Methods of treating pancreatic cancer using RAD51 inhibitors

Abstract

The present application relates to RAD51 inhibitors represented by the following structural formula and methods of using them, such as for treating pancreatic cancer.

Description

[0001] Related applications

[0002] This application claims priority to and the 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.

[0003] background

[0004] RAD51 is a eukaryotic gene. The protein encoded by this gene is a member of the RAD51 protein family, which contributes to the repair of double-strand breaks in DNA. RAD51 family members are homologous to bacterial RecA, archaeal RadA and yeast RAD51. This protein is highly conserved in most eukaryotic organisms from yeast to humans. In humans, RAD51 is a 339 amino acid protein that plays a major role in the homologous recombination of DNA during double-strand break (DSB) repair. RAD51 catalyzes the chain transfer between the break sequence and its undamaged homolog to allow the resynthesis of the damaged area (see homologous recombination model).

[0005] Studies have demonstrated sensitivity to certain DNA-damaging therapies associated with cellular defects in proteins that promote HR DNA repair. This sensitivity is particularly pronounced to DNA-crosslinking chemotherapeutic 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 instabilityand defective recombinational repair in knockout mutants of the five Rad51 paralogs,” Mol. Cell Biol., 21:2858-2866, 2001; Liu et al., "XRCC2 and XRCC3, newhuman Rad51-family members, promote chromosome stability and protect against DNA cross-links and other damages," Mol. Cell, 1:783-793, 1998).

[0006] Several groups have recently demonstrated that HR can be partially inhibited to sensitize cells to DNA damage therapies. Using a synthetic peptide corresponding to another paralogous protein, inhibition of XRCC3 (RAD51 paralogous protein) has been demonstrated. This peptide sensitizes Chinese hamster ovary (CHO) cells to cisplatin and inhibits the formation of subnuclear RAD51 centers in response to DNA damage (Connell et al., Cancer Res., 64:3002-3005, 2004). Other researchers have 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 BRC peptide fragment derived from BRCA2 (Chen et al., J. Biol. Chem., 274:32931-32935, 1999). Given the link between increased sensitivity to certain DNA damaging therapies and cellular defects in HR DNA repair-related proteins, there is a need for additional compounds that inhibit RAD51.

[0007] While AID expression is usually transient and restricted to activated B cells, several cancers display constitutive ectopic AID expression, including pancreatic cancer. AID is a promiscuous DNA-damaging enzyme that targets a wide range of locations throughout the genome, leading to high levels of DNA replication stress. AID-expressing cells are critically dependent on the homologous recombination factor RAD51 to survive this DNA replication stress.

[0008] Overview

[0009] In one aspect, the present disclosure provides a method of treating pancreatic cancer, comprising administering to a subject in need thereof a therapeutically effective dose of a composition of the disclosure, e.g., a composition comprising a RAD51 inhibitor of the disclosure.

[0010] In one aspect, the present disclosure provides a method of treating pancreatic cancer, comprising administering to a subject in need thereof a therapeutically effective dose of a RAD51 inhibitor of the present disclosure.

[0011] In one aspect, the present disclosure provides a method of treating pancreatic cancer, comprising administering to a subject in need thereof a therapeutically effective dose of Compound 67A or a pharmaceutically acceptable salt thereof.

[0012] In one aspect, the disclosure provides compositions (eg, compositions comprising a RAD51 inhibitor of the disclosure) for treating pancreatic cancer in a subject in need thereof.

[0013] In one aspect, the present disclosure provides a RAD51 inhibitor of the present disclosure for use in treating pancreatic cancer in a subject in need thereof.

[0014] 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.

[0015] In one aspect, described herein is the use of a composition (eg, a composition comprising a RAD51 inhibitor of the disclosure) in the preparation of a medicament for treating pancreatic cancer in a subject in need thereof.

[0016] In one aspect, described herein is a use of a RAD51 inhibitor of the present disclosure in the preparation of a medicament for treating pancreatic cancer in a subject in need thereof.

[0017] In one aspect, described herein is the use of Compound 67A, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating pancreatic cancer in a subject in need thereof.

[0018] 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 and resulting in a reduced ability to form an active complex with RAD51. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] Figure 1 Methods are shown for three pancreatic PDX models treated with vehicle or Compound 67A at 80 mg / kg once daily or 1 and 40 mg / kg once daily.

[0021] Figures 2A-2B Shown are re-randomized treatments of Model 1, Model 2, and Model 3 with vehicle and 1 mg / kg of Compound 67A, divided into three groups (i.e., vehicle, 1 mg / kg, and 80 mg / kg; Figure 2A ); and re-randomized treatment with 40 mg / kg and 80 mg / kg of compound 67A, with the treatment group divided into three groups (i.e., 80 mg / kg, 80 mg / kg after a 14-day off-administration period, and 80 mg / kg after a 21-day off-administration period; Figure 2B ).

[0022] Figures 3A-3B The antitumor activity of compound 67A was measured by tumor volume in Model 1 ( Figure 3A ) and percentage of tumor growth inhibition ( Figure 3B ).

[0023] Figures 4A-4B The antitumor activity of compound 67A was measured by tumor volume in Model 2 ( Figure 4A ) and percentage of tumor growth inhibition ( Figure 4B ).

[0024] Figures 5A-5B The antitumor activity of compound 67A was measured by tumor volume in Model 3 ( Figure 5A ) and percentage of tumor growth inhibition ( Figure 5B ).

[0025] Figures 6A-6C The antitumor activity of compound 67A was measured by tumor volume in Model 2 ( Figure 6A ), the change of tumor volume on day 49 compared with day 0 ( Figure 6B ) and progression-free survival ( Figure 6C ).

[0026] Figures 7A-7C show the antitumor activity of compound 67A in Model 2 as measured by tumor volume, following continuous administration of 80 mg / kg of compound 67A (Figure 7A), after a 14-day off-administration period (Figure 7B), and after a 21-day off-administration period (Figure 7C). Figure 7C ).

[0027] Figure 8A Shown is the antitumor activity of Compound 67A measured by tumor volume in PDX mouse model A following administration of 80 mg / kg of Compound 67A once daily or every other day.

[0028] Figure 8B Shown is the antitumor activity of Compound 67A 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.

[0029] Figure 9A Shown is the antitumor activity of Compound 67A measured by tumor volume in PDX mouse model B following daily or every other day administration of 80 mg / kg of Compound 67A.

[0030] Figure 9BShown is the antitumor activity of Compound 67A measured by tumor volume in PDX mouse model B after administration of 80 mg / kg of Compound 67A based on the tumor volume at the start of administration.

[0031] Figures 9C-9D The results were shown based on the period of cessation of administration ( Figure 9C ) and tumor growth during and after the cessation of administration ( Figure 9D ), Antitumor activity of compound 67A measured by tumor volume in PDX mouse model B after administration of 80 mg / kg of compound 67A.

[0032] Figure 10A Shown is the antitumor activity of Compound 67A measured by tumor volume in PDX mouse model C following administration of 80 mg / kg of Compound 67A once daily or every other day.

[0033] Figure 10B Shown is the antitumor activity of Compound 67A measured by tumor volume in PDX mouse model C after administration of 80 mg / kg of Compound 67A based on the tumor volume at the start of administration.

[0034] Figures 10C-10D The results were shown based on the period of cessation of administration ( Figure 9C ) and tumor growth during and after the cessation of administration ( Figure 9D ), Antitumor activity of compound 67A measured by tumor volume in PDX mouse model C after administration of 80 mg / kg of compound 67A.

[0035] Detailed description

[0036] Applicants have developed compounds that are potent inhibitors of RAD51 for the treatment of pancreatic cancer (see Examples 1-75). 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 normal and malignant cells. Some of these RAD51 inhibitors have excellent cell permeability, as measured in Caco-2 cells (see Example 76). Among the RAD51 inhibitors with good cell permeability, several have excellent metabolic stability (as measured by liver microsomal assays, see Example 77) and exposure, including oral exposure (see Example 79).

[0037] In certain embodiments, the present disclosure provides a method for 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 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, immunodeficiency, or neurodegenerative diseases.

[0038] In certain embodiments, described herein is a method of treating pancreatic cancer comprising administering to a subject in need thereof a therapeutically effective dose of a composition of the disclosure, e.g., a composition comprising a RAD51 inhibitor of the disclosure.

[0039] In certain embodiments, described herein is a method of treating pancreatic cancer comprising administering to a subject in need thereof a therapeutically effective dose of a RAD51 inhibitor of the disclosure.

[0040] In certain embodiments, described herein is a method of treating pancreatic cancer comprising administering to a subject in need thereof a therapeutically effective dose of Compound 67A or a pharmaceutically acceptable salt thereof.

[0041] In certain embodiments, described herein are compositions (eg, compositions comprising a RAD51 inhibitor of the disclosure) for treating pancreatic cancer in a subject in need thereof.

[0042] Described herein, in certain embodiments, are RAD51 inhibitors of the disclosure for use in treating pancreatic cancer in a subject in need thereof.

[0043] In certain embodiments, described herein is Compound 67A, or a pharmaceutically acceptable salt thereof, for use in treating pancreatic cancer in a subject in need thereof.

[0044] In certain embodiments, described herein are uses of compositions (eg, compositions comprising a RAD51 inhibitor of the disclosure) for treating pancreatic cancer in a subject in need thereof.

[0045] In certain embodiments, described herein are uses of a RAD51 inhibitor of the present disclosure for treating pancreatic cancer in a subject in need thereof.

[0046] In certain embodiments, described herein are uses of Compound 67A, or a pharmaceutically acceptable salt thereof, for treating pancreatic cancer in a subject in need thereof.

[0047] In certain embodiments, described herein is the use of a composition (e.g., a composition comprising a RAD51 inhibitor of the disclosure) in the preparation of a medicament for treating pancreatic cancer in a subject in need thereof.

[0048] In certain embodiments, described herein are uses of a RAD51 inhibitor of the present disclosure in the preparation of a medicament for treating pancreatic cancer in a subject in need thereof.

[0049] In certain embodiments, described herein is the use of Compound 67A, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating pancreatic cancer in a subject in need thereof.

[0050] In certain embodiments, the subject is a mammal.

[0051] In certain embodiments, the subject is a human.

[0052] In certain embodiments, the dosage is about 1 mg / m 2 to about 500 mg / m 2 The RAD51 inhibitor is administered at a dose within a range (e.g., a human dose).

[0053] In certain embodiments, the dosage is about 2 mg / m 2 to about 500 mg / m 2 The RAD51 inhibitor is administered at a dose within a range (e.g., a human dose).

[0054] In certain embodiments, the dosage is about 3 mg / m 2 to about 500 mg / m 2 The RAD51 inhibitor is administered at a dose within a range (e.g., a human dose).

[0055] In certain embodiments, the dosage is about 1 mg / m 2 to about 400 mg / m 2 The RAD51 inhibitor is administered at a dose within a range (e.g., a human dose).

[0056] In certain embodiments, the dosage is about 2 mg / m 2 to about 400 mg / m 2 The RAD51 inhibitor is administered at a dose within a range (e.g., a human dose).

[0057] In certain embodiments, the dosage is about 3 mg / m 2 to about 400 mg / m 2 The RAD51 inhibitor is administered at a dose within a range (e.g., a human dose).

[0058] In certain embodiments, the dosage is about 1 mg / m 2 to about 300 mg / m 2The RAD51 inhibitor is administered at a dose within a range (e.g., a human dose).

[0059] In certain embodiments, the dosage is about 2 mg / m 2 to about 300 mg / m 2 The RAD51 inhibitor is administered at a dose within a range (e.g., a human dose).

[0060] In certain embodiments, the dosage is about 3 mg / m 2 to about 300 mg / m 2 The RAD51 inhibitor is administered at a dose within a range (e.g., a human dose).

[0061] In certain embodiments, the dosage is about 1 mg / m 2 to about 280 mg / m 2 The RAD51 inhibitor is administered at a dose within a range (e.g., a human dose).

[0062] In certain embodiments, the dosage is about 1 mg / m 2 to about 260 mg / m 2 The RAD51 inhibitor is administered at a dose within a range (e.g., a human dose).

[0063] In certain embodiments, the dosage is about 1 mg / m 2 to about 240 mg / m 2 The RAD51 inhibitor is administered at a dose within a range (e.g., a human dose).

[0064] In certain embodiments, the dosage is about 1 mg / m 2 to about 220 mg / m 2 The RAD51 inhibitor is administered at a dose within a range (e.g., a human dose).

[0065] In certain embodiments, the dosage is about 1 mg / m 2 to about 200 mg / m 2 The RAD51 inhibitor is administered at a dose within a range (e.g., a human dose).

[0066] In certain embodiments, the dosage is about 1 mg / m 2 to about 180 mg / m 2 The RAD51 inhibitor is administered at a dose within a range (e.g., a human dose).

[0067] In certain embodiments, the dosage is about 1 mg / m 2 to about 160 mg / m 2 The RAD51 inhibitor is administered at a dose within a range (e.g., a human dose).

[0068] In certain embodiments, the dosage is about 1 mg / m 2 to about 140 mg / m 2 The RAD51 inhibitor is administered at a dose within a range (e.g., a human dose).

[0069] In certain embodiments, the dosage is about 1 mg / m 2 to about 120 mg / m 2 The RAD51 inhibitor is administered at a dose within a range (e.g., a human dose).

[0070] In certain embodiments, the dosage is about 1 mg / m 2 to about 100 mg / m 2 The RAD51 inhibitor is administered at a dose within a range (e.g., a human dose).

[0071] In certain embodiments, the dosage is about 2 mg / m 2 to about 280 mg / m 2 The RAD51 inhibitor is administered at a dose within a range (e.g., a human dose).

[0072] In certain embodiments, the dosage is about 2 mg / m 2 to about 260 mg / m 2 The RAD51 inhibitor is administered at a dose within a range (e.g., a human dose).

[0073] In certain embodiments, the dosage is about 2 mg / m 2 to about 240 mg / m 2 The RAD51 inhibitor is administered at a dose within a range (e.g., a human dose).

[0074] In certain embodiments, the dosage is about 2 mg / m 2 to about 220 mg / m 2 The RAD51 inhibitor is administered at a dose within a range (e.g., a human dose).

[0075] In certain embodiments, the dosage is about 2 mg / m 2 to about 200 mg / m 2 The RAD51 inhibitor is administered at a dose within a range (e.g., a human dose).

[0076] In certain embodiments, the dosage is about 2 mg / m 2 to about 180 mg / m 2 The RAD51 inhibitor is administered at a dose within a range (e.g., a human dose).

[0077] In certain embodiments, the dosage is about 2 mg / m2 to about 160 mg / m 2 The RAD51 inhibitor is administered at a dose within a range (e.g., a human dose).

[0078] In certain embodiments, the dosage is about 2 mg / m 2 to about 140 mg / m 2 The RAD51 inhibitor is administered at a dose within a range (e.g., a human dose).

[0079] In certain embodiments, the dosage is about 2 mg / m 2 to about 120 mg / m 2 The RAD51 inhibitor is administered at a dose within a range (e.g., a human dose).

[0080] In certain embodiments, the dosage is about 2 mg / m 2 to about 100 mg / m 2 The RAD51 inhibitor is administered at a dose within a range (e.g., a human dose).

[0081] In certain embodiments, the dosage is about 3 mg / m 2 to about 280 mg / m 2 The RAD51 inhibitor is administered at a dose within a range (e.g., a human dose).

[0082] In certain embodiments, the dosage is about 3 mg / m 2 to about 260 mg / m 2 The RAD51 inhibitor is administered at a dose within a range (e.g., a human dose).

[0083] In certain embodiments, the dosage is about 3 mg / m 2 to about 240 mg / m 2 The RAD51 inhibitor is administered at a dose within a range (e.g., a human dose).

[0084] In certain embodiments, the dosage is about 3 mg / m 2 to about 220 mg / m 2 The RAD51 inhibitor is administered at a dose within a range (e.g., a human dose).

[0085] In certain embodiments, the dosage is about 3 mg / m 2 to about 200 mg / m 2 The RAD51 inhibitor is administered at a dose within a range (e.g., a human dose).

[0086] In certain embodiments, the dosage is about 3 mg / m 2 to about 180 mg / m 2The RAD51 inhibitor is administered at a dose within a range (e.g., a human dose).

[0087] In certain embodiments, the dosage is about 3 mg / m 2 to about 160 mg / m 2 The RAD51 inhibitor is administered at a dose within a range (e.g., a human dose).

[0088] In certain embodiments, the dosage is about 3 mg / m 2 to about 140 mg / m 2 The RAD51 inhibitor is administered at a dose within a range (e.g., a human dose).

[0089] In certain embodiments, the dosage is about 3 mg / m 2 to about 120 mg / m 2 The RAD51 inhibitor is administered at a dose within a range (e.g., a human dose).

[0090] In certain embodiments, the dosage is about 3 mg / m 2 to about 100 mg / m 2 The RAD51 inhibitor is administered at a dose within a range (e.g., a human dose).

[0091] In certain embodiments, the dosage is about 50 mg / m 2 to about 500 mg / m 2 The RAD51 inhibitor is administered at a dose within a range (e.g., a human dose).

[0092] In certain embodiments, the dosage is about 60 mg / m 2 to about 500 mg / m 2 The RAD51 inhibitor is administered at a dose within a range (e.g., a human dose).

[0093] In certain embodiments, the dosage is about 70 mg / m 2 to about 500 mg / m 2 The RAD51 inhibitor is administered at a dose within a range (e.g., a human dose).

[0094] In certain embodiments, the dosage is about 80 mg / m 2 to about 500 mg / m 2 The RAD51 inhibitor is administered at a dose within a range (e.g., a human dose).

[0095] In certain embodiments, the dosage is about 90 mg / m 2 to about 500 mg / m 2 The RAD51 inhibitor is administered at a dose within a range (e.g., a human dose).

[0096] In certain embodiments, at about 100 mg / m 2 to about 500 mg / m 2 The RAD51 inhibitor is administered at a dose within a range (e.g., a human dose).

[0097] In certain embodiments, the dosage is about 120 mg / m 2 to about 500 mg / m 2 The RAD51 inhibitor is administered at a dose within a range (e.g., a human dose).

[0098] In certain embodiments, the dosage is about 140 mg / m 2 to about 500 mg / m 2 The RAD51 inhibitor is administered at a dose within a range (e.g., a human dose).

[0099] In certain embodiments, the dosage is about 160 mg / m 2 to about 500 mg / m 2 The RAD51 inhibitor is administered at a dose within a range (e.g., a human dose).

[0100] In certain embodiments, the dosage is about 180 mg / m 2 to about 500 mg / m 2 The RAD51 inhibitor is administered at a dose within a range (e.g., a human dose).

[0101] In certain embodiments, at about 200 mg / m 2 to about 500 mg / m 2 The RAD51 inhibitor is administered at a dose within a range (e.g., a human dose).

[0102] In certain embodiments, the dosage is about 220 mg / m 2 to about 500 mg / m 2 The RAD51 inhibitor is administered at a dose within a range (e.g., a human dose).

[0103] In certain embodiments, the dosage is about 240 mg / m 2 to about 500 mg / m 2 The RAD51 inhibitor is administered at a dose within a range (e.g., a human dose).

[0104] In certain embodiments, the dosage is about 260 mg / m 2 to about 500 mg / m 2 The RAD51 inhibitor is administered at a dose within a range (e.g., a human dose).

[0105] In certain embodiments, the dosage is about 280 mg / m 2 to about 500 mg / m 2 The RAD51 inhibitor is administered at a dose within a range (e.g., a human dose).

[0106] In certain embodiments, the dosage is about 50 mg / m 2 to about 400 mg / m 2 The RAD51 inhibitor is administered at a dose within a range (e.g., a human dose).

[0107] In certain embodiments, the dosage is about 60 mg / m 2 to about 400 mg / m 2 The RAD51 inhibitor is administered at a dose within a range (e.g., a human dose).

[0108] In certain embodiments, the dosage is about 70 mg / m 2 to about 400 mg / m 2 The RAD51 inhibitor is administered at a dose within a range (e.g., a human dose).

[0109] In certain embodiments, the dosage is about 80 mg / m 2 to about 400 mg / m 2 The RAD51 inhibitor is administered at a dose within a range (e.g., a human dose).

[0110] In certain embodiments, the dosage is about 90 mg / m 2 to about 400 mg / m 2 The RAD51 inhibitor is administered at a dose within a range (e.g., a human dose).

[0111] In certain embodiments, at about 100 mg / m 2 to about 400 mg / m 2 The RAD51 inhibitor is administered at a dose within a range (e.g., a human dose).

[0112] In certain embodiments, the dosage is about 120 mg / m 2 to about 400 mg / m 2 The RAD51 inhibitor is administered at a dose within a range (e.g., a human dose).

[0113] In certain embodiments, the dosage is about 140 mg / m 2 to about 400 mg / m 2 The RAD51 inhibitor is administered at a dose within a range (e.g., a human dose).

[0114] In certain embodiments, the dosage is about 160 mg / m 2 to about 400 mg / m 2 The RAD51 inhibitor is administered at a dose within a range (e.g., a human dose).

[0115] In certain embodiments, the dosage is about 180 mg / m 2 to about 400 mg / m 2 The RAD51 inhibitor is administered at a dose within a range (e.g., a human dose).

[0116] In certain embodiments, at about 200 mg / m 2 to about 400 mg / m 2 The RAD51 inhibitor is administered at a dose within a range (e.g., a human dose).

[0117] In certain embodiments, the dosage is about 220 mg / m 2 to about 400 mg / m 2 The RAD51 inhibitor is administered at a dose within a range (e.g., a human dose).

[0118] In certain embodiments, the dosage is about 240 mg / m 2 to about 400 mg / m 2 The RAD51 inhibitor is administered at a dose within a range (e.g., a human dose).

[0119] In certain embodiments, the dosage is about 260 mg / m 2 to about 400 mg / m 2 The RAD51 inhibitor is administered at a dose within a range (e.g., a human dose).

[0120] In certain embodiments, the dosage is about 280 mg / m 2 to about 400 mg / m 2 The RAD51 inhibitor is administered at a dose within a range (e.g., a human dose).

[0121] In certain embodiments, the dosage is about 50 mg / m 2 to about 300 mg / m 2 The RAD51 inhibitor is administered at a dose within a range (e.g., a human dose).

[0122] In certain embodiments, the dosage is about 60 mg / m 2 to about 300 mg / m 2 The RAD51 inhibitor is administered at a dose within a range (e.g., a human dose).

[0123] In certain embodiments, the dosage is about 70 mg / m2 to about 300 mg / m 2 The RAD51 inhibitor is administered at a dose within a range (e.g., a human dose).

[0124] In certain embodiments, the dosage is about 80 mg / m 2 to about 300 mg / m 2 The RAD51 inhibitor is administered at a dose within a range (e.g., a human dose).

[0125] In certain embodiments, the dosage is about 90 mg / m 2 to about 300 mg / m 2 The RAD51 inhibitor is administered at a dose within a range (e.g., a human dose).

[0126] In certain embodiments, at about 100 mg / m 2 to about 300 mg / m 2 The RAD51 inhibitor is administered at a dose within a range (e.g., a human dose).

[0127] In certain embodiments, the dosage is about 120 mg / m 2 to about 300 mg / m 2 The RAD51 inhibitor is administered at a dose within a range (e.g., a human dose).

[0128] In certain embodiments, the dosage is about 140 mg / m 2 to about 300 mg / m 2 The RAD51 inhibitor is administered at a dose within a range (e.g., a human dose).

[0129] In certain embodiments, the dosage is about 160 mg / m 2 to about 300 mg / m 2 The RAD51 inhibitor is administered at a dose within a range (e.g., a human dose).

[0130] In certain embodiments, the dosage is about 180 mg / m 2 to about 300 mg / m 2 The RAD51 inhibitor is administered at a dose within a range (e.g., a human dose).

[0131] In certain embodiments, at about 200 mg / m 2 to about 300 mg / m 2 The RAD51 inhibitor is administered at a dose within a range (e.g., a human dose).

[0132] In certain embodiments, the dosage is about 220 mg / m 2 to about 300 mg / m2 The RAD51 inhibitor is administered at a dose within a range (e.g., a human dose).

[0133] In certain embodiments, the dosage is about 240 mg / m 2 to about 300 mg / m 2 The RAD51 inhibitor is administered at a dose within a range (e.g., a human dose).

[0134] In certain embodiments, the dosage is about 260 mg / m 2 to about 300 mg / m 2 The RAD51 inhibitor is administered at a dose within a range (e.g., a human dose).

[0135] In certain embodiments, the dosage is about 280 mg / m 2 to about 300 mg / m 2 The RAD51 inhibitor is administered at a dose within a range (e.g., a human dose).

[0136] In certain embodiments, the dosage is about 50 mg / m 2 to about 280 mg / m 2 The RAD51 inhibitor is administered at a dose within a range (e.g., a human dose).

[0137] In certain embodiments, the dosage is about 50 mg / m 2 to about 260 mg / m 2 The RAD51 inhibitor is administered at a dose within a range (e.g., a human dose).

[0138] In certain embodiments, the dosage is about 50 mg / m 2 to about 240 mg / m 2 The RAD51 inhibitor is administered at a dose within a range (e.g., a human dose).

[0139] In certain embodiments, the dosage is about 50 mg / m 2 to about 220 mg / m 2 The RAD51 inhibitor is administered at a dose within a range (e.g., a human dose).

[0140] In certain embodiments, the dosage is about 50 mg / m 2 to about 200 mg / m 2 The RAD51 inhibitor is administered at a dose within a range (e.g., a human dose).

[0141] In certain embodiments, the dosage is about 50 mg / m 2 to about 180 mg / m 2The RAD51 inhibitor is administered at a dose within a range (e.g., a human dose).

[0142] In certain embodiments, the dosage is about 50 mg / m 2 to about 160 mg / m 2 The RAD51 inhibitor is administered at a dose within a range (e.g., a human dose).

[0143] In certain embodiments, the dosage is about 50 mg / m 2 to about 140 mg / m 2 The RAD51 inhibitor is administered at a dose within a range (e.g., a human dose).

[0144] In certain embodiments, the dosage is about 60 mg / m 2 to about 280 mg / m 2 The RAD51 inhibitor is administered at a dose within a range (e.g., a human dose).

[0145] In certain embodiments, the dosage is about 60 mg / m 2 to about 260 mg / m 2 The RAD51 inhibitor is administered at a dose within a range (e.g., a human dose).

[0146] In certain embodiments, the dosage is about 60 mg / m 2 to about 240 mg / m 2 The RAD51 inhibitor is administered at a dose within a range (e.g., a human dose).

[0147] In certain embodiments, the dosage is about 60 mg / m 2 to about 220 mg / m 2 The RAD51 inhibitor is administered at a dose within a range (e.g., a human dose).

[0148] In certain embodiments, the dosage is about 60 mg / m 2 to about 200 mg / m 2 The RAD51 inhibitor is administered at a dose within a range (e.g., a human dose).

[0149] In certain embodiments, the dosage is about 60 mg / m 2 to about 180 mg / m 2 The RAD51 inhibitor is administered at a dose within a range (e.g., a human dose).

[0150] In certain embodiments, the dosage is about 60 mg / m 2 to about 160 mg / m 2 The RAD51 inhibitor is administered at a dose within a range (e.g., a human dose).

[0151] In certain embodiments, the dosage is about 60 mg / m 2 to about 140 mg / m 2 The RAD51 inhibitor is administered at a dose within a range (e.g., a human dose).

[0152] In certain embodiments, the dosage is about 70 mg / m 2 to about 280 mg / m 2 The RAD51 inhibitor is administered at a dose within a range (e.g., a human dose).

[0153] In certain embodiments, the dosage is about 70 mg / m 2 to about 260 mg / m 2 The RAD51 inhibitor is administered at a dose within a range (e.g., a human dose).

[0154] In certain embodiments, the dosage is about 70 mg / m 2 to about 240 mg / m 2 The RAD51 inhibitor is administered at a dose within a range (e.g., a human dose).

[0155] In certain embodiments, the dosage is about 70 mg / m 2 to about 220 mg / m 2 The RAD51 inhibitor is administered at a dose within a range (e.g., a human dose).

[0156] In certain embodiments, the dosage is about 70 mg / m 2 to about 200 mg / m 2 The RAD51 inhibitor is administered at a dose within a range (e.g., a human dose).

[0157] In certain embodiments, the dosage is about 70 mg / m 2 to about 180 mg / m 2 The RAD51 inhibitor is administered at a dose within a range (e.g., a human dose).

[0158] In certain embodiments, the dosage is about 70 mg / m 2 to about 160 mg / m 2 The RAD51 inhibitor is administered at a dose within a range (e.g., a human dose).

[0159] In certain embodiments, the dosage is about 70 mg / m 2 to about 140 mg / m 2 The RAD51 inhibitor is administered at a dose within a range (e.g., a human dose).

[0160] In certain embodiments, the dosage is about 80 mg / m 2 to about 280 mg / m 2 The RAD51 inhibitor is administered at a dose within a range (e.g., a human dose).

[0161] In certain embodiments, the dosage is about 80 mg / m 2 to about 260 mg / m 2 The RAD51 inhibitor is administered at a dose within a range (e.g., a human dose).

[0162] In certain embodiments, the dosage is about 80 mg / m 2 to about 240 mg / m 2 The RAD51 inhibitor is administered at a dose within a range (e.g., a human dose).

[0163] In certain embodiments, the dosage is about 80 mg / m 2 to about 220 mg / m 2 The RAD51 inhibitor is administered at a dose within a range (e.g., a human dose).

[0164] In certain embodiments, the dosage is about 80 mg / m 2 to about 200 mg / m 2 The RAD51 inhibitor is administered at a dose within a range (e.g., a human dose).

[0165] In certain embodiments, the dosage is about 80 mg / m 2 to about 180 mg / m 2 The RAD51 inhibitor is administered at a dose within a range (e.g., a human dose).

[0166] In certain embodiments, the dosage is about 80 mg / m 2 to about 160 mg / m 2 The RAD51 inhibitor is administered at a dose within a range (e.g., a human dose).

[0167] In certain embodiments, the dosage is about 80 mg / m 2 to about 140 mg / m 2 The RAD51 inhibitor is administered at a dose within a range (e.g., a human dose).

[0168] In certain embodiments, the dosage is about 90 mg / m 2 to about 280 mg / m 2 The RAD51 inhibitor is administered at a dose within a range (e.g., a human dose).

[0169] In certain embodiments, the dosage is about 90 mg / m2 to about 260 mg / m 2 The RAD51 inhibitor is administered at a dose within a range (e.g., a human dose).

[0170] In certain embodiments, the dosage is about 90 mg / m 2 to about 240 mg / m 2 The RAD51 inhibitor is administered at a dose within a range (e.g., a human dose).

[0171] In certain embodiments, the dosage is about 90 mg / m 2 to about 220 mg / m 2 The RAD51 inhibitor is administered at a dose within a range (e.g., a human dose).

[0172] In certain embodiments, the dosage is about 90 mg / m 2 to about 200 mg / m 2 The RAD51 inhibitor is administered at a dose within a range (e.g., a human dose).

[0173] In certain embodiments, the dosage is about 90 mg / m 2 to about 180 mg / m 2 The RAD51 inhibitor is administered at a dose within a range (e.g., a human dose).

[0174] In certain embodiments, the dosage is about 90 mg / m 2 to about 160 mg / m 2 The RAD51 inhibitor is administered at a dose within a range (e.g., a human dose).

[0175] In certain embodiments, the dosage is about 90 mg / m 2 to about 140 mg / m 2 The RAD51 inhibitor is administered at a dose within a range (e.g., a human dose).

[0176] In certain embodiments, at about 100 mg / m 2 to about 280 mg / m 2 The RAD51 inhibitor is administered at a dose within a range (e.g., a human dose).

[0177] In certain embodiments, at about 100 mg / m 2 to about 260 mg / m 2 The RAD51 inhibitor is administered at a dose within a range (e.g., a human dose).

[0178] In certain embodiments, at about 100 mg / m 2 to about 240 mg / m2 The RAD51 inhibitor is administered at a dose within a range (e.g., a human dose).

[0179] In certain embodiments, at about 100 mg / m 2 to about 220 mg / m 2 The RAD51 inhibitor is administered at a dose within a range (e.g., a human dose).

[0180] In certain embodiments, at about 100 mg / m 2 to about 200 mg / m 2 The RAD51 inhibitor is administered at a dose within a range (e.g., a human dose).

[0181] In certain embodiments, at about 100 mg / m 2 to about 180 mg / m 2 The RAD51 inhibitor is administered at a dose within a range (e.g., a human dose).

[0182] In certain embodiments, at about 100 mg / m 2 to about 160 mg / m 2 The RAD51 inhibitor is administered at a dose within a range (e.g., a human dose).

[0183] In certain embodiments, at about 100 mg / m 2 to about 140 mg / m 2 The RAD51 inhibitor is administered at a dose within a range (e.g., a human dose).

[0184] In certain embodiments, the dosage is about 50 mg / m 2 to about 240 mg / m 2 The RAD51 inhibitor is administered at a dose within a range (e.g., a human dose).

[0185] In certain embodiments, the dosage is about 60 mg / m 2 to about 240 mg / m 2 The RAD51 inhibitor is administered at a dose within a range (e.g., a human dose).

[0186] In certain embodiments, the dosage is about 70 mg / m 2 to about 240 mg / m 2 The RAD51 inhibitor is administered at a dose within a range (e.g., a human dose).

[0187] In certain embodiments, the dosage is about 80 mg / m 2 to about 240 mg / m 2The RAD51 inhibitor is administered at a dose within a range (e.g., a human dose).

[0188] In certain embodiments, the dosage is about 90 mg / m 2 to about 240 mg / m 2 The RAD51 inhibitor is administered at a dose within a range (e.g., a human dose).

[0189] In certain embodiments, at about 100 mg / m 2 to about 240 mg / m 2 The RAD51 inhibitor is administered at a dose within a range (e.g., a human dose).

[0190] In certain embodiments, the dosage is about 120 mg / m 2 to about 240 mg / m 2 The RAD51 inhibitor is administered at a dose within a range (e.g., a human dose).

[0191] In certain embodiments, at 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 80mg / 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 / m2 , 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 about 500 mg / m 2 The RAD51 inhibitor is administered at a dose (e.g., a human dose).

[0192] In certain embodiments, at 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 80mg / 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 about 300 mg / m 2 The RAD51 inhibitor is administered at a dose (e.g., a human dose).

[0193] In certain embodiments, at 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 / m2 , 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 The RAD51 inhibitor is administered at a dose (e.g., a human dose).

[0194] In certain embodiments, at about 3 mg / m 2 The RAD51 inhibitor is administered at a dose (e.g., a human dose).

[0195] In certain embodiments, at about 50 ± 45 mg / m 2 , 50±40 mg / m 2 , 50±35 mg / m 2 , 50±30 mg / m 2 , 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 The RAD51 inhibitor is administered at a dose (e.g., a human dose).

