 4.69 (s, 2H), 2.66 (br t, J = 7.9 Hz, 2H), 2.60 (br t, J = 7.6 Hz, 2H), 2.51 (m, 2H), 2.39 (br t, J = 7.6 Hz, 2H), 1.88 - 1.85 (m, 2H), 1.63 - 1.40 (m, 4H), 1.33 - 1.24 (m, 2H). 13 C NMR (126 MHz, CDCl3) δ 186.0, 170.4, 151.0 (dd, J CF = 254.5 Hz, J C-CF = 12.6 Hz, 2C), 150.4 (dd, J CF = 250.7 Hz, J C-CF = 12.6 Hz, 2C), 136.4, 135.4, 132.2 (2C), 131.4 (d, J C-CF = 34.0 Hz, 2C), 127.1 (d, J C-CF = 45.3 Hz, 2C), 119.1 (dd, J C-C-CF = 39.0 Hz, J C-C-CF = 17.6 Hz, 2C), 118.0 (dd, J C-C-CF = 30.2 Hz, J C-C-CF= 17.6 Hz, 2C), 61.5, 51.1, 46.3, 43.2, 42.3, 32.4, 32.3, 25.7. Due to the slow rotation of the amide bond, double absorption is observed at some carbons. 19 F NMR (376 MHz, CDCl3) δ -134.1 (dd, J FF = 154.1, 30.0 Hz, 2F), -135.8 (dd, J FF = 244.4, 26.3 Hz, 2F). C 29 H 29 HR-APCI m / z calculated for F4N2O2 [M+H] 513.2186, found 513.2159.

[0379] [ka] 3,5-Bis((E)-3,4-difluorobenzylidene)-1-(3-((S)-2-(methoxymethyl)pyrrolidin-1-yl)propanoyl)-piperidin-4-one (JCS126) 1 H NMR (500 MHz, CDCl3) δ 7.70 (br s, 2H), 7.30 - 7.10 (m, 6H), 4.91 - 4.64 (m, 4H), 3.24 (m, 1H), 3.23 (s, 3H), 3.17 (dd, J = 14.8, 7.4 Hz, 1H), 3.10 - 3.04 (m, 1H), 2.87 - 2.83 (m, 1H), 2.55 - 2.34 (m, 4H), 2.01 - 1.98 (m, 1H), 1.84 - 1.48 (m, 4H). 13 C NMR (126 MHz, CDCl3) δ 185.9, 170.2, 151.0 (dd, J CF = 254.5 Hz, J C-CF = 12.6 Hz, 2C), 150.4 (dd, J CF = 250.7 Hz, J C-CF = 12.6 Hz, 2C), 136.1, 135.3, 132.2 (2C), 131.4 (d, J C-CF= 34.0 Hz, 2C), 127.1 (d, J C-CF = 45.3 Hz, 2C), 119.1 (dd, J C-C-CF = 39.0 Hz, J C-C-CF = 17.6 Hz, 2C), 118.0 (dd, J C-C-CF = 30.2 Hz, J C-C-CF = 17.6 Hz, 2C), 75.5, 63.5, 59.0, 54.6, 50.9, 46.4, 42.9, 32.5, 28.0, 22.9. Due to the slow rotation of the amide, two absorptions are observed at some carbons. 19 F NMR (376 MHz, CDCl3) δ -134.2 (dd, J FF = 154.1, 30.0 Hz, 2F), -135.8 (dd, J FF = 244.4, 26.3 Hz, 2F). C 28 H 29 HR-APCI m / z calculated for F4N2O3 [M+H] 517.2130, found 517.2108.

[0380] [ka] 3,5-Bis((E)-3,4-difluorobenzylidene)-1-(3-(isoindolin-2-yl)propanoyl)piperidin-4-one (JCS127) 1 H NMR (500 MHz, CDCl3) δ 7.73 (br s, 2H), 7.33 - 7.12 (m, 10H), 4.88 (s, 2H), 4.75 (s, 2H), 3.78 (s, 4H), 2.96 (t, J = 7.5 Hz, 2H), 2.47 (t, J = 7.5 Hz, 2H). 13 C NMR (126 MHz, CDCl3) δ 186.0, 170.4, 151.0 (dd, J CF = 254.5 Hz, J C-CF = 12.6 Hz, 2C), 150.4 (dd, J CF= 250.7 Hz, J C-CF = 12.6 Hz, 2C), 139.6 (2C), 136.5, 135.4, 132.2 (2C), 131.4 (d, J C-CF = 34.0 Hz, 2C), 127.1 (d, J C-CF = 45.3 Hz, 2C), 126.9 (2C), 122.3 (2C), 119.1 (dd, J C-C-CF = 39.0 Hz, J C-C-CF = 17.6 Hz, 2C), 118.0 (dd, J C-C-CF = 30.2 Hz, J C-C-CF = 17.6 Hz, 2C), 59.1, 51.4, 46.4, 43.2, 32.7. Due to the slow rotation of the amide bond, double absorption is observed at some carbons. 19 F NMR (376 MHz, CDCl3) δ -133.9 (dd, J FF = 154.1, 30.0 Hz, 2F), -135.7 (dd, J FF = 244.4, 26.3 Hz, 2F). C 30 H 25 HR-APCI m / z calculated for F4N2O2 [M+H]: 521.1871, found: 521.1846

