Lactone and lactam-containing compounds useful as immunomodulators

Abstract

The present disclosure generally relates to compounds that contain lactones and lactams and are useful as immunomodulators.The present disclosure provides compounds, compositions that contain the compounds, and methods of using the same.The present disclosure further relates to pharmaceutical compositions that contain at least one of the compounds described in the present disclosure and are useful for treating various diseases, such as cancer and infectious diseases.

Description

[Technical Field]

[0001] This disclosure generally relates to lactone and lactam-containing compounds useful as inhibitors of PD-1 / PD-L1 protein / protein interactions and CD80 / PD-L1 protein / protein interactions. The present invention provides compounds, compositions containing such compounds, and methods of using the same. This disclosure further relates to pharmaceutical compositions containing at least one of the compounds described herein that are useful for treating various diseases, such as cancer and infectious diseases.

[0002] Programmed death-1 (CD279) is a receptor on T cells and is known to suppress activation signals from the T cell receptor when bound to either its ligand (PD-L1, CD274, B7-H1) or PD-L2 (CD273, B7-DC) (Sharpe et al., Nat. Imm. 2007). When PD-1 expressed on T cells comes into contact with cells expressing its ligand, functional activities in response to antigen stimulation, including proliferation, cytokine secretion, and cytolytic activity, are suppressed. PD-1 / PD-ligand interactions downregulate the immune response during the healing of infections or tumors, or during the construction of autoimmune tolerance (Keir Me, Butte MJ, Freeman GJ, et al. Annu. Rev. Immunol. 2008; 26: Epub). For example, chronic antigen stimulation occurring during tumor disease or chronic infection can cause T cells to express high levels of PD-1, leading to dysfunction in their activity against chronic antigens (review of Kim and Ahmed, Curr Opin Imm, 2010). This is called "T cell exhaustion," and B cells also show PD-1 / PD-ligand suppression and "exhaustion."

[0003] PD-L1 is also known to interact with CD80 (Butte MJ et al., Immunity 27:111). -122(2007)). The interaction of PD-L1 / CD80 with expressing immune cells is known to be an inhibitory interaction. It is known that blocking this interaction can reverse this inhibitory interaction (Paterson AM, et al., J Immunol., 187:1097-1105 (2011); Yang J, et al. J Immunol. Aug 1;187(3):1113-9 (2011)).

[0004] Blocking the PD-1 / PD-L1 interaction using antibodies against PD-L1 is known to repair and enhance T cell activation in many systems. Treatment with monoclonal antibodies against PD-L1 is useful for patients with advanced cancer (Brahmer et al., New Engl J Med 2012). In preclinical animal models of tumors, blocking the PD-1 / PD-L1 pathway with monoclonal antibodies has been shown to enhance the immune response and enable immune responses against numerous histologically evident tumors (Dong H, Chen L. J Mol Med. 2003; 81(5):281 287; Dong H, Strome SE, Salamoa DR, et al. Nat Med. 2002; 8(8):793-800).

[0005] Inhibiting PD-1 / PD-L1 interactions has also been shown to enhance T cell activity in chronic infectious disease systems. Chronic lymphocytic choriomeningitis virus infection in mice shows enhanced viral clearance and immune repair upon PD-L1 blockade (Barber DL, Wherry EJ, Masopust D, et al. Nature 2006; 439(7077):682-687). Humanized mice infected with HIV-1 show enhanced defense against viremia and reduced viral depletion of CD4+ T cells (Palmer et al., J. Immunol 2013). PD-1 / PD-L1 blockade using monoclonal antibodies against PD-L1 has been shown to be effective in HIV patients (Day, Nature 2006; Petrovas, J. Exp. Med. 2006; Trautman, Nature Med. 2006; D'Souza, J.Immunol. 2007; Zhang, Blood 2007; Kaufmann, Nature Imm. 2007; Kasu, J. Immunol. 2010; Porichis, Blood 2011), HCV patients (Golden-Mason, J. Virol. 2007; Jeung, J. Leuk. Biol. 2007; Urbani, J. Hepatol. 2008; Nakamoto, PLoS Path. 2009; Nakamoto, Gastroenterology 2008) or HBV patients (Boni, , J. Virol. 2007; Antigen-specific functionality for T cells, obtained from Fisicaro, Gastro. 2010; Fisicaro et al., Gastroenterology, 2012; Boni et al., Gastro., 2012; Penna et al., J Hep, 2012; Raziorrough, Hepatology 2009; Liang, World J Gastro. 2010; Zhang, Gastro. 2008), can be restored in vitro.

[0006] Blocking the PD-L1 / CD80 interaction is known to stimulate the immune system (Yang J., et al., J Immunol. Aug 1;187(3):1113-9 (2011)). The immune stimulation caused by blocking the PD-L1 / CD80 interaction is known to be further enhanced by combining it with blocking the PD-1 / PD-L1 or PD-1 / PD-L2 interaction.

[0007] Alterations in the immune cell phenotype are hypothesized to be important factors in septic shock (Hotchkiss, et al., Nat Rev Immunol (2013)). These include increased PD-1 and PD-L1 levels, and increased T cell apoptosis (Guignant, et al, Crit. Care (2011)). Antibodies against PD-L1 may reduce the level of immune cell apoptosis (Zhang et al, Crit. Care (2011)). Furthermore, PD-1-deficient mice are more resistant to septic shock symptoms than wild-type mice (Yang J., et al., J Immunol. Aug 1;187(3):1113-9 (2011)). Studies have shown that blocking PD-L1 interactions using antibodies can suppress inappropriate immune responses and improve disease symptoms.

[0008] In addition to enhancing the immune response to chronic antigens, blocking the PD-1 / PD-L1 pathway is also known to enhance the response to vaccination, including therapeutic vaccination in chronic infections (SJ Ha, SN Mueller, EJ Wherry et al., The Journal of Experimental Medicine, vol. 205, no. 3, pp. 543-555, 2008; AC Finnefrock, A. Tang, F. Li et al., The Journal of Immunology, vol. 182, no. 2, pp. 980-987, 2009; M.-Y. Song, S.-H. Park, HJ Nam, D.-H. Choi, and Y.-C. Sung, The Journal of Immunotherapy, vol. 34, no. 3, pp. 297-306, 2011).

[0009] The PD-1 pathway is a key inhibitory molecule in T cell exhaustion resulting from chronic antigen stimulation during chronic infections and tumor diseases. Blocking the PD-1 / PD-L1 interaction by targeting the PD-L1 protein is known to restore antigen-specific T cell immune function in vitro and in vivo, including enhancing the response to vaccination in tumor or chronic infection states. Therefore, there is a need for drugs that block the interaction between PD-L1 and either PD-1 or CD80.

[0010] The applicant has discovered potent compounds that have activity as inhibitors of the interaction between PD-L1 and PD-1 and CD80, and therefore may be useful for therapeutic administration (including therapeutic vaccines) to enhance immunity in cancer or infectious diseases. These compounds also possess desirable stability, bioavailability, therapeutic index, and toxicity values ​​important for the drugability of the compounds, and are offered as useful agents.

[0011] In a first embodiment, this disclosure relates to formula (I): [Chemical formula] [In the formula, R 1 is independently -(O) m -(CH2) n -R 1a or -(CH2) n -(O) m -R 1b ; R 1a is independently a 5- to 6-membered heterocycle having 1 to 2 heteroatoms selected from O, N, S, and NR a , where the heterocycle is substituted with 0 to 3 R b ; R 1b is phenyl or a 5- to 6-membered heteroaryl having 1 to 4 heteroatoms selected from O, N, S, and NR a , where the phenyl and heteroaryl are substituted with 0 to 3 R 1c ; R 1c is independently halogen, CN, OH, SH, NH2, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkyl substituted with 0 to 1 OH, or C3-C6 cycloalkyl, -(O) m -(CH2) n -R[[ID=4~6]] 1d or -(CH2) n -NR 7 -R 2a ; R 1d is phenyl or a 5- to 6-membered heteroaryl having 1 to 4 heteroatoms selected from O, N, S, and NR a , where the phenyl and heteroaryl are substituted with 0 to 3 R d ; Z is a bond or C1-C2 alkylene; R 2 is independently a 4- to 8-membered lactone or lactam substituted with 0 to 4 R c ; R 3 R 4 and R5 These are, independently, halogen, CN, OH, SH, NH2, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, or C3-C6 cycloalkyl; R 6 These are independently hydrogen, C1-C4 alkyl, or -(CH2) n -R 6a and; R 6a These are independently phenyl or O, N, S, and NR a A 5-6 membered heteroaryl having 1-4 heteroatoms selected from, where the phenyl and heteroaryl have 0-3 R 6b Replaced by; R 6b These are independently halogens, CN, OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, or C1-C4 haloalkoxy; R 7 These are independently hydrogen, C1-C4 alkyl, -C(O)C1-C4 alkyl, and -(CH2) n -C3-C6 cycloalkyl, or -(CH2) n -phenyl; or, R 6 and R 7 They unite to form W; and W is a 1-4 member linker having elements independently selected from carbon, oxygen, and nitrogen, where the linker has 0-2 R e Replaced by; R a These are independently halogens, C1-C4 alkyls, and -(CH2) n -C3-C6 cycloalkyl, or -(CH2) n -It is phenyl; R b and R c These are, independently, oxo, halogen, CN, OH, C1-C4 alkyl, or C1-C4 alkoxy; R d These are, independently, halogen, CN, OH, C1-C4 alkyl, or C1-C4 alkoxy; R e These are independently oxo, =CH2, halogen, CN, OH, C1-C4 alkyl, or C1-C4 alkoxy; m is either 0 or 1 independently; n is independently 0, 1, or 2; [r, s, and t are each independently 0, 1, or 2.] The present invention provides compounds of or pharmaceutically acceptable salts thereof.

