Combination of small molecule CD-47 inhibitors with other Anti-cancer agents

Abstract

To provide compositions and methods for treating cancer.SOLUTION: The present invention relates to a composition of a CD47-SIRPα blocking agent and one or more anti-cancer agent(s), where the CD47-SIRPα blocking agents are represented by a compound of formula (I). The present invention also relates to a method of treating a cancer in a subject by administering a therapeutically effective amount of a CD47-SIRPα blocking agent represented by formula (I) in combination with one or more anti-cancer agent(s).SELECTED DRAWING: None

Description

[Technical field]

[0001] Related Applications This application is a joint venture with Indian Provisional Patent Application No. 2018410 filed on November 8, 2018. This application claims the benefit of US Pat. No. 4,2108, the contents of which are incorporated herein by reference in their entirety. is incorporated into.

[0002] The present invention relates to small molecule CD-47-SIRPα pathway inhibitors and Fc-receptors (FcRs). or other prophagocytic receptors. The present invention relates to pharmaceutical compositions comprising one or more agents capable of stimulating a receptor to activate the cellular endothelial cell. [Background technology]

[0003] The CD47 / SIRPα axis has been established as a key regulator of myeloid cell activation and is It functions as an immune checkpoint for phage-mediated phagocytosis in some cancers. Due to its frequent upregulation in tumor necrosis factor-binding proteins, CD47 plays a key role in immune evasion and cancer progression. CD47 mediates interactions with SIRP1α, which is expressed primarily on macrophages. Blockade of SIRP1α / CD47 inhibits phagocytosis in preclinical models of cancer. Tumor cell phagocytosis for better antigen presentation resulting in substantially improved anti-tumor responses and has been shown to dramatically enhance dendritic cell maturation (MPChao et al. Curr Opin Immunol.2012(2):225-232). CD47- Disruption of SIRPα interaction is currently being investigated using CD47 or SIRPα and engineered receptor deactivators. Using monoclonal antibodies targeting carp is being evaluated as a therapeutic strategy for cancer There are.

[0004] CD47 is expressed on virtually all non-malignant cells and is a cytoplasmic CD47-dependent cell line. Loss or alteration of CD47 expression is a marker of senescence, particularly on red blood cells (RBCs). Alternatively, blocking SIRPα may also function as a marker for damaged cells. For cells in which prophagocytic signals are also present, this allows for the phagocytosis of targets that would not normally be phagocytosed. CD47 is a broadly expressed membrane-associated protein with a single Ig-like domain and five transmembrane domains. It is a transmembrane glycoprotein that functions as a cellular ligand for SIRPα and SIRPα binds to macrophages via the NH2-terminal V-like domain of SIRPα. Myeloid and hematopoietic stem cells, including phages, granulocytes, myeloid dendritic cells (DCs), and mast cells It is expressed primarily on those precursors that contain

[0005] CD47 is also involved in the expression of non-Hodgkin's lymphoma (NHL), acute myeloid leukemia (AML), and breast cancer. , colon cancer, glioblastoma, glioma, ovarian cancer, bladder cancer, and prostate cancer. Overexpression of CD47 by tumor cells is a signaling pathway that allows tumor cells to target the immune system. This helps to effectively evade surveillance and killing by innate immune cells. However, most tumors In a variety of types, blockade of the CD47-SIRPα interaction as a single agent resulted in significant phagocytosis. In some cases, it may be necessary to combine the drug with other therapeutic agents, as it may not be possible to induce antitumor immunity. Fc-receptors (FcRs) or other phagocytosis-promoting receptors (collectively referred to as phagocytosis receptors) are required. The concomitant involvement of activating receptors such as CD47- This may be necessary to utilize the full potential of SIRPα pathway blockade.

[0006] The role of pro-phagocytic receptor engagement is an important anti-CD47 inhibitor in blocking CD47-SIRPα interaction. CD47 F(ab) fragment, short chain variable fragment of CD-47 or SIRPα containing the non-Fc portion This is evidenced by the insufficiency of the protein to induce phagocytosis by either of the If activated pro-phagocytic receptors are involved, use Fc portion-containing blocking anti-CD47 antibodies CD47-SIRPα blockade induces more efficient phagocytosis, as seen in Combination of CD47-SIRPα blockade with therapeutic antibodies (Fc-containing) targeting tumor antigens The combination stimulates activating Fc receptors (FcRs) resulting in efficient phagocytosis. The Fc portion of antibodies targeting tumor antigens also induces antibody-dependent cellular cytotoxicity (ADCC), which also add therapeutic efficacy. Thus, rituximab, Herceptin, trastuzumab Mab, alemtuzumab, bevacizumab, cetuximab and panitumumab, daratumumab The antibody selected from the group consisting of is more efficient due to its tumor targeting and ADCC. It can induce phagocytosis.

[0007] Initial approaches to disrupt the CD47-SIRPα interaction included CD47 or Using a monoclonal antibody targeting SIRPα, we developed a receptor decoy fused to an Fc fragment. However, a concern with this approach is that CD47 is expressed on both hematopoietic and non-hematopoietic cells. It is highly expressed in both hematopoietic and normal cells, and therefore in tumor cells as well as CD47-SIRPα blockers that contain an Fc portion also target many normal cells and This may possibly result in their elimination by phages. was considered a major safety issue and caused anemia, thrombocytopenia, and leukopenia. These agents also target macrophage-rich solid tissues such as the liver, lung, and brain. Therefore, small molecules, peptides, Fab fragments, etc. that have Fc portions may affect Blocking CD47-SIRPα interaction with a non-specific agent while inhibiting phagocytosis in tumor cells By activating the appropriate combination of promoting receptors, efficient phagocytosis of tumor cells can be induced. would be ideal.

[0008] Apart from Fc receptors, many other pro-phagocytic receptors also mediate phagocytosis by inducing phagocytosis. It has been reported that blocking CD47-SIRPα promotes phagocytosis of tumor cells in response to CD47-SIRPα. These include SLAMF7, Mac-1, the receptor for calreticulin, and and possibly as yet unidentified receptors. B-cell tumor lineages, such as B-cell lymphomas, express SLAMF7 and CD47-SI Involved in induction of prophagocytic signals during blockade of RPα.

[0009] Therefore, therapeutic agents known to activate pro-phagocytic receptors may also be useful in promoting efficient phagocytosis. For use in combination with a CD47-SIRPα blocker to achieve this effect These drugs are ideal partners for proteasome inhibitors (bortezomib, ixazomib and carfilzomib), anthracyclines (doxorubicin, epirubicin Bicin, daunorubicin, idarubicin, mitoxantrone) oxaliplatin, cyclosporine Phosphamide, bleomycin, vorinostat, paclitaxel, 5-fluorouracil le, cytarabine, BRAF inhibitors (dabrafenib, vemurafenib), PI3K inhibitors , docetaxel, mitomycin C, sorafenib, tamoxifen and oncolytic Including Ilus.

[0010] Apart from specific drugs known to have an effect on the "eat-me" signal , abiraterone acetate, afatinib, aldesleukin, aldesleukin, a Lemtuzumab, anastrozole, axitinib, belinostat, bendamustine, bilirubin Calthamide, blinatumomab, bosutinib, brentuximab, busulfan, cabazita Kisel, capecitabine, carboplatin, carfilzomib, carmustine, ceritinib , clofarabine, crizotinib, dacarbazine, dactinomycin, dasatinib, degas Relix, denileukin, denosumab, enzalutamide, eribulin, erlotinib, Verolimus, Exemestane, Exemestane, Fludarabine, Fulvestrant, Gef ibritumomab, imatinib, ipilimumab, irinotecan, ipatitinib, goserelin, Xabepilone, lapatinib, lenalidomide, letrozole, leucovorin, leuprolide , lomustine, mechlorethamine, megestrol, nelarabine, nilotinib, nivolumab , olaparib, omacetaxine, palbociclib, pamidronate, panitumumab, pano Vinostat, pazopanib, pegaspargase, pembrolizumab, pemetrexed sodium, pertuzumab, plerixafor, pomalidomide, ponatinib, pralatrex Seth, procarbazine, radium 223, ramucirumab, regorafenib, rIFNa -2b, romidepsin, sunitinib, temozolomide, temsirolimus, thiotepa, toxin Momab, trametinib, vinorelbine, methotrexate, ibrutinib, afliberce puto, toremifene, vinblastine, vincristine, idelalisib, mercaptopril Other drugs, including thalidomide and thalidomide, have been shown to be effective in combination with CD47-SIRPα blockers. This could potentially have an effect on the "eat-me" signaling pathway.

[0011] In addition to the therapeutic agents mentioned above, other treatments used in cancer therapy also activate phagocytosis-promoting receptors. Activation and therefore efficient phagocytosis can be achieved in combination with CD47-SIRPα blockade. These include hypericin-based photodynamic therapy (Hyp-PDT), radiation therapy, and hypercalcaemia. Includes water pressure, Photofrin-based PDT and Rose Bengal acetate-based PDT.

[0012] However, small molecule CD47-SIRPα pathway inhibitors have been reported to target Fc-receptors (FcRs) or The present invention is a novel method for combining with drugs that can stimulate activating receptors, such as other phagocytosis-promoting receptors. or phagocytosis-promoting receptors to harness the maximum potential of CD47-SIRPα pathway blockade To be combined with other treatments used in cancer therapy to rejuvenate the body, There is a need for this not to be the case. Summary of the Invention

[0013] The present invention provides small molecule CD-47-SIRPα pathway inhibitors that target Fc-receptors (FcRs) and other With agents that stimulate either activating receptors or other phagocytosis-promoting receptors, or C D-47 - A phagocytosis-promoting receptor to harness the maximum potential of SIRPα pathway blockade The present invention provides compositions that can be combined with other treatments used in cancer therapy to activate .

[0014] In one embodiment of the invention, a CD47-SIRPα blocking agent and one or more anti-cancer agents Provided herein is a composition comprising the CD-47-SIRPα blocker of formula (I ):

[0015] [ka] (In the formula, R a is hydrogen; R1 is hydrogen, -(CH2)2CONH2, -(CH2)2CO OH, -(CH2)3NHC(=NH)NH2, -(CH2)4NH2, -CH2CON H2, -CH2-aryl, or -CH2-heteroaryl; or R a Oh and R1 together with the atoms to which they are attached form a pyrrolidine ring; R2 is hydrogen, -(CH2)3NHC(=NH)NH2, -(CH2)2CONH2, -(CH2)2COOH, -CH2-aryl, or -CH2-heteroaryl ; R b is hydrogen; R3 is hydrogen, -CH2-aryl, -(CH2)3NHC(= NH)NH2, -(CH2)2CONH2, -(CH2)2COOH, -(CH2)4N H2 or -CH2-heteroaryl; or R b and R3 is the bond between them forms a pyrrolidine ring together with the atom to be or a pharma- ceutical acceptable salt or amide or ester thereof. ter, or stereoisomer.

[0016] In another embodiment, the present invention provides a method for treating a subject exhibiting a dysregulated CD47 pathway. The method comprises administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharma- ceutical acceptable salt thereof, The amides or esters, or stereoisomers, are combined with one or more anticancer drugs and and administering the same to a subject in need thereof.

[0017] Yet another aspect of the present invention relates to a compound of formula (I) or a pharma- ceutical acceptable salt thereof, Administering the amide or ester, or stereoisomer, in combination with one or more anticancer drugs The present invention provides a method for treating a disease or disorder mediated by CD47, comprising:

[0018] In a further embodiment of the invention, a CD47-SIRPα blocking agent and one or more Provided herein are combinations that include anti-cancer agents, such as small molecule CD-47-SIRPα blockers. The withdrawal is according to formula (I):

[0019] [ka] (In the formula, R a is hydrogen; R1 is hydrogen, -(CH2)2CONH2, -(CH2)2CO OH, -(CH2)3NHC(=NH)NH2, -(CH2)4NH2, -CH2CON H2, -CH2-aryl, or -CH2-heteroaryl; or R a Oh and R1 together with the atoms to which they are attached form a pyrrolidine ring; R2 is hydrogen, -(CH2)3NHC(=NH)NH2, -(CH2)2CONH2, -(CH2)2COOH, -CH2-aryl, or -CH2-heteroaryl ; R b is hydrogen; R3 is hydrogen, -CH2-aryl, -(CH2)3NHC(= NH)NH2, -(CH2)2CONH2, -(CH2)2COOH, -(CH2)4N H2 or -CH2-heteroaryl; or R band R3 is the bond between them forms a pyrrolidine ring together with the atom to be or a pharma- ceutical acceptable salt or amide or ester, or a stereoisomeric Represented by the body. [Brief description of the drawings]

[0020] [Figure 1] Enhanced phagocytosis of lymphoma cells with compound 3 and compound 6 in combination with anti-CD20 antibody. [Diagram 2] Enhanced phagocytosis of multiple myeloma cells of compound 3 and compound 6 in combination with bortezomib. [Diagram 3] Antitumor efficacy of compound 6 alone and in combination with anti-mouse PD-L1 antibody in A20 tumor-bearing mice. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0021] Each embodiment is provided by way of explanation of the invention, and not as a limitation of the invention. Various modifications and variations of the compounds, compositions, and methods described herein are within the scope of the invention. It will be apparent to those skilled in the art that other modifications may be made without departing from the spirit of the present invention. Features illustrated or described as part of one embodiment may yield still further embodiments. It is contemplated that the present invention may be modified or changed in any manner. Other objects, features and aspects of the present invention are as follows: These features are disclosed or apparent from the following detailed description. These are illustrative of embodiments only and should not be construed as limiting the broader aspects of the invention. It will be understood by those skilled in the art.

