Phthalazine derivatives as pyruvate kinase modulators

Abstract

The present invention relates to a compound of formula (I) which is 6-((1H-pyrazol-4-yl)sulfonyl)-2-((1-cyclopropyl-1H-pyrazol-3-yl)methyl)phthalazin-1(2H)-one [Formula 1] or a salt and / or solvate thereof; and its use in the treatment or prevention of an inflammatory disease, a disease associated with an unwanted immune response, cancer, obesity, a diabetic disease, or a blood disorder.

Description

[Technical field]

[0001] FIELD OF THEINVENTION The present invention relates to compounds and their use in the treatment or prevention of inflammatory diseases, diseases associated with an unwanted immune response, cancer, obesity, diabetic diseases, or blood disorders, as well as related compositions, methods, and intermediate compounds. [Background technology]

[0002] BACKGROUND OF THEINVENTION Pyruvate kinase (PK) is the final rate-limiting enzyme in glycolysis, catalyzing the conversion of phosphoenolpyruvate (PEP) and ADP to pyruvate and ATP. In mammals, there are four PK isoforms derived from two separate genes (Alves-Filho et al., 2016). The products of the Pklr gene, PKL and PKR, are expressed in the liver and erythrocytes, respectively. PKM1 and 2 are alternatively spliced ​​products of the Pkm gene. PKM1 is expressed in tissues with high energy demands, such as the heart, muscle, and brain, whereas PKM2 is expressed in embryonic tissues, cancer cells, and normal proliferating cells, such as lymphocytes and intestinal epithelial cells. PKM1 is a constitutively active enzyme, whereas PKM2 is a low activity enzyme that depends on allosteric activation by multiple endogenous regulators, including the upstream glycolytic intermediate fructose-1,6-bisphosphate (FBP). The binding of these allosteric regulators induces a conformational change that promotes tetramerization of PKM2, resulting in an increase in the final rate-limiting step of glycolysis. Pyruvate enters the TCA cycle in mitochondria, where it is used to generate ATP by oxidative phosphorylation. In the absence of allosteric activation, PKM2 adopts a dimeric or monomeric form with low enzymatic activity, leading to the accumulation of glycolytic intermediates that meet the demand for biosynthetic precursors in activated or proliferating cells. Dimeric PKM2 can also translocate to the nucleus, where it can further promote aerobic glycolysis and regulate transcriptional activity, acting as a protein kinase that targets transcription factors and histones.

[0003] Cancer cells primarily utilize glycolysis to generate cellular energy and biosynthetic intermediates (termed the Warburg effect), and PKM2 plays a dominant role in glycolysis to achieve the nutritional demands of cancer cell growth (Chhipa et al., 2018). PKM2 is overexpressed in almost all cancers and has been shown to promote tumor cell proliferation and metastasis. In addition to controlling glycolytic flux, this non-metabolic role of PKM2 as a coactivator and protein kinase contributes to tumorigenesis (Dong et al., 2016). PKM2 directly binds to and phosphorylates histone H3, leading to the expression of c-Myc and Cyclin D1 and the proliferation of cancer cells. Activation of PKM2 tetramers by small molecules could be an attractive therapy to halt tumor growth by interfering with the non-metabolic functions of dimeric PKM2 in cancer.

[0004] Following activation or inflammatory stimuli, PKM2 is upregulated in many immune cells, including macrophages and T cells (Palsson-McDermott et al., 2020). A non-metabolic role of dimeric PKM2 has been shown to regulate immune responses; namely, PKM2 acts as a transcriptional coactivator of Hif-1α, b-catenin, and STAT3, leading to the expression of pro-inflammatory cytokines such as IL-1β and TNFα. Activating PKM2 by small molecules to prevent nuclear translocation may have therapeutic benefit in a range of inflammatory and autoimmune conditions, such as rheumatoid arthritis, inflammatory bowel disease, inflammatory skin conditions, coronary artery disease, and multiple sclerosis.

[0005] In diabetes, PKM2 regulates glucose-responsive pancreatic β-cell function and prevents metabolic stress (Abulizi et al., 2020; Lewandowski et al., 2020). Dimeric PKM2 plays a role in abnormal glycolysis by promoting HIF-1α accumulation, and in diabetic nephropathy, PKM2 has been implicated in a pathogenic role in glomerular injury and epithelial-mesenchymal transition leading to fibrosis (Liu et al., 2020). PKM2 activation has been shown to increase insulin release, improve insulin sensitivity, and prevent the progression of diabetic glomerular symptoms and renal fibrosis (Liu et al., 2020; Abulizi et al., 2020; Lewandowski et al., 2020; Qi et al., 2017).

[0006] Obesity is defined as abnormal or excessive adiposity that presents a risk to health and has been associated with increased incidence of type 2 diabetes and cardiovascular disease. This metabolic disorder is strongly associated with insulin resistance and detrimental effects on glucose metabolism and processing in obese subjects (Barazzoni et al., 2018). Studies on 3T3-L1 adipocytes exposed to different levels of insulin resulted in a significant increase in PKM2 mRNA levels independent of the level of glucose in the medium (Puckett et al., 2021). Studies on the effects of altered PKM2 phosphorylation status and the resulting reduced catalytic activity have confirmed that PKM2 is a likely contributor to insulin resistance in adipose tissue and linked it to metabolic conditions in humans (Bettaieb et al., 2013). Restoring PKM2 activity with small molecule allosteric activators has been shown to improve insulin sensitivity (Abulizi 2020; Lewandowski 2020), justifying further investigation as a novel target for pharmacological intervention in obesity.

[0007] Pyruvate kinase deficiency (PKD) is one of the most common enzyme defects in red blood cells, which manifests as hemolytic anemia, the accelerated destruction of red blood cells (Bianchi et al., 2020). Mature red blood cells are entirely dependent on glycolysis to maintain cellular integrity and function, and pyruvate kinase therefore plays a pivotal role in red blood cell metabolism and survival. Inherited mutations in the PKR enzyme lead to dysregulation of its catalytic activity, causing a deficiency of cellular energy within red blood cells, as evidenced by reduced pyruvate kinase enzyme activity, reduced ATP levels, and accumulation of upstream metabolites. Reduced PKR activity has also been associated with changes in red blood cell morphology and cell membrane surface, suggesting a broader involvement of this enzyme in the overall lifespan of this cell (Cancado et al., 2018). PK-deficient red blood cells are prematurely removed from the circulation through accelerated hemolysis by the spleen, resulting in the accumulation of iron. Increasing and / or restoring PKR activity to subbasal levels is believed to have the potential to treat PK deficiency-related complications. The current standard of care for PKD is supportive, including blood transfusions, splenectomy, chelation therapy to address iron overload, and / or other therapeutic and disease-related interventions for pathologies. There are no approved therapies to treat the underlying cause of PK deficiency. Activation of the PKR enzyme with a small molecule allosteric activator increased PK enzyme activity and enhanced glycolysis in red blood cells from patients with PK deficiency (Kung et al., 2017).

[0008] Pharmacological interventions using small molecule agonists such as TEPP-46 and DASA-58 have been widely utilized in in vitro and in vivo biological settings, showing some potential benefits offered by enhancing PK activity through allosteric modulation (Yi et al., 2021). Although these compounds have demonstrated good levels of in vitro activity, their ADME and pharmacokinetic / pharmacodynamic profiles have prevented them from being developed for the treatment of human disease. The structure of TEPP-46 is as follows: [ka] As stated above.

[0009] The most advanced PK activator that has been extensively tested in clinical practice is mitapivat (AG-348), a PKM2 and PKLR activator that is being investigated for the treatment of several blood disorders resulting from PK mutant forms that exhibit lower catalytic activity than the corresponding wild-type erythrocytes (Kung et al., 2017). The drug has shown a reasonable level of efficacy by increasing basal hemoglobin levels when administered to patients exhibiting PK deficiency. However, despite this promising result, the high dose regimen and BID (twice daily) dosing frequency required to achieve efficacy highlight the need to develop more effective compounds with more favorable pharmacokinetic and improved safety profiles (Grace et al., 2019). The structure of mitapivat is: [ka]

[0010] WO2020 / 167976A1 (Agios Pharmaceuticals) describes compounds for the treatment of cancer, obesity, and diabetes-related disorders that are said to modulate PK activity.

[0011] There remains a need to identify and develop novel disease-modifying PK modulators that meet several unmet medical needs associated with PK dysfunction, in particular to develop compounds that exhibit suitable activity while possessing favorable physical and chemical parameters. The compounds described herein as PK modulators, in particular PKM2 and / or PKLR modulators, in particular PKM2 and / or PKLR activators, address the above-mentioned unmet needs by exhibiting suitable affinity and functional activity for PK enzymes, in particular PKM2 and / or PKLR, while possessing better overall physical / chemical properties with improved ADME and PK profiles, making them suitable for the treatment of human diseases associated with functional alterations in the expression and / or activity of pyruvate kinase enzyme. Summary of the Invention

[0012] (Summary of the invention) The present invention relates to a compound of formula (I): 6-((1H-pyrazol-4-yl)sulfonyl)-2-((1-cyclopropyl-1H-pyrazol-3-yl)methyl)phthalazin-1(2H)-one: [ka] or a salt and / or solvate thereof. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0013] Detailed Description of the Invention The embodiments and preferences described herein for compounds of formula (I) apply equally to the pharmaceutical compositions, compounds for use, uses, methods and process aspects of the invention.

[0014] 6-((1H-pyrazol-4-yl)sulfonyl)-2-((1-cyclopropyl-1H-pyrazol-3-yl)methyl)phthalazin-1(2H)-one, formula (I): [ka] The compound of formula (1) is provided.

[0015] Compounds of formula (I) may be synthesized as shown in the Examples section below.

[0016] In particular, the compound of formula (II): [ka] or a salt (eg, a pharma- ceutically acceptable salt) and / or solvate thereof.

[0017] Also, the formula (III): [ka] or a salt (eg, a pharma- ceutically acceptable salt) and / or solvate thereof.

[0018] Also, the formula (IV): [ka] or a salt (eg, a pharma- ceutically acceptable salt) and / or solvate thereof.

[0019] Also, the formula (V): [ka] or a salt (eg, a pharma- ceutically acceptable salt) and / or solvate thereof.

[0020] Also, the formula (II): [ka] Also provided is a process for the preparation of a compound of formula (I) or a salt (e.g., a pharma- ceutically acceptable salt) and / or solvate thereof as described herein, comprising oxidizing the compound of formula (I) or a salt (e.g., a pharma-ceutically acceptable salt) and / or solvate thereof.

[0021] Also, the formula (IV): [ka] or a salt (e.g., a pharma- ceutically acceptable salt) and / or solvate thereof, wherein under oxidation conditions, the tetrahydropyran ring is removed.

[0022] Those skilled in the art will recognize that protecting groups can be used throughout the synthetic schemes described herein to obtain protected derivatives of any of the above compounds. Protective groups and procedures for their removal are described in "Protective Groups in Organic Synthesis" by Theodora W. Greene and Peter GM Wuts, published by John Wiley & Sons, Inc., 4th Revised Edition, 2006, ISBN-10: 0471697540. Examples of nitrogen protecting groups include trityl (Tr), tert-butyloxycarbonyl (Boc), 9-fluorenylmethyloxycarbonyl (Fmoc), acetyl (Ac), benzyl (Bn), and para-methoxybenzyl (PMB). Examples of oxygen protecting groups include acetyl (Ac), methoxymethyl (MOM), para-methoxybenzyl (PMB), benzyl, tert-butyl, methyl, ethyl, tetrahydropyranyl (THP), and silyl ethers and esters, such as trimethylsilyl (TMS), tert-butyldimethylsilyl (TBDMS), tri-isopropylsilyloxymethyl (TOM), and triisopropylsilyl (TIPS) ethers and esters. Specific examples of carboxylic acid protecting groups include alkyl esters (C 1-6 Alkyl, e.g., C 1-4 alkyl esters), benzyl esters, and silyl esters.

[0023] It will be appreciated that for use in therapy, the salts of the compounds of formula (I) should be pharma- ceutically acceptable. Suitable pharma-ceutically acceptable salts will be apparent to those skilled in the art. Pharmaceutically acceptable salts include acid addition salts, preferably salts of the compounds of the invention containing a basic group, such as an amino group, formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, or phosphoric acid. Also included are salts formed with organic acids, such as succinic acid, maleic acid, acetic acid, fumaric acid, citric acid, tartaric acid, benzoic acid, p-toluenesulfonic acid, methanesulfonic acid, naphthalenesulfonic acid, and 1,5-naphthalenedisulfonic acid. Other salts, such as oxalates or formates, may be used, for example, in the isolation of the compounds of formula (I), and are also included within the scope of the present invention, as are basic addition salts, such as sodium, potassium, calcium, aluminum, zinc, magnesium, and other metal salts.

[0024] Pharmaceutically acceptable salts can also be formed with organic bases such as basic amines, for example, ammonia, meglumine, tromethamine, piperazine, arginine, choline, diethylamine, benzathine, or lysine.

[0025] In one embodiment, the compound of formula (I) is provided in the form of a salt, such as a pharma- ceutical acceptable salt. Alternatively, the compound of formula (I) is provided in the form of a free acid. When a compound contains a basic group and a free acid, it can be a zwitterion.

[0026] Suitably the compound of formula (I) is not in the form of a salt, for example not in the form of a pharma- ceutical acceptable salt.

[0027] Suitably, when the compound of formula (I) is in the form of a salt, the pharma- ceutical acceptable salt is an acid addition salt, such as an ammonium salt (formed, for example, with an inorganic acid, such as HCl).

[0028] The compounds of formula (I) may be prepared in crystalline or non-crystalline form and, if crystalline, may optionally be solvated, for example as hydrates. The invention includes within its scope stoichiometric solvates (e.g. hydrates) and solvates containing variable amounts of solvent (e.g. water). Suitably, the compounds of formula (I) are not solvated, such as pharma- ceutically acceptable solvates.

[0029] In one embodiment, there is provided a compound of formula (I) in the form of a solvate, such as a pharma-ceutically acceptable solvate.

[0030] The present invention extends to pharma- ceutical acceptable derivatives of the compound of formula (I), such as pharma- ceutical acceptable prodrugs.Thus, in one embodiment, the compound of formula (I) is provided as a pharma- ceutical acceptable prodrug.In another embodiment, the compound of formula (I) is not provided as a pharma- ceutical acceptable prodrug.

[0031] It is to be understood that the present invention encompasses all isomeric forms of the compounds of formula (I). In particular, the present invention extends to all tautomeric forms of the compounds of formula (I).

[0032] The present invention also includes all isotopic forms of the compounds provided herein, whether (i) all atoms of a given atomic number have a mass number (or mixture of mass numbers) that is predominant in nature (referred to herein as "natural isotopic forms"), or (ii) one or more atoms are replaced by an atom having the same atomic number but a mass number different from the mass number of the atom that is predominant in nature (referred to herein as "non-natural variant isotopic forms"). It is understood that atoms may naturally occur as a mixture of mass numbers. The term "non-natural variant isotopic forms" also includes embodiments in which the proportion of atoms of a given atomic number that have mass numbers that are less commonly found in nature (referred to herein as "rare isotopes") is increased compared to that occurring in nature, for example, to a level of >20%, >50%, >75%, >90%, >95%, or >99% of the number of atoms of that atomic number (the latter embodiment is referred to as "isotopically enriched variant forms"). The term "non-natural variant isotopic form" also includes embodiments in which the ratio of rare isotopes is reduced compared to that occurring in nature. Isotopic forms can include radioactive forms (i.e., which incorporate a radioactive isotope) and non-radioactive forms. The radioactive form will usually be an isotopically enriched variant form.