[0012] In a second embodiment within the scope of the first embodiment, in the formula, R 2 These are 0 to 4 R independently a A 5-6 member lactone or lactam substituted with; R a These are independently oxo, halogen, OH, or C1-C3 alkyl; W is a 2-3 member linker having elements independently selected from carbon, oxygen, and nitrogen, where the linker has 0-2 R e Replaced by; and R e These are independently oxo, =CH2,OH, or C1-C4 alkyl groups.

[0013] In a third embodiment, this disclosure relates to formula (II): [ka] [In the formula, R 1 It is independently -O-CH2-R 1a or -CH2-OR 1b and; R 1a It is N-(C1-C3 alkyl)-piperidinyl; R 1b This is 1 to 3 R 1c It is a phenyl substituted with; R 1c These are independently halogen, -CH2OH, and -O-CH2-R 1d , or -CH2-NR 7-R 2a and; R 1d It is a cyanosubstituted pyridyl; R 2 and R 2a Each is independent of the others. [ka] and; R 3 These are independently hydrogen, C1-C3 alkyl, or halogen; R 4 These are independently hydrogen, C1-C3 alkyl, or halogen; R 5 These are independently hydrogen, C1-C3 alkyl, or halogen; R 6 These are independently hydrogen, C1-C3 alkyl, or -CH2-(cyanosubstituted pyridyl); and R 7 [These are independently hydrogen, C1-C3 alkyl, -C(O)C1-C3 alkyl, or -CH2-cyclopropyl] The present invention provides compounds of or pharmaceutically acceptable salts thereof.

[0014] In a fourth aspect within the scope of the third aspect, in the formula, R 1 is -O-CH2-R 1a and; R 1a It is N-(C1-C3 alkyl)-piperidinyl; R 6 is -CH2-(cyanosubstituted pyridyl); and R 7 It is hydrogen.

[0015] In the fifth embodiment within the scope of the third embodiment, in the formula, R 1 is -CH2-OR 1b and; R 1b This is 1 to 3 R 1c It is a phenyl substituted with; R 1cis independently halogen, -O-CH2-R 1d or -CH2-NR 7 -R 2a ; and R 1d is cyano-substituted pyridyl; and R 7 is hydrogen.

[0016] In a sixth aspect, the present disclosure provides formula (III):

Chemical formula

Chemical formula

[0017] In another embodiment, compounds selected from the described examples, or pharmaceutically acceptable salts thereof, are provided.

[0018] In another embodiment, compounds selected from a subset of compounds within any range of the above embodiments are also provided.

[0019] Furthermore, this disclosure also provides pharmaceutical compositions comprising the compounds of the present invention, or pharmaceutically acceptable salts thereof, and pharmaceutically acceptable carriers.

[0020] In another embodiment, the present disclosure provides compounds of the present invention, pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof for use as pharmaceuticals.

[0021] In another embodiment, the present disclosure provides compounds of the present invention, pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof for use in the manufacture of pharmaceuticals for treating cancer in a subject of interest.

[0022] In another embodiment, the present disclosure provides the compounds of the present invention or pharmaceutically acceptable salts thereof, characterized by administering a therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof to a subject of interest, for use in enhancing, stimulating, modulating, and / or increasing the immune response in the subject.

[0023] In another embodiment, the present disclosure provides the compounds of the present invention or pharmaceutically acceptable salts thereof, characterized by administering a therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof to a subject of interest, for use in inhibiting the growth, proliferation, or metastasis of cancer cells in the subject.

[0024] In another embodiment, the Disclosure provides a method for a patient in need of enhancing, stimulating, modulating and / or increasing the immune response, characterized by administering to the patient a therapeutically effective amount of the compound of the Invention or a pharmaceutically acceptable salt thereof. In the first embodiment of a third aspect, the Disclosure further provides a method for administering another agent before, after, or concurrently with the administration of the compound of the Invention or a pharmaceutically acceptable salt thereof. In the second embodiment, the other agent is an antibacterial agent, an antiviral agent, a cytotoxic agent, a gene expression modulator, and / or an immunoassay modifier.

[0025] In another embodiment, the present disclosure provides a method for a patient in need of inhibiting the growth, proliferation, or metastasis of cancer cells, characterized by administering to the patient a therapeutically effective amount of the compound or pharmaceutically acceptable salt of the present invention. In the first embodiment of the fourth aspect, the cancer is selected from melanoma, renal cell carcinoma, squamous non-small cell lung cancer (NSCLC), non-squamous NSCLC, colorectal cancer, castration-resistant prostate cancer, ovarian cancer, gastric cancer, hepatocellular carcinoma, pancreatic cancer, squamous cell carcinoma of the head and neck, cancers of the esophagus, gastrointestinal tract and breast, and hematopoietic malignancies.

[0026] In another embodiment, the present disclosure provides a method for treating an infectious disease, to a patient in need thereof, characterized by administering to the patient a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In the first embodiment of the fifth aspect, the infectious disease is caused by a virus. In the second embodiment of the fifth aspect, the virus is selected from HIV, hepatitis A, hepatitis B, hepatitis C, hepatitis D, herpesvirus, papillomavirus, and influenza.

[0027] In another embodiment, the present disclosure provides a method for treating septic shock in a patient in need, characterized by administering to the patient a therapeutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof.

[0028] Unless otherwise specified in this specification, words expressed in the singular form may also include plural forms. For example, "a" and "an" may refer to either "one" or "one or more."

[0029] As used herein, the phrase “compound or a pharmaceutically acceptable salt thereof” means at least one compound, a salt of at least one compound, or a combination thereof. For example, the compounds of the present invention or a pharmaceutically acceptable salt thereof include one compound of the present invention; two compounds of the present invention; a salt of one compound of the present invention; a salt of one compound of the present invention and one or more compounds of the present invention; and salts of two or more compounds of the present invention.

[0030] Unless otherwise specified, any atom whose valence is not met is considered to contain enough hydrogen atoms to satisfy the valence.

[0031] Throughout this specification, groups and substituents may be selected by those skilled in the art to provide stable moieties and compounds.

[0032] The definitions of various terms used in describing this disclosure are listed below. These definitions apply to terms used throughout the specification, individually or as part of a larger group (unless otherwise specified). The definitions set forth herein supersede any definitions set forth in any patent, patent application and / or patent application publication incorporated herein by reference.

[0033] As used herein, the term "C1-C3 alkyl" refers to a group derived from a straight-chain or branched-chain saturated hydrocarbon containing 1 to 3 carbon atoms.

[0034] As used herein, the term "C1-C6 alkyl" refers to a group derived from a straight-chain or branched-chain saturated hydrocarbon containing 1 to 6 carbon atoms.

[0035] As used herein, the term "amide" refers to -C(O)NH2.

[0036] As used herein, the term "aminocarbonyl" refers to -C(O)NH2.

[0037] As used herein, the term "carbonyl" refers to -C(O)-.

[0038] As used herein, the term "carboxyl" refers to -CO2H.

[0039] In this specification, the term "cyano" refers to -CN.

[0040] As used herein, the term "cycloalkyl" refers to a group derived from a non-aromatic monocyclic or polycyclic hydrocarbon molecule obtained by removing one hydrogen atom from a saturated ring carbon atom. Representative examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclopentyl, and cyclohexyl. When a number is subscripted after the symbol "C", the subscript more specifically limits the number of carbon atoms that a particular cycloalkyl group may contain. For example, "C 3-6 "Cycloalkyl" refers to a cycloalkyl group having 3 to 6 carbon atoms.

[0041] As used herein, the term "(C3-C6 cycloalkyl)C1-C3 alkyl" refers to a C1-C3 alkyl group substituted with a C3-C6 cycloalkyl group.

[0042] As used herein, the terms "halo" and "halogen" refer to F, Cl, Br, or I.

[0043] As used herein, the term "C1-C4 haloalkoxy" refers to a halo-C1-C4 alkyl group that is connected to the parent molecule via an oxygen atom.

[0044] As used herein, the term "C1-C3 haloalkyl" refers to a C1-C3 alkyl group substituted with one, two, or three halogen atoms.

[0045] The term "hydroxyalkyl" includes both linear and branched saturated alkyl groups substituted with one or more hydroxyl groups. For example, "hydroxyalkyl" includes -CH2OH, -CH2CH2OH, and C 1-4 It contains hydroxyalkyl.

[0046] As used herein, the term "nitro" refers to -NO2.

[0047] In this specification, the term "oxo" refers to =O.

[0048] The term "heteroatom" refers to oxygen (O), sulfur (S), and nitrogen (N).

[0049] The terms "heterocyclo," "heterocycle," or "heterocyclyl" may be used synonymously and refer to a cyclic group having at least one saturated or partially saturated non-aromatic ring, where one or more rings contain at least one heteroatom (O, S, or N), and the heteroatom-containing ring preferably has 1 to 3 heteroatoms independently selected from O, S, and / or N. The ring of such a heteroatom-containing group may contain 1 or 2 oxygen or sulfur atoms and / or 1 to 4 nitrogen atoms, provided that the ring contains at least one carbon atom. The nitrogen and sulfur atoms may be oxidized as appropriate, and the nitrogen atoms may be quaternized as appropriate. The heterocyclo group may be bonded with any bondable nitrogen or carbon atom. The heterocyclocycle may be unsubstituted or may have one or more substituents as valence permits.

[0050] Examples of monocyclic heterocyclyl groups include pyrrolidinyl, imidazolinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrodinyl, 2-oxoazepinyl, azepinyl, 4-piperidonyl, tetrahydropyranyl, morpholinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, 1,3-dioxolane, tetrahydro-1,1-dioxothienyl, dihydroisoindolyl, and tetrahydroquinolinyl.

[0051] The term "heterocyclyl" also includes heteroaryl compounds.

[0052] Examples of monocyclic heteroaryl groups include pyrrolyl, pyrazolyl, pyrazolinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, furanyl, thiophenyl, oxadiazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, and triazinyl.

