Combination of STAT inhibitors and immune checkpoint inhibitors for the treatment and / or management of cancer

Abstract

Provided herein are methods of treating cancer in a subject in need thereof, the methods comprising administering to the subject an effective amount of a STAT inhibitor and an effective amount of an immune checkpoint inhibitor (e.g., a PD-1 inhibitor or a PD-L1 inhibitor).

Description

[Technical field]

[0001] cross reference This application claims the benefit of and priority to U.S. Provisional Patent Application No. 63 / 268,897, filed March 4, 2022, which is incorporated by reference in its entirety. [Background technology]

[0002] Immune checkpoints are inhibitory pathways that help maintain self-tolerance and regulate the duration and amplitude of physiological immune responses in peripheral tissues to minimize collateral tissue damage. Tumors select certain immune checkpoint pathways as mechanisms of immune resistance, especially to T cells specific for tumor antigens. For example, the development of checkpoint blocking antibodies targeting or directed against the programmed death 1 receptor (PD-1) can facilitate the treatment of cancer. Immunotherapies such as anti-PD-1 antibody therapy or anti-PD-L1 antibody therapy have brought about improvements in the treatment of cancer. However, there are still many patients who do not respond easily or lose responsiveness to treatment over time. Therefore, there is a need to improve the treatment of cancer by combining different therapies. Summary of the Invention

[0003] In certain embodiments, provided herein are combinations (e.g., combinations of compounds described herein, e.g., a STAT3 inhibitor and an immune checkpoint inhibitor), which may be used, e.g., in a method of treating cancer in a subject in need of such treatment.

[0004] In one embodiment, there is provided a method of treating cancer in a subject in need thereof, comprising: a) administering to said subject an effective amount of a compound represented by formula (I)

[0005] [ka] or a pharma- ceutically acceptable salt thereof, wherein R is selected from the group consisting of hydrogen, phenylsulfanyl, 2-hydroxy-naphthalen-1-yl, quinolin-8-ylsulfanyl, triazol-3-ylsulfanyl, and benzothiazol-2-ylsulfanyl; and R 1is selected from the group consisting of hydrogen, methyl, chloro, bromo, methoxy, ethoxy, tert-butyl, nitro, methyl ester, acetamide, 1,4 dioxin, fluoro, trifluoromethoxy, acetyl, trifluoromethyl, propyl, cyclohexene, methoxy-phenoxy, chlorophenoxy, tolyloxy, and phenoxy; and b) administering to the subject an effective amount of an immune checkpoint inhibitor. In some embodiments, the compound of formula (I) is N-(1',2-dihydroxy1,2'-binaphthalen-4'-yl)-4-methoxybenzenesulfonamide, N-(3,1'-dihydroxy[1,2']binaphthalenyl-4'-yl)-4-methoxy-benzenesulfonamide, N-(4,1'-dihydroxy[1,2']binaphthalenyl-4'-yl)-4-methoxy-benzenesulfonamide, N-(5,1'-dihydroxy[1,2']binaphthalenyl-4'-yl)-4-methoxy-benzenesulfonamide, N-(6,1'-dihydroxy[1,2']binaphthalenyl-4'-yl)-4- Methoxy-benzenesulfonamide, N-(7,1'-dihydroxy[1,2']binaphthalenyl4'-yl)-4-methoxy-benzenesulfonamide, N-(8,1'-dihydroxy[1,2']binaphthalenyl4'-yl)-4-methoxy-benzenesulfonamide, 4-bromo-N-(1,6'-dihydroxy[2,2']binaphthalenyl4-yl)-benzenesulfonamide, or 4-bromo-N-[4-hydroxy-3-(1H-[1,2,4]triazol-3-ylsulfanyl)-naphthalen-1-yl]-benzenesulfonamide, or a pharma- ceutically acceptable salt thereof. In some embodiments, the compound of formula (I) is N-(1',2-dihydroxy1,2'-binaphthalen-4'-yl)-4-methoxybenzenesulfonamide. In some embodiments, the immune checkpoint inhibitor is administered parenterally. In some embodiments, the immune checkpoint inhibitor is a PD-1 inhibitor or a PD-L1 inhibitor. In some embodiments, the PD-1 inhibitor is an anti-PD-1 antibody.In some embodiments, the anti-PD-1 antibody is cemiplimab, nivolumab, pembrolizumab, pidilizumab, spartalizumab, camrelizumab, sintilimab, tislelizumab, toripalimab, dostallimab, sasunlimab, retifanlimab, tebotelimab, ABBV-181, AK104, AK105, BCD-100, BI-754091, CBT-501, CC-90006, GLS-010, HLX10, IBI-308, JNJ-3283, JS001, LZM009, MEDI0680 (AMP-514), REGN-2810, SHR-1210, Sym021, TSR-042, or XmAb20717. In some embodiments, the anti-PD-1 antibody is pembrolizumab. In some embodiments, the PD-L1 inhibitor is an anti-PD-L1 antibody. In some embodiments, the anti-PD-L1 antibody is atezolizumab, avelumab, durvalumab, embafolimab, FS118, BCD-135, BGB-A333, BGBA-317, CBT-502, CK-301, CS1001, FAZ053, MDX-1105, MSB2311, SHR-1316, M7824, LY3415244, CA-170, or CX-072. In some embodiments, the immune checkpoint inhibitor is administered prior to administration of the compound of Formula (I). In some embodiments, the immune checkpoint inhibitor is administered simultaneously with administration of the compound of Formula (I). In some embodiments, the immune checkpoint inhibitor is administered after administration of the compound of Formula (I). In some embodiments, the subject exhibits at least a partial response 3 weeks or more after administration of the compound of Formula (I) and the immune checkpoint inhibitor. In some embodiments, the subject exhibits a complete response 3 weeks or more after administration of the compound of Formula (I) and the immune checkpoint inhibitor. In some embodiments, the methods described herein reduce tumor size by at least 20% more within 6 weeks of administration compared to a subject administered an immune checkpoint inhibitor alone.

[0006] In one embodiment, there is provided a method for reducing the risk of cancer recurrence in a subject in need thereof, comprising administering to said subject an effective amount of a compound represented by the formula (I):

[0007] [ka] or a pharma- ceutically acceptable salt thereof, wherein R is selected from the group consisting of hydrogen, phenylsulfanyl, 2-hydroxy-naphthalen-1-yl, quinolin-8-ylsulfanyl, triazol-3-ylsulfanyl, and benzothiazole-

[0008] 2-ylsulfanyl; R 1is selected from the group consisting of hydrogen, methyl, chloro, bromo, methoxy, ethoxy, tert-butyl, nitro, methyl ester, acetamide, 1,4 dioxin, fluoro, trifluoromethoxy, acetyl, trifluoromethyl, propyl, cyclohexene, methoxy-phenoxy, chlorophenoxy, tolyloxy, and phenoxy; and b) administering to the subject an effective amount of an immune checkpoint inhibitor. In some embodiments, the compound of formula (I) is N-(1',2-dihydroxy1,2'-binaphthalen-4'-yl)-4-methoxybenzenesulfonamide, N-(3,1'-dihydroxy[1,2']binaphthalenyl-4'-yl)-4-methoxy-benzenesulfonamide, N-(4,1'-dihydroxy[1,2']binaphthalenyl-4'-yl)-4-methoxy-benzenesulfonamide, N-(5,1'-dihydroxy[1,2']binaphthalenyl-4'-yl)-4-methoxy-benzenesulfonamide, N-(6,1'-dihydroxy[1,2']binaphthalenyl-4'-yl)-4- Methoxy-benzenesulfonamide, N-(7,1'-dihydroxy[1,2']binaphthalenyl4'-yl)-4-methoxy-benzenesulfonamide, N-(8,1'-dihydroxy[1,2']binaphthalenyl4'-yl)-4-methoxy-benzenesulfonamide, 4-bromo-N-(1,6'-dihydroxy[2,2']binaphthalenyl4-yl)-benzenesulfonamide, or 4-bromo-N-[4-hydroxy-3-(1H-[1,2,4]triazol-3-ylsulfanyl)-naphthalen-1-yl]-benzenesulfonamide, or a pharma- ceutically acceptable salt thereof. In some embodiments, the compound of formula (I) is N-(1',2-dihydroxy1,2'-binaphthalen-4'-yl)-4-methoxybenzenesulfonamide. In some embodiments, the immune checkpoint inhibitor is administered parenterally. In some embodiments, the immune checkpoint inhibitor is a PD-1 inhibitor or a PD-L1 inhibitor. In some embodiments, the PD-1 inhibitor is an anti-PD-1 antibody.In some embodiments, the anti-PD-1 antibody is cemiplimab, nivolumab, pembrolizumab, pidilizumab, spartalizumab, camrelizumab, sintilimab, tislelizumab, toripalimab, dostallimab, sasunlimab, retifanlimab, tebotelimab, ABBV-181, AK104, AK105, BCD-100, BI-754091, CBT-501, CC-90006, GLS-010, HLX10, IBI-308, JNJ-3283, JS001, LZM009, MEDI0680 (AMP-514), REGN-2810, SHR-1210, Sym021, TSR-042, or XmAb20717. In some embodiments, the anti-PD-1 antibody is pembrolizumab. In some embodiments, the PD-L1 inhibitor is an anti-PD-L1 antibody. In some embodiments, the anti-PD-L1 antibody is atezolizumab, avelumab, durvalumab, embafolimab, FS118, BCD-135, BGB-A333, BGBA-317, CBT-502, CK-301, CS1001, FAZ053, MDX-1105, MSB2311, SHR-1316, M7824, LY3415244, CA-170, or CX-072. In some embodiments, the immune checkpoint inhibitor is administered prior to administration of the compound of Formula (I). In some embodiments, the immune checkpoint inhibitor is administered simultaneously with administration of the compound of Formula (I). In some embodiments, the immune checkpoint inhibitor is administered following administration of the compound of Formula (I).

[0009] In one embodiment, there is provided a method of preventing cancer recurrence in a subject in need thereof, comprising administering to the subject an effective amount of a compound represented by formula (I).

[0010] [ka] or a pharma- ceutically acceptable salt thereof, wherein R is selected from the group consisting of hydrogen, phenylsulfanyl, 2-hydroxy-naphthalen-1-yl, quinolin-8-ylsulfanyl, triazol-3-ylsulfanyl, and benzothiazol-2-ylsulfanyl; and R 1is selected from the group consisting of hydrogen, methyl, chloro, bromo, methoxy, ethoxy, tert-butyl, nitro, methyl ester, acetamide, 1,4 dioxin, fluoro, trifluoromethoxy, acetyl, trifluoromethyl, propyl, cyclohexene, methoxy-phenoxy, chlorophenoxy, tolyloxy, and phenoxy; and b) administering to the subject an effective amount of an immune checkpoint inhibitor. In some embodiments, the compound of formula (I) is N-(1',2-dihydroxy1,2'-binaphthalen-4'-yl)-4-methoxybenzenesulfonamide, N-(3,1'-dihydroxy[1,2']binaphthalenyl-4'-yl)-4-methoxy-benzenesulfonamide, N-(4,1'-dihydroxy[1,2']binaphthalenyl-4'-yl)-4-methoxy-benzenesulfonamide, N-(5,1'-dihydroxy[1,2']binaphthalenyl-4'-yl)-4-methoxy-benzenesulfonamide, N-(6,1'-dihydroxy[1,2']binaphthalenyl-4'-yl)-4- Methoxy-benzenesulfonamide, N-(7,1'-dihydroxy[1,2']binaphthalenyl4'-yl)-4-methoxy-benzenesulfonamide, N-(8,1'-dihydroxy[1,2']binaphthalenyl4'-yl)-4-methoxy-benzenesulfonamide, 4-bromo-N-(1,6'-dihydroxy[2,2']binaphthalenyl4-yl)-benzenesulfonamide, or 4-bromo-N-[4-hydroxy-3-(1H-[1,2,4]triazol-3-ylsulfanyl)-naphthalen-1-yl]-benzenesulfonamide, or a pharma- ceutically acceptable salt thereof. In some embodiments, the compound of formula (I) is N-(1',2-dihydroxy1,2'-binaphthalen-4'-yl)-4-methoxybenzenesulfonamide. In some embodiments, the immune checkpoint inhibitor is administered parenterally. In some embodiments, the immune checkpoint inhibitor is a PD-1 inhibitor or a PD-L1 inhibitor. In some embodiments, the PD-1 inhibitor is an anti-PD-1 antibody.In some embodiments, the anti-PD-1 antibody is cemiplimab, nivolumab, pembrolizumab, pidilizumab, spartalizumab, camrelizumab, sintilimab, tislelizumab, toripalimab, dostallimab, sasunlimab, retifanlimab, tebotelimab, ABBV-181, AK104, AK105, BCD-100, BI-754091, CBT-501, CC-90006, GLS-010, HLX10, IBI-308, JNJ-3283, JS001, LZM009, MEDI0680 (AMP-514), REGN-2810, SHR-1210, Sym021, TSR-042, or XmAb20717. In some embodiments, the anti-PD-1 antibody is pembrolizumab. In some embodiments, the PD-L1 inhibitor is an anti-PD-L1 antibody. In some embodiments, the anti-PD-L1 antibody is atezolizumab, avelumab, durvalumab, embafolimab, FS118, BCD-135, BGB-A333, BGBA-317, CBT-502, CK-301, CS1001, FAZ053, MDX-1105, MSB2311, SHR-1316, M7824, LY3415244, CA-170, or CX-072. In some embodiments, the immune checkpoint inhibitor is administered prior to administration of the compound of Formula (I). In some embodiments, the immune checkpoint inhibitor is administered simultaneously with administration of the compound of Formula (I). In some embodiments, the immune checkpoint inhibitor is administered following administration of the compound of Formula (I).

[0011] In one embodiment, there is provided a method of treating cancer in a subject in need thereof, comprising administering to said subject an effective amount of a compound represented by the formula (II):

[0012] [ka] or a pharmaceutically acceptable salt thereof, wherein the variables are defined herein; and b) administering to the subject an effective amount of an immune checkpoint inhibitor. In some embodiments, the compound of Formula (II) is administered orally. In some embodiments, the immune checkpoint inhibitor is administered parenterally. In some embodiments, the immune checkpoint inhibitor is a PD-1 inhibitor or a PD-L1 inhibitor. In some embodiments, the PD-1 inhibitor is an anti-PD-1 antibody. In some embodiments, the anti-PD-1 antibody is cemiplimab, nivolumab, pembrolizumab, pidilizumab, spartalizumab, camrelizumab, sintilimab, tislelizumab, toripalimab, dostallimab, sasunlimab, retifanlimab, tebotelimab, ABBV-181, AK104, AK105, BCD-100, BI-754091, CBT-501, CC-90006, GLS-010, HLX10, IBI-308, JNJ-3283, JS001, LZM009, MEDI0680 (AMP-514), REGN-2810, SHR-1210, Sym021, TSR-042, or XmAb20717. In some embodiments, the anti-PD-1 antibody is pembrolizumab. In some embodiments, the PD-L1 inhibitor is an anti-PD-L1 antibody. In some embodiments, the anti-PD-L1 antibody is atezolizumab, avelumab, durvalumab, embafolimab, FS118, BCD-135, BGB-A333, BGBA-317, CBT-502, CK-301, CS1001, FAZ053, MDX-1105, MSB2311, SHR-1316, M7824, LY3415244, CA-170, or CX-072. In some embodiments, the immune checkpoint inhibitor is administered prior to administration of the compound of Formula (II). In some embodiments, the immune checkpoint inhibitor is administered simultaneously with administration of the compound of Formula (II). In some embodiments, the immune checkpoint inhibitor is administered following administration of the compound of Formula (II).

[0013] In one embodiment, there is provided a method for reducing the risk of cancer recurrence in a subject in need thereof, comprising administering to said subject an effective amount of a compound represented by the formula (II):

[0014] [ka] Further provided herein is a method comprising administering to the subject a compound of the formula (II) or a pharma- ceutically acceptable salt thereof, wherein the variables are as defined herein, and b) an effective amount of an immune checkpoint inhibitor. In some embodiments, the compound of formula (II) is administered orally. In some embodiments, the immune checkpoint inhibitor is administered parenterally. In some embodiments, the immune checkpoint inhibitor is a PD-1 inhibitor or a PD-L1 inhibitor. In some embodiments, the PD-1 inhibitor is an anti-PD-1 antibody. In some embodiments, the anti-PD-1 antibody is cemiplimab, nivolumab, pembrolizumab, pidilizumab, spartalizumab, camrelizumab, sintilimab, tislelizumab, toripalimab, dostallimab, sasunlimab, retifanlimab, tebotelimab, ABBV-181, AK104, AK105, BCD-100, BI-754091, CBT-501, CC-90006, GLS-010, HLX10, IBI-308, JNJ-3283, JS001, LZM009, MEDI0680 (AMP-514), REGN-2810, SHR-1210, Sym021, TSR-042, or XmAb20717. In some embodiments, the anti-PD-1 antibody is pembrolizumab. In some embodiments, the PD-L1 inhibitor is an anti-PD-L1 antibody. In some embodiments, the anti-PD-L1 antibody is atezolizumab, avelumab, durvalumab, embafolimab, FS118, BCD-135, BGB-A333, BGBA-317, CBT-502, CK-301, CS1001, FAZ053, MDX-1105, MSB2311, SHR-1316, M7824, LY3415244, CA-170, or CX-072. In some embodiments, the immune checkpoint inhibitor is administered prior to administration of the compound of Formula (II). In some embodiments, the immune checkpoint inhibitor is administered simultaneously with administration of the compound of Formula (II). In some embodiments, the immune checkpoint inhibitor is administered following administration of the compound of Formula (II).