[0381] [ka] 3,5-Bis((E)-3,4-difluorobenzylidene)-1-(3-((R)-3-(dimethylamino)pyrrolidin-1-yl)propanoyl)piperidin-4-one (JCS128) 1H NMR (500 MHz, CDCl3) δ 7.74 (br s, 2H), 7.31 - 7.11 (m, 6H), 4.84 (s, 2H), 4.70 (s, 2H), 2.75 - 2.54 (m, 5H), 2.40 - 2.33 (m, 3H), 2.29 - 2.23 (m, 1H), 2.17 (s, 6H), 1.94 - 1.86 (m, 1H), 1.69 - 1.62 (m, 1H). 13 C NMR (126 MHz, CDCl3) δ 186.0, 170.4, 151.0 (dd, J CF = 254.5 Hz, J C-CF = 12.6 Hz, 2C), 150.4 (dd, J CF = 250.7 Hz, J C-CF = 12.6 Hz, 2C), 136.4, 135.4, 132.2 (2C), 131.4 (d, J C-CF = 34.0 Hz, 2C), 127.1 (d, J C-CF = 45.3 Hz, 2C), 119.1 (dd, J C-C-CF = 39.0 Hz, J C-C-CF = 17.6 Hz, 2C), 118.1 (dd, J C-C-CF = 30.2 Hz, J C-C-CF = 17.6 Hz, 2C), 65.2, 58.5, 53.3, 51.5, 46.4, 43.6, 43.2, 32.1, 28.8. Due to the slow rotation of the amide bond, double absorption is observed at some carbons. 19 F NMR (376 MHz, CDCl3) δ -134.0 (dd, J FF = 154.1, 30.0 Hz, 2F), -135.8 (dd, J FF = 244.4, 26.3 Hz, 2F). C 28 H 30 HR-APCI m / z calculated for F4N3O2 [M+H] 516.2294, found 516.2268.

[0382] [ka] 3,5-Bis((E)-3,4-difluorobenzylidene)-1-(3-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)propanoyl)piperidin-4-one (JCS129) 1 H NMR (500 MHz, CDCl3) δ 7.71 (br s, 2H), 7.29 - 7.09 (m, 6H), 4.83 (s, 2H), 4.69 (s, 2H), 3.04 - 2.88 (m, 2H), 2.75 - 2.56 (m, 4H), 2.37 (t, J = 7.6 Hz, 2H), 2.20 - 1.87 (m, 4H), 1.83 - 1.62 (m, 4H), 1.33 - 1.28 (m, 1H). 13 C NMR (126 MHz, CDCl3) δ 185.9, 170.6, 151.0 (dd, J CF = 254.5 Hz, J C-CF = 12.6 Hz, 2C), 150.4 (dd, J CF = 250.7 Hz, J C-CF = 12.6 Hz, 2C), 136.4, 135.3, 132.2 (2C), 131.4 (d, J C-CF = 34.0 Hz, 2C), 127.1 (d, J C-CF = 45.3 Hz, 2C), 119.1 (dd, J C-C-CF = 39.0 Hz, J C-C-CF = 17.6 Hz, 2C), 118.1 (dd, J C-C-CF = 30.2 Hz, J C-C-CF = 17.6 Hz, 2C), 62.5, 57.7, 53.6, 53.2, 52.3, 51.3, 46.4, 43.2, 30.6, 27.5, 21.3. Due to the slow rotation of the amide bond, double absorption is observed at some carbons. 19 F NMR (376 MHz, CDCl3) δ -134.0 (dd, JFF = 154.1, 30.0 Hz, 2F), -135.8 (dd, J FF = 244.4, 26.3 Hz, 2F). C 29 H 30 HR-APCI m / z calculated for F4N3O2 [M+H] 528.2294, found 528.2268.

