Method for modulating the TIGIT and PD-1 signaling pathways using 1,2,4-oxadiazole compounds

Abstract

To provide compositions for modulating a T cell immunoreceptor signaling pathway with Ig and ITIM domains and a programmed cell death-1 signaling pathway.SOLUTION: The present invention provides a composition comprising a compound of a following formula, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.SELECTED DRAWING: None

Description

[Technical Field]

[0001] Related applications This application is a provisional Indian patent application No. 201841009306, filed on March 14, 2018. This asserts the interest of the patent, and the specification of this provisional patent application, as a whole, is subject to the present invention. It will be included in the detailed specifications.

[0002] Technical field The present invention comprises administering a compound of formula (I) or a pharmaceutically acceptable salt thereof. T cell immune receptors (TIGIT) having Ig and ITIM domains in the target Methods for modulating the programmed cell death-1 (PD-1) signaling pathway Regarding. [Background technology]

[0003] Background of the Invention Immunotherapy, which utilizes the activity of the immune system against tumors, is an effective treatment for multiple malignant tumors. It has been proven to be a therapeutic approach. In fact, many tumors are caused by the accumulation of gene mutations. Furthermore, it expresses antigens that can potentially induce specific tumor immunity. However, tumors also have negative Activating regulatory pathways and checkpoints, such as PD-1 / PD-L1 and CTLA-4 These responses can be suppressed by sexualization.

[0004] TIGIT (T cell immune receptor with Ig and ITIM domains) is a WUCAM , also known as Vstm3 or Vsig9, activated T cells, Treg and It is an inhibitory receptor expressed by NK cells. TIGIT is an immunoglobulin-variable dormant receptor. It has a y-in molecule, a transmembrane domain, and an immunoreceptor-suppressive tyrosine motif (ITIM), It contains the signature sequence element of the PVR protein family. It interacts with the viral receptor (PVR; CD155) and nectin 2 (CD112). It is known that (Stengel et al. (2012) Proc. Nat' (Acad. Sci.(USA)19:5399). TIGIT is a mature immunomodulatory It suppresses T cell activation by promoting the generation of dendritic cells. TIGIT and other Such co-inhibitory molecules (e.g., CTLA-4, PD-1, Lag3, and BTLA) It may play a role in tumor cells avoiding immune surveillance. Several experiments have shown that PVR / CD155 is found in melanoma cells (Inozume et al. (2014) J. I nvest. Dermatol. 134:S121-Abstract 693) and It was shown to be overexpressed in various other tumors. The TIGIT / PVR interaction is T and By inhibiting the antitumor response of NK cells, such tumor cells can be eradicated through the immune system. It may be possible to protect against it (Stanietsky et al. (2009) Proc Nat'l Acad. Sci. (USA) 106:17858 and Lozan et al. (2012) J. Immunol. 188:3869). The TIGIT pathway is , through CD155 / TIGIT interaction, humans (Stanietsky et al. (2 009) Proc. Nat'l Acad. Sci.(USA);106:17858) or mouse (Stanietsky et al. (2013) Eur J Immun) This was demonstrated by reducing the killing of primary NK cells by any of the primary NK cells (ol. 43:2138). As described above, it is known to negatively regulate NK cell function. In addition, MDSCs Suppression of NK cell function (degranulation, IFN-γ production) is performed by TIGIThigh NK cells. This is observed to depend on CD155-TIGIT interaction and greater functional inhibition. This was shown (Sarhan et al. (2016) Cancer Res 201 6;76:5696). Other experiments have shown that modulo selectively suppresses Th1 and Th17 responses. Identifying the TIGIT subset of T cells (Treg) (Joller et al. (20 14) Immunity 40:569), and thereafter TIGIT blockers are antitumor immunotherapy This suggests alternative mechanisms that could enhance the epidemic response.

[0005] TIGIT is similar to other co-inhibitory receptors such as CTLA-4, PD-1, and BTLA. It may act to "turn off" the immune response. CTLA-4 (ipilimumab) and P Antibodies targeting D-1 (nivolumab, pembrolizumab) are approved for the treatment of human cancer. This confirms this therapeutic approach. Antibodies or other drugs that bind to human TIGIT. The agent may also find applications in treating cancer. In mouse models, PD-L1 and TI Blocking both antibodies in GIT leads to a synergistic enhancement of CD8<+> T cell-mediated tumor rejection. (Grogan et al. (2014) J. Immunol. 192(1) Sup pl. 203.15; Johnston et al. (2014) Cancer Ce (ll 26:1-15). Similar results have been obtained in animal models of melanoma (Inozu me et al. (2014) J. Invest. Dermatol. 134:S12 1-Abstract 693).

[0006] Several experiments have shown that TIGIT blockade is related to binding to PVR / CD155. Antitumor CD8<+ only in the presence of the competing co-activated receptor DNAM-1 / CD226 >This suggests that it is effective in enhancing T cell responses (Johnston et al.) al. (2014) Cancer Cell 26:1-15). Further experiments are being conducted at TI. mAbs (monoclonal antibodies) that act for GIT and PD-1 double blockade are black. CD8 to tumor + Clinical efficacy of PD-1 blockade in patients with advanced melanoma by enhancing T cell response. (Joe-Marc Chauvin et al., (2015) ), J Clin Invest. May 1; 125(5): 2046-2058).

[0007] Thus, TIGI, when combined with PD-1 blockade to enhance immune-related diseases such as cancer, Given the fact that the use of T-blocking has not been explored much, TIGIT and DP -1 Unmetney for developing potent therapeutics that exhibit dual inhibition of signaling pathways There is a z. [Overview of the project] [Problems that the invention aims to solve]

[0008] Summary of the Invention The present invention relates to a 1,2,4-oxadiazole compound, or its stereoisomer, or Using pharmaceutically acceptable salts, T cell immune receptors having Ig and ITIM domains (TIGIT) signaling pathway and programmed cell death 1 (PD-1) signaling pathway Regarding methods for modulating paths. [Means for solving the problem]

[0009] In one aspect, this disclosure relates to T cells having Ig and ITIM domains in the subject. Immune receptor (TIGIT) signaling pathway and programmed cell death 1 (PD-1) signaling pathway A method for modulating a null transmission path, wherein the target is given by equation (I): [ka] (In the formula, R1 is hydrogen, or -OH, -COOH, aryl, heteroaryl or aryl. Represents a -(C1~C6) alkyl group that may be substituted with a -OH group; R2 is hydrogen, or -OH, -SH, C(O)NH2, -COOH, aryl, hetero -(C1~C6) alkyl groups, which may be substituted with loaryl or aryl-OH groups. Representation; R a is either representing hydrogen or R a And R2, together with the atom they bond to, pyrrolidine It forms a ring; R3 is hydrogen or formula (I'): [ka] Represents the base represented by; ----- represents a connection point; R b is either representing hydrogen or R b and R c However, along with the atoms to which they bond, pyrolories It forms a ring; R c This is hydrogen, or -OH, -C(O)NH2, COOH, aryl or aryl. Compounds represented by -(C1~C6)alkyl groups, which may be substituted with -OH groups. A method comprising contacting the stereoisomer thereof or a pharmaceutically acceptable salt thereof. To provide. [Brief explanation of the drawing]

[0010] [Figure 1] Antitumor effect of compound 19 in CT26 tumor-carrying mice [Modes for carrying out the invention]

[0011] Detailed description of the invention The present invention relates to a 1,2,4-oxadiazole compound, or its stereoisomer, or Using pharmaceutically acceptable salts, the TIGIT signaling pathway and the PD-1 signaling pathway The present invention provides a method for modulating the pathway. The present invention also provides a compound of formula (I), or the TIGIT and This invention provides a method for treating diseases or disorders mediated by both PD-1 and PD-1.

[0012] Each embodiment is provided for illustrative purposes of the present invention and not as an limitation of the present invention. In fact, Various improvements and modifications can be made to the present invention without departing from the scope and spirit of the invention. This will be obvious to those skilled in the art. For example, as illustrated or described as part of one embodiment. Further embodiments can be created by using the features in other embodiments. The invention includes improvements and modifications such as those included in the scope of the attached claims and their equivalents. Further details are provided below. Other objects, features, and aspects of the present invention are disclosed in the detailed description below. This is or is evident from the following detailed description. This disclosure describes exemplary embodiments. This is merely a limitation of the present invention and should not be interpreted as a limitation of broader embodiments, as will be understood by those skilled in the art. must be.

[0013] In certain embodiments, the invention provides a method of modulating the T cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domains (TIGIT) signaling pathway and the programmed cell death 1 (PD- 1) signaling pathway in a subject, the method comprising administering to the subject a compound of formula (I): [Chemical formula] (wherein R1 represents hydrogen or -(C1-C6)alkyl optionally substituted with -OH, -COOH, aryl, heteroaryl or aryl-OH; R2 represents hydrogen or -(C1-C6)alkyl optionally substituted with -OH, -SH, C(O)NH2, -COOH, aryl, hetero aryl or aryl-OH; R a represents hydrogen; or R a and R2 together with the atom to which they are attached form a pyrrolidine ring; R3 represents hydrogen or a group represented by formula (I’): [Chemical formula] ----- represents a point of attachment; R b represents hydrogen; or R b and R c together with the atom to which they are attached form a pyrrolidine ring; R c represents hydrogen, or -(C1-C6)alkyl optionally substituted with -OH, -C(O)NH2, COOH, aryl or aryl-OH), ​​​​​​​A method comprising contacting the stereoisomer thereof or a pharmaceutically acceptable salt thereof. To provide.

[0014] In certain embodiments, R1 is hydrogen, or -OH, -COOH, phenyl, imi -(C1~C6) alkyl groups optionally substituted with dazolyl or (p-OH)phenyl It represents "ru".

[0015] In certain embodiments, R1 is -OH, -COOH, imidazolyl, phenyl, This represents a -(C1~C6) alkyl group that may be substituted with (p-OH)phenyl.

[0016] In certain embodiments, R1 is -OH, -COOH, imidazolyl, or (p- This represents a -(C1~C6) alkyl group that may be substituted with OH)phenyl.

[0017] In certain embodiments, R2 is hydrogen, or -OH, -SH, -C(O)NH2, -COOH, phenyl, imidazolyl, or (p-OH)phenyl may be substituted as needed. It represents a C1-C6 alkyl group.

[0018] In certain embodiments, R2 is hydrogen, or -C(O)NH2, phenyl or This represents a -(C1~C6) alkyl group that may be substituted with (p-OH)phenyl.

[0019] In certain embodiments, R2 is hydrogen, or -OH, -SH, -COOH, phenyl -(C1~C6) alkyl groups substituted with phenyl, imidazolyl, or (p-OH)phenyl. It represents.

[0020] In certain embodiments, R2 is hydrogen, or -OH, -COOH, phenyl, imi Represents a -(C1~C6) alkyl group substituted with dazolyl or (p-OH)phenyl. .

[0021] In a particular embodiment, R a This represents hydrogen.

[0022] In a particular embodiment, R a R2 and R2, together with the atom they bond to, form a pyrrolidine ring. It forms a structure.

[0023] In a particular embodiment, R3 is [ka] This represents; here, ----- represents a connection point; R b is either representing hydrogen or R b and R c However, along with the atoms to which they bond, pyrolories It forms a ring; R c is hydrogen, or -OH, -C(O)NH2, COOH, phenyl or (p- This represents a -(C1~C6) alkyl group that may be substituted with OH)phenyl.

[0024] In a particular embodiment, R b and R c The pyrrolidine ring, along with the atoms to which they are bonded. It forms a structure.

[0025] In a particular embodiment, the compound described in the present invention is of formula (IA): [ka] (In the formula, R1, R2, R a , R b and R c This is as defined for the compound of formula (I). It is represented by the compound indicated by (ru).

[0026] In certain embodiments, the compounds described in the present invention are R1 is -OH, -COOH, imidazolyl, phenyl, or (p-OH)phenyl This represents a -(C1~C6) alkyl group that may be substituted in some cases; R2 is hydrogen, or -OH, -SH, -COOH, phenyl, imidazolyl or Represents a -(C1~C6) alkyl group substituted with (p-OH)phenyl; R a However, it represents hydrogen, or R a And R2, together with the atom they bond to, pyrrolidine It forms a ring; R b However, it represents hydrogen, or R b and R c However, along with the atoms to which they bond, pyrolories It forms a ring; R c However, hydrogen, or -OH, -C(O)NH2, -COOH, phenyl or (p Represents a -(C1~C6) alkyl group, optionally substituted with -OH)phenyl. The compound of formula (IA), its stereoisomer, or its pharmaceutically acceptable salt is used to describe the compound. It will be done.

[0027] In certain embodiments, the compounds described in the present invention have R1 as -OH, -COOH -(C1~C6) optionally substituted with imidazolyl or (p-OH)phenyl It represents alkyl; R2 can be hydrogen, or -OH, -COOH, phenyl, or imidazolyl. Alternatively, formula (IA) represents a -(C1~C6) alkyl group substituted with (p-OH)phenyl. It is represented by a compound thereof, its stereoisomer, or a pharmaceutically acceptable salt thereof.

[0028] In a particular embodiment, the compound described in the present invention is of formula (IB): [ka] (In the formula, R1, R2 and R a This is shown as defined for the compound of formula (I). It is represented by a compound.

[0029] In certain embodiments, the compounds described in the present invention are R1 is optionally substituted with -OH or (p-OH)phenyl -(C1~C6) Represents alkyl; R2 is optionally substituted with hydrogen, or phenyl or (p-OH)phenyl. - Represents alkyl groups (C1-C6); R a R2 and R2 form a pyrrolidine ring together with the atom to which they are bonded. The compound of formula (IB), its stereoisomer, or its pharmaceutically acceptable salt is used to describe the compound. It will be done.

[0030] In certain embodiments, the term "aryl" refers to phenyl.

[0031] In certain embodiments, the term "heteroaryl" refers to an imidazole.

[0032] In certain embodiments, the TIGIT signaling pathway and the PD-1 signaling pathway The dual modulator of the path is given by equation (I): [ka] (In the formula, R1 is hydrogen, or -OH, COOH, aryl, heteroaryl, or aryl. Represents an -(C1~C6) alkyl group that may be substituted with -OH; R2 is hydrogen, or -OH, -SH, C(O)NH2, -COOH, aryl, hetero -(C1~C6) alkyl groups, which may be substituted with loaryl or aryl-OH groups. Representation; R a is either representing hydrogen or R a And R2, together with the atom they bond to, pyrrolidine It forms a ring; R3 is hydrogen or formula (I'): [ka] Represents the base represented by; ----- is, -NR a Represents the bonding point to the base; R b is either representing hydrogen or R b and R c However, along with the atoms to which they bond, pyrolories It forms a ring; R c This is hydrogen, or -OH, -C(O)NH2, -COOH, aryl or aryl. It is a compound of an alkyl group (representing C1-C6) substituted with an OH group.

[0033] In certain embodiments, the present invention provides a target having Ig and ITIM domains. The T cell immune receptor (TIGIT) signaling pathway and programmed cell death 1 (PD- 1) A method for modulating a signaling pathway, wherein the target is given by formula (I): [ka] (In the formula, R1 is hydrogen, -CH2-aryl-OH, -CH2-COOH, -CH2-imidazo Lil, -(CH2)2-COOH, -CH(CH3)2, -CH2-aryl, -CH( CH3)OH, or -CH2(CH)(CH3)2; R2 is hydrogen, -CH(CH3)OH, -CH2-aryl-OH, -CH2-SH, -CH2-imidazolyl, -CH(CH3)2, -(CH2)2-COOH, -(CH2 ) Represents 2-CONH2, or -CH2-aryl; R a is either representing hydrogen or R a And R2, together with the atom they bond to, pyrrolidine It forms a ring; R3 is hydrogen or formula (I'): [ka] Represents the base represented by; ----- is, -NR a Represents the bonding point to the base; R b is either representing hydrogen or R b and R c However, along with the atoms to which they bond, pyrolories It forms a ring; R c These are hydrogen, -CH2-COOH, -CH(CH3)OH, and -CH2-aryl-O H, -CH2-aryl, -(CH2)2-CONH2, or -CH(CH3)CH2 A compound of CH3, or its stereoisomer, or a pharmaceutically acceptable salt thereof, in contact with The method provides a way that involves touching.

[0034] In certain embodiments, R1 represents hydrogen or -CH(CH3)OH.

[0035] In certain embodiments, R2 represents -(CH2)2-COOH.

[0036] In certain embodiments, the present invention provides a target having Ig and ITIM domains. The T cell immune receptor (TIGIT) signaling pathway and programmed cell death 1 (PD- 1) A method for modulating a signaling pathway, wherein the target is a compound of formula (I), A method comprising contacting the stereoisomer or a pharmaceutically acceptable salt thereof. The compound is provided, [Table 1] TIFF0007830412000013.tif241162, TIFF0007830412000014.tif178162, or their pharmaceutically acceptable salts or stereoisomers.

[0037] In certain embodiments, the present invention provides a target having Ig and ITIM domains. The T cell immune receptor (TIGIT) signaling pathway and programmed cell death 1 (PD- 1) A method for modulating a signaling pathway, wherein the target is a compound of formula (I), A method comprising contacting the stereoisomer or a pharmaceutically acceptable salt thereof. The compound is provided, [Table 2] TIFF0007830412000016.tif121162 or a pharmaceutically acceptable salt thereof.

[0038] In certain embodiments, the compound of the present invention is a prodrug of the compound of formula (I). For example, in that case, the hydroxyl group in the parent compound may exist as an ester, Alternatively, the carbonate or carboxylic acid present in the parent compound may exist as an ester. In a further embodiment, the prodrug is metabolized in vivo to the active parent compound. (For example, esters are hydrolyzed to their corresponding hydroxyl or carboxylic acids.)

[0039] In certain embodiments, the compound of the present invention is one of the atoms constituting such a compound. Or it may contain an unnatural proportion of atomic isotopes in multiple ways. For example, the present invention is referenced herein. This also includes isotope-labeled variants of the present invention that are identical to those described, but in practice, the compound One or more atoms are the main atomic weights or masses commonly found in nature for atoms. It is replaced by an atom having a different atomic weight or mass number. Any specified special All isotopes of other atoms or elements are intended within the scope of the compounds of the present invention and their uses. As shown in the figure, exemplary isotopes that can be incorporated into the compound of the present invention are: 2 H ("D") 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 35 S, 18 F, 36 Cl, 123 I and 125 I, etc., hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, phosphate Examples include isotopes of chlorine, iodine, and chlorine. The isotope-labeled compounds of the present invention are generally This is done by following a procedure similar to that disclosed in the following schemes and / or examples of this specification. By doing so, by using isotope-labeled reagents instead of non-isotope-labeled reagents, It can be prepared.

[0040] The method of the present invention may be used to treat objects that require it. Specific implementation Morphologically, individuals are mammals such as humans or non-human mammals. When administered to a substance, the compound is preferably, for example, the compound of the present invention and pharmaceutically acceptable It is administered as a pharmaceutical composition containing a suitable carrier. A pharmaceutically acceptable carrier is a technologically appropriate carrier. It is well known in the field, for example, water or physiologically buffered saline or glycol, Glycerol, oils such as olive oil, or other solvents such as injectable organic esters or includes a vehicle. In a preferred embodiment, such a pharmaceutical composition is used to treat humans. For administration, especially via invasive routes of administration (i.e., to avoid transport or diffusion through the epithelial barrier). If intended for use in routes such as injection or implantation, the aqueous solution should be pyrogen-free or functional. It is qualitatively pyrogen-free. Excipients are used, for example, to perform delayed release of the excipient. Alternatively, to selectively target one or more types of cells, tissues, or organs, The pharmaceutical composition may be in the form of tablets, capsules (sprinkle capsules and gelatin capsules). Administration methods including granules, lyophilized materials for reconstitution, powders, solutions, syrups, suppositories, and injections. It may be in a single dosage form. The composition may also be present in a transdermal delivery system, such as a skin patch. The composition also includes topical administrations such as eye drops. It may be present in a suitable solution (on).

[0041] The phrase "medically acceptable" means suitable for use in contact with human and animal tissues, and without excessive use. It does not cause toxicity, irritation, allergic reactions or other problems or complications, and provides reasonable benefits / Those compounds, materials, compositions, and / or that fall within the range of sound medical judgment and are appropriate for the risk ratio. Or, as used herein, to refer to a dosage form.

[0042] As used herein, the term "medically acceptable carrier" refers to a liquid or solid filler. Medicinally acceptable materials, compositions, etc., such as diluents, excipients, solvents, or encapsulating materials. 'Vehicle' means vehicle. Each carrier is compatible with the other components of the formulation and is not harmful to the patient. In that sense, it must be "acceptable." A material that can function as a medically acceptable carrier. Some examples of these include (1) sugars such as lactose, glucose and sucrose; (2 ) Starches such as cornstarch and potato starch; (3) Carboxymethyl carboxylate Cellulose sodium, ethylcellulose and cellulose acetate, and other celluloses and so (4) derivatives of; (5) powdered tragacanth; (6) malt; (7) gelatin; (8) talc; (8 ) Excipients such as cocoa butter and suppository wax; (9) Peanut oil, cottonseed oil, safflower Oils such as sesame oil, olive oil, corn oil and soybean oil; (10) Propylene glyco Glycols such as (11) Glycerin, sorbitol, mannitol and polyethylene Polyols such as ethylene glycol; (12) Ethyl oleate and ethyl laurate Which esters; (13) agar; (14) magnesium hydroxide and aluminum hydroxide Which buffering agent; (15) Alginate; (16) Pyrogen-free water; (17) Isotonic physiological food Saltwater; (18) Ringer's solution; (19) Ethyl alcohol; (20) Phosphate buffer; and (21) Other non-toxic, suitable substances used in pharmaceutical preparations.

[0043] In certain embodiments, this disclosure relates to I in any of the prior embodiments. The T cell immune receptor (TIGIT) signaling pathway with g and ITIM domains and programmed cell death 1 (PD-1) signaling pathway (e.g., PD-1, PD-L1) A method for modulating (or PD-L2), wherein the target is a compound of formula (I), and The method involves contacting the stereoisomer or a pharmaceutically acceptable salt thereof. To provide.

[0044] In certain embodiments, this disclosure applies to the compound 19 disclosed herein, and This includes contacting Ig with its stereoisomer or a pharmaceutically acceptable salt thereof. The T cell immune receptor (TIGIT) signaling pathway, which has an ITIM domain, is modular Provides a method for rating.

[0045] In certain embodiments, this disclosure applies to the compound 20 disclosed herein, and This includes contacting Ig with its stereoisomer or a pharmaceutically acceptable salt thereof. The T cell immune receptor (TIGIT) signaling pathway, which has an ITIM domain, is modular Provides a method for rating.

[0046] According to any of the embodiments described above, in a particular embodiment, cells are brought into contact. This occurs in those who need it, thereby leading to cancer, immune disorders, immunodeficiency, and inflammation. To treat diseases or disorders selected from sexual disorders, infectious diseases, and graft rejection.

[0047] In certain embodiments, the disease or disorder is cancer.

[0048] In certain embodiments, the Disclosure provides a therapeutically effective amount of TIGI to a target that requires it. Treatment of tumor cell growth and / or metastasis, including administration of a T / PD-1 dual pathway inhibitor. This provides a method for inhibiting this process.

[0049] In certain embodiments, tumor cells are small cell lung cancer, multiple myeloma, bladder carcinoma (bl Adder carcinoma, primary cholangiocarcinoma, ovarian cancer, Hodgkin lymphoma, gastric cancer Choose from gastric carcinoma, acute myeloid leukemia, and pancreatic cancer. It is a cancer-derived substance.

