Selective BET inhibitors and their uses

Abstract

The present disclosure relates to certain pyrrolopyridone compounds. Certain compounds of the present disclosure are potent and selective bromodomain and extraneous terminus (BET) inhibitors. The present disclosure also relates to pharmaceutically acceptable salts of the compounds or N-oxides thereof; methods of treating diseases and disorders using the compounds, salts, or N-oxides; and compositions comprising the compounds, salts, or N-oxides. The present disclosure further relates to methods of treating inflammatory and autoimmune diseases and disorders (e.g., skin diseases and disorders, joint and joint-related diseases and disorders, and fibrosis or fibrosis-related diseases or disorders) using potent and selective BET inhibitors, and formulations comprising the BET inhibitors of the present disclosure.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority under 35 U.S.C. §119(e) to U.S. Provisional Application No. 63 / 586,684, filed September 29, 2023, U.S. Provisional Application No. 63 / 520,322, filed August 17, 2023, UK Patent Application No. GB2302859.0, filed February 27, 2023, UK Patent Application No. GB2219791.7, filed December 28, 2022, and UK Patent Application No. GB2219706.5, filed December 23, 2022, the contents of each of which are incorporated herein by reference in their entirety.

[0002] The present invention relates to compounds and pharmaceutically acceptable salts comprising a pyrrolopyridone core, as well as compositions of such compounds. The compounds herein are useful as anti-inflammatory and / or other therapeutic agents. Accordingly, the present disclosure also relates to compounds for use as pharmaceuticals, particularly pharmaceuticals for the treatment of inflammatory diseases. [Background technology]

[0003] background Diseases and disorders can be multifactorial and may involve inflammation or cause inflammation-related disorders. Autoimmune diseases and disorders may cause inflammation or cause inflammation-related disorders. Inflammatory or autoimmune diseases or disorders may result in or cause changes, damage, and / or wounds. An important aspect of treating many diseases and disorders is promoting proper healing. Failure or failure of the healing process, insufficient healing, or excessive healing may leave, for example, lesions, sores, wounds, fibrosis, and / or other damage.

[0004] The present disclosure relates to methods for the treatment of inflammatory and autoimmune diseases and disorders, such as skin diseases and disorders (e.g., psoriasis), arthritic diseases and disorders (e.g., joint-related diseases and disorders), and fibrosis or fibrosis-related diseases or disorders (e.g., pulmonary fibrosis and lupus), using potent and selective bromodomain and extraneous terminal (BET) inhibitors and pharmaceutically acceptable salts thereof, their use for the treatment of diseases or disorders, and compositions / formulations (e.g., oral formulations, injections, and infusions) comprising BET inhibitors.

[0005] Psoriasis is a skin disease that most commonly causes a rash of itchy, scaly patches on the knees, elbows, trunk, and scalp. Psoriasis is a long-term (chronic) autoimmune condition. It can be painful, disrupt sleep, and make it difficult to concentrate. There are several types of psoriasis: plaque psoriasis, nail psoriasis, guttate psoriasis, inverse psoriasis, pustular psoriasis, erythrodermic psoriasis, and psoriatic psoriasis. Administration of the BET inhibitors, their salts, and compositions containing them disclosed herein can provide a beneficial treatment for one or more or all of these different types of psoriasis.

[0006] Examples of other inflammatory and / or autoimmune skin diseases or disorders that may benefit from the administration of the BET inhibitors disclosed herein include pyoderma gangrenosum, generalized pustular psoriasis, and palmoplantar pustulosis.

[0007] Pyoderma gangrenosum (PG) is a severe, life-threatening autoimmune neutrophilic dermatosis that causes significant skin ulcers and has an incidence rate of 5.8 per 100,000 in the United States. 2This condition primarily affects adults, although rare childhood cases have been reported. The gender ratio varies from equal to 76% with up to 76% of cases occurring primarily in women. Classic PG most commonly presents as an extremely painful, erythematous lesion that rapidly progresses to a bullous or necrotic ulcer. It often has an irregular, exhumed border with a bluish-purple / erythematous border. PG can appear anywhere, but the lower extremities are most commonly affected. Lesions may be triggered by minor trauma. Most cases of PG are of the classic ulcerative type (approximately 85%), but other subtypes include bullous, vegetative, pustular, peristomal, and superficial granulomatous types, and PG subtypes can transition from one type to another. Because there are no definitive clinical or histologic criteria for PG, the differential diagnosis includes all other causes of skin ulcers. Although the pathogenesis of PG remains unclear, it is recognized that neutrophils play a key role in the disease process. Upregulation of several key proinflammatory and neutrophil chemotactic factors has been identified within the lesions, including IL-1β, IL-17, TNFα, IL-8, IL-6, IL-18, INF-γ, IL-36γ, and IL-23. IL-8 has been demonstrated to contribute to PG in animal models. IL-8 is also induced in fibroblasts in PG ulcers, and its related ligand is overexpressed in PG.

[0008] An important aspect of the treatment of PG is wound healing. Often, wound healing is incomplete and scarring occurs. Attempts to accelerate the healing process can increase the incidence of scarring. If the wound is infected with bacteria, the healing process can be more difficult and take longer. Scarring often occurs after inadequate treatment.

[0009] Despite being a well-recognized condition, PG often fails to be diagnosed early. Potent topical corticosteroids and tacrolimus ointment applied to the ulcer surface are useful, and intralesional corticosteroid injections into the active borders of the erythema may also be considered. In more severe cases, systemic therapy is required. Oral corticosteroids are the mainstay of treatment and are used to achieve rapid control. Cyclosporine is used alone or in combination with corticosteroids as a steroid-sparing agent when long-term treatment is required. Other systemic treatments that have been used with varying success include colchicine, sulfasalazine, dapsone, minocycline, apremilast, and thalidomide.

[0010] Limitations of current treatments include insufficient efficacy of nonsteroidal topical treatments, limited application to certain body areas ("steroid and CNI phobia"), and application site reactions. Potential long-term safety concerns include systemic side effects and skin atrophy (striae and other atrophic changes) with topical corticosteroids, and an increased risk of infection with CNIs.

[0011] Generalized pustular psoriasis (GPP) is a rare, debilitating, and life-threatening inflammatory disease characterized by episodic neutrophil infiltration of the skin, pustular outbreaks, and systemic inflammation. It can occur in the presence or absence of chronic plaque psoriasis. IL-1β, IL-17, IL-8, and IL-36γ are the main cytokines elevated in GPP. Current treatments are unsatisfactory, and a deeper understanding of the pathogenesis of GPP is needed.

[0012] Palmoplantar pustulosis (PPP) is a chronic dermatitis characterized by intraepidermal vesicles / pustules (PMNs) containing neutrophils on the palms and soles. Although several mechanisms underlying PPP, such as concurrent tonsillar ulcers, periodontitis, or metal allergy, have been suggested, the etiology of PPP remains unclear. IL-1, IL-8, IL-17, and IL-36γ are the main cytokines elevated in PPP. Current treatments are unsatisfactory, and a deeper understanding of the pathogenesis of PPP is needed.

[0013] Since many other local or skin disorders involve inflammation and share similar biomarker patterns, a product that can reduce the inflammatory cytokines involved in inflammation and treat or ameliorate the disorder while avoiding or minimizing systemic and skin-related side effects would be advantageous and may improve patient compliance with treatment.

[0014] Joint or joint-related disorders or diseases are diseases that affect human joints. Arthritis is a well-known example of a joint disease. Osteoarthritis, the most common form of arthritis, involves the wear and tear of the cartilage covering the bones in human joints. It is a degenerative joint disease characterized by joint pain and progressive loss of articular cartilage. Rheumatoid arthritis (RA) is a disease in which the immune system attacks the joints, starting from the lining of the joint. RA is the most frequent autoimmune chronic inflammatory rheumatoid arthritis, primarily affecting the synovial membrane of multiple joints. Although its etiology remains unknown, it is recognized that the inflammatory process of arthritis involves three major mediators: pro-inflammatory cytokines TNF-α, IL-1β, and IL-6 (see Mori et al., Int. Immunol., 23(11):701-712 (2011)).

[0015] Regardless of the cause, joint inflammation can cause pain, stiffness, swelling, and some redness of the skin around the joint. Steroids (i.e., corticosteroids) are synthetic drugs used to treat various inflammatory diseases and conditions. However, administration of corticosteroids, especially long-term administration, can have some undesirable side effects or adverse reactions. The effectiveness of corticosteroids generally wears off over time, and their use has the disadvantage of increasing susceptibility to infection and peptic ulcers. Injecting corticosteroids directly into joint tissues can worsen joint damage in some subjects. For example, undesirable adverse reactions of triamcinolone (a corticosteroid) injection include hypersensitivity reactions such as anaphylaxis, joint infection and damage, increased risk of infection, changes in endocrine function, cardiovascular and renal effects, increased intraocular pressure, gastrointestinal perforation, changes in bone density, and behavioral and mood disorders. As yet another example, undesirable adverse reactions of dexamethasone (another corticosteroid) include fluid and electrolyte disturbances, musculoskeletal, gastrointestinal, neurological, dermatological, endocrine, ophthalmic, metabolic, cardiovascular, anaphylactic or hypersensitivity reactions, thromboembolic events, weight gain, increased appetite, and nausea (see, e.g., Brinks et al., BMC Musculoskelet. Disord., 11:206 (2010)).

[0016] Since many disorders involve inflammation and share similar biomarker patterns, products that can reduce the inflammatory cytokines involved in inflammation and treat or ameliorate the disorder while avoiding or minimizing side effects or adverse reactions would be advantageous and may improve patient compliance with treatment.

[0017] In addition to inflammation, fibrosis can be a systemic problem involving organs such as the kidneys, lungs, liver, heart, lymph nodes (e.g., mediastinal fibrosis), bone marrow, skin, tendons, joints, connective tissue, soft tissue, and cavities, e.g., retroperitoneum. Fibrosis can be local or systemic.

[0018] Fibrosis, defined by the pathological accumulation of extracellular matrix (ECM) proteins, leads to scarring that can be coupled with thickening of affected tissues, essentially an excessive wound-healing response that interferes with normal organ function. Pulmonary fibrosis is generally characterized by damage to alveolar epithelial cells, areas of type II cell hyperplasia, accumulation of fibroblasts and myofibroblasts, and deposition of extracellular matrix proteins. This results in the progressive loss of normal lung structure and impaired gas exchange. Accordingly, symptoms may include shortness of breath, dry cough, fatigue, weight loss, and clock-shaped nails (e.g., due to hypoxia in the blood). Renal fibrosis is generally characterized by tubulointerstitial nephritis and / or fibrosis, i.e., renal inflammation and connective tissue deposition (e.g., collagen fiber deposition) in the renal parenchyma, glomerulosclerosis, i.e., scarring of glomeruli, and nephropathy, i.e., decreased renal function. This results in the progressive formation of internal scar tissue, leading to end-stage renal failure. Thus, symptoms can include weight loss and loss of appetite, edema (ie, water retention), shortness of breath, fatigue, frequent urination, blood in the urine, and itchy skin.

[0019] Furthermore, inflammatory and autoimmune diseases and disorders, as well as other diseases and disorders characterized by fibrosis or scarring, such as pulmonary fibrosis (PF), are difficult to treat. As an example, PF is a chronic disease affecting at least 5 million people worldwide, and exhibits abnormal remodeling of lung tissue. PF is part of a large group of over 200 interstitial lung diseases (also known as ILDs or diffuse parenchymal lung diseases (DPLDs)) characterized by lung inflammation and / or scarring. In ILDs, trauma / damage occurs not only in the walls of the lung's air sacs (alveoli), but also in the tissues and spaces (interstitium) surrounding these air sacs. When ILD involves lung scar tissue, it is known as PF.

[0020] There are many different types of PF, grouped into six major categories. Five are based on the type of trigger or exposure: environmental, occupational, drug-induced, radiation-induced, and autoimmune lung disease. The other major classification, idiopathic pulmonary fibrosis (IPF), has no identifiable cause. IPF is a chronic, life-threatening fibrotic lung disease with few treatment options. Patients experience debilitating symptoms, including shortness of breath and difficulty performing daily activities. Current standard treatment options for IPF have been shown to have only a minimal effect on slowing disease progression and are associated with significant side effects, leading to poor adherence to treatment.

[0021] Lung damage (scar tissue) caused by PF is irreparable, and currently approved drug therapies have limited efficacy and multiple side effects. Drug therapies and treatments can improve quality of life, help alleviate symptoms, and slow the progression of scarring. In severe cases, lung transplantation is the only available treatment option. Oxygen supplementation, pulmonary rehabilitation, and symptom management are important treatment options for many types of PF, depending on severity. Additional systemic autoimmune disorders, such as lupus, can induce fibrosis, among other things. There are four types of lupus. Systemic lupus erythematosus (SLE) is the most common type. SLE is an autoimmune disease in which the immune system attacks the body's own tissues, causing widespread inflammation and tissue damage in the brain, blood vessels, joints, kidneys, lungs, and skin. Lupus that affects only the skin is less common and is called cutaneous lupus erythematosus (CLE). There are three types of CLE: discoid lupus, subacute cutaneous lupus, and acute cutaneous lupus. Neonatal lupus and drug-induced lupus are the least common forms of lupus. Lupus can cause severe kidney damage, and kidney failure is one of the leading causes of death in lupus patients. Renal fibrosis is found in several kidney diseases, including lupus nephritis (LN). LN affects a significant proportion of patients with SLE. PF is a severe complication of SLE and can contribute to a poor prognosis in SLE patients. Lupus causes five major lung disorders: pleurisy, acute lupus pneumonia, chronic (fibrosing) lupus pneumonia, pulmonary hypertension, and "constricted lung" syndrome. Another complication of lupus is that many patients develop cardiac abnormalities. Lupus can affect the pericardium, myocardium, and endocardium, as well as the coronary arteries and the broader cardiovascular system. Heart damage can result from cardiac inflammation directly related to lupus or from damage to other organs, such as the lungs and kidneys. Lupus can cause inflammation of blood vessels, leading to blood disorders, including a reduced number of healthy red blood cells (anemia). Lupus affects the brain and can cause cognitive impairment or brain fog. Other complications of lupus include increased risk of infection, cancer, bone tissue death, and pregnancy complications.Previous treatment options for lupus have been limited and primarily focused on symptom management.

[0022] Multiple sclerosis (MS) is a debilitating autoimmune disease characterized by central nervous system (CNS) inflammation and demyelination, which can result in permanent damage and / or deterioration of nerve fibers. Inflammation may be the primary trigger leading to CNS damage. This inflammatory process leads to demyelination and may also result in the destruction of oligodendrocytes. Damage to nerve fibers results in lesions and / or plaques. Axonal loss and gliosis may occur in response to CNS damage. Because MS involves the CNS, symptoms and difficulties associated with MS include visual impairment, muscle weakness, difficulties with coordination and balance, sensations associated with nerve damage, and cognitive impairment and / or decline. There is no cure for MS, and current treatment options are limited to managing symptoms and assisting recovery from "attacks" related to nerve damage and other symptoms associated with MS.

[0023] Bromodomain and extra-terminal (BET) proteins are a family of four bromodomain (BRD)-containing proteins (BRD2, BRD3, BRD4, and BRDT). All four members contain two BRDs (located adjacent to each other toward the N-terminus of the protein) and an extra-terminal domain (Shi et al., Cancer Cell, 25(2):210-225(2014)). The two BRDs in each BET protein are called bromodomain I (BD1) and bromodomain II (BD2). BRDs are functional protein domains that contain a defined, primarily hydrophobic pocket that typically binds to acetylated lysine residues found in the N-terminal tails of transcription factors (Shi et al., Cancer Cell, 25(2):210-225(2014)) or histone proteins. BRDs function as epigenetic regulators, i.e., they functionally alter gene activity and expression without altering DNA sequence. For example, BRD4 recruits the transcription factor P-TEFb to promoters and alters the expression of genes involved in the cell cycle (Yang et al., Mol. Cell Biol., 28:967-976 (2008) (Non-Patent Document 4)). BRD2 and BRD3 also regulate proliferation-promoting genes (Leroy et al., Mol. Cell, 30:51-60 (2008) (Non-Patent Document 5)). Thus, BRDs play a role in transducing signals conveyed by acetylated lysine residues into various phenotypes. BET is considered in the art to be ubiquitously expressed in humans, with the exception of BRDT, which is normally expressed in the testes but is also expressed by some cancers (Ekaterina et al., Cell J., 19(Suppl 1):1-8(2017)).

[0024] BET proteins are involved in the regulation of biochemical pathways such as MYC, BCL2, FOSL1, P-TEFb, NFkB, and glucocorticoid signaling (Shi et al., Mol. Cell., 54(5):728-36(2014) (Non-Patent Document 7); Hajmirza et al., Biomedicines, 6(1):E16(2018) (Non-Patent Document 8); Shan et al., Elife, Sep 11(6):e27861(2017) (Non-Patent Document 9); Huang et al., Mol. Cell. Biol., 29(5):1375-87(2009) (Non-Patent Document 10)). Therefore, BET inhibitors are thought to have potential applications in various inflammatory diseases, cancer, infectious diseases, metabolic diseases, CNS disorders, fibrotic diseases, and heart diseases (Deanna et al., J Exp Med. 210(11):2181-2190(2013) (Non-Patent Document 11); Rab et al., Trends Pharmacol. Sci., 33(3):146-53(2012) (Non-Patent Document 12); Anna et al., J. Immunol., 190(7):3670-3678(2013) (Non-Patent Document 13); Zuber et al., Nature, 478(7370):524-28.(2011) (Non-Patent Document 14); Montserrat et al., Epigenetics, 12(5):323-339(2017) (Non-Patent Document 15); Qiming et al. al.,Sci.Transl.Med.,9(390):eaah5084(2017)(Non-patent document 16), Kristin et al.,J.Biol.Chem.,292(32):13284-13295(2017)(Non-patent document 17),Ning et al. al., PNAS, 112(51):15713-18 (2015) (Non-patent Document 18).

[0025] BET proteins "read" acetylated lysines, enabling chromatin remodeling and recruiting transcription factors. In other words, BRDs are responsible for transducing signals conveyed by acetylated lysine residues into various phenotypes. They play a key role in regulating gene transcription during cell proliferation and differentiation through epigenetic interactions ("reading") between bromodomains and acetylated histones. For example, BRD4 recruits the transcription factor P-TEFb to promoters, altering the expression of genes involved in the cell cycle.

[0026] The two bromodomains of BET proteins (BD1 and BD2) play distinct roles in regulating gene expression. BD1 controls the activity of housekeeping genes, including steady-state gene regulation. Notably, BD1, but not BD2, has been associated with gastrointestinal and hematologic toxicity. BD2, on the other hand, controls the induction of inflammatory genes, particularly those associated with inflammatory diseases and disorders, including autoimmune diseases. Inhibition of the BDII domain of BET proteins has been shown to affect inflammatory diseases, metabolic diseases, cancer, and fibrotic diseases (Gilan et al., Science, 368:387-394 (2020) (Non-Patent Document 19); Tsujikawa et al., Clin. Epigenetics, 11(1):102 (2019) (Non-Patent Document 20); Faivre et al., Nature, 578:306-310 (2020) (Non-Patent Document 21); Zhang et al., Cell. Signal., 61:20-29 (2019) (Non-Patent Document 22)).

[0027] Compounds that can inhibit or affect the function of BET proteins have the potential to modulate gene expression and treat diseases that are caused, at least in part, by dysregulation of BET protein activity.

[0028] A product that is safe, well-tolerated, and avoids unwanted side effects and adverse reactions while, for example, preventing the occurrence and / or reducing the severity of joint or joint-related disorders or diseases would be advantageous and may improve patient compliance with treatment. Therefore, there is a medical need to replace corticosteroids with safer and better drugs to reduce the systemic side effects associated with corticosteroid administration. Additionally, there is a medical need to slow, halt, reverse, or otherwise inhibit structural damage to tissues caused by inflammatory diseases, such as damage to joint tissues caused by osteoarthritis or rheumatoid arthritis. Infiltration of bursae, tendons, and tendon sheaths can be part of arthritic diseases. Similarly, there is a medical need to slow, halt, reverse, or otherwise inhibit fibrosis and its adverse effects, including the decline and eventual failure of organ function. Compounds that can inhibit or affect the function of BET proteins have the potential to modulate gene expression and treat diseases caused, at least in part, by dysregulation of BET protein activity.

[0029] The present disclosure provides novel, potent and selective BET protein inhibitors, their uses as medicines, compositions containing them and processes for their preparation. [Prior art documents] [Non-patent literature]

[0030] [Non-Patent Document 1] Mori et al., Int. Immunol., 23(11):701-712(2011) [Non-patent document 2] Brinks et al.,BMC Musculoskelet.Disord.,11:206(2010) [Non-patent document 3] Shi et al., Cancer Cell, 25(2):210-225(2014) [Non-patent document 4] Yang et al., Mol. Cell Biol., 28:967-976(2008) [Non-licensed Document 5] Leroy et al., Mol. Cell, 30:51-60 (2008) [Non-licensed Document 6] Ekaterina et al.,Cell J.,19(Suppl 1):1-8(2017) [Non-licensed Document 7] Shi et al.,Mol. Cell.,54(5):728-36(2014) [Non-licensed Document 8] Hajmirza et al., Biomedicines, 6(1):E16(2018) [Non-licensed Document 9] Shan et al.,Elife,Sep 11(6):e27861(2017) [Non-licensed Document 10] Huang et al., Mol. Cell. Biol., 29(5):1375-87(2009) [Non-licensed Document 11] Deanna et al.,J Exp Med.210(11):2181-2190(2013) [Non-licensed Document 12] Rab et al., Trends Pharmacol. Sci., 33(3):146-53(2012) [Non-licensed Document 13] Anna et al.,J.Immunol.,190(7):3670-3678(2013) [Non-licensed Document 14] Zuber et al.,Nature, 478(7370):524-28.(2011) [Non-licensed Document 15] Montserrat et al.,Epigenetics,12(5):323-339(2017) [Non-licensed Document 16] Qiming et al.,Sci.Transl.Med.,9(390):eaah5084(2017) [Non-Patent Document 17] Kristin et al.,J.Biol.Chem.,292(32):13284-13295(2017) [Non-Patent Document 18] Ning et al., PNAS, 112(51):15713-18(2015) [Non-Patent Document 19] Gilan et al.,Science,368:387-394(2020) [Non-Patent Document 20] Tsujikawa et al.,Clin.Epigenetics,11(1):102(2019) [Non-Patent Document 21] Faivre et al.,Nature,578:306-310(2020) [Non-Patent Document 22] Zhang et al.,Cell.Signal.,61:20-29(2019) Summary of the Invention

[0031] Summary of the Disclosure The present disclosure provides potent and selective BET protein inhibitors, their pharmaceutical uses, compositions containing them, and processes for their preparation.

[0032] In some embodiments, the present disclosure provides a compound of formula (I), or a pharmaceutically acceptable salt or N-oxide thereof: TIFF2026501324000001.tif58165 (in the formula, Ring A is independently selected from phenyl, 5-membered heterocyclyl, and 6-membered heterocyclyl; X 4 and X 5 are independently selected from carbon and nitrogen; R 1 are independently C1-C5-alkyl, C1-C5-haloalkyl, C2-C6-alkynyl, COR 6 , CO2R 6 , C1-C4-alkylene-NR5 R 6 , C1-C4-alkylene-OR 7 , C1-C4-alkyl-S(O)2R 6 , C3-C6-cycloalkyl, aryl, heteroaryl, and 3- to 6-membered heterocycloalkyl; R 2 is absent or independently represents H, halo, cyano, nitro, SF4, SF5, =O, S(O)2R 6 , alkoxy, C1-C6-haloalkyl, C1-C8-alkyl, C3-C6-cycloalkyl, 4- to 8-membered heterocycloalkenyl, 3- to 8-membered heterocycloalkyl, aryl, and 5- or 6-membered heteroaryl; wherein C1-C8-alkyl, alkoxy, C3-C6-cycloalkyl, 4- to 8-membered heterocycloalkenyl, 3- to 8-membered heterocycloalkyl, aryl, and 5- or 6-membered heteroaryl are optionally substituted independently by one or more groups selected from halogen, cyano, nitro, hydroxy, SF5, amido, ester, alkoxy, and C1-C4-alkyl; R 3 are independently 3a and OR 3b is selected from R 3a is independently selected from H, CN, C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl, C2-C4-haloalkenyl, C3-C8-cycloalkyl, C5-C8-cycloalkenyl, 5- to 9-membered heterocycloalkenyl, 3- to 9-membered heterocycloalkyl, phenyl, and 5- to 9-membered heteroaryl; wherein cycloalkyl, heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl are independently selected from 1 to 4 R 8 may be substituted with a group, Phenyl and 5- to 9-membered heteroaryl are independently selected from 1 to 5 R 9 may be substituted with a group, R 3bis independently selected from C1-C4-alkyl, C2-C4-alkylene-O-C1-C4-alkyl, C1-C4-haloalkyl, C3-C8-cycloalkyl, 3- to 8-membered heterocycloalkyl, phenyl, and 5- or 6-membered heteroaryl, wherein cycloalkyl and 3- to 8-membered heterocycloalkyl are independently 1 to 4 R 8 may be substituted with a group, Phenyl and 5- or 6-membered heteroaryl are independently selected from 1 to 5 R 9 may be substituted with a group, R 4 is independently in each occurrence H, ═O, ═S, halo, nitro, cyano, C0-C4-alkylene-NR 5 R 6 , -NR 5 R 6 , C0-C4-alkylene-OR 7 , -OR 7 , S.R. 6 , SOR 6 , C0-C4-alkylene-S(O)2R 6 , -S(O)2R 6 , SO2NR 6 R 6 , C0-C4-alkylene-CO2R 6 , -CO2R 6 , C0-C4-alkylene-C(O)R 6 , -C(O)R 6 , C0-C4-alkylene-CONR 6 R 6 , -CONR 6 R 6 , C1-C6-alkyl, C1-C4-alkyl-S(O)2R 6 , C2-C4-alkenyl, C2-C4-alkynyl, C1-C6-haloalkyl, C3-C6-cycloalkyl, aryl, 4- to 6-membered heterocycloalkyl, and 5- or 6-membered heteroaryl; wherein aryl, 4- to 6-membered heterocycloalkyl, and 5- or 6-membered heteroaryl are independently selected from 1 to 5 R 9 may be substituted with a group, R 5is independently selected in each occurrence from H, C1-C4-alkyl, C(O)—C1-C4-alkyl, and S(O)2—C1-C4-alkyl, or R 5 and R 6 together with the nitrogen atom to which they are attached, form one to four R 8 forming a C5-C8 heterocycloalkyl group optionally substituted by a group, R 6 is independently selected in each occurrence from H and C1-C6-alkyl, or two R 6 If groups are attached to the same nitrogen, the two R 6 The groups, together with the nitrogen atom to which they are attached, can consist of one to four R 8 may form a C5-C8 heterocycloalkyl group optionally substituted by a group, R 7 is independently selected at each occurrence from H, C-C-alkyl, C(O)—C-C-alkyl, and C-C-haloalkyl; R 8 is independently in each occurrence =O, =S, fluoro, nitro, cyano, NR 5 R 6 , OR 7 , S.R. 6 , SOR 6 , S(O)2R 6 , SO2NR 6 R 6 , CO2R 6 , C(O)R 6 ,CONR 6 R 6 , C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl, 4- to 6-membered heterocycloalkyl, and C3-C6-cycloalkyl; R 9 is, independently in each occurrence, halo, nitro, cyano, NR 5 R 6 , C1-C4-alkyl-OR 7 , OR 7 , S.R. 6 , SOR 6 , C1-C4-alkyl-S(O)2R6 , S(O)2R 6 , SO2NR 6 R 6 , CO2R 6 , C(O)R 6 ,CONR 6 R 6 , C0-C4-alkylene-R 9a , C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl, 4- to 6-membered heterocycloalkyl, and C3-C6-cycloalkyl, or two R 9 If the groups are attached to adjacent atoms, the two R 9 Groups, together with the atoms to which they are attached, consist of one to four R 8 may form a 5- or 6-membered heterocycloalkyl group optionally substituted with a group, R 9a is independently selected at each occurrence from 4- to 6-membered heterocycloalkyl; R 10 is absent or, independently in each occurrence, H, halo, C1-C6-alkyl, C1-C6-haloalkyl, nitro, cyano, NR 5 R 6 , OR 7 , S.R. 6 , SOR 6 , S(O)2R 6 , SO2NR 6 R 6 , CO2R 6 , C(O)R 6 ,CONR 6 R 6 , C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl and 3- to 8-membered heterocycloalkyl; R 11 are independently selected from phenyl, heteroaryl, and heterocyclyl, each of which is selected from 1 to 4 R 2 group and 1 to 3 R 10 may be substituted with a group, R x and R yare each independently H, halo, nitro, cyano, C1-C6-alkylene-NR 5 R 6 , N.R. 5 R 6 , C1-C6-alkylene-OR 7 、 C1~C6-Alkyl-OR 7 , OR 7 , C1-C6-alkyl-SR 6 , S.R. 6 , C1-C6-alkyl-SOR 6 , SOR 6 , C1-C6-alkyl-S(O)2R 6 , S(O)2R 6 , C1-C6-Alkyl-SO2NR 6 R 6 , SO2NR 6 R 6 , C1-C6-alkyl-CO2R 6 , CO2R 6 , C1-C6-alkyl-C(O)R 6 , C(O)R 6 , C1-C6-alkyl-CONR 6 R 6 ,CONR 6 R 6 , C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-haloalkyl, C3-C8-cycloalkyl, 3- to 8-membered heterocycloalkyl, aryl, aryloxy, and 5- to 8-membered heteroaryl; m is an integer selected from 0, 1, 2, 3 and 4; Any of the aforementioned alkyl, alkylene, alkenyl or C3-C6-cycloalkyl groups may, where chemically possible, independently in each case be selected from C1-C4-alkyl, oxo, fluoro, nitro, cyano, NR a R b , OR a , S.R. a , CO2R a , C(O)R a ,CONR a R a , S(O)R a and S(O)2R aand optionally substituted with 1 to 5 substituents selected from the group consisting of: where R a is independently selected at each occurrence from H, C1-C4-alkyl, and C1-C4-haloalkyl; R b is independently in each occurrence selected from H, C1-C4-alkyl, C(O)—C1-C4-alkyl and S(O)2—C1-C4-alkyl).

[0033] In some embodiments, the present disclosure provides a compound of formula (IA), or a pharmaceutically acceptable salt or N-oxide thereof: TIFF2026501324000002.tif58165 (in the formula, Ring A is independently selected from phenyl, 5-membered heterocyclyl, and 6-membered heterocyclyl; X 4 are independently selected from carbon and nitrogen; X 5 are independently selected from carbon and nitrogen; R 1 is independently selected from C1-C3-alkyl, C1-C3-fluoroalkyl, C3-C4-cycloalkyl and 4-membered heterocycloalkyl, R 2 is independently selected from C1-C4-haloalkyl, ethyl, cyano, nitro, isopropyl, tert-butyl, cyclopropyl, and SF5; R 3 are independently 3a , OR 3b , and NR 6 R 3b is selected from R 3a are independently H, CN, C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl, C2-C4-haloalkenyl, and C0-C3-alkylene-R 3c where R 3cis independently selected in each occurrence from C-C-cycloalkyl, C-C-cycloalkenyl, 5- to 8-membered heterocycloalkenyl, 3- to 8-membered heterocycloalkyl, phenyl, and 5- or 6-membered heteroaryl; R 3c is cycloalkyl, heterocycloalkyl, cycloalkenyl, or heterocycloalkenyl, then R 3c is 1 to 4 R 8 may be substituted with R 3c is phenyl or heteroaryl, R 3c is 1 to 5 R 9 may be substituted with a group, R 3b are independently C1-C4-alkyl, C2-C4-alkylene-O-C1-C4-alkyl, C1-C4-haloalkyl and C0-C3-alkylene-R 3d where R 3d is independently selected at each occurrence from C-C-cycloalkyl, 3- to 8-membered heterocycloalkyl, phenyl, and 5- or 6-membered heteroaryl; R 3d When R is cycloalkyl or heterocycloalkyl, 3d is 1 to 4 R 8 may be substituted with R 3d is phenyl or heteroaryl, R 3d is 1 to 5 R 9 may be substituted with a group, R 4 is independently in each occurrence =O, =S, halo, nitro, cyano, C0-C4-alkylene-NR 5 R 6 , C0-C4-alkylene-OR 7 , S.R. 6 , SOR 6 , C0-C4-alkylene-S(O)2R 6 , SO2NR 6 R 6 , C0-C4-alkylene-CO2R 6 , C0-C4-alkylene-C(O)R 6 , C0-C4-alkylene-CONR 6 R6 , C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl, C3-C6-cycloalkyl, and C0-C4-alkylene-R 4c is selected from R 4c is independently selected at each occurrence from C-C-cycloalkyl and 4- to 6-membered heterocycloalkyl; R 5 is independently selected in each occurrence from H, C1-C4-alkyl, C(O)—C1-C4-alkyl and S(O)2—C1-C4-alkyl, or R 5 and R 6 together with the nitrogen atom to which they are attached, form one to four R 8 forming a C5-C8 heterocycloalkyl group optionally substituted by a group, R 6 is independently selected in each occurrence from H and C1-C4-alkyl, or two R 6 If groups are attached to the same nitrogen, the two R 6 The groups, together with the nitrogen atom to which they are attached, can consist of one to four R 8 may form a C5-C8 heterocycloalkyl group optionally substituted by a group, R 7 is independently selected at each occurrence from H, C1-C4-alkyl, C(O)—C1-C4-alkyl and C1-C4-haloalkyl; R 8 is independently in each occurrence =O, =S, fluoro, nitro, cyano, NR 5 R 6 , OR 7 , S.R. 6 , SOR 6 , S(O)2R 6 , SO2NR 6 R 6 , CO2R 6 , C(O)R 6 ,CONR 6 R 6, C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl and cyclopropyl; R 9 is independently in each occurrence halo, nitro, cyano, C0-C4-alkylene-NR 5 R 6 , C0-C4-alkylene-OR 7a , C0-C4-alkylene-SR 6 , C0-C4-alkylene-SOR 6 , C0-C4-alkylene-S(O)2R 6 , C0-C4-alkylene-SO2NR 6 R 6 , C0-C4-alkylene-CO2R 6 , C0-C4-alkylene-C(O)R 6 , C0-C4-alkylene-CONR 6 R 6 , C0-C4-alkylene-R 9a , C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl and C1-C4-haloalkyl, or two R 9 If the groups are attached to adjacent atoms, the two R 9 Groups, together with the atoms to which they are attached, consist of one to four R 8 may form a 5- or 6-membered heterocycloalkyl group optionally substituted with a group, R 7a is independently in each occurrence H, C1-C4-alkyl, C(O)—C1-C4-alkyl, C0-C4-alkylene-NR5R6, —C0-C4-alkyl-OR 7 , C0-C4-alkylene-SR 6 , C0-C4-alkylene-SOR 6 , C0-C4-alkylene-S(O)2R 6 , C0-C4-alkylene-SO2NR 6 R 6 , C0-C4-alkylene-CO2R 6 , C0-C4-alkylene-C(O)R 6 , C0-C4-alkylene-CONR 6 R6 and C1-C4-haloalkyl; R 9a is independently selected at each occurrence from C-C-cycloalkyl and 4- to 6-membered heterocycloalkyl; R 10 is independently in each occurrence halo, C1-C4-alkyl, C1-C4-haloalkyl, nitro, cyano, NR 5 R 6 , OR 7 , S.R. 6 , SOR 6 , S(O)2R 6 , SO2NR 6 R 6 , CO2R 6 , C(O)R 6 ,CONR 6 R 6 , C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl and 4-membered heterocycloalkyl; R x and R y are each independently H, halo, nitro, cyano, or NR 5 R 6 , OR 7 , S.R. 6 , SOR 6 , S(O)2R 6 , SO2NR 6 R 6 , CO2R 6 , C(O)R 6 ,CONR 6 R 6 , C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl, C3-C4-cycloalkyl and 4-membered heterocycloalkyl, m is an integer selected from 0, 1, 2, 3 and 4; n 17 is an integer selected from 0, 1 and 2, Any of the aforementioned alkyl, alkylene, alkenyl, cycloalkyl or heterocycloalkyl groups may, where chemically possible, independently in each case be C1-C4-alkyl, oxo, fluoro, nitro, cyano, NRa R b , OR a , S.R. a , CO2R a , C(O)R a ,CONR a R a , S(O)R a and S(O)2R a and optionally substituted with 1 to 5 substituents selected from the group consisting of: a is independently selected at each occurrence from H, C-C-alkyl, and C-C-haloalkyl; R b is independently in each occurrence selected from H, C1-C4-alkyl, C(O)—C1-C4-alkyl and S(O)2—C1-C4-alkyl).