[0383] [ka] 3,5-Bis((E)-3,4-difluorobenzylidene)-1-(3-(3-(methylsulfonyl)pyrrolidin-1-yl)propanoyl)piperidin-4-one (JCS130) 1 H NMR (500 MHz, CDCl3) δ 7.73 (br s, 2H), 7.32 - 7.08 (m, 6H), 4.83 (s, 2H), 4.68 (s, 2H), 3.50 - 3.44 (m, 1H), 2.91 - 2.88 (m, 1H), 2.77 (s, 3H), 2.75 - 2.57 (m, 4H), 2.46 - 2.42 (m, 1H), 2.35 (t, J = 7.1 Hz, 2H), 2.21 - 2.10 (m, 2H). 13 C NMR (1...

Claims

1. A compound having a structure represented by Formula I, Formula II, Formula III, or a pharmaceutically acceptable salt thereof: 【Chemistry 1】 During the ceremony, A is aryl or heteroaryl; n1 is 1, 2, 3, 4, or 5; X １ is O, S, or NR ７ and X ２ is O, S, or NR ８ and R ２ , R ４ , R １２ , R １３ , R １４ , and R １５ are each independently selected from H, fluoro, chloro, bromo, and iodo; R １ and R ３ are each independently selected from H, fluoro, chloro, bromo, iodo, and —O(alkyl); R ５ , R ７ , and R ８ each is independently selected from H, alkyl, and aralkyl; R Ａ is alkyl, acyl, or amido; R Ｃ is H, alkyl, or acyl; R ６ is alkyl, aryl, heteroaryl, or heterocyclyl.

2. The compound has a structure according to Formula Ia, or a pharmaceutically acceptable salt thereof: 【Chemistry 2】 During the ceremony, X １ is O, S, or NR ７ and X ２ is O, S, or NR ８ and R １ , R ２ , R ３ , and R ４ are each independently selected from fluoro, chloro, bromo, and iodo; R ５ , R ７ , and R ８ each is independently selected from H, alkyl, and aralkyl; R ６ The compound of claim 1 , wherein is alkyl, aryl, heteroaryl, or heterocyclyl.

3. 2. The compound of claim 1, wherein the compound has the structure of Formula I, or a pharmaceutically acceptable salt thereof. 【Transformation 3】

4. 10. The compound of claim 1, wherein the compound has the structure represented by Formula II, or a pharmaceutically acceptable salt thereof. 【Chemistry 4】

5. 10. The compound of claim 1, wherein the compound has a structure represented by Formula III: 【Transformation 5】

6. The compound is 【Chemistry 6-1】 【Chemistry 6-2】 or a pharmaceutically acceptable salt thereof.

7. The compound is 【Chemistry 7-1】 【Chemistry 7-2】 【Transformation 7-3】 【Chemistry 7-4】 【Transformation 7-5】 【Transformation 7-6】 【Transformation 7-7】 [Transformation 7-8] or a pharmaceutically acceptable salt thereof.

8. R １ The compound of any one of claims 1 to 7, wherein is fluoro.

9. R １ The compound according to any one of claims 1 to 7, wherein is chloro.

10. R １ The compound according to any one of claims 1 to 7, wherein is H.

11. R １ The compound of any one of claims 1 to 7, wherein is -O(alkyl) (e.g., methoxy).

12. R ２ The compound according to any one of claims 1 to 11, wherein is fluoro.

13. R ２ The compound according to any one of claims 1 to 11, wherein is chloro.

14. R ２ The compound according to any one of claims 1 to 11, wherein is H.

15. R ３ The compound of any one of claims 1 to 14, wherein is fluoro.

16. R ３ The compound according to any one of claims 1 to 14, wherein is chloro.

17. R ３ The compound according to any one of claims 1 to 14, wherein is H.

18. R ３ The compound of any one of claims 1 to 14, wherein is -O(alkyl) (e.g., methoxy).

19. R ４ The compound of any one of claims 1 to 18, wherein is fluoro.

20. R ４ The compound according to any one of claims 1 to 18, wherein is chloro.

21. R ４ The compound according to any one of claims 1 to 18, wherein is H.

22. R １２ The compound according to any one of claims 1 and 3 to 21, wherein is chloro.

23. R １２ The compound of any one of claims 1 and 3 to 21, wherein is fluoro.

24. R １２ The compound according to any one of claims 1 and 3 to 21, wherein is H.

25. R １３ The compound of any one of claims 1 and 3 to 24, wherein is chloro.

26. R １３ The compound of any one of claims 1 and 3 to 24, wherein is fluoro.

27. R １３ The compound of any one of claims 1 and 3 to 24, wherein is H.

28. R １４ The compound of any one of claims 1 and 3 to 27, wherein is chloro.

29. R １４ The compound of any one of claims 1 and 3 to 27, wherein is fluoro.

30. R １４ The compound of any one of claims 1 and 3 to 27, wherein is H.

31. R １５ The compound of any one of claims 1 and 3 to 30, wherein is chloro.

32. R １５ The compound of any one of claims 1 and 3 to 30, wherein is fluoro.

33. R １５ The compound of any one of claims 1 and 3 to 30, wherein is H.

34. X １ The compound according to any one of claims 1 to 33, wherein is O.

35. 35. The compound of any one of claims 1, 4, or 6-34, wherein A is heteroaryl (eg, indazolyl).