[0050] In certain embodiments, tumor cells include blastoma, breast cancer, epithelial carcinoma, colon cancer, lung cancer, melanoma, Prostate cancer, kidney cancer, bone cancer, pancreatic cancer, skin cancer, head or neck cancer, uterine cancer, ovarian cancer, colon cancer Cancer, rectal cancer, anal cancer, peritoneal cancer, stomach cancer, testicular cancer , fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, esophageal cancer, small intestine cancer, endocrine cancer, type A Glandular carcinoma, parathyroid carcinoma, adrenal carcinoma, sarcoma, urethral carcinoma, testicular carcinoma, chronic or acute leukemia, childhood solid cancer T-cell lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, cutaneous T-cell lymphoma, mesothelioma, thymic carcinoma , myeloma, cancer of the bladder, ureteral cancer, renal pelvis cancer, Liver cancer, pancreatic cancer, post-transplant lymphoproliferative disorder (PTLD), neoplasms of the central nervous system (CNS), tumors Tumor angiogenesis, spinal axis tumor, brainstem glioma, pituitary adenoma, epidermoid carcinoma, salivary gland carcinoma, squamous epithelium Cancer, abnormal angiogenesis associated with nevus disorders, edema (such as that associated with brain tumors), Meigs syndrome It is derived from cancer selected from syndrome, Merkel cell carcinoma, and environmentally induced cancers.

[0051] In certain embodiments, the present invention relates to the growth and / or metastasis of tumor cells in a subject. A method for inhibiting the TIGIT / PD-1 dual pathway in the target that requires it. The present invention provides a method that includes administering an inhibitor.

[0052] In certain embodiments, tumor cells are small cell lung cancer, multiple myeloma, bladder carcinoma, primary From cholangiocarcinoma, ovarian cancer, Hodgkin lymphoma, gastric carcinoma, acute myeloid leukemia, and pancreatic cancer It is a type of cancer that is selected.

[0053] In certain embodiments, tumor cells include blastoma, breast cancer, epithelial carcinoma, colon cancer, lung cancer, melanoma, Prostate cancer, kidney cancer, bone cancer, pancreatic cancer, skin cancer, head or neck cancer, uterine cancer, ovarian cancer, colon cancer Cancer, rectal cancer, anal cancer, peritoneal cancer, stomach cancer, testicular cancer, fallopian tube cancer, endometrial cancer, cervical cancer Vaginal cancer, vulvar cancer, esophageal cancer, small intestine cancer, endocrine cancer, thyroid cancer, parathyroid cancer, adrenal cancer, sarcoma , urethral cancer, testicular cancer, chronic or acute leukemia, solid tumors in children, Hodgkin lymphoma, non-Hodgkin lymphoma, cutaneous T-cell lymphoma, mesothelioma, thymic cancer, myeloma, bladder cancer, ureteral cancer, renal pelvis cancer Liver cancer, pancreatic cancer, post-transplant lymphoproliferative disorder (PTLD), neoplasms of the central nervous system (CNS), Tumor angiogenesis, spinal axial tumor, brainstem glioma, pituitary adenoma, epidermal carcinoma, salivary gland carcinoma, squamous cell carcinoma Abnormal angiogenesis associated with skin cancer, nevus disorders, edema (such as that associated with brain tumors), Meigs These are cancers selected from syndromes, Merkel cell carcinoma, and environment-induced cancers.

[0054] In a particular embodiment, the present invention provides TIGIT / PD-1 to targets that require it. The present invention provides a method for treating cancer, which includes administering a dual-pathway inhibitor.

[0055] According to any of the embodiments described above, in a particular embodiment, TIGIT / PD-1 Dual pathway inhibitors are compounds of formula (I), their stereoisomers, or their pharmaceutically acceptable counterparts. It is a capable salt.

[0056] According to any of the embodiments described above, in a particular embodiment, TIGIT / PD-1 Dual pathway inhibitors are compounds of formula (IA), their stereoisomers, or their pharmaceutically acceptable forms. It is a tolerable salt.

[0057] According to any of the embodiments described above, in a particular embodiment, TIGIT / PD-1 Dual pathway inhibitors are compounds of formula (IB), their stereoisomers, or their pharmaceutically acceptable forms. It is a tolerable salt.

[0058] In certain embodiments, the present invention provides compound 19 or 2 to subjects that require it. The administration of 0, its stereoisomer, or a pharmaceutically acceptable salt thereof, This invention provides a method for treating cancer mediated by IGIT.

[0059] In certain embodiments, the present invention relates to the growth and / or metastasis of tumor cells in a subject. A method for inhibiting the Ig and ITIM domains in the target that requires it. The T cell immune receptor (TIGIT) pathway and programmed cell death 1 (PD1) pathway Administering a compound of formula (I) or a pharmaceutically acceptable salt that can inhibit the Nal signaling pathway. The present invention provides a method that includes the following:

[0060] In certain embodiments, the present invention relates to the growth and / or metastasis of tumor cells in a subject. A method for inhibiting the Ig and ITIM domains in the target that requires it. The T cell immune receptor (TIGIT) pathway and programmed cell death 1 (PD1) pathway Administer a compound of formula (IA) or a pharmaceutically acceptable salt that can inhibit the Nal signaling pathway. To provide a method that includes doing so.

[0061] In certain embodiments, the present invention relates to the growth and / or metastasis of tumor cells in a subject. A method for inhibiting the Ig and ITIM domains in the target that requires it. The T cell immune receptor (TIGIT) pathway and programmed cell death 1 (PD1) pathway Administer a compound of formula (IB) or a pharmaceutically acceptable salt that can inhibit the NAL signaling pathway. To provide a method that includes doing so.

[0062] Upregulation of TIGIT on CD8+ T cells during activation (Joller et al.) Considering (2011) J Immunol. 186:1338), numerous signs of cancer The disease is expected to respond to TIGIT blockers. Available data also shows that it is not small cell lung disease. CD8+ TILs in cancer, colon cancer, and melanoma (Chauvin et al. (2015) ) Clin Investig.125:2046; Johnston et al. ( 2014) Cancer Cell. 26:923), chronic lymphocytic leukemia (Cata kovic et al.,(2017) Oncoimmunology 7(1):E1 371399) and follicular lymphoma (Josefsson et al. (2018) T cells in Clin Cancer Res. 24:870), and acute myeloid white blood cells. Peripheral blood mononuclear cells (PBMCs) from patients with malformed mucosal disease (AML) (Kong et al. (2016)) High levels of TIGIT expression in Clin Cancer Res. 22:3057) This indicates that.

[0063] Representative tumor cells disclosed in these studies include, non-limitingly, blastomas (e.g., glioblastomas). , breast cancer (for example, breast carcinoma, primary ductal carcinoma, tripartite Negative breast cancer, estrogen receptor positive (ER+), progesterone receptor positive (P R+), and / or human epidermal growth factor receptor 2 positive (HER2+), epidermal carcinoma (e.g., colon cancer, lung cancer (e.g. small cell lung cancer, non-small cell lung cancer (NSCLC), lung adenocarcinoma) , and squamous cell carcinoma of the lung), melanoma (e.g., cutaneous melanoma, intraocular melanoma, cutaneous or intraocular malignancies), (Melanoma and lymph node-associated melanoma), prostate cancer (e.g., prostate adenocarcinoma), kidney cancer (r renal cancer) (for example, renal cell carcinoma (RCC) and kidney cancer (kidney cancer) (e.g., bone cancer, osteosarcoma), pancreatic cancer (e.g., pancreatic adenocarcinoma), skin cancer, head cancer Cancers of the head or neck (e.g., squamous cell carcinoma of the head and neck), uterine cancer, ovarian cancer (e.g., ovarian carcinoma) Colorectal cancer (e.g., high-frequency microsatellite instability colorectal cancer and colorectal adenocarcinoma), rectal cancer Cancers of the anal region, cancers of the peritoneum, gastric cancers (e.g., gastric carcinomas and gastrointestinal cancers), testicular cancer, fallopian tube cancers Cancer, endometrial cancer, cervical cancer (e.g., cervical cancer), vaginal cancer (e.g., vaginal cancer), external Genital cancer (e.g., carcinoma of the vulva), esophageal cancer, small intestine cancer, endocrine cancer, thyroid cancer (e.g., thyroid adenoma). Carcinoma of the thyroid gland), parathyroid carcinoma, adrenal carcinoma, sarcoma (e.g., soft tissue sarcoma and Kaposi's sarcoma), urinary Pathological cancer, testicular cancer, chronic or acute leukemia (e.g., acute myeloid leukemia, chronic myeloid leukemia, Acute lymphoblastic leukemia, chronic lymphocytic leukemia, pilocytic cell leukemia, and chronic osteoblastic leukemia Diseases, solid tumors in children, Hodgkin lymphoma (HL) (e.g., lymphocyte-rich type (LRCHL)) ), nodular sclerosing type (NSHL), mixed cell type (MCHL) and lymphopenic type (LDH) L)), B-cell lymphoma (e.g., diffuse large B-cell lymphoma (DLBCL)), Non-Hodgkin lymphoma (NHL) (e.g., low-grade / follicular non-Hodgkin lymphoma, small phosphorus lymphoma) Pacytic (SL) NHL, intermediate-grade / follicular NHL, intermediate-grade diffuse NHL, high-grade immunosuppression Epidemic blastocytic NHL, high-grade lymphoblastic NHL, high-grade small, non-incised nuclear cell NHL (Giant tumor lesions NHL, Burkitt lymphoma, mantle cell lymphoma), AIDS-related lymphoma Parkinson's disease, cutaneous T-cell lymphoma (e.g., mycosis fungoides), Waldenström macroglottic lymphoma Phylliphenemia, post-transplant lymphoproliferative disorder (PTLD), lymphocytic lymphoma, primary CNS lymphocyte Parkinson's disease (Paneoma and T-cell lymphoma), mesothelioma, thymic carcinoma, myeloma (e.g., multiple myeloma), bladder Cancer (e.g., bladder cancer), ureteral cancer, renal pelvis cancer, liver cancer (e.g., hepatocellular carcinoma, liver cancer, Hepatoma, pancreatic cancer, post-transplant lymphoproliferative disorder (PTLD), neonatal disease of the central nervous system (CNS) tumor angiogenesis, spinal axis tumor, brainstem glioma, pituitary adenoma, epidermoid carcinoma, salivary gland carcinoma, squamous Squamous cell carcinoma, abnormal vascular proliferation associated with nevus, edema (such as that associated with brain tumors), May Gus syndrome, Merkel cell carcinoma, environmentally induced cancers (including those induced by asbestos). Examples of cancer cells include ), and combinations thereof.

[0064] In other embodiments, for example, tumor cells include prostate cancer, melanoma, breast cancer, colon cancer, Prostate cancer, lung cancer, kidney cancer, pancreatic cancer, stomach cancer, bladder cancer, esophageal cancer, mesothelioma, thyroid cancer, thymus cancer Carcinoma, sarcoma, glioblastoma, chronic or acute leukemia, lymphoma, myeloma, Merkel cell carcinoma, epithelium Cancers can be selected from cancers such as cancer, colorectal cancer, vaginal cancer, cervical cancer, ovarian cancer, and head and neck cancer. Cut.

[0065] In other embodiments, for example, tumor cells include melanoma, triple-negative breast cancer, Non-small cell lung cancer, renal cell carcinoma, pancreatic cancer, gastric carcinoma, bladder cancer, mesothelioma, Hodgkin lymphoma, child Examples of cancer cells selected from cervical cancer, ovarian cancer, and squamous cell carcinoma of the head and neck can be listed. In other embodiments, for example, tumor cells include prostate cancer, melanoma, breast cancer, colon cancer, Prostate cancer, lung cancer, kidney cancer, pancreatic cancer, stomach cancer, bladder cancer, esophageal cancer, mesothelioma, thyroid cancer, thymus cancer Carcinoma, sarcoma, glioblastoma, chronic or acute leukemia, lymphoma, myeloma, Merkel cell carcinoma, epithelium List cancer cells selected from cancer, colorectal cancer, vaginal cancer, cervical cancer, ovarian cancer, and head and neck cancer. It is possible.

[0066] In other embodiments, for example, tumor cells include melanoma, triple-negative breast cancer, Non-small cell lung cancer, renal cell carcinoma, pancreatic cancer, gastric carcinoma, bladder cancer, mesothelioma, Hodgkin lymphoma, child Examples of cancer cells selected from cervical cancer, ovarian cancer, and squamous cell carcinoma of the head and neck can be listed. .

[0067] In some embodiments, tumor cells and / or subjects have received cancer immunotherapy. There is no such thing. Cancer immunotherapy uses the target immune system to support the fight against cancer. For example, cancer immunotherapy As for epidemic therapy, atezolizumab (a human monoclonal antibody that targets PD-L1) Velumab (a human monoclonal antibody targeting PD-L1), brentuximab vedoti (Antibody-drug conjugate targeting CD30), Rituximab (targeting CD20) (Antibodies that target PD-L1 in humans), durvalumab (a human antibody that targets PD-L1) Monoclonal antibodies), ipilimumab (targeting CTLA-4) (Human monoclonal antibody that targets PD-L1), nivolumab (human monoclonal antibody that targets PD-L1) (Antibody), pembrolizumab (also called lambrolizumab, which targets PD-L1) Human monoclonal antibody), tremelimumab (human monoclonal antibody targeting CTLA-4) (Nal antibody), CT-011 (antibody targeting PD-1), MDX-1106 (PD-1 Antibodies targeting PD-1, MK-3475 (antibody targeting PD-1), YW243.55 .S70 (antibody targeting PD-L1), MPDL3280A (antibody targeting PD-L1) Antibodies (including MDX-1105, an antibody targeting PD-L1), and MEDI4736 Examples include, but are not limited to, antibodies that target PD-L1. In terms of form, cancer immunotherapy involves anti-CTLA-4 antibodies, anti-PD-1 antibodies, and anti-PD-L1 antibodies. , anti-PD-L2 antibody, anti-TIGIT antibody (for example, disclosed in WO2015 / 009856) Selected from (antibodies).

[0068] In further embodiments, the disclosure relates to the TIGIT signaling pathway and PD-1 Blocking of the Gnar transmission pathway, for example PD-1 (e.g., PD-1, PD-L1, or By inhibiting immunosuppressive signals induced by PD-L2 and TIGIT The method provides a method for treating infection, and the method provides a therapeutically effective amount of the compound of formula (I) as needed. This includes administering the drug to the target population.

[0069] In some embodiments, infectious diseases include bacterial infections, viral infections, fungal infections, and It is a parasitic infection, and treatment for bacterial, viral, fungal, or parasitic infections Therefore, this method involves administering a therapeutically effective dose of the compound of formula (I).

[0070] Upregulation of TIGIT on CD8+ T cells during activation (Joller et al.) Considering (2011) J Immunol. 186:1338), TIGIT shielding Drug withdrawal is predicted to be effective for a large number of infectious diseases. TIGIT is LCMV (Jo hnston et al. (2014) Cancer Cell. 26) and HIV (Tauriainen et al. (2017) Sci Rep. 7:40354) It has been reported that this enhances CD8+ T cell depletion in chronic infections caused by [the substance]. It is.

[0071] In some embodiments, for example, bacterial infections include Chlamydia, Bacillus, Bordetella, Botulinum toxin, Campylobacter, Burkholderia, Anthrax, Cholera, Clostridium Listeria, Conococcus, Corynebacterium, Diphtheria, Treponema, Bull Serra, Enterococcus, Mycoplasma, Borrelia, Erwinia, Escherichia, F Lancisera, Haemophilus, Helicobacter, Klebsiella Xanthomonas, Legionella, Leptospira, Leptospirosis, Lyme disease, Menin Gococcus, pneumococcus, Mycobacterium, Neisseria, Vibrio, Pasteurella, Perococcus Bacter, Serratia, plague, Streptococcus, Proteus, Enterobacter, Sch Domonas, Rickettsia, Salmonella, Sigella, Staphylococcus tetanus and E It can be caused by at least one bacterium selected from Lucinia.

[0072] In other embodiments, for example, viral infections include arbovirus encephalitis virus, adenovirus, etc. Virus, herpes simplex virus type 1, herpes simplex virus type 2, varicella-zoster virus, Epstein Barr virus, cytomegalovirus, herpesvirus type 8, papillomavirus, BK virus, coronavirus, echovirus, JC virus, smallpox virus, type B Hepatitis, Bocavirus, Parvovirus B19, Astrovirus, Norwark virus Coxsackievirus, Hepatitis A, Poliovirus, Rhinovirus, Severe Acute Respiratory Disease Syndrome viruses, hepatitis C, yellow fever, dengue virus, West Nile virus, rubella, hepatitis E Inflammation, human immunodeficiency virus (HIV), human T-cell lymphotropic virus (HTLV), Influenza, Guanalitovirus, Junin virus, Lassa virus, Machupovirus S.S., S.A. virus, Crimean-Congo hemorrhagic fever virus, Ebola virus, Marburg Viruses, measles virus, molluscum contagiosum virus, mumps virus, parainfluenza Respiratory syncoviral virus, human metapneumovirus, Hendra virus, Nipah virus Rabies, Hepatitis D, Rotavirus, Orbivirus, Cortivirus, Vaccinia Caused by at least one virus selected from Viruses and Bannaviruses It is possible.

[0073] In other embodiments, for example, fungal infections include oral candidiasis and Coccioides imitata. Blastomyces dermatitidis, Otomycosis, Candida (Albicans) (e.g., tinea crusae, glabrata, tropicalis), tinea capitis, tinea folliculitis, tinea corporis, Tinea cruris, tinea cruris, Sporothrix schenkyi, zygomycosis, Chromoblast mycosis Cryptococcus (such as Neoformans), Histoplasma capsulatum, Tinea pedis Paracoccidioides brasiliensis, pheohypomycosis, tinea, mucoral Aspergillus (Mucor, Abscysia, Rhizophas), Sporotrichosis, Aspergillus (Fumiga) Tas, Niger, etc.), lobomycosis, mycetoma, onicomycosis, piedra Piedra pityriasis versic Color, and linospolydiosis may be selected.

[0074] In some embodiments, for example, parasitic infections include human roundworms, Balantidium coli, Entermoeva histolicha, Giardia lambria, Naegleria fowleri, Neca Tor americanus, Nippostlongirus brasiliensis, Stronyloides Stercolalis, Cryptosporidium muris, Trypanosomatida gambiens (T Trypanosomatida gambiense, Trypanosomatida rhodessie Trypanosomatida rhodesiense, Babesia microclavus Chi, Trypanosoma cruzi, Leishmania mexicana, Leishmania brazi Leishmania liensis, Leishmania tropica, Leishmania donovani, Uchereria ba Nymphalopsis, Dracunculus mejnensis, Toxoplasma gondii, Fascio La gigantea, Heterophies heterophies, Plasmodium vivax, Tri Panosoma brusey, Plasmodium ovale, Plasmodium malaria, Plasmo Zium falsiparum, Pneumocystis carinii, Trichomonas vaginalis, His Tomonas meleagridis, bigastric class, Trichris trichiura, Acanthamoeba, En Thelbiopithelius vermicularis, Ankylostomoma daudenale, Schistosoma, Liver fluke, Intestine Distomy, lung fluke, Schistosoma mansoni, Schistosoma haematobium, Schistosoma Tosoma japonicum, Fasciola hepatica, and Paragonimus westerma It can be caused by at least one parasite selected from two.

[0075] In certain embodiments, the present invention relates to lung cancer, breast cancer, colon cancer, kidney cancer, bladder cancer, and thyroid cancer. We propose methods for treating cancers selected from prostate cancer, osteosarcoma, and Hodgkin lymphoma. To provide.

[0076] In certain embodiments, the present invention relates to a method for modulating an immune response in a target. There are T cell immune receptors (TIGIT) and PD- A biological sample of a subject that overexpresses at least one of L1 or PD-L2 is subjected to formula (I) This includes exposure to a compound, its stereoisomer, or a pharmaceutically acceptable salt thereof. , provide a method.

[0077] In certain embodiments, the present invention relates to a method for modulating an immune response in a target. a) Determining whether the target biological sample overexpresses TIGIT; and b) If the sample overexpresses TIGIT, the target should be a compound of formula (I) or its stereotype. The present invention provides a method comprising contacting the substance or a pharmaceutically acceptable salt thereof.

[0078] In certain embodiments, the present invention relates to a method for modulating an immune response in a target. There is, a) To determine whether the sample overexpresses PD-L1 or PD-L2; and b) If the sample overexpresses either TIGIT and PD-L1 or PD-L2, contacting the subject with a compound of formula (I), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, further provides a method.

[0079] In certain embodiments, the biological sample is selected from whole blood, plasma, serum, cells (e.g., tumor cells), saliva, urine, feces, and tissue.

[0080] In certain embodiments, the subject has cancer, and optionally the sample contains one or more cells from the cancer.

[0081] In certain embodiments, the subject has an infectious disease selected from bacterial infection, viral infection, fungal infection, and parasitic infection.

[0082] In certain embodiments, the control sample is obtained before the subject receives a compound of formula (I), and the subject sample is obtained after the subject receives a compound of formula (I).

[0083] The compounds of the invention may be used as a single drug (monotherapy) or conjointly with one or more other agents (conjoint therapy). The compounds may be used as such or preferably in a pharmaceutical composition in which the compound is mixed with one or more pharmaceutically acceptable materials. used.

[0084] In certain embodiments, the invention provides a compound for use in modulating an immune response mediated by both the TIGIT signaling pathway and the PD-1 signaling pathway in a subject. for.

[0085] In certain embodiments, the immune response involves the TIGIT signaling pathway and PD-1 signaling pathway. Modulated to treat diseases or disorders mediated by both signaling pathways. It can be done.

[0086] In certain embodiments, cancers according to this disclosure include blastoma, breast cancer, epithelial carcinoma, colon cancer, lung cancer, and black carcinoma. Color tumors, prostate cancer, kidney cancer, bone cancer, pancreatic cancer, skin cancer, head or neck cancer, uterine cancer, ovarian cancer Colorectal cancer, rectal cancer, anal cancer, peritoneal cancer, stomach cancer, testicular cancer, fallopian tube cancer, endometrial cancer, child Cervical cancer, vaginal cancer, vulvar cancer, esophageal cancer, small intestine cancer, endocrine cancer, thyroid cancer, parathyroid cancer, adrenal cancer , sarcoma, urethral cancer, testicular cancer, chronic or acute leukemia, solid tumors in children, Hodgkin lymphoma, non Hodgkin lymphoma, cutaneous T-cell lymphoma, mesothelioma, thymic cancer, myeloma, bladder cancer, ureteral cancer, Renal pelvis cancer, liver cancer, pancreatic cancer, post-transplant lymphoproliferative disorder (PTLD), new central nervous system (CNS) cancers Biology, tumor angiogenesis, spinal axial tumor, brainstem glioma, pituitary adenoma, epidermal carcinoma, salivary gland carcinoma, Squamous cell carcinoma, abnormal angiogenesis associated with nevus, edema (such as that associated with brain tumors), The choice is made from Igus syndrome, Merkel cell carcinoma, and environmentally induced cancers.

[0087] In certain embodiments, the present invention provides a target having Ig and ITIM domains. The T cell immune receptor (TIGIT) signaling pathway and programmed cell death 1 (PD- 1) For use when modulating signaling pathways, formula (I): [ka] (In the formula, R1 is hydrogen, or -OH, -COOH, aryl, heteroaryl or aryl. Represents a -(C1~C6) alkyl group that may be substituted with a -OH group; R2 is hydrogen, or -OH, -SH, C(O)NH2, -COOH, aryl, hetero -(C1~C6) alkyl groups, which may be substituted with loaryl or aryl-OH groups. Representation; R a is either representing hydrogen or R a And R2, together with the atom they bond to, pyrrolidine It forms a ring; R3 is hydrogen or formula (I'): [ka] Represents the base represented by; ----- represents a connection point; R b is either representing hydrogen or R b and R c However, along with the atoms to which they bond, pyrolories It forms a ring; R c This is hydrogen, or -OH, -C(O)NH2, COOH, aryl or aryl. A compound (representing a C1-C6 alkyl group) that is optionally substituted with a -OH group, or The present invention provides stereoisomers of or pharmaceutically acceptable salts thereof.