[0034] In some embodiments, the present disclosure provides a compound of formula (XI), or a pharmaceutically acceptable salt or N-oxide thereof: TIFF2026501324000003.tif58165 (in the formula, Ring A is independently selected from phenyl, 5-membered heterocyclyl, and 6-membered heterocyclyl; X 4 are independently selected from carbon and nitrogen; X 5 are independently selected from carbon and nitrogen; R 1 is independently selected from C1-C3-alkyl, C1-C3-fluoroalkyl, C3-C4-cycloalkyl and 4-membered heterocycloalkyl, R 2 is independently selected from C1-C4-haloalkyl, ethyl, cyano, nitro, isopropyl, tert-butyl, cyclopropyl, and SF5; R 3 are independently 3a , OR 3b , and NR 6 R 3b is selected from R 3aare independently H, CN, C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl, C2-C4-haloalkenyl, and C0-C3-alkylene-R 3c where R 3c is independently selected in each occurrence from C-C-cycloalkyl, C-C-cycloalkenyl, 5- to 8-membered heterocycloalkenyl, 3- to 8-membered heterocycloalkyl, phenyl, and 5- or 6-membered heteroaryl; R 3c is cycloalkyl, heterocycloalkyl, cycloalkenyl, or heterocycloalkenyl, then R 3c is 1 to 4 R 8 may be substituted with R 3c is phenyl or heteroaryl, R 3c is 1 to 5 R 9 may be substituted with a group, R 3b are independently C1-C4-alkyl, C2-C4-alkylene-O-C1-C4-alkyl, C1-C4-haloalkyl and C0-C3-alkylene-R 3d where R 3d is independently selected at each occurrence from C-C-cycloalkyl, 3- to 8-membered heterocycloalkyl, phenyl, and 5- or 6-membered heteroaryl; R 3d When R is cycloalkyl or heterocycloalkyl, 3d is 1 to 4 R 8 may be substituted with R 3d is phenyl or heteroaryl, R 3d is 1 to 5 R 9 may be substituted with a group, R 4 is independently in each occurrence =O, =S, halo, nitro, cyano, C0-C4-alkylene-NR 5 R 6 , C0-C4-alkylene-OR 7 , S.R. 6 , SOR 6 , C0-C4-alkylene-S(O)2R 6 , SO2NR6 R 6 , C0-C4-alkylene-CO2R 6 , C0-C4-alkylene-C(O)R 6 , C0-C4-alkylene-CONR 6 R 6 , C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl, C3-C6-cycloalkyl, and C0-C4-alkylene-R 4c is selected from R 4c is independently selected at each occurrence from C-C-cycloalkyl and 4- to 6-membered heterocycloalkyl; R 5 is independently selected in each occurrence from H, C1-C4-alkyl, C(O)—C1-C4-alkyl and S(O)2—C1-C4-alkyl, or R 5 and R 6 together with the nitrogen atom to which they are attached, form one to four R 8 forming a C5-C8 heterocycloalkyl group optionally substituted by a group, R 6 is independently selected in each occurrence from H and C1-C4-alkyl, or two R 6 If groups are attached to the same nitrogen, the two R 6 The groups, together with the nitrogen atom to which they are attached, can consist of one to four R 8 may form a C5-C8 heterocycloalkyl group optionally substituted by a group, R 7 is independently selected at each occurrence from H, C1-C4-alkyl, C(O)—C1-C4-alkyl and C1-C4-haloalkyl; R 8 is independently in each occurrence =O, =S, fluoro, nitro, cyano, NR 5 R 6 , OR 7 , S.R. 6 , SOR 6 , S(O)2R 6 , SO2NR 6 R 6, CO2R 6 , C(O)R 6 ,CONR 6 R 6 , C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl and cyclopropyl; R 9 is independently in each occurrence halo, nitro, cyano, C0-C4-alkylene-NR 5 R 6 , C0-C4-alkylene-OR 7a , C0-C4-alkylene-SR 6 , C0-C4-alkylene-SOR 6 , C0-C4-alkylene-S(O)2R 6 , C0-C4-alkylene-SO2NR 6 R 6 , C0-C4-alkylene-CO2R 6 , C0-C4-alkylene-C(O)R 6 , C0-C4-alkylene-CONR 6 R 6 , C0-C4-alkylene-R 9a , C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl, or two R 9 If the groups are attached to adjacent atoms, the two R 9 Groups, together with the atoms to which they are attached, consist of one to four R 8 may form a 5- or 6-membered heterocycloalkyl group optionally substituted with a group, R 7a is independently in each occurrence H, C1-C4-alkyl, C(O)—C1-C4-alkyl, C0-C4-alkylene-NR5R6, —C0-C4-alkyl-OR 7 , C0-C4-alkylene-SR 6 , C0-C4-alkylene-SOR 6 , C0-C4-alkylene-S(O)2R 6 , C0-C4-alkylene-SO2NR 6 R 6 , C0-C4-alkylene-CO2R 6, C0-C4-alkylene-C(O)R 6 , C0-C4-alkylene-CONR 6 R 6 and C1-C4-haloalkyl; R 9a is independently selected at each occurrence from C-C-cycloalkyl and 4- to 6-membered heterocycloalkyl; R 10 is independently in each occurrence halo, C1-C4-alkyl, C1-C4-haloalkyl, nitro, cyano, NR 5 R 6 , OR 7 , S.R. 6 , SOR 6 , S(O)2R 6 , SO2NR 6 R 6 , CO2R 6 , C(O)R 6 ,CONR 6 R 6 , C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl and 4-membered heterocycloalkyl; R x and R y are each independently H, halo, nitro, cyano, or NR 5 R 6 , OR 7 , S.R. 6 , SOR 6 , S(O)2R 6 , SO2NR 6 R 6 , CO2R 6 , C(O)R 6 ,CONR 6 R 6 , C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl, C3-C4-cycloalkyl and 4-membered heterocycloalkyl, m is an integer selected from 0, 1, 2, 3 and 4; n 17 is an integer selected from 0, 1 and 2, Any of the aforementioned alkyl, alkylene, alkenyl, cycloalkyl or heterocycloalkyl groups may, where chemically possible, independently in each case be C1-C4-alkyl, oxo, fluoro, nitro, cyano, NR a R b , OR a , S.R. a , CO2R a , C(O)R a ,CONR a R a , S(O)R a and S(O)2R a and optionally substituted with 1 to 5 substituents selected from the group consisting of: a is independently selected at each occurrence from H, C-C-alkyl, and C-C-haloalkyl; R b is independently in each occurrence selected from H, C1-C4-alkyl, C(O)—C1-C4-alkyl and S(O)2—C1-C4-alkyl).

[0035] In some embodiments, R 2 is C1-C4-haloalkyl.

[0036] In some embodiments, R x is H.

[0037] In some embodiments, X 4 is carbon.

[0038] In some embodiments, R 1 is selected from methyl and ethyl.

[0039] In some embodiments, R 2 is CF3.

[0040] In some embodiments, n 17 is 0.

[0041] In some embodiments, ring A is a pyridone.

[0042] In some embodiments, ring A is substituted at the nitrogen with one group selected from H, C1-C4-alkyl, cyclopropyl, cyclobutyl, methyl-cyclobutyl, and 4-membered heterocycloalkyl.

[0043] In some embodiments, ring A is TIFF2026501324000004.tif37165, where R 4a is selected from H, C1-C4-alkyl, cyclopropyl and 4-membered heterocycloalkyl.

[0044] In some embodiments, R 4a is selected from methyl, cyclopropyl, oxetane, —CH—CH—OMe, and azetidine.

[0045] In some embodiments, R 3 is R 3a is.

[0046] In some embodiments, R 3a is 1 to 3 R 9 and phenyl optionally substituted by a group.

[0047] In some embodiments, R y is H.

[0048] In some embodiments, R y is a halo.

[0049] In some embodiments, the present disclosure provides: TIFF2026501324000005.tif67145TIFF2026501324000006.tif186145TIFF2026501324000007.tif178145TIFF2026501324000008.tif37144, or a pharmaceutically acceptable salt or N-oxide thereof.

[0050] In some embodiments, the present disclosure provides: TIFF2026501324000009.tif159145TIFF2026501324000010.tif190145TIFF2026501324000011.tif220145TIFF2026501324000012.tif195145TIFF2026501324000013.tif136145, or a pharmaceutically acceptable salt or N-oxide thereof.

[0051] In some embodiments, the present disclosure provides pharmaceutical compositions comprising a compound disclosed herein, or a pharmaceutically acceptable salt thereof, or an N-oxide thereof, and one or more pharmaceutically acceptable excipients.

[0052] In some embodiments, the present disclosure provides a method of treating a disease or disorder selected from one or more of an inflammatory disease or disorder, an immune disease or disorder, and an autoimmune disease or disorder, comprising administering to a warm-blooded animal a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt or N-oxide thereof.

[0053] In some embodiments, the disease or disorder is a joint disease or disorder or a joint-related disease or disorder.

[0054] In some embodiments, the disease or disorder is selected from arthritis, bursitis, Ehlers-Danlos syndrome, epicondylitis, Felty's syndrome, gouty arthritis, psoriatic arthritis, osteoarthritis, rheumatoid arthritis, Still's disease, tenosynovitis, synovitis, Sjogren's syndrome, Lyme disease, Whipple's disease, bone cancer, lupus, and other autoimmune joint disorders.

[0055] In some embodiments, the joint disease or disorder or joint-related disease or disorder is arthritis. In some embodiments, the arthritis is rheumatoid arthritis. In some embodiments, the disease or disorder is a fibrotic disease or disorder. In some embodiments, the disease or disorder is renal fibrosis. In some embodiments, the disease or disorder is pulmonary fibrosis. In some embodiments, the disease or disorder is a skin disease or disorder. In some embodiments, the disease or disorder is psoriasis. In some embodiments, the disease or disorder is a lupus disease or disorder. In some embodiments, the disease or disorder is MS or an MS-related disease or disorder. In some embodiments, the methods of treatment disclosed herein reduce the severity of the disease or disorder. [Brief explanation of the drawings]

[0056] [Figure 1A] 1 shows plasma concentrations of Compound A formulated in 1% methylcellulose in rats after oral administration (per os, PO). [Figure 1B] FIG. 1 shows plasma concentrations of Compound A formulated in propylene glycol in rats after oral administration (per os, PO). [Figure 1C] A comparison of the mean plasma concentrations of the two formulations is provided.

[0057] [Figure 2A] Figure 1 shows the plasma concentration of Compound A over time when formulated in a DMSO-based formulation. Individual animal results are shown after oral delivery (PO). [Figure 2B] 1 shows the change in plasma concentration over time of Compound A when formulated in a DMSO-based formulation. Average plasma concentrations after oral delivery (PO) are shown.

[0058] [Figure 3A] 1 shows the change in plasma concentration of ABBV-744 when administered intravenously (IV). [Figure 3B]1 shows the change in plasma concentration of ABBV-744 when administered orally (PO). [Figure 3C] A comparison of the results of two different routes of administration is provided. [Figure 3D] The mean pharmacokinetics of ABBV-744 are shown in relation to free EC50 BD1 and free EC50 BD2 BRD4.

[0059] [Figure 4A] Figure 1 shows the pharmacokinetics of Compound A when delivered at two different doses in a propylene glycol-based formulation. Figure 2 shows the plasma concentration of Compound A when administered at a dose of 1 mg / kg. [Figure 4B]

[0023] Figure 1 shows the pharmacokinetics of Compound A when delivered at two different doses in a propylene glycol-based formulation.

[0024] Figure 1 shows the plasma concentration of Compound A when administered at a dose of 0.2 mg / kg. [Figure 4C] 1 shows the pharmacokinetics of Compound A when delivered at two different doses in a propylene glycol-based formulation. A comparison of mean plasma concentrations is shown for the two doses (1 mg / kg = squares, 0.2 mg / kg = diamonds). [Figure 4D] Figure 1 shows the pharmacokinetics of Compound A when delivered at two different doses in a propylene glycol-based formulation. Plasma concentrations of Compound A at various doses are shown relative to the free EC50 for BD1 and the free EC50 for BD2 (10 mg / kg = line, 1 mg / kg = diamond, 0.2 mg / kg = circle).

[0060] [Figure 5A] 1 shows the pharmacokinetics of Compound A in a propylene glycol-based formulation when delivered to Beagle dogs via two different routes of administration: intravenous (IV). [Figure 5B] 1 shows the pharmacokinetics of Compound A in a propylene glycol-based formulation when delivered to beagle dogs by two different routes of administration: oral (PO). [Figure 5C]Figure 5A shows the pharmacokinetics of Compound A in a propylene glycol-based formulation when delivered to beagle dogs via two different routes of administration: intravenous (IV; Figure 5A) and oral (PO; Figure 5B). A comparison of the mean plasma concentrations of Compound A between the two routes of administration is provided.

[0061] [Figure 6A] Pharmacokinetics of Compound A in HPβCD formulation. Individual animal results are shown. [Figure 6B] Pharmacokinetics of Compound A in HPβCD formulation. Mean changes in plasma concentrations (IV) are shown.

[0062] [Figure 7A] 1 shows plasma concentrations of Compound A in beagle dogs on day 1 after administration at various doses (5 mg / kg). [Figure 7B] 1 shows plasma concentrations of Compound A in beagle dogs on day 1 after administration at various doses (10 mg / kg). [Figure 7C] 1 shows plasma concentrations of Compound A in beagle dogs on day 1 after administration at various doses (20 mg / kg). [Figure 7D] 1 shows plasma concentrations of Compound A in beagle dogs on day 5 after administration at various doses (5 mg / kg). [Figure 7E] 1 shows plasma concentrations of Compound A in beagle dogs on day 5 after administration at various doses (10 mg / kg). [Figure 7F] 1 shows plasma concentrations of Compound A in beagle dogs on day 5 after administration at various doses (20 mg / kg). [Figure 7G] A comparison of the mean plasma concentrations of the data shown in Figures 7A-7F is provided. [Figure 7H] The change in body weight after administration of a 5 mg / kg dose is shown. [Figure 7I] The change in body weight after administration of a 10 mg / kg dose is shown. [Figure 7J] The change in body weight after administration of a 20 mg / kg dose is shown. [Figure 7K]A comparison of body weight change among the three doses is shown. [Figure 7L] Plasma concentrations of Compound A at three different doses (1 mg / kg, 5 mg / kg, and 10 mg / kg) are shown relative to the previously determined free EC50 for BD1 and the free EC50 for BD2. [Figure 7M] 1 shows the change in plasma concentration of Compound A over 24 hours after daily administration of Compound A at three doses (1 mg / kg, 3 mg / kg, and 10 mg / kg) for 14 days. [Figure 7N] Figure 1 shows that there was no effect on platelet counts after 14 days of daily administration of three doses of Compound A (1 mg / kg, 3 mg / kg, and 10 mg / kg).

[0063] [Figure 8] AC show the inhibition of CXCL10 (A), IL-17A (B), and IL-22 (C) by compound A.

[0064] [Figure 9A] Figure 1 shows the results of testing Compound A in an imiquimod-induced psoriasis model, showing the percent change in Psoriasis Area and Severity Index (PASI) scores of the animals. [Figure 9B] 1 shows the results of testing Compound A in an imiquimod-induced psoriasis model, showing the mean percent change in PASI score at day 15 relative to the baseline score. [Figure 9C] 1 shows the results of testing Compound A in an imiquimod-induced psoriasis model, showing the overall change in PASI score during the test period. [Figure 9D] 1 shows the results of testing Compound A in an imiquimod-induced psoriasis model. Mean PASI scores at day 15 are shown. [Figure 9E] 1 shows the results of testing Compound A in an imiquimod-induced psoriasis model. 1 shows the mean change in erythema score in psoriasis-induced skin. [Figure 9F] 1 shows the results of testing Compound A in an imiquimod-induced psoriasis model. 1 shows the mean change in induration score in psoriasis-induced skin. [Figure 9G] 1 shows the results of testing Compound A in an imiquimod-induced psoriasis model. 1 shows the mean change in desquamation score in psoriasis-induced skin.

[0065] [Figure 10A] The changes in body weight from days 1 to 8 and days 8 to 15 are shown. [Figure 10B] The average changes in body weight from days 1 to 8 and days 8 to 15 are shown.

[0066] [Figure 11] The mean spleen:weight ratio of animals on day 15 is shown.

[0067] [Figure 12A] The mean scratching scores of the animals are shown. [Figure 12B] The mean licking scores of the animals are shown. [Figure 12C] The animals' mean combined scratching and licking scores are shown. [Figure 12D] Enrichment use during the study period is indicated. [Figure 12E] The mean enrichment use scores for days 1-8 and days 8-15 are shown. [Figure 12F] The average number of rearing behaviors of the animals is shown. [Figure 12G] The average distance traveled by the animals in the cage is shown.

[0068] [Figure 13] A-K show representative images of enrichment use by animals in each group: A (sham), B (IMI + vehicle), C (IMI + Compound A 1 mg / kg), D (IMI + Compound A 3 mg / kg), E (IMI + Compound A 10 mg / kg), F (Compound B 1 mg / kg), G (Compound B 3 mg / kg), H (Compound B 10 mg / kg), I (IMI + apremilast 3 mg / kg), J (IMI + dextrovacitinib 3 mg / kg), K (IMI + clobetasol 0.05%).

[0069] [Figure 14] A to H provide representative images of dorsally shaved mice on days 8 (A) and 15 (E) in the placebo group, days 8 (B) and 15 (F) in the compound A (3 mg / kg) treatment group, days 8 (C) and 15 (G) in the duravacitinib (3 mg / kg) treatment group, and days 8 (D) and 15 (H) in the compound B (10 mg / kg) treatment group.

[0070] [Figure 15] Panels A-B show cytokine levels measured in animals with psoriasis induced and various treatments (vehicle, Compound A (1 mg / kg), Compound A (3 mg / kg), Compound A (10 mg / kg), and ducravacitinib (3 mg / kg). Panel A shows levels of IL-17 and IL-22. Panel B shows levels of IL-1β, IL-6, TNF-α, and IL-23.

[0071] [Figure 16] Provides a description of CIA testing protocols.

[0072] [Figure 17A] Actual body weights in grams of Lewis rats under various treatment conditions over a 21-day period following collagen-induced arthritis are shown. [Figure 17B] The calculated percentage weight change of the animals over the course of the study is shown.

[0073] [Figure 18A] Figure 1 shows paw volumes of the left hind paw of Lewis rats under various treatment conditions over 21 days following collagen-induced arthritis. [Figure 18B] Figure 1 shows paw volumes of the right hind paw of Lewis rats under various treatment conditions over 21 days following collagen-induced arthritis. [Figure 18C] The average volumes of the left and right hind paws of the animals over the test period are shown.

[0074] [Figure 19A]1 shows the clinical scores of arthritic symptoms in Lewis rats under various treatment conditions over a 21-day period following collagen-induced arthritis. [Figure 19B] 1 shows the clinical scores of arthritic symptoms in Lewis rats under various treatment conditions over a 21-day period following collagen-induced arthritis.

[0075] [Figure 20A] The mean levels of rat anti-collagen IgG1 antibodies in the animals at the end of the 21-day study are shown, with individual levels also shown. [Figure 20B] The mean levels of rat anti-collagen IgG1 antibodies in the animals at the end of the 21-day study are shown.

[0076] [Figure 21A] 1 shows the pharmacokinetic profile of Compound A in rats on day 0 after oral administration in a CIA study. [Figure 21B] 1 shows the pharmacokinetic profile of Compound A in rats on day 21 after oral administration in a CIA study. [Figure 21C] 21A and 21B show the pharmacokinetic profiles of Compound A in rats after oral administration in a CIA study. A comparison of the mean plasma concentrations of the results from Day 0 and Day 21 is shown.

[0077] [Figure 22A] The mean histopathological scores of tissue samples from animals in groups 1 to 7 are shown. [Figure 22B] The histological scores of the animals on day 21 are shown.

[0078] [Figure 23A-G]Figures 23A-23G show representative tissue samples from animals in Groups 1-6 analyzed by histopathological analysis. A shows a representative sample from Group 1 (no CIA). B shows a representative sample from Group 2 (CIA + vehicle). C shows a representative sample from Group 3 (CIA + dexamethasone), depicting tissue with no histopathological findings. D shows a representative sample from Group 4 (CIA + GSK620). E shows a representative sample from Group 5 (CIA + Compound A, 1 mg / kg). F shows a representative sample from Group 6 (CIA + Compound A, 3 mg / kg). G shows a representative sample from Group 7 (CIA + Compound A, 10 mg / kg). [Figure 23H-I] 23H and I provide a comparison of tissues from vehicle-treated animals versus animals administered Compound A.

[0079] [Figure 24] 1 shows the test design of the UUO rat renal fibrosis model.

[0080] [Figure 25] The mean body weight changes (10A) of sham rats (circles), vehicle-treated UUO rats (squares), and Compound A-treated UUO rats (triangles) are shown.

[0081] [Figure 26A] The mean clinical histopathological scores (including interstitial nephritis, collagen fiber deposition, and renal pathology) are shown. [Figure 26B] Representative stained samples of tissues from vehicle-treated UUO rats are shown. [Figure 26C] Representative stained samples of tissues from UUO rats treated with Compound A (10 mg / kg) are shown.

[0082] [Figure 26D] The mean clinical histological scores for the animals at the completion of the study are shown.

[0083] [Figure 27A]Shown are the mean serum urea levels of sham rats (black bars), vehicle-treated UUO rats (gray bars), and Compound A (10 mg / kg)-treated UUO rats (white bars). [Figure 27B] Figure 1 shows tissue hydroxyproline levels in sham rats, vehicle-treated UUO rats, and Compound A (10 mg / kg)-treated UUO rats. Mean hydroxyproline levels are shown for sham rats (black bars), vehicle-treated UUO rats (gray bars), and Compound A (10 mg / kg)-treated UUO rats (white bars). [Figure 27C] Figure 1 shows tissue hydroxyproline levels in sham rats, vehicle-treated UUO rats, and Compound A (10 mg / kg)-treated UUO rats. Individual results are shown for sham rats (squares), vehicle-treated UUO rats (circles), and Compound A (10 mg / kg)-treated UUO rats (triangles).

[0084] [Figure 28A] Shown are the mean mRNA levels of tissue biomarkers (Col1a1, TGF-b1, MCP-1, IL-1b, IL-6, IL-17, TNF-a, and Timp1) in sham rats (black bars), vehicle-treated UUO rats (gray bars), and Compound A (10 mg / kg)-treated UUO rats (white bars). [Figure 28B] Average mRNA levels of tissue biomarkers (Col1a1, TGF-b1, MCP-1, IL-1b, IL-6, IL-17, TNF-a, and Timp1) are shown in sham rats (black bars), vehicle-treated UUO rats (gray bars), and UUO rats treated with Compound A (10 mg / kg) (white bars). Individual animal results are overlaid. [Figure 28C] 1 shows changes in expression of Col1a1, TGF-b1, IL-1b, IL-17, MCP-1, and IL-6 in animals treated with Compound A compared to vehicle-treated animals.

[0085] [Figure 29A]1 shows the mean percentage weight loss in animals in the IPF study over the 21 day study period.

[0086] [Figure 29B] The mean percentage change in oxygen saturation levels in animals in the IPF study obtained every other day from day 7 to day 21 is shown.

[0087] [Figure 29C] 1 shows the mean Ashcroft scores of lung tissue recorded on day 21 of the IPF study.

[0088] [Figure 29D] 1 shows the mean hydroxyproline levels in lung lysates on day 21 of the IPF study.

[0089] [Figure 29E-J] Representative tissue samples stained with Masson's trichrome are shown. Dashed areas indicate fibrosis, and asterisks (*) indicate areas of normal breathing. Conductive areas ("A"), sporadic airways ("B"), less severe focal fibrosis of the airways ("C"), and less severe focal fibrosis of the parenchyma ("D") are also marked on the image.

[0090] [Figure 29K] 1 shows the mean functional lung volumes in animals from the IPF study. [Figure 29L] Representative CT images of lungs from control animals in which IPF was not induced are shown. [Figure 29M] Representative CT images of lungs from saline-treated IPF control animals are shown. [Figure 29N] Representative CT images of lungs from a group of animals treated with Compound A 10 mg / kg are shown.

[0091] [Figure 30A] Average weight gain from weeks 11 to 19 of the lupus study is shown. [Figure 30B] The mean relative body weight at termination is shown.

[0092] [Figure 30C] 1 shows the proteinuria scores of animals in the lupus study from week 10 to the completion of the study at week 19. [Figure 30D] Mean proteinuria scores at the end of the study are shown.

[0093] [Figure 30E] The histopathological scores for total glomerular lesions after completion of the 19-week study are shown. [Figure 30F] Total tubulointerstitial lesion histopathology scores after completion of the 19-week study are shown. [Figure 30G] The histopathological scores for total renal lesions after completion of the 19-week study are shown. [Figure 30H-L] Representative histology images taken after completion of the study are shown (vehicle, H; Compound A 1 mg / kg, I; Compound A 3 mg / kg, J; Compound A 10 mg / kg, K; cyclophosphamide, L).

[0094] [Figure 30M] Mean kidney weights after completion of the 19-week study are shown. [Figure 30N] The mean spleen weights after completion of the 19-week study are shown.

[0095] [Figure 31] Serum blood urea nitrogen (BUN) concentrations (mg / dL) after completion of the 19-week study are shown.

[0096] [Figure 32] Serum anti-dsDNA antibody levels at 11, 16 and 19 weeks are shown.

[0097] [Figure 33] Shown are gastrointestinal villi from healthy animals treated with a pan-BD BET inhibitor (ABBV-075), vehicle, and BETi1 (10 mg / kg).

[0098] [Figure 34A]The mean EAE scores of the animals over the EAE study period are shown. [Figure 34B] The mean maximum EAE scores of the different groups in the EAE study are shown. [Figure 34C] The mean days of onset of EAE in different groups in the EAE study are shown. [Figure 34D] The incidence (%) of EAE in different groups in the EAE study is shown. [Figure 34E] The mean EAE scores at the end of the EAE study for the different groups are shown. [Figure 34F] Figure 1 shows the relative body weight changes during the study period for different groups in the EAE study. [Figure 34G] The mean relative body weights at the end of the different groups in the EAE study are shown.

[0099] [Figure 35A] 1 shows the mean concentrations of IFN in vehicle-treated animals and animals treated with various doses of Compound A in the EAE study. [Figure 35B] 1 shows the mean concentrations of IL-12 / IL-23p40 in vehicle-treated animals and animals treated with various doses of Compound A in an EAE study. DETAILED DESCRIPTION OF THE INVENTION

[0100] Detailed Description As used herein, the term "about" has its ordinary meaning in pharmaceutical and cosmetic formulations, and reasonable variations in amounts that can achieve the same effect are permitted, typically up to plus or minus 30%. For example, if an amount of "about 1" is provided, the amount can be from 0.70 to or up to 1.3. When "about X" results in a number greater than 100%, in some embodiments, this term can be interpreted as reflecting up to 100% by weight minus the total of the minimum amounts of the other components. Similarly, those skilled in the art will understand that as X is decreased from its upper limit, the amounts of the other components can be appropriately increased. As will be understood by those skilled in the art, there is a certain degree of reasonable flexibility in formulating compositions, so that even if the amount of one or more components varies slightly outside the range, a good formulation can still be made. Therefore, taking this possibility into account, the amounts are modified by about. In some embodiments, for example, the amounts of formulation components can be read as if the term "about" were attached as a prefix. In one or more other embodiments, for example, it can be read without the term "about". In some embodiments, the numbers can be read with the term "about" attached. In one or more other embodiments, the numbers can be read without the term "about". In one or more narrow embodiments, "about" can be plus or minus up to 15% unless the context indicates otherwise. When "about" is used in relation to ">X" or "<X" or a series of such alternatives, it can include about X in some embodiments. When "about" is used only at the beginning of a series of alternative amounts of ">about X" or "<about X" or "about>X" or "about<X", it can be understood in some embodiments to include "about" before all other alternatives in the series.

[0101] C m -C n The term refers to a group having m to n carbon atoms. For example, the term "C0" refers to a group having 0 carbon atoms.

[0102] The term "alkyl" refers to a monovalent linear or branched saturated hydrocarbon chain. For example, C1-C6-alkyl can refer to methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, and n-hexyl. An alkyl group can be unsubstituted or substituted with one or more substituents.

[0103] The term "alkylene" refers to a divalent linear saturated hydrocarbon chain. For example, C1-C3-alkylene can refer to methylene, ethylene, or propylene. An alkylene group can be unsubstituted or substituted with one or more substituents. For example, the term "C0-alkylene" refers to a group in which there is no alkylene chain. For example, "C0-alkylene-R z " is R z (where R z may refer to any of the R groups mentioned in relation to the formulae described herein. z is R z and C1-C4-alkylene-R z means a group selected from:

[0104] The term "haloalkyl" refers to a hydrocarbon chain substituted with at least one halogen atom, independently in each occurrence, selected from fluorine, chlorine, bromine, and iodine. The halogen atom may be present at any position on the hydrocarbon chain. For example, C1-C6-haloalkyl can refer to chloromethyl, fluoromethyl, trifluoromethyl, chloroethyl, e.g., 1-chloromethyl and 2-chloroethyl, trichloroethyl, e.g., 1,2,2-trichloroethyl and 2,2,2-trichloroethyl, fluoroethyl, e.g., 1-fluoromethyl and 2-fluoroethyl, trifluoroethyl, e.g., 1,2,2-trifluoroethyl and 2,2,2-trifluoroethyl, chloropropyl, trichloropropyl, fluoropropyl, or trifluoropropyl. A haloalkyl group can be a fluoroalkyl group, i.e., a hydrocarbon chain substituted with at least one fluorine atom. Thus, a haloalkyl group can have any amount of halogen substituents. The group can contain one halogen substituent, two or three halogen substituents, or be saturated with halogen substituents.

[0105] The term "alkenyl" refers to a branched or linear straight-chain hydrocarbon containing at least one double bond. The double bond(s) may exist as E or Z isomers. The double bond may be at any possible position on the hydrocarbon chain. For example, "C2-C6-alkenyl" may refer to ethenyl, propenyl, butenyl, butadienyl, pentenyl, pentadienyl, hexenyl, and hexadienyl. Alkenyl groups may be unsubstituted or substituted with one or more substituents.

[0106] The term "alkynyl" refers to a branched or linear straight-chain hydrocarbon containing at least one triple bond. The triple bond may be located at any possible position on the hydrocarbon chain. For example, "C2-C6 alkynyl" may refer to ethynyl, propynyl, butynyl, pentynyl, and hexynyl. Alkynyl groups may be unsubstituted or substituted with one or more substituents.

[0107] The term "cycloalkyl" refers to a saturated hydrocarbon ring system containing 3, 4, 5, or 6 carbon atoms. For example, "C3-C6-cycloalkyl" can refer to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl. Cycloalkyl groups can be unsubstituted or substituted with one or more substituents.

[0108] The term "y- to z-membered heterocycloalkyl" refers to a y- to z-membered heterocycloalkyl group. Thus, it can refer to a monocyclic or bicyclic saturated or partially saturated group having y to z atoms in the ring system, including one or two heteroatoms independently selected from O, S, and N (i.e., one or two of the atoms forming the ring system are selected from O, S, and N). Partially saturated means that the ring can contain one or two double bonds. This is particularly true for monocyclic rings having five or six members. The double bond is typically between two carbon atoms, but may also be between a carbon atom and a nitrogen atom. Examples of heterocycloalkyl groups include oxirane, aziridine, thiane, oxetane, azetidine, thietane, piperidine, piperazine, morpholine, thiomorpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, dihydrofuran, tetrahydropyran, dihydropyran, dioxane, and azepine. A heterocycloalkyl group can be unsubstituted or substituted with one or more substituents.

[0109] An aryl group can be any aromatic carbocyclic ring system (i.e., a ring system containing 2(2n+1) pi electrons). An aryl group can have 6 to 10 carbon atoms in the ring system. An aryl group is typically a phenyl group. An aryl group can be a naphthyl group or a biphenyl group.

[0110] The term "heterocyclyl" group refers to a ring containing 1 to 4 heteroatoms independently selected from O, S, and N. The ring can be a heterocycloalkyl ring (including both saturated and partially saturated rings) or a heteroaryl ring. The term "heterocyclyl" also encompasses tautomers of hydroxyheteroaryl groups, such as pyridone, and tautomers of hydroxyheteroaryl groups substituted at nitrogen, such as N-alkylpyridone.

[0111] The term "heterocycloalkenyl" refers to a partially saturated ring containing 1 to 2 heteroatoms independently selected from O, S, and N.

[0112] The term "heteroaryl" refers to any aromatic (i.e., a ring system containing 2(2n+1) π-electrons) five- or six-membered ring system containing one to four heteroatoms independently selected from O, S, and N (i.e., one to four of the atoms forming the ring system are selected from O, S, and N). Thus, any heteroaryl group can be independently selected from five-membered heteroaryl groups in which the aromatic heterocycle is substituted with one to four heteroatoms independently selected from O, S, and N, and six-membered heteroaryl groups in which the aromatic heterocycle is substituted with one to three (e.g., one to two) nitrogen atoms. Specifically, heteroaryl groups can be independently selected from pyrrole, furan, thiophene, pyrazole, imidazole, oxazole, isoxazole, triazole, oxadiazole, thiadiazole, tetrazole; pyridine, pyridazine, pyrimidine, pyrazine, and triazine.

[0113] Variables that can be selected from "carbon" and "nitrogen" (i.e., X 1 , X 2 , X 3 , X 4 , X 5 ), the carbon or nitrogen may be replaced by hydrogen and / or a designated substituent (i.e., -R 2a , R 4 ) can be further included.

[0114] Optional substituents (i.e., -R 2a , R 4 ) is designated, it is understood that that substituent, if present, can replace a hydrogen on any carbon or nitrogen of the ring system.

[0115] Compounds of the present disclosure that contain one or more asymmetric carbon atoms can exist as two or more stereoisomers.Certain compounds of the present disclosure can exist in specific geometric and / or stereoisomeric forms, and the present disclosure contemplates that all such compounds, including cis and trans isomers, R-enantiomers and S-enantiomers, diastereomers, racemic mixtures thereof, and other mixtures thereof, are included within the scope of the present disclosure.Additional asymmetric carbon atoms may be present in substituents such as alkyl groups.All such isomers and mixtures thereof are included in the present disclosure.

[0116] When a compound of the present disclosure contains a double bond, such as a C=C or C=N group, cis / trans (or Z / E) geometric isomers are possible. When structural isomers are interconvertible via a low energy barrier, tautomeric isomerism ("tautomerism") can occur. This can take the form of, for example, proton tautomerism in compounds of the present disclosure containing an imino, keto, or oxime group, or so-called valence tautomerism in compounds containing an aromatic moiety. In other words, a single compound can exhibit more than one type of isomerism.

[0117] All stereoisomeric, geometric isomeric, and tautomeric forms of the compounds of the present disclosure are included within the scope of the present disclosure, including compounds exhibiting more than one type of isomerism, and mixtures of one or more thereof. Also included are acid addition or base salts in which the counterion is optically active, e.g., d-lactate or l-lysine, or racemic, e.g., dl-tartrate or dl-arginine.

[0118] Cis / trans isomers can be separated by conventional techniques well known to those skilled in the art, such as chromatography and fractional crystallization.

[0119] Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis, if necessary, from suitable optically pure precursors, or resolution of the racemate (or racemate of a salt or derivative) using, for example, chiral high-performance liquid chromatography (HPLC). Thus, the chiral compounds of the present disclosure (and their chiral precursors) can be obtained in enantiomerically enriched form by chromatography, typically using HPLC, on an asymmetric resin using a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing about 0 to about 50% by volume, typically about 2% to about 20% isopropanol, and, as a specific example, about 0 to about 5% by volume of an alkylamine, e.g., about 0.1% diethylamine. Concentration of the eluate yields the enriched mixture.

[0120] Alternatively, the racemate (or racemic precursor) may be reacted with a suitable optically active compound, for example, an alcohol, or, if the compound of the present disclosure contains an acidic or basic moiety, with a base or acid such as 1-phenylethylamine or tartaric acid. The resulting diastereomeric mixture may be separated by chromatography and / or fractional crystallization, and one or both of the diastereoisomers may be converted to the corresponding pure enantiomer(s) by means well known to those skilled in the art.

[0121] When any racemic compound crystallizes, two different types of crystals are possible: the first type is the racemate described above (a true racemate), in which one homogeneous crystalline form containing both enantiomers in equimolar amounts is produced; the second type is a racemic mixture or conglomerate, in which two crystalline forms, each containing a single enantiomer, are produced in equimolar amounts.

[0122] Both crystalline forms present in a racemic mixture have identical physical properties, but may have different physical properties compared to the true racemate. Racemic mixtures can be separated by conventional techniques known to those skilled in the art. See, for example, "Stereochemistry of Organic Compounds" by EL Eliel and SH Wilen (Wiley, 1994).

[0123] The present disclosure also includes all pharmaceutically acceptable isotopically labeled compounds of the formulae described herein and their syntheses, in which one or more atoms are replaced by an atom having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number normally found in nature.

[0124] Examples of isotopes suitable for inclusion in compounds of the present disclosure include hydrogen isotopes, e.g., 2 H and 3 H, carbon isotopes, e.g. 11 C. 13 C and 14 C, chlorine isotopes, e.g. 36 Cl, fluorine isotopes, e.g. 18 F, iodine isotopes, e.g. 123 I and 125 I, nitrogen isotopes, e.g. 13 N and 15 N, oxygen isotopes, e.g. 15 O. 17 O and 18 O, phosphorus isotopes, e.g. 32 P, as well as sulfur isotopes, e.g. 35 Examples include S.

[0125] Isotopically labeled compounds can generally be prepared by conventional techniques known to those skilled in the art, or by processes analogous to those described, substituting the appropriate isotopically labeled reagent for the previously used non-isotopically labeled reagent.

[0126] Suitable pharmaceutically acceptable salts include, but are not limited to, salts of pharmaceutically acceptable inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, carbonic acid, boric acid, sulfamic acid, and hydrobromic acid, or salts of pharmaceutically acceptable organic acids such as acetic acid, propionic acid, butyric acid, tartaric acid, maleic acid, hydroxymaleic acid, fumaric acid, malic acid, citric acid, lactic acid, mucic acid, gluconic acid, benzoic acid, succinic acid, oxalic acid, phenylacetic acid, methanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, salicylic acid, sulfanilic acid, aspartic acid, glutamic acid, edetic acid, stearic acid, palmitic acid, oleic acid, lauric acid, pantothenic acid, tannic acid, ascorbic acid, and valeric acid. Suitable base salts are formed from bases which form non-toxic salts. Examples include the aluminum, arginine, benzathine, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine, and zinc salts. Hemisalts of acids and bases can also be formed, such as hemisulfate and hemicalcium salts.

[0127] The activity of the compounds of the present disclosure can be assessed by a variety of in silico, in vitro, and in vivo assays. In silico analysis of various compounds has been demonstrated to be predictive of ultimate in vitro and even in vivo activity.

[0128] As used herein, the term "composition" is intended to encompass a product containing specified ingredients in predetermined amounts or proportions, as well as any product resulting directly or indirectly from the combination of specified ingredients in specified amounts. This term, with respect to pharmaceutical compositions, is intended to encompass products containing one or more active ingredients and optional pharmaceutically acceptable carriers, including inactive ingredients, as well as any product resulting directly or indirectly from the combination, complexation, or aggregation of two or more ingredients, or the dissociation of one or more ingredients, or any other type of reaction or interaction of one or more ingredients. Generally, pharmaceutical compositions are prepared by uniformly and intimately admixing the active ingredients with liquid carriers or finely divided solid carriers, or both, and then, if necessary, shaping the product into the desired formulation. In pharmaceutical compositions, the active compound is present in an amount sufficient to produce the desired effect on a disease process or condition.

[0129] Accordingly, the pharmaceutical compositions of the present invention encompass any composition made by admixing a compound of the present disclosure with a pharmaceutically acceptable carrier, prepared according to conventional mixing, granulating, or coating methods, respectively, and containing a therapeutically effective amount of the active ingredient.

[0130] By "pharmaceutically acceptable" it is meant that the carrier, diluent, or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. Pharmaceutical compositions intended for oral use may be prepared according to any method known in the art for the manufacture of pharmaceutical compositions, and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents, and preservatives in order to provide a pharmaceutically elegant and palatable preparation.

[0131] The composition of the present invention can be provided in unit dosage form and can be prepared by any method known in the pharmaceutical field.The term "unit dosage form" refers to a single dose in which all active and inactive ingredients are combined in a suitable system, so that the patient or the person administering the drug to the patient can open a single container or package containing the entire dose, and does not need to mix any components from two or more containers or packages together.A typical example of a unit dosage form is a tablet or capsule for oral administration.These examples of unit dosage form are not intended to be limiting in any way, but are simply intended to represent typical examples of unit dosage form in the pharmaceutical field.

[0132] As used herein, the term "appendage" includes hands, feet, wrists, ankles, and / or joints.

[0133] References to "treating" or "treatment" should be understood to include prevention as well as the alleviation of established symptoms of a condition. Thus, "treating" or "treatment" of a condition, disorder, or condition includes (1) preventing or delaying the onset of clinical symptoms of the condition, disorder, or condition in a person who may be susceptible to or predisposed to the condition, disorder, or condition but who has not yet experienced or exhibited clinical or subclinical symptoms of the condition, disorder, or condition; (2) inhibiting the condition, disorder, or condition, i.e., arresting, alleviating, or delaying the onset of the disease or its recurrence (in the case of maintenance treatment) or at least one clinical or subclinical symptom thereof; or (3) palliating or attenuating the disease, i.e., causing regression of the condition, disorder, or condition or at least one clinical or subclinical symptom thereof.