[0196] In certain embodiments, at about 50 mg / m 2 The RAD51 inhibitor is administered at a dose (e.g., a human dose).

[0197] In certain embodiments, at 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±9mg / 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±3mg / m 2 、120±2 mg / m 2 or 120 ± 1 mg / m 2 The RAD51 inhibitor is administered at a dose (e.g., a human dose).

[0198] In certain embodiments, at about 120 mg / m 2 The RAD51 inhibitor is administered at a dose (e.g., a human dose).

[0199] In certain embodiments, at 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 / m2 , 240±9mg / 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±3mg / m 2 , 240±2 mg / m 2 or 240 ± 1 mg / m 2 The RAD51 inhibitor is administered at a dose (e.g., a human dose).

[0200] In certain embodiments, at about 240 mg / m 2 The RAD51 inhibitor is administered at a dose (e.g., a human dose).

[0201] In certain embodiments, at 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±9mg / 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±3mg / m 2 、300±2 mg / m 2 or 300 ± 1 mg / m 2 The RAD51 inhibitor is administered at a dose (e.g., a human dose).

[0202] In certain embodiments, at about 300 mg / m2 The RAD51 inhibitor is administered at a dose (e.g., a human dose).

[0203] In certain embodiments, the RAD51 inhibitor is administered at a dose (eg, a human dose) in the range of about 50 mg / day to about 500 mg / day.

[0204] In certain embodiments, the RAD51 inhibitor is administered at a dose (eg, a human dose) in the range of about 60 mg / day to about 500 mg / day.

[0205] In certain embodiments, the RAD51 inhibitor is administered at a dose (eg, a human dose) in the range of about 70 mg / day to about 500 mg / day.

[0206] In certain embodiments, the RAD51 inhibitor is administered at a dose (eg, a human dose) in the range of about 80 mg / day to about 500 mg / day.

[0207] In certain embodiments, the RAD51 inhibitor is administered at a dose (eg, a human dose) in the range of about 90 mg / day to about 500 mg / day.

[0208] In certain embodiments, the RAD51 inhibitor is administered at a dose (eg, a human dose) in the range of about 100 mg / day to about 500 mg / day.

[0209] In certain embodiments, the RAD51 inhibitor is administered at a dose (eg, a human dose) in the range of about 150 mg / day to about 500 mg / day.

[0210] In certain embodiments, the RAD51 inhibitor is administered at a dose (eg, a human dose) in the range of about 200 mg / day to about 500 mg / day.

[0211] In certain embodiments, the RAD51 inhibitor is administered at a dose (eg, a human dose) in the range of about 250 mg / day to about 500 mg / day.

[0212] In certain embodiments, the RAD51 inhibitor is administered at a dose (eg, a human dose) in the range of about 300 mg / day to about 500 mg / day.

[0213] In certain embodiments, the RAD51 inhibitor is administered at a dose (eg, a human dose) in the range of about 350 mg / day to about 500 mg / day.

[0214] In certain embodiments, the RAD51 inhibitor is administered at a dose (eg, a human dose) in the range of about 400 mg / day to about 500 mg / day.

[0215] In certain embodiments, the RAD51 inhibitor is administered at a dose (eg, a human dose) in the range of about 450 mg / day to about 500 mg / day.

[0216] In certain embodiments, the RAD51 inhibitor is administered at a dose (eg, a human dose) in the range of about 50 mg / day to about 450 mg / day.

[0217] In certain embodiments, the RAD51 inhibitor is administered at a dose (eg, a human dose) in the range of about 60 mg / day to about 450 mg / day.

[0218] In certain embodiments, the RAD51 inhibitor is administered at a dose (eg, a human dose) in the range of about 70 mg / day to about 450 mg / day.

[0219] In certain embodiments, the RAD51 inhibitor is administered at a dose (eg, a human dose) in the range of about 80 mg / day to about 450 mg / day.

[0220] In certain embodiments, the RAD51 inhibitor is administered at a dose (eg, a human dose) in the range of about 90 mg / day to about 450 mg / day.

[0221] In certain embodiments, the RAD51 inhibitor is administered at a dose (eg, a human dose) in the range of about 100 mg / day to about 450 mg / day.

[0222] In certain embodiments, the RAD51 inhibitor is administered at a dose (eg, a human dose) in the range of about 150 mg / day to about 450 mg / day.

[0223] In certain embodiments, the RAD51 inhibitor is administered at a dose (eg, a human dose) in the range of about 200 mg / day to about 450 mg / day.

[0224] In certain embodiments, the RAD51 inhibitor is administered at a dose (eg, a human dose) in the range of about 250 mg / day to about 450 mg / day.

[0225] In certain embodiments, the RAD51 inhibitor is administered at a dose (eg, a human dose) in the range of about 300 mg / day to about 450 mg / day.

[0226] In certain embodiments, the RAD51 inhibitor is administered at a dose (eg, a human dose) in the range of about 350 mg / day to about 450 mg / day.

[0227] In certain embodiments, the RAD51 inhibitor is administered at a dose (eg, a human dose) in the range of about 400 mg / day to about 450 mg / day.

[0228] In certain embodiments, the RAD51 inhibitor is administered at a dose (eg, a human dose) in the range of about 50 mg / day to about 400 mg / day.

[0229] In certain embodiments, the RAD51 inhibitor is administered at a dose (eg, a human dose) in the range of about 60 mg / day to about 400 mg / day.

[0230] In certain embodiments, the RAD51 inhibitor is administered at a dose (eg, a human dose) in the range of about 70 mg / day to about 400 mg / day.

[0231] In certain embodiments, the RAD51 inhibitor is administered at a dose (eg, a human dose) in the range of about 80 mg / day to about 400 mg / day.

[0232] In certain embodiments, the RAD51 inhibitor is administered at a dose (eg, a human dose) in the range of about 90 mg / day to about 400 mg / day.

[0233] In certain embodiments, the RAD51 inhibitor is administered at a dose (eg, a human dose) in the range of about 100 mg / day to about 400 mg / day.

[0234] In certain embodiments, the RAD51 inhibitor is administered at a dose (eg, a human dose) in the range of about 150 mg / day to about 400 mg / day.

[0235] In certain embodiments, the RAD51 inhibitor is administered at a dose (eg, a human dose) in the range of about 200 mg / day to about 400 mg / day.

[0236] In certain embodiments, the RAD51 inhibitor is administered at a dose (eg, a human dose) in the range of about 250 mg / day to about 400 mg / day.

[0237] In certain embodiments, the RAD51 inhibitor is administered at a dose (eg, a human dose) in the range of about 300 mg / day to about 400 mg / day.

[0238] In certain embodiments, the RAD51 inhibitor is administered at a dose (eg, a human dose) in the range of about 350 mg / day to about 400 mg / day.

[0239] In certain embodiments, the RAD51 inhibitor is administered at a dose (eg, a human dose) in the range of about 50 mg / day to about 350 mg / day.

[0240] In certain embodiments, the RAD51 inhibitor is administered at a dose (eg, a human dose) in the range of about 60 mg / day to about 350 mg / day.

[0241] In certain embodiments, the RAD51 inhibitor is administered at a dose (eg, a human dose) in the range of about 70 mg / day to about 350 mg / day.

[0242] In certain embodiments, the RAD51 inhibitor is administered at a dose (eg, a human dose) in the range of about 80 mg / day to about 350 mg / day.

[0243] In certain embodiments, the RAD51 inhibitor is administered at a dose (eg, a human dose) in the range of about 90 mg / day to about 350 mg / day.

[0244] In certain embodiments, the RAD51 inhibitor is administered at a dose (eg, a human dose) in the range of about 100 mg / day to about 350 mg / day.

[0245] In certain embodiments, the RAD51 inhibitor is administered at a dose (eg, a human dose) in the range of about 150 mg / day to about 350 mg / day.

[0246] In certain embodiments, the RAD51 inhibitor is administered at a dose (eg, a human dose) in the range of about 200 mg / day to about 350 mg / day.

[0247] In certain embodiments, the RAD51 inhibitor is administered at a dose (eg, a human dose) in the range of about 250 mg / day to about 350 mg / day.

[0248] In certain embodiments, the RAD51 inhibitor is administered at a dose (eg, a human dose) in the range of about 300 mg / day to about 350 mg / day.

[0249] In certain embodiments, the RAD51 inhibitor is administered at a dose (eg, a human dose) in the range of about 50 mg / day to about 300 mg / day.

[0250] In certain embodiments, the RAD51 inhibitor is administered at a dose (eg, a human dose) in the range of about 60 mg / day to about 300 mg / day.

[0251] In certain embodiments, the RAD51 inhibitor is administered at a dose (eg, a human dose) in the range of about 70 mg / day to about 300 mg / day.

[0252] In certain embodiments, the RAD51 inhibitor is administered at a dose (eg, a human dose) in the range of about 80 mg / day to about 300 mg / day.

[0253] In certain embodiments, the RAD51 inhibitor is administered at a dose (eg, a human dose) in the range of about 90 mg / day to about 300 mg / day.

[0254] In certain embodiments, the RAD51 inhibitor is administered at a dose (eg, a human dose) in the range of about 100 mg / day to about 300 mg / day.

[0255] In certain embodiments, the RAD51 inhibitor is administered at a dose (eg, a human dose) in the range of about 150 mg / day to about 300 mg / day.

[0256] In certain embodiments, the RAD51 inhibitor is administered at a dose (eg, a human dose) in the range of about 200 mg / day to about 300 mg / day.

[0257] In certain embodiments, the RAD51 inhibitor is administered at a dose (eg, a human dose) in the range of about 250 mg / day to about 300 mg / day.

[0258] In certain embodiments, the RAD51 inhibitor is administered at a dose (eg, a human dose) in the range of about 50 mg / day to about 250 mg / day.

[0259] In certain embodiments, the RAD51 inhibitor is administered at a dose (eg, a human dose) in the range of about 60 mg / day to about 250 mg / day.

[0260] In certain embodiments, the RAD51 inhibitor is administered at a dose (eg, a human dose) in the range of about 70 mg / day to about 250 mg / day.

[0261] In certain embodiments, the RAD51 inhibitor is administered at a dose (eg, a human dose) in the range of about 80 mg / day to about 250 mg / day.

[0262] In certain embodiments, the RAD51 inhibitor is administered at a dose (eg, a human dose) in the range of about 90 mg / day to about 250 mg / day.

[0263] In certain embodiments, the RAD51 inhibitor is administered at a dose (eg, a human dose) in the range of about 100 mg / day to about 250 mg / day.

[0264] In certain embodiments, the RAD51 inhibitor is administered at a dose (eg, a human dose) in the range of about 150 mg / day to about 250 mg / day.

[0265] In certain embodiments, the RAD51 inhibitor is administered at a dose (eg, a human dose) in the range of about 200 mg / day to about 250 mg / day.

[0266] In certain embodiments, the RAD51 inhibitor is administered at a dose (eg, a human dose) in the range of about 50 mg / day to about 200 mg / day.

[0267] In certain embodiments, the RAD51 inhibitor is administered at a dose (eg, a human dose) in the range of about 60 mg / day to about 200 mg / day.

[0268] In certain embodiments, the RAD51 inhibitor is administered at a dose (eg, a human dose) in the range of about 70 mg / day to about 200 mg / day.

[0269] In certain embodiments, the RAD51 inhibitor is administered at a dose (eg, a human dose) in the range of about 80 mg / day to about 200 mg / day.

[0270] In certain embodiments, the RAD51 inhibitor is administered at a dose (eg, a human dose) in the range of about 90 mg / day to about 200 mg / day.

[0271] In certain embodiments, the RAD51 inhibitor is administered at a dose (eg, a human dose) in the range of about 100 mg / day to about 200 mg / day.

[0272] In certain embodiments, the RAD51 inhibitor is administered at a dose (eg, a human dose) in the range of about 150 mg / day to about 200 mg / day.

[0273] In certain embodiments, the RAD51 inhibitor is administered at a dose (eg, a human dose) in the range of about 50 mg / day to about 150 mg / day.

[0274] In certain embodiments, the RAD51 inhibitor is administered at a dose (eg, a human dose) in the range of about 60 mg / day to about 150 mg / day.

[0275] In certain embodiments, the RAD51 inhibitor is administered at a dose (eg, a human dose) in the range of about 70 mg / day to about 150 mg / day.

[0276] In certain embodiments, the RAD51 inhibitor is administered at a dose (eg, a human dose) in the range of about 80 mg / day to about 150 mg / day.

[0277] In certain embodiments, the RAD51 inhibitor is administered at a dose (eg, a human dose) in the range of about 90 mg / day to about 150 mg / day.

[0278] In certain embodiments, the RAD51 inhibitor is administered at a dose (eg, a human dose) in the range of about 100 mg / day to about 150 mg / day.

[0279] In certain embodiments, the RAD51 inhibitor is administered at a dose (eg, a human dose) in the range of about 50 mg / day to about 100 mg / day.

[0280] In certain embodiments, the RAD51 inhibitor is administered at a dose (eg, a human dose) in the range of about 60 mg / day to about 100 mg / day.

[0281] In certain embodiments, the RAD51 inhibitor is administered at a dose (eg, a human dose) in the range of about 70 mg / day to about 100 mg / day.

[0282] In certain embodiments, the RAD51 inhibitor is administered at a dose (eg, a human dose) in the range of about 80 mg / day to about 100 mg / day.

[0283] In certain embodiments, the RAD51 inhibitor is administered at a dose (eg, a human dose) in the range of about 90 mg / day to about 100 mg / day.

[0284] In certain embodiments, the RAD51 inhibitor is administered at a dose (eg, a human dose) in the range of about 50 mg / day to about 90 mg / day.

[0285] In certain embodiments, the RAD51 inhibitor is administered at a dose (eg, a human dose) in the range of about 60 mg / day to about 90 mg / day.

[0286] In certain embodiments, the RAD51 inhibitor is administered at a dose (eg, a human dose) in the range of about 70 mg / day to about 90 mg / day.

[0287] In certain embodiments, the RAD51 inhibitor is administered at a dose (eg, a human dose) in the range of about 80 mg / day to about 90 mg / day.

[0288] In certain embodiments, the RAD51 inhibitor is administered at a dose (eg, a human dose) in the range of about 50 mg / day to about 80 mg / day.

[0289] In certain embodiments, the RAD51 inhibitor is administered at a dose (eg, a human dose) in the range of about 60 mg / day to about 80 mg / day.

[0290] In certain embodiments, the RAD51 inhibitor is administered at a dose (eg, a human dose) in the range of about 70 mg / day to about 80 mg / day.

[0291] In certain embodiments, the RAD51 inhibitor is administered at a dose (eg, a human dose) in the range of about 50 mg / day to about 70 mg / day.

[0292] In certain embodiments, the RAD51 inhibitor is administered at a dose (eg, a human dose) in the range of about 60 mg / day to about 70 mg / day.

[0293] In certain embodiments, the RAD51 inhibitor is administered at a dose (eg, a human dose) in the range of about 50 mg / day to about 60 mg / day.

[0294] In certain embodiments, the dosage of levofloxacin is 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 The RAD51 inhibitor is administered at a dosage (e.g., a human dosage) of about 100 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, or about 300 mg / day.

[0295] In certain embodiments, the RAD51 inhibitor is administered at a dose of about 50 mg / day (eg, a human dose).

[0296] In certain embodiments, the RAD51 inhibitor is administered at a dose of about 60 mg / day (eg, a human dose).

[0297] In certain embodiments, the RAD51 inhibitor is administered at a dose of about 70 mg / day (eg, a human dose).

[0298] In certain embodiments, the RAD51 inhibitor is administered at a dose of about 80 mg / day (eg, a human dose).

[0299] In certain embodiments, the RAD51 inhibitor is administered at a dose of about 90 mg / day (eg, a human dose).

[0300] In certain embodiments, the RAD51 inhibitor is administered at a dose of about 100 mg / day (eg, a human dose).

[0301] In certain embodiments, the RAD51 inhibitor is administered at a dose of about 110 mg / day (eg, a human dose).

[0302] In certain embodiments, the RAD51 inhibitor is administered at a dose of about 120 mg / day (eg, a human dose).

[0303] In certain embodiments, the RAD51 inhibitor is administered at a dose of about 130 mg / day (eg, a human dose).

[0304] In certain embodiments, the RAD51 inhibitor is administered at a dose of about 140 mg / day (eg, a human dose).

[0305] In certain embodiments, the RAD51 inhibitor is administered at a dose of about 150 mg / day (eg, a human dose).

[0306] In certain embodiments, the RAD51 inhibitor is administered at a dose of about 160 mg / day (eg, a human dose).

[0307] In certain embodiments, the RAD51 inhibitor is administered at a dose of about 170 mg / day (eg, a human dose).

[0308] In certain embodiments, the RAD51 inhibitor is administered at a dose of about 180 mg / day (eg, a human dose).

[0309] In certain embodiments, the RAD51 inhibitor is administered at a dose of about 190 mg / day (eg, a human dose).

[0310] In certain embodiments, the RAD51 inhibitor is administered at a dose of about 200 mg / day (eg, a human dose).

[0311] In certain embodiments, the RAD51 inhibitor is administered at a dose of about 210 mg / day (eg, a human dose).

[0312] In certain embodiments, the RAD51 inhibitor is administered at a dose of about 220 mg / day (eg, a human dose).

[0313] In certain embodiments, the RAD51 inhibitor is administered at a dose of about 230 mg / day (eg, a human dose).

[0314] In certain embodiments, the RAD51 inhibitor is administered at a dose of about 240 mg / day (eg, a human dose).

[0315] In certain embodiments, the RAD51 inhibitor is administered at a dose of about 250 mg / day (eg, a human dose).

[0316] In certain embodiments, the RAD51 inhibitor is administered at a dose of about 260 mg / day (eg, a human dose).

[0317] In certain embodiments, the RAD51 inhibitor is administered at a dose of about 270 mg / day (eg, a human dose).

[0318] In certain embodiments, the RAD51 inhibitor is administered at a dose of about 280 mg / day (eg, a human dose).

[0319] In certain embodiments, the RAD51 inhibitor is administered at a dose of about 290 mg / day (eg, a human dose).

[0320] In certain embodiments, the RAD51 inhibitor is administered at a dose of about 300 mg / day (eg, a human dose).

[0321] In certain embodiments, the RAD51 inhibitor is administered at a dose of about 310 mg / day (eg, a human dose).

[0322] In certain embodiments, the RAD51 inhibitor is administered at a dose of about 320 mg / day (eg, a human dose).

[0323] In certain embodiments, the RAD51 inhibitor is administered at a dose of about 330 mg / day (eg, a human dose).

[0324] In certain embodiments, the RAD51 inhibitor is administered at a dose of about 340 mg / day (eg, a human dose).

[0325] In certain embodiments, the RAD51 inhibitor is administered at a dose of about 350 mg / day (eg, a human dose).

[0326] In certain embodiments, the RAD51 inhibitor is administered at a dose of about 360 mg / day (eg, a human dose).

[0327] In certain embodiments, the RAD51 inhibitor is administered at a dose of about 370 mg / day (eg, a human dose).

[0328] In certain embodiments, the RAD51 inhibitor is administered at a dose of about 380 mg / day (eg, a human dose).

[0329] In certain embodiments, the RAD51 inhibitor is administered at a dose of about 390 mg / day (eg, a human dose).

[0330] In certain embodiments, the RAD51 inhibitor is administered at a dose of about 400 mg / day (eg, a human dose).

[0331] In certain embodiments, the RAD51 inhibitor is administered at a dose of about 410 mg / day (eg, a human dose).

[0332] In certain embodiments, the RAD51 inhibitor is administered at a dose of about 420 mg / day (eg, a human dose).

[0333] In certain embodiments, the RAD51 inhibitor is administered at a dose of about 430 mg / day (eg, a human dose).

[0334] In certain embodiments, the RAD51 inhibitor is administered at a dose of about 440 mg / day (eg, a human dose).

[0335] In certain embodiments, the RAD51 inhibitor is administered at a dose of about 450 mg / day (eg, a human dose).

[0336] In certain embodiments, the RAD51 inhibitor is administered at a dose of about 460 mg / day (eg, a human dose).

[0337] In certain embodiments, the RAD51 inhibitor is administered at a dose of about 470 mg / day (eg, a human dose).

[0338] In certain embodiments, the RAD51 inhibitor is administered at a dose of about 480 mg / day (eg, a human dose).

[0339] In certain embodiments, the RAD51 inhibitor is administered at a dose of about 490 mg / day (eg, a human dose).

[0340] In certain embodiments, the RAD51 inhibitor is administered at a dose of about 500 mg / day (eg, a human dose).

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

[0342] In certain embodiments, the RAD51 inhibitor is administered once daily, eg, at any dose described herein, once a week.

[0343] In certain embodiments, the RAD51 inhibitor is administered once daily, eg, at any dose described herein, 2 days per week.

[0344] In certain embodiments, the RAD51 inhibitor is administered once daily, eg, at any dose described herein, 3 days per week.

[0345] In certain embodiments, the RAD51 inhibitor is administered once daily, eg, at any dose described herein, 4 days per week.

[0346] In certain embodiments, the RAD51 inhibitor is administered once daily, eg, at any dose described herein, 5 days per week.

[0347] In certain embodiments, the RAD51 inhibitor is administered once daily, eg, at any dose described herein, 6 days per week.

[0348] In certain embodiments, the RAD51 inhibitor is administered once daily, eg, at any dose described herein, 7 days per week.

[0349] In certain embodiments, the RAD51 inhibitor is administered once daily, eg, at any dose described herein, for 2 weeks.

[0350] In certain embodiments, the RAD51 inhibitor is administered once daily, eg, at any dose described herein, for 3 weeks.

[0351] In certain embodiments, the RAD51 inhibitor is administered once daily, eg, at any dose described herein, for 4 weeks.

[0352] In certain embodiments, the RAD51 inhibitor is administered, eg, at any dose described herein, once every other day.

[0353] In certain embodiments, the RAD51 inhibitor is administered, eg, at any dose described herein, every other day for 4 days.

[0354] In certain embodiments, the RAD51 inhibitor is administered, eg, at any dose described herein, every other day for 6 days.

[0355] In certain embodiments, the RAD51 inhibitor is administered, eg, at any dose described herein, every other day for 2 weeks.

[0356] In certain embodiments, the RAD51 inhibitor is administered, eg, at any dose described herein, every other day for 3 weeks.

[0357] In certain embodiments, the RAD51 inhibitor is administered, eg, at any dose described herein, every other day for 4 weeks.

[0358] In certain embodiments, the RAD51 inhibitor is administered, eg, at any dose described herein, without a rest period.

[0359] In certain embodiments, administration of the RAD51 inhibitor, eg, at any dose described herein, is followed by a period of no administration.

[0360] In certain embodiments, the RAD51 inhibitor is administered, eg, at any dose described herein, for 2 weeks followed by a period of no administration.

[0361] In certain embodiments, the RAD51 inhibitor is administered, eg, at any dose described herein, for 3 weeks followed by a period of no administration.

[0362] In certain embodiments, the RAD51 inhibitor is administered, eg, at any dose described herein, for 4 weeks followed by a period of no administration.

[0363] In certain embodiments, administration of the RAD51 inhibitor, eg, at any dose described herein, is followed by a 7-day rest period.

[0364] In certain embodiments, administration of the RAD51 inhibitor, eg, at any dose described herein, is followed by a 14-day period off administration.

[0365] In certain embodiments, administration of the RAD51 inhibitor, eg, at any dose described herein, is followed by a 21-day period off administration.

[0366] In certain embodiments, administration of the RAD51 inhibitor, eg, at any dose described herein, is followed by a 28-day period off administration.

[0367] In certain embodiments, administration of the RAD51 inhibitor, eg, at any dose described herein, is followed by a 35-day period off administration.

[0368] In certain embodiments, administration of the RAD51 inhibitor, eg, at any dose described herein, is followed by a 42-day period off administration.

[0369] In certain embodiments, administration of the RAD51 inhibitor, eg, at any dose described herein, is followed by a 49-day period off administration.

[0370] In certain embodiments, at about 300 mg / m 2 The RAD51 inhibitor is administered, followed by a 7-day rest period.

[0371] In certain embodiments, at about 300 mg / m 2The RAD51 inhibitor is administered, followed by a 14-day off-administration period.

[0372] In certain embodiments, at about 300 mg / m 2 The RAD51 inhibitor was administered, followed by a 21-day off-administration period.

[0373] In certain embodiments, at about 300 mg / m 2 Administration of the RAD51 inhibitor is followed by a 28-day rest period.

[0374] In certain embodiments, at about 240 mg / m 2 The RAD51 inhibitor is administered, followed by a 7-day rest period.

[0375] In certain embodiments, at about 240 mg / m 2 Administration of the RAD51 inhibitor is followed by a 14-day off-administration period.

[0376] In certain embodiments, at about 240 mg / m 2 The RAD51 inhibitor was administered, followed by a 21-day off-administration period.

[0377] In certain embodiments, at about 240 mg / m 2 The RAD51 inhibitor is administered, followed by a 28-day off-administration period.

[0378] In certain embodiments, at about 120 mg / m 2 The RAD51 inhibitor is administered, followed by a 7-day rest period.

[0379] In certain embodiments, at about 120 mg / m 2 Administration of the RAD51 inhibitor is followed by a 14-day off-administration period.

[0380] In certain embodiments, at about 120 mg / m 2 The RAD51 inhibitor was administered, followed by a 21-day off-administration period.

[0381] In certain embodiments, at about 120 mg / m 2 Administration of the RAD51 inhibitor is followed by a 28-day rest period.

[0382] In certain embodiments, at about 50 mg / m 2 The RAD51 inhibitor is administered, followed by a 7-day rest period.

[0383] In certain embodiments, at about 50 mg / m 2Administration of the RAD51 inhibitor is followed by a 14-day off-administration period.

[0384] In certain embodiments, at about 50 mg / m 2 The RAD51 inhibitor was administered, followed by a 21-day off-administration period.

[0385] In certain embodiments, at about 50 mg / m 2 The RAD51 inhibitor is administered, followed by a 28-day off-administration period. In certain embodiments, the RAD51 inhibitor is compound 67A:

[0386] (Compound 67A)

[0387] or a pharmaceutically acceptable salt thereof.

[0388] In certain embodiments, the dosage is about 1 mg / m 2 to about 500 mg / m 2 Compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose within a range (e.g., a human dose).

[0389] In certain embodiments, the dosage is about 2 mg / m 2 to about 500 mg / m 2 Compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose within a range (e.g., a human dose).

[0390] In certain embodiments, the dosage is about 3 mg / m 2 to about 500 mg / m 2 Compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose within a range (e.g., a human dose).

[0391] In certain embodiments, the dosage is about 1 mg / m 2 to about 400 mg / m 2 Compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose within a range (e.g., a human dose).

[0392] In certain embodiments, the dosage is about 2 mg / m 2 to about 400 mg / m 2 Compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose within a range (e.g., a human dose).

[0393] In certain embodiments, the dosage is about 3 mg / m 2 to about 400 mg / m 2 Compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose within a range (e.g., a human dose).

[0394] In certain embodiments, the dosage is about 1 mg / m 2 to about 300 mg / m 2 Compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose within a range (e.g., a human dose).

[0395] In certain embodiments, the dosage is about 2 mg / m 2 to about 300 mg / m 2 Compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose within a range (e.g., a human dose).

[0396] In certain embodiments, the dosage is about 3 mg / m 2 to about 300 mg / m 2 Compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose within a range (e.g., a human dose).

[0397] In certain embodiments, the dosage is about 1 mg / m 2 to about 280 mg / m 2 Compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose within a range (e.g., a human dose).

[0398] In certain embodiments, the dosage is about 1 mg / m 2 to about 260 mg / m 2 Compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose within a range (e.g., a human dose).

[0399] In certain embodiments, the dosage is about 1 mg / m 2 to about 240 mg / m 2 Compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose within a range (e.g., a human dose).

[0400] In certain embodiments, the dosage is about 1 mg / m 2 to about 220 mg / m 2 Compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose within a range (e.g., a human dose).

[0401] In certain embodiments, the dosage is about 1 mg / m 2 to about 200 mg / m 2 Compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose within a range (e.g., a human dose).

[0402] In certain embodiments, the dosage is about 1 mg / m 2 to about 180 mg / m 2Compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose within a range (e.g., a human dose).

[0403] In certain embodiments, the dosage is about 1 mg / m 2 to about 160 mg / m 2 Compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose within a range (e.g., a human dose).

[0404] In certain embodiments, the dosage is about 1 mg / m 2 to about 140 mg / m 2 Compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose within a range (e.g., a human dose).

[0405] In certain embodiments, the dosage is about 1 mg / m 2 to about 120 mg / m 2 Compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose within a range (e.g., a human dose).

[0406] In certain embodiments, the dosage is about 1 mg / m 2 to about 100 mg / m 2 Compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose within a range (e.g., a human dose).

[0407] In certain embodiments, the dosage is about 2 mg / m 2 to about 280 mg / m 2 Compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose within a range (e.g., a human dose).

[0408] In certain embodiments, the dosage is about 2 mg / m 2 to about 260 mg / m 2 Compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose within a range (e.g., a human dose).

[0409] In certain embodiments, the dosage is about 2 mg / m 2 to about 240 mg / m 2 Compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose within a range (e.g., a human dose).

[0410] In certain embodiments, the dosage is about 2 mg / m 2 to about 220 mg / m 2 Compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose within a range (e.g., a human dose).

[0411] In certain embodiments, the dosage is about 2 mg / m 2to about 200 mg / m 2 Compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose within a range (e.g., a human dose).

[0412] In certain embodiments, the dosage is about 2 mg / m 2 to about 180 mg / m 2 Compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose within a range (e.g., a human dose).

[0413] In certain embodiments, the dosage is about 2 mg / m 2 to about 160 mg / m 2 Compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose within a range (e.g., a human dose).

[0414] In certain embodiments, the dosage is about 2 mg / m 2 to about 140 mg / m 2 Compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose within a range (e.g., a human dose).

[0415] In certain embodiments, the dosage is about 2 mg / m 2 to about 120 mg / m 2 Compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose within a range (e.g., a human dose).

[0416] In certain embodiments, the dosage is about 2 mg / m 2 to about 100 mg / m 2 Compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose within a range (e.g., a human dose).

[0417] In certain embodiments, the dosage is about 3 mg / m 2 to about 280 mg / m 2 Compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose within a range (e.g., a human dose).

[0418] In certain embodiments, the dosage is about 3 mg / m 2 to about 260 mg / m 2 Compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose within a range (e.g., a human dose).

[0419] In certain embodiments, the dosage is about 3 mg / m 2 to about 240 mg / m 2 Compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose within a range (e.g., a human dose).

[0420] In certain embodiments, the dosage is about 3 mg / m 2 to about 220 mg / m 2 Compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose within a range (e.g., a human dose).

[0421] In certain embodiments, the dosage is about 3 mg / m 2 to about 200 mg / m 2 Compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose within a range (e.g., a human dose).

[0422] In certain embodiments, the dosage is about 3 mg / m 2 to about 180 mg / m 2 Compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose within a range (e.g., a human dose).

[0423] In certain embodiments, the dosage is about 3 mg / m 2 to about 160 mg / m 2 Compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose within a range (e.g., a human dose).

[0424] In certain embodiments, the dosage is about 3 mg / m 2 to about 140 mg / m 2 Compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose within a range (e.g., a human dose).

[0425] In certain embodiments, the dosage is about 3 mg / m 2 to about 120 mg / m 2 Compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose within a range (e.g., a human dose).

[0426] In certain embodiments, the dosage is about 3 mg / m 2 to about 100 mg / m 2 Compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose within a range (e.g., a human dose).

[0427] In certain embodiments, the dosage is about 50 mg / m 2 to about 500 mg / m 2 Compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose within a range (e.g., a human dose).

[0428] In certain embodiments, the dosage is about 60 mg / m 2 to about 500 mg / m 2 Compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose within a range (e.g., a human dose).

[0429] In certain embodiments, the dosage is about 70 mg / m 2 to about 500 mg / m 2 Compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose within a range (e.g., a human dose).

[0430] In certain embodiments, the dosage is about 80 mg / m 2 to about 500 mg / m 2 Compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose within a range (e.g., a human dose).

[0431] In certain embodiments, the dosage is about 90 mg / m 2 to about 500 mg / m 2 Compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose within a range (e.g., a human dose).

[0432] In certain embodiments, at about 100 mg / m 2 to about 500 mg / m 2 Compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose within a range (e.g., a human dose).

[0433] In certain embodiments, the dosage is about 120 mg / m 2 to about 500 mg / m 2 Compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose within a range (e.g., a human dose).

[0434] In certain embodiments, the dosage is about 140 mg / m 2 to about 500 mg / m 2 Compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose within a range (e.g., a human dose).

[0435] In certain embodiments, the dosage is about 160 mg / m 2 to about 500 mg / m 2 Compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose within a range (e.g., a human dose).

[0436] In certain embodiments, the dosage is about 180 mg / m 2 to about 500 mg / m 2 Compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose within a range (e.g., a human dose).

[0437] In certain embodiments, at about 200 mg / m 2 to about 500 mg / m 2Compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose within a range (e.g., a human dose).

[0438] In certain embodiments, the dosage is about 220 mg / m 2 to about 500 mg / m 2 Compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose within a range (e.g., a human dose).

[0439] In certain embodiments, the dosage is about 240 mg / m 2 to about 500 mg / m 2 Compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose within a range (e.g., a human dose).

[0440] In certain embodiments, the dosage is about 260 mg / m 2 to about 500 mg / m 2 Compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose within a range (e.g., a human dose).

[0441] In certain embodiments, the dosage is about 280 mg / m 2 to about 500 mg / m 2 Compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose within a range (e.g., a human dose).

[0442] In certain embodiments, the dosage is about 50 mg / m 2 to about 400 mg / m 2 Compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose within a range (e.g., a human dose).

[0443] In certain embodiments, the dosage is about 60 mg / m 2 to about 400 mg / m 2 Compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose within a range (e.g., a human dose).

[0444] In certain embodiments, the dosage is about 70 mg / m 2 to about 400 mg / m 2 Compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose within a range (e.g., a human dose).

[0445] In certain embodiments, the dosage is about 80 mg / m 2 to about 400 mg / m 2 Compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose within a range (e.g., a human dose).

[0446] In certain embodiments, the dosage is about 90 mg / m2 to about 400 mg / m 2 Compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose within a range (e.g., a human dose).

[0447] In certain embodiments, at about 100 mg / m 2 to about 400 mg / m 2 Compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose within a range (e.g., a human dose).

