Pyrrolidine and imidazolidine DNA polymerase theta inhibitors and uses thereof

Abstract

The present invention relates to pyrrolidine and imidazolidine derivatives and their use in the treatment and prevention of cancer, as well as compositions containing said derivatives and methods for their preparation.

Description

[Technical Field]

[0001] STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT This invention was made with government support under grants 1R41CA239983-01A1 and 1R41CA265430-01 awarded to Recombination Therapeutics, LLC by the National Cancer Institute, and W81XWH2010031 awarded by the Department of Defense. The government has certain rights in this invention.

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 378,161, filed October 3, 2022, which is incorporated herein by reference in its entirety.

[0003] Reference to "Sequence Listing" submitted as an XML file The entire contents of the XML file named "205961-0056-00WO_SequenceListing.xml", created on September 29, 2023, and having a size of 10,036 bytes, in XML format, are incorporated herein by reference.

[0004] The present invention relates to pyrrolidine and imidazolidine derivatives and their use in the treatment and prevention of cancer, as well as compositions containing said derivatives and methods for their preparation. [Background technology]

[0005] Homology-directed repair (HDR), also known as homologous recombination (HR), is an important DNA repair pathway due to its essential role in promoting genome integrity and replication termination (Moynahan ME et al., 2010, Nat. Rev. Mol. Cell. Biol., 11:196-207; Li X et al., 2008, Cell Research, 18:99-113; Sung P et al., 2008, Nature Reviews. Molecular Cell Biology, 7:739-750). Mutations in proteins central to HDR, such as BRCA1 or BRCA2 (BRCA), significantly increase women's susceptibility to breast and ovarian cancer (Moynahan ME et al., 2010, Nat. Rev. Mol. Cell. Biol., 11:196-207). BRCA1 and BRCA2 are essential for HDR because they play a key role in facilitating RAD51 binding to single-stranded DNA (ssDNA), which is essential for HDR repair of DNA breaks and therefore cell proliferation (Moynahan ME et al., 2010, Nat. Rev. Mol. Cell. Biol., 11:196-207; Holloman WK, 2011, Nature Structural & Molecular Biology, 18:748-754; Lok BH et al., 2012, Clin. Cancer Res., 18:6400-6406; Lok BH et al., 2012, Oncogene). BRCA-deficient cells are highly sensitive to DNA damage due to defects in the HDR pathway of DNA repair; therefore, drugs that cause DNA damage or inhibit DNA repair can cause synthetic lethality in BRCA-deficient cells while sparing normal cells (Farmer H et al., 2005, Nature, 434:917-921; Sonnenblick A et al., 2015, Nat. Rev. Clin. Oncol., 12:27-41; Lord CJ et al., 2012, Nature, 481:287-294; Bryant HE et al., 2005, Nature, 434:913-917).

[0006] The development of small molecules targeting BRCA-deficient cancers is crucial for the development of precision medicine. The importance of developing drugs targeting BRCA-deficient cancers through a synthetic lethal approach is exemplified by pioneering studies using poly(ADP-ribose) polymerase 1 (PARP-1) inhibitors (Farmer H et al., 2005, Nature, 434:917-921; Lord CJ et al., 2012, Nature, 481:287-294; Bryant HE et al., 2005, Nature, 434:913-917; Balmana J et al., 2011, Cancer Discov., 1:29-34). PARP-1 plays a key role in DNA base excision repair (BER), and in cells with BER deficiency due to PARP-1 inhibition, ssDNA breaks and PARP-1:DNA adducts frequently occur, which are converted into potentially lethal double-strand breaks (DSBs) during DNA replication. Because BRCA proteins play a major role in repairing DSBs during S phase, BRCA-deficient cells are highly sensitive to DSBs and protein-DNA adducts induced by PARP-1 inhibitors compared with normal cells. Therefore, PARP-1 inhibitors have shown promise in the clinic due to their ability to cause synthetic lethality in BRCA-deficient cells (Sonnenblick A et al., 2015, Nat. Rev. Clin. Oncol., 12:27-41; Lord CJ et al., 2017, Science, 355:1152-1158). However, these drugs cause several side effects and frequently develop drug resistance in patients, indicating the need for the development of other anticancer drug targets (Sonnenblick A et al., 2015, Nat. Rev. Clin. Oncol., 12:27-41; Balmana J et al., 2011, Cancer Discov., 1:29-34; Edwards SL et al., 2008, Nature, 451:1111-1115; Sakai W et al., 2008, Nature, 451:1116-1120).

[0007] Previous studies have identified DNA polymerase theta (also known as Polq, Polθ, POLQ, or Pol-theta) as a promising drug target for BRCA-deficient cancers (Mateos-Gomez PA et al., 2015, Nature, 518:254-257; Ceccaldi RL et al., 2015, Nature, 517). The polymerase domain encoded by the gene POLQ, herein referred to as Polq, is a highly unselective enzyme. For example, unlike other polymerases, Polq promotes the elongation of single-stranded DNA (ssDNA) (Hogg M et al., 2012, Nucleic Acids Res., 40:2611-2622; Kent T et al., 2015, Nature Structural & Molecular Biology, 22). Polq also exhibits low-fidelity DNA synthesis and translesion synthesis (TLS) activity (Hogg M et al., 2011, J. Mol. Biol., 405:642-652; Arana ME et al., 2008, Nucleic Acids Res., 36:3847-3856; Zahn KE et al., 2015, Nature Structural & Molecular Biology, 22:304-311). Studies have shown that human Polq promotes DSB repair through microhomology-mediated end joining (MMEJ), also known as alternative end joining (Mateos-Gomez PA et al., 2015, Nature, 518:254-257; Kent T et al., 2015, Nature Structural & Molecular Biology, 22; Kent T et al., 2015, Nat. Struct. Mol. Biol., 22:230-237; Black SJ et al., 2019, Nat. Commun., 10:4423; Yousefzadeh MJ et al., 2014, PLoS Genet., 10:e1004654).For example, Polq uniquely promotes MMEJ of DNA with 3' ssDNA overhangs containing microhomology tracts in vitro, and Polq has also been shown to promote MMEJ in mammalian cells (Mateos-Gomez PA et al., 2015, Nature, 518:254-257; Kent T et al., 2015, Nature Structural & Molecular Biology, 22; Yousefzadeh MJ et al., 2014, PLoS Genet., 10:e1004654).

[0008] MMEJ is induced in response to DNA damage and replication stress during S phase, whereas DSB repair is primarily carried out by HDR, which depends on BRCA1, BRCA2, and associated proteins including, but not limited to, RAD54, PALB2, RAD51C, and FANCD2 (Moynahan ME et al., 2010, Nat. Rev. Mol. Cell. Biol., 11:196-207; Li X et al., 2008, Cell Research, 18:99-113; San Filippo J et al., 2008, Annual Review of Biochemistry, 77:229-257; Truong LN et al., 2013, Proc. Natl. Acad. Sci. USA, 110:7720-7725; Wang Z et al., 2019, J. Biol. Chem., 294:3909-3919). Because MMEJ serves as an important backup repair pathway, suppression of Polq expression in BRCA-deficient cells causes synthetic lethality but has little or no effect in BRCA-competent cells (Mateos-Gomez PA et al., 2015, Nature, 518:254-257; Cho NW et al., 2015, Nature, 518:174-176). For example, suppression of POLQ expression in cancer cells with BRCA1 mutations severely reduces cell survival (Mateos-Gomez PA et al., 2015, Nature, 518:254-257). In contrast, suppression of POLQ in non-cancerous cells, such as cells immortalized by the expression of telomerase (hTERT), is ineffective (Mateos-Gomez PA et al., 2015, Nature, 518:254-257). Consistent with this, BRCA-deficient ovarian cancer cells have been shown to depend on Polq for their survival in the presence of genotoxic drugs (Ceccaldi RL et al., 2015, Nature, 517). This synthetic lethal relationship between Polq and HDR was further substantiated in a mouse model (Ceccaldi RL et al., 2015, Nature, 517).Most importantly, the DNA synthesis activity of Polq has been shown to promote the survival of BRCA-deficient cells (Mateos-Gomez PA et al., 2015, Nature, 518:254-257), strongly suggesting that pharmacological inhibition of the polymerase domain expressed by POLQ selectively kills BRCA-deficient cancer cells.

[0009] More recent studies have demonstrated that Polq, along with many other DNA damage repair (DDR) factors, is also synthetically lethal. For example, inactivation of Polq in combination with non-homologous end-joining factors such as Ku proteins was also shown to be synthetically lethal (Wyatt DW et al., 2016, Mol. Cell, 63:662-673; Feng W et al., 2019, Nat. Commun., 10:4286). Furthermore, inactivation of Polq in combination with the DDR factors RAD54 or FANCJ also results in synthetic lethality (Feng W et al., 2019, Nat. Commun., 10:4286). Thus, overall, Polq appears to play an important role in the survival of cells with DNA repair defects, such as cells lacking essential HDR or NHEJ factors. Furthermore, recent studies have demonstrated that inactivation of Polq in combination with inhibition of the DDR factor ATR also results in a significant decrease in cell proliferation (Wang Z et al., 2019, J. Biol. Chem., 294:3909-3919). A semisynthetic lethal interaction between Polq and ATM has been identified in previous studies (Shima N et al., 2004, Mol. Cell Biol., 24:10381-10389). Therefore, Polq is also an attractive drug target in cancers with defects in key DDR signaling pathways, including ATR, ATM, and DNA-PKcs.

[0010] Thus, there is a need in the art for compositions and methods that inhibit Polq to prevent or treat various diseases or disorders, such as cancer. The present invention fulfills this unmet need. Summary of the Invention

[0011] In one aspect, the invention relates to compounds having the structure of Formula (I), or a tautomer or stereochemical isomer, or a pharmaceutically acceptable salt or solvate thereof: [ka] (In the formula, U is CH2, O, S, or NR U represents W is C(R 4 ) or N, Y is C(R 6 ) or N, Q represents O or S; R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 8 , R 9 and R 10 are independently hydrogen, deuterium, and C 1~6 Alkyl, C 2~6 Alkenyl, alkynyl, hydroxy, thiol, C 1~6 Alkoxy, halogen, haloC 1~6 Alkyl, halo C1-6 alkoxy, C 3~8 Cycloalkyl, nitrile, NR X R Y and combinations thereof, and two adjacent groups R 1 ~R 4 or R 6 ~R 10 may optionally be joined to form a 5- to 7-membered saturated or unsaturated ring optionally containing one or more heteroatoms selected from O, N, or S; R 5 and R U are independently hydrogen, deuterium, and C 1~6 Alkyl, C 2~6 Alkenyl, alkynyl, hydroxy, thiol, C 1~6 Alkoxy, halogen, haloC1-6 alkyl, haloC1-6 alkoxy, C 3~8 Cycloalkyl, nitrile, -NRX R Y aryl, heteroaryl, heterocyclyl, amide, and combinations thereof. Z is CR Z R Z’ , C=S, or C=O; X is C(R 15 )(R 16 ), N(R 17 ) or O, R 15 , R 16 and R 17 are independently hydrogen, deuterium, and C 1~6 Alkyl, haloC1-6 alkyl, -OR 15a , -SR 15a , nitrile, -COC 1~6 Alkyl, -COOC 1~6 Alkyl, hydroxy, C 1~6 Alkoxy, C 1~6 Alkanol, C3-8 cycloalkyl, halogen, carbonyl, -NR V R W , -CH2-NR V R W , represents —OSO2NH2, —P(O)OH2, aryl, heteroaryl, heterocyclyl, and combinations thereof; R 15 , R 16 , and R 17 may further comprise one or more divalent linkers L selected from the group consisting of alkylene, cycloalkylene, heteroalkylene, heterocycloalkylene, alkenylene, alkynylene, arylene, heteroarylene, silyl, amine, amide, ester, ether, carbonyl, carbamate, sulfamate, sulfonate ester, sulfoximine, sulfonamide, thioether, thioester, disulfide, hydrazine, urea, thiourea, phosphate, phosphonate ester, poly(alkyl ether), heteroatom, and combinations thereof; 15 and R 16 and may be taken together to form a ring, n is 0, 1 or 2, and when n is 0, N is R B and R B’is directly bonded to the carbon to which it is attached, R A , R A’ , R Z , and R Z’ are each independently hydrogen, deuterium, or C 1~6 Alkyl, hydroxy, C 1~6 Alkoxy, C 1~6 Alkanol, halogen, -OR 15b , CO2H, CO2R 15b , Haro C 1~6 alkyl, and combinations thereof; R B and R B’ are independently hydrogen, deuterium, and C 1~6 Alkyl, hydroxy, C 1~6 Alkoxy, C 1~6 Alkanol, halogen, -OR 15b , CO2H, CO2R 15b , Haro C 1~6 alkyl, and combinations thereof, or R B and the carbon to which it is attached form a carbonyl group, R B’ does not exist, R 15a and R 15b are independently hydrogen, deuterium, or C 1~6 Represents alkyl and two groups R 15a and R 15b , or two groups R 15b may be joined together to form a 5- to 7-membered saturated ring system optionally substituted with one or more C1-6 alkyl groups; R V , R W , R X and R Y are independently hydrogen, deuterium, and C 1~6 Alkyl, haloC1-6 alkyl, C 3~8 Cycloalkyl, -COC 1~6 represents an alkyl or heterocyclyl, where the alkyl group may be optionally substituted with one or more deuterium, hydroxy, amino, or sulfone groups, and the heterocyclyl ring may be optionally substituted with one or more deuterium, oxo, hydroxy, C 1~6 Alkanol or -COC 1~6It may be optionally substituted with an alkyl group.

[0012] In one aspect, the present invention relates to a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a compound of formula (I) or a tautomer or stereochemical isomer, pharmaceutically acceptable salt, or solvate thereof.

[0013] In one aspect, the present invention relates to a method of inhibiting the activity of DNA polymerase theta (Polq), the method comprising contacting Polq with a compound of formula (I) or a tautomer or stereochemical isomer, pharmaceutically acceptable salt, or solvate thereof. [Brief explanation of the drawings]

[0014] The following detailed description of embodiments of the present invention will be better understood when read in conjunction with the accompanying drawings, it being understood that the invention is not limited to the precise arrangements and instrumentalities of the embodiments shown in the drawings.

[0015] [Figure 1A] Figure 1, including Figures 1A-1F, illustrates representative results from experiments demonstrating that exemplary Polq inhibitors (Polqi) selectively kill BRCA-mutated cancer cells. Figures 1A-1E show scatter plots demonstrating that treatment with the indicated Polqi significantly reduced the survival of BRCA2-mutated DLD-1 cells compared to BRCA2-wild-type DLD-1 cells, which are largely resistant to Polqi. Figure 1F shows a scatter plot demonstrating that treatment with the indicated Polqi significantly reduced the survival of BRCA2-mutated HCT116 cells compared to BRCA2-wild-type HCT116 cells, which are largely resistant to Polqi. Data are presented as mean, n=3, + / - standard deviation. [Figure 1B]Figure 1, including Figures 1A-1F, illustrates representative results from experiments demonstrating that exemplary Polq inhibitors (Polqi) selectively kill BRCA-mutated cancer cells. Figures 1A-1E show scatter plots demonstrating that treatment with the indicated Polqi significantly reduced the survival of BRCA2-mutated DLD-1 cells compared to BRCA2-wild-type DLD-1 cells, which are largely resistant to Polqi. Figure 1F shows a scatter plot demonstrating that treatment with the indicated Polqi significantly reduced the survival of BRCA2-mutated HCT116 cells compared to BRCA2-wild-type HCT116 cells, which are largely resistant to Polqi. Data are presented as mean, n=3, + / - standard deviation. [Figure 1C] Figure 1, including Figures 1A-1F, illustrates representative results from experiments demonstrating that exemplary Polq inhibitors (Polqi) selectively kill BRCA-mutated cancer cells. Figures 1A-1E show scatter plots demonstrating that treatment with the indicated Polqi significantly reduced the survival of BRCA2-mutated DLD-1 cells compared to BRCA2-wild-type DLD-1 cells, which are largely resistant to Polqi. Figure 1F shows a scatter plot demonstrating that treatment with the indicated Polqi significantly reduced the survival of BRCA2-mutated HCT116 cells compared to BRCA2-wild-type HCT116 cells, which are largely resistant to Polqi. Data are presented as mean, n=3, + / - standard deviation. [Figure 1D] Figure 1, including Figures 1A-1F, illustrates representative results from experiments demonstrating that exemplary Polq inhibitors (Polqi) selectively kill BRCA-mutated cancer cells. Figures 1A-1E show scatter plots demonstrating that treatment with the indicated Polqi significantly reduced the survival of BRCA2-mutated DLD-1 cells compared to BRCA2-wild-type DLD-1 cells, which are largely resistant to Polqi. Figure 1F shows a scatter plot demonstrating that treatment with the indicated Polqi significantly reduced the survival of BRCA2-mutated HCT116 cells compared to BRCA2-wild-type HCT116 cells, which are largely resistant to Polqi. Data are presented as mean, n=3, + / - standard deviation. [Figure 1E]Figure 1, including Figures 1A-1F, illustrates representative results from experiments demonstrating that exemplary Polq inhibitors (Polqi) selectively kill BRCA-mutated cancer cells. Figures 1A-1E show scatter plots demonstrating that treatment with the indicated Polqi significantly reduced the survival of BRCA2-mutated DLD-1 cells compared to BRCA2-wild-type DLD-1 cells, which are largely resistant to Polqi. Figure 1F shows a scatter plot demonstrating that treatment with the indicated Polqi significantly reduced the survival of BRCA2-mutated HCT116 cells compared to BRCA2-wild-type HCT116 cells, which are largely resistant to Polqi. Data are presented as mean, n=3, + / - standard deviation. [Figure 1F] Figure 1, including Figures 1A-1F, illustrates representative results from experiments demonstrating that exemplary Polq inhibitors (Polqi) selectively kill BRCA-mutated cancer cells. Figures 1A-1E show scatter plots demonstrating that treatment with the indicated Polqi significantly reduced the survival of BRCA2-mutated DLD-1 cells compared to BRCA2-wild-type DLD-1 cells, which are largely resistant to Polqi. Figure 1F shows a scatter plot demonstrating that treatment with the indicated Polqi significantly reduced the survival of BRCA2-mutated HCT116 cells compared to BRCA2-wild-type HCT116 cells, which are largely resistant to Polqi. Data are presented as mean, n=3, + / - standard deviation.

[0016] [Figure 2] 1 illustrates representative results from an experiment demonstrating that the Polq inhibitor Example 4 exhibits synergistic activity with the PARP inhibitor olaparib in reducing the survival of BRCA2 mutant cancer cells. A scatter plot shows the survival of BRCA2 mutant DLD1 cells in the presence of the indicated concentrations of olaparib alone compared to olaparib with two different concentrations of the Polq inhibitor Example 4 (left). Data represent the mean, n=3, + / - standard deviation. A synergy plot (right) was generated using ComBenefit software.

[0017] [Figure 3A]Figure 3, including Figures 3A-3E, illustrates representative experimental data demonstrating that Polq inhibitors act synergistically with PARP inhibitors. Figure 3A shows representative scatter plots and synergy plots illustrating the clonogenic survival of HCT116 BRCA2 null cells treated with DMSO or various concentrations of Example 6 and various concentrations of Olaparib. Figure 3B shows representative scatter plots and synergy plots illustrating the clonogenic survival of DLD1 BRCA2 null cells treated with DMSO or various concentrations of Example 6 and various concentrations of Olaparib. Figure 3C shows representative scatter plots and synergy plots illustrating the clonogenic survival of PE01 cells treated with DMSO or various concentrations of Example 6 and various concentrations of Olaparib. Figure 3D shows representative scatter plots and synergy plots illustrating the clonogenic survival of VC8 cells treated with DMSO or various concentrations of Example 6 and various concentrations of Olaparib. Figure 3E shows representative scatter plots and synergy plots demonstrating the clonogenic survival of CAPAN-1 cells treated with DMSO or various concentrations of Example 6 and various concentrations of olaparib. Figure 3F shows representative scatter plots and representative images of colony plates demonstrating the clonogenic survival of MDA-MB-231 cells treated with DMSO or various concentrations of Example 6 and various concentrations of talazoparib. In Figures 3A-3F, data are presented as mean ± SEM, n = 3, and p values ​​were calculated by two-sample t-test. In Figures 3A-3E, * indicates p < 0.05, ** indicates p < 0.01, and *** indicates p < 0.001. In Figure 3F, p = 0.019935 for DMSO vs. Example 6 at 50 nM talazoparib. [Figure 3B]Figure 3, including Figures 3A-3E, illustrates representative experimental data demonstrating that Polq inhibitors act synergistically with PARP inhibitors. Figure 3A shows representative scatter plots and synergy plots illustrating the clonogenic survival of HCT116 BRCA2 null cells treated with DMSO or various concentrations of Example 6 and various concentrations of Olaparib. Figure 3B shows representative scatter plots and synergy plots illustrating the clonogenic survival of DLD1 BRCA2 null cells treated with DMSO or various concentrations of Example 6 and various concentrations of Olaparib. Figure 3C shows representative scatter plots and synergy plots illustrating the clonogenic survival of PE01 cells treated with DMSO or various concentrations of Example 6 and various concentrations of Olaparib. Figure 3D shows representative scatter plots and synergy plots illustrating the clonogenic survival of VC8 cells treated with DMSO or various concentrations of Example 6 and various concentrations of Olaparib. Figure 3E shows representative scatter plots and synergy plots demonstrating the clonogenic survival of CAPAN-1 cells treated with DMSO or various concentrations of Example 6 and various concentrations of olaparib. Figure 3F shows representative scatter plots and representative images of colony plates demonstrating the clonogenic survival of MDA-MB-231 cells treated with DMSO or various concentrations of Example 6 and various concentrations of talazoparib. In Figures 3A-3F, data are presented as mean ± SEM, n = 3, and p values ​​were calculated by two-sample t-test. In Figures 3A-3E, * indicates p < 0.05, ** indicates p < 0.01, and *** indicates p < 0.001. In Figure 3F, p = 0.019935 for DMSO vs. Example 6 at 50 nM talazoparib. [Figure 3C]Figure 3, including Figures 3A-3E, illustrates representative experimental data demonstrating that Polq inhibitors act synergistically with PARP inhibitors. Figure 3A shows representative scatter plots and synergy plots illustrating the clonogenic survival of HCT116 BRCA2 null cells treated with DMSO or various concentrations of Example 6 and various concentrations of Olaparib. Figure 3B shows representative scatter plots and synergy plots illustrating the clonogenic survival of DLD1 BRCA2 null cells treated with DMSO or various concentrations of Example 6 and various concentrations of Olaparib. Figure 3C shows representative scatter plots and synergy plots illustrating the clonogenic survival of PE01 cells treated with DMSO or various concentrations of Example 6 and various concentrations of Olaparib. Figure 3D shows representative scatter plots and synergy plots illustrating the clonogenic survival of VC8 cells treated with DMSO or various concentrations of Example 6 and various concentrations of Olaparib. Figure 3E shows representative scatter plots and synergy plots demonstrating the clonogenic survival of CAPAN-1 cells treated with DMSO or various concentrations of Example 6 and various concentrations of olaparib. Figure 3F shows representative scatter plots and representative images of colony plates demonstrating the clonogenic survival of MDA-MB-231 cells treated with DMSO or various concentrations of Example 6 and various concentrations of talazoparib. In Figures 3A-3F, data are presented as mean ± SEM, n = 3, and p values ​​were calculated by two-sample t-test. In Figures 3A-3E, * indicates p < 0.05, ** indicates p < 0.01, and *** indicates p < 0.001. In Figure 3F, p = 0.019935 for DMSO vs. Example 6 at 50 nM talazoparib. [Figure 3D]Figure 3, including Figures 3A-3E, illustrates representative experimental data demonstrating that Polq inhibitors act synergistically with PARP inhibitors. Figure 3A shows representative scatter plots and synergy plots illustrating the clonogenic survival of HCT116 BRCA2 null cells treated with DMSO or various concentrations of Example 6 and various concentrations of Olaparib. Figure 3B shows representative scatter plots and synergy plots illustrating the clonogenic survival of DLD1 BRCA2 null cells treated with DMSO or various concentrations of Example 6 and various concentrations of Olaparib. Figure 3C shows representative scatter plots and synergy plots illustrating the clonogenic survival of PE01 cells treated with DMSO or various concentrations of Example 6 and various concentrations of Olaparib. Figure 3D shows representative scatter plots and synergy plots illustrating the clonogenic survival of VC8 cells treated with DMSO or various concentrations of Example 6 and various concentrations of Olaparib. Figure 3E shows representative scatter plots and synergy plots demonstrating the clonogenic survival of CAPAN-1 cells treated with DMSO or various concentrations of Example 6 and various concentrations of olaparib. Figure 3F shows representative scatter plots and representative images of colony plates demonstrating the clonogenic survival of MDA-MB-231 cells treated with DMSO or various concentrations of Example 6 and various concentrations of talazoparib. In Figures 3A-3F, data are presented as mean ± SEM, n = 3, and p values ​​were calculated by two-sample t-test. In Figures 3A-3E, * indicates p < 0.05, ** indicates p < 0.01, and *** indicates p < 0.001. In Figure 3F, p = 0.019935 for DMSO vs. Example 6 at 50 nM talazoparib. [Figure 3E]Figure 3, including Figures 3A-3E, illustrates representative experimental data demonstrating that Polq inhibitors act synergistically with PARP inhibitors. Figure 3A shows representative scatter plots and synergy plots illustrating the clonogenic survival of HCT116 BRCA2 null cells treated with DMSO or various concentrations of Example 6 and various concentrations of Olaparib. Figure 3B shows representative scatter plots and synergy plots illustrating the clonogenic survival of DLD1 BRCA2 null cells treated with DMSO or various concentrations of Example 6 and various concentrations of Olaparib. Figure 3C shows representative scatter plots and synergy plots illustrating the clonogenic survival of PE01 cells treated with DMSO or various concentrations of Example 6 and various concentrations of Olaparib. Figure 3D shows representative scatter plots and synergy plots illustrating the clonogenic survival of VC8 cells treated with DMSO or various concentrations of Example 6 and various concentrations of Olaparib. Figure 3E shows representative scatter plots and synergy plots demonstrating the clonogenic survival of CAPAN-1 cells treated with DMSO or various concentrations of Example 6 and various concentrations of olaparib. Figure 3F shows representative scatter plots and representative images of colony plates demonstrating the clonogenic survival of MDA-MB-231 cells treated with DMSO or various concentrations of Example 6 and various concentrations of talazoparib. In Figures 3A-3F, data are presented as mean ± SEM, n = 3, and p values ​​were calculated by two-sample t-test. In Figures 3A-3E, * indicates p < 0.05, ** indicates p < 0.01, and *** indicates p < 0.001. In Figure 3F, p = 0.019935 for DMSO vs. Example 6 at 50 nM talazoparib. [Figure 3F]Figure 3, including Figures 3A-3E, illustrates representative experimental data demonstrating that Polq inhibitors act synergistically with PARP inhibitors. Figure 3A shows representative scatter plots and synergy plots illustrating the clonogenic survival of HCT116 BRCA2 null cells treated with DMSO or various concentrations of Example 6 and various concentrations of Olaparib. Figure 3B shows representative scatter plots and synergy plots illustrating the clonogenic survival of DLD1 BRCA2 null cells treated with DMSO or various concentrations of Example 6 and various concentrations of Olaparib. Figure 3C shows representative scatter plots and synergy plots illustrating the clonogenic survival of PE01 cells treated with DMSO or various concentrations of Example 6 and various concentrations of Olaparib. Figure 3D shows representative scatter plots and synergy plots illustrating the clonogenic survival of VC8 cells treated with DMSO or various concentrations of Example 6 and various concentrations of Olaparib. Figure 3E shows representative scatter plots and synergy plots demonstrating the clonogenic survival of CAPAN-1 cells treated with DMSO or various concentrations of Example 6 and various concentrations of olaparib. Figure 3F shows representative scatter plots and representative images of colony plates demonstrating the clonogenic survival of MDA-MB-231 cells treated with DMSO or various concentrations of Example 6 and various concentrations of talazoparib. In Figures 3A-3F, data are presented as mean ± SEM, n = 3, and p values ​​were calculated by two-sample t-test. In Figures 3A-3E, * indicates p < 0.05, ** indicates p < 0.01, and *** indicates p < 0.001. In Figure 3F, p = 0.019935 for DMSO vs. Example 6 at 50 nM talazoparib. DETAILED DESCRIPTION OF THE INVENTION

[0018] The present invention is based, in part, on the discovery that novel pyrrolidine and imidazolidine compounds inhibit the DNA synthesis activity of Polq. Accordingly, the present invention is directed, in part, to compositions and methods comprising pyrrolidine and imidazolidine compounds for inhibiting Polq in vitro and in vivo. In various embodiments, Polq (e.g., Polq activity, Polq levels, etc.) is essential for the proliferation of cancer cells, such as those defective in HDR or other DNA repair pathways. Accordingly, the present invention also provides, in part, compounds and methods for preventing or treating cancer using pyrrolidine and imidazolidine compounds. The present invention also provides kits for modifying or inhibiting Polq (e.g., Polq activity, Polq levels, etc.).

[0019] definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. As used herein, each of the following terms has the meaning associated with it in this section.

[0020] The articles "a" and "an" are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element.

[0021] As used herein, when referring to a measurable value, e.g., amount, duration, etc., "about" is meant to encompass variations of ±20%, ±10%, ±5%, ±1%, or ±0.1% from the specified value, where such variations are appropriate to the practice of the disclosed methods.

[0022] As used herein, the term "alkyl," by itself or as part of another substituent, means, unless otherwise stated, a straight or branched chain hydrocarbon having the specified number of carbon atoms (i.e., C1-6 means 1 to 6 carbon atoms), including straight, branched, or cyclic substituents. Examples include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, cyclohexyl, (cyclohexyl)methyl, cyclopropylmethyl, homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. The term "alkyl," unless otherwise stated, is also meant to include derivatives of alkyl defined in more detail below, such as "heteroalkyl," "haloalkyl," and "homoalkyl."

[0023] As used herein, a "haloC" is a group or part of a group. 1~6 The term "alkyl" refers to a C alkyl group, as defined herein, in which one or more hydrogen atoms are replaced with halogen. 1~6 It refers to an alkyl group. 1~6 The term "alkyl" refers to monohalo C 1~6 Contains alkyl and polyhalo C 1~6 It also includes alkyl. There may be one, two, three or more hydrogen atoms replaced with halogen, thus haloC 1~6 Alkyl can have one, two, three or more halogens. Examples of such groups include fluoroethyl, fluoromethyl, difluoromethyl, trifluoromethyl or trifluoroethyl.

[0024] Similarly, as used herein as a group or part of a group, “haloC 1~6 The term "alkoxy" refers to a C alkyl group, as defined herein, in which one or more hydrogen atoms are replaced with halogen. 1~6 It refers to an alkoxy group. Therefore, "haloC" 1~6 The term "alkoxy" refers to monohalo C 1~6 Contains alkoxy and polyhalo C 1~6It also includes alkoxy. There may be one, two, three or more hydrogen atoms replaced with halogen, thus haloC 1~6 Alkyl can have one, two, three or more halogens. Examples of such groups include fluoroethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy or trifluoroethoxy.

[0025] As used herein, "C 3~8 The term "cycloalkyl" refers to a saturated monocyclic hydrocarbon having from 3 to 8 carbon atoms. Examples of such groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like.

[0026] As used herein, the term "substituted alkyl" includes any of halogen, -OH, alkoxy, -NH2, -N(CH3)2, -C(=O)OH, trifluoromethyl, [ka] "Alkyl" refers to alkyl as defined above substituted with one, two, or three substituents selected from the group consisting of -C(=O)O(C1-C4)alkyl, -C(=O)NH2, -SON2NH2, -C(=NH)NH2, and -NO2, preferably containing one or two substituents selected from halogen, -OH, alkoxy, -NH2, trifluoromethyl, -N(CH3)2, and -C(=O)OH, more preferably halogen, alkoxy, and -OH. Examples of substituted alkyl include, but are not limited to, 2,2-difluoropropyl, 2-carboxycyclopentyl, and 3-chloropropyl.

[0027] As used herein, the term "alkylene" by itself or as part of another molecule refers to a group consisting of (-CH) nExamples of such groups include, but are not limited to, groups having 24 or fewer carbon atoms, such as the structures -CH2CH2- and -CH2CH2CH2CH2-. The term "alkylene," unless otherwise specified, is also meant to include those groups described below as "heteroalkylene."

[0028] As used herein, the terms "alkoxy," "alkylamino," and "alkylthio" are used in their conventional sense to refer to an alkyl group attached to a molecule via an oxygen atom, an amino group, or a sulfur atom, respectively. As used herein, the term "alkoxy," used alone or in combination with other terms, means, unless otherwise specified, an alkyl group having the specified number of carbon atoms, as defined above, attached to the remainder of the molecule via an oxygen atom, such as methoxy, ethoxy, 1-propoxy, 2-propoxy (isopropoxy), and higher homologs and isomers. (C1-C3)alkoxy, particularly ethoxy and methoxy, are preferred.

[0029] As used herein, unless otherwise stated, the terms “halo” or “halogen,” by themselves or as part of another substituent, mean a fluorine, chlorine, bromine, or iodine atom, preferably fluorine, chlorine, or bromine, and more preferably fluorine or chlorine.

[0030] As used herein, the term "heteroalkyl," by itself or in combination with another term, means, unless otherwise stated, a stable linear or branched alkyl group consisting of the stated number of carbon atoms and one or two heteroatoms selected from the group consisting of O, N, Si, P, and S, wherein the nitrogen and sulfur atoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized. The heteroatom may be positioned at any position in the heteroalkyl group, including between the remainder of the heteroalkyl group and the fragment to which it is attached, or may be attached to the most distal carbon atom in the heteroalkyl group. Examples include -O-CH-CH-CH, -CH-CH-CH-OH, -CH-CH-NH-CH, -CH-S-CH-CH, and -CHCH-S(=O)-CH. Up to two heteroatoms may be consecutive, for example, -CH-NH-OCH, or -CH-CH-SS-CH.

[0031] As used herein, the term "aromatic" refers to a carbocyclic or heterocyclic ring having one or more polyunsaturated rings and having aromatic character, i.e., having (4n+2) delocalized π (pi) electrons, where n is an integer.

[0032] As used herein, the term "aryl," used alone or in combination with other terms, means, unless otherwise specified, a carbocyclic aromatic system containing one or more rings (typically one, two, or three rings), which may be linked together in a pendant manner, such as biphenyl, or may be fused, such as naphthalene. Examples include phenyl, anthracyl, and naphthyl. Phenyl and naphthyl are preferred, and phenyl is most preferred.

[0033] As used herein, the term "heterocycle" or "heterocyclyl" or "heterocyclic," by itself or as part of another substituent, means, unless otherwise stated, a stable unsubstituted or substituted monocyclic or polycyclic heterocyclic ring system, which consists of carbon atoms and at least one heteroatom selected from the group consisting of N, O, and S, where the nitrogen and sulfur heteroatoms are optionally oxidized and the nitrogen atom is optionally quaternized. The heterocyclic ring system may be attached at any heteroatom or carbon atom that results in a stable structure, unless otherwise stated. The heterocycle may be aromatic or non-aromatic in nature. In one embodiment, the heterocycle is heteroaryl.

[0034] As used herein, the term "heteroaryl" or "heteroaromatic" refers to an aryl group containing at least one heteroatom selected from N, O, Si, P, and S, where the nitrogen and sulfur heteroatoms are optionally oxidized and the nitrogen atom is optionally quaternized. Heteroaryl groups can be substituted or unsubstituted. Heteroaryl groups can be attached to the remainder of the molecule through a heteroatom. Polycyclic heteroaryls can contain one or more rings that are partially saturated. Examples include tetrahydroquinoline, 2,3-dihydrobenzofuryl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4 ... Examples include azolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1-isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl, and 6-quinolyl.

[0035] Examples of non-aromatic heterocycles include monocyclic groups such as aziridine, oxirane, thiirane, azetidine, oxetane, thietane, pyrrolidine, pyrroline, imidazoline, pyrazolidine, dioxolane, sulfolane, 2,3-dihydrofuran, 2,5-dihydrofuran, tetrahydrofuran, thiophane, piperidine, 1,2,3,6-tetrahydropyridine, 1,4-dihydropyridine, piperazine, morpholine, thiomorpholine, pyran, 2,3-dihydropyran, tetrahydropyran, 1,4-dioxane, 1,3-dioxane, homopiperazine, homopiperidine, 1,3-dioxepane, 4,7-dihydro-1,3-dioxepine, and hexamethylene oxide.

[0036] Examples of heteroaryl groups include pyridyl, pyrazinyl, pyrimidinyl (especially 2- and 4-pyrimidinyl), pyridazinyl, thienyl, furyl, pyrrolyl (especially 2-pyrrolyl), imidazolyl, thiazolyl, oxazolyl, pyrazolyl (especially 3- and 5-pyrazolyl), isothiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,3,4-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,3,4-thiadiazolyl and 1,3,4-oxadiazolyl.

[0037] Examples of polycyclic heterocycles include indolyl (especially 3-, 4-, 5-, 6-, and 7-indolyl), indolinyl, quinolyl, tetrahydroquinolyl, isoquinolyl (especially 1- and 5-isoquinolyl), 1,2,3,4-tetrahydroisoquinolyl, cinnolinyl, quinoxalinyl (especially 2- and 5-quinoxalinyl), quinazolinyl, phthalazinyl, 1,8-naphthyridinyl, 1,4-benzodioxanyl, coumarin, dihydrocoumarin, 1,5-naphthyridinyl, benzofuryl (especially 3-, 4- , 5-, 6-, and 7-benzofuryl), 2,3-dihydrobenzofuryl, 1,2-benzisoxazolyl, benzothienyl (especially 3-, 4-, 5-, 6-, and 7-benzothienyl), benzoxazolyl, benzothiazolyl (especially 2-benzothiazolyl and 5-benzothiazolyl), purinyl, benzimidazolyl (especially 2-benzimidazolyl), benzotriazolyl, thioxanthinyl, carbazolyl, carbolinyl, acridinyl, pyrrolidinyl, and quinolizidinyl.

[0038] The above lists of heterocyclyl and heteroaryl moieties are intended to be representative and not limiting.

[0039] As used herein, the term "aminoaryl" refers to an aryl moiety containing an amino moiety. Such amino moieties include, but are not limited to, primary amines, secondary amines, tertiary amines, masked amines, or protected amines. Such tertiary amines, masked amines, or protected amines can be converted to primary amine or secondary amine moieties. Furthermore, the amine moiety can include amine-like moieties that have similar chemical properties to the amine moiety, including, but not limited to, chemical reactivity.