[0134] A "therapeutically effective amount" includes the amount of a compound that, when administered to a mammal for treating a disease, is sufficient to effect such treatment for the disease. The "therapeutically effective amount" will vary depending on the compound, the disease and its severity, and the age, weight, etc., of the mammal being treated.

[0135] The compounds of the present disclosure or pharmaceutically acceptable salts thereof may be used alone or may be administered in the form of a pharmaceutical composition in which the compounds of the present disclosure or pharmaceutically acceptable salts thereof are combined with a pharmaceutically acceptable adjuvant, diluent or carrier.

[0136] Conventional procedures for the selection and preparation of suitable pharmaceutical formulations are described, for example, in "Pharmaceuticals - The Science of Dosage Form Designs", MEAulton, Churchill Livingstone, 1988. Examples of topical formulations and dosage forms are found in Remington: The Science and Practice of Pharmacy (21 st Edition), University of the Sciences in Philadelphia. Further exemplary formulations are provided in the Examples section of the present specification. In some embodiments, formulations of the compounds disclosed herein include a 20% propylene glycol / 20% vitamin E TPGS / 60% water formulation; an HPβCD (20% solution (w / v) / DMSO (99 / 1))-based formulation; a 1% methylcellulose formulation; a 5% DMSO / 40% PEG-400 / 55% Milli-Q water formulation; a 5% DMSO / 15% PEG-400 / 80% (10% vitamin E TPGS in water) formulation; a 5% DMSO / 40% PEG-400, 55% water (0.9% NaCl) formulation; and a 5% DMSO / 15% PEG-400 / 80% E-TPGS in purified water formulation.

[0137] Depending on the mode of administration of the compounds of the present disclosure, pharmaceutical compositions used to administer the compounds of the present disclosure, in some embodiments, contain from about 0.005 to about 99 wt.% of a compound of the present disclosure, or from about 0.05 to about 80 wt.% of a compound of the present disclosure, or from about 0.10 to about 70 wt.% of a compound of the present disclosure, or from about 0.10 to about 50 wt.% of a compound of the present disclosure (all weight percentages based on the total composition). In some embodiments, the pharmaceutical composition used to administer a compound of the present disclosure comprises about 0.005 to about 40 wt. % of a compound of the present disclosure, or about 0.005 to about 30 wt. % of a compound of the present disclosure, or about 0.010 to about 20 wt. % of a compound of the present disclosure, or about 0.010 to about 10 wt. % of a compound of the present disclosure, or about 0.005 to about 5 wt. % of a compound of the present disclosure, or about 0.005 to about 2 wt. % of a compound of the present disclosure, or about 0.005 to about 1 wt. % of a compound of the present disclosure, or about 0.005 to about 0.5 wt. % of a compound of the present disclosure, or about 0.010 to about 1 wt. % of a compound of the present disclosure, or about 0.010 to about 0.5 wt. % of a compound of the present disclosure. In some embodiments, the pharmaceutical composition used to administer the compounds of the present disclosure comprises about 0.010 to about 0.3 w / w% of a compound of the present disclosure, and in some embodiments, the pharmaceutical composition comprises about 0.01 w / w%, or about 0.02 w / w%, or about 0.03 w / w%, or about 0.05 w / w%, about 0.075 w / w%, or about 0.1 w / w%, about 0.2 w / w%, or about 0.3 w / w%, about 0.4 w / w%, or about 0.5 w / w% (all weight percentages based on the total composition).

[0138] The pharmaceutical compositions may be administered topically (e.g., to the skin) in the form of, for example, creams, ointments, gels, lotions, solutions, suspensions; or by oral administration, for example, in the form of tablets, lozenges, hard or soft capsules, liquids, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs; or by parenteral administration in the form of sterile aqueous or oily solutions, suspensions, or emulsions for injection (including intra-articular, intravenous, intracoronary, subcutaneous, intramyocardial, intraperitoneal, intramuscular, intravascular or infusion); by rectal administration in the form of suppositories or enemas; or systemically by inhalation, for example, as a finely divided powder or liquid aerosol or mist; or by insufflation (e.g., as a finely divided powder).

[0139] For oral administration, the compounds of the present disclosure may be mixed with adjuvants or carriers such as lactose, saccharose, sorbitol, mannitol; starches such as potato starch, corn starch, or amylopectin; cellulose derivatives; binders such as gelatin or polyvinylpyrrolidone; and / or lubricants such as magnesium stearate, calcium stearate, polyethylene glycol, wax, paraffin, etc., and then compressed into tablets. If coated tablets are required, the cores prepared as described above may be coated with a concentrated sugar solution, which may contain, for example, gum arabic, gelatin, talc, and titanium dioxide. Alternatively, tablets may be coated with a suitable polymer dissolved in a readily volatile organic solvent. Thus, compositions intended for oral use may contain, for example, one or more colorants, sweeteners, flavoring agents, and / or preservatives.

[0140] For the preparation of soft gelatin capsules, the compounds of the present disclosure can be mixed with, for example, vegetable oil or polyethylene glycol.Hard gelatin capsules may contain granules of the compounds using any of the tablet excipients mentioned above.Also, liquid or semisolid formulations of the compounds of the present disclosure can be filled into hard gelatin capsules.Liquid formulations for oral administration can be in the form of syrups or suspensions, for example, a solution containing the compounds of the present disclosure, with the remainder being a mixture of sugar and ethanol, water, glycerol, and propylene glycol.Optionally, such liquid formulations may contain colorants, flavoring agents, sweeteners (such as saccharin), carboxymethylcellulose as a preservative and / or thickener, or other excipients known to those skilled in the art.

[0141] For intravenous (parenteral) administration, the compounds of the present disclosure may be administered as a sterile aqueous / hydrophilic or hydrophobic / oily solution or suspension.

[0142] The magnitude of a dose of a compound of the present disclosure for therapeutic or prophylactic purposes will, of course, vary according to well-known principles of medicine depending on the nature and severity of the condition, the concentration of compound required for efficacy in isolated cells, the concentration of compound required for efficacy in experimental animals, the age and sex of the animal or patient, and the route of administration.

[0143] Dosage levels, frequency of administration, and duration of treatment of the compounds of the present disclosure are expected to vary depending on the formulation and clinical indication, age and coexisting medical conditions of the patient.

[0144] An effective amount of a compound of the present disclosure for use in treating a condition is an amount sufficient to achieve symptomatic alleviation of the symptoms of the condition, reduce the physical manifestations of the condition, or slow the progression of the condition in a warm-blooded animal, particularly a human.

[0145] The compositions described herein can be provided in unit dosage form and can be prepared by any method known in the pharmaceutical field.The term "unit dosage form" refers to a single dose in which all active and inactive ingredients are combined in a suitable system, so that the patient or the person administering the drug to the patient can open a single container or package containing the entire dose, and does not need to mix any components from two or more containers or packages together.A typical example of a unit dosage form is a tablet or capsule for oral administration.These examples of unit dosage form are not intended to be limiting in any way, but are simply intended to represent typical examples of unit dosage form in the pharmaceutical field.

[0146] The concentration of the compounds disclosed herein in the formulations can vary widely and will depend on a variety of factors, including the disease or condition being treated, the selectivity, potency and bioavailability of the compounds disclosed herein, the desired effect, possible adverse reactions, the ability and speed with which the compounds disclosed herein reach their intended target, and other factors within the particular knowledge of the patient and physician.

[0147] The amount of active ingredient that is combined with one or more excipients to produce a single dosage form will necessarily vary depending upon the host treated and the particular route of administration. For example, a formulation intended for oral administration to humans will generally contain, for example, from about 0.5 mg to about 0.5 g of active agent (more preferably, from about 0.5 mg to about 100 mg, e.g., from about 1 mg to about 30 mg), compounded with an appropriate and convenient amount of excipient, which can vary from about 5 to about 98 percent or about 99 percent by weight of the total composition.

[0148] For the compounds of the present disclosure described above, dosages will, of course, vary depending on the compound used, the mode of administration, the desired treatment, and the specific disorder. When using the compounds of the present disclosure for therapeutic or prophylactic purposes, the compounds are generally administered to provide a daily dose within a range, for example, a daily dose selected from about 0.1 mg / kg body weight to about 100 mg / kg body weight, about 1 mg / kg body weight to about 75 mg / kg body weight, about 1 mg / kg body weight to about 50 mg / kg body weight, about 1 mg / kg body weight to about 20 mg / kg body weight, or about 5 mg / kg body weight to about 10 mg / kg body weight, administered in divided doses if necessary. Generally, when a parenteral route is used, lower doses are administered. Thus, for example, when administered intravenously or intraperitoneally, a dose in the range of about 0.1 mg / kg body weight to about 30 mg / kg body weight will generally be used. Similarly, for intraarticular administration, a dose ranging from about 0.01 mg / kg body weight to about 30 mg / kg body weight can generally be used. For inhalation administration, a dose ranging from about 0.05 mg / kg body weight to about 25 mg / kg body weight can be used. Preferably, the compounds of the present disclosure are orally administered, for example, in the form of a tablet or capsule. The daily oral dose can be, for example, a total daily dose selected from about 1 mg to about 1000 mg, about 5 mg to about 1000 mg, about 10 mg to about 750 mg, or about 25 mg to about 500 mg. Typically, a unit dosage form contains about 0.5 mg to about 0.5 g of the compounds of the present disclosure. In some embodiments, the dosage is about 0.1 mg / kg to about 10 mg / kg body weight, or about 0.1 mg / kg to 1 mg / kg body weight, or about 0.1 mg / kg to about 2 mg / kg body weight, or about 1 mg / kg to 10 mg / kg body weight. In some embodiments, the dosage is about 0.1 mg / kg body weight, or about 0.15 mg / kg body weight, or about 0.3 mg / kg body weight, or about 0.5 mg / kg body weight, or about 0.8 mg / kg body weight, or about 1 mg / kg body weight, or about 3 mg / kg body weight, or about 6 mg / kg body weight, or about 10 mg / kg body weight.In some embodiments, if a compound is more active and / or has higher bioavailability, a lower unit dosage, e.g., about 0.2 mg to about 0.2 g, of a compound of the present disclosure may be appropriate. In some embodiments, a compound disclosed herein is administered daily. In some embodiments, a compound disclosed herein is administered every other day. In some embodiments, a compound disclosed herein is administered once a week. The administration period is, in some embodiments, several days, in some embodiments, about 1 to 12 weeks, and in some embodiments, about 3 to 12 months.

[0149] The compound of the present disclosure may be administered together with other active compounds as part of a treatment plan.The other active compounds can be administered simultaneously with, after, or before the administration of the compound of the present disclosure.The pharmaceutical preparation containing the compound of the present disclosure may also contain one or more other active compounds.The other active compounds can be anti-cancer agents, anti-inflammatory agents, antibacterial agents, antiviral agents, antiemetic agents, antithrombotic agents, or compounds that change metabolism.

[0150] Throughout the description and claims of this specification, the words "comprise" and "contain" and variations thereof mean "including, but not limited to," and are not intended to exclude (and do not exclude) other moieties, adjuncts, components, integers, or steps. Throughout the description and claims of this specification, the singular includes the plural unless the context dictates otherwise. In particular, where the indefinite article is used, the specification should be understood as contemplating both the plural and the singular unless the context dictates otherwise.

[0151] It should be understood that any feature, integer, property, compound, chemical moiety, or group described in connection with a particular aspect, embodiment, or example of the present disclosure is also applicable to any other aspect, embodiment, or example described herein, unless inconsistent therewith. All features described herein (including any accompanying claims, abstract, and drawings) and / or all steps of any disclosed method or process may be combined in any combination, except combinations in which at least some of such features and / or steps are mutually exclusive. The present disclosure is not limited to the details of any foregoing embodiment. The present disclosure extends to any novel single or any novel combination of features or any novel combination of steps of any disclosed method or process disclosed herein (including any accompanying claims, abstract, and drawings).

[0152] The embodiments disclosed herein are independent and interchangeable. Any one embodiment can be combined with any other embodiment where chemically permissible and / or biologically appropriate, as will be understood by those skilled in the art. In other words, any feature described in an embodiment can be combined with features described in one or more other embodiments (where chemically permissible and / or biologically appropriate). For example, if a compound or disease or disorder is exemplified or described herein, any two or more of the embodiments listed herein, expressed at any level of generality encompassing that compound or disease or disorder, can be combined to provide additional embodiments that form part of the present disclosure. For the avoidance of doubt, terms encompassing a range of formulas, such as "any of Formulas (XII)-(XX)," encompass subformulas therein, e.g., Formula (XVIIA).

[0153] It will be understood that various modifications may be made to the embodiments disclosed herein. Therefore, the above description should not be construed as limiting, but as exemplifications of preferred embodiments. For example, the above-described functions implemented as the best mode for carrying out the disclosure are for illustrative purposes only. Those skilled in the art may implement other configurations and methods without departing from the scope and spirit of the present disclosure. Furthermore, those skilled in the art will envision other modifications within the scope and spirit of the specification attached hereto.

[0154] The reader's attention is directed to all documents and literature related to this application that have been filed contemporaneously or previously hereto and that have been made publicly available herewith, the contents of which are hereby incorporated by reference in their entirety.

[0155] In some embodiments, the present disclosure provides a compound of formula (I), or a pharmaceutically acceptable salt or N-oxide thereof: TIFF2026501324000014.tif58165

[0156] (In the formula,

[0157] Ring A is independently selected from phenyl, 5-membered heterocyclyl, and 6-membered heterocyclyl; X 4 and X 5 are independently selected from carbon and nitrogen;

[0158] R 1 are independently C1-C5-alkyl, C1-C5-haloalkyl, C2-C6-alkynyl, COR 6 , CO2R 6 , C1-C4-alkylene-NR 5 R 6 , C1-C4-alkylene-OR 7 , C1-C4-alkyl-S(O)2R 6 , C3-C6-cycloalkyl, aryl, heteroaryl, and 3- to 6-membered heterocycloalkyl;

[0159] R 2 is absent or independently represents H, halo, cyano, nitro, SF4, SF5, =O, S(O)2R 6 , alkoxy, C1-C6-haloalkyl, C1-C8-alkyl, C3-C6-cycloalkyl, 4- to 8-membered heterocycloalkenyl, 3- to 8-membered heterocycloalkyl, aryl, and 5- or 6-membered heteroaryl;

[0160] wherein C1-C8-alkyl, alkoxy, C3-C6-cycloalkyl, 4- to 8-membered heterocycloalkenyl, 3- to 8-membered heterocycloalkyl, aryl, and 5- or 6-membered heteroaryl are optionally substituted independently by one or more groups selected from halogen, cyano, nitro, hydroxy, SF5, amido, ester, alkoxy, and C1-C4-alkyl;

[0161] R 3 are independently 3a and OR 3b is selected from

[0162] R 3a is independently selected from H, CN, C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl, C2-C4-haloalkenyl, C3-C8-cycloalkyl, C5-C8-cycloalkenyl, 5- to 9-membered heterocycloalkenyl, 3- to 9-membered heterocycloalkyl, phenyl, and 5- to 9-membered heteroaryl;

[0163] wherein cycloalkyl, heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl are independently selected from 1 to 4 R 8 may be substituted with a group,

[0164] Phenyl and 5- to 9-membered heteroaryl are independently selected from 1 to 5 R 9 may be substituted with a group,

[0165] R 3bis independently selected from C1-C4-alkyl, C2-C4-alkylene-O-C1-C4-alkyl, C1-C4-haloalkyl, C3-C8-cycloalkyl, 3- to 8-membered heterocycloalkyl, phenyl, and 5- or 6-membered heteroaryl,

[0166] wherein cycloalkyl and 3- to 8-membered heterocycloalkyl are independently 1 to 4 R 8 may be substituted with a group,

[0167] Phenyl and 5- or 6-membered heteroaryl are independently selected from 1 to 5 R 9 may be substituted with a group,

[0168] R 4 is independently in each occurrence H, ═O, ═S, halo, nitro, cyano, C0-C4-alkylene-NR 5 R 6 , -NR 5 R 6 , C0-C4-alkylene-OR 7 , -OR 7 , S.R. 6 , SOR 6 , C0-C4-alkylene-S(O)2R 6 , -S(O)2R 6 , SO2NR 6 R 6 , C0-C4-alkylene-CO2R 6 , -CO2R 6 , C0-C4-alkylene-C(O)R 6 , -C(O)R 6 , C0-C4-alkylene-CONR 6 R 6 , -CONR 6 R 6 , C1-C6-alkyl, C1-C4-alkyl-S(O)2R 6 , C2-C4-alkenyl, C2-C4-alkynyl, C1-C6-haloalkyl, C3-C6-cycloalkyl, aryl, 4- to 6-membered heterocycloalkyl, and 5- or 6-membered heteroaryl;

[0169] wherein aryl, 4- to 6-membered heterocycloalkyl, and 5- or 6-membered heteroaryl are independently selected from 1 to 5 R 9 may be substituted with a group,

[0170] R 5 is independently selected in each occurrence from H, C1-C4-alkyl, C(O)—C1-C4-alkyl, and S(O)2—C1-C4-alkyl, or R 5 and R 6 together with the nitrogen atom to which they are attached, form one to four R 8 forming a C5-C8 heterocycloalkyl group optionally substituted by a group,

[0171] R 6 is independently selected in each occurrence from H and C1-C6-alkyl, or two R 6 If groups are attached to the same nitrogen, the two R 6 The groups, together with the nitrogen atom to which they are attached, can consist of one to four R 8 may form a C5-C8 heterocycloalkyl group optionally substituted by a group,

[0172] R 7 is independently selected at each occurrence from H, C-C-alkyl, C(O)—C-C-alkyl, and C-C-haloalkyl;

[0173] R 8 is independently in each occurrence =O, =S, fluoro, nitro, cyano, NR 5 R 6 , OR 7 , S.R. 6 , SOR 6 , S(O)2R 6 , SO2NR 6 R 6 , CO2R 6 , C(O)R 6 ,CONR 6 R 6, C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl, 4- to 6-membered heterocycloalkyl, and C3-C6-cycloalkyl;

[0174] R 9 is, independently in each occurrence, halo, nitro, cyano, NR 5 R 6 , C1-C4-alkyl-OR 7 , OR 7 , S.R. 6 , SOR 6 , C1-C4-alkyl-S(O)2R 6 , S(O)2R 6 , SO2NR 6 R 6 , CO2R 6 , C(O)R 6 ,CONR 6 R 6 , C0-C4-alkylene-R 9a , C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl, 4- to 6-membered heterocycloalkyl, and C3-C6-cycloalkyl, or two R 9 If the groups are attached to adjacent atoms, the two R 9 Groups, together with the atoms to which they are attached, consist of one to four R 8 may form a 5- or 6-membered heterocycloalkyl group optionally substituted with a group,

[0175] R 9a is independently selected at each occurrence from 4- to 6-membered heterocycloalkyl;

[0176] R 10 is absent or, independently in each occurrence, H, halo, C1-C6-alkyl, C1-C6-haloalkyl, nitro, cyano, NR 5 R 6 , OR 7 , S.R. 6 , SOR 6 , S(O)2R 6 , SO2NR 6R 6 , CO2R 6 , C(O)R 6 ,CONR 6 R 6 , C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl and 3- to 8-membered heterocycloalkyl;

[0177] R 11 are independently selected from phenyl, heteroaryl, and heterocyclyl, each of which is selected from 1 to 4 R 2 group and 1 to 3 R 10 may be substituted with a group,

[0178] R x and R y are each independently H, halo, nitro, cyano, C1-C6-alkylene-NR 5 R 6 , N.R. 5 R 6 , C1-C6-alkylene-OR 7 、 C1~C6-Alkyl-OR 7 , OR 7 , C1-C6-alkyl-SR 6 , S.R. 6 , C1-C6-alkyl-SOR 6 , SOR 6 , C1-C6-alkyl-S(O)2R 6 , S(O)2R 6 , C1-C6-Alkyl-SO2NR 6 R 6 , SO2NR 6 R 6 , C1-C6-alkyl-CO2R 6 , CO2R 6 , C1-C6-alkyl-C(O)R 6 , C(O)R 6 , C1-C6-alkyl-CONR 6 R 6 ,CONR 6 R 6, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-haloalkyl, C3-C8-cycloalkyl, 3- to 8-membered heterocycloalkyl, aryl, aryloxy, and 5- to 8-membered heteroaryl;

[0179] m is an integer selected from 0, 1, 2, 3 and 4;

[0180] Any of the aforementioned alkyl, alkylene, alkenyl or C3-C6-cycloalkyl groups may, where chemically possible, independently in each case be selected from C1-C4-alkyl, oxo, fluoro, nitro, cyano, NR a R b , OR a , S.R. a , CO2R a , C(O)R a ,CONR a R a , S(O)R a and S(O)2R a and optionally substituted with 1 to 5 substituents selected from the group consisting of:

[0181] where R a is independently selected at each occurrence from H, C1-C4-alkyl, and C1-C4-haloalkyl;

[0182] R b is independently in each occurrence selected from H, C1-C4-alkyl, C(O)—C1-C4-alkyl and S(O)2—C1-C4-alkyl).

[0183] In embodiment A, the disclosure provides a compound of formula (I), or a pharmaceutically acceptable salt or N-oxide thereof: TIFF2026501324000015.tif58165

[0184] (In the formula,

[0185] Ring A is independently selected from phenyl, 5-membered heterocyclyl, and 6-membered heterocyclyl; X 4 are independently selected from carbon and nitrogen; X 5 are independently selected from carbon and nitrogen;

[0186] R 1 is independently selected from C1-C3-alkyl, C1-C3-fluoroalkyl, C3-C4-cycloalkyl and 4-membered heterocycloalkyl,

[0187] R 11 are independently selected from 5-membered heterocyclyl, 6-membered heterocyclyl, and phenyl, each of which is selected from 1 to 4 R 2a may be substituted with a group,

[0188] R 2a is independently in each occurrence =O, =S, halo, nitro, cyano, SF6, NR 5 R 6 , OR 7 , S.R. 6 , SOR 6 , S(O)2R 6 , SO2NR 6 R 6 , CO2R 6 , C(O)R 6 ,CONR 6 R 6 , C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl, C3-C6 cycloalkyl and 4-6-membered heterocyclyl;

[0189] R 3 are independently 3a , OR 3b , and NR 6 R 3b is selected from

[0190] R 3a are independently H, CN, C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl, C2-C4-haloalkenyl, and C0-C3-alkylene-R3c where R 3c is independently selected in each occurrence from C-C-cycloalkyl, C-C-cycloalkenyl, 5- to 8-membered heterocycloalkenyl, 3- to 8-membered heterocycloalkyl, phenyl, and 5- or 6-membered heteroaryl; R 3c is cycloalkyl, heterocycloalkyl, cycloalkenyl, or heterocycloalkenyl, then R 3c is 1 to 4 R 8 may be substituted with R 3c is phenyl or heteroaryl, R 3c is 1 to 5 R 9 may be substituted with a group,

[0191] R 3b are independently C1-C4-alkyl, C2-C4-alkylene-O-C1-C4-alkyl, C1-C4-haloalkyl and C0-C3-alkylene-R 3d where R 3d is independently selected at each occurrence from C-C-cycloalkyl, 3- to 8-membered heterocycloalkyl, phenyl, and 5- or 6-membered heteroaryl; R 3d When R is cycloalkyl or heterocycloalkyl, 3d is 1 to 4 R 8 may be substituted with R 3d is phenyl or heteroaryl, R 3d is 1 to 5 R 9 may be substituted with a group,

[0192] R 4 is independently in each occurrence =O, =S, halo, nitro, cyano, C0-C4-alkylene-NR 5 R 6 , C0-C4-alkylene-OR 7 , S.R. 6 , SOR 6 , C0-C4-alkylene-S(O)2R 6 , SO2NR 6 R 6, C0-C4-alkylene-CO2R 6 , C0-C4-alkylene-C(O)R 6 , C0-C4-alkylene-CONR 6 R 6 , C1-C4-alkyl, C1-C4-alkyl-S(O)2R 6 , C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl, C3-C6-cycloalkyl, and C0-C4-alkylene-R 4c is selected from

[0193] R 4c is independently selected at each occurrence from C-C-cycloalkyl and 4- to 6-membered heterocycloalkyl;

[0194] R 5 is independently selected in each occurrence from H, C1-C4-alkyl, C(O)—C1-C4-alkyl and S(O)2—C1-C4-alkyl, or R 5 and R 6 together with the nitrogen atom to which they are attached, form one to four R 8 forming a C5-C8 heterocycloalkyl group optionally substituted by a group,

[0195] R 6 is independently selected in each occurrence from H and C1-C4-alkyl, or two R 6 If groups are attached to the same nitrogen, the two R 6 The groups, together with the nitrogen atom to which they are attached, can consist of one to four R 8 may form a C5-C8 heterocycloalkyl group optionally substituted by a group,

[0196] R 7 is independently selected at each occurrence from H, C1-C4-alkyl, C(O)—C1-C4-alkyl and C1-C4-haloalkyl;

[0197] R 8is independently in each occurrence =O, =S, fluoro, nitro, cyano, NR 5 R 6 , OR 7 , S.R. 6 , SOR 6 , S(O)2R 6 , SO2NR 6 R 6 , CO2R 6 , C(O)R 6 ,CONR 6 R 6 , C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl and cyclopropyl;

[0198] R 9 is independently in each occurrence halo, nitro, cyano, C0-C4-alkylene-NR 5 R 6 , C0-C4-alkylene-OR 7a , C0-C4-alkylene-SR 6 , C0-C4-alkylene-SOR 6 , C0-C4-alkylene-S(O)2R 6 , C0-C4-alkylene-SO2NR 6 R 6 , C0-C4-alkylene-CO2R 6 , C0-C4-alkylene-C(O)R 6 , C0-C4-alkylene-CONR 6 R 6 , C0-C4-alkylene-R 9a , C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl, or two R 9 If the groups are attached to adjacent atoms, the two R 9 Groups, together with the atoms to which they are attached, consist of one to four R 8 may form a 5- or 6-membered heterocycloalkyl group optionally substituted with a group,

[0199] R 7ais independently in each occurrence H, C1-C4-alkyl, C(O)—C1-C4-alkyl, C0-C4-alkylene-NR5R6, —C0-C4-alkyl-OR 7 , C0-C4-alkylene-SR 6 , C0-C4-alkylene-SOR 6 , C0-C4-alkylene-S(O)2R 6 , C0-C4-alkylene-SO2NR 6 R 6 , C0-C4-alkylene-CO2R 6 , C0-C4-alkylene-C(O)R 6 , C0-C4-alkylene-CONR 6 R 6 and C1-C4-haloalkyl;

[0200] R 9a is independently selected at each occurrence from C-C-cycloalkyl and 4- to 6-membered heterocycloalkyl;

[0201] R x and R y are each independently H, halo, nitro, cyano, or NR 5 R 6 , OR 7 , S.R. 6 , SOR 6 , S(O)2R 6 , SO2NR 6 R 6 , CO2R 6 , C(O)R 6 ,CONR 6 R 6 , C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl, C3-C4-cycloalkyl and 4-membered heterocycloalkyl,

[0202] m is an integer selected from 0, 1, 2, 3 and 4;

[0203] Any of the aforementioned alkyl, alkylene, alkenyl, cycloalkyl or heterocycloalkyl groups may, where chemically possible, independently in each case be C1-C4-alkyl, oxo, fluoro, nitro, cyano, NR a R b , OR a , S.R. a , CO2R a , C(O)R a ,CONR a R a , S(O)R a and S(O)2R a and optionally substituted with 1 to 5 substituents selected from the group consisting of: a is independently selected at each occurrence from H and C1-C4-alkyl; R b is independently selected in each occurrence from H, C1-C4-alkyl, C(O)-C1-C4-alkyl and S(O)2-C1-C4-alkyl). 11 is selected from pyrazolyl and imidazolyl, each of which has 1 to 4 R 2a may be substituted with a group).

[0204] In one or more embodiments, the compound of formula (I) may be an enantiomer, a mixture of enantiomers, a racemate, a diastereoisomer, a mixture of diastereoisomers, a geometric isomer, a mixture of geometric isomers, a tautomer, or a mixture of tautomers. The compound of formula (I) may also be in the form of a solvate or hydrate.

[0205] The embodiments disclosed herein apply to compounds of formula (I) (as described in embodiment A above). These embodiments are independent and interchangeable. Any one embodiment can be combined with any other embodiment, where chemically permissible. In other words, any feature described in the following embodiments can be combined with features described in one or more other embodiments (where chemically permissible). In particular, when a compound is exemplified or described herein, any two or more of the following listed embodiments, expressed at any level of generality encompassing that compound, can be combined to provide further embodiments that form part of this disclosure.

[0206] R 11 is selected from pyrazolyl and imidazolyl, each of which has 1 to 4 R 2a It may be substituted with a group.

[0207] In some embodiments, R 11 teeth, TIFF2026501324000016.tif32165, wherein: X 1 , X 2 and X 3 are each independently selected from carbon and nitrogen, 1 , X 2 and X 3 Only one of the X is nitrogen. 1 , X 2 and X 3 The other two are carbon, n is an integer independently selected from 0, 1, 2, 3, and 4.

[0208] In some embodiments, R 11 teeth, TIFF2026501324000017.tif32165, where R 2b is independently selected from H, C1-C4-alkyl, C3-C6 cycloalkyl, and 4-6 membered heterocyclyl.

[0209] In some embodiments, X 1 is carbon. In some embodiments, X 1 is nitrogen.

[0210] In some embodiments, X 2 and X 3 are each independently selected from carbon and nitrogen. 2 and X 3 are carbons, respectively.

[0211] In some embodiments, R 11 is a 5-membered heterocyclyl group, and one to four R 2a It may be substituted with a group.

[0212] In some embodiments, R 11 teeth, TIFF2026501324000018.tif32165, where n1 is independently an integer selected from 0, 1, and 2.

[0213] In some embodiments, R 11 teeth, TIFF2026501324000019.tif32165, where n2 is an integer independently selected from 0, 1, 2, and 3.

[0214] In some embodiments, R 11 teeth, TIFF2026501324000020.tif32165, where n3 is independently an integer selected from 0, 1, and 2.

[0215] In some embodiments, R 11 teeth, TIFF2026501324000021.tif32165, where n7 is an integer independently selected from 0, 1, and 2.

[0216] In some embodiments, R 11 teeth, TIFF2026501324000022.tif27165, where n8 is an integer independently selected from 0, 1, and 2.

[0217] R 2b is independently selected from H, C1-C4-alkyl, C3-C6 cycloalkyl, and 4-6 membered heterocyclyl. 2b can be H. R 2b R may be selected from H, C1-C4-alkyl and cyclopropyl. 2b R may be selected from C1-C4-alkyl and cyclopropyl. 2b R can be C1-C4-alkyl, for example, methyl. 2b R can be a 4- to 6-membered heterocyclyl. 2b can be oxetanyl or azetidinyl. In some embodiments, R 2b is oxetanyl. In some embodiments, R 2b is oxetan-3-yl.

[0218] In some embodiments, R 11 teeth, TIFF2026501324000023.tif27165, where n1 is independently an integer selected from 0, 1, and 2.

[0219] In some embodiments, R 11 teeth, TIFF2026501324000024.tif27165, where n2 is an integer independently selected from 0, 1, 2, and 3.

[0220] In some embodiments, R 11 teeth, TIFF2026501324000025.tif27165, where n3 is independently an integer selected from 0, 1, and 2.

[0221] In some embodiments, R 11 teeth, TIFF2026501324000026.tif27165, where n7 is independently an integer selected from 0, 1, 2, and 3.

[0222] In some embodiments, R 11 teeth, TIFF2026501324000027.tif22165, where n8 is independently an integer selected from 0, 1, 2, and 3. In one embodiment, R 2a is not C1-C4-alkyl. 2a is not methyl.

[0223] In some embodiments, R 11 is a substituted or unsubstituted imidazolidine or a substituted or unsubstituted imidazoline.

[0224] R 11 In embodiments where is depicted as containing an NH group in the ring, the nitrogen atom may, where chemically possible, be selected from R as defined herein. 2a substituted with NR groups in the ring 2a It is understood that groups can be provided.

[0225] In some embodiments, R 2a is independently in each occurrence =O, halo, nitro, cyano, NR 5 R 6 , OR 7 , S.R. 6 , S(O)2R 6 , SO2NR 6 R 6 , CO2R 6 , C(O)R 6 ,CONR 6 R 6 , C1-C4-alkyl, C1-C4-haloalkyl, C3-C6 cycloalkyl, and 4- to 6-membered heterocyclyl.

[0226] In some embodiments, R 2a is, independently in each occurrence, ═O, halo, cyano, COR 6 , C(O)R 6 , C1-C4-alkyl, C1-C4-haloalkyl, C3-C6 cycloalkyl, and 4- to 6-membered heterocyclyl.

[0227] In some embodiments, R 2a is, independently in each occurrence, =O, halo, cyano, S(O)R 6 , CO2R 6 ,CONR 6 R 6 , C1-C4-alkyl, C1-C4-haloalkyl, C3-C6 cycloalkyl, and 4- to 6-membered heterocyclyl.

[0228] In some embodiments, R 2a is, independently in each occurrence, =O, halo, cyano, S(O)R 6 , CO2R 6 ,CONR 6 R 6 , C1-C2-alkyl, C1-C2-haloalkyl, C3-C4 cycloalkyl, and 4- to 6-membered heterocyclyl.

[0229] In some embodiments, R 2a is, independently in each occurrence, =O, halo, cyano, S(O)R 6 , CO2R 6 ,CONR 6 R 6 , C1-C2-alkyl, C1-C2-haloalkyl, cyclopropyl, cyclobutyl, and 4-membered heterocyclyl.

[0230] In some embodiments, R 2a is, independently in each occurrence, =O, halo, cyano, S(O)R 6 , CO2R 6 ,CONR 6 R 6, C1-C2-alkyl, C1-C2-haloalkyl, and 4-membered heterocyclyl.

[0231] In some embodiments, R 2a is, in each case independently, =O, halo, OR 7 , C1-C4-alkyl, and C1-C4-haloalkyl.

[0232] In some embodiments, R 2a are, in each case independently, halo, OR 7 , C1-C4-alkyl, and C1-C4-haloalkyl. In some embodiments, R 2a is independently selected at each occurrence from halo, C-C-alkyl, and C-C-haloalkyl. 2a is independently selected at each occurrence from C-alkyl and C-haloalkyl. 2a is C1-C4-alkyl, for example methyl.

[0233] In some embodiments, n is an integer selected from 0, 1, and 2. In some embodiments, n is 2. In some embodiments, n is 0. Preferably, n is 1. In some embodiments, when n is 1, R 2 is X 3 is bonded to.

[0234] In some embodiments, n1 is 0. Preferably, n1 is 1. In some embodiments, when n1 is 1, R 2a is X 3 is bonded to.

[0235] In some embodiments, n is an integer selected from 0, 1, and 2. In some embodiments, n2 is 2. In some embodiments, n2 is 0. In some embodiments, n2 is 1.

[0236] In some embodiments, n3 is 0. Preferably, n3 is 1. In some embodiments, when n3 is 1, R 2a is X 3 is bonded to.

[0237] In some embodiments, n7 is 0. In some embodiments, n7 is 1. In some embodiments, n7 is 2. In some embodiments, n7 is 3.

[0238] In some embodiments, n8 is 0. In some embodiments, n8 is 1. In some embodiments, n8 is 2. In some embodiments, n8 is 3.

[0239] In some embodiments, R 11 teeth, TIFF2026501324000028.tif22165, where n13 is independently an integer selected from 0, 1, 2, 3, 4, and 5.

[0240] In some embodiments, R 11 teeth, TIFF2026501324000029.tif27165, where n14 is independently an integer selected from 0, 1, 2, 3, and 4.

[0241] In some embodiments, R 11 teeth, TIFF2026501324000030.tif22165, where n14 is independently an integer selected from 0, 1, 2, 3, and 4.

[0242] In some embodiments, R 11 teeth, TIFF2026501324000031.tif27165, where n14 is independently an integer selected from 0, 1, 2, 3, and 4.

[0243] In some embodiments, R 11 teeth, TIFF2026501324000032.tif27165, where n15 is independently an integer selected from 0, 1, 2, and 3.

[0244] In some embodiments, R 11 teeth, TIFF2026501324000033.tif27165, where n15 is independently an integer selected from 0, 1, 2, and 3.

[0245] In some embodiments, R 11 teeth, TIFF2026501324000034.tif27165, where n15 is independently an integer selected from 0, 1, 2, and 3.

[0246] In some embodiments, R 11 teeth, TIFF2026501324000035.tif27165, where n15 is independently an integer selected from 0, 1, 2, and 3.

[0247] In some embodiments, R 11 teeth, TIFF2026501324000036.tif32165, where n16 is an integer independently selected from 0, 1, 2, 3, and 4.

[0248] In some embodiments, R 2a is independently in each occurrence =O, halo, nitro, cyano, NR 5 R 6 , OR 7 , S.R. 6 , S(O)2R6 , SO2NR 6 R 6 , CO2R 6 , C(O)R 6 ,CONR 6 R 6 , C1-C4-alkyl, C1-C4-haloalkyl, C3-C6 cycloalkyl, and 4- to 6-membered heterocyclyl.

[0249] In some embodiments, R 2a is, independently in each occurrence, ═O, halo, cyano, COR 6 , C(O)R 6 , C1-C4-alkyl, C1-C4-haloalkyl, C3-C6 cycloalkyl, and 4- to 6-membered heterocyclyl.

[0250] In some embodiments, R 2a is, independently in each occurrence, =O, halo, cyano, S(O)R 6 , CO2R 6 ,CONR 6 R 6 , C1-C4-alkyl, C1-C4-haloalkyl, C3-C6 cycloalkyl, and 4- to 6-membered heterocyclyl.

[0251] In some embodiments, R 2a is, independently in each occurrence, =O, halo, cyano, S(O)R 6 , CO2R 6 ,CONR 6 R 6 , C1-C2-alkyl, C1-C2-haloalkyl, C3-C4 cycloalkyl, and 4- to 6-membered heterocyclyl.

[0252] In some embodiments, R 2a is, independently in each occurrence, =O, halo, cyano, S(O)R 6 , CO2R 6 ,CONR 6 R 6, C1-C2-alkyl, C1-C2-haloalkyl, cyclopropyl, cyclobutyl, and 4-membered heterocyclyl.

[0253] In some embodiments, R 2a is, independently in each occurrence, =O, halo, cyano, S(O)R 6 , CO2R 6 ,CONR 6 R 6 , C1-C2-alkyl, C1-C2-haloalkyl, and 4-membered heterocyclyl.

[0254] In some embodiments, R 2a is, in each case independently, =O, halo, OR 7 , C1-C4-alkyl, and C1-C4-haloalkyl.

[0255] In some embodiments, R 2a are, in each case independently, halo, OR 7 , C1-C4-alkyl, and C1-C4-haloalkyl. In some embodiments, R 2a is independently selected at each occurrence from halo, C-C-alkyl, and C-C-haloalkyl. 2a is independently selected at each occurrence from C-alkyl and C-haloalkyl. 2a is C1-C4-alkyl, for example methyl.