[0088] In certain embodiments, the present invention provides a target having Ig and ITIM domains. The T cell immune receptor (TIGIT) signaling pathway and programmed cell death 1 (PD- 1) Formula for use when modulating signaling pathways: [ka] To provide a compound (Compound 1), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. To do.

[0089] In certain embodiments, the present invention provides a formula for use in modulating the T cell immunoreceptor (TIGIT) signaling pathway and the programmed cell death 1 (PD-1) signaling pathway that have Ig and ITIM domains in a subject: To provide a compound (Compound 2), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. To do.

Chemical formula

[0090] In certain embodiments, the present invention provides a formula for use in modulating the T cell immunoreceptor (TIGIT) signaling pathway and the programmed cell death 1 (PD-1) signaling pathway that have Ig and ITIM domains in a subject: To provide a compound (Compound 4), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. To do.

Chemical formula

[0091] In certain embodiments, the present invention provides a formula for use in modulating the T cell immunoreceptor (TIGIT) signaling pathway and the programmed cell death 1 (PD-1) signaling pathway that have Ig and ITIM domains in a subject: To provide a compound (Compound 19), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. To do.

Chemical formula

[0092] Unless otherwise specified herein, the terms “antibody” or “antibody (plural)” are used broadly. , naturally occurring forms of antibodies (e.g., IgG, IgA, IgM, IgE), as well as single-chain antibodies In addition to recombinant antibodies such as whole antibodies, chimeric antibodies, humanized antibodies and multispecific antibodies, at least This includes all fragments and derivatives of the aforementioned, each possessing a single antigen-binding site. The conductor may contain a protein or chemical moiety conjugated to the antibody.

[0093] As used herein, the term “antibody” also means the “antigen-binding portion” of an antibody (or simply “anti-antibody”). Includes the "body portion"). The term "antigen-binding portion" as used herein refers to the antigen (e.g., via One of the antibodies that possesses the ability to specifically bind to an omarker polypeptide or a fragment thereof. Or it refers to multiple fragments. The antigen-binding function of an antibody can be performed by fragments of a full-length antibody. This has been shown.

[0094] The term "control" is any appropriate reference to provide a comparison to the expression product in the test sample. Refers to a standard. In certain embodiments, the control obtains a “control sample” and the expression product level This includes detecting and comparing the expression product levels from a test sample to those of a control sample. This includes, in a non-limiting sense, samples from control subjects with known outcomes (stored samples or past samples). (This may be a measurement of a sample), tissue or cells isolated from the subject, isolated from the subject Primary cultured cells / tissue, adjacent normal cells obtained from the same organ or body part of the target. / Tissue, tissue or cell samples isolated from normal subjects, or initial samples obtained from a depositary. It may include any suitable sample containing substitute cells / tissues. In certain embodiments, The light is not limited to housekeeping genes, and the level range of expression products from normal tissues. (or other previously analyzed control samples), previously determined in the test samples from the patient group Patients with a range of expression product levels, or patients with specific outcomes or those who have undergone specific treatments. This may include reference standard expression product levels from any suitable source, including a set of individuals. i. Such control samples and reference standard expression product levels are used as controls in the method of the present invention. Those skilled in the art will understand that these can be used in combination.

[0095] "Normal" TIGIT expression levels do not require modulation of the immune response. This refers to the expression level of TIGIT in cells, for example, in human patients. The "excess" of a biomarker. "Expression" or "significantly high expression level" is a label used in assays to evaluate expression. Larger than the quasi-error, and a control sample (e.g., a healthy subject that does not require immunomodulation) Expression activity or T in samples obtained from healthy tissue samples from the same subject (or from samples obtained from the same subject) The IGIT level, preferably the average expression level of the biomarker in multiple control samples, Preferably at least about 10% higher, more preferably about 1.2, 1.3, 1.4, 1.5 , 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.1, 2.2, 2.3, 2.4 , 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.5, 4, 4.5, 5, 5.5, 6 , 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 times or higher, expression level in the test sample This refers to a "significantly low expression level" of a biomarker. A control sample (e.g., an immunomodulatory sample) is used to determine the level of expression of a biomarker. Average expression level of biomarkers in samples from healthy subjects that do not require simulation. Preferably, at least about 1% lower than the average expression level of the biomarker in multiple control samples. 0% lower, more preferably about 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8 , 1.9, 2.0, 2.1, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7 2.8, 2.9, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8 8.5, 9, 9.5, 10, 10.5, 11, 12, 13, 14, 15, 16, 17, This refers to expression levels in the test sample that are 1 / 18, 1 / 19, 1 / 20, or lower.

[0096] The term "sample" is used to detect or determine the presence or level of the TIGIT gene. "Typically, this includes whole blood, plasma, serum, saliva, urine, stool (e.g., feces), tears, and any other samples. Other bodily fluids (for example, those previously listed in the definition of "bodily fluids"), or small intestine, colon, or This is a tissue sample such as surgically excised tissue. In some embodiments, the disclosed method Obtain a sample from the subject before detecting or determining the presence or level of the TIGIT gene. This further includes the following.

[0097] The pharmaceutical composition is administered orally, by inhalation, or by parenteral administration. Good. For example, the composition can be administered orally, intravenously, externally, intraperitoneally, intrabladderally, It can also be administered intrathecally. Examples of parenteral administration include intra-articular (inside the joint), intravenous, and intramuscular. Intramuscular, intradermal, intraperitoneal, and subcutaneous routes are possible, but are not limited to these. Appropriate fluid The body composition may be an aqueous or non-aqueous isotonic sterile injection solution, and may contain antioxidants, buffering agents, Bacteriostatic agents, solutes to make the preparation isotonic with the blood of the intended recipient, and suspensions and solubilizers. It may also contain aqueous and non-aqueous sterile suspensions that may include thickeners, stabilizers, and preservatives. Oral administration, parenteral administration, nasogastric administration, and intravenous administration are preferred methods of administration.

[0098] The dosage of the compound of the present invention depends on the patient's age, weight, or symptoms, as well as the efficacy of the compound. It varies depending on the therapeutic effect, administration regimen, and / or treatment time. Generally appropriate Routes of administration include, for example, oral, ophthalmic, rectal, transmucosal, topical, or intra-intestinal; intramuscular, dermal. In addition to intrathecal injection, this includes intrathecal, direct intraventricular, intravenous, intraperitoneal, intranasal, or intraocular injections. Parenteral delivery is another example. The compound of the present invention is administered in a dose of 0.5 mg per regimen. Alternatively, it may be administered in doses of 1 mg, up to a maximum of 500 mg, 1 g, or 2 g. Dosage: once a week Administered once, once every three days, once every two days, once a day, twice a day, three times a day, or more frequently. In another embodiment, in a particular adult, the compound is designed by a physician. It can be administered continuously by intravenous administration over a period of time. The dosage is affected by various conditions. Therefore, in certain cases, the dosage may be lower or higher than the intended range. Consult your doctor. This allows for the immediate determination of the appropriate dosage for patients receiving therapeutic treatment.

[0099] Combination therapy The compounds of this disclosure complement and / or enhance the effect of the compound of formula (I) (1) (2) A drug that modulates the pharmacokinetics of a compound of formula (I), One or more other drugs that improve yield or reduce dosage, and / or (3) One or more other drugs that reduce or improve the side effects of the compound of formula (I) They may be administered in combination. The term "conjoint administration" as used herein refers to If a second compound is administered while a previously administered therapeutic compound is still effective in the body... This refers to any form of administration of two or more different therapeutic compounds (for example, these two compounds The combination may be effective simultaneously in the patient's body and may contain a synergistic effect of the two compounds. For example, different therapeutic compounds may be present simultaneously in the same formulation or in a different formulation. Alternatively, they can be administered sequentially. In certain embodiments, different therapeutic compounds are Within 1 hour, within 12 hours, within 24 hours, within 36 hours, within 48 hours, 72 hours It may be administered within a few hours or within one week. Thus, individuals receiving such treatment You can benefit from the combined effects of different therapeutic compounds. Each compound is the same or different. It may be administered by the same or different route. Several implementations In this state, the combined effects of conjoint therapy are detectable through immune effects. be.

[0100] The dosage of other drugs may be the dosage used in clinical practice, or the combination of the compounds described herein. It may be a different dosage that is effective when administered in combination with another substance. The ratio of the compounds disclosed herein to other drugs depends on the age and weight of the subjects receiving the drug, the method of administration, and The timing of administration, the disorder being treated, the symptoms, and combinations thereof may vary. Other drugs are used in amounts of 0.01 to 100 parts by weight based on 1 part by weight of the compound disclosed herein. It's okay to do that.

[0101] Conjoint therapy is used to treat any of the diseases discussed herein. To obtain. In certain embodiments, the compound of formula (I) of the present disclosure is used to obtain another therapeutic agent, for example, an anticancer agent. It may also be administered conjointly with drugs, antiviral agents, cytokines, or immune agonists. In some embodiments, other therapeutic agents include CTLA-4 antagonists, PD-1 antagonists, etc. Antagonists, PD-L1 antagonists, or PD-L2 antagonists, and E It is selected from GFR antagonists.

[0102] TIGIT antagonists are predicted to rescue NK cell function from TIGIT-mediated inhibition. NK cells, through antibody-dependent cell-mediated cytotoxicity (ADCC), destroy cancer cell surface proteins. Many antibodies that target quality (such as HER2, EGFR, CD38, and CD20 antibodies) To contribute to efficacy, TIGIT agents contain anti-HER2 antibodies, anti-EGFR antibodies, and anti-CD38 antibodies. It is predicted to work synergistically in combination with many antibodies and anti-cancer antibodies such as anti-CD20 antibodies. It will be done.

[0103] Drugs for combination therapy In certain embodiments, the compound of formula (I) is combined with another therapeutic agent, for example, the following: Can be administered jointly: 1) Aldosterone synthase inhibitors; 2) ALK inhibitors; apoptosis-inducing substances; 3) Aromatase inhibitors; 4) CART cells (e.g., CART cells that target CD19); 5) BCR-ABL inhibitors; 6) BRAF inhibitors; 7) CDK4 / 6 inhibitors; 8) CEACAM inhibitors (e.g., CEACAM-1, -3, and / or -5); 9) c-KIT inhibitors; 10) c-MET inhibitors; 10) cRAP inhibitors; 11) CTLA4 inhibitors; 12) Cytochrome P450 inhibitors (e.g., CYP17 inhibitors); 13) EGF inhibitors; 14) ERK1 / 2 ATP inhibitors; 15) FGF inhibitors (e.g., FGFR2 or FGFR4 inhibitors); 16) Flt3 inhibitors (e.g., FLK2 / STK1); 17) P-glycoprotein 1 inhibitors; 18) HDAC inhibitors; 19) HDM2 inhibitors; 20) HER3 inhibitors; 21) Histamine-releasing inhibitors; 22) HSP90 inhibitors; 23) IAP inhibitors; 24) IDH inhibitors; 25) IDO inhibitors 26) IGF-1R inhibitors; 27) Iron chelating agents; 28) Janus inhibitors; 29) LAG-3 inhibitors; 30) M-CSF inhibitors; 31) MEK inhibitors; 32) mTOR inhibitors; 33) p53 inhibitors (e.g., inhibitors of p53 / Mdm2 interaction); 34) PDGFRβ inhibitors; 35) PKC inhibitors; 36) PI3K inhibitors; 37) PIM inhibitors; 38) PRLR inhibitors; 39) Raf kinase C inhibitors; 40) Smoothed (SMO) receptor inhibitors; 41) Somatostatin agonists and / or growth hormone-releasing inhibitors; 42) Transduction modulator and / or angiogenic inhibitors; 43) VEGFR-2 inhibitors (e.g., FLK-1 / KDR); 44) Tyrosine kinase inhibitors (e.g., CSF-1R tyrosine kinase); 45) Wnt signaling inhibitors; 46) Bcl-2 inhibitors; 47) Mcl-1 inhibitors; 48) BTK inhibitors; 49) Dual-active molecules such as CUDC-907 (dual PI3K / HDAC inhibitor); and to 50) BET bromodomain inhibitors.

[0104] Additional therapeutic treatments suitable for conjoint administration with the compounds and compositions disclosed herein. The drug is listed in the following publication, for example: WO2016 / 100882;WO20 16 / 054555;WO2016 / 040892;WO2015 / 097536;WO 2015 / 088847;WO2015 / 069770;WO2015 / 026634; WO2015 / 009856; European Patent No. 1377609B1; Antonia et al., Clin. Cancer Res. 2014 20:6258-6268; and Melero,et al.,Nature Reviews Cancer2015 15 :457-472. Each publication is incorporated herein by reference in its entirety.

[0105] For example, in a method of this disclosure directed toward the treatment of cancer, the compound of this disclosure is a single pharmaceutical Conjoy as a composition, or as a combination of different pharmaceutical compositions, with other chemotherapeutic agents. They can be used in chemotherapeutic drugs. Non-limiting examples of chemotherapeutic agents include alkylating agents and nitrosourea. antimetabolites, anticancer antibiotics, plant-derived alkaloids, topoisomerase inhibitors, hormones Hormone antagonist, drug for treating leukopenia (neutropenia), thrombocytopenia Treatment drugs, antiemetics, aromatase inhibitors, P-glycoprotein inhibitors, platinum complex derivatives, and others Examples include immunotherapeutic agents and other anticancer drugs.

[0106] Exemplary cytotoxic agents that can be administered conjointly include antimicrotubule agents and topoisomers. -ase inhibitors, antimetabolites, mitotic inhibitors, alkylating agents, anthracyclines, vincaal Kaloids, inserts, drugs that can interfere with signaling pathways, apoptosis promoters, proteo Examples include chromosome inhibitors and radiation (e.g., local or whole-body irradiation).

[0107] Non-exclusive examples of additional therapeutic agents include peptides, polypeptides, proteins, and fusion proteins. Examples include proteins, nucleic acid molecules, small molecules, mimics, synthetic drugs, inorganic molecules, and organic molecules. However, it is not limited to these.

[0108] Conjoint therapy involves other suitable medications, such as chemotherapy agents and cytokines. Interferon therapy (e.g., interferon-alpha, beta, or gamma) Feron α-2a; Interferon α-2b; Interferon α-m; Interferon Interferon α-n3; interferon β-Ia; and interferon γ-Ib), inter - Leukin therapy (e.g., IL-1, IL-2, IL-2Rβ, IL-2Rγ, IL-3) , IL-7, IL7Rα, IL-11, IL-12, IL-15, and IL-21), Differentiation cluster (CD) proteins (e.g., CD2, CD4, CD7, CD8α, CD 8β, CD11a / CD18, CD11b, CD11c, CD11d, CD18, CD1 9, CD19a, CD20, CD27, CD28, CD29, CD30, CD40, CD 40L, CD49a, CD49D, CD49f, CD69, CD84, CD96, CD1 00, CD103, CD137, CD160, CD226, CD229, CD278) Stimulus modulators, for example, agonists of MHC class I molecules (for example, agonist antibodies) (or its antigen-binding fragment, or soluble fusion), TNF receptor protein, immunoglobulin Ion-like protein, Toll ligand receptor, CD83 ligand, cytokine receptor, Lentegrin, signal transduction lymphocyte activating molecule (SLAM protein), activated NK cells This may include receptor therapy, antibody therapy, viral therapy, gene therapy, or a combination thereof.

[0109] Chemotherapy agents and other therapeutic agents that may be administered conjointly with the compounds disclosed herein include: abiraterone, abraxane, acegraton, asibicin, acrasinomycin, Actimide, actinomycin, aflibercept, aldesleukin, aldofosphat Midoglycoside, alectinib, alendronate, alitretinoin, altretamine , aminoglutethimide, aminolevulinic acid, aminopterin, amsacrine, anastro Zole, ancitabine, angiostatin, angiozyme, Nguidine, anthamitocin, anthramycin, antithrombin III, apatin B, Arabinoside, Arboplatin, Asparaginase, Ausramycin (authr amycin, axitinib, azacitidine, azaserine, azetepa, azotomycin , 6-azauridine, baricitinib, batimastat, bendamustine, benimetinib, Benzodopa, Bestlovesil, Bexarotene, Bicalutamide, Bisanthren, Bleoma Icin, bortezomib, bosutinib, brakinal, brivanib, briostatin, bro Pyrimine, Bratacin, Bratacinone, Buserelin, Busulfan, Kakutinomycin, Calicheamicin, calistatin, carsterone, carminomycin, campotecin, Pecitabine, Carabicin, Carboplatin, Carboquinone, Carfilzomib, Carmov Carmustine, Carbicin, Carzeresin, Cardinophilin, Sedefingol , cedilanib, chromafadin, chlorambucil, chloroquine, chlorozotosin, chloro Phosphamide, chromomycin, cyrolemycin, cisplatin, cisdichlorodiamine Platinum(II), cisplatin, cladribine, clodronate, cobimetinib, colchicine N, cristol, crizotinib, cryptophycin 1, cryptophycin 8, cyclo Phosphamide, cyproterone, cytarabine, cytochalasin B, cytosine arabinoside, Dabrafenib, dacarbazine, dactinomycin, danoprevir, dasatinib, diazyne Quon, dibromomannitol, daunorubicin, decitabine, defofamine (def (ofamine), degarelix, 1-dehydrotestosterone, delanzomib, demeco Lucin, demethoxybyridine, denileukin, denenicokin, denopterin, desacetyl Rabidomycin, detrubicin, dexamethasone, dexormaplatin, dezaguanine, Diadiquan, 6-diazo-5-oxo-L-norleucine, dichloroacetate, dide Oxyuridine, dienestrole, diethylstilbestrol, difutitox, difu Luoromethyromitine, dihydroxyanthracene dione, dinaciclib, docetaxel, Dorastatin, dovitinib, doxifluridine, doxolubicin, doxycycline, Droloxifen, Dromostanolone, Duazomycin, Duocalmycin, Dinemi Syn, edatrexate, ephromitin, eriptinium acetate, eleuterobin, emetin Msilomus, Encorafenib, Enloplatin, Enocitabine, Enproma te, epipropidine, epirubicin, epithirone, epithiostanol, erbrozo Lu, erythmodegib, erlotinib, esorubicin, esperamicin, estradiol Estramustine, etanidazole, ethidium bromide, 2-ethylhydrazide, etidium Lonate, etoglucid, etoposide, everolimus, exemestane, fadrozol Fazarabine, fenretinide, filgrastim, floxuridine, fludarabine , fludrocortisone, fluorouracil, fluoxymesterone, flurocitabine, flu Lutamide, foretinib, formestan, fosquidone, fotemustine, floric acid, Gacitosine, gallium nitrate, garnicertib, gandotinib, gefitinib, gerdanama Isine, gemcitabine, genistein, glucocorticoid, goserelin, gramicidin D, Herbimycin, Hiltonol, 4-hydroxytamoxifen, hydroxyurea ibandronate, idarubicin, ifosfamide, irmofosin, imatinib, imi Quimod, improsulfan, indoximod, interferon, iproplatin, i Linotecan, Ironotecan, Ixazomib, Keoxyfen Laharpalepbek, lameotide, lapatinib, lenalidomide, restaurtinib, let Rozole, leucovorin, leuprolide, lentinan, levamizole, rialozole, ri Docaine, linifanib, lometrexo, lomustine, ronidami N, losoxantrone, marcelomycin, marizomib, masitinib, masopropyl, Maytansine, Maytansinol, Mechloretamine, Mechloretamine Oxide Hydrochloride, Ma Nnomustine, medroxyprogesterone, megestrol, melengestrol, meno Galil, Melphalan, Mepichiostan, Mercaptopurine, Mesna, Metformin, Me Totrexate, methoprine, metsuredopa, mitramycin, mitobronitol, mito Guazone, Mitractol, Mitomycin, Mitospel, Mitotan, Mitoxantrone Momerotinib, montanid, mopidamole, motesanib, motlimod, mycophenol Acid, Mylotarg, Nab-paclitaxel, Navelbine, Neratinib, Nilotinib, Ni Lutamide, Nimustine, Nitracrine, Nocodazole, Nogaramycin, Novantrone, Novembichin, Obinutuzumab, Octreotide, Olivoma Icin, Onapristone, Ormaplatin, Oxaliplatin, Paclitaxel, Pacli Tinib, palbociclib, pamidronate, pancratistatin, panobinostat, pa Zopanib, pegaptanib, pegaspargaze, pegfilgrastim, peginterfe Lon α-2b, peritinib, pemetrexed, pentostatin, N4-pentoxycarb Nyl-5-deoxy-5-fluorocytidine, peplomycin, perifosin, fename Fenestrine, Pimasertib, Piposulfan, Piposulfan, Pirarubicin Plicamycin, podophyllic acid, polyfeprosan, pomalidomide, porfimer, po Luflomycin, Potphylomycin, Prednimustine, Procaine, Procarbazine , propranolol, pteropterin, puromycin, keramycin, larcitrex Ced, raloxifene, ranimustine, rapamycin, rabidomycin, razoxane, le Gorafenib, risedronate, resikimod, rituximab, rhodorubicin, logretimin D, Lorizin, Ruxolitinib, Safingol, Sarcodicin, Selumetinib, Sema Xanib, Semustine, Semapimod, Simtrazene, Sirolimus , scizophyllan, sorafenib, sparphosate, sparsomycin, spirogermanium Spiromustin, spiroplatin, spongistatin, streptonigrin, str Putozosin, slofenul, sunitinib, suramin, tarisomycin, tamoxifen, Tarimozin, tasocitinib, taxol, tegafur, teratinib, teloxantrone Temoporfin, temozolomide, temsirolimus, teniposide, tenuazonic acid, telox Silon, testactone, testosterone, tetracaine, tezacitibin, thalidomide , thiamiprine, thioguanine, thiotepa, thiazophrine, chillronate, thirapasami Titanocene, tivozanib, toceranib, tofacitinib, topoisomerase inhibitor R FS2000, Topotecan, Toremifene, Tozacertib, Trametinib, Trastuzma B, triadiquan, tretinoin, 2,2',2''-trichlorotriethylamine, Triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, Lilostane, Trimethylolmelamine, Trimethrexate, Triptorelin, Trophos Famide, tubercidine, tuvizanib, uracil mustard, u Benimex, uredopa, urethane, vandetanib, vapreotide, Vargatef, batalanib, vemurafenib, bellacrin, verteporfin, vemurafenib Binblastine, vincristine, vindesine, vinepidine, bincristine, vinlei Rosine, vinorelbine, vinrosidine, binzolidine, borozol, bismodegib, zero -da, Zactima, Zeniplatin, Zinostatin, Ziv-Affilibercept, Zored Examples include, but are not limited to, lonate and zolubicin.