[0022] In certain embodiments, the present invention provides a method for the treatment of a CD47-SIRPα blocker and one or more The present invention provides a composition comprising a number of anti-cancer agents, the CD47-SIRPα blocking agent being represented by formula (I): [ka] (In the formula, R a is hydrogen; R1 is hydrogen, -(CH2)2CONH2, -(CH2)2CO OH, -(CH2)3NHC(=NH)NH2, -(CH2)4NH2, -CH2CON H2, -CH2-aryl, or -CH2-heteroaryl; or R a Oh and R1 together with the atoms to which they are attached form a pyrrolidine ring; R2 is hydrogen, -(CH2)3NHC(=NH)NH2, -(CH2)2CONH2, -(CH2)2COOH, -CH2-aryl, or -CH2-heteroaryl ; R b is hydrogen; R3 is hydrogen, -CH2-aryl, -(CH2)3NHC(= NH)NH2, -(CH2)2CONH2, -(CH2)2COOH, -(CH2)4N H2 or -CH2-heteroaryl; or R b and R3 is the bond between them forms a pyrrolidine ring together with the atom or a pharma- ceutical acceptable salt or amide or ester, or a stereoisomeric Represented by the body.

[0023] In certain embodiments, the anti-cancer agent is a chemotherapeutic agent or an immunomodulatory agent.

[0024] In certain embodiments, specific compounds of interest for use with CD47-SIRPα blocking agents are Certain combination partners stimulate activating Fc receptors (FcRs) for efficient phagocytosis. In certain embodiments, the therapeutic antibody is a therapeutic antibody that targets a tumor antigen, resulting in Particular combination partners include therapeutic antibodies that stimulate Fc receptor-mediated phagocytosis. Therefore, the antibody selected from the group of agents capable of targeting efficient phagocytosis is anti-C D20, e.g., rituximab, tiuxetan, tositumomab, and combinations thereof It has particular application in the treatment of non-Hodgkin's B-cell lymphoma and chronic lymphocytic leukemia (CLL). Combination with anti-CD22, e.g., epratuzumab, is used to treat B-cell leukemia. and hairy cell leukemia. In combination with tuzumab, etc., it is effective in treating chronic lymphocytic leukemia, including but not limited to B Anti-CD33, e.g., Gemtuzumab, is particularly useful in the treatment of leukemia and T-cell leukemia. Combination with buozogamicin etc. is useful for the treatment of myeloid leukemia such as acute myeloid leukemia. The combination with trastuzumab is of particular use in the treatment of breast cancer. The combination with bevacizumab has been shown to be effective in treating certain types of brain tumors, as well as certain types of kidney tumors. It is of particular use in the treatment of cancers of the liver, lung, colon, rectum, cervix, ovary, or fallopian tubes. Combination with cetuximab finds particular use in the treatment of colon and head and neck cancer. Combination with panitumumab is of particular use in the treatment of colorectal cancer. Combinations with rifabutinib are particularly useful in the treatment of multiple myeloma. Other combinations of interest include, but are not limited to, anti-CD96, anti-CD44 and anti-C Includes D123.

[0025] In certain preferred embodiments, the Fc receptors (FcRs) are Fc-gamma receptors ( FcγR).

[0026] Other therapeutic antibodies of interest for combination with CD47-SIRPα blockers are limited. ofatumumab for chronic lymphocytic leukemia and obinutuzumab for follicular lymphoma , alemtuzumab for B-cell chronic lymphocytic leukemia, and ibrix for B-cell non-Hodgkin's lymphoma. including tumoura tiuxetan, dinutuximab for neuroblastoma and necitumumab for lung cancer .

[0027] In certain embodiments, the anti-cancer agent is rituximab, tiuxetan, tositumomab, etc. It is an anti-CD20 antibody.

[0028] In certain embodiments, a therapeutic agent known to activate a pro-phagocytic receptor is Therefore, combination with CD47-SIRPα blockade to achieve efficient phagocytosis is also required. These drugs are ideal partners for use in combination with proteasome inhibitors. inhibitors (bortezomib, ixazomib and carfilzomib), anthracyclines ( Doxorubicin, epirubicin, daunorubicin, idarubicin, mitoxantrone) Xaliplatin, cyclophosphamide, bleomycin, vorinostat, paclitaxel 5-fluorouracil, cytarabine, BRAF inhibitors (dabrafenib, vemurafenib nib), PI3K inhibitors, docetaxel, mitomycin C, sorafenib, and tamoxifen xifene; or combinations thereof.

[0029] In certain embodiments, the anti-cancer agent is a proteasome inhibitor.

[0030] In certain embodiments, the anticancer agent is bortezomib, ixazomib, or carfilzomib. mib or an analogue or derivative thereof.

[0031] In certain embodiments, the compound is known to have an effect on the "eat-me" signal. In addition to the specific drugs listed above, abiraterone acetate, afatinib, aldesleixirib, , aldesleukin, alemtuzumab, anastrozole, axitinib, belinstaphylococcus aureus bendamustine, bicalutamide, blinatumomab, bosutinib, brentuximab , busulfan, cabazitaxel, capecitabine, carboplatin, carfilzomib, Carmustine, ceritinib, clofarabine, crizotinib, dacarbazine, dactinoma Isin, dasatinib, degarelix, denileukin, denosumab, enzalutamide, erythropoietin Brine, Erlotinib, Everolimus, Exemestane, Exemestane, Fludarabine , Fulvestrant, Gefitinib, Goserelin, Ibritumomab, Imatinib, Ipirinib Mumab, irinotecan, ixabepilone, lapatinib, lenalidomide, letrozole, Icovorin, leuprolide, lomustine, mechlorethamine, megestrol, nelarabine , nilotinib, nivolumab, olaparib, omacetaxine, palbociclib, pamidronate panitumumab, panobinostat, pazopanib, pegaspargase, pembrolizumab izumab, pemetrexed disodium, pertuzumab, plerixafor, pomalidomide, Ponatinib, pralatrexate, procarbazine, radium 223, ramucirumab, Gorafenib, rIFNa-2b, romidepsin, sunitinib, temozolomide, temsirolimus Rimus, thiotepa, tositumomab, trametinib, vinorelbine, methotrexate, Brutinib, aflibercept, toremifene, vinblastine, vincristine, ide Other drugs, including ralisib, mercaptopurine and thalidomide, inhibit CD47-SIRP In combination with alpha blockers, it may have an effect on the eat-me signaling pathway. obtain.

[0032] In yet another embodiment, in addition to the therapeutic agents described above, other treatments used in cancer therapy The method also activates pro-phagocytic receptors and therefore may be combined with CD47-SIRPα blockade. Together, these can achieve efficient phagocytosis. -PDT), radiation therapy, high hydrostatic pressure, Photofrin-based PDT and Rose Bengal acetate Includes steroid-based PDT.

[0033] In certain embodiments, the chemotherapeutic agent is abarelix, aldesleukin, alitoleukin, Chinoin, allopurinol, altretamine, arsenic trioxide, asparaginase, azashi Tetidine, bexarotene, baricitinib, bortezomib, intravenous busulfan, oral busulfan Lufan, Calsterone, Cetuximab, Chlorambucil, Cisplatin, Cladribine , dalteparin sodium, decitabine, diftitox, disulfiram, dexamethasone Razoxane, dromostanolone propionate, eculizumab, estramustine, etoposide Cidrine phosphate, etoposide, fentanyl citrate, filgrastim, floxacin Gemcitabine, histrelin acetate, phosphamide, interferon alpha 2 a, Lapatinib ditosylate, Levamisole, Marizomib, Mechlorethamine, Melphalan , mercaptopurine, methotrexate, methoxsalen, mitotane, nandrolonephen Propionate, nofetumomab, oprozomib, pegfilgrastim, pentostatin , pipobroman, plicamycin, procarbazine, quinacrine, rasburicase, Xolitinib, rucaparib, streptozotocin, teniposide, testolactone, thalid Mydo, thioguanine, topotecan, toremifene, tretinoin, uracil mustard , valrubicin, vinblastine, vincristine, niraparib, veliparib, talazopa Rib or Zoledronate.

[0034] In certain embodiments, the anti-cancer agent is an immunomodulatory agent. Immunomodulatory agents include CTLA-4 (e.g., ipilimumab), 4-1BB (e.g., uremumab), and utomirumab), antibodies against PD-1 and PD-L1 (e.g., nivolumab, pembrolizumab, atezolizumab, durvalumab and camrelizumab), Antibodies against tokine (IL-10, TGF-beta), antibodies against TIM-3, LA Antibodies against G3, B7H3, B7H4 and B7H6 or a combination thereof.

[0035] In some embodiments of the invention, two or more compounds of formula (I) In some embodiments, a CD47-SIRPα blocking agent is administered, the agent being represented by: The CD47-SIRPα blocking agent is administered more than once.

[0036] In certain embodiments, the CD47-SIRPα blocker is an antagonist of the CD47-SIRPα blocker. In certain embodiments, the agent is an agent that blocks the interaction between CD47 and SIRPα. Blocking this interaction inhibits macrophage phagocytosis of CD47-expressing tumor cells. Induce.

[0037] In certain embodiments, the present invention relates to a small molecule CD4 compound as described in formula (I) Compositions are provided that include both a 47-SIRPα blocker and a proteasome inhibitor. In certain embodiments, the proteasome inhibitor is bortezomib, ixazomib or is carfilzomib or any analog or derivative thereof.

[0038] In certain embodiments, the composition comprises a compound of formula (I), wherein R1 is water. element, -(CH2)2CONH2, -(CH2)2COOH, -(CH2)3NHC(=N H) NH2, -(CH2)4NH2, -CH2-phenyl, or -CH2-imidazoline It is.

[0039] In certain embodiments, the composition comprises a compound of formula (I), where R1 is - (CH2)2CONH2, -(CH2)2COOH, -(CH2)3NHC(=NH)N H2, or -(CH2)4NH2.

[0040] In certain embodiments, the composition comprises a compound of formula (I), where R1 is - (CH2)2CONH2, or -(CH2)2COOH.

[0041] In certain embodiments, the composition comprises a compound of formula (I) where R2 is water. Element, -(CH2)3NHC(=NH)NH2, -(CH2)2CONH2, -(CH2) 2COOH, -CH2-phenyl, or -CH2-imidazolyl.

[0042] In certain embodiments, the composition comprises a compound of formula (I) where R2 is water. The substituents are -(CH2)3NHC(=NH)NH2, or -(CH2)2COOH.

[0043] In certain embodiments, the composition comprises a compound of formula (I) where R2 is water. The alkyl group is -(CH2)2CONH2, or -(CH2)2COOH.

[0044] In certain embodiments, the composition comprises a compound of formula (I) where R3 is water. -CH2-phenyl, -(CH2)3NHC(=NH)NH2, -(CH2)2CO NH2, -(CH2)2COOH, -(CH2)4NH2 or -CH2-imidazolyl Represents.

[0045] In certain embodiments, the composition comprises a compound of formula (I) where R3 is water. -CH2-phenyl, -(CH2)3NHC(=NH)NH2, -(CH2)2CO It represents NH2, -(CH2)2COOH, or -(CH2)4NH2.

[0046] In certain embodiments, the composition comprises a compound of formula (I), a is hydrogen; R1 is , hydrogen, -(CH2)2CONH2, -(CH2)2COOH, -(CH2)3NHC( =NH)NH2, -(CH2)4NH2, -CH2CONH2, -CH2-phenyl, or or -CH2-imidazolyl; or R a and R1 are the atoms to which they are bonded. Together with the child it forms a pyrrolidine ring; R2 is hydrogen, -(CH2)3NHC(=NH)NH2, -(CH2)2CONH2, represents -(CH2)2COOH, -CH2-phenyl, or -CH2-imidazolyl; R b is hydrogen; R3 is hydrogen, -CH2-phenyl, -(CH2)3NHC(= NH)NH2, -(CH2)2CONH2, -(CH2)2COOH, -(CH2)4N H2 or -CH2-imidazolyl; or R b and R3 is the bond between them forming a pyrrolidine ring together with the atoms attached thereto.

[0047] In certain embodiments, the composition has formula (IA): [ka] (In the formula, R1, R a and R2 is defined as in the compound of formula (I) is a pharma- ceutical acceptable salt or amide or ester thereof, or a stereoisomer thereof, This includes compounds of formula (I).

[0048] In certain embodiments, the composition comprises a compound of formula (IA), where R1 is: Hydrogen, -(CH2)2CONH2, -(CH2)2COOH, -(CH2)3NHC(= NH)NH2, -(CH2)4NH2, -CH2-phenyl, or -CH2-imidazo Represents Lil.

[0049] In certain embodiments, the composition comprises a compound of formula (IA), where R2 is: Hydrogen, -(CH2)3NHC(=NH)NH2, -(CH2)2CONH2, -(CH2 )2COOH, -CH2-phenyl, or -CH2-imidazolyl.

[0050] In certain embodiments, the compositions of the present invention comprise a compound of formula (IA), wherein R a is hydrogen; R1 is hydrogen, -(CH2)2CONH2, -(CH2)2COOH , -(CH2)3NHC(=NH)NH2, -(CH2)4NH2, -CH2-phenyl or -CH2-imidazolyl; R2 represents hydrogen, -(CH2)3NHC(=NH )NH2, -(CH2)2CONH2, -(CH2)2COOH, -CH2-phenyl, Or -CH2-imidazolyl.

[0051] In another embodiment, the composition comprises a compound of formula (IA), wherein R a Water R1 is -(CH2)2CONH2, -(CH2)2COOH, -(CH2) 3NHC(=NH)NH2 or -(CH2)4NH2. R2 is hydrogen, -(C H2)3NHC(=NH)NH2, -(CH2)2COOH, -CH2-phenyl or -CH2-imidazolyl.