[0040] As used herein, the term "substituted" means that an atom or group of atoms replaces a hydrogen as a substituent attached to another group. For aryl, aryl-(C1-C3)alkyl, and heterocyclyl groups, the term "substituted" as applied to the ring of these groups refers to any level of substitution, i.e., mono-, di-, tri-, tetra-, or penta-substitution, where such substitution is permitted. The substituents are independently selected, and substitution can be at any chemically accessible position. In one embodiment, the number of substituents varies from 1 to 4. In another embodiment, the number of substituents varies from 1 to 3. In yet another embodiment, the number of substituents varies from 1 to 2. In yet another embodiment, the substituents are independently selected from C 1~6 Alkyl, -OH, C 1~6 In yet another embodiment, the substituents are independently selected from the group consisting of alkoxy, halo, amino, acetamido, and nitro. 1~6 Alkyl, C 1~6 In another embodiment, the substituents are selected from the group consisting of hydrogen, deuterium, C 1~6 Alkyl, C 2~6 Alkenyl, Hydroxy, C 1~6 Alkoxy, halogen, haloC1-6 alkyl, haloC1-6 alkoxy, C 3~8

[0023] The substituent is selected from the group consisting of cycloalkyl, nitrile, amino, and combinations thereof. As used herein, when a substituent is an alkyl group or an alkoxy group, the carbon chain may be branched, straight, or cyclic, and is preferably straight.

[0041] As used herein, "combinations thereof" refers to any combination of any two or more of the aforementioned substituents, without limitation.

[0042] Integers and R, R 1 , R 2 , R 3 , R 4 , R 5 , R 6and the like are made in the chemical structures and moieties disclosed and described herein. 1 , R 2 , R 3 , R 4 , R 5 , R 6 Any notation such as R, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 etc. can be applied to all structures or moieties listed.

[0043] As used herein, the term "protected" refers to the presence of a "protecting group" or moiety that prevents reaction of a chemically reactive functional group under certain reaction conditions. Protecting groups vary depending on the type of chemically reactive group being protected. By way of example only: (i) if the chemically reactive group is an amine or hydrazide, the protecting group may be selected from tert-butyloxycarbonyl (t-Boc) and 9-fluorenylmethoxycarbonyl (Fmoc); (ii) if the chemically reactive group is a thiol, the protecting group may be orthopyridyl disulfide; and (iii) if the chemically reactive group is a carboxylic acid, such as butanoic acid or propionic acid, or a hydroxyl group, the protecting group may be benzyl, or an alkyl group, such as methyl, ethyl, or tert-butyl. Further, protecting groups include, but are not limited to, photolabile groups such as Nvoc and MeNvoc, as well as other protecting groups known in the art. Other protecting groups are described in Greene and Wuts, Protective Groups in Organic Synthesis, 3rd Ed., John Wiley & Sons, New York, NY, 1999.

[0044] The term "derivative" refers to a small molecule that differs in structure from a reference molecule but retains essential properties of the reference molecule. A derivative may alter its interactions with certain other molecules compared to the reference molecule. Derivative molecules may also include salts, adducts, tautomers, isomers, or other variants of the reference molecule.

[0045] The term "tautomers" refers to structural isomers of organic compounds that are readily interconvertible by chemical processes (tautomerization).

[0046] The term "isomers" or "stereoisomers" refers to compounds which have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space.

[0047] "Pharmaceutically acceptable" refers to properties and / or substances that are acceptable to the subject from a pharmacological / toxicological standpoint, and to a manufacturing pharmaceutical chemist from a physical / chemical standpoint with regard to composition, formulation, stability, subject tolerance and bioavailability. A "pharmaceutically acceptable carrier" refers to a medium that does not interfere with the effectiveness of the biological activity of the active ingredient and that is not toxic to the host to which it is administered.

[0048] As used herein, the term "pharmaceutically acceptable carrier" refers to a pharmaceutically acceptable material, composition, or carrier, such as a liquid or solid filler, stabilizer, dispersant, suspending agent, diluent, excipient, thickener, solvent, or encapsulating material, that is involved in carrying or transporting a compound useful within the invention within or to a subject so that it can perform its intended function. Typically, such constructs are carried or transported from one organ or part of the body to another. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation, including the compound useful within the invention, and not harmful to the subject. Some examples of materials which can serve as pharmaceutically acceptable carriers include sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethyl cellulose, and cellulose acetate; powdered tragacanth, malt, gelatin, talc, excipients such as cocoa butter and suppository wax; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols such as propylene glycol; polyols such as glycerin, sorbitol, mannitol, and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar, buffers such as magnesium hydroxide and aluminum hydroxide; surfactants; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffer; and other non-toxic, compatible substances used in pharmaceutical formulations. As used herein, "pharmaceutically acceptable carriers" also include any and all coatings, antibacterial and antifungal agents, absorption delaying agents, and the like, that are compatible with the activity of the compounds useful within the present invention and are physiologically acceptable to the subject. Supplementary active compounds can also be incorporated into the compositions. "Pharmaceutically acceptable carriers" can further include pharmaceutically acceptable salts of compounds useful within the present invention. Other additional ingredients that can be included in pharmaceutical compositions used to practice the present invention are known in the art.

[0049] The term "pharmaceutically acceptable salt" refers to any pharmaceutically acceptable salt that, upon administration to a subject, can provide (directly or indirectly) a compound described herein. Such salts are preferably acid addition salts with physiologically acceptable organic or inorganic acids. Examples of acid addition salts include mineral acid addition salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, and phosphate, as well as organic acid addition salts such as acetate, trifluoroacetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, methanesulfonate, and p-toluenesulfonate. Examples of alkali addition salts include inorganic salts such as sodium, potassium, calcium, and ammonium salts, as well as organic alkali salts such as ethylenediamine, ethanolamine, N,N-dialkyleneethanolamine, triethanolamine, and basic amino acid salts. However, it is understood that non-pharmaceutically acceptable salts are also within the scope of the present invention, since they may be useful in the preparation of pharmaceutically acceptable salts. Salt formation procedures are conventional in the art.

[0050] The term "solvates" according to the present invention should be understood to mean all forms of the active compounds of the present invention that are bound by non-covalent bonds to another molecule (usually a polar solvent), and includes in particular hydrates and alcoholates.

[0051] As used herein, the term "pharmaceutical composition" refers to a mixture of at least one compound of the present invention with other chemical components and entities, such as carriers, stabilizers, diluents, dispersing agents, suspending agents, thickeners, and / or excipients. Pharmaceutical compositions facilitate the administration of a compound to an organism. Multiple techniques for administering a compound exist in the art, including, but not limited to, intravenous, topical, intraperitoneal, intramuscular, oral, aerosol, parenteral, ocular, pulmonary, and topical administration.

[0052] As used herein, the terms "therapeutic compound," "therapeutic agent," "drug," "active pharmaceutical," and "active pharmaceutical ingredient" are used interchangeably to refer to chemical moieties that have a specific pharmacological effect in the body and are administered for such purpose. Non-limiting examples of therapeutic agents include antibiotics, analgesics, vaccines, anticonvulsants, antidiabetic agents, antifungal agents, antitumor agents, antiparkinsonian agents, antirheumatic agents, appetite suppressants, biological response modifiers, cardiovascular agents, central nervous system stimulants, contraceptives, dietary supplements, vitamins, minerals, lipids, sugars, metals, metabolites, amino acids (and precursors), nucleic acids and precursors, imaging agents, diagnostic agents, dopamine receptor agonists, erectile dysfunction agents, contraceptives, gastrointestinal These include, but are not limited to, drugs, hormones, immunomodulators, antihypercalcemic agents, mast cell stabilizers, muscle relaxants, nutritional supplements, ophthalmic agents, osteoporosis agents, psychotherapeutic agents, parasympathomimetics, parasympatholytic agents, respiratory agents, sedative-hypnotics, skin and mucous membrane agents, smoking cessation agents, steroids, sympatholytic agents, urinary tract agents, uterine relaxants, vaginal agents, vasodilators, antihypertensive agents, hyperthyroidism agents, antithyroidism agents, antiasthmatic agents, and vertigo agents. In certain embodiments, the one or more therapeutic agents are water-soluble, poorly water-soluble drugs, or drugs with low, medium, or high melting points. The therapeutic agents may be provided with one or more stabilizing salts or without stabilizing salts.

[0053] Some examples of active ingredients suitable for use in the pharmaceutical formulations and methods of the present invention include those that are hydrophilic, lipophilic, amphiphilic, or hydrophobic, and those that can be solubilized, dispersed, or partially solubilized and dispersed on or around the compounds or compositions of the present invention. Alternatively, the active ingredient may be provided separately from the solid pharmaceutical composition, such as for co-administration. Such an active ingredient may be any compound or mixture of compounds that has therapeutic or other value when administered to an animal, particularly a mammal, such as a drug, nutrient, cosmeceutical, dietary supplement, diagnostic agent, nutritional agent, etc. The active agents described herein may be found in their native state, but are generally provided in the form of a salt. The active agents described herein include their isomers, analogs, and derivatives.

[0054] A "therapeutic" treatment is a treatment administered to a subject who exhibits signs or symptoms of a disease or disorder with the intent of reducing or eliminating those signs or symptoms.

[0055] The terms "effective amount" and "pharmaceutically effective amount" refer to an amount of an agent sufficient to achieve a desired biological result. That result may be reduction and / or alleviation of the signs, symptoms, or causes of a disease or disorder, or any other desired alteration of a biological system. An appropriate effective amount in any individual case can be determined by one of ordinary skill in the art using routine experimentation.

[0056] A "therapeutically effective amount" refers to an amount that provides a therapeutic effect for a given condition and administration regimen. In particular, a "therapeutically effective amount" means an amount effective to prevent, alleviate or ameliorate symptoms of disease or prolong the survival of the subject being treated, which can be a human or non-human animal. Determination of a therapeutically effective amount is within the skill of one of ordinary skill in the art.

[0057] As used herein, the term "stabilizer" refers to either or both primary particles and / or secondary stabilizers, which may be polymers or other small molecules. Non-limiting examples of primary particles and / or secondary stabilizers for use in the present invention include, for example, starch, modified starch, and starch derivatives, gums, including, but not limited to, polymers, polypeptides, albumin, amino acids, thiols, amines, carboxylic acids, and combinations or derivatives thereof. Other examples include xanthan gum, alginic acid, other alginates, benitonite, veegum, agar, guar, locust bean gum, gum arabic, quince psyllium, flaxseed, okra gum, arabinoglycan, pectin, tragacanth, scleroglucan, dextran, amylose, amylopectin, dextrin, cross-linked polyvinylpyrrolidone, ion exchange resins, potassium polymethacrylate, carrageenan (and derivatives), karaya gum, and biosynthetic gums. Other examples of useful primary particles and / or secondary stabilizers include polymers such as polycarbonates (linear polyesters of carbonic acid), microporous materials (bisphenols, microporous poly(vinyl chloride), microporous polyamides, microporous modacrylic copolymers, microporous styrene-acrylic and its copolymers), porous polysulfones, halogenated polyvinylidenes, polychloroethers, acetal polymers, polyesters prepared by esterification of dicarboxylic acids or anhydrides with alkene polyols, polyalkylene sulfides, phenolic resins, polyesters, asymmetric porous polymers, crosslinked olefin polymers, hydrophilic microporous homopolymers, copolymers or interpolymers with reduced bulk density, and other similar materials, polyurethanes, crosslinked chain extended polyurethanes, polyimides, polybenzimidazoles, collodions, regenerated proteins, semi-solid crosslinked polyvinylpyrrolidone, and the like.

[0058] As used herein, the terms "targeting domain," "targeting moiety," or "targeting group" are used interchangeably and refer to any molecule that can specifically bind to a particular target molecule and form a binding complex as described above. Thus, a ligand and its corresponding target molecule form a specific binding pair.

[0059] As used herein, the term "specific binding" refers to binding that occurs between pairs of species, such as enzyme / substrate, receptor / agonist, antibody / antigen, and lectin / carbohydrate, mediated by covalent or non-covalent interactions, or a combination of covalent and non-covalent interactions. When the interaction of two species produces a non-covalent complex, the resulting binding is typically the result of electrostatic, hydrogen bonding, or lipophilic interactions. Thus, "specific binding" occurs between pairs of species where there is an interaction between the two that produces a binding complex having the characteristics of an antibody / antigen or enzyme / substrate interaction. In particular, specific binding is characterized by the binding of one member of the pair to a particular species and the absence of binding to other species within the family of compounds to which the corresponding binding member belongs. Thus, for example, an antibody preferably binds to a single epitope and not to other epitopes within a family of proteins.

[0060] As used herein, the terms "peptide," "polypeptide," and "protein" are used interchangeably and refer to compounds composed of amino acid residues covalently linked by peptide bonds. A protein or peptide must contain at least two amino acids, and there is no limit to the maximum number of amino acids that can comprise a protein or peptide sequence. A polypeptide includes any peptide or protein containing two or more amino acids linked to each other by peptide bonds. As used herein, the term refers to both short chains, commonly referred to in the art as peptides, oligopeptides, and oligomers, and longer chains, of which many forms exist, commonly referred to in the art as proteins. "Polypeptides" include, for example, biologically active fragments, substantially homologous polypeptides, oligopeptides, homodimers, heterodimers, variants of polypeptides, modified polypeptides, derivatives, analogs, and fusion proteins, among others. A polypeptide includes natural peptides, recombinant peptides, synthetic peptides, or any combination thereof.

[0061] The terms "patient," "subject," "individual," and the like are used interchangeably herein and refer to any animal or cell thereof, whether in vitro or in situ, suitable for the methods described herein. In certain non-limiting embodiments, the patient, subject, or individual is a human. In various embodiments, the subject is a human subject and may be of any race, ethnicity, sex, and age.

[0062] A "disease" is a condition in an animal's health in which the animal is unable to maintain homeostasis, and if the disease is not ameliorated, the animal's health continues to deteriorate.

[0063] In contrast, a "disorder" in an animal is a state of health in which the animal is able to maintain homeostasis, but the animal's health is less favorable than it would be in the absence of the disorder. If left untreated, the disorder does not necessarily further deteriorate the animal's health.

[0064] As used herein, the term "cancer" or "neoplasm" includes, but is not limited to, benign and malignant cancers of the oral cavity (e.g., mouth, tongue, pharynx, etc.), digestive system (e.g., esophagus, stomach, small intestine, colon, rectum, liver, bile duct, gallbladder, pancreas, etc.), respiratory system (e.g., larynx, lung, bronchi, etc.), bone, joint, skin (e.g., basal cell, squamous cell, melanoma, etc.), breast, reproductive system (e.g., uterus, ovaries, prostate, testes, etc.), urinary system (e.g., bladder, kidney, ureter, etc.), eye, nervous system (e.g., brain, etc.), endocrine system (e.g., thyroid, etc.), and hematopoietic system (e.g., lymphoma, myeloma, leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, etc.).

[0065] As used herein, "treating a disease or disorder" means reducing the severity and / or frequency with which a subject experiences a sign or symptom of the disease or disorder.

[0066] A disease or disorder is "alleviated" if the severity of a sign or symptom of the disease or disorder, the frequency with which a subject experiences such sign or symptom, or both, is reduced.

[0067] As used herein, the term "therapy" or "therapeutic regimen" refers to actions taken to alleviate or alter the state of a disorder or disease, e.g., a course of treatment intended to reduce or eliminate at least one sign or symptom of a disease or disorder using pharmacological, surgical, dietary, and / or other techniques. A therapeutic regimen may include prescribed dosages of one or more drugs or surgery. While therapy is most often beneficial, reducing or eliminating at least one sign or symptom of a disorder or disease state, in some cases, the effects of therapy have undesirable effects or side effects. The effectiveness of treatment is also affected by the physiological state of the subject, e.g., age, sex, genetics, weight, other disease states, etc.

[0068] As used herein, the term "modulate" means causing a detectable increase or decrease in the level of an mRNA, polypeptide, or response in a subject compared to the level of the mRNA, polypeptide, or response in the subject in the absence of the treatment or compound, and / or compared to the level of the mRNA, polypeptide, or response in an otherwise identical subject not receiving the treatment. The term encompasses disrupting and / or affecting the natural signal or response, thereby resulting in a beneficial therapeutic response in a subject, preferably a human.

[0069] As used herein, the terms "alteration," "deletion," "mutation," or "mutation" refer to a mutation in a gene in a cell that affects the function, activity, expression (transcription or translation), or conformation of the polypeptide it encodes. Mutations encompassed by the present invention can be any mutation in a gene in a cell that results in an enhancement or disruption of the function, activity, expression, or conformation of the encoded polypeptide, including complete lack of expression of the encoded protein, and can include, for example, missense and nonsense mutations, insertions, deletions, frameshifts, and premature terminations. Without being limited thereto, mutations encompassed by the present invention can alter the splicing of mRNA (splice site mutations) or cause a shift in the reading frame (frameshifts).

[0070] As used herein, "gene expression" includes transcription of genomic DNA into mRNA and translation of mRNA into protein.

[0071] A "genome" is all of an organism's genetic material. In some instances, the term genome can refer to chromosomal DNA. A genome can be polysomic, such that DNA is distributed within a cell among multiple individual chromosomes. For example, in humans, there are 22 pairs of chromosomes and an XX or XY pair associated with gender. DNA derived from the genetic material in a particular organism's chromosomes is genomic DNA. The term genome can also refer to genetic material from organisms that do not have a chromosomal structure. Additionally, the term genome can refer to mitochondrial DNA. A genomic library is a collection of DNA fragments representing all or part of a genome. Often, a genomic library is a collection of clones made from a randomly generated, sometimes overlapping, set of DNA fragments representing an organism's entire genome or part of its genome.

[0072] "Encoding" refers to the inherent property of a particular sequence of nucleotides in a polynucleotide, e.g., a gene, cDNA, or mRNA, to serve as a template for the synthesis of other polymers and macromolecules in biological processes that have either a defined sequence of nucleotides (i.e., rRNA, tRNA, and mRNA) or a defined sequence of amino acids and the biological properties resulting therefrom. Thus, a gene encodes a protein when the protein is produced in a cell or other biological system by transcription and translation of the mRNA corresponding to that gene. Both the coding strand, whose nucleotide sequence is identical to the mRNA sequence and usually provided in a sequence listing, and the non-coding strand, used as a template for transcription of the gene or cDNA, can be said to encode the protein or other product of that gene or cDNA. Unless otherwise specified, a "nucleotide sequence encoding an amino acid sequence" includes all nucleotide sequences that are degenerate versions of each other and encode the same amino acid sequence. Protein- and RNA-encoding nucleotide sequences can contain introns.

[0073] As used herein, "homologous" or "identical" refers to a comparison between amino acid and nucleic acid sequences. When referring to nucleic acid molecules, "homology," "identity," or "percent identity" refers to the percentage of nucleotides in a subject nucleic acid sequence that are matched to identical nucleotides by a sequence analysis program. Homology can be readily calculated by known methods. Nucleic acid and amino acid sequences can be compared using computer programs that align similar sequences of nucleic acids or amino acids and define differences. A preferred method uses the BLAST program (NCBI) and the parameters used therein to align sequence fragments of genomic DNA sequences using ExPaSy. However, comparable alignment estimates can be obtained using any standard alignment software.

[0074] As used herein, "homologous" refers to the similarity of subunit sequences between two polymer molecules, e.g., between two nucleic acid molecules, e.g., between two DNA molecules or two RNA molecules, or between two polypeptide molecules. If a subunit position in both molecules is occupied by the same subunit, e.g., if a position in each of two DNA molecules is occupied by adenine, they are homologous at that position. Homology between two sequences is a linear function of the number of matching or homologous positions; for example, if half of the positions in the sequences of two compounds (e.g., five positions in a 10-subunit-long polymer) are homologous, the two sequences are 50% homologous; if 90% of the positions, e.g., 9 out of 10, are identical or homologous, the two sequences share 90% homology. As an example, the DNA sequences 5'ATTGCC3' and 5'TATGGC' share 50% homology.

[0075] As used herein, the term "fragment" as applied to a nucleic acid refers to a subsequence of a larger nucleic acid. A "fragment" of a nucleic acid may be at least about 15 nucleotides in length, e.g., at least about 50 to about 100 nucleotides, at least about 100 to about 500 nucleotides, at least about 500 to about 1000 nucleotides, or at least about 1000 to about 1500 nucleotides.

[0076] In one embodiment, it is from about 1500 nucleotides to about 2500 nucleotides.

[0077] In one embodiment, it is about 2500 nucleotides (and any integer value therebetween).

[0078] As used herein, the term "variant" refers to a nucleic acid or peptide sequence that differs in sequence from a reference nucleic acid or peptide sequence, respectively, but retains essential properties of the reference molecule. Changes in the sequence of a nucleic acid variant may not change the amino acid sequence of the peptide encoded by the reference nucleic acid, or may result in amino acid substitutions, additions, deletions, fusions, and truncations. A nucleic acid or peptide variant may be naturally occurring, such as an allelic variant, or it may be a variant that is not known to occur naturally. Non-naturally occurring variants of nucleic acids and peptides may be made by mutagenesis techniques or by direct synthesis.

[0079] As used herein, the terms "purified" or "to purify" refer to the removal of components (e.g., contaminants) from a sample. For example, nucleic acids are purified by the removal of contaminating cellular proteins or other undesired nucleic acid species. Removal of contaminants increases the percentage of desired nucleic acids in the sample.

[0080] As used herein, the term "label" refers to a detectable compound or composition that is directly or indirectly attached to a probe to produce a "labeled" probe. The label may be detectable itself (e.g., a radioisotope label or a fluorescent label) or, in the case of an enzymatic label, may catalyze chemical alteration of a substrate compound or composition that is detectable (e.g., avidin-biotin). In some instances, primers can be labeled to detect PCR products.

[0081] As used herein, the term "nucleic acid" refers to both naturally occurring molecules such as DNA and RNA, but also to various derivatives and analogs. Generally, the probes, hairpin linkers, and target polynucleotides of the present teachings are nucleic acids, typically comprising DNA. As will be appreciated by those skilled in the art, additional derivatives and analogs can be used.

[0082] As used herein, the term "nucleotide base" refers to a substituted or unsubstituted aromatic ring or rings. In certain embodiments, the aromatic ring or rings contain at least one nitrogen atom. In certain embodiments, the nucleotide base is capable of forming Watson-Crick and / or Hoogsteen hydrogen bonds with an appropriately complementary nucleotide base. Exemplary nucleotide bases and analogs thereof include the naturally occurring nucleotide bases adenine, guanine, cytosine, 6-methyl-cytosine, uracil, thymine, and analogs of naturally occurring nucleotide bases such as 7-deazaadenine, 7-deazaguanine, 7-deaza-8-azaguanine, 7-deaza-8-azaadenine, N6 delta 2-isopentenyladenine (6iA), N6-delta 2-isopentenyl-2-methylthioadenine (2ms6iA), N2-dimethylguanine (dmG), 7-methylguanine (7mG), inosine, nebularine, 2-aminopurine, 2-amino-6-chloropurine, 2,6-diaminopurine, hypoxanthine, pseudoglucan, thiazolinone ... These include, but are not limited to, lysine, pseudocytosine, pseudoisocytosine, 5-propynylcytosine, isocytosine, isoguanine, 7-deazaguanine, 2-thiopyrimidine, 6-thioguanine, 4-thiothymine, 4-thiouracil, 6-methylguanine, N6-methyladenine, O4-methylthymine, 5,6-dihydrothymine, 5,6-dihydrouracil, pyrazolo(3,4-D)pyrimidines (see, e.g., U.S. Pat. Nos. 6,143,877 and 6,127,121 and PCT published application WO 01 / 38584), ethenoadenine, indoles such as nitroindole and 4-methylindole, and pyrroles such as nitropyrrole. Certain exemplary nucleotide bases can be found, for example, in Fasman, 1989, Practical Handbook of Biochemistry and Molecular Biology, pp. 385-394, CRC Press, Boca Raton, Florida, and references cited therein.

[0083] As used herein, the term "nucleotide" refers to a compound comprising a nucleotide base attached to the C-1' carbon of a sugar, such as ribose, arabinose, xylose, and pyranose, and sugar analogs thereof. The term nucleotide also encompasses nucleotide analogs. The sugar may be substituted or unsubstituted. Substituted ribose sugars include, but are not limited to, ribose in which one or more carbon atoms, e.g., the 2'-carbon atom, are substituted with one or more of the same or different Cl, F, -R, -OR, -NR2, or halogen groups (each R is independently H, C1-C6 alkyl, or C5-C14 aryl). Exemplary riboses include 2'-(C1-C6)alkoxyribose, 2'-(C5-C14)aryloxyribose, 2',3'-didehydroribose, 2'-deoxy-3'-haloribose, 2'-deoxy-3'-fluororibose, 2'-deoxy-3'-chlororibose, 2'-deoxy-3'-aminoribose, 2'-deoxy-3'-(C1-C6)alkylribose, 2'-deoxy-3'-(C1-C6)alkoxyribose, and 2'-deoxy-3'-(C5-C14)aryloxyribose. Examples of suitable sugar modifications include, but are not limited to, ribose, 2'-deoxyribose, 2',3'-dideoxyribose, 2'-halolibose, 2'-fluororibose, 2'-chlororibose, and 2'-alkylribose, such as 2'-O-methyl, 4'-anomeric nucleotides, 1'-anomeric nucleotides, 2'-4'- and 3'-4'-linked and other "locked" or "LNA," bicyclic sugar modifications (see, e.g., PCT Published Application Nos. WO 98 / 22489, WO 98 / 39352, and WO 99 / 14226). The term "nucleic acid" typically refers to large polynucleotides.

[0084] As used herein, the term "nucleotide analog" includes analogs with altered stacking interactions, such as 7-deazapurines (i.e., 7-deaza-dATP and 7-deaza-dGTP), base analogs with alternative hydrogen-bonding arrangements (e.g., Iso-C and Iso-G, and other non-canonical base pairs described in U.S. Pat. No. 6,001,983 to S. Benner, incorporated herein by reference), non-hydrogen-bonding analogs (e.g., B.A. Schweitzer and E.T. Kool, J. Org. Chem Commun., 1994, 59, 7238-7242; B.A. Schweitzer and Nucleotide analogs refer to modified or non-naturally occurring nucleotides, including, but not limited to, non-polar aromatic nucleoside analogs such as 2,4-difluorotoluene (as described in E.T. Kool, J. Am. Chem. Soc., 1995, 117, 1863-1872), "universal" bases such as 5-nitroindole and 3-nitropyrrole, and universal purines and pyrimidines (such as "K" and "P" nucleotides, respectively; P. Kong, et al., Nucleic Acids Res., 1989, 17, 10373-10383; P. Kong et al., Nucleic Acids Res., 1992, 20, 5149-5152). Nucleotide analogs include nucleotides with one or more modifications in the phosphate, base, or sugar moieties, such as dideoxynucleotides and 2'-O-methyl nucleotides. Nucleotide analogs include deoxyribonucleotides and modified forms of ribonucleotides.

[0085] Conventional notation is used herein to describe polynucleotide sequences, with the left end of a single-stranded polynucleotide sequence being the 5' end. The DNA strand with the same sequence as the mRNA is referred to as the "coding strand," the sequence on the DNA strand located 5' to a reference point on the DNA is referred to as the "upstream sequence," and the sequence on the DNA strand located 3' to a reference point on the DNA is referred to as the "downstream sequence." In the sequences described herein, A = adenine, G = guanine, T=thymine; C=cytosine, U = uracil, H=A, C or T / U, R=A or G, M=A or C, K=G or T / U, S=G or C, Y=C or T / U, W=A or T / U, B=G or C or T / U, D=A or G, or T / U, V=A or G or C, N=A or G or C or T / U.

[0086] Those skilled in the art will understand that all nucleic acid sequences described throughout this specification in a forward orientation are also useful in the compositions and methods of the present invention in reverse orientation, and in complementary forward and reverse orientations, and are described herein as if explicitly set forth herein.

[0087] As used herein, the term "instructional material" includes publications, records, diagrams, or any other medium of expression that can be used to communicate the usefulness of the nucleic acids, peptides, and / or compounds of the invention in kits for identifying, diagnosing, or alleviating or treating various diseases or disorders described herein. Optionally, or alternatively, the instructional material may describe one or more methods of identifying, diagnosing, or alleviating a disease or disorder in a subject's cells or tissues. Kit instructional material may, for example, be affixed to a container containing one or more components of the invention or shipped together with a container containing one or more components of the invention. Alternatively, the instructional material may be shipped separately from the container with the intention that the recipient use the instructional material and the components cooperatively.

[0088] Ranges: Throughout this disclosure, various aspects of the invention may be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as a fixed limitation on the scope of the invention. Accordingly, the description of a range should be considered to have specifically disclosed all possible subranges as well as individual numerical values ​​within that range. For example, description of a range such as 1 to 6 should be considered to have specifically disclosed subranges such as 1 to 3, 1 to 4, 1 to 5, 2 to 4, 2 to 6, 3 to 6, etc., as well as individual numbers within that range, e.g., 1, 2, 2.7, 3, 4, 5, 5.3, and 6. This is true regardless of the breadth of the range.

[0089] Detailed Description of the Invention The present invention relates, in part, to the discovery that various novel pyrrolidine and imidazolidine derivatives selectively inhibit DNA polymerase theta (Polq), the polymerase domain product of the POLQ gene. The present invention also relates, in part, to pharmaceutical compositions comprising the pyrrolidine and imidazolidine derivatives, and methods of treating diseases or disorders, such as cancer, that are deficient in homology-directed repair (HDR) (or homologous recombination), non-homologous end joining, or other DNA damage response pathways by inhibiting Polq (e.g., Polq activity, Polq levels, etc.) using the disclosed pyrrolidine and imidazolidine derivatives and their analogs.

[0090] The present invention is based, in part, on the discovery that the novel pyrrolidine and imidazolidine compounds presented herein inhibit the DNA synthesis activity of Polq. For example, pyrrolidine and imidazolidine compounds containing aryl motifs flanking each end of an amide motif inhibit the DNA synthesis activity of Polq. Accordingly, the present invention provides methods and compositions for inhibiting Polq in vitro and in vivo. The present invention also demonstrates that pyrrolidine and imidazolidine compounds and derivatives thereof that inhibit Polq activity also preferentially inhibit the growth of BRCA-deficient or HDR-deficient cancer cells. The present invention also demonstrates that pyrrolidine and imidazolidine compounds and derivatives thereof that inhibit Polq activity also inhibit the growth of BRCA-deficient or HDR-deficient cancer cells in combination with PARP inhibitor (PARPi) treatment.

[0091] Polq is highly expressed in many types of cancer cells, confers resistance to ionizing radiation and various chemotherapeutic agents, including etoposide, camptothecin, and cisplatin, and promotes the survival of cancer cells, such as those defective in HDR or other DNA repair or DDR pathways. High expression levels of Polq correspond to poor clinical outcomes in cancer patients. Therefore, another aspect of the present invention provides a method for treating cancer in a subject by administering a composition of the present invention.

[0092] In one embodiment, the method comprises administering a composition comprising a pyrrolidine or imidazolidine compound, a pyrrolidine or imidazolidine analog, a prodrug version of a pyrrolidine or imidazolidine compound or derivative thereof, or a combination thereof. In some embodiments, the cancer is resistant to at least one type of chemotherapeutic agent. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is ovarian cancer. In some embodiments, the cancer is leukemia. In some embodiments, the cancer is prostate cancer. In some embodiments, the cancer is pancreatic cancer.

[0093] DNA polymerase theta (Polq) inhibitors In one aspect, the present invention provides, in part, novel A-family polymerase inhibitors. In one embodiment, the A-family polymerase is DNA polymerase theta (Polq). In some embodiments, the A-family polymerase is a fragment of Polq. In some embodiments, the fragment of Polq is a fragment of Polq. 1792~2590 (SEQ ID NO: 1) or a fragment thereof. In some embodiments, the fragment of Polq is Polq 1~2590 (SEQ ID NO: 2). In some embodiments, Polq is encoded by the human POLQ gene. In other embodiments, Polq is encoded by the mouse Polq gene. In other embodiments, Polq is encoded by the Caenorhabditis elegans polq-1 gene.

[0094] Thus, in various embodiments, the present invention provides compounds that modulate or inhibit the level or activity of at least one A-family polymerase (e.g., Polq). In another aspect, the present invention provides compounds useful for preventing or treating a disease or disorder (e.g., cancer). In various aspects, the compounds of the present invention are functionalized pyrrolidine or imidazolidine compounds or derivatives thereof.

[0095] compound In one aspect, the present invention relates to functionalized pyrrolidine or imidazolidine derivatives, such as compounds having the structure of formula (I), or a tautomer or stereochemical isomer, pharmaceutically acceptable salt, or solvate thereof. [ka] (In the formula, U is CH2, O, S, or NR U represents W is C(R 4 ) or N, Y is C(R 6 ) or N, Q represents O or S; R 1 , R 2 , R3 , R 4 , R 6 , R 7 , R 8 , R 9 and R 10 are independently hydrogen, deuterium, and C 1~6 Alkyl, C 2~6 Alkenyl, alkynyl, hydroxy, thiol, C 1~6 Alkoxy, halogen, haloC 1~6 Alkyl, HaloC 1~6 Alkoxy, C 3~8 Cycloalkyl, nitrile, NR X R Y and combinations thereof, and two adjacent groups R 1 ~R 4 or R 6 ~R 10 may optionally be joined to form a 5- to 7-membered saturated or unsaturated ring optionally containing one or more heteroatoms selected from O, N, or S; R 5 and R U are independently hydrogen, deuterium, and C 1~6 Alkyl, C 2~6 Alkenyl, alkynyl, hydroxy, thiol, C 1~6 Alkoxy, halogen, haloC1-6 alkyl, haloC1-6 alkoxy, C 3~8 Cycloalkyl, nitrile, -NR X R Y , aryl, heteroaryl, heterocyclyl, amido, and combinations thereof; Z is CR Z R Z’ , C=S, or C=O; X is C(R 15 )(R 16 ), N(R 17 ) or O, R 15 , R 16 and R 17 are independently hydrogen, deuterium, and C 1~6 Alkyl, haloC1-6 alkyl, -OR 15a , -SR 15a , nitrile, -COC 1~6 Alkyl, -COOC1~6 Alkyl, hydroxy, C 1~6 Alkoxy, C 1~6 Alkanol, C3-8 cycloalkyl, halogen, carbonyl, -NR V R W , -CH2-NR V R W , represents —OSO2NH2, —P(O)OH2, aryl, heteroaryl, heterocyclyl, and combinations thereof; R 15 , R 16 , and R 17 may further comprise one or more divalent linkers L selected from the group consisting of alkylene, cycloalkylene, heteroalkylene, heterocycloalkylene, alkenylene, alkynylene, arylene, heteroarylene, silyl, amine, amide, ester, ether, carbonyl, carbamate, sulfamate, sulfonate ester, sulfoximine, sulfonamide, thioether, thioester, disulfide, hydrazine, urea, thiourea, phosphate, phosphonate ester, poly(alkyl ether), heteroatom, and combinations thereof; and R 15 and R 16 and may be taken together to form a ring, n is 0, 1 or 2, and when n is 0, N is R B and R B’ is directly bonded to the carbon to which it is attached, R A , R A’ , R Z , and R Z’ are each independently hydrogen, deuterium, or C 1~6 Alkyl, hydroxy, C 1~6 Alkoxy, C 1~6 Alkanol, halogen, -OR 15b , CO2H, CO2R 15b , Haro C 1~6 alkyl, and combinations thereof; R B and R B’ are independently hydrogen, deuterium, and C 1~6 Alkyl, hydroxy, C 1~6 Alkoxy, C 1~6Alkanol, halogen, -OR 15b , CO2H, CO2R 15b , Haro C 1~6 alkyl, and combinations thereof, or R B and the carbon to which it is attached form a carbonyl group, R B’ does not exist, R 15a and R 15b are independently hydrogen, deuterium, or C 1~6 Represents alkyl and two groups R 15a and R 15b , or two groups R 15b may be joined together to form a 5-7 membered saturated ring system which may be optionally substituted with one or more C1-6 alkyl groups; R V , R W , R X and R Y are independently hydrogen, deuterium, and C 1~6 Alkyl, haloC1-6 alkyl, C 3~8 Cycloalkyl, -COC 1~6 represents an alkyl or heterocyclyl, wherein the alkyl group is optionally substituted with one or more deuterium, hydroxy, amino, or sulfone groups, and the heterocyclyl ring is optionally substituted with one or more deuterium, oxo, hydroxy, C 1~6 Alkanol or -COC 1~6 It may be optionally substituted with an alkyl group.

[0096] In one embodiment, the compound of formula (I) has formula (Ia): [ka]

[0097] In one embodiment, the compound of formula (I) has formula (1b): [ka]

[0098] In one embodiment, the compound of formula (I) has formula (1c) or formula (1c'). [ka] In one embodiment, the compound of formula (I) has formula (1d) or formula (1d'). [ka]

[0099] In one embodiment, the compound of formula (I) has formula (1e) or formula (1e'). [ka]

[0100] In one embodiment, U is O. In one embodiment, U is CH. In one embodiment, U is S. In one embodiment, Q is O. In one embodiment, Q is S.

[0101] In one embodiment, R 7 and R 8 or R 8 and R 9 are linked to form an optionally substituted pyrrolyl ring. In one embodiment, Y is N. In one embodiment, R A and R A’ each represent hydrogen or deuterium. In one embodiment, Z represents C=O. In one embodiment, Z represents C=S. In one embodiment, Z represents CR Z R Z’ In one embodiment, R Z and R Z’ represents hydrogen or deuterium, respectively.

[0102] In one embodiment, R 17 are hydrogen, deuterium, and C 1~6 Alkyl, halo 1-6 alkyl, -OR 15a , -SR 15a , nitrile, -COC 1~6 Alkyl, -COOC 1~6 Alkyl, hydroxy, C1~6 Alkoxy, C 1~6 Alkanol, C3-8 cycloalkyl, halogen, carbonyl, -NR V R W , -CH2-NR V R W , -OSO2NH2, -P(O)OH, aryl, heteroaryl, heterocyclyl, and combinations thereof. 17 further comprises a bivalent linker selected from the group consisting of alkylene, cycloalkylene, heteroalkylene, heterocycloalkylene, alkenylene, alkynylene, arylene, heteroarylene, silyl, amine, amide, ester, ether, carbonyl, carbamate, sulfamate, thioether, thioester, disulfide, hydrazine, urea, thiourea, phosphate, phosphonate ester, poly(alkyl ether), heteroatom, and combinations thereof. 17 comprises one or more bivalent linkers. In one embodiment, R 17 The structure -CH2CH2O-LR 17’ and R 17’ are hydrogen, deuterium, and C 1~6 Alkyl, haloC1-6 alkyl, -OR 15a -, SR 15a , nitrile, -COC 1~6 Alkyl, -COOC 1~6 Alkyl, hydroxy, C 1~6 Alkoxy, C 1~6 Alkanol, C3-8 cycloalkyl, halogen, carbonyl, -NR V R W , -CH2-NR V R W , -OSO2NH2, aryl, heteroaryl, heterocyclyl, and combinations thereof.

[0103] In one embodiment, R 17 represents a substituent selected from the following: [ka] [ka] [ka] [ka]

[0104] In one embodiment, W is C(R 4 In one embodiment, W represents N. In one embodiment, W represents C(H), C(CN), or N. In one embodiment, W represents C(Cl) or C(F).

[0105] In one embodiment, R 1 and R 3 At least one of the groups is halogen or haloC 1~6 In one embodiment, R 1 and R 3 are independently halogen or haloC 1~6 In one embodiment, R 1 and R 3 At least one of the following is a halo C- 1~6 In one embodiment, R 1 and R 3 At least one of R represents a halogen. 1 and R 3 are respectively, Halo C 1~6 In one embodiment, R 1 and R 3 each independently represents a halogen.