[0110] In certain embodiments, exemplary chemotherapeutic agents include ABT-869 and ACP-19. 6, ADXS11-001, ADXS31-142, AEE788, AG-490, AM 0010, AMN-107, AMP-224, AMP-514, AP24534, ARR Y-142886, AST-6, AZD1480, AZD4547, AZD6094, A ZD6244, AZD8055, AZD9291, B7-H3, BAFFR, 4-1BB , BEZ235, BGT 226, BHG712, BIBF 1120, BIBW2992 , BIX 02188, BJG398, BKM-120, BMS-599626, BMS -690154, BMS-777607, BMS-911543, BMS-936558 , BMS-936559, BMS-986016, BRAF V600E, BTLA, B UW078, BYL719, CAL-101, CAL-263, CBI-TMI, CC- 1065, CC-4047, CC-5013, CDS, CDX-1127, CEACAM 1, CEP-701, CEP-11981, CGM097, Chi Lob 7 / 4, CI -1040、CO-1686、CP-673451、CP-870,893、CpG 7 909、CPT-11、CRTAM、CT-011、CTL019、CTLA-4、CU DC-101、CYC116、CYT 387、DCC-2036、DNAM1、E62 01、E7080、EGF816、FOLFOX6、G02443714、G-3896 3、GADS、GC1008、G-CSF、GDC-0032、GDC-0973、GD C-0980、GITR、GM CSF、GR-MD-02、GSK1059615、G VAX、HVEM(LIGHTR)、IA4、ICAM-1、ICOS、IMC-TR1 、IMP321、INC280、INC424、INCB18424、INCB0243 60、INCB028050、IPH2012、IPI926、IRX-2、ISA 5 1VG、ITGA4、ITGA6、ITGAD、ITGAE、ITGAL、ITGAM、 ITGAX、ITGB1、ITGB2、ITGB7、JNJ-26483327、Ki8 751、KIRDS2、KU-0063794、KW-289LAT、LBH589、L CL161、LGH447、LTBR、LDK378、LEE011、LGX818、L IGHT、LJM716、LY117018、LY2157299、LY294002、 LY2940680、M-CSF、MARTI、MDX-1105、MDX-1106、 MEDI0562、MEDI4736、MEDI4737、MEDI6383、MEDI 6469、MEK162、MG-132、MGCD265、MK-3475、MK 41 66、MM-121、MOXR0916、MP470、MPDL3280A、MSB-0 010718C、NKG2C、NKG2D、NKp30、NKp44、NKp46、NK p80(KLRF1), NY-ESO-1, ODC-0879, ODC-0980, ON X-0912, ODC-0941, OSI-027, OSI-930, OSK-1120 212, OSK 2118436, OSK 2126458, OX40, P529, PAG / Cbp, PD153035, PD173074, PD0325901, PF-2998 04, PF-02341066, PF-04217903, PF-046915032, PF-05082566, PD98059, Poly(I:C), PKI-587, PL X4032, PLX4720, PSGL1, PSK, PX-886, Rad-001, R AF265, rHIgM12B7, R07204, RO4987655, RO68958 82, RO7009789, SAR 245408, SAR 245409, SB-131 7, SB-1518, SB-1578, SELPLG, SF1126, SGX523, S LAM, SLAMF4, SLAMF6, SLAMF7, SLAML_BLAME, SLP -76, SU 5402, T2 toxin, TEW 7197, TGN1412, TNFR2, T RANCE / RANKL, TriMix-DC, TRP-2, TRX518, TSU-6 8, VLA1, VLA-6, WYE-354, WZ3146, WZ4002, WZ804 0, XL-147, XL-184, XL-228, XL-281, XL-647, XL- 756, XL-765, XL-880, Yttrium 90 / MX-DTPA, and YW Examples of cytokines include 243.55.S70, but are not limited to these.

[0111] Exemplary paclitaxel agents that can be used in conjoint with the compounds disclosed herein. For example, nanoparticle albumin-conjugated paclitaxel (Abraxis Bioscien ABRAXANE (sold by CE), docosahexaenoic acid-conjugated paclitaxel (D HA-Paclitaxel (Taxoprexin, marketed by Protarga), Riglutamate-conjugated paclitaxel (PG-paclitaxel, Cell Therape Paclitaxel Polygrumex, CT-2103, XYOT, sold by utic AX), tumor-activating prodrug (TAP), ANG105 (by ImmunoGen) Angiopep-2), which is bound to three molecules of paclitaxel that will be sold, paclitaxel -EC-1(Paclitaxel bound to erbB2-recognizing peptide EC-1; Li et a (See i., Biopolymers (2007) 87:225-230), and Gluco Paclitaxel conjugated with 2'-paclitaxel-methyl2- Glucopyranosyl succinate, Liu et al., Bioorganic & Medi See *Cinal Chemistry Letters* (2007) 17:617-620. ) are some examples, but are not limited to these.

[0112] In a particular embodiment, exemplary chemotherapeutic agents include the following, but Not limited to these: 1)(S)-N-((S)-1-cyclohexyl-2-((S)-2-(4-(4-full Olobenzoyl, thiazol-2-yl, pyrrolidine-1-yl, 2-oxoethyl )-2-(methylamino)propanamide; 2)((1R,9S,12S,15R,16E,18R,19R,21R,23S,24 E,26E,28E,30S,32S,35R)-1,18-dihydroxy-12-{( 1R)-2-[(1S,3R,4R)-4-(2-hydroxyethoxy)-3-methoxy Cyclohexyl]-1-methylethyl}-19,30-dimethoxy-15,17,21, 23,29,35-Hexamethyl-11,36-Dioxa-4-Azatricyclo[30. 3.1.04,9] Hexatriaconta-16,24,26,28-tetraene-2,3 ,10,14,20-pentaon); 3)(S)-1-(4-chlorophenyl)-7-isopropoxy-6-methoxy-2-( 4-{methyl-[4-(4-methyl-3-oxopiperazine-1-yl)-trans)- Cyclohexylmethyl[-amino}phenyl)-1,4-dihydro-2H-isoquinoline -3 on; 4) N-(4-((1R,3S,5S)-3-amino-5-methylcyclohexyl)pyri Zin-3-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide ; 5) VH and Sequence ID No. 141 as described in U.S. Patent No. 8,735,551 Anti-HER3 monoclonal antibody or its antigen-binding fragment, including the VL of SEQ ID NO: 140; 6)(E)-N-hydroxy-3-(4-(((2-(2-methyl-1H-indole- 3-Iyl(ethyl)amino(methyl)phenyl(acrylamide); 7)(3R)-3-cyclopentyl-3-[4-(7H-pyrrolo-[2,3-d]pyrim [Zin-4-yl)-1H-pyrazole-1-yl]propannitrile; and / or 8)8-(2,6-difluoro-3,5-dimethoxyphenyl)-quinoxaline-5- Carboxylic acid (4-dimethylaminomethyl-1H-imidazole-2-yl)amide.

[0113] In other embodiments, exemplary chemotherapeutic agents include the following, but Not limited to: 1)3-(1H-indole-3-yl)-4-[2-(4-methyl-1-piperazinyl] )-4-quinazolinyl]-1H-pyrrole-2,5-diene; 2) 5-(2,4-dihydroxy-5-isopropylphenyl)-N-ethyl-4-(4 -(morpholinomethyl)phenyl)isoxazole-3-carboxamide; 3) 2-methyl-2-(4-(3-methyl-2-oxo-8-(quinoline-3-yl)- 2,3-Dihydro-1H-imidazo[4,5-c]quinoline-1-yl)phenyl)pro Pannitrile (ductile); 4) Compound D (CYP17 inhibitor); 5) 4-[3,5-bis(2-hydroxyphenyl)-1H-1,2,4-triazole -1-yl-benzoic acid (defeasirox); 6) 4,4'-(1H-1,2,4-triazole-1-ylmethylene)bis-benzo Trill (letrozole); 7)(4S,5R)-3-(2'-amino-2-morpholino-4'-(trifluoromethicone) (Lu)-[4,5'-bipyrimidine]-6-yl)-4-(hydroxymethyl)-5-methyl Luoxazolidine-2-one; 8)(S)-5-(5-chloro-1-methyl-2-oxo-1,2-dihydropyridine- 3-yl)-6-(4-chlorophenyl)-2-(2,4-dimethoxypyrimidine-5) -yl)-1-isopropyl-5,6-dihydropyrrolo[3,4-d]imidazole-4 (1H)-on; 9) 4-[(4-methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4 -(3-pyridinyl)-2-pyrimidinyl]amino]phenyl]-methanesulfonate- Benzamide; 10)4-[(R)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole-5 -yl-3-fluorobenzonitrile (osilodrostat); 11) N-[6-[(2R,6S)-2,6-dimethyl-4-morpholinyl]-3-pyri [Dinyl]-2-methyl-4'(trifluoromethoxy)-[1,1'-biphenyl]-3 -Carboxamide, diphosphate (sonidegibrine); 12)(R)-2-(5-(4-(6-benzyl-4,5-dimethylpyridazine-3- (L)-2-methylpiperazine-1-yl)pyrazine-2-yl)propan-2-ol; 13) Compound M (human monoclonal antibody against PRLR); 14)2-(2',3-dimethyl-[2,4'-bipyridine]-5-yl)-N-(5- (Pyrazine-2-yl)pyridine-2-yl)acetamide; 15)7-Cyclopentyl-N,N-dimethyl-2-((5-((1R,6S)-9-Me Chil-4-oxo-3,9-diazabicyclo[4.2.1]nonane-3-yl)pyridine -2-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide; 16) Compound P (FGFR2 and / or FGFR4 antibody drug conjugate, mAb) 12425); 17) Compound Q (Fab's monoclonal antibody against M-CSF); 18)N-[(9S,10R,11R,13R)-2,3,10,11,12,13-He Xahydro-10-methoxy-9-methyl-1-oxo-9,13-epoxy-1H,9 H-diindro[1,2,3m]pyrrolo[3,4-j][1,7]benzodiazonin-1 1-yl]-N-methylbenzamide(midostaurin); 19) 1-methyl-5-((2-(5-(trifluoromethyl)-1H-imidazole- 2-yl)pyridine-4-yl)oxy)-N-(4-(trifluoromethyl)phenyl )-1H-benzo[d]imidazole-2-amine; 20) Cyclo((4R)-4-(2-aminoethylcarbamoyloxy)-L-prolyl -L-phenylglycyl-D-tryptophyl-L-lysyl-4-0-benzyl-L-chy Rosyl-L-phenylalanyl-)(pasireotide niaspartate); 21) 1-amino-5-fluoro-3-[6-(4-methyl-1-piperazinyl)-1H -Benzimidazole-2-yl]-2(1H)-quinolinone (dovitinib); 22)8-(6-methoxypyridine-3-yl)-3-methyl-1-(4-piperazine) -1-yl-3-trifluoromethylphenyl)-1,3-dihydroimidazo[4, 5-c]Quinoline-2-one; 23)N6-(2-isopropoxy-5-methyl-4-(1-methylpiperidine-4- (Lu)phenyl)-N4-(2-(isopropylsulfonyl)phenyl)-1H-pyrazolo [3,4-d]pyrimidine-4,6-diamine; 24)3-(4-(4-((5-chloro-4-((5-methyl-1H-pyrazole-3- Il)amino)pyrimidine-2-yl)amino)-5-fluoro-2-methylphenyl) Piperidine-1-yl-1)thiethane 1,1-dioxide; 25) 5-Chloro-N2-(2-Fluoro-5-methyl-4-(1-(Tetrahydro-2 H-pyran-4-yl)piperidine-4-yl)phenyl)-N4-(5-methyl-1H )-pyrazole-3-yl)pyrimidine-2,4-diamine; 26) 5-Chloro-N2-(4-(1-ethylpiperidine-4-yl)-2-fluoro- 5-methylphenyl)-N4-(5-methyl-1Hpyrazole-3-yl)pyrimidine- 2,4-diamine; 27)6-[(2S,4R,6E)-4-methyl-2-(methylamino)-3-oxo- [6-Octenoic acid]Cyclosporine D. Amdray. PSC833. [3'-Desoxy -3'-Oxo-MeBmt]1-[Val]2-Cyclosporine (Valspodar) ); 28) N-(4-chlorophenyl)-4-(4-pyridinylmethyl)-1-phthalazine Minsuccinate (Vatalanib succinate); 29) Compound CC (IDH inhibitor); 30)(R)-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-hydro Xypyrrolidine-1-yl)-5-(1H-pyrazole-5-yl)nicotinamide; 31) Compound EE (cRAF inhibitor); 32) Compound FF (ERK1 / 2ATP competitive inhibitor); and 33)4-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benn Zo[d]thiazole-6-yl)oxy)-N-methylpicolinamide. For example, the whole and See WO2016 / 100882, which is incorporated herein by reference.

[0114] In a particular embodiment, an exemplary therapeutic agent for conjoint administration is monoclonal It is an antibody or a fragment thereof (e.g., Bolliger (1993) Proc. Nat l.Acad.Sci.USA 90:6444-6448;Poljak(1994) See Structure 2:1121-1123). These therapeutic monoclonal anti The whole and / or fragments include anti-LAG-3 monoclonal antibodies and anti-PD-1 antibodies. , anti-PD-L1 antibody, anti-PD-L2 antibody, anti-TIM-3 antibody, anti-CTLA-4 antibody, anti-T IGIT antibody, anti-OX40 antibody, anti-GITR antibody, adalimumab, afatinib, Aftuz Zumab, alemtuzumab, atezolizumab, avelumab, axitinib, basiliximab Babituximab, belimumab, bevacizumab, brentuximab, canakinumab, cell Tolizumab, cetuximab, daclizumab, denosumab, durvalumab, eculizumab , ephalizumab, elotuzumab, fostamatinib, gemtuzumab ozogamicin, Limumab, ibritumomab tiuxetan, infliximab, ipilimumab, lambroli Zumab, lapatinib, lenvatinib, lirirumab, mogamlizumab, motabizumab, mbu Litinib, natalizumab, nivolumab, obinutuzumab, ofatumumab, omalizumab Palivizumab, Panitumumab, Pegaptanib, Pembrolizuma Pertuzumab, pizilizumab, ranibizumab, laxibakumab, rilotumumab, ritizumab Ximab, tocilizumab, tocitumomab-I-13, trastuzumab, tremelimumab, Examples include, but are not limited to, urelumab, ustekinumab, and valrilumab. stomach.

[0115] Combination therapy may also include the administration of bispecific antibodies. Bispecific antibodies are two separate antibodies. It can be used to target antigens. For example, anti-Fc receptor / antitumor antigen (e.g., H The ER-2 / Neu) bispecific antibody is used to direct macrophages to tumor sites. This has been done. This targeting may more effectively activate tumor-specific responses. The T cell arm will be enhanced by the use of PD-1 blockade. Alternatively, the antigen, By using bispecific antibodies that bind to tumor antigens and dendritic cell-specific cell surface markers, DC It can be delivered directly.

[0116] Other antibodies that may be used to activate the host immune response are described herein. They can be used in combination with other therapies. These affect DC function and on the surface of dendritic cells. It contains molecules that activate antigen presentation. Anti-CD40 antibodies effectively affect T cell helper activity. It can be replaced (Ridge, J. et al. (1998) Nature 393: 474-478), and can be used in combination with PD-1 antibodies (Ito, N. et al.). al. (2000) Immunobiology 201(5)527-40). CTL A-4 (e.g., U.S. Patent No. 5,811,097), OX-40 (Weinberg, A.et al.,(2000)Immunol164:2160-2169), 4-1 BB (Melero, I et al. (1997) Nature Medicine 3: 682-685 (1997), and ICOS (Hutloff, A. et al. (1 Antibodies against T cell costimulatory molecules such as (999)Nature 397:262-266) It may also provide an increase in the level of T cell activation.

[0117] Immunomodulatory agents suitable for use in compositions and conjoint methods described herein And as a treatment, anti-T cell receptor antibodies, for example, anti-CD3 antibodies (e.g., Nuvio n(Protein Design Labs), OKT3(Johnson&Johns (on), or anti-CD20 antibody Rituxan (IDEC), anti-CD52 antibody (e.g., C AMPATH 1H(Ilex)), anti-CD11a antibody (e.g., Xanelim(Ge nentech)); anti-cytokine or anti-cytokine receptor antibodies, as well as anti Gonist, for example, anti-IL-2 receptor antibody (Zenapax (Protein Desi gn Labs), anti-IL-6 receptor antibodies (e.g., MRA (Chugai)), and anti-IL-12 antibody (CNT01275 (Janssen)), anti-TNF alpha antibody ( Remicade (Janssen) or TNF receptor antagonist (Enbre l(Immunex)), anti-IL-6 antibody (BE8(Diaclone) and silk Simab (CNT032(Centocor)) binds immunospecifically to tumor-associated antigens. Examples of antibodies that do this (for example, trastuzimab (Genentech)) Not limited.

[0118] The combination therapies disclosed herein involve cancer cells, purified tumor antigens (recombinant proteins, peptides). Genes encoding cytokines (including cytoplasm and carbohydrate molecules), cells, and immune-stimulating cytokines. It can be further combined with immunogenic factors such as genetically transfected cells (H e et al., (2004) J.Immunol. 173:49 19-28). Non-limiting examples of tumor vaccines include melanoma antigen peptides, such as gp10 Peptides of 0, MAGE antigen, Trp-2, MARTI and / or tyrosinase, Alternatively, tumor cells transfected to express the cytokine GM-CSF may be mentioned. It can be done.

[0119] The compounds disclosed herein are recombinant proteins and / Alternatively, it can be used with peptide aspirates to induce an immune response against these proteins. These proteins can be recognized as autoantigens by the immune system. Therefore, it is tolerant of them. Tumor antigens also include the protein telomerase, and This is necessary for the synthesis of chromosome telomeres and is present in over 85% of human cancers, and not limited to... It is expressed only in a limited number of somatic cells (Kim, Net al., (1994)S (Science 266:2011-2013). (These body tissues are immune through various means.) (They can be protected from attack). Tumor antigens also alter the protein sequence, or both. Fusion proteins between unrelated sequences (i.e., bcr-A in the Philadelphia chromosome) Because it is a somatic mutation that produces an idiotype derived from bl or B-cell tumors, cancer cells It may also be a "neoantigen" expressed in that state.

[0120] The compounds disclosed herein may be combined with vaccination protocols for tumors. Many experimental strategies have been devised for vaccination against this (Rosenberg, S., 2000, Development of Cancer Vaccines, A.S. CO Educational Book Spring:60-62;Logothet is,C.,2000,ASCO Educational Book Spring:3 00-302;Khayat,D.2000,ASCO Educational Boo k Spring:414-428;Foon,K.2000,ASCO Educati See Onal Book Spring: 730-738; also see Restifo, N. and Sznol, M., Cancer Vaccines, Ch. 61, pp. 302 3-3043 in DeVita,V.et al.(eds.),1997,Canc er:Principles and Practice of Oncology,Fif (See th Edition). In one of these strategies, vaccines are autologous or co-developed. These cell vaccines are prepared using various types of tumor cells. These cell vaccines are prepared by tumor cells that produce GM-CSF. It has been shown to be most effective when transduced to express GM-C. SF has been shown to be a potent activator of antigen presentation for tumor vaccination. (Dranoff et al. (1993) Proc. Natl. Acad. Sci. (USA90:3539-43). In some embodiments, malignant plasma cells Vaccination using immunoglobulin idiotypes produced by the body is utilized. Other treatments Therapeucel-T, gp100 vaccine, HPV-16 Vaccination and the GVAX pancreatic vaccine are examples, but are not limited to, these.

[0121] Other tumor vaccines include those for human papillomavirus (HPV), hepatitis virus (HBV), and (HCV), Kaposi's herpes sarcoma virus (KHSV) and melanoma preferential expression antigen (Pr Eferentially Expressed Antigen In Melanoma It may also contain proteins derived from viruses involved in human cancer, such as (PRAME). In a specified embodiment, the vaccine is a viral vector vaccine, a bacterial vaccine, or a cell vaccine. Based vaccines, DNA vaccines, RNA vaccines, peptide vaccines, or protein It is selected from a variety of vaccines. For example, Jeffrey Schlom, "Thera peutic Cancer Vaccines:Current Status and Moving Forward'',J Natl Cancer Inst;104:59 See 9-613 (2012). Tumors that can be used in combination with PD-1 blockade. Another form of specific antigen is purified heat shock protein isolated from the tumor tissue itself. These are HSPs. These heat shock proteins break down proteins derived from tumor cells. These HSPs contain fragrant ions, and these HSPs are delivered to antigen-presenting cells to induce tumor immunity. It is very efficient (Suot, R & Srivastava, P (1995) Scie nce 269:1585-1588;Tamura,Y. et al.(1997)S Science 278:117-120).

[0122] Exemplary agents that can be administered conjointly with the compounds disclosed herein include: Examples include therapeutic cancer vaccines or adoptive T-cell therapy. In certain embodiments, therapeutic cancer The vaccine is a dendritic cell vaccine. The dendritic cell vaccine is made from autologous dendritic cells and / or It may be composed of allogeneic dendritic cells. In certain embodiments, autologous or allogeneic dendritic cells are The target is loaded with a cancer antigen before administration. In certain embodiments, autologous or allogeneic dendritic cells are used. The cells are loaded with cancer antigens through direct administration to the tumor. In certain embodiments, the adopted T Cell therapy includes autologous and / or allogeneic T cells. In certain embodiments, autologous and T cells and / or allogeneic T cells are targeted against tumor antigens.

[0123] In certain embodiments, non-limiting examples of cancer vaccines include tumor cell vaccines and antigens. Examples include vaccines, dendritic cell vaccines, DNA vaccines, and vector-based vaccines. Antigen vaccines are developed by using one or more antigens, such as peptides. Boost the immune system. Each tumor type can be identified by its specific antigen profile. Therefore, antigen vaccines can be specific to certain types of cancer. Dendritic cell vaccines are numerous. In this case, it is an autologous vaccine, and in many cases, it must be prepared individually for each target group. No. Non-exclusive examples of dendritic vaccines are Sipuleucel-T and DCvax. To prepare a DNA vaccine, the vector contains specific DNA that can be injected into the target. It may be designed to contain this DNA so that it is taken up by cells. When a cell takes in DNA, the DNA programs the cell to produce a specific antigen, and that Subsequently, this can trigger the desired immune response.

[0124] Pancreatic cancer Examples of compounds disclosed herein that may be used conjointly for the treatment of pancreatic cancer. Examples of exemplary drugs include TAXOL and albumin-stabilized nanoparticle paclitaxel preparations (for example). ABRAXANE) or liposomal paclitaxel preparations; gemcitabine (e.g., gem) Mucitabine alone or in combination with AXP107-11; other chemotherapeutic agents, for example Oxaliplatin, 5-fluorouracil, capecitabine, rubitecan, epirubicin Hydrochloride, NC-6004, cisplatin, docetaxel (e.g., TAXOTERE), Mitomycin C, ifosfamide; interferon; tyrosine kinase inhibitors (for example) For example, EGFR inhibitors (e.g., erlotinib, panitumumab, cetuximab, nimotuzumab) HER2 / neu receptor inhibitors (e.g., trastuzumab); dual kinase inhibitors (e.g., bosutinib, salacatinib, lapatinib, vandetanib); multikinase inhibitors Harmful agents (e.g., sorafenib, sunitinib, XL184, pazopanib); VEGF inhibitors (e.g., bevacizumab, AV-951, brivanib); radioimmunotherapy (e.g., XR3) 03); Cancer vaccines (e.g., GVAX, Survivin peptide); COX-2 inhibitors (e.g.) For example, celecoxib); IGF-1 receptor inhibitors (e.g., AMG479, MK-064) 6); mTOR inhibitors (e.g., everolimus, temsirolimus); IL-6 inhibitors (e.g.) For example, CNTO328); cyclin-dependent kinase inhibitors (e.g., P276-00, UCN-01); Altered Energy Metabolism lism-directed (AEMD) compounds (e.g., CPI-613); HDA C inhibitors (e.g., vorinostat); TRAIL receptor 2 (TR-2) agonists (e.g., For example, conatumumab); MEK inhibitors (e.g., AS703026, selumetinib, GS) K1120212); Raf / MEK dual kinase inhibitor (e.g., R05126766) ); Notch signaling inhibitors (e.g., MK0752); monoclonal antibodies - anti Body fusion proteins (e.g., L19IL2); curcumin; HSP90 inhibitors (e.g., Tanespimycin, STA-9090); riL-2; Deniloquine difutitex; Topo Isomerase 1 inhibitors (e.g., irinotecan, PEP02); statins (e.g., syn Vastatin; Factor VIIa inhibitors (e.g., PCI-27483); AKT inhibitors ( For example, RX-0201); hypoxia-activated prodrugs (for example, TH-302); methotrexate Formin hydrochloride, gamma-secretase inhibitor (e.g., R04929097); ribonu Cleotide reductase inhibitors (e.g., 3-AP); immunotoxins (e.g., HuC242) -DM4); PARP inhibitors (e.g., KU-0059436, veliparib); CTLA -4 inhibitors (e.g., CP-675, 206, ipilimumab); AdVtk therapy; prote Asome inhibitors (e.g., bortezomib (Velcade), NPI-0052); thia Zolidinedione (e.g., pioglitazone); NPC-1C; Aurora kinase inhibitors ( For example, R763 / AS703569), CTGF inhibitors (for example, FG-3019); siG 12D LODER; and radiotherapy (e.g., Tomotherapy, stereotactic radiotherapy, positivity). Treatment options include, but are not limited to, radiating therapy, surgery, and combinations thereof. stomach.

