How to use RAD51 inhibitors to treat pancreatic cancer

Abstract

The present application is directed to a RAD51 inhibitor represented by the following structural formula and a method of using the same for the treatment of pancreatic cancer, etc.

Description

[Background technology]

[0001] Related Applications This application claims priority to and benefit of U.S. Provisional Application No. 62 / 864,861, filed June 21, 2019, and U.S. Provisional Application No. 62 / 895,138, filed September 3, 2019, the contents of each of which are incorporated herein in their entirety.

[0002] RAD51 is a eukaryotic gene. The protein encoded by this gene is a member of the RAD51 protein family and aids in the repair of DNA double-strand breaks. RAD51 family members are homologous to bacterial RecA, archaeal RadA, and yeast RAD51. This protein is highly conserved in most eukaryotes, from yeast to humans. In humans, RAD51 is a 339-amino acid protein that plays a key role in DNA homologous recombination during double-strand break (DSB) repair. RAD51 catalyzes the transfer of strands between the broken sequence and its undamaged homolog, allowing for the resynthesis of the damaged region (see homologous recombination model).

[0003] Multiple studies have demonstrated sensitivity to some DNA damaging therapies that is associated with cellular defects in proteins that promote HR DNA repair. This sensitivity is particularly dramatic to DNA cross-linking chemotherapy drugs (30-100-fold) and ionizing radiation (3-5-fold) (Godthelp et al., "Mammalian Rad51C contributes to DNA cross-link resistance, sister chromatid cohesion, and genomic stability," Nucleic Acids Res., 30:2172-2182, 2002; Tebbs et al., "Correction of chromosomal instability and sensitivity to diverse mutagens by a cloned cDNA of the XRCC3 DNA repair gene," Proc. Natl. Acad. Sci. USA, 92:6354-6358, 1995; Takata et al., "Chromosome instability and defective recombinational repair in knockout mutants of the five Rad51 paralogs," Mol. Cell Biol., 21:2858-2866, 2001; Liu et al., “XRCC2 and XRCC3, new human Rad51-family members, promote chromosome stability and protect against DNA cross-links and other damages,” Mol. Cell, 1:783-793, 1998).

[0004] Several groups have recently demonstrated that partial inhibition of HR can sensitize cells to DNA-damaging therapies. Inhibition of XRCC3 (a RAD51 paralogous protein) has been demonstrated using a synthetic peptide corresponding to another paralogous protein. This peptide sensitized Chinese hamster ovary (CHO) cells to cisplatin and inhibited the formation of intranuclear RAD51 aggregates in response to DNA damage (Connell et al., Cancer Res., 64:3002-3005, 2004). Other researchers have either inhibited the expression of the RAD51 protein itself (Russell et al., Cancer Res., 63:7377-7383, 2003; Hansen et al., Int. J. Cancer, 105:472-479, 2003; Ohnishi et al., Biochem. Biophys. Res. Commun., 245:319-324, 1998; Ito et al., J. Gene Med., 7(8):1044-1052, 2005; Collins et al., Nucleic Acids Res., 29:1534-1538, 2001) or blocked its function by overexpressing a dominant-negative BRCA2 peptide fragment (Chen et al., J. Biol. Chem., 274:32931-32935, 2001). 1999). Given the relationship between increased sensitivity to several DNA-damaging therapies and cellular defects in HR DNA repair-related proteins, additional compounds that inhibit RAD51 are needed.

[0005] Although AID expression is usually transient and restricted to activated B cells, some cancers, including pancreatic cancer, exhibit constitutive ectopic AID expression. AID is a promiscuous DNA-damaging enzyme that targets multiple sites spread throughout the genome, leading to high levels of DNA replication stress. AID-expressing cells become critically dependent on the homologous recombination factor RAD51 to survive this DNA replication stress. Summary of the Invention

[0006] In one aspect, the present disclosure provides a method for treating pancreatic cancer, the method comprising administering to a subject in need thereof a therapeutically effective amount of a composition of the present disclosure, for example a composition comprising a RAD51 inhibitor of the present disclosure.

[0007] In one aspect, the present disclosure provides a method of treating pancreatic cancer, the method comprising administering to a subject in need thereof a therapeutically effective amount of a RAD51 inhibitor of the present disclosure.

[0008] In one aspect, the present disclosure provides a method of treating pancreatic cancer, the method comprising administering to a subject in need thereof a therapeutically effective amount of compound 67A or a pharmaceutically acceptable salt thereof.

[0009] In one aspect, the present disclosure provides compositions, eg, compositions comprising a RAD51 inhibitor of the present disclosure, for use in treating pancreatic cancer in a subject in need thereof.

[0010] In one aspect, the present disclosure provides RAD51 inhibitors for use in treating pancreatic cancer in a subject in need thereof.

[0011] In one aspect, the present disclosure provides compound 67A, or a pharmaceutically acceptable salt thereof, for use in treating pancreatic cancer in a subject in need thereof.

[0012] In one aspect, the present specification describes the use of a composition (e.g., a composition comprising a RAD51 inhibitor of the present disclosure) in the manufacture of a medicament for the treatment of pancreatic cancer in a subject in need thereof.

[0013] In one aspect, described herein is the use of a RAD51 inhibitor of the present disclosure in the manufacture of a medicament for the treatment of pancreatic cancer in a subject in need thereof.

[0014] In one aspect, described herein is the use of compound 67A, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of pancreatic cancer in a subject in need thereof.

[0015] Although applicants do not wish to be bound by any mechanism, it is believed that the compounds of the present disclosure inhibit RAD51 by binding to MDC1, reducing the ability of RAD51 to form an active complex. [Brief explanation of the drawings]

[0016] [Figure 1] FIG. 1 shows the methods for three pancreatic PDX models treated with vehicle, 80 mg / kg QD of Compound 67A, or 1 and 40 mg / kg QD of Compound 67A.

[0017] [Figure 2] Figures 2A-B show the results of the randomized split of Models 1, 2, and 3 treated with vehicle and 1 mg / kg Compound 67A into three groups (i.e., vehicle, 1 mg / kg, and 80 mg / kg; Figure 2A) and the randomized split of Models 1, 2, and 3 treated with 40 mg / kg and 80 mg / kg Compound 67A into three groups (i.e., 80 mg / kg, 80 mg / kg with a 14-day washout, and 80 mg / kg with a 21-day washout; Figure 2B).

[0018] [Figure 3] 3A-3B show the antitumor activity of compound 67A in Model 1 as measured by tumor volume (FIG. 3A) and tumor growth inhibition rate (FIG. 3B).

[0019] [Figure 4] 4A-4B show the antitumor activity of compound 67A in Model 2 as measured by tumor volume (FIG. 4A) and tumor growth inhibition rate (FIG. 4B).

[0020] [Figure 5]5A-5B show the antitumor activity of compound 67A in model 3 as measured by tumor volume (FIG. 5A) and tumor growth inhibition rate (FIG. 5B).

[0021] [Figure 6] Figures 6A-6C show the antitumor activity of compound 67A in model 2 as measured by tumor volume (Figure 6A), change in tumor volume at day 49 compared to day 0 (Figure 6B), and progression-free survival (Figure 6C).

[0022] [Figure 7] Figures 7A-7C show the antitumor activity of Compound 67A in Model 2, measured by tumor volume, for 80 mg / kg of Compound 67A continuously (Figure 7A), after a 14-day drug holiday (Figure 7B), and after a 21-day drug holiday (Figure 7C).

[0023] [Figure 8] Figure 8A shows the antitumor activity of Compound 67A as measured by tumor volume in PDX mouse model A after administration of Compound 67A at 80 mg / kg once daily or once every two days. Figure 8B shows the antitumor activity of Compound 67A as measured by tumor volume in PDX mouse model A after administration of 80 mg / kg of Compound 67A based on the tumor volume at the start of administration.

[0024] [Figure 9-1] Figure 9A shows the antitumor activity of Compound 67A as measured by tumor volume after administration of 80 mg / kg of Compound 67A once daily or once every two days in PDX mouse model B. Figure 9B shows the antitumor activity of Compound 67A as measured by tumor volume after administration of 80 mg / kg of Compound 67A based on the tumor volume at the start of administration in PDX mouse model B.

[0025] [Figure 9-2]Figures 9C-9D show the antitumor activity of Compound 67A in PDX mouse model B, as measured by tumor volume after administration of 80 mg / kg of Compound 67A on the drug holiday (Figure 9C) and tumor growth during and after the drug holiday (Figure 9D).

[0026] [Figure 10-1] Figure 10A shows the antitumor activity of Compound 67A as measured by tumor volume after administration of 80 mg / kg of Compound 67A once daily or once every two days in PDX mouse model C. Figure 10B shows the antitumor activity of Compound 67A as measured by tumor volume after administration of 80 mg / kg of Compound 67A based on the tumor volume at the start of administration in PDX mouse model C.

[0027] [Figure 10-2] Figures 10C-10D show the antitumor activity of Compound 67A in PDX mouse model C, as measured by tumor volume after administration of 80 mg / kg of Compound 67A on the drug holiday (Figure 9C) and tumor growth during and after the drug holiday (Figure 9D). DETAILED DESCRIPTION OF THE INVENTION

[0028] Applicants have developed compounds that are effective inhibitors of RAD51 (see Examples 1-75) for use in the treatment of pancreatic cancer. The RAD51 inhibitors of the present disclosure inhibit homologous recombination by altering the nucleocytoplasmic distribution of RAD51 following DNA damage induction. The RAD51 inhibitors of the present disclosure reduce the repair of AID-induced DNA double-strand breaks, leading to AID-dependent cytotoxicity in both normal and malignant cells. Some of these RAD51 inhibitors exhibit excellent cell permeability as measured in Caco-2 cells (see Example 76). Some of the RAD51 inhibitors with good cell permeability also have excellent metabolic stability (measured by liver microsome assay, see Example 77) and exposure (including oral exposure) (see Example 79).

[0029] In some embodiments, the present disclosure provides methods of treating a subject having a disease that can be ameliorated by inhibition of RAD51 by administering to the subject an effective amount of one or more of the disclosed compounds or pharmaceutically acceptable salts thereof, or corresponding pharmaceutical compositions. Diseases that can be ameliorated by inhibition of RAD51 include the treatment of cancer, autoimmune diseases, immune disorders, or neurodegenerative diseases.

[0030] In some embodiments, described herein are methods for treating pancreatic cancer, the methods comprising administering to a subject in need thereof a therapeutically effective dose of a composition of the present disclosure, e.g., a composition comprising a RAD51 inhibitor of the present disclosure.

[0031] In some embodiments, described herein are methods for treating pancreatic cancer, the methods comprising administering a therapeutically effective dose of a RAD51 inhibitor of the present disclosure to a subject in need thereof.

[0032] In some embodiments, described herein are methods for treating pancreatic cancer, the methods comprising administering a therapeutically effective dose of compound 67A, or a pharmaceutically acceptable salt thereof, to a subject in need thereof.

[0033] In some embodiments, described herein are compositions (e.g., compositions comprising a RAD51 inhibitor of the present disclosure) for use in treating pancreatic cancer in a subject in need thereof.

[0034] In some embodiments, described herein are RAD51 inhibitors of the present disclosure for use in treating pancreatic cancer in a subject in need thereof.

[0035] In some embodiments, described herein is compound 67A, or a pharmaceutically acceptable salt thereof, for use in treating pancreatic cancer in a subject in need thereof.

[0036] In some embodiments, described herein is the use of a composition (e.g., a composition comprising a RAD51 inhibitor of the present disclosure) for treating pancreatic cancer in a subject in need thereof.

[0037] In some embodiments, described herein is the use of a RAD51 inhibitor of the present disclosure to treat pancreatic cancer in a subject in need thereof.

[0038] In some embodiments, described herein is the use of compound 67A, or a pharmaceutically acceptable salt thereof, for treating pancreatic cancer in a subject in need thereof.

[0039] In some embodiments, described herein is the use of a composition (e.g., a composition comprising a RAD51 inhibitor of the present disclosure) in the manufacture of a medicament for the treatment of pancreatic cancer in a subject in need thereof.

[0040] In some embodiments, described herein is the use of a RAD51 inhibitor of the present disclosure in the manufacture of a medicament for the treatment of pancreatic cancer in a subject in need thereof.

[0041] In some embodiments, described herein is the use of compound 67A, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating pancreatic cancer in a subject in need thereof.

[0042] In some embodiments, the subject is a mammal.

[0043] In some embodiments, the subject is a human.

[0044] In some embodiments, the RAD51 inhibitor is administered at a dose of about 1 mg / m 2 ~about 500 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0045] In some embodiments, the RAD51 inhibitor is administered at a dose of about 2 mg / m 2 ~about 500 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0046] In some embodiments, the RAD51 inhibitor is administered at a dose of about 3 mg / m 2 ~about 500 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0047] In some embodiments, the RAD51 inhibitor is administered at a dose of about 1 mg / m 2 ~about 400 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0048] In some embodiments, the RAD51 inhibitor is administered at a dose of about 2 mg / m 2 ~about 400 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0049] In some embodiments, the RAD51 inhibitor is administered at a dose of about 3 mg / m 2 ~about 400 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0050] In some embodiments, the RAD51 inhibitor is administered at a dose of about 1 mg / m 2 ~about 300 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0051] In some embodiments, the RAD51 inhibitor is administered at a dose of about 2 mg / m 2 ~about 300 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0052] In some embodiments, the RAD51 inhibitor is administered at a dose of about 3 mg / m 2 ~about 300 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0053] In some embodiments, the RAD51 inhibitor is administered at a dose of about 1 mg / m 2 ~about 280 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0054] In some embodiments, the RAD51 inhibitor is administered at a dose of about 1 mg / m 2 ~about 260 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0055] In some embodiments, the RAD51 inhibitor is administered at a dose of about 1 mg / m 2 ~about 240 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0056] In some embodiments, the RAD51 inhibitor is administered at a dose of about 1 mg / m 2 ~about 220 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0057] In some embodiments, the RAD51 inhibitor is administered at a dose of about 1 mg / m 2 ~about 200 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0058] In some embodiments, the RAD51 inhibitor is administered at a dose of about 1 mg / m 2 ~about 180 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0059] In some embodiments, the RAD51 inhibitor is administered at a dose of about 1 mg / m 2 ~about 160 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0060] In some embodiments, the RAD51 inhibitor is administered at a dose of about 1 mg / m 2 ~about 140 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0061] In some embodiments, the RAD51 inhibitor is administered at a dose of about 1 mg / m 2 ~about 120 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0062] In some embodiments, the RAD51 inhibitor is administered at a dose of about 1 mg / m 2 ~about 100 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0063] In some embodiments, the RAD51 inhibitor is administered at a dose of about 2 mg / m 2 ~about 280 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0064] In some embodiments, the RAD51 inhibitor is administered at a dose of about 2 mg / m 2 ~about 260 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0065] In some embodiments, the RAD51 inhibitor is administered at a dose of about 2 mg / m 2 ~about 240 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0066] In some embodiments, the RAD51 inhibitor is administered at a dose of about 2 mg / m 2 ~about 220 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0067] In some embodiments, the RAD51 inhibitor is administered at a dose of about 2 mg / m 2 ~about 200 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0068] In some embodiments, the RAD51 inhibitor is administered at a dose of about 2 mg / m 2 ~about 180 mg / m 2The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0069] In some embodiments, the RAD51 inhibitor is administered at a dose of about 2 mg / m 2 ~about 160 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0070] In some embodiments, the RAD51 inhibitor is administered at a dose of about 2 mg / m 2 ~about 140 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0071] In some embodiments, the RAD51 inhibitor is administered at a dose of about 2 mg / m 2 ~about 120 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0072] In some embodiments, the RAD51 inhibitor is administered at a dose of about 2 mg / m 2 ~about 100 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0073] In some embodiments, the RAD51 inhibitor is administered at a dose of about 3 mg / m 2 ~about 280 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0074] In some embodiments, the RAD51 inhibitor is administered at a dose of about 3 mg / m 2 ~about 260 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0075] In some embodiments, the RAD51 inhibitor is administered at a dose of about 3 mg / m 2 ~about 240 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0076] In some embodiments, the RAD51 inhibitor is administered at a dose of about 3 mg / m 2~about 220 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0077] In some embodiments, the RAD51 inhibitor is administered at a dose of about 3 mg / m 2 ~about 200 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0078] In some embodiments, the RAD51 inhibitor is administered at a dose of about 3 mg / m 2 ~about 180 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0079] In some embodiments, the RAD51 inhibitor is administered at a dose of about 3 mg / m 2 ~about 160 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0080] In some embodiments, the RAD51 inhibitor is administered at a dose of about 3 mg / m 2 ~about 140 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0081] In some embodiments, the RAD51 inhibitor is administered at a dose of about 3 mg / m 2 ~about 120 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0082] In some embodiments, the RAD51 inhibitor is administered at a dose of about 3 mg / m 2 ~about 100 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0083] In some embodiments, the RAD51 inhibitor is administered at a dose of about 50 mg / m 2 ~about 500 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0084] In some embodiments, the RAD51 inhibitor is administered at a dose of about 60 mg / m 2 ~about 500 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0085] In some embodiments, the RAD51 inhibitor is administered at a dose of about 70 mg / m 2 ~about 500 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0086] In some embodiments, the RAD51 inhibitor is administered at a dose of about 80 mg / m 2 ~about 500 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0087] In some embodiments, the RAD51 inhibitor is administered at a dose of about 90 mg / m 2 ~about 500 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0088] In some embodiments, the RAD51 inhibitor is administered at a dose of about 100 mg / m 2 ~about 500 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0089] In some embodiments, the RAD51 inhibitor is administered at a dose of about 120 mg / m 2 ~about 500 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0090] In some embodiments, the RAD51 inhibitor is administered at a dose of about 140 mg / m 2 ~about 500 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0091] In some embodiments, the RAD51 inhibitor is administered at a dose of about 160 mg / m 2 ~about 500 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0092] In some embodiments, the RAD51 inhibitor is administered at a dose of about 180 mg / m 2 ~about 500 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0093] In some embodiments, the RAD51 inhibitor is administered at a dose of about 200 mg / m 2 ~about 500 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0094] In some embodiments, the RAD51 inhibitor is administered at a dose of about 220 mg / m 2 ~about 500 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0095] In some embodiments, the RAD51 inhibitor is administered at a dose of about 240 mg / m 2 ~about 500 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0096] In some embodiments, the RAD51 inhibitor is administered at a dose of about 260 mg / m 2 ~about 500 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0097] In some embodiments, the RAD51 inhibitor is administered at a dose of about 280 mg / m 2 ~about 500 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0098] In some embodiments, the RAD51 inhibitor is administered at a dose of about 50 mg / m 2 ~about 400 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0099] In some embodiments, the RAD51 inhibitor is administered at a dose of about 60 mg / m 2 ~about 400 mg / m 2The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0100] In some embodiments, the RAD51 inhibitor is administered at a dose of about 70 mg / m 2 ~about 400 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0101] In some embodiments, the RAD51 inhibitor is administered at a dose of about 80 mg / m 2 ~about 400 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0102] In some embodiments, the RAD51 inhibitor is administered at a dose of about 90 mg / m 2 ~about 400 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0103] In some embodiments, the RAD51 inhibitor is administered at a dose of about 100 mg / m 2 ~about 400 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0104] In some embodiments, the RAD51 inhibitor is administered at a dose of about 120 mg / m 2 ~about 400 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0105] In some embodiments, the RAD51 inhibitor is administered at a dose of about 140 mg / m 2 ~about 400 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0106] In some embodiments, the RAD51 inhibitor is administered at a dose of about 160 mg / m 2 ~about 400 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0107] In some embodiments, the RAD51 inhibitor is administered at a dose of about 180 mg / m2 ~about 400 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0108] In some embodiments, the RAD51 inhibitor is administered at a dose of about 200 mg / m 2 ~about 400 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0109] In some embodiments, the RAD51 inhibitor is administered at a dose of about 220 mg / m 2 ~about 400 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0110] In some embodiments, the RAD51 inhibitor is administered at a dose of about 240 mg / m 2 ~about 400 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0111] In some embodiments, the RAD51 inhibitor is administered at a dose of about 260 mg / m 2 ~about 400 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0112] In some embodiments, the RAD51 inhibitor is administered at a dose of about 280 mg / m 2 ~about 400 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0113] In some embodiments, the RAD51 inhibitor is administered at a dose of about 50 mg / m 2 ~about 300 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0114] In some embodiments, the RAD51 inhibitor is administered at a dose of about 60 mg / m 2 ~about 300 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0115] In some embodiments, the RAD51 inhibitor is administered at a dose of about 70 mg / m 2 ~about 300 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0116] In some embodiments, the RAD51 inhibitor is administered at a dose of about 80 mg / m 2 ~about 300 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0117] In some embodiments, the RAD51 inhibitor is administered at a dose of about 90 mg / m 2 ~about 300 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0118] In some embodiments, the RAD51 inhibitor is administered at a dose of about 100 mg / m 2 ~about 300 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0119] In some embodiments, the RAD51 inhibitor is administered at a dose of about 120 mg / m 2 ~about 300 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0120] In some embodiments, the RAD51 inhibitor is administered at a dose of about 140 mg / m 2 ~about 300 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0121] In some embodiments, the RAD51 inhibitor is administered at a dose of about 160 mg / m 2 ~about 300 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0122] In some embodiments, the RAD51 inhibitor is administered at a dose of about 180 mg / m 2 ~about 300 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0123] In some embodiments, the RAD51 inhibitor is administered at a dose of about 200 mg / m 2 ~about 300 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0124] In some embodiments, the RAD51 inhibitor is administered at a dose of about 220 mg / m 2 ~about 300 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0125] In some embodiments, the RAD51 inhibitor is administered at a dose of about 240 mg / m 2 ~about 300 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0126] In some embodiments, the RAD51 inhibitor is administered at a dose of about 260 mg / m 2 ~about 300 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0127] In some embodiments, the RAD51 inhibitor is administered at a dose of about 280 mg / m 2 ~about 300 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0128] In some embodiments, the RAD51 inhibitor is administered at a dose of about 50 mg / m 2 ~about 280 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0129] In some embodiments, the RAD51 inhibitor is administered at a dose of about 50 mg / m 2 ~about 260 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0130] In some embodiments, the RAD51 inhibitor is administered at a dose of about 50 mg / m 2 ~about 240 mg / m 2The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0131] In some embodiments, the RAD51 inhibitor is administered at a dose of about 50 mg / m 2 ~about 220 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0132] In some embodiments, the RAD51 inhibitor is administered at a dose of about 50 mg / m 2 ~about 200 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0133] In some embodiments, the RAD51 inhibitor is administered at a dose of about 50 mg / m 2 ~about 180 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0134] In some embodiments, the RAD51 inhibitor is administered at a dose of about 50 mg / m 2 ~about 160 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0135] In some embodiments, the RAD51 inhibitor is administered at a dose of about 50 mg / m 2 ~about 140 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0136] In some embodiments, the RAD51 inhibitor is administered at a dose of about 60 mg / m 2 ~about 280 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0137] In some embodiments, the RAD51 inhibitor is administered at a dose of about 60 mg / m 2 ~about 260 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0138] In some embodiments, the RAD51 inhibitor is administered at a dose of about 60 mg / m 2~about 240 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0139] In some embodiments, the RAD51 inhibitor is administered at a dose of about 60 mg / m 2 ~about 220 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0140] In some embodiments, the RAD51 inhibitor is administered at a dose of about 60 mg / m 2 ~about 200 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0141] In some embodiments, the RAD51 inhibitor is administered at a dose of about 60 mg / m 2 ~about 180 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0142] In some embodiments, the RAD51 inhibitor is administered at a dose of about 60 mg / m 2 ~about 160 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0143] In some embodiments, the RAD51 inhibitor is administered at a dose of about 60 mg / m 2 ~about 140 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0144] In some embodiments, the RAD51 inhibitor is administered at a dose of about 70 mg / m 2 ~about 280 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0145] In some embodiments, the RAD51 inhibitor is administered at a dose of about 70 mg / m 2 ~about 260 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0146] In some embodiments, the RAD51 inhibitor is administered at a dose of about 70 mg / m 2 ~about 240 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0147] In some embodiments, the RAD51 inhibitor is administered at a dose of about 70 mg / m 2 ~about 220 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0148] In some embodiments, the RAD51 inhibitor is administered at a dose of about 70 mg / m 2 ~about 200 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0149] In some embodiments, the RAD51 inhibitor is administered at a dose of about 70 mg / m 2 ~about 180 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0150] In some embodiments, the RAD51 inhibitor is administered at a dose of about 70 mg / m 2 ~about 160 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0151] In some embodiments, the RAD51 inhibitor is administered at a dose of about 70 mg / m 2 ~about 140 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0152] In some embodiments, the RAD51 inhibitor is administered at a dose of about 80 mg / m 2 ~about 280 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0153] In some embodiments, the RAD51 inhibitor is administered at a dose of about 80 mg / m 2 ~about 260 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0154] In some embodiments, the RAD51 inhibitor is administered at a dose of about 80 mg / m 2 ~about 240 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0155] In some embodiments, the RAD51 inhibitor is administered at a dose of about 80 mg / m 2 ~about 220 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0156] In some embodiments, the RAD51 inhibitor is administered at a dose of about 80 mg / m 2 ~about 200 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0157] In some embodiments, the RAD51 inhibitor is administered at a dose of about 80 mg / m 2 ~about 180 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0158] In some embodiments, the RAD51 inhibitor is administered at a dose of about 80 mg / m 2 ~about 160 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0159] In some embodiments, the RAD51 inhibitor is administered at a dose of about 80 mg / m 2 ~about 140 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0160] In some embodiments, the RAD51 inhibitor is administered at a dose of about 90 mg / m 2 ~about 280 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0161] In some embodiments, the RAD51 inhibitor is administered at a dose of about 90 mg / m 2 ~about 260 mg / m 2The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0162] In some embodiments, the RAD51 inhibitor is administered at a dose of about 90 mg / m 2 ~about 240 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0163] In some embodiments, the RAD51 inhibitor is administered at a dose of about 90 mg / m 2 ~about 220 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0164] In some embodiments, the RAD51 inhibitor is administered at a dose of about 90 mg / m 2 ~about 200 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0165] In some embodiments, the RAD51 inhibitor is administered at a dose of about 90 mg / m 2 ~about 180 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0166] In some embodiments, the RAD51 inhibitor is administered at a dose of about 90 mg / m 2 ~about 160 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0167] In some embodiments, the RAD51 inhibitor is administered at a dose of about 90 mg / m 2 ~about 140 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0168] In some embodiments, the RAD51 inhibitor is administered at a dose of about 100 mg / m 2 ~about 280 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0169] In some embodiments, the RAD51 inhibitor is administered at a dose of about 100 mg / m 2~about 260 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0170] In some embodiments, the RAD51 inhibitor is administered at a dose of about 100 mg / m 2 ~about 240 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0171] In some embodiments, the RAD51 inhibitor is administered at a dose of about 100 mg / m 2 ~about 220 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0172] In some embodiments, the RAD51 inhibitor is administered at a dose of about 100 mg / m 2 ~about 200 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0173] In some embodiments, the RAD51 inhibitor is administered at a dose of about 100 mg / m 2 ~about 180 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0174] In some embodiments, the RAD51 inhibitor is administered at a dose of about 100 mg / m 2 ~about 160 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0175] In some embodiments, the RAD51 inhibitor is administered at a dose of about 100 mg / m 2 ~about 140 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0176] In some embodiments, the RAD51 inhibitor is administered at a dose of about 50 mg / m 2 ~about 240 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0177] In some embodiments, the RAD51 inhibitor is administered at a dose of about 60 mg / m 2 ~about 240 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0178] In some embodiments, the RAD51 inhibitor is administered at a dose of about 70 mg / m 2 ~about 240 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0179] In some embodiments, the RAD51 inhibitor is administered at a dose of about 80 mg / m 2 ~about 240 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0180] In some embodiments, the RAD51 inhibitor is administered at a dose of about 90 mg / m 2 ~about 240 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0181] In some embodiments, the RAD51 inhibitor is administered at a dose of about 100 mg / m 2 ~about 240 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0182] In some embodiments, the RAD51 inhibitor is administered at a dose of about 120 mg / m 2 ~about 240 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0183] In some embodiments, the RAD51 inhibitor is administered at a dose of about 1 mg / m 2 , about 2 mg / m 2 , about 3 mg / m 2 , about 4 mg / m 2 , about 5 mg / m 2 , about 10 mg / m 2 , about 20 mg / m 2 , about 30 mg / m 2 , about 40 mg / m 2 , about 50 mg / m2 , about 60 mg / m 2 , about 70 mg / m 2 , about 80 mg / m 2 , about 90 mg / m 2 , about 100 mg / m 2 , about 120 mg / m 2 , about 140 mg / m 2 , about 160 mg / m 2 , about 180 mg / m 2 , about 200 mg / m 2 , about 220 mg / m 2 , about 240 mg / m 2 , about 260 mg / m 2 , about 280 mg / m 2 , about 300 mg / m 2 , about 320 mg / m 2 , about 340 mg / m 2 , about 360 mg / m 2 , about 380 mg / m 2 , about 400 mg / m 2 , about 420 mg / m 2 , about 440 mg / m 2 , about 460 mg / m 2 , about 480 mg / m 2 , or approximately 500 mg / m 2 is administered in a dose (e.g., a human dose).

[0184] In some embodiments, the RAD51 inhibitor is administered at a dose of about 1 mg / m 2 , about 2 mg / m 2 , about 3 mg / m 2 , about 4 mg / m 2 , about 5 mg / m 2 , about 10 mg / m 2 , about 20 mg / m 2 , about 30 mg / m 2 , about 40 mg / m 2 , about 50 mg / m 2 , about 60 mg / m 2 , about 70 mg / m 2 , about 80 mg / m 2 , about 90 mg / m 2 , about 100 mg / m 2 , about 120 mg / m2 , about 140 mg / m 2 , about 160 mg / m 2 , about 180 mg / m 2 , about 200 mg / m 2 , about 220 mg / m 2 , about 240 mg / m 2 , about 260 mg / m 2 , about 280 mg / m 2 , or approximately 300 mg / m 2 is administered in a dose (e.g., a human dose).

[0185] In some embodiments, the RAD51 inhibitor is administered at a dose of about 3±2 mg / m 2 , 3±1.8 mg / m 2 , 3±1.6 mg / m 2 , 3±1.5 mg / m 2 , 3±1.4 mg / m 2 , 3±1.3 mg / m 2 , 3±1.2 mg / m 2 , 3±1.1 mg / m 2 , 3±1 mg / m 2 , 3±0.9 mg / m 2 , 3±0.8 mg / m 2 , 3±0.7 mg / m 2 , 3±0.6 mg / m 2 , 3±0.5 mg / m 2 , 3±0.4 mg / m 2 , 3±0.3 mg / m 2 , 3±0.2 mg / m 2 , or 3±0.1 mg / m 2 is administered in a dose (e.g., a human dose).

[0186] In some embodiments, the RAD51 inhibitor is administered at a dose of about 3 mg / m 2 is administered in a dose (e.g., a human dose).

[0187] In some embodiments, the RAD51 inhibitor is administered at a dose of about 50±45 mg / m 2 , 50±40 mg / m 2 , 50±35 mg / m 2 , 50±30 mg / m2 , 50±25 mg / m 2 , 50±20 mg / m 2 , 50±15 mg / m 2 , 50±10 mg / m 2 , 50±9 mg / m 2 , 50±8 mg / m 2 , 50±7 mg / m 2 , 50±6 mg / m 2 , 50±5 mg / m 2 , 50±4 mg / m 2 , 50±3 mg / m 2 , 50±2 mg / m 2 , or 50±1 mg / m 2 is administered in a dose (e.g., a human dose).

[0188] In some embodiments, the RAD51 inhibitor is administered at a dose of about 50 mg / m 2 is administered in a dose (e.g., a human dose).

[0189] In some embodiments, the RAD51 inhibitor is administered at a dose of about 120±100 mg / m 2 , 120±90 mg / m 2 , 120±80 mg / m 2 , 120±70 mg / m 2 , 120±60 mg / m 2 , 120±50 mg / m 2 , 120±45 mg / m 2 , 120±40 mg / m 2 , 120±35 mg / m 2 , 120±30 mg / m 2 , 120±25 mg / m 2 , 120±20 mg / m 2 , 120±15 mg / m 2 , 120±10 mg / m 2 , 120±9 mg / m 2 , 120±8 mg / m 2 , 120±7 mg / m 2 , 120±6 mg / m 2 , 120±5 mg / m 2 , 120±4 mg / m 2, 120±3 mg / m 2 , 120±2 mg / m 2 , or 120±1 mg / m 2 is administered in a dose (e.g., a human dose).

[0190] In some embodiments, the RAD51 inhibitor is administered at a dose of about 120 mg / m 2 is administered in a dose (e.g., a human dose).