[0106] In one embodiment, R 1 are hydrogen, deuterium, methyl, CD3, haloC 1~6 alkyl (e.g., CF3, CHF2, or CH2F), haloC 1~6 It represents alkoxyl (for example, OCF3, OCHF2, or OCH2F) or halogen (for example, fluorine or chlorine).

[0107] In one embodiment, R 2 are hydrogen, deuterium, and C 1~6alkyl (e.g., methyl or ethyl), C 2~6 alkenyl (e.g., ethenyl), C 1~6 In one embodiment, R 2 is NR X R Y (e.g., N(Me) or N(Me)(Et)). In one embodiment, R 2 is hydrogen, C 1~6 Alkyl (e.g., methyl), C 1~6 In one embodiment, R represents alkoxy (e.g., methoxy). 2 is -NR X R Y (e.g., -N(Me)2 or In one embodiment, R represents —N(Me)(Et). 2 is C 1~6 In one embodiment, R 2 represents hydrogen, halogen (e.g., chlorine). In one embodiment, R 2 is C 1~6 In one embodiment, R 2 represents hydrogen.

[0108] In one embodiment, R 3 are hydrogen, deuterium, methyl, CD3, haloC 1~6 alkyl (e.g., CF3, CHF2, or CH2F), haloC 1~6 represents alkoxy (e.g., OCF, OCHF, or OCHF), or halogen (e.g., fluorine or chlorine). 3 is C 1~6 alkyl (e.g., methyl, ethyl, or isopropyl), C 2~6 Alkenyl (e.g., -C(=CH2)(Me)), halogen (e.g., bromine), haloC 1~6 alkyl (e.g., trifluoromethyl or -C(H)(Me)-CF3).

[0109] In one embodiment, R 3 is Haro C 1~6In one embodiment, R represents alkoxy (e.g., difluoromethoxy). 3 is C 1~6 It represents alkyl (for example, methyl, ethyl or isopropyl).

[0110] In one embodiment, R 3 is Haro C 1~6 In one embodiment, R represents alkyl (e.g., trifluoromethyl). 3 is Haro C 1~6 It represents alkyl (for example, trifluoromethyl).

[0111] In one embodiment, R 4 are hydrogen, deuterium, and C 1~6 represents alkyl (e.g., methyl, ethyl, or isopropyl), C, C alkynyl, or nitrile. 4 represents hydrogen.

[0112] In one embodiment, R 5 represents CH3 or CD3. In one embodiment, R 5 represents the following structure: [ka] In the formula, R 5’ are hydrogen, deuterium, and C 1~6 Alkyl, C 2~6 Alkenyl, alkynyl, hydroxy, thiol, C 1~6 Alkoxy, halogen, haloC1-6 alkyl, haloC1-6 alkoxy, C 3~8 Cycloalkyl, nitrile, -NR X R Y , aryl, heteroaryl, heterocyclyl, amido, and combinations thereof.

[0113] In one embodiment, R 5 represents one of the following substituents: [ka]

[0114] In one embodiment, R X and R Y is C 1~6 In one embodiment, R X and R Y Both are C 1~6 In one embodiment, R X and R Y Both represent methyl, or one represents methyl and the other represents ethyl.

[0115] In one embodiment, W is C(R 4 ) and R 1 is C 1~6 represents alkyl (e.g., methyl), and R 2 represents hydrogen, and R 3 Halo C 1~6 alkyl (e.g., trifluoromethyl), and R 4 represents a nitrile.

[0116] In one embodiment, R 1 is C 1~6 represents alkyl (e.g., methyl), and R 2 represents hydrogen, and R 3 is C 1~6 alkyl (e.g., methyl or isopropyl), and R 4 represents a nitrile.

[0117] In one embodiment, R 1 is C 1~6 represents alkyl (e.g., methyl or ethyl), R 2 represents hydrogen, and R 3 Halo C 1~6 Alkyl (e.g., trifluoromethyl or —CH(Me)—CF3), and R 4 represents hydrogen.

[0118] In one embodiment, R 1 is C 1~6 represents alkyl (e.g., methyl), and R 2 represents hydrogen, and R 3is C 1~6 alkyl (e.g., isopropyl), and R 4 represents hydrogen.

[0119] In one embodiment, R 1 is C 1~6 represents alkyl (e.g., methyl), and R 2 represents a halogen (e.g., chlorine), and R 3 is C 1~6 represents alkyl (e.g., methyl), and R 4 represents hydrogen.

[0120] In one embodiment, R 1 is C 1~6 represents alkoxy (e.g., methoxy), and R 2 represents hydrogen, and R 3 Halo C 1~6 alkyl (e.g., trifluoromethyl), and R 4 represents a nitrile.

[0121] In one embodiment, R 1 Ha-NR X R Y (e.g., -N(Me)2 or -N(Me)(Et)), and R 2 represents hydrogen, and R 3 Halo C 1~6 alkyl (e.g., trifluoromethyl), and R 4 represents a nitrile.

[0122] In one embodiment, R 1 represents hydrogen, and R 2 represents hydrogen, and R 3 Halo C 1~6 alkyl (e.g., trifluoromethyl), and R 4 represents a nitrile.

[0123] In one embodiment, R 1 represents hydrogen, and R 2 is C 1~6 represents alkyl (e.g., methyl), and R 3 is C 1~6 represents alkyl (e.g., ethyl), and R4 represents hydrogen.

[0124] In one embodiment, R 1 represents a halogen (e.g., chlorine), and R 2 represents hydrogen, and R 3 Halo C 1~6 alkyl (e.g., trifluoromethyl), and R 4 represents hydrogen.

[0125] In one embodiment, R 1 represents a halogen (e.g., chlorine), and R 2 represents hydrogen, and R 3 Halo C 1~6 alkoxy (e.g., difluoromethoxy), and R 4 represents hydrogen.

[0126] In one embodiment, R 1 is C 2~6 represents alkenyl (e.g., ethenyl), and R 2 represents hydrogen, and R 3 Halo C 1~6 alkyl (e.g., trifluoromethyl), and R 4 represents hydrogen.

[0127] In one embodiment, R 1 is C 1~6 represents alkyl (e.g., methyl), and R 2 represents hydrogen, and R 3 Halo C 1~6 alkoxy (e.g., difluoromethoxy), and R 4 represents hydrogen.

[0128] In one embodiment, R 1 is C 1~6 represents alkyl (e.g., methyl), and R 2 represents hydrogen, and R 3 is C 2~6 alkenyl (e.g., —C(Me)(═CH)), and R 4 represents hydrogen.

[0129] In one embodiment, R1 is C 1~6 represents alkyl (e.g., methyl), and R 2 represents hydrogen, and R 3 represents a halogen (e.g., bromine), and R 4 represents hydrogen.

[0130] In one embodiment, R 1 is C 1~6 represents alkyl (e.g., methyl), and R 2 represents hydrogen, and R 3 Halo C 1~6 alkyl (e.g., trifluoromethyl), and R 4 represents a nitrile. In one embodiment, R 1 is C 1~6 represents alkyl (e.g., methyl), and R 2 represents hydrogen, and R 3 is C 1~6 alkyl (e.g., methyl or isopropyl), and R 4 represents a nitrile.

[0131] In one embodiment, R 1 is C 1~6 represents alkyl (e.g., methyl), and R 2 represents hydrogen, and R 3 Halo C 1~6 alkyl (e.g., trifluoromethyl), and R 4 represents hydrogen.

[0132] In one embodiment, R 1 is C 1~6 represents alkyl (e.g., methyl), and R 2 represents hydrogen, and R 3 is C 1~6 alkyl (e.g., isopropyl), and R 4 represents hydrogen.

[0133] In one embodiment, R 1 is C 1~6 represents alkyl (e.g., methyl), and R 2 represents a halogen (e.g., chlorine), and R 3 is C1~6 represents alkyl (e.g., methyl), and R 4 represents hydrogen.

[0134] In one embodiment, R 1 is C 1~6 represents alkoxy (e.g., methoxy), and R 2 represents hydrogen, and R 3 Halo C 1~6 alkyl (e.g., trifluoromethyl), and R 4 represents a nitrile.

[0135] In one embodiment, R 1 Ha-NR x R y (e.g., -N(Me)2 or -N(Me)(Et)), and R 2 represents hydrogen, and R 3 Halo C 1~6 alkyl (e.g., trifluoromethyl), and R 4 represents a nitrile.

[0136] In one embodiment, R 1 represents hydrogen, and R 2 represents hydrogen, and R 3 Halo C 1~6 alkyl (e.g., trifluoromethyl), and R 4 represents a nitrile.

[0137] In one embodiment, R 1 represents hydrogen, and R 2 is C 1~6 represents alkyl (e.g., methyl), and R 3 is C 1~6 represents alkyl (e.g., ethyl), and R 4 represents hydrogen.

[0138] In one embodiment, R 1 is C 1~6 represents alkyl (e.g., methyl), and R 2 represents hydrogen, and R 3 Halo C 1~6 alkyl (e.g., trifluoromethyl), and R 4represents hydrogen.

[0139] In one embodiment, W represents N and R 1 is C 1~6 represents alkyl (e.g., methyl), and R 2 represents hydrogen, and R 3 Halo C 1~6 It represents alkyl (for example, trifluoromethyl).

[0140] In one embodiment, X is C(R 15 )(R 16 ) or O. In one embodiment, X represents C(R 15 )(R 16 ). In one embodiment, X represents O. In one embodiment, X represents -N(R 17 )- represents.

[0141] In one embodiment, Z represents CH2 or C=O. In one embodiment, Z represents CH2. In one embodiment, Z represents C=O. In one embodiment, Z represents C(R Z )(H). In one embodiment, Z represents C(CH3)(H).

[0142] In one embodiment, R 15 and R 16 are independently hydrogen, -OR 15a (e.g., hydroxy), halogen (e.g., fluorine), C 1~6 Alkanols (e.g., CHOH), C 1~6 Alkoxy (e.g., methoxy), -NR V R W(e.g., —NH, —NMe, —N(H)(Me), —N(H)(COMe), —N(H)((CH)OH), —N(H)((CH)SOMe), N(Me)((CH)SOMe), —N(H)(pyrrolidinyl), —N(Me)(pyrrolidinyl), —N(H)(azetidinyl), —N(H)(oxetanyl), —N(Me)(oxetanyl), —N(H)(cyclopentyl), —N(Me)(cyclopentyl), —N(H)(tetrahydropyranyl), —N(Me)(tetrahydropyranyl) or —N(H)((CH)NH)), wherein the pyrrolidinyl, tetrahydropyranyl or cyclopentyl ring may be one or more of oxo, hydroxy, —COC 1~6 Alkyl (e.g., -COMe) or -COOC 1~6 Alkyl (e.g., -COOtBu) groups, -CH2-NR V R W (e.g., -CH2-N(Me)2), L-aryl (e.g., -CH2-O-CH2-phenyl).

[0143] In one embodiment, the heterocyclyl (e.g., azetidinyl, pyrrolidinyl, morpholinyl, or piperazinyl) is substituted with one or more hydroxy or C 1~6 Optionally substituted with alkanol (e.g., CH2OH) groups.

[0144] In one embodiment, R 15 and R 16 are independently hydrogen, hydroxy, halogen (e.g., fluorine), C 1~6 Alkoxy (e.g., methoxy), -NR V R W (e.g., -NH2, -NMe2, -N(H)(Me), -N(H)(COMe), -N(H)(CH2)2OH), -N(H)((CH2)2SO2Me), N(Me)((CH2)2SO2Me), -N(H)(pyrrolidinyl), -N(Me)(pyrrolidinyl), -N(H)(azetidinyl), -N(H)((CH2)2NH2)), wherein the pyrrolidinyl ring is oxo or -COC 1~6 It may be optionally substituted with an alkyl (eg, -COMe) group.

[0145] In one embodiment, it is heterocyclyl (eg, morpholinyl or piperazinyl).

[0146] In one embodiment, R 15 represents hydroxy.

[0147] In one embodiment, R A , R A’ , R B , and R B’ are each hydrogen or -OR 16b (e.g., hydroxy).

[0148] In one embodiment, R A , R A’ , R B , and R B’ Each represents hydrogen or hydroxy.

[0149] In one embodiment, R B -OR 15b (e.g., hydroxy).

[0150] In one embodiment, X is —C(H)(R 16 )-, and R Z , R Z’ , R 16 , R A , R A’ , R B , and R B’ each represent hydrogen. In one embodiment, X is —C(H)(R 16 )-, and R 16 HA-OR 15a (e.g., hydroxy). In one embodiment, X represents —C(H)(R 16 )-, and R Z , R Z’ , R 15 , and R 16 represents hydrogen, and R B HA-OR 15b (e.g., hydroxy). In one embodiment, R 16 represents a halogen (e.g., fluorine). In one embodiment, R 16 is C1~6 In one embodiment, R represents alkoxy (e.g., methoxy). 16 Ha-NR V R W (e.g., —NH, —NMe, —N(H)(Me), —N(H)((CH)OH), —N(H)((CH)SOMe), N(Me)((CH)SOMe), —N(H)(pyrrolidinyl), —N(Me)(pyrrolidinyl), —N(H)(azetidinyl), —N(H)(oxetanyl), —N(Me)(oxetanyl), —N(H)(cyclopentyl), —N(Me)(cyclopentyl), —N(H)(tetrahydropyranyl), —N(Me)(tetrahydropyranyl) or —N(H)((CH)NH)), wherein the pyrrolidinyl, tetrahydropyranyl or cyclopentyl ring may be one or more of oxo, hydroxy, —COC 1~6 Alkyl (e.g., -COMe) or -COOC 1~6 It may be optionally substituted with an alkyl (e.g., -COOtBu) group. In one embodiment, R 16 is heterocyclyl (e.g., one or more hydroxy or C 1~6 In one embodiment, R represents an alkanol (i.e., azetidinyl, pyrrolidinyl, morpholinyl, or piperazinyl) optionally substituted with a CHOH group. 16 and R B are OR 15b (e.g., hydroxy).

[0151] In one embodiment, Z represents C=O and X is CR 15 R 16 represents R 15 , R 16 , R A , R A’ , R B , and R B’ each represent hydrogen. In one embodiment, Z represents C=O and X is CHR 16 represents R 16 Ha-NR V R W (e.g., —NH or —N(H)(COMe)), and R A , R A’ , R B , and RB’ each represents hydrogen. In one embodiment, Z represents C=O and X is CR 15 R 16 represents R 15 , R 16 , R A , R A’ , R B , and R B’ each represents hydrogen, and R 16 represents heterocyclyl (e.g., morpholinyl). In one embodiment, Z represents C=O and X is CR 15 R 16 represents R 15 , R A , R A’ , and R B’ each represents hydrogen, and R 16 HA-OR 15a (e.g., hydroxy), and R B is OR 15b (e.g., hydroxy). In one embodiment, Z represents C=O and X is CR 15 R 16 represents R 15 , R A , R A’ , R B , and R B’ each represents hydrogen, and R 16 HA-OR 15a (e.g., hydroxy). In one embodiment, Z represents C=O and X is CR 15 R 16 represents R 15 , R A , R A’ , R B , and R B’ each represents hydrogen, and R 16 represents -L-aryl (e.g., -CH2-O-CH2-phenyl). In one embodiment, Z represents C=O and X is CR 15 R 16 represents R 15 , R A , R A’ , R B , and R B’ each represents hydrogen, and R 16 is C 1~6 In one embodiment, X represents an alkanol (e.g., CHOH). In one embodiment, X represents C=O and CR15 R 16 represents R 15 , R 16 , R A , R A’ , and R B’ each represents hydrogen, and R B HA-OR 15b (e.g., hydroxy). In one embodiment, Z represents C=O and X is CR 15 R 16 represents R 15 , R A , R A’ , R B , and R B’ each represents hydrogen, and R 16 is CH2-NR V R W (e.g., —CH—N(Me)). In one embodiment, Z represents C═O and X represents CR 15 R 16 represents R 15 , R A , R A’ , and R B’ each represents hydrogen, and R 16 HA-OR 15a represents R B HA-OR 15b represents R 15a and R 15b are joined together to form one or more C 1~6 In one embodiment, Z represents C=O and X represents CR 15 R 16 represents R 15 , R A , R A’ , and R B’ each represents hydrogen, and R 16 HA-OR 15a represents R B HA-OR 15b represents R 15a and R 15b are joined together to form one or more C 1~6 It forms a 5- to 7-membered (eg, 5-membered) saturated ring system (eg, dioxolanyl) which may be optionally substituted with alkyl groups (eg, two methyl groups).

[0152] In one embodiment, R 15 , R 16 , R A , R A’ , R B , and R B’ each represents hydrogen, and R Z represents methyl. In one embodiment, X is —C(H)(R 16 )-, and R 16 , R A , R A’ , R B , and R B’ each represent hydrogen. In one embodiment, X is —C(H)(R 16 )-, and R 16 , R Z , R Z’ , R A , R A’ , R B , and R B’ Each represents hydrogen. In one embodiment, R Z , R Z’ , R A , R A’ , R B , and R B’ each represents hydrogen, and R 16 HA-OR 15a (e.g., hydroxy). In one embodiment, R 16 , R Z , R Z’ , R A , R A’ , and R B’ each represents hydrogen, and R B HA-OR 15b (e.g., hydroxy). In one embodiment, R Z , R Z’ , R A , R A’ , R B , and R B’ represents hydrogen, and R 16 represents a halogen (e.g., fluorine). In one embodiment, R Z , R Z’ , R A , R A’ , R B , and R B’ represents hydrogen, and R16 is C 1~6 In one embodiment, R represents alkoxy (e.g., methoxy). Z , R Z’ , R A , R A’ , R B , and R B’ represents hydrogen, and R 16 Ha-NR V R W (e.g., —NH, —NMe, —N(H)(Me), —N(H)((CH)OH), —N(H)((CH)SOMe), N(Me)(CH)SOMe), —N(H)(pyrrolidinyl), —N(Me)(pyrrolidinyl), —N(H)(azetidinyl), —N(H)(oxetanyl)-N(Me)(oxetanyl), —N(H)(cyclopentyl), —N(Me)(cyclopentyl), —N(H)(tetrahydropyranyl)-N(Me)(tetrahydropyranyl) or —N(H)((CH)NH)), wherein the pyrrolidinyl, tetrahydropyranyl or cyclopentyl ring may be one or more of oxo, hydroxy, —COC 1~6 Alkyl (e.g., -COMe) or -COOC 1~6 In one embodiment, R Z , R Z’ , R A , R A’ , R B , and R B’ represents hydrogen, and R 16 is heterocyclyl (e.g., one or more hydroxy or C 1~6 In one embodiment, R represents an alkanol (i.e., azetidinyl, pyrrolidinyl, morpholinyl, or piperazinyl) optionally substituted with a CHOH group. Z , R Z’ , R A , R A’ , and R B’ represents hydrogen, and R 16 -OR 15a (e.g., hydroxy), and R B is OR 15b (e.g., hydroxy).

[0153] In one embodiment, Z represents C═O and X is —C(H)(R 16 )-, and R 16 , R A , R A’ , R B , and R B’ each represent hydrogen. In one embodiment, Z represents C=O and X is -C(H)(R 16 )-, and R A , R A’ , R B , and R B’ each represents hydrogen, and R 16 Ha-NR V R W (e.g., -IMH2 or -N(H)(COMe)). In one embodiment, Z represents C=O and X represents -C(H)(R 16 )-, and R A , R A’ , R B , and R B’ each represents hydrogen, and R 16 represents heterocyclyl (e.g., morpholinyl). In one embodiment, Z represents C=O and X is -C(H)(R 16 )-, and R A , R A’ , R B , and R B’ each represents hydrogen, and R 16 HA-OR 15a (e.g., hydroxy), and R B HA-OR 15b (e.g., hydroxy). In one embodiment, Z represents C=O and X is -C(H)(R 16 )-, and R A , R A’ , R B , and R B’ each represents hydrogen, and R 16 HA-OR 15a (e.g., hydroxy). In one embodiment, Z represents C=O and X is -C(H)(R 16 )-, and R A , R A’ , R B , and R B’ each represents hydrogen, and R 16represents -L-aryl (e.g., -CH-O-CH-phenyl). In one embodiment, Z represents C=O and X is -C(H)(R 16 )-, and R A , R A’ , R B , and R B’ each represents hydrogen, and R 16 is C 1~6 In one embodiment, Z represents C=O and X represents -C(H)(R 16 )-, and R 16 , R A , R A’ , and R B’ each represents hydrogen, and R B HA-OR 15b (e.g., hydroxy). In one embodiment, Z represents C=O and X is -C(H)(R 16 )-, and R A , R A’ , R B , and R B’ each represents hydrogen, and R 16 -CH2-NR V R W (e.g., —CH—N(Me)). In one embodiment, Z represents C═O and X represents —C(H)(R 16 )-, and R A , R A’ , and R B’ each represents hydrogen, and R 16 HA-OR 15a represents R B HA-OR 15b (e.g., hydroxy), and R 15a and R 15b are joined together to form one or more C 1~6 It forms a 5- to 7-membered (eg, 5-membered) saturated ring system (eg, dioxolanyl) which may be optionally substituted with alkyl groups (eg, two methyl groups).

[0154] In one embodiment, X is —C(H)(R 16 )-, and R A , R A’ , R B , and R B’Each represents hydrogen. In one embodiment, R 16 represents hydroxyl. In one embodiment, R B represents hydroxy. In one embodiment, R 16 represents a halogen (e.g., fluorine). In one embodiment, R 16 is C 1~6 In one embodiment, R represents alkoxy (e.g., methoxy). 16 is -NR V R W (e.g., -NH2, -NMe2, -N(H)(Me), -N(H)((CH2)2OH), -N(H)((CH2)2SO2Me), N(Me)(CH2)2SO2Me), -N(H)(pyrrolidinyl), -N(Me)(pyrrolidinyl), -N(H)(azetidinyl), -N(H)(CH2)2NH2)), wherein the pyrrolidinyl ring is oxo or -COC 1~6 It may be optionally substituted with an alkyl (e.g., -COMe) group. In one embodiment, R 16 represents heterocyclyl (e.g., morpholinyl or piperazinyl). In one embodiment, R 16 and R B Both represent hydroxy.

[0155] In one embodiment, Z represents C═O and X is —C(H)(R 16 )-, and R 16 , R A , R A’ , R B , and R B’ Each represents hydrogen. In one embodiment, R 16 Ha-NR V R W (e.g., —NH or —N(H)(COMe)). In one embodiment, R 16 represents heterocyclyl (e.g., morpholinyl). In one embodiment, R 16 and R B and X both represent hydroxy. In one embodiment, Z represents C=O and X is -C(H)(R 16 )-, and R 16 and R B Both represent hydroxy.

[0156] In one embodiment, Z represents C=O, X represents O, and R A , R A’ , R B , and R B’ Each represents hydrogen.

[0157] In one embodiment, Z represents C=O and X is -N(R 17 )-, and R 17 represents hydrogen. In one embodiment, Z represents C=O and X is -N(R 17 )-, and R 17 is C 1~6 Alkanols (e.g., -CH2-CH(OH)Me, -(CH2)2-OH, -CH2-CHOH-CH2OH, or -(CH2)2-CHOH-CH2OH), -L-SO2-C 1~6 Alkyl (e.g., -SO2-Me or -(CH2)2-SO2-Me), -L-SO2-NR V R W (e.g., -(CH2)2-SO2-N(Me)2), -L-NR V R W (e.g., -(CH2)2-N(Me)2, -(CH2)3-N(Me)2 or -CH2-CHOH-CH2-NMe2), -L-CO-NR V R W (e.g., -CH2-CONH2, -CH2-CON(Me)2, -(CH2)2-CON(Me)2 or -(CH2)2-CON(H)(Me)), -L-NH-SO2-C 1~6 Alkyl (e.g., -(CH2)2-NH-SO2-Me), -LS(=NH)(=O)(C 1~6 alkyl) (e.g., -(CH2)2-S(=NH)(=O)(Me)), -LO-SO2-NR V R W (e.g., -(CH2)2-O-SO2-NH2), -LN=S(=O)(C 1~6 alkyl)2 (e.g., —(CH2)2—N═S(═O)(Me)2).

[0158] In one embodiment, the heterocyclyl ring is -L-heterocyclyl (e.g., -CH2-oxetanyl, -CH2-azetidinyl, -CH2)2-azetidinyl, -CH2-oxazolidinyl, -(CH2)2-piperidinyl, -(CH2)2-piperazinyl, -(CH2)3-piperazinyl, -CH2-morpholinyl, -(CH2)2-morpholinyl, -CH2-CHOH-CH2-morpholinyl, -(CH2)2-thiomorpholinyl, -CH2-pyrrolidinyl, -(CH2)2-pyrrolidinyl, or -CH2-CHOH-CH2-pyrrolidinyl), wherein the heterocyclyl ring is substituted with one or more of oxo, hydroxy, halogen (e.g., fluorine), nitrile, C 1~6 Alkyl (e.g., methyl), -COC 1~6 Alkyl (e.g., -COMe), -NR V -COC 1~6 Alkyl (e.g., -NMe-COMe) or C 1~6 It may be optionally substituted with an alkanol (eg, —CH2OH or —(CH2)2—OH) group.

[0159] In one embodiment, Z represents C=O and X is -N(R 17 )-, and R B represents hydrogen, and R 17 is C 1~6 Alkanols (e.g., -CH2-CH(OH)Me, -(CH2)2-OH, -CH2-CHOH-CH2OH, or -(CH2)2-CHOH-CH2OH), -L-SO2-C 1~6 Alkyl (e.g., -SO2-Me or -(CH2)2-SO2-Me), -L-SO2-NR V R W (e.g., -(CH2)2-SO2-N(Me)2), -L-NR V R W (e.g., -(CH2)2-N(Me)2, -(CH2)3-N(Me)2 or -CH2-CHOH-CH2-NMe2), -L-CO-NR V R W (e.g., -CH2-CONH2, -CH2-CON(Me)2, -(CH2)2-CON(Me)2 or -(CH2)2-CON(H)(Me)), -L-NH-SO2-C 1~6Alkyl (e.g., -(CH2)2-NH-SO2-Me), -LS(=NH)(=O)(C 1~6 alkyl) (e.g., -(CH2)2-S(=NH)(=O)(Me)), -LO-SO2-NR V R W (e.g., -(CH2)2-O-SO2-NH2), -LN=S(=O)(C 1~6 alkyl)2 (e.g., —(CH2)2—N═S(═O)(Me)2).

[0160] In one embodiment, R 17 represents -L-heterocyclyl (e.g., -CH2-oxetanyl, -CH2azetidinyl, -(CH2)2-azetidinyl, -CH2-oxazolidinyl, -(CH2)2-piperidinyl, -(CH2)2-piperazinyl, -(CH2)3-piperazinyl, -CH2-morpholinyl, -(CH2)2-morpholinyl, -CH2-CHOH-CH2-morpholinyl, -(CH2)2-thiomorpholinyl, -CH2-pyrrolidinyl, -(CH2)2-pyrrolidinyl, or -CH2-CHOH-CH2-pyrrolidinyl), wherein the heterocyclyl ring may contain one or more oxo, hydroxy, halogen (e.g., fluorine), nitrile, C 1~6 Alkyl (e.g., methyl), -COC 1~6 Alkyl (e.g., -COMe), -NR V -COC 1~6 Alkyl (e.g., -NMe-COMe) or C 1~6 It may be optionally substituted with an alkanol (eg, —CH2OH or —(CH2)2—OH) group.

[0161] In one embodiment, Z represents C=O and X is -N(R 17 )-, and R B and R 17 represents hydrogen. In one embodiment, R 17 is C 1~6 represents an alkanol (e.g., —CH—CH(OH)Me). In one embodiment, R 17 -SO2-C 1~6 Represents alkyl (e.g., -SO2-Me).

[0162] In one embodiment, R V and R W is hydrogen, C 1~6 Alkyl (e.g., methyl), -COC 1~6 Alkyl (e.g., -COMe), C 3~8 represents a cycloalkyl (e.g., cyclopentyl) or heterocyclyl (e.g., oxetanyl, azetidinyl, tetrahydropyranyl, or pyrrolidinyl) in which the alkyl group is optionally substituted with one or more hydroxy (e.g., (Chb^OH), amino (e.g., (Chb^Nhb), or sulfone (e.g., (CH2)2SO2Me) groups, and the heterocyclyl ring is optionally substituted with one or more oxo or -COC 1~6 It may be optionally substituted with an alkyl (e.g., -COMe) group. In one embodiment, R V and R W is hydrogen, C 1~6 Alkyl (e.g., methyl), -COC 1~6 represents an alkyl (e.g., -COMe) or heterocyclyl (e.g., azetidinyl or pyrrolidinyl) group, the alkyl group being optionally substituted with one or more hydroxy (e.g., (Chb^OH)), amino (e.g., (CH2)2NH2) or sulfone (e.g., (CH2)2SO2Me) groups, and the heterocyclyl ring is optionally substituted with one or more oxo or -COC 1~6 In one embodiment, R V and R W are both hydrogen or C 1~6 alkyl (e.g., methyl), or one represents hydrogen and the other C 1~6 alkyl (e.g., methyl), or one of them is hydrogen or C 1~6 alkyl (e.g., methyl), and the other represents -COC 1~6 Alkyl (e.g., -COMe), C 3~8represents a cycloalkyl (e.g., cyclopentyl) or heterocyclyl (e.g., azetidinyl, tetrahydropyranyl, or pyrrolidinyl) in which the alkyl group is optionally substituted with one or more hydroxy (e.g., (Chb^OH)), amino (e.g., (Chb^Nhb)), or sulfone (e.g., (CH2)2SO2Me) groups, and the heterocyclyl ring is optionally substituted with one or more oxo or -COC 1~6 It may be optionally substituted with an alkyl (e.g., -COMe) group. In one embodiment, R V and R W are both hydrogen or C 1~6 alkyl (e.g., methyl), or one represents hydrogen and the other C 1~6 alkyl (e.g., methyl), or one of them is hydrogen or C 1~6 alkyl (e.g., methyl), and the other represents -COC 1~6 represents an alkyl (e.g., -COMe) or heterocyclyl (e.g., azetidinyl or pyrrolidinyl) group, the alkyl group being optionally substituted with one or more hydroxy (e.g., (Chb^OH)), amino (e.g., (Chb^Nhb)), or sulfone (e.g., CH2)2SO2Me) groups, and the heterocyclyl ring is optionally substituted with one or more oxo or -COC 1~6 It may be optionally substituted with an alkyl (eg, -COMe) group.

[0163] In one embodiment, R 5 is C 1~6 alkyl (e.g., CH3, CD3, ethyl, or isopropyl) or C 3~8 In one embodiment, R 5 is C 1~6 In one embodiment, R 5 is C 1~6 In one embodiment, R 5 is C 1~6 In still further embodiments, R 5 is C 1~6It represents alkyl (eg, CHs or CDs).

[0164] In one embodiment, Y is —C(R 6 In another embodiment, Y represents N. In one embodiment, R 6 represents hydrogen or halogen (e.g., fluorine or chlorine).

[0165] In one embodiment, R 6 is C 1~6 In one embodiment, R represents alkoxy (e.g., methoxy). 6 represents hydrogen, halogen (e.g., fluorine). In one embodiment, R 6 is C 1~6 In one embodiment, R represents alkoxy (e.g., methoxy). 6 represents hydrogen. In one embodiment, R 6 represents a halogen (e.g., fluorine). In one embodiment, R 6 represents hydrogen.

[0166] In one embodiment, R 7 is hydrogen, halogen (e.g., fluorine, bromine, chlorine), C 1~6 alkyl (e.g., methyl or ethyl), C 2~6 Alkenyl (e.g., ethenyl), hydroxy, C 1~6 Alkoxy (e.g., methoxy), -NR X R Y (e.g., —NH, —NHMe, or —NMe). In one embodiment, R 7 is hydrogen, halogen (e.g., fluorine, bromine, chlorine), C 1~6 alkyl (e.g., methyl, ethyl, CD3, or C2D5), C 2~6 Alkenyl (e.g., ethenyl), hydroxy, C 1~6 In one embodiment, R represents alkoxy (e.g., methoxy). 7 represents hydrogen or halogen (e.g., fluorine or chlorine).

[0167] In one embodiment, R X and R Y is C 1~6In one embodiment, R 7 represents a halogen (e.g., chlorine). In one embodiment, R X and R Y independently represent hydrogen or methyl. In one embodiment, R X and R Y Both represent hydrogen, or R X and R Y Both represent methyl, or R X and R Y One of these represents hydrogen and the other represents methyl.

[0168] In one embodiment, R 8 , R 9 , and R 10 Each represents a halogen. In one embodiment, R 8 represents fluorine. In one embodiment, R 9 represents chlorine. In one embodiment, R 10 represents fluorine.

[0169] In one embodiment, R 8 is hydrogen, halogen (e.g., fluorine, bromine, chlorine), C 1~6 alkyl (e.g., methyl or ethyl), C 2~6 alkenyl (e.g., ethenyl), C 3~8 cycloalkyl (e.g., cyclopropyl), haloC 1~6 In one embodiment, R represents alkyl (e.g., trifluoromethyl). 8 is hydrogen, halogen (e.g., fluorine, bromine, chlorine), C 1~6 alkyl (e.g., methyl or ethyl), C 2~6 alkenyl (e.g., ethenyl), haloC 1~6 In one embodiment, R represents alkyl (e.g., trifluoromethyl). 8 and R 7 are joined to form a 5-7 membered saturated or unsaturated ring (e.g., a pyrrolinyl or tetrahydropyranyl ring) optionally containing one or more heteroatoms selected from O, N, or S. In one embodiment, R 8 represents hydrogen or halogen (e.g., fluorine or chlorine).

[0170] In one embodiment, R 8 Halo C 1~6 In one embodiment, R represents alkyl (e.g., trifluoromethyl). 8 represents a halogen (e.g., fluorine).

[0171] In one embodiment, R 7 and R 8 are joined to form a 5-7 membered saturated or unsaturated ring optionally containing one or more heteroatoms selected from O, N, or S (e.g., a benzyl, pyridinyl, purinyl, pyrimidinyl, diazinyl, pyrrolyl, pyrrolinyl, tetrahydropyranyl, pyrazolyl, morpholinyl, pyridyl, furanyl, or thiophenyl ring optionally substituted with one or more methyl or fluorine groups). In one embodiment, R 7 and R 8 are joined to form a 5-7 membered saturated or unsaturated ring (e.g., a pyrrolinyl or tetrahydropyranyl ring) optionally containing one or more heteroatoms selected from O, N, or S. In one embodiment, R 8 and R 7 are joined to form a 5-7 membered saturated or unsaturated ring optionally containing one or more heteroatoms selected from O, N, or S (e.g., a benzyl, pyridinyl, purinyl, pyrimidinyl, diazinyl, pyrrolyl, pyrrolinyl, tetrahydropyranyl, pyrazolyl, morpholinyl, pyridyl, furanyl, or thiophenyl ring optionally substituted with one or more methyl or fluorine groups).

[0172] In one embodiment, R 9 is hydrogen, halogen (e.g., fluorine, chlorine), C 1~6 Alkyl (e.g., methyl), haloC 1~6 In one embodiment, R represents alkyl (e.g., fluoromethyl, difluoromethyl, or trifluoromethyl). 9 is C 1~6 In one embodiment, R represents alkoxy (e.g., methoxy). 9 represents hydrogen.

[0173] In one embodiment, R10 represents hydrogen.

[0174] In one embodiment, R 10 represents a halogen (e.g., fluorine). In one embodiment, R 10 represents hydrogen.

[0175] In one embodiment, Y is —C(R 6 )=, and R 6 , R 7 , R 8 , R 9 and R 10 Each of represents hydrogen.

[0176] In one embodiment, R 6 , R 7 , R 8 and R 10 Each of represents hydrogen, and R 9 is C 1~6 It represents alkyl (eg, methyl).

[0177] In one embodiment, R 6 , R 7 and R 10 Each of represents hydrogen, and R 8 and R 9 both represent halogen (e.g., fluorine or chlorine).

[0178] In one embodiment, R 6 , R 7 and R 10 Each of represents hydrogen, and R 8 represents a halogen (e.g., fluorine), and R 9 is C 1~6 It represents alkyl (eg, methyl).

[0179] In one embodiment, R 6 , R 7 and R 10 Each of represents hydrogen, and R 8 represents a halogen (e.g., fluorine), and R 9 Halo C 1~6 It represents alkyl (for example, fluoromethyl or trifluoromethyl).

[0180] In one embodiment, R 6 , R 7 , R 8 and R 10 Each of represents hydrogen, and R 9 Halo C 1~6 It represents alkyl (for example, fluoromethyl or difluoromethyl).

[0181] In one embodiment, R 6 , R 7 , R 8 and R 10 Each of represents hydrogen, and R 9 represents a halogen (e.g., chlorine).

[0182] In one embodiment, R 6 , R 7 and R 10 Each of represents hydrogen, and R 8 represents a halogen (e.g., fluorine), and R 9 is C 1~6 It represents alkoxy (eg, methoxy).

[0183] In one embodiment, R 6 , R 8 and R 10 Each of represents hydrogen, and R 7 and R 9 both represent halogen (e.g., fluorine or chlorine).

[0184] In one embodiment, R 6 , R 7 and R 10 Each of represents hydrogen, and R 8 Halo C 1~6 represents alkyl (e.g., trifluoromethyl), R 9 represents a halogen (e.g., fluorine).

[0185] In one embodiment, R 6 , R 8 , R 9 and R 10 Each of represents hydrogen, and R 7 is C 1~6alkyl (e.g., methyl, ethyl, CD3, or C2D5), and R 6 , R 8 , R 9 and R 10 Each of represents hydrogen, and R 7 represents a halogen (e.g., chlorine), and R 6 , R 9 and R 10 Each of represents hydrogen, and R 7 and R 8 both represent halogen (e.g., fluorine, bromine, or chlorine), and R 6 , R 9 , and R 10 Each of represents hydrogen, and R 7 is C 1~6 alkyl (e.g., methyl, ethyl, CD3, or C2D5), R 8 represents a halogen (e.g., fluorine), and R 6 , R 7 and R 10 Each of represents hydrogen, and R 8 is C 1~6 represents alkyl (e.g., methyl), and R 9 represents a halogen (e.g., chlorine), and R 6 , R 9 and R 10 Each of represents hydrogen, and R 7 is C 1~6 represents alkyl (e.g., methyl or ethyl), R 8 represents a halogen (e.g., chlorine or fluorine), and R 6 , R 9 and R 10 Each of represents hydrogen, and R 7 is C 1~6 represents alkoxy (e.g., methoxy), and R 8 represents a halogen (e.g., fluorine), and R 6 , R 9 and R 10 Each of represents hydrogen, and R 7 is C 1~6 represents alkoxy (e.g., methoxy), and R 8 is C 1~6 alkyl (e.g., methyl), and R 6 , R9 and R 10 Each of represents hydrogen, and R 7 represents a halogen (e.g., chlorine), and R 8 is C 1~6 alkyl (e.g., methyl), and R 9 and R 10 Both represent hydrogen, and R 6 and R 8 and R represent halogen (e.g., fluorine). 7 is C 1~6 alkyl (e.g., methyl or ethyl), and R 7 , R 9 and R 10 Each of represents hydrogen, and R 6 and R 8 both represent halogen (e.g., chlorine, bromine, or fluorine), and R 6 and R 9 Both represent hydrogen, and R 7 , R 8 and R 10 each represents a halogen (e.g., chlorine or fluorine), and R 8 , R 9 , R 10 Each of represents hydrogen, and R 6 , R 7 both represent halogen (e.g., chlorine or fluorine), and R 6 , R 9 and R 10 Each of represents hydrogen, and R 7 represents hydroxy, and R 8 represents a halogen (e.g., fluorine), and R 6 , R 9 and R 10 Each of represents hydrogen, and R 7 is C 2~6 represents alkenyl (e.g., ethenyl), and R 8 represents a halogen (e.g., fluorine), and R 6 , R 9 and R 10 Each of represents hydrogen, and R 7 represents hydroxy, and R 8 is C 1~6 alkyl (e.g., methyl), and R 7 , R8 , R 10 Each of represents hydrogen, and R 6 , R 9 both represent halogen (e.g., fluorine or chlorine), and R 7 and R 10 Both represent hydrogen, and R 8 and R 9 and both represent halogen (e.g., fluorine or chlorine), and R 6 is C 1~6 alkoxy (e.g., methoxy), and R 9 and R 10 Both represent hydrogen, and R 6 , R 7 and R 8 each represents a halogen (e.g., fluorine or chlorine), and R 9 and R 10 Both represent hydrogen, and R 6 and R 8 and R represent halogen (e.g., fluorine). 7 C 2~6 alkenyl (e.g., ethenyl), and R 6 , R 9 and R 10 Each of represents hydrogen, and R 7 and R 8 are joined to form a pyrrolinyl, tetrahydropyranyl, pyrazolyl or pyridyl ring optionally substituted with a methyl group, and R 7 and R 10 Both represent hydrogen, and R 6 , R 8 and R 9 Each of represents a halogen (eg, chlorine or fluorine).

