Lactone- and lactam-containing compounds useful as immunomodulators - Patents.com

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] The present disclosure generally relates to lactone and lactam containing compounds useful as inhibitors of the PD-1 / PD-L1 protein / protein interaction and the CD80 / PD-L1 protein / protein interaction. The present invention provides compounds, compositions comprising the compounds, and methods of use thereof. The present disclosure further relates to pharmaceutical compositions comprising at least one compound described in the present disclosure, useful in the treatment of various diseases, such as cancer and infectious diseases.

[0002] Programmed death-1 (CD279) is a receptor on T cells that suppresses activation signals from the T cell receptor when either the ligand of programmed death-1 (PD-L1, CD274, B7-H1) or PD-L2 (CD273, B7-DC) (Sharpe et al., Nat. Imm. 2007) binds to it. When PD-1 expressed on T cells contacts cells expressing the PD-1 ligand, functional activities in response to antigen stimulation, including proliferation, cytokine secretion, and cytolytic activity, are suppressed. PD-1 / PD-ligand interaction downregulates immune responses during the healing of infections or tumors, or during the establishment of self-tolerance (Keir Me, Butte MJ, Freeman GJ, et al. Annu. Rev. Immunol. 2008; 26: Epub). Chronic antigen stimulation, which occurs for example during tumor disease or chronic infection, causes T cells to express high PD-1 levels and become dysfunctional in their activity against chronic antigens (reviewed in 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 on expressing immune cells is known to be an inhibitory interaction. Blocking this interaction is known to abrogate 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] Blockade of PD-1 / PD-L1 interaction using antibodies against PD-L1 is known to restore and enhance T cell activation in many systems. Patients with advanced cancers benefit from treatment with monoclonal antibodies against PD-L1 (Brahmer et al., New Engl J Med 2012). In preclinical animal models of tumors, blockade of the PD-1 / PD-L1 pathway with monoclonal antibodies has been shown to enhance immune responses and can be directed against a number of 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] Blockade of PD-1 / PD-L1 interaction has also been shown to enhance T cell activity in chronic infection 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 protection against viremia and reduced viral exhaustion of CD4+ T cells (Palmer et al., J. Immunol 2013). PD-1 / PD-L1 blockade using monoclonal antibodies against PD-L1 has demonstrated improved immune response in patients with HIV (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 (Golden-Mason, J. Virol. 2007; Jeung, J. Leuk. Biol. 2007; Urbani, J. Hepatol. 2008; Nakamoto, PLoS Path. 2009; Nakamoto, Gastroenterology 2008) or HBV (Boni, ,J. Virol. 2007; The antigen-specific functionality of T cells from primary inflammatory bowel diseases (e.g., 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] Blockade of PD-L1 / CD80 interaction is also known to stimulate immunity (Yang J., et al., J Immunol. Aug 1;187(3):1113-9 (2011)). It is known that the immune stimulation caused by blockade of PD-L1 / CD80 interaction can be enhanced by further combining blockade of PD-1 / PD-L1 or PD-1 / PD-L2 interaction.

[0007] Alterations in immune cell phenotype have been 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 T cell apoptosis (Guignant, et al, Crit. Care (2011)). Antibodies against PD-L1 can reduce the levels 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 revealed that blocking PD-L1 interactions with antibodies can suppress inappropriate immune responses and ameliorate disease symptoms.

[0008] In addition to enhancing immune responses to chronic antigens, blockade of the PD-1 / PD-L1 pathway is also known to enhance responses to vaccinations, including therapeutic vaccinations in conditions of chronic infection (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 infection and tumor disease. Blockade of 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 responses to vaccination in tumor or chronic infection conditions. Therefore, agents that block the interaction of PD-L1 with either PD-1 or CD80 are desirable.

[0010] Applicants have discovered potent compounds that have activity as inhibitors of the interaction of PD-L1 with PD-1 and CD80 and may therefore be useful for curative administration (including therapeutic vaccines) to boost immunity in cancer or infectious diseases. These compounds also possess desirable stability, bioavailability, therapeutic index, and toxicity values ​​important to the druggability of the compounds, providing them as useful pharmaceutical agents.

[0011] In a first aspect, the present disclosure provides a compound of formula (I): [ka] [In the formula, R 1 is independent - (O) m -(CH2) n -R 1a or -(CH2) n -(O) m -R 1b and; R 1a are independently O, N, S, and NR a wherein the heterocycle is a 5- to 6-membered heterocycle having 1 to 2 heteroatoms selected from b Replaced with; R 1b is phenyl or O, N, S, and NR a wherein the phenyl and heteroaryl are each independently selected from 0 to 3 R 1c Replaced with; R 1c are independently halogen, CN, OH, SH, NH2, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkyl substituted with 0-1 OH, or C3-C6 cycloalkyl, -(O) m -(CH2) n -R 1d , or -(CH2) n -NR 7 -R 2a and; R 1d is phenyl or O, N, S, and NR a wherein the phenyl and heteroaryl are each independently selected from 0 to 3 R d Replaced with; Z is a bond or C1-C2 alkylene; R 2 is independently 0 to 4 R c is a 4-8 membered lactone or lactam substituted with; R 3 , R 4 and R5 are each independently halogen, CN, OH, SH, NH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, or C3-C6 cycloalkyl; R 6 are independently hydrogen, C1-C4 alkyl, or -(CH2) n -R 6a and; R 6a are independently phenyl or O, N, S, and NR a wherein the phenyl and heteroaryl are each independently selected from 0 to 3 R 6b Replaced with; R 6b are independently halogen, CN, OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, or C1-C4 haloalkoxy; R 7 are independently hydrogen, C1-C4 alkyl, -C(O)C1-C4 alkyl, -(CH2) n -C3-C6 cycloalkyl, or -(CH2) n -phenyl; or R 6 and R 7 together form W; and W is a 1-4 membered linker having elements independently selected from carbon, oxygen, and nitrogen, wherein the linker is comprised of 0-2 R e Replaced with; R a are independently halogen, C1-C4 alkyl, -(CH2) n -C3-C6 cycloalkyl, or -(CH2) n -phenyl; R b and R c are each independently oxo, halogen, CN, OH, C1-C4 alkyl, or C1-C4 alkoxy; R d are each independently halogen, CN, OH, C1-C4 alkyl, or C1-C4 alkoxy; R e is independently oxo, ═CH2, halogen, CN, OH, C1-C4 alkyl, or C1-C4 alkoxy; Each m is independently 0 or 1; Each n is independently 0, 1, or 2; r, s, and t are each independently 0, 1, or 2. or a pharma- ceutically acceptable salt thereof.

[0012] In a second embodiment within the first embodiment, R 2 is independently 0 to 4 R a is a 5-6 membered lactone or lactam substituted with; R a is independently oxo, halogen, OH, or C1-C3 alkyl; W is a 2-3 membered linker having elements independently selected from carbon, oxygen, and nitrogen, wherein the linker is comprised of 0-2 R e is replaced by; and R e is independently oxo, ═CH2, OH, or C1-C4 alkyl.