[0125] small cell lung cancer Used in conjoint with the compounds disclosed herein to treat small cell lung cancer. Examples of drugs that can be obtained include etoposide, carboplatin, cisplatin, irinotecan, Topotecan, gemcitabine, liposome SN-38, bendamustine, temozolomide, be Lothecan, NK012, FR901228, Flavopyridol; Tyrosine kinase inhibitor Drugs (e.g., EGFR inhibitors (e.g., erlotinib, gefitinib, cetuximab, pa Nitumumab; multi-kinase inhibitors (e.g., sorafenib, sunitinib); VEGF Inhibitors (e.g., bevacizumab, vandetanib); cancer vaccines (e.g., GVAX); B Cl-2 inhibitors (e.g., oblimersen sodium, ABT-263); proteaso Antibiotics (e.g., bortezomib (Velcade), NPI-0052), paclitaxel Cell or paclitaxel agents; docetaxel; IGF-1 receptor inhibitors (e.g., AMG) 479); HGF / SF inhibitors (e.g., AMG102, MK-0646); Chloroquine Aurora kinase inhibitors (e.g., MLN8237); radioimmunotherapy (e.g., TF2) ); HSP90 inhibitors (e.g., tanespimycin, STA-9090); mTOR inhibitors Agents (e.g., everolimus); Ep-CAM- / CD3- bispecific antibodies (e.g., MT 110); CK-2 inhibitors (e.g., CX-4945); HDAC inhibitors (e.g., Veri Nostat); SMO antagonist (e.g., BMS833923); peptide cancer vaccine Chin, and radiotherapy (e.g., intensity-modulated radiation therapy (IMRT), fractional radiotherapy) These include hypoxia-induced radiotherapy, surgery, and combinations thereof. It is not limited to them.

[0126] non-small cell lung cancer The compounds disclosed herein are used in conjoint with non-small cell lung cancer to treat non-small cell lung cancer. Examples of possible drugs include vinorelbine, cisplatin, docetaxel, and pemetrexate. Disodium, etoposide, gemcitabine, carboplatin, liposomal SN-38, TLK286, temozolomide, topotecan, pemetrexed disodium, azacitidine Irinotecan, tegaflugimeracil-oteracil potassium, sapacitabine; tyrosine Kinase inhibitors (e.g., EGFR inhibitors (e.g., erlotinib, gefitinib, cetylamine) Ximab, Panitumumab, Necitumumab, PF-00299804, Nimotuzumab, R0 5083945), MET inhibitors (e.g., PF-02341066, ARQ197), PI3K kinase inhibitors (e.g., XL147, GDC-0941), Raf / MEK2 Heavy kinase inhibitors (e.g., R05126766), PI3K / mTOR bikinase inhibitors Harmful agents (e.g., XL765), SRC inhibitors (e.g., dasatinib), dual inhibitors (e.g., BIBW2992, GSK1363089, ZD6474, AZD0530, AG- 013736, lapatinib, MEHD7945A, linifanib), multikinase inhibitor Drugs (e.g., sorafenib, sunitinib, pazopanib, AMG706, XL184, MG) CD265, BMS-690514, R935788), VEGF inhibitors (e.g., En Dostar, Endostatin, Bevacizumab, Cedilanib, BIBF1120, Axitinib (e.g., tivozanib, AZD2171), cancer vaccines (e.g., BLP25 liposomal vaccine) Adenovirus expressing GVAX, recombinant DNA, and L523S protein, Bcl-2 inhibitors (e.g., oblimersen sodium), proteasome inhibitors (e.g.) For example, bortezomib, carfilzomib, NPI-0052, ixazomib, paclita Xel or paclitaxel, docetaxel, IGF-1 receptor inhibitors (e.g., cyclophorexate, docetaxel, IGF-1 receptor inhibitors) Tummumab (MK-0646, OSI906, CP-751, 871, BIIB022), Hydroxychloroquine, HSP90 inhibitors (e.g., tanespimycin, STA-909) (0, AUY922, XL888), mTOR inhibitors (e.g., everolimus, temsilloli) Muss, ridafololimus), Ep-CAM- / CD3-bispecific antibody (e.g., MT1 10) CK-2 inhibitors (e.g., CX-4945), HDAC inhibitors (e.g., MS2 75, LBH589, vorinostat, valproic acid, FR901228), DHFR inhibitor Drugs (e.g., pralatrexate), retinoids (e.g., bexarotene, tretinoin) ), antibody-drug conjugates (e.g., SGN-15), bisphosphonates (e.g., Zoledronic acid), cancer vaccines (e.g., Bellagen pumacell-L), low molecular weight heparin ( LMWH) (e.g., tinzaparin, enoxaparin), GSK1572932A, Mela Tonin, taractoferrin, dimesuna, topoisomerase inhibitors (e.g., amrubicin) (e.g., etoposide, calenitecin), nelfinavir, sirengitide, ErbB3 inhibitors) For example, MM-121, U3-1287), survivin inhibitors (e.g., YM155, LY 2181308), eribulin mesylate, COX-2 inhibitors (e.g., celecoxib), Pegfilgrastim, polo-like kinase 1 inhibitor (e.g., BI6727), TRAIL Receptor 2 (TR-2) agonist (e.g., CS-1008), CNGRC peptide-T NF alpha conjugate, dichloroacetic acid (DCA), HGF inhibitor (e.g., SCH 900105), SAR240550, PPAR-gamma agonist (e.g., CS- 7017), gamma-secretase inhibitors (e.g., R04929097), epigenetics Tick ​​therapy (e.g., 5-azacitidine), nitroglycerin, MEK inhibitors (e.g., AZD6244), cyclin-dependent kinase inhibitors (e.g., UCN-01), Sterol-Fus1, antitubulin agents (e.g., E7389), farnesyl-OH Transferase inhibitors (e.g., ronafarnib), immunotoxins (e.g., BB-10) 901, SS1(dsFv)PE38), fondaparinux, vasoconstrictors (e.g., A VE8062), PD-L1 inhibitors (e.g., MDX-1105, MDX-1106), Beta-glucan, NGR-hTNF, EMD521873, MEK inhibitor (e.g., G SK1120212), epothyron analogs (e.g., ixabepyrone), kinesin-spi Tuberculosis inhibitors (e.g., 4SC-205), telomere targeting drugs (e.g., KML-001) P70 pathway inhibitors (e.g., LY2584702), AKT inhibitors (e.g., MK-2 206), angiogenesis inhibitors (e.g., lenalidomide), Notch signaling inhibitors ( For example, OMP-21M18), radiotherapy, surgery, and combinations thereof are listed. These are some examples, but they are not limited to these.

[0127] Ovarian cancer The compounds disclosed herein may be used in conjoint with other compounds to treat ovarian cancer. Examples of drugs include chemotherapeutic agents (e.g., paclitaxel or paclitaxel preparations); Cetaxel; Carboplatin; Gemcitabine; Doxorubicin; Topotecan; Cisplatin Irinotecan, TLK286, ifosfamide, olaparib, oxaliplatin, Ruphalan, pemetrexed disodium, SJG-136, cyclophosphamide, et Poside, decitabine; ghrelin antagonists (e.g., AEZS-130); immunotherapy Methods (e.g., APC8024, olegovomab, OPT-821), tyrosine kinase inhibition Drugs (e.g., EGFR inhibitors (e.g., erlotinib), dual inhibitors (e.g., E708) 0) Multi-kinase inhibitors (e.g., AZD0530, JI-101, sorafenib, Sunitinib, pazopanib), ON 01910.Na), VEGF inhibitors (e.g., Beva Cizumab, BIBF1120, cediranib, AZD2171), PDGFR inhibitors (examples) For example, IMC-303), paclitaxel, topoisomerase inhibitors (e.g., Calenite) Syn, irinotecan), HDAC inhibitors (e.g., valproate, vorinostat), leaves Acid receptor inhibitors (e.g., phaletuzumab), angiopoietin inhibitors (e.g., AMG) 386), epothyron analogs (e.g., ixabepyrone), proteasome inhibitors (e.g.) For example, carfilzomib, IGF-1 receptor inhibitors (e.g., OSI906, AMG47) 9) PARP inhibitors (e.g., veliparib, AG014699, iniparib, MK-4) 827), Aurora kinase inhibitors (e.g., MLN8237, ENMD-2076), Angiogenesis inhibitors (e.g., lenalidomide), DHFR inhibitors (e.g., pralatrexate) (t) Radioimmunotherapy agents (e.g., Hu3S193), statins (e.g., lovastatin) topoisomerase 1 inhibitors (e.g., NKTR-102), cancer vaccines (e.g., p5 3. Synthetic long-chain peptide vaccines, autologous OC-DC vaccines), mTOR inhibitors (e.g., te mucilolimus, everolimus), BCR / ABL inhibitors (e.g., imatinib), ET- A receptor antagonist (e.g., ZD4054), TRAIL receptor 2 (TR-2) Gonists (e.g., CS-1008), HGF / SF inhibitors (e.g., AMG102), EGEN-001, Polo-like kinase 1 inhibitor (e.g., BI6727), Gamma Secreta Wee-1 inhibitors (e.g., R04929097), Wee-1 inhibitors (e.g., MK-177) 5) Antitubulin agents (e.g., vinorelbine, E7389), immunotoxins (e.g., de Nileikin difutitox), SB-485232, vasoconstrictor (e.g., AVE806) 2) Integrin inhibitors (e.g., EMD525797), Kinesin-spindle inhibitors Drugs (e.g., 4SC-205), revlimide, HER2 inhibitors (e.g., MGAH22) ErrB3 inhibitors (e.g., MM-121), radiotherapy; and combinations thereof. These include, but are not limited to, the following:

[0128] Multiple myeloma The compounds disclosed herein may be administered conjointly with other compounds to treat myeloma. Examples of drugs include thalidomide analogs (e.g., lenalidomide) and HSCT (Coo k, R. (2008) J Manag Care Pharm.14(7 Suppl):1 9-25), anti-TIM-3 antibody (Hallett, WHD et al. (2011)J of American Society for Blood and Marrow Tr. Ansplantation 17(8):1133-145), tumor antigen pulsed dendritic cells , fusion of tumor cells and dendritic cells (e.g., electrofusion), or production by malignant plasma cells Vaccination based on immunoglobulin idiotype (Yi, Q. (2009) Ca (As discussed in ncer J.15(6):502-10), but not limited to these. It will not be done.

[0129] Renal cell carcinoma The compounds disclosed herein are administered conjointly with the treatment of renal cell carcinoma. Examples of drugs that can be obtained include interleukin-2 or interferon-α, and targeted drugs. (For example, VEGF inhibitors such as monoclonal antibodies against VEGF, e.g., Bevasi Zumab (Rini, BI et al. (2010) J. Clin. Oncol. 28) (13):2137-2143)); sunitinib, sorafenib, axitinib and pa Zopanib and other VEGF tyrosine kinase inhibitors (Pal SK et al. (201 4)Clin.Advances in Hematology&Oncology12( 2): As discussed in 1990-1999; RNAi inhibitors), or VEGF signaling Inhibitors of downstream mediators, for example, the mammalian target (mTOR) of rapamycin. Inhibitors of the drug, for example, everolimus and temsirolimus (Hudes, G. et al.) (2007)N.Engl.J.Med.356(22):2271-2281,Mot Zer, RJet al. (2008) Lancet 372:449-456) is cited. These are some examples, but they are not limited to these.

[0130] Chronic myeloid leukemia Compounds disclosed herein and conjugates for the treatment of chronic myeloid leukemia (CML) Examples of drugs that may be administered in the intestinal tract include chemotherapeutic agents (e.g., cytarabine, hydroxygen). Siurea, Clopharabine, Melphalan, Thiotepa, Fludarabine, Busulfan, E Toposide, cordycepin, pentostatin, capecitabine, azacitidine, cyclophosph (Amid, cladribine, topotecan), tyrosine kinase inhibitors (e.g., BCR / AB) L inhibitors (e.g., imatinib, nilotinib), bi-inhibitors (e.g., dasatinib, vos) Tinib), multi-kinase inhibitors (e.g., DCC-2036, ponatinib, soraphenib) Sunitinib, RGB-286638), interferon alpha, steroids, Apoptotic agents (for example, omacetaxine mepescinate) epesuccinat), immunotherapy (e.g., allogeneic CD4+ memory Th1-like T cells / microparticles) Child-bound anti-CD3 / anti-CD28, autologous cytokine-induced killer cells (CIK), AHN-1 2) CD52-targeted drugs (e.g., alemtuzumab), HSP90 inhibitors (e.g., Tanes) Pimycin, STA-9090, AUY922, XL888), mTOR inhibitors (e.g.) (e.g., Everolimus), SMO antagonist (e.g., BMS833923), Ribonucle Ocidoreductase inhibitors (e.g., 3-AP), JAK-2 inhibitors (e.g., INCB) 018424), hydroxychloroquine, retinoids (e.g., fenretinide), cy Clin-dependent kinase inhibitors (e.g., UCN-01), HDAC inhibitors (e.g., Veri Nostat, vorinostat (JNJ-26481585), PARP inhibitors (e.g., Veriparib), MDM2 Antagonist (e.g., R05045337), Aurora B Key Nase inhibitors (e.g., TAK-901), radioimmunotherapy (e.g., actinium-22) 5-labeled anti-CD33 antibody (HuM195), hedgehog inhibitor (e.g., PF-04449) 913), STAT3 inhibitors (e.g., OPB-31121), KB0004, cancer vaccine (e.g., AG858), bone marrow transplantation, stem cell transplantation, radiotherapy, and combinations thereof Examples include, but are not limited to, those listed above.

[0131] Chronic lymphocytic leukemia The compounds disclosed herein and condyloma for the treatment of chronic lymphocytic leukemia (CLL) Examples of drugs that may be administered at the joint include chemotherapeutic agents (e.g., fludarabine, cyclophosphamide). Lophosfamide, doxorubicin, vincristine, chlorambucil, bendamustine, Chlorambucil, busulfan, gemcitabine, melphalan, pentostatin, mitox Santrone, 5-azacitidine, pemetrexed disodium) tyrosine kinase inhibitor Drugs (e.g., EGFR inhibitors (e.g., erlotinib), BTK inhibitors (e.g., PCI) -32765), multi-kinase inhibitors (e.g., MGCD265, RGB-28663) 8) CD-20 targeted drugs (e.g., rituximab, offatumumab, R05072759) , LFB-R603), CD52-targeted drugs (e.g., alemtuzumab), prednisolone, Darbepoetin alfa, lenalidomide, Bcl-2 inhibitors (e.g., ABT-263) , immunotherapy (e.g., allogeneic CD4+ memory Th1-like T cells / microparticle-bound anti-CD3 / anti-CD2 8. Autologous cytokine-induced killer cells (CIKs), HDAC inhibitors (e.g., Borinos) Tat, valproic acid, LBH589, JNJ-26481585, AR-42), XIA P inhibitors (e.g., AEG35156), CD-74 targeted drugs (e.g., milatuzumab), mTOR inhibitors (e.g., everolimus), AT-101, immunotoxins (e.g., CAT- 8015, anti-Tac(Fv)-PE38(LMB-2)), CD37 targeted drugs (e.g., T RU-5016), radioimmunotherapy (e.g., 131-tositumomab), hydroxychloro Kin, perifosin, SRC inhibitors (e.g., dasatinib), thalidomide, PI3K Retinoid inhibitors (e.g., CAL-101), retinoids (e.g., fenretinide), MD M2 antagonist (e.g., R05045337), prelixaphor, aurorakiner ZE inhibitors (e.g., MLN8237, TAK-901), proteasome inhibitors (e.g., , bortezomib), CD-19 targeted drugs (e.g., MEDI-551, MOR208), M EK inhibitors (e.g., ABT-348), JAK-2 inhibitors (e.g., INCB0184) 24) Hypoxia-activated prodrugs (e.g., TH-302), paclitaxel or pa Clitaxel, HSP90 inhibitors, AKT inhibitors (e.g., MK2206), HMG- CoA inhibitors (e.g., simvastatin), GNKG186, radiotherapy, bone marrow transplantation, stem This includes, but is not limited to, cell transplantation and combinations thereof.

[0132] Acute lymphoblastic leukemia The compounds disclosed herein and condyloma for the treatment of acute lymphoblastic leukemia (ALL) Examples of drugs that may be administered at the joint include chemotherapeutic agents (e.g., prednisolone, dermatologic agents). Xamethasone, vincristine, asparaginase, daunorubicin, cyclophosphamide D, cytarabine, etoposide, thioguanine, mercaptopurine, clopharabine, lipo Somal anamycin, busulfan, etoposide, capecitabine, decitabine, azaci (Thidin, topotecan, temozolomide), tyrosine kinase inhibitors (e.g., BCR / AB) L inhibitors (e.g., imatinib, nilotinib), ON 01910.Na, multikinase C inhibitors (e.g., sorafenib), CD-20 targeted drugs (e.g., rituximab), C D52-targeted drugs (e.g., alemtuzumab), HSP90 inhibitors (e.g., STA-909) 0) mTOR inhibitors (e.g., everolimus, rapamycin), JAK-2 inhibitors (e.g.) For example, INCB018424), HER2 / neu receptor inhibitors (e.g., trastuzma) (B), proteasome inhibitors (e.g., bortezomib), methotrexate, asparagus Nase, CD-22 targeted drugs (e.g., epratuzumab, inotuzumab), immunotherapy (for example) For example, autologous cytokine-induced killer cells (CIK), AHN-12, blinatumomab, Icrin-dependent kinase inhibitors (e.g., UCN-01), CD45-targeted drugs (e.g., B C8), MDM2 antagonist (e.g., R05045337), immunotoxin (e.g., CAT-8015, DT2219ARL), HDAC inhibitors (e.g., JNJ-2648) 1585), JVRS-100, paclitaxel or paclitaxel agent, STAT3 inhibitor Harmful agents (e.g., OPB-31121), PARP inhibitors (e.g., veliparib), EZN -2285, bone marrow transplantation, stem cell transplantation, radiotherapy, and combinations thereof are listed. However, it is not limited to these.

[0133] Acute myeloid leukemia Compounds disclosed herein and conjugates for the treatment of acute myeloid leukemia (AML) Examples of drugs that may be administered in the intestinal tract include chemotherapeutic agents (e.g., cytarabine, daunol). Bicin, Idarubicin, Clopharabine, Decitabine, Bosaroxine, Azacitidine, C Lofarabine, ribavirin, CPX-351, treosulfan, elasitarabine, az Cytidine), tyrosine kinase inhibitors (e.g., BCR / ABL inhibitors (e.g., Imachi) Nib, nilotinib), ON 01910.Na, multikinase inhibitor (e.g., midos Taurine, SU11248, quizartinib, sorafinib), immunotoxins (e.g., gem Tuzumab ozogamicin), DT388IL3 fusion protein, HDAC inhibitors (e.g.) , vorinostat, LBH589), prelixafor, mTOR inhibitors (e.g., evero Limus), SRC inhibitors (e.g., dasatinib), HSP90 inhibitors (e.g., STA- 9090), retinoids (e.g., bexarotene), aurora kinase inhibitors (e.g., B I 811283), JAK-2 inhibitors (e.g., INCB018424), polois quinine -ase inhibitors (e.g., BI6727), senersen, CD45-targeted drugs (e.g., BC8) , cyclin-dependent kinase inhibitors (e.g., UCN-01), MDM2 antagonists (e.g., R05045337), mTOR inhibitors (e.g., everolimus), LY57 3636-sodium, ZRx-101, MLN4924, lenalidomide, immunotherapy (example) For example, AHN-12), histamine dihydrochloride, bone marrow transplant, stem cell transplant, radiation therapy, and These are some examples, but are not limited to, combinations thereof.

[0134] Multiple myeloma The compounds disclosed herein are administered conjointly with the treatment of multiple myeloma. Examples of possible drugs include chemotherapeutic agents (e.g., melphalan, amiphostine, cyclophosphate). Phosphamide, doxorubicin, clofarabine, bendamustine, fludarabine, adenocarcinoma Riamycin (SyB L-0501), thalidomide, lenalidomide, dexamethasone Prednisone, pomalidomide, proteasome inhibitors (e.g., bortezomib, calf) Irzomib, ixazomid), cancer vaccines (e.g., GVAX), CD-40 targeted drugs (e.g., For example, SGN-40, CHIR-12, Perifosin, Zoledronic acid, Immunotherapy (e.g., MAGE-A3, NY-ES0-1, HuMax-CD38), HDAC inhibition Agents (e.g., vorinostat, LBH589, AR-42), apridin, cycline derivatives Existential kinase inhibitors (e.g., PD-0332991, dinacyclib), arsenic trioxide, C B3304, HSP90 inhibitors (e.g., KW-2478), tyrosine kinase inhibitors ( For example, EGFR inhibitors (e.g., cetuximab), multi-kinase inhibitors (e.g., A T9283), VEGF inhibitors (e.g., bevacizumab), plerixafor, MEK inhibitors Harmful agents (e.g., AZD6244), IPH2101, atorvastatin, immunotoxins (e.g.) For example, BB-10901), NPI-0052, radioimmunotherapy agents (e.g., yttrium Y 90 ibritumomab tiuxetan), STAT3 inhibitors (e.g., OPB-31121) MLN4924, Aurora kinase inhibitors (e.g., ENMD-2076), IMGN 901, ACE-041, CK-2 inhibitors (e.g., CX-4945), bone marrow transplantation, stem cells This includes, but is not limited to, cyst transplantation, radiation therapy, and combinations thereof. .

[0135] prostate cancer The compounds disclosed herein may be administered conjointly with the treatment of prostate cancer. Examples of such drugs include chemotherapeutic agents (e.g., docetaxel, carboplatin, fludara). (Bin), abiraterone, hormone therapy (e.g., flutamide, bicalutamide, nilutamide) Cyproterone acetate, ketoconazole, aminoglutethimide, abalelix, degarelix (S, leuprolide, goserelin, triptorelin, buserelin), tyrosine kinase inhibitors Drugs (for example, dual kinase inhibitors (for example, lapatanib), multi-kinase inhibitors (for example) (e.g., sorafenib, sunitinib), VEGF inhibitors (e.g., bevacizumab), TAK -700, cancer vaccines (e.g., BPX-101, PEP223), lenalidomide, TO K-001, IGF-1 receptor inhibitors (e.g., cictumumab), TRC105, Aurora A kinase inhibitors (e.g., MLN8237), proteasome inhibitors (e.g., Vol. Tezomib, OGX-011, radioimmunotherapy (e.g., HuJ591-GS), HDAC Inhibitors (e.g., valproic acid, SB939, LBH589), hydroxychloroquine, m TOR inhibitors (e.g., everolimus), dovitinib lactate, diindolylmethane, ef Avirenz, OGX-427, Genistein, IMC-303, Bafetinib, CP-6 75,206, radiotherapy, surgery, or a combination thereof are listed, but this It is not limited to them.