[0186] In one embodiment, R 6 , R 9 and R 10 Each of represents hydrogen, and R 7 represents a halogen (e.g., chlorine), and R 8 is C 3~8 It represents cycloalkyl (eg cyclopropyl).

[0187] In one embodiment, Y is —C(R 6)=, and R 6 , R 7 , R 8 , R 9 and R 10 Each of represents hydrogen.

[0188] In one embodiment, R 6 , R 7 , R 8 and R 10 Each of represents hydrogen, and R 9 is C 1~6 It represents alkyl (eg, methyl).

[0189] In one embodiment, R 6 , R 7 and R 10 Each of represents hydrogen, and R 8 and R 9 both represent halogen (e.g., fluorine or chlorine).

[0190] In one embodiment, R 6 , R 7 and R 10 Each of represents hydrogen, and R 8 represents a halogen (e.g., fluorine), and R 9 is C 1~6 It represents alkyl (eg, methyl).

[0191] In one embodiment, R 6 , R 7 and R 10 Each of represents hydrogen, and R 8 represents a halogen (e.g., fluorine), and R 9 Halo C 1~6 It represents alkyl (for example, fluoromethyl or trifluoromethyl).

[0192] In one embodiment, R 6 , R 7 , R 8 and R 10 Each of represents hydrogen, and R 9 Halo C 1~6 It represents alkyl (for example, fluoromethyl or difluoromethyl).

[0193] In one embodiment, R 6 , R 7 , R 8 and R 10 Each of represents hydrogen, and R 9 represents a halogen (e.g., chlorine).

[0194] In one embodiment, R 6 , R 7 and R 10 Each of represents hydrogen, and R 8 represents a halogen (e.g., fluorine), and R 9 is C 1~6 It represents alkoxy (eg, methoxy).

[0195] In one embodiment, R 6 , R 8 and R 10 Each of represents hydrogen, and R 7 and R 9 both represent halogen (e.g., fluorine or chlorine).

[0196] In one embodiment, R 6 , R 7 and R 10 Each of represents hydrogen, and R 8 Halo C 1~6 represents alkyl (e.g., trifluoromethyl), R 9 represents a halogen (e.g., fluorine).

[0197] In one embodiment, R 6 , R 8 , R 9 and R 10 Each of represents hydrogen, and R 7 is C 1~6 alkyl (e.g., methyl, ethyl, CD3, or C2D5), and R 6 , R 8 , R 9 and R 10 Each of represents hydrogen, and R 7 represents a halogen (e.g., chlorine), and R 6 , R 9 and R 10 Each of represents hydrogen, and R 7and R 8 both represent halogen (e.g., fluorine, bromine, or chlorine), and R 6 , R 9 , and R 10 Each of represents hydrogen, and R 7 is C 1~6 alkyl (e.g., methyl, ethyl, CD3, or C2D5), and R 6 , R 7 and R 10 Each of represents hydrogen, and R 8 is C 1~6 represents alkyl (e.g., methyl), and R 9 represents a halogen (e.g., chlorine), and R 6 , R 9 and R 10 Each of represents hydrogen, and R 7 is C 1~6 represents alkyl (e.g., methyl or ethyl), R 8 represents a halogen (e.g., chlorine or fluorine), and R 6 , R 9 and R 10 Each of represents hydrogen, and R 7 is C 1~6 represents alkoxy (e.g., methoxy), and R 8 represents a halogen (e.g., fluorine), and R 6 , R 9 and R 10 Each of represents hydrogen, and R 7 is C 1~6 represents alkoxy (e.g., methoxy), and R 8 is C 1~6 alkyl (e.g., methyl), and R 6 , R 9 and R 10 Each of represents hydrogen, and R 7 represents a halogen (e.g., chlorine), and R 8 is C 1~6 alkyl (e.g., methyl), and R 9 and R 10 Both represent hydrogen, and R 6 and R 8 and R represent halogen (e.g., fluorine). 7 is C 1~6alkyl (e.g., methyl or ethyl), and R 7 , R 9 and R 10 Each of represents hydrogen, and R 6 and R 8 both represent halogen (e.g., chlorine, bromine, or fluorine), and R 6 and R 9 Both represent hydrogen, and R 7 , R 8 and R 10 each represents a halogen (e.g., chlorine or fluorine), and R 8 , R 9 , R 10 Each of represents hydrogen, and R 6 , R 7 both represent halogen (e.g., chlorine or fluorine), and R 6 , R 9 and R 10 Each of represents hydrogen, and R 7 represents hydroxy, and R 8 represents a halogen (e.g., fluorine), and R 6 , R 9 and R 10 Each of represents hydrogen, and R 7 is C 2~6 represents alkenyl (e.g., ethenyl), and R 8 represents a halogen (e.g., fluorine), and R 6 , R 9 and R 10 Each of represents hydrogen, and R 7 represents hydroxy, and R 8 is C 1~6 alkyl (e.g., methyl), and R 7 , R 8 , R 10 Each of represents hydrogen, and R 6 , R 9 both represent halogen (e.g., fluorine or chlorine), and R 7 and R 10 Both represent hydrogen, and R 8 and R 9 and both represent halogen (e.g., fluorine or chlorine), and R 6 is C 1~6alkoxy (e.g., methoxy), and R 9 and R 10 Both represent hydrogen, and R 6 , R 7 and R 8 each represents a halogen (e.g., fluorine or chlorine), and R 9 and R 10 Both represent hydrogen, and R 6 and R 8 and R represent halogen (e.g., fluorine). 7 is C 2~6 alkenyl (e.g., ethenyl), and R 6 , R 9 and R 10 Each of represents hydrogen, and R 7 and R 8 are linked to form a pyrrolinyl or tetrahydropyranyl ring.

[0198] In one embodiment, R 7 and R 10 Both represent hydrogen, and R 6 , R 8 and R 9 Each of represents a halogen (eg, chlorine or fluorine).

[0199] In one embodiment, Y is —C(R 6 )=, and R 6 , R 7 , R 8 , R 9 and R 10 Each of represents hydrogen.

[0200] In one embodiment, R 6 , R 7 , R 8 and R 10 Each of represents hydrogen, and R 9 is C 1~6 It represents alkyl (eg, methyl).

[0201] In one embodiment, R 6 , R 7 and R 10 Each of represents hydrogen, and R 8 and R 9both represent halogen (e.g., fluorine or chlorine).

[0202] In one embodiment, R 6 , R 7 and R 10 Each of represents hydrogen, and R 8 represents a halogen (e.g., fluorine), and R 9 is C 1~6 It represents alkyl (eg, methyl).

[0203] In one embodiment, R 6 , R 7 and R 10 Each of represents hydrogen, and R 8 represents a halogen (e.g., fluorine), and R 9 Halo C 1~6 It represents alkyl (for example, fluoromethyl or trifluoromethyl).

[0204] In one embodiment, R 6 , R 7 , R 8 and R 10 Each of represents hydrogen, and R 9 Halo C 1~6 It represents alkyl (for example, fluoromethyl or difluoromethyl).

[0205] In one embodiment, R 6 , R 7 , R 8 and R 10 Each of represents hydrogen, and R 9 represents a halogen (e.g., chlorine).

[0206] In one embodiment, R 6 , R 7 and R 10 Each of represents hydrogen, and R 8 represents a halogen (e.g., fluorine), and R 9 is C 1~6 It represents alkoxy (eg, methoxy).

[0207] In one embodiment, R 6 , R 8 and R10 Each of represents hydrogen, and R 7 and R 9 Both represent halogen (e.g., fluorine).

[0208] In one embodiment, R 6 , R 7 and R 10 Each of represents hydrogen, and R 8 Halo C 1~6 represents alkyl (e.g., trifluoromethyl), R 9 represents a halogen (e.g., fluorine).

[0209] In one embodiment, R 6 , R 8 , R 9 and R 10 Each of represents hydrogen, and R 7 is C 1~6 It represents alkyl (eg, methyl).

[0210] In one embodiment, R 6 , R 9 and R 10 Each of represents hydrogen, and R 7 and R 8 both represent halogen (e.g., fluorine or chlorine).

[0211] In one embodiment, Y is —C(R 6 )=, and R 6 , R 9 and R 10 Each of represents hydrogen, and R 7 represents a halogen (e.g., chlorine), and R 8 represents a halogen (e.g., fluorine), and R 6 , R 9 and R 10 Each of represents hydrogen, and R 7 and R 8 both represent halogen (e.g., fluorine or chlorine).

[0212] In another embodiment, Y represents -N= and R 8 and R 10 Both represent hydrogen, and R 7 is C1~6 represents alkyl (e.g., methyl), and R 9 Halo C 1~6 It represents alkyl (for example, trifluoromethyl).

[0213] R 7 and R 8 are linked to form a pyrrolinyl ring, and R 9 and R 10 Both represent hydrogen.

[0214] R 9 and R 10 Both represent hydrogen, and R 7 is C 1~6 represents alkyl (e.g., methyl), and R 8 represents a halogen (e.g., fluorine), and R 8 , R 9 and R 10 Each of represents hydrogen, and R 7 Ha-NR m R n (e.g., -NH2, -NHMe or -NMe2).

[0215] R 9 and R 10 Both represent hydrogen, and R 7 and R 8 are linked to form a pyrrolinyl, morpholinyl, furanyl or thiophenyl ring optionally substituted with methyl, fluorine or chlorine groups.

[0216] In one embodiment, R 10 represents hydrogen, and R 9 represents a halogen (e.g., chlorine), and R 7 and R 8 are joined to form a pyrrolinyl ring optionally substituted with a methyl group.

[0217] In one embodiment, Y represents -N= and R 8 and R 10 Both represent hydrogen, and R 7 is C 1~6 represents alkyl (e.g., methyl), and R 9 Halo C 1~6It represents alkyl (for example, trifluoromethyl).

[0218] In one embodiment, Y represents -N= and R 9 and R 10 Both represent hydrogen, and R 7 is C 1~6 alkyl (e.g., methyl, ethyl, CD3, or C2D5), R 8 represents a halogen (e.g., fluorine).

[0219] In one embodiment, Y represents -N= and R 9 and R 10 Both represent hydrogen, and R 7 and R 8 both represent halogen (e.g., fluorine or chlorine).

[0220] In one embodiment, R 7 and R 8 are linked to form a pyrrolinyl ring, and R 9 and R 10 Both represent hydrogen.

[0221] In one embodiment, Y represents -N= and R 8 and R 10 Both represent hydrogen, and R 7 is C 1~6 represents alkyl (e.g., methyl), and R 9 Halo C 1~6 It represents alkyl (for example, trifluoromethyl).

[0222] In one embodiment, the compound of formula (I) is represented by one of the following compounds: [ka] [ka] [ka] [ka]

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[0223] Salt Certain compounds of formula (I) can exist in the form of salts, such as acid addition salts, or in certain cases, salts of organic and inorganic bases, such as carboxylates, sulfonates, and phosphates. The term "salt" includes addition salts of free acids or free bases that are compounds of the present invention. The term "pharmaceutically acceptable salt" refers to salts that have toxicity profiles within a range that makes them useful in pharmaceutical applications. Pharmaceutically unacceptable salts may nevertheless have properties, such as high crystallinity, that make them useful in the practice of the present invention, for example, in the synthesis, purification, or formulation processes of the compounds of the present invention.

[0224] All such salts are within the scope of the present invention, and a reference to a compound of formula (I) includes the salt forms of the compound. The salts of the present invention can be synthesized from a parent compound containing a basic or acidic moiety by conventional chemical methods, such as those described in Pharmaceutical Salts: Properties, Selection, and Use, P. Heinrich Stahl (Editor), Camille G. Wermuth (Editor), ISBN: 3-90639-026-8, Hardcover, 388 pages, August 2002. Generally, such salts can be prepared by reacting the free acid or base form of these compounds with the appropriate base or acid in water or an organic solvent, or in a mixture of the two; typically, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are used.

[0225] Acid addition salts (mono- or di-salts) can be formed with a variety of acids, both inorganic and organic. Examples of acid addition salts include acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid (e.g., L-ascorbic acid), L-aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, butanoic acid, (+)camphoric acid, camphorsulfonic acid, (+)-(1S)-camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric ... Cloramic acid, dodecylsulfonic acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, D-gluconic acid, glucuronic acid (e.g., D-glucuronic acid), glutamic acid (e.g., L-glutamic acid), α-oxoglutaric acid, glycolic acid, hippuric acid, hydrohalic acids (e.g., hydrobromic acid), , hydrochloric acid, hydroiodic acid), isethionic acid, lactic acid (e.g., (+)-L-lactic acid, (±)-DL-lactic acid), lactobionic acid, maleic acid, malic acid, (-)-L-malic acid, malonic acid, (±)-DL-mandelic acid, methanesulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, oleic acid, orotic acid, oxalic acid, paprika Mono- or di-salts formed with acids selected from the group consisting of lumitic, pamoic, phosphoric, propionic, pyruvic, L-pyroglutamic, salicylic, 4-aminosalicylic, sebacic, stearic, succinic, sulfuric, tannic, (+)-L-tartaric, thiocyanic, p-toluenesulfonic, undecylenic, and valeric acids, as well as acylated amino acids and cation exchange resins. One particular group of salts consists of salts formed with acetic, hydrochloric, hydroiodic, phosphoric, nitric, sulfuric, citric, lactic, succinic, maleic, malic, isethionic, fumaric, benzenesulfonic, toluenesulfonic, methanesulfonic (mesylate), ethanesulfonic, naphthalenesulfonic, valeric, acetic, propanoic, butanoic, malonic, glucuronic, and lactobionic acids. One particular salt is the hydrochloride salt.When the compounds of formula (I) contain an amine function, they can form quaternary ammonium salts, for example, by reacting with an alkylating agent according to methods known to those skilled in the art. Such quaternary ammonium compounds are within the scope of formula (I). The compounds of the present invention can exist as mono- or di-salts depending on the pKa of the acid with which the salt is formed. It will be understood that for use in medicine, the salts of the compounds of formula (I) must be pharmaceutically acceptable. Suitable pharmaceutically acceptable salts will be apparent to those skilled in the art.

[0226] Pharmaceutically acceptable salts include those described in Berge, Bighley and Monkhouse, J. Pharm. Sci. 1977, 66, pp. 1-19. Suitable pharmaceutically acceptable acid addition salts can be prepared from inorganic and organic acids. Examples of inorganic acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, sulfuric acid, and phosphoric acid. Suitable organic acids are selected from the aliphatic, alicyclic, aromatic, araliphatic, heterocyclic, carboxylic, and sulfonic acid classes, including formic acid, acetic acid, pivalic acid, propionic acid, furoic acid, mucic acid, isethionic acid, succinic acid, glycolic acid, gluconic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, glucuronic acid, maleic acid, fumaric acid, pyruvic acid, aspartic acid, glutamic acid, benzoic acid, anthranilic acid, 4- Examples of pharmaceutically unacceptable acid addition salts include hydroxybenzoic acid, phenylacetic acid, mandelic acid, embonic acid (pamoic acid), methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, pantothenic acid, trifluoromethanesulfonic acid, 2-hydroxyethanesulfonic acid, p-toluenesulfonic acid, sulfanilic acid, cyclohexylaminosulfonic acid, stearic acid, alginic acid, β-hydroxybutyric acid, salicylic acid, galactaric acid, camphorsulfonic acid, and galacturonic acid. Examples of pharmaceutically unacceptable acid addition salts include perchlorates and tetrafluoroborates. However, pharmaceutically unacceptable salts may also be prepared as intermediates and then converted to pharmaceutically acceptable salts. Such pharmaceutically unacceptable salt forms, which may be useful, for example, in the purification or separation of the compounds of the present invention, also form part of the present invention. Some of the compounds of formula (I) can form acid addition salts with one or more equivalents of the acid. The present invention includes within its scope all possible stoichiometric and non-stoichiometric forms.

[0227] Suitable pharmaceutically acceptable base addition salts of the compounds of the present invention include, for example, metal salts, including alkali metal, alkaline earth metal, and transition metal salts, such as calcium, magnesium, potassium, sodium, and zinc salts. Pharmaceutically acceptable base addition salts also include organic salts made from basic amines, such as N,N'-dibenzylethylenediamine, chlooprocaine, choline, diethanolamine, ethylenediamine, tromethamine, meglumine (N-methylglucamine), and procaine. Examples of pharmaceutically unacceptable base addition salts include lithium salts and cyanate salts.

[0228] All of these salts can be prepared by conventional means from the corresponding compound of formula I, for example, by reacting an appropriate acid or base with the compound of formula I. Preferably, the salts are in crystalline form and are preferably prepared by crystallization of the salt from a suitable solvent. Those skilled in the art will know how to prepare and select suitable salts, for example, as described in Handbook of Pharmaceutical Salts: Properties, Selection and Use by P.H. Stahl and C.G. Wermuth (Wiley-VCH 2002).

[0229] solvate Those skilled in the art of organic chemistry will recognize that many organic compounds can form complexes with solvents in which they are reacted or from which they precipitate or crystallize. These complexes are known as "solvates." For example, complexes with water are known as "hydrates." Pharmaceutically acceptable solvates of the compounds of the present invention are within the scope of the present invention. In one embodiment, a pharmaceutically acceptable solvate of a compound of the present invention includes a hydrate thereof. In one embodiment, the crystalline form of the compound of Formula (I) is a cocrystal or coformer. Such cocrystals or coformers can be prepared using water-soluble molecules such as saccharin, caffeine, nicotinamide, or carboxylic acids. Coformers can be prepared as described in Emami S et al. (2018) Biol. mpacts 8(4), 305-320, the techniques of which are incorporated herein by reference. It will be understood that the present invention includes pharmaceutically acceptable derivatives of the compound of Formula (I), which are included within the scope of the present invention. As used herein, "pharmaceutically acceptable derivative" includes any pharmaceutically acceptable ester of a compound of formula (I), or a salt of such an ester, which, upon administration to a recipient, is capable of providing (directly or indirectly) a compound of formula (I) or an active metabolite or residue thereof.

[0230] N-oxide Compounds of formula (I) containing an amine functional group can also form N-oxides. Reference herein to compounds of formula (I) containing an amine functional group also includes N-oxides. When a compound contains several amine functional groups, one or more nitrogen atoms may be oxidized to form N-oxides. Specific examples of N-oxides are the N-oxides of tertiary amines or nitrogen atoms of nitrogen-containing heterocycles. N-oxides can be formed by treating the corresponding amine with an oxidizing agent such as hydrogen peroxide or a peracid (e.g., a peroxycarboxylic acid); see, for example, Jerry March, Advanced Organic Chemistry, 4th Edition, Wiley Interscience. In particular, N-oxides can be prepared by the method of L.W. Deady (Syn. Commun. 1977, 7, 509-514), in which an amine compound is reacted with m-chloroperbenzoic acid (mCPBA) in an inert solvent such as dichloromethane.

[0231] Prodrug It will be understood by those skilled in the art that certain protected derivatives of the compound of formula (I) that may be prepared before the final deprotection step may not have pharmacological activity themselves, but in some cases may be administered orally or parenterally and then metabolized in the body to form the pharmacologically active compound of the present invention. Therefore, such derivatives can be described as "prodrugs." All such prodrugs of the compounds of the present invention are included within the scope of the present invention. Examples of prodrug functional groups suitable for the compounds of the present invention are described in Drugs of Today, 19, 9, 1983, 499-538 and Topics in Chemistry, Chapter 31, pp. 306-316, and H. Bundgaard, "Design of Prodrugs," Elsevier, 1985, Chapter 1 (the disclosures of which are incorporated herein by reference). Furthermore, those skilled in the art will recognize that certain moieties known to those skilled in the art as "promoieties," as described, for example, by H. Bundgaard in "Design of Prodrugs," the disclosure of which is incorporated herein by reference, can be placed on appropriate functional groups, if such groups are present in the compounds of the invention. Also included within the scope of the compounds of the invention and various salts thereof are polymorphs thereof.

[0232] Enantiomers Where chiral centers are present in compounds of formula (I), the present invention includes within its scope all possible enantiomers and diastereoisomers, including mixtures thereof. The different isomeric forms may be separated or resolved one from the other by conventional methods, or any given isomer may be obtained by conventional synthetic methods or by stereospecific or asymmetric syntheses. The present invention also includes all tautomers or mixtures thereof.

[0233] Isotopes The present invention also includes all pharmaceutically acceptable isotopically labeled compounds that are identical to those set forth in formula (I) except for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number most commonly found in nature. Examples of isotopes suitable for inclusion in compounds of the present invention include isotopes of hydrogen, e.g. 2 H(D) and 3 H(T), an isotope of carbon, e.g. 11 C. 13 C, and 14 C, an isotope of chlorine, e.g. 36 Cl, an isotope of fluorine, e.g. 18 F, an isotope of iodine, e.g. 123 I, 125 I, and 131 I, isotopes of nitrogen, e.g. 13 N and 15 N, isotopes of oxygen, e.g. 15 O. 17 O, and 18 O, isotopes of phosphorus, e.g. 32 P, sulfur isotopes, e.g. 35 Certain isotopically labeled compounds of the compound of formula (I), for example those incorporating a radioisotope, are useful in drug and / or substrate tissue distribution studies. The compounds of formula (I) can also have valuable diagnostic properties in that they can be used to detect or identify the formation of complexes between the labeled compound and other molecules, peptides, proteins, enzymes, or receptors. Detection or identification methods can use compounds labeled with labeling agents such as radioisotopes, enzymes, fluorescent substances, luminescent substances (e.g., luminol, luminol derivatives, luciferin, aequorin, and luciferase). The radioisotope tritium, i.e. 3 H(T), and carbon-14, i.e. 14 C are particularly useful for this purpose in view of their ease of incorporation and convenient means of detection. 2Substitution with heavier isotopes, such as H), may afford certain therapeutic advantages due to greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements, and therefore may be preferable in some circumstances. 11 C. 18 F, 15 O and 13 Substitution with positron emitting isotopes, such as N, can be useful in Positron Emission Topography (PET) studies for examining target occupancy.

[0234] Isotopically labeled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying examples and preparations, substituting an appropriate isotopically labeled reagent for the previously used non-labeled reagent.

[0235] purity It will be readily appreciated that, because the compounds of formula (I) are intended for use in pharmaceutical compositions, they are each preferably provided in substantially pure form, for example at least 60% pure, more suitably at least 75% pure, preferably at least 85%, and especially at least 98% pure (percentages given by weight). Impure preparations of the compounds may be used to prepare purer forms for use in pharmaceutical compositions.

[0236] process In a further aspect of the present invention, there is provided a process for preparing compounds of formula (I) and derivatives thereof. The following schemes are examples of synthetic schemes that can be used to synthesize compounds of the present invention. In the following schemes, reactive groups can be protected and deprotected with protecting groups according to well-established techniques.

[0237] Compounds of formula I can be prepared according to the general methods set forth in Schemes 4-5. Certain compounds of formula I, identified as having the structure of formula Ia, can be prepared using the general method set forth in Scheme 4. Other compounds of formula I, identified as having the structure of formula Ib, can be prepared using the general method set forth in Scheme 5. It is understood that compounds of formula Ia are compounds of formula I in which U is O, while compounds of formula Ib are compounds of formula I in which U is CH. Intermediates 2, 5, and X can be prepared using the general methods set forth in Schemes 1-3. Scheme 1 [ka]

[0238] Compounds of formula 2 can be prepared as shown in Scheme 1. Compound 1, which is a known compound or a compound prepared according to known methods, can be reacted with pyridine, N,N-dimethylpyridine, triethylamine, diisopropylethylamine, diazabicyclononene, diazabicycloundecene, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydride, potassium hydride, sodium tert-butoxide, potassium tert-butoxide, N-butyllithium, lithium diisopropylamide, or an appropriate base, such as, optionally, water, hexane, heptane, cyclohexane, dichloromethane, or the like. , chloroform, carbon tetrachloride, ethyl acetate, tetrahydrofuran, benzene, toluene, diethyl ether, methanol, ethanol, N-methylpyrrolidone, dimethyl sulfoxide, dimethylformamide, and the like, optionally in the presence of a phase transfer agent such as tetrabutylammonium bromide, benzyltriethylammonium chloride, methyltribenzylammonium chloride, hexadecyltributylphosphonium bromide, 18-crown-6, and the like, optionally with heating and optionally with microwave irradiation to provide a compound of formula 2. Scheme 2 [ka]

[0239] Compounds of formula 5 can be prepared as shown in Scheme 2. Compound 3, which is a known compound or a compound prepared using known methods, can be reacted with pyridine, N,N-dimethylpyridine, triethylamine, diisopropylethylamine, diazabicyclononene, diazabicycloundecene, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydride, potassium hydride, sodium tert-butoxide, potassium tert-butoxide, N-butyllithium, lithium diisopropylamide, or the like, in the presence of a suitable base, such as, optionally, water, hexane, heptane, cyclohexane, dichloromethane, chloroform, carbon tetrachloride, ethyl acetate, tetrahydrofuran, benzene, toluene, diethyl ether, or the like.

[0043] Treatment with a carbamoylating agent 4, such as phosgene, diphosgene, triphosgene, carbonyldiimidazole, disuccinimidyl carbonate, in the presence of a suitable solvent such as ether, methanol, ethanol, N-methylpyrrolidone, dimethyl sulfoxide, dimethylformamide, and the like, optionally in the presence of a phase transfer agent such as tetrabutylammonium bromide, benzyltriethylammonium chloride, methyltribenzylammonium chloride, hexadecyltributylphosphonium bromide, 18-crown-6, and the like, optionally with heating and optionally with microwave irradiation, provides a compound of formula 5, wherein LG is a leaving group such as halogen, imidazole, succinimide, and the like. Scheme 3 [ka]

[0240] Some of the compounds of formula I can be prepared as shown in Scheme 3. In Scheme 3, a compound of formula 2 is reacted with a compound of formula 5 in the presence of a suitable base such as pyridine, N,N-dimethylpyridine, triethylamine, diisopropylethylamine, diazabicyclononene, diazabicycloundecene, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydride, potassium hydride, sodium tert-butoxide, potassium tert-butoxide, N-butyllithium, lithium diisopropylamide, optionally in the presence of a suitable solvent such as water, hexane, heptane, cyclohexane, dichloromethane, chloroform, carbon tetrachloride, ethyl acetate, tetrahydrofuran, benzene, toluene, diethyl ether, methanol, ethanol, N-methylpyrrolidone, dimethyl sulfoxide, dimethylformamide, optionally in the presence of a phase transfer agent such as tetrabutylammonium bromide, benzyltriethylammonium chloride, methyltribenzylammonium chloride, hexadecyltributylphosphonium bromide, 18-crown-6, optionally with heating and optionally with microwave irradiation, to provide a compound of formula 6. The compound of formula 6 is then reacted with a compound of formula 7, which is a known compound or a compound prepared by a known method, in the presence of a suitable catalyst such as copper(I) bromide, copper(I) iodide, nickel bromide, a suitable coordinating agent such as N,N-dimethylethylenediamine, a suitable base such as potassium carbonate, potassium phosphate, cesium carbonate, sodium tert-butoxide, a suitable ligand such as cesium fluoride, a suitable solvent such as water, tetrahydrofuran, 1,4-dioxane, dimethylsulfoxide, dimethylformamide, acetonitrile, optionally in the presence of molecular sieves, optionally with heating, and optionally with microwave irradiation, to obtain a compound of formula I. Scheme 4 [ka]

[0241] Alternatively, some of the compounds of formula I can be prepared as shown in Scheme 4. In Scheme 4, a compound of formula 8, which is a known compound or a compound prepared using known methods, is treated with a compound of formula 7, which is a known compound or a compound prepared using known methods, in the presence of a suitable base such as sodium tert-butoxide, lithium hexamethyldisilazide, cesium carbonate, potassium phosphate, etc., a suitable catalyst such as palladium(0) bis(dibenzylidyneacetone), palladium acetate, (DPPF)PdCl2, a suitable ligand such as 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (BINAP), tri-tert-butylphosphine, xantphos, etc., and a suitable solvent such as toluene, xylene, tetrahydrofuran, 1,4-dioxane, dimethoxyethane, butanol, tert-butanol, etc., optionally with heating and optionally with microwave irradiation, to provide a compound of formula 9, where PG represents a suitable protecting group such as benzyl, tert-butyldimethylsilyl, methoxymethyl, tetrahydropyranyl, etc., and LG 2represents a suitable leaving group such as chloro, bromo, iodo, mesyl, trifluoromesyl, p-toluenesulfonyl, etc. The compound of formula 9 is then reacted under suitable conditions for removing the protecting group, such as catalytic hydrogenation in the presence of a suitable catalyst such as palladium on carbon, palladium hydroxide, hydrogen fluoride / pyridine, diaminoethylsulfur trifluoride, aqueous acid, etc., to provide the compound of formula 10. The compound of formula 10 is then reacted with a compound of formula 5 in the presence of a suitable base such as pyridine, N,N-dimethylpyridine, triethylamine, diisopropylethylamine, diazabicyclononene, diazabicycloundecene, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydride, potassium hydride, sodium tert-butoxide, potassium tert-butoxide, N-butyllithium, lithium diisopropylamide, optionally in the presence of a suitable solvent such as water, hexane, heptane, cyclohexane, dichloromethane, chloroform, carbon tetrachloride, ethyl acetate, tetrahydrofuran, benzene, toluene, diethyl ether, methanol, ethanol, N-methylpyrrolidone, dimethyl sulfoxide, dimethylformamide, optionally in the presence of a phase transfer agent such as tetrabutylammonium bromide, benzyltriethylammonium chloride, methyltribenzylammonium chloride, hexadecyltributylphosphonium bromide, 18-crown-6, optionally with heating and optionally with microwave irradiation, to provide a compound of formula I.

[0242] In the above processes, certain functional groups that are sensitive to the reaction conditions may be protected by protecting groups. Protecting groups are derivatives of chemical functional groups that are otherwise incompatible with the conditions required to carry out a particular reaction, and can be removed to regenerate the original functional group after the reaction is carried out, thereby being considered "protected." Any chemical functional group that is a structural component of any of the reagents used to synthesize the compounds of the present invention can be optionally protected with a chemical protecting group if such a protecting group is useful in synthesizing the compounds of the present invention. Methods for selecting and using protecting groups are widely described in the chemical literature, and therefore those skilled in the art will know how to select such groups, if any, and the processes that can be used to selectively introduce and remove them, if any. Techniques for selecting, incorporating, and removing chemical protecting groups can be found, for example, in Protective Groups in Organic Synthesis by Theodora W. Greene and Peter G.M.Wuts, John Wiley & Sons Ltd., the entire disclosure of which is incorporated herein by reference.

[0243] Those skilled in the art will understand that the described processes are not the only means by which compounds of Formula I can be synthesized, and that a repertoire of synthetic organic reactions is available for potential use in synthesizing the compounds of the present invention. Those skilled in the art will know how to select and implement appropriate synthetic routes. Suitable synthetic methods can be identified by reference to the literature, for example, Comprehensive Organic Synthesis, Ed. B.M. Trost and I. Fleming (Pergamon Press, 1991); Comprehensive Organic Functional Group Transformations, Ed. A.R. Katrittzky, O. Meth-Cohn, and C.W. Rees (Pergamon Press, 1996); Comprehensive Organic Functional Group Transformations II, Ed. A. R. Katrittzky and R.J.K. Taylor (Editors) (Elsevier, 2002); nd Edition, 2004), Comprehensive Heterocyclic Chemistry, Ed. A.R. Katrittzky and C.W. Rees (Pergamon Press, 1984), and Comprehensive Heterocyclic Chemistry II, Ed. A.R. Katrittzky, C.W. Rees and E.F.V. Scriven (Pergamon Press, 1996).

[0244] The compounds of formula I and intermediates can be isolated from their reaction mixtures and purified by standard techniques, such as filtration, liquid-liquid extraction, solid phase extraction, distillation, recrystallization, or chromatography.

[0245] It is understood that when the compounds of formula I of the present invention contain one or more chiral centers, the compounds may exist and be isolated in the form of pure enantiomers or diastereomers, or as racemic mixtures. Accordingly, the present invention includes all possible enantiomers, diastereomers, racemates, or mixtures thereof, of the compounds of the present invention that are biologically active in the treatment of cancer.

[0246] Preparation of Compounds of the Invention Compounds of formula (I) can be prepared according to the general schemes described herein using synthetic methods known to those skilled in the art. The following examples illustrate non-limiting embodiments of the present invention.

[0247] The compounds of the present invention may possess one or more stereocenters, and each stereocenter may independently exist in either the R or S configuration. In one embodiment, the compounds described herein exist in optically active or racemic forms. It is understood that the compounds described herein encompass racemates, optically active forms, regioisomers, and stereoisomers, or combinations thereof, that possess the therapeutically useful properties described herein. Optically active forms may be prepared in any suitable manner, including, but not limited to, resolution of racemates using recrystallization techniques, synthesis from optically active starting materials, chiral synthesis, or chromatographic separation using chiral stationary phases. In one embodiment, a mixture of one or more isomers is utilized as a therapeutic compound described herein. In another embodiment, the compounds described herein contain one or more chiral centers. These compounds are prepared by any means, including stereoselective synthesis, enantioselective synthesis, and / or separation of a mixture of enantiomers and / or diastereomers. Resolution of the compounds and their isomers may be performed by any means, including, but not limited to, chemical processes, enzymatic processes, fractional crystallization, distillation, and chromatography.

[0248] The methods and formulations described herein include the use of N-oxides (where appropriate), crystalline forms (also known as polymorphs), solvates, amorphous phases, and / or pharmaceutically acceptable salts of compounds having the structure of any of the compounds of the invention, as well as metabolites and active metabolites of these compounds having the same type of activity. Solvates include water, ether (e.g., tetrahydrofuran, methyl tert-butyl ether) or alcohol (e.g., ethanol) solvates, acetate salts, and the like. In one embodiment, the compounds described herein exist in a solvated form with a pharmaceutically acceptable solvent, such as water or ethanol. In another embodiment, the compounds described herein exist in a non-solvated form.

[0249] In one embodiment, the compounds of the invention may exist as tautomers, and all tautomers are included within the scope of the compounds presented herein.

[0250] In one embodiment, the compounds described herein are prepared as prodrugs. A "prodrug" refers to an agent that is converted into the parent drug in vivo. In one embodiment, upon in vivo administration, the prodrug is chemically converted into the biologically, pharmaceutically, or therapeutically active form of the compound. In another embodiment, the prodrug is enzymatically metabolized by one or more steps or processes into the biologically, pharmaceutically, or therapeutically active form of the compound.

[0251] In one embodiment, for example, sites on the aromatic ring portion of the compounds of the present invention are susceptible to various metabolic reactions. By incorporating appropriate substituents on the aromatic ring structure, this metabolic pathway can be reduced, minimized, or eliminated. In one embodiment, suitable substituents for reducing or eliminating the susceptibility of the aromatic ring to metabolic reactions are, by way of example only, deuterium, halogen, or alkyl groups.

[0252] The compounds described herein also include isotopically labeled compounds in which one or more atoms are replaced by an atom having the same atomic number but an atomic mass or mass number different from that usually found in nature. Examples of isotopes suitable for inclusion in the compounds described herein include, but are not limited to: 2 H, 3 H, 11 C. 13 C. 14 C. 36 Cl, 18 F, 123 I, 125 I, 13 N, 15 N, 15 O. 17 O. 18 O. 32 P, and 35 In one embodiment, isotopically labeled compounds are useful in drug and / or substrate tissue distribution studies. In another embodiment, substitution with heavier isotopes, such as deuterium, affords greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements). In yet another embodiment, 11 C. 18 F, 15 O and 13 Substitution with positron emitting isotopes, such as N, is useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy. Isotopically labeled compounds are prepared by any suitable method or process that employs a suitable isotopically labeled reagent in place of a non-labeled reagent used in other methods.

[0253] In one embodiment, the compounds described herein are labeled by other means, including but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.

[0254] The compounds described herein, and other related compounds having different substituents, can be prepared by the methods described herein and in other publications, for example, Fieser & Fieser's Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991), Rodd's Chemistry of Carbon Compounds, Volumes 1-5 and Supplements (Elsevier Science Publishers, 1989), Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989), March, Advanced Organic Chemistry 4 th Ed., (Wiley 1992), Carey & Sundberg, Advanced Organic Chemistry 4th Ed., Vols. A and B (Plenum 2000, 2001), and Green & Wuts, Protective Groups in Organic Synthesis 3rd Ed., (Wiley 1999), all of which are incorporated by reference for such disclosures. The general methods for the preparation of the compounds described herein are modified by using appropriate reagents and conditions for the introduction of the various moieties found in the formulas provided herein.

[0255] The compounds described herein are synthesized using any suitable procedure starting from compounds available from commercial sources or prepared using the procedures described herein.

[0256] In one embodiment, reactive functional groups such as hydroxyl, amino, imino, thio, or carboxy groups are protected to prevent their undesired participation in reactions. Protecting groups are used to block some or all of the reactive moieties and prevent such groups from participating in chemical reactions until the protecting group is removed. In another embodiment, each protecting group can be removed by a different means. Protecting groups that are cleaved under completely different reaction conditions meet the requirement of specific removal.

[0257] In one embodiment, protecting groups are removed by acid, base, reducing conditions (e.g., hydrogenolysis), and / or oxidative conditions. Groups such as trityl, dimethoxytrityl, acetal, and t-butyldimethylsilyl are used to protect carboxy and hydroxy reactive moieties in the presence of amino groups protected with Cbz groups, which are acid labile and removable by hydrogenolysis, and Fmoc groups, which are base labile. Carboxylic acid and hydroxy reactive moieties are blocked with acid labile groups such as t-butyl carbamate, or with base labile groups such as, but not limited to, methyl, ethyl, and acetyl in the presence of amines blocked with carbamates, which are both acid and base stable but removable by hydrolysis.

