WO2023034530A1 - Methods of improving growth and function of immune cells - Google Patents

Methods of improving growth and function of immune cells Download PDF

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Publication number
WO2023034530A1
WO2023034530A1 PCT/US2022/042384 US2022042384W WO2023034530A1 WO 2023034530 A1 WO2023034530 A1 WO 2023034530A1 US 2022042384 W US2022042384 W US 2022042384W WO 2023034530 A1 WO2023034530 A1 WO 2023034530A1
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compound
cells
patient
interleukin
modulator
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PCT/US2022/042384
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French (fr)
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Peidong Fan
Lina Yao
Jiwen Liu
Elfatih Elzein
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Teon Therapeutics, Inc.
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Publication of WO2023034530A1 publication Critical patent/WO2023034530A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/04—Immunostimulants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • FIELD Described herein are methods of increasing production of interferon gamma (IFN ⁇ ), activation, and/or proliferation of immune cells using cannabinoid receptor type 2 modulators or pharmaceutical compositions and medicaments comprising cannabinoid receptor type 2 modulators.
  • the disclosure also pertains to improving immunotherapy and treating, reducing, or preventing immune cell exhaustion in patients in need thereof.
  • BACKGROUND [0003]
  • T cells are the immune system’s primary killers of infected and diseased cells. Cancer immunotherapy relies on getting T cells to attack and kill tumor cells.
  • T cell function can fade with chronic infection (e.g., viral infection) and/or disease (e.g., progressive development of cancer), a phenomenon referred to as T cell exhaustion.
  • Other immune cells such as natural killer (NK) cells and B cells can also become exhausted.
  • NK natural killer
  • Exhausted immune cells exhibit aberrant expression of transcription factors, cell surface antigens, and effector molecules that contribute to decreased T cell function.
  • exhausted T cells exhibit increased appearance of immune checkpoint proteins on the cellular surface such as PD-1 and CTLA-4, which can prevent a T cell’s ability to kill infected and diseased cells.
  • checkpoint inhibitors e.g., anti-PD-1, anti-PD-L1, and anti CTLA-4.
  • studies suggest that checkpoint inhibitor therapy is often ineffective alone. (See, e.g., Zhang et al., “T Cell Dysfunction and Exhaustion in Cancer,” Front. Cell Dev. Biol.8(17): 1-13 (2020) (reporting that the response rate of checkpoint inhibitor therapy is less than 30% in solid tumors)).
  • combination therapies are being investigated with some success, challenges remain for development of immunotherapy for wide clinical applications.
  • CB 2 R cannabinoid type 2 receptor
  • provided herein is a method for increasing the production of interferon gamma (IFN ⁇ ) or growth or proliferation of immune cells in a patient in need thereof, comprising administering to the patient an effective amount of a cannabinoid type 2 receptor (CB 2 R) modulator.
  • the patient has a viral infection or cancer.
  • a method for treating, reducing, or preventing immune cell exhaustion in a patient in need thereof comprising administering to the patient an effective amount of a cannabinoid type 2 receptor (CB2R) modulator.
  • CB2R cannabinoid type 2 receptor
  • the CB2R modulator is an agent which antagonizes, reverse agonizes, negatively modulates, or otherwise inhibits or partially inhibits CB2R.
  • FIG.1A illustrates a graph showing proliferation of CD4 + T cells treated with Compound 8 in a MLR assay (MoDC/CD4 + ) model, according to one embodiment.
  • FIG.1B illustrates a graph showing IFN ⁇ production of CD4 + T cells treated with Compound 8 in a MLR assay (MoDC/CD4 + ) model.according to one embodiment.
  • FIG.1C illustrates graphs showing proliferation of CD4 + T cells treated with SR144528 (SR), AM630 (AM) and MAB36551 (MAB), with or without anti-PD-1 (pembrolizumab, pembro or nivolumab, nivo), in a MLR assay (MoDC/CD4 + ) model, according to one embodiment.
  • FIG.1D illustrates graphs showing IFN ⁇ production of CD4 + T cells treated with SR144528 (SR), AM630 (AM) and MAB36551 (MAB), with or without anti-PD-1 (pembrolizumab, pembro or nivolumab, nivo), in a MLR assay (MoDC/CD4 + ) model.according to one embodiment.
  • FIGS.2A-C illustrate graphs showing total IFN ⁇ production and normalized (basal subtracted) IFN ⁇ production of CD4 + T cells treated with Compound 8 with or without anti-PD-1 (nivolumab) in a MLR assay (MoDC/CD4 + ) model, according to one embodiment.
  • FIG.3A illustrates graphs showing expression of LAG-3, TIM-3, and PD-1 of CD4 + and CD8 + T cells treated with vehicle, Compound 8, anti-PD-1 (nivolumab), and the combination of Compound 8 in a TCE assay model, according to one embodiment.
  • FIG.3B illustrates graphs showing expression of CD38, CTLA-4, LAG-3, PD-1, TIGIT, TIM-3, TOX and IL-2 of CD3 + , CD4 + , and CD8 + T cells treated with vehicle, Compound 8, anti-PD-1 (nivolumab/pembrolozimab), and the combination of Compound 8 and anti-PD-1 in a TCE assay model, according to one embodiment.
  • FIG.3C illustrates graphs showing expression of CD38, CTLA-4, LAG-3, PD-1, TIGIT, TIM-3, TOX and IL-2 of CD3 + , CD4 + , and CD8 + T cells treated with vehicle, SR144528 (SR), anti- PD-1 (nivolumab/pembrolozimab), and the combination of SR144528 and anti-PD-1 in a TCE assay model, according to one embodiment.
  • SR144528 SR
  • anti- PD-1 nivolumab/pembrolozimab
  • FIG.3D illustrates graphs showing expression of CD38, CTLA-4, LAG-3, PD-1, TIGIT, TIM-3, TOX and IL-2 of CD3 + , CD4 + , and CD8 + T cells treated with vehicle, AM630 (AM), anti-PD- 1 (nivolumab/pembrolozimab), and the combination of AM630 and anti-PD-1 in a TCE assay model, according to one embodiment.
  • AM630 AM
  • anti-PD- 1 nivolumab/pembrolozimab
  • FIG.3E illustrates graphs showing expression of CD38, CTLA-4, LAG-3, PD-1, TIGIT, TIM-3, TOX and IL-2 of CD3 + , CD4 + , and CD8 + T cells treated with vehicle, MAB36551 (MAB), anti-PD-1 (nivolumab/pembrolozimab), and the combination of MAB36551 and anti-PD-1 in a TCE assay model, according to one embodiment.
  • MAB36551 MAB
  • anti-PD-1 nivolumab/pembrolozimab
  • FIG.4A illustrates a graph showing expression of IL2 of CD4 + and CD8 + T cells four, six, and eight days after treatment with T-Activator CD3/CD28 dynabeads (activates T cells) without Compound 8 in a TCE assay model, according to one embodiment.
  • FIG.4B illustrates a graph showing expression if IL2 of CD4 + and CD8 + T cells eight days after treatment with T-Activator CD3/CD28 dynabeads (activates T cells) with different concentrations of Compound 8 in a TCE assay model, according to one embodiment.
  • FIGS.5A-C illustrate graphs showing natural killer (NK) cell activation, capacity for killing cancer cells (K562 cell line), and IFN ⁇ expression after treatment with Compound 8 in a cytotoxicity assay, according to one embodiment.
  • FIGS.6A-B illustrate graphs showing the effect of oral administration of Compound 8 on B16F10 and MC38 derived tumors in a mouse model, according to one embodiment.
  • FIGS.7A-B illustrate graphs showing the effect of intraperitoneal administration of Compound 8 on B16F10 and MC38 derived tumors in a mouse model, according to one embodiment.
  • FIGS.8A-B illustrate graphs showing the effect of oral administration of vehicle and 4 mg/kg Compound 8, intraperitoneal administration of 5 mg/kg anti-PD-1 antibody, and combination of 4 mg/kg Compound 8 with 5 mg/kg anti-PD-1 antibody on B16F10 and MC38 derived tumors in a mouse model, according to one embodiment.
  • FIG.9A illustrates graphs shwoing the effect of oral administration of vehicle and 4 mg/kg Compound 8, intraperitoneal administration of 5 mg/kg anti-PD-1 antibody, and combination of 4 mg/kg Compound 8 with 5 mg/kg anti-PD-1 antibody on tumor-infiltrating immune cells on B16F10 derived tumors in a mouse model, according to one embodiment.
  • FIG.9B illustrates graphs showing effect of oral administration of vehicle and 4 mg/kg Compound 8, intraperitoneal administration of 5 mg/kg anti-PD-1 antibody, and combination of 4 mg/kg Compound 8 with 5 mg/kg anti-PD-1 antibody on expression of PD-1 and LAG3 by CD8+ T cells on B16F10 derived tumors in a mouse model.
  • DETAILED DESCRIPTION [0026] Exhausted immune cells (e.g., exhausted T cells) can emerge during chronic high grade infections such as hepatitis B, hepatitis C, or long Covid, during immunodeficiency virus infections such as AIDS, and during tumor outgrowth.
  • CART chimeric antigen receptor T cell
  • a drawback of CART therapy is that the CAR T cells circulate in the blood and are unable to penetrate deep into tumor tissue. Due to their presence in the circulatory system, the CAR T cells have a limited life, possibly due to exposure to cytokine storms associated with the underlying infection or disease, thereby leading to exhausted CAR T cells.
  • the methods described herein comprise administration of a CB 2 modulator as an adjunct and/or adjuvant to immunetherapies.
  • Treatment with a CB 2 modulator activates immune cells such as T cells and NK cells, including exhausted T cells and exhausted NK cells. Accordingly, the methods described herein prolong the therapeutic effect of immunotherapies such as CAR T cells and/or re-activate exhausted immune cells such as exhausted T cells and/or reverse or delay the decline in efficay of immunotherapies such as CAR T cell therapy.
  • immunotherapies such as CAR T cells and/or re-activate exhausted immune cells such as exhausted T cells and/or reverse or delay the decline in efficay of immunotherapies such as CAR T cell therapy.
  • Exhausted T cells exhibit increased appearance on their surface of checkpoint proteins like PD-1 and CTLA-4, which can cause those T cells to stand down. Immune checkpoint inhibitors block these checkpoint proteins and were expected to ramp up the immune response against tumors. However, treatment with checkpoint inhibitors does not address the underlying T cell exhaustion, which reduces therapeutic effectiveness of checkpoint inhibitors.
  • C1-Cx includes C1-C2, C1-C 3 ... C1-Cx.
  • C1-C4 indicates that there are one to four carbon atoms in the moiety, i.e. groups containing 1 carbon atom, 2 carbon atoms, 3 carbon atoms or 4 carbon atoms.
  • C1-C4 alkyl indicates that there are one to four carbon atoms in the alkyl group, i.e., the alkyl group is selected from among methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and t-butyl.
  • An “alkyl” group refers to an aliphatic hydrocarbon group.
  • the alkyl group is branched or straight chain.
  • the “alkyl” group has 1 to 10 carbon atoms, i.e. a C1-C10alkyl.
  • a numerical range such as “1 to 10” refers to each integer in the given range; e.g., “1 to 10 carbon atoms” means that the alkyl group consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 10 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated.
  • an alkyl is a C 1 -C 6 alkyl.
  • the alkyl is methyl, ethyl, propyl, iso-propyl, n- butyl, iso-butyl, sec-butyl, or t-butyl.
  • Typical alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tertiary butyl, pentyl, neopentyl, or hexyl.
  • An “alkylene” group refers to a divalent alkyl radical. Any of the above mentioned monovalent alkyl groups may be an alkylene by abstraction of a second hydrogen atom from the alkyl.
  • an alkylene is a C 1 -C 6 alkylene. In other embodiments, an alkylene is a C 1 -C 4 alkylene.
  • Typical alkylene groups include, but are not limited to, -CH 2 -, -CH(CH 3 )-, -C(CH 3 ) 2 -, -CH 2 CH 2 -, -CH 2 CH(CH 3 )-, -CH 2 C(CH 3 ) 2 -, -CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 -, and the like.
  • alkenyl refers to a type of alkyl group in which at least one carbon-carbon double bond is present.
  • R is H or an alkyl.
  • alkynyl refers to a type of alkyl group in which at least one carbon-carbon triple bond is present.
  • an alkenyl group has the formula -C ⁇ C-R, wherein R refers to the remaining portions of the alkynyl group.
  • R is H or an alkyl.
  • alkynyl group include -C ⁇ CH, -C ⁇ CCH 3 -C ⁇ CCH 2 CH 3 , -CH 2 C ⁇ CH.
  • An “alkoxy” group refers to a (alkyl)O- group, where alkyl is as defined herein.
  • alkylamine refers to -NH(alkyl), or -N(alkyl)2.
  • aromatic refers to a planar ring having a delocalized pi-electron system containing 4n+2 pi electrons, where n is an integer.
  • aromatic includes both carbocyclic aryl (“aryl”, e.g., phenyl) and heterocyclic aryl (or “heteroaryl” or “heteroaromatic”) groups (e.g., pyridine).
  • aryl e.g., phenyl
  • heterocyclic aryl or “heteroaryl” or “heteroaromatic” groups (e.g., pyridine).
  • the term includes monocyclic or fused-ring polycyclic (i.e., rings which share adjacent pairs of carbon atoms) groups.
  • carbocyclic or “carbocycle” refers to a ring or ring system where the atoms forming the backbone of the ring are all carbon atoms.
  • aryl refers to an aromatic ring wherein each of the atoms forming the ring is a carbon atom. In one aspect, aryl is phenyl or a naphthyl. In some embodiments, an aryl is a phenyl. In some embodiments, an aryl is a C 6 -C10aryl.
  • an aryl group is a monoradical or a diradical (i.e., an arylene group).
  • cycloalkyl refers to a monocyclic or polycyclic aliphatic, non-aromatic radical, wherein each of the atoms forming the ring (i.e. skeletal atoms) is a carbon atom.
  • a cycloalkyl may be saturated or partially saturated.
  • cycloalkyls are spirocyclic or bridged compounds.
  • cycloalkyls are optionally fused with an aromatic ring, and the point of attachment is at a carbon that is not an aromatic ring carbon atom.
  • Cycloalkyl groups include groups having from 3 to 10 ring atoms.
  • cycloalkyl groups are selected from among cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, spiro[2.2]pentyl, norbornyl and bicycle[1.1.1]pentyl, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, cis-decalin, trans-decalin, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, and bicyclo[3.3.2]decane, adamantyl, norbornyl, and decalinyl.
  • a cycloalkyl is a C 3 -C 6 cycloalkyl.
  • Cycloalkylene refers to -cycloalkyl-, i.e., a cycloalkyl ring as defined herein which is bonded to two groups.
  • 1,4-dioxanyl ring fused to ring C refers .
  • Deuteroalkyl refers to an alkyl group as defined herein, in which at least one H is replaced by an isotope of hydrogen, i.e., by deuterium ( 2 H) or tritium ( 3 H).
  • Deuteroalkoxy refers to an alkoxy group as defined herein, in which at least one H is replaced by an isotope of hydrogen, i.e., by deuterium ( 2 H) or tritium ( 3 H).
  • halo or, alternatively, “halogen” or “halide” means fluoro, chloro, bromo or iodo. In some embodiments, halo is fluoro, chloro, or bromo.
  • fluoroalkyl refers to an alkyl in which one or more hydrogen atoms are replaced by a fluorine atom.
  • a fluoroalkyl is a C 1 -C 6 fluoroalkyl.
  • “Fluoroalkoxy” refers to an alkoxy group as defined herein, in which at least one H is replaced by a fluorine atom.
  • the term “heteroalkyl” refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, e.g., oxygen, nitrogen (e.g. –NH-, -N(alkyl)-, sulfur, or combinations thereof.
  • a heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl.
  • a heteroalkyl is a C1-C 6 heteroalkyl.
  • Examples of such heteroalkyl are, for example, -CH2OCH3, -CH2CH2OCH3, -CH2CH2OCH2CH2OCH3, -CH(CH3)OCH3, -CH2NHCH3, -CH2N(CH3)2, and -CH2SCH3.
  • heterocycle refers to heteroaromatic rings (also known as heteroaryls) and heterocycloalkyl rings (also known as heteroalicyclic groups) containing one to four heteroatoms in the ring(s), where each heteroatom in the ring(s) is selected from O, S and N, wherein each heterocyclic group has from 3 to 10 atoms in its ring system, and with the proviso that any ring does not contain two adjacent O or S atoms.
  • Non-aromatic heterocyclic groups also known as heterocycloalkyls
  • aromatic heterocyclic groups include rings having 5 to 10 atoms in its ring system.
  • the heterocyclic groups include benzo- fused ring systems.
  • non-aromatic heterocyclic groups are pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, oxazolidinonyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, thioxanyl, piperazinyl, aziridinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridinyl, pyrrolin-2-yl, pyrrolin-3-yl, indolinyl, 2H-
  • aromatic heterocyclic groups are pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinox
  • a group derived from pyrrole includes both pyrrol-1-yl (N-attached) or pyrrol-3-yl (C-attached).
  • a group derived from imidazole includes imidazol-1-yl or imidazol-3-yl (both N-attached) or imidazol-2-yl, imidazol-4-yl or imidazol-5-yl (all C-attached).
  • the heterocyclic groups include benzo-fused ring systems.
  • at least one of the two rings of a bicyclic heterocycle is aromatic.
  • both rings of a bicyclic heterocycle are aromatic.
  • heteroaryl or, alternatively, “heteroaromatic” refers to an aryl group that includes one or more ring heteroatoms selected from nitrogen, oxygen and sulfur.
  • Illustrative examples of heteroaryl groups include monocyclic heteroaryls and bicyclic heteroaryls.
  • Monocyclic heteroaryls include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, pyridazinyl, triazinyl, oxadiazolyl, thiadiazolyl, and furazanyl.
  • Bicyclic heteroaryls include indolizine, indole, benzofuran, benzothiophene, indazole, benzimidazole, purine, quinolizine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, 1,8- naphthyridine, and pteridine.
  • a heteroaryl contains 0-4 N atoms in the ring.
  • a heteroaryl contains 1-4 N atoms in the ring.
  • a heteroaryl contains 0-4 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring.
  • a heteroaryl contains 1-4 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring.
  • heteroaryl is a C 1 -C 9 heteroaryl.
  • monocyclic heteroaryl is a C 1 -C 5 heteroaryl.
  • monocyclic heteroaryl is a 5-membered or 6-membered heteroaryl.
  • bicyclic heteroaryl is a C 6 -C 9 heteroaryl.
  • a “heterocycloalkyl” or “heteroalicyclic” group refers to a cycloalkyl group that includes at least one heteroatom selected from nitrogen, oxygen and sulfur.
  • a heterocycloalkyl is fused with an aryl or heteroaryl.
  • the heterocycloalkyl is oxazolidinonyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, piperidin-2-onyl, pyrrolidine-2,5-dithionyl, pyrrolidine-2,5-dionyl, pyrrolidinonyl, imidazolidinyl, imidazolidin-2-onyl, or thiazolidin-2-onyl.
  • the sulfur atom in a heterocycloalkyl is not oxidized.
  • heteroalicyclic also includes all ring forms of the carbohydrates, including but not limited to the monosaccharides, the disaccharides and the oligosaccharides.
  • a heterocycloalkyl is a C 2 -C 10 heterocycloalkyl.
  • a heterocycloalkyl is a C 4 -C 10 heterocycloalkyl.
  • a heterocycloalkyl contains 0-2 N atoms in the ring.
  • a heterocycloalkyl contains 0-2 N atoms, 0-2 O atoms and 0-1 S atoms in the ring.
  • bond refers to a chemical bond between two atoms, or two moieties when the atoms joined by the bond are considered to be part of larger substructure. In one aspect, when a group described herein is a bond, the referenced group is absent thereby allowing a bond to be formed between the remaining identified groups.
  • moiety refers to a specific segment or functional group of a molecule. Chemical moieties are often recognized chemical entities embedded in or appended to a molecule.
  • optional substituents are independently selected from halogen, -CN, -NH 2 , -OH, -NH(CH 3 ), -N(CH 3 ) 2 , -CH 3 , -CH 2 CH 3 , -CF 3 , -OCH 3 , and -OCF 3 .
  • substituted groups are substituted with one or two of the preceding groups.
  • modulate means to interact with a target either directly or indirectly so as to alter the activity of the target, including, by way of example only, to enhance the activity of the target, to inhibit the activity of the target, to limit the activity of the target, or to extend the activity of the target. In some embodiments, “modulate” means to interact with a target either directly or indirectly so as to decrease or inhibit receptor activity, [0057]
  • modulator refers to a molecule that interacts with a target either directly or indirectly. The interactions include, but are not limited to, the interactions of an agonist, partial agonist, an inverse agonist, antagonist, or combinations thereof. In some embodiments, a modulator is an antagonist.
  • Receptor antagonists are inhibitors of receptor activity. Antagonists mimic ligands that bind to a receptor and prevent receptor activation by a natural ligand. Preventing activation may have many effects. If a natural agonist binding to a receptor leads to an increase in cellular function, an antagonist that binds and blocks this receptor decreases the function.
  • administer refers to the methods that may be used to enable delivery of compounds or compositions to the desired site of biological action. These methods include, but are not limited to oral routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular or infusion), topical and rectal administration.
  • the compounds and compositions described herein are administered orally.
  • co-administration or the like, as used herein, are meant to encompass administration of the selected therapeutic agents to a single patient, and are intended to include treatment regimens in which the agents are administered by the same or different route of administration or at the same or different time.
  • effective amount or “therapeutically effective amount,” as used herein, refer to a sufficient amount of an agent or a compound being administered, which will relieve to some extent one or more of the symptoms of the disease or condition being treated.
  • an “effective amount” for therapeutic uses is the amount of the composition comprising a compound as disclosed herein required to provide a clinically significant decrease in disease symptoms.
  • An appropriate “effective” amount in any individual case is optionally determined using techniques, such as a dose escalation study.
  • the terms “enhance” or “enhancing,” as used herein, means to increase or prolong either in potency or duration a desired effect.
  • the term “enhancing” refers to the ability to increase or prolong, either in potency or duration, the effect of other therapeutic agents on a system.
  • an “enhancing-effective amount,” as used herein, refers to an amount adequate to enhance the effect of another therapeutic agent in a desired system.
  • the term “subject” or “patient” encompasses mammals. Examples of mammals include, but are not limited to, any member of the Mammalian class: humans, non-human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like. In one aspect, the mammal is a human.
  • the terms “treat,” “treating” or “treatment,” as used herein, include alleviating, abating or ameliorating at least one symptom of a disease or condition, preventing additional symptoms, inhibiting the disease or condition, e.g., arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, or stopping the symptoms of the disease or condition either prophylactically and/or therapeutically.
  • the term “in vitro,” as used herein, means experimentation using components of an organism that have been isolated from their usual biological surroundings.
  • in vitro experiments include cells derived from multicellular organisms (cell culture or tissue culture), subcellular components (e.g., mitochondria or ribosomes), cellular or subcellular extracts, and purified molecules (e.g., DNA, RNA, and proteins).
  • in vivo means experimentation using a whole, living organism as opposed to a partial or dead organism, or an in vitro controlled environment.
  • ex vivo means experimentation or measurement done in or on tissue in an artificial environment outside of an organism with minimum alteration of natural conditions.
  • Immune cell therapies are forms of treatment using the cells of the immune system to target and eliminate cells that have become infected, damaged, and/or cancerous. Immune cell therapies include engineered T cell receptor (TCR) therapy, chimeric antigen receptor (CAR) therapy, and tumor-infiltrating lymphocyte (TIL) therapy.
  • TCR T cell receptor
  • CAR chimeric antigen receptor
  • TIL tumor-infiltrating lymphocyte
  • immune cells may be targeted and treated inside a patient (in situ) using a vector comprising a nucleic acid and a targeting protein against an immune cell-associated antigen.
  • the nucleic acid encodes an engineered receptor against a disease- associated antigen.
  • the engineered receptor comprises a chimeric antigen receptor (CAR) or T cell receptor (TCR).
  • the immune cell-associated antigen is an antigen presented on a T cell, B cell, natural killer (NK) cell, or a tumor-infiltrating lymphocyte (TIL).
  • the vector may target an immune cell in a patient and deliver a CAR or TCR to the immune cell, thereby providing an immune cell therapy in situ.
  • immune cells e.g., T cells, natural killer (NK) cells, and B cells
  • TCR therapy targets and eliminates cells that present their antigens via major histocompatibility complex (MHC).
  • MHC major histocompatibility complex
  • immune cells e.g., T cells, natural killer (NK) cells, and B cells
  • CAR chimeric antigen receptors
  • Immune cells equipped with CAR may bind specific cells (e.g., cancer cells) regardless of whether antigens are presented on the cellular surface via major histocompatibility complex (MHC).
  • MHC major histocompatibility complex
  • tumor-infiltrating lymphocytes (TIL) e.g., immune cells
  • TIL tumor-infiltrating lymphocytes
  • a method for increasing the production of interferon gamma (IFN ⁇ ) or growth or proliferation of immune cells in a patient in need thereof comprising administering to the patient an effective amount of a cannabinoid type 2 receptor (CB2R) modulator.
  • the CB2R modulator is not an agonist of the receptor.
  • the patient has a viral infection or cancer.
  • the patient suffers from immune cell exhaustion or is at risk for immune cell exhaustion.
  • a method for treating, reducing, or preventing immune cell exhaustion in a patient in need thereof comprising administering to the patient an effective amount of a CB2R modulator.
  • the CB2R modulator is not an agonist of the receptor.
  • the patient is currently or has previously been treated with an immunotherapeutic agent.
  • the immune cell activating agent is administered to the patient after cessation of administration of the immunotherapeutic agent.
  • the immune cell activating agent is administered to the patient concurrently with administration of the immunotherapeutic agent.
  • the immune cell activating agent is administered to the patient concurrently and after administration of the immunotherapeutic agent.
  • the immune cell is a T cell, B cell or NK cell. In some embodiments, the immune cell is a T cell and the immune cell exhaustion is T cell exhaustion. In some embodiments, the immune cell is a B cell and the immune cell exhaustion is B cell exhaustion. In some embodiments, the immune cell is a NK cell and the immune cell exhaustion is NK cell exhaustion.
  • the immunotherapeutic agent is a check-point inhibitor.
  • the check-point inhibitor is selected from atezolizumab, avelumab, cemiplimab, labrolizumab, durvalumab, ipilimumab, nivolumab, and pembrolizumab.
  • patient selection is determined by identifying abnormal (high or low) biomarker levels in immune cells compared to the biological marker levels in the immune cells of healthy individuals (i.e., those that are not in need of CB2R administration).
  • a method of diagnosing immune cell exhaustion in a patient comprising: (a) obtaining a biological sample comprising immune cells from a patient; (b) detecting and quantifying the presence of one or more biological markers in the biological sample; (c) comparing the levels of the one or more biological markers in the biological sample of the patient to the levels of the one or more biological markers in a healthy individual; and (d) diagnosing the patient with immune cell exhaustion when the levels of the one or more biological markers in the biological sample are abnormal; and wherein the one or more biological markers are selected from the group consisting of 2B4, BTLA, CD160, CTLA-4, LAG-3, PD-1, TIM-3, TIGIT, granzyme B, interferon gamma (IFN ⁇ ), interleukin 1 (IL-1), interleukin 2 (IL-2), interleukin 4 (IL-4), interleukin 5 (IL-5), interleukin 6 (IL-6), interleukin 10 (IL-10), inter
  • the patient after hours, days, or weeks, the patient exhibits an improvement in expression levels of biological markers in immune cells (e.g., lymphocytes (T cells, B cells, and NK cells), neutrophils, and monocytes/macrophages) compared to the biological markers before administration of the CB 2 R modulator.
  • biological markers are immunomodulatory receptors selected from the group consisting of: 2B4, BTLA, CD160, CTLA-4, LAG-3, PD-1, TIM-3, and TIGIT.
  • the biological markers are effector molecules selected from the group consisting of: granzyme B, interferon gamma (IFN ⁇ ), interleukin 1 (IL-1), interleukin 2 (IL-2), interleukin 4 (IL-4), interleukin 5 (IL-5), interleukin 6 (IL-6), interleukin 10 (IL-10), interleukin 12 (IL-12), interleukin 13 (IL-13), interleukin 17 (IL-17), interleukin 22 (IL-22), transforming growth factor beta (TGF- ⁇ ), and tumor necrosis factor alpha (TNF ⁇ ).
  • IFN ⁇ interferon gamma
  • IL-1 interleukin 1
  • IL-2 interleukin 2
  • IL-4 interleukin 4
  • IL-5 interleukin 5
  • IL-6 interleukin 6
  • IL-10 interleukin 10
  • IL-12 interleukin 12
  • IL-13 interleukin 13
  • IL-17 interleukin 17
  • IL-22
  • the biological markers are transcription factors selected from the group consisting of: nuclear factor of activated T-cells (NFAT), nuclear receptor subfamily 4 group A (NR4A), T-cell-specific transcription factor 1 (TCF-1), thymocyte selection-associated high mobility group box protein (TOX), and TOX high mobility group box family member 2 (TOX2).
  • NFAT nuclear factor of activated T-cells
  • NFR4A nuclear receptor subfamily 4 group A
  • TCF-1 T-cell-specific transcription factor 1
  • TOX thymocyte selection-associated high mobility group box protein
  • TOX TOX high mobility group box family member 2
  • the CB 2 R modulator is not a CB 2 R agonist.
  • the CB 2 R modulator is a CB 2 R antagonist selected from the group consisting of: Compound 8, Compound 13, Compound 109, Compound 121, Compound 149, Compound 265, Compound 266, Compound 267, Compound 268, Compound 269, Compound 270, cannabidiol, AM630, and combinations thereof.
  • the CB2R modulator is a CB2R inverse agonist selected from the group consisting of: SR144528, XL-001, and combinations thereof.
  • the CB2R modulator is a negative allosteric modulator selected from the group consisting of Dihydro-gambogic acid (DHGA), trans- ⁇ -caryophyllene (TBC), mambaquaretin-1, Exenetide (Byetta), and combinations thereof.
  • the CB2R modulator is an agent that causes gene knockout of CB2R in immune cells (e.g., lymphocytes (T cells, B cells, and NK cells), neutrophils, and monocytes/macrophages).
  • the agent is a site-specific nuclease selected from the group consisting of: zinc finger nuclease, transcription activator-like effector nuclease (TALENS), clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPER-associated systems (Cas) complexes, and combinations thereof.
  • the methods described herein further comprise administering a chimeric antigen receptor T-cell (CART) therapy to the patient.
  • CART chimeric antigen receptor T-cell
  • a method for re-activating exhausted immune cells in a patient in need thereof, comprising administering to the patient an effective amount of a cannabinoid type 2 receptor (CB2R) modulator.
  • CB2R cannabinoid type 2 receptor
  • the patient has cancer, a chronic infection, an acute infection, or an immunodeficiency.
  • the patient is being treated with, or has been treated with, a chimeric antigen receptor T-cell (CART) therapy.
  • the patient is being treated with, or has been treated with, a check point inhibitor.
  • the checkpoint inhibitor is selected from atezolizumab, avelumab, cemiplimab, labrolizumab, durvalumab, ipilimumab, nivolumab, and pembrolizumab.
  • the CART therapy comprises allogeneic CAR T cells. In some embodiments, CART therapy comprises alloreactive CAR T cells. In some embodiments, the CART therapy comprises autologous CAR T cells. In some embodiments, the CART therapy comprises bispecific CAR T cells.
  • the CAR T-cell therapy targets antigens on B cells, e.g., CD19, CD22, CD38, CS1, or BCMA, or combinations thereof.
  • the CART therapy is ABECMA® (idecabtagene vicleucel), BREYANZI® (lisocabtagene maraleucel), KYMRIAH® (tisagenlecleucel), TECARTUS® (brexucabtagene autoleucel), or YESCARTA® (axicabtagene ciloleucel).
  • ABECMA® idecabtagene vicleucel
  • BREYANZI® laisocabtagene maraleucel
  • KYMRIAH® tisagenlecleucel
  • TECARTUS® TECARTUS®
  • YESCARTA® axicabtagene ciloleucel
  • the target immune cell is an endogenous cell, optionally being activated, in situ, to have therapeutic activities.
  • an in situ activated immune cell can also be at risk of exhaustion.
  • the target immune cell can be contacted with a CB2R modulator to prevent or reduce its exhaustion.
  • CB 2 R cannabinoid type 2 receptor
  • a method for treating, reducing, or preventing immune cell exhaustion in a patient in need thereof comprising administering to the patient an effective amount of a cannabinoid type 2 receptor (CB 2 R) modulator, and a vector comprising a nucleic acid, optionally with a targeting protein against an immune cell-associated antigen, wherein the nucleic acid encodes an engineered receptor against a disease-associated antigen.
  • CB 2 R cannabinoid type 2 receptor
  • Ex-vivo therapy [0097] Also contemplated within the scope of embodiments of this disclosue are ex-vivo methods of therapy.
  • the CAR T cells prior to injection of CAR T cells in a patient in need thereof, the CAR T cells are pre-treated with a CB2 modulator described herein.
  • provided herein is a method of treating, preventing, reducing, or delaying T cell exhaustion in a patient in need thereof, comprising administering CB2 modulator-pre-treated CAR T cells to the patient in need thereof.
  • the CB2 modulator is administered in combination with the pre- treated CAR T cells.
  • pre- treatment of other immune cells such as, e.g., NK cells.
  • co-admininstration of a CB2 modulator with CB2-modulator pre- treated- immune cells such as, e.g., pre-treated NK cells.
  • the immune cell target of the methods described herein may be from an external source, such as from a cellular immunotherapeutic composition.
  • the CB2R inhibition can also be carried out ex vivo. That is, the CB2R inhibition can be carried out in the immune cell before it is administered to the patient.
  • Such a pre-administration/ex vivo treatment it is contemplated, can also be effective in preventing exhaustion of the immune cell.
  • a composition that includes a cannabinoid type 2 receptor (CB 2 R) modulator and an immune cell.
  • the immune cell has been engineered to express a receptor that has specificity to a disease-associated antigen.
  • the immune cell is a T cell, B cell, natural killer (NK) cell, or tumor-infiltrating lymphocyte (TIL).
  • T cell or TIL are selected from the group consisting of CD4+ T, memory CD4+ T, CD8+ T, and memory CD8+ T cell.
  • the B cell or TIL are selected from the group consisting of plasmablast, plasma, lymphoplasmacytoid, memory B, B-1, B-2, and regulatory B cells.
  • the NK cell or TIL are selected from the group consisting of primary NK, NK-92, NK-92.26.5, NK 92.MI, NK-92Ci, NK-92Fc, NK3.3, NKL, NKG, NK-YT, NK-YTS, KHYG-1, HATAK, umbilical cord blood (UCB)-derived NK, stem cell-derived NK, induced pluripotent stem cell (iPSC)-derived NK, human induced pluripotent stem cell (HPC)-derived NK, and cytokine-induced memory-like NK cell.
  • URB umbilical cord blood
  • iPSC induced pluripotent stem cell
  • HPC human induced pluripotent stem cell
  • the engineered receptor is a chimeric antigen receptor (CAR) or a T cell receptor (TCR).
  • the engineered receptor is an antibody or fragment thereof.
  • the antibody or fragment thereof are selected from the group consisting of hR1 (anti-IGF-1R), hPAM4 (anti-mucin), KC4 (anti-mucin), hA20 (anti-CD20), hA19 (anti-CD19), hIMMU31 (anti-AFP), hLL1 (anti-CD74), hLL2 (anti-CD22), RFB4 (anti-CD22), hMu-9 (anti- CSAp), hL243 (anti-HLA-DR), hMN-14 (anti-CEACAM-5), hMN-15 (anti-CEACAM-6), hRS7 (anti-TROP-2), hMN-3 (anti-CEACAM-6), CC49 (anti-TAG-72), J591
  • the antibody or fragment thereof may be an scFv or Fab antibody fragment.
  • the disease-associated antigen is selected from the group consisting of CD19, CD20, CD21, CD22, CD44, CD62L, CD74, CD79b, HLA-DR, ⁇ 7-integrin, and BCR.
  • the TAA may be an oncogenic viral gene. In some embodiments, the TAA may be an oncogenic mutated gene. [00104] In some embodiments is a method of making an immune cell comprising: (a) obtaining an immune cell from a patient with a disease in need of treatment; and (b) transducing the immune cell with a viral vector comprising a cannabinoid type 2 receptor (CB 2 R) modulator. In some embodiments, the immune is also transduced, or has been transduced, with a nucleic acid encoding a receptor having specificity to a disease-associated antigen. In some embodiments, the receptor is a chimeric antigen receptor (CAR) or a T cell receptor (TCR).
  • CAR chimeric antigen receptor
  • TCR T cell receptor
  • an engineered immune cell comprising an engineered receptor having specificity to a disease-associated antigen and having reduced or no CB2R activity.
  • the immune cell may be treated with an agent that causes gene knockout of CB2R.
  • the agent that causes gene knockout of CB2R may be a site-specific nuclease.
  • the site-specific nuclease is selected from the group consisting of zinc finger nuclease, transcription activator-like effector nuclease (TALENS), and clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPER-associated systems (Cas) complexes.
  • Immune Cell Exhaustion [00107] Patients suffering from a variety of conditions will benefit from the methods provided herein. In some embodiments, disclosed herein are methods of treating immune cell exhaustion with a CB2R modulator as described herein.
  • immune cell exhaustion referes to varied, but distinct, epigenetic and metabolic states of immune cells observed in the presence of persistent antigen and chronic immune cell receptor, e.g., T cell receptor, stimulation, typically as a result of chronic infections (e.g., HIV infections, SARS CoV-2 infections) and cancer progression.
  • persistent antigen and chronic immune cell receptor e.g., T cell receptor
  • stimulation typically as a result of chronic infections (e.g., HIV infections, SARS CoV-2 infections) and cancer progression.
  • T cells for example, compared with memory or effector T cells, exhausted T cells exhibit reduced responses to antigens, altered effector functions (e.g., decreased cytokine expression), increased chemokine expression, high expression levels of inhibitory receptors (e.g., PD1, TIM3, LAG3, CTLA4, CD39, CD73, and TIGIT), reduced proliferative capacity, altered transcriptional program involving the transcription factor TOX, a unique epigenetic landscape, and reduced levels of signaling proteins associated with activation and/or increased levels of negative regulatory proteins (e.g., diacylglycerol kinases, phosphatases, and E3 ubiquitin ligases).
  • altered effector functions e.g., decreased cytokine expression
  • increased chemokine expression e.g., high expression levels of inhibitory receptors (e.g., PD1, TIM3, LAG3, CTLA4, CD39, CD73, and TIGIT)
  • reduced proliferative capacity e.g., altered transcriptional
  • NK cells and B cells exhibit an exhausted status similar with exhausted T cells, displaying decreased proliferation, poor effector function, and altered phenotype.
  • a CB 2 R modulator described herein, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof increases immune cell responses to antigens, increases immune cell cytokine expression, decreases immune cell chemokine expression, reduces immune cell expression of inhibitory receptors, increases immune cell proliferative capacity, increases immune cell expression of signaling proteins associated with immune cell activation, and/or reduces immune cell expression of negative regulatory proteins thereby reversing or reducing immune cell exhaustion.
  • a patient treated with a CB2R modulator suffers from chronic infection or disease associated with decreased immune cell function and/or immune cell exhaustion.
  • the chronic infection or disease is cancer and/or viral infection.
  • a CB2R modulator described herein, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof reduces, ameliorates, or inhibits the immunosuppression and decreased cell proliferation associated with decreased immune cell function and/or immune cell exhaustion.
