Treatment of autoimmune or inflammatory disease

Abstract

Provided herein are compositions and methods for the treatment of an autoimmune or inflammatory disease, such as rheumatoid arthritis. Said compositions comprise a TNFR1 inhibitor. Some embodiments comprise combination therapy featuring the TNFR1 inhibitor with at least one additional anti-inflammatory therapeutic agent.

Description

TREATMENT OF AUTOIMMUNE OR INFLAMMATORY DISEASECROSS-REFERENCE

[0001] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 648,000 filed on May 15, 2024, which is incorporated by reference in its entirety.BACKGROUND OF THE INVENTION

[0002] Tumor necrosis factor alpha (TNF-a) is an inflammatory cytokine that is responsible for a wide range of signaling events within cells. Aberrant TNF-a signaling gives rise to inflammatory conditions and is thought to be an important component of inflammatory disease, such as rheumatoid arthritis.BRIEF SUMMARY

[0003] One embodiment provides a method of treating an inflammatory or autoimmune disease in a patient in need thereof, comprising administering to the patient (7R,14R)-1- (difluoromethoxy)-l l-(4-(dimethylphosphoryl)-3-fluorophenyl)-10-fluoro-6-(methyl-d3)-6,7- dihydro-7, 14-methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,4]diazocin-5(14H)-one, or pharmaceutically acceptable salt or solvate thereof.

[0004] One embodiment provides a method of treating inflammatory or autoimmune disease in a patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising (7R, 14R)-l-(difluorom ethoxy)- 11 -(4-(dimethylphosphoryl)-3 - fluorophenyl)- 10-fluoro-6-(methyl-d3 )-6, 7-dihy dro-7, 14- methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,4]diazocin-5(14H)-one, or pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient.BRIEF DESCRIPTION OF THE DRAWINGS

[0005] Figure 1 provides a schematic for an exemplary mechanism of action of Compound 1.

[0006] Figure 2A provides a summary of the results of IL-6 cytokine production in response to lipopolysaccharide (LPS) stimulation in mice following intraperitoneal injection of Compound 1.

[0007] Figure 2B provides a summary of the results of MCP-1 cytokine production in response to LPS stimulation in mice following intraperitoneal injection of Compound 1.

[0008] Figure 3A provides a summary of the results of the mouse collagen induced arthritis model of disease as measured by disease scoring following oral administration of Compound 1.

[0009] Figure 3B provides a summary of the results of the mouse collagen induced arthritis model of disease as measured by paw swelling following oral administration of Compound 1.

[0010] Figure 4 provides a summary of the results of the human whole blood target occupancy assay.

[0011] Figure 5 provides a summary of the results of a soluble TNF binding assay in human peripheral blood mononuclear cells (PBMCs).

[0012] Figure 6 provides a summary of the results of a mouse mannan-induced psoriasis model of disease as measured by the severity of psoriasis-like lesions following administration of Compound 1, Deucravacitinib, or Etanercept.

[0013] Figure 7 provides a summary of the results of a mouse collagen-induced arthritis model of disease as measured by X-ray examination of the hind paw following administration of Compound 1 or Etanercept.

[0014] Figure 8 provides a summary of the results of a mouse T cell transfer induced colitis model of disease as measured by colon length and weight following intraperitoneal injection of Compound 1 or Adalimumab.

[0015] Figure 9A provides a summary of the results of a mouse T cell transfer induced colitis model of disease as measured by body weight and stool consistency following administration of anti-mIL23 biologic, Compound 1, or a combination of anti-mIL23 biologic and Compound 1.

[0016] Figure 9B provides a summary of the results of a mouse T cell transfer induced colitis model of disease as measured by differential gene expression (DGE) following administration of anti-mIL23 biologic, Compound 1, or a combination of anti-mIL23 biologic and Compound 1.

[0017] Figure 10A provides a summary of the results of a membrane TNF inhibition assay following treatment with Adalimumab.

[0018] Figure 10B provides a summary of the results of a membrane TNF inhibition assay following treatment with Compound 1.

[0019] Figure 11 provides a summary of the results of a mouse infected with Listeria monocytogenes as measured by survival following intravenous injection of Etanercept or Compound 1.INCORPORATION BY REFERENCE

[0020] All publications, patents, and patent applications mentioned in this specification are hereby incorporated by reference for the specific purposes identified herein.DETAILED DESCRIPTIONCertain Terminology

[0021] As used herein and in the appended claims, the singular forms "a," "and," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "an agent" includes a plurality of such agents, and reference to "the cell" includes reference to one or more cells (or to a plurality of cells) and equivalents thereof known to those skilled in the art, and so forth. When ranges are used herein for physical properties, such as molecular weight, or chemical properties, such as chemical formulae, all combinations and subcombinations of ranges and specific embodiments therein are intended to be included. The term "about" when referring to a number or a numerical range means that the number or numerical range referred to is an approximation within experimental variability (or within statistical experimental error), and thus the number or numerical range, in some instances, will vary between 1% and 15% of the stated number or numerical range. The term "comprising" (and related terms such as "comprise" or "comprises" or "having" or "including") is not intended to exclude that in other certain embodiments, for example, an embodiment of any composition of matter, composition, method, or process, or the like, described herein, "consist of or "consist essentially of' the described features.

[0022] As used in the specification and appended claims, unless specified to the contrary, the following terms have the meaning indicated below.

[0023] "Pharmaceutically acceptable salt" includes both acid and base addition salts. A pharmaceutically acceptable salt of the heterocyclic TNFR1 inhibitor described herein is intended to encompass any and all pharmaceutically suitable salt forms. Preferred pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

[0024] "Pharmaceutically acceptable acid addition salt" refers to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, and the like. Also included are salts that are formed with organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids,alkanedioic acids, aromatic acids, aliphatic and. aromatic sulfonic acids, etc. and include, for example, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Exemplary salts thus include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, caprylates, isobutyrates, oxalates, malonates, succinate suberates, sebacates, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenyl acetates, citrates, lactates, malates, tartrates, methanesulfonates, and the like. Also contemplated are salts of amino acids, such as arginates, gluconates, and galacturonates (see, for example, Berge S.M. et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 66: 1- 19 (1997)). Acid addition salts of basic compounds are, in some embodiments, prepared by contacting the free base forms with a sufficient amount of the desired acid to produce the salt according to methods and techniques with which a skilled artisan is familiar.

[0025] "Pharmaceutically acceptable base addition salt" refers to those salts that retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared from addition of an inorganic base or an organic base to the free acid. Pharmaceutically acceptable base addition salts are, in some embodiments, formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, for example, isopropyl amine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, N,N- dibenzylethylenediamine, chloroprocaine, hydrabamine, choline, betaine, ethylenediamine, ethylenedianiline, A-methylglucamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like. See Berge et al., supra.

[0026] "Pharmaceutically acceptable solvate" refers to a composition of matter that is the solvent addition form. In some embodiments, solvates contain either stoichiometric or non- stoichiometric amounts of a solvent, and are formed during the process of making with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formedwhen 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. The compounds provided herein optionally exist in unsolvated as well as solvated forms.

[0027] 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.

[0028] As used herein, the terms “treatment” or “treating,” or “palliating” or “ameliorating” are used interchangeably. These terms refer to therapeutic intervention for obtaining beneficial or desired results including but not limited to therapeutic benefit or a prophylactic benefit. By “therapeutic benefit” is meant eradication or amelioration of the underlying disorder being treated. Also, a therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the patient, notwithstanding that the patient is still afflicted with the underlying disorder. For prophylactic benefit, the compositions are, in some embodiments, administered to a patient at risk of developing a particular disease, or to a patient reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease has not been made. In some embodiments, the term "treating", as used herein, unless otherwise indicated, means reversing, alleviating, inhibiting the progress of the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition. In other embodiments, the term "treating", as used herein, unless otherwise indicated, means preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition. In some embodiments, the tern “treating” includes slowing or delaying the progression of the disease or disorder to which the term is applied. Additionally, in some embodiments, the term “treating” is applied to one or more of the complications resulting from the disease or disorder to which the term is applied. The term "treatment", as used herein, unless otherwise indicated, refers to the act of treating as "treating" is defined immediately above.

[0029] The phrase "therapeutically effective amount", as used herein, refers to that amount of drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal, or human that is being sought by a researcher, veterinarian, medical doctor or other.

[0030] Other aspects, advantages, and features of the invention will become apparent from the detailed description below.Tumor Necrosis Factor Alpha (TNF-a) Protein and Function

[0031] Tumor necrosis factor alpha (TNF-a) proteins are members of the TNF superfamily, comprising various transmembrane proteins with a homologous TNF domain forming trimers. The TNF superfamily comprises 19 family members, including, but not limited to tumor necrosis factor alpha (also known as tumor necrosis factor, or TNF), lymphotoxin alpha (TNF-P), lymphotoxin beta (TNFy), 0X40 ligand, CD40 ligand, Fas ligand, CD27 ligand, CD30 ligand, CD137 ligand, CD137 ligand, and TNF-related apoptosis-inducing ligand. TNF-a proteins are cytokines and adipokines (cytokines secreted by adipose tissue).

[0032] TNF-a exists as a transmembrane protein (mTNF-a), and as a soluble protein (sTNF-a), which is released via protein cleavage. Both forms of TNF-a are biologically active yet have distinctly different roles. The transmembrane form of TNF-a has been shown to play a crucial role in maintaining innate immune response to infections (e.g., tuberculosis, listeriosis), is required for effective regulatory and tolerogenic immune functions, and promotes the survival of multiple cell types. Inhibition of transmembrane TNF-a results in increased sensitivity to infection and exacerbation of demyelination. In contrast, sTNF-a plays an important role in driving the acute and chronic inflammatory response, and inhibition of sTNF-a has been shown to cause an anti-inflammatory effect. There are two receptors for TNF signaling, TNFR1 and TNFR2. Signaling from sTNF-a - TNFR1 binding promotes immune cell activation, cell death and drives acute and chronic inflammation. Transmembrane TNF-a - TNFR2 signaling promotes inflammation resolution, immune cell regulatory functions and cell survival. Thus, TNF-a is a key regulator of immune responses, tissue damage and repair.

[0033] The extracellular region of both TNFR1 and TNFR2 have four homologous cysteine-rich domains, but they have structurally different intracellular regions. TNFR1 has a protein binding region called a death domain which allows homo- and hetero-typic interactions with other death domain-containing proteins. TNFR2 has a TNF Receptor Associated Factor (TRAF) that interacts with the TRAF family of signaling adaptors. The distinct profiles of the two TNF receptors influence different cellular activities and physiological roles. TNFR1 can activate NF-KB and MAPK signaling, and cell death, and is important in the regulation of inflammatory diseases. TNFR2 is highly regulated and restricted to specific cell types such as endothelial cells, neuronal cells, myeloid and lymphoid cells. TNFR1 primarily promotes tissue inflammation and degeneration, while TNFR2 typically mediates local homeostatic effects suchas immune regulation, tissue regeneration and cell survival (D. Fresegna et al., Cells, 2020, 9, 2290).

[0034] Binding of TNF-a to TNFR1 can activate NF-KB for mediating transcription of various proteins involved in cell survival and proliferation, such as anti-apoptotic factors, and inflammatory response proteins. Further, the MAPK pathway can also be activated by binding of TNF-a to TNFR1, which is involved in cell differentiation and proliferation. When TNF-a binds to TNFR1, it triggers receptor trimerization, leading to the assembly of a TNFR1 -associated signaling complex. This complex recruits the receptor interacting protein 1 (RIP1) and TNF receptor associated death domain (TRADD) to the TNFR1 through the death domain regions. TRADD then recruits adaptor proteins TRAF2 and TRAF5, which can engage the E3 ubiquitin ligases c-IAPl and C-IAP2 (cellular inhibitors of apoptosis proteins 1 and 2, respectively). C- IAP1 / 2 are important for TNFR1 complex signaling, which can lead to the recruitment of the signaling kinase complexes comprising kinase IKKa and IKKP (inhibitors of kappa B kinase 1 and 2, respectively) and transforming growth factor beta-activated kinase 1 (TAK1), resulting in the activation of NF-KB and MAPK signaling. Activation of these signaling pathways can result in gene activation and expression of pro-inflammatory cytokines and pro-survival proteins.

[0035] TNF signaling is regulated by post-translational ubiquitination, which is essential for many biological processes. Post-translational modifications of TNFR1 -associated signaling complexes can result in a change from inflammatory gene signaling to cell death. This switch is dependent upon the ubiquitination status of RIP 1, which is formed as part of the TNFR1- associated signaling complex from TNF-a binding.

[0036] TNF-a has long been known to be a key regulator of the inflammatory response, and recently has been demonstrated to be involved in brain functioning (D. Fresegna et al., Cells, 2020, 9, 2290). In normal adult brains, TNF-a is expressed at low levels, and it is believed that the expression could be influenced by the presence, or absence, of cytokines that can cross the blood brain barrier. TNFRs in the brain are expressed by glia and neurons cells, and have regulatory functions, including, but not limited to, homeostatic synaptic plasticity, astrocyte- mediated synaptic transmission, and neurogenesis. These functions regulate learning and memory functions, amongst other roles.

[0037] TNF-a is also recognized to be a physiological gliotransmitter for the communication between neurons and glial cells, which in turn affects synaptic regulation. Glial TNF-a is important for maintenance of the normal surface expression of AMPA receptors, and for homeostatic synaptic scaling, which allows for adjustment of the strength of all synapses on a neuron.Prior Art Small Molecules TNF-a Inhibitors

[0038] Diseases treated with biologic TNF-a inhibitors include, but are not limited to, rheumatoid arthritis, inflammatory bowel disease, psoriatic arthritis, psoriasis, and ankylosing spondylitis. Patients with neuroinflammatory conditions and degenerative disease, including, but not limited to Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, treatment resistant depression, and tinnitus, may benefit from treatment with central nervous system (CNS) sTNF-a inhibitors by disrupting the sTNF-a signaling and sparing the transmembrane TNF-a signaling. Previous reports have also indicated targeting TNFR2 for treating Alzheimer’s Disease (N. Orti- Casan et al., Front Neurosci. 2019; 13: 49).

[0039] Small molecules have been developed as an alternative to anti-TNFa biologies since long-term clinical response rates are insufficient in multiple patient populations (Clunie et al, Rheumatol Adv Pract. 2018 Oct 17;2(2); Fumery et al, Liver Dis. 2024 Jan;56(l):21-28; Blesl et al. Aliment Pharmacol Ther. 2021 Sep;54(5):667-677; Rubbert-Roth et al. Autoimmun Rev. 2019 Dec;18(12): 102398).