[0256] In some embodiments, n13 is 0. In some embodiments, n13 is 1. In some embodiments, n13 is 2. In some embodiments, n13 is 3.

[0257] In some embodiments, n14 is 0. In some embodiments, n14 is 1. In some embodiments, n14 is 2. In some embodiments, n14 is 3.

[0258] In some embodiments, n15 is 0. In some embodiments, n15 is 1. In some embodiments, n15 is 2. In some embodiments, n15 is 3.

[0259] In some embodiments, n16 is 0. In some embodiments, n16 is 1. In some embodiments, n16 is 2.

[0260] In embodiment B, the present disclosure provides a compound of formula (IA), a tautomer, stereoisomer or mixture of stereoisomers, a pharmaceutically acceptable salt, a hydrate, a deuterated derivative, or an N-oxide thereof: TIFF2026501324000037.tif58165

[0261] (In the formula, Ring A is independently selected from phenyl, 5-membered heterocyclyl, and 6-membered heterocyclyl; X 4 are independently selected from carbon and nitrogen; X 5 are independently selected from carbon and nitrogen;

[0262] R 1 is independently selected from C1-C3-alkyl, C1-C3-fluoroalkyl, C3-C4-cycloalkyl and 4-membered heterocycloalkyl,

[0263] R 2 is independently selected from C1-C4-haloalkyl, ethyl, cyano, nitro, isopropyl, tert-butyl, cyclopropyl, and SF5;

[0264] R 3 are independently 3a , OR3b , and NR 6 R 3b is selected from

[0265] R 3a are independently H, CN, C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl, C2-C4-haloalkenyl, and C0-C3-alkylene-R 3c where R 3c is independently selected in each occurrence from C-C-cycloalkyl, C-C-cycloalkenyl, 5- to 8-membered heterocycloalkenyl, 3- to 8-membered heterocycloalkyl, phenyl, and 5- or 6-membered heteroaryl; R 3c is cycloalkyl, heterocycloalkyl, cycloalkenyl, or heterocycloalkenyl, then R 3c is 1 to 4 R 8 may be substituted with R 3c is phenyl or heteroaryl, R 3c is 1 to 5 R 9 may be substituted with a group,

[0266] R 3b are independently C1-C4-alkyl, C2-C4-alkylene-O-C1-C4-alkyl, C1-C4-haloalkyl and C0-C3-alkylene-R 3d where R 3d is independently selected at each occurrence from C-C-cycloalkyl, 3- to 8-membered heterocycloalkyl, phenyl, and 5- or 6-membered heteroaryl; R 3d When R is cycloalkyl or heterocycloalkyl, 3d is 1 to 4 R 8 may be substituted with R 3d is phenyl or heteroaryl, R 3d is 1 to 5 R 9 may be substituted with a group,

[0267] R 4is independently in each occurrence =O, =S, halo, nitro, cyano, C0-C4-alkylene-NR 5 R 6 , C0-C4-alkylene-OR 7 , S.R. 6 , SOR 6 , C0-C4-alkylene-S(O)2R 6 , SO2NR 6 R 6 , C0-C4-alkylene-CO2R 6 , C0-C4-alkylene-C(O)R 6 , C0-C4-alkylene-CONR 6 R 6 , C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl, C3-C6-cycloalkyl, and C0-C4-alkylene-R 4c is selected from

[0268] R 4c is independently selected at each occurrence from C-C-cycloalkyl and 4- to 6-membered heterocycloalkyl;

[0269] R 5 is independently selected in each occurrence from H, C1-C4-alkyl, C(O)—C1-C4-alkyl and S(O)2—C1-C4-alkyl, or R 5 and R 6 together with the nitrogen atom to which they are attached, form one to four R 8 forming a C5-C8 heterocycloalkyl group optionally substituted by a group,

[0270] R 6 is independently selected in each occurrence from H and C1-C4-alkyl, or two R 6 If groups are attached to the same nitrogen, the two R 6 The groups, together with the nitrogen atom to which they are attached, can consist of one to four R 8 may form a C5-C8 heterocycloalkyl group optionally substituted by a group,

[0271] R 7 is independently selected at each occurrence from H, C1-C4-alkyl, C(O)—C1-C4-alkyl and C1-C4-haloalkyl;

[0272] R 8 is independently in each occurrence =O, =S, fluoro, nitro, cyano, NR 5 R 6 , OR 7 , S.R. 6 , SOR 6 , S(O)2R 6 , SO2NR 6 R 6 , CO2R 6 , C(O)R 6 ,CONR 6 R 6 , C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl and cyclopropyl;

[0273] R 9 is independently in each occurrence halo, nitro, cyano, C0-C4-alkylene-NR 5 R 6 , C0-C4-alkylene-OR 7a , C0-C4-alkylene-SR 6 , C0-C4-alkylene-SOR 6 , C0-C4-alkylene-S(O)2R 6 , C0-C4-alkylene-SO2NR 6 R 6 , C0-C4-alkylene-CO2R 6 , C0-C4-alkylene-C(O)R 6 , C0-C4-alkylene-CONR 6 R 6 , C0-C4-alkylene-R 9a , C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl and C1-C4-haloalkyl, or two R 9 If the groups are attached to adjacent atoms, the two R 9 Groups, together with the atoms to which they are attached, consist of one to four R8 may form a 5- or 6-membered heterocycloalkyl group optionally substituted with a group,

[0274] R 7a is independently in each occurrence H, C1-C4-alkyl, C(O)—C1-C4-alkyl, C0-C4-alkylene-NR5R6, —C0-C4-alkyl-OR 7 , C0-C4-alkylene-SR 6 , C0-C4-alkylene-SOR 6 , C0-C4-alkylene-S(O)2R 6 , C0-C4-alkylene-SO2NR 6 R 6 , C0-C4-alkylene-CO2R 6 , C0-C4-alkylene-C(O)R 6 , C0-C4-alkylene-CONR 6 R 6 and C1-C4-haloalkyl;

[0275] R 9a is independently selected at each occurrence from C-C-cycloalkyl and 4- to 6-membered heterocycloalkyl;

[0276] R 10 is independently in each occurrence halo, C1-C4-alkyl, C1-C4-haloalkyl, nitro, cyano, NR 5 R 6 , OR 7 , S.R. 6 , SOR 6 , S(O)2R 6 , SO2NR 6 R 6 , CO2R 6 , C(O)R 6 ,CONR 6 R 6 , C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl and 4-membered heterocycloalkyl;

[0277] R x and R yare each independently H, halo, nitro, cyano, or NR 5 R 6 , OR 7 , S.R. 6 , SOR 6 , S(O)2R 6 , SO2NR 6 R 6 , CO2R 6 , C(O)R 6 ,CONR 6 R 6 , C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl, C3-C4-cycloalkyl and 4-membered heterocycloalkyl,

[0278] m is an integer selected from 0, 1, 2, 3 and 4;

[0279] n 17 is an integer selected from 0, 1 and 2,

[0280] Any of the aforementioned alkyl, alkylene, alkenyl, cycloalkyl or heterocycloalkyl groups may, where chemically possible, independently in each case be C1-C4-alkyl, oxo, fluoro, nitro, cyano, NR a R b , OR a , S.R. a , CO2R a , C(O)R a ,CONR a R a , S(O)R a and S(O)2R a and optionally substituted with 1 to 5 substituents selected from the group consisting of: a is independently selected at each occurrence from H, C-C-alkyl, and C-C-haloalkyl; R b is independently in each occurrence selected from H, C1-C4-alkyl, C(O)—C1-C4-alkyl and S(O)2—C1-C4-alkyl).

[0281] In embodiment C, the present disclosure provides a compound of formula (IA), its tautomer, stereoisomer or mixture of stereoisomers, pharmaceutically acceptable salt, hydrate, deuterated derivative, or N-oxide: TIFF2026501324000038.tif58165

[0282] (In the formula, Ring A is independently selected from phenyl, 5-membered heterocyclyl, and 6-membered heterocyclyl; X 4 are independently selected from carbon and nitrogen; X 5 are independently selected from carbon and nitrogen;

[0283] R 1 is independently selected from C1-C3-alkyl, C1-C3-fluoroalkyl, C3-C4-cycloalkyl and 4-membered heterocycloalkyl,

[0284] R 2 is C1-C4-haloalkyl,

[0285] R 3 are independently 3a , OR 3b , and NR 6 R 3b is selected from

[0286] R 3a are independently H, CN, C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl, C2-C4-haloalkenyl, and C0-C3-alkylene-R 3c where R 3c is independently selected in each occurrence from C-C-cycloalkyl, C-C-cycloalkenyl, 5- to 8-membered heterocycloalkenyl, 3- to 8-membered heterocycloalkyl, phenyl, and 5- or 6-membered heteroaryl; R 3c is cycloalkyl, heterocycloalkyl, cycloalkenyl, or heterocycloalkenyl, then R 3c is 1 to 4 R 8may be substituted with R 3c is phenyl or heteroaryl, R 3c is 1 to 5 R 9 may be substituted with a group,

[0287] R 3b are independently C1-C4-alkyl, C2-C4-alkylene-O-C1-C4-alkyl, C1-C4-haloalkyl and C0-C3-alkylene-R 3d where R 3d is independently selected at each occurrence from C-C-cycloalkyl, 3- to 8-membered heterocycloalkyl, phenyl, and 5- or 6-membered heteroaryl; R 3d When R is cycloalkyl or heterocycloalkyl, 3d is 1 to 4 R 8 may be substituted with R 3d is phenyl or heteroaryl, R 3d is 1 to 5 R 9 may be substituted with a group,

[0288] R 4 is independently in each occurrence =O, =S, halo, nitro, cyano, C0-C4-alkylene-NR 5 R 6 , C0-C4-alkylene-OR 7 , S.R. 6 , SOR 6 , C0-C4-alkylene-S(O)2R 6 , SO2NR 6 R 6 , C0-C4-alkylene-CO2R 6 , C0-C4-alkylene-C(O)R 6 , C0-C4-alkylene-CONR 6 R 6 , C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl, C3-C6-cycloalkyl, and C0-C4-alkylene-R 4c is selected from

[0289] R4c is independently selected at each occurrence from C-C-cycloalkyl and 4- to 6-membered heterocycloalkyl;

[0290] R 5 is independently selected in each occurrence from H, C-C-alkyl, C(O)-C-C-alkyl and S(O)-C-C-alkyl, or R 5 and R 6 together with the nitrogen atom to which they are attached, form one to four R 8 forming a C5-C8 heterocycloalkyl group optionally substituted by a group,

[0291] R 6 is independently selected in each occurrence from H and C1-C4-alkyl, or two R 6 If groups are attached to the same nitrogen, the two R 6 The groups, together with the nitrogen atom to which they are attached, can consist of one to four R 8 may form a C5-C8 heterocycloalkyl group optionally substituted by a group,

[0292] R 7 is independently selected at each occurrence from H, C1-C4-alkyl, C(O)—C1-C4-alkyl and C1-C4-haloalkyl;

[0293] R 8 is independently in each occurrence =O, =S, fluoro, nitro, cyano, NR 5 R 6 , OR 7 , S.R. 6 , SOR 6 , S(O)2R 6 , SO2NR 6 R 6 , CO2R 6 , C(O)R 6 ,CONR 6 R 6 , C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl and cyclopropyl;

[0294] R 9 is independently in each occurrence halo, nitro, cyano, C0-C4-alkylene-NR 5 R 6 , C0-C4-alkylene-OR 7a , C0-C4-alkylene-SR 6 , C0-C4-alkylene-SOR 6 , C0-C4-alkylene-S(O)2R 6 , C0-C4-alkylene-SO2NR 6 R 6 , C0-C4-alkylene-CO2R 6 , C0-C4-alkylene-C(O)R 6 , C0-C4-alkylene-CONR 6 R 6 , C0-C4-alkylene-R 9a , C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl, or two R 9 If the groups are attached to adjacent atoms, the two R 9 Groups, together with the atoms to which they are attached, consist of one to four R 8 may form a 5- or 6-membered heterocycloalkyl group optionally substituted with a group,

[0295] R 7a is, independently in each occurrence, H, C1-C4-alkyl, C(O)—C1-C4-alkyl, C0-C4-alkylene-NR 5 R 6 , -C0-C4-alkyl-OR 7 , C0-C4-alkylene-SR 6 , C0-C4-alkylene-SOR 6 , C0-C4-alkylene-S(O)2R 6 , C0-C4-alkylene-SO2NR 6 R 6 , C0-C4-alkylene-CO2R 6 , C0-C4-alkylene-C(O)R 6 , C0-C4-alkylene-CONR 6R 6 and C1-C4-haloalkyl;

[0296] R 9a is independently selected at each occurrence from C-C-cycloalkyl and 4- to 6-membered heterocycloalkyl;

[0297] R 10 is independently in each occurrence halo, C1-C4-alkyl, C1-C4-haloalkyl, nitro, cyano, NR 5 R 6 , OR 7 , S.R. 6 , SOR 6 , S(O)2R 6 , SO2NR 6 R 6 , CO2R 6 , C(O)R 6 ,CONR 6 R 6 , C2-C4-alkenyl, C2-C4-alkynyl and 4-membered heterocycloalkyl;

[0298] R x and R y are each independently H, halo, nitro, cyano, or NR 5 R 6 , OR 7 , S.R. 6 , SOR 6 , S(O)2R 6 , SO2NR 6 R 6 , CO2R 6 , C(O)R 6 ,CONR 6 R 6 , C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl, C3-C4-cycloalkyl and 4-membered heterocycloalkyl,

[0299] m is an integer selected from 0, 1, 2, 3 and 4;

[0300] n 17is an integer selected from 0, 1 and 2,

[0301] Any of the aforementioned alkyl, alkylene, alkenyl, cycloalkyl or heterocycloalkyl groups may, where chemically possible, independently in each case be C1-C4-alkyl, oxo, fluoro, nitro, cyano, NR a R b , OR a , S.R. a , CO2R a , C(O)R a ,CONR a R a , S(O)R a and S(O)2R a and optionally substituted with 1 to 5 substituents selected from the group consisting of: a is independently selected at each occurrence from H, C-C-alkyl, and C-C-haloalkyl; R b is independently in each occurrence selected from H, C1-C4-alkyl, C(O)—C1-C4-alkyl and S(O)2—C1-C4-alkyl).

[0302] In one or more embodiments, the compound of formula (IA) may be an enantiomer, a mixture of enantiomers, a racemate, a diastereoisomer, a mixture of diastereoisomers, a geometric isomer, a mixture of geometric isomers, a tautomer, or a mixture of tautomers. The compound of formula (IA) may also be in the form of a solvate or hydrate.

[0303] In one or more embodiments, the compound of formula (IA) is a compound of formula (XII): TIFF2026501324000039.tif58165

[0304] In the formula, X 4 , X 5 , ring A, R 1 , R 2 , R 3 , R 4 , R 10and m is as described for compounds of formula (IA) in embodiment B or C above.

[0305] In one or more embodiments, the compound of formula (IA) is a compound of formula (XIIIa) or (XIIIb): TIFF2026501324000040.tif109165

[0306] In the formula, X 4 , X 5 , ring A, R 2 , R 3 , R 4 and m is as described for compounds of formula (IA) in embodiment B or C above;

[0307] R 1a is selected from methyl and ethyl;

[0308] R 10a is selected from H and methyl;

[0309] R 10b is selected from H and methyl.

[0310] In one or more embodiments, the compound of formula (IA) is a compound of formula (XIV): TIFF2026501324000041.tif63165

[0311] In the formula, R 2 , R 3b , R 4 , R 10 and n 17 is as described for compounds of formula (IA) in embodiment B or C above;

[0312] R 1a is selected from methyl and ethyl;

[0313] m is an integer selected from 0, 1, or 2;

[0314] R4a are independently H, C1-C4-alkyl, cyclopropyl, cyclobutyl, and C0-C4-alkylene-R 4c In some embodiments, R 4c is independently selected at each occurrence from C-C-cycloalkyl and 4- to 6-membered heterocycloalkyl. 4a is independently selected from H, C-C-alkyl, and cyclopropyl. In some embodiments, R 4a is independently selected from H, methyl, cyclopropyl, and oxetan-3-yl. 4a may be selected from H, methyl, and cyclopropyl.

[0315] In some embodiments, the compound of Formula (IA) is a compound of Formula (XV): TIFF2026501324000042.tif63165

[0316] In the formula, R 2 , R 3a , R 4 , R 10 and n 17 is as described for compounds of formula (IA) in embodiment B or C above;

[0317] R 1a is selected from methyl and ethyl;

[0318] m is an integer selected from 0, 1, or 2;

[0319] R 4a are independently H, C1-C4-alkyl, cyclopropyl, cyclobutyl, and C0-C4-alkylene-R 4c Selected from: R 4c is independently selected at each occurrence from C-C-cycloalkyl and 4- to 5-membered heterocycloalkyl. 4c R may be independently selected from C3-C5-cycloalkyl. 4amay be independently selected from H, C1-C4-alkyl, and cyclopropyl.

[0320] In some embodiments, the compound of Formula (IA) is a compound of Formula (XVI): TIFF2026501324000043.tif63165

[0321] In the formula, R 2 , R 4 , R 9 , R 10 and n 17 is as described for compounds of formula (IA) in embodiment B or C above;

[0322] R 1a is selected from methyl and ethyl;

[0323] m is an integer selected from 0, 1, or 2;

[0324] p is an integer selected from 0, 1, 2, 3, 4 and 5;

[0325] R 4a are independently H, C1-C4-alkyl, cyclopropyl, cyclobutyl, and C0-C4-alkylene-R 4c Selected from: R 4c is independently selected at each occurrence from C-C-cycloalkyl and 4- to 5-membered heterocycloalkyl. 4c R may be independently selected from C3-C5-cycloalkyl. 4a may be independently selected from H, C1-C4-alkyl, and cyclopropyl.

[0326] In some embodiments, the compound of Formula (IA) is a compound of Formula (XVIIa) or (XVIIb): TIFF2026501324000044.tif119165

[0327] In the formula, R 2 , R 3band R 4 is as described for compounds of formula (IA) in embodiment B or C above;

[0328] R 1a is selected from methyl and ethyl;

[0329] m is an integer selected from 0, 1, or 2;

[0330] R 4a are independently H, C1-C4-alkyl, cyclopropyl, cyclobutyl, and C0-C4-alkylene-R 4c Selected from: R 4c is independently selected at each occurrence from C-C-cycloalkyl and 4- to 5-membered heterocycloalkyl. 4c R may be independently selected from C3-C5-cycloalkyl. 4a may be independently selected from H, C1-C4-alkyl, and cyclopropyl;

[0331] R 10a is selected from H and methyl;

[0332] R 10b is selected from H and methyl.

[0333] In some embodiments, the compound of Formula (IA) is a compound of Formula (XVIII): TIFF2026501324000045.tif58165

[0334] In the formula, R 2 , R 3b , R 4 , R 10 , n 17 and m is as described for compounds of formula (IA) in embodiment B or C above;

[0335] R 1a is selected from methyl and ethyl.

[0336] In some embodiments, the compound of Formula (IA) is a compound of Formula (XIX): TIFF2026501324000046.tif63165

[0337] In the formula, R 2 , R 4 , R 9 , R 10 , and n 17 is as described for compounds of formula (IA) in embodiment B or C above;

[0338] m is an integer selected from 0, 1, or 2;

[0339] p is an integer selected from 0, 1, 2, 3, 4, and 5;

[0340] R 1a is selected from methyl and ethyl;

[0341] R 4a are independently H, C1-C4-alkyl, cyclopropyl, cyclobutyl, and C0-C4-alkylene-R 4c Selected from: R 4c is independently selected at each occurrence from C-C-cycloalkyl and 4- to 5-membered heterocycloalkyl. 4c may be independently selected from C3-C5-cycloalkyl.

[0342] In some embodiments, the compound of formula (IA) is a compound of formula (XX): TIFF2026501324000047.tif53165

[0343] In the formula, X 4 , X 5 , R 2 , R 4 , R 9 , R 10 and n 17 is as described for compounds of formula (IA) in embodiment B or C above;

[0344] each TIFF2026501324000048.tif17165 are independently selected from a single bond and a double bond;

[0345] R 1a is selected from methyl and ethyl;

[0346] X 6 are independently selected from carbon and nitrogen;

[0347] X 7 are independently selected from carbon and nitrogen;

[0348] m is an integer selected from 0, 1, 2, or 3;

[0349] p is an integer selected from 0, 1, 2, 3, 4 and 5.

[0350] In some embodiments, R 1a R may be selected from methyl and ethyl. 1a R can be methyl. 1a may be ethyl.

[0351] In some embodiments, R 2 R may be selected from C1-C4-haloalkyl, ethyl, isopropyl, tert-butyl and cyclopropyl. 2 R can be C1-C4-haloalkyl, for example, C1-C4-fluoroalkyl. 2 may be selected from -CF3, -CHF2, -CH2-CF3, and -CH2-CH2F.

[0352] In some embodiments, R 10 R may be selected from halo, C1-C4-alkyl, C1-C4-haloalkyl, C2-C4-alkenyl, C2-C4-alkynyl and 4-membered heterocycloalkyl. 10 can be C1-C4-alkyl, for example methyl.

[0353] In some embodiments, n 17 is an integer selected from 0 and 1. 17 can be 0. n 17 can be 1.

[0354] In some embodiments, R 1 is C1-C3-alkyl. In some embodiments, R 1 is C1-C3-fluoroalkyl. In some embodiments, R 1 is C-cycloalkyl. In some embodiments, R 1 are independently selected from C1-alkyl, C1-fluoroalkyl, C2-alkyl, C2-fluoroalkyl and C3-cycloalkyl. 1 is C1-alkyl, i.e., methyl.

[0355] In some embodiments, X 4 is carbon. In some embodiments, X 4 is nitrogen.

[0356] In some embodiments, X 5 is carbon. In some embodiments, X 5 is nitrogen.

[0357] In some embodiments, ring A is a phenyl ring. In some embodiments, ring A is a 5- or 6-membered heterocyclyl. In some embodiments, ring A is a 5- or 6-membered heteroaryl. In some embodiments, ring A is a 5-membered heteroaryl ring. In some embodiments, ring A is a 6-membered heterocyclyl ring. In some embodiments, ring A is a 6-membered heteroaryl ring.

[0358] In some embodiments, when ring A is a 5-membered heterocyclyl, it is not pyrrolidone.

[0359] In some embodiments, ring A is phenyl. In some embodiments, ring A is pyridone. The pyridone may be substituted at the nitrogen with a C1-C4-alkyl group, cyclopropyl, cyclobutyl, or a 4-membered heterocycloalkyl group. The pyridone may be substituted at the nitrogen with either a C1-C4-alkyl group or a cyclopropyl group. In some embodiments, ring A is an N-C1-C4-alkylpyridone. In some embodiments, ring A is pyridine. In some embodiments, ring A is pyrrole. In some embodiments, ring A is imidazole. In some embodiments, ring A is pyrazole. In some embodiments, ring A is triazole. In some embodiments, ring A is tetrazole.

[0360] In some embodiments, TIFF2026501324000049.tif32165 is TIFF2026501324000050.tif37165, In the formula, R 4a is H, C1-C4-alkyl (e.g., methyl), cyclopropyl, cyclobutyl, C0-C4-alkylene-R 4c , SOR 6 , S(O)2R 6 , SO2NR 6 R 6 , C0-C4-alkylene-CO2R 6 , C0-C4-alkylene-C(O)R 6 , C0-C4-alkylene-CONR 6 R 6 , C1-C4-alkyl-S(O)2R 6 , C2-C4-alkylene-NR 5 R 6 , C2-C4-alkylene-OR 7 , and cyclopropyl-OR a and optionally R 3 is OR 3b In one embodiment, heterocycloalkyl is oxetanyl or azetidinyl.

[0361] In some embodiments, TIFF2026501324000051.tif32165 is TIFF2026501324000052.tif37165, where R 4a is H, C1-C4-alkyl (e.g., methyl), cyclopropyl, SOR 6 , S(O)2R 6 , SO2NR 6 R 6 , C0-C4-alkylene-CO2R 6 , C0-C4-alkylene-C(O)R 6 , C0-C4-alkylene-CONR 6 R 6 , C1-C4-alkyl-S(O)2R 6 , C2-C4-alkylene-NR 5 R 6 , C2-C4-alkylene-OR 7 , and cyclopropyl-OR a and optionally R 3 is OR 3b is.

[0362] In some embodiments, TIFF2026501324000053.tif32165 is TIFF2026501324000054.tif37165, where R 4a is selected from H, C1-C4-alkyl (e.g., methyl), cyclopropyl, cyclobutyl, and 4-membered heterocycloalkyl, and optionally, R 3 is OR 3b R 4a may be selected from C1-C4-alkyl (eg, methyl), cyclopropyl, and oxetan-3-yl.

[0363] In some embodiments, TIFF2026501324000055.tif32165 is TIFF2026501324000056.tif37165, where R 4a is selected from H, C1-C4-alkyl (e.g., methyl), and cyclopropyl, and optionally R 3 is OR 3b R 4a may be selected from C1-C4-alkyl (eg methyl) and cyclopropyl.

[0364] In some embodiments, TIFF2026501324000057.tif32165 is TIFF2026501324000058.tif37165, In the formula, R 4a is H, C1-C4-alkyl (e.g., methyl), cyclopropyl, cyclobutyl, 4-membered heterocycloalkyl, SOR 6 , S(O)2R 6 , SO2NR 6 R 6 , C0-C4-alkylene-CO2R 6 , C0-C4-alkylene-C(O)R 6 , C0-C4-alkylene-CONR 6 R 6 , C1-C4-alkyl-S(O)2R 6 , C2-C4-alkylene-NR 5 R 6 , C2-C4-alkylene-OR 7 , and cyclopropyl-OR a and optionally R 3 is OR 3b is.

[0365] In some embodiments, TIFF2026501324000059.tif32165 is TIFF2026501324000060.tif37165, where R 4a is H, C1-C4-alkyl (e.g., methyl), cyclopropyl, SOR 6 , S(O)2R 6 , SO2NR6 R 6 , C0-C4-alkylene-CO2R 6 , C0-C4-alkylene-C(O)R 6 , C0-C4-alkylene-CONR 6 R 6 , C1-C4-alkyl-S(O)2R 6 , C2-C4-alkylene-NR 5 R 6 , C2-C4-alkylene-OR 7 , and cyclopropyl-OR a and optionally R 3 is OR 3b is.

[0366] In some embodiments, TIFF2026501324000061.tif32165 is TIFF2026501324000062.tif37165, where R 4a is selected from H, C1-C4-alkyl (e.g., methyl), cyclopropyl, cyclobutyl, and 4-membered heterocycloalkyl, and optionally, R 3 is OR 3b R 4a may be selected from C1-C4-alkyl (eg, methyl), cyclopropyl, and oxetan-3-yl.

[0367] In some embodiments, TIFF2026501324000063.tif32165 is TIFF2026501324000064.tif37165, where R 4a is selected from H, C1-C4-alkyl (e.g., methyl), and cyclopropyl, and optionally R 3 is OR 3b R 4a may be selected from C1-C4-alkyl (eg methyl) and cyclopropyl.

[0368] In some embodiments, TIFF2026501324000065.tif32165 is TIFF2026501324000066.tif32165, where R 4a is H, C1-C4-alkyl (e.g., methyl), cyclopropyl, cyclobutyl, 4-membered heterocycloalkyl, SOR 6 , S(O)2R 6 , SO2NR 6 R 6 , C0-C4-alkylene-CO2R 6 , C0-C4-alkylene-C(O)R 6 , C0-C4-alkylene-CONR 6 R 6 , C1-C4-alkyl-S(O)2R 6 , C2-C4-alkylene-NR 5 R 6 , C2-C4-alkylene-OR 7 , and cyclopropyl-OR a and optionally R 3 is OR 3b is.

[0369] In some embodiments, TIFF2026501324000067.tif32165 is TIFF2026501324000068.tif32165, where R 4a is H, C1-C4-alkyl (e.g., methyl), cyclopropyl, SOR 6 , S(O)2R 6 , SO2NR 6 R 6 , C0-C4-alkylene-CO2R 6 , C0-C4-alkylene-C(O)R 6 , C0-C4-alkylene-CONR 6 R 6 , C1-C4-alkyl-S(O)2R 6 , C2-C4-alkylene-NR 5 R 6 , C2-C4-alkylene-OR 7 , and cyclopropyl-OR aand optionally R 3 is OR 3b is.

[0370] In some embodiments, TIFF2026501324000069.tif32165 is TIFF2026501324000070.tif32165, where R 4a is selected from H, C1-C4-alkyl (e.g., methyl), cyclopropyl, cyclobutyl, and 4-membered heterocycloalkyl, and optionally, R 3 is OR 3b R 4a may be selected from C1-C4-alkyl (eg, methyl), cyclopropyl, and oxetan-3-yl.

[0371] In some embodiments, TIFF2026501324000071.tif32165 is TIFF2026501324000072.tif32165, where R 4a is selected from H, C1-C4-alkyl (e.g., methyl), and cyclopropyl, and optionally R 3 is OR 3b R 4a may be selected from C1-C4-alkyl (eg methyl) and cyclopropyl.

[0372] In some embodiments, TIFF2026501324000073.tif32165 is TIFF2026501324000074.tif37165, where R 4a is H, C1-C4-alkyl (e.g., methyl), cyclopropyl, cyclobutyl, 4-membered heterocycloalkyl, SOR 6 , S(O)2R 6 , SO2NR 6 R 6 , C0-C4-alkylene-CO2R 6 , C0-C4-alkylene-C(O)R6 , C0-C4-alkylene-CONR 6 R 6 , C1-C4-alkyl-S(O)2R 6 , C2-C4-alkylene-NR 5 R 6 , C2-C4-alkylene-OR 7 , and cyclopropyl-OR a and optionally R 3 is OR 3b is.

[0373] In some embodiments, TIFF2026501324000075.tif32165 is TIFF2026501324000076.tif37165, where R 4a is H, C1-C4-alkyl (e.g., methyl), cyclopropyl, SOR 6 , S(O)2R 6 , SO2NR 6 R 6 , C0-C4-alkylene-CO2R 6 , C0-C4-alkylene-C(O)R 6 , C0-C4-alkylene-CONR 6 R 6 , C1-C4-alkyl-S(O)2R 6 , C2-C4-alkylene-NR 5 R 6 , C2-C4-alkylene-OR 7 , and cyclopropyl-OR a and optionally R 3 is OR 3b is.

[0374] In some embodiments, TIFF2026501324000077.tif32165 is TIFF2026501324000078.tif37165, where R 4ais selected from H, C1-C4-alkyl (e.g., methyl), cyclopropyl, cyclobutyl, and 4-membered heterocycloalkyl, and optionally, R 3 is OR 3b R 4a may be selected from C1-C4-alkyl (eg methyl), cyclopropyl, and oxetan-3-yl.

[0375] In some embodiments, TIFF2026501324000079.tif32165 is TIFF2026501324000080.tif37165, where R 4a is selected from H, C1-C4-alkyl (e.g., methyl), and cyclopropyl, and optionally R 3 is OR 3b R 4a may be selected from C1-C4-alkyl (eg methyl) and cyclopropyl.

[0376] In some embodiments, TIFF2026501324000081.tif32165 is TIFF2026501324000082.tif37165, where R 4a is H, C1-C4-alkyl (e.g., methyl), cyclopropyl, cyclobutyl, 4-membered heterocycloalkyl, SOR 6 , S(O)2R 6 , SO2NR 6 R 6 , C0-C4-alkylene-CO2R 6 , C0-C4-alkylene-C(O)R 6 , C0-C4-alkylene-CONR 6 R 6 , C1-C4-alkyl-S(O)2R 6 , C2-C4-alkylene-NR 5 R 6 , C2-C4-alkylene-OR 7 , and cyclopropyl-OR a and optionally R 3is OR 3b is.

[0377] In some embodiments, TIFF2026501324000083.tif32165 is TIFF2026501324000084.tif42165, where R 4a is H, C1-C4-alkyl (e.g., methyl), cyclopropyl, SOR 6 , S(O)2R 6 , SO2NR 6 R 6 , C0-C4-alkylene-CO2R 6 , C0-C4-alkylene-C(O)R 6 , C0-C4-alkylene-CONR 6 R 6 , C1-C4-alkyl-S(O)2R 6 , C2-C4-alkylene-NR 5 R 6 , C2-C4-alkylene-OR 7 , and cyclopropyl-OR a and optionally R 3 is OR 3b is.

[0378] In some embodiments, TIFF2026501324000085.tif32165 is TIFF2026501324000086.tif42165, where R 4a is selected from H, C1-C4-alkyl (e.g., methyl), cyclopropyl, cyclobutyl, and 4-membered heterocycloalkyl, and optionally, R 3 is OR 3b R 4a may be selected from C1-C4-alkyl (eg methyl), cyclopropyl, and oxetan-3-yl.

[0379] In some embodiments, TIFF2026501324000087.tif32165 is TIFF2026501324000088.tif42165, where R 4a is selected from H, C1-C4-alkyl (e.g., methyl), and cyclopropyl, and optionally R 3 is OR 3b R 4a may be selected from C1-C4-alkyl (eg methyl) and cyclopropyl.

[0380] In some embodiments, TIFF2026501324000089.tif32165 is TIFF2026501324000090.tif32165, and optionally wherein R 3 is OR 3b is.

[0381] In some embodiments, TIFF2026501324000091.tif32165 is TIFF2026501324000092.tif32165, and optionally wherein R 3 is R 3a is.

[0382] In some embodiments, TIFF2026501324000093.tif37165 is TIFF2026501324000094.tif37165, where R 4b is S(O)2R 6 , C1-C4-alkyl, C1-C4-alkyl-S(O)2R 6 , C1-C4-haloalkyl, cyclopropyl, and cyclobutyl, and optionally R 3 is R 3a is.

[0383] In some embodiments, TIFF2026501324000095.tif37165 is TIFF2026501324000096.tif37165, where R 4b is S(O)2R 6 , C1-C4-alkyl, C1-C4-alkyl-S(O)2R 6 , C1-C4-haloalkyl, and cyclopropyl; and optionally R 3 is R 3a is.

[0384] In some embodiments, TIFF2026501324000097.tif32165 is TIFF2026501324000098.tif32165, and optionally wherein R 3 is R 3a is.

[0385] In some embodiments, TIFF2026501324000099.tif32165 is TIFF2026501324000100.tif32165, and optionally, wherein R 3 is R 3a is.

[0386] In some embodiments, TIFF2026501324000101.tif32165 is TIFF2026501324000102.tif42165, wherein: m is an integer selected from 0, 1 and 2; p is an integer selected from 0, 1, 2, 3, 4, and 5; R 4a are independently H, C1-C4-alkyl, cyclopropyl, cyclobutyl, and C0-C4-alkylene-R 4c is selected from.

[0387] In some embodiments, R 3 are independently 3a and OR 3bIn some embodiments, R 3 is R 3a In some embodiments, R 3 is OR 3b When ring A is a 5-membered heteroaryl group, R 3 is R 3a When ring A is a pyridone group, R 3 is R 3a When ring A is phenyl or pyridone, R 3 is OR 3b It may be the case.

[0388] In some embodiments, R 3a are independently H, CN, C1-C4-alkyl, C2-C4-alkenyl, C1-C4-haloalkyl, C2-C4-haloalkenyl, and C0-C3-alkylene-R 3c where R 3c is independently selected at each occurrence from C-C cycloalkyl, C-C cycloalkenyl, 3- to 8-membered heterocycloalkyl, phenyl, and 5- or 6-membered heteroaryl; R 3c When R is cycloalkyl or heterocycloalkyl, 3c is 1 to 4 R 8 may be substituted with R 3c is phenyl or heteroaryl, R 3c is 1 to 5 R 9 It may be substituted with a group.

[0389] In some embodiments, R 3a are independently selected from CN, C1-C4-alkyl, C1-C4-haloalkyl, C2-C4-haloalkenyl, and C0-C3-alkylene-R 3c where R 3c is independently selected at each occurrence from C-C-cycloalkyl, C-C-cycloalkenyl, 5- to 8-membered heterocycloalkenyl, 3- to 8-membered heterocycloalkyl, and phenyl; R 3cis cycloalkyl, heterocycloalkyl, cycloalkenyl, or heterocycloalkenyl, then R 3c is 1 to 4 R 8 may be substituted with R 3c is phenyl, R 3c is 1 to 5 R 9 It may be substituted with a group.

[0390] In some embodiments, R 3a are independently selected from CN, C1-C4-alkyl, C1-C4-haloalkyl, C2-C4-haloalkenyl, and C0-C3-alkylene-R 3c where R 3c is independently selected at each occurrence from C-C cycloalkyl, C-C cycloalkenyl, 3- to 8-membered heterocycloalkyl, and phenyl; R 3c When R is cycloalkyl or heterocycloalkyl, 3c is 1 to 4 R 8 may be substituted with R 3c is phenyl, R 3c is 1 to 5 R 9 It may be substituted with a group.

[0391] In some embodiments, R 3a are independently C-C-alkyl, C-C-haloalkyl, C-haloalkenyl, and C-C-alkylene-R 3c where R 3c is independently selected at each occurrence from C-C-cycloalkyl, C-C-cycloalkenyl, 5- to 6-membered heterocycloalkenyl, 4- to 6-membered heterocycloalkyl, and phenyl; R 3c is cycloalkyl, heterocycloalkyl, cycloalkenyl, or heterocycloalkenyl, then R 3c is 1 to 4 R 8 may be substituted with R 3c is phenyl, R 3c is 1 to 5 R 9It may be substituted with a group.

[0392] In some embodiments, R 3a are independently C-C-alkyl, C-C-haloalkyl, C-haloalkenyl, and C-C-alkylene-R 3c where R 3c is independently selected at each occurrence from C-C-cycloalkyl, C-C-cycloalkenyl, 4- to 6-membered heterocycloalkyl, and phenyl; R 3c When R is cycloalkyl or heterocycloalkyl, 3c is 1 to 4 R 8 may be substituted with R 3c is phenyl, R 3c is 1 to 5 R 9 It may be substituted with a group.

[0393] In some embodiments, R 3a is C0-C3-alkylene-R 3c where R 3c is independently selected at each occurrence from C-cycloalkyl, C-cycloalkenyl, 6-membered heterocycloalkenyl, 6-membered heterocycloalkyl, and phenyl; R 3c is cycloalkyl, cycloalkenyl, heterocycloalkenyl, or heterocycloalkyl, R 3c is 1 to 4 R 8 may be substituted with R 3c is phenyl, R 3c is 1 to 5 R 9 It may be substituted with a group.

[0394] In some embodiments, R 3a is C0-C3-alkylene-R 3c where R 3c is independently selected at each occurrence from C-cycloalkyl, C-cycloalkenyl, 6-membered heterocycloalkyl, and phenyl; R 3cWhen R is cycloalkyl, cycloalkenyl, or heterocycloalkyl, 3c is 1 to 4 R 8 may be substituted with R 3c is phenyl, R 3c is 1 to 5 R 9 It may be substituted with a group.