  • Cancer In some embodiments, patients who may benefit from the methods described herein have cancer.
  • cancer refers to an abnormal growth of cells that tend to proliferate in an uncontrolled way and, in some cases, to metastasize (spread).
  • Types of cancer include, but are not limited to, solid tumors (such as those of the bladder, bowel, brain, breast, endometrium, heart, kidney, lung, liver, uterus, lymphatic tissue (lymphoma), ovary, pancreas or other endocrine organ (thyroid), prostate, skin (melanoma or basal cell cancer)) or hematological tumors (such as the leukemias and lymphomas) at any stage of the disease with or without metastases.
  • solid tumors such as those of the bladder, bowel, brain, breast, endometrium, heart, kidney, lung, liver, uterus, lymphatic tissue (lymphoma), ovary, pancreas or other endocrine organ (thyroid), prostate, skin (melanoma or basal cell cancer)
  • hematological tumors such as the leukemias and lymphomas
  • cancers include and are not limited to carcinomas, sarcomas, benign tumors, primary tumors, tumor metastases, solid tumors, non-solid tumors, blood tumors, leukemias and lymphomas, and/or primary and metastatic tumors.
  • the patient may have solid tumours.
  • a solid tumor is an abnormal mass of tissue that usually does not contain cysts or liquid areas. Solid tumors may be benign (not cancer), or malignant (cancer). Different types of solid tumors are named for the type of cells that form them. Examples of solid tumors are carcinomas, sarcomas, and lymphomas.
  • Carcinomas include, but are not limited to, esophageal carcinoma, hepatocellular carcinoma, basal cell carcinoma, squamous cell carcinoma, bladder carcinoma, bronchogenic carcinoma, colon carcinoma, colorectal carcinoma, gastric carcinoma, lung carcinoma, including small cell carcinoma and non-small cell carcinoma of the lung, adrenocortical carcinoma, thyroid carcinoma, pancreatic carcinoma, breast carcinoma, ovarian carcinoma, prostate carcinoma, adenocarcinoma, renal cell carcinoma, Wilm's tumor, cervical carcinoma, uterine carcinoma, testicular carcinoma, osteogenic carcinoma, epithelial carcinoma, and nasopharyngeal carcinoma.
  • Sarcomas include, but are not limited to, fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, chordoma, osteogenic sarcoma, osteosarcoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's sarcoma, leiomyosarcoma, rhabdomyosarcoma, and other soft tissue sarcomas.
  • Leukemias include, but are not limited to, a) chronic myeloproliferative syndromes (neoplastic disorders of multipotential hematopoietic stem cells); b) acute myelogenous leukemias; c) chronic lymphocytic leukemias (CLL), including B-cell CLL, T-cell CLL prolymphocyte leukemia, and hairy cell leukemia; and d) acute lymphoblastic leukemias (characterized by accumulation of lymphoblasts).
  • Lymphomas include, but are not limited to, B-cell lymphomas (e.g., Burkitt's lymphoma); Hodgkin's lymphoma; and the like.
  • Benign tumors include, e.g., hemangiomas, hepatocellular adenoma, cavernous hemangioma, focal nodular hyperplasia, acoustic neuromas, neurofibroma, bile duct adenoma, bile duct cystanoma, fibroma, lipomas, leiomyomas, mesotheliomas, teratomas, myxomas, nodular regenerative hyperplasia, trachomas and pyogenic granulomas.
  • hemangiomas e.g., hemangiomas, hepatocellular adenoma, cavernous hemangioma, focal nodular hyperplasia, acoustic neuromas, neurofibroma, bile duct adenoma, bile duct cystanoma, fibroma, lipomas, leiomyomas, mesotheliomas, teratomas,
  • Primary and metastatic tumors include, e.g., lung cancer; breast cancer; colorectal cancer; anal cancer; pancreatic cancer; prostate cancer; ovarian carcinoma; liver and bile duct carcinoma; esophageal carcinoma; bladder carcinoma; carcinoma of the uterus; glioma, glioblastoma, medulloblastoma, and other tumors of the brain; kidney cancers; cancer of the head and neck; cancer of the stomach; multiple myeloma; testicular cancer; germ cell tumor; neuroendocrine tumor; cervical cancer; carcinoids of the gastrointestinal tract, breast, and other organs.
  • lung cancer e.g., breast cancer; colorectal cancer; anal cancer; pancreatic cancer; prostate cancer; ovarian carcinoma; liver and bile duct carcinoma; esophageal carcinoma; bladder carcinoma; carcinoma of the uterus; glioma, glioblastoma, medulloblastoma, and other tumors of the brain;
  • chronic infection refers to an infection characterized by the continued presence or recurrence of infectious bacteria or virus for weeks, months, years, or a lifetime after a primary infection.
  • viral infections include lymphocytic choriomeningitis (LCMV), hepatitis B virus (HBV), hepatitis C virus (HCV), human immunodeficiency virus (HIV), Epstein-Barr virus (EBV), SARS CoV-2 infections including long Covid, and cytomegalovirus (CMV).
  • Non-limiting examples of bacterial infections include Mycobacterium tuberculosis, Salmonella Typhi, Pseudomonas aeruginosa, and Escherichia coli.
  • the patient has a disease or disorder that is or is associated with a chronic infection.
  • the chronic infections are associated with decreased immune cell function and/or immune cell exhaustion.
  • the chronic infection is a viral infection (e.g., long covid, HIV).
  • the chronic infection is a bacterial infection. 4.
  • Cannabinoid type 2 receptor (CB 2 R) modulators [0114] Cannabinoid type 2 receptor (CB 2 R) modulators interact with binding sites on CB 2 R.
  • CB 2 R modulators that inhibit canonical CB 2 R function (i.e., immunosuppression), restore immune cell (e.g., T cell, NK cell, and B cell) functions and relieve innate and adaptive immunosuppression caused by immune cell exhaustion.
  • a CB2R modulator is a CB2R antagonist and/or inverse agonist.
  • a CB2R antagonist and/or inverse agonist is SR144528 or any other CB2R antagonist and/or inverse agonist described in WO 2001/64212, which compounds are incorporated herein by reference.
  • a CB2R antagonist and/or inverse agonist is AM630 or any other CB2R antagonist and/or inverse agonist described in WO 2019/025474 and/or WO 2017/149387, which compounds are incorporated herein by reference.
  • a CB2R antagonist and/or inverse agonist is XL-001 or any other CB2R antagonist and/or inverse agonist described in US 2013/0172388, which compounds are incorporated herein by reference.
  • a CB2R modulator is a CB2R allosteric modulator.
  • CB2R allosteric modulators include and are not limited to Dihydro-gambogic acid (DHGA), TBC (trans - ⁇ - caryophyllene), IQM311, and N-[5-Bromo-1,2-dihydro-1-(4’-fluorobenzyl)-4-methyl-2-oxo-pyridin- 3-yl]cycloheptanecarboxamide.
  • the compound is a CB 2 R antagonist.
  • the CB 2 R antagonist is 2-[(1R,6R)-3-methyl-6-prop-1-en-2-ylcyclohex-2-en-1-yl]-5-pentylbenzene-1,3-diol (cannabidiol), [6-iodo-2-methyl-1-(2-morpholin-4-ylethyl)indol-3-yl]-(4-methoxyphenyl)methanone (AM630), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.
  • the compound is a CB2R inverse agonist.
  • the CB2R inverse agonist is 5-(4-chloro-3-methylphenyl)-1-[(4-methylphenyl)methyl]-N-[(1S,2S,4R)- 1,3,3-trimethyl-2-bicyclo[2.2.1]heptanyl]pyrazole-3-carboxamide (SR144528), N-(1,3-benzodioxol- 5-ylmethyl)-7-methoxy-2-oxo-8-pentoxy-1H-quinoline-3-carboxamide (JTE 907), N-[[4- (diethylamino)phenyl]methyl]-4-methoxy-N-(4-methylphenyl)benzenesulfonamide (XL-001), 2-[4- [(Z)-1,2-diphenylbut-1-enyl]phenoxy]-N,N-dimethylethanamine (tamoxifen) and its metabolites, or a pharmaceutically acceptable salt, solvate or stereoi
  • the compound is a CB 2 R negative allosteric modulator.
  • the CB 2 R negative allosteric modulator is (Z)-4-[12,18-dihydroxy-8,21,21-trimethyl-5- (3-methylbut-2-enyl)-8-(4-methylpent-3-enyl)-14-oxo-3,7,20- trioxahexacyclo[15.4.1.0 2,15 .0 2,19 .0 4,13 .0 6,11 ]docosa-4(13),5,9,11,15-pentaen-19-yl]-2-methylbut-2- enoic acid (Dihydro-gambogic acid, or DHGA), (1R,4E,9S)-4,11,11-trimethyl-8- methylidenebicyclo[7.2.0]undec-4-ene (trans- ⁇ -caryophyllene, or TBC), mambaquaretin-1, Exenetide (e.
  • CB2 receptor (CB 2 R) modulators are CB2 receptor (CB 2 R) modulators.
  • the compound may be selected from those compounds described in International Application No.
  • the modulator is a compound of Formula (I), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof: Formula (I) wherein, R 1 is -OH, C1-C4alkyl, C2-C4alkenyl, C2-C4alkynyl, C1-C4alkoxy, C1-C4deuteroalkyl, C1- C4deuteroalkoxy, C1-C4fluoroalkyl, C1-C4fluoroalkoxy, C1-C4heteroalkyl, C 3 -C 6 cycloalkyl, C 3 -C 6 heterocycloalkyl containing 1-2 N atom and 0 or 1 O or S atom, or a C 3 - C 6 heterocycloalkyl containing 0 or
  • R 4 when R 6 is H, R 4 is not cyclohexyl, 4-methylcyclohexyl, or cycloheptyl. In some embodiments, R 6 is H and R 4 is cis-4-methylcyclohexyl.
  • R 3 is H or -CH3;
  • L 1 is absent, -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH(CH3)-, -C(CH3)2-, or cyclopropyl-1,1-diyl;
  • R 10 and R 11 are independently selected from H or -CH3; or R 10 and R 11 are taken together with the carbon atom to which they are attached to form a cyclopropyl-1,1-diyl;
  • X 1 is N; and
  • X 2 is CR 8 ; or X 1 is CR 8 ; and X 2 is N.
  • R 1 is -OH, -CH 3 , -OCH 3 , -CD 3 , -OCD 3 , -CFH 2 , -CHF 2 , -CF 3 , -OCFH 2 , -OCHF 2 , -OCF 3 , cyclopropyl, aziridinyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, piperazinyl, or piperidinyl.
  • R 1 is -OH, -CH 3 , - OCH3, -OC(CH3)2, -CD3, -OCD3, -CFH2, -CHF2, -CF3, -OCFH2, -OCHF2, -OCF3, cyclopropyl, aziridinyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, piperazinyl, or piperidinyl. [0126] In some embodiments, R 1 is -OH or -CH3. In some embodiments, R 1 is -O-C1-C 3 alkyl.
  • the compound of Formula (I) has the following structure of Formula (II), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof: Formula (II); wherein L 1 , R 2 , R 4 , R 6 , and R 7 are as defined in some or any embodiments of Formula (I).
  • R 5 is a ring B that is unsubstituted or is substituted with 1, 2, 3, or 4 R b ;
  • ring B is a monocyclic C 3 -C 8 cycloalkyl, or bicyclic C 5 -C 12 cycloalkyl that is a fused bicyclic C 5 - C 12 cycloalkyl, bridged bicyclic C 5 -C 12 cycloalkyl, or spiro bicyclic C 5 -C 12 cycloalkyl; or ring B is a monocyclic C2-C 6 heterocycloalkyl, or bicyclic C5-C8heterocycloalkyl that is a fused bicyclic C5- C8heterocycloalkyl, bridged bicyclic C5-C8heterocycloalkyl, or spiro bicyclic C5-C8heterocycloalkyl; or ring B is a phenyl; or
  • L 2 is absent;
  • R 5 is a ring B that is unsubstituted or is substituted with 1, 2, 3, or 4 R b ;
  • ring B is a monocyclic C 3 -C8cycloalkyl, or bicyclic C5-C12cycloalkyl that is a fused bicyclic C5-C12cycloalkyl, bridged bicyclic C5-C12cycloalkyl, or spiro bicyclic C5-C12cycloalkyl; or
  • ring B is a monocyclic C 3 -C 6 heterocycloalkyl, or bicyclic C5-C8heterocycloalkyl that is a fused bicyclic C5-C8heterocycloalkyl, bridged bicyclic C5-C8heterocycloalkyl, or spiro bicyclic C5-C8heterocycloalkyl.
  • L 2 is absent;
  • R 5 is a ring B that is unsubstituted or is substituted with 1, 2, 3, or 4 R b ;
  • ring B is cyclobutyl, cyclopentyl, or cyclohexyl; or
  • ring B is a bicyclic C5-C12cycloalkyl that is a spiro[2.2]pentanyl, spiro[3.3]heptanyl, spiro[4.3]octanyl, spiro[3.4]octanyl, spiro[3.5]nonanyl, spiro[4.4]nonanyl, spiro[4.5]decanyl, spiro[5.4]decanyl, spiro[5.5]undecanyl, bicyclo[1.1.1]pentanyl, bicyclo[2.2.2]octanyl, bicyclo[2.2.1]heptanyl, adamantyl, or decalin
  • L 2 is absent;
  • R 5 is a ring B that is unsubstituted or is substituted with 1, 2, 3, or 4 R b ;
  • ring B is cyclobutyl, cyclopentyl, or cyclohexyl; or ring B is spiro[3.3]heptanyl, bicyclo[1.1.1]pentanyl, or bicyclo[2.2.2]octanyl.
  • each R b is independently selected from the group consisting of F, Cl, Br, -CN, -OH, -NH 2 , -NH(CH 3 ), -N(CH 3 ) 2 , -CH 3 , -OCH 3 , -CD 3 , -OCD 3 , -CFH 2 , -CHF 2 , -CF 3 , -OCFH 2 , -OCHF 2 , and -OCF 3 ; or two R b that are attached to the same carbon atom are taken together with the carbon atom to form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, thietanyl,
  • R 4 is a bridged C5-C12 cycloalkyl selected from [0139]
  • L 2 is absent or -CR 10 R 11 -;
  • R 10 and R 11 are independently selected from H or -CH3; or
  • R 10 and R 11 are taken together with the carbon atom to which they are attached to form a cyclopropyl-1,1-diyl;
  • R 5 is a ring B that is unsubstituted or is substituted with 1, 2, 3, or 4 R b ;
  • ring B is phenyl or monocyclic heteroaryl.
  • ring B is phenyl, pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl.
  • L 2 is absent or -CR 10 R 11 -; R 10 and R 11 are independently selected from H or -CH3; or R 10 and R 11 are taken together with the carbon atom to which they are attached to form from H or -CH 3 ; or R 10 and R 11 are taken together with the carbon atom to which they are attached to form a cyclopropyl-1,1-diyl; m is 0, 1, or 2; each R b is independently selected from the group consisting of F, Cl, Br, -CN, -OH, -NH 2 , -NH(CH 3 ), -N(CH 3 ) 2 , -CH 3 , -OCH 3 , -CD 3 , -OCD 3 , -CFH 2 , - CHF 2
  • L 1 is -CH 2 CH 2 -;
  • R 2 is a ring A that is unsubstituted or is substituted with 1, 2, 3, or 4 R a ;
  • ring A is C 3 -C 6 heterocycloalkyl containing 1-2 N atoms and 0 or 1 O or S atom, or C4-C7 heterocycloalkyl containing 0 or 1 N atom and 1 O or S atom;
  • R 6 is a ring C that is unsubstituted or is substituted with 1, 2, 3, or 4 R c ;
  • ring C is phenyl, naphthyl, heteroaryl, C 3 - C12cycloalkyl, or C 3 -C 6 heterocycloalkyl.
  • -L 1 -R 2 is [0146]
  • the compound of Formula (I) has the following structure of Formula (III), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof:
  • R 6 is a ring C that is unsubstituted or is substituted with 1, 2, 3, or 4 R c ;
  • ring C is phenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, thiomorpholinyl, or piperidinyl.
  • the compound of Formula (I) has the following structure of Formula (IV), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof: Formula (IV); wherein R 2 , R 4 , R 6 , and R 7 are as defined in some or any embodiments of Formula (I).
  • L 1 is -CH2-, -CH(CH3)-, -C(CH3)2-, or cyclopropyl-1,1-diyl
  • R 2 is a ring A that is unsubstituted or is substituted with 1, 2, 3, or 4 R a ;
  • ring A is phenyl, or 6-membered heteroaryl.
  • R 1 is hydrogen, -OH, C1-C4alkyl, C2-C4alkenyl, C2-C4alkynyl, C1-C4alkoxy, C1-C4deuteroalkyl, C1-C4deuteroalkoxy, C1-C4fluoroalkyl, C1-C4fluoroalkoxy, C1-C4heteroalkyl, C 3 -C 6 cycloalkyl, C 3 -C 6 heterocycloalkyl containing 1 N atom and 0 or 1 O or S atom, or a C 3 -C 6 heterocycloalkyl containing 0 or 1 N atom and 1 O or S atom; L 1 is absent, C1-C4alkylene, or C 3 -C5cycloalkylene
  • R 4 when R 1 is H, R 4 is not cyclohexyl substituted by 0, 1, 2, 3 or 4 methyl groups.
  • the bridged cycloalkyl is bridged bicyclic C 5 - C 12 cycloalkyl.
  • R 3 is H or -CH 3 ;
  • L 1 is absent, -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH(CH 3 )-, -C(CH 3 ) 2 -, or cyclopropyl-1,1-diyl;
  • X 1 is N; and
  • X 2 is CR 8 ; or
  • X 1 is CR 8 ; and X 2 is N.
  • R 1 is hydrogen, -OH, -CH 3 , -OCH 3 , -CD 3 , -OCD 3 , -CFH 2 , -CHF 2 , -CF 3 , -OCFH 2 , -OCHF 2 , -OCF 3 , cyclopropyl, aziridinyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, piperazinyl or piperidinyl.
  • R 1 is hydrogen, -OH or -CH3.
  • the compound of Formula (X) has the following structure of Formula (XI), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof: Formula (XI); wherein L 1 , R b , u, v, R 1 , R 2 , R 4 , R 6 , and R 7 are as defined in some or any embodiments of Formula (X).
  • each R b is independently selected from the group consisting of F, Cl, Br, -CN, -OH, -NH 2 , -NH(CH 3 ), -N(CH 3 ) 2 , -CH 3 , -OCH 3 , -CD 3 , -OCD 3 , -CFH 2 , -CHF 2 , -CF 3 , -OCFH 2 , -OCHF 2 , and -OCF 3 ; or two R b that are attached to the same carbon atom are taken together with the carbon atom to form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, thiomorpholinyl, or piperidinyl.
  • the compound of Formula (X) has the following structure of Formula (XIII), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof: Formula (XIII); wherein L 1 , R 1 , R 2 , R 5 , R 6 , R 7 , R 10 and R 11 are as defined in some or any embodiments of Formula (X).
  • R 5 is a ring B that is unsubstituted or is substituted with 1, 2, 3, or 4 R b ; ring B is phenyl or monocyclic heteroaryl.
  • R 5 is a ring B that is unsubstituted or is substituted with 1, 2, 3, or 4 R b ; or ring B is phenyl, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, or triazinyl.
  • ring B is phenyl, pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl.
  • each R b is independently selected from the group consisting of F, Cl, Br, -CN, -OH, -NH2, -NH(CH3), -N(CH3)2, -CH3, -OCH3, -CD3, -OCD3, -CFH2, -CHF2, -CF3, -OCFH2, -OCHF2, and -OCF3.
  • L 1 is -CH2CH2-;
  • R 2 is a ring A that is unsubstituted or is substituted with 1, 2, 3, or 4 R a ;
  • ring A is C 3 -C 6 heterocycloalkyl containing 1-2 N atoms and 0 or 1 O or S atom, or C 3 -C 6 heterocycloalkyl containing 0 or 1 N atom and 1 O or S atom;
  • R 6 is a ring C that is unsubstituted or is substituted with 1, 2, 3, or 4 R c ;
  • ring C is phenyl, naphthyl, heteroaryl, C 3 - C12cycloalkyl, or C2-C10heterocycloalkyl.
  • L 1 is -CH 2 CH 2 -;
  • R 2 is a ring A that is unsubstituted or is substituted with 1, 2, 3, or 4 R a ;
  • ring A is azetidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, piperidinyl, or piperazinyl.
  • the compound of Formula (X) has the following structure of Formula (XIA), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof: Formula (XIA); wherein R b , u, v, R 1 , R 6 , and R 7 are as defined in some or any embodiments of Formula (X).
  • the compound of Formula (X) has the following structure of Formula (XIIA), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof:
  • Formula (XIIA); wherein X 1 , X 2 , R 1 , R 6 , and R 7 are as defined in some or any embodiments of Formula (X); n1, n2, and n3 are each independently 1, 2 or 3; and R d is halogen, - -NR 13 C( O)(R 12 ), -NR 1 C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 alkoxy, C 1 -C 4 deuteroalkyl, C 1 -C 4 deuteroalkoxy, C 1 -C 4 fluoroalkyl, C 1 - C 4 fluoroalkoxy, C 1 -C 4 heteroalkyl, or substituted or unsubstituted monocyclic C 3 -C 6 heterocycloalkyl.
  • the compound of Formula (X) has the following structure of Formula (XIIIA), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof: Formula (XIIIA); wherein R 1 , R 5 , R 6 , R 7 , R 10 , and R 11 , are as defined in some or any embodiments of Formula (X).
  • R 6 is a ring C that is unsubstituted or is substituted with 1, 2, 3, or 4 R c ;
  • ring C is phenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, thiomorpholinyl, or piperidinyl.
  • L 1 is -CH2-, -CH(CH3)-, -C(CH3)2-, or cyclopropyl-1,1-diyl
  • R 2 is a ring A that is unsubstituted or is substituted with 1, 2, 3, or 4 R a ;
  • ring A is phenyl, C 3 -C10cycloalkyl, 5-membered heteroaryl, or 6-membered heteroaryl.
  • the compound of Formula (X) has the following structure of Formula (XI), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof: Formula (XIB); wherein R b , u, v, R 1 , R 2 , R 6 , and R 7 are as defined in some or any embodiments of Formula (X).
  • the compound of Formula (X) has the following structure of Formula (XII), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof: Formula (XIIIB); wherein R 1 , R 5 , R 6 , R 7 , R 10 , and R 11 , are as defined in some or any embodiments of Formula (X). , .
  • R 6 is a ring C that is unsubstituted or is substituted with 1, 2, 3, or 4 R c , where R c is as defined herein; ring C is phenyl, naphthyl, heteroaryl,C 3 -C 6 cycloalkyl, or C 2 -C 6 heterocycloalkyl; R 4 is a bridged cycloalkyl selected from any -L 1 -R 2 selected from Table 1. In some of such embodiments, R 1 is H. In some other such embodiments, R 1 is OH or O-C 1 - C 3 alkyl.
  • R 6 is halo; R 4 is a bridged cycloalkyl selected from , and -L 1 -R 2 is any -L 1 -R 2 selected from Table 1.
  • R 1 is H.
  • R 1 is OH or O-C 1 -C 3 alkyl.
  • an agent that activates activation of immune cells e.g., dendritic cell (DC) mediated activation of T cells
  • DC dendritic cell
  • T cells is a compound that has a structure of any one of compounds 1– 109 as shown in Table 1, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.
  • an agent that activates immune cells is a compound selected from compounds 1- 6, 8-11, 13-17, 19-23, 26-63, 65-70, 72-73, 76-112, 114-119, 121-122, 125, 128, 132-135, 137-138, 140-143, 145, 148-150, 152-153, 158-159, and 161 as shown in Table 1, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.
  • an agent that activates immune cells is a compound selected from compounds 1-136, 138-142, and 145-180 as shown in Table 1, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.
  • an agent that activates immune cells is a compound selected from compounds 1-136, 138-142, and 145-257 as shown in Table 1, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.
  • an agent that activates immune cells is a compound selected from compounds 1-136, 138-142, 145-220, 223, 225-228, 233a-233b, 237, 242, and 247-248b as shown in Table 1, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.
  • an agent that activates immune cells is a compound selected from compounds 258-270 as shown in Table 1, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.
  • the modulator has one of the following structures of Table 1, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof: Table 1.
  • a CB2 modulator is a compound selected from Table 1A, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof. In some embodiments, a CB2 modulator is a compound that is not disclosed in PCT/US2021/030838 filed on May 5, 2021. Table 1A
  • CB2R modulators described herein are in the form of pharmaceutically acceptable salts.
  • active metabolites of these compounds having the same type of activity are included in the scope of the present disclosure.
  • the compounds described herein can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like.
  • “Pharmaceutically acceptable,” as used herein, refers a material, such as a carrier or diluent, which does not abrogate the biological activity or properties of the compound, and is relatively nontoxic, i.e., the material is administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.
  • pharmaceutically acceptable salt refers to a form of a therapeutically active agent that consists of a cationic form of the therapeutically active agent in combination with a suitable anion, or in alternative embodiments, an anionic form of the therapeutically active agent in combination with a suitable cation.
  • Handbook of Pharmaceutical Salts Properties, Selection and Use. International Union of Pure and Applied Chemistry, Wiley-VCH 2002. S.M. Berge, L.D. Bighley, D.C. Monkhouse, J. Pharm. Sci.1977, 66, 1-19. P. H. Stahl and C. G.
  • Pharmaceutical salts typically are more soluble and more rapidly soluble in stomach and intestinal juices than non-ionic species and so are useful in solid dosage forms. Furthermore, because their solubility often is a function of pH, selective dissolution in one or another part of the digestive tract is possible and this capability can be manipulated as one aspect of delayed and sustained release behaviors. Also, because the salt-forming molecule can be in equilibrium with a neutral form, passage through biological membranes can be adjusted.
  • pharmaceutically acceptable salts are obtained by reacting a compound of Formula (I), (II), (III), (IV), (X), (XI), (XIA), (XIB), (XII), (XIIA), (XIIB), (XIII), (XIIIA), and/or (XIIIB) with an acid.
  • the compound of Formula (I), (II), (III), (IV), (X), (XI), (XIA), (XIB), (XII), (XIIA), (XIIB), (XIII), (XIIIA), and/or (XIIIB), (i.e. free base form) is basic and is reacted with an organic acid or an inorganic acid.
  • Inorganic acids include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and metaphosphoric acid.
  • Organic acids include, but are not limited to, 1-hydroxy-2-naphthoic acid; 2,2- dichloroacetic acid; 2-hydroxyethanesulfonic acid; 2-oxoglutaric acid; 4-acetamidobenzoic acid; 4- aminosalicylic acid; acetic acid; adipic acid; ascorbic acid (L); aspartic acid (L); benzenesulfonic acid; benzoic acid; camphoric acid (+); camphor-10-sulfonic acid (+); capric acid (decanoic acid); caproic acid (hexanoic acid); caprylic acid (octanoic acid); carbonic acid; cinnamic acid; citric acid; cyclamic acid; dodecylsulfuric acid; ethane-1,2-disulfonic
  • pharmaceutically acceptable salts are obtained by reacting a compound of Formula (I), (II), (III), (IV), (X), (XI), (XIA), (XIB), (XII), (XIIA), (XIIB), (XIII), (XIIIA), and/or (XIIIB), with a base.
  • the compound of Formula (I), (II), (III), (IV), (X), (XI), (XIA), (XIB), (XII), (XIIA), (XIIB), (XIII), (XIIIA), and/or (XIIIB) is acidic and is reacted with a base.
  • a metal ion e.g., lithium, sodium, potassium, magnesium, calcium, or an aluminum ion.
  • compounds described herein coordinate with an organic base, such as, but not limited to, ethanolamine, diethanolamine, triethanolamine, tromethamine, meglumine, N-methylglucamine, dicyclohexylamine, tris(hydroxymethyl)methylamine.
  • compounds described herein form salts with amino acids such as, but not limited to, arginine, lysine, and the like.
  • Acceptable inorganic bases used to form salts with compounds that include an acidic proton include, but are not limited to, aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydroxide, lithium hydroxide, and the like.
  • the compounds provided herein are prepared as a sodium salt, calcium salt, potassium salt, magnesium salt, meglumine salt, N-methylglucamine salt or ammonium salt.
  • solvates contain either stoichiometric or non- stoichiometric amounts of a solvent, and are formed during the process of crystallization with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of compounds described herein are conveniently prepared or formed during the processes described herein. In addition, the compounds provided herein optionally exist in unsolvated as well as solvated forms.
  • the methods and formulations described herein include the use of N-oxides (if appropriate), or pharmaceutically acceptable salts of compounds having the structure of Formula (I), (II), (III), (IV), (X), (XI), (XIA), (XIB), (XII), (XIIA), (XIIB), (XIII), (XIIIA), and/or (XIIIB) as well as active metabolites of these compounds having the same type of activity.
  • sites on the organic radicals e.g.
  • the compounds described herein are labeled isotopically (e.g. with a radioisotope) or by another other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.
  • Compounds described herein include isotopically-labeled compounds, which are identical to those recited in the various formulae and structures presented herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes that can be incorporated into the present compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine chlorine, iodine, phosphorus, such as, for example, 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 35 S, 18 F, 36 Cl, 123 I, 124 I, 125 I, 131 I, 32 P and 33 P.
  • isotopically-labeled compounds described herein, for example those into which radioactive isotopes such as 3 H and 14 C are incorporated, are useful in drug and/or substrate tissue distribution assays.
  • substitution with isotopes such as deuterium affords certain therapeutic advantages resulting from greater metabolic stability, such as, for example, increased in vivo half-life or reduced dosage requirements.
  • one or more hydrogens of the compounds of Formula (I) are replaced with deuterium.
  • the compounds presented herein include all diastereomeric, individual enantiomers, atropisomers, and epimeric forms as well as the appropriate mixtures thereof.
  • the compounds and methods provided herein include all cis, trans, syn, anti,
  • Z isomers as well as the appropriate mixtures thereof.
  • Individual stereoisomers are obtained, if desired, by methods such as, stereoselective synthesis and/or the separation of stereoisomers by chiral chromatographic columns or the separation of diastereomers by either non-chiral or chiral chromatographic columns or crystallization and recrystallization in a proper solvent or a mixture of solvents.
  • compounds of Formula (I), (II), (III), (IV), (X), (XI), (XIA), (XIB), (XII), (XIIA), (XIIB), (XIII), (XIIIA), and/or (XIIIB), are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds/salts, separating the diastereomers and recovering the optically pure individual enantiomers.
  • resolution of individual enantiomers is carried out using covalent diastereomeric derivatives of the compounds described herein.
  • diastereomers are separated by separation/resolution techniques based upon differences in solubility.
  • separation of stereoisomers is performed by chromatography or by the forming diastereomeric salts and separation by recrystallization, or chromatography, or any combination thereof. Jean Jacques, Andre Collet, Samuel H. Wilen, “Enantiomers, Racemates and Resolutions”, John Wiley And Sons, Inc., 1981.
  • stereoisomers are obtained by stereoselective synthesis.
  • compounds described herein are prepared as prodrugs.
  • a “prodrug” refers to an agent that is converted into the parent drug in vivo.
  • Prodrugs are often useful because, in some situations, they are easier to administer than the parent drug. They are, for instance, bioavailable by oral administration whereas the parent is not. Further or alternatively, the prodrug also has improved solubility in pharmaceutical compositions over the parent drug. In some embodiments, the design of a prodrug increases the effective water solubility.
  • An example, without limitation, of a prodrug is a compound described herein, which is administered as an ester (the “prodrug”) but then is metabolically hydrolyzed to provide the active entity.
  • a further example of a prodrug is a short peptide (polyaminoacid) bonded to an acid group where the peptide is metabolized to reveal the active moiety.
  • a prodrug upon in vivo administration, is chemically converted to the biologically, pharmaceutically or therapeutically active form of the compound. In certain embodiments, a prodrug is enzymatically metabolized by one or more steps or processes to the biologically, pharmaceutically or therapeutically active form of the compound.
  • Prodrugs of the compounds described herein include, but are not limited to, esters, ethers, carbonates, thiocarbonates, N-acyl derivatives, N-acyloxyalkyl derivatives, N-alkyloxyacyl derivatives, quaternary derivatives of tertiary amines, N-Mannich bases, Schiff bases, amino acid conjugates, phosphate esters, and sulfonate esters.
  • a hydroxyl group in the compounds disclosed herein is used to form a prodrug, wherein the hydroxyl group is incorporated into an acyloxyalkyl ester, alkoxycarbonyloxyalkyl ester, alkyl ester, aryl ester, phosphate ester, sugar ester, ether, and the like.
  • a hydroxyl group in the compounds disclosed herein is a prodrug wherein the hydroxyl is then metabolized in vivo to provide a carboxylic acid group.
  • a carboxyl group is used to provide an ester or amide (i.e. the prodrug), which is then metabolized in vivo to provide a carboxylic acid group.
  • compounds described herein are prepared as alkyl ester prodrugs.
  • Prodrug forms of the herein described compounds, wherein the prodrug is metabolized in vivo to produce a compound of Formula (I), (II), (III), (IV), (X), (XIA), (XIB), (XII), (XIIA), (XIIB), (XIII), (XIIIA), and/or (XIIIB), as set forth herein are included within the scope of the claims.
  • some of the herein-described compounds is a prodrug for another derivative or active compound.
  • any one of the hydroxyl group(s), amino group(s) and/or carboxylic acid group(s) are functionalized in a suitable manner to provide a prodrug moiety.
  • the prodrug moiety is as described above.
  • the compounds described herein are metabolized upon administration to an organism in need to produce a metabolite that is then used to produce a desired effect, including a desired therapeutic effect. 5.
  • the methods comprise administering at least one additional therapy to the patient.
  • the modulator described herein i.e., a CB 2 R antagonist, inverse agonist, or negative allosteric modulator
  • Immune checkpoint inhibitors include, but are not limited to, anti-natural killer cell receptor 2B4 (2B4), anti-B- and T-lymphocyte attenuator (BTLA), anti-CD160 antigen (CD160), anti- cytotoxic T-lymphocyte protein 4 (CTLA-4), anti-lymphocyte activation gene 3 protein (LAG-3), anti-programmed cell death protein 1 (PD-1), anti-T-cell immunoglobulin mucin receptor 3 (TIM-3), or anti-T-cell immunoreceptor with Ig and ITIM domains (TIGIT) agents/inhibitors.
  • BTLA anti-natural killer cell receptor 2B4
  • CTLA-4 anti-cytotoxic T-lymphocyte protein 4
  • LAG-3 anti-lymphocyte activation gene 3 protein
  • PD-1 anti-programmed cell death protein 1
  • TIM-3 anti-T-cell immunoglobul
  • the modulator i.e., a CB2R antagonist, inverse agonist, or negative allosteric modulator
  • an immune checkpoint inhibitor that is an immune checkpoint inhibitor other than a PD-1 inhibitor.
  • the compound of formula I is not administered with a PD-1 inhibitor.
  • immune checkpoint inhibitors include, but are not limited to anti-2B4, anti-BTLA, anti-CD160, anti-CTLA-4, anti-LAG-3, anti-PD-1, anti-TIM-3, or anti-TIGIT antibodies.
  • immune checkpoint inhibitors include, but are not limited to anti-2B4, anti- BTLA, anti-CD160, anti-CTLA-4, anti-LAG-3, anti-TIM-3, or anti-TIGIT antibodies.
  • a compound described herein i.e., a CB2R antagonist, inverse agonist, or negative allosteric modulator, or a pharmaceutically acceptable salt thereof, is administered in combination with an inhibitor to an immune checkpoint ligand.
  • Inhibitors to immune checkpoint ligands include, but are not limited to, anti-CD48 antigen (CD48), anti-CD80 antigen (CD80), anti- CD86 antigen (CD86), anti-CD112 antigen (CD112), anti-CD155 antigen (CD155), anti- carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1), anti-fibrinogen-like protein 1 (FGL1), anti-galectin-9 (Gal-9), anti-HLA class I histocompatibility antigen, alpha chain B (HLA- B), anti-HLA class I histocompatibility antigen, alpha chain C (HLA-C), anti-HLA class I histocompatibility antigen, alpha chain E (HLA-E), anti-HLA class I histocompatibility antigen, alpha chain G (HMG1), anti-herpesvirus entry mediator A (HVEM), anti-programmed cell death 1
  • HLA-B anti-CD80 antigen
  • a compound described herein i.e., a CB 2 R antagonist, inverse agonist, or negative allosteric modulator
  • a pharmaceutically acceptable salt thereof is administered in combination with an inhibitor to an immune checkpoint ligand other than a PD-L1/2 ligand.
  • inhibitors to immune checkpoint ligands include, but are not limited to anti-CD48, anti-CD80, anti-CD86, anti-CD112, anti-CD155, anti-CEACAM1, anti-FGL1, anti-Gal-9, anti-HLA-B, anti-HLA-C, anti-HLA-E, anti-HLA-G, anti-HMG1, anti-HVEM, anti-PD- L1, and anti-PD-L2 antibodies.
  • inhibitors to immune checkpoint ligands include, but are not limited to anti-CD48, anti-CD80, anti-CD86, anti-CD112, anti-CD155, anti- CEACAM1, anti-FGL1, anti-Gal-9, anti-HLA-B, anti-HLA-C, anti-HLA-E, anti-HLA-G, anti- HMG1, and anti-HVEM.
  • Anti-2B4/Anti-CD48 Agents [0221] As used herein, “2B4” refers to the natural killer cell (2B4) receptor.
  • NK cell activation-ligand NAIL
  • NK cell type I receptor protein 2B4 NK cell type I receptor protein 2B4
  • signaling lymphocytic activation molecule 4 SAM4
  • CD244 cluster of differentiation 244
  • targeting 2B4 restores immune function in the tumor microenvironment.
  • the anti-2B4 or anti-CD48 agent is an antibody, a peptide, a small molecule or a nucleic acid.
  • a CB2R antagonist, inverse agonist, or negative allosteric modulator), or a pharmaceutically acceptable salt thereof is administered in combination with an anti-2B4 or anti-CD48 agent.
  • the anti-2B4 agent is an anti-2B4 antibody.
  • the anti-CD48 agent is an anti-CD48 antibody.
  • Anti-2B4 antibody refers to an antibody directed towards the natural killer cell (2B4) receptor.
  • an anti-2B4 antibody binds an epitope of 2B4 which blocks the binding of 2B4 to any one or more of its putative ligands.
  • an anti-2B4 antibody binds an epitope of a 2B4 protein which blocks the binding of 2B4 to CD48.
  • Anti-CD48 antibody refers to an antibody directed towards CD48 antigen (CD48) [0224]
  • the terms “antibody” and “antibodies” as used herein is inclusive of all types of immunoglobulins, including IgG, IgM, IgA, IgD, and IgE, or fragments thereof, that may be appropriate for the medical uses disclosed herein.
  • the antibodies may be monoclonal or polyclonal and may be of any species of origin, including, for example, mouse, rat, rabbit, horse, or human.
  • Antibody fragments that retain specific binding to the protein or epitope, for example, 2B4 or CD48, bound by the antibody used in the present disclosure are included within the scope of the term “antibody.”
  • the antibodies may be chimeric or humanized, particularly when they are used for therapeutic purposes.
  • Antibodies and antibody fragments may be obtained or prepared using various methods.
  • Anti-BTLA/Anti-HVEM Agents [0225] As used herein, “BTLA” refers to B- and T-lymphocyte attenuator (BTLA) receptor. Other names include B- and T-lymphoctye-associated protein and CD272 (cluster of differentiation 272). BTLA has at least one ligand, herpesvirus entry mediator A (HVEM).
  • HVEM herpesvirus entry mediator A
  • targeting BTLA restores immune function in the tumor microenvironment.
