Combination of small molecule cd-47 inhibitors with other anticancer agents

Abstract

The present invention relates to combinations of small molecule CD-47 inhibitors with other anti-cancer agents. More specifically, the present invention relates to pharmaceutical combinations comprising a small molecule CD-47-SIRP alpha pathway inhibitor and one or more agents capable of stimulating a receptor, such as an activated Fc receptor (FcR) or other phagostimulant receptor.

Description

[0001] This application is a divisional application, and the parent application is an application with an application date of November 8, 2019, an application number of 201980071532.5, and an invention title of "Combination of Small Molecule CD-47 Inhibitors and Other Anti-Cancer Agents".

[0002] Related Applications

[0003] This application claims the benefit of Indian Provisional Application No. 201841042108, filed on November 08, 2018, the content of which is incorporated herein by reference in its entirety. Technical Field

[0004] The present invention relates to pharmaceutical compositions comprising a small molecule CD-47-SIRPα pathway inhibitor and one or more agents capable of stimulating receptors such as activating Fc receptors (FcR) or other phagocytosis-promoting receptors. Background Art

[0005] The CD47 / SIRPα axis has been established as a key regulator of myeloid cell activation and serves as an immune checkpoint for macrophage-mediated phagocytosis. Since CD47 is frequently upregulated in several cancers, it contributes to immune evasion and cancer progression. CD47 regulates phagocytosis mainly by interacting with SIRP1α expressed on macrophages. Blockade of SIRP1α / CD47 has been shown to significantly enhance tumor cell phagocytosis and dendritic cell maturation for better antigen presentation, resulting in a substantial improvement in anti-tumor responses in preclinical models of cancer (M.P. Chao et al. Curr Opin Immunol. 2012(2):225-232). Currently, disrupting the CD47-SIRPα interaction as a cancer treatment strategy is being evaluated by using monoclonal antibodies targeting CD47 or SIRPα and engineered receptor decoys.

[0006] CD47 is actually expressed on all non-malignant cells, and blockade of CD47 or loss of CD47 expression or changes in membrane distribution can be used as a marker of aged or damaged cells, especially on red blood cells (RBCs). Alternatively, for those cells where pre-phagocytic signals are also present, blockade of SIRPα can also phagocytose targets that are not normally phagocytosed. CD47 is a widely expressed transmembrane glycoprotein with a single Ig-like domain and five transmembrane regions, which serves as the cellular ligand for SIRPα and mediates binding through the NH2-terminal V-like domain of SIRPα. SIRPα is mainly expressed on myeloid cells, including macrophages, granulocytes, myeloid dendritic cells (DCs), mast cells, and their precursors, including hematopoietic stem cells.

[0007] CD47 is also constitutively upregulated in many cancers, such as non-Hodgkin lymphoma (NHL), acute myeloid leukemia (AML), breast cancer, colon cancer, glioblastoma, glioma, ovarian cancer, bladder cancer, and prostate cancer. Tumor cells overexpress CD47, which effectively helps tumor cells evade immune surveillance and the killing by innate immune cells. However, in most tumor types, blocking the CD47-SIRPα interaction as a single agent may not induce significant phagocytosis and anti-tumor immunity, so it is necessary to combine with other therapeutic agents. To exert the maximum potential of CD-47-SIPRα pathway blockade, the simultaneous involvement of activating receptors such as Fc receptor (FcR) or other pro-phagocytic receptors (collectively referred to as "eat me" signals) may be required.

[0008] The involvement of pro-phagocytic receptors was demonstrated by the inefficient triggering of phagocytosis in blocking the CD47-SIRPα interaction by anti-CD47 F(ab) fragments, single-chain variable fragments of CD-47, or SIRPα proteins without the Fc portion. When activating pro-phagocytic receptors are involved, as is evident in the case of using blocking anti-CD47 antibodies with an Fc portion, CD47-SIRPα blockade can trigger more efficient phagocytosis. Combining CD47-SIRPα blockers with therapeutic antibodies (with Fc) targeting tumor antigens stimulates the activation of Fc receptor (FcR), resulting in highly efficient phagocytosis. The Fc portion of therapeutic antibodies targeting tumor antigens also induces antibody-dependent cell cytotoxicity (ADCC), which also increases the therapeutic efficacy. Therefore, antibodies selected from the group consisting of the following can trigger more efficient phagocytosis due to their tumor targeting and ADCC: rituximab, herceptin, trastuzumab, alemtuzumab, bevacizumab, cetuximab, panitumumab, daratumumab.

[0009] Methods for disrupting the CD47-SIRPα interaction early on utilize monoclonal antibodies targeting CD47 or SIRPα and engineered receptor decoys fused to Fc fragments. However, a concern with this approach is that CD47 is highly expressed on both hematopoietic and non-hematopoietic normal cells. Thus, together with tumor cells, CD47-SIRPα blockers containing an Fc portion may also target many normal cells, potentially leading to their elimination by macrophages. Interaction of the blocking antibody with normal cells is considered a major safety concern, resulting in anemia, thrombocytopenia, and leukopenia. These agents may also affect solid tissues rich in macrophages, such as the liver, lung, and brain. Thus, it may be desirable to disrupt the CD47-SIRPα interaction with agents lacking an Fc portion, such as small molecules, peptides, Fab fragments, etc., while activating pro-phagocytic receptors in tumor cells by appropriate combinations to induce efficient phagocytosis of tumor cells.

[0010] In addition to Fc receptors, many other pro-phagocytic receptors have been reported to promote phagocytosis of tumor cells in response to CD47-SIRPα blockade by triggering phagocytosis. These receptors include SLAMF7, Mac-1, the receptor for calreticulin, and possibly receptors yet to be identified. B cell tumor lines such as Raji and other diffuse large B cell lymphomas express SLAMF7 and are involved in triggering pro-phagocytic signals during CD47-SIRPα blockade.

[0011] Thus, therapeutic agents known to activate pro-phagocytic receptors are also ideal partners to be used in combination with CD47-SIRPα blockers to achieve efficient phagocytosis. These agents include proteasome inhibitors (bortezomib, ixazomib, and carfilzomib), anthracyclines (doxorubicin, epirubicin, daunorubicin, idarubicin, mitoxantrone), oxaliplatin, cyclophosphamide, bleomycin, vorinostat, paclitaxel, 5-fluorouracil, cytarabine, BRAF inhibitory drugs (dabrafenib, vemurafenib), PI3K inhibitors, docetaxel, mitomycin C, sorafenib, tamoxifen, and oncolytic viruses.

[0012] In addition to specific agents known to affect the 'eat me' signal, other agents include Abiraterone acetate, Afatinib, Aldesleukin, Aldesleukin, Alemtuzumab, Anastrozole, Axitinib, Belinostat, Bendamustine, Bicalutamide, Blinatumomab, Bosutinib, Brentuximab, Busulfan, Cabazitaxel, Capecitabine, Carboplatin, Carfilzomib, Carmustine, Ceritinib, Clofarabine, Crizotinib, Dacarbazine, Dactinomycin, Dasatinib, Degarelix, Denileukin, Denosumab, Enzalutamide, Eribulin, Erlotinib, Everolimus, Exemestane, Exemestane, Fludarabine, Fulvestrant, Gefitinib, Goserelin, Ibritumomab, Imatinib, Ipilimumab, Irinotecan, Ixabepilone, Lapatinib, Lenalidomide, Letrozole, Leucovorin, Leuprolide, Lomustine, Mechlorethamine, Megestrol, Nelarabine, Nilotinib, Nivolumab, Olaparib, Omacetaxine, Palbociclib,Pamidronate, Panitumumab, Panobinostat, Pazopanib, Pegaspargase, Pembrolizumab, Pemetrexed Disodium, Pertuzumab, Plerixafor, Pomalidomide, Ponatinib, Pralatrexate, Procarbazine, Radium-223, Ramucirumab, Regorafenib, rIFNa-2b, Romidepsin, Sunitinib, Temozolomide, Temsirolimus, Thiotepa, Tositumomab, Trametinib, Vinorelbine, Methotrexate, Ibrutinib, Aflibercept, Toremifene, Vinblastine, Vincristine, Idelalisib, Mercaptopurine, and Thalidomide may have an impact on the "eat me" signaling pathway when combined with a CD-47-SIRPα blocker.

[0013] In addition to the above therapeutic agents, other treatment modalities used in cancer therapy can also activate phagocytic receptors and can thus be combined with a CD47-SIRPα blocker to achieve efficient phagocytosis. These treatment modalities include hypericin-based photodynamic therapy (Hyp-PDT), radiotherapy, high hydrostatic pressure, porphyrin-based PDT, and rose bengal acetate-based PDT.

[0014] However, there is a need that has not been met to combine small molecule CD-47-SIRPα pathway inhibitors with agents that can stimulate activating receptors such as Fc receptors (FcR) or other phagocytic receptors, or with other treatment modalities used in cancer therapy to activate phagocytic receptors, in order to exert the maximum potential of CD-47-SIRPα pathway blockade. SUMMARY OF THE INVENTION

[0015] The present invention provides a composition comprising a small molecule CD-47-SIRPα pathway inhibitor in combination with an agent that stimulates activating receptors such as Fc receptors (FcR) or other phagocytosis-promoting receptors, or with other therapeutic modalities used in cancer therapy to activate phagocytosis-promoting receptors, to exert the maximum potential of CD-47-SIRPα pathway blockade.

[0016] In one aspect of the present invention, there is provided a composition comprising a CD47-SIRPα blocker and one or more anti-cancer agents, wherein the CD-47-SIRPα blocker is a small molecule represented by a compound of formula (I):

[0017]

[0018] or a pharmaceutically acceptable salt or amide or ester thereof, or a stereoisomer thereof; wherein,

[0019] R a is hydrogen; and R1 represents hydrogen, -(CH2)2CONH2, -(CH2)2COOH, -(CH2)3NHC(=NH)NH2, -(CH2)4NH2, -CH2CONH2, -CH2-aryl or -CH2-heteroaryl; or R a and R1 together with the atoms to which they are attached form a pyrrolidine ring;

[0020] R2 represents hydrogen, -(CH2)3NHC(=NH)NH2, -(CH2)2CONH2, -(CH2)2COOH, -CH2-aryl or -CH2-heteroaryl;

[0021] R b is hydrogen; and R3 represents hydrogen, -CH2-aryl, -(CH2)3NHC(=NH)NH2, -(CH2)2CONH2, -(CH2)2COOH, -(CH2)4NH2 or -CH2-heteroaryl; or R b and R3 together with the atoms to which they are attached form a pyrrolidine ring.

[0022] In another aspect, the present invention relates to a method for treating a subject presenting with CD47 pathway dysregulation, which comprises administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or amide or ester thereof, or a stereoisomer in combination with one or more anti-cancer agents.

[0023] Yet another aspect of the present invention provides a method for treating a CD47-mediated disease or disorder, which comprises administering a compound of formula (I) or a pharmaceutically acceptable salt or amide or ester thereof, or a stereoisomer in combination with one or more anti-cancer agents.

[0024] In another aspect of the present invention, there is provided a combination comprising a CD47-SIRPα blocker and one or more anti-cancer agents, wherein the small molecule CD-47-SIRPα blocker is represented by a compound of formula (I):

[0025]

[0026] or a pharmaceutically acceptable salt or amide or ester or a stereoisomer thereof; wherein,

[0027] R a is hydrogen; and R1 represents hydrogen, -(CH2)2CONH2, -(CH2)2COOH, -(CH2)3NHC(=NH)NH2, -(CH2)4NH2, -CH2CONH2, -CH2-aryl or -CH2-heteroaryl; or R a and R1 together with the atoms to which they are attached form a pyrrolidine ring;

[0028] R2 represents hydrogen, -(CH2)3NHC(=NH)NH2, -(CH2)2CONH2, -(CH2)2COOH, -CH2-aryl or -CH2-heteroaryl;

[0029] R b is hydrogen; and R3 represents hydrogen, -CH2-aryl, -(CH2)3NHC(=NH)NH2, -(CH2)2CONH2, -(CH2)2COOH, -(CH2)4NH2 or -CH2-heteroaryl; or R b and R3 together with the atoms to which they are attached form a pyrrolidine ring. BRIEF DESCRIPTION OF THE DRAWINGS

[0031] Figure 1 : Compounds 3 and 6 in combination with an anti-CD20 antibody enhance phagocytosis of lymphoma cells

[0032] Figure 2 : Compounds 3 and 6 in combination with bortezomib enhance phagocytosis of multiple myeloma cells

[0033] Figure 3 : Anti-tumor efficacy of compound 6 alone or in combination with an anti-mouse PD-L1 antibody in A20 tumor-bearing mice DETAILED DESCRIPTION

[0034] Each embodiment is provided in a manner that explains the invention, not limits it. In fact, those skilled in the art will readily understand that various modifications and variations can be made to the compounds, compositions, and methods described herein without departing from the scope or spirit of the invention. For example, features described or illustrated as part of one embodiment can be applied to another embodiment to yield yet another embodiment. Accordingly, it is intended that the invention include such modifications and variations and their equivalents. Other objects, features, and aspects of the invention are disclosed in or are obvious from the following detailed description. Those of ordinary skill in the art will understand that this discussion is merely a description of exemplary embodiments and should not be construed as limiting the broader aspects of the invention.

