Phthalazine derivatives as pyruvate kinase modulators

Abstract

The present invention relates to compounds of formula (Ia) and related aspects. # imgabs0 #

Description

TECHNICAL FIELD

[0001] The present invention relates to compounds and their use in the treatment or prevention of inflammatory diseases, diseases associated with unwanted immune responses, cancer, obesity, diabetic diseases or blood disorders, as well as related compositions, methods and intermediate compounds. BACKGROUND OF THE INVENTION

[0002] Pyruvate kinase (PK) is the enzyme responsible for the final rate-limiting step of glycolysis, catalyzing the conversion of phosphoenolpyruvate (PEP) and ADP into pyruvate and ATP. Four PK isotypes from two independent genes exist in mammals (Alves-Filho et al., 2016). PKL and PKR, the products of the Pklr gene, are expressed in the liver and red blood cells, respectively. PKM1 and PKM2 are alternative splicing products of the Pkm gene. PKM1 is expressed in tissues with high energy demands such as the heart, muscle, and brain, and PKM2 is expressed in embryonic tissues, cancer, and normal proliferating cells such as lymphocytes and intestinal epithelial cells. However, while PKM1 is a constitutively active enzyme, PKM2 is a low-activity enzyme that is allosterically activated by a variety of endogenous regulators such as the upstream glycolytic intermediate, fructose-1,6-bisphosphate (FBP). Binding of these allosteric regulators induces a conformational change that promotes the tetramerization of PKM2, resulting in an increase in the final rate-limiting step of glycolysis. Pyruvate will enter the TCA cycle in the mitochondria, where it is used to generate ATP via oxidative phosphorylation. In the absence of allosteric activation, PKM2 exists as a dimer or monomer with low enzyme activity, causing the accumulation of glycolytic intermediates that satisfy the biosynthetic precursor requirements of 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 targeting transcription factors and histones.

[0003] Cancer cells mainly utilize glycolysis to generate cellular energy and biosynthetic intermediates, a phenomenon known as the Warburg effect, and PKM2 plays a dominant role in the glycolysis that meets the nutrient requirements for cancer cell proliferation (Chhipa et al., 2018). PKM2 is overexpressed in almost all cancers and has been shown to promote the proliferation and metastasis of tumor cells. In addition to controlling glycolytic flux, the non-metabolic role of PKM2 as a co-activator and protein kinase promotes tumor formation (Dong et al., 2016). PKM2 binds directly to histone H3 and phosphorylates it, leading to the expression of c-Myc and cyclin D1 and cancer cell proliferation. Activation of PKM2 tetramers by small molecules could be an attractive cancer therapy that limits tumor growth by blocking the non-metabolic functions of dimeric PKM2.

[0004] After activation or inflammatory stimuli, PKM2 is upregulated in many immune cells, including macrophages and T cells ( et al., 2020). The non-metabolic role of dimeric PKM2 has been shown to regulate immune responses: PKM2 acts as a transcriptional co-activator of Hif-1α, β-catenin, and STAT3, leading to the expression of pro-inflammatory cytokines such as IL-1β and TNFα. Activation of PKM2 by small molecules that prevent nuclear translocation may have therapeutic benefits in a variety of inflammatory and autoimmune disorders, such as rheumatoid arthritis, inflammatory bowel disease, inflammatory skin lesions, coronary artery disease, and multiple sclerosis.

[0005] In diabetes, PKM2 regulates glucose-responsive pancreatic β-cell function and protects against metabolic stress (Abulizi et al., 2020; Lewandowski et al., 2020). Dimeric PKM2 functions in abnormal glycolysis by promoting the accumulation of HIF-1α, and in diabetic nephropathy, PKM2 is associated with the pathogenic role of fibrotic glomerular injury and epithelial-to-mesenchymal transition (Liu et al., 2020). Activation of PKM2 has been shown to enhance insulin release, improve insulin sensitivity, and prevent the development of diabetic glomerular pathology 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 fat accumulation that poses a risk to health and is associated with a higher incidence of type 2 diabetes and cardiovascular disease. This metabolic disorder is closely related to insulin resistance in obese individuals and adverse effects on glucose metabolism and handling (Barazzoni et al., 2018). Studies of 3T3-L1 adipocytes exposed to different levels of insulin have led to a significant increase in PKM2 mRNA levels, independent of the glucose level in the culture medium (Puckett et al., 2021). Studies of the effects of altered PKM2 phosphorylation status and the resulting decrease in catalytic activity have identified PKM2 as a potential facilitator of insulin resistance in adipose tissue and as being associated with the metabolic state in humans (Bettaieb et al., 2013). Restoration of PKM2 activity by small molecule allosteric activators has been shown to improve insulin sensitivity (Abulizi et al., 2020; Lewandowski et al., 2020) and warrants further investigation as a novel target for pharmacological intervention in obesity.

[0007] Pyruvate kinase deficiency (PKD) is one of the most common enzyme deficiencies in red blood cells, presenting as hemolytic anemia and accelerated destruction of red blood cells (Bianchi et al., 2020). Mature red blood cells rely entirely on glycolysis to maintain cell integrity and function, and thus pyruvate kinase plays a key role in red blood cell metabolism and survival. Genetic mutations in the PKR enzyme lead to dysregulation of its catalytic activity and cause cellular energy deficiency within red blood cells, as evidenced by lower pyruvate kinase activity, reduced ATP levels, and accumulation of upstream metabolites. Reduced PKR activity is also associated with changes in red blood cell morphology and cell membrane surface, indicating a broader relevance of this enzyme throughout the life cycle of these cells ( et al., 2018). PKD-deficient red blood cells are prematurely removed from the circulation by the spleen via accelerated hemolysis, causing iron accumulation. Increasing and / or restoring PKR activity to near-basal levels is thought to have the potential to treat PKD-related complications. The current standard treatment for PKD is supportive and includes blood transfusions, splenectomy, chelation therapy to address iron overload, and / or interventions for other treatments and disease-related morbidities. There are no approved therapies for treating the underlying cause of PKD. Activation of the PKR enzyme by small molecule allosteric activators can increase PKR enzyme activity and enhanced glycolysis in red blood cells from PKD patients (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 to demonstrate several potential benefits provided by enhancing PKR activity via allosteric regulation (Yi et al., 2021). Although these compounds exhibit good in vitro activity levels, their ADME and pharmacokinetic / pharmacodynamic profiles have precluded their development for treating human diseases. The structure of TEPP-46 is as follows:

[0009]

[0010] The most advanced PKR activator widely studied in the clinical setting is Mitapivat (AG-348), a PKM2 and PKLR activator that has been investigated for treating several blood disorders caused by PKR mutant forms that exhibit lower catalytic activity compared to their corresponding wild-type red blood cells (Kung et al., 2017). When administered to patients presenting with PKD, this agent demonstrates sufficient efficacy levels by increasing basal heme levels. However, despite promising results, high-dose regimens and BID (twice daily) dosing frequencies are required to achieve efficacy, highlighting the need to develop more effective compounds with more favorable pharmacokinetics and improved safety profiles (Grace et al., 2019). The structure of Mitapivat is as follows:

[0011]

[0012] WO2020 / 167976A1 (Agios Pharmaceuticals, Inc.) describes compounds that purportedly modulate PK activity and are used to treat cancer, obesity-related diabetes disorders.

[0013] WO2023 / 052783, WO2023 / 079294, and WO2023 / 118875 (Sitryx Therapeutics Limited) disclose compounds as PK modulators.

[0014] There is still a need to identify and develop novel disease-improving PK modulators to meet several unmet medical needs related to PK dysfunction. In particular, there is a need to develop compounds that exhibit suitable activity while also having favorable physicochemical parameters. Compounds described herein as PK modulators, particularly PKM2 and / or PKLR modulators, especially PKM2 and / or PKLR activators, address the aforementioned unmet needs by presenting suitable affinity and functional activity against PK enzymes, particularly PKM2 and / or PKLR, improved cellular pyruvate kinase activity compared to mitapivat, while having better overall physical / chemical properties and improved ADME and PK profiles, making them suitable for treating human diseases related to functional alterations in pyruvate kinase expression and / or activity. Summary of the Invention

[0015] The present invention provides compounds of formula (Ia):

[0016]

[0017] Wherein:

[0018] (a) R A is pyrazolyl, and R B is pyridinyl substituted with one OMe group to obtain 6 - ((1H-pyrazol-4-yl)sulfonyl)-2 - ((5-methoxypyridin-2-yl)methyl)phthalazin-1(2H)-one

[0019]

[0020] (b) R A is pyrazolyl substituted with CHF2, and R B is pyrazolyl to obtain 2 - ((1H-pyrazol-3-yl)methyl)-6 - ((1-(difluoromethyl)-1H-pyrazol-4-yl)sulfonyl)phthalazin-1(2H)-one

[0021]

[0022] (c) R A is a pyrazolyl group substituted by CH2CH2OH, and R B is dihydrofuro[3,2-b]pyridinyl, to obtain 2-((2,3-dihydrofuro[3,2-b]pyridin-5-yl)methyl)-6-((1-(2-hydroxyethyl)-1H-pyrazol-4-yl)sulfonyl)phthalazin-1(2H)-one

[0023]

[0024] (d) R A is a pyrazolyl group, and R B is 2,3-dihydropyrazolo[5,1-b]oxazolyl, to obtain 6-((1H-pyrazol-4-yl)sulfonyl)-2-((2,3-dihydropyrazolo[5,1-b]oxazol-6-yl)methyl)phthalazin-1(2H)-one

[0025]

[0026] (e) R A is a pyrazolyl group substituted by methyl, and R B is 2,3-dihydropyrazolo[5,1-b]oxazolyl, to obtain 2-((2,3-dihydropyrazolo[5,1-b]oxazol-6-yl)methyl)-6-((1-methyl-1H-pyrazol-4-yl)sulfonyl)phthalazin-1(2H)-one

[0027] or

[0028] (f) R A is a pyrazolyl group, and R B is a pyrazolyl group substituted by one Cl and one methyl, to obtain 6-((1H-pyrazol-3-yl)sulfonyl)-2-((4-chloro-5-methyl-1H-pyrazol-3-yl)methyl)phthalazin-1(2H)-one

[0029]

[0030] or a salt and / or solvate thereof. Detailed Description of the Invention

[0031] In one embodiment, 6-((1H-pyrazol-4-yl)sulfonyl)-2-((5-methoxypyridin-2-yl)methyl)phthalazin-1(2H)-one is provided

[0032]

[0033] or a salt and / or solvate thereof.

[0034] In another embodiment, 6-((1H-pyrazol-4-yl)sulfonyl)-2-((5-methoxypyridin-2-yl)methyl)phthalazin-1(2H)-one is provided.

[0035]

[0036] In another embodiment, salts of 6-((1H-pyrazol-4-yl)sulfonyl)-2-((5-methoxypyridin-2-yl)methyl)phthalazin-1(2H)-one are provided, such as pharmaceutically acceptable salts.

[0037]

[0038] In one embodiment, 2-((1H-pyrazol-3-yl)methyl)-6-((1-(difluoromethyl)-1H-pyrazol-4-yl)sulfonyl)phthalazin-1(2H)-one is provided.

[0039]

[0040] or a salt and / or solvate thereof.

[0041] In another embodiment, 2-((1H-pyrazol-3-yl)methyl)-6-((1-(difluoromethyl)-1H-pyrazol-4-yl)sulfonyl)phthalazin-1(2H)-one is provided.

[0042]

[0043] In another embodiment, salts of 2-((1H-pyrazol-3-yl)methyl)-6-((1-(difluoromethyl)-1H-pyrazol-4-yl)sulfonyl)phthalazin-1(2H)-one are provided, such as pharmaceutically acceptable salts.

[0044]

[0045] In one embodiment, 2-((2,3-dihydrofuro[3,2-b]pyridin-5-yl)methyl)-6-((1-(2-hydroxyethyl)-1H-pyrazol-4-yl)sulfonyl)phthalazin-1(2H)-one is provided.

[0046]

[0047] or a salt and / or solvate thereof.

[0048] In another embodiment, 2-((2,3-dihydrofuro[3,2-b]pyridin-5-yl)methyl)-6-((1-(2-hydroxyethyl)-1H-pyrazol-4-yl)sulfonyl)phthalazin-1(2H)-one is provided.

[0049]

[0050] In another embodiment, salts of 2-((2,3-dihydrofuro[3,2-b]pyridin-5-yl)methyl)-6-((1-(2-hydroxyethyl)-1H-pyrazol-4-yl)sulfonyl)phthalazin-1(2H)-one are provided, such as pharmaceutically acceptable salts.

[0051]

[0052] In one embodiment, 6-((1H-pyrazol-4-yl)sulfonyl)-2-((2,3-dihydropyrazolo[5,1-b]oxazol-6-yl)methyl)phthalazin-1(2H)-one is provided.

[0053]

[0054] or a salt and / or solvate thereof.

[0055] In another embodiment, 6-((1H-pyrazol-4-yl)sulfonyl)-2-((2,3-dihydropyrazolo[5,1-b]oxazol-6-yl)methyl)phthalazin-1(2H)-one is provided.

[0056]

[0057] In another embodiment, salts of 6-((1H-pyrazol-4-yl)sulfonyl)-2-((2,3-dihydropyrazolo[5,1-b]oxazol-6-yl)methyl)phthalazin-1(2H)-one are provided, such as pharmaceutically acceptable salts.

[0058]

[0059] In one embodiment, 2-((2,3-dihydropyrazolo[5,1-b]oxazol-6-yl)methyl)-6-((1-methyl-1H-pyrazol-4-yl)sulfonyl)phthalazin-1(2H)-one is provided.

[0060]

[0061] or a salt and / or solvate thereof.

[0062] In another embodiment, 2-((2,3-dihydropyrazolo[5,1-b]oxazol-6-yl)methyl)-6-((1-methyl-1H-pyrazol-4-yl)sulfonyl)phthalazin-1(2H)-one is provided.

[0063]

[0064] In another embodiment, salts of 2-((2,3-dihydropyrazolo[5,1-b]oxazol-6-yl)methyl)-6-((1-methyl-1H-pyrazol-4-yl)sulfonyl)phthalazin-1(2H)-one are provided, such as pharmaceutically acceptable salts.

[0065]

[0066] In one embodiment, 6-((1H-pyrazol-3-yl)sulfonyl)-2-((4-chloro-5-methyl-1H-pyrazol-3-yl)methyl)phthalazin-1(2H)-one is provided.

[0067]

[0068] Or salts and / or solvates thereof.

[0069] In another embodiment, 6-((1H-pyrazol-3-yl)sulfonyl)-2-((4-chloro-5-methyl-1H-pyrazol-3-yl)methyl)phthalazin-1(2H)-one is provided.

[0070]

[0071] In another embodiment, salts of 6-((1H-pyrazol-3-yl)sulfonyl)-2-((4-chloro-5-methyl-1H-pyrazol-3-yl)methyl)phthalazin-1(2H)-one are provided, such as pharmaceutically acceptable salts.

[0072]

[0073] Accordingly, the present invention provides compounds selected from the following:

[0074] 6-((1H-pyrazol-4-yl)sulfonyl)-2-((5-methoxypyridin-2-yl)methyl)phthalazin-1(2H)-one;

[0075] 2-((1H-pyrazol-3-yl)methyl)-6-((1-(difluoromethyl)-1H-pyrazol-4-yl)sulfonyl)phthalazin-1(2H)-one;

[0076] 2-((2,3-dihydrofuro[3,2-b]pyridin-5-yl)methyl)-6-((1-(2-hydroxyethyl)-1H-pyrazol-4-yl)sulfonyl)phthalazin-1(2H)-one;

[0077] 6-((1H-pyrazol-4-yl)sulfonyl)-2-((2,3-dihydropyrazolo[5,1-b]oxazol-6-yl)methyl)phthalazin-1(2H)-one;

[0078] 2-((2,3-dihydropyrazolo[5,1-b]oxazol-6-yl)methyl)-6-((1-methyl-1H-pyrazol-4-yl)sulfonyl)phthalazin-1(2H)-one;

[0079] 6-((1H-pyrazol-3-yl)sulfonyl)-2-((4-chloro-5-methyl-1H-pyrazol-3-yl)methyl)phthalazin-1(2H)-one; or a salt and / or solvate thereof.

[0080] The compound of formula (Ia) can be prepared as described in the following Examples section.

[0081] The present invention provides a compound selected from the group consisting of:

[0082] 2-((5-methoxypyridin-2-yl)methyl)-6-((1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)thio)phthalazin-1(2H)-one;

[0083] 6-((1-(difluoromethyl)-1H-pyrazol-4-yl)thio)-2-((1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)methyl)phthalazin-1(2H)-one;

[0084] 6-((1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1H-pyrazol-4-yl)thio)-2-((2,3-dihydrofuro[3,2-b]pyridin-5-yl)methyl)phthalazin-1(2H)-one;

[0085] 2-((2,3-dihydropyrazolo[5,1-b]oxazol-6-yl)methyl)-6-((1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)thio)phthalazin-1(2H)-one;

[0086] 2-((2,3-dihydropyrazolo[5,1-b]oxazol-6-yl)methyl)-6-((1-methyl-1H-pyrazol-4-yl)thio)phthalazin-1(2H)-one; and

[0087] 2-((4-chloro-5-methyl-1H-pyrazol-3-yl)methyl)-6-((1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)sulfonyl)phthalazin-1(2H)-one;

[0088] or a salt and / or solvate thereof.

[0089] The present invention provides a process for preparing a compound of formula (Ia), which comprises oxidizing a compound of formula (IIa) using an oxidizing agent such as Oxone:

[0090]

[0091] or a salt and / or solvate thereof;

[0092] wherein R A and R B are defined elsewhere herein.

[0093] Suitably, the compounds of formula (IIa) are selected from the group consisting of:

[0094]

[0095] or a salt and / or solvate thereof.

[0096] It should be understood that, for use in therapy, the salts of the compounds of formula (Ia) should be pharmaceutically acceptable. Suitable pharmaceutically acceptable salts will be apparent to those skilled in the art. Pharmaceutically acceptable salts include acid addition salts, and salts of the compounds of the present invention containing basic groups (such as amino groups) are preferably formed from inorganic acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid or phosphoric acid). Also included are salts formed from organic acids (e.g., 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, can be used, for example, for isolating the compounds of formula (Ia) and are included within the scope of the present invention, as are base addition salts, such as sodium, potassium, calcium, aluminum, zinc, magnesium and other metal salts.

[0097] Pharmaceutically acceptable salts can also be formed from organic bases (such as basic amines, e.g., ammonia, glucosamine, tromethamine, piperazine, arginine, choline, diethylamine, benzathine or lysine). Thus, in one embodiment, a compound of formula (Ia) in the form of a pharmaceutically acceptable salt is provided. Alternatively, a compound of formula (Ia) in the free acid form is provided. When the compound contains a basic group and a free acid, it can be zwitterionic.

[0098] Suitably, the compounds of formula (Ia) are not salts, for example, not pharmaceutically acceptable salts.

[0099] Suitably, the compound of formula (Ia) or a salt and / or solvate thereof is a pharmaceutically acceptable salt of the compound of formula (Ia).

[0100] Alternatively, the compound of formula (Ia) or a salt and / or solvate thereof is the compound of formula (Ia).

[0101] Suitably, when the compound of formula (Ia) is in salt form, the pharmaceutically acceptable salt is an acid addition salt, such as an ammonium salt (e.g., formed from an inorganic acid, such as HCl).

[0102] The compounds of formula (Ia) can be prepared in crystalline or non-crystalline form and, if prepared in crystalline form, may optionally be solvated, for example in the form of a hydrate. The present invention includes within its scope stoichiometric solvates (such as hydrates) and compounds containing variable amounts of solvent (such as water). Suitably, the compounds of formula (Ia) are not solvates.

[0103] The present invention encompasses its pharmaceutically acceptable derivatives, such as pharmaceutically acceptable prodrugs of the compounds of formula (Ia). Typical prodrugs of compounds of formula (Ia) containing a carboxylic acid include esters (e.g., C 1-6 alkyl, such as C 1-4 alkyl esters), and their derivatives. Thus, in one embodiment, the compounds of formula (Ia) are provided in the form of a pharmaceutically acceptable prodrug. In another embodiment, the compounds of formula (Ia) are not provided in the form of a pharmaceutically acceptable prodrug.

[0104] It is to be understood that the present invention encompasses all isomers of the compounds of formula (Ia), including all geometric, tautomeric, and optical forms, and mixtures thereof (e.g., racemic mixtures). Specifically, the present invention encompasses all tautomeric forms of the compounds of formula (Ia). When other chiral centers are present in the compounds of formula (Ia), the present invention includes within its scope all possible diastereoisomers, including mixtures thereof. The different isomeric forms can be separated or resolved from other isomeric forms by conventional methods, or any given isomer can be obtained by conventional synthetic methods or by stereospecific or asymmetric synthesis.

