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

Abstract

Provided herein are methods of treating cancer in a subject in need thereof, 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

[0001] Cross-references

[0002] This application claims the benefit of and priority to U.S. Provisional Patent Application No. 63 / 268,897, filed on March 4, 2022, the entire contents of which are incorporated herein by reference. Background Art

[0003] 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 co-opt certain immune checkpoint pathways as a mechanism of immune resistance, particularly T cells specific for tumor antigens. The development of checkpoint blocking antibodies that target or are directed against, for example, the programmed death 1 receptor (PD-1) may advance the treatment of cancer. Immunotherapies, such as anti-PD-1 antibody or anti-PD-L1 antibody therapy, have improved the treatment of cancer; however, there are still many patients who do not respond well to treatment or lose response to treatment over time. Therefore, there is a need to improve cancer treatment by combining different therapies. Summary of the invention

[0004] In certain embodiments, provided herein is a combination (e.g., a combination of a compound described herein such as a STAT3 inhibitor and an immune checkpoint inhibitor) that can be used, for example, in a method of treating cancer in a subject in need thereof.

[0005] In certain embodiments, provided herein are methods of treating cancer in a subject in need thereof, comprising a) orally administering to the subject an effective amount of a compound of formula (I):

[0006]

[0007] or a pharmaceutically 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; R 1Selected from the group consisting of hydrogen, methyl, chloro, bromo, methoxy, ethoxy, tert-butyl, nitro, methyl ester, acetamide, 1,4-dioxine, fluorine, trifluoromethoxy, acetyl, trifluoromethyl, propyl, cyclohexene, methoxy-phenoxy, chlorophenoxy, tolyloxy and phenoxy; and b) administering an effective amount of an immune checkpoint inhibitor to the subject. In some embodiments, the compound of formula (I) is N-(1',2-dihydroxy-1,2'-binaphthyl-4'-yl)-4-methoxybenzenesulfonamide, N-(3,1'-dihydroxy-[1,2']binaphthyl-4'-yl)-4-methoxybenzenesulfonamide, N-(4,1'-dihydroxy-[1,2']binaphthyl-4'-yl)-4-methoxybenzenesulfonamide, N-(5,1'-dihydroxy-[1,2']binaphthyl-4'-yl)-4-methoxybenzenesulfonamide, N-(6,1'-dihydroxy-[1,2']binaphthyl-4'-yl)-4-methoxybenzenesulfonamide, In some embodiments, the compound of formula (I) is N-(1',2-dihydroxy-1,2'-binaphthyl-4'-yl)-4-methoxybenzenesulfonamide, N-(7,1'-dihydroxy-[1,2']binaphthyl-4'-yl)-4-methoxybenzenesulfonamide, N-(8,1'-dihydroxy-[1,2']binaphthyl-4'-yl)-4-methoxybenzenesulfonamide, 4-bromo-N-(1,6'-dihydroxy-[2,2']binaphthyl-4-yl)-benzenesulfonamide or 4-bromo-N-[4-hydroxy-3-(1H-[1,2,4]triazol-3-ylsulfanyl)-naphthalene-1-yl]-benzenesulfonamide, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of formula (I) is N-(1',2-dihydroxy-1,2'-binaphthyl-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, dostarlimab, sarabinoside ... 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, envafolimab, 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 before the compound of formula (I). In some embodiments, the immune checkpoint inhibitor is administered simultaneously with the compound of formula (I). In some embodiments, the immune checkpoint inhibitor is administered after the compound of formula (I). In some embodiments, after three weeks or more of administration of a compound of formula (I) and an immune checkpoint inhibitor, the subject is at least partially relieved. In some embodiments, after six weeks or more of administration of a compound of formula (I) and an immune checkpoint inhibitor, the subject is completely relieved. In some embodiments, the methods described herein reduce tumor size by at least 20% within six weeks of administration, compared to subjects administered an immune checkpoint inhibitor alone.

[0008] In certain embodiments, further provided herein are methods of reducing the risk of cancer recurrence in a subject in need thereof, comprising a) orally administering to the subject an effective amount of a compound of formula (I):

[0009]

[0010] or a pharmaceutically 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; R 1Selected from the group consisting of hydrogen, methyl, chloro, bromo, methoxy, ethoxy, tert-butyl, nitro, methyl ester, acetamide, 1,4-dioxine, fluorine, trifluoromethoxy, acetyl, trifluoromethyl, propyl, cyclohexene, methoxy-phenoxy, chlorophenoxy, tolyloxy and phenoxy; and b) administering an effective amount of an immune checkpoint inhibitor to the subject. In some embodiments, the compound of formula (I) is N-(1',2-dihydroxy-1,2'-binaphthyl-4'-yl)-4-methoxybenzenesulfonamide, N-(3,1'-dihydroxy-[1,2']binaphthyl-4'-yl)-4-methoxybenzenesulfonamide, N-(4,1'-dihydroxy-[1,2']binaphthyl-4'-yl)-4-methoxybenzenesulfonamide, N-(5,1'-dihydroxy-[1,2']binaphthyl-4'-yl)-4-methoxybenzenesulfonamide, N-(6,1'-dihydroxy-[1,2']binaphthyl-4'-yl)-4-methoxybenzenesulfonamide, In some embodiments, the compound of formula (I) is N-(1',2-dihydroxy-1,2'-binaphthyl-4'-yl)-4-methoxybenzenesulfonamide, N-(7,1'-dihydroxy-[1,2']binaphthyl-4'-yl)-4-methoxybenzenesulfonamide, N-(8,1'-dihydroxy-[1,2']binaphthyl-4'-yl)-4-methoxybenzenesulfonamide, 4-bromo-N-(1,6'-dihydroxy-[2,2']binaphthyl-4-yl)-benzenesulfonamide or 4-bromo-N-[4-hydroxy-3-(1H-[1,2,4]triazol-3-ylsulfanyl)-naphthalene-1-yl]-benzenesulfonamide, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of formula (I) is N-(1',2-dihydroxy-1,2'-binaphthyl-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 cemiprilimab, nivolumab, pembrolizumab, pidilizumab, spartalizumab, carrelizumab, sintilimab, tislelizumab, toripalimab, dotalimumab, sazanlimab, riflimab, tepolizumab, ABBV-181, AK104, AK105, BCD-100, BI-754091, CBT-501, CC-90006, GLS-010, HLX10, IBI-308, JNJ-3283, JS001, LZM009, MEDI0680 (AMP-514), REGEN-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, envoli monoclonal antibody, 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 before the compound of formula (I). In some embodiments, the immune checkpoint inhibitor is administered simultaneously with the compound of formula (I). In some embodiments, the immune checkpoint inhibitor is administered after the compound of formula (I).

[0011] In certain embodiments, provided herein is a method for preventing cancer recurrence in a subject in need thereof, comprising a) orally administering to the subject an effective amount of a compound of formula (I):

[0012]

[0013] or a pharmaceutically 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; R 1Selected from the group consisting of hydrogen, methyl, chloro, bromo, methoxy, ethoxy, tert-butyl, nitro, methyl ester, acetamide, 1,4-dioxine, fluorine, trifluoromethoxy, acetyl, trifluoromethyl, propyl, cyclohexene, methoxy-phenoxy, chlorophenoxy, tolyloxy and phenoxy; and b) administering an effective amount of an immune checkpoint inhibitor to the subject. In some embodiments, the compound of formula (I) is N-(1',2-dihydroxy-1,2'-binaphthyl-4'-yl)-4-methoxybenzenesulfonamide, N-(3,1'-dihydroxy-[1,2']binaphthyl-4'-yl)-4-methoxybenzenesulfonamide, N-(4,1'-dihydroxy-[1,2']binaphthyl-4'-yl)-4-methoxybenzenesulfonamide, N-(5,1'-dihydroxy-[1,2']binaphthyl-4'-yl)-4-methoxybenzenesulfonamide, N-(6,1'-dihydroxy-[1,2']binaphthyl-4'-yl)-4-methoxybenzenesulfonamide, In some embodiments, the compound of formula (I) is N-(1',2-dihydroxy-1,2'-binaphthyl-4'-yl)-4-methoxybenzenesulfonamide, N-(7,1'-dihydroxy-[1,2']binaphthyl-4'-yl)-4-methoxybenzenesulfonamide, N-(8,1'-dihydroxy-[1,2']binaphthyl-4'-yl)-4-methoxybenzenesulfonamide, 4-bromo-N-(1,6'-dihydroxy-[2,2']binaphthyl-4-yl)-benzenesulfonamide or 4-bromo-N-[4-hydroxy-3-(1H-[1,2,4]triazol-3-ylsulfanyl)-naphthalene-1-yl]-benzenesulfonamide, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of formula (I) is N-(1',2-dihydroxy-1,2'-binaphthyl-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 cemiprilimab, nivolumab, pembrolizumab, pidilizumab, spartalizumab, carrelizumab, sintilimab, tislelizumab, toripalimab, dotalimumab, sazanlimab, riflimab, tepolizumab, ABBV-181, AK104, AK105, BCD-100, BI-754091, CBT-501, CC-90006, GLS-010, HLX10, IBI-308, JNJ-3283, JS001, LZM009, MEDI0680 (AMP-514), REGEN-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, envoli monoclonal antibody, 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 before the compound of formula (I). In some embodiments, the immune checkpoint inhibitor is administered simultaneously with the compound of formula (I). In some embodiments, the immune checkpoint inhibitor is administered after the compound of formula (I).

[0014] In certain embodiments, provided herein are methods of treating cancer in a subject in need thereof, the method comprising administering to the subject a) an effective amount of a compound of formula (II):

[0015]

[0016] or a pharmaceutically 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 cemiprilimab, nivolumab, pembrolizumab, pidilizumab, spartalizumab, carrelizumab, sintilimab, tislelizumab, toripalimab, dotalimumab, sazanlimab, riflimab, tepolizumab, ABBV-181, AK104, AK105, BCD-100, BI-754091, CBT-501, CC-90006, GLS-010, HLX10, IBI-308, JNJ-3283, JS001, LZM009, MEDI0680 (AMP-514), REGEN-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, envoli monoclonal antibody, 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 applied before the compound of formula (II). In some embodiments, the immune checkpoint inhibitor is applied simultaneously with the compound of formula (II). In some embodiments, the immune checkpoint inhibitor is applied after the compound of formula (II) is applied.

[0017] In certain embodiments, provided herein are methods for reducing the risk of cancer recurrence in a subject in need thereof, comprising administering to the subject a) an effective amount of a compound of formula (II):

[0018]

[0019] or a pharmaceutically 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 cemiprilimab, nivolumab, pembrolizumab, pidilizumab, spartalizumab, carrelizumab, sintilimab, tislelizumab, toripalimab, dotalimumab, sazanlimab, riflimab, tepolizumab, ABBV-181, AK104, AK105, BCD-100, BI-754091, CBT-501, CC-90006, GLS-010, HLX10, IBI-308, JNJ-3283, JS001, LZM009, MEDI0680 (AMP-514), REGEN-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, envoli monoclonal antibody, 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 applied before the compound of formula (II). In some embodiments, the immune checkpoint inhibitor is applied simultaneously with the compound of formula (II). In some embodiments, the immune checkpoint inhibitor is applied after the compound of formula (II) is applied.

[0020] In certain embodiments, provided herein is a method for preventing cancer recurrence in a subject in need thereof, comprising administering to the subject a) an effective amount of a compound of formula (II):

[0021]

[0022] or a pharmaceutically 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 cemiprilimab, nivolumab, pembrolizumab, pidilizumab, spartalizumab, carrelizumab, sintilimab, tislelizumab, toripalimab, dotalimumab, sazanlimab, riflimab, tepolizumab, ABBV-181, AK104, AK105, BCD-100, BI-754091, CBT-501, CC-90006, GLS-010, HLX10, IBI-308, JNJ-3283, JS001, LZM009, MEDI0680 (AMP-514), REGEN-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, envoli monoclonal antibody, 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 applied before the compound of formula (II). In some embodiments, the immune checkpoint inhibitor is applied simultaneously with the compound of formula (II). In some embodiments, the immune checkpoint inhibitor is applied after the compound of formula (II) is applied.

[0023] Other objects and advantages will become apparent to those skilled in the art from consideration of the ensuing detailed description, examples, and claims. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] The various features of the present disclosure are specifically described in the appended claims. The features and advantages of the present disclosure can be better understood by referring to the following detailed description and drawings of illustrative embodiments, which illustrate the principles of the present disclosure:

[0025] Figure 1In vivo efficacy results of TTI-101±anti-PD-1 antibody administered for 21 days in a syngeneic H22 liver cancer model are shown.

[0026] Figure 2 In vivo efficacy results of TTI-101±anti-PD-1 antibody administered for 47 days in a syngeneic H22 liver cancer model are shown.

[0027] Figure 3 Shown are the results of a tumor rechallenge study of H22 hepatoma cells following treatment with a combination of TTI-101 and anti-PD-1 antibodies.

[0028] Figure 4 The PK properties of TTI-101 after oral administration to SD rats are shown.

[0029] Figure 5 Shown are the percent changes in tumor volume following oral (PO) versus intraperitoneal (IP) administration of TTI-101 in the mouse H22 liver cancer model. DETAILED DESCRIPTION

[0030] As described herein, the present disclosure provides a method of treating cancer or preventing cancer recurrence in a subject in need thereof, 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.