[0013] In a third aspect, the present disclosure provides a compound of formula (II): [ka] [In the formula, R 1 are independently -O-CH2-R 1a OR -CH2-OR 1b and; R 1a is N-(C1-C3 alkyl)-piperidinyl; R 1b 1 to 3 R 1c is a phenyl substituted with; R 1c are independently halogen, -CH2OH, -O-CH2-R 1d , or -CH2-NR 7-R 2a and; R 1d is a cyano substituted pyridyl; R 2 and R 2a are each independently [ka] and; R 3 are independently hydrogen, C1-C3 alkyl or halogen; R 4 are independently hydrogen, C1-C3 alkyl or halogen; R 5 are independently hydrogen, C1-C3 alkyl or halogen; R 6 are independently hydrogen, C1-C3 alkyl, or -CH2- (cyano-substituted pyridyl); and R 7 are independently hydrogen, C1-C3 alkyl, -C(O)C1-C3 alkyl, or -CH2-cyclopropyl. or a pharma- ceutically acceptable salt thereof.

[0014] In a fourth embodiment within the third embodiment, R 1 is -O-CH2-R 1a and; R 1a is N-(C1-C3 alkyl)-piperidinyl; R 6 is -CH2-(cyano substituted pyridyl); and R 7 is hydrogen.

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

[0016] In a sixth aspect, the present disclosure provides a compound of formula (III): [ka] [In the formula, R 1 are independently -O-CH2-R 1a OR -CH2-OR 1b and; R 1a is N-(C1-C3 alkyl)-piperidinyl; R 1b 1 to 3 R 1c is a phenyl substituted with; R 1c are independently halogen, -O-CH2-R 1d , or -CH2-NR 7 -R 2a and; R 1d is a cyano substituted pyridyl; R 2 and R 2a are each independently [ka] and; R 3 are independently hydrogen, C1-C3 alkyl or halogen; R 4 are independently hydrogen, C1-C3 alkyl or halogen; R 5 are independently hydrogen, C1-C3 alkyl or halogen; and W is independently -CH2C(O)-, -CH2C(=CH2)CH2-, or -CH2C(OH)CH2-. or a pharma- ceutically acceptable salt thereof.

[0017] In another aspect, there is provided a compound selected from the examples described, or a pharma- ceutically acceptable salt thereof.

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

[0019] The present disclosure also provides a pharmaceutical composition comprising a compound of the invention, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier.

[0020] In another aspect, the disclosure provides a compound of the invention, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use as a medicament.

[0021] In another aspect, the disclosure provides a compound of the invention, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in the manufacture of a medicament for treating cancer in a subject in need thereof.

[0022] In another aspect, the disclosure provides a compound of the invention, or a pharma- ceutical acceptable salt thereof, for use in enhancing, stimulating, modulating, and / or increasing an immune response in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of said compound, or a pharma-ceutical acceptable salt thereof.

[0023] In another aspect, the disclosure provides a compound of the invention, or a pharma- ceutically acceptable salt thereof, for use in inhibiting the growth, proliferation, or metastasis of cancer cells in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of said compound, or a pharma- ceutically acceptable salt thereof.

[0024] In another aspect, the disclosure provides a method for enhancing, stimulating, modulating and / or increasing an immune response in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of the invention, or a pharma- ceutically acceptable salt thereof. In a first embodiment of the third aspect, the disclosure further provides a method of administering another agent before, after or simultaneously with administering the compound of the invention, or a pharma- ceutically acceptable salt thereof. In a second embodiment, the another agent is an antibacterial agent, an antiviral agent, a cytotoxic agent, a gene expression modulator agent, and / or an immune response modifier.

[0025] In another aspect, the disclosure provides a method for inhibiting the growth, proliferation, or metastasis of cancer cells in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound or a pharma- ceutical acceptable salt of the invention. In a 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, cancer of the esophagus, gastrointestinal tract, and breast, and hematopoietic tumors.

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

[0027] In another aspect, the disclosure provides a method for treating septic shock in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of the invention, or a pharma- ceutically acceptable salt thereof.

[0028] Unless otherwise specified herein, words referred to in the singular may also include the plural. For example, "a" and "an" can refer to either "one" or "one or more."

[0029] As used herein, the phrase "a compound or a pharma- ceutically acceptable salt thereof" refers to at least one compound, a salt of at least one compound, or a combination thereof. For example, a compound of the present invention or a pharma- ceutically acceptable salt thereof includes one compound of the present invention; two compounds of the present invention; a salt of one compound of the present invention; one compound of the present invention and one or more salts of compounds of the present invention; and a salt of two or more compounds of the present invention.

[0030] Unless otherwise specified, any atom with unsatisfied valences is assumed to include enough hydrogen atoms to satisfy the valences.

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

[0032] Listed below are definitions of various terms used to describe this disclosure. These definitions apply to the terms as they are used throughout the specification, either individually (unless otherwise limited in specific instances) or as part of a larger group. The definitions set forth herein supersede definitions set forth in any patents, patent applications, and / or patent application publications incorporated herein by reference.

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

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

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

[0036] The term "aminocarbonyl" as used herein refers to -C(O)NH2.

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

[0038] The term "carboxy" as used herein refers to -CO2H.

[0039] As used herein, the term "cyano" refers to --CN.

[0040] The term "cycloalkyl" as used herein refers to a group derived from a non-aromatic monocyclic or polycyclic hydrocarbon molecule 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 the symbol "C" is followed by a number in subscript, the subscript more specifically qualifies 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] The term "(C3-C6 cycloalkyl)C1-C3 alkyl" as used herein refers to a C1-C3 alkyl group substituted with a C3-C6 cycloalkyl group.

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

[0043] The term "C1-C4 haloalkoxy," as used herein, refers to a haloC1-C4 alkyl group attached to the parent molecule through an oxygen atom.

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

[0045] The term "hydroxyalkyl" includes both straight-chain and branched-chain saturated alkyl groups substituted with one or more hydroxyl groups. For example, "hydroxyalkyl" includes -CHOH, -CHCHOH, and -CHCHOH. 1-4 Contains hydroxyalkyl.

[0046] As used herein, the term "nitro" refers to --NO.sub.2.

[0047] The term "oxo" as used herein refers to =O.

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

[0049] The terms "heterocyclo", "heterocycle", or "heterocyclyl", which may be used interchangeably, refer to a cyclic group having at least one saturated or partially saturated non-aromatic ring, where one or more of the rings contains at least one heteroatom (O, S, or N), and said heteroatom-containing rings preferably have 1 to 3 heteroatoms independently selected from O, S, and / or N. The rings of such groups containing heteroatoms may contain 1 or 2 oxygen or sulfur atoms and / or 1 to 4 nitrogen atoms, provided that the total number of heteroatoms in each ring is 4 or less, and further includes at least one carbon atom in the ring. The nitrogen and sulfur atoms may be optionally oxidized, and the nitrogen atoms may be optionally quaternized. The heterocyclo group may be bonded at any available nitrogen or carbon atom. The heterocyclo ring may be unsubstituted or may have one or more substituents, as valences permit.

[0050] Examples of single-ring heterocyclyl groups include pyrrolidinyl, imidazolinyl, oxazolidinyl, isoxazolinyl, thiazolidinyl, isothiazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 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 single-ring 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, benzopyranyl, indolizinyl, benzofuranyl, chromonyl, coumarinyl, benzopyranyl, cinnolinyl, quinoxalinyl, indazolyl, and pyrrolopyridyl.

[0054] As used herein, the phrase "pharmacologically acceptable" refers to compounds, substances, compositions, and / or dosage forms that are suitable, within the scope of ordinary medical judgment, for contact with the tissues of human beings and animals without undue toxicity, irritation, allergic response, or other problem or complication and that afford a reasonable benefit / risk ratio.