  • the anti-BTLA or anti-HVEM agent is an antibody, a peptide, a small molecule or a nucleic acid.
  • a compound described herein i.e. a CB 2 R antagonist, inverse agonist, or negative allosteric modulator, or a pharmaceutically acceptable salt thereof, is administered in combination with an anti-BTLA or anti-HVEM agent.
  • the anti-BTLA agent is an anti-BTLA antibody.
  • the anti-HVEM agent is an anti-HVEM antibody.
  • Anti-BTLA antibody refers to an antibody directed towards the B- and T-lymphocyte attenuator (BTLA) receptor. In some embodiments, an anti-BTLA antibody binds an epitope of BTLA which blocks the binding of BTLA to any one or more of its putative ligands. In some embodiments, an anti-BTLA antibody binds an epitope of a BTLA protein which blocks the binding of BTLA to HVEM. “Anti-HVEM antibody” refers to an antibody directed towards herpesvirus entry mediator A (HVEM). Anti-CD160/Anti-MHC class I Agents [0229] As used herein, “CD160” refers to CD160 antigen (CD160) receptor.
  • CD160 has at least two ligands, herpesvirus entry mediator A (HVEM) and major histocompatibility complex (MHC) class I proteins including HLA class I histocompatibility antigen, alpha chain B (HLA-B), HLA class I histocompatibility antigen, alpha chain C (HLA-C), HLA class I histocompatibility antigen, alpha chain E (HLA-E), and HLA class I histocompatibility antigen, alpha chain G (HLA-G).
  • HVEM herpesvirus entry mediator A
  • MHC major histocompatibility complex
  • targeting CD160 restores immune function in the tumor microenvironment.
  • the anti-CD160, anti-HLA-B, anti-HLA-C, anti-HLA-E, anti-HLA-G, or anti-HVEM agent is an antibody, a peptide, a small molecule or a nucleic acid.
  • a compound described herein i.e. a CB 2 R antagonist, inverse agonist, or negative allosteric modulator, or a pharmaceutically acceptable salt thereof, is administered in combination with an anti-CD160, anti-HLA-B, anti-HLA-C, anti-HLA-E, anti-HLA-G, or anti- HVEM agent.
  • the anti-CD160 agent is an anti-CD160 antibody.
  • the anti-HLA-B agent is an anti-HLA-B antibody.
  • the anti- HLA-C agent is an anti-HLA-C antibody.
  • the anti-HLA-E agent is an anti- HLA-E antibody.
  • the anti-HLA-G agent is an anti-HLA-G antibody.
  • the anti-HVEM agent is an anti-HVEM antibody.
  • an anti-CD160 antibody binds an epitope of a CD160 protein which blocks the binding of CD160 to HLA-B, HLA-C, HLA-E, HLA-G, or HVEM.
  • Anti- HLA-B antibody refers to an antibody directed towards HLA class I histocompatibility antigen, alpha chain B (HLA-B).
  • Anti- HLA-C antibody refers to an antibody directed towards HLA class I histocompatibility antigen, alpha chain C (HLA-C).
  • Anti- HLA-E antibody refers to an antibody directed towards HLA class I histocompatibility antigen, alpha chain E (HLA-E).
  • Anti- HLA-G antibody refers to an antibody directed towards HLA class I histocompatibility antigen, alpha chain G (HLA-G).
  • Anti-CTLA-4/Anti-CD80/Anti-CD86 Agents [0233] As used herein, “CTLA-4” or “CTLA4” refers to cytotoxic T-lymphocyte protein 4 (CTLA-4) receptor. Other names include cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and CD152 (cluster of differentiation 152). CTLA-4 has at least two ligands, T-lymphocyte activation antigen CD80 (CD80) and T-lymphocyte activation antigen CD86 (CD86). In some embodiments, targeting CTLA-4 restores immune function in the tumor microenvironment.
  • the anti-CTLA-4, anti-CD80, or anti-CD86 agent is an antibody, a peptide, a small molecule or a nucleic acid.
  • a compound described herein i.e. a CB2R antagonist, inverse agonist, or negative allosteric modulator, or a pharmaceutically acceptable salt thereof, is administered in combination with an anti-CTLA-4, anti-CD80, or anti-CD86 agent.
  • the anti- CTLA-4 agent is an anti-CTLA-4 antibody.
  • the anti-CD80 agent is an anti- CD80 antibody.
  • the anti-CD86 agent is an anti-CD86 antibody.
  • Anti-CTLA-4 antibody refers to an antibody directed towards the cytotoxic T-lymphocyte protein 4 (CTLA-4) receptor.
  • CTLA-4 antibody binds an epitope of CTLA-4 which blocks the binding of CTLA-4 to any one or more of its putative ligands.
  • an anti- CTLA-4 antibody binds an epitope of a CTLA-4 protein which blocks the binding of CTLA-4 to CD80 or CD86.
  • Anti-CD80 antibody refers to an antibody directed towards CD80 antigen (CD80).
  • Anti-CD86 antibody refers to an antibody directed towards CD86 antigen (CD80).
  • LAG-3 refers to lymphocyte activation gene 3 protein (LAG-3) receptor. Other names include CD223 (cluster of differentiation 223). LAG-3 has at least two ligands, fibrinogen-like protein 1 (FGL1) and major histocompatibility complex (MHC) class II proteins. In some embodiments, targeting CD160 restores immune function in the tumor microenvironment.
  • the anti-LAG-3, anti-FGL1, or anti-MHC class II agent is an antibody, a peptide, a small molecule or a nucleic acid.
  • a compound described herein i.e. a CB 2 R antagonist, inverse agonist, or negative allosteric modulator
  • a pharmaceutically acceptable salt thereof is administered in combination with an anti-LAG-3, anti-FGL1, or anti-MHC class II agent.
  • the anti-LAG-3 agent is an anti-LAG-3 antibody.
  • the anti-FGL1 agent is an anti- FGL1 antibody.
  • the anti-MHC class II agent is an anti-MHC class II antibody.
  • “Anti- LAG-3 antibody” refers to an antibody directed towards the lymphocyte activation gene 3 protein (LAG-3) receptor.
  • an anti- LAG-3 antibody binds an epitope of LAG-3 which blocks the binding of LAG-3 to any one or more of its putative ligands. In some embodiments, an anti- LAG-3 antibody binds an epitope of a LAG-3 protein which blocks the binding of LAG-3 to FGL1, or MHC class II.
  • Anti-FGL1 antibody refers to an antibody directed towards fibrinogen-like protein 1 (FGL1).
  • Anti-MHC class II antibody refers to an antibody directed towards major histocompatibility complex (MHC) class II protein.
  • PD-1 refers to the Programmed Death 1 (PD-1) receptor. Other names include programmed cell death protein 1 and CD279 (cluster of differentiation 279). PD-1 has two ligands, PD-L1 and PD-L2. In some embodiments, targeting PD-1 restores immune function in the tumor microenvironment.
  • PD-L1 refers to the programmed death ligand 1 (PD-L1).
  • P-L2 refers to the programmed death ligand 2 (PD-L2).
  • the anti-PD-1 or anti-PDL-1 agent is an antibody, a peptide, a small molecule or a nucleic acid.
  • a compound described herein i.e. a CB 2 R antagonist, inverse agonist, or negative allosteric modulator, or a pharmaceutically acceptable salt thereof, is administered in combination with an anti-PD-1 or anti-PD-L1 agent.
  • the anti PD-l agent for use in combination with compound described herein i.e.
  • a CB 2 R antagonist or inverse agonist is nivolumab, pembrolizumab, atezolizumab, durvalumab, pidilizumab, avelumab, TSR-042, PDR-001, tislelizumab (BGB-A317), cemiplimab (REGN2810), LY-3300054, JNJ-63723283, MGA012, BI- 754091, IBI-308, camrelizumab (HR-301210), BCD-100, JS-001, CX-072, BGB-A333, AMP-514 (MEDI-0680), AGEN- 2034, CSIOOI, Sym-021, SHR-1316, PF-06801591, LZM009, KN-035, AB122, genolimzumab (CBT-501), FAZ-053, CK-301, AK 104, or GLS-010, B
  • the anti PD-l agent is an anti PD-l antibody.
  • Anti-PD-1 antibody refers to an antibody directed towards programmed death protein 1 (PD1).
  • PD1 programmed death protein 1
  • an anti-PD-1 antibody binds an epitope of PD-1 which blocks the binding of PD-1 to any one or more of its putative ligands.
  • an anti-PD1 antibody binds an epitope of a PD-1 protein which blocks the binding of PD-1 to PD-L1 and/or PD-L2.
  • Exemplary anti-PD-l antibodies include but are not limited to: nivolumab/MDX-l106/BMS- 9300/ONO1152, a fully human lgG4 anti-PD-l monoclonal antibody; pidilizumab (MDV9300/CT- 011), a humanized IgGl monoclonal antibody; pembrolizumab (MK-3475/ pembrolizumab/lambrolizumab), a humanized monoclonal IgG4 antibody; durvalumab (MEDI-4736) and atezolizumab.
  • pidilizumab MDV9300/CT- 011
  • pembrolizumab MK-3475/ pembrolizumab/lambrolizumab
  • durvalumab MEDI-4736
  • the anti-PD-1 antibody is nivolumab (OPDIVO®, Bristol-Myers Squibb), pembrolizumab (KEYTRUDA®, Merck), cemiplimab (Libtayo), labrolizumab (Merck), or BGB-A317.
  • the anti-PD1 antibody is an antibody set forth in U.S. Patent Nos. 7,029,674, 7,488,802, 7,521,051, 8,008,449, 8,354,509, 8,617,546, 8,709,417, or WO2014/179664.
  • the anti PD-l agent for use in combination with a compound described herein is atezolizumab, avelumab, AMP-224, MEDI-0680, RG-7446, GX-P2, durvalumab, KY-1003, KD-033, MSB-0010718C, TSR-042, ALN-PDL, STI-A1014, CX- 072, BMS-936559, KN035, CK-301 (Checkpoint Therapeutics), AUNP12, CA-170 (Aurigene/Curis), MEDI4736, MSB0010718C, MDX 1105-01, or BMS-986189.
  • a compound described herein i.e. a CB2R antagonist or inverse agonist
  • a pharmaceutically acceptable salt thereof is atezolizumab, avelumab, AMP-224, MEDI-0680, RG-7446, GX-P2, durvalumab, KY-1003, KD-033, MSB
  • the anti PD-Ll agent is an anti PD-Ll antibody.
  • Anti-PD-L1 antibody refers to an antibody directed towards programmed death ligand 1 (PD-L1).
  • Anti-PD-Ll antibodies for use in combination with a compound described herein include: avelumab; BMS- 936559, a fully human IgG4 antibody; atezolizumab (MPDL3280A/RG-7446), a human monoclonal antibody; MEDI4736; MSB0010718C, and MDX 1105-01.
  • the anti-PD-L1 antibody is avelumab (Bavencio®, Merck KGA/Pfizer), durvalumab (AstraZeneca) and atezolizumab (TECENTRIQ®, Roche).
  • Additional exemplary antibodies include, but are not limited to, the antibodies set forth in U.S. Patent Nos.8,217,149, 8,383,796, 8,552,154 and 8,617,546.
  • Peptide anti-PD-1/PD-L1 agents include AUNP12 (a 29-mer peptide by Aurigene and Laboratoires Pierre Fabre), CA-170 (Aurigene/Curis), BMS-986189 (a macrocyclic peptide by BMS).
  • Small molecule anti-PD-1/PD-L1 agents include those described in WO/2020/086556, WO/2020/014643, WO/2019/204609, WO/2019/160882, WO/2018/195321, WO2018026971, US20180044329, US20180044305, US20180044304, US20180044303, US20180044350, US20180057455, US20180057486, US20180045142, WO20180044963, WO2018044783, WO2018009505, WO20180044329, WO2017066227, WO2017087777, US20170145025, WO2017079669, W02017070089, US2017107216, WO2017222976, US20170262253, WO2017205464, US20170320875, WO2017192961, WO2017112730, US20170174679, WO2017106634, WO2017202744, WO2017202275, WO2017202273, WO201719296
  • the small molecule anti-PD-1/PD-L1 agent is GS-4224.
  • Anti-TIM-3/Anti-Gal-9/Anti-HMG1/Anti-CEACAM1 Agents [0258]
  • TIM-3 refers to T-cell immunoglobulin mucin receptor 3 (TIM-3) receptor.
  • Other names include hepatitis A virus cellular receptor 2 (HAVcr-2), T-cell immunoglobulin and mucin domain-containing protein 3 (TIMD-3), T-cell membrane protein 3, and CD366 (cluster of differentiation 366).
  • TIM-3 has at least three ligands, galectin-9 (Gal-9), high mobility group protein B1 (HMG1), and carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1). In some embodiments, targeting TIM-3 restores immune function in the tumor microenvironment.
  • the anti-TIM-3, anti-Gal-9, anti-HMG1, or anti-CEACAM1 agent is an antibody, a peptide, a small molecule or a nucleic acid.
  • a compound described herein i.e.
  • a CB 2 R antagonist, inverse agonist, or negative allosteric modulator), or a pharmaceutically acceptable salt thereof is administered in combination with an anti-TIM-3, anti-Gal-9, anti-HMG1, or anti-CEACAM1 agent.
  • the anti-TIM-3 agent is an anti-TIM-3 antibody.
  • the anti-Gal-9 agent is an anti-Gal-9 antibody.
  • the anti-HMG1 agent is an anti-HMG1 antibody.
  • the anti-CEACAM1 agent is an anti-CEACAM1 antibody.
  • Anti-TIM-3 antibody refers to an antibody directed towards the T-cell immunoglobulin mucin receptor 3 (TIM-3) receptor.
  • an anti-TIM-3 antibody binds an epitope of TIM-3 which blocks the binding of TIM-3 to any one or more of its putative ligands. In some embodiments, an anti-TIM-3 antibody binds an epitope of a TIM-3 protein which blocks the binding of TIM-3 to Gal-9, HMG1, or CEACAM1.
  • Anti-Gal-9 antibody refers to an antibody directed towards galectin 9 (Gal-9).
  • Anti-HMG1 antibody refers to an antibody directed towards high mobility group protein B1 (HMG1).
  • Anti-CEACAM1 antibody refers to an antibody directed towards carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1).
  • TIGIT refers to T-cell immunoreceptor with Ig and ITIM domains (TIGIT) receptor.
  • Other names include V-set and immunoglobulin domain-containing protein 9 (VSIG9) and V-set and transmembrane domain-containing protein 3 (VSTM3).
  • VSIG9 V-set and immunoglobulin domain-containing protein 9
  • VSTM3 V-set and transmembrane domain-containing protein 3
  • TIGIT has at least two ligands, CD112 (cluster of differentiation 112) and CD155 (cluster of differentiation 155). In some embodiments, targeting TIGIT restores immune function in the tumor microenvironment.
  • the anti-TIGIT, anti-CD112, or CD155 agent is an antibody, a peptide, a small molecule or a nucleic acid.
  • a compound described herein i.e., a CB2R antagonist, inverse agonist, or negative allosteric modulator), or a pharmaceutically acceptable salt thereof, is administered in combination with an anti-TIGIT, anti-CD112, or CD155 agent.
  • the anti-TIGIT agent is an anti-TIGIT antibody.
  • the anti-CD112 agent is an anti-CD112 antibody.
  • the anti-CD155 agent is an anti-CD155 antibody.
  • Anti-TIGIT antibody refers to an antibody directed towards the T-cell immunoreceptor with Ig and ITIM domains (TIGIT) receptor. In some embodiments, an anti-TIGIT antibody binds an epitope of TIGIT which blocks the binding of TIGIT to any one or more of its putative ligands. In some embodiments, an anti-TIGIT antibody binds an epitope of a TIGIT protein which blocks the binding of TIGIT to CD112 or CD155. “Anti-CD112 antibody” refers to an antibody directed towards CD112 (cluster of differentiation 112). “Anti-CD155 antibody” refers to an antibody directed towards CD155 (cluster of differentiation 155).
  • a compound described herein i.e., a CB 2 R antagonist, inverse agonist, or negative allosteric modulator
  • a pharmaceutically acceptable salt thereof is administered in combination with chemotherapy, radiation therapy, monoclonal antibodies, or combinations thereof.
  • Chemotherapy includes the use of anti-cancer agents.
  • a compound described herein i.e., a CB 2 R antagonist, inverse agonist, or negative allosteric modulator
  • a pharmaceutically acceptable salt thereof is administered in combination with any CAR T cell therapy described herein.
  • a compound described herein i.e., a CB2R antagonist, inverse agonist, or negative allosteric modulator
  • a pharmaceutically acceptable salt thereof is administered in combination with bi-specific T-cell engagers, a class of artificial bispecific monoclonal antibodies that are anti-cancer drugs.
  • Bi-specific T-cell engagers direct a host’s immune system, e.g., by specifically directing the T cells’ cytotoxic activity, against cancer cells.
  • CB 2 R antagonists or inverse agonists are also contemplated within the scope of embodiments presented herein for use in the combination therapies described herein for the treatment of cancer: 5-(4-chloro- 3-methylphenyl)-1-[(4-methylphenyl)methyl]-N-[(1S,2S,4R)-1,3,3-trimethylbicyclo[2.2.1]hept-2-yl]- 1H-pyrazole-3-carboxamide (SR144528), [6-iodo-2-methyl-1-[2-(4-morpholinyl)ethyl]-1H-indol-3- yl](4-methoxyphenyl)-methanone (AM630), or N-(1,3-benzodioxol-5-ylmethyl)-1,2-dihydro-7- methoxy-2-oxo-8-(pentyloxy)-3-quinoline
  • an agent that activates immune cells is any CB2R modulator described herein wherein the CB2R modulator is not a compound of Formula (I) described herein.
  • an agent that activates immune cells is any CB2R modulator described herein, and the CB2R modulator is administered to a patient suffering from cancer in combination with any immunotherapeutic agent wherein the immunotherapeutic agent is not a PD-L1/2 inhibitor. 6.
  • Biomarkers [0268] In one aspect, provided herein is a method for increasing the activation and/or proliferation of immune cells in a patient in need thereof, wherein the method comprises determining the level of at least one biomarker in a biological sample obtained from the patient, and providing the subject with an effective amount of a CB2R modulator when the level of the at least one biomarker is higher or lower than a reference level.
  • the at least one biomarker is an immunomodulatory receptor selected from the group consisting of 2B4, BTLA, CD160, CTLA-4, LAG-3, PD-1, TIM-3, and TIGIT.
  • the at least one biomarker is an effector molecule selected from the group consisting of granzyme B, interferon gamma (IFN ⁇ ), interleukin 1 (IL-1), interleukin 2 (IL-2), interleukin 4 (IL-4), interleukin 5 (IL-5), interleukin 6 (IL-6), interleukin 10 (IL-10), interleukin 12 (IL-12), interleukin 13 (IL-13), interleukin 17 (IL-17), interleukin 22 (IL-22), transforming growth factor beta (TGF- ⁇ ), and tumor necrosis factor alpha (TNF ⁇ ).
  • IFN ⁇ interferon gamma
  • IL-1 interleukin 1
  • IL-2 interleukin 2
  • IL-4 interleukin 4
  • IL-5 interleukin 5
  • IL-6 interleukin 6
  • IL-10 interleukin 10
  • IL-12 interleukin 12
  • IL-13 interleukin 13
  • IL-17 interleukin 17
  • the at least one biomarker is a transcription factor selected from the group consisting of nuclear factor of activated T-cells (NFAT), nuclear receptor subfamily 4 group A (NR4A), T-cell-specific transcription factor 1 (TCF-1), thymocyte selection-associated high mobility group box protein (TOX), and TOX high mobility group box family member 2 (TOX2).
  • NFAT nuclear factor of activated T-cells
  • NFR4A nuclear receptor subfamily 4 group A
  • TCF-1 T-cell-specific transcription factor 1
  • TOX thymocyte selection-associated high mobility group box protein
  • TOX TOX high mobility group box family member 2
  • the biological sample is selected from the group consisting of blood, plasma, serum, and tissue.
  • the method comprises determining the level of the at least one biomarker in the biological sample from the patient.
  • the method further comprises comparing the measured level of the at least one biomarker in the sample from the patient against a reference level of the at least one biomarker from a suitable control population.
  • the reference level may be the level of the biomarker in a healthy patient, or the level of the biomarker in the patient prior to start of immune therapy.
  • compositions that contain one or more of the compounds described herein or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof and one or more pharmaceutically acceptable vehicles selected from carriers, adjuvants and excipients.
  • suitable pharmaceutically acceptable vehicles may include, for example, inert solid diluents and fillers, diluents, including sterile aqueous solution and various organic solvents, permeation enhancers, solubilizers and adjuvants.
  • Such compositions are prepared in a manner well known in the pharmaceutical art. See, e.g., Remington’s Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, Pa.17th Ed.
  • the pharmaceutical compositions may be administered in either single or multiple doses.
  • the pharmaceutical composition may be administered by various methods including, for example, rectal, buccal, intranasal and transdermal routes.
  • the pharmaceutical composition may be administered by intra-arterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, or as an inhalant.
  • One mode for administration is parenteral, for example, by injection.
  • Oral administration may be another route for administration of the compounds described herein. Administration may be via, for example, capsule or enteric coated tablets.
  • the active ingredient is usually diluted by an excipient and/or enclosed within such a carrier that can be in the form of a capsule, sachet, paper or other container.
  • a carrier that can be in the form of a capsule, sachet, paper or other container.
  • the excipient serves as a diluent, it can be in the form of a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient.
  • compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, sterile injectable solutions, and sterile packaged powders.
  • excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methyl cellulose.
  • the formulations can additionally include lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl and propylhydroxy-benzoates; sweetening agents; and flavoring agents.
  • compositions that include at least one compound described herein or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the subject by employing procedures known in the art.
  • Controlled release drug delivery systems for oral administration include osmotic pump systems and dissolutional systems containing polymer-coated reservoirs or drug-polymer matrix formulations. Examples of controlled release systems are given in U.S. Patent Nos.3,845,770; 4,326,525; 4,902,514; and 5,616,345.
  • Another formulation for use in the methods disclosed herein employ transdermal delivery devices (“patches”).
  • transdermal patches may be used to provide continuous or discontinuous infusion of the compounds described herein in controlled amounts.
  • the construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art. See, e.g., U.S. Patent Nos. 5,023,252, 4,992,445 and 5,001,139.
  • Such patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.
  • the principal active ingredient may be mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound described herein or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof.
  • the active ingredient may be dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.
  • the tablets or pills of the compounds described herein may be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action, or to protect from the acid conditions of the stomach.
  • the tablet or pill can include an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former.
  • the two components can be separated by an enteric layer that serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release.
  • compositions for inhalation or insufflation may include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders.
  • the liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described herein.
  • the compositions are administered by the oral or nasal respiratory route for local or systemic effect.
  • compositions in pharmaceutically acceptable solvents may be nebulized by use of inert gases.
  • Nebulized solutions may be inhaled directly from the nebulizing device or the nebulizing device may be attached to a facemask tent, or intermittent positive pressure breathing machine.
  • Solution, suspension, or powder compositions may be administered, preferably orally or nasally, from devices that deliver the formulation in an appropriate manner.
  • Dosing and Treatment Regimens [0283]
  • the compounds described herein, or a pharmaceutically acceptable salt thereof are used in the preparation of medicaments for the treatment of diseases or conditions in a patient that would benefit from inhibition or reduction of CB2R activity.
  • compositions that include at least one compound described herein or a pharmaceutically acceptable salt, active metabolite, prodrug, or pharmaceutically acceptable solvate thereof, in therapeutically effective amounts to said patient.
  • the compositions containing the compound(s) described herein are administered for prophylactic and/or therapeutic treatments.
  • the compositions are administered to a patient already suffering from a disease or condition, in an amount sufficient to cure or at least partially arrest at least one of the symptoms of the disease or condition.
  • compositions containing the compounds described herein are administered to a patient susceptible to or otherwise at risk of a particular disease, disorder or condition. Such an amount is defined to be a “prophylactically effective amount or dose.” In this use, the precise amounts also depend on the patient’s state of health, weight, and the like.
  • prophylactic treatments include administering to a patient, who previously experienced at least one symptom of the disease being treated and is currently in remission, a pharmaceutical composition comprising a compound described herein, or a pharmaceutically acceptable salt thereof, in order to prevent a return of the symptoms of the disease or condition.
  • the administration of the compounds are administered chronically, that is, for an extended period of time, including throughout the duration of the patient’s life in order to ameliorate or otherwise control or limit the symptoms of the patient’s disease or condition.
  • the dose of drug being administered is temporarily reduced or temporarily suspended for a certain length of time (i.e., a “drug holiday”).
  • the length of the drug holiday is between 2 days and 1 year, including by way of example only, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, or more than 28 days.
  • the dose reduction during a drug holiday is, by way of example only, by 10%-100%, including by way of example only 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, and 100%.
  • the dosage or the frequency of administration, or both is reduced, as a function of the symptoms, to a level at which the improved disease, disorder or condition is retained.
  • the patient requires intermittent treatment on a long-term basis upon any recurrence of symptoms.
  • the amount of a given agent that corresponds to such an amount varies depending upon factors such as the particular compound, disease condition and its severity, the identity (e.g., weight, sex) of the subject or host in need of treatment, but nevertheless is determined according to the particular circumstances surrounding the case, including, e.g., the specific agent being administered, the route of administration, the condition being treated, and the subject or host being treated.
  • doses employed for adult human treatment are typically in the range of 0.01 mg-5000 mg per day. In one aspect, doses employed for adult human treatment are from about 1 mg to about 1000 mg per day. In one embodiment, the desired dose is conveniently presented in a single dose or in divided doses administered simultaneously or at appropriate intervals, for example as two, three, four or more sub-doses per day. [0291] In one embodiment, the daily dosages appropriate for the compound described herein, or a pharmaceutically acceptable salt thereof, are from about 0.01 to about 50 mg/kg per body weight. In some embodiments, the daily dosage or the amount of active in the dosage form are lower or higher than the ranges indicated herein, based on a number of variables in regard to an individual treatment regime.
  • the daily and unit dosages are altered depending on a number of variables including, but not limited to, the activity of the compound used, the disease or condition to be treated, the mode of administration, the requirements of the individual subject, the severity of the disease or condition being treated, and the judgment of the practitioner.
  • Toxicity and therapeutic efficacy of such therapeutic regimens are determined by standard pharmaceutical procedures in cell cultures or experimental animals, including, but not limited to, the determination of the LD50 and the ED50.
  • the dose ratio between the toxic and therapeutic effects is the therapeutic index and it is expressed as the ratio between LD50 and ED50.
  • the data obtained from cell culture assays and animal studies are used in formulating the therapeutically effective daily dosage range and/or the therapeutically effective unit dosage amount for use in patients, including humans.
  • the daily dosage amount of the compounds described herein lies within a range of circulating concentrations that include the ED50 with minimal toxicity.
  • the daily dosage range and/or the unit dosage amount varies within this range depending upon the dosage form employed and the route of administration utilized.
  • the effective amount of the compound described herein, or a pharmaceutically acceptable salt thereof is: (a) systemically administered to the patient; and/or (b) administered orally to the patient; and/or (c) intravenously administered to the patient; and/or (d) administered by injection to the patient; and/or (e) administered topically to the patient; and/or (f) administered non-systemically or locally to the patient.
  • the pharmaceutical composition further comprises one or more anti-cancer agents.
  • the therapeutic effectiveness of one of the compounds described herein is enhanced by administration of an adjuvant (i.e., by itself the adjuvant has minimal therapeutic benefit, but in combination with another therapeutic agent, the overall therapeutic benefit to the patient is enhanced).
  • an adjuvant i.e., by itself the adjuvant has minimal therapeutic benefit, but in combination with another therapeutic agent, the overall therapeutic benefit to the patient is enhanced.
  • the benefit experienced by a patient is increased by administering one of the compounds described herein with another agent (which also includes a therapeutic regimen) that also has therapeutic benefit.
  • a compound described herein, or a pharmaceutically acceptable salt thereof is co-administered with a second therapeutic agent, wherein the compound described herein, or a pharmaceutically acceptable salt thereof, and the second therapeutic agent modulate different aspects of the disease, disorder or condition being treated, thereby providing a greater overall benefit than administration of either therapeutic agent alone.
  • the overall benefit experienced by the patient is simply additive of the two therapeutic agents or the patient experiences a synergistic benefit.
  • different therapeutically-effective dosages of the compounds disclosed herein will be utilized in formulating pharmaceutical composition and/or in treatment regimens when the compounds disclosed herein are administered in combination with one or more additional agent, such as an additional therapeutically effective drug, an adjuvant or the like.
  • additional agent such as an additional therapeutically effective drug, an adjuvant or the like.
  • Therapeutically-effective dosages of drugs and other agents for use in combination treatment regimens is optionally determined by means similar to those set forth hereinabove for the actives themselves.
  • the methods of prevention/treatment described herein encompasses the use of metronomic dosing, i.e., providing more frequent, lower doses in order to minimize toxic side effects.
  • a combination treatment regimen encompasses treatment regimens in which administration of a compound described herein, or a pharmaceutically acceptable salt thereof, is initiated prior to, during, or after treatment with a second agent described herein, and continues until any time during treatment with the second agent or after termination of treatment with the second agent. It also includes treatments in which a compound described herein, or a pharmaceutically acceptable salt thereof, and the second agent being used in combination are administered simultaneously or at different times and/or at decreasing or increasing intervals during the treatment period. Combination treatment further includes periodic treatments that start and stop at various times to assist with the clinical management of the patient.
  • the dosage regimen to treat, prevent, or ameliorate the disease(s) for which relief is sought is modified in accordance with a variety of factors (e.g. the disease or disorder from which the subject suffers; the age, weight, sex, diet, and medical condition of the subject).
  • the dosage regimen actually employed varies and, in some embodiments, deviates from the dosage regimens set forth herein.
  • dosages of the co-administered compounds vary depending on the type of co-drug employed, on the specific drug employed, on the disease or condition being treated and so forth.
  • the compound provided herein when co-administered with one or more other therapeutic agents, is administered either simultaneously with the one or more other therapeutic agents, or sequentially.
  • the multiple therapeutic agents are administered in any order or even simultaneously. If administration is simultaneous, the multiple therapeutic agents are, by way of example only, provided in a single, unified form, or in multiple forms (e.g., as a single pill or as two separate pills).
  • the compounds or agents described herein, or a pharmaceutically acceptable salt thereof, as well as combination therapies are administered before, during or after the occurrence of a disease or condition, and the timing of administering the composition containing a compound varies.
  • the compounds described herein are used as a prophylactic and are administered continuously to subjects with a propensity to develop conditions or diseases in order to prevent the occurrence of the disease or condition.
  • the compounds and compositions are administered to a subject during or as soon as possible after the onset of the symptoms.
  • a compound described herein is administered as soon as is practicable after the onset of a disease or condition is detected or suspected, and for a length of time necessary for the treatment of the disease. In some embodiments, the length required for treatment varies, and the treatment length is adjusted to suit the specific needs of each subject.
  • a compound described herein or a formulation containing the compound or agent is administered for at least 2 weeks, about 1 month to about 5 years.
  • the compounds of Formula (I) and/or (X) are prepared as described in the schemes below. [0304] Scheme 1 shows an embodiment for preparing compounds of Formula (I) and/or Formula (X).
  • Scheme 3 [0309] Starting with compound 3-1, wherein X 1 and X 2 are as defined herein, and R may be H, halo or a triflate group, or any other suitable leaving group, reaction with diethyl malonate in the presence of a base (e.g., piperidine) provides compound 3-2 which can be cyclized in the presence of a metal (e.g., Fe) and an acid (e.g., acetic acid) to provide compound 3-3 which can be converted to compounds of Formula (X).
  • a base e.g., piperidine
  • Scheme 4 shows an embodiment wherein R 1 is H or OH, and compounds 1-3 and/or 2-3 and/or 3-3 shown above (collectively summarized as compound 4-1) can be converted to compounds of Formula (I) and/or Formula (X).
  • R 4 in compound 4-5 is as defined herein.
  • Compound 4-6 is converted to compound 4-7 using any suitable borylating agent.
  • Each R’’ in compound 4-7 is independently H, C 1 -C 3 alkyl, or phenyl, or, the two R’’ together with the atoms to which they are attached, form a dioxaborolane ring.
  • Compound 4-7 is coupled with a suitable compound 4-8 to provide compounds of Formula (I) or Formula (X).
  • R 6 is as defined herein and LG’’ is any suitable leaving group (e.g., halo).
  • Scheme 5 shows an embodiment wherein R 1 is H or OH, and compounds 1-3 and/or 2-3 and/or 3-3 shown above (collectively summarized as compound 4-1) can be converted to compounds of Formula (I) and/or Formula (X).
  • Each R’’ in compound 5-1 is independently H, C1-C 3 alkyl, or phenyl, or, the two R’’ together with the atoms to which they are attached, form a dioxaborolane ring.
  • Compound 5-1 is coupled with a suitable compound 4-8 to provide a compound 5-2.
  • the coupling reaction between compounds 5-1 and 4-8 may be mediated by any suitable palladium catalyst or any other similar organometallic coupling method known to one of skill in the art.
  • R 6 is as defined herein and LG’’ is any suitable leaving group (e.g., halo).
  • the ester in compound 5-2 is hydrolyzed to provide compound 5- 3.
  • Compound 5-3 is coupled with compound 4-5 under any suitable amide coupling conditions (e.g., HATU, EDCI) to provide compounds of Formula (I) and/or Formula (X).
  • any suitable amide coupling conditions e.g., HATU, EDCI
  • Scheme 6 shows an embodiment wherein R 1 is H or OH, and compounds 1-3 and/or 2-3 and/or 3-3 shown above (collectively summarized as compound 4-1) can be converted to compounds of Formula (I) and/or Formula (X).
  • each R’’ is independently H, C 1 -C 3 alkyl, or phenyl, or, the two R’’ together with the atoms to which they are attached, form a dioxaborolane ring.
  • the coupling reaction between compounds 6-2 and 6-3 may be mediated by any suitable palladium catalyst or any other similar organometallic coupling method known to one of skill in the art.
  • Compound 6-4 is converted to an amide 6-5 via a reaction with compound 4-5, wherein R 4 is as defined herein.
  • ketal in compound 6-5 is hydrolyzed under acidic conditions (e.g., HCl) to provide the aldehyde 6-6 which is aminated with compound 6-7 to provide compounds of Formula (I) and/or (X).
  • R 2 in compound 6-7 is as defined herein.
  • Scheme 7 shows an embodiment for preparation of compounds of Formula (I) and/or (X) wherein R 1 is alkyl.
  • Scheme 7 [0317] Starting with compound 7-1, wherein X 1 and X 2 is a defined herein and R may be H, halo or a triflate group, or any other suitable leaving group, conversion to a Weinreb amide provides compound 7-2.
  • protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions.
  • Suitable protecting groups for various functional groups as well as suitable conditions for protecting and deprotecting particular functional groups are well known in the art. For example, numerous protecting groups are described in T. W. Greene and G. M. Wuts (1999) Protecting Groups in Organic Synthesis, 3rd Edition, Wiley, New York, and references cited therein.
  • the compounds of this disclosure may contain one or more chiral centers. Accordingly, if desired, such compounds can be prepared or isolated as pure stereoisomers, i.e., as individual enantiomers or diastereomers or as stereoisomer-enriched mixtures.
  • stereoisomers and enriched mixtures are included within the scope of this disclosure, unless otherwise indicated.
  • Pure stereoisomers may be prepared using, for example, optically active starting materials or stereoselective reagents well-known in the art. Alternatively, racemic mixtures of such compounds can be separated using, for example, chiral column chromatography, chiral resolving agents, and the like.
  • the starting materials for the following reactions are generally known compounds or can be prepared by known procedures or obvious modifications thereof. For example, many of the starting materials are available from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA), Bachem (Torrance, California, USA), Emka-Chemie or Sigma (St.
  • Example 1 CB2R Binding Assays
  • CB2R binding assays are carried out with two different buffers: incubation buffer (Tris-HCl, 50 mM; MgCl2, 5 mM; CaCl 2 1 mM; BSA, 0.2% at pH 7.4) and washing buffer (Tris-HCl, 50 mM; NaCl 500 mM; BSA, 0.1% at pH 7.4).
  • the assay mixture contained incubation buffer, 0.4 nM [3H]CP-55,940, test substances (concentrations from 0.001 to 10 ⁇ M), and 4 ⁇ g/sample membrane in a total assay volume of 200 ⁇ L.
  • Assays are performed in duplicate and incubated for 120 min at 37 °C. After the incubation, the assay mixture is filtered through 96 GF/C filter plates (Perkin Elmer #6005174) using Perkin Elmer Filtermate Harvester, and then washed four times with ice-cold washing buffer. The filters are dried for 1 hour at 50°C and [3H] trapped on filter counted for radioactivity in Perkin Elmer Microscint 20 cocktail (#6013329) using Perkin Elmer MicroBeta2 Reader.
  • %Inhibition (1-(Assay well-Average_LC)/(Average_HC-Average_LC))x100%.
  • Data are analyzed and IC50 is calculated using GraphPad Prism 5 and the model “log(inhibitor) vs. response -- Variable slope”.
  • Ki IC50/(1+ [radioligand]/Kd).
  • Example 2 CB2R cAMP Assay [0327] cAMP Hunter CHO-K-1 cell lines expressing human CB2R (Eurofins) are expanded from freezer stocks according to standard procedures.
  • cAMP modulation in agonist, inverse agonist or antagonist format was determined using the DiscoverX HitHunter cAMP XS+ assay (Eurofins). For agonist determination, cells are incubated with sample in the presence of EC80 forskolin to induce response. Media is aspirated from cells and replaced with 15 ⁇ L 2:1 HBSS/10mM Hepes: cAMP XS+ Ab reagent.
  • Final assay vehicle concentration is 1%.
  • cells were pre ⁇ incubated with sample followed by agonist challenge at the EC80 concentration.
  • Media is aspirated from cells and replaced with 10 ⁇ L 1:1 HBSS/Hepes: cAMP XS+ Ab reagent.5 ⁇ L of 4X compound is added to the cells and incubated at 37 °C or room temperature for 30 minutes.5 ⁇ L of 4X EC80 agonist is added to cells and incubated at 37 °C or room temperature for 30 or 60 minutes. EC80 forksolin was included.
  • assay signal is generated through incubation with 20 ⁇ L cAMP XS+ ED/CL lysis cocktail for one hour followed by incubation with 20 ⁇ L cAMP XS+ EA reagent for three hours at room temperature.
  • Microplates are read following signal generation with a PerkinElmer Envision instrument for chemiluminescent signal detection.
  • Compound activity is analyzed using CBIS data analysis suite (ChemInnovation, CA).
  • % Inverse Agonist Activity 100% x ((mean RLU of test sample - mean RLU of EC 20 forskolin) / (mean RLU of forskolin positive control - mean RLU of EC 20 control)).
  • percentage inhibition 100% x (mean RLU of test sample - mean RLU of EC 80 control) / (mean RLU of forskolin positive control - mean RLU of EC 80 control).
  • IC 50 is calculated using GraphPad Prism 5 and the model “log(inhibitor) vs. response -- Variable slope”.
  • CD14 + monocytes were purified from peripheral blood mononuclear cells of healthy donors using EasySepTM Human Monocyte Isolation Kit (STEMCELL, Cambridge, MA) according to the manufacturer’s protocol. Purified human monocytes were cultured in RPMI 1640 medium containing 10% FBS (Invitrogen, Carlsbad, CA) at 5 x 10 5 cells/mL in the presence of 20 ng/mL GM-CSF and 10 ng/mL IL-4 (R&D Systems, Minneapolis, MN) in 24-well plate for 7 days.