[0035] In certain embodiments, the present invention provides a composition comprising a CD47-SIRPα blocker and one or more anti-cancer agents: wherein the CD47-SIRPα blocker is represented by a compound of formula (I):

[0036]

[0037] or a pharmaceutically acceptable salt or amide or ester or a stereoisomer thereof; wherein,

[0038] R a is hydrogen; and R1 represents hydrogen, -(CH2)2CONH2, -(CH2)2COOH, -(CH2)3NHC(=NH)NH2, -(CH2)4NH2, -CH2CONH2, -CH2-aryl or -CH2-heteroaryl; or R a and R1 together with the atoms to which they are attached form a pyrrolidine ring;

[0039] R2 represents hydrogen, -(CH2)3NHC(=NH)NH2, -(CH2)2CONH2, -(CH2)2COOH, -CH2-aryl or -CH2-heteroaryl;

[0040] R b is hydrogen; and R3 represents hydrogen, -CH2-aryl, -(CH2)3NHC(=NH)NH2, -(CH2)2CONH2, -(CH2)2COOH, -(CH2)4NH2 or -CH2-heteroaryl; or R b and R3 together with the atoms to which they are attached form a pyrrolidine ring.

[0041] In certain embodiments, the anti-cancer agent is a chemotherapeutic agent or an immunomodulator.

[0042] In certain embodiments, specific combination partners of interest for use with CD47-SIRPα blockers include therapeutic antibodies that target tumor antigens that stimulate activation of Fc receptors (FcR), thereby resulting in potent phagocytosis. In certain embodiments, specific combination partners of interest include therapeutic antibodies that stimulate Fc receptor-mediated phagocytosis. Thus, antibodies selected from the group consisting of agents capable of triggering potent phagocytosis include anti-CD20, such as rituximab, tiuxetan, tositumomab, etc., the combinations of which are particularly suitable for treating non-Hodgkin's B-cell lymphoma and chronic lymphocytic leukemia (CLL). Combinations with anti-CD22, such as epratuzumab, etc., are particularly suitable for treating B-cell leukemia and hairy cell leukemia. Combinations with anti-CD52, such as alemtuzumab, etc., are particularly suitable for treating B-cell and T-cell leukemias, including but not limited to chronic lymphocytic leukemia. Combinations with anti-CD33, such as gemtuzumab ozogomicin, etc., are particularly suitable for treating myeloid leukemias, such as acute myeloid leukemia. Combinations with trastuzumab are particularly suitable for treating breast cancer. Combinations with bevacizumab are particularly suitable for treating certain types of brain tumors as well as certain types of kidney cancer, lung cancer, colon cancer, rectal cancer, cervical cancer, ovarian cancer, or fallopian tube cancer. Combinations with cetuximab are particularly suitable for treating colon cancer and head and neck cancer. Combinations with panitumumab are particularly suitable for treating colorectal cancer. Combinations with daratumumab are particularly suitable for treating multiple myeloma. Other combinations of interest for treating myeloid leukemia include but are not limited to anti-CD96, anti-CD44, and anti-CD123.

[0043] In certain preferred embodiments, the Fc receptor (FcR) comprises an Fc gamma receptor (FcγR).

[0044] Other therapeutic antibodies of interest in combination with CD47-SIRPα blockers include but are not limited to ofatumumab for chronic lymphocytic leukemia, obinutuzumab for follicular lymphoma, alemtuzumab for B-cell chronic lymphocytic leukemia, ibritumomab tiuxetan for B-cell non-Hodgkin's lymphoma, dinutuximab for neuroblastoma, and necitumumab for lung cancer.

[0045] In certain embodiments, the anti-cancer agent is an anti-CD20 antibody, such as rituximab, tiuxetan, tositumomab.

[0046] In certain embodiments, therapeutic agents known to activate phagocytic receptors are thus ideal partners for use in combination with CD47-SIRPα blockers to achieve efficient phagocytosis. Such agents include proteasome inhibitors (bortezomib, ixazomib, and carfilzomib), anthracyclines (doxorubicin, epirubicin, daunorubicin, idarubicin, mitoxantrone), oxaliplatin, cyclophosphamide, bleomycin, vorinostat, paclitaxel, 5-fluorouracil, cytarabine, BRAF inhibitory drugs (dabrafenib, vemurafenib), PI3K inhibitors, docetaxel, mitomycin C, sorafenib, and tamoxifen; or combinations thereof.

[0047] In certain embodiments, the anti-cancer agent is a proteasome inhibitor.

[0048] In certain embodiments, the anti-cancer agent is bortezomib, ixazomib, or carfilzomib or an analogue or derivative thereof.

[0049] In certain embodiments, in addition to specific agents known to affect the "eat me" signal, other agents, including abiraterone acetate, afatinib, aldesleukin, alemtuzumab, anastrozole, axitinib, belinostat, bendamustine, bicalutamide, blinatumomab, bosutinib, brentuximab vedotin, busulfan, cabazitaxel, capecitabine, carboplatin, carfilzomib, carmustine, ceritinib, clofarabine, crizotinib, dacarbazine, actinomycin D, dasatinib, degarelix, denileukin diftitox, denosumab, enzalutamide, eribulin, erlotinib, everolimus, exemestane, fludarabine, fulvestrant, gefitinib, goserelin, ibritumomab tiuxetan, imatinib, ipilimumab, irinotecan, ixabepilone, lapatinib, lenalidine, letrozole, leucovorin, leuprolide, lomustine, mechlorethamine, megestrol acetate, nelarabine, nilotinib, nivolumab, olaparib, omacetaxine mepesuccinate, palbociclib, pamidronate, panitumumab, panobinostat, pazopanib, pegaspargase, pembrolizumab, pemetrexed disodium, pertuzumab, plerixafor, pomalidomide, ponatinib, pralatrexate, procarbazine, radium-223, ramucirumab, regorafenib, rIFNa-2b, romidepsin, sunitinib, temozolomide, temsirolimus, thiotepa, tositumomab, trametinib, vinorelbine, methotrexate, ibrutinib, aflibercept, toremifene, vinblastine, vincristine, idelalisib, mercaptopurine, and thalidomide, may have an impact on the "eat me" signaling pathway when combined with a CD-47-SIRPα blocker.

[0050] In other embodiments, in addition to the above therapeutic agents, other treatment modalities used in cancer therapy can also activate phagocytosis-promoting receptors and thus can be combined with CD47-SIRPα blockers to achieve efficient phagocytosis. These treatment modalities include hypericin-based photodynamic therapy (Hyp-PDT), radiotherapy, high hydrostatic pressure, porphyrin-based PDT, and rose bengal acetate-based PDT.

[0051] In certain embodiments, the chemotherapeutic agent is abarelix, aldesleukin, alitretinoin, allopurinol, altretamine, arsenic trioxide, asparaginase, azacitidine, bexarotene, baricitinib, bortezomib, intravenous busulfan, oral busulfan, calusterone, cetuximab, chlorambucil, cisplatin, cladribine, dalteparin sodium, decitabine, diftitox, disulfiram, dexrazoxane, dromostanolone propionate, eculizumab, estramustine, etoposide phosphate, etoposide, fentanyl citrate, filgrastim, floxuridine, gemcitabine, histrelin acetate, fosfamide, interferon α2a, lapatinibditosylate), levamisole, marizomib, meclorethamine, melphalan, mercaptopurine, methotrexate, methoxsalen, mitotane, nandrolone phenpropionate, nofetumomab, oprozomib, pegfilgrastim, pentostatin, pipobroman, plicamycin, procarbazine, quinacrine, rasburicase, ruxolitinib, rucaparib, streptozocin, teniposide, testolactone, thalidomide, thioguanine, topotecan, toremifene, tretinoin, uracil mustard, valrubicin, vinblastine, vincristine, niraparib, veliparib, talazoparib or zoledronate.

[0052] In certain embodiments, the anti-cancer agent is an immunomodulator. In further embodiments, the immunomodulator is a co-stimulatory or co-inhibitory molecule, such as CTLA-4 (e.g., ipilimumab), 4-1BB (e.g., urelumab and utomilumab), antibodies against PD-1 and PD-L1 (e.g., nivolumab, pembrolizumab, atezolizumab, durvalumab, and camrelizumab), cytokine antibodies (IL-10, TGF-β), TIM-3 antibodies, LAG3 antibodies, B7H3 antibodies, B7H4 antibodies, and B7H6 antibodies; or a combination thereof.

[0053] In some embodiments of the present invention, two or more CD47-SIRPα blockers represented by the compound of formula (I) are administered. In some embodiments, the CD47-SIRPα blocker is administered more than once.

[0054] In certain embodiments, a CD47-SIRPα blocker is an agent that blocks the interaction between CD47 and SIRPα. In certain embodiments, blocking the interaction between CD47 and SIRPα induces macrophages to phagocytose tumor cells expressing CD47.

[0055] In certain embodiments, the present invention provides a composition comprising a small molecule CD47-SIRPα blocker as described in a compound of formula (I) and a proteasome inhibitor. In certain embodiments, the proteasome inhibitor is bortezomib, ixazomib or carfilzomib or any analogue or derivative thereof.

[0056] In certain embodiments, the composition of the present invention comprises a compound of formula (I), wherein R1 is hydrogen, -(CH2)2CONH2, -(CH2)2COOH, -(CH2)3NHC(=NH)NH2, -(CH2)4NH2, -CH2-phenyl or -CH2-imidazolyl.

[0057] In certain embodiments, the composition of the present invention comprises a compound of formula (I), wherein R1 is -(CH2)2CONH2, -(CH2)2COOH, -(CH2)3NHC(=NH)NH2 or -(CH2)4NH2.

[0058] In certain embodiments, the composition of the present invention comprises a compound of formula (I), wherein R1 is -(CH2)2CONH2 or -(CH2)2COOH.

[0059] In certain embodiments, the composition of the present invention comprises a compound of formula (I), wherein R2 represents hydrogen, -(CH2)3NHC(=NH)NH2, -(CH2)2CONH2, -(CH2)2COOH, -CH2-phenyl or -CH2-imidazolyl.

[0060] In certain embodiments, the composition of the present invention comprises a compound of formula (I), wherein R2 is hydrogen, -(CH2)3NHC(=NH)NH2 or -(CH2)2COOH.

[0061] In certain embodiments, the composition of the present invention comprises a compound of formula (I), wherein R2 is hydrogen, -(CH2)2CONH2 or -(CH2)2COOH.

[0062] In certain embodiments, the composition of the present invention comprises a compound of formula (I), wherein R3 represents hydrogen, -CH2-phenyl, -(CH2)3NHC(=NH)NH2, -(CH2)2CONH2, -(CH2)2COOH, -(CH2)4NH2 or -CH2-imidazolyl.

[0063] In certain embodiments, the compositions of the present invention comprise a compound of formula (I), wherein R3 represents hydrogen, -CH2-phenyl, -(CH2)3NHC(=NH)NH2, -(CH2)2CONH2, -(CH2)2COOH or -(CH2)4NH2.

[0064] In certain embodiments, the compositions of the present invention comprise a compound of formula (I), wherein R a is hydrogen; and R1 represents hydrogen, -(CH2)2CONH2, -(CH2)2COOH, -(CH2)3NHC(=NH)NH2, -(CH2)4NH2, -CH2CONH2, -CH2-phenyl or -CH2-imidazolyl; or R a and R1 together with the atoms to which they are attached form a pyrrolidine ring;

[0065] R2 represents hydrogen, -(CH2)3NHC(=NH)NH2, -(CH2)2CONH2, -(CH2)2COOH, -CH2-phenyl or -CH2-imidazolyl;

[0066] R b is hydrogen; and R3 represents hydrogen, -CH2-phenyl, -(CH2)3NHC(=NH)NH2, -(CH2)2CONH2, -(CH2)2COOH, -(CH2)4NH2 or -CH2-imidazolyl; or R b and R3 together with the atoms to which they are attached form a pyrrolidine ring.

[0067] In certain embodiments, the compositions of the present invention comprise a compound of formula (I) which is a compound of formula (IA):

[0068]

[0069] or a pharmaceutically acceptable salt or amide or ester or a stereoisomer thereof; wherein R1,, R a and R2 are as defined for the compound of formula (I).

[0070] In certain embodiments, the compositions of the present invention comprise a compound of formula (IA), wherein R1 represents hydrogen, -(CH2)2CONH2, -(CH2)2COOH, -(CH2)3NHC(=NH)NH2, -(CH2)4NH2, -CH2-phenyl or -CH2-imidazolyl.

[0071] In certain embodiments, the compositions of the present invention comprise a compound of formula (IA), wherein R2 represents hydrogen, -(CH2)3NHC(=NH)NH2, -(CH2)2CONH2, -(CH2)2COOH, -CH2-phenyl or -CH2-imidazolyl.

[0072] In certain embodiments, the compositions of the present invention comprise a compound of formula (IA), wherein R a is hydrogen; and R1 represents 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.

[0073] In another embodiment, the compositions of the present invention comprise a compound of formula (IA): wherein R a is hydrogen; and R1 represents -(CH2)2CONH2, -(CH2)2COOH, -(CH2)3NHC(=NH)NH2 or -(CH2)4NH2. R2 represents hydrogen, -(CH2)3NHC(=NH)NH2, -(CH2)2COOH, -CH2-phenyl or -CH2-imidazolyl.

[0074] In certain embodiments, the compositions of the present invention comprise a compound of formula (I), which is selected from,

[0075]

[0076] Or

[0077]

[0078] or a pharmaceutically acceptable salt or amide or ester or a stereoisomer thereof.

[0079] In certain embodiments, the compositions of the present invention comprise a compound of formula (I), which is selected from,

[0080]

[0081] Or

[0082] or a pharmaceutically acceptable salt or amide or ester or a stereoisomer thereof.

[0083] In certain embodiments, the compositions of the invention comprise a compound of formula (IA), which may also be written by showing its absolute stereochemistry, as

[0084]

[0085] In certain embodiments, the compositions of the invention comprise a compound of formula (I), which is a compound of formula (IB):

[0086]

[0087] or a pharmaceutically acceptable salt or amide or ester or a stereoisomer thereof; wherein R1, R a , R b and R3 are as defined for the compound of formula (I).