[0055] The compounds of the present invention may form salts, which are also within the scope of the present disclosure. Unless otherwise specified, a reference to a compound of the present invention is understood to include a reference to one or more salts thereof. The term "salt" refers to acid salts and / or base salts formed with inorganic and / or organic acids and bases. In addition, the term "salt" may include zwitterions (internal salts), for example, when the compound of the present invention has both a basic moiety (e.g., an amine or a pyridine or imidazole ring) and an acidic moiety (e.g., a carboxylic acid). Pharmaceutically acceptable (i.e., non-toxic and physiologically acceptable) salts are preferred, for example, acceptable metal salts and amine salts, where 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 the present disclosure. Salts of the compounds of the present invention may be formed, for example, by reacting the compound of the present invention with an amount of acid or base (e.g., one equivalent) and then precipitating the salt in a solvent, for example, or by lyophilizing the aqueous solution.

[0056] Examples of acid addition salts include acetate (e.g., salts prepared from acetic acid or trihaloacetic acid (e.g., trifluoroacetic acid)), adipate, alginate, ascorbate, aspartate, benzoate, benzenesulfonate, hydrogensulfate, borate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride (prepared from hydrochloric acid), hydrobromide (prepared from hydrogen bromide), iodide, and the like. Salts include hydrochloride, maleate (prepared from maleic acid), 2-hydroxyethanesulfonate, lactate, methanesulfonate (prepared from methanesulfonic acid), 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pyruvate, propionate, salicylate, succinate, sulfate (e.g., salts prepared from sulfuric acid), sulfonate (e.g., those described herein), tartrate, thiocyanate, toluenesulfonate (e.g., tosylate), undecanoate, and the like.

[0057] Examples of base salts include ammonium salts, alkali metal salts (e.g., sodium, lithium, and potassium salts); alkaline earth metal salts (e.g., calcium and magnesium salts); barium, zinc, and aluminum salts; salts with organic bases (e.g., organic amines (e.g., trialkylamines such as triethylamine, procaine, dibenzylamine, N-benzyl-β-phenethylamine, 1-ephenamine, N,N'-dibenzylethylene-diamine, dehydroabietylamine, N-ethylpiperidine, benzylamine, dicyclohexylamine), or salts with similar pharma- ceutically acceptable amines and amino acids (e.g., arginine, lysine), and the like. Basic nitrogen-containing groups can be reacted with reagents (e.g., lower alkylhalides, The alkyl groups may be quaternized with alkyl halides (e.g., methyl, ethyl, propyl, and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g., dimethyl, diethyl, dibutyl, and diamyl 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 monohydrochlorides, hydrogen sulfates, methanesulfonates, phosphates, or nitrates.

[0058] Various forms of prodrugs are well known in the art: 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 in.

[0059] The compounds of the present disclosure may include stereoisomers where asymmetric or chiral centers are present. A particular stereochemistry may be designated with the symbols "R" or "S" depending on the configuration of the substituents around the chiral carbon atom. The present invention contemplates various 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 the present invention may be prepared synthetically from commercially available starting materials that contain asymmetric or chiral centers, or may be prepared by preparation of a racemic mixture followed by resolution, as known to those of skill in the art.

[0060] In addition, the compounds of the invention, once prepared, can be isolated and purified to obtain compositions containing 99% or more of the compounds of the invention ("substantially pure"), which can then be used or formulated as described herein. Such "substantially pure" compounds of the invention are also considered herein to be part of the invention.

[0061] By "stable compound" and "stable structure" is intended a compound that is sufficiently robust that it will not decompose upon isolation to a useful degree of purity from a reaction mixture or upon formulation into an efficacious therapeutic agent. The present disclosure is intended to embody stable compounds.

[0062] A "therapeutically effective amount" is intended to include an amount of a compound of the disclosure alone, or in combination with the claimed compounds, or an amount of a compound of the disclosure in combination with other active ingredients that is effective in inhibiting PD-1 / PD-L1 protein / protein and / or CD80 / PD-L1 protein / protein interactions, or in treating or preventing cancer or infectious diseases (e.g., septic shock, HIV, or Hepatitis B, Hepatitis C, and Hepatitis D).

[0063] As used herein, the term "treating" or "treatment" includes the treatment of a disease condition in a mammal, particularly a human, and may include (a) preventing a mammal from acquiring a disease, particularly where the mammal is predisposed to a disease state but has not yet been diagnosed as suffering from the disease; (b) inhibiting the disease condition, i.e., arresting the progression of the disease condition; and / or (C) alleviating the disease condition, i.e., causing regression of the disease condition.

[0064] Compounds of the present disclosure are intended to include all isotopes of atoms contained in the compounds. Isotopes include atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include deuterium (D) and tritium (T). Isotopes of carbon include 13 C and 14 C. Isotopically labeled compounds of the invention can generally be prepared by conventional techniques known to those of skill in the art, or by methods analogous to those described herein, substituting the appropriate isotopically labeled reagent for the non-labeled reagent used elsewhere. For example, methyl (-CH3) also includes deuterated methyl groups (e.g., -CD3).

[0065] The compounds and / or pharma- ceutically acceptable salts thereof according to the present invention may be administered by any method appropriate for the condition to be treated, which may vary according to the need or the amount of the compounds of the present invention to be delivered depending on the site of need. This disclosure also includes a class of pharmaceutical compositions that contain the compounds and / or pharma- ceutically acceptable salts thereof according to the present disclosure and one or more non-toxic, pharma- ceutically 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 suitable route, preferably in the form of a pharmaceutical composition adapted for 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 carriers, adjuvants, and vehicles that are pharma- cetically acceptable for, for example, oral, mucosal, rectal, or parenteral administration, such as intravascular, intravenous, intraperitoneal, subcutaneous, intramuscular, and intrasternal. For example, the pharmaceutical carrier may include mannitol or a mixture of lactose and microcrystalline cellulose. The mixture may include additional ingredients such as lubricants (e.g., magnesium stearate) and disintegrants (e.g., crospovidone). The carrier mixture may be filled into gelatin capsules or compressed into tablets. The pharmaceutical composition may be administered, for example, as an oral dosage form or infusion.

[0066] For oral administration, the pharmaceutical composition may be in the form of, for example, a tablet, capsule, liquid capsule, suspension, or liquid. The pharmaceutical composition is preferably formulated in a dosage unit form with a specific amount of active ingredient. For example, the pharmaceutical composition may be provided as a tablet or capsule containing an amount of active ingredient ranging from about 0.1 to 1000 mg, preferably from about 0.25 to 250 mg, more preferably from about 0.5 to 100 mg. The appropriate daily dose to be administered to a human or other mammal may vary widely depending on the patient's condition and other factors, but can be determined using routine methods.

[0067] Any pharmaceutical composition discussed herein may be delivered orally, for example, by any suitable acceptable oral formulation. Examples of oral formulations include, but are not limited to, tablets, troches, 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 prepared according to any method known in the art for preparing pharmaceutical compositions for oral administration. In order to provide a medicament that is easy to swallow, the pharmaceutical compositions described in the present disclosure may include at least one substance selected from sweeteners, flavoring agents, coloring agents, demulcents, antioxidants, and preservatives.

