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CA-3136348-C - 3-SUBSTITUTED PIPERIDINE COMPOUNDS FOR CBL-B INHIBITION, AND USE OF A CBL-B INHIBITOR IN COMBINATION WITH A CANCER VACCINE AND/OR ONCOLYTIC VIRUS

CA3136348CCA 3136348 CCA3136348 CCA 3136348CCA-3136348-C

Abstract

Compounds, compositions, and methods for use in inhibiting the E3 enzyme Cbl-b in the ubiquitin proteasome pathway are disclosed. The compounds, compositions, and methods can be used to modulate the immune system, to treat diseases amenable to immune system modulation, and for treatment of cells in vivo, in vitro, or ex vivo. Also disclosed are pharmaceutical compositions comprising a Cbl-b inhibitor and a cancer vaccine, as well as methods for treating cancer using a Cbl-b inhibitor and a cancer vaccine; and pharmaceutical compositions comprising a Cbl-b inhibitor and an oncolytic virus, as well as methods for treating cancer using a Cbl-b inhibitor and an oncolytic virus.

Inventors

  • Arthur T. Sands
  • Dahlia Weiss
  • Jennifa Gosling
  • Neil F. Bence
  • Christoph W. Zapf
  • Frederick Cohen
  • Chenbo Wang
  • Thomas Cummins
  • Hiroko Tanaka
  • Hunter Shunatona
  • Mario Cardozo

Assignees

  • NURIX THERAPEUTICS, INC.

Dates

Publication Date
20260505
Application Date
20200409
Priority Date
20190409

Claims (2)

  1. CLAIMS: 1. A compound of Formula (I) (I) or a tautomer thereof, stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein X is CH or nitrogen; Z1 is CH or nitrogen; Z2 is CH or nitrogen; is or ; R1a and R1b are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 alkyl-OH; R2a is -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkyl-OH, C1-C6 alkyl-CN, or -(C1-C6 alkylene)-O-(C1-C6 alkyl); R2b is hydrogen, halo, or C1-C6 alkyl; 246 or R2a and R2b are taken together with the carbon atom to which they are attached to form a spiro 3- to 6-membered heterocyclyl or a spiro C3-C6 cycloalkyl, wherein at least one of the atoms of the spiro heterocyclyl which is adjacent to the connecting piperidinyl ring is carbon; R3a and R3b are independently hydrogen, halo, or C1-C6 alkyl; or R3a and R3b are taken together with the carbon atom to which they are attached to form C3-C4 cycloalkyl; R4 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 alkyl-OH; or is is W is oxygen or a bond; and Y is CR5aR5b or sulfur; and Y is a bond; R5a and R5b are independently hydrogen, halo, or C1-C6 alkyl; or R5a and R5b are taken together with the carbon atom to which they are attached to form a C3-C6 cycloalkyl; R6 is C1-C6 alkyl, C1-C6 haloalkyl, or C3-C6 cycloalkyl; R7 is hydrogen, halo, C3-C6 cycloalkyl, -NH-(3- to 6-membered heterocyclyl), -NH-(C1-C6 alkyl), -NH-(C3-C6 cycloalkyl), -O-(3- to 6-membered heterocyclyl), -O-(C1-C6 alkyl), or -O-(C3-C6 cycloalkyl); R8 is C1-C6 alkyl, C1-C6 haloalkyl, or C3-C6 cycloalkyl; 247 R9 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 alkyl-OH; and R10 is -CF3 or cyclopropyl.
  2. 2. The compound of claim 1, wherein wherein Z1 is CH; or wherein wherein Z1 is nitrogen; or wherein 3. is is The compound of claim 1, wherein wherein Z2 is CH; or wherein is or is or . ; or or is 248 ; or ; or ; or wherein Z2 is nitrogen; or wherein is 4. or The compound of any one of claims 1, 2, or 3, wherein Y is CR5aR5b or sulfur; or wherein W is a bond; or W is oxygen; or . wherein is and Y is a bond; or wherein R8 is C1-C3 alkyl, C1-C3 haloalkyl, or C3-C4 cycloalkyl; or wherein R8 is -CH3, -CF3, or cyclopropyl. 5. The compound of any one of claims 1-4, wherein X is CH; or X is nitrogen; and/or wherein Y is a bond; or Y is CR5aR5b; or Y is sulfur. 6. is The compound of claim 5, wherein Y is CR5aR5b and R5a and R5b are independently hydrogen, halo, or C1-C3 alkyl, or 249 and R5a and R5b are taken together with the carbon atom to which they are attached to form a C3-C4 cycloalkyl; or wherein R5a and R5b are independently hydrogen, fluorine, or -CH3; or R5a and R5b are taken together with the carbon atom to which they are attached to form cyclopropyl; or wherein R5a and R5b are independently hydrogen or fluorine. 7. The compound of any one of claims 1-6, wherein R1a and R1b are independently hydrogen, C1-C3 alkyl, C1-C3 haloalkyl, or C1-C3 alkyl-OH; or wherein R1a and R1b are independently hydrogen, -CH3, -CF3, or -CH2OH; or wherein R1b is hydrogen. 8. The compound of any one of claims 1-7, wherein R2a is -CN, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkyl-OH, C1-C3 alkyl-CN, or -(C1-C3 alkylene)-O-(C1-C3 alkyl); or wherein R2a is -CN, -CH3, -CF3, -CH2OH, -CH2CN, or -CH2-O-CH3; and/or wherein R2b is hydrogen, halo, or C1-C3 alkyl; or wherein R2b is hydrogen, fluorine, or -CH3. 9. The compound of any one of claims 1-7, wherein R2a and R2b are taken together with the carbon atom to which they are attached to form a spiro 4- to 5-membered heterocyclyl or a spiro C3-C4 cycloalkyl; or wherein R2a and R2b are taken together with the carbon atom to which they are attached to form spiro cyclopropyl, , or . 250 10. The compound of any one of claims 1-9, wherein R3a and R3b are independently hydrogen, halo, or C1-C3 alkyl; or R3a and R3b are taken together with the carbon atom to which they are attached to form C3-C4 cycloalkyl; or wherein R3a and R3b are independently hydrogen, fluorine, or -CH3; or R3a and R3b are taken together with the carbon atom to which they are attached to form cyclopropyl. 11. The compound of any one of claims 1-10, wherein R4 is hydrogen, C1-C3 alkyl, C1-C3 haloalkyl, or C1-C3 alkyl-OH; or wherein R4 is hydrogen, -CH3, -CF3, or -CH2OH; and/or wherein R6 is C1-C3 alkyl, C1-C3 haloalkyl, or C3-C4 cycloalkyl; or R6 is -CH3, -CHF2, or cyclopropyl. 