[0088] In certain embodiments, the compositions of the invention comprise a compound wherein R1 represents hydrogen, -(CH2)2CONH2, -(CH2)2COOH, -(CH2)3NHC(=NH)NH2, -(CH2)4NH2 or -CH2-phenyl.

[0089] In certain embodiments, the compositions of the invention comprise a compound wherein R1 is -(CH2)2CONH2 or -(CH2)2COOH.

[0090] In certain embodiments, the compositions of the invention comprise a compound wherein R3 is hydrogen, -CH2-phenyl, -(CH2)2CONH2 or -(CH2)2COOH.

[0091] In certain embodiments, the compositions of the invention comprise a compound wherein R3 is hydrogen or -CH2-phenyl.

[0092] In certain embodiments, the compositions of the invention comprise a compound of formula (IB) wherein R b is hydrogen.

[0093] In certain embodiments, in formula (IB), R b and R3 together with the atoms to which they are attached form a pyrrolidine ring.

[0094] In certain embodiments, the compositions of the invention comprise a compound of formula (IB) wherein R1 represents -(CH2)2CONH2 or -(CH2)2COOH; R b is hydrogen; and R3 represents hydrogen or -CH2-phenyl; or R b and R3 together with the atoms to which they are attached form a pyrrolidine ring.

[0095] In certain embodiments, the compositions of the invention comprise a compound of formula (I), wherein the compound is selected from,

[0096]

[0097] or

[0098] or a pharmaceutically acceptable salt or amide or ester or a stereoisomer thereof.

[0099] In certain embodiments, the compositions of the invention comprise a compound of formula (I) which is a compound of formula (IC):

[0100]

[0101] or a pharmaceutically acceptable salt or amide or ester or a stereoisomer thereof; wherein R1, R a , R3 and R b are as defined for the compound of formula (I).

[0102] In certain embodiments, the compositions of the invention comprise a compound wherein R1 is -(CH2)2CONH2, -(CH2)3NHC(=NH)NH2 or -(CH2)4NH2.

[0103] In certain embodiments, the compositions of the invention comprise a compound wherein R1 is -(CH2)2CONH2 or -(CH2)3NHC(=NH)NH2.

[0104] In certain embodiments, the compositions of the invention comprise a compound of formula (IC) wherein R a is hydrogen. In certain embodiments, in formula (IC), R a and R1 together with the atoms to which they are attached form a pyrrolidine ring.

[0105] In certain embodiments, the compositions of the invention comprise a compound wherein R3 is hydrogen, -CH2-phenyl, -(CH2)3NHC(=NH)NH2 or -CH2-imidazolyl.

[0106] In certain embodiments, the compositions of the invention comprise a compound of formula (IC) wherein R b is hydrogen.

[0107] In certain embodiments, in formula (IC), R b and R3 together with the atoms to which they are attached form a pyrrolidine ring.

[0108] In another embodiment, the compositions of the invention comprise a compound of formula (IC): wherein R ais hydrogen; and R1 represents -(CH2)2CONH2, -(CH2)3NHC(=NH)NH2 or -(CH2)4NH2; or R a and R1 together with the atoms to which they are attached form a pyrrolidine ring; and R b is hydrogen; and R3 represents -CH2-phenyl, -(CH2)3NHC(=NH)NH2 or -CH2-imidazolyl; or R b and R3 together with the atoms to which they are attached form a pyrrolidine ring.

[0109] In certain embodiments, the compositions of the invention comprise a compound of formula (I), wherein the compound is selected from,

[0110]

[0111] or

[0112] or a pharmaceutically acceptable salt or amide or ester or a stereoisomer thereof.

[0113] In certain embodiments, the compositions of the invention comprise a compound of formula (I) which is a compound of formula (ID):

[0114]

[0115] or a pharmaceutically acceptable salt or amide or ester or a stereoisomer thereof; wherein R1, R a , R3 and R b are as defined for the compounds of formula (I).

[0116] In certain embodiments, the compositions of the invention comprise a compound wherein R1 is -(CH2)3NHC(=NH)NH2, -(CH2)4NH2 or -CH2CONH2.

[0117] In certain embodiments, the compositions of the invention comprise a compound wherein R3 is hydrogen, -(CH2)3NHC(=NH)NH2 or -(CH2)4NH2.

[0118] In certain embodiments, the compositions of the invention comprise a compound of formula (ID) wherein R b is hydrogen.

[0119] In certain embodiments, in formula (ID), R b and R3 together with the atoms to which they are attached form a pyrrolidine ring.

[0120] In another embodiment, the composition of the present invention comprises a compound of formula (ID): wherein R1 represents -(CH2)3NHC(=NH)NH2, -(CH2)4NH2 or -CH2CONH2; R b is hydrogen; and R3 represents hydrogen, -(CH2)3NHC(=NH)NH2 or -(CH2)4NH2; or R b and R3 together with the atoms to which they are attached form a pyrrolidine ring.

[0121] In certain embodiments, the composition of the present invention comprises a compound of formula (I), wherein the compound is selected from,

[0122]

[0123] or

[0124]

[0125] or a pharmaceutically acceptable salt or amide or ester or a stereoisomer thereof. In certain embodiments, the composition of the present invention comprises a compound of formula (I) which is a compound of formula (IE):

[0126]

[0127] or a pharmaceutically acceptable salt or amide or ester or a stereoisomer thereof; wherein R2, R3 and R b are as defined for the compound of formula (I).

[0128] In certain embodiments, the composition of the present invention comprises a compound wherein R2 is hydrogen or -(CH2)3NHC(=NH)NH2.

[0129] In certain embodiments, the composition of the present invention comprises a compound of formula (IE), wherein R b and R3 together with the atoms to which they are attached form a pyrrolidine ring.

[0130] In another embodiment, the composition of the present invention comprises a compound of formula (IE): wherein R2 represents hydrogen or -(CH2)3NHC(=NH)NH2; R b and R3 together with the atoms to which they are attached form a pyrrolidine ring. In certain embodiments, the composition of the present invention comprises a compound of formula (I) which is a compound of formula (IF):

[0131]

[0132] or a pharmaceutically acceptable salt or amide or ester or a stereoisomer thereof; wherein R2, R3 and Rb As defined by the compound of formula (I).

[0133] In certain embodiments, the compositions of the invention comprise a compound wherein R2 is hydrogen, -CH2-phenyl, -(CH2)3NHC(=NH)NH2 or -(CH2)2COOH.

[0134] In certain embodiments, the compositions of the invention comprise a compound wherein R3 is -CH2-phenyl, -(CH2)2CONH2 or -(CH2)2COOH.

[0135] In certain embodiments, the compositions of the invention comprise a compound of formula (IF) wherein R b is hydrogen.

[0136] In certain embodiments, in formula (IF), R b and R3 together with the atoms to which they are attached form a pyrrolidine ring.

[0137] In certain embodiments, the compositions of the invention comprise a compound of formula (IF): wherein R2 represents hydrogen, -CH2-phenyl, -(CH2)3NHC(=NH)NH2 or -(CH2)2COOH; R b is hydrogen; and R3 represents -CH2-phenyl, -(CH2)2CONH2 or -(CH2)2COOH; or R b and R3 together with the atoms to which they are attached form a pyrrolidine ring.

[0138] In certain embodiments, the compositions of the invention comprise a compound of formula (I), wherein the compound is selected from,

[0139]

[0140] Or

[0141]

[0142] or a pharmaceutically acceptable salt or amide or ester or a stereoisomer thereof.

[0143] In certain embodiments, the compositions of the invention comprise a compound, wherein the compound is selected from:

[0144]

[0145]

[0146]

[0147]

[0148] or a pharmaceutically acceptable salt or amide or ester thereof, or a stereoisomer thereof.

[0149] In certain embodiments, the present invention relates to a composition comprising a CD47-SIRPα blocker and one or more anti-cancer agents, which is used as a drug, wherein the CD47-SIRPα blocker is a compound of formula (I) or a pharmaceutically acceptable salt or amide or ester thereof, or a stereoisomer thereof, as described herein; the anti-cancer agent is a chemotherapeutic agent or an immunomodulator, as described herein.

[0150] In certain embodiments, the present invention relates to a composition comprising a CD47-SIRPα blocker, one or more anti-cancer agents, and a pharmaceutically acceptable carrier, wherein the CD47-SIRPα blocker is a compound of formula (I) or a pharmaceutically acceptable salt or amide or ester thereof, or a stereoisomer thereof, as described herein; the anti-cancer agent is a chemotherapeutic agent or an immunomodulator, as described herein.

[0151] In certain embodiments, the present invention provides a combination comprising a CD47-SIRPα blocker and one or more anti-cancer agents: wherein the CD47-SIRPα blocker is represented by a compound of formula (I):

[0152]

[0153] or a pharmaceutically acceptable salt or amide or ester thereof, or a stereoisomer thereof; wherein,

[0154] R a is hydrogen; and R1 represents hydrogen, -(CH2)2CONH2, -(CH2)2COOH, -(CH2)3NHC(=NH)NH2, -(CH2)4NH2, -CH2CONH2, -CH2-aryl or -CH2-heteroaryl; or R a and R1 together with the atoms to which they are attached form a pyrrolidine ring;

[0155] R2 represents hydrogen, -(CH2)3NHC(=NH)NH2, -(CH2)2CONH2, -(CH2)2COOH, -CH2-aryl or -CH2-heteroaryl;

[0156] R b is hydrogen; and R3 represents hydrogen, -CH2-aryl, -(CH2)3NHC(=NH)NH2, -(CH2)2CONH2, -(CH2)2COOH, -(CH2)4NH2 or -CH2-heteroaryl; or R b and R3 together with the atoms to which they are attached form a pyrrolidine ring.

[0157] In certain embodiments, the combination of the invention comprises a CD47-SIRPα blocker of a compound of formula (I) and a proteasome inhibitor.

[0158] In certain embodiments, the combination of the invention comprises a CD47-SIRPα blocker of a compound of formula (I) and an anti-CD-20 antibody.

[0159] In certain embodiments, the combination of the invention comprises a CD47-SIRPα blocker of a compound of formula (IA), (IB), (IC), (ID), (IE) or (IF).

[0160] In certain embodiments, the invention relates to a method for treating cancer in a subject presenting with CD47 pathway dysregulation, the method comprising administering to the subject a combination of a therapeutically effective amount of a CD47-SIRPα blocker and a therapeutically effective amount of one or more anti-cancer agents: wherein the CD47-SIRPα blocker is represented by a compound of formula (I):

[0161]

[0162] or a pharmaceutically acceptable salt or amide or ester thereof; or a stereoisomer thereof;

[0163] wherein,

[0164] R a is hydrogen; and R1 represents hydrogen, -(CH2)2CONH2, -(CH2)2COOH, -(CH2)3NHC(=NH)NH2, -(CH2)4NH2, -CH2CONH2, -CH2-aryl or -CH2-heteroaryl; or R a and R1 together with the atoms to which they are attached form a pyrrolidine ring; R2 represents hydrogen, -(CH2)3NHC(=NH)NH2, -(CH2)2CONH2, -(CH2)2COOH, -CH2-aryl or -CH2-heteroaryl; R b is hydrogen; and R3 represents hydrogen, -CH2-aryl, -(CH2)3NHC(=NH)NH2, -(CH2)2CONH2, -(CH2)2COOH, -(CH2)4NH2 or -CH2-heteroaryl; or R b and R3 together with the atoms to which they are attached form a pyrrolidine ring.

[0165] In certain embodiments, a subject presenting with CD47 pathway dysregulation is a subject presenting with CD47+ disease cells. In certain embodiments, the CD47+ disease cells are CD47+ cancer cells.

[0166] In certain embodiments, the present invention relates to a method in which treatment with one or more anti-cancer agents is before, at the same time as, or after treatment with a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0167] In certain embodiments, the present invention relates to a method for treating a disease or disorder mediated by the CD47 pathway or delaying the progression of the disease or disorder in a subject, the method comprising administering to a subject in need thereof a combination of a therapeutically effective amount of an agent that blocks the CD47-SIRPα pathway and a therapeutically effective amount of one or more anti-cancer agents: wherein the agent that blocks the CD47-SIRPα pathway is represented by a compound of formula (I):

[0168]

[0169] or a pharmaceutically acceptable salt or amide or ester thereof; or a stereoisomer thereof;

[0170] wherein,

[0171] R a is hydrogen; and R1 represents hydrogen, -(CH2)2CONH2, -(CH2)2COOH, -(CH2)3NHC(=NH)NH2, -(CH2)4NH2, -CH2CONH2, -CH2-aryl or -CH2-heteroaryl; or R a and R1 together with the atoms to which they are attached form a pyrrolidine ring; R2 represents hydrogen, -(CH2)3NHC(=NH)NH2, -(CH2)2CONH2, -(CH2)2COOH, -CH2-aryl or -CH2-heteroaryl; R b is hydrogen; and R3 represents hydrogen, -CH2-aryl, -(CH2)3NHC(=NH)NH2, -(CH2)2CONH2, -(CH2)2COOH, -(CH2)4NH2 or -CH2-heteroaryl; or R b and R3 together with the atoms to which they are attached form a pyrrolidine ring.

[0172] In certain embodiments, the present invention relates to a method in which the disease or disorder mediated by the CD47-SIRPα pathway is cancer.

[0173] In certain embodiments, the present invention relates to a method in which the disease or disorder mediated by the CD47 pathway is atherosclerosis.

[0174] In certain embodiments, the present invention relates to a method in which the disease or disorder mediated by the CD47 pathway is multiple sclerosis.

[0175] In certain embodiments, the present invention provides a pharmaceutical composition comprising a compound as disclosed herein, optionally admixed with a pharmaceutically acceptable carrier or diluent.

[0176] In certain embodiments, the present invention provides the use of a composition as described herein comprising a CD47-SIRPα blocker and one or more anti-cancer agents in the manufacture of a medicament for treating cancer in a subject presenting with CD47 pathway dysregulation.