[0068] Tablets can be prepared, for example, by mixing at least one compound of the present invention and / or at least one pharma- ceutically acceptable salt thereof with at least one non-toxic, pharma- cetically acceptable additive suitable for tablet preparation. Examples of additives include, but are not limited to, inert diluents (e.g., calcium carbonate, sodium carbonate, lactose, calcium phosphate, and sodium phosphate), granulating and disintegrating agents (e.g., microcrystalline cellulose, croscarmellose sodium, corn starch, and alginic acid), binding agents (e.g., starch, gelatin, polyvinylpyrrolidone, and gum arabic), and lubricants (e.g., magnesium stearate, stearic acid, and talc). In addition, tablets can be uncoated or coated by known techniques to mask the unpleasant taste of unpleasant drugs or to delay disintegration and absorption of the active ingredient in the digestive tract, thus prolonging the effect of the active ingredient for a longer period of time. Examples of water-soluble taste-masking materials include, but are not limited to, hydroxypropyl methylcellulose and hydroxypropyl cellulose. Examples of time delay materials include, but are not limited to, ethyl cellulose and cellulose acetate butyrate.

[0069] Hard gelatin capsules can be prepared, for example, by mixing at least one compound of the 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 prepared, for example, by mixing at least one compound of the present invention and / or at least one pharma- ceutically acceptable salt thereof with at least one water-soluble carrier (e.g., polyethylene glycol) and at least one oil 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 pharma- ceutically acceptable salt thereof with at least one excipient suitable for the preparation of aqueous suspensions. Examples of excipients suitable for the preparation of aqueous suspensions include, but are not limited to, suspending agents (e.g., sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, alginic acid, polyvinylpyrrolidone, gum tragacanth, and gum arabic), dispersing 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), condensation products of ethylene oxide and fatty acids and Examples of suitable condensation products include condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides (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-hydroxybenzoate), at least one coloring agent, at least one flavoring agent, and / or at least one sweetening agent (e.g., but not limited to, sucrose, saccharin, and aspartame).

[0072] Oil suspensions can be prepared, for example, by suspending at least one compound of the present invention and / or at least one pharma- ceutically acceptable salt thereof in either vegetable oil (e.g., peanut oil, olive oil, sesame oil, and coconut oil) or mineral oil (e.g., liquid paraffin). Oil suspensions can also include at least one thickening agent (e.g., beeswax, hard paraffin, and cetyl alcohol). To provide a palatable oil suspension, at least one sweetener already described above and / or at least one flavoring agent can be added to the oil suspension. Oil suspensions can further include at least one preservative, including but not limited to, for example, an antioxidant (e.g., butylated hydroxyanisole, and alpha-tocopherol).

[0073] Dispersible powders and granules can be prepared, for example, by mixing at least one compound of the present invention and / or at least one pharma- ceutically acceptable salt thereof with at least one dispersing agent and / or wetting agent, at least one suspending agent, and / or at least one preserving agent.Suitable dispersing agents, wetting agents, and suspending agents have already been described above. Examples of preservatives include, but are not limited to, antioxidants (e.g., ascorbic acid).In addition, dispersible powders and granules can also include at least one excipient (e.g., but are not limited to, sweeteners, flavoring agents, and coloring agents).

[0074] The emulsion of at least one compound of the invention and / or at least one pharma- ceutically acceptable salt thereof may be prepared, for example, as an oil-in-water emulsion. The oil phase of the emulsion containing the compound of the invention may be composed of known ingredients in a known manner. The oil phase may be provided, for example, but 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 include only an emulsifier, but may also include a mixture of at least one emulsifier and a fat or oil, or both a fat and an oil. Suitable emulsifiers include, but are not limited to, naturally occurring phosphatides (e.g., soybean lecithin), esters or partial esters derived from fatty acids and hexitol anhydrides (e.g., sorbitan monooleate), and condensation products of partial esters and ethylene oxide (e.g., polyoxyethylene sorbitan monooleate). Preferably, a hydrophilic emulsifier is included together with a lipophilic emulsifier acting as a stabilizer. It is also preferred to include both an oil and a fat. Together, emulsifiers, with or without stabilizers, make up what is called emulsifying wax, and the wax, together with oils and fats, makes up what is called emulsifying ointment base, which forms the oily dispersed phase of cream.Emulsions can also include sweeteners, flavorings, preservatives, and / or antioxidants.Emulsifiers and emulsion stabilizers suitable for use in the formulations of the present disclosure include Tween 60, Span 80, cetostearyl alcohol, myristyl alcohol, glyceryl monostearate, sodium lauryl sulfate, glyceryl distearate, alone or with wax; or other materials known in the art.

[0075] The compound of the present invention and / or at least one of its pharmaceutically acceptable salts can also be delivered, for example, intravenously, subcutaneously, and / or intramuscularly via any pharmaceutically acceptable and suitable injection form. Examples of injection forms include, but are not limited to, sterile aqueous solutions containing acceptable vehicles and solvents (e.g., water, Ringer's solution, and isotonic sodium chloride solution), sterile oil-in-water microemulsions, and aqueous or oily suspensions.

[0076] Preparations for parenteral administration 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 preparations for oral administration, or by using other suitable dispersing or wetting agents 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 buffer solutions. Other adjuvants and methods of administration are known and widely known in the pharmaceutical field. The active ingredient may also be administered by injection in a composition with a suitable carrier (e.g., saline, dextrose, or water), or cyclodextrin (i.e., Captisol), solubilizing cosolvent (i.e., propylene glycol), or solubilizing micelle (i.e., Tween 80).

[0077] A sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent (e.g., a solution in 1,3-butanediol). Among the acceptable vehicles and solvents that may be used are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally used as a solvent or suspending medium. For this purpose, any sterile fixed oil may be used, including synthetic monoglycerides or diglycerides. In addition, fatty acids such as oleic acid are used as injectable preparations.

[0078] Sterile injectable oil-in-water microemulsions can be prepared, for example, by 1) dissolving at least one compound of the invention in an oil phase (e.g., a mixture of soybean oil and lecithin), 2) combining the oil phase containing the invention with a mixture of water and glycerol, and 3) treating the combination to form a microemulsion.

[0079] Sterile aqueous suspension or sterile oily suspension can be prepared according to a method known to those skilled in the art. For example, sterile aqueous solution or sterile aqueous suspension can be prepared using a non-toxic, parenterally acceptable diluent or solvent (e.g., 1,3-butanediol), and sterile oily suspension can be prepared using a non-toxic, acceptable solvent or suspension medium (e.g., sterile fixed oil (e.g., synthetic monoglyceride or diglyceride), and fatty acid (e.g., oleic acid).

[0080] Pharmaceutically acceptable carriers, adjuvants, and vehicles that may be used in the pharmaceutical compositions of the present 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 surfactants (BASF), or other similar polymeric delivery matrices), serum proteins (e.g., human serum albumin), buffer 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, 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-cyclodextrin, or chemically modified derivatives (e.g., hydroxyalkyl cyclodextrins, including 2- and 3-hydroxypropyl cyclodextrin, or other solubilizing derivatives)) may also be effectively used to enhance the delivery of the compounds of the formulae described herein.

[0081] The pharma- ceutical active compounds of the present disclosure can be processed according to conventional pharmaceutical methods to prepare medicaments for administration to patients (e.g., humans and other mammals). The pharmaceutical compositions can be subjected to conventional pharmaceutical operations (e.g., sterilization) and / or can contain conventional adjuvants (e.g., preservatives, stabilizers, wetting agents, emulsifiers, buffers, etc.). Tablets and pills can additionally be prepared with enteric coatings. Such compositions can also contain adjuvants (e.g., wetting agents, sweeteners, flavoring agents, and aromatic agents).