[0040] Small molecule sTNF-a inhibitors are active in pharmacology models of sTNF-a / TNFR1 signaling, in addition to demonstrating efficacy in preclinical models of arthritis. There is currently limited data in the public domain for small molecule sTNF-a inhibitors, with current knowledge highlighted in “TNF-a: The Shape of Small Molecules to Come?” (A. Dbmling and X. Li, Drug Discov Today 2022 Jan; 27(l):3-7) and “Small Molecules that Inhibit TNF Signaling by Stabilising an Asymmetric Form of the Trimer” (J. O’Connell et al., Nature Communications 10, 5795 (2019)). Additional small molecule inhibitors of TNF-a include, but are not limited to, the inhibitors described in “Biologic-like In Vivo Efficacy with Small Molecule Inhibitors of TNF-a Identified Using Scaffold Hopping and Structure-Based Drug Design Approaches” (H-Y Xiao et al., J. Med. Chem. 2020, 15050-15071) and “Development of Orally Efficacious Allosteric Inhibitors of TNF-a via Fragment-Based Drug Design” (J. D.Dietrich et al., J. Med. Chem. 2021, 64, 417-429),

[0041] Small molecule sTNF-a inhibitors have potential as a valuable therapy for patients currently treated with biologic TNF-a inhibitors, given that these biologies inhibit both sTNF-a and transmembrane TNF-a. This lack of specificity leads to the inhibition of not only the inflammatory response (through sTNF-a inhibition), but also the protective and regulatory responses (through transmembrane TNF-a inhibition). Thus, patients treated with biologic TNF- a inhibitors are at increased risk for developing serious infections and exacerbated demyelination. Furthermore, many more diseases could benefit from TNF-a inhibitors, such as neuroinflammatory conditions and degenerative diseases, but the nature of biologic TNF-ainhibitors prohibit CNS applications due to the difficulty of surmounting the blood brain barrier. In addition, the use of biologic TNF-a inhibitors remains restricted to a subset of the potential patient population due to high drug production costs and pricing, as well as supply chain complexity. This, coupled with the lack of specificity, and antidrug immune reactions, restrict the application of TNF-a inhibitor biologies.

[0042] The lack of specificity of currently approved TNF-a inhibitors (e.g., global TNF-a inhibitors targeting sTNF-a and mTNF-a) often results in an immunosuppressive effect, increasing the risk of adverse events, such as serious infections. Medications inhibiting both sTNF-a and mTNF-a can impair the body's ability to defend against pathogens, leading to a higher susceptibility to various infections, particularly in the early stages of treatment and for those with pre-existing conditions or prolonged treatment regimens. Thus, a TNF-a inhibitor which selectively inhibits sTNF-a could potentially improve treatment outcomes by avoiding the unintended consequences of broadly inhibiting TNF (such as the detrimental effects on the immune system). In addition, selective sTNF-a inhibitors could allow for improved combination therapies by improving efficacy and minimizing side effects compared to global TNF inhibitors. In view of the considerable limitations of current TNF-a inhibitors, there is a serious unmet clinical need for a small molecule drug with the efficacy of a TNF-a inhibitor biologic, but also with increased specificity and the ability to fine tune oral dosing requirements, thus maintaining the physiological innate immune response to infections, avoiding anti-drug antibody responses, and consequently improving short and long treatment outcomes (A. Dbmling and X. Li, Drug Discov Today 2022 Jan; 27(l):3-7).Novel Heterocyclic Soluble TNFa / TNFRl Inhibitors

[0043] One heterocyclic TNFR1 inhibitor described herein refers to Compound 1 having the structure below and the chemical name (7R,14R)-l-(difluoromethoxy)-l l-(4- (dimethylphosphoryl)-3-fluorophenyl)-10-fluoro-6-(methyl-d3)-6,7-dihydro-7,14- methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,4]diazocin-5(14H)-one.Compound 1

[0044] Compound 1 is a small molecule TNFR1 inhibitor. The synthesis and characterization of Compound 1 has been presented in PCT International Patent Application PCT / US2023 / 080758. Throughout this disclosure when reference is made to a heterocyclic TNFR1 inhibitor, or pharmaceutically acceptable salt or solvate thereof, the reference is to Compound 1, and pharmaceutically acceptable salts, solvates or deuteroisotopes thereof.Inflammatory Disease, Autoimmune Disease and Methods of Treatment

[0045] One embodiment provides (7R,14R)-l-(difhroromethoxy)-l l-(4- (dimethylphosphoryl)-3-fluorophenyl)-10-fluoro-6-(methyl-d3)-6,7-dihydro-7,14- methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,4]diazocin-5(14H)-one, or pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment of the human or animal body.

[0046] One embodiment provides (7R,14R)-l-(difhroromethoxy)-l l-(4- (dimethylphosphoryl)-3-fluorophenyl)-10-fluoro-6-(methyl-d3)-6,7-dihydro-7,14- methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,4]diazocin-5(14H)-one, or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment of inflammatory or autoimmune disease.

[0047] One embodiment provides a use of (7R, 14R)-l-(difhrorom ethoxy)- 11 -(4-(dimethylphosphoryl)-3-fluorophenyl)-10-fluoro-6-(methyl-d3)-6,7-dihydro-7,14- methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,4]diazocin-5(14H)-one, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of an inflammatory or autoimmune disease.

[0048] One embodiment provides a method of treating an inflammatory or autoimmune disease in a patient in need thereof, comprising administering to the patient (7R,14R)-1- (difluoromethoxy)-l l-(4-(dimethylphosphoryl)-3-fluorophenyl)-10-fluoro-6-(methyl-d3)-6,7- dihydro-7, 14-methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,4]diazocin-5(14H)-one, or pharmaceutically acceptable salt or solvate thereof.

[0049] One embodiment provides a method of treating inflammatory or autoimmune disease in a patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising (7R, 14R)-l-(difluorom ethoxy)- 11 -(4-(dimethylphosphoryl)-3 - fluorophenyl)- 10-fluoro-6-(methyl-d3 )-6, 7-dihy dro-7, 14- methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,4]diazocin-5(14H)-one, or pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient.

[0050] One embodiment provides a method of treating inflammatory or autoimmune disease in a patient in need thereof, comprising administering to the patient:(a) a composition comprising (7R,14R)-l-(difluoromethoxy)-l l-(4- (dimethylphosphoryl)-3-fluorophenyl)-10-fluoro-6-(methyl-d3)-6,7-dihydro-7,14- methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,4]diazocin-5(14H)-one, or pharmaceutically acceptable salt or solvate thereof; and(b) at least one therapeutic for the treatment of inflammatory or autoimmune disease selected from the group consisting of anti-inflammatory steroid, methotrexate, mesalazine, a JAK kinase inhibitor, a TYK2 kinase inhibitor, and a SIP receptor modulator.

[0051] One embodiment provides a method of treating inflammatory or autoimmune disease in a patient in need thereof, comprising administering to the patient:(a) a composition comprising (7R, 14R)-l-(difluorom ethoxy)- 11 -(4- (dimethylphosphoryl)-3-fluorophenyl)-10-fluoro-6-(methyl-d3)-6,7-dihydro-7,14- methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,4]diazocin-5(14H)-one, or pharmaceutically acceptable salt or solvate thereof; and(b) at least one therapeutic for the treatment of inflammatory or autoimmune disease selected from the group consisting of abatacept, vedolizumab, azathioprine, prednisone, budesonide, tofacitinib, upadacitanib, mesalazine, and methotrexate.

[0052] One embodiment provides a method of treating inflammatory or autoimmune disease in a patient in need thereof, comprising administering to the patient:(a) a composition comprising (7R, 14R)-l-(difluorom ethoxy)- 11 -(4- (dimethylphosphoryl)-3-fluorophenyl)-10-fluoro-6-(methyl-d3)-6,7-dihydro-7,14- methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,4]diazocin-5(14H)-one, or pharmaceutically acceptable salt or solvate thereof; and(b) at least one therapeutic for the treatment of inflammatory or autoimmune disease selected from the group consisting of CD20 biologic therapy, IL- lb biologic therapy, IL 12 / 23 biologic therapy, IL-23 biologic therapy, IL- 17 biologic therapy, IL-36 biologic therapy, integrin a4b7 biologic therapy, IL-4R biologic therapy, and TNFa biologic therapy.

[0053] One embodiment provides a method of treating inflammatory or autoimmune disease in a patient in need thereof, comprising administering to the patient:(a) a composition comprising (7R,14R)-l-(difluoromethoxy)-l l-(4- (dimethylphosphoryl)-3-fluorophenyl)-10-fluoro-6-(methyl-d3)-6,7-dihydro-7,14- methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,4]diazocin-5(14H)-one, or pharmaceutically acceptable salt or solvate thereof; and(b) at least one therapeutic for the treatment of inflammatory or autoimmune disease selected from the group consisting of BTK inhibitors, CD38 targeted biologies, FcRn targeted biologies, and TL la targeted biologies.

[0054] One embodiment provides a method of treating inflammatory or autoimmune disease in a patient in need thereof, comprising administering to the patient:(a) a composition comprising (7R, 14R)-l-(difluorom ethoxy)- 11 -(4- (dimethylphosphoryl)-3-fluorophenyl)-10-fluoro-6-(methyl-d3)-6,7-dihydro-7,14- methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,4]diazocin-5(14H)-one, or pharmaceutically acceptable salt or solvate thereof; and(b) at least one therapeutic for the treatment of inflammatory or autoimmune disease selected from the group consisting of mesalamine, a corticosteroid, tacrolimus, apremilast, ciclosporin, cyclophosphamide, hydroxychloroquine, leflunomide, mycophenolate, sulfasalazine, upadacitinib, baricitinib, adalimumab, etanercept, infliximab, certolizumab, golimumab, rituximab, anakinra, sarilumab, secukinumab, ixekizumab, ustekinumab, guselkumab, tildrakizumab, and apremilast.

[0055] One embodiment provides a method of treating inflammatory or autoimmune disease in a patient in need thereof, comprising administering to the patient:(a) a composition comprising (7R, 14R)-l-(difluorom ethoxy)- 11 -(4- (dimethylphosphoryl)-3-fluorophenyl)-10-fluoro-6-(methyl-d3)-6,7-dihydro-7,14- methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,4]diazocin-5(14H)-one, or pharmaceutically acceptable salt or solvate thereof; and(b) at least one therapeutic selected from the group consisting of GLP-1 agonist, GIP agonist, dual GLP-l / GIP agonist or SGLT2 inhibitor.

[0056] In another embodiment the GLP-1 agonist is selected from exenatide, albiglutide, lixisenatide, semaglutide, dulaglutide, liraglutide or tirzepatide.

[0057] In another embodiment, the GIP agonist is selected from tirzepatide.

[0058] In another embodiment, the dual GLP-l / GIP agonist is selected from tirzepatide,CT-388, or maridebart cafraglutide (AMG133).

[0059] In another embodiment, the SGLT2 inhibitor is selected from bexagliflozin, canagliflozin, dapagliflozin, empagliflozin, or ertugliflozin.

[0060] Another embodiment provides a compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment of the human or animal body, wherein Formula (I) is:wherein,W-XRing A is selected fromz-- Y, wherein the * denotes point of attachment to L, or an optionally substituted heteroarylene selected from pyrazolene, imidazoline, oxazolene, or thiazolene;V is N or C-R11;W is N or C-R5;X is N or C-R6;Y is N or C-R7;Z is N or C-R8;L is a bond,wherein the * denotes point of attachment to phosphorous; n is 1, 2, or 3;R1is selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted C4-C7 cycloalkylalkyl;R2is hydrogen, or optionally substituted C1-C3 alkyl;R3is hydroxy, optionally substituted C1-C3 alkoxy, or optionally substituted C1-C6 alkyl;R4is hydroxy, optionally substituted C1-C3 alkoxy, or optionally substituted C1-C6 alkyl; or R3and R4join to form optionally substituted phosphorus-containing 3- to 8-membered ring; each R5, R6, R7, and R8is independently selected from hydrogen, halogen, -CN, -NH2, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 alkoxy, or -NH(optionally substituted C1-C3 alkyl);R9is selected from hydrogen, halogen, or optionally substituted C1-C6 alkyl;R10is selected from hydrogen or halogen;R11is selected from hydrogen, halogen, or optionally substituted C1-C6 alkyl; andR12and R13are independently selected from hydrogen, -OH, F, and CH3.

[0061] Another embodiment provides a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment of inflammatory or autoimmune disease, wherein Formula (I) is:wherein,W-XRing A is selected fromZ-Y, wherein the * denotes point of attachment to L, or an optionally substituted heteroarylene selected from pyrazolene, imidazoline, oxazolene, or thiazolene;V is N or C-R11;W is N or C-R5;X is N or C-R6;Y is N or C-R7;Z is N or C-R8;L is a bond,wherein the * denotes point of attachment to phosphorous; n is 1, 2, or 3;R1is selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted C4-C7 cycloalkylalkyl;R2is hydrogen, or optionally substituted C1-C3 alkyl;R3is hydroxy, optionally substituted C1-C3 alkoxy, or optionally substituted C1-C6 alkyl;R4is hydroxy, optionally substituted C1-C3 alkoxy, or optionally substituted C1-C6 alkyl; or R3and R4join to form optionally substituted phosphorus-containing 3- to 8-membered ring;each R5, R6, R7, and R8is independently selected from hydrogen, halogen, -CN, -NH2, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 alkoxy, or -NH(optionally substituted C1-C3 alkyl);R9is selected from hydrogen, halogen, or optionally substituted C1-C6 alkyl;R10is selected from hydrogen or halogen;R11is selected from hydrogen, halogen, or optionally substituted C1-C6 alkyl; andR12and R13are independently selected from hydrogen, -OH, F, and CH3.

[0062] Another embodiment provides a use of a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of an inflammatory or autoimmune disease, wherein Formula (I) is:wherein,* W-XRing A is selected from , wherein the * denotes point of attachment to L, or an optionally substituted heteroarylene selected from pyrazolene, imidazoline, oxazolene, or thiazolene;V is N or C-R11;W is N or C-R5;X is N or C-R6;Y is N or C-R7;Z is N or C-R8;L is a bond,wherein the * denotes point of attachment to phosphorous; n is 1, 2, or 3;R1is selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted C4-C7 cycloalkylalkyl;R2is hydrogen, or optionally substituted C1-C3 alkyl;R3is hydroxy, optionally substituted C1-C3 alkoxy, or optionally substituted C1-C6 alkyl;R4is hydroxy, optionally substituted C1-C3 alkoxy, or optionally substituted C1-C6 alkyl; or R3and R4join to form optionally substituted phosphorus-containing 3- to 8-membered ring; each R5, R6, R7, and R8is independently selected from hydrogen, halogen, -CN, -NH2, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 alkoxy, or -NH(optionally substituted C1-C3 alkyl);R9is selected from hydrogen, halogen, or optionally substituted C1-C6 alkyl;R10is selected from hydrogen or halogen;R11is selected from hydrogen, halogen, or optionally substituted C1-C6 alkyl; and R12and R13are independently selected from hydrogen, -OH, F, and CH3.

[0063] Another embodiment provides a method of treating an inflammatory or autoimmune disease in a patient in need thereof, comprising administering to the patient a compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein Formula (I) is:wherein,* W-XH='HRing A is selected fromz Y, wherein the * denotes point of attachment to L, or an optionally substituted heteroarylene selected from pyrazolene, imidazoline, oxazolene, or thiazolene;V is N or C-R11;W is N or C-R5;X is N or C-R6;Y is N or C-R7;Z is N or C-R8;L is a bond,wherein the * denotes point of attachment to phosphorous; n is 1, 2, or 3;R1is selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted C4-C7 cycloalkylalkyl;R2is hydrogen, or optionally substituted C1-C3 alkyl;R3is hydroxy, optionally substituted C1-C3 alkoxy, or optionally substituted C1-C6 alkyl;R4is hydroxy, optionally substituted C1-C3 alkoxy, or optionally substituted C1-C6 alkyl; or R3and R4join to form optionally substituted phosphorus-containing 3- to 8-membered ring; each R5, R6, R7, and R8is independently selected from hydrogen, halogen, -CN, -NH2, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 alkoxy, or -NH(optionally substituted C1-C3 alkyl);R9is selected from hydrogen, halogen, or optionally substituted C1-C6 alkyl;R10is selected from hydrogen or halogen;R11is selected from hydrogen, halogen, or optionally substituted C1-C6 alkyl; andR12and R13are independently selected from hydrogen, -OH, F, and CH3.