[0053] Examples of bicyclic heteroaryl groups include indolyl, benzothiazolyl, benzodioxolyl, benzoxazolyl, benzothienyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranil, indolidinyl, benzofuranil, chromonyl, coumalinil, benzopyranil, sinnolinyl, quinoxalinyl, indazolyl, and pyrrolopyridyl.

[0054] As used herein, the phrase "pharmaceutically acceptable" means a compound, substance, composition, and / or dosage form that, within the bounds of ordinary medical judgment, is suitable for contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, and that provides a reasonable benefit-risk ratio.

[0055] The compounds of the present invention may form salts, and these salts are also within the scope of this disclosure. Unless otherwise specified, references to compounds relating to the invention are understood to include references to one or more of its salts. The term “salt” refers to acid salts and / or base salts formed by inorganic and / or organic acids and bases. Furthermore, the term “salt” may include zwitterions (intramolecular salts) if, for example, the compounds of the present invention have both a basic moiety (e.g., an amine, pyridine, or imidazole ring) and an acidic moiety (e.g., a carboxylic acid). Medicinally acceptable (i.e., non-toxic and physiologically acceptable) salts are preferably acceptable metal salts and amine salts, for example, in which the cation does not significantly contribute to the toxicity or biological activity of the salt. However, other salts may also be useful, for example, in isolation or purification steps that may be used in the manufacturing process, and therefore other salts are also considered to be within the scope of this disclosure. Salts of the compounds of the present invention may be formed, for example, by reacting the compounds of the present invention with a certain amount of acid or base (e.g., 1 equivalent), by precipitating the salt in a solvent, for example, or by subsequently freeze-drying an aqueous solution.

[0056] Examples of acid addition salts include acetic acid (e.g., salts prepared from acetic acid or trihaloacetic acid (e.g., trifluoroacetic acid)), adipine, alginate, ascorbate, aspartate, benzoate, benzenesulfonic acid, bisulfate, borate, butyrate, citric acid, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride (prepared from hydrochloric acid), hydrobromide (prepared from hydrogen bromide), and iodine. These include hydrochlorides, maleates (prepared from maleic acid), 2-hydroxyethanesulfonates, lactates, methanesulfonates (prepared from methanesulfonic acid), 2-naphthalenesulfonates, nicotinates, nitrates, oxalates, pectins, persulfates, 3-phenylpropionates, phosphates, picrinates, pyruvates, propions, salicylates, succinates, sulfates (e.g., salts prepared from sulfuric acid), sulfonates (e.g., those described herein), tartrates, thiocyanates, toluenesulfonates (e.g., tosylate), and undecanoates.

[0057] Examples of basic salts include ammonium salts, alkali metal salts (e.g., sodium, lithium, and potassium salts); alkaline earth metal salts (e.g., calcium and magnesium salts); salts of barium, zinc, and aluminum; salts with organic bases (e.g., trialkylamines such as triethylamine, procaine, dibenzylamine, N-benzyl-β-phenethylamine, 1-efenamine, N,N'-dibenzylethylenediamine, dehydroabiethylamine, N-ethylpiperidine, benzylamine, dicyclohexylamine), or salts with similar pharmaceutically acceptable amines and amino acids (e.g., arginine, lysine). Basic nitrogenous groups include reagents (e.g., lower alkylhalides). They may be quaternized by dialkyl sulfates (e.g., methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides), dialkyl sulfates (e.g., dimethyl, diethyl, dibutyl, and di-amyl sulfates), long-chain halides (e.g., decyl, lauryl, myristyl, and stearyl chlorides, bromides, and iodides), aralkyl halides (e.g., benzyl and phenethyl bromides), and others). Preferred salts include monohydrochloride, hydrogen sulfate, methanesulfonate, phosphate, or nitrate.

[0058] Various forms of prodrugs are well known in this field: a) The Practice of Medicinal Chemistry, Camille G. Wermuth et al., Ch 31, (Academic Press, 1996); b) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985); c) A Textbook of Drug Design and Development, P. Krogsgaard-Larson and H. Bundgaard, eds. Ch 5, pgs 113 - 191 (Harwood Academic Publishers, 1991); and d) Hydrolysis in Drug and Prodrug Metabolism, Bernard Testa and Joachim M. Mayer, (Wiley-VCH, 2003) It is described there.

[0059] The compounds of this disclosure may include stereoisomers containing a chiral or asymmetric center. Specific stereochemistrys may be designated with the symbols "R" or "S" based on the arrangement of substituents around the chiral carbon atom. The present invention envisions a variety of stereoisomers (i.e., enantiomers and diastereomers) and mixtures thereof, and is intended to encompass all stereoisomers that bind to PD-L1. Each stereoisomer of the compounds of this invention may be produced by synthesis from commercially available starting materials containing a chiral or asymmetric center, or by division following the preparation of a racemic mixture, as known to those skilled in the art.

[0060] In addition, after preparation, the compounds of the present invention are isolated and purified to obtain a composition containing 99% or more of the compounds of the present invention ("substantially pure"), which is then used or formulated as described herein. Such "substantially pure" compounds of the present invention are also considered to be part of the present invention.

[0061] "Stable compounds" and "stable structures" are intended to be compounds that are sufficiently robust to not degrade even when isolated from a reaction mixture to a usable purity or when formulated into an effective therapeutic agent. This disclosure embodies stable compounds.

[0062] "Therapeutic dose" is intended to include the amount of the compound in this disclosure alone, or the amount of the compounds in the claims combined, or the amount of the compound in this disclosure combined with other active ingredients that are effective in inhibiting PD-1 / PD-L1 protein / protein and / or CD80 / PD-L1 protein / protein interactions, or effective in treating or preventing cancer or infectious diseases (e.g., septic shock, HIV, or hepatitis B, C, and D).

[0063] As used herein, the terms “treat” or “treat” include treatment of a disease in mammals, in particular humans, and may include (a) preventing a mammal from becoming ill with a disease, in particular when the mammal is susceptible to a disease state but has not yet been diagnosed with the disease; (b) suppressing the disease, i.e., preventing its progression; and / or (c) alleviating the disease, i.e., causing regression of the disease.

[0064] The compounds disclosed herein are intended to contain all isotopes of the atoms present in the compounds. Isotopes include atoms with the same atomic number but different mass numbers. Common examples include, but are not limited to, deuterium (D) and tritium (T) as isotopes of hydrogen. Isotopes of carbon include 13 C and 14 C is included. The isotope-labeled compounds of the present invention can be prepared by conventional techniques generally known to those skilled in the art, or by methods similar to those described herein, using appropriate isotope-labeling reagents instead of other unlabeled reagents. For example, methyl (-CH3) also includes deuterated methyl groups (e.g., -CD3).

[0065] The compounds and / or pharmaceutically acceptable salts thereof described in the present invention may be administered by any method appropriate to the symptom to be treated, the method of which may vary depending on the site required or the amount of the compound of the present invention to be delivered. The disclosure also includes a class of pharmaceutical compositions comprising the compounds of the present disclosure and / or pharmaceutically acceptable salts thereof, one or more non-toxic and pharmaceutically acceptable carriers and / or diluents and / or adjuvants (substances collectively referred to herein as “carriers”), and optionally other active ingredients. The compounds of the present invention may be administered by any appropriate route, preferably in the form of a pharmaceutical composition adapted to such route, and in a dosage effective for the intended treatment. The compounds and compositions of the present disclosure may be administered in dosage unit formulations containing conventional pharmaceutically acceptable carriers, adjuvants, and vehicles by oral, transmucosal, transrectal, or parenteral administration such as intravascular, intravenous, intraperitoneal, subcutaneous, intramuscular, and intrasternal administration. For example, the pharmaceutical carrier may include a mixture of mannitol or lactose and microcrystalline cellulose. The mixture may contain additives such as a lubricant (e.g., magnesium stearate) and a disintegrant (e.g., crospovidone). The carrier mixture may be filled into gelatin capsules or compressed into tablets. The pharmaceutical composition may be administered, for example, in oral dosage form or by intravenous infusion.

[0066] For oral administration, the pharmaceutical composition may be in the form of, for example, tablets, capsules, liquid capsules, suspensions, or liquids. The pharmaceutical composition is preferably formulated in dosage units having a specific amount of the active ingredient. For example, the pharmaceutical composition may be provided as tablets or capsules containing an amount of the active ingredient ranging from about 0.1 to 1000 mg, preferably about 0.25 to 250 mg, and more preferably about 0.5 to 100 mg. An appropriate daily dose for administration to humans or other mammals may be determined using conventional methods, although this may vary considerably depending on the patient's condition and other factors.

[0067] Any pharmaceutical composition discussed herein may be delivered orally, for example, by an optional and suitable oral formulation. Examples of oral formulations include, but are not limited to, tablets, lozenges, tablets, lozenges, aqueous and oily suspensions, dispersible powders or granules, emulsions, hard and soft capsules, liquid capsules, syrups, and elixirs. Pharmaceutical compositions for oral administration may be manufactured according to any method known in the art of manufacturing pharmaceutical compositions for oral administration. To provide a pharmaceutically acceptable formulation, the pharmaceutical compositions described herein may include at least one substance selected from sweeteners, flavoring agents, coloring agents, lubricants, antioxidants, and preservatives.

[0068] Tablets may be manufactured, for example, by mixing at least one compound of the present invention and / or at least one pharmaceutically acceptable salt thereof with at least one non-toxic and pharmaceutically acceptable additive suitable for the manufacture of tablets. Examples of additives include, but are not limited to, inert diluents (e.g., calcium carbonate, sodium carbonate, lactose, calcium phosphate, and sodium phosphate), granulators and disintegrants (e.g., microcrystalline cellulose, croscarmellose sodium, corn starch, and alginic acid), binders (e.g., starch, gelatin, polyvinylpyrrolidone, and gum arabic), and lubricants (e.g., magnesium stearate, stearic acid, and talc). Furthermore, tablets may be left uncoated or coated by known techniques to mask the unpleasant taste of an unpleasant drug or to delay the disintegration and absorption of the active ingredient in the gastrointestinal tract, thereby prolonging the effect of the active ingredient over a longer period. Examples of water-soluble taste-masking materials include, but are not limited to, hydroxypropyl methylcellulose and hydroxypropylcellulose. Examples of time-delaying materials include, but are not limited to, ethylcellulose and cellulose acetate-butyrate.