[0448] In certain embodiments, the dosage is about 120 mg / m 2 to about 400 mg / m 2 Compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose within a range (e.g., a human dose).

[0449] In certain embodiments, the dosage is about 140 mg / m 2 to about 400 mg / m 2 Compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose within a range (e.g., a human dose).

[0450] In certain embodiments, the dosage is about 160 mg / m 2 to about 400 mg / m 2 Compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose within a range (e.g., a human dose).

[0451] In certain embodiments, the dosage is about 180 mg / m 2 to about 400 mg / m 2 Compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose within a range (e.g., a human dose).

[0452] In certain embodiments, at about 200 mg / m 2 to about 400 mg / m 2 Compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose within a range (e.g., a human dose).

[0453] In certain embodiments, the dosage is about 220 mg / m 2 to about 400 mg / m 2 Compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose within a range (e.g., a human dose).

[0454] In certain embodiments, the dosage is about 240 mg / m 2 to about 400 mg / m 2 Compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose within a range (e.g., a human dose).

[0455] In certain embodiments, the dosage is about 260 mg / m 2 to about 400 mg / m 2 Compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose within a range (e.g., a human dose).

[0456] In certain embodiments, the dosage is about 280 mg / m 2 to about 400 mg / m 2 Compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose within a range (e.g., a human dose).

[0457] In certain embodiments, the dosage is about 50 mg / m 2 to about 300 mg / m 2 Compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose within a range (e.g., a human dose).

[0458] In certain embodiments, the dosage is about 60 mg / m 2 to about 300 mg / m 2 Compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose within a range (e.g., a human dose).

[0459] In certain embodiments, the dosage is about 70 mg / m 2 to about 300 mg / m 2 Compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose within a range (e.g., a human dose).

[0460] In certain embodiments, the dosage is about 80 mg / m 2 to about 300 mg / m 2 Compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose within a range (e.g., a human dose).

[0461] In certain embodiments, the dosage is about 90 mg / m 2 to about 300 mg / m 2 Compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose within a range (e.g., a human dose).

[0462] In certain embodiments, at about 100 mg / m 2 to about 300 mg / m 2 Compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose within a range (e.g., a human dose).

[0463] In certain embodiments, the dosage is about 120 mg / m 2 to about 300 mg / m 2Compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose within a range (e.g., a human dose).

[0464] In certain embodiments, the dosage is about 140 mg / m 2 to about 300 mg / m 2 Compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose within a range (e.g., a human dose).

[0465] In certain embodiments, the dosage is about 160 mg / m 2 to about 300 mg / m 2 Compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose within a range (e.g., a human dose).

[0466] In certain embodiments, the dosage is about 180 mg / m 2 to about 300 mg / m 2 Compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose within a range (e.g., a human dose).

[0467] In certain embodiments, at about 200 mg / m 2 to about 300 mg / m 2 Compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose within a range (e.g., a human dose).

[0468] In certain embodiments, the dosage is about 220 mg / m 2 to about 300 mg / m 2 Compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose within a range (e.g., a human dose).

[0469] In certain embodiments, the dosage is about 240 mg / m 2 to about 300 mg / m 2 Compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose within a range (e.g., a human dose).

[0470] In certain embodiments, the dosage is about 260 mg / m 2 to about 300 mg / m 2 Compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose within a range (e.g., a human dose).

[0471] In certain embodiments, the dosage is about 280 mg / m 2 to about 300 mg / m 2 Compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose within a range (e.g., a human dose).

[0472] In certain embodiments, the dosage is about 50 mg / m2 to about 280 mg / m 2 Compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose within a range (e.g., a human dose).

[0473] In certain embodiments, the dosage is about 50 mg / m 2 to about 260 mg / m 2 Compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose within a range (e.g., a human dose).

[0474] In certain embodiments, the dosage is about 50 mg / m 2 to about 240 mg / m 2 Compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose within a range (e.g., a human dose).

[0475] In certain embodiments, the dosage is about 50 mg / m 2 to about 220 mg / m 2 Compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose within a range (e.g., a human dose).

[0476] In certain embodiments, the dosage is about 50 mg / m 2 to about 200 mg / m 2 Compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose within a range (e.g., a human dose).

[0477] In certain embodiments, the dosage is about 50 mg / m 2 to about 180 mg / m 2 Compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose within a range (e.g., a human dose).

[0478] In certain embodiments, the dosage is about 50 mg / m 2 to about 160 mg / m 2 Compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose within a range (e.g., a human dose).

[0479] In certain embodiments, the dosage is about 50 mg / m 2 to about 140 mg / m 2 Compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose within a range (e.g., a human dose).

[0480] In certain embodiments, the dosage is about 60 mg / m 2 to about 280 mg / m 2 Compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose within a range (e.g., a human dose).

[0481] In certain embodiments, the dosage is about 60 mg / m 2 to about 260 mg / m 2 Compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose within a range (e.g., a human dose).

[0482] In certain embodiments, the dosage is about 60 mg / m 2 to about 240 mg / m 2 Compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose within a range (e.g., a human dose).

[0483] In certain embodiments, the dosage is about 60 mg / m 2 to about 220 mg / m 2 Compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose within a range (e.g., a human dose).

[0484] In certain embodiments, the dosage is about 60 mg / m 2 to about 200 mg / m 2 Compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose within a range (e.g., a human dose).

[0485] In certain embodiments, the dosage is about 60 mg / m 2 to about 180 mg / m 2 Compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose within a range (e.g., a human dose).

[0486] In certain embodiments, the dosage is about 60 mg / m 2 to about 160 mg / m 2 Compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose within a range (e.g., a human dose).

[0487] In certain embodiments, the dosage is about 60 mg / m 2 to about 140 mg / m 2 Compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose within a range (e.g., a human dose).

[0488] In certain embodiments, the dosage is about 70 mg / m 2 to about 280 mg / m 2 Compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose within a range (e.g., a human dose).

[0489] In certain embodiments, the dosage is about 70 mg / m 2 to about 260 mg / m 2Compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose within a range (e.g., a human dose).

[0490] In certain embodiments, the dosage is about 70 mg / m 2 to about 240 mg / m 2 Compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose within a range (e.g., a human dose).

[0491] In certain embodiments, the dosage is about 70 mg / m 2 to about 220 mg / m 2 Compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose within a range (e.g., a human dose).

[0492] In certain embodiments, the dosage is about 70 mg / m 2 to about 200 mg / m 2 Compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose within a range (e.g., a human dose).

[0493] In certain embodiments, the dosage is about 70 mg / m 2 to about 180 mg / m 2 Compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose within a range (e.g., a human dose).

[0494] In certain embodiments, the dosage is about 70 mg / m 2 to about 160 mg / m 2 Compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose within a range (e.g., a human dose).

[0495] In certain embodiments, the dosage is about 70 mg / m 2 to about 140 mg / m 2 Compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose within a range (e.g., a human dose).

[0496] In certain embodiments, the dosage is about 80 mg / m 2 to about 280 mg / m 2 Compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose within a range (e.g., a human dose).

[0497] In certain embodiments, the dosage is about 80 mg / m 2 to about 260 mg / m 2 Compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose within a range (e.g., a human dose).

[0498] In certain embodiments, the dosage is about 80 mg / m 2to about 240 mg / m 2 Compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose within a range (e.g., a human dose).

[0499] In certain embodiments, the dosage is about 80 mg / m 2 to about 220 mg / m 2 Compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose within a range (e.g., a human dose).

[0500] In certain embodiments, the dosage is about 80 mg / m 2 to about 200 mg / m 2 Compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose within a range (e.g., a human dose).

[0501] In certain embodiments, the dosage is about 80 mg / m 2 to about 180 mg / m 2 Compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose within a range (e.g., a human dose).

[0502] In certain embodiments, the dosage is about 80 mg / m 2 to about 160 mg / m 2 Compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose within a range (e.g., a human dose).

[0503] In certain embodiments, the dosage is about 80 mg / m 2 to about 140 mg / m 2 Compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose within a range (e.g., a human dose).

[0504] In certain embodiments, the dosage is about 90 mg / m 2 to about 280 mg / m 2 Compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose within a range (e.g., a human dose).

[0505] In certain embodiments, the dosage is about 90 mg / m 2 to about 260 mg / m 2 Compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose within a range (e.g., a human dose).

[0506] In certain embodiments, the dosage is about 90 mg / m 2 to about 240 mg / m 2 Compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose within a range (e.g., a human dose).

[0507] In certain embodiments, the dosage is about 90 mg / m 2 to about 220 mg / m 2 Compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose within a range (e.g., a human dose).

[0508] In certain embodiments, the dosage is about 90 mg / m 2 to about 200 mg / m 2 Compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose within a range (e.g., a human dose).

[0509] In certain embodiments, the dosage is about 90 mg / m 2 to about 180 mg / m 2 Compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose within a range (e.g., a human dose).

[0510] In certain embodiments, the dosage is about 90 mg / m 2 to about 160 mg / m 2 Compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose within a range (e.g., a human dose).

[0511] In certain embodiments, the dosage is about 90 mg / m 2 to about 140 mg / m 2 Compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose within a range (e.g., a human dose).

[0512] In certain embodiments, at about 100 mg / m 2 to about 280 mg / m 2 Compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose within a range (e.g., a human dose).

[0513] In certain embodiments, at about 100 mg / m 2 to about 260 mg / m 2 Compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose within a range (e.g., a human dose).

[0514] In certain embodiments, at about 100 mg / m 2 to about 240 mg / m 2 Compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose within a range (e.g., a human dose).

[0515] In certain embodiments, at about 100 mg / m 2 to about 220 mg / m 2Compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose within a range (e.g., a human dose).

[0516] In certain embodiments, at about 100 mg / m 2 to about 200 mg / m 2 Compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose within a range (e.g., a human dose).

[0517] In certain embodiments, at about 100 mg / m 2 to about 180 mg / m 2 Compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose within a range (e.g., a human dose).

[0518] In certain embodiments, at about 100 mg / m 2 to about 160 mg / m 2 Compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose within a range (e.g., a human dose).

[0519] In certain embodiments, at about 100 mg / m 2 to about 140 mg / m 2 Compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose within a range (e.g., a human dose).

[0520] In certain embodiments, the dosage is about 120 mg / m 2 to about 240 mg / m 2 Compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose within a range (e.g., a human dose).

[0521] In certain embodiments, at 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 80mg / m 2 , about 90 mg / m 2 , about 100 mg / m 2 , about 120 mg / m 2 , about 140 mg / m2 , 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 about 500 mg / m 2 Compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose (e.g., a human dose).

[0522] In certain embodiments, at 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 80mg / 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 about 300 mg / m 2 Compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose (e.g., a human dose).

[0523] In certain embodiments, at 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 Compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose (e.g., a human dose).

[0524] In certain embodiments, at about 3 mg / m 2 Compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose (e.g., a human dose).

[0525] In certain embodiments, at about 50 ± 2 mg / m 2 , 50±1.8 mg / m 2 , 50±1.6 mg / m 2 , 50±1.5mg / 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 / m2 , 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 Compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose (e.g., a human dose).

[0526] In certain embodiments, at about 50 mg / m 2 Compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose (e.g., a human dose).

[0527] In certain embodiments, at 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±9mg / 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±3mg / m 2 、120±2 mg / m 2 or 120 ± 1 mg / m 2 Compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose (e.g., a human dose).

[0528] In certain embodiments, at about 120 mg / m 2 Compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose (e.g., a human dose).

[0529] In certain embodiments, at 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±9mg / 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±3mg / m 2 , 240±2 mg / m 2 or 240 ± 1 mg / m 2 Compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose (e.g., a human dose).

[0530] In certain embodiments, at about 240 mg / m 2 Compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose (e.g., a human dose).

[0531] In certain embodiments, at 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 / m2 、300±20 mg / m 2 、300±15 mg / m 2 、300±10 mg / m 2 300±9mg / 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±3mg / m 2 、300±2 mg / m 2 or 300 ± 1 mg / m 2 Compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose (e.g., a human dose).

[0532] In certain embodiments, at about 300 mg / m 2 Compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose (e.g., a human dose).

[0533] In certain embodiments, Compound 67A, or a pharmaceutically acceptable salt thereof, is administered at a dose (eg, a human dose) in the range of about 50 mg / day to about 500 mg / day.

[0534] In certain embodiments, Compound 67A, or a pharmaceutically acceptable salt thereof, is administered at a dose (eg, a human dose) in the range of about 60 mg / day to about 500 mg / day.

[0535] In certain embodiments, Compound 67A, or a pharmaceutically acceptable salt thereof, is administered at a dose (eg, a human dose) in the range of about 70 mg / day to about 500 mg / day.

[0536] In certain embodiments, Compound 67A, or a pharmaceutically acceptable salt thereof, is administered at a dose (eg, a human dose) in the range of about 80 mg / day to about 500 mg / day.

[0537] In certain embodiments, Compound 67A, or a pharmaceutically acceptable salt thereof, is administered at a dose (eg, a human dose) in the range of about 90 mg / day to about 500 mg / day.

[0538] In certain embodiments, Compound 67A, or a pharmaceutically acceptable salt thereof, is administered at a dose (eg, a human dose) in the range of about 100 mg / day to about 500 mg / day.

[0539] In certain embodiments, Compound 67A, or a pharmaceutically acceptable salt thereof, is administered at a dose (eg, a human dose) in the range of about 150 mg / day to about 500 mg / day.

[0540] In certain embodiments, Compound 67A, or a pharmaceutically acceptable salt thereof, is administered at a dose (eg, a human dose) in the range of about 200 mg / day to about 500 mg / day.

[0541] In certain embodiments, Compound 67A, or a pharmaceutically acceptable salt thereof, is administered at a dose (eg, a human dose) in the range of about 250 mg / day to about 500 mg / day.

[0542] In certain embodiments, Compound 67A, or a pharmaceutically acceptable salt thereof, is administered at a dose (eg, a human dose) in the range of about 300 mg / day to about 500 mg / day.

[0543] In certain embodiments, Compound 67A, or a pharmaceutically acceptable salt thereof, is administered at a dose (eg, a human dose) in the range of about 350 mg / day to about 500 mg / day.

[0544] In certain embodiments, Compound 67A, or a pharmaceutically acceptable salt thereof, is administered at a dose (eg, a human dose) in the range of about 400 mg / day to about 500 mg / day.

[0545] In certain embodiments, Compound 67A, or a pharmaceutically acceptable salt thereof, is administered at a dose (eg, a human dose) in the range of about 450 mg / day to about 500 mg / day.

[0546] In certain embodiments, Compound 67A, or a pharmaceutically acceptable salt thereof, is administered at a dose (eg, a human dose) in the range of about 50 mg / day to about 450 mg / day.

[0547] In certain embodiments, Compound 67A, or a pharmaceutically acceptable salt thereof, is administered at a dose (eg, a human dose) in the range of about 60 mg / day to about 450 mg / day.

[0548] In certain embodiments, Compound 67A, or a pharmaceutically acceptable salt thereof, is administered at a dose (eg, a human dose) in the range of about 70 mg / day to about 450 mg / day.

[0549] In certain embodiments, Compound 67A, or a pharmaceutically acceptable salt thereof, is administered at a dose (eg, a human dose) in the range of about 80 mg / day to about 450 mg / day.

[0550] In certain embodiments, Compound 67A, or a pharmaceutically acceptable salt thereof, is administered at a dose (eg, a human dose) in the range of about 90 mg / day to about 450 mg / day.

[0551] In certain embodiments, Compound 67A, or a pharmaceutically acceptable salt thereof, is administered at a dose (eg, a human dose) in the range of about 100 mg / day to about 450 mg / day.

[0552] In certain embodiments, Compound 67A, or a pharmaceutically acceptable salt thereof, is administered at a dose (eg, a human dose) in the range of about 150 mg / day to about 450 mg / day.

[0553] In certain embodiments, Compound 67A, or a pharmaceutically acceptable salt thereof, is administered at a dose (eg, a human dose) in the range of about 200 mg / day to about 450 mg / day.

[0554] In certain embodiments, Compound 67A, or a pharmaceutically acceptable salt thereof, is administered at a dose (eg, a human dose) in the range of about 250 mg / day to about 450 mg / day.

[0555] In certain embodiments, Compound 67A, or a pharmaceutically acceptable salt thereof, is administered at a dose (eg, a human dose) in the range of about 300 mg / day to about 450 mg / day.

[0556] In certain embodiments, Compound 67A, or a pharmaceutically acceptable salt thereof, is administered at a dose (eg, a human dose) in the range of about 350 mg / day to about 450 mg / day.

[0557] In certain embodiments, Compound 67A, or a pharmaceutically acceptable salt thereof, is administered at a dose (eg, a human dose) in the range of about 400 mg / day to about 450 mg / day.

[0558] In certain embodiments, Compound 67A, or a pharmaceutically acceptable salt thereof, is administered at a dose (eg, a human dose) in the range of about 50 mg / day to about 400 mg / day.

[0559] In certain embodiments, Compound 67A, or a pharmaceutically acceptable salt thereof, is administered at a dose (eg, a human dose) in the range of about 60 mg / day to about 400 mg / day.

[0560] In certain embodiments, Compound 67A, or a pharmaceutically acceptable salt thereof, is administered at a dose (eg, a human dose) in the range of about 70 mg / day to about 400 mg / day.

[0561] In certain embodiments, Compound 67A, or a pharmaceutically acceptable salt thereof, is administered at a dose (eg, a human dose) in the range of about 80 mg / day to about 400 mg / day.

[0562] In certain embodiments, Compound 67A, or a pharmaceutically acceptable salt thereof, is administered at a dose (eg, a human dose) in the range of about 90 mg / day to about 400 mg / day.

[0563] In certain embodiments, Compound 67A, or a pharmaceutically acceptable salt thereof, is administered at a dose (eg, a human dose) in the range of about 100 mg / day to about 400 mg / day.

[0564] In certain embodiments, Compound 67A, or a pharmaceutically acceptable salt thereof, is administered at a dose (eg, a human dose) in the range of about 150 mg / day to about 400 mg / day.

[0565] In certain embodiments, Compound 67A, or a pharmaceutically acceptable salt thereof, is administered at a dose (eg, a human dose) in the range of about 200 mg / day to about 400 mg / day.

[0566] In certain embodiments, Compound 67A, or a pharmaceutically acceptable salt thereof, is administered at a dose (eg, a human dose) in the range of about 250 mg / day to about 400 mg / day.

[0567] In certain embodiments, Compound 67A, or a pharmaceutically acceptable salt thereof, is administered at a dose (eg, a human dose) in the range of about 300 mg / day to about 400 mg / day.

[0568] In certain embodiments, Compound 67A, or a pharmaceutically acceptable salt thereof, is administered at a dose (eg, a human dose) in the range of about 350 mg / day to about 400 mg / day.

[0569] In certain embodiments, Compound 67A, or a pharmaceutically acceptable salt thereof, is administered at a dose (eg, a human dose) in the range of about 50 mg / day to about 350 mg / day.

[0570] In certain embodiments, Compound 67A, or a pharmaceutically acceptable salt thereof, is administered at a dose (eg, a human dose) in the range of about 60 mg / day to about 350 mg / day.

[0571] In certain embodiments, Compound 67A, or a pharmaceutically acceptable salt thereof, is administered at a dose (eg, a human dose) in the range of about 70 mg / day to about 350 mg / day.

[0572] In certain embodiments, Compound 67A, or a pharmaceutically acceptable salt thereof, is administered at a dose (eg, a human dose) in the range of about 80 mg / day to about 350 mg / day.

[0573] In certain embodiments, Compound 67A, or a pharmaceutically acceptable salt thereof, is administered at a dose (eg, a human dose) in the range of about 90 mg / day to about 350 mg / day.

[0574] In certain embodiments, Compound 67A, or a pharmaceutically acceptable salt thereof, is administered at a dose (eg, a human dose) in the range of about 100 mg / day to about 350 mg / day.

[0575] In certain embodiments, Compound 67A, or a pharmaceutically acceptable salt thereof, is administered at a dose (eg, a human dose) in the range of about 150 mg / day to about 350 mg / day.

[0576] In certain embodiments, Compound 67A, or a pharmaceutically acceptable salt thereof, is administered at a dose (eg, a human dose) in the range of about 200 mg / day to about 350 mg / day.

[0577] In certain embodiments, Compound 67A, or a pharmaceutically acceptable salt thereof, is administered at a dose (eg, a human dose) in the range of about 250 mg / day to about 350 mg / day.

[0578] In certain embodiments, Compound 67A, or a pharmaceutically acceptable salt thereof, is administered at a dose (eg, a human dose) in the range of about 300 mg / day to about 350 mg / day.

[0579] In certain embodiments, Compound 67A, or a pharmaceutically acceptable salt thereof, is administered at a dose (eg, a human dose) in the range of about 50 mg / day to about 300 mg / day.

[0580] In certain embodiments, Compound 67A, or a pharmaceutically acceptable salt thereof, is administered at a dose (eg, a human dose) in the range of about 60 mg / day to about 300 mg / day.

[0581] In certain embodiments, Compound 67A, or a pharmaceutically acceptable salt thereof, is administered at a dose (eg, a human dose) in the range of about 70 mg / day to about 300 mg / day.

[0582] In certain embodiments, Compound 67A, or a pharmaceutically acceptable salt thereof, is administered at a dose (eg, a human dose) in the range of about 80 mg / day to about 300 mg / day.

[0583] In certain embodiments, Compound 67A, or a pharmaceutically acceptable salt thereof, is administered at a dose (eg, a human dose) in the range of about 90 mg / day to about 300 mg / day.

[0584] In certain embodiments, Compound 67A, or a pharmaceutically acceptable salt thereof, is administered at a dose (eg, a human dose) in the range of about 100 mg / day to about 300 mg / day.

[0585] In certain embodiments, Compound 67A, or a pharmaceutically acceptable salt thereof, is administered at a dose (eg, a human dose) in the range of about 150 mg / day to about 300 mg / day.

[0586] In certain embodiments, Compound 67A, or a pharmaceutically acceptable salt thereof, is administered at a dose (eg, a human dose) in the range of about 200 mg / day to about 300 mg / day.

[0587] In certain embodiments, Compound 67A, or a pharmaceutically acceptable salt thereof, is administered at a dose (eg, a human dose) in the range of about 250 mg / day to about 300 mg / day.

[0588] In certain embodiments, Compound 67A, or a pharmaceutically acceptable salt thereof, is administered at a dose (eg, a human dose) in the range of about 50 mg / day to about 250 mg / day.

[0589] In certain embodiments, Compound 67A, or a pharmaceutically acceptable salt thereof, is administered at a dose (eg, a human dose) in the range of about 60 mg / day to about 250 mg / day.

[0590] In certain embodiments, Compound 67A, or a pharmaceutically acceptable salt thereof, is administered at a dose (eg, a human dose) in the range of about 70 mg / day to about 250 mg / day.

[0591] In certain embodiments, Compound 67A, or a pharmaceutically acceptable salt thereof, is administered at a dose (eg, a human dose) in the range of about 80 mg / day to about 250 mg / day.

[0592] In certain embodiments, Compound 67A, or a pharmaceutically acceptable salt thereof, is administered at a dose (eg, a human dose) in the range of about 90 mg / day to about 250 mg / day.

[0593] In certain embodiments, Compound 67A, or a pharmaceutically acceptable salt thereof, is administered at a dose (eg, a human dose) in the range of about 100 mg / day to about 250 mg / day.

[0594] In certain embodiments, Compound 67A, or a pharmaceutically acceptable salt thereof, is administered at a dose (eg, a human dose) in the range of about 150 mg / day to about 250 mg / day.

[0595] In certain embodiments, Compound 67A, or a pharmaceutically acceptable salt thereof, is administered at a dose (eg, a human dose) in the range of about 200 mg / day to about 250 mg / day.

[0596] In certain embodiments, Compound 67A, or a pharmaceutically acceptable salt thereof, is administered at a dose (eg, a human dose) in the range of about 50 mg / day to about 200 mg / day.

[0597] In certain embodiments, Compound 67A, or a pharmaceutically acceptable salt thereof, is administered at a dose (eg, a human dose) in the range of about 60 mg / day to about 200 mg / day.

[0598] In certain embodiments, Compound 67A, or a pharmaceutically acceptable salt thereof, is administered at a dose (eg, a human dose) in the range of about 70 mg / day to about 200 mg / day.

[0599] In certain embodiments, Compound 67A, or a pharmaceutically acceptable salt thereof, is administered at a dose (eg, a human dose) in the range of about 80 mg / day to about 200 mg / day.

[0600] In certain embodiments, Compound 67A, or a pharmaceutically acceptable salt thereof, is administered at a dose (eg, a human dose) in the range of about 90 mg / day to about 200 mg / day.

[0601] In certain embodiments, Compound 67A, or a pharmaceutically acceptable salt thereof, is administered at a dose (eg, a human dose) in the range of about 100 mg / day to about 200 mg / day.

[0602] In certain embodiments, Compound 67A, or a pharmaceutically acceptable salt thereof, is administered at a dose (eg, a human dose) in the range of about 150 mg / day to about 200 mg / day.

[0603] In certain embodiments, Compound 67A, or a pharmaceutically acceptable salt thereof, is administered at a dose (eg, a human dose) in the range of about 50 mg / day to about 150 mg / day.

[0604] In certain embodiments, Compound 67A, or a pharmaceutically acceptable salt thereof, is administered at a dose (eg, a human dose) in the range of about 60 mg / day to about 150 mg / day.

[0605] In certain embodiments, Compound 67A, or a pharmaceutically acceptable salt thereof, is administered at a dose (eg, a human dose) in the range of about 70 mg / day to about 150 mg / day.

[0606] In certain embodiments, Compound 67A, or a pharmaceutically acceptable salt thereof, is administered at a dose (eg, a human dose) in the range of about 80 mg / day to about 150 mg / day.

[0607] In certain embodiments, Compound 67A, or a pharmaceutically acceptable salt thereof, is administered at a dose (eg, a human dose) in the range of about 90 mg / day to about 150 mg / day.

[0608] In certain embodiments, Compound 67A, or a pharmaceutically acceptable salt thereof, is administered at a dose (eg, a human dose) in the range of about 100 mg / day to about 150 mg / day.

[0609] In certain embodiments, Compound 67A, or a pharmaceutically acceptable salt thereof, is administered at a dose (eg, a human dose) in the range of about 50 mg / day to about 100 mg / day.

[0610] In certain embodiments, Compound 67A, or a pharmaceutically acceptable salt thereof, is administered at a dose (eg, a human dose) in the range of about 60 mg / day to about 100 mg / day.

[0611] In certain embodiments, Compound 67A, or a pharmaceutically acceptable salt thereof, is administered at a dose (eg, a human dose) in the range of about 70 mg / day to about 100 mg / day.

[0612] In certain embodiments, Compound 67A, or a pharmaceutically acceptable salt thereof, is administered at a dose (eg, a human dose) in the range of about 80 mg / day to about 100 mg / day.

[0613] In certain embodiments, Compound 67A, or a pharmaceutically acceptable salt thereof, is administered at a dose (eg, a human dose) in the range of about 90 mg / day to about 100 mg / day.

[0614] In certain embodiments, Compound 67A, or a pharmaceutically acceptable salt thereof, is administered at a dose (eg, a human dose) in the range of about 50 mg / day to about 90 mg / day.

[0615] In certain embodiments, Compound 67A, or a pharmaceutically acceptable salt thereof, is administered at a dose (eg, a human dose) in the range of about 60 mg / day to about 90 mg / day.

[0616] In certain embodiments, Compound 67A, or a pharmaceutically acceptable salt thereof, is administered at a dose (eg, a human dose) in the range of about 70 mg / day to about 90 mg / day.

[0617] In certain embodiments, Compound 67A, or a pharmaceutically acceptable salt thereof, is administered at a dose (eg, a human dose) in the range of about 80 mg / day to about 90 mg / day.

[0618] In certain embodiments, Compound 67A, or a pharmaceutically acceptable salt thereof, is administered at a dose (eg, a human dose) in the range of about 50 mg / day to about 80 mg / day.

[0619] In certain embodiments, Compound 67A, or a pharmaceutically acceptable salt thereof, is administered at a dose (eg, a human dose) in the range of about 60 mg / day to about 80 mg / day.

[0620] In certain embodiments, Compound 67A, or a pharmaceutically acceptable salt thereof, is administered at a dose (eg, a human dose) in the range of about 70 mg / day to about 80 mg / day.

[0621] In certain embodiments, Compound 67A, or a pharmaceutically acceptable salt thereof, is administered at a dose (eg, a human dose) in the range of about 50 mg / day to about 70 mg / day.

[0622] In certain embodiments, Compound 67A, or a pharmaceutically acceptable salt thereof, is administered at a dose (eg, a human dose) in the range of about 60 mg / day to about 70 mg / day.

[0623] In certain embodiments, Compound 67A, or a pharmaceutically acceptable salt thereof, is administered at a dose (eg, a human dose) in the range of about 50 mg / day to about 60 mg / day.

[0624] In certain embodiments, the dosage of levofloxacin is 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 Compound 67A, or a pharmaceutically acceptable salt thereof, is administered at a dosage (e.g., a human dosage) of 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.

[0625] In certain embodiments, Compound 67A or a pharmaceutically acceptable salt thereof is administered at a dose of about 50 mg / day (eg, a human dose).

[0626] In certain embodiments, Compound 67A, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 60 mg / day (eg, a human dose).

[0627] In certain embodiments, Compound 67A, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 70 mg / day (eg, a human dose).

[0628] In certain embodiments, Compound 67A, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 80 mg / day (eg, a human dose).

[0629] In certain embodiments, Compound 67A, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 90 mg / day (eg, a human dose).

[0630] In certain embodiments, Compound 67A, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 100 mg / day (eg, a human dose).

[0631] In certain embodiments, Compound 67A, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 110 mg / day (eg, a human dose).

[0632] In certain embodiments, Compound 67A, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 120 mg / day (eg, a human dose).

[0633] In certain embodiments, Compound 67A, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 130 mg / day (eg, a human dose).

[0634] In certain embodiments, Compound 67A, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 140 mg / day (eg, a human dose).

[0635] In certain embodiments, Compound 67A, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 150 mg / day (eg, a human dose).

[0636] In certain embodiments, Compound 67A, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 160 mg / day (eg, a human dose).

[0637] In certain embodiments, Compound 67A, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 170 mg / day (eg, a human dose).

[0638] In certain embodiments, Compound 67A, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 180 mg / day (eg, a human dose).

[0639] In certain embodiments, Compound 67A, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 190 mg / day (eg, a human dose).

[0640] In certain embodiments, Compound 67A, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 200 mg / day (eg, a human dose).

[0641] In certain embodiments, Compound 67A, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 210 mg / day (eg, a human dose).

[0642] In certain embodiments, Compound 67A, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 220 mg / day (eg, a human dose).

[0643] In certain embodiments, Compound 67A, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 230 mg / day (eg, a human dose).

[0644] In certain embodiments, Compound 67A, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 240 mg / day (eg, a human dose).

[0645] In certain embodiments, Compound 67A, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 250 mg / day (eg, a human dose).

[0646] In certain embodiments, Compound 67A, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 260 mg / day (eg, a human dose).

[0647] In certain embodiments, Compound 67A, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 270 mg / day (eg, a human dose).

[0648] In certain embodiments, Compound 67A, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 280 mg / day (eg, a human dose).

[0649] In certain embodiments, Compound 67A, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 290 mg / day (eg, a human dose).

[0650] In certain embodiments, Compound 67A, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 300 mg / day (eg, a human dose).

[0651] In certain embodiments, Compound 67A, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 310 mg / day (eg, a human dose).

[0652] In certain embodiments, Compound 67A, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 320 mg / day (eg, a human dose).

[0653] In certain embodiments, Compound 67A, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 330 mg / day (eg, a human dose).

[0654] In certain embodiments, Compound 67A, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 340 mg / day (eg, a human dose).

[0655] In certain embodiments, Compound 67A, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 350 mg / day (eg, a human dose).

[0656] In certain embodiments, Compound 67A, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 360 mg / day (eg, a human dose).

[0657] In certain embodiments, Compound 67A, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 370 mg / day (eg, a human dose).

[0658] In certain embodiments, Compound 67A, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 380 mg / day (eg, a human dose).

[0659] In certain embodiments, Compound 67A, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 390 mg / day (eg, a human dose).

[0660] In certain embodiments, Compound 67A, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 400 mg / day (eg, a human dose).

[0661] In certain embodiments, Compound 67A, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 410 mg / day (eg, a human dose).

[0662] In certain embodiments, Compound 67A, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 420 mg / day (eg, a human dose).

[0663] In certain embodiments, Compound 67A, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 430 mg / day (eg, a human dose).

[0664] In certain embodiments, Compound 67A, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 440 mg / day (eg, a human dose).

[0665] In certain embodiments, Compound 67A, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 450 mg / day (eg, a human dose).

[0666] In certain embodiments, Compound 67A, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 460 mg / day (eg, a human dose).

[0667] In certain embodiments, Compound 67A, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 470 mg / day (eg, a human dose).

[0668] In certain embodiments, Compound 67A, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 480 mg / day (eg, a human dose).

[0669] In certain embodiments, Compound 67A, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 490 mg / day (eg, a human dose).

[0670] In certain embodiments, Compound 67A, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 500 mg / day (eg, a human dose).

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

[0672] In certain embodiments, Compound 67A, or a pharmaceutically acceptable salt thereof, is administered once daily, for example, one day per week at any dose described herein.

[0673] In certain embodiments, Compound 67A, or a pharmaceutically acceptable salt thereof, is administered once daily, for example, 2 days per week at any dose described herein.

[0674] In certain embodiments, Compound 67A, or a pharmaceutically acceptable salt thereof, is administered once daily, for example, at any dose described herein, 3 days per week.

[0675] In certain embodiments, Compound 67A, or a pharmaceutically acceptable salt thereof, is administered once daily, for example, at any dose described herein, 4 days per week.

[0676] In certain embodiments, Compound 67A, or a pharmaceutically acceptable salt thereof, is administered once daily, for example, at any dose described herein, 5 days per week.

[0677] In certain embodiments, Compound 67A, or a pharmaceutically acceptable salt thereof, is administered once daily, for example, at any dose described herein, 6 days per week.

[0678] In certain embodiments, Compound 67A, or a pharmaceutically acceptable salt thereof, is administered once daily, for example, at any dose described herein, 7 days per week.

[0679] In certain embodiments, Compound 67A, or a pharmaceutically acceptable salt thereof, is administered once daily, eg, at any dose described herein, for 2 weeks.

