Combination therapy with CBL-B inhibitors

Abstract

The present disclosure relates to combination therapies using Cbl-b inhibitor compounds, as well as compositions and kits that include combinations with Cbl-b compounds. Also provided are methods of using the combinations with Cbl-b compounds and compositions thereof, such as in methods of treatment.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 172,644, filed April 8, 2021; U.S. Provisional Patent Application No. 63 / 277,122, filed November 8, 2021; and U.S. Provisional Patent Application No. 63 / 290,619, filed December 16, 2021. The contents of each priority patent application are incorporated herein by reference in their entirety for all purposes.

[0002] Field

[0002] Provided herein are combination therapies using Cbl-b inhibitor compounds, compositions, including pharmaceutical compositions, for administering same, and kits for administering same. The methods and compositions are useful for the treatment and prevention of cell proliferation and cancer. [Background technology]

[0003] background

[0003] Casitas B-lineage lymphoma proto-oncogene-b (Cbl-b) is an E3 ubiquitin ligase that negatively regulates T cell activation (Wallner et al., Clin Dev. Immunol, 2012:692639). Certain Cbl-b inhibitor compounds have been shown to have potential applications in several potential immunotherapies by enhancing T cell-mediated antitumor activity by lowering the activation threshold of T cells in the suppressive tumor microenvironment where Cbl-b plays a role in downregulating T cells. By their mechanism, Cbl-b inhibitors may enhance the effect of another cancer therapeutic agent and in certain cases may synergize. Particularly effective Cbl-b inhibitor combinations include checkpoint inhibitors and agents that induce NK cell-mediated antibody-dependent cellular cytotoxicity (ADCC). Summary of the Invention [Means for solving the problem]

[0004] overview

[0004] Provided herein are Cbl-b inhibitory compounds for use in combination with a second therapeutic agent used to treat cancer. As demonstrated in the examples herein, the combination of a Cbl-b inhibitory compound with a second therapeutic agent results in substantially increased efficacy against solid tumors in in vivo models. The Cbl-b inhibitory compounds are described in detail herein, as are their pharmaceutical compositions and methods for their manufacture. In certain embodiments, the second therapeutic agent is a checkpoint inhibitor. In certain embodiments, the second therapeutic agent is an agent that induces NK cell-mediated ADCC.

[0005] In one aspect, the present disclosure provides a method of using a Cbl-b inhibitor compound in combination with a second anti-cancer agent to treat cancer.In certain embodiments, the second anti-cancer agent is a checkpoint inhibitor.In certain other embodiments, the second anti-cancer agent is an agent that induces NK cell-mediated ADCC.

[0006]

[0006] In another aspect, a kit or composition is provided that includes a Cbl-b inhibitor compound and a second anti-cancer agent. In certain embodiments, the Cbl-b compound and the second anti-cancer agent are in separate pharmaceutical compositions. In certain embodiments, the Cbl-b compound and the second anti-cancer agent are administered separately. In certain embodiments, the Cbl-b compound and the second anti-cancer agent are administered cyclically. In certain embodiments, the composition is a pharmaceutical composition. Any suitable pharmaceutical composition may be used. In certain embodiments, the pharmaceutical composition of the Cbl-b compound is a composition for oral administration. In certain embodiments, the pharmaceutical composition of the second anti-cancer agent is a composition for parenteral administration. In certain embodiments, the second anti-cancer agent is a checkpoint inhibitor. In certain embodiments, the second anti-cancer agent is an agent that induces NK cell-mediated ADCC.

[0007]

[0007] The methods, kits, and compositions are useful for inhibiting cell proliferation. In certain embodiments, the methods, kits, and compositions are useful for treating cancer. [Brief description of the drawings]

[0008] BRIEF DESCRIPTION OF THE DRAWINGS [Figure 1]

[0008] The effect of compound 23 on total primary human T cells is provided. [Diagram 2]

[0009] Tumor volumes in tumor-bearing mice 25 days after administration of vehicle or compound 23 are provided. [Diagram 3]

[0010] 1 provides the effect of compound 23 on the survival rate of mice bearing 4T1 primary tumors, a syngeneic triple-negative breast cancer model. [Figure 4A]

[0011] FIG. 1 provides the effect of orally administered Compound 23 on tumor infiltrating lymphocytes (TILs) after 4 or 19 daily doses. [Figure 4B]

[0011] Figure 2 shows the effect of orally administered Compound 23 on gene expression immune-related pathway scores in CT26 tumor tissues after four doses. [Figure 4C]

[0011] Figure 2 shows the effect of orally administered Compound 23 on gene expression immune-related pathway scores in CT26 tumor tissues after 19 doses. [Diagram 5]

[0012] FIG. 1 shows the antitumor effect in mice bearing CT26 tumors after oral administration of compound 23 at 30 mg / kg in the presence of a depleting antibody against CD4+ cells, CD8+ cells, or NK cells (anti-asialo-GM1). [Figure 6]

[0013] 13 provides synergistic activity of compound 23 and anti-PD1 antibody in mice bearing CT26, MC38, or 4T1 tumors. [Figure 7A]

[0014] Panel 7A provides the effect of compound 23 treatment on CD8+ T cell immunophenotype in both tumor and blood samples from treated 4T1 tumor-bearing mice. [Figure 7B]Panel 7B provides the effect of compound 23 treatment on the CD8+ T cell immunophenotype in both tumor and blood samples from treated 4T1 tumor-bearing mice. [Figure 7C] Panel 7C provides the effect of compound 23 treatment on the CD8+ T cell immunophenotype in both tumor and blood samples from treated 4T1 tumor-bearing mice. [Figure 7D] Panel 7D provides the effect of compound 23 treatment on the CD8+ T cell immunophenotype in both tumor and blood samples from treated 4T1 tumor-bearing mice. [Figure 8A]

[0015] Panel 8A provides the effect of compound 23 treatment on the density and phenotype of tumor-infiltrating leukocytes from treated CT2 v6 tumor-bearing mice. [Figure 8B] Panel 8B provides the effect of compound 23 treatment on the density and phenotype of tumor-infiltrating leukocytes from treated CT2 v6 tumor-bearing mice. [Figure 8C] Panel 8C provides the effect of compound 23 treatment on the density and phenotype of tumor-infiltrating leukocytes from treated CT2 v6 tumor-bearing mice. [Figure 8D] Panel 8D provides the effect of compound 23 treatment on the density and phenotype of tumor-infiltrating leukocytes from treated CT2 v6 tumor-bearing mice. [Figure 8E] Panel 8E provides the effect of compound 23 treatment on the density and phenotype of tumor-infiltrating leukocytes from treated CT2 v6 tumor-bearing mice. [Figure 8F] Panel 8F provides the effect of compound 23 treatment on the density and phenotype of tumor-infiltrating leukocytes from treated CT2 v6 tumor-bearing mice. [Figure 8G] Panel 8G provides the effect of compound 23 treatment on the density and phenotype of tumor-infiltrating leukocytes from treated CT2 v6 tumor-bearing mice. [Figure 8H]Panel 8H provides the effect of compound 23 treatment on the density and phenotype of tumor-infiltrating leukocytes from treated CT2 v6 tumor-bearing mice. [Figure 8I] Panel 8I provides the effect of compound 23 treatment on the density and phenotype of tumor-infiltrating leukocytes from treated CT2 v6 tumor-bearing mice. [Figure 9A]

[0016] Panel 9A provides a strong correlation of the antitumor activity of compound 23 with increased levels of circulating T and NK cells, CD8+ T cells, and activated CD8+ T cells, and decreased levels of circulating myeloid cells (CD11b+) in the blood of treated CT26 tumor-bearing mice. [Figure 9B]

[0016] Panel 9B provides a strong correlation of the antitumor activity of compound 23 with increased levels of circulating T cells and NK cells, CD8+ T cells, and activated CD8+ T cells, and decreased levels of circulating myeloid cells (CD11b+) in the blood of treated CT26 tumor-bearing mice. [Figure 9C]

[0016] Panel 9C provides a strong correlation of the antitumor activity of compound 23 with increased levels of circulating T cells and NK cells, CD8+ T cells, and activated CD8+ T cells, and decreased levels of circulating myeloid cells (CD11b+) in the blood of treated CT26 tumor-bearing mice. [Figure 9D]

[0016] Panel 9D provides a strong correlation of the antitumor activity of compound 23 with increased levels of circulating T cells and NK cells, CD8+ T cells, and activated CD8+ T cells, and decreased levels of circulating myeloid cells (CD11b+) in the blood of treated CT26 tumor-bearing mice. [Figure 9E]

[0016] Panel 9E provides a strong correlation of the antitumor activity of compound 23 with increased levels of circulating T cells and NK cells, CD8+ T cells, and activated CD8+ T cells, and decreased levels of circulating myeloid cells (CD11b+) in the blood of treated CT26 tumor-bearing mice. [Figure 9F]

[0016] Panel 9F provides a strong correlation of the antitumor activity of compound 23 with increased levels of circulating T cells and NK cells, CD8+ T cells, and activated CD8+ T cells, and decreased levels of circulating myeloid cells (CD11b+) in the blood of treated CT26 tumor-bearing mice. [Figure 10A]

[0017] 1 shows the synergistic effect of Compound 23 and anti-CTLA-4 antibody in CT26 tumor-bearing mice. The shaded area indicates QD administration of Compound 23. [Figure 10B]

[0017] Figure 1 shows the synergistic effect of compound 23 and anti-CTLA-4 antibody in CT26 tumor-bearing mice. The shaded area indicates QD administration of compound 23. [Figure 11A]

[0018] 1 shows the synergistic effect of compound 23 and anti-LAG3 antibody in CT26 tumor-bearing mice. The shaded area indicates QD administration of compound 23. [Figure 11B]

[0018] Figure 1 shows the synergistic effect of compound 23 and anti-LAG3 antibody in CT26 tumor-bearing mice. The shaded area indicates QD administration of compound 23. [Figure 12A]

[0019] Panel 12A provides the enhanced efficacy of compound 23 and an anti-CD20 antibody in a human non-Hodgkin's lymphoma animal model, and that the efficacy of the anti-CD20 antibody is primarily mediated by NK cells. [Figure 12B] Panel 12B provides the enhanced efficacy of compound 23 and an anti-CD20 antibody in a human non-Hodgkin's lymphoma animal model, and that the efficacy of the anti-CD20 antibody is primarily mediated by NK cells. [Figure 13A]

[0020] Panel 13A provides the potentiation of the effect of compound 23 and PARP inhibitors in BRCA wild-type and BRCA mutant tumor cell lines. [Figure 13B] Panel 13B provides the potentiation of the effects of compound 23 and PARP inhibitors in BRCA wild-type and BRCA mutant tumor cell lines. [Figure 13C]Panel 13C provides the potentiation of the effects of compound 23 and PARP inhibitors in BRCA wild-type and BRCA mutant tumor cell lines. [Figure 14A]

[0021] Panel 14A shows the potentiation of the effect of compound 23 and taxanes in tumor cells. [Figure 14B] Panel 14B shows the potentiation of the effect of compound 23 and taxanes in tumor cells. [Figure 15A]

[0022] Panel 15A provides the enhancing effect of compound 23 and anti-TIGIT antibody. [Figure 15B] Panel 15B provides the enhancing effect of compound 23 and an anti-TIGIT antibody. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0009] Detailed Description of the Embodiments 1.Definition

[0023] Unless otherwise defined, all technical terms, notations, and other scientific terms used herein are intended to have the meanings commonly understood by those of ordinary skill in the art to which this disclosure pertains. In some cases, terms with commonly understood meanings are defined herein for clarity and / or ease of reference, and the inclusion of such definitions herein should not necessarily be interpreted as representing a difference from what is commonly understood in the art. The techniques and procedures described or referenced herein are generally well understood and commonly employed using conventional methodologies by those of ordinary skill in the art, such as, for example, the widely used molecular cloning methodology described in Sambrook et al., Molecular Cloning: A Laboratory Manual 2nd ed. (1989) Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY. Procedures involving the use of commercially available kits and reagents, where appropriate, are generally carried out according to manufacturer-defined protocols and conditions unless otherwise noted.

[0010]

[0024] Aspects and embodiments described herein as "comprising" are understood to include the embodiments "consisting of" and "consisting essentially of."

[0011]

[0025] As used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless otherwise indicated or clear from the context. For example, the singular form "an" excipient includes one or more excipients.

[0012]

[0026] Reference to "about" a value includes 90% to 110% of that value. For example, about 50 billion cells refers to 45 billion to 55 billion cells, including 50 billion cells. For example, a temperature "about 100 degrees" refers to a temperature of about 90 degrees to about 110 degrees.

[0013]

[0027] When a numerical range of compounds is given, all compounds within that numerical limit, inclusive of the specified "a" and "b", are included unless expressly excluded. For example, a reference to compounds 9-13 refers to compounds 9, 10, 11, 12, and 13.

[0014]

[0028] The term "binding antagonist" with respect to a target refers to a molecule that reduces, blocks, inhibits, suppresses, or interferes with signal transduction resulting from the interaction of such molecule with a target or one or more binding partners of a target.

[0015]

[0029] As used herein, "Cbl-b" refers to Cbl-b protein. The term also includes naturally occurring variants of Cbl-b, including splice variants or allelic variants. The term also includes non-naturally occurring variants of Cbl-b, such as recombinant Cbl-b proteins or truncated variants thereof, which generally retain the binding ability (e.g., ability to bind E2 enzyme) of native Cbl-b or naturally occurring variants of Cbl-b.

[0016]

[0030] As used herein, a "Cbl-b inhibitor" refers to a molecule that inhibits the activity of Cbl-b, c-Cbl, or both Cbl-b and c-Cbl proteins.

[0017]

[0031] As used herein, "c-Cbl" refers to a c-Cbl protein. The term also includes naturally occurring variants of c-Cbl, including splice variants or allelic variants. The term also includes non-naturally occurring variants of c-Cbl, such as recombinant c-Cbl proteins or truncated variants thereof, which generally retain the binding ability (e.g., ability to bind E2 enzyme) of native c-Cbl or naturally occurring variants of c-Cbl.

[0018]

[0032] "CD20" refers to the B lymphocyte antigen CD20, which is encoded by the MS4A1 gene, for example in humans. It is known to enable B cell immune responses, for example against T-independent antigens. Sequences include NM_152866, NM_021950, and NM_152867 (mRNA); and NP_068769, NP_690605, and NP_690606 (protein).

[0019]

[0033] The term "CD20 axis antagonist" refers to a molecule that inhibits the interaction of a CD20 axis binding partner with any one or more of its binding partners.

[0020]

[0034] The term "CD20 binding antagonist" refers to a molecule that reduces, blocks, inhibits, suppresses, or interferes with signal transduction resulting from the interaction of CD20 with one or more of its binding partners.

[0021]

[0035] The term "CD47" refers to a surface immunoglobulin that forms a signaling complex with signal regulatory protein alpha. In cancer cells, CD47 forms a signaling complex that allows the cancer cells to avoid macrophage-mediated phagocytosis. Sequences include NM_001025079, NM_001025080, NM_001777, NM_198793, and NM_001382306 (mRNA); and NP_001768, NP_942088, and NP_001369235 (protein).

[0022]

[0036] The term "CD47 axis antagonist" refers to a molecule that inhibits the interaction of a CD47 axis binding partner with any one or more of its binding partners, such as signal regulatory protein alpha (SIRPα).

[0023]

[0037] The term "CD47 binding antagonist" refers to a molecule that reduces, blocks, inhibits, suppresses, or interferes with signal transduction resulting from the interaction of CD47 with one or more of its binding partners.

[0024]

[0038] The term "checkpoint inhibitor" refers to a compound that blocks immune checkpoints, which are signal transduction pathways that inhibit the activation of immune cells. Examples of T cell checkpoint inhibitors include CTLA-4 axis antagonists, LAG3 binding antagonists, PD-1 axis antagonists, TIGIT binding antagonists, TIM3 binding antagonists, and VISTA binding antagonists. Examples of macrophage checkpoint inhibitors are CD47 binding antagonists.

[0025]

[0039] The term "PARP inhibitor" refers to a compound that repairs DNA when it is damaged (i.e., blocking poly ADP ribose polymerase (PARP) can prevent cancer cells from repairing damaged cancer cell DNA, resulting in cancer cell death). Examples of PARP inhibitors include olaparib, talazoparib, and niraparib.

[0026]

[0040] The term "taxane" refers to a compound that blocks cell growth by halting mitosis (i.e., cell division) through interference with microtubules. Taxane can also refer to a class of mitotic inhibitors and classes of anti-microtubule agents. Examples of taxanes include paclitaxel and docetaxel.

[0027]

[0041] "CTLA-4" refers to cytotoxic T-lymphocyte-associated protein 4. Alternative names or synonyms of CTLA-4 include CD152 (cluster of differentiation 152), ALPS5, CELIAC3, GRD4, GSE, and IDDM12. The mature form of the human CTLA-4 amino acid sequence is set forth as residues 36-223 in NCBI Locus No. NP_005205, which is incorporated by reference. Additional sequences include NM_001037631 and NM_005214 (mRNA) and NP_001032720 (protein).

[0028]

[0042] The term "CTLA-4 axis antagonist" refers to a molecule that inhibits the interaction of a CTLA-4 axis binding partner with any one or more of its binding partners. In certain embodiments, the CTLA-4 axis antagonist eliminates T cell dysfunction resulting from signaling on the CTLA-4 signaling axis. In certain embodiments, the CTLA-4 axis antagonist restores or enhances T cell function (e.g., proliferation, cytokine production, and / or target cell killing). As used herein, CTLA-4 axis antagonists include CTLA-4 binding antagonists, CD80 binding antagonists, CD86 binding antagonists, and combinations thereof.

[0029]

[0043] The term "CTLA-4 binding antagonist" refers to a molecule that reduces, blocks, inhibits, suppresses, or interferes with signal transduction resulting from the interaction of CTLA-4 with one or more of its binding partners, such as CD80 or CD86. In certain embodiments, the CTLA-4 binding antagonist is ipilimumab. In certain embodiments, the CTLA-4 binding antagonist is tremelimumab.

[0030]

[0044] "Enhancing T cell function" means inducing, inducing, or stimulating T cells to have sustained or enhanced biological function, or to restore or reactivate exhausted or inactive T cells. Examples of enhanced T cell function include increased T cell activation (e.g., increased cytokine production, increased expression of T cell activation markers, etc.), increased T cell proliferation, decreased T cell exhaustion, and / or decreased T cell immune tolerance, compared to the state of the T cells before treatment with a Cbl-b inhibitory compound. Methods for measuring enhanced T cell function are known in the art.

[0031]

[0045] "HER2" refers to the receptor tyrosine protein kinase erbB-2. Synonyms include CD340, Neu, Erbb2, ERBB2, and HER2 / neu. Sequences include NM_001005862, NM_001289936, NM_001289937, NM_001289938, and NM_004448 (mRNA); and NP_001005862, NP_001276865, NP_001276866, NP_001276867, and NP_004439.

[0032]

[0046] The term "HER2 axis antagonist" refers to a molecule that inhibits the interaction of a HER2 axis binding partner with any one or more of its binding partners.

[0033]

[0047] The term "HER2 binding antagonist" refers to a molecule that reduces, blocks, inhibits, suppresses, or interferes with signal transduction resulting from the interaction of HER2 with one or more of its binding partners. In certain embodiments, the HER2 binding antagonist is trastuzumab. In certain embodiments, the HER2 binding antagonist is pertuzumab.

[0034]

[0048] As used herein, the term "inhibit proliferation" (e.g., referring to cells, such as tumor cells) is intended to include a measurable decrease in cell proliferation (e.g., tumor cell proliferation) when contacted with a compound or combination described herein, as compared to the proliferation of the same cells not contacted with the same compound or combination. In certain embodiments, proliferation may be inhibited by at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 99%, or 100%. The decrease in cell proliferation may occur by a variety of mechanisms, including, but not limited to, antibody internalization, apoptosis, necrosis, and / or effector function-mediated activity.

[0035]

[0049] "LAG3" refers to lymphocyte activation gene 3 protein. LAG3 is also known as CD223. The amino acid sequence of the mature form of human LAG3 is set forth as residues 23-525 in NCBI Locus No. NP_002277, which is incorporated by reference. The LAG3 mRNA sequence is set forth in NM_002286, which is incorporated by reference.

[0036]

[0050] The term "LAG3 axis antagonist" refers to a molecule that inhibits the interaction of a LAG3 axis binding partner with any one or more of its binding partners.

[0037]

[0051] The term "LAG3 binding antagonist" refers to a molecule that reduces, blocks, inhibits, suppresses, or interferes with signal transduction resulting from the interaction of LAG3 with one or more of its binding partners, such as MHC class II. In certain embodiments, the LAG3 binding antagonist is an anti-LAG3 monoclonal antibody.

[0038]

[0052] As used herein, "monoclonal antibody" or "mAb" or "Mab" refers to a population of substantially homogenous antibodies, i.e., the antibody molecules comprising the population are identical in amino acid sequence except for minor naturally occurring mutations that may be present. In contrast, conventional (polyclonal) antibody preparations typically contain a large number of different antibodies that have different amino acid sequences in their variable domains, particularly in their CDRs, which are often specific for different epitopes. The modifier "monoclonal" indicates the nature of the antibody as being obtained from a population of substantially homogenous antibodies and is not to be construed as requiring production of the antibody by any particular method. For example, monoclonal antibodies used in accordance with the present disclosure may be made by the hybridoma method first described by Kohler et al. (1975) Nature 256:495, or may be made by recombinant DNA methods (see, e.g., U.S. Pat. No. 4,816,567). "Monoclonal antibodies" may also be isolated from phage antibody libraries using the techniques described, for example, in Clackson et al. (1991) Nature 352:624-628 and Marks et al. (1991) J. Mol.Biol.222:581-597. See also Presta (2005) J. Allergy Clin.Immunol.116:731. "PD-1" refers to programmed cell death protein 1. Alternative names or synonyms for PD-1 include PDCD1, PD1, CD279, and SLEB. The human PD-1 amino acid sequence can be found in NCBI Locus No.: NP_005009, which is incorporated herein by reference in its entirety.

[0039]

[0053] "PD-L1" refers to programmed death ligand 1. Other names for PD-L1 include cluster of differentiation 274 (CD274), B7 homolog 1 (B7-H1), PDCD1L1, PDL1, and B7-4. The human PD-L1 amino acid sequence can be found at NCBI Locus No.: NP_054862, which is incorporated herein by reference in its entirety.

[0040]

[0054] "PD-L2" refers to programmed cell death ligand 2. Other names for PD-L2 include cluster of differentiation 273 (CD273), PDCD1L2, PDL2, B7-DC, and Btdc. Human PD-L1 and PD-L2 amino acid sequences can be found at NCBI Locus No.: NP_079515, which is incorporated herein by reference in its entirety.

[0041]

[0055] The term "PD-1 axis antagonist" refers to a molecule that inhibits the interaction of a PD-1 axis binding partner with any one or more of its binding partners. In certain embodiments, the PD-1 axis antagonist eliminates T cell dysfunction resulting from signaling on the PD-1 signaling axis. In certain embodiments, the PD-1 axis antagonist restores or enhances T cell function (e.g., proliferation, cytokine production, and / or target cell killing). As used herein, PD-1 axis antagonists include PD-1 binding antagonists, PD-L1 binding antagonists, PD-L2 binding antagonists, and combinations thereof.