[0033] Thus, non-natural variant isotopic forms of a compound may contain deuterium ( 2 H or D), carbon-11 ( 11 C), carbon-13( 13 C), carbon-14( 14 C), nitrogen-13( 13 N), nitrogen-15( 15 N), oxygen-15( 15 O), oxygen-17( 17 O), oxygen-18( 18 O), phosphorus-32( 32 P), sulfur-35( 35 S), Chlorine-36( 36 Cl), Chlorine-37( 37 Cl), Fluorine-18( 18 F), iodine-123( 123I), iodine-125( 125 I), or may contain an increased proportion of said isotopes at one or more atoms compared to the proportion predominant in nature.

[0034] Non-natural variant isotopic forms containing radioactive isotopes may be used, for example, in drug and / or substrate tissue distribution studies. The radioactive isotope tritium, i.e. 3 H, and carbon-14, i.e. 14 C are particularly useful for this purpose given their ease of incorporation and ready means of detection. Deuterium, i.e. 2 Non-natural variant isotopic forms incorporating H or D may offer certain therapeutic advantages due to greater metabolic stability, e.g., increased in vivo half-life or reduced dosage requirements, and therefore may be preferred in certain circumstances. Additionally, 11 C. 18 F, 15 O, and 13 Non-natural variant isotopic forms can be prepared that incorporate positron emitting isotopes, such as N, which may be useful for positron emission tissue distribution (PET) studies to examine substrate receptor occupancy.

[0035] In one embodiment, the compound of formula (I) is provided in natural isotopic form. In one embodiment, the compound of formula (I) is provided in non-natural variant isotopic form. In a specific embodiment, the non-natural variant isotopic form is a form in which one or more atoms of the compound of formula (I) have deuterium (i.e., 2 In one embodiment, the atom of the compound of formula (I) is in a non-radioactive isotopic form. In one embodiment, one or more atoms of the compound of formula (I) are in a radioactive isotopic form. Preferably, the radioisotope is a stable isotope. Preferably, the non-natural variant isotopic form is a medicamentously acceptable form.

[0036] In one embodiment, compounds of formula (I) are provided in which a single atom of the compound is present in a non-natural variant isotopic form. In another embodiment, compounds of formula (I) are provided in which two or more atoms are present in a non-natural variant isotopic form.

[0037] Non-natural isotopically variant forms can generally be prepared by conventional techniques known to those skilled in the art or by methods described herein, for example, methods similar to those described in the accompanying examples for preparing natural isotopically variant forms. Thus, non-natural isotopically variant forms can be prepared by substituting appropriate isotopically variant (or labeling) reagents for the conventional reagents employed in the examples. It will be readily understood that since the compounds of formula (I) are intended for use in pharmaceutical compositions, they are each preferably provided in substantially pure form, for example at least 60% pure, more preferably at least 75% pure, and preferably at least 85%, especially at least 98% pure (percentages are on a weight-to-weight basis). Impure preparations of the compounds may be used to prepare the purer forms used in pharmaceutical compositions.

[0038] (Therapeutic efficacy) The compounds of formula (I) are for use in therapy, in particular for treating or preventing inflammatory diseases, diseases associated with undesired immune responses, cancer, obesity, diabetic diseases, or blood disorders. As shown in Biological Example 1 below, Example 1 showed improved PKM2 modulator activity compared to mitapivat. As shown in Biological Example 2 below, Example 1 also showed improved PKLR modulator activity, again using mitapivat as a control. As shown in Biological Example 3 below, Example 1 also showed improved pyruvate kinase activity in a CD4+ T cell pyruvate kinase assay, again using mitapivat as a control.

[0039] Thus, in a further aspect, the present invention provides a compound of formula (I) as defined herein or a pharma- ceutically acceptable salt and / or solvate thereof for use as a medicament. There is also provided a pharmaceutical composition comprising a compound of formula (I) as defined herein or a pharma- ceutically acceptable salt and / or solvate thereof. Such a pharmaceutical composition comprises a compound of formula (I) and one or more pharma- ceutically acceptable diluents or carriers.

[0040] In a further aspect, the present invention provides a compound of formula (I) or a pharma- ceutically acceptable salt and / or solvate thereof as defined herein for use in the treatment or prevention of a disease, disorder or condition associated with the function of PK, in particular PKM2 and / or PKLR. In a further aspect, the present invention provides the use of a compound of formula (I) or a pharma- ceutically acceptable salt and / or solvate thereof as defined herein in the manufacture of a medicament for the treatment or prevention of a disease, disorder or condition associated with the function of PK, in particular PKM2 and / or PKLR. In a further aspect, the present invention provides a method for the treatment or prevention of a disease, disorder or condition associated with the function of PK, in particular PKM2 and / or PKLR, comprising administering a compound of formula (I) or a pharma- ceutically acceptable salt and / or solvate thereof as defined herein.

[0041] In a further aspect, the present invention provides a compound of formula (I) or a pharma- ceutically acceptable salt and / or solvate thereof as defined herein for use in the treatment or prevention of symptoms associated with a disease, disorder or condition associated with the function of PK, in particular PKM2 and / or PKLR. In a further aspect, the present invention provides the use of a compound of formula (I) or a pharma- ceutically acceptable salt and / or solvate thereof as defined herein in the manufacture of a medicament for the treatment or prevention of symptoms associated with a disease, disorder or condition associated with the function of PK, in particular PKM2 and / or PKLR. In a further aspect, the present invention provides a method for the treatment or prevention of symptoms associated with a disease, disorder or condition associated with the function of PK, in particular PKM2 and / or PKLR, comprising administering a compound of formula (I) or a pharma- ceutically acceptable salt and / or solvate thereof as defined herein.

[0042] In one embodiment, the compound of formula (I) is a modulator of PKM2. In another embodiment, the compound of formula (I) is an activator of PKM2. In one embodiment, the compound of formula (I) is a modulator of PKLR. In another embodiment, the compound of formula (I) is an activator of PKLR. A compound is an "activator" of PK (e.g., PKM2 and / or PKLR) if it increases the activity of the enzyme, which can be quantified, for example, by determining the concentration of ATP produced in a suitable assay (such as Biological Example 1 for PKM2 and Biological Example 2 for PKLR).

[0043] In a further aspect, the present invention provides a compound of formula (I) or a pharma- ceutically acceptable salt and / or solvate thereof as defined herein for use in the treatment or prevention of an inflammatory disease, a disease associated with an undesired immune response, cancer, obesity, a diabetic disease, or a blood disorder. In a further aspect, the present invention provides the use of a compound of formula (I) or a pharma- ceutically acceptable salt and / or solvate thereof as defined herein in the manufacture of a medicament for treating or preventing an inflammatory disease, a disease associated with an undesired immune response, cancer, obesity, a diabetic disease, or a blood disorder. In a further aspect, the present invention provides a method for treating or preventing an inflammatory disease, a disease associated with an undesired immune response, cancer, obesity, a diabetic disease, or a blood disorder comprising administering a compound of formula (I) or a pharma- ceutically acceptable salt and / or solvate thereof as defined herein.

[0044] In a further aspect, the present invention provides a compound of formula (I) as defined herein or a pharma- ceutically acceptable salt and / or solvate thereof for use in the treatment or prevention of an inflammatory disease, a disease associated with an undesired immune response, cancer, obesity, a diabetic disease, or a condition associated with a blood disorder. In a further aspect, the present invention provides the use of a compound of formula (I) as defined herein or a pharma- ceutically acceptable salt and / or solvate thereof in the manufacture of a medicament for the treatment or prevention of an inflammatory disease, a disease associated with an undesired immune response, cancer, obesity, a diabetic disease, or a condition associated with a blood disorder. In a further aspect, the present invention provides a method for the treatment or prevention of an inflammatory disease, a disease associated with an undesired immune response, cancer, obesity, a diabetic disease, or a condition associated with a blood disorder comprising administering a compound of formula (I) as defined herein or a pharma- ceutically acceptable salt and / or solvate thereof.

[0045] For all aspects of the invention, preferably the compound is administered to a subject in need thereof, which is preferably a human subject.

[0046] In one embodiment, there is provided a compound of formula (I) or a pharma- ceutically acceptable salt and / or solvate thereof as defined herein for use in the treatment of inflammatory diseases, diseases associated with undesired immune responses, cancer, obesity, diabetic diseases, or blood disorders.In one embodiment of the present invention, there is provided the use of a compound of formula (I) or a pharma- ceutically acceptable salt and / or solvate thereof as defined herein in the manufacture of a medicament for treating inflammatory diseases, diseases associated with undesired immune responses, cancer, obesity, diabetic diseases, or blood disorders.In one embodiment of the present invention, there is provided a method for treating inflammatory diseases, diseases associated with undesired immune responses, cancer, obesity, diabetic diseases, or blood disorders, comprising administering a compound of formula (I) or a pharma- ceutically acceptable salt and / or solvate thereof as defined herein.

[0047] In one embodiment, there is provided a compound of formula (I) as defined herein or a pharma- ceutically acceptable salt and / or solvate thereof for use in the treatment of inflammatory diseases, diseases associated with undesired immune responses, cancer, obesity, diabetic diseases, or conditions associated with blood disorders. In one embodiment of the present invention, there is provided the use of a compound of formula (I) as defined herein or a pharma- ceutically acceptable salt and / or solvate thereof in the manufacture of a medicament for treating inflammatory diseases, diseases associated with undesired immune responses, cancer, obesity, diabetic diseases, or conditions associated with blood disorders. In one embodiment of the present invention, there is provided a method of treating inflammatory diseases, diseases associated with undesired immune responses, cancer, obesity, diabetic diseases, or conditions associated with blood disorders, comprising administering a compound of formula (I) as defined herein or a pharma- ceutically acceptable salt and / or solvate thereof.

[0048] In one embodiment, there is provided a compound of formula (I) as defined herein or a pharma- ceutically acceptable salt and / or solvate thereof for use in the prophylaxis of inflammatory diseases, diseases associated with undesired immune responses, cancer, obesity, diabetic diseases, or blood disorders.In one embodiment of the present invention, there is provided a use of a compound of formula (I) as defined herein or a pharma- ceutically acceptable salt and / or solvate thereof in the manufacture of a medicament for the prophylaxis of inflammatory diseases, diseases associated with undesired immune responses, cancer, obesity, diabetic diseases, or blood disorders.In one embodiment of the present invention, there is provided a method for the prophylaxis of inflammatory diseases, diseases associated with undesired immune responses, cancer, obesity, diabetic diseases, or blood disorders, comprising administering a compound of formula (I) as defined herein or a pharma- ceutically acceptable salt and / or solvate thereof.

[0049] In one embodiment, there is provided a compound of formula (I) as defined herein or a pharma- ceutically acceptable salt and / or solvate thereof for use in the prophylaxis of inflammatory diseases, diseases associated with undesired immune responses, cancer, obesity, diabetic diseases, or conditions associated with blood disorders.In one embodiment of the present invention, there is provided the use of a compound of formula (I) as defined herein or a pharma- ceutically acceptable salt and / or solvate thereof in the manufacture of a medicament for the prophylaxis of inflammatory diseases, diseases associated with undesired immune responses, cancer, obesity, diabetic diseases, or conditions associated with blood disorders.In one embodiment of the present invention, there is provided a method for the prophylaxis of inflammatory diseases, diseases associated with undesired immune responses, cancer, obesity, diabetic diseases, or conditions associated with blood disorders, comprising administering a compound of formula (I) as defined herein or a pharma- ceutically acceptable salt and / or solvate thereof.

[0050] In one embodiment, there is provided a compound of formula (I) as defined herein or a pharma- ceutically acceptable salt and / or solvate thereof for use in treating or preventing inflammatory disease.In one embodiment of the present invention, there is provided a use of a compound of formula (I) as defined herein or a pharma- ceutically acceptable salt and / or solvate thereof in the manufacture of a medicament for treating or preventing inflammatory disease.In one embodiment of the present invention, there is provided a method for treating or preventing inflammatory disease, comprising administering a compound of formula (I) as defined herein or a pharma- ceutically acceptable salt and / or solvate thereof.

[0051] In one embodiment, there is provided a compound of formula (I) as defined herein or a pharma- ceutically acceptable salt and / or solvate thereof for use in treating or preventing symptoms associated with inflammatory disease.In one embodiment of the present invention, there is provided the use of a compound of formula (I) as defined herein or a pharma- ceutically acceptable salt and / or solvate thereof in the manufacture of a medicament for treating or preventing symptoms associated with inflammatory disease.In one embodiment of the present invention, there is provided a method for treating or preventing symptoms associated with inflammatory disease, comprising administering a compound of formula (I) as defined herein or a pharma- ceutically acceptable salt and / or solvate thereof.

[0052] In one embodiment, there is provided a compound of formula (I) as defined herein or a pharma- ceutically acceptable salt and / or solvate thereof for use in treating or preventing inflammation associated with inflammatory disease.In one embodiment of the present invention, there is provided a use of a compound of formula (I) as defined herein or a pharma- ceutically acceptable salt and / or solvate thereof in the manufacture of a medicament for treating or preventing inflammation associated with inflammatory disease.In one embodiment of the present invention, there is provided a method for treating or preventing inflammation associated with inflammatory disease, comprising administering a compound of formula (I) as defined herein or a pharma- ceutically acceptable salt and / or solvate thereof.

[0053] In one embodiment, there is provided a compound of formula (I) as defined herein or a pharma- ceutically acceptable salt and / or solvate thereof for use in the treatment or prevention of a disease associated with an undesired immune response.In one embodiment of the invention, there is provided the use of a compound of formula (I) as defined herein or a pharma- ceutically acceptable salt and / or solvate thereof in the manufacture of a medicament for the treatment or prevention of a disease associated with an undesired immune response.In one embodiment of the invention, there is provided a method for the treatment or prevention of a disease associated with an undesired immune response comprising administering a compound of formula (I) as defined herein or a pharma- ceutically acceptable salt and / or solvate thereof.

[0054] In one embodiment, there is provided a compound of formula (I) as defined herein or a pharma- ceutically acceptable salt and / or solvate thereof for use in the treatment or prevention of a condition associated with a disease associated with an undesired immune response. In one embodiment of the invention, there is provided the use of a compound of formula (I) as defined herein or a pharma- ceutically acceptable salt and / or solvate thereof in the manufacture of a medicament for the treatment or prevention of a condition associated with a disease associated with an undesired immune response. In one embodiment of the invention, there is provided a method for the treatment or prevention of a condition associated with a disease associated with an undesired immune response comprising administering a compound of formula (I) as defined herein or a pharma- ceutically acceptable salt and / or solvate thereof.

[0055] In one embodiment, there is provided a compound of formula (I) as defined herein or a pharma- ceutically acceptable salt and / or solvate thereof for use in treating or preventing inflammation associated with a disease associated with an undesired immune response.In one embodiment of the present invention, there is provided a use of a compound of formula (I) as defined herein or a pharma- ceutically acceptable salt and / or solvate thereof in the manufacture of a medicament for treating or preventing inflammation associated with a disease associated with an undesired immune response.In one embodiment of the present invention, there is provided a method for treating or preventing inflammation associated with a disease associated with an undesired immune response, comprising administering a compound of formula (I) as defined herein or a pharma- ceutically acceptable salt and / or solvate thereof.