[0177] In certain embodiments, the present invention provides a kit comprising a composition as described herein and a package insert, the package insert comprising instructions for the administration of a medicament for treating a subject presenting with CD47 pathway dysregulation.

[0178] The present invention also provides methods for formulating the disclosed compounds for pharmaceutical administration.

[0179] The compositions and methods of the present invention can be used to treat an individual in need thereof. In certain embodiments, the individual is a mammal, such as a human or non-human mammal. When administered to an animal such as a human, the compound is preferably administered in the form of a pharmaceutical composition comprising, for example, a compound of the present invention and a pharmaceutically acceptable carrier. In a preferred embodiment, when such a pharmaceutical composition is for human administration, particularly for invasive routes of administration (i.e., routes that circumvent transport or diffusion through an epithelial barrier, such as injection or implantation), the aqueous solution is pyrogen-free or substantially pyrogen-free. Excipients can be selected, for example, to achieve delayed release of the agent or selective targeting of one or more cells, tissues, or organs. The pharmaceutical composition can be in dosage unit form, such as tablets, capsules (including sprinkle capsules and gelatin capsules), granules, lyophilized agents for reconstitution, powders, solutions, syrups, suppositories, injections, etc. The composition can also be present in a transdermal delivery system, such as a skin patch. The composition can also be present in a solution suitable for topical administration, such as eye drops.

[0180] A pharmaceutically acceptable carrier may contain physiologically acceptable agents that serve to, for example, stabilize, increase solubility, or increase absorption of the compound. Such physiologically acceptable agents include, for example, carbohydrates such as glucose, sucrose, or dextran; antioxidants such as ascorbic acid or glutathione; chelating agents; low molecular weight proteins or other stabilizers or excipients. The choice of pharmaceutically acceptable carrier (including physiologically acceptable agents) depends, for example, on the route of administration of the composition. The preparation of the pharmaceutical composition may be a self-emulsifying drug delivery system or a self-microemulsifying drug delivery system. The pharmaceutical composition (preparation) may also be a liposome or other polymeric matrix, in which, for example, the compounds of the present invention may be incorporated. Liposomes, for example, liposomes containing phospholipids or other lipids, may be a relatively simple, non-toxic, physiologically acceptable, and metabolizable carrier for manufacture and administration.

[0181] The agents in the composition are administered simultaneously, i.e., each agent is administered within about 45 days, 30 days, 15 days, 7 days, 3 days, 2 days, 1 day, or substantially simultaneously relative to the other agents in the composition. The agents are considered to be used in combination if the dosing schedule results in serum levels of the two agents reaching therapeutic levels.

[0182] In certain embodiments, for administration, each dose of the combination of the CD47-SIRPα blocker and the anti-cancer agent will be in the range of about 0.0001 to 100 mg / kg of the host body weight, more typically 0.01 to 50 mg / kg. For example, the dose may be 1 mg / kg body weight, 10 mg / kg body weight, or 30 mg / kg body weight, or in the range of 1 - 50 mg / kg. The dose may be adjusted according to the molecular weight of the CD47-SIRPα blocker or the anti-cancer agent and may be reduced relative to the dose required for monotherapy of either agent in the combination. Exemplary treatment regimens require administration daily, every half-week, weekly, every two weeks, monthly, etc.

[0183] As used herein, the phrase "pharmaceutically acceptable" refers to those compounds, materials, compositions, and / or dosage forms that are within the scope of sound medical judgment, suitable for contact with human and animal tissues without excessive toxicity, irritation, allergic response, or other problems or complications, and commensurate with a reasonable benefit / risk ratio.

[0184] As used herein, the phrase "pharmaceutically acceptable carrier" means a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials that can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose, and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol, and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethanol; (20) phosphate buffer solutions; and (21) other non-toxic compatible substances employed in pharmaceutical compositions.

[0185] The pharmaceutical composition (preparation) can be administered to a subject by any of a variety of routes of administration, including, for example, the oral route (e.g., as a medicated water, tablet, capsule (including sprinkle capsules and gelatin capsules), bolus, powder, granule, paste applied to the tongue) in the form of an aqueous solution or a non-aqueous solution or suspension; by the buccal mucosal absorption route (e.g., sublingual); the anal, rectal, or vaginal route (e.g., as a vaginal suppository, cream, or foam); the parenteral route (including intramuscular, intravenous, subcutaneous, or intrathecal, e.g., as a sterile solution or suspension); the nasal route; the intraperitoneal route; the subcutaneous route; the transdermal route (e.g., as a patch applied to the skin); and the topical route (e.g., as a cream, ointment, or spray applied to the skin or as an eye drop). The compound can also be formulated for inhalation. In certain embodiments, the compound can simply be dissolved or suspended in sterile water.

[0186] The formulation can conveniently be in unit dosage form and can be prepared by any method well known in the pharmaceutical art. The amount of each active ingredient that can be combined with the carrier materials to produce a single dosage form will vary depending upon the host to be treated, the particular mode of administration. The amount of each active ingredient that can be combined with the carrier materials to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect. Generally speaking, on a percentage basis, this amount will be between about 1% and about 99% of each active ingredient, preferably about 5% to about 70%, and most preferably about 10% to about 30%.

[0187] The methods for preparing these preparations or compositions include the step of combining the compositions of the present invention with a carrier and optionally one or more auxiliary ingredients. Generally, the preparations are prepared by uniformly and intimately associating the compounds of the present invention with a liquid carrier, or a finely divided solid carrier, or both, and then shaping the product if necessary.

[0188] The preparations of the present invention suitable for oral administration may be in the form of capsules (including sprinkle capsules and gelatin capsules), cachets, pills, tablets, lozenges (using a flavored matrix, usually sucrose and gum arabic or tragacanth), lyophilized products, powders, granules or as solutions or suspensions in aqueous or non-aqueous liquids, or as water-in-oil or oil-in-water emulsions, or as elixirs or syrups, or as pastilles (using an inert matrix such as gelatin and glycerin, or sucrose and gum arabic) and / or as mouthwashes, etc., each containing a predetermined amount of the composition of the present invention as a therapeutically active combination. The composition may also be administered as boluses, electuaries or pastes.

[0189] For preparing solid dosage forms for oral administration (capsules (including sprinkle capsules and gelatin capsules), tablets, pills, troches, powders, granules, etc.), the composition is mixed with one or more pharmaceutically acceptable carriers (such as sodium citrate or dicalcium phosphate) and / or any of the following: (1) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol and / or silicic acid; (2) binders, such as carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and / or gum arabic; (3) wetting agents, such as glycerol; (4) disintegrants, such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate; (5) solution retarders, such as paraffin wax; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as cetyl alcohol and glycerol monostearate; (8) absorbents, such as kaolin and bentonite; (9) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate and mixtures thereof; (10) complexing agents, such as modified and unmodified cyclodextrins; and (11) coloring agents. In the case of capsules (including sprinkle capsules and gelatin capsules), tablets and pills, the pharmaceutical composition may also contain buffering agents. Similar types of solid compositions may also be used as fillers in soft and hard gelatin capsules using excipients such as lactose or milk sugar and high molecular weight polyethylene glycols, etc.

[0190] Tablets can be prepared by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared using binders (such as gelatin or hydroxypropyl methylcellulose), lubricants, inert diluents, preservatives, disintegrants (such as sodium carboxymethyl starch or cross-linked sodium carboxymethyl cellulose), surfactants or dispersants. Molded tablets can be prepared by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.

[0191] The tablets and other solid dosage forms of the pharmaceutical composition, such as troches, capsules (including sprinkle capsules and gelatin capsules), pills and granules, can be optionally scored or prepared with coatings and shells (such as enteric coatings and other coatings well known in the pharmaceutical formulation art). They can also be formulated using, for example, different proportions of hydroxypropyl methylcellulose, other polymeric matrices, liposomes and / or microspheres that provide the desired release profile in order to effect slow or controlled release of the combined active ingredients therein. They can be sterilized by, for example, filtration through a bacteria-retaining filter or by incorporating a sterilizing agent in the form of a sterile solid composition that is soluble in sterile water or some other sterile injectable medium immediately before use. These compositions can also optionally contain opacifying agents and can also be compositions that release the active ingredient only in or preferentially in a certain part of the gastrointestinal tract, optionally in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. The active ingredient can also be in microencapsulated form and suitably have one or more of the above excipients.

[0192] Liquid dosage forms suitable for oral administration include pharmaceutically acceptable emulsions, lyophilized products for reconstitution, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredient, the liquid dosage forms can contain inert diluents commonly used in the art, such as water or other solvents, cyclodextrins and their derivatives, solubilizing agents and emulsifying agents such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butanediol, oils (specifically cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol and fatty acid esters of sorbitan and mixtures thereof.

[0193] In addition to the inert diluent, the oral compositions can also contain adjuvants such as wetting agents, emulsifying agents and suspending agents, sweetening agents, flavoring agents, coloring agents, aromatic agents and preservatives.

[0194] In addition to the active ingredient, the suspensions can also contain suspending agents such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum hydroxide, bentonite, agar and tragacanth and mixtures thereof.

[0195] Preparations of the pharmaceutical composition for rectal, vaginal or urethral administration may exist as suppositories, which may be prepared by mixing one or more active ingredients of the composition of the present invention with one or more suitable non-irritating excipients or carriers (including, for example, cocoa butter, polyethylene glycol, suppository wax or salicylate), and the suppositories are solid at room temperature but liquid at body temperature and will thus melt in the rectal or vaginal cavity and release the active ingredients.

[0196] Preparations of the pharmaceutical composition for oral administration may exist in the form of mouthwashes, oral sprays or oral ointments.

[0197] Alternatively or additionally, the composition may be configured for delivery via a catheter, stent, wire or other intravascular device. Delivery via such devices may be particularly useful for delivery to the bladder, urethra, ureter, rectum or intestine.

[0198] Preparations suitable for vaginal administration also include vaginal suppositories, tampons, creams, gels, pastes, foams or spray preparations containing such suitable carriers known in the art.

[0199] Dosage forms for topical or transdermal administration include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active compound may be mixed with a pharmaceutically acceptable carrier and with any preservatives, buffers or propellants that may be required under sterile conditions.

[0200] In addition to the active compound, the ointments, pastes, creams and gels may contain excipients such as animal and vegetable fats, oils, waxes, paraffin wax, starch, tragacanth, cellulose derivatives, polyethylene glycol, silicone, bentonite, silicic acid, talc and zinc oxide or mixtures thereof.

[0201] In addition to the active compound, the powders and sprays may contain excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate and polyamide powder or mixtures of these substances. Sprays may additionally contain conventional propellants such as chlorofluorocarbons and volatile unsubstituted hydrocarbons (such as butane or propane).

[0202] Transdermal patches have the additional advantage of providing controlled delivery of the compounds of the present invention to the body. Such dosage forms may also be prepared by dissolving or dispersing the active compound in a suitable medium. Penetration enhancers may also be used to increase the flux of the compound through the skin. The rate of such flux may be controlled by providing a rate-controlling membrane or by dispersing the compound in a polymeric matrix or gel.

[0203] As used herein, the phrases "parenteral administration" and "administering parenterally" mean a mode of administration other than enteral and topical administration, typically by injection, and include, but are not limited to, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, intratracheal, subcutaneous, subepidermal, intraarticular, subcapsular, subarachnoid, intraspinal, and intrasternal injection and infusion.

[0204] A pharmaceutical composition suitable for parenteral administration comprises a combination of one or more active compounds with one or more pharmaceutically acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions, or emulsions, or sterile powders that can be reconstituted into sterile injectable solutions or dispersions immediately before use, which combination may contain antioxidants, buffers, bacteriostats, solutes that render the formulation isotonic with the blood of the intended recipient, or suspending or thickening agents.

[0205] Examples of suitable aqueous and non-aqueous carriers that can be used in the pharmaceutical compositions of the present invention include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, etc.) and suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters (such as ethyl oleate). Appropriate fluidity can be maintained, for example, by using coating materials (such as lecithin), in the case of dispersions by maintaining the desired particle size, and by using surfactants.

[0206] These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents, and dispersing agents. The action of microorganisms can be prevented by including various antibacterial and antifungal agents such as parabens, chlorobutanol, phenol, sorbic acid, etc. It may also be desirable to include isotonic agents such as sugars, sodium chloride, etc. in the compositions. Additionally, delayed absorption of injectable drug forms can be achieved by including agents that delay absorption (such as aluminum monostearate and gelatin).

[0207] In some cases, in order to prolong the effect of a drug, it is necessary to slow down the absorption of a drug administered subcutaneously or intramuscularly. This can be achieved by using a liquid suspension of a crystalline or amorphous material having low water solubility. The rate of absorption of the drug then depends on its dissolution rate, which in turn can depend on crystal size and crystal form. Alternatively, delayed absorption of parenterally administered drug forms can be achieved by dissolving or suspending the drug in an oily vehicle.

[0208] Injectable depot forms are prepared by forming a microencapsulated matrix of the subject compound in a biodegradable polymer such as polylactide-co-glycolide. The rate of drug release can be controlled according to the ratio of the drug to the polymer and the nature of the specific polymer employed. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissues.

[0209] The introduced methods can also be provided by rechargeable or biodegradable devices. In recent years, various sustained-release polymer devices have been developed and tested in vivo to control the delivery of drugs, including protein biopharmaceuticals. A variety of biocompatible polymers, including both biodegradable and non-biodegradable polymers (including hydrogels), can be used to form implants for the sustained release of the compounds of the present invention composition at specific target sites.

[0210] The actual dosage level of the active ingredient in the pharmaceutical composition can be varied so as to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, and that is non-toxic to the patient.