[0042]

[0056] The term "PD-1 binding antagonist" refers to a molecule that reduces, blocks, inhibits, suppresses, or prevents signaling resulting from the interaction of PD-1 with one or more of its binding partners, such as PD-L1 and / or PD-L2. In certain embodiments, a PD-1 binding antagonist is a molecule that inhibits the binding of PD-1 to one or more of its binding partners. In certain embodiments, a PD-1 binding antagonist inhibits the binding of PD-1 to PD-L1 and / or PD-L2. For example, PD-1 binding antagonists include anti-PD-1 antibodies, antigen-binding fragments thereof, immunoadhesins, fusion proteins, oligopeptides, and other molecules that reduce, block, inhibit, suppress, or prevent signaling resulting from the interaction of PD-1 with PD-L1 and / or PD-L2. In certain embodiments, the PD-1 binding antagonist reduces negative costimulatory signals mediated by or through cell surface proteins expressed in T lymphocyte-mediated signaling via PD-1, so as to alleviate dysfunction of dysfunctional T cells (e.g., enhancing effector responses to antigen recognition). In certain embodiments, the PD-1 binding antagonist is an anti-PD-1 antibody. In certain embodiments, the PD-11 binding antagonist is pembrolizumab. In certain embodiments, the PD-1 binding antagonist is nivolumab. In certain embodiments, the PD-1 binding antagonist is lambrolizumab. In certain embodiments, the PD-1 binding antagonist is pidilizumab. In certain embodiments, the PD-1 binding antagonist is cemiplimab. In certain embodiments, the PD-1 binding antagonist is AMP-224.

[0043]

[0057] The term "PD-L1 binding antagonist" refers to a molecule that reduces, blocks, inhibits, suppresses, or prevents signaling resulting from the interaction of PD-L1 with any one or more of its binding partners, such as PD-1 and / or CD80. In certain embodiments, a PD-L1 binding antagonist is a molecule that inhibits the binding of PD-L1 to its binding partners. In certain embodiments, a PD-L1 binding antagonist inhibits the binding of PD-L1 to PD-1 and / or CD80. In certain embodiments, PD-L1 binding antagonists include anti-PD-L1 antibodies, antigen-binding fragments thereof, immunoadhesins, fusion proteins, oligopeptides, and other molecules that reduce, block, inhibit, suppress, or prevent signaling resulting from the interaction of PD-L1 with one or more of its binding partners, such as PD-1 and / or CD80. In certain embodiments, the PD-L1 binding antagonist reduces negative costimulatory signals mediated by or through cell surface proteins expressed in T lymphocyte-mediated signaling via PD-L1, so as to alleviate dysfunction of dysfunctional T cells (e.g., enhancing effector responses to antigen recognition). In certain embodiments, the PD-L1 binding antagonist is an anti-PD-L1 antibody. In certain embodiments, the PD-L1 binding antagonist is atezolizumab. In certain embodiments, the PD-L1 binding antagonist is avelumab. In certain embodiments, the PD-L1 binding antagonist is durvalumab.

[0044]

[0058] The term "PD-L2 binding antagonist" refers to a molecule that reduces, blocks, inhibits, suppresses, or prevents signaling resulting from the interaction of PD-L2 with any one or more of its binding partners, such as PD-1. In certain embodiments, a PD-L2 binding antagonist is a molecule that inhibits the binding of PD-L2 to one or more of its binding partners. In certain embodiments, a PD-L2 binding antagonist inhibits the binding of PD-L2 to PD-1. In certain embodiments, PD-L2 binding antagonists include anti-PD-L2 antibodies, antigen-binding fragments thereof, immunoadhesins, fusion proteins, oligopeptides, and other molecules that reduce, block, inhibit, suppress, or prevent signaling resulting from the interaction of PD-L2 with any one or more of its binding partners, such as PD-1. In certain embodiments, the PD-L2 binding antagonist reduces the negative costimulatory signal mediated by or through a cell surface protein expressed in T lymphocyte-mediated signaling via PD-L2, so as to alleviate dysfunction of dysfunctional T cells (e.g., enhancing effector responses to antigen recognition). In certain embodiments, the PD-L2 binding antagonist is an anti-PD-L2 antibody. In certain embodiments, the PD-L2 binding antagonist is an immunoadhesin.

[0045]

[0059] "Proliferation" is used herein to refer to the proliferation of cells. Increased proliferation includes the production of a greater number of cells compared to a baseline value. Decreased proliferation includes the production of a decreased number of cells compared to a baseline value. In certain embodiments, the cells are immune cells, such as T cells, and increased proliferation is desired. In certain embodiments, the cells are cancer cells, and decreased proliferation is desired.

[0046]

[0060] The term "T cell anergy" refers to a state of unresponsiveness to antigenic stimulation resulting from defective or insufficient signals delivered via the T cell receptor. "T cell anergy" can also result from stimulation with an antigen without costimulation, rendering the cells refractory to subsequent activation by antigen even in the context of costimulation.

[0047]

[0061] A "T cell dysfunction disorder" is a disorder or condition characterized by reduced responsiveness of T cells to antigenic stimulation. Reduced responsiveness can result in ineffective control of tumors. In certain embodiments, the term "T cell dysfunction disorder" encompasses cancer, such as hematological or non-hematological cancers. In certain embodiments, a "T cell dysfunction disorder" is one in which T cells are anergic or have a reduced ability to secrete cytokines, proliferate, or achieve cytolytic activity.

[0048]

[0062] As used herein, the term "T cell dysfunction" refers to a state of reduced immune responsiveness to antigenic stimulation. The term "T cell dysfunction" includes the common elements of both T cell exhaustion and / or T cell anergy, in which antigen recognition can occur but the subsequent immune response is ineffective to control tumor growth. The term "T cell dysfunction" can include refractory or unresponsive to antigen recognition, e.g., reduced ability to translate antigen recognition into downstream T cell effector functions, e.g., proliferation, cytokine production, and / or target cell killing.

[0049]

[0063] The term "T cell exhaustion" refers to a state of T cell dysfunction resulting from persistent TCR signaling that can occur during cancer. It is distinct from anergy in that it does not occur through defective or insufficient signaling, but from persistent signaling. It is defined by insufficient effector function, persistent expression of inhibitory receptors, and a transcriptional state that differs from that of functional effector or memory T cells.

[0050]

[0064] "TIGIT" refers to a T cell immune receptor having Ig and ITIM domain proteins. Alternative names or synonyms of TIGIT include VSIG9, V-set and immunoglobulin domain containing 9, VSTM3, V-set and transmembrane domain containing 3, and Washington University cell adhesion molecule (WUCAM). The amino acid sequence of the mature form of human TIGIT is listed as residues 22-244 in NCBI Locus No.: NP_776160, which is incorporated herein by reference. The mRNA sequence of human TIGIT is listed in NM_173799, which is incorporated herein by reference.

[0051]

[0065] The term "TIGIT axis antagonist" refers to a molecule that inhibits the interaction of a TIGIT axis binding partner with any one or more of its binding partners.

[0052]

[0066] The term "TIGIT binding antagonist" refers to a molecule that reduces, blocks, inhibits, suppresses, or interferes with signal transduction resulting from the interaction of TIGIT with one or more of its binding partners, such as CD155 or CD112.

[0053]

[0067] "TIM3" refers to T cell immunoglobulin and mucin domain-containing 3 protein. Alternative names or synonyms of TIM3 include CD366, HAVCR2, Hepatitis A virus cellular receptor 2, KIM3, and SPTCL. The amino acid sequence of the mature form of human TIM3 is set forth as residues 22-301 in NCBI Locus No. NP_116171, which is incorporated herein by reference. The mRNA sequence of human TIM3 is set forth in NM_032782, which is incorporated herein by reference.

[0054]

[0068] The term "TIM3 axis antagonist" refers to a molecule that inhibits the interaction of a TIM3 axis binding partner with any one or more of its binding partners.

[0055]

[0069] The term "TIM3 binding antagonist" refers to a molecule that reduces, blocks, inhibits, suppresses, or interferes with signal transduction resulting from the interaction of TIM3 with one or more of its binding partners, such as immunoglobulin V domains.

[0056]

[0070] "VISTA" refers to V-domain Ig suppressor of T cell activation. Alternative names or synonyms for VISTA include VSIR, V-set immunoregulatory receptor, PD-1H, B7H5, GI24, PP2135, SISP1, Dies1. The amino acid sequence of the mature form of human VISTA is set forth as residues 33-311 in NCBI Locus No.: NP_071436, which is incorporated herein by reference. The mRNA sequence of human VISTA is set forth in NM_022153, which is incorporated herein by reference.

[0057]

[0071] The term "VISTA axis antagonist" refers to a molecule that inhibits the interaction of a VISTA axis binding partner with any one or more of its binding partners.

[0058]

[0072] The term "VISTA binding antagonist" refers to a molecule that reduces, blocks, inhibits, suppresses or interferes with signal transduction resulting from the interaction of VISTA with one or more of its binding partners.

[0059]

[0073] As used herein, "alkyl" refers to a saturated linear (i.e., unbranched) or branched monovalent hydrocarbon chain or combinations thereof. Particular alkyl groups are those having a specified number of carbon atoms, e.g., alkyl groups having 1 to 20 carbon atoms ("C1-C 20 alkyl) having 1 to 10 carbon atoms ("C1-C 10" alkyl), an alkyl group having 1 to 8 carbon atoms ("C1-C8 alkyl"), an alkyl group having 1 to 6 carbon atoms ("C1-C6 alkyl"), an alkyl group having 2 to 6 carbon atoms ("C2-C6 alkyl"), or an alkyl group having 1 to 4 carbon atoms ("C1-C4 alkyl"). Examples of alkyl groups include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, e.g., homologs and isomers of n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like.

[0060]

[0074] As used herein, "alkenyl" refers to an unsaturated linear (i.e., unbranched) or branched monovalent hydrocarbon chain, or combinations thereof, having at least one site of olefinic unsaturation (i.e., having at least one moiety of the formula C=C). Particular alkenyl groups are those having a specified number of carbon atoms, such as alkenyl groups having 2 to 20 carbon atoms ("C2-C 20 alkenyl), alkenyl groups having 2 to 10 carbon atoms ("C2-C 10 " alkenyl"), alkenyl groups having 2 to 8 carbon atoms ("C2-C8 alkenyl"), alkenyl groups having 2 to 6 carbon atoms ("C2-C6 alkenyl"), or alkenyl groups having 2 to 4 carbon atoms ("C2-C4 alkenyl"). Alkenyl groups can be in the cis or trans configuration, or in the E or Z configuration. Examples of alkenyl groups include, but are not limited to, groups such as ethenyl (or vinyl), prop-1-enyl, prop-2-enyl (or allyl), 2-methylprop-1-enyl, but-1-enyl, but-2-enyl, but-3-enyl, buta-1,3-dienyl, 2-methylbuta-1,3-dienyl, homologs, and isomers thereof.

[0061]

[0075] As used herein, "alkynyl" refers to an unsaturated linear (i.e., unbranched) or branched monovalent hydrocarbon chain, or combinations thereof, having at least one site of acetylenic unsaturation (i.e., having at least one moiety of the formula C≡C). Particular alkynyl groups are those having a specified number of carbon atoms, such as alkynyl groups having 2 to 20 carbon atoms ("C2-C 20 alkynyl groups having 2 to 10 carbon atoms ("C2-C 10 An alkynyl group having from 2 to 8 carbon atoms ("C2-C8 alkynyl"), an alkynyl group having from 2 to 6 carbon atoms ("C2-C6 alkynyl"), or an alkynyl group having from 2 to 4 carbon atoms ("C2-C4 alkynyl"). Examples of alkynyl groups include, but are not limited to, groups such as ethynyl (or acetylenyl), prop-1-ynyl, prop-2-ynyl (or propargyl), but-1-ynyl, but-2-ynyl, but-3-ynyl, homologs, and isomers thereof.

[0062]

[0076] As used herein, "alkylene" refers to the same residue as alkyl, but with divalent character or divalency. Particular alkylene groups are those having 1 to 6 carbon atoms ("C1-C6 alkylene"), 1 to 5 carbon atoms ("C1-C5 alkylene"), 1 to 4 carbon atoms ("C1-C4 alkylene"), or 1 to 3 carbon atoms ("C1-C3 alkylene"). Examples of alkylene groups include, but are not limited to, groups such as methylene (-CH2-), -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-.

[0063]

[0077] As used herein, "alkenylene" refers to the same residue as alkenyl, but with divalent character or divalency. Particular alkenylene groups are those having 2 to 6 carbon atoms ("C2-C6 alkenylene"), 2 to 5 carbon atoms ("C2-C5 alkenylene"), 2 to 4 carbon atoms ("C2-C4 alkenylene"), or 2 to 3 carbon atoms ("C2-C3 alkenylene"). Examples of alkylene groups include, but are not limited to, groups such as -CH=CH-, -CH=CHCH2-, -CH=CHCH2CH2-, and the like.

[0064]

[0078] As used herein, "alkynylene" refers to the same residue as alkynyl, but with or without divalency. Particular alkynylene groups are those having 2 to 6 carbon atoms ("C2-C6 alkynylene"), 2 to 5 carbon atoms ("C2-C5 alkynylene"), 2 to 4 carbon atoms ("C2-C4 alkynylene"), or 2 to 3 carbon atoms ("C2-C3 alkylene"). Examples of alkynylene groups include, but are not limited to, groups such as -C≡C-, -C≡CCH2-, -C≡CCH2CH2-, and the like.

[0065]

[0079] "Amino" refers to the group -NH2.

[0066]

[0080] As used herein, "aryl" refers to an aromatic carbocyclic group having a single ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl or anthryl), where one or more of the condensed rings cannot be aromatic. Particular aryl groups are those having 6 to 14 cyclic (i.e., ring) carbon atoms ("C6-C 14 Aryl groups having two or more rings, in which at least one ring is non-aromatic, can be linked to the parent structure at either an aromatic ring position or a non-aromatic ring position. In one form, an aryl group having two or more rings, in which at least one ring is non-aromatic, is linked to the parent structure at an aromatic ring position. Examples of aryl include phenyl, naphthyl, 1-naphthyl, 2-naphthyl, 1,2,3,4-tetrahydronaphthalene-6- ... [ka] Examples of groups include, but are not limited to, the following:

[0067]

[0081] As used herein, "arylene" refers to the same residue as aryl, but with divalency or divalency. Particular arylene groups are those having 6 to 14 cyclic carbon atoms ("C6-C 14 Examples of arylene include, but are not limited to, groups such as phenylene, o-phenylene (i.e., 1,2-phenylene), m-phenylene (i.e., 1,3-phenylene), p-phenylene (i.e., 1,4-phenylene), naphthylene, 1,2-naphthylene, 1,3-naphthylene, 1,4-naphthylene, 2,7-naphthylene, 2,6-naphthylene, and the like.

[0068]

[0082] "Carbocyclyl" or "carbocyclic" refers to an aromatic or non-aromatic monovalent cyclic radical in which all of the ring members are carbon atoms, e.g., cyclohexyl, phenyl, 1,2-dihydronaphthyl, and the like.

[0069]

[0083] As used herein, "cycloalkyl" refers to a non-aromatic, saturated or unsaturated, cyclic monovalent hydrocarbon structure. Particular cycloalkyl groups are those having a specified number of cyclic (i.e., ring) carbon atoms, such as cycloalkyl groups having 3 to 12 cyclic carbon atoms ("C3-C 12 Particular cycloalkyls are cyclic hydrocarbons having from 3 to 8 annular carbon atoms ("C3-C8 cycloalkyl"), or from 3 to 6 annular carbon atoms ("C3-C6 cycloalkyl"). Cycloalkyls can consist of one ring (such as cyclohexyl) or multiple rings (such as adamantyl), but exclude aryl (i.e., aromatic) groups. Cycloalkyls containing more than one ring can be fused, spiro, or bridged, or combinations thereof. Exemplary cycloalkyl groups include cyclopropyl, ... [ka] , cyclobutyl [ka] , cyclopentyl [ka] , cyclohexyl [ka] , 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl [ka] , norbornyl, and the like, but are not limited to these.

[0070]

[0084] As used herein, "cycloalkylene" refers to the same residues as cycloalkyl, but having a divalent character or being divalent. Particular cycloalkylene groups are those having 3 to 12 cyclic carbon atoms ("C3-C 12 Examples of cycloalkylene groups include those having 3 to 8 ring carbon atoms ("C3-C8 cycloalkylene"), and those having 3 to 6 ring carbon atoms ("C3-C6 cycloalkylene"). [ka] , cyclobutylene [ka] , cyclopentylene [ka] , cyclohexylene [ka] , 1,2-cyclohexenylene, 1,3-cyclohexenylene, 1,4-cyclohexenylene, cycloheptylene [ka] , norbornylene, and the like, but are not limited to these.

[0071]

[0085] "Halo" or "halogen" refers to elements in the Group 17 series having atomic numbers 9 to 85. Halo groups include fluoro (F), chloro (Cl), bromo (Br), and iodo (I).

[0072]

[0086] "Haloalkyl", "haloalkylene", "haloaryl", "haloarylene", "haloheteroaryl", and similar terms refer to a moiety substituted with at least one halo group. When a haloalkyl moiety or other halo-substituted moiety is substituted with more than one halogen, it may be indicated by using a prefix corresponding to the number of halogen moieties attached. For example, dihaloaryl, dihaloalkyl, trihaloaryl, trihaloalkyl, etc. refer to aryl and alkyl substituted with two ("di") or three ("tri") halo groups, which may be, but are not necessarily, the same halo; thus, for example, the haloaryl group 4-chloro-3-fluorophenyl is within the scope of dihaloaryl. The subset of haloalkyl groups in which each hydrogen (H) of the alkyl group is replaced with a halo group is referred to as "perhaloalkyl". A particular perhaloalkyl group is trifluoroalkyl (-CF3). Similarly, "perhaloalkoxy" refers to an alkoxy group in which a halogen replaces each hydrogen (H) in the hydrocarbon that makes up the alkyl portion of the alkoxy group. An example of a perhaloalkoxy group is trifluoromethoxy (-OCF3). "Haloalkyl" includes monohaloalkyl, dihaloalkyl, trihaloalkyl, perhaloalkyl, and any other number of halo substituents possible on an alkyl group; and similarly for other groups, such as, for example, haloalkylene, haloaryl, haloarylene, haloheteroaryl, etc.

[0073]

[0087] As used herein, "heteroaryl" refers to an unsaturated aromatic cyclic group having 1 to 14 annular carbon atoms and at least one annular heteroatom, including, but not limited to, heteroatoms such as nitrogen (N), oxygen (O), and sulfur (S). Heteroaryl groups can have a single ring (e.g., pyridyl or imidazolyl) or multiple condensed rings (e.g., indolizinyl, indolyl, or quinolinyl), where at least one of the fused rings is aromatic. Particular heteroaryl groups are 5- to 14-membered rings having 1 to 12 ring carbon atoms and 1 to 6 ring heteroatoms independently selected from the group consisting of nitrogen (N), oxygen (O), and sulfur (S) ("5- to 14-membered heteroaryl"); 5- to 10-membered rings having 1 to 8 ring carbon atoms and 1 to 4 ring heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur ("5- to 10-membered heteroaryl"); or 5-, 6-, or 7-membered rings having 1 to 5 ring carbon atoms and 1 to 4 ring heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur ("5- to 7-membered heteroaryl"). In one form, heteroaryl includes monocyclic aromatic 5-, 6-, or 7-membered rings having 1 to 6 ring carbon atoms and 1 to 4 ring heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur. In another aspect, heteroaryl includes polycyclic aromatic rings having 1-12 ring carbon atoms and 1-6 ring heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur. Heteroaryl groups having two or more rings, where at least one ring is non-aromatic, can be linked to the parent structure at either an aromatic ring position or a non-aromatic ring position. Examples of heteroaryl include, but are not limited to, groups such as pyridyl, benzimidazolyl, benzotriazolyl, benzo[b]thienyl, quinolinyl, indolyl, benzothiazolyl, and the like. "Heteroaryl" refers to [ka] (2,4-dihydro-3H-1,2,4-triazol-3-one-2-yl), which has the aromatic tautomeric structure [ka] (1H-1,2,4-triazol-5-ol-1-yl).

[0074]

[0088] As used herein, "heteroarylene" refers to the same residues as heteroaryl, but with or without divalency. Particular heteroarylene groups are 5- to 14-membered rings having 1 to 12 ring carbon atoms and 1 to 6 ring heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur ("5- to 14-membered heteroarylene"); 5- to 10-membered rings having 1 to 8 ring carbon atoms and 1 to 4 ring heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur ("5- to 10-membered heteroarylene"); or 5-, 6-, or 7-membered rings having 1 to 5 ring carbon atoms and 1 to 4 ring heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur ("5- to 7-membered heteroarylene"). Examples of heteroarylene include, but are not limited to, groups such as pyridylene, benzimidazolylene, benzotriazolylene, benzo[b]thienylene, quinolinylene, indolylene, and benzothiazolylene.

[0075]

[0089] As used herein, "heterocyclyl" and "heterocyclic group" refer to a non-aromatic saturated or partially unsaturated cyclic group having the specified number of atoms and heteroatoms, or if the number of atoms or heteroatoms is not specified, having at least three ring atoms, 1 to 14 ring carbon atoms, and at least one ring heteroatom, including but not limited to heteroatoms such as nitrogen, oxygen, and sulfur. Heterocyclic groups can have a single ring (e.g., tetrahydrothiopheneyl, oxazolidinyl) or multiple condensed rings (e.g., decahydroquinolinyl, octahydrobenzo[d]oxazolyl). Multiple condensed rings include, but are not limited to, bicyclic, tricyclic, and tetracyclic rings, as well as bridged or spirocyclic ring systems. Examples of heterocyclic groups include, but are not limited to, aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, oxazolidinyl, piperazinyl, morpholinyl, dioxanyl, 3,6-dihydro-2H-pyranyl, 2,3-dihydro-1H-imidazolyl, and the like.

[0076]

[0090] "Oxo" refers to the group =O (eg, carbonyl), that is, an oxygen atom that is double bonded to carbon or another chemical element.

[0077]

[0091] "Optionally substituted" means that a group is unsubstituted or substituted with one or more (e.g., 1, 2, 3, 4, or 5) of the substituents listed for that group, unless otherwise specified, where the substituents can be the same or different. In one embodiment, an optionally substituted group is unsubstituted. In one embodiment, an optionally substituted group has one substituent. In another embodiment, an optionally substituted group has two substituents. In another embodiment, an optionally substituted group has three substituents. In another embodiment, an optionally substituted group has four substituents. In certain embodiments, an optionally substituted group has 1-2, 1-3, 1-4, or 1-5 substituents. When multiple substituents are present, each substituent is independently selected unless otherwise indicated. For example, each (C1-C4 alkyl) substituent in the group -N(C1-C4 alkyl)(C1-C4 alkyl) can be selected independently of each other to produce a group such as -N(CH3)(CH2CH3).