[0031] The combinations provided herein, such as oral administration of STAT inhibitors and parenteral administration of immune checkpoint inhibitors, show significant anti-tumor efficacy, and in some embodiments, can lead to complete regression of tumors compared to monotherapy with the same duration and / or dosage alone. Therefore, the combinations provided herein provide an opportunity to improve the overall survival rate of patients, reduce the risk of drug resistance to monotherapy, and inhibit adverse side effects such as those caused by long-term administration of monotherapy. In addition, in some embodiments, the combinations provided herein unexpectedly prevent tumor re-excitation (rechallenge), thereby providing an opportunity to prevent or reduce the risk of cancer recurrence.

[0032] In some embodiments, the methods described herein include oral administration of a STAT3 inhibitor. Compared to intraperitoneal injection of a STAT3 inhibitor, in some embodiments, oral administration of a STAT3 inhibitor as disclosed herein significantly increases the exposure of the STAT3 inhibitor. Therefore, in some embodiments, the methods described herein employ oral administration of a STAT3 inhibitor with significant advantages over methods employing intraperitoneal injection of a STAT3 inhibitor.

[0033] definition

[0034] As used herein, the specification "a" or "an" may mean one or more. As used herein, when used in conjunction with the word "comprising / including", the word "a" or "an" may mean one or more. As used herein, "another" may refer to at least a second or more. In addition, the terms "having", "including", "comprising" and "consisting of..." are interchangeable, and those skilled in the art know that these terms are open terms. Some embodiments of the present disclosure may include or substantially include 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 relative to any other method, compound or composition described herein.

[0035] "About" and "approximately" generally mean the permissible degree of error of a measured quantity given the nature or precision of the measurement. Exemplary degrees of error are within 20%, typically within 10%, and more typically within 5% of a given value or range of values.

[0036] As used herein, "pharmaceutically acceptable salts" refer to salts that are suitable for contact with tissues of humans and lower animals without excessive toxicity, irritation, allergic reactions, etc., and are commensurate with a reasonable benefit / risk ratio, within the scope of reasonable medical judgment. 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 disclosed herein include salts derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts formed by amino groups 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 (e.g., ion exchange). Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cypionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, sulfate), malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. Pharmaceutically acceptable salts derived from appropriate bases include alkali metal salts, alkaline earth metal salts, ammonium and N- + (C 1-4 Representative alkali metal salts or alkaline earth metal salts include sodium salts, lithium salts, potassium salts, calcium salts, magnesium salts, etc. Other pharmaceutically acceptable salts include non-toxic ammonium salts, quaternary ammonium salts, and amine cations formed with counter ions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates, where appropriate.

[0037] As used herein, "pharmaceutically acceptable carrier" refers to a non-toxic carrier, adjuvant or vehicle that does not destroy the pharmacological activity of the compound in which it is formulated. Pharmaceutically acceptable carriers, adjuvants or vehicles that can be used in the compositions described herein include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (such as human serum albumin), buffer substances (such as phosphates, glycine, sorbic acid, potassium sorbate), partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silicon dioxide, magnesium trisilicate, polyvinyl pyrrolidone, cellulosic substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and lanolin.

[0038] As used herein, it is contemplated that "subjects" administered include, but are not limited to, people, i.e., males or females of any age group, for example, pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged people or the elderly) and / or non-human animals, for example, mammals, such as primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents, cats and / or dogs. In some embodiments, the subject is a person. In some embodiments, the subject is a non-human animal. The terms "people," "patient," "subject," and "individual" are used interchangeably herein. None of these terms require active supervision by medical personnel.

[0039] Disease, disorder and condition are used interchangeably herein.

[0040] As used herein, and unless otherwise indicated, the terms "treat," "treating," and "treatment" refer to an action that occurs in a subject suffering from a particular disease, disorder, or condition that reduces the severity of the disease, disorder, or condition, or reverses or slows the progression of the disease, disorder, or condition (also referred to as "therapeutic treatment").

[0041] In general, the "effective amount" of a compound refers to an amount sufficient to cause a desired biological response. As will be appreciated by those of ordinary skill in the art, the effective amount of the compounds of the present disclosure may vary according to factors such as the expected 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. The "therapeutically effective amount" of a compound refers to an amount sufficient to provide a therapeutic benefit (e.g., to treat, prevent and / or improve cancer in a subject with a reasonable benefit / risk ratio applicable to any medical treatment, or to inhibit protein-protein interactions mediated by SH2 domains in a subject), or to delay or alleviate one or more symptoms associated with a disease, disorder or condition. The therapeutically effective amount of a compound refers to the amount of a therapeutic agent, used alone or in combination with other therapies, which provides a therapeutic benefit when treating a disease, disorder or condition. The term "therapeutically effective amount" may encompass an amount that improves the overall therapeutic effect, alleviates or avoids the symptoms or causes of a disease or condition, or enhances the efficacy of another therapeutic agent. A "prophylactically effective amount" of a compound is an amount sufficient to prevent a disease, disorder, or condition, or to prevent one or more symptoms associated with a disease, disorder, or condition, or to prevent its recurrence. A prophylactically effective amount of a compound refers to an amount of a therapeutic agent that has a prophylactic benefit in preventing a disease, disorder, or condition when used alone or in combination with other agents. The term "prophylactically effective amount" may include an amount that improves the overall prophylactic effect or enhances the prophylactic efficacy of another prophylactic agent. "Prophylactic treatment" contemplates treatment performed before a subject begins to suffer from a particular disease, disorder, or condition.

[0042] As used herein, the term "inhibitor", for example with respect to a STAT3 inhibitor, refers to one or more molecules that at least partially interfere with the activity of Stat3 in exerting one or more activities, including the ability of Stat3 to bind to and / or phosphorylate a molecule.

[0043] The following are definitions of terms used in this specification. Unless otherwise specified, the initial definitions provided herein for a group or term apply to that group or term used alone or as part of another group throughout the specification. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art.

[0044] The term "alkyl" refers to a straight or branched alkane (hydrocarbon) free radical containing 1 to 12 carbon atoms, preferably 1 to 6 carbon atoms. Exemplary "alkyl" includes methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl, etc. The term "(C1-C4) alkyl" refers to a straight or branched alkane (hydrocarbon) free radical containing 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl and isobutyl. "Substituted alkyl" refers to an alkyl group substituted by 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: hydrogen, halogen (e.g., monohalogen substituents or polyhalogen substituents, in the latter case forming an alkyl group such as CF3 or with 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)2Oe, P(=O)2Oe, 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)Re, NRdC(=O)NRbRc, NRdS(=O)2NRbRc, NRdP(=O)2NRbRc, NRbC(=O)Ra or NRbP(=O)2Re, wherein Ra is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle or aryl at each occurrence; Rb, Rc and Rd are independently hydrogen, alkyl, cycloalkyl, heterocycle, aryl at each occurrence, or said Rb and Rc together with the N to which they are bound optionally form a heterocycle; and Re is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle or aryl at each occurrence. In the above exemplary substituents, groups such as alkyl, cycloalkyl, alkenyl, alkynyl, cycloalkenyl, heterocycle and aryl can themselves be optionally substituted.

[0045] The term "alkenyl" refers to a straight or branched hydrocarbon radical containing 2 to 12 carbon atoms and at least one carbon-carbon double bond. Exemplary such groups include vinyl or allyl. The term "C2-C6 alkenyl" refers to a straight or branched hydrocarbon radical containing 2 to 6 carbon atoms and at least one carbon-carbon double bond, such as ethenyl, propenyl, 2-propenyl, (E)-but-2-enyl, (Z)-but-2-enyl, 2-methyl (E)-but-2-enyl, 2-methyl (Z)-but-2-enyl, 2,3-dimethyl-but-2-enyl, (Z)-pent-2-enyl, (E)-pent-1-enyl, (Z)-hex-1-enyl, (E)-pent-2-enyl, (Z)-hex-2-enyl, (E)-hex-2-enyl, (Z)-hex-1-enyl, (E)-hex-1-enyl, (Z)-hex-3-enyl, (E)-hex-3-enyl and (E)-hex-1,3-dienyl. "Substituted alkenyl" refers to an alkenyl 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., monohalogen substituents or polyhalogen substituents, in the latter case forming an alkyl group such as CF3 or with 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)2Oe, P(=O)2Oe, 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)Re, NRdC(=O)NRbRc, NRdS(=O)2NRbRc, NRdP(=O)2NRbRc, NRbC(=O)Ra or NRbP(=O)2Re, wherein Ra is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle or aryl at each occurrence; Rb, Rc and Rd are independently hydrogen, alkyl, cycloalkyl, heterocycle, aryl at each occurrence, or said Rb and Rc, together with the N to which they are bound, optionally form a heterocycle; and Re is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle or aryl at each occurrence. Exemplary substituents themselves may be optionally substituted.

[0046] The term "alkynyl" refers to a straight or branched hydrocarbon radical containing 2 to 12 carbon atoms and at least one carbon-carbon triple bond. Exemplary such groups include ethynyl. The term "C2-C6 alkynyl" refers to a straight or branched hydrocarbon radical containing 2 to 6 carbon atoms and at least one carbon-carbon triple bond, such as ethynyl, 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 by 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: hydrogen, halogen (e.g., monohalogen substituents or polyhalogen substituents, in the latter case forming an alkyl group such as CF3 or with 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)2Oe, P(=O)2Oe, 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)Re, NRdC(=O)NRbRc, NRdS(=O)2NRbRc, NRdP(=O)2NRbRc, NRbC(=O)Ra or NRbP(=O)2Re, wherein Ra is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle or aryl at each occurrence; Rb, Rc and Rd are independently hydrogen, alkyl, cycloalkyl, heterocycle, aryl at each occurrence, or said Rb and Rc, together with the N to which they are bound, optionally form a heterocycle; and Re is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle or aryl at each occurrence. Exemplary substituents themselves may be optionally substituted.

[0047] 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 by 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: hydrogen, halogen (e.g., monohalogen substituents or polyhalogen substituents, in the latter case forming an alkyl group such as CF3 or with 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)2Oe, P(=O)2Oe, 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)Re, NRdC(=O)NRbRc, NRdS(=O)2NRbRc, NRdP(=O)2NRbRc, NRbC(=O)Ra or NRbP(=O)2Re, wherein Ra is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle or aryl at each occurrence; Rb, Rc and Rd are independently hydrogen, alkyl, cycloalkyl, heterocycle, aryl at each occurrence, or said Rb and Rc, together with the N to which they are bound, optionally form a heterocycle; and Re is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle or aryl at each occurrence. Exemplary substituents themselves may be optionally substituted. Exemplary substituents also include spiro or fused cyclic substituents, in particular spiro cycloalkyl, spiro cycloalkenyl, spiro heterocycle (excluding heteroaryl), fused cycloalkyl, fused cycloalkenyl, fused heterocycle or fused aryl, wherein the above cycloalkyl, cycloalkenyl, heterocycle and aryl substituents themselves may be optionally substituted.

[0048] The term "cycloalkenyl" refers to a partially unsaturated cyclic hydrocarbon group containing 1 to 4 rings and each ring containing 3 to 8 carbons. Exemplary such groups include cyclobutenyl, cyclopentenyl, cyclohexenyl, etc. "Substituted cycloalkenyl" refers to a cycloalkenyl group substituted by 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: hydrogen, halogen (e.g., monohalogen substituents or polyhalogen substituents, in the latter case forming an alkyl group such as CF3 or with 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)2Oe, P(=O)2Oe, 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)Re, NRdC(=O)NRbRc, NRdS(=O)2NRbRc, NRdP(=O)2NRbRc, NRbC(=O)Ra or NRbP(=O)2Re, wherein Ra is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle or aryl at each occurrence; Rb, Rc and Rd are independently hydrogen, alkyl, cycloalkyl, heterocycle, aryl at each occurrence, or said Rb and Rc, together with the N to which they are bound, optionally form a heterocycle; and Re is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle or aryl at each occurrence. Exemplary substituents themselves may be optionally substituted. Exemplary substituents also include spiro or fused cyclic substituents, in particular spiro cycloalkyl, spiro cycloalkenyl, spiro heterocycle (excluding heteroaryl), fused cycloalkyl, fused cycloalkenyl, fused heterocycle or fused aryl, wherein the above cycloalkyl, cycloalkenyl, heterocycle and aryl substituents themselves may be optionally substituted.

[0049] The term "aryl" refers to a cyclic aromatic hydrocarbon group having 1 to 5 aromatic rings (particularly monocyclic or bicyclic groups, such as phenyl, biphenyl or naphthyl). In the case of containing two or more aromatic rings (bicyclic, etc.), the aromatic rings of the aryl can be connected at a single point (such as biphenyl) or fused (such as naphthyl, phenanthrenyl, etc.). "Substituted aryl" refers to an aryl group substituted by one or more substituents (preferably 1 to 3 substituents) at any available point of attachment. Exemplary substituents include, but are not limited to, one or more of the following: hydrogen, halogen (e.g., monohalogen substituents or polyhalogen substituents, in the latter case forming an alkyl group such as CF3 or with 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)2Oe, P(=O)2Oe, 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)Re, NRdC(=O)NRbRc, NRdS(=O)2NRbRc, NRdP(=O)2NRbRc, NRbC(=O)Ra or NRbP(=O)2Re, wherein Ra is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle or aryl at each occurrence; Rb, Rc and Rd are independently hydrogen, alkyl, cycloalkyl, heterocycle, aryl at each occurrence, or said Rb and Rc, together with the N to which they are bound, optionally form a heterocycle; and Re is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle or aryl at each occurrence. Exemplary substituents themselves may be optionally substituted. Exemplary substituents also include fused cyclic groups, in particular fused cycloalkyl, fused cycloalkenyl, fused heterocycle or fused aryl, wherein the above-mentioned cycloalkyl, cycloalkenyl, heterocycle and aryl substituents themselves may be optionally substituted.