[0258] In one embodiment, the carboxylic acid and hydroxy reactive moieties are blocked with hydrolytically removable protecting groups such as benzyl groups, while amine groups capable of hydrogen bonding with acids are blocked with base-labile groups such as Fmoc. The carboxylic acid reactive moieties are protected by conversion to simple ester compounds as exemplified herein, including conversion to alkyl esters, or are blocked with oxidatively removable protecting groups such as 2,4-dimethoxybenzyl, while coexisting amino groups are blocked with fluoride-labile silyl carbamates.

[0259] Allyl protecting groups are useful in the presence of acidic and basic protecting groups because they are stable and subsequently removed by metal or π-acid catalysts. For example, an allyl-blocked carboxylic acid is deprotected in a palladium-catalyzed reaction in the presence of acid-labile t-butyl carbamate or base-labile acetate amine protecting groups. Yet another form of protecting group is a resin to which a compound or intermediate is attached. As long as the residue is attached to the resin, the functional group is blocked and does not react. Once released from the resin, the functional group is available for reaction.

[0260] Typically, the blocking / protecting group can be selected from: [ka]

[0261] Detailed descriptions of other protecting groups and techniques applicable to the creation of protecting groups and their removal are described in Greene & Wuts, Protective Groups in Organic Synthesis, 3rd Ed., John Wiley & Sons, New York, NY, 1999, and Kocienski, Protective Groups, Thieme Verlag, New York, NY, 1994, which are incorporated herein by reference for such disclosures.

[0262] Method of Invention The present invention includes a method for treating or preventing cancer in a subject in need thereof. The method includes administering to the subject an effective amount of a therapeutic composition comprising a compound of the present invention. Cancers that can be treated include tumors that are not vascularized or not yet substantially vascularized, as well as vascularized tumors. Cancers can include non-solid tumors (such as hematological tumors, e.g., leukemia and lymphoma) or solid tumors. Types of cancer that can be treated with the compositions of the present invention include, but are not limited to, carcinomas, blastomas, and sarcomas, as well as certain leukemias or lymphoid malignancies, benign and malignant tumors, and malignant lesions, such as sarcomas, carcinomas, and melanomas. Adult tumors / cancers and pediatric tumors / cancers are also included.

[0263] Hematological cancers are cancers of the blood or bone marrow. Examples of hematological (or hematogenic) cancers that can be treated with the compositions of the present invention include leukemias, including acute leukemia (e.g., acute lymphocytic leukemia, acute myeloid leukemia, acute myelogenous leukemia, and myeloblastic, promyelocytic, myelomonocytic, monocytic, and erythroleukemia), chronic leukemia (e.g., chronic myelocytic (granulocytic) leukemia, chronic myelogenous leukemia, and chronic lymphocytic leukemia), polycythemia vera, lymphoma, Hodgkin's disease, non-Hodgkin's lymphoma (low-grade and high-grade forms), multiple myeloma, Waldenstrom's macroglobulinemia, heavy chain disease, myelodysplastic syndrome, hairy cell leukemia, and myelodysplasia.

[0264] A solid tumor is an abnormal mass of tissue that usually does not contain cysts or liquid areas. Solid tumors can be benign or malignant. Different types of solid tumors are named after the type of cells that form them (such as sarcoma, carcinoma, and lymphoma). Examples of solid tumors, such as sarcomas and carcinomas, that can be treated with the compositions of the present invention include fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteosarcoma, and other sarcomas, synovial sarcoma, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, colon cancer, malignant lymphoma, pancreatic cancer, breast cancer, lung cancer, ovarian cancer, prostate cancer, hepatocellular carcinoma, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, medullary thyroid carcinoma, papillary thyroid carcinoma, pheochromocytoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinoma, medullary thyroid carcinoma, thyroid carcinoma, pheochromocytoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinoma, and medullary thyroid carcinoma. Cancers that are treated include, but are not limited to, bronchogenic carcinoma, renal cell carcinoma, liver cancer, bile duct carcinoma, choriocarcinoma, Wilms' tumor, cervical cancer, testicular tumor, seminoma, bladder cancer, melanoma, and CNS tumors (e.g., gliomas (such as brain stem gliomas and mixed gliomas), glioblastomas (also known as glioblastoma multiforme), astrocytomas, CNS lymphomas, germinomas, medulloblastomas, schwannomas, craniopharyngiomas, ependymomas, pinealomas, hemangioblastomas, acoustic neuromas, oligodendroglioma, meningiomas, neuroblastomas, retinoblastomas, and brain metastases.

[0265] In one embodiment, the cancer is selected from the group consisting of lung cancer, colon cancer, colorectal cancer, melanoma, breast cancer, ovarian cancer, prostate cancer, liver cancer, pancreatic cancer, CNS tumors (including brain tumors), neuroblastoma, leukemia, bone cancer, intestinal cancer, lymphoma, and combinations thereof. In one embodiment, the cancer is pancreatic cancer. In one embodiment, the cancer is prostate cancer. In one embodiment, the method further comprises administering to the subject an additional therapeutic agent. In one embodiment, the therapeutic agent is gemcitabine.

[0266] The present invention also includes a method for treating or preventing pain or inflammation in a subject in need thereof. The method comprises administering to the subject an effective amount of a therapeutic composition comprising a compound of the present invention. In one embodiment, the inflammation is selected from the group consisting of arthritic disorders, psoriasis, allergies, opioid tolerance, Crohn's disease, migraine, polyarteritis nodosa, thyroiditis, aplastic anemia, Hodgkin's disease, scleroderma, rheumatic fever, type I diabetes, neuromuscular junction diseases including myasthenia gravis, white matter diseases including multiple sclerosis, sarcoidosis, nephrotic syndrome, Behçet's syndrome, polymyositis, gingivitis, nephritis, hypersensitivity, swelling following injury including cerebral edema, and myocardial ischemia. In one embodiment, the arthritic disorder is selected from the group consisting of rheumatoid arthritis, spondyloarthritis, gouty arthritis, osteoarthritis, systemic lupus erythematosus, and juvenile arthritis. In one embodiment, the method further comprises administering to the subject an additional therapeutic agent.

[0267] In one embodiment, the pain is selected from the group consisting of pain resulting from cancer, fever and inflammation of various conditions including rheumatic fever, influenza and other viral infections including the common cold, lower back and neck pain, dysmenorrhea, headache, toothache, sprains and strains, myositis, neuralgia, synovitis, arthritis including rheumatoid arthritis, degenerative joint disease (osteoarthritis), gout and ankylosing spondylitis, bursitis, burns, and trauma following surgical and dental procedures. In one embodiment, the method further comprises administering to the subject an additional therapeutic agent.

[0268] The present invention also includes a method for treating or preventing a disease or disorder associated with the NF-κB pathway in a subject in need thereof. The method comprises administering to the subject an effective amount of a therapeutic composition comprising a compound of the present invention. Non-limiting examples of diseases or disorders associated with reactive oxygen species include ischemic diseases, inflammatory diseases, autoimmune diseases, cancer metastasis and invasion, and cachexia.

[0269] The present invention also includes a method for treating or preventing a disease or disorder associated with reactive oxygen species (ROS) in a subject in need thereof. The method comprises administering to the subject an effective amount of a therapeutic composition comprising a compound of the present invention. Non-limiting examples of diseases or disorders associated with reactive oxygen species include arteriosclerosis, myocardial infarction, diabetes, and cancer.

[0270] In one embodiment, administering a compound of the invention to a subject allows for a lower dose of a therapeutic agent to be administered compared to the dose of the therapeutic agent alone required to achieve a similar result in treating or preventing cancer in the subject. For example, in one embodiment, a compound of the invention enhances the anti-cancer activity of an additional therapeutic compound, thereby allowing for a lower dose of the therapeutic compound to achieve the same effect. In another embodiment, administering a compound of the invention to a subject allows for a lower dose of a therapeutic agent to be administered compared to the dose of the therapeutic agent alone required to achieve a similar result in treating or preventing pain or inflammation in the subject.

[0271] In one embodiment, a compound of the invention and a therapeutic agent are co-administered to a subject. In another embodiment, a compound of the invention and a therapeutic agent are co-formulated and co-administered to a subject.

[0272] In one embodiment, the subject is a mammal, hi one embodiment, the mammal is a human.

[0273] Combination therapy The compounds of the present invention are intended to be useful in combination with one or more additional compounds. In certain embodiments, these additional compounds may include compounds of the present invention or therapeutic agents known to treat or alleviate the symptoms or effects of cancer. Such compounds include, but are not limited to, chemotherapeutic agents. In other embodiments, these additional compounds may include therapeutic agents known to treat or alleviate the symptoms or effects of pain or inflammation.

[0274] In one embodiment, the compounds of formula (I) are used in combination with any known FDA-approved cancer therapeutic agent. In one embodiment, the present invention provides a method of treating cancer comprising treating a subject with a complementary cancer therapy, such as surgery, chemotherapy, chemotherapeutic agents, radiation therapy, or hormonal therapy, or a combination thereof, prior to, concurrently with, or following administration of a compound disclosed herein.

[0275] Chemotherapeutic agents include cytotoxic agents (e.g., 5-fluorouracil, cisplatin, carboplatin, methotrexate, daunorubicin, doxorubicin, vincristine, vinblastine, oxorubicin, carmustine (BCNU), lomustine (CCNU), cytarabine USP, cyclophosphamide, estramucin sodium phosphate, altretamine, hydroxyurea, ifosfamide, procarbazine, mitomycin, busulfan, cyclophosphamide, mitoxantrone, carboplatin, cisplatin, interferon alfa, flufa-2a recombinant, paclitaxel, teniposide, and streptozocine), cytotoxic alkylating agents (e.g., busulfan, chlorambucil, cyclophosphamide, melphalan, or ethylsulfonic acid), alkylating agents (e.g., asarella, AZQ, BCNU, busulfan, bisulfan, carboxyphthalatoplatinum, CBDCA, CCNU, CHIP, chlorambucil, chlorozotocin, cisplatin, clomesone, cyanomorpholinodoxorubicin, cyclodizone, cyclophosphamide, dianhydrogalactitol, fluorodopan, hepsulfam, hycanthone, ifosfamide, melphalan, methyl CCNU, mitomycin C, mitozolamide, nitrogen mustard, PCNU, piperazine, piperazinedione, pipobroman, porfiromycin, spirohydantoin mustard, streptozotocin, teroxylon, tetraplatin, thiotepa, triethylenemelamine, uracil nitrogen mustard, and Yoshi-864), mitotic inhibitors (e.g., allocolchicine, halichondrin M, colchicine, colchicine derivatives, dolastatin 10, maytan cin, rhizoxin, paclitaxel derivatives, paclitaxel, thiocolchicine, trityl cysteine, vinblastine sulfate, and vincristine sulfate), plant alkaloids (e.g., actinomycin D, bleomycin, L-asparaginase, idarubicin, vinblastine sulfate, vincristine sulfate, mithramycin, mitomycin, daunorubicin, VP-16-213, VM-26, navelbine, and taxotere), biological agents (e.g., alpha interferon, BCG, G-CSF, GM-CSF, interleukin-2),These include topoisomerase I inhibitors (e.g., camptothecin, camptothecin derivatives, and morpholinodoxorubicin), topoisomerase II inhibitors (e.g., mitoxantrone, amonafide, m-AMSA, anthrapyrazole derivatives, pyrazoloacridine, bisantrene hydrochloride, daunorubicin, deoxydoxorubicin, menogaril, N,N-dibenzyldaunomycin, oxantrazole, rubidazone, VM-26, and VP-16), and synthetic agents (e.g., hydroxyurea, procarbazine, o,p'-DDD, dacarbazine, CCNU, BCNU, cis-diamminedichloroplatinum, mitoxantrone, CBDCA, levamisole, hexamethylmelamine, all-trans retinoic acid, gliadel, and porfimer sodium).

[0276] Antiproliferative agents are compounds that reduce cell proliferation. Antiproliferative agents include alkylating agents, antimetabolites, enzymes, biological response modifiers, various drugs, hormones and antagonists, androgen inhibitors (e.g., flutamide and leuprolide acetate), antiestrogens (e.g., tamoxifen citrate and its analogs, toremifene, droloxifene, and roloxifene). Further examples of specific antiproliferative agents include, but are not limited to, levamisole, gallium nitrate, granisetron, sargramostim strontium-89 chloride, filgrastim, pilocarpine, dexrazoxane, and ondansetron.

[0277] The compounds of the present invention can be administered alone or in combination with other anti-tumor agents, including cytotoxic / antineoplastic agents and anti-angiogenic agents. Cytotoxic / antineoplastic agents are defined as agents that attack and kill cancer cells. Some cytotoxic / antineoplastic agents are alkylating agents that alkylate genetic material in tumor cells, such as cisplatin, cyclophosphamide, nitrogen mustard, trimethylenethiophosphoramide, carmustine, busulfan, chlorambucil, verstine, uracil mustard, chromafazine, and dacabazine. Other cytotoxic / antineoplastic agents are antimetabolites directed against tumor cells, such as cytosine arabinoside, fluorouracil, methotrexate, mercaptopurine, azathioprine, and procarbazine. Other cytotoxic / antineoplastic agents are antibiotics, such as doxorubicin, bleomycin, dactinomycin, daunorubicin, mithramycin, mitomycin, mitomycin C, and daunomycin. There are numerous liposomal formulations of these compounds commercially available. Still other cytotoxic / antineoplastic agents are the mitotic inhibitors (vinca alkaloids). These include vincristine, vinblastine, and etoposide. Various cytotoxic / antineoplastic agents include taxol and its derivatives, L-asparaginase, antitumor antibodies, dacarbazine, azacitidine, amsacrine, melphalan, VM-26, ifosfamide, mitoxantrone, and vindesine.

[0278] Antiangiogenic agents are known to those skilled in the art. Antiangiogenic agents suitable for use in the methods and compositions of the present disclosure include anti-VEGF antibodies, including humanized and chimeric antibodies, anti-VEGF aptamers, and antisense oligonucleotides. Other known inhibitors of angiogenesis include angiostatin, endostatin, interferon, interleukin 1 (including alpha and beta), interleukin 12, retinoic acid, and tissue inhibitors of metalloproteinases-1 and -2 (TIMP-1 and -2). Small molecules that inhibit topoisomerase II, such as razoxane, which has antiangiogenic activity, can also be used.

[0279] Other anti-cancer agents that can be used in combination with the disclosed compounds include acivicin, aclarubicin, acodazole hydrochloride, acronine, adozelesin, aldesleukin, altretamine, ambomycin, amethanthrone acetate, aminoglutethimide, amsacrine, anastrozole, anthramycin, asparaginase, asperlin, azacytidine, azetepa, azotomycin, batimastat, benzodepa, bicalutamide, bisantrene hydrochloride, bisnafide dimesylate, bizelesin, bleomycin sulfate, brequinar sodium, and bropirimidazole. Methylamine, busulfan, cactinomycin, calsterone, caracemide, carbetimer, carboplatin, carmustine, carubicin hydrochloride, carzelesin, cedefingol, chlorambucil, ciloremycin, cisplatin, cladribine, crisnatol mesylate, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin hydrochloride, decitabine, dexorumaplatin, dezaguanine, dezaguanine mesylate, diaziquone, docetaxel, doxorubicin, doxorubicin hydrochloride, droloxifene, droloxifene citrate, Dromostanolone propionate, duazomycin, edatrexate, eflornithine hydrochloride, elsamitrucin, enloplatin, enpromate, epipropidine, epirubicin hydrochloride, elbrozole, esorubicin hydrochloride, estramustine, estramustine sodium phosphate, etanidazole, etoposide, etoposide phosphate, etopurine, fadrozole hydrochloride, fazarabine, fenretinide, floxuridine, fludarabine phosphate, fluorouracil, fluorocitabine, fosquidone, fostriecin sodium, gemcitabine, gemcitabine hydrochloride Mucitabine, hydroxyurea, idarubicin hydrochloride, ifosfamide, ilmofosine, interleukin II (including recombinant interleukin II, or rIL2), interferon alpha-2a, interferon alpha-2b, interferon alpha-n1, interferon alpha-n3, interferon beta-Ia, interferon gamma-Ib, iproplatin, irinotecan hydrochloride, lanreotide acetate, letrozole, leuprolide acetate, liarozole hydrochloride, lometrexol sodium, lomustine, losoxantrone hydrochloride,Masoprocol, maytansine, mechlorethamine hydrochloride, megestrol acetate, melengestrol acetate, melphalan, menogaril, mercaptopurine, methotrexate, methotrexate sodium, metoprine, meturedepa, mitindomide, mitocalcin, mitochromine, mitogillin, mitomarcine, mitomycin, mitospel, mitotane, mitoxantrone hydrochloride, mycophenolic acid, nocodazole, nogalamycin, ormaplatin, oxisuran, paclitaxel Cell, albumin-bound paclitaxel, pegaspargase, periomycin, pentamustine, peplomycin sulfate, perfosfamide, pipobroman, piposulfan, piroxantrone hydrochloride, plicamycin, promestane, porfimer sodium, porfiromycin, prednimustine, procarbazine hydrochloride, puromycin, puromycin hydrochloride, pyrazofurin, ribopurin, rogletimide, safingol, safingol hydrochloride, semustine, Simtra Zen, sparfosate sodium, sparsomycin, spirogermanium hydrochloride, spiromustine, spiroplatin, streptonigrin, streptozocin, sulofenur, tallysomycin, tecogalan sodium, tegafur, teroxantrone hydrochloride, temoporfin, teniposide, teroxylon, testolactone, thiamiprine, thioguanine, thiotepa, tiazofurin, tirapazamine, toremifene citrate, trestrone acetate, triciribine phosphate, trimetre Other anticancer drugs include, but are not limited to, 20-epi-1,25-dihydroxyvitamin D3, 5-ethynyluracil, abiraterone, aclarubicin, acylfulvene, adecipenol, adzelesin, aldesleukin, ALL-TK antagonists, altretamine, ambamustine, amidox, amifostine, aminolevulinic acid,Amrubicin, amsacrine, anagrelide, anastrozole, andrographolide, angiogenesis inhibitor, antagonist D, antagonist G, antarelix, anti-dorsalizing morphogenetic protein-1, antiandrogen, prostate carcinoma, antiestrogenic, antineoplastic, antisense oligonucleotide, aphidicolin glycinate, apoptosis gene modulator, apoptosis regulator, apurinic acid, ara-CDP-DL-PTBA, arginine deaminase, asulaculin, atamestane, atlimustine, axinastatin 1, axinastatin 2, axinastatin 3, azasetron, azatoxin, azatyrosine, baccatin III derivative, balanol, batimastat, BCR / ABL antagonist Nist, benzochlorin, benzoylstaurosporine, beta-lactam derivatives, beta-arretin, betaclamicin B, betulinic acid, bFGF inhibitors, bicalutamide, bisantrene, bisaziridinylspermine, bisnafide, bistratin A, bizelesin, brefulate, bropirimine, budotitanium, buthionine sulfoximine, calcipotriol, calphostin C, camptothecin derivatives, canarypox IL-2, capecitabine, carboxamido-amino-triazole, carboxyamidotriazole, CaRest M3, CARN 700, cartilage-derived inhibitor, carzelesin, casein kinase inhibitor (ICOS), castanospermine, cecropin B, cetrorelix, chlorin, chloroquinoxaline sulfonamide, cicaprost, cis-porphyrin, cladribine, clomiphene analogue, clotrimazole, colismycin A, colismycin B, combretastatin A4, combretastatin analogue, conagenin, clambecidin 816, crisnatol, crisnatol Cryptophycin 8, cryptophycin A derivative, curacin A, cyclopentaanthraquinone, cycloplatam, sipemycin, cytarabine ocfosfate, cytolytic factor, cytostatin, dacliximab, decitabine, dehydrodidemnin B, deslorelin, dexamethasone, dexphosphamide, dexrazoxane, dexiverapamil, diaziquone, didemnin B, didox, diethylnorspermine, dihydro-5-azacytidine,9-dihydrotaxol, dioxamycin, diphenylspiromustine, docetaxel, docosanol, dolasetron, doxifluridine, droloxifene, dronabinol, duocarmycin SA, ebselen, ecomustine, edelfosine, edrecolomab, eflornithine, elemene, emitefur, epirubicin, epristeride, estramustine analogues, estrogen agonists, estrogen antagonists, etanidazole, etoposide phosphate, exemestane, fadrozole, fazarabine, fenretinide, filgra Stim, finasteride, flavopiridol, flezelastine, fluasterone, fludarabine, fluorodaunornithine hydrochloride, forfenimex, formestane, fostriecin, fotemustine, gadolinium texaphyrin, gallium nitrate, gallocitabine, ganirelix, gelatinase inhibitors, gemcitabine, glutathione inhibitors, hepsulfam, heregulin, hexamethylene bisacetamide, hypericin, ibandronic acid, idarubicin, idoxifene, idramantone, ilmofosine, ilomastat, imidazoacridone, imiki Mod, immune stimulating peptides, insulin-like growth factor-1 receptor inhibitors, interferon agonists, interferons, interleukins, iobenguane, iododoxorubicin, 4-ipomeanol, ilopract, irsogladine, isobengazole, isohomohalichondrin B, itasetron, jasplakinolide, kahalalide F, lamellarin-N triacetate, lanreotide, leinamycin, lenograstim, lentinan sulfate, leptolstatin, letrozole, leukemia inhibitory factor, leukocyte alpha interferon, leuprolide + es Trogen + progesterone, leuprorelin, levamisole, liarozole, linear polyamine analogues, lipophilic disaccharide peptides, lipophilic platinum compounds, lisoclinamide 7, lobaplatin, lombricine, lometrexol, lonidamine, losoxantrone, lovastatin, loxoribine, lutetium texaphyrin, lisofylline, cytolytic peptides, maytansine, mannostatin A, marimastat, massoprocol, maspin, matrilysin inhibitors, matrix metalloproteinase inhibitors, menogaril, mervalone, meterelin,Methioninase, metoclopramide, MIF inhibitors, mifepristone, miltefosine, millimostim, mismatched double-stranded RNA, mitoguazone, mitolactol, mitomycin analogs, mitonafide, mitotoxin fibroblast growth factor-saporin, mitoxantrone, mofalotene, molgramostim, monoclonal antibodies, human chorionic gonadotropin, monophosphoryl lipid A + myobacterial cell wall sk, mopidamol, multidrug resistance gene inhibitors, multi-tumor suppressor 1-based therapy, mustard anticancer drugs, micaperoxide B, mycobacterial Cobacterial cell wall extract, myriaporone, N-acetyldinaline, N-substituted benzamides, nafarelin, nagressip, naloxone + pentazocine, napavine, naphterpine, nartograstim, nedaplatin, nemorubicin, neridronic acid, neutral endopeptidase, nilutamide, nisamycin, nitric oxide modulators, nitroxide antioxidants, nitrulline, O6-benzylguanine, octreotide, oxenone, oligonucleotides, onapristone, ondansetron, oracin, oral cytokine inducers Inducer, ormaplatin, osaterone, oxaliplatin, oxaunomycin, paclitaxel, paclitaxel analogues, paclitaxel derivatives, paclitaxel amine, palmitoylrhizoxin, pamidronate, panaxytriol, panomyphen, parabactin, pazelliptin, pegaspargase, perdecin, pentosan polysulfate sodium, pentostatin, pentrolozole, perflubron, perfosfamide, perillyl alcohol, phenazinomycin, phenylacetic acid esters, phosphatase inhibitors, picibanil, pilocaloride Pine, pirarubicin, piritrexim, prasetin A, prasetin B, plasminogen activator inhibitors, platinum complexes, platinum compounds, platinum-triamine complexes, porfimer sodium, porfiromycin, prednisone, propyl bis-acridone, prostaglandin J2, proteasome inhibitors, protein A-based immunomodulators, protein kinase C inhibitors, microalgae protein kinase C inhibitors, protein tyrosine phosphatase inhibitors, purine nucleoside phosphorylase inhibitors, purpurins, pyrazoloacridines,Pyridoxylated hemoglobin polyoxyethylene conjugates, raf antagonists, raltitrexed, ramosetron, ras farnesyl protein transferase inhibitors, ras inhibitors, ras-GAP inhibitors, demethylated reteriptin, rhenium Re186 etidronate, rhizoxin, ribozyme, RII retinamide, logretimide, rohitukin, , Romurtide, Roquinimex, Rubiginone B1, Ruboxil, Safingol, Saitopine, SarCNU, Sarcophytol A, Sargramostim, Sdi1 mimic, Semustine, Senescence derived inhibitor1, sense oligonucleotide, signal transduction inhibitor, signal transduction modulator, single-stranded antigen binding protein, schizofuran, sobuzoxane, borocaptan sodium, sodium phenylacetate, sorberol, somatomedin binding protein, sonermin, sparfosic acid, spicamycin D, spiromustine, splenopentin, spongistatin 1, squalamine, stem cell inhibitor, stem cell division inhibitor, stypamide, stromelysin inhibitor, sulfinosine, superactive vasoactive intestinal peptide antagonist, suragist, suramin, swainsonine, synthetic glycosaminoglycan, talimustine, tamoxifen methiodide, tauromustine, tazarotene, tecogalan sodium, tegafur, tellapyrylium, telomerase inhibitor, temoporfin, temozolomide, teniposide, tetrachlorodecaoxide, tetrazomine Taliblastine, thiocoraline, thrombopoietin, thrombopoietin mimic, thymalfasin, thymopoietin receptor agonist, thymotrinan, thyroid-stimulating hormone, ethyl etiopurpurin tin, tirapazamine, titanocene dichloride, topsentin, toremifene, totipotent stem cell factor, translation inhibitor, tretinoin, triacetyluridine, triciribine, trimetrexate, triptorelin, tropisetron, losteride, tyrosine kinase inhibitors, tyrphostins, UBC inhibitors, ubenimex, urogenital sinus-derived growth inhibitor, urokinase receptor antagonists, vapreotide, variolin B, erythrocyte gene therapy vector system, veraresol, veramine, verudine, verteporfin, vinorelbine, vinxartin, vitaxin, vorozole, zanoteron, zeniplatin, zilascorub, imilimumab, mirtazapine, BrUOG 278, BrUOG 292, RAD0001, CT-011, forfirinox, tipifarnib, R115777, LDE225, calcitriol, AZD6244, AMG 655, AMG479, BKM120, mFOLFOX6, NC-6004, cetuximab, IM-C225, LGX818, MEK162, BBI608, MEDI4736, vemurafenib, ipilimumab, ivolumab, nivolumab, panobinostat, leflunomide, CEP-32496, alemtuzumab, bevacizumab, ofatumumab, panitumumab, pembrolizumab, rituximab, trastuzumab, STAT3 inhibitors (e.g., STA-21, LLL-3, LLL12, XZH-5, S31-201, SF-1066, SF-1087, STX-0119, cryptotamycin, anti-inflammatory drugs include, but are not limited to, phencinone, curcumin, diferuloylmethane, FLLL11, FLLL12, FLLL32, FLLL62, C3, C30, C188, C188-9, LY5, OPB-31121, pyrimethamine, OPB-51602, AZD9150, etc.), hypoxia-inducible factor 1 (HIF-1) inhibitors (e.g., LW6, digoxin, laurenediterpenol, PX-478, RX-0047, vitexin, KC7F2, YC-1, etc.), zinostatin stimalamer, Lynparza (olaparib), talazoparib, niraparib, and rucaparib.

[0280] In a non-limiting example, the compounds of the invention can be used in combination with one or more therapeutic agents (or salts, solvates or prodrugs thereof).

[0281] In certain embodiments, the compounds of the invention can be administered to a subject in conjunction with (e.g., before, simultaneously with, or after) any number of relevant therapeutic modalities, including chemotherapy, radiation therapy, immunosuppressants such as cyclosporine, azathioprine, methotrexate, mycophenolate, and FK506, antibodies or other immunoablative agents such as CAM PATH, anti-CD3 antibodies or other antibody therapies, cytoxin, fludarabine, cyclosporine, FK506, rapamycin, mycophenolic acid, steroids, FR901228, cytokines, and irradiation. These drugs inhibit the calcium-dependent phosphatase calcineurin (cyclosporine and FK506) or inhibit p70S6 kinase (rapamycin), which is important in growth factor-induced signal transduction (Liu et al., Cell 66:807-815, 1991; Henderson et al., Immun. 73:316-321, 1991; Bierer et al., Curr. Opin. Immun. 5:763-773, 1993). In a further embodiment, the compounds of the invention are administered to patients in conjunction with (e.g., before, concurrently with, or after) T-cell depletion therapy using either bone marrow transplantation, chemotherapeutic agents such as fludarabine, external beam radiation therapy (XRT), cyclophosphamide, or antibodies such as OKT3 or CAMPATH. In another embodiment, the compounds of the invention are administered after B-cell depletion therapy with an agent reactive with CD20, e.g., Rituxan. In another embodiment, the compounds of the present invention are administered in combination with other drugs such as ospemifene, tamoxifen, raloxifene, or ICI 182,780 and RU 58668. Tamoxifen and raloxifene can act as partial antiestrogens, while drugs such as ICI 182,780 and RU 58668 can act as full antiestrogens. In another embodiment, the compounds of the present invention are administered in combination with an aromatase inhibitor. Non-limiting examples of aromatase inhibitors include exemestane, letrozole, and anastrozole. In one embodiment, the therapeutic agent is gemcitabine.

[0282] In certain embodiments, a compound of the invention can be administered to a subject in conjunction with (e.g., before, simultaneously with, or after) an anti-inflammatory agent selected from the group consisting of nonsteroidal agents ("NSAIDS") such as salicylates (e.g., salsalate, mesalamine, diflunisal, choline magnesium trisalicylate), diclofenac, diflunisal, etodolac, fenoprofen, flurbiprofen, ibuprofen, indomethacin, mefenamic acid, nabumetone, naproxen, piroxicam, phenylbutazone, ketoprofen, S-ketoprofen, ketorolac tromethamine, sulindac, tolmetin). Other anti-inflammatory agents include steroids such as beclomethasone, betamethasone, cortisone, dexamethasone, fluocinolone, flunisolide, fluticasone propionate, fluorinated corticoids, triamcinolone diacetate, hydrocortisone, prednisolone, methylprednisolone, and prednisone. Immunosuppressants (e.g., corticosteroids, cyclosporine), antihistamines and decongestants (e.g., astemizole (histamine I / II receptor antagonist), azatidine, brompheniramine, clemastine, chlorpheniramine, cromolyn, cyproheptadine, diphenylimidazole, diphenhydramine hydrochloride, hydroxyzine, glycyrrhetinic acid, homochlorocyclidine hydrochloride, ketotifen, loratadine, naphazoline, phenindamine, pheniramine, promethazine, terfenadine, trimeprazine, tripelennamine, tranilast, and the decongestants phenylpropanolamine and pseudoephedrine. In one embodiment, the therapeutic agent is a nonsteroidal anti-inflammatory drug (NSAID), as will be understood by those skilled in the art.

[0283] The synergistic effect can be achieved by appropriate methods, e.g., Sigmoid-E maxThe drug effect can be calculated using the concentration-effect curve, the isobologram curve, and the combination coefficient curve, respectively. Each of the above-mentioned formulas can be applied to experimental data to generate corresponding graphs to aid in evaluating the effect of drug combinations. The corresponding graphs associated with the above-mentioned formulas are the concentration-effect curve, the isobologram curve, and the combination coefficient curve, respectively.

[0284] In certain aspects, the compound of Formula (I) can be administered to a subject along with a cancer drug that targets DNA repair factors (i.e., PARP1, PARG, ATM, ATR, DNApk, RAD51, CHK1, WEE1, topoisomerase I, topoisomerase II) and / or acts as a genotoxic agent (i.e., chemotherapy and radiation / radiotherapy, proton therapy) to induce DNA damage. In some embodiments, the cancer drug that targets DNA repair factors is one or more selected from the group consisting of DNA damaging agents, platinum agents, DNA damage response inhibitors, ATR inhibitors, WEE1 inhibitors, NDA-PK inhibitors, and ATM inhibitors. The compounds of Formula I are particularly useful as radiosensitizers or chemosensitizers and can act synergistically with PARP inhibitors (i.e., olaparib, niraparib, talazoparib, rucaparib) and topoisomerase inhibitors (etoposide, camptothecin, toptecan, doxorubicin, daunorubicin) and ATR inhibitors and DNApk inhibitors.

[0285] Administration / Dosage / Formulation The administration regimen may affect what constitutes an effective amount. The therapeutic formulation may be administered to a subject either before or after the onset of cancer. Furthermore, several divided doses may be administered daily or continuously, or the dose may be continuously infused or bolus injected. Furthermore, the dosage of the therapeutic formulation may be proportionally increased or decreased as indicated by the exigencies of the therapeutic or preventive situation.

[0286] The compositions of the present invention can be administered to a patient, such as a mammal (e.g., a human), at a dosage and for a duration effective to treat cancer in the patient, using known procedures. The effective amount of the therapeutic compound required to achieve a therapeutic effect can vary depending on factors such as the state of the patient's disease or disorder, the patient's age, sex, and weight, and the ability of the therapeutic compound to treat cancer in the patient. Dosage regimens can be adjusted to obtain optimal therapeutic efficacy. For example, several divided doses may be administered daily. In another example, the dose may be proportionally reduced as indicated by the exigencies of the therapeutic situation. A non-limiting example of an effective dose range for the therapeutic compounds of the present invention is from about 1 mg / kg to about 5,000 mg / kg of body weight per day. One of ordinary skill in the art would be able to evaluate the relevant factors and make the determination regarding the effective amount of the therapeutic compound without undue experimentation.

[0287] Actual dosage levels of the active ingredients in the pharmaceutical compositions of the present invention may be varied to obtain an amount of the active ingredient that is effective for a particular patient, composition, and mode of administration to achieve the desired therapeutic response without causing undue adverse side effects to the patient.

[0288] In particular, the selected dose level will depend on a variety of factors, including the activity of the particular compound used, the time of administration, the rate of excretion of the compound, the duration of treatment, other drugs, compounds or substances used in combination with the compound, the age, sex, weight, condition, general health and previous medical history of the patient being treated, and similar factors known in the medical arts.

[0289] A medical professional, e.g., a physician or veterinarian, having ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required. For example, the physician or veterinarian can start dosages of the compounds of the invention in the pharmaceutical composition at levels lower than those required to achieve the desired therapeutic effect, and then increase the dosage over time until the desired effect is achieved.

[0290] In certain embodiments, it is advantageous to formulate the composition into a unit dosage form for ease of administration and uniformity of dosage.As used herein, "dosage unit form" refers to a physically discrete unit containing a predetermined amount of a therapeutic compound calculated to produce a desired therapeutic effect together with the necessary pharmaceutical vehicle.The dosage unit form of the present invention can be selected based on (a) the unique characteristics of the therapeutic compound and the specific therapeutic effect to be achieved, and (b) the limitations inherent in the technical field of compounding / formulating such therapeutic compounds for the treatment of cancer in patients.

[0291] In one embodiment, the compositions of the invention are formulated using one or more pharmaceutically acceptable excipients or carriers. In one embodiment, the pharmaceutical compositions of the invention comprise a therapeutically effective amount of a compound of the invention and a pharmaceutically acceptable carrier.

[0292] The carrier may be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol), vegetable oils, and suitable mixtures thereof. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants. The action of microorganisms can be prevented by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In some embodiments, it is useful to include isotonic agents, for example, sugars, sodium chloride, or polyalcohols such as mannitol or sorbitol, in the composition. Prolonged absorption of injectable compositions can be achieved by including in the composition an agent that delays absorption, for example, aluminum monostearate or gelatin. In one embodiment, the pharmaceutically acceptable carrier is DMSO, alone or in combination with other carriers.

[0293] The therapeutically effective amount or dose of the compound of the present invention depends on the age, sex, and weight of the patient, the patient's current medical condition, and the severity of the cancer being treated. Those skilled in the art will be able to determine the appropriate dose depending on these and other factors.

[0294] Doses may be administered in a single dose or in multiple doses, e.g., 1 to 4 or more times per day. When multiple doses are used, the doses may be the same or different. For example, a 1 mg dose per day may be administered as two 0.5 mg doses, with about a 12 hour interval between doses.

[0295] The dosage of the compound of the present invention is about 1 μg to about 10,000 mg, about 20 μg to about 9,500 mg, about 40 μg to about 9,000 mg, about 75 μg to about 8,500 mg, about 150 μg to about 7,500 mg, about 200 μg to about 7,000 mg, about 3,050 μg to about 6,000 mg, about 500 μg to about 5,000 mg, about 750 μg to about 4,000 mg, about 1 mg to about 3,000 mg, about 2,000 μg to about 5,000 mg, about 3,000 μg to about 6,000 mg, about 4,000 μg to about 5,000 mg, about 5,000 μg to about 6,000 mg, about 2,000 μg to about 5,000 mg, about 3,000 μg to about 6,000 mg, about 2,000 μg to about 5,000 mg, about 2 ...6,000 mg, about 2,000 μg to about 6 mg, about 10 mg to about 2,500 mg, about 20 mg to about 2,000 mg, about 25 mg to about 1,500 mg, about 30 mg to about 1,000 mg, about 40 mg to about 900 mg, about 50 mg to about 800 mg, about 60 mg to about 750 mg, about 70 mg to about 600 mg, about 80 mg to about 500 mg, and any and all whole or partial increments therebetween.

[0296] In some embodiments, the dosage of the compound of the invention is from about 1 mg to about 2,500 mg. In some embodiments, the dosage of the compound of the invention used in the compositions described herein is less than about 10,000 mg, or less than about 8,000 mg, or less than about 6,000 mg, or less than about 5,000 mg, or less than about 3,000 mg, or less than about 2,000 mg, or less than about 1,000 mg, or less than about 500 mg, or less than about 200 mg, or less than about 50 mg. Similarly, in some embodiments, the dosage of a second compound described elsewhere herein is less than about 1,000 mg, or less than about 800 mg, or less than about 600 mg, or less than about 500 mg, or less than about 400 mg, or less than about 300 mg, or less than about 200 mg, or less than about 100 mg, or less than about 50 mg, or less than about 40 mg, or less than about 30 mg, or less than about 25 mg, or less than about 20 mg, or less than about 15 mg, or less than about 10 mg, or less than about 5 mg, or less than about 2 mg, or less than about 1 mg, or less than about 0.5 mg, and any and all whole or partial increments thereof.

[0297] The compounds for use in the methods of the present invention can be formulated in unit dosage forms. The term "unit dosage form" refers to a physically discrete unit suitable as a single dosage form for a patient receiving treatment, each unit containing a predetermined amount of active substance calculated to produce a desired therapeutic effect, optionally in combination with a suitable pharmaceutical carrier. The unit dosage form may be for a single daily dose or one of multiple daily doses (e.g., about 1 to 4 or more times per day). When multiple daily doses are used, the unit dosage form may be the same or different for each dose.