[0069] Hard gelatin capsules can be produced, for example, by mixing at least one compound of the present invention and / or at least one salt thereof with at least one inert solid diluent (e.g., calcium carbonate, calcium phosphate, and kaolin).

[0070] Soft gelatin capsules can be produced, for example, by mixing at least one compound of the present invention and / or at least one pharmaceutically acceptable salt thereof with at least one water-soluble carrier (e.g., polyethylene glycol) and at least one oily medium (e.g., peanut oil, liquid paraffin, and olive oil).

[0071] Aqueous suspensions can be prepared, for example, by mixing at least one compound of the present invention and / or at least one pharmaceutically acceptable salt thereof with at least one additive suitable for the preparation of aqueous suspensions. Examples of additives suitable for the preparation of aqueous suspensions include, but are not limited to, suspending agents (e.g., sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose, sodium alginate, alginic acid, polyvinylpyrrolidone, tragacanth gum, and gum arabic), dispersants or wetting agents (e.g., naturally occurring phosphatides (e.g., lecithin), condensation products of alkylene oxides and fatty acids (e.g., polyoxyethylene stearate), condensation products of ethylene oxide and long-chain aliphatic alcohols (e.g., heptadecaethyleneoxycetanol), ethylene oxide and fatty acids and Examples include condensation products with partial esters derived from hexitol (e.g., polyoxyethylene sorbitol monooleate), and condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides (e.g., polyethylene sorbitan monooleate). The aqueous suspension may also contain at least one preservative (e.g., ethyl p-hydroxybenzoate and n-propyl p-hydroxybenzoic acid), at least one coloring agent, at least one flavoring agent, and / or at least one sweetener (but not limited to, e.g., sucrose, saccharin, and aspartame).

[0072] An oily suspension may be prepared, for example, by suspending at least one compound of the present invention and / or at least one pharmaceutically acceptable salt thereof in either a vegetable oil (e.g., peanut oil, olive oil, sesame oil, and coconut oil) or a mineral oil (e.g., liquid paraffin). The oily suspension may also contain at least one thickening agent (e.g., beeswax, solid paraffin, and cetyl alcohol). To provide an easily drinkable oily suspension, at least one sweetener already described above and / or at least one flavoring agent may be added to the oily suspension. The oily suspension may further contain at least one preservative (but not limited to, for example, an antioxidant (e.g., butylhydroxyanisole, and α-tocopherol)).

[0073] Dispersible powders and granules may be produced, for example, by mixing at least one compound of the present invention and / or at least one pharmaceutically acceptable salt thereof with at least one dispersant and / or wetting agent, at least one suspending agent, and / or at least one preservative. Suitable dispersants, wetting agents, and suspending agents have already been described above. Examples of preservatives, but not limited to, include antioxidants (e.g., ascorbic acid). Furthermore, dispersible powders and granules may also include at least one excipient (e.g., sweeteners, flavoring agents, and coloring agents, but not limited to)

[0074] An emulsion of at least one compound of the present invention and / or at least one pharmaceutically acceptable salt thereof may be prepared, for example, as an oil-in-water emulsion. The oil phase of an emulsion containing the compounds of the present invention may consist of known components in known ways. The oil phase may be provided by, but is not limited to, vegetable oils (e.g., olive oil and peanut oil), mineral oils (e.g., liquid paraffin), and mixtures thereof. The oil phase may consist only of emulsifiers, or it may consist of at least one emulsifier and fats or oils, or mixtures of both fats and oils. Suitable emulsifiers include, but is not limited to, naturally occurring phosphatides (e.g., soy lecithin), esters or partial esters derived from fatty acids and hexitol anhydrides (e.g., sorbitan monooleate), and condensation products of partial esters and ethylene oxides (e.g., polyoxyethylene sorbitan monooleate). Preferably, a hydrophilic emulsifier is included together with a lipophilic emulsifier acting as a stabilizer. It is also preferable to include both oils and fats. In addition, emulsifiers, together with or without stabilizers, form so-called emulsifying waxes, and these waxes, together with oils and fats, form so-called emulsifying ointment bases, which form the oily dispersion phase of creams. Emulsions may also contain sweeteners, flavorings, preservatives, and / or antioxidants. Suitable emulsifiers and emulsion stabilizers for use in the formulations of this disclosure include Tween 60, Span 80, cetostearyl alcohol, myristyl alcohol, glyceryl monostearate, sodium lauryl sulfate, glyceryl distearate, or other substances known in the art, either alone or in combination with waxes.

[0075] Furthermore, the compounds of the present invention and / or at least one pharmaceutically acceptable salt thereof can be delivered intravenously, subcutaneously, and / or intramuscularly, for example, via any pharmaceutically acceptable and suitable injectable form. Examples of injectable forms include, but are not limited to, sterile aqueous solutions, sterile oil-in-water microemulsions, and aqueous or oily suspensions containing an acceptable vehicle and solvent (e.g., water, Ringer's solution, and sodium chloride isotonic solution).

[0076] Parenteral formulations may be in the form of aqueous or non-aqueous isotonic sterile injection solutions or suspensions. These solutions and suspensions may be prepared from sterile powders or granules by using one or more carriers or diluents described for use in oral formulations, or by using other suitable dispersants or wetting and suspending agents. The compound may be dissolved in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, tragacanth gum, and / or various buffers. Other adjuvants and administration methods are known and widely practiced in the pharmaceutical field. The active ingredient may also be administered by injection as a composition with a suitable carrier (e.g., physiological saline, dextrose, or water), or with cyclodextrin (i.e., Captisol), a solubilizing cosolvent (i.e., propylene glycol), or a solubilizing micelle (i.e., Tween 80).

[0077] Furthermore, sterile injectable formulations may be sterile injectable solutions or suspensions (e.g., solutions in 1,3-butanediol) in non-toxic, parenterally acceptable diluents or solvents. Acceptable vehicles and solvents that may be used include water, Ringer's solution, and sodium chloride isotonic solutions. In addition, sterile non-volatile oils are conventionally used as solvents or suspension media. For this purpose, any sterile non-volatile oil, including synthetic monoglycerides or diglycerides, may be used. Furthermore, fatty acids such as oleic acid are used as injectable formulations.

[0078] A sterile injection oil-in-water microemulsion may be produced, for example, by: 1) dissolving at least one compound of the present invention in an oil phase (e.g., a mixture of soybean oil and lecithin); 2) combining the oil phase containing the present invention with a mixture of water and glycerol; and 3) processing the combination to form a microemulsion.

[0079] Sterile aqueous suspensions or sterile oily suspensions may be prepared according to methods known to those skilled in the art. For example, sterile aqueous solutions or sterile aqueous suspensions may be prepared using non-toxic, parenterally acceptable diluents or solvents (e.g., 1,3-butanediol), and sterile oily suspensions may be prepared using sterile, non-toxic, acceptable solvents or suspension media (e.g., sterile non-volatile oils (e.g., synthetic monoglycerides or diglycerides) and fatty acids (e.g., oleic acid)).

[0080] pharmaceutically acceptable carriers, adjuvants, and vehicles that may be used in the pharmaceutical compositions of this disclosure include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS) (e.g., d-α-tocopherol polyethylene glycol 1000 succinate), surfactants used in pharmaceutical dosage forms (e.g., Tween, polyethoxylated castor oil (e.g., CREMOPHOR surfactant (BASF), or other similar polymer delivery matrices)), serum proteins (e.g., human serum albumin), buffering substances (e.g., phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids), water, salts, or electrolytes (e.g., protamine sulfate). Examples include salts, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate), polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and lanolin. Cyclodextrins (e.g., α-, β-, and γ-cyclodextrins, or chemically modified derivatives (e.g., hydroxyalkyl cyclodextrins including 2- and 3-hydroxypropyl cyclodextrin, or other solubilized derivatives)) may also be effectively used to enhance the transport of compounds of the formulas described herein.

[0081] The pharmaceutically active compounds of this disclosure may be processed according to conventional pharmaceutical methods to prepare drugs for administration to patients (e.g., humans and other mammals). Pharmaceutical compositions may be subjected to conventional pharmaceutical operations (e.g., sterilization) and / or may include conventional adjuvants (e.g., preservatives, stabilizers, wetting agents, emulsifiers, buffers, etc.). Tablets and pills may also be prepared using enteric coatings. Such compositions may also include adjuvants (e.g., wetting agents, sweeteners, flavoring agents, and fragrances).

[0082] The amount of compounds administered to treat a medical condition using the compounds and / or compositions of this disclosure, and the dosage regimen, depend on various factors (e.g., age, weight, sex, patient's condition, type of disease, severity of disease, route and frequency of administration, and the specific compound used). Therefore, the dosage regimen may be significantly modified, but it can be determined according to standard methods. The daily dose may be appropriate between approximately 0.001 and 100 mg / kg body weight, preferably between approximately 0.0025 and 50 mg / kg body weight, and most preferably between approximately 0.005 and 10 mg / kg body weight. The daily dose may be administered one to four times per day. Other dosage regimens include weekly and bi-weekly cycles.

[0083] For therapeutic purposes, the active compounds of this disclosure are typically combined with one or more adjuvants appropriate to the intended route of administration. When administered orally, the compounds may be mixed with lactose, sucrose, starch powder, cellulose esters of alkanates, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric acid and sulfate, gelatin, gum arabic, sodium alginate, polyvinylpyrrolidone, and / or polyvinyl alcohol, and then encapsulated or tableted for convenient administration. Such capsules or tablets may contain a controlled-release formulation and may be provided with the active compound dispersed in hydroxypropyl methylcellulose.