[0191] In some embodiments, the RAD51 inhibitor is administered at a dose of about 240±100 mg / m 2 , 240±90 mg / m 2 , 240±80 mg / m 2 , 240±70 mg / m 2 , 240±60 mg / m 2 , 240±50 mg / m 2 , 240±45 mg / m 2 , 240±40 mg / m 2 , 240±35 mg / m 2 , 240±30 mg / m 2 , 240±25 mg / m 2 , 240±20 mg / m 2 , 240±15 mg / m 2 , 240±10 mg / m 2 , 240±9 mg / m 2 , 240±8 mg / m 2 , 240±7 mg / m 2 , 240±6 mg / m 2 , 240±5 mg / m 2 , 240±4 mg / m 2 , 240±3 mg / m 2 , 240±2 mg / m 2 , or 240±1 mg / m 2 is administered in a dose (e.g., a human dose).

[0192] In some embodiments, the RAD51 inhibitor is administered at a dose of about 240 mg / m 2 is administered in a dose (e.g., a human dose).

[0193] In some embodiments, the RAD51 inhibitor is administered at a dose of about 300±100 mg / m 2 , 300±90 mg / m 2 , 300±80 mg / m 2 , 300±70 mg / m 2 , 300±60 mg / m 2 , 300±50 mg / m 2 , 300±45 mg / m 2 , 300±40 mg / m 2 , 300±35 mg / m 2 , 300±30 mg / m 2 , 300±25 mg / m 2 , 300±20 mg / m 2 , 300±15 mg / m 2 , 300±10 mg / m 2 , 300±9 mg / m 2 , 300±8 mg / m 2 , 300±7 mg / m 2 , 300±6 mg / m 2 , 300±5 mg / m 2 , 300±4 mg / m 2 , 300±3 mg / m 2 , 300±2 mg / m 2 , or 300±1 mg / m 2 is administered in a dose (e.g., a human dose).

[0194] In some embodiments, the RAD51 inhibitor is administered at a dose of about 300 mg / m 2 is administered in a dose (e.g., a human dose).

[0195] In some embodiments, the RAD51 inhibitor is administered at a dose of about 50 mg / m 2 ~about 500 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0196] In some embodiments, the RAD51 inhibitor is administered at a dose of about 60 mg / m 2 ~about 500 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0197] In some embodiments, the RAD51 inhibitor is administered at a dose of about 70 mg / m 2 ~about 500 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0198] In some embodiments, the RAD51 inhibitor is administered at a dose of about 80 mg / m 2 ~about 500 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0199] In some embodiments, the RAD51 inhibitor is administered at a dose of about 90 mg / m 2 ~about 500 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0200] In some embodiments, the RAD51 inhibitor is administered at a dose of about 100 mg / m 2 ~about 500 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0201] In some embodiments, the RAD51 inhibitor is administered at a dose of about 150 mg / m 2 ~about 500 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0202] In some embodiments, the RAD51 inhibitor is administered at a dose of about 200 mg / m 2 ~about 500 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0203] In some embodiments, the RAD51 inhibitor is administered at a dose of about 250 mg / m 2 ~about 500 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0204] In some embodiments, the RAD51 inhibitor is administered at a dose of about 300 mg / m 2 ~about 500 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0205] In some embodiments, the RAD51 inhibitor is administered at a dose of about 350 mg / m 2 ~about 500 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0206] In some embodiments, the RAD51 inhibitor is administered at a dose of about 400 mg / m 2 ~about 500 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0207] In some embodiments, the RAD51 inhibitor is administered at a dose of about 450 mg / m 2 ~about 500 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0208] In some embodiments, the RAD51 inhibitor is administered at a dose of about 50 mg / m 2 ~about 450 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0209] In some embodiments, the RAD51 inhibitor is administered at a dose of about 60 mg / m 2 ~about 450 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0210] In some embodiments, the RAD51 inhibitor is administered at a dose of about 70 mg / m 2 ~about 450 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0211] In some embodiments, the RAD51 inhibitor is administered at a dose of about 80 mg / m 2 ~about 450 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0212] In some embodiments, the RAD51 inhibitor is administered at a dose of about 90 mg / m 2 ~about 450 mg / m 2The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0213] In some embodiments, the RAD51 inhibitor is administered at a dose of about 100 mg / m 2 ~about 450 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0214] In some embodiments, the RAD51 inhibitor is administered at a dose of about 150 mg / m 2 ~about 450 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0215] In some embodiments, the RAD51 inhibitor is administered at a dose of about 200 mg / m 2 ~about 450 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0216] In some embodiments, the RAD51 inhibitor is administered at a dose of about 250 mg / m 2 ~about 450 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0217] In some embodiments, the RAD51 inhibitor is administered at a dose of about 300 mg / m 2 ~about 450 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0218] In some embodiments, the RAD51 inhibitor is administered at a dose of about 350 mg / m 2 ~about 450 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0219] In some embodiments, the RAD51 inhibitor is administered at a dose of about 400 mg / m 2 ~about 450 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0220] In some embodiments, the RAD51 inhibitor is administered at a dose of about 50 mg / m2 ~about 400 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0221] In some embodiments, the RAD51 inhibitor is administered at a dose of about 60 mg / m 2 ~about 400 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0222] In some embodiments, the RAD51 inhibitor is administered at a dose of about 70 mg / m 2 ~about 400 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0223] In some embodiments, the RAD51 inhibitor is administered at a dose of about 80 mg / m 2 ~about 400 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0224] In some embodiments, the RAD51 inhibitor is administered at a dose of about 90 mg / m 2 ~about 400 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0225] In some embodiments, the RAD51 inhibitor is administered at a dose of about 100 mg / m 2 ~about 400 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0226] In some embodiments, the RAD51 inhibitor is administered at a dose of about 150 mg / m 2 ~about 400 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0227] In some embodiments, the RAD51 inhibitor is administered at a dose of about 200 mg / m 2 ~about 400 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0228] In some embodiments, the RAD51 inhibitor is administered at a dose of about 250 mg / m 2 ~about 400 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0229] In some embodiments, the RAD51 inhibitor is administered at a dose of about 300 mg / m 2 ~about 400 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0230] In some embodiments, the RAD51 inhibitor is administered at a dose of about 350 mg / m 2 ~about 400 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0231] In some embodiments, the RAD51 inhibitor is administered at a dose of about 50 mg / m 2 ~about 350 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0232] In some embodiments, the RAD51 inhibitor is administered at a dose of about 60 mg / m 2 ~about 350 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0233] In some embodiments, the RAD51 inhibitor is administered at a dose of about 70 mg / m 2 ~about 350 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0234] In some embodiments, the RAD51 inhibitor is administered at a dose of about 80 mg / m 2 ~about 350 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0235] In some embodiments, the RAD51 inhibitor is administered at a dose of about 90 mg / m 2 ~about 350 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0236] In some embodiments, the RAD51 inhibitor is administered at a dose of about 100 mg / m 2 ~about 350 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0237] In some embodiments, the RAD51 inhibitor is administered at a dose of about 150 mg / m 2 ~about 350 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0238] In some embodiments, the RAD51 inhibitor is administered at a dose of about 200 mg / m 2 ~about 350 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0239] In some embodiments, the RAD51 inhibitor is administered at a dose of about 250 mg / m 2 ~about 350 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0240] In some embodiments, the RAD51 inhibitor is administered at a dose of about 300 mg / m 2 ~about 350 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0241] In some embodiments, the RAD51 inhibitor is administered at a dose of about 50 mg / m 2 ~about 300 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0242] In some embodiments, the RAD51 inhibitor is administered at a dose of about 60 mg / m 2 ~about 300 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0243] In some embodiments, the RAD51 inhibitor is administered at a dose of about 70 mg / m 2 ~about 300 mg / m 2The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0244] In some embodiments, the RAD51 inhibitor is administered at a dose of about 80 mg / m 2 ~about 300 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0245] In some embodiments, the RAD51 inhibitor is administered at a dose of about 90 mg / m 2 ~about 300 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0246] In some embodiments, the RAD51 inhibitor is administered at a dose of about 100 mg / m 2 ~about 300 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0247] In some embodiments, the RAD51 inhibitor is administered at a dose of about 150 mg / m 2 ~about 300 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0248] In some embodiments, the RAD51 inhibitor is administered at a dose of about 200 mg / m 2 ~about 300 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0249] In some embodiments, the RAD51 inhibitor is administered at a dose of about 250 mg / m 2 ~about 300 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0250] In some embodiments, the RAD51 inhibitor is administered at a dose of about 50 mg / m 2 ~about 250 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0251] In some embodiments, the RAD51 inhibitor is administered at a dose of about 60 mg / m2 ~about 250 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0252] In some embodiments, the RAD51 inhibitor is administered at a dose of about 70 mg / m 2 ~about 250 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0253] In some embodiments, the RAD51 inhibitor is administered at a dose of about 80 mg / m 2 ~about 250 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0254] In some embodiments, the RAD51 inhibitor is administered at a dose of about 90 mg / m 2 ~about 250 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0255] In some embodiments, the RAD51 inhibitor is administered at a dose of about 100 mg / m 2 ~about 250 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0256] In some embodiments, the RAD51 inhibitor is administered at a dose of about 150 mg / m 2 ~about 250 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0257] In some embodiments, the RAD51 inhibitor is administered at a dose of about 200 mg / m 2 ~about 250 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0258] In some embodiments, the RAD51 inhibitor is administered at a dose of about 50 mg / m 2 ~about 200 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0259] In some embodiments, the RAD51 inhibitor is administered at a dose of about 60 mg / m 2 ~about 200 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0260] In some embodiments, the RAD51 inhibitor is administered at a dose of about 70 mg / m 2 ~about 200 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0261] In some embodiments, the RAD51 inhibitor is administered at a dose of about 80 mg / m 2 ~about 200 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0262] In some embodiments, the RAD51 inhibitor is administered at a dose of about 90 mg / m 2 ~about 200 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0263] In some embodiments, the RAD51 inhibitor is administered at a dose of about 100 mg / m 2 ~about 200 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0264] In some embodiments, the RAD51 inhibitor is administered at a dose of about 150 mg / m 2 ~about 200 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0265] In some embodiments, the RAD51 inhibitor is administered at a dose of about 50 mg / m 2 ~about 150 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0266] In some embodiments, the RAD51 inhibitor is administered at a dose of about 60 mg / m 2 ~about 150 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0267] In some embodiments, the RAD51 inhibitor is administered at a dose of about 70 mg / m 2 ~about 150 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0268] In some embodiments, the RAD51 inhibitor is administered at a dose of about 80 mg / m 2 ~about 150 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0269] In some embodiments, the RAD51 inhibitor is administered at a dose of about 90 mg / m 2 ~about 150 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0270] In some embodiments, the RAD51 inhibitor is administered at a dose of about 100 mg / m 2 ~about 150 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0271] In some embodiments, the RAD51 inhibitor is administered at a dose of about 50 mg / m 2 ~about 100 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0272] In some embodiments, the RAD51 inhibitor is administered at a dose of about 60 mg / m 2 ~about 100 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0273] In some embodiments, the RAD51 inhibitor is administered at a dose of about 70 mg / m 2 ~about 100 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0274] In some embodiments, the RAD51 inhibitor is administered at a dose of about 80 mg / m 2 ~about 100 mg / m 2The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0275] In some embodiments, the RAD51 inhibitor is administered at a dose of about 90 mg / m 2 ~about 100 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0276] In some embodiments, the RAD51 inhibitor is administered at a dose of about 50 mg / m 2 ~about 90 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0277] In some embodiments, the RAD51 inhibitor is administered at a dose of about 60 mg / m 2 ~about 90 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0278] In some embodiments, the RAD51 inhibitor is administered at a dose of about 70 mg / m 2 ~about 90 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0279] In some embodiments, the RAD51 inhibitor is administered at a dose of about 80 mg / m 2 ~about 90 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0280] In some embodiments, the RAD51 inhibitor is administered at a dose of about 50 mg / m 2 ~about 80 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0281] In some embodiments, the RAD51 inhibitor is administered at a dose of about 60 mg / m 2 ~about 80 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0282] In some embodiments, the RAD51 inhibitor is administered at a dose of about 70 mg / m 2~about 80 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0283] In some embodiments, the RAD51 inhibitor is administered at a dose of about 50 mg / m 2 ~about 70 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0284] In some embodiments, the RAD51 inhibitor is administered at a dose of about 60 mg / m 2 ~about 70 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0285] In some embodiments, the RAD51 inhibitor is administered at a dose of about 50 mg / m 2 ~about 60 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0286] In some embodiments, the RAD51 inhibitor is administered at a dose of about 50 mg / day, about 60 mg / day, about 70 mg / day, about 80 mg / day, about 90 mg / day, about 100 mg / day, about 110 mg / day, about 120 mg / day, about 130 mg / day, about 140 mg / day, about 150 mg / day, about 160 mg / day, about 170 mg / day, about 180 mg / day, about 190 mg / day, about 200 mg / day, about 210 mg / day, about 220 mg / day, about 230 mg / day, about 240 mg / day, about 250 mg / day, about 260 mg / day, about 270 mg / day, about 280 mg / day, about 290 mg / day, about 300 mg / day, about 310 mg / day, about 320 mg / day, about 330 mg / day, about 340 mg / day, about 350 mg / day, about 360 mg / day, about 370 mg / day, about 380 mg / day, about 390 mg / day, about 400 mg / day, about 410 mg / day, about 420 mg / day, about 430 mg / day, about 440 mg / day, about 450 mg / day, about 460 mg / day, about 470 mg / day, about 480 mg / day, about 490 mg / day, about 500 mg / day, about 510 mg / day, about 520 mg / day, about 530 mg / day, about 540 mg / day, about 550 mg / day, about 560 mg / day, about 570 mg / day, about 580 mg / day, about 590 mg / day, about 600 mg / day, about 350 mg / day, about 360 mg / day, about 370 mg / day, about 380 mg / day, about 390 mg / day, about 400 mg / day, about 410 mg / day, about 420 mg / day, about 430 mg / day, about 440 mg / day, about 450 mg / day, about 460 mg / day, about 470 mg / day, about 480 mg / day, about 490 mg / day, or about 500 mg / day (e.g., a human dose).

[0287] In some embodiments, the RAD51 inhibitor is administered at a dose (eg, a human dose) of about 50 mg / day.

[0288] In some embodiments, the RAD51 inhibitor is administered at a dose (eg, a human dose) of about 60 mg / day.

[0289] In some embodiments, the RAD51 inhibitor is administered at a dose (eg, a human dose) of about 70 mg / day.

[0290] In some embodiments, the RAD51 inhibitor is administered at a dose (eg, a human dose) of about 80 mg / day.

[0291] In some embodiments, the RAD51 inhibitor is administered at a dose (eg, a human dose) of about 90 mg / day.

[0292] In some embodiments, the RAD51 inhibitor is administered at a dose (eg, a human dose) of about 100 mg / day.

[0293] In some embodiments, the RAD51 inhibitor is administered at a dose (eg, a human dose) of about 110 mg / day.

[0294] In some embodiments, the RAD51 inhibitor is administered at a dose (eg, a human dose) of about 120 mg / day.

[0295] In some embodiments, the RAD51 inhibitor is administered at a dose (eg, a human dose) of about 130 mg / day.

[0296] In some embodiments, the RAD51 inhibitor is administered at a dose (eg, a human dose) of about 140 mg / day.

[0297] In some embodiments, the RAD51 inhibitor is administered at a dose (eg, a human dose) of about 150 mg / day.

[0298] In some embodiments, the RAD51 inhibitor is administered at a dose (eg, a human dose) of about 160 mg / day.

[0299] In some embodiments, the RAD51 inhibitor is administered at a dose (eg, a human dose) of about 170 mg / day.

[0300] In some embodiments, the RAD51 inhibitor is administered at a dose (eg, a human dose) of about 180 mg / day.

[0301] In some embodiments, the RAD51 inhibitor is administered at a dose (eg, a human dose) of about 190 mg / day.

[0302] In some embodiments, the RAD51 inhibitor is administered at a dose (eg, a human dose) of about 200 mg / day.

[0303] In some embodiments, the RAD51 inhibitor is administered at a dose (eg, a human dose) of about 210 mg / day.

[0304] In some embodiments, the RAD51 inhibitor is administered at a dose (eg, a human dose) of about 220 mg / day.

[0305] In some embodiments, the RAD51 inhibitor is administered at a dose (eg, a human dose) of about 230 mg / day.

[0306] In some embodiments, the RAD51 inhibitor is administered at a dose (eg, a human dose) of about 240 mg / day.

[0307] In some embodiments, the RAD51 inhibitor is administered at a dose (eg, a human dose) of about 250 mg / day.

[0308] In some embodiments, the RAD51 inhibitor is administered at a dose (eg, a human dose) of about 260 mg / day.

[0309] In some embodiments, the RAD51 inhibitor is administered at a dose (eg, a human dose) of about 270 mg / day.

[0310] In some embodiments, the RAD51 inhibitor is administered at a dose (eg, a human dose) of about 280 mg / day.

[0311] In some embodiments, the RAD51 inhibitor is administered at a dose (eg, a human dose) of about 290 mg / day.

[0312] In some embodiments, the RAD51 inhibitor is administered at a dose (eg, a human dose) of about 300 mg / day.

[0313] In some embodiments, the RAD51 inhibitor is administered at a dose (eg, a human dose) of about 310 mg / day.

[0314] In some embodiments, the RAD51 inhibitor is administered at a dose (eg, a human dose) of about 320 mg / day.

[0315] In some embodiments, the RAD51 inhibitor is administered at a dose (eg, a human dose) of about 330 mg / day.

[0316] In some embodiments, the RAD51 inhibitor is administered at a dose (eg, a human dose) of about 340 mg / day.

[0317] In some embodiments, the RAD51 inhibitor is administered at a dose (eg, a human dose) of about 350 mg / day.

[0318] In some embodiments, the RAD51 inhibitor is administered at a dose (eg, a human dose) of about 360 mg / day.

[0319] In some embodiments, the RAD51 inhibitor is administered at a dose (eg, a human dose) of about 370 mg / day.

[0320] In some embodiments, the RAD51 inhibitor is administered at a dose (eg, a human dose) of about 380 mg / day.

[0321] In some embodiments, the RAD51 inhibitor is administered at a dose (eg, a human dose) of about 390 mg / day.

[0322] In some embodiments, the RAD51 inhibitor is administered at a dose (eg, a human dose) of about 400 mg / day.

[0323] In some embodiments, the RAD51 inhibitor is administered at a dose (eg, a human dose) of about 410 mg / day.

[0324] In some embodiments, the RAD51 inhibitor is administered at a dose (eg, a human dose) of about 420 mg / day.

[0325] In some embodiments, the RAD51 inhibitor is administered at a dose (eg, a human dose) of about 430 mg / day.

[0326] In some embodiments, the RAD51 inhibitor is administered at a dose (eg, a human dose) of about 440 mg / day.

[0327] In some embodiments, the RAD51 inhibitor is administered at a dose (eg, a human dose) of about 450 mg / day.

[0328] In some embodiments, the RAD51 inhibitor is administered at a dose (eg, a human dose) of about 460 mg / day.

[0329] In some embodiments, the RAD51 inhibitor is administered at a dose (eg, a human dose) of about 470 mg / day.

[0330] In some embodiments, the RAD51 inhibitor is administered at a dose (eg, a human dose) of about 480 mg / day.

[0331] In some embodiments, the RAD51 inhibitor is administered at a dose (eg, a human dose) of about 490 mg / day.

[0332] In some embodiments, the RAD51 inhibitor is administered at a dose (eg, a human dose) of about 500 mg / day.

[0333] In some embodiments, the RAD51 inhibitor is administered once daily, eg, at any dose described herein.

[0334] In some embodiments, the RAD51 inhibitor is administered once a day, one day a week, eg, at any dose described herein.

[0335] In some embodiments, the RAD51 inhibitor is administered once a day, two days a week, eg, at any dose described herein.

[0336] In some embodiments, the RAD51 inhibitor is administered once daily, three days per week, eg, at any dose described herein.

[0337] In some embodiments, the RAD51 inhibitor is administered once daily, four days per week, eg, at any dose described herein.

[0338] In some embodiments, the RAD51 inhibitor is administered once a day, five days a week, eg, at any dose described herein.

[0339] In some embodiments, the RAD51 inhibitor is administered once a day, six days a week, eg, at any dose described herein.

[0340] In some embodiments, the RAD51 inhibitor is administered once daily, 7 days a week, eg, at any dose described herein.

[0341] In some embodiments, the RAD51 inhibitor is administered once daily for two weeks, eg, at any dose described herein.

[0342] In some embodiments, the RAD51 inhibitor is administered once daily for three weeks, eg, at any dose described herein.

[0343] In some embodiments, the RAD51 inhibitor is administered once daily for four weeks, eg, at any dose described herein.

[0344] In some embodiments, the RAD51 inhibitor is administered once every two days, eg, at any dose described herein.

[0345] In some embodiments, the RAD51 inhibitor is administered, eg, at any dose described herein, every other day for four days.

[0346] In some embodiments, the RAD51 inhibitor is administered, eg, at any dose described herein, every other day for 6 days.

[0347] In some embodiments, the RAD51 inhibitor is administered, eg, at any dose described herein, once every other day for two weeks.

[0348] In some embodiments, the RAD51 inhibitor is administered, for example, at any dose described herein, once every other day for three weeks.

[0349] In some embodiments, the RAD51 inhibitor is administered, for example, at any dose described herein, once every other day for four weeks.

[0350] In some embodiments, the RAD51 inhibitor is administered without drug holidays, eg, at any dose described herein.

[0351] In some embodiments, a RAD51 inhibitor is administered, eg, at any dose described herein, followed by a one-day drug holiday.

[0352] In some embodiments, the RAD51 inhibitor is administered for two weeks, for example at any dose described herein, followed by one drug-free day.

[0353] In some embodiments, the RAD51 inhibitor is administered for three weeks, for example at any dose described herein, followed by one drug-free day.

[0354] In some embodiments, the RAD51 inhibitor is administered for four weeks, for example at any dose described herein, followed by one drug-free day.

[0355] In some embodiments, a RAD51 inhibitor is administered, eg, at any dose described herein, followed by a 7-day drug holiday.

[0356] In some embodiments, a RAD51 inhibitor is administered, eg, at any dose described herein, followed by a 14-day drug holiday.

[0357] In some embodiments, a RAD51 inhibitor is administered, eg, at any dose described herein, followed by a 21-day drug holiday.

[0358] In some embodiments, a RAD51 inhibitor is administered, eg, at any dose described herein, followed by a 28-day drug holiday.

[0359] In some embodiments, a RAD51 inhibitor is administered, eg, at any dose described herein, followed by a 35-day drug holiday.

[0360] In some embodiments, a RAD51 inhibitor is administered, eg, at any dose described herein, followed by a 42-day drug holiday.

[0361] In some embodiments, a RAD51 inhibitor is administered, eg, at any dose described herein, followed by a 49-day drug holiday.

[0362] In some embodiments, the RAD51 inhibitor is administered at a dose of about 300 mg / m 2 followed by a 7-day drug holiday.

[0363] In some embodiments, the RAD51 inhibitor is administered at a dose of about 300 mg / m 2 followed by a 14-day drug holiday.

[0364] In some embodiments, the RAD51 inhibitor is administered at a dose of about 300 mg / m 2 followed by a 21-day drug holiday.

[0365] In some embodiments, the RAD51 inhibitor is administered at a dose of about 300 mg / m 2 followed by a 28-day drug holiday.

[0366] In some embodiments, the RAD51 inhibitor is administered at a dose of about 240 mg / m 2 followed by a 7-day drug holiday.

[0367] In some embodiments, the RAD51 inhibitor is administered at a dose of about 240 mg / m 2 followed by a 14-day drug holiday.

[0368] In some embodiments, the RAD51 inhibitor is administered at a dose of about 240 mg / m 2 followed by a 21-day drug holiday.

[0369] In some embodiments, the RAD51 inhibitor is administered at a dose of about 240 mg / m 2 followed by a 28-day drug holiday.

[0370] In some embodiments, the RAD51 inhibitor is administered at a dose of about 120 mg / m 2followed by a 7-day drug holiday.

[0371] In some embodiments, the RAD51 inhibitor is administered at a dose of about 120 mg / m 2 followed by a 14-day drug holiday.

[0372] In some embodiments, the RAD51 inhibitor is administered at a dose of about 120 mg / m 2 followed by a 21-day drug holiday.

[0373] In some embodiments, the RAD51 inhibitor is administered at a dose of about 120 mg / m 2 followed by a 28-day drug holiday.

[0374] In some embodiments, the RAD51 inhibitor is administered at a dose of about 50 mg / m 2 followed by a 7-day drug holiday.

[0375] In some embodiments, the RAD51 inhibitor is administered at a dose of about 50 mg / m 2 followed by a 14-day drug holiday.

[0376] In some embodiments, the RAD51 inhibitor is administered at a dose of about 50 mg / m 2 followed by a 21-day drug holiday.

[0377] In some embodiments, the RAD51 inhibitor is administered at a dose of about 50 mg / m 2 In some embodiments, the RAD51 inhibitor is compound 67A: [ka] or a pharmaceutically acceptable salt thereof.

[0378] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a concentration of about 1 mg / m 2 ~about 500 mg / m 2The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0379] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a concentration of about 2 mg / m 2 ~about 500 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0380] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a concentration of about 3 mg / m 2 ~about 500 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0381] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a concentration of about 1 mg / m 2 ~about 400 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0382] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a concentration of about 2 mg / m 2 ~about 400 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0383] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a concentration of about 3 mg / m 2 ~about 400 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0384] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a concentration of about 1 mg / m 2 ~about 300 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0385] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a concentration of about 2 mg / m 2 ~about 300 mg / m 2The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0386] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a concentration of about 3 mg / m 2 ~about 300 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0387] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a concentration of about 1 mg / m 2 ~about 280 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0388] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a concentration of about 1 mg / m 2 ~about 260 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0389] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a concentration of about 1 mg / m 2 ~about 240 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0390] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a concentration of about 1 mg / m 2 ~about 220 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0391] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a concentration of about 1 mg / m 2 ~about 200 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0392] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a concentration of about 1 mg / m 2 ~about 180 mg / m 2The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0393] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a concentration of about 1 mg / m 2 ~about 160 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0394] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a concentration of about 1 mg / m 2 ~about 140 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0395] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a concentration of about 1 mg / m 2 ~about 120 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0396] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a concentration of about 1 mg / m 2 ~about 100 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0397] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a concentration of about 2 mg / m 2 ~about 280 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0398] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a concentration of about 2 mg / m 2 ~about 260 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0399] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a concentration of about 2 mg / m 2 ~about 240 mg / m 2The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0400] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a concentration of about 2 mg / m 2 ~about 220 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0401] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a concentration of about 2 mg / m 2 ~about 200 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0402] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a concentration of about 2 mg / m 2 ~about 180 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0403] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a concentration of about 2 mg / m 2 ~about 160 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0404] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a concentration of about 2 mg / m 2 ~about 140 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0405] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a concentration of about 2 mg / m 2 ~about 120 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0406] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a concentration of about 2 mg / m 2 ~about 100 mg / m 2The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0407] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a concentration of about 3 mg / m 2 ~about 280 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0408] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a concentration of about 3 mg / m 2 ~about 260 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0409] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a concentration of about 3 mg / m 2 ~about 240 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0410] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a concentration of about 3 mg / m 2 ~about 220 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0411] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a concentration of about 3 mg / m 2 ~about 200 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0412] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a concentration of about 3 mg / m 2 ~about 180 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0413] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a concentration of about 3 mg / m 2 ~about 160 mg / m 2The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0414] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a concentration of about 3 mg / m 2 ~about 140 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0415] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a concentration of about 3 mg / m 2 ~about 120 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0416] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a concentration of about 3 mg / m 2 ~about 100 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0417] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose of about 50 mg / m 2 ~about 500 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0418] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose of about 60 mg / m 2 ~about 500 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0419] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a concentration of about 70 mg / m 2 ~about 500 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0420] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a concentration of about 80 mg / m 2 ~about 500 mg / m 2The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0421] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a concentration of about 90 mg / m 2 ~about 500 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0422] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a concentration of about 100 mg / m 2 ~about 500 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0423] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose of about 120 mg / m 2 ~about 500 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0424] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose of about 140 mg / m 2 ~about 500 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0425] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose of about 160 mg / m 2 ~about 500 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0426] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a concentration of about 180 mg / m 2 ~about 500 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0427] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose of about 200 mg / m 2 ~about 500 mg / m 2The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0428] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose of about 220 mg / m 2 ~about 500 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0429] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose of about 240 mg / m 2 ~about 500 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0430] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose of about 260 mg / m 2 ~about 500 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0431] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose of about 280 mg / m 2 ~about 500 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0432] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose of about 50 mg / m 2 ~about 400 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0433] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose of about 60 mg / m 2 ~about 400 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0434] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a concentration of about 70 mg / m 2 ~about 400 mg / m 2The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0435] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a concentration of about 80 mg / m 2 ~about 400 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0436] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a concentration of about 90 mg / m 2 ~about 400 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0437] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a concentration of about 100 mg / m 2 ~about 400 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0438] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose of about 120 mg / m 2 ~about 400 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0439] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose of about 140 mg / m 2 ~about 400 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0440] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose of about 160 mg / m 2 ~about 400 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0441] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a concentration of about 180 mg / m 2 ~about 400 mg / m 2The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0442] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose of about 200 mg / m 2 ~about 400 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0443] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose of about 220 mg / m 2 ~about 400 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0444] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose of about 240 mg / m 2 ~about 400 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0445] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose of about 260 mg / m 2 ~about 400 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0446] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose of about 280 mg / m 2 ~about 400 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0447] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose of about 50 mg / m 2 ~about 300 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0448] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose of about 60 mg / m 2 ~about 300 mg / m 2The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0449] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a concentration of about 70 mg / m 2 ~about 300 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0450] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a concentration of about 80 mg / m 2 ~about 300 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0451] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a concentration of about 90 mg / m 2 ~about 300 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0452] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a concentration of about 100 mg / m 2 ~about 300 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0453] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose of about 120 mg / m 2 ~about 300 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0454] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose of about 140 mg / m 2 ~about 300 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0455] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose of about 160 mg / m 2 ~about 300 mg / m 2The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0456] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a concentration of about 180 mg / m 2 ~about 300 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0457] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose of about 200 mg / m 2 ~about 300 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0458] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose of about 220 mg / m 2 ~about 300 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0459] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose of about 240 mg / m 2 ~about 300 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0460] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose of about 260 mg / m 2 ~about 300 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0461] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose of about 280 mg / m 2 ~about 300 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0462] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose of about 50 mg / m 2 ~about 280 mg / m 2The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0463] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose of about 50 mg / m 2 ~about 260 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0464] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose of about 50 mg / m 2 ~about 240 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0465] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose of about 50 mg / m 2 ~about 220 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0466] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose of about 50 mg / m 2 ~about 200 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0467] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose of about 50 mg / m 2 ~about 180 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0468] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose of about 50 mg / m 2 ~about 160 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0469] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose of about 50 mg / m 2 ~about 140 mg / m 2The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0470] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose of about 60 mg / m 2 ~about 280 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0471] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose of about 60 mg / m 2 ~about 260 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0472] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose of about 60 mg / m 2 ~about 240 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0473] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose of about 60 mg / m 2 ~about 220 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0474] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose of about 60 mg / m 2 ~about 200 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0475] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose of about 60 mg / m 2 ~about 180 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0476] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose of about 60 mg / m 2 ~about 160 mg / m 2The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0477] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose of about 60 mg / m 2 ~about 140 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0478] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a concentration of about 70 mg / m 2 ~about 280 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0479] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a concentration of about 70 mg / m 2 ~about 260 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0480] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a concentration of about 70 mg / m 2 ~about 240 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0481] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a concentration of about 70 mg / m 2 ~about 220 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0482] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a concentration of about 70 mg / m 2 ~about 200 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0483] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a concentration of about 70 mg / m 2 ~about 180 mg / m 2The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0484] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a concentration of about 70 mg / m 2 ~about 160 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0485] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a concentration of about 70 mg / m 2 ~about 140 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0486] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a concentration of about 80 mg / m 2 ~about 280 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0487] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a concentration of about 80 mg / m 2 ~about 260 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0488] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a concentration of about 80 mg / m 2 ~about 240 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0489] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a concentration of about 80 mg / m 2 ~about 220 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0490] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a concentration of about 80 mg / m 2 ~about 200 mg / m 2The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0491] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a concentration of about 80 mg / m 2 ~about 180 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0492] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a concentration of about 80 mg / m 2 ~about 160 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0493] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a concentration of about 80 mg / m 2 ~about 140 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0494] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a concentration of about 90 mg / m 2 ~about 280 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0495] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a concentration of about 90 mg / m 2 ~about 260 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0496] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a concentration of about 90 mg / m 2 ~about 240 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0497] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a concentration of about 90 mg / m 2 ~about 220 mg / m 2The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0498] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a concentration of about 90 mg / m 2 ~about 200 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0499] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a concentration of about 90 mg / m 2 ~about 180 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0500] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a concentration of about 90 mg / m 2 ~about 160 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0501] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a concentration of about 90 mg / m 2 ~about 140 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0502] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a concentration of about 100 mg / m 2 ~about 280 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0503] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a concentration of about 100 mg / m 2 ~about 260 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0504] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a concentration of about 100 mg / m 2 ~about 240 mg / m 2The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0505] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a concentration of about 100 mg / m 2 ~about 220 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0506] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a concentration of about 100 mg / m 2 ~about 200 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0507] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a concentration of about 100 mg / m 2 ~about 180 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0508] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a concentration of about 100 mg / m 2 ~about 160 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0509] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a concentration of about 100 mg / m 2 ~about 140 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0510] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose of about 120 mg / m 2 ~about 240 mg / m 2 The compound is administered in a dose (eg, a human dose) ranging from 0.1 to 1.0 mg / kg.