  • FBS Invitrogen, Carlsbad, CA
  • LPS lipopolysaccharides
  • aliquots of the cells (10 5 cells in 100 ml buffer) were incubated with the fluorochrome-conjugated monoclonal antibodies (CD1a-FITC, CD83-Brilliant Violet 4, CD209-R-PE or CD14-APC; all from BD PharMingen, San Diego, CA) for 30 minutes on ice, washed, and analyzed using Attune NxT flow cytometer.
  • CD1a-FITC fluorochrome-conjugated monoclonal antibodies
  • CD83-Brilliant Violet 4 CD209-R-PE or CD14-APC
  • Attune NxT flow cytometer washed, and analyzed using Attune NxT flow cytometer.
  • human CD4 + T cells were purified from peripheral blood mononuclear cells of healthy donors using EasySepTM Human CD4 + T Isolation Kit (STEMCELL, Cambridge, MA) according to the manufacturer’s protocol.
  • MLR was set up by co- culturing 50,000 CD4 + T cells/well with the monocytes-derived DCs (moDCs) at the ratio of 10 to 1 in 96-well plates with or without Compound 8 in the presence or absence of anti-PD-1 antibody nivolumab (1 ⁇ g/ml, InvivoGen, San Diego, CA) for 5 days.
  • IFN ⁇ was measured using Meso Scale Discovery (MSD) from the supernatant of the co-culture.
  • FIGS.1A-B show proliferation and IFN ⁇ expression of CD4 + T cells treated with Compound 8.
  • FIGS.1A-B the CB 2 R antagonist (Compound 8) treated CD4 + T cells exhibited enhanced T cell growth and IFN ⁇ production compared to CD4 + T cells without treatment.
  • MLR was performed on CD4 + T cells using SR144528 (SR, CB 2 R inverse agonist), AM630 (AM, CB 2 R antagonist), and MAB36551 (MAB, CB 2 R antibody), with or without anti PD-1 agents (nivolumab or pembrolizumab).
  • FIG.1C-D show proliferation and IFN ⁇ expression of CD4 + T cells treated with SR144528, AM630, and MAB36551, with or without nivolumab or pembrolizumab.
  • each SR144528, AM630, and MAB36551 treated CD4 + T cells exhibited enhanced T cell growth and IFN ⁇ production compared to CD4 + T cells without treatment (or treated with vehicle). Further, each SR144528, AM630, and MAB36551 treated CD4 + T cells exhibited even more enhanced T cell growth and IFN ⁇ production in combination with pembrolizumab or nivolumab, showing synergistic increase in cell proliferation and IFN ⁇ production.
  • FIG.2A shows total IFN ⁇ expression of CD4 + T cells treated with Compound 8 with or without nivolumab (anti-PD-1).
  • FIG.2B shows normalized (basal subtracted) IFN ⁇ expression of CD4 + T cells treated with Compound 8 with or without nivolumab (anti-PD-1).
  • FIG.2C is another representation of the data.
  • FIGS.2A-C show that CD4 + T cells treated with the CB 2 R antagonist (Compound 8) and nivolumab (anti-PD-1) exhibited a synergistic increase in IFN ⁇ production compared to CD4 + T cells treated with Compound 8 alone.
  • the result also suggests that that CD4 + T cells treated with the CB 2 R antagonist (Compound 8) and nivolumab (anti-PD-1) would exhibit a synergistic increase in cell proliferation compared to CD4 + T cells treated with Compound 8 alone.
  • Example 4 In vitro T cell Exhaustion (TCE) Assay
  • CD3 + pan T cells were negatively isolated from peripheral blood mononuclear cells of healthy donors (AllCells, Alameda, CA). Approximately, 5x10 5 T cells were initially plated in 24 well plates in RPMI 1640 medium containing 10% FBS (Invitrogen, Carlsbad, CA).
  • FIG.3A shows LAG-3 expression of CD4 + and CD8 + T cells treated with vehicle, Compound 8, nivolumab (anti-PD-1), and a combination of Compound 8 and nivolumab; TIM-3 expression of CD4 + and CD8 + T cells treated with vehicle, Compound 8, nivolumab (anti-PD-1), and a combination of Compound 8 and nivolumab; and PD-1 expression of CD4 + and CD8 + T cells treated with vehicle, Compound 8, nivolumab (anti-PD-1), and a combination of Compound 8 and nivolumab.
  • the CB 2 R antagonist (Compound 8) with or without anti-PD-1 (nivolumab) prevented T cell exhaustion (indicated by decreased expression of immune checkpoint proteins) of CD4 + and CD8 + T cells 8 days after stimulation with T cell activator compared to vehicle.
  • TCE was performed on CD3 + , CD4 + , and CD8 + T cells T cells using individual CB2R modulators (Compund 8, SR144528, AM630, MAB36551) with or without anti-PD-1 compounds (pembrolizumab or nivolumab).
  • Exhaustion markers tested included CD38, CTLA4, LAG3, PD-1, TIGIT, TIM-3, TOX, and IL2.
  • FIGS.3B-E show expression of the exhaustion markers after CD4 + and CD8 + T cells treated with CB 2 R modulators (Compund 8, SR144528, AM630, MAB36551) with or without anti-PD-1 compounds (pembrolizumab or nivolumab).
  • CB 2 R modulators with or without anti-PD-1 prevented T cell exhaustion (indicated by exhaustion markers) of CD3 + , CD4 + , and CD8 + T cells within 8 days after stimulation with T cell activator compared to CD3 + , CD4 + , and CD8 + T cells without treatment (or treated with vehicle).
  • FIG.4A shows IL2 expression of CD4 + and CD8 + T cells four, six, and eight days after stimulation with T-Activator CD3/CD28 dynabeads.
  • FIG.4B shows IL2 expression of CD4 + and CD8 + T cells eight days after stimulation with T-Activator CD3/CD28 dynabeads in the presence of CB2R antagonist (Compound 8).
  • FIG.4B show that the CB2R antagonist (Compound 8) prevents T cell exhaustion (indicated by increased expression of IL2) of CD4 + and CD8 + T cells 8 days after stimulation with T cell activator compared to vehicle.
  • Example 5 In vitro NK cell Reaction Assay [0337] PBMCs were separated from whole blood of healthy donors by density gradient. NK cells were then isolated with the Easysep Human NK Cell Enrichment Kit (STEMCELL, Cambridge, MA) according to the manufacturer’s protocol, seeded at 2x10 5 /well in 96-well plate and cultured in complete RPMI medium (RPMI-1640 medium supplemented with 10% FBS, 2 mM L-glutamine, 100 U/mL penicillin, and 100 ug/mL streptomycin) in the presence or absence of Compound 8 for 3 days.
  • RPMI medium RPMI-1640 medium supplemented with 10% FBS, 2 mM L-glutamine, 100 U/mL penicillin, and 100 ug/mL streptomycin
  • FIG.5A shows the cellular killing capacity of NK cells treated with Compound 8.
  • FIG.5B shows the percentage of CD107a + (activated) NK cells treated with Compound 8.
  • FIG.5C shows the expression of IFN ⁇ of NK cells treated with Compound 8.
  • FIGS.5A-C show that CB 2 R antagonist (Compound 8) enhances NK cell function (by virtue of activation, killing capacity, and IFN ⁇ expression) compared to vehicle.
  • TGI Tumor Growth Inhibition
  • MTV Median Tumor Volume
  • FIG.6A shows the effect of oral administration of vehicle, 1 mg/kg Compound 8, 4 mg/kg Compound 8, and 10 mg/kg Compound 8 on B16F10 derived tumor volume in 8-9 week female C57BL/6 mice measured by TGI assay.
  • FIG.6B shows the effect of oral administration of vehicle, 1 mg/kg Compound 8, 4 mg/kg Compound 8, and 10 mg/kg Compound 8 on MC 3 8 derived tumor volume in 8-9 week female C57BL/6 mice measured by TGI assay.
  • FIGS.6A-B show that oral administration of CB2R antagonist (Compound 8) inhibits B16F10 and MC 3 8 tumor growth in 8-9 week female C57BL/6 mice compared to vehicle.
  • CB2R antagonist Compound 8
  • FIG.7A shows the effect of intraperitoneal administration of vehicle, 1 mg/kg Compound 8, 4 mg/kg Compound 8, and 10 mg/kg Compound 8 on B16F10 derived tumor volume in 8-9 week female C57BL/6 mice measured by TGI assay.
  • FIG.7B shows the effect of intraperitoneal administration of vehicle, 1 mg/kg Compound 8, 4 mg/kg Compound 8, and 10 mg/kg Compound 8 on MC38 derived tumor volume in 8-9 week female C57BL/6 mice measured by TGI assay.
  • FIGS. 7A-B show that intraperitoneal administration of CB 2 R antagonist (Compound 8) inhibits B16F10 and MC 3 8 tumor growth in 8-9 week female C57BL/6 mice compared to vehicle.
  • CB 2 R antagonist Compound 8
  • FIG.8A shows the effect of oral administration of vehicle and 4 mg/kg Compound 8, intraperitoneal administration of 5 mg/kg anti-PD-1 antibody, and combination of 4 mg/kg Compound 8 with 5 mg/kg anti-PD-1 antibody on B16F10 derived tumor volume in 8-9 week female C57BL/6 mice measured by TGI assay.
  • FIG.8B shows the effect of oral administration of vehicle and 4 mg/kg Compound 8, intraperitoneal administration of 5 mg/kg anti-PD-1 antibody, and combination of 4 mg/kg Compound 8 with 5 mg/kg anti-PD-1 antibody on MC 3 8 derived tumor volume in 8-9 week female C57BL/6 mice measured by TGI assay.
  • FIGS.8A-B show that oral administration of CB2R antagonist (Compound 8) inhibits B16F10 and MC 3 8 tumor growth in 8-9 week female C57BL/6 mice compared to vehicle, and the combination of Compound 8 with anti-PD-1 antibody synergistically inhibits B16F10 and MC38 tumor growth.
  • FIG.9A shows the effect of oral administration of vehicle and 4 mg/kg Compound 8, intraperitoneal administration of 5 mg/kg anti-PD-1 antibody, and combination of 4 mg/kg Compound 8 with 5 mg/kg anti-PD-1 antibody on tumor-infiltrating immune cells in 8-9 week female C57BL/6 mice bearing B16F10 melanoma measured by flow cytometry.
  • FIG.9A shows that oral administration of CB 2 R antagonist (Compound 8) significantly increases CD8+ T cell and NK infiltration in B16F10 tumor in 8-9 week female C57BL/6 mice compared to vehicle.
  • Compound 8 increases CD4+ and CD8+ T cells by 2-fold and 5.3-fold, respectively when compared to vehicle controls.
  • Both CD4+ and CD8+ T cell populations further increase in number in the combination treatment with anti-PD-1 antibody by 5.7-fold and 10-fold, respectively.
  • Compound 8 also significantly increases NK infiltration by 2.5-fold when used alone.
  • NK cells further increase in the combination treatment by 4.9-fold.
  • FIG.9B shows the effect of oral administration of vehicle and 4 mg/kg Compound 8, intraperitoneal administration of 5 mg/kg anti-PD-1 antibody, and combination of 4 mg/kg Compound 8 with 5 mg/kg anti-PD-1 antibody on the expression of PD-1 and LAG-3 by CD8 + T cells in 8-9 week female C57BL/6 mice bearing B16F10 melanoma measured by flow cytometry.
  • FIG.9B shows that oral administration of CB2R antagonist (Compound 8) significantly decreased expression of PD-1 among CD8+ T cells in B16F10 tumor in 8-9 week female C57BL/6 mice compared to vehicle. Specifically, Compound 8 increased the percentage of PD-1 + /CD8+ cells among the CD8+ by less than half when compared to vehicle controls.
  • FIG.9B further shows that oral administration of CB 2 R antagonist (Compound 8) significantly decreased expression of LAG-3 among CD8 + T cells in B16F10 tumor in 8-9 week female C57BL/6 mice compared to vehicle. Specifically, Compound 8 decreased the percentage of LAG3 + /CD8+ cells among the CD8 + cells by less than half when compared to vehicle controls.

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Abstract

Disclosed herein are methods of increasing production of interferon gamma (IFNγ) or activation or proliferation of immune cells using a CB2R modulator.

Description

METHODS OF IMPROVING GROWTH AND FUNCTION OF IMMUNE CELLS CROSS REFERENCE TO RELATED APPLICATIONS [0001] This application claims the benefit under 35 U.S.C. §119(e) of U.S. Provisional Application No.63/240,334, filed on September 2, 2021, U.S. Provisional Application No.63/275,198, filed on November 3, 2021, U.S. Provisional Application No.63/318,737, filed on March 10, 2022, and U.S. Provisional Application No.63/352,746, filed on June 16, 2022, which are incorproated herein by reference in their entireties. FIELD [0002] Described herein are methods of increasing production of interferon gamma (IFNγ), activation, and/or proliferation of immune cells using cannabinoid receptor type 2 modulators or pharmaceutical compositions and medicaments comprising cannabinoid receptor type 2 modulators. The disclosure also pertains to improving immunotherapy and treating, reducing, or preventing immune cell exhaustion in patients in need thereof. BACKGROUND [0003] In humans, T cells are the immune system’s primary killers of infected and diseased cells. Cancer immunotherapy relies on getting T cells to attack and kill tumor cells. T cell function, however, can fade with chronic infection (e.g., viral infection) and/or disease (e.g., progressive development of cancer), a phenomenon referred to as T cell exhaustion. Other immune cells such as natural killer (NK) cells and B cells can also become exhausted. Exhausted immune cells exhibit aberrant expression of transcription factors, cell surface antigens, and effector molecules that contribute to decreased T cell function. For example, exhausted T cells exhibit increased appearance of immune checkpoint proteins on the cellular surface such as PD-1 and CTLA-4, which can prevent a T cell’s ability to kill infected and diseased cells. One of the most popular and successful strategies to combat T cell exhaustion is the use of checkpoint inhibitors (e.g., anti-PD-1, anti-PD-L1, and anti CTLA-4). However, studies suggest that checkpoint inhibitor therapy is often ineffective alone. (See, e.g., Zhang et al., “T Cell Dysfunction and Exhaustion in Cancer,” Front. Cell Dev. Biol.8(17): 1-13 (2020) (reporting that the response rate of checkpoint inhibitor therapy is less than 30% in solid tumors)). Moreover, while combination therapies are being investigated with some success, challenges remain for development of immunotherapy for wide clinical applications. [0004] Thus, there remains a need for safe, effective, and convenient methods to treat various immunosuppression associated with chronic infection and disease, e.g., patients with immune cell exhaustion. SUMMARY [0005] It has been found that inhibition of the cannabinoid type 2 receptor (CB2R) restores immune cell (e.g., T cell, NK cell, and B cell) function and relieves innate and adaptive immunosuppression. Provided herein are methods for treating, reducing, or preventing immune cell exhaustion (e.g., in cancer patients and/or patients suffering from viral infection). In some embodiments, provided herein is a method for increasing the production of interferon gamma (IFNγ) or growth or proliferation of immune cells in a patient in need thereof, comprising administering to the patient an effective amount of a cannabinoid type 2 receptor (CB2R) modulator. In some embodiments, the patient has a viral infection or cancer. [0006] In some embodiments, provided herein is a method for treating, reducing, or preventing immune cell exhaustion in a patient in need thereof, comprising administering to the patient an effective amount of a cannabinoid type 2 receptor (CB2R) modulator. [0007] In some embodiments, the CB2R modulator is an agent which antagonizes, reverse agonizes, negatively modulates, or otherwise inhibits or partially inhibits CB2R. BRIEF DESCRIPTION OF DRAWINGS [0008] FIG.1A illustrates a graph showing proliferation of CD4+ T cells treated with Compound 8 in a MLR assay (MoDC/CD4+) model, according to one embodiment. [0009] FIG.1B illustrates a graph showing IFNγ production of CD4+ T cells treated with Compound 8 in a MLR assay (MoDC/CD4+) model.according to one embodiment. [0010] FIG.1C illustrates graphs showing proliferation of CD4+ T cells treated with SR144528 (SR), AM630 (AM) and MAB36551 (MAB), with or without anti-PD-1 (pembrolizumab, pembro or nivolumab, nivo), in a MLR assay (MoDC/CD4+) model, according to one embodiment. [0011] FIG.1D illustrates graphs showing IFNγ production of CD4+ T cells treated with SR144528 (SR), AM630 (AM) and MAB36551 (MAB), with or without anti-PD-1 (pembrolizumab, pembro or nivolumab, nivo), in a MLR assay (MoDC/CD4+) model.according to one embodiment. [0012] FIGS.2A-C illustrate graphs showing total IFNγ production and normalized (basal subtracted) IFNγ production of CD4+ T cells treated with Compound 8 with or without anti-PD-1 (nivolumab) in a MLR assay (MoDC/CD4+) model, according to one embodiment. [0013] FIG.3A illustrates graphs showing expression of LAG-3, TIM-3, and PD-1 of CD4+ and CD8+ T cells treated with vehicle, Compound 8, anti-PD-1 (nivolumab), and the combination of Compound 8 in a TCE assay model, according to one embodiment. [0014] FIG.3B illustrates graphs showing expression of CD38, CTLA-4, LAG-3, PD-1, TIGIT, TIM-3, TOX and IL-2 of CD3+, CD4+, and CD8+ T cells treated with vehicle, Compound 8, anti-PD-1 (nivolumab/pembrolozimab), and the combination of Compound 8 and anti-PD-1 in a TCE assay model, according to one embodiment. [0015] FIG.3C illustrates graphs showing expression of CD38, CTLA-4, LAG-3, PD-1, TIGIT, TIM-3, TOX and IL-2 of CD3+, CD4+, and CD8+ T cells treated with vehicle, SR144528 (SR), anti- PD-1 (nivolumab/pembrolozimab), and the combination of SR144528 and anti-PD-1 in a TCE assay model, according to one embodiment. [0016] FIG.3D illustrates graphs showing expression of CD38, CTLA-4, LAG-3, PD-1, TIGIT, TIM-3, TOX and IL-2 of CD3+, CD4+, and CD8+ T cells treated with vehicle, AM630 (AM), anti-PD- 1 (nivolumab/pembrolozimab), and the combination of AM630 and anti-PD-1 in a TCE assay model, according to one embodiment. [0017] FIG.3E illustrates graphs showing expression of CD38, CTLA-4, LAG-3, PD-1, TIGIT, TIM-3, TOX and IL-2 of CD3+, CD4+, and CD8+ T cells treated with vehicle, MAB36551 (MAB), anti-PD-1 (nivolumab/pembrolozimab), and the combination of MAB36551 and anti-PD-1 in a TCE assay model, according to one embodiment. [0018] FIG.4A illustrates a graph showing expression of IL2 of CD4+ and CD8+ T cells four, six, and eight days after treatment with T-Activator CD3/CD28 dynabeads (activates T cells) without Compound 8 in a TCE assay model, according to one embodiment. [0019] FIG.4B illustrates a graph showing expression if IL2 of CD4+ and CD8+ T cells eight days after treatment with T-Activator CD3/CD28 dynabeads (activates T cells) with different concentrations of Compound 8 in a TCE assay model, according to one embodiment. [0020] FIGS.5A-C illustrate graphs showing natural killer (NK) cell activation, capacity for killing cancer cells (K562 cell line), and IFNγ expression after treatment with Compound 8 in a cytotoxicity assay, according to one embodiment. [0021] FIGS.6A-B illustrate graphs showing the effect of oral administration of Compound 8 on B16F10 and MC38 derived tumors in a mouse model, according to one embodiment. [0022] FIGS.7A-B illustrate graphs showing the effect of intraperitoneal administration of Compound 8 on B16F10 and MC38 derived tumors in a mouse model, according to one embodiment. [0023] FIGS.8A-B illustrate graphs showing the effect of oral administration of vehicle and 4 mg/kg Compound 8, intraperitoneal administration of 5 mg/kg anti-PD-1 antibody, and combination of 4 mg/kg Compound 8 with 5 mg/kg anti-PD-1 antibody on B16F10 and MC38 derived tumors in a mouse model, according to one embodiment. [0024] FIG.9A illustrates graphs shwoing the effect of oral administration of vehicle and 4 mg/kg Compound 8, intraperitoneal administration of 5 mg/kg anti-PD-1 antibody, and combination of 4 mg/kg Compound 8 with 5 mg/kg anti-PD-1 antibody on tumor-infiltrating immune cells on B16F10 derived tumors in a mouse model, according to one embodiment. [0025] FIG.9B illustrates graphs showing effect of oral administration of vehicle and 4 mg/kg Compound 8, intraperitoneal administration of 5 mg/kg anti-PD-1 antibody, and combination of 4 mg/kg Compound 8 with 5 mg/kg anti-PD-1 antibody on expression of PD-1 and LAG3 by CD8+ T cells on B16F10 derived tumors in a mouse model. DETAILED DESCRIPTION [0026] Exhausted immune cells (e.g., exhausted T cells) can emerge during chronic high grade infections such as hepatitis B, hepatitis C, or long Covid, during immunodeficiency virus infections such as AIDS, and during tumor outgrowth. Provided herein are methods to prevent, reduce or reverse exhausted immune cells such as exhausted T cells or NK cells. In other words, provided herein are methods for keeping immune cells healthy and functioning. [0027] Typically, treatment with chimeric antigen receptor T cell (CART) therapy is initially succesful when treating cancer. A drawback of CART therapy is that the CAR T cells circulate in the blood and are unable to penetrate deep into tumor tissue. Due to their presence in the circulatory system, the CAR T cells have a limited life, possibly due to exposure to cytokine storms associated with the underlying infection or disease, thereby leading to exhausted CAR T cells. The methods described herein comprise administration of a CB2 modulator as an adjunct and/or adjuvant to immunetherapies. Treatment with a CB2 modulator activates immune cells such as T cells and NK cells, including exhausted T cells and exhausted NK cells. Accordingly, the methods described herein prolong the therapeutic effect of immunotherapies such as CAR T cells and/or re-activate exhausted immune cells such as exhausted T cells and/or reverse or delay the decline in efficay of immunotherapies such as CAR T cell therapy. [0028] Exhausted T cells exhibit increased appearance on their surface of checkpoint proteins like PD-1 and CTLA-4, which can cause those T cells to stand down. Immune checkpoint inhibitors block these checkpoint proteins and were expected to ramp up the immune response against tumors. However, treatment with checkpoint inhibitors does not address the underlying T cell exhaustion, which reduces therapeutic effectiveness of checkpoint inhibitors. In other instances, development of resistance to checkpoint inhibitors reduces the therapeutic effectiveness of checkpoint inhibitors. The methods described herein can treat, prevent, reduce, reverse, or delay T cell exhaustion, thereby improving effectiveness of immunotherapeutics like check point inhibitors. 1. Definitions [0029] Unless otherwise stated, the following terms used in this application have the definitions given below. The use of the term “including” as well as other forms, such as “include”, “includes,” and “included,” is not limiting. The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described. [0030] As used herein, C1-Cx includes C1-C2, C1-C3... C1-Cx. By way of example only, a group designated as “C1-C4” indicates that there are one to four carbon atoms in the moiety, i.e. groups containing 1 carbon atom, 2 carbon atoms, 3 carbon atoms or 4 carbon atoms. Thus, by way of example only, “C1-C4 alkyl” indicates that there are one to four carbon atoms in the alkyl group, i.e., the alkyl group is selected from among methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and t-butyl. [0031] An “alkyl” group refers to an aliphatic hydrocarbon group. The alkyl group is branched or straight chain. In some embodiments, the “alkyl” group has 1 to 10 carbon atoms, i.e. a C1-C10alkyl. Whenever it appears herein, a numerical range such as “1 to 10” refers to each integer in the given range; e.g., “1 to 10 carbon atoms” means that the alkyl group consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 10 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated. In some embodiments, an alkyl is a C1-C6alkyl. In one aspect the alkyl is methyl, ethyl, propyl, iso-propyl, n- butyl, iso-butyl, sec-butyl, or t-butyl. Typical alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tertiary butyl, pentyl, neopentyl, or hexyl. [0032] An “alkylene” group refers to a divalent alkyl radical. Any of the above mentioned monovalent alkyl groups may be an alkylene by abstraction of a second hydrogen atom from the alkyl. In some embodiments, an alkylene is a C1-C6alkylene. In other embodiments, an alkylene is a C1-C4alkylene. Typical alkylene groups include, but are not limited to, -CH2-, -CH(CH3)-, -C(CH3)2-, -CH2CH2-, -CH2CH(CH3)-, -CH2C(CH3)2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, and the like. [0033] The term “alkenyl” refers to a type of alkyl group in which at least one carbon-carbon double bond is present. In one embodiment, an alkenyl group has the formula –C(R)=CR2, wherein R refers to the remaining portions of the alkenyl group, which may be the same or different. In some embodiments, R is H or an alkyl. Non-limiting examples of an alkenyl group include -CH=CH2, - C(CH3)=CH2, -CH=CHCH3, -C(CH3)=CHCH3, and -CH2CH=CH2. [0034] The term “alkynyl” refers to a type of alkyl group in which at least one carbon-carbon triple bond is present. In one embodiment, an alkenyl group has the formula -C≡C-R, wherein R refers to the remaining portions of the alkynyl group. In some embodiments, R is H or an alkyl. Non-limiting examples of an alkynyl group include -C≡CH, -C≡CCH3 -C≡CCH2CH3, -CH2C≡CH. [0035] An “alkoxy” group refers to a (alkyl)O- group, where alkyl is as defined herein. [0036] The term “alkylamine” refers to -NH(alkyl), or -N(alkyl)2. [0037] The term “aromatic” refers to a planar ring having a delocalized pi-electron system containing 4n+2 pi electrons, where n is an integer. The term “aromatic” includes both carbocyclic aryl (“aryl”, e.g., phenyl) and heterocyclic aryl (or “heteroaryl” or “heteroaromatic”) groups (e.g., pyridine). The term includes monocyclic or fused-ring polycyclic (i.e., rings which share adjacent pairs of carbon atoms) groups. [0038] The term “carbocyclic” or “carbocycle” refers to a ring or ring system where the atoms forming the backbone of the ring are all carbon atoms. The term thus distinguishes carbocyclic from “heterocyclic” rings or “heterocycles” in which the ring backbone contains at least one atom which is different from carbon. In some embodiments, at least one of the two rings of a bicyclic carbocycle is aromatic. In some embodiments, both rings of a bicyclic carbocycle are aromatic. [0039] As used herein, the term “aryl” refers to an aromatic ring wherein each of the atoms forming the ring is a carbon atom. In one aspect, aryl is phenyl or a naphthyl. In some embodiments, an aryl is a phenyl. In some embodiments, an aryl is a C6-C10aryl. Depending on the structure, an aryl group is a monoradical or a diradical (i.e., an arylene group). [0040] The term “cycloalkyl” refers to a monocyclic or polycyclic aliphatic, non-aromatic radical, wherein each of the atoms forming the ring (i.e. skeletal atoms) is a carbon atom. A cycloalkyl may be saturated or partially saturated. In some embodiments, cycloalkyls are spirocyclic or bridged compounds. In some embodiments, cycloalkyls are optionally fused with an aromatic ring, and the point of attachment is at a carbon that is not an aromatic ring carbon atom. Cycloalkyl groups include groups having from 3 to 10 ring atoms. In some embodiments, cycloalkyl groups are selected from among cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, spiro[2.2]pentyl, norbornyl and bicycle[1.1.1]pentyl, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, cis-decalin, trans-decalin, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, and bicyclo[3.3.2]decane, adamantyl, norbornyl, and decalinyl. In some embodiments, a cycloalkyl is a C3-C6cycloalkyl. [0041] “Cycloalkylene” refers to -cycloalkyl-, i.e., a cycloalkyl ring as defined herein which is bonded to two groups. [0042] “1,4-dioxanyl ring fused to ring C” refers
Figure imgf000009_0001
. [0043] “Deuteroalkyl” refers to an alkyl group as defined herein, in which at least one H is replaced by an isotope of hydrogen, i.e., by deuterium (2H) or tritium (3H). [0044] “Deuteroalkoxy” refers to an alkoxy group as defined herein, in which at least one H is replaced by an isotope of hydrogen, i.e., by deuterium (2H) or tritium (3H). [0045] The term “halo” or, alternatively, “halogen” or “halide” means fluoro, chloro, bromo or iodo. In some embodiments, halo is fluoro, chloro, or bromo. [0046] The term “fluoroalkyl” refers to an alkyl in which one or more hydrogen atoms are replaced by a fluorine atom. In one aspect, a fluoroalkyl is a C1-C6fluoroalkyl. [0047] “Fluoroalkoxy” refers to an alkoxy group as defined herein, in which at least one H is replaced by a fluorine atom. [0048] The term “heteroalkyl” refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, e.g., oxygen, nitrogen (e.g. –NH-, -N(alkyl)-, sulfur, or combinations thereof. A heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl. In one aspect, a heteroalkyl is a C1-C6heteroalkyl. [0049] Examples of such heteroalkyl are, for example, -CH2OCH3, -CH2CH2OCH3, -CH2CH2OCH2CH2OCH3, -CH(CH3)OCH3, -CH2NHCH3, -CH2N(CH3)2, and -CH2SCH3. [0050] The term “heterocycle” or “heterocyclic” refers to heteroaromatic rings (also known as heteroaryls) and heterocycloalkyl rings (also known as heteroalicyclic groups) containing one to four heteroatoms in the ring(s), where each heteroatom in the ring(s) is selected from O, S and N, wherein each heterocyclic group has from 3 to 10 atoms in its ring system, and with the proviso that any ring does not contain two adjacent O or S atoms. Non-aromatic heterocyclic groups (also known as heterocycloalkyls) include rings having 3 to 10 atoms in its ring system and aromatic heterocyclic groups include rings having 5 to 10 atoms in its ring system. The heterocyclic groups include benzo- fused ring systems. Examples of non-aromatic heterocyclic groups are pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, oxazolidinonyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, thioxanyl, piperazinyl, aziridinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridinyl, pyrrolin-2-yl, pyrrolin-3-yl, indolinyl, 2H-pyranyl, 4H- pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo[3.1.0]hexanyl, 3- azabicyclo[4.1.0]heptanyl, 3H-indolyl, indolin-2-onyl, isoindolin-1-onyl, isoindoline-1,3-dionyl, 3,4- dihydroisoquinolin-1(2H)-onyl, 3,4-dihydroquinolin-2(1H)-onyl, isoindoline-1,3-dithionyl, benzo[d]oxazol-2(3H)-onyl, 1H-benzo[d]imidazol-2(3H)-onyl, benzo[d]thiazol-2(3H)-onyl, and quinolizinyl. Examples of aromatic heterocyclic groups are pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl. The foregoing groups are either C-attached (or C- linked) or N-attached where such is possible. For instance, a group derived from pyrrole includes both pyrrol-1-yl (N-attached) or pyrrol-3-yl (C-attached). Further, a group derived from imidazole includes imidazol-1-yl or imidazol-3-yl (both N-attached) or imidazol-2-yl, imidazol-4-yl or imidazol-5-yl (all C-attached). The heterocyclic groups include benzo-fused ring systems. Non-aromatic heterocycles are optionally substituted with one or two oxo (=O) moieties, such as pyrrolidin-2-one. In some embodiments, at least one of the two rings of a bicyclic heterocycle is aromatic. In some embodiments, both rings of a bicyclic heterocycle are aromatic. The terms “heteroaryl” or, alternatively, “heteroaromatic” refers to an aryl group that includes one or more ring heteroatoms selected from nitrogen, oxygen and sulfur. Illustrative examples of heteroaryl groups include monocyclic heteroaryls and bicyclic heteroaryls. Monocyclic heteroaryls include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, pyridazinyl, triazinyl, oxadiazolyl, thiadiazolyl, and furazanyl. Bicyclic heteroaryls include indolizine, indole, benzofuran, benzothiophene, indazole, benzimidazole, purine, quinolizine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, 1,8- naphthyridine, and pteridine. In some embodiments, a heteroaryl contains 0-4 N atoms in the ring. In some embodiments, a heteroaryl contains 1-4 N atoms in the ring. In some embodiments, a heteroaryl contains 0-4 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring. In some embodiments, a heteroaryl contains 1-4 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring. In some embodiments, heteroaryl is a C1-C9heteroaryl. In some embodiments, monocyclic heteroaryl is a C1-C5heteroaryl. In some embodiments, monocyclic heteroaryl is a 5-membered or 6-membered heteroaryl. In some embodiments, bicyclic heteroaryl is a C6-C9heteroaryl. [0051] A “heterocycloalkyl” or “heteroalicyclic” group refers to a cycloalkyl group that includes at least one heteroatom selected from nitrogen, oxygen and sulfur. In some embodiments, a heterocycloalkyl is fused with an aryl or heteroaryl. In some embodiments, the heterocycloalkyl is oxazolidinonyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, piperidin-2-onyl, pyrrolidine-2,5-dithionyl, pyrrolidine-2,5-dionyl, pyrrolidinonyl, imidazolidinyl, imidazolidin-2-onyl, or thiazolidin-2-onyl. In some embodiments, the sulfur atom in a heterocycloalkyl is not oxidized. The term heteroalicyclic also includes all ring forms of the carbohydrates, including but not limited to the monosaccharides, the disaccharides and the oligosaccharides. In one aspect, a heterocycloalkyl is a C2-C10heterocycloalkyl. In another aspect, a heterocycloalkyl is a C4-C10heterocycloalkyl. In some embodiments, a heterocycloalkyl contains 0-2 N atoms in the ring. In some embodiments, a heterocycloalkyl contains 0-2 N atoms, 0-2 O atoms and 0-1 S atoms in the ring. [0052] The term “bond” or “single bond” refers to a chemical bond between two atoms, or two moieties when the atoms joined by the bond are considered to be part of larger substructure. In one aspect, when a group described herein is a bond, the referenced group is absent thereby allowing a bond to be formed between the remaining identified groups. [0053] The term “moiety” refers to a specific segment or functional group of a molecule. Chemical moieties are often recognized chemical entities embedded in or appended to a molecule. [0054] The term “optionally substituted” or “substituted” means that the referenced group is optionally substituted with one or more additional group(s) individually and independently selected from halogen, -CN, -NH2, -NH(alkyl), -N(alkyl)2, -OH, -CO2H, -CO2alkyl, -C(=O)NH2, -C(=O)NH(alkyl), -C(=O)N(alkyl)2, -S(=O)2NH2, -S(=O)2NH(alkyl), -S(=O)2N(alkyl)2, alkyl, cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy, fluoroalkoxy, heterocycloalkyl, aryl, heteroaryl, aryloxy, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, and arylsulfone. In some other embodiments, optional substituents are independently selected from halogen, -CN, -NH2, -NH(CH3), -N(CH3)2, -OH, -CO2H, -CO2(C1-C4alkyl), -C(=O)NH2, - C(=O)NH(C1-C4alkyl), -C(=O)N(C1-C4alkyl)2, -S(=O)2NH2, -S(=O)2NH(C1-C4alkyl), -S(=O)2N(C1- C4alkyl)2, C1-C4alkyl, C3-C6cycloalkyl, C1-C4fluoroalkyl, C1-C4heteroalkyl, C1-C4alkoxy, C1- C4fluoroalkoxy, -SC1-C4alkyl, -S(=O)C1-C4alkyl, and -S(=O)2C1-C4alkyl. In some embodiments, optional substituents are independently selected from halogen, -CN, -NH2, -OH, -NH(CH3), -N(CH3)2, -CH3, -CH2CH3, -CF3, -OCH3, and -OCF3. In some embodiments, substituted groups are substituted with one or two of the preceding groups. In some embodiments, an optional substituent on an aliphatic carbon atom (acyclic or cyclic) includes oxo (=O). [0055] The term “acceptable” with respect to a formulation, composition or ingredient, as used herein, means having no persistent detrimental effect on the general health of the subject being treated. [0056] The term “modulate” as used herein, means to interact with a target either directly or indirectly so as to alter the activity of the target, including, by way of example only, to enhance the activity of the target, to inhibit the activity of the target, to limit the activity of the target, or to extend the activity of the target. In some embodiments, “modulate” means to interact with a target either directly or indirectly so as to decrease or inhibit receptor activity, [0057] The term “modulator” as used herein, refers to a molecule that interacts with a target either directly or indirectly. The interactions include, but are not limited to, the interactions of an agonist, partial agonist, an inverse agonist, antagonist, or combinations thereof. In some embodiments, a modulator is an antagonist. Receptor antagonists are inhibitors of receptor activity. Antagonists mimic ligands that bind to a receptor and prevent receptor activation by a natural ligand. Preventing activation may have many effects. If a natural agonist binding to a receptor leads to an increase in cellular function, an antagonist that binds and blocks this receptor decreases the function. [0058] The terms “administer,” “administering,” “administration,” and the like, as used herein, refer to the methods that may be used to enable delivery of compounds or compositions to the desired site of biological action. These methods include, but are not limited to oral routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular or infusion), topical and rectal administration. Those of skill in the art are familiar with administration techniques that can be employed with the compounds and methods described herein. In some embodiments, the compounds and compositions described herein are administered orally. [0059] The terms “co-administration” or the like, as used herein, are meant to encompass administration of the selected therapeutic agents to a single patient, and are intended to include treatment regimens in which the agents are administered by the same or different route of administration or at the same or different time. [0060] The terms “effective amount” or “therapeutically effective amount,” as used herein, refer to a sufficient amount of an agent or a compound being administered, which will relieve to some extent one or more of the symptoms of the disease or condition being treated. The result includes reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an “effective amount” for therapeutic uses is the amount of the composition comprising a compound as disclosed herein required to provide a clinically significant decrease in disease symptoms. An appropriate “effective” amount in any individual case is optionally determined using techniques, such as a dose escalation study. [0061] The terms “enhance” or “enhancing,” as used herein, means to increase or prolong either in potency or duration a desired effect. Thus, in regard to enhancing the effect of therapeutic agents, the term “enhancing” refers to the ability to increase or prolong, either in potency or duration, the effect of other therapeutic agents on a system. An “enhancing-effective amount,” as used herein, refers to an amount adequate to enhance the effect of another therapeutic agent in a desired system. [0062] The term “subject” or “patient” encompasses mammals. Examples of mammals include, but are not limited to, any member of the Mammalian class: humans, non-human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like. In one aspect, the mammal is a human. [0063] The terms “treat,” “treating” or “treatment,” as used herein, include alleviating, abating or ameliorating at least one symptom of a disease or condition, preventing additional symptoms, inhibiting the disease or condition, e.g., arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, or stopping the symptoms of the disease or condition either prophylactically and/or therapeutically. [0064] The term “in vitro,” as used herein, means experimentation using components of an organism that have been isolated from their usual biological surroundings. Common examples of in vitro experiments include cells derived from multicellular organisms (cell culture or tissue culture), subcellular components (e.g., mitochondria or ribosomes), cellular or subcellular extracts, and purified molecules (e.g., DNA, RNA, and proteins). [0065] The term “in vivo,” as used herein, means experimentation using a whole, living organism as opposed to a partial or dead organism, or an in vitro controlled environment. [0066] The term “ex vivo,” as used herein, means experimentation or measurement done in or on tissue in an artificial environment outside of an organism with minimum alteration of natural conditions. A widely used example of ex vivo experimentation is the chorioallantoic membrane (CAM) assay, which involves the implantation of a material or compound on the extraembryonic membrane of the developing chicken egg. 2. Immune Cell Therapies [0067] In some embodiments, disclosed herein are methods of improving immune cell therapies using cannabinoid receptor type 2 (CB2R) modulators. [0068] Immune cell therapies (or, adoptive cell therapies) are forms of treatment using the cells of the immune system to target and eliminate cells that have become infected, damaged, and/or cancerous. Immune cell therapies include engineered T cell receptor (TCR) therapy, chimeric antigen receptor (CAR) therapy, and tumor-infiltrating lymphocyte (TIL) therapy. [0069] In some embodiments, immune cells may be targeted and treated inside a patient (in situ) using a vector comprising a nucleic acid and a targeting protein against an immune cell-associated antigen. In some embodiments, the nucleic acid encodes an engineered receptor against a disease- associated antigen. In some embodiments, the engineered receptor comprises a chimeric antigen receptor (CAR) or T cell receptor (TCR). In some embodiments, the immune cell-associated antigen is an antigen presented on a T cell, B cell, natural killer (NK) cell, or a tumor-infiltrating lymphocyte (TIL). Thus, in some embodiments, the vector may target an immune cell in a patient and deliver a CAR or TCR to the immune cell, thereby providing an immune cell therapy in situ. [0070] In some embodiments, immune cells (e.g., T cells, natural killer (NK) cells, and B cells) may be isolated from a patient, equipped with T cell receptors (hence, TCR therapy) that enables them to target specific cell antigens, activated, expanded, and re-infused into the patient. TCR therapy targets and eliminates cells that present their antigens via major histocompatibility complex (MHC). [0071] In some embodiments, immune cells (e.g., T cells, natural killer (NK) cells, and B cells) may be equipped with chimeric antigen receptors (CAR). Immune cells equipped with CAR may bind specific cells (e.g., cancer cells) regardless of whether antigens are presented on the cellular surface via major histocompatibility complex (MHC). [0072] In some embodiments, tumor-infiltrating lymphocytes (TIL) (e.g., immune cells) that have already infiltrated a patient’s tumor(s) may be isolated from the patient, activated, expanded, and re- infused into the patient. 