[0105] The present invention also includes all isotopic forms of the compounds provided herein, which may be in the form of: (i) all atoms having a given atomic number have the mass numbers (or mixtures of mass numbers) that predominate in nature (referred to herein as "naturally occurring isotopic forms"), or (ii) one or more atoms are replaced by atoms having the same atomic number but a mass number different from the mass number of the atoms that predominate in nature (referred to herein as "unnatural variant isotopic forms"). It should be understood that atoms may naturally exist as mixtures of mass numbers. The term "unnatural variant isotopic form" also includes embodiments in which the proportion of atoms having a given atomic number with mass numbers that are not common in nature (referred to herein as "uncommon isotopes") is increased relative to the naturally occurring atoms, for example, to levels of >20%, >50%, >75%, >90%, >95% or >99% of the number of atoms having that atomic number (the latter embodiment is referred to as "isotope-enriched variant forms"). The term "unnatural variant isotopic form" also includes embodiments in which the proportion of uncommon isotopes is decreased relative to the naturally occurring isotopes. Isotopic forms may include radioactive forms (i.e., those incorporating radioactive isotopes) and non-radioactive forms. Radioactive forms are generally isotope-enriched variant forms.

[0106] Thus, unnatural variant isotopic forms of the compounds may contain one or more artificial or uncommon isotopes in one or more atoms, such as 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 ( 123 I), iodine-125 ( 125 I) or may contain an increased proportion of these isotopes in one or more atoms relative to the proportion that predominates in nature.

[0107] For example, unnatural variant isotopic forms containing radioactive isotopes can be used in drug and / or substrate tissue distribution studies. Given the ease of incorporation and well-established detection means, the radioactive isotope tritium, i.e., 3H, and carbon-14, i.e., 14 C, are particularly suitable for this purpose. Non-natural variant isotopic forms incorporating deuterium (i.e., 2 H or D) may have certain therapeutic advantages due to greater metabolic stability, such as an extended in vivo half-life or reduced dose requirements, and may thus be preferred in some cases. In addition, non-natural variant isotopic forms incorporating positron-emitting isotopes such as 11 C, 18 F, 15 O and 13 N can be prepared and will be suitable for positron emission tomography (PET) studies to examine substrate receptor occupancy.

[0108] In one embodiment, the compound of formula (Ia) is provided in a natural isotopic form. In one embodiment, the compound of formula (Ia) is provided in a non-natural variant isotopic form. In certain embodiments, the non-natural variant isotopic form is one in which deuterium (i.e., 2 H or D) is incorporated at the positions in the chemical structure that specify hydrogen in one or more atoms of the compound of formula (Ia). In one embodiment, the atoms of the compound of formula (Ia) are in non-radioactive isotopic forms. In one embodiment, one or more atoms of the compound of formula (Ia) are in radioactive isotopic forms. The radioactive isotopes are preferably stable isotopes. The non-natural variant isotopic forms are preferably pharmaceutically acceptable forms.

[0109] In one embodiment, a compound of formula (Ia) is provided wherein a single atom in the compound is in a non-natural variant isotopic form. In another embodiment, a compound of formula (Ia) is provided wherein two or more atoms are in non-natural variant isotopic forms.

[0110] Non-natural isotopic variant forms can generally be prepared by conventional techniques known to those skilled in the art or by the methods described herein (e.g., similar to the methods described in the accompanying examples for preparing natural isotopic forms). Thus, non-natural isotopic variant forms can be prepared by using appropriate isotopic variant (or labeled) reagents in place of the normal reagents used in the examples. Since the compounds of formula (Ia) are intended for use in pharmaceutical compositions, it will be readily understood that they are each preferably provided in a substantially pure form, e.g., at least 60% purity, more suitably at least 75% purity and preferably at least 85%, especially at least 98% purity (percentages are by weight on a weight basis). Impure preparations of the compounds can be used to prepare forms of higher purity for pharmaceutical compositions.

[0111] Therapeutic Indications

[0112] Compounds of formula (Ia) can be used in therapy, especially for the treatment or prevention of inflammatory diseases, diseases associated with unwanted immune responses, cancer, obesity, diabetic diseases or blood disorders. As shown in Biological Example 1 below, the exemplary compounds of formula (Ia) tested showed improved regulatory activity against PKM2 compared to mitapivat. As shown in Biological Example 2 below, also using mitapivat as a comparator, the exemplary compounds of formula (Ia) tested showed improved regulatory activity against PKLR. As shown in Biological Example 3 below, the exemplary compounds of formula (Ia) tested also showed an in vitro antiproliferative effect. Thus, compounds of formula (Ia) are expected to be suitable for the treatment of diseases associated with PK, especially PKM2 and PKLR activities.

[0113] Accordingly, in a first aspect, the present invention provides a compound of formula (Ia) as defined herein or a pharmaceutically acceptable salt and / or solvate thereof, which is suitable for use as a medicament. Also provided is a pharmaceutical composition comprising a compound of formula (Ia) as defined herein or a pharmaceutically acceptable salt and / or solvate thereof. Such pharmaceutical compositions contain a compound of formula (Ia) and one or more pharmaceutically acceptable diluents or carriers. Suitably, the present invention provides a pharmaceutical composition as defined above, which is used as a medicament. The following description of the use of compounds of formula (Ia) also applies to the pharmaceutical compositions defined herein, which comprise a compound of formula (Ia) as defined herein or a pharmaceutically acceptable salt and / or solvate thereof.

[0114] In another aspect, the present invention provides a compound of formula (Ia) as defined herein or a pharmaceutically acceptable salt and / or solvate thereof for the treatment or prevention of a disease, disorder or condition associated with the function of PK, especially PKM2 and / or PKLR. In another aspect, the present invention provides the use of a compound of formula (Ia) as defined herein or a pharmaceutically acceptable salt and / or solvate thereof for the manufacture of a medicament for the treatment or prevention of a disease, disorder or condition associated with the function of PK, especially PKM2 and / or PKLR. In another aspect, the present invention provides a method for the treatment or prevention of a disease, disorder or condition associated with the function of PK, especially PKM2 and / or PKLR, which comprises administering a compound of formula (Ia) as defined herein or a pharmaceutically acceptable salt and / or solvate thereof.

[0115] In another aspect, the present invention provides a compound of formula (Ia) or a pharmaceutically acceptable salt and / or solvate as defined herein for treating or preventing symptoms associated with a disease, disorder or condition related to the function of PK, in particular PKM2 and / or PKLR. In another aspect, the present invention provides the use of a compound of formula (Ia) or a pharmaceutically acceptable salt and / or solvate thereof as defined herein for the manufacture of a medicament for treating or preventing symptoms associated with a disease, disorder or condition related to the function of PK, in particular PKM2 and / or PKLR. In another aspect, the present invention provides a method for treating or preventing symptoms associated with a disease, disorder or condition related to the function of PK, in particular PKM2 and / or PKLR, the method comprising administering a compound of formula (Ia) or a pharmaceutically acceptable salt and / or solvate thereof as defined herein.

[0116] In one embodiment, the compound of formula (Ia) is a modulator of PKM2. In another embodiment, the compound of formula (Ia) is an activator of PKM2. In one embodiment, the compound of formula (Ia) is a modulator of PKLR. In another embodiment, the compound of formula (Ia) is an activator of PKLR. If a compound increases enzyme activity, then it is an "activator" of PK (e.g., PKM2 and / or PKLR), and the enzyme activity can be quantified by measuring the concentration of ATP produced, for example, in a suitable assay (such as Biological Example 1 for PKM2 and Biological Example 2 for PKLR).

[0117] In another aspect, the present invention provides a compound of formula (Ia) or a pharmaceutically acceptable salt and / or solvate thereof as defined herein for treating or preventing inflammatory diseases, diseases associated with an unwanted immune response, cancer, obesity, diabetic diseases or blood disorders. In another aspect, the present invention provides the use of a compound of formula (Ia) or a pharmaceutically acceptable salt and / or solvate thereof as defined herein for the manufacture of a medicament for treating or preventing inflammatory diseases, diseases associated with an unwanted immune response, cancer, obesity, diabetic diseases or blood disorders. In another aspect, the present invention provides a method for treating or preventing inflammatory diseases, diseases associated with an unwanted immune response, cancer, obesity, diabetic diseases or blood disorders, which comprises administering a compound of formula (Ia) or a pharmaceutically acceptable salt and / or solvate thereof as defined herein.

[0118] In another aspect, the present invention provides a compound of formula (Ia) as defined herein or a pharmaceutically acceptable salt and / or solvate thereof for treating or preventing symptoms associated with an inflammatory disease, a disease associated with an unwanted immune response, cancer, obesity, a diabetic disease or a blood disorder. In another aspect, the present invention provides the use of a compound of formula (Ia) as defined herein or a pharmaceutically acceptable salt and / or solvate thereof for the manufacture of a medicament for treating or preventing symptoms associated with an inflammatory disease, a disease associated with an unwanted immune response, cancer, obesity, a diabetic disease or a blood disorder. In another aspect, the present invention provides a method for treating or preventing symptoms associated with an inflammatory disease, a disease associated with an unwanted immune response, cancer, obesity, a diabetic disease or a blood disorder, which comprises administering a compound of formula (Ia) as defined herein or a pharmaceutically acceptable salt and / or solvate thereof.

[0119] For all aspects of the present invention, it is preferred to administer the compound to an individual in need thereof, wherein the individual is preferably a human individual.

[0120] In one embodiment, there is provided a compound of formula (Ia) as defined herein or a pharmaceutically acceptable salt and / or solvate thereof for treating an inflammatory disease, a disease associated with an unwanted immune response, cancer, obesity, a diabetic disease or a blood disorder. In one embodiment of the present invention, there is provided the use of a compound of formula (Ia) as defined herein or a pharmaceutically acceptable salt and / or solvate thereof for the manufacture of a medicament for treating an inflammatory disease, a disease associated with an unwanted immune response, cancer, obesity, a diabetic disease or a blood disorder. In one embodiment of the present invention, there is provided a method for treating an inflammatory disease, a disease associated with an unwanted immune response, cancer, obesity, a diabetic disease or a blood disorder, which comprises administering a compound of formula (Ia) as defined herein or a pharmaceutically acceptable salt and / or solvate thereof.

[0121] In one embodiment, there is provided a compound of formula (Ia) as defined herein or a pharmaceutically acceptable salt and / or solvate thereof for treating symptoms associated with inflammatory diseases, diseases associated with unwanted immune responses, cancer, obesity, diabetic diseases or blood disorders. In one embodiment of the invention, there is provided the use of a compound of formula (Ia) as defined herein or a pharmaceutically acceptable salt and / or solvate thereof for the manufacture of a medicament for treating symptoms associated with inflammatory diseases, diseases associated with unwanted immune responses, cancer, obesity, diabetic diseases or blood disorders. In one embodiment of the invention, there is provided a method for treating symptoms associated with inflammatory diseases, diseases associated with unwanted immune responses, cancer, obesity, diabetic diseases or blood disorders, which comprises administering a compound of formula (Ia) as defined herein or a pharmaceutically acceptable salt and / or solvate thereof.

[0122] In one embodiment, there is provided a compound of formula (Ia) as defined herein or a pharmaceutically acceptable salt and / or solvate thereof for preventing inflammatory diseases, diseases associated with unwanted immune responses, cancer, obesity, diabetic diseases or blood disorders. In one embodiment of the invention, there is provided the use of a compound of formula (Ia) as defined herein or a pharmaceutically acceptable salt and / or solvate thereof for the manufacture of a medicament for preventing inflammatory diseases, diseases associated with unwanted immune responses, cancer, obesity, diabetic diseases or blood disorders. In one embodiment of the invention, there is provided a method for preventing inflammatory diseases, diseases associated with unwanted immune responses, cancer, obesity, diabetic diseases or blood disorders, which comprises administering a compound of formula (Ia) as defined herein or a pharmaceutically acceptable salt and / or solvate thereof.

[0123] In one embodiment, there is provided a compound of formula (Ia) as defined herein or a pharmaceutically acceptable salt and / or solvate thereof for preventing symptoms associated with inflammatory diseases, diseases associated with unwanted immune responses, cancer, obesity, diabetic diseases or blood disorders. In one embodiment of the invention, there is provided the use of a compound of formula (Ia) as defined herein or a pharmaceutically acceptable salt and / or solvate thereof for the manufacture of a medicament for preventing symptoms associated with inflammatory diseases, diseases associated with unwanted immune responses, cancer, obesity, diabetic diseases or blood disorders. In one embodiment of the invention, there is provided a method for preventing symptoms associated with inflammatory diseases, diseases associated with unwanted immune responses, cancer, obesity, diabetic diseases or blood disorders, which comprises administering a compound of formula (Ia) as defined herein or a pharmaceutically acceptable salt and / or solvate thereof.

[0124] In one embodiment, there is provided a compound of formula (Ia) as defined herein or a pharmaceutically acceptable salt and / or solvate thereof for use in the treatment or prevention of an inflammatory disease. In one embodiment of the invention, there is provided the use of a compound of formula (Ia) as defined herein or a pharmaceutically acceptable salt and / or solvate thereof for the manufacture of a medicament for treating or preventing an inflammatory disease. In one embodiment of the invention, there is provided a method for treating or preventing an inflammatory disease, which comprises administering a compound of formula (Ia) as defined herein or a pharmaceutically acceptable salt and / or solvate thereof.

[0125] In one embodiment, there is provided a compound of formula (Ia) as defined herein or a pharmaceutically acceptable salt and / or solvate thereof for use in the treatment or prevention of symptoms associated with an inflammatory disease. In one embodiment of the invention, there is provided the use of a compound of formula (Ia) as defined herein or a pharmaceutically acceptable salt and / or solvate thereof for the manufacture of a medicament for treating or preventing symptoms associated with an inflammatory disease. In one embodiment of the invention, there is provided a method for treating or preventing symptoms associated with an inflammatory disease, which comprises administering a compound of formula (Ia) as defined herein or a pharmaceutically acceptable salt and / or solvate thereof.

[0126] In one embodiment, there is provided a compound of formula (Ia) as defined herein or a pharmaceutically acceptable salt and / or solvate thereof for use in the treatment or prevention of inflammation associated with an inflammatory disease. In one embodiment of the invention, there is provided the use of a compound of formula (Ia) as defined herein or a pharmaceutically acceptable salt and / or solvate thereof for the manufacture of a medicament for treating or preventing inflammation associated with an inflammatory disease. In one embodiment of the invention, there is provided a method for treating or preventing inflammation associated with an inflammatory disease, which comprises administering a compound of formula (Ia) as defined herein or a pharmaceutically acceptable salt and / or solvate thereof.

[0127] In one embodiment, there is provided a compound of formula (Ia) as defined herein or a pharmaceutically acceptable salt and / or solvate thereof for use in the treatment or prevention of a disease associated with an unwanted immune response. In one embodiment of the invention, there is provided the use of a compound of formula (Ia) as defined herein or a pharmaceutically acceptable salt and / or solvate thereof for the manufacture of a medicament for treating or preventing a disease associated with an unwanted immune response. In one embodiment of the invention, there is provided a method for treating or preventing a disease associated with an unwanted immune response, which comprises administering a compound of formula (Ia) as defined herein or a pharmaceutically acceptable salt and / or solvate thereof.

[0128] In one embodiment, there is provided a compound of formula (Ia) as defined herein or a pharmaceutically acceptable salt and / or solvate thereof for treating or preventing symptoms associated with a disease associated with an unwanted immune response. In one embodiment of the invention, there is provided the use of a compound of formula (Ia) as defined herein or a pharmaceutically acceptable salt and / or solvate thereof for the manufacture of a medicament for treating or preventing symptoms associated with a disease associated with an unwanted immune response. In one embodiment of the invention, there is provided a method for treating or preventing symptoms associated with a disease associated with an unwanted immune response, the method comprising administering a compound of formula (Ia) as defined herein or a pharmaceutically acceptable salt and / or solvate thereof.

[0129] In one embodiment, there is provided a compound of formula (Ia) as defined herein or a pharmaceutically acceptable salt and / or solvate thereof for treating or preventing inflammation associated with a disease associated with an unwanted immune response. In one embodiment of the invention, there is provided the use of a compound of formula (Ia) as defined herein or a pharmaceutically acceptable salt and / or solvate thereof for the manufacture of a medicament for treating or preventing inflammation associated with a disease associated with an unwanted immune response. In one embodiment of the invention, there is provided a method for treating or preventing inflammation associated with a disease associated with an unwanted immune response, the method comprising administering a compound of formula (Ia) as defined herein or a pharmaceutically acceptable salt and / or solvate thereof.

[0130] In one embodiment, there is provided a compound of formula (Ia) as defined herein or a pharmaceutically acceptable salt and / or solvate thereof for treating or preventing cancer. In one embodiment of the invention, there is provided the use of a compound of formula (Ia) as defined herein or a pharmaceutically acceptable salt and / or solvate thereof for the manufacture of a medicament for treating or preventing cancer. In one embodiment of the invention, there is provided a method for treating or preventing cancer, which comprises administering a compound of formula (Ia) as defined herein or a pharmaceutically acceptable salt and / or solvate thereof.

[0131] In one embodiment, there is provided a compound of formula (Ia) as defined herein or a pharmaceutically acceptable salt and / or solvate thereof for treating or preventing cancer-related symptoms. In one embodiment of the present invention, there is provided the use of a compound of formula (Ia) as defined herein or a pharmaceutically acceptable salt and / or solvate thereof for manufacturing a medicament for treating or preventing cancer-related symptoms. In one embodiment of the present invention, there is provided a method for treating or preventing cancer-related symptoms, which comprises administering a compound of formula (Ia) as defined herein or a pharmaceutically acceptable salt and / or solvate thereof.

[0132] In one embodiment, there is provided a compound of formula (Ia) as defined herein or a pharmaceutically acceptable salt and / or solvate thereof for treating or preventing obesity. In one embodiment of the present invention, there is provided the use of a compound of formula (Ia) as defined herein or a pharmaceutically acceptable salt and / or solvate thereof for manufacturing a medicament for treating or preventing obesity. In one embodiment of the present invention, there is provided a method for treating or preventing obesity, which comprises administering a compound of formula (Ia) as defined herein or a pharmaceutically acceptable salt and / or solvate thereof.

[0133] In one embodiment, there is provided a compound of formula (Ia) as defined herein or a pharmaceutically acceptable salt and / or solvate thereof for treating or preventing obesity-related symptoms. In one embodiment of the present invention, there is provided the use of a compound of formula (Ia) as defined herein or a pharmaceutically acceptable salt and / or solvate thereof for manufacturing a medicament for treating or preventing obesity-related symptoms. In one embodiment of the present invention, there is provided a method for treating or preventing obesity-related symptoms, which comprises administering a compound of formula (Ia) as defined herein or a pharmaceutically acceptable salt and / or solvate thereof.

[0134] In one embodiment, there is provided a compound of formula (Ia) as defined herein or a pharmaceutically acceptable salt and / or solvate thereof for treating or preventing diabetic diseases. In one embodiment of the present invention, there is provided the use of a compound of formula (Ia) as defined herein or a pharmaceutically acceptable salt and / or solvate thereof for manufacturing a medicament for treating or preventing diabetic diseases. In one embodiment of the present invention, there is provided a method for treating or preventing diabetic diseases, which comprises administering a compound of formula (Ia) as defined herein or a pharmaceutically acceptable salt and / or solvate thereof.

[0135] In one embodiment, there is provided a compound of formula (Ia) as defined herein or a pharmaceutically acceptable salt and / or solvate thereof for treating or preventing symptoms associated with diabetic diseases. In one embodiment of the invention, there is provided the use of a compound of formula (Ia) as defined herein or a pharmaceutically acceptable salt and / or solvate thereof for the manufacture of a medicament for treating or preventing symptoms associated with diabetic diseases. In one embodiment of the invention, there is provided a method for treating or preventing symptoms associated with diabetic diseases, which comprises administering a compound of formula (Ia) as defined herein or a pharmaceutically acceptable salt and / or solvate thereof.

[0136] In one embodiment, there is provided a compound of formula (Ia) as defined herein or a pharmaceutically acceptable salt and / or solvate thereof for treating or preventing blood disorders. In one embodiment of the invention, there is provided the use of a compound of formula (Ia) as defined herein or a pharmaceutically acceptable salt and / or solvate thereof for the manufacture of a medicament for treating or preventing blood disorders. In one embodiment of the invention, there is provided a method for treating or preventing blood disorders, which comprises administering a compound of formula (Ia) as defined herein or a pharmaceutically acceptable salt and / or solvate thereof.

[0137] In one embodiment, there is provided a compound of formula (Ia) as defined herein or a pharmaceutically acceptable salt and / or solvate thereof for treating or preventing symptoms associated with blood disorders. In one embodiment of the invention, there is provided the use of a compound of formula (Ia) as defined herein or a pharmaceutically acceptable salt and / or solvate thereof for the manufacture of a medicament for treating or preventing symptoms associated with blood disorders. In one embodiment of the invention, there is provided a method for treating or preventing symptoms associated with blood disorders, which comprises administering a compound of formula (Ia) as defined herein or a pharmaceutically acceptable salt and / or solvate thereof.

[0138] An unwanted immune response will generally be an immune response that causes pathology, i.e., a pathological immune response or reaction.

[0139] In one embodiment, the inflammatory disease or the disease associated with an unwanted immune response is an autoimmune disease.