[0511] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a concentration of about 1 mg / m 2 , about 2 mg / m 2, about 3 mg / m 2 , about 4 mg / m 2 , about 5 mg / m 2 , about 10 mg / m 2 , about 20 mg / m 2 , about 30 mg / m 2 , about 40 mg / m 2 , about 50 mg / m 2 , about 60 mg / m 2 , about 70 mg / m 2 , about 80 mg / m 2 , about 90 mg / m 2 , about 100 mg / m 2 , about 120 mg / m 2 , about 140 mg / m 2 , about 160 mg / m 2 , about 180 mg / m 2 , about 200 mg / m 2 , about 220 mg / m 2 , about 240 mg / m 2 , about 260 mg / m 2 , about 280 mg / m 2 , about 300 mg / m 2 , about 320 mg / m 2 , about 340 mg / m 2 , about 360 mg / m 2 , about 380 mg / m 2 , about 400 mg / m 2 , about 420 mg / m 2 , about 440 mg / m 2 , about 460 mg / m 2 , about 480 mg / m 2 , or approximately 500 mg / m 2 is administered in a dose (e.g., a human dose).

[0512] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a concentration of about 1 mg / m 2 , about 2 mg / m 2 , about 3 mg / m 2 , about 4 mg / m 2 , about 5 mg / m 2 , about 10 mg / m 2 , about 20 mg / m 2 , about 30 mg / m2 , about 40 mg / m 2 , about 50 mg / m 2 , about 60 mg / m 2 , about 70 mg / m 2 , about 80 mg / m 2 , about 90 mg / m 2 , about 100 mg / m 2 , about 120 mg / m 2 , about 140 mg / m 2 , about 160 mg / m 2 , about 180 mg / m 2 , about 200 mg / m 2 , about 220 mg / m 2 , about 240 mg / m 2 , about 260 mg / m 2 , about 280 mg / m 2 , or approximately 300 mg / m 2 is administered in a dose (e.g., a human dose).

[0513] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a concentration of about 3±2 mg / m 2 , 3±1.8 mg / m 2 , 3±1.6 mg / m 2 , 3±1.5 mg / m 2 , 3±1.4 mg / m 2 , 3±1.3 mg / m 2 , 3±1.2 mg / m 2 , 3±1.1 mg / m 2 , 3±1 mg / m 2 , 3±0.9 mg / m 2 , 3±0.8 mg / m 2 , 3±0.7 mg / m 2 , 3±0.6 mg / m 2 , 3±0.5 mg / m 2 , 3±0.4 mg / m 2 , 3±0.3 mg / m 2 , 3±0.2 mg / m 2 , or 3±0.1 mg / m 2 is administered in a dose (e.g., a human dose).

[0514] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a concentration of about 3 mg / m 2 is administered in a dose (e.g., a human dose).

[0515] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a concentration of about 50±2 mg / m 2 , 50±1.8 mg / m 2 , 50±1.6 mg / m 2 , 50±1.5 mg / m 2 , 50±1.4 mg / m 2 , 50±1.3 mg / m 2 , 50±1.2 mg / m 2 , 50±1.1 mg / m 2 , 50±1 mg / m 2 , 50±0.9 mg / m 2 , 50±0.8 mg / m 2 , 50±0.7 mg / m 2 , 50±0.6 mg / m 2 , 50±0.5 mg / m 2 , 50±0.4 mg / m 2 , 50±0.3 mg / m 2 , 50±0.2 mg / m 2 , or 50±0.1 mg / m 2 is administered in a dose (e.g., a human dose).

[0516] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose of about 50 mg / m 2 is administered in a dose (e.g., a human dose).

[0517] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a concentration of about 120±100 mg / m 2 , 120±90 mg / m 2 , 120±80 mg / m 2 , 120±70 mg / m 2 , 120±60 mg / m 2 , 120±50 mg / m 2 , 120±45 mg / m 2 , 120±40 mg / m2 , 120±35 mg / m 2 , 120±30 mg / m 2 , 120±25 mg / m 2 , 120±20 mg / m 2 , 120±15 mg / m 2 , 120±10 mg / m 2 , 120±9 mg / m 2 , 120±8 mg / m 2 , 120±7 mg / m 2 , 120±6 mg / m 2 , 120±5 mg / m 2 , 120±4 mg / m 2 , 120±3 mg / m 2 , 120±2 mg / m 2 , or 120±1 mg / m 2 is administered in a dose (e.g., a human dose).

[0518] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose of about 120 mg / m 2 is administered in a dose (e.g., a human dose).

[0519] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a concentration of about 240±100 mg / m 2 , 240±90 mg / m 2 , 240±80 mg / m 2 , 240±70 mg / m 2 , 240±60 mg / m 2 , 240±50 mg / m 2 , 240±45 mg / m 2 , 240±40 mg / m 2 , 240±35 mg / m 2 , 240±30 mg / m 2 , 240±25 mg / m 2 , 240±20 mg / m 2 , 240±15 mg / m 2 , 240±10 mg / m 2 , 240±9 mg / m 2 , 240±8 mg / m 2, 240±7 mg / m 2 , 240±6 mg / m 2 , 240±5 mg / m 2 , 240±4 mg / m 2 , 240±3 mg / m 2 , 240±2 mg / m 2 , or 240±1 mg / m 2 is administered in a dose (e.g., a human dose).

[0520] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose of about 240 mg / m 2 is administered in a dose (e.g., a human dose).

[0521] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a concentration of about 300±100 mg / m 2 , 300±90 mg / m 2 , 300±80 mg / m 2 , 300±70 mg / m 2 , 300±60 mg / m 2 , 300±50 mg / m 2 , 300±45 mg / m 2 , 300±40 mg / m 2 , 300±35 mg / m 2 , 300±30 mg / m 2 , 300±25 mg / m 2 , 300±20 mg / m 2 , 300±15 mg / m 2 , 300±10 mg / m 2 , 300±9 mg / m 2 , 300±8 mg / m 2 , 300±7 mg / m 2 , 300±6 mg / m 2 , 300±5 mg / m 2 , 300±4 mg / m 2 , 300±3 mg / m 2 , 300±2 mg / m 2 , or 300±1 mg / m 2 is administered in a dose (e.g., a human dose).

[0522] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a concentration of about 300 mg / m 2 is administered in a dose (e.g., a human dose).

[0523] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose (eg, a human dose) ranging from about 50 mg / day to about 500 mg / day.

[0524] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose (eg, a human dose) ranging from about 60 mg / day to about 500 mg / day.

[0525] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose (eg, a human dose) ranging from about 70 mg / day to about 500 mg / day.

[0526] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose (eg, a human dose) ranging from about 80 mg / day to about 500 mg / day.

[0527] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose (eg, a human dose) ranging from about 90 mg / day to about 500 mg / day.

[0528] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose (eg, a human dose) ranging from about 100 mg / day to about 500 mg / day.

[0529] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose (eg, a human dose) ranging from about 150 mg / day to about 500 mg / day.

[0530] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose (eg, a human dose) ranging from about 200 mg / day to about 500 mg / day.

[0531] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose (eg, a human dose) ranging from about 250 mg / day to about 500 mg / day.

[0532] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose (eg, a human dose) ranging from about 300 mg / day to about 500 mg / day.

[0533] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose (eg, a human dose) ranging from about 350 mg / day to about 500 mg / day.

[0534] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose (eg, a human dose) ranging from about 400 mg / day to about 500 mg / day.

[0535] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose (eg, a human dose) ranging from about 450 mg / day to about 500 mg / day.

[0536] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose (eg, a human dose) ranging from about 50 mg / day to about 450 mg / day.

[0537] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose (eg, a human dose) ranging from about 60 mg / day to about 450 mg / day.

[0538] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose (eg, a human dose) ranging from about 70 mg / day to about 450 mg / day.

[0539] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose (eg, a human dose) ranging from about 80 mg / day to about 450 mg / day.

[0540] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose (eg, a human dose) ranging from about 90 mg / day to about 450 mg / day.

[0541] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose (eg, a human dose) ranging from about 100 mg / day to about 450 mg / day.

[0542] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose (eg, a human dose) ranging from about 150 mg / day to about 450 mg / day.

[0543] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose (eg, a human dose) ranging from about 200 mg / day to about 450 mg / day.

[0544] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose (eg, a human dose) ranging from about 250 mg / day to about 450 mg / day.

[0545] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose (eg, a human dose) ranging from about 300 mg / day to about 450 mg / day.

[0546] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose (eg, a human dose) ranging from about 350 mg / day to about 450 mg / day.

[0547] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose (eg, a human dose) ranging from about 400 mg / day to about 450 mg / day.

[0548] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose (eg, a human dose) ranging from about 50 mg / day to about 400 mg / day.

[0549] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose (eg, a human dose) ranging from about 60 mg / day to about 400 mg / day.

[0550] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose (eg, a human dose) ranging from about 70 mg / day to about 400 mg / day.

[0551] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose (eg, a human dose) ranging from about 80 mg / day to about 400 mg / day.

[0552] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose (eg, a human dose) ranging from about 90 mg / day to about 400 mg / day.

[0553] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose (eg, a human dose) ranging from about 100 mg / day to about 400 mg / day.

[0554] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose (eg, a human dose) ranging from about 150 mg / day to about 400 mg / day.

[0555] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose (eg, a human dose) ranging from about 200 mg / day to about 400 mg / day.

[0556] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose (eg, a human dose) ranging from about 250 mg / day to about 400 mg / day.

[0557] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose (eg, a human dose) ranging from about 300 mg / day to about 400 mg / day.

[0558] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose (eg, a human dose) ranging from about 350 mg / day to about 400 mg / day.

[0559] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose (eg, a human dose) ranging from about 50 mg / day to about 350 mg / day.

[0560] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose (eg, a human dose) ranging from about 60 mg / day to about 350 mg / day.

[0561] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose (eg, a human dose) ranging from about 70 mg / day to about 350 mg / day.

[0562] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose (eg, a human dose) ranging from about 80 mg / day to about 350 mg / day.

[0563] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose (eg, a human dose) ranging from about 90 mg / day to about 350 mg / day.

[0564] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose (eg, a human dose) ranging from about 100 mg / day to about 350 mg / day.

[0565] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose (eg, a human dose) ranging from about 150 mg / day to about 350 mg / day.

[0566] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose (eg, a human dose) ranging from about 200 mg / day to about 350 mg / day.

[0567] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose (eg, a human dose) ranging from about 250 mg / day to about 350 mg / day.

[0568] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose (eg, a human dose) ranging from about 300 mg / day to about 350 mg / day.

[0569] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose (eg, a human dose) ranging from about 50 mg / day to about 300 mg / day.

[0570] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose (eg, a human dose) ranging from about 60 mg / day to about 300 mg / day.

[0571] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose (eg, a human dose) ranging from about 70 mg / day to about 300 mg / day.

[0572] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose (eg, a human dose) ranging from about 80 mg / day to about 300 mg / day.

[0573] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose (eg, a human dose) ranging from about 90 mg / day to about 300 mg / day.

[0574] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose (eg, a human dose) ranging from about 100 mg / day to about 300 mg / day.

[0575] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose (eg, a human dose) ranging from about 150 mg / day to about 300 mg / day.

[0576] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose (eg, a human dose) ranging from about 200 mg / day to about 300 mg / day.

[0577] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose (eg, a human dose) ranging from about 250 mg / day to about 300 mg / day.

[0578] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose (eg, a human dose) ranging from about 50 mg / day to about 250 mg / day.

[0579] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose (eg, a human dose) ranging from about 60 mg / day to about 250 mg / day.

[0580] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose (eg, a human dose) ranging from about 70 mg / day to about 250 mg / day.

[0581] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose (eg, a human dose) ranging from about 80 mg / day to about 250 mg / day.

[0582] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose (eg, a human dose) ranging from about 90 mg / day to about 250 mg / day.

[0583] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose (eg, a human dose) ranging from about 100 mg / day to about 250 mg / day.

[0584] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose (eg, a human dose) ranging from about 150 mg / day to about 250 mg / day.

[0585] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose (eg, a human dose) ranging from about 200 mg / day to about 250 mg / day.

[0586] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose (eg, a human dose) ranging from about 50 mg / day to about 200 mg / day.

[0587] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose (eg, a human dose) ranging from about 60 mg / day to about 200 mg / day.

[0588] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose (eg, a human dose) ranging from about 70 mg / day to about 200 mg / day.

[0589] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose (eg, a human dose) ranging from about 80 mg / day to about 200 mg / day.

[0590] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose (eg, a human dose) ranging from about 90 mg / day to about 200 mg / day.

[0591] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose (eg, a human dose) ranging from about 100 mg / day to about 200 mg / day.

[0592] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose (eg, a human dose) ranging from about 150 mg / day to about 200 mg / day.

[0593] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose (eg, a human dose) ranging from about 50 mg / day to about 150 mg / day.

[0594] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose (eg, a human dose) ranging from about 60 mg / day to about 150 mg / day.

[0595] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose (eg, a human dose) ranging from about 70 mg / day to about 150 mg / day.

[0596] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose (eg, a human dose) ranging from about 80 mg / day to about 150 mg / day.

[0597] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose (eg, a human dose) ranging from about 90 mg / day to about 150 mg / day.

[0598] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose (eg, a human dose) ranging from about 100 mg / day to about 150 mg / day.

[0599] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose (eg, a human dose) ranging from about 50 mg / day to about 100 mg / day.

[0600] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose (eg, a human dose) ranging from about 60 mg / day to about 100 mg / day.

[0601] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose (eg, a human dose) ranging from about 70 mg / day to about 100 mg / day.

[0602] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose (eg, a human dose) ranging from about 80 mg / day to about 100 mg / day.

[0603] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose (eg, a human dose) ranging from about 90 mg / day to about 100 mg / day.

[0604] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose (eg, a human dose) ranging from about 50 mg / day to about 90 mg / day.

[0605] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose (eg, a human dose) ranging from about 60 mg / day to about 90 mg / day.

[0606] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose (eg, a human dose) ranging from about 70 mg / day to about 90 mg / day.

[0607] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose (eg, a human dose) ranging from about 80 mg / day to about 90 mg / day.

[0608] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose (eg, a human dose) ranging from about 50 mg / day to about 80 mg / day.

[0609] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose (eg, a human dose) ranging from about 60 mg / day to about 80 mg / day.

[0610] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose (eg, a human dose) ranging from about 70 mg / day to about 80 mg / day.

[0611] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose (eg, a human dose) ranging from about 50 mg / day to about 70 mg / day.

[0612] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose (eg, a human dose) ranging from about 60 mg / day to about 80 mg / day.

[0613] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose (eg, a human dose) ranging from about 50 mg / day to about 60 mg / day.

[0614] In some embodiments, Compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose of about 50 mg / day, about 60 mg / day, about 70 mg / day, about 80 mg / day, about 90 mg / day, about 100 mg / day, about 110 mg / day, about 120 mg / day, about 130 mg / day, about 140 mg / day, about 150 mg / day, about 160 mg / day, about 170 mg / day, about 180 mg / day, about 190 mg / day, about 200 mg / day, about 210 mg / day, about 220 mg / day, about 230 mg / day, about 240 mg / day, about 250 mg / day, about 260 mg / day, about 270 mg / day, about 280 mg / day, about 290 mg / day, about 300 mg / day, about 310 mg / day, about 320 mg / day, about 330 mg / day, about 340 mg / day, about 350 mg / day, about 360 mg / day, about 370 mg / day, about 380 mg / day, about 390 mg / day, about 400 mg / day, about 410 mg / day, about 420 mg / day, about 430 mg / day, about 440 mg / day, about 450 mg / day, about 460 mg / day, about 470 mg / day, about 480 mg / day, about 490 mg / day, about 500 mg / day, about 510 mg / day, about 520 mg / day, about 530 mg / day, about 540 mg / day, about 550 mg / day, about 560 mg / day, about 570 mg / day, about 580 mg / day, about 590 mg / day mg / day, about 340 mg / day, about 350 mg / day, about 360 mg / day, about 370 mg / day, about 380 mg / day, about 390 mg / day, about 400 mg / day, about 410 mg / day, about 420 mg / day, about 430 mg / day, about 440 mg / day, about 450 mg / day, about 460 mg / day, about 470 mg / day, about 480 mg / day, about 490 mg / day, or about 500 mg / day (e.g., a human dose).

[0615] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose (eg, a human dose) of about 50 mg / day.

[0616] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose (eg, a human dose) of about 60 mg / day.

[0617] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose (eg, a human dose) of about 70 mg / day.

[0618] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose (eg, a human dose) of about 80 mg / day.

[0619] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose (eg, a human dose) of about 90 mg / day.

[0620] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose (eg, a human dose) of about 100 mg / day.

[0621] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose (eg, a human dose) of about 110 mg / day.

[0622] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose (eg, a human dose) of about 120 mg / day.

[0623] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose (eg, a human dose) of about 130 mg / day.

[0624] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose (eg, a human dose) of about 140 mg / day.

[0625] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose (eg, a human dose) of about 150 mg / day.

[0626] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose (eg, a human dose) of about 160 mg / day.

[0627] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose (eg, a human dose) of about 170 mg / day.

[0628] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose (eg, a human dose) of about 180 mg / day.

[0629] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose (eg, a human dose) of about 190 mg / day.

[0630] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose (eg, a human dose) of about 200 mg / day.

[0631] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose (eg, a human dose) of about 210 mg / day.

[0632] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose (eg, a human dose) of about 220 mg / day.

[0633] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose (eg, a human dose) of about 230 mg / day.

[0634] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose (eg, a human dose) of about 240 mg / day.

[0635] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose (eg, a human dose) of about 250 mg / day.

[0636] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose (eg, a human dose) of about 260 mg / day.

[0637] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose (eg, a human dose) of about 270 mg / day.

[0638] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose (eg, a human dose) of about 280 mg / day.

[0639] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose (eg, a human dose) of about 290 mg / day.

[0640] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose (eg, a human dose) of about 300 mg / day.

[0641] In some embodiments, compound 67A, or a pharmaceutically acceptable salt thereof, is administered at a dose (eg, a human dose) of about 310 mg / day.

[0642] In some embodiments, compound 67A, or a pharmaceutically acceptable salt thereof, is administered at a dose (eg, a human dose) of about 320 mg / day.

[0643] In some embodiments, compound 67A, or a pharmaceutically acceptable salt thereof, is administered at a dose (eg, a human dose) of about 330 mg / day.

[0644] In some embodiments, compound 67A, or a pharmaceutically acceptable salt thereof, is administered at a dose (eg, a human dose) of about 340 mg / day.

[0645] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose (eg, a human dose) of about 350 mg / day.

[0646] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose (eg, a human dose) of about 360 mg / day.

[0647] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose (eg, a human dose) of about 370 mg / day.

[0648] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose (eg, a human dose) of about 380 mg / day.

[0649] In some embodiments, compound 67A, or a pharmaceutically acceptable salt thereof, is administered at a dose (eg, a human dose) of about 390 mg / day.

[0650] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose (eg, a human dose) of about 400 mg / day.

[0651] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose (eg, a human dose) of about 410 mg / day.

[0652] In some embodiments, compound 67A, or a pharmaceutically acceptable salt thereof, is administered at a dose (eg, a human dose) of about 420 mg / day.

[0653] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose (eg, a human dose) of about 430 mg / day.

[0654] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose (eg, a human dose) of about 440 mg / day.

[0655] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose (eg, a human dose) of about 450 mg / day.

[0656] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose (eg, a human dose) of about 460 mg / day.

[0657] In some embodiments, compound 67A, or a pharmaceutically acceptable salt thereof, is administered at a dose (eg, a human dose) of about 470 mg / day.

[0658] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose (eg, a human dose) of about 480 mg / day.

[0659] In some embodiments, compound 67A, or a pharmaceutically acceptable salt thereof, is administered at a dose (eg, a human dose) of about 490 mg / day.

[0660] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose (eg, a human dose) of about 500 mg / day.

[0661] In some embodiments, compound 67A, or a pharmaceutically acceptable salt thereof, is administered once daily, eg, at any dose described herein.

[0662] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered once a day, one day a week, eg, at any dose described herein.

[0663] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered once daily, two days per week, eg, at any dose described herein.

[0664] In some embodiments, compound 67A, or a pharmaceutically acceptable salt thereof, is administered once daily, three days a week, eg, at any dose described herein.

[0665] In some embodiments, compound 67A, or a pharmaceutically acceptable salt thereof, is administered once daily, four days a week, eg, at any dose described herein.

[0666] In some embodiments, compound 67A, or a pharmaceutically acceptable salt thereof, is administered once daily, five days a week, eg, at any dose described herein.

[0667] In some embodiments, compound 67A, or a pharmaceutically acceptable salt thereof, is administered once daily, six days a week, eg, at any dose described herein.

[0668] In some embodiments, compound 67A, or a pharmaceutically acceptable salt thereof, is administered once daily, 7 days a week, eg, at any dose described herein.

[0669] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered, for example, at any dose described herein, once daily for two weeks.

[0670] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered, for example, at any dose described herein, once daily for three weeks.

[0671] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered, for example, at any dose described herein, once daily for four weeks.

[0672] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered once every two days, eg, at any dose described herein.

[0673] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered, for example, at any dose described herein, once every other day for four days.

[0674] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered, for example, at any dose described herein, once every two days for six days.

[0675] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered, for example, at any dose described herein, once every other day for two weeks.

[0676] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered, for example, at any dose described herein, once every other day for three weeks.

[0677] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered, for example, at any dose described herein, once every other day for four weeks.

[0678] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered without drug holidays, eg, at any dose described herein.

[0679] In some embodiments, compound 67A, or a pharmaceutically acceptable salt thereof, is administered, eg, at any dose described herein, followed by a one-day drug holiday.

[0680] In some embodiments, compound 67A, or a pharmaceutically acceptable salt thereof, is administered for one week, for example, at any dose described herein, followed by one drug-free day.

[0681] In some embodiments, compound 67A, or a pharmaceutically acceptable salt thereof, is administered, for example, at any dose described herein, for two weeks followed by one drug-free day.

[0682] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered, for example, at any dose described herein, for three weeks followed by one drug-free day.

[0683] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered, for example, at any dose described herein, for four weeks followed by one drug-free day.

[0684] In some embodiments, compound 67A, or a pharmaceutically acceptable salt thereof, is administered, eg, at any dose described herein, followed by a 7-day drug holiday.

[0685] In some embodiments, compound 67A, or a pharmaceutically acceptable salt thereof, is administered, eg, at any dose described herein, followed by a 14-day drug holiday.

[0686] In some embodiments, compound 67A, or a pharmaceutically acceptable salt thereof, is administered, eg, at any dose described herein, followed by a 21-day drug holiday.

[0687] In some embodiments, compound 67A, or a pharmaceutically acceptable salt thereof, is administered, eg, at any dose described herein, followed by a 28-day drug holiday.

[0688] In some embodiments, compound 67A, or a pharmaceutically acceptable salt thereof, is administered, for example, at any dose described herein, followed by a 35-day drug holiday.

[0689] In some embodiments, compound 67A, or a pharmaceutically acceptable salt thereof, is administered, for example, at any dose described herein, followed by a 42-day drug holiday.

[0690] In some embodiments, compound 67A, or a pharmaceutically acceptable salt thereof, is administered, for example, at any dose described herein, followed by a 49-day drug holiday.

[0691] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a concentration of about 300 mg / m 2 followed by a 7-day drug holiday.

[0692] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a concentration of about 300 mg / m 2 followed by a 14-day drug holiday.

[0693] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a concentration of about 300 mg / m 2 followed by a 21-day drug holiday.

[0694] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a concentration of about 300 mg / m 2 followed by a 28-day drug holiday.

[0695] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose of about 240 mg / m 2 followed by a 7-day drug holiday.

[0696] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose of about 240 mg / m 2followed by a 14-day drug holiday.

[0697] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose of about 240 mg / m 2 followed by a 21-day drug holiday.

[0698] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose of about 240 mg / m 2 followed by a 28-day drug holiday.

[0699] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose of about 120 mg / m 2 followed by a 7-day drug holiday.

[0700] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose of about 120 mg / m 2 followed by a 14-day drug holiday.

[0701] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose of about 120 mg / m 2 followed by a 21-day drug holiday.

[0702] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose of about 120 mg / m 2 followed by a 28-day drug holiday.

[0703] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose of about 50 mg / m 2 followed by a 7-day drug holiday.

[0704] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose of about 50 mg / m 2 followed by a 14-day drug holiday.

[0705] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose of about 50 mg / m 2 followed by a 21-day drug holiday.

[0706] In some embodiments, compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose of about 50 mg / m 2 followed by a 28-day drug holiday.

[0707] RAD51 inhibitors

[0708] In a first embodiment, the RAD51 inhibitor is a compound represented by structural formula I: [ka] or a pharmaceutically acceptable salt thereof, provided that in this structural formula: the thiazole ring is optionally substituted with -F or -Cl; Cy is -(C3-C7)cycloalkyl, bridged (C6-C 12 ) cycloalkyl, or a 4- to 10-membered heterocycle, each of which is optionally substituted with one or more groups selected from the group consisting of halogen, —OH, (C1-C4) alkyl, and (C1-C4) alkoxy; X 5 is attached to the nitrogen ring atom of Cy, X 5 is absent; X 5 is attached to a carbon ring atom of Cy, X 5 is NR a or O; X 6 is NR a or O; R 1 is (C1-C5) alkyl; R 3 is (C1-C5) alkyl, -CH2-phenyl, -(C3-C7) cycloalkyl, -CH2-(C3-C7) cycloalkyl, -CH2-monocyclic 3- to 7-membered heterocycle, or monocyclic 3- to 7-membered heterocycle, and R3 or R 3 wherein the (C1-C5) alkyl, -(C3-C7) cycloalkyl, phenyl, or monocyclic 3- to 7-membered heterocycle in the group represented by is optionally substituted with one or more groups selected from the group consisting of halogen, -OH, (C1-C4) alkyl, halomethyl, halomethoxy, -CN, and (C1-C4) alkoxy; R 2 is -NR a C(O)O(C1-C4) alkyl; -NR a C(O)NR a (C1-C4) alkyl; -NR a C(O)O(C2-C4)alkenyl; -NR a C(O)NR a (C2-C4)alkenyl; -NR a C(O)O-(C3-C6)cycloalkyl; -NR a C(O)NR a -(C3-C7)cycloalkyl; -NR a C(O)O-phenyl;-NR a C(O)NR a -phenyl; -NR a C(O)O-monocyclic 3- to 7-membered heterocycle; -NR a C(O)NR a -Monocyclic 3- to 7-membered heterocycle; -NR a C(O)O-monocyclic 5-6 membered heteroaromatic ring; -NR a C(O)NR a - a monocyclic 5-6 membered heteroaromatic ring; R 2 The (C1-C4) alkyl and (C2-C4) alkenyl in the group represented by the formula (I) may each independently optionally be selected from halogen, N3, -OR a , -NR a R a , -(C3-C6)cycloalkyl, phenyl, a monocyclic 3- to 7-membered heterocyclic ring, and a monocyclic 5- to 6-membered heteroaromatic ring; R 2 The (C3-C7)cycloalkyl in the group represented by the formula (I) may optionally be selected from halogen, -CH3, =O, -ORa , and -NR a R a and is substituted with one or more groups selected from the group consisting of: R 2 The phenyl in the group represented by the formula (I) may optionally be selected from halogen, -CH3, halomethyl, halomethoxy, -CN, -OR a -N3; and -N3; R 2 The heterocycle in the group represented by the formula (I) may optionally be substituted with ═O, halogen, —OR a , -CH3, halomethyl, and halomethoxy; R 2 The heteroaromatic ring in the group represented by is optionally selected from halogen, —CN, —CH3, halomethyl, halomethoxy, —OR a , and -NR a R a and is substituted with one or more groups selected from the group consisting of: Each R a are independently -H or -CH3).

[0709] In a second embodiment, the RAD51 inhibitor is a compound represented by structural formula II: [ka] or a pharmaceutically acceptable salt thereof, provided that in this structural formula: the thiazole ring is optionally substituted with -F or -Cl; Cy is cycloalkyl or a 6-membered monocyclic heterocycle; X 5 and X 6 are each independently NR a or O; R 1 is (C1-C5) alkyl; R 3 is (C1-C5) alkyl or a monocyclic 3- to 7-membered heterocycle; R 2 is -NR a C(O)O(C1-C4) alkyl; -NR a C(O)NR a (C1-C4) alkyl; -NR a C(O)O(C2-C4)alkenyl; -NR a C(O)NR a (C2-C4)alkenyl; -NR a C(O)—O(C3-C6)cycloalkyl; -NR a C(O)NR a -(C3-C6)cycloalkyl; -NR a C(O)O-phenyl;-NR a C(O)NR a -phenyl; -NR a C(O)O-monocyclic 3- to 7-membered heterocycle; -NR a C(O)NR a -Monocyclic 3- to 7-membered heterocycle; -NR a C(O)O-monocyclic 5-6 membered heteroaromatic ring; -NR a C(O)NR a - a monocyclic 5-6 membered heteroaromatic ring; Here, R 2 The (C1-C4) alkyl and (C2-C4) alkenyl in the group represented by the formula (I) may each optionally independently be selected from one or more halogens, N3, -OR a , -NR a R a , -(C3-C6)cycloalkyl, phenyl, a monocyclic 3- to 7-membered heterocyclic ring, or a monocyclic 5- to 6-membered heteroaromatic ring; R 2 The -(C3-C6)cycloalkyl in the group represented by the formula (I) may optionally be substituted with one or more halogens, -CH3, -OR a , or -NR a R a is replaced by; R 2 The phenyl in the group represented by the formula (I) may optionally be substituted with one or more halogens, -CH3, halomethyl, halomethoxy, -OR a , or substituted with -N3; R 2The heterocycle in the group represented by is optionally substituted with one or more =0, halogen, -CH3, halomethyl, or halomethoxy; R 2 The heteroaromatic ring in the group represented by the formula (I) may optionally be substituted with one or more halogens, -CH3, halomethyl, halomethoxy, -OR a , or -NR a R a is replaced by; Each R a are independently -H or -CH3).

[0710] In a third embodiment, the RAD51 inhibitor is a compound according to structural formula I, or a pharmaceutically acceptable salt thereof, wherein Cy is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl; azetidinyl, azepanyl, diazaspiro[4.4]nonyl, diazaspiro[3.5]nonyl, diazepanyl, dihydroimidazole, dihydrofuranyl, dihydropyranyl, dihydropyridinyl, dihydropyrimidinyl, dihydrothienyl, dihydrothiophenyl, dihydrothiophene ... Pyranyl, hexahydropyridazinyl, hexahydropyrimidinyl, hydantoinyl, indolinyl, isoindolinyl, morpholinyl, oxiranyl, oxetanyl, piperidinyl, piperazinyl, pyrrolidinonyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydroimidazole, tetrahydroindolyl, tetrahydropyranyl, tetrahydrothienyl, tetrahydropyridinyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, thiomorpholinyl, tropanyl, ValerolactamilBicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, bicyclo[4.3.1]decyl, bicyclo[3.3.1]nonyl, bornyl, bornenyl, norbornyl, norbornenyl, 6,6-dimethylbicyclo[3.1.1]heptyl, tricyclobutyl, adamanthyl; azanorbornyl, quinuclidinyl, isoquinuclidinyl, tropanyl, azabicyclo[2.2.1]heptyl and octahydropyrrolo[3,4-b]pyrrolyl, octahydropyrrolo[3,4-c]pyrrolyl; the remainder of the variables are as defined in the first embodiment.