[0078]

[0092] The term "substituted," when used to modify a specified group or radical, can also mean that one or more hydrogen atoms (H) of the specified group or radical are each, independently of one another, replaced with the same or different substituents as defined herein. In certain embodiments, a substituted group has 1, 2, 3, or 4 substituents, 1, 2, or 3 substituents, 1 or 2 substituents, or 1 substituent.

[0079]

[0093] Substituents may be attached to any chemically possible position on a given group or radical unless otherwise indicated. Thus, in one embodiment, -C1-C8 alkyl-OH includes, for example, -CH2CH2OH, -CH(OH)-CH3, -CH2C(OH)(CH3)2, and the like. By way of further example, in one embodiment, -C1-C6 alkyl-OH includes, for example, -CH2CH2OH, -CH(OH)-CH3, -CH2C(OH)(CH3)2, and the like. By way of further example, in one embodiment, -C1-C6 alkyl-CN includes, for example, -CH2CH2CN, -CH(CN)-CH3, -CH2C(CN)(CH3)2, and the like.

[0080]

[0094] Unless a specific isotope of an element is indicated in a formula, the disclosure also includes, for example, deuterated derivatives of a compound (where H is, 2 H, i.e., deuterium (D), and all isotopic species of the compounds disclosed herein. Deuterium compounds may provide favorable changes in pharmacokinetic (ADME) properties. Isotopic species may have isotopic substitutions at any or all positions in the structure, or may have atoms present at natural abundance at any or all positions in the structure.

[0081]

[0095] As used herein, a "small molecule" refers to a compound with a molecular weight below 1,000 daltons.

[0082]

[0096] Hydrogen atoms can also be replaced with bioisosteres or close bioisosteres, such as fluorine, so long as such replacement results in a stable compound.

[0083]

[0097] The present disclosure also includes any enantiomeric or diastereomeric form of the compounds described herein, and all stereochemical forms, including cis / trans or E / Z isomers. Unless stereochemistry is explicitly indicated in a chemical structure or chemical name, the structure or name is intended to encompass all possible stereoisomers of the compound depicted. Furthermore, when a specific stereochemical form is depicted, it is understood that all other stereochemical forms, as well as general non-stereospecific forms and mixtures of the disclosed compounds in any ratio, including mixtures of two or more stereochemical forms of the disclosed compounds in any ratio, are also described and encompassed by the present disclosure, thus encompassing racemic, non-racemic, enantiomerically enriched, and scalemic mixtures of the compounds. Compositions comprising the disclosed compounds, such as compositions of substantially pure compounds, including specific stereochemical forms thereof, are also contemplated. Compositions comprising mixtures of the disclosed compounds in any ratio, including compositions comprising mixtures of two or more stereochemical forms of the disclosed compounds in any ratio, are also encompassed by the disclosure, such that racemic, non-racemic, enantiomerically enriched, and scalemic mixtures of the compounds are encompassed by the disclosure. When stereochemistry is explicitly shown for one or more positions in a molecule, but not for another one or more portions of the molecule, the structure is intended to encompass all possible stereoisomers for the one or more portions where stereochemistry is not explicitly shown.

[0084]

[0098] The present disclosure also encompasses all tautomers of the compounds described herein.

[0085]

[0099] The present disclosure is intended to encompass all salts of the compounds described herein, as well as methods of using such salts of the compounds. In one embodiment, the salts of the compounds include pharmaceutically acceptable salts. A pharmaceutically acceptable salt is a salt that can be administered to humans and / or animals as a drug or pharmaceutical agent and that retains at least some of the biological activity of the free compound (i.e., the neutral or non-salt compound) after administration. The desired salt of a basic compound can be prepared by methods known to those skilled in the art by treating the compound with an acid. Examples of inorganic acids include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid. Examples of organic acids include, but are not limited to, formic acid, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, sulfonic acid, and salicylic acid. Salts of basic compounds with amino acids, such as aspartic acid and glutamic acid, can also be prepared. The desired salt of an acidic compound can be prepared by methods known to those skilled in the art by treating the compound with a base. Examples of inorganic salts of acidic compounds include, but are not limited to, alkali metal and alkaline earth metal salts, such as sodium salt, potassium salt, magnesium salt, and calcium salt; ammonium salt; and aluminum salt. Examples of organic salts of acidic compounds include, but are not limited to, procaine, dibenzylamine, N-ethylpiperidine, N,N'-dibenzylethylenediamine, and triethylamine salt. Salts of acidic compounds with amino acids, such as lysine salts, can also be prepared. For a list of pharmaceutically acceptable salts, see, for example, P.H. Stahl and C.G. Wermuth (eds.) "Handbook of Pharmaceutical Salts, Properties, Selection and Use" Wiley-VCH, 2011 (ISBN: 978-3-90639-051-2). Some pharma- ceutically acceptable salts are also disclosed in Berge, J. Pharm. Sci. 66:1 (1977).

[0086]

[0100] The terms "pharmaceutical formulation" and "pharmaceutical composition" refer to a preparation that is in a form that allows the biological activity of the active ingredient to be effective and does not contain additional ingredients that are unacceptably toxic to the individual to whom the formulation or composition may be administered. Such a formulation or composition may be sterile. Such a formulation or composition may be sterile, except for containing an oncolytic virus.

[0087]

[0101] As used herein, an "excipient" includes a pharma- ceutically acceptable excipient, carrier, vehicle, or stabilizer that is non-toxic to cells or mammals exposed thereto at the dosages and concentrations employed. Often the physiologically acceptable excipient is an aqueous pH buffered solution.

[0088]

[0102] References to a compound described in a pharmaceutical composition, or in a claim of a pharmaceutical composition, refer to the compound represented by the formula described in the pharmaceutical composition, without other elements of the pharmaceutical composition, i.e., without carriers, excipients, etc.

[0089]

[0103] "Treating" or "treatment" of any disease or disorder refers, in certain embodiments, to ameliorating the disease or disorder present in a subject. In another embodiment, "treating" or "treatment" includes improving at least one physical parameter, which may be indiscernible to the subject. In yet another embodiment, "treating" or "treatment" includes modulating the disease or disorder physically (e.g., stabilization of a discernible symptom) or physiologically (e.g., stabilization of a physical parameter) or both. In yet another embodiment, "treating" or "treatment" includes delaying or preventing the onset of the disease or disorder.

[0090]

[0104] As used herein, the term "subject" refers to a mammalian subject. Examples of subjects include, but are not limited to, humans, monkeys, dogs, cats, mice, rats, cows, horses, camels, birds, goats, and sheep. In certain embodiments, the subject is a human. In certain embodiments, the subject has a disease that can be treated or diagnosed using an antibody, an effective amount of a Cbl-b inhibitory compound described herein, one or more checkpoint inhibitors described herein, and combinations thereof provided herein. In certain embodiments, the disease is gastric cancer, colorectal cancer, renal cell carcinoma, cervical cancer, non-small cell lung cancer, ovarian cancer, breast cancer, triple negative breast cancer, endometrial cancer, prostate cancer, and / or cancer of epithelial origin.

[0091]

[0105] An "effective amount" of an agent disclosed herein is an amount sufficient to accomplish a specifically described purpose. An "effective amount" can be determined empirically and in a routine manner for a described purpose. An "effective amount" or a "sufficient amount" of an agent is an amount sufficient to produce a desired biological effect, such as a beneficial outcome, including a beneficial clinical outcome. In certain embodiments, the term "effective amount" refers to an amount of an agent effective to "treat" a disease or disorder in an individual (e.g., a mammal, such as a human).

[0092] 2.Cbl-b compound

[0106] Cbl-b is a negative regulator of immune cell activation and is expressed in white blood cells such as lymphocytes (e.g., T cells and NK cells) and macrophages. As such, the Cbl-b signaling pathway is often exploited by cancer cells to evade and limit the antitumor effector functions of these immune cells. Because Cbl-b inhibitors act across multiple immune cell types, inhibiting the Cbl-b signaling pathway may reverse these effects and enhance the effector functions of various immune cells. For example, in CT26 tumor-bearing mice treated with Cbl-b inhibitors, T cells (especially CD8 +Increased levels of CD8 T cells, IL-2 and IFNγ secretion, and NK cells are observed. This translates into antitumor effects as shown in Figure 3. Experiments such as those shown in Figure 5 show that in some cancers, the antitumor effect of compound 23 is mainly due to CD8 T cells. + It has been shown to be mediated by T cells and NK cells.

[0093]

[0107] Cbl-b inhibitors include small molecules, peptides, nucleic acids, or antibodies that inhibit Cbl-b ligase. Illustrative Cbl-b inhibitors include those described in WO 2019 / 148005, WO 2021 / 210508, WO 2020 / 236654, WO 2020 / 2643298, and WO 2021 / 021761. In certain embodiments, the Cbl-b inhibitor compound has formula (I): [ka] or a tautomer thereof, or a pharma- ceutically acceptable salt thereof, During the ceremony, [ka] teeth, [ka] and; Z 1 is CH or nitrogen; Z 2 is CH or nitrogen; R 1 is -CF3 or cyclopropyl; R 2 is -CF3 or cyclopropyl; R 3 is hydrogen, C1-C2 alkyl, or C1-C2 haloalkyl; R 4is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, 4- to 8-membered heterocyclyl, or C3-C6 cycloalkyl, where the heterocyclyl or cycloalkyl group is selected from 1 to 5 R 6 optionally substituted with a group; or R 3 and R 4 together with the carbon atom to which they are attached form a C3-C5 cycloalkyl or a 4- to 6-membered heterocyclyl, each of which is represented by 1 to 5 R 6 optionally substituted with a group; R 5 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or C3-C6 cycloalkyl; Each R 6 is independently C1-C6 alkyl, halo, hydroxy, -O-(C1-C6 alkyl), -CN, C1-C6 alkyl-CN, C1-C6 alkyl-OH, or C1-C6 haloalkyl; or two R attached to the same carbon atom 6 the groups, together with the carbon atoms to which they are attached, form a spiro C3-C6 cycloalkyl or a spiro 4- to 6-membered heterocyclyl; X is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkyl-OH, C1-C6 alkyl-CN, 1 to 5 R 8 C-C cycloalkyl optionally substituted with a group; or [ka] and; [ka] is a 4- to 7-membered heterocyclyl or a 5- to 8-membered heteroaryl, each of which optionally contains 1 to 2 additional heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and each of which optionally contains 1 to 5 R 8 optionally substituted with a group; Each R7 are independently hydrogen, C1-C6 alkyl, C1-C6 alkyl-OH, or C1-C6 haloalkyl; Or two R's 7 the groups, together with the carbon atoms to which they are attached, form a C3-C5 cycloalkyl or a 3- to 5-membered heterocyclyl; Each R 8 is independently halo, C1-C6 alkyl, C1-C6 alkyl-CN, C1-C6 alkyl-OH, C1-C6 haloalkyl, -CN, oxo, or -O(C1-C6 alkyl); Or two R's 8 The groups, together with the carbon atom or carbon atoms to which they are attached, form a spiro or fused C3-C5 cycloalkyl or a 3- to 5-membered heterocyclyl.

[0094]

[0108] In certain embodiments, [ka] (i.e., the ring A portion) is [ka] In certain embodiments, Z 1 is -CH. In another embodiment, Z 1 is nitrogen. In certain embodiments, R 1 is -CF3. In other embodiments, R 1 is cyclopropyl. In certain embodiments, the Ring A moiety is [ka] In certain embodiments, Z 2 is CH. In another embodiment, Z 2 is nitrogen. In certain embodiments, R 2 is -CF3. In other embodiments, R 2is cyclopropyl. In certain embodiments, the Ring A moiety is [ka] In certain embodiments, the Ring A moiety is selected from the group consisting of: [ka] In certain embodiments, the Ring A moiety is: [ka] In certain embodiments, the Ring A moiety is: [ka] In certain embodiments, the Ring A moiety is: [ka] In certain embodiments, the Ring A moiety is: [ka] In certain embodiments, the Ring A moiety is: [ka] In certain embodiments, the Ring A moiety is: [ka] In certain embodiments, the Ring A moiety is: [ka] It is.

[0095]

[0109] In certain embodiments, R 3 is hydrogen, C-C alkyl, or C-C haloalkyl. 3 is hydrogen, -CH3, or -CF3.

[0096]

[0110] In certain embodiments, R 3 is hydrogen.

[0097]

[0111] In certain embodiments, R 3 is C1-C2 alkyl. In certain embodiments, R 3 is methyl. In certain embodiments, R 3 is ethyl.

[0098]

[0112] In certain embodiments, R 3 is C1-C2 haloalkyl. In certain embodiments, R 3 is a C1-C2 haloalkyl containing 1 to 5 halogen atoms. In certain embodiments, R 3 is a C1-C2 haloalkyl containing 1 to 3 halogen atoms. In certain embodiments, R 3 is C haloalkyl. In certain embodiments, R 3 is a C2 haloalkyl. In certain embodiments, the halogen atoms are independently selected from the group consisting of chloro, bromo, and fluoro atoms. In certain embodiments, the halogen atoms are independently selected from the group consisting of chloro and fluoro atoms. In certain embodiments, all of the halogen atoms are fluoro atoms. In certain embodiments, the halogen atoms are a combination of chloro and fluoro atoms. In certain embodiments, R 3 is -CF3, -CCl3, -CF2Cl, -CFCl2, -CHF2, -CH2F, -CHCl2, -CH2Cl, or -CHFCl. 3 is -CF3.

[0099]

[0113] In certain embodiments, R4 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, 4- to 8-membered heterocyclyl, or C3-C6 cycloalkyl, where the heterocyclyl or cycloalkyl group is selected from 1 to 5 R 6 In certain embodiments, R 4 is hydrogen, C1-C3 alkyl, C1-C3 haloalkyl, 4- to 6-membered heterocyclyl, or C4-C5 cycloalkyl, where the heterocyclyl or cycloalkyl group is selected from 1 to 3 R 6 In certain embodiments, R 4 is hydrogen, -CH3, -CF3, cyclobutyl, or [ka] It is.

[0100]

[0114] In certain embodiments, R 4 is hydrogen.

[0101]

[0115] In certain embodiments, R 4 is C1-C6 alkyl. In certain embodiments, R 4 is C1-C3 alkyl. In certain embodiments, R 4 is methyl, ethyl, n-propyl, or isopropyl. 4 is -CH3.

[0102]

[0116] In certain embodiments, R 4 is C-C haloalkyl. In certain embodiments, R 4 is a C1-C6 haloalkyl containing 1 to 7 halogen atoms. In certain embodiments, R 4 is C1-C3 haloalkyl. In certain embodiments, R 4 is a C1-C3 haloalkyl containing 1 to 7 halogen atoms. In certain embodiments, R 4is a C1-C2 haloalkyl containing 1-5 halogen atoms. In certain embodiments, the halogen atoms are independently selected from the group consisting of chloro, bromo, and fluoro atoms. In certain embodiments, the halogen atoms are independently selected from the group consisting of chloro and fluoro atoms. In certain embodiments, all of the halogen atoms are fluoro atoms. In certain embodiments, the halogen atoms are a combination of chloro and fluoro atoms. In certain embodiments, R 4 is -CF, -CCl, -CFCl, -CFCl, -CHF, -CHF, -CHCl, -CHF, or -CHFCl. 4 is -CF3.

[0103]

[0117] In certain embodiments, R 4 is 1 to 5 R 6 In certain embodiments, R is a 4- to 8-membered heterocyclyl optionally substituted with a group. 4 1 to 3 R 6 In certain embodiments, R is a 4- to 6-membered heterocyclyl optionally substituted with a group. 4 1 to 2 R 6 In certain embodiments, the heterocyclyl is a 4-membered heterocyclyl optionally substituted with a R group. 6 In certain embodiments, the heterocyclyl is substituted with four R 6 In certain embodiments, the heterocyclyl is substituted with three R 6 In certain embodiments, the heterocyclyl is substituted with two R 6 In certain embodiments, the heterocyclyl is substituted with one R 6In certain embodiments, the heterocyclyl is substituted with a group. In certain embodiments, the heterocyclyl is unsubstituted. In certain embodiments, the heterocyclyl contains 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In certain embodiments, the heterocyclyl contains one nitrogen atom. In certain embodiments, the heterocyclyl contains two nitrogen atoms. In certain embodiments, the heterocyclyl contains one oxygen atom. In certain embodiments, the heterocyclyl contains two oxygen atoms. In certain embodiments, the heterocyclyl contains one oxygen atom and one nitrogen atom. In certain embodiments, the heterocyclyl contains one sulfur atom. In certain embodiments, the heterocyclyl contains one nitrogen atom and one sulfur atom. In certain embodiments, R 4 is oxetanyl, azetidinyl, tetrahydrofuranyl, dioxolanyl, pyrrolidinyl, pyrazolidinyl, piperidinyl, isoxazolidinyl, or tetrahydropyranyl, each of which is represented by 1 to 5 R 6 In certain embodiments, R 4 teeth, [ka] In certain embodiments, R 4 teeth, [ka] It is.

[0104]

[0118] In certain embodiments, R 4 is 1 to 5 R 6 In certain embodiments, R is a C-C cycloalkyl optionally substituted with a group. 4 1 to 3 R 6 In certain embodiments, cycloalkyl is a C4-C5 cycloalkyl optionally substituted with 5 R groups. 6In certain embodiments, the cycloalkyl is substituted with four R groups. 6 In certain embodiments, the cycloalkyl is substituted with three R 6 In certain embodiments, the cycloalkyl is substituted with two R 6 In certain embodiments, the cycloalkyl is substituted with one R 6 In certain embodiments, the cycloalkyl is unsubstituted. In certain embodiments, R 4 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each of which is represented by 1 to 5 R 6 In certain embodiments, R 4 is cyclopropyl or cyclobutyl. In certain embodiments, R 4 is cyclobutyl.

[0105]

[0119] In certain embodiments, R 3 and R 4 together with the carbon atom to which they are attached form a C3-C5 cycloalkyl or a 4- to 6-membered heterocyclyl, each of which is represented by 1 to 5 R 6 In certain embodiments, R 3 and R 4 together with the carbon atom to which they are attached form a C4-C5 cycloalkyl or a 4- to 6-membered heterocyclyl, each of which is represented by 1 to 3 R 6 In certain embodiments, R 3 and R 4 together with the carbon atoms to which they are attached, [ka] Each of these is formed by 1 to 3 R 6 In certain embodiments, R 3 and R 4together with the carbon atom to which they are attached, one R that is a methyl 6 is substituted with a group, [ka] Form.

[0106]

[0120] In certain embodiments, R 3 and R 4 Together with the carbon atom to which they are attached, they are one to five R 6 In certain embodiments, R 3 and R 4 Together with the carbon atom to which they are attached, they are one to three R 6 In certain embodiments, the cycloalkyl is a C4-C5 cycloalkyl optionally substituted with 5 R groups. 6 In certain embodiments, the cycloalkyl is substituted with four R groups. 6 In certain embodiments, the cycloalkyl is substituted with three R 6 In certain embodiments, the cycloalkyl is substituted with two R 6 In certain embodiments, the cycloalkyl is substituted with one R 6 In certain embodiments, the cycloalkyl is unsubstituted. In certain embodiments, R 3 and R 4 together with the carbon atoms to which they are attached, [ka] Each of these is formed by 1 to 3 R 6 In certain embodiments, R 3 and R 4 together with the carbon atom to which they are attached, one R that is a methyl 6 is substituted with a group, [ka] In certain embodiments, [ka] The absolute stereochemistry at the carbon atom to which the methyl group is attached is (R)- (using the Cahn-Ingold-Prelog sequencing rules). [ka] The absolute stereochemistry at the carbon atom to which the methyl group is attached is (S)-.

[0107]

[0121] In certain embodiments, R 3 and R 4 Together with the carbon atom to which they are attached, they are one to five R 6 In certain embodiments, R 3 and R 4 Together with the carbon atom to which they are attached, they are one to three R 6 In certain embodiments, the heterocyclyl is a 4- to 6-membered heterocyclyl optionally substituted with a R group. 6 In certain embodiments, the heterocyclyl is substituted with four R 6 In certain embodiments, the heterocyclyl is substituted with three R 6 In certain embodiments, the heterocyclyl is substituted with two R 6 In certain embodiments, the heterocyclyl is substituted with one R 6In certain embodiments, the heterocyclyl is substituted with a group. In certain embodiments, the heterocyclyl is unsubstituted. In certain embodiments, the heterocyclyl contains 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In certain embodiments, the heterocyclyl contains one nitrogen atom. In certain embodiments, the heterocyclyl contains two nitrogen atoms. In certain embodiments, the heterocyclyl contains one oxygen atom. In certain embodiments, the heterocyclyl contains two oxygen atoms. In certain embodiments, the heterocyclyl contains one oxygen atom and one nitrogen atom. In certain embodiments, the heterocyclyl contains one sulfur atom. In certain embodiments, the heterocyclyl contains one nitrogen atom and one sulfur atom. In certain embodiments, R 4 is oxetanyl, azetidinyl, tetrahydrofuranyl, dioxolanyl, pyrrolidinyl, pyrazolidinyl, piperidinyl, isoxazolidinyl, or tetrahydropyranyl, each of which is represented by 1 to 5 R 6 In certain embodiments, R 3 and R 4 together with the carbon atoms to which they are attached, [ka] Each of these is formed by 1 to 3 R 6 In certain embodiments, R 3 and R 4 together with the carbon atoms to which they are attached, [ka] In certain embodiments, R 3 and R 4 together with the carbon atoms to which they are attached, [ka] Form.

[0108]

[0122] In certain embodiments, each R 6 is independently C1-C6 alkyl, halo, hydroxy, -O-(C1-C6 alkyl), -CN, C1-C6 alkyl-CN, C1-C6 alkyl-OH, or C1-C6 haloalkyl. 6 is independently C1-C3 alkyl, halo, hydroxy, -O-(C1-C3 alkyl), -CN, C1-C3 alkyl-CN, C1-C3 alkyl-OH, or C1-C3 haloalkyl. 6 is independently -CH3, fluoro (F), hydroxy, -OCH3, -CN, -CH2CN, -CH2OH, or -CF3.

[0109]

[0123] In certain embodiments, R 6 is C1-C6 alkyl. In certain embodiments, R 6 is C1-C3 alkyl. In certain embodiments, R 6 is methyl, ethyl, n-propyl, or isopropyl. 6 is -CH3.

[0110]

[0124] In certain embodiments, R 6 is halo. In certain embodiments, R 6 is chloro, fluoro, or bromo. In certain embodiments, R 6 is chloro or fluoro. In certain embodiments, R 7 is fluoro.

[0111]

[0125] In certain embodiments, R 6 is hydroxyl.

[0112]

[0126] In certain embodiments, R 6 is -O(C1-C6 alkyl). In certain embodiments, R 6is -O-(C1-C3 alkyl). In certain embodiments, R 6 is -O(methyl), -O(ethyl), -O(n-propyl), or -O(isopropyl). 6 is -OCH3 or -OCH2CH3. In certain embodiments, R 6 is -OCH3.