3. Methods and Patients [0073] In some embodiments provided is a method for increasing the production of interferon gamma (IFNγ) or growth or proliferation of immune cells in a patient in need thereof, comprising administering to the patient an effective amount of a cannabinoid type 2 receptor (CB2R) modulator. In some embodiments, the CB2R modulator is not an agonist of the receptor. In some embodiments, the patient has a viral infection or cancer. In some embodiments, the patient suffers from immune cell exhaustion or is at risk for immune cell exhaustion. [0074] Also provided is a method for treating, reducing, or preventing immune cell exhaustion in a patient in need thereof, comprising administering to the patient an effective amount of a CB2R modulator. In some embodiments, the CB2R modulator is not an agonist of the receptor. [0075] In some embodiments, the patient is currently or has previously been treated with an immunotherapeutic agent. In some embodiments, the immune cell activating agent is administered to the patient after cessation of administration of the immunotherapeutic agent. In some embodiments, the immune cell activating agent is administered to the patient concurrently with administration of the immunotherapeutic agent. In some embodiments, the immune cell activating agent is administered to the patient concurrently and after administration of the immunotherapeutic agent. [0076] In some embodiments, the immune cell is a T cell, B cell or NK cell. In some embodiments, the immune cell is a T cell and the immune cell exhaustion is T cell exhaustion. In some embodiments, the immune cell is a B cell and the immune cell exhaustion is B cell exhaustion. In some embodiments, the immune cell is a NK cell and the immune cell exhaustion is NK cell exhaustion. [0077] In some embodiments, the immunotherapeutic agent is a check-point inhibitor. In some embodiments, the check-point inhibitor is selected from atezolizumab, avelumab, cemiplimab, labrolizumab, durvalumab, ipilimumab, nivolumab, and pembrolizumab. [0078] In some embodiments, patient selection is determined by identifying abnormal (high or low) biomarker levels in immune cells compared to the biological marker levels in the immune cells of healthy individuals (i.e., those that are not in need of CB2R administration). [0079] In some embodiments is a method of diagnosing immune cell exhaustion in a patient, comprising: (a) obtaining a biological sample comprising immune cells from a patient; (b) detecting and quantifying the presence of one or more biological markers in the biological sample; (c) comparing the levels of the one or more biological markers in the biological sample of the patient to the levels of the one or more biological markers in a healthy individual; and (d) diagnosing the patient with immune cell exhaustion when the levels of the one or more biological markers in the biological sample are abnormal; and wherein the one or more biological markers are selected from the group consisting of 2B4, BTLA, CD160, CTLA-4, LAG-3, PD-1, TIM-3, TIGIT, granzyme B, interferon gamma (IFNγ), interleukin 1 (IL-1), interleukin 2 (IL-2), interleukin 4 (IL-4), interleukin 5 (IL-5), interleukin 6 (IL-6), interleukin 10 (IL-10), interleukin 12 (IL-12), interleukin 13 (IL-13), interleukin 17 (IL-17), interleukin 22 (IL-22), transforming growth factor beta (TGF-β), tumor necrosis factor alpha (TNFα), nuclear factor of activated T-cells (NFAT), nuclear receptor subfamily 4 group A (NR4A), T-cell-specific transcription factor 1 (TCF-1), thymocyte selection-associated high mobility group box protein (TOX), and TOX high mobility group box family member 2 (TOX2). [0080] In some embodiments, after hours, days, or weeks, the patient exhibits an improvement in expression levels of biological markers in immune cells (e.g., lymphocytes (T cells, B cells, and NK cells), neutrophils, and monocytes/macrophages) compared to the biological markers before administration of the CB2R modulator. [0081] In some embodiments, the biological markers are immunomodulatory receptors selected from the group consisting of: 2B4, BTLA, CD160, CTLA-4, LAG-3, PD-1, TIM-3, and TIGIT. [0082] In some embodiments, the biological markers are effector molecules selected from the group consisting of: granzyme B, interferon gamma (IFNγ), interleukin 1 (IL-1), interleukin 2 (IL-2), interleukin 4 (IL-4), interleukin 5 (IL-5), interleukin 6 (IL-6), interleukin 10 (IL-10), interleukin 12 (IL-12), interleukin 13 (IL-13), interleukin 17 (IL-17), interleukin 22 (IL-22), transforming growth factor beta (TGF-β), and tumor necrosis factor alpha (TNFα). [0083] In some embodiments, the biological markers are transcription factors selected from the group consisting of: nuclear factor of activated T-cells (NFAT), nuclear receptor subfamily 4 group A (NR4A), T-cell-specific transcription factor 1 (TCF-1), thymocyte selection-associated high mobility group box protein (TOX), and TOX high mobility group box family member 2 (TOX2). [0084] In some embodiments, the CB2R modulator is not a CB2R agonist. [0085] In some embodiments, the CB2R modulator is a CB2R antagonist selected from the group consisting of: Compound 8, Compound 13, Compound 109, Compound 121, Compound 149, Compound 265, Compound 266, Compound 267, Compound 268, Compound 269, Compound 270, cannabidiol, AM630, and combinations thereof. [0086] In some embodiments, the CB2R modulator is a CB2R inverse agonist selected from the group consisting of: SR144528, XL-001, and combinations thereof. [0087] In some embodiments, the CB2R modulator is a negative allosteric modulator selected from the group consisting of Dihydro-gambogic acid (DHGA), trans-β-caryophyllene (TBC), mambaquaretin-1, Exenetide (Byetta), and combinations thereof. [0088] In some embodiments, the CB2R modulator is an agent that causes gene knockout of CB2R in immune cells (e.g., lymphocytes (T cells, B cells, and NK cells), neutrophils, and monocytes/macrophages). In some embodiments, the agent is a site-specific nuclease selected from the group consisting of: zinc finger nuclease, transcription activator-like effector nuclease (TALENS), clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPER-associated systems (Cas) complexes, and combinations thereof. [0089] In some embodiments, the methods described herein further comprise administering a chimeric antigen receptor T-cell (CART) therapy to the patient. [0090] In some embodiments, provided is a method for re-activating exhausted immune cells (e.g., T cells) in a patient in need thereof, comprising administering to the patient an effective amount of a cannabinoid type 2 receptor (CB2R) modulator. In some embodiments, the patient has cancer, a chronic infection, an acute infection, or an immunodeficiency. [0091] In some embodiments, the patient is being treated with, or has been treated with, a chimeric antigen receptor T-cell (CART) therapy. [0092] In some embodiments, the patient is being treated with, or has been treated with, a check point inhibitor. In some embodiments, the checkpoint inhibitor is selected from atezolizumab, avelumab, cemiplimab, labrolizumab, durvalumab, ipilimumab, nivolumab, and pembrolizumab. [0093] In some embodiments, the CART therapy comprises allogeneic CAR T cells. In some embodiments, CART therapy comprises alloreactive CAR T cells. In some embodiments, the CART therapy comprises autologous CAR T cells. In some embodiments, the CART therapy comprises bispecific CAR T cells. In some embodiments, the CAR T-cell therapy targets antigens on B cells, e.g., CD19, CD22, CD38, CS1, or BCMA, or combinations thereof. In some embodiments, the CART therapy is ABECMA® (idecabtagene vicleucel), BREYANZI® (lisocabtagene maraleucel), KYMRIAH® (tisagenlecleucel), TECARTUS® (brexucabtagene autoleucel), or YESCARTA® (axicabtagene ciloleucel). In situ therapy [0094] The immune cell target of the methods described herein may be one that is introduced to the patient, as part of a cellular immunotherapeutic composition. Alternatively, the target immune cell is an endogenous cell, optionally being activated, in situ, to have therapeutic activities. Such an in situ activated immune cell can also be at risk of exhaustion. Accordingly, prior to or following the in situ activation, the target immune cell can be contacted with a CB2R modulator to prevent or reduce its exhaustion. [0095] In some embodiments is a method for treating a disease in a patient in need thereof comprising administering to the patient an effective amount of a cannabinoid type 2 receptor (CB2R) modulator, along with a vector comprising a nucleic acid, optionally with a targeting protein against an immune cell-associated antigen, wherein the nucleic acid encodes an engineered receptor against a disease-associated antigen. [0096] In some embodiments is a method for treating, reducing, or preventing immune cell exhaustion in a patient in need thereof comprising administering to the patient an effective amount of a cannabinoid type 2 receptor (CB2R) modulator, and a vector comprising a nucleic acid, optionally with a targeting protein against an immune cell-associated antigen, wherein the nucleic acid encodes an engineered receptor against a disease-associated antigen. Ex-vivo therapy [0097] Also contemplated within the scope of embodiments of this disclosue are ex-vivo methods of therapy. In some embodiments, prior to injection of CAR T cells in a patient in need thereof, the CAR T cells are pre-treated with a CB2 modulator described herein. In some embodiments, provided herein is a method of treating, preventing, reducing, or delaying T cell exhaustion in a patient in need thereof, comprising administering CB2 modulator-pre-treated CAR T cells to the patient in need thereof. In some embodiments, the CB2 modulator is administered in combination with the pre- treated CAR T cells. Further contemplated within the scope of embodiments of this disclosure is pre- treatment of other immune cells such as, e.g., NK cells. Also contemplated within the scope of embodiments of this disclosure is co-admininstration of a CB2 modulator with CB2-modulator pre- treated- immune cells such as, e.g., pre-treated NK cells. [0098] The immune cell target of the methods described herein may be from an external source, such as from a cellular immunotherapeutic composition. In such embodiments, the CB2R inhibition can also be carried out ex vivo. That is, the CB2R inhibition can be carried out in the immune cell before it is administered to the patient. Such a pre-administration/ex vivo treatment, it is contemplated, can also be effective in preventing exhaustion of the immune cell. [0099] In accordance with one embodiment of the present disclosure, therefore, provided is a composition that includes a cannabinoid type 2 receptor (CB2R) modulator and an immune cell. In some embodiments, the immune cell has been engineered to express a receptor that has specificity to a disease-associated antigen. [00100] In some embodiments of in situ or ex vivo therapy described above, the immune cell is a T cell, B cell, natural killer (NK) cell, or tumor-infiltrating lymphocyte (TIL). In some embodiments, the T cell or TIL are selected from the group consisting of CD4+ T, memory CD4+ T, CD8+ T, and memory CD8+ T cell. In some embodiments, the B cell or TIL are selected from the group consisting of plasmablast, plasma, lymphoplasmacytoid, memory B, B-1, B-2, and regulatory B cells. In some embodiments, the NK cell or TIL are selected from the group consisting of primary NK, NK-92, NK-92.26.5, NK 92.MI, NK-92Ci, NK-92Fc, NK3.3, NKL, NKG, NK-YT, NK-YTS, KHYG-1, HATAK, umbilical cord blood (UCB)-derived NK, stem cell-derived NK, induced pluripotent stem cell (iPSC)-derived NK, human induced pluripotent stem cell (HPC)-derived NK, and cytokine-induced memory-like NK cell. [00101] In some embodiments, the engineered receptor is a chimeric antigen receptor (CAR) or a T cell receptor (TCR). [00102] In some embodiments, the engineered receptor is an antibody or fragment thereof. In some embodiments, the antibody or fragment thereof are selected from the group consisting of hR1 (anti-IGF-1R), hPAM4 (anti-mucin), KC4 (anti-mucin), hA20 (anti-CD20), hA19 (anti-CD19), hIMMU31 (anti-AFP), hLL1 (anti-CD74), hLL2 (anti-CD22), RFB4 (anti-CD22), hMu-9 (anti- CSAp), hL243 (anti-HLA-DR), hMN-14 (anti-CEACAM-5), hMN-15 (anti-CEACAM-6), hRS7 (anti-TROP-2), hMN-3 (anti-CEACAM-6), CC49 (anti-TAG-72), J591 (anti-PSMA), D2/B (anti- PSMA), G250 (anti-carbonic anhydrase IX), infliximab (anti-TNF-α), certolizumab pegol (anti-TNF- α), adalimumab (anti-TNF-α), alemtuzumab (anti-CD52), bevacizumab (anti-VEGF), cetuximab (anti-EGFR), gemtuzumab (anti-CD33), ibritumomab tiuxetan (anti-CD20), panitumumab (anti- EGFR), rituximab (anti-CD20), tositumomab (anti-CD20), GA101 (anti-CD20), trastuzumab (anti- HER2/neu), tocilizumab (anti-IL-6 receptor), basiliximab (anti-CD25), daclizumab (anti-CD25), efalizumab (anti-CD11a), muromonab-CD3 (anti-CD3 receptor), natalizumab (anti-α4 integrin), BWA-3 (anti-histone H2A/H4), LG2-1 (anti-histone H3), MRA12 (anti-histone H1), PR1-1 (anti- histone H2B), LG11-2 (anti-histone H2B), and LG2-2 (anti-histone H2B). In some embodiments, the antibody or fragment thereof may be an scFv or Fab antibody fragment. [00103] In some embodiments, the disease-associated antigen is selected from the group consisting of CD19, CD20, CD21, CD22, CD44, CD62L, CD74, CD79b, HLA-DR, β7-integrin, and BCR. In some embodiments the disease-associated antigen is selected from the group consisting of tumor-associated antigen (TAA) such as alpha-fetoprotein (AFP), α-actinin-4, A3, antigen specific for A33 antibody, ART-4, B7, Ba 733, BAGE, BrE3-antigen, CA125, CAMEL, CAP-1, carbonic anhydrase IX, CASP-8/m, CCL19, CCL21, CD1, CD1a, CD2, CD3, CD4, CD5, CD8, CD11A, CD14, CD15, CD16, CD18, CD19, CD20, CD21, CD22, CD23, CD25, CD29, CD30, CD32b, CD33, CD37, CD38, CD40, CD40L, CD44, CD45, CD46, CD52, CD54, CD55, CD59, CD64, CD66a-e, CD67, CD70, CD70L, CD74, CD79a, CD79b, CD80, CD83, CD95, CD126, CD132, CD133, CD138, CD147, CD154, CDC27, CDK-4/m, CDKN2A, CTLA4, CXCR4, CXCR7, CXCL12, HIF-1α, colon- specific antigen-p (CSAp), CEA (CEACAM-5), CEACAM-6, c-Met, DAM, EGFR, EGFRvIII, EGP- 1 (TROP-2), EGP-2, ELF2-M, Ep-CAM, fibroblast growth factor (FGF), Flt-1, Flt-3, folate receptor, G250 antigen, GAGE, gp100, GRO-β, HLA-DR, HM1.24, human chorionic gonadotropin (HCG) and its subunits, HER2/neu, HMGB-1, hypoxia inducible factor (HIF-1), HSP70-2M, HST-2, Ia, IGF-1R, IFN-γ, IFN-α, IFN-β, IFN-λ, IL-4R, IL-6R, IL-13R, IL-15R, IL-17R, IL-18R, IL-2, IL-6, IL-8, IL-12, IL-15, IL-17, IL-18, IL-23, IL-25, insulin-like growth factor-1 (IGF-1), KC4-antigen, KS-1-antigen, KS1-4, Le-Y, LDR/FUT, macrophage migration inhibitory factor (MIF), MAGE, MAGE-3, MART- 1, MART-2, NY-ESO-1, TRAG-3, mCRP, MCP-1, MIP-1A, MIP-1B, MIF, MUC1, MUC2, MUC3, MUC4, MUC5ac, MUC13, MUC16, MUM-1/2, MUM-3, NCA66, NCA95, NCA90, pancreatic cancer mucin, PD1 receptor, placental growth factor, p53, PLAGL2, prostatic acid phosphatase, PSA, PRAME, PSMA, PlGF, ILGF, ILGF-R, L-6, IL-25, RS5, RANTES, T101, SAGE, S100, survivin, survivin-2B, TAC, TAG-72, tenascin, TRAIL receptors, TNF-α, Tn antigen, Thomson-Friedenreich antigens, tumor necrosis antigens, VEGFR, ED-B fibronectin, WT-1, 17-1A-antigen, complement factors C3, C3a, C3b, C5a, C5, an angiogenesis marker, bcl-2, bcl-6, Kras, an oncogene marker, and an oncogene product. In some embodiments, the TAA may be an oncogenic viral gene. In some embodiments, the TAA may be an oncogenic mutated gene. [00104] In some embodiments is a method of making an immune cell comprising: (a) obtaining an immune cell from a patient with a disease in need of treatment; and (b) transducing the immune cell with a viral vector comprising a cannabinoid type 2 receptor (CB2R) modulator. In some embodiments, the immune is also transduced, or has been transduced, with a nucleic acid encoding a receptor having specificity to a disease-associated antigen. In some embodiments, the receptor is a chimeric antigen receptor (CAR) or a T cell receptor (TCR). [00105] In some embodiments is an engineered immune cell comprising an engineered receptor having specificity to a disease-associated antigen and having reduced or no CB2R activity. In some embodiments, the immune cell may be treated with an agent that causes gene knockout of CB2R. In some embodiments, the agent that causes gene knockout of CB2R may be a site-specific nuclease. In some embodiments, the site-specific nuclease is selected from the group consisting of zinc finger nuclease, transcription activator-like effector nuclease (TALENS), and clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPER-associated systems (Cas) complexes. [00106] Also provided is a method for treating a disease and/or treating, reducing, or preventing immune cell exhaustion in a patient in need thereof, comprising administering to the patient an immune cell transduced with a viral vector comprising an effective amount of a CB2R modulator and a nucleic acid encoding an engineered receptor, wherein the engineered receptor has specificity to a disease-associated antigen. Immune Cell Exhaustion [00107] Patients suffering from a variety of conditions will benefit from the methods provided herein. In some embodiments, disclosed herein are methods of treating immune cell exhaustion with a CB2R modulator as described herein. [00108] The term “immune cell exhaustion” as used herein, referes to varied, but distinct, epigenetic and metabolic states of immune cells observed in the presence of persistent antigen and chronic immune cell receptor, e.g., T cell receptor, stimulation, typically as a result of chronic infections (e.g., HIV infections, SARS CoV-2 infections) and cancer progression. Regarding T cells, for example, compared with memory or effector T cells, exhausted T cells exhibit reduced responses to antigens, altered effector functions (e.g., decreased cytokine expression), increased chemokine expression, high expression levels of inhibitory receptors (e.g., PD1, TIM3, LAG3, CTLA4, CD39, CD73, and TIGIT), reduced proliferative capacity, altered transcriptional program involving the transcription factor TOX, a unique epigenetic landscape, and reduced levels of signaling proteins associated with activation and/or increased levels of negative regulatory proteins (e.g., diacylglycerol kinases, phosphatases, and E3 ubiquitin ligases). (See, e.g., Blank et al., “Defining T Cell Exhaustion,” Nat. Rev. Immunol.19(11): 665-674 (2019)). Under the settings of tumors and chronic infections, NK cells and B cells exhibit an exhausted status similar with exhausted T cells, displaying decreased proliferation, poor effector function, and altered phenotype. [00109] In some embodiments, a CB2R modulator described herein, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, increases immune cell responses to antigens, increases immune cell cytokine expression, decreases immune cell chemokine expression, reduces immune cell expression of inhibitory receptors, increases immune cell proliferative capacity, increases immune cell expression of signaling proteins associated with immune cell activation, and/or reduces immune cell expression of negative regulatory proteins thereby reversing or reducing immune cell exhaustion. [0100] In some embodiments, a patient treated with a CB2R modulator suffers from chronic infection or disease associated with decreased immune cell function and/or immune cell exhaustion. In some embodiments, the chronic infection or disease is cancer and/or viral infection. [0101] In another aspect, a CB2R modulator described herein, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, reduces, ameliorates, or inhibits the immunosuppression and decreased cell proliferation associated with decreased immune cell function and/or immune cell exhaustion. Cancer [0102] In some embodiments, patients who may benefit from the methods described herein have cancer. [0103] The term “cancer” as used herein, refers to an abnormal growth of cells that tend to proliferate in an uncontrolled way and, in some cases, to metastasize (spread). Types of cancer include, but are not limited to, solid tumors (such as those of the bladder, bowel, brain, breast, endometrium, heart, kidney, lung, liver, uterus, lymphatic tissue (lymphoma), ovary, pancreas or other endocrine organ (thyroid), prostate, skin (melanoma or basal cell cancer)) or hematological tumors (such as the leukemias and lymphomas) at any stage of the disease with or without metastases. [0104] In some embodiments, a patient treated with a modulator described herein has a disease or disorder that is associated with a cancer. Examples of cancers include and are not limited to carcinomas, sarcomas, benign tumors, primary tumors, tumor metastases, solid tumors, non-solid tumors, blood tumors, leukemias and lymphomas, and/or primary and metastatic tumors. [0105] In some embodiments, the patient may have solid tumours. A solid tumor is an abnormal mass of tissue that usually does not contain cysts or liquid areas. Solid tumors may be benign (not cancer), or malignant (cancer). Different types of solid tumors are named for the type of cells that form them. Examples of solid tumors are carcinomas, sarcomas, and lymphomas. [0106] Carcinomas include, but are not limited to, esophageal carcinoma, hepatocellular carcinoma, basal cell carcinoma, squamous cell carcinoma, bladder carcinoma, bronchogenic carcinoma, colon carcinoma, colorectal carcinoma, gastric carcinoma, lung carcinoma, including small cell carcinoma and non-small cell carcinoma of the lung, adrenocortical carcinoma, thyroid carcinoma, pancreatic carcinoma, breast carcinoma, ovarian carcinoma, prostate carcinoma, adenocarcinoma, renal cell carcinoma, Wilm's tumor, cervical carcinoma, uterine carcinoma, testicular carcinoma, osteogenic carcinoma, epithelial carcinoma, and nasopharyngeal carcinoma. [0107] Sarcomas include, but are not limited to, fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, chordoma, osteogenic sarcoma, osteosarcoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's sarcoma, leiomyosarcoma, rhabdomyosarcoma, and other soft tissue sarcomas. [0108] Leukemias include, but are not limited to, a) chronic myeloproliferative syndromes (neoplastic disorders of multipotential hematopoietic stem cells); b) acute myelogenous leukemias; c) chronic lymphocytic leukemias (CLL), including B-cell CLL, T-cell CLL prolymphocyte leukemia, and hairy cell leukemia; and d) acute lymphoblastic leukemias (characterized by accumulation of lymphoblasts). Lymphomas include, but are not limited to, B-cell lymphomas (e.g., Burkitt's lymphoma); Hodgkin's lymphoma; and the like. [0109] Benign tumors include, e.g., hemangiomas, hepatocellular adenoma, cavernous hemangioma, focal nodular hyperplasia, acoustic neuromas, neurofibroma, bile duct adenoma, bile duct cystanoma, fibroma, lipomas, leiomyomas, mesotheliomas, teratomas, myxomas, nodular regenerative hyperplasia, trachomas and pyogenic granulomas. [0110] Primary and metastatic tumors include, e.g., lung cancer; breast cancer; colorectal cancer; anal cancer; pancreatic cancer; prostate cancer; ovarian carcinoma; liver and bile duct carcinoma; esophageal carcinoma; bladder carcinoma; carcinoma of the uterus; glioma, glioblastoma, medulloblastoma, and other tumors of the brain; kidney cancers; cancer of the head and neck; cancer of the stomach; multiple myeloma; testicular cancer; germ cell tumor; neuroendocrine tumor; cervical cancer; carcinoids of the gastrointestinal tract, breast, and other organs. Chronic Infections [0111] In some embodiments, disclosed herein are methods of treating patients having chronic infections with a CB2R modulator described herein. [0112] The term “chronic infection” as used herein, refers to an infection characterized by the continued presence or recurrence of infectious bacteria or virus for weeks, months, years, or a lifetime after a primary infection. Non-limiting examples of viral infections include lymphocytic choriomeningitis (LCMV), hepatitis B virus (HBV), hepatitis C virus (HCV), human immunodeficiency virus (HIV), Epstein-Barr virus (EBV), SARS CoV-2 infections including long Covid, and cytomegalovirus (CMV). Non-limiting examples of bacterial infections include Mycobacterium tuberculosis, Salmonella Typhi, Pseudomonas aeruginosa, and Escherichia coli. [0113] In some embodiments, the patient has a disease or disorder that is or is associated with a chronic infection. In some embodiments, the chronic infections are associated with decreased immune cell function and/or immune cell exhaustion. In some embodiments, the chronic infection is a viral infection (e.g., long covid, HIV). In some embodiments, the chronic infection is a bacterial infection. 4. Cannabinoid type 2 receptor (CB2R) modulators [0114] Cannabinoid type 2 receptor (CB2R) modulators interact with binding sites on CB2R. CB2R modulators that inhibit canonical CB2R function (i.e., immunosuppression), restore immune cell (e.g., T cell, NK cell, and B cell) functions and relieve innate and adaptive immunosuppression caused by immune cell exhaustion. [0115] In some embodiments a CB2R modulator is a CB2R antagonist and/or inverse agonist. In some embodiments a CB2R antagonist and/or inverse agonist is SR144528 or any other CB2R antagonist and/or inverse agonist described in WO 2001/64212, which compounds are incorporated herein by reference. In some embodiments a CB2R antagonist and/or inverse agonist is AM630 or any other CB2R antagonist and/or inverse agonist described in WO 2019/025474 and/or WO 2017/149387, which compounds are incorporated herein by reference. In some embodiments a CB2R antagonist and/or inverse agonist is XL-001 or any other CB2R antagonist and/or inverse agonist described in US 2013/0172388, which compounds are incorporated herein by reference. [0116] In some embodiments a CB2R modulator is a CB2R allosteric modulator. Examples of CB2R allosteric modulators include and are not limited to Dihydro-gambogic acid (DHGA), TBC (trans -β- caryophyllene), IQM311, and N-[5-Bromo-1,2-dihydro-1-(4’-fluorobenzyl)-4-methyl-2-oxo-pyridin- 3-yl]cycloheptanecarboxamide. [0117] In some embodiments, the compound is a CB2R antagonist. In some embodiments, the CB2R antagonist is 2-[(1R,6R)-3-methyl-6-prop-1-en-2-ylcyclohex-2-en-1-yl]-5-pentylbenzene-1,3-diol (cannabidiol), [6-iodo-2-methyl-1-(2-morpholin-4-ylethyl)indol-3-yl]-(4-methoxyphenyl)methanone (AM630), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof. [0118] In some embodiments, the compound is a CB2R inverse agonist. In some embodiments, the CB2R inverse agonist is 5-(4-chloro-3-methylphenyl)-1-[(4-methylphenyl)methyl]-N-[(1S,2S,4R)- 1,3,3-trimethyl-2-bicyclo[2.2.1]heptanyl]pyrazole-3-carboxamide (SR144528), N-(1,3-benzodioxol- 5-ylmethyl)-7-methoxy-2-oxo-8-pentoxy-1H-quinoline-3-carboxamide (JTE 907), N-[[4- (diethylamino)phenyl]methyl]-4-methoxy-N-(4-methylphenyl)benzenesulfonamide (XL-001), 2-[4- [(Z)-1,2-diphenylbut-1-enyl]phenoxy]-N,N-dimethylethanamine (tamoxifen) and its metabolites, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof. [0119] In some embodiments, the compound is a CB2R negative allosteric modulator. In some embodiments, the CB2R negative allosteric modulator is (Z)-4-[12,18-dihydroxy-8,21,21-trimethyl-5- (3-methylbut-2-enyl)-8-(4-methylpent-3-enyl)-14-oxo-3,7,20- trioxahexacyclo[15.4.1.02,15.02,19.04,13.06,11]docosa-4(13),5,9,11,15-pentaen-19-yl]-2-methylbut-2- enoic acid (Dihydro-gambogic acid, or DHGA), (1R,4E,9S)-4,11,11-trimethyl-8- methylidenebicyclo[7.2.0]undec-4-ene (trans-β-caryophyllene, or TBC), mambaquaretin-1, Exenetide (e.g., Byetta®) as described in US 2013/023494 and incorporated herein by reference, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof. [0120] Compounds described herein, including pharmaceutically acceptable salts, prodrugs, active metabolites and solvates thereof, are CB2 receptor (CB2R) modulators. [0121] In one embodiment, the compound may be selected from those compounds described in International Application No. PCT/US2021/030838, filed on May 5, 2021, entitled “Cannabinoid Receptor Type 2 (CB2) Modulators And Uses Thereof.” [0122] In some embodiments, the modulator is a compound of Formula (I), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof:
Figure imgf000024_0001
Formula (I) wherein, R1 is -OH, C1-C4alkyl, C2-C4alkenyl, C2-C4alkynyl, C1-C4alkoxy, C1-C4deuteroalkyl, C1- C4deuteroalkoxy, C1-C4fluoroalkyl, C1-C4fluoroalkoxy, C1-C4heteroalkyl, C3-C6cycloalkyl, C3-C6 heterocycloalkyl containing 1-2 N atom and 0 or 1 O or S atom, or a C3- C6heterocycloalkyl containing 0 or 1 N atom and 1 O or S atom; L1 is absent, C1-C4alkylene, or C3-C5cycloalkylene; R2 is a ring A that is unsubstituted or is substituted with 1, 2, 3, or 4 Ra; ring A is C3-C6heterocycloalkyl containing 1-2 N atom and 0 or 1 O or S atom, C3-C6heterocycloalkyl containing 0 or 1 N atom and 1 O or S atom, phenyl, C3-C10cycloalkyl, 5-membered heteroaryl, or 6-membered heteroaryl; each Ra is independently selected from the group consisting of halogen, -CN, -OH, -OR12, -SR12, -S(=O)R12, -S(=O)2R12, -S(=O)2N(R13)2, -NR13S(=O)2R12, -N(R13)2, -OC(=O)(R12), -CO2R13, -C(=O)N(R12)2, -NR13C(=O)(R12), -NR13C(=O)O(R12), -OC(=O)N(R13)2, -NR13C(=O)N(R13)2, C1-C4alkyl, C2-C4alkenyl, C2-C4alkynyl, C1-C4deuteroalkyl, C1-C4fluoroalkyl, C1-C4heteroalkyl, or substituted or unsubstituted monocyclic C3- C6heterocycloalkyl; R3 is H or C1-C4alkyl; R4 is -L2-R5; L2 is absent or -CR10R11-; R5 is a ring B that is unsubstituted or is substituted with 1, 2, 3, or 4 Rb; ring B is C3-C12cycloalkyl, C2-C10heterocycloalkyl, phenyl, naphthyl, or heteroaryl; each Rb is independently selected from the group consisting of halogen, -CN, -OH,
Figure imgf000025_0001
C2-C4alkenyl, C2-C4alkynyl, C1-C4alkoxy, C1-C4deuteroalkyl, C1-C4deuteroalkoxy, C1-C4fluoroalkyl, C1-C4fluoroalkoxy, C1-C4heteroalkyl, or substituted or unsubstituted monocyclic C3- C6heterocycloalkyl; or two Rb that are attached to the same carbon atom are taken together with the carbon atom to form a C3-C6cycloalkyl or a C3-C6heterocycloalkyl; R10 and R11 are independently selected from H or -CH3; or R10 and R11 are taken together with the carbon atom to which they are attached to form a C3-C6cycloalkyl; R6 is a ring C that is unsubstituted or is substituted with 1, 2, 3, or 4 Rc; ring C is phenyl, naphthyl, heteroaryl, C3-C12cycloalkyl, or C2-C10heterocycloalkyl; or R6 is hydrogen, halogen, -CN, -OH, -OR12, -SR12, -S(=O)R12, -S(=O)2R12, -S(=O)2N(R13)2, -NR13S(=O)2R12, -N(R13)2, -OC(=O)(R12), -CO2R13, -C(=O)N(R13)2, -NR13C(=O)(R12), -NR13C(=O)O(R12), -OC(=O)N(R13)2, -NR13C(=O)N(R13)2, C1-C4alkyl, C2- C4alkenyl, C2-C4alkynyl, C1-C4deuteroalkyl, C1-C4fluoroalkyl, C1-C4heteroalkyl, or substituted or unsubstituted monocyclic C3-C6heterocycloalkyl; each Rc is independently selected from the group consisting of halogen, -CN, -OH,
Figure imgf000025_0002
C1-C4deuteroalkyl, C1-C4fluoroalkyl, C1-C4heteroalkyl, substituted or unsubstituted C3-C6cycloalkyl, substituted or unsubstituted C3-C7heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted monocyclic heteroaryl or a 1,4-dioxanyl ring fused to ring C; R7 is H, halogen, -CN, -OH, -N(R13)2, C1-C4alkyl, C3-C6cycloalkyl, C2-C4alkenyl, C2-C4alkynyl, C1-C4alkoxy, C1-C4deuteroalkyl, C1-C4deuteroalkoxy, C1-C4fluoroalkyl, C1-C4fluoroalkoxy, or C1-C4heteroalkyl or C3-C6heterocycloalkyl; X1 is N; and X2 is CR8 or N; or X1 is CR8 or N; and X2 is N; R8 is H, halogen, -CN, -OH, -N(R13)2, C1-C4alkyl, C2-C4alkenyl, C2-C4alkynyl, C1-C4alkoxy, C1-C4deuteroalkyl, C1-C4deuteroalkoxy, C1-C4fluoroalkyl, C1-C4fluoroalkoxy, C3-C6cycloalkyl, C1-C4heteroalkyl or C3-C6heterocycloalkyl; each R12 is independently selected from the group consisting of C1-C4alkyl, C1-C4deuteroalkyl, C1-C4fluoroalkyl, C1-C4heteroalkyl, substituted or unsubstituted C3-C6cycloalkyl, substituted or unsubstituted C3-C6 heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted monocyclic heteroaryl; each R13 is independently selected from the group consisting of hydrogen, C1-C4alkyl, C1-C4deuteroalkyl, C1-C4fluoroalkyl, C1-C4heteroalkyl, substituted or unsubstituted C3-C6cycloalkyl, substituted or unsubstituted C3-C6 heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted monocyclic heteroaryl. [0123] In some embodiments of Formula (I), when R6 is H, R4 is not cyclohexyl, 4-methylcyclohexyl, or cycloheptyl. In some embodiments, R6 is H and R4 is cis-4-methylcyclohexyl. [0124] In some embodiments, R3 is H or -CH3; L1 is absent, -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH(CH3)-, -C(CH3)2-, or cyclopropyl-1,1-diyl; R10 and R11 are independently selected from H or -CH3; or R10 and R11 are taken together with the carbon atom to which they are attached to form a cyclopropyl-1,1-diyl; X1 is N; and X2 is CR8; or X1 is CR8; and X2 is N. [0125] In some embodiments, R1 is -OH, -CH3, -OCH3, -CD3, -OCD3, -CFH2, -CHF2, -CF3, -OCFH2, -OCHF2, -OCF3, cyclopropyl, aziridinyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, piperazinyl, or piperidinyl. In some embodiments, R1 is -OH, -CH3, - OCH3, -OC(CH3)2, -CD3, -OCD3, -CFH2, -CHF2, -CF3, -OCFH2, -OCHF2, -OCF3, cyclopropyl, aziridinyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, piperazinyl, or piperidinyl. [0126] In some embodiments, R1 is -OH or -CH3. In some embodiments, R1 is -O-C1-C3alkyl. [0127] In some embodiments, the compound of Formula (I) has the following structure of Formula (II), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof:
Figure imgf000026_0001
Formula (II); wherein L1, R2, R4, R6, and R7 are as defined in some or any embodiments of Formula (I). [0128] In some embodiments, R5 is a ring B that is unsubstituted or is substituted with 1, 2, 3, or 4 Rb; ring B is a monocyclic C3-C8cycloalkyl, or bicyclic C5-C12cycloalkyl that is a fused bicyclic C5- C12cycloalkyl, bridged bicyclic C5-C12cycloalkyl, or spiro bicyclic C5-C12cycloalkyl; or ring B is a monocyclic C2-C6heterocycloalkyl, or bicyclic C5-C8heterocycloalkyl that is a fused bicyclic C5- C8heterocycloalkyl, bridged bicyclic C5-C8heterocycloalkyl, or spiro bicyclic C5-C8heterocycloalkyl; or ring B is a phenyl; or ring B is a monocyclic heteroaryl selected from furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, and triazinyl. [0129] In some embodiments, L2 is absent; R5 is a ring B that is unsubstituted or is substituted with 1, 2, 3, or 4 Rb; ring B is a monocyclic C3-C8cycloalkyl, or bicyclic C5-C12cycloalkyl that is a fused bicyclic C5-C12cycloalkyl, bridged bicyclic C5-C12cycloalkyl, or spiro bicyclic C5-C12cycloalkyl; or ring B is a monocyclic C3-C6heterocycloalkyl, or bicyclic C5-C8heterocycloalkyl that is a fused bicyclic C5-C8heterocycloalkyl, bridged bicyclic C5-C8heterocycloalkyl, or spiro bicyclic C5-C8heterocycloalkyl. [0130] In some embodiments, L2 is absent; R5 is a ring B that is unsubstituted or is substituted with 1, 2, 3, or 4 Rb; ring B is cyclobutyl, cyclopentyl, or cyclohexyl; or ring B is a bicyclic C5-C12cycloalkyl that is a spiro[2.2]pentanyl, spiro[3.3]heptanyl, spiro[4.3]octanyl, spiro[3.4]octanyl, spiro[3.5]nonanyl, spiro[4.4]nonanyl, spiro[4.5]decanyl, spiro[5.4]decanyl, spiro[5.5]undecanyl, bicyclo[1.1.1]pentanyl, bicyclo[2.2.2]octanyl, bicyclo[2.2.1]heptanyl, adamantyl, or decalinyl. [0131] In some embodiments, L2 is absent; R5 is a ring B that is unsubstituted or is substituted with 1, 2, 3, or 4 Rb; ring B is cyclobutyl, cyclopentyl, or cyclohexyl; or ring B is spiro[3.3]heptanyl, bicyclo[1.1.1]pentanyl, or bicyclo[2.2.2]octanyl. [0132] In some embodiments, L2 is absent; R5 is a ring B that is unsubstituted or is substituted with 1,
Figure imgf000027_0002
[0133] In some embodiments,
Figure imgf000027_0001
[0134] In some embodiments, each Rb is independently selected from the group consisting of F, Cl, Br, -CN, -OH, -NH2, -NH(CH3), -N(CH3)2, -CH3, -OCH3, -CD3, -OCD3, -CFH2, -CHF2, -CF3, -OCFH2, -OCHF2, and -OCF3; or two Rb that are attached to the same carbon atom are taken together with the carbon atom to form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, thiomorpholinyl, or piperidinyl.