[0056] In one embodiment, there is provided a compound of formula (I) as defined herein or a pharma- ceutically acceptable salt and / or solvate thereof for use in treating or preventing cancer.In one embodiment of the present invention, there is provided a use of a compound of formula (I) as defined herein or a pharma- ceutically acceptable salt and / or solvate thereof in the manufacture of a medicament for treating or preventing cancer.In one embodiment of the present invention, there is provided a method for treating or preventing cancer, comprising administering a compound of formula (I) as defined herein or a pharma- ceutically acceptable salt and / or solvate thereof.

[0057] In one embodiment, there is provided a compound of formula (I) as defined herein or a pharma- ceutically acceptable salt and / or solvate thereof for use in treating or preventing a condition associated with cancer.In one embodiment of the present invention, there is provided a use of a compound of formula (I) as defined herein or a pharma- ceutically acceptable salt and / or solvate thereof in the manufacture of a medicament for treating or preventing a condition associated with cancer.In one embodiment of the present invention, there is provided a method for treating or preventing a condition associated with cancer, comprising administering a compound of formula (I) as defined herein or a pharma- ceutically acceptable salt and / or solvate thereof.

[0058] In one embodiment, there is provided a compound of formula (I) as defined herein or a pharma- ceutically acceptable salt and / or solvate thereof for use in treating or preventing obesity.In one embodiment of the invention, there is provided the use of a compound of formula (I) as defined herein or a pharma- ceutically acceptable salt and / or solvate thereof in the manufacture of a medicament for treating or preventing obesity.In one embodiment of the invention, there is provided a method for treating or preventing obesity comprising administering a compound of formula (I) as defined herein or a pharma- ceutically acceptable salt and / or solvate thereof.

[0059] In one embodiment, there is provided a compound of formula (I) as defined herein or a pharma- ceutically acceptable salt and / or solvate thereof for use in the treatment or prevention of a condition associated with obesity.In one embodiment of the invention, there is provided the use of a compound of formula (I) as defined herein or a pharma- ceutically acceptable salt and / or solvate thereof in the manufacture of a medicament for the treatment or prevention of a condition associated with obesity.In one embodiment of the invention, there is provided a method for the treatment or prevention of a condition associated with obesity, comprising administering a compound of formula (I) as defined herein or a pharma- ceutically acceptable salt and / or solvate thereof.

[0060] In one embodiment, there is provided a compound of formula (I) or a pharma- ceutically acceptable salt and / or solvate thereof as defined herein for use in the treatment or prevention of diabetic disease. In one embodiment of the invention, there is provided the use of a compound of formula (I) or a pharma- ceutically acceptable salt and / or solvate thereof as defined herein in the manufacture of a medicament for treating or preventing diabetic disease. In one embodiment of the invention, there is provided a method of treating or preventing diabetic disease comprising administering a compound of formula (I) or a pharma- ceutically acceptable salt and / or solvate thereof as defined herein.

[0061] In one embodiment, there is provided a compound of formula (I) or a pharma- ceutically acceptable salt and / or solvate thereof as defined herein for use in the treatment or prevention of symptoms associated with diabetic disease. In one embodiment of the invention, there is provided the use of a compound of formula (I) or a pharma- ceutically acceptable salt and / or solvate thereof as defined herein in the manufacture of a medicament for treating or preventing symptoms associated with diabetic disease. In one embodiment of the invention, there is provided a method for treating or preventing symptoms associated with diabetic disease comprising administering a compound of formula (I) or a pharma- ceutically acceptable salt and / or solvate thereof as defined herein.

[0062] In one embodiment, there is provided a compound of formula (I) as defined herein or a pharma- ceutically acceptable salt and / or solvate thereof for use in treating or preventing a hematological disorder.In one embodiment of the invention, there is provided a use of a compound of formula (I) as defined herein or a pharma- ceutically acceptable salt and / or solvate thereof in the manufacture of a medicament for treating or preventing a hematological disorder.In one embodiment of the invention, there is provided a method for treating or preventing a hematological disorder comprising administering a compound of formula (I) as defined herein or a pharma- ceutically acceptable salt and / or solvate thereof.

[0063] In one embodiment, there is provided a compound of formula (I) as defined herein or a pharma- ceutically acceptable salt and / or solvate thereof for use in the treatment or prevention of a condition associated with a blood disorder.In one embodiment of the invention, there is provided the use of a compound of formula (I) as defined herein or a pharma- ceutically acceptable salt and / or solvate thereof in the manufacture of a medicament for the treatment or prevention of a condition associated with a blood disorder.In one embodiment of the invention, there is provided a method for the treatment or prevention of a condition associated with a blood disorder, comprising administering a compound of formula (I) as defined herein or a pharma- ceutically acceptable salt and / or solvate thereof.

[0064] An unwanted immune response will typically be one that gives rise to a pathology, i.e., it is a pathological immune response or reaction.

[0065] In one embodiment, said inflammatory disease or disease associated with an unwanted immune response is an autoimmune disease.

[0066] In one embodiment, the inflammatory disease or disease associated with an unwanted immune response is: psoriasis (including chronic plaque psoriasis, erythrodermic psoriasis, pustular psoriasis, guttate psoriasis, inverse psoriasis, and nail psoriasis), asthma, chronic obstructive pulmonary disease (including COPD, chronic bronchitis, and emphysema), heart failure (including left ventricular failure), myocardial infarction, angina pectoris, other atherosclerosis and / or atherothrombosis related disorders (including peripheral vascular disease and ischemic stroke), mitochondrial and neurodegenerative diseases (e.g. for example, Parkinson's disease, Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis, retinitis pigmentosa, or mitochondrial encephalomyopathy), autoimmune paraneoplastic retinopathy, transplant rejection (including antibody-mediated and T-cell mediated forms), multiple sclerosis, transverse myelitis, ischemia-reperfusion injury (e.g., during elective surgery such as cardiopulmonary bypass for coronary artery bypass grafting or other cardiac surgery, following percutaneous coronary intervention, treatment of acute ST-segment elevation myocardial infarction or ischemic stroke), , organ transplant, or acute compartment syndrome), AGE-induced genomic damage, inflammatory bowel disease (e.g., Crohn's disease or ulcerative colitis), primary sclerosing cholangitis (PSC), PSC-autoimmune hepatitis overlap syndrome, nonalcoholic fatty liver disease (nonalcoholic steatohepatitis), rheumatoid, granuloma annulare, cutaneous lupus erythematosus (CLE), systemic lupus erythematosus (SLE), lupus nephritis, drug-induced lupus, autoimmune myocarditis or myopericarditis, Dressler syndrome, giant cell myocarditis, postpericardiotomy syndrome, drug-induced hypersensitivity syndrome (including hypersensitivity myocarditis), eczema, sarcoidosis, erythema nodosum, acute disseminated encephalomyelitis (ADEM), neuromyelitis optica spectrum disorder, myelin oligodendrocyte glycoprotein (MOG) antibody-associated disorders (including MOG-EM), optic neuritis, CLIPPERS (chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids), diffuse myelinoclastic sclerosis, Addison's disease, alopecia areata, ankylosing spondylitis, other spondyloarthritis (including peripheral spondyloarthritis associated with psoriasis, inflammatory bowel disease, reactive arthritis, or juvenile-onset forms of spondyloarthritis), antiphospholipid syndrome, autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune inner ear disease, pemphigoid (bullous pemphigoid, mucous membrane pemphigoid,cicatricial pemphigoid, herpes gestationis or pemphigoid of gestationis, ophthalmic cicatricial pemphigoid), linear IgA disease, celiac disease, Chagas disease, dermatomyositis, type I diabetes mellitus, endometriosis, Goodpasture's syndrome, Graves' disease, Guillain-Barre syndrome and its subtypes (acute inflammatory demyelinating polyneuropathy, AIDP, acute motor axonal neuropathy (AMAN), acute motor and sensory axonal neuropathy (AMSAN), pharyngeal -cervico-brachial, Miller-Fisher, and Bickerstaff brainstem encephalitis), progressive inflammatory neuropathies, Hashimoto's thyroiditis, hidradenitis suppurativa, inclusion body myositis, necrotizing myopathy, Kawasaki disease, IgA nephropathy, Henoch-Schönlein purpura, idiopathic thrombocytopenic purpura, thrombotic thrombocytopenic purpura (TTP), Evans syndrome, interstitial cystitis, mixed connective tissue disease, undifferentiated connective tissue disease, morphea, myasthenia gravis (MuSK antibodies) positive and seronegative types), narcolepsy, neuromyotonia, pemphigus vulgaris, pernicious anemia, psoriatic arthritis, polymyositis, primary biliary cholangitis (also known as primary biliary cirrhosis), rheumatoid arthritis, relapsing rheumatoid arthritis, schizophrenia, autoimmune (meningo)encephalitis syndrome, scleroderma, Sjögren's syndrome, stiff-body syndrome, polymyalgia rheumatica, giant cell arteritis (temporal arteritis), Takayasu's arteritis, polyarteritis nodosa, Kawasaki disease, granulomatous polyangiitis Granulomatosis with polyangiitis (GPA; formerly Wegener's granulomatosis), Eosinophilic granulomatosis with polyangiitis (EGPA; formerly Churg-Strauss syndrome), Microscopic polyarteritis / polyangiitis, Hypocomplementemic urticarial vasculitis, Hypersensitivity vasculitis, Cryoglobulinemia, Thromboangiitis obliterans (Buerger's disease), Vasculitis, Leukocytoclastic vasculitis, Vitiligo, Acute disseminated encephalomyelitis, Adrenoleukodystrophy, Alexander disease, Alper's disease disease), Barrow concentric sclerosis or Marburg disease, idiopathic organizing pneumonia (formerly bronchiolitis obliterans organizing pneumonia), Canavan disease, central nervous system vasculitis syndromes, Charcot-Marie-Tooth disease, ataxia of childhood with central nervous system hypomyelination, chronic inflammatory demyelinating polyneuropathy (CIDP), diabetic retinopathy, globoid cell leukodystrophy (Krabbe disease), graft-versus-host disease (GVHD) (including acute and chronic forms and intestinal GVHD), hepatitis C (HCV) infection or complications, herpes simplex virus infection or complications,Human immunodeficiency virus (HIV) infection or complications, lichen planus, Hirayama disease, fibrosis, cystic fibrosis, pulmonary arterial hypertension (PAH, including idiopathic PAH), pulmonary sarcoidosis, idiopathic pulmonary fibrosis, renal fibrosis, childhood asthma, atopic dermatitis, allergic dermatitis, contact dermatitis, allergic rhinitis, rhinitis, sinusitis, conjunctivitis, allergic conjunctivitis, keratoconjunctivitis sicca, dry eye, xerophthalmia, glaucoma, macular edema, diabetic macular edema, central retinal vein occlusion (CRVO), macular degeneration (including dry and / or wet age-related macular degeneration, AMD), inflammation after cataract surgery, uveitis Autoimmune idiopathies (including posterior, anterior, intermediate and panuveitis), iridocyclitis, scleritis, corneal transplant and limbal cell graft rejection, gluten-sensitive enteropathy (celiac disease), dermatitis herpetiformis, eosinophilic esophagitis, esophageal obstruction, autoimmune autonomic neuropathy, autoimmune encephalomyelitis, autoimmune oophoritis, autoimmune orchitis, autoimmune pancreatitis, aortitis and periaortitis, autoimmune retinopathy, autoimmune urticaria, Behçet's disease, (idiopathic) Castleman's disease, Cogan's syndrome, IgG4-related disease, retroperitoneal fibrosis, juvenile idiopathic arthritis including systemic juvenile idiopathic arthritis (Still's disease), adult Human-onset Still's disease, lignoconjunctivitis, Mooren's ulcer, pityriasis lichenoides varicella (PLEVA, also known as Mucha-Habermann disease), multifocal motor neuropathy (MMN), childhood acute-onset neuropsychiatric syndromes (PANS) (including pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS)), paraneoplastic syndromes (including paraneoplastic cerebellar degeneration, Lambert-Eaton myasthenic syndrome, limbic encephalitis, brainstem encephalitis, opsoclonus-myoclonus ataxia syndrome, anti-NMDA receptor encephalitis, and thymoma-associated multisystem autoimmunity), perivenous encephalomyelitis, and reflex sympathetic dystrophy relapsing polychondritis, sperm and testicular autoimmunity, Susac syndrome, Tolosa-Hunt syndrome, Vogt-Koyanagi-Harada disease, antisynthetase syndrome, autoimmune enteropathy, X-linked immunodysregulation-polyendocrinopathy enteropathy (IPEX), microscopic colitis, autoimmune lymphoproliferative syndrome (ALPS), autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome (APEX), gout, pseudogout, amyloid (including AA or secondary amyloidosis), eosinophilic fasciitis (Schulman syndrome), progesterone hypersensitivity (including progesterone dermatitis),Familial Mediterranean Fever (FMF), Tumor Necrosis Factor (TNF) Receptor-Associated Periodic Fever Syndrome (TRAPS), Hyperglobulin Demia with Periodic Fever Syndrome (HIDS), PAPA (Septic Arthritis, Pyoderma Gangrenosum, and Severe Cystic Acne) Syndrome, Deficiency of Interleukin-1 Receptor Antagonist (DIRA), Deficiency of Interleukin-36-Receptor Antagonist (DITRA), Cryopyrin-Associated Periodic Syndrome (CAPS) (Familial Cold Autoinflammation Syndrome with periodic fever (FCAS), Muckle-Wells syndrome, and neonatal-onset multisystem inflammatory disease (NOMID), NLRP12-associated autoinflammatory disorder (NLRP12AD), Periodic febrile aphthous stomatitis (PFAPA), Chronic atypical neutrophilic dermatosis with lipodystrophy and high fever (CANDLE), Majeed syndrome, Blau syndrome (also known as juvenile systemic granulomatosis), Macrophage activation syndrome, Chronic relapsing multifocal osteomyelitis (CRMO), and familial Cold autoinflammatory syndrome, mutant adenosine deaminase 2 and monogenic interferonopathies (including Aicardi-Goutières syndrome, retinal vasculopathy with cerebral leukodystrophy, spinal intrachondrodysplasia, infantile-onset STING [stimulator of interferon genes]-associated vasculopathy, proteasome-associated autoinflammatory syndrome, familial lupus pernio, hereditary symmetrical pigmentary dysplasia), Schnitzler syndrome; familial cylindromatosis, congenital B-cell lymphoma The disease is or is associated with a disease selected from the group consisting of hypertension, OTULIN-associated autoinflammatory syndrome, type 2 diabetes, insulin resistance and metabolic syndrome (including obesity-associated inflammation), atherosclerotic disorders (e.g., myocardial infarction, angina pectoris, ischemic heart failure, ischemic renal damage, ischemic stroke, peripheral vascular disease, aortic aneurysm), and renal inflammatory disorders (e.g., diabetic nephropathy, membranous nephropathy, minimal change disease, crescentic glomerulonephritis, acute kidney injury, and kidney transplantation).