[0298] In one embodiment, the compositions of the present invention are administered to a patient from about 1 to about 5 or more times per day. In various embodiments, the compositions of the present invention are administered to a patient from 1 to 7 times per day, 1 to 7 times every 2 days, 1 to 7 times every 3 days, 1 to 7 times weekly, 1 to 7 times every 2 weeks, and 1 to 7 times monthly. It will be readily apparent to those skilled in the art that the frequency of administration of the various combination compositions of the present invention will vary between individuals depending on many factors, including, but not limited to, age, the disease or disorder being treated, the severity of the disease or disorder being treated, gender, overall health, and other factors. Therefore, the present invention should not be construed as limited to any particular dosing regimen, and the precise dosage and composition to be administered to any patient will be determined by a medical professional, taking into account all other factors relevant to the patient.

[0299] If the patient's condition improves, at the physician's discretion, administration of the inhibitor of the present invention is optionally continued, or the administered dose of drug is temporarily reduced or temporarily discontinued for a period of a specified length (i.e., a "drug holiday"). The length of the drug holiday optionally varies from 2 days to 1 year, and includes, by way of example only, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, 35 days, 50 days, 70 days, 100 days, 120 days, 150 days, 180 days, 200 days, 250 days, 280 days, 300 days, 320 days, 350 days, or 365 days. Dose reductions during drug holidays include 10% to 100%, by way of example only, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%.

[0300] After improvement of the patient's condition occurs, a maintenance dose is administered as needed. Thereafter, the dosage or frequency of administration, or both, can be reduced to a level at which improvement in the disease is maintained. In some embodiments, patients may require intermittent treatment on a long-term basis or upon recurrence of the disease or disorder.

[0301] The toxicity and therapeutic efficacy of such treatment regimens are optionally determined in cell cultures or experimental animals, and the LD 50 (lethal dose for 50% of the population) and ED 50 These include, but are not limited to, determining the LD (the dose that is therapeutically effective in 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index, and the LD 50 and ED 50 The data obtained from cell culture assays and animal studies are optionally used in formulating a range of dosage for human use. The dosage of such compounds is preferably at an ED that produces minimal toxicity. 50 The dosage optionally varies within this range depending upon the dosage form used and the route of administration.

[0302] In one embodiment, the present invention is directed to a packaged pharmaceutical composition comprising a container holding a therapeutically effective amount of a compound of the invention, alone or in combination with a second pharmaceutical agent, and instructions for using the compound to treat or prevent cancer in a patient.

[0303] The formulations may be used in admixture with conventional excipients, i.e., pharmaceutically acceptable organic or inorganic carrier substances suitable for oral, parenteral, nasal, intravenous, subcutaneous, enteral, or any other suitable mode of administration known in the art. Pharmaceutical preparations may be sterilized and, if desired, may be mixed with auxiliary substances, such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic buffering agents, coloring agents, and / or aromatic substances. They may also, if desired, be combined with other active agents, such as other analgesics.

[0304] Optional routes of administration of the compositions of the invention include oral, nasal, rectal, intravaginal, parenteral, buccal, sublingual, or topical. The compounds for use in the invention can be formulated for administration by any suitable route, such as oral or parenteral, for example, transdermal, transmucosal (e.g., sublingual, lingual, (trans)buccal, (trans)urethral, ​​vaginal (e.g., vaginal and perivaginal), (intra)nasal, and (trans)rectal), intravesical, intrapulmonary, intraduodenal, intragastric, intrathecal, subcutaneous, intramuscular, intradermal, intraarterial, intravenous, intrabronchial, inhalation, and topical administration.

[0305] Suitable compositions and dosage forms include, for example, tablets, capsules, caplets, pills, gel capsules, troches, dispersions, suspensions, liquids, syrups, granules, beads, transdermal patches, gels, powders, pellets, magmas, lozenges, creams, pastes, plasters, lotions, discs, suppositories, liquid sprays for nasal or oral administration, dry powder or aerosolized formulations for inhalation, compositions and formulations for intravesical administration, etc. It is understood that the formulations and compositions useful in the present invention are not limited to the specific formulations and compositions described herein.

[0306] Oral administration Suitable forms for oral administration include tablets, dragees, liquids, drops, suppositories, or capsules, caplets, and gel capsules. Compositions formulated for oral use can be prepared according to any method known in the art, and such compositions may contain one or more agents selected from the group consisting of inert, non-toxic pharmaceutical additives suitable for tablet manufacture. Examples of such additives include inert diluents such as lactose, granulating and disintegrating agents such as cornstarch, binders such as starch, and lubricants such as magnesium stearate. Tablets may be uncoated or may be coated by known techniques for elegance or to delay the release of the active ingredient. Formulations for oral use may also be presented as hard gelatin capsules in which the active ingredient is mixed with an inert diluent.

[0307] For oral administration, the compounds of the present invention may be in the form of tablets or capsules prepared by conventional means with pharmaceutically acceptable additives, such as binders (e.g., polyvinylpyrrolidone, hydroxypropyl cellulose, or hydroxypropylmethylcellulose), fillers (e.g., corn starch, lactose, microcrystalline cellulose, or calcium phosphate), lubricants (e.g., magnesium stearate, talc, or silica), disintegrants (e.g., sodium starch glycolate), wetting agents (e.g., sodium lauryl sulfate), and the like. If desired, tablets may be coated using a suitable method and coating material, such as the OPADRY™ film coating system (e.g., OPADRY™ OY type, OYC type, organic enteric-coated OY-P type, aqueous enteric-coated OY-A type, OY-PM type, and OPADRY™ White, 32K18400), available from Colorcon (West Point, Pennsylvania). Liquid preparations for oral administration may be in the form of solutions, syrups, or suspensions. Liquid preparations can be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, methylcellulose or hydrogenated edible fats), emulsifying agents (e.g., lecithin or acacia), non-aqueous vehicles (e.g., almond oil, oily esters or ethyl alcohol), preservatives (e.g., methyl or propyl p-hydroxybenzoate or sorbic acid), and the like.

[0308] Granulation techniques for modifying starting powders of active ingredients or other particulate materials are known in the pharmaceutical field. The powder is typically mixed with a binder material to form larger, permanent, free-flowing aggregates or granules, called "granulations." For example, "wet" granulation methods using solvents are generally characterized by combining the powder with a binder material, wetting it with water or an organic solvent under conditions that form a wet granulation mass, and then evaporating the solvent.

[0309] Melt granulation essentially uses materials that are solid or semi-solid at room temperature (i.e., have a relatively low softening point or melting point range) to facilitate the granulation of powdered or other materials without the addition of water or other liquid vehicles. When the low-melting solid is heated to a temperature in its melting point range, it liquefies and acts as a binder or granulation medium. The liquefied solid spreads over the surfaces of the powdered materials it contacts and, upon cooling, forms a solid granular mass that binds the original materials together. The resulting molten granules may then be fed into a tablet press or encapsulated to prepare an oral dosage form. Melt granulation improves the dissolution rate and bioavailability of the active substance (i.e., drug) by forming a solid dispersion or solid solution.

[0310] U.S. Patent No. 5,169,645 discloses directly compressible wax-containing granules with improved flow properties. The granules are obtained by mixing the wax with certain flow-improving additives in the melt, then cooling the mixture and granulating. In certain embodiments, in the melt combination of the wax and the additive, only the wax itself melts, and in other cases, both the wax and the additive melt.

[0311] The present invention also includes multi-layer tablets comprising a layer that provides delayed release of one or more compounds of the present invention and a further layer that provides immediate release of a drug for the treatment of a G-protein receptor-related disease or disorder. A wax / pH-sensitive polymer mixture can be used to obtain a gastric insoluble composition in which the active ingredient is encapsulated and ensures its delayed release.

[0312] Parenteral administration For parenteral administration, the compounds of the invention can be formulated for injection or infusion, e.g., intravenous, intramuscular, or subcutaneous injection or infusion, or for administration in a bolus dose and / or continuous infusion. Suspensions, solutions, or emulsions in oily or aqueous vehicles, optionally containing other formulatory agents such as suspending, stabilizing, and / or dispersing agents, can be used.

[0313] Further dosage forms Additional dosage forms of the present invention include those described in U.S. Patent Nos. 6,340,475, 6,488,962, 6,451,808, 5,972,389, 5,582,837, and 5,007,790. Additional dosage forms of the present invention also include those described in U.S. Patent Application Nos. 20030147952, 20030104062, 20030104053, 20030044466, 20030039688, and 20020051820. Further dosage forms of the present invention also include those described in PCT applications WO03 / 35041, WO03 / 35040, WO03 / 35029, WO03 / 35177, WO03 / 35039, WO02 / 96404, WO02 / 32416, WO01 / 97783, WO01 / 56544, WO01 / 32217, WO98 / 55107, WO98 / 11879, WO97 / 47285, WO93 / 18755 and WO90 / 11757.

[0314] Controlled-Release Formulations and Drug Delivery Systems In one embodiment, the formulations of the present invention may be short-acting, fast-acting, and controlled, including, but not limited to, sustained-release, delayed-release, and pulsed-release formulations.

[0315] The term "sustained release" refers to a drug formulation that provides sustained release of a drug over an extended period of time and can, although not necessarily, provide a substantially constant blood concentration of the drug over an extended period of time. The period may be a day, a week, a month, or longer, and must be longer than the release of the same amount of drug administered in bolus form. The term "delayed release" is used herein in its conventional sense to refer to a drug formulation that provides an initial release of drug with some delay after drug administration, including, but not necessarily, from about 10 minutes to about 12 hours.

[0316] For sustained release, the compounds can be formulated with a suitable polymer or hydrophobic material that provides sustained release properties to the compound. Thus, the compounds for use in the methods of the invention may be administered, for example, in the form of microparticles by injection or in the form of wafers or discs by implantation.

[0317] In one embodiment of the present invention, the compounds of the invention are administered to a patient, alone or in combination with another pharmaceutical agent, using a sustained release formulation.

[0318] The term pulsatile release refers to a drug formulation that provides release of the drug in a manner that results in a pulsatile plasma profile of the drug after drug administration.

[0319] The term immediate release refers to a drug formulation that provides release of the drug immediately after drug administration.

[0320] As used herein, a short period of time refers to any time up to, including, about 8 hours, about 7 hours, about 6 hours, about 5 hours, about 4 hours, about 3 hours, about 2 hours, about 1 hour, about 40 minutes, about 20 minutes, or about 10 minutes after drug administration, and any or all whole or partial increments thereof.

[0321] As used herein, immediate action refers to any time up to, including, about 8 hours, about 7 hours, about 6 hours, about 5 hours, about 4 hours, about 3 hours, about 2 hours, about 1 hour, about 40 minutes, about 20 minutes, or about 10 minutes after drug administration, and any and all whole or partial increments thereof.

[0322] Therapeutic utility The compounds of the present invention, subgroups and examples thereof, are inhibitors of Polq polymerase activity and may be useful in the prevention or treatment of the disease states or conditions described herein. Furthermore, the compounds of the present invention and subgroups thereof are useful in the prevention or treatment of Polq-mediated diseases or conditions.

[0323] References to the prophylaxis or prevention or treatment of a disease state or condition such as cancer include within their scope the alleviation or reduction of the incidence of cancer. Thus, for example, the compounds of the invention are believed to be useful in alleviating or reducing the incidence of cancer.

[0324] In one embodiment, compounds of Formula I (referred to herein as Polq inhibitors (Polqi)) are expected to exhibit preferential killing of BRCA-deficient cells, or alternatively, cancer cells defective in homologous recombination repair (HDR). This is due to the fact that BRCA-deficient ovarian cancer cells have been shown to depend on Polq for survival in the presence of genotoxic agents. This synthetic lethal relationship between Polq and HDR has been further demonstrated in mouse models. Most importantly, the DNA synthesis activity of Polq has been shown to promote the survival of BRCA-deficient cells, strongly suggesting that pharmacological inhibition of the polymerase domain by the compounds provided herein will selectively kill BRCA-deficient cancer cells, including, but not limited to, cancers of prostate, breast, ovary, and pancreas origin.

[0325] Certain blood cancers, including but not limited to acute myeloid leukemia (AML), have been shown to have defective HDR as a result of the effects of certain genetic mutations (i.e., BCR-ABL) or due to certain treatment regimens.

[0326] In one embodiment, the Polqi presented herein may also be particularly effective in AML or other blood cancers.

[0327] Several factors important for HDR may be defective and / or downregulated in cancer cells, including, but not limited to, Mrel 1, Rad50, Nbs1, CtIP, Exo1, PALB2, BARD1, RAD51B, RAD51C, RAD51D, XRCC2, and XRCC3. Thus, in one embodiment, cancer cells in which one or more of these HDR factors are defective or downregulated are sensitive to the Polq inhibitors described herein.

[0328] In one embodiment, the HDR gene is selected from any of ATM, ATR, BRCA1, BRCA2, BARD1, RAD51C, RAD50, CHEK1, CHEK2, FANCA, FANCB, FANCC, FANCD2, FANCE, FANCF, FANCG, FANCI, FANCL, FANCM, PALB2 (FANCN), FANCP (BTBD12), ERCC4 (FANCQ), PTEN, CDK12, MRE11, NBS1, NBN, CLASPIN, BLM, WRN, SMARCA2, SMARCA4, LIG1, RPA1, RPA2, BRIP1, and PTEN.

[0329] Furthermore, inactivation of Polq in combination with the DDR factors RAD54 or FANCJ also results in synthetic lethality. Thus, in one embodiment, the Polqi described herein is expected to preferentially kill cancer cells that have a deficiency or downregulation of RAD54 and / or FANCJ.

[0330] Furthermore, recent studies have demonstrated that inactivation of Polq in combination with inhibition of the DDR factor ATR also significantly reduces cell proliferation. Semisynthetic lethality between Polq and ATM has also been identified in previous studies. Thus, in one embodiment, the Polqi described herein is expected to exhibit preferential killing of cancer cells in which ATR or ATM DDR factors are deficient or downregulated. In one embodiment, the Polqi described herein is also expected to exhibit synergistic or additive antiproliferative effects when combined with ATR inhibitors or ATM inhibitors. In another embodiment, the Polqi described herein is also expected to exhibit effective killing of cancer cells exhibiting replication stress, particularly when combined with other anticancer drugs that exacerbate replication stress, including, but not limited to, gemcitabine, ATR inhibitors, cytarabine, topoisomerase inhibitors (i.e., etoposide), cisplatin, and the like.

[0331] Polq has also been shown to confer resistance to ionizing radiation (IR), bleomycin, cisplatin, mitomycin C, and topoisomerase inhibitors (etoposide, camptothecin). Thus, in another embodiment, the Polqi described herein is expected to promote the sensitivity of cancer cells to a variety of anti-cancer drugs, including, but not limited to, IR, bleomycin, cisplatin, mitomycin C, and topoisomerase inhibitors.

[0332] Both PARP inhibitors (PARPi) and inactivation of Polq reduce the resistance of cancer cells to IR. Therefore, in another embodiment, combining a Polqi described herein with a PARPi is expected to sensitize cancer cells to IR and overcome the resistance of cancer cells to IR. Furthermore, suppression of Polq in combination with a DNApk inhibitor has been shown to sensitize cancer cells to IR. Therefore, in another embodiment, the Polqi described herein is expected to exhibit synergistic antiproliferative effects when combined with a DNApk inhibitor and IR or other anticancer agents that cause DNA double-strand breaks.

[0333] It has also been shown that suppression of Polq expression confers cellular sensitivity to PARP inhibition in HDR-deficient cancer cells. Thus, in one embodiment, the Polqi described herein is expected to act synergistically with PARP inhibitors (PARPi), particularly in HDR-deficient cells. In one embodiment, Polqi in combination with PARPi, including but not limited to Lynparza (olaparib), talazoparib, niraparib, and rucaparib, is expected to enhance the effects of PARPi in solid tumors and hematological malignancies. In one embodiment, the Polqi described herein is expected to suppress cancer cell resistance to PARPi when combined with PARPi.

[0334] In one embodiment, Polqi as described herein is expected to induce synthetic lethality in cancer cells with deficient or suppressed expression of non-homologous end-joining NHEJ factors, such as LIG4 or KU70 / 80. In one embodiment, the non-homologous end-joining gene is selected from any one or more of LIG4, NHEJ1, POLL, POLM, PRKDC, XRCC4, XRCC5, XRCC6, and DCRRE1C. In a further aspect of the invention, there is provided a compound of formula (I) as defined herein for use in treating tumors with elevated levels of ligase IIIa, decreased levels of ligase IV, and increased dependency on MMEJ (altEJ) DSB repair.

[0335] Suppression of Polq expression enhances and reduces the off-target effects of genome engineering using CRISPR-Cas9 RNA-guided endonucleases, as described in WO2017 / 062754. Thus, in one embodiment, the Polqi described herein is expected to benefit CRISPR-Cas9-based genome engineering by reducing off-target effects, thereby improving the fidelity and safety of CRISPR-Cas9 RNA-guided genome engineering for therapeutic and basic research applications. In one embodiment, the Polqi described herein, when combined with a DNApk inhibitor, is expected to have an even greater effect on improving the fidelity and safety of CRISPR-Cas9 RNA-guided genome engineering for therapeutic and basic research applications. [Example]

[0336] Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, numerous equivalents to the specific procedures, embodiments, claims, and examples described herein. Such equivalents are considered to be within the scope of the present invention and are encompassed by the claims appended hereto. For example, it is understood that modifications of reaction conditions, including but not limited to reaction times, reaction sizes / volumes, and experimental reagents, e.g., solvents, catalysts, pressure, atmospheric conditions, e.g., nitrogen atmosphere, and reducing / oxidizing agents, using art-recognized substitutes and no more than routine experimentation, are within the scope of this application.

[0337] Whenever values ​​and ranges are provided herein, it is understood that all values ​​and ranges encompassed by those values ​​and ranges are intended to be encompassed within the scope of the present invention. Moreover, all values ​​that fall within these ranges, as well as the upper or lower limits of a range of values, are also contemplated by the application.

[0338] The following examples further illustrate aspects of the present invention, but do not in any way limit the teachings or disclosure of the present invention set forth herein.

[0339] Example 1 2-(3-(2-morpholinoethyl)-2-oxoimidazolidin-1-yl)-4,6-bis(trifluoromethyl)phenyl(4-fluorophenyl)(methyl)carbamate [ka]

[0340] Step 1: Synthesis of (4-fluorophenyl)(methyl)carbamic acid chloride [ka] To a solution of 4-fluoro-N-methylaniline (0.58 g, 4.66 mmol) and pyridine (0.73 g, 9.34 mmol) in dichloromethane (12 mL) at 0° C., triphosgene (0.69 g, 2.33 mmol) dissolved in dichloromethane (6 mL) was added dropwise under an inert atmosphere. The reaction was stirred at ambient temperature (room temperature) for 2 hours. The reaction mixture was diluted with 20 mL of dichloromethane and extracted with 20 mL of 1N HCl. The organic layer was separated, dried over anhydrous sodium sulfate, filtered, and concentrated to a solid under reduced pressure. 1 1H NMR(400MHz,CDCl3)δ 7.15(m,2H),7.04(m,2H),3.3(s,3H), MS(ESI):m / z 188.0[(M+H) + ].

[0341] Step 2: Synthesis of 2-iodo-4,6-bis(trifluoromethyl)phenol [ka] 2,4-Bis(trifluoromethyl)phenol (1.00 g, 4.35 mmol) in THF:HO (3:1, 24 mL) was dissolved in 0 mL of water under nitrogen in an ice bath. o The reaction mixture was cooled to 0°C. Iodine (1.18 g, 4.64 mmol) and Na2CO3 (491 mg, 4.64 mmol) were added sequentially. The ice bath was removed and the reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was then cooled to 0°C in an ice bath. o Cool to 0°C and quench with saturated aqueous sodium metabisulfite solution until all of the solution turns yellow. o The mixture was stirred at rt. The mixture was extracted with EtOAc (3X). The combined organic extracts were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography using a gradient solvent system of 0-10% ethyl acetate in hexanes to afford the title compound as a colorless crystalline solid (711 mg, 46%). 1 H NMR (400MHz, CDCl3) δ 8.10 (s, 1H), 7.82 (s, 1H), 6.15 (s, 1H).

[0342] Step 3: Synthesis of 2-iodo-4,6-bis(trifluoromethyl)phenyl(4-fluorophenyl)(methyl)carbamate [ka] 2-Iodo-4,6-bis(trifluoromethyl)phenol (570 mg, 1.60 mmol) and (4-fluorophenyl)(methyl)carbamic acid chloride (751 mg, 4.00 mmol) were dissolved in anhydrous pyridine (10 mL). The solution was stirred at 90° C. for 4 hours. The reaction was cooled to room temperature and concentrated. The residual solid was partitioned between EtOAc and 1N aqueous HCl. The aqueous phase was separated and extracted twice with EtOAc. The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography using a gradient solvent system of 0 to 20% ethyl acetate in hexane to afford the title compound as a yellow oil (683 mg, 84%). 1 H NMR(400MHz,CDCl3)δ 8.21-8.27(1H),7.84-7.92(1H),7.39(m,2H),7.12(m,2H),3.38-3.56(3H), ESIMS:m / z 508.0[(M+H) + ].

[0343] Step 4: Synthesis of 1-(2-morpholinoethyl)imidazolidin-2-one [ka] A solution of 1-(2-chloroethyl)-2-imidazolidinone (0.673 mmol, 100 mg) in morpholine (1.0 mL) was microwaved at 120° C. for 1 hour. The reaction was concentrated, and the residual solid was partially dissolved in dichloromethane. A basic ion exchange resin was added, and the mixture was stirred at room temperature for 1 hour. The resin was filtered off, and the filtrate was concentrated to give the title compound as a yellow solid (101 mg, 75%). 1H NMR(400MHz,CDCl3)δ 4.34(s,1H),3.73(s,4H),3.53(m,2H),3.42(m,2H),3.36(m,2H),2.54(s,6H),ESIMS:m / z 421.3[(2M+Na) + ].

[0344] Step 5: Synthesis of 2-(3-(2-morpholinoethyl)-2-oxoimidazolidin-1-yl)-4,6-bis(trifluoromethyl)phenyl(4-fluorophenyl)(methyl)carbamate [ka] 2-Iodo-4,6-bis(trifluoromethyl)phenyl(4-fluorophenyl)(methyl)carbamate (0.1972 mmol, 100 mg), 1-(2-morpholinoethyl)imidazolidin-2-one (0.3539 mmol, 70.5 mg), copper(I) iodide (0.0961 mmol, 18.3 mg), cesium fluoride (0.3995 mmol, 60.7 mg), N,N'-dimethylethylenediamine (0.1972 mmol, 21.2 μL), and anhydrous potassium carbonate powder (0.3641 mmol, 50.3 mg) were added to anhydrous 1,4-dioxane (3.0 mL) degassed under nitrogen. The resulting mixture was stirred at 90 °C overnight. The reaction was cooled to room temperature, diluted with methanol, and filtered. The clear filtrate was concentrated to give a semisolid. This was suspended in dichloromethane, filtered through a plug of Celite, and concentrated. The crude product was purified by silica gel column chromatography using a gradient solvent system of 0 to 10% methanol in ethyl acetate to give the title compound as a yellow oil (13.9 mg, 12%). 1 H NMR(400MHz,CDCl3)δ 7.66-8.02(2H),7.32(m,2H),7.09(m,2H),3.31-4.04(15H),2.54(m,4H), ESIMS:m / z 579.2[(M+H) + ].

[0345] Example 2 2-(3-(2-(4-acetylpiperazin-1-yl)ethyl)-2-oxoimidazolidin-1-yl)-4,6-bis(trifluoromethyl)phenyl(4-fluorophenyl)(methyl)carbamate [ka]

[0346] Step 1: Synthesis of 1-(2-(4-acetylpiperazin-1-yl)ethyl)imidazolidin-2-one [ka] A suspension of 1-(2-chloroethyl)-2-imidazolidinone (3.365 mmol, 500 mg), 1-acetylpiperazine (4.038 mmol, 518 mg), and powdered anhydrous potassium carbonate (4.038 mmol, 558 mg) in anhydrous dimethylacetamide (5 mL) was microwaved at 120 °C for 1 h. The solid was filtered off and washed with DMA. The clear filtrate was concentrated. The crude product was purified by silica gel column chromatography using a gradient solvent system of 0 to 100% solvent B (10% [2N NH in MeOH] in DCM) in solvent A (DCM) to afford the title compound as a pale orange crystalline solid (620 mg, 77%). 1 1H NMR(400MHz,DMSO-d6)δ 6.24(s,1H),3.35(m.5H),3.19(m,5H),2.36(m,6H),1.97(m,3H), ESIMS:m / z 241.2[(M+H) + ].

[0347] Step 2: Synthesis of 2-(3-(2-(4-acetylpiperazin-1-yl)ethyl)-2-oxoimidazolidin-1-yl)-4,6-bis(trifluoromethyl)phenyl(4-fluorophenyl)(methyl)carbamate [ka] 2-Iodo-4,6-bis(trifluoromethyl)phenyl(4-fluorophenyl)(methyl)carbamate (0.3944 mmol, 200 mg), 1-(2-(4-acetylpiperazin-1-yl)ethyl)imidazolidin-2-one (0.7078 mmol, 170 mg), copper(I) iodide (0.1922 mmol, 37 mg), cesium fluoride (0.7990 mmol, 121 mg), N,N'-dimethylethylenediamine (0.3944 mmol, 43 μL), and anhydrous potassium carbonate powder (0.7282 mmol, 101 mg) were added to anhydrous 1,4-dioxane (4.0 mL) degassed under nitrogen. The resulting suspension was stirred at 90 °C overnight. The reaction was cooled to room temperature, diluted with methanol, and filtered. The clear filtrate was concentrated to give a semi-solid. This was suspended in dichloromethane, filtered through a plug of Celite, and concentrated. The crude product was purified by silica gel column chromatography using a gradient solvent system of 0 to 100% (10% MeOH in EtOAc) in hexanes to elute side products. The solvent system was then changed to (10% [2N NH in MeOH] in DCM) to afford the title compound as a pale yellow glassy solid (25.6 mg, 10%).

[0348] 1 H NMR(400MHz,CDCl3)δ 7.66-8.04(2H),7.32(m,2H),7.09(m,2H),3.29-4.05(14H),2.32-2.84(5H),2.08(s,3H), ESIMS:m / z 620.2[(M+H) + ].

[0349] Example 3 2-(3-(2-(4-cyanopiperidin-1-yl)ethyl)-2-oxoimidazolidin-1-yl)-4,6-bis(trifluoromethyl)phenyl(4-fluorophenyl)(methyl)carbamate [ka]

[0350] Step 1: Synthesis of 1-(2-(2-oxoimidazolidin-1-yl)ethyl)piperidine-4-carbonitrile [ka] A suspension of 1-(2-chloroethyl)-2-imidazolidinone (3.365 mmol, 500 mg), piperidine-4-carbonitrile (4.038 mmol, 454 μL), and anhydrous potassium carbonate powder (4.038 mmol, 558 mg) in anhydrous dimethylacetamide (5 mL) was microwaved at 120 °C for 1 h. The solid was filtered off and washed with DMA. The clear filtrate was concentrated. The crude product was purified by silica gel column chromatography using a gradient solvent system of 0-10% MeOH in DCM to afford the title compound as an off-white solid (265 mg, 35%).

[0351] 1 H NMR(400MHz,DMSO-d6)δ 6.22(s,1H),3.34(m.2H),3.19(t,J=8.12Hz,2H),3.12(t,J=6.68Hz,2H),2.84(m,1H), 2.55(m,2H),2.36(t,J=6.68Hz,2H),2.27(m,2H),1.82(m,2H),1.66(m,2H),ESIMS:m / z 223.1[(M+H) + ].

[0352] Step 2: Synthesis of 2-(3-(2-(4-cyanopiperidin-1-yl)ethyl)-2-oxoimidazolidin-1-yl)-4,6-bis(trifluoromethyl)phenyl(4-fluorophenyl)(methyl)carbamate [ka] 2-Iodo-4,6-bis(trifluoromethyl)phenyl(4-fluorophenyl)(methyl)carbamate (0.3944 mmol, 200 mg), 1-(2-(2-oxoimidazolidin-1-yl)ethyl)piperidine-4-carbonitrile (0.7078 mmol, 157 mg), copper(I) iodide (0.192 mmol, 37 mg), cesium fluoride (0.7990 mmol, 121 mg), N,N'-dimethylethylenediamine (0.3944 mmol, 43 μL), and anhydrous potassium carbonate powder (0.7282 mmol, 101 mg) were added to anhydrous 1,4-dioxane (4.0 mL) degassed under nitrogen. The resulting suspension was stirred at 90 °C overnight. The reaction was cooled to room temperature, diluted with methanol, and filtered. The clear filtrate was concentrated to give a semi-solid. This was suspended in dichloromethane, filtered through a plug of Celite, and concentrated. The crude product was purified by silica gel column chromatography using a gradient solvent system of 0 to 100% (10% MeOH in EtOAc) in hexanes to give the title compound as a colorless oil (18.6 mg, 8%). 1 H NMR(400MHz,CDCl3)δ 7.66-8.04(2H),7.31(m.2H),7.09(m,2H),3.30-3.99(10H),2.25-2.96(7H),1.91(m,3H), ESIMS:m / z 602.2[(M+H) + ].

[0353] Example 4 2,4-Bis(trifluoromethyl)-6-(2-oxoimidazolidin-1-yl)phenyl(4-fluorophenyl)(methyl)carbamate [ka] 2-Iodo-4,6-bis(trifluoromethyl)phenyl(4-fluorophenyl)(methyl)carbamate (0.39 mmol, 200 mg), 2-imidazolidone (0.7 mmol, 64 mg), copper(I) iodide (0.19 mmol, 37 mg), cesium fluoride (0.79 mmol, 120 mg), N,N'-dimethylethylenediamine (0.39 mmol, 43 μL), and anhydrous potassium carbonate powder (0.72 mmol, 100 mg) were added to anhydrous 1,4-dioxane (16.0 mL) degassed under nitrogen. The resulting suspension was stirred at 90 °C overnight. The reaction was cooled to room temperature and concentrated to give a semi-solid. The crude product was purified by silica gel column chromatography using a gradient solvent system of 0 to 3% methanol in dichloromethane to give the title compound as an off-white solid. Repurification on a 20 x 20 cm silica gel 60GF254, 1 mm, PLC glass plate using 2% methanol in dichloromethane as eluent gave 28 mg of a white solid (28 mg, 15%).

[0354] 1 H NMR(500MHz)δ 8.39(m,2H),7.75(m,2H),7.54(m,2H),4.52(m,2H),4.32(m,2H),3.91(m,3H),ESIMS:m / z 465.05[(M+H) + ].

[0355] Example 5 2,4-Bis(trifluoromethyl)-6-(3-methyl-2-oxoimidazolidin-1-yl)phenyl(4-fluorophenyl)(methyl)carbamate [ka] 2-Iodo-4,6-bis(trifluoromethyl)phenyl(4-fluorophenyl)(methyl)carbamate (0.1972 mmol, 100 mg), 1-methyl-2-imidazolidinone (0.39 mmol, 39 mg), copper(I) iodide (0.0961 mmol, 18.3 mg), cesium fluoride (0.3995 mmol, 60.7 mg), N,N'-dimethylethylenediamine (0.1972 mmol, 21.2 μL), and anhydrous potassium carbonate powder (0.3641 mmol, 50.3 mg) were added to anhydrous 1,4-dioxane (5.0 mL) degassed under nitrogen. The resulting suspension was stirred at 90 °C overnight. The reaction was cooled to room temperature, filtered, and the filtrate was concentrated to give a semi-solid. The crude product was purified by silica gel column chromatography using a gradient solvent system of 0-100% ethyl acetate in hexanes to afford the title compound as a yellow oil (2 mg, 2%).

[0356] 1 H NMR(400MHz,CDCl3)δ 7.86-7.7(m,2H),7.32(m,2H),7.09(m,2H),3.70(m,2H),3.51(m,2H),3.45(d,J=44Hz,3H),2.92(s,3H),ESIMS:m / z 480.14[(M+H) + ].

[0357] Example 6 2,4-Bis(trifluoromethyl)-6-(3-(2-hydroxylethyl)-2-oxoimidazolidin-1-yl)phenyl(4-fluorophenyl)(methyl)carbamate [ka] 2-Iodo-4,6-bis(trifluoromethyl)phenyl(4-fluorophenyl)(methyl)carbamate (0.1972 mmol, 100 mg), 1-(2-hydroxyethyl-2-imidazolidinone (0.39 mmol, 51 mg), copper(I) iodide (0.0961 mmol, 18.3 mg), cesium fluoride (0.3995 mmol, 60.7 mg), N,N'-dimethylethylenediamine (0.1972 mmol, 21.2 μL) and anhydrous potassium carbonate powder (0.3641 mmol, 50.3 mg) were added to anhydrous 1,4-dioxane (5.0 mL) that had been degassed under nitrogen. The resulting suspension was stirred at 90 °C overnight. The reaction was cooled to room temperature, filtered, and the filtrate was concentrated to give a semi-solid. The crude product was purified by silica gel column chromatography using a gradient solvent system of 0 to 100% ethyl acetate in hexane to give the title compound as a yellow oil (11 mg, 11%).

[0358] 1 H NMR(400MHz,CDCl3)δ 7.81(m,2H),7.32(m,2H),7.09(m,2H),3.85(s,3H),3.70(s,1H),3.61(m,2H),3,47(m,4H),3.36(m,2H),ESIMS:m / z 510.48[(M+H) + ].

[0359] Example 7 2,4-Bis(trifluoromethyl)-6-(2-oxoimidazolidin-1-yl)phenyl(3-chloro-2,4-difluorophenyl)(methyl)carbamate [ka]

[0360] Step 1: Synthesis of (3-chloro-2,4-difluorophenyl)(methyl)carbamic acid chloride [ka] To a solution of 3-chloro-2,4-fluoro-N-methylaniline (0.827 g, 4.66 mmol) and pyridine (0.73 g, 9.34 mmol) in dichloromethane (12 mL) at 0° C., triphosgene (0.69 g, 2.33 mmol) dissolved in 6 mL of dichloromethane was added dropwise under an inert atmosphere. The reaction was stirred at ambient temperature (room temperature) for 2 hours. The reaction mixture was diluted with 20 mL of dichloromethane and extracted with 20 mL of 1N HCl. The organic layer was separated, dried over anhydrous sodium sulfate, filtered, and concentrated to a solid under reduced pressure.

[0361] ESIMS: m / z 240.09 [(M+H) + ].

[0362] Step 2: Synthesis of 2,4-bis(trifluoromethyl)-6-iodophenyl (2-chloro-3,4-difluorophenyl)(methyl)carbamate [ka] 2-Iodo-4,6-bis(trifluoromethyl)phenol (570 mg, 1.60 mmol) and (3-chloro-2,4-difluorophenyl)(methyl)carbamic acid chloride (300 mg, 0.84 mmol) were dissolved in anhydrous pyridine (5 mL). The solution was stirred at 90 °C for 4 h. The reaction was cooled to room temperature and concentrated. The residual solid was partitioned between EtOAc and 1N aqueous HCl. The aqueous phase was separated and extracted twice with EtOAc. The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography using a gradient solvent system of 0-20% ethyl acetate in hexane to give the title compound as a yellow oil (227 mg, 48%). ESIMS: m / z 560.21 [(M+H) + ].

[0363] Step 3: Synthesis of 2,4-bis(trifluoromethyl)-6-(2-oxoimidazolidin-1-yl)phenyl(3-chloro-2,4-difluorophenyl)(methyl)carbamate [ka] 2,4-Bis(trifluoromethyl)-6-iodophenyl (2-chloro-3,4-difluorophenyl)(methyl)carbamate (0.2269 mmol, 126 mg), 2-imidazolidone (0.4548 mmol, 39 mg), copper(I) iodide (0.11135 mmol, 22 mg), cesium fluoride (0.4538 mmol, 69 mg), N,N'-dimethylethylenediamine (0.2269 mmol, 25 μL), and anhydrous potassium carbonate powder (0.4538 mmol, 63 mg) were added to anhydrous 1,4-dioxane (5.0 mL) degassed under nitrogen. The resulting suspension was stirred at 90 °C overnight. The reaction was cooled to room temperature, filtered, and the filtrate was concentrated to give a semi-solid. The crude product was purified by silica gel column chromatography using a gradient solvent system of 0-100% ethyl acetate in hexanes to afford the title compound as a yellow oil (6 mg, 5%). 1 H NMR(400MHz,CDCl3)δ 7.83(m,2H),7.19(m,2H),3.88(m,2H),3.64(t,J=12Hz,2H),3.4(d,J=56Hz,3H),3.21(s,1H),ESIMS:m / z 518.3[(M+H) + ].

[0364] Example 8 2,4-Bis(trifluoromethyl)-6-(3-methyl-2-oxoimidazolidin-1-yl)phenyl(3-chloro-2,4-difluorophenyl)(methyl)carbamate [ka] 2,4-Bis(trifluoromethyl)-6-iodophenyl (5-chloro-2,4-difluorophenyl)(methyl)carbamate (0.276 mmol, 140 mg), 1-methyl-2-imidazolidinone (0.552 mmol, 55 mg), copper(I) iodide (0.136 mmol, 26 mg), cesium fluoride (0.552 mmol, 84 mg), N,N'-dimethylethylenediamine (0.276 mmol, 30 μL), and anhydrous potassium carbonate powder (0.552 mmol, 76 mg) were added to anhydrous 1,4-dioxane (5.0 mL) degassed under nitrogen. The resulting suspension was stirred at 90 °C overnight. The reaction was cooled to room temperature, filtered, and the filtrate was concentrated to give a semi-solid. The crude product was purified by silica gel column chromatography using a gradient solvent system of 0-100% ethyl acetate in hexanes to afford the title compound as a yellow oil (7 mg, 5%).

[0365] 1 H NMR(400MHz,CDCl3)δ 7.81(m,2H),7.30(m,1H),7.05(m,1H),3.72(m,2H),3.51(m,2H),3.38(d,J=52Hz,3H),2.93(s,3H),ESIMS:m / z 532.3[(M+H) + ].

[0366] Example 9 2,4-Bis(trifluoromethyl)-6-(2-oxoimidazolidin-1-yl)phenyl(5-chloro-2,4-difluorophenyl)(methyl)carbamate [ka]

[0367] Step 1: Synthesis of (5-chloro-2,4-difluorophenyl)(methyl)carbamic acid chloride [ka] To a solution of 5-chloro-2,4-fluoro-N-methylaniline (0.827 g, 4.66 mmol) and pyridine (0.73 g, 9.34 mmol) in dichloromethane (12 mL) at 0° C., triphosgene (0.69 g, 2.33 mmol) dissolved in 6 mL of dichloromethane was added dropwise under an inert atmosphere. The reaction was stirred at ambient temperature (room temperature) for 2 hours. The reaction mixture was diluted with 20 mL of dichloromethane and extracted with 20 mL of 1N HCl. The organic layer was separated, dried over anhydrous sodium sulfate, filtered, and concentrated to a solid under reduced pressure.

[0368] ESIMS: m / z 225.42 [(M-35+22+H) + ].

[0369] Step 2: Synthesis of 2,4-bis(trifluoromethyl)-6-iodophenyl(5-chloro-2,4-difluorophenyl)(methyl)carbamate [ka] Same experimental procedure as in step 3 of Example 1. ESIMS: m / z 559.91 [(M+H) + ].