[0140] In one embodiment, the inflammatory disease or a disease associated with an undesired immune response is selected from or associated with a disease of the group consisting of: psoriasis (including chronic plaque, erythrodermic, pustular, guttate, inverse, and nail / onychodermal variants), asthma, chronic obstructive pulmonary disease (COPD, including chronic bronchitis and emphysema), heart failure (including left ventricular failure), myocardial infarction, angina, other atherosclerosis and / or atherosclerotic thrombosis-related disorders (including peripheral vascular disease and ischemic stroke), mitochondrial and neurodegenerative diseases (such as 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, after percutaneous coronary intervention, after acute ST elevation myocardial infarction or ischemic stroke, organ transplantation, or treatment of 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, non-alcoholic fatty liver disease (non-alcoholic steatohepatitis), rheumatism, granuloma annulare, cutaneous lupus erythematosus (CLE), systemic lupus erythematosus (SLE), lupus nephritis, drug-induced lupus, autoimmune myocarditis or myopericarditis, Dressler's 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, MOG (myelin oligodendrocyte glycoprotein) antibody-related disorders (including MOG-EM), optic neuritis, CLIPPERS (chronic lymphocytic inflammation with perivascular enhancement in the pons responsive to steroids), diffuse myelinoclastic sclerosis, Addison's disease, alopecia areata, ankylosing spondylitis, other spondyloarthritides (including peripheral spondyloarthritis, which is associated with psoriasis, inflammatory bowel disease, reactive arthritis, or juvenile-onset forms), antiphospholipid antibody syndrome, autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune inner ear disease, pemphigoid (including bullous pemphigoid, mucous membrane pemphigoid, cicatricial pemphigoid, herpes gestationis or pemphigoid gestationis, ocular cicatricial pemphigoid), linear IgA disease, Behçet's disease (disease), celiac disease, Chagas disease, dermatomyositis, type I diabetes, endometriosis, Goodpasture's syndrome, Graves' disease, Guillain-Barre syndrome and its subtypes (including acute inflammatory demyelinating polyneuropathy, AIDP, acute motor axonal neuropathy (AMAN), acute motor and sensory axonal neuropathy (AMSAN), pharyngeal-cervical-brachial variant, Miller-Fisher variant and Bickerstaff's 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 (including MuSK antibody positive and seronegative variants), narcolepsy, neuromyotonia, pemphigus vulgaris, pernicious anemia, psoriatic arthritis, polymyositis, primary biliary cholangitis (also known as primary biliary cirrhosis), rheumatoid arthritis, relapsing polychondritis, schizophrenia, autoimmune (meningo) encephalitis syndrome, scleroderma (including limited and diffuse), Sjogren's syndrome, stiff-person syndrome, polymyalgia rheumatica, giant cell arteritis (temporal arteritis), Takayasu arteritis, polyarteritis nodosa, Kawasaki disease, granulomatosis with polyangiitis (GPA; previously known as Wegener's granulomatosis), eosinophilic granulomatosis with polyangiitis (EGPA; previously known as Churg-Strauss syndrome), microscopic polyangiitis / polyarteritis, hypocomplementemic urticarial vasculitis, hypersensitivity vasculitis, cryoglobulinemia, thromboangiitis obliterans (Buerger's disease), vasculitis, leukocytoclastic vasculitis, vitiligo, acute disseminated encephalomyelitis, adrenoleukodystrophy, Alexander'sdisease), Alper's disease, balo concentric sclerosis or Marburg disease, cryptogenic organizing pneumonia (previously known as bronchiolitis obliterans with organizing pneumonia), Canavan disease, central nervous system vasculitis syndrome, Charcot-Marie-Tooth disease, childhood ataxia 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 virus (HCV) infection or complications, herpes simplex virus infection or complications, human immunodeficiency virus (HIV) infection or complications, lichen planus, monomelic amyotrophy, fibrosis, cystic fibrosis, pulmonary arterial hypertension (PAH, including idiopathic PAH), pulmonary sarcoidosis, idiopathic pulmonary fibrosis, renal fibrosis, liver fibrosis, pulmonary fibrosis, pediatric asthma, atopic dermatitis, allergic dermatitis, contact dermatitis, allergic rhinitis, rhinitis, sinusitis, conjunctivitis, allergic conjunctivitis, keratoconjunctivitis sicca, dry eye, dry eye syndrome, glaucoma, macular edema, diabetic macular edema, central retinal vein occlusion (CRVO), macular degeneration (including dry and / or wet age-related macular degeneration, AMD), postoperative cataract inflammation, uveitis (including posterior, anterior, intermediate and panuveitis), iridocyclitis, scleritis, corneal graft and limbal cell transplant rejection, gluten-sensitive enteropathy (celiac disease), dermatitis herpetiformis, eosinophilic esophagitis, achalasia, autoimmune autonomic neuropathy, autoimmune encephalomyelitis, autoimmune oophoritis, autoimmune orchitis, autoimmune pancreatitis, aortitis and periaortitis, autoimmune retinopathy, autoimmune rubella, Behcet'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-onset Still's disease, ligneous conjunctivitis, Mooren's ulcer, acute pityriasis lichenoides et varioliformis acuta (PLEVA, also known as Mucha-Habermanndisease)), multifocal motor neuropathy (MMN), pediatric acute-onset neuropsychiatric syndrome (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, thymoma-associated multi-organ autoimmunity), venous encephalomyelitis, reflex sympathetic dystrophy, relapsing polychondritis, sperm and testicular autoimmunity, Susac's syndrome, Tolosa-Hunt syndrome, Vogt-Koyanagi-Harada Disease, anti-synthetase syndrome, autoimmune enteropathy, X-linked immunodysregulation polyendocrinopathy enteropathy (IPEX), microscopic colitis, autoimmune lymphoproliferative syndrome (ALPS), autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome (APEX), gout, pseudogout, amyloidosis (including AA or secondary amyloidosis), eosinophilic fasciitis (Shulman syndrome), progesterone hypersensitivity (including progesterone dermatitis), familial Mediterranean fever (FMF), tumor necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS), hyperimmunoglobulinemia D with periodic fever syndrome (HIDS), PAPA (pyogenic arthritis, pyoderma gangrenosum, severe cystic acne) syndrome, interleukin-1 receptor antagonist deficiency (DIRA), interleukin-36-receptor antagonist deficiency (DITRA), cryopyrin-associated periodic syndrome (CAPS) (including familial cold autoinflammatory syndrome [FCAS], Muckle-Wells syndrome, neonatal-onset multisystem inflammatory disease [NOMID]), NLRP12-associated autoinflammatory disorder (NLRP12AD), periodic fever aphthous stomatitis (PFAPA), chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE), Majeed syndrome, Blau syndrome (also known as juvenile systemic granulomatosis), macrophage activation syndrome, chronic recurrent multifocal osteomyelitis (CRMO), familial cold autoinflammatory syndrome, mutant adenosine deaminase 2 and monogenic interferonopathies (including Aicardi-Goutièressyndrome, retinal vasculopathy with leukodystrophy, vertebral chondrodysplasia, infantile-onset STING [stimulator of interferon genes]-associated vasculopathy, proteasome-associated autoinflammatory syndrome, familial lupus pernio, hereditary symmetric dyschromatosis), Schnitzler syndrome; familial cylindroma, congenital B-cell lymphocytosis, OTULIN-associated autoinflammatory syndrome, type 2 diabetes mellitus, insulin resistance and metabolic syndrome (including inflammation associated with obesity), atherosclerotic disorders (e.g., myocardial infarction, angina, ischemic heart failure, ischemic renal disease, ischemic stroke, peripheral vascular disease, aortic aneurysm), renal inflammatory disorders (e.g., diabetic nephropathy, membranous nephropathy, minimal change nephropathy, crescentic glomerulonephritis, acute kidney injury, renal transplantation), wound healing, keloid formation, and prurigo nodularis.

[0141] In one embodiment, the inflammatory disease or disease associated with an undesirable immune response is selected from or is associated with an autoinflammatory disease, familial Mediterranean fever (FMF), tumor necrosis factor (TNF) receptor-associated periodic fever syndrome (TRAPS), hyperimmunoglobulinemia D with periodic fever syndrome (HIDS), PAPA (pyogenic arthritis, pyoderma gangrenosum, and severe cystic acne) syndrome, interleukin-1 receptor antagonist deficiency (DIRA), interleukin-36-receptor antagonist deficiency (DITRA), cold pyrin-associated periodic syndrome (CAPS) (including familial cold autoinflammatory syndrome [FCAS], Mueller syndrome, and neonatal onset multisystem inflammatory disease [NOMID]), NLRP12-associated autoinflammatory syndrome (AIP), inflammatory bowel disease (EGFR ... The patients were diagnosed with NLRP12AD, PFAPA, CANDLE, Magid syndrome, Blau syndrome (also known as systemic granulomatosis of the juvenile), macrophage activation syndrome, chronic relapsing multifocal osteomyelitis (CRMO), familial cold autoinflammatory syndrome, mutant adenosine deaminase 2, and monogenic interferonopathies (including Acardi-Guterres syndrome, retinal vasculopathy with leukodystrophy, vertebral chondrodysplasia, infantile-onset STING [stimulator of interferon genes]-associated vasculopathy, proteasome-associated autoinflammatory syndrome, familial lupus chilblains, hereditary symmetric dyschromatosis), and Schnitzler syndrome.

[0142] In one embodiment, the inflammatory disease or the disease associated with an undesired immune response is selected from or associated with the following diseases: diseases mediated by excessive NF-κB or gain-of-function in the NF-κB signaling pathway or having a major contribution to the abnormal pathogenesis (including atypical NF-κB signaling): familial cylindromatosis, congenital B cell lymphocytosis, OTULIN-related autoinflammatory syndrome, type 2 diabetes, insulin resistance, and metabolic syndrome (including obesity-related inflammation), atherosclerotic disorders (such as myocardial infarction, angina pectoris, ischemic heart failure, ischemic nephropathy, ischemic stroke, peripheral vascular disease, aortic aneurysm), nephritic disorders (such as diabetic nephropathy, membranous nephropathy, minimal change disease, crescentic glomerulonephritis, acute kidney injury, kidney transplantation), asthma, COPD, type 1 diabetes, rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease (including ulcerative colitis and Crohn's disease), and SLE.

[0143] In one embodiment, the inflammatory disease or the disease associated with an adverse immune response is selected from or associated with the diseases consisting of the following group: Crohn's disease, ulcerative colitis, type 2 diabetes, atopic dermatitis, hidradenitis suppurativa, psoriasis, bullous pemphigoid, pemphigus vulgaris, localized and diffuse scleroderma, Sjogren's syndrome, polymyositis, dermatomyositis, Behcet's disease, wound healing, rheumatoid arthritis, systemic lupus erythematosus, cutaneous lupus erythematosus, graft-versus-host disease, multiple sclerosis, organ fibrosis (including liver, lung, kidney), COPD, and asthma.

[0144] In one embodiment, the inflammatory disease or the disease associated with an adverse immune response is selected from or associated with the diseases consisting of the following group: 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 syndromes, Muckle-Wells syndrome, juvenile idiopathic arthritis, chronic obstructive pulmonary disease, and asthma.

[0145] In one embodiment, the disease is multiple sclerosis.

[0146] In one embodiment, the disease is psoriasis.

[0147] In one embodiment, the disease is asthma.

[0148] In one embodiment, the disease is chronic obstructive pulmonary disease.

[0149] In one embodiment, the disease is systemic lupus erythematosus.

[0150] In one embodiment, the disease is rheumatoid arthritis.

[0151] In one embodiment, the disease is inflammatory bowel disease (including ulcerative colitis and Crohn's disease).

[0152] In one embodiment, the disease is atopic dermatitis.

[0153] In one embodiment, the disease is fibrosis.

[0154] In one embodiment, the cancer is selected from the group consisting of: acute lymphoblastic leukemia, adult; acute lymphoblastic leukemia, childhood; acute myeloid leukemia, adult; adrenocortical carcinoma; adrenocortical carcinoma, childhood; AIDS-related lymphoma; AIDS-related malignancies; anal cancer; astrocytoma, childhood cerebellum; astrocytoma, childhood brain; Barrett's esophagus (precancerous syndrome); bile duct cancer, extrahepatic; bladder cancer; bladder cancer, childhood; bone cancer, osteosarcoma / malignant fibrous histiocytoma; brainstem glioma, childhood; brain tumor, adult; brain tumor, brainstem glioma, childhood; brain tumor, cerebellar astrocytoma, childhood; brain tumor, cerebral astrocytoma / malignant glioma, childhood; brain tumor, ependymoma, childhood; brain tumor, medulloblastoma, childhood; brain tumor, supratentorial primitive neuroectodermal tumor, childhood; brain tumor, visual pathway and hypothalamic glioma, childhood; brain tumor, childhood (other); breast cancer; breast cancer and pregnancy; breast cancer, childhood; breast cancer, male; bronchial adenoma / carcinoid, childhood; carcinoid tumor, childhood; carcinoid tumor, gastrointestinal; carcinoma, adrenocortical; carcinoma, islet cell; carcinoma of unknown primary site; central nervous system lymphoma, primary; cerebellar astrocytoma, childhood; cerebral astrocytoma / malignant glioma, childhood; cervical cancer; childhood cancer; chronic lymphocytic leukemia; chronic myelogenous leukemia; chronic myeloproliferative disorders; clear cell sarcoma of tendon sheath; colon cancer; colorectal cancer; colorectal cancer, childhood; cutaneous T-cell lymphoma; endometrial cancer; ependymoma, childhood; epithelial cancer, ovary; esophageal cancer; esophageal cancer, childhood; Ewing's family of tumours; extracranial germ cell tumor, childhood; extragonadal germ cell tumor; extrahepatic bile duct cancer; eye cancer, intraocular melanoma; eye cancer, retinoblastoma; gallbladder cancer; gastric (stomach) cancer; gastric (stomach) cancer, childhood; gastrointestinal carcinoid tumor; germ cell tumor, extracranial, childhood; germ cell tumor, extragonadal; germ cell tumor, ovary; gestational trophoblastic tumor; glioma, childhood brainstem; glioma, childhood visual pathway and hypothalamus; hairy cell leukemia; head and neck cancer; hepatocellular (liver) cancer; hepatocellular (liver) cancer, adult (primary); hepatocellular (liver) cancer, childhood (primary); esophageal cancer; Hodgkin's lymphoma; Hodgkin's lymphoma, adult; Hodgkin's lymphoma, childhood; Hodgkin's lymphoma, during pregnancy; hypopharyngeal cancer; hypothalamic and visual pathway glioma, childhood; intraocular melanoma; islet cell carcinoma (endocrine pancreas); endocrine system cancer (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's, adult; lymphoma, Hodgkin's, childhood; lymphoma, Hodgkin's, during pregnancy; lymphoma, non-Hodgkin's, adult; lymphoma, non-Hodgkin's, childhood; lymphoma, non-Hodgkin's, during pregnancy; lymphoma, primary central nervous system; macroglobulinemia, Waldenstrom's; male breast cancer; malignant mesothelioma, adult; malignant mesothelioma, childhood; malignant thymoma; neuroblastoma, childhood; melanoma; melanoma, intraocular; Merkel cell carcinoma; mesothelioma, malignant; occult primary metastatic squamous neck cancer; multiple endocrine neoplasia syndrome, childhood; multiple myeloma / plasma cell neoplasm; mycosis fungoides; myelodysplastic syndrome; myeloid leukemia, chronic; myeloid leukemia, childhood acute; myeloma, multiple; myelodysplasia, chronic; nasal and paranasal sinus cancer; nasopharyngeal cancer; nasopharyngeal cancer, childhood; neoplastic skin diseases; neuroblastoma; non-Hodgkin's lymphoma, adult; non-Hodgkin's lymphoma, childhood; non-Hodgkin's lymphoma, during pregnancy; non-small cell lung cancer; central nervous system neoplasms (e.g., primary CNS lymphoma, spinal axis tumors, neuroblastoma, brainstem glioma, or pituitary adenoma); oat cell cancer; oral cancer, childhood; oral and lip cancer; 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; pediatric malignancies; pancreatic cancer; pancreatic cancer, childhood; pancreatic cancer, islet cell; sinus and nasal cancer; parathyroid cancer; penile cancer; pheochromocytoma; pineal and supratentorial primitive neuroectodermal tumors, childhood; pituitary tumor; plasma cell neoplasm / 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, adult; primary liver cancer, childhood; prostate cancer (especially hormone-resistant); chronic or acute leukemia; childhood solid tumors; hypereosinophilic syndrome; rectal cancer;Renal cell (kidney) cancer; renal cell carcinoma, childhood; transitional cell cancer of the renal pelvis and ureter; retinoblastoma; rhabdomyosarcoma, childhood; salivary gland cancer; salivary gland cancer, childhood; sarcoma, Ewing's tumor family; sarcoma, Kaposi's; sarcoma (osteosarcoma) / malignant fibrous histiocytoma of bone; sarcoma, rhabdomyosarcoma, childhood; soft tissue sarcoma; soft tissue sarcoma, adult; soft tissue sarcoma, 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; occult primary squamous carcinoma of the neck, metastatic; stomach (gastric) cancer; stomach (gastric) cancer, childhood; supratentorial primitive neuroectodermal tumor, childhood; T-cell lymphoma, cutaneous; testicular cancer; thymoma, childhood; thymoma, malignant; thyroid cancer; thyroid cancer, childhood; transitional cell cancer of the renal pelvis and ureter; trophoblastic tumor, gestational; cancer of unknown primary site, childhood; childhood cancer of abnormal origin; transitional cell cancer of the ureter and renal pelvis; urethral cancer; ureteral cancer (e.g., renal cell carcinoma, pyelocarcinoma); penile cancer; gynecologic tumors; uterine cancer; uterine sarcoma; fallopian tube cancer; endometrial cancer; vaginal cancer; vaginal carcinoma; vulvar cancer; visual pathway and hypothalamic glioma, childhood; vulvar cancer; Waldenstrom's macroglobulinemia; and Wilms' tumor.;

[0155] In one embodiment, the cancer is selected from the group consisting of: lung cancer; NSCLC (non-small cell lung cancer); oat cell cancer; bone cancer; pancreatic cancer; skin cancer; dermatofibrosarcoma protuberans; head and neck cancer; cutaneous or intraocular melanoma; uterine cancer; ovarian cancer; colorectal cancer; anal cancer; gastric cancer; colon cancer; breast cancer; gynecologic tumors (e.g., uterine sarcoma, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer or vulvar cancer); Hodgkin's Disease; hepatocellular carcinoma; esophageal cancer; small intestine cancer; endocrine system cancer (e.g., cancer of the thyroid, pancreas, parathyroid or adrenal gland); soft tissue sarcoma; urethral cancer; penile cancer; prostate cancer (especially hormone resistant); chronic or acute leukemia; childhood solid tumors; hypereosinophilic syndrome; lymphocytic lymphoma; bladder cancer; kidney cancer; ureteral cancer (e.g., renal cell carcinoma, pyelocarcinoma); pediatric malignancies; central nervous system neoplasms (e.g., primary CNS lymphoma, spinal axis tumors, neuroblastoma, brainstem glioma or pituitary adenoma); Barrett's esophagus (precancerous syndrome) and neoplastic skin diseases.

[0156] "Obesity" refers to a condition in which an individual has a body mass index greater than or equal to 30. The body mass index (BMI) is based on the "NIH Clinical Guidelines on the Identification and Evaluation, and Treatment of Overweight and Obesity in Adults" (1998).

[0157] In one embodiment, administration of a compound of formula (Ia) to an individual can reduce the individual's BMI to less than 30, such as less than 29, less than 28, less than 27, less than 26, or less than 25. In one embodiment, a compound of formula (Ia) is used to treat or prevent abnormal or inappropriate weight gain, metabolic rate, or fat deposition, such as for the treatment of anorexia, bulimia, obesity, diabetes, or hyperlipidemia (e.g., elevated triglycerides and / or cholesterol), and lipid or lipid metabolism disorders. In one embodiment, a compound of formula (Ia) is used to treat or prevent metabolic syndrome.

[0158] In one embodiment, a compound of formula (Ia) is used to treat obesity associated with Prader-Willi Syndrome (PWS). In one embodiment, a compound of formula (Ia) is used to reduce body fat, prevent body fat gain, lower cholesterol (e.g., total cholesterol and / or the ratio of total cholesterol to HDL cholesterol), and / or reduce the appetite of an individual with obesity associated with PWS, and / or reduce comorbidities such as diabetes, cardiovascular disease, and stroke.

[0159] "Diabetic disease" refers to diabetes mellitus ("diabetes") or diabetic complications. The two main types of diabetes are (i) type 1 diabetes, which is caused by the pancreas not producing insulin and is commonly treated with insulin replacement therapy, and (ii) type 2 diabetes, in which patients produce insufficient insulin or have insulin resistance. Diabetic complications include microvascular and macrovascular complications and include coronary artery disease, peripheral artery disease, stroke, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, diabetic kidney disease, and NASH.

[0160] In one embodiment, "blood disorder" is selected from the group consisting of: thalassemia (e.g., β-thalassemia), hereditary spherocytosis, hereditary elliptocytosis, β-lipoprotein deficiency (or Bassen-Kornzweig syndrome), paroxysmal nocturnal hemoglobinuria, acquired hemolytic anemia (e.g., congenital anemia (e.g., enzyme diseases)), anemia of chronic disease, pyruvate kinase deficiency (PKD), and sickle cell disease.