[0067] In one embodiment, the inflammatory disease or disease associated with an unwanted immune response is selected from the following autoinflammatory diseases: Familial Mediterranean Fever (FMF), Tumor Necrosis Factor (TNF) Receptor-Associated Periodic Fever Syndrome (TRAPS), Hyperglobulinemia with Periodic Fever Syndrome (HIDS), PAPA (Septic Arthritis, Pyoderma Gangrenosum, and Severe Cystic Acne) Syndrome, Interleukin-1 Receptor Antagonist Deficiency (DIRA), Interleukin-36-Receptor Antagonist Deficiency (DITRA), Cryopyrin-Associated Periodic Syndromes (CAPS) (including Familial Cold Autoinflammatory Syndrome [FCAS], Muckle-Wells Syndrome, and Neonatal-Onset Multisystem Inflammatory Disease [NOMID]), NLRP12-Associated Autoinflammatory Disorder (NLRP12AD), being or associated with a disease selected from periodic fever with aphthous stomatitis (PFAPA), chronic atypical neutrophilic dermatosis with lipodystrophy and hyperpyrexia (CANDLE), Majeed syndrome, Blau syndrome (also known as juvenile systemic granulomatosis), macrophage activation syndrome, chronic relapsing multifocal osteomyelitis (CRMO), familial cold autoinflammatory syndrome, mutant adenosine deaminase 2 and monogenic interferonopathies (including Aicardi-Goutières syndrome, retinal vasculopathy with cerebral leukodystrophy, spinal enchondrodysplasia, infantile-onset STING [stimulator of interferon genes]-associated vasculopathy, proteasome-associated autoinflammatory syndrome, familial lupus pernio, hereditary symmetrical pigmentary dysplasia), and Schnitzler syndrome.

[0068] In one embodiment, the inflammatory disease or disease associated with an undesired immune response is mediated by excess NF-κB or gain of function in the NF-κB signaling pathway or has a significant contribution to abnormal pathogenesis from them (including non-canonical NF-κB signaling): familial cylindromatosis, congenital B-cell lymphocytosis, OTULIN-associated autoinflammatory syndrome, type 2 diabetes, insulin resistance, and metabolic syndrome (obesity). In one embodiment, the present invention relates to a disease selected from or associated with a disease selected from the group consisting of chronic obstructive pulmonary disease (COPD), chronic obstructive pulmonary disease (COPD), chronic pulmonary disease (COPD), chronic pulmonary arthritis (COPD), chronic pulmonary disease (CPD), chronic obstructive pulmonary disease ...

[0069] In one embodiment, the disease is selected from the group consisting of rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, systemic lupus erythematosus, multiple sclerosis, psoriasis, inflammatory bowel disease (including ulcerative colitis and Crohn's disease), atopic dermatitis, fibrosis, uveitis, cryopyrin-associated periodic syndrome, Muckle-Wells syndrome, juvenile idiopathic arthritis, chronic obstructive pulmonary disease, and asthma.

[0070] In one embodiment, the disease is multiple sclerosis.

[0071] In one embodiment, the disease is psoriasis.

[0072] In one embodiment, the disease is asthma.

[0073] In one embodiment, the disease is chronic obstructive pulmonary disease.

[0074] In one embodiment, the disease is systemic lupus erythematosus.

[0075] In one embodiment, the disease is rheumatoid arthritis.

[0076] In one embodiment, the disease is inflammatory bowel disease (including ulcerative colitis and Crohn's disease).

[0077] In one embodiment, the disease is atopic dermatitis.

[0078] In one embodiment, the disease is fibrosis.

[0079] In one embodiment, the cancer is acute lymphoblastic leukemia, adult; acute lymphoblastic leukemia, pediatric; acute myeloid leukemia, adult; adrenocortical carcinoma; adrenocortical carcinoma, pediatric; AIDS-related lymphoma; AIDS-related malignancies; anal cancer; astrocytoma, pediatric cerebellum; astrocytoma, pediatric cerebral; Barrett's esophagus (precancerous syndrome); cholangiocarcinoma, extrahepatic; bladder cancer; bladder cancer, pediatric; bone cancer, osteosarcoma / malignant fibrous histiocytoma; brain stem glioma, pediatric; brain tumor, adult; brain tumor, brain stem glioma, pediatric; brain tumor, cerebellar astrocytoma, pediatric; brain tumor, cerebral astrocytoma / malignant glioma, pediatric; brain tumor, ependymoma, pediatric; brain tumor. tumor, medulloblastoma, children;brain tumor, supratentorial primitive neuroectodermal tumor, children;brain tumor, optic tract and hypothalamic glioma, children;brain tumor, children (other);breast cancer;breast cancer and pregnancy;breast cancer, children;breast cancer, male;bronchial adenoma / carcinoid, children;carcinoid tumor, children;carcinoid tumor, gastrointestinal;cancer, adrenal cortex;cancer, islet cell;cancer of unknown primary;central nervous system lymphoma, primary;cerebellar astrocytoma, children;cerebral astrocytoma / malignant glioma, children;cervical cancer;childhood cancer;chronic lymphocytic leukemia;chronic myeloid leukemia;chronic myeloproliferative disorder;clear cell sarcoma of tendon sheath;colon cancer;colon Rectal cancer;Colorectal cancer, children;Cutaneous T-cell lymphoma;Endometrial cancer;Ependymoma, children;Epithelial carcinoma, ovarian;Esophageal cancer;Esophageal cancer, children;Ewing family tumors;Extracranial germ cell tumors, children;Extragonadal germ cell tumors;Extrahepatic bile duct carcinoma;Eye cancer, intraocular melanoma;Eye cancer, retinoblastoma;Gallbladder cancer;Gastric cancer;Gastric cancer, children;Gastrointestinal carcinoid tumors;Germ cell tumors, extracranial, children;Germ cell tumors, extragonadal;Germ cell tumors, ovarian;Gestational trophoblastic tumors;Glioma, children's brain stem;Glioma, children's visual pathway and hypothalamus;Hairy cell leukemia;Head and neck cancer;Hepatocellular (liver) cancer;Hepatocellular (liver) cancer ) cancer, adult (primary);hepatocellular (liver) cancer, childhood (primary);cancer of the esophagus;Hodgkin's lymphoma;Hodgkin's lymphoma, adult;Hodgkin's lymphoma, childhood;Hodgkin's lymphoma, pregnancy;hypopharyngeal cancer;hypothalamic and optic tract glioma, childhood;intraocular melanoma;islet cell carcinoma (endocrine pancreas);cancer of the endocrine system (e.g., cancer of the thyroid, pancreas, parathyroid, or adrenal gland);Kaposi's sarcoma;kidney cancer;laryngeal cancer;laryngeal cancer, childhood;leukemia, acute lymphoblastic, adult;leukemia, acute lymphoblastic, childhood;leukemia, acute myeloid, adult;leukemia, acute myeloid, childhood;leukemia, chronic lymphocytic;Leukemia, chronic myeloid;Leukemia, hairy cell;Lymphocytic lymphoma;Lip and oral cavity cancer;Liver cancer, adult (primary);Liver cancer, childhood (primary);Lung cancer;Lung cancer, non-small cell;Lung cancer, small cell;Lymphoblastic leukemia, adult acute;Lymphoblastic leukemia, childhood acute;Lymphocytic leukemia, chronic;Lymphoma, AIDS-related;Lymphoma, central nervous system (primary);Lymphoma, cutaneous T-cell;Lymphoma, Hodgkin, adult;Lymphoma, Hodgkin, childhood;Lymphoma, Hodgkin, pregnancy;Lymphoma, non-Hodgkin, adult;Lymphoma, non-Hodgkin, childhood;Lymphoma, non-Hodgkin , pregnancy;Lymphoma, primary central nervous system;Macroglobulinemia, Waldenström;Male breast cancer;Malignant mesothelioma, adult;Malignant mesothelioma, childhood;Malignant thymoma;Medulloblastoma, childhood;Melanoma;Melanoma, intraocular;Merkel cell carcinoma;Mesothelioma, malignant;Metastatic squamous neck cancer of unknown primary;Multiple endocrine neoplasia syndrome, childhood;Multiple myeloma / plasma cell neoplasm;Mycosis fungoides;Myelodysplastic syndrome;Myeloid leukemia, chronic;Myeloid leukemia, acute, childhood;Myeloma, multiple;Myeloproliferative disorder, chronic;Nasal cavity and paranasal sinus cancer;Nasopharyngeal carcinoma;Nasopharyngeal carcinoma, childhood;Neuroblastoma;Non-homologous skin disease Hodgkin's lymphoma, adult;Non-Hodgkin's lymphoma, childhood;Non-Hodgkin's lymphoma, pregnancy;Non-small cell lung cancer;Neoplasms of the central nervous system (e.g., primary CNS lymphoma, spinal axis tumor, medulloblastoma, brain stem glioma, or pituitary adenoma);Oat cell carcinoma;Oral cavity cancer, childhood;Cancer of the oral cavity and lip;Oropharyngeal cancer;Osteosarcoma / malignant fibrous histiocytoma of bone;Ovarian cancer;Ovarian cancer, childhood;Ovarian epithelial cancer;Ovarian germ cell tumor;Ovarian low malignant potential tumor;Childhood malignant tumors;Pancreatic cancer;Pancreatic cancer, childhood;Pancreatic islet cell cancer;Sino-nasal and nasal cancer;Parathyroid cancer;Penile cancer;Pheochromocytoma;Pineal and tentorial cancer Superior primitive neuroectodermal tumors, children;Pituitary tumors;Plasma cell neoplasms / multiple myeloma;Pleuropulmonary blastoma;Pregnancy and breast cancer;Pregnancy and Hodgkin's lymphoma;Pregnancy and non-Hodgkin's lymphoma;Primary central nervous system lymphoma;Primary liver cancer, adults;Primary liver cancer, children;Prostate cancer (especially hormone refractory);Chronic or acute leukemia;Solid tumors of childhood;Hypereosinophilia;Rectal cancer;Renal cell (kidney) cancer;Renal cell carcinoma, children;Renal pelvis and ureter, transitional cell carcinoma;Retinoblastoma;Rhabdomyosarcoma, children;Salivary gland cancer;Salivary gland cancer, children;Sarcoma, Ewing family tumors;Sarcoma, Kaposi;Sarcoma (osteosarcoma) / malignant fibrous histiocytoma of bone;Sarcoma, rhabdomyosarcoma, childhood;Sarcoma of soft tissue;Sarcoma, soft tissue, adult;Sarcoma, soft tissue, childhood;Sezary syndrome;Skin cancer;Skin cancer, childhood;Skin cancer (melanoma);Skin cancer, Merkel cell;Small cell lung cancer;Dermatofibrosarcoma protuberans;Small intestine cancer;Soft tissue sarcoma, adult;Soft tissue sarcoma, childhood;Head and neck cancer;Squamous cell neck carcinoma of unknown primary, metastatic;Gastric cancer;Gastric cancer, childhood;Supratentorial primitive neuroectodermal tumor, childhood;T-cell lymphoma, skin;Testicular cancer;Thymoma, small The tumor is selected from the group consisting of: pediatric; thymoma, malignant; thyroid cancer; thyroid cancer, pediatric; transitional cell carcinoma of the renal pelvis and ureter; trophoblastic tumor, gestational; cancer of unknown primary site, pediatric; rare cancers of childhood; ureter and renal pelvis, transitional cell carcinoma; urethral cancer; cancer of the ureter (e.g., renal cell carcinoma, renal pelvis cancer); cancer of the penis; gynecological tumors; uterine cancer; uterine sarcoma; cancer of the fallopian tube; cancer of the endometrium; vaginal cancer; cancer of the vagina; cancer of the vulva; optic tract and hypothalamic glioma, pediatric; vulvar cancer; Waldenstrom's macroglobulinemia; and Wilms' tumor.

[0080] In one embodiment, the cancer is selected from the group consisting of lung cancer; NSCLC (non-small cell lung cancer); oat cell carcinoma; bone cancer; pancreatic cancer; skin cancer; dermatofibrosarcoma protuberans; cancer of the head and neck; cutaneous or intraocular melanoma; uterine cancer; ovarian cancer; colorectal cancer; anal cancer; gastric cancer; colon cancer; breast cancer; gynecological tumors (e.g., uterine sarcoma, cancer of the fallopian tubes, cancer of the endometrium, cancer of the cervix, cancer of the vagina, or cancer of the vulva); Hodgkin's disease; hepatocellular carcinoma; cancer of the esophagus; small intestine cancer; cancer of the endocrine system (e.g., thyroid, pancreatic, parathyroid, gland, adrenal, or adrenal gland cancer); soft tissue sarcoma; urethral cancer; penile cancer; prostate cancer (especially hormone refractory); chronic or acute leukemia; childhood solid tumors; hypereosinophilia; lymphocytic lymphoma; bladder cancer; kidney cancer; ureteral cancer (e.g., renal cell carcinoma, renal pelvis carcinoma); childhood malignancies; central nervous system neoplasms (e.g., primary CNS lymphoma, spinal axis tumor, medulloblastoma, brain stem glioma, or pituitary adenoma); Barrett's esophagus (precancerous syndrome), and neoplastic skin diseases.

[0081] "Obesity" means the condition in which a subject has a body mass index of greater than or equal to 30. Body mass index (BMI) is according to the NIH Clinical Guidelines on the Identification and Evaluation, and Treatment of Overweight and Obesity in Adults (1998).

[0082] In one embodiment, administering the compound of formula (I) to the subject reduces the subject's BMI to less than 30, for example, less than 29, less than 28, less than 27, less than 26, less than 25, less than 24, less than 23, less than 22, less than 21, or less than 20. In one embodiment, the compound of formula (I) is used to treat or prevent abnormal or inappropriate weight gain, metabolic rate, or fat accumulation, for example, anorexia, bulimia, obesity, diabetes, or hyperlipidemia (e.g., high triglyceride levels and / or high cholesterol levels), and disorders of fat or lipid metabolism. In one embodiment, the compound of formula (I) is used to treat or prevent metabolic syndrome.

[0083] In one embodiment, the compounds of formula (I) are used to treat obesity associated with Prader-Willi syndrome (PWS). In one embodiment, the compounds of formula (I) are used to reduce body fat, prevent gain of body fat, reduce cholesterol (e.g., total cholesterol and / or the ratio of total cholesterol to HDL cholesterol), and / or reduce appetite, and / or reduce co-morbidities such as diabetes, cardiovascular disease, and stroke in individuals with PWS-associated obesity.

[0084] "Diabetic disease" means diabetes mellitus ("diabetes") or diabetic complications. The two main types of diabetes are (i) type 1 diabetes, which results from the pancreas not producing insulin and the usual treatment is insulin replacement therapy, and (ii) type 2 diabetes, in which patients either produce insufficient insulin or are insulin resistant. Diabetic complications include microvascular and macrovascular complications, including coronary artery disease, peripheral artery disease, stroke, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, diabetic kidney disease, and NASH.

[0085] In one embodiment, the "blood disorder" is selected from the group consisting of thalassemia (e.g., β-thalassemia), hereditary spherocytosis, hereditary elliptocytosis, abetalipoproteinemia (or Bassen-Kornzweig syndrome), paroxysmal nocturnal hemoglobinuria, acquired hemolytic anemia (e.g., congenital anemia (e.g., enzymopathies)), and anemia of chronic disease.