[0050] The term "carbocycle" refers to a fully saturated or partially saturated cyclic hydrocarbon group containing 1 to 4 rings and each ring containing 3 to 8 carbons, or a cyclic aromatic hydrocarbon group with 1 to 5 aromatic rings (particularly monocyclic or bicyclic groups, such as phenyl, biphenyl or naphthyl). The term "carbocycle" encompasses cycloalkyl, cycloalkenyl, cycloalkynyl and aryl as defined above. The term "substituted carbocycle" refers to a carbocycle or carbocyclic group substituted by one or more substituents (preferably 1 to 4 substituents) at any available point of attachment. Exemplary substituents include but are not limited to the substituents described by the above substituted cycloalkyl, substituted cycloalkenyl, substituted cycloalkynyl and substituted aryl. Exemplary substituents also include spiro or fused cyclic substituents at any available point of attachment or multiple points of attachment, in particular spiro cycloalkyl, spiro cycloalkenyl, spiro heterocycle (excluding heteroaryl), fused cycloalkyl, fused cycloalkenyl, fused heterocycle or fused aryl, wherein the above cycloalkyl, cycloalkenyl, heterocycle and aryl substituents themselves may be optionally substituted.

[0051] The terms "heterocycle" and "heterocyclic" refer to fully saturated, partially unsaturated, or fully unsaturated, including aromatic (e.g., "heteroaryl"), cyclic groups (e.g., 4- to 7-membered monocyclic, 7- to 11-membered bicyclic, or 8- to 16-membered tricyclic ring systems) having at least one heteroatom in at least one carbon-containing ring. Each heteroatom-containing ring of the heterocyclic group may have 1, 2, 3, or 4 heteroatoms selected from nitrogen atoms, oxygen atoms, and / or sulfur atoms, wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized. (The term "heteroarylium" refers to a heteroaryl group with a tetravalent nitrogen atom and thus a positive charge). The heterocyclic group may be attached to the rest 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, furanyl, tetrahydrofuranyl, thienyl, oxadiazolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepinetrienyl, azepinetrienyl, hexahydrodiazepinetrienyl, 4-piperidonyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazine, triazine, tetrazolyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, 1,3-dioxolane and tetrahydro-1,1-dioxothienyl, etc. Exemplary bicyclic heterocyclic groups include indolyl, isoindolyl, benzothiazolyl, benzoxazolyl, benzoxadiazolyl, benzothienyl, benzo[d][1,3]dioxolyl, 2,3-dihydrobenzo[b][1,4]dioxinyl, quinuclidinyl, quinolyl, tetrahydroisoquinolyl, isoquinolyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuranyl, benzofurazanyl, chromonyl, coumarin ... The invention also includes pyranyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridinyl, furopyridinyl (e.g., furano[2,3-c]pyridinyl, furano[3,2-b]pyridinyl] or furano[2,3-b]pyridinyl), dihydroisoindolyl, dihydroquinazolinyl (e.g., 3,4-dihydro-4-oxoquinazolinyl), triazinylazepinyl, tetrahydroquinolinyl, etc. Exemplary tricyclic heterocyclic groups include carbazolyl, benzidolyl, phenanthrolinyl, acridinyl, phenanthridinyl, xanthenyl, etc.

[0052] "Substituted heterocycle" (e.g., "substituted heteroaryl") refers to a heterocycle or heterocyclic 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., monohalogen substituents or polyhalogen substituents, in the latter case forming an alkyl group such as CF3 or with 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)2Oe, P(=O)2Oe, 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)Re, NRdC(=O)NRbRc, NRdS(=O)2NRbRc, NRdP(=O)2NRbRc, NRbC(=O)Ra or NRbP(=O)2Re, wherein Ra is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle or aryl at each occurrence; Rb, Rc and Rd are independently hydrogen, alkyl, cycloalkyl, heterocycle, aryl at each occurrence, or said Rb and Rc and the N to which they are optionally bonded together form a heterocycle; and Re is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle or aryl at each occurrence. Exemplary substituents themselves may be optionally substituted. Exemplary substituents also include spiro or fused cyclic substituents at any available point of attachment or multiple points of attachment, in particular spiro cycloalkyl, spiro cycloalkenyl, spiro heterocycle (excluding heteroaryl), fused cycloalkyl, fused cycloalkenyl, fused heterocycle or fused aryl, wherein the above cycloalkyl, cycloalkenyl, heterocycle and aryl substituents themselves may be optionally substituted.

[0053] The term "alkylamino" refers to a group having the structure -NHR', wherein R' is hydrogen, an alkyl or substituted alkyl as defined herein, or a cycloalkyl or substituted cycloalkyl. Examples of alkylamino include, but are not limited to, methylamino, ethylamino, n-propylamino, isopropylamino, cyclopropylamino, n-butylamino, tert-butylamino, neopentylamino, n-pentylamino, hexylamino, cyclohexylamino, and the like.

[0054] The term "dialkylamino" refers to a group having the structure -NRR', wherein R and R' are each independently alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, or heterocyclic or substituted heterocyclic as defined herein. R and R' can be the same or different in the dialkylamino moiety. Examples of dialkylamino include but are not limited to dimethylamino, methylethylamino, diethylamino, methylpropylamino, di(n-propyl)amino, di(isopropyl)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, etc. In some embodiments, R and R' are connected to form a ring structure. The resulting ring structure can 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-triazolyl, and tetrazolyl.

[0055] The term "halogen" or "halo" refers to chlorine, bromine, fluorine or iodine.

[0056] Unless otherwise stated, any heteroatom with unsatisfied valences is assumed to have sufficient hydrogen atoms to satisfy the valences.

[0057] The compounds of the present disclosure and their salts or solvates may exist in their tautomeric forms (e.g., as amides or imino ethers). All such tautomeric forms are also contemplated as part of the present disclosure.

[0058] All stereoisomers of the compounds of the present invention (e.g., stereoisomers that may exist due to asymmetric carbons on various substituents), including enantiomeric and diastereomeric forms, are contemplated within the scope of the present disclosure. Each stereoisomer 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 specific activity), or may be mixed, for example, as a racemate or mixed with all other or selected other stereoisomers. The chiral center of the present disclosure may have an S configuration or an R configuration as defined by the International Union of Pure and Applied Chemistry (IUPAC) in 1974. The racemic form may be separated by physical methods, such as fractional crystallization, separation or crystallization of diastereomeric derivatives, or separation by chiral column chromatography. Individual optical isomers may be obtained from the racemate by any suitable method, including but not limited to conventional methods, such as forming a salt with an optically active acid and then crystallizing.

[0059] The compounds of the present disclosure are preferably isolated and purified after their preparation to obtain a composition containing an amount of the compound equal to or greater than 90%, such as equal to or greater than 95%, equal to or greater than 99% by weight ("substantially pure" compound), and then used or formulated as described herein. Such "substantially pure" compounds of the present disclosure are also contemplated as part of the present disclosure.

[0060] All configurational isomers of the compounds of the present disclosure are contemplated in mixture or in pure or substantially pure form.The definition of the compounds of the present disclosure encompasses both cis (Z) and trans (E) olefin isomers, as well as cis and trans isomeric forms of cyclic hydrocarbons or heterocycles.

[0061] The definition of specific functional groups and chemical terms is described in more detail below. For the purpose of this disclosure, chemical elements are according to the periodic table, CAS version, Handbook of Chemistry and Physics, 75th edition, inner cover, and specific functional groups are generally defined as described herein. In addition, the general principles of organic chemistry and specific functional parts and reactivity are described in Organic Chemistry, Thomas Sorrell, University Science Books, Sausalito (1999), the entire contents of which are incorporated herein by reference.

[0062] Certain compounds of the present disclosure may exist in specific geometric or stereoisomeric forms. The present disclosure contemplates all such compounds including cis- and trans-isomers, R- and S-enantiomers, diastereomers, (D)-isomers, (L)-isomers, their racemic mixtures and other mixtures thereof, all falling within the scope of the present disclosure. Additional asymmetric carbon atoms may be present in a substituent such as an alkyl. All of these isomers and mixtures thereof are intended to be included in the present disclosure.

[0063] According to the present disclosure, isomeric mixtures containing any of a variety of different isomeric ratios may be used. For example, in the case of combining only two isomers, the present disclosure contemplates 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. One of ordinary skill in the art will readily appreciate that similar ratios may be contemplated for more complex isomeric mixtures.

[0064] The present disclosure also includes isotopically labeled compounds which are identical to the compounds disclosed herein except for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number 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, e.g. 2 H. 3 H. 13 C. 11 C. 14 C. 15 N. 18 O. 17 O. 31 P. 32 P. 35 S. 18 F and 36 Cl. Compounds of the present disclosure or enantiomers, diastereomers, tautomers, or pharmaceutically acceptable salts or solvates thereof containing the aforementioned isotopes and / or other isotopes of other atoms are within the scope of the present disclosure. Certain isotopically labeled compounds of the present disclosure, for example, those incorporating radioactive isotopes such as 3 H and 14 C, can be used for tissue distribution determination of drugs and / or substances. 3 H and carbon-14 14 C are particularly preferred because they are easy to prepare and detect. In addition, heavier isotopes such as deuterium (i.e. 2 H) substitution may provide certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and therefore may be preferred in some cases. Isotopically labeled compounds can generally be prepared by performing the procedures disclosed in the following schemes and / or examples by substituting readily available isotopically labeled reagents for non-isotopically labeled reagents.

[0065] If, for example, a specific enantiomer of a compound of the present disclosure is desired, it can be prepared by asymmetric synthesis or by derivatization with a chiral auxiliary reagent, wherein separation affords a diastereomeric mixture, followed by cleavage of the auxiliary group to provide the pure desired enantiomer. Alternatively, if the molecule contains a basic functional group (e.g., amino) or an acidic functional group (e.g., carboxyl), diastereomeric salts can be formed with an appropriate optically active acid or base, followed by separation of the diastereomers thus formed by fractional crystallization or chromatography means well known in the art, followed by recovery of the pure enantiomer.

[0066] It should be understood that compounds as described herein can be substituted by any number of substituents or functional groups (functional moiety). In general, the term "substituted" (whether or not there is the term "optionally / optionally" in front) and the substituents contained in the chemical formula of the present disclosure refer to the substitution of the hydrogen radical in a given structure by the group of the specified substituent. When more than one position in any given structure can be substituted by more than one substituent selected from a specified group, the substituent at each position can be the same or different. When used in this article, the term "substituted" is considered to include all allowed substituents of organic compounds. In a broad sense, allowed substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. For the purpose of the present disclosure, heteroatoms such as nitrogen may have hydrogen substituents and / or any allowable substituents of organic compounds described herein that satisfy the valence of heteroatoms. In addition, the present disclosure is not intended to be limited in any way to the substituents allowed by organic compounds. The combination of substituents and variables envisioned by the present disclosure is preferably a combination of stable compounds that can be used to treat, for example, infectious diseases or proliferative disorders. As used herein, the term "stable" preferably refers to a compound having stability sufficient to allow manufacture and the integrity of the compound is maintained for a period of time sufficient to be detected, and preferably for a period of time sufficient to be useful for the purposes detailed herein.

[0067] Treatment

[0068] In certain embodiments, disclosed herein are methods of treating cancer in a subject in need thereof, comprising a) orally administering to the subject an effective amount of a compound of formula (I):

[0069]

[0070] or a pharmaceutically 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; R 1 Selected from the group consisting of hydrogen, methyl, chloro, bromo, methoxy, ethoxy, tert-butyl, nitro, methyl ester, acetamide, 1,4-dioxine, fluorine, trifluoromethoxy, acetyl, trifluoromethyl, propyl, cyclohexene, methoxy-phenoxy, chlorophenoxy, tolyloxy and phenoxy; and b) administering an effective amount of an immune checkpoint inhibitor to the subject.

[0071] In some embodiments, the compound of formula (I) is N-(1',2-dihydroxy-1,2'-binaphthyl-4'-yl)-4-methoxybenzenesulfonamide, N-(3,1'-dihydroxy-[1,2']binaphthyl-4'-yl)-4-methoxybenzenesulfonamide, N-(4,1'-dihydroxy-[1,2']binaphthyl-4'-yl)-4-methoxybenzenesulfonamide, N-(5,1'-dihydroxy-[1,2']binaphthyl-4'-yl)-4-methoxybenzenesulfonamide, N-(6,1'-dihydroxy-[1,2']binaphthyl-4'-yl)-4-methoxybenzenesulfonamide, 1-yl)-4-methoxybenzenesulfonamide, N-(7,1'-dihydroxy-[1,2']binaphthyl-4'-yl)-4-methoxybenzenesulfonamide, N-(8,1'-dihydroxy-[1,2']binaphthyl-4'-yl)-4-methoxybenzenesulfonamide, 4-bromo-N-(1,6'-dihydroxy-[2,2']binaphthyl-4-yl)-benzenesulfonamide or 4-bromo-N-[4-hydroxy-3-(1H-[1,2,4]triazol-3-ylsulfanyl)-naphthalen-1-yl]-benzenesulfonamide, or a pharmaceutically acceptable salt thereof.

[0072] In some embodiments, the compound of formula (I) is N-(1',2-dihydroxy-1,2'-binaphthyl-4'-yl)-4-methoxybenzenesulfonamide.