[0161] Drug administration

[0162] In this section, the compounds of formula (Ia) mentioned include the compounds of formula (Ia) or their pharmaceutically acceptable salts and / or solvates, preferably the compounds of formula (Ia).

[0163] The compounds of formula (Ia) are generally administered in the form of a pharmaceutical composition. Thus, in one embodiment, there is provided a pharmaceutical composition comprising a compound of formula (Ia) and one or more pharmaceutically acceptable diluents or carriers.

[0164] The compounds of formula (Ia) can be administered by any convenient method, such as by oral, parenteral, buccal, sublingual, nasal, rectal, intrathecal or transdermal drug administration, and the pharmaceutical composition is adjusted accordingly.

[0165] The compounds of formula (Ia) can be administered locally to the target organ, such as locally to the eye, lung, nose or skin. Thus, the present invention provides a pharmaceutical composition comprising a compound of formula (Ia), optionally in combination with one or more locally acceptable diluents or carriers.

[0166] The compounds of formula (Ia) that are active upon oral administration can be formulated as a liquid or a solid, such as a syrup, suspension, emulsion, tablet, capsule or lozenge.

[0167] Liquid formulations will generally consist of a suspension or solution of a compound of formula (Ia) in a suitable liquid carrier. The carrier is preferably non-aqueous, such as polyethylene glycol or an oil. The formulation can also contain suspending agents, preservatives, flavoring agents and / or coloring agents.

[0168] Compositions in tablet form can be prepared using any suitable pharmaceutical carriers conventionally used for preparing solid formulations (such as magnesium stearate, starch, lactose, sucrose and cellulose).

[0169] Compositions in capsule form can be prepared using conventional encapsulation procedures. For example, pellets containing the active ingredient can be prepared using standard carriers and then filled into hard gelatin capsules; alternatively, a dispersion or suspension can be prepared using any suitable pharmaceutical carrier (such as aqueous gums, celluloses, silicates, or oils) and then the dispersion or suspension can be filled into soft gelatin capsules.

[0170] Typical parenteral compositions consist of a solution or suspension of a compound of formula (Ia) in a sterile aqueous carrier or a parenterally acceptable oil (such as polyethylene glycol, polyvinylpyrrolidone, lecithin, peanut oil, or sesame oil). Alternatively, the solution can be freeze-dried and then reconstituted with a suitable solvent immediately prior to administration.

[0171] Compositions for nasal administration are preferably formulated as aerosols, drops, gels, and powders. A spray formulation typically contains a solution or fine suspension of a compound of formula (Ia) in a pharmaceutically acceptable aqueous or non-aqueous solvent and is usually present in a sterile form in a sealed container in single-dose or multi-dose amounts, which sealed container can be in the form of a cartridge or refill for use with an atomizing device. Alternatively, the sealed container can be a disposable dispensing device, such as a single-dose nasal inhaler or a spray dispenser equipped with a metering valve. In the case where the dosage form contains a spray dispenser, it will contain a propellant, which can be a compressed gas, such as air, or an organic propellant, such as a chlorofluorocarbon (CFC) or a hydrofluorocarbon (HFC). The spray dosage form can also be in the form of a pump nebulizer.

[0172] Local administration to the lung can be achieved using a spray formulation. The spray formulation typically contains the active ingredient suspended or dissolved in a suitable spray propellant, such as a chlorofluorocarbon (CFC) or a hydrofluorocarbon (HFC).

[0173] Local administration to the lung can also be achieved using a non-pressurized formulation, such as an aqueous solution or suspension. These formulations can be administered using a nebulizer (e.g., a hand-held and portable nebulizer or a nebulizer for home or hospital use (i.e., non-portable)). The formulation can contain excipients, such as water, buffers, tonicity regulators, pH regulators, surfactants, and co-solvents.

[0174] Local administration to the lung can also be achieved using a dry powder formulation. The formulation will typically contain a locally acceptable diluent, such as lactose, glucose, or mannitol (preferably lactose).

[0175] The compounds of the present invention can also be administered rectally, for example, in the form of suppositories or enemas, which include 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 room temperature but liquid at rectal temperature and will thus melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycol.

[0176] Generally, for compositions intended for topical administration to the eye in the form of eye drops or ophthalmic ointments, the total amount of the compounds of the present invention will be from about 0.0001 to less than 4.0% (w / w).

[0177] Preferably, for topical ocular administration, the compositions administered according to the present invention will be formulated as solutions, suspensions, emulsions, and other dosage forms.

[0178] 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, co-solvents, and viscosity modifiers. Suitable pharmaceutical compositions of the present invention include the compounds of the present invention formulated with tonicity agents and buffers. The pharmaceutical compositions of the present invention may also optionally include surfactants and / or emollients and / or stabilizing polymers.

[0179] The tonicity of the composition can be adjusted using various tonicity agents, and for ophthalmic compositions, it is preferably adjusted to the tonicity of natural tears. For example, sodium chloride, potassium chloride, magnesium chloride, calcium chloride, monosaccharides (such as dextrose, fructose, galactose), and / or individual polyols (such as sugar alcohols, mannitol, sorbitol, xylitol, lactitol, isomaltitol, maltitol, and hydrogenated starch hydrolysates) can be added to the composition to resemble physiological tonicity. The amount of such tonicity agents will vary depending on the specific reagent added. However, the composition will generally have an amount of tonicity agent sufficient to cause the final composition to have an ophthalmically acceptable osmotic pressure (usually about 150 - 450 mOsm, preferably 250 - 350 mOsm, and most preferably about 290 mOsm). Generally, the tonicity agents of the present invention will be in the range of 2 to 4% w / w. Preferred tonicity agents of the present invention include monosaccharides or sugar alcohols such as D-mannitol.

[0180] A suitable buffer system (e.g., sodium phosphate, sodium acetate, sodium citrate, sodium borate, or boric acid) can be added to the composition to prevent the pH from shifting under storage conditions. The specific concentration will vary depending on the reagent used. However, the buffer is preferably selected to maintain the target pH value within the range of a target pH value of pH 5 to 8 and more preferably pH 5 to 7.

[0181] Optionally, surfactants can be used to deliver higher concentrations of the compounds of the present invention. Surfactants are used to solubilize the compounds and stabilize colloidal dispersions, such as micellar solutions, microemulsions, emulsions, and suspensions. Examples of surfactants that can be optionally used include polysorbates, poloxamers, polyethylene glycol 40 stearate, polyethylene glycol castor oil, tyloxapol, Triton, and sorbitan monolaurate. Preferred surfactants used in the present invention have a hydrophilic / lipophilic / balance "HLB" in the range of 12.4 to 13.2 and are acceptable for ocular use, such as Triton X114 and tyloxapol.

[0182] Other reagents that can be added to the ophthalmic compositions of the compounds of the present invention are buffering agents, which act as stabilizing polymers. The stabilizing polymers should be ionic / charged examples preferably used for topical ocular use, more specifically, polymers having a negative charge on the surface, which can exhibit a ζ potential of (-)10 - 50 mV to achieve physical stability and are capable of producing a dispersion in water (i.e., water-soluble). Preferred stabilizing polymers of the present invention will be one or more polyelectrolytes from the cross-linked polyacrylate family at 0.1 - 0.5% w / w, such as carbomer and Pemulen(R), especially carbomer 974p (polyacrylic acid).

[0183] Other compounds can also be added to the ophthalmic compositions of the compounds of the present invention to increase the viscosity of the vehicle. Examples of thickening agents include (but are not limited to): polysaccharides, such as hyaluronic acid and its salts, chondroitin sulfate and its salts, dextran, various polymers of the cellulose family; vinyl polymers; and acrylic polymers.

[0184] Topical ophthalmic products are usually packaged in multi-dose forms. Therefore, preservatives are needed to prevent microbial contamination during use. Suitable preservatives include: benzalkonium chloride, chlorobutanol, dodecyl dimethyl benzyl ammonium bromide, methyl paraben, propyl paraben, phenethyl alcohol, disodium edetate, sorbic acid, polyquaternium-1, or other reagents known to those skilled in the art. Such preservatives are usually used at a content of 0.001 to 1.0 w / v%. The unit-dose compositions of the present invention will be sterile but are usually unpreserved. Therefore, such compositions will generally be free of preservatives.

[0185] Compositions suitable for buccal or sublingual administration include tablets, lozenges, and pellets, in which the compound of formula (Ia) is formulated with carriers such as sugars and acacia, tragacanth, or gelatin and glycerol.

[0186] Compositions suitable for transdermal administration include ointments, gels and patches.

[0187] Depending on the method of administration, the composition may contain from 0.1% to 100% by weight, such as from 10% to 60% by weight, of the compound of formula (Ia). Depending on the method of administration, the composition may contain from 0% to 99.9% by weight, such as from 40% to 90% by weight, of a carrier. Depending on the method of administration, the composition may contain from 0.05 mg to 1000 mg, such as from 1.0 mg to 500 mg, such as from 1.0 mg to 50 mg, for example about 10 mg, of the compound of formula (Ia). Depending on the method of administration, the composition may contain from 50 mg to 1000 mg, such as from 100 mg to 400 mg, of a carrier. The dosage of the compound for treating the aforementioned disorders will vary in the usual manner according to the severity of the disorder, the weight of the patient and other similar factors. However, as a general guide, suitable unit doses may be from 0.05 to 1000 mg, more suitably from 1.0 to 500 mg, such as from 1.0 mg to 50 mg, for example about 10 mg, and such unit doses may be administered more than once a day, such as twice or three times a day. Such therapy may continue for several weeks or months.

[0188] In one embodiment of the invention, the compound of formula (Ia) is used in combination with one or more other therapeutic agents. When the compound of formula (Ia) is used in combination with other therapeutic agents, the compounds may be administered sequentially or simultaneously by any convenient route. Alternatively, the compounds may be administered separately.

[0189] When the compound of formula (Ia) is used for treating or preventing an inflammatory disease or a disease associated with an unwanted immune response, therapeutic agents that can be used in combination with the compound of formula (Ia) include: corticosteroids (glucocorticoids), retinoids (e.g., acitretin, isotretinoin, tazarotene), anthralin, vitamin D analogs (e.g., calcipotriol, calcipotriol), calcineurin inhibitors (e.g., tacrolimus, pimecrolimus), phototherapy or photochemotherapy (e.g., psoralen ultraviolet irradiation, PUVA) or other forms of ultraviolet light irradiation therapy, ciclosporine, thiopurines (e.g., azathioprine, 6-mercaptopurine), methotrexate, 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), plasmapheresis, intravenous immunoglobulin (IVIG), cyclophosphamide, anti-CD20 B cell depleting agents (e.g., rituximab, ocrelizumab, ofatumumab, obinutuzumab), anthracycline analogs (e.g., mitoxantrone), cladribine, sphingosine 1-phosphate receptor modulators or sphingosine analogs (e.g.,Fingolimod, siponimod, ozanimod, etrasimod, interferon beta preparations (including interferon beta 1b / 1a), glatiramer, anti-CD3 therapy (e.g., OKT3), anti-CD52 targeting agents (e.g., alemtuzumab), leflunomide, teriflunomide, gold compounds, laquinimod, potassium channel blockers (e.g., dalfampridine / 4-aminopyridine), mycophenolic acid, mycophenolate mofetil, purine analogues (e.g., pentostatin), mTOR (mechanistic 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 stimulator) inhibitors (e.g., belimumab, blisibimod), other B cell targeting therapies (including fusion proteins targeting APRIL (a proliferation-inducing ligand) and BlyS, e.g., atacicept), PI3K inhibitors (including pan-inhibitors or inhibitors targeting isotypes containing p110δ and / or p110γ, 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 therapies (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 inhibitors against C5, e.g., eculizumab), immunoadsorbents, antithymocyte globulin, 5-aminosalicylic acid esters and their derivatives (e.g., sulfasalazine, balsalazide, mesalamine), anti-integrin agents (including agents targeting α4β1 and / or α4β7 integrin, e.g., natalizumab, vedolizumab), anti-CD11-α agents (e.g., efalizumab), non-steroidal anti-inflammatory drugs (NSAIDs), including salicylates (e.g., aspirin), propionic acids (e.g., ibuprofen, naproxen), acetic acids (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, dibutyl squarate), anti-IL-1 receptor therapy (e.g., anakinra), IL-1β inhibitors (e.g., canakinumab), IL-1 neutralization therapy (e.g.,Rilonacept, chlorambucil, specific antibiotics with immunomodulatory properties and / or the ability to modulate NRF2 (e.g., tetracyclines, including minocycline, clindamycin, macrolide antibiotics), antiandrogen therapies (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.,

[0190] When a compound of formula (Ia) is used for treating or preventing cancer, therapeutic agents that can be used in combination with the compound of formula (Ia) include active agents used in combination with cancer therapies, such as agents used for palliative treatment to ameliorate undesirable side effects. Thus, in one embodiment, the other therapeutic agents are agents used for palliative treatment, such as those selected from the group consisting of: antiemetics, drugs intended to relieve pain (such as opioids), drugs for reducing elevated blood uric acid levels (such as allopurinol or rasburicase), antidepressants, sedatives, antispasmodic drugs, laxatives, antidiarrheal drugs, and / or antacids.

[0191] In another embodiment, the other therapeutic agents are other cancer treatments, such as chemotherapy, targeted therapy, immunotherapy, and hormone therapy.

[0192] Examples of chemotherapeutic agents include antimetabolites (e.g., folic acid, purine, and pyrimidine derivatives) and alkylating agents (e.g., nitrogen mustards, nitrosoureas, platinum, alkyl sulfonates, hydrazines, triazenes, aziridines, spindle toxins, cytotoxic agents, topoisomerase inhibitors, etc.). In one embodiment, other therapeutic agents are chemotherapeutic agents selected from the group consisting of: Aclarubicin, Actinomycin, Alitretinon, Altretamine, Aminopterin, Aminolevulinicacid), Amrubicin, Amsacrine, Anagrelide, arsenic trioxide, asparaginase, Atrasentan, Belotecan, Bexarotene, Bendamustine, Bleomycin, Bortezomib, Busulfan, Camptothecin, Capecitabine, Carboplatin, 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, Etoglucid, Etoposide, Floxuridine, Fludarabine, Fluorouracil; 5FU, Fotemustine, Gemcitabine, Gliadelimplants), Hydroxycarbamide, Hydroxyurea, Idarubicin, Ifosfamide, Irinotecan, Irofulven, Ixabepilone, Larotaxel, Leucovorin, Liposomal doxorubicin, Liposomal daunorubicin, Lonidamine, Lomustine, Lucanthone, Mannosulfan, Masoprocol, Melphalan, Mercaptopurine, Mesna, Methotrexate, 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, Sapacitabine, Semustine, Sitimageneceradenovec), satraplatin, streptozocin, talaporfin, tegafur-uracil, temoporfin, temozolomide, teniposide, tesetaxel, testolactone, tetranitrate, thiotepa, tiazofurin, tioguanine, tipifarnib, topotecan, trabectedin, triaziquone, triethylenemelamine, triplatin, tretinoin, treosulfan, trofosfamide, uramustine, valrubicin, verteporfin, vinblastine, vincristine, vindesine, vinflunine, vinorelbine, vorinostat, and zorubicin.

[0193] Examples of targeted therapies include tyrosine kinase inhibitors, cyclin-dependent kinase inhibitors, monoclonal antibodies, and fusion proteins. In one embodiment, other therapeutic agents are 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 Bexxar.

[0194] When the compound of formula (Ia) is used for treating or preventing obesity, therapeutic agents that can be used in combination with the compound of formula (Ia) include gastric or pancreatic lipase inhibitors (such as orlistat); lipid-lowering agents (such as statin, fibrate, niacin or their derivatives (such as acipimox), lecithin, bile acid sequestrants, ezetimibe, lomitapide, phytosterol, ω-3 supplements, PCSK9 inhibitors); CB-1 antagonists; lipoxygenase inhibitors; somostatin analogs; insulin compounds or insulin analogs (such as human insulin, insulin lispro, insulin aspart, insulin glulisine, insulin glargine, insulin degludec); insulin sensitizers, such as PPAR-γ agonists, PPAR-α agonists or mixed PPAR-γ / α agonists (such as metformin, pioglitazone or rosiglitazone); insulin secretagogues (such as nateglinide or repaglinide, or sulfonylureas such as gliclazide, glimeperide, limepiride, 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 (such as albiglutide, dulaglutide, exenatide, liraglutide, semaglutide or lixisenatide); α-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.;

[0195] When the compound of formula (Ia) is used for the treatment or prevention of diabetic diseases, therapeutic agents that can be used in combination with the compound of formula (Ia) include gastric or pancreatic lipase inhibitors (such as orlistat); lipid-lowering agents (such as statins, fibrates, niacin or their derivatives (such as acipimox), lecithin, bile acid sequestrants, ezetimibe, lomitapide, phytosterols, ω-3 supplements, PCSK9 inhibitors); CB-1 antagonists; lipoxygenase inhibitors; somatostatin analogs; insulin compounds or insulin analogs (such as human insulin, lispro insulin, aspart insulin, glulisine insulin, insulin glargine, insulin degludec); insulin sensitizers, such as PPAR-γ agonists, PPAR-α agonists or mixed PPAR-γ / α agonists (such as metformin, pioglitazone or rosiglitazone); insulin secretagogues (such as nateglinide or repaglinide, or sulfonylureas, such as gliclazide, glimepiride, glipizide, glibenclamide); 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 (such as albiglutide, dulaglutide, exenatide, liraglutide, semaglutide or lixisenatide); α-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.

[0196] The compound of formula (Ia) may exhibit one or more of the following desired properties:

[0197] · Low EC for activating PKM2 50 and / or high E max value;

[0198] · Low EC for activating PKLR 50 and / or high E max value;

[0199] · Low EC for activating PKM2 and PKLR 50 and / or high E max value;

[0200] · Low IC for reducing cell proliferation 50 value;

[0201] · Reduced dose and dosing frequency via improved pharmacokinetics;

[0202] · Improved oral systemic bioavailability;

[0203] · Reduced plasma clearance after intravenous administration;

[0204] · Enhanced cell permeability;

[0205] · Low toxicity at relevant therapeutic doses.

[0206] Abbreviation

[0207] Ac Acetyl

[0208] ADP Adenosine diphosphate

[0209] ADME Absorption, distribution, metabolism, and excretion

[0210] Aq. Aqueous

[0211] ATP Adenosine triphosphate

[0212] BBFO Broadband fluorine observation

[0213] BEH Ethylene-bridged hybrid

[0214] t-Bu tert-Butyl

[0215] CB-1 Cannabinoid-1

[0216] CSH Charged surface hybrid

[0217] DAD Diode array detector

[0218] DCM Dichloromethane

[0219] DHP Dihydropyran

[0220] DIPEA N,N-Diisopropylethylamine

[0221] DMF Dimethylformamide

[0222] DMSO Dimethyl sulfoxide

[0223] DPPIV Dipeptidyl peptidase-4

[0224] ES + Electrospray

[0225] Eq Equivalent

[0226] Et ethyl

[0227] FBP fructose-1,6-diphosphate

[0228] FBS fetal bovine serum

[0229] g gram

[0230] GLP-1 glucagon-like peptide 1

[0231] GSK glycogen synthase kinase

[0232] h hour

[0233] HIF hypoxia-inducible factor

[0234] HPLC high performance liquid chromatography

[0235] IL interleukin

[0236] LAH lithium aluminum hydride

[0237] LCMS liquid chromatography-mass spectrometry

[0238] M molarity / molar mass

[0239] MeCN acetonitrile

[0240] MCH melanin-concentrating hormone

[0241] Me methyl

[0242] mm millimeter

[0243] (M)Hz (mega)hertz

[0244] min(s) minute

[0245] mL milliliter

[0246] mmol millimole

[0247] MS mass spectrometry

[0248] nm nanometer

[0249] NASH non-alcoholic steatohepatitis

[0250] NCS N-chlorosuccinimide

[0251] NMP N-methyl-2-pyrrolidone

[0252] NMR nuclear magnetic resonance

[0253] o / n overnight

[0254] PBS phosphate buffered saline

[0255] PDA Photoelectric Diode Array

[0256] PEP Phosphoenolpyruvate

[0257] PK Pyruvate Kinase

[0258] PPAR Peroxisome Proliferator-Activated Receptor

[0259] PTP1B Protein Tyrosine Phosphatase 1B

[0260] Red-Al Sodium bis(2-methoxyethoxy)aluminum hydride

[0261] rpm Revolutions Per Minute

[0262] RT / r.t. Room Temperature

[0263] SGLT2 Sodium-Glucose Transporter 2

[0264] STAT3 Signal Transducer and Activator of Transcription 3

[0265] TBS Tert-Butyldimethylsilyl

[0266] TCA Tricarboxylic Acid Cycle

[0267] TFA Trifluoroacetic Acid

[0268] THF Tetrahydrofuran

[0269] THP Tetrahydropyranyl

[0270] TNF Tumor Necrosis Factor

[0271] Ts Tosyl

[0272] μL Microliter

[0273] μM Micromole

[0274] wt. Weight

[0275] ℃ Degree Celsius

[0276] Examples

[0277] Analytical equipment

[0278] 1H NMR spectra were recorded on a Bruker 400 MHz Avance III spectrometer equipped with a BBFO 5 mm probe or a Bruker 500 MHz Avance III HD spectrometer equipped with a Bruker 5 mm SmartProbeTM. Spectra were measured at 298 K unless otherwise specified and referenced to the solvent resonance. Chemical shifts were reported in parts per million. Data were acquired using Bruker TopSpin software.