[0370] Step 3: Synthesis of 2,4-bis(trifluoromethyl)-6-(2-oxoimidazolidin-1-yl)phenyl(5-chloro-2,4-difluorophenyl)(methyl)carbamate [ka] 2-Iodo-4,6-bis(trifluoromethyl)phenyl(2,4-difluoro-5-chlorophenyl)(methyl)carbamate (0.276 mmol, 140 mg), 2-imidazolidone (0.552 mmol, 48 mg), copper(I) iodide (0.136 mmol, 26 mg), cesium fluoride (0.552 mmol, 84 mg), N,N'-dimethylethylenediamine (0.276 mmol, 30 μL), and anhydrous potassium carbonate powder (0.552 mmol, 76 mg) were added to anhydrous 1,4-dioxane (5.0 mL) degassed under nitrogen. The resulting suspension was stirred at 90 °C overnight. The reaction was cooled to room temperature, filtered, and the filtrate was concentrated to give a semi-solid. The crude product was purified by silica gel column chromatography using a gradient solvent system of 0-100% ethyl acetate in hexanes to afford the title compound as a yellow oil (4 mg, 3%).

[0371] 1 H NMR(400MHz,CDCl3)δ7.82(m,2H),7.50(m,1H),7.05(m,1H),3.86(m,2H),3.63(t,J=8Hz,2H),3.39(d,J=56Hz,3H),ESIMS:m / z 518.32[(M+H) + ].

[0372] Example 10 2,4-Bis(trifluoromethyl)-6-(2-oxopyrrolidin-1-yl)phenyl(4-fluorophenyl)(methyl)carbamate [ka] 2-Bromo-4,6-bis(trifluoromethyl)phenyl(4-fluorophenyl)(methyl)carbamate (0.152 mmol, 70 mg), 2-pyrrolidone (0.304 mmol, 23 μL), copper(I) iodide (0.076 mmol, 14 mg), N,N'-dimethylethylenediamine (0.152 mmol, 18 μL), and anhydrous potassium carbonate powder (0.465 mmol, 63 mg) were added to anhydrous 1,4-dioxane (10 mL) that had been degassed under nitrogen. The resulting suspension was stirred at 90 °C overnight. The reaction was cooled to room temperature, diluted with methanol, and filtered. The clear filtrate was concentrated to give a semi-solid. This was suspended in dichloromethane, filtered through a plug of Celite, and concentrated. The crude product was purified by silica gel column chromatography using a gradient solvent system of 0-100% ethyl acetate in hexanes to afford the title compound as a yellow oil (5 mg, 7%). 1 H NMR(400MHz,CDCl3)δ 7.75(m,2H),7.29(m,2H),7.10(m,2H),3.80(m,2H),3.51(m,2H),3.42(d,J=56Hz,3H),2.57(s,3m,2H)2.22(m,2H),ESIMS:m / z 465.34[(M+H) + ].

[0373] Example 11 2,4-Bis(trifluoromethyl)-6-(pyrrolidin-1-yl)phenyl 4-fluorophenylmethylcarbamate [ka]

[0374] Step 1: Synthesis of 1-(2-(benzyloxy)-3,5-bis(trifluoromethyl)phenyl)pyrrolidine [ka] A mixture of 1-((2-bromo-4,6-bis(trifluoromethyl)phenoxy)methyl)benzene (0.25 g, 0.626 mmol), pyrrolidine (0.223 g, 3.13 mmol), [2,2'-bis(diphenylphosphino)-1,1'-binaphthyl] (0.058 g, 0.09 mmol), palladium(0) bis(dibenzylideneacetone) (0.057 g, 0.062 mmol), and sodium tert-butoxide (0.073 g, 0.75 mmol) in 10 mL of toluene was stirred at 96 °C for 20 h under an inert atmosphere. The reaction was cooled to room temperature, filtered through a plug of Celite, and concentrated. The crude product was purified by silica gel column chromatography using a gradient solvent system of 0 to 20% ethyl acetate in hexanes to afford 0.100 g of the title compound as a yellow oil. ESIMS: m / z 390.36 [(M+H) + ].

[0375] Step 2: Synthesis of 2,4-bis(trifluoromethyl)-6-(pyrrolidin-1-yl)phenol [ka] To 1-(2-(benzyloxy)-3,5-bis(trifluoromethyl)phenyl)pyrrolidine (0.100 g, 0.25 mmol) in 10 mL of methanol was added Pd / C (0.03 g, 0.28 mmol) under an inert atmosphere. The reaction flask was degassed and stirred under a hydrogen balloon for 20 hours. The reaction was evacuated of hydrogen, purged with nitrogen gas, filtered, and concentrated to give 0.068 g of the title compound as an oil. ESIMS: m / z 301.39 [(M+H) + ].

[0376] Step 3: Synthesis of 2,4-bis(trifluoromethyl)-6-(pyrrolidin-1-yl)phenyl 4-fluorophenylmethylcarbamate [ka] To a solution of 2,4-bis(trifluoromethyl)-6-(pyrrolidin-1-yl)phenol (0.065 g, 0.21 mmol) in acetonitrile (10 mL) was added anhydrous potassium carbonate (0.06 g, 0.41 mmol) and stirred for 30 minutes. (4-Fluorophenyl)(methyl)carbamic acid chloride (0.04 g, 0.21 mmol) was added to the reaction and stirred for 18 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give an oil. The crude product was purified by silica gel flash column chromatography using 0-100% ethyl acetate in hexanes as eluent to give 0.05 g of an off-white solid. 1 H NMR (400MHz, CDCl3) δ 7.32(m,2H),7.10(m,4H),7.3(bs,2H),3.54(m,2H),3.40(m,2H),3.36(s,3H),2.05(m,2H), MS(ESI): m / z 451.38.

[0377] Example 12 (R)-2-(4-hydroxy-2-oxopyrrolidin-1-yl)-6-methyl-4-(trifluoromethyl)phenyl(4-fluorophenyl)(methyl)carbamate [ka]

[0378] Step 1: Synthesis of 4,4,5,5-tetramethyl-2-(2-methyl-4-(trifluoromethyl)phenyl)-1,3,2-dioxaborolane [ka] A solution of 1-bromo-2-methyl-4-(trifluoromethyl)benzene (1 g, 0.0041 mol) in 1,4-dioxane (20 mL) was purged with N2 in a sealed tube for 30 minutes. Then, under inert atmosphere, bis-pinacolatodiboron (2.12 g, 0.00837 mol), potassium acetate (0.82 g, 0.00836 mol), and Pd(dppf)Cl2.DCM (0.34 g, 0.00042 mol) were added with stirring. The sealed tube was heated to 100 °C in an oil bath with stirring for 6 hours. The reaction progress was monitored by TLC (Rf = 0.6, 10% EtOAc in hexane). Upon completion of the reaction, the reaction mixture was concentrated under reduced pressure to give the crude product. The crude product was washed with n-hexane (5 × 50 mL), and the collected washings were concentrated under reduced pressure to give a yellow sticky solid (crude product 3 g, quantitative). The product was used directly in the next step without further purification.

[0379] Step 2: Synthesis of 2-methyl-4-(trifluoromethyl)phenol [ka] To a cold (0°C) solution of 4,4,5,5-tetramethyl-2-(2-methyl-4-(trifluoromethyl)phenyl)-1,3,2-dioxaborolane (crude product 6 g) in EtOH (50 mL) was added 30% aqueous hydrogen peroxide (4.1 mL) with stirring under an inert atmosphere. The reaction mixture was stirred at ambient temperature for 16 hours. Completion of the reaction was confirmed by TLC (R f After checking with a 0.2 ml solution of 10% EtOAc in hexanes, the reaction mixture was cooled to 0 °C and quenched with aqueous sodium metabisulfite, followed by extraction with EtOAc (2 × 30 mL). The collected organic layers were washed with water and then brine, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give the crude product. The resulting crude product was purified by column chromatography (100-200 silica gel, 10-15% EtOAc in hexanes as eluent) to give the title compound as a pale yellow liquid (0.7 g, 95% yield).

[0380] Step 3: Synthesis of 2-iodo-6-methyl-4-(trifluoromethyl)phenol [ka] A solution of 2-methyl-4-(trifluoromethyl)phenol (0.7 g, 0.00397 mol) in THF:HO (3:1, 19 mL) was cooled to 0 °C in an ice bath with stirring. After 15 min, with stirring under an inert atmosphere, I (1.1 g, 0.00433 mol) was added, followed by NaCO (0.46 g, 0.00433 mol). The reaction mixture was stirred at ambient temperature for 24 h. Completion of the reaction (TLC: R f After 20 min at −0.35° C. (10% EtOAc in hexanes), the reaction mixture was cooled to 0° C. and then quenched with aqueous sodium metabisulfite, followed by extraction with EtOAc (2×50 mL). The collected organic layers were washed with water and then brine, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give the crude product. The resulting crude product was purified by column chromatography (100-200 silica gel, 0-5% EtOAc in hexanes as eluent) to give the title compound as a pale yellow liquid (1.0 g, 83% yield).

[0381] Step 4: Synthesis of (4-fluorophenyl)(methyl)carbamic acid chloride [ka] To a cold (0 °C) solution of triphosgene (0.57 g, 0.002 mol) in DCM (15 mL), a solution of N-methyl-4-fluoroaniline (0.5 g, 0.0039 mol) and pyridine (0.61 g, 0.62 mL, 0.0078 mol) was added dropwise over 10 min. Stirring was then continued at room temperature for 16 h. The progress of the reaction was monitored by TLC. Upon completion of the reaction, the reaction mixture was quenched with 1 M aqueous HCl (15 mL) and then extracted with DCM (2 × 40 mL). The separated DCM layer was dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give the title compound as a green solid (0.7 g, 93%).

[0382] Step 5: Synthesis of 2-iodo-6-methyl-4-(trifluoromethyl)phenyl(4-fluorophenyl)(methyl)carbamate [ka] To a stirred solution of 2-iodo-6-methyl-4-(trifluoromethyl)phenol, 5-difluorophenol (1 g, 0.0033 mol) in DMF (15 mL) was added K2CO3 (0.91 g, 0.0066 mol) at room temperature and stirring was continued at room temperature for 30 minutes. To the above mixture was added dropwise a solution of (4-fluorophenyl)(methyl)carbamic acid chloride (0.62 g, 0.0033 mol) in DCM (15 mL). The resulting reaction mixture was stirred at room temperature for an additional 7 hours. Completion of the reaction was confirmed by TLC (R f After checking with HCl (-0.25, 5% EtOAc in hexanes), the reaction mixture was quenched with cold water (15 mL) and extracted with EtOAc (2 x 40 mL). The separated organic layers were combined, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give the crude product. The resulting crude product was purified by silica gel chromatography (100-200, 5-10% EtOAc in hexanes as eluent) to give the title compound as an off-white solid (0.8 g, 53%).

[0383] Step 6: Synthesis of (R)-2-(4-hydroxy-2-oxopyrrolidin-1-yl)-6-methyl-4-(trifluoromethyl)phenyl(4-fluorophenyl)(methyl)carbamate [ka] 2-Iodo-6-methyl-4-(trifluoromethyl)phenyl(4-fluorophenyl)(methyl)carbamate (0.3 g, 0.000662 mol), (R)-4-hydroxypyrrolidin-2-one (0.133 g, 0.0013 mol), copper(I) iodide (0.063 g, 0.00033 mol), N,N'-dimethylethylenediamine (0.07 mL, 0.00066 mol), and potassium carbonate (0.32 g, 0.002 mol) were suspended in 1,4-dioxane (25 mL) that had been pre-purged with N for 30 minutes. The reaction mixture was heated in an oil bath at 100 °C for 24 hours. TLC (R f After completion of the reaction with 0.4, 7% MeOH in DCM), the reaction mixture was concentrated under reduced pressure. The resulting residue was purified by column chromatography (100-200 silica gel, 0-3% MeOH in DCM as eluent) to give the title compound as a yellow solid (65 mg, 23%).

[0384] 1 H NMR(400MHz,Trifluoroacetic acid-D)δ 7.53(m,2H),7,31(m,2H),7.09(m,2H),4.95(m,1H),4.30(m,1H),3.95(m,1H),3.5 5(d,J=76.8Hz,3H),3.36(m,1H),2.93(m,1H),2,35(d,J=57.2Hz,3H),MS(ESI):m / z 427.0(M+H) + .

[0385] Example 13 2-Methyl-6-(2-oxoimidazolidin-1-yl)-4-(trifluoromethyl)phenyl(4-fluorophenyl)(methyl)carbamate [ka]

[0386] Step 1: Synthesis of 4,4,5,5-tetramethyl-2-(2-methyl-4-(trifluoromethyl)phenyl)-1,3,2-dioxaborolane [ka] A solution of 1-bromo-2-methyl-4-(trifluoromethyl)benzene (1 g, 0.0042 mol) in 1,4-dioxane (20 mL) was purged with N2 in a sealed tube for 30 minutes, and then bis-pinacolatodiboron (2.12 g, 0.00837 mol), potassium acetate (0.82 g, 0.00836 mol), and Pd(dppf)Cl2.DCM (0.34 g, 0.00042 mol) were added with stirring under an inert atmosphere. The sealed tube was heated to 100 °C in an oil bath with stirring for 6 hours. The reaction progress was monitored by TLC (Rf = 0.6, 10% EtOAc in hexane). Upon completion of the reaction, the reaction mixture was concentrated under reduced pressure to give the crude product. The crude product was washed with 5 × 50 mL of n-hexane, and the collected washings were concentrated under reduced pressure to give a yellow sticky solid (crude product 3 g, quantitative). The product was used directly in the next step without further purification.

[0387] Step 2: Synthesis of 2-methyl-4-(trifluoromethyl)phenol [ka] To a cold (0°C) solution of 4,4,5,5-tetramethyl-2-(2-methyl-4-(trifluoromethyl)phenyl)-1,3,2-dioxaborolane (crude product 6 g) in EtOH (50 mL) was added 30% aqueous hydrogen peroxide (4.1 mL) with stirring under an inert atmosphere. The reaction mixture was stirred at ambient temperature for 16 hours. Completion of the reaction was confirmed by TLC (R f After checking with a 0.2 ml solution of 10% EtOAc in hexanes, the reaction mixture was cooled to 0 °C and quenched with aqueous sodium metabisulfite, followed by extraction with EtOAc (2 × 30 mL). The collected organic layers were washed with water and then brine, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give the crude product. The resulting crude product was purified by column chromatography (100-200 silica gel, 10-15% EtOAc in hexanes as eluent) to give the title compound as a pale yellow liquid (0.7 g, 95% yield).

[0388] Step 3: Synthesis of 2-iodo-6-methyl-4-(trifluoromethyl)phenol [ka] A solution of 2-methyl-4-(trifluoromethyl)phenol (0.7 g, 0.00397 mol) in THF:HO (3:1, 19 mL) was cooled to 0 °C in an ice bath with stirring. After 15 min, with stirring under an inert atmosphere, I (1.1 g, 0.00433 mol) was added, followed by NaCO (0.46 g, 0.00433 mol). The reaction mixture was stirred at ambient temperature for 24 h. Completion of the reaction (TLC: R f After 20 min at 4° C. (−0.35, 10% EtOAc in hexanes), the reaction mixture was cooled to 0° C. and then quenched with aqueous sodium metabisulfite, followed by extraction with EtOAc (2×50 mL). The collected organic layers were washed with water and then brine, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give the crude product. The resulting crude product was purified by column chromatography (100-200 silica gel, 0-5% EtOAc in hexanes as eluent) to give the title compound as a pale yellow liquid (1.0 g, 83% yield).

[0389] Step 4: Synthesis of (4-fluorophenyl)(methyl)carbamic acid chloride [ka] To a cold (0 °C) solution of triphosgene (0.57 g, 0.002 mol) in DCM (15 mL), a solution of N-methyl-4-fluoroaniline (0.5 g, 0.0039 mol) and pyridine (0.61 g, 0.62 mL, 0.0078 mol) was added dropwise over 10 min. Stirring was then continued at room temperature for 16 h. The progress of the reaction was monitored by TLC. Upon completion of the reaction, the reaction mixture was quenched with 1 M aqueous HCl (15 mL) and then extracted with DCM (2 × 40 mL). The separated DCM layer was dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give the title compound as a green solid (0.7 g, 93%).

[0390] Step 5: Synthesis of 2-iodo-6-methyl-4-(trifluoromethyl)phenyl(4-fluorophenyl)(methyl)carbamate [ka] To a stirred solution of 2-iodo-6-methyl-4-(trifluoromethyl)phenol, 5-difluorophenol (1 g, 0.0033 mol) in DMF (15 mL) was added K2CO3 (0.91 g, 0.0066 mol) at room temperature and stirring was continued at room temperature for 30 minutes. To the above mixture was added dropwise a solution of (4-fluorophenyl)(methyl)carbamic acid chloride (0.62 g, 0.0033 mol) in DCM (15 mL). The resulting reaction mixture was stirred at room temperature for an additional 7 hours. Completion of the reaction was confirmed by TLC (R f After checking with HCl (-0.25, 5% EtOAc in hexanes), the reaction mixture was quenched with cold water (15 mL) and extracted with EtOAc (2 x 40 mL). The separated organic layers were combined, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give the crude product. The resulting crude product was purified by silica gel chromatography (100-200, 5-10% EtOAc in hexanes as eluent) to give the title compound as an off-white solid (0.8 g, 53%).

[0391] Step 6: Synthesis of 2-methyl-6-(2-oxoimidazolidin-1-yl)-4-(trifluoromethyl)phenyl(4-fluorophenyl)(methyl)carbamate [ka] 2-Iodo-6-methyl-4-(trifluoromethyl)phenyl(4-fluorophenyl)(methyl)carbamate (0.3 g, 0.000662 mol), 2-imidaziridinone (0.114 g, 0.0013 mol), copper(I) iodide (0.063 g, 0.00033 mol), N,N'-dimethylethylenediamine (0.07 mL, 0.00079 mol), and potassium carbonate (0.27 g, 0.002 mol) were suspended in 1,4-dioxane (25 mL) that had been purged with N for 30 minutes. The reaction mixture was heated in an oil bath at 100 °C for 48 hours. TLC (R f After completion of the reaction with 0.4, 7% MeOH in DCM), the reaction mixture was concentrated under reduced pressure. The resulting residue was purified by column chromatography (100-200 silica gel, 0-3% MeOH in DCM as eluent) to give the title compound as an off-white solid (25 mg, 9%).

[0392] 1 H NMR(400MHz,Trifluoroacetic acid-D)δ 7.50(m,2H),7.29(m,2H),7.07(dd,J=15.3Hz,J=8.2Hz,2H),4.07(m,1H),3.92( m,1H),3.81(m,2H),3.47(d,J=64.6Hz,3H),2.33(d,J=42.2Hz,3H),MS(ESI):m / z 412.05(M+H) + .

[0393] Example 14 2-Methyl-6-(2-oxoimidazolidin-1-yl)-4-(trifluoromethyl)phenyl(3-chloro-4-fluorophenyl)(methyl)carbamate [ka]

[0394] Step 1: Synthesis of 4,4,5,5-tetramethyl-2-(2-methyl-4-(trifluoromethyl)phenyl)-1,3,2-dioxaborolane [ka] A solution of 1-bromo-2-methyl-4-(trifluoromethyl)benzene (1 g, 0.0041 mol) in 1,4-dioxane (20 mL) was purged with N2 in a sealed tube for 30 minutes. Then, under inert atmosphere, bis-pinacolatodiboron (2.12 g, 0.00837 mol), potassium acetate (0.82 g, 0.00836 mol), and Pd(dppf)Cl2.DCM (0.34 g, 0.00042 mol) were added with stirring. The sealed tube was heated to 100 °C in an oil bath with stirring for 6 hours. The reaction progress was monitored by TLC (Rf = 0.6, 10% EtOAc in hexane). Upon completion of the reaction, the reaction mixture was concentrated under reduced pressure to give the crude product. The crude product was washed with n-hexane (5 × 50 mL), and the collected washings were concentrated under reduced pressure to give a yellow sticky solid (crude product 3 g, quantitative). The product was used directly in the next step without further purification.

[0395] Step 2: Synthesis of 2-methyl-4-(trifluoromethyl)phenol [ka] To a cold (0°C) solution of 4,4,5,5-tetramethyl-2-(2-methyl-4-(trifluoromethyl)phenyl)-1,3,2-dioxaborolane (crude product, 6 g) in EtOH (50 mL) was added 30% aqueous hydrogen peroxide (4.1 mL) with stirring under an inert atmosphere. The reaction mixture was stirred at ambient temperature for 16 hours. Completion of the reaction was confirmed by TLC (R f After checking with a 0.2 ml solution of 10% EtOAc in hexanes, the reaction mixture was cooled to 0 °C and quenched with aqueous sodium metabisulfite, followed by extraction with EtOAc (2 × 30 mL). The collected organic layers were washed with water and then brine, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give the crude product. The resulting crude product was purified by column chromatography (100-200 silica gel, 10-15% EtOAc in hexanes as eluent) to give the title compound as a pale yellow liquid (0.7 g, 95% yield).

[0396] Step 3: Synthesis of 2-iodo-6-methyl-4-(trifluoromethyl)phenol [ka] A solution of 2-methyl-4-(trifluoromethyl)phenol (0.05 g, 0.00028 mol) in THF:HO (3:1, 3 mL) was cooled to 0 °C in an ice bath with stirring. After 15 min, I (0.078 g, 0.00030 mol) was added followed by NaCO (0.032 g, 0.00030 mol) with stirring under an inert atmosphere. The reaction mixture was stirred at ambient temperature for 16 h. Completion of the reaction (TLC: R f After 20 min (-0.5, 10% EtOAc in hexanes), the reaction mixture was cooled to 0 °C and then quenched with aqueous sodium metabisulfite, followed by extraction with EtOAc (2 × 30 mL). The collected organic layers were washed with water and then brine, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give the crude product. The resulting crude product was purified by column chromatography (100-200 silica gel, 10% EtOAc in hexanes as eluent) to give the title compound as a pale yellow solid (0.015 g, 17% yield).

[0397] Step 4: Synthesis of (3-chloro-4-fluorophenyl)(methyl)carbamic acid chloride [ka] To a cold (0 °C) solution of triphosgene (0.091 g, 0.00031 mol) in DCM (3 mL), a solution of 3-chloro-4-fluoro-N-methylaniline (0.1 g, 0.0006 mol) and pyridine (0.07 g, 0.08 mL, 0.0012 mol) was added dropwise over 10 min. Stirring was then continued at room temperature for 16 h. The reaction progress was monitored by TLC. Upon completion of the reaction, the reaction mixture was quenched with 1 M aqueous HCl (5 mL) and then extracted with DCM (2 × 30 mL). The separated DCM layer was dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give the title compound as a green solid (0.08 g, 58%).

[0398] Step 5: Synthesis of 2-iodo-6-methyl-4-(trifluoromethyl)phenyl(3-chloro-4-fluorophenyl)(methyl)carbamate [ka] To a stirred solution of 2-iodo-6-methyl-4-(trifluoromethyl)phenol (0.1 g, 0.00033 mol) in DMF:DCM (1:1, 4 mL) at room temperature was added KCO (0.091 g, 0.00066 mol) and (3-chloro-4-fluorophenyl)(methyl)carbamic acid chloride (0.07 g, 0.00033 mol), and stirring was continued at room temperature for 7 h. The completion of the reaction was confirmed by TLC (R f After checking with HCl (-0.2, 10% EtOAc in hexanes), the reaction mixture was quenched with ice-cold water (20 mL) and extracted with EtOAc (2 × 30 mL). The separated organic layers were combined, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give the crude product. The resulting crude product was purified by silica gel chromatography (100-200, 2-4% EtOAc in hexanes as eluent) to give the title compound as a pale yellow liquid (0.1 g, 62%).

[0399] Step 6: Synthesis of 2-methyl-6-(2-oxoimidazolidin-1-yl)-4-(trifluoromethyl)phenyl(3-chloro-4-fluorophenyl)(methyl)carbamate [ka] 2-Iodo-6-methyl-4-(trifluoromethyl)phenyl (3-chloro-4-fluorophenyl) (methyl)carbamate (0.1 g, 0.0002 mol), imidazolidin-2-one (0.035 g, 0.0004 mol), potassium carbonate (0.055 g, 0.0004 mol), and cesium fluoride (0.06 g, 0.0004 mol) were suspended in 1,4-dioxane (8 mL) that had been purged with N for 20 minutes under stirring, followed by the addition of copper(I) iodide (0.02 g, 0.00010 mol) and N,N'-dimethylethylenediamine (0.017 g, 0.020 mL, 0.00026 mol) with stirring. The reaction mixture was heated in an oil bath at 90 °C for 24 hours. TLC (R f After completion of the reaction with 0.4, 5% MeOH in DCM), the reaction mixture was concentrated under reduced pressure. The resulting residue was purified by column chromatography (100-200 silica gel, 1-2% MeOH in DCM as eluent) to give the title compound as an off-white solid (15 mg, 17%).

[0400] 1 H NMR(500MHz,Trifluoroacetic acid-D)δ 7.46(m,3H),7.18(m,2H),3.93(m,4H),3.54(s,1H),3.37(s,2H),2.31(d,J=48.7Hz,3H),MS(ESI):m / z 446.05(M+H) + .

[0401] Example 15 4-(trifluoromethyl)-2-methyl-6-(2-oxooxazolidin-3-yl)phenyl 4-fluorophenylmethylcarbamate [ka]

[0402] Step 1: Synthesis of 4,4,5,5-tetramethyl-2-(2-methyl-4-(trifluoromethyl)phenyl)-1,3,2-dioxaborolane [ka] A solution of 1-bromo-2-methyl-4-(trifluoromethyl)benzene (1 g, 0.0041 mol) in 1,4-dioxane (20 mL) was purged with N2 in a sealed tube for 30 minutes. Then, under inert atmosphere, bis-pinacolatodiboron (2.12 g, 0.00837 mol), potassium acetate (0.82 g, 0.00836 mol), and Pd(dppf)Cl2.DCM (0.34 g, 0.00042 mol) were added with stirring. The sealed tube was heated to 100 °C in an oil bath with stirring for 6 hours. The reaction progress was monitored by TLC (Rf = 0.6, 10% EtOAc in hexane). Upon completion of the reaction, the reaction mixture was concentrated under reduced pressure to give the crude product. The crude product was washed with n-hexane (5 × 50 mL), and the collected washings were concentrated under reduced pressure to give a yellow sticky solid (crude product 3 g, quantitative). The product was used directly in the next step without further purification.

[0403] Step 2: Synthesis of 2-methyl-4-(trifluoromethyl)phenol [ka] To a cold (0°C) solution of 4,4,5,5-tetramethyl-2-(2-methyl-4-(trifluoromethyl)phenyl)-1,3,2-dioxaborolane (crude product, 6 g) in EtOH (50 mL) was added 30% aqueous hydrogen peroxide (4.1 mL) with stirring under an inert atmosphere. The reaction mixture was stirred at ambient temperature for 16 hours. Completion of the reaction was confirmed by TLC (R f After checking with a 0.2 ml solution of 10% EtOAc in hexanes, the reaction mixture was cooled to 0 °C and quenched with aqueous sodium metabisulfite, followed by extraction with EtOAc (2 × 30 mL). The collected organic layers were washed with water and then brine, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give the crude product. The resulting crude product was purified by column chromatography (100-200 silica gel, 10-15% EtOAc in hexanes as eluent) to give the title compound as a pale yellow liquid (0.7 g, 95% yield).

[0404] Step 3: Synthesis of 2-iodo-6-methyl-4-(trifluoromethyl)phenol [ka] A solution of 2-methyl-4-(trifluoromethyl)phenol (0.05 g, 0.00028 mol) in THF:HO (3:1, 3 mL) was cooled to 0 °C in an ice bath with stirring. After 15 min, I (0.078 g, 0.00030 mol) was added followed by NaCO (0.68 g, 0.00030 mol) with stirring under an inert atmosphere. The reaction mixture was stirred at ambient temperature for 16 h. Completion of the reaction (TLC: R f After 20 min (-0.5, 10% EtOAc in hexanes), the reaction mixture was cooled to 0 °C and then quenched with aqueous sodium metabisulfite, followed by extraction with EtOAc (2 × 30 mL). The collected organic layers were washed with water and then brine, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give the crude product. The resulting crude product was purified by column chromatography (100-200 silica gel, 10% EtOAc in hexanes as eluent) to give the title compound as a pale yellow solid (0.015 g, 17% yield).

[0405] Step 4: Synthesis of (4-fluorophenyl)(methyl)carbamic acid chloride [ka] To a cold (0 °C) solution of triphosgene (0.57 g, 0.002 mol) in DCM (15 mL), a solution of N-methyl-4-fluoroaniline (0.5 g, 0.0039 mol) and pyridine (0.61 g, 0.62 mL, 0.0078 mol) was added dropwise over 10 min. Stirring was then continued at room temperature for 16 h. The progress of the reaction was monitored by TLC. Upon completion of the reaction, the reaction mixture was quenched with 1 M aqueous HCl (15 mL) and then extracted with DCM (2 × 40 mL). The separated DCM layer was dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give the title compound as a green solid (0.7 g, 93%).

[0406] Step 5: Synthesis of 2-iodo-6-methyl-4-(trifluoromethyl)phenyl(4-fluorophenyl)(methyl)carbamate [ka] To a stirred solution of 2-iodo-6-methyl-4-(trifluoromethyl)phenol (1.0 g, 0.0033 mol) in a mixture of DMF:DCM (1:1, 30 mL) at room temperature was added KCO (0.91 g, 0.0066 mol) and (4-fluorophenyl)(methyl)carbamic acid chloride (0.62 g, 0.0033 mol), and stirring was continued at room temperature for 7 h. The completion of the reaction was confirmed by TLC (R f After checking with HCl (-0.25, 5% EtOAc in hexanes), the reaction mixture was quenched with ice-cold water (50 mL) and extracted with EtOAc (2 x 40 mL). The separated organic layers were combined, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give the crude product. The resulting crude product was purified by silica gel chromatography (100-200, 5-10% EtOAc in hexanes as eluent) to give the title compound as an off-white solid (0.8 g, 53%).

[0407] Step 6: Synthesis of 2-methyl-6-(2-oxooxazolidin-3-yl)-4-(trifluoromethyl)phenyl(4-fluorophenyl)(methyl)carbamate [ka] 2-Iodo-6-methyl-4-(trifluoromethyl)phenyl(4-fluorophenyl)(methyl)carbamate (0.1 g, 0.00022 mol), oxazolidin-2-one (0.0383 g, 0.00044 mol), potassium carbonate (0.91 g, 0.00066 mol), and cesium fluoride (0.066 g, 0.00044 mol) were suspended in 1,4-dioxane (8 mL) that had been purged with N for 20 minutes. Copper(I) iodide (0.02 g, 0.00010 mol) and N,N'-dimethylethylenediamine (0.022 g, 0.027 mL, 0.00026 mol) were added with stirring. The reaction mixture was heated in an oil bath at 100 °C for 24 hours. TLC (R f After completion of the reaction with 0.5, 60% EtOAc / hexane), the reaction mixture was concentrated under reduced pressure. The resulting residue was purified by column chromatography (100-200 silica gel, 30-35% EtOAc in hexane as eluent) to give the title compound as an off-white solid (20 mg, 22%).

[0408] 1 H NMR(500MHz,Trifluoroacetic acid-D)δ 7.54(dd,J=36.8Hz,J=31.3Hz,2H),7.31(dq J=31.7Hz,J=4.4Hz,2H),7.10(m,2H),4.68(td,J=16.5Hz,J=8.3Hz,2H),4.11(m,2H),3.48(d,J=84.7Hz,2H),2.35(d,J=62.7Hz,3H),MS(ESI):m / z 412.0(M+H) + .

[0409] Example 16 2-(4,5-dihydroxy-2-oxoimidazolidin-1-yl)-4,6-bis(trifluoromethyl)phenyl N-(4-fluorophenyl)-N-methylcarbamate [ka]

[0410] Step 1: Synthesis of 1-(2-hydroxy-3,5-bis(trifluoromethyl)phenyl)-1,3-dihydro-2H-imidazol-2-one [ka] To a solution of compound 1 (1.0 g, 2.81 mmol, 1.0 equiv.) and compound 2 (474 ​​mg, 5.63 mmol, 2.0 equiv.) in DMA (10 mL) at room temperature, CuI (270 mg, 1.4 mmol, 0.5 equiv.), DMEDA (249 mg, 2.81 mmol, 1.0 equiv.), KCO (782 mg, 5.62 mmol, 2.0 equiv.), and CsF (855 mg, 5.62 mmol, 2.0 equiv.) were added. The reaction mixture was heated in an oil bath at 110 °C for 4 hours. TLC (R f After the completion of the reaction was monitored by LC-MS (0.3, PE:EA=2:1), water (20 mL) was added. The mixture was adjusted to pH=6 with HCl (2N). The mixture was extracted with ethyl acetate (30 ml×2). The combined organic layers were washed with brine, dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (100-200 silica gel, 50% EA in PE) to give compound 3 (320 mg, 36%) as a pale yellow solid.

[0411] Step 2: Synthesis of tert-butyl 3-(2-hydroxy-3,5-bis(trifluoromethyl)phenyl)-2-oxo-2,3-dihydro-1H-imidazole-1-carboxylate [ka] To a solution of compound 3 (150 mg, 0.48 mmol, 1.0 equiv.) and BocO (125 mg, 0.58 mmol, 1.2 equiv.) in DMF (10 mL) at room temperature was added KCO (167 mg, 1.2 mmol, 2.5 equiv.). The reaction mixture was heated in an oil bath at 60 °C for 2 h. The mixture was extracted with ethyl acetate (30 mL × 2). The combined organic layers were washed with brine, dried over NaSO, and filtered. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (100-200 silica gel, 20-50% EA in PE) to give compound 4 (110 mg, 55%) as a pale yellow solid.

[0412] Step 3: Synthesis of tert-butyl 3-(2-(((4-fluorophenyl)(methyl)carbamoyl)oxy)-3,5-bis(trifluoromethyl)phenyl)-2-oxo-2,3-dihydro-1H-imidazole-1-carboxylate [ka] To a solution of compound 4 (110 mg, 0.35 mmol, 1.0 equiv) in DCM (10 mL) at −10° C., DIEA (60 mg, 0.467 mmol, 1.5 equiv) and triphosgene (117 mg, 0.395 mmol, 1.1 equiv) in DCM (2 mL) were added. The reaction mixture was stirred at room temperature under N2 for 1 h. The reaction was concentrated under reduced pressure to remove the solvent. DCM (3 mL) was then added to the above residue. This solution was used in the next step.

[0413] The above solution was added to a solution of compound 5 (85 mg, 0.52 mmol, 1.5 equiv.) and DIEA (68 mg, 0.52 mmol, 1.5 equiv.) in DCM (5 mL) at 0° C. The mixture was stirred at room temperature under N for 1 h. TLC (R fAfter confirming the completion of the reaction by HPLC (0.5, PE:EA=2:1) ​​and LC-MS, HCl (1N, 15 mL) was added. The mixture was then extracted with DCM (20 mL × 2). The combined organic layers were washed with brine, dried over NaSO, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (100-200 silica gel, 50% EA in PE as eluent) to give compound 6 (80 mg, 53%) as an off-white solid.

[0414] Step 4: Synthesis of AB25934 [ka] To a solution of HCl in dioxane (3 mL, 4N) was added compound 6 (80 mg, 0.14 mmol, 1.0 equiv.) at room temperature. The mixture was stirred at room temperature under N for 30 minutes. TLC (R f After completion of the reaction with 0.3, PE:EA=1:1), aqueous Na2CO3 was added to adjust the solution to pH 8-9. The mixture was extracted with ethyl acetate (30 mL × 2). The combined organic layers were washed with brine, dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (100-200 silica gel, 50% ethyl acetate in PE as eluent) to give the title compound (AB25934, 28 mg, 42%) as a pale yellow solid.

[0415] 1 H NMR(400MHz,CD3OD):δ8.15-8.18(m,1H),7.99-8.05(m,1H),7.27-7.32(m,2H),7.10-7.16(m,2 H),6.69(s,0.38H),6.66(s,1H),6.64(s,0.57H),3.46(s,1H),3.22(s,2H),LC-MS:464.00[M+1] + .

[0416] Step 5: Synthesis of 2-(4,5-dihydroxy-2-oxoimidazolidin-1-yl)-4,6-bis(trifluoromethyl)phenyl N-(4-fluorophenyl)-N-methylcarbamate [ka] To a solution of AB25943 (AB25943, 60 mg, 0.12 mmol, 1.0 equiv.) in t-BuOH / THF / HO (2 mL / 2 mL / 1 mL), NMO (20 mg, 0.16 mmol, 1.4 equiv.) and KOsO (0.7 mg, 0.0024 mmol, 0.02 equiv.) were added at 0 °C. The reaction mixture was stirred at room temperature for 1 h. TLC (R f After monitoring the completion of the reaction by HPLC (0.1, PE:EA=1:1) and LC-MS, the mixture was extracted with ethyl acetate (30 mL × 2). The combined organic layers were washed with brine, dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (100-200 silica gel, 70% ethyl acetate in PE as eluent) to give the title compound (AB25792, 22.3 mg, 34% yield) as a white solid.

[0417] 1 H NMR(400MHz,CD3OD):δ 7.88-7.99(m,1H),7.81(s,1H),7.27-7.32(m,1H),7.30-7.42(m,1H),7.11-7.0 5(m,2H)5.12(m,1H),4.94(s,1H),3.47(s,1H),3.32(s,2H),LCMS:495.95[M-1] - .

[0418] Example 17 2-[(2R)-2-Methyl-5-oxopyrrolidin-1-yl]-4,6-bis(trifluoromethyl)phenyl N-(4-fluorophenyl)-N-methylcarbamate [ka]

[0419] Step 1: Synthesis of 2-(2,4-bis(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane [ka] A solution of 1-bromo-2,4-bis(trifluoromethyl)benzene (25.0 g, 85.3 mmol, 1.0 equiv.) in dioxane (300 mL) was purged with N2 in a sealed tube for 2 minutes. Then, under inert atmosphere, bis(pinacolato)diboron (43.4 g, 170 mmol, 2.0 equiv.), potassium acetate (16.8 g, 170 mmol), and Pd(dppf)Cl2-DCM (2.4 g, 8.53 mmol, 0.1 equiv.) were added with stirring. The sealed tube was heated in an oil bath at 100 °C with stirring for 16 hours. The reaction progress was monitored by TLC (Rf = 0.5, 10% EtOAc in hexanes). Upon completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was partitioned between ethyl acetate (200 mL) and water (150 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE:EA=1:20) to give compound 2 (23.0 g, 79%).

[0420] Step 2: Synthesis of 2,4-bis(trifluoromethyl)phenol [ka] To a solution of 2-(2,4-bis(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (23.0 g, 67.6 mmol, 1.0 equiv) in ethanol (300 mL) at 0 °C, hydrogen peroxide (30% aqueous solution, 24 mL) was added with stirring under an inert atmosphere. The reaction mixture was stirred at ambient temperature for 16 h. After completion of the reaction was confirmed by TLC (Rf = 0.2, 10% EtOAc in hexanes), the reaction mixture was cooled to 0 °C and quenched with sodium metabisulfite solution, followed by extraction with EtOAc (2 × 100 mL). The collected organic layers were washed with water, followed by brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude mixture, which was purified by column chromatography (silica gel, 0–20% EtOAc in hexanes as eluent) to give compound 3 (8.1, 52%) as a pale yellow liquid.