[0073] In certain embodiments, the immune checkpoint inhibitor is administered parenterally.

[0074] In certain embodiments, the immune checkpoint inhibitor is a PD-1 inhibitor or a PD-L1 inhibitor.

[0075] In some embodiments, the PD-1 inhibitor is an anti-PD-1 antibody. In some embodiments, the anti-PD-1 antibody is cemiprilimab, nivolumab, pembrolizumab, pidilizumab, spartalizumab, carrelizumab, sintilimab, tislelizumab, toripalimab, dotalimumab, sazanlimab, riflimab, tepolizumab, ABBV-181, AK104, AK105, BCD-100, BI-754091, CBT-501, CC-90006, GLS-010, HLX10, IBI-308, JNJ-3283, JS001, LZM009, MEDI0680 (AMP-514), REGEN-2810, SHR-1210, Sym021, TSR-042, or XmAb20717. In some embodiments, the anti-PD-1 antibody is pembrolizumab.

[0076] 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, envolimab, 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.

[0077] In some embodiments, the immune checkpoint inhibitor is administered before the compound of formula (I). In some embodiments, the immune checkpoint inhibitor is administered simultaneously with the compound of formula (I). In some embodiments, the immune checkpoint inhibitor is administered after the compound of formula (I). In some embodiments, after three weeks or more of administering the compound of formula (I) and the immune checkpoint inhibitor, the subject is at least partially relieved. In some embodiments, after six weeks or more of administering the compound of formula (I) and the immune checkpoint inhibitor, the subject is completely relieved. In some embodiments, the methods described herein reduce tumor size by at least 20% within six weeks of administration, compared to subjects administered the immune checkpoint inhibitor alone.

[0078] In certain embodiments, disclosed herein are methods of reducing the risk of cancer recurrence in a subject in need thereof, comprising a) orally administering to the subject an effective amount of a compound of formula (I):

[0079]

[0080] or a pharmaceutically 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; R 1 Selected from the group consisting of hydrogen, methyl, chloro, bromo, methoxy, ethoxy, tert-butyl, nitro, methyl ester, acetamide, 1,4-dioxine, fluorine, trifluoromethoxy, acetyl, trifluoromethyl, propyl, cyclohexene, methoxy-phenoxy, chlorophenoxy, tolyloxy and phenoxy; and b) administering an effective amount of an immune checkpoint inhibitor to the subject.

[0081] In some embodiments, the compound of formula (I) is N-(1',2-dihydroxy-1,2'-binaphthyl-4'-yl)-4-methoxybenzenesulfonamide, N-(3,1'-dihydroxy-[1,2']binaphthyl-4'-yl)-4-methoxybenzenesulfonamide, N-(4,1'-dihydroxy-[1,2']binaphthyl-4'-yl)-4-methoxybenzenesulfonamide, N-(5,1'-dihydroxy-[1,2']binaphthyl-4'-yl)-4-methoxybenzenesulfonamide, N-(6,1'-dihydroxy-[1,2']binaphthyl-4'-yl)-4-methoxybenzenesulfonamide, 1-yl)-4-methoxybenzenesulfonamide, N-(7,1'-dihydroxy-[1,2']binaphthyl-4'-yl)-4-methoxybenzenesulfonamide, N-(8,1'-dihydroxy-[1,2']binaphthyl-4'-yl)-4-methoxybenzenesulfonamide, 4-bromo-N-(1,6'-dihydroxy-[2,2']binaphthyl-4-yl)-benzenesulfonamide or 4-bromo-N-[4-hydroxy-3-(1H-[1,2,4]triazol-3-ylsulfanyl)-naphthalen-1-yl]-benzenesulfonamide, or a pharmaceutically acceptable salt thereof.

[0082] In some embodiments, the compound of formula (I) is N-(1',2-dihydroxy-1,2'-binaphthyl-4'-yl)-4-methoxybenzenesulfonamide.

[0083] In certain embodiments, the immune checkpoint inhibitor is administered parenterally.

[0084] In certain embodiments, the immune checkpoint inhibitor is a PD-1 inhibitor or a PD-L1 inhibitor.

[0085] In certain embodiments, the PD-1 inhibitor is an anti-PD-1 antibody. In some embodiments, the anti-PD-1 antibody is cemiprilimab, nivolumab, pembrolizumab, pidilizumab, spartalizumab, carrelizumab, sintilimab, tislelizumab, toripalimab, dotalimumab, sazanlimab, riflimab, tepolizumab, ABBV-181, AK104, AK105, BCD-100, BI-754091, CBT-501, CC-90006, GLS-010, HLX10, IBI-308, JNJ-3283, JS001, LZM009, MEDI0680 (AMP-514), REGEN-2810, SHR-1210, Sym021, TSR-042, or XmAb20717. In some embodiments, the anti-PD-1 antibody is pembrolizumab.

[0086] 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, envolimab, 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.

[0087] In some embodiments, the immune checkpoint inhibitor is administered before the compound of formula (I). In some embodiments, the immune checkpoint inhibitor is administered simultaneously with the compound of formula (I). In some embodiments, the immune checkpoint inhibitor is administered after the compound of formula (I).

[0088] In certain embodiments, disclosed herein are methods of preventing cancer recurrence in a subject in need thereof, comprising a) orally administering to the subject an effective amount of a compound of formula (I):

[0089]

[0090] or a pharmaceutically 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; R 1 Selected from the group consisting of hydrogen, methyl, chloro, bromo, methoxy, ethoxy, tert-butyl, nitro, methyl ester, acetamide, 1,4-dioxine, fluorine, trifluoromethoxy, acetyl, trifluoromethyl, propyl, cyclohexene, methoxy-phenoxy, chlorophenoxy, tolyloxy and phenoxy; and b) administering an effective amount of an immune checkpoint inhibitor to the subject.

[0091] In some embodiments, the compound of formula (I) is N-(1',2-dihydroxy-1,2'-binaphthyl-4'-yl)-4-methoxybenzenesulfonamide, N-(3,1'-dihydroxy-[1,2']binaphthyl-4'-yl)-4-methoxybenzenesulfonamide, N-(4,1'-dihydroxy-[1,2']binaphthyl-4'-yl)-4-methoxybenzenesulfonamide, N-(5,1'-dihydroxy-[1,2']binaphthyl-4'-yl)-4-methoxybenzenesulfonamide, N-(6,1'-dihydroxy-[1,2']binaphthyl-4'-yl)-4-methoxybenzenesulfonamide, 1-yl)-4-methoxybenzenesulfonamide, N-(7,1'-dihydroxy-[1,2']binaphthyl-4'-yl)-4-methoxybenzenesulfonamide, N-(8,1'-dihydroxy-[1,2']binaphthyl-4'-yl)-4-methoxybenzenesulfonamide, 4-bromo-N-(1,6'-dihydroxy-[2,2']binaphthyl-4-yl)-benzenesulfonamide or 4-bromo-N-[4-hydroxy-3-(1H-[1,2,4]triazol-3-ylsulfanyl)-naphthalen-1-yl]-benzenesulfonamide, or a pharmaceutically acceptable salt thereof.

[0092] In some embodiments, the compound of formula (I) is N-(1',2-dihydroxy-1,2'-binaphthyl-4'-yl)-4-methoxybenzenesulfonamide.

[0093] In certain embodiments, the immune checkpoint inhibitor is administered parenterally.

[0094] In certain embodiments, the immune checkpoint inhibitor is a PD-1 inhibitor or a PD-L1 inhibitor.

[0095] In certain embodiments, disclosed herein are methods of treating cancer in a subject in need thereof, the method comprising administering to the subject a) an effective amount of a compound of formula (II):

[0096]

[0097] or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein, and b) an effective amount of an immune checkpoint inhibitor.

[0098] In certain embodiments, the compound of Formula (II) or a pharmaceutically acceptable salt thereof is administered orally.

[0099] In certain embodiments, the immune checkpoint inhibitor is administered parenterally.

[0100] In certain embodiments, the immune checkpoint inhibitor is a PD-1 inhibitor or a PD-L1 inhibitor.

[0101] In certain embodiments, the PD-1 inhibitor is an anti-PD-1 antibody. In some embodiments, the anti-PD-1 antibody is cemiprilimab, nivolumab, pembrolizumab, pidilizumab, spartalizumab, carrelizumab, sintilimab, tislelizumab, toripalimab, dotalimumab, sazanlimab, riflimab, tepolizumab, ABBV-181, AK104, AK105, BCD-100, BI-754091, CBT-501, CC-90006, GLS-010, HLX10, IBI-308, JNJ-3283, JS001, LZM009, MEDI0680 (AMP-514), REGEN-2810, SHR-1210, Sym021, TSR-042, or XmAb20717. In some embodiments, the anti-PD-1 antibody is pembrolizumab.

[0102] 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, envolimab, 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.

[0103] In some embodiments, the immune checkpoint inhibitor is administered before the compound of formula (II). In some embodiments, the immune checkpoint inhibitor is administered simultaneously with the compound of formula (II). In some embodiments, the immune checkpoint inhibitor is administered after the compound of formula (II).

[0104] In certain embodiments, disclosed herein are methods of reducing the risk of cancer recurrence in a subject in need thereof, comprising administering to the subject a) an effective amount of a compound of formula (II):

[0105]

[0106] or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein, and b) an effective amount of an immune checkpoint inhibitor.

[0107] In certain embodiments, the compound of Formula (II) or a pharmaceutically acceptable salt thereof is administered orally.

[0108] In certain embodiments, the immune checkpoint inhibitor is administered parenterally.

[0109] In certain embodiments, the immune checkpoint inhibitor is a PD-1 inhibitor or a PD-L1 inhibitor.

[0110] In certain embodiments, the PD-1 inhibitor is an anti-PD-1 antibody. In some embodiments, the anti-PD-1 antibody is cemiprilimab, nivolumab, pembrolizumab, pidilizumab, spartalizumab, carrelizumab, sintilimab, tislelizumab, toripalimab, dotalimumab, sazanlimab, riflimab, tepolizumab, ABBV-181, AK104, AK105, BCD-100, BI-754091, CBT-501, CC-90006, GLS-010, HLX10, IBI-308, JNJ-3283, JS001, LZM009, MEDI0680 (AMP-514), REGEN-2810, SHR-1210, Sym021, TSR-042, or XmAb20717. In some embodiments, the anti-PD-1 antibody is pembrolizumab.

[0111] 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, envolimab, 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.

[0112] In some embodiments, the immune checkpoint inhibitor is administered before the compound of formula (II). In some embodiments, the immune checkpoint inhibitor is administered simultaneously with the compound of formula (II). In some embodiments, the immune checkpoint inhibitor is administered after the compound of formula (II).

[0113] In certain embodiments, disclosed herein are methods of preventing cancer recurrence in a subject in need thereof, comprising administering to the subject a) an effective amount of a compound of formula (II):

[0114]

[0115] or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein, and b) an effective amount of an immune checkpoint inhibitor.

[0116] In certain embodiments, the compound of Formula (II) or a pharmaceutically acceptable salt thereof is administered orally.

[0117] In certain embodiments, the immune checkpoint inhibitor is administered parenterally.

[0118] In certain embodiments, the immune checkpoint inhibitor is a PD-1 inhibitor or a PD-L1 inhibitor.

[0119] In certain embodiments, the PD-1 inhibitor is an anti-PD-1 antibody. In some embodiments, the anti-PD-1 antibody is cemiprilimab, nivolumab, pembrolizumab, pidilizumab, spartalizumab, carrelizumab, sintilimab, tislelizumab, toripalimab, dotalimumab, sazanlimab, riflimab, tepolizumab, ABBV-181, AK104, AK105, BCD-100, BI-754091, CBT-501, CC-90006, GLS-010, HLX10, IBI-308, JNJ-3283, JS001, LZM009, MEDI0680 (AMP-514), REGEN-2810, SHR-1210, Sym021, TSR-042, or XmAb20717. In some embodiments, the anti-PD-1 antibody is pembrolizumab.

[0120] 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, envolimab, 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.

[0121] In some embodiments, the immune checkpoint inhibitor is administered before the compound of formula (II). In some embodiments, the immune checkpoint inhibitor is administered simultaneously with the compound of formula (II). In some embodiments, the immune checkpoint inhibitor is administered after the compound of formula (II).

[0122] Targeting STAT proteins

[0123] There are seven STAT proteins (1, 2, 3, 4, 5A, 5B and 6), which can transmit peptide hormone signals from the cell surface to the cell nucleus. The STAT inhibitor used herein is a compound that targets STAT proteins.

[0124] In some embodiments, the STAT3 inhibitor used herein refers to one or more molecules that at least partially interfere with the activity of STAT3 to exert one or more activities (including the ability of Stat3 to bind to molecules and / or the ability to be phosphorylated). In some embodiments, for example, the STAT3 inhibitor interacts with the Stat3 SH2 domain, competitively inhibits the binding of recombinant Stat3 to its fixed pY-peptide ligand, and / or inhibits IL-6-mediated tyrosine phosphorylation of Stat3. In some embodiments, for example, the STAT3 inhibitor meets the criteria of interaction analysis (CIA): 1) global minimum energy score ≤-30; 2) forming a salt bridge and / or hydrogen bond network within the pY-residue binding site of Stat3; and / or 3) forming a hydrogen bond with the amide hydrogen of E638 of Stat3 or blocking contact with the amide hydrogen of E638 of Stat3. In some embodiments, the STAT3 inhibitor interacts with the hydrophobic binding pocket of the Stat3 SH2 domain. In some embodiments, the STAT3 inhibitor inhibits the binding of Stat3 to its cognate phosphopeptide ligand. In some embodiments, the STAT3 inhibitor inhibits cytokine-mediated Stat3 phosphorylation in a cell. In some embodiments, the STAT3 inhibitor inhibits nuclear translocation of Stat3 in a cell.