[0064] Another embodiment provides a method of treating inflammatory or autoimmune disease in a patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising a compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient, wherein Formula (I) is:wherein,W-X7= yRing A is selected from , wherein the * denotes point of attachment to L, or an optionally substituted heteroarylene selected from pyrazolene, imidazoline, oxazolene, or thiazolene;V is N or C-R11;W is N or C-R5;X is N or C-R6;Y is N or C-R7;Z is N or C-R8;L is a bond,wherein the * denotes point of attachment to phosphorous; n is 1, 2, or 3;R1is selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted C4-C7 cycloalkylalkyl;R2is hydrogen, or optionally substituted C1-C3 alkyl;R3is hydroxy, optionally substituted C1-C3 alkoxy, or optionally substituted C1-C6 alkyl;R4is hydroxy, optionally substituted C1-C3 alkoxy, or optionally substituted C1-C6 alkyl; or R3and R4join to form optionally substituted phosphorus-containing 3- to 8-membered ring; each R5, R6, R7, and R8is independently selected from hydrogen, halogen, -CN, -NH2, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 alkoxy, or -NH(optionally substituted C1-C3 alkyl);R9is selected from hydrogen, halogen, or optionally substituted C1-C6 alkyl;R10is selected from hydrogen or halogen;R11is selected from hydrogen, halogen, or optionally substituted C1-C6 alkyl; andR12and R13are independently selected from hydrogen, -OH, F, and CH3.

[0065] Another embodiment provides a method of treating inflammatory or autoimmune disease in a patient in need thereof, comprising administering to the patient:(a) a composition comprising a compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein Formula (I) is:wherein,* w-xH='HRing A is selected fromz Y, wherein the * denotes point of attachment to L, or an optionally substituted heteroarylene selected from pyrazolene, imidazoline, oxazolene, or thiazolene;V is N or C-R11;W is N or C-R5;X is N or C-R6;Y is N or C-R7;Z is N or C-R8;L is a bond,wherein the * denotes point of attachment to phosphorous; n is 1, 2, or 3;R1is selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted C4-C7 cycloalkylalkyl;R2is hydrogen, or optionally substituted C1-C3 alkyl;R3is hydroxy, optionally substituted C1-C3 alkoxy, or optionally substituted C1-C6 alkyl;R4is hydroxy, optionally substituted C1-C3 alkoxy, or optionally substituted C1-C6 alkyl; or R3and R4join to form optionally substituted phosphorus-containing 3- to 8-membered ring; each R5, R6, R7, and R8is independently selected from hydrogen, halogen, -CN, -NH2, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 alkoxy, or -NH(optionally substituted C1-C3 alkyl);R9is selected from hydrogen, halogen, or optionally substituted C1-C6 alkyl;R10is selected from hydrogen or halogen;R11is selected from hydrogen, halogen, or optionally substituted C1-C6 alkyl; andR12and R13are independently selected from hydrogen, -OH, F, and CH3; and(b) at least one therapeutic for the treatment of inflammatory or autoimmune disease selected from the group consisting of anti-inflammatory steroid, methotrexate, mesalazine, a JAK kinase inhibitor, a TYK2 kinase inhibitor, and a SIP receptor modulator.

[0066] Another embodiment provides a method of treating inflammatory or autoimmune disease in a patient in need thereof, comprising administering to the patient:(a) a composition comprising a compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, or pharmaceutically acceptable salt or solvate thereof, wherein Formula (I) is:wherein,Ring A is selected from, wherein the * denotes point of attachment to L, or an optionally substituted heteroarylene selected from pyrazolene, imidazoline, oxazolene, or thiazolene;V is N or C-R11;W is N or C-R5;X is N or C-R6;Y is N or C-R7;Z is N or C-R8;L is a bond,wherein the * denotes point of attachment to phosphorous; n is 1, 2, or 3;R1is selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted C4-C7 cycloalkylalkyl;R2is hydrogen, or optionally substituted C1-C3 alkyl;R3is hydroxy, optionally substituted C1-C3 alkoxy, or optionally substituted C1-C6 alkyl;R4is hydroxy, optionally substituted C1-C3 alkoxy, or optionally substituted C1-C6 alkyl; or R3and R4join to form optionally substituted phosphorus-containing 3- to 8-membered ring; each R5, R6, R7, and R8is independently selected from hydrogen, halogen, -CN, -NH2, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 alkoxy, or -NH(optionally substituted C1-C3 alkyl);R9is selected from hydrogen, halogen, or optionally substituted C1-C6 alkyl;R10is selected from hydrogen or halogen;R11is selected from hydrogen, halogen, or optionally substituted C1-C6 alkyl; and R12and R13are independently selected from hydrogen, -OH, F, and CH3; and (b) at least one therapeutic for the treatment of inflammatory or autoimmune disease selected from the group consisting of abatacept, vedolizumab, azathioprine, prednisone, budesonide, tofacitinib, upadacitanib, mesalazine, and methotrexate.

[0067] Another embodiment provides a method of treating inflammatory or autoimmune disease in a patient in need thereof, comprising administering to the patient:(a) a composition comprising a compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein Formula (I) is:wherein,Ring A is selected from, wherein the * denotes point of attachment to L, or an optionally substituted heteroarylene selected from pyrazolene, imidazoline, oxazolene, or thiazolene;V is N or C-R11;W is N or C-R5;X is N or C-R6;Y is N or C-R7;Z is N or C-R8;L is a bond,wherein the * denotes point of attachment to phosphorous; n is 1, 2, or 3;R1is selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted C4-C7 cycloalkylalkyl;R2is hydrogen, or optionally substituted C1-C3 alkyl;R3is hydroxy, optionally substituted C1-C3 alkoxy, or optionally substituted C1-C6 alkyl;R4is hydroxy, optionally substituted C1-C3 alkoxy, or optionally substituted C1-C6 alkyl; or R3and R4join to form optionally substituted phosphorus-containing 3- to 8-membered ring; each R5, R6, R7, and R8is independently selected from hydrogen, halogen, -CN, -NH2, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 alkoxy, or -NH(optionally substituted C1-C3 alkyl);R9is selected from hydrogen, halogen, or optionally substituted C1-C6 alkyl;R10is selected from hydrogen or halogen;R11is selected from hydrogen, halogen, or optionally substituted C1-C6 alkyl; andR12and R13are independently selected from hydrogen, -OH, F, and CH3; and (b) at least one therapeutic for the treatment of inflammatory or autoimmune disease selected from the group consisting of CD20 biologic therapy, IL- lb biologic therapy, IL 12 / 23 biologic therapy, IL-23 biologic therapy, IL- 17 biologic therapy, IL-36 biologic therapy, integrin a4b7 biologic therapy, IL-4R biologic therapy, and TNFa biologic therapy.

[0068] Another embodiment provides a method of treating inflammatory or autoimmune disease in a patient in need thereof, comprising administering to the patient:(a) a composition comprising a compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, or pharmaceutically acceptable salt or solvate thereof, wherein Formula (I) is:wherein,W-XRing A is selected from , wherein the * denotes point of attachment to L, or an optionally substituted heteroarylene selected from pyrazolene, imidazoline, oxazolene, or thiazolene;V is N or C-R11;W is N or C-R5;X is N or C-R6;Y is N or C-R7;Z is N or C-R8;L is a bond,wherein the * denotes point of attachment to phosphorous; n is 1, 2, or 3;R1is selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted C4-C7 cycloalkylalkyl;R2is hydrogen, or optionally substituted C1-C3 alkyl;R3is hydroxy, optionally substituted C1-C3 alkoxy, or optionally substituted C1-C6 alkyl;R4is hydroxy, optionally substituted C1-C3 alkoxy, or optionally substituted C1-C6 alkyl; or R3and R4join to form optionally substituted phosphorus-containing 3- to 8-membered ring; each R5, R6, R7, and R8is independently selected from hydrogen, halogen, -CN, -NH2, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 alkoxy, or -NH(optionally substituted C1-C3 alkyl);R9is selected from hydrogen, halogen, or optionally substituted C1-C6 alkyl;R10is selected from hydrogen or halogen;R11is selected from hydrogen, halogen, or optionally substituted C1-C6 alkyl; andR12and R13are independently selected from hydrogen, -OH, F, and CH3; and(b) at least one therapeutic for the treatment of inflammatory or autoimmune disease selected from the group consisting of BTK inhibitors, CD38 targeted biologies, FcRn targeted biologies, and TL la targeted biologies.

[0069] Another embodiment provides a method of treating inflammatory or autoimmune disease in a patient in need thereof, comprising administering to the patient:(a) a composition comprising a compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, or pharmaceutically acceptable salt or solvate thereof, wherein Formula (I) is:wherein,W-XRing A is selected fromz-- Y, wherein the * denotes point of attachment to L, or an optionally substituted heteroarylene selected from pyrazolene, imidazoline, oxazolene, or thiazolene;V is N or C-R11;W is N or C-R5;X is N or C-R6;Y is N or C-R7;Z is N or C-R8;L is a bond,wherein the * denotes point of attachment to phosphorous; n is 1, 2, or 3;R1is selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted C4-C7 cycloalkylalkyl;R2is hydrogen, or optionally substituted C1-C3 alkyl;R3is hydroxy, optionally substituted C1-C3 alkoxy, or optionally substituted C1-C6 alkyl;R4is hydroxy, optionally substituted C1-C3 alkoxy, or optionally substituted C1-C6 alkyl; or R3and R4join to form optionally substituted phosphorus-containing 3- to 8-membered ring; each R5, R6, R7, and R8is independently selected from hydrogen, halogen, -CN, -NH2, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 alkoxy, or -NH(optionally substituted C1-C3 alkyl);R9is selected from hydrogen, halogen, or optionally substituted C1-C6 alkyl;R10is selected from hydrogen or halogen;R11is selected from hydrogen, halogen, or optionally substituted C1-C6 alkyl; andR12and R13are independently selected from hydrogen, -OH, F, and CH3; and (b) at least one therapeutic for the treatment of inflammatory or autoimmune disease selected from the group consisting of mesalamine, a corticosteroid, tacrolimus, apremilast, ciclosporin, cyclophosphamide, hydroxychloroquine, leflunomide, mycophenolate, sulfasalazine, upadacitinib, baricitinib, adalimumab, etanercept, infliximab, certolizumab, golimumab, rituximab, anakinra, sarilumab, secukinumab, ixekizumab, ustekinumab, guselkumab, tildrakizumab, and apremilast.

[0070] Another embodiment provides the use, wherein Formula (I), or pharmaceutically acceptable salt or solvate thereof, is:wherein,Ring A is selected from, wherein the * denotes point of attachment to L;V is C-R11;W is N or C-R5;X is C-R6;Y is C-R7;Z is N or C-R8;L is a bond;R1is optionally substituted C1-C6 alkyl;R2is hydrogen, or optionally substituted C1-C3 alkyl;R3is optionally substituted C1-C6 alkyl;R4is optionally substituted C1-C6 alkyl; or R3and R4join to form optionally substituted phosphorus-containing 3- to 8-membered ring; each R5, R6, R7, and R8is independently selected from hydrogen, or halogen;R9is selected from hydrogen, halogen, or optionally substituted C1-C6 alkyl;R10is selected from hydrogen or halogen;R11is selected from hydrogen, or halogen; andR12and R13are independently selected from hydrogen, -OH, F, and CH3.