36. 36. The compound of any one of claims 1, 4, or 6-35, wherein n1 is 1.

37. R Ａ The compound of any one of claims 1, 4, or 6-36, wherein is an alkylamide (e.g., N-diethylamide).

38. X ２ The compound of any one of claims 1 to 3 or 5 to 37, wherein is O.

39. R ５ is H.

40. R ６ The compound of any one of claims 1 to 3 or 6 to 39, wherein is alkyl.

41. R ６ The compound of any one of claims 1-3 or 6-39, wherein is heteroaryl (e.g., pyridinyl, pyrimidinyl, indolyl, or pyrazolopyridinyl).

42. R ６ 40. The compound of any one of claims 1-3 or 6-39, wherein is heteroaryl (e.g., pyridinyl, pyrimidinyl, indolyl, quinazolinyl, phthalazinyl, or pyrazolopyridinyl).

43. R ６ is pyridinyl or pyrimidinyl.

44. R ６ The compound of any one of claims 1 to 3 or 6 to 39, wherein is aryl.

45. R ６ is substituted with alkyl, alkenyl, alkynyl, halo, hydroxyl, carboxyl, acyl, acetyl, ester, thioester, alkoxy, phosphoryl, amino, amido, cyano, nitro, azido, alkylthio, cycloalkyl, alkylsulfonyl, sulfonamido, cycloalkyl, aryl, heteroaryl, and heterocyclyl.

46. R ６ is substituted with heterocyclyl (e.g., pyrrolidinylpyrrolidinyl, piperazinyl, piperidinyl, or (1-ethylpyrrolidin-2-yl)methanamine).

47. R ６ is substituted with pyrrolidinyl or (1-ethylpyrrolidin-2-yl)methanamine).

48. R ６ is alkylamino (e.g., —N(CH ２ ) ２ N (C ４ H ８ 48. The compound of any one of claims 45 to 47, substituted with ).

49. R ６ is substituted with an alkylamide (for example, N-diethylamide).

50. R ６ is substituted with nitro.

51. R ６ is substituted with alkoxy.

52. R ６ is an amino (e.g., —NH ２ 52. The compound of any one of claims 1 to 3 or 6 to 51, substituted with:

53. R ６ is substituted with heterocyclyl.

54. The compound has a structure represented by Formula Ib, or a pharmaceutically acceptable salt thereof: 【Transformation 8】 During the ceremony, Each R ９ is independently selected from alkyl, alkenyl, alkynyl, halo, hydroxyl, carboxyl, acyl, acetyl, ester, thioester, alkoxy, phosphoryl, amino, amido, cyano, nitro, azido, alkylthio, cycloalkyl, alkylsulfonyl, sulfonamido, cycloalkyl, aryl, heteroaryl, and heterocyclyl; The compound of any one of claims 1-3 or 6-7, wherein n is 1, 2, 3, 4, or 5.

55. The compound has a structure represented by Formula Ic, Formula IIa, or Formula IIIa, or a pharmaceutically acceptable salt thereof: 【Chemistry 9】 During the ceremony, X ３ is alkyl or N(R １８ ) ２ and Each R ９ is independently selected from alkyl, alkenyl, alkynyl, halo, hydroxyl, carboxyl, acyl, acetyl, ester, thioester, alkoxy, phosphoryl, amino, amido, cyano, nitro, azido, alkylthio, cycloalkyl, alkylsulfonyl, sulfonamido, cycloalkyl, aryl, heteroaryl, and heterocyclyl; Each R １６ , R １７ , and R １８ are independently H or alkyl; 40. The compound of any one of claims 1 to 39, wherein n2 is 1, 2, 3, 4, or 5.