12. The compound of any one of claims 1-11, wherein R7 is hydrogen, halo, C3-C4 cycloalkyl, -NH(4- to 5-membered heterocyclyl), -NH(C1-C3 alkyl), -NH(C3-C5 cycloalkyl), -O(C1-C3 alkyl), -O(4- to 5-membered heterocyclyl), or -O(C3-C5 cycloalkyl); or wherein R7 is hydrogen, chlorine, cyclopropyl, -NH(CH2CH3), -NH(cyclopropyl), -OCH2CH3, -O(cyclopropyl), , or ; and/or wherein R9 is hydrogen, C1-C3 alkyl, C1-C3 haloalkyl, or C1-C3 alkyl-OH; or wherein R9 is hydrogen, -CH3, -CF3, or -CH2OH. 13. The compound of claim 1, wherein the compound is a compound of Formula (I-a) 251 (I-a) or a tautomer thereof, stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein X is CH or nitrogen; Z1 is CH or nitrogen; Z2 is CH or nitrogen; is or ; R1a and R1b are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 alkyl-OH; R2a is -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkyl-OH, C1-C6 alkyl-CN, or -(C1-C6 alkylene)-O-(C1-C6 alkyl); R2b is hydrogen, halo, or C1-C6 alkyl; or R2a and R2b are taken together with the carbon atom to which they are attached to form a spiro 3- to 6-membered heterocyclyl or a spiro C3-C6 cycloalkyl, wherein at least one of the atoms of the spiro heterocyclyl which is adjacent to the connecting piperidinyl ring is carbon; 252 R3a and R3b are independently hydrogen, halo, or C1-C6 alkyl; or R3a and R3b are taken together with the carbon atom to which they are attached to form C3-C4 cycloalkyl; R4 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 alkyl-OH; or is is W is oxygen or a bond; and Y is CR5aR5b or sulfur; and Y is a bond; R5a and R5b are independently hydrogen, halo, or C1-C6 alkyl; or R5a and R5b are taken together with the carbon atom to which they are attached to form a C3-C6 cycloalkyl; R6 is C1-C6 alkyl, C1-C6 haloalkyl, or C3-C6 cycloalkyl; R7 is hydrogen, C3-C6 cycloalkyl, -NH-(3- to 6-membered heterocyclyl), -NH-(C1-C6 alkyl), -NH-(C3-C6 cycloalkyl), -O-(3- to 6-membered heterocyclyl), -O-(C1-C6 alkyl), or -O-(C3-C6 cycloalkyl); R8 is C1-C6 alkyl, C1-C6 haloalkyl, or C3-C6 cycloalkyl; R9 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 alkyl-OH; and R10 is -CF3 or cyclopropyl. 14. The compound of claim 1, selected from 253 254 Compound No. Structure Compound No. Structure 1 2 3 4 5 6 7 8 9 10 11 12 13 14 255 15 16 17 18 19 20 21 22 23 24 25 26 27 28 256 29 30 31 32 33 34 35 36 37 38 39 40 41 42 257 43 44 45 47 48 49 50 51 52 . 15. The compound of claim 1, selected from Compound No. Structure Compound No. Structure 47 48 49 50 51 52 . 16. A pharmaceutical composition comprising the compound of any one of claims 1-15, and a pharmaceutically acceptable excipient. 17. A method of modulating activity of an immune cell in vitro or ex vivo, the method comprising contacting the immune cell with an effective amount of a Cbl-b inhibitor to modulate activity of the immune cell, wherein the Cbl-b inhibitor is a compound of any one of claims 1 15; wherein the immune cell comprises a T-cell, a B-cell, or a natural killer (NK)-cell; or wherein the immune cell has been or is isolated from a blood sample from a mammalian subject; or wherein the immune cell is a tumor infiltrating lymphocyte (TIL) that has been or is isolated from a tumor of a mammalian subject with cancer; or wherein the immune cell comprises a T-cell, and wherein modulating activity of the T-cell comprises one or more of increased T-cell activation, increased T-cell proliferation, decreased T cell exhaustion, and decreased T-cell tolerance; or 258 wherein increased T-cell activation comprises increased production of a cytokine, and/or wherein the cytokine comprises one or more selected from the group consisting of IL-2, IFN-γ, TNFα, and GM-CSF; and/or wherein increased T-cell activation comprises increased cell surface expression of one or more T-cell activation markers, and/or wherein the T-cell activation markers comprise one or more selected from the group consisting of CD25, CD69, and CTLA4; and/or wherein the T-cell has been or is in contact with an anti-CD3 antibody alone or in combination with an anti-CD28 antibody; and/or further comprising culturing the immune cell with IL-2 alone or in combination with an anti-CD3 antibody and/or an anti-CD28 antibody; or wherein the immune cell comprises a NK-cell, and wherein modulating activity of an NK-cell comprises increased NK-cell activation; and/or wherein increased NK-cell activation comprises increased production of a cytokine; and/or wherein the cytokine comprises one or more selected from the group consisting of IFN-γ, TNFα, and MIP1β; or wherein the immune cell comprises a B-cell, and wherein modulating activity of a B-cell comprises increased B-cell activation, optionally wherein increased B-cell activation comprises increased expression of CD69; and/or wherein the immune cell is a human immune cell; and/or wherein the immune cell comprises a recombinant chimeric receptor, optionally wherein the recombinant chimeric receptor is a chimeric antigen receptor. 18. A method of producing a modified immune cell, comprising culturing a cell population containing an immune cell in the presence of an effective amount of a Cbl-b inhibitor to 259 modulate activity of the immune cell, thereby producing the modified immune cell, wherein the Cbl-b inhibitor is a compound of any one of claims 1-15. 