[0071] Another embodiment provides the use, wherein the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, is selected from the group consisting of:(7R,14R)-l-(difluoromethoxy)-l l-(2-(dimethylphosphoryl)pyrimidin-5-yl)-6,7-dihydro- 7,14-methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,4]diazocin-5(14H)-one;(7R,14R)-l-(difluoromethoxy)-l l-(6-(dimethylphosphoryl)pyridin-3-yl)-6-methyl-6,7- dihydro-7, 14-methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,4]diazocin-5(14H)-one;(7R, 14R)- 1 -(difluoromethoxy)- 11 -(6-(dimethylphosphoryl)pyri din-3 -yl)-6,7-dihydro- 7,14-methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,4]diazocin-5(14H)-one;(7R,14R)-l-(difluoromethoxy)-l l-(6-(dimethylphosphoryl)-5-fluoropyridin-3-yl)-6- methyl-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,4]diazocin-5(14H)-one;(17?,117?)-18-(difhroromethoxy)-12-methyl-5-[6-(l-oxo-llambda5-phospholan-l- yl)pyridin-3-yl]-2,9,12-triazapentacyclo[9.8.1.0A{2,10}.0A{3,8}.0A{14,19}]icosa- 3(8), 4, 6, 9, 14(19), 15,17-heptaen- 13 -one;( 1R, 11R)~ 18-(difluorom ethoxy)- 12-methyl-5-[6-(4-oxo- 1 ,41ambda5-oxaphosphinan-4- yl)pyridin-3-yl]-2,9,12-triazapentacyclo[9.8.1.0A{2,10}.0A{3,8}.0A{14,19}]icosa- 3(8), 4, 6, 9, 14(19), 15,17-heptaen- 13 -one;(17?,117?)-18-(difhroromethoxy)-5-{6-[(dimethylphosphoryl)methoxy]pyridin-3-yl}-12- methyl-2,9,12-triazapentacyclo[9.8.1.0A{2,10}.0A{3,8}.0A{14,19}]icosa- 3(8), 4, 6, 9, 14(19), 15,17-heptaen- 13 -one;(17?,117?)-18-(difluoromethoxy)-5-[2-(dimethylphosphoryl)pyrimidin-5-yl]-12-methyl- 2,9,12-triazapentacyclo[9.8.1.0A{2,10}.0A{3,8}.0A{14,19}]icosa-3(8),4,6,9,14(19),15,17- heptaen-13-one;(17?,117?)-18-(difluoromethoxy)-5-{2-[(dimethylphosphoryl)methoxy]pyrimidin-5-yl}- 12-methyl-2,9,12-triazapentacyclo[9.8.1.0A{2,10}.0A{3,8}.0A{14,19}]icosa- 3(8), 4, 6, 9, 14(19), 15,17-heptaen- 13 -one;(1R,1 lR)-18-(difluoromethoxy)-5-{6-[(dimethylphosphoryl)methoxy]-5-fluoropyridin- 3-yl}-12-methyl-2,9,12-triazapentacyclo [9.8.1.0A{2,10}.0A{3,8}.0A{14,19}] icosa- 3(8), 4, 6, 9, 14(19), 15,17-heptaen- 13 -one;(17?,117?)-18-(difluoromethoxy)-5-{6-[(dimethylphosphoryl)methoxy]pyridin-3-yl}- 2,9,12-triazapentacyclo[9.8.1.0A{2,10}.0A{3,8}.0A{14,19}]icosa-3(8),4,6,9,14(19),15,17- heptaen-13-one;(17?,117?)-18-(difluoromethoxy)-5-{2-[(dimethylphosphoryl)methoxy]pyrimidin-5-yl}- 2,9,12-triazapentacyclo[9.8.1.0A{2,10}.0A{3,8}.0A{ 14,19}]icosa-3(8),4,6,9,14(19),15,17- heptaen-13-one;(lR,HR)-18-(difluoromethoxy)-5-[4-(dimethylphosphoryl)phenyl]-12-methyl-2,9,12- triazapentacyclo[9.8.1.0A{2,10}.0A{3,8}.0A{ 14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13- one;(lR,HR)-18-(difluoromethoxy)-5-[4-(dimethylphosphoryl)-3-fluorophenyl]-12-methyl- 2,9,12-triazapentacyclo[9.8.1.0A{2,10}.0A{3,8}.0A{ 14,19}]icosa-3(8),4,6,9,14(19),15,17- heptaen-13-one;(7R, 147?)- 1 -(difluoromethoxy)- 11 -(6-((dimethylphosphoryl)methoxy)pyri din-3 -yl)-6- (methyl-tZ?)-6,7-dihydro-7,14-methanobenzo[ / ]benzo[4,5]imidazo[l,2-a][l,4]diazocin-5(1477)- one;(lR,HR)-18-(difluoromethoxy)-5-(6-{[(dimethylphosphoryl)methyl]amino}-5- fluoropyridin-3-yl)-12-methyl-2,9,12-triazapentacyclo[9.8.1.0A{2,10}.0A{3,8}.0A{ 14,19}]icosa- 3(8), 4, 6, 9, 14(19), 15,17-heptaen- 13 -one;(77?, 147?)- l-(difluorom ethoxy)- 1 l-(6-(dimethylphosphoryl)pyri din-3 -yl)-6-(methyl-t7?)- 6,7-dihydro-7,14-methanobenzo[ / ]benzo[4,5]imidazo[l,2-a][l,4]diazocin-5(1477)-one;(1R,1 lR)-18-(difluoromethoxy)-5-{4-[(dimethylphosphoryl)methoxy]-3-fluorophenyl}- 12-methyl-2,9,12-triazapentacyclo[9.8.1.0A{2,10}.0A{3,8}.0A{ 14,19}]icosa- 3(8), 4, 6, 9, 14(19), 15,17-heptaen- 13 -one;(17?,117?)-18-(difluoromethoxy)-5-[6-(dimethylphosphoryl)pyridin-3-yl]-12-ethyl-2,9,12- tri azapentacyclo[9.8.1.0A{2, 10}.0A{3,8 } ,0A{ 14,19}]icosa-3(8), 4, 6, 9, 14(19), 15,17-heptaen- 13- one;( 1 R, 11 R)- 18-(difluoromethoxy)-5 - { 6- [(dimethylphosphoryl)amino]pyri din-3 -yl}-12- methyl-2,9,12-triazapentacyclo[9.8.1.0A{2,10}.0A{3,8}.0A{ 14,19}]icosa- 3(8), 4, 6, 9, 14(19), 15,17-heptaen- 13 -one;(lR,HR)-18-(difluoromethoxy)-5-{ l-[(dimethylphosphoryl)methyl]pyrazol-4-yl}-12- methyl-2,9,12-triazapentacyclo[9.8.1.0A{2,10}.0A{3,8}.0A{ 14,19}]icosa- 3(8), 4, 6, 9, 14(19), 15,17-heptaen- 13 -one;( 1 R, 11 R)- 18-(difluoromethoxy)-5 - { 6- [(dimethylphosphoryl)methyl]pyri din-3 -yl}-12- methyl-2,9,12-triazapentacyclo[9.8.1.0A{2,10}.0A{3,8}.0A{ 14,19}]icosa- 3(8), 4, 6, 9, 14(19), 15,17-heptaen- 13 -one;(lR,HR)-18-(difluoromethoxy)-5-(6-{[(dimethylphosphoryl)methyl]amino}pyridin-3- yl)-12-methyl-2,9,12-triazapentacyclo[9.8.1.0A{2,10}.0A{3,8}.0A{ 14,19}]icosa- 3(8), 4, 6, 9, 14(19), 15,17-heptaen- 13 -one;(7R, 14R)-1 -(difluoromethoxy)- 1 l-(4-(dimethylphosphoryl)-3-fluorophenyl)-6-(m ethyl- d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,4]diazocin-5(14H)-one;(1R,1 lR)-18-(difluorornethoxy)-5-{2-[(dimethylphosphoryl)methoxy]-l,3-thiazol-5-yl}- 12-methyl-2,9,12-triazapentacyclo[9.8.1.0A{2,10}.0A{3,8}.0A{ 14,19}]icosa- 3(8), 4, 6, 9, 14(19), 15,17-heptaen- 13 -one;(lR,HR)-18-(difluoromethoxy)-5-{2-[(dimethylphosphoryl)amino]pyrimidin-5-yl}-12- methyl-2,9,12-triazapentacyclo[9.8.1.0A{2,10}.0A{3,8}.0A{ 14,19}]icosa- 3(8), 4, 6, 9, 14(19), 15,17-heptaen- 13 -one;(1R,1 lR)-5-[2-chloro-4-(dimethylphosphoryl)phenyl]-18-(difluoromethoxy)-12-methyl-2,9,12-triazapentacyclo[9.8.1.0A{2,10}.0A{3,8}.0A{ 14,19}]icosa-3(8),4,6,9,14(19),15,17- heptaen-13-one;(1R,1 lR)-18-(difluoromethoxy)-5-[4-(dimethylphosphoryl)-2-fluorophenyl]-12-methyl-2,9,12-triazapentacyclo[9.8.1.0A{2,10}.0A{3,8}.0A{ 14,19}]icosa-3(8),4,6,9,14(19),15,17- heptaen-13-one;(lR,HR)-18-(difluoromethoxy)-5-[4-(dimethylphosphoryl)-2-methylphenyl]-12-methyl-2,9,12-triazapentacyclo[9.8.1.0A{2,10}.0A{3,8}.0A{ 14,19}]icosa-3(8),4,6,9,14(19),15,17- heptaen-13-one;(1R, 11R)- 18-(difluoromethoxy)-5-(6- {[(dimethylphosphoryl)methyl](methyl)amino}pyridin-3-yl)-12-methyl-2,9,12- tri azapentacyclo[9.8.1.0A{2, 10}.0A{3,8 } ,0A{ 14,19}]icosa-3(8), 4, 6, 9, 14(19), 15,17-heptaen- 13- one;(1R,1 lR)-18-(difluoromethoxy)-5-[4-(dimethylphosphoryl)-2-fluorophenyl]-2,9,12- tri azapentacyclo[9.8.1.0A{2, 10}.0A{3,8}.0A{ 14,19}]icosa-3(8), 4, 6, 9, 14(19), 15,17-heptaen- 13- one;(1R,1 lR)-18-(difluoromethoxy)-5-[4-(dimethylphosphoryl)-2-methylphenyl]-2,9,12- tri azapentacyclo[9.8.1.0A{2, 10}.0A{3,8}.0A{ 14,19}]icosa-3(8), 4, 6, 9, 14(19), 15,17-heptaen- 13- one;(lR,HR)-18-(difluoromethoxy)-5-{4-[(dimethylphosphoryl)methyl]phenyl}-12-methyl-2,9,12-triazapentacyclo[9.8.1.0A{2,10}.0A{3,8}.0A{ 14,19}]icosa-3(8),4,6,9,14(19),15,17- heptaen-13-one;( 1 R, 11 R)- 18-(difluoromethoxy)-5 - [4-(dimethylphosphoryl)-2, 3 -difluorophenyl] -2, 9, 12- triazapentacyclo[9.8.1.0A{2,10}.0A{3,8}.0A{ 14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13- one;(lR,HR)-18-(difluoromethoxy)-5-[4-(dimethylphosphoryl)-3,5-difluorophenyl]-2,9,12- triazapentacyclo[9.8.1.0A{2,10}.0A{3,8}.0A{ 14,19}]icosa-3(8),4,6,9,14(19),15,17-heptaen-13- one;( 1 R, 11 R)- 18-(difluoromethoxy)-5 - [4-(dimethylphosphoryl)-2,3 -difluorophenyl] - 12- methyl-2,9,12-triazapentacyclo[9.8.1.0A{2,10}.0A{3,8}.0A{ 14,19}]icosa- 3(8), 4, 6, 9, 14(19), 15,17-heptaen- 13 -one;( 1 R, 11 R)- 18-(difluoromethoxy)-5 - [4-(dimethylphosphoryl)-3 , 5 -difluorophenyl] - 12- methyl-2,9,12-triazapentacyclo[9.8.1.0A{2,10}.0A{3,8}.0A{ 14,19}]icosa- 3(8), 4, 6, 9, 14(19), 15,17-heptaen- 13 -one;(lR,HR)-18-(difluoromethoxy)-5-{4-[(dimethylphosphoryl)methoxy]phenyl}-12- methyl-2,9,12-triazapentacyclo[9.8.1.0A{2,10}.0A{3,8}.0A{ 14,19}]icosa- 3(8), 4, 6, 9, 14(19), 15,17-heptaen- 13 -one;( 1 R, 11 R)- 18-(difluoromethoxy)-5 - { 6- [2-(dimethylphosphoryl)ethoxy ]pyridin-3 -yl } - 12- methyl-2,9,12-triazapentacyclo[9.8.1.0A{2,10}.0A{3,8}.0A{ 14,19}]icosa- 3(8), 4, 6, 9, 14(19), 15,17-heptaen- 13 -one;(lR,HR)-18-(difluoromethoxy)-5-{6-[3-(dimethylphosphoryl)propoxy]pyridin-3-yl}- 12-methyl-2,9,12-triazapentacyclo[9.8.1.0A{2,10}.0A{3,8}.0A{ 14,19}]icosa- 3(8), 4, 6, 9, 14(19), 15,17-heptaen- 13 -one;(1R,1 lR)-5-[2-chloro-4-(dimethylphosphoryl)phenyl]-18-(difluoromethoxy)-2,9,12- tri azapentacyclo[9.8.1.0A{2, 10}.0A{3,8}.0A{ 14,19}]icosa-3(8), 4, 6, 9, 14(19), 15,17-heptaen- 13- one;(1R,1 lR)-18-(difluoromethoxy)-5-{2-[(dimethylphosphoryl)methoxy]-l,3-thiazol-5-yl}- 2,9,12-triazapentacyclo[9.8.1.0A{2,10}.0A{3,8}.0A{ 14,19}]icosa-3(8),4,6,9,14(19),15,17- heptaen-13-one;(lR,HR)-18-(difluoromethoxy)-5-[4-(dimethylphosphoryl)-3-fluorophenyl]-2,9,12- tri azapentacyclo[9.8.1.0A{2, 10}.0A{3,8}.0A{ 14,19}]icosa-3(8), 4, 6, 9, 14(19), 15,17-heptaen- 13- one;(lR,HR)-18-(difluoromethoxy)-5-{4-[(dimethylphosphoryl)methoxy]phenyl}-12-ethyl- 2,9,12-triazapentacyclo[9.8.1.0A{2,10}.0A{3,8}.0A{ 14,19}]icosa-3(8),4,6,9,14(19),15,17- heptaen-13-one;(lR,HR)-18-(difluoromethoxy)-5-[4-(dimethylphosphoryl)-3-fluorophenyl]-12-ethyl-2,9,12-triazapentacyclo[9.8.1.0A{2,10}.0A{3,8}.0A{ 14,19}]icosa-3(8),4,6,9,14(19),15,17- heptaen-13-one;( 1 R, 11 R)- 18-(difluoromethoxy)-5 - [4-(dimethylphosphoryl)-3 , 5 -difluorophenyl] - 12- ethyl-2,9,12-triazapentacyclo[9.8.1.0A{2,10}.0A{3,8}.0A{ 14,19}]icosa-3(8),4,6,9,14(19),15,17- heptaen-13-one;(lR,HR)-12-cyclopropyl-18-(difluoromethoxy)-5-[6-(dimethylphosphoryl)pyridin-3-yl]-2,9,12-triazapentacyclo[9.8.1.0A{2,10}.0A{3,8}.0A{ 14,19}]icosa-3(8),4,6,9,14(19),15,17- heptaen-13-one;(lR,HR)-12-cyclopropyl-18-(difluoromethoxy)-5-[4-(dimethylphosphoryl)-3- fluorophenyl]-2,9,12-triazapentacyclo[9.8.1.0A{2,10}.0A{3,8}.0A{ 14,19}]icosa- 3(8), 4, 6, 9, 14(19), 15,17-heptaen- 13 -one;(lR,HR)-18-(difluoromethoxy)-5-[4-(dimethylphosphoryl)phenyl]-12-ethyl-2,9,12- tri azapentacyclo[9.8.1.0A{2, 10}.0A{3,8}.0A{ 14,19}]icosa-3(8), 4, 6, 9, 14(19), 15,17-heptaen- 13- one;(lR,HR)-18-(difluoromethoxy)-5-{4-[(dimethylphosphoryl)amino]phenyl}-12-methyl-2,9,12-triazapentacyclo[9.8.1.0A{2,10}.0A{3,8}.0A{ 14,19}]icosa-3(8),4,6,9,14(19),15,17- heptaen-13-one;(lR,HR)-5-[4-(diethylphosphoryl)-3-fluorophenyl]-18-(difluoromethoxy)-2,9,12- tri azapentacyclo[9.8.1.0A{2, 10}.0A{3,8}.0A{ 14,19}]icosa-3(8), 4, 6, 9, 14(19), 15,17-heptaen- 13- one;(7R, 14R)- 1 -(difluoromethoxy)- 11 -(4-(dimethylphosphoryl)-2,3-difluorophenyl)-6- (methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,4]diazocin-5(14H)- one;(7R, 14R)-1 -(difluoromethoxy)- 1 l-(4-(dimethylphosphoryl)-2-fluorophenyl)-6-(m ethyl- d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,4]diazocin-5(14H)-one;(7R,14R)-l-(difluoromethoxy)-l l-(4-(dimethylphosphoryl)-2,5-difluorophenyl)-6- (methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,4]diazocin-5(14H)- one;(17?,117?)-18-(difluoromethoxy)-5-[4-(dimethylphosphoryl)-2,3-difluorophenyl]-6- fluoro-12-methyl-2,9,12-triazapentacyclo[9.8.1.0A{2,10}.0A{3,8}.0A{ 14,19}]icosa- 3(8), 4, 6, 9, 14(19), 15,17-heptaen- 13 -one;( 1 R, 11 R)- 18-(difluoromethoxy)-5 - [4-(dimethylphosphoryl)-2, 5 -difluorophenyl] - 12- methyl-2,9,12-triazapentacyclo[9.8.1.0A{2,10}.0A{3,8}.0A{ 14,19}]icosa- 3(8), 4, 6, 9, 14(19), 15,17-heptaen- 13 -one;(17?,117?)-18-(difluoromethoxy)-5-[4-(dimethylphosphoryl)-3-fluorophenyl]-6-fluoro-12- methyl-2,9,12-triazapentacyclo[9.8.1.0A{2,10}.0A{3,8}.0A{ 14,19}]icosa- 3(8), 4, 6, 9, 14(19), 15,17-heptaen- 13 -one;(17?,117?)