[0113]

[0127] In certain embodiments, R 6 is -CN. In certain embodiments, R 6 is C1-C6 alkyl-CN. In certain embodiments, R 6 is C1-C3 alkyl-CN. In certain embodiments, R 6 is -CHCN, -CHCH-CN, -CHCHCH-CN, or -C(CH)-CN. In certain embodiments, R 6 is -CHCN.

[0114]

[0128] In certain embodiments, R 6 is C1-C6 alkyl-OH. In certain embodiments, R 6 is C1-C3 alkyl-OH. In certain embodiments, R 6 is -CHOH, -CHCH-OH, -CHCHCH-OH, or -C(CH)-OH. 6 is -CHOH.

[0115]

[0129] In certain embodiments, R 6 is C-C haloalkyl. In certain embodiments, R 6 is a C1-C6 haloalkyl containing 1 to 7 halogen atoms. In certain embodiments, R 6 is C1-C3 haloalkyl. In certain embodiments, R 6 is a C1-C3 haloalkyl containing 1 to 7 halogen atoms. In certain embodiments, R 6is a C1-C3 haloalkyl containing 1-5 halogen atoms. In certain embodiments, the halogen atoms are independently selected from the group consisting of chloro, bromo, and fluoro atoms. In certain embodiments, the halogen atoms are independently selected from the group consisting of chloro and fluoro atoms. In certain embodiments, all of the halogen atoms are fluoro atoms. In certain embodiments, the halogen atoms are a combination of chloro and fluoro atoms. In certain embodiments, R 6 is -CF3, -CCl3, -CF2Cl, -CFCl2, -CHF2, -CH2F, -CHCl2, -CH2Cl, or -CHFCl. 6 is -CF3.

[0116]

[0130] In certain embodiments, two R 6 The groups, taken together with the carbon atom to which they are attached, form a spiro C3-C6 cycloalkyl or a spiro 4- to 6-membered heterocyclyl. In certain embodiments, two R 6 The groups, together with the carbon atoms to which they are attached, form a spiro C3-C6 cycloalkyl or a spiro 4- to 5-membered heterocyclyl.

[0117]

[0131] In certain embodiments, two R 6 The groups, taken together with the carbon atom to which they are attached, form a spiro C-C cycloalkyl. In certain embodiments, two R 6 The groups, taken together with the carbon atom to which they are attached, form a spiro C-C cycloalkyl. In certain embodiments, two R 6 The groups, taken together with the carbon atom to which they are attached, form a spiro C-C cycloalkyl. In certain embodiments, two R 6The groups together with the carbon atom to which they are attached form a spirocyclopropyl, cyclobutyl, or cyclopentyl. In certain embodiments, two R 6 The groups together with the carbon atom to which they are attached form a spirocyclopropyl.

[0118]

[0132] In certain embodiments, two R 6 The groups, taken together with the carbon atom to which they are attached, form a spiro 4- to 6-membered heterocyclyl. In certain embodiments, two R 6 The groups, taken together with the carbon atom to which they are attached, form a spiro 4- to 5-membered heterocyclyl. In certain embodiments, the heterocyclyl contains 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In certain embodiments, the heterocyclyl contains one nitrogen atom. In certain embodiments, the heterocyclyl contains two nitrogen atoms. In certain embodiments, the heterocyclyl contains one oxygen atom. In certain embodiments, the heterocyclyl contains two oxygen atoms. In certain embodiments, the heterocyclyl contains one oxygen atom and one nitrogen atom. In certain embodiments, the heterocyclyl contains one sulfur atom. In certain embodiments, the heterocyclyl contains one nitrogen atom and one sulfur atom. In certain embodiments, two R bonded to the same carbon atom are 6 The groups, together with the carbon atom to which they are attached, form a spirooxetanyl, azetidinyl, tetrahydrofuranyl, dioxolanyl, pyrrolidinyl, pyrazolidinyl, piperidinyl, isoxazolidinyl, or tetrahydropyranyl.

[0119]

[0133] In certain embodiments, R 5 is hydrogen, C-C alkyl, C-C haloalkyl, or C-C cycloalkyl. In certain embodiments, R 5is hydrogen, C1-C3 alkyl, C1-C3 haloalkyl, or C3-C4 cycloalkyl. In certain embodiments, R 5 is hydrogen, -CH3, -CHF2, or cyclopropyl.

[0120]

[0134] In certain embodiments, R 5 is hydrogen.

[0121]

[0135] In certain embodiments, R 5 is C1-C6 alkyl. In certain embodiments, R 5 is C1-C3 alkyl. In certain embodiments, R 5 is methyl, ethyl, n-propyl, or isopropyl. 5 is -CH3.

[0122]

[0136] In certain embodiments, R 5 is C-C haloalkyl. In certain embodiments, R 5 is a C1-C6 haloalkyl containing 1 to 7 halogen atoms. In certain embodiments, R 5 is C1-C3 haloalkyl. In certain embodiments, R 5 is a C1-C3 haloalkyl containing 1 to 7 halogen atoms. In certain embodiments, R 5 is a C1-C3 haloalkyl containing 1-5 halogen atoms. In certain embodiments, the halogen atoms are independently selected from the group consisting of chloro, bromo, and fluoro atoms. In certain embodiments, the halogen atoms are independently selected from the group consisting of chloro and fluoro atoms. In certain embodiments, all of the halogen atoms are fluoro atoms. In certain embodiments, the halogen atoms are a combination of chloro and fluoro atoms. In certain embodiments, R 5 is -CF3, -CCl3, -CF2Cl, -CFCl2, -CHF2, -CH2F, -CHCl2, -CH2Cl, or -CHFCl. 5is -CHF2.

[0123]

[0137] In certain embodiments, R 5 is C-C cycloalkyl. In certain embodiments, R 5 is C-C cycloalkyl. In certain embodiments, R 5 is C-C cycloalkyl. In certain embodiments, R 5 is cyclopropyl, cyclobutyl, or cyclopentyl. In certain embodiments, R 5 is cyclopropyl.

[0124]

[0138] In certain embodiments, X is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkyl-OH, C1-C6 alkyl-CN, or 1 to 5 R 8 In certain embodiments, X is hydrogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkyl-OH, C1-C3 alkyl-CN, or one to three R 8 In certain embodiments, X is a C3-C5 cycloalkyl optionally substituted with a group. In certain embodiments, X is hydrogen or -CH3.

[0125]

[0139] In certain embodiments, X is hydrogen.

[0126]

[0140] In certain embodiments, X is C1-C6 alkyl. In certain embodiments, X is C1-C3 alkyl. In certain embodiments, X is methyl, ethyl, n-propyl, or isopropyl. In certain embodiments, X is -CH3.

[0127]

[0141] In certain embodiments, X is a C1-C6 haloalkyl. In certain embodiments, X is a C1-C6 haloalkyl containing 1-7 halogen atoms. In certain embodiments, X is a C1-C3 haloalkyl. In certain embodiments, X is a C1-C3 haloalkyl containing 1-7 halogen atoms. In certain embodiments, X is a C1-C3 haloalkyl containing 1-5 halogen atoms. In certain embodiments, the halogen atoms are independently selected from the group consisting of chloro, bromo, and fluoro atoms. In certain embodiments, the halogen atoms are independently selected from the group consisting of chloro and fluoro atoms. In certain embodiments, all of the halogen atoms are fluoro atoms. In certain embodiments, the halogen atoms are a combination of chloro and fluoro atoms. In certain embodiments, X is -CF3, -CCl3, -CF2Cl, -CFCl2, -CHF2, -CH2F, -CHCl2, -CH2Cl, or -CHFCl. In certain embodiments, X is -CF3.

[0128]

[0142] In certain embodiments, X is C1-C6 alkyl-OH. In certain embodiments, X is C1-C3 alkyl-OH. In certain embodiments, X is -CH2OH, -CH2CH2-OH, -CH2CH2CH2-OH, or -C(CH3)2-OH. In certain embodiments, X is -CH2OH.

[0129]

[0143] In certain embodiments, X is C1-C6 alkyl-CN. In certain embodiments, X is C1-C3 alkyl-CN. In certain embodiments, X is -CH2CN, -CH2CH2-CN, -CH2CH2CH2-CN, or -C(CH3)2-CN. In certain embodiments, X is -CH2CN.

[0130]

[0144] In certain embodiments, X is 1 to 5 R 8 In certain embodiments, X is a C3-C6 cycloalkyl optionally substituted with one to three R8 In certain embodiments, cycloalkyl is a C3-C5 cycloalkyl optionally substituted with 5 R groups. 8 In certain embodiments, the cycloalkyl is substituted with four R groups. 8 In certain embodiments, the cycloalkyl is substituted with three R 8 In certain embodiments, the cycloalkyl is substituted with two R 8 In certain embodiments, the cycloalkyl is substituted with one R 8 In certain embodiments, cycloalkyl is unsubstituted. In certain embodiments, X is cyclopropyl, cyclobutyl, or cyclopentyl, each of which is selected from 1 to 5 R 8 In certain embodiments, X is optionally substituted with a group.

[0131]

[0145] In certain embodiments, X is [ka] where: [ka] and the Ring B moiety depicted as: 8 In certain embodiments, the Ring B moiety is a 4- to 6-membered heterocyclyl or a 5- to 6-membered heteroaryl, each of which optionally contains 1-2 additional heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and each of which optionally contains 1-5 R 8In certain embodiments, the Ring B moiety is a 4- to 5-membered heterocyclyl or a 5- to 6-membered heteroaryl, each of which optionally contains one additional heteroatom selected from the group consisting of nitrogen and oxygen, and each of which optionally contains 1 to 5 R 8 Groups are optionally substituted.

[0132]

[0146] In certain embodiments, the Ring B moiety is a 4- to 7-membered heterocyclyl optionally containing 1-2 additional heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, where the heterocyclyl is selected from 1-5 R 8 In certain embodiments, the Ring B moiety is a 4-6 membered heterocyclyl optionally containing 1-2 additional heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, where the heterocyclyl is optionally substituted with 1-5 R 8 In certain embodiments, the Ring B moiety is a 4-5 membered heterocyclyl optionally containing one additional heteroatom selected from the group consisting of nitrogen and oxygen, where the heterocyclyl is optionally substituted with 1 to 5 R 8 In certain embodiments, the heterocyclyl is optionally substituted with five R groups. 8 In certain embodiments, the heterocyclyl is substituted with four R 8 In certain embodiments, the heterocyclyl is substituted with three R 8 In certain embodiments, the heterocyclyl is substituted with two R 8 In certain embodiments, the heterocyclyl is substituted with one R 8In certain embodiments, the heterocyclyl is unsubstituted. In certain embodiments, the heterocyclyl contains 1-2 additional heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In certain embodiments, the heterocyclyl contains 1 additional nitrogen atom. In certain embodiments, the heterocyclyl contains 2 additional nitrogen atoms. In certain embodiments, the heterocyclyl contains 1 additional oxygen atom. In certain embodiments, the heterocyclyl contains 2 additional oxygen atoms. In certain embodiments, the heterocyclyl contains 1 additional oxygen atom and 1 additional nitrogen atom. In certain embodiments, the heterocyclyl contains 1 additional sulfur atom. In certain embodiments, the heterocyclyl contains no additional heteroatoms. In certain embodiments, the heterocyclyl is azetidinyl, pyrrolidinyl, pyrazolidinyl, piperidinyl, or isoxazolidinyl, each of which is selected from 1-5 R 8 Groups are optionally substituted.

[0133]

[0147] In certain embodiments, the Ring B moiety is a 5-8 membered heteroaryl optionally containing 1-2 additional heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, where the heteroaryl is selected from 1-5 R 8 In certain embodiments, the Ring B moiety is a 5-6 membered heteroaryl optionally containing 1-2 additional heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, where the heteroaryl is optionally substituted with 1-5 R 8 In certain embodiments, the Ring B moiety is a 5-6 membered heteroaryl optionally containing one additional heteroatom selected from the group consisting of nitrogen and oxygen, where the heteroaryl is selected from 1-5 R 8 In certain embodiments, the heteroaryl is optionally substituted with five R groups. 8 In certain embodiments, the heteroaryl is substituted with four R 8In certain embodiments, the heteroaryl is substituted with three R 8 In certain embodiments, the heteroaryl is substituted with two R 8 In certain embodiments, a heteroaryl is substituted with one R 8 In certain embodiments, the heteroaryl is unsubstituted. In certain embodiments, the heteroaryl contains 1-2 additional heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In certain embodiments, the heteroaryl contains 1 additional nitrogen atom. In certain embodiments, the heteroaryl contains 2 additional nitrogen atoms. In certain embodiments, the heteroaryl contains 1 additional oxygen atom. In certain embodiments, the heteroaryl contains 2 additional oxygen atoms. In certain embodiments, the heteroaryl contains 1 additional oxygen atom and 1 additional nitrogen atom. In certain embodiments, the heteroaryl contains 1 additional sulfur atom. In certain embodiments, the heteroaryl contains no additional heteroatoms. In certain embodiments, the heteroaryl is pyrrolyl, imidazolyl, pyrazolyl, isoxazolyl, oxazolyl, thiazolyl, isothiazolyl, triazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, or triazyl, each of which is selected from 1-5 R 8 Groups are optionally substituted.

[0134]

[0148] In certain embodiments, the Ring B moiety is [ka] where Y is oxygen, -CH2-, CHR 8 , or -C(R 8 )2-, and X is [ka] In certain embodiments, Y is oxygen (O). In other embodiments, Y is -CH2-, -CHR 8 - or -C(R 8 In certain embodiments, Y is -CH-. In certain embodiments, Y is -CHR 8 In certain embodiments, Y is -C(R 8 In certain embodiments, the Ring B moiety is a ring having a total of 1 to 5 R 8 In certain embodiments, the Ring B moiety is substituted with a total of 1 to 3 R 8 Therefore, Y is substituted with a CHR group. 8 When the ring B moiety is 8 Similarly, Y can be substituted with a -C(R 8 )2-, the ring B moiety may have up to three additional R 8 In certain embodiments, the Ring B moiety can be substituted with five R 8 In certain embodiments, the Ring B moiety is substituted with four R 8 In certain embodiments, the Ring B moiety is substituted with three R 8 In certain embodiments, the Ring B moiety is substituted with two R 8 In certain embodiments, the Ring B moiety is substituted with one R 8 In certain embodiments, the Ring B moiety is unsubstituted. In certain embodiments, the Ring B moiety is substituted with a group. [ka] where each R 8 are independently as described herein.

[0135]

[0149] In certain embodiments, each R 7 is independently hydrogen, C-C alkyl, C-C alkyl-OH, or C-C haloalkyl. 7is independently hydrogen, C-C alkyl, C-C alkyl-OH, or C-C haloalkyl. 7 is independently hydrogen, -CH3, -CH2OH, or -CF3.

[0136]

[0150] In certain embodiments, both R 7 The group is hydrogen (H). In certain embodiments, one R 7 In certain embodiments, one R 7 The group is hydrogen and the other R 7 The group is C1-C6 alkyl, C1-C6 alkyl-OH, or C1-C6 haloalkyl. In certain embodiments, one R 7 The group is hydrogen and the other R 7 The group is C1-C6 alkyl. In certain embodiments, one R 7 The group is hydrogen and the other R 7 The group is C1-C3 alkyl. In certain embodiments, one R 7 The group is hydrogen and the other R 7 The group is -CH3.

[0137]

[0151] In certain embodiments, R 7 is C1-C6 alkyl. In certain embodiments, R 7 is C1-C3 alkyl. In certain embodiments, R 7 is methyl, ethyl, n-propyl, or isopropyl. 7 The group is methyl, ethyl, n-propyl, or isopropyl, and the other R 7 The group is hydrogen. In certain embodiments, R 7 is -CH3.

[0138]

[0152] In certain embodiments, R 7 is C1-C6 alkyl-OH. In certain embodiments, R 7 is C1-C3 alkyl-OH. In certain embodiments, R7 is -CHOH, -CHCH-OH, -CHCHCH-OH, or -C(CH)-OH. 7 is -CHOH. In certain embodiments, one R 7 The group is C1-C6 alkyl-OH, and the other R 7 In certain embodiments, one R 7 The group is C1-C3 alkyl-OH, and the other R 7 In certain embodiments, one R 7 The group is -CHOH, -CHCH-OH, -CHCHCH-OH, or -C(CH)-OH, and the other R 7 In certain embodiments, one R 7 The group is -CHOH, and the other R 7 The group is hydrogen.

[0139]

[0153] In certain embodiments, R 7 is C-C haloalkyl. In certain embodiments, R 7 is a C1-C6 haloalkyl containing 1 to 7 halogen atoms. In certain embodiments, R 7 is C1-C3 haloalkyl. In certain embodiments, R 7 is a C1-C3 haloalkyl containing 1 to 7 halogen atoms. In certain embodiments, R 7 is a C1-C3 haloalkyl containing 1-5 halogen atoms. In certain embodiments, the halogen atoms are independently selected from the group consisting of chloro, bromo, and fluoro atoms. In certain embodiments, the halogen atoms are independently selected from the group consisting of chloro and fluoro atoms. In certain embodiments, all of the halogen atoms are fluoro atoms. In certain embodiments, the halogen atoms are a combination of chloro and fluoro atoms. In certain embodiments, R 7is -CF, -CCl, -CFCl, -CFCl, -CHF, -CHF, -CHCl, -CHF, or -CHFCl. 7 is -CF3.

[0140]

[0154] In certain embodiments, two R 7 The groups, together with the carbon atom to which they are attached, form a C3-C5 cycloalkyl or a 3- to 5-membered heterocyclyl. In certain embodiments, two R 7 The groups together with the carbon atom to which they are attached form a cyclopropyl or oxetanyl.

[0141]

[0155] In certain embodiments, two R 7 The groups, together with the carbon atom to which they are attached, form a C-C cycloalkyl. In certain embodiments, two R 7 The groups, together with the carbon atom to which they are attached, form a cyclopropyl or cyclobutyl. In certain embodiments, two R 7 The groups together with the carbon atom to which they are attached form a cyclopropyl.

[0142]

[0156] In certain embodiments, two R 7 The groups, together with the carbon atom to which they are attached, form a 3- to 5-membered heterocyclyl. In certain embodiments, two R 7The groups together with the carbon atom to which they are attached form a 3- to 4-membered heterocyclyl. In certain embodiments, the heterocyclyl contains 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In certain embodiments, the heterocyclyl contains one nitrogen atom. In certain embodiments, the heterocyclyl contains two nitrogen atoms. In certain embodiments, the heterocyclyl contains one oxygen atom. In certain embodiments, the heterocyclyl contains two oxygen atoms. In certain embodiments, the heterocyclyl contains one oxygen atom and one nitrogen atom. In certain embodiments, the heterocyclyl contains one sulfur atom. In certain embodiments, the heterocyclyl contains one nitrogen atom and one sulfur atom. In certain embodiments, R 7 is aziridinyl, oxiranyl, oxetanyl, azetidinyl, tetrahydrofuranyl, dioxolanyl, pyrrolidinyl, pyrazolidinyl, or isoxazolidinyl.

[0143]

[0157] In certain embodiments, each R 8 is independently halo, C-C alkyl, C-C alkyl-CN, C-C alkyl-OH, C-C haloalkyl, -CN, oxo, or -O(C-C alkyl). 8 is independently halo, C1-C3 alkyl, C1-C3 alkyl-CN, C1-C3 alkyl-OH, C1-C3 haloalkyl, -CN, oxo, or -O(C1-C3 alkyl). 8 is independently fluoro (F), -CH3, -CH2CH3, -CH2CN, -CH2OH, -CF3, -CN, oxo, or -OCH3.

[0144]

[0158] In certain embodiments, R 8 is halo. In certain embodiments, R 8 is chloro, fluoro, or bromo. In certain embodiments, R 8is chloro or fluoro. In certain embodiments, R 8 is fluoro.

[0145]

[0159] In certain embodiments, R 8 is C1-C6 alkyl. In certain embodiments, R 8 is C1-C3 alkyl. In certain embodiments, R 8 is methyl, ethyl, n-propyl, or isopropyl. 8 is -CH3 or -CH2CH3.

[0146]

[0160] In certain embodiments, R 8 is -CN. In certain embodiments, R 8 is C1-C6 alkyl-CN. In certain embodiments, R 8 is C1-C3 alkyl-CN. In certain embodiments, R 8 is -CHCN, -CHCH-CN, -CHCHCH-CN, or -C(CH)-CN. In certain embodiments, R 8 is -CHCN.

[0147]

[0161] In certain embodiments, R 8 is C1-C6 alkyl-OH. In certain embodiments, R 8 is C1-C3 alkyl-OH. In certain embodiments, R 8 is -CHOH, -CHCH-OH, -CHCHCH-OH, or -C(CH)-OH. 8 is -CHOH.

[0148]

[0162] In certain embodiments, R 8 is C-C haloalkyl. In certain embodiments, R 8 is a C1-C6 haloalkyl containing 1 to 7 halogen atoms. In certain embodiments, R 8is C1-C3 haloalkyl. In certain embodiments, R 8 is a C1-C3 haloalkyl containing 1 to 7 halogen atoms. In certain embodiments, R 8 is a C1-C3 haloalkyl containing 1-5 halogen atoms. In certain embodiments, the halogen atoms are independently selected from the group consisting of chloro, bromo, and fluoro atoms. In certain embodiments, the halogen atoms are independently selected from the group consisting of chloro and fluoro atoms. In certain embodiments, all of the halogen atoms are fluoro atoms. In certain embodiments, the halogen atoms are a combination of chloro and fluoro atoms. In certain embodiments, R 8 is -CF, -CCl, -CFCl, -CFCl, -CHF, -CHF, -CHCl, -CHF, or -CHFCl. 8 is -CF3.

[0149]

[0163] In certain embodiments, R 8 is oxo.

[0150]

[0164] In certain embodiments, R 8 is -O(C1-C6 alkyl). In certain embodiments, R 8 is -O-(C1-C3 alkyl). In certain embodiments, R 8 is -O(methyl), -O(ethyl), -O(n-propyl), or -O(isopropyl). 8 is -OCH3 or -OCH2CH3. In certain embodiments, R 8 is -OCH3.

[0151]

[0165] In certain embodiments, two R 8 The groups, taken together with the carbon atom or carbon atoms to which they are attached, form a spiro or fused C-C cycloalkyl or a 3- to 5-membered heterocyclyl. In certain embodiments, two R 8The groups, together with the carbon atom or carbon atoms to which they are attached, form a spiro or fused cyclopropyl or oxetanyl.