[0125] In some embodiments, the STAT inhibitor described herein is a STAT1 inhibitor. Studies on Stat1-deficient mice (Meraz et al., 1996; Durbin et al., 1996; Ryan et al., 1998) support the important role of Stat1 in innate immunity, particularly against viral pathogens. In addition, Stat1 is also a potent growth inhibitor and promoter of apoptosis (Bromberg and Darnell, 2000). In addition, since tumors from wild-type animals treated with carcinogens grow faster when transplanted into Stat1-deficient animals than into wild-type hosts, Stat1 helps with tumor monitoring (Kaplan et al., 1998).

[0126] 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 in performing one or more activities (including the ability of STAT5 to bind to a molecule and / or the ability to phosphorylate).

[0127] In some embodiments, the STAT inhibitor (eg, STAT3 inhibitor) is a compound of formula (I):

[0128]

[0129] wherein R is selected from hydrogen, phenylsulfanyl, hydroxynaphthyl, quinolylsulfanyl, triazolylsulfanyl and benzothiazolylsulfanyl,

[0130] Where R 1 Selected from the group consisting of hydrogen, methyl, chlorine, bromine, methoxy, ethoxy, tert-butyl, nitro, methyl ester, acetamide, 1,4-dioxine, fluorine, trifluoromethoxy, acetyl, trifluoromethyl, propyl, cyclohexene, methoxy-phenoxy, chlorophenoxy, tolyloxy and phenoxy.

[0131] In some embodiments, the STAT inhibitor is N-(1',2-dihydroxy-1,2'-binaphthyl-4'-yl)-4-methoxybenzenesulfonamide, N-(3,1'-dihydroxy-[1,2']binaphthyl-4'-yl)-4-methoxybenzenesulfonamide, N-(4,1'-dihydroxy-[1,2']binaphthyl-4'-yl)-4-methoxybenzenesulfonamide, N-(5,1'-dihydroxy-[1,2']binaphthyl-4'-yl)-4-methoxybenzenesulfonamide, N-(6,1'-dihydroxy-[1,2']binaphthyl-4'-yl)-4-methoxybenzenesulfonamide, In some embodiments, the STAT inhibitor is N-(1',2-dihydroxy-1,2'-binaphthyl-4'-yl)-4-methoxybenzenesulfonamide, N-(7,1'-dihydroxy-[1,2']binaphthyl-4'-yl)-4-methoxybenzenesulfonamide, N-(8,1'-dihydroxy-[1,2']binaphthyl-4'-yl)-4-methoxybenzenesulfonamide, 4-bromo-N-(1,6'-dihydroxy-[2,2']binaphthyl-4-yl)-benzenesulfonamide or 4-bromo-N-[4-hydroxy-3-(1H-[1,2,4]triazol-3-ylsulfanyl)-naphthalen-1-yl]-benzenesulfonamide, or a pharmaceutically acceptable salt thereof. In some embodiments, the STAT inhibitor is N-(1',2-dihydroxy-1,2'-binaphthyl-4'-yl)-4-methoxybenzenesulfonamide (also referred to herein as TTI-101).

[0132] In some embodiments, the STAT inhibitor is a compound of formula (II):

[0133]

[0134] or a pharmaceutically acceptable salt thereof, wherein

[0135] R1, at each occurrence, 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;

[0136] n1 is 0, 1, 2, 3 or 4;

[0137] R2, at each occurrence, 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 aryloxy, or optionally substituted heterocycle;

[0138] n2 is 0, 1, 2, 3, 4 or 5;

[0139] R3 is hydrogen, halogen, cyano, nitro, CF3, OCF3, ORa, SRa, OC(=O)Ra, alkyl, alkenyl, cycloalkyl or optionally substituted aryl or heteroaryl;

[0140] R4 is hydrogen, halogen, cyano, nitro, CF3, OCF3, ORa, SRa, NRbRc, OC(=O)Ra, alkyl, alkenyl or cycloalkyl;

[0141] R5, R6 and R7 are independently, at each occurrence, 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;

[0142] n3 is 0, 1, 2, 3 or 4; and

[0143] Ra, Rb and Rc are independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle or aryl at each occurrence; or Rb and Rc, together with the nitrogen atom to which they are bound, optionally form a heterocycle containing 1-4 heteroatoms.

[0144] In some embodiments of formula (II), R1 is independently hydrogen, halogen, cyano, nitro, CF3, OCF3, ORa or SRa at each occurrence. In some embodiments of formula (II), R1 is independently C(=O)Ra, OC(=O)Ra, C(=O)ORa, NRR, NRC(=O)Ra, C(=O)NRbRc, NRC(=O)ORa, OC(=O)NRbRc or NRC(=O)NRbRc at each occurrence. In some embodiments of formula (II), R1 is independently alkyl, alkenyl, cycloalkyl, optionally substituted aryl or optionally substituted heterocycle at each occurrence. In some embodiments of formula (II), R1 is hydrogen.

[0145] 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.

[0146] In some embodiments of formula (II), R2 is independently hydrogen, halogen, cyano, nitro, CF3, OCF3, ORa or SRa at each occurrence. In some embodiments of formula (II), R2 is independently C(=O)Ra, OC(=O)Ra, C(=O)ORa, NRR, NRC(=O)Ra, C(=O)NRbRc, NRC(=O)ORa, OC(=O)NRbRc or NRC(=O)NRbRc at each occurrence. In some embodiments of formula (II), R2 is independently alkyl, alkenyl, cycloalkyl, optionally substituted aryl or optionally substituted heterocycle at each occurrence. In some embodiments of formula (II), R2 is hydrogen.

[0147] 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.

[0148] 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.

[0149] 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.

[0150] 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), R5, R6 and R7 are hydrogen at each occurrence.

[0151] 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.

[0152] In some embodiments of formula (II), R is independently hydrogen, alkyl, heterocycle or aryl at each occurrence. In some embodiments of formula (II), R is independently hydrogen or alkyl at each occurrence. In some embodiments of formula (II), R and R are independently hydrogen, alkyl, heterocycle or aryl at each occurrence. In some embodiments of formula (II), R and R are independently hydrogen or alkyl at each occurrence. In some embodiments of formula (II), R and R are optionally formed together with the nitrogen atom to which they are bonded to a heterocycle containing 1-4 heteroatoms.

[0153] In some embodiments, the compound of formula (II) is a compound of formula (III):

[0154]

[0155] or a pharmaceutically acceptable salt thereof.

[0156] 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.

[0157] In some embodiments of formula (III), R3 is H, OH, alkyl, alkoxy or halogen. In some embodiments of formula (III), R3 is H.

[0158] 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.

[0159] In some embodiments, the compound of formula (III) is a compound of formula (IV):

[0160]

[0161] or a pharmaceutically acceptable salt thereof.

[0162] In some embodiments, the compound of formula (II) is a compound selected from the examples of compounds shown in Table A, or a pharmaceutically acceptable salt thereof.

[0163] Table A. Alternative compounds of formula (II) wherein n1, n2 and n3 are independently 1 or 2.

[0164]

[0165]

[0166] In some embodiments, the compound of formula (III) is a compound selected from the examples of compounds shown in Table B, or a pharmaceutically acceptable salt thereof.

[0167] Table B. Alternative compounds of formula (III)

[0168]

[0169]

[0170] Immune checkpoint inhibitors

[0171] Immune checkpoint inhibitors block proteins called checkpoints that are produced by certain types of immune system cells (such as T cells) and certain cancer cells. These checkpoints help prevent the immune response from being too strong and sometimes prevent T cells from killing cancer cells. When these checkpoints are blocked, T cells are better able to kill cancer cells.

[0172] PD-1 inhibitors and PD-L1 inhibitors

[0173] In certain embodiments, disclosed herein are methods for treating cancer and preventing cancer recurrence in subjects in need thereof, 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.

[0174] Antibody therapy is an antibody protein produced by the immune system and bound to a target antigen on the cell surface. Antibodies are usually encoded by immunoglobulin genes or their gene fragments. Under normal physiological conditions, antibodies are used by the immune system to fight pathogens. Each antibody is specific to one or several proteins, and those antibodies that bind to cancer antigens can be used, for example, to treat cancer. Antibodies can specifically bind to antigens or epitopes. (Fundamental Immunology, 3rd Edition, We, Paul, ed., Raven Press, NY (1993)). Even in the presence of heterogeneous proteins and other organisms, they will specifically bind to the corresponding antigen or epitope. The specific binding of an antibody indicates that its binding affinity to the target antigen or epitope is significantly higher than its binding to an unrelated antigen. The relative difference in affinity is usually at least 25% higher, more commonly at least 50% higher, and most commonly at least 100% higher. For example, the relative difference can be at least 2 times, at least 5 times, at least 10 times, at least 25 times, at least 50 times, at least 100 times, or at least 1000 times.

[0175] Exemplary types of antibodies include, but are not limited to, human antibodies, humanized antibodies, chimeric antibodies, monoclonal antibodies, polyclonal antibodies, single-chain antibodies, antibody binding fragments, and diabodies. Once bound to a cancer antigen, the antibody can induce antibody-dependent cell-mediated cytotoxicity, activate the complement system, prevent a receptor from interacting with its ligand, or deliver a payload of chemotherapy or radiation, all of which can lead to cell death.

[0176] In some embodiments, the anti-PD-1 antibody is cemiprilimab, nivolumab, pembrolizumab, pidilizumab, spartalizumab, carrelizumab, sintilimab, tislelizumab, toripalimab, dotalimumab, sazanlimab, riflimab, tepolizumab, ABBV-181, AK104, AK105, BCD-100, BI-754091, CBT-501, CC-90006, GLS-010, HLX10, IBI-308, JNJ-3283, JS001, LZM009, MEDI0680 (AMP-514), REGEN-2810, SHR-1210, Sym021, TSR-042, or XmAb20717.

[0177] In some embodiments, the anti-PD-L1 antibody is atezolizumab, avelumab, durvalumab, envobalizumab, 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.

[0178] Diseases and disorders

[0179] Signal transducer and activator of transcription 3 (STAT3) is the core of regulating anti-tumor immune response. STAT3 is widely overactivated in cancer cells and non-cancerous cells in the tumor ecosystem, and plays an important role in suppressing the expression of key immune activation regulatory factors and promoting the production of immunosuppressive factors. The method provided herein can be used to treat cancer, including, for example, solid tumors, soft tissue tumors and metastases thereof.

[0180] 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, gastric 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, head and neck squamous cell carcinoma, non-small cell lung cancer or estrogen receptor positive breast cancer.

[0181] 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.

[0182] combination

[0183] As used herein, the phrase "in combination with" and the terms "co-administration," "co-administering," or "co-providing" used in the context of administering a compound described herein or a therapy described herein refers to the administration of two (or more) different compounds or therapies to a subject during the course of the subject's suffering from a disease or disorder (e.g., a disease or disorder as described herein, such as cancer), for example, the delivery of two (or more) different compounds or therapies to a subject after the subject has been diagnosed with a disease or disorder (e.g., a disease or disorder as described herein, such as cancer) and before the disease or disorder has been cured or eliminated or treatment has been stopped for other reasons.

[0184] In some embodiments, the delivery of a compound or therapy is still ongoing when the second compound or therapy begins to be delivered, so there is overlap in terms of administration. This situation is sometimes referred to as "simultaneous" or "concurrent delivery" in this article. In other embodiments, the delivery of a compound or therapy ends before another compound or therapy begins. In some embodiments of either case, treatment (e.g., the administration of a compound, composition, or therapy) is more effective due to combined administration. For example, compared with the administration of the second compound or therapy in the absence of the first compound or therapy, the second compound or therapy is more effective when combined, for example, an equivalent effect is observed when using less of the second compound or therapy, or the second compound or therapy alleviates symptoms to a greater extent; or similar situations are seen in the first compound or therapy. In some embodiments, delivery causes the reduction of symptoms or parameters related to the disorder to be greater than the degree observed when delivering a compound or therapy without using another compound or therapy. The effects of two compounds or therapies can be partially added, completely added, or greater than addition (e.g., synergistic effect). Delivery can make it possible to detect the first compound or therapy when the second compound or therapy is delivered.

[0185] In some embodiments, the first compound or therapy and the second compound or therapy can be administered simultaneously (simultaneously) (for example, at the same time (at the same time)), in the same or different compositions, or in order (sequential). Sequential administration refers to the administration of a compound or therapy before the administration of another compound or therapy (for example, the second compound or therapy) (for example, 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 or more hours; 4, 5, 6, 7, 8, 9 or more days; 1, 2, 3, 4, 5, 6, 7, 8 or more weeks). The order of administration of the first compound or therapy and the second compound or therapy can also be reversed.

[0186] The combinations described herein can be used for first-line treatment of cancer, i.e., for patients who have not been previously administered another drug to treat cancer; for second-line treatment of cancer, i.e., for subjects in need who have previously been administered another drug to treat cancer; for third or fourth-line treatment of cancer, i.e., for subjects who have previously been administered two or three other drugs to treat cancer.