-18-(difluoromethoxy)-5-[4-(dimethylphosphoryl)-2-fluorophenyl]-6-fluoro-12- methyl-2,9,12-triazapentacyclo[9.8.1.0A{2,10}.0A{3,8}.0A{ 14,19}]icosa- 3(8), 4, 6, 9, 14(19), 15,17-heptaen- 13 -one;(7R, 14R)- 1 -(difluoromethoxy)- 11 -(4-(dimethylphosphoryl)-3 -fluorophenyl)- 10-fluoro-6- (methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,4]diazocin-5(14H)- one;(7R, 14R)- 1 -(difluoromethoxy)- 11 -(4-(dimethylphosphoryl)-3 , 5-difluorophenyl)-6- (methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,4]diazocin-5(14H)- one;(7R, 14R)- 1 -(difluoromethoxy)- 11 -(4-(dimethylphosphoryl)-2-fluorophenyl)- 10-fluoro-6- (methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,4]diazocin-5(14H)- one;(1R,1 lR)-18-(difluoromethoxy)-5-[4-(dimethylphosphoryl)-2,6-difluorophenyl]-12- methyl-2,9,12-triazapentacyclo[9.8.1.0A{2,10}.0A{3,8}.0A{ 14,19}]icosa- 3(8), 4, 6, 9, 14(19), 15,17-heptaen- 13 -one;(7R, 14R)-1 -(difluoromethoxy)- 1 l-(4-(dimethylphosphoryl)-2,6-difluorophenyl)-6- (methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,4]diazocin-5(14H)- one;(7R, 14R)- 1 -(difluoromethoxy)- 11 -(4-(dimethylphosphoryl)phenyl)- 10-fluoro-6-(methyl- d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,4]diazocin-5(14H)-one;(7R,14R)-l-(difluoromethoxy)-l l-(4-(dimethylphosphoryl)phenyl)-6-(methyl-d3)-6,7- dihydro-7, 14-methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,4]diazocin-5(14H)-one;(7R, 14R)- 1 -(difluoromethoxy)- 11 -(4-(dimethylphosphoryl)-3 -fluorophenyl)- 10-fluoro- 6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,4]diazocin-5(14H)-one;(7R, 14R)- 1 -(difluoromethoxy)- 11 -(4-((dimethylphosphoryl)methyl)-2-fluorophenyl)-6- (methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,4]diazocin-5(14H)- one;(7R, 14R)- 1 -(difluoromethoxy)- 11 -(4-((dimethylphosphoryl)methyl)-3 -fluorophenyl)-6-(methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,4]diazocin-5(14H)- one;(7R, 14R)- 1 -(difluoromethoxy)- 11 -(4-((dimethylphosphoryl)methyl)-3 , 5 - difluorophenyl)-6-(methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[l,2- a] [ 1 ,4] diazocin-5 ( 14H)-one;(7R, 14R)-1 -(difluoromethoxy)- 1 l-(4-((dimethylphosphoryl)methyl)phenyl)-6-(m ethyl- d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,4]diazocin-5(14H)-one;(7R,14R)-1 l-(4-(dimethylphosphoryl)-2,5-difluorophenyl)-l-hydroxy-6-(methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,4]diazocin-5(14H)-one;(7R, 14R)- 1 -(difluoromethoxy)- 11 -(4-((dimethylphosphoryl)methyl)-3 -fluorophenyl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,4]diazocin-5(14H)-one;(7R,14R)-l-(difluoromethoxy)-l l-(4-((dimethylphosphoryl)methyl)-2,5- difluorophenyl)-6-methyl-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[l,2- a] [ 1 ,4] diazocin-5 ( 14H)-one;(7R,14R)-1 l-(4-(dimethylphosphoryl)-2,5-difluorophenyl)-l-methoxy-6-(methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,4]diazocin-5(14H)-one;(7R,14R)-1 l-(4-(dimethylphosphoryl)-2,5-difluorophenyl)-l-ethoxy-6-(methyl-d3)-6,7- dihydro-7, 14-methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,4]diazocin-5(14H)-one;(7R, 14R)- 1 -(difluoromethoxy)- 11 -(4-((dimethylphosphoryl)methyl)-2,3- difluorophenyl)-6-(methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[l,2- a] [ 1 ,4] diazocin-5 ( 14H)-one;(7R, 14R)- 1 -(difluoromethoxy)- 11 -(4-((dimethylphosphoryl)methyl)-3 , 5 - difluorophenyl)-6-methyl-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[l,2- a] [ 1 ,4] diazocin-5 ( 14H)-one;(7R, 14R)- 1 -(difluoromethoxy)- 11 -(4-((dimethylphosphoryl)methyl)-3 -fluorophenyl)- 10- fluoro-6-(methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,4]diazocin- 5(14H)-one;(7R, 14R)- 1 -(difluoromethoxy)- 11 -(4-((dimethylphosphoryl)methyl)-3 -fluorophenyl)-6- methyl-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,4]diazocin-5(14H)-one;(7R, 14R)- 1 -(difluoromethoxy)- 11 -(4-((dimethylphosphoryl)methyl)-2-fluorophenyl)-6- methyl-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,4]diazocin-5(14H)-one;(7R, 14R)- 1 -(difluoromethoxy)- 11 -(4-((dimethylphosphoryl)methyl)-3 , 5 - difluorophenyl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,4]diazocin- 5(14H)-one;(7R,14R)-l-(difluoromethoxy)-l l-(4-((dimethylphosphoryl)methyl)-2,5- difluorophenyl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,4]diazocin- 5(14H)-one; dimethyl (4-((7R, 14R)-l-(difluoromethoxy)-6-(methyl-d3)-5-oxo-5,6,7, 14-tetrahydro- 7, 14-methanobenzo[f]benzo[4, 5]imidazo[ 1 ,2-a] [ 1 ,4]diazocin- 11 -yl)benzyl)phosphonate;(7R, 14R)- 1 -(difluoromethoxy)- 11 -(4-((dimethylphosphoryl)(hydroxy)methyl)phenyl)-6- (methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,4]diazocin-5(14H)- one;(7R, 14R)-1 -(difluoromethoxy)- 1 l-(4-((S or R)-l-(dimethylphosphoryl)ethyl)phenyl)-6- (methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,4]diazocin-5(14H)- one ;(7R, 14R)-1 -(difluoromethoxy)- 1 l-(4-((R or S)-l-(dimethylphosphoryl)ethyl)phenyl)-6- (methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,4]diazocin-5(14H)- one;(7R, 14R)-l-(difluorom ethoxy)- 1 l-(6-(dimethylphosphoryl)-4-methylpyri din-3 -yl)-6- (methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,4]diazocin-5(14H)- one;(7R,14R)-l-(difluoromethoxy)-l l-(4-(dimethylphosphoryl)-5-fluoro-2-methylphenyl)-6- (methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,4]diazocin-5(14H)- one;(7R, 14R)- 1 -(difluoromethoxy)- 11 -(6-(dimethylphosphoryl)-4-methylpyri din-3 -yl)-10- fluoro-6-(methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,4]diazocin- 5(14H)-one;(7R, 14R)- 1 -(difluoromethoxy)- 11 -(4-(dimethylphosphoryl)-3 -fluoro-2-methylphenyl)-6- (methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,4]diazocin-5(14H)- one;(7R, 14R)-l-(difluorom ethoxy)- 1 l-(6-(dimethylphosphoryl)-2-methylpyri din-3 -yl)-6- (methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,4]diazocin-5(14H)- one;(7R, 14R)- 1 -(difluoromethoxy)- 11 -(6-(dimethylphosphoryl)-2-fluoropyri din-3 -yl)-6- (methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,4]diazocin-5(14H)- one;(7R,14R)-1 l-(4-chl oro-6-(dimethylphosphoryl)pyri din-3 -yl)-l-(difluoromethoxy)-6- (methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,4]diazocin-5(14H)- one;(7R,14R)-1 l-(2-chl oro-6-(dimethylphosphoryl)pyri din-3 -yl)-l-(difluoromethoxy)-6- (methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,4]diazocin-5(14H)- one;(7R, 14R)- 1 -(difluoromethoxy)- 11 -(4-((dimethylphosphoryl)difluoromethyl)phenyl)-6- (methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,4]diazocin-5(14H)- one;(7R, 14R)- 1 -(difluoromethoxy)- 11 -(4-((dimethylphosphoryl)methyl)-2-fluorophenyl)- 6,7-dihydro-7,14-methanobenzo[ / ]benzo[4,5]imidazo[l,2-a][l,4]diazocin-5(14J7)-one;(7R, 14R)- 1 -(difluoromethoxy)- 11 -(6-(dimethylphosphoryl)-2-methylpyri din-3 -yl)-10- fluoro-6-(methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,4]diazocin- 5(14H)-one;(7R, 14R)-l-(difluorom ethoxy)- 1 l-(6-(((dimethylphosphoryl)methyl)amino)pyri din-3- yl)-6-(methyl-t / 3)-6,7-dihydro-7,14-methanobenzo[ / ]benzo[4,5]imidazo[l,2-a][l,4]diazocin- 5(14J7)-one;(7R, 14R)-1 -(difluoromethoxy)- 1 l-(4-((S or R)-l-(dimethylphosphoryl)ethyl)-3- fluorophenyl)-6-(methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[l,2- a][l,4]diazocin-5(14H)-one ;(7R, 14R)-1 -(difluoromethoxy)- 1 l-(4-((R or S)-l-(dimethylphosphoryl)ethyl)-3- fluorophenyl)-6-(methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[l,2- a] [ 1 ,4] diazocin-5 ( 14H)-one;(7R, 14R)- 11 -(4-((diethylphosphoryl)(hydroxy)methyl)phenyl)- 1 -(difluoromethoxy)-6- (methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,4]diazocin-5(14H)- one;(7R,14R)-l-(difluoromethoxy)-l l-(2-(difluoromethyl)-4-(dimethylphosphoryl)phenyl)- 6-(methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,4]diazocin- 5(14H)-one;(7R, 14R)- 1 -(difluoromethoxy)- 11 -(3 -(difluoromethyl)-4-(dimethylphosphoryl)phenyl)- 6-(methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,4]diazocin- 5(14H)-one;(7R, 14R)- 1 -(difluoromethoxy)- 11 -(4-(dimethylphosphoryl)-2-(trifluoromethyl)phenyl)- 6-(methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,4]diazocin- 5(14H)-one;(7Rfl 4R)-l-(difluorom ethoxy)- 1 l-(4-(dimethylphosphoryl)-3-methylphenyl)-6-(m ethyl- d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,4]diazocin-5(14H)-one;(7R, 14R)- 1 -(difluoromethoxy)- 11 -(4-(dimethylphosphoryl)-3 -fluoro-5 -methylphenyl)-6- (methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,4]diazocin-5(14H)- one;(7R, 14R)- 1 -(difluoromethoxy)- 11 -(4-(dimethylphosphoryl)-2-fluoro-3 -methylphenyl)-6- (methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,4]diazocin-5(14H)- one;(7R,14R)-l-(difluoromethoxy)-l l-(4-((dimethylphosphoryl)methyl)-5-fluoro-2- methylphenyl)-6-(methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[l,2- a] [ 1 ,4] diazocin-5 ( 14H)-one;(7R, 14R)-1 -(difluoromethoxy)- 1 l-(4-((R or S)-l-(dimethylphosphoryl)ethyl)-3,5- difluorophenyl)-6-(methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[l,2- a] [ 1 ,4] diazocin-5 ( 14H)-one;(7R, 14R)-1 -(difluoromethoxy)- 1 l-(4-((S or R)-l-(dimethylphosphoryl)-l- hydroxyethyl)phenyl)-6-(methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[l,2- a][l,4]diazocin-5(14H)-one ;(7R, 14R)-1 -(difluoromethoxy)- 1 l-(4-((R or S)-l-(dimethylphosphoryl)-l- hydroxyethyl)phenyl)-6-(methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[l,2- a] [ 1 ,4] diazocin-5 ( 14H)-one;(7R, 14R)-1 -(difluoromethoxy)- 1 l-(4-((S or R)-l-(dimethylphosphoryl)ethyl)-3,5- difluorophenyl)-6-(methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[l,2- a] [ 1 ,4] diazocin-5 ( 14H)-one;(7R, 14R)-1 -(difluoromethoxy)- 1 l-(4-((R or S)-l-(dimethylphosphoryl)ethyl)-3-fluoro-2- methylphenyl)-6-(methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[l,2- a][l,4]diazocin-5(14H)-one ;(7R, 14R)-1 -(difluoromethoxy)- 1 l-(4-((S or R)-l-(dimethylphosphoryl)ethyl)-3-fluoro-2- methylphenyl)-6-(methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[l,2- a] [ 1 ,4] diazocin-5 ( 14H)-one;(7R, 14R)- 1 -(difluoromethoxy)- 11 -(5 -(dimethylphosphoryl)-6-fluoropyridin-2-yl)-6- (methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,4]diazocin-5(14H)- one;(7R, 14R)- 1 -(difluoromethoxy)- 11 -(6-( 1 -(dimethylphosphoryl)ethyl)pyri din-3 -yl)-6- (methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,4]diazocin-5(14H)- one;(7R,14R)-1 l-(3-chloro-4-(dimethylphosphoryl)phenyl)-l-(difluoromethoxy)-6-(methyl- d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,4]diazocin-5(14H)-one;(7R, 14R)-1 -(difluoromethoxy)- 1 l-(4-((R or S)-l-(dimethylphosphoryl)ethyl)-5-fluoro-2- methylphenyl)-6-(methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[l,2- a] [ 1 ,4] diazocin-5 ( 14H)-one;(7R, 14R)-1 -(difluoromethoxy)- 1 l-(4-((S or R)-l-(dimethylphosphoryl)ethyl)-5-fluoro-2- methylphenyl)-6-(methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[l,2- a] [ 1 ,4] diazocin-5 ( 14H)-one;(7R,14R)-l-(difluorom ethoxy)- l l-(6-(2-(dimethylphosphoryl)propan-2-yl)pyri din-3 -yl)- 6-(methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,4]diazocin- 5(14H)-one;(7R, 14R)- 11 -(6-chloro-5-(dimethylphosphoryl)pyri din-2 -yl)- 1 -(difluoromethoxy)-6- (methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,4]diazocin-5(14H)- one;(7R, 14R)- 1 -(difluoromethoxy)- 11 -(4-(dimethylphosphoryl)-3 -(trifluoromethyl)phenyl)- 6-(methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,4]diazocin- 5(14H)-one;(7R, 14R)- 1 -(difluoromethoxy)- 11 -(5 -(dimethylphosphoryl)-4-fluoro-6-methylpyridin-2- yl)-6-(methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,4]diazocin- 5(14H)-one;(7R,14R)-l-(difluoromethoxy)-l l-(6-(dimethylphosphoryl)-5-fluoropyridin-3-yl)-6- (methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,4]diazocin-5(14H)- one;(7R,14R)-1 l-(4-(di ethylphosphoryl)-3 -fluorophenyl)- l-(difluoromethoxy)-6-(m ethyl- d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,4]diazocin-5(14H)-one;(7R,14R)-l l-(6-(diethylphosphoryl)pyridin-3-yl)-l-(difluoromethoxy)-6-(methyl-d3)- 6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,4]diazocin-5(14H)-one;(7R,14R)-l l-(6-(diethylphosphoryl)-5-fluoropyridin-3-yl)-l-(difluoromethoxy)-6- (methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,4]diazocin-5(14H)- one;(7R, 14R)- 11 -(4-(dimethylphosphoryl)-3 -fluorophenyl)-6-(methyl-d3 )- 1 - (trifluoromethoxy )-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,4]diazocin- 5(14H)-one;(7R, 14R)- 1 -(difluoromethoxy)- 11 -(4-(dimethylphosphoryl)-3 -fluoro-5-methoxyphenyl)- 6-(methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,4]diazocin- 5(14H)-one;(7R,14R)-l-(difluoromethoxy)-l l-(4-(dimethylphosphoryl)-5-fluoro-2-methoxyphenyl)- 6-(methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,4]diazocin- 5(14H)-one;(7R, 14R)- 11 -(3 -amino-4-(dimethylphosphoryl)-5 -fluorophenyl)- 1 -(difluoromethoxy)-6- (methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,4]diazocin-5(14H)- one;(7R, 14R)- 1 -(difluoromethoxy)- 11 -(5 -(dimethylphosphoryl)-6-fluoro-4-methylpyridin-2- yl)-6-(methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,4]diazocin- 5(14H)-one;5-((7R,14R)-l-(difluoromethoxy)-6-(methyl-d3)-5-oxo-5,6,7,14-tetrahydro-7,14- methanobenzo[f]benzo[4, 5]imidazo[ 1 ,2-a] [ 1 , 4] di azocin- 11 -yl)-2-(dimethylphosphoryl)-3 - fluorobenzonitrile;(7R,14R)-l-(difluoromethoxy)-l l-(6-(dimethylphosphoryl)-5-methylpyridin-3-yl)-6- (methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,4]diazocin-5(14H)- one;(7R, 14R)- 1 -(difluoromethoxy)- 11 -(4-(dimethylphosphoryl)-3 -fluorophenyl)-9-fluoro-6- (methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,4]diazocin-5(14H)- one; dimethyl (4-((7R, 14R)-l-(difluoromethoxy)-6-(methyl-d3)-5-oxo-5,6,7, 14-tetrahydro- 7, 14-methanobenzo[f]benzo[4, 5]imidazo[ 1 ,2-a] [ 1 ,4]diazocin- 11 -yl)-2- fluorobenzyl)phosphonate;(7R, 14R)- 11 -(6-(diethylphosphoryl)pyri din-3 -yl)- 1 -(difluoromethoxy)-6, 7-dihy dro-7, 14- methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,4]diazocin-5(14H)-one;(7R,14R)-l l-(4-(diethylphosphoryl)-2-fluorophenyl)-l-(difluoromethoxy)-6,7-dihydro- 7,14-methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,4]diazocin-5(14H)-one;(7R, 14R)- 1 -(difluoromethoxy)- 11 -(4-(dimethylphosphoryl)-3 -fluorophenyl)- 12-fluoro-6- (methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,4]diazocin-5(14H)- one;(7R, 14R)- 1 -(difluoromethoxy)- 11 -(4-(dimethylphosphoryl)-3 -fluorophenyl)- 12-fluoro- 6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,4]diazocin-5(14H)-one;(7R, 14R)-1 -(difluoromethoxy)- 1 l-(4-(dimethylphosphoryl)-3-fluorophenyl)-6-(m ethyl- d3)-6,7-dihydro-7,14-methanobenzo[f]pyrido[3',2':4,5]imidazo[l,2-a][l,4]diazocin-5(14H)-one; and(7R,14R)-l-(difluoromethoxy)-l l-(4-(dimethylphosphoryl)-2,5-difluorophenyl)-6- (methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]pyrido[3',2':4,5]imidazo[l,2-a][l,4]diazocin- 5(14H)-one.Indications