[0015] In one embodiment, there is provided a method of preventing cancer recurrence in a subject in need thereof, comprising administering to the subject an effective amount of a compound represented by formula (II):

[0016] [ka] Further provided herein is a method comprising administering to the subject a compound of the formula (II) or a pharma- ceutically acceptable salt thereof, wherein the variables are as defined herein, and b) an effective amount of an immune checkpoint inhibitor. In some embodiments, the compound of formula (II) is administered orally. In some embodiments, the immune checkpoint inhibitor is administered parenterally. In some embodiments, the immune checkpoint inhibitor is a PD-1 inhibitor or a PD-L1 inhibitor. In some embodiments, the PD-1 inhibitor is an anti-PD-1 antibody. In some embodiments, the anti-PD-1 antibody is cemiplimab, nivolumab, pembrolizumab, pidilizumab, spartalizumab, camrelizumab, sintilimab, tislelizumab, toripalimab, dostallimab, sasunlimab, retifanlimab, tebotelimab, ABBV-181, AK104, AK105, BCD-100, BI-754091, CBT-501, CC-90006, GLS-010, HLX10, IBI-308, JNJ-3283, JS001, LZM009, MEDI0680 (AMP-514), REGN-2810, SHR-1210, Sym021, TSR-042, or XmAb20717. In some embodiments, the anti-PD-1 antibody is pembrolizumab. In some embodiments, the PD-L1 inhibitor is an anti-PD-L1 antibody. In some embodiments, the anti-PD-L1 antibody is atezolizumab, avelumab, durvalumab, embafolimab, FS118, BCD-135, BGB-A333, BGBA-317, CBT-502, CK-301, CS1001, FAZ053, MDX-1105, MSB2311, SHR-1316, M7824, LY3415244, CA-170, or CX-072. In some embodiments, the immune checkpoint inhibitor is administered prior to administration of the compound of Formula (II). In some embodiments, the immune checkpoint inhibitor is administered simultaneously with administration of the compound of Formula (II). In some embodiments, the immune checkpoint inhibitor is administered following administration of the compound of Formula (II).

[0017] Other objects and advantages will become apparent to those skilled in the art from consideration of the following detailed description, examples, and claims. [Brief description of the drawings]

[0018] Various features of the present disclosure are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present disclosure will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the disclosure are utilized, and the accompanying drawings. [Figure 1] FIG. 1 shows the in vivo efficacy results of TTI-101±anti-PD-1 in a syngeneic H22 liver cancer model over 21 days of dosing. [Diagram 2] FIG. 2 shows the in vivo efficacy results of TTI-101±anti-PD-1 in a syngeneic H22 liver cancer model over 47 days and 47 days of dosing. [Diagram 3] FIG. 3 shows the results of a tumor rechallenge study using H22 liver cancer cells following treatment with TTI-101 and anti-PD-1 recombinant. [Figure 4] FIG. 4 shows the PK characteristics of TTI-101 upon oral administration in SD rats. [Diagram 5] FIG. 5 shows the percent change in tumor volume when TTI-101 was administered PO vs. IP in a mouse H22 liver cancer model. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0019] As generally described herein, the disclosure provides methods of treating cancer in a subject in need of such treatment or preventing recurrence of cancer in a subject in need of such prevention, comprising administering to the subject an effective amount of a signal transducer and activator of transcription 3 (STAT3) inhibitor and an effective amount of an immune checkpoint inhibitor, such as a PD-1 inhibitor or a PD-L1 inhibitor.

[0020] The combinations provided herein, for example, oral administration of STAT3 inhibitors and parenteral administration of immune checkpoint inhibitors, show significant antitumor efficacy, and in some embodiments, result in complete tumor regression, when compared with monotherapy alone administered at comparable duration and / or dosage.Therefore, the combinations provided herein provide the opportunity to improve overall patient survival, reduce the risk of developing resistance to monotherapy, and suppress, for example, the adverse side effects of long-term administration of monotherapy.In addition, the combinations provided herein, in some embodiments, provide the opportunity to unexpectedly protect against tumor re-attack, thus preventing cancer recurrence or reducing the risk of cancer recurrence.

[0021] In some embodiments, the method described herein comprises orally administering STAT3 inhibitor.Compared with intraperitoneal injection of STAT3 inhibitor, oral administration of STAT3 inhibitor disclosed herein in some embodiments results in significantly greater exposure of STAT3 inhibitor.Therefore, in some embodiments, the method described herein using oral administration of STAT3 inhibitor provides significant advantages over the method using intraperitoneal administration of STAT3 inhibitor.

[0022] definition As used herein, "a" or "an" may mean one or more. As used herein, when used in conjunction with the term "comprising," the term "a" or "an" may mean one or more. As used herein, "another" may mean at least a second or more. Furthermore, the terms "having," "including," "containing," and "comprising" are interchangeable, and one of skill in the art will recognize that these terms are open-ended terms. Some embodiments of the present disclosure may consist of, or consist essentially of, one or more elements, method steps, and / or methods of the present disclosure. It is contemplated that any method, compound, or composition described herein may be implemented with respect to any other method, compound, or composition described herein.

[0023] "About" and "approximately" are intended to mean an acceptable degree of error for the quantity measured, generally given the nature or precision of the measurement. Exemplary degrees of error are within 20 percent (%), typically within 10%, and more typically within 5% of a given value or range of values.

[0024] As used herein, "pharmaceutically acceptable salt" refers to a salt that is suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic reaction, etc., within the scope of sound medical judgment, and commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences (1977) 66:1-19. Pharmaceutically acceptable salts of the compounds of the present disclosure include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of amino groups formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or by using other methods used in the art, such as ion exchange. Other pharma- ceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy- Pharmaceutically acceptable salts derived from appropriate bases include alkali metal salts, alkaline earth metal salts, ammonium salts and N-alkyl salts. Pharmaceutically acceptable salts derived from appropriate bases include alkali metal salts, alkaline earth metal salts, ammonium salts and N-alkyl salts. Pharmaceutically acceptable salts derived from appropriate bases include alkali metal salts, alkaline earth metal salts, ammonium salts and N-alkyl salts. Pharmaceutically acceptable salts derived from appropriate bases include alkali metal salts, alkaline earth metal salts, ammonium salts and N-alkyl salts. Pharmaceutically acceptable salts derived from appropriate bases include alkali metal salts, alkaline earth metal salts, ammonium salts and N-alkyl salts. + (C 1-4Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharma- ceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations formed, where appropriate, using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates.

[0025] As used herein, "pharmaceutical acceptable carrier" refers to a non-toxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound that is formulated with it.The pharmaceutical acceptable carrier, adjuvant, or vehicle that can be used in the compositions described herein includes, but is not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphate, glycine, sorbic acid, potassium sorbate, partial glyceride mixture of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylate, wax, polyethylene-polyoxypropylene block polymer, polyethylene glycol, and wool fat.

[0026] As used herein, a "subject" to which administration is contemplated includes, but is not limited to, a human (i.e., male or female of any age group, e.g., a pediatric subject (e.g., infant, child, adolescent) or an adult subject (e.g., young adult, middle-aged adult, or elderly) and / or a non-human animal, e.g., a mammal such as a primate (e.g., cynomolgus monkey, rhesus monkey), cow, pig, horse, sheep, goat, rodent, cat, and / or dog. In some embodiments, the subject is a human. In some embodiments, the subject is a non-human animal. The terms "human," "patient," "subject," and "individual" are used interchangeably herein. None of these terms require active supervision by a medical professional.

[0027] Disease, disorder, and illness are used interchangeably herein.

[0028] As used herein, unless otherwise specified, the terms "treat," "treating," and "treatment" contemplate actions that occur while a subject is afflicted with a particular disease, disorder, or condition, which reduces the severity of the disease, disorder, or condition, or reverses or slows the progression of the disease, disorder, or condition (similar to "therapeutic treatment").

[0029] In general, an "effective amount" of a compound refers to an amount sufficient to induce a desired biological response. As will be understood by those skilled in the art, an effective amount of a compound of the present disclosure may vary depending on factors such as the desired biological endpoint, the pharmacokinetics of the compound, the disease to be treated, the mode of administration, and the age, weight, health, and condition of the subject. A "therapeutically effective amount" of a compound is an amount sufficient to provide a therapeutic benefit in the treatment of a disease, disorder, or illness (e.g., treating, preventing, and / or ameliorating cancer in a subject, or inhibiting protein-protein interactions mediated by SH2 domains in a subject, at a reasonable benefit / risk ratio applicable to any medical treatment), or to delay or minimize one or more symptoms associated with a disease, disorder, or illness. A therapeutically effective amount of a compound refers to an amount of a therapeutic agent, alone or in combination with other therapies, that provides a therapeutic benefit in the treatment of a disease, disorder, or illness. The term "therapeutically effective amount" can encompass an amount that improves overall treatment, reduces or avoids symptoms or causes of a disease or illness, or enhances the therapeutic effectiveness of another therapeutic agent. A "prophylactically effective amount" of a compound is an amount sufficient to prevent or prevent the recurrence of a disease, disorder or condition, or one or more symptoms associated with a disease, disorder or condition. A prophylactically effective amount of a compound refers to an amount of a therapeutic agent, alone or in combination with other agents, that provides a prophylactic benefit in the prevention of a disease, disorder or condition. The term "prophylactically effective amount" can include an amount that improves overall prophylaxis or enhances the prophylactic effectiveness of another prophylactic agent. "Prophylactic treatment" contemplates actions that occur before a subject begins to suffer from a particular disease, disorder or condition.

[0030] The term "inhibitor," as used herein, for example with respect to a STAT3 inhibitor, refers to one or more molecules that at least partially interfere with the activity of STAT3 to carry out one or more activities, including the ability of STAT3 to bind to a molecule and / or its ability to be phosphorylated.

[0031] The following are definitions of terms used herein. The initial definition provided for a group or term herein applies to that group or term throughout the specification, individually or as part of another group, unless otherwise indicated. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art.

[0032] "Alkyl" refers to straight or branched chain alkane (hydrocarbon) groups containing 1 to 12 carbon atoms, preferably 1 to 6 carbon atoms. Exemplary "alkyl" groups include methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, isobutylpentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl, and the like. "(C1-C4) alkyl" refers to straight or branched chain alkane (hydrocarbon) groups containing 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, and isobutyl. "Substituted alkyl" refers to an alkyl group substituted with one or more substituents, preferably 1 to 4 substituents, at any available point of attachment. Exemplary substituents include, but are not limited to, one or more of the following groups: hydrogen, halogen (e.g., a single halogen substituent or multiple halo substituents forming a group such as an alkyl group with CF, or CCl, in the latter case), cyano, nitro, oxo (i.e., =O), CF, OCF, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl, ORa, SRa, S(=O)Re, S(=O)2Re, P(=O)2Re, S(=O)2ORe, P(=O)2ORe, NRbRc, NRbS(=O)2Re, NRbP(=O)2Re, S(=O)2NRbRc, P(=O)2NRbRc, C(=O)ORd, C(=O)Ra, C(=O)NRbRc, OC(=O)Ra , OC(=O)NRbRc, NRbC(=O)ORe, NRdC(=O)NRbRc, NRdS(=O)2NRbRc, NRdP(=O)2NRbRc, NRbC(=O)Ra, or NRbP(=O)2Re, where each occurrence of Ra is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl, and each occurrence of Rb, Rc, and Rd is independently hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or Rb and Rc together with the N to which they are attached optionally form a heterocycle, or each occurrence of Re is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl).In the foregoing exemplary substituents, groups such as alkyl, cycloalkyl, alkenyl, alkynyl, cycloalkenyl, heterocycle, and aryl can themselves be optionally substituted.

[0033] The term "alkenyl" refers to a straight or branched chain hydrocarbon group containing 2 to 12 carbon atoms and at least one carbon-carbon double bond. Exemplary such groups include ethenyl or aryl. The term "C2-C6 alkenyl" refers to a straight or branched chain hydrocarbon group containing 2 to 6 carbon atoms and at least one carbon-carbon double bond, such as ethylenyl, propenyl, 2-propenyl, (E)-but-2-enyl, (Z)-but-2-enyl, 2-methy(E)-but-2-enyl, 2-methy(Z)-but-2-enyl, 2,3-dimethyl ... "Alkenyl" refers to alkenyl groups substituted with one or more substituents, preferably from one to four substituents, at any available point of attachment.Exemplary substituents include, but are not limited to, one or more of the following groups: hydrogen, halogen (e.g., a single halogen substituent or multiple halo substituents, in the latter case forming a group such as an alkyl group with CF3 or CCl3), cyano, nitro, oxo (i.e., =O), CF3, OCF3, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl, ORa, SRa, S(=O)Re, S(=O)2Re, P(=O)2Re, S(=O)2ORe, P(=O)2ORe, NRbRc, NRbS(=O)2Re, NRbP(=O)2Re, S(=O)2NRbRc, P(=O)2NRbRc, C(=O)ORd, C(=O)Ra, C(=O)NRbRc, OC(=O). Ra, OC(=O)NRbRc, NRbC(=O)ORe, NRdC(=O)NRbRc, NRdS(=O)2NRbRc, NRdP(=O)2NRbRc, NRbC(=O)Ra, or NRbP(=O)2Re, where each occurrence of Ra is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl, each occurrence of Rb, Rc, and Rd is independently hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or Rb and Rc together with the N to which they are attached optionally form a heterocycle, and each occurrence of Re is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl. Exemplary substituents may themselves be substituted.

[0034] The term "alkynyl" refers to a straight or branched chain hydrocarbon group containing 2 to 12 carbon atoms and at least one carbon-carbon triple bond. Exemplary such groups include ethenyl. The term "C2-C6 alkynyl" refers to a straight or branched chain hydrocarbon group containing 2 to 6 carbon atoms and at least one carbon-carbon triple bond, such as ethenyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, pent-1-ynyl, pent-2-ynyl, hex-1-ynyl, hex-2-ynyl, or hex-3-ynyl. "Substituted alkynyl" refers to an alkynyl group substituted with one or more substituents, preferably 1 to 4 substituents, at any available point of attachment. Exemplary substituents include, but are not limited to, one or more of the following groups: hydrogen, halogen (e.g., a single halogen substituent or multiple halo substituents forming a group such as an alkyl group with CF or CCl, in the latter case), cyano, nitro, oxo (i.e., =O), CF, OCF, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl, ORa, SRa, S(=O)Re, S(=O)2Re, P(=O)2Re, S(=O)2ORe, P(=O)2ORe, NRbRc, NRbS(=O)2Re, NRbP(=O)2Re, S(=O)2NRbRc, P(=O)2NRbRc, C(=O)ORd, C(=O)Ra, C(=O)NRbRc, OC(=O). Ra, OC(=O)NRbRc, NRbC(=O)ORe, NRdC(=O)NRbRc, NRdS(=O)2NRbRc, NRdP(=O)2NRbRc, NRbC(=O)Ra, or NRbP(=O)2Re, where each occurrence of Ra is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl, each occurrence of Rb, Rc, and Rd is independently hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or Rb and Rc, together with the N to which they are attached, optionally form a heterocycle, and each occurrence of Re is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl. Exemplary substituents may themselves be substituted.

[0035] The term "cycloalkyl" refers to a fully saturated cyclic hydrocarbon group containing 1 to 4 rings and 3 to 8 carbons per ring. "C3-C7 cycloalkyl" refers to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl. "Substituted cycloalkyl" refers to a cycloalkyl group substituted with one or more substituents, preferably 1 to 4 substituents, at any available point of attachment. Exemplary substituents include, but are not limited to, one or more of the following groups: hydrogen, halogen (e.g., a single halogen substituent or multiple halo substituents, in the latter case forming a group such as an alkyl group with CF3 or CCl3), cyano, nitro, oxo (i.e., =O), CF3, OCF3, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl, ORa, SRa, S(=O)Re, S(=O)2Re, P(=O)2Re, S(=O)2ORe, P(=O)2ORe, NRbRc, NRbS(=O)2Re, NRbP(=O)2Re, S(=O)2NRbRc, P(=O)2NRbRc, C(=O)ORd, C(=O)Ra, C(=O)NRbRc, OC(=O). Ra, OC(=O)NRbRc, NRbC(=O)ORe, NRdC(=O)NRbRc, NRdS(=O)2NRbRc, NRdP(=O)2NRbRc, NRbC(=O)Ra, or NRbP(=O)2Re, where each occurrence of Ra is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl, each occurrence of Rb, Rc, and Rd is independently hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or Rb and Rc together with the N to which they are attached optionally form a heterocycle, and each occurrence of Re is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl. Exemplary substituents may themselves be substituted.Exemplary substituents also include spiro-linked or fused ring substituents, particularly spiro-linked cycloalkyl, spiro-linked cycloalkenyl, spiro-linked heterocycle (excluding heteroaryl), fused cycloalkyl, fused cycloalkenyl, fused heterocycle, or fused aryl, the foregoing cycloalkyl, cycloalkenyl, heterocycle, and aryl substituents may themselves be optionally substituted.