[0086] (Administration) Typically, the compound of formula (I) is administered as a pharmaceutical composition. Thus, in one embodiment, there is provided a pharmaceutical composition comprising a compound of formula (I) and one or more pharma- ceutically acceptable diluents or carriers.

[0087] The compounds of formula (I) may be administered by any convenient way, for example, oral, parenteral, buccal, sublingual, nasal, rectal, intrathecal or transdermal administration, the pharmaceutical compositions being adapted accordingly.

[0088] The compounds of formula (I) may be administered locally to a target organ, for example to the eye, lung, nose, or skin.Thus, the present invention provides pharmaceutical compositions comprising a compound of formula (I), optionally in combination with one or more topically acceptable diluents or carriers.

[0089] Compounds of formula (I) that are active when given orally can be formulated as liquids or solids, for example, as syrups, suspensions, emulsions, tablets, capsules, or lozenges.

[0090] Liquid formulations generally consist of a suspension or solution of the compound of formula (I) in a suitable liquid carrier(s). Preferably, the carrier is non-aqueous, for example, polyethylene glycol or oil. The formulation may also contain a suspending agent, a preservative, a flavoring agent, and / or a coloring agent.

[0091] A composition in the form of a tablet can be prepared using any suitable pharmaceutical carrier(s) normally used for preparing solid formulations, such as magnesium stearate, starch, lactose, sucrose, and cellulose.

[0092] A composition in the form of a capsule may be prepared using commonly used encapsulation procedures, for example, pellets containing the active ingredient may be prepared using standard carriers and then filled into a hard gelatin capsule; alternatively, a dispersion or suspension may be prepared using any suitable pharmaceutical carrier(s), for example, aqueous gums, celluloses, silicates, or oils, and the dispersion or suspension may then be filled into a soft gelatin capsule.

[0093] A typical parenteral composition will consist of a solution or suspension of the compound of formula (I) in a sterile aqueous carrier or parenterally acceptable oil, such as polyethylene glycol, polyvinylpyrrolidone, lecithin, peanut oil, or sesame oil. Alternatively, the solution can be lyophilized and then reconstituted with a suitable solvent just prior to administration.

[0094] Conveniently, compositions for nasal administration can be formulated as aerosols, drops, gels, and powders. Aerosol formulations usually contain a solution or fine suspension of the compound of formula (I) in a medicamentously acceptable aqueous or non-aqueous solvent, and are usually provided in a sterile form in a sealed container in single or multiple doses, and can take the form of cartridges or refills for use with a nebulizer. Alternatively, the sealed container can be a disposable dispensing device, such as a single-dose nasal inhaler or an aerosol dispenser with a metering valve. When the dosage form includes an aerosol dispenser, it will contain a propellant, which can be a compressed gas, e.g., air, or an organic propellant, such as a chlorofluorocarbon (CFC) or a hydrofluorocarbon (HFC). The aerosol dosage form can also take the form of a pump-action atomizer.

[0095] Topical administration to the lung can be achieved by means of an aerosol formulation, which typically contains the active ingredient suspended or dissolved in a suitable aerosol propellant, such as a chlorofluorocarbon (CFC) or hydrofluorocarbon (HFC).

[0096] Topical administration to the lung may also be achieved using non-pressurized formulations, such as aqueous solutions or suspensions, which may be administered by a nebulizer, for example a hand-held or home or hospital (i.e., non-portable) nebulizer. Such formulations may include excipients such as water, buffers, osmolality adjusters, pH adjusters, surfactants, and co-solvents.

[0097] Topical administration to the lung may also be achieved using a dry powder formulation, which will normally contain a locally acceptable diluent such as lactose, glucose or mannitol, preferably lactose.

[0098] The compounds of the present invention can also be administered rectally in the form of suppositories or enemas, including, for example, aqueous or oily solutions, as well as suspensions and emulsions and foams. Such compositions are prepared according to standard procedures well known to those skilled in the art. For example, suppositories can be prepared by mixing the active ingredient with a conventional suppository base, such as cocoa butter or other glycerides. In this case, the drug is mixed with a suitable non-irritating excipient that is solid at normal temperature but liquid at rectal temperature, and therefore melts in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycol.

[0099] Generally, for compositions intended to be administered topically to the eye in the form of eye drops or eye ointment, the total amount of the compounds of the invention will be from about 0.0001% (w / w) to less than 4.0% (w / w).

[0100] Preferably, for topical administration to the eye, the compositions administered according to the present invention will be formulated as solutions, suspensions, emulsions, and other dosage forms.

[0101] The compositions administered according to the present invention may also include various other ingredients, including, but not limited to, tonicity agents, buffers, surfactants, stabilizing polymers, preservatives, cosolvents, and viscosity enhancing agents. A suitable pharmaceutical composition of the present invention includes a compound of the present invention formulated with a tonicity agent and a buffer. In addition, the pharmaceutical composition of the present invention may optionally include a surfactant and / or a emollient and / or a stabilizing polymer.

[0102] In the ophthalmic composition, various tonicity agents may be employed to adjust the osmolality of the composition, preferably to that of natural tears. For example, sodium chloride, potassium chloride, magnesium chloride, calcium chloride, monosaccharides such as glucose, fructose, galactose, and / or polyols such as simple sugar alcohols mannitol, sorbitol, xylitol, lactitol, isomaltitol, maltitol, and hydrogenated starch hydrolysates may be added to the composition to approximate physiological osmolality. The amount of such tonicity agents will vary depending on the particular agent added. Generally, however, the composition will contain a sufficient amount of tonicity agent to provide the final composition with an ophthalmologically acceptable osmolality (generally about 150-450 mOsm, preferably 250-350 mOsm, and most preferably about 290 mOsm). Generally, the tonicity agents of the present invention will be present in the range of 2-4% w / w. Suitable tonicity agents of the present invention include the above-mentioned monosaccharides or sugar alcohols, such as D-mannitol.

[0103] A suitable buffer system (e.g., sodium phosphate, sodium acetate, sodium citrate, sodium borate, or boric acid) may be added to the composition to prevent pH drift under storage conditions. The specific concentration will vary depending on the agent employed. However, preferably, the buffer will be selected to maintain a target pH in the range of pH 5-8, more preferably a target pH of pH 5-7.

[0104] Surfactants may optionally be employed to deliver higher concentrations of the compounds of the present invention. Surfactants serve to solubilize the compounds and stabilize colloidal dispersions such as micellar solutions, microemulsions, emulsions, and suspensions. Examples of surfactants that may be optionally used include polysorbates, poloxamers, polyosyl 40 stearate, polyoxyl castor oil, tyloxapol, Triton, and sorbitan monolaurate. Suitable surfactants to be employed in the present invention have a hydrophilic lipophilic balance "HLB" in the range of 12.4 to 13.2, such as Triton X114 and tyloxapol, and are acceptable for ophthalmic use.

[0105] An additional agent that may be added to the ophthalmic composition of the compounds of the present invention is a demulcent, which acts as a stabilizing polymer. The stabilizing polymer should be an ionic / charged example preferred for topical ocular use, more specifically a polymer that has a negative charge on its surface capable of exhibiting a zeta potential of (-)10-50 mV for physical stability, and that is capable of forming a dispersion in water (i.e., is water-soluble). A suitable stabilizing polymer of the present invention would be a polyelectrolyte (singular) or polyelectrolyte (s) of the family of crosslinked polyacrylates, such as Carbomer and Pemulen®, specifically Carbomer 974p (polyacrylic acid), at 0.1-0.5% w / w.

[0106] Other compounds may also be added to the ophthalmic compositions of the compounds of the present invention to increase the viscosity of the carrier. Examples of viscosity enhancing agents include, but are not limited to: hyaluronic acid and its salts, chondroitin sulfate and its salts, polysaccharides such as dextran, various polymers of the cellulose family; vinyl polymers; and acrylic acid polymers.

[0107] Topical ophthalmic products are usually packaged in multi-dose form. Thus, preservatives are required to prevent microbial contamination during use. Suitable preservatives include: benzalkonium chloride, chlorobutanol, benzododecinium bromide, methylparaben, propylparaben, phenylethyl alcohol, disodium edetate, sorbic acid, polyquaternium-1, or other agents known to those skilled in the art. Such preservatives are usually employed at a level of 0.001-1.0% w / v. The unit dose compositions of the present invention are sterile but usually not preserved. Thus, such compositions generally do not contain preservatives.

[0108] Compositions suitable for buccal or sublingual administration include tablets, lozenges, and pastilles wherein the compound of formula (I) is formulated with carriers such as sugar and acacia, tragacanth, or gelatin and glycerin.

[0109] Compositions suitable for transdermal administration include ointments, gels, and patches.

[0110] The composition may contain 0.1% to 100% by weight, for example 10 to 60% by weight, of the compound of formula (I) depending on the method of administration. The composition may contain 0% to 99.9% by weight, for example 40% to 90% by weight, of the carrier depending on the method of administration. The composition may contain 0.05 mg to 1000 mg, for example 1.0 mg to 500 mg, 1.0 mg to 50 mg, for example about 10 mg of the compound of formula (I) depending on the method of administration. The composition may contain 50 mg to 1000 mg, for example 100 mg to 400 mg of the carrier depending on the method of administration. The dose of the compound used in the treatment of the above-mentioned disorders will vary in the usual manner with the severity of the disorder, the weight of the patient, and other similar factors. However, as a general guideline, a suitable unit dose may be from 0.05 to 1000 mg, more preferably from 1.0 to 500 mg, for example from 1.0 mg to 50 mg, for example about 10 mg, and such unit doses may be administered more than once a day, for example two or three times a day. Such therapy may extend for a period of several weeks or months.

[0111] In one embodiment of the present invention, the compound of formula (I) is used in combination with additional therapeutic agent(s).When the compound of formula (I) is used in combination with other therapeutic agents, the compounds can be administered either sequentially or simultaneously by any convenient route.Alternatively, the compounds can be administered separately.

[0112] When the compounds of formula (I) are used to treat or prevent inflammatory diseases or diseases associated with an undesired immune response, therapeutic agents which may be used in combination with the compounds of formula (I) include corticosteroids (glucocorticoids), retinoids (e.g., acitretin, isotretinoin, tazarotene), anthralins, vitamin D analogues (e.g., cacitriol, calcipotriol), calcineurin inhibitors (e.g., tacrolimus, pimecrolimus), phototherapy or photochemotherapy (e.g., psoralen ultraviolet irradiation, PUVA) or other forms of ultraviolet light radiation therapy, cyclosporines, thiopurines (e.g., azathioprine, 6-mercaptopurine), methadone, ... Thotrexate, anti-TNFα agents (e.g., infliximab, etanercept, adalimumab, certolizumab, golimumab, and biosimilars), phosphodiesterase-4 (PDE4) inhibitors (e.g., apremilast, crisaborole), anti-IL-17 agents (e.g., brodalumab, ixekizumab, secukinumab), anti-IL12 / IL-23 agents (e.g., ustekinumab, briakinumab), anti-IL-23 agents (e.g., guselkumab, tildrakizumab), JAK (Janus kinase) inhibitors (e.g., tofacitinib, ruxolitinib, baricitinib, filgotinib, upadacitinib), plasma exchange, intravenous immunoglobulin (IVIG), cyclophosphamide, anti-CD20 B cell depleting agents (e.g., rituximab, ocrelizumab, ofatumumab, obinutuzumab), anthracycline analogues (e.g., mitoxantrone), cladribine, sphingosine 1-phosphate receptor modulators or sphingosine analogues (e.g., fingolimod, siponimod, ozanimod, etrasimod), interferon beta preparations (interferon beta 1b / 1a), glatiramer, anti-CD3 therapy (e.g., OKT3), anti-CD52 targeted agents (e.g., alemtuzumab), leflunomide, teriflunomide, gold compounds, laquinimod, potassium channel blockers (e.g., dalfampridine / 4-aminopyridine), mycophenolic acid, mycophenolate mofetil, purine analogs (e.g., pentostatin), mTOR (target of rapamycin) pathway inhibitors (e.g., sirolimus, everolimus), antithymocyte globulin (ATG),IL-2 receptor (CD25) inhibitors (e.g., basiliximab, daclizumab), anti-IL-6 receptor or anti-IL-6 agents (e.g., tocilizumab, siltuximab), Bruton's tyrosine kinase (BTK) inhibitors (e.g., ibrutinib), tyrosine kinase inhibitors (e.g., imatinib), ursodeoxycholic acid, hydroxychloroquine, chloroquine, B-cell activating factor (BAFF, also known as BlyS, B-lymphocyte stimulating factor) inhibitors (e.g., belimumab, blissibimod), fusion proteins targeting both APRIL (proliferative ligand) and BlyS. Other B-cell targeted therapies including proteins (e.g., atacicept), PI3K inhibitors, including pan inhibitors or those targeting p110δ and / or p110γ-containing isoforms (e.g., idelalisib, copanlisib, duvelisib), interferon alpha receptor inhibitors (e.g., anifrolumab, sifalimumab), T-cell costimulation blockers (e.g., abatacept, belatacept), thalidomide and its derivatives (e.g., lenalidomide), dapsone, clofazimine, leukotriene antagonists (e.g., montelukast), theophylline, anti-IgE therapy (e.g., omalizumab), anti-IL-5 agents (e.g., mepolizumab, reslizumab), long-acting muscarinic agents (e.g., tiotropium, aclidinium, umeclidinium), PDE4 inhibitors (e.g., roflumilast), riluzole, free radical scavengers (e.g., edaravone), proteasome inhibitors (e.g., bortezomib), complement cascade inhibitors including those against C5 (e.g., eculizumab), immunoadsorbents, antithymocyte globulin, 5-aminosalicylates and their derivatives (e.g., sulfasalazine, baclofenac, rusalazide, mesalamine), anti-integrin agents including those targeting α4β1 and / or α4β7 integrins (e.g., natalizumab, vedolizumab), anti-CD11-α agents (e.g., efalizumab), nonsteroidal anti-inflammatory drugs (NSAIDs) including salicylates (e.g., aspirin), propionic acids (e.g., ibuprofen, naproxen), acetates (e.g., indomethacin, diclofenac, etodolac), oxicams (e.g., meloxicam) and fenamates (e.g., mefenamic acid), selective or relatively selective COX-2 inhibitors (e.g.,Celecoxib, etroxicoxib, valdecoxib and etodolac, meloxicam, nabumetone), colchicine, IL-4 receptor inhibitors (e.g., dupilumab), topical / contact immunotherapy (e.g., diphenylcyclopropenone, squaric acid dibutyl ester), anti-IL-1 receptor therapy (e.g., anakinra), IL-1β inhibitors (e.g., canakinumab), IL-1 neutralizing therapy (e.g., rilonacept), chlorambucil, certain anticancer drugs with immunomodulatory properties and / or the ability to modulate NRF2. Biologics (e.g., minocycline, tetracyclines including clindamycin, macrolide antibiotics), antiandrogen therapy (e.g., cyproterone, spironolactone, finasteride), pentoxifylline, ursodeoxycholic acid, obeticholic acid, fibrates, cystic fibrosis transmembrane conductance regulator (CFTR) modulators, VEGF (vascular endothelial growth factor) inhibitors (e.g., bevacizumab, ranibizumab, pegaptanib, aflibercept), pirfenidone, and mizoribine.