[0136] Hodgkin lymphoma For use in conjoint with the compounds disclosed herein for the treatment of Hodgkin lymphoma. Examples of possible drugs include chemotherapeutic agents, such as doxorubicin (adriamycin). ), bleomycin (Blenoxane), vinblastine (Velban, Vels ar), dacarbazine, etoposide (Toposar, VePesid), cyclophosph Amid (Cytoxan, Neosar), Vincristine (Vincasar PFS) Oncovin, procarbazine (Matulane), prednisone, ifospha Mid (Ifex), Carboplatin (Paraplatin), Mechloretamine, Chloride Mubucil, methylprednisolone (Solu-Medrol), cytarabine (Cytos ar-U), cisplatin (Platinol), gemcitabine (Gemzar), vinol Navelbine, oxaliplatin, lomustine , Mitoxantrone, Carmustine, Melphalan, Bendamustine, Lenalidomide, Vinorelbine; alone or in combination; brentuximab vedotin (Ad Cetris-CD30 antibody drug conjugate; Iodine-131-CHT25 antibody conjugate Jugate; HDAC inhibitors (e.g., vorinostat); m-TOR inhibitors (e.g., Everolimus, temsirolimus); PI3K inhibitors (e.g., CAL-101, BAY8) 0-6946, TGR-1202, BKM-120, AMG-319);JAK / STA T pathway inhibitors; Bcl-2 inhibitors (e.g., venetoclax); Mcl-1 inhibitors; M Thikinase inhibitors, e.g., BAY43-9006 (sorafenib); proteasome inhibitors Harmful agents (e.g., bortezomib (Velcade), NPI-0052); dual PI3K / HDAC-targeted inhibitors (e.g., CUDC-907); NF-κB inhibitors; anti-PD-1 antibodies (For example, nivolumab, pembrolizumab), anti-CTLA-4 antibodies (for example, ipilimumab) Anti-CD-20 antibody (e.g., rituximab); anti-CD40 antibody; anti-CD80 antibody; and radiotherapy (e.g., tomotherapy, stereotactic radiotherapy, proton therapy), surgery, Examples include, but are not limited to, combinations thereof.

[0137] Non-Hodgkin lymphoma For use in conjoint with the compounds disclosed herein for the treatment of Hodgkin lymphoma. Examples of possible drugs include chemotherapeutic agents, such as doxorubicin (adriamycin). ), bleomycin (Blenoxane), vinblastine (Velban, Vels ar), dacarbazine, etoposide (Toposar, VePesid), cyclophosph Amid (Cytoxan, Neosar), Vincristine (Vincasar PFS) Oncovin, procarbazine (Matulane), prednisone, ifospha Mid (Ifex), carboplatin (paraplatin), mechloretamine, chlorambucil , methylprednisolone (Solu-Medrol), cytarabine (Cytosar-U ), cisplatin (Platinol), gemcitabine (Gemzar), vinorelbine (Navelbine), oxaliplatin (Eloxatin), lomustine, mitox Santrone, methotrexate, carmustine, melphalan, bendamustine, lenali Domide and vinorelbine; either alone or in combination; tyrosine kinase inhibitors Drugs (e.g., EGFR inhibitors (e.g., erlotinib, panitumumab, cetuximab, ni) Motuzumab; HDAC inhibitors (e.g., vorinostat); IRAK-4 inhibitors; HS P90 inhibitors (e.g., tanespimycin, STA-9090, CUDC-305); m -TOR inhibitors (e.g., everolimus, temsirolimus); PI3K inhibitors (e.g., CAL-101, BAY80-6946, TGR-1202, BKM-120, AMG- 319); JAK / STAT pathway inhibitors; AKT inhibitors (e.g., RX-0201); B Cl-2 inhibitors (e.g., venetoclax); Mcl-1 inhibitors; multikinase inhibitors For example, BAY43-9006 (sorafenib); proteasome inhibitors (for example, bolus) Lutezomib (Velcade, NPI-0052); dual PI3K / HDAC target inhibition Agents (e.g., CUDC-907); NF-κB inhibitors; BTK inhibitors (e.g., Ibulch) Nib; BET bromodomain inhibitors; anti-PD-1 antibodies (e.g., nivolumab, pembrolase); Rizumab); anti-CTLA-4 antibody (e.g., ipilimumab); anti-CD-20 antibody (e.g., , rituximab); anti-CD40 antibodies; anti-CD80 antibodies; and radiotherapy (e.g., tomo Treatment options include therapy, stereotactic radiotherapy, proton therapy, surgery, and combinations thereof. These are possible, but are not limited to these.

[0138] In certain embodiments, the compound of formula (I) of the present disclosure is used in non-chemical cancer treatment methods and It may be administered jointly. In further embodiments, compounds of formula (I) of the present disclosure It may be administered conjointly with radiotherapy. In further embodiments, The compound of formula (I) shown is used in surgical procedures, thermal excision, focused ultrasound therapy, cryotherapy, or similar treatments. They may be administered conjointly with any combination of the following:

[0139] In certain embodiments, different compounds of the Disclosure may be one or more other compounds of the Disclosure. It may be administered as a combination or conjoint. Furthermore, such combinations are effective against cancer and immunology. Other agents suitable for treating medical or neurological disorders, such as previously identified drugs. It may be administered conjointly with other therapeutic agents. In certain embodiments, one or The administration of multiple additional chemotherapeutic agents conjointly with the compound of formula (I) of this disclosure is , resulting in a synergistic effect. In certain embodiments, one or more additional chemotherapeutic agents are used. Administering in a conjoint manner produces an additive effect.

[0140] Pharmaceutical composition In certain embodiments, the Disclosure may optionally provide a pharmaceutically acceptable carrier or diluent. The present invention provides a pharmaceutical composition comprising a compound of formula (I) disclosed herein, which is miscible with [another compound].

[0141] This disclosure also relates to a method for formulating a compound of the disclosed formula (I) for pharmaceutical administration. provide.

[0142] The compositions and methods of this disclosure may be used to treat individuals that require them. In certain embodiments, the individual is a mammal, such as a human or a non-human mammal. When administered to animals such as humans, the composition or compound is preferably, for example, the formula of this disclosure. (I) is administered as a pharmaceutical composition containing the compound and a pharmaceutically acceptable carrier. Pharmacologically acceptable carriers are well known in the art, for example, water or physiological Aqueous solutions such as buffered saline solution, or glycol, glycerol, olive Contains oils or other solvents or vehicles such as oils or injectable organic esters. In a particular embodiment, such a pharmaceutical composition is for administration to humans, especially invasive administration. For routes (i.e., routes such as injection or transplantation that avoid transport or diffusion through the epithelial barrier) If so, the aqueous solution is pyrogen-free or substantially pyrogen-free. It is. Excipients are used, for example, to perform delayed release of the drug, or one or Pharmaceutical compositions may be selected to selectively target multiple cells, tissues, or organs. This includes tablets, capsules (including sprinkle capsules and gelatin capsules), granules, and refills. It can be in the form of a lyophilized product, powder, solution, syrup, suppository, or injection. The composition may also be present in transdermal delivery systems, such as skin patches. It may be present in solutions suitable for topical administration, such as eye drops.

[0143] A pharmaceutically acceptable carrier stabilizes a compound, such as the compound of formula (I) of this disclosure. To do so, it acts to increase the solubility of the compound or to increase its absorption. It may contain physiologically acceptable drugs. For example, carbohydrates such as glucose, sucrose, or dextran, ascorbic acid, etc. Antioxidants such as vinic acid or glutathione, chelating agents, low molecular weight proteins, or Other stabilizers or excipients may be used. This includes physiologically acceptable drugs, including pharmaceutically acceptable drugs. The choice of suitable carrier depends, for example, on the route of administration of the composition. The preparation of the pharmaceutical composition is It may be a self-emulsifying drug delivery system or a self-microemulsifying drug delivery system. Pharmaceutical composition (preparation) The substance may also be a liposome or other polymer matrix, which is, for example, a book. It incorporates the compound of formula (I) disclosed. For example, lipo, which includes phospholipids or other lipids. Somes are relatively easy to produce and administer, non-toxic, physiologically acceptable, and alternative. It is a carrier that can be transmitted.

[0144] The phrase "medically acceptable" means suitable for use in contact with human and animal tissues, and without excessive use. It does not cause toxicity, irritation, allergic reactions or other problems or complications, and provides reasonable benefits / Those compounds, materials, compositions, and / as used herein to refer to a dosage form.

[0145] As used herein, the term "medically acceptable carrier" refers to a liquid or solid filler. Medicinally acceptable materials and compositions such as diluents, excipients, solvents, or encapsulating materials. "T" means vehicle. Each carrier is compatible with the other components of the formulation and is not harmful to the patient. In that sense, it must be "acceptable." Some examples of materials include (1) sugars such as lactose, glucose and sucrose; 2) Starches such as cornstarch and potato starch; (3) Carboxymethyl Cellulose sodium, ethylcellulose and cellulose acetate, and other celluloses (4) its derivatives; (5) powdered tragacanth; (6) malt; (7) gelatin; (8) talc; ( 8) Excipients such as cocoa butter and suppository wax; (9) Peanut oil, cottonseed oil, safflower oil Oils such as sesame oil, olive oil, corn oil and soybean oil; (10) Propylene Glycol Glycols such as (11) Glycerin, sorbitol, mannitol and polyethylene Polyols such as ethylene glycol; (12) Ethyl oleate and ethyl laurate (13) Esters such as (14) Agar; (15) Magnesium hydroxide and aluminum hydroxide (15) Buffering agents such as (16) alginate; (17) pyrogen-free water; (18) isotonic physiological (18) Saline solution; (19) Ringer's solution; (20) Ethyl alcohol; (20) Phosphate buffer; (21) Other non-toxic, suitable substances used in pharmaceutical preparations are also included.

[0146] The pharmaceutical composition (preparation) can be administered via any number of routes, for example, orally (for example, Aqueous or non-aqueous solution or suspension of oral medication, tablets, capsules (sprinkle capsules) (Including capsules and gelatin capsules), bolus, powder, granules, for application to the tongue Paste); absorption through the oral mucosa (e.g., sublingual); anal, rectal or vaginal (e.g., , as a pessary, cream or foam); parenteral (intramuscular, intravenous, subcutaneous or Intrathecal cavity, for example, as a sterile solution or suspension; intranasal cavity; intraperitoneal cavity; subcutaneous; percutaneous ( For example, as a patch applied to the skin; and as a topical application (for example, applied to the skin) Administered to the subject as a cream, ointment, or spray, or as eye drops. To obtain. The compound can also be formulated for inhalation. In certain embodiments, the compound is simply It may be dissolved or suspended in sterile water. Details of appropriate administration routes and suitable compositions. For example, U.S. Patent No. 6,110,973, No. 5,763,493, and No. 5,7 No. 31,000, No. 5,541,231, No. 5,427,798, No. 5,35 Findings in Patent Nos. 8,970 and 4,172,896, and the patents cited herein It is possible.

[0147] The preparation may be provided in a simple unit-dose form, and by any method well known in the field of pharmaceutical dispensing. Therefore, it may be prepared. It can be combined with a carrier material to produce a single-dose dosage form. The amount of the active ingredient will vary depending on the treated host and the specific administration method. (Single dose) The amount of active ingredient that can be combined with a carrier material to form a shape generally has a therapeutic effect. This is likely the amount of the compound. Generally, this amount is about 1 / 1 of the active ingredient. 100% to about 99%, preferably about 5% to about 70%, most preferred The percentage is probably in the range of approximately 10 percent to 30 percent.

[0148] Methods for preparing these formulations or compositions involve the activation of compounds such as those of formula (I) of the present disclosure. The process includes the step of associating the compound with a carrier and, optionally, one or more auxiliary components. Generally, formulations involve the compound of this disclosure in a liquid carrier, a finely powdered solid carrier, or both. Prepared by homogeneously and closely assembling the materials, and then shaping the product as needed. ru.

[0149] The formulations of this disclosure suitable for oral administration include capsules (sprinkle capsules and gelatin capsules). (including capsules), cachets, pills, tablets, lozenges (flavored base, usually sucrose) (Using sugar and gum arabic or tragacanth), in the form of freeze-dried products, powders, or granules. However, it can also be used as a solution or suspension in an aqueous or non-aqueous liquid, or as an oil-in-water type. Alternatively, as a water-in-oil liquid emulsion, or as an elixir or syrup. , or as a lozenge (with an inert base, e.g., gelatin and glycerin, or sucrose). (using rose gum and gum arabic), and / or existing as mouthwash, etc., each The composition or chemical may contain a predetermined amount of the compound of this disclosure as an active ingredient. The compound may also be administered as a bolus, lick, or paste.

[0150] Solid dosage forms for oral administration (capsules (sprinkle capsules and gelatin capsules)) To prepare tablets, pills, sugar-coated tablets, powders, granules, etc. (including), the active ingredient is one type Alternatively, multiple pharmaceutically acceptable carriers, such as sodium citrate or nical phosphate. Cium, and / or mixed with any of the following: (1) starch, lactose, sodium Fillers or bulking agents such as claustrophobic acid, glucose, mannitol, and / or silicate. (2) For example, carboxymethylcellulose, alginate, gelatin, polyvinyl acetate (3) Binders such as roridone, sucrose and / or gum arabic; (4) Glycerol Which moisturizer; (4) Agar, calcium carbonate, potato starch or tapioca starch (5) Disintegrants such as alginic acid, certain silicates, and sodium carbonate; (6) paraffin (6) Dissolution retarders such as quaternary ammonium compounds; (7) For example, (8) Kaolin (9) Absorbents such as bentonite clay; (9) Talc, calcium stearate, stear Magnesium phosphate, solid polyethylene glycol, sodium lauryl sulfate, and Lubricants such as mixtures thereof; (10) Complexing agents such as modified and unmodified cyclodextrins ; and (11) colorants. Capsules (sprinkle capsules and gelatin capsules) In the case of tablets and pills, the pharmaceutical composition may also contain a buffering agent. The solid composition of the product contains an excipient such as lactose or milk sugar, and high molecular weight polyethylene. It may also be used as a filler in soft and hard gelatin capsules using glycols, etc. stomach.

[0151] Tablets are formed by compression or molding, sometimes with one or more auxiliary ingredients. Compressed tablets can be manufactured. The compressed tablets contain a binder (e.g., gelatin or hydroxypropylmethyl Cellulose), lubricants, inert diluents, preservatives, disintegrants (e.g., starch glycolic acid) Sodium or cross-linked sodium carboxymethylcellulose, surfactant or dispersion It may be prepared using a diluent. The molded tablets are made from a powder compound humidified with an inert liquid diluent. The mixture may be produced by molding it with a suitable machine.

[0152] Tablets, as well as sugar-coated tablets and capsules (including sprinkle capsules and gelatin capsules). Other solid dosage forms of pharmaceutical compositions, such as pills and granules, may have notches added. or enteric coatings and other coatings known in the field of pharmaceutical technology, etc. They may be prepared using coatings and shells. They can also, for example, emit the desired material. Hydroxypropyl methylcellulose in various proportions to provide a profile, etc. Using a polymer matrix, liposomes and / or microspheres, They may be formulated to provide sustained or controlled release of the active ingredient. For example, By filtration through a bacterial-retaining filter, or by sterilizing water or some other method immediately before use. By incorporating a sterilizer in the form of a sterile solid composition that can be dissolved in a sterile injectable medium, They may be sterilized. These compositions may also optionally contain an opaque agent, and they However, in some cases, the active ingredient(s) may be delayed in a manner that causes a delay in the absorption of the active ingredient(s) in a specific part of the digestive tract. It may be a composition that preferentially releases one or more active ingredients. Examples of embedding compositions include polymer substances and waxes. The active ingredient is also The microencapsulated form may contain, if appropriate, one or more of the above excipients.

[0153] Liquid dosage forms useful for oral administration include pharmaceutically acceptable emulsions and reconstituted emulsions. Examples include freeze-dried products, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active ingredient, the liquid dosage form may contain, for example, water or other solvents, cyclodextrin. Inert diluents commonly used in the art, such as trine and its derivatives, Solubilizers, and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate L, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1, 3-Butylene glycol, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, Castor oil and sesame oil), glycerol, tetrahydrofuryl alcohol, polyethylene Even if it contains glycol and sorbitan fatty acid esters, or mixtures thereof good.

[0154] In addition to inert diluents, oral compositions also contain adjuvants, such as wetting agents, emulsifiers, and It may also contain suspending agents, sweeteners, flavoring agents, coloring agents, fragrances, and preservatives.

[0155] The suspension, in addition to the active compound, includes, for example, ethoxylated isostearyl alcohol, poly Oxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum Mumetha hydroxide, bentonite, agar, and tragacanth, as well as mixtures thereof. It may contain a suspending agent as such.

[0156] Pharmaceutical compositions for rectal, vaginal, or urethral administration are provided as suppositories. Typically, suppositories contain one or more active compounds and one or more appropriate non-irritating excipients. Agents, or for example, cocoa butter, polyethylene glycol, suppository wax or saline It can be prepared by mixing with a carrier containing cylate, and is solid at room temperature, but not at body temperature. It is a liquid, and therefore melts in the rectum or vaginal cavity, releasing active compounds.

[0157] Formulations of pharmaceutical compositions for oral administration include mouthwashes, oral sprays, or oral softeners. It may be provided as an ointment.

[0158] Alternatively or in addition, the composition may be a catheter, stent, wire, or other It can be formulated for delivery via an intraluminal device. Delivery by such a device is to the bladder It may be particularly useful for delivery to the urethra, ureters, rectum, or intestines.

[0159] Suitable formulations for intravaginal administration include carriers known to be appropriate in the art. Pessaries, tampons, creams, gels, pastes, foams, or sprays containing these ingredients. Pharmaceutical formulations are another example.

[0160] Dosage forms for topical or transdermal administration include powder, spray, ointment, paste, and Examples include creams, lotions, gels, solutions, patches, and inhalants. The active compound is used to eliminate Even when mixed with a pharmaceutically acceptable carrier under microbial conditions, and with any necessary preservatives It may be mixed with a buffer or propellant.

[0161] Ointments, pastes, creams, and gels contain active compounds as well as excipients, such as animal-derived excipients. and vegetable fats, oils, waxes, paraffin, starch, tragacanth, cellulose S derivatives, polyethylene glycol, silicone, bentonite, silicic acid, talc and It may contain zinc oxide or a mixture thereof.

[0162] The powder and spray contain excipients in addition to the active compound, such as lactose, talc, and ke. Aluminum acid, aluminum hydroxide, calcium silicate, and polyamide powder, or these materials It may contain a mixture of substances of varying quality. The spray may also contain, for example, chlorofluorohydrocarbons. It may contain conventional propellants, as well as volatile unsubstituted hydrocarbons such as butane and propane. .

[0163] Transdermal patches have the additional advantage of providing controlled delivery of the compounds of this disclosure to the body. Such dosage forms are obtained by dissolving or dispersing the active compound in a suitable medium. Absorption enhancers can also be used to increase the flow of compounds across the skin. Such flow rates can provide a rate-controlled membrane or polymerize the compound. It can be controlled by dispersing it in a trix or gel.

[0164] Ophthalmic preparations, eye ointments, powders, liquids, etc., are also intended to fall within the scope of this disclosure. An exemplary ophthalmic formulation is described in U.S. Patent Application Publication No. 2005 / 0080056, and the same publication No. 2005 Issues / 0059744, 2005 / 0031697, and 2005 / 00407 This is described in U.S. Patent No. 4 and U.S. Patent No. 6,583,124, and the contents of these patents as a whole are referenced. This is incorporated herein by reference. If desired, the liquid ophthalmic preparation may be tear fluid, aqueous humor or It has properties similar to or is compatible with vitreous fluid. Preferred dosage. The route of administration is local administration (e.g., topical administration such as eye drops, or administration via implant). )

[0165] Suppositories are also intended to be within the scope of this disclosure.

[0166] As used herein, the terms “parenteral administration” and “administered parenterally” are usually This refers to administration methods other than enteral and topical administration by injection, including intravenous, intramuscular, intra-arterial, and spinal injections. Intracavitary, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcutaneous, intraarticular, subcapsular, This includes, but is not limited to, subarachnoid, intraspinal, and intrasternal injections and fluid resuscitation.

[0167] Pharmaceutical compositions suitable for parenteral administration include one or more pharmaceutically acceptable sterile isotonic waters. Solution or non-aqueous solution, dispersion, suspension or emulsion, or sterile injection immediately before use. One or more active ingredients can be combined with sterile powder that can be reconstituted into an injectable solution or dispersion. It contains compounds that act as antioxidants, buffers, and bacteriostatic agents, and are intended for use in the blood of recipients. It may contain a solute, suspension, or thickener to make it isotonic.

[0168] Examples of suitable aqueous and non-aqueous carriers that may be used in the pharmaceutical compositions of this disclosure include water, Ethanol, polyol (glycerol, propylene glycol, polyethylene glycol) (such as oleic acid), and suitable mixtures thereof, vegetable oils such as olive oil, and oleic acid Examples of injectable organic esters include ethyl esters. Suitable fluidity is, for example, lecithin. By using coating materials such as these, and in the case of dispersions, the required particle size can be maintained, It can be maintained by using surfactants.

[0169] These compositions also contain adjuvants such as preservatives, humectants, emulsifiers, and dispersants. May contain. Prevention of microbial action can be achieved with various antimicrobial and antifungal agents, such as parabens, c This can be ensured by including lolobutanol, phenolsorbic acid, etc. It may also be desirable to include isotonic agents such as sodium chloride in the composition. In addition, The formula should include absorption-delaying agents such as aluminum monostearate and gelatin. This may result in long-term absorption of the injectable pharmaceutical form.

[0170] In some cases, to prolong the effects of the drug, the drug may be absorbed from subcutaneous or intramuscular injection. It is desirable to allow the absorption process to be gradual. This is because it is a suspension of crystalline or amorphous material with poor water solubility. This may be achieved by using [a specific method]. In that case, the absorption rate of the drug is equal to its dissolution rate. The dissolution rate, in turn, may depend on the crystal size and morphology. Alternatively, the dissolution rate may depend on the crystal size and morphology. Delayed absorption of orally administered drug forms is due to the need to dissolve or suspend the drug in an oily vehicle. This is achieved by [method].

[0171] The injectable depot form contains biodegradable polymers such as polylactide-polyglycolide. It is produced by forming a microencapsulation matrix of the target compound. The drug release rate depends on the ratio of the polymer to the drug and the properties of the individual polymers used. This can be controlled. Other examples of biodegradable polymers include poly(orthoester) and poly(poly(orthoester)). Examples include liposomal anhydrides. Depot injection formulations also include liposomal anhydrides that are compatible with body tissues. It is prepared by encapsulating the drug in a foam or microemulsion.

[0172] For use in the methods disclosed herein, the active compound may be used as itself or, for example, Combined with a pharmaceutically acceptable carrier, 0.1-99.5% (more preferably 0.5-9%) It may be given as a pharmaceutical composition containing 0% of the active ingredient.

[0173] The installation method may also be provided by a refillable or biodegradable device. Various sustained-release polymer devices, including proteinaceous biopharmaceuticals, are used for controlled drug delivery. These have been developed in recent years and tested in vivo. Biodegradable polymers and non-degradable polymers. Using various biocompatible polymers (including hydrogels) that include both, individual targets An implant can be formed at the site to continuously release the compound.

[0174] The actual dose level of the active ingredient in a pharmaceutical composition varies depending on the individual patient, composition, and dosage. The amount of active ingredient that is effective in achieving the desired therapeutic response to the formula and is not toxic to the patient. It may be modified to obtain.

[0175] The selected dosage level depends on the individual compound or combination of compounds used, The activity of the ester, salt, or amide, the route of administration, the time of administration, and the individual used The excretion rate of the compound(s), the treatment period, and the individual compound(s) used in combination with the compound(s) used. Other drugs, compounds, and / or materials used in combination, age of the patient being treated , gender, weight, condition, general health status and past medical history, as well as information known in the medical technology field. It will depend on various factors, including similar factors.