19. The method of claim 18, further comprising culturing the immune cell with an anti-CD3 antibody alone or in combination with an anti-CD28 antibody; or further comprising culturing of the immune cell with IL-2 alone or in combination with an anti CD3 antibody and/or an anti-CD28 antibody; or further comprising recovering the modified immune cell. 20. The method of claim 18 or 19, wherein the immune cell has been or is isolated from a blood sample from a mammalian subject, or the immune cell is a tumor infiltrating lymphocyte (TIL) that has been or is isolated from a tumor of a mammalian subject with cancer; or wherein the immune cell is a cell selected from the group consisting of a hematopoietic cell, a multipotent stem cell, a myeloid progenitor cell, a lymphoid progenitor cell, a T-cell, a B-cell, and a NK-cell; or wherein the modified immune cell is a cell selected from the group consisting of a hematopoietic cell, a multipotent stem cell, a myeloid progenitor cell, a lymphoid progenitor cell, a T-cell, a B cell, and a NK-cell; or wherein the immune cell is a tumor infiltrating lymphocyte (TIL); or wherein the immune cell is a human immune cell; or wherein the immune cell or modified immune cell comprises a recombinant chimeric receptor; or wherein the recombinant chimeric receptor is a chimeric antigen receptor. 21. 22. A modified immune cell produced by the method of any one of claims 18-20. A modified immune cell comprising a Cbl-b inhibitor, wherein the Cbl-b inhibitor is a compound of any one of claims 1-15. 260 23. An isolated modified immune cell, wherein the immune cell has been contacted or is in contact with a Cbl-b inhibitor, wherein the Cbl-b inhibitor is a compound of any one of claims 1 15. 24. The modified immune cell of claim 22 or claim 23, wherein the immune cell has been or is isolated from a blood sample from a mammalian subject, or the immune cell is a tumor infiltrating lymphocyte (TIL) that has been or is isolated from a tumor of a mammalian subject with cancer; or wherein the immune cell is a tumor-infiltrating lymphocyte (TIL) isolated from a tumor of a mammalian subject with cancer before the immune cell is contacted with the Cbl-b inhibitor; or wherein the modified immune cell is a T-cell, and wherein the T-cell exhibits one or more of increased T-cell activation, increased T-cell proliferation, decreased T-cell exhaustion, and decreased T-cell tolerance; or wherein increased T-cell activation comprises increased production of a cytokine; or wherein the cytokine comprises one or more selected from the group consisting of IL-2, IFN-γ, TNFα, and GM-CSF; or wherein increased T-cell activation comprises increased cell surface expression of one or more T-cell activation markers; or wherein the T-cell activation markers comprise one or more selected from the group consisting of CD25, CD69, and CTLA4; or wherein the T-cell has been or is in contact with an anti-CD3 antibody alone or in combination with an anti-CD28 antibody; or wherein the T-cell has been or is in contact with IL-2 alone or in combination with an anti-CD3 antibody and/or an anti-CD28 antibody; or wherein the modified immune cell is a NK-cell, and wherein the NK-cell exhibits increased NK cell activation; or 261 wherein increased NK-cell activation comprises increased production of a cytokine; or wherein the cytokine comprises one or more selected from the group consisting of IFN-γ, TNFα, and MIP1β; or wherein the modified immune cell is a B-cell, and wherein the B-cell exhibits increased B-cell activation, optionally wherein increased B-cell activation comprises increased expression of CD69; or wherein the modified immune cell is a human immune cell; or wherein the modified immune cell comprises a recombinant chimeric receptor; or wherein the recombinant chimeric receptor is a chimeric antigen receptor. 25. A composition comprising a cell population containing the modified immune cell of any one of claims 21-24; or wherein the composition further comprising a pharmaceutically acceptable excipient; or wherein the composition is in a culture vessel; or wherein the culture vessel is a tube, a dish, a bag, a multiwell plate, or a flask; or wherein the composition is in a suitable container; or wherein the suitable container is a bottle, a vial, a syringe, an intravenous bag, or a tube. 26. The modified immune cell of any one of claims 21-24 or the composition of claim 25 for use in modulating the immune response. 27. The use of claim 26, wherein the immune response is caused by a cancer; or wherein the cancer is a hematologic cancer; or wherein the hematologic cancer is a lymphoma, a leukemia, or a myeloma; or 262 wherein the cancer is a non-hematologic cancer; or wherein the non-hematologic cancer is a sarcoma, a carcinoma, or a melanoma. 28. The modified immune cell of any one of claims 21-24 or the composition of claim 25 for use in treating a cancer responsive to inhibition of Cbl-b activity. 29. The use of claim 28, wherein the cancer is a hematologic cancer; or wherein the hematologic cancer is a lymphoma, a leukemia, or a myeloma; or wherein the cancer is a non-hematologic cancer; or wherein the non-hematologic cancer is a sarcoma, a carcinoma, or a melanoma. 30. The modified immune cell of any one of claims 21-24 or the composition of claim 25 for use in inhibiting abnormal cell proliferation. 31. The use of claim 30, wherein the abnormal cell proliferation is hyperplasia or cancer cell proliferation; or wherein the cancer cell is from a hematologic cancer; or wherein the hematologic cancer is a lymphoma, a leukemia, or a myeloma; or wherein the cancer cell is from a non-hematologic cancer. wherein the non-hematologic cancer is a sarcoma, a carcinoma, or a melanoma. 32. The Cbl-b inhibitor of any one of claims 1-15 for use in modulating the immune response. 33. 34. The Cbl-b inhibitor of any one of claims 1-15 for use in inhibiting Cbl-b activity. The Cbl-b inhibitor of any one of claims 1-15 for use in treating a cancer responsive to inhibition of Cbl-b activity. 