[0052] In certain embodiments, the composition comprises: [ka] or a pharma- ceutical acceptable salt, amide, or ester thereof, or a stereoisomer thereof. The present invention includes compounds of formula (I) selected from the group consisting of

[0053] In certain embodiments, the composition comprises: [ka] or a pharma- ceutical acceptable salt, amide, or ester thereof, or a stereoisomer thereof. The present invention includes compounds of formula (I) selected from the group consisting of

[0054] In certain embodiments, the compositions may also be described by indicating the absolute stereochemistry. Formula (IA) [ka] This includes compounds of the formula:

[0055] In certain embodiments, the composition has formula (IB): [ka] (In the formula, R1, R a , R b and R3 is defined as in the compound of formula (I). or a pharma- ceutical acceptable salt or amide or ester, or a stereoisomeric The present invention includes compounds of formula (I) which are

[0056] In certain embodiments, the composition comprises a compound, wherein R is hydrogen, -(C H2)2CONH2, -(CH2)2COOH, -(CH2)3NHC(=NH)NH2 , -(CH2)4NH2, or -CH2-phenyl.

[0057] In certain embodiments, the composition comprises a compound where R is -(CH) 2CONH2, or -(CH2)2COOH.

[0058] In certain embodiments, the composition comprises a compound where R is hydrogen, -CH 2-phenyl, -(CH2)2CONH2, or -(CH2)2COOH.

[0059] In certain embodiments, the composition comprises a compound where R3 is hydrogen, or -CH2-phenyl.

[0060] In certain embodiments, the composition comprises a compound of formula (IB), where R b teeth, It is hydrogen.

[0061] In certain embodiments, in formula (IB), R b and R3 are the atoms to which they are bonded. Together with the alkyl group it forms a pyrrolidine ring.

[0062] In certain embodiments, the composition comprises a compound of formula (IB), where R is: -(CH2)2CONH2 or -(CH2)2COOH; R b is hydrogen R3 represents hydrogen or -CH2-phenyl; or R b and R3 are those together with the atom to which it is attached forms a pyrrolidine ring.

[0063] In certain embodiments, the composition comprises a compound of formula (I), wherein the compound is below, [ka] or a pharma- ceutical acceptable salt, amide, or ester thereof, or a stereoisomer thereof. It is selected.

[0064] In certain embodiments, the composition has formula (IC): [ka] (In the formula, R1, R a , R3 and R b is defined in the compound of formula (I) or a pharma- ceutically acceptable salt or amide or ester, or a stereoisomer thereof. This includes compounds of formula (I):

[0065] In certain embodiments, the composition comprises a compound where R is -(CH) 2CONH2, -(CH2)3NHC(=NH)NH2, or -(CH2)4NH2 be.

[0066] In certain embodiments, the composition comprises a compound where R is -(CH) 2CONH2, or -(CH2)3NHC(=NH)NH2.

[0067] In certain embodiments, the composition comprises a compound of formula (IC), wherein R a teeth, In certain embodiments, in formula (IC), R a and R1 are the results of Together with the atoms to which it is bonded it forms a pyrrolidine ring.

[0068] In certain embodiments, the composition comprises a compound where R is hydrogen, -CH 2-Phenyl, -(CH2)3NHC(=NH)NH2, or -CH2-Imidazolyl It is.

[0069] In certain embodiments, the composition comprises a compound of formula (IC), wherein R b teeth, It is hydrogen.

[0070] In certain embodiments, in formula (IC), R b and R3 are the atoms to which they are bonded. Together with the alkyl group it forms a pyrrolidine ring.

[0071] In another embodiment, the composition comprises a compound of formula (IC): a Water R1 is -(CH2)2CONH2, -(CH2)3NHC(=NH)NH2 or -(CH2)4NH2; or R a and R1 is the group where they are joined Together with the atom forms a pyrrolidine ring; R b is hydrogen; R3 is -CH2-phenyl -(CH2)3NHC(=NH)NH2, or -CH2-imidazolyl; Ruiha R b and R3 together with the atoms to which they are attached form a pyrrolidine ring.

[0072] In certain embodiments, the composition comprises a compound of formula (I), wherein the compound is below, [ka] or a pharma- ceutical acceptable salt, amide, or ester thereof, or a stereoisomer thereof. It is selected.

[0073] In certain embodiments, the composition has the formula (ID): [ka] (In the formula, R1, R a , R3 and R b is defined in the compound of formula (I) or a pharma- ceutically acceptable salt or amide or ester, or a stereoisomer thereof. The present invention includes compounds of formula (I).

[0074] In certain embodiments, the composition comprises a compound where R is -(CH) 3NHC(=NH)NH2, -(CH2)4NH2, or -CH2CONH2.

[0075] In certain embodiments, the composition comprises a compound wherein R is hydrogen, -(C H2)3NHC(=NH)NH2, or -(CH2)4NH2.

[0076] In certain embodiments, the composition comprises a compound of formula (ID), wherein R b teeth, It is hydrogen.

[0077] In certain embodiments, in formula (ID), R b and R3 are the atoms to which they are bonded. Together with the alkyl group it forms a pyrrolidine ring.

[0078] In another embodiment, the composition comprises a compound of formula (ID), wherein R1 is - (CH2)3NHC(=NH)NH2, -(CH2)4NH2, or -CH2CONH Represents 2;R b is hydrogen; R3 is hydrogen, -(CH2)3NHC(=NH)NH2 or -(CH2)4NH2; or R b and R3 is the group where they are joined. Together with the atoms form a pyrrolidine ring.

[0079] In certain embodiments, the composition comprises a compound of formula (I), wherein the compound is below, [ka] or a pharma- ceutical acceptable salt, amide, or ester thereof, or a stereoisomer thereof. In certain embodiments, the composition comprises a compound of formula (IE): [ka] (Wherein, R2, R3 and R b is defined in the compound of formula (I) is a pharma- ceutical acceptable salt or amide or ester thereof, or a stereoisomer of the formula ( I)

[0080] In certain embodiments, the composition comprises a compound where R2 is hydrogen, or -(CH2)3NHC(=NH)NH2.

[0081] In certain embodiments, the composition comprises a compound of formula (IE), where R b Oh and R3 together with the atoms to which they are attached form a pyrrolidine ring.

[0082] In another embodiment, the composition comprises a compound of formula (IE), wherein R2 is water. or -(CH2)3NHC(=NH)NH2, R b and R3 are Together with the atoms to which it is attached, it forms a pyrrolidine ring. In certain embodiments, the composition , Formula (IF): [ka] (Wherein, R2, R3 and R b is defined in the compound of formula (I) is a pharma- ceutical acceptable salt or amide or ester thereof, or a stereoisomer of the formula ( I)

[0083] In certain embodiments, the composition comprises a compound where R2 is hydrogen, -CH 2-Phenyl, -(CH2)3NHC(=NH)NH2, or -(CH2)2COOH It is.

[0084] In certain embodiments, the composition comprises a compound wherein R3 is -CH2- phenyl, -(CH2)2CONH2, or -(CH2)2COOH.

[0085] In certain embodiments, the composition comprises a compound of formula (IF), wherein R b teeth, It is hydrogen.

[0086] In certain embodiments, in formula (IF), R b and R3 are the atoms to which they are bonded. Together with the alkyl group it forms a pyrrolidine ring.

[0087] In certain embodiments, the composition comprises a compound of formula (IF), where R2 is: Hydrogen, -CH2-phenyl, -(CH2)3NHC(=NH)NH2, or -(CH2 )2COOH;R b is hydrogen; R is -CH-phenyl, -(CH) 2CONH2, or -(CH2)2COOH; or R b and R3 is together with the atom to which they are attached form a pyrrolidine ring.

[0088] In certain embodiments, the composition comprises a compound of formula (I), the compound having the following structure: [ka] or a pharma- ceutical acceptable salt, amide, or ester thereof, or a stereoisomer thereof. It is selected.

[0089] In certain embodiments, the composition comprises a compound, the compound being: [Table 1] TIFF2025063207000018.tif238161TIFF2025063207000019.tif238161TIFF2025063207000020.tif239161 or a pharma- ceutical acceptable salt or amide or ester, or a stereoisomer thereof. It is selected.

[0090] In a particular embodiment, the present invention provides a CD47-SIRPα antibody for use as a medicament. A composition comprising a blocking agent and one or more anti-cancer agents, is a compound of formula (I) or a pharma- ceutical acceptable salt thereof as described herein, is an amide or ester, or a stereoisomer; the anticancer agent is as described herein These drugs are chemotherapeutic agents such as cyclophosphamide, ...

[0091] In certain embodiments, the present invention provides a method for the treatment of a CD47-SIRPα blocker and one or more The present invention relates to a composition comprising an anti-cancer agent and a pharma- ceutical carrier, wherein the anti-cancer agent is a CD47-SI The RPα blocker may be a compound of formula (I) as described herein or a pharma- ceutical acceptable salt thereof. or a salt or amide or ester, or a stereoisomer thereof; the anticancer agent is as defined herein. A chemotherapeutic agent, or an immunomodulatory agent, as described herein.

[0092] In certain embodiments, the present invention provides a method for the treatment of a CD47-SIRPα blocker and one or more The present invention provides a combination comprising a number of anti-cancer agents, wherein the CD47-SIRPα blocker is a compound represented by the formula (I ):

[0093] [ka] (In the formula, R a is hydrogen; R1 is hydrogen, -(CH2)2CONH2, -(CH2)2CO OH, -(CH2)3NHC(=NH)NH2, -(CH2)4NH2, -CH2CON H2, -CH2-aryl, or -CH2-heteroaryl; or R a Oh and R1 together with the atoms to which they are attached form a pyrrolidine ring; R2 is hydrogen, -(CH2)3NHC(=NH)NH2, -(CH2)2CONH2, -(CH2)2COOH, -CH2-aryl, or -CH2-heteroaryl ; R b is hydrogen; R3 is hydrogen, -CH2-aryl, -(CH2)3NHC(= NH)NH2, -(CH2)2CONH2, -(CH2)2COOH, -(CH2)4N H2 or -CH2-heteroaryl; or R b and R3 is the bond between them forms a pyrrolidine ring together with the atom to be or a pharma- ceutical acceptable salt or amide or ester, or a stereoisomeric Represented by the body.

[0094] In a particular embodiment, the combination of the present invention comprises a CD47-SI Includes RPα blockers and proteasome inhibitors.

[0095] In a particular embodiment, the combination of the present invention comprises a CD47-SI These include RPα blockers and anti-CD20 antibodies.

[0096] In certain embodiments, the combination of the present invention is represented by formula (IA), (IB), (IC), (ID), (IE), or (IF) compound CD47-SIRPα blocker.

[0097] In certain embodiments, the present invention relates to a cancer in a subject exhibiting a dysregulated CD47 pathway. The present invention relates to a method for treating a patient suffering from atopic dermatitis, the method comprising administering a therapeutically effective amount of a CD47-SIRPα blocking agent to a patient suffering from atopic dermatitis, the ... administering to a subject in combination with an effective amount of one or more anti-cancer agents, SIRPα blockers have the formula (I):

[0098] [ka] (In the formula, R a is hydrogen; R1 is hydrogen, -(CH2)2CONH2, -(CH2)2CO OH, -(CH2)3NHC(=NH)NH2, -(CH2)4NH2, -CH2CON H2, -CH2-aryl, or -CH2-heteroaryl; or R a Oh and R1 together with the atoms to which they are attached form a pyrrolidine ring; R2 is hydrogen, - (CH2)3NHC(=NH)NH2, -(CH2)2CONH2, -(CH2)2CO represents OH, -CH2-aryl, or -CH2-heteroaryl; R b is hydrogen R3 is hydrogen, -CH2-aryl, -(CH2)3NHC(=NH)NH2, -( CH2)2CONH2, -(CH2)2COOH, -(CH2)4NH2 or -CH2 -heteroaryl; or R b and R3 together with the atom to which they are attached forming a pyrrolidine ring) or a pharma- ceutical acceptable salt or amide or ester, or a stereoisomeric Represented by the body.

[0099] In certain embodiments, a subject exhibiting a dysregulated CD47 pathway is a subject having CD47+ disease cells. In certain embodiments, the CD47+ disease cells are It is a cancer cell.

[0100] In certain embodiments, the present invention relates to a method for treating cancer with one or more anti-cancer agents comprising administering to a patient of formula (I or a pharma- ceutical or pharmaceutical acceptable salt thereof. The following relates to the method.

[0101] In certain embodiments, the present invention relates to a method for treating a disease mediated by the CD47 pathway in a subject. or a method for treating or slowing the progression of a disorder, A therapeutically effective amount of CD47-SIRPα transduction inhibitor in combination with an effective amount of one or more anti-cancer agents. administering to a subject in need thereof an agent that blocks the CD47-SIRP pathway; Agents that block the alpha pathway include those represented by formula (I):

[0102] [ka] (In the formula, R a is hydrogen; R1 is hydrogen, -(CH2)2CONH2, -(CH2)2COO H, -(CH2)3NHC(=NH)NH2, -(CH2)4NH2, -CH2CONH 2, -CH2-aryl, or -CH2-heteroaryl; or R a and R1 together with the atoms to which they are attached form a pyrrolidine ring; R2 is hydrogen, -( CH2)3NHC(=NH)NH2, -(CH2)2CONH2, -(CH2)2COO H, -CH2-aryl, or -CH2-heteroaryl; R b is hydrogen ; R3 is hydrogen, -CH2-aryl, -(CH2)3NHC(=NH)NH2, -(C H2)2CONH2, -(CH2)2COOH, -(CH2)4NH2 or -CH2- represents heteroaryl; or R b and R3 together with the atom to which they are attached Forms a rolidine ring) or a pharma- ceutical acceptable salt or amide or ester, or a stereoisomeric Represented by the body.