[0036] The term "cycloalkenyl" refers to a partially unsaturated cyclic hydrocarbon group containing 1 to 4 rings and 3 to 8 carbons per ring. Exemplary such groups include cyclobutenyl, cyclopentenyl, cyclohexenyl, and the like, and "substituted cycloalkenyl" refers to a cycloalkenyl group substituted with one or more substituents, preferably 1 to 4 substituents, at any available point of attachment. Exemplary substituents include, but are not limited to, one or more of the following groups: hydrogen, halogen (e.g., a single halogen substituent or multiple halo substituents forming a group such as an alkyl group with CF or CCl, in the latter case), cyano, nitro, oxo (i.e., =O), CF, OCF, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl, ORa, SRa, S(=O)Re, S(=O)2Re, P(=O)2Re, S(=O)2ORe, P(=O)2ORe, NRbRc, NRbS(=O)2Re, NRbP(=O)2Re, S(=O)2NRbRc, P(=O)2NRbRc, C(=O)ORd, C(=O)Ra, C(=O)NRbRc, OC(=O)R a, OC(=O)NRbRc, NRbC(=O)ORe, NRdC(=O)NRbRc, NRdS(=O)2NRbRc, NRdP(=O)2NRbRc, NRbC(=O)Ra, or NRbP(=O)2Re, where each occurrence of Ra is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl, each occurrence of Rb, Rc, and Rd is independently hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or Rb and Rc together with the N to which they are attached optionally form a heterocycle, and each occurrence of Re is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl. Exemplary substituents may themselves be substituted.Exemplary substituents also include spiro-linked or fused ring substituents, particularly spiro-linked cycloalkyl, spiro-linked cycloalkenyl, spiro-linked heterocycle (excluding heteroaryl), fused cycloalkyl, fused cycloalkenyl, fused heterocycle, or fused aryl, the foregoing cycloalkyl, cycloalkenyl, heterocycle, and aryl substituents may themselves be optionally substituted.

[0037] The term "aryl" refers to a cyclic aromatic hydrocarbon group having one to five aromatic rings, particularly a monocyclic or bicyclic group such as phenyl, biphenyl, or naphthyl. When containing more than one aromatic ring (such as a bicyclic ring), the aromatic rings of the aryl group may be attached at a single point (e.g., biphenyl) or fused (e.g., naphthyl, phenanthrenyl, etc.). "Substituted aryl" refers to an aryl group substituted with one or more substituents, preferably one to three substituents, at any available point of attachment. Exemplary substituents include, but are not limited to, one or more of the following groups: hydrogen, halogen (e.g., a single halogen substituent or multiple halo substituents forming a group such as an alkyl group with CF or CCl, in the latter case), cyano, nitro, oxo (i.e., =O), CF, OCF, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl, ORa, SRa, S(=O)Re, S(=O)2Re, P(=O)2Re, S(=O)2ORe, P(=O)2ORe, NRbRc, NRbS(=O)2Re, NRbP(=O)2Re, S(=O)2NRbRc, P(=O)2NRbRc, C(=O)ORd, C(=O)Ra, C(=O)NRbRc, OC(=O)R a, OC(=O)NRbRc, NRbC(=O)ORe, NRdC(=O)NRbRc, NRdS(=O)2NRbRc, NRdP(=O)2NRbRc, NRbC(=O)Ra, or NRbP(=O)2Re, where each occurrence of Ra is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl, each occurrence of Rb, Rc, and Rd is independently hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or Rb and Rc together with the N to which they are attached optionally form a heterocycle, and each occurrence of Re is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl. Exemplary substituents may themselves be substituted.Exemplary substituents also include fused ring groups, particularly fused cycloalkyl, fused cycloalkenyl, fused heterocycle, or fused aryl, wherein the foregoing cycloalkyl, cycloalkenyl, heterocycle, and aryl substituents can themselves be optionally substituted.

[0038] The term "carbocycle" refers to a fully saturated or partially saturated cyclic hydrocarbon group containing 1 to 4 rings and 3 to 8 carbons per ring, or a cyclic aromatic hydrocarbon group having 1 to 5 aromatic rings, particularly a monocyclic or bicyclic group such as phenyl, biphenyl, or naphthyl. The term "carbocycle" includes cycloalkyl, cycloalkenyl, cycloalkynyl, and aryl as defined above. The term "substituted carbocycle" refers to a carbocycle or carbocyclic group substituted at any available point of attachment with one or more substituents, preferably 1 to 4 substituents. Exemplary substituents include, but are not limited to, those listed above for substituted cycloalkyl, substituted cycloalkenyl, substituted cycloalkynyl, and substituted aryl. Exemplary substituents also include spiro-linked or fused ring substituents at any available point of attachment or points, particularly spiro-linked cycloalkyls, spiro-linked cycloalkenyls, spiro-linked heterocycles (excluding heteroaryls), fused cycloalkyls, fused cycloalkenyls, fused heterocycles, or fused aryls, the foregoing cycloalkyl, cycloalkenyl, heterocycle, and aryl substituents may themselves be optionally substituted.

[0039] The terms "heterocycle" and "heterocyclic" refer to fully saturated, or partially or fully unsaturated, including aromatic (i.e., "heteroaryl") ring groups having at least one heteroatom in at least one carbon atom-containing ring (e.g., 4- to 7-membered monocyclic, 7- to 11-membered bicyclic, or 8- to 16-membered tricyclic ring systems). Each ring of a heteroatom-containing heterocyclic group may have 1, 2, 3, or 4 heteroatoms selected from nitrogen, oxygen, and / or sulfur atoms, the nitrogen and sulfur heteroatoms may be optionally oxidized, and the nitrogen heteroatom may be optionally quaternized. (The term "heteroaryl" refers to a heteroaryl group having a quaternary nitrogen atom and thus a positive charge.) The heterocyclic group may be attached to the remainder of the molecule at any heteroatom or carbon atom of the ring or ring system. Exemplary monocyclic heterocyclic groups include azetidinyl, pyrrolidinyl, pyrrolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, furyl, tetrahydrofuryl, thienyl, oxadiazolyl, piperidinyl, piperazinyl, and 2-oxopiperazinyl. , 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, hexahydrodiazepinyl, 4-piperidonyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, triazolyl, tetraazolyl, tetrahydropyranyl, morpholinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, 1,3-dioxolane, and tetrahydro-1,1-dioxothienyl.Exemplary bicyclic heterocyclic groups include indolyl, isoindolyl, benzothiazolyl, benzoxazolyl, benzoxadiazolyl, benzothienyl, benzo[d][1,3]dioxolyl, 2,3-dihydrobenzo[b][1,4]dioxinyl, quinuclidinyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuryl, and benzofurazanyl. , chromonyl, coumarinyl, benzopyranyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl, furopyridinyl (such as furo[2,3-c]pyridinyl, furo[3,2-b]pyridinyl, or furo[2,3-b]pyridinyl), dihydroisoindolyl, dihydroquinazolinyl (such as 3,4-dihydro-4-oxo-quinazolinyl), triazinylazepinyl, tetrahydroquinolinyl, etc. Exemplary tricyclic heterocyclic groups include carbazolyl, benzidolyl, phenanthrolinyl, acridinyl, phenanthridinyl, xanthenyl, etc.

[0040] "Substituted heterocycle" and "substituted heterocycle" (as in "substituted heteroaryl") refer to a heterocycle or heterocycle group substituted with one or more substituents, preferably 1 to 4 substituents, at any available point of attachment. Exemplary substituents include, but are not limited to, one or more of the following groups: hydrogen, halogen (e.g., a single halogen substituent or multiple halo substituents, in the latter case forming a group such as an alkyl group with CF3 or CCl3), cyano, nitro, oxo (i.e., =O), CF3, OCF3, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl, ORa, SRa, S(=O)Re, S(=O)2Re, P(=O)2Re, S(=O)2ORe, P(=O)2ORe, NRbRc, NRbS(=O)2Re, NRbP(=O)2Re, S(=O)2NRbRc, P(=O)2NRbRc, C(=O)ORd, C(=O)Ra, C(=O)NRbRc, OC(=O). Ra, OC(=O)NRbRc, NRbC(=O)ORe, NRdC(=O)NRbRc, NRdS(=O)2NRbRc, NRdP(=O)2NRbRc, NRbC(=O)Ra, or NRbP(=O)2Re, where each occurrence of Ra is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl, each occurrence of Rb, Rc, and Rd is independently hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or Rb and Rc together with the N to which they are attached optionally form a heterocycle, and each occurrence of Re is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl. Exemplary substituents may themselves be substituted. Exemplary substituents also include spiro-linked or fused ring substituents at any available point of attachment or points, particularly spiro-linked cycloalkyls, spiro-linked cycloalkenyls, spiro-linked heterocycles (excluding heteroaryls), fused cycloalkyls, fused cycloalkenyls, fused heterocycles, or fused aryls, the foregoing cycloalkyl, cycloalkenyl, heterocycle, and aryl substituents may themselves be optionally substituted.

[0041] The term "alkylamino" refers to a group having the structure -NHR', where R' is hydrogen, alkyl or substituted alkyl, or cycloalkyl or substituted cycloalkyl as defined herein. Examples of alkylamino groups include, but are not limited to, methylamino, ethylamino, n-propylamino, iso-propylamino, cyclopropylamino, n-butylamino, tert-butylamino, neopentylamino, n-pentylamino, hexylamino, cyclohexylamino, and the like.

[0042] The term "dialkylamino" refers to a group having the structure -NRR', where R and R' are each independently alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, or heterosilyl or substituted heterocyclyl, as defined herein. R and R' may be the same or different dialkylamino moieties. Examples of dialkylamino groups include, but are not limited to, dimethylamino, methylethylamino, diethylamino, methylpropylamino, di(n-propyl)amino, di(iso-propyl)amino, di(cyclopropyl)amino, di(n-butyl)amino, di(tert-butyl)amino, di(neopentyl)amino, di(n-pentyl)amino, di(hexyl)amino, di(cyclohexyl)amino, and the like. In some embodiments, R and R' are linked to form a cyclic structure. The resulting cyclic structure may be aromatic or non-aromatic. Examples of cyclic diaminoalkyl groups include, but are not limited to, aziridinyl, pyrrolidinyl, piperidinyl, morpholinyl, pyrrolyl, imidazolyl, 1,3,4-trianolyl, and tetrazolyl.

[0043] The term "halogen" or "halo" refers to chlorine, bromine, fluorine, or iodine.

[0044] Unless otherwise specified, heteroatoms with unsatisfied valences are assumed to have sufficient hydrogen atoms to satisfy the valences.

[0045] The compounds of the present disclosure, and salts or solvates thereof, may exist in their tautomeric forms (for example, as an amide or imino ether). All such tautomeric forms are contemplated herein as part of the disclosure.

[0046] All stereoisomers of the compounds, including enantiomeric and diastereomeric forms (e.g., those that may exist due to asymmetric carbons on various substituents), are contemplated within the scope of the present disclosure. Individual stereoisomers of the compounds of the present disclosure may, for example, be substantially free of other isomers (e.g., as pure or substantially pure optical isomers with a particular activity), or may, for example, be mixed as racemates or with all other or other selected stereoisomers. The chiral centers of the present disclosure may have the S or R configuration as defined by the International Union of Pure and Applied Chemistry (IUPAC) 1974 Recommendations. Racemic forms can be resolved by physical methods, such as fractional crystallization, separation or crystallization of diastereomeric derivatives, or separation by chiral column chromatography. Individual optical isomers can be obtained from the racemates by any suitable method, including, but not limited to, conventional methods such as, for example, salt formation with an optically active acid followed by crystallization.

[0047] The compounds of the present disclosure are preferably isolated and purified after their preparation to obtain compositions containing 90% by weight or more, for example 95% by weight or more, 99% by weight or more of the compound ("substantially pure" compound), which are then used or formulated as described herein. Such "substantially pure" compounds of the present disclosure are also contemplated herein as part of the present disclosure.

[0048] All configurational isomers of the compounds of the present disclosure are contemplated, either in admixture or in pure or substantially pure form. The definition of the compounds of the present disclosure includes both cis (Z) and trans (E) alkene isomers, as well as cis and trans isomers of cyclic hydrocarbons or heterocycles.

[0049] Definitions of certain functional groups and chemical terms are described in more detail below. For purposes of this disclosure, chemical elements are identified according to the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Ed., inside cover, and certain functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as certain functional moieties and reactivities, are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito (1999), the entire contents of which are incorporated herein by reference.

[0050] Certain compounds of the present disclosure may exist in specific geometric or stereoisomeric forms. The present disclosure contemplates all such compounds as falling within the scope of the present disclosure, including cis- and trans-isomers, R- and S-enantiomers, diastereomers, (d)-isomers, (l)-isomers, racemic mixtures thereof, and other mixtures thereof. Additional asymmetric carbon atoms may be present in a substituent, such as an alkyl group. All such isomers, as well as mixtures thereof, are intended to be included in the present disclosure.

[0051] Isomeric mixtures containing any of a variety of isomeric ratios can be utilized according to the present disclosure.For example, when only two isomers are combined, mixtures containing 50:50, 60:40, 70:30, 80:20, 90:10, 95:5, 96:4, 97:3, 98:2, 99:1, or 100:0 isomeric ratios are all contemplated by the present disclosure.Those skilled in the art will easily understand that similar ratios are contemplated for more complex isomeric mixtures.

[0052] The present disclosure also includes isotopically labeled compounds that are identical to the compounds disclosed herein, except for the fact that one or more atoms are replaced by an atom with a different atomic mass or mass number than the atomic mass or mass number that is usually found in nature. Examples of isotopes that can be incorporated into the compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as 2H, 3H, 13C, 11C, 14C, 15N, 18O, 17O, 31P, 32P, 35S, 18F, and 36Cl, respectively. Compounds of the present disclosure that contain the aforementioned isotopes and / or other isotopes of other atoms, or their enantiomers, diastereomers, tautomers, or pharma-ceutically acceptable salts or solvates, are within the scope of the present disclosure. Certain isotopically labeled compounds of the present disclosure, such as those that incorporate radioactive isotopes such as 3H and 14C, are useful in drug and / or substrate tissue distribution assays. Tritiated, i.e., 3H, and carbon-14, i.e., 14C, isotopes are particularly preferred due to their ease of preparation and detectability. In addition, substitution with heavier isotopes such as deuterium, i.e., 2H, can provide certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced required dosage, and therefore may be preferred in some circumstances. Isotopically labeled compounds can generally be prepared by carrying out the procedures disclosed in the schemes and / or examples below, by using readily available isotopically labeled reagents in place of non-isotopically labeled reagents.

[0053] For example, if a particular enantiomer of a compound of the present disclosure is desired, it may be prepared by asymmetric synthesis or by derivatization with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to yield the pure desired enantiomer. Alternatively, if the molecule contains a basic functional group, such as amino, or an acidic functional group, such as carboxyl, a diastereomeric salt can be formed with a suitable optically active acid or base, followed by separation of the diastereomers thus formed by fractional crystallization or chromatographic means well known in the art, followed by recovery of the pure enantiomer.

[0054] It will be understood that the compounds described herein may be substituted with any number of substituents or functional moieties. In general, the term "substituted" (whether preceded by the term "optionally" or not) and the substituents contained in the formulas of the present disclosure refer to the replacement of hydrogen radicals in a given structure with the radical of a specified substituent. When multiple positions in any given structure may be substituted with multiple substituents selected from a specified group, the substituents may be the same or different at all positions. As used herein, the term "substituted" is intended to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. For purposes of this disclosure, heteroatoms such as nitrogen may have hydrogen substituents and / or any permissible substituent of organic compounds described herein that satisfies the valence of the heteroatom. Furthermore, this disclosure is not intended to be limited in any way by the permissible substituents of organic compounds. Combinations of substituents and variables envisioned by this disclosure are preferably those that result in the formation of stable compounds useful, for example, in the treatment of infectious diseases or proliferative disorders. As used herein, the term "stable" preferably refers to compounds that have sufficient stability to permit manufacture and maintain the integrity of the compound for a period of time sufficient to be detectable, preferably to be useful for the purposes detailed herein.

[0055] Treatment In one embodiment, there is provided a method of treating cancer in a subject in need thereof, comprising: a) administering to said subject an effective amount of a compound represented by formula (I)

[0056] [ka] or a pharma- ceutically acceptable salt thereof, wherein R is selected from the group consisting of hydrogen, phenylsulfanyl, 2-hydroxy-naphthalen-1-yl, quinolin-8-ylsulfanyl, triazol-3-ylsulfanyl, and benzothiazol-2-ylsulfanyl; and R 1 is selected from the group consisting of hydrogen, methyl, chloro, bromo, methoxy, ethoxy, tert-butyl, nitro, methyl ester, acetamide, 1,4 dioxin, fluoro, trifluoromethoxy, acetyl, trifluoromethyl, propyl, cyclohexene, methoxy-phenoxy, chlorophenoxy, tolyloxy, and phenoxy; and b) administering to the subject an effective amount of an immune checkpoint inhibitor.