[0176] A physician or veterinarian skilled in the art can immediately determine the therapeutically effective amount of the required pharmaceutical composition. and may be prescribed. For example, a physician or veterinarian may prescribe the necessary to achieve the desired therapeutic effect. Administration of the pharmaceutical composition or compound is initiated at a level lower than the desired level, and the desired effect is achieved. The dosage can be gradually increased until the desired therapeutic effect is achieved. This refers to the concentration of the compound sufficient to produce the desired effect. The effective amount of the compound depends on the subject's weight, sex, and other factors. It is generally understood that the effective dose will vary depending on age and medical history. Other factors include the severity of the patient's condition, the disorder being treated, the stability of the compound, and the desired outcome. Then we can give an example of another type of therapeutic agent administered together with the compound of formula (I) of this disclosure. However, it is not limited to these. Larger total doses may be delivered by repeated administration of the drug. Methods for determining efficacy and dosage are known to those skilled in the art (see reference herein). It is incorporated, Isselbacher et al. (1996) Harrison' s Principles of Internal Medicine 13ed.,18 (14-1882).

[0177] Generally, a suitable daily dose of the active compound used in the compositions and methods of this disclosure is: This would be the minimum effective dose of the compound required to produce a therapeutic effect. This will generally depend on the factors mentioned above.

[0178] If desired, the effective daily dose of the active compound may be appropriate throughout the day, depending on the unit dosage form. Administered separately at intervals as 1, 2, 3, 4, 5, 6 or more divided doses. It may be administered. In certain embodiments of this disclosure, the active compound is administered two or three times a day. It may be administered. In a preferred embodiment, the active compound will be administered once daily.

[0179] Patients undergoing this procedure include primates, especially humans, and other mammals, such as horses. Cattle, pigs, and sheep; as well as any necessary poultry and pets in general. It is an animal.

[0180] Wetting agents, emulsifiers, and lubricants, such as sodium lauryl sulfate and magnesium stearate. In addition to nesium, it contains colorants, release agents, coating agents, sweeteners, flavoring agents and fragrances, and preservatives. Agents and antioxidants may also be present in the composition.

[0181] Examples of pharmaceutically acceptable antioxidants include (1) water-soluble antioxidants, such as ascorbyl. Vitic acid, cysteine ​​hydrochloride, sodium bicarbonate, sodium metabisulfite, sodium sulfite (2) Lipid-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyl Anisole (BHA), butylated hydroxytoluene (BHT), lecithin, gallate Ropil, alpha-tocopherol, etc.; and (3) metal chelating agents, e.g., citric acid Examples include ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, and phosphoric acid. ru.

[0182] Definitions and abbreviations Unless otherwise defined, all technical and scientific terms used herein are as defined herein. The subject matter of the detailed document has the same meaning as it would be generally understood by those skilled in the art in the field of the art, and The meaning of such terms is independent in each instance. Nevertheless, unless otherwise stated... Unless otherwise specified, the following definitions apply throughout this specification and the claims: Chemistry The name, common name, and chemical structure can be used interchangeably to describe the same structure. Compounds are referred to using both their chemical structure and chemical name, and there is ambiguity between structure and name. If a difference exists, the structure takes precedence. Unless otherwise specified, the term is used alone. These definitions apply whether used in combination with other terms. Thus, the definition of "alkyl" includes, in addition to "alkyl," "hydroalkyl," and "halo This applies to the "alkyl" part of "alkyl" and "--O-alkyl".

[0183] The term "compound(s) of the present invention" refers to formula (I) or, unless otherwise specifically indicated, This refers to compounds of formula (IA) or formula (IB), or their pharmaceutically acceptable salts and stereochemicals. Includes isomers.

[0184] As used herein, the terms “any” or “if applicable” refer to the events described below. Or the fact that a situation may or may not occur, and that the description thereof, Or it means including both the cases in which the situation occurs and the cases in which it does not occur. For example, "in the case" "More substituted alkyl" refers to the event or situation in which an alkyl is substituted, and the alkyl is substituted This refers to events or situations that do not occur.

[0185] Unless otherwise specified, the term “substituted” means one or more substituents on the skeleton. This refers to a part that has a substituent that replaces a hydrogen atom on a carbon atom. "Substitution" or "~substituted" "However, such substitutions follow the allowed valence of the substituted atom, and the substitution is an example For example, it yields stable compounds that do not undergo transformations such as rearrangement, cyclization, or removal. It will be understood that this includes the implicit condition. The term "replaced" as used in this specification " is intended to include all permissible substitutions of organic compounds in a broad manner. These permitted substitutions include acyclic and cyclic, branched and unbranched, and carbocyclic substitutions of organic compounds. Formulas and heterocyclic compounds, including aromatic and non-aromatic substituents. Allowed substituents are one or There may be multiple, and they may be the same or different for a suitable organic compound. For the purposes of the present invention This is when a heteroatom such as nitrogen satisfies the hydrogen substituent and / or the valence of the heteroatom. The organic compounds described herein may have any permitted substituents. any substituent as described herein, for example halogens, hydroxyls, carbonyls ( Luboxyl, etc., alkoxyl, oxo, amino, amide, amidine, nitro, azide, It may include heteroaryl, aralkyl, or aromatic or heteroaromatic moieties. If the substituent is not substituted, it will be understood by those skilled in the art that the substituent itself can be substituted.

[0186] As used herein, the term "alkyl" is used non-limitingly to C1-C1 10 Linear alkyl groups Or C3~C 10 This refers to saturated aliphatic groups, including branched alkyl groups. Preferably, "alkyl The "alkyl" group refers to a C1-C6 linear alkyl group or a C3-C6 branched alkyl group. The "alkyl" group is either a C1-C4 linear alkyl group or a C3-C8 branched alkyl group. It refers to a group. Examples of "alkyl" groups include methyl, ethyl, 1-propyl, and 2-propyl. n-butyl, sec-butyl, tert-butyl, 1-pentyl, 2-pentyl, 3- Pentyl, neo-pentyl, 1-hexyl, 2-hexyl, 3-hexyl, 1-heptyl Lu, 2-heptyl, 3-heptyl, 4-heptyl, 1-octyl, 2-octyl, 3-o Examples include, but are not limited to, ctyl and 4-octyl. The "alkyl" group is It may be replaced in some cases.

[0187] As used herein, the term "aryl" refers to a ring in which each atom is carbon, and is substituted or non-substituted. It contains a replacement monocyclic aromatic group. Preferably, the ring is a 5- to 7-membered ring, more preferably a 6-membered ring. In particular, the term "aryl" includes phenyl.

[0188] The expression "(p-OH)aryl" used herein refers to the aryl group, which was defined first. As the name suggests, it refers to an aryl group that is para-substituted with a hydroxyl (-OH) group.

[0189] The term "heteroaryl" refers to the substitution or non-substitution of a 5- to 7-membered ring, more preferably a 5- to 6-membered ring. It contains a substituted aromatic monocyclic structure, and the ring structure contains at least one heteroatom, preferably 1 to 4. The term "heteroatoms" is particularly used to describe heteroatoms comprising 1 or 2 heteroatoms. "Liel" includes imidazole. Heteroaryl groups, if permitted in valence, Even if one or more positions are substituted with any substituent described herein good.

[0190] As used herein, the term "aralkyl" refers to one or more heteroatoms. By replacing it, it can include aryl groups substituted with alkyl radicals (multiple radicals are possible). .

[0191] The term "aryloxy" as used herein refers to the aryl group as previously defined. It refers to a certain -O-aryl group.

[0192] As used herein, the term "heteroarylalkyl" is derived from "alkyl" and "heteroarylalkyl". As previously defined, the "roaryl" group is an alkyl group attached to a heteroaryl group. To point.

[0193] The therapeutic agents used herein to “prevent” a disorder or disease are, in a statistical sample, A compound that reduces the occurrence of damage or disease in the treated sample compared to the untreated control sample. Compared to an object or an untreated control sample, it delays the onset of one or more disorders or diseases. This refers to compounds that prolong symptoms or reduce their severity.

[0194] The term "to treat" includes defensive and / or therapeutic treatments. A “treatment” is recognized in the art and is one or more of the composition in question. This includes administration to the host. It is used to treat unwanted diseases (e.g., diseases of the host animal or other unwanted conditions). If administered before the clinical manifestation of (a condition that does not occur), the treatment is defensive (i.e., it is, (It protects the host from the onset of unwanted diseases), and is administered after the onset of unwanted diseases. If so, the treatment is therapeutic (i.e., it is an existing unwanted illness or its side effect). (Intended to mitigate, improve, or stabilize)

[0195] The term "prodrug" refers to the therapeutic activator of the present invention (for example, formula (I)) under physiological conditions. It shall include compounds that are converted to (compounds of) a prodrug. A typical method involves one or more molecules that are hydrolyzed under physiological conditions to expose the desired molecule. The selected portion is included. In other embodiments, the prodrug is a host animal It is converted by the enzymatic activity of the following: for example, esters or carbonates (e.g., alcohols). A preferred prodrug of the present invention is an ester or carbonate of a carboxylic acid. Yes. In certain embodiments, some of the compounds of formula (I) in the formulations described above or All of them can be replaced with the appropriate prodrug, for example, in that case, the parent compounds The hydroxyl in the substance is provided as an ester, or is present in the parent compound. Bonate or carboxylic acid is provided as an ester.

[0196] As used herein, the terms “including” or “including” generally mean “to encompass,” i.e., 1 It is used to mean that the presence of one or more additional (unspecified) features or components is permitted. .

[0197] In addition to the term "to include" as used herein, the term "include" is also used. Other forms such as "includes" and "included" are limited and do not have.

[0198] Throughout this specification and the claims, the "L-" referred to structurally in the compounds of the present invention is used. A threonine residue and / or a preparation thereof can be represented by any one of the following formulas. This expression may also be interpreted as referring to other compounds having similar structural motifs. [ka]

[0199] The present invention relates to pharmaceutically acceptable salts of the compounds of the present invention, as well as compositions and methods of the present invention. This includes their use in law. In certain embodiments, the salts of the present invention and Examples include alkyl, dialkyl, trialkyl, or tetraalkylammonium salts. However, it is not limited to these. In certain embodiments, the salt of the present invention intended to be used For example, L-arginine, benenthamine, benzathine, Tine, calcium hydroxide, choline, denol, diethanolamine, diethylamine , 2-(diethylamino)ethanol, ethanolamine, ethylenediamine, N-methyl Luglucamine, hydravamin, 1H-imidazole, lithium, L-lysine, magnesium Mu, 4-(2-hydroxyethyl)morpholine, piperazine, potassium, 1-(2-Hyd Roxyethyl pyrrolidine, sodium, triethanolamine, tromethamine and sodium triethanolamine. Examples include, but are not limited to, lead salts. In certain embodiments, the intended product Examples of salts of the invention include salts of Na, Ca, K, Mg, Zn, or other metals. These are not the only options.

[0200] Medicinally acceptable acid addition salts are also those that can be added with water, methanol, ethanol, and dimethylformaldehyde. It can exist as various solvates with mids, etc. Mixtures of such solvates can also be prepared It can be prepared. The source of such solvates is a solvent for crystallization, preparation or crystallization It could be something that is naturally present as a solvent, or something that is external to such a solvent.

[0201] The term "stereoisomer" refers to any enantiomer or diastereoisomer of the compound of the present invention. Or it refers to geometric isomers. If the compounds of the present invention are chiral, they are racemic. Alternatively, it may exist in an optically active form. Pharmaceuticals of the compound according to the present invention: racemic mixture or stereoisomer Since the activity can vary, it is desirable to use a compound that is rich in one of its enantiomers. wax. In these cases, the target product or even intermediate is chemically or as known to those skilled in the art. It can be separated by physical procedures or used in synthesis as such. In the case of semi-amines, the diastereomer is formed from the mixture by reaction with an optically active resolving agent. This is done. Examples of suitable dividing agents include tartaric acid, diacetyl tartaric acid, dibenzoyl tartaric acid, and man. Delic acid, malic acid, lactic acid, appropriate N-protective amino acids (e.g., N-benzoylproline) (or N-benzenesulfonylproline) or various optically active camphor sulfonic acids And optically active acids such as S-forms. Another advantage is optically active resolving agents (for example, Dinitrobenzoylphenylglycine and cellulose triacetate, fixed on silica gel. Alternatively, with the aid of other carbohydrate derivatives or chiral derivatized methacrylate polymers This is enantiomer resolution in chromatography.

[0202] In certain embodiments, the compounds of the present invention may be in racemic form. In this state, the compound of the present invention may be rich in one enantiomer. For example, the present invention The compounds are 30% ee, 40% ee, 50% ee, 60% ee, 70% ee, and 80% ee. Even if you have more than 90% ee or even more than 95% ee, Good. In certain embodiments, the compounds of the present invention have more than one stereocenter. In certain such embodiments, the compounds of the present invention may be one or more. The compound may be rich in diastereomers. For example, the compound of the present invention is rich in 30% de and 40% d e, 50%de, 60%de, 70%de, 80%de, 90%de, or 95%de It may have a de that exceeds or is greater than .

[0203] The term "subject" refers to mammals (especially humans) and other animals, such as domesticated animals (e.g., neutrons). This includes domestic pets (such as dogs and other domestic animals) and non-domesticated animals (such as wild animals).

[0204] The abbreviations used throughout this specification, along with their individual meanings, can be summarized below.

[0205] °C (degrees Celsius); % (percentage); brine (NaCl solution); BOC (tert- Butyloxycarbonyl; DIC: N,N'-diisopropylcarbodiimide; DIP EA (N,N-diisopropylethylamine); DMF (dimethylformamide); Et OH (ethanol); alkyl acetate; Fmoc (9-fluorenylmethyl ethanol) Xycarbonyl); g or gr (grams); HOBt (1-hydroxybenzotrizo hr (hours); h or hr (hours); HPLC (high-performance liquid chromatography); LCMS ( Liquid chromatography / mass spectrometry); mmol (millimole); M (molar); μl (ma) chloroliter (milliliter) (mL) (milligram) (mg) (min) (minute) (NaH) CO3 (sodium bicarbonate); NMM (N-methylmorpholine); Na2SO4 (sodium sulfate) Thorium); NH2OH.HCl (hydroxylamine hydrochloride); prep-HPLC / Preparative HPLC (Preparative High-Performance Liquid Chromatography); TEA / Et3N (Triethylamine) n); TLC (thin-layer chromatography); THF (tetrahydrofuran); TIPS ( Triisopropylsilane; t R (Holding time, etc.)

[0206] experiment Analytical HPLC method: Method 1: Hilic method Column: ZIC-HILLIC (Sequant), C18 (4.6×250mm, 5μ m)200Å Flow rate: 1.0 mL / min; Column temperature: 25.0°C Mobile phase: A = 5 mM ammonium acetate, pH 4.0 (acetic acid), B = ACN Gradient (time / %B): 0 / 85, 2 / 85, 20 / 40, 20.1 / 85, 30 / 85. Method 2: DiBoc method Column: Phenomenex Aeris peptide C18(2) 100A (250×4 (0.6mm, 3.6μ) Flow rate: 1.0 mL / min; Column temperature: 25°C Mobile phase: A=0.1%TFA(Aq), B=ACN Gradient (time / %B): 0 / 2, 2 / 2, 15 / 70, 20 / 95, 25 / 100, 30 / 100, 32 / 2, 42 / 2

[0207] Preparative HPLC method: Preparative HPLC was performed using a SeQuant ZIC HILIC 200Å column (10mm x 2 The procedure was performed at a 50 mm, 5 μm diameter and a flow rate of 5.0 mL / min. The elution conditions used were as follows: Buffer A: 5 mmol ammonium acetate (adjusted to pH 4 with acetic acid), Buffer B: A Equilibrate the column with cetonitrile, 90% buffer B, and slow down for 20 minutes at 90%-40%. Elution due to the gradient of liquid B.

[0208] Agilent 1100 series HPLC using Mercury MS columns AP1 2000 LC / MS / MS Triple Quadrupole (A) with G1315 B DAD (using applied biosystems) or using Mercury MS columns Agilent 1100 series HPLC and G1315 B DAD are available. Using a gilent LC / MSD VL single quadrupole, or Prominence Shimadzu LCMS with UFLC system and SPD-20 A DAD LCMS was performed using a 2020 single quadrupole.

[0209] Example 1: ((S)-2-(3-((S)-1-amino-2-(4-hydroxyphenyl )Ethyl)-1,2,4-Oxadiazole-5-yl)pyrroridine-1-carbonyl) -L-aspartic acid (compound 1) [ka]

[0210] Step 1A: Synthesis of Compound 1b [ka] Ethyl chloroformate (4.8g, 44.4mmol) and NMM (4.5g, 44.4mmol) ( mmol) Compound 1a (10.0 g, 29.63 mmol) in THF (120 mL) It was added to the solution of ) and stirred at -20°C for 20 minutes. After 20 minutes, 25% aqueous ammonia ( 30 mL was added to the active mixed acid anhydride and stirred at 0-5°C for 30 minutes. The reaction was complete. This was confirmed by TLC analysis. The volatile substances were evaporated under reduced pressure and partitioned into water and ethyl acetate. The chamber was washed with NaHCO3 solution, then with citric acid solution and brine solution. The separated organic layer was dehydrated with Na2SO4, filtered, and evaporated under reduced pressure to obtain 8.9 g of compound 1b. This occurred. LCMS: 337.4[M+H] + .

[0211] Step 1b: Synthesis of compound 1c [ka] Trifluoroacetic anhydride (TFAA) (14.2g, 67.77 mmol) is mixed with pyridine. Compound 1b (7.6g, 22.59mmol) in (9.92mL, 112.96mmol) The solution was added to (1) and stirred at room temperature for 2 hours. The completion of the reaction was confirmed by TLC analysis. The volatile substances were evaporated under reduced pressure and partitioned into water and ethyl acetate. The organic layer was washed with NaHCO3 solution. The solution was purified and then washed with citric acid and brine. The separated organic layer was Na2SO4 Dehydration is performed, followed by filtration and reduced-pressure evaporation to produce 5.5 g of compound 1c, which is then directly used in the next step. I used it in P.

[0212] Step 1c: Synthesis of compound 1d [ka] Hydroxylamine hydrochloride (1.62g, 23.56mmol), water (9.4mL) And potassium carbonate (2.17g, 15.7 mmol) in EtOH (28mL) The substance was added to a solution of 1c (2.5g, 7.8 mmol) and stirred at 86°C for 4 hours. Completion was confirmed by TLC analysis. The volatile substances were evaporated under reduced pressure and partitioned into water and ethyl acetate. The organic layer is washed with brine solution, dehydrated with Na2SO4, filtered, and evaporated under reduced pressure. 4 g of compound 1d was produced. LC-MS: 351.8[M+H] + .

[0213] Step 1d: Synthesis of compound 1e [ka] In a solution of Fmoc-Pro-OH (1.5g, 4.5 mmol) in DMF (20mL) HOBt (1.92g, 14.23 mmol) and DIC (1.8g, 14.23 mmol) The compound 1d (2g, 5.7 mmol) was added at 0°C and stirred for 15 minutes. Then, compound 1d (2g, 5.7 mmol) was added. l) was added at the same temperature and stirred for 1 hour, then at room temperature for 2 hours. The reaction was complete. This was confirmed by TLC analysis. The reaction mixture was quenched with ice water, and the precipitated white solid was filtered. The solid was rinsed with water (150 mL) and dried under high pressure. The solid was then treated with diethyl ether (2 The mixture was stirred in 50 mL for 15 minutes, filtered, and dried to yield 3.2 g of compound 1e. LC MS:671.1[M+H] + .

[0214] Step 1e: Synthesis of compound 1f [ka] A solution of compound 1e (3.2 g, 4.7 mmol) in acetonitrile (30 ml) Acetic acid (3.2 mL) was added at room temperature, and the mixture was refluxed at 90°C for 12 hours. The completion of the reaction was confirmed by TL. Confirmed by 14C analysis. The volatile matter was evaporated under reduced pressure to obtain a crude semi-solid, which was then mixed with water and Diluted with ethyl acetate. The organic layer was washed with NaHCO3 solution, and then citric acid and b The organic layer was washed with line solution. The organic layer was dehydrated with Na2SO4, filtered, and evaporated under reduced pressure to obtain the crude product. A solid is obtained, which is then diluted with 10% acetonitrile in hexane (50 ml) and stirred for 2 hours. The mixture was mixed to obtain a white solid. The resulting white solid was filtered and washed with p-pentane (50 mL). After purification and drying, 0.9 g of compound 1f was obtained. LC-MS: 653.4[M+H] + .

[0215] Step 1f: Synthesis of 1 g of compound [ka] In a 20% piperidine solution in DCM (15 mL), compound 1f (1.2 g, 1.83) was added. The molecule (mol) was added at 0°C and stirred at the same temperature for 1 hour. The completion of the reaction was determined by TLC analysis. The reaction mixture was confirmed. The reaction mixture was concentrated under reduced pressure, diluted with hexane, stirred, and filtered. Dissolve the solid in siRNA, wash with saturated NaHCO3 solution and brine solution, and then use Na2SO Dehydration was performed in step 4, followed by filtration and evaporation to yield 0.65 g of compound and 1 g of compound. LCMS 431. 1[M+H] + .

[0216] Step 1g: Synthesis of compound 1i [ka] DipEA (0.19g, 1.5 mmol) in EtOH (10mL) for 1h ( 0.74 g, 1.81 mmol (prepared according to the procedure shown below) and 1 g of compound (0 It was added to a 0.65g (1.5 mmol) solution and stirred at room temperature for 3 hours. The volatile components were evaporated. The organic layer was partitioned into ethyl acetate and water. The organic layer was dissolved in saturated NaHCO3, 10% citric acid, and brine. The compound was washed with a solution, dehydrated with Na2SO4, and concentrated under reduced pressure. The crude compound was then concentrated in hexane at 25% Purified by column chromatography using ethyl acetate with neutral alumina, yielding 0.7 5 g of compound 1i was produced. LC-MS: 702.4[M+H] + .

[0217] Step 1h: Synthesis of Compound 1 [ka] In a solution of compound 1i (0.75 g, 1.06 mmol), add trifluoroacetic acid: TIPS Add 7.5 mL of a cocktail mixture of water (95:2.5:2.5) and stir at room temperature for 2 hours. The resulting reaction mixture was evaporated under reduced pressure, diluted with diethyl ether, and filtered to obtain 0.4 A crude compound 1 was obtained in g. The crude solid material was subjected to preparative HPLC according to the experimental conditions. Purified by LCMS: 434.3[M+H] + HPLC RT(min): 11.1

[0218] Synthesis of compound 1h: [ka] H-Asp(O) in CH2Cl2 (20 mL) t Bu)-O t Bu(1.0g, 3.5 Add pyridine (0.55 g, 7.08 mmol) to a 4 mmol solution, and the solution The mixture was stirred at room temperature for 10 minutes. To this mixture, 4-chlorophyll in CH2Cl2 (20 mL) was added. Add a solution of nitrophenyl acid (0.86 g, 4.25 mmol) to the resulting mixture. The mixture was stirred at room temperature for 1 hour. After the reaction was complete (confirmed by TLC), it was converted to CH2Cl2(50). Dilute (mL), wash with 1.0 M sodium bicarbonate solution (50 mL x 2), then 1 Washed with 0.0M sodium carbonate solution (50 mL x 2). Dehydrated the organic layer with Na2SO4. The compound was filtered and evaporated under reduced pressure to obtain crude compound 1h, which was then subjected to silica gel column chromatography. Purified by Graph (eluent: 0-20% ethyl acetate in hexane), 0.75 g A compound was formed.