[0279] LCMS analysis was performed using a Waters Acquity CSH C18 (4.6 × 30 mm) or BEH C18 column (4.6 × 30 mm) on an Agilent LCMS system at a constant flow rate of 2.5 mL / min for 4 or 15 minutes. The column was maintained at a temperature of 40 °C and eluted with a linear acetonitrile gradient suitable for the lipophilicity of the compound. The aqueous portion of the mobile phase was 0.1% formic acid (CSH C18 column) or 10 mM ammonium bicarbonate (BEH C18 column). LC-UV chromatograms were recorded using an Agilent VWD or DAD detector at 254 nm. Mass spectra were recorded using an Agilent MSD detector by electrospray ionization with switching between positive and negative ion modes. The sample concentration was adjusted to produce sufficient UV response.

[0280] Preparative HPLC purification method

[0281] Acidic method (A):

[0282] The product was dissolved in DMSO (mL), filtered and eluted with a water-MeCN gradient containing 0.1% formic acid using a Waters X-Select CSH C18 ODB preparative column ( 5 μm, 30 mm × 100 mm, flow rate 40 mL / min), and purified by reverse-phase preparative HPLC (Waters 2767 Sample Manager, Waters 2545 Binary Gradient Module, Waters Systems Fluidics Organiser, Waters 515 ACD Pump, Waters 515 Makeup Pump, Waters 2998 Photodiode Array Detector, Waters Qda) over 12.5 min. The column end dilution pump provided 2 mL / min of MeCN throughout the method, which was included in the following MeCN percentages. Gradient information: 0.0 - 0.5 min, 1% MeCN; 0.5 - 10.5 min, rising from 1% MeCN to fp% MeCN; 10.5 - 10.6 min, rising from fp% MeCN to 100% MeCN; 10.6 - 12.5 min, holding at 100% MeCN. The pure eluate was evaporated in a Genevac.

[0283] Basic method (B):

[0284] The product was dissolved in DMSO (0.5 mL), filtered and eluted with a 0.3% ammonia - MeCN gradient using a Waters X - Bridge BEH C18 ODB preparative column ( 5 μm, 30 mm × 100 mm, flow rate 40 mL / min) and purified by reverse-phase preparative HPLC over 12.5 min using UV detection across all wavelengths by PDA as well as QDA and ELS detectors. The column end dilution pump provided 2 mL / min of MeCN throughout the method, which was included in the following MeCN percentages. Gradient information: 0.0 - 0.5 min, 20% MeCN; 0.5 - 10.5 min, rising from 20% MeCN to 50% MeCN; 10.5 - 10.6 min, rising from 50% MeCN to 100% MeCN; 10.6 - 12.5 min, holding at 100% MeCN. The pure eluate was evaporated in a Genevac.

[0285] Alternatively, the following analytical LCMS equipment and methods were also used:

[0286]

[0287]

[0288] Commercially available materials

[0289] All starting materials and solvents were obtained from commercial sources or prepared according to literature citations.

[0290] General method

[0291] Unless otherwise stated, all reactants are stirred. The organic solution is usually dried over anhydrous magnesium sulfate. Hydrogenation is carried out using a Thales H-cube flow reactor under the stated conditions or in a gas autoclave (pressure vessel) under pressure.

[0292] Synthesis of intermediates Intermediate 1: 6-(Chloromethyl)-2,3-dihydropyrazolo[5,1-b]oxazole

[0293]

[0294] Step 1

[0295] To a mixture of ethyl 5-hydroxy-1H-pyrazole-3-carboxylate (1 g, 6.4 mmol) and 1,2-dibromoethane (1302 mg, 7 mmol) in MeCN (5 mL) at 0 °C was added K2CO3 (1.9 g, 14 mmol). The reactants were stirred at room temperature for 5 h. After LCMS indicated complete reaction, water (10 ml) was added to the reaction mixture. The mixture was extracted with EtOAc (10 mL × 3). The organic layer was concentrated under reduced pressure at 40 °C, and the residue was purified by flash column chromatography (12 g, petroleum ether / tert-butyl methyl ether = 100:0 - 40:60) to give ethyl 2,3-dihydropyrazolo[5,1-b]oxazole-6-carboxylate (800 mg, 100% purity) as a yellow solid. MS (ES+): 183.3 (M+H)+.

[0296] Step 2

[0297] To a solution of ethyl 2,3-dihydropyrazolo[5,1-b]oxazole-6-carboxylate (800 mg, 4.4 mmol) in THF (10 mL) at 0 °C was added LAH (2.8 mL, 5.7 mmol, 2 M THF solution). The reaction mixture was stirred at 0 °C for 2 h. After LCMS indicated completion of the reaction, water (10 mL) was added to the mixture and it was extracted with EtOAc (10 mL × 3). The organic layer was concentrated under reduced pressure at 40 °C. The residue was purified by flash column chromatography (20 g, petroleum ether / tert-butyl methyl ether = 100:00 - 20:80) to give (2,3-dihydropyrazolo[5,1-b]oxazol-6-yl)methanol (260 mg, 100% purity) as a yellow solid. MS (ES+): 141.4 (M+H)+.

[0298] Step 3

[0299] At 0 °C, SOCl2 (221 mg, 1.8 mmol) was added to a solution of (2,3-dihydropyrazolo[5,1-b]oxazol-6-yl)methanol (200 mg, 1.43 mmol) in DCM (5 mL), and the reaction mixture was stirred at room temperature for 0.5 h. After LCMS indicated completion of the reaction, the mixture was concentrated under reduced pressure at 30 °C to remove DCM and most of the excess SOCl2. The residue was quenched with ice water (10 mL), adjusted to pH = 9 with 2N aqueous K2CO3 solution, and extracted with DCM (10 mL × 3). The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure at 30 °C to give the title compound as a yellow oil (200 mg, 100% purity), which was used directly in the next step without further purification. MS (ES+): 159.3 (M+H)+.

[0300] Intermediate 2: 6-((1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)thio)phthalazin-1(2H)-one

[0301]

[0302] A suspension of 6-mercaptopthalazin-1(2H)-one (1.26 g, 80 wt%, 1 equiv, 5.66 mmol), 4-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (1.82 g, 95 wt%, 1.1 equiv, 6.22 mmol), K2CO3 (1.56 g, 2.0 equiv, 11.3 mmol) and 1,10-phenanthroline (408 mg, 0.4 equiv, 2.26 mmol) in DMF (28.0 mL) was purged with N2 for 10 - 15 min, followed by the addition of copper(I) iodide (215 mg, 0.2 equiv, 1.13 mmol). The reaction mixture was purged with N2 for 10 min and then heated at 100 °C overnight. The reaction was cooled to room temperature and poured onto a mixture of ice and water, causing a precipitate to form, which was filtered and washed with water (50 mL). The resulting dark brown gummy solid was dissolved in DCM (250 mL) and washed with semi-concentrated brine (200 mL). The organic matter was dried (MgSO4), filtered and concentrated under reduced pressure to give a solid (1.87 g). The crude material was combined with the crude mixture (1.63 g) obtained from a separate experiment, dissolved in DCM (20 mL) and MeOH (2 mL), concentrated onto silica and purified by chromatography to give the title compound as a light brown solid (982.9 mg, 2.9 mmol). MS (ES + ): 195.1 (M+H)+.

[0303] Intermediate 3: 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-4-thiol

[0304]

[0305] Step 1

[0306] At room temperature, TsOH (708 mg, 4.2 mmol) was added to a solution of 4-iodo-1H-pyrazole (80 g, 412 mmol) and 3,4-dihydro-2H-pyran (54 g, 618 mmol) in MeCN (1.2 L). The reaction mixture was stirred at 85 °C for 16 h. After the reaction was indicated to be complete by LCMS, the mixture was concentrated under reduced pressure at 45 °C. The residue was purified by flash column chromatography to give 4-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (100 g) as a white solid. MS (ES + ): 279.2 (M+H) +

[0307] Step 2

[0308] At room temperature, DIPEA (140 g, 1080 mmol) was added to a solution of 4-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (100 g, 360 mmol), 2-ethylhexyl 3-mercaptopropionate (94 g, 432 mmol), Pd2dba3 (13 g, 14.4 mmol) and Xantphos (16.6 g, 28.8 mmol) in DMF (1 L). The reaction mixture was stirred at 100 °C for 16 h. After the reaction was indicated to be complete by LCMS, the mixture was extracted with EtOAC (600 mL×3) and concentrated under reduced pressure at 45 °C. The residue was purified by flash column chromatography to give 2-ethylhexyl 3-((1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)thio)propionate (116 g) as a yellow oil. MS (ES + ): 369.3 (M+H) +

[0309] Step 3

[0310] At 0 °C, NaOEt (252 mL, 630 mmol, 2.5 M EtOH solution) was added to a mixture of 2-ethylhexyl 3-((1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)thio)propionate (116 g, 315 mmol) in THF (2 L). The reaction mixture was stirred at 0 °C for 0.5 h. After the LCMS indicated the completion of the reaction, the reaction mixture was quenched with HCl (1 M) until the pH reached 6. The mixture was extracted with EtOAC (600 mL × 3). The organic layer was concentrated under reduced pressure at 40 °C and purified by flash column chromatography to give 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-4-thiol (45 g) as an oil, which was used in the next step without further purification. MS (ES + ): 101.4 (M+H) +

[0311] Intermediate 4: 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-thiol

[0312]

[0313] Step 1

[0314] At room temperature, p-TsOH (43 mg, 0.3 mmol) was added to a solution of 3-iodo-1H-pyrazole (5.0 g, 25.8 mmol) and 3,4-dihydro-2H-pyran (3.3 g, 38.7 mmol) in MeCN (50 mL), and the reaction mixture was stirred at 80 °C for 16 h. After the LCMS indicated the completion of the reaction, the reaction mixture was concentrated under reduced pressure at 45 °C. The residue was purified by flash column chromatography (25 g, petroleum ether / tert-butyl methyl ether = 100:0 - 90:10) to give 3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (6.6 g, 100% purity) as a yellow oil. MS (ES + ): 279.1 (M+H)+.

[0315] Step 2

[0316] At room temperature, DIPEA (9.2 g, 71.1 mmol) was added to a solution of 3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (6.6 g, 23.7 mmol), 2-ethylhexyl 3-mercaptopropionate (6.7 g, 30.8 mmol), Pd2dba3 (540 mg, 0.59 mmol) and Xantphos (685 mg, 1.19 mmol) in DMF (100 mL). The reaction mixture was stirred at 100 °C for 16 h. After LCMS indicated the completion of the reaction, water (50 mL) was added and the mixture was extracted with EtOAC (50 mL × 3). At 45 °C, the combined organic layers were concentrated under reduced pressure. The residue was purified by flash column chromatography (120 g, petroleum ether / tert-butyl methyl ether = 100:00 - 80:20) to give 2-ethylhexyl 3-((1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)thio)propionate as a yellow oil (7.1 g, 44.18% purity). MS(ES + ): 369.3 (M+H) +

[0317] Step 3

[0318] At 0 °C, EtONa (15 mL, 2.5 M EtOH solution) was added to a mixture of 2-ethylhexyl 3-((1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)thio)propionate (7.1 g, 19.3 mmol) in THF (150 mL). The reactants were stirred at 0 °C for 0.5 h. After LCMS indicated the completion of the reaction, the pH of the reaction mixture was adjusted to pH = 6 by carefully adding aqueous HCl solution (1 M). The mixture was extracted with EtOAC (800 mL × 3). At 40 °C, the organic layer was concentrated under reduced pressure. The residue was purified by flash column chromatography (40 g, petroleum ether / tert-butyl methyl ether = 100:0 - 60:40) to give 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-thiol as a yellow oil (2.8 g, 100% purity). MS(ES + ): 185.3 (M+H)+. Intermediate 5: (4-chloro-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)methanol

[0319]

[0320] Step 1

[0321] A mixture of ethyl 5-methyl-1H-pyrazole-3-carboxylate (2.0 g, 12.97 mmol) and NCS (2.42 g, 18.16 mmol) in DMF (30 mL) was stirred at room temperature for 1 hour. After LCMS indicated completion of the reaction, the reaction mixture was diluted with water (30 mL) and extracted with EtOAc (50 mL × 4). The organic layer was washed with saturated aqueous NH4Cl solution (100 mL × 2), concentrated and purified by flash column chromatography (40 g, petroleum ether / tert-butyl methyl ether = 100:00 - 20:80) to give ethyl 4-chloro-5-methyl-1H-pyrazole-3-carboxylate as a white solid (2.0 g, 68% purity). MS(ES + ): 189.1 (M+H)+.

[0322] Step 2

[0323] A mixture of ethyl 4-chloro-5-methyl-1H-pyrazole-3-carboxylate (2.0 g, 5.30 mmol), 3,4-dihydro-2H-pyran (892 mg, 10.6 mmol) and 4-methylbenzenesulfonic acid (86 mg, 0.5 mmol) in MeCN (15 mL) was stirred at 70 °C overnight. After LCMS indicated completion of the reaction, the reaction mixture was concentrated to remove MeCN. The crude product was purified by flash column chromatography (20 g, petroleum ether / tert-butyl methyl ether = 100:00 - 85:15) to give ethyl 4-chloro-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-carboxylate as a yellow oil (760 mg, 79% purity). MS(ES + ): 189.2 (M+H)+.

[0324] Step 3

[0325] To a solution of ethyl 4-chloro-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-carboxylate (760 mg, 2.79 mmol) in THF (4 mL) was added LiBH4 (5.6 mL, 5.60 mmol, 1 M in THF), and the reaction mixture was stirred at room temperature for 4 hours. After LCMS indicated completion of the reaction, the reaction mixture was quenched with saturated aqueous NH4Cl solution until gas evolution ceased. The suspension was extracted with DCM (50 mL × 4). Subsequently, the organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure at 40 °C to give the title compound as a white solid (540 mg, 86% purity). MS(ES + ): 231.2 (M+H)+.

[0326] Intermediate 6: 6-Mercapto-2-((1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)methyl)phthalazin-1(2H)-one

[0327] Step 1

[0328] A suspension of 6-bromophthalazin-1(2H)-one (2.117 g, 98% Wt, 1 equivalent, 9.217 mmol) and cesium carbonate (6.006 g, 2.0 equivalents, 18.43 mmol) in DMF (40 mL) was stirred at 80 °C for 1 hour and then cooled to room temperature. A solution of 3-(chloromethyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (2.055 g, 9.217 mmol) in DMF (10 mL) was added, and the reaction mixture was stirred at room temperature for 20 hours. EtOAc (150 mL) was added and the reaction mixture was washed with water (100 mL). The organic layer was collected and the aqueous layer was extracted with EtOAc (3 × 100 mL). The combined organic extracts were washed with 50% brine (2 × 100 mL), brine (100 mL) and concentrated in vacuo to give the crude product. The crude product was purified by silica gel chromatography to give 6-bromo-2-((1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)methyl)phthalazin-1(2H)-one (Intermediate 6A, 2.192 g) as an off-white solid. MS(ES + ): 389 / 391 (M+H) + 。

[0329] Step 2

[0330] A solution of 6-bromo-2-((1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)methyl)phthalazin-1(2H)-one (1.47 g, 3.40 mmol) in DMF (30 mL) was bubbled with N2 for 5 minutes. DIPEA (879 mg, 1.18 mL, 2.00 eq, 6.80 mmol), Xantphos (197 mg, 340 μmol), Pd2(dba)3 (156 mg, 170 μmol) and 2-ethylhexyl 3-mercaptopropionate (852 mg, 3.90 mmol) were added successively, and the reaction mixture was stirred at 100 °C for 90 minutes. 2-Ethylhexyl 3-mercaptopropionate (0.20 mL, 0.876 mmol) was added and the mixture was stirred at 100 °C for 90 minutes. The reaction mixture was concentrated in vacuo and the residue was azeotroped with toluene (3 times) to give the crude product. The crude product was purified by silica gel chromatography to give 2-ethylhexyl 3-((1-oxo-2-((1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)methyl)-1,2-dihydrophthalazin-6-yl)thio)propionate (1.648 g) as a thick yellow oil. MS(ES + ): 527 (M+H) + .

[0331] Step 3

[0332] A stirred solution of 2-ethylhexyl 3-((1-oxo-2-((1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)methyl)-1,2-dihydrophthalazin-6-yl)thio)propionate (1.64 g, 2.77 mmol) in THF (25 mL) was treated dropwise with sodium ethoxide (2.13 g, 6.56 mmol). The reaction mixture was stirred at room temperature for 1 h and then diluted with DCM (100 mL) and saturated aqueous NH4Cl (100 mL). The organic layer was collected and the aqueous layer was extracted with DCM (2 × 50 mL). The combined organic extracts were washed with 50% brine (50 mL), dried (phase separator) and concentrated in vacuo to give the crude product. The crude product was purified by silica gel chromatography to give the title compound (715 mg) as a pale pink solid. 11H NMR (400 MHz, DMSO-d6) δ 8.29 (s, 1H), 8.10 (d, J = 8.4 Hz, 1H), 7.83–7.72 (m, 3H), 6.34 (s, 1H), 6.15 (d, J = 2.4 Hz, 1H), 5.31 (dd, J = 10.3, 2.4 Hz, 1H), 5.24 (s, 2H), 3.94–3.85 (m, 1H), 3.58 (ddd, J = 11.5, 8.6, 6.3 Hz, 1H), 2.03 (tdd, J = 12.5, 10.0, 3.6 Hz, 1H), 1.95–1.81 (m, 2H), 1.70–1.57 (m, 1H), 1.50 (tq, J = 8.0, 3.9 Hz, 2H). MS (ES + ): 343 (M+H) + .

[0333] Intermediate 7: 6-Mercaptophtalazin-1(2H)-one

[0334]

[0335] A mixture of 6-bromophthalazin-1(2H)-one (0.60 g, 1 eq., 2.7 mmol), 2-ethylhexyl 3-mercaptopropionate (0.61 g, 0.64 mL, 1.05 eq., 2.8 mmol), cesium carbonate (1.7 g, 2 eq., 5.3 mmol), Xantphos (0.15 g, 0.1 eq., 0.27 mmol) and Pd2(dba)3 (0.12 g, 0.05 eq., 0.13 mmol) in DMF (12 mL) was heated to 100 °C and maintained for 12 h. After cooling to room temperature, the reaction mixture was diluted with water (50 mL) and then extracted with DCM (20 mL). The aqueous layer was acidified with 1 M HCl and then extracted with EtOAc (2 × 50 mL). The organic phases were collected, dried (MgSO4) and evaporated under reduced pressure to give the title compound as a viscous orange solid (0.33 g). MS (ES + ): 179 (M+H) + .

[0336] Intermediate 8: 1-(2-((tert-Butyldimethylsilyl)oxy)ethyl)-4-iodo-1H-pyrazole

[0337]

[0338] A mixture of 3-iodopyrazole (300 mg, 1 equiv, 1.55 mmol), (2-bromoethoxy)dimethyl-tert-butylsilane (407 mg, 366 μL, 1.1 equiv, 1.70 mmol), and potassium carbonate (321 mg, 1.5 equiv, 2.32 mmol) in MeCN (10.0 mL) was heated to 85 °C and maintained for 24 h. The reaction mixture was cooled to room temperature, diluted with DCM (10 mL), then filtered through celite and washed with DCM (20 mL) and MeOH (10 mL). The residue (oil and solid) was partitioned between EtOAc (20 mL) and water (10 mL). The organic layer was washed with brine (10 mL × 2), dried over MgSO4 and concentrated under reduced pressure to give the crude product (536 mg) as a clear yellow liquid containing a mixture of regioisomers. The crude material was dissolved in DCM (5 mL), concentrated onto silica gel and purified by chromatography to give the title compound (108.5 mg) as a clear colorless oil. 1 H NMR (400 MHz, MeOD) δ 7.51 (d, J = 2.3 Hz, 1H), 6.45 (d, J = 2.3 Hz, 1H), 4.25 (t, J = 5.1 Hz, 2H), 3.96 (t, J = 5.1 Hz, 2H), 0.86 (s, 9H), -0.03 (s, 6H). MS (ES + ): 353 (M+H) + 。

[0339] Intermediate 9: 5-(Chloromethyl)-2,3-dihydrofuro[3,2-b]pyridine

[0340]

[0341] Step 1

[0342] To a solution of methyl furo[3,2-b]pyridine-5-carboxylate (800 mg, 4.52 mmol) was added a solution of 10% Pd / C (320 mg, 50% water content) in MeOH (10 mL). The mixture was stirred under H2 at 25 °C for 10 h. After LCMS indicated completion of the reaction, the mixture was dried over Na2SO4, filtered and concentrated under reduced pressure at 30 °C. The residue was purified by flash column chromatography to give methyl 2,3-dihydrofuro[3,2-b]pyridine-5-carboxylate (750 mg) as a yellow solid. MS (ES + ): 180.3 (M+H) + 。

[0343] Step 2

[0344] At 0 °C, Red-Al (2.42 g, 8.38 mmol, 70 wt% toluene solution) was added to a solution of methyl 2,3-dihydrofuro[3,2-b]pyridine-5-carboxylate (750 mg, 4.19 mmol) in THF (10 mL), and the reaction mixture was stirred at room temperature for 2 h. After LCMS indicated completion of the reaction, NH4Cl (1 mL) was added to the mixture. The mixture was quenched with Na2SO4, filtered and concentrated under reduced pressure at 30 °C. The residue was purified by flash column chromatography to give (2,3-dihydrofuro[3,2-b]pyridin-5-yl)methanol (360 mg) as a yellow solid. MS(ES + ): 152.4 (M+H) + .