263 35. The use of claim 34, wherein the cancer is a hematologic cancer, optionally wherein the hematologic cancer is a lymphoma, a leukemia, or a myeloma; or wherein the cancer is a non-hematologic cancer, optionally wherein the non-hematologic cancer is a sarcoma, a carcinoma, or a melanoma. 36. The use of claim 34 or 35, further comprising the modified immune cell of any one of claims 21-24 or the composition of claim 25 to treat the cancer. 37. The Cbl-b inhibitor of any one of claims 1-15 for use in inhibiting abnormal cell proliferation. 38. The use of claim 37, wherein the abnormal cell proliferation is hyperplasia or cancer cell proliferation; or wherein the cancer cell is from a hematologic cancer, optionally wherein the hematologic cancer is a lymphoma, a leukemia, or a myeloma; or wherein the cancer cell is from a non-hematologic cancer, optionally wherein the non hematologic cancer is a sarcoma, a carcinoma, or a melanoma. 39. The use of any one of claims 32-38, wherein modulating the immune response, inhibiting Cbl-b activity, treating a cancer responsive to inhibition of Cbl-b activity, and/or inhibiting abnormal cell proliferation comprises one or more of increased T-cell activation, increased T-cell proliferation, decreased T-cell exhaustion, and decreased T-cell tolerance after administration of the Cbl-b inhibitor. 40. The use of claim 39, wherein increased T-cell activation comprises increased production of a cytokine; or wherein the cytokine comprises one or more selected from the group consisting of IL-2, IFN-γ, TNFα, and GM-CSF; or wherein increased T-cell activation comprises increased cell surface expression of one or more T-cell activation markers; or 264 wherein the T-cell activation markers comprise one or more selected from the group consisting of CD25, CD69, and CTLA4. 41. The use of any one of claims 32-40, wherein modulating the immune response, inhibiting Cbl-b activity, treating a cancer responsive to inhibition of Cbl-b activity, and/or inhibiting abnormal cell proliferation comprises increased NK-cell activation after administration of the Cbl-b inhibitor. 42. The use of claim 41, wherein increased NK-cell activation comprises increased production of a cytokine; or wherein the cytokine comprises one or more selected from the group consisting of IFN-γ, TNFα, and MIP1β. 43. The use of any one of claims 32-42, wherein modulating the immune response, inhibiting Cbl-b activity, treating a cancer responsive to inhibition of Cbl-b activity, and/or inhibiting abnormal cell proliferation comprises increased B-cell activation after administration of the Cbl b inhibitor, optionally wherein increased B-cell activation comprises increased expression of CD69. 44. A cell culture composition comprising a cell population containing an immune cell and a Cbl-b inhibitor of any one of claims 1-15. 45. The cell culture composition of claim 44, wherein the immune cell is a cell selected from the group consisting of a hematopoietic cell, a multipotent stem cell, a myeloid progenitor cell, a lymphoid progenitor cell, a T-cell, a B-cell, and a NK-cell; or further comprising an anti-CD3 antibody alone or in combination with an anti-CD28 antibody; or wherein the immune cell is an engineered immune cell comprising a recombinant chimeric receptor; or wherein the recombinant chimeric receptor is a chimeric antigen receptor. 265 46. A pharmaceutical composition comprising a Cbl-b inhibitor of any one of claims 1-15 and one or both of an adjuvant and an antigen. 47. 48. The pharmaceutical composition of claim 46, wherein the antigen is a cancer antigen. An article of manufacture comprising the modified immune cell of any one of claims 21 24, the composition of claim 25, the cell culture composition of claim 44 or 45, or the pharmaceutical composition of claim 16. 49. The article of manufacture of claim 48, wherein the modified immune cell or cell culture composition is in a tube, a dish, a bag, a multiwell plate, or a flask; or wherein the modified immune cell or pharmaceutical composition is in a bottle, a vial, a syringe, an intravenous bag, or a tube. 50. A kit comprising the modified immune cell of any one of claims 21-24 or the composition of claim 25. 51. The kit of claim 50, wherein the modified immune cell is in a tube, a dish, a bag, a multiwell plate, or a flask; or wherein the modified immune cell is in a bottle, a vial, a syringe, an intravenous bag, or a tube; or wherein the kit comprises instructions for administering the modified immune cell or composition according to the use of any one of claims 26-31. 52. 53. A kit comprising the pharmaceutical composition of claim 16. The kit of claim 52, wherein the kit comprises instructions for administering the pharmaceutical composition according to the use of any one of claims 32-34. 54. A kit comprising the cell culture composition of claim 44 or 45. 266 55. The kit of claim 54, wherein the kit comprises instructions for producing a modified immune cell according to the method of any one of claims 18-20. 56. The Cbl-b inhibitor of any one of claims 1-15 for use in treating or preventing a disease or condition associated with Cbl-b activity. 57. Use of a Cbl-b inhibitor of any one of claims 1-15 in the manufacture of a medicament for treating or preventing a disease or condition associated with Cbl-b activity. 58. Use of a Cbl-b inhibitor of any one of claims 1-15 in the manufacture of a medicament for treating cancer. 59. A Cbl-b inhibitor for use in treating cancer, wherein the Cbl-b inhibitor is a compound of any one of claims 1-15. 