[0219] The following compounds were reacted using a procedure similar to that described in Example 1 (Compound 1), using a reagent and a reagent. The compound was prepared by appropriately varying the amount of drug, solvent, and reaction conditions. The characterization data of the compound was then obtained. The following is a summary in the table below. [Table 3] TIFF0007830412000035.tif121161

[0220] Example 2: 4-((S)-2-amino-2-(5-((S)-pyrrolidine-2-yl)- 1,2,4-Oxadiazole-3-yl)ethyl)phenol (Compound 14) [ka]

[0221] Step 2a: Synthesis of compound 2a [ka] Compound 2a is Boc-Tyr( t By using Bu)-OH, Example 1 (compound It was synthesized using a procedure similar to that described in steps 1a to 1c of item 1).

[0222] Step 2b: Synthesis of compound 2b [ka] Dissolution of Boc-Pro-OH (0.86g, 3.41 mmol) in DMF (20mL) Add HOBt (1.4g, 10.6 mmol) and DIC (1.7 mL, 10.6 mL) to the solution. The compound 2a (1.8g, 5.12) was added at 0°C and stirred for 30 minutes. mmol) was added at the same temperature and stirred for 10 minutes, then at room temperature for 1 hour. Completion was confirmed by TLC analysis. The reaction mixture was quenched with ice water, and a precipitated white solid was obtained. The solid was filtered, washed with water, and dried under high pressure. The solid was then mixed with diethyl ether (50 mL) and Both were stirred for 15 minutes, filtered, and dried to yield 1.8 g of compound 2b. LCMS: 5 49.5 [M+H] + .

[0223] Step 2c: Synthesis of compound 2c [ka] In a solution of compound 2b (1.8 g, 3.3 mmol) in acetonitrile (35 mL), Acetic acid (1.8 mL) was added at room temperature, and the mixture was refluxed at 85°C for 12 hours. The completion of the reaction was confirmed by TLC. This was confirmed by analysis. The volatile substances were evaporated under reduced pressure to obtain a crude semi-solid, which was then mixed with water and acetic acid. Diluted with ethyl acetate. The organic layer was washed with NaHCO3 solution, and then with citric acid solution and b The organic layer was washed with line solution. The organic layer was dehydrated with Na2SO4, filtered, and evaporated under reduced pressure to obtain the crude product. I obtained the substance. I used a silica gel column with 20% ethyl acetate in hexane to process the crude compound. The compound 2c was purified by chromatography, yielding 0.5 g. LCMS: 531 .3[M+H] + .

[0224] Step 2d: Synthesis of Compound 14 [ka] In a solution of compound 2c (0.5 g, 0.94 mmol), add trifluoroacetic acid: TIPS: 5 mL of a water (95:2.5:2.5) cocktail mixture was added and stirred at room temperature for 2 hours. The resulting reaction mixture was evaporated under reduced pressure, diluted with diethyl ether, filtered, and 0.45 g was obtained. Crude compound 14 was produced. The crude solid material was subjected to preparative HPL as described in the experimental conditions. Purified by the C method. HPLC (at mins) R ):9.99;LCMS:275.4[M+ H] + .

[0225] The following compounds were reacted using a procedure similar to that described in Example 2 (Compound 14), The compounds were prepared by appropriately varying the amount of reagents, solvents, and reaction conditions. The characterization data of the compounds was obtained from the following: The following table summarizes the findings. [Table 4]

[0226] The synthesis procedure for preparing compounds 19 and 20 of the present invention is described in WO2016142833. It was described in A1. [Table 5]

[0227] Example 3: Salvage of mouse splenocyte proliferation in the presence of recombinant PD-L1 / PD-L2 Recombinant mouse PD-L1 (rm-PDL-1, catalog number: 1019-B7-100) R&D Systems was used as the source of PD-L1.

[0228] Requirements: Mouse splenocytes collected from 6-8 week old C57 BL6 mice; RPMI1640(G IBCO, catalog number 11875); High glucose-containing DMEM (GIBCO, catalog number 11875); Catalog number D6429); Fetal bovine serum [Hyclone, catalog number SH30071.0 3]; Penicillin (10,000 units / mL) - Streptomycin (10,000 μg / m³) L) Solution (GIBCO, catalog number 15140-122); MEM sodium pyruvate Solution 100 mM (100x) solution (GIBCO, catalog number 11360); non-essential mesh No acids (GIBCO, catalog number 11140); L-glutamine (GIBCO, catalog number 11140); (Item No. 25030); Anti-CD3 antibody (eBiosciences-16-0032); Anti CD28 antibody (eBiosciences- 16-0281); ACK lysis buffer (1 mL) (GIBCO, catalog number - A10492); Histopaque (density - 1 0.083 gm / mL) (SIGMA 10831); Trypan blue solution (SIGMA-T 8154); 2mL Norm Ject Luer Lock Syringe (Sigma 20 14-12); 40μm nylon cell strainer (BD FALCON 35230); Hemocytometer (Bright line-SIGMA Z359629); FACS buffer (PB S / 0.1% BSA): 0.1% Bovine Serum Albumin (BSA) (SIGMA A705 0) and phosphate-buffered saline containing sodium azide (SIGMA 08591) PBS) pH 7.2 (HiMedia TS1006); 5mM CFSE stock solution: CFS E. Add 180 μL of freeze-dried CFSE to dimethyl sulfoxide (DMSO C2H6) solution. Prepared by diluting with SO (SIGMA-D-5879) for further use. The solution was divided into test tubes. The practical concentration was titrated at 10 μM to 1 μM. (eBioscienc e-650850-85); 0.05% trypsin and 0.02% EDTA (SIG MA 59417C); 96-well ELISA plate (Corning CLS339) 0); BD FACS Caliber (E6016); Recombinant Mouse B7-H1 / PDL 1. Fc Chimera (rm-PD-L1, catalog number: 1019-B7-100).

[0229] protocol Preparation and culture of spleen cells: By crushing mouse spleens in a 40 μm cell strainer, 50 mL of Falco The splenic cells collected in the n-tube were further treated with 1 mL of ACL lysis buffer at room temperature for 5 minutes. The cells were processed. After washing with 9 mL of RPMI complete medium, they were placed in a 15 mL test tube with 3 mL of... The splenocyte suspension was resuspended in 1×PBS. 3 mL of Histopaque was added to the layered splenocyte suspension. It was carefully added to the bottom of the tube without disturbing it. Centrifuged at 800 × g for 20 minutes at room temperature. Afterward, the opaque layer of spleen cells was carefully collected without disturbing or mixing the layers. The spleen cells were then chilled to 1 After washing twice with PBS, the total number of cells was counted using the trypan blue removal method. Furthermore, it was used in cell-based assays.

[0230] Splenocytes are cultured in RPMI complete medium (RPMI + 10% fetal bovine serum + 1 mM sodium pyruvate). Um+ 10,000 units / mL penicillin and 10,000 μg / mL streptomycin The cells were cultured in (Syn) and kept in a CO2 incubator with 5% CO2 and at 37°C.

[0231] CFSE proliferation assay: CFSE is a dye that passively diffuses into cells and binds to intracellular proteins. 1×1 0 6 The collected splenocytes (cells / mL) were placed in a pre-warmed 1×PBS / 0.1% BSA solution. The cells were treated with 5 μM CFSE at 37°C for 10 minutes. Excess CFSE was applied to the cells. The cells were then quenched using 5 times the volume of ice-cold medium and incubated on ice for 5 minutes. CFSE Labeled splenocytes were washed three more times with ice-cold complete RPMI medium. CFSE-labeled 1 x 10 5 Individual splenocytes were cultured in MDA-MB231 cells (high glucose DMEM medium). 1 x 10 5 Tested with either cells or recombinant human PDL-1 (100 ng / mL). The test compound was added to wells containing the test compounds. Splenocytes were treated with anti-mouse CD3 and anti-mouse CD2. The cultures were stimulated with 8 antibodies (1 μg / mL each) and incubated at 37°C and 5% CO2 for 72 hours. Further incubation was performed. Cells were harvested, washed three times with ice-cold FACS buffer, and the growth rate was measured. This is done using a flow cytometry filter with a 488nm excitation filter and a 521nm emission filter. Analyzed by Tory.

[0232] Data editing, processing, and inference The splenic cell proliferation rate (%) was analyzed using the CellQuest FACS program, and the compound The rescue rate % of splenocyte proliferation by this method is set to 100% by subtracting the background proliferation rate %. The stimulated splenocyte proliferation rate (%) was normalized and then estimated.

[0233] Stimulated spleen cells: Spleen cells + anti-CD3 / CD28 stimulation Background proliferation: Splenocytes + anti-CD3 / CD28 + PD-L1 Compound proliferation: Splenocytes + anti-CD3 / CD28 + PD-L1 + compound The effect of the compound was observed in the anti-CD3 / CD28 stimulated spleen in the presence of ligand (PDL-1). The test is performed by adding the required concentration of the compound to the cells. The results are shown in the table below. [Table 6]

[0234] Example 4: Mouse CD8 in the presence of recombinant mPVR + T cell proliferation rescue reagent: 96-well plate, Corning; RPMI, catalog number R6504, Sigma a; Easy Sep magnet, catalog number 18000, STEMCELL; Ea sy Sep Mouse CD8 T cell isolation kit, catalog number 19853, STE MCELL; Corning (registered trademark) Cell Strainer (70μm), Catalog Number 431751, Corning; Purified anti-mouse CD3 antibody, Catalog Number 100201, Biolegend; Recombinant mouse PVR, Catalog Number 6909-CD-050, R& D Systems; Recombinant mouse anti-TIGIT antibody, Catalog Number 142101, Bi olegend; FBS, Catalog Number SH30070.03, Hyclone; Mouse IL-2 ELISA Kit, R&D Systems Catalog Number DY402; Mouse IFN-γ ELISA Kit R&D Systems Catalog Number DY485; Sterile P BS; FicollHistopaque, Catalog Number 10831-6X100ML, Sigma

[0235] Protocol: Spleens were harvested from 6-8 week-old C57BL / 6 male mice. The spleens were gently crushed between sterile glass slides in RPMI + 10% FBS and passed through a 70μm strainer to isolate splenocytes. The cell suspension was centrifuged at 912 × g for 10 minutes at room temperature to separate, and the supernatant was discarded. The splenocytes were resuspended in RPMI + 10% FBS (complete RPMI) . The resuspended splenocytes were layered on top of Ficoll H istopaque-1083 in a 50ml Tarson tube. The layered cells were centrifuged at 584 × g for 30 minutes at room temperature without disruption. The clear buffy coat was carefully aspirated into sterile PBS . The isolated cells were washed with PBS and resuspended in complete RPMI medium to obtain a suspension of approximately 5 × 10 cells / ml. Mouse CD8 7 T cells were obtained using EasySep Mou + se CD8 se CD8+ T cells were isolated using a T cell isolation kit, following the manufacturer's instructions for use.

[0236] A 96-well cell culture plate was treated with purified anti-mouse CD3, 1 μg / mL (50 μL / well). (L) and recombinant mouse PVR Fc chimera 0.5 μg / mL (50 μl / well) The plates were coated at 37°C for 4 hours. After 4 hours, the coated plates were sterilized. Washed with BS. Mouse CD8 isolated from the spleen. + T cells, 200,000 cells / well (18 It was added to a 96-well cell culture plate at a concentration of 0 μL. Prepared in water or DMSO. Various concentrations of the test compound were added to each well (20 μL / well), for a total volume of 20 The volume was reduced to 0 μL / well. The plate was incubated in a 37°C CO2 incubator for 3 days. On the third day, the cell supernatant was collected and cytokine levels (IL-) were analyzed using ELISA. CD8 was determined (2 or IFN-γ) in the presence or absence of the test compound. + T The degree of cell proliferation is measured according to the manufacturer's instructions for use with mouse IL-2 or IFN-γEL. By analyzing the amount of IL-2 or IFN-γ in the culture supernatant using the ISA kit... The measurement was performed using recombinant mouse anti-TIGIT antibody as a positive control, and CD8 + T cell increase We decided to increase the population.

[0237] Data editing, processing, and inference CD8 + The T cell proliferation rate (%) was measured by measuring IL-2 levels using an IL-2 ELISA kit. By determining the CD8 of the test compound, analysis was performed. + T cell rescue rate %, background Subtracting the percentage of the growth rate, the value of CD stimulated by anti-TIGIT antibodies is set to 100%. 8 + Estimated after normalization against the T cell proliferation rate % (positive control). The results are shown in the following table as follows.

Table 7

[0238] Example 5: Evaluation of the efficacy of compound 19 in a CT-26 syngeneic (Balb / c male) mouse tumor model The purpose of this test was to evaluate the antitumor activity of compound 19 in a CT26 syngeneic colon adenocarcinoma model. This test aimed to evaluate the antitumor activity of compound 19 in a CT26 syngeneic colon adenocarcinoma model.

[0239] Reagents and materials

Table 8

[0240] Cell line proliferation and inoculation The CT26 cell line was obtained from ATCC and maintained and stored at the ADTL-Bangalore cell line repository. One vial of the CT26 cell line was thawed and regenerated in RPMI medium supplemented with 10% FBS (Gibco), 10 mM 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES), 1 mM sodium pyruvate, 4.5 g / L glucose, 1% penicillin-streptomycin (Sigma), and 1.5 g / L sodium bicarbonate. Flasks containing CT26 cells at a cell density of 250,000 cells / ml were incubated in an incubator at 37 ± 1°C supplemented with 5% carbon dioxide. Cell expansion was performed in T-150cm flasks, and the cell density was maintained between 250,000 cells / flask and 12 2 flasks while separating the cells every other day. in RPMI medium supplemented with 10% FBS (Gibco), 10 mM 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES), 1 mM sodium pyruvate, 4.5 g / L glucose, 1% penicillin-streptomycin (Sigma), and 1.5 g / L sodium bicarbonate. Flasks containing CT26 cells at a cell density of 250,000 cells / ml were incubated in an incubator at 37 ± 1°C supplemented with 5% carbon dioxide. Cell expansion was performed in T-150cm flasks, and the cell density was maintained between 250,000 cells / flask and 12 while separating the cells every other day. flasks 2 flasks while separating the cells every other day, with the cell density ranging from 250,000 cells / flask to 12 The number was maintained between 0.000 cells / flask. After the final step of separation, the cells reached the logarithmic growth phase. Then, the cells were processed for injection. T-150cm 2 Cells in a flask are treated with trypsin, Transfer to a 50 ml test tube and centrifuge at 1200 rpm for 5 minutes at controlled room temperature to separate the cells. A pellet was obtained. The supernatant was discarded, the cell pellet was suspended in culture medium, and counted using a hemocytometer. The cell pellet was then placed in RPMI medium in a 10x10 cm layer. 6 Resuspend at the final cell / ml concentration. To establish the tumor, 1 × 10 6 Cells (0.1 ml of cell suspension) are used in mice. It was administered as a subcutaneous injection into the right flank.

[0241] Animal grouping and allocation When the mean tumor volume reached approximately 30 ± 5 mm³, the animals were randomized based on tumor volume into five groups (G1-G5) of 10 animals each (N=10), as described below. After 14 days of treatment, overall efficacy and tolerability were evaluated based on tumor volume and weight changes observed during the treatment period. On day 14 of treatment, animals in all groups were euthanized at 0.5 hours, 1 hour, and 4 hours after the final dose. In one embodiment, the present invention provides the following. [Item 1] A method for modulating the T cell immune receptor (TIGIT) signaling pathway and programmed cell death 1 (PD-1) signaling pathway having Ig and ITIM domains in a subject, wherein the subject is given formula (I): [ka] (In the formula, R1 represents a hydrogen atom, or a -(C1-C6) alkyl group optionally substituted with -OH, -COOH, aryl, heteroaryl, or aryl-OH; R2 represents hydrogen, or a -(C1-C6) alkyl group optionally substituted with -OH, -SH, C(O)NH2, -COOH, aryl, heteroaryl, or aryl-OH; Ra represents hydrogen; or Ra and R2 form a pyrrolidine ring together with the atom they bond to; R3 is hydrogen or formula (I'): [ka] Represents the base represented by; ----- represents a point of connection; Rb represents hydrogen; or Rb and Rc form a pyrrolidine ring together with the atom they bond to; A method comprising contacting a compound (where Rc represents a -(C1-C6) alkyl group optionally substituted with hydrogen, -OH, -C(O)NH2, COOH, aryl, or aryl-OH), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. [Item 2] The method according to item 1, wherein R1 represents a hydrogen atom or an -(C1-C6) alkyl group optionally substituted with -OH, -COOH, phenyl, imidazolyl, or (p-OH)phenyl. [Item 3] The method according to any one of items 1 to 2, wherein R1 represents a -(C1-C6) alkyl group optionally substituted with -OH, -COOH, imidazolyl, phenyl, or (p-OH)phenyl. [Item 4] The method according to any one of items 1 to 3, wherein R1 represents a -(C1-C6) alkyl group optionally substituted with -OH, -COOH, imidazolyl, or (p-OH)phenyl. [Item 5] The method according to item 1, wherein R2 represents hydrogen, or a -(C1-C6) alkyl group optionally substituted with -OH, -SH, -C(O)NH2, -COOH, phenyl, imidazolyl, or (p-OH)phenyl. [Item 6] The method according to either item 1 or 5, wherein R2 represents hydrogen, or a -(C1-C6) alkyl group substituted with -OH, -SH, -COOH, phenyl, imidazolyl, or (p-OH)phenyl. [Item 7] The method according to any one of items 1, 5, or 6, wherein R2 represents hydrogen or a -(C1-C6) alkyl group substituted with -OH, -COOH, phenyl, imidazolyl, or (p-OH)phenyl. [Item 8] The method according to item 1, wherein Ra and R2 form a pyrrolidine ring together with the atom to which they are bonded. [Item 9] R3

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[0242] In this study, none of the treatments had any effect on body weight, and the administered dose was effective. The stimulant exhibits excellent tolerability. Treatment with compound 19 has dose-dependent inhibition of tumor growth. (42% at 10 mg / kg (qd) dose and 53% at 30 mg / kg (qd) dose) %). The percentage of tumor growth inhibition observed at a dose of 30 mg / kg (qd) was observed in vehicle-treated animals. This was statistically significant compared to the previous result. The results of the test are shown graphically in Figure 1.

Claims

1. For subjects requiring modulation of the Ig and ITIM domain-containing T cell immune receptor (TIGIT) signaling pathway and programmed cell death 1 (PD-1) signaling pathway, the following formula is provided for use in modulating the Ig and ITIM domain-containing T cell immune receptor (TIGIT) signaling pathway and programmed cell death 1 (PD-1) signaling pathway: 【Chemistry 13】 A composition comprising a compound (compound 19), an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

2. The composition for use according to claim 1, wherein the subject is suffering from cancer.

3. The aforementioned cancers include blastoma, breast cancer, epithelial cancer, colon cancer, lung cancer, melanoma, prostate cancer, kidney cancer, bone cancer, pancreatic cancer, skin cancer, head or neck cancer, uterine cancer, ovarian cancer, colorectal cancer, rectal cancer, anal cancer, peritoneal cancer, stomach cancer, testicular cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, esophageal cancer, small intestine cancer, endocrine cancer, thyroid cancer, parathyroid cancer, adrenal cancer, sarcoma, urethral cancer, testicular cancer, chronic or acute leukemia, and pediatric cancer. A composition for use according to claim 2, selected from solid tumors, Hodgkin lymphoma, non-Hodgkin lymphoma, cutaneous T-cell lymphoma, mesothelioma, thymic carcinoma, myeloma, bladder cancer, ureteral cancer, renal pelvis cancer, liver cancer, pancreatic cancer, neoplasms of the central nervous system (CNS), tumor angiogenesis, spinal axial tumors, brainstem gliomas, pituitary adenomas, epidermoid carcinomas, salivary gland carcinomas, squamous cell carcinomas, Merkel cell carcinomas, and environmentally induced cancers.

4. For use in the treatment of diseases or disorders mediated by both the Ig and ITIM domain T cell immune receptor (TIGIT) signaling pathway and the programmed cell death 1 (PD-1) signaling pathway in subjects requiring treatment, the formula is: 【Chemistry 13】 A composition comprising a compound (compound 19), an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

5. The composition for use according to claim 4, wherein the disease or disorder is cancer.

6. The aforementioned cancers include blastoma, breast cancer, epithelial cancer, colon cancer, lung cancer, melanoma, prostate cancer, kidney cancer, bone cancer, pancreatic cancer, skin cancer, head or neck cancer, uterine cancer, ovarian cancer, colorectal cancer, rectal cancer, anal cancer, peritoneal cancer, stomach cancer, testicular cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, esophageal cancer, small intestine cancer, endocrine cancer, thyroid cancer, parathyroid cancer, adrenal cancer, sarcoma, urethral cancer, testicular cancer, chronic or acute leukemia, and pediatric cancer. A composition for use according to claim 5, selected from solid tumors, Hodgkin lymphoma, non-Hodgkin lymphoma, cutaneous T-cell lymphoma, mesothelioma, thymic carcinoma, myeloma, bladder cancer, ureteral cancer, renal pelvis cancer, liver cancer, pancreatic cancer, neoplasms of the central nervous system (CNS), tumor angiogenesis, spinal axial tumors, brainstem gliomas, pituitary adenomas, epidermoid carcinomas, salivary gland carcinomas, squamous cell carcinomas, Merkel cell carcinomas, and environmentally induced cancers.

7. For use in modulating the T cell immune receptor (TIGIT) signaling pathway having Ig and ITIM domains in subjects requiring modulation of the T cell immune receptor (TIGIT) signaling pathway having Ig and ITIM domains, the formula is: 【Chemistry 13】 A composition comprising a compound (compound 19), an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

8. The composition for use according to claim 7, further comprising the use modulating the PD-1 signaling pathway.

9. The composition for use according to claim 7, wherein the subject is suffering from cancer.

10. The composition for use according to claim 7, wherein the modulate inhibits the growth and / or metastasis of tumor cells.

11. The composition for use according to claim 10, wherein the tumor cells are tumor cells of small cell lung cancer, multiple myeloma, bladder carcinoma, primary cholangiocarcinoma, ovarian cancer, Hodgkin lymphoma, gastric carcinoma, acute myeloid leukemia, or pancreatic cancer.

12. For use in the treatment of diseases or disorders mediated by the T-cell immune receptor (TIGIT) signaling pathway having Ig and ITIM domains in subjects requiring treatment, the formula for use in the treatment of diseases or disorders mediated by the T-cell immune receptor (TIGIT) signaling pathway having Ig and ITIM domains is: 【Chemistry 13】 A composition comprising a compound (compound 19), an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

13. The composition for use according to claim 12, wherein the disease or disorder is cancer.

14. The aforementioned cancers include blastoma, breast cancer, epithelial cancer, colon cancer, lung cancer, melanoma, prostate cancer, kidney cancer, bone cancer, pancreatic cancer, skin cancer, head or neck cancer, uterine cancer, ovarian cancer, colorectal cancer, rectal cancer, anal cancer, peritoneal cancer, stomach cancer, testicular cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, esophageal cancer, small intestine cancer, endocrine cancer, thyroid cancer, parathyroid cancer, adrenal cancer, sarcoma, urethral cancer, testicular cancer, chronic or acute leukemia, and childhood cancers. A composition for use according to claim 13, selected from solid tumors, Hodgkin lymphoma, non-Hodgkin lymphoma, cutaneous T-cell lymphoma, mesothelioma, thymic carcinoma, myeloma, bladder cancer, ureteral cancer, renal pelvis cancer, liver cancer, pancreatic cancer, neoplasms of the central nervous system (CNS), tumor angiogenesis, spinal axial tumors, brainstem gliomas, pituitary adenomas, epidermoid carcinomas, salivary gland carcinomas, squamous cell carcinomas, Merkel cell carcinomas, and environmentally induced cancers.

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