[0072] In some embodiments, the inflammatory or autoimmune disease is selected from the group consisting of rheumatoid arthritis, inflammatory bowel disease, psoriatic arthritis, psoriasis, and ankylosing spondylitis.

[0073] In some embodiments, the inflammatory or autoimmune disease is selected from the group consisting of Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, treatment resistant depression, and tinnitus.

[0074] In some embodiments the inflammatory or autoimmune disease is selected from the group consisting of rheumatoid arthritis, psoriatic arthritis, systemic onset juvenile idiopathic arthritis, multiple sclerosis, lupus nephritis, systemic lupus erythematosus, psoriasis, Crohn's disease, colitis, asthma, graft versus host disease, allograft rejection, chronic obstructive pulmonary disease, multiple sclerosis, Alzheimer’s disease, Graves' disease, cutaneous lupus, ankylosing spondylitis, cryopyrin-associated periodic syndromes (CAPS), gout, gouty arthritis, ulcerative TNF receptor associated periodic syndrome (TRAPS), Wegener’s granulomatosis, sarcoidosis, familial Mediterranean fever (FMF), neuropathic pain, and adult onset stills.

[0075] In other embodiments, the inflammatory or autoimmune disease is selected from the group consisting of rheumatoid arthritis (RA), psoriatic arthritis (PsA), psoriasis, juvenile idiopathic arthritis (JIA), ankylosing spondylitis (AS), inflammatory bowel diseases (IBD), Crohn’s disease, ulcerative colitis, systemic lupus erythematosus (SLE), spondyloarthritis (SpA), Behcet's disease, sarcoidosis, multiple sclerosis (MS), palmoplantar pustulosis (PPP), palmoplantar pustulosis (PPP), atopic dermatitis, graft versus host disease, sepsis, neuropathicpain, fibromyalgia, Schnitzler syndrome, Blau syndrome, TNF receptor-associated periodic syndrome (TRAPS), pyogenic arthritis, pyoderma Gangrenosum, and chronic recurrent multifocal osteomyelitis (CRMO).

[0076] In some embodiments, the inflammatory or autoimmune disease is rheumatoid arthritis. In some embodiments, the inflammatory or autoimmune disease is psoriatic arthritis. In some embodiments, the psoriatic arthritis is juvenile psoriatic arthritis. In some embodiments, the inflammatory or autoimmune disease is juvenile idiopathic arthritis. In some embodiments, the juvenile idiopathic arthritis is polyarticular juvenile idiopathic arthritis, or systemic onset juvenile idiopathic arthritis. In some embodiments, the inflammatory or autoimmune disease is juvenile enthesitis-related arthritis.

[0077] In some embodiments, the inflammatory or autoimmune disease is ankylosing spondylitis. In some embodiments, the inflammatory or autoimmune disease is axial spondyloarthritis. In some embodiments, the axial spondyloarthritis is non-radiographic axial spondyloarthritis. In some embodiments, the inflammatory or autoimmune disease is spondyloarthropathy.

[0078] In some embodiments, the inflammatory or autoimmune disease is multiple sclerosis.

[0079] In some embodiments, the inflammatory or autoimmune disease is lupus nephritis.

[0080] In some embodiments, the inflammatory or autoimmune disease is systemic lupus erythematosus.

[0081] In some embodiments, the inflammatory or autoimmune disease is psoriasis. In some embodiments, the inflammatory or autoimmune disease is plaque psoriasis. In some embodiments, the plaque psoriasis is pediatric plaque psoriasis or chronic severe plaque psoriasis.

[0082] In some embodiments, the inflammatory or autoimmune disease is Crohn's disease. In some embodiments, the Crohn's disease is pediatric Crohn's disease. In some embodiments, the inflammatory or autoimmune disease is fistulizing Crohn's disease.

[0083] In some embodiments, the inflammatory or autoimmune disease is Inflammatory Bowel Disease (IBD). In some embodiments, the Inflammatory Bowel Disease (IBD) is Crohn' s-like IBD.

[0084] In some embodiments, the inflammatory or autoimmune disease is colitis. In some embodiments, the colitis is ulcerative colitis or pediatric ulcerative colitis. In some embodiments, the inflammatory or autoimmune disease is enterocolitis.

[0085] In some embodiments, the inflammatory or autoimmune disease is graft versus host disease. In some embodiments, the inflammatory or autoimmune disease is allograft rejection.

[0086] In some embodiments, the inflammatory or autoimmune disease is multiple sclerosis.

[0087] In some embodiments, the inflammatory or autoimmune disease is Alzheimer’s disease.

[0088] In some embodiments, the inflammatory or autoimmune disease is Graves' disease.

[0089] In some embodiments, the inflammatory or autoimmune disease is cutaneous lupus.

[0090] In some embodiments, the inflammatory or autoimmune disease is cryopyrin- associated periodic syndromes (CAPS).

[0091] In some embodiments, the inflammatory or autoimmune disease is gout or gouty arthritis.

[0092] In some embodiments, the inflammatory or autoimmune disease is ulcerative TNF receptor associated periodic syndrome (TRAPS).

[0093] In some embodiments, the inflammatory or autoimmune disease is granulomatous disease. In some embodiments, the inflammatory or autoimmune disease is Wegener’s granulomatosis.

[0094] In some embodiments, the inflammatory or autoimmune disease is sarcoidosis.

[0095] In some embodiments, the inflammatory or autoimmune disease is familialMediterranean fever (FMF).

[0096] In some embodiments, the inflammatory or autoimmune disease is neuropathic pain.

[0097] In some embodiments, the inflammatory or autoimmune disease is adult onset stills.

[0098] In some embodiments, the inflammatory or autoimmune disease is selected from the group consisting of inflammatory arthritis, vasculitis, pemphigus vulgaris (PV), oligoarthritis, steroid-refractory acute graft versus host disease (Sr-aGvHD), chronic beryllium disease (CBD), pustular psoriasis, Takayasu's arteritis, uveitis, immune-mediated colitis, enthesitis, myocardial inflammation, hidradenitis suppurativa, systemic sclerosis and myositis. Patient Selection

[0099] One embodiment provides a method of treating an inflammatory or autoimmune disease in a patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising (7R, 14R)-l-(difluorom ethoxy)- 11 -(4-(dimethylphosphoryl)-3 - fluorophenyl)- 10-fluoro-6-(methyl-d3 )-6, 7-dihy dro-7, 14-methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,4]diazocin-5(14H)-one, or pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient, wherein the patient has been excluded from biologic TNFa therapy.

[0100] One embodiment provides a method of treating an inflammatory or autoimmune disease in a patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising (7R, 14R)-l-(difluorom ethoxy)- 11 -(4-(dimethylphosphoryl)-3 - fluorophenyl)- 10-fluoro-6-(methyl-d3 )-6, 7-dihy dro-7, 14- methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,4]diazocin-5(14H)-one, or pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient, wherein the patient has a demyelinating disease of the CNS. Another embodiment provides the method wherein the demyelinating disease is multiple sclerosis. Another embodiment provides the method wherein the demyelinating disease is selected from the group consisting of optic neuritis, neuromyelitis optica spectrum disorder, myelin oligodendrocyte glycoprotein antibody- associated disease, transverse myelitis, and acute disseminated encephalomyelitis.

[0101] One embodiment provides a method of treating an inflammatory or autoimmune disease in a patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising (7R, 14R)-l-(difluorom ethoxy)- 11 -(4-(dimethylphosphoryl)-3 - fluorophenyl)- 10-fluoro-6-(methyl-d3 )-6, 7-dihy dro-7, 14- methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,4]diazocin-5(14H)-one, or pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient, wherein the patient exhibits polymorphism or mutations in TNFa pathway relevant loci. Another embodiment provides the method wherein the polymorphism or mutations in TNFa pathway relevant loci is determined by QPCR or hybridization technique. Another embodiment provides the method wherein the polymorphism or mutations in TNFa pathway relevant loci is determined by detection of proteins by ELISA or histology.

[0102] One embodiment provides a method of treating an inflammatory or autoimmune disease in a patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising (7R, 14R)-l-(difluorom ethoxy)- 11 -(4-(dimethylphosphoryl)-3 - fluorophenyl)- 10-fluoro-6-(methyl-d3 )-6, 7-dihy dro-7, 14- methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,4]diazocin-5(14H)-one, or pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient, wherein the patient has anti-drug antibodies to a TNFa biologic therapeutic. Another embodiment provides the method, wherein the patient desires to switch from an alternative therapy. One embodiment provides a method of treating an inflammatory or autoimmune diseasein a patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising (7R, 14R)-l-(difluorom ethoxy)- 11 -(4-(dimethylphosphoryl)-3 - fluorophenyl)- 10-fluoro-6-(methyl-d3 )-6, 7-dihy dro-7, 14- methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,4]diazocin-5(14H)-one, or pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient, wherein the patient is a secondary non-responder to TNFa biologic therapy.Administration

[0103] Provided herein is the method wherein the pharmaceutical composition is administered orally. Provided herein is the method wherein the pharmaceutical composition is administered by injection.

[0104] Another embodiment provides the method, wherein the oral administration occurs every other day, once per day, twice per day, or three times per day.Pharmaceutical Compositions

[0105] In certain embodiments, the heterocyclic TNFR1 inhibitor described herein is administered as a pure chemical. In other embodiments, the heterocyclic TNFR1 inhibitor described herein is combined with a pharmaceutically suitable or acceptable carrier (also referred to herein as a pharmaceutically suitable or acceptable excipient, a physiologically suitable or acceptable excipient, or a physiologically suitable or acceptable carrier) selected on the basis of a chosen route of administration and standard pharmaceutical practice.

[0106] Provided herein is a pharmaceutical composition comprising the heterocyclic TNFR1 inhibitor as described herein, or a stereoisomer, pharmaceutically acceptable salt, hydrate, or solvate thereof, together with one or more pharmaceutically acceptable carriers. The carrier(s) (or excipient(s)) is acceptable or suitable if the carrier is compatible with the other ingredients of the composition and not deleterious to the recipient (i.e., the subject or the patient) of the composition.

[0107] One embodiment provides a method of preparing a pharmaceutical composition comprising mixing the heterocyclic TNFR1 inhibitor as described herein, or a stereoisomer, pharmaceutically acceptable salt, hydrate, or solvate thereof, and a pharmaceutically acceptable carrier.

[0108] Provided herein is the method wherein the pharmaceutical composition is administered orally. Suitable oral dosage forms include, for example, tablets, pills, sachets, or capsules of hard or soft gelatin, methylcellulose or of another suitable material easily dissolved in the digestive tract. In some embodiments, suitable nontoxic solid carriers are used which include, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate,sodium saccharin, talcum, cellulose, glucose, sucrose, magnesium carbonate, and the like. (See, e.g., Remington: The Science and Practice of Pharmacy (Gennaro, 21stEd. Mack Pub. Co., Easton, PA (2005)).

[0109] Provided herein is the method wherein the pharmaceutical composition is administered by injection. In some embodiments, the heterocyclic TNFR1 inhibitor as described herein, or pharmaceutically acceptable salt or solvate thereof, is formulated for administration by injection. In some instances, the injection formulation is an aqueous formulation. In some instances, the injection formulation is a non-aqueous formulation. In some instances, the injection formulation is an oil-based formulation, such as sesame oil, or the like.