[0680] In certain embodiments, Compound 67A, or a pharmaceutically acceptable salt thereof, is administered once daily, eg, at any dose described herein, for 3 weeks.

[0681] In certain embodiments, Compound 67A, or a pharmaceutically acceptable salt thereof, is administered once daily, eg, at any dose described herein, for 4 weeks.

[0682] In certain embodiments, Compound 67A, or a pharmaceutically acceptable salt thereof, is administered once, for example, every other day at any dose described herein.

[0683] In certain embodiments, Compound 67A, or a pharmaceutically acceptable salt thereof, is administered once, for example, every other day for 4 days at any dose described herein.

[0684] In certain embodiments, Compound 67A, or a pharmaceutically acceptable salt thereof, is administered once, for example, at any dose described herein, every other day for 6 days.

[0685] In certain embodiments, Compound 67A, or a pharmaceutically acceptable salt thereof, is administered once, for example, at any dose described herein, every other day for 2 weeks.

[0686] In certain embodiments, Compound 67A, or a pharmaceutically acceptable salt thereof, is administered once, for example, at any dose described herein, every other day for 3 weeks.

[0687] In certain embodiments, Compound 67A, or a pharmaceutically acceptable salt thereof, is administered once, for example, at any dose described herein, every other day for 4 weeks.

[0688] In certain embodiments, Compound 67A, or a pharmaceutically acceptable salt thereof, is administered, eg, at any dose described herein, without a rest period.

[0689] In certain embodiments, administration of Compound 67A, or a pharmaceutically acceptable salt thereof, eg, at any dose described herein, is followed by a period of no administration.

[0690] In certain embodiments, Compound 67A, or a pharmaceutically acceptable salt thereof, is administered, for example, at any dose described herein, for 1 week followed by a period of no administration.

[0691] In certain embodiments, Compound 67A, or a pharmaceutically acceptable salt thereof, is administered, for example, at any dose described herein, for 2 weeks followed by a period of no administration.

[0692] In certain embodiments, Compound 67A, or a pharmaceutically acceptable salt thereof, is administered, for example, at any dose described herein, for 3 weeks followed by a period of no administration.

[0693] In certain embodiments, Compound 67A, or a pharmaceutically acceptable salt thereof, is administered, for example, at any dose described herein, for 4 weeks followed by a period of no administration.

[0694] In certain embodiments, administration of Compound 67A, or a pharmaceutically acceptable salt thereof, eg, at any dose described herein, is followed by a 7-day rest period.

[0695] In certain embodiments, administration of Compound 67A, or a pharmaceutically acceptable salt thereof, eg, at any dose described herein, is followed by a 14-day period off administration.

[0696] In certain embodiments, administration of Compound 67A, or a pharmaceutically acceptable salt thereof, eg, at any dose described herein, is followed by a 21-day period off administration.

[0697] In certain embodiments, administration of Compound 67A, or a pharmaceutically acceptable salt thereof, eg, at any dose described herein, is followed by a 28-day period off administration.

[0698] In certain embodiments, administration of Compound 67A, or a pharmaceutically acceptable salt thereof, eg, at any dose described herein, is followed by a 35-day period off administration.

[0699] In certain embodiments, administration of Compound 67A, or a pharmaceutically acceptable salt thereof, eg, at any dose described herein, is followed by a 42-day period off administration.

[0700] In certain embodiments, administration of Compound 67A, or a pharmaceutically acceptable salt thereof, eg, at any dose described herein, is followed by a 49-day period off administration.

[0701] In certain embodiments, at about 300 mg / m 2 Administration of Compound 67A or a pharmaceutically acceptable salt thereof is followed by a 7-day rest period.

[0702] In certain embodiments, at about 300 mg / m 2 Administration of Compound 67A or a pharmaceutically acceptable salt thereof is followed by a 14-day non-administration period.

[0703] In certain embodiments, at about 300 mg / m 2 Administration of Compound 67A or a pharmaceutically acceptable salt thereof is followed by a 21-day non-administration period.

[0704] In certain embodiments, at about 300 mg / m 2 Administration of Compound 67A or a pharmaceutically acceptable salt thereof is followed by a 28-day rest period.

[0705] In certain embodiments, at about 240 mg / m 2 Administration of Compound 67A or a pharmaceutically acceptable salt thereof is followed by a 7-day rest period.

[0706] In certain embodiments, at about 240 mg / m 2 Administration of Compound 67A or a pharmaceutically acceptable salt thereof is followed by a 14-day non-administration period.

[0707] In certain embodiments, at about 240 mg / m 2 Administration of Compound 67A or a pharmaceutically acceptable salt thereof is followed by a 21-day non-administration period.

[0708] In certain embodiments, at about 240 mg / m 2 Administration of Compound 67A or a pharmaceutically acceptable salt thereof is followed by a 28-day rest period.

[0709] In certain embodiments, at about 120 mg / m 2 Administration of Compound 67A or a pharmaceutically acceptable salt thereof is followed by a 7-day rest period.

[0710] In certain embodiments, at about 120 mg / m 2 Administration of Compound 67A or a pharmaceutically acceptable salt thereof is followed by a 14-day non-administration period.

[0711] In certain embodiments, at about 120 mg / m 2 Administration of Compound 67A or a pharmaceutically acceptable salt thereof is followed by a 21-day non-administration period.

[0712] In certain embodiments, at about 120 mg / m 2 Administration of Compound 67A or a pharmaceutically acceptable salt thereof is followed by a 28-day rest period.

[0713] In certain embodiments, at about 50 mg / m 2 Administration of Compound 67A or a pharmaceutically acceptable salt thereof is followed by a 7-day rest period.

[0714] In certain embodiments, at about 50 mg / m 2 Administration of Compound 67A or a pharmaceutically acceptable salt thereof is followed by a 14-day non-administration period.

[0715] In certain embodiments, at about 50 mg / m 2 Administration of Compound 67A or a pharmaceutically acceptable salt thereof is followed by a 21-day non-administration period.

[0716] In certain embodiments, at about 50 mg / m 2 Administration of Compound 67A or a pharmaceutically acceptable salt thereof is followed by a 28-day rest period.

[0717] RAD51 inhibitors

[0718] In a first embodiment, the RAD51 inhibitor is a compound represented by structural formula I or a pharmaceutically acceptable salt thereof:

[0719]

[0720] in:

[0721] The thiazole ring is optionally substituted with -F or -Cl;

[0722] Cy is -(C3-C7)cycloalkyl, bridged (C6-C 12 )cycloalkyl or 4-12 membered heterocycle, each of which is optionally substituted by one or more groups selected from halogen, -OH, (C1-C4)alkyl and (C1-C4)alkoxy;

[0723] When X 5 When connected to the nitrogen ring atom of Cy, X 5 does not exist;

[0724] When X 5 When attached to a carbon ring atom of Cy, X 5 It is NR a or O;

[0725] X 6 It is NR a or O;

[0726] R 1 is (C1-C5)alkyl;

[0727] R 3 is (C1-C5) alkyl, -CH2-phenyl, -(C3-C7) cycloalkyl, -CH2-(C3-C7) cycloalkyl, -CH2-monocyclic 3-7 membered heterocycle or monocyclic 3-7 membered heterocycle, wherein R 3 Indicates or in 3 (C1-C5)alkyl, -(C3-C7)cycloalkyl, phenyl or monocyclic 3-7 membered heterocycle in the group represented by is optionally substituted by one or more groups selected from halogen, -OH, (C1-C4)alkyl, halomethyl, halomethoxy, -CN and (C1-C4)alkoxy;

[0728] R 2 Yes-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 3-7 membered heterocycle; -NR a C(O)NR a -monocyclic 3-7 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;

[0729] Among them, R 2 The (C1-C4)alkyl and (C2-C4)alkenyl groups in the groups represented by are each optionally and independently substituted by one or more radicals selected from halogen, N3, -OR a 、-NR a R a , -(C3-C6)cycloalkyl, phenyl, monocyclic 3-7 membered heterocyclic ring and monocyclic 5-6 membered heteroaromatic ring;

[0730] Among them, R 2 The (C3-C7) cycloalkyl group in the group represented by is optionally replaced by one or more halogen, -CH3, =O, -OR a and -NR a R a The group substitution;

[0731] Among them, R 2 The phenyl group in the group represented by is optionally replaced by one or more selected from halogen, -CH3, halomethyl, halomethoxy, -CN, -OR a and -N3 group substitution;

[0732] Among them, R 2 The heterocyclic ring in the group represented by is optionally substituted by one or more selected from =O, halogen, -OR a , -CH3, halomethyl and halomethoxy groups;

[0733] Among them, R 2 The heteroaromatic ring in the group represented by is optionally substituted by one or more selected from halogen, -CN, -CH3, halomethyl, halomethoxy, -OR a and -NR a R a and

[0734] Each R a are independently -H or -CH3.

[0735] In a second embodiment, the RAD51 inhibitor is a compound represented by structural formula II:

[0736]

[0737] or a pharmaceutically acceptable salt thereof, wherein

[0738] The thiazole ring is optionally substituted with -F or -Cl;

[0739] Cy is a cyclohexyl group or a 6-membered monocyclic heterocycle;

[0740] X 5 and X 6 Each is independently NR a or O;

[0741] R 1 is (C1-C5)alkyl;

[0742] R 3 is (C1-C5)alkyl or a monocyclic 3-7-membered heterocycle;

[0743] R 2 Yes-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 3-7 membered heterocycle; -NR a C(O)NR a -monocyclic 3-7 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;

[0744] Among them, R 2 The (C1-C4)alkyl and (C2-C4)alkenyl groups in the groups represented by are each optionally and independently substituted with one or more halogen, N3, -OR a 、-NR aR a , -(C3-C6)cycloalkyl, phenyl, monocyclic 3-7-membered heterocycle or monocyclic 5-6-membered heteroaromatic ring substitution;

[0745] Among them, R 2 The -(C3-C6)cycloalkyl group in the group represented by is optionally replaced by one or more halogen, -CH3, -OR a or -NR a R a replace;

[0746] Among them, R 2 The phenyl group in the group represented by is optionally replaced by one or more halogen, -CH3, halomethyl, halomethoxy, -OR a or -N3 substitution;

[0747] Among them, R 2 The heterocycle in the group represented is optionally substituted by one or more =0, halogen, -CH3, halomethyl or halomethoxy;

[0748] Among them, R 2 The heteroaromatic ring in the group represented by is optionally substituted by one or more halogen, -CH3, halomethyl, halomethoxy, -OR a or -NR a R a replace; and

[0749] Each R a are independently -H or -CH3.

[0750] In a third embodiment, the RAD51 inhibitor is a compound according to formula I or a pharmaceutically acceptable salt thereof, wherein Cy is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl; azetidinyl, azepanyl, diazaspiro[4.4]nonyl, diazaspiro[3.5]nonyl, diazepanyl, dihydroimidazole, dihydrofuranyl, dihydropyranyl, dihydropyridinyl, dihydropyrimidinyl, dihydrothiophenyl ... 1.1.1]hexyl, 1.1.1.1]cyclo ... [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, bornyl, norbornyl, norbornyl, 6,6-dimethylbicyclo[3.1.1]heptyl, tricyclobutyl, adamantyl; azanorbornyl, quinuclidinyl, isoquinuclidinyl, tropane, azabicyclo[2.2.1]heptyl, 2-azabicyclo[ 3.2.1]octyl, azabicyclo[3.2.1]octyl, azabicyclo[3.2.2]nonyl, azabicyclo[3.3.0]nonyl, azabicyclo[3.3.1]nonyl, diazabicyclo[2.2.1]heptyl, diazabicyclo[3.2.1]octyl, octahydropyrrolo[3,4-b]pyrrolyl, octahydropyrrolo[3,4-c]pyrrolyl; and the remaining variables are as defined in the first embodiment.

[0751] In a fourth embodiment, the RAD51 inhibitor is a compound according to formula I or II, or a pharmaceutically acceptable salt thereof, wherein Cy is cyclohexyl, morpholinyl, thiomorpholinyl, piperidinyl, piperazinyl, hexahydropyridazinyl, hexahydropyrimidinyl, valerolactamyl, dihydropyranyl, dihydropyridinyl, dihydropyrimidinyl, dihydrothiopyranyl, tetrahydropyranyl, tetrahydropyridinyl, tetrahydropyrimidinyl or tetrahydrothiopyranyl; and the remaining variables are as defined in the first, second and / or third embodiment.

[0752] In a fifth embodiment, the RAD51 inhibitor is a compound represented by structural formula III,

[0753]

[0754] or a pharmaceutically acceptable salt thereof, wherein:

[0755] X 7 is NH or O;

[0756] R 4 is (C1-C4)alkyl, (C3-C6)cycloalkyl or a monocyclic 3-7 membered heterocycle;

[0757] Among them, R 4 The (C1-C4)alkyl represented by the present invention is optionally substituted by one or more radicals selected from halogen, N3, -OR a 、-NR a R a , -(C3-C6)cycloalkyl, phenyl, monocyclic 3-7 membered heterocyclic ring and monocyclic 5-6 membered heteroaromatic ring,

[0758] Among them, R 4 (C3-C6) cycloalkyl or monocyclic 3-7 membered heterocycle represented by R 4 The (C3-C6) cycloalkyl or monocyclic 3-7 membered heterocycle in the group represented by is optionally replaced by one or more selected from halogen, -OR a , =O and -CH3 groups,

[0759] Among them, R 4 The phenyl groups represented by are optionally substituted by one or more groups selected from halogen, -CH3, halomethyl, halomethoxy, -OR a and -N3 group substitution;

[0760] Among them, R 4 The heteroaromatic ring in the group represented by is optionally substituted with one or more groups selected from halogen and -CH3; and the remaining variables are as defined in the first, second, third and / or fourth embodiment.

[0761] In a sixth embodiment, the RAD51 inhibitor is a compound according to 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, wherein R 4 The (C1-C4)alkyl represented by a 、-NR a R a , -(C3-C6)cycloalkyl, phenyl (optionally substituted by one or more halogen, -CH3, halomethyl, halomethoxy, OR a or N3), a monocyclic 3-7-membered heterocycle (optionally substituted with =0, halogen, or -CH3), or a monocyclic 5-6-membered heteroaromatic ring (optionally substituted with halogen or -CH3); and the remaining variables are as defined in the first, second, third, fourth, and / or fifth embodiment.

[0762] In a seventh embodiment, the RAD51 inhibitor is a compound represented by structural formula IV,

[0763]

[0764] or a pharmaceutically acceptable salt thereof; and the variables are as defined in the first, second, third, fourth, fifth and / or sixth embodiment.

[0765] In an eighth embodiment, the RAD51 inhibitor is a compound represented by structural formula V,

[0766]

[0767] or a pharmaceutically acceptable salt thereof; and the variables are as defined in the first, second, third, fourth, fifth and / or sixth embodiment.

[0768] In a ninth embodiment, the RAD51 inhibitor is a compound represented by structural formula VI:

[0769]

[0770] or a pharmaceutically acceptable salt thereof; and the variables are as defined in the first, second, third, fourth, fifth and / or sixth embodiment.

[0771] In a tenth embodiment, the RAD51 inhibitor is a compound represented by structural formula VII:

[0772]

[0773] or a pharmaceutically acceptable salt thereof; and the variables are as defined in the first, second, third, fourth, fifth and / or sixth embodiment.

[0774] In an eleventh embodiment, the RAD51 inhibitor is a compound represented by structural formula VIII:

[0775]

[0776] or a pharmaceutically acceptable salt thereof; and the variables are as defined in the first, second, third, fourth, fifth and / or sixth embodiment.

[0777] In a twelfth embodiment, the RAD51 inhibitor is a compound represented by structural formula IX:

[0778]

[0779] or a pharmaceutically acceptable salt thereof; and the variables are as defined in the first, second, third, fourth, fifth and / or sixth embodiment.

[0780] 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, and the nitrogen ring atom is linked to the thiazole ring; and the remaining variables are as defined in the first, second, third, fourth, fifth and / or sixth embodiment.

[0781] In a fourteenth embodiment, the RAD51 inhibitor is a compound according to 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-diazacycloheptyl, 2,5-diazabicyclo[2.2.1]heptyl, 3,8-diazabicyclo[3.2.1]octyl, octahydropyrrolo[3,4-b]pyrrolyl or octahydropyrrolo[3,4-c]pyrrolyl, and the two nitrogen ring atoms are independently connected to the thiazole ring and -X 5 C(O)X 6 R 3 and the remaining variables are as defined in the first, second, third, fourth, fifth, and / or sixth embodiment.

[0782] In a fifteenth embodiment, the RAD51 inhibitor is a compound according to 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 3-7 membered heterocycle, wherein the -(C1-C3)alkyl is optionally substituted with: (i) phenyl optionally substituted with one or more halogens or -CH3; (ii) a monocyclic 5-6 membered heteroaromatic ring optionally substituted with one or more halogens or -CH3; or (iii) a monocyclic 3-7 membered heterocycle optionally substituted with one or more groups selected from halogen and -CH3; and the remaining variables are as defined in the first, second, third, fourth, fifth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, and / or fourteenth embodiment.

[0783] In a sixteenth embodiment, the RAD51 inhibitor is a compound according to 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 -3-7 membered monocyclic heterocyclic ring, wherein R 4The phenyl, 5-6 membered heteroaromatic ring or 3-7 membered monocyclic heterocycle in the group represented by is optionally substituted with one or more groups selected from halogen and -CH3; and the remaining variables are as defined in the first, second, third, fourth, fifth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth and / or fourteenth embodiment.

[0784] In a seventeenth embodiment, the RAD51 inhibitor is a compound according to formula III, IV, V, VI, VII, VIII or IX, or a pharmaceutically acceptable salt thereof, wherein R 4 is -(C1-C3)alkyl, which is optionally substituted with: (i) optionally substituted with one or more halogen, -CH3, halomethyl, halomethoxy, OR a or N3 substituted phenyl; (ii) a monocyclic 5-6-membered heteroaromatic ring optionally substituted with one or more halogen or -CH3; or (iii) a monocyclic 3-7-membered heterocycle optionally substituted with one or more =0 or -CH3; and the remaining variables are as defined in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth and / or fourteenth embodiment.

[0785] In an eighteenth embodiment, the RAD51 inhibitor is a compound according to formula III, IV, V, VI, VII, VIII or IX, or a pharmaceutically acceptable salt thereof, wherein R 4 is -(C1-C3)alkyl, which is optionally substituted with: (i) optionally substituted with one or more halogen, -CH3, halomethyl, halomethoxy, OR a or N3 substituted phenyl; (ii) a monocyclic 5-6-membered heteroaromatic ring optionally substituted with one or more halogen or -CH3; or (iii) a monocyclic 3-7-membered heterocycle optionally substituted with one or more =0 or -CH3; and the remaining variables are as defined in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth and / or seventeenth embodiment.

[0786] In a nineteenth embodiment, the RAD51 inhibitor is a compound according to 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 4-6 membered heterocycle or monocyclic 4-6 membered heterocycle, wherein R 3 Indicates or in 3 The phenyl group or the monocyclic 4-6 membered heterocycle in the group represented by is optionally replaced by one or more selected from halogen, -OR aand -CH3; and the remaining variables are as defined in the first, third, fourth, fifth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth and / or eighteenth embodiment.

[0787] In a twentieth embodiment, the RAD51 inhibitor is a compound represented by structural formula X:

[0788]

[0789] 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 embodiment.

[0790] In a twenty-first embodiment, the RAD51 inhibitor is a compound represented by structural formula XI:

[0791]

[0792] 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 embodiment.

[0793] In a twenty-second embodiment, the RAD51 inhibitor is a compound represented by structural formula XII:

[0794]

[0795] 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 embodiment.

[0796] In a twenty-third embodiment, the RAD51 inhibitor is a compound represented by structural formula XIII(a) or XIII(b):

[0797]

[0798]

[0799] 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 embodiment.

[0800] In a twenty-fourth embodiment, the RAD51 inhibitor is a compound represented by structural formula XIV:

[0801]

[0802] 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 embodiment.

[0803] In the twenty-fifth embodiment, the RAD51 inhibitor is a compound according to 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, tert-butyl, cyclobutyl, cyclopentyl, benzyl, oxetanyl, tetrahydro-2H-pyranyl or 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 embodiment. In an alternative embodiment, R 3 In another alternative embodiment, R 3 It is isopropyl.

[0804] In the twenty-sixth embodiment, the RAD51 inhibitor is a compound according to 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 tert-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 embodiment.

[0805] In the twenty-seventh embodiment, the RAD51 inhibitor is a compound according to formula III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII(a), XIII(b), XIV, or a pharmaceutically acceptable salt thereof, wherein R 4 yes

[0806]

[0807] 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 embodiment. In certain embodiments, R 4 yes

[0808] In another alternative embodiment, R 4 yes

[0809] In certain embodiments, R 4 yes In certain embodiments, R 4 yes In certain embodiments, R 4 yes .

[0810] The present disclosure provides compounds represented by Structural Formula I' for use in treating pancreatic cancer.

[0811] In a first embodiment, the RAD51 inhibitor is a compound represented by structural formula I':

[0812]

[0813] or a pharmaceutically acceptable salt thereof, wherein:

[0814] The thiazole ring is optionally substituted with -F or -Cl;

[0815] X 4 It is NR a or O;

[0816] X 5 and X 6 Each is independently NR b or O;

[0817] R 1 is (C1-C5)alkyl;

[0818] R 3 is (C1-C5)alkyl, -(C3-C7)cycloalkyl or -(CH2) q heterocyclyl (wherein heterocyclyl is a monocyclic 3-7-membered heterocycle optionally substituted with one or more occurrences of methyl) or benzyl (wherein the benzyl ring is optionally substituted with one or more occurrences of halogen, methoxy, halomethoxy, methyl, halomethyl, or cyano);

[0819] R a 、R b and R c Each of is independently hydrogen or methyl;

[0820] R d is independently halogen, methoxy, halomethoxy, methyl, halomethyl, or cyano;

[0821] m is 0, 1, 2, or 3;

[0822] n is 0, 1, or 2; and

[0823] q is 0 or 1.

[0824] In a second embodiment, the RAD51 inhibitor is a compound represented by structural formula I'-1:

[0825]

[0826] or a pharmaceutically acceptable salt thereof, and the variables are as defined in the first embodiment.

[0827] In a third embodiment, the RAD51 inhibitor is a compound represented by structural formula I'-2:

[0828]

[0829] or a pharmaceutically acceptable salt thereof, and the variables are as defined in the first embodiment.

[0830] In a fourth embodiment, the RAD51 inhibitor is a compound represented by structural formula I'-3:

[0831]

[0832] or a pharmaceutically acceptable salt thereof, and the variables are as defined in the first embodiment.

[0833] In a fifth embodiment, the RAD51 inhibitor is a compound represented by structural formula I'-4:

[0834]

[0835] or a pharmaceutically acceptable salt thereof, and the variables are as defined in the first embodiment.

[0836] In a sixth embodiment, the RAD51 inhibitor is a compound according to 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.

[0837] In a seventh embodiment, the RAD51 inhibitor is a compound according to formula I', I'-1, I'-2, I'-3 or I'-4, or a pharmaceutically acceptable salt thereof, wherein R 3 (C1-C4) alkyl, -(C4-C6) cycloalkyl, -(CH2) q In certain embodiments, R 3 is isopropyl, tert-butyl, cyclobutyl, cyclopentyl, oxetanyl, benzyl, tetrahydro-2H-pyranyl or In certain embodiments, R 3 is isopropyl or oxetanyl.

[0838] In an eighth embodiment, the RAD51 inhibitor is a compound according to formula I', I'-1, I'-2, I'-3 or I'-4, or a pharmaceutically acceptable salt thereof, wherein R d is halogen, and m is 0 or 1, and the remaining variables are as defined in the first, sixth, and / or seventh embodiment. In certain embodiments, yes .

[0839] In a ninth embodiment, the RAD51 inhibitor is a compound according to formula I', I'-1, I'-2, I'-3 or I'-4, or a pharmaceutically acceptable salt thereof, wherein R 1 is tert-butyl, and the remaining variables are as defined in the first, sixth, seventh, and / or eighth embodiment.

[0840] In a tenth embodiment, the RAD51 inhibitor is a compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

[0841]

[0842]

[0843] .

[0844] In an eleventh embodiment, the RAD51 inhibitor is a compound represented by structural formula II':

[0845]

[0846] or a pharmaceutically acceptable salt thereof, wherein:

[0847] The thiazole ring is optionally substituted with -F or -Cl;

[0848] X 4 It is NR a or O;

[0849] X 5 and X 6 Each is independently NR b or O;

[0850] R 1 is (C1-C5)alkyl;

[0851] R 4 is (C1-C4) alkyl, -(C3-C7) cycloalkyl, -(CH(R c )) q -heterocyclyl (wherein heterocyclyl is a monocyclic 3-7-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-pyridyl (wherein the 2-pyridyl ring is optionally substituted with one or more occurrences of halogen, methoxy, halomethoxy, methyl, halomethyl or cyano);

[0852] R a 、R b and R c Each of is independently hydrogen or methyl;

[0853] n is 0, 1, or 2; and

[0854] q is 0 or 1.

[0855] In a twelfth embodiment, the RAD51 inhibitor is a compound represented by structural formula II'-1:

[0856]

[0857] or a pharmaceutically acceptable salt thereof, and the variables are as defined in the eleventh embodiment.

[0858] In a thirteenth embodiment, the RAD51 inhibitor is a compound represented by structural formula II'-2:

[0859]

[0860] or a pharmaceutically acceptable salt thereof, and the variables are as defined in the eleventh embodiment.

[0861] In a fourteenth embodiment, the RAD51 inhibitor is a compound according to formula II', II'-1 or II'-2, or a pharmaceutically acceptable salt thereof, wherein R 4 It is 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, and the phenyl and 2-pyridinyl rings are each independently and optionally substituted with one or more occurrences of halogen, and the remaining variables are as defined in the eleventh embodiment. In certain embodiments, R 4 yes In certain embodiments, R 4 yes .

[0862] In a fifteenth embodiment, the RAD51 inhibitor is a compound according to formula II', II'-1 or II'-2, or a pharmaceutically acceptable salt thereof, wherein X 4 is NH, and the remaining variables are as defined in the eleventh and / or fourteenth embodiment.

[0863] In a sixteenth embodiment, the RAD51 inhibitor is a compound according to formula II', II'-1 or II'-2, or a pharmaceutically acceptable salt thereof, wherein R 1 is tert-butyl, and the remaining variables are as defined in the eleventh, fourteenth, and fifteenth embodiments.

[0864] In a seventeenth embodiment, the RAD51 inhibitor is a compound selected from the group consisting of:

[0865]

[0866] .

[0867] In an eighteenth embodiment, the RAD51 inhibitor is the following compound:

[0868] (Also referred to as "Compound 67A" or "67A").

[0869] Also included are the compounds disclosed in the Examples in pharmaceutically acceptable salt forms and neutral forms.

[0870] The term "pharmaceutically acceptable salt" means a pharmaceutical salt which is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation or allergic response, and commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, SM Berge et al. J. Pharm. Sci. Pharmacologically acceptable salts are described in Pharmacopoeia, 1977, 66, 1-19.

[0871] The present teachings include pharmaceutically acceptable salts of the compounds disclosed herein. Compounds having a basic group can form pharmaceutically acceptable salts with one or more pharmaceutically acceptable acids. Suitable pharmaceutically acceptable acid addition salts of the compounds described herein include salts of inorganic acids (such as hydrochloric acid, hydrobromic acid, phosphoric acid, metaphosphoric acid, nitric acid, and sulfuric acid) and organic acids (such as acetic acid, benzenesulfonic acid, benzoic acid, ethanesulfonic acid, methanesulfonic acid, succinic acid, and trifluoroacetic acid). Compounds of the present teachings having an acidic group (such as a carboxylic acid) can form pharmaceutically acceptable salts with one or more pharmaceutically acceptable bases. Suitable pharmaceutically acceptable basic salts include ammonium salts, alkali metal salts (such as sodium and potassium salts), and alkaline earth metal salts (such as magnesium and calcium salts).

[0872] definition

[0873] As used herein, the term "halo" refers to halogen and includes fluorine, chlorine, bromine, and iodine.

[0874] The term "alkyl," used alone or as part of a larger group such as "alkoxy" or "haloalkyl," refers to a saturated aliphatic straight or branched monovalent hydrocarbon radical. Unless otherwise indicated, an alkyl group typically has 1 to 5 carbon atoms, i.e., a (C1-C5)alkyl group. As used herein, "(C1-C5)alkyl" refers to a group having 1 to 5 carbon atoms arranged in a straight or branched chain. Examples include methyl, ethyl, n-propyl, isopropyl, and the like.

[0875] 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.

[0876] The terms "haloalkyl" and "haloalkoxy" refer to an alkyl or alkoxy group, as the case may be, substituted with one or more halogen atoms.

[0877] "Alkylene" is a saturated aliphatic branched or straight chain divalent hydrocarbon group. Unless otherwise specified, an alkylene group typically has 2 to 6 carbon atoms, for example (C2-C6) alkylene.

[0878] The term "alkenyl" refers to a branched or straight-chain monovalent hydrocarbon radical containing at least one double bond. Alkenyl groups may be mono- or polyunsaturated and may exist in the E or Z configuration. Unless otherwise indicated, alkenyl groups typically have 2 to 6 carbon atoms, i.e. ， (C2-C6)alkenyl. For example, "(C2-C4)alkenyl" refers to a group having 2 to 4 carbon atoms arranged in a straight or branched chain.

[0879] The term "cycloalkyl" refers to a monocyclic saturated hydrocarbon ring system. For example, C3-C6 cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Unless otherwise specified, a "cycloalkyl" has 3-7 ring carbon atoms.

[0880] A bridged cycloalkyl group refers to a bicyclic non-aromatic hydrocarbon ring system in which the two rings share at least three adjacent ring carbon atoms. Bridged cycloalkyl groups typically have 6-12 ring carbon atoms. Examples include, but are not limited to, 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, bornyl, norbornyl, norbornyl, 6,6-dimethylbicyclo[3.1.1]heptyl, tricyclobutyl, and adamantyl.

[0881] The terms "heterocyclyl," "heterocycle," and "heterocyclic group" are used interchangeably herein and refer to a saturated or unsaturated, non-aromatic 4-10 membered ring radical containing 1 to 4 ring heteroatoms selected from N, O, or S, which may be the same or different. It may be monocyclic, bicyclic, or tricyclic (e.g., a fused or bridged bicyclic or tricyclic ring). Examples include, but are not limited to, azetidinyl, morpholinyl, thiomorpholinyl, pyrrolidonyl, pyrrolidinyl, piperidinyl, piperazinyl, hydantoinyl, valerolactamyl, oxirane, oxetanyl, dihydroimidazole, dihydrofuranyl, dihydropyranyl, dihydropyridinyl, dihydropyrimidinyl, dihydrothiophenyl, dihydrothiophenyl, dihydrothiopyranyl, tetrahydroimidazole, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, tetrahydropyridinyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, and tetrahydrothiopyranyl. The heterocyclic ring optionally contains one or more double bonds and / or is optionally fused to one or more aromatic rings (eg, tetrahydronaphthyridine, indolinone, dihydropyrrolotriazole, imidazopyrimidine, quinolinone, dioxaspirodecane).

[0882] Examples of 3-7 membered monocyclic heterocycles include, but are not limited to, azetidinyl, morpholinyl, thiomorpholinyl, pyrrolidonyl, pyrrolidinyl, piperidinyl, piperazinyl, hydantoinyl, valerolactamyl, oxirane, oxetanyl, dihydroimidazole, dihydrofuranyl, dihydropyranyl, dihydropyridinyl, dihydropyrimidinyl, dihydrothiophenyl, dihydrothiophenyl, dihydrothiopyranyl, tetrahydroimidazole, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, tetrahydropyridinyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, and tetrahydrothiopyranyl.

[0883] A bridged heterocyclic group refers to a bicyclic non-aromatic ring system containing 1-4 ring heteroatoms, wherein the two rings share at least three adjacent ring atoms. Bridged heterocyclic groups typically have 6-12 ring atoms. Examples include, but are not limited to, azanorbornyl, quinuclidinyl, isoquinuclidinyl, tropane, 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.

[0884] The terms "heteroaryl," "heteroaromatic," "heteroaryl ring," "heteroaryl group," "heteroaromatic ring," and "heteroaromatic group" are used interchangeably herein. When used alone or as part of a larger group (such as in "heteroaralkyl" or "heteroarylalkoxy"), "heteroaryl" refers to an aromatic ring group having five to ten ring atoms selected from carbon and at least one (typically 1 to 4, more typically 1 or 2) heteroatom (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.

[0885] "Monocyclic 5-6 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 5-6 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), pyrazolyl (e.g., 3-pyrazolyl, 4-pyrazolyl), pyrrolyl (e.g., 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), pyridinyl (e.g., 2-pyridinyl, 3-pyridinyl, 4-pyridinyl), 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).

[0886] If a group is described as "substituted", a non-hydrogen substituent replaces a hydrogen on the carbon or nitrogen of the substituent. Thus, for example, a substituted alkyl is an alkyl group in which at least one non-hydrogen substituent replaces a hydrogen substituent on the alkyl substituent. For illustration, a monofluoroalkyl group is an alkyl group substituted with one fluorine substituent, and a difluoroalkyl group is an alkyl group substituted with two fluorine substituents. It should be appreciated that if there is more than one substitution on a substituent, each non-hydrogen substituent may be the same or different (unless otherwise indicated). Many groups used herein (e.g., alkyl, cycloalkyl, or heterocycle) are referred to as "substituted" or "optionally substituted". When a group is modified by one of these terms, unless otherwise indicated, it means that any portion of a substituted group known to those skilled in the art may be substituted, including one or more substituents. If there is more than one substituent, each substituent is selected independently. Such substitution patterns are well known in the art and / or taught by this disclosure. An optional substituent may be any substituent suitable for attachment to the group. Those of ordinary skill in the art will recognize that provided compound and definition do not include the substituent pattern (for example, methyl substituted by 5 different groups etc.) that does not allow. Those of ordinary skill in the art clearly recognize such substitution pattern that does not allow.When a group is described as being optionally substituted by " one or more " substituents, it represents that the group is optionally substituted by 1,2,3,4,5 or 6 substituents. In one embodiment, the group is optionally substituted by 1-3 substituents. In one embodiment, the group is optionally substituted by 1-2 substituents. In one embodiment, the group is optionally substituted by a substituent.

[0887] Suitable substituents are those that do not have a significant adverse effect on the ability of the compound to inhibit RAD51. When suitable substituents are not specifically listed, exemplary substituents include, but are not limited to, 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’ Rb’ 、-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. Each R a’ and each R b’ Independently selected from -H and (C1-C5) alkyl, wherein R a’ or R b’ The (C1-C5)alkyl group represented by R is optionally substituted by a hydroxyl group or a (C1-C3)alkoxy group; c’ is -H, halo(C1-C5)alkyl or (C1-C5)alkyl, wherein R c wherein the (C1-C5)alkyl group is optionally substituted with hydroxy or (C1-C3)alkoxy; and i is 0, 1 or 2. =0 is also a suitable substituent for alkyl, cycloalkyl and heterocycle.