56. 56. The compound of claim 55, wherein the compound has the structure of Formula Ic, or a pharmaceutically acceptable salt thereof. 【Chemistry 10】

57. 56. The compound of claim 55, wherein the compound has a structure represented by Formula IIa, or a pharmaceutically acceptable salt thereof. 【Chemistry 11】

58. 56. The compound of claim 55, wherein the compound has a structure represented by Formula IIIa: 【Chemistry 12】

59. 56. The compound of claim 55, wherein the compound has a structure represented by Formula Id, Formula IIb, or Formula IIIb, or a pharmaceutically acceptable salt thereof. 【Chemistry 13】

60. 60. The compound of claim 59, wherein the compound has a structure represented by Formula Id, or a pharmaceutically acceptable salt thereof. 【Chemistry 14】

61. 60. The compound of claim 59, wherein the compound has a structure represented by Formula IIb, or a pharmaceutically acceptable salt thereof. 【Chemistry 15】

62. 60. The compound of claim 59, wherein the compound has a structure represented by Formula IIIb: or a pharmaceutically acceptable salt thereof. 【Chemistry 16】

63. The compound has a structure represented by formula Ie, or a pharmaceutically acceptable salt thereof: 【Chemistry 17】 During the ceremony, R ９ is selected from alkyl, alkenyl, alkynyl, halo, hydroxyl, carboxyl, acyl, acetyl, ester, thioester, alkoxy, phosphoryl, amino, alkylamino, amido, cyano, nitro, azido, alkylthio, cycloalkyl, alkylsulfonyl, sulfonamido, carbamoylamino, cycloalkyl, aryl, heteroaryl, and heterocyclyl.

64. The compound has a structure represented by Formula If, Formula IIc, or Formula IIIc, or a pharmaceutically acceptable salt thereof: [Chemistry 18] During the ceremony, z is 0, 1 or 2; R ９ is selected from alkyl, alkenyl, alkynyl, halo, hydroxyl, carboxyl, acyl, acetyl, ester, thioester, alkoxy, phosphoryl, amino, alkylamino, amido, cyano, nitro, azido, alkylthio, cycloalkyl, alkylsulfonyl, sulfonamido, carbamoylamino, cycloalkyl, aryl, heteroaryl, and heterocyclyl; R ２０ 60. The compound of claim 59, wherein is selected from H, cycloalkyl, cycloalkenyl, heterocycloalkyl, and heterocyclyl.

65. 65. The compound of claim 64, wherein the compound has a structure represented by Formula If, or a pharmaceutically acceptable salt thereof. 【Chemistry 19】

66. 65. The compound of claim 64, wherein the compound has a structure represented by Formula IIc, or a pharmaceutically acceptable salt thereof. 【Chemistry 20】

67. 65. The compound of claim 64, wherein the compound has a structure represented by Formula IIIc or a pharmaceutically acceptable salt thereof. 【Chemistry 21】

68. R １ The compound of any one of claims 64 to 67, wherein is fluoro.

69. R ２ The compound of any one of claims 64 to 68, wherein is fluoro.

70. R ３ The compound of any one of claims 64 to 69, wherein is fluoro.

71. R ４ The compound of any one of claims 64 to 70, wherein is fluoro.

72. R １２ The compound of any one of claims 64 to 71, wherein is fluoro.

73. R １３ The compound of any one of claims 64 to 72, wherein is fluoro.

74. R １４ The compound of any one of claims 64 to 73, wherein is fluoro.

75. R １５ The compound of any one of claims 64 to 74, wherein is fluoro.

76. R ９ 66. The compound of claim 64 or 65, wherein is alkoxy.

77. R ９ is amino.

78. R ９ 66. The compound of claim 64 or 65, wherein is aryl (e.g., phenyl) or heterocyclyl (e.g., pyrrolidinyl, or N-methylpiperazinyl).

79. R ９ is alkylamino.

80. R １６ 67. The compound of claim 64 or 66, wherein is H.

81. R １６ is alkyl (e.g., methyl).

82. R １７ 67. The compound of claim 64 or 66, wherein is H.

83. R １７ is alkyl (e.g., methyl).

84. 68. The compound of claim 64 or 67, wherein z is 1.

85. 68. The compound of claim 64 or 67, wherein z is 2.

86. The compound has the structure of Formula Ig, or a pharmaceutically acceptable salt thereof: 【Chemistry 22】 R １０ is selected from alkyl, alkenyl, alkynyl, halo, hydroxyl, carboxyl, acyl, acetyl, ester, thioester, alkoxy, phosphoryl, amino, alkylamino, amido, carbamyl, cyano, nitro, azido, alkylthio, cycloalkyl, alkylsulfonyl, sulfonamido, carbamoylamino, cycloalkyl, aryl, heteroaryl, and heterocyclyl; 66. The compound of claim 64 or 65, wherein m is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