[0057] In some embodiments, the compound of formula (I) is N-(1',2-dihydroxy1,2'-binaphthalen-4'-yl)-4-methoxybenzenesulfonamide, N-(3,1'-dihydroxy[1,2']binaphthalenyl-4'-yl)-4-methoxy-benzenesulfonamide, N-(4,1'-dihydroxy[1,2']binaphthalenyl-4'-yl)-4-methoxy-benzenesulfonamide, N-(5,1'-dihydroxy[1,2']binaphthalenyl-4'-yl)-4-methoxy-benzenesulfonamide, N-(6,1'-dihydroxy[1,2']binaphthalenyl-4'-yl)-4- methoxy-benzenesulfonamide, N-(7,1'-dihydroxy[1,2']binaphthalenyl-4'-yl)-4-methoxy-benzenesulfonamide, N-(8,1'-dihydroxy[1,2']binaphthalenyl-4'-yl)-4-methoxy-benzenesulfonamide, 4-bromo-N-(1,6'-dihydroxy[2,2']binaphthalenyl-4-yl)-benzenesulfonamide, or 4-bromo-N-[4-hydroxy-3-(1H-[1,2,4]triazol-3-ylsulfanyl)-naphthalen-1-yl]-benzenesulfonamide, or a pharma- ceutically acceptable salt thereof.

[0058] In some embodiments, the compound of formula (I) is N-(1',2-dihydroxy-1,2'-binaphthalen-4'-yl)-4-methoxybenzenesulfonamide.

[0059] In one embodiment, the immune checkpoint inhibitor is administered parenterally.

[0060] In one embodiment, the immune checkpoint inhibitor is a PD-1 inhibitor or a PD-L1 inhibitor.

[0061] In some embodiments, the PD-1 inhibitor is an anti-PD-1 antibody. In some embodiments, the anti-PD-1 antibody is cemiplimab, nivolumab, pembrolizumab, pidilizumab, spartalizumab, camrelizumab, sintilimab, tislelizumab, toripalimab, dostallimab, sasunlimab, retifanlimab, tebotelimab, ABBV-181, AK104, AK105, BCD-100, BI-754091, CBT-501, CC-90006, GLS-010, HLX10, IBI-308, JNJ-3283, JS001, LZM009, MEDI0680 (AMP-514), REGN-2810, SHR-1210, Sym021, TSR-042, or XmAb20717. In some embodiments, the anti-PD-1 antibody is pembrolizumab.

[0062] In some embodiments, the PD-L1 inhibitor is an anti-PD-L1 antibody. In some embodiments, the anti-PD-L1 antibody is atezolizumab, avelumab, durvalumab, embafolimab, FS118, BCD-135, BGB-A333, BGBA-317, CBT-502, CK-301, CS1001, FAZ053, MDX-1105, MSB2311, SHR-1316, M7824, LY3415244, CA-170, or CX-072.

[0063] In some embodiments, the immune checkpoint inhibitor is administered prior to administration of the compound of Formula (I). In some embodiments, the immune checkpoint inhibitor is administered simultaneously with administration of the compound of Formula (I). In some embodiments, the immune checkpoint inhibitor is administered after administration of the compound of Formula (I). In some embodiments, the subject exhibits at least a partial response 3 weeks or more after administration of the compound of Formula (I) and the immune checkpoint inhibitor. In some embodiments, the subject exhibits a complete response 3 weeks or more after administration of the compound of Formula (I) and the immune checkpoint inhibitor. In some embodiments, the methods described herein reduce tumor size by at least 20% more within 6 weeks of administration compared to subjects administered an immune checkpoint inhibitor alone.

[0064] In one embodiment, there is provided a method for reducing the risk of cancer recurrence in a subject in need thereof, comprising administering to said subject an effective amount of a compound represented by the formula (I):

[0065] [ka] or a pharma- ceutically acceptable salt thereof, wherein R is selected from the group consisting of hydrogen, phenylsulfanyl, 2-hydroxy-naphthalen-1-yl, quinolin-8-ylsulfanyl, triazol-3-ylsulfanyl, and benzothiazol-2-ylsulfanyl; and R 1 is selected from the group consisting of hydrogen, methyl, chloro, bromo, methoxy, ethoxy, tert-butyl, nitro, methyl ester, acetamide, 1,4 dioxin, fluoro, trifluoromethoxy, acetyl, trifluoromethyl, propyl, cyclohexene, methoxy-phenoxy, chlorophenoxy, tolyloxy, and phenoxy; and b) administering to the subject an effective amount of an immune checkpoint inhibitor.

[0066] In some embodiments, the compound of formula (I) is N-(1',2-dihydroxy1,2'-binaphthalen-4'-yl)-4-methoxybenzenesulfonamide, N-(3,1'-dihydroxy[1,2']binaphthalenyl-4'-yl)-4-methoxy-benzenesulfonamide, N-(4,1'-dihydroxy[1,2']binaphthalenyl-4'-yl)-4-methoxy-benzenesulfonamide, N-(5,1'-dihydroxy[1,2']binaphthalenyl-4'-yl)-4-methoxy-benzenesulfonamide, N-(6,1'-dihydroxy[1,2']binaphthalenyl-4'-yl)-4- methoxy-benzenesulfonamide, N-(7,1'-dihydroxy[1,2']binaphthalenyl-4'-yl)-4-methoxy-benzenesulfonamide, N-(8,1'-dihydroxy[1,2']binaphthalenyl-4'-yl)-4-methoxy-benzenesulfonamide, 4-bromo-N-(1,6'-dihydroxy[2,2']binaphthalenyl-4-yl)-benzenesulfonamide, or 4-bromo-N-[4-hydroxy-3-(1H-[1,2,4]triazol-3-ylsulfanyl)-naphthalen-1-yl]-benzenesulfonamide, or a pharma- ceutically acceptable salt thereof.

[0067] In some embodiments, the compound of formula (I) is N-(1',2-dihydroxy-1,2'-binaphthalen-4'-yl)-4-methoxybenzenesulfonamide.

[0068] In one embodiment, the immune checkpoint inhibitor is administered parenterally.

[0069] In one embodiment, the immune checkpoint inhibitor is a PD-1 inhibitor or a PD-L1 inhibitor.

[0070] In one embodiment, the PD-1 inhibitor is an anti-PD-1 antibody. In some embodiments, the anti-PD-1 antibody is cemiplimab, nivolumab, pembrolizumab, pidilizumab, spartalizumab, camrelizumab, sintilimab, tislelizumab, toripalimab, dostallimab, sasunlimab, retifanlimab, tebotelimab, ABBV-181, AK104, AK105, BCD-100, BI-754091, CBT-501, CC-90006, GLS-010, HLX10, IBI-308, JNJ-3283, JS001, LZM009, MEDI0680 (AMP-514), REGN-2810, SHR-1210, Sym021, TSR-042, or XmAb20717. In some embodiments, the anti-PD-1 antibody is pembrolizumab.

[0071] In some embodiments, the PD-L1 inhibitor is an anti-PD-L1 antibody. In some embodiments, the anti-PD-L1 antibody is atezolizumab, avelumab, durvalumab, embafolimab, FS118, BCD-135, BGB-A333, BGBA-317, CBT-502, CK-301, CS1001, FAZ053, MDX-1105, MSB2311, SHR-1316, M7824, LY3415244, CA-170, or CX-072.

[0072] In some embodiments, the immune checkpoint inhibitor is administered prior to administration of the compound of Formula (I). In some embodiments, the immune checkpoint inhibitor is administered simultaneously with administration of the compound of Formula (I). In some embodiments, the immune checkpoint inhibitor is administered after administration of the compound of Formula (I).

[0073] In one embodiment, there is provided a method of preventing cancer recurrence in a subject in need thereof, comprising administering to the subject an effective amount of a compound represented by formula (I).

[0074] [ka] or a pharma- ceutically acceptable salt thereof, wherein R is selected from the group consisting of hydrogen, phenylsulfanyl, 2-hydroxy-naphthalen-1-yl, quinolin-8-ylsulfanyl, triazol-3-ylsulfanyl, and benzothiazol-2-ylsulfanyl; and R 1 is selected from the group consisting of hydrogen, methyl, chloro, bromo, methoxy, ethoxy, tert-butyl, nitro, methyl ester, acetamide, 1,4 dioxin, fluoro, trifluoromethoxy, acetyl, trifluoromethyl, propyl, cyclohexene, methoxy-phenoxy, chlorophenoxy, tolyloxy, and phenoxy; and b) administering to the subject an effective amount of an immune checkpoint inhibitor.

[0075] In some embodiments, the compound of formula (I) is N-(1',2-dihydroxy1,2'-binaphthalen-4'-yl)-4-methoxybenzenesulfonamide, N-(3,1'-dihydroxy[1,2']binaphthalenyl-4'-yl)-4-methoxy-benzenesulfonamide, N-(4,1'-dihydroxy[1,2']binaphthalenyl-4'-yl)-4-methoxy-benzenesulfonamide, N-(5,1'-dihydroxy[1,2']binaphthalenyl-4'-yl)-4-methoxy-benzenesulfonamide, N-(6,1'-dihydroxy[1,2']binaphthalenyl-4'-yl)-4- methoxy-benzenesulfonamide, N-(7,1'-dihydroxy[1,2']binaphthalenyl-4'-yl)-4-methoxy-benzenesulfonamide, N-(8,1'-dihydroxy[1,2']binaphthalenyl-4'-yl)-4-methoxy-benzenesulfonamide, 4-bromo-N-(1,6'-dihydroxy[2,2']binaphthalenyl-4-yl)-benzenesulfonamide, or 4-bromo-N-[4-hydroxy-3-(1H-[1,2,4]triazol-3-ylsulfanyl)-naphthalen-1-yl]-benzenesulfonamide, or a pharma- ceutically acceptable salt thereof.

[0076] In some embodiments, the compound of formula (I) is N-(1',2-dihydroxy-1,2'-binaphthalen-4'-yl)-4-methoxybenzenesulfonamide.

[0077] In one embodiment, the immune checkpoint inhibitor is administered parenterally.

[0078] In one embodiment, the immune checkpoint inhibitor is a PD-1 inhibitor or a PD-L1 inhibitor.

[0079] In one embodiment, there is provided a method of treating cancer in a subject in need thereof, comprising administering to said subject an effective amount of a compound represented by the formula (II):

[0080] [ka] or a pharma- ceutically acceptable salt thereof, wherein the variables are defined herein; and b) administering to the subject an effective amount of an immune checkpoint inhibitor.

[0081] In one embodiment, the compound of formula (II) or a pharma- ceutically acceptable salt thereof is administered orally.

[0082] In one embodiment, the immune checkpoint inhibitor is administered parenterally.

[0083] In one embodiment, the immune checkpoint inhibitor is a PD-1 inhibitor or a PD-L1 inhibitor.

[0084] In one embodiment, the PD-1 inhibitor is an anti-PD-1 antibody. In some embodiments, the anti-PD-1 antibody is cemiplimab, nivolumab, pembrolizumab, pidilizumab, spartalizumab, camrelizumab, sintilimab, tislelizumab, toripalimab, dostallimab, sasunlimab, retifanlimab, tebotelimab, ABBV-181, AK104, AK105, BCD-100, BI-754091, CBT-501, CC-90006, GLS-010, HLX10, IBI-308, JNJ-3283, JS001, LZM009, MEDI0680 (AMP-514), REGN-2810, SHR-1210, Sym021, TSR-042, or XmAb20717. In some embodiments, the anti-PD-1 antibody is pembrolizumab.

[0085] In some embodiments, the PD-L1 inhibitor is an anti-PD-L1 antibody. In some embodiments, the anti-PD-L1 antibody is atezolizumab, avelumab, durvalumab, embafolimab, FS118, BCD-135, BGB-A333, BGBA-317, CBT-502, CK-301, CS1001, FAZ053, MDX-1105, MSB2311, SHR-1316, M7824, LY3415244, CA-170, or CX-072.

[0086] In some embodiments, the immune checkpoint inhibitor is administered prior to administration of the compound of Formula (II). In some embodiments, the immune checkpoint inhibitor is administered simultaneously with administration of the compound of Formula (II). In some embodiments, the immune checkpoint inhibitor is administered after administration of the compound of Formula (II).

[0087] In one embodiment, there is provided a method for reducing the risk of cancer recurrence in a subject in need thereof, comprising administering to said subject an effective amount of a compound represented by the formula (II):

[0088] [ka] or a pharma- ceutically acceptable salt thereof, wherein the variables are defined herein; and b) administering to the subject an effective amount of an immune checkpoint inhibitor.

[0089] In one embodiment, the compound of formula (II) or a pharma- ceutically acceptable salt thereof is administered orally.

[0090] In one embodiment, the immune checkpoint inhibitor is administered parenterally.

[0091] In one embodiment, the immune checkpoint inhibitor is a PD-1 inhibitor or a PD-L1 inhibitor.

[0092] In one embodiment, the PD-1 inhibitor is an anti-PD-1 antibody. In some embodiments, the anti-PD-1 antibody is cemiplimab, nivolumab, pembrolizumab, pidilizumab, spartalizumab, camrelizumab, sintilimab, tislelizumab, toripalimab, dostallimab, sasunlimab, retifanlimab, tebotelimab, ABBV-181, AK104, AK105, BCD-100, BI-754091, CBT-501, CC-90006, GLS-010, HLX10, IBI-308, JNJ-3283, JS001, LZM009, MEDI0680 (AMP-514), REGN-2810, SHR-1210, Sym021, TSR-042, or XmAb20717. In some embodiments, the anti-PD-1 antibody is pembrolizumab.

[0093] In some embodiments, the PD-L1 inhibitor is an anti-PD-L1 antibody. In some embodiments, the anti-PD-L1 antibody is atezolizumab, avelumab, durvalumab, embafolimab, FS118, BCD-135, BGB-A333, BGBA-317, CBT-502, CK-301, CS1001, FAZ053, MDX-1105, MSB2311, SHR-1316, M7824, LY3415244, CA-170, or CX-072.

[0094] In some embodiments, the immune checkpoint inhibitor is administered prior to administration of the compound of Formula (II). In some embodiments, the immune checkpoint inhibitor is administered simultaneously with administration of the compound of Formula (II). In some embodiments, the immune checkpoint inhibitor is administered after administration of the compound of Formula (II).

[0095] In one embodiment, there is provided a method of preventing cancer recurrence in a subject in need thereof, comprising administering to the subject an effective amount of a compound represented by formula (II):

[0096] [ka] or a pharma- ceutically acceptable salt thereof, wherein the variables are defined herein; and b) administering to the subject an effective amount of an immune checkpoint inhibitor.

[0097] In one embodiment, the compound of formula (II) or a pharma- ceutically acceptable salt thereof is administered orally.

[0098] In one embodiment, the immune checkpoint inhibitor is administered parenterally.

[0099] In one embodiment, the immune checkpoint inhibitor is a PD-1 inhibitor or a PD-L1 inhibitor.

[0100] In one embodiment, the PD-1 inhibitor is an anti-PD-1 antibody. In some embodiments, the anti-PD-1 antibody is cemiplimab, nivolumab, pembrolizumab, pidilizumab, spartalizumab, camrelizumab, sintilimab, tislelizumab, toripalimab, dostallimab, sasunlimab, retifanlimab, tebotelimab, ABBV-181, AK104, AK105, BCD-100, BI-754091, CBT-501, CC-90006, GLS-010, HLX10, IBI-308, JNJ-3283, JS001, LZM009, MEDI0680 (AMP-514), REGN-2810, SHR-1210, Sym021, TSR-042, or XmAb20717. In some embodiments, the anti-PD-1 antibody is pembrolizumab.

[0101] In some embodiments, the PD-L1 inhibitor is an anti-PD-L1 antibody. In some embodiments, the anti-PD-L1 antibody is atezolizumab, avelumab, durvalumab, embafolimab, FS118, BCD-135, BGB-A333, BGBA-317, CBT-502, CK-301, CS1001, FAZ053, MDX-1105, MSB2311, SHR-1316, M7824, LY3415244, CA-170, or CX-072.

[0102] In some embodiments, the immune checkpoint inhibitor is administered prior to administration of the compound of Formula (II). In some embodiments, the immune checkpoint inhibitor is administered simultaneously with administration of the compound of Formula (II). In some embodiments, the immune checkpoint inhibitor is administered after administration of the compound of Formula (II).

[0103] STAT proteins, of which there are seven (1, 2, 3, 4, 5A, 5B and 6), transmit peptide hormone signals from the cell surface to the nucleus. As used herein, a STAT inhibitor is a compound that targets a STAT protein.

[0104] In some embodiments, a STAT3 inhibitor, as used herein, refers to one or more molecules that at least partially interfere with the activity of STAT3 to perform one or more activities, including the ability of STAT3 to bind to a molecule and / or to be phosphorylated. In some embodiments, a STAT3 inhibitor interacts with the Stat3 SH2 domain, e.g., competitively inhibits the binding of recombinant Stat3 to its immobilized pY-peptide ligand, and / or inhibits IL-6-mediated tyrosine phosphorylation of Stat3. In some embodiments, a STAT3 inhibitor meets the following criteria of interaction analysis (CIA): 1) a global minimum energy score of ≦−30, 2) formation of a salt bridge and / or H-bond network within the pY residue binding site of Stat3, and / or 3) formation of an H-bond with or blocking access to the amide hydrogen of, e.g., E638 of Stat3. In some embodiments, a STAT3 inhibitor interacts with a hydrophobic binding pocket with the STAT3 SH2 domain. In some embodiments, a STAT3 inhibitor inhibits the binding of STAT3 to its cognate phosphopeptide ligand. In some embodiments, the STAT3 inhibitor inhibits cytokine-mediated STAT3 phosphorylation in cells. In some embodiments, the STAT3 inhibitor inhibits nuclear translocation of STAT3 in cells.