[0211] The selected dosage level will depend upon a variety of factors including the activity of the specific compound combination or its ester, salt, or amide being employed, the route of administration, the time of administration, the rate of excretion of the specific compound being used, the duration of the treatment, other drugs, compounds and / or materials used in combination with the specific compound being employed, the age, sex, weight, condition, general health, and prior medical history of the patient being treated, and like factors well known in the medical arts.

[0212] In general, the appropriate daily dosage of the active compound used in the compositions and methods of the present invention will be that amount of the compound that is the lowest dosage effective to produce a therapeutic effect. Such effective dosage will generally depend upon the above factors.

[0213] The patients receiving such treatment are any animals in need, including primates, particularly humans, as well as other mammals such as horses, cattle, pigs, and sheep; and generally poultry and pets.

[0214] Wetting agents, emulsifying agents, and lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening agents, flavoring agents, and perfuming agents, preservatives, and antioxidants may also be present in the composition.

[0215] Examples of pharmaceutically acceptable antioxidants include: (1) water-soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, etc.; (2) oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, α-tocopherol, etc.; and (3) metal chelating agents such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, etc.

[0216] In certain embodiments, the compositions described herein enhance macrophage phagocytic activity against cancer cells such as AML cells. In other embodiments, the phagocytic activity is enhanced, for example, 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% relative to macrophages in the absence of the compositions described herein.

[0217] In certain embodiments, the present invention provides for the use of the compositions of the present invention in the preparation of a medicament.

[0218] In certain embodiments, the present invention provides for the use of the compositions of the present invention in the preparation of a medicament for treating, for example, cancer.

[0219] In certain embodiments, the present invention provides a method for treating cancer, the method comprising administering to a subject in need thereof a therapeutically effective amount of, for example, the compositions of the present invention.

[0220] In certain embodiments, the present invention provides a method for inhibiting tumor cell growth and / or metastasis by administering to a subject in need thereof a therapeutically effective amount of, for example, the compositions of the present invention.

[0221] Representative tumor cells include cells of cancers such as, but not limited to, melanoma, renal cancer, prostate cancer, breast cancer, colon cancer and lung cancer, bone cancer, pancreatic cancer, skin cancer, head or neck cancer, cutaneous or intraocular malignant melanoma, uterine cancer, ovarian cancer, rectal cancer, anal area cancer, stomach cancer, testicular cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, non-Hodgkin's lymphoma, esophageal cancer, small intestine cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, chronic or acute leukemia including (acute myelogenous leukemia, acute lymphocytic leukemia, chronic myelogenous leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia), childhood solid tumors, lymphocytic lymphoma, bladder cancer, kidney or ureteral cancer, renal pelvic cancer, central nervous system (CNS) tumors, non-small cell lung cancer (NSCLC), primary CNS lymphoma, tumor angiogenesis, spinal tumors, brainstem glioma, pituitary adenoma, Kaposi's sarcoma, epidermoid carcinoma, squamous cell carcinoma, T-cell lymphoma, B-cell lymphoma, myeloproliferative disorders / tumors (MPDs), myelodysplastic syndromes, macroglobulinemia, heavy chain myeloma, light chain myeloma, and Bence-Jones myeloma, cancers caused by the environment including cancers caused by asbestos (e.g., mesothelioma), and combinations of such cancers. The term "treatment" includes prophylactic and / or therapeutic treatment. The term "prophylactic or therapeutic" treatment is recognized in the art and includes administering to a host one or more of the subject compositions. If administered before the manifestation of an undesired condition (e.g., a disease or other undesired state in a host animal), then the treatment is prophylactic (i.e., it protects the host from developing the undesired condition), and if administered after the manifestation of the undesired condition, then the treatment is therapeutic (i.e., it is intended to attenuate, ameliorate, or stabilize the existing undesired condition or its side effects).

[0222] As used herein, the term 'compound' includes compounds of formula (I), (IA), (IB), (IC), (ID), (IE), (IF) and pharmaceutically acceptable salts or stereoisomers thereof.

[0223] As used herein, the term "aryl" includes substituted or unsubstituted monocyclic aromatic groups in which each atom of the ring is carbon. Preferably, the ring is a 5- to 7-membered ring, more preferably a 6-membered ring. The term "aryl" also includes polycyclic systems having two or more rings in which two or more carbons are common to two adjacent rings, where at least one ring is aromatic, e.g., the other rings may be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclic. Aryl groups include benzene, naphthalene, phenanthrene, etc. Preferably, the term 'aryl' includes phenyl.

[0224] The term "heteroaryl" includes substituted or unsubstituted aromatic monocyclic structures, preferably 5- to 7-membered rings, more preferably 5- to 6-membered rings, the ring structure of which includes at least one heteroatom, preferably one to four heteroatoms, more preferably one or two heteroatoms. The terms "heteroaryl" and "hetaryl" also include polycyclic systems having two or more rings, where two or more carbons are common to two adjacent rings and where at least one ring is heteroaromatic; for example, the other rings may be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclic. Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrazine, pyridazine, indole, 1,2,4-oxadiazole, 1,3,4-oxadiazole, 1,3,4-thiadiazole, benzimidazole, pyrimidine, and the like. Heteroaryl groups may be substituted at one or more positions where valence allows with any of the optional substituents described herein. Preferably, the term 'heteroaryl' includes imidazolyl and indolyl.

[0225] As used herein, a therapeutic agent that "prevents" a disorder or condition is a compound that, in a statistical sample, reduces the incidence of the disorder or condition in the treated sample relative to an untreated control sample, or delays the onset or reduces the severity of one or more symptoms of the disorder or condition relative to an untreated control sample.

[0226] The term "treatment" includes prophylactic and / or therapeutic treatment. The term "prophylactic or therapeutic" treatment is recognized in the art and includes administering one or more of the subject compositions to a host. If administered before the manifestation of an undesired condition (e.g., a disease or other undesired state in a host animal), then the treatment is prophylactic (i.e., it protects the host from developing the undesired condition), while if administered after the manifestation of the undesired condition, then the treatment is therapeutic (i.e., it is intended to attenuate, ameliorate, or stabilize the existing undesired condition or its side effects).

[0227] As used herein, the phrase "delaying progression" refers to a procedure or application that is intended to delay in time the development of a disease or the symptoms of a disease (including delaying in time the appearance or occurrence of at least one symptom of a particular disease).

[0228] The term "prodrug" is intended to cover compounds that are converted under physiological conditions into a therapeutic active agent of the present invention (e.g., a compound of formula (I)). Common methods for preparing prodrugs include one or more selected moieties that are hydrolyzed under physiological conditions to reveal the desired molecule. In other embodiments, the prodrug is converted by the enzymatic activity of the host animal. For example, esters or carbonates (e.g., esters or carbonates of alcohols or carboxylic acids) are preferred prodrugs of the present invention. In certain embodiments, some or all of the compounds of formula (I) in the formulations represented above can be replaced with the corresponding suitable prodrugs, e.g., where the hydroxyl group in the parent compound is present in ester form, or where the carbonate or carboxylic acid present in the parent compound is present in ester form.

[0229] As used herein, the term "comprise" or "comprising" generally means to include, that is, to allow for the presence of one or more additional (unspecified) features or components.

[0230] As used herein, the use of the term "including" and other forms such as "include", "includes" and "included" are not restrictive.

[0231] As used herein, the term "disease" or "disorder" refers to a pathological condition in a living organism caused by a causative agent or condition (including but not limited to infection, acquired condition, genetic condition), and characterized by recognizable symptoms.

[0232] As used herein, a "patient" or "subject" or "individual" to be treated includes humans and / or non-human animals, including mammals. Mammals include primates such as humans, chimpanzees, gorillas and monkeys; domesticated animals such as dogs, horses, cats, pigs, goats, cows; and rodents such as mice, rats, hamsters and gerbils.

[0233] The term CD47+ disease cells refers to cells that have a CD47+ phenotype and are associated with a disease. In one embodiment, the CD47+ disease cells are cancer cells.

[0234] The term "CD47+" is used to refer to the phenotype of the cells targeted by the CD47-SIRPα blockers of the present invention. CD47+ cells can be identified by flow cytometry using a CD47 antibody as an affinity ligand. Appropriately labeled CD47 antibodies are commercially available for this purpose (e.g., the antibody product of clone B6H12 is available from Santa Cruz Biotechnology). The cells examined for the CD47 phenotype can include standard tumor biopsy samples, particularly blood samples collected from a subject suspected of harboring endogenous CD47+ cancer cells. Of particular interest as targets for treatment with the pharmaceutical combinations of the present invention are CD47 disease cells that "overexpress" CD47. These CD47+ cells are generally disease cells in which the density of CD47 on the surface exceeds the normal CD47 density of a given cell type. CD47 overexpression will vary between different cell types, but herein refers to any CD47 level determined by, for example, flow cytometry or by immunostaining or by gene expression analysis, etc., that is greater than the measurable level on healthy counterpart cells having the normal CD47 phenotype of that cell type.

[0235] The present invention includes compositions comprising pharmaceutically acceptable salts of the compounds described herein and their use in the compositions and methods of the present invention. In certain embodiments, the expected salts include, but are not limited to, alkyl, dialkyl, trialkyl, or tetraalkylammonium salts. In certain embodiments, the expected salts of the present invention include, but are not limited to, L-arginine, benenthamine, benzathine penicillin, betaine, calcium hydroxide, choline, danthron, diethanolamine, diethylamine, 2-(diethylamino)ethanol, ethanolamine, ethylenediamine, N-methylglucamine, hydrabamine salts, 1H-imidazole, lithium, L-lysine, magnesium, 4-(2-hydroxyethyl)morpholine, piperazine, potassium, 1-(2-hydroxyethyl)pyrrolidine, sodium, triethanolamine, tromethamine, and zinc salts. In certain embodiments, the expected salts of the present invention include, but are not limited to, Na, Ca, K, Mg, Zn, or other metal salts.

[0236] Pharmaceutically acceptable acid addition salts can also exist in the form of various solvates, such as solvates with water, methanol, ethanol, dimethylformamide, etc. Mixtures of such solvate agents can also be prepared. The source of such solvates can be from the crystallization solvent, be inherent in the solvent used for preparation or crystallization, or be insoluble in such solvents.

[0237] As used herein, the term "pharmaceutically acceptable salts" is intended to include all salts known and used in the pharmaceutical art. Pharmaceutically acceptable salts include, but are not limited to, amine salts such as, but not limited to, chloroprocaine, choline, N,N'-dibenzylethylenediamine, ammonia, diethanolamine and other hydroxyalkylamines, ethylenediamine, N-methylglucamine, procaine, N-benzylphenethylamine, 1-p-chlorobenzyl-2-pyrrolidin-1'-ylmethylbenzimidazole, diethylamine and other alkylamines, piperazine and tris(hydroxymethyl)aminomethane; alkali metal salts such as, but not limited to, lithium, potassium and sodium; alkaline earth metal salts such as, but not limited to, barium, calcium and magnesium; 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; and also include, but are not limited to, salts of inorganic acids such as, but not limited to, hydrochloride and sulfate; and salts of organic acids such as, but not limited to, acetate, lactate, malate, tartrate, citrate, ascorbate, succinate, butyrate, valerate and fumarate. Exemplary pharmaceutically acceptable salts include acetate, lactobionate, besylate, laurate, benzoate, malate, bicarbonate, maleate, bisulfate, mandelate, bitartrate, mesylate, borate, bromide, methyl bromide, methyl nitrate, calcium edetate, methyl sulfate, camsylate, mucate, carbonate, naphthalenesulfonate, bromide, chloride, nitrate, clavulanate, N-methylglucamine, citrate, ammonium salt, dihydrochloride, oleate, edetate, oxalate, ethanedisulfonate, pamoate (pamoate), etidronate, palmitate, esylate, pantothenate, fumarate, phosphate / hydrogen phosphate, glucoheptonate, pectinate, gluconate, salicylate, glutamate, stearate, glycollylarsanilate, sulfate, hexylresorcinate, basic acetate, hydrabamine, succinate, hydrobromide, tannate, hydrochloride, tartrate, hydroxynaphthoate, theophyllinate, iodide, tosylate, isethionate, triethyl iodide, lactate, pantothenate and valerate, which can be used as dosage forms to modify solubility or hydrolysis characteristics, or can be used in sustained release or prodrug formulations. The preparation of the above pharmaceutically acceptable salts and other typical pharmaceutically acceptable salts is more fully described in Berg et al., "Pharmaceutical Salts," J. Pharm. Sci. 66:1-19 (1977).

[0238] The term "stereoisomer" refers to any enantiomer, diastereomer or geometric isomer of a compound such as those described herein. When such compounds are chiral, they can exist in racemic or optically active forms. Since the pharmacological activities of the racemates or stereoisomers of the compounds according to the invention may differ, it may be necessary to use compounds enriched in one enantiomer. In these cases, the end products or even intermediates can be separated into enantiomeric compounds by chemical or physical measures known to those skilled in the art, or even used as such in synthesis. In the case of racemic amines, diastereoisomers are formed from the mixture by reaction with an optically active resolving agent. Examples of suitable resolving agents are optically active acids such as tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, suitable N-protected amino acids (e.g. N-benzoylproline or N-benzenesulfonylproline) or various optically active camphorsulfonic acids. Also advantageous is the chromatographic enantiomeric separation with the aid of an optically active resolving agent (e.g. dinitrobenzoylphenylglycine, cellulose triacetate or other derivatives of carbohydrates or chiral derivatized methacrylate polymers immobilized on silica gel).

[0239] As used herein, the term "ester" refers to the group -C(O)OR 11 , where R 11 represents a hydrocarbyl group.

[0240] As used herein, the term "amide" refers to the group -C(O)NH2.