[0711] In a fourth embodiment, the RAD51 inhibitor is a compound according to structural formula I or II, or a pharmaceutically acceptable salt thereof, wherein Cy is cyclohexyl, morpholinyl, thiomorpholinyl, piperidinyl, piperazinyl, hexahydropyridazinyl, hexahydropyrimidinyl, Valerolactamil , dihydropyranyl, dihydropyridinyl, dihydropyrimidinyl, dihydrothiopyranyl, tetrahydropyranyl, tetrahydropyridinyl, tetrahydropyrimidinyl, or tetrahydrothiopyranyl; the remainder of the variables are as defined in the first, second, and / or third embodiment.

[0712] In a fifth embodiment, the RAD51 inhibitor is a compound represented by structural formula III: [ka] or a pharmaceutically acceptable salt thereof, provided that in this structural formula: X 7 is NH or O; R 4is (C1-C4) alkyl, (C3-C6) cycloalkyl, or a monocyclic 3- to 7-membered heterocycle; R 4 The (C1-C4) alkyl represented by the formula (I) may optionally be substituted with halogen, N3, -OR a , -NR a R a , -(C3-C6)cycloalkyl, phenyl, a monocyclic 3- to 7-membered heterocyclic ring, and a monocyclic 5- to 6-membered heteroaromatic ring; R 4 (C3-C6)cycloalkyl or monocyclic 3- to 7-membered heterocycle represented by 4 The (C3-C6)cycloalkyl or monocyclic 3- to 7-membered heterocycle in the group represented by the formula (I) may optionally be substituted with halogen, -OR a , ═O, and —CH3; R 4 The phenyl in the group represented by the formula (I) may optionally be selected from halogen, -CH3, halomethyl, halomethoxy, -OR a -N3; and -N3; R 4 wherein the heteroaromatic ring in the group represented by is optionally substituted with one or more groups selected from the group consisting of halogen and —CH3; The remaining variables are as defined in the first, second, third, and / or fourth embodiments).

[0713] In a sixth embodiment, the RAD51 inhibitor is a compound according to structural formula III, or a pharmaceutically acceptable salt thereof, wherein X 7 is NH or O; R 3 is (C1-C5) alkyl, and R 4 is (C1-C4) alkyl, and R 4 The (C1-C4) alkyl represented by the formula: optionally contains one or more halogens, -OR a , -NR a R a, -(C3-C6)cycloalkyl, phenyl (optionally one or more halogens, -CH3, halomethyl, halomethoxy, OR a , or N), a monocyclic 3- to 7-membered heterocycle (optionally substituted with =O, halogen, or -CH), or a monocyclic 5- to 6-membered heteroaromatic ring (optionally substituted with halogen or -CH); the remainder of the variables are as defined in the first, second, third, fourth, and / or fifth embodiment.

[0714] In a seventh embodiment, the RAD51 inhibitor is a compound represented by structural formula IV: [ka] or a pharmaceutically acceptable salt thereof; and the variables are as defined in the first, second, third, fourth, fifth, and / or sixth embodiment.

[0715] In an eighth embodiment, the RAD51 inhibitor is a compound represented by structural formula V: [ka] or a pharmaceutically acceptable salt thereof; and the variables are as defined in the first, second, third, fourth, fifth, and / or sixth embodiment.

[0716] In a ninth embodiment, the RAD51 inhibitor is a compound represented by structural formula VI: [ka] or a pharmaceutically acceptable salt thereof; and the variables are as defined in the first, second, third, fourth, fifth, and / or sixth embodiment.

[0717] In a tenth embodiment, the RAD51 inhibitor is a compound represented by structural formula VII: [ka] or a pharmaceutically acceptable salt thereof; and the variables are as defined in the first, second, third, fourth, fifth, and / or sixth embodiment.

[0718] In an eleventh embodiment, the RAD51 inhibitor is a compound represented by structural formula VIII: [ka] or a pharmaceutically acceptable salt thereof; and the variables are as defined in the first, second, third, fourth, fifth, and / or sixth embodiment.

[0719] In a twelfth embodiment, the RAD51 inhibitor is a compound represented by structural formula IX: [ka] or a pharmaceutically acceptable salt thereof; and the variables are as defined in the first, second, third, fourth, fifth, and / or sixth embodiment.

[0720] In a thirteenth embodiment, the RAD51 inhibitor is a compound according to structural formula I, II, or III, or a pharmaceutically acceptable salt thereof, wherein Cy is azetidinyl or pyrrolidinyl, the nitrogen ring atom is connected to the thiazole ring; and the remaining variables are as defined in the first, second, third, fourth, fifth, and / or sixth embodiments.

[0721] In a fourteenth embodiment, the RAD51 inhibitor is a compound according to structural formula I, II, or III, or a pharmaceutically acceptable salt thereof, wherein Cy is 1,7-diazaspiro[4.4]nonyl, 2,7-diazaspiro[4.4]nonyl, 2,7-diazaspiro[3.5]nonyl, 1,4-diazepanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 3,8-diazabicyclo[3.2.1]octanyl, octahydropyrrolo[3,4-b]pyrrolyl, or octahydropyrrolo[3,4-c]pyrrolyl, and the two nitrogen ring atoms are connected to the thiazole ring and -X 5 C(O)X 6 R 3 the remaining variables are as defined in the first, second, third, fourth, fifth, and / or sixth embodiments.

[0722] In a fifteenth embodiment, the RAD51 inhibitor is a compound according to structural formula III, IV, V, VI, VII, VIII, or IX, or a pharmaceutically acceptable salt thereof, wherein R 4 is -(C1-C3)alkyl, (C3-C6)cycloalkyl, or a monocyclic 3- to 7-membered heterocycle, wherein -(C1-C3)alkyl is optionally substituted with: (i) phenyl optionally substituted with one or more halogens or -CH3; (ii) a monocyclic 5- to 6-membered heteroaromatic ring optionally substituted with one or more halogens or -CH3; or (iii) a monocyclic 3- to 7-membered heterocycle optionally substituted with one or more groups selected from the group consisting of halogens and -CH3; and the remainder of the variables are as defined in the first, second, third, fourth, fifth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, and / or fourteenth embodiments.

[0723] In a sixteenth embodiment, the RAD51 inhibitor is a compound according to structural formula III, IV, V, VI, VII, VIII, or IX, or a pharmaceutically acceptable salt thereof, wherein R 4 is -(C1-C3) alkyl, -CHR a -phenyl, -CHR a-5-6 membered heteroaromatic ring, or -CHR a - a 3- to 7-membered monocyclic heterocycle, and R 4 is optionally substituted with one or more groups selected from the group consisting of halogen and —CH; and the remaining variables are as defined in the first, second, third, fourth, fifth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, and / or fourteenth embodiments.

[0724] In a seventeenth embodiment, the RAD51 inhibitor is a compound according to structural formula III, IV, V, VI, VII, VIII, or IX, or a pharmaceutically acceptable salt thereof, wherein R 4 optionally, (i) optionally, one or more halogens, —CH3, halomethyl, halomethoxy, OR a or N3; (ii) a monocyclic 5-6 membered heteroaromatic ring optionally substituted with one or more halogens or —CH3; or (iii) a monocyclic 3-7 membered heterocyclic ring optionally substituted with one or more —(C1-C3)alkyl substituted with one or more =O or —CH3; and the remainder of the variables are as defined in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, and / or fourteenth embodiments.

[0725] In an eighteenth embodiment, the RAD51 inhibitor is a compound according to structural formula III, IV, V, VI, VII, VIII, or IX, or a pharmaceutically acceptable salt thereof, wherein R 4 optionally, (i) optionally, one or more halogens, —CH3, halomethyl, halomethoxy, OR aor N3; (ii) a monocyclic 5-6 membered heteroaromatic ring optionally substituted with one or more halogens or —CH3; or (iii) a monocyclic 3-7 membered heterocyclic ring optionally substituted with one or more ═O or —CH3, and the remainder of the variables are as defined in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, and / or seventeenth embodiments.

[0726] In a nineteenth embodiment, the RAD51 inhibitor is a compound according to structural formula I, III, IV, V, VI, VII, VIII, or IX, or a pharmaceutically acceptable salt thereof, wherein R 3 is (C1-C4) alkyl, -(C4-C6) cycloalkyl, -CH2-phenyl, -CH2-monocyclic 4- to 6-membered heterocycle, or monocyclic 4- to 6-membered heterocycle, and R 3 or R 3 The phenyl or monocyclic 4- to 6-membered heterocyclic ring in the group represented by a and -CH3; and the remainder of the variables are as defined in the first, third, fourth, fifth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, and / or eighteenth embodiments.

[0727] In a twentieth embodiment, the RAD51 inhibitor is a compound represented by structural formula X: [ka] or a pharmaceutically acceptable salt thereof; and the variables are as defined in the first, second, third, fourth, fifth, sixth, seventh, fifteenth, sixteenth, seventeenth, eighteenth, and / or nineteenth embodiments.

[0728] In a twenty-first embodiment, the RAD51 inhibitor is a compound represented by structural formula XI: [ka] or a pharmaceutically acceptable salt thereof; and the variables are as defined in the first, second, third, fourth, fifth, sixth, seventh, fifteenth, sixteenth, seventeenth, eighteenth, and / or nineteenth embodiments.

[0729] In a twenty-second embodiment, the RAD51 inhibitor is a compound represented by structural formula XII: [ka] or a pharmaceutically acceptable salt thereof; and the variables are as defined in the first, second, third, fourth, fifth, sixth, eighth, fifteenth, sixteenth, seventeenth, eighteenth, and / or nineteenth embodiments.

[0730] In a twenty-third embodiment, the RAD51 inhibitor is a compound represented by structural formula XIII(a) or XIII(b): [ka] or [ka] or a pharmaceutically acceptable salt thereof; wherein the variables are as defined in the first, second, third, fourth, fifth, sixth, eighth, fifteenth, sixteenth, seventeenth, eighteenth, and / or nineteenth embodiments.

[0731] In a twenty-fourth embodiment, the RAD51 inhibitor is a compound represented by structural formula XIV: [ka] or a pharmaceutically acceptable salt thereof; and the variables are as defined in the first, second, third, fourth, fifth, sixth, tenth, fifteenth, sixteenth, seventeenth, eighteenth, and / or nineteenth embodiments.

[0732] In a twenty-fifth embodiment, the RAD51 inhibitor is a compound according to structural formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII(a), XIII(b), XIV, or a pharmaceutically acceptable salt thereof, wherein R 3 is isopropyl, t-butyl, cyclobutyl, cyclopentyl, benzyl, oxetanyl, tetrahydro-2H-pyranyl, or [ka] and the variables are as defined in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, and / or twenty-fourth embodiments. 3 is isopropyl or oxetanyl. In an alternative embodiment, R 3 is isopropyl.

[0733] In a twenty-sixth embodiment, the RAD51 inhibitor is a compound according to structural formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII(a), XIII(b), XIV, or a pharmaceutically acceptable salt thereof, wherein R 1 is t-butyl, and the variables are as defined in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, twenty-fourth, and / or twenty-fifth embodiments.

[0734] In a twenty-seventh embodiment, the RAD51 inhibitor is a compound according to structural formula III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII(a), XIII(b), XIV, or a pharmaceutically acceptable salt thereof; 4 teeth, [ka] and the variables are as defined in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, twenty-fourth, twenty-fifth, and / or twenty-sixth embodiments. In some embodiments, R 4 teeth, [ka] In an alternative embodiment, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] is.

[0735] The present disclosure provides compounds represented by structural formula I' for use in the treatment of pancreatic cancer.

[0736] In a first embodiment, the RAD51 inhibitor is a compound represented by structural formula I': [ka] or a pharmaceutically acceptable salt thereof, provided that in this structural formula: the thiazole ring is optionally substituted with -F or -Cl; X 4 is NR a or O; X 5 and X 6 are each independently NR b or O; R 1 is (C1-C5) alkyl; R 3 is (C1-C5) alkyl, -(C3-C7) cycloalkyl, or -(CH2) q heterocyclyl (wherein heterocyclyl is a monocyclic 3- to 7-membered heterocycle optionally substituted by one or more occurrences of methyl), or benzyl (wherein the benzyl ring is optionally substituted by one or more occurrences of halogen, methoxy, halomethoxy, methyl, halomethyl, or cyano); R a , R b , and R c each is independently hydrogen or methyl; R d are independently halogen, methoxy, halomethoxy, methyl, halomethyl, or cyano; m is 0, 1, 2, or 3; n is 0, 1, or 2; (q is 0 or 1).

[0737] In a second embodiment, the RAD51 inhibitor is a compound represented by structural formula I'-1: [ka] or a pharmaceutically acceptable salt thereof; the variables are as defined in the first embodiment.

[0738] In a third embodiment, the RAD51 inhibitor is a compound represented by structural formula I'-2: [ka] or a pharmaceutically acceptable salt thereof; the variables are as defined in the first embodiment.

[0739] In a fourth embodiment, the RAD51 inhibitor is a compound represented by structural formula I'-3: [ka] or a pharmaceutically acceptable salt thereof; the variables are as defined in the first embodiment.

[0740] In a fifth embodiment, the RAD51 inhibitor is a compound represented by structural formula I'-4: [ka] or a pharmaceutically acceptable salt thereof; the variables are as defined in the first embodiment.

[0741] In a sixth embodiment, the RAD51 inhibitor is of structural formula I', I'-1, I'-2, I'-3, or I'-4, or a pharmaceutically acceptable salt thereof, wherein X 4 is NH, and the remaining variables are as defined in the first embodiment.

[0742] In a seventh embodiment, the RAD51 inhibitor is a compound according to structural formula I', I'-1, I'-2, I'-3, or I'-4, wherein R 3 is (C1-C4) alkyl, -(C4-C6) cycloalkyl, -(CH2) q In some embodiments, R is a 4- to 6-membered heterocyclic ring optionally substituted with one methyl, or benzyl, and the remaining variables are as defined in the first and / or sixth embodiments. 3is isopropyl, t-butyl, cyclobutyl, cyclopentyl, oxetanyl, benzyl, tetrahydro-2H-pyranyl, or [ka] In some embodiments, R 3 is isopropyl or oxetanyl.

[0743] In an eighth embodiment, the RAD51 inhibitor is a compound according to structural formula I', I'-1, I'-2, I'-3, or I'-4, or a pharmaceutically acceptable salt thereof, wherein R d is halogen, m is 0 or 1, and the remainder of the variables are as defined in the first, sixth, and / or seventh embodiments. [ka] teeth, [ka] is.

[0744] In a ninth embodiment, the RAD51 inhibitor is a compound according to structural formula I', I'-1, I'-2, I'-3, or I'-4, or a pharmaceutically acceptable salt thereof, wherein R 1 is t-butyl, and the remainder of the variables are as defined in the first, sixth, seventh, and / or eighth embodiment.

[0745] In a tenth embodiment, the RAD51 inhibitor is a compound, or a pharmaceutically acceptable salt thereof, which compound is [ka] is selected from the group consisting of:

[0746] In an eleventh embodiment, the RAD51 inhibitor is a compound represented by structural formula II': [ka] or a pharmaceutically acceptable salt thereof, provided that in this structural formula: the thiazole ring is optionally substituted with -F or -Cl; X 4 is NR a or O; X 5 and X 6 are each independently NR b or O; R 1 is (C1-C5) alkyl; R 3 is (C1-C5) alkyl, -(C3-C7) cycloalkyl, or -(CH2) q -heterocyclyl (wherein heterocyclyl is a monocyclic 3- to 7-membered heterocycle optionally substituted with one or more occurrences of methyl), -(CH(R c )) q -phenyl, wherein the phenyl ring is optionally substituted with one or more occurrences of halogen, methoxy, halomethoxy, methyl, halomethyl, or cyano, or -(CH(R c )) q -2-pyridinyl, in which the 2-pyridinyl ring is optionally substituted with one or more occurrences of halogen, methoxy, halomethoxy, methyl, halomethyl, or cyano; R a , R b , and R c each is independently hydrogen or methyl; where n is 0, 1, or 2). q is 0 or 1).

[0747] In a twelfth embodiment, the RAD51 inhibitor is a compound represented by structural formula II'-1: [ka] or a pharmaceutically acceptable salt thereof, wherein the variables are as defined in the eleventh embodiment.

[0748] In a thirteenth embodiment, the RAD51 inhibitor is a compound represented by structural formula II'-2: [ka] or a pharmaceutically acceptable salt thereof, wherein the variables are as defined in the eleventh embodiment.

[0749] In a fourteenth embodiment, the RAD51 inhibitor is a compound according to structural formula II', II'-1, or II'-2, or a pharmaceutically acceptable salt thereof, wherein R 4 isopropyl, oxetanyl, cyclobutyl, -CH2-2-pyrrolidinyl, -CH2-N-methyl-2-pyrrolidinyl, -CH2-3-piperidinyl, -CH2-2-pyrazinyl, -CH2-2-pyrimidinyl, -CH(R c )-phenyl, or -CH(R c )-2-pyridinyl, wherein the phenyl and 2-pyridinyl rings are each independently optionally substituted with one or more halogens, where applicable, and the remaining variables are as defined in the eleventh embodiment. 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] is.

[0750] In a fifteenth embodiment, the RAD51 inhibitor is a compound according to structural formula II', II'-1, or II'-2, or a pharmaceutically acceptable salt thereof, wherein X 4is NH, and the remaining variables are as defined in the eleventh and / or fourteenth embodiments.

[0751] In a sixteenth embodiment, the RAD51 inhibitor is a compound according to structural formula II', II'-1, or II'-2, or a pharmaceutically acceptable salt thereof, wherein R 1 is t-butyl, and the remainder of the variables are as defined in the eleventh, and / or fourteenth, and fifteenth embodiments.

[0752] In a seventeenth embodiment, the RAD51 inhibitor is [ka] The compound is selected from the group consisting of:

[0753] In an eighteenth embodiment, the RAD51 inhibitor is [ka] (also referred to as "compound 67A" or "67").

[0754] Also included are the compounds disclosed in the examples (both in the form of pharmaceutically acceptable salts and in neutral form).

[0755] The term "pharmaceutically acceptable salt" refers to a pharmaceutical salt that, within the scope of sound medical judgment, is suitable for use in contact with the tissues of humans and lower animals, is free from undue toxicity, irritation, and allergic response, and is consistent with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, SM Berge et al. describe pharmaceutically acceptable salts in J. Pharm. Sci., 1977, 66, 1-19.

[0756] The present teachings include pharmaceutically acceptable salts of the compounds disclosed herein. Compounds having a basic group can form pharmaceutically acceptable salts with pharmaceutically acceptable acids. Suitable pharmaceutically acceptable acid addition salts of the compounds described herein include salts with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, phosphoric acid, metaphosphoric acid, nitric acid, and sulfuric acid) and organic acids (e.g., acetic acid, benzenesulfonic acid, benzoic acid, ethanesulfonic acid, methanesulfonic acid, succinic acid, and trifluoroacetic acid). Compounds of the present teachings having an acidic group (e.g., carboxylic acid) can form pharmaceutically acceptable salts with pharmaceutically acceptable bases. Suitable pharmaceutically acceptable base salts include ammonium salts, alkali metal salts (e.g., sodium salts and potassium salts), and alkaline earth metal salts (e.g., magnesium salts and calcium salts).

[0757] definition

[0758] As used herein, the term "halo" means halogen and includes fluoro, chloro, bromo, and iodo.

[0759] The term "alkyl," used alone or as part of a larger moiety such as "alkoxy" or "haloalkyl," refers to a saturated, straight- or branched-chain monovalent aliphatic hydrocarbon radical. Unless otherwise specified, an alkyl group typically has from 1 to 5 carbon atoms (i.e., (C1-C5) alkyl). As used herein, a "(C1-C5) alkyl" group refers to a group having from 1 to 5 carbon atoms in a linear or branched arrangement. Examples include methyl, ethyl, n-propyl, isopropyl, and the like.

[0760] The term "alkoxy" refers to an alkyl group attached through an oxygen linking atom represented by -O-alkyl. For example, "(C1-C4)alkoxy" includes methoxy, ethoxy, propoxy, and butoxy.

[0761] The terms "haloalkyl" and "haloalkoxy" mean alkyl or alkoxy, optionally substituted with one or more halogen atoms.

[0762] An "alkylene group" is a saturated branched or straight-chain divalent aliphatic hydrocarbon group. Unless otherwise specified, an alkylene group typically has from 2 to 6 carbon atoms (e.g., (C2-C6) alkylene).

[0763] The term "alkenyl" refers to a branched or straight-chain divalent hydrocarbon group containing at least one double bond. Alkenyl can be mono- or polyunsaturated and can exist in the E or Z configuration. Unless otherwise specified, alkenyl groups typically have from 2 to 6 carbon atoms (i.e., (C2-C6)alkenyl). For example, "(C2-C4)alkenyl" refers to a group having from 2 to 4 carbon atoms in a linear or branched configuration.

[0764] The term "cycloalkyl" means a monocyclic saturated hydrocarbon ring system. For example, C3-C6 cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Unless otherwise specified, a "cycloalkyl" has from 3 to 7 ring carbon atoms.

[0765] A bridged cycloalkyl refers to a bicyclic non-aromatic hydrocarbon ring system in which the two rings share at least three adjacent ring carbon atoms. Bridged cycloalkyls typically have 6 to 12 ring carbon atoms. Non-limiting examples include bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, bicyclo[4.3.1]decyl, bicyclo[3.3.1]nonyl, bornyl, bornenyl, norbornyl, norbornenyl, 6,6-dimethylbicyclo[3.1.1]heptyl, tricyclobutyl, and adamantyl.

[0766] The terms "heterocyclyl," "heterocycle," and "heterocyclic group" are used interchangeably herein and refer to a saturated or unsaturated non-aromatic 4- to 10-membered ring group containing 1 to 4 ring heteroatoms (which may be the same or different and are selected from N, O, or S). It can be monocyclic, bicyclic, or tricyclic (e.g., fused or bridged bicyclic or tricyclic). Non-limiting examples include azetidinyl, morpholinyl, thiomorpholinyl, pyrrolidinonyl, pyrrolidinyl, piperidinyl, piperazinyl, hydantoinyl, Valerolactamil , oxiranyl, oxetanyl, dihydroimidazole, dihydrofuranyl, dihydropyranyl, dihydropyridinyl, dihydropyrimidinyl, dihydrothienyl, dihydrothiophenyl, dihydrothiopyranyl, tetrahydroimidazole, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl, tetrahydropyridinyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, and tetrahydrothiopyranyl. The heterocycle optionally contains one or more double bonds and / or is optionally fused to one or more aromatic rings (e.g., tetrahydronaphthyridine, indolinone, dihydropyrrolotriazole, imidazopyrimidine, quinolinone, dioxaspirodecane).

[0767] Non-limiting examples of 3- to 7-membered monocyclic heterocycles include azetidinyl, morpholinyl, thiomorpholinyl, pyrrolidinonyl, pyrrolidinyl, piperidinyl, piperazinyl, hydantoinyl, Valerolactamil , oxiranyl, oxetanyl, dihydroimidazole, dihydrofuranyl, dihydropyranyl, dihydropyridinyl, dihydropyrimidinyl, dihydrothienyl, dihydrothiophenyl, dihydrothiopyranyl, tetrahydroimidazole, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl, tetrahydropyridinyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, and tetrahydrothiopyranyl.

[0768] A bridged heterocyclyl refers to a bicyclic non-aromatic ring system containing one to four ring heteroatoms, where the two rings share at least three adjacent ring atoms. Bridged heterocyclyls typically have six to twelve ring atoms. Non-limiting examples include azanorbornyl, quinuclidinyl, isoquinuclidinyl, tropanyl, azabicyclo[3.2.1]octanyl, azabicyclo[2.2.1]heptanyl, 2-azabicyclo[3.2.1]octanyl, azabicyclo[3.2.1]octanyl, azabicyclo[3.2.2]nonanyl, azabicyclo[3.3.0]nonanyl, and azabicyclo[3.3.1]nonanyl.

[0769] The terms "heteroaryl," "heteroaromatic," "heteroaryl ring," "heteroaryl group," "heteroaromatic ring," and "heteroaromatic group" are used interchangeably herein. "Heteroaryl," when used alone or as part of a larger moiety, such as in "heteroaralkyl" or "heteroarylalkoxy," refers to an aromatic ring group having 5 to 10 ring atoms selected from carbon and at least one (typically 1 to 4, more typically 1 or 2) heteroatoms (e.g., oxygen, nitrogen, or sulfur). "Heteroaryl" includes monocyclic and polycyclic rings in which a monocyclic heteroaromatic ring is fused to one or more other aromatic or heteroaromatic rings. "Heteroaryl" includes monocyclic and bicyclic ring systems.

[0770] "Monocyclic 5- to 6-membered heteroaromatic ring (or heteroaryl)" refers to a monocyclic heteroaromatic ring having 5 or 6 ring atoms selected from carbon and at least one (typically 1 to 3, more typically 1 or 2) heteroatom (e.g., oxygen, nitrogen, or sulfur). Examples of monocyclic 5- to 6-membered heteroaromatic ring groups include furanyl (e.g., 2-furanyl, 3-furanyl), imidazolyl (e.g., N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), isoxazolyl (e.g., 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl), oxadiazolyl (e.g., 2-oxadiazolyl, 5-oxadiazolyl), oxazolyl (e.g., 2-oxazolyl, 4-oxazolyl, 5-oxazolyl), and pyrazolyl (e.g., 3-pyrazolyl, 4-pyrazolyl). , pyrrolyl (e.g., 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), pyridyl (e.g., 2-pyridyl, 3-pyridyl, 4-pyridyl), pyrimidinyl (e.g., 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl), pyridazinyl (e.g., 3-pyridazinyl), thiazolyl (e.g., 2-thiazolyl, 4-thiazolyl, 5-thiazolyl), isothiazolyl, triazolyl (e.g., 2-triazolyl, 5-triazolyl), tetrazolyl (e.g., tetrazolyl), and thienyl (e.g., 2-thienyl, 3-thienyl).

[0771] When a group is described as "substituted," a non-hydrogen substituent replaces a hydrogen on a carbon or nitrogen of the substituent. Thus, for example, a substituted alkyl is an alkyl in which at least one non-hydrogen substituent replaces a hydrogen substituent on the alkyl substituent. Specifically, a monofluoroalkyl is an alkyl substituted with a fluoro substituent, and a difluoroalkyl is an alkyl substituted with two fluoro substituents. It should be recognized that when there are two or more substitutions on a substituent, each non-hydrogen substituent can be the same or different (unless otherwise specified). Many moieties (e.g., alkyl, cycloalkyl, or heterocycle) are referred to herein as "substituted" or "optionally substituted." When a moiety is modified with one of these terms, unless otherwise specified, it represents that the moiety can be substituted with moieties known to those skilled in the art as being available for substitution, and includes one or more substituents. When two or more substituents are present, each substituent is independently selected. Such means for substitution are well known in the art and / or are taught by this disclosure. Optional substituents can be any suitable substituent for attachment to a moiety. Those of ordinary skill in the art will recognize that the compounds and definitions provided do not include impermissible substitution patterns (e.g., methyl substituted with five different groups). Such impermissible substitution patterns are clearly recognized by those of ordinary skill in the art. When a group is described as being optionally substituted with "one or more" substituents, this means that the group is optionally substituted with 1, 2, 3, 4, 5, or 6 substituents. In one embodiment, a group is optionally substituted with 1 to 3 substituents. In one embodiment, a group is optionally substituted with 1 to 2 substituents. In one embodiment, a group is optionally substituted with 1 substituent.

[0772] Suitable substituents are those that do not have a significant detrimental effect on the ability of the compound to inhibit RAD51. If a suitable substituent is not specifically recited, non-limiting examples of representative substituents include halo, -CN, alkyl, alkoxy, halomethyl, halomethoxy, (C1-C5)alkyl, halo(C1-C5)alkyl, (C1-C5)alkoxy, -NO2, -OR c’ , -NR a’ R b’ , -S(O) i R a’ , -NR a S(O) i R b’ , -S(O) i NR a’ R b’ , -C(=O)OR a’ , -OC(=O)OR a’ , -C(=S)OR a’ , -O(C=S)R a’ , -C(=O)NR a’ R b’ , -NR a’ C(=O)R b’ , -C(=S)NR a’ R b’ , -NR a’ C(=S)R b’ , -NR a’ (C=O)OR b’ , -O(C=O)NR a’ R b’ , -NR a’ (C=S)OR b’ , -O(C=S)NR a’ R b’ , -NR a’ (C=O)NR a’ R b’ , -NR a’ (C=S)NR a’ R b’ , -C(=S)R a’ , -C(=O)R a’ , (C3-C6)cycloalkyl, monocyclic heteroaryl, and phenyl, wherein the (C3-C6)cycloalkyl, monocyclic heteroaryl, and phenyl substituents are optionally and independently substituted with -CH3, halomethyl, halo, methoxy, or halomethoxy.a’ and each R b are independently selected from —H and (C1-C5) alkyl, wherein R a’ or R b’ (C1-C5) alkyl groups represented by the formula (I) are optionally substituted with hydroxyl or (C1-C3) alkoxy; c’ is —H, halo(C1-C5)alkyl, or (C1-C5)alkyl, wherein R c The (C1-C5) alkyl group represented by is optionally substituted with hydroxyl or (C1-C3) alkoxy; i is 0, 1, or 2. =0 is also a suitable substituent for alkyl, cycloalkyl, and heterocycle.

[0773] Compounds with one or more chiral centers can exist in different stereoisomeric forms. Stereoisomers are compounds that differ from each other only in their spatial arrangement. Stereoisomers include all diastereomeric, enantiomeric, and epimeric forms, as well as racemates and mixtures thereof.

[0774] The term "geometric isomer" refers to a cyclic compound having at least two substituents, either both on the same side of the ring (cis) or both on opposite sides of the ring (trans). When a disclosed compound is given a name or structure without indicating stereochemistry, it is to be understood that the name and structure encompasses one or more of the stereoisomers or geometric isomers, or a mixture of the encompassed stereoisomers or geometric isomers.

[0775] When a geometric isomer is designated by name or structure, it is to be understood that the isomer designated by name or structure is present in greater abundance than another isomer, i.e., the geometric isomer designated by name or structure has a geometric isomeric purity of greater than 50% (e.g., at least 60%, 70%, 80%, 90%, 99%, or 99.9%) by weight. Geometric isomeric purity is determined by dividing the geometric isomer designated by name or structure in a mixture by the total weight of all geometric isomers in the mixture.

[0776] A racemic mixture means 50% of one enantiomer, and 50% is the corresponding enantiomer. When a compound with one chiral center is depicted by name or structure without indicating the stereochemistry of the chiral center, it is to be understood that the name or structure encompasses both possible enantiomeric forms of the compound (e.g., both enantiomerically pure forms, both enantiomerically enriched forms, or racemic forms). When a compound with two or more chiral centers is depicted by name or structure without indicating the stereochemistry of the chiral centers, it is to be understood that the name or structure encompasses all possible diastereomeric forms of the compound (e.g., diastereomerically pure forms, diastereomerically enriched forms, and equimolar mixtures of one or more diastereomers (e.g., racemic mixtures)).

[0777] Enantiomeric and diastereomeric mixtures can be resolved into their component enantiomers or stereoisomers by well-known methods, such as chiral-phase gas chromatography, chiral-phase high-performance liquid chromatography, crystallizing the compound as a chiral salt complex, or crystallizing the compound in a chiral solvent. Enantiomers and diastereomers can also be obtained from diastereomerically- or enantiomerically-pure intermediates, reagents, and catalysts by well-known asymmetric synthetic chemistry.

[0778] When a compound is designated by a name and structure that indicates it is a single enantiomer, unless otherwise specified, the compound is at least 60%, 70%, 80%, 90%, 99%, or 99.9% optically pure (also called "enantiomerically pure"). Optical purity is the weight of the mixture of the enantiomer designated by name or structure divided by the total weight of the mixture of both enantiomers.

[0779] When the stereochemistry of a disclosed compound is indicated by name or structure, and the name or indicated structure encompasses more than one stereoisomer (e.g., as in a diastereomeric pair), it is to be understood that any one of the encompassed stereoisomers or any mixture of the encompassed stereoisomers is included. Furthermore, it is to be understood that the stereoisomer depicted by name or structure has a stereoisomeric purity of at least 60%, 70%, 80%, 90%, 99%, or 99.9% by weight. Stereoisomeric purity in this case is determined by dividing the total weight of the mixture of stereoisomers encompassed by the name and structure by the combined weight of the mixture of all stereoisomers.

[0780] Pharmaceutical Composition

[0781] The compounds disclosed herein are RAD51 inhibitors. Pharmaceutical compositions of the disclosure include one or more RAD51 inhibitors, or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier or diluent.