[0084] The pharmaceutical compositions of this disclosure comprise, as appropriate, at least one compound of the present invention and / or at least one pharmaceutically acceptable salt thereof, and any additives selected from pharmaceutically acceptable carriers, adjuvants, and vehicles. Another composition of this disclosure comprises a compound of the present invention as described herein, or its prodrug, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

[0085] The compounds disclosed herein inhibit PD-1 / PD-L1 (protein / protein) and lead to PD-L1 blockade. PD-L1 blockade may enhance the immune response to cancer cells and infections in mammals, including humans.

[0086] In one embodiment, this disclosure relates to the in vivo treatment of patients using compounds or salts thereof of the present invention that inhibit the growth of cancerous tumors. The compounds or salts thereof of the present invention may be used alone to inhibit the growth of cancerous tumors. Alternatively, the compounds of formula (I) or salts thereof may be used in combination with other immunogens or standard cancer treatments as shown below.

[0087] In one embodiment, the present disclosure provides a method for inhibiting the growth of tumor cells in a patient, characterized by administering a therapeutically effective amount of the compound of the present invention or a salt thereof to the patient.

[0088] In one embodiment, a method for treating cancer is provided, characterized by administering a therapeutically effective amount of the compound of the present invention or a salt thereof to a patient in need. Examples of cancers whose growth can be inhibited using the compounds of the present disclosure include cancers that generally respond to immunotherapy. Examples of cancers preferred for treatment include, but are not limited to, melanoma (e.g., metastatic melanoma), renal cancer (e.g., clear cell carcinoma), prostate cancer (e.g., hormone-refractory prostate cancer), breast cancer, colon cancer, and lung cancer (e.g., non-small cell lung cancer). Furthermore, the present disclosure includes refractory or recurrent malignancies whose growth can be inhibited using the compounds of the present disclosure.

[0089] Other cancers that can be treated using the methods of this disclosure include bone cancer, pancreatic cancer, skin cancer, head and neck cancer, cutaneous or intraocular malignant melanoma, uterine cancer, ovarian cancer, rectal cancer, perianal cancer, gastric cancer, testicular cancer, uterine cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin lymphoma, non-Hodgkin lymphoma, esophageal cancer, small intestine cancer, endocrine cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, acute myeloid leukemia, chronic bone cancer. Chronic or acute leukemias, including myelic leukemia, acute lymphoblastic leukemia, and chronic lymphocytic leukemia; pediatric solid tumors; lymphocytic lymphomas; bladder cancer; kidney or urethral cancer; renal pelvis cancer; central nervous system (CNS) tumors; primary CNS lymphomas; tumor angiogenesis; axis tumors; brainstem gliomas; pituitary adenomas; Kaposi's sarcoma; epidermoid carcinoma; squamous cell carcinoma; T-cell lymphoma; cancers caused by environmental factors, including asbestos-related cancers; and combinations of the above cancers. This disclosure is also useful for the treatment of metastatic cancers, particularly metastatic cancers expressing PD-L1 (Iwai et al. (2005) Int. Immunol. 17:133-144).

[0090] The compounds of the present invention or their salts may be combined with other immunogens, such as cancer cells, purified tumor antigens (e.g., recombinant proteins, peptides, and carbohydrate molecules), cells, and transfected cells into which genes encoding cytokine-stimulating immunity have been introduced (He et al (2004) J. Immunol. 173:4919-28). Examples of tumor vaccines that may be used include, but are not limited to, melanoma antigen peptides, such as gp100 peptide, MAGE antigen, Trp-2, MART1 and / or tyrosinase, or transfected tumor cells expressing the cytokine GM-CSF.

[0091] In humans, some tumors (e.g., melanoma) are known to be immunogenic. It is expected that blocking PD-L1 will increase the baseline level of T cell activation, thereby activating the tumor response in the host.

[0092] PD-L1 blockade can be combined with vaccination protocols. Numerous experimental strategies for tumor vaccination have been devised (see Rosenberg, S., 2000, Development of Cancer Vaccines, ASCO Educational Book Spring: 60-62; Logothetis, C., 2000, ASCO Educational Book Spring: 300-302; Khayat, D. 2000, ASCO Educational Book Spring: 414-428; Foon, K. 2000, ASCO Educational Book Spring: 730-738; and Restifo, N. and Sznol, M., Cancer Vaccines, Ch. 61, pp. 3023-3043 in DeVita, V. et al. (eds.), 1997, Cancer: Principles and Practice of Oncology. Fifth Edition). In one of these strategies, the vaccine is prepared using autologous or allogeneic tumor cells. These cell vaccines are known to be most effective when tumor cells are transduced to express GM-CSF. GM-CSF is known to be a potent activator of antigen presentation for tumor vaccination (Dranoff et al. (1993) Proc. Natl. Acad. Sci. USA 90: 3539-43).

[0093] Studies of gene expression and broad gene expression patterns in various tumors have led to the definition of so-called tumor-specific antigens (Rosenberg, SA (1999) Immunity 10: 281-7). In many cases, these tumor-specific antigens are differentiation antigens expressed in tumors and tumor-derived cells (e.g., melanocyte antigen gp100, MAGE antigen, and Trp-2). More importantly, many of these antigens can be shown to be targets of tumor-specific T cells found in the host. PD-L1 blockade may be used in conjunction with a collection of recombinant proteins and / or peptides expressed in tumors to generate an immune response to these proteins. These proteins are normally found in the immune system as autoantigens and are therefore tolerant to them. Tumor antigens may also include the telomerase of their proteins. Telomerase is necessary for the synthesis of telomeres on chromosomes and is expressed in more than 85% of human cancers, but only in very limited numbers in somatic tissues (Kim, N et al. (1994) Science 266: 2011-2013). (These somatic tissues may be protected from immune attack in various ways.) Tumor antigens may be "neoantigens" expressed in cancer cells by somatic mutations that alter protein sequences or produce fusion proteins between two unrelated sequences (i.e., the Philadelphia chromosome bcr-abl), or idiotypes of B-cell tumors.

[0094] Other tumor vaccines may include proteins from viruses involved in human cancer (e.g., human papillomavirus (HPV), hepatitis viruses (HBV, HDV, and HCV), and Kaposi's sarcoma herpesvirus (KHSV)). Another form of tumor-specific antigen that can be used in combination with PD-L1 blockade is purified heat shock proteins (HSPs) isolated from tumor tissue itself. These heat shock proteins contain protein fragments from tumor cells, and these HSPs are highly efficient in delivering antigens to antigen-presenting cells to induce tumor immunity (Suot, R & Srivastava, P (1995) Science 269:1585-1588; Tamura, Y. et al. (1997) Science 278:117-120).

[0095] Dendritic cells (DCs) are potent antigen-presenting cells that can be used to induce antigen-specific responses. DCs are produced ex vivo and can contain a wide variety of protein and peptide antigens as well as tumor cell extracts (Nestle, F. et al. (1998) Nature Medicine 4: 328-332). DCs may also be transduced genetically to express these tumor antigens. DCs are also fused directly to tumor cells for immunization (Kugler, A. et al. (2000) Nature Medicine 6: 332-336). As a method of vaccination, DC immunization may be effectively combined with PD-L1 blockade to activate a more potent antitumor response.

[0096] Furthermore, PD-L1 blockade may be combined with standard cancer treatments. PD-L1 blockade may also be effectively combined with chemotherapy. In these examples, it may be possible to reduce the dose of chemotherapy agents administered (Mokyr, M. et al. (1998) Cancer Research 58: 5301-5304). An example of such a combination is the combination of the compound disclosed herein with dacarbazine, used in the treatment of melanoma. Another example of such a combination is the combination of the compound disclosed herein with interleukin-2 (IL-2), used in the treatment of melanoma. The scientific rationale behind combining PD-L1 blockade and chemotherapy is that cell death, a result of the cytotoxic effects of most chemotherapy compounds, should lead to an increase in tumor antigen levels in the antigen-presenting pathway. Other combination therapies that may produce synergistic effects with PD-L1 blockade via cell death include radiotherapy, surgery, and hormone deprivation therapy. Each of these protocols generates a host tumor antigen source. Angiogenesis inhibitors may also be combined with PD-L1 blockade. Inhibition of angiogenesis allows tumor antigens to be delivered to the host's antigen-presenting pathway, leading to tumor cell death.

[0097] Furthermore, the compounds disclosed herein may be used in combination with bispecific compounds that target tumor cells to Fc-alpha or Fc-gamma receptor-expressing effector cells (see, e.g., US Pat. Nos. 5,922,845 and 5,837,243). Bispecific compounds may target two distinct antigens. For example, bispecific compounds of anti-Fc receptor / antitumor antigen (e.g., Her-2 / neu) have been used to target macrophages to tumor sites. This targeting may more effectively activate tumor-specific responses. T cells in these responses are increased by PD-L1 blockade. Alternatively, antigens may be delivered directly to DCs by the use of bispecific compounds that bind to tumor antigens and cell surface markers specific to dendritic cells.

[0098] Tumors evade host immune surveillance through a wide variety of mechanisms. Many of these mechanisms can be overcome by inactivating tumor-expressed proteins and immunosuppressive proteins. These proteins include, in particular, TGF-β (Kehrl, J. et al. (1986) J. Exp. Med. 163: 1037-1050), IL-10 (Howard, M. & O'Garra, A. (1992) Immunology Today 13: 198-200), and Fas ligand (Hahne, M. et al. (1996) Science 274: 1363-1365). Inhibitors that bind to and block each of these proteins may be used in combination with the compounds disclosed herein to weaken the effects of immunosuppressants and to promote the host's tumor immune response.