87. The compound has a structure represented by formula Ih or IIId, or a pharmaceutically acceptable salt thereof: 【Chemistry 23】 During the ceremony, E is heterocyclyl; R Ｂ is selected from alkyl, amino, hydroxyl, halo, alkoxy, and sulfonyl; R １０ is selected from alkyl, alkenyl, alkynyl, halo, hydroxyl, carboxyl, acyl, acetyl, ester, thioester, alkoxy, phosphoryl, amino, alkylamino, amido, carbamyl, cyano, nitro, azido, alkylthio, cycloalkyl, alkylsulfonyl, sulfonamido, carbamoylamino, cycloalkyl, aryl, heteroaryl, and heterocyclyl; n3 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; 65. The compound of claim 64, wherein m is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

88. 88. The compound of claim 87, wherein the compound has the structure represented by Formula Ih, or a pharmaceutically acceptable salt thereof. 【Chemistry 24】

89. 88. The compound of claim 87, wherein the compound has a structure represented by Formula IIId: or a pharmaceutically acceptable salt thereof. 【Chemistry 25】

90. 89. The compound of claim 87 or 88, wherein m is 1.

91. 89. The compound of claim 87 or 88, wherein m is 2.

92. R １ The compound of any one of claims 87 to 91, wherein is chloro.

93. R １ 92. The compound of any one of claims 87 to 91, wherein is -O(alkyl) (e.g., methoxy).

94. R １ The compound of any one of claims 87 to 93, wherein is fluoro.

95. R １ The compound according to any one of claims 87 to 93, wherein is H.

96. R ２ The compound of any one of claims 87 to 95, wherein is fluoro.

97. R ３ The compound of any one of claims 87 to 95, wherein is chloro.

98. R ３ 96. The compound of any one of claims 87 to 95, wherein is -O(alkyl) (e.g., methoxy).

99. R ３ The compound of any one of claims 87 to 95, wherein is fluoro.

100. R ３ The compound according to any one of claims 87 to 95, wherein is H.

101. R ４ The compound of any one of claims 87 to 100, wherein is fluoro.

102. R １０ is selected from alkyl, alkenyl, alkynyl, halo, hydroxyl, carboxyl, acyl, acetyl, ester, thioester, alkoxy, phosphoryl, amino, alkylamino, amido, carbamyl, cyano, nitro, azido, alkylthio, cycloalkyl, alkylsulfonyl, sulfonamido, carbamoylamino, cycloalkyl, aryl, heteroaryl, heterocyclylalkyl, and heterocyclyl.

103. R １０ is alkylamino (e.g., ethylamino, diethylamino, or —N(CH ２ ) ２ O (CH ３ ))) the compound of claim 102.

104. R １０ is ethylamino.

105. R １０ is diethylamino.

106. R １０ is heterocyclyl (e.g., 2-oxa-6-azaspiro[3.3]heptyl, piperidinyl, pyrrolidinyl, octahydrocyclopenta[c]pyrrolidinyl, or 3-azabicyclo[3.1.0]hexyl).

107. R １０ is piperidinyl.

108. R １０ is 2-oxa-6-azaspiro[3.3]heptyl.

109. R １０ is pyrrolidinyl.

110. R １０ is 3-azabicyclo[3.1.0]hexyl.

111. R １０ is octahydrocyclopenta[c]pyrrolidinyl.

112. R １２ The compound of any one of claims 87 to 111, wherein is fluoro.

113. R １３ The compound of any one of claims 87 to 112, wherein is fluoro.

114. R １４ The compound of any one of claims 87 to 113, wherein is fluoro.

115. R １５ The compound of any one of claims 87 to 114, wherein is fluoro.

116. 102. The compound of any one of claims 87 or 89-101, wherein E is heterocyclyl (e.g., pyrrolidinyl, azetidinyl, octahydrocyclopenta[c]pyrrolidinyl, octahydropyrrolo[1,2-a]pyrazinyl, or 3-azabicyclo[3.1.0]hexyl).

117. R Ｂ is alkyl (e.g., methyl).

118. R Ｂ 117. The compound of claim 87, 89-101, or 116, wherein is halo (e.g., fluoro).

119. R Ｂ is amino (e.g., dimethylamino).

120. R Ｂ is alkoxy (e.g., methoxy).

121. R Ｂ is a sulfonyl (e.g., —S(O) ２ CH ３ 117. The compound of claim 87, 89 to 101, or 116, wherein

122. The compound of claims 87, 89-101, or 116-121, wherein n3 is 0.

123. The compound of claims 87, 89-101, or 116-121, wherein n3 is 1.

124. The compound has a structure represented by Formula Ii, or a pharmaceutically acceptable salt thereof: 【Chemistry 26】 R １０ is selected from alkyl, alkenyl, alkynyl, halo, hydroxyl, carboxyl, acyl, acetyl, ester, thioester, alkoxy, phosphoryl, amino, alkylamino, amido, carbamyl, cyano, nitro, azido, alkylthio, cycloalkyl, alkylsulfonyl, sulfonamido, carbamoylamino, cycloalkyl, aryl, heteroaryl, and heterocyclyl; R １１ is H, alkyl, or aralkyl; 66. The compound of claim 64 or 65, wherein m is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