[0105] In some embodiments, the STAT inhibitor described herein is a STAT1 inhibitor. Studies in Stat1-deficient mice (Meraz et al., 1996; Durbin et al., 1996; Ryan et al., 1998) support the essential role of Stat1 in innate immunity, especially against viral pathogens. In addition, Stat1 is a strong inhibitor of proliferation and promoter of apoptosis (Bromberg and Darnell, 2000). Stat1 also contributes to tumor surveillance, since tumors from carcinogen-treated wild-type animals grow more rapidly when transplanted into Stat1-deficient animals than wild-type hosts (Kaplan et al., 1998).

[0106] In some embodiments, the STAT inhibitor described herein is a STAT5 inhibitor. A STAT5 inhibitor refers to one or more molecules that at least partially interfere with the activity of STAT5 to perform one or more activities, including the ability of STAT5 to bind to a molecule and / or to be phosphorylated.

[0107] In some embodiments, the STAT inhibitor (e.g., STAT3 inhibitor) is a compound represented by formula (I):

[0108] [ka] is a compound of During the ceremony, R is selected from the group consisting of hydrogen, phenylsulfanyl, hydroxynaphthalenyl, quinolinylsulfanyl, triazolylsulfanyl, and benzothiazolylsulfanyl; R 1 is selected from the group consisting of hydrogen, methyl, chloro, bromo, methoxy, ethoxy, tert-butyl, nitro, methyl ester, acetamide, 1,4-dioxine, fluoro, trifluoromethoxy, acetyl, trifluoromethyl, propyl, cyclohexene, methoxyphenoxy, chlorophenoxy, tolyloxy, and phenoxy.

[0109] In some embodiments, the STAT inhibitor is N-(1',2-dihydroxy-1,2'-binaphthalen-4'-yl)-4-methoxybenzenesulfonamide, N-(3,1'-dihydroxy-[1,2']binaphthalenyl-4'-yl)-4-methoxy-benzenesulfonamide, N-(4,1'-dihydroxy-[1,2']binaphthalenyl-4'-yl)-4-methoxy-benzenesulfonamide, N-(5,1'-dihydroxy-[1,2']binaphthalenyl-4'-yl)-4-methoxy-benzenesulfonamide, N-(6,1'-dihydroxy-[1,2']binaphthalenyl-4'-yl)-4- Methoxy-benzenesulfonamide, N-(7,1'-dihydroxy-[1,2']binaphthalenyl-4'-yl)-4-methoxy-benzenesulfonamide, N-(8,1'-dihydroxy-[1,2']binaphthalenyl-4'-yl)-4-methoxy-benzenesulfonamide, 4-bromo-N-(1,6'-dihydroxy-[2,2']binaphthalenyl-4-yl)-benzenesulfonamide, or 4-bromo-N-[4-hydroxy-3-(1H-[1,2,4]triazol-3-ylsulfanyl)-naphthalen-1-yl]-benzenesulfonamide, or a pharma-ceutically acceptable salt thereof. In some embodiments, the STAT inhibitor is N-(1',2-dihydroxy-1,2'-binaphthalen-4'-yl)-4-methoxybenzenesulfonamide (also referred to herein as TTI-101).

[0110] In some embodiments, the STAT inhibitor is of formula (II):

[0111] [ka] is a compound of During the ceremony, Each occurrence of R1 is independently hydrogen, halogen, cyano, nitro, CF3, OCF3, ORa, SRa, C(=O)Ra, OC(=O)Ra, C(=O)OR a, NRbRc, NRbC(=O)Rc, C(=O)NRbRc, NRbC(=O)ORc, OC(=O)NRbRc, NRaC(=O)NRbRc, alkyl, alkenyl, cycloalkyl, optionally substituted aryl, or optionally substituted heterocycle; n1 is 0, 1, 2, 3, or 4; each occurrence of R2 is independently hydrogen, halogen, cyano, nitro, CF3, OCF3, ORa, SRa, C(=O)Ra, OC(=O)Ra, C(=O)ORa, NRbRc, NRbC(=O)Rc, C(=O)NRbRc, NRbC(=O)ORc, OC(=O)NRbRc, NRaC(=O)NRbRc, alkyl, alkenyl, cycloalkyl, cycloalkenyl, optionally substituted aryl, optionally substituted aryloxyl, or optionally substituted heterocycle; n2 is 0, 1, 2, 3, 4, or 5 R3 is hydrogen, halogen, cyano, nitro, CF3, OCF3, ORa, SRa, OC(=O)Ra, alkyl, alkenyl, cycloalkyl, or optionally substituted aryl or heteroaryl; R4 is hydrogen, halogen, cyano, nitro, CF3, OCF3, ORa, SRa, NRbRc, OC(=O)Ra, alkyl, alkenyl, or cycloalkyl; each occurrence of R5, R6, and R7 is independently hydrogen, halogen, cyano, nitro, CF3, OCF3, ORa, SRa, C(=O)Ra, OC(=O)Ra, C(=O)ORa, NRbRc, NRbC(=O)Rc, C(=O)NRbRc, NRbC(=O)ORc, OC(=O)NRbRc, NRaC(=O)NRbRc, alkyl, alkenyl, cycloalkyl, optionally substituted aryl, or optionally substituted heterocycle; n3 is 0, 1, 2, 3, or 4; Each occurrence of Ra, Rb, and Rc is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl, or Rb and Rc together with the nitrogen atom to which they are attached optionally form a heterocycle containing 1 to 4 heteroatoms.

[0112] In some embodiments of formula (II), each occurrence of R1 is independently hydrogen, halogen, cyano, nitro, CF3, OCF3, ORa, or SRa. In some embodiments of formula (II), each occurrence of R1 is independently C(=O)Ra, OC(=O)Ra, C(=O)ORa, NRaRb, NRbC(=O)Ra, C(=O)NRbRc, NRbC(=O)ORa, OC(=O)NRbRc, or NRaC(=O)NRbRc. In some embodiments of formula (II), each occurrence of R1 is independently alkyl, alkenyl, cycloalkyl, optionally substituted aryl, or optionally substituted heterocycle. In some embodiments of formula (II), R1 is hydrogen.

[0113] In some embodiments of Formula (II), n1 is 0, 1, or 2. In some embodiments of Formula (II), n1 is 1. In some embodiments of Formula (II), n1 is 0.

[0114] In some embodiments of formula (II), each occurrence of R2 is independently hydrogen, halogen, cyano, nitro, CF3, OCF3, ORa, or SRa. In some embodiments of formula (II), each occurrence of R2 is independently C(=O)Ra, OC(=O)Ra, C(=O)ORa, NRaRb, NRbC(=O)Ra, C(=O)NRbRc, NRbC(=O)ORa, OC(=O)NRbRc, or NRaC(=O)NRbRc. In some embodiments of formula (II), each occurrence of R2 is independently alkyl, alkenyl, cycloalkyl, optionally substituted aryl, or optionally substituted heterocycle. In some embodiments of formula (II), R2 is hydrogen.

[0115] In some embodiments of Formula (II), n2 is 0, 1, or 2. In some embodiments of Formula (II), n2 is 1. In some embodiments of Formula (II), n2 is 0.

[0116] In some embodiments of formula (II), R3 is hydrogen, halogen, cyano, nitro, or CF3. In some embodiments of formula (II), R3 is OCF3, ORa, SRa, or OC(=O)Ra. In some embodiments of formula (II), R3 is alkyl, alkenyl, or cycloalkyl. In some embodiments of formula (II), R3 is hydrogen.

[0117] In some embodiments of formula (II), R4 is hydrogen, halogen, cyano, nitro, or ORa. In some embodiments of formula (II), R4 is OCF3, SRa, or OC(=O)Ra. In some embodiments of formula (II), R4 is alkyl, alkenyl, or cycloalkyl. In some embodiments of formula (II), R4 is OH. In some embodiments of formula (II), R4 is OMe.

[0118] In some embodiments of formula (II), R5, R6, and R7 are each independently selected from the group consisting of hydrogen, halogen, cyano, nitro, and CF3. In some embodiments of formula (II), R5, R6, and R7 are each independently selected from the group consisting of OCF3, ORa, and SRa. In some embodiments of formula (II), R5, R6, and R7 are each independently selected from the group consisting of OCF3 and ORa. In some embodiments of formula (II), R5, R6, and R7 are each independently selected from the group consisting of C(=O)Ra, OC(=O)Ra, C(=O)ORa, NRaRb, NRbC(=O)Ra, C(=O)NRbRc, NRbC(=O)ORa, OC(=O)NRbRc, and NRaC(=O)NRbRc. In some embodiments of formula (II), R5, R6, and R7 are each independently selected from the group consisting of alkyl, alkenyl, cycloalkyl, optionally substituted aryl, and optionally substituted heterocycle. In some embodiments of formula (II), each occurrence of R5, R6, and R7 is hydrogen.

[0119] In some embodiments of Formula (II), n3 is 0, 1, or 2. In some embodiments of Formula (II), n3 is 1. In some embodiments of Formula (II), n3 is 0.

[0120] In some embodiments of formula (II), each occurrence of Ra is independently hydrogen, alkyl, heterocycle, or aryl. In some embodiments of formula (II), each occurrence of Ra is independently hydrogen or alkyl. In some embodiments of formula (II), each occurrence of Rb and Rc is independently hydrogen, alkyl, heterocycle, or aryl. In some embodiments of formula (II), each occurrence of Rb and Rc is independently hydrogen or alkyl. In some embodiments of formula (II), Rb and Rc, together with the nitrogen atom to which they are attached, optionally form a heterocycle containing 1-4 heteroatoms each selected from the group consisting of N, O, and S.

[0121] In some embodiments, the compound of formula (II) is represented by formula (III):

[0122] [ka] or a pharma- ceutically acceptable salt thereof.

[0123] In some embodiments of formula (III), R2 is H, OH, alkyl, alkoxy, halogen, NRbRc, CF3, OCF3, or CN. In some embodiments of formula (III), R2 is NH2, OH, OMe, OEt, OCH2CH2CH3, or OCH(CH3)2. In some embodiments of formula (III), R2 is selected from the group consisting of hydrogen, methyl, ethyl, propyl, tert-butyl, F, Cl, Br, CF3, nitro, methoxy, ethoxy, OCF3, -C(=O)Me, -C(=O)OMe, -NHC(=O)Me, 1,4-dioxanyl, cyclohexanyl, cyclohexenyl, phenoxy, 2-methoxyphenoxy, 3-methoxyphenoxy, 4-methoxyphenoxy, 2-chlorophenoxy, 3-chlorophenoxy, 4-chlorophenoxy, 2-methylphenoxy, 3-methylphenoxy, and 4-methylphenoxy. In some embodiments of formula (III), R2 is OMe.

[0124] In some embodiments of formula (III), R3 is H, OH, alkyl, alkoxy, or halogen. In some embodiments of formula (III), R3 is H.

[0125] In some embodiments of formula (III), R4 is H, alkyl, OH, NH2, alkoxy, halogen, CF3, or CN. In some embodiments of formula (III), R4 is H, OH, or alkoxy. In some embodiments of formula (III), R4 is OH. In some embodiments of formula (III), R4 is OMe.

[0126] In some embodiments, the compound of formula (III) is represented by formula (IV):

[0127] [ka] or a pharma- ceutically acceptable salt thereof.

[0128] In some embodiments, the compound of formula (II) is a compound selected from the example compounds set forth in Table A, or a pharma- ceutically acceptable salt thereof.

[0129] [Table 1-1]

[0130] [Table 1-2]

[0131] [Table 2-1]

[0132] [Table 2-2]

[0133] In some embodiments, the compound of formula (III) is a compound selected from the example compounds set forth in Table B, or a pharma- ceutically acceptable salt thereof.

[0134] Immune checkpoint inhibitors Immune checkpoint inhibitors block proteins called checkpoints that are made by several types of immune system cells, such as T cells, and by some cancer cells. These checkpoints help keep the immune response from becoming too strong and can sometimes stop T cells from killing cancer cells. When these checkpoints are blocked, T cells are better able to kill cancer cells.

[0135] PD-1 and PD-L1 inhibitors In certain embodiments, methods of treating cancer in a subject in need of such treatment and preventing recurrence of cancer in a subject in need of such prevention are disclosed, the methods comprising administering to the subject an effective amount of a signal transducer and activator of transcription 3 (STAT3) inhibitor and an effective amount of an immune checkpoint inhibitor, such as a PD-1 inhibitor or a PD-L1 inhibitor. In some embodiments, the PD-1 inhibitor is an anti-PD-1 antibody. In some embodiments, the PD-L1 inhibitor is an anti-PD-L1 antibody.

[0136] Antibody therapy is an antibody protein that is produced by the immune system and binds to a target antigen on the surface of a cell. Antibodies are typically encoded by immunoglobulin genes or fragments thereof. In normal physiology, antibodies are used by the immune system to fight pathogens. Each antibody is specific for one or a few proteins, and those that bind to cancer antigens are used, for example, to treat cancer. An antibody can specifically bind to an antigen or epitope. (Fundamental Immunology, 3rd Edition, We, Paul, ed., Raven Press, NY (1993)). Specific binding occurs to a corresponding antigen or epitope even in the presence of a heterogeneous population of proteins and other biologics. Specific binding of an antibody indicates that it binds to its target antigen or epitope with substantially greater affinity than binding to an unrelated antigen. The relative difference in affinity is often at least 25% greater, more often at least 50% greater, and most often at least 100% greater. The relative difference can be, for example, at least 2-fold, at least 5-fold, at least 10-fold, at least 25-fold, at least 50-fold, at least 100-fold, or at least 1000-fold.

[0137] Exemplary types of antibodies include, but are not limited to, human, humanized, chimeric, monoclonal, polyclonal, single chain, antibody-binding fragments, and bispecific antibodies. Once bound to a cancer antigen, antibodies can induce antibody-dependent cell-mediated cytotoxicity, activate the complement system, prevent receptors from interacting with their ligands, or deliver chemotherapeutic or radiation payloads, all of which can result in cell death.

[0138] In some embodiments, the anti-PD-1 antibody is cemipimab, nivolumab, pembrolizumab, pidilizumab, spartalizumab, canrelizumab, sintilimab, ticelizumab, toripalimab, dostarimab, sasunlimab, retifanlimab, tebotelimab, ABBV-181, AK104, AK105, BCD-100, BI-754091, CBT-501, CC-90006, GLS-010, HLX10, IBI-308, JNJ-3283, JS001, LZM009, MEDI0680 (AMP-514), REGN-2810, SHR-1210, Sym021, TSR-042, or XmAb20717.

[0139] In some embodiments, the anti-PD-L1 antibody is atezolizumab, avelumab, durvalumab, embafolimab, FS118, BCD-135, BGB-A333, BGBA-317, CBT-502, CK-301, CS1001, FAZ053, MDX-1105, MSB2311, SHR-1316, M7824, LY3415244, CA-170, or CX-072.

[0140] Diseases and Disorders Signal Transducer and Activator of Transcription 3 (STAT3) is central to the regulation of antitumor immune response.STAT3 is widely overactivated in both cancer and non-cancerous cells in tumor ecosystem, and plays an important role in inhibiting the expression of important immune activation regulators and promoting the production of immune suppressive factors.It is contemplated that the methods provided herein are useful for the treatment of cancer, including, for example, solid tumors, soft tissue tumors, and their metastases.

[0141] In some embodiments, the cancer treated according to the methods provided herein is liver cancer, lung cancer, head and neck cancer, breast cancer, skin cancer, kidney cancer, testicular cancer, colon cancer, rectal cancer, stomach cancer, metastatic melanoma, prostate cancer, ovarian cancer, cervical cancer, bone cancer, spleen cancer, gallbladder cancer, brain cancer, pancreatic cancer, stomach cancer, anal cancer, prostate cancer, multiple myeloma, post-transplant lymphoproliferative disease, restenosis, myelodysplastic syndrome, leukemia, lymphoma, or acute myeloid leukemia. In some embodiments, the cancer treated according to the methods provided herein is liver cancer, lung cancer, hepatocellular carcinoma, squamous cell carcinoma of the head and neck, non-small cell lung cancer, or estrogen receptor positive breast cancer.

[0142] In some embodiments, the cancer treated according to the methods provided herein is head and neck cancer, lung cancer, liver cancer, breast cancer, ovarian cancer, colon cancer, multiple myeloma, leukemia, or pancreatic cancer. In some embodiments, the leukemia is acute myeloid leukemia.

[0143] combination As used herein in the context of administration of a compound described herein or a therapy described herein, the phrase "in combination with," and the terms "co-administration," "co-administrating," or "co-providing," mean that two (or more) different compounds or therapies are delivered to a subject during the course of the subject's illness (e.g., a disease or disorder described herein, e.g., cancer), e.g., two (or more) different compounds or therapies are delivered to a subject after the subject has been diagnosed with a disease or disorder (e.g., a disease or disorder described herein, e.g., cancer) and before the disease or disorder is cured or eliminated or treatment is discontinued for other reasons.