[0099] Compounds that activate the host immune response can be used in combination with PD-L1 blockade. These compounds include dendritic cell surface molecules that activate DC function and antigen presentation. Anti-CD40 compounds effectively function as a substitute for helper T cell activity (Ridge, J. et al. (1998) Nature 393: 474-478) and can be used in combination with PD-L1 blockade (Ito, N. et al. (2000) Immunobiology 201 (5) 527-40). Furthermore, activating compounds targeting T cell costimulatory molecules (e.g., CTLA-4 (e.g., US Pat. No. 5,811,097), OX-40 (Weinberg, A. et al. (2000) Immunol 164: 2160-2169), 4-1BB (Melero, I. et al. (1997) Nature Medicine 3: 682-685 (1997)), and ICOS (Hutloff, A. et al. (1999) Nature 397: 262-266)) can provide high levels of T cell activation.

[0100] Bone marrow transplantation is currently used to treat various hematopoietic tumors. While graft-versus-host disease can develop as a result of this treatment, the benefits of the treatment can be derived from the graft-versus-tumor response. PD-L1 blockade may be used to enhance the effectiveness of donor-transplant tumor-specific T cells.

[0101] Another method of this disclosure is used to treat a patient who has been exposed to a particular toxin or pathogen. Accordingly, another aspect of this disclosure is a method for treating an infectious disease in a patient, characterized by administering to the patient a therapeutically effective amount of the compound of the present invention or a salt thereof.

[0102] Similar to the applications to tumors described above, the compounds or salts of the present invention can be used alone, as adjuvants, or in combination with vaccines to stimulate immune responses against pathogens, toxins, and autoantigens. Examples of pathogens for which this therapeutic method may be particularly useful include those for which there are currently no effective vaccines, or for which conventional vaccines are not completely effective. These include, but are not limited to, HIV, hepatitis (A, B, C, or D), influenza, herpes, giardia, malaria, leishmania, Staphylococcus aureus, and Pseudomonas aeruginosa. PD-L1 blockade is particularly useful against established drug-induced infections (which exhibit antigenic changes during the course of infection), such as HIV. These novel epitopes are recognized as foreign substances upon administration and therefore evoke a strong T-cell response that is not attenuated by PD-1-mediated negative signaling.

[0103] Some examples of pathogenic viruses that cause infections treatable by the methods of this disclosure include HIV, hepatitis (A, B, C, or D), herpesviruses (e.g., VZV, HSV-1, HAV-6, HHv-7, HHV-8, HSV-2, CMV, and Epstein-Barr virus), adenoviruses, influenza viruses, flaviviruses, echoviruses, rhinoviruses, coxsackieviruses, coronaviruses, respiratory syncytial virus (RSV), mumps virus, rotavirus, measles virus, rubella virus, parvovirus, vaccinia virus, HTLV virus, dengue virus, papillomavirus, molluscum contagiosum virus, poliovirus, rabies virus, JC virus, and arbovirus encephalitis virus.

[0104] Some examples of pathogenic bacteria that cause infections treatable by the methods of this disclosure include Chlamydia, Rickettsia, Mycobacteria, Staphylococcus, Streptococcus, Pneumococcus, Meningococcus and Neisseria gonorrhoeae, Klebsiella, Proteus, Serratia, Pseudomonas, Legionaires, Diphtheria, Salmonella, Bacillus, Cholera, Tetanus, Clostridium botulinum, Bacillus anthrax, Plague, Leptospira, and Lyme disease bacteria.

[0105] Some examples of pathogenic fungi that cause infections treatable by the methods of this disclosure include Candida (e.g., Candida albicans, Candida crusei, Candida glabrata, Candida tropicalis), Cryptococcus neoformans, Aspergillus (e.g., Aspergillus fumigatus, Aspergillus niger), Mucor (Mucus rufipes, Mucorus humilis, Rhizopus), Sporotrix schenkyi, Blastomyces dermatichidis, Paracoccidioides brasiliensis, Coccidioides imithis, and Histoplasma capsulatum.

[0106] Some examples of pathogenic parasites that cause infections treatable by the methods of this disclosure include Entamoeba histolytica, Balantidium colonis, Naegleria fowleri, Acanthamoeba species, Giardia lamblia, Cryptosporidium species, Pneumocystis pneumocarini, Plasmodium vivax, Babesia microti, Trypanosoma brusei, Trypanosoma cruzi, Donovan leishmania, Toxoplasma gondii, and Hookworm brachycephalus.

[0107] In all of the above methods, PD-L1 blockade may be combined with other forms of immunotherapy (e.g., cytokine therapy (e.g., interferon, GM-CSF, G-CSF, IL-2), or bispecific antibody therapy that strongly expresses tumor antigens (e.g., see Holliger (1993) Proc. Natl. Acad. Sci. USA 90:6444-6448; Poljak (1994) Structure 2:1121-1123), vaccines, or agents that modulate gene expression).

[0108] The compounds disclosed herein may induce and enhance autoimmune responses. Indeed, induction of antitumor responses using tumor cells and peptide vaccines has revealed that many antitumor responses are involved in anti-autoreactivity (depigmentation observed in anti-CTLA-4+GM-CSF modified B16 melanoma (see van Elsas et al. above); depigmentation in Trp-2 vaccinated mice (Overwijk, W. et al. (1999) Proc. Natl. Acad. Sci. USA 96: 2982-2987); autoimmune prostatitis induced by TRAMP tumor cell vaccine (Hurwitz, A. (2000) supra); vitiligo observed in melanoma peptide antigen vaccination and human clinical trials (Rosenberg, SA and White, DE (1996) J. Immunother Emphasis Tumor Immunol 19 (1): 81-4)).

[0109] Therefore, it is possible to consider using anti-PD-L1 blockade in combination with various autoproteins in order to devise vaccination protocols that efficiently induce an immune response against these autoproteins for disease treatment. For example, Alzheimer's disease is related to the inadequate accumulation of amyloid-beta (A.β.) peptides in amyloid deposits in the brain; antibody responses against amyloid can remove these amyloid deposits (Schenk et al., (1999) Nature 400: 173-177).

[0110] Furthermore, other autologous proteins can be used as targets (e.g., IgE for the treatment of allergies and asthma, and TNFα for the treatment of rheumatoid arthritis). Ultimately, antibody responses to various hormones can be induced by the use of the compounds of the present invention or salts thereof. Neutralizing antibody responses to reproductive hormones can be used for contraception. Neutralizing antibody responses to hormones and other soluble factors necessary for the growth of certain tumors can also be considered as potential targets for vaccination.

[0111] Similar methods described above using anti-PD-L1 antibodies may be used to induce a therapeutic autoimmune response and treat patients who have an inappropriate accumulation of other autoantigens (e.g., amyloid deposits such as amyloid-beta in Alzheimer's disease, cytokines (e.g., TNFα, and IgE)).

[0112] The compounds disclosed herein may be used to stimulate an antigen-specific immune response by co-administration of the compounds of the present invention or salts thereof with an antigen of interest (e.g., a vaccine). Accordingly, in another embodiment, the herein disclosure provides a method for enhancing a patient's immune response to an antigen, characterized by administering to the patient (i) the antigen; and (ii) a compound of the present invention or a salt thereof such that the patient's immune response to the antigen is enhanced. The antigen may be, for example, a tumor antigen, a viral antigen, a bacterial antigen, or an antigen derived from a pathogen. Such antigens include, but are not limited to, the antigens discussed in the above section, e.g., the tumor antigens (or tumor vaccines) discussed above, or antigens derived from viruses, bacteria or other pathogens discussed above.

[0113] As described above, the compounds of this disclosure may be administered concurrently with one or more other therapeutic agents (e.g., cytotoxic agents, radiotoxic agents, or immunosuppressant agents). The compounds of this disclosure may be administered before, after, or concurrently with other therapeutic agents, or concurrently with other known treatments (e.g., anticancer therapy (e.g., radiation)). Such therapeutic agents include, in particular, antitumor agents that, on their own, are only effective at doses that are toxic or semi-toxic to the patient (e.g., doxorubicin (adriamycin), cisplatin bleomycin sulfate, carmustine, chlorambucil, dacarbazine, and cyclophosphamide hydroxyurea). Cisplatin is administered intravenously at a dose of 100 mg / dose once every four weeks, and adriamycin is administered intravenously at a dose of 60-75 mg / mL once every 21 days. The concurrent administration of the compounds of the present invention or salts thereof with chemotherapeutic agents provides two anticancer agents that act through different mechanisms to produce cytotoxic effects on human tumor cells. Such co-administration can resolve problems caused by the progression of drug resistance or by antigenic changes in tumor cells that become unresponsive to antibodies.

[0114] Furthermore, a kit comprising the compound or a salt thereof of the present invention, and instructions for use, is also within the scope of this disclosure. The kit may further include at least one other reagent. The kit generally includes a label indicating the intended use of the contents of the kit. The term “label” includes any letters, or recording materials provided on or with the kit, or otherwise attached to the kit.

[0115] The other therapeutic agents described above, when used in combination with the compounds of this disclosure, may be used, for example, in amounts specified in the U.S. Pharmaceutical Handbook (PDR) or in amounts determined by those skilled in the art. In the method of the present invention, the other therapeutic agents may be administered before, simultaneously with, or after the administration of the compounds of this disclosure.

[0116] Examples The present invention is further defined in the following embodiments, which should be understood to be given solely by description. From the above discussion and embodiments, those skilled in the art can elucidate the essential features of the invention and make changes and modifications to adapt it to a wide range of conditions and applications without departing from the essence and scope of the invention. As a result, the present invention is not limited by the embodiments described below, but rather is defined by the claims appended herein.

[0117] The compounds may be prepared by methods known in the art, including those described below, and may be modified within the scope of those skilled in the art. Some reagents and intermediates are known to those skilled in the art. Other reagents and intermediates can be prepared by methods known in the art using readily available chemicals. Variables (such as numbered "R" substituents) are intended solely to illustrate methods for preparing the compounds and should not be confused with variables used in the claims or other sections of this specification. The methods described below are illustrative and do not limit the scope of the invention.