60. The Cbl-b inhibitor of any one of claims 1-15, and an additional therapeutic agent for use in treating cancer. 61. The use of claim 60, wherein the Cbl-b inhibitor and the additional therapeutic agent are for administration consecutively in either order; or wherein the Cbl-b inhibitor and the additional therapeutic agent are administered concurrently; or wherein the additional therapeutic agent comprises an immune checkpoint inhibitor; or wherein the immune checkpoint inhibitor is an antagonist of at least one inhibitory checkpoint molecule selected from the group consisting of PD-1 (CD279), PD-L1 (CD274), CTLA-4 (CD125), LAG3 (CD223), PVR (CD155), PVRL2 (CD112), PVRL3 (CD113), TIGIT, TIM3 (CD366), and VISTA; or wherein the immune checkpoint inhibitor is an antagonist of at least one inhibitory checkpoint molecule selected from the group consisting of PD-1 (CD279), PD-L1 (CD274), and CTLA-4 (CD152); or 267 wherein the at least one inhibitory checkpoint molecule comprises PD-1, optionally wherein the immune checkpoint inhibitor is selected from the group consisting of pembrolizumab, nivolumab, cemiplimab, and biosimilars thereof; or wherein the at least one inhibitory checkpoint molecule comprises PD-L1, optionally wherein the immune checkpoint inhibitor is selected from the group consisting of atezolizumab, avelumab, durvalumab, and biosimilars thereof; or wherein the at least one inhibitory checkpoint molecule comprises CTLA-4, optionally wherein the immune checkpoint inhibitor is selected from the group consisting of ipilimumab, tremelimumab, and biosimilars thereof; or wherein the immune checkpoint inhibitor comprises an antibody or antigen-binding fragment thereof, optionally wherein the antibody or fragment is human or humanized; or wherein the additional therapeutic agent comprises an antineoplastic agent; or wherein the antineoplastic agent is classified as one of the group consisting of a cytotoxic antibiotic, a plant alkaloid, an antimetabolite, an alkylating agent, and other antineoplastic agent; or wherein the antineoplastic agent comprises a cytotoxic antibiotic, optionally wherein the cytotoxic antibiotic is selected from the group consisting of ixabepilone, mitomycin, plicamycin, bleomycin, pixantrone, amrubicin, valrubicin, pirarubicin, mitoxantrone, idarubicin, zorubicin, aclarubicin, epirubicin, daunorubicin, doxorubicin, and dactinomycin; or wherein the antineoplastic agent comprises a plant alkaloid, optionally wherein the plant alkaloid is selected from the group consisting of trabectedin, cabazitaxel, paclitaxel poliglumex, docetaxel, paclitaxel, demecolcine, teniposide, etoposide, vintafolide, vinflunine, vinorelbine, vindesine, vincristine, and vinblastine; or wherein the antineoplastic agent comprises an antimetabolite, optionally wherein the antimetabolite is a pyrimidine analog, a purine analog, or a folic acid analog, optionally wherein the antimetabolite is selected from the group consisting of floxuridine, trifluridine, tegafur, 268 fluorouracil, decitabine, azacitidine, capecitabine, gemcitabine, carmofur, tegafur, fluorouracil, cytarabine, nelarabine, clofarabine, fludarabine, cladribine, tioguanine, mercaptopurine, pralatrexate, pemetrexed, raltitrexed, and methotrexate; or wherein the antineoplastic agent comprises an alkylating agent, optionally wherein the alkylating agent is selected from the group consisting of dacarbazine, temozolomide, pipobroman, mitobronitol, etoglucid, uracil mustard, ranimustine, nimustine, fotemustine, streptozocin, semustine, lomustine, carmustine, carboquone, triaziquone, thiotepa, mannosulfan, treosulfan, busulfan, bendamustine, prednimustine, trofosfamide, ifosfamide, mechlorethamine, melphalan, chlorambucil, and cyclophosphamide; or wherein the antineoplastic agent comprises an other antineoplastic agent selected from the group consisting of a platinum compound, a protein kinase inhibitor, and an other agent; or wherein the antineoplastic agent comprises a platinum compound, optionally wherein the platinum compound is selected from the group consisting of cisplatin, carboplatin, oxaliplatin, satraplatin, and polyplatillen; or wherein the antineoplastic agent comprises a protein kinase inhibitor; or wherein the antineoplastic agent comprises an other agent; or wherein the use further comprises administration of radiation therapy. 62. The Cbl-b inhibitor of any one of claims 1-15 for use in treating cancer, wherein the use further comprises administration of radiation therapy. 63. The use of claim 62, wherein the radiation therapy is external beam radiation therapy; or wherein the radiation therapy is internal radiation therapy. 64. The use of any one of claims 60-63, wherein the cancer is a hematologic cancer; or wherein the hematologic cancer is a lymphoma, a leukemia, or a myeloma; or 269 wherein the cancer is a non-hematologic cancer; or wherein the non-hematologic cancer is a carcinoma, a sarcoma, or a melanoma. 65. A method of producing an expanded population of tumor infiltrating lymphocytes (TILs), the method comprising (a) obtaining a biological sample comprising TILs according to the use of any one of claims 60-64, and (b) culturing the TILs in cell culture medium comprising at least one T-cell growth factor to produce the expanded population of TILs. 66. The method of claim 65, wherein the at least one T-cell growth factor comprises IL-2; or wherein the cell culture medium further comprises an anti-CD3 antibody, or both an anti-CD3 antibody and an anti-CD28 antibody; or wherein the cell culture medium further comprises the Cbl-b inhibitor; or wherein the cell culture medium further comprises irradiated feeder cells. 