[0345] Step 3

[0346] At 0 °C, SOCl2 (221 mg, 1.86 mmol) was added dropwise to a solution of (2,3-dihydrofuro[3,2-b]pyridin-5-yl)methanol (140 mg, 0.93 mmol) in DCM (5 mL), and the reaction mixture was stirred at room temperature for 2 h. After LCMS indicated completion of the reaction, the mixture was concentrated under reduced pressure at 30 °C to remove DCM and SOCl2, giving 5-(chloromethyl)-2,3-dihydrofuro[3,2-b]pyridine (150 mg) as a yellow oil, which was used directly in the next step. MS(ES + ): 170.4 (M+H) + .

[0347] Intermediate 10: 1-Methyl-1H-pyrazole-4-thiol

[0348]

[0349] Step 1

[0350] A mixture of 4-iodo-1-methyl-1H-pyrazole (1.00 g, 1 equiv, 4.81 mmol), 2-ethylhexyl 3-mercaptopropionate (1.05 g, 1.10 mL, 1 equiv, 4.81 mmol), DIPEA (684 mg, 921 μL, 1.1 equiv, 5.29 mmol), Pd2dba3 (220 mg, 0.05 equiv, 240 μmol), and Xantphos (278 mg, 0.1 equiv, 481 μmol) in DMF (25 mL) was stirred at 100 °C under nitrogen for 1.5 h and then cooled to room temperature. Water and DCM were added, and the layers were separated. The organic layer was washed with water, brine, dried (MgSO4), and adsorbed onto silica. The crude product was purified by silica gel chromatography (40 g column, 0 - 50% EtOAc / isohexane) to give 2-ethylhexyl 3-((1-methyl-1H-pyrazol-4-yl)thio)propionate as a pale yellow oil (1.27 g, 4.1 mmol, 85%, 96% purity). MS(ES + ): 299 (M+H) +

[0351] Step 2

[0352] Sodium ethoxide (543 mg, 625 μL, 21% Wt, 2.5 equiv, 1.68 mmol) was added dropwise to a solution of 2-ethylhexyl 3-((1-methyl-1H-pyrazol-4-yl)thio)propionate (200 mg, 1 equiv, 670 μmol) in THF (3.00 mL) at 0 °C under nitrogen, and the mixture was warmed to room temperature and stirred for 20 min. 1N HCl (1 mL) and DCM were added, and the layers were separated by a phase separator. The organic layer was washed with brine, dried (MgSO4), and concentrated in vacuo to give the crude title product as a pale yellow oil. The product was used in the next step without further purification.

[0353] Synthesis of examples

[0354] Example 1: 6-((1H-Pyrazol-4-yl)sulfonyl)-2-((5-methoxypyridin-2-yl)methyl)phthalazin-1(2H)-one

[0355]

[0356] Step 1

[0357] A mixture of 6-((1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)thio)phthalazin-1(2H)-one (Intermediate 2, 75.0 mg, 1 equiv, 228 μmol) and cesium carbonate (223 mg, 3 equiv, 685 μmol) in DMF (1.50 mL) was stirred at 70 °C for 30 minutes. 2-(Chloromethyl)-5-methoxypyridine hydrochloride (48.8 mg, 1.1 equiv, 25 μmol) was added and the mixture was stirred overnight at room temperature. Water and DCM were added and the layers were separated by a phase separator. The organic layer was washed with brine, dried (MgSO4) and concentrated in vacuo to give the crude 2-((5-methoxypyridin-2-yl)methyl)-6-((1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)thio)phthalazin-1(2H)-one. The product was used in the next step without further purification. The yield was assumed to be quantitative.

[0358] Step 2

[0359] A mixture of 2-((5-methoxypyridin-2-yl)methyl)-6-((1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)thio)phthalazin-1(2H)-one and Oxone (309 mg, 2.2 equiv, 502 μmol) in DMF (1.50 mL) was stirred overnight. Saturated NaHCO3 and DCM were added and the layers were separated. The organic layer was washed with brine, dried (MgSO4) and concentrated in vacuo to give a crude mixture of 2-((5-methoxypyridin-2-yl)methyl)-6-((1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)sulfonyl)phthalazin-1(2H)-one and 6-((1H-pyrazol-4-yl)sulfonyl)-2-((5-methoxypyridin-2-yl)methyl)phthalazin-1(2H)-one. The mixture was dissolved in MeOH (1.5 mL) and hydrogen chloride (4 N in dioxane) (41.6 mg, 285 μL, 4.00 mmol, 5 equiv, 1.14 mmol) was added. The mixture was stirred for 1 h and then concentrated in vacuo. Saturated NaHCO3, 2 N NaOH and DCM were added and the layers were separated. The organic layer was washed with brine and then adsorbed onto silica gel. The crude product was purified by silica gel chromatography (4 g column, 0 - 50% 10% (MeOH(0.7 M NH3):DCM):DCM) to give 6-((1H-pyrazol-4-yl)sulfonyl)-2-((5-methoxypyridin-2-yl)methyl)phthalazin-1(2H)-one as a white solid (40.8 mg, 98% purity). 1H NMR (DMSO) δ: 13.91 (s, 1H), 8.64–8.59 (m, 2H), 8.57–7.96 (s(br), 2H), 8.43 (d, J = 8.4 Hz, 1H), 8.31 (dd, J = 8.4, 1.9 Hz, 1H), 8.16 (d, J = 2.9 Hz, 1H), 7.33 (dd, J = 8.6, 3.0 Hz, 1H), 7.24 (d, J = 8.6 Hz, 1H), 5.38 (s, 2H), 3.78 (s, 3H). MS (ES+): 398 (M + H)+.

[0360] Example 2: 2-((1H-Pyrazol-3-yl)methyl)-6-((1-(difluoromethyl)-1H-pyrazol-4-yl)sulfonyl)phthalazin-1(2H)-one

[0361]

[0362] Step 1

[0363] Bubble nitrogen through a mixture of 6-mercapto-2-((1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)methyl)phthalazin-1(2H)-one (Intermediate 6, 150 mg, 91% Wt, 1 equivalent, 399 μmol), 1-(difluoromethyl)-4-iodo-1H-pyrazole (126 mg, 1.3 equivalents, 518 μmol), 1,10-phenanthroline (32.3 mg, 0.45 equivalent, 179 μmol) and potassium carbonate (93.7 mg, 1.7 equivalents, 678 μmol) in DMF (2.5 mL) for 5 minutes. Add copper(I) iodide (16.7 mg, 0.22 equivalent, 87.7 μmol) and stir the mixture under nitrogen at 100 °C for 4 hours, then cool to room temperature. Add water and EtOAc and separate the layers. Wash the organic layer with brine and then adsorb it onto silica. Purify the crude product by silica gel chromatography (12 g column, 0 - 100% EtOAc / isohexane) to give 6-((1-(difluoromethyl)-1H-pyrazol-4-yl)thio)-2-((1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)methyl)phthalazin-1(2H)-one as a white solid (165 mg, 0.36 mmol, 99% purity). MS(ES+): 459(M + H)+

[0364] Step 2

[0365] A mixture of 6-((1-(difluoromethyl)-1H-pyrazol-4-yl)thio)-2-((1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)methyl)phthalazin-1(2H)-one (165 mg, 99% Wt, 1 equivalent, 356 μmol) and Oxone (482 mg, 2.2 equivalents, 784 μmol) in DMF (1.5 mL) was stirred overnight. Saturated NaHCO3 and DCM were added, and the layers were separated by a phase separator. The organic layer was washed with brine, dried (MgSO4) and concentrated in vacuo to give a crude mixture of 6-((1-methyl-1H-pyrazol-3-yl)sulfonyl)-2-((1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)methyl)phthalazin-1(2H)-one and 2-((1H-pyrazol-3-yl)methyl)-6-((1-(difluoromethyl)-1H-pyrazol-4-yl)sulfonyl)phthalazin-1(2H)-one. The mixture was dissolved in MeOH (1.5 mL), and hydrogen chloride (4N in dioxane) (64.9 mg, 445 μL, 4.00 mmol, 5 equivalents, 1.78 mmol) was added. The mixture was stirred for 1.5 h and then concentrated in vacuo. Saturated NaHCO3, 2N NaOH and DCM were added, and the layers were separated. The organic layer was washed with brine and then adsorbed onto silica gel. The crude product was purified by silica gel chromatography (4 g column, 0 - 50% 10% (MeOH(0.7M NH3):DCM)):DCM) to give the title compound as a white solid (48.5 mg, 99% purity). 1H NMR (DMSO) δ: 12.65 (s, 1H), 9.15 (s, 1H), 8.67 (d, J = 1.8 Hz, 1H), 8.61 (s, 1H), 8.47 (d, J = 8.5 Hz, 1H), 8.40 (s, 1H), 8.36 (dd, J = 8.5, 1.9 Hz, 1H), 7.85 (t, J = 58.3, 1H), 7.62 (s, 1H), 7.37 (s, 1H), 6.16–6.11 (m, 1H), 5.31 (s, 2H). MS (ES+): 407 (M + H)+

[0366] Example 3: 2-((2,3-Dihydrofuro[3,2-b]pyridin-5-yl)methyl)-6-((1-(2-hydroxyethyl)-1H-pyrazol-4-yl)sulfonyl)phthalazin-1(2H)-one

[0367]

[0368] Step 1

[0369] 6-Mercaptophtalazin-1(2H)-one (Intermediate 7, 235 mg, 92% Wt, 1 equivalent, 1.21 mmol), 1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-4-iodo-1H-pyrazole (Intermediate 8, 540 mg, 86% Wt, 1.09 equivalents, 1.32 mmol), 1,10-phenanthroline (87.5 mg, 0.4 equivalent, 485 μmol) and potassium carbonate (335 mg, 2 equivalents, 2.43 mmol) were suspended in DMF (6.00 mL), purged with N2 for 5 - 10 minutes, then copper(I) iodide (46.2 mg, 0.2 equivalent, 243 μmol) was added and the mixture was purged with N2 for another 5 - 10 minutes. The reaction mixture was stirred at 100 °C overnight and then cooled to room temperature. The reaction mixture was partitioned between DCM (20 mL) and water (10 mL). The organic layer was further washed with semi-concentrated brine (20 mL × 2), filtered through a phase separator and concentrated under reduced pressure to give a dark green crude oil (964 mg). The crude material was dissolved in DCM (20 mL), concentrated onto silica and purified by silica gel chromatography (24 g column, 0 - 100% (3:1 EtOAc / EtOH) / isohexane) to give 6-((1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1H-pyrazol-4-yl)thio)phtalazin-1(2H)-one as an off-white solid (308.6 mg, 0.74 mmol, 97% purity). MS (ES+): 403.1 (M+H)+. 1H NMR (400 MHz, DMSO) δ 12.59 (s, 1H), 8.19 (d, J = 0.8 Hz, 1H), 8.13 (d, J = 0.7 Hz, 1H), 8.05 (d, J = 8.4 Hz, 1H), 7.75 (d, J = 0.7 Hz, 1H), 7.53 (d, J = 1.9 Hz, 1H), 7.46 (dd, J = 8.5, 1.9 Hz, 1H), 4.28 (t, J = 5.1 Hz, 2H), 3.95 (t, J = 5.2 Hz, 2H), 0.78 (s, 9H), -0.06 (s, 6H).

[0370] Step 2

[0371] A suspension of 6 - ((1 - (2 - ((tert - butyldimethylsilyl)oxy)ethyl)-1H - pyrazol - 4 - yl)thio)phthalazin - 1(2H)-one (164 mg, 97% Wt, 1.00 equivalent, 395 μmol) and cesium carbonate (463 mg, 3.6 equivalents, 1.42 mmol) in DMF (2.00 mL) was stirred at 70 °C for 45 minutes, and then a solution of 5 - (chloromethyl)-2,3 - dihydrofuro[3,2 - b]pyridine, HCl (Intermediate 9, 90.0 mg, 92% Wt, 1.02 equivalents, 402 μmol) in DMF (1.80 mL) was added. The reaction mixture was stirred at 50 °C for 5 hours and then allowed to stand overnight at room temperature. The reaction mixture was reheated at 50 °C for 5 hours. The reaction mixture was precipitated with water (15 mL) and diluted and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with semi - concentrated brine (50 mL × 3), dried over Mg2SO4, filtered, and concentrated under reduced pressure to give a yellow oil (204 mg). The crude material was dissolved in DCM (10 mL), concentrated onto silica, and purified by silica gel chromatography (12 g column, 0 - 50% (3:1, EtOAc / EtOH) / isohexane) to give 6 - ((1 - (2 - ((tert - butyldimethylsilyl)oxy)ethyl)-1H - pyrazol - 4 - yl)thio)-2 - ((2,3 - dihydrofuro[3,2 - b]pyridine - 5 - yl)methyl)phthalazin - 1(2H)-one as a yellow solid (109.1 mg, 0.20 mmol, 97% purity). MS(ES+): 536.1(M + H)+. 1H NMR(400 MHz, MeOD) δ 8.19(s, 1H), 8.16(d, J = 8.6 Hz, 1H), 7.96(s, 1H), 7.71(s, 1H), 7.54(dd, J = 8.5, 1.9 Hz, 1H), 7.49(d, J = 1.8 Hz, 1H), 7.03(s, 2H), 5.39(s, 2H), 4.64(t, J = 8.9 Hz, 2H), 4.33(t, J = 5.0 Hz, 2H), 4.02(t, J = 5.0 Hz, 2H), 3.26(t, J = 8.9 Hz, 2H), 0.82(s, 9H), - 0.02(s, 6H).

[0372] Step 3

[0373] To a solution of 6-((1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1H-pyrazol-4-yl)thio)-2-((2,3-dihydrofuro[3,2-b]pyridin-5-yl)methyl)phthalazin-1(2H)-one (109 mg, 97% Wt, 1 equiv, 197 μmol) in MeOH (2.00 mL) was added Oxone (243 mg, 2.0 equiv, 395 μmol). The reaction was stirred at room temperature, then Oxone (24.3 mg, 0.2 equiv, 39.5 μmol) was added and stirring was continued for an additional 3 h at room temperature. The reaction mixture was diluted with MeOH (15 mL) to give a white solid (359 mg). The crude material was dissolved in DCM (20 mL) and MeOH (3 mL), concentrated onto silica and purified by silica gel chromatography (12 g column, 0-5% (0.7 M ammonia / MeOH) / DCM) to give 2-((2,3-dihydrofuro[3,2-b]pyridin-5-yl)methyl)-6-((1-(2-hydroxyethyl)-1H-pyrazol-4-yl)sulfonyl)phthalazin-1(2H)-one as a white solid (41.4 mg, 89 μmol, 98% purity). MS (ES+): 454.2 (M+H)+. 1H NMR (400 MHz, DMSO) δ 8.62 (d, J = 2.5 Hz, 2H), 8.53 (s, 1H), 8.44 (d, J = 8.5 Hz, 1H), 8.31 (dd, J = 8.4, 1.8 Hz, 1H), 8.05 (d, J = 0.7 Hz, 1H), 7.05 (d, J = 8.3 Hz, 1H), 6.98 (d, J = 8.3 Hz, 1H), 5.34 (s, 2H), 4.94 (s, 1H), 4.59 (t, J = 8.8 Hz, 2H), 4.18 (t, J = 5.3 Hz, 2H), 3.74–3.70 (m, 2H), 3.18 (t, J = 8.8 Hz, 2H).

[0374] Example 4: 6-((1H-Pyrazol-4-yl)sulfonyl)-2-((2,3-dihydropyrazolo[5,1-b]oxazol-6-yl)methyl)phthalazin-1(2H)-one

[0375]

[0376] Step 1

[0377] At room temperature, t-BuOK (54 g, 482 mmol) was added to a mixture of 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-4-thiol (Intermediate 3, 62 g, 337 mmol), 6-bromophthalazin-1(2H)-one (54 g, 241 mmol), CuI (6.4 g, 33.7 mmol) and 1,2,3-benzotriazole (8 g, 67.4 mmol) in NMP (2 L). The reaction mixture was stirred overnight at 100 °C under a nitrogen atmosphere. After LCMS indicated completion of the reaction, the reaction mixture was added to water (10 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 (75 g, 98% purity) as a yellow solid. MS (ES+): 329.1 (M+H)+.

[0378] Step 2

[0379] At room temperature, Cs2CO3 (652 mg, 2 mmol) was added to a solution of 6-((1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)thio)phthalazin-1(2H)-one (328 mg, 1 mmol) and 6-(chloromethyl)-2,3-dihydropyrazolo[5,1-b]oxazole (Intermediate 1, 200 mg, 1.3 mmol) in DMF (10 mL), and the reaction mixture was stirred at 60 °C for 16 hours. After LCMS indicated completion of the reaction, water (30 mL) was added to the reaction mixture, and the organic matter was extracted with EtOAc (20 mL × 3). The combined organic layers were washed with an aqueous NH4Cl solution, dried over Na2SO4, filtered and concentrated under reduced pressure at 45 °C. The residue was purified by flash column chromatography (12 g, dichloromethane / ethyl acetate = 100:0 to 60:40) to give 2-((2,3-dihydropyrazolo[5,1-b]oxazol-6-yl)methyl)-6-((1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)thio)phthalazin-1(2H)-one (170 mg, 89.77% purity) as a yellow solid. MS (ES+): 451.1 (M+H)+.

[0380] Step 3

[0381] To a solution of 2-((2,3-dihydropyrazolo[5,1-b]oxazol-6-yl)methyl)-6-((1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)thio)phthalazin-1(2H)-one (170 mg, 0.38 mmol) in DMF (3 mL) was added OXONE (700 mg, 1.14 mmol) at room temperature. The reaction mixture was stirred at 60 °C for 0.5 h. After LCMS indicated the completion of the reaction, water (10 mL) was added to the reaction mixture. The mixture was extracted with EtOAc (10 mL × 3). The organic layer was concentrated under reduced pressure at 40 °C. The residue was purified by preparative HPLC (column: Waters X-Bridge C18 OBD 10 μm 19*250 mm; flow rate: 20 mL / min; solvent system: MeCN / (10 mmol / L NH4HCO3 / water) gradient: MeCN: 38% - 95%; collection wavelength: 214 nm). The relevant fractions were concentrated under reduced pressure at 42 °C to remove MeCN, and the residue was lyophilized to give the title compound as a white solid (27.87 mg, 100% purity). MS(ES+): 399.2(M + H)+. 1HNMR(400 MHz, DMSO-d6)δ: 13.91(s, 1H), 8.60(d, J = 1.6 Hz, 1H), 8.59(d, J = 0.4 Hz, 1H), 8.44 - 8.29(m, 4H), 5.31(s, 1H), 5.16(s, 2H), 4.99(t, J = 8.0 Hz, 2H), 4.17(t, J = 8.0 Hz, 2H). 1H NMR(400 MHz, DMSO-d6 + TFA-D)δ: 8.60(d, J = 0.4 Hz, 1H), 8.59(d, J = 2.0 Hz, 1H), 8.43(d, J = 8.4 Hz, 1H), 8.34(s, 2H), 8.30(dd, J = 8.4, 2.0 Hz, 1H), 5.31(s, 1H), 5.16(s, 2H), 4.99(t, J = 7.6 Hz, 2H), 4.17(d, J = 8.4 Hz, 2H).

[0382] Example 5: 2-((2,3-Dihydropyrazolo[5,1-b]oxazol-6-yl)methyl)-6-((1-methyl-1H-pyrazol-4-yl)sulfonyl)phthalazin-1(2H)-one

[0383]

[0384] Step 1

[0385] At room temperature, t-BuOK (38 g, 338 mmol) was added to a mixture of 1-methyl-1H-pyrazole-4-thiol (Intermediate 10, 27 g, 237 mmol), 6-bromophthalazin-1(2H)-one (38 g, 169 mmol), CuI (3.2 g, 16.9 mmol) and 1,2,3-benzotriazole (4 g, 33.8 mmol) in NMP (1 L). The reaction mixture was stirred overnight at 100 °C under a nitrogen atmosphere. After LCMS indicated completion of the reaction, the reaction mixture was added to water (10 L), stirred at room temperature for 3 hours and then filtered. The residue was lyophilized to give 7-((1-methyl-1H-pyrazol-4-yl)thio)phthalazin-1(2H)-one (32.5 g, 100% purity) as a yellow solid. MS (ES+): 259.1 (M+H)+.