[0103] In a specific embodiment, the present invention relates to a disease mediated by the CD47-SIRPα pathway. Or the disorder is cancer.

[0104] In certain embodiments, the present invention relates to a method for treating a disease or disorder mediated by the CD47 pathway. The present invention relates to a method for treating atherosclerosis.

[0105] In certain embodiments, the present invention relates to a method for treating a disease or disorder mediated by the CD47 pathway. The method relates to multiple sclerosis.

[0106] In certain embodiments, the present invention provides a pharmaceutical composition comprising a pharmaceutical composition, optionally in admixture with a pharma- ceutical acceptable carrier or diluent. In addition, pharmaceutical compositions are provided that include the compounds as disclosed herein in combination.

[0107] In certain embodiments, the present invention relates to a cancer in a subject exhibiting a dysregulated CD47 pathway. In the manufacture of a medicament for the treatment of Use of a composition comprising an RPα blocker and one or more anti-cancer agents is provided.

[0108] In certain embodiments, the present invention provides compositions and methods for treating dysregulation as described herein. A package insert containing instructions for administration of the agent to treat a subject presenting the entire CD47 pathway. A kit comprising:

[0109] The invention also provides methods for formulating the disclosed compounds for pharmaceutical administration. do.

[0110] The compositions and methods of the present invention may be utilized to treat an individual in need thereof. In certain embodiments, the individual is a mammal, such as a human, or a non-human mammal. When administered to an animal, such as a human, the composition preferably contains, for example, a compound of the invention and The compound is administered as a pharmaceutical composition comprising a medicament and a pharma- ceutical acceptable carrier. Therefore, such pharmaceutical compositions are suitable for administration to humans, particularly via non-invasive routes of administration (i.e. , for routes such as injection or implantation that avoid transport or diffusion through epithelial barriers. In such cases, the aqueous solution is pyrogen-free or substantially pyrogen-free. The excipient may be, for example, used to affect delayed release of the drug or to provide one or more The pharmaceutical compositions can be selected to selectively target a cell, tissue or organ. Capsules (including sprinkle capsules and gelatin capsules), granules, frozen for reconstitution It may be in the form of a unit dosage such as a lyophile, a powder, a solution, a syrup, a suppository, an injection, etc. The composition may also be present in a transdermal delivery system, such as a skin patch. It may also be in a solution suitable for topical administration, such as eye drops.

[0111] The pharma- ceutically acceptable carrier may, for example, stabilize the compound or increase its solubility. , or may contain a physiologically acceptable agent which acts to enhance its absorption. Such physiologically acceptable agents include, for example, glucose, sucrose or dextran. Carbohydrates such as tolan, antioxidants such as ascorbic acid or glutathione, chelates Physiologically acceptable. The choice of pharma- ceutical acceptable carrier that contains the drug will depend, for example, on the route of administration of the compound. The preparation of the pharmaceutical composition may be carried out using a self-emulsifying drug delivery system or a self-microemulsifying drug delivery system. The pharmaceutical composition (formulation) can also be, for example, a pharmaceutical composition that contains the compound of the present invention. The liposome or other polymer matrix may be incorporated into the Liposomes, which contain phospholipids or other lipids, are relatively easy to prepare and administer, and are non-toxic. It is a non-toxic, physiologically acceptable and metabolizable carrier.

[0112] The agents in the composition are administered simultaneously, i.e., each agent is administered in a manner consistent with the other agents in the combination. Within about 45 days, within about 30 days, within about 15 days, within about 7 days, within about 3 days, within about 2 The drugs are administered within a day, within about a day, or substantially simultaneously. When the dosing schedule is set to achieve therapeutic serum levels, the drugs It can be thought that this is the case.

[0113] In certain embodiments, for administration, each CD47-SIRPα blockade is administered in combination. The dose of each of the drugs and anticancer drugs is within the range of about 0.0001 to 100 mg / kg of the host body weight, preferably 0.0001 to 0.1 mg / kg. The dosage is usually 0.01 to 50 mg / kg. For example, the dosage is 1 mg / kg body weight, 1 It may be 0 mg / kg body weight or 30 mg / kg body weight, or it may be 1 to 50 mg / kg The dose may be within the range of 0.5-1.5 mg / kg of CD47-SIRPα blocking agent or anti-cancer agent. The molecular weight of each agent can be adjusted for the molecular weight of each agent, as required for monotherapy of either agent in the combination. Typical treatment regimes include daily, twice weekly, weekly, or biweekly. It requires administration once a week, once a month, etc.

[0114] The expression "pharmaceutical acceptable" means, within the bounds of good medical common sense, a substance that is free from undue toxicity, irritation, or acidity. No allergic reactions or other problems or complications have been reported, and there is a reasonable benefit / risk ratio , compounds, materials and compositions thereof suitable for use in contact with human and animal tissues - Patents.com and / or dosage forms.

[0115] As used herein, the expression "pharmaceutical acceptable carrier" refers to solid fillers, A pharma- ceutically acceptable material, composition or liquid, such as a diluent, excipient, solvent or encapsulating material. Each carrier must be compatible with the other ingredients of the formulation and must not be harmful to the patient. It must be "acceptable" in the sense that it is not a medicament that is Some examples of materials that can be used are: (1) sugars such as lactose, glucose, and sucrose; (2) Starches such as corn starch and potato starch; (3) Carboxymethyl cellulose cellulose and cellulose acetate, such as sodium cellulose, ethyl cellulose and cellulose acetate; its derivatives; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; ( 8) Excipients such as cocoa butter and suppository wax; (9) Peanut oil, cottonseed oil, safflower oil (10) propylene glycol; (11) Glycols such as glycerin, sorbitol, mannitol and polyethylene; (12) Polyols such as ethyl oleate and ethyl laurate; (13) Agar; (14) Magnesium hydroxide and aluminum hydroxide (15) Alginic acid; (16) Pyrogen-free water; (17) etc. (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solution ; and (21) other non-toxic, compatible materials used in pharmaceutical formulations.

[0116] The pharmaceutical composition (formulation) can be, for example, administered orally (e.g., in an aqueous or non-aqueous solution or as a suspension). Liquid potions, tablets, and capsules (including sprinkle capsules and gelatin capsules) , bolus, powder, granule, paste for application to the tongue); absorption through the oral mucosa (e.g. sublingually; anally, enterally or vaginally (e.g., by pessaries, creams or as a foam; parenterally (e.g., intramuscularly, intravenously, subcutaneously, as a sterile solution or suspension) or intrathecal; intranasal; intraperitoneal; subcutaneous; transdermal (e.g., a patch applied to the skin) as a medicament; as a topical (e.g., cream, ointment or spray applied to the skin) or as eye drops) to a subject by any of a number of routes of administration. The compounds can also be formulated for inhalation. In certain embodiments, The compound may simply be dissolved or suspended in sterile water.

[0117] The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. The amount of each active ingredient in the composition that can be combined with a carrier material to produce a single dosage form can be The dosage form will vary depending on the host being treated and the particular mode of administration. The amount of each active ingredient in a composition that can produce a single dosage form is generally determined by the amount of compound that produces a therapeutic effect. Generally, out of 100%, this amount will be about 1% to about 99% of each active ingredient, preferably Most preferably, it will be in the range of about 5% to about 70%, and most preferably, about 10% to about 30%.

[0118] Methods for preparing these formulations or compositions include incorporating the composition into a carrier and optionally one or more Generally, the formulations include combining the compounds of the present invention in a liquid carrier or or finely divided solid carriers, or both, and then If necessary, the article is shaped to prepare a shape.

[0119] Formulations of the present invention suitable for oral administration include capsules (sprinkle capsules and gelatin capsules). capsules), cachets, pills, tablets, lozenges (flavor-based, usually spaghetti) sucrose and acacia or tragacanth), in lyophilized, powdered, or granular form as a liquid, or as a solution or suspension in an aqueous or non-aqueous liquid, or as an oil-in-water liquid or as a water-in-oil emulsion, or as an elixir or syrup, or as a lozenge Pastille (gelatin and glycerin, or sucrose and acacia, etc.) active base) and / or mouthwash, etc., Each of the compositions contains a predetermined amount of the composition of the present invention as a therapeutically active combination. It may also be administered as a bolus, electuary or paste.

[0120] Solid dosage forms for oral administration (capsules (including sprinkle capsules and gelatin capsules) For the preparation of pharmaceutical preparations such as tablets, pills, dragees, powders, granules, etc., compositions as described. may be one or more pharma- ceutical acceptable salts, such as sodium citrate or dicalcium phosphate. and / or the following: (1) starch, lactose, sucrose, glucose, (2) fillers or extenders, such as mannitol, and / or silicic acid; Dimethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and (3) a humectant such as glycerol; (4) agar, charcoal, etc. calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and carbonates (5) solution retarding agents such as paraffin (6) absorption enhancers such as quaternary ammonium compounds; (7) e.g., cetyl alcohol (8) wetting agents such as glycerol and glycerol monostearate; (9) kaolin and ventolin (9) Absorbents such as talc, calcium stearate, magnesium stearate, etc. Solid polyethylene glycol, sodium lauryl sulfate and mixtures thereof. (10) complexing agents such as modified and unmodified cyclodextrins; and (11 ) coloring agent. Capsules (sprinkle capsules and gelatin capsules) In the case of capsules, tablets and pills, the pharmaceutical compositions may also comprise buffering agents. This type of solid composition also contains lactose or milk sugar, as well as high molecular weight polyethylene glycol. Filling agent in soft and hard filled gelatin capsules using excipients such as choler may be used as.

[0121] A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may contain binders (e.g., gelatin or hydroxypropyl methylcellulose). syrup), lubricants, inert diluents, preservatives, disintegrants (e.g., sodium starch glycolate or cross-linked sodium carboxymethylcellulose), surfactants or dispersants are not used. Molded tablets can be prepared by mixing the powdered compound moistened with an inert liquid diluent. It can be produced by molding in a suitable machine.

[0122] Tablets, sugar-coated tablets, capsules (including sprinkle capsules and gelatin capsules) ), other solid dosage forms of the pharmaceutical composition, such as pills and granules, may optionally be enterically coated and and other coatings well known in the pharmaceutical formulation art. They can also be obtained or prepared in various ways, e.g., to provide a desired release profile. Hydroxypropyl methylcellulose in various proportions, other polymer matrices, lipopolysaccharides, Using serosomes and / or microspheres, the active ingredients in the complex are slowly or They can be formulated to give controlled release. For example, they can be passed through a bacteria-retaining filter. By filtration through a filter, or with sterile water, or some other sterile injectable medium, immediately before use. Sterilization can be achieved by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved in water. The composition may also optionally include an opacifying agent, which allows the absorption of the drug in a particular portion of the digestive tract, optionally in a delayed manner. The compositions may be compositions that release only the active ingredients or preferentially release them. Examples of embedding compositions include polymeric substances and waxes. The active ingredient may also optionally be The pharmaceutical compositions may be in microencapsulated form with one or more excipients as noted above.

[0123] Liquid dosage forms useful for oral administration include pharma- ceutical acceptable emulsions, lyophilizates for reconstitution, malic acids, and the like. Includes emulsions, solutions, suspensions, syrups and elixirs. Liquid dosage forms can be prepared by dissolving inert diluents commonly used in the art, such as water or other liquids. Solvents, cyclodextrin and its derivatives, ethyl alcohol, isopropyl alcohol ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol Coal, 1,3-butylene glycol, oils (especially cottonseed oil, peanut oil, corn oil, germ oil) , olive oil, castor oil and sesame oil), glycerol, tetrahydrofuryl alcohol , fatty acid esters of polyethylene glycol and sorbitan, and mixtures thereof The composition may include solubilizers and emulsifiers such as:

[0124] Besides inert diluents, the oral compositions also include usable agents such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents, and the like. Adjuvants such as flavourings, colourings, fragrances and preservatives may be included.

[0125] The suspension may contain, in addition to the active ingredient, e.g., ethoxylated isostearyl alcohol, polyoxyethylene Dioxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, methacrylate crosspolymer Suspensions such as aluminum, bentonite, agar and tragacanth, and mixtures thereof. The composition may contain a shaping agent.

[0126] Formulations of the pharmaceutical composition for rectal, vaginal, or urethral administration may include one or more of the compositions. The active ingredient is, for example, cocoa butter, polyethylene glycol, a suppository wax or saponaria. It contains a lithylate salt and is solid at room temperature but liquid at body temperature, so it can be administered rectally or One or more suitable non-irritating excipients or carriers that melt in the vaginal cavity and release the active ingredient(s). It may also be present as a suppository which can be prepared by mixing with a pharmaceutical agent.

[0127] Formulations of the pharmaceutical composition for administration to the mouth may be in the form of a mouthwash, or a mouth spray, or It may be present as a mouth ointment.

[0128] Alternatively, or in addition, the composition may be applied to a catheter, stent, wire, or other cavity. The drug may be formulated for delivery via an intravesical device. Delivery via such a device may be It may be particularly useful for delivery to the bladder, urethra, ureter, rectum, or intestine.

[0129] Formulations suitable for vaginal administration also include those carriers known in the art to be suitable. Body products including diaphragms, tampons, creams, gels, pastes, foams or sprays Contains agents.

[0130] Dosage forms for topical or transdermal administration include powders, sprays, ointments, pastes, creams, The active compound is administered under sterile conditions in a pharmaceutical preparation, including lotions, gels, solutions, patches and inhalants. and mixed with a commercially acceptable carrier, and with any preservatives, buffers, or propellants which may be required. It is okay to do so.

[0131] Ointments, pastes, creams and gels contain, in addition to the active compound, animal fats and vegetable oils. Fatty fats, oils, waxes, paraffins, starches, tragacanth, cellulose derivatives, polyethylene Excipients such as ethylene glycol, silicone, bentonite, silicic acid, talc and zinc oxide , or a mixture thereof.