[0395] In some embodiments, R 3a is C0-C3-alkylene-R 3c where R 3c is phenyl and R 3c is 1 to 5 R 9 It may be substituted with a group.

[0396] In some embodiments, R 3a is 1 to 3 R 9 R is phenyl optionally substituted with a group. 3c , R 3a or R 3 When is phenyl, the phenyl is selected from 1 to 3 R 9 It may be substituted with a group.

[0397] In some embodiments, R 3a is R 3c where R 3c is phenyl and R 3c is one or two R 9 The phenyl group may be substituted with a group, and the para position on the phenyl group is unsubstituted.

[0398] In some embodiments, R 3a is C-C-alkyl. In some embodiments, R 3a is C-C-haloalkyl. In some embodiments, R 3a is C-C-haloalkenyl. In some embodiments, R 3a is C0-C3-alkylene-R 3c where R 3cis independently selected at each occurrence from C-C-cycloalkyl, C-C-cycloalkenyl, 5- to 6-membered heterocycloalkenyl, and 4- to 6-membered heterocycloalkyl. 3a is C-C-cycloalkyl. In some embodiments, R 3a is C-C-cycloalkenyl. In some embodiments, R 3a is a 5- to 6-membered heterocycloalkenyl. In some embodiments, R 3a is a 4-membered heterocycloalkyl. In some embodiments, R 3a is a 5-membered heterocycloalkyl. In some embodiments, R 3a is a 6-membered heterocycloalkyl. 3a or R 3c When R is cycloalkyl or heterocycloalkyl, 3c is 1 to 4 R 8 It may be substituted with a group.

[0399] In some embodiments, R 3a is C-C-alkyl. In some embodiments, R 3a is C-C-haloalkyl. In some embodiments, R 3a is C-C-haloalkenyl. In some embodiments, R 3a is C0-C3-alkylene-R 3c where R 3c is independently selected at each occurrence from C-C-cycloalkyl, C-C-cycloalkenyl, and 4- to 6-membered heterocycloalkyl. 3a is C-C-cycloalkyl. In some embodiments, R 3a is C-C-cycloalkenyl. In some embodiments, R 3a is a 4-membered heterocycloalkyl. In some embodiments, R 3a is a 5-membered heterocycloalkyl. In some embodiments, R3a is a 6-membered heterocycloalkyl. 3a or R 3c When R is cycloalkyl or heterocycloalkyl, 3c is 1 to 4 R 8 It may be substituted with a group.

[0400] In some embodiments, R 3 is selected from phenyl or -O-phenyl, where R 3 is 1 to 5 R 9 In some embodiments, R 3 is unsubstituted phenyl. In some embodiments, R 3 is -O-phenyl, where R 3 are two R 9 is substituted with a group.

[0401] When ring A is a 5-membered heteroaryl, R 3a When ring A is a 5-membered heteroaryl, R 3a can be an optionally substituted 6-membered heteroaryl.

[0402] In some embodiments, R 3b are independently C1-C4-alkyl, C2-C4-alkylene-O-C1-C4-alkyl, C1-C4-haloalkyl and C0-C3-alkylene-R 3d where R 3d is independently selected at each occurrence from C-C-cycloalkyl, 3- to 8-membered heterocycloalkyl, and phenyl; R 3d When R is cycloalkyl or heterocycloalkyl, 3d is 1 to 4 R 8 may be substituted with R 3d is phenyl, R 3d is 1 to 5 R 9 It may be substituted with a group.

[0403] In some embodiments, R 3b are independently C4-alkyl, C2-C4-alkylene-O-C1, C4-haloalkyl and C0-C3-alkylene-R 3d where R 3d is independently selected at each occurrence from C-C-cycloalkyl, 4- to 6-membered heterocycloalkyl, and phenyl; R 3d When R is cycloalkyl or heterocycloalkyl, 3d is 1 to 4 R 8 may be substituted with R 3d is phenyl, R 3d is 1 to 5 R 9 It may be substituted with a group.

[0404] In some embodiments, R 3b is C0-C3-alkylene-R 3d where R 3d is independently selected at each occurrence from C-C-cycloalkyl, 4- to 6-membered heterocycloalkyl, and phenyl; R 3d When R is cycloalkyl or heterocycloalkyl, 3d is 1 to 4 R 8 may be substituted with R 3d is phenyl, R 3d is 1 to 5 R 9 It may be substituted with a group.

[0405] In some embodiments, R 3b is C0-C3-alkylene-R 3d where R 3d is independently selected at each occurrence from C-cycloalkyl, 6-membered heterocycloalkyl, and phenyl; R 3d When R is cycloalkyl or heterocycloalkyl, 3d is 1 to 4 R 8 may be substituted with R 3d is phenyl, R 3d is 1 to 5 R 9It may be substituted with a group.

[0406] In some embodiments, R 3b is C0-C3-alkylene-R 3d where R 3d is phenyl and R 3d is 1 to 5 R 9 It may be substituted with a group.

[0407] In some embodiments, R 3b is phenyl and 1 to 3 R 9 It may be substituted with a group.

[0408] In some embodiments, R 3b is C0-C3-alkylene-R 3d where R 3d is independently selected at each occurrence from C-C-cycloalkyl and 4- to 6-membered heterocycloalkyl; R 3d is 1 to 4 R 8 It may be substituted with a group.

[0409] In some embodiments, R 3b is C0-C3-alkylene-R 3d where R 3d is C3-C6-cycloalkyl, and R 3d is 1 to 4 R 8 It may be substituted with a group.

[0410] In some embodiments, R 3b is C0-C3-alkylene-R 3d where R 3d is a 4- to 6-membered heterocycloalkyl, and R 3d is 1 to 4 R 8 It may be substituted with a group.

[0411] In some embodiments, R 3b is a 4- to 6-membered heterocycloalkyl, and 1 to 4 R 8In some embodiments, R 3b is a 4-membered heterocycloalkyl, and one to two R 8 In some embodiments, R 3b is a 5-membered heterocycloalkyl, and one to three R 8 In some embodiments, R 3b is a 6-membered heterocycloalkyl, and one to four R 8 It may be substituted with a group.

[0412] In some embodiments, R 3b is C1-C4-alkyl. In some embodiments, R 3b is C2-C4-alkylene-O-C1-C4-alkyl. In some embodiments, R 3b is C1-C4-haloalkyl.

[0413] In some embodiments, R 3b is C-C-alkyl. In some embodiments, R 3b is C2-C4-alkylene-O-C1-C4-alkyl. In some embodiments, R 3b is C3-C4-haloalkyl.

[0414] When ring A is a 5-membered heteroaryl, R 3b may be an optionally substituted C-cycloalkyl. When ring A is a 5-membered heteroaryl, R 3b When ring A is a 5-membered heteroaryl, R 3b may be substituted or unsubstituted phenyl. When ring A is a 5-membered heteroaryl, R 3b can be an optionally substituted 6-membered heteroaryl.

[0415] In some embodiments, R 4is, independently in each occurrence, cyano, C0-C4-alkylene-NR 5 R 6 , C0-C4-alkylene-OR 7 , S(O)2R 6 , C1-C4-alkyl, C0-C4-alkylene-R 4c , C0-C4-alkylene-S(O)2R 6 and C1-C4-haloalkyl. In some embodiments, R 4c is independently selected at each occurrence from C3-C6-cycloalkyl and 4- to 6-membered heterocycloalkyl.

[0416] In some embodiments, R 4 is, independently in each occurrence, cyano, C0-C4-alkylene-NR 5 R 6 , C0-C4-alkylene-OR 7 , S(O)2R 6 , C1-C4-alkyl, 4- to 6-membered heterocycloalkyl, C0-C4-alkylene-S(O)2R 6 and C1-C4-haloalkyl.

[0417] In some embodiments, R 4 is, independently in each occurrence, cyano, C0-C4-alkylene-NR 5 R 6 , C0-C4-alkylene-OR 7 , S(O)2R 6 , C1-C4-alkyl, C0-C4-alkylene-S(O)2R 6 and C1-C4-haloalkyl.

[0418] In some embodiments, R 4 is, independently in each occurrence, cyano, C0-C4-alkylene-NR 5 R 6 , C0-C4-alkylene-OR 7 , S(O)2R 6, C1-C2-alkyl, 4-membered heterocycloalkyl, C(CH3)2OH, C1-C2-alkyl-S(O)2R 6 and C1-C2-haloalkyl.

[0419] In some embodiments, R 4 is, independently in each occurrence, cyano, C0-C4-alkylene-NR 5 R 6 , C0-C4-alkylene-OR 7 , S(O)2R 6 , C1-C2-alkyl, C(CH3)2OH, C1-C2-alkyl-S(O)2R 6 and C1-C2-haloalkyl.

[0420] In some embodiments, R 4 is, independently in each occurrence, C0-C4-alkylene-NR 5 R 6 , S(O)2R 6 , C1-alkyl, 4-membered heterocycloalkyl, C(CH3)2OH, C1-alkyl-S(O)2R 6 and C1-haloalkyl.

[0421] In some embodiments, R 4 is, independently in each occurrence, C0-C4-alkylene-NR 5 R 6 , S(O)2R 6 , C1-alkyl, C(CH3)2OH, C1-alkyl-S(O)2R 6 and C1-haloalkyl.

[0422] In some embodiments, R 4 are, independently in each case, cyano, NR 5 R 6 , OR 7 , S(O)2R 6 , C1-C2-alkyl, 4-membered heterocycloalkyl, C(CH3)2OH, C1-C2-alkyl-S(O)2R 6and C1-C2-haloalkyl.

[0423] In some embodiments, R 4 are, independently in each case, cyano, NR 5 R 6 , OR 7 , S(O)2R 6 , C1-C2-alkyl, C(CH3)2OH, C1-C2-alkyl-S(O)2R 6 and C1-C2-haloalkyl.

[0424] In some embodiments, R 4 is, in each case independently, NR 5 R 6 , S(O)2R 6 , C1-alkyl, oxetanyl (e.g., oxetan-3-yl), C(CH3)2OH, C1-alkyl-S(O)2R 6 and C1-haloalkyl.

[0425] In some embodiments, R 4 is, in each case independently, NR 5 R 6 , S(O)2R 6 , C1-alkyl, C(CH3)2OH, C1-alkyl-S(O)2R 6 and C1-haloalkyl.

[0426] In some embodiments, R 4 are, independently in each case, N(H)S(O)2Me, S(O)2MeR 6 , C(CH3)2OH, C1-alkyl-S(O)2Me.

[0427] In some embodiments, m is an integer selected from 0, 1, and 2. In some embodiments, m is 2. In some embodiments, m is 1. In some embodiments, m is 0.

[0428] In some embodiments, R 4a is H. In some embodiments, R 4a is methyl. In some embodiments, R 4a is cyclopropyl. In some embodiments, R 4a is C0-C4-alkylene-R 4c In some embodiments, R 4c is independently selected at each occurrence from C-C-cycloalkyl and 4- to 6-membered heterocycloalkyl. 4a is a 4-membered heterocycloalkyl. In some embodiments, R 4a is oxetanyl. In some embodiments, R 4a is oxetan-3-yl. In some embodiments, R 4a is oxetanyl or azetidinyl. In some embodiments, R 4a is independently selected from H, C1-C4-alkyl, and cyclopropyl. 4a is independently selected from C1-C4-alkyl, cyclopropyl, and cyclobutyl. 4a is cyclopropyl.

[0429] In some embodiments, R 4b is S(O)2R 6 In some embodiments, R 4b is C1-C4-alkyl. In some embodiments, R 4b is C1-C4-alkyl-S(O)2R 6 In some embodiments, R 4b is C1-C4-haloalkyl. In some embodiments, R 4b is cyclopropyl.

[0430] In some embodiments, R 4bis selected from S(O)2-C1-C3-alkyl, for example, S(O)2Me. 4b is C1-C4-alkyl, for example, methyl. In some embodiments, R 4b is C1-C4-alkyl-S(O)2-C1-C4-alkyl, for example -CH2-S(O)2-Me.

[0431] In some embodiments, R 4c is C-C-cycloalkyl. In some embodiments, R 4c is a 4- to 6-membered heterocycloalkyl.

[0432] In some embodiments, R 5 is independently selected at each occurrence from H, C1-C4-alkyl, and S(O)2-C1-C4-alkyl.

[0433] In some embodiments, R 5 is S(O)-C-C-alkyl, and optionally R 5 is S(O)-C-alkyl. In some embodiments, R 5 is H. In some embodiments, R 5 is methyl.

[0434] In some embodiments, R 6 is independently selected at each occurrence from H and C1-C4 alkyl. 6 is H. In some embodiments, R 6 is methyl.

[0435] In some embodiments, R 7 is independently selected at each occurrence from H, C1-C4-alkyl, and C1-C4-haloalkyl.

[0436] In some embodiments, R 7is independently selected at each occurrence from H and C1-C4-alkyl.

[0437] In some embodiments, R 7 is independently selected at each occurrence from H, C1-C2-alkyl, and C1-C2-haloalkyl.

[0438] In some embodiments, R 7 is independently selected in each occurrence from H and C1-C2-alkyl.

[0439] In some embodiments, R 7 is, independently in each case, H.

[0440] In some embodiments, R 8 is independently in each occurrence =O, fluoro, nitro, cyano, NR 5 R 6 , OR 7 , C(O)R 6 , C1-C4-alkyl, C1-C4-haloalkyl and cyclopropyl.

[0441] In some embodiments, R 8 is, independently in each occurrence, ═O, fluoro, C(O)R 6 , C1-C2-alkyl, and C1-C2-haloalkyl.

[0442] In some embodiments, R 8 is, independently in each occurrence, ═O, fluoro, and C(O)R 6 In some embodiments, R 8 is independently selected at each occurrence from ═O, fluoro, and C(O)Me.

[0443] In some embodiments, R 9 is independently in each occurrence halo, nitro, cyano, C0-C4-alkylene-OR 7 , S.R.6 , SOR 6 , S(O)2R 6 , SO2NR 6 R 6 , CO2R 6 , C(O)R 6 ,CONR 6 R 6 , C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl and C1-C4-haloalkyl.

[0444] In some embodiments, R 9 is, independently in each occurrence, halo, nitro, cyano, NR 5 R 6 , OR 7 , C(O)R 6 , C1-C4-alkyl, C1-C4-haloalkyl and cyclopropyl.

[0445] In some embodiments, R 9 is independently selected at each occurrence from halo, C1-C4-alkyl, and C1-C4-haloalkyl.

[0446] In some embodiments, R 9 is independently selected at each occurrence from halo, C1-C2-alkyl, and C1-C2-haloalkyl.

[0447] In some embodiments, R 9 is independently selected at each occurrence from halo, and C-C-alkyl. 9 is independently selected at each occurrence from fluoro and methyl.

[0448] In some embodiments, R x and R y are each independently H, halo, nitro, cyano, or NR 5 R 6 , OR 7 , S.R. 6, C1-C4-alkyl, C1-C4-haloalkyl and C3-C4-cycloalkyl.

[0449] In some embodiments, R x and R y are each independently selected from H, halo, cyano, C1-C2-alkyl, C1-C2-haloalkyl and C3-cycloalkyl.

[0450] In some embodiments, R x is H. In some embodiments, R y is H. In some embodiments, R x and R y are H, respectively.

[0451] In some embodiments, either the alkyl or alkenyl group may, independently in each occurrence, be selected from oxo, fluoro, NR a R b , OR a , and S(O)2R a and optionally substituted with 1 to 5 substituents selected from: a is independently selected at each occurrence from H and C1-C4-alkyl; R b is independently in each occurrence selected from H, C1-C4-alkyl, C(O)—C1-C4-alkyl and S(O)2—C1-C4-alkyl.

[0452] In some embodiments, X 6 is carbon. In some embodiments, X 6 is nitrogen.

[0453] In some embodiments, X 7 is carbon. In some embodiments, X 7 is nitrogen.

[0454] In some embodiments, p is an integer selected from 0, 1, 2, and 3. In some embodiments, p is 3. In some embodiments, p is 2. In some embodiments, p is 1. In some embodiments, p is 0.

[0455] In some embodiments, the compound of Formula (IA) is a compound of Formula (XXI), a tautomer, stereoisomer or mixture of stereoisomers, a pharmaceutically acceptable salt, a hydrate, a deuterated derivative, or an N-oxide thereof: TIFF2026501324000103.tif53165In formula, R1 is C1-C4-haloalkyl; R2 is C1-C4-alkyl, where C1-C4-alkyl is optionally substituted by SR3 or OR3, R3 is selected from H, C1-C3-alkyl, C(O)—C1-C3-alkyl, and C1-C3-haloalkyl; R y is hydrogen or halo.

[0456] In some embodiments, R1 is independently selected from CF3, CHF2, CH2CF3, and CH2CH2F. In some embodiments, R1 is independently selected from CBr3, CHBr2, CH2CBr3, and CH2CH2Br. In some embodiments, R1 is independently selected from CCl3, CHCl2, CH2CCl3, and CH2CH2Cl. In some embodiments, R1 is CH2CH2F. In some embodiments, R1 is CHF2. In some embodiments, R1 is CF3.

[0457] In some embodiments, R2 is selected from -CH3, -CH2-CH2-S-CH3, -CH2-CH2-O-CH3, -CH2-CH2-SCH2-CH3, and -CH2-CH2-OCH2-CH3. In some embodiments, R2 is -CH3. In some embodiments, R2 is -CH2-CH2-O-CH3. In some embodiments, R2 is -CH2-CH2-S-CH3.

[0458] In some embodiments, R2 is C1-C4-alkyl, where the C1-C4-alkyl is substituted with OR3. In some embodiments, R2 is C1-C4-alkyl, where the C1-C4-alkyl is substituted with SR3. In some embodiments, R2 is -CH3.

[0459] In some embodiments, R y is halo. In some embodiments, R y is fluorine.

[0460] In some embodiments, the compound of Formula (XXI) is a compound of Formula (XXIA), a tautomer, stereoisomer or mixture of stereoisomers, a pharmaceutically acceptable salt, a hydrate, a deuterated derivative, or an N-oxide thereof: TIFF2026501324000104.tif53165In formula, R1 is C1-C4-haloalkyl; R2 is C1-C4-alkyl, where C1-C4-alkyl is optionally substituted by SR3 or OR3, R3 is selected from H, C1-C3-alkyl, C(O)-C1-C3-alkyl, and C1-C3-haloalkyl.

[0461] In some embodiments, R1 is independently selected from CF3, CHF2, CH2CF3, and CH2CH2F. In some embodiments, R1 is independently selected from CBr3, CHBr2, CH2CBr3, and CH2CH2Br. In some embodiments, R1 is independently selected from CCl3, CHCl2, CH2CCl3, and CH2CH2Cl. In some embodiments, R1 is CH2CH2F. In some embodiments, R1 is CHF2. In some embodiments, R1 is CF3.

[0462] In some embodiments, R2 is C1-C4-alkyl, where the C1-C4-alkyl is substituted with OR3. In some embodiments, R2 is C1-C4-alkyl, where the C1-C4-alkyl is substituted with SR3. In some embodiments, R2 is selected from -CH3, -CH2-CH2-O-CH3, and -CH2-CH2-OCH2-CH3. In some embodiments, R2 is selected from -CH3, -CH2-CH2-S-CH3, and -CH2-CH2-SCH2-CH3.

[0463] In some embodiments, R2 is -CH3. In some embodiments, R2 is -CH2-CH2-O-CH3. In some embodiments, R2 is -CH2-CH2-S-CH3.

[0464] In some embodiments, the compound of Formula (XXI) is a compound of Formula (XXIB), a tautomer, stereoisomer or mixture of stereoisomers, a pharmaceutically acceptable salt, a hydrate, a deuterated derivative, or an N-oxide thereof: TIFF2026501324000105.tif47165In formula, R1 is C1-C4-haloalkyl.

[0465] In some embodiments, R1 is independently selected from CF3, CHF2, CH2CF3, and CH2CH2F. In some embodiments, R1 is independently selected from CBr3, CHBr2, CH2CBr3, and CH2CH2Br. In some embodiments, R1 is independently selected from CCl3, CHCl2, CH2CCl3, and CH2CH2Cl. In some embodiments, R1 is CH2CH2F. In some embodiments, R1 is CHF2. In some embodiments, R1 is CF3.

[0466] In some embodiments, the compound is TIFF2026501324000106.tif67128TIFF2026501324000107.tif186144TIFF2026501324000108.tif218132TIFF2026501324000109.tif190144TIFF2026501324000110.tif195141TIFF2026501324000111.tif187133TIFF2026501324000112.tif196143TIFF2026501324000113.tif134135, or a pharmaceutically acceptable salt thereof, or an N-oxide thereof.

[0467] In some embodiments, a compound of the formulae disclosed herein is a tautomer, stereoisomer or mixture of stereoisomers, a pharmaceutically acceptable salt, a hydrate, a deuterated derivative, or an N-oxide thereof.

[0468] In some embodiments, the present disclosure provides a pharmaceutical composition comprising a compound defined in the present disclosure and one or more pharmaceutically acceptable excipients. In some embodiments, the present disclosure refers to a "disease" or "disorder." In all cases, reference to a "disease" or "disorder" should be understood to mean "disease" and / or "disorder."

[0469] In some embodiments, the present disclosure provides a compound or pharmaceutical composition defined in the present disclosure for use as a medicament.

[0470] In some embodiments, the present disclosure provides the use of a compound or pharmaceutical composition defined in the present disclosure for the manufacture of a medicament.

[0471] In some embodiments, the medicament has therapeutic benefit in the treatment of immune or autoimmune diseases, such as arthritis, rheumatoid arthritis, psoriasis / psoriatic arthritis, and / or inflammatory diseases, such as inflammatory skin disorders, respiratory diseases, gastrointestinal diseases, eye diseases, cancer, rheumatic diseases, demyelinating diseases, fibrotic diseases, and / or myeloproliferative neoplastic disorders.

[0472] In some embodiments, the present disclosure provides a compound disclosed herein, or a pharmaceutical composition comprising the compound, for use in a method for treating an immune or autoimmune disease, e.g., arthritis, rheumatoid arthritis, psoriasis / psoriatic arthritis, and / or an inflammatory disease, e.g., an inflammatory skin disorder, a respiratory disease, a gastrointestinal disease, an eye disease, cancer, a rheumatic disease, a demyelinating disease, a fibrotic disease, and / or a myeloproliferative neoplastic disorder.

[0473] In some embodiments, the present disclosure provides a method for the treatment of an immune or autoimmune disease, e.g., arthritis, rheumatoid arthritis, psoriasis / psoriatic arthritis, and / or an inflammatory disease, e.g., an inflammatory skin disorder, a respiratory disease, a gastrointestinal disease, an eye disease, cancer, a rheumatic disease, a demyelinating disease, a fibrotic disease, and / or a myeloproliferative neoplastic disorder, the method comprising administering to a subject an effective amount of a compound as defined in any of the embodiments disclosed herein, or a pharmaceutical composition as defined in any of the embodiments disclosed herein.

[0474] In some embodiments, the present disclosure provides for the use of a compound, or a pharmaceutical composition comprising the compound, for the manufacture of a medicament for treating inflammatory diseases, such as skin diseases, rheumatic diseases and fibrotic diseases, or immune or autoimmune diseases, such as arthritis, rheumatoid arthritis, psoriasis / psoriatic arthritis, the method comprising administering to a subject an effective amount of a compound as defined in any of the embodiments disclosed herein, or a pharmaceutical composition as defined in any of the embodiments disclosed herein.

[0475] Selective BET BDII inhibitors, such as the compounds disclosed herein, may be of value and may be used, in one or more embodiments, in the treatment of inflammatory, immune, and autoimmune disorders, including diseases that have or may have an inflammatory or autoimmune component, including the following non-limiting example disorders and diseases:

[0476] In some embodiments, the disclosure provides a compound or pharmaceutical composition defined in the disclosure for use in a method for the treatment or prevention of an inflammatory disease, such as inflammatory skin disorders, respiratory diseases, gastrointestinal diseases, eye diseases, cancer, rheumatic diseases, demyelinating diseases, and fibrotic diseases, and / or an immune or autoimmune disease, such as arthritis, rheumatoid arthritis, psoriasis / psoriatic arthritis, multiple sclerosis, lupus, systemic lupus erythematosus, inflammatory bowel disease, Addison's disease, Graves' disease, Sjogren's syndrome, thyroiditis, myasthenia gravis, Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy, scleroderma, and autoimmune vasculitis, and / or a myeloproliferative neoplastic disorder, such as chronic myeloid leukemia, polycythemia vera, primary myelofibrosis (also called chronic idiopathic myelofibrosis), essential thrombocythemia, chronic neutrophilic leukemia, chronic eosinophilic leukemia, and acute leukemia. Immunoinflammatory indications include rheumatoid arthritis, systemic lupus erythematosus, and multiple sclerosis.

[0477] In some embodiments, the disclosure provides a compound or pharmaceutical composition defined in the disclosure for use in a method for the treatment of an inflammatory disease, such as inflammatory skin disorders, respiratory diseases, gastrointestinal diseases, eye diseases, cancer, rheumatic diseases, demyelinating diseases, and fibrotic diseases, and / or an immune or autoimmune disease, such as arthritis, rheumatoid arthritis, psoriasis / psoriatic arthritis, multiple sclerosis, lupus, systemic lupus erythematosus, inflammatory bowel disease, Addison's disease, Graves' disease, Sjogren's syndrome, thyroiditis, myasthenia gravis, Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy, scleroderma, and autoimmune vasculitis, and / or a myeloproliferative neoplastic disorder, such as chronic myeloid leukemia, polycythemia vera, primary myelofibrosis (also called chronic idiopathic myelofibrosis), essential thrombocythemia, chronic neutrophilic leukemia, chronic eosinophilic leukemia, and acute leukemia. Immunoinflammatory indications include rheumatoid arthritis, systemic lupus erythematosus, and multiple sclerosis.

[0478] In some embodiments, the present disclosure provides methods for the treatment or prevention of inflammatory diseases, such as inflammatory skin disorders, respiratory diseases, gastrointestinal diseases, eye diseases, cancer, rheumatic diseases, demyelinating diseases, and fibrotic diseases, and / or immune or autoimmune diseases, such as arthritis, rheumatoid arthritis, psoriasis / psoriatic arthritis, multiple sclerosis, lupus, systemic lupus erythematosus, inflammatory bowel disease, Addison's disease, Graves' disease, Sjogren's syndrome, thyroiditis, myasthenia gravis, Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy, scleroderma, and autoimmune vasculitis, and / or myeloproliferative neoplastic disorders, such as chronic myeloid leukemia, polycythemia vera, primary myelofibrosis (also called chronic idiopathic myelofibrosis), essential thrombocythemia, chronic neutrophilic leukemia, chronic eosinophilic leukemia, and acute leukemia. Immunoinflammatory indications include rheumatoid arthritis, systemic lupus erythematosus, and multiple sclerosis, and the methods comprise administering to a subject an effective amount of a compound or pharmaceutical composition defined in the present disclosure.

[0479] In some embodiments, the present disclosure provides methods for the treatment of inflammatory diseases, such as inflammatory skin disorders, respiratory diseases, gastrointestinal diseases, eye diseases, cancer, rheumatic diseases, demyelinating diseases, and fibrotic diseases, and / or immune or autoimmune diseases, such as arthritis, rheumatoid arthritis, psoriasis / psoriatic arthritis, multiple sclerosis, lupus, systemic lupus erythematosus, inflammatory bowel disease, Addison's disease, Graves' disease, Sjogren's syndrome, thyroiditis, myasthenia gravis, Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy, scleroderma, and autoimmune vasculitis, and / or myeloproliferative neoplastic disorders, such as chronic myeloid leukemia, polycythemia vera, primary myelofibrosis (also called chronic idiopathic myelofibrosis), essential thrombocythemia, chronic neutrophilic leukemia, chronic eosinophilic leukemia, and acute leukemia. Immunoinflammatory indications include rheumatoid arthritis, systemic lupus erythematosus, and multiple sclerosis, and the methods comprise administering to a subject an effective amount of a compound or pharmaceutical composition defined in the present disclosure.

[0480] In some embodiments, the disclosure provides use of a compound or pharmaceutical composition defined in the disclosure for the manufacture of a medicament for treating or preventing an inflammatory disease, such as inflammatory skin disorders, respiratory diseases, gastrointestinal diseases, eye diseases, cancer, rheumatic diseases, demyelinating diseases, and fibrotic diseases, and / or an immune or autoimmune disease, such as arthritis, rheumatoid arthritis, psoriasis / psoriatic arthritis, multiple sclerosis, lupus, systemic lupus erythematosus, inflammatory bowel disease, Addison's disease, Graves' disease, Sjogren's syndrome, thyroiditis, myasthenia gravis, Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy, scleroderma, and autoimmune vasculitis, and / or a myeloproliferative neoplastic disorder, such as chronic myeloid leukemia, polycythemia vera, primary myelofibrosis (also called chronic idiopathic myelofibrosis), essential thrombocythemia, chronic neutrophilic leukemia, chronic eosinophilic leukemia, and acute leukemia. Immunoinflammatory indications include rheumatoid arthritis, systemic lupus erythematosus, and multiple sclerosis, and the methods comprise administering to a subject an effective amount of a compound or pharmaceutical composition defined in the present disclosure.

[0481] In some embodiments, the present disclosure provides a method of inhibiting bromodomain and extraterminal protein activity in a subject, the method comprising administering to the subject an effective amount of a compound or pharmaceutical composition defined in the present disclosure.

[0482] In some embodiments, the present disclosure provides a compound, or a pharmaceutical composition comprising the compound, for use in a method of inhibiting bromodomain and extraterminal protein activity in a subject, the method comprising administering to the subject an effective amount of a compound or pharmaceutical composition defined in the present disclosure.

[0483] In some embodiments, the present disclosure provides the use of a compound, or a pharmaceutical composition comprising the compound, for use in the manufacture of a medicament for inhibiting bromodomain and extraterminal protein activity in a subject, the method comprising administering to the subject an effective amount of a compound or pharmaceutical composition defined in the present disclosure.

[0484] In some embodiments, the present disclosure provides a method of treating a disorder associated with bromodomain and extraterminal protein activity in a subject, the method comprising administering to the subject an effective amount of a compound or pharmaceutical composition defined in the present disclosure.

[0485] In some embodiments, the present disclosure provides a compound, or a pharmaceutical composition comprising the compound, for use in a method of treating a disorder associated with bromodomain and extraterminal protein activity in a subject, the method comprising administering to the subject an effective amount of a compound or pharmaceutical composition defined in the present disclosure.

[0486] In some embodiments, the present disclosure provides a compound, or a pharmaceutical composition comprising the compound, for use in the manufacture of a medicament for treating a disorder associated with bromodomain and extra-terminal protein activity in a subject, the method comprising administering to the subject an effective amount of a compound or pharmaceutical composition defined in the present disclosure.

[0487] Selective BET BDII inhibitors, such as the compounds disclosed herein, may be of value and may be used, in one or more embodiments, in the treatment or amelioration of the following non-limiting example disorders and diseases:

[0488] Selective BET BDII inhibitors, such as the compounds disclosed herein, may be of value and may be used in one or more embodiments to treat or ameliorate inflammatory, immune, and autoimmune disorders, including diseases that have or may have an inflammatory or autoimmune component.

[0489] Selective BET BDII inhibitors, such as the compounds disclosed herein, may be of value and may be used in one or more embodiments in the treatment or amelioration of myeloproliferative neoplastic disorders, which may include diseases that have or may have an inflammatory or autoimmune component.

[0490] Inflammatory, immune, or autoimmune disorders include acne, inflammatory acne, acne fulminans, angiofibroma, nodular papulopustular acne, acne conglobata, acute erysipelas, alopecia, alopecia areata, alopecia totalis, atopic dermatitis, alopecia universalis, autoimmune bullous skin disorders such as pemphigus vulgaris (PV) or bullous pemphigoid (BP), recent skin infections, viral skin infections, bullous diseases, cellulitis, and skin abscesses. , carbuncles, chronic hand eczema, cutaneous mastocytosis, Dercum's disease, skin pain, skin inflammation, contact dermatitis, dermatitis, dermatitis herpetiformis, dermatomyositis, chronic atypical neutrophilic dermatosis with lipodystrophy and fever (CANDLE), neutrophilic dermatitis such as pyoderma gangrenosum and Sweet's syndrome, nail fold infections, edematous palmoplantar pustulosis, erythema multiforme, erythema nodosum, granuloma annulare, pemphigus, epidermal necrotizing pemphigus, paraneoplastic pemphigus , erythrasma, ecthyma, eczema, folliculitis, carbuncles, gustatory sweating, hyperhidrosis, Hailey-Hailey disease, urticaria, hidradenitis suppurativa, hypertrophic scars, impetigo, ichthyosis, ischemic necrosis, keloids, necrotizing subcutaneous infections, actinic keratosis, keratosis pilaris, miliaria, molluscum contagiosum, lichen planus, Netherton syndrome, pityriasis rubra pilaris, psoriasis, pruritus, prurigo nodularis, rash, rosacea, pediculosis, pityriasis rosea, scleroderma, scalded skin syndrome The skin disorder may be selected from the group consisting of skin rash, skin irritation, skin sensitization (e.g., contact dermatitis or allergic contact dermatitis), trauma or injury to the skin, post-operative or post-surgical skin conditions, wounds, burns (including chemical, electrical fire, friction, radiation, temperature-related, heat and cold), sunburn, scarring, scabies, skin ulcers, urticaria pigmentosa, urticarial and chronic idiopathic pruritus, vitiligo, warts, and xerosis.

[0491] The inflammatory, immune, or autoimmune disorder may be a respiratory disease selected from asthma, bronchiectasis, bronchiolitis, byssinosis, chronic obstructive pulmonary disease (COPD), cystic fibrosis, hypersensitivity pneumonitis, mesothelioma, pneumoconiosis, (idiopathic) pulmonary fibrosis, rhinitis, rhinosinusitis, and sarcoidosis.

[0492] The inflammatory, immune, or autoimmune disorder can be a gastrointestinal disorder selected from celiac disease, eosinophilic esophagitis, inflammatory bowel disease, and retroperitoneal fibrosis.

[0493] The inflammatory, immune, or autoimmune disorder can be an ocular disease selected from conjunctivitis, dry eye syndrome, iritis, keratitis, macular degeneration, myasthenia gravis, scleritis, Sjogren's syndrome, and uveitis.

[0494] The inflammatory, immune, or autoimmune disorder can be a cardiovascular disease or related disorder selected from cerebrovascular disease, aortic disease, arrhythmia, atherosclerosis, aneurysm, angina, stroke, carditis, cardiac hypertrophy, cardiomyopathy, endocarditis, coronary artery disease, deep vein thrombosis, heart attack, heart disease, heart failure, Marfan syndrome, myocarditis, peripheral arterial disease, pericarditis, pulmonary embolism, rheumatic heart disease, thrombosis, valvular heart disease, ventricular heart disease, ventricular dysfunction, and vascular disease.

[0495] Inflammatory, immune, or autoimmune disorders include, but are not limited to, Addison's disease, AIDS, ankylosing spondylitis, atherosclerosis, arthritis, Behçet's disease, cryopyrin-associated periodic fever syndromes (CAPS), chronic kidney disease (including, but not limited to, nephritis, nephropathy, hypertensive nephropathy, HIV-associated nephropathy, IgA nephropathy, familial Mediterranean fever, focal segmental glomerulosclerosis, Graves' disease, juvenile arthritis, lymphangitis, lymphadenitis, lupus nephritis, minimal change disease, neurofibromatosis, polycystic kidney disease, and tubulointerstitial nephritis), acute kidney injury diseases or conditions (including, but not limited to, ischemia-reperfusion-induced, cardiac surgery and major surgery-induced, percutaneous coronary intervention-induced, radiological contrast-enhanced kidney disease, and urinary tract infections and conditions). The systemic indication may be selected from the group consisting of: inflammatory bowel disease (including, but not limited to, inflammatory bowel disease ...

[0496] The inflammatory, immune, or autoimmune disorder may be, for example, an autoimmune disease or indication in which immunosuppression is desired to avoid transplant rejection and graft-versus-host disease (chronic or acute).

[0497] Selective BET BDII inhibitors, such as the compounds disclosed herein, may be of value and may be used in one or more embodiments to treat or ameliorate cancer.

[0498] Cancers include acoustic neuroma, anal cancer, bladder cancer, Bowen's disease, brain cancer, breast cancer, carcinomas such as basal cell carcinoma, cholangiocarcinoma, bronchogenic carcinoma, choriocarcinoma, embryonal carcinoma, cystadenocarcinoma, epithelial carcinoma, medullary carcinoma, NUT midline carcinoma (NMC), papillary carcinoma, papillary adenocarcinoma, renal cell carcinoma, sebaceous gland carcinoma, small cell lung carcinoma, squamous cell carcinoma, and sweat gland carcinoma, cervical cancer, chordoma, colon cancer, colorectal cancer, craniopharyngioma, neoproliferative changes (dysplasia and dysplasia), endometrial cancer, ependymoma, esophageal cancer, essential thrombocythemia, estrogen receptor positive breast cancer, Ewing's tumor, genital cancer, cervical cancer, vulvar cancer, vulvar intraepithelial neoplasia (VIN), vaginal cancer, reproductive testicular cancer, gastrointestinal cancer, stomach cancer, glioblastoma, glioma, heavy chain disease, hemangioblastoma, hepatocellular carcinoma, hepatoma, hormone refractory prostate cancer, keratinocyte carcinoma, kidney cancer, leukemias, e.g., acute leukemia, acute lymphocytic leukemia, acute myeloid leukemia, acute myeloid leukemia (monocytic, myeloblastic, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic and promyelocytic), acute T-cell leukemia, chronic leukemia, chronic lymphocytic leukemia, chronic myelocytic (granulocytic) leukemia, chronic myeloid leukemia, erythroleukemia, lymphoblastic leukemia, and myeloid leukemia, liver Cancer, lung cancer, lymphoid malignancies of T-cell or B-cell origin, lymphomas (Hodgkin's lymphoma and non-Hodgkin's lymphoma), e.g., cutaneous T-cell lymphoma, diffuse large B-cell lymphoma, and follicular lymphoma, cutaneous (skin) lymphoma, malignant tumors and hyperproliferative disorders of the bladder, breast, colon, lung, ovary, pancreas, prostate, skin, and uterus, etc., advanced malignancies, medulloblastoma, melanoma, meningioma, Merkel cell carcinoma mesothelioma, metastatic cancer, multiple myeloma, myeloma, metastatic cancer, myelofibrosis, myeloproliferative neoplasms, neuroblastoma, non-small cell lung cancer, head and neck cancer, oligodendroglioma, The cancer may be a skin or systemic cancer selected from tumors, oral cancer, ovarian cancer, pancreatic cancer, pinealoma, polycythemia vera, prostate cancer, rectal cancer, retinoblastoma, sarcomas such as chondrosarcoma, endothelial tumor, fibrosarcoma, gliosarcoma, leiomyosarcoma, liposarcoma, lymphangioendothelial tumor, lymphangiosarcoma, myxosarcoma, Castleman's disease and Kaposi's sarcoma, osteogenic sarcoma, and rhabdomyosarcoma, seminoma, skin cancer, skin adnexal tumors, and sarcomas, small cell lung cancer, solid tumors, gastric cancer, synovium, testicular tumor, thyroid cancer, uterine cancer, Waldenstrom's macroglobulinemia, and Wilms' tumor.