[0144] In some embodiments, the delivery of one compound or therapy still occurs when the delivery of the second compound or therapy begins, and thus there is an overlap in terms of administration. This may be referred to herein as "simultaneous" or "concurrent delivery". In other embodiments, the delivery of one compound or therapy ends before the delivery of the other compound or therapy begins. In some embodiments in either case, the treatment (e.g., administration of a compound, composition, or treatment) is more effective due to the combined administration. For example, the second compound or therapy is more effective, e.g., a comparable effect is seen with less of the second compound or therapy, or the second compound or therapy reduces symptoms to a greater extent than would be seen if the second compound or therapy were administered in the absence of the first compound or therapy, or a similar situation would be seen with the first compound or therapy. In some embodiments, the delivery is such that the reduction in symptoms or other parameters associated with the disorder is greater than that observed with one compound or therapy delivered in the absence of the other compound. The effect of the two compounds or therapies can be partially additive, fully additive, or greater than additive (e.g., synergistic). Delivery can be such that the first compound or therapy delivered is still detectable when the second compound or therapy is delivered.

[0145] In some embodiments, the first compound or therapy and the second compound or therapy can be administered simultaneously (e.g., at the same time), in the same or separate compositions, or sequentially.Sequential administration refers to administering one compound or therapy before (e.g., immediately before, less than 5, 10, 15, 30, 45, 60 minutes; 1, 2, 3, 4, 6, 8, 10, 12, 16, 20, 24, 48, 72, 96 hours or more; 4, 5, 6, 7, 8, 9 days or more; 1, 2, 3, 4, 5, 6, 7, 8 weeks or more) the administration of additional, e.g., secondary, compound or therapy.The order of administration of the first and second compound or therapy can also be reversed.

[0146] The combinations described herein may be used as first line treatments of cancer, i.e., in patients who have not previously been administered another drug intended to treat cancer; second line treatments of cancer, i.e., in subjects in need thereof who have previously been administered another drug intended to treat cancer; or third or fourth line treatments of cancer, i.e., in subjects who have previously been administered two or three other drugs intended to treat cancer.

[0147] Administration and Dosage The combinations of the present disclosure may be administered orally, parenterally, topically, rectally, or via an implanted reservoir, preferably by oral administration (e.g., in the case of STAT3 inhibitors) or by injection (e.g., in the case of anti-PD-1). In some cases, the pH of a composition (e.g., pharmaceutical composition) comprising a STAT3 inhibitor or a composition (e.g., pharmaceutical composition) comprising an immune checkpoint inhibitor may be adjusted with a pharma- ceutical acceptable acid, base, or buffer to enhance the stability or efficacy of the composition.

[0148] In some embodiments, the subject is orally administered a composition (e.g., pharmaceutical composition) comprising a STAT3 inhibitor. In some embodiments, the composition (e.g., pharmaceutical composition) is orally administered in any orally acceptable dosage form, including, but not limited to, liqui-gel tablets or capsules, syrups, emulsions, and aqueous suspensions. The liqui-gel may contain gelatin, plasticizers, and / or opacifiers as necessary to achieve the appropriate consistency, and may be coated with an enteric coating approved for use, such as shellac. Additional thickening agents, such as gums, such as xanthan gum, starches, such as corn starch, or gluten, may be added to achieve the desired consistency of the composition (e.g., pharmaceutical composition) when used as an oral dosage. If desired, certain sweeteners and / or flavorings and / or colorings may be added.

[0149] In some embodiments, the subject is administered a composition (e.g., a pharmaceutical composition) that includes a STAT3 inhibitor in a form suitable for oral administration, such as a tablet, capsule, pill, powder, sustained release formulation, solution, and suspension. The composition (e.g., a pharmaceutical composition) can be in a unit dosage form suitable for single administration of a precise dosage. The pharmaceutical composition may include a pharmaceutically acceptable carrier in addition to the compound described herein, and may further include one or more pharmaceutically acceptable excipients, such as, for example, stabilizers, diluents, binders, and lubricants. In addition, the tablet may include other drugs or drugs, carriers, and / or adjuvants.

[0150] Dosage may vary depending on the dosage form used and the route of administration utilized. The exact formulation, route of administration and dosage can be selected by the individual physician in consideration of the patient's condition. (See, for example, Fingl et al., 1975, "The Pharmacological Basis of Therapeutics"). Lower or higher doses than those listed above may be required. The specific dosage and treatment regimen for any particular subject will depend on a variety of factors, including the activity of the specific compound used, age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, severity and course of the disease, disorder or condition, predisposition of the subject to the disease, disorder or condition, and the judgment of the treating physician. A course of treatment may include one or more separate administrations of the compounds described herein.

[0151] In some embodiments, the compound of formula (I) is N-(1',2-dihydroxy-1,2'-binaphthalen-4'-yl)-4-methoxybenzenesulfonamide, and the N-(1',2-dihydroxy-1,2'-binaphthalen-4'-yl)-4-methoxybenzenesulfonamide is administered to the subject in an oral dosage form comprising a composition comprising: a. a therapeutically effective amount of N-(1',2-dihydroxy-1,2'-binaphthalen-4'-yl)-4-methoxybenzenesulfonamide; b. an emulsifier (e.g., a glyceride) present in the composition in a weight ratio of the compound of formula (I) to emulsifier of about 1:1 to about 1:2 (e.g., about 1:1.5); c. a solubilizing agent, wherein the solubilizing agent is present in the composition in a weight ratio of the compound of formula (I) to the solubilizing agent of about 1:1 to about 1:5 (e.g., about 1:2 to about 1:4, e.g., about 1:3); d. polyethylene glycol (PEG), wherein the PEG is present in the composition in a weight ratio of the compound of formula (I) to polyethylene glycol of about 1:2 to about 1:6 (e.g., about 1:3 to about 1:5, e.g., about 1:4); e. a surfactant, the surfactant being present in the composition in a weight ratio of the compound of formula (I) to surfactant of about 2:1 to about 1:2 (e.g., about 1:1 to about 1:2, e.g., about 1:2); and f. An antioxidant, wherein the antioxidant is present in the composition in a weight ratio of the compound of formula (I) to antioxidant of about 10:1 to about 30:1 (e.g., about 15:1 to about 25:1, e.g., about 20:1).

[0152] In some embodiments, the emulsifier is present in the composition in a weight ratio of the compound of formula (I) to the emulsifier of about 1:1. In some embodiments, the emulsifier is present in the composition in a weight ratio of the compound of formula (I) to the emulsifier of about 1:2. In some embodiments, the emulsifier is present in the composition in a weight ratio of the compound of formula (I) to the emulsifier of about 1:3. In some embodiments, the emulsifier is present in the composition in a weight ratio of the compound of formula (I) to the emulsifier of about 1:4. In some embodiments, the emulsifier is present in the composition in a weight ratio of the compound of formula (I) to the emulsifier of about 1:5. In some embodiments, the emulsifier is present in the composition in a weight ratio of the compound of formula (I) to the emulsifier of about 1:6. In some embodiments, the emulsifier is present in the composition in a weight ratio of the compound of formula (I) to the emulsifier of about 1:7. In some embodiments, the emulsifier is present in the composition in a weight ratio of the compound of formula (I) to the emulsifier of about 1:1.5.

[0153] In some embodiments, the solubilizer is present in the composition in a weight ratio of the compound of formula (I) to the solubilizer of about 1:1. In some embodiments, the solubilizer is present in the composition in a weight ratio of the compound of formula (I) to the solubilizer of about 1:2. In some embodiments, the solubilizer is present in the composition in a weight ratio of the compound of formula (I) to the solubilizer of about 1:3. In some embodiments, the solubilizer is present in the composition in a weight ratio of the compound of formula (I) to the solubilizer of about 1:4. In some embodiments, the solubilizer is present in the composition in a weight ratio of the compound of formula (I) to the solubilizer of about 1:5. In some embodiments, the solubilizer is present in the composition in a weight ratio of the compound of formula (I) to the solubilizer of about 1:4. In some embodiments, the solubilizer is present in the composition in a weight ratio of the compound of formula (I) to the solubilizer of about 1:6. In some embodiments, the solubilizer is present in the composition at a weight ratio of the compound of formula (I) to the solubilizer of about 1:4. In some embodiments, the solubilizer is present in the composition at a weight ratio of the compound of formula (I) to the solubilizer of about 1:7. In some embodiments, the solubilizer is present in the composition at a weight ratio of the compound of formula (I) to the solubilizer of about 1:4. In some embodiments, the solubilizer is present in the composition at a weight ratio of the compound of formula (I) to the solubilizer of about 1:8. In some embodiments, the solubilizer is present in the composition at a weight ratio of the compound of formula (I) to the solubilizer of about 1:4. In some embodiments, the solubilizer is present in the composition at a weight ratio of the compound of formula (I) to the solubilizer of about 1:9. In some embodiments, the solubilizer is present in the composition at a weight ratio of the compound of formula (I) to the solubilizer of about 1:10. In some embodiments, the solubilizer is present in the composition at a weight ratio of the compound of formula (I) to the solubilizer of about 1:11. In some embodiments, the solubilizer is present in the composition at a weight ratio of the compound of formula (I) to the solubilizer of about 1:12. In some embodiments, the solubilizer is present in the composition at a weight ratio of the compound of formula (I) to the solubilizer of about 1:13. In some embodiments, the solubilizer is present in the composition at a weight ratio of the compound of formula (I) to the solubilizer of about 1:14. In some embodiments, the solubilizer is present in the composition at a weight ratio of the compound of formula (I) to the solubilizer of about 1:15.In some embodiments, the solubilizer is present in the composition at a weight ratio of the compound of formula (I) to the solubilizer of about 1:16. In some embodiments, the solubilizer is present in the composition at a weight ratio of the compound of formula (I) to the solubilizer of about 1:17. In some embodiments, the solubilizer is present in the composition at a weight ratio of the compound of formula (I) to the solubilizer of about 1:18. In some embodiments, the solubilizer is present in the composition at a weight ratio of the compound of formula (I) to the solubilizer of about 1:19. In some embodiments, the solubilizer is present in the composition at a weight ratio of the compound of formula (I) to the solubilizer of about 1:20.

[0154] In some embodiments, polyethylene glycol is present in the composition in a weight ratio of the compound of Formula (I) to polyethylene glycol of about 1:1. In some embodiments, polyethylene glycol is present in the composition in a weight ratio of the compound of Formula (I) to polyethylene glycol of about 1:2. In some embodiments, polyethylene glycol is present in the composition in a weight ratio of the compound of Formula (I) to polyethylene glycol of about 1:3. In some embodiments, polyethylene glycol is present in the composition in a weight ratio of the compound of Formula (I) to polyethylene glycol of about 1:4. In some embodiments, polyethylene glycol is present in the composition in a weight ratio of the compound of Formula (I) to polyethylene glycol of about 1:5. In some embodiments, polyethylene glycol is present in the composition in a weight ratio of the compound of Formula (I) to polyethylene glycol of about 1:6. In some embodiments, polyethylene glycol is present in the composition in a weight ratio of the compound of Formula (I) to polyethylene glycol of about 1:7. In some embodiments, polyethylene glycol is present in the composition in a weight ratio of the compound of Formula (I) to polyethylene glycol of about 1:8. In some embodiments, polyethylene glycol is present in the composition in a weight ratio of the compound of formula (I) to polyethylene glycol of about 1:9. In some embodiments, polyethylene glycol is present in the composition in a weight ratio of the compound of formula (I) to polyethylene glycol of about 1:10. In some embodiments, polyethylene glycol is present in the composition in a weight ratio of the compound of formula (I) to polyethylene glycol of about 1:11. In some embodiments, polyethylene glycol is present in the composition in a weight ratio of the compound of formula (I) to polyethylene glycol of about 1:12. In some embodiments, polyethylene glycol is present in the composition in a weight ratio of the compound of formula (I) to polyethylene glycol of about 1:13. In some embodiments, polyethylene glycol is present in the composition in a weight ratio of the compound of formula (I) to polyethylene glycol of about 1:14. In some embodiments, polyethylene glycol is present in the composition in a weight ratio of the compound of formula (I) to polyethylene glycol of about 1:15.In some embodiments, polyethylene glycol is present in the composition in a weight ratio of the compound of formula (I) to polyethylene glycol of about 1:16. In some embodiments, polyethylene glycol is present in the composition in a weight ratio of the compound of formula (I) to polyethylene glycol of about 1:17. In some embodiments, polyethylene glycol is present in the composition in a weight ratio of the compound of formula (I) to polyethylene glycol of about 1:18. In some embodiments, polyethylene glycol is present in the composition in a weight ratio of the compound of formula (I) to polyethylene glycol of about 1:19. In some embodiments, polyethylene glycol is present in the composition in a weight ratio of the compound of formula (I) to polyethylene glycol of about 1:20.

[0155] In some embodiments, the surfactant is present in the composition in a weight ratio of the compound of formula (I) to the surfactant of about 4:1. In some embodiments, the surfactant is present in the composition in a weight ratio of the compound of formula (I) to the surfactant of about 3:1. In some embodiments, the surfactant is present in the composition in a weight ratio of the compound of formula (I) to the surfactant of about 2:1. In some embodiments, the surfactant is present in the composition in a weight ratio of the compound of formula (I) to the surfactant of about 1:1. In some embodiments, the surfactant is present in the composition in a weight ratio of the compound of formula (I) to the surfactant of about 1:2. In some embodiments, the surfactant is present in the composition in a weight ratio of the compound of formula (I) to the surfactant of about 1:3. In some embodiments, the surfactant is present in the composition in a weight ratio of the compound of formula (I) to the surfactant of about 1:4. In some embodiments, the surfactant is present in the composition in a weight ratio of the compound of formula (I) to the surfactant of about 1:5. In some embodiments, the surfactant is present in the composition in a weight ratio of the compound of formula (I) to the surfactant of about 1:6.

[0156] In some embodiments, the antioxidant is present in the composition in a weight ratio of the compound of Formula (I) to antioxidant of about 2:1. In some embodiments, the antioxidant is present in the composition in a weight ratio of the compound of Formula (I) to antioxidant of about 3:1. In some embodiments, the antioxidant is present in the composition in a weight ratio of the compound of Formula (I) to antioxidant of about 4:1. In some embodiments, the antioxidant is present in the composition in a weight ratio of the compound of Formula (I) to antioxidant of about 5:1. In some embodiments, the antioxidant is present in the composition in a weight ratio of the compound of Formula (I) to antioxidant of about 6:1. In some embodiments, the antioxidant is present in the composition in a weight ratio of the compound of Formula (I) to antioxidant of about 7:1. In some embodiments, the antioxidant is present in the composition in a weight ratio of the compound of Formula (I) to antioxidant of about 8:1. In some embodiments, the antioxidant is present in the composition in a weight ratio of the compound of Formula (I) to antioxidant of about 9:1. In some embodiments, the antioxidant is present in the composition in a weight ratio of the compound of Formula (I) to antioxidant of about 10:1. In some embodiments, the antioxidant is present in the composition in a weight ratio of the compound of Formula (I) to antioxidant of about 11:1. In some embodiments, the antioxidant is present in the composition in a weight ratio of the compound of Formula (I) to antioxidant of about 12:1. In some embodiments, the antioxidant is present in the composition in a weight ratio of the compound of Formula (I) to antioxidant of about 13:1. In some embodiments, the antioxidant is present in the composition in a weight ratio of the compound of Formula (I) to antioxidant of about 14:1. In some embodiments, the antioxidant is present in the composition in a weight ratio of the compound of Formula (I) to antioxidant of about 15:1. In some embodiments, the antioxidant is present in the composition in a weight ratio of the compound of Formula (I) to antioxidant of about 16:1. In some embodiments, the antioxidant is present in the composition in a weight ratio of the compound of Formula (I) to antioxidant of about 17:1. In some embodiments, the antioxidant is present in the composition in a weight ratio of the compound of Formula (I) to antioxidant of about 18:1. In some embodiments, the antioxidant is present in the composition in a weight ratio of the compound of Formula (I) to antioxidant of about 19:1. In some embodiments, the antioxidant is present in the composition in a weight ratio of the compound of Formula (I) to antioxidant of about 20:1.In some embodiments, the antioxidant is present in the composition in a weight ratio of the compound of Formula (I) to antioxidant of about 21:1. In some embodiments, the antioxidant is present in the composition in a weight ratio of the compound of Formula (I) to antioxidant of about 22:1. In some embodiments, the antioxidant is present in the composition in a weight ratio of the compound of Formula (I) to antioxidant of about 23:1. In some embodiments, the antioxidant is present in the composition in a weight ratio of the compound of Formula (I) to antioxidant of about 24:1. In some embodiments, the antioxidant is present in the composition in a weight ratio of the compound of Formula (I) to antioxidant of about 25:1. In some embodiments, the antioxidant is present in the composition in a weight ratio of the compound of Formula (I) to antioxidant of about 26:1. In some embodiments, the antioxidant is present in the composition in a weight ratio of the compound of Formula (I) to antioxidant of about 27:1. In some embodiments, the antioxidant is present in the composition in a weight ratio of the compound of Formula (I) to antioxidant of about 28: 1. In some embodiments, the antioxidant is present in the composition in a weight ratio of the compound of Formula (I) to antioxidant of about 29: 1. In some embodiments, the antioxidant is present in the composition in a weight ratio of the compound of Formula (I) to antioxidant of about 30: 1.