[0113] When the compound of formula (I) is used to treat or prevent cancer, therapeutic agents that may be used in combination with the compound of formula (I) include active agents used in combination with cancer therapy, such as agents used as palliative treatments to improve unwanted side effects.Thus, in one embodiment, the additional therapeutic agent is an agent used as palliative treatment, such as those selected from the group consisting of: antiemetics, drugs intended to relieve pain, such as opioids, drugs used to reduce high blood uric acid levels, such as allopurinol or rasburicase, antidepressants, sedatives, anticonvulsants, laxatives, antidiarrheals, and / or antacids.

[0114] In another embodiment, the additional therapeutic agent is an additional cancer treatment, such as chemotherapy, targeted therapy, immunotherapy, and hormonal therapy.

[0115] Examples of chemotherapeutic agents include antimetabolites (e.g., folic acid, purine, and pyrimidine derivatives) and alkylating agents (e.g., nitrogen mustards, nitrosoureas, platinum, alkylsulfonates, hydrazines, triazenes, aziridines, spindle poisons, cytotoxic agents, toposimerase inhibitors, and others). In one embodiment, the additional therapeutic agent is a chemotherapeutic agent, such as aclarubicin, actinomycin, alitretinone, altretamine, aminopterin, aminolevulinic acid, amrubicin, amsacrine, anagrelide, arsenic trioxide, asparaginase, atrasentan, belotecan, bexarotene, endamustine, bleomycin, bortezomib, busulfan, camptothecin, capecitabine, carbo Platinum, Carboquone, Carmofur, Carmustine, Celecoxib, Chlorambucil, Chlormethine, Cisplatin, Cladribine, Clofarabine, Crisantaspase, Cyclophosphamide, Cytarabine, Dacarbazine, Dactinomycin, Daunorubicin, Decitabine, Demecolcine, Docetaxel, Doxorubicin, Efaproxiral, Elesclomol, Elsamitrucin, Enocitabine, Epirubicin, Estramustine, Etoglucide, Etoposide, Floxuridine, fludarabine, fluorouracil (5FU), fotemustine, gemcitabine, gliadel implant, hydroxycarbamide, hydroxyurea, idarubicin, ifosfamide, irinotecan, irofulven, ixabepilone, larotaxel, leucovorin, liposomal doxorubicin, liposomal daunorubicin, lonidamine, lomustine, lucantone, mannosulfan, masoprocol, melphalan, mercaptopurine, mesna, meth Trexate, methyl aminolevulinate, mitobronitol, mitoguazone, mitotane, mitomycin, mitoxantrone, nedaplatin, nimustine, oblimersen, omacetaxine, ortataxel, oxaliplatin, paclitaxel, pegaspargase, pemetrexed, pentostatin, pirarubicin, pixantrone, plicamycin, porfimer sodium, prednimustine, procarbazine, raltitrexed, ranimustine, rubitecan,The agent is selected from the group consisting of sapacitabine, semustine, sitimagene seradenovec, satraplatin, streptozocin, talaporfin, tegafur-uracil, temoporfin, temozolomide, teniposide, tesetaxel, testolactone, tetranitrate, thiotepa, tiazofurin, thioguanine, tipifarnib, topotecan, trabectedin, triazicon, triethylenemelamine, triplatin, tretinoin, treosulfan, trofosfamide, uramustine, valrubicin, verteporfin, vinblastine, vincristine, vindesine, vinfhmine, vinorelbine, vorinostat, and zorubicin.

[0116] Examples of targeted therapy include tyrosine kinase inhibitors, cyclin-dependent kinase inhibitors, monoclonal antibodies, and fusion proteins.In one embodiment, the additional therapeutic agent is selected from the group consisting of axitinib, bosutinib, cediranib, dasatinib, erlotinib, imatinib, gefitinib, lapatinib, lestaurtinib, nilotinib, semaxanib, sorafenib, sunitinib, vandetanib, alvocidib, seliciclib, herceptin, rituximab, tositumomab, cetuximab, panitumumab, trastuzumab, alemtuzumab, bevacizumab, edrecolomab, gemtuzumab, aflibercept, denileukin diftitox, and bexar.

[0117] When a compound of formula (I) is used to treat or prevent obesity, therapeutic agents which may be used in combination with the compound of formula (I) include gastric or pancreatic lipase inhibitors (such as orlistat); lipid lowering agents (such as statins, fibrates, niacin or its derivatives (such as acipimox), lecithin, bile acid sequestrants, ezetimibe, lomitapide, phytosterols, omega-3 supplements, PCSK9 inhibitors); CB-1 antagonists; lipoxygenase inhibitors; somostatin ( somostatin analogues; insulin compounds or insulin analogues (e.g., human insulin, insulin lispro, insulin aspart, insulin glulisine, insulin glargine, insulin degludec); insulin sensitizers such as PPAR-gamma agonists, PPAR-alpha agonists, or mixed PPAR-gamma / alpha agonists (e.g., metformin, pioglitazone, or rosiglitazone); insulin secretagogues (e.g., nateglinide or repag linide, or sulfonylureas such as gliclazide, glimeperide, limepiride, or glyburide; SGLT2 inhibitors (such as dapagliflozin, canagliflozin, or empagliflozin); amylin analogs (such as pramlintide); DPPIV inhibitors (such as sitagliptin, saxagliptin, linagliptin, alogliptin, or vildagliptin); GLP-1 agonists (albiglutide, dulaglutide, exenatide, liraglutide, semaglutide, or lixisenatide); alpha-glucosidase inhibitors (such as acarbose, miglitol, or voglibose); phosphodiesterase inhibitors (such as pentoxifylline); glycogen phosphorylase inhibitors; MCH-1 antagonists; glucokinase activators; glucagon antagonists; insulin signaling agonists; PTP1B inhibitors; gluconeogenesis inhibitors; GSK inhibitors or galanin receptor agonists.

[0118] When the compounds of formula (I) are used to treat or prevent diabetic diseases, therapeutic agents that may be used in combination with the compounds of formula (I) include gastric or pancreatic lipase inhibitors (such as orlistat); lipid lowering agents (such as statins, fibrates, niacin or its derivatives (such as acipimox), lecithin, bile acid sequestrants, ezetimibe, lomitapide, phytosterols, omega-3 supplements, PCSK9 inhibitors); CB-1 antagonists; lipoxygenase inhibitors; somostat. somostatin analogs; insulin compounds or insulin analogs (e.g., human insulin, insulin lispro, insulin aspart, insulin glulisine, insulin glargine, insulin degludec); insulin sensitizers such as PPAR-gamma agonists, PPAR-alpha agonists, or mixed PPAR-gamma / alpha agonists (e.g., metformin, pioglitazone, or rosiglitazone); insulin secretagogues (e.g., nateglinide or levoglitinide); paglinide, or sulfonylureas such as gliclazide, glimeperide, limepiride, or glyburide; SGLT2 inhibitors (such as dapagliflozin, canagliflozin, or empagliflozin); amylin analogs (such as pramlintide); DPPIV inhibitors (such as sitagliptin, saxagliptin, linagliptin, alogliptin, or vildagliptin); GLP-1 agonists (albiglutide, dulaglutide) , exenatide, liraglutide, semaglutide, or lixisenatide); alpha-glucosidase inhibitors (such as acarbose, miglitol, or voglibose); phosphodiesterase inhibitors (such as pentoxifylline); glycogen phosphorylase inhibitors; MCH-1 antagonists; glucokinase activators; glucagon antagonists; insulin signaling agonists; PTP1B inhibitors; gluconeogenesis inhibitors; GSK inhibitors or galanin receptor agonists.

[0119] Compounds of formula (I) have the following desirable properties: Low EC for PKM2 activation 50 Value and / or high Emax value; Low EC for PKLR activation 50 Value and / or high E max value; Low EC for activation of PKM2 and PKLR 50 Value and / or high E max value; Low IC for reduced cell proliferation 50 value; Reduced dose and dosing frequency due to improved pharmacokinetics; · Improved oral systemic bioavailability; Decreased plasma clearance after intravenous administration; Enhanced cell permeability; Low toxicity at appropriate therapeutic doses may indicate one or more of:

[0120] (abbreviation) [Table 1] TIFF2025501756000013.tif249170TIFF2025501756000014.tif71170 EXAMPLES

[0121] (Example) (Analysis equipment) NMR spectra were recorded using a Bruker 400MHz Avance III™ spectrometer fitted with a BBFO 5mm probe or a Bruker 500MHz Avance II™ I HD spectrometer fitted with a Bruker 5mm SmartProbe™. Spectra were measured at 298K and referenced to the solvent resonance unless otherwise indicated. Chemical shifts are reported in parts per million. Data was acquired using Bruker TopSpin software.

[0122] UPLC / MS analysis was performed on a Waters™ Acquity UPLC system using either a Waters™ Acquity CSH C18 or BEH C18 column (2.1 x 30 mm) maintained at a temperature of 40°C and eluted at a constant flow rate of 0.77 mL / min for 3 or 10 min with a linear acetonitrile gradient appropriate for the lipophilicity of the compound. The aqueous portion of the mobile phase was either 0.1% formic acid (CSH C18 column) or 10 mM ammonium bicarbonate (BEH C18 column). LC-UV chromatograms were recorded between 210 and 400 nm using a Waters™ Acquity PDA detector. Mass spectra were recorded using a Waters™ Acquity Qda detector with electrospray ionization switched between positive and negative ion modes. Sample concentrations were adjusted to obtain an appropriate UV response.

[0123] LCMS analysis was performed on an Agilent LCMS system using either a Waters™ Acquity CSH C18 (4.6×30 mm) or BEH C18 column (4.6×30 mm) maintained at a temperature of 40° C. and eluted at a constant flow rate of 2.5 mL / min for 4 or 15 min with a linear acetonitrile gradient appropriate for the lipophilicity of the compound. The aqueous portion of the mobile phase was either 0.1% formic acid (CSH C18 column) or 10 mM ammonium bicarbonate (BEH C18 column). LC-UV chromatograms were recorded at 254 nm using an Agilent VWD or DAD detector. Mass spectra were recorded using an Agilent MSD detector with electrospray ionization switched between positive and negative ion modes. Sample concentrations were adjusted to obtain an appropriate UV response.

[0124] (Commercially available materials) All starting materials and solvents were either obtained from commercial suppliers or prepared according to the literature.

[0125] (Example 1: 6-((1H-pyrazol-4-yl)sulfonyl)-2-((1-cyclopropyl-1H-pyrazol-3-yl)methyl)phthalazin-1(2H)-one) (Synthetic Route 1) (Synthesis of 3-(chloromethyl)-1-cyclopropyl-1H-pyrazole hydrochloride) [ka] SOCl2 (206 μL, 2.82 mmol, 3.00 equiv) was added dropwise to a stirred solution of commercially available 1-cyclopropyl-1H-pyrazol-3-yl)methanol (130 mg, 941 μmol, 1 equiv) in DCM (5 mL) at 0° C. The resulting mixture was stirred at room temperature for 20 h and then evaporated under reduced pressure. The residue was co-evaporated three times with toluene to give the title compound (0.16 g) as a dark orange oil. MS (ES + ):157 / 159(M+H) + . 1-Cyclopropyl-1H-pyrazol-3-yl)methanol can also be prepared as described herein below.

[0126] (Synthesis of 6-((1H-pyrazol-4-yl)sulfonyl)-2-((1-cyclopropyl-1H-pyrazol-3-yl)methyl)phthalazin-1(2H)-one) [ka] (Process 1) A stirred suspension of commercially available 6-bromophthalazin-1(2H)-one (407 mg, 1 equiv, 1.81 mmol) and cesium carbonate (2.36 g, 4.0 equiv, 7.24 mmol) in DMF (10 mL) was heated to 85° C. for 2 h and then allowed to cool to room temperature. A solution of 3-(chloromethyl)-1-cyclopropyl-1H-pyrazole hydrochloride (349 mg, 100 wt %, 1 equiv, 1.81 mmol) in DMF (2 mL) was added and the reaction mixture was stirred at room temperature for 18 h. Water (50 mL) was added and the resulting solid was collected by filtration and washed with water to give 6-bromo-2-((1-cyclopropyl-1H-pyrazol-3-yl)methyl)phthalazin-1(2H)-one (500 mg) as a yellow solid. MS (ES) + ):345(M+H) +

[0127] (Process 2) A suspension of 6-bromo-2-((1-cyclopropyl-1H-pyrazol-3-yl)methyl)phthalazin-1(2H)-one (500 mg, 79 wt%, 1 equiv, 1.14 mmol) in DMF (8 mL) was aerated with N2 for 10 min. DIPEA (223 mg, 300 μL, 1.51 equiv, 1.72 mmol), Xantphos (84 mg, 0.13 equiv, 0.15 mmol), Pd2(dba)3 (66 mg, 0.063 equiv, 72 μmol), and 2-ethylhexyl 3-mercaptopropanoate (384 mg, 400 μL, 1.54 equiv, 1.76 mmol) were added sequentially. The reaction mixture was stirred at 120 °C under N2 for 1 h. The reaction mixture was allowed to cool to room temperature and then partitioned between EtOAc (50 mL) and saturated aqueous NaHCO3 (50 mL). The organic layer was collected and the aqueous layer was extracted with EtOAc (50 mL). The combined organic extracts were washed with 50% brine (50 mL), brine (50 mL), dried (MgSO4) and concentrated in vacuo to give the crude product. The crude product was purified by chromatography on silica gel to give 2-ethylhexyl 3-((2-((1-cyclopropyl-1H-pyrazol-3-yl)methyl)-1-oxo-1,2-dihydrophthalazin-6-yl)thio)propanoate (630 mg) as a yellow oil. MS (ES) +):483(M+H) +

[0128] (Step 3) A solution of 2-ethylhexyl 3-((2-((1-cyclopropyl-1H-pyrazol-3-yl)methyl)-1-oxo-1,2-dihydrophthalazin-6-yl)thio)propanoate (630 mg, 88 wt%, 1 equiv, 1.15 mmol) in THF (10 mL) was treated with sodium ethoxide (1.04 g, 1.20 mL, 21 wt%, 2.80 equiv, 3.21 mmol). The reaction mixture was stirred at room temperature for 15 min and then water (10 mL) was added. The mixture was acidified with 1M HCl(aq) and then extracted with EtOAc (3×40 mL). The combined organic extracts were washed with brine (40 mL), dried (MgSO4) and concentrated in vacuo to give the crude product as an orange solid. The crude product was purified by chromatography on silica gel to give the title compound (379 mg) as a pale yellow solid. MS (ES + ):299(M+H) +