[0499] Myeloproliferative neoplastic disorders can be chronic myeloid leukemia, polycythemia vera, primary myelofibrosis (also called chronic idiopathic myelofibrosis), essential thrombocythemia, chronic neutrophilic leukemia, chronic eosinophilic leukemia, or can develop into acute leukemia.

[0500] Selective BET BDII inhibitors, such as the compounds disclosed herein, can be used in one or more embodiments to provide male contraception.

[0501] Selective BET BDII inhibitors, such as the compounds disclosed herein, may, in one or more embodiments, be useful in treating or ameliorating obesity, dyslipidemia, cholesteatoma, hypercholesterolemia, Alzheimer's disease, metabolic syndrome, hepatic steatosis, type I diabetes, type II diabetes, and complications from diabetes, insulin resistance, and diabetic retinopathy or diabetic neuropathy.

[0502] Selective BET BDII inhibitors, such as the compounds disclosed herein, may, in one or more embodiments, be useful in treating or ameliorating immune dysfunction, viral diseases, bacterial diseases, yeast diseases, non-inflammatory acne, allergic diseases, asthma, food allergies, rhinitis, IL-6 pathway-related diseases, immune responses, and hyperproliferative disorders.

[0503] Selective BET BDII inhibitors, such as the compounds disclosed herein, may, in one or more embodiments, be useful in treating or ameliorating Aicardi-Goutieres syndrome, chilblain lupus erythematosus, infantile-onset interferon gene stimulator-associated vasculitis (SAVI), Singleton-Merten syndrome, retinal vasculopathy with cerebral leukodystrophy, autoimmune uveitis, lupus, systemic sclerosis, autoimmune thyroid disease, allograft rejection, graft-versus-host disease, allograft rejection, and graft-versus-host reaction.

[0504] Selective BET BDII inhibitors, such as the compounds disclosed herein, may, in one or more embodiments, be useful in treating or ameliorating disorders caused by viruses such as Epstein-Barr virus (EBV), HIV, HTLV1, herpes simplex virus (HSV), varicella-zoster virus (VZV), and human papillomavirus (HPV).

[0505] Selective BET BDII inhibitors, such as the compounds disclosed herein, may be useful in one or more embodiments for treating or ameliorating mucopurulent cervicitis (MPC), urethritis, nongonococcal urethritis (NGU), vulvar disorders, vulvodynia, vulvodynia, vulvar dystrophy, pelvic inflammation, endometritis, salpingitis, oophoritis, dyspareunia, anal and rectal diseases, perianal abscess / fistula, anal fissures, anal warts, hemorrhoids, anal itch, ani pruritus, fecal incontinence, constipation, and polyps of the colon and rectum.

[0506] Selective BET BDII inhibitors, such as the compounds disclosed herein, may be useful in one or more embodiments for restoring or promoting the restoration of integrity to areas of destroyed or damaged tissue, skin or mucosa, as well as reducing and ameliorating scar formation or scarring.

[0507] Selective BET BDII inhibitors, such as the compounds disclosed herein, may, in one or more embodiments, be useful in treating or ameliorating pyoderma gangrenosum (PG), palmoplantar pustulosis (PPP), and generalized pustular psoriasis (GPP).

[0508] Selective BET BDII inhibitors, such as the compounds disclosed herein, may, in one or more embodiments, be useful in treating or ameliorating multiple sclerosis, rheumatoid arthritis, and rhinosinusitis.

[0509] Selective BET BDII inhibitors, such as the compounds disclosed herein, may, in one or more embodiments, be useful in treating or ameliorating cryopyrin-associated periodic fever syndromes (CAPS), cardiovascular disease, cerebrovascular disease, familial Mediterranean fever, Graves' disease, liver fibrosis, neurofibromatosis, myocarditis, pericarditis, prostate disease, prostatitis, benign prostatic hyperplasia (BPH), systemic mastocytosis, and warm autoimmune hemolytic anemia.

[0510] Selective BET BDII inhibitors, such as the compounds disclosed herein, may, in one or more embodiments, be useful in the treatment or amelioration of angiofibroma, chronic hand eczema, cutaneous mastocytosis, urticaria pigmentosa, neutrophilic dermatitis such as pyoderma gangrenosum and Sweet's syndrome, chronic atypical neutrophilic dermatosis with lipodystrophy and fever (CANDLE), ichthyosis, keloids, scars, hypertrophic scars, Netherton syndrome, cutaneous pruritus, prurigo nodularis, and urticaria pigmentosa.

[0511] Selective BET BDII inhibitors, such as the compounds disclosed herein, may also be of value and may be used, in one or more embodiments, for the palliative, diagnosis, or prevention of any disease, disorder, or condition in humans with one or more of the foregoing non-limiting example disorders and diseases.

[0512] The present disclosure provides certain BET inhibitors (e.g., Compound A) that have been found to be surprisingly effective against the inflammatory autoimmune skin disorder psoriasis and can provide effective treatment for other skin diseases and disorders, e.g., skin diseases and disorders with an inflammatory and / or autoimmune component. In some embodiments, the present disclosure provides potent and selective BET inhibitors (e.g., compounds of the formulas disclosed herein) that can provide novel and effective treatments and relief for skin disorders or diseases, e.g., psoriasis, pyoderma gangrenosum (PG), palmoplantar pustulosis (PP), psoriasis, generalized pustular psoriasis (GPP), or other skin or skin-related diseases and disorders.

[0513] The present disclosure provides certain BET inhibitors (e.g., Compound A) that have been found to be surprisingly effective against arthritis, joint, or joint-related disorders or diseases. In some embodiments, the present disclosure provides potent and selective BET inhibitors (e.g., compounds of the formulas disclosed herein) that may provide novel and effective treatments and relief for joint disorders or diseases, such as arthritis, bursitis, Ehlers-Danlos syndrome, epicondylitis, Felty's syndrome, gouty arthritis, psoriatic arthritis, osteoarthritis, rheumatoid arthritis, Still's disease, tenosynovitis, synovitis, Sjogren's syndrome, Lyme disease, Whipple's disease, bone cancer, lupus, or other autoimmune joint disorders. In some embodiments, the disease is rheumatoid arthritis.

[0514] The present disclosure provides selective BET inhibitors (e.g., compounds of the formulae disclosed herein) that may provide novel and effective treatments and relief for joint-related diseases and disorders. Joints can be infected by many types of microorganisms (bacteria, fungi, viruses) and sometimes animal parasites. Infectious diseases and disorders of the joints include direct infection, infection via the bloodstream, e.g., synovial vessels, and spread from adjacent bone infection (osteomyelitis). Infectious arthritis can affect one joint (monoarthritis) or several joints (oligoarthritis) rather than many joints (polyarthritis). Joints or parts thereof can be damaged, for example, by staphylococcal, hemolytic streptococcal, and pneumococcal infections, which can damage cartilage; bone, for example, by tuberculous spondylitis (Pott's disease); brucellosis (Coccidioides immitis, Brucella suis, etc.); leprosy (Hansen's disease), rubella (German measles), and serum hepatitis; viral synovitis; sexually transmitted diseases (including dracunculiasis, Guinea worm disease, and gonorrhea); reactive arthritis (Reiter's disease); congenital syphilis (Clatton's joint disease); and yaws, which can lead to skeletal lesions. Inflammation can destroy the cartilage and underlying bone of the joint, resulting in irreparable deformity. In such cases, adhesions between joints frequently occur, resulting in loss of mobility and referred to as ankylosing spondylitis (Marie-Strümpel disease or Bechterew disease). Other types of arthritis are associated with chronic enteropathy, regional enteritis, inflammatory bowel disease, cirrhosis of the liver, and Whipple's disease.

[0515] In addition to joint disorders and diseases caused by any of the above, the present disclosure provides potent and selective BET inhibitors (e.g., compounds of the formulas disclosed herein) that may also provide novel and effective treatments or relief for non-inflammatory joint diseases, trauma, and degenerative disorders. Joint trauma includes blunt injury, minor sprains, fractures and dislocations, ligament, tendon, and capsular tears, meniscus tears, and hemarthrosis. Degenerative joint diseases include osteoarthritis, osteoarthritis, premature osteoarthritis, congenital dysplasia, senile hip arthropathy, spondylosis, chondromalacia patellar, metabolic diseases such as gouty arthritis, foot gout, alkaptonuric arthropathy, chondrocalcinosis, or pseudogout, mucopolysaccharidoses, Hurler syndrome, Morquio disease, and multiple epiphyseal dysplasia.

[0516] The present disclosure provides potent and selective BET inhibitors (e.g., compounds of the formulae disclosed herein) that may also provide novel and effective treatments or relief for secondary joint diseases and disorders, including hemorrhagic joints, hemarthrosis, villonodular synovitis, diseases occurring in association with aseptic osteonecrosis, such as those that may occur with fractures, osteochondritis dissecans, spondylolisthesis, Osgood-Schlatter, Legg-Calvé-Perthes, joint disorders due to endocrine insufficiency, acromegaly, neurogenic arthropathy, Charcot joints, hypertrophic osteoarthropathy, reflex sympathetic dystrophy, joint tumors, synovial chondromatosis, cartilage nodules, synovial chondromatosis, synovoma, synovial sarcoma, and polymyalgia rheumatica.

[0517] The present disclosure provides selective BET inhibitors (e.g., compounds of the formulae disclosed herein) that can provide novel and effective treatments and relief for fibrosis or fibrosis-related conditions. The present disclosure provides certain BET inhibitors (e.g., Compound A, Compound B, Compound C, Compound D) that can slow the progression of or the severity of indicators of fibrosis, e.g., pulmonary fibrosis, renal fibrosis, or kidney fibrosis.

[0518] In some embodiments, the disclosed methods and compositions may be therapeutically useful for fibrosis or fibrosis-associated conditions affecting any tissue, including, for example, visceral fibrosis, fibrotic disorders of the skin or dermis, and ocular fibrotic conditions. In some embodiments, the fibrosis or fibrosis-associated conditions include fibrosis of visceral organs (e.g., liver, lung, kidney, cardiovascular, gastrointestinal tract). In some embodiments, the fibrosis or fibrosis-associated conditions include pulmonary fibrosis, idiopathic fibrosis, autoimmune fibrosis, myelofibrosis, liver cirrhosis, veno-occlusive disease, mesangial proliferative glomerulonephritis, rapidly progressive glomerulonephritis, diabetic nephropathy, renal interstitial fibrosis, renal fibrosis in subjects receiving cyclosporine, allograft rejection, and HIV-associated nephropathy. In some embodiments, the fibrosis-associated disorders include systemic sclerosis, eosinophilia-myalgia syndrome, and fibrosis-associated CNS disorders, such as intraocular fibrosis. In some embodiments, dermal fibrosis disorders include, for example, scleroderma, morphea, keloids, hypertrophic scars, familial cutaneous collagenous fibroma, and collagenous connective tissue nevi. In some embodiments, ocular fibrotic conditions include conditions such as diabetic retinopathy, post-surgical scarring (e.g., after glaucoma filtration surgery and after cross-eye surgery), and proliferative vitreoretinopathy. In some embodiments, fibrotic conditions that can be treated by the compounds, compositions, and methods disclosed herein can result from, for example, rheumatoid arthritis, diseases associated with long-term joint pain and joint deterioration, progressive systemic sclerosis, polymyositis, dermatomyositis, eosinophilic fasciitis, morphea, Raynaud's syndrome, and nasal polyposis.

[0519] Organ disease often leads to organ fibrosis and even death. Fibrosis can progress independently of the organ. Fibrosis can also be the result of excessive wound healing. In the kidney, this primarily results in glomerular sclerosis, tubular atrophy and dilation, tubulointerstitial fibrosis, and capillary rarefaction. Renal fibrosis can be characterized by excessive accumulation and deposition of extracellular matrix components. Renal fibrosis is not a simple, uniform scarring process but a dynamic process involving many, but not all, kidney and infiltrating cell types. Kidneys often do not fully repair themselves. Renal cells can promote and increase the secretion of profibrotic factors. If the normal healing response fails, scarring continues, potentially leading to chronic kidney disease (CKD). Progressive scarring can replace normal kidney tissue with fibrotic tissue, leading to loss of kidney function and kidney failure. MMP-2, MCP-1 and TGF-β have been shown to identify patients with fibrosis and future poor renal outcome.

[0520] The present disclosure provides certain BET inhibitors (e.g., Compound A) that have been found to be surprisingly effective against renal fibrosis and renal fibrosis-related conditions and / or may provide suitable treatments in limiting or slowing their progression. In some embodiments, the present disclosure provides potent and selective BET inhibitors (e.g., compounds of the formulae disclosed herein) that may provide novel and effective treatments and relief for, and / or limit or slow the progression of, fibrosis and fibrosis-related conditions, e.g., renal fibrosis and renal fibrosis-related conditions. The present disclosure provides potent and selective BET inhibitors (e.g., compounds of the formulae described herein) that, for example, when administered orally, may provide novel and effective treatments or relief for, and / or limit or slow the progression of, inflammatory fibrosis (e.g., renal fibrosis).

[0521] The present disclosure provides potent and selective BET inhibitors (e.g., compounds of the formulae disclosed herein) that, for example, when administered orally, may also provide novel and effective treatments or relief for, and / or limit or slow the progression of, non-inflammatory fibrotic (e.g., renal fibrosis) diseases, trauma, and degenerative disorders.

[0522] The present disclosure further provides certain BET inhibitors (e.g., Compound A) that have been found to be surprisingly effective against PF and PF-related conditions and / or may provide suitable treatments in limiting or slowing their progression. In some embodiments, the present disclosure provides potent and selective BET inhibitors (e.g., compounds of the formulae disclosed herein) that may provide novel and effective treatments and mitigation for, and / or limit or slow the progression of, fibrosis and fibrosis-related conditions, such as PF and PF-related conditions. The present disclosure provides potent and selective BET inhibitors (e.g., compounds of the formulae disclosed herein) that may provide novel and effective treatments or mitigation for, and / or limit or slow the progression of, inflammatory fibrosis (e.g., pulmonary fibrosis). In some embodiments, effective treatment is achieved using oral administration of the potent and selective BET inhibitors. In some embodiments, treatment with a BET inhibitor (e.g., a compound of a formula disclosed herein) may improve lung function in a PF patient (e.g., an IPF patient), e.g., restore normal or near-normal lung function (e.g., at least about 80% to about 90% of normal oxygen saturation and / or at least about 40% to about 60% of normal functional lung capacity), or improve lung function levels (e.g., about a 5% to about 10% improvement in oxygen saturation and / or about a 20% to about 60%, or about a 40% to about 60% improvement in functional lung capacity). In some embodiments, treatment with a BET inhibitor (e.g., a compound of a formula disclosed herein) reduces pulmonary fibrosis (e.g., about a 20% to about 60% reduction in pulmonary fibrosis score). In some embodiments, treatment with a BET inhibitor (e.g., a compound of a formula disclosed herein) reduces fibrotic tissue deposition. In some embodiments, treatment with a BET inhibitor (e.g., a compound of a formula disclosed herein) reduces hydroxyproline levels in a fibrotic subject.

[0523] The present disclosure also provides potent and selective BET inhibitors (e.g., compounds of the formulae disclosed herein) that, for example, when administered orally, can provide novel and effective treatments or relief from, and / or limit or slow the progression of, non-inflammatory fibrotic (e.g., PF, IPF) diseases, trauma, and degenerative disorders.

[0524] BET inhibitors, such as the compounds disclosed herein, may be of value and may be used, in one or more embodiments, in the treatment of inflammatory, immune, and autoimmune disorders, including diseases that have or may have an inflammatory or autoimmune component.

[0525] The present disclosure further provides certain BET inhibitors (e.g., Compound A) that have been found to be surprisingly effective against SLE and lupus-related conditions and / or may provide suitable treatments in limiting or slowing their progression. In some embodiments, the present disclosure provides potent and selective BET inhibitors (e.g., compounds of the formulae disclosed herein) that, for example, when administered orally, may provide novel and effective treatments and relief for lupus and lupus-related conditions and / or may limit or slow their progression. In some embodiments, treatment with a BET inhibitor (e.g., a compound of the formulae disclosed herein) may improve renal function in lupus patients, e.g., SLE or CLE patients, by improving renal function compared to untreated patients (e.g., as shown by reduced proteinuria, reduced total glomerular lesions, reduced total tubulointerstitial lesions, and / or reduced total renal lesions). In some embodiments, treatment with a BET inhibitor (e.g., a compound of the formulae disclosed herein) may improve renal function in lupus patients (e.g., reduce the total glomerular lesion score by at least about 20% to about 30%, reduce the total tubulointerstitial lesion score by at least about 40% to about 50%, and / or reduce the total renal lesion score by at least about 30% to about 40%), or reduce the total renal lesion score by 15% to about 80%, or about 20% to about 75%. In some embodiments, administration of a BET inhibitor (e.g., a compound of the formulae disclosed herein) may reduce the severity of lupus and / or suppress lupus disease in a dose-dependent manner.

[0526] The present disclosure further provides certain BET inhibitors (e.g., Compound A) that have been found to be surprisingly effective against CNS diseases, including autoimmune diseases, CNS inflammation, and demyelinating diseases that attack the central nervous system (CNS), e.g., MS and MS-related conditions, and / or may provide suitable treatments in limiting, slowing, and / or delaying their progression or reversing the course of the disease. In some embodiments, the present disclosure provides potent and selective BET inhibitors (e.g., compounds of the formulae disclosed herein) that, e.g., when administered orally, may provide novel and effective treatments for MS and MS-related conditions and / or may limit, slow, and / or delay their progression. In some embodiments, treatment with a BET inhibitor (e.g., a compound of the formulae disclosed herein) may reduce MS-associated inflammation in MS patients compared to untreated patients, as indicated, for example, by reduced levels of IFNγ and / or IL-12 / IL-23p40. In some embodiments, treatment with a BET inhibitor (e.g., a compound of the formulae disclosed herein) may reduce the severity of MS and MS-related symptoms and / or limit, slow, and / or delay the progression of MS and MS-related symptoms. In some embodiments, treatment with a BET inhibitor (e.g., a compound of the formulae disclosed herein) may limit, slow, and / or delay the progression of demyelination and / or its severity. In some embodiments, treatment with a BET inhibitor (e.g., a compound of the formulae disclosed herein) may suppress CNS inflammation and / or its severity. In some embodiments, treatment with a BET inhibitor (e.g., a compound of the formulae disclosed herein) may limit, slow, and / or delay the progression of CNS inflammation and / or its severity. In some embodiments, treatment with a BET inhibitor (e.g., a compound of the formulae disclosed herein) may limit, slow, and / or delay the progression of autoimmune diseases that attack the CNS and / or their severity. In some embodiments, treatment with a BET inhibitor (e.g., a compound of the formulae disclosed herein) can result in reversal (e.g., partial or substantial) of the disease course and promote recovery.In some embodiments, treatment with a BET inhibitor (e.g., a compound of a formula disclosed herein) can modulate immune cells infiltrating the CNS. In some embodiments, treatment with a BET inhibitor (e.g., a compound of a formula disclosed herein) can reduce the severity of axonal damage and / or limit, slow, and / or delay the progression of axonal damage that can lead to weakness and / or paralysis (e.g., weakness and / or paralysis of the lower limbs).

[0527] In some embodiments, the potent and selective BET inhibitor is highly selective for BDII over BDI.

[0528] In some embodiments, references to quantities, such as selectivity or activity, may represent averages.

[0529] It has been found that certain compounds of the present disclosure may have increased activity against BRD4 BD2. In some embodiments, compounds of the present disclosure have a BD2 IC50 of less than about 10 nM. In some embodiments, compounds of the present disclosure may have increased selectivity for BRD4 BD2 over BRD4 BD1. In some embodiments, compounds of the present disclosure have a selectivity of greater than about 1000 for BRD4 BD2 over BRD4 BD1. In some embodiments, compounds of the present disclosure may have increased bioavailability. In some embodiments, compounds of the present disclosure have sufficiently high bioavailability after oral delivery to enable systemic delivery of the compound via oral administration. In some embodiments, compounds of the present disclosure have satisfactory chemical and metabolic stability. In some embodiments, the compounds have a chemical half-life of greater than 24 hours, e.g., a plasma half-life of greater than 2 hours in humans.

[0530] Treatment or improvement with a selective BET BDII inhibitor, such as a composition comprising a compound disclosed herein or a salt thereof (or a combination thereof), can be effective in some embodiments when applied orally, in some other embodiments when applied by injection, in some other embodiments when applied topically, and in some further embodiments when applied topically and orally, or by injection and topically, or orally and by injection. In one or more embodiments, treatment or improvement with a selective BET BDII inhibitor, such as a composition comprising a compound disclosed herein or a salt thereof (or a combination thereof), can be effective orally if the compound has reasonable bioavailability, e.g., greater than about 20%, or good bioavailability, e.g., greater than about 25%. In some embodiments, the bioavailability is greater than about 35%, or greater than about 45%, or greater than about 55%, or greater than about 65%, or greater than about 75%, or greater than about 85%, and if the compound has good bioavailability, e.g., greater than about 25%, it may be orally effective.

[0531] In one or more embodiments, the compounds disclosed herein are active against BRD4 BD2 and selective for BRD4 BD1. In one or more embodiments, BET BDII-selective protein inhibitors exhibit, for example, greater than about 100-fold selectivity, greater than about 200-fold selectivity, greater than about 250-fold selectivity, greater than about 300-fold selectivity, greater than about 350-fold selectivity, greater than about 400-fold selectivity, greater than about 500-fold selectivity, greater than about 600-fold selectivity, greater than about 700-fold selectivity, greater than about 800-fold selectivity, greater than about 900-fold selectivity, greater than about 1000-fold selectivity, greater than about 2000-fold selectivity, or greater than about 5000-fold selectivity for BDII over BD1, depending on the structure. In one embodiment, a BET BDII-selective protein inhibitor exhibits greater than about 1000-fold selectivity. In one or more embodiments, the BET BDII selective protein inhibitors exhibit an IC50 against BRD4 BDII of less than about 200 nM, less than about 150 nM, less than about 100 nM, less than about 50 nM, or less than about 10 nM. In one or more embodiments, the BET BDII selective protein inhibitors exhibit an IC50 in the range of less than about 200 nM to less than about 10 nM. In some embodiments, the BET BDII selective protein inhibitors disclosed herein exhibit an IC50 against BRD4 BDII of about 10 nM to about 1 nM, or about 5 nM to about 0.1 nM. In some embodiments, the BET BDII selective protein inhibitors disclosed herein exhibit an IC50 against BRD4 BDII of about 5 nM to about 1 nM, or about 5 nM to about 0.1 nM. In some embodiments, the IC50 is the average of two or more measurements.

[0532] In one or more embodiments, the compounds disclosed herein are surprisingly active against BRD4 BD2 and surprisingly highly selective over BRD4 BD1. In one or more embodiments, certain compounds disclosed herein surprisingly exhibit an IC50 of less than about 10 nM as BET BDII-selective protein inhibitors. In some embodiments, certain compounds exhibit an IC50 of less than about 8 nM, or less than about 6 nM, or less than about 5 nM, or less than about 4 nM, or less than about 3 nM, or less than about 2 nM, or less than about 1 nM. In one or more embodiments, certain compounds disclosed herein exhibit greater than about 1000-fold selectivity as BET BDII-selective protein inhibitors. In some embodiments, certain compounds exhibit greater than about 2000-fold selectivity, or greater than about 3000-fold selectivity, or greater than about 4000-fold selectivity, or greater than about 5000-fold selectivity, or greater than about 6000-fold selectivity, or greater than about 7000-fold selectivity, or greater than about 8000-fold selectivity, or greater than about 9000-fold selectivity, or greater than about 10,000-fold selectivity. In one or more embodiments, certain compounds disclosed herein surprisingly exhibit selectivity of greater than about 1000 and an IC50 of less than about 10 nM as BET BDII-selective protein inhibitors. In some embodiments, certain compounds disclosed herein surprisingly exhibit selectivity of greater than about 2000 and an IC50 of less than about 5 nM as BET BDII-selective protein inhibitors. In some embodiments, certain compounds disclosed herein surprisingly exhibit selectivity of greater than about 2500 and an IC50 of less than about 4 nM as BET BDII-selective protein inhibitors. In some embodiments, certain compounds disclosed herein surprisingly exhibit a selectivity of greater than about 3000 and an IC50 of less than about 4 nM, or in some embodiments, a selectivity of greater than about 3000 and an IC50 of less than about 3 nM, as BET BDII selective protein inhibitors.In some embodiments, certain compounds disclosed herein surprisingly exhibit selectivity of greater than about 4000 and an IC50 of less than about 3 nM as BET BDII-selective protein inhibitors. In some embodiments, certain compounds disclosed herein surprisingly exhibit selectivity of greater than about 5000 and an IC50 of less than about 2 nM as BET BDII-selective protein inhibitors. In some embodiments, certain compounds disclosed herein surprisingly exhibit selectivity of about 1000 to about 2000 and an IC50 of less than about 10 nM as BET BDII-selective protein inhibitors. In some embodiments, certain compounds disclosed herein surprisingly exhibit selectivity of about 2000 to about 5000 and an IC50 of less than about 5 nM as BET BDII-selective protein inhibitors. In some embodiments, certain compounds disclosed herein surprisingly exhibit selectivity of about 3000 to about 5000 and an IC50 of less than about 4 nM as BET BDII-selective protein inhibitors. In some embodiments, certain compounds disclosed herein surprisingly exhibit selectivity of about 4,000 to about 11,000 and an IC50 of less than about 3 nM as BET BDII selective protein inhibitors. In some embodiments, certain compounds disclosed herein surprisingly exhibit selectivity of about 4,000 to about 15,000 and an IC50 of less than about 3 nM as BET BDII selective protein inhibitors. In some embodiments, certain compounds disclosed herein surprisingly exhibit selectivity of about 5,000 to about 15,000 and an IC50 of less than about 2.5 nM as BET BDII selective protein inhibitors. In one or more embodiments, selectivity represents an average.

[0533] In addition to compounds that exhibit activity and selectivity, other factors in selecting promising drug candidates may include, for example, bioavailability, clearance, chemical stability, plasma stability, pK, and an IC50 of less than about 100 nM for inflammatory biomarkers such as IL17 and IL22. For drug candidates for oral delivery, higher bioavailability may allow for lower dosages and potentially fewer gastrointestinal side effects, for example. For drug candidates for oral delivery, a sustained plasma concentration above the free EC50 for BD2 for about 4 hours or more may be effective. In one or more embodiments, the plasma concentration above the free EC50 for BD2 is sustained for about 4 hours or more. In some embodiments, the sustained plasma concentration is about 6 hours or more, or about 8 hours or more, or about 12 hours or more, or about 15 hours or more. In one or more embodiments, a therapeutically effective amount of drug is administered once daily. In some embodiments, the drug is administered twice daily, e.g., when the plasma concentration is higher than the free EC50 for less than 12 hours. In some embodiments, the drug is administered three times daily.

[0534] In one or more embodiments, the BET BDII selective protein inhibitor exhibits a rat microsomal stability of less than about 5, about 4, about 3, about 2, or about 1 ml / min per gram of liver, hi some embodiments, the BET BDII selective protein inhibitor exhibits a microsomal stability of less than about 2 ml / min per gram of liver.

[0535] In some embodiments, BET BDII selective protein inhibitors with rat microsomal stabilities of less than about 4 ml / min or less than about 3 ml / min per gram of liver are promising drug candidates, while in some other embodiments, compounds with lower rat microsomal stabilities that have higher degradation rates may be useful in certain situations. In some embodiments, a BET BDII selective protein inhibitor has a rat microsomal stability of less than 2 ml / m / g.

[0536] In one or more embodiments, the BET BDII selective protein inhibitors exhibit rat microsomal stability with a half-life of greater than about 20 minutes, greater than about 40 minutes, greater than about 60 minutes, greater than about 80 minutes, greater than about 100 minutes, or greater than about 120 minutes. In some embodiments, the BET BDII selective protein inhibitors exhibit rat microsomal stability with a half-life of greater than about 60 minutes. In some embodiments, the BET BDII selective protein inhibitors exhibit rat microsomal stability with a half-life of greater than about 80 minutes.

[0537] In some embodiments, BET BDII selective protein inhibitors with rat microsomal stability and a half-life of greater than about 20 minutes are promising drug candidates, although in some other embodiments, compounds with lower rat microsomal stability may be useful in certain circumstances.

[0538] In one or more embodiments, the BET BDII selective protein inhibitors exhibit an IL-22 IC50 of less than about 250 nM, less than about 50 nM, or less than about 10 nM and / or an IL-17A IC50 of less than about 250 nM, less than about 50 nM, or less than about 10 nM. In some embodiments, the BET BDII selective protein inhibitors exhibit an IL-22 IC50 of less than about 20 nM and / or an IL-17A IC50 of less than about 20 nM. In some embodiments, the BET BDII selective protein inhibitors exhibit an IL-22 IC50 of less than about 10 nM and / or an IL-17A IC50 of less than about 10 nM. In some embodiments, the BET BDII selective protein inhibitors exhibit an IL-22 IC50 of less than about 2 nM and / or an IL-17A IC50 of less than about 2 nM. In some embodiments, the BET BDII selective protein inhibitor exhibits an IL-22 IC50 of less than about 1 nM and / or an IL-17A IC50 of less than about 1 nM.

[0539] In some embodiments, BET BDII selective protein inhibitors with an IL-22 IC50 of less than about 20 nM and / or an IL-17A IC50 of less than about 20 nM are promising drug candidates, although in some other embodiments, less active compounds may be useful in certain situations.

[0540] In one or more embodiments, the BET BDII selective protein inhibitor exhibits a bioavailability of greater than about 12%, or greater than about 20%, or greater than about 25%, or greater than about 30%, or greater than about 40%, or greater than about 50%, or greater than about 60%, or greater than about 70%, or greater than about 80%, or greater than about 90%, or greater than about 95%. In some embodiments, the BET BDII selective protein inhibitor exhibits a bioavailability of greater than about 20%, or greater than about 25%. In some embodiments, the BET BDII selective protein inhibitor has a bioavailability of greater than about 55%.

[0541] In one or more embodiments, a BET BDII selective protein inhibitor has a bioavailability of greater than about 20% to be a promising drug candidate, and greater than about 25% to be an advantageous drug candidate for oral administration, although in some embodiments, compounds with a bioavailability of about 20% or less may be useful in certain situations. In one embodiment, compounds with a bioavailability of greater than about 12% may be useful when administered orally.

[0542] In one or more embodiments, some compounds have good activity and greater than about 1000-fold selectivity, as well as two or more or all of the following characteristics: an IL-22 IC50 of less than about 20 nM, an IL-17A IC50 of less than about 20 nM, a bioavailability of greater than about 12%, a rat microsomal stability of less than about 4 ml / min per gram of liver, and a rat microsomal stability half-life of greater than about 20 minutes.

[0543] In one or more embodiments, some compounds have good activity and greater than about 2000-fold selectivity, as well as two or more or all of the following characteristics: an IL-22 IC50 of less than about 10 nM, an IL-17A IC50 of less than about 10 nM, a bioavailability of greater than about 12% or greater than about 25%, a rat microsomal stability of less than about 4 ml / min per gram of liver, and a rat microsomal stability half-life of greater than about 20 minutes.

[0544] In one or more embodiments, some compounds have good activity with an IC50 BD2 of less than about 3 nM and selectivity of greater than about 4000-fold, as well as two or more or all of the following characteristics: an IL-22 IC50 of less than about 10 nM, an IL-17A IC50 of less than about 10 nM, a bioavailability of greater than about 12% or greater than about 25%, a rat microsomal stability of less than about 4 ml / min per gram of liver, and a rat microsomal stability half-life of greater than about 20 minutes.

[0545] In one or more embodiments, some compounds have good activity with an IC50 BD2 of less than about 2 nM and selectivity of greater than about 5000-fold, as well as two or more or all of the following characteristics: an IL-22 IC50 of less than about 10 nM, an IL-17A IC50 of less than about 10 nM, a bioavailability of greater than about 12% or greater than about 25%, a rat microsomal stability of less than about 4 ml / min per gram of liver, and a rat microsomal stability half-life of greater than about 20 minutes.

[0546] In addition to compounds that exhibit activity and selectivity, other factors in selecting promising drug candidates may include, for example, plasma stability, clearance, pK, and bioavailability. For drug candidates for oral delivery, higher bioavailability may allow for lower dosages and may also result in fewer side effects, for example, in the gastrointestinal tract.

[0547] Compounds disclosed herein, or compounds including salts thereof (or combinations thereof), in one or more embodiments, can be administered bucally, by inhalation (e.g., spray, nebulizer, or powder puff), epidurally, by injection (including intra-articular, intravenous, intracoronary, subcutaneous, intramyocardial, intraperitoneal, intramuscular, intravascular or infusion), intradermally, intraperitoneally, intrapulmonary, intra-articular (e.g., by injection), nasally, orally, parenterally, rectally, sublingually, topically, transdermally, vaginally, or via an implanted reservoir.

[0548] In some embodiments, the compounds disclosed herein, or salts thereof (or combinations thereof) are orally administered, for example, as a solid dosage form, such as a tablet or capsule, or as a semi-solid or fluid dosage form, such as a gel or liquid. In a fluid or semi-solid dosage form, the compound may, in one or more embodiments, be delivered as a suspension or solution.

[0549] In some embodiments, a compound disclosed herein, or a salt thereof (or combination thereof) is applied by injection, for example, as a solution or suspension, which in one or more embodiments can be, for example, aqueous-based, oil-based, anhydrous, hydrophilic, hydrophobic, amphiphilic, and / or emulsion.

[0550] In some embodiments, the compounds disclosed herein, or salts thereof (or combinations thereof) are applied by inhalation, for example, as a powder, spray, or mist. In the form of a fluid or liquid that can be used to form a mist (e.g., using a nebulizer) or spray (e.g., using an aerosol), the compounds can, in one or more embodiments, be delivered as a suspension or solution.

[0551] In some embodiments, the compounds disclosed herein, or salts thereof (or combinations thereof), are applied topically, for example, as a cream, emulsion, lotion, gel, ointment, mousse, foam, spray, or other topical dosage form known in the art. In some embodiments, when applied topically, the compounds disclosed herein may be effective if the compound is delivered primarily or substantially to the skin and the level of transdermal penetration is low. In some embodiments, when applied topically, the compounds disclosed herein may be effective if the compound is delivered primarily or substantially transdermally. In some embodiments, when applied topically, the compounds disclosed herein may be effective if the compound is delivered both intradermally and transdermally. In some embodiments, the penetration of the compound in the epidermis may be greater than the penetration in the dermis. In some embodiments, the penetration of the compound in the dermis may be greater than the penetration in the epidermis. In some embodiments, the penetration of the compound in the dermis is similar to the penetration in the epidermis. In some embodiments, the concentration of the compound per unit volume in the epidermis may be greater than the concentration in the dermis. In some embodiments, the concentration of the compound per unit volume in the dermis may be greater than the concentration in the epidermis. In some embodiments, the concentration of the compound per unit volume in the dermis is the same as the concentration in the epidermis.

[0552] The pharmaceutical compositions of the present disclosure may be suitable for oral administration, for example, via a solid, such as a tablet, caplet, capsule, semi-solid, such as a gel, or liquid delivery form, such as a syrup.

[0553] Tablets and similar forms contain the active ingredient mixed with non-toxic pharmaceutically acceptable excipients suitable for tablet manufacture. These excipients can be, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, or sodium phosphate; granulating and disintegrating agents such as corn starch or alginic acid; binders such as starch, gelatin, or gum arabic; and lubricants such as magnesium stearate, stearic acid, or talc. Tablets can be uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained action over a longer period. Tablets can be made by compressing or molding the active ingredient, optionally with one or more pharmaceutically acceptable ingredients. Compressed tablets can be prepared by compressing a free-flowing active ingredient, such as a powder or granules, mixed with, optionally, a binder, lubricant, inert diluent, surfactant, or dispersing agent, in a suitable machine. Molded tablets may be made by molding in a suitable machine, a mixture of the powdered active ingredient and a suitable carrier moistened with an inert liquid diluent.

[0554] Compositions for oral use can be presented as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, such as calcium carbonate, calcium phosphate, or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with a suitable hydrophilic or hydrophobic medium, such as an oil medium, such as peanut oil, liquid paraffin, or olive oil.In particular, the pharmaceutical composition of the present invention can include a liquid-filled capsule dosage form, in which the active ingredient is in suspension, partial suspension, or solution in a combination of certain liquid and semi-solid excipients.

[0555] Compositions for oral administration can also be formulated as aqueous or non-aqueous suspensions of the active ingredient, or as emulsions in which the active ingredient is suspended. The compositions contain the active ingredient in admixture with excipients suitable for the preparation of such suspensions. Oily suspensions can be formulated by suspending the active ingredient in a suitable oil. Water-in-oil emulsions can also be employed. Dispersible powders and granules suitable for preparation of aqueous / hydrophilic suspensions by the addition of water / hydrophilic excipients provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent, and one or more preservatives.

[0556] The active ingredient of the present invention can be administered in a sustained-release oral formulation. " Sustained-release " refers to the release of the active agent from the dosage form at a rate effective to allow therapeutic amounts of the active agent or its active metabolites to reach the systemic blood circulation for a longer period than that achieved by the oral administration of conventional formulations.The release of the agent occurs over a long period, for example, for at least 6 hours, at least 8 hours, at least 12 hours, or at least 24 hours.

[0557] The pharmaceutical compositions of the present disclosure may be suitable for topical or transdermal administration.

[0558] Exemplary dosage forms for topical or transdermal administration of a compound disclosed herein or its salts include creams, drops, lotions, emulsions, foams, gels, inhalants, mousses, ointments, pastes, patches, powders, solutions, or sprays. Suitable such topical formulations and dosage forms are described in Remington: The Science and Practice of Pharmacy (21st Edition, University of the Sciences in Philadelphia).

[0559] In some embodiments, the compound is micronized when provided as a powder or suspension, hi some embodiments, the compound comprises nanoparticles.

[0560] In some embodiments, compositions comprising the novel compounds disclosed herein or salts thereof (or combinations thereof) may be administered to young children. In some embodiments, compositions comprising the compounds of the present disclosure or salts thereof (or combinations thereof) may be administered to adolescents or teenagers. In some embodiments, compositions comprising the compounds of the present disclosure or salts thereof (or combinations thereof) may be administered to adults.

[0561] For drug candidates for oral delivery, higher bioavailability may allow for lower dosages and, for example, fewer gastrointestinal side effects. For drug candidates for oral delivery, in some embodiments, a drug may be effective if its plasma concentration exceeds the free EC50 for BD2 for a sufficient period of time to have a therapeutic effect, e.g., in some embodiments, for several hours. In some embodiments, oral delivery results in a plasma concentration exceeding the free EC50 for BD2 for about 4 hours or more. In some embodiments, this is for about 6 hours or more, or about 8 hours or more, or about 12 hours or more, or about 15 hours or more. In some embodiments, a therapeutically effective amount of the drug is applied once daily. In some embodiments, a therapeutically effective amount of the drug is applied twice daily, e.g., the period during which the plasma concentration exceeds the free EC50 is less than 12 hours, or less than 9 hours, or less than 6 hours, or about 6 to about 12 hours, or about 9 to about 12 hours. In some embodiments, a therapeutically effective amount of the drug is applied three times daily.