[0157] In some embodiments, the compound of formula (I) is present in the formulation at a concentration of at least 50 mg / g (e.g., at least 60 mg / g, at least 70 mg / g, at least 80 mg / g, or at least 90 mg / g) (e.g., excluding the mass of the capsule shell). In some embodiments, the compound of formula (I) is present in the formulation at a concentration of at least 50 mg / g. In some embodiments, the compound of formula (I) is present in the formulation at a concentration of at least 60 mg / g. In some embodiments, the compound of formula (I) is present in the formulation at a concentration of at least 70 mg / g. In some embodiments, the compound of formula (I) is present in the formulation at a concentration of at least 80 mg / g. In some embodiments, the compound of formula (I) is present in the formulation at a concentration of at least 90 mg / g.

[0158] In some embodiments, the emulsifier is a glyceride emulsifier. In some embodiments, the emulsifier optionally comprises polyglycolized medium and / or long chain mono-, di-, and / or triglycerides. In some embodiments, the emulsifier comprises medium chain monoglycerides. In some embodiments, the emulsifier comprises polysaccharolyzed medium chain monoglycerides. In some embodiments, the emulsifier comprises long chain monoglycerides. In some embodiments, the emulsifier comprises polyglycolized long chain monoglycerides. In some embodiments, the emulsifier comprises medium chain diglycerides. In some embodiments, the emulsifier comprises polysaccharolyzed medium chain diglycerides. In some embodiments, the emulsifier comprises long chain diglycerides. In some embodiments, the emulsifier comprises polysaccharolyzed long chain diglycerides. In some embodiments, the emulsifier comprises medium chain triglycerides. In some embodiments, the emulsifier comprises polysaccharolyzed medium chain triglycerides. In some embodiments, the emulsifier comprises long chain triglycerides. In some embodiments, the emulsifier comprises a polyglycolized long chain triglyceride.

[0159] In some embodiments, the emulsifier is Labrasol®. In some embodiments, the emulsifier is Capmul® MCM. In some embodiments, the emulsifier is Capmul® MCM EP. In some embodiments, the emulsifier is Capmul® C8 EP. In some embodiments, the emulsifier is Capryol® 90.

[0160] In some embodiments, the solubilizer is polyoxyl castor oil or vitamin E polyethylene glycol succinate (TPGS). In some embodiments, the solubilizer is polyoxyl castor oil. In some embodiments, the solubilizer is vitamin E polyethylene glycol succinate. In some embodiments, the surfactant is Kolliphor® RH40. In some embodiments, the solubilizer is vitamin ETPGS.

[0161] In some embodiments, the polyethylene glycol (PEG) has an average molecular weight of about 200 to about 1000 (e.g., about 500 to about 700, or about 550 to about 650, or about 600). In some embodiments, the polyethylene glycol (PEG) has an average molecular weight of about 200 to 1000. In some embodiments, the polyethylene glycol (PEG) has an average molecular weight of about 500 to 700. In some embodiments, the polyethylene glycol (PEG) has an average molecular weight of about 550 to 650. In some embodiments, the polyethylene glycol (PEG) has an average molecular weight of about 600.

[0162] In some embodiments, the polyethylene glycol (PEG) is PEG 200. In some embodiments, the polyethylene glycol (PEG) is PEG 300. In some embodiments, the polyethylene glycol (PEG) is PEG 400. In some embodiments, the polyethylene glycol (PEG) is PEG 500. In some embodiments, the polyethylene glycol (PEG) is PEG 600. In some embodiments, the polyethylene glycol (PEG) is PEG 700. In some embodiments, the polyethylene glycol (PEG) is PEG 800. In some embodiments, the polyethylene glycol (PEG) is PEG 900. In some embodiments, the polyethylene glycol (PEG) is PEG 1000.

[0163] In some embodiments, the surfactant is a polysorbate (e.g., polysorbate 20). In some embodiments, the surfactant is polysorbate 20. In some embodiments, the surfactant is polysorbate 40. In some embodiments, the surfactant is polysorbate 60. In some embodiments, the surfactant is polysorbate 80.

[0164] In some embodiments, the antioxidant is vitamin E. In some embodiments, the antioxidant is ascorbyl palmitate. In some embodiments, the antioxidant is butylated hydroxytoluene. In some embodiments, the antioxidant is triethyl citrate. In some embodiments, the antioxidant is citric acid.

[0165] In some embodiments, the composition further comprises a co-solvent (e.g., Transcutol®). In some embodiments, the composition further comprises Transcutol® HP.

[0166] In some embodiments, the methods described herein contemplate administering to a subject an oral dosage form comprising a pharmaceutical composition described herein contained within a capsule. EXAMPLES

[0167] In the examples below, the following abbreviations are used: ROA = route of administration; ip = intraperitoneal (intraperitoneally); po = oral (by mouth); BID = twice daily; BIW = twice weekly; PBS = phosphate buffered saline; FBS = fetal bovine serum; N / A = not available or applicable; SD = standard deviation; SEM = standard error of the mean; TGI = tumor growth inhibition; TV = tumor volume.

[0168] Example 1. In vivo efficacy study and rechallenge study of TTI-101 ± anti-PD-1 in treating a subcutaneous liver cancer syngeneic model (H22) in female BALB / c mice The aim of the efficacy study was to preclinically evaluate the in vivo therapeutic efficacy of TTI-101 alone and in combination with anti-PD-1 in the treatment of the subcutaneous syngeneic model H22 liver cancer in female BALB / c mice.The aim of the rechallenge study was to evaluate the immune memory of female BALB / c mice previously cured of the subcutaneous syngeneic model H22 liver cancer with TTI-101 in combination with anti-PD-1.

[0169] formulation The dosing volume of anti-PD-1 (clone RMP1-14) was adjusted according to body weight. The concentration of anti-PD-1 was 1 mg / mL, and the dosing volume was 10 μL / g. The anti-PD-1 dosing solution was prepared by diluting 1.372 mL of anti-PD-1 (8.2 mg / mL) with 9.878 mL of PBS.

[0170] Isotype controls were made by diluting the isotype control with PBS. The dosing volume was adjusted for body weight. The concentration of the isotype control was 1 mg / mL and the dosing volume was 10 μL / g. For each preparation, 7.5 mL of dosing solution was prepared by diluting the isotype control with PBS.

[0171] A composition of TTI-101 (72 mg / mL) dissolved in Kolliphor RH40, PEG600, Labrasol, Tween 20, and citric acid solution was then dispersed (vortexed) 1:2 in water to form a dosing emulsion, with the concentration of TTI-101 in the dosing emulsion being 24 mg / mL.

[0172] A vehicle formulation consisting of Kolliphor RH40, PEG600, Labrasol, Tween 20, and citric acid solution was then dispersed (vortexed) 1:2 in water to form the emulsion for dosing.

[0173] cell culture H22 tumor cells were maintained in vitro using RPMI 1640 medium supplemented with 10% fetal bovine serum (FBS) at 37°C in an atmosphere of 5% CO2 in air. Exponentially growing cells were harvested and quantified by cell counter prior to tumor inoculation.

[0174] Tumor inoculation In the efficacy study, each mouse was injected with tumor cells (1 × 10 ) in 0.1 ml of PBS for tumor development. 6 ) was inoculated subcutaneously into the right anterior abdomen.

[0175] In the rechallenge study, each mouse was administered 1×10 tumor cells in 0.1 ml of PBS for tumor development. 6 ) was inoculated subcutaneously into the left anterior abdomen. The day of inoculation was designated as day 0.

[0176] Randomization Randomization in the efficacy trial occurred in patients with a mean tumor size of approximately 73 mm 3 (Groups 1-5) and 96 mm 3 The study began when the first 12 months of age (groups 6–9) were reached. A total of 82 mice were enrolled in the study and randomly assigned to 9 study groups, with 10 mice per group (groups 1–5) and 8 mice per group (groups 6–9). Randomization was based on the “Matched distribution” method (Study Director TM software, version 3.1.399.19). The day of randomization was designated as day 1.

[0177] Each treatment group was administered according to the schedule shown in Table 1.

[0178] [Table 3]

[0179] In the rechallenge study, groups 4, 5 and 10 were rechallenged according to Table 2.

[0180] [Table 4]

[0181] Tumor volume measurement Tumor volumes were measured twice weekly after randomization in two dimensions using calipers and volumes were expressed in mm using the formula V=(L×W×W) / 2, where V is tumor volume, L is tumor length (the longest tumor dimension), and W is tumor width (the longest tumor dimension perpendicular to L). 3 Dosing and tumor and body weight measurements were performed in a Laminar Flow Cabinet.

[0182] Tumor growth inhibition (TGI), T / C value and survival were applied as end points.

[0183] Tumor regression (REG)=[(T0-T i ) / T0]×100%;

[0184] Ti is the mean tumor volume of the treatment group on the day of measurement;

[0185] TO is the mean tumor volume of the treatment group on day 0.

[0186] Tumor growth inhibition; TGI%=(1-Ti / Ci)*100;

[0187] Ti is the mean tumor volume of the treatment group on the day of measurement;

[0188] Ci is the mean tumor volume of the control group on the day of measurement.

[0189] The treated / control (T / C) value (%) is an index of tumor response to treatment and is one of the commonly used antitumor activity endpoints; T and C are the mean tumor volumes of the treated and control groups, respectively, on a given day.

[0190] Tumor volume change_treatment / tumor volume change_control (ΔT / ΔC)=(T i -T0) / (C i -C0)*100%;T i and C i is the mean tumor volume of the treated and control groups on the day of measurement; T0 and C0 are the mean tumor volumes of the treated and control groups on day 0.

[0191] End of exam Treatment was for 21 days. Groups 1 and 2 were terminated on day 21; Group 3 was terminated on day 51; Groups 4 and 5 were extended for a rechallenge study and were terminated on day 130 (day 24 of the rechallenge study).

[0192] result Figures 1 and 2 show the in vivo efficacy of TTI-101 ± anti-PD-1 in the H22 model through days 21 and 47, respectively.

[0193] Tumor Growth Inhibition (TGI) Tumor growth inhibition in the treatment of the subcutaneous hepatoma syngeneic model H22 is summarized in Table 3.

[0194] [Table 5]

[0195] In this study, the mean tumor size in vehicle mice was 2647 mm 21 days after randomization. 3TTI-101 administered at 1.2 mg / mouse BID showed slight antitumor efficacy against the H22 model, with a TGI value of 21.67% at day 21, but no statistically significant difference (P>0.05) was observed compared to the vehicle group. Anti-PD-1 administered at 100 mg / kg BIW showed significant antitumor efficacy against the H22 model, with a TGI value of 78.95% at day 21 (P<0.0001), with 6 animals in group 3 showing tumor regression at day 51.

[0196] Co-administration of TTI-101 and anti-PD-1 resulted in significant anti-tumor efficacy in the H22 model, with a TGI value of 60.31% on day 21, resulting in a statistically significant difference of P<0.0001 when compared with the vehicle group.

[0197] Sequential administration of TTI-101 on day 7 after anti-PD-1 resulted in significant antitumor efficacy against the H22 model, with a TGI of 68.67% on day 21, a statistically significant difference of P<0.0001 when compared to the vehicle group. Two animals (2 / 10) in group 5 showed complete tumor regression on day 51 and remained tumor-free until the end of the study on day 130.

[0198] Figure 3 shows that combination therapy of TTI-101 and anti-PD-1, which results in tumor regression, protects against tumor rechallenge. All naive animals in group 10 developed tumors, with 2 of 7 animals reaching 3000 mm 24 days after reinoculation. 3 Throughout the rechallenge study, 3 animals co-administered with TTI-101 and anti-PD-1 (Group 4) and 2 animals sequentially administered with TTI-101 (starting on day 7) and anti-PD-1 (Group 5) experienced complete tumor regression and remained tumor-free for both the first H22 tumor administration in the right flank and H22 rechallenge in the left flank until the study was terminated 24 days after rechallenge.

[0199] Example 2. Bioavailability and Pharmacokinetics of TTI-101 Following IP or PO Administration The bioavailability and pharmacokinetics of TTI-101 in male Sprague-Dawley rats were evaluated after a single oral (PO) dose at 25 mg / kg (in labrasol:PEG400, 60:40% v / v) and a single intraperitoneal (IP) dose at 25.6 mg / kg (in PBS / propylene glycol / ethanol / DMSO at pH 7.4, 20:70:5:5% v / v). Table 4 shows the exposure in rats administered a single dose of TTI-101. The results show that exposure was unexpectedly 90% greater with oral administration compared to intraperitoneal administration.

[0200] [Table 6]

[0201] Additionally, Figure 5 shows a comparison of PO administration vs. IP administration for its efficacy in cancer models such as the mouse H22 liver cancer model. Tumor volumes were measured 18 days after twice daily administration (50 mg / kg) of ip vs. po delivery in H22 mice (syngeneic liver cancer model) (n=8). Percent change in normalized tumor volume for both ip and po=mean of TTI-101-treated mice / mean of vehicle-treated mice.

Claims

1. A compound of formula (I) for use in the treatment of cancer in a subject in need thereof. 【Chemistry 1】 or a pharma- ceutically acceptable salt thereof, and an immune checkpoint inhibitor, During the ceremony, R is selected from the group consisting of hydrogen, phenylsulfanyl, 2-hydroxy-naphthalen-1-yl, quinolin-8-ylsulfanyl, triazol-3-ylsulfanyl, and benzothiazol-2-ylsulfanyl; R １ is selected from the group consisting of hydrogen, methyl, chloro, bromo, methoxy, ethoxy, tert-butyl, nitro, methyl ester, acetamide, 1,4 dioxin, fluoro, trifluoromethoxy, acetyl, trifluoromethyl, propyl, cyclohexene, methoxy-phenoxy, chlorophenoxy, tolyloxy, and phenoxy; The treatment comprises: a) orally administering to said subject an effective amount of said compound of formula (I) or a pharma- ceutically acceptable salt thereof; b) administering to the subject an effective amount of the immune checkpoint inhibitor. A compound or a pharma- ceutically acceptable salt thereof, and an immune checkpoint inhibitor.

2. 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, wherein the compound of formula (I) inhibits signal transducer and activator of transcription 3 (STAT3), and an immune checkpoint inhibitor.

3. 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, wherein the compound of formula (I) inhibits signal transducer and activator of transcription 1 (STAT1), and an immune checkpoint inhibitor.

4. 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, wherein the compound of formula (I) inhibits signal transducer and activator of transcription 5 (STAT5), and an immune checkpoint inhibitor.

5. The compound of formula (I) is N-(1',2-dihydroxy1,2'-binaphthalen-4'-yl)-4-methoxybenzenesulfonamide, N-(3,1'-dihydroxy[1,2']binaphthalenyl-4'-yl)-4-methoxy-benzenesulfonamide, N-(4,1'-dihydroxy[1,2']binaphthalenyl-4'-yl)-4-methoxy-benzenesulfonamide, N-(5,1'-dihydroxy[1,2']binaphthalenyl-4'-yl)-4-methoxy-benzenesulfonamide, N-(6,1'-dihydroxy[1,2']binaphthalenyl-4'-yl)-4-methoxy-benzenesulfonamide, N-(7,1'-dihydroxy 2. The compound according to claim 1, or a pharma- ceutically acceptable salt thereof, which is selected from the group consisting of N-(4-hydroxy-3-(1H-[1,2,4]triazol-3-ylsulfanyl)-naphthalen-1-yl)-benzenesulfonamide, N-(8,1'-dihydroxy[1,2']binaphthalenyl-4'-yl)-4-methoxy ... 4-bromo-N-(1,6'-dihydroxy[2,2']binaphthalenyl-4-yl)-benzenesulfonamide, and 4-bromo-N-[4-hydroxy-3-(1H-[1,2,4]triazol-3-ylsulfanyl)-naphthalen-1-yl]-benzenesulfonamide, or a pharma- ceutically acceptable salt thereof, and an immune checkpoint inhibitor.

6. The compound or a pharma- ceutically acceptable salt thereof according to claim 5, wherein the compound of formula (I) is N-(1',2-dihydroxy1,2'-binaphthalen-4'-yl)-4-methoxybenzenesulfonamide, and an immune checkpoint inhibitor.

7. The compound or a pharma- ceutically acceptable salt thereof according to claim 1, wherein the immune checkpoint inhibitor is a PD-1 inhibitor or a PD-L1 inhibitor, and an immune checkpoint inhibitor.

8. The compound or a pharma- ceutically acceptable salt thereof according to claim 7, wherein the PD-1 inhibitor is an anti-PD-1 antibody, and an immune checkpoint inhibitor.

9. The anti-PD-1 antibody is selected from the group consisting of cemiplimab, nivolumab, pembrolizumab, pidilizumab, spartalizumab, camrelizumab, sintilimab, tislelizumab, toripalimab, dostallimab, sasanlimab, retifanlimab, tebotelimab, ABBV-181, AK104, AK105, BCD-100, BI-754091, CBT-501, CC- 90006, GLS-010, HLX10, IBI-308, JNJ-3283, JS001, LZM009, MEDI0680 (AMP-514), REGN-2810, SHR-1210, Sym021, TSR-042, or XmAb20717, or a pharma- ceutically acceptable salt thereof, and an immune checkpoint inhibitor.

10. The compound of claim 9 or a pharma- ceutically acceptable salt thereof, wherein the anti-PD-1 antibody is pembrolizumab, and an immune checkpoint inhibitor.