[0386] Step 2

[0387] At room temperature, Cs2CO3 (652 mg, 2 mmol) was added to a solution of 7-((1-methyl-1H-pyrazol-4-yl)thio)phthalazin-1(2H)-one (258 mg, 1 mmol) and 6-(chloromethyl)-2,3-dihydropyrazolo[5,1-b]oxazole (Intermediate 1, 200 mg, 1.3 mmol) in DMF (10 mL), and the reaction mixture was stirred at 60 °C for 16 hours. After LCMS indicated completion of the reaction, water (30 mL) was added to the reaction mixture and it was extracted with EtOAc (20 mL × 3). The combined organic layers were washed with an aqueous NH4Cl solution, dried over Na2SO4, filtered and concentrated under reduced pressure at 45 °C. The residue was purified by flash column chromatography (12 g, dichloromethane / ethyl acetate = 100:0 to 60:40) to give 2-((2,3-dihydropyrazolo[5,1-b]oxazol-6-yl)methyl)-6-((1-methyl-1H-pyrazol-4-yl)thio)phthalazin-1(2H)-one (140 mg, 89.77% purity) as a yellow solid. MS (ES+): 381.1 (M+H)+.

[0388] Step 3

[0389] To a mixture of 2-((2,3-dihydropyrazolo[5,1-b]oxazol-6-yl)methyl)-6-((1-methyl-1H-pyrazol-4-yl)thio)phthalazin-1(2H)-one (140 mg, 0.37 mmol) in DMF (3 mL) at room temperature was added OXONE (700 mg, 1.14 mmol). The reaction mixture was stirred at 60 °C for 0.5 h. After LCMS indicated the completion of the reaction, water (10 mL) was added to the reaction mixture. Then the mixture was extracted with EtOAc (10 mL × 3). The organic layer was concentrated under reduced pressure at 40 °C. The residue was purified by preparative HPLC (column: Waters X-Bridge C18 OBD 10 μm 19*250 mm; flow rate: 20 mL / min; solvent system: MeCN / (10 mmol / L NH4HCO3 / water) gradient: MeCN: 38% - 95%; collection wavelength: 214 nm). The relevant fractions were concentrated under reduced pressure at 42 °C to remove MeCN, and the residue was lyophilized to give the title compound as a white solid (44.63 mg, 100% purity). MS(ES+): 413.2(M + H)+. 1H NMR(400 MHz, DMSO-d6) δ: 8.59(s, 2H), 8.56(s, 1H), 8.43(d, J = 8.4 Hz, 1H), 8.29(dd, J = 8.4, 2.0 Hz, 1H), 8.02(d, J = 0.8 Hz, 1H), 5.31(s, 1H), 5.16(s, 2H), 4.99(t, J = 7.8 Hz, 2H), 4.17(t, J = 8.0 Hz, 2H), 3.87(s, 3H).

[0390] Example 6: 6-((1H-Pyrazol-3-yl)sulfonyl)-2-((4-chloro-5-methyl-1H-pyrazol-3-yl)methyl)phthalazin-1(2H)-one

[0391]

[0392] Step 1

[0393] At room temperature, t-BuOK (3.4 g, 30.4 mmol) was added to a mixture of 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-thiol (Intermediate 4, 2.8 g, 15.2 mmol), 6-bromophthalazin-1(2H)-one (2.9 g, 12.9 mmol), CuI (246 mg, 1.29 mmol) and 1,2,3-benzotriazole (307 mg, 2.58 mmol) in DMF (30 mL). The reaction mixture was stirred overnight at 100 °C under a nitrogen atmosphere. After LCMS indicated the completion of the reaction, the reaction mixture was added to water (200 mL), the solid was filtered and dried to give 6-((1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)thio)phthalazin-1(2H)-one (2.4 g, purity 72.75%) as a yellow solid. MS(ES+): 329.1(M+H)+.

[0394] Step 2

[0395] SOCl2 (178 mg, 1.5 mmol) was added to a mixture of (4-chloro-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)methanol (Intermediate 5, 230 mg, 1.0 mmol) in DCM (4 mL). The reaction mixture was stirred at room temperature for 30 minutes. After LCMS analysis indicated the completion of the reaction, the mixture was concentrated to remove the excess SOCl2 and DCM to give 4-chloro-3-(chloromethyl)-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole in the form of a crude product. It was used in the next step without further purification.

[0396] Step 3

[0397] At room temperature, Cs2CO3 (1.95 g, 6.0 mmol) and 6-((1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)thio)phthalazin-1(2H)-one (328 mg, 1.0 mmol) were added to a solution of crude 4-chloro-3-(chloromethyl)-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole in DMF (4 mL), and the reaction mixture was stirred at room temperature overnight. After LCMS indicated completion of the reaction, the reaction mixture was diluted with water (15 mL) and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with saturated ammonium chloride solution (40 mL × 2), dried over Na2SO4, filtered and concentrated under reduced pressure at 40 °C. The residual solid was purified by flash column chromatography (12 g, petroleum ether / ethyl acetate = 100:00 - 60:30) to give 2-((4-chloro-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)methyl)-6-((1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)thio)phthalazin-1(2H)-one (200 mg, 100% purity) as a yellow solid. MS(ES+): 541.2(M + H)+.

[0398] Step 4

[0399] OXONE (682 mg, 1.11 mmol) was added to a solution of 2-((4-chloro-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)methyl)-6-((1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)thio)phthalazin-1(2H)-one (200 mg, 0.37 mmol) in DMF (3 mL), and the mixture was stirred at 60 °C for 1 hour. After LCMS indicated completion of the reaction, the reaction mixture was diluted with water (5 mL), neutralized with K2CO3, and extracted with EtOAc (10 mL × 4). The organic layer was washed with saturated aqueous NH4Cl solution (100 mL × 2), concentrated and purified by flash column chromatography (12 g, dichloromethane / methanol = 100:00 - 95:5) to give 2-((4-chloro-5-methyl-1H-pyrazol-3-yl)methyl)-6-((1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)sulfonyl)phthalazin-1(2H)-one (180 mg, 81% purity) as a white solid. MS(ES+): 489.2(M + H)+.

[0400] Step 5

[0401] To a solution of 2-((4-chloro-5-methyl-1H-pyrazol-3-yl)methyl)-6-((1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)sulfonyl)phthalazin-1(2H)-one (180 mg, 0.37 mmol) in DCM (1 mL) was added TFA (3 mL), and the mixture was stirred at room temperature for 1 h. After LCMS indicated completion of the reaction, the mixture was concentrated under reduced pressure. The residue was diluted with H2O (15 mL), and the pH was adjusted to 8 with K2CO3. A solid precipitated, and the suspension was filtered. The filter cake was purified by preparative HPLC (column: Waters Xbridge Prep C18 OBD 10 μm 19*250 mm; flow rate: 20 mL / min; solvent system: MeCN / (10 mmol / L NH4HCO3 / water) gradient: MeCN: 25% - 95%; collection wavelength: 214 nm). The fractions were concentrated under reduced pressure at 40 °C to remove MeCN, and the residue was lyophilized to give the title compound as a white solid (24.64 mg, 100% purity). MS(ES+): 405.2(M+H)+. 1 H NMR(400MHz,DMSO-d6)δ:13.98(br,1H),12.79(br,1H),8.62(s,2H),8.46(d,J=8.4Hz,1H),8.29(dd,J=8.4Hz,1.6Hz,1H),8.03(d,J=2.4Hz,1H),6.96(d,J=2.4Hz,1H),5.28(s,2H),2.14(s,3H).

[0402] Biological Example 1 - Human PKM2 Activation Assay

[0403] Measure the in vitro activation of recombinant human PKM2

[0404] Compound activation of recombinant human PKM2 pyruvate kinase activity was determined by biochemical assay. N-terminal His-tagged hPKM2 was from R&D Systems and its substrates phosphoenolpyruvate (PEP) and ADP were from Sigma-Aldrich and 2Bscientific Ltd., respectively. Plus luminescence assay was from Promega. All other reagents were from Sigma-Aldrich. Test compounds were prepared as 10 mM DMSO stocks and a series of dilutions in DMSO for direct dilution into an assay buffer (pH 7.2) containing 50 mM imidazole, 50 mM KCl, 7 mM MgCl2, 0.01% Tween20, 0.05% BSA.

[0405] Assay procedure

[0406] Human PKM2 was diluted to a final concentration of 5 pM in an assay buffer (pH 7.2) containing 50 mM imidazole, 50 mM KCl, 7 mM MgCl2, 0.01% Tween 20, and 0.05% BSA. The enzyme - assay buffer mixture was dispensed into 384 - well shallow - well white - walled plates (PerkinElmer) and test compounds ( Labcyte Inc.) were added by acoustic dispensing. After incubation at room temperature for 10 minutes, the enzyme reaction was initiated by acoustic dispensing of the ADP + PEP substrates to final concentrations of 254 μM ADP and 53 μM ADP.

[0407] After incubation (300 rpm, 26 °C) on an orbital shaker for 60 minutes, the enzyme activity was quantified by luminescence detection of the ATP produced. Plus reagent was added to each well and the plate was incubated again on the orbital shaker in the dark (300 rpm, 26 °C) for 15 minutes, followed by luminescence measurement using a plate reader ( FSX, BMG Labtech).

[0408] The percentage of activation was calculated by normalizing the fluorescence signal against plate LOW (DMSO vehicle) and HIGH (5 μM TEPP - 46) controls. The EC 50 and E max values were determined by four - parameter logistic fitting of the compound concentration - response curve.

[0409] Compounds of formula (Ia) were tested and the results are shown in Table 1 below.

[0410] Table 1 - PKM2EC 50 Value (μM) and E max Value (%)

[0411]

[0412] * Indicates data from replicate experiments

[0413] Examples 1 to 6 were tested in this assay and all showed improved PKM2 regulatory activity compared to mitapivat, as indicated by their lower EC 50 and / or higher E max values for PKM2 activation. Biological Example 2 - Human PKLR Activation Assay

[0414] Measure the in vitro activation of recombinant human PKLR

[0415] Compound activation of recombinant human PKLR pyruvate kinase activity was determined by biochemical assay. The N-terminal His-tagged enzyme was from R&D Systems and the substrates phosphoenolpyruvate (PEP) and ADP were from Sigma-Aldrich and 2Bscientific Ltd., respectively. The Plus luminescence assay was from Promega. All other reagents were from Sigma-Aldrich. Test compounds were prepared as 10 mM DMSO stocks and a series of dilutions in DMSO for direct dilution into the assay buffer (pH 7.2) containing 50 mM imidazole, 50 mM KCl, 7 mM MgCl2, 0.01% Tween20, 0.05% BSA.

[0416] Assay procedure

[0417] Human PKLR was diluted in the assay buffer to a final concentration of 5 pM. The enzyme-assay buffer mixture was dispensed into 384-well shallow-well white-wall plates and test compounds were added by acoustic dispensing ( Labcyte Inc.). After incubation for 10 minutes at room temperature, the enzyme reaction was initiated by acoustic dispensing of the ADP + PEP substrates to final concentrations of 254 μM ADP and 53 μM PEP.

[0418] After incubation on an orbital shaker (300 rpm, 26 °C) for 60 minutes, enzyme activity was quantified by luminescence detection of the ATP produced. Plus reagent was added to each well and the plate was incubated again on an orbital shaker in the dark (300 rpm, 26 °C) for 15 minutes, followed by luminescence measurement with a plate reader ( FSX, BMG Labtech). The percentage of activation was calculated by normalizing the fluorescence signal against plate LOW (DMSO vehicle) and HIGH (5 μM TEPP-46) controls. The EC

[0419] and E 50 and max values were determined by four-parameter logistic fitting of the compound concentration-response curve.

[0420] A variety of exemplary compounds of formula (Ia) were tested and the results are shown in Table 2 below.

[0421] Table 2 - PKLREC 50 Value (μM) and E max Value (%)

[0422]

[0423] * Indicates data from replicate experiments

[0424] In this assay, Examples 1 to 5 were tested and showed improved PKLR regulatory activity compared to mitapivat, as indicated by their lower EC for PKLR activation 50 and / or higher E max values.

[0425] Biological Example 3 - CD4+ T Cell Pyruvate Kinase Assay

[0426] Measure the pyruvate kinase (PK) activity in human CD4+ T cell lysates

[0427] PKM2 activators can increase the recombinant human PKM2 protein and the pyruvate kinase activity of PKM2 in human cell lysates (Kung et al., 2012). Compound activation of pyruvate kinase in human CD4+ T cell lysates was determined by biochemical assay. Primary CD4+ T cells were used instead of cancer cell lines to improve the disease relevance of the assay. The PK assay was sourced from Abcam. All other reagents were sourced from ThermoFisher. Test compounds were prepared as 10 mM DMSO stock solutions and dilution series were prepared in DMSO for addition to intact CD4+ T cells cultured in RPMI medium containing 10% FBS.

[0428] Assay procedure

[0429] Human CD4+ T cells were incubated with the compounds for 20 minutes and then washed twice in 1xPBS and then resuspended in Abcam PK lysis buffer to prepare cell lysates. 10 μl of the PK assay reaction mixture, including OXIRED TM PROBE, was added to each well. The plate was read at OD570nm in kinetic mode (25 two-minute cycles) using a BMG Labtech Pherastar plate reader and read for 48 minutes in the dark at 25 °C.

[0430] Data analysis

[0431] The plate was subtracted from the blank, and the Δ absorbance was calculated by subtracting the first plate reading in the linear range from the plate readings at the time points of interest. The PK activity was expressed as Δ absorbance and plotted against log[compound].

[0432] Examples 1 to 6 were tested and the results are shown in Table 3 below. Mitapivat was tested as a comparative compound.

[0433] Table 3 – CD4+ T Cell Pyruvate Kinase Activity

[0434] Compound <![CDATA[PK activity EC 50 (μM)]]> Mitapivat 0.311 Example 1 0.097 Example 2 0.168 Example 3 0.070 Example 4 0.125 Example 5 0.093 Example 6 0.094

[0435] In this analysis, Examples 1 to 6 were tested and showed improved pyruvate kinase activity compared to mitapivat, as shown by its EC 50 value.

[0436] References

[0437] Abulizi et al., Cell Metab. 2020, 32(5):751-766.e11.

[0438] Alves-Filho et al., Front Immunol. 2016, 7(145), 1-7.

[0439] Barazzoni et al., Eating and Weight Disorders–Studies on Anorexia, Bulimia and Obesity 2018, 23, 149-157.

[0440] Bettaieb et al., The Journal of Biological Chemistry 2013, 288(24), 17360-17371.

[0441] Bianchi et al., Haematologica 2020, 105(9), 2218-2228.

[0442] et al.,, Hematology, Transfusion and Cell Therapy, 2018, 40(1), 1-2.

[0443] Chhipa et al., Life Sciences 2018, 280, DOI:10.1016 / j.lfs.2021.119694.

[0444] Dong et al., Oncol Lett. 2016, 11(3), 1980–1986.

[0445] Grace et al., N.Engl.J.Med. 2019, 381(10), 933-944.

[0446] Kung et al., Chemistry&Biology 2012, 19, 1187-1198.

[0447] Kung et al., Blood 2017, 14; 130(11), 1347-1356.

[0448] Lewandowski et al., Cell Metab. 2020, 32(5):736-750.e5.

[0449] Liu et al., J. Diabetes Investig. 2020, 12(5):697-709.

[0450] et al., Cell Research 2020, 30:300–314.

[0451] Puckett et al., International Journal of Molecular Sciences 2021, 22, 1171.

[0452] Qi et al., Nat Med. 2017, 23(6), 753-762.

[0453] Yi et al., Front. Immunol. 2021, DOI:10.3389 / fimmu.2020.595316.

[0454] Miscellaneous

[0455] All references, including patents and patent applications, mentioned in this application are incorporated herein by reference to the maximum extent possible.

[0456] Throughout the specification and the following claims, unless the context requires otherwise, the word "comprise" and variations thereof (such as "comprises" and "comprising") shall be understood to imply the inclusion of the stated integer, step, group of integers or group of steps, but not the exclusion of any other integer, step, group of integers or group of steps.

[0457] This application, which includes the specification and claims as a part, may be used as a basis for priority in any subsequent application. The claims of such subsequent applications may relate to any feature or combination of features described herein. They may be in the form of product, composition, method or use claims and may include, for example (but not limited to), the following claims.

Claims

1. A compound of formula (Ia), wherein: (a)R A is a pyrazolyl group and R B is a pyridinyl group substituted by an OMe group to obtain 6-((1H-pyrazol-4-yl)sulfonyl)-2-((5-methoxypyridin-2-yl)methyl)phthalazin-1(2H)-one (b)R A is a pyrazolyl group substituted by CHF2 and R B is a pyrazolyl group, to obtain 2-((1H-pyrazol-3-yl)methyl)-6-((1-(difluoromethyl)-1H-pyrazol-4-yl)sulfonyl)phthalazin-1(2H)-one (c)R A is a pyrazolyl group substituted by CH2CH2OH and R B is dihydrofuro[3,2-b]pyridinyl to obtain 2-((2,3-dihydrofuro[3,2-b]pyridin-5-yl)methyl)-6-((1-(2-hydroxyethyl)-1H-pyrazol-4-yl)sulfonyl)phthalazin-1(2H)-one (d)R A is a pyrazolyl group and R B is 2,3-dihydropyrazolo[5,1-b]oxazolyl to obtain 6-((1H-pyrazol-4-yl)sulfonyl)-2-((2,3-dihydropyrazolo[5,1-b]oxazol-6-yl)methyl)phthalazin-1(2H)-one (e)R A is a pyrazolyl group substituted with a methyl group and R B is 2,3-dihydropyrazolo[5,1-b]oxazolyl, to obtain 2-((2,3-dihydropyrazolo[5,1-b]oxazol-6-yl)methyl)-6-((1-methyl-1H-pyrazol-4-yl)sulfonyl)phthalazin-1(2H)-one or (f)R A is a pyrazolyl group and R B is a pyrazolyl group substituted by one Cl and one methyl group to obtain 6-((1H-pyrazol-3-yl)sulfonyl)-2-((4-chloro-5-methyl-1H-pyrazol-3-yl)methyl)phthalazin-1(2H)-one or its salts and / or solvates.

2. The compound of formula (Ia) according to claim 1 or a salt and / or solvate thereof, which is 6 - ((1H - pyrazol - 4 - yl)sulfonyl)-2 - ((5 - methoxypyridin - 2 - yl)methyl)phthalazin - 1(2H)-one or a salt and / or solvate thereof.

3. The compound of formula (Ia) according to claim 2 or a salt and / or solvate thereof, which is 6 - ((1H - pyrazol - 4 - yl)sulfonyl)-2 - ((5 - methoxypyridin - 2 - yl)methyl)phthalazin - 1(2H)-one 4. The compound of formula (Ia) according to claim 2 or a salt and / or solvate thereof, which is a salt of 6 - ((1H - pyrazol - 4 - yl)sulfonyl)-2 - ((5 - methoxypyridin - 2 - yl)methyl)phthalazin - 1(2H)-one, such as a pharmaceutically acceptable salt 5. The compound of formula (Ia) according to claim 1 or a salt and / or solvate thereof, which is 2 - ((1H - pyrazol - 3 - yl)methyl)-6 - ((1-(difluoromethyl)-1H - pyrazol - 4 - yl)sulfonyl)phthalazin - 1(2H)-one or a salt and / or solvate thereof.

6. The compound of formula (Ia) according to claim 5, or a salt and / or solvate thereof, which is 2-((1H-pyrazol-3-yl)methyl)-6-((1-(difluoromethyl)-1H-pyrazol-4-yl)sulfonyl)phthalazin-1(2H)-one 7. The compound of formula (Ia) according to claim 5, or a salt and / or solvate thereof, which is a salt of 2-((1H-pyrazol-3-yl)methyl)-6-((1-(difluoromethyl)-1H-pyrazol-4-yl)sulfonyl)phthalazin-1(2H)-one, such as a pharmaceutically acceptable salt 8. The compound of formula (Ia) according to claim 1, or a salt and / or solvate thereof, which is 2-((2,3-dihydrofuro[3,2-b]pyridin-5-yl)methyl)-6-((1-(2-hydroxyethyl)-1H-pyrazol-4-yl)sulfonyl)phthalazin-1(2H)-one or a salt and / or solvate thereof.

9. The compound of formula (Ia) according to claim 8, or a salt and / or solvate thereof, which is 2-((2,3-dihydrofuro[3,2-b]pyridin-5-yl)methyl)-6-((1-(2-hydroxyethyl)-1H-pyrazol-4-yl)sulfonyl)phthalazin-1(2H)-one 10. The compound of formula (Ia) according to claim 8, or a salt and / or solvate thereof, which is a salt of 2-((2,3-dihydrofuro[3,2-b]pyridin-5-yl)methyl)-6-((1-(2-hydroxyethyl)-1H-pyrazol-4-yl)sulfonyl)phthalazin-1(2H)-one, such as a pharmaceutically acceptable salt 11. The compound of formula (Ia) according to claim 1, or a salt and / or solvate thereof, which is 6-((1H-pyrazol-4-yl)sulfonyl)-2-((2,3-dihydropyrazolo[5,1-b]oxazol-6-yl)methyl)phthalazin-1(2H)-one or a salt and / or solvate thereof.