Figure imgf000028_0001
. [0136] In some embodiments, for any Formula described herein, R4 is
Figure imgf000028_0002
,
Figure imgf000028_0003
Figure imgf000029_0001
. [0138] In some embodiments, for any Formula described herein, R4 is a bridged C5-C12 cycloalkyl selected from
Figure imgf000029_0002
[0139] In some embodiments, L2 is absent or -CR10R11-; R10 and R11 are independently selected from H or -CH3; or R10 and R11 are taken together with the carbon atom to which they are attached to form a cyclopropyl-1,1-diyl; R5 is a ring B that is unsubstituted or is substituted with 1, 2, 3, or 4 Rb; ring B is phenyl or monocyclic heteroaryl. [0140] In some embodiments, ring B is phenyl, pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl. [0141] In some embodiments, L2 is absent or -CR10R11-; R10 and R11 are independently selected from H or -CH3; or R10 and R11 are taken together with the carbon atom to which they are attached to form
Figure imgf000029_0003
from H or -CH3; or R10 and R11 are taken together with the carbon atom to which they are attached to form a cyclopropyl-1,1-diyl; m is 0, 1, or 2; each Rb is independently selected from the group consisting of F, Cl, Br, -CN, -OH, -NH2, -NH(CH3), -N(CH3)2, -CH3, -OCH3, -CD3, -OCD3, -CFH2, - CHF2, -CF3, -OCFH2, -OCHF2, and -OCF3. [0144] In some embodiments, L1 is -CH2CH2-; R2 is a ring A that is unsubstituted or is substituted with 1, 2, 3, or 4 Ra; ring A is C3-C6 heterocycloalkyl containing 1-2 N atoms and 0 or 1 O or S atom, or C4-C7 heterocycloalkyl containing 0 or 1 N atom and 1 O or S atom; R6 is a ring C that is unsubstituted or is substituted with 1, 2, 3, or 4 Rc; ring C is phenyl, naphthyl, heteroaryl, C3- C12cycloalkyl, or C3-C6 heterocycloalkyl. [0145] In some embodiments, L1 is -CH2CH2-; R2 is a ring A that is unsubstituted or is substituted with 1, 2, 3, or 4 Ra; ring A is azetidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, piperidinyl, or piperazinyl. In some embodiments, for any Formula described herein, -L1-R2 is
Figure imgf000030_0001
[0146] In some embodiments, the compound of Formula (I) has the following structure of Formula (III), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof:
Figure imgf000031_0001
Formula (III); wherein R4, R6, and R7 are as defined in some or any embodiments of Formula (I). [0147] In some embodiments, R6 is a ring C that is unsubstituted or is substituted with 1, 2, 3, or 4 Rc; ring C is phenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, thiomorpholinyl, or piperidinyl.
Figure imgf000031_0002
[0149] In some embodiments, each Rc is independently selected from the group consisting of F, Cl, Br, -CN, -OH, -OCH3, -OCD3, -OCFH2, -OCHF2, -OCF3, -O-cyclopropyl, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NH(CH3), -S(=O)2N(CH3)2, -NHS(=O)2CH3, -NH2, -NH(CH3), -N(CH3)2, -OC(=O)CH3, -CO2H, -CO2CH3, -CO2CH2CH3, -C(=O)N(R15)2, -C(=O)-NH2, -C(=O)NH(CH3), -C(=O)N(CH3)2, -NHC(=O)CH3, -CH3, -CH2CH3, -CH(CH3)2, -C(CH3)3, -CD3, -CFH2, -CHF2, -CF3, -CH=CH2, -C(CH3)=CH2, -CH≡CH, -CH≡CCH3, cyclopropyl, or oxetanyl.
Figure imgf000031_0003
Figure imgf000031_0004
. In some of such embodiments, Rc is CN, CH3, F, O-C1-C3alkyl or O-C1-C3haloalkyl.
Figure imgf000031_0005
,
Figure imgf000032_0001
some embodiments, R6 is not H. In some embodiments, R6 is halo. [0151] In some embodiments, the compound of Formula (I) has the following structure of Formula (IV), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof:
Figure imgf000032_0002
Formula (IV); wherein R2, R4, R6, and R7 are as defined in some or any embodiments of Formula (I). [0152] In some embodiments, L1 is -CH2-, -CH(CH3)-, -C(CH3)2-, or cyclopropyl-1,1-diyl; R2 is a ring A that is unsubstituted or is substituted with 1, 2, 3, or 4 Ra; ring A is phenyl, or 6-membered heteroaryl.
Figure imgf000032_0003
[0155] In some embodiments, each Ra is independently selected from the group consisting of F, Cl, Br, -CN, -OH, -OCH3, -OCD3, -OCFH2, -OCHF2, -OCF3, -O-cyclopropyl, -S(=O)2CH3, -NH2, -NH(CH3), -N(CH3)2, -CH3, -CH2CH3, -CH(CH3)2, -C(CH3)3, -CD3, -CFH2, -CHF2, -CF3, cyclopropyl, or oxetanyl. [0156] In some embodiments, for any Formula described herein, R6 is H, F, Cl, Br, -CN, -OH, -OCH3, -OCD3, -OCFH2, -OCHF2, -OCF3, -O-cyclopropyl, -S(=O)2CH3, -S(=O)2NH2,
Figure imgf000033_0001
-C(=O)NH(CH3), -C(=O)N(CH3)2, -NHC(=O)CH3, -CH3, -CH2CH3, -CH(CH3)2, -C(CH3)3, -CD3, -CFH2, -CHF2, -CF3, -CH=CH2, -C(CH3)=CH2, -CH≡CH, -CH≡CCH3, cyclopropyl, or oxetanyl. [0157] In some embodiments, for any Formula described herein, R6 is H, F, Cl, Br, -CN, -OH, -OCH3, -OCD3, -OCFH2, -OCHF2, -OCF3, -O-cyclopropyl, -S(=O)2CH3, -CH3, -CH2CH3, -CH(CH3)2, -C(CH3)3, -CD3, -CFH2, -CHF2, -CF3, -CH=CH2, -C(CH3)=CH2, cyclopropyl, or oxetanyl. [0158] In another aspect, described herein is a compound that has the structure of Formula (X), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof:
Figure imgf000033_0002
Formula (X) wherein, R1 is hydrogen, -OH, C1-C4alkyl, C2-C4alkenyl, C2-C4alkynyl, C1-C4alkoxy, C1-C4deuteroalkyl, C1-C4deuteroalkoxy, C1-C4fluoroalkyl, C1-C4fluoroalkoxy, C1-C4heteroalkyl, C3-C6cycloalkyl, C3-C6 heterocycloalkyl containing 1 N atom and 0 or 1 O or S atom, or a C3-C6heterocycloalkyl containing 0 or 1 N atom and 1 O or S atom; L1 is absent, C1-C4alkylene, or C3-C5cycloalkylene; R2 is a ring A that is unsubstituted or is substituted with 1, 2, 3, or 4 Ra; ring A is C3-C6 heterocycloalkyl containing 1-2 N atom and 0 or 1 O or S atom, C3-C6heterocycloalkyl containing 0 or 1 N atom and 1 O or S atom, phenyl, C3-C10cycloalkyl, 5-membered heteroaryl, or 6-membered heteroaryl; each Ra is independently selected from the group consisting of halogen, -CN, -OH, -OR12, -SR12, -S(=O)R12, -S(=O)2R12, -S(=O)2N(R13)2, -NR13S(=O)2R12, -N(R13)2, -OC(=O)(R12), -CO2R13, -C(=O)N(R13)2, -NR13C(=O)(R12), -NR13C(=O)O(R12), -OC(=O)N(R13)2, -NR13C(=O)N(R13)2, C1-C4alkyl, C2-C4alkenyl, C2-C4alkynyl, C1-C4deuteroalkyl, C1-C4fluoroalkyl, C1-C4heteroalkyl, or substituted or unsubstituted monocyclic C3- C6heterocycloalkyl; R3 is H or C1-C4alkyl;
Figure imgf000034_0001
or R4 is -L2-R5; L2 is absent or -CR10R11-; R10 is -CH3; R11 is H or -CH3; or R10 and R11 are taken together with the carbon atom to which they are attached to form a cyclopropyl-1,1-diyl; R5 is a ring B that is unsubstituted or is substituted with 1, 2, 3, or 4 Rb; ring B is bridged C5-C12 cycloalkyl, phenyl, naphthyl, or heteroaryl; each Rb is independently selected from the group consisting of halogen, -CN, -OH, -N(R13)2, -OC(=O)(R12), -CO2R13, -C(=O)N(R13)2, -NR13C(=O)(R12), -NR15C(=O)O(R12), -OC(=O)N(R13)2, -NR13C(=O)N(R13)2, C1-C4alkyl, C2-C4alkenyl, C2-C4alkynyl, C1-C4alkoxy, C1-C4deuteroalkyl, C1-C4deuteroalkoxy, C1-C4fluoroalkyl, C1-C4fluoroalkoxy, C1-C4heteroalkyl, or substituted or unsubstituted monocyclic C3- C6heterocycloalkyl; or two Rb that are attached to the same carbon atom are taken together with the carbon atom to form a C3-C6cycloalkyl or a C3-C6heterocycloalkyl; R6 is a ring C that is unsubstituted or is substituted with 1, 2, 3, or 4 Rc; ring C is phenyl, naphthyl, heteroaryl, C3-C12cycloalkyl, or C2-C10heterocycloalkyl; or R6 is hydrogen, halogen, -CN, -OH, -OR12, -SR12, -S(=O)R12, -S(=O)2R12, -S(=O)2N(R13)2, -NR13S(=O)2R12, -N(R13)2, -OC(=O)(R12), -CO2R13, -C(=O)N(R13)2, -NR15C(=O)(R12), -NR13C(=O)O(R12), -OC(=O)N(R13)2, -NR13C(=O)N(R13)2, C1-C4alkyl, C2-C4alkenyl, C2-C4alkynyl, C1-C4deuteroalkyl, C1-C4fluoroalkyl, C1-C4heteroalkyl, or substituted or unsubstituted monocyclic C3-C6heterocycloalkyl; each Rc is independently selected from the group consisting of halogen, -CN, -OH, -OR12, -SR12, -S(=O)R12, -S(=O)2R12, -S(=O)2N(R13)2, -NR13S(=O)2R12, -N(R13)2, -OC(=O)(R12), -CO2R13, -C(=O)N(R13)2, -NR13C(=O)(R12), -NR13C(=O)O(R12), -OC(=O)N(R13)2, -NR13C(=O)N(R13)2, C1-C4alkyl, C2-C4alkenyl, C2-C4alkynyl, C1-C4deuteroalkyl, C1-C4fluoroalkyl, C1-C4heteroalkyl, substituted or unsubstituted C3-C6cycloalkyl, substituted or unsubstituted C3-C6heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted monocyclic heteroaryl or a 1,4-dioxanyl ring fused to ring C; R7 is H, halogen, -CN, -OH, -N(R13)2, C1-C4alkyl, C2-C4alkenyl, C2-C4alkynyl, C1-C4alkoxy, C1-C4deuteroalkyl, C1-C4deuteroalkoxy, C1-C4fluoroalkyl, C1-C4fluoroalkoxy, or C1-C4heteroalkyl; X1 is N; and X2 is CR8 or N; or X1 is CR8 or N; and X2 is N; R8 is H, halogen, -CN, -OH, -N(R13)2, C1-C4alkyl, C2-C4alkenyl, C2-C4alkynyl, C1-C4alkoxy, C1-C4deuteroalkyl, C1-C4deuteroalkoxy, C1-C4fluoroalkyl, C1-C4fluoroalkoxy, or C1-C4heteroalkyl; each R12 is independently selected from the group consisting of C1-C4alkyl, C1-C4deuteroalkyl, C1-C4fluoroalkyl, C1-C4heteroalkyl, substituted or unsubstituted C3-C6cycloalkyl, substituted or unsubstituted C3-C6heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted monocyclic heteroaryl; each R13 is independently selected from the group consisting of hydrogen, C1-C4alkyl, C1-C4deuteroalkyl, C1-C4fluoroalkyl, C1-C4heteroalkyl, substituted or unsubstituted C3-C6cycloalkyl, substituted or unsubstituted C3-C6heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted monocyclic heteroaryl. [0159] In some embodiments of Formula (X), when R1 is H, R4 is not cyclohexyl substituted by 0, 1, 2, 3 or 4 methyl groups. In some embodiments, the bridged cycloalkyl is bridged bicyclic C5- C12cycloalkyl. [0160] In some embodiments, R3 is H or -CH3; L1 is absent, -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH(CH3)-, -C(CH3)2-, or cyclopropyl-1,1-diyl; X1 is N; and X2 is CR8; or X1 is CR8; and X2 is N. [0161] In some embodiments, R1 is hydrogen, -OH, -CH3, -OCH3, -CD3, -OCD3, -CFH2, -CHF2, -CF3, -OCFH2, -OCHF2, -OCF3, cyclopropyl, aziridinyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, piperazinyl or piperidinyl. [0162] In some embodiments, R1 is hydrogen, -OH or -CH3. [0163] In some embodiments, the compound of Formula (X) has the following structure of Formula (XI), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof:
Figure imgf000036_0001
Formula (XI); wherein L1, Rb, u, v, R1, R2, R4, R6, and R7 are as defined in some or any embodiments of Formula (X).
Figure imgf000036_0002
[0166] In some embodiments, each Rb is independently selected from the group consisting of F, Cl, Br, -CN, -OH, -NH2, -NH(CH3), -N(CH3)2, -CH3, -OCH3, -CD3, -OCD3, -CFH2, -CHF2, -CF3, -OCFH2, -OCHF2, and -OCF3; or two Rb that are attached to the same carbon atom are taken together with the carbon atom to form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, thiomorpholinyl, or piperidinyl.
Figure imgf000036_0003
. [0168] In some embodiments, the compound of Formula (X) has the following structure of Formula (XII), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof:
Figure imgf000037_0001
Formula (XII) wherein X1, X2, L1, R1, R2, R6, and R7 are as defined in some or any embodiments of Formula (X); n1, n2, and n3 are each independently 1, 2 or 3; and Rd is halogen, -CN, -OH, -N(R13)2, -OC(=O)(R12), -CO2R13, -C(=O)N(R13)2, -NR13C(=O)(R12), -NR15C(=O)O(R12), -OC(=O)N(R13)2, -NR13C(=O)N(R13)2, C1-C4alkyl, C2- C4alkenyl, C2-C4alkynyl, C1-C4alkoxy, C1-C4deuteroalkyl, C1-C4deuteroalkoxy, C1-C4fluoroalkyl, C1- C4fluoroalkoxy, C1-C4heteroalkyl, or substituted or unsubstituted monocyclic C3-C6heterocycloalkyl. [0169] In some embodiments, the compound of Formula (X) has the following structure of Formula (XIII), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof:
Figure imgf000037_0002
Formula (XIII); wherein L1, R1, R2, R5, R6, R7, R10 and R11 are as defined in some or any embodiments of Formula (X). [0170] In some embodiments, R5 is a ring B that is unsubstituted or is substituted with 1, 2, 3, or 4 Rb; ring B is phenyl or monocyclic heteroaryl. [0171] In some embodiments, R5 is a ring B that is unsubstituted or is substituted with 1, 2, 3, or 4 Rb; or ring B is phenyl, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, or triazinyl. [0172] In some embodiments, ring B is phenyl, pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl.
Figure imgf000038_0001
[0174] In some embodiments, each Rb is independently selected from the group consisting of F, Cl, Br, -CN, -OH, -NH2, -NH(CH3), -N(CH3)2, -CH3, -OCH3, -CD3, -OCD3, -CFH2, -CHF2, -CF3, -OCFH2, -OCHF2, and -OCF3. [0175] In some embodiments, L1 is -CH2CH2-; R2 is a ring A that is unsubstituted or is substituted with 1, 2, 3, or 4 Ra; ring A is C3-C6heterocycloalkyl containing 1-2 N atoms and 0 or 1 O or S atom, or C3-C6heterocycloalkyl containing 0 or 1 N atom and 1 O or S atom; R6 is a ring C that is unsubstituted or is substituted with 1, 2, 3, or 4 Rc; ring C is phenyl, naphthyl, heteroaryl, C3- C12cycloalkyl, or C2-C10heterocycloalkyl. [0176] In some embodiments, L1 is -CH2CH2-; R2 is a ring A that is unsubstituted or is substituted with 1, 2, 3, or 4 Ra; ring A is azetidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, piperidinyl, or piperazinyl. [0177] In some embodiments, the compound of Formula (X) has the following structure of Formula (XIA), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof:
Figure imgf000038_0002
Formula (XIA); wherein Rb, u, v, R1, R6, and R7 are as defined in some or any embodiments of Formula (X). [0178] In some embodiments, the compound of Formula (X) has the following structure of Formula (XIIA), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof:
Figure imgf000039_0001
Formula (XIIA); wherein X1, X2, R1, R6, and R7 are as defined in some or any embodiments of Formula (X); n1, n2, and n3 are each independently 1, 2 or 3; and Rd is halogen, - -NR13C(=O)(R12), -NR1
Figure imgf000039_0002
C4alkenyl, C2-C4alkynyl, C1-C4alkoxy, C1-C4deuteroalkyl, C1-C4deuteroalkoxy, C1-C4fluoroalkyl, C1- C4fluoroalkoxy, C1-C4heteroalkyl, or substituted or unsubstituted monocyclic C3-C6heterocycloalkyl. [0179] In some embodiments, the compound of Formula (X) has the following structure of Formula (XIIIA), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof:
Figure imgf000039_0003
Formula (XIIIA); wherein R1, R5, R6, R7, R10, and R11, are as defined in some or any embodiments of Formula (X). [0180] In some embodiments, R6 is a ring C that is unsubstituted or is substituted with 1, 2, 3, or 4 Rc; ring C is phenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, thiomorpholinyl, or piperidinyl.
Figure imgf000040_0002
[0184] In some embodiments, L1 is -CH2-, -CH(CH3)-, -C(CH3)2-, or cyclopropyl-1,1-diyl; R2 is a ring A that is unsubstituted or is substituted with 1, 2, 3, or 4 Ra; ring A is phenyl, C3-C10cycloalkyl, 5-membered heteroaryl, or 6-membered heteroaryl. [0185] In some embodiments, the compound of Formula (X) has the following structure of Formula (XI), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof:
Figure imgf000040_0001
Formula (XIB); wherein Rb, u, v, R1, R2, R6, and R7 are as defined in some or any embodiments of Formula (X). [0186] In some embodiments, the compound of Formula (X) has the following structure of Formula (XIIB), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof:
Figure imgf000041_0001
Formula (XIIB) wherein R1, R2, R6, and R7 are as defined in some or any embodiments of Formula (X); n1, n2, and n3 are each independently 1, 2 or 3; and Rd is halogen, -CN, -OH, -N(R13)2, -OC(=O)(R12), -CO2R13, -C(=O)N(R13)2, -NR13C(=O)(R12), -NR15C(=O)O(R12), -OC(=O)N(R13)2, -NR13C(=O)N(R13)2, C1-C4alkyl, C2- C4alkenyl, C2-C4alkynyl, C1-C4alkoxy, C1-C4deuteroalkyl, C1-C4deuteroalkoxy, C1-C4fluoroalkyl, C1- C4fluoroalkoxy, C1-C4heteroalkyl, or substituted or unsubstituted monocyclic C3-C6heterocycloalkyl. [0187] In some embodiments, the compound of Formula (X) has the following structure of Formula (XII), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof:
Figure imgf000041_0002
Formula (XIIIB); wherein R1, R5, R6, R7, R10, and R11, are as defined in some or any embodiments of Formula (X).
Figure imgf000041_0003
Figure imgf000042_0001
, . [0191] In some embodiments, each Ra is independently selected from the group consisting of F, Cl, Br, -CN, -OH, -OCH3, -OCD3, -OCFH2, -OCHF2, -OCF3, -O-cyclopropyl, -S(=O)2CH3, -NH2, -NH(CH3), -N(CH3)2, -CH3, -CH2CH3, -CH(CH3)2, -C(CH3)3, -CD3, -CFH2, -CHF2, -CF3, cyclopropyl, or oxetanyl. [0192] In some embodiments, for any Formula described herein, R6 is H, F, Cl, Br, -CN, -OH, -OCH3, -OCD3, -OCFH2, -OCHF2, -OCF3, -O-cyclopropyl, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NH(CH3), -S(=O)2N(CH3)2, -NHS(=O)2CH3, -NH2, -NH(CH3), -N(CH3)2, -OC(=O)CH3, -CO2H, -CO2CH3, -CO2CH2CH3, -C(=O)N(R15)2, -C(=O)-NH2, -C(=O)NH(CH3), -C(=O)N(CH3)2, -NHC(=O)CH3, -CH3, -CH2CH3, -CH(CH3)2, -C(CH3)3, -CD3, -CFH2, -CHF2, -CF3, -CH=CH2, -C(CH3)=CH2, -CH≡CH, -CH≡CCH3, cyclopropyl, or oxetanyl. [0193] In some embodiments, for any Formula described herein, R6 is H, F, Cl, Br, -CN, -OH, -OCH3, -OCD3, -OCFH2, -OCHF2, -OCF3, -O-cyclopropyl, -S(=O)2CH3, -CH3, -CH2CH3, -CH(CH3)2, -C(CH3)3, -CD3, -CFH2, -CHF2, -CF3, -CH=CH2, -C(CH3)=CH2, cyclopropyl, or oxetanyl. [0194] In some embodiments, for any Formula described herein, R6 is a ring C that is unsubstituted or is substituted with 1, 2, 3, or 4 Rc; ring C is phenyl, naphthyl, heteroaryl, C3-C12cycloalkyl, or C2-C10heterocycloalkyl; or R6 is halogen, -CN, -OH, -OR12, -SR12, -S(=O)R12, -S(=O)2R12, -S(=O)2N(R13)2, -NR13S(=O)2R12, -N(R13)2, -OC(=O)(R12), -CO2R13, -C(=O)N(R13)2, -NR13C(=O)(R12), -NR13C(=O)O(R12), -OC(=O)N(R13)2, -NR13C(=O)N(R13)2, C1-C4alkyl, C2-C4alkenyl, C2-C4alkynyl, C1-C4deuteroalkyl, C1-C4fluoroalkyl, C1-C4heteroalkyl, or substituted or unsubstituted monocyclic C3-C6heterocycloalkyl; each Rc is independently selected from the group consisting of halogen, -CN, -OH, -OR12, -SR12, -S(=O)R12, -S(=O)2R12, -S(=O)2N(R13)2, -NR13S(=O)2R12, -N(R13)2, -OC(=O)(R12), -CO2R13, -C(=O)N(R13)2, -NR13C(=O)(R12), -NR13C(=O)O(R12), -OC(=O)N(R13)2, -NR13C(=O)N(R13)2, C1-C4alkyl, C2-C4alkenyl, C2-C4alkynyl, C1-C4deuteroalkyl, C1-C4fluoroalkyl, C1-C4heteroalkyl, substituted or unsubstituted C3-C6cycloalkyl, substituted or unsubstituted C3-C7heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted monocyclic heteroaryl or a 1,4-dioxanyl ring fused to ring C. [0195] In some embodiments, for any Formula described herein, R6 is a ring C that is unsubstituted or is substituted with 1, 2, 3, or 4 Rc, where Rc is as defined herein; ring C is phenyl, naphthyl, heteroaryl,C3-C6cycloalkyl, or C2-C6heterocycloalkyl; R4 is a bridged cycloalkyl selected from
Figure imgf000043_0001
any -L1-R2 selected from Table 1. In some of such embodiments, R1 is H. In some other such embodiments, R1 is OH or O-C1- C3alkyl. [0196] In some embodiments, for any Formula described herein, R6 is halo; R4 is a bridged cycloalkyl selected from
Figure imgf000043_0002
, and -L1-R2 is any -L1-R2 selected from Table 1. In some of such embodiments, R1 is H. In some other such embodiments, R1 is OH or O-C1-C3alkyl. [0197] In some embodiments, an agent that activates activation of immune cells (e.g., dendritic cell (DC) mediated activation of T cells) is a compound that has a structure of any one of compounds 1– 109 as shown in Table 1, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof. In some embodiments, an agent that activates immune cells is a compound selected from compounds 1- 6, 8-11, 13-17, 19-23, 26-63, 65-70, 72-73, 76-112, 114-119, 121-122, 125, 128, 132-135, 137-138, 140-143, 145, 148-150, 152-153, 158-159, and 161 as shown in Table 1, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof. In some embodiments, an agent that activates immune cells is a compound selected from compounds 1-136, 138-142, and 145-180 as shown in Table 1, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof. In some embodiments, an agent that activates immune cells is a compound selected from compounds 1-136, 138-142, and 145-257 as shown in Table 1, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof. In some embodiments, an agent that activates immune cells is a compound selected from compounds 1-136, 138-142, 145-220, 223, 225-228, 233a-233b, 237, 242, and 247-248b as shown in Table 1, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof. In some embodiments, an agent that activates immune cells is a compound selected from compounds 258-270 as shown in Table 1, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof. [0198] In some embodiments, the modulator has one of the following structures of Table 1, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof: Table 1.
Figure imgf000044_0001
Figure imgf000045_0001
Figure imgf000046_0001
Figure imgf000047_0001
Figure imgf000048_0001
Figure imgf000049_0001
Figure imgf000050_0001
Figure imgf000051_0001
Figure imgf000052_0001
Figure imgf000053_0001
Figure imgf000054_0001
Figure imgf000055_0001
Figure imgf000056_0001
Figure imgf000057_0001
Figure imgf000058_0001
Figure imgf000059_0001
Figure imgf000060_0001
Figure imgf000061_0001
Figure imgf000062_0001
Figure imgf000063_0001
Figure imgf000064_0001
Figure imgf000065_0001
Figure imgf000066_0001
Figure imgf000067_0001
Figure imgf000068_0001
Figure imgf000069_0001
Figure imgf000070_0001
Figure imgf000071_0001
Figure imgf000072_0001
Figure imgf000073_0001
Figure imgf000074_0001
Figure imgf000075_0001
Figure imgf000076_0001
Figure imgf000077_0001
Figure imgf000078_0001
Figure imgf000079_0001
Figure imgf000080_0001
Figure imgf000081_0001
Figure imgf000082_0001
Figure imgf000083_0001
Figure imgf000084_0001
Figure imgf000085_0001
Figure imgf000086_0001
Figure imgf000087_0001
Figure imgf000088_0001
Figure imgf000089_0001
Figure imgf000090_0001
Figure imgf000091_0001
Figure imgf000092_0001
Figure imgf000093_0001
Figure imgf000094_0001
Figure imgf000095_0001
[0199] In some embodiments, a CB2 modulator is a compound selected from Table 1A, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof. In some embodiments, a CB2 modulator is a compound that is not disclosed in PCT/US2021/030838 filed on May 5, 2021. Table 1A
Figure imgf000095_0002
Figure imgf000096_0001
Figure imgf000097_0001
Figure imgf000098_0001
Figure imgf000099_0001
Figure imgf000100_0001
Figure imgf000101_0001
Figure imgf000102_0001
Figure imgf000103_0001
Figure imgf000104_0001
Figure imgf000105_0001
Figure imgf000106_0001
Figure imgf000107_0001
Figure imgf000108_0001
Figure imgf000109_0001
Figure imgf000110_0001
Figure imgf000111_0001
Figure imgf000112_0001
Figure imgf000113_0001
Figure imgf000114_0001
Figure imgf000115_0001
Further Forms of Compounds [0200] In one aspect, CB2R modulators described herein (e.g., compounds of Formula (I), (II), (III), (IV), (X), (XI), (XIA), (XIB), (XII), (XIIA), (XIIB), (XIII), (XIIIA), and/or (XIIIB)), are in the form of pharmaceutically acceptable salts. As well, active metabolites of these compounds having the same type of activity are included in the scope of the present disclosure. In addition, the compounds described herein can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. The solvated forms of the compounds presented herein are also considered to be disclosed herein. [0201] “Pharmaceutically acceptable,” as used herein, refers a material, such as a carrier or diluent, which does not abrogate the biological activity or properties of the compound, and is relatively nontoxic, i.e., the material is administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained. [0202] The term “pharmaceutically acceptable salt” refers to a form of a therapeutically active agent that consists of a cationic form of the therapeutically active agent in combination with a suitable anion, or in alternative embodiments, an anionic form of the therapeutically active agent in combination with a suitable cation. Handbook of Pharmaceutical Salts: Properties, Selection and Use. International Union of Pure and Applied Chemistry, Wiley-VCH 2002. S.M. Berge, L.D. Bighley, D.C. Monkhouse, J. Pharm. Sci.1977, 66, 1-19. P. H. Stahl and C. G. Wermuth, editors, Handbook of Pharmaceutical Salts: Properties, Selection and Use, Weinheim/Zürich:Wiley-VCH/VHCA, 2002. Pharmaceutical salts typically are more soluble and more rapidly soluble in stomach and intestinal juices than non-ionic species and so are useful in solid dosage forms. Furthermore, because their solubility often is a function of pH, selective dissolution in one or another part of the digestive tract is possible and this capability can be manipulated as one aspect of delayed and sustained release behaviors. Also, because the salt-forming molecule can be in equilibrium with a neutral form, passage through biological membranes can be adjusted. [0203] In some embodiments, pharmaceutically acceptable salts are obtained by reacting a compound of Formula (I), (II), (III), (IV), (X), (XI), (XIA), (XIB), (XII), (XIIA), (XIIB), (XIII), (XIIIA), and/or (XIIIB) with an acid. In some embodiments, the compound of Formula (I), (II), (III), (IV), (X), (XI), (XIA), (XIB), (XII), (XIIA), (XIIB), (XIII), (XIIIA), and/or (XIIIB), (i.e. free base form) is basic and is reacted with an organic acid or an inorganic acid. Inorganic acids include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and metaphosphoric acid. Organic acids include, but are not limited to, 1-hydroxy-2-naphthoic acid; 2,2- dichloroacetic acid; 2-hydroxyethanesulfonic acid; 2-oxoglutaric acid; 4-acetamidobenzoic acid; 4- aminosalicylic acid; acetic acid; adipic acid; ascorbic acid (L); aspartic acid (L); benzenesulfonic acid; benzoic acid; camphoric acid (+); camphor-10-sulfonic acid (+); capric acid (decanoic acid); caproic acid (hexanoic acid); caprylic acid (octanoic acid); carbonic acid; cinnamic acid; citric acid; cyclamic acid; dodecylsulfuric acid; ethane-1,2-disulfonic acid; ethanesulfonic acid; formic acid; fumaric acid; galactaric acid; gentisic acid; glucoheptonic acid (D); gluconic acid (D); glucuronic acid (D); glutamic acid; glutaric acid; glycerophosphoric acid; glycolic acid; hippuric acid; isobutyric acid; lactic acid (DL); lactobionic acid; lauric acid; maleic acid; malic acid (- L); malonic acid; mandelic acid (DL); methanesulfonic acid; naphthalene-1,5-disulfonic acid; naphthalene-2-sulfonic acid; nicotinic acid; oleic acid; oxalic acid; palmitic acid; pamoic acid; phosphoric acid; proprionic acid; pyroglutamic acid (- L); salicylic acid; sebacic acid; stearic acid; succinic acid; sulfuric acid; tartaric acid (+ L); thiocyanic acid; toluenesulfonic acid (p); and undecylenic acid. [0204] In some embodiments, pharmaceutically acceptable salts are obtained by reacting a compound of Formula (I), (II), (III), (IV), (X), (XI), (XIA), (XIB), (XII), (XIIA), (XIIB), (XIII), (XIIIA), and/or (XIIIB), with a base. In some embodiments, the compound of Formula (I), (II), (III), (IV), (X), (XI), (XIA), (XIB), (XII), (XIIA), (XIIB), (XIII), (XIIIA), and/or (XIIIB), is acidic and is reacted with a base. In such situations, an acidic proton of the compound of Formula (I), (II), (III), (IV), (X), (XI), (XIA), (XIB), (XII), (XIIA), (XIIB), (XIII), (XIIIA), and/or (XIIIB), is replaced by a metal ion, e.g., lithium, sodium, potassium, magnesium, calcium, or an aluminum ion. In some cases, compounds described herein coordinate with an organic base, such as, but not limited to, ethanolamine, diethanolamine, triethanolamine, tromethamine, meglumine, N-methylglucamine, dicyclohexylamine, tris(hydroxymethyl)methylamine. In other cases, compounds described herein form salts with amino acids such as, but not limited to, arginine, lysine, and the like. Acceptable inorganic bases used to form salts with compounds that include an acidic proton, include, but are not limited to, aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydroxide, lithium hydroxide, and the like. In some embodiments, the compounds provided herein are prepared as a sodium salt, calcium salt, potassium salt, magnesium salt, meglumine salt, N-methylglucamine salt or ammonium salt. [0205] It should be understood that a reference to a pharmaceutically acceptable salt includes the solvent addition forms. In some embodiments, solvates contain either stoichiometric or non- stoichiometric amounts of a solvent, and are formed during the process of crystallization with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of compounds described herein are conveniently prepared or formed during the processes described herein. In addition, the compounds provided herein optionally exist in unsolvated as well as solvated forms. [0206] The methods and formulations described herein include the use of N-oxides (if appropriate), or pharmaceutically acceptable salts of compounds having the structure of Formula (I), (II), (III), (IV), (X), (XI), (XIA), (XIB), (XII), (XIIA), (XIIB), (XIII), (XIIIA), and/or (XIIIB) as well as active metabolites of these compounds having the same type of activity. [0207] In some embodiments, sites on the organic radicals (e.g. alkyl groups, aromatic rings) of compounds of Formula (I), (II), (III), (IV), (X), ((XIA), (XIB), (XII), (XIIA), (XIIB), (XIII), (XIIIA), and/or (XIIIB), are susceptible to various metabolic reactions. Incorporation of appropriate substituents on the organic radicals will reduce, minimize or eliminate this metabolic pathway. In specific embodiments, the appropriate substituent to decrease or eliminate the susceptibility of the aromatic ring to metabolic reactions is, by way of example only, a halogen, deuterium, an alkyl group, a haloalkyl group, or a deuteroalkyl group. [0208] In another embodiment, the compounds described herein are labeled isotopically (e.g. with a radioisotope) or by another other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels. [0209] Compounds described herein include isotopically-labeled compounds, which are identical to those recited in the various formulae and structures presented herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into the present compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine chlorine, iodine, phosphorus, such as, for example, 2H, 3H, 13C, 14C, 15N, 18O, 17O, 35S, 18F, 36Cl, 123I, 124I, 125I, 131I, 32P and 33P. In one aspect, isotopically-labeled compounds described herein, for example those into which radioactive isotopes such as 3H and 14C are incorporated, are useful in drug and/or substrate tissue distribution assays. In one aspect, substitution with isotopes such as deuterium affords certain therapeutic advantages resulting from greater metabolic stability, such as, for example, increased in vivo half-life or reduced dosage requirements. In some embodiments, one or more hydrogens of the compounds of Formula (I) are replaced with deuterium. [0210] In some embodiments, the compounds of Formula (I), (II), (III), (IV), (X), (XI), (XIA), (XIB), (XII), (XIIA), (XIIB), (XIII), (XIIIA), and/or (XIIIB), possess one or more stereocenters and each stereocenter exists independently in either the R or S configuration. In some embodiments, the compound of Formula (I), (II), (III), (IV), (X), (XI), (XIA), (XIB), (XII), (XIIA), (XIIB), (XIII), (XIIIA), and/or (XIIIB), exists in the R configuration. In some embodiments, the compound of Formula (I), (II), (III), (IV), (X), (XI), (XIA), (XIB), (XII), (XIIA), (XIIB), (XIII), (XIIIA), and/or (XIIIB), exists in the S configuration. The compounds presented herein include all diastereomeric, individual enantiomers, atropisomers, and epimeric forms as well as the appropriate mixtures thereof. The compounds and methods provided herein include all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers as well as the appropriate mixtures thereof. [0211] Individual stereoisomers are obtained, if desired, by methods such as, stereoselective synthesis and/or the separation of stereoisomers by chiral chromatographic columns or the separation of diastereomers by either non-chiral or chiral chromatographic columns or crystallization and recrystallization in a proper solvent or a mixture of solvents. In certain embodiments, compounds of Formula (I), (II), (III), (IV), (X), (XI), (XIA), (XIB), (XII), (XIIA), (XIIB), (XIII), (XIIIA), and/or (XIIIB), are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds/salts, separating the diastereomers and recovering the optically pure individual enantiomers. In some embodiments, resolution of individual enantiomers is carried out using covalent diastereomeric derivatives of the compounds described herein. In another embodiment, diastereomers are separated by separation/resolution techniques based upon differences in solubility. In other embodiments, separation of stereoisomers is performed by chromatography or by the forming diastereomeric salts and separation by recrystallization, or chromatography, or any combination thereof. Jean Jacques, Andre Collet, Samuel H. Wilen, “Enantiomers, Racemates and Resolutions”, John Wiley And Sons, Inc., 1981. In some embodiments, stereoisomers are obtained by stereoselective synthesis. [0212] In some embodiments, compounds described herein are prepared as prodrugs. A “prodrug” refers to an agent that is converted into the parent drug in vivo. Prodrugs are often useful because, in some situations, they are easier to administer than the parent drug. They are, for instance, bioavailable by oral administration whereas the parent is not. Further or alternatively, the prodrug also has improved solubility in pharmaceutical compositions over the parent drug. In some embodiments, the design of a prodrug increases the effective water solubility. An example, without limitation, of a prodrug is a compound described herein, which is administered as an ester (the “prodrug”) but then is metabolically hydrolyzed to provide the active entity. A further example of a prodrug is a short peptide (polyaminoacid) bonded to an acid group where the peptide is metabolized to reveal the active moiety. In certain embodiments, upon in vivo administration, a prodrug is chemically converted to the biologically, pharmaceutically or therapeutically active form of the compound. In certain embodiments, a prodrug is enzymatically metabolized by one or more steps or processes to the biologically, pharmaceutically or therapeutically active form of the compound. [0213] Prodrugs of the compounds described herein include, but are not limited to, esters, ethers, carbonates, thiocarbonates, N-acyl derivatives, N-acyloxyalkyl derivatives, N-alkyloxyacyl derivatives, quaternary derivatives of tertiary amines, N-Mannich bases, Schiff bases, amino acid conjugates, phosphate esters, and sulfonate esters. See for example Design of Prodrugs, Bundgaard, A. Ed., Elseview, 1985 and Method in Enzymology, Widder, K. et al., Ed.; Academic, 1985, vol.42, p.309-396; Bundgaard, H. “Design and Application of Prodrugs” in A Textbook of Drug Design and Development, Krosgaard-Larsen and H. Bundgaard, Ed., 1991, Chapter 5, p.113-191; and Bundgaard, H., Advanced Drug Delivery Review, 1992, 8, 1-38, each of which is incorporated herein by reference. In some embodiments, a hydroxyl group in the compounds disclosed herein is used to form a prodrug, wherein the hydroxyl group is incorporated into an acyloxyalkyl ester, alkoxycarbonyloxyalkyl ester, alkyl ester, aryl ester, phosphate ester, sugar ester, ether, and the like. In some embodiments, a hydroxyl group in the compounds disclosed herein is a prodrug wherein the hydroxyl is then metabolized in vivo to provide a carboxylic acid group. In some embodiments, a carboxyl group is used to provide an ester or amide (i.e. the prodrug), which is then metabolized in vivo to provide a carboxylic acid group. In some embodiments, compounds described herein are prepared as alkyl ester prodrugs. [0214] Prodrug forms of the herein described compounds, wherein the prodrug is metabolized in vivo to produce a compound of Formula (I), (II), (III), (IV), (X), (XIA), (XIB), (XII), (XIIA), (XIIB), (XIII), (XIIIA), and/or (XIIIB), as set forth herein are included within the scope of the claims. In some cases, some of the herein-described compounds is a prodrug for another derivative or active compound. [0215] In some embodiments, any one of the hydroxyl group(s), amino group(s) and/or carboxylic acid group(s) are functionalized in a suitable manner to provide a prodrug moiety. In some embodiments, the prodrug moiety is as described above. [0216] In additional or further embodiments, the compounds described herein are metabolized upon administration to an organism in need to produce a metabolite that is then used to produce a desired effect, including a desired therapeutic effect. 