[0082] The amount of compound administered to treat a condition using the disclosed compounds and / or compositions, and the dosing schedule will depend on a variety of factors (e.g., age, weight, sex, the condition of the patient, the type of disease, the severity of the disease, the route and frequency of administration, and the specific compound utilized). Thus, the dosing schedule may vary widely, but can be routinely determined using standard methods. A daily dose of about 0.001 to 100 mg / kg body weight, preferably between about 0.0025 to about 50 mg / kg body weight, and most preferably between about 0.005 to 10 mg / kg body weight, may be appropriate. The daily dose may be administered 1 to 4 times a day. Other dosing schedules include weekly and biday cycles.

[0083] For treatment, the active compound of the present disclosure is usually combined with one or more adjuvants suitable for intended administration route.When administered orally, the compound can be mixed with lactose, sucrose, starch powder, cellulose ester of alkanoic acid, cellulose alkyl ester, 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 tableted or encapsulated for convenient administration.Such capsules or tablets can include controlled release formulations, and can be provided with active compound dispersed in hydroxypropylmethylcellulose.

[0084] The pharmaceutical compositions of the present disclosure include at least one compound of the present invention and / or at least one pharma- ceutically acceptable salt thereof, and optionally an additive selected from a pharma- ceutically acceptable carrier, adjuvant, and vehicle. Another composition of the present disclosure includes a compound of the present invention as described herein, or a prodrug thereof, and a pharma- ceutically acceptable carrier, adjuvant, or vehicle.

[0085] The compounds of the present disclosure inhibit PD-1 / PD-L1 (protein / protein), leading to PD-L1 blockade, which can enhance immune responses against cancer cells and infectious diseases in mammals, including humans.

[0086] In some embodiments, the present disclosure relates to the treatment of patients in vivo using the compounds of the present invention or their salts to inhibit the growth of cancer tumors. The compounds of the present invention or their salts may be used alone to inhibit the growth of cancer tumors. Alternatively, the compounds of formula (I) or their salts may be used in conjunction with other immunogens or standard cancer treatments as described below.

[0087] In certain embodiments, the disclosure provides a method of inhibiting the growth of tumor cells in a patient, the method comprising administering to the patient a therapeutically effective amount of a compound of the invention, or a salt thereof.

[0088] In some embodiments, a method for treating cancer is provided, which comprises administering to a patient in need thereof a therapeutically effective amount of the compound of the present invention or its salt.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 that are preferred for treatment include, but are not limited to, melanoma (e.g., metastatic malignant 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 malignant tumors whose growth can be inhibited using the compounds of the present disclosure.

[0089] Other examples of cancers that may be treated using the methods of the present 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's lymphoma, non-Hodgkin's lymphoma, esophageal cancer, small intestine cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, acute myeloid leukemia, chronic bone marrow sarcoma, and the like. These include chronic or acute leukemias, including myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, childhood solid tumors, lymphocytic lymphomas, bladder cancer, kidney or urethral cancer, renal pelvis cancer, tumors of the central nervous system (CNS), primary CNS malignant lymphoma, tumor angiogenesis, axial tumors, brain stem gliomas, pituitary adenomas, Kaposi's sarcoma, epidermoid carcinoma, squamous cell carcinoma, T-cell lymphoma, environmentally-driven cancers, including asbestos-driven cancers, and combinations of the above cancers. The present disclosure is also useful for treating metastatic cancers, particularly those that express PD-L1 (Iwai et al. (2005) Int. Immunol. 17:133-144).

[0090] Optionally, the compounds of the invention or salts thereof 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 that have been introduced with genes encoding immune stimulating cytokines (He et al (2004) J. Immunol. 173:4919-28). Non-limiting examples of tumor vaccines that may be used include transfected tumor cells expressing melanoma antigen peptides, such as peptides of gp100, MAGE antigens, Trp-2, MART1, and / or tyrosinase, or the cytokine GM-CSF.

[0091] In humans, some tumors (e.g., melanoma) are known to be immunogenic, and PD-L1 blockade would be expected to increase baseline T cell activation and thus activate tumor responses in the host.

[0092] PD-L1 blockade can be combined with vaccination protocols. Many 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 see 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, vaccines are prepared using autologous or allogeneic tumor cells. These cellular vaccines are known to be most effective when the 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 global 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 on tumors and the cells from which they arise (e.g., melanocyte antigen gp100, MAGE antigens, 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 on tumors to generate an immune response against these proteins. These proteins are normally seen by the immune system as self-antigens and are therefore tolerant to them. Tumor antigens may also include the protein telomerase. Telomerase is required for the synthesis of chromosomal telomeres and is expressed in over 85% of human cancers, but only in a limited number of 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 due to somatic mutations that alter the protein sequence or create fusion proteins between two unrelated sequences (i.e., bcr-abl for the Philadelphia chromosome), or idiotypes in B-cell tumors.

[0094] Other tumor vaccines may include proteins from viruses involved in human cancers, such as human papillomavirus (HPV), hepatitis viruses (HBV, HDV, and HCV), and Kaposi's sarcoma herpesvirus (KHSV). Another form of tumor-specific antigen that may be used in conjunction with PD-L1 blockade is purified heat shock proteins (HSPs) isolated from the tumor tissue itself. These heat shock proteins contain fragments of tumor cell proteins, and these HSPs are highly efficient in delivering them 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 can be produced ex vivo and enriched with various protein and peptide antigens as well as tumor cell extracts (Nestle, F. et al. (1998) Nature Medicine 4: 328-332). DCs can also be transduced by genetic methods to express these tumor antigens as well. DCs have also been fused directly to tumor cells to effect immunization (Kugler, A. et al. (2000) Nature Medicine 6:332-336). As a method of vaccination, DC immunization can be effectively combined with PD-L1 blockade to activate stronger antitumor responses.

[0096] PD-L1 blockade may also be combined with standard cancer treatments. PD-L1 blockade may also be effectively combined with chemotherapy. In these instances, it may be possible to reduce the dose of chemotherapy administered (Mokyr, M. et al. (1998) Cancer Research 58: 5301-5304). An example of such a combination is the combination of the compounds disclosed herein with dacarbazine for the treatment of melanoma. Another example of such a combination is the combination of the compounds disclosed herein with interleukin-2 (IL-2) for the treatment of melanoma. The scientific rationale behind the combined use of PD-L1 blockade and chemotherapy is that cell death, which is the result of the cytotoxic action of most chemotherapeutic compounds, should result in increased levels of tumor antigens in the antigen presentation pathway. Other combination therapies that may result in synergy with PD-L1 blockade through cell death include radiation therapy, surgery, and hormone ablation therapy. Each of these protocols creates a source of tumor antigens for the host. Angiogenesis inhibitors may also be combined with PD-L1 blockade. Inhibition of angiogenesis routes tumor antigens into the host antigen presentation pathway, leading to tumor cell death.

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

[0098] Tumors evade host immune surveillance by a wide variety of mechanisms. Many of these mechanisms can be overcome by inactivation of tumor-expressed and immunosuppressive proteins, including 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), among others. Inhibitors that bind to and block each of these proteins may be used in combination with the compounds disclosed herein to counteract the effects of immunosuppressants and favor the host's tumor immune response.