[0782] "Pharmaceutically acceptable carrier" and "pharmaceutically acceptable diluent" refer to substances that aid in the formulation of an active agent and / or its administration to and / or absorption by a subject, and can be included in the compositions of the present disclosure without causing significant adverse toxicological effects to the subject. Non-limiting examples of pharmaceutically acceptable carriers and / or diluents include water, NaCl, normal saline, lactated Ringer's solution, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavoring agents, salt solutions (such as Ringer's solution), alcohols, oils, gelatin, carbohydrates (such as lactose, amylose, or starch), fatty acid esters, hydroxymethylcellulose, polyvinylpyrrolidine, and coloring agents. Such preparations can be sterilized and, if desired, mixed with auxiliary substances (such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring agents, and / or flavoring substances) that do not deleteriously react with or interfere with the activity of the compounds presented herein. Those skilled in the art will recognize that other pharmaceutical excipients are suitable for use with the disclosed compounds.

[0783] Pharmaceutical compositions of the present teachings optionally include one or more pharmaceutically acceptable bases and / or diluents thereof, such as lactose, starch, cellulose, and dextrose. Other excipients, such as flavoring agents; sweeteners; and preservatives, such as methylparaben, ethylparaben, propylparaben, and butylparaben, can also be included. A more complete list of suitable excipients can be found in the Handbook of Pharmaceutical Excipients (5 thEd., Pharmaceutical Press (2005). A person skilled in the art would know how to prepare formulations suitable for various types of administration routes. Conventional procedures and ingredients for the selection and preparation of appropriate formulations are described, for example, in Remington's Pharmaceutical Sciences (2003 - 20th edition) and The United States Pharmacopeia: The National Formulary, 1999 (USP 24 NF19). A carrier, diluent, and / or excipient is "acceptable" in the sense of being compatible with the other ingredients of the pharmaceutical composition and not deleterious to the recipient thereof.

[0784] The term "drug holiday," also referred to as a "drug holiday," refers to a period of time during which a subject receives no medication or receives a lower dose of a therapeutic agent (i.e., a RAD51 inhibitor). The timing of the drug holiday depends on the timing of the regular dosing regimen and the purpose of the drug holiday (e.g., to regain drug sensitivity and / or reduce unwanted side effects of continuous long-term administration). In some embodiments, a drug holiday can involve a reduction in the dose of the drug (e.g., below a therapeutically effective amount for a specified period of time). In other embodiments, drug administration is suspended for a specified period of time, followed by resumption of administration at the same or a different dosing regimen (e.g., at a lower or higher dose and / or frequency of administration). Thus, drug holidays of the present disclosure can be selected from a wide range of durations and dosing regimens.

[0785] Additional aspects of the treatment method

[0786] In some embodiments, the subject may be a subject that is determined to have increased levels of DNA damage in one or more types of cells compared to a reference level. As used herein, "DNA damage" refers to breaks, nicks, and mutations in the DNA present in a cell. In some embodiments, DNA damage can include one or more of a single-strand break (e.g., a "nick"), a double-strand break (DSB), and a mutation. In some embodiments, the DNA damage can be one or more DSBs. As used herein, "mutation" refers to a change or difference in the genetic material (e.g., deletion, insertion, SNP, gene rearrangement, and / or introduction of a foreign gene or sequence) in a cell compared to a reference wild-type cell.

[0787] In some embodiments, a subject can be determined to have an increased level of DNA damage if the subject is determined to have an increased level and / or activity of a DNA damaging process or DNA editing enzyme. As used herein, "DNA damaging process" refers to any activity or process within a cell that results in the generation of one or more types of DNA damage.

[0788] In some embodiments, the increased level of DNA damage can be an increased level of mutation, for example, by determining the global mutation status in all or a portion of a cell's genome. A global mutation status that is at least 2% greater (e.g., 2% or more, 3% or more, 5% or more, 10% or more, or 20% or more) than the global mutation status in a reference cell can indicate an increased, elevated, and / or significant level of DNA editing enzyme activity. In some embodiments, the level of hypermutation can be determined. In some embodiments, the global mutation status of the entire genome, or a portion thereof, can be determined using FISH, whole genome sequencing, high-throughput sequencing, exome sequencing, hybridization, and / or PCR. In some embodiments, the activity of a DNA editing enzyme can be measured by determining the level of hypermutation in specific target genes (non-limiting examples of which include IGH, BCL6, MYC, BCL1 1A, CD93, PIM1, and / or PAX5). In some embodiments, the DNA editing enzyme is AID. In some embodiments, a level of mutation in a particular target gene (including IGH, BCL6, MYC, BCL1 1A, CD93, PIM1, and / or PAX5) that is at least 2% greater (e.g., 2% or more greater, 3% or more greater, 5% or more greater, 10% or more greater, or 20% or more greater) than the level of mutation in IGH, BCL6, MYC, BCL1 1A, CD93, PIM1, and / or PAX5 in a reference cell may indicate an increased, elevated, and / or significant level of AID activity.

[0789] In some embodiments, the increased level of DNA damage can be an increased level of double-strand breaks (DSBs).The level of DSBs can be determined, for example, by karyotyping, by γ-H2AC aggregate formation, and / or by using FISH analysis, and DNA double-strand breaks can be detected, for example, by DNA break detection fish (DBD-FISH) (Volpi and Bridger, BioTechniques, Vol. 45, No. 4, October 2008, pp. 385-409).

[0790] In some embodiments, the increased level of DNA damage can be the increased level of single-strand breaks.The level of single-strand breaks in DNA can be determined by, for example, COMET assay, FISH, or by using single-strand break specific probes.The detection of DNA (both single-strand and double-strand) breaks is well known in the art, and is further described in, for example, Kumari et al. EXCLI Journal 2009 7:44-62 and Motalleb et al. Research Journal of Applied Sciences, Engineering and Technology.2012 4:1888-1894; each of which is incorporated herein by reference in its entirety.

[0791] In some embodiments, an increased level of activity of a DNA damage process can include an increased level and / or activity of a DNA editing enzyme. In some embodiments, the technology described herein is directed to treating cells with an active DNA editing enzyme with a compound of the present disclosure. In some embodiments, the technology described herein is directed to treating cells with an increased level and / or activity of a DNA editing enzyme with a compound of the present disclosure. As used herein, "DNA editing enzyme" generally refers to an enzyme that catalyzes the mutation, exchange, or excision of a DNA segment, particularly an enzyme that can generate or facilitate the production of point mutations, DNA single-strand breaks, DNA double-strand breaks, or protein-DNA adducts. A DNA editing enzyme (as so referred to herein) need not necessarily be site-specific in its action. Likewise, it need not be cell-specific. In some embodiments, the cell is a B cell expressing such an enzyme in detectable amounts.

[0792] Non-limiting examples of DNA editing enzymes include recombination activating gene 1 (RAG1; NCBI Gene ID: 5896), recombination activating gene 1 (RAG2; NCBI Gene ID: 5897), sporulation specific protein 11 (SPO1 1; NCBI Gene ID: 23626), type 1 topoisomerases that are members of the APOBEC family; type 2 topoisomerases; and / or AID. In some embodiments, the DNA editing enzyme can be AID.

[0793] In some embodiments, the DNA editing enzyme can be a member of the APOBEC (apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like) family. As used herein, "APOBEC family" refers to a family of cytidine deaminase enzymes that have an N-terminal zinc-dependent cytidine deaminase catalytic domain containing a C-terminal pseudocatalytic domain. Non-limiting examples of members of the APOBEC family include AID, APOBEC 1 (e.g., NCBI Gene ID: 339), APOBEC2 (e.g., NCBI Gene ID: 10930), APOBEC3A (e.g., NCBI Gene ID: 200315), APOBEC3B (e.g., NCBI Gene ID: 9582), APOBEC3C (e.g., NCBI Gene ID: 27350), APOBEC3D (e.g., NCBI Gene ID: 140564), APOBEC3E (e.g., NCBI Gene ID: 140564), APOBEC3F (e.g., NCBI Gene ID: 200316), APOBEC3G (e.g., NCBI Gene ID: 60489), APOBEC3H (e.g., NCBI Gene ID: 164668), and APOBEC4 (e.g., NCBI Gene ID: 403314).

[0794] In some embodiments, the DNA editing enzyme can be a type 1 topoisomerase. In some embodiments, the DNA editing enzyme can be a type 2 topoisomerase. Topoisomerases create breaks in DNA, helping to unwind or loosen strands. Type II topoisomerases hydrolyze ATP to create DSB cuts, while type I topoisomerases create single-strand breaks. Non-limiting examples of type II topoisomerases can include topoisomerase II (e.g., NCBI Gene ID: 7153 and 7155). Non-limiting examples of type I topoisomerases can include topoisomerase I (e.g., NCBI Gene ID: 7150).

[0795] An embodiment of the technology described herein is based on the discovery that the compounds described herein can inhibit DNA repair mechanisms (e.g., homologous repair). Activation-induced cytidine deaminase (AID, also referred to as AICDA and also known as ARP2, CDA2, or HIGM2) is a DNA editing enzyme that is a member of the apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like (APOBEC) family, and causes extensive genomic breaks and cell death in cells with reduced homologous recombination ability (e.g., cells with reduced DNA double-strand break repair ability). Therefore, provided herein is a method for inducing cell death, comprising detecting increased expression of a DNA editing enzyme (e.g., AID) in a cell, and then contacting the cell with a compound of the present disclosure, thereby achieving cell death. Therefore, provided herein is a method for inducing cell death, comprising increasing expression of a DNA editing enzyme (e.g., AID) in a cell, and then contacting the cell with a compound of the present disclosure, thereby achieving cell death. Thus, provided herein is a method for inducing cell death, comprising administering to a cell a therapeutically effective amount of a DNA editing enzyme (e.g., AID), and then contacting the cell with a compound of the present disclosure; thereby obtaining cell death.

[0796] AID, encoded by the AICDA gene (NCBI Gene ID: 57379), is required for intrinsic B cell function and is most predominantly expressed in germinal center blast B cells. This protein is involved in somatic hypermutation, gene conversion, and immunoglobulin class switch recombination. AID is normally expressed almost exclusively in antigen-activated germinal center B cells, where it initiates immunoglobulin isotype class switching (Manis et al. 2002, Trends Immunol, 23, 31-39; Chaudhuri and Alt, Nat Rev Immunol, 2004, 4, 541-552; Longerich et al., Curr Opin Immunol, 2006, 18, 164-174; Chaudhuri et al., Adv Immunol 2007, 94, 157-214). AID is required for somatic hypermutation and immunoglobulin class switching in activated B cells. AID expression is regulated by stimulation of CD40 ligand, B cell receptor, IL4R, or Toll-like receptors (Crouch et al., J Exp Med 2007 204: 1145-1156; Muramatsu et al., J Biol Chem 1999 274: 18470-6). AID is transiently upregulated after activation and induces point mutations or DNA double-strand breaks in immunoglobulin genes in a sequence-nonspecific manner, followed by downregulation (Longerich et al., Curr Opin Immunol, 2006, 18, 164-176; Chaudhuri et al., Adv Immunol 2007, 94, 157-214). Ultimately, AID is active only in a small population of normal cells (antigen-activated B cells) at any given time. AID-regulated genomic rearrangements and mutations lead to the diversity of antigen recognition, receptor editing, and lymphoid effector functions required for functional adaptive immunity (Mills, et al. Immunol Rev 2003 194:77-95).Recently, it has been reported that AID has off-target point mutation activity (Liu, M. et al., Nature 2008, 451, 841-845; Liu and Schatz, Trends Immunol. 2009, 30, 173-181; Perez-Duran et al., Carcinogenesis. 2007, 28(12):2427-33). Robbiani et al. reported the off-target activity of AID in B cells, particularly c-myc / IgH translocations (Robbiani et al., Mol Cell 2009, 36(4):631-41). Expression of AID accelerates the rate of tumor development in Bcl6 transgenic mice (Pasqualucci et al., 2008, Nat. Genet. 40, 108-112). However, aberrant AID itself does not necessarily cause malignancies or translocation-associated cancers in B cells (Muto et al., 2006, Proc. Natl. Acad. Sci. USA 103, 2752-2757; Okazaki et al., 2003, J. Exp. Med. 197, 1173-1181; Shen et al., 2008, Mol. Immunol. 45, 1883-1892). In addition, despite its essential role in the c-myc / IgH translocation, AID is not required for the development of plasmacytosis or plasmacytoma in IL-6 transgenic mice or pristane-treated mice, respectively (Kovalchuk et al., 2007, J. Exp. Med. 204, 2989-3001; Ramiro et al., 2004, J. Exp. Med. 200, 1103-1110). However, most human B-cell lymphoma-associated translocations do not involve c-myc, and many may not involve Ig genes (Kuppers, 2005, Oncogene 20, 5580-5594).

[0797] Overexpression of AID has been reported in chronic lymphocytic leukemia (CLL) (Hancer et al. Leuk Lymphoma. 2011 Jan;52(1):79-84; Heintel et al., Leukemia. 2004 Apr;18(4):756-62). Furthermore, AID expression has been shown to correlate with blast crisis B-cell leukemia and treatment resistance in myeloid leukemia, and to be associated with a generally poor prognosis in chronic B-lymphocytic leukemia (Mao et al., Br J Dermatol 2001, 145:117-122; Chaudhuri et al., Nature 2004, 430:992-8).Further expression of AID has been reported in tumor cells from a variety of cancers, including, but not limited to, cancers of the lung, breast, stomach, colon, intestine, liver, and cholangiocarcinoma (Greeve et al., Blood 2003, 1010, 3574-3580; Feldhahn et al., J Exp Med 2007, 204, 1157-1166; Kotani et al., PNAS USA 2007, 104, 1616-1620; Engels et al., 2008, Appl Immunohistochem Mol Morphol 16, 521-529; Klemm et al., 2009, Cancer Cell 6, 232-245; Palacios et al., 2010, Blood 115(22), 4488-4496; Leuenberger et al., 2009, Mod Pathol 32, 177-186;Gruber et al., 2010, Cancer Res 70, 7411-7420;Inflammatory cancer (Marusawa 2008, Int J Biochem Cell Biol.40, 399-402);Follicular lymphoma (Hardianti et al., 2004, Leukemia 18, 826-831;Shikata et al., 2012, Cancer Sci. 103(3):415-21);Thyroid cancer (Qiu et al. 2012, Mod Pathol 25(l),36-45);Breast cancer (Borchert et al. 2011, BMC Cancer 11:347);Marusawa, et al., 2011, Adv Immunol 111: 109-41; Zhang et al. 2012, Hum Pathol 43(3):423-34; Komori et al., 2008, Hepatology 47(3):888-896; Hockley 2010, Leukemia 24(5): 1084-6; Adult T-cell leukemia (Nakamura et al., 2011, Br J Dermatol. 165(2):437-9). All references in this paragraph are incorporated herein by reference in their entirety.

[0798] Elevated levels of AID have been reported in arthritis (Xu et al. Scand. J. Immunol. 2009, 296, 2033-6) and in the MRL / Fas(lpr / lpr) mouse lupus model (White et al. 2011, Autoimmunity 44(8), 585-98). All references in this paragraph are incorporated herein by reference in their entirety.

[0799] When DSB repair is inhibited, the extent of DSBs generated by AID is much greater than previously suspected, and the extent of genomic damage is severe enough to result in cell death. Accordingly, one embodiment of the technology described herein provides a method of treatment comprising: (a) selecting a subject with cells expressing elevated levels of activation-induced cytidine deaminase (AID); and (b) administering to the subject a therapeutically effective amount of an inhibitor of double-strand break repair (e.g., a compound of the present disclosure); the elevated level of AID is higher than the level of AID in the same type of cell from a healthy individual. In some embodiments, the cells expressing elevated levels of AID are B cells. In some embodiments, the B cells expressing elevated levels of AID are cancerous B cells or B cells associated with an autoimmune disease. In some embodiments, the subject can be a human subject.

[0800] The method provided herein treats cancer and / or autoimmune disorders by inhibiting DNA double-strand break repair. The method provided herein treats pancreatic cancer by inhibiting DNA double-strand break repair. This inhibition proves lethal to cells expressing AID. Because AID causes widespread genomic breaks, treatment with a double-strand break repair inhibitor prevents the cells from repairing these lesions as they are being generated. As a result, cell death specific to AID-expressing cells (e.g., cancerous B cells and / or autoimmune cells) occurs in the subject. Thus, as described herein, one embodiment provides a therapeutic paradigm that selectively induces the self-destruction of certain diseased cells while reducing unintended side effects in healthy tissues.

[0801] In some embodiments, the increased level and / or activity of a DNA editing enzyme can be an increased level of DNA editing enzyme mRNA. mRNA levels can be assessed, for example, using biochemical and molecular biology techniques, such as Northern blotting or other hybridization assays, nuclease protection assays, reverse transcription (quantitative RT-PCR) techniques, RNA-Seq, high-throughput sequencing, etc. Such assays are well known in the art. In one embodiment, a nuclear "run-on" (or "run-off) transcription assay is utilized (see, e.g., Methods in Molecular Biology, Volume: 49, September 27, 1995, Page Range: 229-238). Arrays may also be used; arrays and methods for analyzing mRNA using such arrays have previously been described, e.g., in EP 0 834 575, EP 0 834 576, WO 96 / 31622, U.S. Pat. No. 5,837,832, or WO 98 / 30883. WO 97 / 10365 provides a method for monitoring the expression levels of a variety of genes using high-density oligonucleotide assays.

[0802] In some embodiments, a subject can be determined to have an increased level of DNA damage in one or more cell types compared to a reference level if the subject has been exposed to an agent known to cause such DNA damage. Non-limiting examples of such agents can include viral infections with DNA-integrating viruses (e.g., adeno-associated viruses, retroviruses, human T-cell leukemia viruses, HIV-1, oncoviruses, hepatitis viruses, and hepatitis B viruses); DNA-damaging chemicals (e.g., acetaldehyde, polycyclic aromatic hydrocarbons, benzene, nitrosamines, tobacco smoke, aflatoxins, etc.); DNA-damaging chemotherapeutic agents (e.g., bleomycin, mitomycin, nitrogen mustards (e.g., mechlorethamine, cyclophosphamide, melphalan, chlorambucil, ifosfen, etc.); These include: amides, and busulfan), nitrosoureas (e.g., N-nitroso-N-methylurea (MNU), carmustine (BCNU), lomustine (CCNU) and semustine (MeCCNU), fotemustine, and streptozotocin), tetrazines (e.g., dacarbazine, mitozolomide, and temozolomide), aziridines (e.g., thiotepa, mitomycin, and diaziquone (AZQ)), cisplatins (e.g., cisplatin, carboplatin, and oxaliplatin), procarbazine, and hexamethylmelamine); and ionizing radiation or ultraviolet light. Exposure to such agents may be the result of accidents, infections, and / or environmental exposures, or the result of therapeutic administration of such agents.

[0803] In some embodiments, the increased level of DNA damage may occur in cell types affected by cancer, autoimmune diseases, and / or neurodegenerative diseases. In some embodiments, the subject is determined to have increased levels of DNA damage occurring in cells selected from the group consisting of cancer cells (e.g., pancreatic cancer cells); immune system cells; or nervous system cells.

[0804] In some embodiments, the DNA editing enzyme can be AID. In some embodiments, the level of AID can be the level of AID in blood cells. In some embodiments, the level of AID can be the level of AID in B cells.

[0805] In some embodiments, an increased level of AID can be a detectable level of AID (eg, as described herein below).

[0806] In some embodiments, the subject can be a human subject.

[0807] The methods provided herein treat cancer and / or autoimmune disorders by inhibiting DNA double-strand break repair. The methods provided herein treat pancreatic cancer by inhibiting DNA double-strand break repair. This inhibition proves lethal to cells expressing AID because AID generates widespread breaks, and treatment with double-strand break repair inhibitors prevents the cells from repairing these lesions as they are being generated. This results in specific cell death of AID-expressing cells, such as cancerous B cells and / or autoimmune cells, in a subject. Thus, as described herein, one embodiment provides a therapeutic paradigm that selectively induces the self-destruction of selected diseased cells while reducing unintended side effects in healthy tissues.

[0808] Methods for detecting cancer in patients with increased levels of DNA damage or increased levels of DNA editing enzymes are disclosed in WO2016 / 094897, which is incorporated herein by reference.

[0809] In some embodiments, the cancer to be treated is a type in which DNA editing enzymes are overexpressed. In some embodiments, the cancer to be treated is a B-cell neoplasm.

[0810] Another embodiment is a method of treating cancer by administering to a subject an effective amount of one or more of the disclosed compounds, or pharmaceutically acceptable salts thereof, or corresponding pharmaceutical compositions. In one aspect, the cancer is selected from the group consisting of lymphoma, leukemia, and plasma cell neoplasm. In another aspect, the cancer is selected from the group consisting of carcinoma and sarcoma.

[0811] In some embodiments, the cancer to be treated is pancreatic cancer.

[0812] In some embodiments, the pancreatic cancer is exocrine pancreatic cancer. In some embodiments, the exocrine pancreatic cancer is adenocarcinoma. In some embodiments, the exocrine pancreatic cancer is squamous cell carcinoma. In some embodiments, the exocrine pancreatic cancer is squamous cell adenocarcinoma. In some embodiments, the exocrine pancreatic cancer is mucinous carcinoma.

[0813] In some embodiments, the pancreatic cancer is neuroendocrine pancreatic cancer. In some embodiments, the neuroendocrine pancreatic cancer is a non-functioning neuroendocrine tumor. In some embodiments, the neuroendocrine pancreatic cancer is a gastrinoma. In some embodiments, the neuroendocrine pancreatic cancer is an insulinoma. In some embodiments, the neuroendocrine pancreatic cancer is a glucagonoma.

[0814] In some embodiments, the neuroendocrine pancreatic cancer is a VIPoma (i.e., a pancreatic islet cell tumor that affects vasoactive intestinal peptide). In some embodiments, the neuroendocrine pancreatic cancer is a somatostatinoma (i.e., a pancreatic islet cell tumor that affects somatostatin).

[0815] In some embodiments, the pancreatic cancer is a benign precancerous lesion.

[0816] In some embodiments, the cancer to be treated is lymphoma. Lymphomas that can be treated by the disclosed methods include non-Hodgkin's lymphoma, Burkitt's lymphoma, small lymphocytic lymphoma, lymphoplasmacytic lymphoma, MALT lymphoma, follicular lymphoma, diffuse large B-cell lymphoma, and T-cell lymphoma.

[0817] Lymphoma is a malignant tumor in the lymphatic cells of the immune system (e.g., B cells, T cells, or natural killer (NK) cells). Lymphoma often arises in the lymph nodes and presents as a solid tumor. Lymphoma can metastasize to other organs (e.g., brain, bone, or skin). Extranodal sites are often located in the abdomen. Lymphoma is closely related to lymphocytic leukemia, and in some cases, a particular form of cancer is categorized as both a lymphoma and a leukemia.

[0818] Leukemias that can be treated by the disclosed methods include acute lymphoblastic leukemia (ALL); Burkitt's leukemia; B-cell leukemia; B-cell acute lymphoblastic leukemia; chronic lymphocytic leukemia (CLL); acute myeloid leukemia (AML); chronic myeloid leukemia (CML); and T-cell acute lymphoblastic leukemia (T-ALL).

[0819] In some embodiments, the cancer to be treated is a B-cell neoplasm, B-cell leukemia, B-cell acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, Burkitt's leukemia, acute myeloid leukemia, and / or T-ALL. B-cell maturation most typically terminates or is substantially reduced when foreign antigens are neutralized. However, sometimes proliferation of certain B cells will continue unabated; such proliferation can result in cancers called "B-cell lymphomas" or "B-cell leukemias." In some embodiments, the cancer to be treated is chronic lymphocytic leukemia (CLL) or chronic myelogenous leukemia (CML).

[0820] In some embodiments, the condition to be treated is a plasma cell neoplasm. Examples of plasma cell neoplasms include multiple myeloma; plasma cell myeloma; plasma cell leukemia, and plasmacytoma.

[0821] Cancers that can be treated by the disclosed methods include colon cancer; liver cancer; stomach cancer; intestinal cancer; esophageal cancer; breast cancer; ovarian cancer; head and neck cancer; lung cancer; and thyroid cancer.

[0822] Sarcomas that can be treated by the disclosed methods include soft tissue sarcomas and osteosarcomas.

[0823] Any cancer characterized by high levels of DNA damage and / or DNA editing enzyme expression can be treated using the compounds described herein (e.g., compounds of the present disclosure). For example, sarcoma, epithelial cell carcinoma (cancer), colon cancer, gastric cancer, intestinal cancer, liver cancer, hepatocellular carcinoma, breast cancer, thyroid cancer, esophageal cancer, lung cancer, brain cancer, head and neck cancer, melanoma, kidney cancer, prostate cancer, hemangioma, rhabdomyosarcoma, chondrosarcoma, osteosarcoma, fibrosarcoma, and cholangiocarcinoma may be characterized by high levels of DNA editing enzyme expression (e.g., AID). In some embodiments, the cancer to be treated is colon cancer, liver cancer, gastric cancer, intestinal cancer, breast cancer, lung cancer, thyroid cancer, and / or cholangiocarcinoma.

[0824] Some cancers that can be treated by the disclosed methods include bladder, blood, bone, bone marrow, brain, breast, colon, esophagus, gastrointestinal, gingival, head, kidney, liver, lung, nasopharynx, neck, ovarian, prostate, skin, stomach, testis, tongue, or uterine cancer. In addition, the cancer can be of the following histological types, including, but not limited to: neoplasia, malignant; carcinoma; carcinoma, undifferentiated; giant cell spindle cell carcinoma; sarcoma; small cell carcinoma; papillary carcinoma; squamous cell carcinoma; lymphoepithelial carcinoma; basal cell carcinoma; pilomatricoma; transitional cell carcinoma; papillary transitional cell carcinoma; adenocarcinoma; gastrinoma, malignant; cholangiocarcinoma; hepatocellular carcinoma. Cancer; mixed type of hepatocellular carcinoma and cholangiocarcinoma; funicular adenocarcinoma; adenoid cystic carcinoma; adenocarcinoma in the form of adenomatous polyps; adenocarcinoma, familial adenomatous polyposis; solid tumor; carcinoid tumor, malignant; bronchioloalveolar adenocarcinoma; papillary adenocarcinoma; chromophobe carcinoma; eosinophilic (ac idophil) carcinoma; oxyphilic adenocarcinoma; basophilic carcinoma; clear cell adenocarcinoma; granular cell carcinoma; follicular adenocarcinoma; follicular papillary adenocarcinoma; non-encapsulated sclerosing carcinoma; adrenocortical carcinoma; endometrioid carcinoma; skin adnexal carcinoma; apocrine adenocarcinoma; Sebaceous gland carcinoma; Cerumen adenocarcinoma; Mucoepidermoid carcinoma; Cystadenocarcinoma; Papillary cystadenocarcinoma; Papillary serous cystadenocarcinoma; Mucinous cystadenocarcinoma; Mucinous adenocarcinoma; Signet ring cell carcinoma; Invasive ductal carcinoma; Medullary carcinoma; Lobular carcinoma; Inflammatory carcinoma; Paget's disease of the breast; Acinic cell carcinoma; Adenosquamous carcinoma; Adenocarcinoma with squamous metaplasia; Thymoma, malignant; Ovarian stromal tumor, malignant; Sex cord-stromal tumor, malignant; Granulosa cell tumor, malignant; Male germ cell tumor, malignant; Sertoli cell carcinoma; Leydig cell tumor, malignant; Lipid cell tumor , malignant;paraganglioma, malignant;extramammary paraganglioma, malignant;pheochromocytoma;glomus sarcoma;malignant melanoma;amelanotic melanoma;superficial spreading melanoma;malignant melanoma in giant pigmented nevus;epithelioid cell melanoma;blue nevus, malignant;sarcoma;fibrosarcoma;fibrous histiocytoma, malignant;myxosarcoma;liposarcoma;leiomyosarcoma;rhabdomyosarcoma;embryonic rhabdomyosarcoma;alveolar rhabdomyosarcoma;stromal sarcoma;mixed tumor, malignant;mixed Müllerian tumor;nephroblastoma;hepatoblastoma;carcinosarcoma;interstitial Phylloma, malignant; Brenner tumor, malignant; phyllodes tumor, malignant; synovial sarcoma; mesothelioma, malignant; dysgerminoma; embryonal carcinoma; teratoma, malignant; ovarial goiter, malignant; choriocarcinoma; mesonephroma, malignant; angiosarcoma; hemangioendothelioma, malignant; Kaposi's sarcoma; hemangiopericytoma, malignant; lymphangiosarcoma; osteosarcoma; parosteal osteosarcoma; osteosarcoma; chondroblastoma, malignant; mesenchymal chondrosarcoma; giant cell; giant cell tumor of bone; Ewing's sarcoma; odontogenic tumor, malignant; ameloblastoma; odontosarcoma;Ameloblastoma, malignant; Ameloblastic fibrosarcoma; Pinealoma, malignant; Chordoma; Glioma, malignant; Ependymoma; Astrocytoma; Protoplasmic astrocytoma; Fibrous astrocytoma; Astroblastoma; Glioblastoma; Oligodendroglioma; Oligodendroglioma; Primitive neuroectodermal; Cerebellar sarcoma; Ganglioblastoma; Neuroblastoma; Retinoblastoma; Olfactory neurogenic tumor; Meningioma, malignant; Neurofibrosarcoma; Nerve sheath tumor, malignant; Granular cell tumor, malignant; Malignant lymphoma; Hodgkin's disease; Hodgkin's; Paragranuloma; Malignant lymphoma Lymphoma, small lymphocytic; malignant lymphoma, large cell, diffuse; malignant lymphoma, follicular; mycosis fungoides; other specified non-Hodgkin's lymphoma; malignant histiocytosis; multiple myeloma; mast cell sarcoma; immunoproliferative small intestinal disease; leukemia; lymphocytic leukemia; plasma cell leukemia; erythroleukemia; lymphosarcoma cell leukemia; myeloid leukemia; basophilic leukemia; eosinophilic leukemia; monocytic leukemia; mast cell leukemia; megakaryoblastic leukemia; myeloid sarcoma; and hairy cell leukemia.

[0825] In another embodiment of the disclosed method, the cancer is characterized by a mutation in a mutS homolog (e.g., MSH2, MSH3, and MSH6), a mutL homolog (e.g., MLH1), or the mismatch repair endonuclease PMS2. Mutations are changes in the genetic code. Mutations include point mutations and frameshift mutations. In a point mutation, one nucleotide is replaced with another nucleotide. Thus, the mutation occurs at a single point or position within the DNA strand. Frameshift mutations result from the insertion or deletion of a nucleotide, which causes an expansion or contraction in the overall size of the DNA strand. Thus, a frameshift mutation can change the entire codon that occurs after the deletion or insertion. Non-limiting examples of mutations referred to herein include insertions, deletions, duplications, inversions, or other known point mutations. It has now been discovered that RAD51 inhibitors are particularly effective in treating cancers with mutations in MSH (e.g., MSH6), MLH, or PMS2.