[0562] In some embodiments, compounds of the present disclosure exhibit a microsomal half-life of greater than about 20 minutes, greater than about 30 minutes, greater than about 40 minutes, greater than about 50 minutes, greater than about 60 minutes, greater than about 80 minutes, greater than about 100 minutes, or greater than about 120 minutes, or between about 20 and 180 minutes, or between about 60 and 180 minutes, or between about 120 and 180 minutes, or between about 100 and 150 minutes.

[0563] In some embodiments, compounds of the present disclosure exhibit a thermodynamic solubility in fasting state simulated intestinal fluid (FaSSIF) buffer at pH 6.5 of about 0.1 μM, greater than about 0.5 μM, greater than about 1 μM, greater than about 10 μM, greater than about 50 μM, greater than about 100 μM, greater than about 150 μM, or greater than about 200 μM, or between about 0.1 μM and about 200 μM, or between about 0.5 μM and about 100 μM, or between about 1 μM and about 50 μM, or between about 0.1 μM and about 50 μM, or between about 0.5 μM and about 10 μM, or between about 1 μM and about 10 μM.

[0564] In one or more embodiments, the compounds of the present disclosure exhibit a bioavailability of greater than about 10%, greater than about 12%, greater than about 20%, greater than about 25%, greater than about 30%, greater than about 40%, greater than about 50%, greater than about 60%, greater than about 70%, greater than about 80%, greater than about 90%, or greater than about 95%, or between about 20% and about 95%, or between about 20% and about 95%, or between about 20% and about 80%. As used herein, bioavailability refers to the fraction of an administered drug that reaches the systemic circulation (blood).

[0565] In one or more embodiments, the BET BDII selective protein inhibitor exhibits an IL-22 IC50 of less than about 250 nM, less than about 50 nM, or less than about 10 nM and / or an IL-17A IC50 of less than about 250 nM, less than about 50 nM, or less than about 10 nM. In some embodiments, the BET BDII selective protein inhibitor exhibits an IL-22 IC50 of less than about 20 nM and / or an IL-17A IC50 of less than about 20 nM. In some embodiments, the BET BDII selective protein inhibitor exhibits an IL-22 IC50 of less than about 10 nM and / or an IL-17A IC50 of less than about 10 nM. In some embodiments, the BET BDII selective protein inhibitor exhibits an IL-22 IC50 of less than about 2 nM and / or an IL-17A IC50 of less than about 2 nM. In some embodiments, a BET BDII selective protein inhibitor exhibits an IL-22 IC50 of less than about 1 nM and / or an IL-17A IC50 of less than about 1 nM. In some embodiments, a BET BDII selective protein inhibitor exhibits an IL-22 IC50 of about 10 nM to about 0.1 nM and / or an IL-17A IC50 of about 10 nM to about 0.1 nM. In some embodiments, a BET BDII selective protein inhibitor exhibits an IL-22 IC50 of about 5 nM to about 0.1 nM and / or an IL-17A IC50 of about 5 nM to about 0.1 nM. In some embodiments, the IC50 is the average of two or more measurements.

[0566] The present disclosure includes the following numbered embodiments:

[0567] 1. A compound of formula (I), its tautomer, stereoisomer or mixture of stereoisomers, pharmaceutically acceptable salt, hydrate, deuterated derivative, or N-oxide: TIFF2026501324000114.tif58165 (in the formula, Ring A is independently selected from phenyl, 5-membered heterocyclyl, and 6-membered heterocyclyl; X 4 and X 5 are independently selected from carbon and nitrogen; R 1 are independently C1-C5-alkyl, C1-C5-haloalkyl, C2-C6-alkynyl, COR 6 , CO2R 6 , C1-C4-alkylene-NR 5 R 6 , C1-C4-alkylene-OR 7 , C1-C4-alkyl-S(O)2R 6 , C3-C6-cycloalkyl, aryl, heteroaryl, and 3- to 6-membered heterocycloalkyl; R 2 is absent or independently represents H, halo, cyano, nitro, SF4, SF5, =O, S(O)2R 6 , alkoxy, C1-C6-haloalkyl, C1-C8-alkyl, C3-C6-cycloalkyl, 4- to 8-membered heterocycloalkenyl, 3- to 8-membered heterocycloalkyl, aryl, and 5- or 6-membered heteroaryl; wherein the C1-C8 alkyl, the alkoxy, the C3-C6 cycloalkyl, the 4- to 8-membered heterocycloalkenyl, the 3- to 8-membered heterocycloalkyl, the aryl, and the 5- or 6-membered heteroaryl are independently optionally substituted with one or more groups selected from halogen, cyano, nitro, hydroxy, SF5, amido, ester, alkoxy, and C1-C4 alkyl; R 3 are independently 3a and OR 3b is selected from R 3a is independently selected from H, CN, C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl, C2-C4-haloalkenyl, C3-C8-cycloalkyl, C5-C8-cycloalkenyl, 5- to 9-membered heterocycloalkenyl, 3- to 9-membered heterocycloalkyl, phenyl, and 5- to 9-membered heteroaryl; wherein the cycloalkyl, the heterocycloalkyl, the cycloalkenyl, and the heterocycloalkenyl are independently 1 to 4 R 8 may be substituted with a group, The phenyl and the 5- to 9-membered heteroaryl are independently selected from 1 to 5 R 9 may be substituted with a group, R 3b is independently selected from C1-C4-alkyl, C2-C4-alkylene-O-C1-C4-alkyl, C1-C4-haloalkyl, C3-C8-cycloalkyl, 3- to 8-membered heterocycloalkyl, phenyl, and 5- or 6-membered heteroaryl, wherein the cycloalkyl and the 3- to 8-membered heterocycloalkyl are independently 1 to 4 R 8 may be substituted with a group, The phenyl and the 5- or 6-membered heteroaryl are independently selected from 1 to 5 R 9 may be substituted with a group, R 4 is independently in each occurrence H, ═O, ═S, halo, nitro, cyano, C0-C4-alkylene-NR 5 R 6 , -NR 5 R 6 , C0-C4-alkylene-OR 7 , -OR 7 , S.R. 6 , SOR 6 , C0-C4-alkylene-S(O)2R 6 , -S(O)2R 6 , SO2NR 6 R 6 , C0-C4-alkylene-CO2R 6 , -CO2R 6 , C0-C4-alkylene-C(O)R 6 , -C(O)R 6 , C0-C4-alkylene-CONR 6 R 6 , -CONR 6 R 6 , C1-C6-alkyl, C1-C4-alkyl-S(O)2R 6 , C2-C4-alkenyl, C2-C4-alkynyl, C1-C6-haloalkyl, C3-C6-cycloalkyl, aryl, 4- to 6-membered heterocycloalkyl, and 5- or 6-membered heteroaryl; wherein the aryl, the 4- to 6-membered heterocycloalkyl, and the 5- or 6-membered heteroaryl are independently selected from 1 to 5 R 9 may be substituted with a group, R 5 is independently selected in each occurrence from H, C1-C4-alkyl, C(O)—C1-C4-alkyl, and S(O)2—C1-C4-alkyl, or R 5 and R 6 together with the nitrogen atom to which they are attached, form one to four R 8 forming a C5-C8 heterocycloalkyl group optionally substituted by a group, R 6 is independently selected in each occurrence from H and C1-C6-alkyl, or two R 6 If groups are attached to the same nitrogen, the two R 6 The groups, together with the nitrogen atom to which they are attached, can consist of one to four R 8 may form a C5-C8 heterocycloalkyl group optionally substituted by a group, R 7 is independently selected at each occurrence from H, C-C-alkyl, C(O)—C-C-alkyl, and C-C-haloalkyl; R 8 is independently in each occurrence =O, =S, fluoro, nitro, cyano, NR 5 R 6 , OR 7 , S.R. 6 , SOR 6 , S(O)2R 6 , SO2NR 6 R 6 , CO2R 6 , C(O)R 6 ,CONR 6 R 6 , C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl, 4- to 6-membered heterocycloalkyl, and C3-C6-cycloalkyl; R 9 is, independently in each occurrence, halo, nitro, cyano, NR 5R 6 , C1-C4-alkyl-OR 7 , OR 7 , S.R. 6 , SOR 6 , C1-C4-alkyl-S(O)2R 6 , S(O)2R 6 , SO2NR 6 R 6 , CO2R 6 , C(O)R 6 ,CONR 6 R 6 , C0-C4-alkylene-R 9a , C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl, 4- to 6-membered heterocycloalkyl, and C3-C6-cycloalkyl, or two R 9 If the groups are attached to adjacent atoms, the two R 9 Groups, together with the atoms to which they are attached, consist of one to four R 8 may form a 5- or 6-membered heterocycloalkyl group optionally substituted with a group, R 9a is independently selected at each occurrence from 4- to 6-membered heterocycloalkyl; R 10 is absent or, independently in each occurrence, H, halo, C1-C6-alkyl, C1-C6-haloalkyl, nitro, cyano, NR 5 R 6 , OR 7 , S.R. 6 , SOR 6 , S(O)2R 6 , SO2NR 6 R 6 , CO2R 6 , C(O)R 6 ,CONR 6 R 6 , C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl and 3- to 8-membered heterocycloalkyl; R 11 are independently selected from phenyl, heteroaryl, and heterocyclyl, each of which is selected from 1 to 4 R 2group and 1 to 3 R 10 may be substituted with a group, R x and R y are each independently H, halo, nitro, cyano, C1-C6-alkylene-NR 5 R 6 , N.R. 5 R 6 , C1-C6-alkylene-OR 7 、 C1~C6-Alkyl-OR 7 , OR 7 , C1-C6-alkyl-SR 6 , S.R. 6 , C1-C6-alkyl-SOR 6 , SOR 6 , C1-C6-alkyl-S(O)2R 6 , S(O)2R 6 , C1-C6-Alkyl-SO2NR 6 R 6 , SO2NR 6 R 6 , C1-C6-alkyl-CO2R 6 , CO2R 6 , C1-C6-alkyl-C(O)R 6 , C(O)R 6 , C1-C6-alkyl-CONR 6 R 6 ,CONR 6 R 6 , C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-haloalkyl, C3-C8-cycloalkyl, 3- to 8-membered heterocycloalkyl, aryl, aryloxy, and 5- to 8-membered heteroaryl; m is an integer selected from 0, 1, 2, 3 and 4; Any of the aforementioned alkyl, alkylene, alkenyl or C3-C6-cycloalkyl groups may, where chemically possible, independently in each case be selected from C1-C4-alkyl, oxo, fluoro, nitro, cyano, NR a R b , OR a , S.R. a , CO2R a , C(O)R a,CONR a R a , S(O)R a and S(O)2R a and optionally substituted with 1 to 5 substituents selected from the group consisting of: where R a is independently selected at each occurrence from H, C1-C4-alkyl, and C1-C4-haloalkyl; R b is independently in each occurrence selected from H, C1-C4-alkyl, C(O)—C1-C4-alkyl and S(O)2—C1-C4-alkyl).

[0568] 2. Ring A is a 6-membered heterocyclyl and X 4 and X 5 are independently selected from carbon and nitrogen; R 1 is independently selected from C1-C3-alkyl, C1-C3-haloalkyl, C2-C4-alkynyl, C3-C5-cycloalkyl, and 3- to 5-membered heterocycloalkyl; R 2 are independently H, halo, cyano, nitro, SF4, SF5, ═O, C1-C3-haloalkyl, C1-C3-alkyl, and C3-C5-cycloalkyl; S(O)2R 6 , alkoxy, 4- to 5-membered heterocycloalkenyl, and 3- to 5-membered heterocycloalkyl; wherein the C1-C3-alkyl, the alkoxy, the C3-C5-cycloalkyl, the 4- to 6-membered heterocycloalkenyl, and the 3- to 5-membered heterocycloalkyl are optionally substituted independently with one or more groups selected from halogen, cyano, nitro, hydroxy, SF5, amido, ester, alkoxy, and C1-C4-alkyl; R 3 But independently, R 3a and OR 3b is selected from R 3aare independently selected from H, CN, C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl, C2-C4-haloalkenyl, C3-C8-cycloalkyl, C5-C8-cycloalkenyl, 5- to 9-membered heterocycloalkenyl, 3- to 9-membered heterocycloalkyl, phenyl, and 5- to 9-membered heteroaryl; wherein the cycloalkyl, the heterocycloalkyl, the cycloalkenyl, and the heterocycloalkenyl are independently 1 to 4 R 8 may be substituted with a group, The phenyl and the 5- to 9-membered heteroaryl are independently selected from 1 to 5 R 9 may be substituted with a group, R 3b is independently selected from C1-C4-alkyl, C2-C4-alkylene-O-C1-C4-alkyl, C1-C4-haloalkyl, C3-C8-cycloalkyl, 3- to 8-membered heterocycloalkyl, phenyl, and 5- or 6-membered heteroaryl; wherein the cycloalkyl and the 3- to 8-membered heterocycloalkyl are independently 1 to 4 R 8 may be substituted with a group, The phenyl and the 5- or 6-membered heteroaryl are independently selected from 1 to 5 R 9 may be substituted with a group, R 4 is independently in each occurrence H, ═O, ═S, halo, nitro, cyano, C0-C4-alkylene-NR 5 R 6 , -NR 5 R 6 , C0-C4-alkylene-OR 7 , -OR 7 , S.R. 6 , SOR 6 , C0-C4-alkylene-S(O)2R 6 , -S(O)2R 6 , SO2NR 6 R 6 , C0-C4-alkylene-CO2R 6 , -CO2R 6 , C0-C4-alkylene-C(O)R6 , -C(O)R 6 , C0-C4-alkylene-CONR 6 R 6 , -CONR 6 R 6 , C1-C6-alkyl, C0-C4-alkyl-S(O)2R 6 , C2-C4-alkenyl, C2-C4-alkynyl, C1-C6-haloalkyl, C3-C6-cycloalkyl, aryl, 4- to 6-membered heterocycloalkyl, and 5- or 6-membered heteroaryl; wherein the aryl, the 4- to 6-membered heterocycloalkyl, and the 5- or 6-membered heteroaryl are independently selected from 1 to 5 R 9 may be substituted with a group, R 5 is independently selected in each occurrence from H, C1-C4-alkyl, C(O)—C1-C4-alkyl, and S(O)—C1-C4-alkyl, or R 5 and R 6 together with the nitrogen atom to which they are attached, form 1 to 4 R 8 forming a C5-C8 heterocycloalkyl group optionally substituted by a group, R 6 is independently selected in each occurrence from H and C1-C6-alkyl, or two R 6 If groups are attached to the same nitrogen, the two R 6 The groups, together with the nitrogen atom to which they are attached, can consist of one to four R 8 may form a C5-C8 heterocycloalkyl group optionally substituted by a group, R 7 is independently selected at each occurrence from H, C-C-alkyl, C(O)—C-C-alkyl, and C-C-haloalkyl; R 8 and independently in each occurrence, ═O, ═S, fluoro, nitro, cyano, NR 5 R 6 , OR 7 , S.R. 6 , SOR 6 , S(O)2R6 , SO2NR 6 R 6 , CO2R 6 , C(O)R 6 ,CONR 6 R 6 , C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl, 4- to 6-membered heterocycloalkyl, and C3-C6-cycloalkyl; R 9 independently in each occurrence halo, nitro, cyano, NR 5 R 6 , C1-C4-alkyl-OR 7 , OR 7 , S.R. 6 , SOR 6 , C1-C4-alkyl-S(O)2R 6 , S(O)2R 6 , SO2NR 6 R 6 , CO2R 6 , C(O)R 6 ,CONR 6 R 6 , C0-C4-alkylene-R 9a , C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl, 4- to 6-membered heterocycloalkyl, and C3-C6-cycloalkyl, or two R 9 If the groups are attached to adjacent atoms, the two R 9 Groups, together with the atoms to which they are attached, consist of one to four R 8 may form a 5- or 6-membered heterocycloalkyl group optionally substituted with a group, R 9a is independently selected in each occurrence from 4- to 6-membered heterocycloalkyl; R 10 is absent or independently in each occurrence H, halo, C1-C6-alkyl, C1-C6-haloalkyl, nitro, cyano, NR 5 R 6 , OR 7 , S.R. 6 , SOR 6, S(O)2R 6 , SO2NR 6 R 6 , CO2R 6 , C(O)R 6 ,CONR 6 R 6 , C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl and 3- to 8-membered heterocycloalkyl; R 11 are independently selected from phenyl, heteroaryl, and heterocyclyl, each of which is selected from one to two R 2 group and one to two R 10 may be substituted with a group, R x and R y each independently represents H, halo, nitro, cyano, C1-C4-alkylene-NR 5 R 6 , N.R. 5 R 6 , C1-C4-alkylene-OR 7 、 C1~C4-Alkyl-OR 7 , OR 7 , C1-C4-alkyl-SR 6 , S.R. 6 , C1-C4-alkyl-SOR 6 , SOR 6 , C1-C4-alkyl-S(O)2R 6 , S(O)2R 6 , C1-C4-Alkyl-SO2NR 6 R 6 , SO2NR 6 R 6 , C1-C4-Alkyl-CO2R 6 , CO2R 6 , C1-C4-alkyl-C(O)R 6 , C(O)R 6 , C1-C4-alkyl-CONR 6 R 6 ,CONR 6 R 6, C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl, C3-C6-cycloalkyl, 3- to 6-membered heterocycloalkyl, aryl, aryloxy, and 5- to 6-membered heteroaryl; m is an integer selected from 0, 1, and 2; Any of the aforementioned alkyl, alkylene, alkenyl or C3-C6-cycloalkyl groups may, where chemically possible, independently in each case be C1-C4-alkyl, oxo, fluoro, nitro, cyano, NR a R b , OR a , S.R. a , CO2R a , C(O)R a ,CONR a R a , S(O)R a and S(O)2R a and optionally substituted with 1 to 3 substituents selected from the group consisting of: where R a is independently selected at each occurrence from H, C1-C3-alkyl, and C1-C3-haloalkyl; R b is independently selected in each occurrence from H, C1-C3-alkyl, C(O)—C1-C3-alkyl and S(O)2—C1-C3-alkyl, A compound of formula (I), its tautomer, stereoisomer or mixture of stereoisomers, pharmaceutically acceptable salt, hydrate, deuterated derivative, or N-oxide.

[0569] 3. A compound of formula (IA) or a tautomer, stereoisomer or mixture of stereoisomers, pharmaceutically acceptable salt, hydrate, deuterated derivative, or N-oxide thereof: TIFF2026501324000115.tif58165(in the formula, 4 , X 5 , R 2 , R 3 , R 4 , and R 10 is as defined in embodiment 1; R 1 are independently selected from C1-C4-alkyl; R x and R y are each independently selected from H, halo, nitro, cyano, C-C-alkyl, C-C-alkenyl, C-C-alkynyl, and C-C-haloalkyl; m is an integer selected from 0, 1, and 2; n 17 is an integer selected from 0, 1 and 2).

[0570] 4. The compound of any one of the preceding embodiments, wherein Ring A is independently selected from 5-membered and 6-membered heteroaryl, a tautomer, stereoisomer or mixture of stereoisomers, a pharmaceutically acceptable salt, a hydrate, a deuterated derivative, or an N-oxide thereof.

[0571] 5. Ring A is TIFF2026501324000116.tif37165, R 4a is selected from H, C1-C4-alkyl, C3-C8-cycloalkyl, and 4- to 6-membered heterocycloalkyl, wherein said C1-C4-alkyl, said C3-C8-cycloalkyl, and said 4- to 6-membered heterocycloalkyl are selected from C1-C3-alkyl, SR 6 , OR 7 , and -NR 5 R 6 and optionally independently substituted with R 3 , R 4 and m is as defined in embodiment 1. A compound according to any one of the preceding embodiments, or a tautomer, stereoisomer or mixture of stereoisomers, pharmaceutically acceptable salt, hydrate, deuterated derivative, or N-oxide thereof.

[0572] 6.R 4ais selected from methyl, cyclopropyl, oxetane, cyclobutanol, methylcyclobutane, ethylmorpholine, —CH—CH—OMe, —CH—CH—OH, —CH—CH—N(CH)—, —CH—CH—S—CH, —CH—CH—O—CHF, and azetidine, or a tautomer, stereoisomer or mixture of stereoisomers, pharmaceutically acceptable salt, hydrate, deuterated derivative, or N-oxide thereof.

[0573] 7.R 3a and R 3b However, 1 to 3 R 9 or a tautomer, stereoisomer or mixture of stereoisomers, pharmaceutically acceptable salt, hydrate, deuterated derivative, or N-oxide thereof.

[0574] 8.R x is H, halogen, or C1-C4-alkyl, or a tautomer, stereoisomer or mixture of stereoisomers, pharmaceutically acceptable salt, hydrate, deuterated derivative, or N-oxide thereof.

[0575] 9.R y is H, halogen, or C1-C3-alkyl, or a tautomer, stereoisomer or mixture of stereoisomers, pharmaceutically acceptable salt, hydrate, deuterated derivative, or N-oxide thereof.

[0576] 10. A compound of formula (IV) or a tautomer, stereoisomer or mixture of stereoisomers, pharmaceutically acceptable salt, hydrate, deuterated derivative, or N-oxide thereof: TIFF2026501324000117.tif58165 (in the formula, R 1a is selected from C1-C4-alkyl, m is an integer selected from 0, 1, and 2; n 17 is an integer selected from 0, 1 and 2, R 4a is selected from H, C1-C6-alkyl, C1-C6-haloalkyl, C3-C6-cycloalkyl, aryl, and 4- to 6-membered heterocycloalkyl, wherein said C1-C6-alkyl, said C1-C6-haloalkyl, said C3-C6-cycloalkyl, said aryl, and said 4- to 6-membered heterocycloalkyl are selected from C1-C3-alkyl, SR 6 , OR 7 , and -NR 5 R 6 and optionally independently substituted with R 2 , R 3b , R 4 , R 5 , R 6 , R 7 , and R 10 is as defined in embodiment 1).

[0577] 11. A compound of formula (V) or a tautomer, stereoisomer or mixture of stereoisomers, pharmaceutically acceptable salt, hydrate, deuterated derivative, or N-oxide thereof: TIFF2026501324000118.tif58165 (in the formula, R 1a is selected from C1-C4-alkyl, m is an integer selected from 0, 1, and 2; n 17 is an integer selected from 0, 1 and 2, R 4a is selected from H, C1-C6-alkyl, C1-C6-haloalkyl, C3-C6-cycloalkyl, aryl, and 4- to 6-membered heterocycloalkyl, wherein said C1-C6-alkyl, said C1-C6-haloalkyl, said C3-C6-cycloalkyl, said aryl, and said 4- to 6-membered heterocycloalkyl are selected from C1-C3-alkyl, SR 6 , OR 7 , and -NR 5 R 6and optionally independently substituted with R 2 , R 3a , R 4 , R 5 , R 6 , R 7 , and R 10 is as defined in embodiment 1).

[0578] 12. A compound of formula (VA) or a tautomer, stereoisomer or mixture of stereoisomers, a pharmaceutically acceptable salt, a hydrate, a deuterated derivative, or an N-oxide thereof: TIFF2026501324000119.tif58165 (in the formula, R 1a is selected from C1-C3-alkyl, m is an integer selected from 0 and 1; R 4a is selected from H, C1-C6-alkyl, C1-C6-haloalkyl, C3-C6-cycloalkyl, aryl, and 4- to 6-membered heterocycloalkyl, wherein said C1-C6-alkyl, said C1-C6-haloalkyl, said C3-C6-cycloalkyl, said aryl, and said 4- to 6-membered heterocycloalkyl are selected from C1-C3-alkyl, SR 6 , OR 7 , and -NR 5 R 6 and optionally independently substituted with R 2 is C1-C4-haloalkyl, R 3a , R 4 , R 5 , R 6 , and R 7 is as defined in embodiment 1).

[0579] 13. The compound according to any one of the preceding embodiments, a tautomer, stereoisomer or mixture of stereoisomers, pharmaceutically acceptable salt, hydrate, deuterated derivative, or N-oxide thereof, wherein Ring A is substituted on the nitrogen with one group selected from C1-C4-alkyl, cyclopropyl, cyclobutyl, methyl-cyclobutyl, and 4-membered heterocycloalkyl.

[0580] 14. A compound of formula (VI) or a tautomer, stereoisomer or mixture of stereoisomers, a pharmaceutically acceptable salt, a hydrate, a deuterated derivative, or an N-oxide thereof: TIFF2026501324000120.tif63165 (in the formula, each X is independently selected from carbon and nitrogen; R 1a is selected from C1-C4-alkyl, m is an integer selected from 0, 1, and 2; n 17 is an integer selected from 0, 1 and 2, R 4a is selected from H, C1-C6-alkyl, C1-C6-haloalkyl, C3-C6-cycloalkyl, aryl, and 4- to 6-membered heterocycloalkyl, wherein said C1-C6-alkyl, said C1-C6-haloalkyl, said C3-C6-cycloalkyl, said aryl, and said 4- to 6-membered heterocycloalkyl are selected from C1-C3-alkyl, SR 6 , OR 7 , and -NR 5 R 6 and optionally independently substituted with R 2 , R 3a , R 4 , R 5 , R 6 , R 7 , and R 10 is as defined in embodiment 1).

[0581] 15. A compound of formula (VIA) or a tautomer, stereoisomer or mixture of stereoisomers, pharmaceutically acceptable salt, hydrate, deuterated derivative, or N-oxide thereof: TIFF2026501324000121.tif63165 (in the formula, each X is independently selected from carbon and nitrogen; R 1a is selected from C1-C4-alkyl, m is an integer selected from 0, 1, and 2; n 17 is an integer selected from 0, 1 and 2, R 4a is selected from H, C1-C6-alkyl, C1-C6-haloalkyl, C3-C6-cycloalkyl, aryl, and 4- to 6-membered heterocycloalkyl, wherein said C1-C6-alkyl, said C1-C6-haloalkyl, said C3-C6-cycloalkyl, said aryl, and said 4- to 6-membered heterocycloalkyl are selected from C1-C3-alkyl, SR 6 , OR 7 , and -NR 5 R 6 and optionally independently substituted with R 2 , R 3b , R 4 , R 5 , R 6 , R 7 , and R 10 is as defined in embodiment 1).

[0582] 16. A compound of formula (VIB) or a tautomer, stereoisomer or mixture of stereoisomers, pharmaceutically acceptable salt, hydrate, deuterated derivative, or N-oxide thereof: TIFF2026501324000122.tif63165 (in the formula, each X is independently selected from carbon and nitrogen; R 1a is selected from C1-C4-alkyl, m is an integer selected from 0, 1, and 2; n 17is an integer selected from 0, 1 and 2, R 4a is selected from H, C1-C6-alkyl, C1-C6-haloalkyl, C3-C6-cycloalkyl, aryl, and 4- to 6-membered heterocycloalkyl, wherein said C1-C6-alkyl, said C1-C6-haloalkyl, said C3-C6-cycloalkyl, said aryl, and said 4- to 6-membered heterocycloalkyl are selected from C1-C3-alkyl, SR 6 , OR 7 , and -NR 5 R 6 and optionally independently substituted with R 2 , R 3a , R 4 , R 5 , R 6 , R 7 , and R 10 is as defined in embodiment 1).

[0583] 17. A compound of formula (VIC), or a tautomer, stereoisomer or mixture of stereoisomers, a pharmaceutically acceptable salt, a hydrate, a deuterated derivative, or an N-oxide thereof: TIFF2026501324000123.tif63165 (in the formula, each X is independently selected from carbon and nitrogen; R 1a is selected from C1-C4-alkyl, m is an integer selected from 0, 1, and 2; n 17 is an integer selected from 0, 1 and 2, R 4a is selected from H, C1-C6-alkyl, C1-C6-haloalkyl, C3-C6-cycloalkyl, aryl, and 4- to 6-membered heterocycloalkyl, wherein said C1-C6-alkyl, said C1-C6-haloalkyl, said C3-C6-cycloalkyl, said aryl, and said 4- to 6-membered heterocycloalkyl are selected from C1-C3-alkyl, SR 6 , OR 7 , and -NR 5 R 6and optionally independently substituted with R 2 , R 3b , R 4 , R 5 , R 6 , R 7 , and R 10 is as defined in embodiment 1).

[0584] 18. A compound of formula (VID) or a tautomer, stereoisomer or mixture of stereoisomers, pharmaceutically acceptable salt, hydrate, deuterated derivative, or N-oxide thereof: TIFF2026501324000124.tif63165 (in the formula, R 1a is selected from C1-C4-alkyl, m is an integer selected from 0, 1, and 2; n 17 is an integer selected from 0, 1 and 2, R 4a is selected from H, C1-C6-alkyl, C1-C6-haloalkyl, C3-C6-cycloalkyl, aryl, and 4- to 6-membered heterocycloalkyl, wherein said C1-C6-alkyl, said C1-C6-haloalkyl, said C3-C6-cycloalkyl, said aryl, and said 4- to 6-membered heterocycloalkyl are selected from C1-C3-alkyl, SR 6 , OR 7 , and -NR 5 R 6 and optionally independently substituted with R 2 , R 3a , R 4 , R 5 , R 6 , R 7 , and R 10 is as defined in embodiment 1).

[0585] 19. A compound of formula (VIE) or a tautomer, stereoisomer or mixture of stereoisomers, pharmaceutically acceptable salt, hydrate, deuterated derivative, or N-oxide thereof: TIFF2026501324000125.tif63165 (in the formula, R 1a is selected from C1-C4-alkyl, m is an integer selected from 0, 1, and 2; n 17 is an integer selected from 0, 1 and 2, R 4a is selected from H, C1-C6-alkyl, C1-C6-haloalkyl, C3-C6-cycloalkyl, aryl, and 4- to 6-membered heterocycloalkyl, wherein said C1-C6-alkyl, said C1-C6-haloalkyl, said C3-C6-cycloalkyl, said aryl, and said 4- to 6-membered heterocycloalkyl are selected from C1-C3-alkyl, SR 6 , OR 7 , and -NR 5 R 6 and optionally independently substituted with R 2 , R 3b , R 4 , R 5 , R 6 , R 7 , and R 10 is as defined in embodiment 1).

[0586] 20. A compound of formula (VIF) or a tautomer, stereoisomer or mixture of stereoisomers, pharmaceutically acceptable salt, hydrate, deuterated derivative, or N-oxide thereof: TIFF2026501324000126.tif63165 (in the formula, R 1a is selected from C1-C4-alkyl, m is an integer selected from 0, 1, and 2; n 17 is an integer selected from 0, 1 and 2, R 4ais selected from H, C1-C6-alkyl, C1-C6-haloalkyl, C3-C6-cycloalkyl, aryl, and 4- to 6-membered heterocycloalkyl, wherein said C1-C6-alkyl, said C1-C6-haloalkyl, said C3-C6-cycloalkyl, said aryl, and said 4- to 6-membered heterocycloalkyl are selected from C1-C3-alkyl, SR 6 , OR 7 , and -NR 5 R 6 and optionally independently substituted with R 2 , R 3a , R 4 , R 5 , R 6 , R 7 , and R 10 is as defined in embodiment 1).

[0587] 21. A compound of formula (VIG) or a tautomer, stereoisomer or mixture of stereoisomers, pharmaceutically acceptable salt, hydrate, deuterated derivative, or N-oxide thereof: TIFF2026501324000127.tif58165 (in the formula, R 1a is selected from C1-C4-alkyl, m is an integer selected from 0, 1, and 2; n 17 is an integer selected from 0, 1 and 2, R 4a is selected from H, C1-C6-alkyl, C1-C6-haloalkyl, C3-C6-cycloalkyl, aryl, and 4- to 6-membered heterocycloalkyl, wherein said C1-C6-alkyl, said C1-C6-haloalkyl, said C3-C6-cycloalkyl, said aryl, and said 4- to 6-membered heterocycloalkyl are selected from C1-C3-alkyl, SR 6 , OR 7 , and -NR 5 R 6 and optionally independently substituted with R 2 , R 3a , R 4 , R 5, R 6 , R 7 , and R 10 is as defined in embodiment 1).

[0588] 22. A compound of formula (VIH) or a tautomer, stereoisomer or mixture of stereoisomers, a pharmaceutically acceptable salt, a hydrate, a deuterated derivative, or an N-oxide thereof: TIFF2026501324000128.tif68165 (in the formula, R 1a is selected from C1-C4-alkyl, m is an integer selected from 0, 1, and 2; n 17 is an integer selected from 0, 1 and 2, R 4a is selected from H, C1-C6-alkyl, C1-C6-haloalkyl, C3-C6-cycloalkyl, aryl, and 4- to 6-membered heterocycloalkyl, wherein said C1-C6-alkyl, said C1-C6-haloalkyl, said C3-C6-cycloalkyl, said aryl, and said 4- to 6-membered heterocycloalkyl are selected from C1-C3-alkyl, SR 6 , OR 7 , and -NR 5 R 6 and optionally independently substituted with R 2 , R 3b , R 4 , R 5 , R 6 , R 7 , and R 10 is as defined in embodiment 1).

[0589] 23. A compound of formula (VIi), or a tautomer, stereoisomer or mixture of stereoisomers, a pharmaceutically acceptable salt, a hydrate, a deuterated derivative, or an N-oxide thereof: TIFF2026501324000129.tif68165 (in the formula, R 1a is selected from C1-C4-alkyl, m is an integer selected from 0, 1, and 2; n 17 is an integer selected from 0, 1 and 2, R 4a is selected from H, C1-C6-alkyl, C1-C6-haloalkyl, C3-C6-cycloalkyl, aryl, and 4- to 6-membered heterocycloalkyl, wherein said C1-C6-alkyl, said C1-C6-haloalkyl, said C3-C6-cycloalkyl, said aryl, and said 4- to 6-membered heterocycloalkyl are selected from C1-C3-alkyl, SR 6 , OR 7 , and -NR 5 R 6 and optionally independently substituted with R 2 , R 3a , R 4 , R 5 , R 6 , R 7 , and R 10 is as defined in embodiment 1).

[0590] 24. A compound of formula (VII) or a tautomer, stereoisomer or mixture of stereoisomers, a pharmaceutically acceptable salt, a hydrate, a deuterated derivative, or an N-oxide thereof: TIFF2026501324000130.tif63165 (in the formula, X 1 are independently selected from carbon, sulfur, and nitrogen; R 1a is selected from C1-C4-alkyl, m is an integer selected from 0, 1, and 2; n 17 is an integer selected from 0, 1 and 2, R 4ais selected from H, C1-C6-alkyl, C1-C6-haloalkyl, C3-C6-cycloalkyl, aryl, and 4- to 6-membered heterocycloalkyl, wherein said C1-C6-alkyl, said C1-C6-haloalkyl, said C3-C6-cycloalkyl, said aryl, and said 4- to 6-membered heterocycloalkyl are selected from C1-C3-alkyl, SR 6 , OR 7 , and -NR 5 R 6 and optionally independently substituted with R 2 , R 3a , R 4 , R 5 , R 6 , R 7 , and R 10 is as defined in embodiment 1).

[0591] 25. A compound of formula (VIII), or a tautomer, stereoisomer or mixture of stereoisomers, a pharmaceutically acceptable salt, a hydrate, a deuterated derivative, or an N-oxide thereof: TIFF2026501324000131.tif63165 (in the formula, X 1 are independently selected from carbon, sulfur, and nitrogen; R 1a is selected from C1-C4-alkyl, m is an integer selected from 0, 1, and 2; n 17 is an integer selected from 0, 1 and 2, R 4a is selected from H, C1-C6-alkyl, C1-C6-haloalkyl, C3-C6-cycloalkyl, aryl, and 4- to 6-membered heterocycloalkyl, wherein said C1-C6-alkyl, said C1-C6-haloalkyl, said C3-C6-cycloalkyl, said aryl, and said 4- to 6-membered heterocycloalkyl are selected from C1-C3-alkyl, SR 6 , OR 7 , and -NR 5 R 6 and optionally independently substituted with R2 , R 3b , R 4 , R 5 , R 6 , R 7 , and R 10 is as defined in embodiment 1).

[0592] 26. A compound of formula (VIIIA), or a tautomer, stereoisomer or mixture of stereoisomers, a pharmaceutically acceptable salt, a hydrate, a deuterated derivative, or an N-oxide thereof: TIFF2026501324000132.tif63165 (in the formula, R 1a is selected from C1-C4-alkyl, m is an integer selected from 0, 1, and 2; R 4a is selected from H, C1-C6-alkyl, C1-C6-haloalkyl, C3-C6-cycloalkyl, aryl, and 4- to 6-membered heterocycloalkyl, wherein said C1-C6-alkyl, said C1-C6-haloalkyl, said C3-C6-cycloalkyl, said aryl, and said 4- to 6-membered heterocycloalkyl are selected from C1-C3-alkyl, SR 6 , OR 7 , and -NR 5 R 6 and optionally independently substituted with R 2 , R 3b , R 4 , R 5 , R 6 , and R 7 is as defined in embodiment 1).

[0593] 27.R 2 is independently selected from halogen, C1-C6-alkyl, alkoxy, C1-C6-haloalkyl, ethyl, cyano, nitroisopropyl, tert-butyl, cyclopropyl, SF4 and SF5, or a tautomer, stereoisomer or mixture of stereoisomers, pharmaceutically acceptable salt, hydrate, deuterated derivative, or N-oxide thereof.

[0594] 28.R 2 is independently selected from C1-C4-haloalkyl, ethyl, cyano, nitro, isopropyl, tert-butyl, cyclopropyl, SF4, and SF5, or a tautomer, stereoisomer or mixture of stereoisomers, pharmaceutically acceptable salt, hydrate, deuterated derivative, or N-oxide thereof.

[0595] 29.R 2 is independently selected from halogen, C1-C6-alkyl, alkoxy, and C1-C6-haloalkyl, or a tautomer, stereoisomer or mixture of stereoisomers, pharmaceutically acceptable salt, hydrate, deuterated derivative, or N-oxide thereof.

[0596] 30.R 2 is independently selected from CF3, CHF2, CH2CF3, and CH2CH2F, or a tautomer, stereoisomer or mixture of stereoisomers, pharmaceutically acceptable salt, hydrate, deuterated derivative, or N-oxide thereof.

[0597] 31.R 2 is independently selected from CBr3, CHBr2, CH2CBr3, and CH2CH2Br, or a tautomer, stereoisomer or mixture of stereoisomers, pharmaceutically acceptable salt, hydrate, deuterated derivative, or N-oxide thereof.

[0598] 32.R 2 are independently selected from CCl3, CHCl2, CH2CCl3, and CH2CH2Cl, or a tautomer, stereoisomer or mixture of stereoisomers, pharmaceutically acceptable salt, hydrate, deuterated derivative, or N-oxide thereof.

[0599] 33.R 2is independently selected from —CH—CH—OCF, —CH—CH—OCF, SF, or SF, or a tautomer, stereoisomer or mixture of stereoisomers, pharmaceutically acceptable salt, hydrate, deuterated derivative, or N-oxide thereof.