[0099] Compounds that activate host immune responsiveness can be used in combination with PD-L1 blockade. These compounds include molecules on the surface of dendritic cells that activate DC function and antigen presentation. Anti-CD40 compounds effectively 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). Activating compounds against 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)) may also provide high levels of T cell activation.

[0100] Bone marrow transplantation is currently used to treat a variety of hematopoietic derived tumors. While this treatment can result in graft-versus-host disease, therapeutic benefit can come from a graft-versus-tumor response. PD-L1 blockade can be used to enhance the efficacy of donor transplanted tumor-specific T cells.

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

[0102] Similar to the tumor application described above, the compounds of the present invention or their salts can be used alone or as adjuvants in combination with vaccines to stimulate immune responses against pathogens, toxins, and self-antigens. Examples of pathogens for which this method of treatment may be particularly useful include those for which there is currently no effective vaccine or for which traditional vaccines are incompletely 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 infections with agents, such as HIV, which show antigenic changes during the course of infection. These novel epitopes are recognized as foreign upon administration and therefore trigger a strong T cell response that is not attenuated by negative signals via PD-1.

[0103] Some examples of pathogenic viruses causing infections treatable by the methods of the present disclosure include HIV, hepatitis (A, B, C, or D), herpes viruses (e.g., VZV, HSV-1, HAV-6, HHv-7, HHV-8, HSV-2, CMV, and Epstein-Barr virus), adenovirus, influenza virus, flavivirus, echovirus, rhinovirus, coxsackievirus, coronavirus, respiratory syncytial virus, mumps virus, rotavirus, measles virus, rubella virus, parvovirus, vaccinia virus, HTLV virus, dengue virus, papilloma virus, molluscum contagiosum virus, poliovirus, rabies virus, JC virus, and arboviral encephalitis virus.

[0104] Some examples of pathogenic bacteria causing infections treatable by the methods of the present disclosure include Chlamydia, Rickettsia, Mycobacteria, Staphylococcus, Streptococcus, Pneumococcus, Meningococcus and Gonococcus, Klebsiella, Proteus, Serratia, Pseudomonas, Legionella, Diphtheria, Salmonella, Bacillus, Cholera, Tetanus, Botulinum, Anthrax, Plague, Leptospira, and Lyme disease bacteria.

[0105] Some examples of pathogenic fungi causing infections treatable by the methods of the present disclosure include Candida (such as Candida albicans, Krusei, Glabrata, Tropicalis, etc.), Cryptococcus neoformans, Aspergillus (such as Aspergillus fumigatus and Aspergillus niger), Mucor (Mucococcus, Rhizopus, Rhizopus), Sporothrix schenckii, Blastomyces dermatitidis, Paracoccidioides braziliensis, Coccidioides immitis, and Histoplasma capsulatum.

[0106] Some examples of pathogenic parasites that cause infections treatable by the methods of the present disclosure include Entamoeba histolytica, Balantidium coli, Naegleria fowleri, Acanthamoeba spp., Giardia lamblia, Cryptosporidium spp., Pneumocystinii carinii, Plasmodium vivax, Babesia microti, Trypanosoma brucei, Trypanosoma cruzi, Leishmania donovani, Toxoplasma gondii, and Ancylostoma braziliensis.

[0107] In all of the above methods, PD-L1 blockade may be combined with other forms of immunotherapy, such as cytokine therapy (e.g., interferon, GM-CSF, G-CSF, IL-2), or bispecific antibody therapy directed against strongly expressing tumor antigens (see, e.g., 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 can induce and enhance autoimmune responses. Indeed, induction of antitumor responses using tumor cells and peptide vaccines has demonstrated that many antitumor responses involve anti-self reactivity (depigmentation observed in anti-CTLA-4+GM-CSF modified B16 melanoma (see van Elsas et al., supra); depigmentation in Trp-2 vaccinated mice (Overwijk, W. et al. (1999) Proc. Natl. Acad. Sci. USA 96: 2982-2987); autoimmune prostatitis caused 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 self-proteins to devise vaccination protocols that efficiently induce immune responses against these self-proteins for disease treatment. For example, Alzheimer's disease is associated with the inappropriate accumulation of amyloid beta (A.β.) peptides in amyloid deposits in the brain; antibody responses against amyloid can clear these amyloid deposits (Schenk et al., (1999) Nature 400: 173-177).

[0110] Other self-proteins may also be used as targets (e.g., IgE for the treatment of allergies and asthma, and TNFα for the treatment of rheumatoid arthritis). Finally, antibody responses against various hormones may be induced by the use of the compounds of the present invention or their salts. Neutralizing antibody responses against reproductive hormones may be used for contraception. Neutralizing antibody responses against hormones and other soluble factors required for the growth of certain tumors may also be considered as possible vaccination targets.

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

[0112] The compounds disclosed herein can be used to stimulate antigen-specific immune responses by co-administration of a compound of the present invention or a salt thereof with an antigen of interest (e.g., a vaccine). Thus, in another aspect, the disclosure provides a method for enhancing an immune response to an antigen in a patient, comprising administering to the patient (i) the antigen; and (ii) a compound of the present invention or a salt thereof, such that the immune response to the antigen in the patient is enhanced. The antigen can 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 sections, such as the tumor antigens (or tumor vaccines) discussed above, or the antigens derived from viruses, bacteria, or other pathogens discussed above.

[0113] As described above, the compounds of the present disclosure may be administered simultaneously with one or more other therapeutic agents (e.g., cytotoxic, radiotoxic, or immunosuppressive agents). The compounds of the present disclosure may be administered before, after, or simultaneously with the other therapeutic agents, or may be administered simultaneously with other known therapies (e.g., anti-cancer therapies (e.g., radiation)). Such therapeutic agents include, among others, anti-tumor agents that, when administered alone, are only effective at doses that are toxic or subtoxic to the patient (e.g., doxorubicin (adriamycin), cisplatin bleomycin sulfate, carmustine, chlorambucil, dacarbazine, and cyclophosphamide hydroxyurea). Cisplatin is administered intravenously at 100 mg / dose once every four weeks, and adriamycin is administered intravenously at a dose of 60-75 mg / mL once every 21 days. Coadministration of the compounds of the present disclosure, or salts thereof, with chemotherapeutic agents provides two anti-cancer agents that act via different mechanisms to produce a cytotoxic effect on human tumor cells. Such co-administration may overcome problems due to the development of drug resistance or due to changes in the antigenicity of tumor cells that become unresponsive to antibodies.

[0114] Also within the scope of this disclosure is a kit that includes the compound of the present invention or its salt and instructions for use.The kit may further include at least one other reagent.The kit generally includes a label that indicates the intended use of the contents of the kit.The term "label" includes any written or recorded material that is provided on or with the kit, or that is otherwise attached to the kit.

[0115] The other therapeutic agents described above, when used in combination with the compounds of the present disclosure, may be used, for example, in amounts as set forth in the Pharmaceutical and Medical Devices Handbook (PDR) or as determined by one of ordinary skill in the art. In the methods of the present invention, the other therapeutic agents may be administered prior to, simultaneously with, or after administration of the compounds of the present disclosure.

[0116] Working Example The present invention is further defined in the following examples, which should be understood to be given by way of illustration only. From the above discussion and examples, those skilled in the art can ascertain the essential features of the present invention, and can make changes and modifications to adapt the present invention 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 examples described below, but rather is defined by the claims appended hereto.