[0129] (Step 4) Nitrogen was bubbled through a mixture of 2-((1-cyclopropyl-1H-pyrazol-3-yl)methyl)-6-mercaptophthalazin-1(2H)-one (100 mg, 1 eq, 335 μmol), tert-butyl 4-iodo-1H-pyrazole-1-carboxylate (123 mg, 1.25 eq, 419 μmol), 1,10-phenanthroline (24.2 mg, 0.4 eq, 134 μmol), and potassium carbonate (92.6 mg, 2 eq, 670 μmol) in DMF (1.5 mL) for 5 min. Copper(I) iodide (12.8 mg, 0.2 eq, 67.0 μmol) was added and the mixture was stirred at 100° C. under nitrogen overnight and then allowed to cool to room temperature. Water and DCM were added and the layers were separated through a phase separator. The organic layer was washed with brine and absorbed onto silica. The crude product was purified by chromatography on silica gel (12 g cartridge, 0-100% 10% MeOH / DCM:DCM) to give 6-((1H-pyrazol-4-yl)thio)-2-((1-cyclopropyl-1H-pyrazol-3-yl)methyl)phthalazin-1(2H)-one as a white solid (38 mg). The aqueous layer was acidified with 1N HCl and back extracted with DCM. The organic layer was washed with brine and then absorbed onto silica. The crude product was purified by chromatography on silica gel (4 g cartridge, 0-100% 10% MeOH / DCM:DCM). Both batches were combined to give 6-((1H-pyrazol-4-yl)thio)-2-((1-cyclopropyl-1H-pyrazol-3-yl)methyl)phthalazin-1(2H)-one (74 mg, 99% purity) as a white solid. MS (ES+): 365 (M+H)+

[0130] (Step 5) A mixture of 6-((1H-pyrazol-4-yl)thio)-2-((1-cyclopropyl-1H-pyrazol-3-yl)methyl)phthalazin-1(2H)-one (74 mg, 1 eq, 0.20 mmol) and oxone (0.26 g, 2.1 eq, 0.43 mmol) in DMF (1 mL) was stirred for 3.5 h. Water and DCM were added and the layers were separated through a phase separator. The organic layer was washed with brine and then absorbed onto silica. The crude product was purified by chromatography on silica gel (4 g cartridge, 0-75% 10% MeOH / DCM:DCM) to give 6-((1H-pyrazol-4-yl)sulfonyl)-2-((1-cyclopropyl-1H-pyrazol-3-yl)methyl)phthalazin-1(2H)-one (32.3 mg, 99% purity) as a white solid. [ka]

[0131] (Synthetic Route 2) (Synthesis of 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-4-thiol) [ka] (Process 1) To a solution of 4-iodo-1H-pyrazole (200 g, 1031 mmol) and 3,4-dihydro-2H-pyran (130 g, 1546 mmol) in MeCN (3 L) was added TsOH (1.77 g, 10.3 mmol) at room temperature. The reaction mixture was stirred at 85 °C for 16 h. After LCMS showed the reaction was complete, the mixture was concentrated under reduced pressure at 45 °C. The residue was purified by flash column chromatography (120 g × 8, petroleum ether / tert-butyl methyl ether = 100:00 to 83:17) to give 4-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (200 g, 92.32% purity) as a white solid. MS (ES + ):279.2(M+H) +

[0132] (Process 2) To a solution of 4-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (200 g, 719 mmol), 2-ethylhexyl 3-mercaptopropanoate (204 g, 935 mmol), Pd2dba3 (16 g, 18 mmol), and Xantphos (21 g, 36 mmol) in DMF (3 L) was added DIPEA (278 g, 2157 mmol) at room temperature. The reaction mixture was stirred at 100 °C for 16 h. After LCMS showed the reaction was complete, the mixture was quenched with water (2 L) and extracted with EtOAc (1600 mL x 3). The combined organic layers were washed with aqueous NH4Cl, dried over Na2SO4, filtered, and concentrated under reduced pressure at 45 °C. The residue was purified by flash column chromatography (120 g × 10, petroleum ether / tert-butyl methyl ether = 100:00 to 80:20) to give 2-ethylhexyl 3-((1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)thio)propanoate (140 g, 91.91% purity) as a yellow oil. MS (ES) + ):369.3(M+H) +

[0133] (Step 3) To a mixture of 2-ethylhexyl 3-((1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)thio)propanoate (90 g, 244 mmol) in THF (1.2 L) was added EtONa (195 mL, 488 mmol, solution 2.5 M in EtOH) at 0° C. The reaction was stirred at 0° C. for 0.5 h. After LCMS showed the reaction was complete, the reaction mixture was quenched with HCl (1 M) until the pH was 6. The mixture was extracted with EtOAc (500 mL×3). The organic layer was concentrated under reduced pressure at 40° C. The residue was purified by flash column chromatography (120 g x 3, petroleum ether / tert-butyl methyl ether = 100:0-63:37) to give 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-4-thiol (40 g, 80.54% purity) as an oil. MS (ES + ):185.3(M+H)+

[0134] (Synthesis of 3-(chloromethyl)-1-cyclopropyl-1H-pyrazole) [ka] (Process 1) To a mixture of methyl 1H-pyrazole-3-carboxylate (100 g, 793.65 mmol) in dichloroethane (DCE) (2000 mL) was added cyclopropylboronic acid (137.9 g, 1587.30 mmol), sodium carbonate (133.3 g, 1587.30 mmol), 2,2'-bipyridine (2,2-biPy) (123.8 g, 793.65 mmol), and copper acetate (144.2 g, 793.65 mmol). The reaction mixture was stirred at 70° C. under oxygen atmosphere for 40 h. After LCMS showed the reaction was complete, the reaction mixture was concentrated under reduced pressure at 45° C., then quenched with water (1000 mL) and extracted with EtOAc (1000 mL×3). The combined organic layers were washed with saturated HCl (aq.) (1000 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure at 45 °C. The residue was purified by flash column chromatography (120 g cartridge, eluted with 0-70% petroleum ether / tert-butyl methyl ether, 55%) to give methyl 1-cyclopropyl-1H-pyrazole-3-carboxylate (48.0 g, 95.20% purity) as a colorless oil. MS (ES) + ):167.4(M+H) +

[0135] (Process 2) To a solution of methyl 1-cyclopropyl-1H-pyrazole-3-carboxylate (48.0 g, 289.16 mmol) in THF (400 mL) was added lithium aluminum hydride (LAH) (138.8 mL, 346.99 mmol, 2.5 M) at 0 °C, and the reaction mixture was stirred at 0 °C for 1 h. After LCMS showed the reaction was complete, the mixture was quenched with Na2SO4·10H2O, filtered, and concentrated under reduced pressure at 45 °C. The residue was purified by flash column chromatography (120 g, eluted with 0-100% petroleum ether / tert-butyl methyl ether, 100%) to give (1-cyclopropyl-1H-pyrazol-3-yl)methanol (28.12 g, 100% purity) as a colorless oil. [ka]

[0136] (Step 3) To a solution of (1-cyclopropyl-1H-pyrazol-3-yl)methanol (22.2 g, 161 mmol) in DCM (0.5 L) was added SOCl2 (19 mL, 225 mmol) and the mixture was stirred at room temperature for 30 min. After LCMS showed the reaction was complete, the mixture was concentrated and diluted with water (100 mL). The mixture was alkalized with K2CO3 to pH 8 and extracted with DCM (100 mL x 3). The organic layer was dried over Na2SO4 and concentrated under reduced pressure at 40 °C to give ethyl 3-(chloromethyl)-1-cyclopropyl-1H-pyrazole (25 g, 96% purity) as a yellow oil. MS (ES) + ):157.3(M+H) +

[0137] (Synthesis of 6-((1H-pyrazol-4-yl)sulfonyl)-2-((1-cyclopropyl-1H-pyrazol-3-yl)methyl)phthalazin-1(2H)-one) [ka] (Process 1) To a mixture of 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-4-thiol (40 g, 217 mmol), commercially available 6-bromophthalazin-1(2H)-one (34.9 g, 155 mmol), CuI (4.1 g, 21.7 mmol), and 1,2,3-benzotriazole (5.1 g, 43.4 mmol) in N-methyl-2-pyrrolidone (NMP) (1.3 L) was added t-BuOK (34.7 g, 310 mmol) at room temperature. The reaction was stirred overnight at 100° C. under a nitrogen atmosphere. After LCMS showed the reaction was complete, the reaction mixture was added to water (3 L), stirred at room temperature for 3 hours, and filtered. The residue was lyophilized to give 6-((1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)thio)phthalazin-1(2H)-one (45 g, 97% purity) as a greenish-grey solid. MS (ES) + ):329.2(M+H) +

[0138] (Process 2) A mixture of 6-((1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)thio)phthalazin-1(2H)-one (45 g, 137 mmol) and Cs2CO3 (89 g, 274 mmol) in DMF (150 mL) was stirred at 70° C. for 1 h. The reaction mixture was cooled to room temperature and ethyl 3-(chloromethyl)-1-cyclopropyl-1H-pyrazole (25 g, 159 mmol) was added and stirred at room temperature for 5 h. After LCMS showed the reaction was complete, the mixture was diluted with water (500 mL) and extracted with EtOAc (600 mL×3). The combined organic extracts were washed with saturated aqueous NH4Cl (800 mL x 2), concentrated under reduced pressure at 45 °C, and purified by flash column chromatography (120 g x 8, petroleum ether / ethyl acetate = 100:0 to 30:70) to give 2-((1-cyclopropyl-1H-pyrazol-3-yl)methyl)-6-((1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)thio)phthalazin-1(2H)-one (38 g, 92% purity) as a yellow solid. MS (ES) + ):449.2(M+H) +

[0139] (Step 3) To a mixture of 2-((1-cyclopropyl-1H-pyrazol-3-yl)methyl)-6-((1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)thio)phthalazin-1(2H)-one (38 g, 84.72 mmol) in DMF (150 mL) was added oxone (156.3 g, 245.2 mmol) at room temperature. The reaction was stirred at 60° C. for 1 h. After LCMS showed the reaction was complete, the mixture was filtered and the filter cake was washed with EtOAc until no residue remained. The filtrate was diluted with saturated aqueous NaHCO3 (800 mL), separated and extracted with EtOAc (700 mL×3). The combined organic layer was washed with saturated aqueous NH4Cl (800 mL x 2), concentrated under reduced pressure at 45 °C, and purified by flash column chromatography (120 g x 3, dichloromethane / methanol = 100:00 to 97:3) to give the crude product. First, the crude was triturated with MeCN (2 x 300 mL) to give a white solid. The residue was dissolved in DMSO, and the corresponding solution was added to H2O with stirring. The precipitate was collected and dried to give the title compound (25.5 g, 100% purity) as a white solid. [ka]

[0140] Biological Example 1 - Human PKM2 Activation Assay Measurement of in vitro activation of recombinant human PKM2 Compound activation of recombinant human PKM2 pyruvate kinase activity was determined by biochemical assay. N-terminal His-tagged hPKM2 was supplied by R&D Systems, and its substrates phosphoenolpyruvate (PEP) and ADP were supplied by Sigma-Aldrich and 2Bscientific, respectively. Kinase-Glo® Plus luminescent assay was obtained from Promega. All other reagents were obtained from Sigma-Aldrich. Test compounds were prepared as 10 mM DMSO stocks and dilution series were prepared in DMSO for direct dilution into assay buffer (pH 7.2) containing 50 mM imidazole, 50 mM KCl, 7 mM MgCl2, 0.01% Tween20, 0.05% BSA.

[0141] Assay Procedure Human PKM2 was diluted in assay buffer (pH 7.2) containing 50 mM imidazole, 50 mM KCl, 7 mM MgCl2, 0.01% Tween20, 0.05% BSA to a final concentration of 5 pM. The Enzyme-Assay Buffer mix was dispensed into a 384-well shallow-well white-walled plate (PerkinElmer) and test compounds were added by acoustic dispense (Echo®, Labcyte). After 10 min incubation at room temperature, the enzyme reaction was initiated by ultrasonic dispense of ADP+PEP substrate to a final concentration of 254 μM ADP and 53 μM ADP.

[0142] After 60 min of incubation on an orbital shaker (300 rpm, 26° C.), enzyme activity was quantified by luminescent detection of the ATP generated. Kinase-Glo® Plus reagent was added to each well and the plate was incubated for an additional 15 min on an orbital shaker in the dark (300 rpm, 26° C.) before measuring luminescence in a plate reader (PHERAstar® FSX, BMG Labtech).

[0143] Percentage activation was calculated by normalizing the fluorescent signal to the LOW (DMSO vehicle) and HIGH (5 μM TEPP-46) controls on the plate. EC 50 Value and E max value was determined.

[0144] Example 1 was tested. The results are shown below in Table 1. Mitapivat was tested as a comparative compound. (Table 1 - PKM2 EC 50 Value (μM) and E max value(%)) [Table 2] *Data from replicate experiments

[0145] Example 1 shows a lower EC 50 Value and higher E max As demonstrated by the values, it showed improved PKM2 modulator activity compared to mitapivat.

[0146] Biological Example 2 - Human PKLR Activation Assay Measurement of in vitro activation of recombinant human PKLR Compound activation of recombinant human PKLR pyruvate kinase activity was determined by biochemical assay. N-terminal His-tagged enzyme was supplied by R&D Systems, and its substrates phosphoenolpyruvate (PEP) and ADP were supplied by Sigma-Aldrich and 2Bscientific, respectively. Kinase-Glo® Plus luminescence assay was obtained from Promega. All other reagents were obtained from Sigma-Aldrich. Test compounds were prepared as 10 mM DMSO stocks, and dilution series were prepared in DMSO for direct dilution into assay buffer (pH 7.2) containing 50 mM imidazole, 50 mM KCl, 7 mM MgCl2, 0.01% Tween20, 0.05% BSA.

[0147] Assay Procedure Human PKLR was diluted in assay buffer to a final concentration of 5 pM. The Enzyme-Assay Buffer mix was dispensed into a 384-well shallow-well white-walled plate and test compounds were added by ultrasonic dispensing (Echo®, Labcyte). After 10 min incubation at room temperature, the enzyme reaction was initiated by ultrasonic dispensing of ADP+PEP substrate to a final concentration of 254 μM ADP and 53 μM ADP.

[0148] After 60 min of incubation on an orbital shaker (300 rpm, 26° C.), enzyme activity was quantified by luminescent detection of the ATP generated. Kinase-Glo® Plus reagent was added to each well and the plate was incubated for an additional 15 min in the dark on an orbital shaker (300 rpm, 26° C.) before measuring luminescence in a plate reader (PHERAstar® FSX, BMG Labtech).

[0149] Percentage activation was calculated by normalizing the fluorescent signal to the LOW (DMSO vehicle) and HIGH (5 μM TEPP-46) controls on the plate. EC50 Value and E max value was determined.

[0150] Example 1 was tested and the results are shown below in Table 2. Mitapivat was tested as a comparative compound. (Table 2 - PKLR EC 50 Value (μM) and E max value(%)) [Table 3] *Data from replicate experiments

[0151] Example 1 was tested in this assay and showed a lower EC 50 Value and / or higher E max As demonstrated by the values, it showed improved PKLR modulator activity compared to mitapivat.

[0152] Biological Example 3 - CD4+ T Cell Pyruvate Kinase Assay (Measurement of pyruvate kinase (PK) activity in human CD4+ T cell lysates) PKM2 activators increase pyruvate kinase activity of both recombinant human PKM2 protein and PKM2 in human cell lysates (Kung et al., 2012). Compound activation of pyruvate kinase in human CD4+ T cell lysates was determined by a biochemical assay. To improve the disease relevance of the assay, primary CD4+ T cells were used rather than cancer cell lines. PK assays were sourced from Abcam. All other reagents were sourced from ThermoFisher. Test compounds were prepared as 10 mM DMSO stocks and serial dilutions were prepared in DMSO for addition to intact CD4+ T cells cultured in RPMI medium containing 10% FBS.