[0187] Administration and Dosage

[0188] The combination of the present disclosure can be administered orally, parenterally, topically, rectally or via an implanted kit, preferably by oral administration (e.g., for STAT3 inhibitors) or by injection (e.g., for anti-PD-1 antibodies). In some cases, the pH of a composition (e.g., a pharmaceutical composition) comprising a STAT3 inhibitor or a composition (e.g., a pharmaceutical composition) comprising an immune checkpoint inhibitor can be adjusted with a pharmaceutically acceptable acid, base or buffer to enhance the stability or effect of the composition.

[0189] In some embodiments, the subject orally administers a composition (e.g., a pharmaceutical composition) comprising a STAT3 inhibitor. In some embodiments, the composition (e.g., a pharmaceutical composition) is orally administered in any oral acceptable dosage form, including but not limited to liquid-gel tablets or capsules, syrups, emulsions, and aqueous suspensions. As needed, the liquid-gel may include gelatin, a plasticizer, and / or a sunscreen to achieve a suitable consistency, and may be coated with an enteric coating approved for use, such as shellac. When used as an oral agent, an additional thickener may be added, such as gum (e.g., xanthan gum), starch (e.g., corn starch), or gluten to achieve the desired consistency of the composition (e.g., pharmaceutical composition). If desired, additional sweeteners and / or flavoring agents and / or coloring agents may also be added.

[0190] In some embodiments, a composition (e.g., a pharmaceutical composition) comprising a STAT3 inhibitor is administered to a subject in a form suitable for oral administration, such as tablets, capsules, pills, powders, sustained-release formulations, solutions, and suspensions. The composition (e.g., a pharmaceutical composition) may be in a unit dosage form suitable for single administration of a precise dose. In addition to the compounds described herein, the pharmaceutical composition may further comprise a pharmaceutically acceptable carrier, and may optionally further comprise one or more pharmaceutically acceptable excipients, such as stabilizers, diluents, binders, and lubricants. In addition, tablets may include other drugs or agents, carriers, and / or adjuvants.

[0191] The dosage may vary according to the dosage form used and the route of administration used. The specific preparation, route of administration and dosage may be selected by each doctor according to the patient's condition. (See, for example, Fingl et al., 1975, "The Pharmacological Basis of Therapeutics"). A dosage lower or higher than the above dosage may be required. The specific dosage and treatment regimen of any particular subject will depend on a variety of factors, including the activity of the specific compound used, the subject's age, weight, general health, sex, diet, administration time, excretion rate, drug combination, severity and course of disease, illness or symptom, susceptibility of the subject to disease, illness or symptom, and the judgment of the attending physician. The course of treatment may include one or more separate administrations of the compounds described herein.

[0192] In some embodiments, the compound of formula (I) is N-(1',2-dihydroxy-1,2'-binaphthyl-4'-yl)-4-methoxybenzenesulfonamide, and N-(1',2-dihydroxy-1,2'-binaphthyl-4'-yl)-4-methoxybenzenesulfonamide is administered to a subject in an oral dosage form comprising a composition comprising:

[0193] a. a therapeutically effective amount of N-(1',2-dihydroxy-1,2'-binaphthyl-4'-yl)-4-methoxybenzenesulfonamide;

[0194] b. an emulsifier (eg, a glyceride) present in the composition in a weight ratio of the compound of formula (I) to the emulsifier of from about 1:1 to about 1:2 (eg, about 1:1.5);

[0195] c. a solubilizer, the solubilizer being present in the composition in a weight ratio of the compound of formula (I) to the solubilizer of about 1:1 to about 1:5 (e.g., about 1:2 to about 1:4, e.g., about 1:3);

[0196] d. polyethylene glycol (PEG), the polyethylene glycol being present in the composition in a weight ratio of the compound of formula (I) to the polyethylene glycol of about 1:2 to about 1:6 (e.g., about 1:3 to about 1:5, e.g., about 1:4);

[0197] e. a surfactant, the surfactant being present in the composition in a weight ratio of the compound of formula (I) to the surfactant of from about 2:1 to about 1:2 (e.g., from about 1:1 to about 1:2, e.g., about 1:2); and

[0198] f. an antioxidant, the antioxidant being present in the composition in a weight ratio of the compound of formula (I) to the antioxidant of about 10:1 to about 30:1 (eg, about 15:1 to about 25:1, such as about 20:1).

[0199] In some embodiments, the emulsifier is present in the composition at a weight ratio of about 1:1 of the compound of formula (I) to the emulsifier. In some embodiments, the emulsifier is present in the composition at a weight ratio of about 1:2 of the compound of formula (I) to the emulsifier. In some embodiments, the emulsifier is present in the composition at a weight ratio of about 1:3 of the compound of formula (I) to the emulsifier. In some embodiments, the emulsifier is present in the composition at a weight ratio of about 1:4 of the compound of formula (I) to the emulsifier. In some embodiments, the emulsifier is present in the composition at a weight ratio of about 1:5 of the compound of formula (I) to the emulsifier. In some embodiments, the emulsifier is present in the composition at a weight ratio of about 1:6 of the compound of formula (I) to the emulsifier. In some embodiments, the emulsifier is present in the composition at a weight ratio of about 1:7 of the compound of formula (I) to the emulsifier. In some embodiments, the emulsifier is present in the composition at a weight ratio of about 1:1.5 of the compound of formula (I) to the emulsifier.

[0200] In some embodiments, the solubilizer is present in the composition at a weight ratio of about 1:1 of the compound of formula (I). In some embodiments, the solubilizer is present in the composition at a weight ratio of about 1:2 of the compound of formula (I). In some embodiments, the solubilizer is present in the composition at a weight ratio of about 1:3 of the compound of formula (I). In some embodiments, the solubilizer is present in the composition at a weight ratio of about 1:4 of the compound of formula (I). In some embodiments, the solubilizer is present in the composition at a weight ratio of about 1:5 of the compound of formula (I). In some embodiments, the solubilizer is present in the composition at a weight ratio of about 1:4 of the compound of formula (I). In some embodiments, the solubilizer is present in the composition at a weight ratio of about 1:6 of the compound of formula (I). In some embodiments, the solubilizer is present in the composition at a weight ratio of about 1:4 of the compound of formula (I). In some embodiments, the solubilizer is present in the composition at a weight ratio of about 1:7 of the compound of formula (I). In some embodiments, the solubilizer is present in the composition at a weight ratio of about 1:4 of the compound of formula (I) to the solubilizer. In some embodiments, the solubilizer is present in the composition at a weight ratio of about 1:8 of the compound of formula (I) to the solubilizer. In some embodiments, the solubilizer is present in the composition at a weight ratio of about 1:4 of the compound of formula (I) to the solubilizer. In some embodiments, the solubilizer is present in the composition at a weight ratio of about 1:9 of the compound of formula (I) to the solubilizer. In some embodiments, the solubilizer is present in the composition at a weight ratio of about 1:10 of the compound of formula (I) to the solubilizer. In some embodiments, the solubilizer is present in the composition at a weight ratio of about 1:11 of the compound of formula (I) to the solubilizer. In some embodiments, the solubilizer is present in the composition at a weight ratio of about 1:12 of the compound of formula (I) to the solubilizer. In some embodiments, the solubilizer is present in the composition at a weight ratio of about 1:13 of the compound of formula (I) to the solubilizer. In some embodiments, the solubilizer is present in the composition at a weight ratio of about 1:14 of the compound of formula (I) to the solubilizer. In some embodiments, the solubilizer is present in the composition at a weight ratio of about 1:15 of the compound of formula (I) to the solubilizer. In some embodiments, the solubilizer is present in the composition at a weight ratio of about 1:16 of the compound of formula (I) to the solubilizer. In some embodiments, the solubilizer is present in the composition at a weight ratio of about 1:17 of the compound of formula (I) to the solubilizer. In some embodiments, the solubilizer is present in the composition at a weight ratio of about 1:18 of the compound of formula (I) to the solubilizer. In some embodiments, the solubilizer is present in the composition at a weight ratio of about 1:19 of the compound of formula (I) to the solubilizer. In some embodiments, the solubilizer is present in the composition at a weight ratio of about 1:20 of the compound of formula (I) to the solubilizer.

[0201] In some embodiments, the polyethylene glycol is present in the composition at a weight ratio of about 1:1 of the compound of formula (I) to the polyethylene glycol. In some embodiments, the polyethylene glycol is present in the composition at a weight ratio of about 1:2 of the compound of formula (I) to the polyethylene glycol. In some embodiments, the polyethylene glycol is present in the composition at a weight ratio of about 1:3 of the compound of formula (I) to the polyethylene glycol. In some embodiments, the polyethylene glycol is present in the composition at a weight ratio of about 1:4 of the compound of formula (I) to the polyethylene glycol. In some embodiments, the polyethylene glycol is present in the composition at a weight ratio of about 1:5 of the compound of formula (I) to the polyethylene glycol. In some embodiments, the polyethylene glycol is present in the composition at a weight ratio of about 1:6 of the compound of formula (I) to the polyethylene glycol. In some embodiments, the polyethylene glycol is present in the composition at a weight ratio of about 1:7 of the compound of formula (I) to the polyethylene glycol. In some embodiments, the polyethylene glycol is present in the composition at a weight ratio of about 1:8 of the compound of formula (I) to the polyethylene glycol. In some embodiments, the polyethylene glycol is present in the composition at a weight ratio of about 1:9 of the compound of formula (I) to the polyethylene glycol. In some embodiments, the polyethylene glycol is present in the composition at a weight ratio of about 1:10 of the compound of formula (I) to the polyethylene glycol. In some embodiments, the polyethylene glycol is present in the composition at a weight ratio of about 1:11 of the compound of formula (I) to the polyethylene glycol. In some embodiments, the polyethylene glycol is present in the composition at a weight ratio of about 1:12 of the compound of formula (I) to the polyethylene glycol. In some embodiments, the polyethylene glycol is present in the composition at a weight ratio of about 1:13 of the compound of formula (I) to the polyethylene glycol. In some embodiments, the polyethylene glycol is present in the composition at a weight ratio of about 1:14 of the compound of formula (I) to the polyethylene glycol. In some embodiments, the polyethylene glycol is present in the composition at a weight ratio of about 1:15 of the compound of formula (I) to the polyethylene glycol. In some embodiments, the polyethylene glycol is present in the composition at a weight ratio of about 1:16 of the compound of formula (I) to the polyethylene glycol. In some embodiments, the polyethylene glycol is present in the composition at a weight ratio of about 1:17 of the compound of formula (I) to the polyethylene glycol. In some embodiments, the polyethylene glycol is present in the composition at a weight ratio of about 1:18 of the compound of formula (I) to the polyethylene glycol. In some embodiments, the polyethylene glycol is present in the composition at a weight ratio of about 1:19 of the compound of formula (I) to the polyethylene glycol. In some embodiments, the polyethylene glycol is present in the composition at a weight ratio of about 1:20 of the compound of formula (I) to the polyethylene glycol.

[0202] In some embodiments, the surfactant is present in the composition at a weight ratio of about 4:1 of the compound of formula (I) to the surfactant. In some embodiments, the surfactant is present in the composition at a weight ratio of about 3:1 of the compound of formula (I) to the surfactant. In some embodiments, the surfactant is present in the composition at a weight ratio of about 2:1 of the compound of formula (I) to the surfactant. In some embodiments, the surfactant is present in the composition at a weight ratio of about 1:1 of the compound of formula (I) to the surfactant. In some embodiments, the surfactant is present in the composition at a weight ratio of about 1:2 of the compound of formula (I) to the surfactant. In some embodiments, the surfactant is present in the composition at a weight ratio of about 1:3 of the compound of formula (I) to the surfactant. In some embodiments, the surfactant is present in the composition at a weight ratio of about 1:4 of the compound of formula (I) to the surfactant. In some embodiments, the surfactant is present in the composition at a weight ratio of about 1:5 of the compound of formula (I) to the surfactant. In some embodiments, the surfactant is present in the composition at a weight ratio of about 1:6 of the compound of formula (I) to the surfactant.