67. A composition comprising the expanded population of TILs produced by the method of claim 65 or 66, and a physiologically acceptable buffer. 68. 69. The composition of claim 67 for use in treating cancer. The use of claim 68, further comprising further administration of an effective amount of the Cbl-b inhibitor. 70. A method of producing an expanded population of tumor infiltrating lymphocytes (TILs) in vitro or ex vivo, the method comprising (a) obtaining a biological sample comprising TILs from a cancer that has received or is receiving an effective amount of a Cbl-b inhibitor of any one of claims 1-15; and (b) culturing the TILs in cell culture medium comprising at least one T-cell growth factor to produce an expanded population of TILs. 270 71. The method of claim 70, wherein the at least one T-cell growth factor comprises IL-2; or wherein the cell culture medium further comprises an anti-CD3 antibody, or both an anti-CD3 antibody and an anti-CD28 antibody; or wherein the cell culture medium further comprises the Cbl-b inhibitor. 72. The method of claim 70 or 71, wherein the cancer is a non-hematologic cancer, optionally wherein the non-hematologic cancer is a sarcoma, a carcinoma, or a melanoma. 73. A composition comprising the expanded population of TILs produced by the method of any one of claims 70-72, and a physiologically acceptable buffer. 74. 75. The composition of claim 73 for use in treating cancer. The composition of claim 74, further comprising further administration of an effective amount of the Cbl-b inhibitor. 76. A combination of a Cbl-b inhibitor of any one of claims 1-15 and a vaccine for use in immunizing. 77. 78. The combination of claim 76, wherein the immunizing is for treating cancer, comprising administration of the Cbl-b inhibitor, and administration of a therapeutic cancer vaccine. The combination of claim 77, wherein the Cbl-b inhibitor and the cancer vaccine are administered consecutively; or wherein the Cbl-b inhibitor and the cancer vaccine are administered concurrently; or wherein the cancer vaccine is an immunogenic composition comprising at least one tumor antigen and a pharmaceutically acceptable excipient; or wherein the at least one tumor antigen comprises at least one synthetic peptide or recombinant protein; or 271 wherein the immunogenic composition further comprises an adjuvant; or wherein the adjuvant comprises one or more ingredients of the group consisting of aluminum salts, squalene, and saponins; or wherein the immunogenic composition further comprises antigen-presenting cells (APCs), optionally wherein the APCs are dendritic cells, optionally wherein the cancer vaccine is PROVENGE; or wherein the cancer vaccine comprises a microbial vector, optionally wherein the microbial vector is TICE-BCG; or wherein the microbial vector is a recombinant viral vector or a recombinant bacterial vector; or wherein the cancer vaccine comprises killed cancer cells or a cancer cell lysate. 79. A combination of a Cbl-b inhibitor of any one of claims 1-15 and oncolytic virus for use in treating cancer. 80. The combination of claim 79, wherein the Cbl-b inhibitor and the oncolytic virus are administered consecutively; or wherein the Cbl-b inhibitor and the oncolytic virus are administered concurrently; or wherein the oncolytic virus is a virus selected from the group consisting of adenovirus, coxsackievirus, echovirus, fowlpox virus, herpes simplex virus, maraba virus, measles virus, myxoma virus, Newcastle disease virus, parvovirus, poliovirus, retrovirus, reovirus, Seneca Valley virus, Semiliki Forest virus, vaccinia virus, and vesicular stomatitis virus; or wherein the oncolytic virus is a recombinant virus comprising one or both of a functional deletion of at least one viral gene, and an insertion of at least one transgene; or wherein the recombinant virus comprises a functional deletion of at least one viral gene and an insertion of at least one transgene; or 272 wherein the transgene encodes human granulocyte macrophage colony stimulating factor (GM-CSF); or wherein the oncolytic virus is a transgenic serotype 5 adenovirus; or wherein the oncolytic virus is a transgenic herpes simplex virus type-1 (HSV-1), optionally wherein the transgenic HSV-1 is talimogene laherparepvec; or wherein the oncolytic virus is a transgenic vaccinia virus, optionally wherein the transgenic vaccinia virus is pexastimogene devacirepvec; or wherein the oncolytic virus is a non-recombinant oncolytic virus, optionally wherein the non recombinant oncolytic virus is a virus selected from the group consisting of an echovirus, a Newcastle disease virus, a parvovirus, a reovirus, and a Seneca Valley virus; or wherein the cancer is a hematologic cancer; or wherein the hematologic cancer is a lymphoma, a leukemia, or a myeloma; or wherein the cancer is a non-hematologic cancer; or wherein the non-hematologic cancer is a carcinoma, a sarcoma, or a melanoma. 81. The combination of any one of claims 76-80, wherein the Cbl-b inhibitor is a compound selected from Compound No. Structure Compound No. 1 Structure 2 3 4 273 274 5 6 7 8 9 10 11 12 13 14 15 16 17 18 275 19 20 21 22 23 24 25 26 27 28 29 30 31 32 276 33 34 35 36 37 38 39 40 41 42 43 44 277 45 47 48 49 50 51 52 Example No. Structure Example No. Structure 53 54 55 56 57 58 Example No. Structure Structure Example No. 59 60 61 or a tautomer thereof, stereoisomer thereof, or a pharmaceutically acceptable salt thereof. 