[0153] Assay Procedure Human CD4+ T cells were incubated with compound for 20 minutes, then washed twice in 1x PBS and resuspended in Abcam PK lysis buffer to prepare cell lysates. 10μl PK assay Reaction Mix containing OXIRED™ PROBE was added to each well. Plates were read at OD570nm in kinetic mode for 48 minutes (25 cycles of 2 minutes) at 25°C in the dark using a BMG Labtech Pherastar plate reader.

[0154] (Data Analysis) Blanks were subtracted from the plates and delta absorbance was calculated by subtracting the first plate reading within the linear range from the plate reading at the time point of interest. PK activity is expressed as delta absorbance and plotted against log[compound].

[0155] Example 1 was tested and the results are shown below in Table 3. Mitapivat was tested as a comparative compound. (Table 3 - CD4+ T cell pyruvate kinase activity) [Table 4]

[0156] Example 1 was tested in this assay and has an EC 50 As demonstrated by the values, it showed improved pyruvate kinase activity compared to mitapivat.

[0157] (References) [Table 5]

[0158] (others) All references mentioned in this application, including patents and patent applications, are incorporated by reference to the fullest extent possible.

[0159] Unless the context requires otherwise, throughout this specification and the claims which follow, the word "comprise", as well as variations such as "comprises" and "comprising", are understood to mean the inclusion of a stated integer, step, group of integers, or group of steps, but not to the exclusion of any other integer, step, group of integers, or group of steps.

[0160] This application of which this specification and claims form part may be used as a basis for priority in respect of any subsequent application. The claims of such subsequent application may be directed to any or any combination of features described herein. They may take the form of product, composition, process, or use claims and may include, by way of example and without limitation, the following claims:

Claims

1. 6-((1H-pyrazol-4-yl)sulfonyl)-2-((1-cyclopropyl-1H-pyrazol-3-yl)methyl)phthalazin-1(2H)-one, formula (I): 【Chemistry 1】 or a salt and / or solvate thereof.

2. 2. The compound according to claim 1, which is a compound of formula (I) or a pharma- ceutically acceptable salt and / or solvate thereof.

3. 3. The pharma- ceutical acceptable salts and solvates thereof according to claim 2.

4. 3. A pharma- ceutical acceptable salt according to claim 2.

5. 3. A pharma- ceutical acceptable solvate according to claim 2.

6. 2. The compound of claim 1.

7. A pharmaceutical composition comprising a compound according to any one of claims 2 to 6 or a pharma- ceutically acceptable salt and / or solvate thereof, and one or more pharma- ceutically acceptable diluents or carriers.

8. A compound according to any one of claims 2 to 6 or a pharma- ceutically acceptable salt and / or solvate thereof, or a pharmaceutical composition according to claim 7, for use as a medicament.

9. A compound according to any one of claims 2 to 6 or a pharma- ceutically acceptable salt and / or solvate thereof, or a pharmaceutical composition according to claim 7, for use in the treatment or prevention of a disease, disorder or condition associated with the function of PK, in particular PKM2 and / or PKLR.

10. Use of a compound according to any one of claims 2 to 6 or a pharma- ceutically acceptable salt and / or solvate thereof, or a pharmaceutical composition according to claim 7, in the manufacture of a medicament for the treatment or prevention of a disease, disorder or condition associated with the function of PK, in particular PKM2 and / or PKLR.

11. A method for treating a subject suffering from a disease, disorder or condition associated with the function of PK, in particular PKM2 and / or PKLR, said method comprising administering to said subject an effective amount of a compound according to any one of claims 2 to 6 or a pharma- ceutically acceptable salt and / or solvate thereof, or a pharmaceutical composition according to claim 7.

12. A compound according to any one of claims 2 to 6 or a pharma- ceutically acceptable salt and / or solvate thereof, or a pharmaceutical composition according to claim 7, for use in the treatment or prevention of an inflammatory disease, a disease associated with an undesired immune response, cancer, obesity, a diabetic disease, or a blood disorder.

13. Use of a compound according to any one of claims 2 to 6 or a pharma- ceutically acceptable salt and / or solvate thereof, or a pharmaceutical composition according to claim 7, in the manufacture of a medicament for treating or preventing an inflammatory disease, a disease associated with an undesired immune response, cancer, obesity, a diabetic disease, or a blood disorder.

14. 13. A method of treating a subject with an inflammatory disease, a disease associated with an unwanted immune response, cancer, obesity, a diabetic disease, or a blood disorder, comprising administering to the subject an effective amount of a compound according to any one of claims 2 to 6 or a pharma- ceutically acceptable salt and / or solvate thereof, or a pharmaceutical composition according to claim 7.

15. The inflammatory disease or disease associated with an undesired immune response is: psoriasis (including chronic plaque psoriasis, erythrodermic psoriasis, pustular psoriasis, guttate psoriasis, inverse psoriasis, and nail psoriasis), asthma, chronic obstructive pulmonary disease (including COPD, chronic bronchitis, and emphysema), heart failure (including left ventricular failure), myocardial infarction, angina pectoris, other atherosclerosis and / or atherothrombosis related disorders (including peripheral vascular disease and ischemic stroke), mitochondrial and neurodegenerative diseases (including Parkinson's disease, Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis, retinitis pigmentosa, or mitochondrial encephalomyopathy), autoimmune paraneoplastic retinopathy, transplant rejection (including antibody-mediated and T-cell mediated forms), multiple sclerosis, transverse myelitis, ischemia-reperfusion injury (e.g., during elective surgery such as cardiopulmonary bypass for coronary artery bypass grafting or other cardiac surgery, following percutaneous coronary intervention, treatment of acute ST-segment elevation myocardial infarction or ischemic stroke, organ transplantation, or after acute compartment syndrome), AGE-induced genomic damage, inflammatory bowel disease (e.g., Crohn's disease or ulcerative colitis), primary sclerosing cholangitis (PSC), PSC-autoimmune hepatitis overlap syndrome, nonalcoholic fatty liver disease (nonalcoholic steatohepatitis), rheumatoid, granuloma annulare, cutaneous lupus erythematosus (CLE), systemic lupus erythematosus (SLE), lupus nephritis, drug-induced lupus, autoimmune myocarditis or myopericarditis, dread Sluller syndrome, giant cell myocarditis, post-pericardiotomy syndrome, drug-induced hypersensitivity syndrome (including hypersensitivity myocarditis), eczema, sarcoidosis, erythema nodosum, acute disseminated encephalomyelitis (ADEM), neuromyelitis optica spectrum disorder, myelin oligodendrocyte glycoprotein (MOG) antibody-associated disorders (including MOG-EM), optic neuritis, CLIPPERS (chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids), diffuse myelinoclastic sclerosis, Addison's disease, alopecia areata, ankylosing spondylitis, other spondyloarthritis (including peripheral spondyloarthritis associated with psoriasis, inflammatory bowel disease, reactive arthritis, or juvenile-onset forms of spondyloarthritis), antiphospholipid syndrome, autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune inner ear disease, pemphigoid (bullous pemphigoid, mucous membrane pemphigoid, cicatricial pemphigoid,Herpes gestationis or pemphigoid of gestationis, including ophthalmic cicatricial pemphigoid), linear IgA disease, Behcet's disease, celiac disease, Chagas disease, dermatomyositis, type I diabetes mellitus, endometriosis, Goodpasture's syndrome, Graves' disease, Guillain-Barré syndrome and its subtypes (acute inflammatory demyelinating polyneuropathy, AIDP, acute motor axonal neuropathy (AMAN), acute motor and sensory axonal neuropathy (AMSAN), pharyngeal - including cervicobachial, Miller-Fisher, and Bickerstaff brainstem encephalitis), progressive inflammatory neuropathy, Hashimoto's disease, hidradenitis suppurativa, inclusion body myositis, necrotizing myopathy, Kawasaki disease, IgA nephropathy, Henoch-Schonlein purpura, idiopathic thrombocytopenic purpura, thrombotic thrombocytopenic purpura (TTP), Evans syndrome, interstitial cystitis, mixed connective tissue disease, undifferentiated connective tissue disease, morphea, myasthenia gravis (MuSK antibodies) positive and seronegative types), narcolepsy, neuromyotonia, pemphigus vulgaris, pernicious anemia, psoriatic arthritis, polymyositis, primary biliary cholangitis (also known as primary biliary cirrhosis), rheumatoid arthritis, relapsing rheumatoid arthritis, schizophrenia, autoimmune (meningo)encephalitis syndrome, scleroderma, Sjögren's syndrome, stiff-body syndrome, polymyalgia rheumatica, giant cell arteritis (temporal arteritis), Takayasu's arteritis, polyarteritis nodosa, Kawasaki disease, granulomatous polyangiitis Granulomatosis with polyangiitis (GPA; formerly Wegener's granulomatosis), eosinophilic granulomatosis with polyangiitis (EGPA; formerly Churg-Strauss syndrome), microscopic polyarteritis / polyangiitis, hypocomplementemic urticarial vasculitis, hypersensitivity vasculitis, cryoglobulinemia, thromboangiitis obliterans (Buerger's disease), vasculitis, leukocytoclastic vasculitis, vitiligo, acute disseminated encephalomyelitis, adrenoleukodystrophy, Alexander disease, Alper's disease disease), Barro concentric sclerosis or Marburg disease, idiopathic organizing pneumonia (formerly bronchiolitis obliterans organizing pneumonia), Canavan disease, central nervous system vasculitis syndrome, Charcot-Marie-Tooth disease, ataxia of childhood with central nervous system hypomyelination, chronic inflammatory demyelinating polyneuropathy (CIDP), diabetic retinopathy, globoid cell leukodystrophy (Krabbe disease), graft-versus-host disease (GVHD) (including acute and chronic forms and intestinal GVHD), hepatitis C (HCV) infection or complications, herpes simplex virus infection or complications,Human immunodeficiency virus (HIV) infection or complications, lichen planus, Hirayama disease, fibrosis, cystic fibrosis, pulmonary arterial hypertension (PAH, including idiopathic PAH), pulmonary sarcoidosis, idiopathic pulmonary fibrosis, renal fibrosis, childhood asthma, atopic dermatitis, allergic dermatitis, contact dermatitis, allergic rhinitis, rhinitis, sinusitis, conjunctivitis, allergic conjunctivitis, keratoconjunctivitis sicca, dry eye, xerophthalmia, glaucoma, macular edema, diabetic macular edema, central retinal vein occlusion (CRVO), macular degeneration (including dry and / or wet age-related macular degeneration, AMD), inflammation after cataract surgery, uveitis Autoimmune idiopathies (including posterior, anterior, intermediate and panuveitis), iridocyclitis, scleritis, corneal transplant and limbal cell graft rejection, gluten-sensitive enteropathy (celiac disease), dermatitis herpetiformis, eosinophilic esophagitis, esophageal obstruction, autoimmune autonomic neuropathy, autoimmune encephalomyelitis, autoimmune oophoritis, autoimmune orchitis, autoimmune pancreatitis, aortitis and periaortitis, autoimmune retinopathy, autoimmune urticaria, Behçet's disease, (idiopathic) Castleman's disease, Cogan's syndrome, IgG4-related disease, retroperitoneal fibrosis, juvenile idiopathic arthritis including systemic juvenile idiopathic arthritis (Still's disease), adult Human-onset Still's disease, lignoconjunctivitis, Mooren's ulcer, pityriasis lichenoides varioliformis (PLEVA, also known as Mucha-Habermann disease), multifocal motor neuropathy (MMN), childhood acute-onset neuropsychiatric syndromes (PANS) (including pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS)), paraneoplastic syndromes (including paraneoplastic cerebellar degeneration, Lambert-Eaton myasthenic syndrome, limbic encephalitis, brainstem encephalitis, opsoclonus-myoclonus ataxia syndrome, anti-NMDA receptor encephalitis, and thymoma-associated multisystem autoimmunity), perivenous encephalomyelitis, and reflex sympathetic dystrophy relapsing polychondritis, sperm and testicular autoimmunity, Susac syndrome, Tolosa-Hunt syndrome, Vogt-Koyanagi-Harada disease, antisynthetase syndrome, autoimmune enteropathy, X-linked immunodysregulation-polyendocrinopathy enteropathy (IPEX), microscopic colitis, autoimmune lymphoproliferative syndrome (ALPS), autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome (APEX), gout, pseudogout, amyloid (including AA or secondary amyloidosis), eosinophilic fasciitis (Schulman syndrome), progesterone hypersensitivity (including progesterone dermatitis),Familial Mediterranean fever (FMF), tumor necrosis factor (TNF) receptor-associated periodic fever syndrome (TRAPS), hyperglobulinemia with periodic fever syndrome (HIDS), PAPA (septic arthritis, pyoderma gangrenosum, severe cystic acne) syndrome, deficiency of interleukin-1 receptor antagonist (DIRA), deficiency of interleukin-36-receptor antagonist (DITRA), cryopyrin-associated periodic syndrome (CAPS) (familial cold autoinflammatory syndrome [FCAS], myelopathy), and myelopathy. NLRP12-associated autoinflammatory disorder (NLRP12AD), periodic febrile aphthous stomatitis (PFAPA), chronic atypical neutrophilic dermatosis with lipodystrophy and hyperthermia (CANDLE), Majeed syndrome, Blau syndrome (also known as juvenile systemic granulomatosis), macrophage activation syndrome, chronic relapsing multifocal osteomyelitis (CRMO), familial cold autoinflammatory syndrome, mutant adenosine deaminase Ze2 and monogenic interferonopathies (including Aicardi-Goutieres syndrome, retinal vasculopathy with cerebral leukodystrophy, spinal intrachondrodysplasia, infantile-onset STING [stimulator of interferon genes]-associated vasculopathy, proteasome-associated autoinflammatory syndrome, familial lupus pernio, hereditary symmetrical pigmentary dysplasia), Schnitzler syndrome; familial cylindromatosis, congenital B-cell lymphocytosis, OTULIN-associated autoinflammatory syndrome, type 2 diabetes, insulin resistance and the compound for use, pharmaceutical composition for use, use or method according to any one of claims 12 to 14, which is or is associated with a disease selected from the group consisting of metabolic syndrome (including obesity-related inflammation), atherosclerotic disorders (e.g., myocardial infarction, angina pectoris, ischemic heart failure, ischemic renal damage, ischemic stroke, peripheral vascular disease, aortic aneurysm), and renal inflammatory disorders (e.g., diabetic nephropathy, membranous nephropathy, minimal change disease, crescentic glomerulonephritis, acute kidney injury, kidney transplant).

16. Formula (II): 【Chemistry 2】 or a salt (e.g., a pharma- ceutically acceptable salt) and / or solvate thereof.

17. Formula (III): 【Chemistry 3】 or a salt (e.g., a pharma- ceutically acceptable salt) and / or solvate thereof.

18. Formula (IV): 【Chemistry 4】 or a salt (e.g., a pharma- ceutically acceptable salt) and / or solvate thereof.

19. Formula (V): 【Chemistry 5】 or a salt (e.g., a pharma- ceutically acceptable salt) and / or solvate thereof.

20. Formula (II): 【Chemistry 6】 or a salt (e.g. a pharma- ceutically acceptable salt) and / or solvate thereof.

21. Formula (IV): 【Chemistry 7】 or a salt (e.g. a pharma- ceutically acceptable salt) and / or solvate thereof, wherein under the conditions of oxidation, the tetrahydropyran ring is removed.

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