[0203] In some embodiments, the antioxidant is present in the composition at a weight ratio of about 2:1 of the compound of formula (I) to the antioxidant. In some embodiments, the antioxidant is present in the composition at a weight ratio of about 3:1 of the compound of formula (I) to the antioxidant. In some embodiments, the antioxidant is present in the composition at a weight ratio of about 4:1 of the compound of formula (I) to the antioxidant. In some embodiments, the antioxidant is present in the composition at a weight ratio of about 5:1 of the compound of formula (I) to the antioxidant. In some embodiments, the antioxidant is present in the composition at a weight ratio of about 6:1 of the compound of formula (I) to the antioxidant. In some embodiments, the antioxidant is present in the composition at a weight ratio of about 7:1 of the compound of formula (I) to the antioxidant. In some embodiments, the antioxidant is present in the composition at a weight ratio of about 8:1 of the compound of formula (I) to the antioxidant. In some embodiments, the antioxidant is present in the composition at a weight ratio of about 9:1 of the compound of formula (I) to the antioxidant. In some embodiments, the antioxidant is present in the composition at a weight ratio of about 10:1 of the compound of formula (I) to the antioxidant. In some embodiments, the antioxidant is present in the composition at a weight ratio of about 11:1 of the compound of formula (I) to the antioxidant. In some embodiments, the antioxidant is present in the composition at a weight ratio of about 12:1 of the compound of formula (I) to the antioxidant. In some embodiments, the antioxidant is present in the composition at a weight ratio of about 13:1 of the compound of formula (I) to the antioxidant. In some embodiments, the antioxidant is present in the composition at a weight ratio of about 14:1 of the compound of formula (I) to the antioxidant. In some embodiments, the antioxidant is present in the composition at a weight ratio of about 15:1 of the compound of formula (I) to the antioxidant. In some embodiments, the antioxidant is present in the composition at a weight ratio of about 16:1 of the compound of formula (I) to the antioxidant. In some embodiments, the antioxidant is present in the composition at a weight ratio of about 17:1 of the compound of formula (I) to the antioxidant. In some embodiments, the antioxidant is present in the composition at a weight ratio of about 18:1 of the compound of formula (I) to the antioxidant. In some embodiments, the antioxidant is present in the composition at a weight ratio of about 19:1 of the compound of formula (I) to the antioxidant. In some embodiments, the antioxidant is present in the composition at a weight ratio of about 20:1 of the compound of formula (I) to the antioxidant. In some embodiments, the antioxidant is present in the composition at a weight ratio of about 21:1 of the compound of formula (I) to the antioxidant. In some embodiments, the antioxidant is present in the composition at a weight ratio of about 22:1 of the compound of formula (I) to the antioxidant. In some embodiments, the antioxidant is present in the composition at a weight ratio of about 23:1 of the compound of formula (I) to the antioxidant.In some embodiments, the antioxidant is present in the composition at a weight ratio of about 24:1 of the compound of formula (I) to the antioxidant. In some embodiments, the antioxidant is present in the composition at a weight ratio of about 25:1 of the compound of formula (I) to the antioxidant. In some embodiments, the antioxidant is present in the composition at a weight ratio of about 26:1 of the compound of formula (I) to the antioxidant. In some embodiments, the antioxidant is present in the composition at a weight ratio of about 27:1 of the compound of formula (I) to the antioxidant. In some embodiments, the antioxidant is present in the composition at a weight ratio of about 28:1 of the compound of formula (I) to the antioxidant. In some embodiments, the antioxidant is present in the composition at a weight ratio of about 29:1 of the compound of formula (I) to the antioxidant. In some embodiments, the antioxidant is present in the composition at a weight ratio of about 30:1 of the compound of formula (I) to the antioxidant.

[0204] 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.

[0205] In some embodiments, the emulsifier is a glyceride emulsifier. In some embodiments, the emulsifier includes optional polyglycolyzed medium and / or long chain monoglycerides, diglycerides and / or triglycerides. In some embodiments, the emulsifier includes medium chain monoglycerides. In some embodiments, the emulsifier includes polyglycolyzed medium chain monoglycerides. In some embodiments, the emulsifier includes long chain monoglycerides. In some embodiments, the emulsifier includes polyglycolyzed long chain monoglycerides. In some embodiments, the emulsifier includes medium chain diglycerides. In some embodiments, the emulsifier includes polyglycolyzed medium chain diglycerides. In some embodiments, the emulsifier includes long chain diglycerides. In some embodiments, the emulsifier includes polyglycolyzed long chain diglycerides. In some embodiments, the emulsifier includes medium chain triglycerides. In some embodiments, the emulsifier includes polyglycolyzed medium chain triglycerides. In some embodiments, the emulsifier includes long chain triglycerides. In some embodiments, the emulsifier comprises polyethylene glycolated long chain triglycerides.

[0206] In some embodiments, the emulsifier is In some embodiments, the emulsifier is MCM. In some embodiments, the emulsifier is MCM EP. In some embodiments, the emulsifier is C8 EP. In some embodiments, the emulsifier is 90.

[0207] In some embodiments, the solubilizing agent is polyethylene glycol castor oil or vitamin E polyethylene glycol succinate (TPGS). In some embodiments, the solubilizing agent is polyethylene glycol castor oil. In some embodiments, the solubilizing agent is vitamin E polyethylene glycol succinate. In some embodiments, the surfactant is RH 40. In some embodiments, the solubilizing agent is Vitamin E TPGS.

[0208] In some embodiments, the average molecular weight of polyethylene glycol (PEG) is from about 200 to about 1000 (e.g., from about 500 to about 700, or from about 550 to about 650, or about 600). In some embodiments, the average molecular weight of polyethylene glycol (PEG) is from about 200 to 1000. In some embodiments, the average molecular weight of polyethylene glycol (PEG) is from about 500 to 700. In some embodiments, the average molecular weight of polyethylene glycol (PEG) is from about 550 to 650. In some embodiments, the average molecular weight of polyethylene glycol (PEG) is about 600.

[0209] In some embodiments, the polyethylene glycol (PEG) is PEG200. In some embodiments, the polyethylene glycol (PEG) is PEG300. In some embodiments, the polyethylene glycol (PEG) is PEG400. In some embodiments, the polyethylene glycol (PEG) is PEG500. In some embodiments, the polyethylene glycol (PEG) is PEG600. In some embodiments, the polyethylene glycol (PEG) is PEG700. In some embodiments, the polyethylene glycol (PEG) is PEG800. In some embodiments, the polyethylene glycol (PEG) is PEG900. In some embodiments, the polyethylene glycol (PEG) is PEG1000.

[0210] 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.

[0211] 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.

[0212] In some embodiments, the composition further comprises a co-solvent (e.g. In some embodiments, the composition further comprises HP.

[0213] In some embodiments, the methods described herein contemplate administering to a subject an oral dosage form comprising a pharmaceutical composition as described herein contained within a capsule.

[0214] Example

[0215] In the examples described below, the following abbreviations are used: ROA = route of administration; ip = intraperitoneal injection; po = oral; BID = twice a day; BIW = twice a week; PBS = phosphate buffered saline; FBS = fetal bovine serum; N / A = not available or not applicable; SD = standard deviation; SEM = standard error of the mean; TGI = tumor growth inhibition; TV = tumor volume.

[0216] Example 1. In vivo efficacy study and re-stimulation study of TTI-101± anti-PD-1 antibody in the treatment of female BALB / c mouse subcutaneous liver cancer syngeneic model (H22)

[0217] The efficacy study aims to preclinically evaluate the in vivo efficacy of TTI-101 alone or in combination with anti-PD-1 antibodies in the subcutaneous liver cancer syngeneic model H22 in female BALB / c mice. The purpose of the re-challenge study is to evaluate the immune memory of the subcutaneous liver cancer syngeneic model H22 in female BALB / c mice that was previously cured by TTI-101 combined with anti-PD-1 antibodies.

[0218] formula

[0219] The dosing volume of anti-PD-1 antibody (clone RMP1-14) was adjusted according to body weight. The concentration of anti-PD-1 antibody was 1 mg / mL and the dosing volume was 10 μL / g. The anti-PD-1 antibody dosing solution was prepared by diluting 1.372 mL of anti-PD-1 antibody (8.2 mg / mL) with 9.878 mL of PBS.

[0220] Isotype control was prepared by diluting isotype control with PBS. The dosing volume was adjusted according to body weight. The concentration of isotype control was 1 mg / mL and the dosing volume was 10 μL / g. For each formulation, 7.5 mL of dosing solution was prepared by diluting isotype control with PBS.

[0221] Then, a composition of TTI-101 (72 mg / mL) dissolved in Kolliphor RH40, PEG600, Labrasol, Tween 20 and citric acid solution was dispersed in water at a ratio of 1:2 (vortexed) to form a dosing emulsion. The concentration of TTI-101 in the dosing emulsion was 24 mg / mL.

[0222] A vehicle formulation consisting of Kolliphor RH40, PEG600, Labrasol, Tween20 and citric acid solution was then dispersed in water (vortexed) to form an emulsion for dosing.

[0223] Cell culture

[0224] H22 tumor cells were cultured in vitro at 37°C in an atmosphere containing 5% CO2 in air in RPMI1640 medium supplemented with 10% fetal bovine serum (FBS). Before tumor inoculation, cells in the exponential growth phase were harvested and quantified using a cell counter.

[0225] Tumor inoculation

[0226] In the efficacy study, each mouse was inoculated subcutaneously with tumor cells (1×10 6 ), for tumor development.

[0227] In the rechallenge study, each mouse was inoculated subcutaneously with tumor cells (1×10 6 The inoculation date was day 0.

[0228] Randomization

[0229] When the average tumor size reaches about 73 mm 3 (Groups 1-5) and 96mm 3(Group 6-9), randomization for efficacy study was started. A total of 82 mice participated in the study and were randomly assigned to 9 study groups, with 10 mice (Group 1-5) and 8 mice (Group 6-9) in each group. Randomization was performed using the "matched distribution" method (Study Director TM software, version 3.1.399.19). The date of randomization was recorded as day 1.

[0230] Drug administration

[0231] Drugs were administered to each group according to the schedule shown in Table 1.

[0232] Table 1. Efficacy study design

[0233]

[0234]

[0235] N: number of animals in each group;

[0236] BID means 8 hours between two doses in one day;

[0237] For vehicle and TTI-101, dosing was done only once on the day of randomization and termination.

[0238] Test samples were given between 8:00-9:00 AM and again between 4:00-5:00 PM.

[0239] For Group 5, TTI-101 was started 5 days after anti-PD-1 antibody administration as requested.

[0240] In the rechallenge study, Groups 4, 5, and 10 were rechallenged according to Table 2.

[0241] Table 2. Rechallenge study design

[0242]

[0243] No treatment was administered in the rechallenge study.

[0244] Tumor volume measurement

[0245] Tumor volume was measured twice a week in two dimensions with a caliper after randomization. The volume was expressed as V = (L × W × W) / 2 in mm. 3 , where V is the tumor volume, L is the tumor length (the longest dimension of the tumor), and W is the tumor width (the longest dimension of the tumor perpendicular to L). Dosing and tumor and body weight measurements were performed in a Laminar Flow Cabinet.

[0246] Endpoints

[0247] Tumor growth inhibition (TGI), T / C value and survival rate were recorded at the endpoint.

[0248] Tumor regression rate (REG) = [(T0-T i ) / T0]×100%;

[0249] Ti: mean tumor volume of treatment group on measurement day;

[0250] T0: mean tumor volume of treatment groups on day 0.

[0251] Tumor growth inhibition; TGI% = (1-Ti / Ci)*100;

[0252] Ti: mean tumor volume of treatment group on measurement day;

[0253] Ci: average tumor volume of the control group on the measurement day.

[0254] The treatment / control (T / C) value (%) is an indicator of tumor response to treatment and is also one of the commonly used anti-tumor activity endpoints; T and C are the average tumor volumes of the treatment group and the control group, respectively, on a given day.

[0255] Tumor volume change_treatment / tumor volume change_control (ΔT / ΔC) = (T i -T0) / (C i -C0)*100%;T i and C i The average tumor volumes of the treatment and control groups on day 0 were measured; T0 and C0 were taken as the average tumor volumes of the treatment and control groups on day 0.

[0256] Study Termination

[0257] Treatment was continued 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 into a re-challenge study and terminated on day 130 (re-challenge study day 24).

[0258] result

[0259] Figure 1 and Figure 2 The in vivo efficacy of TTI-101±anti-PD-1 antibody on H22 model is shown respectively (day 21 and day 47).

[0260] Tumor Growth Inhibition (TGI)

[0261] Table 3 summarizes the tumor growth inhibition of the treatment in the subcutaneous hepatocellular carcinoma syngeneic model H22.

[0262] Table 3. Summary of tumor growth inhibition

[0263]

[0264] Note: a. Mean ± SEM; b. Comparison of tumor volume on day 21 with that of group 1 using Conover nonparametric test, LOCF TV cutoff = 3000 mm 3 ; c. Six animals in group 3 showed tumor regression on day 51. According to the sponsor's request, the animals were discontinued from treatment on day 51. CR: Complete tumor response, tumor regression to 0.

[0265] In this study, the mean tumor size of mice in the vehicle group reached 2647 mm on day 21 after randomization. 3 . TTI-101 administered at 1.2 mg / mouse, BID, showed mild antitumor efficacy in the H22 model, with a TGI value of 21.67% on day 21, however, no statistically significant difference was observed compared with the vehicle group (P>0.05). Anti-PD-1 antibody administered at 100 mg / kg, BIW showed significant antitumor efficacy in the H22 model, with a TGI value of 78.95% on day 21 (P<0.0001). Six animals in Group 3 showed tumor regression on day 51.

[0266] Compared with the vehicle group, the co-administration of TTI-101 and anti-PD-1 antibody produced 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. On day 51, 3 animals (3 / 10) of group 4 showed complete regression of tumors and remained tumor-free until the end of the study on day 130.

[0267] Compared with the vehicle group, the sequential administration of TTI-101 7 days after the administration of anti-PD-1 antibody produced significant anti-tumor efficacy in the H22 model, with a TGI value of 68.67% on day 21, resulting in a statistically significant difference of P < 0.0001; 2 animals (2 / 10) in Group 5 showed complete regression of tumors on day 51 and remained tumor-free until the end of the study on day 130.

[0268] Figure 3 Combination therapy of TTI-101 and anti-PD-1, which resulted in tumor regression, prevented tumor re-ignition. All controls in group 10 All animals developed tumors, and 2 of the 7 animals had tumors that reached 3000 mm 24 days after inoculation. 3In the rechallenge study, 3 animals co-administered with TTI-101 and anti-PD-1 antibody (Group 4) and 2 animals sequentially dosed with TTI-101 (starting on day 7) and anti-PD-1 antibody (Group 5) had complete tumor regression in both the first H22 tumor challenge on the right side and the H22 tumor rechallenge on the left side and remained tumor-free until the end of the study 24 days after re-inoculation.