[0888] Compounds with one or more chiral centers can exist in different stereoisomeric forms. Stereoisomers are compounds that differ only in their arrangement in space. Stereoisomers include all diastereomeric, enantiomeric and epimeric forms, as well as racemates and mixtures thereof.

[0889] The term "geometric isomer" refers to a cyclic compound having at least two substituents, wherein the two substituents are on the same side of the ring (cis) or wherein the substituents are each on opposite sides of the ring (trans). When a disclosed compound is named or depicted by structure without indicating stereochemistry, it is understood that the name or structure encompasses one or more possible stereoisomers or geometric isomers, or mixtures of such stereoisomers or geometric isomers.

[0890] When geometric isomers are depicted by name or structure, it is understood that the named or depicted isomer is present to a greater extent than the other isomer, i.e., the geometric purity of the named or depicted geometric isomer is greater than 50%, such as at least 60%, 70%, 80%, 90%, 99%, or 99.9% pure by weight. Geometric purity is determined by dividing the weight of the named or depicted geometric isomer in the mixture by the total weight of all geometric isomers in the mixture.

[0891] A racemic mixture refers to 50% of one enantiomer and 50% of the corresponding enantiomer. When a compound having one chiral center is named or depicted without indicating the stereochemistry of the chiral center, it is understood that the name or structure encompasses both possible enantiomeric forms of the compound (e.g., two enantiomerically pure, enantiomerically enriched, or racemic). When a compound having two or more chiral centers is named or depicted without indicating the stereochemistry of the chiral center, it is understood that the name or structure encompasses all possible diastereomeric forms of the compound (e.g., diastereomerically pure, diastereomerically enriched, and an equimolar mixture of one or more diastereomers (e.g., a racemic mixture)).

[0892] Enantiomeric and diastereomeric mixtures can be separated into their component enantiomers or stereoisomers by well-known methods such as chiral gas chromatography, chiral high performance liquid chromatography, crystallization of the compound as a chiral salt complex, or crystallization of the compound in a chiral solvent. Enantiomers and diastereomers can also be obtained from diastereomerically pure or enantiomerically pure intermediates, reagents, and catalysts by well-known asymmetric synthetic methods.

[0893] When a compound is designated by a name or structure indicating a single enantiomer, unless otherwise indicated, the compound is at least 60%, 70%, 80%, 90%, 99%, or 99.9% optically pure (also referred to as "enantiomerically pure"). Optical purity is the weight of the mixture of the named or depicted enantiomers divided by the total weight of the mixture of the two enantiomers.

[0894] When the stereochemistry of a disclosed compound is named or depicted by structure, and the named or depicted structure encompasses more than one stereoisomer (e.g., in the form of a diastereomeric pair), it is understood that one of the encompassed stereoisomers or any mixture of encompassed stereoisomers is included. It is further understood that the stereoisomeric purity of the named or depicted stereoisomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% by weight. In this case, the stereoisomeric purity is determined by dividing the total weight of the mixture of stereoisomers encompassed by the name or structure by the total weight of the mixture of all stereoisomers.

[0895] Pharmaceutical composition

[0896] The compounds disclosed herein are RAD51 inhibitors. The pharmaceutical compositions of the present disclosure comprise one or more RAD51 inhibitors or pharmaceutically acceptable salts thereof and a pharmaceutically acceptable carrier or diluent.

[0897] "Pharmaceutically acceptable carrier" and "pharmaceutically acceptable diluent" refer to substances that aid in the formulation and / or administration of an active agent to a subject and / or absorption by a subject, and can be included in the compositions of the present disclosure without causing significant adverse toxicological effects on the subject. Non-limiting examples of pharmaceutically acceptable carriers and / or diluents include water, NaCl, physiological saline solutions, lactated Ringer's solution, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavorings, salt solutions (such as Ringer's solution), alcohols, oils, gelatin, carbohydrates such as lactose, amylose or starch, fatty acid esters, hydroxymethylcellulose, polyvinylpyrrolidine, and pigments. Such preparations can be sterilized and, if desired, mixed with adjuvants such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for affecting osmotic pressure, buffers, colorants, and / or aromatic substances that do not adversely react with or interfere with the activity of the compounds provided herein. Those of ordinary skill in the art will recognize that other pharmaceutical excipients are suitable for use with the disclosed compounds.

[0898] The pharmaceutical compositions of the present teachings optionally include one or more pharmaceutically acceptable carriers and / or diluents therefor, such as lactose, starch, cellulose, and dextrose. Other excipients may also be included, such as flavoring agents; sweeteners; and preservatives, such as methylparaben, ethylparaben, propylparaben, and butylparaben. A more complete list of suitable excipients can be found in the Handbook of Pharmaceutical Excipients (5th edition, Pharmaceutical Press (2005)). Those skilled in the art know how to prepare formulations suitable for different types of administration routes. Conventional procedures and ingredients for selecting and preparing suitable formulations are described in, for example, Remington's Pharmaceutical Sciences (2003 - The 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.

[0899] The term "off-administration period" is also referred to as a "drug holiday" and refers to a period of time during which a therapeutic agent is not administered to a subject or is administered at a lower dose ( Right now, RAD51 inhibitors). The timing of the cessation of administration depends on the timing of the conventional administration regimen and the purpose of taking the cessation of administration (e.g., restoring drug sensitivity and / or reducing undesirable side effects of continuous, long-term administration). In certain embodiments, the cessation of administration may be a reduction in the drug dosage (e.g., less than a therapeutically effective amount within a certain time interval). In other embodiments, the administration of the dosage is stopped for a certain time interval and then administration is restarted with the same or a different administration regimen (e.g., with a lower or higher dosage and / or administration frequency). Therefore, the cessation of administration of the present disclosure can be selected from a wide range of time periods and dosage regimens.

[0900] Other aspects of treatment

[0901] In certain embodiments, the object can be an object determined to have an increased DNA damage level relative to a reference level that occurs in one or more cell types." DNA damage " used herein refers to a breakage, nick and mutation of the DNA present in a cell. In certain embodiments, the DNA damage can include one or more single-strand breaks (e.g., "nicks"), double-strand breaks (DSBs) and mutations. In certain embodiments, the DNA damage can be one or more DSBs. " Mutation " used herein refers to a change or difference in cellular genetic material compared to a reference wild-type cell, such as a deletion, insertion, SNP, gene rearrangement and / or the introduction of an exogenous gene or sequence.

[0902] In certain embodiments, a subject can be determined to have increased levels of DNA damage if it is determined that the subject has increased levels and / or activity of a DNA damaging process or DNA editing enzyme. As used herein, "DNA damaging process" refers to any activity or process in a cell that causes one or more types of DNA damage to occur.

[0903] In certain embodiments, the increased DNA damage level can be an increased mutation level, for example, by determining the overall mutation status in all or part of the genome of a cell. An overall mutation status that is at least 2% higher (e.g., 2% or more, 3% or more, 5% or more, 10% or more, or 20% or more) than the overall mutation status in a reference cell can indicate increased, elevated, and / or significant DNA editing enzyme activity levels. In certain embodiments, the level of hypermutation can be determined. In certain embodiments, using FISH, whole genome sequencing, high-throughput sequencing, exome sequencing, hybridization, and / or PCR, the overall mutation status in a full genome or a portion thereof can be determined. In certain embodiments, the activity of a DNA editing enzyme can be measured by determining the hypermutation level in a specific target gene, the target gene including, but not limited to, IGH, BCL6, MYC, BCL11A, CD93, PIM1, and / or PAX5. In certain embodiments, the DNA editing enzyme is AID. In certain embodiments, mutation levels in specific target genes including IGH, BCL6, MYC, BCL11A, CD93, PIM1 and / or PAX5 that are at least 2% higher (e.g., 2% higher or more, 3% higher or more, 5% higher or more, 10% higher or more, or 20% higher or more) than the mutation levels of IGH, BCL6, MYC, BCL11A, CD93, PIM1 and / or PAX5 in reference cells may indicate increased, elevated and / or significant levels of AID activity.

[0904] In certain embodiments, the increased level of DNA damage can be an increased level of double-strand breaks (DSBs). As non-limiting examples, the level of DSBs can be determined by karyotyping, by γ-H2AX center formation, and / or by detecting DNA double-strand breaks using FISH analysis (e.g., DNA break detection fish (DBD-FISH) (Volpi and Bridger, BioTechniques, Vol. 45, No. 4, October 2008, pp. 385-409).

[0905] In certain embodiments, the increased level of DNA damage can be an increased level of single-strand breaks. As non-limiting examples, the level of single-strand breaks in DNA can be determined by the use of COMET assays, FISH, or single-strand break-specific probes. Detection of single-strand and double-strand DNA breaks is 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).

[0906] In certain embodiments, the increased activity level of the DNA damage process can include the level and / or activity of the DNA editing enzyme increased. In certain embodiments, the technology described herein relates to cells with active DNA editing enzymes treated with compounds of the present disclosure. In certain embodiments, the technology described herein relates to cells with increased levels and / or activity of DNA editing enzymes treated with compounds of the present disclosure. "DNA editing enzyme" as used herein means an enzyme that generally catalyzes the mutation, exchange or excision of a DNA segment, particularly an enzyme that can produce point mutations, single-strand breaks of DNA, double-strand breaks of DNA or protein-DNA adducts or promote their production. The DNA editing enzymes mentioned herein are not necessarily site-specific in their effect. Similarly, it is not necessarily cell-specific. In certain embodiments, the cell is a B cell expressing a detectable amount of such an enzyme.

[0907] Non-limiting examples of DNA editing enzymes include, but are not limited to, recombination activation gene 1 (RAG1; NCBI Gene ID: 5896), recombination activation gene 1 (RAG2; NCBI Gene ID: 5897), sporulation-specific protein 11 (SPO1 1; NCBI Gene ID: 23626), APOBEC family member type 1 topoisomerase; type 2 topoisomerase; and / or AID. In certain embodiments, the DNA editing enzyme may be AID.

[0908] In certain 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 deaminases that contain an N-terminal zinc-dependent cytidine deaminase catalytic domain and a C-terminal pseudocatalytic domain. Non-limiting examples of APOBEC family members 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).

[0909] In certain embodiments, the DNA editing enzyme can be a type 1 topoisomerase. In certain embodiments, the DNA editing enzyme can be a type 2 topoisomerase. Topoisomerases produce breaks in DNA to help unwind or relax chains. Type II topoisomerases hydrolyze ATP to generate DSB nicks, while type I topoisomerases produce 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).

[0910] Embodiments of the technology described herein are based on the discovery that the compounds described herein can inhibit DNA repair mechanisms, such as homologous repair. Activation-induced cytidine deaminase (AID or AICDA, also known as ARP2, CDA2 or HIGM2), a DNA editing enzyme that is a member of apolipoprotein B mRNA editing enzyme catalytic polypeptide-like (APOBEC), causes extensive genomic breakage and cell death in cells with reduced homologous recombination capacity (e.g., cells with reduced DNA double-strand break repair capacity). Accordingly, provided herein is a method for causing cell death, the method 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 causing cell death. Accordingly, provided herein is a method for causing cell death, the method 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 causing cell death. Accordingly, provided herein is a method for causing cell death, the method comprising administering to the cell a therapeutically effective amount of a DNA editing enzyme ( For example AID), and then contacting the cells with a compound of the disclosure; thereby resulting in cell death.

[0911] AID, encoded by the AICDA gene (NCBI Gene ID: 57379), is essential for proper B cell function and is most significantly expressed in centroblast B cells. This protein is involved in somatic hypermutation, gene conversion, and class switching of immunoglobulin genes. AID is usually 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 receptor (Crouch et al., J Exp Med 2007 204: 1145-1156; Muramatsu et al., J Biol Chem 1999 274: 18470-6). After activation, AID is transiently upregulated, inducing point mutations or DNA double-strand breaks in a sequence-nonspecific manner within immunoglobulin genes, and then downregulated (Longerich et al., Curr Opin Immunol, 2006, 18, 164-176; Chaudhuri et al., Adv Immunol 2007, 94, 157-214). Overall, at any given time, AID is active only in a very small population of normal cells (antigen-activated B cells). The genomic rearrangement and mutation controlled by AID lead to the development of antigen recognition diversity, receptor editing and lymphoid effector functions required for functional adaptive immunity (Mills, et al. Immunol Rev 2003 194:77-95). It has recently 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. have reported the off-target activity of AID in B cells, particularly c-myc / IgH translocation (Robbiani et al., Mol Cell 2009, 36 (4): 631-41).AID expression accelerates the rate of tumor development in Bcl6 transgenic mice (Pasqualucci et al., 2008, Nat. Genet. 40, 108-112). However, dysregulated AID itself does not necessarily lead to malignancies or translocation-related 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, although it plays a crucial role in c-myc / IgH translocation, AID is not required for the development of plasmacytosis or plasmacytoma in IL-6 transgenic 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 do not involve Ig genes (Kuppers, 2005, Oncogene 20, 5580-5594).

[0912] 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). In addition, AID expression has been shown to be associated with treatment resistance in blast crisis B-lineage leukemia and 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, lung, breast, stomach, colon, intestinal, liver and bile duct cancer (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 cancers (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 the preceding paragraphs are incorporated herein by reference in their entirety.

[0913] Elevated AID levels 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 the preceding paragraphs are incorporated herein by reference in their entirety.

[0914] When DSB repair is inhibited, the extent of DSBs generated by AID is much higher than previously suspected, and the extent of genomic damage is so severe that it leads to cell death. Therefore, in one embodiment of the technology described herein, a treatment method is provided, which includes: (a) selecting a subject having cells that express elevated levels of activation-induced cytidine deaminase (AID); and (b) administering a therapeutically effective amount of an inhibitor of double-strand break repair (e.g., a compound of the present disclosure) to the subject; wherein the elevated AID level is an AID level that is higher than the AID level in the same type of cells from a healthy individual. In certain embodiments, the cells expressing elevated levels of AID are B cells. In certain embodiments, the B cells expressing elevated levels of AID are cancerous B cells or B cells associated with autoimmune diseases. In certain embodiments, the subject can be a human subject.

[0915] 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 has been shown to be lethal to cells expressing AID because AID produces extensive genomic breaks, and treatment with double-strand break repair inhibitors prevents the repair of these damages that the cells themselves are producing. This results in cell death in the subject, which is specific to cells expressing AID (e.g., cancerous B cells and / or autoimmune cells). Therefore, as described herein, in one embodiment, a treatment paradigm is provided that selectively induces the self-destruction of certain diseased cells while reducing undesirable side effects in healthy tissues.

[0916] In certain embodiments, the level and / or activity of the increased DNA editing enzyme can be an increased DNA editing enzyme mRNA level. Using, for example, biochemistry and molecular biology techniques such as Northern blotting or other hybridization assays, nuclease protection assays, reverse transcription (quantitative RT-PCR) technology, RNA-Seq, high-throughput sequencing, etc., mRNA levels can be assessed. Such determination is well known to those skilled in the art. In one embodiment, nuclear "concatenation" (or "out of control") transcription assays are used (see, for example, Methods in Molecular Biology, Vol. 49, September 27, 1995, page range: 229-238). Arrays can also be used; in the past, arrays and methods for analyzing mRNA using such arrays have been described, for example, in EP0834575, EP0834576, WO96 / 31622, U.S. Patent No. 5,837,832 or WO98 / 30883. WO97 / 10365 provides a method for monitoring the expression level of multiple genes using high-density oligonucleotide arrays.

[0917] In certain embodiments, a subject can be determined to have an increased level of DNA damage relative to a reference level in one or more cell types if the subject has been exposed to an agent known to cause such DNA damage. Non-limiting examples of such agents can include viral infection with DNA integrating viruses (e.g., adeno-associated viruses, retroviruses, human T-lymphotropic viruses, HIV-1, tumor viruses, hepatitis viruses, hepatitis B viruses), chemicals that damage DNA (e.g., acetaldehyde, polycyclic aromatic hydrocarbons, benzene, nitrosamines, tobacco smoke, aflatoxins, etc.), chemotherapeutic agents that damage DNA (e.g., bleomycin, mitomycin, nitrogen mustards (e.g., mechlorethamine, cyclophosphamide, melphalan, chlorambucil, isocyclobutane, chlorambucil ... The invention also includes but is not limited to: phosphamide 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 diazocone (AZQ)), cisplatins (e.g., cisplatin, carboplatin and oxaliplatin), procarbazine and hexamethylmelamine), and ionizing radiation or ultraviolet radiation. Exposure to such agents can be the result of accident, infection and / or environmental exposure, or the result of therapeutic administration of such agents.

[0918] In certain embodiments, increased DNA damage levels can occur in cell types affected by cancer, autoimmune diseases, and / or neurodegenerative diseases. In certain embodiments, a subject is determined to have increased DNA damage levels occurring in specific cells selected from cancer cells (e.g., pancreatic cancer cells); immune system cells; or nervous system cells.

[0919] In certain embodiments, the DNA editing enzyme may be AID. In certain embodiments, the AID level may be the AID level in blood cells. In certain embodiments, the AID level may be the AID level in B cells.

[0920] In certain embodiments, the increased level of AID can be a detectable level of AID, eg, as described below.

[0921] In certain embodiments, the subject can be a human subject.

[0922] 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 has been shown to be lethal to cells expressing AID because AID produces extensive genomic breaks, and treatment with double-strand break repair inhibitors prevents the repair of these damages that the cells themselves are producing. This results in cell death in the subject, which is specific to cells expressing AID (e.g., cancerous B cells and / or autoimmune cells). Therefore, as described herein, in one embodiment, a treatment paradigm is provided that selectively induces the self-destruction of certain diseased cells while reducing undesirable side effects in healthy tissues.

[0923] Methods for defective cancer in patients with increased levels of DNA damage or increased levels of DNA editing enzymes are disclosed in WO 2016 / 094897, which is incorporated herein by reference.

[0924] In certain embodiments, the cancer to be treated is of a type that has high expression of a DNA editing enzyme. In certain embodiments, the cancer to be treated is a B-cell tumor.

[0925] Another embodiment is a method of treating cancer by administering to the subject an effective amount of one or more disclosed compounds or pharmaceutically acceptable salts thereof or corresponding pharmaceutical compositions. In one aspect, the cancer is selected from lymphoma, leukemia, and plasmacytoma. In another aspect, the cancer is selected from carcinoma and sarcoma.

[0926] In certain embodiments, the cancer to be treated is pancreatic cancer.

[0927] In certain embodiments, the pancreatic cancer is exocrine pancreatic cancer. In certain embodiments, the exocrine pancreatic cancer is an adenocarcinoma. In certain embodiments, the exocrine pancreatic cancer is a squamous cell carcinoma. In certain embodiments, the exocrine pancreatic cancer is an adenosquamous carcinoma. In certain embodiments, the exocrine pancreatic cancer is a colloid carcinoma.

[0928] In certain embodiments, the pancreatic cancer is a neuroendocrine pancreatic cancer. In certain embodiments, the neuroendocrine pancreatic cancer is a non-functioning neuroendocrine tumor. In certain embodiments, the neuroendocrine pancreatic cancer is a gastrinoma. In certain embodiments, the neuroendocrine pancreatic cancer is an insulinoma. In certain embodiments, the neuroendocrine pancreatic cancer is a glucagonoma.

[0929] In certain embodiments, the neuroendocrine pancreatic cancer is a vasoactive intestinal peptide tumor (i.e., a pancreatic islet cell tumor that affects vasoactive intestinal peptide). In certain embodiments, the neuroendocrine pancreatic cancer is a somatostatinoma (i.e., a pancreatic islet cell tumor that affects somatostatin).

[0930] In certain embodiments, the pancreatic cancer is a benign precancerous lesion.

[0931] In certain embodiments, the cancer to be treated is a lymphoma. Lymphomas that can be treated by the disclosed methods include: non-Hodgkin lymphoma; Burkitt lymphoma; small lymphocytic lymphoma; lymphoplasmacytic lymphoma; MALT lymphoma; follicular lymphoma; diffuse large B-cell lymphoma; and T-cell lymphoma.

[0932] Lymphoma is a malignant tumor of the lymphocytes (e.g., B cells, T cells, or natural killer (NK) cells) of the immune system. Lymphomas often originate in the lymph nodes and exist as solid tumors. They can metastasize to other organs such as the brain, bones, or skin. Extranodal sites are often located in the abdomen. Lymphomas are closely related to lymphoid leukemias, and in some cases, specific forms of cancer are classified as both lymphomas and leukemias.

[0933] Leukemias that can be treated by the disclosed methods include: acute lymphoblastic leukemia (ALL); Burkitt's leukemia; B-cell leukemias; 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).

[0934] In certain embodiments, the cancer to be treated is a B-cell neoplasm, a B-cell leukemia, a B-cell acute lymphoblastic leukemia, a chronic lymphocytic leukemia, a chronic myeloid leukemia, a Burkitt's leukemia, an acute myeloid leukemia, and / or a T-ALL. When foreign antigens have been neutralized, the maturation of B cells most typically stops or is significantly reduced. However, occasionally, the proliferation of specific B cells continues unabated; such proliferation can lead to a cancer known as a "B-cell lymphoma" or "B-cell leukemia." In certain embodiments, the cancer to be treated is chronic lymphocytic leukemia (CLL) or chronic myeloid leukemia (CML).

[0935] In certain embodiments, the cancer to be treated is a plasma cell neoplasm. Examples of plasma cell neoplasms include: multiple myeloma; plasma cell myeloma; plasma cell leukemia and plasma cell neoplasm.

[0936] Cancers that may 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.

[0937] Sarcomas treatable by the disclosed methods include soft tissue sarcomas and bone sarcomas.

[0938] Any cancer characterized by high levels of DNA damage and / or DNA editing enzyme expression can be treated with compounds as 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 bile duct epithelial carcinoma may be characterized by high levels of DNA editing enzyme expression, such as AID. In certain embodiments, the cancer to be treated is colon cancer, liver cancer, gastric cancer, intestinal cancer, breast cancer, lung cancer, thyroid cancer, and / or bile duct epithelial carcinoma.

[0939] Some of the cancers that can be treated by the disclosed methods include bladder cancer, blood cancer, bone cancer, bone marrow cancer, brain cancer, breast cancer, colon cancer, esophageal cancer, gastrointestinal cancer, gum cancer, head cancer, kidney cancer, liver cancer, lung cancer, nasopharyngeal cancer, neck cancer, ovarian cancer, prostate cancer, skin cancer, stomach cancer, testicular cancer, tongue cancer, or uterine cancer. Furthermore, the cancer may be of the following histological types, although it is not limited thereto: malignant neoplasm; carcinoma; undifferentiated carcinoma; giant cell and 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; malignant gastrinoma; cholangiocarcinoma; hepatocellular carcinoma; combined hepatocellular and cholangiocarcinoma; trabecular adenocarcinoma; adenoid cystic carcinoma; adenocarcinoma in adenomatous polyps; adenocarcinoma, familial polyposis coli; solid carcinoma; malignant carcinoid tumor; bronchioalveolar adenocarcinoma; papillary adenocarcinoma; chromophobe cell carcinoma; oncocytic carcinoma; oncocytic adenocarcinoma; basophilic cell carcinoma; hyaline cell carcinoma adenocarcinoma; granulosa cell carcinoma; follicular adenocarcinoma; papillary and follicular adenocarcinomas; non-cystic sclerosing carcinoma; adrenocortical carcinoma; endometrioid carcinoma; skin appendage carcinoma; apocrine sweat gland carcinoma; sebaceous gland carcinoma; cervical gland carcinoma; 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; acinar cell carcinoma; adenosquamous carcinoma; adenocarcinoma with squamous transformation; malignant thymoma; malignant ovarian stromal tumor; malignant thecoma cell tumor; malignant granulosa cell tumor; malignant testicular blastoma; Sertoli cell carcinoma; malignant Leydig cell tumor; Malignant lipid cell tumor; malignant paraganglioma; malignant extramammary paraganglioma; pheochromocytoma; glomus sarcoma; malignant melanoma; amelanotic melanoma; superficial spreading melanoma; malignant melanoma in giant nevus; epithelioid cell melanoma; malignant blue nevus; sarcoma; fibrosarcoma; malignant fibrous histiocytoma; myxosarcoma; liposarcoma; leiomyosarcoma; rhabdomyosarcoma; embryonal rhabdomyosarcoma; alveolar rhabdomyosarcoma; stromal sarcoma; malignant mixed tumor; mixed Müllerian tumor; Wilms' tumor; hepatoblastoma; carcinosarcoma; malignant mesenchymal tumor; malignant Brenner tumor; malignant phyllodes tumor; synovial sarcoma; malignant mesothelioma; dysgerminoma; embryonal carcinoma; malignant teratoma fetal tumor; malignant ovarian goiter; choriocarcinoma; malignant mesonephroma; angiosarcoma; malignant hemangioendothelioma; Kaposi's sarcoma; malignant hemangiopericytoma; lymphangiosarcoma; osteosarcoma; juxtacortical osteosarcoma; chondrosarcoma; malignant chondroblastoma; mesenchymal chondrosarcoma; giant cell tumor of bone; Ewing's sarcoma; malignant odontoma; ameloblastic odontosarcoma; malignant ameloblastoma; ameloblastic fibrosarcoma; malignant pinealoma; chordoma; malignant glioma; ependymoma; astrocytoma; protoplasmic astrocytoma; fibrillary astrocytoma; astroblastoma; glioblastoma; oligodendroglioma; oligodendroglioma; primitive neuroectodermal tumor;Cerebellar sarcoma; ganglioblastoma; neuroblastoma; retinoblastoma; olfactory neurogenic tumor; malignant meningioma; neurofibrosarcoma; malignant neurilemoma; malignant granular cell tumor; malignant lymphoma; Hodgkin's disease; Hodgkin's; paragranuloma; small lymphocytic malignant lymphoma; diffuse large cell malignant lymphoma; follicular malignant lymphoma; mycosis fungoides; other specified non-Hodgkin's lymphomas; malignant histiocytosis; multiple myeloma; mast cell sarcoma; immunoproliferative small intestinal disease; leukemia; lymphoid 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.

[0940] In another embodiment of the disclosed method, the cancer is characterized by mutS Homologs (e.g., MSH2, MSH3, and MSH6), mutL Homologs ( For example MLH1) or mutations in the mismatch repair endonuclease PMS2. Mutations are changes in the genetic code. They include point mutations and frameshift mutations. In a point mutation, one nucleotide is exchanged for another. Therefore, the mutation occurs at a single point or position within the DNA chain. Frameshift mutations are due to the insertion or deletion of nucleotides. This results in an elongation or reduction in the size of the entire DNA chain. Therefore, frameshift mutations can change all codons that appear after the deletion or insertion. Mutations referred to herein include, but are not limited to, insertions, deletions, duplications, inversions or other recognized point mutations. It has now been found that RAD51 inhibitors are effective in treating patients with MSH ( For example, MSH6) It is particularly effective in cancers harboring mutations in MLH, PMS2, or PD-L1.

[0941] MutS homolog 2 ( MSH2 ) is located on chromosome 2 in humans. MSH2 Protein encoded by a gene. MSH2 is a tumor suppressor gene and, for example, a watchdog gene that encodes a DNA mismatch repair (MMR) protein MSH2 , which forms a heterodimer with MSH6 to generate 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. Examples of mutations in MSH2 include, but are not limited to

[0942]

[0943]

[0944]

[0945]

[0946]

[0947]

[0948] .

[0949] MutS homolog 3 ( MSH3 ) is a human homolog of the bacterial mismatch repair protein MutS, which participates in the mismatch repair (MMR) system. MSH3 normally forms a heterodimer with MSH2, MutSβ, to correct long insertion / deletion loops and base-base mismatches in microsatellites during DNA synthesis. Defective MMR 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. Examples of mutations in MSH3 include, but are not limited to, g.79970809del.

[0950] MSH6 Encodes MutS homolog 6 (MSH6), a member of the Mutator S (MutS) family of proteins involved in DNA mismatch repair (MMR). In both humans and yeast, the MSH6 protein forms a heterodimer with MutS homolog 2 (MSH2). Human MSH2 / 6 recognizes single base-base mismatches and short insertion / deletion loops. Following mismatch recognition, the MSH2 / 6 complex binds ADP and exchanges it for ATP, leading to conformational changes in the complex prior to base pair dissolution, base excision, and repair.

[0951] MSH6 Mutations include frameshift and / or nonsense mutations and can result in non-functional MSH6 Examples include a frameshift mutation at amino acid residue 290 of MSH6 and the compound missense T1189I mutation.

[0952] Inactivation can be detected in cancer by conventional diagnostic methods MSH6Mutations. These methods include, but are not limited to, obtaining cancer cells and other diagnostic indicators such as peripheral blood mononuclear cells (PBMCs), PBMC subsets, circulating blasts (CD34+ cells), circulating tumor cells, and circulating exonuclear cancer cells by biopsy and blood tests, as well as by obtaining lymph or other body fluids. Whether the cancer is positive is then determined from the cancer cells or other diagnostic indicators 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 TM Gene expression profiles showed inactivation MSH6 Mutation, or expression of MSH6 protein by immunohistochemistry, flow cytometry, immunocytochemistry, or Western blot. MSH6 The mutation method is disclosed in Houlleberghs H, Goverde A, Lusseveld 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.

[0953] MSH6 Examples of mutations include, but are not limited to

[0954]

[0955]

[0956] .

[0957] MutL homolog 1, colon cancer, nonpolyposis type 2 (Escherichia coli) is a protein encoded by the MLH1 gene located on chromosome 3 in humans. It is a gene commonly associated with hereditary nonpolyposis colorectal cancer.

[0958] MSH6 Examples of mutations in include, but are not limited to

[0959]

[0960]

[0961]

[0962]

[0963] .

[0964] people PMS2 The relevant genes are located on bands 7p12, 7p13, 7q11, and 7q22. Exons 1 to 5 of these homologs share high identity with human PMS2. The product of this gene is involved in DNA mismatch repair. The 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 the cause of supratentorial primitive neuroectodermal tumors.

[0965] Examples of mutations in PMS2 include, but are not limited to

[0966]

[0967]

[0968] .

[0969] The present disclosure provides methods of treating a patient with Lynch syndrome to reduce the likelihood of developing or treat cancer derived from Lynch syndrome by administering to the subject an effective amount of one or more disclosed compounds or pharmaceutically acceptable salts thereof or corresponding pharmaceutical compositions.

[0970] Lynch syndrome is an inherited disorder caused by mutations in mismatch repair genes in which affected individuals have a higher than normal chance of developing colorectal cancer, endometrial cancer, and various other types of aggressive cancers, often at a young age, also known as hereditary nonpolyposis colon cancer (HNPCC).

[0971] Mutations in specific mismatch repair (MMR) genes, including but not limited to MLH1, MSH2, MSH6, PMS2, and EPCAM-TACSTD1 deletions, are the cause of Lynch syndrome. These genes play a role in repairing errors made when DNA is replicated in preparation for cell division. Defects in the genes do not allow DNA errors to be repaired, and as cells divide, errors accumulate and uncontrolled cell growth can lead to cancer.

[0972] Those with Lynch syndrome have up to an 85% risk of developing colon cancer and also have a higher-than-average risk of developing cancers of the endometrium, stomach, pancreas, kidney / ureter, hepatobiliary tract, gastric duct, prostate, ovary, cystic duct, brain, small intestine, breast, and skin.

[0973] In certain embodiments of the disclosed methods, the method is a method of treating a cancer derived from Lynch syndrome selected from the group consisting of colon cancer, endometrial cancer, gastric cancer, pancreatic cancer, kidney / ureter cancer, hepatobiliary tract cancer, gastric duct cancer, prostate cancer, ovarian cancer, cystic duct cancer, brain cancer, small intestine cancer, breast cancer, and skin cancer.

[0974] In certain embodiments, the method is a method of 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; subacute cutaneous lupus erythematosus; cutaneous lupus erythematosus, including pernio-like lupus erythematosus; chronic arthritis; Sjögren's syndrome; inflammatory chronic rhinosinusitis; 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 diseases.

[0975] In certain embodiments, the method is a method of treating an immunodeficiency selected from the group consisting of autoimmune lymphoproliferative syndrome (ALPS), autoimmune polyglandular syndrome type 1 (APS-1), BENTA disease, caspase 8 deficiency state (CEDS), chronic granulomatous disease (CGD), common variable immunodeficiency (CVID), congenital neutropenia syndrome, CTLA4 deficiency, DOCK8 deficiency, GATA2 deficiency, glycosylation disorders with immunodeficiency, hyperimmunoglobulin E syndrome (HIES), hyperimmunoglobulin M (Hyper-IgM) syndrome, leukocyte adhesion deficiency (LAD), LRBA deficiency, PI3 kinase disease, PLCG2-related antibody deficiency and immunoregulatory dysregulation (PLAID), severe combined immunodeficiency (SCID), STAT3 gain of function disease, warts, hypogammaglobulinemia, infection and congenital myelocytic syndrome (WHIMS), X-linked agammaglobulinemia (XLA), X-linked lymphoproliferative disease (XLP) and XMEN disease.

[0976] As used herein, the term "immunodeficiency" refers to a condition in which a portion or parts of the cellular components that make up the immune system are defective or dysfunctional, thereby impairing normal immune mechanisms. In other words, "immunodeficiency" refers to a condition in which innate immunity and / or acquired immunity are suppressed and / or reduced. In certain embodiments, an immunodeficient subject is an immunocompromised subject. Non-limiting examples of immunodeficiency can include AIDS, hypogammaglobulinemia, agammaglobulinemia, agranulocytosis, chronic granulomatous disease, asplenia, SCID, complement deficiency, and / or sickle cell anemia.

[0977] In certain embodiments, the method is a method of treating a neurodegenerative disorder selected from multiple sclerosis, Parkinson's disease (PD), Alzheimer's disease (AD), dentatorubral pallidohypothalamic 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), spinobulbar muscular ataxia / Kennedy's disease (SBMA), fragile X syndrome (FRAXA), fragile XE mental retardation (FRAXE), and myotonic dystrophy (DM).

[0978] A "subject" is a mammal, preferably a human, but can also be an animal requiring veterinary treatment, for example, companion animals (e.g., dogs, cats, etc.), farm animals (e.g., cattle, sheep, pigs, horses, etc.), and laboratory animals (e.g., rats, mice, guinea pigs, etc.).

[0979] In certain embodiments, the methods disclosed herein further comprise co-administering an effective amount of a DNA repair inhibitor, a DNA damage response (DDR) inhibitor, a DNA damaging agent, or an immunomodulatory agent to a subject being treated for cancer in addition to an effective amount of a disclosed RAD51 inhibitor.

[0980] The term "DNA repair inhibitor" refers to any agent that targets the components / processes that cells use to repair mutations or changes in DNA and restore 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.