[0152]

[0166] In certain embodiments, two R 8 The groups, taken together with the carbon atom or carbon atoms to which they are attached, form a spiro or fused C-C cycloalkyl. In certain embodiments, two R 8 The groups, together with the carbon atom or carbon atoms to which they are attached, form a spiro C-C cycloalkyl. In certain embodiments, two R 8 The groups, together with the carbon atom or carbon atoms to which they are attached, form a spirocyclopropyl. In certain embodiments, two R 8 The groups, together with the carbon atom or carbon atoms to which they are attached, form a spirocyclobutyl. In certain embodiments, two R 8 The groups, together with the carbon atom or carbon atoms to which they are attached, form a spirocyclopentyl. In certain embodiments, two R 8 The groups, taken together with the carbon atom or carbon atoms to which they are attached, form a fused C-C cycloalkyl. In certain embodiments, two R 8 The groups, taken together with the carbon atom or carbon atoms to which they are attached, form a fused cyclopropyl. In certain embodiments, two R 8 The groups, taken together with the carbon atom or carbon atoms to which they are attached, form a fused cyclobutyl. In certain embodiments, two R 8 The groups, taken together with the carbon atom or carbon atoms to which they are attached, form a fused cyclopentyl. In certain embodiments, two R 8 The groups, together with the carbon atom or carbon atoms to which they are attached, form a spiro or fused cyclopropyl.

[0153]

[0167] In certain embodiments, two R 8The groups, taken together with the carbon atom or carbon atoms to which they are attached, form a spiro or fused 3- to 5-membered heterocyclyl. In certain embodiments, two R 8 The groups, taken together with the carbon atom or carbon atoms to which they are attached, form a spiro 3- to 5-membered heterocyclyl. In certain embodiments, two R 8 The groups, together with the carbon atom or carbon atoms to which they are attached, form a spirooxetanyl. In certain embodiments, two R 8 The groups, taken together with the carbon atom or carbon atoms to which they are attached, form a fused 3- to 5-membered heterocyclyl. In certain embodiments, two R 8 The groups, taken together with the carbon atom or carbon atoms to which they are attached, form a fused oxetanyl. In certain embodiments, two R 8 The groups, taken together with the carbon atom or atoms to which they are attached, form a spiro or fused oxetanyl. In certain embodiments, the heterocyclyl contains 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In certain embodiments, the heterocyclyl contains one nitrogen atom. In certain embodiments, the heterocyclyl contains two nitrogen atoms. In certain embodiments, the heterocyclyl contains one oxygen atom. In certain embodiments, the heterocyclyl contains two oxygen atoms. In certain embodiments, the heterocyclyl contains one oxygen atom and one nitrogen atom. In certain embodiments, the heterocyclyl contains one sulfur atom. In certain embodiments, the heterocyclyl contains one nitrogen atom and one sulfur atom. In certain embodiments, two R 8 The groups, together with the carbon atom to which they are attached, form spiroaziridinyl, oxiranyl, oxetanyl, azetidinyl, tetrahydrofuranyl, dioxolanyl, pyrrolidinyl, pyrazolidinyl, or isoxazolidinyl. In certain embodiments, two R 8The groups, together with the carbon atom to which they are attached, form a fused aziridinyl, oxiranyl, oxetanyl, azetidinyl, tetrahydrofuranyl, dioxolanyl, pyrrolidinyl, pyrazolidinyl, or isoxazolidinyl.

[0154]

[0168] In certain embodiments, X is [ka] In certain embodiments, X is [ka] In certain embodiments, X is [ka] In certain embodiments, X is [ka] In certain embodiments, X is [ka] In certain embodiments, X is [ka] In any of these embodiments, both R 7 The group may be hydrogen (H). In any of these embodiments, one R 7 The group can be hydrogen and one R 7 The group can be -CH3. In any of these embodiments, both R 7 The group can be -CH3.

[0155]

[0169] In certain embodiments, the compound has formula (IA) or (IB): [ka] The

[0170] In the formula, R 1 , R 2 , R 3 , R 4 , R 5 , Z 1 , Z 2 and X are as described for compounds of formula (I).

[0156]

[0171] In certain embodiments, the compound has formula (Ia) or (Ib): [ka] wherein R 1 , R 2 , R 5 , R 6 , Z 1 , Z 2 and X are as described for compounds of formula (I).

[0157]

[0172] In certain embodiments, the compound has formula (IC), (ID), (IE), (IF), (IG), (IH), or (IJ): [ka] wherein R 3 , R 4 , R 5 and X are as described for compounds of formula (I).

[0158]

[0173] In certain embodiments, the compound has formula (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G), or (II-H): [ka] wherein R 3 , R 4 , R 5 , R 7 , R 8 and the Ring B moiety are as described for compounds of formula (I).

[0159]

[0174] In certain embodiments, the compound has formula (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), or (III-H): [ka] wherein R 3 , R 4 , R 5 , R 7 , R 8 and Y are as described for compounds of formula (I).

[0160]

[0175] In certain embodiments, the compound has formula (IV-A), (IV-B), (IV-C), (IV-D), (IV-E), (IV-F), (IV-G), or (IV-H): [ka] wherein R 3 , R 4 , and R 5 is as described for compounds of formula (I), and X is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkyl-OH, C1-C6 alkyl-CN, or 1 to 5 R 8In certain embodiments, X is a C3-C6 cycloalkyl optionally substituted with a group. In certain embodiments, X is hydrogen. In certain embodiments, X is a C1-C6 alkyl. In certain embodiments, X is a C1-C6 haloalkyl. In certain embodiments, X is a C1-C6 alkyl-OH. In certain embodiments, X is a C1-C6 alkyl-CN. In certain embodiments, X is a C1-C6 alkyl group selected from the group consisting of 1 to 5 R 8 is a C3-C6 cycloalkyl optionally substituted with a group.

[0161]

[0176] In certain embodiments, the compound is from Table 1, or a pharma- ceutically acceptable stereoisomer, tautomer, or salt thereof.

[0162] [Table 1]

[0163] [Table 2]

[0164] [Table 3]

[0165] [Table 4]

[0166] [Table 5]

[0167] 3. Combination

[0177] Considering the mechanism of Cbl-b, a particularly effective combination for treating cancer includes a Cbl-b inhibitor and a second anti-cancer agent that enhances the effector function of immune cells. In certain embodiments, the second anti-cancer agent mediates its effect through T cells or natural killer (NK) cells, and is further preferred in combination with a Cbl-B inhibitor. In certain embodiments, the combination is synergistic.

[0168]

[0178] In certain embodiments, the second anticancer agent is a checkpoint inhibitor. Checkpoint inhibitors include compounds that block immune checkpoints, which are signal transduction pathways that inhibit the activation of immune cells, such as T cells, NK cells, or macrophages. Most well-known checkpoint inhibitors are binding antagonists to T cell targets. Examples of T cell checkpoint inhibitors include CTLA-4 axis antagonists, LAG3 binding antagonists, PD-1 axis antagonists, TIGIT binding antagonists, TIM3 binding antagonists, and VISTA binding antagonists. Examples of macrophage checkpoint inhibitors are CD47 binding antagonists.

[0169]

[0179] In certain embodiments, the second anticancer agent is a PARP inhibitor (PARPi).PARP inhibitors include compounds that repair DNA when DNA is damaged.For example, PARP-based therapy works by inhibiting single-strand DNA repair, causing genomic instability, increasing tumor mutation load, releasing neoantigens, and enhancing PD-L1 expression, which makes tumors more responsive to immunotherapy.

[0170]

[0180] In certain embodiments, the second anticancer agent is a taxane. Taxanes include compounds that arrest mitosis through interference with microtubules. For example, the antitumor activity of certain chemotherapeutic agents, such as taxanes, is currently believed to involve the induction of immunogenic cell death of cancer cells, which leads to the presentation of novel tumor-specific antigens and adaptive T cell responses [Miura et al. (2014) J Nippon Med Sch. 81: 211-220; Lau et al. (2020) Cancer Immunol Res. 8: 1099-111]. For example, paclitaxel-induced antitumor activity has also been shown to promote the infiltration and activation of NK cells in the tumor microenvironment [Garafolo et al. (2021) Front. Oncol. 11: 1-19].

[0171]

[0181] In certain embodiments, the second anti-cancer agent is an agent that induces antibody-dependent cellular cytotoxicity (ADCC). ADCC, also called antibody-dependent cell-mediated cytotoxicity, is a process in which immune effector cells bind to antibodies on target cells, thereby lysing the target cells. In certain embodiments, the second anti-cancer agent induces NK cell-mediated ADCC. Examples of ADCC inducers include anti-CD20 binding antagonists and HER2 binding antagonists. In certain embodiments, the ADCC inducer is rituximab. In certain embodiments, the ADCC inducer is ofatumumab. In certain embodiments, the ADCC inducer is trastuzumab.

[0172]

[0182] Provided herein is a Cbl-b inhibitory compound for use in combination with a second anti-cancer agent.Generally, the Cbl-b inhibitory compound and the second anti-cancer agent are administered according to their respective doses and schedules.Thus, in certain embodiments, the Cbl-b inhibitory compound is administered at a dose and schedule that is deemed useful by those skilled in the art.In certain embodiments, the second anti-cancer agent is administered at a dose and schedule that is deemed useful by those skilled in the art.In certain embodiments, the second anti-cancer agent is administered according to the instructions on its label.

[0173]

[0183] In certain embodiments, the amount of the Cbl-b inhibitory compound is a therapeutically effective amount. In certain embodiments, the amount of the second anti-cancer agent is a therapeutically effective amount. In certain embodiments, the amount of the Cbl-b inhibitory compound is a therapeutically effective amount and the amount of the second anti-cancer agent is a therapeutically effective amount. In certain embodiments, the amount of the Cbl-b inhibitory compound is sub-therapeutic. In certain embodiments, the amount of the second anti-cancer agent is sub-therapeutic. In certain embodiments, the amount of the Cbl-b inhibitory compound is sub-therapeutic and the amount of the second anti-cancer agent is sub-therapeutic. In certain sub-therapeutic embodiments, the combination is therapeutic even if one or more components are at a sub-therapeutic dose.

[0174]

[0184] In certain embodiments, the Cbl-b inhibitory compound and the second anti-cancer agent are administered consecutively in any order. As used herein, the terms "consecutively," "sequentially," and "sequentially" refer to administration of the Cbl-b inhibitory compound after the second anti-cancer agent, or administration of the second anti-cancer agent after the Cbl-b inhibitory compound. For example, the sequential administration may include administration of the Cbl-b inhibitory compound in the absence of the second anti-cancer agent during an induction phase (primary therapy), followed by a post-induction treatment phase including administration of the second anti-cancer agent. The method may further include a maintenance phase including administration of the Cbl-b inhibitory compound or the second anti-cancer agent, or both. Alternatively, the sequential administration may include administration of the second anti-cancer agent in the absence of the Cbl-b inhibitory compound during an induction phase (primary therapy), followed by a post-induction treatment phase including administration of the Cbl-b inhibitory compound. The method may further include a maintenance phase comprising administration of a Cbl-b inhibitor compound, or a second anti-cancer agent, or both.

[0175]

[0185] In certain embodiments, the Cbl-b inhibitory compound and the second anti-cancer agent are administered simultaneously. As used herein, the terms "concurrently", "simultaneously" and "concurrently" refer to the administration of the Cbl-b inhibitory compound and the second anti-cancer agent during the same visit or during the same treatment phase. For example, both the Cbl-b inhibitory compound and the second anti-cancer agent can be administered during one or more of the induction phase, treatment phase and maintenance phase. However, simultaneous administration does not require that the Cbl-b inhibitory compound and the second anti-cancer agent be present together in a single formulation or pharmaceutical composition, or that the Cbl-b inhibitory compound and the second anti-cancer agent be administered at exactly the same time.

[0176]

[0186] In certain embodiments, the combinations provided herein can be administered directly to an individual to treat the individual's cancer.

[0177]

[0187] In certain embodiments, provided herein are methods of treating cancer comprising administering to an individual an effective amount of a combination provided herein to treat cancer in the individual, in certain embodiments, the individual has cancer, such as a hematological or non-hematological cancer described herein.

[0178]

[0188] In certain embodiments, provided herein is a method of treating a cancer that responds to inhibition of Cbl-b activity, comprising administering to an individual an effective amount of a combination provided herein to treat the cancer that responds to inhibition of Cbl-b activity. In certain embodiments, the cancer is a hematological or non-hematological cancer, such as those described herein.

[0179]

[0189] In certain embodiments, provided herein is a method of treating a cancer responsive to checkpoint inhibition comprising administering to an individual an effective amount of a combination provided herein to treat the cancer responsive to checkpoint inhibition, in certain embodiments, the cancer is a hematological or non-hematological cancer, such as those described herein.

[0180]

[0190] In certain embodiments, provided herein is a method of treating a cancer responsive to PARP inhibition, comprising administering to an individual an effective amount of a combination provided herein to treat the cancer responsive to PARP inhibition. In certain embodiments, the cancer is a hematological or non-hematological cancer, such as those described herein.

[0181]

[0191] In certain embodiments, provided herein is a method of treating a taxane-responsive cancer comprising administering to an individual an effective amount of a combination provided herein to treat the taxane-responsive cancer, in certain embodiments, the cancer is a hematological or non-hematological cancer, such as those described herein.

[0182]

[0192] In certain embodiments, provided herein are methods of treating a cancer that is unresponsive to checkpoint inhibition alone, comprising administering to such an individual an effective amount of a combination provided herein to treat the cancer that is unresponsive to checkpoint inhibition, in certain embodiments, the cancer is a hematological or non-hematological cancer, such as those described herein.

[0183]

[0193] The Cbl-b inhibitory compound or composition thereof is suitably administered to an individual at one time or over a series of treatments. In certain embodiments, the treatment includes multiple administrations of the Cbl-b inhibitory compound or composition, where the interval between administrations can vary. For example, the interval between the first administration and the second administration is about 1 month, and the interval between subsequent administrations is about 3 months. In certain embodiments, the Cbl-b inhibitory compound is administered in a flat dose. In certain embodiments, the Cbl-b inhibitory compound described herein is administered to an individual in a fixed dose based on the individual's body weight (e.g., mg / kg).

[0184]

[0194] The second anti-cancer agent or composition thereof is suitably administered to the individual at one time or over a series of treatments. In certain embodiments, the treatment includes multiple administrations of the second anti-cancer agent or composition, where the interval between administrations can vary. For example, the interval between the first administration and the second administration is about 1 month, and the interval between subsequent administrations is about 3 months. In certain embodiments, the second anti-cancer agent is administered at a fixed dose. In certain embodiments, the second anti-cancer agent is administered to the individual at a fixed dose based on the individual's body weight (e.g., mg / kg).

[0185]

[0195] In certain embodiments of the present disclosure, the cancer is a hematological cancer. For example, the hematological cancer may be lymphoma, leukemia, or myeloma. In other aspects of the present disclosure, the cancer is a non-hematological cancer. In particular, the non-hematological cancer may be carcinoma, sarcoma, or melanoma.

[0186]

[0196] In certain embodiments, the effectiveness of the combinations in the methods herein (e.g., methods of modulating an immune response in an individual) can be assessed by measuring the biological activity of immune cells present in a sample (e.g., a blood sample) isolated from the treated individual. For example, the ability of immune cells isolated from an individual after treatment with a combination provided herein to destroy target cells in a cytotoxicity assay can be measured to assess treatment effectiveness. In certain embodiments, the biological activity of immune cells present in a sample (e.g., a blood sample) can be measured by assaying the expression and / or secretion of certain cytokines, such as IL-2 and IFNγ.

[0187] 4. Second anticancer drug

[0197] In certain embodiments, the second anti-cancer agent is a checkpoint inhibitor. In certain embodiments, the second anti-cancer agent is an agent that induces NK cell-mediated antibody-dependent cellular cytotoxicity (ADCC). In certain embodiments, the second anti-cancer agent is a PARP inhibitor. In certain embodiments, the second anti-cancer agent is a taxane.

[0188]

[0198] In certain embodiments, the second anti-cancer agent is a T-cell checkpoint inhibitor. In certain embodiments, the second anti-cancer agent is a CTLA-4 axis antagonist. In certain embodiments, the second anti-cancer agent is a CTLA-4 binding antagonist. Useful CTLA-4 antagonists include ipilimumab. In certain embodiments, the second anti-cancer agent is a LAG3 axis antagonist. In certain embodiments, the second anti-cancer agent is a LAG3 binding antagonist. Useful LAG3 antagonists include relatlimab (Bristol Meyers) and fianlimab (Regeneron). In certain embodiments, the second anti-cancer agent is a PD-1 axis antagonist. In certain embodiments, the second anti-cancer agent is a PD-1 binding antagonist. Useful PD-1 antagonists are described below. In certain embodiments, the second anti-cancer agent is a TIGIT axis antagonist. In certain embodiments, the second anti-cancer agent is a TIGIT binding antagonist. Useful TIGIT antagonists include BMS-986207 (Bristol Meyers). In certain embodiments, the second anti-cancer agent is a TIM3 axis antagonist. In certain embodiments, the second anti-cancer agent is a TIM3 binding antagonist. Useful TIGIT antagonists include BMS-986258 (Bristol Meyers). In certain embodiments, the second anti-cancer agent is a VISTA axis antagonist. In certain embodiments, the second anti-cancer agent is a VISTA binding antagonist.

[0189]

[0199] In certain embodiments, the second anti-cancer agent is a macrophage checkpoint inhibitor. In certain embodiments, the second anti-cancer agent is a CD47 axis antagonist. In certain embodiments, the second anti-cancer agent is a CD47 binding antagonist. Useful CD47 antagonists include CC-90002 (Celgene).

[0190]

[0200] In certain embodiments, the second anti-cancer agent is an agent that induces NK-mediated ADCC. In certain embodiments, the second anti-cancer agent is a HER2 inhibitor. In certain embodiments, the second anti-cancer agent is a HER2 axis antagonist. In certain embodiments, the second anti-cancer agent is a HER2 binding antagonist. Useful HER2 antagonists include neratinib, trastuzumab, dacomitinib, lapatinib, tucatinib, pertuzumab, margetuximab, ado-trastuzumab emtansine, and fam-trastuzumab deruxtecan. In certain embodiments, the second anti-cancer agent is a CD20 inhibitor. In certain embodiments, the second anti-cancer agent is a CD20 axis antagonist. In certain embodiments, the second anti-cancer agent is a CD20 binding antagonist. Useful CD20 antagonists include ocrelizumab, rituximab, ofatumumab, and ibritumomab.

[0191]

[0201] In certain embodiments, the second anticancer agent is a PARP inhibitor selected from the group consisting of olaparib, talazoparib, and niraparib.

[0192]

[0202] In certain embodiments, the second anticancer agent is a taxane selected from the group consisting of paclitaxel and docetaxel.

[0193]

[0203] In the combinations provided herein, the PD-1 axis antagonist can be any PD-1 axis antagonist known to one of skill in the art. In certain embodiments, the PD-1 axis antagonist is a small molecule. In certain embodiments, the PD-1 axis antagonist is an antibody. In certain embodiments, the PD-1 axis antagonist binds to PD-1. In certain embodiments, the PD-1 axis antagonist binds to PD-L1. In certain embodiments, the PD-1 axis antagonist binds to PD-L2. In certain embodiments, the PD-1 axis antagonist inhibits PD-1 activity. In certain embodiments, the PD-1 axis antagonist inhibits PD-L1 activity. In certain embodiments, the PD-1 axis antagonist inhibits PD-L2 activity.

[0194]

[0204] In certain embodiments, a PD-1 binding antagonist is a molecule that inhibits the binding of PD-1 to its ligand binding partner. In certain embodiments, the PD-1 ligand binding partner is PD-L1 and / or PD-L2. In another embodiment, a PD-L1 binding antagonist is a molecule that inhibits the binding of PD-L1 to its binding partner. In certain embodiments, the PD-L1 binding partner is PD-1 and / or CD80. In another embodiment, a PD-L2 binding antagonist is a molecule that inhibits the binding of PD-L2 to its binding partner. In certain embodiments, the PD-L2 binding partner is PD-1. The antagonist may be an antibody, antigen-binding fragment thereof, immunoadhesin, fusion protein, or oligopeptide.

[0195]

[0205] In certain embodiments, the PD-1 binding antagonist is an anti-PD-1 antibody (e.g., a human antibody, a humanized antibody, or a chimeric antibody). In certain embodiments, the anti-PD-1 antibody is a monoclonal antibody. In certain embodiments, the anti-PD-1 antibody is an antibody fragment selected from the group consisting of Fab, Fab'-SH, Fv, scFv, and (Fab')2 fragments. The anti-PD-1 antibody may be a human antibody, a humanized antibody, or a chimeric antibody and may comprise a human constant region. In certain embodiments, the anti-PD-1 antibody is a humanized antibody. In certain embodiments, the anti-PD-L antibody is a human antibody. In certain embodiments, the human constant region is selected from the group consisting of IgG1, IgG2, IgG3, and IgG4 constant regions, and in certain embodiments, the human constant region is an IgG1 or IgG4 constant region.

[0196]

[0206] Examples of monoclonal antibodies that bind to human PD-1 are described in U.S. Patent Nos. 7,488,802, 7,521,051, 8,008,449, 8,354,509, and 8,168,757, and WO 2004 / 004771, WO 2004 / 072286, WO 2004 / 056875, and U.S. Patent Application Publication No. 2011 / 0271358. Specific anti-human PD-1 monoclonal antibodies include pembrolizumab (also known as MK-3475), a humanized IgG4 mAb with a structure described in WHO Drug Information, Vol. 27, No. 2, pages 161-162 (2013); nivolumab (BMS-936558), a human IgG4 mAb with a structure described in WHO Drug Information, Vol. 27, No. 1, pages 68-69 (2013); humanized antibodies h409A11, h409A16, and h409A17 described in WO 2008 / 156712, and AMP-514, which is under development by MedImmune.

[0197]

[0207] In certain embodiments, the anti-PD-1 antibody is selected from the group consisting of MDX-1106 (nivolumab), MK-3475 (lambrolizumab), and CT-011 (pidilizumab). MDX-1106, also known as MDX-1106-04, ONO-4538, BMS-936558, or nivolumab, is an anti-PD-1 antibody described in WO 2006 / 121168. MK-3475, also known as lambrolizumab, is an anti-PD-1 antibody described in WO 2009 / 114335. CT-011, also known as hBAT, hBAT-1, or pidilizumab, is an anti-PD-1 antibody described in WO 2009 / 101611.

[0198]

[0208] In certain embodiments, the PD-1 axis binding antagonist is an anti-PD-L1 antibody. In certain embodiments, the anti-PD-L1 antibody can inhibit the binding between PD-L1 and PD-1 and / or the binding between PD-L1 and CD80. In certain embodiments, the anti-PD-L1 antibody is an antibody fragment selected from the group consisting of Fab, Fab'-SH, Fv, scFv, and (Fab')2 fragments. The anti-PD-L1 antibody may be a human antibody, a humanized antibody, or a chimeric antibody and may comprise a human constant region. In certain embodiments, the anti-PD-L1 antibody is a humanized antibody. In certain embodiments, the anti-PD-L1 antibody is a human antibody. In certain embodiments, the human constant region is selected from the group consisting of IgG1, IgG2, IgG3, and IgG4 constant regions, and in certain embodiments, the human constant region is an IgG1 or IgG4 constant region.