[0110] The dose of the composition comprising the heterocyclic TNFR1 inhibitor as described herein, or a stereoisomer, pharmaceutically acceptable salt, hydrate, or solvate thereof, differs depending upon the subject or patient's (e.g., human) condition. In some embodiments, such factors include general health status, age, and other factors. Pharmaceutical compositions are administered in a manner appropriate to the disease to be treated (or prevented). An appropriate dose and a suitable duration and frequency of administration will be determined by such factors as the condition of the patient, the type and severity of the patient's disease, the particular form of the active ingredient, and the method of administration. In general, an appropriate dose and treatment regimen provides the composition(s) in an amount sufficient to provide therapeutic and / or prophylactic benefit (e.g., an improved clinical outcome, such as more frequent complete or partial remissions, or longer disease-free and / or overall survival, or a lessening of symptom severity. Optimal doses are generally determined using experimental models and / or clinical trials. The optimal dose depends upon the body mass, weight, or blood volume of the patient.EXAMPLES

[0111] These examples are provided for illustrative purposes only and not to limit the scope of the claims provided herein.Example 1: TNF-oc Binding Activity of Compound 1Binding activity

[0112] METHOD. Compounds were received in DMSO. Serial dilutions of 1 :2.5 were prepared for 10 total concentrations per compound (top concentration 1 pM final). The compounds were dispensed into the assay plate using an ECHO 655, adding 50 nL to each assay plate. Assay buffer was prepared containing 20 mM Hepes pH 7.5 (Gibco), 10 mM MgCh (Sigma), 0.015% Brij-35 (Thermo), 4 mM dithiothreitol (Sigma), and 0.05 mg / mL bovine serumalbumin (Solarbio). A 2* concentration of anti-his antibody Tb-labeled (Cis Bio) was prepared in assay buffer. A 2* His-TNF concentration was added (in-house) to a final assay concentration of 8 nM. 2* antibody stock was added to each assay plate (final assay concentration 0.2nM) and preincubated with the compound for 1 h at room temperature. 10 pL of a fluorescent probe (Xiao et al. J Med. Chem. 2020 63: 15050-15071) was added to all wells (final concentration lOOnM). Assay plates were covered again and incubated for 3 h at room temperature. Plates were read at an excitation of 340 nm and a dual emission of 490 and 520 nm. Data obtained were used to plot dose response curves using XLfit data analysis software processing tool.TABLE 1

[0113] RESUTS. The binding of Compound 1 to soluble TNFa was determined using an HTRF based probe displacement assay. Compound l is a high potency, soluble TNF-a binding molecule.Example 2: Compound 1 Selectively Inhibits Soluble TNFa Function in Cell CultureFunctional activity in vitro

[0114] METHOD. Compound 1 functional activity was evaluated in vitro in cellular assay format. HEK-Blue TNFa SEAP (InvivoGen) reporter cells express TNF receptor 1 (TNFR1) and allow the measurement of soluble TNFa signaling via TNFR1. HEK-Blue CD40L SEAP (InvivoGen) reporter cells express CD40 and allow the measurement of CD40L signaling via CD40. HEK-Blue TNFa SEAP and HEK-Blue CD40L SEAP cells were grown according to the manufacturer’s instructions. Compounds were received in DMSO. Serial dilutions of 1 :2.5 were prepared for 10 total concentrations per compound (top concentration 3, 10 or 50 pM final) and 45 nL added to 384-well polypropylene cell culture plates. For the HEK-Blue TNFa SEAP Reporter Assay 10,000 cells are added to each well in 40 pL culture media. An aliquot of 5 pL TNFa (R&D) is then added into each well to a final concentration of 500 pg / mL. The plates are then incubated for 18 h at 37 °C with 5% CO2. For the HEK-Blue CD40L SEAP Reporter Assay 10,000 cells are added to each well in 40 pL test media. An aliquot of 5 pL CD40L (InvivoGen) is then added into each well to a final concentration of 150 ng / mL. The plates are then incubated for 18 h at 37 °C with 5% CO2.

[0115] SEAP activities mediated via TNFa or CD40L are assessed using the QUANTI- Blue reagent (InvivoGen) with optical absorbance readouts at 620 nm. Percent inhibition iscalculated based on the average signals of the stimulated and unstimulated controls and is reported in Table 2. Data obtained were used to plot dose response curves using XLfit data analysis software processing tool.TABLE 2

[0116] RESULTS. Compound 1 demonstrated potent inhibition of human soluble TNFa signaling via TNFR1 in the HEK-Blue TNFa cellular reporter assay. No activity was detected in the HEK-Blue CD40L reporter demonstrating the high selectivity of compound 1.Example 3: Compound 1 Demonstrates Activity in an Animal Model of Acute Inflammatory StimulusLPS induced cytokine model

[0117] MODEL DESCRIPTION. The acute Lipopolysaccharide (LPS) challenge model is an in vivo model of TLR4 and cytokine signaling. The LPS assay evaluates the ability to respond to an inflammatory stimulus by mounting an acute phase response. TNFa enhances the production of cytokines in this model, enhancing the production of IL-6 and MCP-1 in response to LPS stimulation. This model allows the measurement of TNF-a pathway modulators in vivo.

[0118] METHOD. Briefly, Compound 1 was added to 0.5% MC, and 0.1% Tween 80 (oral vehicle) with vortexing and sonication to obtain a suspension. Etanercept was diluted in PBS (intraperitoneal vehicle) before each injection. Lipopolysaccharide (LPS) was dissolved in saline solution to a final concentrations of 1 mg / ml.

[0119] Mice in experimental group 7 were intraperitoneal injected with Etanercept 16 hours before LPS stimulation (day 0). On day 1, mice in experimental groups 1 and 2 were orally dosed with the oral vehicle, while mice in experimental groups 3-6 were dosed with Compound 1. On day 1, 2 hours after Compound 1 administration, mice in experimental groups 2-7 were injected via intraperitoneal injection with either 10 ml / kg LPS solution or 10 ml / kg saline (experimental group 1 only).

[0120] On day 1, 3 hours after LPS injection and 5 hours after Compound 1 administration, a terminal blood collection was performed from all mice using the cardiac puncture method. Blood collected was prepared for serum separation and used for cytokinesanalysis of mouse MCP-1 and IL-6 by ELISA. Data are summarized in Fig. 2A and Fig, 2B for IL-6 and MCP-1, respectively.

[0121] RESULT. Treatment with Compound 1 significantly reduced IL-6 and MCP-1 cytokine production in LPS treated mice, demonstrating that treatment with Compound 1 can inhibit TNF-a signaling in vivo.Example 4: Compound 1 Exhibits Anti-Inflammatory Activity in an Animal Model of DiseaseMouse collagen induced arthritis

[0122] MODEL DESCRIPTION. Collagen-induced arthritis (CIA) is an experimental autoimmune disease that can be elicited in susceptible strains of rodents (e.g., DBA1 mouse) by immunization with type II collagen (CII). Following immunization, the animals develop an autoimmune-mediated polyarthritis that shares several clinical, histological, and immunological features with human rheumatoid arthritis.

[0123] METHOD. Collagen II was prepared in 100 mM acetic acid to a final concentration of 8 mg / mL. Collagen solution was emulsified in an equal volume of CFA on ice for 1 hour, using a high-speed homogenizer (30,000 rpm). Mice were immunized with the collagen-CFA emulsion (study day 0). Three weeks later, the collagen-CFA emulsion was injected for booster immunization (study day 21).

[0124] TREATMENT. When the average arthritis score of immunized mice reached 1-2 (study day 28), the model groups were selected and divided into treatment groups (n=18). Treatment began on the day of re-grouping (treatment day 1). Compound 1 was formulated in the vehicle, 0.5% MC, and 0.1% Tween 80 with vortexing and sonication to obtain a suspension. Oral dosing of either vehicle or test article was administered twice per day every day.

[0125] ASSESSMENT. For the arthritic score, the severity of pathological changes of four paws in arthritis mice were scored 2 times a week after booster immunization throughout the study according to the following standard: score 0, no arthritis; score 1, swelling and / or redness of one to two interphalangeal (IP) joints; score 2, involvement of three to four IP joints or one larger joint; score 3, more than four joints red / swollen; score 4, severe arthritis of an entire paw. Data are summarized in Fig. 3 A. For paw swelling, the thickness of both left and right footpads of hind limbs were measured using a micrometer 2 times a week after booster immunization throughout the study. Data are summarized in Fig. 3B.

[0126] RESULT. Treatment with Compound 1 resulted in significantly reduced paw swelling, and disease score. These data demonstrate the anti-inflammatory, disease modifying and tissue protective activities of Compound 1.Example 5: Compound 1 Occupies TNF in Human Whole BloodHuman whole blood target occupancy

[0127] MODEL DESCRIPTION. An enzyme-linked immunosorbent assay (ELISA) was used to determine the potency at which Compound 1 occupies TNF in human whole blood.

[0128] METHOD. Compound 1 was added to 0.5% MC, and 0.1% Tween 80 with vortexing and sonication to obtain a suspension (test article). Fresh human whole blood was mixed with prediluted test article in DMSO in a 96 well plate and incubated for 1 hour. Lipopolysaccharide (LPS) was added to stimulate the production of cytokines in the human whole blood sample. After 3 hours of incubation, ice cold PBS was added to the blood sample and the sample was then centrifuged to separate the cells. The level of asymmetric soluble TNF- a present in the serum was measured via colorimetric ELISA (CAI 974 capture, BAF210 detection).

[0129] ASSESSMENT. The level of target occupancy in serum samples from human whole blood, was determined relative to samples saturated with sTNF-a inhibitor test article. Concentration-response curves were generated to determine the concentrations of Compound 1 to achieve percent target occupancy (e.g., 50% occupancy (OCC50)). Data are summarized in Fig. 4.

[0130] RESULT. TNF occupancy increased proportionally with Compound 1 concentration. Concentration-response curves (see Fig. 4) were generated to determine the concentrations of Compound 1 to achieve percent target occupancy (e.g., 50% occupancy (OCC50)). Results suggest that Compound 1 can inhibit TNF-a signaling in human whole blood, demonstrating that Compound 1 can be a potent and soluble TNF-a inhibitor.Example 6: Compound 1 Occupies soluble TNF in Human Peripheral Blood Mononuclear Cells (PBMCs)Human peripheral blood mononuclear cell (PBMC) target occupancy

[0131] MODEL DESCRIPTION. An enzyme-linked immunosorbent assay (ELISA) was used to determine the potency at which Compound 1 occupies soluble TNF in human PBMCs.

[0132] METHOD. Compound 1 was dissolved in DMSO (test article) and added to plate a 96 well plate at increasing concentrations (see Fig. 5). Human PBMCs were seeded into the 96 well plate and incubated for 1 hour. Lipopolysaccharide (LPS) was added to stimulate the production of cytokines in the human PBMCs and incubated for 4 hours or 24 hours. After incubation, samples were added to ELISA plates coated in CAI 974 antibody. The level of asymmetric soluble TNF-a present in the samples was then measured via colorimetric ELISA (CAI 974 capture, BAF210 detection).

[0133] ASSESSMENT. The level of target occupancy in PBMCs, was determined relative to samples saturated with sTNF-a inhibitor test article. Concentration-response curves were generated and data are summarized in Fig. 5.

[0134] RESULT. TNF occupancy increased proportionally with Compound 1 concentration. Results suggest that Compound 1 can inhibit TNF -a signaling in human PBMCs, demonstrating that Compound 1 can be a potent and soluble TNF-a inhibitor.Example 7: Compound 1 Activity in an Animal Model of Mannan-Induced PsoriasisMouse mannan-induced psoriasis model

[0135] MODEL DESCRIPTION. Mannan-induced psoriasis is an experimental autoimmune disease that can be elicited in susceptible strains of rodents (e.g., Balb / c mice) by inducing inflammation with mannan, a yeast cell wall component. Following treatment with mannan, the animals develop a psoriasis that shares several clinical, histological, and immunological features with human psoriasis and psoriatic arthritis (PsA).

[0136] METHOD. Mice were briefly shaved with an electric razor, and the remaining hairs were removed with the application of depilatory cream. On day 0 to day 2, the backs of the mice were smeared with Mannan solution, and the control group was smeared with the same amount of saline.

[0137] TREATMENT. Compound 1 was added to 0.5% MC, 0.1% Tween 80 with vertexing and sonication to obtain a suspension. Mice were administered Compound 1 suspension PO BID at varying concentrations (see Fig. 6). Administration of etanercept (a biologic which blocks TNF alpha activity), or deucravacitinib (a tyrosine kinase 2 inhibitor) occurred once per day for 6 days.

[0138] ASSESSMENT. For the PASI (Psoriasis Area and Severity Index) scores, the severity of pathological changes in psoriasis-like lesions (e.g., erythema, scaling and thickness) were scored every day after administration throughout the study according to the following standard: score 0, no clinical signs; score 1, slight clinical signs; score 2, moderate clinical signs; score 3, marked clinical signs; score 4, very marked clinical signs. Data for the AUC (Area Under the Curve) for PASI scores are summarized in Fig. 6.

[0139] RESULT. Treatment with Compound 1 resulted in significantly reduced AUC for PASI scores. These data demonstrate the anti-inflammatory and disease modifying activities of Compound 1.Example 8: Compound 1 Exhibits Anti-Inflammatory Activity in an Animal Model of DiseaseMouse collagen-induced arthritis model

[0140] MODEL DESCRIPTION. Collagen-induced arthritis (CIA) is an experimental autoimmune disease that can be elicited in susceptible strains of rodents (e.g., DBA1 mouse) by immunization with type II collagen (CII). Following immunization, the animals develop an autoimmune-mediated polyarthritis that shares several clinical, histological, and immunological features with human rheumatoid arthritis.

[0141] METHOD. Collagen II was prepared in 100 mM acetic acid to a final concentration of 8 mg / mL. Collagen solution was emulsified in an equal volume of CFA on ice for 1 hour, using a high-speed homogenizer (30,000 rpm). Mice were immunized with the collagen-CFA emulsion (study day 0). Three weeks later, the collagen-CFA emulsion was injected for booster immunization (study day 21).

[0142] TREATMENT. When the average arthritis score of immunized mice reached 1-2 (study day 28), the model groups were selected and divided into treatment groups (n=18). Treatment began on the day of re-grouping (treatment day 1). Compound 1 was formulated in the vehicle, 0.5% MC, and 0.1% Tween 80 with vortexing and sonication to obtain a suspension. Oral dosing of either vehicle or Compound 1 suspension at varying concentrations (see Fig. 7) was administered once per day for 20 days. Etanercept was administered by intraperitoneal injection every 3 days for 20 days.

[0143] ASSESSMENT. For the X-ray score, the severity of pathological changes of the left hind paw was assessed and scored at the end of the study according to the following standard: score 0, bone structure and geometry appeared normal with no signs of radiolucency; score 1, minimal: Small radiolucent lesions indicative of bone destruction; score 2, mild: Increased number and size of lesions and loss of cancellous bone; score 3, moderate: Loss of cancellous bone and destruction of cortical bone; score 4, marked: Cross cortical bone loss and / or deformation fracture. Data are summarized in Fig. 7.

[0144] RESULT. Treatment with Compound 1 resulted in significantly reduced severity of pathological changes. These data demonstrate the anti-inflammatory and disease modifying activities of Compound 1.Example 9: Compound 1 Exhibits Anti-Inflammatory Activity in an Animal Model of DiseaseMouse T cell transfer induced colitis model

[0145] MODEL DESCRIPTION. T cell transfer induced colitis is an experimental autoimmune disease that can be elicited in susceptible strains of rodents (e.g., SCID mouse) by inducing colitis in immunodeficient mice via the transfer of T cells. Specifically, the model involves the transfer of naive CD4+ T cells, often depleted of T regulatory cells (Treg), into Rag-deficient mice, leading to chronic colitis that mimics the pathology of human inflammatory bowel disease (IBD).

[0146] METHOD. Purified CD4+CD45RBhi cells from wildtype Balb / c mice were injected intraperitonealy (IP) into female SCID mice to establish T cell induced chronic colitis model, and purified CD4+CD45RBlow were transferred as a negative control. Following adoptive cell transfer (ACT), body weight of the mice was evaluated and recorded every other day. Adalimumab (a biologic which inhibits TNF), and Compound 1 were dosed (every 3 days and every day, respectively) from Day 0 to Day 41. Day 42 was the study endpoint.

[0147] TREATMENT. When the average arthritis score of immunized mice reached 1-2 (study day 28), the model groups were selected and divided into treatment groups (n=18). Treatment began on the day of re-grouping (treatment day 1). Compound 1 was formulated in the vehicle, 0.5% MC, and 0.1% Tween 80 with vortexing and sonication to obtain a suspension. Oral dosing of either vehicle or Compound 1 suspension at varying concentrations (see Fig. 8) was administered. Adalimumab was administered by intraperitoneal injection.