[0981] 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 DNA damage repair. Examples of DNA damage response inhibitors include checkpoint inhibitors, ATM and ATR inhibitors, DNA-PK inhibitors, and the like.

[0982] The term "DNA damaging agent" refers to any agent that directly or indirectly damages DNA (which can be repaired by homologous recombination). The DNA damaging agent is selected from the group consisting of: exposure to chemicals that damage DNA, exposure to chemotherapeutic agents, exposure to radiochemotherapy, and exposure to ionizing radiation or ultraviolet radiation. Some examples of chemotherapeutic agents that damage DNA include alkylating agents, nitrosoureas, antimetabolites, plant alkaloids, plant extracts, and radioisotopes. Some examples of chemotherapeutic agents also include DNA damaging drugs, for example, 5-fluorouracil (5-FU), capecitabine, S-1 (tegafur, 5-chloro-2,4-dihydroxypyridine and oxonic acid), 5-ethynyluracil, arabinosylcytosine (cytarabine), 5-azacytidine (5-AC), 2',2'-difluoro-2'-deoxycytidine (dFdC), purine antimetabolites (mercaptopurine, azathioprine, thioguanine), gemcitabine hydrochloride (gemcitabine), pentostatin, allopurinol, 2-fluoro-arabinosyl-adenine (2F-ara-A), hydroxyurea, sulfur mustard (bischloroethyl sulfide), nitrogen mustard, melphalan, chlorambucil, cyclophosphamide, ifosfamide, thiotepa, AZQ, mitomycin C, cyclopentol, dibromodulcitol, alkyl sulfonates (busulfan), nitrosoureas (BCNU, CCNU, 4-methyl CCNU or ACNU), procarbazine, decamidine, photinib, anthracyclines such as doxorubicin (adriamycin; ADR), daunorubicin (Cerubicin), idarubicin (idarubicin) and epirubicin (epirubicin hydrochloride), anthracycline analogs such as mitoxantrone, actinomycin D, non-intercalating topoisomerase inhibitors such as epipodophyllotoxins (etoposide or VP16, teniposide or VM-26), podophyllotoxin, bleomycin (Bleo), peplomycin, 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 α-, β- or γ-radiation, and environmental shock, such as excessive heat.

[0983] "Immunomodulator" refers to an agent that modulates the immune response to an antigen but is not an antigen and is not derived from an antigen. As used herein, "modulate" means to induce, enhance, inhibit, direct or redirect an immune response. Such agents include immunostimulants, such as adjuvants, which stimulate (or enhance) the immune response to an antigen but are not an antigen and are not derived from an antigen. There are several different types of immunomodulators, including but not limited to Toll-like receptor (TLR) agonists and Toll-like receptor (TLR) antagonists. Such agents also include immunosuppressants. Immunomodulators are selected from immune checkpoint regulators, Toll-like receptor (TLR) agonists, cell-based therapies, cytokines and cancer vaccines.

[0984] In certain embodiments, it is determined that the subject has an increased DNA damage process or the level and / or activity of a DNA editing enzyme. In one aspect of this embodiment, the DNA editing enzyme is selected from activation-induced cytidine deaminase (AID or AICDA), APOBEC2, APOBEC3A, APOBEC3C, APOBEC3D, APOBEC3F, APOBEC3G, APOBEC3H, APOBEC4, type 1 topoisomerase, type 2 topoisomerase, recombination activation gene 1 (RAG 1) and recombination activation gene 2 (RAG2).

[0985] In certain embodiments, blood cells obtained from a subject have been determined to have detectable levels of activation-induced cytidine deaminase (AID).

[0986] In certain embodiments, B cells obtained from the subject have been determined to have detectable levels of activation-induced cytidine deaminase (AID).

[0987] In certain 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 healthy subjects.

[0988] Method of administration and dosage form

[0989] The precise 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 on characteristics of the subject, such as general health, age, sex, weight, and tolerance to drugs. A skilled artisan will be able to determine an appropriate dosage based on these and other factors. When administered in combination with other therapeutic agents, for example, when administered in combination with an anticancer agent, an "effective amount" of any additional therapeutic agent or agents will depend on the type of drug used. For approved therapeutic agents, appropriate dosages are known and can be adjusted by the skilled artisan depending on the condition of the subject, the type of condition being treated, and the amount of a compound of the disclosure being used, for example by following the guidelines reported in the literature and Physician's Desk Reference (57th edition, 2003) recommended dosage.

[0990] The term "effective amount" refers to an amount that, when administered to a subject, results in a beneficial or desired outcome (including a clinical outcome, such as inhibition, suppression, or alleviation of symptoms of the condition being treated in the subject) compared to a control. For example, a therapeutically effective amount can be administered in a unit dosage form (e.g., 0.1 mg to about 50 g per day, alternatively 1 mg to about 5 grams per day).

[0991] As used herein, the terms "administer," "administering," "administration," and the like refer to methods that can be used to enable delivery of a composition to a desired site of biological action. These methods include, but are not limited to, intraarticularly (in a joint), intravenously, intramuscularly, intratumorally, intradermally, intraperitoneally, subcutaneously, orally, topically, intrathecally, by inhalation, transdermally, rectally, and the like. Administration techniques that can be used with the agents and methods described herein are described, for example, in Goodman and Gilman, The Pharmacological Basis of Therapeutics , current edition; Pergamon; and Remington's, Pharmaceutical Sciences (Current Edition), Mack Publishing Co., Easton, Pa.

[0992] In addition, the disclosed RAD51 inhibitors can be co-administered with other therapeutic agents. The terms "co-administered," "administered in conjunction with ... " and their grammatical equivalents used herein are intended to encompass administration of two or more therapeutic agents to a single subject, and are intended to include treatment regimens in which the medicament is administered by the same or different routes of administration or at the same or different times. In certain embodiments, one or more compounds described herein will be co-administered with other agents. These terms encompass administration of two or more medicaments to an object so that two medicaments and / or their metabolites are present in the object simultaneously. They are included in simultaneous administration in separate compositions, administration at different times in separate compositions, and / or administration in compositions in which both medicaments are present. Therefore, in certain embodiments, compounds described herein and other agents are administered in a single composition. In certain embodiments, compounds described herein and other agents are mixed in a composition.

[0993] The specific mode of administration and dosage regimen will be selected by the attending clinician taking into account the details of the case (e.g., subject, disease, disease state involved, specific treatment). Treatment may include daily or multiple daily doses or less than daily doses (e.g., weekly or monthly, etc.) over a period of several days to several months or even several years. However, those of ordinary skill in the art will immediately recognize appropriate and / or equivalent doses by reviewing the dosages of the approved compositions for treating RAD51-mediated diseases using the disclosed RAD51 inhibitors as a guide.

[0994] As will be appreciated by those skilled in the art, the compounds or corresponding pharmaceutical compositions of the present teachings can be administered to the patient in various forms, depending on the route of administration selected. For example, the compounds of the present teachings can be administered orally, parenterally, buccally, sublingually, nasally, rectally, by patch, pump, or transdermally and correspondingly formulated pharmaceutical compositions. Parenteral administration includes intravenous, intraperitoneal, subcutaneous, intramuscular, transepithelial, nasal, intrapulmonary, intrathecal, rectal, and topical administration. Parenteral administration can be by continuous infusion over a selected time period.

[0995] The pharmaceutical compositions of the present disclosure are formulated to be compatible with their intended route of administration. In one embodiment, the compositions are formulated into pharmaceutical compositions suitable for intravenous, subcutaneous, intramuscular, oral, intranasal or topical administration to humans according to conventional procedures. In a preferred embodiment, the pharmaceutical compositions are formulated for intravenous administration.

[0996] Typically, for oral therapeutic administration, compounds of the present teachings may be incorporated with excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like.

[0997] Generally, for parenteral administration, solutions of the compounds of the present teachings can be prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycol, DMSO, and mixtures thereof with or without alcohol, as well as in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.

[0998] Generally, for injectable use, sterile aqueous solutions or dispersions of the compounds described herein and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions are suitable. Example

[0999] abbreviation:

[1000] Ac acetyl

[1001] ACN acetonitrile

[1002] aq water-based

[1003] Bn benzyl

[1004] Boc tert-Butoxycarbonyl

[1005] br. wide

[1006] d Doublet (only when used in 1H NMR spectra)

[1007] DCM dichloromethane

[1008] DIEA(DIPEA) Diisopropylethylamine

[1009] DMA dimethylacetamide

[1010] DMAP 4-dimethylaminopyridine

[1011] DMF N,N-dimethylformamide

[1012] DMSO dimethyl sulfoxide

[1013] dppf 1,1'-bis(diphenylphosphino)ferrocene

[1014] eq equivalent

[1015] EtOAc

[1016] hr hours

[1017] HBTU N,N,N',N', -Tetramethyl-O-(1 H -Benzotriazol-1-yl)uronium hexafluorophosphate

[1018] HPLC high-performance liquid chromatography

[1019] LC-MS Liquid chromatography coupled with mass spectrometry

[1020] m multiplet

[1021] MS ESI mass spectrometry, electrospray ionization

[1022] NBS N -Bromosuccinimide

[1023] NMR Nuclear Magnetic Resonance

[1024] prep

[1025] Py pyridine

[1026] s single peak

[1027] sat saturated

[1028] SFC Supercritical Fluid Chromatography

[1029] t Triplet

[1030] TEA triethylamine

[1031] TFA trifluoroacetic acid

[1032] THF Tetrahydrofuran

[1033] TLC thin layer chromatography

[1034] Tol Toluene

[1035] General approach Reaction name A B C D E F G H I J K L M N O

[1036] Example 1. Synthesis of (S)-(1-methylpyrrolidin-2-yl)methyl (4-(2-(4-((benzylcarbamoyl)oxy)piperidin-1-yl)thiazol-5-yl)-3-(N-(tert-butyl)sulfamoyl)phenyl)carbamate

[1037] Option 1:

[1038]

[1039] General Method D for the Preparation of Sulfonamide Compound 12

[1040]

[1041] Towards 5-Amino-2-(2-bromothiazol-5-yl)-N-tert-butyl-benzenesulfonamideTo a solution of 4-[4-[4-[4-[4-[4-[4-[4-[4-[4-dimethylamino]-1-piperidin-1-yl]-1-oxo-1-yl]propane-2 ... N-[4-(2-bromothiazol-5-yl)-3-(tert-butylsulfamoyl) acyl)phenyl]acetamide (1.5 g, 3.5 mmol, 27% yield). ESI [M+H] = 433.9 / 431.9.

[1042] General Method A for the Preparation of Sulfonamide Compound 13

[1043]

[1044] Towards N-[4-(2-Bromothiazol-5-yl)-3-(tert-butylsulfamoyl)phenyl]acetamide To a solution of 4-piperidin-4-ol (700 mg, 1.6 mmol, 1 equivalent) in DMF (20 mL) was added KCO (448 mg, 3.3 mmol, 2 equivalents) and piperidine-4-ol (246 mg, 2.4 mmol, 1.5 equivalents). The mixture was stirred at 100 ° C for 12 hours and then poured into H O (100 mL). The aqueous phase was extracted with EtOAc (50 mL x 3), the combined organic layer was washed with brine (100 mL), dried over Na SO, filtered and concentrated. The residue was purified by column chromatography (SiO , petroleum ether: ethyl acetate = 1: 2) to obtain 4-piperidin-4-ol as a yellow solid. N-[3-(tert-Butylsulfamoyl)-4-[2-(4-hydroxy-1-piperidinyl)thiazol-5-yl]phenyl]acetamide (550 mg, 1.2 mmol, 13.2% yield). 1 H NMR (400 MHz, 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.

[1045] General Method F for the preparation of sulfonamide compound 15.

[1046]

[1047] Will N-Benzylcarbamic acid [1-[5-[4-acetylamino-2-(tert-butylsulfamoyl)phenyl]thiazol-2-yl]- 4-piperidinyl] ester (380 mg, 649 umol, 1 equivalent) was dissolved in HCl / MeOH (4 M, 20 mL) and the mixture was stirred at 20 ° C for 1 hour. The mixture was concentrated, diluted with saturated Na2CO3 aqueous solution (20 mL), and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (SiO2, petroleum ether: ethyl acetate = 10: 1 to 1: 1) to obtain N-Benzylcarbamic acid 1-[5-[4-amino-2-(tert-butylsulfamoyl)phenyl]thiazol-2-yl]-4-piperidinyl] ester (300 mg, 552 umol, 85% yield). ESI [M+H] = 544.2.

[1048] General Method H for the Preparation of Example 1

[1049]

[1050] To a solution of [(2S)-1-methylpyrrolidin-2-yl]methanol (42 mg, 367 umol, 2 eq.) and DIEA (71.11 mg, 550 umol, 3 eq.) in MeCN (5 mL) was added N-Benzylcarbamic acid [1-[5-[2-(tert-butyl 4-[(4-nitrophenoxy)carbonylamino]phenyl]thiazol-2-yl]-4-piperidinyl]sulfamoyl) (130 mg, 184 umol, 1 eq) in DCM (2 mL) and the mixture was refluxed for 1 hour. The mixture was concentrated and the residue was purified by preparative HPLC to give (4-(2-(4-((Benzylcarbamoyl)oxy)piperidin-1-yl) (S)-(1-methylpyrrolidin-2-yl)methyl thiazol-5-yl)-3-(N-(tert-butyl)sulfamoyl)phenyl)carbamate (19.87 mg, 28.8 umol, 15.7% yield, 99.3% purity). 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.

[1051] Example 2. N-Benzylcarbamate [1-[5-[2-(tert-butylsulfamoyl)-4-[[(2R)-1-methylpyrrole [alkyl-2-yl]methoxycarbonylamino]phenyl]thiazol-2-yl]-4-piperidinyl] ester The synthesis of.

[1052] Through key intermediates 16 The following compounds were synthesized by the same method.

[1053]

[1054] N-Benzylcarbamic acid [1-[5-[2-(tert-butylsulfamoyl)-4-[[(2R)-1-methylpyrrolidin-2-yl]methyl] [oxycarbonylamino]phenyl]thiazol-2-yl]-4-piperidinyl] ester . 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, 8.5Hz, 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.

[1055] Example 3. N-isopropylcarbamate [1-[5-[4-(benzylcarbamoylamino)-2-(tert-butylaminosulfonyl) 1-[4-(2-[4-thiazol-2-yl)phenyl]thiazol-2-yl]-4-piperidinyl] ester synthesis.

[1056] Option 2:

[1057]

[1058] Preparation of compound 23.

[1059]

[1060] General Method A, 1-Benzyl-3-[3-(tert-butylsulfamoyl)-4-[2-(4-hydroxy-1-piperidinyl)thiazole-5- phenyl]urea . ESI [M+H] = 544.1.

[1061] Preparation of Example 3.

[1062]

[1063] Towards 1-Benzyl-3-[3-(tert-butylsulfamoyl)-4-[2-(4-hydroxy-1-piperidinyl)thiazol-5-yl]phenyl] urea To a solution of 4-[[(4-[ ... N-isopropylamino [1-[5-[4-(benzylcarbamoylamino)-2-(tert-butylsulfamoyl)phenyl]thiazol-2-yl]-4-piperidinyl] ester (28.31 mg, 99.2% purity). 1H NMR (400 MHz, 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.

[1064] Example 4. 4-[5-[2-(tert-butylsulfamoyl)-4-(2-pyridylmethylcarbamoylamino)phenyl]thiol [2-oxazol-2-yl]piperidine-1-carboxylic acid isopropyl ester The synthesis of.

[1065] Option 3:

[1066]

[1067] Preparation of compound 45

[1068]

[1069] General method D, 4-Nitrophenyl (4-bromo-3-(N-(tert-butyl)sulfamoyl)phenyl)carbamate . ESI[M+H] =474.1

[1070] General Method E for the Preparation of Sulfonamide Compound 46

[1071]

[1072] To a solution of 2-pyridylmethylamine (352 mg, 3.3 mmol, 5 eq.) and DIEA (84 mg, 650 umol, 1 eq.) in DCM (3 mL) was added N-[4-Bromo-3-(tert-butylsulfamoyl)phenyl]carbamic acid (4-nitrobenzene ester (307 mg, 650 umol, 1 eq) in DCM (3 mL). The mixture was stirred at 25 ° C for 1 hour, then diluted with DCM (30 mL) and washed with H2O (20 mL x 2). The organic layer was concentrated and the residue was purified by preparative TLC (SiO2, petroleum ether: ethyl acetate = 0:1) to give 1-[4-bromo-3-(tert-butylaminosulfonyl) acyl)phenyl]-3-(2-pyridylmethyl)urea(180 mg, crude). ESI [M+H] = 441.2 / 443.2.

[1073] Preparation of compound 47

[1074]

[1075] Will 1-[4-Bromo-3-(tert-butylsulfamoyl)phenyl]-3-(2-pyridylmethyl)urea A mixture of 4-(140 mg, 317.21 umol, 1 eq), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (322.21 mg, 1.27 mmol, 4 eq), Pd(dppf)Cl2 (116.05 mg, 158.61 umol, 0.5 eq) and KOAc (93.39 mg, 951.64 umol, 3 eq) in dioxane (4 mL) was degassed and purged with N2 three times, and then the mixture was stirred at 80° C. under N2 atmosphere for 12 hours. 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-(Uncle butylsulfamoyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3-(2-pyridyl Methylurea (50 mg, 89.37 umol, 28.17% yield, 87.3% purity). ESI [M+H] = 489.4.

[1076] General Method K for the Preparation of Compound Example 4

[1077]

[1078] Will 1-[3-(tert-butylsulfamoyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2- 1-(2-pyridylmethyl)phenyl)urea (26.38 mg, 54.01 umol, 1.2 equivalents), 4-(5-bromothiazol-2-yl) Isopropyl piperidine-1-carboxylate(15 mg, 45.01 umol, 1 equivalent), Na2CO3 (9.54 mg, 90.02 umol, 2 equivalents), KF (7.85 mg, 135.04 umol, 3 equivalents) and Pd(PPh3)4 (5.20 mg, 4.50 umol, 0.1 equivalent) in H2O (0.1 mL) / EtOH (0.3 mL) / toluene (0.3 mL) was degassed and purged 3 times with N2, and the mixture was then stirred at 85°C under N2 atmosphere for 12 hours. The reaction mixture was filtered and concentrated. The residue was purified by preparative TLC (SiO2, petroleum ether / ethyl acetate = 1 / 2) and then purified by preparative HPLC (TFA conditions) to obtain 4-[5-[2-(tert-butylsulfamoyl)-4-(2-pyridylmethylcarbamoylamino)phenyl]thiazole-2- 1-[4-[[4-[4-[4-amino]piperidine-1-carboxylic acid isopropyl ester]] (6.36 mg, 8.21 umol, 18.24% yield, 94.07% purity, TFA). 1 H 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.

[1079] Example 5. 4-[5-[2-(tert-Butylsulfamoyl)-4-(isopropoxycarbonylamino)phenyl]thiazol-2-yl] Isopropyl piperazine-1-carboxylate The synthesis of.

[1080] Option 4:

[1081]

[1082] Preparation of compound 56

[1083]

[1084] General Method A, 4-[5-[4-Acetylamino-2-(tert-butylsulfamoyl)phenyl]thiazol-2-yl]piperazine-1- tert-Butyl formate . ESI [M+H] = 538.2.

[1085] General Method C for the Preparation of Sulfonamide Compound 57.

[1086]

[1087] Towards tert-Butyl 4-[5-[4-acetylamino-2-(tert-butylsulfamoyl)phenyl]thiazol-2-yl]piperazine-1-carboxylate To a solution of (110 mg, 205 umol, 1 eq) in DCM (2 mL) was added TFA (1 mL) and the mixture was stirred at 25°C for 30 minutes. The mixture was concentrated to give N-[3-(tert-butylsulfamoyl)-4-(2-piperazine-1- 5-(2-Methylthiazol-5-yl)phenyl]acetamide (80 mg, 183 umol, 89.4% yield). ESI [M+H] = 438.2.

[1088] Preparation of compound 58

[1089]

[1090] General method D, 4-[5-[4-Acetylamino-2-(tert-butylsulfamoyl)phenyl]thiazol-2-yl]piperazine-1- Isopropyl formate . ESI [M+H] = 524.1.

[1091] Preparation of compound 59

[1092]

[1093] General method F, 4-[5-[4-amino-2-(tert-butylsulfamoyl)phenyl]thiazol-2-yl]piperazine-1-carboxylic acid isopropyl Propyl ester . ESI [M+H] = 482.1.

[1094] Preparation of Compound Example 5

[1095]

[1096] General method D, 4-[5-[2-(tert-butylsulfamoyl)-4-(isopropoxycarbonylamino)phenyl]thiazole-2- 1-[4-[ ...methyl]piperazine-1-carboxylic acid isopropyl ester]]] . 1 H NMR (400 MHz, 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.

[1097] Example 6. 4-[5-[4-(Benzyloxycarbonylamino)-2-(tert-butylsulfamoyl)phenyl]thiazol-2-yl]piperidin Isopropyl oxazine-1-carboxylate synthesis

[1098] Option 5:

[1099] Preparation of Compound Example 6

[1100]

[1101] General method D, 4-[5-[4-(Benzyloxycarbonylamino)-2-(tert-butylsulfamoyl)phenyl]thiazol-2-yl] Isopropyl piperazine-1-carboxylate . 1 H NMR (400 MHz, 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.

[1102] Example 7. trans-N-[3-(tert-butylsulfamoyl)-4-[2-[4-(cyclopentyloxycarbonylamino)cyclohexyl] Isopropyl thiazol-5-yl]phenyl]carbamate The synthesis of.

[1103] Option 6:

[1104]

[1105] General Method B for the Preparation of Sulfonamide Compound 83.

[1106]

[1107] Towards tert-Butyl (trans-4-(5-bromothiazol-2-yl)cyclohexyl)carbamate (1.3 g, 3.6 mmol, 2 eq) and N-[3-(tert-Butylsulfamoyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzene Isopropyl]carbamateTo a mixture of dioxane (12 mL) and H2O (2 mL) was added Na2CO3 (579 mg, 5.5 mmol, 3 eq) and Pd(dppf)Cl2 (133 mg, 182 umol, 0.1 eq). The mixture was stirred at 80 ° C for 12 hours under N2 atmosphere and then concentrated. The residue was diluted with H2O (5 mL) and extracted with ethyl acetate (5 mL x 3), dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (SiO2, petroleum ether: ethyl acetate = 1:0 to 3:1) to give trans-N-[4-[2-[4-(tert-butoxycarbonylamino) Isopropyl]cyclohexyl]thiazol-5-yl]-3-(tert-butylsulfamoyl)phenyl]carbamate (660 mg, crude), of which 60 mg was purified by preparative HPLC (column: Agela Durashell C18 150X25 5u; mobile phase: [water (0.04% NH3H2O)-ACN]; B%: 60%-90%, 10 min) to give pure Compound 83 (40.92 mg, 99.64% purity) for delivery. 1 H 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.

[1108] Preparation of compound 84

[1109]

[1110] General method F, trans-N-[4-[2-(4-aminocyclohexyl)thiazol-5-yl]-3-(tert-butylsulfamoyl)benzene Isopropyl] carbamate.ESI [M+H] = 495.2.

[1111] Preparation of Example 7.

[1112]

[1113] General method D, trans-N-[3-(tert-butylsulfamoyl)-4-[2-[4-(cyclopentyloxycarbonylamino)cyclohexyl] 5-Yl]thiazol-5-yl]phenyl]carbamic acid isopropyl ester . 1 H 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=6.1Hz, 6H), 1.04 (s, 9H). ESI [M+Na] = 629.3.

[1114] Example 8. N-[4-[5-[2-(tert-butylsulfamoyl)-4-(isopropoxycarbonylamino)phenyl]thiazole-2- [(2R)-1-methylpyrrolidin-2-yl]methyl]cyclohexyl]carbamate The synthesis of.

[1115] Option 7:

[1116]

[1117] Preparation of compound 85

[1118]

[1119] General method D, trans-N-[4-[5-[2-(tert-butylsulfamoyl)-4-(isopropoxycarbonylamino)phenyl] Thiazol-2-yl]cyclohexyl]carbamic acid (4-nitrophenyl) ester . ESI [M+H] = 660.2.

[1120] Preparation of Compound Example 8

[1121]

[1122] General method H, N-[4-[5-[2-(tert-butylsulfamoyl)-4-(isopropoxycarbonylamino)phenyl]thiazole- (2R)-1-methylpyrrolidin-2-yl]methyl 2-methyl-1-pyrrolidin-2-yl]cyclohexylcarbamate . 1 H NMR (400 MHz, 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=8.3Hz, 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.

[1123] Example 9. Synthesis of isopropyl (3-(N-(tert-butyl)sulfamoyl)-4-(2-((1S,4r)-4-(((((S)-1-methylpyrrolidin-2-yl)methoxy)carbonyl)amino)cyclohexyl)thiazol-5-yl)phenyl)carbamate.

[1124] Through key intermediates 85 The following compounds were synthesized by the same method.

[1125]

[1126] 1H 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=6.2Hz, 6H), 1.13 (s, 9H). ESI [M+H] = 636.3.

[1127] Example 10. trans-N-[4-[5-[4-(benzylcarbamoylamino)-2-(tert-butylsulfamoyl)phenyl] tert-Butyl thiazol-2-yl]cyclohexyl]carbamate The synthesis of.

[1128]

[1129] General method B, trans-N-[4-[5-[4-(benzylcarbamoylamino)-2-(tert-butylsulfamoyl)phenyl] tert-Butyl thiazol-2-yl]cyclohexyl]carbamate . 1 H NMR (400 MHz, 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.

[1130] Example 11. N-[4-[5-[4-(Benzylcarbamoylamino)-2-(tert-butylsulfamoyl)phenyl]thiazole- (2R)-1-methylpyrrolidin-2-yl]methyl 2-methyl-1-pyrrolidin-2-yl]cyclohexylcarbamate The synthesis of.

[1131] Option 8:

[1132]

[1133]

[1134] Preparation of Compound 86

[1135]

[1136] General method F, trans-1-[4-[2-(4-aminocyclohexyl)thiazol-5-yl]-3-(tert-butylsulfamoyl)benzene Benzyl]-3-benzyl-urea . ESI [M+H] = 542.3.

[1137] Preparation of Compound 87

[1138]

[1139] General method D, trans-N-[4-[5-[4-(benzylcarbamoylamino)-2-(tert-butylsulfamoyl)phenyl] Thiazol-2-yl]cyclohexyl]carbamic acid (4-nitrophenyl) ester .

[1140] Preparation of Example 11.

[1141]

[1142] General method H, N-[4-[5-[4-(Benzylcarbamoylamino)-2-(tert-butylsulfamoyl)phenyl]thiazole- (2R)-1-methylpyrrolidin-2-yl]methyl 2-methyl-1-pyrrolidin-2-yl]cyclohexylcarbamate . 1 H NMR (400 MHz, 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.

[1143] Example 12. Synthesis of ((S)-1-methylpyrrolidin-2-yl)methyl ((1r,4S)-4-(5-(4-(3-benzylureido)-2-(N-(tert-butyl)sulfamoyl)phenyl)thiazol-2-yl)cyclohexyl)carbamate

[1144] Through key intermediates 87 The following compounds were synthesized by the same method.

[1145]

[1146] 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.

[1147] Example 13. Synthesis of Isopropyl (S)-(4-(5-(2-(N-(tert-butyl)sulfamoyl)-4-(3-(1-phenylethyl)ureido)phenyl)thiazol-2-yl)bicyclo[2.2.2]octan-1-yl)carbamate.

[1148] Option 9:

[1149]

[1150] Preparation of compound 89

[1151]

[1152] General method D, 4-(Isopropoxycarbonylamino)bicyclo[2.2.2]octane-1-carboxylate .

[1153] General Method for the Preparation of Compound 90

[1154]

[1155] Towards 4-(Isopropoxycarbonylamino)bicyclo[2.2.2]octane-1-carboxylic acid methyl ester To a solution of 4-[ ... 4-(Isopropyloxycarbonylamino)bicyclic [2.2.2] Octane-1-carboxylic acid (270 mg, crude). 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).

[1156] General Method N for the Preparation of Compound 91

[1157]

[1158] Towards 4-(Isopropoxycarbonylamino)bicyclo[2.2.2]octane-1-carboxylic acidTo a solution of 4-[4-[4-[4-[4-[4-[4-[4-[4-dioxo-3-yl]-1-yl]-1-oxo-4 ... Isopropyl N-(1-carbamoyl-4-bicyclo[2.2.2]octyl)carbamate . 1 H NMR (400 MHz, 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.

[1159] General Method L for the Preparation of Compound 92

[1160]

[1161] Towards Isopropyl N-(1-carbamoyl-4-bicyclo[2.2.2]octyl)carbamate To a solution of 2,4-bis(4-methoxyphenyl)-2,4-dithio-1,3,2,4-dithiadiphosphatane (60 mg, 235.92 umol, 1 equivalent) in 2-Me-THF (2 mL) was added 2,4-bis(4-methoxyphenyl)-2,4-dithio-1,3,2,4-dithiadiphosphatane (95.42 mg, 235.92 umol, 1 equivalent) and the mixture was stirred at 80 ° C for 0.5 hours. The mixture was poured into a saturated aqueous Na2CO3 solution (10 mL) and extracted with EtOAc (10 mL*3). The combined organic phases were dried over Na2SO4, filtered and concentrated. The residue was purified by preparative TLC (petroleum ether / ethyl acetate = 2:3) to obtain Isopropyl N-(1-thiocarbamoyl-4-bicyclo[2.2.2]octyl)carbamate (30 mg, crude). ESI [M+H] = 271.1.

[1162] General Method M for the Preparation of Compound 93

[1163]

[1164] Towards Isopropyl N-(1-thiocarbamoyl-4-bicyclo[2.2.2]octyl)carbamate(85 mg, 314.36 umol, 1 equivalent) was added to a solution of TsOH.H2O (119.59 mg, 628.72 umol, 2 equivalents) and 2-bromo-1,1-diethoxy-ethane (123.90 mg, 628.72 umol, 2 equivalents) in EtOH (2 mL). The mixture was stirred at 80 ° C for 1 hour and then concentrated and diluted with EtOAc (30 mL). The mixture was washed with saturated Na2CO3 aqueous solution (10 mL * 2) and the combined organic phases were dried over Na2SO4, filtered and concentrated. The residue was purified by preparative TLC (petroleum ether / ethyl acetate = 3:1) to obtain N-(1-thiazol-2-yl-4-bicyclo[2.2.2]octanyl) Isopropyl carbamate (80 mg, crude). ESI [M+H]=295.3.

[1165] Preparation of Compound 94

[1166]

[1167] General method J, Isopropyl N-[1-(5-bromothiazol-2-yl)-4-bicyclo[2.2.2]octyl]carbamate .ESI[M+H]=375.2 / 373.2.

[1168] Preparation of Compound 95

[1169]

[1170] General method B, N-[1-[5-[4-amino-2-(tert-butylsulfamoyl)phenyl]thiazol-2-yl]-4-bicyclo [2.2.2]octyl]carbamic acid isopropyl . ESI [M+H] = 521.2.

[1171] Preparation of Compound 96

[1172]

[1173] General method D, N-[3-(tert-butylsulfamoyl)-4-[2-[4-(isopropoxycarbonylamino)-1-bicyclo [2.2.2]Octyl]thiazol-5-yl]phenyl]carbamic acid (4-nitrophenyl) ester . ESI [M+H] = 686.4.

[1174] Preparation of Example 13.

[1175]

[1176] General method E, N-[1-[5-[2-(tert-butylsulfamoyl)-4-[[(1S)-1-phenylethyl]carbamoylamino 1-[4-(2-amino-1-methylphenyl)thiazol-2-yl)-4-bicyclo[2.2.2]octyl]carbamic acid isopropyl ester . 1H NMR (400 MHz, 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.

[1177] Example 14. Synthesis of Isopropyl (R)-(4-(5-(2-(N-(tert-butyl)sulfamoyl)-4-(3-(1-phenylethyl)ureido)phenyl)thiazol-2-yl)bicyclo[2.2.2]octan-1-yl)carbamate.

[1178] Through key intermediates 96 The following compounds were synthesized by the same method.

[1179]

[1180] 1 H NMR (400 MHz, 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.

[1181] Example 15. Synthesis of Isopropyl (S)-(4-(5-(2-(N-(tert-butyl)sulfamoyl)-4-(3-(1-(pyridin-2-yl)ethyl)ureido)phenyl)thiazol-2-yl)bicyclo[2.2.2]octan-1-yl)carbamate.

[1182] Through key intermediates 96 The following compounds were synthesized by the same method.

[1183]

[1184] 1 H NMR (400MHz, methanol-d4) δ = 8.72 (d, J=5.6 Hz, 1H), 8.46 (t, J=7.9Hz, 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.

[1185] Example 16. Synthesis of Isopropyl (R)-(4-(5-(2-(N-(tert-butyl)sulfamoyl)-4-(3-(1-(pyridin-2-yl)ethyl)ureido)phenyl)thiazol-2-yl)bicyclo[2.2.2]octan-1-yl)carbamate.

[1186] Through key intermediates 96 The following compounds were synthesized by the same method.

[1187]

[1188] 1H NMR (400 MHz, 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.

[1189] Example 17. N-[3-(tert-butylsulfamoyl)-4-[2-[4-(isopropoxycarbonylamino)-1-bicyclo [2.2.2]octyl]thiazol-5-yl]phenyl]carbamic acid isopropyl ester synthesis.

[1190] Option 10:

[1191] Preparation of Compound Example 17

[1192]

[1193] General method B, N-[3-(tert-butylsulfamoyl)-4-[2-[4-(isopropoxycarbonylamino)-1-bicyclo Isopropyl [2.2.2]octyl]thiazol-5-yl]phenyl]carbamate . 1 H NMR (400 MHz, 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.

[1194] Example 18. Synthesis of Isopropyl (4-(5-(4-(3-benzylureido)-2-(N-(tert-butyl)sulfamoyl)phenyl)thiazol-2-yl)bicyclo[2.2.2]octan-1-yl)carbamate.

[1195] Through key intermediates 94 The following compounds were synthesized by the same method.

[1196]

[1197] 1 H NMR (400 MHz, 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.

[1198] Example 19. Synthesis of Isopropyl (4-(5-(2-(N-(tert-butyl)sulfamoyl)-4-(3-(pyridin-2-ylmethyl)ureido)phenyl)thiazol-2-yl)bicyclo[2.2.2]octan-1-yl)carbamate.

[1199] Through key intermediates 94 The following compounds were synthesized by the same method.

[1200]

[1201] 1H 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=6.8Hz, 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.

[1202] Example 20. trans-N-[3-(tert-butylsulfamoyl)-4-[2-[4-(isopropylcarbamoyloxy)cyclohexane] 1-[4-[4-[4-thiazol-5-yl]phenyl]carbamic acid isopropyl ester synthesis.