[0132] Powders and sprays contain, in addition to the active compound, lactose, talc, silicic acid, aluminum hydroxide, etc. Common excipients such as ammonium nitrate, calcium silicate and polyamide powder, or The spray may contain a mixture of substances. It may additionally include volatile unsubstituted hydrocarbons such as butane and propane.

[0133] Transdermal patches have the added advantage of providing controlled delivery of a compound of the present invention to the body. Such dosage forms can be made by dissolving or dispersing the active compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate of such flow can be controlled by providing a rate controlling membrane or by providing a polymer matrix or can be controlled by either dispersing the compound in the gel.

[0134] As used herein, the expressions "parenteral administration" and "parenterally administered" refer to It refers to a mode of administration other than enteral administration and topical administration, usually by injection, including but not limited to: , intravenous, intramuscular, intraarterial, intrathecal, intravesical, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, transdermal This includes subcutaneous, subcutaneous, intra-articular, subcapsular, subarachnoid, intraspinal and intrasternal injections and infusions.

[0135] Pharmaceutical compositions suitable for parenteral administration may be prepared in the form of one or more pharma- ceutical acceptable sterile isotonic aqueous solutions. liquid or non-aqueous solution, dispersion, suspension or emulsion, or as a sterile injectable solution or The dispersion contains one or more active compounds in combination with a sterile powder that can be reconstituted with a dispersion liquid. These include antioxidants, buffers, bacteriostats, and solvents that make the formulation isotonic with the blood of the intended recipient. The formulation may contain a suspending or thickening agent.

[0136] Examples of suitable aqueous and non-aqueous carriers that can be used in the pharmaceutical compositions of the present invention include water, ethanol, and the like. Alcohols, polyols (glycerol, propylene glycol, polyethylene glycol, etc.) etc.), and suitable mixtures thereof, vegetable oils such as olive oil, and ethyl oleate. Suitable fluidity includes, for example, a coating such as lecithin. By using a lining material, by maintaining the required particle size in the case of dispersions, and by This can be maintained by using an activator.

[0137] These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. The prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, e.g., parabens, chlorhexidine gluconate, chlorhexidine dichloride ... dichloride, chlorhexidine dichloride, chlorhexidine dichloride, chlorhexidine dichloride, chlorhexidine dichloride, This can be ensured by including isopropyl alcohol, phenol sorbic acid, etc. It may be desirable to include isotonic agents such as sodium chloride, etc. in the composition. In addition, the long-term absorption of injectable pharmaceutical forms is due to the presence of aluminum monostearate and gelatin. This can be brought about by the inclusion of agents which delay absorption, such as.

[0138] In some cases, the absorption of drugs from subcutaneous or intramuscular injections can be increased to prolong the drug's effect. This is desirable in liquid suspensions of crystalline or amorphous material that is poorly water soluble. This can be achieved by using a liquid. Therefore, the rate of absorption of the drug depends on its rate of dissolution, which is This in turn may depend on the crystal size and crystal form. Delayed absorption of a prescribed drug form is accomplished by dissolving or suspending the drug in an oil vehicle. .

[0139] Injectable depot dosage forms may be formulated by encapsulating the subject pharmaceutical compositions in biodegradable polymers such as polylactide-polyglycolide. These are produced by forming microencapsulated matrices of the compound. Drug to Polymer Depending on the ratio of polymers used, and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and polyanhydrides. Depot formulations also contain the drug in liposomes or microemulsions that are compatible with body tissues. It is prepared by encapsulation.

[0140] Methods of introduction may also be provided by reinjectable or biodegradable devices. Low release polymeric devices have been recently developed for the controlled delivery of drugs, including protein biologics. Developed and tested in vivo. Both biodegradable and non-degradable polymers. A variety of biocompatible polymers (including hydrogels) are available for use at specific target sites. The present compositions can be used to form implants for sustained release of the compounds.

[0141] The actual dosage level of the active ingredient in the pharmaceutical composition may be determined to be sufficient for a particular patient without toxicity to the patient. and the amount, composition, and mode of administration of the active ingredients that are effective to achieve the desired therapeutic response for may be varied to achieve

[0142] The dosage level selected will depend on the compound, or its ester, salt or amide, being used. The activity of the particular combination of, the route of administration, the time of administration, and the excretion of the particular compound used. The rate of progression, duration of treatment, other drugs used in combination with the particular compound used, objects and / or materials, the age, sex, weight, medical condition, general health and medical history of the patient to be treated The nature of the disease depends on a variety of factors, including the patient's medical history, as well as factors well known in the medical arts.

[0143] In general, suitable daily doses of the active compounds used in the compositions and methods of the present invention are: The lowest effective dose of a compound is that amount that is effective to produce a therapeutic effect. Such an effective dose is , generally depends on the factors mentioned above.

[0144] The patient receiving this treatment may be any animal in need, generally a primate, particularly mainly in humans and other mammals such as horses, cattle, pigs and sheep; as well as poultry and This includes pets.

[0145] Wetting agents, emulsifying agents and additives such as sodium lauryl sulfate and magnesium stearate Lubricants, as well as coloring agents, release agents, coating agents, sweeteners, flavorings and fragrances, preservatives Antioxidants and antioxidants may also be present in the composition.

[0146] Examples of pharma- ceutically acceptable antioxidants include: (1) ascorbic acid, cysteine ​​hydrochloride, sulfuric acid, and the like. Water-soluble antioxidants such as sodium hydrogen sulfite, sodium metabisulfite, and sodium sulfite (2) Ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated Hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol (3) oil-soluble antioxidants such as citric acid, ethylenediaminetetraacetic acid (EDT) A) metal chelating agents such as sorbitol, tartaric acid, and phosphoric acid.

[0147] In certain embodiments, the compositions described herein are administered to cancer cells, e.g., AML cells. In another embodiment, the phagocytic activity is enhanced by the macrophage phagocytic activity of the For macrophages in the absence of the composition described in the document, for example, 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% stronger.

[0148] In certain embodiments, the present invention provides the use of a composition of the present invention for the preparation of a medicament. do.

[0149] In certain embodiments, the present invention relates to a method for the preparation of a medicament, e.g., for the treatment of cancer. Uses of the compositions of the invention are provided.

[0150] In certain embodiments, the present invention provides a method for treating cancer, the method comprising: This involves administering a composition of the invention to a subject in need thereof, for example in a therapeutically effective amount.

[0151] In certain embodiments, the present invention provides a method for administering to a subject in need thereof, e.g., in a therapeutically effective amount. and inhibiting tumor cell proliferation and / or metastasis by administering the composition of the present invention. The present invention provides a method for

[0152] Representative tumor cells include, but are not limited to, melanoma, renal carcinoma, prostate cancer, breast cancer, colon cancer, and Lung cancer, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, cutaneous or intraocular malignant melanoma, uterine cancer, ovarian cancer, Rectal cancer, cancer of the anal region, stomach cancer, testicular cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, vagina cancer of the esophagus, cancer of the vulva, Hodgkin's disease, non-Hodgkin's lymphoma, esophageal cancer, small intestine cancer, cancer of the endocrine system , thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, acute myeloid leukemia, acute This includes myeloid leukemia, chronic myelogenous leukemia, acute lymphocytic leukemia, and chronic lymphocytic leukemia. Chronic or acute leukemia, solid tumors of childhood, lymphocytic lymphoma, bladder cancer, kidney or urinary Carcinoma of the renal duct, carcinoma of the renal pelvis, neoplasms of the central nervous system (CNS), non-small cell lung cancer (NSCLC), Primary central nervous system malignant lymphoma, tumor angiogenesis, spinal axis tumor, brain stem glioma, pituitary adenoma, caput sarcoma, epidermoid carcinoma, squamous cell carcinoma, T-cell lymphoma, B-cell lymphoma, myeloproliferative disorder / new Myelodysplastic syndromes; Giant cell myeloma, heavy chain myeloma, light chain myeloma and vein myeloma myeloma, including asbestos-induced (e.g., mesothelioma) The present invention includes cells of cancers such as tumor-associated cancers, tumor-associated cancers, and combinations of the aforementioned cancers.

[0153] The term "treating" includes prophylactic and / or therapeutic treatments. "Therapeutic" treatments are art-recognized and include one or more of the subject compositions. This includes the administration of a compound to a host that causes an undesired condition (e.g., a disease in the host animal or an undesired If administered prior to clinical symptoms of the disease (presence of the disease), then the treatment is prophylactic (i.e., i.e., to protect the host from progressing to undesirable disease states), but If administered after symptoms, the treatment is curative (i.e., to treat an existing undesired condition). or is intended to reduce, ameliorate, or stabilize the side effects thereof).

[0154] As used herein, the term "compound" refers to a compound of formula (I), (IA), (IB), Compounds of formula (I), (I), (I), (I), (I) and their pharma- ceutically acceptable salts This includes salts thereof or stereoisomers thereof.

[0155] As used herein, the term "aryl" refers to a substituted or unsubstituted ring in which each atom of the ring is carbon. or an unsubstituted monocyclic aromatic group. Preferably, the ring is a 5- to 7-membered ring, more preferably , 6-membered ring. The term "aryl" also refers to rings in which at least one of the rings is aromatic, e.g. The other cyclic ring is a cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heterocyclic, and / or heterocyclyl, Also includes polycyclic ring systems having two or more rings common to two adjacent rings. Aryl groups include benzene, naphthalene, phenanthrene, etc. Preferably, the term "Aryl" includes phenyl.

[0156] The term "heteroaryl" refers to a ring structure containing at least one heteroatom, preferably , substituted or unsubstituted, containing 1 to 4 heteroatoms, more preferably 1 or 2 heteroatoms. The substituted aromatic monocyclic structure preferably contains a 5- to 7-membered ring, more preferably a 5- to 6-membered ring. "Heteroaryl" and "hetaryl" also refer to two or more carbon having two or more cyclic rings which are common to adjacent rings, and at least one of the rings is a heterocycle, for example, the other cyclic ring is a cycloalkyl, cycloalkenyl, cyclo Polycyclic, which may be alkynyl, aryl, heteroaryl and / or heterocyclyl Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazoline, and the like. azole, oxazole, thiazole, pyrazole, pyridine, pyrazine, pyridazine, indole 1,2,4-oxadiazole, 1,3,4-oxadiazole, 1,3,4-thiol Heteroaryl groups include diazole, benzimidazole, pyrimidine, etc. Any optional substituent described herein may have one or more groups as permitted by valency. Preferably, the term "heteroaryl" includes imidazolyl and and indolyl.

[0157] As used herein, a treatment that "prevents" a disorder or condition is a statistically significant event. In a method of treating a subject, the present invention provides a method for treating a subject, the method comprising: or the occurrence of one or more symptoms of a disorder or condition relative to an untreated control sample. It refers to a compound that delays or reduces its severity.

[0158] The term "treating" includes prophylactic and / or therapeutic treatments. "Therapeutic" treatments are art-recognized and include one or more of the subject compositions. This includes the administration of a compound to a host that causes an undesired condition (e.g., a disease in the host animal or an undesired If administered prior to clinical symptoms (i.e., a state in which the patient is not at risk of developing a disease), then the treatment is prophylactic (i.e., , protecting the host from progressing to undesired disease states), while If administered after symptoms, the treatment is curative (i.e., corrects existing unwanted disease). (intended to reduce, ameliorate, or stabilize the symptoms or side effects of

[0159] As used herein, the expression "delayed progression" refers to the slowing down of disease progression or progression of a disease. Delaying symptoms in time (the appearance or onset of at least one symptom of a particular disease) This refers to a procedure or application intended to affect a given action (including a time delay).

[0160] The term "prodrug" refers to a compound that, under physiological conditions, produces a therapeutically active agent of the present invention, e.g. The prodrug is intended to include compounds that are converted to the compound of formula (I). A common method for preparation is to hydrolyze under physiological conditions to reveal the desired molecule, 1 In another embodiment, the prodrug may be a medicament that includes one or more selected moieties. The enzymes are converted to esters or carbonates (e.g., The preferred prodrugs of the present invention are esters or carbonates of alcohols or carboxylic acids. In certain embodiments, the compound of formula (I) in the formulation depicted above is Some or all of the hydroxyl groups in the parent compound can be replaced with the corresponding suitable prodrugs, e.g. Hydroxyl may exist as an ester or carbonate, or may be free of the carboxylates present in the parent compound. The carboxylic acids exist as esters.

[0161] As used herein, the term "comprise" or "including" "Including" is generally used in the sense of including, i.e. including one or more additional (non- Allows the presence of a particular) function or ingredient.

[0162] As used herein, the terms "including" and "comprise Other forms such as "include", "includes" and "included" are , but is not limited to.

[0163] As used herein, the term "disease" or "disorder" refers to, but is not limited to, Symptoms that are attributable to and identifiable by a cause or condition, including an infectious disease, acquired condition, or genetic condition It refers to a pathological condition in an organism that is characterized by

[0164] As used herein, a "patient" or a "subject" or an "individual" to be treated. " includes non-human animals, including humans and / or mammals. Mammals include humans, chimps, Primates such as dogs, horses, cats, pigs, goats, cows, etc. Any domestic animals; as well as rodents such as mice, rats, hamsters and gerbils Includes.

[0165] The term CD47+ disease cells refers to cells that have the phenotype CD47+ and are associated with disease. In one embodiment, the CD47+ disease cells are cancer cells.