82. A use of a compound of Formula (I) (I) or a tautomer thereof, stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein X is CH or nitrogen; Z1 is CH or nitrogen; Z2 is CH or nitrogen; is or ; R1a and R1b are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 alkyl OH; 278 R2a is -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkyl-OH, C1-C6 alkyl-CN, or -(C1-C6 alkylene)-O-(C1-C6 alkyl); R2b is hydrogen, halo, or C1-C6 alkyl; or R2a and R2b are taken together with the carbon atom to which they are attached to form a spiro 3- to 6-membered heterocyclyl or a spiro C3-C6 cycloalkyl, wherein at least one of the atoms of the spiro heterocyclyl which is adjacent to the connecting piperidinyl ring is carbon; R3a and R3b are independently hydrogen, halo, or C1-C6 alkyl; or R3a and R3b are taken together with the carbon atom to which they are attached to form C3-C4 cycloalkyl; R4 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 alkyl-OH; or is is W is oxygen or a bond; and Y is CR5aR5b or sulfur; and Y is a bond; R5a and R5b are independently hydrogen, halo, or C1-C6 alkyl; or R5a and R5b are taken together with the carbon atom to which they are attached to form a C3-C6 cycloalkyl; R6 is C1-C6 alkyl, C1-C6 haloalkyl, or C3-C6 cycloalkyl; R7 is hydrogen, halo, C3-C6 cycloalkyl, -NH-(3- to 6-membered heterocyclyl), -NH-(C1-C6 alkyl), -NH-(C3-C6 cycloalkyl), -O-(3- to 6-membered heterocyclyl), -O-(C1-C6 alkyl), or -O-(C3-C6 cycloalkyl); R8 is C1-C6 alkyl, C1-C6 haloalkyl, or C3-C6 cycloalkyl; R9 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 alkyl-OH; and R10 is -CF3 or cyclopropyl, and either a therapeutic cancer vaccine; or 279 an oncolytic virus for use in treating cancer. 83. A pharmaceutical composition comprising a cancer vaccine and the compound of any one of claims 1-15, optionally wherein the composition further comprises a pharmaceutically acceptable excipient. 84. A kit for treating cancer, the kit comprising (a) a Cbl-b inhibitor of any one of claims 1-15; (b) a therapeutic cancer vaccine; and (c) instructions for administration of the Cbl-b inhibitor and the therapeutic cancer vaccine to treat the cancer. 85. A kit for treating cancer, the kit comprising (a) a pharmaceutical composition comprising a Cbl-b inhibitor of any one of claims 1-15 and a therapeutic cancer vaccine; and (b) instructions for administration of the pharmaceutical composition comprising the Cbl b inhibitor and the therapeutic cancer vaccine to treat the cancer. 86. The use, composition, or kit of any one of claims 82-85, wherein the cancer vaccine is an immunogenic composition comprising at least one tumor antigen and a pharmaceutically acceptable excipient; or wherein the at least one tumor antigen comprises at least one synthetic peptide or recombinant protein; or wherein the immunogenic composition further comprises an adjuvant; or wherein the adjuvant comprises one or more ingredients of the group consisting of aluminum salts, squalene, and saponins; or wherein the immunogenic composition further comprises antigen-presenting cells (APCs), optionally wherein the APCs are dendritic cells, optionally wherein the cancer vaccine is PROVENGE; or 280 wherein the cancer vaccine comprises a microbial vector, optionally wherein the microbial vector is TICE-BCG; or wherein the microbial vector is a recombinant viral vector or a recombinant bacterial vector; or wherein the cancer vaccine comprises killed cancer cells or a cancer cell lysate. 87. A pharmaceutical composition comprising an oncolytic virus and the compound of any one of claims 1-15, optionally wherein the composition further comprises a pharmaceutically acceptable excipient. 88. A kit for treating cancer, the kit comprising (a) a Cbl-b inhibitor of any one of claims 1-15; (b) an oncolytic virus; and (c) instructions for administration of the Cbl-b inhibitor and the oncolytic virus to treat the cancer. 89. A kit for treating cancer, the kit comprising (a) a pharmaceutical composition comprising a Cbl-b inhibitor of any one of claims 1-15 and an oncolytic virus; and (b) instructions for administration of the pharmaceutical composition comprising the small molecule Cbl-b inhibitor and the oncolytic virus to treat the cancer. 90. The use, composition, or kit of any one of claims 82 or 87-89, wherein the oncolytic virus is a virus selected from the group consisting of adenovirus, coxsackievirus, echovirus, fowlpox virus, herpes simplex virus, maraba virus, measles virus, myxoma virus, Newcastle disease virus, parvovirus, poliovirus, retrovirus, reovirus, Seneca Valley virus, Semiliki Forest virus, vaccinia virus, and vesicular stomatitis virus; or wherein the oncolytic virus is a recombinant virus comprising one or both of a functional deletion of at least one viral gene, and an insertion of at least one transgene; or 281 wherein the recombinant virus comprises a functional deletion of at least one viral gene and an insertion of at least one transgene; or wherein the transgene encodes human granulocyte macrophage colony stimulating factor (GM-CSF); or wherein the oncolytic virus is a transgenic serotype 5 adenovirus; or wherein the oncolytic virus is a transgenic herpes simplex virus type-1 (HSV-1), optionally wherein the transgenic HSV-1 is talimogene laherparepvec; or wherein the oncolytic virus is a transgenic vaccinia virus, optionally wherein the transgenic vaccinia virus is pexastimogene devacirepvec; or wherein the oncolytic virus is a non-recombinant oncolytic virus, optionally wherein the non recombinant oncolytic virus is a virus selected from the group consisting of an echovirus, a Newcastle disease virus, a parvovirus, a reovirus, and a Seneca Valley virus; or wherein the cancer is a hematologic cancer; or wherein the hematologic cancer is a lymphoma, a leukemia, or a myeloma; or wherein the cancer is a non-hematologic cancer; or wherein the non-hematologic cancer is a carcinoma, a sarcoma, or a melanoma. 91. The use, composition, or kit of any one of claims 82-90, wherein the Cbl-b inhibitor is a compound of any one of claims 1-15; or wherein the Cbl-b inhibitor is a compound selected from Compound No. Structure Compound No. 282 Structure 283 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 284 17 18 19 20 21 22 23 24 25 26 27 28 29 30 285 31 32 33 34 35 36 37 38 39 40 41 42 286 43 44 45 47 48 49 50 51 52 Example No. Structure Example No. Structure 53 54 287 Example No. Structure Example No. Structure 55 56 57 58 59 60 61 or a tautomer thereof, stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