[1203] Option 11:

[1204]

[1205] Preparation of compound 111.

[1206]

[1207] Towards trans-4-Hydroxycyclohexanecarboxylic acid To a solution of 1-[4-[ ... trans-4-Hydroxycyclohexanecarboxamide (1 g, crude), which was used without any purification.

[1208] Preparation of compound 112.

[1209]

[1210] Towards trans-4-HydroxycyclohexanecarboxamideTo a solution of 1-[4-[ ... trans-4-[tert-Butyl(diphenyl)silyl]oxycyclohexanecarboxamide (31.5 g, crude). 1 H NMR (400 MHz, 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).

[1211] Preparation of compound 113.

[1212]

[1213] General method L, trans-4-[tert-Butyl(diphenyl)silyl]oxycyclohexanecarbothioamide . 1 H NMR (400 MHz, 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.

[1214] Preparation of compound 114.

[1215]

[1216] General method M, trans-tert-Butyl-diphenyl-(4-thiazol-2-ylcyclohexyloxy)silane . 1 H NMR (400 MHz, 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.

[1217] Preparation of compound 114A.

[1218]

[1219] General method J, trans-[4-(5-bromothiazol-2-yl)cyclohexyloxy]-tert-butyl-diphenyl-silane (1.8 g, crude). ESI [M+H] = 502.0.

[1220] Preparation of compound 115.

[1221]

[1222] Towards trans-[4-(5-bromothiazol-2-yl)cyclohexyloxy]-tert-butyl-diphenyl-silane To a solution of 4-[ ... trans-4-(5-bromothiazol-2-yl)cyclohexanol (500 mg, 1.91 mmol, 63.64% yield).

[1223] Preparation of compound 116.

[1224]

[1225] Towards trans-4-(5-bromothiazol-2-yl)cyclohexanolTo a solution of 2-isocyanatopropane (500 mg, 1.91 mmol, 1 equivalent) in DMF (5 mL) were added 2-isocyanatopropane (486.93 mg, 5.72 mmol, 3 equivalents) and DIEA (739.47 mg, 5.72 mmol, 3 equivalents). The mixture was stirred at 100 ° C for 40 hours and then poured into H2O (50 mL) and extracted with EtOAc (10 mL*3). The combined organic phases were dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 10: 1-1: 1) to obtain N-isopropylcarbamic acid trans-[4-(5-bromo thiazol-2-yl)cyclohexyl]ester (180 mg, 518.33 umol, 27.18% yield). 1 H NMR (400 MHz, 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.

[1226] Preparation of Example 20.

[1227]

[1228] General method B, trans-N-[3-(tert-butylsulfamoyl)-4-[2-[4-(isopropylcarbamoyloxy)cyclohexane] 5-Yl]thiazol-5-yl]phenyl]carbamic acid isopropyl ester . 1 H NMR (400 MHz, 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.

[1229] Example 21. Synthesis of (1r,4r)-4-(5-(4-(3-benzylureido)-2-(N-(tert-butyl)sulfamoyl)phenyl)thiazol-2-yl)cyclohexyl isopropylcarbamate

[1230] Through key intermediates 116 The following compounds were synthesized by the same method.

[1231]

[1232] 1 H NMR (400 MHz, 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 (brs, 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] = 628.4.

[1233] Example 22. trans-N-[4-[5-[2-(tert-butylsulfamoyl)-4-(4-pyridylmethylcarbamoylamino] 1-[(1,2 ...phenyl]thiazol-2-yl]cyclohexyl]carbamic acid isopropyl]ester)]] The synthesis of.

[1234] Option 12:

[1235]

[1236] Preparation of compound 117.

[1237]

[1238] General method K, trans-N-[4-[5-[4-amino-2-(tert-butylsulfamoyl)phenyl]thiazol-2-yl]cyclohexane Isopropyl]carbamate . 1 H NMR (400 MHz, methanol-d4) δ = 7.68 -7.57 (s, 1H), 7.43 (d, J=2.4 Hz, 1H), 7.13 (d, J=8.2 Hz, 1H), 6.82 (dd, J=2.4, 8.2 Hz, 1H), 4.84 - 4.77(m, 1H), 3.44 (tt, J=3.9, 11.5 Hz, 1H), 2.97 (tt, J=3.6, 12.1 Hz, 1H), 2.26 - 2.13 (m, 2H), 2.11 - 2.02 (m, 2H), 1.67 (dq, J=3.0, 12.9 Hz, 2H), 1.49 - 1.32 (m,2H), 1.22 (dd, J=2.5, 6.7 Hz, 6H), 1.09 (s, 9H). ESI [M+H] =495.2.

[1239] Preparation of compound 118.

[1240]

[1241] General method D, trans-N-[3-(tert-butylsulfamoyl)-4-[2-[4-(isopropoxycarbonylamino)cyclohexane] 4-nitrophenyl]thiazol-5-yl]phenyl]carbamate . ESI [M+H] =660.1.

[1242] Preparation of Example 22.

[1243]

[1244] General method E, trans-N-[4-[5-[2-(tert-butylsulfamoyl)-4-(4-pyridylmethylcarbamoylamino] 1-[(1,2 ...phenyl]thiazol-2-yl]cyclohexyl]carbamic acid isopropyl]ester)]] . 1 H NMR (400MHz, methanol-d4) δ = 8.79 (d,J=6.7 Hz, 2H), 8.34 (d, J=2.3 Hz, 1H), 8.07 (d, J=6.6 Hz, 2H), 7.76 (s, 1H),7.69 (dd, J=2.3, 8.4 Hz, 1H), 7.39 (d, J=8.3 Hz, 1H), 4.85 - 4.83 (m, 1H), 4.73 (s, 2H), 3.47 (tt, J=3.6, 11.5 Hz, 1H), 3.04 (tt, J=3.4, 12.0 Hz, 1H), 2.30 -2.19 (m, 2H), 2.09 (br d, J=10.1 Hz, 2H), 1.71 (dq, J=3.0, 12.9 Hz, 2H), 1.43(dq, J=3.3, 12.6 Hz, 2H), 1.24 (br d, J=6.1 Hz, 6H), 1.12 (s, 9H). ESI [M+H] =629.2.

[1245] Example 23. Synthesis of Isopropyl ((1r,4r)-4-(5-(2-(N-(tert-butyl)sulfamoyl)-4-(3-(4-fluorobenzyl)ureido)phenyl)thiazol-2-yl)cyclohexyl)carbamate

[1246] Through key intermediates 118 The following compounds were synthesized by the same method.

[1247]

[1248] 1 H NMR (400 MHz, methanol-d4) δ = 8.27 (d, J = 2.3 Hz, 1H), 7.77 (s, 1H), 7.71 (dd, J = 2.4, 8.4 Hz, 1H), 7.38 (td, J = 2.7, 8.6 Hz, 3H), 7.12 - 7.04 (m,2H), 5.00 - 4.92 (m, 1H), 4.41 (s, 2H), 3.54 - 3.41 (m, 1H), 3.05 (tt, J=3.5,12.0 Hz, 1H),2.13 - 2.05 (m, 2H), 2.05 - 2.04 (m, 2H), 1.72 (dq, J=3.0, 12.8 Hz, 2H), 1.43 (dq, J=3.2, 12.5 Hz, 2H), 1.24 (br d, J=6.1 Hz, 6H), 1.14 (s, 9H). ESI [M+H] =646.2.

[1249] Example 24. Synthesis of Isopropyl ((1R,4r)-4-(5-(2-(N-isopropylsulfamoyl)-4-(3-((R)-1-phenylethyl)ureido)phenyl)thiazol-2-yl)cyclohexyl)carbamate

[1250] Through key intermediates 118The following compounds were synthesized by the same method.

[1251]

[1252] 1 H NMR (400 MHz, methanol-d4) δ = 8.20 (d, J = 2.2 Hz, 1H), 7.73 (s, 1H), 7.64 (dd, J = 2.4, 8.4 Hz, 1H), 7.38 - 7.29 (m, 5H), 7.26 - 7.19 (m, 1H), 4.94 - 4.89(m, 1H), 4.81 (br d, J=6.2 Hz, 1H), 3.44 (tt, J=3.9, 11.6 Hz, 1H), 3.01 (tt,J=3.5, 12.0 Hz, 1H), 2.26 - 2.17 (m, 2H), 2.10 - 2.01 (m, 2H), 1.68 (dq, J=2.9,12.8 Hz, 2H), 1.48 (d, J=7.1 Hz, 3H), 1.43 - 1.33 (m, 2H), 1.21 (br d, J=6.2Hz, 6H), 1.10 (s, 9H). ESI [M+H] =642.3.

[1253] Example 25. Synthesis of Isopropyl ((1r,4r)-4-(5-(2-(N-(tert-butyl)sulfamoyl)-4-(3-(pyridin-3-ylmethyl)ureido)phenyl)thiazol-2-yl)cyclohexyl)carbamate.

[1254] Through key intermediates 118 The following compounds were synthesized by the same method.

[1255]

[1256] 1H NMR (400MHz, methanol-d4) δ = 8.84 (s, 1H), 8.74 (d, J=5.7 Hz, 1H), 8.60 (d, J=8.2 Hz, 1H), 8.30 (d, J=2.2 Hz, 1H), 8.04 (dd, J=5.8, 7.8 Hz, 1H),7.72 (s, 1H), 7.65 (dd, J=2.4, 8.4 Hz, 1H), 7.36 (d, J=8.4 Hz, 1H), 4.85 - 4.77(m, 1H), 4.60 (s, 2H), 3.44 (tt, J=3.9, 11.5 Hz, 1H), 3.10 - 2.93 (m, 1H), 2.28 - 2.17 (m, 2H), 2.13 - 2.01 (m, 2H), 1.69 (dq, J=3.0, 12.8 Hz, 2H), 1.50 - 1.33 (m, 2H), 1.22 (br d, J=6.2 Hz, 6H), 1.09 (s, 9H). ESI [M+H] =629.3.

[1257] Example 26. Synthesis of Isopropyl ((1S,4r)-4-(5-(2-(N-(tert-butyl)sulfamoyl)-4-(3-((S)-1-phenylethyl)ureido)phenyl)thiazol-2-yl)cyclohexyl)carbamate.

[1258] Through key intermediates 118 The following compounds were synthesized by the same method.

[1259]

[1260] 1 H NMR (400 MHz, methanol-d4) δ = 8.19 (d, J = 2.4 Hz, 1H), 7.70 (s, 1H), 7.65 (dd, J = 2.4, 8.4 Hz, 1H), 7.39 - 7.30 (m, 5H), 7.26 - 7.21 (m, 1H), 4.93 (q,J=6.5 Hz, 1H), 4.83 - 4.81 (m, 1H), 3.49 - 3.40 (m, 1H), 3.05 -2.96 (m, 1H), 2.22(br d, J=11.7 Hz, 2H), 2.06 (br d, J=11.5 Hz, 2H), 1.73 - 1.62 (m, 2H), 1.49 (d, J=6.8 Hz, 3H), 1.43 - 1.36 (m, 2H), 1.22 (br d, J=6.0 Hz, 6H), 1.10 (s,9H). ESI[M+H] =642.3.

[1261] Example 27. Synthesis of Isopropyl ((1r,4r)-4-(5-(2-(N-(tert-butyl)sulfamoyl)-4-(3-(3-fluorobenzyl)ureido)phenyl)thiazol-2-yl)cyclohexyl)carbamate.

[1262] Through key intermediates 118 The following compounds were synthesized by the same method.

[1263]

[1264] 1 H NMR (400 MHz, methanol-d4) δ = 8.27 (d, J = 2.2 Hz, 1H), 7.74 (s, 1H), 7.71 (dd, J = 2.3, 8.3 Hz, 1H), 7.40 - 7.32 (m, 2H), 7.18 (d, J=7.7 Hz, 1H), 7.10 (br d, J=9.9 Hz, 1H), 6.99 (dt, J=2.2, 8.5 Hz, 1H), 4.87 (br s, 1H), 4.44 (s,2H), 3.47 (tt, J=3.8, 11.6 Hz, 1H), 3.02 (tt, J=3.5, 12.0 Hz, 1H), 2.24 (brd, J=12.2 Hz, 2H), 2.14 - 2.04 (m, 2H), 1.71 (dq, J=3.0, 12.9 Hz, 2H), 1.50 - 1.36 (m, 2H), 1.24 (br d, J=6.1 Hz, 6H), 1.14 (s, 9H). ESI [M+H] =646.2.

[1265] Example 28. Synthesis of Isopropyl ((1r,4r)-4-(5-(2-(N-(tert-butyl)sulfamoyl)-4-(3-(2-fluorobenzyl)ureido)phenyl)thiazol-2-yl)cyclohexyl)carbamate.

[1266] Through key intermediates 118 The following compounds were synthesized by the same method.

[1267]

[1268] 1 H NMR (400MHz, methanol-d4) δ = 8.23 ​​(d, J=2.2 Hz, 1H), 7.71 (s, 1H), 7.68 (dd, J=2.4, 8.4 Hz, 1H), 7.41 (dt, J=1.5, 7.6 Hz, 1H), 7.35 (d, J=8.4Hz, 1H), 7.29 (ddt, J=1.8, 5.5, 7.7 Hz, 1H), 7.15 (dt, J=1.0, 7.6 Hz, 1H), 7.11 - 7.05 (m, 1H), 4.81 (br s, 1H), 4.46 (s, 2H), 3.45 (tt, J=3.7, 11.6 Hz, 1H), 3.00 (tt, J=3.5, 12.0 Hz, 1H), 2.27 - 2.18 (m, 2H), 2.06 (br d, J=10.1 Hz, 2H), 1.69 (dq, J=3.1, 12.9 Hz, 2H), 1.46 - 1.34 (m, 2H), 1.22 (br d, J=6.2 Hz, 6H), 1.11 (s, 9H). ESI [M+H] =646.2.

[1269] Example 29. Synthesis of Isopropyl ((1r,4r)-4-(5-(2-(N-(tert-butyl)sulfamoyl)-4-(3-(pyridin-2-ylmethyl)ureido)phenyl)thiazol-2-yl)cyclohexyl)carbamate.

[1270] Through key intermediates 118 The following compounds were synthesized by the same method.

[1271]

[1272] 1 H NMR (400 MHz, methanol-d4) δ = 8.79- 8.73 (m, 1H), 8.56 (dt, J=1.5, 7.9Hz, 1H), 8.35 (d, J=2.2 Hz, 1H), 8.06 (d, J=8.1 Hz, 1H), 7.94 (t, J=6.4 Hz,1H), 7.77 (s, 1H), 7.69 (dd, J=2.3, 8.4 Hz, 1H), 7.39 (d, J=8.3 Hz, 1H), 4.86 - 4.83 (m, 1H), 4.79 (s, 2H), 3.47 (tt, J=3.9, 11.6 Hz, 1H), 3.05 (tt, J=3.5, 12.0 Hz, 1H), 2.29 - 2.21 (m, 2H), 2.09 (br d, J=10.1 Hz, 2H), 1.71 (dq, J=2.9, 12.8 Hz, 2H), 1.43 (dq, J=3.3, 12.6 Hz, 2H), 1.24 (br d, J=6.2 Hz, 6H),1.11 (s, 9H). ESI [M+H] =629.3.

[1273] Example 30. Synthesis of Isopropyl ((1R,4r)-4-(5-(2-(N-(tert-butyl)sulfamoyl)-4-(3-((R)-1-(pyridin-2-yl)ethyl)ureido)phenyl)thiazol-2-yl)cyclohexyl)carbamate.

[1274] Through key intermediates 118 The following compounds were synthesized by the same method.

[1275]

[1276] 1 H NMR (400 MHz, methanol-d4) δ = 8.73 (d, J = 5.7 Hz, 1H), 8.53 (dt, J = 1.8,7.9 Hz, 1H), 8.28 (d, J = 2.2 Hz, 1H), 8.08 (d, J = 8.3 Hz, 1H), 7.94 - 7.85 (m,1H), 7.80 - 7.68 (m, 1H), 7.61 (dd, J=2.2, 8.3 Hz, 1H), 7.35 (d, J=8.3 Hz, 1H), 5.13 (q, J=7.0 Hz, 1H), 4.85- 4.78 (m, 1H), 3.49 - 3.39 (m, 1H), 3.08 - 2.96 (m,1H), 2.22 (br d, J=12.3 Hz, 2H), 2.06 (br d, J=10.1 Hz, 2H), 1.76 - 1.61 (m,5H), 1.49 - 1.34 (m, 2H), 1.22 (br d, J=6.1 Hz, 6H), 1.14 - 1.02 (m, 9H). ESI [M+H] =643.3.

[1277] Example 31. Synthesis of Isopropyl ((1r,4r)-4-(5-(2-(N-(tert-butyl)sulfamoyl)-4-(3-((3-fluoropyridin-2-yl)methyl)ureido)phenyl)thiazol-2-yl)cyclohexyl)carbamate.

[1278] Through key intermediates 118 The following compounds were synthesized by the same method.

[1279]

[1280] 1 H NMR (400 MHz, methanol-d4) δ = 8.42 (d, J = 4.8 Hz, 1H), 8.28 (d, J = 2.2 Hz, 1H), 7.78 - 7.62 (m, 3H), 7.44 (td, J=4.4, 8.5 Hz, 1H), 7.38 (d, J=8.4 Hz, 1H), 4.86 - 4.81 (m, 1H), 4.65 (s, 2H), 3.47 (ddd, J=4.0, 7.7, 11.4 Hz, 1H), 3.10 - 3.00 (m, 1H), 2.25 (br d, J=12.1 Hz, 2H), 2.09 (br d, J=10.5 Hz, 2H), 1.72 (dq, J=3.0, 12.9 Hz, 2H), 1.43 (dq, J=3.2, 12.6 Hz, 2H), 1.24 (br d, J=6.1 Hz, 6H), 1.14 (s, 9H). ESI [M+H] =647.2.

[1281] Example 32. Synthesis of Isopropyl ((1S,4r)-4-(5-(2-(N-(tert-butyl)sulfamoyl)-4-(3-((S)-1-(pyridin-2-yl)ethyl)ureido)phenyl)thiazol-2-yl)cyclohexyl)carbamate.

[1282] Through key intermediates 118 The following compounds were synthesized by the same method.

[1283]

[1284] 1 H NMR (400MHz, methanol-d4) δ = 8.72 (d, J=5.3 Hz, 1H), 8.50 (dt, J=1.8,7.9 Hz, 1H), 8.27 (d, J=2.2 Hz, 1H), 8.05 (d, J=8.3 Hz, 1H), 7.88 (t, J=6.6Hz, 1H), 7.72 (s, 1H), 7.61 (dd, J=2.6, 8.3 Hz, 1H), 7.34 (d, J=8.8 Hz, 1H), 5.12 (q, J=7.0 Hz, 1H), 4.87 - 4.68 (m, 1H), 3.51 - 3.38 (m, 1H), 3.01 (tt, J=3.3, 12.0 Hz, 1H), 2.21 (br d, J=11.8 Hz, 2H), 2.10 - 1.97 (m, 2H), 1.76 - 1.57(m, 5H), 1.48 - 1.33 (m, 2H), 1.22 (d, J=6.1 Hz, 6H), 1.13 - 1.00 (m, 9H). ESI [M+H] =643.3.

[1285] Example 33. trans-N-[3-(tert-butylsulfamoyl)-4-[2-[4-(isopropoxycarbonylamino)cyclohexane] 4-Piperidinylmethyl]thiazol-5-yl]phenyl]carbamate synthesis.

[1286] Option 13:

[1287]

[1288]

[1289] Preparation of compound 119.

[1290]

[1291] General method H, trans-4-[[3-(tert-butylsulfamoyl)-4-[2-[4-(isopropoxycarbonylamino)cyclohexane tert-Butyl]thiazol-5-yl]phenyl]carbamoyloxymethyl]piperidine-1-carboxylate . ESI [M+H] =736.5.

[1292] Preparation of Example 33.

[1293]

[1294] General method C, trans-N-[3-(tert-butylsulfamoyl)-4-[2-[4-(isopropoxycarbonylamino)cyclohexane] 4-Piperidinylmethyl]thiazol-5-yl]phenyl]carbamate . 1 H NMR (400 MHz, methanol-d4) δ = 8.37 (d, J = 2.2 Hz, 1H), 7.78 (s, 1H), 7.68 (br d, J = 7.9 Hz, 1H), 7.40 (d, J = 8.4 Hz, 1H), 4.86 - 4.78 (m, 1H), 4.11 (d, J=6.2 Hz, 2H), 3.50 - 3.39 (m, 3H), 3.11 - 2.96(m, 3H), 2.23 (br d, J=12.3 Hz, 2H), 2.13 - 1.98 (m, 5H), 1.70 (dq, J=2.8, 12.8Hz, 2H), 1.60 - 1.34 (m, 4H), 1.22 (br d, J=6.2 Hz, 6H), 1.11 (s, 9H). ESI [M / 2+H] = 318.6.

[1295] Example 34. Synthesis of Isopropyl ((1R,4r)-4-(5-(2-(N-(tert-butyl)sulfamoyl)-4-(((((R)-1-methylpyrrolidin-2-yl)methoxy)carbonyl)amino)phenyl)thiazol-2-yl)cyclohexyl)carbamate.

[1296] Through key intermediates 118 The following compounds were synthesized by the same method.

[1297]

[1298] 1 H NMR (400 MHz, methanol-d4) δ = 8.41 (d, J = 2.2 Hz, 1H), 7.80 - 7.73 (m,2H), 7.45 (d, J=8.4 Hz, 1H), 4.86- 4.81 (m, 1H), 4.67 (dd, J=3.2, 12.8 Hz, 1H), 4.35 (dd, J=7.1, 12.8 Hz, 1H), 3.85 - 3.71 (m, 2H), 3.47 (tt, J=3.9, 11.6Hz, 1H), 3.26 (td, J=8.1, 11.5 Hz, 1H), 3.10 (s, 3H), 3.08 - 2.98 (m, 1H), 2.46 - 2.35 (m, 1H), 2.30 - 2.18 (m, 3H), 2.15 - 1.95 (m, 4H), 1.72 (dq, J=3.1,12.9 Hz, 2H), 1.43 (dq, J=3.3, 12.6 Hz, 2H), 1.25 (br d, J=6.2 Hz, 6H), 1.13(s, 9H). ESI [M+H] = 636.3.

[1299] Example 35. Synthesis of Isopropyl ((1S,4r)-4-(5-(2-(N-(tert-butyl)sulfamoyl)-4-(((((S)-1-methylpyrrolidin-2-yl)methoxy)carbonyl)amino)phenyl)thiazol-2-yl)cyclohexyl)carbamate.

[1300] Through key intermediates 118 The following compounds were synthesized by the same method.

[1301]

[1302] 1 H NMR (400 MHz, methanol-d4) δ = 8.41 (d, J = 2.0 Hz, 1H), 7.80 - 7.71 (m,2H), 7.44 (d, J=8.3 Hz, 1H), 4.86 - 4.79 (m, 1H), 4.67 (dd, J=3.2, 13.0 Hz,1H), 4.40 - 4.31 (m, 1H), 3.87 -3.66 (m, 2H), 3.47 (tt, J=3.8, 11.6 Hz, 1H), 3.26 (td, J=8.3, 11.4 Hz, 1H), 3.10 (s, 3H), 3.04 (tt, J=3.4, 12.0 Hz, 1H), 2.48 - 2.33 (m, 1H), 2.30 - 2.16 (m, 3H), 2.15 - 1.92 (m, 4H), 1.72 (dq, J=2.7,12.8 Hz, 2H), 1.51 - 1.36 (m, 2H), 1.25 (br d, J=6.4 Hz, 6H), 1.13 (s, 9H). ESI[M / 2+H] = 318.6.

[1303] Example 36. Synthesis of Isopropyl ((1R,4r)-4-(5-(2-(N-(tert-butyl)sulfamoyl)-4-(((((R)-pyrrolidin-2-yl)methoxy)carbonyl)amino)phenyl)thiazol-2-yl)cyclohexyl)carbamate.

[1304] Through key intermediates 118 The following compounds were synthesized by the same method.

[1305]

[1306] 1 H NMR (400 MHz, methanol-d4) δ = 8.38 (br d, J = 2.2 Hz, 1H), 7.75 - 7.66 (m,2H), 7.41 (d, J=8.4 Hz, 1H), 4.81 (br s, 1H), 4.48 (br dd, J=3.4, 12.5 Hz,1H), 4.33 (dd, J=7.8, 12.5 Hz, 1H), 3.93 (dq, J=3.6, 8.0 Hz, 1H), 3.49 - 3.33(m, 3H), 3.00 (ddd, J=3.5, 8.5, 12.0 Hz, 1H), 2.30 - 2.18 (m, 3H), 2.10 - 2.00(m, 3H), 1.85 (qd, J=8.5, 12.9 Hz, 2H), 1.74 - 1.61 (m, 2H), 1.46- 1.34 (m, 2H), 1.22 (br d, J=6.2 Hz, 6H), 1.09 (s, 9H). ESI [M / 2+H] = 311.6.

[1307] Example 37. Synthesis of Isopropyl ((1S,4r)-4-(5-(2-(N-(tert-butyl)sulfamoyl)-4-(((((S)-pyrrolidin-2-yl)methoxy)carbonyl)amino)phenyl)thiazol-2-yl)cyclohexyl)carbamate.

[1308] Through key intermediates 118 The following compounds were synthesized by the same method.

[1309]

[1310] 1 H NMR (400 MHz, methanol-d4) δ = 8.38 (d, J = 1.8 Hz, 1H), 7.79 - 7.68 (m,2H), 7.41 (d, J=8.2 Hz, 1H), 4.85 - 4.78 (m, 1H), 4.49 (dd, J=3.4, 12.5 Hz, 1H), 4.33 (dd, J=7.9, 12.3 Hz, 1H), 3.94 (dq, J=3.4, 8.0 Hz, 1H), 3.49 - 3.40(m, 1H), 3.40 - 3.33 (m, 2H), 3.08 - 2.97 (m, 1H), 2.31 - 2.19 (m, 3H), 2.17 - 2.00(m, 4H), 1.85 (qd, J=8.5, 13.0 Hz, 1H), 1.75 - 1.62 (m, 2H), 1.46 - 1.35 (m, 2H), 1.22 (br d, J=6.2 Hz, 6H), 1.10 (s, 9H). ESI [M / 2+H] = 311.6.

[1311] Example 38. Synthesis of Isopropyl ((1r,4r)-4-(5-(2-(N-(tert-butyl)sulfamoyl)-4-(((oxetan-3-yloxy)carbonyl)amino)phenyl)thiazol-2-yl)cyclohexyl)carbamate.

[1312] Through key intermediates 118 The following compounds were synthesized by the same method.

[1313]

[1314] 1 H NMR (methanol-d4, 400MHz): δ = 8.33 (s, 1H), 7.63-7.72 (m, 2H), 7.38(d, J=8.4 Hz, 1H), 5.50 (br t, J=5.5 Hz, 1H), 4.92 (t, J=6.9 Hz, 2H), 4.81-4.83 (m, 1H), 4.64-4.73 (m, 2H), 3.44 (br t, J=11.7 Hz, 1H), 2.99 (br t, J=11.8 Hz, 1H), 2.21 (br d, J=12.3 Hz, 2H), 2.06 (br d, J=11.7 Hz, 2H), 1.59-1.75 (m, 2H), 1.30-1.47 (m, 2H), 1.21 (br d, J=6.0 Hz, 6H), 1.10 ppm (s, 9H). ESI [M+H] = 595.1.

[1315] Example 39. Synthesis of benzyl (3-(N-(tert-butyl)sulfamoyl)-4-(2-((1r,4r)-4-((isopropoxycarbonyl)amino)cyclohexyl)thiazol-5-yl)phenyl)carbamate.

[1316] Through key intermediates 118 The following compounds were synthesized by the same method.

[1317]

[1318] 1 H NMR (400 MHz, methanol-d4) δ = 8.36 (s, 1H), 7.75 - 7.67 (m, 2H), 7.46 - 7.28 (m, 6H), 5.28 - 5.14 (m, 2H), 4.85 -4.76 (m, 1H), 3.47 (br d, J=11.8 Hz,1H), 3.01 (br s, 1H), 2.23 (br d, J=12.7 Hz, 2H), 2.07 (br d, J=14.5 Hz, 2H), 1.70 (br d, J=11.0 Hz, 2H), 1.40 (br d, J=12.7 Hz, 2H), 1.22 (br d, J=6.1 Hz, 6H), 1.12 (s, 9H). ESI [M+H] = 629.2.

[1319] Example 40. Synthesis of 2-fluorobenzyl (3-(N-(tert-butyl)sulfamoyl)-4-(2-((1r,4r)-4-((isopropoxycarbonyl)amino)cyclohexyl)thiazol-5-yl)phenyl)carbamate.

[1320] Through key intermediates 118 The following compounds were synthesized by the same method.

[1321]

[1322] 1H NMR (400MHz, methanol-d4) δ = 8.36 (s, 1H), 7.77 - 7.63 (m, 2H), 7.52(t, J=7.0 Hz, 1H), 7.44 - 7.31 (m, 2H), 7.23 - 7.08 (m, 2H), 5.29 (s, 2H), 4.83(br s, 1H), 3.46 (br d, J=11.8 Hz, 1H), 3.00 (br t, J=11.8 Hz, 1H), 2.22 (brd, J=12.7 Hz, 2H), 2.07 (br d, J=11.4 Hz, 2H), 1.76 - 1.62 (m, 2H), 1.47 - 1.35 (m, 2H), 1.22 (br d, J=6.1 Hz, 6H), 1.12 (s, 9H). ESI [M+H] = 647.2.

[1323] Example 41. Synthesis of (S)-1-phenylethyl (3-(N-(tert-butyl)sulfamoyl)-4-(2-((1r,4S)-4-((isopropoxycarbonyl)amino)cyclohexyl)thiazol-5-yl)phenyl)carbamate.

[1324] Through key intermediates 118 The following compounds were synthesized by the same method.

[1325]

[1326] 1 H NMR (400 MHz, methanol-d4) δ = 8.35 (br s, 1H), 7.81 - 7.65 (m, 2H), 7.48 - 7.36 (m, 5H), 7.31 (br d, J=6.8 Hz, 1H), 5.89 (br d, J=6.2 Hz, 1H), 4.85 (br d, J=5.5 Hz, 1H), 3.47 (br s, 1H), 3.03 (br s, 1H), 2.24 (br d, J=11.2Hz, 2H), 2.08 (br d, J=11.0 Hz, 2H), 1.71 (q, J=11.9 Hz, 2H), 1.61 (br d, J=6.4 Hz, 3H), 1.49 - 1.37 (m, 2H), 1.24 (br d, J=5.4 Hz, 6H), 1.13 (s, 9H). ESI[M+H] =643.2.

[1327] Example 42. Synthesis of pyridin-2-ylmethyl (3-(N-(tert-butyl)sulfamoyl)-4-(2-((1r,4r)-4-((isopropoxycarbonyl)amino)cyclohexyl)thiazol-5-yl)phenyl)carbamate.

[1328] Through key intermediates 118 The following compounds were synthesized by the same method.

[1329]

[1330] 1 H NMR (400 MHz, methanol-d4) δ = 8.56 (br d, J = 4.5 Hz, 1H), 8.38 (d, J = 1.8 Hz, 1H), 7.94 - 7.87 (m, 1H), 7.78 - 7.72 (m, 2H), 7.59 (br d, J=7.8 Hz, 1H),7.44 -7.38 (m, 2H), 5.32 (s, 2H), 4.85 (td, J=5.9, 12.0 Hz, 1H), 3.47 (br t, J=11.8 Hz, 1H), 3.07 - 2.96 (m, 1H), 2.24 (br d, J=12.3 Hz, 2H), 2.13 - 2.04 (m,2H), 1.77 - 1.65 (m, 2H), 1.48 - 1.37 (m, 2H), 1.24 (br d, J=6.1 Hz, 6H), 1.14 (s, 9H). ESI [M+H] =630.2.

[1331] Example 43. Synthesis of (R)-1-phenylethyl (3-(N-(tert-butyl)sulfamoyl)-4-(2-((1r,4R)-4-((isopropoxycarbonyl)amino)cyclohexyl)thiazol-5-yl)phenyl)carbamate.

[1332] Through key intermediates 118 The following compounds were synthesized by the same method.

[1333]

[1334] 1 H NMR (400MHz, DMSO-d6) δ = 8.28 (d, J=2.2 Hz, 1H), 7.70 - 7.57 (m,2H), 7.47 - 7.24 (m, 7H), 7.05 - 6.84 (m, 2H), 5.82 (q, J=6.6 Hz, 1H), 4.79 - 4.65(m, 1H), 3.35 - 3.24 (m, 1H), 2.88 (tt, J=3.4, 11.9 Hz, 1H), 2.11 (br d, J=11.7Hz, 2H), 1.89 (br d, J=9.9 Hz, 2H), 1.54 (d, J=6.6 Hz, 5H), 1.30 (br s, 2H), 1.14 (d, J=6.2 Hz, 6H), 1.08 - 0.99 (m, 9H). ESI [M+H] = 643.3.

[1335] Example 44. trans-N-[4-[2-[4-(tert-Butoxycarbonylamino)cyclohexyl]thiazol-5-yl]-3-(tert-Butyl Isopropyl]aminosulfonyl)phenyl]carbamate synthesis.

[1336] Option 14:

[1337]

[1338] General method B, trans-N-[4-[2-[4-(tert-butoxycarbonylamino)cyclohexyl]thiazol-5-yl]-3-(tert- Isopropyl butylsulfamoylphenyl]carbamate . 1 H 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] =595.1.

[1339] Example 45. Synthesis of tert-butyl ((1r,4r)-4-(5-(2-(N-(tert-butyl)sulfamoyl)-4-(3-(pyridin-2-ylmethyl)ureido)phenyl)thiazol-2-yl)cyclohexyl)carbamate.

[1340] Through key intermediates 82 The following compounds were synthesized by the same method.

[1341]

[1342] 1 H NMR (400 MHz, methanol-d4) δ = 8.17 (d, J = 2.2 Hz, 1H), 7.75 - 7.59 (m,2H), 7.43 - 7.22 (m, 3H), 7.21 -7.03 (m, 2H), 4.53 (m, 2H), 3.43 (br t, J=11.8Hz, 1H), 2.99 (br t, J=12.1 Hz, 1H), 2.22 (br d, J=12.7 Hz, 2H), 2.06 (br d,J=10.5 Hz, 2H), 1.77 - 1.60 (m, 2H), 1.58 - 1.34 (m, 11H), 1.09 (s, 9H). ESI [M+H]=643.3.

[1343] Example 46. N-[3-(tert-butylsulfamoyl)-4-[2-[3-(isopropoxycarbonylamino)azetidine- 1-yl]thiazol-5-yl]phenyl]carbamic acid isopropyl ester synthesis.

[1344] Option 15:

[1345]

[1346] Preparation of compound 129.