[0241] In certain embodiments, the compounds described herein may be racemic. In certain embodiments, the compounds described herein may be enriched in one enantiomer. For example, the compounds described herein may have an ee of greater than 30%, 40%, 50%, 60%, 70%, 80%, 90% or even 95% or higher. In certain embodiments, the compounds described herein may have more than one stereocenter. In certain such embodiments, the compounds described herein may be enriched in one or more diastereomers. For example, the compounds described herein may have a de of greater than 30%, 40%, 50%, 60%, 70%, 80%, 90% or even 95% or higher.

[0242] The term "subject" includes mammals (especially humans) and other animals such as domesticated animals (e.g., household pets including cats and dogs) and non-domesticated animals (such as wild animals).

[0243] In certain embodiments, the present invention provides a composition comprising a small molecule CD-47-SIRPα pathway inhibitor and an agent capable of activating a receptor such as an Fc receptor (FcR) or a phagocytosis-promoting receptor or other therapeutic modalities for activating phagocytosis-promoting receptors in cancer therapy to exert the maximum potential of CD-47-SIRPα pathway blockade.

[0244] The present invention also provides the following specific embodiments:

[0245] Embodiment 1. A composition comprising a CD47-SIRPα blocker and one or more anti-cancer agents: wherein the CD47-SIRPα blocker is represented by a compound of formula (I):

[0246]

[0247] or a pharmaceutically acceptable salt or amide or ester or a stereoisomer thereof; wherein,

[0248] R a is hydrogen; and R1 represents hydrogen, -(CH2)2CONH2, -(CH2)2COOH, -(CH2)3NHC(=NH)NH2, -(CH2)4NH2, -CH2CONH2, -CH2-aryl or -CH2-heteroaryl; or R a and R1 together with the atoms to which they are attached form a pyrrolidine ring;

[0249] R2 represents hydrogen, -(CH2)3NHC(=NH)NH2, -(CH2)2CONH2, -(CH2)2COOH, -CH2-aryl or -CH2-heteroaryl;

[0250] R b is hydrogen; and R3 represents hydrogen, -CH2-aryl, -(CH2)3NHC(=NH)NH2, -(CH2)2CONH2, -(CH2)2COOH, -(CH2)4NH2 or -CH2-heteroaryl; or R b and R3 together with the atoms to which they are attached form a pyrrolidine ring.

[0251] Embodiment 2. The composition according to Embodiment 1, wherein the anti-cancer agent is a chemotherapeutic agent or an immunomodulator.

[0252] Embodiment 3. The composition according to Embodiment 1, wherein the anti-cancer agent is a therapeutic antibody targeting a tumor antigen that stimulates activation of an Fc receptor (FcR).

[0253] Embodiment 4. The composition according to Embodiment 3, wherein the antibody is selected from the group capable of triggering high-efficiency phagocytosis.

[0254] Embodiment 5. The composition according to Embodiment 4, wherein the group capable of triggering efficient phagocytosis includes anti-CD20 (rituximab, tezepelumab, tositumomab), the combination of which is particularly suitable for the treatment of non-Hodgkin B-cell lymphoma and chronic lymphocytic leukemia (CLL); anti-CD22 (epratuzumab), the combination of which is particularly suitable for the treatment of B-cell leukemia and hairy cell leukemia; anti-CD52 (alemtuzumab), the combination of which is particularly suitable for the treatment of B-cell and T-cell leukemia (chronic lymphocytic leukemia); anti-CD33 (gemtuzumab ozogamicin), the combination of which is particularly suitable for the treatment of myeloid leukemia (acute myeloid leukemia); trastuzumab, the combination of which is particularly suitable for the treatment of breast cancer; bevacizumab, the combination of which is particularly suitable for the treatment of certain types of brain tumors and certain types of kidney cancer, lung cancer, colon cancer, rectal cancer, cervical cancer, ovarian cancer or fallopian tube cancer; cetuximab, the combination of which is particularly suitable for the treatment of colon cancer and head and neck cancer; panitumumab, the combination of which is particularly suitable for the treatment of colorectal cancer; anti-CD38 (daratumumab), the combination of which is particularly suitable for the treatment of multiple myeloma; CD96, anti-CD44, anti-CD123, the combination of which is particularly suitable for the treatment of myeloid leukemia; ofatumumab, the combination of which is particularly suitable for the treatment of chronic lymphocytic leukemia; obinutuzumab, the combination of which is particularly suitable for the treatment of follicular lymphoma; alemtuzumab, the combination of which is particularly suitable for the treatment of B-cell chronic lymphocytic leukemia; ibritumomab tiuxetan, the combination of which is particularly suitable for the treatment of B-cell non-Hodgkin lymphoma; dinutuximab, the combination of which is particularly suitable for the treatment of neuroblastoma; and necitumumab, the combination of which is particularly suitable for the treatment of lung cancer.

[0255] Embodiment 6. The composition according to any one of Embodiments 1 to 5, wherein the anti-cancer agent is an anti-CD20 antibody selected from rituximab, tezepelumab and tositumomab.

[0256] Embodiment 7. The composition according to Embodiment 2, wherein the chemotherapeutic agent is a proteasome inhibitor (bortezomib, ixazomib and carfilzomib), an anthracycline (doxorubicin, epirubicin, daunorubicin, idarubicin, mitoxantrone), oxaliplatin, cyclophosphamide, bleomycin, vorinostat, paclitaxel, 5-fluorouracil, cytarabine, a BRAF inhibitory drug (dabrafenib, vemurafenib), a PI3K inhibitor, docetaxel, mitomycin C, sorafenib or tamoxifen; or a combination thereof.

[0257] Embodiment 8. The composition according to any one of Embodiments 1 to 2, wherein the anti-cancer agent is a proteasome inhibitor.

[0258] Embodiment 9. The composition according to Embodiment 8, wherein the anti-cancer agent is bortezomib, ixazomib or carfilzomib, or a derivative thereof.

[0259] Embodiment 10. The composition according to Embodiment 2, wherein the chemotherapeutic agent is abiraterone acetate, afatinib, aldesleukin, alemtuzumab, anastrozole, axitinib, belinostat, bendamustine, bicalutamide, blinatumomab, bosutinib, brentuximab vedotin, busulfan, cabazitaxel, capecitabine, carboplatin, carfilzomib, carmustine, ceritinib, clofarabine, crizotinib, dacarbazine, actinomycin D, dasatinib, degarelix, denileukin diftitox, denosumab, enzalutamide, eribulin, erlotinib, everolimus, exemestane, exemestane, fludarabine, fulvestrant, gefitinib, goserelin, iodine 131 tositumomab, imatinib, ipilimumab, irinotecan, ixabepilone, lapatinib, lenalidine, letrozole, leucovorin, leuprorelin, lomustine, mechlorethamine, medroxyprogesterone acetate, nelarabine, nilotinib, nivolumab, olaparib, omacetaxine mepesuccinate, palbociclib, pamidronate, panitumumab, panobinostat, pazopanib, pegaspargase, pembrolizumab, pemetrexed disodium, pertuzumab, plerixafor, pomalidomide, ponatinib, pralatrexate, procarbazine, radium 223, ramucirumab, regorafenib, rIFNa-2b, romidepsin, sunitinib, temozolomide, temsirolimus, thiotepa, tositumomab, trametinib, vinorelbine, abarelix, aldesleukin, alitretinoin, allopurinol, altretamine, arsenic trioxide, asparaginase, azacitidine, bexarotene, baricitinib, bortezomib, intravenous busulfan, oral busulfan, dimethandrolone, cetuximab, chlorambucil, cisplatin, cladribine, dalteparin sodium, decitabine, defucosylated anti-CD30 monoclonal antibody, disulfiram, dexrazoxane, dihydrotestosterone propionate, eculizumab, estramustine phosphate, etoposide, etoposide phosphate, fentanyl citrate, filgrastine, floxuridine, gemcitabine, histrelin acetate, cyclophosphamide, interferon alpha 2a, lapatinib ditosylate, levamisole, marizomib, mechlorethamine, melphalan, mercaptopurine, methotrexate, methoxsalen, mitotane, nandrolone phenylpropionate, norfumagillin, oprozomib, pegfilgrastine, pentostatin, pipobroman, plicamycin, procarbazine, quinacrine, rasburicase, ruxolitinib, olaparib, streptozocin, teniposide, testolactone, thalidomide, thioguanine, topotecan, toremifene, tretinoin, uracil mustard, valrubicin, vinblastine, vincristine, niraparib, veliparib, talazoparib, zoledronate, ibrutinib, aflibercept and idelalisib.

[0260] Embodiment 11. The composition according to Embodiment 2, wherein the immunomodulator is a costimulatory or coinhibitory molecule, including antibodies against CTLA-4 (e.g., ipilimumab), 4-1BB (e.g., urelumab and utomilumab), PD-1 and PD-L1 (e.g., nivolumab, pembrolizumab, atezolizumab, durvalumab, and camrelizumab), cytokine antibodies (IL-10, TGF-β), TIM-3 antibodies, LAG3 antibodies, B7H3 antibodies, B7H4 antibodies, or B7H6 antibodies; or a combination thereof.

[0261] Embodiment 12. The composition according to Embodiment 1, wherein the CD47-SIRPα blocker is an agent that blocks the interaction between CD47 and SIRPα.

[0262] Embodiment 13. The composition according to Embodiment 1, wherein blocking the interaction between CD47 and SIRPα induces macrophages to phagocytose tumor cells expressing CD47.

[0263] Embodiment 14. The composition according to Embodiment 1, wherein R1 represents hydrogen, -(CH2)2CONH2, -(CH2)2COOH, -(CH2)3NHC(=NH)NH2, -(CH2)4NH2, -CH2CONH2, -CH2-phenyl, or -CH2-imidazolyl.

[0264] Embodiment 15. The composition according to Embodiment 1, wherein R2 represents hydrogen, -(CH2)3NHC(=NH)NH2, -(CH2)2CONH2, -(CH2)2COOH, -CH2-phenyl, or -CH2-imidazolyl.

[0265] Embodiment 16. The composition according to Embodiment 1, wherein R3 represents hydrogen, -CH2-phenyl, -(CH2)3NHC(=NH)NH2, -(CH2)2CONH2, -(CH2)2COOH, -(CH2)4NH2, or -CH2-imidazolyl.

[0266] Embodiment 17. The composition according to Embodiment 16, wherein R3 represents hydrogen, -CH2-phenyl, -(CH2)3NHC(=NH)NH2, -(CH2)2CONH2, -(CH2)2COOH, or -(CH2)4NH2.

[0267] Embodiment 18. The composition according to any one of Embodiments 1 to 17, wherein

[0268] R ais hydrogen; and R1 represents hydrogen, -(CH2)2CONH2, -(CH2)2COOH, -(CH2)3NHC(=NH)NH2, -(CH2)4NH2, -CH2CONH2, -CH2-phenyl or -CH2-imidazolyl; or R a and R1 together with the atoms to which they are attached form a pyrrolidine ring;

[0269] R2 represents hydrogen, -(CH2)3NHC(=NH)NH2, -(CH2)2CONH2, -(CH2)2COOH, -CH2-phenyl or -CH2-imidazolyl;

[0270] R b is hydrogen; and R3 represents hydrogen, -CH2-phenyl, -(CH2)3NHC(=NH)NH2, -(CH2)2CONH2, -(CH2)2COOH, -(CH2)4NH2 or -CH2-imidazolyl; or R b and R3 together with the atoms to which they are attached form a pyrrolidine ring.

[0271] Embodiment 19. The composition according to Embodiment 1, which is represented by a compound of formula (IA):

[0272]

[0273] or a pharmaceutically acceptable salt or amide or ester or a stereoisomer thereof; wherein R1, R a and R2 are as defined in Embodiment 1.

[0274] Embodiment 20. The composition according to Embodiment 19, wherein R1 represents hydrogen, -(CH2)2CONH2, -(CH2)2COOH, -(CH2)3NHC(=NH)NH2, -(CH2)4NH2, -CH2-phenyl or -CH2-imidazolyl.

[0275] Embodiment 21. The composition according to Embodiment 19, wherein R2 represents hydrogen, -(CH2)3NHC(=NH)NH2, -(CH2)2CONH2, -(CH2)2COOH, -CH2-phenyl or -CH2-imidazolyl.

[0276] Embodiment 22. The composition according to Embodiment 19, 20 or 21, wherein

[0277] R a is hydrogen; and R1 represents hydrogen, -(CH2)2CONH2, -(CH2)2COOH, -(CH2)3NHC(=NH)NH2, -(CH2)4NH2, -CH2-phenyl or -CH2-imidazolyl;

[0278] R2 represents hydrogen, -(CH2)3NHC(=NH)NH2, -(CH2)2COOH, -CH2-phenyl or -CH2-imidazolyl.

[0279] Embodiment 23. The composition according to Embodiment 1, which is represented by the compound of formula (IB)

[0280]

[0281] or a pharmaceutically acceptable salt or amide or ester thereof or a stereoisomer thereof; wherein R1, R a , R b and R3 are as defined in Embodiment 1.

[0282] Embodiment 24. The composition according to Embodiment 23, wherein R1 represents hydrogen, -(CH2)2CONH2, -(CH2)2COOH, -(CH2)3NHC(=NH)NH2, -(CH2)4NH2 or -CH2-phenyl.

[0283] Embodiment 25. The composition according to Embodiment 23, wherein R3 represents hydrogen, -CH2-phenyl, -(CH2)2CONH2 or -(CH2)2COOH.

[0284] Embodiment 26. The composition according to Embodiment 23, wherein R b and R3 together with the atoms to which they are attached form a pyrrolidine ring.

[0285] Embodiment 27. The composition according to any one of Embodiments 23 to 26, wherein

[0286] R1 represents -(CH2)2CONH2 or -(CH2)2COOH;

[0287] R b is hydrogen; and R3 represents hydrogen or -CH2-phenyl; or R b and R3 together with the atoms to which they are attached form a pyrrolidine ring.