[0166] The term "CD47+" refers to the CD47-SIRPα antagonists that are targeted for binding. The term is used in reference to the phenotype of cells that are CD47+. Cells that are CD47+ have a specific affinity for They can be identified by flow cytometry using CD47 antibodies. 47 antibodies are commercially available for this use (e.g., antibody generation of clone B6H12). (The material is available from Santa Cruz Biotechnology.) The cells examined are specifically taken from subjects suspected of harboring endogenous CD47+ cancer cells. For therapy with the present drug combinations, standard tumor biopsy samples may be included, including blood samples. CD47 disease cells that are of particular interest as targets for this purpose are those that "overexpress" CD47. These CD47+ cells are typically diseased cells and do not represent the positive control for a given type of cell. CD47 overexpression. The current methods vary across different cell types, but as used herein, e.g., flow cytometry By cytometry, immunohistochemistry, gene expression analysis, etc., the cells Measurable levels in healthy counterpart cells with a CD47 phenotype that is normal for the species The term refers to any CD47 level determined to be greater than 100%.

[0167] The present invention also provides compositions comprising pharma- ceutical acceptable salts of the compounds described herein, and In certain embodiments, the present invention includes compositions and methods for their use. The salts include, but are not limited to, alkyl, dialkyl, trialkyl or tetra-alkyl. In certain embodiments, contemplated salts of the present invention include, but are not limited to, ammonium salts. However, L-arginine, benethamine, benzathine, betaine, calcium hydroxide, choline , diethanolamine, diethylamine, 2-(diethylamino)ethanol ethanolamine, ethylenediamine, N-methylglucamine, hydrabamine, 1H -Imidazole, lithium, L-lysine, magnesium, 4-(2-hydroxyethyl) Morpholine, piperazine, potassium, 1-(2-hydroxyethyl)pyrrolidine, sodium In certain embodiments, the amine salts include ammonium, triethanolamine, tromethamine, and zinc salts. In this regard, contemplated salts of the present invention include, but are not limited to, Na, Ca, K, Mg, Zn or other salts. This includes metal salts of

[0168] Pharmaceutically acceptable acid addition salts also include those obtained by dissolving in water, methanol, ethanol, dimethylformamide, or the like. Mixtures of such solvates may exist. The source of such solvates can be the solvent of crystallization, the solvent of preparation or crystallization. The solvent may be inherent in the solvent or may be associated with such solvent.

[0169] As used herein, the term "pharmaceutically acceptable salt" refers to a salt that is known and can be used in pharmaceutical The term "pharmaceutical acceptable salt" is intended to include all salts used in the art. , including but not limited to, chloroprocaine, choline, N,N'-dibenzyl-ethylenediamine amine, ammonia, diethanolamine and other hydroxyalkylamines, ethylenediamine amine, N-methylglucamine, procaine, N-benzyl-phenethylamine, 1-pa Benzyl-2-chloro-pyrrolidin-1'-ylmethyl-benzimidazole, diene ethylamine and other alkylamines, piperazine and tris(hydroxy-methyl) amine salts such as aminomethane; salts of alkali metals; such as, but not limited to, barium, calcium and manganese potassium earth metal salts; transition metal salts, such as, but not limited to, zinc; and Other metal salts such as, but not limited to, sodium hydrogen phosphate and disodium phosphate salts of mineral acids, such as, but not limited to, hydrochlorides and sulfates; and Including but not limited to acetate, lactate, malate, tartrate, citrate, ascorbate salts of organic acids such as, but not limited to, succinate, butyrate, valerate and fumarate salts. Representative pharma- ceutically acceptable salts include acetate, lactobionate, benzenesulfonate, and phenylsulfonate. Phosphates, laurates, benzoates, malates, bicarbonates, maleates, bisulfates, Mandelate, bitartrate, mesylate, borate, methyl bromide, methyl nitrate, edetic acid Calcium, methylsulfate, camsylate, mucate, carbonate, napsylate, bromide , chloride, nitrate, clavulanic acid, N-methylglucamine, citrate, ammonium salt , dihydrochloride, oleate, edetate, oxalate, edisylate, pamoate (embol phosphate), estolate, palmitate, esylate, pantothenate, fumarate, Phosphates / diphosphates, gluceptates, polygalacturonates, gluconates, salicylate Salts, glutamate, stearate, glycolyl arsenate, sulfate, hexahydrate Silresorcinate, Acetate, Hydrabamine, Succinate, Hydrobromide, Tannic acid salt phosphate, hydrochloride, tartrate, hydroxynaphthoate, theoclate, iodide, tosyl acid salts, isothionates, triethiodides, lactates, panoates and valerates, They can be used as dosage forms to modify the solubility or hydrolysis characteristics or The pharma- ceuticals described above can be used in sustained release or prodrug formulations. The preparation of these and other typical pharma- ceutical acceptable salts is described in detail in Berg et al., "P ``harmaceutical salts'', J.Pharm.Sci.66:1-19 (1977) for a more complete description.

[0170] The term "stereoisomer" refers to any enantiomer, diastereoisomer, or mixture of any of the compounds described herein. When such compounds are chiral, they are called stereoisomers, or geometric isomers. may exist in racemic or optically active form. The racemic compounds according to the invention The pharmaceutical activity of the enantiomers or stereoisomers may differ, so one enantiomer is more likely to be used. In these cases, it may be desirable to use compounds such as Furthermore, intermediates may be chemically modified compounds known to those skilled in the art or may be used per se in the synthesis. Alternatively, the enantiomeric compounds can be separated by physical means. In some cases, diastereomers are formed from the mixture by reaction with an optically active resolving agent. Examples of suitable resolving agents are tartaric acid, diacetyl tartaric acid, dibenzoyl tartaric acid, mandelic acid, and malonic acid. acid, lactic acid, an appropriate N-protected amino acid (e.g., N-benzoylproline or N-benzene camphorsulfonylproline), or the R and S forms of various optically active camphorsulfonic acids Optically active acids such as dinitrobenzoylphenyl glycine, cellulose triacetate or other derivatives of carbohydrates or immobilized on silica gel Chromatographic enantiomerization with the aid of chiral derivatized methacrylate polymers Mer decomposition is advantageous.

[0171] The term "ester" as used herein refers to the group -C(O)OR 11 Finger where R 11 represents a hydrocarbyl group.

[0172] The term "amide," as used herein, refers to the group C(O)NH2.

[0173] In certain embodiments, the compounds described herein may be racemic. In embodiments, the compounds described in this invention may be enriched in one enantiomer. For example, the compounds described in the present invention may be used in the form of 30% ee, 40% ee, 50% ee, 60% ee, 70%ee, 80%ee, 90%ee or even 95% In certain embodiments, the compounds described herein may have an ee of 10 or more. The product may have two or more stereocenters. In certain such embodiments, the present invention provides The compounds described may contain one or more diastereomers. The compounds described in the invention are 30% de, 40% de, 50% de, 60% de, 70% de, 80%de, 90%de or even 95% or more It may have a threshold.

[0174] The term "subject" refers to mammals, particularly humans, as well as domestic animals, such as cats and dogs. This includes other animals, such as domestic animals (including household pets) and non-domestic animals (such as wildlife).

[0175] In certain embodiments, the present invention provides a small molecule CD-47-SIRPα pathway inhibitor, with agents capable of activating receptors such as Fe(+)-receptors (FcRs) or phagocytosis-promoting receptors or to utilize the maximum potential of CD-47-SIRPα pathway blockade. Further treatment methods for use in cancer therapy for activating pro-phagocytic receptors are provided.

[0176] Example-1: Synthetic procedures for the preparation of compounds described in this invention are described in PCT application PCT / Co-pending Injunction dated January 12, 2018, converted as IB2019 / 050219 No. 201841001438, the contents of which are incorporated by reference in their entirety. No. 6,399,433, filed on Oct. 23, 2003, and is incorporated

[0177] Biological example:

[0178] Reagents: DPBS (Gibco), RPMI1640 containing HEPES and L-GLN 500ML (Lonza), recombinant human M-CSF (R&D Systems), CD47 monoclonal antibody Clonal antibody (B6H12), functional grade antibody (Ebioscienc e), Mouse IgG1 kappa isotype control, functional grade (E bioscience), Vacutainer (multi-sample lure adapter) (BD), Vacutainer Cyutainer (Heparin Sodium (NH) 158 USP Units, Blood Collection Tube (BD,), His topaque (density - 1.077gm / mL) (SIGMA1077), tripan blue -Solution (SIGMA-T8154), Blood cell counter (Emission line-SIGMA Z359629) , scalp vein infusion set (JMS), cell dissociation buffer (Gibco), 48-well sterile flat-bottom Plates (Corning), luciferase-expressing Raji cells (luciferase in Raji cells) (Generated in-house by transfection of enzyme genes) Luminometer, Hygroma Isin B (Invitrogen), Bright Glo Luciferase Assay System (Promega), 96-well plate, polystyrene, high band, white flat-bottom well (Si gma CLS3912), anti-human CD20 antibody (Invitrogen hcd20-mab 1), Bortezomib (Selleckchem, S1013).

[0179] Example-2: Luciferase-based phagocytosis assay

[0180] In vitro phagocytosis to evaluate the ability of test items to enhance the phagocytic activity of macrophages The action assay was carried out. Mononuclear cells were isolated from the blood of healthy donors and incubated in 10% RPMI (Roche). Culture for 6–8 days using Zuwelt Park Memorial Institute (Zuwelt) medium and recombinant human M-CSF. The medium was changed every other day. After differentiation, the adherent macrophages Phages were harvested by gentle scraping and incubated overnight in 10% RPMI in a 48-well plate. The cells were cultured in a culture plate at a density of 100,000 per well. Raji (lymphoma cell line) cells were cultured in tissue culture flasks with 100 μg / mL hygroscopic endothelial cell suspension. The macrophages were cultured in 10% RPMI medium containing mycin B. On the day of phagocytosis, the macrophages were cultured for 2 h. Each well was serum-starved for 37 h. Anti-human CD47 antibody or mouse IgG1 K isotype were incubated in serum-free medium at 37 °C for 30 min. The antibodies were administered alone or in combination with a control antibody or various concentrations of selected compounds of the invention. 48-well plate containing macrophages incubated with human CD20 antibody After 2 hours, the cells were washed twice with PBS and then added to each well of the plate. 100 μL was added to each well. In addition, 50 μL of bright glow reagent was added to each well. The contents of each well were then mixed and incubated in the dark for 5 minutes. After transferring the material to a white plate, luminescence was read using a plate reader. Light intensity indicated the degree of phagocytosis. Each experimental condition was performed in duplicate. The results are given in Figure 1. .

[0181] The results in Figure 1 show that treatment of tumor cells with anti-human CD20 antibody significantly inhibited CD47-SIRPα blockade. 4 shows that it results in a significant increase in phagocytosis compared to the compound alone.

[0182] Example-3: Human macrophage diet to evaluate compounds in combination with bortezomib Action assay

[0183] In vitro phagocytosis to evaluate the ability of test items to enhance the phagocytic activity of macrophages A functional assay was performed. Mononuclear cells were isolated from the blood of healthy donors and were treated with 20 ng / mL recombinant human IgG. For 6 h, complete RPMI (Roswell Park Memorial Institute) supplemented with human M-CSF was used. They were cultured for ~8 days to allow differentiation into macrophages, with medium changed every other day. At the same time, H929 cells were cultured in complete RPMI medium and treated with 10 nM bortezomib for 48 h. Macrophages were starved with serum-free RPMI for 2 hours. CFSE staining was performed. Lutezomib-treated / untreated H929 (multiple myeloma cell line) cells were cultured in a 96-well low-attachment plate. 0.2×10 6 Cells were seeded at a density of 1000 cells / well and incubated with anti-human CD47 purified B6H12 (5 μg / mL) / Mouse IgG1 K isotype control antibody (5 μg / mL) / Differential The mice were treated with a selected compound of the present invention at a concentration of 100 mg / mL for 30 minutes at 37° C. in serum-free medium. Serum-starved macrophages were cultured on H929 cells at a ratio of 1:4 (macrophage:H9 29 cells) and incubated for 2 hours at 37°C. The cells in each well were stained with anti-human CD 11b Staining with APC for 30 min at 4°C in the dark, followed by fixation and FACS analysis. FITC and APC positive cells were identified as H cells phagocytosed by macrophages. Data obtained using FACS Verse were analyzed using Flow Jo The software was used for analysis, and the results are given in FIG.

[0184] The results in Figure 2 show that treatment of tumor cells with a proteasome inhibitor (bortezomib) significantly increased the CD4 7-SIRPα blockade was shown to result in a significant increase in phagocytosis compared to the compound alone. vinegar.

[0185] Example-4: Compound 6 in combination with PD-L1 antibody in the A20 syngeneic lymphoma model Efficacy test

[0186] In-house bred female Balb / c (BALB / cAnNTac) mice (6–8 weeks) were Animals were used in this efficacy study in the A20 syngeneic lymphoma model. Each animal is individually marked with a cage card indicating the study code, date of the experiment, sex and number of animals. The animals were kept in separate cages. The animals were weighed daily during the experiment. B-cell lymphoma derived from a spontaneous reticular cell neoplasm discovered in BALB / cAnN mice. The tumor lines were obtained from ATCC.

[0187] The average tumor volume was approximately 75 mm 3 When the animals reached 100 mg / kg, they were divided into 1000 mg / kg and 10000 mg / kg, based on tumor volume. The subjects were randomized into four groups (G1-G4) (N=12) of two mice each, and were assigned to the vehicle, compound, or combination of the following: Compound 6, anti-mouse PD-L1 antibody, and combination of compound 6 and anti-mouse PD-L1 antibody Administered:

[0188] [Table 2]

[0189] Treatment lasted for a period of 21 days, during which time the overall efficacy and tolerability were evaluated during the treatment period. The results were evaluated based on the tumor volume and body weight changes observed in the study.