[0826] MutS homolog 2 (MSH2) is a protein encoded by the MSH2 gene, which in humans is located on chromosome 2. MSH2 is a tumor suppressor gene and a caretaker gene that encodes, for example, a DNA mismatch repair (MMR) protein, and it heterodimerizes with MSH6 to form the human MutSα mismatch repair complex. It also dimerizes with MSH3 to form the MutSβ DNA repair complex. MSH2 is involved in many different forms of DNA repair, including transcription-coupled repair, homologous recombination, and base excision repair. Non-limiting examples of mutations in MSH2 include g.47630253_47630254del, g.47702411_47702421del, g.47709913_47709915inv, g.47635629_47635634del, g.47637227_47637236dup, g.47639550_47639561del, g.(?_47630206) _(47710367_?)del, g.(?_47630206)_(47643569_47656880)del, g.47630263_47643568del, g.(?_47630 206)_(47657081_47672686)del, g.47630263_47657080del, g.(?_47630206)_(47672797_47690169)del , g.47630263_47672796del, g.(?_47630206)_(47672797_47690169)del, g.(?_47630206)_(47693948_4 7698103)del, g.47630263_47693947del, g.(?_47630206)_(47698202_47702163)del, g.(?_47630206)_ (47630542_47635539)del, g.(?_47630206)_(47708011_47709917)del, g.(?_47630206)_(47635695_47 637232)del, g.(?_47630206)_(47635695_47637232)del, g.(?_47630206)_(47637512_47639552)del, g.(?_47630206)_(47639700_47641407)del、g.(?_47630206)_(47641558_47643434)del、g.47618487_47650860delins(155)、g.47628578_47638433del、g.47595033_47662777del、g.47583175_47667707del、g.47625602_47636880del、g.47554933_47699909del、g.47629508_47649552del、g.47629375_47651274del、g.(?_47630206)_(47630542_47635539)del、g.(?_47630206)_(47635695_47637232)del、g.47643509_47643510del、g.47643529_47643530dup、g.47656746_47657199dup、g.47656661_47663325del、g.(47643569_47656880)_(47710367_?)del、g.(47643569_47656880)_(47710367_?)del、g.47656881_47657080del、g.(47643569_47656880)_(47657081_47672686)del、g.(47643569_47656880)_(47657081_47672686)del、g.(47643569_47656880)_(47657081_47672686)del、g.(47643569_47656880)_(47657081_47672686)dup、g.(47643569_47656880)_(47657081_47672686)dup、g.(47643569_47656880)_(47672797_47690169)del、g.(47643569_47656880)_(47693948_47698103)del、g.47656881_47693947del、g.(47643569_47656880)_(47702410_47703505)del、g.47656881_47656882ins(173)、g.47656901_47656902insA、g.47656903del、g.47656912del、g.47630440del、g.47656923del、g.47656931_47656932dup、g.47656943del、g.47656943_47656949delinsCCCAGA、g.47656948dup、g.47656996dup、g.47657000_47657001dup、g.47630449del、g.47657007dup、g.47657008del、g.47657020_47657023dup、g.47657025_47657026del、g.47657026dup、g.47657030_47657031del、g.47657047_47657050del、g.47657053del、g.47657053_47657057del、g.47657064del、g.47657073dup、g.47657312_47676594del、g.47668611_47674615del、g.47672116_47675123del、g.47666463_47677632del、g.47666403_47677572del、g.(47657081_47672686)_(47710367_?)del、g.(47657081_47672686)_(47710367_?)inv、g.47671507_47675022delinsCATTCTCTTTGAAAA、g.47657278_47676557del、g.47672687_47672796del、g.(47657081_47672686)_(47672797_47690169)del、g.(47657081_47672686)_(47672797_47690169)del、g.(47657081_47672686)_(47693948_47698103)del、g.(47657081_47672686)_(47698202_47702163)del、g.(47657081_47672686)_(47708011_47709917)del、g.47672691dup、g.47672697dup、g.47672721_47672744delins47672748_47672771inv、g.47672728_47672729del、g.47672731dup、g.47672750_47672751insGG、g.47672755_47672758del、g.47672762_47672763del、g.47630466_47630494del、g.47686194_47697740del、g.(47672797_47690169)_(47710367_?)del、g.(47672797_47690169)_(47690294_47693796)del、g.(47672797_47690169)_(47693948_47698103)del、g.47690170_47693947del、g.(47672797_47690169)_(47693948_47698103)del、g.(47672797_47690169)_(47693948_47698103)dup、g.(47672797_47690169)_(47705659_47707834)del、g.47690173del、g.47690191del、g.47690216_47690217dup、g.47690227del、g.47690227dup、g.47690228_47690232del、g.47690230_47690231del、g.47690240del、g.47690240_47690243del、g.47630475del、g.47630475_47630476del、g.47690259_47690260delinsCT、g.47690277dup、g.47690280del、g.47690283dup、g.(47690294_47693796)_(47702410_47703505)del、g.47630484_47630485insG, g.47693838_47693839del、g.47693862del、g.47693864del、g.47693873del、g.47693880dup、g.47693913del、g.47693924_47693925dup、g.47630493del、g.47697730_47706125del、g.(47693948_47698103)_(47710367_?)del、g.(47693948_47698103)_(47698202_47702163)del、g.(47693948_47698103)_(47705659_47707834)del、g.47698107del、g.47698109del、g.47698109_47698110insA、g.47630496del、g.47698118del、g.47698125del、g.47698129dup、g.47698138_47698139del、g.47698142_47698146del、g.47698144dup、g.47698147_47698148del、g.47698147_47698148dup、g.47698147_47698148insT、g.47698159del、g.47698162del、g.47698506_47703472del、g.47701803_47708848del、g.(47698202_47702163)_(47710367_?)del、g.(47698202_47702163)_(47702410_47703505)del、g.(47698202_47702163)_(47703711_47705410)del、g.(47698202_47702163)_(47705659_47707834)del、g.47702164del、g.47702175_47702176insA、g.47702183_47702186del、g.47702185_47702186insCT、g.47702190_47702192del、g.47702191dup、g.47702192_47702193del、g.47702213del、g.47702231del、g.47702242dup、g.47702257del、g.47702262_47702263dup、g.47630516_47630517dup、g.47630517del、g.47630517dup、g.47702289_47702290inv、g.47702293_47702296del、g.47702301dup、g.47702315del、g.47702315del、g.47702328_47702329del、g.47630522dup、g.47702339del、g.47702371_47702374dup、g.47702384_47702385del、g.47702386_47702389del、g.47702388del、g.47702388_47702389del、g.47702390del、g.47702390_47702391del、g.47702400_47702401del、g.47703506_47703710del、g.47703506_47708010del、g.47703510del、g.47703515del、g.47703521_47703522del、g.47703535_47703536del、g.47703546_47703547del、g.47703548_47703611dup、g.47630534del、g.47703571dup、g.47703574_47703581del、g.47703585dup、g.47630350del、g.47632107_47668733del、g.47703613del、g.(47630542_47635539)_(47643569_47656880)del、g.(47630542_47635539)_(47643569_47656880)inv、g.(47630542_47635539)_(47657081_47672686)del、g.47635540_47657080del、g.(47630542_47635539)_(47672797_47690169)del、g.(47630542_47635539)_(47690294_47693796)del、g.(47630542_47635539)_(47705659_47707834)del、g.47635540_47635694del、g.(47630542_47635539)_(47635695_47637232)del、g.(47630542_47635539)_(47635695_47637232)del、g.(47630542_47635539)_(47637512_47639552)del、g.47703635dup、g.47703641dup、g.47635542_47635549del、g.47703660_47703663del、g.47703667dup、g.47630351dup、g.47703704del、g.47703826_47707938del、g.(47703711_47705410)_(47705659_47707834)del、g.47705428_47705431del、g.47705437_47705438insA、g.47635551_47635552del、g.47705440_47705441del、g.47705461del、g.47705490del、g.47705494del、g.47705495del、g.47635557_47635558del、g.47705505del、g.47705535dup、g.47705547del、g.47705560_47705561dup、g.47705561dup、g.47705562dup、g.47705588del、g.47705608_47705609del、g.47705618dup、g.47705627dup、g.47635571_47635601delins(217)、g.(47705659_47707834)_(47710367_?)del、g.(47705659_47707834)_(47708011_47709917)del、g.47707842_47707843del、g.47707861del、g.47707861_47707874dup、g.47707878_47707884del、g.47707878_47707884del、g.47707883del、g.47707895_47707905del、g.47707897del、g.47707901_47707902del、g.47707905_47707906del、g.47707921del、g.47635583dup、g.47635583_47635584del、g.47707969_47707973del、g.47707996_47707997ins(115)、g.47708009_47708010del、g.(47708011_47709917)_(47710367_?)del、g.47635591_47635592del、g.47635597_47635618dup、g.47635606_47635607del、g.47630359dup、g.47635672del、g.47635675_47635678del、g.47630364dup、g.47635680dup、g.47636862_47639040del、g.47636781_47638831del、g.47636753_47638155del、g.47636552_47638597del、g.(47635695_47637232)_(47643569_47656880)del、g.(47635695_47637232)_(47643569_47656880)del、g.(47635695_47637232)_(47657081_47672686)del、g.(47635695_47637232)_(47672797_47690169)del、g.(47635695_47637232)_(47698202_47702163)del、g.(47635695_47637232)_(47637512_47639552)del、g.(47635695_47637232)_(47641558_47643434)del、g.47637234del、g.47637246_47637247del、g.47637253_47637254del、g.47637254_47637255del、g.47637254_47637255del、g.47637265del、g.47637274del、g.47637282del、g.47637320del、g.47637372_47637375del、g.47637377_47637449dup、g.47637379del、g.47637384del、g.47637394_47637395del、g.47637396_47637397del、g.47637417del、g.47637427_47637435del、g.47637437_47637439del、g.47637453del、g.47637458dup、g.47637479_47637482dup、g.47637482dup、g.47637504_47637505del、g.47637508_47637511del、g.47638050_47653430del、g.47638302_47648462del、g.47638478_47648643del、g.(47637512_47639552)_(47710367_?)del、g.(47637512_47639552)_(47643569_47656880)del、g.47639553_47643568del、g.(47637512_47639552)_(47657081_47672686)del、g.(47637512_47639552)_(47657081_47672686)del、g.(47637512_47639552)_(47672797_47690169)del、g.(47637512_47639552)_(47639700_47641407)del、g.(47637512_47639552)_(47641558_47643434)del、g.47639557_47639561del、g.47639582_47639586delinsTAAT、g.47639583_47639584del、g.47639594del、g.47639594dup、g.47639598del、g.47639603_47639604del、g.47639611_47639612del、g.47639612del、g.47639618_47639621del、g.47639624_47639628delinsTTA、g.47630401dup、g.47639632dup、g.47639638_47639641dup、g.47639638_47639641dup、g.47639639del、g.47639639del、g.47639642dup、g.47630403_47630404insC、g.47639653del、g.47639666del、g.47639666_47639669del、g.47639668del、g.47639670_47639673delinsTT、g.47639674_47639675dup、g.47639695_47639696del、g.47639707_47642985del、g.47641402_47642007del、g.(47639700_47641407)_(47643569_47656880)del、g.47641408_47643568del、g.(47639700_47641407)_(47657081_47672686)del、g.(47639700_47641407)_(47672797_47690169)del、g.(47639700_47641407)_(47641558_47643434)del, g.(47639700_47641407)_(47641558_ 47643434)del, g.47641410del, g.47641425_47641426del, g.47641426_47641429del, g.4 7630412del, g.47641451del, g.47641454dup, g.47641455dup, g.47641469del, g.4764147 8del, g.47641488_47641491del, g.47641496_47641497del, g.47641503del, g.47641513_ 47641514dup, g.47641530_47641537dup, g.47642509_47655432del, g.(47641558_476434 34)_(47643569_47656880)del, g.(47641558_47643434)_(47693948_47698103)del, g.47 630424_47630433del, g.47643450dup, g.47643462_47643463del, g.47643462_47643463ins(4), g.47643464_47643465insNC_000022.10:35788169_35788352, g.47643465dup.

[0827] MutS homolog 3 (MSH3) is the human homolog of the bacterial mismatch repair protein MutS, which is involved in the mismatch repair (MMR) system. MSH3 typically forms the heterodimer MutSβ with MSH2 to correct long insertion / deletion loops and base-base mispairs within microsatellites during DNA synthesis. MMR deficiency is found in approximately 15% of colorectal cancers, and somatic mutations in the MSH3 gene can be found in nearly 50% of MMR-deficient colorectal cancers. A non-limiting example of a mutation in MSH3 is g.79970809del.

[0828] MSH6 encodes MutS homolog 6 (MSH6), a member of the Mutator S (MutS) family of proteins involved in DNA mismatch repair (MMR). The MSH6 protein forms a heterodimer with MutS homolog 2 (MSH2) in both humans and yeast. Human MSH2 / 6 recognizes single base-base mismatches and short insertion / deletion loops. Upon mismatch recognition, the MSH2 / 6 complex binds ADP and exchanges it for ATP, resulting in a conformational change in the complex that leads to base pair resolution, base excision, and repair.

[0829] MSH6 mutations include frameshift and / or nonsense mutations that can result in nonfunctional MSH6 and loss of protein expression. Examples include a frameshift mutation at MSH6 amino acid residue 290 and the combined missense mutation T1189I.

[0830] Inactivating MSH6 mutations can be detected in cancers by routine diagnostic methods. Non-limiting examples of these methods include biopsy and blood tests to obtain cancer cells and other diagnostic indicators (such as peripheral blood mononuclear cells (PBMCs), PBMC subpopulations, circulating blasts (CD34+ cells), circulating tumor cells, and circulating exome cancer cells), and lymphocytes and other bodily fluids. The cancer cells or other diagnostic indicators can then be used to determine whether the cancer exhibits an inactivating MSH6 mutation by methods known in the art (e.g., direct DNA sequencing and multiplex ligation-dependent probe amplification, RNA sequencing (RNA-Seq), microarrays, quantitative PCR, or NanoString™ gene expression panels), or whether it exhibits MSH6 protein by immunohistochemistry, flow cytometry, immunocytochemistry, or Western blot. A method for identifying inactivating MSH6 mutations is disclosed in Houlleberghs H, Goverde A, Lussevel d J, Dekker M, Bruno MJ, et al. (2017) Suspected Lynch syndrome associated MSH6 variants: A functional assay to determine their pathogenicity. PLOS Genetics 13(5): e1006765. https: / / doi.org / 10.1371 / journal.pgen.1006765.

[0831] Non-limiting examples of mutations in MSH6 include g.48032846_48032849del, g.48032846_48032849del, g.48032846_48032849del, g.48033337_48033342del, g.48033420_48033422del, g.(?_48010221)_(48034092)del, g.(?_48010221)_(48018263_48023032)del, g.47998510_48020183del, g.48007276_4802 0272del, g.48026207del, g.48026223del, g.48026223del, g.48026257_48026261del, g.48026261_48026265del, g.48026312_48026313del, g.4 8026398del, g.48026543_48026544dup, g.48026693dup, g.48026702del, g.48026712del, g.48026718dup, g.48026736_48026737delinsAG, g.48 026736_48026737delinsG, g.48026750_48026751del, g.48026754_48026757del, g.48026756_48026759del, g.48026759_48026760del, g.48026 906del, g.48026928_48026931del, g.48026941dup, g.48026991del, g.48027023_48027024del, g.48027079del, g.48027079_48027082dup, g.48 027167_48027168del, g.48027172_48027173dup, g.48027178_48027185del, g.48027184_48027185del, g.48027272_48027275del, g.48027470_ 48027471del, g.48027501_48027502del, g.48027501_48027502delTG, g.48027657dup, g.48027691_48027694del, g.48027733_48027736dup, g.48027794_48027796delinsC、g.48027841_48027842del、g.48027887del、g.48027890dup、g.48027973_48027980del、g.48028067del、g.48028098del、g.48028106del、g.48028175_48028176del、g.48028241_48028242del、g.48028241_48028242delTT、g.48028272_48028284dup、g.48028277_48028278del、g.48030558_48030559del、g.48030126_48032394del、g.48030568del、g.48030581_48030584del、g.48030584_48030585dup、g.48030607del、g.48030645_48030646insT、g.48030647del、g.48030647dup、g.48030649dup、g.48030654_48030660del、g.48030659dup、g.48030697_48030698del、g.48030698del、g.48030706del、g.48030710dup、g.48030727_48030728insC、g.48030765_48030829del, c.3438+797_3438+798insTATins1839_3439-428、c.3438+797_3438+798insTATins1839_3439-428、g.48032121_48032122del、g.48032123_48032124del、g.48032124dup、g.48032126_48032129del、g.48032129_48032130insA, g.48032129_48032132dup、g.(48032167_48032756)_(48034092_?)del、g.48032809_48032812del、g.48032835dup、g.48032846_48032849del、g.48033374_48033402dup、g.48033395_48033398del、g.48033421_48033433del、g.48033425_48033428dup、g.48033453_48033454insA, g.48033494_48033523del, g.48033495_48033496del, g.48033593dup, g.48033610_48033613dup, g.48033629_48033635del, g.48033636_48033639dup, g.48033676_48033682del, g.48033707dup, g .48033709_48033716dup, g.48033721_48033724dup, g.48033727_48033730dup, g.48033728_4803 3746dup, g.(48033742_48033743)_(48033742_48033743)ins(32), g.48033746dup, g.48033748_48 033751del, g.48033758_48033768del, g.48033773_48033774insATCA, g.48033773_48033776dup, g.48033785_48033789dup, g.48033887_48033910inv, g.(48018263_48023032)_(48032167_480327 56)del, g.(48018263_48023032)_(48023203_48025749)del, g.48023097_48023098del, g.48025773dup, g.48025832del, g.48025860_48025861insT, g.48025884_48025885del, g.48025967dup.

[0832] MutL homolog 1, colorectal cancer, nonpolyposis type 2 (E. coli) is a protein encoded by the MLH1 gene, which in humans is located on chromosome 3. This is a gene commonly associated with hereditary nonpolyposis colorectal cancer.

[0833] Non-limiting examples of mutations in MSH6 include g.37089113_37089115del, g.37089175del, g.37090379_37090393del, g.37038201_37038202del, g.37042531_37042542del, g.37053339_37053355del, g.37053354del, g.37053590_37053591insT, g.37034841_37092337del, g.(?_37034841)_(37092337_?)del, g .(?_37034841)_(37061955_37067127)del, g.(?_37034841)_(37035155 _37038109)del, g.(?_37034841)_(37035155_37038109)del, g.(?_37034 841)_(37070424_37081676)del, g.(?_37034841)_(37083823_37089009) del, g.37034841_37083822del, g.(?_37034841)_(37038201_37042445)d el, g.(?_37034841)_(37042545_37045891)del, g.37034841_37042544d el, g.(?_37034841)_(37042545_37045891) del, g.(?_37034841)_(37042 545_37045891)del, g.(?_37034841)_(37045966_37048481)del, g.(?_37 034841)_(37050397_37053310)del, g.(?_37034841)_(37059091_370618 00)del, g.37034658_37038806del, g.36961079_37138741del, g.37061923del, g.37061927del, g.37061933del, g.37061939del, g.37061942dup, g.37035140_37035141del, g.37070417del, g.37070417_37070418insT, g.37070419dup, g.37070422_37070423insT, g.37080355_37083368del, g.(37070424_37081676)_(37092337_?)del、g.(37070424_37081676)_(370 81786_37083758)del、g.(37070424_37081676)_(37083823_37089009)de l、g.37038148_37038151del、g.37038149del、g.37038149dup、g.3708169 0_37081691del、g.37081691_37081692del、g.37081706_37081708del、g. 37081710_37081711del、g.37035053_37035066del、g.37038154del、g.37 038154_37038157del、g.37081738_37081739del、g.37081740del、g.3708 1753dup、g.37081757_37081761dup、g.37081782_37081783insAAGT、g.37 081787_37081793delinsATTT、g.(37081786_37083758)_(37083823_37089 009)del、g.(37081786_37083758)_(37089175_37090007)del、g.37083759del、g.37083780dup、g.37083781_37083784del、g.37083781_37083784d elCTCA、g.37083808_37083809del、g.37083816del、g.37086069_37089606del、g.37084092_37089247del、g.37084590_37089786del、g.(37083823 _37089009)_(37092337_?)del、g.(37083823_37089009)_(37089175_370 90007)del、g.37089010_37089174del、g.(37083823_37089009)_(370905 09_37091976)del、g.37089023del、g.37089026_37089027del、g.37089027del、g.37089036del、g.37089036dup、g.37038168dup、g.37089042del、g.37089047del、g.37089050_37089053del、g.37089056_37089057del、g.37089061_37089062del、g.37089078_37089096del、g.37089090dup、g.37089099dup、g.37089107_37089110dup、g.37089109_37089110del、g.37089130_37089132del、g.37089130_37089132delAAG、g.37089131delinsTTCTT、g.37089133del、g.37089133del、g、g.37089144del、g.37089155del、g.37089155_37089161del、g.37089158_37089161del、g.37089162_37089166del、g.37089171del、g.(37089175_37090007)_(37090101_37090394)del、g.37035056_37035072del、g.37090013del、g.37090015dup、g.37038183_37038184del、g.37090024_37090037dup、g.37090025_37090053dup、g.37090027dup、g.37038184dup、g.37090031_37090032insT、g.37090041del、g.37090057del、g.37090064_37090067del、g.37038188del、g.37090082del、g.37090086_37090087del、g.37090087_37090088del、g.37090097_37090101delinsC、g.37090099del、g.37038191dup、g.(37090101_37090394)_(37092337_?)del、g.37035057_37035073del、g.37090405dup、g.37090411_37090415del、g.37090414del、g.37038194del、g.37038198del、g.37090472_37090478del、g.37039445_37059613dup、g.37039760_37052440del、g.37090481_37090482del、g.37090483_37090484del、g.37090483_37092045del、g.37040732_37043185delinsACATAGTA、g.37042445_37042446del、g.(37038201_37042445)_(37042545_37045891)del、g.(37038201_37042445)_(37048555_37050304)del、g.(37038201_37042445)_(37050397_37053310)del、g.(37038201_37042445)_(37053591_37055922)del、g.37090497_37090498del、g.37090497_37090498delTC、g.37090504_37090507del、g.(37090509_37091976)_(37092337_?)del、g.(37090509_37091976)_(37092337_?)dup、g.37091977_37091978del、g.37091978_37091987del、g.37042448_37042451del、g.37091984_37091990del、g.37042451_37042453del、g.37092020_37092021del、g.37092022_37092068dup、g.37092027_37092028del、g.37092027_37092028dup、g.37092030dup、g.37092052_37092055del、g.37092054_37092055del、g.37092068_37092071dup、g.37092091dup、g.37092094_37092097delins(30)、g.37092096_37092106del、g.37092097del、g.37092125_37092126delAA、g.37092125_37092126del、g.37092139_37092142dup、g.37092142dup、g.37035060dup、g.37042469_37042470del、g.37042470del、g.37042482dup、g.37042485del、g.37042499del、g.37042546dup、g.37044472_37046589del、g.37045648_37049941del、g.37045095_37054651del、g.37045072_37046861del、g.(37042545_37045891)_(37045966_37048481)del、g.(37042545_37045891)_(37092337_?)del、g.(37042545_37045891)_(37048555_37050304)del、g.(37042545_37045891)_(37050397_37053310)del、g.37045892_37050396del、g.37035069del、g.37045926del、g.37045931del、g.37045939_37045940dup、g.37045957_37045958del、g.37045963del、g.37035075del、g.37048067_37049287del、g.(37045966_37048481)_(37048555_37050304)del、g.(37045966_37048481)_(37050397_37053310)del、g.37048483del、g.37048483_37048503delinsT、g.37048486_37048487delinsGTT、g.37048489del、g.37048490del、g.37035076_37035077insCCCA、g.37035077_37035078dup、g.37048505_37048508del、g.37048521del、g.37048529dup、g.37035082dup、g.37049873_37052281del、g.37049839_37052249del、g.37049800_37052209del、g.37049640_37050445del、g.37050305_37050396del、g.(37048555_37050304)_(37050397_37053310)del、g.37050305_37050396del、g.37050319_37050320del、g.37050339del、g.37050348del、g.37050353_37050354del、g.37050354dup、g.37050364del、g.37050375_37050376insGA、g.37035090del、g.37050382_37050383delinsAT、g.37050382_37050383delinsCT、g.37050390_37050396del、g.37052950_37060990del、g.(37050397_37053310)_(37067499_37070274)dup、g.(37050397_37053310)_(37053591_37055922)del、g.(37050397_37053310)_(37056036_37058996)del、g.37053353del、g.37053510_37053511del、g.37035099del、g.37053545_37053546insT、g.37053562del、g.37053578del、g.37053578dup、g.37053585del、g.37053586_37053589del、g.37053591del、g.37053590_37053591delinsAT、g.37055920_37055921del、g.37055914_37055938del、g.(37053591_37055922)_(37070424_37081676)del、g.(37053591_37055922)_(37083823_37089009)del、g.(37053591_37055922)_(37059091_37061800)del、g.37035105del、g.37055928dup、g.37035106_37035116del、g.37055938del、g.37035108del、g.37055972_37055975del、g.37055976_37055979del、g.37035111del、g.37055990dup、g.37035114del、g.37035116del、g.37056036del、g.37056037dup、g.37058993_37059001del、g.(37056036_37058996)_(37070424_37081676)del、g.(37056036_37058996)_(37059091_37061800)del、g.37058997_37059000del、g.37059014_37059017del、g.37059017_37059021del、g.37059027_37059030dup、g.37035122del、g.37059062_37059063insT、g.37059065_37 059066del、g.37059066del、g.37059066dup、g.37059072_37059073del、g.37059072_37059073dup、g.37059090_37059093del、g.37061595_37061913del、g.37061308_37066756del、g.37061207_37063077del、g.(3705909 1_37061800)_(37092337_?)del、g.(37059091_37061800)_(37061955_37067127)del、g.37061801_37061954d el、g.(37059091_37061800)_(37083823_37089009)del、g.37061803dup、g.37061804del、g.37061817del、g.3 7061837_37061838dup 06del、g.37061910del、g.37035047del、g.[37049179_37051317delinsTG;37051667_37054327delinsCA]である。.

[0834] The human PMS2-related genes are located in bands 7p12, 7p13, 7q11, and 7q22. Exons 1-5 of these homologs share high identity with human PMS2. The product of this gene is involved in DNA mismatch repair. This protein forms a heterodimer with MLH1, and this complex interacts with MSH2 bound to mismatched bases. Defects in this gene are associated with hereditary nonpolyposis colorectal cancer, Turcot syndrome, and are a cause of supratentorial primitive neuroectodermal tumors.

[0835] Non-limiting examples of mutations in PMS2 include g.(?_6012870)_(6048737_?)del, g.6012870_6048737del, g.(6027252_6029430)_(6048737_?)del, g.(6045663_6048627)_(6048737_?)del, g.6029554del, g.6029499dup, g.6029495_6029496del, g.6029462_6029463delinsTAAA, g.5992485_6028601del, g .(6018328_6022454)_(6027252_6029430)del, g.(6013174_6017218)_(6027252_6029430)del, g.6027226_6027227ins(20), g.6027175del, g .6027090dup, g.6036705_6044207delinsCG, g.6026666dup, g.6026628del, g.6043671del, g.6026565dup, g.6026565dupT, g.6018315_6018316 del, g.6018306_6018310del, g.6018306_6018310delAGTTA, g.6043633_6043634dup, g.6018256_6018259del, g.6015623_6017501del, g.6016 429_6017479del, g.6017300_6017303del, g.6045579_6045674delinsATTT, g.(6043690_6045522)_(6045663_6048627)del, g.(?_6012870)_(6 042268_6043320) del, g.(6035265_6036956)_(6042268_6043320) del, g.6038283_6039384del, g.6038901del, g.6038851dup, g. 6956)_(6037055_6038738)del, g.6037019_6037024delinsCTTCACACACA, g.6036980del, g.6036958dup, g.6035323_6035324insJN866832.1, g.(6022623_6026389)_(6035265_6036956)del, g.(6031689_6035164)_(6035265_603695 6) del, g.6035204_6035207del, g.6035205_6035206del, g.(?_6012870)_(6031689_6035 164)del, g.(6027252_6029430)_(6031689_6035164)del, g.(6029587_6031603)_(6031689_6035164)del, g.6028725_6029882del, g.(?_6012870)_(6029587_6031603)del.

[0836] The present disclosure provides methods for treating patients with Lynch syndrome to reduce the likelihood of developing cancer, or for treating cancer resulting from Lynch syndrome, by administering to the subject an effective amount of one or more of the disclosed compounds, or a pharmaceutically acceptable salt thereof, or a corresponding pharmaceutical composition.

[0837] Lynch syndrome (also known as hereditary nonpolyposis colorectal cancer (HNPCC)) is a genetic disorder caused by mutations in mismatch repair genes; affected individuals have a higher-than-normal chance of developing colon cancer, endometrial cancer, and various other types of aggressive cancer, often at an earlier age.

[0838] Mutations in certain mismatch repair (MMR) genes (non-limiting examples include MLH1, MSH2, MSH6, PMS2, and EPCAM-TACSTD1 deletions) are responsible for Lynch syndrome. These genes function to repair mistakes that occur when DNA is copied for cell division. Defects in these genes result in an inability to repair DNA errors, which can lead to an accumulation of errors as cells divide, resulting in uncontrolled cell growth and potentially cancer.

[0839] Subjects with Lynch syndrome have up to an 85% risk of developing colorectal cancer, as well as a higher-than-average risk of endometrial, stomach, pancreatic, kidney / ureteral, hepatobiliary, gastrointestinal, prostate, ovarian, gallbladder, brain, small intestine, breast, and skin cancer.

[0840] In some embodiments of the disclosed methods, the method is a method of treating a Lynch syndrome-derived cancer selected from the group consisting of colon cancer, endometrial cancer, gastric cancer, pancreatic cancer, kidney / ureter cancer, hepatobiliary cancer, gastrointestinal cancer, prostate cancer, ovarian cancer, gallbladder cancer, brain cancer, small intestine cancer, breast cancer, and skin cancer.

[0841] In some embodiments, the method is a method for treating an autoimmune disease. Exemplary autoimmune diseases include lupus erythematosus, Wiskott-Aldrich syndrome, autoimmune lymphoproliferative syndrome, myasthenia gravis, rheumatoid arthritis (RA), lupus nephritis, multiple sclerosis, systemic lupus erythematosus, discoid lupus erythematosus, subacute cutaneous lupus erythematosus, cutaneous lupus erythematosus including chilblain lupus erythematosus, chronic arthritis, Sjogren's syndrome, inflammatory chronic sinusitis, colitis, celiac disease, inflammatory bowel disease, Barrett's esophagus, inflammatory gastritis, autoimmune nephritis, autoimmune vasculitis, autoimmune hepatitis, autoimmune carditis, autoimmune encephalitis, autoimmune diabetes, autoimmune diabetic nephritis, psoriasis, graft-versus-host disease (GvHD), and autoimmune-mediated blood disorders.

[0842] In some embodiments, the method is directed to treating a variety of conditions, including autoimmune lymphoproliferative syndrome (ALPS), autoimmune polyglandular syndrome type 1 (APS-1), BENTA disease, caspase 8 deficiency (CEDS), chronic granulomatous disease (CGD), common variable immunodeficiency (CVID), congenital neutropenic syndrome, CTL, A4 deficiency, DOCK8 deficiency, GATA2 deficiency, glycosylation disorders associated with immune deficiency, hyperimmunoglobulin E syndrome (HIES), hyperimmunoglobulin M (hyper-IgM) syndrome, white blood cells, and the like. A method for treating an immunodeficiency selected from the group consisting of hemocyte adhesion deficiency (LAD), LRBA deficiency, PI3 kinase disease, PLCG2-associated antibody deficiency immunodeficiency (PLAID), severe combined immunodeficiency (SCID), STAT3 gain-of-function disease, Warts hypogammaglobulinemia, infection, and myelokathexis syndrome (WHIMS), X-linked agammaglobulinemia (XLA), X-linked lymphoproliferative disorder (XLP), and XMEN disease.

[0843] As used herein, the term "immunodeficiency" refers to a condition in which normal immune mechanisms are impaired due to the deficiency or dysfunction of one or more of the cellular components that make up the immune system. In other words, "immunodeficiency" refers to a condition in which innate and / or adaptive immunity is suppressed and / or impaired. In some embodiments, an immunodeficient subject is an immunocompromised subject. Non-limiting examples of immunodeficiencies can include AIDS, hypogammaglobulinemia, agammaglobulinemia, granulocyte deficiency, chronic granulomatous disease, asplenia, SCID, complement deficiency, and / or sickle cell anemia.

[0844] In some embodiments, the method is for treating a neurodegenerative disorder selected from the group consisting of multiple sclerosis, Parkinson's disease (PD), Alzheimer's disease (AD), dentatorubral-pallidoluysian atrophy (DRPLA), Huntington's disease (HD), spinocerebellar ataxia type 1 (SCA1), spinocerebellar ataxia type 2 (SCA2), spinocerebellar ataxia type 3 (SCA3), spinocerebellar ataxia type 6 (SCA6), spinocerebellar ataxia type 7 (SCA7), spinocerebellar ataxia type 8 (SCA8), spinocerebellar ataxia type 12 (SCA12), spinocerebellar ataxia type 17 (SCA17), spinal-bulbar muscular atrophy / Kennedy disease (SBMA), Fragile X syndrome (FRAXA), Fragile XE mental retardation (FRAXE), and myotonic dystrophy (DM).

[0845] A "subject" is a mammal, preferably a human, but can also be an animal requiring veterinary care, such as a companion animal (e.g., dog, cat, etc.), livestock (e.g., cows, sheep, pigs, horses, etc.), and laboratory animals (e.g., rats, mice, guinea pigs, etc.).

[0846] In some embodiments, the methods disclosed herein further comprise administering to a subject being treated for cancer an effective amount of a DNA repair inhibitor, a DNA damage response (DDR) inhibitor, a DNA damaging agent, or an immunomodulatory agent in addition to an effective amount of a disclosed RAD51 inhibitor. Use in combination This includes administering.

[0847] The term "DNA repair inhibitor" refers to any agent that targets the components / processes that cells utilize to repair DNA mutations or changes, restoring the DNA to its original state, and prevents DNA repair. Examples of DNA repair inhibitors include RPA inhibitors, APE1 inhibitors, DNA ligase inhibitors, DNA polymerase inhibitors, Parp inhibitors, etc.

[0848] The term "DNA damage response inhibitor" refers to any agent that targets components / processes involved in detecting DNA damage, signaling the presence of DNA damage, and / or promoting repair of DNA damage. Examples of DNA damage response inhibitors include checkpoint inhibitors, inhibitors of ATM and ATR, DNA-PK inhibitors, etc.