5. Combination Therapy [0217] In some or any of the preceding embodiments, the methods comprise administering at least one additional therapy to the patient. Checkpoint Inhibitors [0218] In some embodiments, the modulator described herein (i.e., a CB2R antagonist, inverse agonist, or negative allosteric modulator) is administered in combination with an immune checkpoint inhibitor. Immune checkpoint inhibitors include, but are not limited to, anti-natural killer cell receptor 2B4 (2B4), anti-B- and T-lymphocyte attenuator (BTLA), anti-CD160 antigen (CD160), anti- cytotoxic T-lymphocyte protein 4 (CTLA-4), anti-lymphocyte activation gene 3 protein (LAG-3), anti-programmed cell death protein 1 (PD-1), anti-T-cell immunoglobulin mucin receptor 3 (TIM-3), or anti-T-cell immunoreceptor with Ig and ITIM domains (TIGIT) agents/inhibitors. In some embodiments, the modulator (i.e., a CB2R antagonist, inverse agonist, or negative allosteric modulator), is administered in combination with an immune checkpoint inhibitor that is an immune checkpoint inhibitor other than a PD-1 inhibitor. In one embodiment, the compound of formula I is not administered with a PD-1 inhibitor. [0219] In some embodiments, immune checkpoint inhibitors include, but are not limited to anti-2B4, anti-BTLA, anti-CD160, anti-CTLA-4, anti-LAG-3, anti-PD-1, anti-TIM-3, or anti-TIGIT antibodies. In some embodiments, immune checkpoint inhibitors include, but are not limited to anti-2B4, anti- BTLA, anti-CD160, anti-CTLA-4, anti-LAG-3, anti-TIM-3, or anti-TIGIT antibodies. [0220] In some embodiments, a compound described herein (i.e., a CB2R antagonist, inverse agonist, or negative allosteric modulator), or a pharmaceutically acceptable salt thereof, is administered in combination with an inhibitor to an immune checkpoint ligand. Inhibitors to immune checkpoint ligands include, but are not limited to, anti-CD48 antigen (CD48), anti-CD80 antigen (CD80), anti- CD86 antigen (CD86), anti-CD112 antigen (CD112), anti-CD155 antigen (CD155), anti- carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1), anti-fibrinogen-like protein 1 (FGL1), anti-galectin-9 (Gal-9), anti-HLA class I histocompatibility antigen, alpha chain B (HLA- B), anti-HLA class I histocompatibility antigen, alpha chain C (HLA-C), anti-HLA class I histocompatibility antigen, alpha chain E (HLA-E), anti-HLA class I histocompatibility antigen, alpha chain G (HLA-G), anti-high mobility group protein B1 (HMG1), anti-herpesvirus entry mediator A (HVEM), anti-programmed cell death 1 ligand 1 (PD-L1), and anti-programmed cell death 1 ligand 2 (PD-L2) agents/inhibitors. In some embodiments, a compound described herein (i.e., a CB2R antagonist, inverse agonist, or negative allosteric modulator), or a pharmaceutically acceptable salt thereof, is administered in combination with an inhibitor to an immune checkpoint ligand other than a PD-L1/2 ligand. In some embodiments, inhibitors to immune checkpoint ligands include, but are not limited to anti-CD48, anti-CD80, anti-CD86, anti-CD112, anti-CD155, anti-CEACAM1, anti-FGL1, anti-Gal-9, anti-HLA-B, anti-HLA-C, anti-HLA-E, anti-HLA-G, anti-HMG1, anti-HVEM, anti-PD- L1, and anti-PD-L2 antibodies. In some embodiments, inhibitors to immune checkpoint ligands include, but are not limited to anti-CD48, anti-CD80, anti-CD86, anti-CD112, anti-CD155, anti- CEACAM1, anti-FGL1, anti-Gal-9, anti-HLA-B, anti-HLA-C, anti-HLA-E, anti-HLA-G, anti- HMG1, and anti-HVEM. Anti-2B4/Anti-CD48 Agents [0221] As used herein, “2B4” refers to the natural killer cell (2B4) receptor. Other names include NK cell activation-ligand (NAIL), NK cell type I receptor protein 2B4, signaling lymphocytic activation molecule 4 (SLAM4), and CD244 (cluster of differentiation 244).2B4 has at least one ligand, CD48 (cluster of differentiation 48). In some embodiments, targeting 2B4 restores immune function in the tumor microenvironment. In some embodiments, the anti-2B4 or anti-CD48 agent is an antibody, a peptide, a small molecule or a nucleic acid. [0222] In some embodiments, a compound described herein (i.e. a CB2R antagonist, inverse agonist, or negative allosteric modulator), or a pharmaceutically acceptable salt thereof, is administered in combination with an anti-2B4 or anti-CD48 agent. In some embodiments, the anti-2B4 agent is an anti-2B4 antibody. In some embodiments, the anti-CD48 agent is an anti-CD48 antibody. [0223] “Anti-2B4 antibody” refers to an antibody directed towards the natural killer cell (2B4) receptor. In some embodiments, an anti-2B4 antibody binds an epitope of 2B4 which blocks the binding of 2B4 to any one or more of its putative ligands. In some embodiments, an anti-2B4 antibody binds an epitope of a 2B4 protein which blocks the binding of 2B4 to CD48. “Anti-CD48 antibody” refers to an antibody directed towards CD48 antigen (CD48) [0224] The terms “antibody” and “antibodies” as used herein is inclusive of all types of immunoglobulins, including IgG, IgM, IgA, IgD, and IgE, or fragments thereof, that may be appropriate for the medical uses disclosed herein. The antibodies may be monoclonal or polyclonal and may be of any species of origin, including, for example, mouse, rat, rabbit, horse, or human. Antibody fragments that retain specific binding to the protein or epitope, for example, 2B4 or CD48, bound by the antibody used in the present disclosure are included within the scope of the term “antibody.” The antibodies may be chimeric or humanized, particularly when they are used for therapeutic purposes. Antibodies and antibody fragments may be obtained or prepared using various methods. Anti-BTLA/Anti-HVEM Agents [0225] As used herein, “BTLA” refers to B- and T-lymphocyte attenuator (BTLA) receptor. Other names include B- and T-lymphoctye-associated protein and CD272 (cluster of differentiation 272). BTLA has at least one ligand, herpesvirus entry mediator A (HVEM). In some embodiments, targeting BTLA restores immune function in the tumor microenvironment. [0226] In some embodiments, the anti-BTLA or anti-HVEM agent is an antibody, a peptide, a small molecule or a nucleic acid. [0227] In some embodiments, a compound described herein (i.e. a CB2R antagonist, inverse agonist, or negative allosteric modulator), or a pharmaceutically acceptable salt thereof, is administered in combination with an anti-BTLA or anti-HVEM agent. In some embodiments, the anti-BTLA agent is an anti-BTLA antibody. In some embodiments, the anti-HVEM agent is an anti-HVEM antibody. [0228] “Anti-BTLA antibody” refers to an antibody directed towards the B- and T-lymphocyte attenuator (BTLA) receptor. In some embodiments, an anti-BTLA antibody binds an epitope of BTLA which blocks the binding of BTLA to any one or more of its putative ligands. In some embodiments, an anti-BTLA antibody binds an epitope of a BTLA protein which blocks the binding of BTLA to HVEM. “Anti-HVEM antibody” refers to an antibody directed towards herpesvirus entry mediator A (HVEM). Anti-CD160/Anti-MHC class I Agents [0229] As used herein, “CD160” refers to CD160 antigen (CD160) receptor. Other names include natural killer cell receptor BY55 (BY55) and CD160 (cluster of differentiation 160). CD160 has at least two ligands, herpesvirus entry mediator A (HVEM) and major histocompatibility complex (MHC) class I proteins including HLA class I histocompatibility antigen, alpha chain B (HLA-B), HLA class I histocompatibility antigen, alpha chain C (HLA-C), HLA class I histocompatibility antigen, alpha chain E (HLA-E), and HLA class I histocompatibility antigen, alpha chain G (HLA-G). In some embodiments, targeting CD160 restores immune function in the tumor microenvironment. [0230] In some embodiments, the anti-CD160, anti-HLA-B, anti-HLA-C, anti-HLA-E, anti-HLA-G, or anti-HVEM agent is an antibody, a peptide, a small molecule or a nucleic acid. [0231] In some embodiments, a compound described herein (i.e. a CB2R antagonist, inverse agonist, or negative allosteric modulator), or a pharmaceutically acceptable salt thereof, is administered in combination with an anti-CD160, anti-HLA-B, anti-HLA-C, anti-HLA-E, anti-HLA-G, or anti- HVEM agent. In some embodiments, the anti-CD160 agent is an anti-CD160 antibody. In some embodiments, the anti-HLA-B agent is an anti-HLA-B antibody. In some embodiments, the anti- HLA-C agent is an anti-HLA-C antibody. In some embodiments, the anti-HLA-E agent is an anti- HLA-E antibody. In some embodiments, the anti-HLA-G agent is an anti-HLA-G antibody. In some embodiments, the anti-HVEM agent is an anti-HVEM antibody. [0232] “Anti-CD160 antibody” refers to an antibody directed towards the CD160 antigen (CD160) receptor. In some embodiments, an anti-CD160 antibody binds an epitope of CD160 which blocks the binding of CD160 to any one or more of its putative ligands. In some embodiments, an anti-CD160 antibody binds an epitope of a CD160 protein which blocks the binding of CD160 to HLA-B, HLA-C, HLA-E, HLA-G, or HVEM. “Anti- HLA-B antibody” refers to an antibody directed towards HLA class I histocompatibility antigen, alpha chain B (HLA-B). “Anti- HLA-C antibody” refers to an antibody directed towards HLA class I histocompatibility antigen, alpha chain C (HLA-C). “Anti- HLA-E antibody” refers to an antibody directed towards HLA class I histocompatibility antigen, alpha chain E (HLA-E). “Anti- HLA-G antibody” refers to an antibody directed towards HLA class I histocompatibility antigen, alpha chain G (HLA-G). Anti-CTLA-4/Anti-CD80/Anti-CD86 Agents [0233] As used herein, “CTLA-4” or “CTLA4” refers to cytotoxic T-lymphocyte protein 4 (CTLA-4) receptor. Other names include cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and CD152 (cluster of differentiation 152). CTLA-4 has at least two ligands, T-lymphocyte activation antigen CD80 (CD80) and T-lymphocyte activation antigen CD86 (CD86). In some embodiments, targeting CTLA-4 restores immune function in the tumor microenvironment. [0234] In some embodiments, the anti-CTLA-4, anti-CD80, or anti-CD86 agent is an antibody, a peptide, a small molecule or a nucleic acid. [0235] In some embodiments, a compound described herein (i.e. a CB2R antagonist, inverse agonist, or negative allosteric modulator), or a pharmaceutically acceptable salt thereof, is administered in combination with an anti-CTLA-4, anti-CD80, or anti-CD86 agent. In some embodiments, the anti- CTLA-4 agent is an anti-CTLA-4 antibody. In some embodiments, the anti-CD80 agent is an anti- CD80 antibody. In some embodiments, the anti-CD86 agent is an anti-CD86 antibody. Anti-CTLA-4 antibody” refers to an antibody directed towards the cytotoxic T-lymphocyte protein 4 (CTLA-4) receptor. In some embodiments, an anti-CTLA-4 antibody binds an epitope of CTLA-4 which blocks the binding of CTLA-4 to any one or more of its putative ligands. In some embodiments, an anti- CTLA-4 antibody binds an epitope of a CTLA-4 protein which blocks the binding of CTLA-4 to CD80 or CD86. “Anti-CD80 antibody” refers to an antibody directed towards CD80 antigen (CD80). “Anti-CD86 antibody” refers to an antibody directed towards CD86 antigen (CD80). Anti-LAG-3/Anti-FGL1/Anti-MHC class II Agents [0236] As used herein, “LAG-3” refers to lymphocyte activation gene 3 protein (LAG-3) receptor. Other names include CD223 (cluster of differentiation 223). LAG-3 has at least two ligands, fibrinogen-like protein 1 (FGL1) and major histocompatibility complex (MHC) class II proteins. In some embodiments, targeting CD160 restores immune function in the tumor microenvironment. [0237] In some embodiments, the anti-LAG-3, anti-FGL1, or anti-MHC class II agent is an antibody, a peptide, a small molecule or a nucleic acid. [0238] In some embodiments, a compound described herein (i.e. a CB2R antagonist, inverse agonist, or negative allosteric modulator), or a pharmaceutically acceptable salt thereof, is administered in combination with an anti-LAG-3, anti-FGL1, or anti-MHC class II agent. In some embodiments, the anti-LAG-3 agent is an anti-LAG-3 antibody. In some embodiments, the anti-FGL1 agent is an anti- FGL1 antibody. In some embodiments, the anti-MHC class II agent is an anti-MHC class II antibody. [0239] “Anti- LAG-3 antibody” refers to an antibody directed towards the lymphocyte activation gene 3 protein (LAG-3) receptor. In some embodiments, an anti- LAG-3 antibody binds an epitope of LAG-3 which blocks the binding of LAG-3 to any one or more of its putative ligands. In some embodiments, an anti- LAG-3 antibody binds an epitope of a LAG-3 protein which blocks the binding of LAG-3 to FGL1, or MHC class II. “Anti-FGL1 antibody” refers to an antibody directed towards fibrinogen-like protein 1 (FGL1). “Anti-MHC class II antibody” refers to an antibody directed towards major histocompatibility complex (MHC) class II protein. Anti-PD-1/Anti-PD-L1/Anti-PDL2 Agents [0240] As used herein, “PD-1” or “PD1” refers to the Programmed Death 1 (PD-1) receptor. Other names include programmed cell death protein 1 and CD279 (cluster of differentiation 279). PD-1 has two ligands, PD-L1 and PD-L2. In some embodiments, targeting PD-1 restores immune function in the tumor microenvironment. [0241] As used herein, “PD-L1” or “PDL1” refers to the programmed death ligand 1 (PD-L1). [0242] As used herein, “PD-L2” or “PDL2” refers to the programmed death ligand 2 (PD-L2). [0243] In some embodiments, the anti-PD-1 or anti-PDL-1 agent is an antibody, a peptide, a small molecule or a nucleic acid. [0244] In some embodiments, a compound described herein (i.e. a CB2R antagonist, inverse agonist, or negative allosteric modulator), or a pharmaceutically acceptable salt thereof, is administered in combination with an anti-PD-1 or anti-PD-L1 agent. [0245] In some embodiments, the anti PD-l agent for use in combination with compound described herein (i.e. a CB2R antagonist or inverse agonist), or a pharmaceutically acceptable salt thereof, is nivolumab, pembrolizumab, atezolizumab, durvalumab, pidilizumab, avelumab, TSR-042, PDR-001, tislelizumab (BGB-A317), cemiplimab (REGN2810), LY-3300054, JNJ-63723283, MGA012, BI- 754091, IBI-308, camrelizumab (HR-301210), BCD-100, JS-001, CX-072, BGB-A333, AMP-514 (MEDI-0680), AGEN- 2034, CSIOOI, Sym-021, SHR-1316, PF-06801591, LZM009, KN-035, AB122, genolimzumab (CBT-501), FAZ-053, CK-301, AK 104, or GLS-010, BGB-108, SHR-1210, PDR-001, PF-06801591, STI-1110, mDX-400, Spartalizumab (PDR001), Camrelizumab (SHR1210), Sintilimab (IBI308), Tislelizumab (BGB-A317), Toripalimab (JS 001), Dostarlimab (TSR-042, WBP- 285), INCMGA00012 (MGA012), AMP-224, or AMP-514 (MEDI0680). [0246] In some embodiments, the anti PD-l agent is an anti PD-l antibody. “Anti-PD-1 antibody” refers to an antibody directed towards programmed death protein 1 (PD1). In some embodiments, an anti-PD-1 antibody binds an epitope of PD-1 which blocks the binding of PD-1 to any one or more of its putative ligands. In some embodiments, an anti-PD1 antibody binds an epitope of a PD-1 protein which blocks the binding of PD-1 to PD-L1 and/or PD-L2. [0247] Exemplary anti-PD-l antibodies include but are not limited to: nivolumab/MDX-l106/BMS- 9300/ONO1152, a fully human lgG4 anti-PD-l monoclonal antibody; pidilizumab (MDV9300/CT- 011), a humanized IgGl monoclonal antibody; pembrolizumab (MK-3475/ pembrolizumab/lambrolizumab), a humanized monoclonal IgG4 antibody; durvalumab (MEDI-4736) and atezolizumab. [0248] In some embodiments, the anti-PD-1 antibody is nivolumab (OPDIVO®, Bristol-Myers Squibb), pembrolizumab (KEYTRUDA®, Merck), cemiplimab (Libtayo), labrolizumab (Merck), or BGB-A317. [0249] In some embodiments, the anti-PD1 antibody is an antibody set forth in U.S. Patent Nos. 7,029,674, 7,488,802, 7,521,051, 8,008,449, 8,354,509, 8,617,546, 8,709,417, or WO2014/179664. [0250] In some embodiments, the anti PD-l agent for use in combination with a compound described herein (i.e. a CB2R antagonist or inverse agonist), or a pharmaceutically acceptable salt thereof, is atezolizumab, avelumab, AMP-224, MEDI-0680, RG-7446, GX-P2, durvalumab, KY-1003, KD-033, MSB-0010718C, TSR-042, ALN-PDL, STI-A1014, CX- 072, BMS-936559, KN035, CK-301 (Checkpoint Therapeutics), AUNP12, CA-170 (Aurigene/Curis), MEDI4736, MSB0010718C, MDX 1105-01, or BMS-986189. [0251] In some embodiments, the anti PD-Ll agent is an anti PD-Ll antibody. [0252] “Anti-PD-L1 antibody” refers to an antibody directed towards programmed death ligand 1 (PD-L1). [0253] Anti-PD-Ll antibodies for use in combination with a compound described herein (i.e. a CB2R antagonist or inverse agonist), or a pharmaceutically acceptable salt thereof, include: avelumab; BMS- 936559, a fully human IgG4 antibody; atezolizumab (MPDL3280A/RG-7446), a human monoclonal antibody; MEDI4736; MSB0010718C, and MDX 1105-01. [0254] In some embodiments, the anti-PD-L1 antibody is avelumab (Bavencio®, Merck KGA/Pfizer), durvalumab (AstraZeneca) and atezolizumab (TECENTRIQ®, Roche). [0255] Additional exemplary antibodies include, but are not limited to, the antibodies set forth in U.S. Patent Nos.8,217,149, 8,383,796, 8,552,154 and 8,617,546. [0256] Peptide anti-PD-1/PD-L1 agents include AUNP12 (a 29-mer peptide by Aurigene and Laboratoires Pierre Fabre), CA-170 (Aurigene/Curis), BMS-986189 (a macrocyclic peptide by BMS). [0257] Small molecule anti-PD-1/PD-L1 agents include those described in WO/2020/086556, WO/2020/014643, WO/2019/204609, WO/2019/160882, WO/2018/195321, WO2018026971, US20180044329, US20180044305, US20180044304, US20180044303, US20180044350, US20180057455, US20180057486, US20180045142, WO20180044963, WO2018044783, WO2018009505, WO20180044329, WO2017066227, WO2017087777, US20170145025, WO2017079669, W02017070089, US2017107216, WO2017222976, US20170262253, WO2017205464, US20170320875, WO2017192961, WO2017112730, US20170174679, WO2017106634, WO2017202744, WO2017202275, WO2017202273, WO2017202274, WO2017202276, WO2017180769, WO2017118762, W02016041511, WO2016039749, WO2016142835, WO2016142852, WO2016142886, WO2016142894, and WO2016142833. In some embodiments, the small molecule anti-PD-1/PD-L1 agent is GS-4224. Anti-TIM-3/Anti-Gal-9/Anti-HMG1/Anti-CEACAM1 Agents [0258] As used herein, “TIM-3” refers to T-cell immunoglobulin mucin receptor 3 (TIM-3) receptor. Other names include hepatitis A virus cellular receptor 2 (HAVcr-2), T-cell immunoglobulin and mucin domain-containing protein 3 (TIMD-3), T-cell membrane protein 3, and CD366 (cluster of differentiation 366). TIM-3 has at least three ligands, galectin-9 (Gal-9), high mobility group protein B1 (HMG1), and carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1). In some embodiments, targeting TIM-3 restores immune function in the tumor microenvironment. [0259] In some embodiments, the anti-TIM-3, anti-Gal-9, anti-HMG1, or anti-CEACAM1 agent is an antibody, a peptide, a small molecule or a nucleic acid. [0260] In some embodiments, a compound described herein (i.e. a CB2R antagonist, inverse agonist, or negative allosteric modulator), or a pharmaceutically acceptable salt thereof, is administered in combination with an anti-TIM-3, anti-Gal-9, anti-HMG1, or anti-CEACAM1 agent. In some embodiments, the anti-TIM-3 agent is an anti-TIM-3 antibody. In some embodiments, the anti-Gal-9 agent is an anti-Gal-9 antibody. In some embodiments, the anti-HMG1 agent is an anti-HMG1 antibody. In some embodiments, the anti-CEACAM1 agent is an anti-CEACAM1 antibody. [0261] “Anti-TIM-3 antibody” refers to an antibody directed towards the T-cell immunoglobulin mucin receptor 3 (TIM-3) receptor. In some embodiments, an anti-TIM-3 antibody binds an epitope of TIM-3 which blocks the binding of TIM-3 to any one or more of its putative ligands. In some embodiments, an anti-TIM-3 antibody binds an epitope of a TIM-3 protein which blocks the binding of TIM-3 to Gal-9, HMG1, or CEACAM1. “Anti-Gal-9 antibody” refers to an antibody directed towards galectin 9 (Gal-9). “Anti-HMG1 antibody” refers to an antibody directed towards high mobility group protein B1 (HMG1). “Anti-CEACAM1 antibody” refers to an antibody directed towards carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1). Anti-TIGIT/Anti-CD112/Anti-CD155 Agents [0262] As used herein, “TIGIT” refers to T-cell immunoreceptor with Ig and ITIM domains (TIGIT) receptor. Other names include V-set and immunoglobulin domain-containing protein 9 (VSIG9) and V-set and transmembrane domain-containing protein 3 (VSTM3). TIGIT has at least two ligands, CD112 (cluster of differentiation 112) and CD155 (cluster of differentiation 155). In some embodiments, targeting TIGIT restores immune function in the tumor microenvironment. [0263] In some embodiments, the anti-TIGIT, anti-CD112, or CD155 agent is an antibody, a peptide, a small molecule or a nucleic acid. [0264] In some embodiments, a compound described herein (i.e., a CB2R antagonist, inverse agonist, or negative allosteric modulator), or a pharmaceutically acceptable salt thereof, is administered in combination with an anti-TIGIT, anti-CD112, or CD155 agent. In some embodiments, the anti-TIGIT agent is an anti-TIGIT antibody. In some embodiments, the anti-CD112 agent is an anti-CD112 antibody. In some embodiments, the anti-CD155 agent is an anti-CD155 antibody. “Anti-TIGIT antibody” refers to an antibody directed towards the T-cell immunoreceptor with Ig and ITIM domains (TIGIT) receptor. In some embodiments, an anti-TIGIT antibody binds an epitope of TIGIT which blocks the binding of TIGIT to any one or more of its putative ligands. In some embodiments, an anti-TIGIT antibody binds an epitope of a TIGIT protein which blocks the binding of TIGIT to CD112 or CD155. “Anti-CD112 antibody” refers to an antibody directed towards CD112 (cluster of differentiation 112). “Anti-CD155 antibody” refers to an antibody directed towards CD155 (cluster of differentiation 155). Additional Combination Therapies [0265] In some embodiments, a compound described herein (i.e., a CB2R antagonist, inverse agonist, or negative allosteric modulator), or a pharmaceutically acceptable salt thereof, is administered in combination with chemotherapy, radiation therapy, monoclonal antibodies, or combinations thereof. Chemotherapy includes the use of anti-cancer agents. In some embodiments, a compound described herein (i.e., a CB2R antagonist, inverse agonist, or negative allosteric modulator), or a pharmaceutically acceptable salt thereof, is administered in combination with any CAR T cell therapy described herein. In some embodiments, a compound described herein (i.e., a CB2R antagonist, inverse agonist, or negative allosteric modulator), or a pharmaceutically acceptable salt thereof, is administered in combination with bi-specific T-cell engagers, a class of artificial bispecific monoclonal antibodies that are anti-cancer drugs. Bi-specific T-cell engagers direct a host’s immune system, e.g., by specifically directing the T cells’ cytotoxic activity, against cancer cells. [0266] In addition to the CB2R antagonists or inverse agonists described above, the following CB2R antagonists or inverse agonists are also contemplated within the scope of embodiments presented herein for use in the combination therapies described herein for the treatment of cancer: 5-(4-chloro- 3-methylphenyl)-1-[(4-methylphenyl)methyl]-N-[(1S,2S,4R)-1,3,3-trimethylbicyclo[2.2.1]hept-2-yl]- 1H-pyrazole-3-carboxamide (SR144528), [6-iodo-2-methyl-1-[2-(4-morpholinyl)ethyl]-1H-indol-3- yl](4-methoxyphenyl)-methanone (AM630), or N-(1,3-benzodioxol-5-ylmethyl)-1,2-dihydro-7- methoxy-2-oxo-8-(pentyloxy)-3-quinolinecarboxamide (JTE 907), or any one of the CB2R antagonists or inverse agonists described in V. Lucchesi et al., J. Med. Chem.2014, 57, 8777−8791. [0267] In some embodiments, an agent that activates immune cells is any CB2R modulator described herein wherein the CB2R modulator is not a compound of Formula (I) described herein. In some embodiments, an agent that activates immune cells is any CB2R modulator described herein, and the CB2R modulator is administered to a patient suffering from cancer in combination with any immunotherapeutic agent wherein the immunotherapeutic agent is not a PD-L1/2 inhibitor. 6. Biomarkers [0268] In one aspect, provided herein is a method for increasing the activation and/or proliferation of immune cells in a patient in need thereof, wherein the method comprises determining the level of at least one biomarker in a biological sample obtained from the patient, and providing the subject with an effective amount of a CB2R modulator when the level of the at least one biomarker is higher or lower than a reference level. [0269] In certain embodiments, the at least one biomarker is an immunomodulatory receptor selected from the group consisting of 2B4, BTLA, CD160, CTLA-4, LAG-3, PD-1, TIM-3, and TIGIT. [0270] In some embodiments, the at least one biomarker is an effector molecule selected from the group consisting of granzyme B, interferon gamma (IFNγ), interleukin 1 (IL-1), interleukin 2 (IL-2), interleukin 4 (IL-4), interleukin 5 (IL-5), interleukin 6 (IL-6), interleukin 10 (IL-10), interleukin 12 (IL-12), interleukin 13 (IL-13), interleukin 17 (IL-17), interleukin 22 (IL-22), transforming growth factor beta (TGF-β), and tumor necrosis factor alpha (TNFα). [0271] In some embodiments, the at least one biomarker is a transcription factor selected from the group consisting of nuclear factor of activated T-cells (NFAT), nuclear receptor subfamily 4 group A (NR4A), T-cell-specific transcription factor 1 (TCF-1), thymocyte selection-associated high mobility group box protein (TOX), and TOX high mobility group box family member 2 (TOX2). [0272] In certain embodiments, the biological sample is selected from the group consisting of blood, plasma, serum, and tissue. [0273] In certain embodiments, the method comprises determining the level of the at least one biomarker in the biological sample from the patient. The method further comprises comparing the measured level of the at least one biomarker in the sample from the patient against a reference level of the at least one biomarker from a suitable control population. In some embodiments, the reference level may be the level of the biomarker in a healthy patient, or the level of the biomarker in the patient prior to start of immune therapy. 7. Pharmaceutical Compositions and Modes of Administration [0274] Compounds provided herein are usually administered in the form of pharmaceutical compositions. Thus, provided herein are also pharmaceutical compositions that contain one or more of the compounds described herein or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof and one or more pharmaceutically acceptable vehicles selected from carriers, adjuvants and excipients. Suitable pharmaceutically acceptable vehicles may include, for example, inert solid diluents and fillers, diluents, including sterile aqueous solution and various organic solvents, permeation enhancers, solubilizers and adjuvants. Such compositions are prepared in a manner well known in the pharmaceutical art. See, e.g., Remington’s Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, Pa.17th Ed. (1985); and Modern Pharmaceutics, Marcel Dekker, Inc.3rd Ed. (G.S. Banker & C.T. Rhodes, Eds.). [0275] The pharmaceutical compositions may be administered in either single or multiple doses. The pharmaceutical composition may be administered by various methods including, for example, rectal, buccal, intranasal and transdermal routes. In certain embodiments, the pharmaceutical composition may be administered by intra-arterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, or as an inhalant. [0276] One mode for administration is parenteral, for example, by injection. The forms in which the pharmaceutical compositions described herein may be incorporated for administration by injection include, for example, aqueous or oil suspensions, or emulsions, with sesame oil, corn oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose, or a sterile aqueous solution, and similar pharmaceutical vehicles. [0277] Oral administration may be another route for administration of the compounds described herein. Administration may be via, for example, capsule or enteric coated tablets. In making the pharmaceutical compositions that include at least one compound described herein or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof, the active ingredient is usually diluted by an excipient and/or enclosed within such a carrier that can be in the form of a capsule, sachet, paper or other container. When the excipient serves as a diluent, it can be in the form of a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, sterile injectable solutions, and sterile packaged powders. [0278] Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methyl cellulose. The formulations can additionally include lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl and propylhydroxy-benzoates; sweetening agents; and flavoring agents. [0279] The compositions that include at least one compound described herein or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the subject by employing procedures known in the art. Controlled release drug delivery systems for oral administration include osmotic pump systems and dissolutional systems containing polymer-coated reservoirs or drug-polymer matrix formulations. Examples of controlled release systems are given in U.S. Patent Nos.3,845,770; 4,326,525; 4,902,514; and 5,616,345. Another formulation for use in the methods disclosed herein employ transdermal delivery devices (“patches”). Such transdermal patches may be used to provide continuous or discontinuous infusion of the compounds described herein in controlled amounts. The construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art. See, e.g., U.S. Patent Nos. 5,023,252, 4,992,445 and 5,001,139. Such patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents. [0280] For preparing solid compositions such as tablets, the principal active ingredient may be mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound described herein or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof. When referring to these preformulation compositions as homogeneous, the active ingredient may be dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. [0281] The tablets or pills of the compounds described herein may be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action, or to protect from the acid conditions of the stomach. For example, the tablet or pill can include an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer that serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate. [0282] Compositions for inhalation or insufflation may include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described herein. In some embodiments, the compositions are administered by the oral or nasal respiratory route for local or systemic effect. In other embodiments, compositions in pharmaceutically acceptable solvents may be nebulized by use of inert gases. Nebulized solutions may be inhaled directly from the nebulizing device or the nebulizing device may be attached to a facemask tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions may be administered, preferably orally or nasally, from devices that deliver the formulation in an appropriate manner. 8. Dosing and Treatment Regimens [0283] In one embodiment, the compounds described herein, or a pharmaceutically acceptable salt thereof, are used in the preparation of medicaments for the treatment of diseases or conditions in a patient that would benefit from inhibition or reduction of CB2R activity. Methods for treating any of the diseases or conditions described herein in a patient in need of such treatment, involves administration of pharmaceutical compositions that include at least one compound described herein or a pharmaceutically acceptable salt, active metabolite, prodrug, or pharmaceutically acceptable solvate thereof, in therapeutically effective amounts to said patient. [0284] In certain embodiments, the compositions containing the compound(s) described herein are administered for prophylactic and/or therapeutic treatments. In certain therapeutic applications, the compositions are administered to a patient already suffering from a disease or condition, in an amount sufficient to cure or at least partially arrest at least one of the symptoms of the disease or condition. Amounts effective for this use depend on the severity and course of the disease or condition, previous therapy, the patient’s health status, weight, and response to the drugs, and the judgment of a healthcare practitioner. Therapeutically effective amounts are optionally determined by methods including, but not limited to, a dose escalation and/or dose ranging clinical trial. [0285] In prophylactic applications, compositions containing the compounds described herein are administered to a patient susceptible to or otherwise at risk of a particular disease, disorder or condition. Such an amount is defined to be a “prophylactically effective amount or dose.” In this use, the precise amounts also depend on the patient’s state of health, weight, and the like. When used in patients, effective amounts for this use will depend on the severity and course of the disease, disorder or condition, previous therapy, the patient’s health status and response to the drugs, and the judgment of a healthcare professional. In one aspect, prophylactic treatments include administering to a patient, who previously experienced at least one symptom of the disease being treated and is currently in remission, a pharmaceutical composition comprising a compound described herein, or a pharmaceutically acceptable salt thereof, in order to prevent a return of the symptoms of the disease or condition. [0286] In certain embodiments wherein the patient’s condition does not improve, upon the discretion of a healthcare professional the administration of the compounds are administered chronically, that is, for an extended period of time, including throughout the duration of the patient’s life in order to ameliorate or otherwise control or limit the symptoms of the patient’s disease or condition. [0287] In certain embodiments wherein a patient’s status does improve, the dose of drug being administered is temporarily reduced or temporarily suspended for a certain length of time (i.e., a “drug holiday”). In specific embodiments, the length of the drug holiday is between 2 days and 1 year, including by way of example only, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, or more than 28 days. The dose reduction during a drug holiday is, by way of example only, by 10%-100%, including by way of example only 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, and 100%. [0288] Once improvement of the patient's conditions has occurred, a maintenance dose is administered if necessary. Subsequently, in specific embodiments, the dosage or the frequency of administration, or both, is reduced, as a function of the symptoms, to a level at which the improved disease, disorder or condition is retained. In certain embodiments, however, the patient requires intermittent treatment on a long-term basis upon any recurrence of symptoms. [0289] The amount of a given agent that corresponds to such an amount varies depending upon factors such as the particular compound, disease condition and its severity, the identity (e.g., weight, sex) of the subject or host in need of treatment, but nevertheless is determined according to the particular circumstances surrounding the case, including, e.g., the specific agent being administered, the route of administration, the condition being treated, and the subject or host being treated. [0290] In general, however, doses employed for adult human treatment are typically in the range of 0.01 mg-5000 mg per day. In one aspect, doses employed for adult human treatment are from about 1 mg to about 1000 mg per day. In one embodiment, the desired dose is conveniently presented in a single dose or in divided doses administered simultaneously or at appropriate intervals, for example as two, three, four or more sub-doses per day. [0291] In one embodiment, the daily dosages appropriate for the compound described herein, or a pharmaceutically acceptable salt thereof, are from about 0.01 to about 50 mg/kg per body weight. In some embodiments, the daily dosage or the amount of active in the dosage form are lower or higher than the ranges indicated herein, based on a number of variables in regard to an individual treatment regime. In various embodiments, the daily and unit dosages are altered depending on a number of variables including, but not limited to, the activity of the compound used, the disease or condition to be treated, the mode of administration, the requirements of the individual subject, the severity of the disease or condition being treated, and the judgment of the practitioner. [0292] Toxicity and therapeutic efficacy of such therapeutic regimens are determined by standard pharmaceutical procedures in cell cultures or experimental animals, including, but not limited to, the determination of the LD50 and the ED50. The dose ratio between the toxic and therapeutic effects is the therapeutic index and it is expressed as the ratio between LD50 and ED50. In certain embodiments, the data obtained from cell culture assays and animal studies are used in formulating the therapeutically effective daily dosage range and/or the therapeutically effective unit dosage amount for use in patients, including humans. In some embodiments, the daily dosage amount of the compounds described herein lies within a range of circulating concentrations that include the ED50 with minimal toxicity. In certain embodiments, the daily dosage range and/or the unit dosage amount varies within this range depending upon the dosage form employed and the route of administration utilized. [0293] In any of the aforementioned aspects are further embodiments in which the effective amount of the compound described herein, or a pharmaceutically acceptable salt thereof, is: (a) systemically administered to the patient; and/or (b) administered orally to the patient; and/or (c) intravenously administered to the patient; and/or (d) administered by injection to the patient; and/or (e) administered topically to the patient; and/or (f) administered non-systemically or locally to the patient. [0294] In certain instances, it is appropriate to administer at least one compound or agent as described herein, or a pharmaceutically acceptable salt thereof, in combination with one or more other therapeutic agents. In certain embodiments, the pharmaceutical composition further comprises one or more anti-cancer agents. [0295] In one embodiment, the therapeutic effectiveness of one of the compounds described herein is enhanced by administration of an adjuvant (i.e., by itself the adjuvant has minimal therapeutic benefit, but in combination with another therapeutic agent, the overall therapeutic benefit to the patient is enhanced). Or, in some embodiments, the benefit experienced by a patient is increased by administering one of the compounds described herein with another agent (which also includes a therapeutic regimen) that also has therapeutic benefit. [0296] In one specific embodiment, a compound described herein, or a pharmaceutically acceptable salt thereof, is co-administered with a second therapeutic agent, wherein the compound described herein, or a pharmaceutically acceptable salt thereof, and the second therapeutic agent modulate different aspects of the disease, disorder or condition being treated, thereby providing a greater overall benefit than administration of either therapeutic agent alone. [0297] In any case, regardless of the disease, disorder or condition being treated, the overall benefit experienced by the patient is simply additive of the two therapeutic agents or the patient experiences a synergistic benefit. [0298] In certain embodiments, different therapeutically-effective dosages of the compounds disclosed herein will be utilized in formulating pharmaceutical composition and/or in treatment regimens when the compounds disclosed herein are administered in combination with one or more additional agent, such as an additional therapeutically effective drug, an adjuvant or the like. Therapeutically-effective dosages of drugs and other agents for use in combination treatment regimens is optionally determined by means similar to those set forth hereinabove for the actives themselves. Furthermore, the methods of prevention/treatment described herein encompasses the use of metronomic dosing, i.e., providing more frequent, lower doses in order to minimize toxic side effects. In some embodiments, a combination treatment regimen encompasses treatment regimens in which administration of a compound described herein, or a pharmaceutically acceptable salt thereof, is initiated prior to, during, or after treatment with a second agent described herein, and continues until any time during treatment with the second agent or after termination of treatment with the second agent. It also includes treatments in which a compound described herein, or a pharmaceutically acceptable salt thereof, and the second agent being used in combination are administered simultaneously or at different times and/or at decreasing or increasing intervals during the treatment period. Combination treatment further includes periodic treatments that start and stop at various times to assist with the clinical management of the patient. [0299] It is understood that the dosage regimen to treat, prevent, or ameliorate the disease(s) for which relief is sought, is modified in accordance with a variety of factors (e.g. the disease or disorder from which the subject suffers; the age, weight, sex, diet, and medical condition of the subject). Thus, in some instances, the dosage regimen actually employed varies and, in some embodiments, deviates from the dosage regimens set forth herein. [0300] For combination therapies described herein, dosages of the co-administered compounds vary depending on the type of co-drug employed, on the specific drug employed, on the disease or condition being treated and so forth. In additional embodiments, when co-administered with one or more other therapeutic agents, the compound provided herein is administered either simultaneously with the one or more other therapeutic agents, or sequentially. [0301] In combination therapies, the multiple therapeutic agents (one of which is one of the compounds described herein) are administered in any order or even simultaneously. If administration is simultaneous, the multiple therapeutic agents are, by way of example only, provided in a single, unified form, or in multiple forms (e.g., as a single pill or as two separate pills). [0302] The compounds or agents described herein, or a pharmaceutically acceptable salt thereof, as well as combination therapies, are administered before, during or after the occurrence of a disease or condition, and the timing of administering the composition containing a compound varies. Thus, in one embodiment, the compounds described herein are used as a prophylactic and are administered continuously to subjects with a propensity to develop conditions or diseases in order to prevent the occurrence of the disease or condition. In another embodiment, the compounds and compositions are administered to a subject during or as soon as possible after the onset of the symptoms. In specific embodiments, a compound described herein is administered as soon as is practicable after the onset of a disease or condition is detected or suspected, and for a length of time necessary for the treatment of the disease. In some embodiments, the length required for treatment varies, and the treatment length is adjusted to suit the specific needs of each subject. For example, in some embodiments, a compound described herein or a formulation containing the compound or agent is administered for at least 2 weeks, about 1 month to about 5 years. 8. General Synthetic Methods for Certain Compounds [0303] The compounds of Formula (I) and/or (X) are prepared as described in the schemes below. [0304] Scheme 1 shows an embodiment for preparing compounds of Formula (I) and/or Formula (X). Scheme 1
Figure imgf000135_0001
[0305] Starting with compound 1-1, wherein X1 and X2 is as defined herein, and R may be H, halo or a triflate group, or any other suitable leaving group, reaction with ethyl 3-chloro-3-oxopropanoate provides compound 1-2 which can be cyclized in the presence of a base and a protic solvent to provide compound 1-3 which can be converted to compounds of Formula (I) and/or Formula (X). Examples of suitable bases for the cyclization include sodium methoxide, sodium ethoxide and the like. Suitable solvents include methanol, ethanol and the like. [0306] Scheme 2 shows a further embodiment for the preparation of compounds of Formula (I) and/or Formula (X).