[0190] The body weight of each animal was recorded daily for the duration of the experiment prior to administration of Compound 6. Animals were observed daily for mortality / morbidity and for clinical signs once daily for the duration of the study. Tumor volumes were measured using digital Vernier calipers at weekly intervals in animals from all treatment groups. The efficacy was measured once every 2-3 days. %TGI (%Tumor Growth Inhibition) values ​​were calculated. Graphing and statistical analysis were performed by GRaphPa. d Performed using Prism®, version 7.0. Tumor volume data For analysis, statistical comparisons were performed using one-way ANOVA with Dunnett's multiple comparison test. All analyses and comparisons were performed at the 5% (p<0.05) level. A "p" value of less than 0.05 was considered significant. The results and statistics are presented below. The results are summarized in the table given.

[0191] [Table 3]

[0192] Compound 6 at a dose of 30 mg / kg bid was used as a single agent and in combination with a PD-L1 antibody. Both combinations were well tolerated with no treatment-related clinical signs or mortality. These results suggest that the tested drug was well tolerated at the doses administered. Compound 6, anti-mouse PD-L1 antibody alone and anti-mouse PD-L1 antibody alone were administered at 30 mg / kg. Compound 6 in combination with the D-L1 antibody showed 72%, 41% and 90% tumor inhibition, respectively. The effect of treatment on tumor growth kinetics is shown graphically in Figure 3. show.

[0193] When combined with an anti-mouse PD-L1 antibody, compound 6 showed better efficacy compared to the individual treatments. It was further observed that the 5'-aminobutyric acid agonist produced significantly enhanced tumor growth inhibition with a more durable response. Cysts from 11 animals treated with the combination of Compound 6 and anti-mouse PD-L1 antibody Five of the mice showed complete tumor regression. The tumor growth inhibition observed with combination treatment with L1 antibody was statistically significant.

Claims

1. A composition comprising a CD47-SIRPα blocking agent and one or more anti-cancer agents, The CD47-SIRPα blocker has the formula (I): 【Chemistry 1】 (In the formula, R ａ is hydrogen; and R １ is hydrogen, -(CH ２ ) ２ CONH ２ , -(CH ２ ) ２ COOH、-(CH ２ ) ３ I'm sorry ２ 、-(CH ２ ) ４ NH ２ 、-CH ２ C O.N.H. ２ , -CH ２ -aryl, or -CH ２ represents heteroaryl; or R ａ and R １ form a pyrrolidine ring together with the atoms to which they are attached; R ２ is hydrogen, -(CH ２ ) ３ NHC (=NH)NH ２ , -(CH ２ ) ２ CONH ２ , - (CH ２ ) ２ COOH, -CH ２ -aryl, or -CH ２ - represents heteroaryl ； R ｂ is hydrogen; and R ３ is hydrogen, -CH ２ -aryl, -(CH ２ ) ３ N.H.C. (Related) ２ 、-(CH ２ ) ２ P. ２ 、-(CH ２ ) ２ COOH、-(CH ２ ) ４ N.H. ２ or -CH ２ represents heteroaryl; or R ｂ and R ３ are those forms a pyrrolidine ring together with the atoms to which it is attached. or a pharma- ceutical acceptable salt or amide or ester, or a stereoisomeric A composition represented by a body.

2. The composition of claim 1 , wherein the anti-cancer agent is a chemotherapeutic agent or an immunomodulatory agent.

3. The anti-cancer agent is a therapeutic agent that targets tumor antigens that stimulate activating Fc receptors (FcRs). The composition of claim 1 which is an antibody.

4. The composition of claim 3, wherein the antibody is selected from the group capable of inducing effective phagocytosis. 。

5. The group that can induce effective phagocytosis is characterized by the fact that the combination is effective in treating non-Hodgkin's B-cell lymphoma and Anti-CD20 (Rituxima), which is of particular use in the treatment of chronic lymphocytic leukemia (CLL), combination for B-cell leukemia and hairy cell leukemia Anti-CD22 (epratuzumab), which is of particular use in the treatment of diseases such as B-cell and anti-CD52, which is of particular use in the treatment of T-cell leukemia, (chronic lymphocytic leukemia); (alemtuzumab); the combination is of particular interest in the treatment of myeloid leukemia (acute myeloid leukemia). Anti-CD33 (gemtuzumab ozogamicin) for use in the treatment of breast cancer; trastuzumab, which is of particular use in certain types of brain cancer; It is particularly useful in the treatment of cancers of the kidney, lung, colon, rectum, cervix, ovary, or fallopian tubes. bevacizumab, which is of particular use in the treatment of colon cancer and head and neck cancer; ximab; the combination is of particular use in the treatment of colorectal cancer; panitumumab; the combination anti-CD38 (daratumumab), which is of particular use in the treatment of multiple myeloma; The combination of CD96, anti-CD44, and anti-CD123 is of particular use in the treatment of myeloid leukemia. ofatumumab, the combination of which is of particular use in the treatment of chronic lymphocytic leukemia; The combination is particularly useful in the treatment of follicular lymphoma; Alemtuzumab, which is of particular use in the treatment of chronic lymphocytic leukemia; Ibritumomab tiuxetan, particularly useful in the treatment of non-Hodgkin's lymphoma; Dinutuximab, the combination of which is of particular use in the treatment of neuroblastoma; and combinations The composition of claim 4, comprising necitumumab, which is of particular use in the treatment of lung cancer.

6. The anti-cancer agent is an anti-C11 agent selected from rituximab, tiuxetan, and tositumomab. The composition of any one of claims 1 to 5, which is a D20 antibody.

7. The chemotherapeutic agent is a proteasome inhibitor (bortezomib, ixazomib, and carboplatin). iruzomib), anthracyclines (doxorubicin, epirubicin, daunorubicin, Idarubicin, Mitoxantrone) Oxaliplatin, Cyclophosphamide, Bleomycin Synth, vorinostat, paclitaxel, 5-fluorouracil, cytarabine, BRAF Inhibitors (dabrafenib, vemurafenib), PI3K inhibitors, docetaxel, mitomas isin C, sorafenib, or tamoxifen; or a combination thereof; The composition of claim 2.

8. The composition of claim 1 or 2, wherein the anticancer agent is a proteasome inhibitor.

9. The anticancer drug is bortezomib, ixazokib, or carfilzomib, or any of them. The composition of claim 8 which is a derivative.

10. The chemotherapeutic agent is abiraterone acetate, afatinib, aldesleukin, Lemtuzumab, anastrozole, axitinib, belinostat, bendamustine, bilirubin Calthamide, blinatumomab, bosutinib, brentuximab, busulfan, cabazita Kisel, capecitabine, carboplatin, carfilzomib, carmustine, ceritinib , clofarabine, crizotinib, dacarbazine, dactinomycin, dasatinib, degas Relix, denileukin, denosumab, enzalutamide, eribulin, erlotinib, Verolimus, Exemestane, Exemestane, Fludarabine, Fulvestrant, Gef ibritumomab, imatinib, ipilimumab, irinotecan, ipatitinib, goserelin, Xabepilone, lapatinib, lenalidomide, letrozole, leucovorin, leuprolide , lomustine, mechlorethamine, megestrol, nelarabine, nilotinib, nivolumab , olaparib, omacetaxine, palbociclib, pamidronate, panitumumab, pano Vinostat, pazopanib, pegaspargase, pembrolizumab, pemetrexed sodium, pertuzumab, plerixafor, pomalidomide, ponatinib, pralatrex Seth, procarbazine, radium 223, ramucirumab, regorafenib, rIFNa -2b, romidepsin, sunitinib, temozolomide, temsirolimus, thiotepa, toxin Momab, trametinib, vinorelbine abarelix, aldesleukin, alitretinoin arsenic trioxide, asparaginase, azacytidine, allopurinol, altretamine , bexarotene, baricitinib, bortezomib, intravenous busulfan, oral busulfan , calsterone, cetuximab, chlorambucil, cisplatin, cladribine, dal Teparin sodium, decitabine, diftitox, disulfiram, dexrazox San, dromostanolone propionate, eculizumab, estramustine, etoposide phosphate, etoposide, fentanyl citrate, filgrastim, floxuridine, Gemcitabine, histrelin acetate, phosphamide, interferon alpha 2a, Lapatinib tosylate, levamisole, marizomib, mechlorethamine, melphalan, mel Captopurine, methotrexate, methoxsalen, mitotane, nandrolone fenpropionate Onate, nofetumomab, oprozomib, pegfilgrastim, pentostatin, Pobroman, plicamycin, procarbazine, quinacrine, rasburicase, ruxoli Tinib, rucaparib, streptozotocin, teniposide, testolactone, thalidomide , thioguanine, topotecan, toremifene, tretinoin, uracil mustard, bal Rubicin, vinblastine, vincristine, niraparib, veliparib, talazoparib, Claim 2: Zoledronate, ibrutinib, aflibercept and idelalisib The composition described in

11. The immunomodulatory agent is selected from the group consisting of CTLA-4 (e.g., ipilimumab), 4-1BB (e.g., uveitis), and the like. relmab, and utomirumab), antibodies against PD-1 and PD-L1 (e.g., Nivolumab, volumab, pembrolizumab, atezolizumab, durvalumab and camrelizumab) , antibodies against cytokines (IL-10, TGF-beta), antibodies against TIM-3 , an antibody against LAG3, an antibody against B7H3, an antibody against B7H4 or an antibody against B7H6 3. The composition of claim 2, which is an antibody against

12. A CD47-SIRPα blocker is a drug that blocks the interaction between CD47 and SIRPα.

2. The composition of claim 1 ,

13. Blocking the interaction between CD47 and SIRPα is an effective treatment for tumors expressing CD47. The composition of claim 1 , which induces macrophage phagocytosis of cells.

14. R １ is hydrogen, -(CH ２ ) ２ CONH ２ , -(CH ２ ) ２ COOH, -(CH ２ ) ３ I'm sorry ２ 、-(CH ２ ) ４ NH ２ 、-CH ２ P. ２ 、-CH ２ -フェ nyl, or -CH ２ The composition of claim 1, wherein the moiety represents -imidazolyl.

15. R ２ is hydrogen, -(CH ２ ) ３ NHC (=NH)NH ２ , -(CH ２ ) ２ CONH ２ , - (CH ２ ) ２ COOH, -CH ２ -phenyl, or -CH ２ - represents imidazolyl, The composition of claim 1.

16. R ３ is hydrogen, -CH ２ -phenyl, -(CH ２ ) ３ NHC (=NH)NH ２ , -(C H ２ ) ２ CONH ２ , -(CH ２ ) ２ COOH, -(CH ２ ) ４ N.H. ２ or -CH ２ - The composition of claim 1 which represents an imidazolyl.

17. R ３ is hydrogen, -CH ２ -phenyl, -(CH ２ ) ３ NHC (=NH)NH ２ , -(C H ２ ) ２ CONH ２ , -(CH ２ ) ２ COOH, or -(CH ２ ) ４ N.H. ２ Represents, request The composition of claim 16.

18. R ａ is hydrogen; and R １ is hydrogen, -(CH ２ ) ２ CONH ２ , -(CH ２ ) ２ COOH、-(CH ２ ) ３ I'm sorry ２ 、-(CH ２ ) ４ NH ２ 、-CH ２ C O.N.H. ２ , -CH ２ -phenyl, or -CH ２ -imidazolyl; or R ａ oh Yobi R １ together with the atoms to which they are attached form a pyrrolidine ring; R ２ is hydrogen, -(CH ２ ) ３ NHC (=NH)NH ２ , -(CH ２ ) ２ CONH ２ , - (CH ２ ) ２ COOH, -CH ２ -phenyl, or -CH ２ -imidazolyl; R ｂ is hydrogen; and R ３ is hydrogen, -CH ２ -phenyl, -(CH ２ ) ３ N.H.C. (Related) ２ 、-(CH ２ ) ２ P. ２ 、-(CH ２ ) ２ COOH、-(CH ２ ) ４ N.H. ２ or -CH ２ -imidazolyl; or R ｂ and R ３ But they ended up forms a pyrrolidine ring together with the atoms to which it is attached; The composition according to any one of claims 1 to 17.

19. Formula (IA) 【Chemistry 2】 (In the formula, R １ , R ａ and R ２ is defined in claim 1) or a pharma- ceutical acceptable salt or amide or ester, or a stereoisomer of The composition of claim 1 , wherein the composition is represented by a compound represented by the formula:

20. R １ is hydrogen, -(CH ２ ) ２ CONH ２ , -(CH ２ ) ２ COOH, -(CH ２ ) ３ NHC (=NH)NH ２ , -(CH ２ ) ４ N.H. ２ , -CH ２ -phenyl, or -CH ２ The composition of claim 19, wherein the moiety represents -imidazolyl.

21. R ２ is hydrogen, -(CH ２ ) ３ NHC (=NH)NH ２ , -(CH ２ ) ２ CONH ２ , - (CH ２ ) ２ COOH, -CH ２ -phenyl, or -CH ２ - represents imidazolyl, 20. The composition of claim 19.

22. R ａ is hydrogen; and R １ is hydrogen, -(CH ２ ) ２ CONH ２ , -(CH ２ ) ２ COOH、-(CH ２ ) ３ I'm sorry ２ 、-(CH ２ ) ４ NH ２ 、-CH ２ - Phenyl, or -CH ２ -imidazolyl; R ２ is hydrogen, -(CH ２ ) ３ NHC (=NH)NH ２ , -(CH ２ ) ２ COOH, - CH ２ -phenyl, or -CH ２ - represents imidazolyl, 22. The composition of claim 19, 20 or 21.

23. Formula (IB) 【Chemistry 3】 (In the formula, R １ , R ａ , R ｂ and R ３ is defined in claim 1) or a pharma- ceutical acceptable salt or amide or ester, or a stereoisomeric The composition of claim 1 , wherein the composition is represented by a body.