[0849] The term "DNA damaging agent" refers to any agent that directly or indirectly damages DNA, potentially allowing homologous recombination to repair the damage. The DNA damaging agent is selected from the group consisting of exposure to DNA damaging chemicals; exposure to chemotherapeutic agents; exposure to radiotherapy, and exposure to ionizing radiation or ultraviolet light. Some examples of DNA damaging chemotherapeutic agents include alkylating agents, nitrosoureas, antimetabolites, plant alkaloids, plant extracts, and radioisotopes.Some examples of chemotherapeutic agents also include DNA damaging drugs such as 5-fluorouracil (5-FU), capecitabine, S-1 (Tegafur, 5-chloro-2,4-dihydroxypyridine, and oxonic acid), 5-ethynyluracil, arabinosylcytosine (ara-C), 5-azacytidine (5-AC), 2',2'-difluoro-2'-deoxycytidine (dFdC), purine antimetabolites (mercaptopurine, azathioprine, thioguanidine), and cyclosporine-1-phosphate dehydrogenase (CSD). anine), gemcitabine hydrochloride (Gemzar), pentostatin, allopurinol, 2-fluoro-arabinosyl, adenine (2F-ara-A), hydroxyurea, sulfur mustard (bischloroethyl sulfide), mechlorethamine, melphalan, chlorambucil, cyclophosphamide, ifosfamide, thiotepa, AZQ, mitomycin C, dianhydrogalactitol, dibromodacitol, alkyl sulfonate (busulfan), nitrite Rosourea (BCNU, CCNU, 4-methylCCNU, or ACNU), procarbazine, decarbazine, rebeccamycin, anthracyclines (such as doxorubicin (adriamycin; ADR), daunorubicin (cerubicin), idarubicin (idamycin), and epirubicin (Ellence)), anthracycline analogs (such as mitoxantrone, actinomycin D), non-intercalating topoisomerase inhibitors (epipodophyllotoxin), These include steroids (such as etoposide or VP16, teniposide or VM-26), podophyllotoxin, bleomycin (Bleo), pepleomycin, compounds that form adducts with nucleic acids (including platinum derivatives such as cisplatin (CDDP), trans-analogs of cisplatin, carboplatin, iproplatin, tetraplatin, and oxaliplatin), as well as camptothecin, topotecan, irinotecan (CPT-11), and SN-38. Some examples of nucleic acid-damaging treatments include radiation, such as ultraviolet (UV), infrared (IR), or alpha, beta, or gamma radiation, as well as environmental shock, such as heat stroke.

[0850] "Immunomodulatory agent" refers to an agent that modulates the immune response to an antigen but is not an antigen or derived from an antigen. "Modulate," as used herein, means to induce, enhance, suppress, direct, or redirect the immune response. Included in these agents are immunostimulants (e.g., adjuvants) that stimulate (boost) the immune response to an antigen but are not an antigen or derived from an antigen. There are several distinct types of immunomodulatory agents, non-limiting examples of which include Toll I-like receptor (TLR) agonists and Toll I-like receptor (TLR) antagonists. Such agents also include immunosuppressants. The immunomodulatory agent may be selected from the group consisting of immune checkpoint modulators, Toll I-like receptor (TLR) agonists, cell-based therapies, cytokines, and cancer vaccines.

[0851] In some embodiments, the subject is determined to have an elevated level and / or activity of a DNA damaging process or DNA editing enzyme. In one aspect of this embodiment, the DNA editing enzyme is selected from the group consisting of activation-induced cytidine deaminase (AID or AICDA), APOBEC2, APOBEC3A, APOBEC3C, APOBEC3D, APOBEC3F, APOBEC3G, APOBEC3H, APOBEC4, topoisomerase type 1, topoisomerase type 2, recombination activating gene 1 (RAG 1), and recombination activating gene 2 (RAG2).

[0852] In some embodiments, blood cells obtained from the subject have been determined to have a detectable level of activation-induced cytidine deaminase (AID).

[0853] In some embodiments, B cells obtained from the subject have been determined to have a detectable level of activation-induced cytidine deaminase (AID).

[0854] In some embodiments, the detectable level of activation-induced cytidine deaminase (AID) is statistically significantly higher than the level of AID expressed in non-activated B cells or normal non-immune cells from a healthy subject.

[0855] Method of administration and dosage form

[0856] The exact amount of compound administered to provide an "effective amount" to a subject will depend on the mode of administration, the type and severity of the disease, and the subject's characteristics, such as overall health, age, sex, weight, and tolerance to the drug. One of ordinary skill in the art will be able to determine appropriate dosages based on these and other factors. When administered in combination with other therapeutic agents, for example, when administered in combination with an anti-cancer agent, the "effective amount" of any additional therapeutic agent will depend on the type of drug used. Appropriate dosages are known for approved therapeutic agents and can be adjusted by one of ordinary skill in the art depending on the subject's condition, the type of condition being treated, and the amount of compound of the present disclosure used, for example, according to dosages reported in the literature and recommended in the Physician's Desk Reference (57th ed., 2003).

[0857] The term "effective amount" means an amount that, when administered to a subject, results in a beneficial or desired result (including a clinical result), e.g., an amount that inhibits, suppresses, or reduces the symptoms of the condition being treated in the subject compared to a control. For example, a therapeutically effective amount can be provided in a unit dosage form (e.g., 0.1 mg to about 50 g per day, or 1 mg to about 5 grams per day).

[0858] The terms "administer," "administering," "administration," and the like, as used herein, refer to methods that can be used to deliver a composition to a site of desired biological effect. Non-limiting examples of these methods include intra-articular (inside a joint), intravenous, intramuscular, intratumor, intradermal, intraperitoneal, subcutaneous, oral, topical, intrathecal, inhalation, transdermal, rectal, and the like. Administration techniques that can be used with the agents and methods described herein can be found, for example, in Goodman and Gilman, The Pharmacological Basis of Therapeutics, current ed.; Pergamon; and Remington's, Pharmaceutical Sciences (latest edition), Mack Publishing Co., Easton, Pa.

[0859] In addition, the disclosed RAD51 inhibitors are useful in combination with other therapeutic agents. Use in combination As used herein, " Use in combination The terms "administered," "administered in combination with," and grammatical equivalents are meant to encompass the administration of two or more therapeutic agents to a single subject, and are intended to include treatment regimens in which the agents are administered by the same or different routes of administration, at the same time or at different times. In some embodiments, one or more compounds described herein are administered in combination with other agents. Use in combination The compounds described herein and the other agent(s) will be administered in a single composition. These terms encompass administering two or more agents to a subject such that both agents and / or their metabolites are present in the subject at the same time. These terms include simultaneous administration of separate compositions, staggered administration of separate compositions, and / or administration of a composition in which both agents are present. Thus, in some embodiments, the compounds described herein and the other agent(s) are administered in a single composition. In some embodiments, the compounds described herein and the other agent(s) are mixed in a composition.

[0860] The specific mode of administration and dosing regimen will be selected by the attending physician in light of the specifics of the case (e.g., the subject, the disease, the disease state involved, and the specific treatment). Treatment may involve once-daily, multiple-daily, or less-daily (e.g., once-weekly, once-monthly, etc.) dosing over a period of several days to several months or even years. However, one of skill in the art will readily recognize appropriate and / or equivalent doses using the disclosed RAD51 inhibitors, looking to the doses of compositions approved for treating RAD51-mediated diseases for guidance.

[0861] As will be appreciated by those skilled in the art, the compounds taught herein or corresponding pharmaceutical compositions can be administered to patients in a variety of forms depending on the selected administration route.The compounds of the present teachings can be administered, for example, orally, parenterally, bucally, sublingually, nasally, rectally, by patch, pump, or transdermal administration, and the pharmaceutical compositions are formulated accordingly.Parenteral administration includes intravenous, intraperitoneal, subcutaneous, intramuscular, transepithelial, nasal, intrapulmonary, intrathecal, rectal, and topical modes of administration.Parenteral administration can be by continuous infusion over a selected period of time.

[0862] The pharmaceutical compositions of the present disclosure are formulated to suit their intended route of administration. In one embodiment, the compositions are formulated according to routine procedures as pharmaceutical compositions suitable for intravenous, subcutaneous, intramuscular, oral, intranasal, or topical administration to humans. In a preferred embodiment, the pharmaceutical composition is formulated for intravenous administration.

[0863] Typically, for oral therapeutic administration, compounds of the present teachings can be incorporated with excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like.

[0864] Typically, for parenteral administration, solutions of the compounds of the present teachings can be prepared, generally in water, suitably mixed with a surfactant (such as hydroxypropylcellulose). Dispersions can also be prepared in glycerol, liquid polyethylene glycols, DMSO, and mixtures thereof, with or without alcohol, and in oils. Under ordinary conditions of storage and use, these preparations contain preservatives to prevent the growth of microorganisms.

[0865] Typically, for injectable use, sterile aqueous solutions or dispersions and sterile powders of the compounds described herein are suitable for the extemporaneous preparation of sterile injectable solutions or dispersions. [Example]

[0866] Abbreviation: Ac Acetyl ACN Acetonitrile aq water-based Bn Benzyl Boc t-butoxycarbonyl br. Wide d doublet (only when used in 1H NMR spectra) DCM dichloromethane DIEA (DIPEA) Diisopropylethylamine DMA Dimethylacetamide DMAP 4-dimethylaminopyridine DMF N,N-dimethylformamide DMSO dimethyl sulfoxide dppf 1,1'-bis(diphenylphosphino)ferrocene eq equivalent EtOAc ethyl acetate hr time HBTU Hexafluorophosphate N,N,N',N'-tetramethyl-O-(1H-benzotriazol-1-yl)uronium HPLC High Performance Liquid Chromatography LC-MS Liquid Chromatography Coupled with Mass Spectrometry m multiplet MS ESI mass spectrum, electrospray ionization NBS N-Bromosuccinimide NMR nuclear magnetic resonance prep preparative Py Pyridine s singlet sat saturation SFC Supercritical Fluid Chromatography t triplet TEA Triethylamine TFA trifluoroacetic acid THF tetrahydrofuran TLC thin layer chromatography Tol Toluene

[0867] [ka]

[0868] Example 1: Synthesis of (S)-(1-methylpyrrolidin-2-yl)methyl (4-(2-(4-((benzylcarbamoyl)oxy)piperidin-1-yl)thiazol-5-yl)-3-(N-(t-butyl)sulfamoyl)phenyl)carbamate

[0869] Scheme 1: [ka]

[0870] General Method D for the Preparation of Sulfonamide Compounds 12.

[0871] [ka]

[0872] To a solution of 5-amino-2-(2-bromothiazol-5-yl)-N-t-butyl-benzenesulfonamide (5 g, 12.8 mmol, 1 eq.) in DCM (30 mL) was added DMAP (156 mg, 1.3 mmol, 0.1 eq.) and AcO (1.96 g, 19.2 mmol, 1.5 eq.). The mixture was stirred at 20 °C for 1 h and then washed with 1 M HCl (50 mL) and saturated aqueous NaCO (50 mL). The organic layer was dried over NaSO, filtered, and concentrated. The residue was purified by column chromatography (SiO, petroleum ether:ethyl acetate = 5:1 to 2:1) to give N-[4-(2-bromothiazol-5-yl)-3-(t-butylsulfamoyl)phenyl]acetamide (1.5 g, 3.5 mmol, 27% yield) as a yellow solid. ESI [M+H] = 433.9 / 431.9

[0873] General Method A for the Preparation of Sulfonamide Compounds 13.

[0874] [ka]

[0875] To a solution of N-[4-(2-bromothiazol-5-yl)-3-(t-butylsulfamoyl)phenyl]acetamide (700 mg, 1.6 mmol, 1 eq.) in DMF (20 mL) was added KCO (448 mg, 3.3 mmol, 2 eq.) and piperidin-4-ol (246 mg, 2.4 mmol, 1.5 eq.). The mixture was stirred at 100 °C for 12 h and then poured into HO (100 mL). The aqueous phase was extracted with EtOAc (50 mL × 3), and the combined organic layers were washed with brine (100 mL), dried over NaSO, filtered, and concentrated. The residue was purified by column chromatography (SiO, petroleum ether:ethyl acetate=1:2) to give N-[3-(t-butylsulfamoyl)-4-[2-(4-hydroxy-1-piperidyl)thiazol-5-yl]phenyl]acetamide (550 mg, 1.2 mmol, 13.2% yield) as a yellow solid. 1 H NMR (400MHz, chloroform-d) δ = 8.26 (dd, J=2.2, 8.6 Hz, 2H), 7.93 (d, J=2.4 Hz, 1H), 7.37 (d, J=8.4 Hz, 1H), 7.31 (s, 1H), 4.02 - 3.94 (m, 1H), 3.88 - 3.80 (m, 2H), 3.30 (ddd, J=3.5, 9.2, 13.1 Hz, 2H), 2.21 (s, 3H), 2.03 - 1.95 (m, 2H), 1.67 (dtd, J=4.0, 8.7, 13.0 Hz, 2H), 1.09 (s, 9H). ESI [M+H] = 453.1

[0876] General Method F for the Preparation of Sulfonamide Compounds 15.

[0877] [ka]

[0878] N-Benzylcarbamate [1-[5-[4-acetamido-2-(t-butylsulfamoyl)phenyl]thiazol-2-yl]-4-piperidyl] (380 mg, 649 μmol, 1 eq.) was dissolved in HCl / MeOH (4 M, 20 mL), and the mixture was stirred at 20 °C for 1 h. The mixture was concentrated, diluted with saturated aqueous NaCO (20 mL), and extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine (20 mL), dried over NaSO, filtered, and concentrated. The residue was purified by column chromatography (SiO, petroleum ether:ethyl acetate = 10:1 to 1:1) to give N-benzylcarbamate [1-[5-[4-amino-2-(t-butylsulfamoyl)phenyl]thiazol-2-yl]-4-piperidyl] (300 mg, 552 μmol, 85% yield) as a yellow solid. ESI [M+H] = 544.2

[0879] General Method H for preparing Example 1.

[0880] [ka]

[0881] To a solution of [(2S)-1-methylpyrrolidin-2-yl]methanol (42 mg, 367 μmol, 2 eq.) and DIEA (71.11 mg, 550 μmol, 3 eq.) in MeCN (5 mL) was added a solution of N-benzylcarbamate [1-[5-[2-(tert-butylsulfamoyl)-4-[(4-nitrophenoxy)carbonylamino]phenyl]thiazol-2-yl]-4-piperidyl] (130 mg, 184 μmol, 1 eq.) in DCM (2 mL), and the mixture was refluxed for 1 h. The mixture was concentrated, and the residue was purified by prep-HPLC to afford (S)-(1-methylpyrrolidin-2-yl)methyl (4-(2-(4-((benzylcarbamoyl)oxy)piperidin-1-yl)thiazol-5-yl)-3-(N-(t-butyl)sulfamoyl)phenyl)carbamate (19.87 mg, 28.8 μmol, 15.7% yield, 99.3% purity) as a pale yellow solid. 1 H NMR (400MHz, DMSO-d6) δ = 10.06 (s, 1H), 8.26 (d, J=2.0 Hz, 1H), 7.71 (t, J=6.2 Hz, 1H), 7.60 (dd, J=2.3, 8.5 Hz, 1H), 7.37 - 7.14 (m, 7H), 6.94 (s, 1H), 4.81 - 4.71 (m, 1H), 4.16 (br d, J=6.2 Hz, 2H), 4.10 - 4.03 (m, 1H), 4.02 - 3.96 (m, 1H), 3.73 - 3.63 (m, 2H), 3.28 (br s, 2H), 2.94 - 2.87 (m, 1H), 2.44 - 2.37 (m, 1H), 2.30 (s, 3H), 2.18 - 2.05 (m, 1H), 1.99 - 1.82 (m, 3H), 1.68 - 1.52 (m, 5H), 1.12 - 1.03 (m, 9H). ESI [M+H] = 685.2

[0882] Example 2: Synthesis of N-benzylcarbamate [1-[5-[2-(t-butylsulfamoyl)-4-[[(2R)-1-methylpyrrolidin-2-yl]methoxycarbonylamino]phenyl]thiazol-2-yl]-4-piperidyl]

[0883] The following compounds were synthesized via the same method with key intermediate 16:

[0884] [ka]

[0885] N-Benzylcarbamate [1-[5-[2-(t-butylsulfamoyl)-4-[[(2R)-1-methylpyrrolidin-2-yl]methoxycarbonylamino]phenyl]thiazol-2-yl]-4-piperidyl]. 1 H NMR (400MHz, DMSO-d6) δ = 10.07 (s, 1H), 8.29 (d, J=2.2 Hz, 1H), 7.73 (t, J=6.2 Hz, 1H), 7.63 (dd, J=2.3, 8.5 Hz, 1H), 7.39 - 7.19 (m, 7H), 6.94 (s, 1H), 4.80 (td, J=4.1, 8.0 Hz, 1H), 4.20 (br d, J=6.1 Hz, 2H), 4.14 - 4.07 (m, 1H), 4.06 - 3.99 (m, 1H), 3.72 (br d, J=13.6 Hz, 2H), 3.29 - 3.22 (m, 2H), 2.98 - 2.92 (m, 1H), 2.45 - 2.41 (m, 1H), 2.33 (s, 3H), 2.22 - 2.13 (m, 1H), 2.02 - 1.79 (m, 3H), 1.72 - 1.56 (m, 5H), 1.20 - 1.03 (m, 9H). ESI [M+H] = 685.2

[0886] Example 3: Synthesis of N-isopropylcarbamate [1-[5-[4-(benzylcarbamoylamino)-2-(t-butylsulfamoyl)phenyl]thiazol-2-yl]-4-piperidyl]

[0887] Scheme 2: [ka]

[0888] Preparation of compound 23.

[0889] [ka]

[0890] General Method A, 1-benzyl-3-[3-(t-butylsulfamoyl)-4-[2-(4-hydroxy-1-piperidyl)thiazol-5-yl]phenyl]urea. ESI [M+H] = 544.1

[0891] Preparation of Example 3.

[0892] [ka]

[0893] To a solution of 1-benzyl-3-[3-(t-butylsulfamoyl)-4-[2-(4-hydroxy-1-piperidyl)thiazol-5-yl]phenyl]urea (50 mg, 91.96 μmol, 1 eq.) in Toluene (2 mL) was added DMAP (22.47 mg, 183.92 μmol, 2 eq.) and [isopropyl(methyl)-azanylidene]methanone (78.26 mg, 919.62 μmol, 10 eq.). The mixture was stirred at 100°C for 4 h and then concentrated. The residue was purified by prep-TLC (petroleum ether / EtOAc = 1:3) and then by acidic prep-HPLC to give N-isopropylcarbamate [1-[5-[4-(benzylcarbamoylamino)-2-(t-butylsulfamoyl)phenyl]thiazol-2-yl]-4-piperidyl] (28.31 mg, 99.2% purity) as a yellow solid. 1H NMR (400MHz, methanol-d4) δ = 8.29 (d, J=2.0 Hz, 1H), 7.71 (dd, J=2.0, 8.3 Hz, 1H), 7.43 (d, J=8.8 Hz, 1H), 7.35 (d, J=3.9 Hz, 5H), 7.27 (dt, J=2.7, 5.7 Hz, 1H), 4.98 - 4.93 (m, 1H), 4.43 (s, 2H), 3.90 - 3.59 (m, 5H), 2.19 - 2.07 (m, 2H), 1.99 - 1.86 (m, 2H), 1.22 (s, 9H), 1.16 (d, J=6.8 Hz, 6H). ESI [M+H] = 629.1

[0894] Example 4: Synthesis of isopropyl 4-[5-[2-(t-butylsulfamoyl)-4-(2-pyridylmethylcarbamoylamino)phenyl]thiazol-2-yl]piperidine-1-carbamate

[0895] Scheme 3: [ka]

[0896] Preparation of Compound 45

[0897] [ka]

[0898] General Method D, 4-nitrophenyl (4-bromo-3-(N-(t-butyl)sulfamoyl)phenyl)carbamate. ESI [M+H] = 474.1

[0899] General Method E for the Preparation of Sulfonamide Compounds 46

[0900] [ka]

[0901] To a solution of 2-pyridylmethanamine (352 mg, 3.3 mmol, 5 eq.) and DIEA (84 mg, 650 μmol, 1 eq.) in DCM (3 mL) was added a solution of 4-nitrophenyl N-[4-bromo-3-(t-butylsulfamoyl)phenyl]carbamate (307 mg, 650 μmol, 1 eq.) in DCM (3 mL). The mixture was stirred at 25 °C for 1 h, then diluted with DCM (30 mL) and washed with HO (20 mL × 2). The organic layer was concentrated, and the residue was purified by prep-TLC (SiO, petroleum ether:ethyl acetate = 0:1) to give 1-[4-bromo-3-(t-butylsulfamoyl)phenyl]-3-(2-pyridylmethyl)urea (180 mg, crude) as a yellow solid. ESI [M+H] = 441.2 / 443.2

[0902] Preparation of compound 47

[0903] [ka]

[0904] A mixture of 1-[4-bromo-3-(t-butylsulfamoyl)phenyl]-3-(2-pyridylmethyl)urea (140 mg, 317.21 μmol, 1 eq.), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (322.21 mg, 1.27 mmol, 4 eq.), Pd(dppf)Cl (116.05 mg, 158.61 μmol, 0.5 eq.), and KOAc (93.39 mg, 951.64 μmol, 3 eq.) in dioxane (4 mL) was degassed and purged with N three times. The mixture was then stirred at 80 °C under N for 12 h. The mixture was concentrated, and the residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1:0 to 1:1) to give 1-[3-(t-butylsulfamoyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3-(2-pyridylmethyl)urea (50 mg, 89.37 μmol, 28.17% yield, 87.3% purity). ESI [M+H] = 489.4

[0905] General Method K for Preparing Compound Example 4

[0906] [ka]

[0907] A mixture of 1-[3-(t-butylsulfamoyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3-(2-pyridylmethyl)urea (26.38 mg, 54.01 μmol, 1.2 eq.), isopropyl 4-(5-bromothiazol-2-yl)piperidine-1-carboxylate (15 mg, 45.01 μmol, 1 eq.), Na2CO3 (9.54 mg, 90.02 μmol, 2 eq.), KF (7.85 mg, 135.04 μmol, 3 eq.), and Pd(PPh3)4 (5.20 mg, 4.50 μmol, 0.1 eq.) in HO (0.1 mL) / EtOH (0.3 mL) / Tet (0.3 mL). After degassing and purging with N three times, the mixture was stirred at 85 °C under N atmosphere for 12 h. The reaction mixture was filtered and concentrated. The residue was purified by prep-TLC (SiO, petroleum ether / ethyl acetate = 1 / 2) and then by prep-HPLC (TFA condition) to give isopropyl 4-[5-[2-(t-butylsulfamoyl)-4-(2-pyridylmethylcarbamoylamino)phenyl]thiazol-2-yl]piperidine-1-carboxylate (6.36 mg, 8.21 μmol, 18.24% yield, 94.07% purity, TFA) as a pale yellow solid. 1H NMR (400MHz, methanol-d4) δ = 8.75 (br d, J=5.6 Hz, 1H), 8.53 (br t, J=7.9 Hz, 1H), 8.34 (d, J=2.0 Hz, 1H), 8.04 (br d, J=8.1 Hz, 1H), 7.92 (br t, J=6.5 Hz, 1H), 7.75 (s, 1H), 7.69 (dd, J=2.3, 8.4 Hz, 1H), 7.39 (d, J=8.3 Hz, 1H), 4.94 - 4.92 (m, 1H), 4.77 (s, 2H), 4.24 (br d, J=13.4 Hz, 2H), 3.31 - 3.25 (m, 1H), 3.02 (br s, 2H), 2.15 (br d, J=11.5 Hz, 2H), 1.76 (dq, J=4.2, 12.3 Hz, 2H), 1.28 (d, J=6.2 Hz, 6H), 1.11 (s, 9H). ESI [M+H] = 615.2

[0908] Example 5: Synthesis of isopropyl 4-[5-[2-(t-butylsulfamoyl)-4-(isopropoxycarbonylamino)phenyl]thiazol-2-yl]piperazine-1-carboxylate

[0909] Scheme 4: [ka]

[0910] Preparation of Compound 56

[0911] [ka]

[0912] General Method A, t-Butyl 4-[5-[4-acetamido-2-(t-butylsulfamoyl)phenyl]thiazol-2-yl]piperazine-1-carboxylate. ESI [M+H] = 538.2

[0913] General Method C for the Preparation of Sulfonamide Compounds 57

[0914] [ka]

[0915] To a solution of tert-butyl 4-[5-[4-acetamido-2-(tert-butylsulfamoyl)phenyl]thiazol-2-yl]piperazine-1-carboxylate (110 mg, 205 μmol, 1 eq.) in DCM (2 mL) was added TFA (1 mL), and the mixture was stirred at 25 °C for 30 min. The mixture was concentrated to give N-[3-(tert-butylsulfamoyl)-4-(2-piperazin-1-ylthiazol-5-yl)phenyl]acetamide (80 mg, 183 μmol, 89.4% yield) as a yellow solid. ESI [M+H] = 438.2

[0916] Preparation of compound 58

[0917] [ka]

[0918] General Method D, Isopropyl 4-[5-[4-acetamido-2-(t-butylsulfamoyl)phenyl]thiazol-2-yl]piperazine-1-carboxylate. ESI [M+H] = 524.1

[0919] Preparation of compound 59

[0920] [ka]

[0921] General Method F, Isopropyl 4-[5-[4-amino-2-(t-butylsulfamoyl)phenyl]thiazol-2-yl]piperazine-1-carboxylate. ESI [M+H] = 482.1

[0922] Preparation of Compound Example 5

[0923] [ka]

[0924] General Method D, isopropyl 4-[5-[2-(t-butylsulfamoyl)-4-(isopropoxycarbonylamino)phenyl]thiazol-2-yl]piperazine-1-carboxylate. 1 H NMR (400MHz, methanol-d4) δ = 8.22 (d, J=2.1 Hz, 1H), 7.56 (dd, J=2.2, 8.3 Hz, 1H), 7.30 (d, J=8.3 Hz, 1H), 7.20 (s, 1H), 4.94 - 4.81 (m, 2H), 3.61 - 3.43 (m, 8H), 1.20 (dd, J=6.2, 14.5 Hz, 12H), 1.07 (s, 9H). ESI [M+H] = 568.3

[0925] Example 6: Synthesis of isopropyl 4-[5-[4-(benzyloxycarbonylamino)-2-(t-butylsulfamoyl)phenyl]thiazol-2-yl]piperazine-1-carboxylate

[0926] Scheme 5: Preparation of Compound Example 6 [ka]

[0927] General Method D, isopropyl 4-[5-[4-(benzyloxycarbonylamino)-2-(t-butylsulfamoyl)phenyl]thiazol-2-yl]piperazine-1-carboxylate. 1H NMR (400MHz, methanol-d4) δ = 8.33 (d, J=2.0 Hz, 1H), 7.68 (dd, J=2.2, 8.4 Hz, 1H), 7.45 - 7.27 (m, 7H), 5.21 (s, 2H), 4.94 - 4.88 (m, 1H), 3.68 - 3.51 (m, 8H), 1.27 (d, J=6.4 Hz, 6H), 1.19 - 1.11 (m, 9H). ESI [M+H] = 616.3

[0928] Example 7: Synthesis of trans-isopropyl N-[3-(t-butylsulfamoyl)-4-[2-[4-(cyclopentoxycarbonylamino)cyclohexyl]thiazol-5-yl]phenyl]carbamate

[0929] Scheme 6: [ka]

[0930] General Method B for the Preparation of Sulfonamide Compound 83

[0931] [ka]

[0932] To a mixture of tert-butyl (trans-4-(5-bromothiazol-2-yl)cyclohexyl)carbamate (1.3 g, 3.6 mmol, 2 eq.) and isopropyl N-[3-(tert-butylsulfamoyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamate (800 mg, 1.8 mmol, 1 eq.) in dioxane (12 mL) and HO (2 mL) was added NaCO (579 mg, 5.5 mmol, 3 eq.) and Pd(dppf)Cl (133 mg, 182 μmol, 0.1 eq.). The mixture was stirred at 80 °C under N atmosphere for 12 h and then concentrated. The residue was diluted with HO (5 mL), extracted with ethyl acetate (5 mL × 3), dried over NaSO, filtered, and concentrated. The residue was purified by column chromatography (SiO, petroleum ether:ethyl acetate = 1:0 to 3:1) to give trans-isopropyl-N-[4-[2-[4-(t-butoxycarbonylamino)cyclohexyl]thiazol-5-yl]-3-(t-butylsulfamoyl)phenyl]carbamate (660 mg, crude), of which 60 mg was purified by prep-HPLC (column: Agela Durashell C18 150 × 25 5μ; mobile phase: [water (0.04% NH3HO)-ACN]; B%: 60% to 90%, 10 min) to give pure compound 83 (40.92 mg, 99.64% purity) as a white solid for delivery. 1H NMR (400MHz, DMSO-d6) δ = 10.06 (s, 1H), 8.32 (d, J=2.1 Hz, 1H), 7.70 - 7.60 (m, 2H), 7.38 (d, J=8.4 Hz, 1H), 6.96 (s, 1H), 6.81 (br d, J=7.9 Hz, 1H), 4.99 - 4.87 (m, 1H), 3.27 (br s, 1H), 2.94 - 2.84 (m, 1H), 2.13 (br d, J=11.7 Hz, 2H), 1.90 (br d, J=11.1 Hz, 2H), 1.63 - 1.49 (m, 2H), 1.39 (s, 9H), 1.33 (br d, J=14.4 Hz, 2H), 1.28 (d, J=6.4 Hz, 6H), 1.07 (s, 9H). ESI [M+H] =595.3

[0933] Preparation of Compound 84

[0934] [ka]

[0935] General Method F, trans-isopropyl N-[4-[2-(4-aminocyclohexyl)thiazol-5-yl]-3-(t-butylsulfamoyl)phenyl]carbamate. ESI [M+H] = 495.2

[0936] Preparation of Example 7

[0937] [ka]

[0938] General Method D, trans-isopropyl N-[3-(t-butylsulfamoyl)-4-[2-[4-(cyclopentoxycarbonylamino)cyclohexyl]thiazol-5-yl]phenyl]carbamate. 1H NMR (400MHz, DMSO-d6) δ = 10.04 (s, 1H), 8.29 (d, J=2.2 Hz, 1H), 7.61 - 7.59 (m, 2H), 7.35 (d, J=8.8 Hz, 1H), 7.00 (br d, J=7.9 Hz, 1H), 6.96 - 6.93 (m, 1H), 4.96 - 4.87 (m, 2H), 3.29 - 3.22 (m, 1H), 2.87 (br t, J=11.8 Hz, 1H), 2.10 (br d, J=12.7 Hz, 2H), 1.88 (br d, J=12.7 Hz, 2H), 1.75 (br s, 2H), 1.61 - 1.48 (m, 8H), 1.36 - 1.27 (m, 2H), 1.25 (d, J=6.1 Hz, 6H), 1.04 (s, 9H). ESI [M+Na] = 629.3

[0939] Example 8 Synthesis of [(2R)-1-methylpyrrolidin-2-yl]methyl N-[4-[5-[2-(t-butylsulfamoyl)-4-(isopropoxycarbonylamino)phenyl]thiazol-2-yl]cyclohexyl]carbamate

[0940] Scheme 7: [ka]

[0941] Preparation of Compound 85

[0942] [ka]

[0943] General Method D, trans-(4-nitrophenyl)N-[4-[5-[2-(t-butylsulfamoyl)-4-(isopropoxycarbonylamino)phenyl]thiazol-2-yl]cyclohexyl]carbamate. ESI [M+H] = 660.2

[0944] Preparation of Compound Example 8

[0945] [ka]

[0946] General Method H, [(2R)-1-methylpyrrolidin-2-yl]methyl N-[4-[5-[2-(t-butylsulfamoyl)-4-(isopropoxycarbonylamino)phenyl]thiazol-2-yl]cyclohexyl]carbamate. 1 H NMR (400MHz, methanol-d4) δ = 8.38 (s, 1H), 7.80 - 7.73 (m, 1H), 7.69 (dd, J=2.2, 8.4 Hz, 1H), 7.40 (d, J=8.3 Hz, 1H), 5.05 - 5.00 (m, 1H), 4.48 (br dd, J=3.0, 12.8 Hz, 1H), 4.21 (br dd, J=7.2, 12.6 Hz, 1H), 3.78 - 3.66 (m, 2H), 3.57 - 3.46 (m, 1H), 3.22 (td, J=8.3, 11.2 Hz, 1H), 3.07 - 3.01 (m, 3H), 2.43 - 1.99 (m, 8H), 1.98 - 1.88 (m, 1H), 1.80 - 1.66 (m, 2H), 1.47 (q, J=12.5 Hz, 2H), 1.34 (d, J=6.2 Hz, 6H), 1.20 - 1.12 (m, 9H). ESI [M+H] = 636.2

[0947] Example 9: Synthesis of isopropyl (3-(N-(t-butyl)sulfamoyl)-4-(2-((1S,4r)-4-(((((S)-1-methylpyrrolidin-2-yl)methoxy)carbonyl)amino)cyclohexyl)thiazol-5-yl)phenyl)carbamate

[0948] The following compounds were synthesized via the same method with key intermediate 85:

[0949] [ka]

[0950] 1 H NMR (methanol-d4, 400MHz): δ = 8.34 (d, J=2.2 Hz, 1H), 7.71 (s, 1H), 7.66 (dd, J=8.5, 2.1 Hz, 1H), 7.36 (d, J=8.4 Hz, 1H), 4.93-5.04 (m, 1H), 4.46 (dd, J=13.0, 2.9 Hz, 1H), 4.18 (dd, J=13.0, 7.1 Hz, 1H), 3.64-3.75 (m, 2H), 3.42-3.58 (m, 1H), 3.12-3.25 (m, 1H), 3.00-3.06 (m, 3H), 1.97-2.39 (m, 8H), 1.84-1.96 (m, 1H), 1.64-1.77 (m, 2H), 1.44 (q, J=12.6 Hz, 2H), 1.31 (d, J=6.2 Hz, 6H), 1.13 (s, 9H). ESI [M+H] = 636.3

[0951] Example 10: Synthesis of trans-t-butyl N-[4-[5-[4-(benzylcarbamoylamino)-2-(t-butylsulfamoyl)phenyl]thiazol-2-yl]cyclohexyl]carbamate

[0952] [ka]

[0953] General Method B, trans-t-butyl N-[4-[5-[4-(benzylcarbamoylamino)-2-(t-butylsulfamoyl)phenyl]thiazol-2-yl]cyclohexyl]carbamate. 1H NMR (400MHz, methanol-d4) δ = 8.24 (d, J=2.4 Hz, 1H), 7.72 - 7.66 (m, 2H), 7.37 - 7.29 (m, 5H), 7.28 - 7.21 (m, 1H), 4.40 (s, 2H), 3.39 (br t, J=11.6 Hz, 1H), 2.98 (tt, J=3.4, 12.1 Hz, 1H), 2.25 - 2.17 (m, 2H), 2.04 (br d, J=11.5 Hz, 2H), 1.67 (dq, J=2.9, 12.9 Hz, 2H), 1.44 (s, 9H), 1.41 - 1.32 (m, 2H), 1.10 (s, 9H). ESI [M+H] = 642.3

[0954] Example 11: Synthesis of [(2R)-1-methylpyrrolidin-2-yl]methyl N-[4-[5-[4-(benzylcarbamoylamino)-2-(t-butylsulfamoyl)phenyl]thiazol-2-yl]cyclohexyl]carbamate

[0955] Scheme 8: [ka]

[0956] Preparation of Compound 86

[0957] [ka]

[0958] General Method D, trans-(4-nitrophenyl)N-[4-[5-[4-(benzylcarbamoylamino)-2-(t-butylsulfamoyl)phenyl]thiazol-2-yl]cyclohexyl]carbamate.