[0118] The abbreviations used in the scheme follow the meanings commonly used in the art. The abbreviations for compounds used in the specification and examples are as follows: "THF" is tetrahydrofuran, "DMF" is N,N-dimethylformamide, "MeOH" is methanol, "EtOH" is ethanol, "n-PrOH" is 1-propyl alcohol or propane-1-ol, "i-PrOH" is 2-propyl alcohol or propane-2-ol, "Ar" is aryl, "TFA" is trifluoroacetic acid, "DMSO" is dimethyl sulfoxide, " Depositphotos" is ethyl acetate, "Et2O" is diethyl ether, "DMAP" is 4-dimethylaminopyridine, "DCE" is 1,2-dichloroethane, "ACN" is acetonitrile, "DME" is 1,2-dimethoxyethane, "h" is time, "rt" is room temperature or retention time (depending on the context), "min" is minutes, and "HOBt" is 1-hydroxy Benzotriazole hydrate, "HCTU" is defined as 1-[bis(dimethylamino)methylene]-5-chlorobenzotriazolium 3-oxide hexafluorophosphate or N,N,N',N'-tetramethyl-O-(6-chloro-1H-benzotriazol-1-yl)uronium hexafluorophosphate, "HATU" is defined as 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate or N-[(dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridine-1-ylmethylene]-N-methylmethaneaminium hexafluorophosphate N-oxide, "DIEA" and "iPrNEt2" are defined as diisopropylethylamine, and "Et3N" is defined as triethylamine.

[0119] Abbreviations are as follows: "1x" for 1 time, "2x" for 2 times, "3x" for 3 times, "℃" for Celsius temperature, "eq" for equivalent, "g" for grams, "mg" for milligrams, "L" for liters, "mL" for milliliters, "μL" for microliters, "N" for normal, "M" for molar, "mmol" for millimoles, "min" for minutes, "h" for hours, "rt" for room temperature, "RT" for retention time, "atm" for atmosphere, "psi" for pounds per square inch, "conc." for concentration, "sat" or "sat'd" for saturation, "MW" for molecular weight, "mp" for melting point, "ee" for enantiomer excess, "MS" or "Mass Spec" for mass spectrometry, "ESI" for electrospray ionization mass spectrometry, "HR" for high resolution, "HRMS" for high resolution mass spectrometry, "LC" for liquid chromatography, "LCMS" for liquid chromatography mass spectrometry, "HPLC" for high-performance liquid chromatography, "RP" "HPLC" stands for reversed-phase HPLC, "TLC" or "tlc" stands for thin-layer chromatography, and "NMR" stands for nuclear magnetic resonance spectroscopy. 1 "H" is defined as a proton, "δ" as a delta, "s" as a singlet, "d" as a doublet, "t" as a triplet, "q" as a quartet, "m" as a multiplet, "br" as a broad, and "Hz" as Hertz. "α", "β", "R", "S", "E", and "Z" are stereochemical symbols well known to those skilled in the art.

[0120] [ka] [ka] [ka] [ka] [ka]

[0121] A general method for producing the compounds of the present invention from intermediates 1-5 and an aminolactone or lactam: In THF, dioxane, DME, MeOH, EtOH, or a mixture thereof (with 1-20 equivalents of AcOH added as appropriate), a mixture of one of any intermediates 1-5 (1 equivalent) and a reagent (1-20 equivalents) was stirred at room temperature for 0.5-48 hours, and NaCNBH3 (1-20 equivalents) was added. The reaction was stirred at room temperature to 100°C for 0.5-48 hours, and then quenched with methanol or water. After removing all solvent under reduced pressure, the resulting residue was purified by preparative HPLC to obtain the compound of the present invention.

[0122] [Table 1] [Table 2] [Table 3] [Table 4] [Table 5] [Table 6] [Table 7] [Table 8] [Table 9] [Table 10] [Table 11] [Table 12] Table 13 Table 14 Table 15 Table 16 Table 17 Table 18 Table 19 Table 20 Table 21 Table 22 Table 23 Table 24 Table 25 Table 26 Table 27 Table 28 Table 29 Table 30

[0123] A general method for producing the compound of the present invention from intermediate 6: A mixture of intermediate 6 (1 equivalent), reagent (1 equivalent), iPr2NEt (1-10 equivalents), and Cs2CO3 or K2CO3 (1-20 equivalents) was stirred at room temperature to 100°C for 0.5-48 hours in THF, dioxane, DME, or a mixture thereof, and then quenched with methanol or water. After removing all solvent under reduced pressure, the resulting residue was purified by preparative HPLC to obtain the compound of the present invention.

[0124] A general method for producing the compound of the present invention from intermediate 7: A mixture of intermediate 7 (1 equivalent) and reagent (1-20 equivalents) was stirred at room temperature to 100°C for 0.5-48 hours in THF, dioxane, DME, or a mixture thereof (with iPr2NEt or Et3N (1-20 equivalents) added as appropriate), and then quenched with methanol or water. After removing all solvent under reduced pressure, the resulting residue was purified by preparative HPLC to obtain the compound of the present invention. [Table 31] [Table 32] [Table 33]

[0125] A general method for producing the compounds of the present invention from reference compounds 1-5 and an aminolactone or lactam in the presence of an aldehyde or ketone: In DCM, THF, dioxane, DME, MeOH, EtOH, or a mixture thereof (with iP2NEt added as appropriate), a mixture of one of any reference compound 1-5 (1 equivalent) and a reagent (1-20 equivalents) was stirred at room temperature for 0.5-48 hours, and AcOH (1-20 equivalents) was added. The mixture was stirred at room temperature for 0.5-48 hours, and then NaCNBH3 (1-20 equivalents) was added. The reaction was stirred at room temperature to 100°C for 0.5-48 hours, and then an aldehyde or ketone (1-20 equivalents) was added. After stirring at room temperature to 100°C for 0.5-48 hours, the reaction was quenched with methanol or water. After removing all solvent under reduced pressure, the resulting residue was purified by preparative HPLC to obtain the compound of the present invention. [Table 34] [Table 35] [Table 36]

[0126] Biological assays The binding ability of the compounds of the present invention to PD-L1 was measured using a PD-1 / PD-L1 homogeneous time-resolved fluorescence (HTRF) binding assay. The interaction between PD-1 and PD-L1 can be evaluated using the extracellular domains of these two soluble and purified proteins. The extracellular domains of the PD-1 and PD-L1 proteins are expressed as fusion proteins with detection tags (the tag in PD-1 is the Fc region of immunoglobulin (PD-1-Ig), and the tag in PD-L1 is a 6x histidine tag (PD-L1-His)). All binding assays were performed in HTRF assay buffer consisting of dPBS supplemented with 0.1% bovine serum albumin and 0.05% (v / v) Tween-20. In the h / PD-L1-His binding assay, the inhibitor was pre-incubated with PD-L1-His (final 10 nM) in assay buffer (4 μL) for 15 minutes, followed by the addition of PD-1-Ig (final 20 nM) / assay buffer (1 μL) and incubation for another 15 minutes. HTRF detection was performed using europium cryptotate-labeled anti-Ig (final 1 nM) and allophycocyanin (APC)-labeled anti-His (final 20 nM). These antibodies were diluted in HTRF detection buffer and 5 μL were dispensed during the binding assay reaction. The reaction was equilibrated for 30 minutes, and the signal (665 nm / 620 nm ratio) was measured using a spectrofluorometer (EnVision). Further binding assays were established between human proteins PD-1-Ig / PD-L2-His (20 nM and 5 nM, respectively) and CD80-His / PD-L1-Ig (100 nM and 10 nM, respectively). Recombinant proteins: Human PD-1(25-167)[hPD-1(25-167)-3S-IG], which has a human Fc region at the C-terminus of an IgG epitope tag, and human PD-L1(18-239)[hPD-L1(18-239)-TVMV-His], which has a His epitope tag at the C-terminus, were expressed in HEK293T cells and purified sequentially by protein A affinity chromatography and size exclusion chromatography. Human PD-L2-His and CD80-His were purchased commercially.

[0127] (method) Homogeneous time-resolved fluorescence (HTRF) assay for the binding of soluble PD-1 to soluble PD-L1 Soluble PD-1 and soluble PD-L1 refer to proteins obtained by cleaving the carboxyl terminus, removing the transmembrane region, and fusing them with a heterologous sequence (specifically, the Fc region of a human IgG sequence or a hexahistidine epitope (His) tag). All binding assays were performed in HTRF assay buffer consisting of dPBS supplemented with 0.1% (w / v) bovine serum albumin and 0.05% (v / v) Tween-20. In the PD-1-Ig / PD-L1-His binding assay, the inhibitor was pre-incubated in PD-L1-His (final 10 nM) / assay buffer (4 μL) for 15 minutes, followed by the addition of PD-1-Ig (final 20 nM) / assay buffer (1 μL) and incubation for another 15 minutes. PD-L1 fusion proteins obtained from humans, cynomolgus monkeys, mice, or other species were used. HTRF detection was performed using europium cryptotate-labeled anti-Ig monoclonal antibody (final 1 nM) and allophycocyanin (APC)-labeled anti-His monoclonal antibody (final 20 nM). The antibodies were diluted in HTRF detection buffer and 5 μL were dispensed during the binding assay reaction. This reaction was equilibrated for 30 minutes, and the signal (665 nm / 620 nm ratio) was measured using a spectrofluorometer (EnVision). Further binding assays were established between PD-1-Ig / PD-L2-His (20 nM and 5 nM, respectively), CD80-His / PD-L1-Ig (100 nM and 10 nM, respectively), and CD80-His / CTLA4-Ig (10 nM and 5 nM, respectively).