[0199]

[0209] Examples of monoclonal antibodies that bind to human PD-L1 are described in WO 2013 / 019906, WO 2010 / 077634A1, and U.S. Patent No. 8,383,796. Particular anti-human PD-L1 monoclonal antibodies useful as PD-1 antagonists in the treatment methods, medicaments, and uses of the present disclosure include MPDL3280A, BMS-936559, MEDI4736, MSB0010718C, and antibodies comprising the heavy and light chain variable regions of SEQ ID NO:24 and SEQ ID NO:21, respectively, of WO 2013 / 019906. In certain embodiments, the anti-PD-L1 antibody is atezolizumab. In certain embodiments, the anti-PD-L1 antibody is avelumab. In certain embodiments, the anti-PD-L1 antibody is durvalumab. In certain embodiments, the anti-PD-L1 antibody is selected from the group consisting of YW243.55.570, MPDL3280A, MDX-1105, and MED14736. Antibody YW243.55.570 is an anti-PD-L1 antibody described in WO 2010 / 077634. ​​MDX-1105, also known as BMS-936559, is an anti-PD-L1 antibody described in WO 2007 / 005874. MED14736 is an anti-PD-L1 monoclonal antibody described in WO 2011 / 066389 and US Patent Application Publication No. 2013 / 034559.

[0200]

[0210] In certain embodiments, the PD-1 axis binding antagonist is an anti-PD-L2 antibody. In certain embodiments, the anti-PD-L2 antibody is capable of inhibiting the binding between PD-L2 and PD-1. In certain embodiments, the anti-PD-L2 antibody is a monoclonal antibody. In certain embodiments, the anti-PD-L2 antibody is an antibody fragment selected from the group consisting of Fab, Fab'-SH, Fv, scFv, and (Fab')2 fragments. The anti-PD-L2 antibody may be a human antibody, a humanized antibody, or a chimeric antibody and may comprise a human constant region. In certain embodiments, the anti-PD-L2 antibody is a humanized antibody. In certain embodiments, the anti-PD-L2 antibody is a human antibody. In certain embodiments, the human constant region is selected from the group consisting of IgG1, IgG2, IgG3, and IgG4 constant regions, and in certain embodiments, the human constant region is an IgG1 or IgG4 constant region.

[0201]

[0211] Other useful PD-1 axis antagonists include immunoadhesins, e.g., fusion proteins that contain the extracellular or PD-1-binding portion of PD-L1 or PD-L2 fused to a constant region, such as the Fc region, of an immunoglobulin molecule, that specifically bind to PD-1 or PD-L1 or PD-L2, and in certain embodiments, specifically bind to human PD-1 or human PD-L1 or human PD-L2. Examples of immunoadhesion molecules that specifically bind to PD-1 are described in WO 2010 / 027827 and WO 2011 / 066342. Particular fusion proteins useful as PD-1 axis antagonists include AMP-224 (also known as B7-DCIg), which is a PD-L2-FC fusion protein and binds to human PD-1.

[0202]

[0212] In certain embodiments, the PD-1 axis antagonist is selected from the group consisting of CA-170, BMS-8, BMS-202, BMS-936558, CK-301, and AUNP12. In certain embodiments, the PD-1 axis antagonist is selected from the group consisting of avelumab, nivolumab, pembrolizumab, atezolizumab, durvalumab, AMP-224 (GlaxoSmithKline), MEDI0680 / AMP-514 (AstraZeneca), PDR001 (Novartis), cemiplimab, TSR-042 (Tesaro), Tizlelizumab / BGB-A317 (Beigene), CK-301 (Checkpoint Therapeutics), BMS-936559 (Bristol-Meyers Squibb), camrelizumab, sintilimab, toripalimab, genolimu- zumab, and A167 (Sichuan Kelun-Biotech Biopharmaceutical). In certain embodiments, the PD-1 axis antagonist is MGA012 (Incyte / MacroGenics), PF-06801591 (Pfizer / Merck KGaA), LY3300054 (Eli Lilly), FAZ053 (Novartis), PD-11 (Novartis), CX-072 (CytomX), BGB-A333 (Beigene), BI754091 (Boehringer Ingelheim), JNJ-63723283 (Johnson and Johnson / Jannsen), AGEN2034(Agenus), CA-327(Agenus), CX-188(CytomX), STI-A1110(Servier), JTX-4014(Jounce), (LLY)AM0001(Armo Biosciences), CBT-502(CBT Pharmaceuticals), FS118 (F-Star / Merck KGaA), XmAb20717 (Xencor), XmAb23104 (Xencor), AB122 (Arcus Biosciences), KY1003 (Kymab), and RXI-762 (RXi).In certain embodiments, the PD-1 axis antagonist is selected from the group consisting of PRS-332 (Pieris Pharmaceuticals), ALPN-202 (Alpine Immune Science), TSR-075 (Tesaro / Anaptys Bio), MCLA-145 (Merus), MGD013 (Macrogenics), and MGD019 (Macrogenics). In certain embodiments, the PD-1 axis antagonist is selected from anti-PD1 monospecific or bispecific antibodies described, for example, in WO 2016 / 077397, WO 2018 / 156777, and International Application No. PCT / US2013 / 034213, filed May 23, 2018.

[0203]

[0213] In certain embodiments, the PD-1 axis antagonist is selected from the group consisting of pembrolizumab (MK-3475 or lambrolizumab, Keytruda; Merck); nivolumab (Opdivo; Bristol-Myers Squibb); and cemiplimab (Libtayo; Regeneron). In certain embodiments, the PD-1 axis antagonist is selected from the group consisting of JTX-4014 (Jounce Therapeutics); spartalizumab (PDR001; Novartis); camrelizumab (SHR1210; Jiangsu HengRui Medicine Co., Ltd); sintilimab (IBI308; Innovent and Eli Lilly); tislelizumab (BGB-A317; Novartis); toripalimab (JS001; Coherus); dostallimab (TSR-042, WBP-285; GlaxoSmithKline); INCMGA00012 (MGA012; Incyte and MacroGenics); AMP-224 (AstraZeneca / MedImmune and GlaxoSmithKline); and AMP-514 (MEDI0680; AstraZeneca). In certain embodiments, the PD-1 axis antagonist is pembrolizumab. In certain embodiments, the PD-1 axis antagonist is nivolumab. In certain embodiments, the PD-1 axis antagonist is cemiplimab.

[0204]

[0214] In certain embodiments, the PD-1 axis antagonist is selected from the group consisting of atezolizumab (Tecentriq; Roche Genentech); avelumab (Bavencio; Merck Serono and Pfizer); and durvalumab (Imfinzi; AstraZeneca). In certain embodiments, the PD-1 axis antagonist is selected from the group consisting of embafolimab (KN035; TRACON); CK-301 (Checkpoint Therapeutics); AUNP12 (Aurigene and Laboratoires Pierre Fabre); CA-170 (Aurigene and Curis); and BMS-986189 (Bristol-Myers Squibb). In certain embodiments, the PD-1 axis antagonist is atezolizumab. In certain embodiments, the PD-1 axis antagonist is avelumab. In certain embodiments, the PD-1 axis antagonist is durvalumab.

[0205] 5. Pharmaceutical Compositions and Methods of Administration

[0215] The Cbl-b inhibitory compounds and second agents provided herein can be formulated into pharmaceutical compositions using methods available in the art and disclosed herein. In certain embodiments, the Cbl-b inhibitory compounds are formulated in pharmaceutical compositions comprising the compounds and one or more pharma- ceutically acceptable carriers, diluents, or excipients. In certain embodiments, the PD-1 axis antagonists are formulated according to formulations known in the art for inhibitors. In certain embodiments, the Cbl-b inhibitory compounds are formulated in pharmaceutical compositions suitable for oral administration. In certain embodiments, the PD-1 axis antagonists are formulated in pharmaceutical compositions suitable for parenteral administration. It is not expected that the Cbl-b inhibitory compounds and the PD-1 axis antagonists will be formulated in the same composition, but this embodiment is not excluded from the description herein.

[0206]

[0216] The methods provided herein include administering a pharmaceutical composition comprising a Cbl-b compound or a PD-1 axis antagonist and one or more compatible pharma- ceutically acceptable carriers. In this context, the term "pharmaceutical acceptable" means approved by a federal or state regulatory agency or listed in the United States Pharmacopeia or other generally recognized pharmacopoeias for use in animals, more particularly in humans. The term "carrier" includes a diluent, adjuvant (e.g., Freund's adjuvant (complete and incomplete)), excipient, or vehicle with which a therapeutic agent is administered. Such pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, and the like. Water can be used as a carrier when the pharmaceutical composition is administered intravenously. Saline solutions and aqueous dextrose and glycerol solutions can also be utilized as liquid carriers, particularly for injectable solutions. Examples of suitable pharmaceutical carriers are described in Martin, EW, Remington's Pharmaceutical Sciences.

[0207]

[0217] In clinical practice, the pharmaceutical compositions provided herein can be administered by any route known in the art. Examples of administration routes include, but are not limited to, oral, intravenous, inhalation, intraarterial, intradermal, intramuscular, intraperitoneal, intravenous, nasal, parenteral, pulmonary, and subcutaneous routes. In certain embodiments, the pharmaceutical compositions provided herein are administered parenterally.

[0208]

[0218] The composition for parenteral administration may be an emulsion or a sterile solution. The parenteral composition may contain, for example, propylene glycol, polyethylene glycol, vegetable oils, and injectable organic esters (e.g., ethyl oleate). These compositions may also contain wetting agents, isotonicity agents, emulsifying agents, dispersing agents, and stabilizing agents. Sterilization may be carried out in several ways, such as by using a bacteriological filter, by irradiation or by heat. The parenteral composition may also be prepared in the form of a sterile solid composition that can be dissolved at the time of use in sterile water or any other injectable sterile medium.

[0209]

[0219] In certain embodiments, the compositions provided herein are pharmaceutical compositions or single unit dosage forms. The pharmaceutical compositions and single unit dosage forms provided herein comprise a prophylactically or therapeutically effective amount of one or more prophylactic or therapeutic agents.

[0210]

[0220] The pharmaceutical composition may include one or more pharmaceutical excipients. Any suitable pharmaceutical excipient may be used, and one of ordinary skill in the art can select a suitable pharmaceutical excipient. Non-limiting examples of suitable excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, nonfat dry milk, glycerol, propylene, glycol, water, ethanol, and the like. Whether a particular excipient is suitable for incorporation into a pharmaceutical composition or dosage form depends on a variety of factors well known in the art, including, but not limited to, the manner in which the dosage form is administered to a subject and the particular antibody in the dosage form. The composition or single unit dosage form can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents, if desired. Thus, the pharmaceutical excipients provided herein are intended to be exemplary and not limiting. Additional pharmaceutical excipients include, for example, those described in Handbook of Pharmaceutical Excipients, Rowe et al. (Eds.) 6th Ed. (2009), which is incorporated by reference in its entirety.

[0211]

[0221] In certain embodiments, the pharmaceutical composition includes an antifoaming agent. Any suitable antifoaming agent may be used. In certain embodiments, the antifoaming agent is selected from alcohols, ethers, oils, waxes, silicones, surfactants, and combinations thereof. In certain embodiments, the antifoaming agent is selected from mineral oils, vegetable oils, ethylene bisstearic acid amide, paraffin wax, ester wax, fatty alcohol wax, long chain fatty alcohols, fatty acid soaps, fatty acid esters, silicone glycols, fluorosilicones, polyethylene glycol-polypropylene glycol copolymers, polydimethylsiloxane-silicon dioxide, ethers, octyl alcohol, capryl alcohol, sorbitan trioleate, ethyl alcohol, 2-ethylhexanol, dimethicone, oleyl alcohol, simethicone, and combinations thereof.

[0212]

[0222] In certain embodiments, the pharmaceutical composition comprises a co-solvent. Illustrative co-solvents include ethanol, poly(ethylene) glycol, butylene glycol, dimethylacetamide, glycerin, and propylene glycol.

[0213]

[0223] In certain embodiments, the pharmaceutical composition comprises a buffering agent, examples of which include acetate, borate, carbonate, lactate, malate, phosphate, citrate, hydroxide, diethanolamine, monoethanolamine, glycine, methionine, guar gum, and monosodium glutamate.

[0214]

[0224] In certain embodiments, the pharmaceutical composition comprises a carrier or filler. Illustrative examples of carriers or fillers include lactose, maltodextrin, mannitol, sorbitol, chitosan, stearic acid, xanthan gum, and guar gum.

[0215]

[0225] In certain embodiments, the pharmaceutical composition comprises a surfactant.Examples of surfactants include d-alpha tocopherol, benzalkonium chloride, benzethonium chloride, cetrimide, cetylpyridinium chloride, sodium docusate, glyceryl behenate, glyceryl monooleate, lauric acid, macrogol 15 hydroxystearate, myristyl alcohol, phospholipids, polyoxyethylene alkyl ether, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene stearate, polyoxylglyceride, sodium lauryl sulfate, sorbitan ester, and vitamin E polyethylene (glycol) succinate.

[0216]

[0226] In certain embodiments, the pharmaceutical composition comprises an anti-caking agent. Illustrative examples of anti-caking agents include calcium phosphate (tribasic), hydroxymethylcellulose, hydroxypropylcellulose, and magnesium oxide.

[0217]

[0227] Other excipients that may be used with the pharmaceutical composition include, for example, albumin, antioxidants, antibacterial agents, antifungal agents, bioabsorbable polymers, chelating agents, controlled release agents, diluents, dispersants, solubility enhancers, emulsifiers, gelling agents, ointment bases, penetration enhancers, preservatives, solubilizers, solvents, stabilizers, and sugars.Specific examples of each of these agents are described, for example, in Handbook of Pharmaceutical Excipients, Rowe et al.(Eds.) 6th Ed.(2009), The Pharmaceutical Press, the entire contents of which are incorporated herein by reference.

[0218]

[0228] In certain embodiments, the pharmaceutical composition includes a solvent. In certain embodiments, the solvent is a saline solution, such as sterile isotonic saline, or a glucose solution. In certain embodiments, the solvent is water for injection.

[0219]

[0229] In certain embodiments, the pharmaceutical composition is in the form of a particle, such as a microparticle or nanoparticle. The microparticles and nanoparticles can be formed from any suitable material, such as a polymer or lipid. In certain embodiments, the microparticle or nanoparticle is a micelle, liposome, or polymersome.

[0220]

[0230] Further provided herein, in certain embodiments, are anhydrous pharmaceutical compositions and dosage forms comprising a therapeutic agent, since water can facilitate the degradation of some antibodies.

[0221]

[0231] Anhydrous pharmaceutical compositions and dosage forms provided herein can be prepared using anhydrous or low moisture containing ingredients and low moisture or low humidity conditions. Pharmaceutical compositions and dosage forms that contain lactose and at least one active ingredient that contains a primary or secondary amine can be anhydrous if substantial contact with moisture and / or humidity during manufacturing, packaging, and / or storage is expected.

[0222]

[0232] Anhydrous pharmaceutical compositions can be prepared and stored in such a way that their anhydrous nature is maintained.Therefore, anhydrous compositions can be packaged using materials known to prevent exposure to water, so that they can be included in suitable formulation kits.Examples of suitable packaging include, but are not limited to, hermetically sealed foils, plastics, unit dose containers (e.g., vials), blister packs, and strip packs.

[0223]

[0233] The lactose-free compositions provided herein may include excipients that are well known in the art and are listed, for example, in the United States Pharmacopoeia (USP) SP (XXI) / NF (XVI). In general, lactose-free compositions include active ingredients, binders / fillers, and lubricants in pharma- ceutically compatible and pharma-ceutically acceptable amounts. Lactose-free dosage forms include active ingredients, microcrystalline cellulose, pregelatinized starch, and magnesium stearate.

[0224]

[0234] Also provided are pharmaceutical compositions and dosage forms that contain one or more excipients that reduce the rate at which the antibody or antibody conjugate will decompose. Such excipients, which are referred to herein as "stabilizers," include, but are not limited to, antioxidants such as ascorbic acid, pH buffers, or salt buffers.

[0225]

[0235] In human therapy, the physician will determine the dosage and administration which he considers most appropriate depending on the prophylactic or therapeutic treatment, and on the age, weight, condition and other specific factors of the subject to be treated.

[0226]

[0236] In certain embodiments, the compositions provided herein are pharmaceutical compositions or single unit dosage forms. The pharmaceutical compositions and single unit dosage forms provided herein comprise a prophylactically or therapeutically effective amount of one or more prophylactic or therapeutic antibodies.

[0227]

[0237] The amount of Cbl-b compound or composition and PD-1 axis antagonist or composition effective for preventing or treating a disorder or one or more symptoms thereof varies depending on the nature and severity of the disease or condition, and the route by which the agent is administered. The frequency and dosage also vary depending on factors specific to each subject, depending on the particular therapy (e.g., therapeutic or prophylactic agent) administered, the severity of the disorder, disease, or condition, the route of administration, and the age, weight, body weight, response, and past medical history of the subject. Effective doses may be extrapolated from dose-response curves derived from in vitro or animal model test systems.

[0228]

[0238] In certain embodiments, exemplary doses of the compositions include milligram or microgram amounts of antibody per kilogram of subject or sample body weight (e.g., from about 10 micrograms per kilogram to about 50 milligrams per kilogram, from about 100 micrograms per kilogram to about 25 milligrams per kilogram, or from about 100 micrograms per kilogram to about 10 milligrams per kilogram).

[0229]

[0239] In certain embodiments, the dosage of a Cbl-b compound provided herein administered to prevent, treat, manage, or ameliorate a disorder or one or more symptoms thereof in a subject is greater than 0.1 mg / kg, 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 10 mg / kg, or 15 mg / kg of the subject's body weight based on the weight of the compound. In another embodiment, the dosage of the Cbl-b compound is from 0.1 mg to 1000 mg, 0.1 mg to 900 mg, 0.1 mg to 800 mg, 0.1 mg to 750 mg, 0.1 mg to 700 mg, 0.1 mg to 600 mg, 0.1 mg to 500 mg, 0.1 mg to 400 mg, 0.1 mg to 300 mg, 0.1 mg to 250 mg, 0.1 mg to 200 mg, 0.1 mg to 200 mg, 0.1 mg to 100 mg, 0.1 mg to 50 mg, 0.1 mg to 25 mg, 0.1 mg to 20 mg, 0.1 mg to 15 mg, 0.1 mg to 10 mg, 0.1 mg to 7.5 mg, 0.1 mg to 800 mg, 0.1 mg to 900 mg, 0.1 mg to 100 mg, 0.1 mg to 25 mg, 0.1 mg to 20 mg, 0.1 mg to 15 mg, 0.1 mg to 10 mg, 0.1 mg to 7.5 mg, 0.1 mg to 800 mg, 0.1 mg to 100 mg, 0.1 mg to 150 mg, 0.1 mg to 800 mg, 0.1 mg to 100 mg, 0.1 mg to 150 mg, 0.1 mg to 1 ... .1mg to 5mg, 0.1mg to 2.5mg, 0.25mg to 20mg, 0.25mg to 15mg, 0.25mg to 12mg, 0.25mg to 10mg, 0.25mg to 7.5mg, 0.25mg to 5mg, 0.25mg to 2.5mg, 0.5mg to 20mg, 0.5 to 15mg, 0.5mg to 12mg, 0.5mg to 10mg, 0.5mg to 7.5mg, 0.5mg to 5mg, 0.5mg to 2.5mg, 1mg to 20mg, 1mg to 15mg, 1mg to 12mg, 1mg to 10mg, 1mg to 7.5mg, 1mg to 5mg, or 1mg to 2.5mg.

[0230]

[0240] In certain embodiments, the dosage of the PD-1 axis antagonist is in accordance with the product label or other instructions. In certain embodiments, the dosage of the PD-1 axis antagonist administered to prevent, treat, manage, or ameliorate a disorder or one or more symptoms thereof in a subject is greater than 0.1 mg / kg, 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 10 mg / kg, or 15 mg / kg of the subject's body weight, based on weight of the antagonist. In another embodiment, the dosage of the PD-1 axis antagonist is from 0.1 mg to 1000 mg, 0.1 mg to 900 mg, 0.1 mg to 800 mg, 0.1 mg to 750 mg, 0.1 mg to 700 mg, 0.1 mg to 600 mg, 0.1 mg to 500 mg, 0.1 mg to 400 mg, 0.1 mg to 300 mg, 0.1 mg to 250 mg, 0.1 mg to 200 mg, 0.1 mg to 200 mg, 0.1 mg to 100 mg, 0.1 mg to 50 mg, 0.1 mg to 25 mg, 0.1 mg to 20 mg, 0.1 mg to 15 mg, 0.1 mg to 10 mg, 0.1 mg to 7.5 mg, 0.1mg to 5mg, 0.1mg to 2.5mg, 0.25mg to 20mg, 0.25mg to 15mg, 0.25mg to 12mg, 0.25mg to 10mg, 0.25mg to 7.5mg, 0.25mg to 5mg, 0.25mg to 2.5mg, 0.5mg to 20mg, 0.5mg to 15mg, 0.5mg to 12mg, 0.5mg to 10mg, 0.5mg to 7.5mg, 0.5mg to 5mg, 0.5mg to 2.5mg, 1mg to 20mg, 1mg to 15mg, 1mg to 12mg, 1mg to 10mg, 1mg to 7.5mg, 1mg to 5mg, or 1mg to 2.5mg.

[0231]

[0241] The dose of any drug can be administered according to a suitable schedule, for example, once, twice, three times or four times a week.As will be clear to those skilled in the art, in some cases, it may be necessary to use the dose of drug outside the range disclosed herein.Furthermore, it should be noted that the clinician or treating physician will know when and how to interrupt, adjust or terminate treatment depending on the subject's response.

[0232]

[0242] As those skilled in the art will readily know, different therapeutically effective amounts may be applicable to different diseases and conditions.Similarly, amounts sufficient to prevent, manage, treat or improve such disorders, but insufficient to cause or reduce the adverse effects associated with the agents provided herein, are also encompassed by the dosage and frequency of administration schedules described herein.Furthermore, when a subject is administered multiple doses of the compositions provided herein, not all doses need to be the same.For example, the dosage administered to a subject may be increased to improve the preventive or therapeutic effect of the composition, or may be decreased to reduce one or more side effects experienced by a particular subject.

[0233]

[0243] In certain embodiments, treatment or prophylaxis may be initiated with one or more loading doses of the agents provided herein, followed by one or more maintenance doses.

[0234]

[0244] In certain embodiments, doses of agents provided herein can be administered to achieve a steady state concentration of the antibody in the blood or serum of the subject. The steady state concentration can be determined by measurement according to techniques available to those of skill in the art, or can be determined based on the subject's physical characteristics, such as height, weight, and age.

[0235]

[0245] In certain embodiments, repeated administrations of the same composition may occur at intervals of at least 1 day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days, 2 months, 75 days, 3 months, or 6 months. In other embodiments, repeated administrations of the same prophylactic or therapeutic agent may occur at intervals of at least 1 day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days, 2 months, 75 days, 3 months, or 6 months.

[0236] 6.Therapeutic uses

[0246] The combinations provided herein may be useful for treating any disease or condition involving abnormal cell growth or proliferation. In certain embodiments, the disease or condition is a disease or condition that may benefit from treatment with a Cbl-b inhibitory compound or a PD-1 axis antagonist, or both. In certain embodiments, the disease or condition is cancer. In certain embodiments, the disease or condition is a solid tumor. In certain embodiments, the disease or condition is a hematological cancer.