[0421] Step 3: Synthesis of 2-iodo-4,6-bis(trifluoromethyl)phenol [ka] A solution of 2,4-bis(trifluoromethyl)phenol (8.0 g, 34.8 mol) in THF:HO (3:1, 160 mL) was cooled to 0 °C in an ice bath with stirring. After 15 min, iodine (10.6 g, 41.7 mmol) was added, followed by sodium carbonate (4.4 g, 41.5 mmol) with stirring under nitrogen. After stirring at ambient temperature for 24 h, the reaction mixture was cooled to 0 °C and then quenched with aqueous sodium metabisulfite, followed by extraction with ethyl acetate (2 × 150 mL). The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude mixture was purified by column chromatography (silica gel, 0–5% EtOAc in hexanes) to give compound 4 (5.8 g, 46%) as a pale yellow solid.

[0422] Step 4: Synthesis of (R)-1-(2-hydroxy-3,5-bis(trifluoromethyl)phenyl)-5-methylpyrrolidin-2-one [ka] To a solution of compound 4 (356 mg, 1.0 mmol, 1.0 equiv.) and compound 5 (200 mg, 2 mmol, 2.0 equiv.) in dioxane (10 mL) at room temperature was added CuI (95 mg, 0.5 mmol, 0.5 equiv.), CsF (304 mg, 2 mmol, 2.0 equiv.), and N,N′-dimethylethylenediamine (44 mg, 0.5 mmol, 0.5 equiv.).

[0423] The reaction mixture was heated in an oil bath at 110° C. for 24 hours. The completion of the reaction was confirmed by TLC (R fAfter monitoring with HCl (0.3, PE:EA=1:1), water (20 mL) was added and the pH was adjusted to 6 with HCl (2N). The mixture was extracted with ethyl acetate (30 mL × 2). The combined organic layers were washed with brine, dried over NaSO, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 50% EA in PE as eluent) to give compound 6 (50 mg, 15%) as a pale yellow solid.

[0424] Step 5: Synthesis of AB25793 [ka] To a solution of compound 6 (30 mg, 0.092 mmol, 1.0 equiv.) in DCM (10 mL) was added DIEA (13 mg, 0.101 mmol, 1.1 equiv.) and triphosgene (24 mg, 0.092 mmol, 1.0 equiv.) in DCM (2 mL) at −10° C. under N. The reaction mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure to remove the solvent. Then, DCM (3 mL) was added to the above reaction mixture, which was used in the next step.

[0425] Step 6: Synthesis of 2-[(2R)-2-methyl-5-oxopyrrolidin-1-yl]-4,6-bis(trifluoromethyl)phenyl N-(4-fluorophenyl)-N-methylcarbamate To a solution of compound 7 (20 mg, 0.16 mmol, 1.7 equiv) in DCM (5 mL) at 0° C., the above solution was added. The mixture was stirred at room temperature under N2 for 1 hour. HCl (1N, 15 mL) was added. The mixture was extracted with DCM (20 mL × 2). The combined organic layers were washed with brine, dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (silica gel) and preparative HPLC (C-18) to give the title compound (AB25793, 10.8 mg, 24%) as an off-white solid.

[0426] 1H NMR(400MHz,CDCl3):δ 8.00-7.95(m,2H),7.37(m,2H),7.17-7.15(m,2H),4.33-4.16(m,1H),3.47(s,1H)3.47(s,2.09H),2.54-2. 45(m,2H),2.44-2.41(m,1H),1.82-1.80(m,1H),1.16(d,J=4Hz,1H)1.01(d,J=4Hz,2H),LC-MS:479.10[M+H] + .

[0427] Example 18 2-(2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)-4,6-bis(trifluoromethyl)phenyl(4-fluorophenyl)(methyl)carbamate [ka]

[0428] Step 1: Synthesis of 2-iodo-4,6-bis(trifluoromethyl)phenol [ka] A solution of 2,4-bis(trifluoromethyl)phenol (1.0 g, 0.0043 mol) in THF:HO (3:1, 20 mL) was cooled to 0 °C in an ice bath with stirring. After 15 min, I (1.4 g, 0.0056 mol) was added followed by NaCO (0.68 g, 0.0064 mol) with stirring under an inert atmosphere. The reaction mixture was stirred at ambient temperature for 24 h. Completion of the reaction (TLC: R fAfter 2 min (−0.4, 30% EtOAc in hexanes, followed by 30% DCM in hexanes), the reaction mixture was cooled to 0 °C and then quenched with aqueous sodium metabisulfite, followed by extraction with EtOAc (2 × 100 mL). The collected organic layers were washed with water and then brine, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give the crude product. The resulting crude product was purified by column chromatography (100–200 silica gel, 5–10% EtOAc in hexanes as eluent) to give the title compound (0.98 g, 64% yield) as a pale yellow solid.

[0429] Step 2: Synthesis of 2-iodo-4,6-bis(trifluoromethyl)phenyl(4-fluorophenyl)(methyl)carbamate [ka] To a stirred solution of 2-iodo-4,6-bis(trifluoromethyl)phenol (0.5 g, 0.0014 mol) in pyridine (10 mL) was added (4-fluorophenyl)(methyl)carbamic acid chloride (0.34 g, 0.0018 mol) at room temperature and stirring was continued at 80° C. for 4 hours. The completion of the reaction was confirmed by TLC (R f After checking with HCl (0.8, 20% EtOAc in hexanes), the reaction mixture was quenched with 1 M HCl (50 mL) and extracted with EtOAc (2 × 50 mL). The separated organic layers were combined, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give the crude product. The resulting crude product was purified by silica gel chromatography (100-200, 0-10% EtOAc in hexanes as eluent) to give the title compound as an off-white solid (0.66 g, 93%).

[0430] Step 3: Synthesis of 2-(2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)-4,6-bis(trifluoromethyl)phenyl(4-fluorophenyl)(methyl)carbamate [ka] 2-Iodo-4,6-bis(trifluoromethyl)phenyl(4-fluorophenyl)(methyl)carbamate (200 mg, 0.3944 mmol), 4-trifluoromethyl-2-imidazolidinone (109 mg, 0.7078 mmol), copper(I) iodide (37 mg, 0.1922 mmol), cesium fluoride (121 mg, 0.7990 mmol), N,N'-dimethylethylenediamine (43 μL, 0.3944 mmol), and anhydrous potassium carbonate powder (0.7282 mmol, 101 mg) were added to anhydrous 1,4-dioxane (4.0 mL) degassed under nitrogen. The resulting suspension was stirred at 90 °C overnight. The reaction was cooled to room temperature, diluted with methanol, and filtered. The clear blue filtrate was concentrated to give a gray solid. This was suspended in dichloromethane, filtered through a plug of Celite, and concentrated. The crude product was purified by silica gel column chromatography using a gradient solvent system of 0 to 10% MeOH in DCM to give still impure product. It was repurified by silica gel column chromatography using a gradient solvent system of 0 to 100% EtOAc in hexane to give the pure title compound as a yellow oil (21 mg, 10%).

[0431] 1 H NMR(400MHz,CDCl3)δ 7.81-7.89(2H),7.28(m,2H),7.09(m,2H),5.37-5.44(1H),4.28(bs,1H),4.05(bs,1H),3.49(m,1H),3.33(m,2H),ESIMS:m / z 534.1[(M+H) + ].

[0432] Example 19 2,4-Bis(trifluoromethyl)-6-((S)-3-hydroxy-2-oxopyrrolidin-1-yl)phenyl 4-fluorophenylmethylcarbamate [ka]

[0433] Step 1: Synthesis of 2-(2,4-bis(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane [ka] A solution of 1-bromo-2,4-bis(trifluoromethyl)benzene (3 g, 0.0102 mol) in 1,4-dioxane (90 mL) was purged with N2 in a sealed tube for 30 minutes. Then, under inert atmosphere, bis-pinacolatodiboron (2.12 g, 0.00837 mol), potassium acetate (0.82 g, 0.00836 mol), and Pd(dppf)Cl2·DCM (0.34 g, 0.00042 mol) were added with stirring. The sealed tube was heated to 100 °C in an oil bath with stirring for 6 hours. The reaction progress was monitored by TLC (Rf = 0.6, 10% EtOAc in hexane). After completion of the reaction, the reaction mixture was concentrated under reduced pressure to give the crude product. The crude product was washed with n-hexane (4 × 75 mL), and the collected washings were concentrated under reduced pressure to give a yellow sticky solid (crude 6 g, quantitative yield). The product was used directly in the next step without further purification.

[0434] Step 2: Synthesis of 2,4-bis(trifluoromethyl)phenol [ka] To a cold (0°C) solution of 2-(2,4-bis(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (crude product, 6 g) in EtOH (120 mL) was added 30% aqueous hydrogen peroxide (6.0 mL) with stirring under an inert atmosphere. The reaction mixture was stirred at ambient temperature for 16 hours. Completion of the reaction was confirmed by TLC (R fAfter checking with a 0.2 ml solution of 10% EtOAc in hexanes, the reaction mixture was cooled to 0 °C and quenched with aqueous sodium metabisulfite, followed by extraction with EtOAc (2 × 100 mL). The collected organic layers were washed with water and then brine, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give the crude product. The resulting crude product was purified by column chromatography (100-200 silica gel, 10-15% EtOAc in hexanes as eluent) to give the title compound as a pale yellow liquid (1.5 g, 65% yield).

[0435] Step 3: Synthesis of 2-iodo-4,6-bis(trifluoromethyl)phenol [ka] A solution of 2,4-bis(trifluoromethyl)phenol (1.0 g, 0.0043 mol) in THF:HO (3:1, 20 mL) was cooled to 0 °C in an ice bath with stirring. After 15 min, I (1.4 g, 0.0056 mol) was added followed by NaCO (0.68 g, 0.0064 mol) with stirring under an inert atmosphere. The reaction mixture was stirred at ambient temperature for 24 h. Completion of the reaction (TLC: R f After 2 min (−0.4, 30% EtOAc in hexanes, followed by 30% DCM in hexanes), the reaction mixture was cooled to 0° C. and then quenched with aqueous sodium metabisulfite, followed by extraction with EtOAc (2×100 mL). The collected organic layers were washed with water and then brine, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give the crude product. The resulting crude product was purified by column chromatography (100-200 silica gel, 5-10% EtOAc in hexanes as eluent) to give the title compound as a pale yellow solid (0.98 g, 64% yield).

[0436] Step 4: Synthesis of (4-fluorophenyl)(methyl)carbamic acid chloride [ka] To a cold (0 °C) solution of triphosgene (1.6 g, 0.0128 mol) in DCM (40 mL), a solution of N-methyl-4-fluoroaniline (1.89 g, 0.0063 mol) and pyridine (2.0 g, 2.0 mL, 0.025 mol) was added dropwise over 10 min. Stirring was then continued at room temperature for 16 h. The progress of the reaction was monitored by TLC. Upon completion of the reaction, the reaction mixture was quenched with 1 M aqueous HCl (50 mL) and then extracted with DCM (2 × 50 mL). The separated DCM layer was dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give the title compound as a green solid (1.8 g, 75%).

[0437] Step 5: Synthesis of 2-iodo-4,6-bis(trifluoromethyl)phenyl(4-fluorophenyl)(methyl)carbamate [ka] To a stirred solution of 2-iodo-4,6-bis(trifluoromethyl)phenol (0.5 g, 0.0014 mol) in pyridine (10 mL) was added (4-fluorophenyl)(methyl)carbamic acid chloride (0.34 g, 0.0018 mol) at room temperature and stirring was continued at 80° C. for 4 hours. The completion of the reaction was confirmed by TLC (R f After checking with HCl (0.8, 20% EtOAc in hexanes), the reaction mixture was quenched with 1 M HCl (50 mL) and extracted with EtOAc (2 × 50 mL). The separated organic layers were combined, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give the crude product. The resulting crude product was purified by silica gel chromatography (100-200, 0-10% EtOAc in hexanes as eluent) to give the title compound as an off-white solid (0.66 g, 93%).

[0438] Step 6: Synthesis of (S)-2-(3-hydroxy-2-oxopyrrolidin-1-yl)-4,6-bis(trifluoromethyl)phenyl(4-fluorophenyl)(methyl)carbamate [ka] 2-Iodo-4,6-bis(trifluoromethyl)phenyl(4-fluorophenyl)(methyl)carbamate (0.2 g, 0.00039 mol), (S)-3-hydroxypyrrolidin-2-one (0.079 g, 0.00078 mol), potassium carbonate (0.10 g, 0.00078 mol), and cesium fluoride (0.12 g, 0.00078 mol) were suspended in 1,4-dioxane (16 mL) that had been purged with N for 30 minutes, followed by the addition of copper(I) iodide (0.037 g, 0.00019 mol) and N,N'-dimethylethylenediamine (0.034 g, 0.42 mL, 0.00039 mol) with stirring. The reaction mixture was heated in an oil bath at 100 °C for 24 hours. TLC (R f After completion of the reaction with 0.4, 5% MeOH in DCM, the reaction mixture was concentrated under reduced pressure. The resulting residue was purified by column chromatography (100-200 silica gel, 0-3% MeOH in DCM as eluent) to give a solid. The solid was further purified by preparative TLC using CHCl / MeOH (98 / 2) as the mobile phase to give the title compound as an off-white solid (17 mg, 9%).

[0439] 1 H NMR(500MHz,DMSO-d6)δ 8.26(d,J=28.9Hz,1H),8.08(d,J=40.6Hz,1H),7.44(s,2H),7.26(t,2H),4.32(s,1H),3.80( s,1H),3.81(m,1H),3.39(s,2H),3.25(d,J=69.5Hz,3H),1.95(d,J=37.9Hz,1H),MS(ESI):m / z 481.25(M+H) + .

[0440] Example 20 2,4-Bis(trifluoromethyl)-6-(3-(2-hydroxypropyl)-2-oxoimidazolidin-1-yl)phenyl 4-fluorophenylmethylcarbamate [ka]

[0441] Step 1: Synthesis of 2-(2,4-bis(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane [ka] A solution of 1-bromo-2,4-bis(trifluoromethyl)benzene (3 g, 0.01 mol) in 1,4-dioxane (90 mL) was purged with N2 in a sealed tube for 30 minutes, and then bis-pinacolatodiboron (5.07 g, 0.02 mol), potassium acetate (1.96 g, 0.02 mol), and Pd(dppf)Cl2·DCM (0.816 g, 0.001 mol) were added with stirring under an inert atmosphere. The sealed tube was heated to 100 °C in an oil bath with stirring for 6 hours. The reaction progress was monitored by TLC (Rf = 0.6, 10% EtOAc in hexane). After completion of the reaction, the reaction mixture was concentrated under reduced pressure to give the crude product. The crude product was washed with n-hexane (4 × 75 mL), and the collected washings were concentrated under reduced pressure to give a yellow sticky solid (crude 6 g, quantitative). The product was used directly in the next step without further purification.

[0442] Step 2: Synthesis of 2,4-bis(trifluoromethyl)phenol [ka] To a cold (0°C) solution of 2-(2,4-bis(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (crude product, 6 g) in EtOH (120 mL) was added 30% aqueous hydrogen peroxide (6.0 mL) with stirring under an inert atmosphere. The reaction mixture was stirred at ambient temperature for 16 hours. Completion of the reaction was confirmed by TLC (R fAfter checking with a 0.2 ml solution of 10% EtOAc in hexanes, the reaction mixture was cooled to 0 °C and quenched with aqueous sodium metabisulfite, followed by extraction with EtOAc (2 × 100 mL). The collected organic layers were dried over anhydrous NaSO and concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography (100–200 silica gel, 10–15% EtOAc in hexanes as eluent) to give the title compound as a pale yellow liquid (1.5 g, 65% yield).

[0443] Step 3: Synthesis of 2-iodo-4,6-bis(trifluoromethyl)phenol [ka] A solution of 2,4-bis(trifluoromethyl)phenol (1.0 g, 0.0043 mol) in THF:HO (3:1, 20:6 mL) was cooled to 0 °C in an ice bath with stirring. After 15 min, with stirring under an inert atmosphere, I (1.43 g, 0.0056 mol) was added, followed by NaCO (0.68 g, 0.0064 mol). The reaction mixture was stirred at ambient temperature for 24 h. Completion of the reaction (TLC: R f After 2 min (-0.4, 30% EtOAc in hexanes, followed by 30% DCM in hexanes), the reaction mixture was cooled to 0 °C and then quenched with aqueous sodium metabisulfite, followed by extraction with EtOAc (2 × 100 mL). The collected organic layers were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography (100-200 silica gel, 5-10% EtOAc in hexanes as eluent) to give the title compound as a pale yellow solid (0.98 g, 64% yield).

[0444] Step 4: Synthesis of (4-fluorophenyl)(methyl)carbamic acid chloride [ka] To a cold (0°C) solution of triphosgene (1.6 g, 0.0128 mol) in DCM (40 mL) was added a solution of N-methyl-4-fluoroaniline (1.89 g, 0.0064 mol) and pyridine (2.52 g, 2.6 mL, 0.032 mol) dropwise over 10 min. Stirring was then continued at room temperature for 16 h. The progress of the reaction was monitored by TLC (R f The reaction mixture was monitored with 10% EtOAc in hexane (×4) at −0.7° C. After completion of the reaction, the reaction mixture was quenched with 1 M aqueous HCl (50 mL) and then extracted with DCM (2×50 mL). The separated DCM layer was dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give the title compound as a green solid (1.8 g, 75%).

[0445] Step 5: Synthesis of 2-iodo-4,6-bis(trifluoromethyl)phenyl(4-fluorophenyl)(methyl)carbamate [ka] To a stirred solution of 2-iodo-4,6-bis(trifluoromethyl)phenol (0.5 g, 0.0014 mol) in pyridine (10 mL) was added (4-fluorophenyl)(methyl)carbamic acid chloride (0.34 g, 0.0018 mol) at room temperature and stirring was continued at 80° C. for 4 hours. The completion of the reaction was confirmed by TLC (R f After checking with HCl (0.8, 20% EtOAc in hexanes), the reaction mixture was quenched with 1 M HCl (50 mL) and extracted with EtOAc (2 × 50 mL). The separated organic layers were combined, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give the crude product. The resulting crude product was purified by silica gel chromatography (100-200, 5-10% EtOAc in hexanes as eluent) to give the title compound as an off-white solid (0.66 g, 93%).

[0446] Step 6: Synthesis of 2-(2-oxoimidazolidin-1-yl)-4,6-bis(trifluoromethyl)phenyl(4-fluorophenyl)(methyl)carbamate [ka] 2-Iodo-4,6-bis(trifluoromethyl)phenyl(4-fluorophenyl)(methyl)carbamate (0.2 g, 0.00039 mol), 2-imidaziridinone (0.064 g, 0.0007 mol), copper(I) iodide (0.037 g, 0.00019 mol), N,N'-dimethylethylenediamine (0.07 mL, 0.00039 mol), cesium fluoride (0.12 g, 0.00079 mol), and potassium carbonate (0.1 g, 0.00072 mol) were suspended in 1,4-dioxane (16 mL) that had been pre-purged with N for 30 minutes. The reaction mixture was heated in an oil bath at 90 °C for 24 hours. TLC (R f After completion of the reaction with 0.4, 5% MeOH in DCM, the reaction mixture was concentrated under reduced pressure. The resulting residue was purified by column chromatography (100-200 silica gel, 0-3% MeOH in DCM as eluent) to give the title compound as an off-white solid (50 mg). The solid was purified by preparative TLC (solid phase: Merck, 20 × 20 cm, silica gel 60GF 254 Re-purification by HPLC on a 1 mm PLC glass plate (2% MeOH in DCM as eluent) afforded the title compound as a white solid (28 mg, 15%).

[0447] Step 7: Synthesis of 2-(2-oxo-3-(2-oxopropyl)imidazolidin-1-yl)-4,6-bis(trifluoromethyl)phenyl(4-fluorophenyl)(methyl)carbamate [ka] A solution of 2-(2-oxoimidazolidin-1-yl)-4,6-bis(trifluoromethyl)phenyl(4-fluorophenyl)(methyl)carbamate (0.11 g, 0.0002 mol) in DMF in a sealed tube was purged with N for 10 minutes, and then cesium carbonate (0.23 g, 0.0007 mol), potassium iodide (0.066 g, 0.0004 mol), and 1-bromopropan-2-one (0.05 mL, 0.0004 mol) were added. The mixture was heated at 80 °C for 24 hours. Completion of the reaction was confirmed by TLC (R fAfter checking with 2% MeOH / DCM (-0.6), cold water was added, followed by extraction with ethyl acetate (2 x 50 mL). The organic layers were separated and combined, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the crude product. The crude product was analyzed by preparative TLC (solid phase: 20 x 20 cm, silica gel 60GF 254 , 1 mm, PLC Merck glass plate, 1% MeOH in DCM as eluent) to afford the title compound as a sticky white solid (35 mg, 34%).

[0448] Step 8: Synthesis of 2-(3-(2-hydroxypropyl)-2-oxoimidazolidin-1-yl)-4,6-bis(trifluoromethyl)phenyl(4-fluorophenyl)(methyl)carbamate [ka] To a stirred solution of 2-(2-oxo-3-(2-oxopropyl)imidazolidin-1-yl)-4,6-bis(trifluoromethyl)phenyl(4-fluorophenyl)(methyl)carbamate (0.04 g, 0.000076 mol) in methanol cooled to 0 °C, sodium borohydride (0.0058 g, 0.00015 mol) was added under a N atmosphere, and the mixture was stirred at 20 °C for 1 h. The completion of the reaction was confirmed by TLC (R f After checking with HCl (-0.3, 5% MeOH / DCM), the reaction mixture was concentrated under reduced pressure to give the crude product. The crude product was washed with water and then extracted with ethyl acetate (2 x 20 mL). The organic layers were separated and combined, dried over anhydrous Na2S...

Claims

1. A compound having the structure of formula (I), or a tautomer or stereochemical isomer, pharmaceutically acceptable salt, or solvate thereof. 【Chemical 1】 (In the formula, U is CH ２ , O, S, or NR Ｕ represents W is C(R ４ ) or N, Y is C(R ６ ) or N, Q represents O or S; R １ , R ２ , R ３ , R ４ , R ６ , R ７ , R ８ , R ９ and R １０ are independently hydrogen, deuterium, C １～６ Alkyl, C ２～６ Alkenyl, alkynyl, hydroxy, thiol, C １～６ Alkoxy, halogen, haloC １～６ Alkyl, haloC １～６ Alkoxy, C ３～８ Cycloalkyl, nitrile, NR Ｘ R Ｙ and combinations thereof, and two adjacent groups R １ ~R ４ or R ６ ~R １０ may optionally be joined to form a 5-7 membered saturated or unsaturated ring optionally containing one or more heteroatoms selected from O, N or S; R ５ and R Ｕ are independently hydrogen, deuterium, C １～６ Alkyl, C ２～６ Alkenyl, alkynyl, hydroxy, thiol, C １～６ Alkoxy, halogen, haloC １ ~ ６ Alkyl, haloC １ ~ ６ Alkoxy, C ３～８ Cycloalkyl, nitrile, -NR Ｘ R Ｙ , aryl, heteroaryl, heterocyclyl, amido, and combinations thereof; Z is CR Ｚ R Ｚ’ , C═S, or C═O; X is C(R １５ ) (R １６ ), N(R １７ ) or O, R １５ , R １６ and R １７ are independently hydrogen, deuterium, C １～６ Alkyl, haloC １ ~ ６ Alkyl, -OR １５ａ , -SR １５ａ , nitrile, -COC １～６ Alkyl, -COOC １～６ Alkyl, hydroxy, C １～６ Alkoxy, C １～６ Alkanol, C ３ ~ ８ Cycloalkyl, halogen, carbonyl, -NR Ｖ R Ｗ , -CH ２ -NR Ｖ R Ｗ , -OSO ２ NH ２ , —P(O)OH ２ , aryl, heteroaryl, heterocyclyl, and combinations thereof; R １５ , R １６ , and R １７ may further comprise one or more divalent linkers L selected from the group consisting of alkylene, cycloalkylene, heteroalkylene, heterocycloalkylene, alkenylene, alkynylene, arylene, heteroarylene, silyl, amine, amide, ester, ether, carbonyl, carbamate, sulfamate, sulfonate ester, sulfoximine, sulfonamide, thioether, thioester, disulfide, hydrazine, urea, thiourea, phosphate, phosphonate ester, poly(alkyl ether), heteroatom, and combinations thereof; and R １５ and R １６ and may be taken together to form a ring, n is 0, 1 or 2, and when n is 0, N is R Ｂ and R Ｂ’ is directly bonded to the carbon to which it is attached, R Ａ , R Ａ’ , R Ｚ , and R Ｚ’ are each independently hydrogen, deuterium, or C １～６ Alkyl, hydroxy, C １～６ Alkoxy, C １～６ Alkanol, halogen, -OR １５ｂ , CO ２ H, CO ２ R １５ｂ , Halo C １～６ alkyl, and combinations thereof; R Ｂ and R Ｂ’ are independently hydrogen, deuterium, C １～６ Alkyl, hydroxy, C １～６ Alkoxy, C １～６ Alkanol, halogen, -OR １５ｂ , CO ２ H, CO ２ R １５ｂ , Halo C １～６ alkyl, and combinations thereof, or R Ｂ and the carbon to which it is attached together form a carbonyl group, R Ｂ’ does not exist, R １５ａ and R １５ｂ are independently hydrogen, deuterium, or C １～６ represents alkyl, and two groups R １５ａ and R １５ｂ , or two groups R １５ｂ are bonded together to form one or more C １ ~ ６ may form a 5- to 7-membered saturated ring system optionally substituted with alkyl groups; R Ｖ , R Ｗ , R Ｘ and R Ｙ are independently hydrogen, deuterium, C １～６ Alkyl, haloC １ ~ ６ Alkyl, C ３～８ Cycloalkyl, -COC １～６ represents an alkyl or heterocyclyl, wherein the alkyl group is optionally substituted with one or more deuterium, hydroxy, amino, or sulfone groups, and the heterocyclyl ring is optionally substituted with one or more deuterium, oxo, hydroxy, C １～６ Alkanol or -COC １～６ It may be optionally substituted with an alkyl group.

2. The compound of claim 1 , wherein U is O.

3. U is CH ２ 2. The compound of claim 1, wherein:

4. 2. The compound of claim 1, wherein U is S.

5. The compound of claim 1 , wherein Q is O.

6. 2. The compound of claim 1, wherein Q is S.

7. R １ and R ３ At least one of the groups is halogen or haloC １～６ The compound of claim 1 , wherein the compound represents alkyl.

8. R １ and R ３ are each independently halogen or haloC- １－６ The compound of claim 1 , wherein the compound represents alkyl.

9. R １ and R ３ are CFs ３ 2. The compound of claim 1, wherein

10. R ２ However, hydrogen, deuterium, halogens, C １ ~ ６ Alkyl and haloC １～６ 2. The compound of claim 1, wherein the compound is selected from the group consisting of alkyl.

11. R ４ 2. The compound of claim 1, wherein is selected from the group consisting of hydrogen, deuterium, halogen, nitrile, methyl, and ethynyl.

12. R ５ is CH ３ or CD ３ 2. The compound of claim 1, wherein

13. R ５ 2. The compound of claim 1, wherein: 【Chemistry 2】 (In the formula, R ５’ is hydrogen, deuterium, C １～６ Alkyl, C ２～６ Alkenyl, alkynyl, hydroxy, thiol, C １～６ Alkoxy, halogen, haloC １ ~ ６ Alkyl, haloC １ ~ ６ Alkoxy, C ３～８ Cycloalkyl, nitrile, -NR Ｘ R Ｙ , aryl, heteroaryl, heterocyclyl, amido, and combinations thereof.

14. R ５ A compound according to claim 1, wherein represents one of the following substituents: 【Chemistry 3】

15. R ８ , R ９ , and R １０ 2. The compound of claim 1, wherein each represents a halogen.

16. R ８ 2. The compound of claim 1, wherein represents fluorine.

17. R ７ However, hydrogen, fluorine, chlorine, CH ３ , or CD ３ 17. The compound of claim 16, wherein

18. 18. The compound of claim 17, wherein Y is N.

19. R ９ 2. The compound of claim 1, wherein represents chlorine.

20. R １０ 2. The compound of claim 1, wherein represents fluorine.

21. R ７ and R ８ or R ８ and R ９ The compound of claim 1 , wherein:

22. 22. The compound of claim 21, wherein Y is N.

23. R Ａ and R Ａ’ 2. The compound of claim 1, wherein each represents hydrogen or deuterium.

24. 2. The compound of claim 1, wherein Z represents C=O or C=S.

25. Z is CR Ｚ R Ｚ’ 2. The compound of claim 1, wherein

26. Z is CR Ｚ R Ｚ’ represents R Ｚ and R Ｚ’ 2. The compound of claim 1, wherein each represents hydrogen or deuterium.

27. X is NR １７ represents R １７ 2. The compound of claim 1, wherein represents a substituent selected from the group consisting of: 【Chemistry 4】 【Chemistry 5】 【Chemistry 6】 【Chemistry 7】

28. The compound of claim 1 , wherein the compound of formula (I) is represented by formula (Ia): 【Chemistry 8】

29. The compound of claim 1 , wherein the compound of formula (I) is represented by formula (Ib): 【Chemistry 9】

30. The compound according to claim 1, wherein the compound of formula (I) is represented by formula (Ic) or formula (Ic'): 【Chemistry 10】

31. The compound according to claim 1, wherein the compound of formula (I) is represented by formula (Id) or formula (Id'): 【Chemistry 11】

32. The compound according to claim 1, wherein the compound of formula (I) is represented by formula (Ie) or formula (Ie'): 【Chemistry 12】

33. 1. A method of treating cancer in a subject in need thereof, comprising administering to said subject a compound of formula (I) or a tautomeric or stereochemical isomer, pharmaceutically acceptable salt, or solvate thereof. 【Chemistry 13】 (In the formula, U is CH ２ , O, S, or NR Ｕ represents W is C(R ４ ) or N, Y is C(R ６ ) or N, Q represents O or S; R １ , R ２ , R ３ , R ４ , R ６ , R ７ , R ８ , R ９ and R １０ are independently hydrogen, deuterium, C １～６ Alkyl, C ２～６ Alkenyl, alkynyl, hydroxy, thiol, C １～６ Alkoxy, halogen, haloC １～６ Alkyl, haloC １～６ Alkoxy, C ３～８ Cycloalkyl, nitrile, NR Ｘ R Ｙ and combinations thereof, and two adjacent groups R １ ~R ４ or R ６ ~R １０ may optionally be joined to form a 5-7 membered saturated or unsaturated ring optionally containing one or more heteroatoms selected from O, N or S; R ５ and R Ｕ are independently hydrogen, deuterium, C １～６ Alkyl, C ２～６ Alkenyl, alkynyl, hydroxy, thiol, C １～６ Alkoxy, halogen, haloC １ ~ ６ Alkyl, haloC １ ~ ６ Alkoxy, C ３～８ Cycloalkyl, nitrile, -NR Ｘ R Ｙ , aryl, heteroaryl, heterocyclyl, amido, and combinations thereof; Z is CR Ｚ R Ｚ’ , C═S, or C═O; X is C(R １５ ) (R １６ ), N(R １７ ) or O, R １５ , R １６ and R １７ are independently hydrogen, deuterium, C １～６ Alkyl, haloC １ ~ ６ Alkyl, -OR １５ａ , -SR １５ａ , nitrile, -COC １～６ Alkyl, -COOC １～６ Alkyl, hydroxy, C １～６ Alkoxy, C １～６ Alkanol, C ３ ~ ８ Cycloalkyl, halogen, carbonyl, -NR Ｖ R Ｗ , -CH ２ -NR Ｖ R Ｗ , -OSO ２ NH ２ , —P(O)OH ２ , aryl, heteroaryl, heterocyclyl, and combinations thereof; R １５ , R １６ , and R １７ may further comprise one or more divalent linkers L selected from the group consisting of alkylene, cycloalkylene, heteroalkylene, heterocycloalkylene, alkenylene, alkynylene, arylene, heteroarylene, silyl, amine, amide, ester, ether, carbonyl, carbamate, sulfamate, sulfonate ester, sulfoximine, sulfonamide, thioether, thioester, disulfide, hydrazine, urea, thiourea, phosphate, phosphonate ester, poly(alkyl ether), heteroatom, and combinations thereof; and R １５ and R １６ and may be taken together to form a ring, n is 0, 1 or 2, and when n is 0, N is R Ｂ and R Ｂ’ is directly bonded to the carbon to which it is attached, R Ａ , R Ａ’ , R Ｚ , and R Ｚ’ are each independently hydrogen, deuterium, or C １～６ Alkyl, hydroxy, C １～６ Alkoxy, C １～６ Alkanol, halogen, -OR １５ｂ , CO ２ H, CO ２ R １５ｂ , Halo C １～６ alkyl, and combinations thereof; R Ｂ and R Ｂ’ are independently hydrogen, deuterium, C １～６ Alkyl, hydroxy, C １～６ Alkoxy, C １～６ Alkanol, halogen, -OR １５ｂ , CO ２ H, CO ２ R １５ｂ , Halo C １～６ alkyl, and combinations thereof, or R Ｂ and the carbon to which it is attached together form a carbonyl group, R Ｂ’ does not exist, R １５ａ and R １５ｂ are independently hydrogen, deuterium, or C １～６ represents alkyl, and two groups R １５ａ and R １５ｂ , or two groups R １５ｂ are bonded together to form one or more C １ ~ ６ may form a 5- to 7-membered saturated ring system optionally substituted with alkyl groups; R Ｖ , R Ｗ , R Ｘ and R Ｙ are independently hydrogen, deuterium, C １～６ Alkyl, haloC １ ~ ６ Alkyl, C ３～８ Cycloalkyl, -COC １～６ represents an alkyl or heterocyclyl, wherein the alkyl group is optionally substituted with one or more deuterium, hydroxy, amino, or sulfone groups, and the heterocyclyl ring is optionally substituted with one or more deuterium, oxo, hydroxy, C １～６ Alkanol or -COC １～６ It may be optionally substituted with an alkyl group.

34. 34. The method of claim 33, further comprising administering to the subject one or more PARP inhibitors, one or more topoisomerase inhibitors, one or more DNA damaging agents, one or more platinum agents, one or more DNA damage response inhibitors, one or more ATR inhibitors, one or more WEE1 inhibitors, one or more DNA-PK inhibitors, one or more ATM inhibitors, anti-cancer radiation therapy, or proton beam therapy.

35. A method for inhibiting the activity of DNA polymerase theta (Polq), comprising contacting Polq with a compound of formula (I) or a tautomer or stereochemical isomer, pharmaceutically acceptable salt, or solvate thereof. 【Chemistry 14】 (In the formula, U is CH ２ , O, S, or NR Ｕ represents W is C(R ４ ) or N, Y is C(R ６ ) or N, Q represents O or S; R １ , R ２ , R ３ , R ４ , R ６ , R ７ , R ８ , R ９ and R １０ are independently hydrogen, deuterium, C １～６ Alkyl, C ２～６ Alkenyl, alkynyl, hydroxy, thiol, C １～６ Alkoxy, halogen, haloC １～６ Alkyl, haloC １～６ Alkoxy, C ３～８ Cycloalkyl, nitrile, NR Ｘ R Ｙ and combinations thereof, and two adjacent groups R １ ~R ４ or R ６ ~R １０ may optionally be joined to form a 5-7 membered saturated or unsaturated ring optionally containing one or more heteroatoms selected from O, N or S; R ５ and R Ｕ are independently hydrogen, deuterium, C １～６ Alkyl, C ２～６ Alkenyl, alkynyl, hydroxy, thiol, C １～６ Alkoxy, halogen, haloC １ ~ ６ Alkyl, haloC １ ~ ６ Alkoxy, C ３～８ Cycloalkyl, nitrile, -NR Ｘ R Ｙ , aryl, heteroaryl, heterocyclyl, amido, and combinations thereof; Z is CR Ｚ R Ｚ’ , C═S, or C═O; X is C(R １５ ) (R １６ ), N(R １７ ) or O, R １５ , R １６ and R １７ are independently hydrogen, deuterium, C １～６ Alkyl, haloC １ ~ ６ Alkyl, -OR １５ａ , -SR １５ａ , nitrile, -COC １～６ Alkyl, -COOC １～６ Alkyl, hydroxy, C １～６ Alkoxy, C １～６ Alkanol, C ３ ~ ８ Cycloalkyl, halogen, carbonyl, -NR Ｖ R Ｗ , -CH ２ -NR Ｖ R Ｗ , -OSO ２ NH ２ , —P(O)OH ２ , aryl, heteroaryl, heterocyclyl, and combinations thereof; R １５ , R １６ , and R １７ may further comprise one or more divalent linkers L selected from the group consisting of alkylene, cycloalkylene, heteroalkylene, heterocycloalkylene, alkenylene, alkynylene, arylene, heteroarylene, silyl, amine, amide, ester, ether, carbonyl, carbamate, sulfamate, sulfonate ester, sulfoximine, sulfonamide, thioether, thioester, disulfide, hydrazine, urea, thiourea, phosphate, phosphonate ester, poly(alkyl ether), heteroatom, and combinations thereof; and R １５ and R １６ and may be taken together to form a ring, n is 0, 1 or 2, and when n is 0, N is R Ｂ and R Ｂ’ is directly bonded to the carbon to which it is attached, R Ａ , R Ａ’ , R Ｚ , and R Ｚ’ are each independently hydrogen, deuterium, or C １～６ Alkyl, hydroxy, C １～６ Alkoxy, C １～６ Alkanol, halogen, -OR １５ｂ , CO ２ H, CO ２ R １５ｂ , Halo C １～６ alkyl, and combinations thereof; R Ｂ and R Ｂ’ are independently hydrogen, deuterium, C １～６ Alkyl, hydroxy, C １～６ Alkoxy, C １～６ Alkanol, halogen, -OR １５ｂ , CO ２ H, CO ２ R １５ｂ , Halo C １～６ alkyl, and combinations thereof, or R Ｂ and the carbon to which it is attached together form a carbonyl group, R Ｂ’ does not exist, R １５ａ and R １５ｂ are independently hydrogen, deuterium, or C １～６ represents alkyl, and two groups R １５ａ and R １５ｂ , or two groups R １５ｂ are bonded together to form one or more C １ ~ ６ may form a 5- to 7-membered saturated ring system optionally substituted with alkyl groups; R Ｖ , R Ｗ , R Ｘ and R Ｙ are independently hydrogen, deuterium, C １～６ Alkyl, haloC １ ~ ６ Alkyl, C ３～８ Cycloalkyl, -COC １～６ represents an alkyl or heterocyclyl, wherein the alkyl group is optionally substituted with one or more deuterium, hydroxy, amino, or sulfone groups, and the heterocyclyl ring is optionally substituted with one or more deuterium, oxo, hydroxy, C １～６ Alkanol or -COC １～６ It may be optionally substituted with an alkyl group.

36. 36. The method of claim 35, further comprising administering to the subject one or more PARP inhibitors, one or more topoisomerase inhibitors, one or more DNA damaging agents, one or more platinum agents, one or more DNA damage response inhibitors, one or more ATR inhibitors, one or more WEE1 inhibitors, one or more DNA-PK inhibitors, one or more ATM inhibitors, anti-cancer radiation therapy, or proton beam therapy.

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