Figure imgf000135_0002
[0307] Starting with compound 2-1, wherein R may be H, halo or a triflate group, or any other suitable leaving group, reaction with dibenzyl malonate provides compound 2-2 which can be converted to compounds of Formula (I) and/or Formula (X). [0308] Scheme 3 shows an embodiment for the preparation of compounds of Formula (X). Scheme 3
Figure imgf000136_0001
[0309] Starting with compound 3-1, wherein X1 and X2 are as defined herein, and R may be H, halo or a triflate group, or any other suitable leaving group, reaction with diethyl malonate in the presence of a base (e.g., piperidine) provides compound 3-2 which can be cyclized in the presence of a metal (e.g., Fe) and an acid (e.g., acetic acid) to provide compound 3-3 which can be converted to compounds of Formula (X). [0310] Scheme 4 shows an embodiment wherein R1 is H or OH, and compounds 1-3 and/or 2-3 and/or 3-3 shown above (collectively summarized as compound 4-1) can be converted to compounds of Formula (I) and/or Formula (X).
Scheme 4
Figure imgf000137_0001
[0311] Starting with compound 1-3, or 2-3, or 3-3, collectively summarized as compound 4-1, wherein X1 and X2 are as defined herein and R may be H, halo or a triflate group, or any other suitable leaving group, and R’ is a C1-C3 alkyl or benzyl, a reaction of compound 4-1 with compound 4-2 provides compound 4-3. Any suitable base may be used for this reaction (e.g., K2CO3, Cs2CO3). R2 in compound 4-2 is as defined herein and LG may be any suitable leaving group (e.g., halo). The ester in compound 4-3 is hydrolyzed to provide compound 4-4. Coupling of compound 4-4 with compound 4-5 under any suitable amide coupling conditions (e.g., HATU, EDCI) provides compound 4-6. R4 in compound 4-5 is as defined herein. Compound 4-6 is converted to compound 4-7 using any suitable borylating agent. Each R’’ in compound 4-7 is independently H, C1-C3 alkyl, or phenyl, or, the two R’’ together with the atoms to which they are attached, form a dioxaborolane ring. Compound 4-7 is coupled with a suitable compound 4-8 to provide compounds of Formula (I) or Formula (X). In compound 4-8, R6 is as defined herein and LG’’ is any suitable leaving group (e.g., halo). The coupling reaction between compounds 4-7 and 4-8 may be mediated by any suitable palladium catalyst or any other similar organometallic coupling method known to one of skill in the art. [0312] Scheme 5 shows an embodiment wherein R1 is H or OH, and compounds 1-3 and/or 2-3 and/or 3-3 shown above (collectively summarized as compound 4-1) can be converted to compounds of Formula (I) and/or Formula (X). Scheme 5
Figure imgf000138_0001
[0313] Starting with compound 1-3, or 2-3, or 3-3, collectively summarized as compound 4-1, wherein X1 and X2 are as defined herein and R may be H, halo or a triflate group, or any other suitable leaving group, and R’ is a C1-C3 alkyl or benzyl, a reaction of compound 4-1 with compound 4-2 provides compound 4-3. Any suitable base may be used for this reaction (e.g., K2CO3, Cs2CO3). R2 in compound 4-2 is as defined herein and LG may be any suitable leaving group (e.g., halo). Compound 4-3 is converted to compound 5-1 using any suitable borylating agent. Each R’’ in compound 5-1 is independently H, C1-C3 alkyl, or phenyl, or, the two R’’ together with the atoms to which they are attached, form a dioxaborolane ring. Compound 5-1 is coupled with a suitable compound 4-8 to provide a compound 5-2. The coupling reaction between compounds 5-1 and 4-8 may be mediated by any suitable palladium catalyst or any other similar organometallic coupling method known to one of skill in the art. In compound 4-8, R6 is as defined herein and LG’’ is any suitable leaving group (e.g., halo). The ester in compound 5-2 is hydrolyzed to provide compound 5- 3. Compound 5-3 is coupled with compound 4-5 under any suitable amide coupling conditions (e.g., HATU, EDCI) to provide compounds of Formula (I) and/or Formula (X). [0314] Scheme 6 shows an embodiment wherein R1 is H or OH, and compounds 1-3 and/or 2-3 and/or 3-3 shown above (collectively summarized as compound 4-1) can be converted to compounds of Formula (I) and/or Formula (X). Scheme 6
Figure imgf000139_0001
[0315] Starting with compound 1-3, or 2-3, or 3-3, collectively summarized as compound 4-1, wherein X1 and X2 is as defined herein and R may be H, halo or a triflate group, or any other suitable leaving group, and R’ is a C1-C3 alkyl or benzyl, reaction with 2-bromo-1,1-diethoxyethane provides compound 6-2. Compound 6-2 is coupled with a boronate 6-3 to provide compound 6-4. In compound 6-3, R6 is as defined herein. In compound 6-3, each R’’ is independently H, C1-C3 alkyl, or phenyl, or, the two R’’ together with the atoms to which they are attached, form a dioxaborolane ring. The coupling reaction between compounds 6-2 and 6-3 may be mediated by any suitable palladium catalyst or any other similar organometallic coupling method known to one of skill in the art. Compound 6-4 is converted to an amide 6-5 via a reaction with compound 4-5, wherein R4 is as defined herein. The ketal in compound 6-5 is hydrolyzed under acidic conditions (e.g., HCl) to provide the aldehyde 6-6 which is aminated with compound 6-7 to provide compounds of Formula (I) and/or (X). R2 in compound 6-7 is as defined herein. [0316] Scheme 7 shows an embodiment for preparation of compounds of Formula (I) and/or (X) wherein R1 is alkyl. Scheme 7
Figure imgf000140_0001
[0317] Starting with compound 7-1, wherein X1 and X2 is a defined herein and R may be H, halo or a triflate group, or any other suitable leaving group, conversion to a Weinreb amide provides compound 7-2. Reaction with a suitable Grignard reagent provides compound 7-3 which is converted to compound 7-4 by reaction with ethyl 3-chloro-3-oxopropanoate. Compound 7-4 is cyclized in the presence of a base to provide compound 7-5 which can be converted to compounds of Formula (I) and/or (X) using the methods described in Schemes 4-6. [0318] Scheme 8 shows an embodiment for preparation of compounds of Formula (I) and/or (X) wherein R1 is alkoxy. Scheme 8
Figure imgf000140_0002
[0319] Compound 8-1, wherein X1 and X2 is as defined herein and R may be H, halo or a triflate group, or any other suitable leaving group, and R’ is a C1-C3 alkyl or benzyl is reacted with an alkylating agent to provide compound 8-2 wherein R’’’ is C1-C6 alkyl, which can be converted to compounds of Formula (I) and/or (X) using the using the methods described in Schemes 4-6. By way of example, reaction of compound 8-1 with DMSO gives R’’’ methyl, reaction of compound 8-1 with propyl iodide gives R’’’ isopropyl. [0320] Any combination of steps described above may be used in the preparation of compounds described herein, including any procedures described in PCT/US2021/030838 filed on May 5, 2021 which is hereby incorporated by reference in its entirety.. [0321] The compounds of this disclosure can be prepared from readily available starting materials using, for example, the following general methods and procedures. It will be appreciated that where typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures. [0322] Additionally, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions. Suitable protecting groups for various functional groups as well as suitable conditions for protecting and deprotecting particular functional groups are well known in the art. For example, numerous protecting groups are described in T. W. Greene and G. M. Wuts (1999) Protecting Groups in Organic Synthesis, 3rd Edition, Wiley, New York, and references cited therein. [0323] Furthermore, the compounds of this disclosure may contain one or more chiral centers. Accordingly, if desired, such compounds can be prepared or isolated as pure stereoisomers, i.e., as individual enantiomers or diastereomers or as stereoisomer-enriched mixtures. All such stereoisomers (and enriched mixtures) are included within the scope of this disclosure, unless otherwise indicated. Pure stereoisomers (or enriched mixtures) may be prepared using, for example, optically active starting materials or stereoselective reagents well-known in the art. Alternatively, racemic mixtures of such compounds can be separated using, for example, chiral column chromatography, chiral resolving agents, and the like. [0324] The starting materials for the following reactions are generally known compounds or can be prepared by known procedures or obvious modifications thereof. For example, many of the starting materials are available from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA), Bachem (Torrance, California, USA), Emka-Chemie or Sigma (St. Louis, Missouri, USA). Others may be prepared by procedures or obvious modifications thereof, described in standard reference texts such as Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-15 (John Wiley, and Sons, 1991), Rodd's Chemistry of Carbon Compounds, Volumes 1-5, and Supplementals (Elsevier Science Publishers, 1989) organic Reactions, Volumes 1-40 (John Wiley, and Sons, 1991), March's Advanced Organic Chemistry, (John Wiley, and Sons, 5th Edition, 2001), and Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989). EXAMPLES [0325] The following examples are included to demonstrate specific embodiments of the disclosure. It should be appreciated by those of skill in the art that the techniques disclosed in the examples which follow represent techniques to function well in the practice of the disclosure, and thus can be considered to constitute specific modes for its practice. However, those of skill in the art should, in light of the present disclosure, appreciate that many changes can be made in the specific embodiments which are disclosed and still obtain a like or similar result without departing from the spirit and scope of the disclosure. Example 1: CB2R Binding Assays [0326] Putative CB2R modulators may be evaluated in CB2R binding assays using membranes from HEK-293 cells transfected with cDNAs encoding the human recombinant CB2R (Bmax = 4.7 pmol/mg protein) (Perkin-Elmer). These membranes are incubated with [3H]-(−)-cis-3-[2-hydroxy-4- (1,1-dimethylheptyl)phenyl]-trans-4-(3-hydroxypropyl)cyclohexanol ([3H]CP-55,940) (0.084 nM/Kd = 0.31 nM for CB2R) as high-affinity ligand and displaced with 100 nM (R)-(+)-[2,3-dihydro- 5-methyl-3-(4-morpholinylmethyl)pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphthalenylmethanone (WIN-55,212-2) as heterologous competitor for nonspecific binding (Ki = 2.1 nM for CB2R). Compounds are tested following the procedure described by the cell membrane manufacturer. CB2R binding assays are carried out with two different buffers: incubation buffer (Tris-HCl, 50 mM; MgCl2, 5 mM; CaCl21 mM; BSA, 0.2% at pH 7.4) and washing buffer (Tris-HCl, 50 mM; NaCl 500 mM; BSA, 0.1% at pH 7.4). The assay mixture contained incubation buffer, 0.4 nM [3H]CP-55,940, test substances (concentrations from 0.001 to 10 μM), and 4 μg/sample membrane in a total assay volume of 200 μL. Assays are performed in duplicate and incubated for 120 min at 37 °C. After the incubation, the assay mixture is filtered through 96 GF/C filter plates (Perkin Elmer #6005174) using Perkin Elmer Filtermate Harvester, and then washed four times with ice-cold washing buffer. The filters are dried for 1 hour at 50°C and [3H] trapped on filter counted for radioactivity in Perkin Elmer Microscint 20 cocktail (#6013329) using Perkin Elmer MicroBeta2 Reader. The results are expressed as a percent inhibition of the control radioligand specific binding calculated using the following equation: %Inhibition=(1-(Assay well-Average_LC)/(Average_HC-Average_LC))x100%. Data are analyzed and IC50 is calculated using GraphPad Prism 5 and the model “log(inhibitor) vs. response -- Variable slope”. The binding affinity of the compounds is determined by using the Cheng and Prusoff equation Ki = IC50/(1+ [radioligand]/Kd). Example 2: CB2R cAMP Assay [0327] cAMP Hunter CHO-K-1 cell lines expressing human CB2R (Eurofins) are expanded from freezer stocks according to standard procedures. Cells are seeded in a total volume of 20 μL into white walled, 384‐well microplates and incubated at 37°C for the appropriate time prior to testing. cAMP modulation in agonist, inverse agonist or antagonist format was determined using the DiscoverX HitHunter cAMP XS+ assay (Eurofins). For agonist determination, cells are incubated with sample in the presence of EC80 forskolin to induce response. Media is aspirated from cells and replaced with 15 μL 2:1 HBSS/10mM Hepes: cAMP XS+ Ab reagent. Intermediate dilution of sample stocks is performed to generate 4X sample in assay buffer containing 4X EC80 forskolin.5 μL of 4X sample is added to cells and incubated at 37°C or room temperature for 30 or 60 minutes. Final assay vehicle concentration is 1%. For inverse agonist determination, cells were preincubated with sample in the presence of EC20 forskolin. Media was aspirated from cells and replaced with 15μL 2:1 HBSS/10mM Hepes: cAMP XS+ Ab reagent. Intermediate dilution of sample stocks was performed to generate 4X sample in assay buffer containing 4X EC20 forskolin.5 μL of 4X sample is added to cells and incubated at 37°C or room temperature for 30 or 60 minutes. Final assay vehicle concentration is 1%. For antagonist determination, cells were pre‐incubated with sample followed by agonist challenge at the EC80 concentration. Media is aspirated from cells and replaced with 10 μL 1:1 HBSS/Hepes: cAMP XS+ Ab reagent.5 μL of 4X compound is added to the cells and incubated at 37 °C or room temperature for 30 minutes.5 μL of 4X EC80 agonist is added to cells and incubated at 37 °C or room temperature for 30 or 60 minutes. EC80 forksolin was included. After appropriate incubation, assay signal is generated through incubation with 20 μL cAMP XS+ ED/CL lysis cocktail for one hour followed by incubation with 20 μL cAMP XS+ EA reagent for three hours at room temperature. Microplates are read following signal generation with a PerkinElmer Envision instrument for chemiluminescent signal detection. Compound activity is analyzed using CBIS data analysis suite (ChemInnovation, CA). For agonist mode assay, percentage activity is calculated using the following formula: % Activity = 100% x (1 - (mean RLU of test sample - mean RLU of MAX control) / (mean RLU of vehicle control - mean RLU of MAX control)). For inverse agonist mode assay, percentage activity is calculated using the following formula: % Inverse Agonist Activity =100% x ((mean RLU of test sample - mean RLU of EC20 forskolin) / (mean RLU of forskolin positive control - mean RLU of EC20 control)). For antagonist mode assay, percentage inhibition is calculated using the following formula: % Inhibition = 100% x (mean RLU of test sample - mean RLU of EC80 control) / (mean RLU of forskolin positive control - mean RLU of EC80 control). Data is analyzed and IC50 is calculated using GraphPad Prism 5 and the model “log(inhibitor) vs. response -- Variable slope”. [0328] Illustrative binding affinities for representative compounds are described in Table 2 and Table 2A. The potencies are divided into three criteria: + means that IC50 is greater than 1000 nM; ++ means IC50 is between 100 nM and 999 nM; +++ means IC50 is below 100 nM. In some embodiments, compounds with IC50 designated “+” may have IC50s between 1 mM to 30 mM. Table 2.
Figure imgf000144_0001
Figure imgf000145_0001
Figure imgf000146_0001
Figure imgf000147_0001
Blank means not tested Table 2A
Figure imgf000147_0002
Figure imgf000148_0001
Example 3: In vitro Mixed Lymphocyte Reaction (MLR) Assay [0329] CD14+ monocytes were purified from peripheral blood mononuclear cells of healthy donors using EasySep™ Human Monocyte Isolation Kit (STEMCELL, Cambridge, MA) according to the manufacturer’s protocol. Purified human monocytes were cultured in RPMI 1640 medium containing 10% FBS (Invitrogen, Carlsbad, CA) at 5 x 105 cells/mL in the presence of 20 ng/mL GM-CSF and 10 ng/mL IL-4 (R&D Systems, Minneapolis, MN) in 24-well plate for 7 days. For maturation of dendritic cells (DCs), 1 mg/mL lipopolysaccharides (LPS, ThermoFisher, Waltham, MA) was added for an additional 3 days of culture. Half of the medium was replenished with fresh medium with cytokines every 3 days. To characterize the monocyte-derived DCs (MoDCs), aliquots of the cells (105 cells in 100 ml buffer) were incubated with the fluorochrome-conjugated monoclonal antibodies (CD1a-FITC, CD83-Brilliant Violet 4, CD209-R-PE or CD14-APC; all from BD PharMingen, San Diego, CA) for 30 minutes on ice, washed, and analyzed using Attune NxT flow cytometer. For allogeneic mixed lymphocyte reaction (MLR), human CD4+ T cells were purified from peripheral blood mononuclear cells of healthy donors using EasySep™ Human CD4+ T Isolation Kit (STEMCELL, Cambridge, MA) according to the manufacturer’s protocol. MLR was set up by co- culturing 50,000 CD4+ T cells/well with the monocytes-derived DCs (moDCs) at the ratio of 10 to 1 in 96-well plates with or without Compound 8 in the presence or absence of anti-PD-1 antibody nivolumab (1 µg/ml, InvivoGen, San Diego, CA) for 5 days. IFNγ was measured using Meso Scale Discovery (MSD) from the supernatant of the co-culture. [0330] FIGS.1A-B show proliferation and IFNγ expression of CD4+ T cells treated with Compound 8. As shown in FIGS.1A-B, the CB2R antagonist (Compound 8) treated CD4+ T cells exhibited enhanced T cell growth and IFNγ production compared to CD4+ T cells without treatment. [0331] Using the same method, MLR was performed on CD4+ T cells using SR144528 (SR, CB2R inverse agonist), AM630 (AM, CB2R antagonist), and MAB36551 (MAB, CB2R antibody), with or without anti PD-1 agents (nivolumab or pembrolizumab). FIG.1C-D show proliferation and IFNγ expression of CD4+ T cells treated with SR144528, AM630, and MAB36551, with or without nivolumab or pembrolizumab. As shown in FIGS.1C-D, each SR144528, AM630, and MAB36551 treated CD4+ T cells exhibited enhanced T cell growth and IFNγ production compared to CD4+ T cells without treatment (or treated with vehicle). Further, each SR144528, AM630, and MAB36551 treated CD4+ T cells exhibited even more enhanced T cell growth and IFNγ production in combination with pembrolizumab or nivolumab, showing synergistic increase in cell proliferation and IFNγ production. [0332] FIG.2A, shows total IFNγ expression of CD4+ T cells treated with Compound 8 with or without nivolumab (anti-PD-1). FIG.2B shows normalized (basal subtracted) IFNγ expression of CD4+ T cells treated with Compound 8 with or without nivolumab (anti-PD-1). FIG.2C is another representation of the data. FIGS.2A-C show that CD4+ T cells treated with the CB2R antagonist (Compound 8) and nivolumab (anti-PD-1) exhibited a synergistic increase in IFNγ production compared to CD4+ T cells treated with Compound 8 alone. The result also suggests that that CD4+ T cells treated with the CB2R antagonist (Compound 8) and nivolumab (anti-PD-1) would exhibit a synergistic increase in cell proliferation compared to CD4+ T cells treated with Compound 8 alone. Example 4: In vitro T cell Exhaustion (TCE) Assay [0333] CD3+ pan T cells were negatively isolated from peripheral blood mononuclear cells of healthy donors (AllCells, Alameda, CA). Approximately, 5x105 T cells were initially plated in 24 well plates in RPMI 1640 medium containing 10% FBS (Invitrogen, Carlsbad, CA). Cells were stimulated the same day (Day 0) with T-Activator CD3/CD28 dynabeads (ThermoFisher, Waltham, MA) following the manufacturer’s recommendations and treated with CB2 antagonist Compound 8 in the presence or absence of anti-PD-1 antibody nivolumab (30 µg/ml, InvivoGen, San Diego, CA).2-days after the first stimulation, cell culture supernatant was collected, cells were counted and washed, and beads were removed using a magnet. This was followed by a second, third and fourth round of 2-day stimulations with fresh batches of CD3/CD28 beads. In each stimulation step, the amount of supernatant collected and beads used, the number of viable cells plated and the concentrations of Compound 8 and anti-PD-1 were kept same. On Day 8, cells were incubated with the fluorochrome- conjugated monoclonal antibodies (APC mouse anti-human LAG-3 antibody, SB436 mouse anti- human TIM-3 antibody, PE mouse anti-human PD-1 antibody, SB600 mouse anti human CD4+ antibody, AlexaFluor700 anti-human CD8+ antibody; all from Invitrogen, Carlsbad, CA) for 30 minutes on ice, washed, and analyzed using Attune NxT flow cytometer to detect CD38, LAG3, TIM3 and PD-1 expression on CD4+ and CD8+ T cells. IL2 was measured using Meso Scale Discovery (MSD) from the supernatant of the cell culture. [0334] FIG.3A shows LAG-3 expression of CD4+ and CD8+ T cells treated with vehicle, Compound 8, nivolumab (anti-PD-1), and a combination of Compound 8 and nivolumab; TIM-3 expression of CD4+ and CD8+ T cells treated with vehicle, Compound 8, nivolumab (anti-PD-1), and a combination of Compound 8 and nivolumab; and PD-1 expression of CD4+ and CD8+ T cells treated with vehicle, Compound 8, nivolumab (anti-PD-1), and a combination of Compound 8 and nivolumab. As shown in FIG.3A, the CB2R antagonist (Compound 8) with or without anti-PD-1 (nivolumab) prevented T cell exhaustion (indicated by decreased expression of immune checkpoint proteins) of CD4+ and CD8+ T cells 8 days after stimulation with T cell activator compared to vehicle. [0335] TCE was performed on CD3+, CD4+, and CD8+ T cells T cells using individual CB2R modulators (Compund 8, SR144528, AM630, MAB36551) with or without anti-PD-1 compounds (pembrolizumab or nivolumab). Exhaustion markers tested included CD38, CTLA4, LAG3, PD-1, TIGIT, TIM-3, TOX, and IL2. FIGS.3B-E show expression of the exhaustion markers after CD4+ and CD8+ T cells treated with CB2R modulators (Compund 8, SR144528, AM630, MAB36551) with or without anti-PD-1 compounds (pembrolizumab or nivolumab). As shown in FIGS.3B-E, CB2R modulators with or without anti-PD-1 prevented T cell exhaustion (indicated by exhaustion markers) of CD3+, CD4+, and CD8+ T cells within 8 days after stimulation with T cell activator compared to CD3+, CD4+, and CD8+ T cells without treatment (or treated with vehicle). [0336] FIG.4A, shows IL2 expression of CD4+ and CD8+ T cells four, six, and eight days after stimulation with T-Activator CD3/CD28 dynabeads. FIG.4B shows IL2 expression of CD4+ and CD8+ T cells eight days after stimulation with T-Activator CD3/CD28 dynabeads in the presence of CB2R antagonist (Compound 8). FIG.4B show that the CB2R antagonist (Compound 8) prevents T cell exhaustion (indicated by increased expression of IL2) of CD4+ and CD8+ T cells 8 days after stimulation with T cell activator compared to vehicle. Example 5: In vitro NK cell Reaction Assay [0337] PBMCs were separated from whole blood of healthy donors by density gradient. NK cells were then isolated with the Easysep Human NK Cell Enrichment Kit (STEMCELL, Cambridge, MA) according to the manufacturer’s protocol, seeded at 2x105/well in 96-well plate and cultured in complete RPMI medium (RPMI-1640 medium supplemented with 10% FBS, 2 mM L-glutamine, 100 U/mL penicillin, and 100 ug/mL streptomycin) in the presence or absence of Compound 8 for 3 days. Cells were then washed twice with the complete medium to get rid of Compound 8, counted and resuspended at 1x106 cells/mL with complete RPMI medium. Functional assay was set up by co- culturing 1x105 NK cells/well with 1x104 of carboxyfluorescein succinimidyl ester (CFSE)- prelabelled K562 cells at a ratio of 10 to 1 in 96-well plates for 24 hours. After centrifugation, supernatant was collected for IFNγ analysis by Meso Scale Discovery (MSD). The cell pellets were then resuspended in FACS buffer and stained with anti-CD56-PE and anti-CD107-FITC. The CD107a expression on CD3-CD56+ NK cells and Live-or-Dye™ Fixable Viability eFluor™ 506 Stains (Invitrogen, Carlsbad, CA) were analyzed using Attune NxT flow cytometer. [0338] FIG.5A shows the cellular killing capacity of NK cells treated with Compound 8. FIG.5B shows the percentage of CD107a+ (activated) NK cells treated with Compound 8. FIG.5C shows the expression of IFNγ of NK cells treated with Compound 8. FIGS.5A-C show that CB2R antagonist (Compound 8) enhances NK cell function (by virtue of activation, killing capacity, and IFNγ expression) compared to vehicle. Example 6: In vivo Tumor Growth Inhibition (TGI) Assay [0339] C57BL/6 inbred female mice, aged at 8-9 week, were purchased from Charles River. On the day of inoculation (Day 0), B16F10 or MC38 cells were harvested, washed and counted. Cells were re-suspended as single cell solution in PBS at a concentration of 5x106 cells/mL at the final step. Immediately, five hundred thousand (5x105) of B16F10 or MC38 cells suspended in 0.1 mL PBS were injected in the right flank of C57BL/6 mice subcutaneously using 27G needles. When palpable, tumors were measured by a caliper and tumor volumes (mm3) were calculated by length x width x height x 0.5236. Mice with the tumor size approximate to 100 mm3 were randomly assigned into one of four groups (n=10). Each group received vehicle (BID), CB2R antagonists at 1 mg/kg (QD) and/or mouse anti-PD-1 (RMP1-14) at 5 mg/kg (Q2D), intraperitoneally. Tumor size and body weight were determined every 2-3 days. Percent tumor growth inhibition (TGI) was defined as the difference between the Median Tumor Volume (MTV) of a test group and control group, using the formula: % TGI = ((MTVcontrol-MTVtreated/MTVcontrol)) x 100. [0340] FIG.6A shows the effect of oral administration of vehicle, 1 mg/kg Compound 8, 4 mg/kg Compound 8, and 10 mg/kg Compound 8 on B16F10 derived tumor volume in 8-9 week female C57BL/6 mice measured by TGI assay. FIG.6B shows the effect of oral administration of vehicle, 1 mg/kg Compound 8, 4 mg/kg Compound 8, and 10 mg/kg Compound 8 on MC38 derived tumor volume in 8-9 week female C57BL/6 mice measured by TGI assay. FIGS.6A-B show that oral administration of CB2R antagonist (Compound 8) inhibits B16F10 and MC38 tumor growth in 8-9 week female C57BL/6 mice compared to vehicle. [0341] FIG.7A shows the effect of intraperitoneal administration of vehicle, 1 mg/kg Compound 8, 4 mg/kg Compound 8, and 10 mg/kg Compound 8 on B16F10 derived tumor volume in 8-9 week female C57BL/6 mice measured by TGI assay. FIG.7B shows the effect of intraperitoneal administration of vehicle, 1 mg/kg Compound 8, 4 mg/kg Compound 8, and 10 mg/kg Compound 8 on MC38 derived tumor volume in 8-9 week female C57BL/6 mice measured by TGI assay. FIGS. 7A-B show that intraperitoneal administration of CB2R antagonist (Compound 8) inhibits B16F10 and MC38 tumor growth in 8-9 week female C57BL/6 mice compared to vehicle. [0342] FIG.8A, shows the effect of oral administration of vehicle and 4 mg/kg Compound 8, intraperitoneal administration of 5 mg/kg anti-PD-1 antibody, and combination of 4 mg/kg Compound 8 with 5 mg/kg anti-PD-1 antibody on B16F10 derived tumor volume in 8-9 week female C57BL/6 mice measured by TGI assay. FIG.8B shows the effect of oral administration of vehicle and 4 mg/kg Compound 8, intraperitoneal administration of 5 mg/kg anti-PD-1 antibody, and combination of 4 mg/kg Compound 8 with 5 mg/kg anti-PD-1 antibody on MC38 derived tumor volume in 8-9 week female C57BL/6 mice measured by TGI assay. FIGS.8A-B show that oral administration of CB2R antagonist (Compound 8) inhibits B16F10 and MC38 tumor growth in 8-9 week female C57BL/6 mice compared to vehicle, and the combination of Compound 8 with anti-PD-1 antibody synergistically inhibits B16F10 and MC38 tumor growth. [0343] FIG.9A shows the effect of oral administration of vehicle and 4 mg/kg Compound 8, intraperitoneal administration of 5 mg/kg anti-PD-1 antibody, and combination of 4 mg/kg Compound 8 with 5 mg/kg anti-PD-1 antibody on tumor-infiltrating immune cells in 8-9 week female C57BL/6 mice bearing B16F10 melanoma measured by flow cytometry. FIG.9A shows that oral administration of CB2R antagonist (Compound 8) significantly increases CD8+ T cell and NK infiltration in B16F10 tumor in 8-9 week female C57BL/6 mice compared to vehicle. Specifically, Compound 8 increases CD4+ and CD8+ T cells by 2-fold and 5.3-fold, respectively when compared to vehicle controls. Both CD4+ and CD8+ T cell populations further increase in number in the combination treatment with anti-PD-1 antibody by 5.7-fold and 10-fold, respectively. Compound 8 also significantly increases NK infiltration by 2.5-fold when used alone. NK cells further increase in the combination treatment by 4.9-fold. In the same experimental setting, Compound 8 reduces the numbers of immunosuppressive MDSCs by about 56% and normalizes the negative effect of anti-PD- 1 antibody on the MDSCs. FIG.9B shows the effect of oral administration of vehicle and 4 mg/kg Compound 8, intraperitoneal administration of 5 mg/kg anti-PD-1 antibody, and combination of 4 mg/kg Compound 8 with 5 mg/kg anti-PD-1 antibody on the expression of PD-1 and LAG-3 by CD8+ T cells in 8-9 week female C57BL/6 mice bearing B16F10 melanoma measured by flow cytometry. FIG.9B shows that oral administration of CB2R antagonist (Compound 8) significantly decreased expression of PD-1 among CD8+ T cells in B16F10 tumor in 8-9 week female C57BL/6 mice compared to vehicle. Specifically, Compound 8 increased the percentage of PD-1+/CD8+ cells among the CD8+ by less than half when compared to vehicle controls. FIG.9B further shows that oral administration of CB2R antagonist (Compound 8) significantly decreased expression of LAG-3 among CD8+ T cells in B16F10 tumor in 8-9 week female C57BL/6 mice compared to vehicle. Specifically, Compound 8 decreased the percentage of LAG3+/CD8+ cells among the CD8+ cells by less than half when compared to vehicle controls. [0344] Further, as shown in FIG.9B, the treatment with Compound 8 in combination with anti-PD-1 agent further decreased the expression of PD-1.The examples and embodiments described herein are for illustrative purposes only and various modifications or changes suggested to persons skilled in the art are to be included within the spirit and purview of this application and scope of the appended claims.

Claims

CLAIMS WHAT IS CLAIMED IS: 1. A method for increasing the production of interferon gamma (IFNγ) or growth or proliferation of immune cells in a patient in need thereof, comprising administering to the patient an effective amount of a cannabinoid type 2 receptor (CB2R) modulator. 2. The method of claim 1, wherein the immune cells are selected from T cells, B cells or NK cells. 3. The method of claim 2, wherein the immune cells are T cells. 4. The method of any preceding claim, wherein the patient has a viral infection or cancer. 5. The method of any preceding claim, wherein the patient suffers from immune cell exhaustion or is at risk for immune cell exhaustion. 6. A method for treating, reducing, or preventing immune cell exhaustion in a patient in need thereof, comprising administering to the patient an effective amount of a CB2R modulator. 7. The method of claim 6, wherein the immune cells are selected from T cells, B cells or NK cells. 8. The method of claim 7, wherein the immune cells are T cells. 9. The method of any preceding claim, wherein the patient is currently or has previously been treated with an immunotherapeutic agent. 10. The method of claim 9, wherein the CB2R modulator is administered to the patient after cessation of administration of the immunotherapeutic agent. 11. The method of claim 9, wherein the CB2R modulator is administered to the patient concurrently with administration of the immunotherapeutic agent. 12. The method of claim 9, wherein the CB2R modulator is administered to the patient concurrently and after administration of the immunotherapeutic agent. 13. The method of any one of claims 9-12, wherein the immunotherapeutic agent is a check-point inhibitor. 14. The method of claim 13, wherein the check-point inhibitor is selected from atezolizumab, avelumab, cemiplimab, labrolizumab, durvalumab, ipilimumab, nivolumab, and pembrolizumab. 15. A method of diagnosing immune cell exhaustion in a patient, the method comprising: a) obtaining a biological sample comprising immune cells from a patient; b) detecting and quantifying the presence of one or more biological markers in the biological sample; c) comparing the levels of the one or more biological markers in the biological sample of the patient to the levels of the one or more biological markers in a healthy individual; and d) diagnosing the patient with immune cell exhaustion when the levels of the one or more biological markers in the biological sample are abnormal; and wherein the one or more biological markers are selected from the group consisting of 2B4, BTLA, CD160, CTLA-4, LAG-3, PD-1, TIM-3, TIGIT, granzyme B, interferon gamma (IFNγ), interleukin 1 (IL-1), interleukin 2 (IL-2), interleukin 4 (IL-4), interleukin 5 (IL-5), interleukin 6 (IL- 6), interleukin 10 (IL-10), interleukin 12 (IL-12), interleukin 13 (IL-13), interleukin 17 (IL-17), interleukin 22 (IL-22), transforming growth factor beta (TGF-β), tumor necrosis factor alpha (TNFα), nuclear factor of activated T-cells (NFAT), nuclear receptor subfamily 4 group A (NR4A), T-cell- specific transcription factor 1 (TCF-1), thymocyte selection-associated high mobility group box protein (TOX), and TOX high mobility group box family member 2 (TOX2). 16. The method of claim 15, wherein the immune cells in the biological sample of the patient exhibit decreased proliferation compared to the immune cell proliferation in the healthy individual. 17. The method of claim 15, further comprising a treatment step, comprising administering an effective amount of a cannabinoid type 2 receptor (CB2R) modulator to the diagnosed patient. 18. The method of any preceding claim, wherein, after hours, days, or weeks, the patient exhibits an improvement in expression levels of one or more biological markers in a biological sample comprising immune cells compared to the one or more biological markers of the patient before administration of the CB2R modulator. 19. The method of claim 18, wherein the one or more biological markers are immunomodulatory receptors selected from the group consisting of: 2B4, BTLA, CD160, CTLA-4, LAG-3, PD-1, TIM-3, and TIGIT. 20. The method of claim 18, wherein the one or more biological markers are effector molecules selected from the group consisting of: granzyme B, interferon gamma (IFNγ), interleukin 1 (IL-1), interleukin 2 (IL-2), interleukin 4 (IL-4), interleukin 5 (IL-5), interleukin 6 (IL-6), interleukin 10 (IL- 10), interleukin 12 (IL-12), interleukin 13 (IL-13), interleukin 17 (IL-17), interleukin 22 (IL-22), transforming growth factor beta (TGF-β), and tumor necrosis factor alpha (TNFα). 21. The method of claim 18, wherein the one or more biological markers are transcription factors selected from the group consisting of: nuclear factor of activated T-cells (NFAT), nuclear receptor subfamily 4 group A (NR4A), T-cell-specific transcription factor 1 (TCF-1), thymocyte selection- associated high mobility group box protein (TOX), and TOX high mobility group box family member 2 (TOX2). 22. The method of any preceding claim, wherein the CB2R modulator activates dendritic cell (DC)-mediated activation of T cells. 23. The method of any preceding claim, wherein the CB2R modulator is a CB2R antagonist selected from the group consisting of: Compound 8, Compound 13, Compound 109, Compound 121, Compound 149, Compound 265, Compound 266, Compound 267, Compound 268, Compound 269, Compound 270, cannabidiol, AM630, and combinations thereof. 24. The method of any preceding claim, wherein the CB2R modulator is a CB2R inverse agonist selected from the group consisting of: SR144528, XL-001, Tamoxifen, and combinations thereof. 25. The method of any preceding claim, wherein the CB2R modulator is a negative allosteric modulator selected from the group consisting of Dihydro-gambogic acid (DHGA), trans-β- caryophyllene (TBC), mambaquaretin-1, Exenetide (Byetta), and combinations thereof. 26. The method of any preceding claim, wherein the CB2R modulator is a compound selected from Table 1 or Table 1A. 27. The method of any preceding claim, wherein the CB2R modulator is an agent that causes gene knockout of CB2R in immune cells. 28. The method of claim 27, wherein the agent that causes gene knockout of CB2R is a site- specific nuclease selected from the group consisting of zinc finger nuclease, transcription activator- like effector nuclease (TALENS), clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPER-associated systems (Cas) complexes, and combinations thereof. 29. The method of any preceding claim further comprising administering a chimeric antigen receptor T-cell (CART) therapy to the patient. 30. A method for re-activating exhausted T cells in a patient in need thereof, comprising administering to the patient an effective amount of a cannabinoid type 2 receptor (CB2R) modulator. 31. The method of claim 30, wherein the patient has cancer, a chronic infection, an acute infection, or an immunodeficiency. 32. The method of claim 30 or 31, wherein the patient is being treated with, or has been treated with, a chimeric antigen receptor T-cell (CART) therapy. 33. The method of claim 30 or 31, wherein the patient is being treated with, or has been treated with, a check point inhibitor. 34. The method of claim 33, wherein the checkpoint inhibitor is selected from atezolizumab, avelumab, cemiplimab, labrolizumab, durvalumab, ipilimumab, nivolumab, and pembrolizumab.
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