[0237]

[0247] Any suitable cancer may be treated with the combinations provided herein. Examples of suitable cancers include, for example, acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), adrenocortical carcinoma, anal cancer, appendix cancer, astrocytoma, basal cell carcinoma, brain tumor, bile duct cancer, bladder cancer, bone cancer, breast cancer (including triple negative breast cancer, or TNBC), bronchial tumor, cancer of unknown primary, cardiac tumor, cervical cancer, chordoma, colon cancer, colorectal cancer, craniopharyngioma, ductal carcinoma, germinoma, endometrial cancer, ependymoma, esophageal cancer, nasal neuroblastoma, fallopian tube cancer, fibrous histiocytoma, Ewing's sarcoma, eye cancer, germ cell tumor, gallbladder cancer, gastric cancer, cancer), gastric / gastroesophageal junction (GEJ) cancer, gastrointestinal carcinoid tumors, gastrointestinal stromal tumors, gestational trophoblastic disease, glioma, head and neck cancer, hepatocellular carcinoma, histiocytosis, Hodgkin lymphoma, diffuse large B-cell lymphoma including Richter transformation (RT), hypopharyngeal cancer, intraocular melanoma, pancreatic islet cell tumors, Kaposi's sarcoma, kidney cancer, Langerhans cell histiocytosis, laryngeal cancer, lip and oral cavity cancer, liver cancer, lobular carcinoma in situ, lung cancer, lymphoma, macroglobulinemia, malignant fibrous histiocytoma, melanoma, metastatic melanoma, Merkel cell carcinoma, mesothelioma, malignant pleural mesothelioma (MPM), metastatic squamous neck cancer of unknown primary, head and neck squamous cell carcinoma (HNSCC), midline tract carcinoma involving NUT gene gene), oral cancer, multiple endocrine neoplasia syndrome, multiple myeloma, mycosis fungoides, myelodysplastic syndrome, myelodysplastic / myeloproliferative neoplasms, cancer of the nasal cavity and paranasal sinuses, nasopharyngeal carcinoma, neuroblastoma, non-small cell lung cancer, oropharyngeal cancer, osteosarcoma, ovarian cancer, platinum-resistant epithelial ovarian cancer (EOC), pancreatic cancer, papillomatosis, paraganglioma, parathyroid cancer, penile cancer, pharyngeal cancer, pheochromocytoma, pituitary tumor, pleuropulmonary blastoma, primary central nervous system lymphoma, primary peritoneal cancer, prostate cancer, metastatic castration-resistant prostate cancer (mCRPC), rectal cancer, renal cell carcinoma, cancer of the renal pelvis and ureter, retinoblastoma, rhabdoid tumor, salivary gland cancer, Sézary syndrome, skin cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, spinal cord tumor, gastric cancer These include T-cell lymphoma, teratoma, testicular cancer, laryngeal cancer, thymoma and thymic carcinoma, thyroid cancer, urethral cancer, uterine cancer, vaginal cancer, vulvar cancer, urothelial carcinoma, muscle invasive urothelial carcinoma, and Wilms' tumor.

[0238]

[0248] In certain embodiments, the disease treated with the combinations provided herein is gastric cancer, colorectal cancer, renal cell carcinoma, cervical cancer, non-small cell lung cancer, ovarian cancer, uterine cancer, fallopian tube cancer, primary peritoneal cancer, uterine cancer, endometrial cancer, prostate cancer, breast cancer, head and neck cancer, brain cancer, liver cancer, pancreatic cancer, mesothelioma, and / or cancer of epithelial origin. In certain embodiments, the disease is colorectal cancer. In certain embodiments, the disease is ovarian cancer. In certain embodiments, the disease is breast cancer. In certain embodiments, the disease is triple negative breast cancer (TNBC). In certain embodiments, the disease is lung cancer. In certain embodiments, the disease is non-small cell lung cancer (NSCLC). In certain embodiments, the disease is head and neck cancer. In certain embodiments, the disease is renal cell carcinoma. In certain embodiments, the disease is brain cancer. In certain embodiments, the disease is endometrial cancer.

[0239] 7. Kit

[0249] In certain embodiments, the compounds or combinations provided herein are provided in the form of a kit, i.e., a packaged combination of predetermined amounts of reagents with instructions for carrying out the procedure. In other embodiments, the procedure is a therapeutic procedure. In certain embodiments, the kit comprises a Cbl-b inhibitory compound or composition thereof, and instructions for use in combination with a PD-1 axis antagonist. In certain embodiments, the kit comprises a PD-1 axis antagonist or composition thereof, and instructions for use in combination with a Cbl-b inhibitory compound. In certain embodiments, the kit comprises a Cbl-b inhibitory compound or composition thereof, and a PD-1 axis antagonist or composition thereof. EXAMPLES

[0240] Working Example Example 1

[0250] This example provides assays and results for treating tumor models in vivo with single agent Cbl-b compounds described herein.

[0241]

[0251] The effect of compound 23 on total primary human T cells was evaluated as shown in Figure 1. Cells were stimulated with plate-bound anti-CD3 (right) or anti-CD3 / anti-CD28 (left) in the presence or absence of the indicated concentrations of compound 23. IL-2 or IFN-γ release was assessed by ELISA. Inhibition of Cbl-b by compound 23 enhanced IL-2 and IFN-γ secretion in primary human T cells stimulated with anti-CD3 antibody both in the presence and absence of CD28 costimulation, but to a lesser extent in the absence of costimulation.

[0242]

[0252] The effect of compound 23 on CT26 tumor volume in a mouse model was evaluated, as shown in Figure 2. Mice bearing tumors on the left and right flank were treated with oral compound 23 at 10 mg / kg (blue circles) or 30 mg / kg (red circles), or vehicle (black squares), from day 7 to day 32. Volumes on day 25 are shown. Statistics were calculated by one-way ANOVA and Dunn's multiple comparison test **P≦0.01.

[0243]

[0253] Another in vivo study evaluated the ability of compound 23 treatment initiated prior to primary tumor resection to eradicate 4T1 breast cancer metastatic disease. 4T1 triple-negative breast cancer is a transplantable tumor cell line that is highly tumorigenic and invasive and, unlike most tumor models, spontaneously metastasizes from the primary tumor growing in the mammary gland to multiple distant sites, including lymph nodes, blood, liver, lung, brain, and bone. Tumor cells readily engraft into the mammary gland and grow at sites anatomically related to the primary tumor. The progressive spread of 4T1 metastases to other organs is very similar to that of human breast cancer. Animals die from disseminated metastatic disease despite resection of the primary tumor (Pulaski et al., 2000, Current Protocols in Immunology 39(1):20.2.1-20.2.16). As shown in Figure 3, mice bearing 4T1 tumors in the fourth mammary fat pad in the flank were treated from days 8 to 46 by daily oral administration of either vehicle (0.5% methylcellulose, 0.2% polysorbate 80 + 1 equivalent of HCl in deionized water) or compound 23 at 30 mg / kg daily. Primary tumors were excised on days 14 and 15, yielding a mean tumor volume of 145 mm. 3 Tumor volumes were measured twice weekly from day 7 until a median survival of 100% was reached (dotted line). Median survival for each group was calculated and body weight was monitored until the end of the study at day 140. Body weight was measured twice weekly and once weekly from day 47. Figure 3 shows the survival percentage over time up to day 140. Statistical significance of the difference in conditional survival between groups was assessed using the log-rank (Mantel-Cox) test. Significance was reported as not significant (ns). P>0.05, *P≦0.05, **P≦0.01, ***P≦0.001, and ****P≦0.0001. Treatment with compound 23 administered orally at 30 mg / kg significantly increased median survival compared to vehicle control. Median survival for the compound 23 group was >50% survival at day 140 and is reported as indeterminate. Importantly, 54% of mice treated with compound 23 remained tumor-free at the end of the study, suggesting that compound 23 can significantly extend survival in a model of metastatic disease.

[0244]

[0254] As shown in these experiments, in vivo oral administration of compound 23 in mice demonstrated significant antitumor activity in a colon cancer tumor model, CT26, and a metastatic triple-negative breast cancer model, 4T1.

[0245] Example 2

[0255] In this example, gene expression changes induced in tumors from mice treated in a study with Compound 23 were investigated. To perform this evaluation, the nCounter PanCancer Immune Profiling Panel was used. This is a multiplex gene expression panel developed by NanoString Technologies that measures the expression of 770 immune and cancer-related genes (Eastel et al., 2019, Expert Review of Molecular Diagnostics, 19(7):591-598). This technology is a unique gene expression tool that covers many key features of the immune response in the tumor microenvironment and was used to facilitate understanding of immune-related changes in tumors treated with Compound 23.

[0246]

[0256] In Figure 4A, CT26 tumors were harvested after 4 and 19 doses of compound 23 or vehicle and gene expression was measured directly using the nCounter Mouse PanCancer Immune Profiling Panel. Analysis was performed using nSolver 4.0 and nCounter Advanced Analysis software to compare gene expression in compound 23 to vehicle-treated tumors. Figure 4A (top row) shows the scores of individual TILs, T cells, and cytotoxic cells between vehicle-treated and compound 23-treated groups after 4 doses. Figure 4A (bottom row) shows the scores of individual TILs, T cells, and cytotoxic cells between vehicle-treated and compound 23-treated groups after 19 doses. Statistical significance of the difference in mean cell type scores between compound 23 and vehicle-treated groups was assessed using the Mann-Whitney test (*P ≤ 0.05, **P ≤ 0.01, and ***P ≤ 0.001).

[0247]

[0257] In Figure 4B, CT26 tumors were harvested after four treatment doses and gene expression was measured directly using the nCounter Mouse PanCancer Immune Profiling Panel. Analysis was performed using nSolver 4.0 and nCounter Advanced Analysis software to compare gene expression in compound 23 to vehicle-treated tumors. Scatter plots of individual Pathway Signature Scores for vehicle- and compound 23-treated tumors are shown as indicated in the caption above each panel. Statistical significance of differences in Pathway Signature Scores between compound 23 and vehicle-treated groups was assessed using the Mann-Whitney test (*P ≤ 0.05, **P ≤ 0.01, and ***P ≤ 0.001).

[0248]

[0258] In Figure 4C, CT26 tumors were harvested after 19 treatment doses and gene expression was measured directly using the nCounter Mouse PanCancer Immune Profiling Panel. Analysis was performed using nSolver 4.0 and nCounter Advanced Analysis software to compare gene expression in compound 23 to vehicle-treated tumors. Scatter plots of individual pathway signature scores for vehicle- and compound 23-treated tumors are shown as indicated in the caption above each panel. Statistical significance of differences in pathway signature scores between compound 23 and vehicle-treated groups was assessed using the Mann-Whitney test (*P ≤ 0.05, **P ≤ 0.01, and ***P ≤ 0.001).

[0249]

[0259] The immune status of tumors from mice treated with compound 23 was significantly altered compared to tumors from vehicle-treated mice. After four doses, single-agent oral compound 23 administered daily at 30 mg / kg produced a clear trend toward increased infiltration of tumor-infiltrating lymphocytes (TILs) (P=0.6679), T cells (P=0.7551), and cytotoxic cells (P=0.1061) (Figure 4A). After 19 doses of oral compound 23, TILs (P=0.0044), T cells (P=0.0098), and cytotoxic cells (P=0.0002) infiltration was significantly increased in CT26 tumors compared to vehicle-treated animals (Figure 4B).

[0250]

[0260] After four doses of compound 23, tumors showed significant gene expression changes in pathways related to innate immune signaling, including dendritic cell and macrophage function and chemokine receptors and pathways (Figure 4C). There was a trend toward increased T cell, B cell, NK cell, and adaptive immune function, but these changes were not significant. However, after 19 doses, CT26 tumors treated with compound 23 showed significant enhancement of function in immune-related pathway scores, including dendritic cell function, macrophage function, T cell function, NK cell function, B cell function, and those related to interferon function, adaptive immunity, chemokine and receptor responses, and cytokine and receptor signature responses (Figure 4C). Overall, these data demonstrate that compound 23 induces antitumor activity in the CT26 syngeneic tumor model and enhances both the intratumoral density and function of immune cells.

[0251]

[0261] As shown in Figure 5, mice bearing CT26 tumors on the left and right flanks were treated with oral compound 23 at 30 mg / kg, PO QD from days 9 to 25 in the presence of depleting antibodies against CD4+ cells, CD8+ cells, or NK cells (anti-asialo GM1). Tumor volumes on day 25 are shown. Compound 23 activity is lost upon depletion of CD8+ T cells or NK cells. Statistics were calculated by Mann-Whitney (vehicle vs. compound 23) or one-way ANOVA with Dunn's multiple comparison test (compound 23 vs. depleted group); (*P ≤ 0.05, **P ≤ 0.01, ****P ≤ 0.0001). Compound 23 efficacy against tumors is in terms of CD8+ T function and NK cell function.

[0252] Example 3

[0262] This example provides assays and results for treating tumor models in vivo with a combination of Cbl-b compounds and anti-PD1 antibodies described herein. The antibody is a murine anti-PD1 RMP1-14 antibody, which is useful in mouse in vivo assays as a model for administration of human PD-1 axis antagonists for the treatment of human cancers.

[0253]

[0263] Figure 6 provides results in three tumor models. In the CT26 model, mice bearing CT26 tumors on the left and right flanks were treated from day 10 to day 33 by administering either vehicle (0.5% methylcellulose, 0.2% polysorbate 80 + 1 equivalent of HCl in deionized water) daily, orally (PO) compound 23 daily at 30 mg / kg, PO; anti-PD-1 antibody at 10 mg / kg twice weekly intraperitoneally (IP) injection; or a combination of compound 23 daily at 30 mg / kg, PO, and anti-PD-1 antibody at 10 mg / kg twice weekly IP injection. Beginning at day 10, tumor volumes were measured twice weekly. In Figure 6 (CT26), the graph on the left shows group mean tumor volumes ± SEM from days 10 to 24. The statistical significance of the differences in mean tumor volumes between groups was assessed from day 10 to day 24 using repeated measures two-way ANOVA with Dunnett's multiple comparison test (not significant (ns) P>0.05, *P≦0.05, **P≦0.01, ***P≦0.001, and ****P≦0.0001). In Figure 6 (CT26), the graph on the right shows the mean tumor volumes of 2000 mm2 or ... 3 The percentage of animals that were surviving from days 10 to 80, as defined by reaching the conditional survival endpoint of bearing a tumor with a volume of ≥ 100 mg / kg / day, is shown.

[0254]

[0264] In the results reported in Figure 6 (CT26), single agent compound 23 administered orally at 30 mg / kg demonstrated antitumor activity in the CT26 syngeneic tumor model, with a significant reduction in tumor volume, a TGI of 62% compared to vehicle control, and a median survival of 38 days compared to 27 days for controls. Anti-PD-1 administered at 10 mg / kg was less effective than compound 23, with a TGI of 47% and a median survival of 34 days. However, the combination of compound 23 administered in conjunction with anti-PD-1 provided the most potent antitumor activity, with a TGI of 88% and a median survival of 77.5 days. 50% of mice treated with the combination were tumor-free at the end of the study. Thus, treatment with compound 23 significantly reduced tumor growth and synergized with PD-1 antibody blockade, resulting in established tumor rejection.

[0255]

[0265] In the MC38 model, mice bearing MC38 tumors on the left and right flanks were treated from days 10 to 29 by administering either vehicle (0.5% methylcellulose, 0.2% polysorbate 80 + 1 equivalent of HCl in deionized water) daily, orally (PO) compound 23 daily at 30 mg / kg, PO; anti-PD-1 antibody at 10 mg / kg twice weekly intraperitoneally (IP) injections; or a combination of compound 23 daily at 30 mg / kg, PO, and anti-PD-1 antibody at 10 mg / kg twice weekly IP injections. Beginning on day 10, tumor volumes were measured twice weekly. In Figure 6 (MC38), the graph on the left shows group mean tumor volumes ± SEM from days 10 to 24. Statistical significance of differences in mean tumor volumes between groups was assessed from days 7 to 23 using repeated measures two-way ANOVA with Dunnett's multiple comparison test (not significant (ns) P>0.05, *P≦0.05, **P≦0.01, ***P≦0.001, and ****P≦0.0001). In Figure 6 (MC38), the graph on the right shows the percentage of animals that were surviving from days 7 to 56, defined by reaching the conditional survival endpoint of bearing a tumor with a volume of 2000 mm3 or greater, unless a humane endpoint had been met previously.

[0256]

[0266] In the results reported in Figure 6 (MC38), single agent Compound 23 demonstrated antitumor activity, resulting in significantly smaller primary tumors compared to the vehicle control group. Single agent anti-PD-1 also significantly reduced the size of primary tumors compared to the vehicle control group. The combination of Compound 23 and anti-PD-1 therapy provided potent antitumor activity, resulting in a significant reduction in primary tumor volume compared to either vehicle control or treatment with single agent Compound 23 or single agent anti-PD-1. The combination therapy showed a significant improvement in primary tumor volume compared to vehicle control or treatment with single agent Compound 23 or single agent anti-PD-1 (Figure 6, MC38). Thus, treatment with Compound 23 significantly reduced tumor growth and synergized with PD-1 antibody blockade, resulting in established tumor rejection and reduced tumor burden.

[0257]

[0267] In the 4T1 model, mice bearing orthotopic 4T1 tumors in the fourth mammary fat pad on the left flank were treated from days 9 to 28 by administering either vehicle control (0.5% methylcellulose, 0.2% polysorbate 80 + 1 equivalent HCl in deionized water) daily PO; compound 23 at 30 mg / kg daily PO; anti-PD-1 blocking antibody at 10 mg / kg injected IP twice weekly; or a combination of compound 23 at 30 mg / kg daily PO and anti-PD-1 antibody at 10 mg / kg injected IP twice weekly. Beginning on day 9, tumor volumes and body weights were measured twice weekly. In Figure 6 (4T1), the graph on the left shows group mean tumor volumes ± SEM from days 9 to 28. The statistical significance of the differences in mean tumor volumes between groups was assessed from day 9 to day 28 using a mixed effects model and Dunnett's multiple comparison test (brackets or lines between groups summarize statistical significance: not significant (ns) P>0.05, *P≦0.05, **P≦0.01, ***P≦0.001, and ****P≦0.0001). In Figure 6 (4T1), the graph on the right shows the number of 4T1 metastatic tumor cell colonies measured in lungs from the four treatment groups harvested on day 28, with group medians indicated by bars. The statistical significance of the differences in colony numbers between groups was assessed using a Kruskal-Wallis one-way ANOVA with Dunn's multiple comparison test.

[0258]

[0268] In the experiment shown in Figure 6 (4T1), single-agent compound 23 demonstrated antitumor activity, resulting in significantly smaller primary tumors and reduced metastatic lung tumor burden compared to the vehicle control group. Single-agent anti-PD-1 also significantly reduced the size of primary tumors and reduced metastatic lung tumor burden compared to the vehicle control group. The combination of compound 23 and anti-PD-1 therapy provided potent antitumor activity, resulting in significant reductions in primary tumor volume and metastatic lung tumor burden compared to either vehicle control or treatment with single-agent compound 23 or single-agent anti-PD-1. Furthermore, combination therapy resulted in complete regression of primary tumors in 16% of mice, and no metastatic colonies were detected in the lungs in 47% of mice. Combination therapy demonstrated significant improvements in primary tumor volume and metastatic lung tumor burden compared to vehicle control or treatment with single-agent compound 23 or single-agent anti-PD-1 (Figure 6, 4T1). Thus, treatment with compound 23 significantly reduces tumor growth and synergizes with PD-1 antibody blockade, resulting in rejection of established tumors and reduction in metastatic tumor burden.

[0259] Example 4

[0269] This example provides assays and results for the effect of Cbl-b compound treatment on immune cell phenotype in mouse tumor models and the correlation of treatment effect with immune cell levels.

[0260]

[0270] In FIG. 7, mice bearing orthotopic 4T1 tumors in the fourth mammary fat pad on the left flank were treated from days 9 to 28 with either vehicle control (0.5% methylcellulose, 0.2% polysorbate 80 + 1 equivalent HCl in deionized water) administered PO daily; compound 23 at 30 mg / kg PO daily; tumor and blood samples were taken on day 28 and analyzed by flow cytometry.

[0261]

[0271] Figure 7A shows that compound 23 increased the frequency of tumor gp70 antigen-specific CD8+ T cells (AH1 dextramer+ CD8+ T cells) in 4T1 tumors from treated mice. Figure 7B shows that compound 23 decreased the frequency of tumor gp70 antigen-specific CD8+ T cells (AH1 dextramer+ CD8+ T cells) with exhaustion phenotype (PD-1+ LAG3+) in 4T1 tumors from treated mice. Figure 7C shows that compound 23 increased the frequency of circulating CD8+ T cells with activation phenotype (PD-1+) in the blood of treated 4T1 tumor-bearing mice. Figure 7D shows that compound 23 increased the frequency of circulating CD8+ T cells with memory phenotype (CD44+ CD27+ CD127+) in the blood of treated 4T1 tumor-bearing mice.

[0262]

[0272] In Figure 8, mice bearing CT26 tumors on the left and right flank were treated from days 10 to 28 with either vehicle (0.5% methylcellulose, 0.2% polysorbate 80 + 1 equivalent of HCl in deionized water) administered daily or oral (PO) compound 23 at 30 mg / kg administered daily. CT26 tumors were harvested after 19 doses of compound 23 or vehicle and tumor-infiltrating immune cell density and phenotype were assessed by flow cytometry.

[0263]

[0273] Figure 8A shows that compound 23 increased the number of tumor infiltrating leukocytes (TILs) per gram of tumor in CT26 tumors from treated mice. Figure 8B shows that compound 23 increased the frequency of total CD3+ T cells as a percentage of CD45+ leukocytes in CT26 tumors from treated mice. Figures 8C and 8D show that compound 23 increased the frequency of total CD8+ T cells as a percentage of CD45+ leukocytes and the number of total CD8+ T cells per gram of tumor in CT26 tumors from treated mice. Figure 8E shows that compound 23 increased the frequency of CD8+ T cells expressing the activation marker CD29 (CD29+) in CT26 tumors from treated mice. Figures 8F and 8G show that compound 23 increased the ratio of CD8+ T cells to Tregs and the ratio of CD8+ effector T cells (identified as PD1+) to Tregs in CT26 tumors from treated mice. Figures 8H and 8I show that compound 23 increased the frequency of tumor-infiltrating NK cells with a cytotoxic phenotype in CT26 tumors from treated mice. Figure 8H shows the frequency of granzyme+-expressing activated NK cells (CD11b+), and Figure 8I shows the frequency of granzyme+-expressing activated NK cells (CD27+CD11b+) in CT26 tumors from mice treated with compound 23.