Description

1 3-SUBSTITUTED PIPERIDINE COMPOUNDS FOR CBL-B INHIBITION, AND USE OF A CBL-B INHIBITOR IN COMBINATION WITH A CANCER VACCINE AND/OR ONCOLYTIC VIRUS CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application claims the benefit under 35 U.S.C. § 119 of U.S. provisional application numbers: 62/831,392, filed April 9, 2019; 62/866,909, filed June 26 2019; 62/880,267, filed July 30, 2019; 62/888,845, filed August 19, 2019; and 62/888,870, filed August 19, 2019. TECHNICAL FIELD OF THE INVENTION [0002] Provided herein are compounds and compositions for inhibition of the Cbl-b enzyme and methods of use thereof in modulating the immune system, treatment of diseases, and treatment of cells in vivo, in vitro, or ex vivo. Also provided herein are pharmaceutical compositions, kits, and methods of treating cancer comprising a combination of an inhibitor of the Cbl-b enzyme and a cancer vaccine; and pharmaceutical compositions, kits, and methods of treating cancer comprising a combination of an inhibitor of the Cbl-b enzyme and an oncolytic virus. BACKGROUND [0003] The ubiquitin proteasome pathway is a complex system involved in the regulation of protein function and catabolism. Proteins in eukaryotic cells are conjugated with ubiquitin, a 76 amino acid, 8.5 kilodalton protein. This conjugation, known as ubiquitination, results in altered function or degradation of the target protein. Ubiquitination of the target protein occurs via a coupled series of reactions involving ubiquitin and a set of enzymes known as E1, E2, and E3 enzymes. Ubiquitin is activated by the ubiquitin-activating enzyme, or E1 enzyme. Ubiquitin is then transferred to a ubiquitin-conjugating enzyme, or E2 enzyme. Finally, a ubiquitin ligase, or E3 enzyme, promotes the transfer of ubiquitin from the E2 enzyme to the target protein. Polyubiquitination of the target protein predominantly serves as a signal leading to degradation of the ubiquitin-conjugated protein by the proteasome, where it undergoes proteolysis. Ubiquitination by E3 ligases can also result in altered protein activity, interactions, or localization. Ubiquitination regulates diverse biology including cell division, DNA repair, and cellular signaling. CA 3136348 2 [0004] The synthesis and degradation of proteins in the cell is critical for cell cycle regulation, cell proliferation, apoptosis, and many other cellular processes. Thus, the ability to modulate the ubiquitin proteasome pathway offers a wealth of opportunities to intervene in disease processes. Mechanisms for intervention can include enhanced degradation of oncogene products, reduced degradation of tumor-suppressor proteins, modulation of immune cell response, and modulation of anti-tumor immune responses. [0005] Therapeutic cancer vaccines have been evaluated in numerous clinical trials. However, only two therapeutic cancer vaccines have been licensed for use in the United States. In particular, the Bacillus of Calmette and Guerin strain of Mycobacterium bovis has been approved for treatment of bladder cancer, and an ex vivo-activated, autologous cell vaccine has been approved for treatment of prostate cancer. Even so, the response rates and overall survival of patients treated with cancer vaccines are considerably lower than desirable. Thus, what is needed in the art are methods of improving the efficacy of cancer vaccines. [0006] Although numerous clinical trials employing an oncolytic virus to treat cancer have been conducted, only one oncolytic virus has been licensed for use in the United States and Europe. In particular, talimogene laherparepvec is a genetically modified herpes simplex virus approved for treatment of melanoma. However, even talimogene laherparepvec has not been shown to improve overall survival or to benefit patients with visceral metastases. Thus, what is needed in the art are methods of improving the efficacy of oncolytic virus therapy. [0007] Approximately 35 E2 enzymes and over 500 E3 enzymes are encoded in the human genome. 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). Discovery of agents that modulate E2 or E3 enzymes accordingly provides the potential for therapies directed against disease processes involving a particular E2 or E3 enzyme. The present patent application is directed to agents that inhibit one such E3 enzyme, Casitas B-lineage lymphoma proto-oncogene-b (Cbl-b); agents that inhibit Cbl-b, for use in combination with cancer vaccines, and to pharmaceutical compositions comprising Cbl-b inhibitors and cancer vaccines; and agents that inhibit Cbl-b, for use in combination with oncolytic viruses, and to pharmaceutical compositions comprising Cbl-b inhibitors and oncolytic viruses. CA 3136348 3 SUMMARY OF THE INVENTION [0008] Disclosed herein are compounds and compositions for inhibition of the Cbl-b enzyme and methods of use thereof in modulating the immune syst