11. The compound or a pharma- ceutically acceptable salt thereof according to claim 7, wherein the PD-L1 inhibitor is an anti-PD-L1 antibody, and an immune checkpoint inhibitor.

12. The compound according to claim 11 or a pharma- ceutically acceptable salt thereof, wherein the anti-PD-L1 antibody is atezolizumab, avelumab, durvalumab, emvaforimab, FS118, BCD-135, BGB-A333, BGBA-317, CBT-502, CK-301, CS1001, FAZ053, MDX-1105, MSB2311, SHR-1316, M7824, LY3415244, CA-170, or CX-072, and an immune checkpoint inhibitor.

13. 13. The compound of any one of claims 1 to 12, or a pharma- ceutically acceptable salt thereof, and an immune checkpoint inhibitor, wherein the immune checkpoint inhibitor is administered prior to administration of the compound of formula (I).

14. 13. The compound of any one of claims 1 to 12, or a pharma- ceutically acceptable salt thereof, and an immune checkpoint inhibitor, wherein said immune checkpoint inhibitor is administered simultaneously with administration of said compound of formula (I).

15. The compound according to any one of claims 1 to 12, or a pharma- ceutically acceptable salt thereof, and an immune checkpoint inhibitor, wherein the immune checkpoint inhibitor is administered following administration of the compound of formula (I).

16. The compound or a pharma- ceutically acceptable salt thereof according to any one of claims 1 to 15, and an immune checkpoint inhibitor, wherein the subject exhibits at least a partial response 3 weeks or more after administration of the compound of formula (I) and the immune checkpoint inhibitor.

17. 17. The compound of any one of claims 1 to 16, or a pharma- ceutically acceptable salt thereof, and an immune checkpoint inhibitor, wherein the subject exhibits a complete remission 6 weeks or more after administration of the compound of formula (I) and the immune checkpoint inhibitor.

18. 18. The compound or pharma- ceutically acceptable salt thereof of any one of claims 1 to 17, and an immune checkpoint inhibitor, wherein the method reduces tumor size by at least 20% within 6 weeks of administration compared to a subject administered the immune checkpoint inhibitor alone.

19. 2. A compound according to claim 1, wherein the compound is a compound of formula (I) 【Chemistry 2】 or a pharma- ceutically acceptable salt thereof, and an immune checkpoint inhibitor, During the ceremony, R is selected from the group consisting of hydrogen, phenylsulfanyl, 2-hydroxy-naphthalen-1-yl, quinolin-8-ylsulfanyl, triazol-3-ylsulfanyl, and benzothiazol-2-ylsulfanyl; R １ is selected from the group consisting of hydrogen, methyl, chloro, bromo, methoxy, ethoxy, tert-butyl, nitro, methyl ester, acetamide, 1,4 dioxin, fluoro, trifluoromethoxy, acetyl, trifluoromethyl, propyl, cyclohexene, methoxy-phenoxy, chlorophenoxy, tolyloxy, and phenoxy; The method comprises: a) orally administering to said subject an effective amount of said compound of formula (I) or a pharma- ceutically acceptable salt thereof; b) administering to the subject an effective amount of the immune checkpoint inhibitor. A compound or a pharma- ceutically acceptable salt thereof, and an immune checkpoint inhibitor.

20. A compound of formula (I) for use in a method for preventing the recurrence of cancer in a subject in need thereof. 【Chemistry 3】 or a pharma- ceutically acceptable salt thereof, and an immune checkpoint inhibitor, During the ceremony, R is selected from the group consisting of hydrogen, phenylsulfanyl, 2-hydroxy-naphthalen-1-yl, quinolin-8-ylsulfanyl, triazol-3-ylsulfanyl, and benzothiazol-2-ylsulfanyl; R １ is selected from the group consisting of hydrogen, methyl, chloro, bromo, methoxy, ethoxy, tert-butyl, nitro, methyl ester, acetamide, 1,4 dioxin, fluoro, trifluoromethoxy, acetyl, trifluoromethyl, propyl, cyclohexene, methoxy-phenoxy, chlorophenoxy, tolyloxy, and phenoxy; The method comprises: a) orally administering to said subject an effective amount of said compound of formula (I) or a pharma- ceutically acceptable salt thereof; b) administering to the subject an effective amount of the immune checkpoint inhibitor. A compound or a pharma- ceutically acceptable salt thereof, and an immune checkpoint inhibitor.

21. 21. The compound of claim 19 or 20, or a pharma- ceutically acceptable salt thereof, and an immune checkpoint inhibitor, wherein the immune checkpoint inhibitor is administered parenterally to the subject.

22. A compound of formula (II) for use in the treatment of cancer in a subject in need thereof 【Chemistry 4】 or a pharma- ceutically acceptable salt thereof, and an immune checkpoint inhibitor, During the ceremony, R １ Each occurrence of is independently hydrogen, halogen, cyano, nitro, CF ３ , O.C.F. ３ , ORa, SRa, C(=O)Ra, OC(=O)Ra, C(=O)ORa, NRbRc, NRbC(=O)Rc, C(=O)NRbRc, NRbC(=O)ORc, OC(=O)NRbRc, NRaC(=O)NRbRc, alkyl, alkenyl, cycloalkyl, optionally substituted aryl, or optionally substituted heterocycle; n １ is 0, 1, 2, 3, or 4, R ２ Each occurrence of is independently hydrogen, halogen, cyano, nitro, CF ３ , O.C.F. ３ , ORa, SRa, C(=O)Ra, OC(=O)Ra, C(=O)ORa, NRbRc, NRbC(=O)Rc, C(=O)NRbRc, NRbC(=O)ORc, OC(=O)NRbRc, NRaC(=O)NRbRc, alkyl, alkenyl, cycloalkyl, cycloalkenyl, optionally substituted aryl, optionally substituted aryloxyl, or optionally substituted heterocycle; n ２ is 0, 1, 2, 3, 4, or 5, R ３ is hydrogen, halogen, cyano, nitro, CF ３ , O.C.F. ３ , ORa, SRa, OC(=O)R ａ , alkyl, alkenyl, cycloalkyl, or optionally substituted aryl or heteroaryl; R ４ is hydrogen, halogen, cyano, nitro, CF ３ , O.C.F. ３ , ORa, SRa, NRbRc, OC(=O)R ａ , alkyl, alkenyl, or cycloalkyl; R ５ , R ６ , and R ７ Each occurrence of is independently hydrogen, halogen, cyano, nitro, CF ３ , O.C.F. ３ , ORa, SRa, C(=O)Ra, OC(=O)Ra, C(=O)ORa, NRbRc, NRbC(=O)Rc, C(=O)NRbRc, NRbC(=O)ORc, OC(=O)NRbRc, NRaC(=O)NRbRc, alkyl, alkenyl, cycloalkyl, optionally substituted aryl, or optionally substituted heterocycle; n ３ is 0, 1, 2, 3, or 4, each occurrence of Ra, Rb, and Rc is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl, or Rb and Rc together with the nitrogen atom to which they are attached optionally form a heterocycle containing 1 to 4 heteroatoms; The treatment comprises: a) an effective amount of a compound of formula (II) or a pharma- ceutically acceptable salt thereof; and b) an effective amount of said immune checkpoint inhibitor. administering to said subject a compound or a pharma- ceutically acceptable salt thereof, and an immune checkpoint inhibitor.

23. 23. The compound of claim 22, or a pharma- ceutically acceptable salt thereof, wherein the compound of formula (II) inhibits signal transducer and activator of transcription 3 (STAT3), and an immune checkpoint inhibitor.

24. 23. The compound of claim 22, or a pharma- ceutically acceptable salt thereof, wherein the compound of formula (II) inhibits signal transducer and activator of transcription 1 (STAT1), and an immune checkpoint inhibitor.

25. 23. The compound of claim 22, or a pharma- ceutically acceptable salt thereof, wherein the compound of formula (II) inhibits signal transducer and activator of transcription 5 (STAT5), and an immune checkpoint inhibitor.

26. The compound of formula (II) is represented by formula (III) 【Chemistry 5】 or a pharma- ceutically acceptable salt thereof, and an immune checkpoint inhibitor.

27. The compound of formula (III) is a compound of formula (IV) 【Chemistry 6】 or a pharma- ceutically acceptable salt thereof, and an immune checkpoint inhibitor.

28. The compound or a pharma- ceutically acceptable salt thereof according to any one of claims 22 to 27, and an immune checkpoint inhibitor, wherein the immune checkpoint inhibitor is a PD-1 inhibitor or a PD-L1 inhibitor.

29. 29. The compound of claim 28, or a pharma- ceutically acceptable salt thereof, wherein the PD-1 inhibitor is an anti-PD-1 antibody, and an immune checkpoint inhibitor.

30. The anti-PD-1 antibody is selected from the group consisting of cemiplimab, nivolumab, pembrolizumab, pidilizumab, spartalizumab, camrelizumab, sintilimab, tislelizumab, toripalimab, dostallimab, sasanlimab, retifanlimab, tebotelimab, ABBV-181, AK104, AK105, BCD-100, BI-754091, CBT-501, and CC-9. 0006, GLS-010, HLX10, IBI-308, JNJ-3283, JS001, LZM009, MEDI0680 (AMP-514), REGN-2810, SHR-1210, Sym021, TSR-042, or XmAb20717, or a pharma- ceutically acceptable salt thereof, and an immune checkpoint inhibitor.

31. 31. The compound of claim 30, or a pharma- ceutically acceptable salt thereof, wherein the anti-PD-1 antibody is pembrolizumab, and an immune checkpoint inhibitor.

32. The compound or a pharma- ceutically acceptable salt thereof according to claim 28, wherein the PD-L1 inhibitor is an anti-PD-L1 antibody, and an immune checkpoint inhibitor.

33. The compound of claim 32 or a pharma- ceutically acceptable salt thereof, wherein the anti-PD-L1 antibody is atezolizumab, avelumab, durvalumab, embaforimab, FS118, BCD-135, BGB-A333, BGBA-317, CBT-502, CK-301, CS1001, FAZ053, MDX-1105, MSB2311, SHR-1316, M7824, LY3415244, CA-170, or CX-072, and an immune checkpoint inhibitor.

34. The compound of any one of claims 22 to 33, or a pharma- ceutically acceptable salt thereof, and an immune checkpoint inhibitor, wherein the immune checkpoint inhibitor is administered prior to administration of the compound of formula (II).

35. The compound of any one of claims 22 to 33, or a pharma- ceutically acceptable salt thereof, and an immune checkpoint inhibitor, wherein the immune checkpoint inhibitor is administered simultaneously with administration of the compound of formula (II).

36. The compound according to any one of claims 22 to 33, or a pharma- ceutically acceptable salt thereof, and an immune checkpoint inhibitor, wherein the immune checkpoint inhibitor is administered following administration of the compound of formula (II).

37. The compound of any one of claims 22 to 36, or a pharma- ceutically acceptable salt thereof, and an immune checkpoint inhibitor, wherein the compound of formula (II) is orally administered to the subject.

38. 2. A compound of formula (II) for use in a method for reducing the risk of cancer recurrence in a subject in need thereof 【Chemistry 7】 or a pharma- ceutically acceptable salt thereof, and an immune checkpoint inhibitor, During the ceremony, R １ Each occurrence of is independently hydrogen, halogen, cyano, nitro, CF ３ , O.C.F. ３ , ORa, SRa, C(=O)Ra, OC(=O)Ra, C(=O)OR ａ , NRbRc, NRbC(=O)Rc, C(=O)NRbRc, NRbC(=O)ORc, OC(=O)NRbRc, NRaC(=O)NRbRc, alkyl, alkenyl, cycloalkyl, optionally substituted aryl, or optionally substituted heterocycle; n １ is 0, 1, 2, 3, or 4, R ２ Each occurrence of is independently hydrogen, halogen, cyano, nitro, CF ３ , O.C.F. ３ , ORa, SRa, C(=O)Ra, OC(=O)Ra, C(=O)OR ａ , NRbRc, NRbC(=O)Rc, C(=O)NRbRc, NRbC(=O)ORc, OC(=O)NRbRc, NRAC(=O)NRbRc, alkyl, alkenyl, cycloalkyl, cycloalkenyl, optionally substituted aryl, optionally substituted aryloxyl, or optionally substituted heterocycle; n ２ is 0, 1, 2, 3, 4, or 5, R ３ is hydrogen, halogen, cyano, nitro, CF ３ , O.C.F. ３ , ORa, SRa, OC(=O)Ra, alkyl, alkenyl, cycloalkyl, or optionally substituted aryl or heteroaryl; R ４ is hydrogen, halogen, cyano, nitro, CF ３ , O.C.F. ３ , ORa, SRa, NRbRc, OC(=O)Ra, alkyl, alkenyl, or cycloalkyl; R ５ , R ６ , and R ７ Each occurrence of is independently hydrogen, halogen, cyano, nitro, CF ３ , O.C.F. ３ , ORa, SRa, C(=O)Ra, OC(=O)Ra, C(=O)ORa, NRbRc, NRbC(=O)Rc, C(=O)NRbRc, NRbC(=O)ORc, OC(=O)NRbRc, NRaC(=O)NRbRc, alkyl, alkenyl, cycloalkyl, optionally substituted aryl, or optionally substituted heterocycle; n ３ is 0, 1, 2, 3, or 4, each occurrence of Ra, Rb, and Rc is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl, or Rb and Rc together with the nitrogen atom to which they are attached optionally form a heterocycle containing 1 to 4 heteroatoms; The method comprises: a) an effective amount of a compound of formula (II) or a pharma- ceutically acceptable salt thereof; and b) an effective amount of said immune checkpoint inhibitor. or a pharma- ceutically acceptable salt thereof, and an immune checkpoint inhibitor, comprising the step of administering to said subject

39. 2. A compound of formula (II) for use in a method for preventing the recurrence of cancer in a subject in need thereof 【Chemistry 8】 or a pharma- ceutically acceptable salt thereof, and an immune checkpoint inhibitor, During the ceremony, R １ Each occurrence of is independently hydrogen, halogen, cyano, nitro, CF ３ , O.C.F. ３ , ORa, SRa, C(=O)Ra, OC(=O)Ra, C(=O)OR ａ , NRbRc, NRbC(=O)Rc, C(=O)NRbRc, NRbC(=O)ORc, OC(=O)NRbRc, NRaC(=O)NRbRc, alkyl, alkenyl, cycloalkyl, optionally substituted aryl, or optionally substituted heterocycle; n １ is 0, 1, 2, 3, or 4, R ２ Each occurrence of is independently hydrogen, halogen, cyano, nitro, CF ３ , O.C.F. ３ , ORa, SRa, C(=O)Ra, OC(=O)Ra, C(=O)OR ａ , NRbRc, NRbC(=O)Rc, C(=O)NRbRc, NRbC(=O)ORc, OC(=O)NRbRc, NRAC(=O)NRbRc, alkyl, alkenyl, cycloalkyl, cycloalkenyl, optionally substituted aryl, optionally substituted aryloxyl, or optionally substituted heterocycle; n ２ is 0, 1, 2, 3, 4, or 5, R ３ is hydrogen, halogen, cyano, nitro, CF ３ , O.C.F. ３ , ORa, SRa, OC(=O)Ra, alkyl, alkenyl, cycloalkyl, or optionally substituted aryl or heteroaryl; R ４ is hydrogen, halogen, cyano, nitro, CF ３ , O.C.F. ３ , ORa, SRa, NRbRc, OC(=O)Ra, alkyl, alkenyl, or cycloalkyl; R ５ , R ６ , and R ７ Each occurrence of is independently hydrogen, halogen, cyano, nitro, CF ３ , O.C.F. ３ , ORa, SRa, C(=O)Ra, OC(=O)Ra, C(=O)ORa, NRbRc, NRbC(=O)Rc, C(=O)NRbRc, NRbC(=O)ORc, OC(=O)NRbRc, NRaC(=O)NRbRc, alkyl, alkenyl, cycloalkyl, optionally substituted aryl, or optionally substituted heterocycle; n ３ is 0, 1, 2, 3, or 4, each occurrence of Ra, Rb, and Rc is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl, or Rb and Rc together with the nitrogen atom to which they are attached optionally form a heterocycle containing 1 to 4 heteroatoms; The method comprises: a) an effective amount of a compound of formula (II) or a pharma- ceutically acceptable salt thereof; and b) an effective amount of said immune checkpoint inhibitor. or a pharma- ceutically acceptable salt thereof, and an immune checkpoint inhibitor, comprising the step of administering to said subject

40. 40. The compound of any one of claims 1 to 39, or a pharma- ceutically acceptable salt thereof, and an immune checkpoint inhibitor, wherein the immune checkpoint inhibitor is administered parenterally.

41. The compound according to any one of claims 1 to 40, or a pharma- ceutically acceptable salt thereof, and an immune checkpoint inhibitor, wherein the cancer is head and neck cancer, lung cancer, liver cancer, breast cancer, ovarian cancer, colon cancer, multiple myeloma, prostate cancer, cervical cancer, brain cancer, pancreatic cancer, myelodysplastic syndrome, neuroblastoma, renal cancer, or metastatic melanoma.

42. 42. The compound of claim 41, or a pharma- ceutically acceptable salt thereof, and an immune checkpoint inhibitor, wherein the cancer is head and neck cancer, lung cancer, liver cancer, breast cancer, ovarian cancer, colon cancer, multiple myeloma, or pancreatic cancer.

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