[0264]

[0274] In Figure 9, mice bearing CT26 tumors on the left and right flanks were treated from day 10 to day 28 by administering either vehicle (0.5% methylcellulose, 0.2% polysorbate 80 + 1 equivalent HCl in deionized water) daily or oral (PO) compound 23 at 30 mg / kg daily. CT26 tumors were harvested after 19 doses of compound 23 or vehicle, and the frequency and phenotype of immune cells in the blood were evaluated by flow cytometry. Spearman correlation test was applied to calculate the correlation between the levels of circulating immune cells and tumor volume at day 28.

[0265]

[0275] Tumor regression in response to compound 23 treatment was strongly correlated with increased frequencies of total circulating T cells (Figure 9A) and NK cells (Figure 9B) in the blood of treated CT26 tumor-bearing mice. A similar positive correlation was observed between tumor volume and the frequency of circulating CD8+ T cells (Figure 9C) and activated CD8+ T cells expressing the activation markers CD44 (Figure 9D) and CD29 (Figure 9E). In contrast, increased tumor growth inhibition correlated with decreased levels of circulating myeloid cells characterized by expression of the CD11b marker (Figure 9F).

[0266] Example 5

[0276] This example provides assays and results for treating tumor models in vivo using combinations of Cbl-b compounds and checkpoint inhibitors described herein.Two illustrative checkpoint inhibitors include anti-CTLA binding antagonists and anti-LAG3 binding antagonists.

[0267]

[0277] Mice bearing CT26 tumors on the left and right flanks were treated from days 14 to 40 by administering either vehicle (0.5% methylcellulose, 0.2% polysorbate 80 + 1 equivalent of HCl in deionized water) daily, orally (PO) compound 23 daily at 30 mg / kg, PO; anti-CTLA-4 antibody at 10 mg / kg (day 14) and 5 mg / kg (days 18, 26, 33) intraperitoneally (IP) injection; or a combination of compound 23 and anti-CTLA-4 antibody. Beginning on day 14, tumor volumes were measured twice weekly. Figure 10A shows group mean tumor volumes ± SEM from days 14 to 40. The statistical significance of the differences in mean tumor volumes between groups was assessed from day 14 to day 40 using a repeated measures two-way ANOVA with Dunnett's multiple comparison test (not significant (ns) P>0.05, *P≦0.05, **P≦0.01, ***P≦0.001, and ****P≦0.0001). Figure 10B shows that mice were treated with 2000 mm 3 The percentage of animals surviving from days 14 to 106, as defined by reaching the conditional survival endpoint of bearing a tumor with a volume of ≥ 100 mg / kg / day, is shown.

[0268]

[0278] Mice bearing CT26 tumors on the left and right flanks were treated from days 12 to 30 by administering either vehicle (0.5% methylcellulose, 0.2% polysorbate 80 + 1 equivalent of HCl in deionized water) daily, oral (PO) compound 23 daily at 30 mg / kg, PO; anti-LAG3 antibody at 10 mg / kg intraperitoneally (IP) on days 12, 15, 20, 24, and 27; or a combination of compound 23 and anti-LAG3 antibody. Beginning on day 12, tumor volumes were measured twice weekly. Figure 11A shows group mean tumor volumes ± SEM from days 12 to 30. The statistical significance of the differences in mean tumor volumes between groups was assessed from day 10 to day 30 using a repeated measures two-way ANOVA with Dunnett's multiple comparison test (not significant (ns) P>0.05, *P≦0.05, **P≦0.01, ***P≦0.001, and ****P≦0.0001). Figure 11B shows that mice were treated with 2000 mm 3 The percentage of animals surviving from days 12 to 65, as defined by reaching the conditional survival endpoint of bearing a tumor with a volume of ≥ 100 mg / kg / day, is shown.

[0269] Example 6

[0279] This example provides assays and results for treating tumor models in vivo with a combination of Cbl-b compounds and macrophage checkpoint inhibitors.

[0270]

[0280] Mice bearing A20 tumors in the flank were treated by administering either vehicle (0.5% methylcellulose, 0.2% polysorbate 80 + 1 equivalent of HCl in deionized water) daily, compound 23 at 30 mg / kg daily, PO; anti-CD47 antibody intraperitoneally (IP) injection; or a combination of compound 23 and anti-CD47 antibody. Tumor volumes were measured twice weekly. Statistical significance of differences in mean tumor volumes between groups was assessed using a repeated measures two-way ANOVA with Dunnett's multiple comparison test (not significant (ns) P>0.05, *P≦0.05, **P≦0.01, ***P≦0.001, and ****P≦0.0001). The percentage of animals surviving between the relevant time points was calculated using 2000 mm 3 The survival endpoint is defined as reaching a conditional survival endpoint of bearing a tumor having a volume of ≥ 1.

[0271] Example 7

[0281] This example provides assays and results for treating tumor models in vivo with a combination of Cbl-b compounds and ADCC inducers.

[0272]

[0282] Female CB17 mice with severe combined immunodeficiency (SCID) were injected intravenously (IV) with Raji cells into the tail vein on day 0 and treated from day 5 to day 37 by administering either vehicle (0.5% methylcellulose, 0.2% polysorbate 80 + 1 equivalent HCl in deionized water) orally (PO) daily, or compound 23 at 30 mg / kg, PO daily. Anti-CD20 antibody (rituximab) at 20 mg / kg was administered intraperitoneally (IP) PO on days 5, 10, and 15, either alone or in combination with compound 23 at 30 mg / kg daily. In SCID-Beige mice, Raji tumors have a primary tropism for bone marrow, and untreated mice reliably develop hind limb paralysis within 3 to 5 weeks as a result of spinal cord compression by tumors spreading from the vertebral bodies. Mice that developed hind leg paralysis over time were sacrificed, and the percentage of animals surviving from days 5 to 58 was plotted, and the results are shown in Figure 12A. The survival rate of mice treated with compound 23 alone or rituximab alone was significantly higher than that of untreated mice (p<0.0001), but was significantly lower than that of mice treated with the combination of compound 23 and rituximab (p<0.0001).

[0273]

[0283] Female CB17 mice with severe combined immunodeficiency (SCID) were injected intravenously (IV) with Raji cells into the tail vein on day 0 and treated from day 5 to day 37 by administering either vehicle (0.5% methylcellulose, 0.2% polysorbate 80 + 1 equivalent of HCl in deionized water) daily orally (PO); Compound 23 at 30 mg / kg daily, PO; or a combination of Compound 23 at 30 mg / kg daily, PO, and Rituximab at 20 mg / kg IP injection on days 5, 10, and 15. Three additional groups of mice were treated in the presence of a depleting antibody against NK cells (anti-asialo GM1).

[0274]

[0284] In SCID-Beige mice, Raji tumors have a primary tropism for bone marrow, and untreated mice steadily develop hind limb paralysis in 3-5 weeks as a result of spinal cord compression by tumors spreading from the vertebral bodies. Mice that developed hind limb paralysis over time were sacrificed, and the percentage of animals surviving from days 5 to 58 was plotted and shown in Figure 12B. As shown, depletion of NK cells resulted in loss of activity of compound 23 (p<0.0001) and partial loss of activity of the combination of compound 23 and rituximab (p<0.0001).

[0275] Example 8

[0285] This example provides assays and results for treating in vitro tumor models with a combination of Cbl-b compounds and PARP inhibitors.

[0276]

[0286] BT549 (BRCA wild type) (A) and DoTc4510 (BRCA2 mutated) (B) cells were seeded in duplicate at 5,000 cells / well in tissue culture treated, black sided, clear bottom 96 well plates and allowed to adhere and settle for 24 hours. Cells were treated with the indicated concentrations of DMSO, Compound 23, or Olaparib (Figures 13A and 13B), alone or in combination, and labeled with 1X Essen Bioscience IncuCyte® Caspase-3 / 7 Green Reagent (final concentration 5 μM). Treated plates were imaged every 2 hours for 72 hours with an IncuCyte® S3 Live-Cell Analysis System. At each time point, one image was taken per well in both the bright field and FITC channels of the IncuCyte® S3 Live-Cell Analysis System. Imaging was performed using IncuCyte S3 v2017A software. 2 The images were analyzed for the number of green objects per hit.

[0277]

[0287] Using the caspase 3 / 7 apoptosis Incucyte® assay, the effects of compound 23, PARPi, and the combination of compound 23 and PARPi on tumor cell apoptosis were evaluated in vitro in both BRCA wild-type and mutant tumor cell lines. BT549 tumor cells (BRCA wild-type) treated with 1 μM compound 23 or 0.05 μM olaparib alone did not undergo a significant increase in apoptosis compared to 0.05% DMSO control. However, a significant increase in the number of tumor cells undergoing apoptosis in response to the combination of compound 23 and olaparib was observed compared to either DMSO control (p<0.0001), compound 23 alone (p<0.0001), or olaparib alone (p<0.0001) (Figure 13A).

[0278]

[0288] Treatment of DoTc4510 tumor cells (uterine tissue with mutant BRCA2) with compound 23 or olaparib alone did not significantly increase tumor cell apoptosis compared to the 0.05% DMSO control. However, a significant increase in the number of tumor cells undergoing apoptosis in response to the combination of compound 23 and olaparib was observed compared to either the DMSO control (p<0.0001), compound 23 alone (p<0.0001), or olaparib alone (p<0.0001) (Figure 13B).

[0279]

[0289] A caspase 3 / 7 tumor cell apoptosis assay was used to evaluate tumor cell apoptosis in response to either compound 23 alone or in combination with PARPi in multiple cell lines: A caspase 3 / 7 tumor cell apoptosis assay was used to evaluate tumor cell apoptosis in response to either compound 23 alone or in combination with PARPi in multiple cell lines: MCF-7 (BRCA wild type), UWB1.289 (BRCA1-deficient human ovarian cancer line), UWB1.289BRCA+ (BRCA1-deficient human ovarian cancer line in which wild type BRCA1 has been restored), HCC1937 (a cell line that synthesizes a truncated BRCA1 protein that is the product of a disease-causing mutant allele (5382insC) and does not contain the wild type protein), and DoTc4510 cell line (uterine tissue that is mutant for BRCA2). All cell lines tested showed an increase in the number of tumor cells undergoing apoptosis following combined treatment with compound 23 and PARPi compared to compound 23, PARPi, or 0.05% DMSO alone (Figure 13C).

[0280] Example 9

[0290] This example provides assays and results for treating in vitro tumor models with a combination of a Cbl-b compound and a taxane.

[0281]

[0291] BT549 cells were seeded in duplicate at 5,000 cells / well in tissue culture treated black sided, clear bottom 96 well plates and allowed to attach and settle for 24 hours. Cells were treated with DMSO, Compound 23, or paclitaxel, alone or in combination, and labeled with 1X Essen Bioscience IncuCyte® Caspase-3 / 7 Green Reagent (final concentration 5 μM). Treated plates were imaged every 2 hours for 48 hours with an IncuCyte® S3 Live-Cell Analysis System. At each time point, one image was taken per well in both the bright field and FITC channels of the IncuCyte® S3 Live-Cell Analysis System. The IncuCyte S3 v2017A software was used to image the cells in mm 2 The images were analyzed for the number of green objects per hit.

[0282]

[0292] Using the caspase 3 / 7 apoptosis Incucyte® assay, the effects of compound 23, paclitaxel, and the combination of compound 23 and paclitaxel on tumor cell apoptosis were evaluated in vitro in the BT549 tumor cell line (breast adenocarcinoma). BT549 cells treated with 0.1 μM compound 23 or 0.002 μM paclitaxel alone did not undergo a significant increase in apoptosis compared to the 0.05% DMSO control. However, a significant increase in the number of tumor cells undergoing apoptosis in response to the combination of compound 23 and paclitaxel was observed compared to either the DMSO control (p<0.0001), compound 23 alone (p<0.0001), or paclitaxel alone (p<0.0001) (Figure 14A).

[0283]

[0293] A caspase 3 / 7 tumor cell apoptosis assay was used to evaluate tumor cell apoptosis in response to compound 23 alone or in combination with paclitaxel in multiple cell lines: MCF-7 (breast adenocarcinoma), UWB1.289 (ovarian cancer), HCC1937 (peripheral blood B lymphoblasts), and DoTc4510 (cervical cancer). All cell lines tested showed an increase in the number of tumor cells undergoing apoptosis after treatment with the combination of compound 23 and paclitaxel compared to compound 23, paclitaxel, or 0.05% DMSO alone (Figure 14B).

[0284] Example 10

[0294] This example provides assays and results for treating tumors in vivo with a combination of Cbl-b compounds and anti-TIGIT antibodies.

[0285]

[0295] Mice bearing CT26 tumors on the left and right flanks were treated until day 13 post-implantation by administering either vehicle (0.5% methylcellulose, 0.2% polysorbate 80 + 1 equivalent of HCl in deionized water) daily, orally (PO) compound 23 daily at 30 mg / kg, PO; anti-TIGIT antibody at 10 mg / kg BioXcell Clone 1G9 (days 13, 16, 20, 24) intraperitoneally (IP) injection; or a combination of compound 23 and anti-TIGIT antibody. Beginning on day 13, tumor volumes were measured twice weekly. The bottom graph shows the percentage of animals that were alive at day 30, defined by reaching a conditional survival endpoint of bearing a tumor with a volume of 2000 mm3 or greater, unless a humane endpoint had been met previously. Statistical significance of differences in survival rates was calculated using the log-rank (Mantel-Cox) test (Figure 15B).

[0286] Equivalent

[0296] The above disclosure may encompass multiple separate embodiments having independent utility. Although each of these embodiments is disclosed in a specific format, many variations are possible, and therefore the specific embodiments disclosed and illustrated herein should not be considered in a limiting sense. The subject matter of the present disclosure includes all novel and non-obvious combinations and subcombinations of the various elements, features, functions, and / or properties disclosed herein. The following claims are intended to specifically point out certain combinations and subcombinations that are considered novel and non-obvious. Embodiments in other combinations and subcombinations of features, functions, elements, and / or properties may be claimed in this application, any application claiming priority to this application, or any related application. Such claims are also considered to be within the subject matter of the present disclosure, whether directed to different or the same embodiment, and whether broader, narrower, equal, or different in scope compared to the scope of the original claims.

[0287]

[0297] One or more features from any embodiment described in this specification or drawings may be combined with one or more features of any other embodiment described in this specification or drawings without departing from the scope of the disclosure.

[0288]

[0298] All publications, patents, and patent applications cited in this specification are incorporated by reference herein as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. Although the foregoing disclosure has been described in some detail by way of illustration and example for purposes of clarity of understanding, it will be readily apparent to those skilled in the art that, in light of the teachings of the present disclosure, certain changes and modifications can be made without departing from the spirit or scope of the appended claims.

Claims

1. A pharmaceutical composition for treating or preventing a disease or condition in combination with one or more checkpoint inhibitors, comprising an effective amount of a Cbl-b inhibitor compound.

2. 2. The pharmaceutical composition of claim 1, wherein the one or more checkpoint inhibitors comprise an agent that induces NK cell-mediated ADCC.

3. 2. The pharmaceutical composition of claim 1, wherein the one or more checkpoint inhibitors comprise a CTLA-4 axis antagonist, a CTLA-4 binding antagonist, a LAG3 axis antagonist, a LAG3 binding antagonist, a PD-1 axis antagonist, a PD-1 binding antagonist, a TIGIT axis antagonist, a TIGIT binding antagonist, a TIM3 binding antagonist, a TIM3 axis antagonist, a VISTA axis antagonist, a VISTA binding antagonist, a CD47 axis antagonist, a CD47 binding antagonist, a HER2 axis antagonist, or a HER2 binding antagonist.

4. 2. The pharmaceutical composition of claim 1, wherein the one or more checkpoint inhibitors comprises a HER2 binding antagonist.

5. 2. The pharmaceutical composition of claim 1, wherein the one or more checkpoint inhibitors comprises rituximab.

6. 2. The pharmaceutical composition of claim 1, wherein the one or more checkpoint inhibitors comprises ofatumumab.

7. 2. The pharmaceutical composition of claim 1, wherein the one or more checkpoint inhibitors comprises trastuzumab.

8. 4. The pharmaceutical composition of claim 3, wherein the one or more PD-1 axis antagonists comprise a small molecule blocker of the PD-1 axis.

9. The pharmaceutical composition of claim 3, wherein the one or more PD-1 axis antagonists comprise an antibody that inhibits the PD-1 axis.

10. 4. The pharmaceutical composition of claim 3, wherein the one or more PD-1 axis antagonists comprise a PD-1 binding antagonist.

11. 4. The pharmaceutical composition of claim 3, wherein the one or more PD-1 axis antagonists comprise an antibody PD-1 binding antagonist.

12. 4. The pharmaceutical composition of claim 3, wherein the antibody PD-1 binding antagonist is pembrolizumab.

13. 4. The pharmaceutical composition of claim 3, wherein the antibody PD-1 binding antagonist is nivolumab.

14. 4. The pharmaceutical composition of claim 3, wherein the antibody PD-1 binding antagonist is cemiplimab.

15. 4. The pharmaceutical composition of claim 3, wherein the one or more PD-1 axis antagonists comprises a PD-L1 binding antagonist.

16. 4. The pharmaceutical composition of claim 3, wherein the one or more PD-1 axis antagonists comprise an antibody PD-L1 binding antagonist.

17. 16. The pharmaceutical composition of claim 15, wherein the PD-L1 binding antagonist is atezolizumab.

18. 11. The pharmaceutical composition of claim 10, wherein the PD-L1 binding antagonist is avelumab.

19. 11. The pharmaceutical composition of claim 10, wherein the PD-L1 binding antagonist is durvalumab.

20. 4. The pharmaceutical composition of claim 3, wherein the one or more PD-1 axis antagonists comprises a PD-L2 binding antagonist.

21. 4. The pharmaceutical composition of claim 3, wherein the one or more PD-1 axis antagonists comprise an antibody PD-L2 binding antagonist.

22. The one or more checkpoint inhibitors are selected from the group consisting of CA-170, BMS-8, BMS-202, BMS-936558, CK-301, AUNP12, avelumab, nivolumab, pembrolizumab, atezolizumab, durvalumab, AMP-224, MEDI0680 / AMP-514, PDR001, cemprima , TSR-042, tislelizumab / BGB-A317, CK-301, BMS-936559, camrelizumab, sintilimab, toripalimab, genolimuzumab, A167, MGA012, PF-06801591, LY3300054, FAZ053, PD-11, CX-072, BGB-A333, BI 754091, JNJ-63723283, AGEN2034, CA-327, CX-188, STI-A1110, JTX-4014, (LLY)AM0001, CBT-502, FS118, XmAb20717, XmAb23104, AB122, KY1003, RXI-762, PRS-33, ALPN-202, TSR-075, MCLA-145, MGD013, and MGD019.

23. A pharmaceutical composition for treating or preventing a disease or condition in combination with one or more PARP inhibitors, comprising an effective amount of a Cbl-b inhibitor compound.

24. 24. The pharmaceutical composition of claim 23, wherein the one or more PARP inhibitors are selected from the group consisting of olaparib, talazoparib, and niraparib.

25. 24. The pharmaceutical composition of claim 23, wherein the one or more PARP inhibitors comprises olaparib.

26. 24. The pharmaceutical composition of claim 23, wherein the one or more checkpoint inhibitors comprises talazoparib.

27. 24. The pharmaceutical composition of claim 23, wherein the one or more PARP inhibitors comprises niraparib.

28. A pharmaceutical composition for treating or preventing a disease or condition in combination with one or more taxane inhibitors, comprising an effective amount of a Cbl-b inhibitor compound.

29. 29. The pharmaceutical composition of claim 28, wherein the one or more taxane inhibitors are selected from the group consisting of paclitaxel and docetaxel.

30. 29. The pharmaceutical composition of claim 28, wherein the one or more taxane inhibitors comprises paclitaxel.

31. 29. The pharmaceutical composition of claim 28, wherein the one or more taxane inhibitors comprises docetaxel.

32. The Cbl-b inhibitor compound is according to formula (I) or a pharma- ceutically acceptable stereoisomer, tautomer, salt or solvate thereof. 【Chemistry 1】 or a tautomer thereof, or a pharma- ceutically acceptable salt thereof, wherein: 【Chemistry 2】 teeth, 【Chemistry 3】 and Z １ is CH or nitrogen; Z ２ is CH or nitrogen; R １ is -CF ３ or cyclopropyl; R ２ is -CF ３ or cyclopropyl, R ３ is hydrogen, C １ -C ２ Alkyl, or C １ -C ２ haloalkyl; R ４ is hydrogen, C １ -C ６ Alkyl, C １ -C ６ haloalkyl, 4- to 8-membered heterocyclyl, or C ３ -C ６ is cycloalkyl, Here, the heterocyclyl or cycloalkyl group is one to five R ６ optionally substituted with a group; Or R ３ and R ４ together with the carbon atom to which they are attached, ３ -C ５ cycloalkyl or 4- to 6-membered heterocyclyl, each of which is represented by 1 to 5 R ６ optionally substituted with a group; R ５ is hydrogen, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, or C ３ -C ６ is cycloalkyl; Each R ６ is independently １ -C ６ Alkyl, halo, hydroxy, -O(C １ -C ６ Alkyl), -CN, C １ -C ６ Alkyl-CN,C １ -C ６ Alkyl-OH or C １ -C ６ haloalkyl; Or two R bonded to the same carbon atom ６ The groups, together with the carbon atom to which they are attached, are spiro C ３ -C ６ forming a cycloalkyl or spiro 4- to 6-membered heterocyclyl; X is hydrogen, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Alkyl-OH, C １ -C ６ Alkyl-CN, 1 to 5 R ８ C optionally substituted with a group ３ -C ６ cycloalkyl, or 【Chemistry 4】 and 【Chemistry 5】 is a 4- to 7-membered heterocyclyl or a 5- to 8-membered heteroaryl, where each heterocyclyl or heteroaryl optionally contains 1 to 2 additional heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and each heterocyclyl or heteroaryl optionally contains 1 to 5 R ８ optionally substituted with a group; Each R ７ are independently hydrogen, C １ -C ６ Alkyl, C １ -C ６ Alkyl-OH or C １ -C ６ haloalkyl; Or two R's ７ The groups, together with the carbon atom to which they are attached, are C ３ -C ５ forms a cycloalkyl or a 3- to 5-membered heterocyclyl; Each R ８ are independently halo, C １ -C ６ Alkyl, C １ -C ６ Alkyl-CN,C １ -C ６ Alkyl-OH, C １ -C ６ Haloalkyl, -CN, oxo, or -O(C １ -C ６ alkyl); Or two R's ８ Groups, together with the carbon atom or carbon atoms to which they are attached, may form spiro or fused C ３ -C ５ The pharmaceutical composition according to any one of claims 1, 23 and 28, which forms a cycloalkyl or a 3- to 5-membered heterocyclyl.

33. 33. The pharmaceutical composition of claim 32, wherein the Cbl-b inhibitor compound is selected from the compounds of Table 1, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt thereof.

34. 30. The pharmaceutical composition of any one of claims 1, 23, and 28, wherein the disease or condition is cancer.

35. 30. The pharmaceutical composition of any one of claims 1, 23, and 28, wherein the disease or condition is a solid tumor.

36. 30. The pharmaceutical composition of any one of claims 1, 23, and 28, wherein the disease or condition is a hematological cancer.

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