24. R １ is hydrogen, -(CH ２ ) ２ CONH ２ , -(CH ２ ) ２ COOH, -(CH ２ ) ３ NHC (=NH)NH ２ , -(CH ２ ) ４ N.H. ２ , or -CH ２ -phenyl, 24. The composition of claim 23.

25. R ３ is hydrogen, -CH ２ -phenyl, -(CH ２ ) ２ CONH ２ , or -(CH ２ ) ２ 24. The composition of claim 23, wherein said COOH.

26. R ｂ and R ３ together with the atoms to which they are attached form a pyrrolidine ring.

24. The composition described in 23.

27. R １ But -(CH ２ ) ２ CONH ２ , or -(CH ２ ) ２ represents COOH; R ｂ is hydrogen; and R ３ is hydrogen or -CH ２ -phenyl; or R ｂ and R ３ together with the atoms to which they are attached form a pyrrolidine ring, The composition according to any one of claims 23 to 26.

28. Formula (IC) 【Chemistry 4】 (In the formula, R １ , R ａ , R ３ and R ｂ is defined in claim 1) or a pharma- ceutical acceptable salt or amide or ester, or a stereoisomeric The composition of claim 1 , wherein the composition is represented by a body.

29. R １ But -(CH ２ ) ４ N.H. ２ , -(CH ２ ) ３ NHC (=NH)NH ２ Or - (C H ２ ) ２ CONH ２ 29. The composition of claim 28, wherein

30. R ｂ is hydrogen; R ３ is hydrogen, -CH ２ -phenyl, or -CH ２ - Heteroa Reel; or R ｂ and R ３ pyrrolidine together with the atom to which they are attached The composition of claim 28 which forms a ring.

31. R １ But -(CH ２ ) ４ N.H. ２ , -(CH ２ ) ３ NHC (=NH)NH ２ Or - (C H ２ ) ２ CONH ２ Represents; R ｂ is hydrogen; R ３ is hydrogen, -CH ２ -phenyl, or -CH ２ - Heteroa Reel; or R ｂ and R ３ pyrrolidine together with the atom to which they are attached The composition according to any one of claims 28 to 30, which forms a ring.

32. Formula (ID) 【Chemistry 5】 (In the formula, R １ , R ａ , R ３ and R ｂ is defined in claim 1) or a pharma- ceutical acceptable salt or amide or ester, or a stereoisomeric The composition of claim 1 , wherein the composition is represented by a body.

33. R １ But -CH ２ CONH ２ , -(CH ２ ) ４ N.H. ２ , or (CH ２ ) ３ NHC (= NH) NH ２ The composition of claim 32, wherein

34. R １ But -(CH ２ ) ４ N.H. ２ , or (CH ２ ) ３ NHC (=NH)NH ２ Represents; R ｂ is hydrogen; R ３ is hydrogen, -(CH ２ ) ３ NHC (=NH)NH ２ ,or - (CH ２ ) ４ N.H. ２ or R ｂ and R ３ are the same as the atoms to which they are bonded. Together they form a pyrrolidine ring. The composition according to any one of claims 32 to 33.

35. Formula (IE) 【Chemistry 6】 (In the formula, R ２ , R ３ and R ｂ is defined in claim 1) or a pharma- ceutical acceptable salt or amide or ester, or a stereoisomeric The composition of claim 1 , wherein the composition is represented by a body.

36. R ２ is hydrogen or -(CH ２ ) ３ NHC (=NH)NH ２ The compound according to claim 35, The composition described above.

37. R １ is hydrogen or -(CH ２ ) ３ NHC (=NH)NH ２ represents R ｂ and R ３ Any of claims 34 to 35, wherein together with the atoms to which they are attached, they form a pyrrolidine ring. The composition according to any one of claims 1 to 4.

38. Formula (IF) 【Chemistry 7】 (In the formula, R ２ , R ３ and R ｂ is defined in claim 1) or a pharma- ceutical acceptable salt or amide or ester, or a stereoisomeric The composition of claim 1 , wherein the composition is represented by a body.

39. R ２ is hydrogen, -CH ２ -phenyl, -(CH ２ ) ２ COOH, or -(CH ２ ) ３ NHC (=NH)NH ２ 39. The composition of claim 38, wherein

40. R ２ is hydrogen, -CH ２ -phenyl, -(CH ２ ) ２ COOH, or -(CH ２ ) ３ NHC (=NH)NH ２ Represents; R ｂ is hydrogen; and R ３ But -CH ２ -phenyl, -(CH ２ ) ２ CONH ２ , - (CH ２ ) ４ N.H. ２ Or - (CH ２ ) ２ R represents COOH; ｂ and R ３ But those forms a pyrrolidine ring together with the atom to which it is attached, The composition according to any one of claims 38 to 39.

41. The compound is 【Table 1】 or a pharma- ceutical acceptable salt, intermediate or ester, or stereoisomer thereof. The composition according to any one of claims 1 to 40,

42. CD47-SIRP according to any one of claims 1 to 41 for use as a medicament A composition comprising an alpha blocker and one or more anti-cancer agents.

43. 1. A method for treating cancer in a subject exhibiting a dysregulated CD47 pathway, comprising: The method comprises administering a therapeutically effective amount of CD47- administering to the subject a SIRPα blocking agent, wherein the CD47-SIRPα blocking agent , Formula (I): 【Chemistry 8】 (In the formula, R ａ is hydrogen; and R １ is hydrogen, -(CH ２ ) ２ CONH ２ , -(CH ２ ) ２ COOH、-(CH ２ ) ３ I'm sorry ２ 、-(CH ２ ) ４ NH ２ 、-CH ２ C O.N.H. ２ , -CH ２ -aryl, or -CH ２ represents heteroaryl; or R ａ and R １ form a pyrrolidine ring together with the atoms to which they are attached; R ２ is hydrogen, -(CH ２ ) ３ NHC (=NH)NH ２ , -(CH ２ ) ２ CONH ２ , - (CH ２ ) ２ COOH, -CH ２ -aryl, or -CH ２ - represents heteroaryl ； R ｂ is hydrogen; and R ３ is hydrogen, -CH ２ -aryl, -(CH ２ ) ３ N.H.C. (Related) ２ 、-(CH ２ ) ２ P. ２ 、-(CH ２ ) ２ COOH、-(CH ２ ) ４ N.H. ２ or -CH ２ represents heteroaryl; or R ｂ and R ３ are those forms a pyrrolidine ring together with the atoms to which it is attached. or a pharma- ceutical acceptable salt or amide or ester, or a stereoisomeric The method is represented by the body.

44. The subject presenting with a dysregulated CD47 pathway is a subject presenting with CD47+ disease cells.

44. The method of claim 43,

45. 45. The method of claim 44, wherein the CD47+ disease cells are CD47+ cancer cells.

46. Said treatment with one or more anti-cancer agents is preferably a compound of formula (I) or a pharma- ceutical acceptable salt thereof.

44. The method of claim 43, prior to, concurrent with, or following treatment with an acceptable salt. Method of posting.

47. 44. The method of claim 43, wherein the anti-cancer agent is an anti-CD20 antibody.

48. 44. The method of claim 43, wherein the anti-cancer agent is a proteasome inhibitor.

49. 44. The method of claim 43, wherein the anti-cancer drug is bortezomib or any derivative thereof. 。

50. The present invention relates to a method for treating a disease or disorder mediated by the CD47-SIRPα pathway in a subject. and / or administering to the patient a therapeutically effective amount of one or more The present invention provides a method for treating cancer by administering a therapeutically effective amount of a drug that blocks the CD47-SIRPα pathway in combination with a number of anti-cancer drugs. and administering to a subject in need thereof a drug that blocks the CD47-SIRPα pathway. The agent has the formula (I): 【Chemistry 9】 (In the formula, R ａ is hydrogen; and R １ is hydrogen, -(CH ２ ) ２ CONH ２ , -(CH ２ ) ２ COOH、-(CH ２ ) ３ I'm sorry ２ 、-(CH ２ ) ４ NH ２ 、-CH ２ C O.N.H. ２ , -CH ２ -aryl, or -CH ２ represents heteroaryl; or R ａ and R １ form a pyrrolidine ring together with the atoms to which they are attached; R ２ is hydrogen, -(CH ２ ) ３ NHC (=NH)NH ２ , -(CH ２ ) ２ CONH ２ , - (CH ２ ) ２ COOH, -CH ２ -aryl, or -CH ２ - represents heteroaryl ； R ｂ is hydrogen; and R ３ is hydrogen, -CH ２ -aryl, -(CH ２ ) ３ N.H.C. (Related) ２ 、-(CH ２ ) ２ P. ２ 、-(CH ２ ) ２ COOH、-(CH ２ ) ４ N.H. ２ or -CH ２ represents heteroaryl; or R ｂ and R ３ are those forms a pyrrolidine ring together with the atoms to which it is attached. or a pharma- ceutical acceptable salt or amide or ester, or a stereoisomeric The method is represented by the body.

51. The disease or disorder mediated by the CD47-SIRPα pathway is cancer.

50. The method according to claim 50.

52. The cancer is melanoma, renal cancer, prostate cancer, breast cancer, colon cancer and lung cancer, bone cancer, pancreatic cancer, skin cancer, Head and neck cancer, malignant melanoma of the skin or eye, uterine cancer, ovarian cancer, rectal cancer, anal cancer, stomach cancer, Testicular cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin's disease, non-Hodgkin's lymphoma, esophageal cancer, small intestine cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, Renal cancer, soft tissue sarcoma, urethral cancer, penile cancer, acute myeloid leukemia, acute lymphocytic leukemia, chronic myeloma Chronic or acute leukemia, including childhood leukemia, acute lymphocytic leukemia, and chronic lymphocytic leukemia Stage 1 solid tumor, lymphocytic lymphoma, bladder cancer, kidney or ureter cancer, renal pelvis carcinoma, central nervous system CNS neoplasms, non-small cell lung cancer (NSCLC), primary central nervous system malignant lymphoma, Tumor angiogenesis, spinal axis tumor, brain stem glioma, pituitary adenoma, Kaposi's sarcoma, epidermoid carcinoma, squamous epithelial tumor Cancer, T-cell lymphoma, B-cell lymphoma, Myeloproliferative Disorders / Neoplasms (MPDS); Myelodysplastic Giant cell myeloma, heavy chain myeloma, light chain myeloma and Bence Jones myeloma, Environmentally induced cancers, including those induced by sbestos (e.g., mesothelioma); and 52. The method of claim 51 , wherein the cancer is selected from the combination of cancers.

53. In the manufacture of a medicament for the treatment of cancer in a subject exhibiting a dysregulated CD47 pathway. A method for treating a cancer comprising administering to a patient a therapeutically effective amount of a CD47-SIRPα blocking agent according to any one of claims 1 to 41 and one or more anti-cancer agents. Use of a composition comprising:

54. The cancer is melanoma, renal cancer, prostate cancer, breast cancer, colon cancer and lung cancer, bone cancer, pancreatic cancer, skin cancer, Head and neck cancer, malignant melanoma of the skin or eye, uterine cancer, ovarian cancer, rectal cancer, anal cancer, stomach cancer, Testicular cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin's disease, non-Hodgkin's lymphoma, esophageal cancer, small intestine cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, Renal cancer, soft tissue sarcoma, urethral cancer, penile cancer, acute myeloid leukemia, acute lymphocytic leukemia, chronic myeloma Chronic or acute leukemia, including childhood leukemia, acute lymphocytic leukemia, and chronic lymphocytic leukemia Stage 1 solid tumor, lymphocytic lymphoma, bladder cancer, kidney or ureter cancer, renal pelvis carcinoma, central nervous system CNS neoplasms, non-small cell lung cancer (NSCLC), primary central nervous system malignant lymphoma, Tumor angiogenesis, spinal axis tumor, brain stem glioma, pituitary adenoma, Kaposi's sarcoma, epidermoid carcinoma, squamous epithelial tumor Cancer, T-cell lymphoma, B-cell lymphoma, asbestos-induced (e.g., mesothelial and combinations of said cancers.

53. Use according to claim 53.

55. Present a composition according to any one of claims 1 to 41 and a dysregulated CD47 pathway. A kit comprising a package insert containing directions for administration of the agent to treat a subject.

56. A CD47-SIRPα blocking agent according to any one of claims 1 to 41 and one or A pharmaceutical composition comprising a plurality of anti-cancer agents and a pharma- ceutically acceptable carrier.

57. A combination comprising a CD47-SIRPα blocking agent and one or more anti-cancer agents. , a CD47-SIRPα blocker has the formula (I): 【Chemistry 10】 (In the formula, R ａ is hydrogen; and R １ is hydrogen, -(CH ２ ) ２ CONH ２ , -(CH ２ ) ２ COOH、-(CH ２ ) ３ I'm sorry ２ 、-(CH ２ ) ４ NH ２ 、-CH ２ C O.N.H. ２ , -CH ２ -aryl, or -CH ２ represents heteroaryl; or R ａ and R １ form a pyrrolidine ring together with the atoms to which they are attached; R ２ is hydrogen, -(CH ２ ) ３ NHC (=NH)NH ２ , -(CH ２ ) ２ CONH ２ , - (CH ２ ) ２ COOH, -CH ２ -aryl, or -CH ２ - represents heteroaryl ； R ｂ is hydrogen; and R ３ is hydrogen, -CH ２ -aryl, -(CH ２ ) ３ N.H.C. (Related) ２ 、-(CH ２ ) ２ P. ２ 、-(CH ２ ) ２ COOH、-(CH ２ ) ４ N.H. ２ or -CH ２ represents heteroaryl; or R ｂ and R ３ are those forms a pyrrolidine ring together with the atoms to which it is attached. or a pharma- ceutical acceptable salt or amide or ester, or a stereoisomeric A combination, represented by a body.

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