[1347]

[1348] tert-Butyl N-(azetidin-3-yl)carbamate hydrochloride (72.40 mg, 346.94 umol, 1.50 equivalents), N-[4-(2-Bromothiazol-5-yl)-3-(tert-butylsulfamoyl)phenyl]acetamide A mixture of 1,2-dimethylaminobenzoic acid (100 mg, 231.29 umol, 1 eq), t-BuONa (66.68 mg, 693.87 umol, 3 eq), [2-(2-aminoethyl)phenyl]-chloro-palladium; di-tert-butyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphane (15.88 mg, 23.13 umol, 0.1 eq) in tert-amyl alcohol (2 mL) was degassed and purged with N2 three times, and then the mixture was stirred at 100°C under N2 atmosphere for 12 hours and then concentrated. The residue was diluted with ethyl acetate (20 mL) and washed with H2O (20 mL). The organic layer was dried and concentrated and the residue was purified by preparative TLC (EtOAc) to give N-[1-[5-[4-acetylamino-2- tert-Butyl (tert-butylsulfamoyl)phenyl]thiazol-2-yl]azetidin-3-yl]carbamate (46 mg, crude). ESI [M+H] = 524.3.

[1349] Preparation of compound 130.

[1350]

[1351] General method F, 5-amino-2-[2-(3-aminoazetidin-1-yl)thiazol-5-yl]-N-tert-butyl-benzene Sulfonamide. ESI [M+H] =382.0.

[1352] Preparation of Example 46

[1353]

[1354] General method D, N-[3-(tert-butylsulfamoyl)-4-[2-[3-(isopropoxycarbonylamino)azetidine] Isopropyl]thiazol-5-yl]alkyl-1-yl]phenyl]carbamate . 1 H NMR (400 MHz, methanol-d4) δ = 8.35 (d, J = 2.0 Hz, 1H), 7.67 (dd, J = 2.2, 8.4 Hz, 1H), 7.45 - 7.32 (m, 2H), 5.04 - 4.94 (m,1H), 4.92 - 4.88 (m, 1H), 4.73 - 4.63 (m, 1H), 4.56 (br t, J=8.5 Hz, 2H), 4.27 (br s, 2H), 1.31 (d, J=6.2 Hz, 6H), 1.27 - 1.19 (m, 15H). ESI [M+H] =554.2.

[1355] Example 47. trans-N-[4-[5-[4-(benzylcarbamoylamino)-2-(tert-butylsulfamoyl)phenyl] 2-thiazol-2-yl]cyclohexyl]carbamic acid oxetan-3-yl ester Synthesis

[1356] Option 16:

[1357]

[1358]

[1359] Preparation of compound 131.

[1360]

[1361] General method F, trans-4-(5-bromothiazol-2-yl)cyclohexylamine . ESI [M+H] =260.9 / 262.9.

[1362] Preparation of compound 132.

[1363]

[1364] To a solution of oxetane-3-ol (1.15 g, 15.51 mmol, 3 eq) in DCE (10 mL) were added DIEA (3.34 g, 25.84 mmol, 4.50 mL, 5 eq) and triphosgene (1.53 g, 5.17 mmol, 1 eq). The mixture was stirred at 25-50 °C for 1 hour and then added trans-4-(5-bromothiazol-2-yl)cyclohexylamine (1.35 g, 5.17 mmol, 1 eq.), DIEA (3.34 g, 25.84 mmol, 4.50 mL, 5 eq.) in DCE (10 mL). The mixture was stirred at 25 ° C for 0.5 hours. The mixture was concentrated and the residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 30 / 1-5:1) to give trans-N-[4-(5-bromothiazol-2-yl)cyclohexane 1-Oxetane-3-yl]carbamate (1.5 g, crude). ESI [M+H] = 363.1 / 361.1.

[1365] Preparation of Example 47.

[1366]

[1367] General method K, trans-N-[4-[5-[4-(benzylcarbamoylamino)-2-(tert-butylsulfamoyl)phenyl] 2-thiazol-2-yl]cyclohexyl]carbamic acid oxetan-3-yl ester . 1 H NMR (400 MHz, methanol-d4) δ = 8.23 ​​(d, J = 2.2 Hz, 1H), 7.71 - 7.66 (m, 2H), 7.37 - 7.29 (m, 5H), 7.24 (br s, 1H),5.40 - 5.27 (m, 2H), 4.66 - 4.55 (m, 3H), 4.40 (s, 2H), 3.45 (br d, J=11.0 Hz,1H), 3.00 (br t, J=11.8 Hz, 1H), 2.22 (br d, J=13.0 Hz, 2H), 2.07 (br d, J=11.2 Hz, 2H), 1.74 - 1.63 (m, 2H), 1.47 - 1.37 (m, 2H), 1.10 (s, 9H). ESI [M+H] =642.3.

[1368] Example 48. Synthesis of oxetan-3-yl ((1r,4r)-4-(5-(2-(N-(tert-butyl)sulfamoyl)-4-((isopropoxycarbonyl)amino)phenyl)thiazol-2-yl)cyclohexyl)carbamate.

[1369] Through key intermediates 132 The following compounds were synthesized by the same method.

[1370]

[1371] 1 H NMR (400 MHz, methanol-d4) δ = 8.33 (d, J = 2.0 Hz, 1H), 7.71 - 7.64 (m,2H), 7.36 (d, J=8.4 Hz, 1H), 5.41 - 5.27 (m, 2H), 4.98 (td, J=6.4, 12.6 Hz,1H), 4.87 (br s, 1H), 4.63 - 4.56 (m, 2H), 3.45 (br d, J=12.3 Hz, 1H), 3.00 (brt, J=12.0 Hz, 1H), 2.22 (br d, J=13.0 Hz, 2H), 2.11 - 2.02 (m, 2H), 1.74 - 1.63 (m, 2H), 1.42 (q, J=12.7 Hz, 2H), 1.31 (d, J=6.2 Hz, 6H), 1.11 (s, 9H). ESI [M+H] =595.3.

[1372] Example 49. trans-N-[3-(tert-butylsulfamoyl)-4-[2-[4-(oxetan-3-yloxycarbonyl [amino]cyclohexyl]thiazol-5-yl]phenyl]carbamic acid oxetan-3-yl ester synthesis

[1373] Option 17:

[1374]

[1375] Preparation of compound 133.

[1376]

[1377] General method K, trans-N-[4-[5-[4-amino-2-(tert-butylsulfamoyl)phenyl]thiazol-2-yl]cyclohexane 1-Oxetane-3-yl]carbamate . ESI [M+H] =509.0.

[1378] Preparation of compound 134.

[1379]

[1380] General method D, trans-N-[4-[5-[2-(tert-butylsulfamoyl)-4-[(4-nitrophenoxy)carbonylamino 1-Hydroxyphenyl]thiazol-2-yl]cyclohexyl]carbamic acid oxetan-3-yl ester . ESI [M+H] =674.2.

[1381] Preparation of Example 49.

[1382]

[1383] General method H, trans-N-[3-(tert-butylsulfamoyl)-4-[2-[4-oxetan-3-yloxycarbonyl] [3-Oxetan-4-yl]thiazol-5-yl]phenyl]carbamate . 1 H NMR (400MHz, DMSO-d6) δ = 10.39 (s, 1H), 8.28 (d, J=2.2 Hz, 1H), 7.71 - 7.58 (m, 2H), 7.48 - 7.34(m, 2H), 6.97(s, 1H), 5.50 - 5.39 (m, 1H), 5.32 - 5.20 (m, 1H), 4.87 - 4.68 (m,4H), 4.61 - 4.36 (m, 4H), 3.30 - 3.23 (m, 1H), 3.01 - 2.82 (m, 1H), 2.12 (br d, J=11.7 Hz, 2H), 1.90 (br d, J=10.4 Hz, 2H), 1.66 - 1.47 (m, 2H), 1.43 - 1.26 (m,2H), 1.04 (s, 9H). ESI [M+H] =609.2.

[1384] Example 50. Synthesis of oxetan-3-yl ((1r,4r)-4-(5-(2-(N-(tert-butyl)sulfamoyl)-4-(3-(pyridin-2-ylmethyl)ureido)phenyl)thiazol-2-yl)cyclohexyl)carbamate.

[1385] Through key intermediates 134 The following compounds were synthesized by the same method.

[1386]

[1387] 1H NMR (400 MHz, methanol-d4) δ = 8.49 (d, J = 4.8 Hz, 1H), 8.25 (d, J = 2.2 Hz, 1H), 7.82 (dt, J = 1.8, 7.7 Hz, 1H), 7.73 - 7.63 (m, 2H), 7.45 (d, J=7.9 Hz,1H), 7.38 - 7.26 (m, 2H), 5.39 - 5.28 (m, 1H), 4.84 (br s, 1H), 4.70 - 4.56 (m,3H), 4.53 (s, 2H), 3.44 (br t, J=12.1 Hz, 1H), 3.06 - 2.92 (m, 1H), 2.22 (br d,J=13.2 Hz, 2H), 2.07 (br d, J=11.0 Hz, 2H), 1.79 - 1.60 (m, 2H), 1.50 - 1.35 (m,2H), 1.10 (s, 9H). ESI [M+H] =643.2.

[1388] Example 51. Synthesis of oxetan-3-yl ((1S,4r)-4-(5-(2-(N-(tert-butyl)sulfamoyl)-4-(3-((S)-1-phenylethyl)ureido)phenyl)thiazol-2-yl)cyclohexyl)carbamate.

[1389] Through key intermediates 134 The following compounds were synthesized by the same method.

[1390]

[1391] 1 H NMR (400 MHz, methanol-d4) δ = 8.19 (d, J = 2.2 Hz, 1H), 7.70 - 7.63 (m,2H), 7.39 - 7.30 (m, 5H), 7.27 - 7.20 (m, 1H), 5.35 (t, J=5.7 Hz, 1H), 4.92 (q, J=6.8 Hz, 2H), 4.84 (br s, 1H), 4.60 (t, J=6.4 Hz, 2H), 3.49 -3.38 (m, 1H), 3.05 - 2.95 (m, 1H), 2.22 (br d, J=12.3 Hz, 2H), 2.10 - 2.02 (m, 2H), 1.74 - 1.61(m, 2H), 1.49 (d, J=7.1 Hz, 3H), 1.45 - 1.34 (m, 2H), 1.09 (s, 9H). ESI [M+H] =656.3.

[1392] Example 52. Synthesis of oxetan-3-yl ((1R,4r)-4-(5-(2-(N-(tert-butyl)sulfamoyl)-4-(3-((R)-1-phenylethyl)ureido)phenyl)thiazol-2-yl)cyclohexyl)carbamate.

[1393] Through key intermediates 134 The following compounds were synthesized by the same method.

[1394]

[1395] 1 HNMR (400MHz, methanol-d4) δ = 8.19 (d, J=2.2 Hz, 1H), 7.75 - 7.61 (m,2H), 7.42 - 7.18 (m, 6H), 5.35 (quin, J=5.7 Hz, 1H), 5.01 - 4.87 (m, 3H), 4.70 - 4.52 (m, 2H), 3.51 - 3.38 (m, 1H), 3.06 - 2.92 (m, 1H), 2.22 (br d, J=11.9 Hz, 2H), 2.07 (br d, J=11.7 Hz, 2H), 1.77 - 1.62 (m, 2H), 1.54 - 1.35 (m, 5H), 1.10 (s, 9H). ESI [M+H] =656.2.

[1396] Example 53. Synthesis of oxetan-3-yl ((1r,4r)-4-(5-(2-(N-(tert-butyl)sulfamoyl)-4-(3-(2-fluorobenzyl)ureido)phenyl)thiazol-2-yl)cyclohexyl)carbamate.

[1397] Through key intermediates 134 The following compounds were synthesized by the same method.

[1398]

[1399] 1 HNMR (400MHz, methanol-d4) δ = 8.23 ​​(d, J=2.4 Hz, 1H), 7.75 - 7.63 (m,2H), 7.46 - 7.24 (m, 3H), 7.20 - 7.03 (m, 2H), 5.43 - 5.28 (m, 1H), 4.85 (br s,2H), 4.67 - 4.56 (m, 2H), 4.47 (s, 2H), 3.53 - 3.37 (m, 1H), 3.08 - 2.93 (m, 1H), 2.29 - 1.99 (m, 4H), 1.78 - 1.61 (m, 2H), 1.53 - 1.35 (m, 2H), 1.11 (s, 9H). ESI [M+H] =660.2.

[1400] Example 54. Synthesis of oxetan-3-yl ((1R,4r)-4-(5-(2-(N-(tert-butyl)sulfamoyl)-4-(3-((R)-1-(2-fluorophenyl)ethyl)ureido)phenyl)thiazol-2-yl)cyclohexyl)carbamate.

[1401] Through key intermediates 134 The following compounds were synthesized by the same method.

[1402]

[1403] 1 H NMR (400 MHz, methanol-d4) δ = 8.20 (d, J = 2.3 Hz, 1H), 7.73 - 7.65 (m,2H), 7.45 - 7.39 (m, 1H), 7.38 - 7.26 (m, 2H), 7.21 -7.04 (m, 2H), 5.37 (quin, J=5.7 Hz, 1H), 5.20 (q, J=7.0 Hz, 1H), 4.89 - 4.86 (m, 2H), 4.65 - 4.59 (m, 2H), 3.52 - 3.41 (m, 1H), 3.08 - 2.96 (m, 1H), 2.24 (br d, J=12.2 Hz, 2H), 2.13 - 2.05(m, 2H), 1.76 - 1.64 (m, 2H), 1.52 (d, J=7.0 Hz, 3H), 1.47 - 1.39 (m, 2H), 1.12 (s, 9H). ESI [M+H] =674.2.

[1404] Example 55. Synthesis of oxetan-3-yl ((1S,4r)-4-(5-(2-(N-(tert-butyl)sulfamoyl)-4-(3-((S)-1-(2-fluorophenyl)ethyl)ureido)phenyl)thiazol-2-yl)cyclohexyl)carbamate.

[1405] Through key intermediates 134 The following compounds were synthesized by the same method.

[1406]

[1407] 1 HNMR (400MHz, methanol-d4) δ = 8.17 (d, J = 2.2 Hz, 1H), 7.75 - 7.59 (m,2H), 7.43 - 7.22 (m, 3H), 7.21 - 7.03 (m, 2H), 5.39 - 5.28 (m, 1H), 5.17 (q, J=7.0Hz, 1H), 4.90 - 4.87 (m, 1H), 4.84 (s, 1H), 4.66 -4.54 (m, 2H), 3.43 (br t, J=11.8 Hz, 1H), 2.99 (br t, J=12.1 Hz, 1H), 2.22 (br d, J=12.7 Hz, 2H), 2.06 (br d, J=10.5 Hz, 2H), 1.77 - 1.60 (m, 2H), 1.58 - 1.34 (m, 5H), 1.09 (s, 9H). ESI[M+H] =674.2.

[1408] Example 56. N-[3-(tert-butylsulfamoyl)-4-[2-[5-(isopropoxycarbonylamino)-3-methoxy- 2-pyridyl]thiazol-5-yl]phenyl]carbamic acid 4-piperidinylmethyl ester synthesis

[1409] Plan 18:

[1410]

[1411]

[1412] Preparation of compound 136.

[1413]

[1414] Na (8.75 g, 380.60 mmol, 9.02 mL, 1.51 equiv) was added portionwise to MeOH (300 mL) and after Na was dissolved, the mixture was concentrated to dryness. The resulting gray solid (NaOMe) was added to DMF (300 mL) and heated at 0°C. 3-Chloropyridine-2-carbonitrile (35 g, 252.61 mmol, 1 eq.). The reaction mixture was stirred at 20°C for 12 h, and then diluted with H2O (800 mL) and filtered. The filter cake was dried to give 3-Methoxypyridine- 2-Carbononitrile (25 g, crude). ESI [M+H] = 135.1.

[1415] Preparation of Compound 137

[1416]

[1417] At 0℃ 3-Methoxypyridine-2-carbonitrileTo a solution of 4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4- 3-Methoxy-5-nitro-pyridine-2-carbonitrile (27 g, crude). 1 H NMR (400 MHz, chloroform-d) δ =9.06 (d, J=2.2 Hz, 1H), 8.13 (d, J=2.2 Hz, 1H), 4.16 - 4.08 (m, 3H). ESI [M+H] =180.1.

[1418] General Method G for the Preparation of Compound 138

[1419]

[1420] Towards 3-Methoxy-5-nitro-pyridine-2-carbonitrile To a solution of 4-[4-[4-[4-[4-(4-oxo-1-yl)-2-nitropropene]-1-piperidin-1-yl]-1-nitropropene]-1-nitropropene]-1-nitropropene]-1-nitropropene]-1-nitropropene) ... 5-Amino-3-methoxy-pyridine-2-carbonitrile (14.5 g, crude). ESI [M+H] = 150.1.

[1421] Preparation of compound 139.

[1422]

[1423] General method D, Isopropyl N-(6-cyano-5-methoxy-3-pyridyl)carbamate . 1H NMR (400 MHz, methanol-d4) δ = 8.13 (d, J = 2.2 Hz, 1H), 7.95 (d, J = 1.8 Hz, 1H), 5.04 - 4.95 (m,1H), 3.96 (s, 3H), 1.31 (d, J=6.2 Hz, 6H). ESI [M+H] =236.1.

[1424] Preparation of compound 140.

[1425]

[1426] Towards Isopropyl N-(6-cyano-5-methoxy-3-pyridyl)carbamate To a solution of 4-[ ... Isopropyl N-(6-thiocarbamoyl-5-methoxy-3-pyridyl)carbamate (21 g, crude). 1 H NMR(400MHz, DMSO-d6) δ = 9.92 - 9.84 (m, 2H), 9.38 (br s, 1H), 8.08 (d, J=1.8 Hz,1H), 7.66 (s, 1H), 4.89 (spt, J=6.3 Hz, 1H), 3.74 (s, 3H), 1.24 (d, J=6.1 Hz,6H). ESI [M+H] =270.0.

[1427] Preparation of compound 141.

[1428]

[1429] General method M, Isopropyl N-(5-methoxy-6-thiazol-2-yl-3-pyridyl)carbamate 1H NMR(400MHz, DMSO-d6) δ = 10.07 (s, 1H), 8.26 (d, J=2.0 Hz, 1H), 7.88 (d, J=3.1Hz, 1H), 7.85 (d, J=1.3 Hz, 1H), 7.71 (d, J=3.3 Hz, 1H), 4.91 (spt, J=6.2 Hz, 1H), 3.88 (s, 3H), 1.26 (d, J=6.4 Hz, 6H). ESI [M+H] =294.1.

[1430] Preparation of compound 142.

[1431]

[1432] General method J, Isopropyl N-[6-(5-bromothiazol-2-yl)-5-methoxy-3-pyridyl]carbamate . 1 HNMR (400MHz, DMSO-d6) δ = 10.17 (s, 1H), 8.28 (d, J=1.8 Hz, 1H), 8.08 - 7.86 (m, 2H), 4.99 (br s, 1H), 3.93 (s, 3H), 1.29 (d, J=6.4 Hz, 6H). ESI [M+H] =371.8 / 373.8.

[1433] Preparation of compound 143.

[1434]

[1435] General method B, N-[6-[5-[4-Acetylamino-2-(tert-butylsulfamoyl)phenyl]thiazol-2-yl]-5-methyl Isopropyl]oxy-3-pyridylcarbamate . ESI [M+H] =562.0.

[1436] Preparation of compound 144.

[1437]

[1438] General method F, N-[6-[5-[4-amino-2-(tert-butylsulfamoyl)phenyl]thiazol-2-yl]-5-methoxy Isopropyl-3-pyridyl]carbamate. ESI [M+H] =520.2.

[1439] Preparation of compound 145.

[1440]

[1441] General method D, N-[3-(tert-butylsulfamoyl)-4-[2-[5-(isopropoxycarbonylamino)-3-methoxy- 2-Pyridyl]thiazol-5-yl]phenyl]carbamic acid (4-nitrophenyl) ester . ESI [M+H] =685.1.

[1442] Preparation of compound 146.

[1443]

[1444] General method H, 4-[[3-(tert-butylsulfamoyl)-4-[2-[5-(isopropoxycarbonylamino)-3-methoxy tert-Butyl]-2-pyridinyl]thiazol-5-yl]phenyl]carbamoyloxymethyl]piperidine-1-carboxylate . ESI [M+H] =761.4.

[1445] Preparation of Example 56.

[1446]

[1447] General method C, N-[3-(tert-butylsulfamoyl)-4-[2-[5-(isopropoxycarbonylamino)-3-methoxy- 4-Piperidinylmethyl 2-pyridyl]thiazol-5-yl]phenyl]carbamate . 1 H NMR (400MHz, DMSO-d6) δ =10.19 - 10.10 (m, 2H), 8.35 (d, J=2.1 Hz, 1H), 8.30 (d, J=1.8 Hz, 1H), 7.89 (s,2H), 7.68 (dd, J=2.0, 8.4 Hz, 1H), 7.46 (d, J=8.4 Hz, 1H), 7.12 (br s, 1H), 4.95 (td, J=6.2, 12.5 Hz, 1H), 3.98 (d, J=6.5 Hz, 2H), 3.93 (s, 3H), 3.00 (brd, J=12.1 Hz, 2H), 2.70 - 2.56 (m, 2H), 1.77 (br d, J=4.0 Hz, 1H), 1.67 (br d,J=12.1 Hz, 2H), 1.30 (d, J=6.2 Hz, 6H), 1.16 (br dd, J=3.4, 12.0 Hz, 2H), 1.09 (s, 9H). ESI [M+H] =661.3.

[1448] Example 57. trans-N-[4-[5-[4-(Benzylcarbamoylamino)-2-(tert-butylsulfamoyl)phenyl]- 4-Fluoro-thiazol-2-yl]cyclohexyl]carbamic acid isopropyl ester synthesis.

[1449] Scheme 19:

[1450]

[1451] Preparation of Compound 147

[1452]

[1453] Towards trans-Isopropyl N-[4-(5-bromothiazol-2-yl)cyclohexyl]carbamateTo a solution of 1-(chloromethyl)-4-fluoro-1,4-dihydro-1-(chloromethyl)-2-nitropropane (1.50 g, 4.32 mmol, 1 eq.) in ACN (20 mL) was added 1-(chloromethyl)-4-fluoro-1,4-dihydro-1-nitropropane - Diazonia bicyclo[2.2.2]octane bistetrafluoroborate (3.06 g, 8.64 mmol, 2 eq) was added and the mixture was stirred at 80° C. for 12 h. The mixture was then concentrated and the residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 3 / 1-3:1) to give trans-N-[4-(5-bromo-4-fluoro-thiazol-2-yl)cyclohexyl]carbamic acid isopropyl ester (0.2 g, 547.55 umol, 12.68% yield). ESI [M+H] = 365.1 / 367.1.

[1454] Preparation of Example 57.

[1455]

[1456] General method B, trans-N-[4-[5-[4-(Benzylcarbamoylamino)-2-(tert-butylsulfamoyl)benzene 4-Fluoro-thiazol-2-yl]cyclohexyl]carbamic acid isopropyl ester . 1 H NMR (400 MHz, methanol-d4) δ = 8.24 (d, J = 2.0 Hz, 1H), 7.67 (dd, J = 2.0, 8.4 Hz, 1H), 7.37 - 7.29 (m, 5H), 7.24 (brd, J=2.6 Hz, 1H), 4.82 - 4.77 (m, 1H), 4.40 (s, 2H), 3.42 (br t, J=11.6 Hz,1H), 2.87 (br t, J=12.0 Hz, 1H), 2.20 (br d, J=12.3 Hz, 2H), 2.05 (br d, J=11.0 Hz, 2H), 1.69 - 1.57 (m, 2H), 1.43 - 1.30 (m, 2H), 1.21 (br d, J=5.7 Hz, 6H), 1.15 (s, 9H). ESI [M+H] =646.2.

[1457] Example 58. Synthesis of Isopropyl ((1r,4r)-4-(5-(2-(N-(tert-butyl)sulfamoyl)-4-((isopropoxycarbonyl)amino)phenyl)-4-fluorothiazol-2-yl)cyclohexyl)carbamate

[1458] Through key intermediates 147 The following compounds were synthesized by the same method.

[1459]

[1460] 1 H NMR (400MHz, methanol-d4) δ = 8.35 (s, 1H), 7.69 (br d, J=8.1 Hz, 1H), 7.37 (d, J=8.3 Hz, 1H), 5.01 (td, J=6.1, 12.4 Hz, 1H), 4.83 (br s, 1H), 3.53 - 3.39 (m, 1H), 2.96 - 2.85 (m, 1H), 2.23 (br d, J=12.3 Hz, 2H), 2.08 (br d, J=10.5 Hz, 2H), 1.75 - 1.60 (m, 2H), 1.47 - 1.38 (m, 2H), 1.34 (d, J=6.2 Hz, 6H), 1.24 (br d, J=6.0 Hz, 6H), 1.18 (s, 9H). ESI [M+H] =599.2.

[1461] Example 59. trans-N-[6-[5-[4-(benzylcarbamoylamino)-2-(tert-butylsulfamoyl)phenyl]thiophene Isopropyl]oxazol-2-yl]tetrahydropyran-3-yl]carbamate Synthesis

[1462] Option 20:

[1463]

[1464]

[1465] Preparation of Compound 149

[1466]

[1467] Towards 2-Oxoethyl acetate (250 g, 1.22 mol, 1 eq.) in toluene (1.5 L) was added Butadiene-1,3-diene (92.72 g, 1.71 mol, 149.55 mL, 1.4 eq) and 2,6-di-tert-butyl-4-methyl-phenol (5.40 g, 24.49 mmol, 0.02 eq). The mixture was stirred at 170 ° C for 8 hours under 1 MPa in a high pressure tube and then concentrated. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 100: 1-10: 1) to give 3,6-Dihydro-2H-pyran-2-carboxylic acid ethyl ester(26 g, 166.48 mmol, 13.60% yield). 1 H NMR (400 MHz, chloroform-d) δ = 5.82 - 5.74 (m, 1H), 5.71 - 5.64 (m, 1H), 4.36 - 4.27 (m, 1H), 4.23 - 4.12 (m, 4H), 2.39 - 2.23 (m, 2H), 1.24 (t, J=7.1 Hz, 3H).

[1468] Preparation of Compound 150

[1469]

[1470] General Methods 3,6-Dihydro-2H-pyran-2-carboxylic acid . 1 H NMR (400 MHz, chloroform-d) δ = 5.88 (qdd, J = 2.3, 5.1, 10.2 Hz, 1H), 5.80 - 5.71 (m, 1H), 4.43 - 4.19 (m, 3H), 2.53 - 2.31 (m, 2H).

[1471] Preparation of Compound 151

[1472]

[1473] General method N, 3,6-Dihydro-2H-pyran-2-carboxamide . 1 H NMR (400 MHz, chloroform-d) δ = 6.50 (br s, 1H), 5.89 - 5.76 (m, 1H), 5.67 (br d, J=9.8 Hz, 1H), 5.50 (br s, 1H), 4.22 (br s, 2H), 3.97 (dd, J=3.9, 10.8 Hz, 1H), 2.49 - 2.35 (m, 1H), 2.28 - 2.09 (m, 1H).

[1474] Preparation of compound 152

[1475]

[1476] General method L, 3,6-Dihydro-2H-pyran-2-carbothioamide . ESI [M+H]=144.1

[1477] Preparation of compound 153

[1478]

[1479] General method M, 2-(3,6-Dihydro-2H-pyran-2-yl)thiazole . 1 H NMR (400 MHz, chloroform-d) δ =7.69 (d, J=2.9 Hz, 1H), 7.26 (d, J=2.9 Hz, 1H), 5.93 - 5.83 (m, 1H), 5.70 - 5.63(m, 1H), 4.86 (dd, J=3.9, 9.8 Hz, 1H), 4.33 (br s, 2H), 2.61 - 2.37 (m, 2H). ESI[M+H]=168.1.

[1480] Preparation of compound 154

[1481]

[1482] At 0℃ 2-(3,6-Dihydro-2H-pyran-2-yl)thiazole To a solution of 4-[ ... The residue was purified by column (petroleum ether: EtOAc=5:1-1:1) to give 6-thiazol-2-yltetrahydropyran-3-ol (7 g, crude). ESI [M+H]=186.2.

[1483] Preparation of compound 155

[1484]

[1485] Towards 6-thiazol-2-yltetrahydropyran-3-ol To a solution of 4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-dimethylamino]-1-piperidin-1-yl]propane]-2-yl]-4-nitropropane-2-yl]propane-2 ... (6-thiazol-2-yltetrahydropyran-3-yl) methanesulfonate (7 g, crude), which was used directly.

[1486] Towards (6-thiazol-2-yltetrahydropyran-3-yl) methanesulfonate To a solution of 4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-phenyl]-1,2-d ... 2-(5-azide (2-(2-Yl)tetrahydropyran-2-yl)thiazole (5 g, crude), which was used without any purification.

[1487] Preparation of Compound 156

[1488]

[1489] Towards 2-(5-Azidotetrahydropyran-2-yl)thiazole To a solution of 5-[4-[ ... 6-thiazol-2-yltetrahydropyran-3-amine (3 g, crude). ESI [M+H] = 185.2.

[1490] Preparation of Compound 157

[1491]

[1492] General method D, trans-Isopropyl N-(6-thiazol-2-ylt...

Claims

1. Use of compound 67A represented by the following structural formula or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating pancreatic cancer in a subject in need thereof: Wherein Compound 67A or a pharmaceutically acceptable salt thereof is used in a dosage of from about 250 mg / day to about 500 mg / day.

2. The use according to claim 1, wherein the subject is a human.

3. The use according to any one of claims 1-2, wherein the dosage range of the compound 67A or a pharmaceutically acceptable salt thereof is about 300 mg / day to about 500 mg / day.

4. The use according to any one of claims 1-2, wherein the dosage range of the compound 67A or a pharmaceutically acceptable salt thereof is about 400 mg / day to about 500 mg / day.

5. The use of any one of claims 1-2, wherein the dose of compound 67A or a pharmaceutically acceptable salt thereof is selected from about 250 mg / day, about 260 mg / day, 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 and about 500 mg / day.

6. The use of any one of claims 1-2, wherein the dose of compound 67A or a pharmaceutically acceptable salt thereof is selected from 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 and about 500 mg / day.

7. The use of any one of claims 1-2, wherein the dose of compound 67A or a pharmaceutically acceptable salt thereof is selected from 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 and about 500 mg / day.

8. The use according to any one of claims 1-2, wherein the dose of Compound 67A or a pharmaceutically acceptable salt thereof is about 400 mg / day.

9. The use according to any one of claims 1 to 8, wherein the dosage of the compound 67A or a pharmaceutically acceptable salt thereof is from about 180 mg / m 2 About 500 mg / m 2 .

10. The use according to any one of claims 1 to 9, wherein the dosage of the compound 67A or a pharmaceutically acceptable salt thereof is from about 180 mg / m 2 About 400 mg / m 2 .

11. The use according to any one of claims 1 to 9, wherein the dosage of the compound 67A or a pharmaceutically acceptable salt thereof is from about 240 mg / m 2 About 500 mg / m 2 .

12. The use according to any one of claims 1 to 11, wherein the dosage of the compound 67A or a pharmaceutically acceptable salt thereof is from about 240 mg / m 2 About 400 mg / m 2 .

13. The use according to any one of claims 1 to 9, wherein the dose of the compound 67A or a pharmaceutically acceptable salt thereof is selected from about 180 mg / m 2 , about 200mg / m 2 , about 220mg / m 2 , about 240mg / m 2 , about 260mg / m 2 , about 280mg / m 2 , about 300mg / m 2 , about 320mg / m 2 , about 340mg / m 2 , about 360mg / m 2 , about 380mg / m 2 , about 400mg / m 2 , about 420mg / m 2 , about 440mg / m 2 , about 460mg / m 2 , about 480mg / m 2 and about 500 mg / m 2 。 14. The use according to any one of claims 1 to 9, wherein the dose of the compound 67A or a pharmaceutically acceptable salt thereof is selected from about 240 mg / m 2 , about 260mg / m 2 , about 280mg / m 2 , about 300mg / m 2 , about 320mg / m 2 , about 340mg / m 2 , about 360mg / m 2 , about 380mg / m 2 , about 400mg / m 2 , about 420mg / m 2 , about 440mg / m 2 , about 460mg / m 2 , about 480mg / m 2 and about 500 mg / m 2 .

15. The use according to any one of claims 1 to 12, wherein the dose of the compound 67A or a pharmaceutically acceptable salt thereof is selected from about 240 mg / m 2 , about 260mg / m 2 , about 280mg / m 2 , about 300mg / m 2 , about 320mg / m 2 , about 340mg / m 2 , about 360mg / m 2 , about 380mg / m 2 and about 400 mg / m 2 .

16. The use according to any one of claims 1 to 12, wherein the dose of the compound 67A or a pharmaceutically acceptable salt thereof is selected from about 240 mg / m 2 , about 260mg / m 2 , about 280mg / m 2 , about 300mg / m 2 , about 320mg / m 2 , about 340mg / m 2 and about 360 mg / m 2 .

17. The use according to any one of claims 1 to 16, wherein the administration of the compound 67A or a pharmaceutically acceptable salt thereof is followed by a 14-day non-administration period.

18. The use of any one of claims 1 to 16, wherein the administration of the compound 67A or a pharmaceutically acceptable salt thereof is followed by a 21-day cessation period.

19. The use of any one of claims 1 to 16, wherein the dose of compound 67A or a pharmaceutically acceptable salt thereof is about 240 mg / m 2 , followed by a 14-day rest period.

20. The use of any one of claims 1-16, wherein the dose of compound 67A or a pharmaceutically acceptable salt thereof is about 240 mg / m 2 , followed by a 21-day rest period.

21. The use of any one of claims 1 to 8, wherein the dose of compound 67A or a pharmaceutically acceptable salt thereof is about 120 mg / m 2 , followed by a 14-day rest period.

22. The use of any one of claims 1 to 8, wherein the dose of compound 67A or a pharmaceutically acceptable salt thereof is about 120 mg / m 2 , followed by a 21-day rest period.

23. The use according to any one of claims 1 to 16, wherein the compound 67A or a pharmaceutically acceptable salt thereof is administered once a day.

24. The use according to any one of claims 1 to 16, wherein the compound 67A or a pharmaceutically acceptable salt thereof is administered once every other day.

25. The use according to any one of claims 1 to 16, wherein the compound 67A or a pharmaceutically acceptable salt thereof is administered once a day for 4 weeks.

26. The use according to any one of claims 1 to 16, wherein the compound 67A or a pharmaceutically acceptable salt thereof is administered once a day for 4 weeks followed by a period of no administration.

27. Use of a composition for the preparation of a medicament for treating pancreatic cancer in a subject in need thereof, wherein the composition comprises compound 67A: or a pharmaceutically acceptable salt thereof.

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