[0269] Example 2. Bioavailability and Pharmacokinetics of TTI-101 Following IP or PO Administration

[0270] The bioavailability and pharmacokinetics of TTI-101 were evaluated in male Sprague-Dawley rats after a single oral (PO) dose of 25 mg / kg (in labrasol:PEG400, 60:40% v / v) and a single intraperitoneal (IP) dose of 25.6 mg / kg (pH 7.4 PBS / propylene glycol / ethanol / DMSO, 20:70:5:5% v / v). Table 4 shows the exposure in rats after a single TTI-101 administration. The results show that the exposure of oral administration was unexpectedly increased by 90% compared to intraperitoneal administration.

[0271] Table 4. Area under the curve (AUC) of TTI-101 for PO and IP administration to rats

[0272] ROA dose AUC PO 25 mg / kg 95,700 IP 25.6mg / kg 50,300

[0273] also, Figure 5 The efficacy comparison of PO administration and IP administration in cancer models such as the mouse H22 liver cancer model is shown. In H22 mice (syngeneic liver cancer model) (n=8), tumor volume was measured 18 days after twice daily dosing (50 mg / kg) (ip vs po). Percent change in normalized tumor volume = mean value of TTI-101 treated mice / mean value of ip and po vehicle treated mice.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof and an immune checkpoint inhibitor for use in treating cancer in a subject in need thereof, comprising: a) orally administering an effective amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof to the subject, and b) administering an effective amount of the immune checkpoint inhibitor to the subject; in 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 Selected from the group consisting of hydrogen, methyl, chlorine, bromine, methoxy, ethoxy, tert-butyl, nitro, methyl ester, acetamide, 1,4-dioxine, fluorine, trifluoromethoxy, acetyl, trifluoromethyl, propyl, cyclohexene, methoxy-phenoxy, chlorophenoxy, tolyloxy and phenoxy.

2. The compound and immune checkpoint inhibitor for use according to claim 1, wherein the compound of formula (I) inhibits signal transducer and activator of transcription 3 (STAT3).

3. The compound and immune checkpoint inhibitor for use according to claim 1, wherein the compound of formula (I) inhibits signal transducer and activator of transcription 1 (STAT1).

4. The compound and immune checkpoint inhibitor for use according to claim 1, wherein the compound of formula (I) inhibits signal transducer and activator of transcription 5 (STAT5).

5. The compound and immune checkpoint inhibitor for use according to claim 1, wherein the compound of formula (I) is N-(1',2-dihydroxy-1,2'-binaphthyl-4'-yl)-4-methoxybenzenesulfonamide, N-(3,1'-dihydroxy-[1,2']binaphthyl-4'-yl)-4-methoxybenzenesulfonamide, N-(4,1'-dihydroxy-[1,2']binaphthyl-4'-yl)-4-methoxybenzenesulfonamide, N-(5,1'-dihydroxy-[1,2']binaphthyl-4'-yl)-4-methoxybenzenesulfonamide, N-(6,1'-dihydroxy-[1,2']binaphthyl-4'-yl)-4-methoxybenzenesulfonamide, hydroxy-[1,2']binaphthyl-4'-yl)-4-methoxybenzenesulfonamide, N-(7,1'-dihydroxy-[1,2']binaphthyl-4'-yl)-4-methoxybenzenesulfonamide, N-(8,1'-dihydroxy-[1,2']binaphthyl-4'-yl)-4-methoxybenzenesulfonamide, 4-bromo-N-(1,6'-dihydroxy-[2,2']binaphthyl-4-yl)-benzenesulfonamide or 4-bromo-N-[4-hydroxy-3-(1H-[1,2,4]triazol-3-ylsulfanyl)-naphthalen-1-yl]-benzenesulfonamide, or a pharmaceutically acceptable salt thereof.

6. The compound and immune checkpoint inhibitor for use according to claim 5, wherein the compound of formula (I) is N-(1',2-dihydroxy-1,2'-binaphthyl-4'-yl)-4-methoxybenzenesulfonamide.

7. The compound and immune checkpoint inhibitor for use according to claim 1, wherein the immune checkpoint inhibitor is a PD-1 inhibitor or a PD-L1 inhibitor.

8. The compound and immune checkpoint inhibitor for use according to claim 7, wherein the PD-1 inhibitor is an anti-PD-1 antibody.

9. The compound and immune checkpoint inhibitor for use according to claim 8, wherein the anti-PD-1 antibody is cemiprilimab, nivolumab, pembrolizumab, pidilizumab, spartalizumab, carrelizumab, sintilimab, tislelizumab, toripalimab, dotalimumab, sazanalizumab, rivulizumab, tepolizumab, ABBV-181, AK104, AK10 5. BCD-100, BI-754091, CBT-501, CC-90006, GLS-010, HLX10, IBI-308, JNJ-3283, JS00 1. LZM009, MEDI0680 (AMP-514), REGEN-2810, SHR-1210, Sym021, TSR-042 or XmAb20717.

10. The compound and immune checkpoint inhibitor for use according to claim 9, wherein the anti-PD-1 antibody is pembrolizumab.

11. The compound and immune checkpoint inhibitor for use according to claim 7, wherein the PD-L1 inhibitor is an anti-PD-L1 antibody.

12. The compound and immune checkpoint inhibitor for use according to claim 11, wherein the anti-PD-L1 antibody is atezolizumab, avelumab, durvalumab, envolimab, 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.

13. The compound and immune checkpoint inhibitor for use according to any one of claims 1 to 12, wherein the immune checkpoint inhibitor is administered before the compound of formula (I).

14. The compound for use according to any one of claims 1 to 12 and an immune checkpoint inhibitor, wherein the immune checkpoint inhibitor is administered simultaneously with the compound of formula (I).

15. The compound and immune checkpoint inhibitor for use according to any one of claims 1 to 12, wherein the immune checkpoint inhibitor is administered after the compound of formula (I).

16. A compound and an immune checkpoint inhibitor for use according to any one of claims 1 to 15, wherein the subject is in at least partial remission after three weeks or more of administration of the compound of formula (I) and the immune checkpoint inhibitor.

17. A compound and an immune checkpoint inhibitor for use according to any one of claims 1 to 16, wherein the subject is in complete remission after six weeks or more of administration of the compound of formula (I) and the immune checkpoint inhibitor.

18. The compound and immune checkpoint inhibitor for use according to any one of claims 1 to 17, wherein the method reduces tumor size by at least 20% within six weeks of administration compared to administration of the immune checkpoint inhibitor alone to the subject.

19. A compound of formula (I) or a pharmaceutically acceptable salt thereof and an immune checkpoint inhibitor for use in a method for reducing the risk of cancer recurrence in a subject in need thereof, comprising: a) orally administering an effective amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof to the subject, and b) administering an effective amount of the immune checkpoint inhibitor to the subject; in 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 Selected from the group consisting of hydrogen, methyl, chlorine, bromine, methoxy, ethoxy, tert-butyl, nitro, methyl ester, acetamide, 1,4-dioxine, fluorine, trifluoromethoxy, acetyl, trifluoromethyl, propyl, cyclohexene, methoxy-phenoxy, chlorophenoxy, tolyloxy and phenoxy.

20. A compound of formula (I) or a pharmaceutically acceptable salt thereof and an immune checkpoint inhibitor for use in a method for preventing cancer recurrence in a subject in need thereof, comprising: a) orally administering an effective amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof to the subject, and b) administering the effective amount of the immune checkpoint inhibitor to the subject; in R is selected from hydrogen, phenylsulfanyl, 2-hydroxy-naphthalen-1-yl, quinolin-8-ylsulfanyl, triazol-3-ylsulfanyl, and benzothiazol-2-ylsulfanyl; R 1 Selected from the group consisting of hydrogen, methyl, chlorine, bromine, methoxy, ethoxy, tert-butyl, nitro, methyl ester, acetamide, 1,4-dioxine, fluorine, trifluoromethoxy, acetyl, trifluoromethyl, propyl, cyclohexene, methoxy-phenoxy, chlorophenoxy, tolyloxy and phenoxy.

21. The compound and immune checkpoint inhibitor for use according to claim 19 or 20, wherein the immune checkpoint inhibitor is administered to the subject parenterally.

22. A compound of formula (II) or a pharmaceutically acceptable salt thereof and an immune checkpoint inhibitor for use in treating cancer in a subject in need thereof, comprising administering to the subject: a) an effective amount of the compound of formula (II) or a pharmaceutically acceptable salt thereof, and b) an effective amount of the immune checkpoint inhibitor; in R1, at each occurrence, 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; n1 is 0, 1, 2, 3 or 4; R2, at each occurrence, 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 aryloxy, 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; R5, R6 and R7 are independently, at each occurrence, 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; and Ra, Rb and Rc are independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle or aryl at each occurrence; or Rb and Rc, together with the nitrogen atom to which they are bound, optionally form a heterocycle containing 1-4 heteroatoms.

23. The compound and immune checkpoint inhibitor for use according to claim 22, wherein the compound of formula (II) inhibits signal transducer and activator of transcription 3 (STAT3).

24. The compound and immune checkpoint inhibitor for use according to claim 22, wherein the compound of formula (II) inhibits signal transducer and activator of transcription 1 (STAT1).

25. The compound and immune checkpoint inhibitor for use according to claim 22, wherein the compound of formula (II) inhibits signal transducer and activator of transcription 5 (STAT5).

26. The compound and immune checkpoint inhibitor for use according to claim 22, wherein the compound of formula (II) is a compound of formula (III): or a pharmaceutically acceptable salt thereof.

27. The compound and immune checkpoint inhibitor for use according to claim 26, wherein the compound of formula (III) is a compound of formula (IV): or a pharmaceutically acceptable salt thereof.

28. The compound and immune checkpoint inhibitor for use according to any one of claims 22 to 27, wherein the immune checkpoint inhibitor is a PD-1 inhibitor or a PD-L1 inhibitor.

29. The compound and immune checkpoint inhibitor for use according to claim 28, wherein the PD-1 inhibitor is an anti-PD-1 antibody.

30. The compound and immune checkpoint inhibitor for use according to claim 29, wherein: The anti-PD-1 antibody is cemiprilimab, nivolumab, pembrolizumab, pidilizumab, spartalizumab, carrelizumab, sintilimab, tislelizumab, toripalimab, dotalimab, sazanlimab, refulimab, tepolizumab, ABBV-181, AK104, AK105, BCD-100, BI-754091, CBT-501, CC-90006, GLS-010, HLX10, IBI-308, JNJ-3283, JS001, LZM009, MEDI0680 (AMP-514), REGEN-2810, SHR-1210, Sym021, TSR-042 or XmAb20717.

31. The compound and immune checkpoint inhibitor for use according to claim 30, wherein the anti-PD-1 antibody is pembrolizumab.

32. The compound and immune checkpoint inhibitor for use according to claim 28, wherein the PD-L1 inhibitor is an anti-PD-L1 antibody.

33. The compound and immune checkpoint inhibitor for use according to claim 32, wherein the anti-PD-L1 antibody is atezolizumab, avelumab, durvalumab, envolimab, 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.

34. The compound and immune checkpoint inhibitor for use according to any one of claims 22 to 33, wherein the immune checkpoint inhibitor is administered before the compound of formula (II).

35. A compound for use according to any one of claims 22 to 33 and an immune checkpoint inhibitor, wherein the immune checkpoint inhibitor is administered simultaneously with the compound of formula (II).

36. The compound and immune checkpoint inhibitor for use according to any one of claims 22 to 33, wherein the immune checkpoint inhibitor is administered after administration of the compound of formula (II).

37. The compound and immune checkpoint inhibitor for use according to any one of claims 22 to 36, wherein the compound of formula (II) is orally administered to the subject.

38. A compound of formula (II) or a pharmaceutically acceptable salt thereof and an immune checkpoint inhibitor for use in a method of reducing the risk of cancer recurrence in a subject in need thereof, comprising administering to the subject: a) an effective amount of the compound of formula (II) or a pharmaceutically acceptable salt thereof, and b) an effective amount of the immune checkpoint inhibitor; in R1, at each occurrence, 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; n1 is 0, 1, 2, 3 or 4; R2, at each occurrence, 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 aryloxy, 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; R5, R6 and R7 are independently, at each occurrence, 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; and Ra, Rb and Rc are independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle or aryl at each occurrence; or Rb and Rc, together with the nitrogen atom to which they are bound, optionally form a heterocycle containing 1-4 heteroatoms.

39. A compound of formula (II) or a pharmaceutically acceptable salt thereof and an immune checkpoint inhibitor for use in a method for preventing cancer recurrence in a subject in need thereof, comprising administering to the subject: a) an effective amount of the compound of formula (II) or a pharmaceutically acceptable salt thereof, and b) an effective amount of the immune checkpoint inhibitor; in R1, at each occurrence, 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; n1 is 0, 1, 2, 3 or 4; R2, at each occurrence, 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 aryloxy, 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; R5, R6 and R7 are independently, at each occurrence, 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; and Ra, Rb and Rc are independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle or aryl at each occurrence; or Rb and Rc, together with the nitrogen atom to which they are bound, optionally form a heterocycle containing 1-4 heteroatoms.

40. The compound and immune checkpoint inhibitor for use according to any one of claims 1 to 39, wherein the immune checkpoint inhibitor is administered parenterally.

41. A compound and an immune checkpoint inhibitor for use according to any one of claims 1-40, 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. The compound and immune checkpoint inhibitor for use according to claim 41, wherein the cancer is head and neck cancer, lung cancer, liver cancer, breast cancer, ovarian cancer, colon cancer, multiple myeloma or pancreatic cancer.

Images