[0288] Embodiment 28. The composition according to Embodiment 1, which is represented by the compound of formula (IC), wherein

[0289]

[0290] or a pharmaceutically acceptable salt or amide or ester thereof or a stereoisomer thereof; wherein R1, R a , R3 and R b are as defined in Embodiment 1.

[0291] Embodiment 29. The composition according to Embodiment 28, wherein R1 represents -(CH2)4NH2, -(CH2)3NHC(=NH)NH2 or -(CH2)2CONH2.

[0292] Embodiment 30. The composition according to Embodiment 28, wherein R b is hydrogen; R3 represents hydrogen, -CH2-phenyl or -CH2-heteroaryl; or R b and R3 together with the atoms to which they are attached form a pyrrolidine ring.

[0293] Embodiment 31. The composition according to any one of Embodiments 28 to 30, wherein:

[0294] R1 represents -(CH2)4NH2, -(CH2)3NHC(=NH)NH2 or -(CH2)2CONH2;

[0295] R b is hydrogen; R3 represents hydrogen, -CH2-phenyl or -CH2-heteroaryl; or R b and R3 together with the atoms to which they are attached form a pyrrolidine ring.

[0296] Embodiment 32. The composition according to Embodiment 1, which is represented by the compound of formula (ID), wherein

[0297]

[0298] or a pharmaceutically acceptable salt or amide or ester or a stereoisomer thereof; wherein R1, R a , R3 and R b are as defined in Embodiment 1.

[0299] Embodiment 33. The composition according to Embodiment 32, wherein R1 represents -CH2CONH2, -(CH2)4NH2 or (CH2)3NHC(=NH)NH2.

[0300] Embodiment 34. The composition according to any one of Embodiments 32 to 33, wherein:

[0301] R1 represents -(CH2)4NH2 or (CH2)3NHC(=NH)NH2;

[0302] R b is hydrogen; R3 represents hydrogen, -(CH2)3NHC(=NH)NH2 or -(CH2)4NH 2； or R b and R3 together with the atoms to which they are attached form a pyrrolidine ring.

[0303] Embodiment 35. The composition according to Embodiment 1, which is represented by the compound of formula (IE), wherein

[0304]

[0305] or a pharmaceutically acceptable salt or amide or ester thereof or its stereoisomer; wherein R2, R3 and R b are as defined in Embodiment 1.

[0306] Embodiment 36. The composition according to Embodiment 35, wherein R2 represents hydrogen or -(CH2)3NHC(=NH)NH2.

[0307] Embodiment 37. The composition according to any one of Embodiments 34 to 35, wherein:

[0308] R1 represents hydrogen or -(CH2)3NHC(=NH)NH2; and R b and R3 together with the atoms to which they are attached form a pyrrolidine ring.

[0309] Embodiment 38. The composition according to Embodiment 1, which is represented by the compound of formula (IF), wherein

[0310]

[0311] or a pharmaceutically acceptable salt or amide or ester thereof or its stereoisomer; wherein R2, R3 and R b are as defined in Embodiment 1.

[0312] Embodiment 39. The composition according to Embodiment 38, wherein R2 represents hydrogen, -CH2-phenyl, -(CH2)2COOH or -(CH2)3NHC(=NH)NH2.

[0313] Embodiment 40. The composition according to any one of Embodiments 38 to 39, wherein:

[0314] R2 represents hydrogen, -CH2-phenyl, -(CH2)2COOH or -(CH2)3NHC(=NH)NH2;

[0315] R b is hydrogen; and R3 represents -CH2-phenyl, -(CH2)2CONH2, -(CH2)4NH2 or -(CH2)2COOH; R b and R3 together with the atoms to which they are attached form a pyrrolidine ring.

[0316] Embodiment 41. The composition according to any one of Embodiments 1 to 40, wherein the compound is selected from

[0317]

[0318]

[0319]

[0320]

[0321]

[0322] or a pharmaceutically acceptable salt or amide or ester thereof, or a stereoisomer thereof.

[0323] Embodiment 42. A composition comprising a CD47-SIRPα blocker and one or more anti-cancer agents according to any one of Embodiments 1 to 41, for use as a medicament.

[0324] Embodiment 43. A method of treating cancer in a subject presenting with CD47 pathway dysregulation, the method comprising administering to the subject a combination of a therapeutically effective amount of a CD47-SIRPα blocker and a therapeutically effective amount of one or more anti-cancer agents: wherein the CD47-SIRPα blocker is represented by a compound of formula (I):

[0325]

[0326] or a pharmaceutically acceptable salt or amide or ester thereof, or a stereoisomer thereof; wherein,

[0327] R a is hydrogen; and R1 represents hydrogen, -(CH2)2CONH2, -(CH2)2COOH, -(CH2)3NHC(=NH)NH2, -(CH2)4NH2, -CH2CONH2, -CH2-aryl or -CH2-heteroaryl; or R a and R1 together with the atoms to which they are attached form a pyrrolidine ring;

[0328] R2 represents hydrogen, -(CH2)3NHC(=NH)NH2, -(CH2)2CONH2, -(CH2)2COOH, -CH2-aryl or -CH2-heteroaryl;

[0329] R b is hydrogen; and R3 represents hydrogen, -CH2-aryl, -(CH2)3NHC(=NH)NH2, -(CH2)2CONH2, -(CH2)2COOH, -(CH2)4NH2 or -CH2-heteroaryl; or R b and R3 together with the atoms to which they are attached form a pyrrolidine ring.

[0330] Embodiment 44. The method according to embodiment 43, wherein the subject presenting CD47 pathway dysregulation is a subject presenting CD47+ diseased cells.

[0331] Embodiment 45. The method according to embodiment 44, wherein the CD47+ diseased cells are CD47+ cancer cells.

[0332] Embodiment 46. The method according to embodiment 43, wherein treatment with one or more anti-cancer agents is before, simultaneous with, or after treatment with a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0333] Embodiment 47. The method according to embodiment 43, wherein the anti-cancer agent is an anti-CD20 antibody.

[0334] Embodiment 48. The method according to embodiment 43, wherein the anti-cancer agent is a proteasome inhibitor.

[0335] Embodiment 49. The method according to embodiment 43, wherein the anti-cancer agent is bortezomib or any derivative thereof.

[0336] Embodiment 50. A method for treating a disease or disorder mediated by the CD47-SIRPα pathway in a subject or delaying the progression of the disease or disorder, the method comprising administering to a subject in need thereof a combination of a therapeutically effective amount of an agent that blocks the CD47-SIRPα pathway and a therapeutically effective amount of one or more anti-cancer agents: wherein the agent that blocks the CD47-SIRPα pathway is represented by a compound of formula (I):

[0337]

[0338] or a pharmaceutically acceptable salt or amide or ester or a stereoisomer thereof; wherein,

[0339] R a is hydrogen; and R1 represents hydrogen, -(CH2)2CONH2, -(CH2)2COOH, -(CH2)3NHC(=NH)NH2, -(CH2)4NH2, -CH2CONH2, -CH2-aryl or -CH2-heteroaryl; or R a and R1 together with the atoms to which they are attached form a pyrrolidine ring;

[0340] R2 represents hydrogen, -(CH2)3NHC(=NH)NH2, -(CH2)2CONH2, -(CH2)2COOH, -CH2-aryl or -CH2-heteroaryl;

[0341] R bis hydrogen; and R3 represents hydrogen, -CH2-aryl, -(CH2)3NHC(=NH)NH2, -(CH2)2CONH2, -(CH2)2COOH, -(CH2)4NH2 or -CH2-heteroaryl; or R b and R3 together with the atoms to which they are attached form a pyrrolidine ring.

[0342] Embodiment 51. The method according to Embodiment 50, wherein the disease or disorder mediated by the CD47-SIRPα pathway is cancer.

[0343] Embodiment 52. The method according to Embodiment 51, wherein the cancer is selected from the following: melanoma, renal cancer, prostate cancer, breast cancer, colon cancer and lung cancer, bone cancer, pancreatic cancer, skin cancer, head or neck cancer, cutaneous or intraocular malignant melanoma, uterine cancer, ovarian cancer, rectal cancer, anal area cancer, gastric cancer, testicular cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, non-Hodgkin lymphoma, esophageal cancer, small intestine cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, chronic or acute leukemia including (acute myeloid leukemia, acute lymphoblastic leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia), childhood solid tumors, lymphocytic lymphoma, bladder cancer, kidney or ureteral cancer, renal pelvic cancer, central nervous system (CNS) tumors, non-small cell lung cancer (NSCLC), primary CNS lymphoma, tumor angiogenesis, spinal tumors, brainstem gliomas, pituitary adenomas, Kaposi's sarcoma, epidermoid carcinoma, squamous cell carcinoma, T cell lymphoma, B cell lymphoma, myeloproliferative disorders / tumors (MPDS), myelodysplastic syndromes, macroglobulin myeloma, heavy chain myeloma, light chain myeloma and Bence Jones myeloma, cancers caused by the environment including cancers caused by asbestos (e.g., mesothelioma), and combinations of said cancers.

[0344] Embodiment 53. Use of a composition comprising a CD47-SIRPα blocker and one or more anti-cancer agents according to Embodiments 1 to 41 in the manufacture of a medicament for treating cancer in a subject presenting with CD47 pathway dysregulation.

[0345] Embodiment 54. The use according to Embodiment 53, wherein the cancer is selected from the following: melanoma, renal cancer, prostate cancer, breast cancer, colon cancer and lung cancer, bone cancer, pancreatic cancer, skin cancer, head or neck cancer, cutaneous or intraocular malignant melanoma, uterine cancer, ovarian cancer, rectal cancer, anal area cancer, gastric cancer, testicular cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, non-Hodgkin's lymphoma, esophageal cancer, small intestine cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, chronic or acute leukemia (including acute myeloid leukemia, acute lymphocytic leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia), childhood solid tumors, lymphocytic lymphoma, bladder cancer, kidney or ureteral cancer, renal pelvic cancer, central nervous system (CNS) tumors, non-small cell lung cancer (NSCLC), primary CNS lymphoma, tumor angiogenesis, spinal tumors, brainstem glioma, pituitary adenoma, Kaposi's sarcoma, epidermoid carcinoma, squamous cell carcinoma, T cell lymphoma, B cell lymphoma, environmentally induced cancers including cancers caused by asbestos (e.g., mesothelioma), and combinations of said cancers.

[0346] Embodiment 55. A kit comprising the composition according to any one of Embodiments 1 to 41 and a package insert, the package insert comprising instructions for drug administration for treating a subject presenting with CD47 pathway dysregulation.

[0347] Embodiment 56. A pharmaceutical composition comprising a CD47-SIRPα blocker as described in any one of Embodiments 1 to 41, one or more anti-cancer agents, and a pharmaceutically acceptable carrier.

[0348] Embodiment 57. A combination comprising a CD47-SIRPα blocker and one or more anti-cancer agents: wherein the CD47-SIRPα blocker is represented by a compound of formula (I):

[0349]

[0350] or a pharmaceutically acceptable salt or amide or ester or a stereoisomer thereof; wherein,

[0351] R a is hydrogen; and R1 represents hydrogen, -(CH2)2CONH2, -(CH2)2COOH, -(CH2)3NHC(=NH)NH2, -(CH2)4NH2, -CH2CONH2, -CH2-aryl or -CH2-heteroaryl; or R a and R1 together with the atoms to which they are attached form a pyrrolidine ring;

[0352] R2 represents hydrogen, -(CH2)3NHC(=NH)NH2, -(CH2)2CONH2, -(CH2)2COOH, -CH2-aryl or -CH2-heteroaryl;

[0353] R b is hydrogen; and R3 represents hydrogen, -CH2-aryl, -(CH2)3NHC(=NH)NH2, -(CH2)2CONH2, -(CH2)2COOH, -(CH2)4NH2 or -CH2-heteroaryl; or R b and R3 together with the atoms to which they are attached form a pyrrolidine ring.

[0354] Example - 1: The synthetic procedures for preparing the compounds of the present invention are described in Indian Provisional Patent Application No. 201841001438, co-pending as of January 12, 2018, which was converted to PCT Application No. PCT / IB2019 / 050219, the content of which is hereby incorporated by reference in its entirety.

[0355] Biological Example:

[0356] Reagents DPBS (Gibco), RPMI 1640 with HEPES and L-GLN - 500ML (Lonza), recombinant human M-CSF (R&D systems), CD47 monoclonal antibody (B6H12), functional grade antibody (Ebioscience), functional grade mouse IgG1κ isotype control (Ebioscience), vacuum blood collection tubes (multiple sample luer connectors) (BD), vacuum blood collection tubes (heparin sodium (NH) 158 USP units), blood collection tubes (BD), Histopaque (density 1.077 gm / ml) (SIGMA1077), trypan blue solution (SIGMA-T8154), hemocytometer (Bright line - SIGMAZ359629), scalp vein infusion set (JMS), cell dissociation buffer (Gibco), 48-well sterile flat bottom plates (Corning), Raji cells expressing luciferase (produced internally by transfecting Raji cells with the luciferase gene) photometer, hygromycin B (Invitrogen), Bright Glo luciferase assay system (Promega), 96-well plates, polystyrene, high binding, white flat bottom wells (Sigma CLS3912), anti-human CD20 antibody (Invivogen hcd20-mab1), bortezomib (Selleckchem, S1013)

[0357] Example - 2: Luciferase-based phagocytosis assay

[0358] An in vitro phagocytosis assay was performed to evaluate the ability of the test item to enhance macrophage phagocytic activity. Monocytes were isolated from the blood of healthy donors and cultured for 6 - 8 days using 10% RPMI (Roswell Park Memorial Institute) medium supplemented with recombinant human M - CSF to differentiate into macrophages. The medium was changed every other day. After differentiation, the adherent macrophages were collected by gentle scraping and cultured overnight in a 48 - well tissue culture plate at a density of 100,000 per well in 10% RPMI. Meanwhile, Raji (lymphoma cell line) cells expressing luciferase were cultured in a tissue culture flask in 10% RPMI medium containing 100 μg / mL hygromycin B. On the day of phagocytosis, the macrophages were serum - starved for 2 hours. Four hundred thousand luciferase - expressing Raji cells per well were incubated in serum - free medium at 37 °C for 30 minutes with anti - human CD47 antibody or mouse IgG1 K isotype control antibody or various concentrations of the selected compound of the present invention alone or in combination with anti - human CD20 antibody, and then added to each well of the 48 - well plate seeded with macrophages. After 2 hours, the cells were washed twice with PBS, and 100 μl of serum - free RPMI was added to each well. In addition, 50 μl of bright glow reagent was added to each well, then the cells were mixed and incubated for 5 minutes in the dark. After transferring the contents of each well to a white plate, the luminescence readings were measured using a microplate reader. The luminescence intensity indicates the degree of phagocytosis. Each experimental condition was performed in duplicate. The results are shown in Figure 1 are shown.