[0148] ASSESSMENT. For the colon histology score, the severity of pathological changes of the colon in treated mice was scored at the end of the study. The colon histology score conveys the level of inflammation in a colon biopsy. Data are summarized in Fig. 8.RESULT. Treatment with Compound 1 resulted in significantly reduced colon inflammation. These data demonstrate the anti-inflammatory and disease modifying activities of Compound 1. Example 10: Combination Therapy of Compound 1 in an Animal Model of Disease Mouse T cell transfer induced colitis model

[0149] MODEL DESCRIPTION. T cell transfer induced colitis is an experimental autoimmune disease that can be elicited in susceptible strains of rodents (e.g., SCID mouse) by inducing colitis in immunodeficient mice via the transfer of T cells. Specifically, the model involves the transfer of naive CD4+ T cells, often depleted of T regulatory cells (Treg), into Rag-deficient mice, leading to chronic colitis that mimics the pathology of human inflammatory bowel disease (IBD).

[0150] METHOD. Purified CD4+CD45RBhi cells from wildtype Balb / c mice were injected intraperitonealy (IP) into female SCID mice to establish T cell induced chronic colitis model, and purified CD4+CD45RBlow were transferred as a negative control. Following adoptive cell transfer (ACT), body weight of the mice was evaluated and recorded every other day. Anti-mIL23 (a mouse antibody which inhibits IL23), and Compound 1 were dosed (every 3 days and every day, respectively) from Day 0 to Day 41. Day 42 was the study endpoint. Anti- IL-23 therapies have shown promise in treating inflammatory diseases, such as IBD. These therapies work by blocking the IL-23 signaling pathway, which plays a crucial role in promoting inflammation. In addition, combination therapies of TNF inhibitors and anti -IL-23 agents have been shown to be effective in treating refractory or severe cases of inflammatory diseases.

[0151] TREATMENT. When the average arthritis score of immunized mice reached 1-2 (study day 28), the model groups were selected and divided into treatment groups (n=18). Treatment began on the day of re-grouping (treatment day 1). Compound 1 was formulated in the vehicle, 0.5% MC, and 0.1% Tween 80 with vortexing and sonication to obtain a suspension. Dosing of Compound 1 suspension was orally administered. Anti-mIL23 and combination therapy of anti-mIL23 was administered by intraperitoneal injection, and Compound 1 was administered orally.

[0152] ASSESSMENT. For the disease activity index score, the severity of pathological changes of the treated mice was scored throughout the duration of the study. The disease activity index score conveys the level of chronic colitis. Data are summarized in Fig. 9A. Differential gene expression analysis was performed on groups treated with Compound 1, anti- mIL23 and combination therapy of anti-mIL23 and Compound 1. Data are summarized in Fig. 9B.

[0153] RESULT. Treatment with combination therapy of anti-mIL23 and Compound 1 resulted in a decrease in disease activity and an increase in differentially expressed genes, demonstrating the disease modifying activities of Compound 1 in combination with anti-mIL23.Example 11: Compound 1 Selectively for TNF in Cell CultureFunctional activity in vitro

[0154] METHOD. Compound 1 functional activity was evaluated in vitro in cellular assay format. HEK-Blue TNFa reporter cells express TNF receptor 2 (TNFR2) and allow the measurement of membrane TNFa signaling via TNFR2. HEK-Blue TNFa cells were grown according to the manufacturer’s instructions. Serial dilutions of Compound 1 and Adalimumab were prepared (see Fig. 10A and Fig. 10B, respectively) and added to cell culture plates. For the HEK-Blue TNFa Reporter Assay cells are added to each well in culture media. An aliquot ofTNFa (R&D) is then added into each well. The plates are then incubated for 18 h at 37 °C with 5% CO2.

[0155] Activities mediated via TNFa were assessed using the QUANTI-Blue reagent (InvivoGen) with optical absorbance readouts at 620 nm. Percent inhibition is calculated based on the average signals of the stimulated and unstimulated controls and is reported in Fig. 10A and Fig. 10B. Data obtained was used to plot dose response curves using XLfit data analysis software processing tool.

[0156] RESULTS. Adalimumab demonstrated potent inhibition of human membrane TNFa signaling via TNFR2 in the HEK-Blue TNFa cellular reporter assay. For Compound 1 treatment, no activity was detected in the HEK-Blue TNFa cellular reporter assay demonstrating the high selectivity of Compound 1 for soluble TNF and not membrane TNF.Example 12: Compound 1 Anti-immunosuppressive Activity in an Animal Model infected with Listeria monocytogenesMouse infected with Listeria monocytogenes

[0157] MODEL DESCRIPTION. In preclinical studies, sublethal Listeria monocytogenes infections are often used to test the efficacy of TNF inhibitors as the immunosuppressive nature of TNF inhibitors exacerbates the effects of Listeria infections.

[0158] METHOD. Mice were infected with Listeria monocytogenes via the intravenous route through lateral tail vein injection. The target dose of infection was 1 x 102CFU / mouse, and the actual dose was 5.4 x 101CFU / mouse. Mice were weighed prior to infection to obtain starting weights and weighed at least twice daily during the study.

[0159] TREATMENT. Four hours post-infection, mice were administered the vehicle (subcutaneous injection or oral administration), Etanercept (subcutaneously injected once every 3 days), or Compound 1 (orally administered once every day) through the end of the study (day 10).

[0160] ASSESSMENT. At the end of the study, survival curves were analyzed using Mantel-Cox log-rank test and Kaplan-Meier survival plots were generated. Data are summarized in Fig. 11.

[0161] RESULT. Mice treated with Etanercept showed 100% mortality rate, while mice treated with Compound 1 survived through the study with minimal to no visible disease modifying activities observed. The analysis shows that the survival of Compound 1 treated group performed better compared with the Etanercept and vehicle groups. These data demonstrate the anti-immunosuppressive and disease modifying activities of Compound 1.

Claims

CLAIMSWHAT IS CLAIMED IS:

1. A method of treating an inflammatory or autoimmune disease in a patient in need thereof, comprising administering to the patient (7R,14R)-l-(difluoromethoxy)-l l-(4- (dimethylphosphoryl)-3-fluorophenyl)-10-fluoro-6-(methyl-d3)-6,7-dihydro-7,14- methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,4]diazocin-5(14H)-one, or pharmaceutically acceptable salt or solvate thereof.

2. A method of treating an inflammatory or autoimmune disease in a patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising (7R, 14R)- 1 -(diflu orom ethoxy)- 11 -(4-(dimethylphosphoryl)-3 -fluorophenyl)- 10-fluoro-6-(methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[l,2- a][l,4]diazocin-5(14H)-one, or pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient.

3. The method of claim 1 or 2, wherein the inflammatory or autoimmune disease is selected from the group consisting of rheumatoid arthritis (RA), psoriatic arthritis (PsA), psoriasisjuvenile idiopathic arthritis (JIA), ankylosing spondylitis (AS), inflammatory bowel diseases (IBD), Crohn’s disease, ulcerative colitis, systemic lupus erythematosus (SLE), spondyloarthritis (SpA), Behcet's disease, sarcoidosis, multiple sclerosis (MS), palmoplantar pustulosis (PPP), palmoplantar pustulosis (PPP), atopic dermatitis, graft versus host disease, sepsis, neuropathic pain, fibromyalgia, Schnitzler syndrome, Blau syndrome, TNF receptor-associated periodic syndrome (TRAPS), pyogenic arthritis, pyoderma Gangrenosum, and chronic recurrent multifocal osteomyelitis (CRMO).

4. The method of claim 3, wherein the inflammatory or autoimmune disease is rheumatoid arthritis (RA).

5. The method of claim 3, wherein the inflammatory or autoimmune disease is psoriatic arthritis (PsA).

6. The method of claim 3, wherein the inflammatory or autoimmune disease is psoriasis.

7. The method of claim 3, wherein the inflammatory or autoimmune disease is juvenile idiopathic arthritis (JIA).

8. The method of claim 3, wherein the inflammatory or autoimmune disease is ankylosing spondylitis (AS).

9. The method of claim 3, wherein the inflammatory or autoimmune disease is inflammatory bowel diseases (IBD).

10. The method of claim 3, wherein the inflammatory or autoimmune disease is Crohn’s disease.

11. The method of claim 3, wherein the inflammatory or autoimmune disease is ulcerative colitis.

12. The method of claim 3, wherein the inflammatory or autoimmune disease is systemic lupus erythematosus (SLE).

13. The method of claim 3, wherein the inflammatory or autoimmune disease is spondyloarthritis (SpA).

14. The method of claim 3, wherein the inflammatory or autoimmune disease is Behget' s disease.

15. The method of claim 3, wherein the inflammatory or autoimmune disease is sarcoidosis.

16. The method of claim 3, wherein the inflammatory or autoimmune disease is multiple sclerosis (MS).

17. The method of claim 3, wherein the inflammatory or autoimmune disease is palmoplantar pustulosis (PPP).

18. The method of claim 3, wherein the inflammatory or autoimmune disease is atopic dermatitis.

19. The method of claim 3, wherein the inflammatory or autoimmune disease is graft versus host disease.

20. The method of claim 3, wherein the inflammatory or autoimmune disease is sepsis.

21. The method of claim 3, wherein the inflammatory or autoimmune disease is neuropathic pain.

22. The method of claim 3, wherein the inflammatory or autoimmune disease is fibromyalgia.

23. A method of treating inflammatory or autoimmune disease in a patient in need thereof, comprising administering to the patient: a) a composition comprising (7R, 14R)-1 -(difluoromethoxy)- 11 -(4- (dimethylphosphoryl)-3-fluorophenyl)-10-fluoro-6-(methyl-d3)-6,7-dihydro- 7,14-methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,4]diazocin-5(14H)-one, or pharmaceutically acceptable salt or solvate thereof; and b) at least one therapeutic for the treatment of inflammatory or autoimmune disease selected from the group consisting of anti-inflammatory steroid, methotrexate, mesalazine, a JAK kinase inhibitor, a TYK2 kinase inhibitor, and a SIP receptor modulator.

24. The method of claim 23, wherein the at least one therapeutic for the treatment of inflammatory or autoimmune disease is abatacept, vedolizumab, azathioprine, prednisone, budesonide, tofacitinib, upadacitanib, mesalazine, or methotrexate.

25. A method of treating inflammatory or autoimmune disease in a patient in need thereof, comprising administering to the patient: a) a composition comprising (7R, 14R)-l-(difluorom ethoxy)- 11 -(4- (dimethylphosphoryl)-3-fluorophenyl)-10-fluoro-6-(methyl-d3)-6,7-dihydro- 7,14-methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,4]diazocin-5(14H)-one, or pharmaceutically acceptable salt or solvate thereof; and b) at least one therapeutic for the treatment of inflammatory or autoimmune disease selected from the group consisting of CD20 biologic therapy, IL-lb biologic therapy, IL 12 / 23 biologic therapy, IL-23 biologic therapy, IL- 17 biologic therapy, IL-36 biologic therapy, integrin a4b7 biologic therapy, IL-4R biologic therapy, and TNFa biologic therapy.

26. A method of treating inflammatory or autoimmune disease in a patient in need thereof, comprising administering to the patient: a) a composition comprising (7R, 14R)-l-(difluorom ethoxy)- 11 -(4- (dimethylphosphoryl)-3-fluorophenyl)-10-fluoro-6-(methyl-d3)-6,7-dihydro- 7,14-methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,4]diazocin-5(14H)-one, or pharmaceutically acceptable salt or solvate thereof; and b) at least one therapeutic for the treatment of inflammatory or autoimmune disease selected from the group consisting of BTK inhibitors, CD38 targeted biologies, FcRn targeted biologies, and TLla targeted biologies.

27. The method of any one of claims 23-26, wherein the inflammatory or autoimmune disease is rheumatoid arthritis (RA).

28. The method of any one of claims 23-26, wherein the inflammatory or autoimmune disease is psoriatic arthritis (PsA).

29. The method of any one of claims 23-26, wherein the inflammatory or autoimmune disease is psoriasis.

30. The method of any one of claims 23-26, wherein the inflammatory or autoimmune disease is juvenile idiopathic arthritis (JIA).

31. The method of any one of claims 23-26, wherein the inflammatory or autoimmune disease is ankylosing spondylitis (AS).

32. The method of any one of claims 23-26, wherein the inflammatory or autoimmune disease is inflammatory bowel diseases (IBD).

33. The method of any one of claims 23-26, wherein the inflammatory or autoimmune disease is Crohn’s disease.

34. The method of any one of claims 23-26, wherein the inflammatory or autoimmune disease is ulcerative colitis.

35. The method of any one of claims 23-26, wherein the inflammatory or autoimmune disease is systemic lupus erythematosus (SLE).

36. The method of any one of claims 23-26, wherein the inflammatory or autoimmune disease is spondyloarthritis (SpA).

37. The method of any one of claims 23-26, wherein the inflammatory or autoimmune disease is Behcet's disease.

38. The method of any one of claims 23-26, wherein the inflammatory or autoimmune disease is sarcoidosis.

39. The method of any one of claims 23-26, wherein the inflammatory or autoimmune disease is multiple sclerosis (MS).

40. The method of any one of claims 23-26, wherein the inflammatory or autoimmune disease is palmoplantar pustulosis (PPP).

41. The method of any one of claims 23-26, wherein the inflammatory or autoimmune disease is atopic dermatitis.

42. The method of any one of claims 23-26, wherein the inflammatory or autoimmune disease is graft versus host disease.

43. The method of any one of claims 23-26, wherein the inflammatory or autoimmune disease is sepsis.

44. The method of any one of claims 23-26, wherein the inflammatory or autoimmune disease is neuropathic pain.

45. The method of any one of claims 23-26, wherein the inflammatory or autoimmune disease is fibromyalgia.

46. The method of any one of the preceding claims, wherein the patient exhibits polymorphism or mutations in TNFa pathway relevant loci.

47. The method of claim 46, wherein the polymorphism or mutations in TNFa pathway relevant loci is determined by QPCR or hybridization technique.

48. The method of claim 46, wherein the polymorphism or mutations in TNFa pathway relevant loci is determined by detection of proteins by ELISA or histology.

49. The method of any one of the preceding claims, wherein the patient has been treated with a TNFa biologic therapeutic.

50. The method of any one of the preceding claims, wherein the patient wherein the patient has anti-drug antibodies to a TNFa biologic therapeutic.

51. The method of any one of the preceding claims, wherein the patient is a secondary nonresponder to TNFa biologic therapy.

52. The method of any one of the preceding claims, wherein the patient has been excluded from biologic TNFa therapy.

53. The method of any one of the preceding claims, wherein the patient is immunocompromised.

54. The method of any one of the preceding claims, wherein the (7R,14R)-1- (difluoromethoxy)- 11 -(4-(dimethylphosphoryl)-3 -fluorophenyl)- 10-fluoro-6-(methyl- d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[l,2-a][l,4]diazocin-5(14H)- one, or pharmaceutically acceptable salt or solvate thereof, is administered orally.

55. The method of any one of the preceding claims, wherein the administration occurs every other day, once per day, twice per day, or three times per day.

56. A method of treating inflammatory or autoimmune disease in a patient in need thereof, comprising administering to the patient: a) a composition comprising an sTNF-a inhibitor, or pharmaceutically acceptable salt or solvate thereof; and b) at least one therapeutic for the treatment of inflammatory or autoimmune disease selected from the group consisting of BTK inhibitors, CD38 targeted biologies, FcRn targeted biologies, TLla targeted biologies, CD20 biologic therapy, IL-lb biologic therapy, IL 12 / 23 biologic therapy, IL-23 biologic therapy, IL- 17 biologic therapy, IL-36 biologic therapy, integrin a4b7 biologic therapy, IL-4R biologic therapy, and TNFa biologic therapy.

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