[0959] Preparation of Example 11

[0960] [ka]

[0961] General Method H, [(2R)-1-methylpyrrolidin-2-yl]methyl N-[4-[5-[4-(benzylcarbamoylamino)-2-(t-butylsulfamoyl)phenyl]thiazol-2-yl]cyclohexyl]carbamate. 1 H NMR (400MHz, methanol-d4) δ = 8.30 (d, J=2.2 Hz, 1H), 7.79 (s, 1H), 7.70 (dd, J=2.3, 8.4 Hz, 1H), 7.42 - 7.31 (m, 5H), 7.27 (dt, J=2.6, 5.7 Hz, 1H), 4.54 - 4.41 (m, 3H), 4.21 (dd, J=7.1, 12.7 Hz, 1H), 3.79 - 3.66 (m, 2H), 3.52 (br t, J=11.6 Hz, 1H), 3.26 - 3.17 (m, 1H), 3.04 (s, 3H), 2.42 - 1.98 (m, 8H), 1.97 - 1.87 (m, 1H), 1.80 - 1.65 (m, 2H), 1.54 - 1.40 (m, 2H), 1.15 (s, 9H). ESI [M+H] = 683.3

[0962] Example 12: Synthesis of ((S)-1-methylpyrrolidin-2-yl)methyl ((1r,4S)-4-(5-(4-(3-benzylureido)-2-(N-(t-butyl)sulfamoyl)phenyl)thiazol-2-yl)cyclohexyl)carbamate

[0963] The following compounds were synthesized via the same method with key intermediate 87:

[0964] [ka]

[0965] 1H NMR (400MHz, methanol-d4) δ = 8.29 (d, J=2.3 Hz, 1H), 7.83 - 7.74 (m, 1H), 7.73 - 7.65 (m, 1H), 7.43 - 7.31 (m, 5H), 7.30 - 7.22 (m, 1H), 4.55 - 4.35 (m, 3H), 4.21 (br dd, J=7.1, 12.7 Hz, 1H), 3.79 - 3.61 (m, 2H), 3.58 - 3.42 (m, 1H), 3.23 (br s, 1H), 3.08 - 3.02 (m, 3H), 2.43 - 1.98 (m, 8H), 1.97 - 1.86 (m, 1H), 1.80 - 1.65 (m, 2H), 1.54 - 1.39 (m, 2H), 1.19 - 1.07 (m, 9H). ESI [M+H] = 683.3

[0966] Example 13: Synthesis of isopropyl (S)-(4-(5-(2-(N-(t-butyl)sulfamoyl)-4-(3-(1-phenylethyl)ureido)phenyl)thiazol-2-yl)bicyclo[2.2.2]octan-1-yl)carbamate

[0967] Scheme 9: [ka]

[0968] Preparation of Compound 89

[0969] [ka]

[0970] General Method D, 4-(isopropoxycarbonylamino)bicyclo[2.2.2]octane-1-carboxylate.

[0971] General method for preparing compound 90

[0972] [ka]

[0973] To a solution of methyl 4-(isopropoxycarbonylamino)bicyclo[2.2.2]octane-1-carboxylate (400 mg, 1.49 mmol, 1 eq.) in MeOH (5 mL) was added LiOH (106.70 mg, 4.46 mmol, 3 eq.) in HO (5 mL), and the mixture was stirred at 50 °C for 1 h. The mixture was concentrated to remove MeOH and then extracted with MTBE (10 mL × 2). The pH of the aqueous phase was adjusted to 1–2 by adding 4 N HCl solution, and then extracted with EtOAc (10 mL × 3). The combined organic phase was dried over NaSO, filtered, and concentrated to give 4-(isopropoxycarbonylamino)bicyclo[2.2.2]octane-1-carboxylic acid (270 mg, crude) as a yellow solid. 1 H NMR (400 MHz, chloroform-d) δ = 4.86 (br d, J = 6.4 Hz, 1H), 4.46 (br s, 1H), 2.00 - 1.80 (m, 12H), 1.23 (br d, J = 5.9 Hz, 6H).

[0974] General Method N for Preparing Compound 91

[0975] [ka]

[0976] To a solution of 4-(isopropoxycarbonylamino)bicyclo[2.2.2]octane-1-carboxylic acid (270 mg, 1.06 mmol, 1 eq.) in DCM (5 mL) were added DMF (7.73 mg, 105.75 μmol, 0.1 eq.) and (COCl) (201.34 mg, 1.59 mmol, 1.5 eq.). The mixture was stirred at 26 °C for 0.2 h and then concentrated. The residue was dissolved in THF (5 mL) and added dropwise to a solution of NH H O (741.24 mg, 5.29 mmol, 5 eq.) in dioxane (5 mL). The mixture was stirred at 26 °C for 0.3 h. The mixture was concentrated, diluted with EtOAc (20 mL), and washed with H O (10 mL). The organic phase was dried over Na2SO4, filtered, and concentrated to give isopropyl N-(1-carbamoyl-4-bicyclo[2.2.2]octanyl)carbamate as a yellow solid. 1 H NMR (400MHz, chloroform-d) δ = 5.43 (br s, 1H), 5.17 (br s, 1H), 4.85 - 4.71 (m, 1H), 4.35 (br s, 1H), 1.82 (s, 12H), 1.13 (d, J=6.2 Hz, 6H). ESI [M+H] = 255.2

[0977] General Method L for Preparing Compound 92

[0978] [ka]

[0979] To a solution of isopropyl N-(1-carbamoyl-4-bicyclo[2.2.2]octanyl)carbamate (60 mg, 235.92 μmol, 1 eq.) in 2-Me-THF (2 mL) was added 2,4-bis(4-methoxyphenyl)-2,4-dithioxo-1,3,2,4-dithiadiphosphetane (95.42 mg, 235.92 μmol, 1 eq.), and the mixture was stirred at 80 °C for 0.5 h. The mixture was poured into saturated aqueous NaCO (10 mL) and extracted with EtOAc (10 mL × 3). The combined organic phase was dried over NaSO, filtered, and concentrated. The residue was purified by prep-TLC (petroleum ether / ethyl acetate=2:3) to give isopropyl N-(1-carbamothioyl-4-bicyclo[2.2.2]octanyl)carbamate (30 mg, crude) as a yellow solid. ESI [M+H]=271.1

[0980] General Method M for Preparing Compound 93

[0981] [ka]

[0982] To a solution of isopropyl N-(1-carbamothioyl-4-bicyclo[2.2.2]octanyl)carbamate (85 mg, 314.36 μmol, 1 eq.) in EtOH (2 mL) was added TsOH·HO (119.59 mg, 628.72 μmol, 2 eq.) and 2-bromo-1,1-diethoxyethane (123.90 mg, 628.72 μmol, 2 eq.). The mixture was stirred at 80 °C for 1 h, concentrated, and diluted with EtOAc (30 mL). The mixture was washed with saturated aqueous NaCO (10 mL × 2), and the combined organic phase was dried over NaSO, filtered, and concentrated. The residue was purified by prep-TLC (petroleum ether / ethyl acetate=3:1) to give isopropyl N-(1-thiazol-2-yl-4-bicyclo[2.2.2]octanyl)carbamate (80 mg, crude) as a yellow solid. ESI [M+H]=295.3

[0983] Preparation of Compound 94

[0984] [ka]

[0985] General Method J, N-[1-(5-bromothiazol-2-yl)-4-bicyclo[2.2.2]octanyl]carbamate isopropyl. ESI [M+H] = 375.2 / 373.2

[0986] Preparation of Compound 95

[0987] [ka]

[0988] General Method B, N-[1-[5-[4-amino-2-(t-butylsulfamoyl)phenyl]thiazol-2-yl]-4-bicyclo[2.2.2]octanyl]carbamate isopropyl. ESI [M+H] = 521.2

[0989] Preparation of Compound 96

[0990] [ka]

[0991] General Method D, N-[3-(t-butylsulfamoyl)-4-[2-[4-(isopropoxycarbonylamino)-1-bicyclo[2.2.2]octanyl]thiazol-5-yl]phenyl]carbamic acid (4-nitrophenyl). ESI [M+H] = 686.4

[0992] Preparation of Example 13

[0993] [ka]

[0994] General Method E, isopropyl N-[1-[5-[2-(t-butylsulfamoyl)-4-[[(1S)-1-phenylethyl]carbamoylamino]phenyl]thiazol-2-yl]-4-bicyclo[2.2.2]octanyl]carbamate. 1 H NMR (400MHz, methanol-d4) δ = 8.21 (d, J=2.3 Hz, 1H), 7.75 (s, 1H), 7.67 (dd, J=2.3, 8.3 Hz, 1H), 7.41 - 7.32 (m, 5H), 7.29 - 7.23 (m, 1H), 4.99 - 4.93 (m, 1H), 4.83 - 4.76 (m, 1H), 2.17 - 2.08 (m, 6H), 2.07 - 1.99 (m, 6H), 1.51 (d, J=7.0 Hz, 3H), 1.22 (br d, J=6.0 Hz, 6H), 1.12 (s, 9H). ESI [M+H] = 668.3

[0995] Example 14: Synthesis of isopropyl (R)-(4-(5-(2-(N-(t-butyl)sulfamoyl)-4-(3-(1-phenylethyl)ureido)phenyl)thiazol-2-yl)bicyclo[2.2.2]octan-1-yl)carbamate

[0996] The following compounds were synthesized via the same method with key intermediate 96:

[0997] [ka]

[0998] 1H NMR (400MHz, methanol-d4) δ = 8.18 (d, J=2.6 Hz, 1H), 7.74 - 7.69 (m, 1H), 7.64 (dd, J=2.2, 8.3 Hz, 1H), 7.38 - 7.29 (m, 5H), 7.26 - 7.19 (m, 1H), 4.92 (q, J=7.0 Hz, 1H), 4.82 - 4.71 (m, 1H), 2.15 - 2.05 (m, 6H), 2.04 - 1.95 (m, 6H), 1.48 (d, J=7.0 Hz, 3H), 1.20 (br d, J=6.1 Hz, 6H), 1.09 (s, 9H). ESI [M+H] = 668.3

[0999] Example 15: Synthesis of isopropyl (S)-(4-(5-(2-(N-(t-butyl)sulfamoyl)-4-(3-(1-(pyridin-2-yl)ethyl)ureido)phenyl)thiazol-2-yl)bicyclo[2.2.2]octan-1-yl)carbamate

[1000] The following compounds were synthesized via the same method with key intermediate 96:

[1001] [ka]

[1002] 1H NMR (400MHz, methanol-d4) δ = 8.72 (d, J=5.6 Hz, 1H), 8.46 (t, J=7.9 Hz, 1H), 8.28 (d, J=2.3 Hz, 1H), 8.02 (d, J=7.9 Hz, 1H), 7.85 (t, J=6.6 Hz, 1H), 7.72 (s, 1H), 7.63 (dd, J=2.3, 8.4 Hz, 1H), 7.35 (d, J=8.4 Hz, 1H), 5.13 (q, J=7.1 Hz, 1H), 4.84 - 4.74 (m, 1H), 2.15 - 2.07 (m, 6H), 2.07 - 1.98 (m, 6H), 1.65 (d, J=7.1 Hz, 3H), 1.22 (br d, J=6.1 Hz, 6H), 1.09 (s, 9H). ESI [M+H] = 669.2

[1003] Example 16: Synthesis of isopropyl (R)-(4-(5-(2-(N-(t-butyl)sulfamoyl)-4-(3-(1-(pyridin-2-yl)ethyl)ureido)phenyl)thiazol-2-yl)bicyclo[2.2.2]octan-1-yl)carbamate

[1004] The following compounds were synthesized via the same method with key intermediate 96:

[1005] [ka]

[1006] 1H NMR (400MHz, methanol-d4) δ = 8.75 (d, J=5.1 Hz, 1H), 8.57 (dt, J=1.5, 7.9 Hz, 1H), 8.29 (d, J=2.2 Hz, 1H), 8.11 (d, J=8.1 Hz, 1H), 7.98 - 7.90 (m, 1H), 7.75 (s, 1H), 7.62 (dd, J=2.3, 8.3 Hz, 1H), 7.36 (d, J=8.4 Hz, 1H), 5.15 (q, J=7.1 Hz, 1H), 4.84 - 4.75 (m, 1H), 2.16 - 2.07 (m, 6H), 2.06 - 1.97 (m, 6H), 1.67 (d, J=7.2 Hz, 3H), 1.22 (br d, J=6.1 Hz, 6H), 1.09 (s, 9H). ESI [M+H] = 669.2

[1007] Example 17: Synthesis of isopropyl N-[3-(t-butylsulfamoyl)-4-[2-[4-(isopropoxycarbonylamino)-1-bicyclo[2.2.2]octanyl]thiazol-5-yl]phenyl]carbamate

[1008] Scheme 10: Preparation of Compound Example 17 [ka]

[1009] General Method B, isopropyl N-[3-(t-butylsulfamoyl)-4-[2-[4-(isopropoxycarbonylamino)-1-bicyclo[2.2.2]octanyl]thiazol-5-yl]phenyl]carbamate. 1H NMR (400MHz, methanol-d4) δ = 8.33 (d, J=2.0 Hz, 1H), 7.74 (s, 1H), 7.66 (dd, J=2.2, 8.4 Hz, 1H), 7.36 (d, J=8.4 Hz, 1H), 5.03 - 4.91 (m, 1H), 4.78 (br d, J=6.4 Hz, 1H), 2.16 - 2.05 (m, 6H), 2.04 - 1.95 (m, 6H), 1.31 (d, J=6.4 Hz, 6H), 1.20 (br d, J=6.0 Hz, 6H), 1.11 (s, 9H). ESI [M+H] =607.3

[1010] Example 18: Synthesis of isopropyl (4-(5-(4-(3-benzylureido)-2-(N-(t-butyl)sulfamoyl)phenyl)thiazol-2-yl)bicyclo[2.2.2]octan-1-yl)carbamate

[1011] The following compounds were synthesized via the same method with key intermediate 94:

[1012] [ka]

[1013] 1 H NMR (400MHz, methanol-d4) δ = 8.26 (d, J=2.2 Hz, 1H), 7.77 (s, 1H), 7.72 (dd, J=2.4, 8.4 Hz, 1H), 7.38 - 7.33 (m, 5H), 7.27 (td, J=2.6, 8.6 Hz, 1H), 4.80 (br d, J=5.7 Hz, 1H), 4.43 (s, 2H), 2.17 - 2.10 (m, 6H), 2.06 - 2.00 (m, 6H), 1.25 - 1.20 (m, 6H), 1.13 (s, 9H). ESI [M+H] =654.1

[1014] Example 19: Synthesis of isopropyl (4-(5-(2-(N-(t-butyl)sulfamoyl)-4-(3-(pyridin-2-ylmethyl)ureido)phenyl)thiazol-2-yl)bicyclo[2.2.2]octan-1-yl)carbamate

[1015] The following compounds were synthesized via the same method with key intermediate 94:

[1016] [ka]

[1017] 1 H NMR (400MHz, methanol-d4) δ = 8.73(d, J=5.7 Hz, 1H), 8.51 (dt, J=1.3, 7.9 Hz, 1H), 8.31 (d, J=2.2 Hz, 1H), 8.02 (d, J=8.3 Hz, 1H), 7.90 (t, J=6.8 Hz, 1H), 7.72 (s, 1H), 7.66 (dd, J=2.2, 8.3 Hz, 1H), 7.35 (d, J=8.3 Hz, 1H), 4.75 (s, 3H), 2.15 - 1.93 (m, 12H), 1.20 (br d, J=6.1 Hz, 6H), 1.07 (s, 9H). ESI [M+H] = 655.3

[1018] Example 20: Synthesis of trans-isopropyl N-[3-(t-butylsulfamoyl)-4-[2-[4-(isopropylcarbamoyloxy)cyclohexyl]thiazol-5-yl]phenyl]carbamate

[1019] Scheme 11: [ka]

[1020] Preparation of Compound 111.

[1021] [ka]

[1022] To a solution of trans-4-hydroxycyclohexanecarboxylic acid (1 g, 6.94 mmol, 1 eq.) in MeCN (10 mL) were added HBTU (2.89 g, 7.63 mmol, 1.1 eq.) and TEA (2.11 g, 20.81 mmol, 2.90 mL, 3 eq.), followed by NHCl (742.07 mg, 13.87 mmol, 2 eq.), and the mixture was stirred at 26 °C for 1 h. The mixture was then filtered and dried to give trans-4-hydroxycyclohexanecarboxamide (1 g, crude) as a white solid, which could be used without any purification.

[1023] Preparation of Compound 112.

[1024] [ka]

[1025] To a solution of trans-4-hydroxycyclohexanecarboxamide (12 g, 83.81 mmol, 1 eq.) in DCM (150 mL) was added imidazole (11.41 g, 167.62 mmol, 2 eq.) and t-butyl-chloro-diphenyl-silane (27.64 g, 100.57 mmol, 25.83 mL, 1.2 eq.). The mixture was stirred at 26 °C for 12 h, poured into 1 N HCl (200 mL), and the organic phase was washed with saturated aqueous NaCO (100 mL). The organic phase was dried over NaSO, filtered, and concentrated. The residue was washed with a solution of petroleum ether: EtOAc (10:1, 100 mL) and then filtered. The filter cake was dried to give trans-4-[t-butyl(diphenyl)silyl]oxycyclohexanecarboxamide (31.5 g, crude). 1H NMR (400MHz, methanol-d4) δ = 7.72 - 7.64 (m, 4H), 7.49 - 7.36 (m, 6H), 3.69 - 3.55 (m, 1H), 2.21 - 2.08 (m, 1H), 1.96 - 1.83 (m, 2H), 1.82 - 1.69 (m, 2H), 1.50 - 1.23 (m, 4H), 1.12 - 0.98 (m, 9H).

[1026] Preparation of Compound 113.

[1027] [ka]

[1028] General Method L, trans-4-[t-butyl(diphenyl)silyl]oxycyclohexanecarbothioamide. 1 H NMR (400MHz, methanol-d4) δ = 7.73 - 7.64 (m, 4H), 7.52 - 7.36 (m, 6H), 3.73 - 3.59 (m, 1H), 2.59 - 2.44 (m, 1H), 1.91 (br d, J=8.3 Hz, 2H), 1.80 - 1.66 (m, 2H), 1.57 - 1.35 (m, 4H), 1.08 - 1.04 (m, 9H). ESI [M+H] =398.1

[1029] Preparation of Compound 114.

[1030] [ka]

[1031] General Method M, trans-t-butyl-diphenyl-(4-thiazol-2-ylcyclohexoxy)silane. 1H NMR (400MHz, methanol-d4) δ = 7.63 - 7.55 (m, 5H), 7.42 - 7.25 (m, 7H), 4.05 - 3.96 (m, 1H), 2.97 (tt, J=3.7, 11.7 Hz, 1H), 2.05 (dq, J=3.2, 12.5 Hz, 2H), 1.84 - 1.62 (m, 4H), 1.44 (tt, J=2.9, 13.5 Hz, 2H), 1.01 - 0.98 (m, 9H). ESI [M+H] =422.2

[1032] Preparation of Compound 114A.

[1033] [ka]

[1034] General Method J, trans-[4-(5-bromothiazol-2-yl)cyclohexoxy]-t-butyl-diphenyl-silane (1.8 g, crude). ESI [M+H] = 502.0

[1035] Preparation of Compound 115.

[1036] [ka]

[1037] To a solution of trans-[4-(5-bromothiazol-2-yl)cyclohexoxy]-t-butyl-diphenyl-silane (1.5 g, 3.00 mmol, 1 eq.) in THF (10 mL) was added TBAF (1 M, 4.49 mL, 1.5 eq.), and the mixture was stirred at 26 °C for 12 h and then concentrated. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 20:1 to 1:1) to give trans-4-(5-bromothiazol-2-yl)cyclohexanol (500 mg, 1.91 mmol, 63.64% yield) as a yellow solid.

[1038] Preparation of Compound 116.

[1039] [ka]

[1040] To a solution of trans-4-(5-bromothiazol-2-yl)cyclohexanol (500 mg, 1.91 mmol, 1 eq.) in DMF (5 mL) was added 2-isocyanatopropane (486.93 mg, 5.72 mmol, 3 eq.) and DIEA (739.47 mg, 5.72 mmol, 3 eq.). The mixture was stirred at 100 °C for 40 h, poured into HO (50 mL), and extracted with EtOAc (10 mL × 3). The combined organic phase was dried over NaSO, filtered, and concentrated. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 10:1 to 1:1) to give trans-[4-(5-bromothiazol-2-yl)cyclohexyl] N-isopropylcarbamate (180 mg, 518.33 μmol, 27.18% yield) as a yellow solid. 1 H NMR (400MHz, methanol-d4) δ = 7.61 (s, 1H), 3.85 - 3.64 (m, 2H), 3.15 - 2.99 (m, 1H), 1.98 - 1.83 (m, 6H), 1.73 (br d, J=13.5 Hz, 2H), 1.14 - 1.12 (m, 6H). ESI [M+H] =347.1 / 349.1

[1041] Preparation of Example 20.

[1042] [ka]

[1043] General Method B, trans-isopropyl N-[3-(t-butylsulfamoyl)-4-[2-[4-(isopropylcarbamoyloxy)cyclohexyl]thiazol-5-yl]phenyl]carbamate. 1H NMR (400MHz, methanol-d4) δ = 8.34 (d, J=2.0 Hz, 1H), 7.75 (s, 1H), 7.67 (dd, J=2.0, 8.4 Hz, 1H), 7.37 (d, J=8.4 Hz, 1H), 5.05 - 4.93 (m, 1H), 4.89 (br s, 1H), 3.83 - 3.64 (m, 1H), 3.15 (br s, 1H), 2.12 - 1.88 (m, 6H), 1.84 - 1.64 (m, 2H), 1.31 (d, J=6.2 Hz, 6H), 1.19 - 1.04 (m, 15H). ESI [M+H] = 581.4

[1044] Example 21: Synthesis of (1r,4r)-4-(5-(4-(3-benzylureido)-2-(N-(t-butyl)sulfamoyl)phenyl)thiazol-2-yl)cyclohexyl isopropylcarbamate

[1045] The following compounds were synthesized via the same method via key intermediate 116:

[1046] [ka]

[1047] 1 H NMR (400MHz, methanol-d4) δ = 8.24 (d, J=2.2 Hz, 1H), 7.74 (s, 1H), 7.69 (dd, J=2.4, 8.4 Hz, 1H), 7.40 - 7.28 (m, 5H), 7.28 - 7.17 (m, 1H), 4.89 (br s, 1H), 4.41 (s, 2H), 3.79 - 3.64 (m, 1H), 3.14 (br s, 1H), 2.04 - 1.94 (m, 6H), 1.84 - 1.65 (m, 2H), 1.16 - 1.08 (m, 15H). ESI [M+H] = ...

Claims

1. The structural formula: 【Chemistry 1】 or a pharma- ceutically acceptable salt thereof for treating pancreatic cancer in a subject.

2. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is administered to a subject at a dose ranging from 250 mg / day to 500 mg / day of the compound or a pharma- ceutically acceptable salt thereof.

3. The pharmaceutical composition of claim 1 or 2, wherein the pharmaceutical composition is administered to provide a dosage ranging from 300 mg / day to 500 mg / day of the compound or a pharma- ceutically acceptable salt thereof.

4. The pharmaceutical composition of any one of claims 1 to 3, wherein the pharmaceutical composition is administered to provide a dose ranging from 400 mg / day to 500 mg / day of the compound or a pharma- ceutically acceptable salt thereof.

5. 3. The pharmaceutical composition of claim 1 or 2, wherein the pharmaceutical composition is administered to provide a dose of the compound or a pharma- ceutically acceptable salt thereof selected from the group consisting of 250 mg / day, 260 mg / day, 270 mg / day, 280 mg / day, 290 mg / day, 300 mg / day, 310 mg / day, 320 mg / day, 330 mg / day, 340 mg / day, 350 mg / day, 360 mg / day, 370 mg / day, 380 mg / day, 390 mg / day, 400 mg / day, 410 mg / day, 420 mg / day, 430 mg / day, 440 mg / day, 450 mg / day, 460 mg / day, 470 mg / day, 480 mg / day, 490 mg / day, and 500 mg / day of the compound or a pharma- ceutical acceptable salt thereof.

6. 4. The pharmaceutical composition of any one of claims 1 to 3, wherein the pharmaceutical composition is administered to provide a dose of the compound or a pharma- ceutically acceptable salt thereof selected from the group consisting of 300 mg / day, 310 mg / day, 320 mg / day, 330 mg / day, 340 mg / day, 350 mg / day, 360 mg / day, 370 mg / day, 380 mg / day, 390 mg / day, 400 mg / day, 410 mg / day, 420 mg / day, 430 mg / day, 440 mg / day, 450 mg / day, 460 mg / day, 470 mg / day, 480 mg / day, 490 mg / day, and 500 mg / day of the compound or a pharma- ceutical acceptable salt thereof.

7. 5. The pharmaceutical composition of any one of claims 1 to 4, wherein the pharmaceutical composition is administered to provide a dose of the compound or a pharma- ceutically acceptable salt thereof selected from the group consisting of 400 mg / day, 410 mg / day, 420 mg / day, 430 mg / day, 440 mg / day, 450 mg / day, 460 mg / day, 470 mg / day, 480 mg / day, 490 mg / day, and 500 mg / day.

8. The pharmaceutical composition according to any one of claims 1 to 7, wherein the pharmaceutical composition is administered at a dose of 400 mg / day of the compound or a pharma- ceutically acceptable salt thereof.

9. The pharmaceutical composition contains 180 mg / m ２ ~500mg / m ２ The pharmaceutical composition according to any one of claims 1 to 8, wherein the pharmaceutical composition is administered at a dose of

10. The pharmaceutical composition contains 180 mg / m ２ ~400mg / m ２ The pharmaceutical composition according to any one of claims 1 to 9, wherein the composition is administered to achieve a dose in the range of

11. The pharmaceutical composition contains 240 mg / m ２ ~500mg / m ２ The pharmaceutical composition according to any one of claims 1 to 9, wherein the composition is administered to achieve a dose in the range of

12. The pharmaceutical composition contains 240 mg / m ２ ~400mg / m ２ The pharmaceutical composition according to any one of claims 1 to 11, wherein the pharmaceutical composition is administered at a dose of

13. The pharmaceutical composition contains 180 mg / m ２ , 200 mg / m ２ , 220 mg / m ２ , 240 mg / m ２ , 260 mg / m ２ , 280 mg / m ２ , 300 mg / m ２ , 320 mg / m ２ , 340 mg / m ２ , 360 mg / m ２ , 380 mg / m ２ , 400 mg / m ２ , 420 mg / m ２ , 440 mg / m ２ , 460 mg / m ２ , 480 mg / m ２ , and 500 mg / m ２ The pharmaceutical composition according to any one of claims 1 to 9, wherein the composition is administered at a dose selected from the group consisting of:

14. The pharmaceutical composition contains 240 mg / m ２ , 260 mg / m ２ , 280 mg / m ２ , 300 mg / m ２ , 320 mg / m ２ , 340 mg / m ２ , 360 mg / m ２ , 380 mg / m ２ , 400 mg / m ２ , 420 mg / m ２ , 440 mg / m ２ , 460 mg / m ２ , 480 mg / m ２ , and 500 mg / m ２ The pharmaceutical composition according to any one of claims 1 to 9, 11 and 13, wherein the composition is administered at a dose selected from the group consisting of:

15. The pharmaceutical composition contains 240 mg / m ２ , 260 mg / m ２ , 280 mg / m ２ , 300 mg / m ２ , 320 mg / m ２ , 340 mg / m ２ , 360 mg / m ２ , 380 mg / m ２ , and 400 mg / m ２ The pharmaceutical composition according to any one of claims 1 to 14, wherein the composition is administered at a dose selected from the group consisting of:

16. The pharmaceutical composition contains 240 mg / m ２ , 260 mg / m ２ , 280 mg / m ２ , 300 mg / m ２ , 320 mg / m ２ , 340 mg / m ２ , and 360 mg / m ２ The pharmaceutical composition according to any one of claims 1 to 15, wherein the composition is administered at a dose selected from the group consisting of:

17. The pharmaceutical composition according to any one of claims 1 to 16, wherein the administration of the pharmaceutical composition is followed by a drug holiday of 14 days.

18. The pharmaceutical composition according to any one of claims 1 to 16, wherein the administration of the pharmaceutical composition is followed by a drug holiday of 21 days.

19. The pharmaceutical composition contains 240 mg / m ２ The pharmaceutical composition according to any one of claims 1 to 16, wherein the pharmaceutical composition is administered at a dose of 0.01 mg / kg or more, followed by a drug holiday of 14 days.

20. The pharmaceutical composition contains 240 mg / m ２ The pharmaceutical composition according to any one of claims 1 to 16, wherein the pharmaceutical composition is administered at a dose of 0.01 mg / kg or more, followed by a drug holiday of 21 days.

21. The pharmaceutical composition contains 120 mg / m ２ The pharmaceutical composition according to any one of claims 1 to 8, wherein the composition is administered at a dose of 0.01 mg / kg or more, followed by a drug holiday of 14 days.

22. The pharmaceutical composition contains 120 mg / m ２ The pharmaceutical composition according to any one of claims 1 to 8, wherein the pharmaceutical composition is administered at a dose of 0.01 mg / kg or more, followed by a drug holiday of 21 days.

23. The pharmaceutical composition according to any one of claims 1 to 16, wherein the pharmaceutical composition is administered once a day.

24. The pharmaceutical composition according to any one of claims 1 to 16, wherein the pharmaceutical composition is administered once every two days.

25. The pharmaceutical composition according to any one of claims 1 to 16, wherein the pharmaceutical composition is administered once a day for four weeks.

26. The pharmaceutical composition of any one of claims 1 to 16, wherein the pharmaceutical composition is administered once daily for four weeks, followed by a drug holiday.

27. 2. The method of claim 1, further comprising administering to a subject a compound of the following structural formula: 【Chemistry 2】 or a pharma- ceutically acceptable salt thereof.

28. 2. The method of claim 1, further comprising administering to a subject a compound of the following structural formula: 【Chemistry 3】 or a pharma- ceutical acceptable salt thereof.

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