125. The compound has the structure of Formula Ij, or a pharmaceutically acceptable salt thereof: 【Chemistry 27】 R １０ is selected from alkyl, alkenyl, alkynyl, halo, hydroxyl, carboxyl, acyl, acetyl, ester, thioester, alkoxy, phosphoryl, amino, alkylamino, amido, carbamyl, cyano, nitro, azido, alkylthio, cycloalkyl, alkylsulfonyl, sulfonamido, carbamoylamino, cycloalkyl, aryl, heteroaryl, and heterocyclyl; R １１ is H, alkyl, or aralkyl; 66. The compound of claim 64 or 65, wherein m is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

126. 126. The compound of claim 124 or 125, wherein m is 1.

127. 126. The compound of claim 124 or 125, wherein m is 2.

128. 126. The compound of claim 124 or 125, wherein m is 3.

129. R １０ The compound according to any one of claims 124 to 128, wherein is amino.

130. R １０ is NH ２ , alkylamino (e.g., propylamino, pentylamino, or hexylamino), alkyloxyalkylamino (e.g., methoxypropylamino, methoxyethylamino, methoxyethylamino, or ethoxyethylamino), dialkylamino (e.g., diethylamino, dipropylamino, diisopropylamino, dibutylamino, dipentylamino, dihexylamino, or dioctylamino), dialkenylamino (e.g., diallylamino), dialkynylamino (e.g., dibutylamino), dialkyloxyalkylamino (e.g., dimethoxyethylamino), heterocyclylalkylamino (e.g., tetrahydrofuranylmethaneamino, N-methylpyrrolidinylmethaneamino, or N-ethylpyrrolidinylmethaneamino), dialkoxyalkylamino (e.g., diethoxyethylamino), cycloalkylamino (e.g., dicyclohexylamino), aralkylamino (e.g., dibenzylamino), (alkyl)(cycloalkyl)amino (e.g., (methyl)(cyclohexyl)amino or (ethyl)(cyclohexyl)amino).

131. R １０ is heterocyclyl (e.g., pyrrolidinyl, piperidinyl, piperazinyl such as N-methylpiperazinyl, azepanyl, azocanyl, morpholinyl, oxazolidinonyl, and phthalimidyl).

132. R １０ is heterocyclyl (e.g., pyrrolidinyl such as N-methylpyrrolidinyl, piperidinyl, azetidinyl, octahydrocyclopenta[c]pyrrolidinyl, octahydropyrrolo[1,2-a]pyrazinyl, 3-azabicyclo[3.1.0]hexyl, 2-oxa-6-azaspiro[3.3]heptyl, hexahydro-5H-[1,4]dioxino[2,3-c]pyrrolyl, piperazinyl such as N-methylpiperazinyl, azepanyl, azocanyl, morpholinyl, oxazolidinonyl, phthalimidyl).

133. R １０ is carbamyl (e.g., tert-butylcarbamoyl).

134. R １０ The compound of any one of claims 124 to 128, wherein is heteroaryl (e.g., triazolyl).

135. The compound has the structure of formula Ik, or a pharmaceutically acceptable salt thereof: 【Chemistry 28】 R １０ is selected from alkyl, alkenyl, alkynyl, halo, hydroxyl, carboxyl, acyl, acetyl, ester, thioester, alkoxy, phosphoryl, amino, alkylamino, amido, carbamyl, cyano, nitro, azido, alkylthio, cycloalkyl, alkylsulfonyl, sulfonamido, carbamoylamino, cycloalkyl, aryl, heteroaryl, and heterocyclyl; R １１ is H, alkyl, or aralkyl; 66. The compound of claim 64 or 65, wherein m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

136. The compound has a structure represented by Formula II, or a pharmaceutically acceptable salt thereof: 【Chemistry 29】 R １０ is selected from alkyl, alkenyl, alkynyl, halo, hydroxyl, carboxyl, acyl, acetyl, ester, thioester, alkoxy, phosphoryl, amino, alkylamino, amido, carbamyl, cyano, nitro, azido, alkylthio, cycloalkyl, alkylsulfonyl, sulfonamido, carbamoylamino, cycloalkyl, aryl, heteroaryl, and heterocyclyl; R １１ is H, alkyl, or aralkyl; 66. The compound of claim 64 or 65, wherein m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

137. 137. The compound of claim 136, wherein m is 0.