[0128] A binding / competition assay between biotinylated compound number 71 and human PD-L1-His was performed as follows: The compound of the present invention was pre-incubated with PD-L1-His (final 10 nM) / assay buffer (4 μL) for 60 minutes, followed by the addition of biotinylated compound number 71 (final 0.5 nM) / assay buffer (1 μL). The mixture was equilibrated for 30 minutes to allow binding, followed by the addition of europium cryptotate-labeled streptavidin (final 2.5 pM) and APC-labeled anti-His (final 20 nM) / HTRF buffer (5 μL). The reaction was equilibrated for 30 minutes, and the signal (ratio of 665 nm / 620 nm) was measured using a spectrofluorometer (EnVision). Recombinant proteins: Human PD-1 (amino acids 25-167) [hPD-1(25-167)-3S-IG] with a C-terminal human Ig epitope tag and carboxy-terminated, and human PD-L1 (amino acids 18-239) [hPD-L1(18-239)-tobacco vein mottling virus protease cleavage site (TVMV)-His] with a C-terminal His epitope tag were expressed in HEK293T cells and purified sequentially by recombinant protein A affinity chromatography and size exclusion chromatography. Human PD-L2-His (Sino Biologicals), CD80-His (Sino Biologicals), and CTLA4-Ig (RnD Systems) were all purchased commercially.

[0129] The following table shows representative ICs of the disclosed samples measured by a PD-1 / PD-L1 homogeneous time-resolved fluorescence (HTRF) binding assay. 50 List the values. [Table 37] [Table 38]

[0130] The test compounds of the present invention are active as inhibitors of PD-1 / PD-L1 interaction and can therefore be used to treat diseases or deficiencies related to PD-1 / PD-L1 interaction. Through inhibition of PD-1 / PD-L1 interaction, the compounds of this disclosure can be used to treat infectious diseases (e.g., HIV), septic shock, hepatitis A, B, C, or D, and cancer.

[0131] Since the general nature of the present invention is sufficiently disclosed by the description of the specific embodiments described above, persons other than the inventors can easily modify and / or adapt the above-described specific embodiments for various uses by applying the knowledge of those skilled in the art, without excessive experimentation and without deviating from the basic concepts of the present invention. Therefore, such modifications and adaptations are intended to be equivalent in meaning and scope to the embodiments of this disclosure, based on the content and guidance set forth herein. The expressions and technical terms used herein are for illustrative purposes only and should be understood not to be limited to the expressions or technical terms used herein as interpreted by those skilled in the art in light of the content and guidance.

[0132] Other embodiments of the present invention will become apparent to those skilled in the art by considering the specification and embodiments of the invention disclosed herein. The specification and embodiments are intended to be illustrative only from the true scope and essence of the invention as set forth in the following claims.

Claims

1. Equation (I): 【Chemistry 1】 [In the formula, R 1 is independently -(O) m -(CH 2 ) n -R 1a or -(CH 2 ) n -(O) m -R 1b and; R 1a These are independently O, N, S, and NR a A 5-6 membered heteroring having 1-2 heteroatoms selected from, where the heteroring has 0-3 R b Replaced by; R 1b These are phenyl or O, N, S, and NR a A 5-6 membered heteroaryl having 1-4 heteroatoms selected from, where the phenyl and heteroaryl have 0-3 R 1c Replaced by; R 1c These are independently halogen, CN, OH, SH, and NH 2 , C 1 -C 4 Haloalkyl, C 1 -C 4 Alkoxy, C 1 -C 4 Haloalkoxy, carbon substituted with 0-1 OH groups 1 -C 4 Alkyl, or C 3 -C 6 Cycloalkyl, -(O) m -(CH 2 ) n -R 1d , or -(CH 2 ) n -NR 7 -R 2a and; R 1d These are phenyl or O, N, S, and NR a A 5-6 membered heteroaryl having 1-4 heteroatoms selected from, where the phenyl and heteroaryl have 0-3 R d Replaced by; Z is a combination or C 1 -C 2 It is alkylene; R 2 These are 0 to 4 R independently c A 4- to 8-membered lactone or lactam substituted with; R 2a Independently 【Transformation 3】 and; R 3 , R 4 and R 5 These are, independently, halogen, CN, OH, SH, and NH. 2 , C 1 -C 4 Alkyl, C 1 -C 4 Haloalkyl, C 1 -C 4 Alkoxy, C 1 -C 4 Haloalkoxy, or C 3 -C 6 It is a cycloalkyl; R 6 These are hydrogen and C, which are independent of each other. 1 -C 4 Alkyl, or -(CH 2 ) n -R 6a and; R 6a These are independently phenyl or O, N, S, and NR a A 5-6 membered heteroaryl having 1-4 heteroatoms selected from, where the phenyl and heteroaryl have 0-3 R 6b Replaced by; R 6b These are independently halogen, CN, OH, and C 1 -C 4 Alkyl, C 1 -C 4 Haloalkyl, C 1 -C 4 Alkoxy, or C 1 -C 4 It is a haloalkoxy; R 7 These are hydrogen and C, which are independent of each other. 1 -C 4 Alkyl, -C(O)C 1 -C 4 Alkyl, -(CH 2 ) n -C 3 -C 6 Cycloalkyl, or -(CH 2 ) n - Is it phenyl? Or, R 6 and R 7 They unite to form W; and W is -CH₂C(O)-, -CH₂C(=CH₂)CH₂-, or -CH₂CH(OH)CH₂-; R a is independently halogen, C 1 -C 4 -alkyl, -(CH 2 ) n -C 3 -C 6 -cycloalkyl, or -(CH 2 ) n -phenyl; R b and R c These are independently oxo, halogen, CN, OH, and C. 1 -C 4 Alkyl, or C 1 -C 4 It is an alkoxy; R d These are, independently, halogen, CN, OH, and C. 1 -C 4 Alkyl, or C 1 -C 4 It is an alkoxy; m is either 0 or 1 independently; n is independently 0, 1, or 2; r, s, and t are each independently 0, 1, or 2. Compounds of or pharmaceutically acceptable salts thereof.

2. During the ceremony, R 2 These are 0 to 4 R independently c A 5- to 6-membered lactone or lactam substituted with; R c These are independently oxo, halogen, OH, or C 1 -C 3 It is alkyl; W is -CH₂C(O)-, -CH₂C(=CH₂)CH₂-, or -CH₂CH(OH)CH₂-. The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

3. Formula (II): 【Transformation 3】 [In the formula, R 1 It is independently -O-CH 2 -R 1a or -CH 2 -OR 1b and; R 1a is N-(C 1 -C 3 It is alkyl)-piperidinyl; R 1b This is 1 to 3 R 1c It is a phenyl substituted with; R 1c These are halogen and -CH, independently. 2 OH, -O-CH 2 -R 1d , or -CH 2 -NR 7 -R 2a and; R 1d It is a cyanosubstituted pyridyl; R 2 and R 2a Each is independent of the others. 【Chemistry 4】 and; R 3 These are hydrogen and C, which are independent of each other. 1 -C 3 It is an alkyl or halogen; R 4 These are hydrogen and C, which are independent of each other. 1 -C 3 It is an alkyl or halogen; R 5 These are hydrogen and C, which are independent of each other. 1 -C 3 It is an alkyl or halogen; R 6 These are hydrogen and C, which are independent of each other. 1 -C 3 Alkyl, or -CH 2 -(cyanosubstituted pyridyl); and R 7 These are hydrogen and C, which are independent of each other. 1 -C 3 Alkyl, -C(O)C 1 -C 3 Alkyl or -CH 2 -It is cyclopropyl. The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

4. During the ceremony, R 1 is, -O-CH 2 -R 1a and; R 1a is N-(C 1 -C 3 It is alkyl)-piperidinyl; R 6 is, -CH 2 -(cyanosubstituted pyridyl); and R 7 The compound according to claim 3 or a pharmaceutically acceptable salt thereof, wherein is hydrogen.

5. During the ceremony, R 1 is, -CH 2 -OR 1b and; R 1b This is 1 to 3 R 1c It is a phenyl substituted with; R 1c These are halogens, -O-CH 2 -R 1d , or -CH 2 -NR 7 -R 2a and; R 1d is a cyanosubstituted pyridyl; and R 7 The compound according to claim 3 or a pharmaceutically acceptable salt thereof, wherein is hydrogen.

6. Formula (III): 【Transformation 5】 [In the formula, R 1 It is independently -O-CH 2 -R 1a or -CH 2 -OR 1b and; R 1a is N-(C 1 -C 3 It is alkyl)-piperidinyl; R 1b This is 1 to 3 R 1c It is a phenyl substituted with; R 1c These are halogens, -O-CH 2 -R 1d , or -CH 2 -NR 7 -R 2a and; R 1d It is a cyanosubstituted pyridyl; R 2 and R 2a Each is independent of the others. 【Transformation 6】 and; R 3 These are hydrogen and C, which are independent of each other. 1 -C 3 It is an alkyl or halogen; R 4 These are hydrogen and C, which are independent of each other. 1 -C 3 It is an alkyl or halogen; R 5 These are hydrogen and C, which are independent of each other. 1 -C 3 Being alkyl or halogen; and W is independently -CH 2 C(O)-, -CH 2 C(=CH 2 )CH 2 -, or -CH 2 CH(OH)CH 2 -is] The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

7. The compounds are as follows: Table 1 Table 2 Table 3 Table 4 Table 5 Table 6 Table 7 Table 8 Table 9 Table 10 Table 11 A compound according to claim 1 or a pharmaceutically acceptable salt thereof, selected from the group consisting of the following.

8. A pharmaceutical composition comprising a compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

9. A pharmaceutical composition for use as a pharmaceutical, comprising a compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof.

10. A pharmaceutical composition for treating cancer, comprising a compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof.

11. A pharmaceutical composition comprising a compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof, for use in enhancing, stimulating, modulating, and / or increasing the immune response.

12. A pharmaceutical composition comprising a compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof, for use in inhibiting the growth, proliferation, or metastasis of cancer cells.

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