[0600] 34.R 2 But CH(CH3) 2、 A compound according to any one of the preceding embodiments, or a tautomer, stereoisomer or mixture of stereoisomers, pharmaceutically acceptable salt, hydrate, deuterated derivative, or N-oxide thereof, which is not CH3, or oxetanyl.

[0601] 35.R 1 is selected from methyl, ethyl, and C1-C4-haloalkyl, or a tautomer, stereoisomer or mixture of stereoisomers, pharmaceutically acceptable salt, hydrate, deuterated derivative, or N-oxide thereof.

[0602] 36.R 1a is selected from methyl, ethyl, and C1-C4-haloalkyl, or a tautomer, stereoisomer or mixture of stereoisomers, pharmaceutically acceptable salt, hydrate, deuterated derivative, or N-oxide thereof.

[0603] 37.n 17 is 0 or 1, or a tautomer, stereoisomer or mixture of stereoisomers, pharmaceutically acceptable salt, hydrate, deuterated derivative, or N-oxide thereof.

[0604] 38.n 17 If is 1, R 10 is not CH or cyano, or a tautomer, stereoisomer or mixture of stereoisomers, pharmaceutically acceptable salt, hydrate, deuterated derivative, or N-oxide thereof.

[0605] 39. The compound according to any one of the preceding embodiments, comprising at least one halogen, or at least two halogens, or at least three halogens, a tautomer, stereoisomer or mixture of stereoisomers, a pharmaceutically acceptable salt, a hydrate, a deuterated derivative, or an N-oxide thereof.

[0606] 40. The compound, TIFF2026501324000133.tif136145 TIFF2026501324000134.tif212145 TIFF2026501324000135.tif203145 TIFF2026501324000136.tif189145 TIFF2026501324000137.tif217145 TIFF2026501324000138.tif197145 TIFF2026501324000139.tif163145 TIFF2026501324000140.tif66145, or a stereoisomer, or a pharmaceutically acceptable salt or N-oxide thereof.

[0607] 41. A pharmaceutical composition comprising a compound according to any one of the preceding embodiments and one or more pharmaceutically acceptable excipients.

[0608] 42. A compound according to any one of the preceding embodiments for use as a medicament.

[0609] 43. A compound according to any one of the preceding embodiments for use in the treatment or prevention of an inflammatory disorder or disease.

[0610] 44. A compound according to any one of the preceding embodiments for use in the treatment or prevention of an immune disorder.

[0611] 45. A compound according to any one of the preceding embodiments for use in the treatment or prevention of an autoimmune disease.

[0612] 46. ​​A compound according to any one of the preceding embodiments for use in the treatment of cancer.

[0613] 47. The compound of any one of the preceding embodiments, wherein said use comprises topical or oral administration of said compound.

[0614] 48. The compound of any one of the preceding embodiments, wherein said use comprises administering said compound by injection.

[0615] 49. The compound of any one of the preceding embodiments, wherein said use comprises topical administration of said compound to the skin.

[0616] The present disclosure further includes the following numbered embodiments:

[0617] 1. A method for the treatment of an inflammatory and / or autoimmune disease or disorder or a disease or disorder related thereto, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (XXIA), a tautomer, stereoisomer or mixture of stereoisomers, a pharmaceutically acceptable salt, a hydrate, a deuterated derivative, or an N-oxide thereof: TIFF2026501324000141.tif53165 (in the formula, R1 is C1-C4-haloalkyl; R2 is C1-C4-alkyl, where C1-C4-alkyl is optionally substituted by SR3 or OR3, R3 is selected from H, C1-C3-alkyl, C(O)-C1-C3-alkyl, and C1-C3-haloalkyl).

[0618] 2. The method of any one of the preceding embodiments, wherein R1 is independently selected from CF3, CHF2, CH2CF3, and CH2CH2F.

[0619] 3. The method of any one of the preceding embodiments, wherein R1 is independently selected from CBr3, CHBr2, CH2CBr3, and CH2CH2Br.

[0620] 4. The method of any one of the preceding embodiments, wherein R1 is independently selected from CCl3, CHCl2, CH2CCl3, and CH2CH2Cl.

[0621] 5. The method of any one of the preceding embodiments, wherein R1 is CH2CH2F.

[0622] 6. The method of any one of the preceding embodiments, wherein R1 is CHF2.

[0623] 7. The method of any one of the preceding embodiments, wherein R1 is CF3.

[0624] 8. The method of any one of the preceding embodiments, wherein R2 is C1-C4-alkyl, wherein said C1-C4-alkyl is substituted with OR3.

[0625] 9. The method of any one of the preceding embodiments, wherein R2 is C1-C4-alkyl, wherein said C1-C4-alkyl is substituted with SR3.

[0626] 10. The method of any one of the preceding embodiments, wherein R2 is selected from -CH3, -CH2-CH2-O-CH3, and -CH2-CH2-OCH2-CH3.

[0627] 11. The method of any one of the preceding embodiments, wherein R2 is selected from -CH3, -CH2-CH2-S-CH3, and -CH2-CH2-SCH2-CH3.

[0628] 12. The method of any one of the preceding embodiments, wherein R2 is -CH3.

[0629] 13. The method of any one of the preceding embodiments, wherein R2 is -CH2-CH2-O-CH3.

[0630] 14. The method of any one of the preceding embodiments, wherein R2 is -CH2-CH2-S-CH3.

[0631] 15. A compound of formula (XXIA) TIFF2026501324000142.tif109165 or a tautomer, stereoisomer or mixture of stereoisomers, pharmaceutically acceptable salt, hydrate, deuterated derivative, or N-oxide thereof.

[0632] 16. A compound of formula (XXIA) TIFF2026501324000143.tif47165 or a tautomer, stereoisomer or mixture of stereoisomers, pharmaceutically acceptable salt, hydrate, deuterated derivative, or N-oxide thereof.

[0633] 17. A compound of formula (XXIA): TIFF2026501324000144.tif58165 or a tautomer, stereoisomer or mixture of stereoisomers, pharmaceutically acceptable salt, hydrate, deuterated derivative, or N-oxide thereof.

[0634] 18. A compound of formula (XXIA) TIFF2026501324000145.tif58165 or a tautomer, stereoisomer or mixture of stereoisomers, pharmaceutically acceptable salt, hydrate, deuterated derivative, or N-oxide thereof.

[0635] 19. The method of any one of the preceding embodiments, wherein said disease or disorder is a joint or joint-related disorder.

[0636] 20. The method of any one of the preceding embodiments, wherein the joint-related disease or disorder is selected from arthritis, bursitis, Ehlers-Danlos syndrome, epicondylitis, Felty's syndrome, gouty arthritis, psoriatic arthritis, osteoarthritis, rheumatoid arthritis, Still's disease, tenosynovitis, synovitis, Sjogren's syndrome, Lyme disease, Whipple's disease, bone cancer, lupus, and other autoimmune joint disorders.

[0637] 21. The method of any one of the preceding embodiments, wherein the joint or joint-related disease or disorder comprises arthritis.

[0638] 22. The method of any one of the preceding embodiments, wherein said arthritis comprises rheumatoid arthritis.

[0639] 23. The method of any one of the preceding embodiments, wherein the disorder is arthritis and wherein, upon administration of the therapeutically effective amount of the compound, its tautomer, stereoisomer or mixture of stereoisomers, pharmaceutically acceptable salt, hydrate, deuterated derivative, or N-oxide, there is a therapeutic effect associated with reducing inflammation.

[0640] 24. The method of any one of the preceding embodiments, wherein said therapeutic effect associated with reduced inflammation is a decrease in joint or limb thickening or circumference.

[0641] 25. There is a reduction in arthritis scoring or severity, wherein the reduction in arthritis scoring or severity is (a) Visible redness and swelling of the ankle / wrist or confined to individual digits, regardless of the number of digits affected; (b) severe redness and swelling of the ankles / wrists; (c) redness and swelling of the entire appendage, including the digits; and / or (d) The method of any one of the preceding embodiments, wherein the relief is in the extremity with the greatest inflammation, where multiple joints are involved.

[0642] 26. The method of any one of the preceding embodiments, wherein said attenuation / reduction is dose-dependent.

[0643] 27. The method of any one of the preceding embodiments, wherein the reduction / decrease is greater than about 50%.

[0644] 28. A method for treating a joint or joint-related disease, comprising administering to a subject in need thereof a therapeutically effective amount of The method comprises orally administering a compound selected from TIFF2026501324000146.tif109165, or a tautomer, stereoisomer or mixture of stereoisomers, pharmaceutically acceptable salt, hydrate, deuterated derivative, or N-oxide thereof.

[0645] 29. A method for treating a joint or joint-related disease, comprising administering to a subject in need thereof a therapeutically effective amount of TIFF2026501324000147.tif47165, or a tautomer, stereoisomer or mixture of stereoisomers, pharmaceutically acceptable salt, hydrate, deuterated derivative, or N-oxide thereof.

[0646] 30. A method for treating a joint or joint-related disease, comprising administering to a subject in need thereof a therapeutically effective amount of TIFF2026501324000148.tif58165 or a tautomer, stereoisomer or mixture of stereoisomers, pharmaceutically acceptable salt, or hydrate, deuterated derivative, or N-oxide thereof.

[0647] 31. A method for treating a joint or joint-related disease, comprising administering to a subject in need thereof a therapeutically effective amount of TIFF2026501324000149.tif58165 or a tautomer, stereoisomer or mixture of stereoisomers, pharmaceutically acceptable salt, or hydrate, deuterated derivative, or N-oxide thereof.

[0648] 32. A method for treating arthritis disease, comprising administering to a subject in need thereof a therapeutically effective amount of TIFF2026501324000150.tif109165, or a tautomer, stereoisomer or mixture of stereoisomers, pharmaceutically acceptable salt, hydrate, deuterated derivative, or N-oxide thereof, wherein upon administration of a therapeutically effective amount of the compound, tautomer, stereoisomer or mixture of stereoisomers, pharmaceutically acceptable salt, hydrate, deuterated derivative, or N-oxide thereof, the therapeutic effect is related to reduced inflammation.

[0649] 33. A method for treating arthritis disease, comprising administering to a subject in need thereof a therapeutically effective amount of TIFF2026501324000151.tif47165 or a tautomer, stereoisomer or mixture of stereoisomers, pharmaceutically acceptable salt, hydrate, deuterated derivative, or N-oxide thereof, wherein upon administration of a therapeutically effective amount of the compound, tautomer, stereoisomer or mixture of stereoisomers, pharmaceutically acceptable salt, hydrate, deuterated derivative, or N-oxide thereof, the therapeutic effect is related to reduced inflammation.

[0650] 34. A method for treating arthritis disease, comprising administering to a subject in need thereof a therapeutically effective amount of TIFF2026501324000152.tif58165 or a tautomer, stereoisomer or mixture of stereoisomers, pharmaceutically acceptable salt, hydrate, deuterated derivative, or N-oxide thereof, wherein upon administration of a therapeutically effective amount of the compound, tautomer, stereoisomer or mixture of stereoisomers, pharmaceutically acceptable salt, hydrate, deuterated derivative, or N-oxide thereof, the therapeutic effect is related to reduced inflammation.

[0651] 35. A method for treating arthritis disease, comprising administering to a subject in need thereof a therapeutically effective amount of TIFF2026501324000153.tif58165 or a tautomer, stereoisomer or mixture of stereoisomers, pharmaceutically acceptable salt, hydrate, deuterated derivative, or N-oxide thereof, wherein upon administration of a therapeutically effective amount of the compound, tautomer, stereoisomer or mixture of stereoisomers, pharmaceutically acceptable salt, hydrate, deuterated derivative, or N-oxide thereof, the therapeutic effect is related to reduced inflammation.

[0652] 36. The method of any one of the preceding embodiments, wherein said disease or disorder is a fibrotic disease or disorder.

[0653] 37. The method of any one of the preceding embodiments, wherein said disease or disorder is renal fibrosis.

[0654] 38. The method of any one of the preceding embodiments, wherein said disease or disorder is pulmonary fibrosis (PF).

[0655] 39. The method of any one of the preceding embodiments, wherein said disease or disorder is idiopathic pulmonary fibrosis (IPF).

[0656] 40. The method of any one of the preceding embodiments, wherein, upon administration of the therapeutically effective amount of the compound, its tautomer, stereoisomer or mixture of stereoisomers, pharmaceutically acceptable salt, hydrate, deuterated derivative, or N-oxide, there is a therapeutic effect associated with reducing fibrosis.

[0657] 41. The method of any one of the preceding embodiments, wherein said reducing fibrosis comprises reducing a pathology.

[0658] 42. The method of any one of the preceding embodiments, wherein the reduction in the pathology comprises a reduction in a renal pathology, wherein the reduction in the renal pathology comprises a reduction in interstitial nephritis, collagen fiber deposition, and nephropathy.

[0659] 43. The method of any one of the preceding embodiments, wherein said reducing fibrosis comprises a decrease in inflammatory tissue biomarkers.

[0660] 44. The method of any one of the preceding embodiments, wherein the inflammatory tissue biomarkers comprise Col1A1, TGF-b1, MCP-1, IL-1b, IL-6, IL-17, and Timp1.

[0661] 45. The method of any one of the preceding embodiments, wherein pulmonary fibrosis is reduced in a fibrotic subject.

[0662] 46. ​​The method of any one of the preceding embodiments, wherein deposition of fibrous tissue is reduced.

[0663] 47. The method of any one of the preceding embodiments, wherein hydroxyproline levels are reduced in a fibrotic subject.

[0664] 48. The method of any one of the preceding embodiments, wherein blood oxygen saturation and functional lung capacity are improved in fibrotic subjects.

[0665] 49. The method of any one of the preceding embodiments, wherein the compound, tautomer, stereoisomer or mixture of stereoisomers, pharmaceutically acceptable salt, hydrate, deuterated derivative, or N-oxide thereof is administered in an amount sufficient to reduce or reverse pulmonary fibrotic remodeling compared to vehicle-treated controls challenged with bleomycin.

[0666] 50. The method of any one of the preceding embodiments, wherein the compound, tautomer, stereoisomer or mixture of stereoisomers, pharmaceutically acceptable salt, hydrate, deuterated derivative, or N-oxide thereof is administered in an amount sufficient to reduce interstitial fibrosis and subacute interstitial inflammation compared to subjects stimulated with bleomycin and treated with vehicle.

[0667] 51. A method for treating a fibrotic disease, comprising administering to a subject in need thereof a therapeutically effective amount of The method comprises orally administering a compound selected from TIFF2026501324000154.tif109165, or a tautomer, stereoisomer or mixture of stereoisomers, pharmaceutically acceptable salt, hydrate, deuterated derivative, or N-oxide thereof.

[0668] 52. A method for treating a fibrotic disease, comprising administering to a subject in need thereof a therapeutically effective amount of TIFF2026501324000155.tif47165 or a tautomer, stereoisomer or mixture of stereoisomers, pharmaceutically acceptable salt, hydrate, deuterated derivative, or N-oxide thereof.

[0669] 53. A method for treating a fibrotic disease, comprising administering to a subject in need thereof a therapeutically effective amount of TIFF2026501324000156.tif58165, or a tautomer, stereoisomer or mixture of stereoisomers, pharmaceutically acceptable salt, hydrate, deuterated derivative, or N-oxide thereof.

[0670] 54. A method for treating a fibrotic disease, comprising administering to a subject in need thereof a therapeutically effective amount of TIFF2026501324000157.tif58165, or a tautomer, stereoisomer or mixture of stereoisomers, pharmaceutically acceptable salt, hydrate, deuterated derivative, or N-oxide thereof.

[0671] 55. A method for treating renal fibrosis, comprising administering to a subject in need thereof a therapeutically effective amount of TIFF2026501324000158.tif109165, or a tautomer, stereoisomer or mixture of stereoisomers, pharmaceutically acceptable salt, hydrate, deuterated derivative, or N-oxide thereof, wherein upon administration of a therapeutically effective amount of the compound, tautomer, stereoisomer or mixture of stereoisomers, pharmaceutically acceptable salt, hydrate, deuterated derivative, or N-oxide thereof, a therapeutic effect is associated with a reduction in fibrosis.

[0672] 56. A method for treating renal fibrosis, comprising administering to a subject in need thereof a therapeutically effective amount of TIFF2026501324000159.tif47165 or a tautomer, stereoisomer or mixture of stereoisomers, pharmaceutically acceptable salt, hydrate, deuterated derivative, or N-oxide thereof, wherein upon administration of a therapeutically effective amount of the compound, tautomer, stereoisomer or mixture of stereoisomers, pharmaceutically acceptable salt, hydrate, deuterated derivative, or N-oxide thereof, the therapeutic effect is associated with a reduction in fibrosis.

[0673] 57. A method for treating renal fibrosis, comprising administering to a subject in need thereof a therapeutically effective amount of TIFF2026501324000160.tif58165 or a tautomer, stereoisomer or mixture of stereoisomers, pharmaceutically acceptable salt, hydrate, deuterated derivative, or N-oxide thereof, wherein upon administration of the therapeutically effective amount of the compound, tautomer, stereoisomer or mixture of stereoisomers, pharmaceutically acceptable salt, hydrate, deuterated derivative, or N-oxide thereof, the therapeutic effect is associated with a reduction in fibrosis.

[0674] 58. A method for treating renal fibrosis, comprising administering to a subject in need thereof a therapeutically effective amount of TIFF2026501324000161.tif58165 or a tautomer, stereoisomer or mixture of stereoisomers, pharmaceutically acceptable salt, hydrate, deuterated derivative, or N-oxide thereof, wherein upon administration of the therapeutically effective amount of the compound, tautomer, stereoisomer or mixture of stereoisomers, pharmaceutically acceptable salt, hydrate, deuterated derivative, or N-oxide thereof, a therapeutic effect is associated with a reduction in fibrosis.

[0675] 59. A method for treating pulmonary fibrosis, comprising administering to a subject in need thereof a therapeutically effective amount of TIFF2026501324000162.tif109165, or a tautomer, stereoisomer or mixture of stereoisomers, pharmaceutically acceptable salt, hydrate, deuterated derivative, or N-oxide thereof, wherein upon administration of a therapeutically effective amount of the compound, tautomer, stereoisomer or mixture of stereoisomers, pharmaceutically acceptable salt, hydrate, deuterated derivative, or N-oxide thereof, a therapeutic effect is associated with a reduction in fibrosis.

[0676] 60. A method for treating pulmonary fibrosis, comprising administering to a subject in need thereof a therapeutically effective amount of TIFF2026501324000163.tif47165 or a tautomer, stereoisomer or mixture of stereoisomers, pharmaceutically acceptable salt, hydrate, deuterated derivative, or N-oxide thereof, wherein upon administration of a therapeutically effective amount of the compound, tautomer, stereoisomer or mixture of stereoisomers, pharmaceutically acceptable salt, hydrate, deuterated derivative, or N-oxide thereof, the therapeutic effect is associated with a reduction in fibrosis.

[0677] 61. A method for treating pulmonary fibrosis, comprising administering to a subject in need thereof a therapeutically effective amount of TIFF2026501324000164.tif58165 or a tautomer, stereoisomer or mixture of stereoisomers, pharmaceutically acceptable salt, hydrate, deuterated derivative, or N-oxide thereof, wherein upon administration of the therapeutically effective amount of the compound, tautomer, stereoisomer or mixture of stereoisomers, pharmaceutically acceptable salt, hydrate, deuterated derivative, or N-oxide thereof, the therapeutic effect is associated with a reduction in fibrosis.

[0678] 62. A method for treating pulmonary fibrosis, comprising administering to a subject in need thereof a therapeutically effective amount of TIFF2026501324000165.tif58165 or a tautomer, stereoisomer or mixture of stereoisomers, pharmaceutically acceptable salt, hydrate, deuterated derivative, or N-oxide thereof, wherein upon administration of a therapeutically effective amount of the compound, tautomer, stereoisomer or mixture of stereoisomers, pharmaceutically acceptable salt, hydrate, deuterated derivative, or N-oxide thereof, a therapeutic effect is associated with a reduction in fibrosis.

[0679] 63. The method of any one of the preceding embodiments, wherein the progression of the severity of the fibrosis is slowed or delayed.

[0680] 64. The method of any one of the preceding embodiments, wherein the appearance or increase of one or more indicators of the severity of said fibrosis is slowed or delayed.

[0681] 65. The method of any one of the preceding embodiments, wherein said disease or disorder is a lupus disease or disorder.

[0682] 66. The method of any one of the preceding embodiments, wherein said disease or disorder is systemic lupus erythematosus (SLE).

[0683] 67. The method of any one of the preceding embodiments, wherein the disease or disorder is cutaneous lupus erythematosus (CLE).

[0684] 68. The method of any one of the preceding embodiments, wherein, upon administration of the therapeutically effective amount of the compound, its tautomer, stereoisomer or mixture of stereoisomers, pharmaceutically acceptable salt, hydrate, deuterated derivative, or N-oxide, there is a therapeutic effect associated with reducing proteinuria.

[0685] 69. The method of any one of the preceding embodiments, wherein, upon administration of the therapeutically effective amount of the compound, its tautomer, stereoisomer or mixture of stereoisomers, pharmaceutically acceptable salt, hydrate, deuterated derivative, or N-oxide, there is a therapeutic effect associated with alleviating a pathological condition.

[0686] 70. The method of any one of the preceding embodiments, wherein, upon administration of the therapeutically effective amount of the compound, its tautomer, stereoisomer or mixture of stereoisomers, pharmaceutically acceptable salt, hydrate, deuterated derivative, or N-oxide, there is a therapeutic effect associated with a reduction in glomerular lesions, tubulointerstitial lesions, and total kidney lesions.

[0687] 71. The method of any one of the preceding embodiments, wherein, upon administration of the therapeutically effective amount of the compound, its tautomer, stereoisomer or mixture of stereoisomers, pharmaceutically acceptable salt, hydrate, deuterated derivative, or N-oxide, there is a therapeutic effect associated with a decrease in blood urea nitrogen (BUN).

[0688] 72. The method of any one of the preceding embodiments, wherein, upon administration of the therapeutically effective amount of the compound, its tautomer, stereoisomer or mixture of stereoisomers, pharmaceutically acceptable salt, hydrate, deuterated derivative, or N-oxide, there is a therapeutic effect associated with a reduction in anti-dsDNA antibodies.

[0689] 73. The method of any one of the preceding embodiments, wherein one or more inflammatory tissue biomarkers are reduced.

[0690] 74. The method of any one of the preceding embodiments, wherein the severity of the disease or disorder is reduced.

[0691] 75. The method of any one of the preceding embodiments, wherein the disease or disorder is a skin disorder.

[0692] 76. The method of any one of the preceding embodiments, wherein the disease or disorder is psoriasis.

[0693] 77. The method of any one of the preceding embodiments, wherein, upon administration of the therapeutically effective amount of the compound, its tautomer, stereoisomer or mixture of stereoisomers, pharmaceutically acceptable salt, hydrate, deuterated derivative, or N-oxide, there is a therapeutic effect associated with reducing inflammation.

[0694] 78. The method of any one of the preceding embodiments, wherein said reducing inflammation comprises reducing a pathology.

[0695] 79. The method of any one of the preceding embodiments, wherein the alleviation of the condition comprises a decrease in the Psoriasis Area and Severity Index score.

[0696] 80. The method of any one of the preceding embodiments, wherein said attenuation / reduction is followed by and / or accompanied by a decrease in inflammatory tissue biomarkers.

[0697] 81. The method of any one of the preceding embodiments, wherein the inflammatory tissue biomarker is associated with psoriasis.

[0698] 82. The method of any one of the preceding embodiments, wherein the inflammatory tissue biomarkers comprise one or more of IL-17, IL-22, IL-1β, IL-6, TNF-α, and IL-23.

[0699] 83. A method for treating a skin disease, comprising administering to a subject in need thereof a therapeutically effective amount of The method comprises orally administering a compound selected from TIFF2026501324000166.tif109165, or a tautomer, stereoisomer or mixture of stereoisomers, pharmaceutically acceptable salt, hydrate, deuterated derivative, or N-oxide thereof.

[0700] 84. A method for treating a skin disease, comprising administering to a subject in need thereof a therapeutically effective amount of TIFF2026501324000167.tif47165 or a tautomer, stereoisomer or mixture of stereoisomers, pharmaceutically acceptable salt, hydrate, deuterated derivative, or N-oxide thereof.

[0701] 85. A method for treating a skin disease, comprising administering to a subject in need thereof a therapeutically effective amount of TIFF2026501324000168.tif58165, or a tautomer, stereoisomer or mixture of stereoisomers, pharmaceutically acceptable salt, hydrate, deuterated derivative, or N-oxide thereof.

[0702] 86. A method for treating a skin disease, comprising administering to a subject in need thereof a therapeutically effective amount of TIFF2026501324000169.tif58165, or a tautomer, stereoisomer or mixture of stereoisomers, pharmaceutically acceptable salt, hydrate, deuterated derivative, or N-oxide thereof.

[0703] 87. A method for treating psoriasis, comprising administering to a subject in need thereof a therapeutically effective amount of TIFF2026501324000170.tif109165, or a tautomer, stereoisomer or mixture of stereoisomers, pharmaceutically acceptable salt, hydrate, deuterated derivative, or N-oxide thereof, wherein upon administration of a therapeutically effective amount of the compound, tautomer, stereoisomer or mixture of stereoisomers, pharmaceutically acceptable salt, hydrate, deuterated derivative, or N-oxide thereof, a therapeutic effect is associated with alleviation of psoriasis.

[0704] 88. A method for treating psoriasis, comprising administering to a subject in need thereof a therapeutically effective amount of TIFF2026501324000171.tif47165 or a tautomer, stereoisomer or mixture of stereoisomers, pharmaceutically acceptable salt, hydrate, deuterated derivative, or N-oxide thereof, wherein upon administration of the therapeutically effective amount of the compound, tautomer, stereoisomer or mixture of stereoisomers, pharmaceutically acceptable salt, hydrate, deuterated derivative, or N-oxide thereof, a therapeutic effect is associated with alleviation of psoriasis.

[0705] 89. A method for treating psoriasis, comprising administering to a subject in need thereof a therapeutically effective amount of TIFF2026501324000172.tif58165 or a tautomer, stereoisomer or mixture of stereoisomers, pharmaceutically acceptable salt, hydrate, deuterated derivative, or N-oxide thereof, wherein upon administration of the therapeutically effective amount of the compound, tautomer, stereoisomer or mixture of stereoisomers, pharmaceutically acceptable salt, hydrate, deuterated derivative, or N-oxide thereof, the therapeutic effect is associated with alleviation of psoriasis.

[0706] 90. A method for treating psoriasis, comprising administering to a subject in need thereof a therapeutically effective amount of TIFF2026501324000173.tif58165 or a tautomer, stereoisomer or mixture of stereoisomers, pharmaceutically acceptable salt, hydrate, deuterated derivative, or N-oxide thereof, wherein upon administration of the therapeutically effective amount of the compound, tautomer, stereoisomer or mixture of stereoisomers, pharmaceutically acceptable salt, hydrate, deuterated derivative, or N-oxide thereof, a therapeutic eff...

Claims

1. A compound of formula (XI), or a pharmaceutically acceptable salt or N-oxide thereof: (In the formula, Ring A is independently selected from phenyl, 5-membered heterocyclyl, and 6-membered heterocyclyl; X ４ are independently selected from carbon and nitrogen; X ５ are independently selected from carbon and nitrogen; R １ are independently １ ~C ３ -Alkyl, C １ ~C ３ -fluoroalkyl, C ３ ~C ４ - is selected from cycloalkyl and 4-membered heterocycloalkyl; R ２ are independently １ ~C ４ -haloalkyl, ethyl, cyano, nitro, isopropyl, tert-butyl, cyclopropyl, and SF ５ is selected from R ３ are independently R ３ａ , OR ３ｂ , and N.R. ６ R ３ｂ is selected from R ３ａ are independently H, CN, C １ ~C ４ -Alkyl, C ２ ~C ４ -alkenyl, C ２ ~C ４ -alkynyl, C １ ~C ４ -haloalkyl, C ２ ~C ４ -haloalkenyl, and C ０ ~C ３ -Alkylene-R ３ｃ where R ３ｃ is, independently in each case, C ３ ~C ８ -cycloalkyl, C ５ ~C ８ - selected from cycloalkenyl, 5- to 8-membered heterocycloalkenyl, 3- to 8-membered heterocycloalkyl, phenyl, and 5- or 6-membered heteroaryl; R ３ｃ is cycloalkyl, heterocycloalkyl, cycloalkenyl, or heterocycloalkenyl, R ３ｃ is 1 to 4 R ８ may be substituted with a group, R ３ｃ is phenyl or heteroaryl, R ３ｃ is 1 to 5 R ９ may be substituted with a group, R ３ｂ are independently １ ~C ４ -Alkyl, C ２ ~C ４ -Alkylene-O-C １ ~C ４ -Alkyl, C １ ~C ４ -haloalkyl and C ０ ~C ３ -Alkylene-R ３ｄ where R ３ｄ is, independently in each case, C ３ ~C ８ - selected from cycloalkyl, 3- to 8-membered heterocycloalkyl, phenyl, and 5- or 6-membered heteroaryl; R ３ｄ When R is cycloalkyl or heterocycloalkyl, ３ｄ is 1 to 4 R ８ may be substituted with a group, R ３ｄ is phenyl or heteroaryl, R ３ｄ is 1 to 5 R ９ may be substituted with a group, R ４ is independently in each occurrence =O, =S, halo, nitro, cyano, C ０ ~C ４ -Alkylene-NR ５ R ６ , C ０ ~C ４ -Alkylene-OR ７ , S.R. ６ , SOR ６ , C ０ ~C ４ -Alkylene-S(O) ２ R ６ , S.O. ２ NR ６ R ６ , C ０ ~C ４ -Alkylene-CO ２ R ６ , C ０ ~C ４ -Alkylene-C(O)R ６ , C ０ ~C ４ -Alkylene-CONR ６ R ６ , C １ ~C ４ -Alkyl, C ２ ~C ４ -alkenyl, C ２ ~C ４ -alkynyl, C １ ~C ４ -haloalkyl, C ３ ~C ６ -cycloalkyl, and C ０ ~C ４ -Alkylene-R ４ｃ is selected from R ４ｃ is, independently in each case, C ３ ~C ６ - selected from cycloalkyl and 4- to 6-membered heterocycloalkyl; R ５ are, independently in each occurrence, H, C １ ~C ４ -alkyl, C(O)-C １ ~C ４ -Alkyl and S(O) ２ -C １ ~C ４ -alkyl or R ５ and R ６ together with the nitrogen atom to which they are attached, form one to four R ８ C optionally substituted with a group ５ ~C ８ - forming a heterocycloalkyl group, R ６ is, independently in each occurrence, H and C １ ~C ４ -alkyl, or two R ６ If groups are attached to the same nitrogen, the two R ６ The groups, together with the nitrogen atom to which they are attached, can be one to four R ８ C optionally substituted with a group ５ ~C ８ - may form a heterocycloalkyl group, R ７ are, independently in each occurrence, H, C １ ~C ４ -alkyl, C(O)-C １ ~C ４ -Alkyl and C １ ~C ４ -haloalkyl; R ８ is independently in each occurrence =O, =S, fluoro, nitro, cyano, NR ５ R ６ , OR ７ , S.R. ６ , SOR ６ , S(O) ２ R ６ , S.O. ２ NR ６ R ６ , CO ２ R ６ , C(O)R ６ , C.O.R. ６ R ６ , C １ ~C ４ -Alkyl, C ２ ~C ４ -alkenyl, C ２ ~C ４ -alkynyl, C １ ~C ４ - selected from haloalkyl and cyclopropyl, R ９ is independently in each occurrence halo, nitro, cyano, C ０ ~C ４ -Alkylene-NR ５ R ６ , C ０ ~C ４ -Alkylene-OR ７ａ , C ０ ~C ４ -Alkylene-SR ６ , C ０ ~C ４ -Alkylene-SOR ６ , C ０ ~C ４ -Alkylene-S(O) ２ R ６ , C ０ ~C ４ -Alkylene-SO ２ NR ６ R ６ , C ０ ~C ４ -Alkylene-CO ２ R ６ , C ０ ~C ４ -Alkylene-C(O)R ６ , C ０ ~C ４ -Alkylene-CONR ６ R ６ , C ０ ~C ４ -Alkylene-R ９ａ , C １ ~C ４ -Alkyl, C ２ ~C ４ -alkenyl, C ２ ~C ４ -alkynyl, C １ ~C ４ -haloalkyl, or two R ９ When groups are attached to adjacent atoms, the two R ９ The groups, together with the atoms to which they are attached, can consist of one to four R ８ may form a 5- or 6-membered heterocycloalkyl group optionally substituted by a group, R ７ａ are, independently in each occurrence, H, C １ ~C ４ -alkyl, C(O)-C １ ~C ４ -Alkyl, C ０ ~C ４ -Alkylene-NR ５ R ６ , -C ０ ~C ４ -Alkyl-O-R ７ , C ０ ~C ４ -Alkylene-SR ６ , C ０ ~C ４ -Alkylene-SOR ６ , C ０ ~C ４ -Alkylene-S(O) ２ R ６ , C ０ ~C ４ -Alkylene-SO ２ NR ６ R ６ , C ０ ~C ４ -Alkylene-CO ２ R ６ , C ０ ~C ４ -Alkylene-C(O)R ６ , C ０ ~C ４ -Alkylene-CONR ６ R ６ and C １ ~C ４ -haloalkyl; R ９ａ is, independently in each case, C ３ ~C ６ - selected from cycloalkyl and 4- to 6-membered heterocycloalkyl; R １０ independently in each occurrence, halo, C １ ~C ４ -Alkyl, C １ ~C ４ -haloalkyl, nitro, cyano, NR ５ R ６ , OR ７ , S.R. ６ , SOR ６ , S(O) ２ R ６ , S.O. ２ NR ６ R ６ , CO ２ R ６ , C(O)R ６ , C.O.R. ６ R ６ , C １ ~C ４ -Alkyl, C ２ ~C ４ -alkenyl, C ２ ~C ４ - selected from alkynyl and 4-membered heterocycloalkyl; R ｘ and R ｙ are each independently H, halo, nitro, cyano, NR ５ R ６ , OR ７ , S.R. ６ , SOR ６ , S(O) ２ R ６ , S.O. ２ NR ６ R ６ , CO ２ R ６ , C(O)R ６ , C.O.R. ６ R ６ , C １ ~C ４ -Alkyl, C ２ ~C ４ -alkenyl, C ２ ~C ４ -alkynyl, C １ ~C ４ -haloalkyl, C ３ ~C ４ - is selected from cycloalkyl and 4-membered heterocycloalkyl; m is an integer selected from 0, 1, 2, 3 and 4; n １７ is an integer selected from 0, 1 and 2, Any of the foregoing alkyl, alkylene, alkenyl, cycloalkyl or heterocycloalkyl groups may, independently in each case, be selected from the group consisting of C, ... １ ~C ４ - alkyl, oxo, fluoro, nitro, cyano, NR ａ R ｂ , OR ａ , S.R. ａ , CO ２ R ａ , C(O)R ａ , C.O.R. ａ R ａ , S(O)R ａ and S(O) ２ R ａ and optionally substituted with 1 to 5 substituents selected from the group consisting of: ａ are, independently in each occurrence, H, C １ ~C ４ -Alkyl and C １ ~C ４ -haloalkyl, R ｂ are, independently in each occurrence, H, C １ ~C ４ -alkyl, C(O)-C １ ~C ４ -Alkyl and S(O) ２ -C １ ~C ４ -alkyl).

2. R ２ But C １ ~C ４ The compound of claim 1, wherein the aryl group is -haloalkyl.

3. R ｘ The compound of claim 1 or claim 2, wherein is H.

4. X ４ The compound according to any one of claims 1 to 3, wherein is carbon.

5. R １ The compound according to any one of claims 1 to 4, wherein is selected from methyl and ethyl.

6. R ２ But CF ３ The compound according to any one of claims 1 to 5,

7. n １７ The compound according to any one of claims 1 to 6, wherein is 0.

8. The compound according to any one of claims 1 to 7, wherein ring A is a pyridone.

9. Ring A has H, C at the nitrogen １ ~C ４ 9. The compound of claim 8, wherein the compound is substituted with one group selected from -alkyl, cyclopropyl, cyclobutyl, methyl-cyclobutyl, and 4-membered heterocycloalkyl.

10. Ring A is where R ４ａ is H, C １ ~C ４ 10. The compound of claim 9, wherein the aryl group is selected from -alkyl, cyclopropyl, and 4-membered heterocycloalkyl.

11. R ４ａ Methyl, cyclopropyl, oxetane, -CH ２ -CH ２ The compound of claim 10, wherein the compound is selected from -OMe and azetidine.

12. R ３ But, R ３ａ The compound according to any one of claims 1 to 11,

13. R ３ａ However, 1 to 3 R ９ The compound of claim 12, which is a phenyl optionally substituted with a group.

14. R ｙ The compound according to any one of claims 1 to 13, wherein is H.

15. R ｙ The compound of any one of claims 1 to 13, wherein is halo.

16. The compound of claim 1, or a pharmaceutically acceptable salt or N-oxide thereof, selected from:

17. The compound of claim 1, or a pharmaceutically acceptable salt or N-oxide thereof, selected from:

18. 10. A pharmaceutical composition comprising the compound of claim 1 or a pharmaceutically acceptable salt or N-oxide thereof, and one or more pharmaceutically acceptable excipients.

19. 10. A method for treating a disease or disorder selected from one or more of an inflammatory disease or disorder, an immune disease or disorder, and an autoimmune disease or disorder, comprising administering to a warm-blooded animal a therapeutically effective amount of the compound of claim 1, or a pharmaceutically acceptable salt or N-oxide thereof.

20. 20. The method of claim 19, wherein the disease or disorder is a joint disease or disorder or a joint-related disease or disorder.

21. 21. The method of claim 19 or 20, wherein the disease or disorder is selected from arthritis, bursitis, Ehlers-Danlos syndrome, epicondylitis, Felty's syndrome, gouty arthritis, psoriatic arthritis, osteoarthritis, rheumatoid arthritis, Still's disease, tenosynovitis, synovitis, Sjogren's syndrome, Lyme disease, Whipple's disease, bone cancer, lupus, and other autoimmune joint disorders.

22. 21. The method of claim 20, wherein the joint disease or disorder or the joint-related disease or disorder is arthritis.

23. 23. The method of claim 22, wherein the arthritis is rheumatoid arthritis.

24. 20. The method of treatment of claim 19, wherein the disease or disorder is a fibrotic disease or disorder.

25. 25. The method of treatment of claim 19 or 24, wherein the disease or disorder is renal fibrosis.

26. 25. The method of treatment of claim 19 or 24, wherein the disease or disorder is pulmonary fibrosis.

27. 20. The method of treatment of claim 19, wherein the disease or disorder is a skin disease or disorder.

28. 30. The method of treatment of claim 19 or 27, wherein the disease or disorder is psoriasis.

29. 20. The method of claim 19, wherein the disease or disorder is a lupus disease or disorder.

30. 20. The method of claim 19, wherein the disease or disorder is MS or an MS-related disease or disorder.

31. The method of any one of claims 19 to 30, wherein the severity of the disease or disorder is reduced.

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