[0117] The compounds may be prepared by methods known in the art, including those described below, and may be modified within the skill of 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. The variables (such as the numbered "R" substituents) are intended only to illustrate how to prepare the compounds, and are not to be confused with the variables used in the claims or other sections of this specification. The following methods are for illustrative purposes and are not intended to limit the scope of the invention.

[0118] The abbreviations used in the schemes follow the meanings commonly used in the art. The abbreviations of the 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 propan-1-ol, "i-PrOH" is 2-propyl alcohol or propan-2-ol, "Ar" is aryl, "TFA" is trifluoroacetic acid, "DMSO" is dimethylsulfoxide, "EtOAc" 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 hour, "rt" is room temperature or retention time (depending on the context), "min" is minute, "HOBt" is 1-hydroxyl group, "H" is hydrogen ... Benzotriazole hydrate, "HCTU" is 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 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]pyridin-1-ylmethylene]-N-methylmethanaminium hexafluorophosphate N-oxide, "DIEA" and "iPrNEt2" are defined as diisopropylethylamine, and "Et3N" is triethylamine.

[0119] Abbreviations are as follows: "1x" is one time, "2x" is two times, "3x" is three times, "°C" is degrees Celsius, "eq" is equivalent, "g" is gram, "mg" is milligram, "L" is liter, "mL" is milliliter, "μL" is microliter, "N" is normal, "M" is molar, "mmol" is millimole, "min" is minute, "h" is hour, "rt" is room temperature, "RT" is retention time, "atm" is atmosphere, "psi" is pounds per square inch, "conc." is concentration, "sat" or "sat'd" is saturation, "MW" is molecular weight, "mp" is melting point, "ee" is enantiomeric excess, "MS" or "Mass Spec" is mass spectrometry, "ESI" is electrospray ionization mass spectrometry, "HR" is high resolution, "HRMS" is high resolution mass spectrometry, "LC" is liquid chromatography, "LCMS" is liquid chromatography mass spectrometry, "HPLC" is high performance liquid chromatography, "RP ... "HPLC" stands for reverse phase HPLC, "TLC or "tlc" stands for thin layer chromatography, "NMR" stands for nuclear magnetic resonance spectroscopy, 1 "H" is defined as proton, "δ" is delta, "s" is singlet, "d" is doublet, "t" is triplet, "q" is quartet, "m" is multiplet, "br" is broad, and "Hz" is Hertz, and "α", "β", "R", "S", "E", and "Z" are stereochemical symbols well known to those of ordinary skill in the art.

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

[0121] General methods for preparing compounds of the present invention from intermediates 1-5 and aminolactones or lactams: A mixture of any one of intermediates 1-5 (1 eq.) and reagent (1-20 eq.) in THF or dioxane or DME or MeOH or EtOH or a mixture of these solvents (with appropriate addition of AcOH (1-20 eq.)) was stirred at room temperature for 0.5-48 hours, and NaCNBH3 (1-20 eq.) was added. The reaction was stirred at room temperature to 100°C for 0.5-48 hours and quenched with methanol or water. After removal of all solvents under reduced pressure, the resulting residue was purified by preparative HPLC to give the compounds 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] General method for preparing compounds 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) in THF, dioxane, DME or a mixture of these solvents was stirred at room temperature to 100°C for 0.5-48 hours, and quenched with methanol or water. After removing all the solvents under reduced pressure, the resulting residue was purified by preparative HPLC to obtain the compound of the present invention.

[0124] General method for preparing compounds of the present invention from intermediate 7: A mixture of intermediate 7 (1 equivalent) and reagents (1-20 equivalents) in THF, dioxane, DME, or a mixture of these solvents (with iPr2NEt or Et3N (1-20 equivalents) added as appropriate) was stirred at room temperature to 100°C for 0.5-48 hours, and quenched with methanol or water. After removing all the solvents 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 preparing compounds of the present invention from Reference Compounds 1-5 and an aminolactone or lactam in the presence of an aldehyde or ketone: A mixture of any one of the reference compounds 1-5 (1 eq.), reagent (1-20 eq.) in DCM or THF or dioxane or DME or MeOH or EtOH or their mixed solvents (with iP2NEt added as appropriate) was stirred at room temperature for 0.5-48 hours, and AcOH (1-20 eq.) was added. The mixture was stirred at room temperature for 0.5-48 hours, and then NaCNBH3 (1-20 eq.) was added. The reaction was stirred at room temperature-100°C for 0.5-48 hours, and an aldehyde or ketone (1-20 eq.) was added. After stirring at room temperature-100°C for 0.5-48 hours, the reaction was quenched with methanol or water. After removing all the solvents under reduced pressure, the resulting residue was purified by preparative HPLC to obtain the compounds 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 of PD-1 and PD-L1 can be assessed using the soluble and purified extracellular domains of the two proteins. The extracellular domains of 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. For the h / PD-L1-His binding assay, inhibitors were pre-incubated with PD-L1-His (10 nM final) in assay buffer (4 μL) for 15 min, followed by the addition of PD-1-Ig (20 nM final) / assay buffer (1 μL) and further incubation for 15 min. HTRF detection was performed using europium cryptate-labeled anti-Ig (1 nM final) and allophycocyanin (APC)-labeled anti-His (20 nM final). These antibodies were diluted in HTRF detection buffer and dispensed in 5 μL aliquots during the binding assay reaction. The reaction was equilibrated for 30 min 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) with a C-terminal human Fc region of an IgG epitope tag [hPD-1(25-167)-3S-IG], and human PD-L1(18-239) with a C-terminal His epitope tag [hPD-L1(18-239)-TVMV-His] 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 binding of soluble PD-1 to soluble PD-L1 Soluble PD-1 and soluble PD-L1 refer to proteins that have been truncated at the carboxy terminus to remove the transmembrane domain and fused to a heterologous sequence, specifically the Fc region of 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, inhibitors were pre-incubated with PD-L1-His (10 nM final) / assay buffer (4 μL) for 15 min, followed by the addition of PD-1-Ig (20 nM final) / assay buffer (1 μL) and further incubation for 15 min. PD-L1 fusion proteins from either human, cynomolgus monkey, mouse, or other species were used. HTRF detection was performed using europium cryptate-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 dispensed in 5 μL aliquots during the binding assay reaction. The reaction was equilibrated for 30 min 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] The binding / competition assay between biotinylated Compound No. 71 and human PD-L1-His was performed as follows: Compounds of the invention were pre-incubated with PD-L1-His (10 nM final) / assay buffer (4 μL) for 60 minutes, followed by the addition of biotinylated Compound No. 71 (0.5 nM final) / assay buffer (1 μL). Equilibration and binding were allowed for 30 minutes, followed by the addition of europium cryptate-labeled streptavidin (2.5 pM final) and APC-labeled anti-His (20 nM final) / HTRF buffer (5 μL). The reaction was equilibrated for 30 minutes and the signal (665 nm / 620 nm ratio) was measured using a spectrofluorometer (EnVision). Recombinant proteins: Carboxy-terminally truncated human PD-1 (amino acids 25-167) with a C-terminal human Ig epitope tag [hPD-1(25-167)-3S-IG], and human PD-L1 (amino acids 18-239) with a C-terminal His epitope tag [hPD-L1(18-239)-tobacco vein mottling virus protease cleavage site (TVMV)-His] 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 the IC of representative examples of the disclosure as 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 have activity as inhibitors of PD-1 / PD-L1 interaction and therefore can be used to treat diseases or defects related to PD-1 / PD-L1 interaction. Through inhibition of PD-1 / PD-L1 interaction, the compounds of the present disclosure can be used to treat infectious diseases (e.g., HIV), septic shock, hepatitis A, B, C, or D, and cancer.