138. 137. The compound of claim 136, wherein m is 1.

139. R １０ is heterocyclyl (e.g., azetidine, pyrrolidinyl, pyrrolidinonyl, morpholinyl, piperidinyl, piperazinyl (such as N-methylpiperazinyl), or isoindolinyl).

140. R １０ The compound according to any one of claims 136 to 138, wherein is amino.

141. R １０ is alkylamino (e.g., diethylamino or dibutylamino), or alkoxyalkylamino (e.g., dimethoxyethylamino).

142. R １０ is heteroaryl (e.g., isoindoline).

143. R １０ is substituted with alkyl, alkenyl, alkynyl, aralkyl, halo, hydroxyl, carboxyl, acyl, acetyl, ester, thioester, alkoxy, phosphoryl, amino, alkylamino, amido, carbamyl, cyano, nitro, azido, alkylthio, cycloalkyl, alkylsulfonyl, sulfonamido, carbamoylamino, cycloalkyl, aryl, heteroaryl, and heterocyclyl.

144. R １０ is substituted with alkyl (e.g., trifluoromethyl or thiophenylethyl).

145. R １０ is substituted with aryl (e.g., phenyl).

146. R １０ is substituted with acyl (e.g., cyclopropylmethanonyl).

147. R １０ is substituted with amino (e.g., dimethylamino).

148. R １０ is substituted with heterocyclyl (e.g., benzopyranyl or pyrrolidinyl).

149. R １０ is substituted with an amide (e.g., pyridinylmethylamide).

150. R １０ is substituted with an ester (e.g., a tert-butyl ester).

151. R １０ is substituted with aralkyl.

152. R １１ The compound according to any one of claims 136 to 142, wherein is H.

153. R １１ is alkyl (e.g., ethyl).

154. The compound is 【Chemistry 30-1】 【Chemistry 30-2】 【Transformation 30-3】 【Chemistry 30-4】 【Transformation 30-5】 【Transformation 30-6】 【Transformation 30-7】 【Transformation 30-8】 【Chemistry 30-9】 [Transformation 30-10] 【Chemistry 30-11】 【Transformation 30-12】 【Transformation 30-13】 【Chemistry 30-14】 or a pharmaceutically acceptable salt thereof.

155. The compound is 【Chemistry 31-1】 【Chemistry 31-2】 【Chemistry 31-3】 【Chemistry 31-4】 【Chemistry 31-5】 【Chemistry 31-6】 【Chemistry 31-7】 【Chemistry 31-8】 【Chemistry 31-9】 【Chemistry 31-10】 【Chemistry 31-11】 【Chemistry 31-12】 【Chemistry 31-13】 【Chemistry 31-14】 【Chemistry 31-15】 【Chemistry 31-16】 【Chemistry 31-17】 【Chemistry 31-18】 【Chemistry 31-19】 【Chemistry 31-20】 【Chemistry 31-21】 【Chemistry 31-22】 [Chemistry 31-23] [Chemistry 31-24] [Chemistry 31-25] or a pharmaceutically acceptable salt thereof.

156. 156. A pharmaceutical composition comprising a compound according to any one of claims 1 to 155 and a pharmaceutically acceptable excipient.

157. 156. A method of treating cancer in a subject in need thereof, comprising administering to the subject an effective amount of a compound of any one of claims 1 to 155, or a pharmaceutically acceptable salt thereof.

158. 158. The method of claim 157, wherein the cancer is breast cancer, head and neck cancer, lung cancer, prostate cancer, or ovarian cancer.

159. 158. The method of claim 157, wherein the cancer is testicular cancer, cervical cancer, bladder cancer, esophageal cancer, mesothelioma, or brain cancer (e.g., neuroblastoma).

160. 160. The method of any one of claims 157 to 159, wherein the cancer is recurrent.

161. The method of any one of claims 157 to 160, wherein the cancer is refractory.

162. 162. The method of any one of claims 157-161, wherein the cancer is resistant to treatment with olaparib.

163. 163. The method of any one of claims 157 to 162, wherein the cancer is resistant to treatment with cisplatin.

164. 156. A method of inhibiting DNA repair in a subject in need thereof, comprising administering to the subject an effective amount of a compound of any one of claims 1 to 155, or a pharmaceutically acceptable salt thereof.

165. 156. A method of inhibiting PARP and ATR in a subject in need thereof, comprising administering to the subject an effective amount of a compound of any one of claims 1 to 155, or a pharmaceutically acceptable salt thereof.

Images