[0359] Figure 1 The results in show that treatment of tumor cells with anti - human CD20 antibody resulted in a significant increase in phagocytosis compared to treatment with the CD47 - SIRPα blocking compound alone.

[0360] Example - 3: Human macrophage phagocytosis assay to evaluate compounds in combination with bortezomib

[0361] An in vitro phagocytosis assay was performed to evaluate the ability of the test item to enhance macrophage phagocytic activity. Monocytes were isolated from the blood of healthy donors and cultured for 6 - 8 days using complete RPMI (Roswell Park Memorial Institute) medium supplemented with 20 ng / mL recombinant human M - CSF to differentiate into macrophages. The medium was changed every other day. Meanwhile, H929 cells were cultured in complete RPMI medium and treated with 10 nM bortezomib for 48 hours. The macrophages were starved in serum - free RPMI for 2 hours. CFSE - stained, bortezomib - treated / untreated H929 (multiple myeloma cell line) cells at 0.2x10 6Cells / well were seeded at a density of in 96-well low-attachment plates and treated with purified B6H12 (5 μg / mL) / mouse IgG1 κ isotype control antibody (5 μg / mL) / selected compound 6 of the present invention at different concentrations in serum-free medium for 30 minutes at 37 °C. Serum-starved macrophages were added to H929 cells at a ratio of 1:4 (macrophages:H929 cells) and incubated for 2 hours at 37 °C. Cells in each well were stained with anti-human CD11b APC for 30 minutes at 4 °C in the dark and then fixed and subjected to FACS analysis. FITC- and APC-positive cells were considered H929 cells phagocytosed by macrophages. Data obtained using FACS verse were analyzed using Flow Jo software. The results are shown in Figure 2 as shown below.

[0362] Figure 2 The results in show that treatment of tumor cells with a proteasome inhibitor (bortezomib) resulted in a significant increase in phagocytosis compared to treatment with the CD47-SIRPα blocking compound alone.

[0363] Example - 4: Efficacy study of compound 6 in combination with a PD-L1 antibody in an A20 syngeneic lymphoma model

[0364] Internal-bred female Balb / c (BALB / cAnNTac) mice (6 - 8 weeks old) were used for this efficacy study of the A20 syngeneic lymphoma model. Animals were individually tail-tagged and housed in cages, and the cage cards should indicate the study code, date of experiment, sex, and number of animals. Animals were weighed daily during the experiment. The A20 cell line (a B-cell lymphoma line derived from a spontaneous reticulosarcoma of an old BALB / cAnN mouse) was purchased from ATCC.

[0365] When the average tumor volume reached approximately 75 mm 3 , the animals were randomly divided into four groups (G1 to G4) of twelve animals each (N = 12) based on tumor volume and were administered vehicle, compound 6, anti-mouse PD-L1 antibody, and a combination of compound 6 and anti-mouse PD-L1 antibody as described below:

[0366]

[0367] Treatment continued for 21 days, during which overall efficacy and tolerance were evaluated based on changes in tumor volume and body weight observed during treatment.

[0368] During the entire experimental period, the body weight of each animal was recorded daily before administering Compound 6. During the entire experimental period, the mortality / incidence of the animals was observed once a day, and during the entire experimental period, the clinical signs of the animals were observed once a day. The tumor volume of all animals in the treatment groups was measured three times a week (once every 2 - 3 days) using a digital vernier caliper. As a measure of efficacy, the values of T (treatment) / C (control) % and TGI (tumor growth inhibition %) were calculated. Using GraphPad Prism version 7.0 for graphical and statistical analysis. To analyze the tumor volume data, a one-way analysis of variance and Dunnett's multiple comparison test were used to perform statistical comparisons for all groups on Day 18. All analyses and comparisons were evaluated at the 5% (p < 0.05) level. A "p" value less than 0.05 was considered significant. The results and statistics are summarized in the table below.

[0369]

[0370] One-way analysis of variance, Dunnett's multiple comparison test: * - p < 0.05, *** - p < 0.001; TGI - tumor growth inhibition;

[0371] Compound 6 was well tolerated at a dose of 30 mg / kg bid, both as a single agent and in combination with the PD-L1 antibody, without any treatment-related clinical signs and mortality, indicating that the test drug had excellent tolerance at the administered doses. At the end of the treatment period, the tumor growth inhibition (TGI) values shown by Compound 6 administered alone at 30 mg / kg, the anti-mouse PD-L1 antibody alone, and the combination of Compound 6 and anti-mouse PD-L1 were 72%, 41%, and 90%, respectively. The effect of the treatment on tumor growth kinetics is graphically represented in Figure 3 Figure.

[0372] It was further observed that when compared with the treatment alone, the combination of Compound 6 and the anti-mouse PD-L1 antibody significantly enhanced tumor growth inhibition and a more durable response. Five out of 11 animals treated with the combination of Compound 6 and the anti-mouse PD-L1 antibody showed complete tumor regression. The tumor growth inhibition observed with Compound 6 treatment alone and the combination of Compound 6 and the anti-mouse PD-L1 antibody was statistically significant.

Claims

1. Use of a combination of a small molecule CD47-SIRPα pathway inhibitor and one or more substances that stimulate activating receptors in the preparation of one or more drugs for activating phagocytic receptors, wherein the activating receptors are selected from Fc-receptors (FcR) or pro-phagocytic receptors.

2. Use of a combination of a small molecule CD47-SIRPα pathway inhibitor and one or more substances that stimulate activating receptors in the preparation of one or more drugs for treating cancer, wherein the activating receptors are selected from Fc-receptors (FcR) or pro-phagocytic receptors.

3. The use according to claim 1 or claim 2, wherein the Fc-receptor (FcR) includes Fc-gamma receptor (FcγR).

4. The use according to any one of claims 1-3, wherein the substance that stimulates the activating receptor is an antibody selected from the following: anti-CD20, anti-CD22, anti-CD52, anti-CD33, anti-HER2, anti-VEGF, anti-CD96, anti-CD44, anti-CD123 or anti-CD38 antibody.

5. The use according to any one of the above claims, wherein the substance that stimulates the activating receptor is selected from rituximab, tazemetostat, tositumomab, epratuzumab, alemtuzumab, gemtuzumab ozogomicin, trastuzumab, bevacizumab, cetuximab, panitumumab, daratumumab, ofatumumab, obinutuzumab, ibritumomab tiuxetan, dinutuximab and necitumumab.

6. The use according to claim 1 or claim 2, wherein the substance that stimulates the pro-phagocytic receptor is selected from proteasome inhibitors, anthracyclines, BRAF inhibitory drugs, or PI3K inhibitors, or a combination thereof.

7. The use according to claim 1 or claim 2, wherein the substance that stimulates the pro-phagocytic receptor is selected from bortezomib, ixazomib, carfilzomib, doxorubicin, epirubicin, daunorubicin, idarubicin, mitoxantrone, oxaliplatin, cyclophosphamide, bleomycin, vorinostat, paclitaxel, 5-fluorouracil, cytarabine, dabrafenib, vemurafenib, docetaxel, mitomycin C, sorafenib and tamoxifen, or a combination thereof.

8. Use of a combination of a small molecule CD47-SIRPα pathway inhibitor and one or more chemotherapeutic agents or immunomodulators in the preparation of one or more drugs for treating cancer.

9. The use according to any one of the above claims, wherein the combination further comprises one or more substances selected from the following: abiraterone acetate, afatinib, aldesleukin, anastrozole, axitinib, belinostat, bendamustine, bicalutamide, blinatumomab, bosutinib, brentuximab vedotin, busulfan, cabazitaxel, capecitabine, carmustine, ceritinib, clofarabine, crizotinib, dacarbazine, actinomycin D, dasatinib, degarelix, denileukin diftitox, denosumab, enzalutamide, eribulin, erlotinib, everolimus, exemestane, fludarabine, fulvestrant, gefitinib, goserelin, ibritumomab tiuxetan, imatinib, ipilimumab, irinotecan, ixabepilone, lapatinib, lenalidomide, letrozole, leucovorin, leuprorelin, lomustine, mechlorethamine, medroxyprogesterone acetate, nelarabine, nilotinib, nivolumab, olaparib, omacetaxine mepesuccinate, palbociclib, pamidronate, panitumumab, panobinostat, pazopanib, pegaspargase, pembrolizumab, pemetrexed disodium, pertuzumab, plerixafor, pomalidomide, ponatinib, pralatrexate, procarbazine, radium-223, ramucirumab, regorafenib, rIFNa-2b, romidepsin, sunitinib, temozolomide, temsirolimus, thiotepa, tositumomab, trametinib, vinorelbine, methotrexate, ibrutinib, aflibercept, toremifene, vinblastine, vincristine, idelalisib, mercaptopurine or thalidomide.

10. The use according to claim 9, wherein the substance is pembrolizumab or nivolumab.

11. The use according to any one of the above claims, wherein the combination further comprises hypericin-based photodynamic therapy (Hyp-PDT), radiotherapy, high hydrostatic pressure, porphyrin-based PDT and rose bengal acetate-based PDT.

12. The use according to claim 8, wherein the chemotherapeutic agent is selected from abarelix, aldesleukin, alitretinoin, allopurinol, altretamine, arsenic trioxide, asparaginase, azacitidine, bexarotene, baricitinib, bortezomib, intravenous busulfan, oral busulfan, dimethyltestosterone, cetuximab, chlorambucil, cisplatin, cladribine, dalteparin sodium, decitabine, defucosylated rituximab, disulfiram, dexrazoxane, drostanolone propionate, eculizumab, estramustine, etoposide phosphate, etoposide, fentanyl citrate, filgrastim, floxuridine, gemcitabine, histrelin acetate, cyclophosphamide, interferon α2a, lapatinib ditosylate, levamisole, marizomib, mechlorethamine, melphalan, mercaptopurine, methotrexate, methoxsalen, mitotane, nandrolone phenylpropionate, nolovumab, oprozomib, pegfilgrastim, pentostatin, pipobroman, plicamycin, procarbazine, quinacrine, rasburicase, ruxolitinib, lucitanib, streptozocin, teniposide, testolactone, thalidomide, thioguanine, topotecan, toremifene, tretinoin, uracil mustard, valrubicin, vinblastine, vincristine, niraparib, veliparib, talazoparib or zoledronate.

13. The use according to claim 12, wherein the chemotherapeutic agent is azacitidine.

14. The use according to claim 8, wherein the immunomodulator is a costimulatory or coinhibitory molecule.

15. The use according to claim 8 or claim 14, wherein the immunomodulator is an antibody against CTLA-4, 4-1BB, PD-1, PDL-1, IL-10, TGF-β, TIM-3, LAG-3, B7H3, B7H4, B7-H6, or a combination thereof.

16. The use according to claim 8 or claim 14, wherein the immunomodulator is ipilimumab, urelumab, utomilumab, nivolumab, pembrolizumab, atezolizumab, durvalumab, camrelizumab, or a combination thereof.

17. The use according to any one of the above claims, wherein the drug is used to delay the progression of cancer presenting CD47 pathway dysregulation.

18. Use according to any one of claims 2 - 17, wherein the cancer is selected from melanoma, renal cancer, prostate cancer, breast cancer, colon cancer and lung cancer, bone cancer, pancreatic cancer, skin cancer, head or neck cancer, cutaneous or intraocular malignant melanoma, uterine cancer, ovarian cancer, rectal cancer, anal area cancer, gastric cancer, testicular cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, non - Hodgkin's lymphoma, esophageal cancer, small intestine cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, chronic or acute leukemia, including acute myeloid leukemia, acute lymphoblastic leukemia, chronic myeloid leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, childhood solid tumors, lymphocytic lymphoma, bladder cancer, kidney or ureteral cancer, renal pelvic cancer, central nervous system (CNS) tumors, non - small cell lung cancer (NSCLC), primary CNS lymphoma, tumor angiogenesis, spinal tumors, brainstem glioma, pituitary adenoma, Kaposi's sarcoma, epidermoid carcinoma, squamous cell carcinoma, T - cell lymphoma, B - cell lymphoma, myeloproliferative disorders / tumors (MPDs), myelodysplastic syndromes, giant cell myeloma, heavy chain myeloma, light chain myeloma and Bence - Jones myeloma, cancers caused by the environment, including cancers caused by asbestos, mesothelioma, or a combination thereof.

19. Use according to claim 18, wherein the cancer is selected from: - chronic or acute leukemia, including acute myeloid leukemia, acute lymphoblastic leukemia, chronic myeloid leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia; - lymphocytic lymphoma, T - cell lymphoma, B - cell lymphoma; or - myeloproliferative disorders / tumors (MPDs); myelodysplastic syndromes; giant cell myeloma, heavy chain myeloma, light chain myeloma or Bence - Jones myeloma; or a combination of the cancers.

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