[0131] The description of the specific embodiments above fully discloses the general nature of the present invention, so that those other than the inventors can easily modify and / or adapt the specific embodiments described above for various applications by applying the knowledge of those skilled in the art without undue experimentation and without departing from the basic concept of the present invention. Therefore, such modifications and adaptations are intended to be within the meaning and scope equivalent to the embodiments of the present disclosure based on the content and guidance described herein. It should be understood that the expressions or terminology used in this specification are for explanatory purposes and are not limited to the expressions or terminology used in this specification that would be interpreted by a person skilled in the art in light of the content and guidance.

[0132] Other embodiments of the invention will be apparent to those skilled in the art from consideration of the specification and practice of the invention disclosed herein. It is intended that the specification and examples be considered as exemplary only, with a true scope and spirit of the invention being set forth in the following claims.

Claims

1. Formula (I): 【Chemistry 1】 [In the formula, R 1 is independent - (O) m -(CH 2 ) n -R 1a or -(CH 2 ) n -(O) m -R 1b and; R 1a are independently O, N, S, and NR a wherein the heterocycle is a 5-6 membered heterocycle having 1-2 heteroatoms selected from 0-3 R b Replaced with; R 1b is phenyl or O, N, S, and NR a wherein the phenyl and heteroaryl are each independently selected from 0 to 3 R 1c Replaced with; R 1c are independently halogen, CN, OH, SH, NH 2 , C 1 -C 4 Haloalkyl, C 1 -C 4 Alkoxy, C 1 -C 4 Haloalkoxy, C substituted with 0-1 OH 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 is phenyl or O, N, S, and NR a wherein the phenyl and heteroaryl are each independently selected from 0 to 3 R d Replaced with; Z is a bond or C 1 -C 2 is alkylene; R 2 is independently 0 to 4 R c is a 4-8 membered lactone or lactam substituted with; R 2a is independently 【Chemistry 3】 and; R 3 , R 4 and R 5 are each independently halogen, CN, OH, SH, or 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 is cycloalkyl; R 6 are independently hydrogen, C 1 -C 4 Alkyl, or -(CH 2 ) n -R 6a and; R 6a are independently phenyl or O, N, S, and NR a wherein the phenyl and heteroaryl are each independently selected from 0 to 3 R 6b Replaced with; R 6b are independently halogen, CN, OH, C 1 -C 4 Alkyl, C 1 -C 4 Haloalkyl, C 1 -C 4 Alkoxy, or C 1 -C 4 haloalkoxy; R 7 are independently hydrogen, C 1 -C 4 Alkyl, -C(O)C 1 -C 4 Alkyl, -(CH 2 ) n -C 3 -C 6 Cycloalkyl, or -(CH 2 ) n -phenyl; or R 6 and R 7 together form W; and W is a 1-4 membered linker having elements independently selected from carbon, oxygen, and nitrogen, wherein said linker is comprised of 0-2 R e Replaced with; R a are 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 are each independently oxo, halogen, CN, OH, or C 1 -C 4 Alkyl, or C 1 -C 4 is alkoxy; R d are independently halogen, CN, OH, C 1 -C 4 Alkyl, or C 1 -C 4 is alkoxy; R e are independently oxo, =CH 2 , halogen, CN, OH, C 1 -C 4 Alkyl, or C 1 -C 4 is alkoxy; Each m is independently 0 or 1; Each n is independently 0, 1, or 2; r, s, and t are each independently 0, 1, or 2. or a pharma- ceutically acceptable salt thereof.

2. During the ceremony, R 2 is a 5-6 membered lactone or lactam independently substituted with 0-4 Rc; Rc is independently oxo, halogen, OH, or C 1 -C 3 is alkyl; W is a 2-3 membered linker having elements independently selected from carbon, oxygen, and nitrogen, wherein said linker is comprised of 0-2 R e is replaced by; and R e are independently oxo, =CH 2 , OH, or C 1 -C 4 is alkyl, 2. The compound of claim 1 or a pharma- ceutically acceptable salt thereof.

3. Formula (II): 【Chemistry 3】 [In the formula, R 1 are independently -O-CH 2 -R 1a or -CH 2 -OR 1b and; R 1a is N-(C 1 -C 3 alkyl)-piperidinyl; R 1b is 1 to 3 R 1c is a phenyl substituted with; R 1c are independently halogen, -CH 2 OH, -O-CH 2 -R 1d , or -CH 2 -NR 7 -R 2a and; R 1d is a cyano substituted pyridyl; R 2 and R 2a are each independently 【Chemistry 4】 and; R 3 are independently hydrogen, C 1 -C 3 is alkyl or halogen; R 4 are independently hydrogen, C 1 -C 3 is alkyl or halogen; R 5 are independently hydrogen, C 1 -C 3 is alkyl or halogen; R 6 are independently hydrogen, C 1 -C 3 Alkyl, or -CH 2 -(cyano-substituted pyridyl); and R 7 are independently hydrogen, C 1 -C 3 Alkyl, -C(O)C 1 -C 3 Alkyl or -CH 2 -cyclopropyl] 2. The compound of claim 1 or a pharma- ceutically acceptable salt thereof.

4. During the ceremony, R 1 is -O-CH 2 -R 1a and; R 1a is N-(C 1 -C 3 alkyl)-piperidinyl; R 6 is -CH 2 -(cyano-substituted pyridyl); and R 7 is hydrogen; or a pharma- ceutically acceptable salt thereof.

5. During the ceremony, R 1 is -CH 2 -OR 1b and; R 1b is 1 to 3 R 1c is a phenyl substituted with; R 1c are independently halogen, -O-CH 2 -R 1d , or -CH 2 -NR 7 -R 2a and; R 1d is a cyano-substituted pyridyl; and R 7 is hydrogen; or a pharma- ceutically acceptable salt thereof.

6. Formula (III): 【Chemistry 5】 [In the formula, R 1 are independently -O-CH 2 -R 1a or -CH 2 -OR 1b and; R 1a is N-(C 1 -C 3 alkyl)-piperidinyl; R 1b is 1 to 3 R 1c is a phenyl substituted with; R 1c are independently halogen, -O-CH 2 -R 1d , or -CH 2 -NR 7 -R 2a and; R 1d is a cyano substituted pyridyl; R 2 and R 2a are each independently 【Chemistry 6】 and; R 3 are independently hydrogen, C 1 -C 3 is alkyl or halogen; R 4 are independently hydrogen, C 1 -C 3 is alkyl or halogen; R 5 are independently hydrogen, C 1 -C 3 is alkyl or halogen; and W is independently -CH 2 C(O)-, -CH 2 C(=CH 2 )CH 2 -, or -CH 2 C(OH)CH 2 -is 2. The compound of claim 1 or a pharma- ceutically acceptable salt thereof.

7. The compound is 【Table 1】 【Table 2】 【Table 3】 【Table 4】 【Table 5】 【Table 6】 【Table 7】 【Table 8】 【Table 9】 【Table 10】 【Table 11】 2. The compound of claim 1, selected from the group consisting of:

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

9. A pharmaceutical composition comprising a compound according to any one of claims 1 to 7 or a pharma- ceutically acceptable salt thereof for use as a medicament.

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

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

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

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