12. The compound of formula (Ia) according to claim 11, or a salt and / or solvate thereof, which is 6-((1H-pyrazol-4-yl)sulfonyl)-2-((2,3-dihydropyrazolo[5,1-b]oxazol-6-yl)methyl)phthalazin-1(2H)-one 13. The compound of formula (Ia) according to claim 11, or a salt and / or solvate thereof, which is a salt of 6-((1H-pyrazol-4-yl)sulfonyl)-2-((2,3-dihydropyrazolo[5,1-b]oxazol-6-yl)methyl)phthalazin-1(2H)-one, such as a pharmaceutically acceptable salt 14. The compound of formula (Ia) according to claim 1, or a salt and / or solvate thereof, which is 2-((2,3-dihydropyrazolo[5,1-b]oxazol-6-yl)methyl)-6-((1-methyl-1H-pyrazol-4-yl)sulfonyl)phthalazin-1(2H)-one or a salt and / or solvate thereof.

15. The compound of formula (Ia) according to claim 14, or a salt and / or solvate thereof, which is 2-((2,3-dihydropyrazolo[5,1-b]oxazol-6-yl)methyl)-6-((1-methyl-1H-pyrazol-4-yl)sulfonyl)phthalazin-1(2H)-one 16. The compound of formula (Ia) according to claim 14, or a salt and / or solvate thereof, which is a salt of 2-((2,3-dihydropyrazolo[5,1-b]oxazol-6-yl)methyl)-6-((1-methyl-1H-pyrazol-4-yl)sulfonyl)phthalazin-1(2H)-one, such as a pharmaceutically acceptable salt 17. The compound of formula (Ia) according to claim 1, or a salt and / or solvate thereof, which is 6-((1H-pyrazol-3-yl)sulfonyl)-2-((4-chloro-5-methyl-1H-pyrazol-3-yl)methyl)phthalazin-1(2H)-one or a salt and / or solvate thereof.

18. The compound of formula (Ia) according to claim 17, or a salt and / or solvate thereof, which is 6-((1H-pyrazol-3-yl)sulfonyl)-2-((4-chloro-5-methyl-1H-pyrazol-3-yl)methyl)phthalazin-1(2H)-one 19. The compound of formula (Ia) according to claim 17, or a salt and / or solvate thereof, which is a salt of 6-((1H-pyrazol-3-yl)sulfonyl)-2-((4-chloro-5-methyl-1H-pyrazol-3-yl)methyl)phthalazin-1(2H)-one, such as a pharmaceutically acceptable salt.

20. A pharmaceutical composition comprising the compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt and / or solvate thereof, and one or more pharmaceutically acceptable diluents or carriers.

21. The compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt and / or solvate thereof, or the pharmaceutical composition according to claim 20, for use as a medicament.

22. The compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt and / or solvate thereof, or the pharmaceutical composition according to claim 20, for the treatment or prevention of a disease, disorder or condition associated with the function of PK, in particular PKM2 and / or PKLR.

23. Use of the compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt and / or solvate thereof, or the pharmaceutical composition according to claim 20, for 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.

24. 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, the method comprising administering the compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt and / or solvate thereof, or the pharmaceutical composition according to claim 20.

25. The compound or a pharmaceutically acceptable salt and / or solvate thereof for use, the pharmaceutical composition for use, the use or the method according to any one of claims 22 to 24, for 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.

26. The compound or a pharmaceutically acceptable salt and / or solvate thereof for use, the pharmaceutical composition for use, the use or the method according to claim 25, for the treatment of an inflammatory disease or a disease associated with an unwanted immune response.

27. The compound or a pharmaceutically acceptable salt and / or solvate thereof for use, the pharmaceutical composition for use, the use or the method according to claim 25, for the prevention of an inflammatory disease or a disease associated with an unwanted immune response.

28. A compound or a pharmaceutically acceptable salt and / or solvate thereof for use, a pharmaceutical composition for use, a use or a method for use according to claim 25, which is for treating or preventing an inflammatory disease.

29. A compound or a pharmaceutically acceptable salt and / or solvate thereof for use, a pharmaceutical composition for use, a use or a method for use according to claim 25, which is for treating or preventing a disease associated with an undesired immune response.

30. A compound or a pharmaceutically acceptable salt and / or solvate thereof for use, a pharmaceutical composition for use, a use or a method for use according to claim 25, wherein the inflammatory disease or the disease associated with an adverse immune response is a disease selected from the group consisting of or associated with: Crohn's disease, ulcerative colitis, type 2 diabetes, atopic dermatitis, hidradenitis suppurativa, psoriasis, bullous pemphigoid, pemphigus vulgaris, localized and diffuse scleroderma, Sjogren's syndrome, polymyositis, dermatomyositis, Behcet's disease, wound healing, rheumatoid arthritis, systemic lupus erythematosus, cutaneous lupus erythematosus, graft-versus-host disease, multiple sclerosis, organ fibrosis (including liver, lung, kidney), COPD, and asthma.

31. A compound or a pharmaceutically acceptable salt and / or solvate thereof for use, a pharmaceutical composition for use, a use or a method for use according to claim 25, wherein the inflammatory disease or the disease associated with an undesired immune response 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 syndromes, Muckle-Wells syndrome, juvenile idiopathic arthritis, chronic obstructive pulmonary disease, and asthma.

32. A compound or a pharmaceutically acceptable salt and / or solvate thereof for use, a pharmaceutical composition for use, a use or a method for use according to claim 31, wherein the inflammatory disease or the disease associated with an undesired immune response is multiple sclerosis.

33. A compound or a pharmaceutically acceptable salt and / or solvate thereof for use, a pharmaceutical composition for use, a use or a method for use according to claim 31, wherein the inflammatory disease or the disease associated with an undesired immune response is psoriasis.

34. A compound or a pharmaceutically acceptable salt and / or solvate thereof for use, a pharmaceutical composition for use, a use or a method for use according to claim 31, wherein the inflammatory disease or the disease associated with an undesired immune response is asthma.

35. The compound for use or a pharmaceutically acceptable salt and / or solvate thereof, the pharmaceutical composition for use, the use or the method according to claim 31, wherein the inflammatory disease or the disease associated with an undesired immune response is chronic obstructive pulmonary disease.

36. The compound for use or a pharmaceutically acceptable salt and / or solvate thereof, the pharmaceutical composition for use, the use or the method according to claim 31, wherein the inflammatory disease or the disease associated with an undesired immune response is systemic lupus erythematosus.

37. The compound for use or a pharmaceutically acceptable salt and / or solvate thereof, the pharmaceutical composition for use, the use or the method according to claim 31, wherein the inflammatory disease or the disease associated with an undesired immune response is rheumatoid arthritis.

38. The compound for use or a pharmaceutically acceptable salt and / or solvate thereof, the pharmaceutical composition for use, the use or the method according to claim 31, wherein the inflammatory disease or the disease associated with an undesired immune response is inflammatory bowel disease (including ulcerative colitis and Crohn's disease).

39. The compound for use or a pharmaceutically acceptable salt and / or solvate thereof, the pharmaceutical composition for use, the use or the method according to claim 31, wherein the inflammatory disease or the disease associated with an undesired immune response is atopic dermatitis.

40. The compound for use or a pharmaceutically acceptable salt and / or solvate thereof, the pharmaceutical composition for use, the use or the method according to claim 31, wherein the inflammatory disease or the disease associated with an undesired immune response is fibrosis.

41. The compound for use or a pharmaceutically acceptable salt and / or solvate thereof, the pharmaceutical composition for use, the use or the method according to claim 25, which is used for treating cancer.

42. The compound for use or a pharmaceutically acceptable salt and / or solvate thereof, the pharmaceutical composition for use, the use or the method according to claim 25, which is used for preventing cancer.

43. A compound or a pharmaceutically acceptable salt and / or solvate thereof for use, a pharmaceutical composition for use, a use or a method, wherein the cancer is selected from the group consisting of: acute lymphoblastic leukemia, adult; acute lymphoblastic leukemia, childhood; acute myeloid leukemia, adult; adrenocortical carcinoma; adrenocortical carcinoma, childhood; AIDS-related lymphoma; AIDS-related malignancies; anal cancer; astrocytoma, childhood cerebellum; astrocytoma, childhood brain; Barrett's esophagus (precancerous syndrome); extrahepatic bile duct cancer; bladder cancer; bladder cancer, childhood; bone cancer, osteosarcoma / malignant fibrous histiocytoma; brainstem glioma, childhood; brain tumor, adult; brain tumor, brainstem glioma, childhood; brain tumor, cerebellar astrocytoma, childhood; brain tumor, cerebral astrocytoma / malignant glioma, childhood; brain tumor, ependymoma, childhood; brain tumor, medulloblastoma, childhood; brain tumor, supratentorial primitive neuroectodermal tumor, childhood; brain tumor, visual pathway and hypothalamic glioma, childhood; brain tumor, childhood (others); breast cancer; breast cancer and pregnancy; breast cancer, childhood; breast cancer, male; bronchial adenoma / carcinoid, childhood; carcinoid tumor, childhood; carcinoid tumor, gastrointestinal; carcinoma, adrenocortical; carcinoma, islet cell; carcinoma of unknown primary site; central nervous system lymphoma, primary; Cerebellar astrocytoma, childhood; cerebral astrocytoma / glioblastoma, childhood; cervical cancer; childhood cancer; chronic lymphocytic leukemia; chronic myelogenous leukemia; chronic myeloproliferative disorders; clear cell sarcoma of tendon sheath; colon cancer; colorectal cancer; colorectal cancer, childhood; cutaneous T-cell lymphoma; endometrial cancer; ependymoma, childhood; epithelial cancer, ovary; esophageal cancer; esophageal cancer, childhood; Ewing's tumor family; Extracranial germ cell tumor, childhood; extragonadal germ cell tumor; extrahepatic bile duct cancer; eye cancer, intraocular melanoma; eye cancer, retinoblastoma; gallbladder cancer; gastric (stomach) cancer; gastric (stomach) cancer, childhood; gastrointestinal carcinoid tumor; germ cell tumor, extracranial, childhood; germ cell tumor, extragonadal; germ cell tumor, ovary; gestational trophoblastic tumor; glioma, childhood brainstem; Glioma, childhood visual pathway and hypothalamus; hairy cell leukemia; head and neck cancer; hepatocellular (liver) cancer; hepatocellular (liver) cancer, adult (primary); hepatocellular (liver) cancer, childhood (primary); esophageal cancer; Hodgkin's lymphoma; Hodgkin's lymphoma, adult; Hodgkin's lymphoma, childhood; Hodgkin's lymphoma, during pregnancy; hypopharyngeal cancer; hypothalamus and visual pathway glioma, childhood; intraocular melanoma; islet cell carcinoma (endocrine pancreas); endocrine system cancer (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 myelogenous; 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's, adult; lymphoma, Hodgkin's, childhood; lymphoma, Hodgkin's, during pregnancy; lymphoma, non-Hodgkin's, adult; lymphoma, non-Hodgkin's, childhood; lymphoma, non-Hodgkin's, during pregnancy; lymphoma, primary central nervous system; macroglobulinemia, Waldenström's; male breast cancer; malignant mesothelioma, adult; malignant mesothelioma, childhood; malignant thymoma; neuroblastoma, childhood; melanoma; melanoma, intraocular; Merkel cell carcinoma; mesothelioma, malignant; Occult primary metastatic squamous neck cancer; multiple endocrine neoplasia syndrome, childhood; multiple myeloma / plasma cell neoplasm; mycosis fungoides; myelodysplastic syndrome; myelogenous leukemia, chronic; Myeloid leukemia, acute, childhood; Multiple myeloma; Myelodysplastic syndromes, chronic; Nasal and paranasal sinus cancer; Nasopharyngeal carcinoma; Nasopharyngeal carcinoma, childhood; Neoplastic skin diseases; Neuroblastoma; Non-Hodgkin lymphoma, adult; Non-Hodgkin lymphoma, childhood; Non-Hodgkin lymphoma, during pregnancy; Non-small cell lung cancer; Central nervous system neoplasms (e.g., primary CNS lymphoma, spinal axis tumors, medulloblastoma, brainstem glioma, or pituitary adenoma); Oat cell cancer; Oral cancer, childhood; Oral and lip cancer; Oropharyngeal cancer; Osteosarcoma / malignant fibrous histiocytoma of bone; Ovarian cancer; Ovarian cancer, childhood; Ovarian epithelial cancer; Ovarian germ cell tumors; Ovarian tumors of low malignant potential; Pediatric malignancies; Pancreatic cancer; Pancreatic cancer, childhood; Pancreatic cancer, islet cell; Sinus and nasal cavity cancer; Parathyroid cancer; Penile cancer; Pheochromocytoma; Pineal and supratentorial primitive neuroectodermal tumors, childhood; Pituitary tumors; Plasma cell neoplasms / multiple myeloma; Pleuropulmonary blastoma; Pregnancy and breast cancer; Pregnancy and Hodgkin lymphoma; Pregnancy and non-Hodgkin lymphoma; Primary central nervous system lymphoma; Primary liver cancer, adult; Primary liver cancer, childhood; Prostate cancer (especially hormone resistant); Chronic or acute leukemia; Childhood solid tumors; Hypereosinophilic syndrome; Rectal cancer; Renal cell (kidney) cancer; Renal cell carcinoma, childhood; Renal pelvis and ureter, transitional cell cancer; Retinoblastoma; Rhabdomyosarcoma, childhood; Salivary gland cancer; Salivary gland cancer, childhood; Sarcoma, Ewing's tumor family; Sarcoma, Kaposi's; Sarcoma (osteosarcoma) / malignant fibrous histiocytoma of bone; Sarcoma, rhabdomyosarcoma, childhood; Soft tissue sarcoma; Soft tissue sarcoma, adult; Soft tissue sarcoma, childhood; Sézary 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; Occult primary squamous carcinoma of the neck, metastatic; Stomach (gastric) cancer; Stomach (gastric) cancer, childhood; Supratentorial primitive neuroectodermal tumors, childhood; T-cell lymphoma, cutaneous; Testicular cancer; Thymoma, childhood; Thymoma, malignant; Thyroid cancer; Thyroid cancer, childhood; Renal pelvis and ureter transitional cell cancer; Trophoblastic tumors, gestational; Unknown primary site cancer, childhood; Abnormal cancers, childhood; Ureter and renal pelvis, transitional cell cancer; Urethral cancer; Ureter cancer (e.g., renal cell carcinoma, renal pelvic carcinoma); Penile cancer; Gynecologic tumors; Uterine cancer; Uterine sarcoma; Fallopian tube cancer; Endometrial cancer; Vaginal cancer; Vaginal carcinoma; Vulvar cancer; Visual pathway and hypothalamic gliomas, childhood; Vulvar cancer; Waldenström macroglobulinemia; and Wilms tumor.

44. The compound for use or a pharmaceutically acceptable salt and / or solvate thereof, the pharmaceutical composition for use, the use or the method according to claim 43, wherein the cancer is selected from the group consisting of: lung cancer; NSCLC (non-small cell lung cancer); oat cell cancer; bone cancer; pancreatic cancer; skin cancer; dermatofibrosarcoma protuberans; head and neck cancer; cutaneous or intraocular melanoma; uterine cancer; ovarian cancer; colorectal cancer; anal cancer; gastric cancer; colon cancer; breast cancer; gynecological tumors (such as uterine sarcoma, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer or vulvar cancer); Hodgkin's disease; hepatocellular carcinoma; esophageal cancer; small intestine cancer; endocrine system cancer (such as cancer of the thyroid, pancreas, parathyroid or adrenal gland); soft tissue sarcoma; urethral cancer; penile cancer; prostate cancer (especially hormone-resistant); chronic or acute leukemia; pediatric solid tumors; hypereosinophilic syndrome; lymphocytic lymphoma; bladder cancer; kidney cancer; ureteral cancer (such as renal cell carcinoma, renal pelvic carcinoma); pediatric malignancies; central nervous system neoplasms (such as primary CNS lymphoma, spinal axis tumors, neuroblastoma, brainstem glioma or pituitary adenoma); Barrett's esophagus (precancerous syndrome) and neoplastic skin diseases.

45. The compound for use or a pharmaceutically acceptable salt and / or solvate thereof, the pharmaceutical composition for use, the use or the method according to claim 25, which is for the treatment of obesity.

46. The compound for use or a pharmaceutically acceptable salt and / or solvate thereof, the pharmaceutical composition for use, the use or the method according to claim 25, which is for the prevention of obesity.

47. The compound for use or a pharmaceutically acceptable salt and / or solvate thereof, the pharmaceutical composition for use, the use or the method according to claim 25, which is for the treatment of diabetic diseases.

48. The compound for use or a pharmaceutically acceptable salt and / or solvate thereof, the pharmaceutical composition for use, the use or the method according to claim 25, which is for the prevention of diabetic diseases.

49. The compound for use or a pharmaceutically acceptable salt and / or solvate thereof, the pharmaceutical composition for use, the use or the method according to claim 47 or 48, wherein the diabetic disease is selected from diabetes and diabetic complications.

50. The compound for use or a pharmaceutically acceptable salt and / or solvate thereof, the pharmaceutical composition for use, the use or the method according to claim 49, wherein the diabetes is type 1 diabetes.

51. The compound for use or a pharmaceutically acceptable salt and / or solvate thereof, the pharmaceutical composition for use, the use or the method according to claim 49, wherein the diabetes is type 2 diabetes.

52. The compound or its pharmaceutically acceptable salt and / or solvate for use, the pharmaceutical composition for use, the use or method according to claim 49, wherein the diabetic complication is selected from the group consisting of: coronary artery disease, peripheral artery disease, stroke, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, diabetic kidney disease and NASH.

53. The compound or its pharmaceutically acceptable salt and / or solvate for use, the pharmaceutical composition for use, the use or method according to claim 25, which is for the treatment of blood disorders.

54. The compound or its pharmaceutically acceptable salt and / or solvate for use, the pharmaceutical composition for use, the use or method according to claim 25, which is for the prevention of blood disorders.

55. The compound or its pharmaceutically acceptable salt and / or solvate for use, the pharmaceutical composition for use, the use or method according to claim 53 or 54, wherein 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., enzyme diseases)), anemia of chronic diseases, pyruvate kinase deficiency (PKD) and sickle cell disease.

56. The compound or its pharmaceutically acceptable salt and / or solvate for use, the pharmaceutical composition for use, the use or method according to any one of claims 21 to 55, wherein the compound is for administration to a human individual.

57. The compound or its pharmaceutically acceptable salt and / or solvate for use, the pharmaceutical composition for use, the use or method according to any one of claims 21 to 56, which is used in combination with other therapeutic agents.

58. A compound or a pharmaceutically acceptable salt and / or solvate thereof for use, a pharmaceutical composition for use, a use or a method according to any one of claims 26 to 40, which is used in combination with other therapeutic agents selected from the group consisting of: corticosteroids (glucocorticoids); retinoids (e.g., acitretin, isotretinoin, tazarotene); anthralin; vitamin D analogs (e.g., calcipotriol, calcipotriol); calcineurin inhibitors (e.g., tacrolimus, pimecrolimus); phototherapy or photochemotherapy (e.g., psoralen ultraviolet irradiation, PUVA) or other forms of ultraviolet light irradiation therapy; ciclosporine; thiopurines (e.g., azathioprine, 6-mercaptopurine); methotrexate; 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); plasmapheresis; intravenous immunoglobulin (IVIG); cyclophosphamide; anti-CD20 B cell depleting agents (e.g., rituximab, ocrelizumab, ofatumumab, obinutuzumab); anthracycline analogs (e.g., mitoxantrone); cladribine;Sphingosine-1-phosphate receptor modulators or sphingosine analogs (e.g., fingolimod, siponimod, ozanimod, etrasimod); interferon-β preparations (including interferon-β1b / 1a); glatiramer; anti-CD3 therapy (e.g., OKT3); anti-CD52 targeting 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 (mechanistic 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 stimulator) inhibitors (e.g., belimumab, blisibimod); other B cell targeting therapies, including fusion proteins targeting APRIL (a proliferation-inducing ligand) and BlyS (e.g., atacicept); PI3K inhibitors, including pan-inhibitors or inhibitors targeting isotypes containing p110δ and / or p110γ (e.g., idelalisib, copanlisib, duvelisib); interferon-α 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 therapies (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 inhibitors against C5 (e.g., eculizumab); immunoadsorbents; antithymocyte globulin; 5-aminosalicylic acid esters and their derivatives (e.g., sulfasalazine, balsalazide, mesalamine); anti-integrin agents, including agents targeting α4β1 and / or α4β7 integrins (e.g., natalizumab, vedolizumab); anti-CD11-α agents (e.g., efalizumab); non-steroidal anti-inflammatory drugs (NSAIDs), including salicylates (e.g., aspirin); propionic acid (e.g., ibuprofen, naproxen); acetic acid (e.g., indomethacin, diclofenac, etodolac); oxicams (e.g., meloxicam); 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 immunotherapies (e.g., diphenylcyclopropenone, dibutyl squarate); anti-IL-1 receptor therapies (e.g., anakinra); IL-1β inhibitors (e.g., canakinumab);IL-1 neutralizing therapy (e.g., rilonacept); chlorambucil; specific antibiotics with immunomodulatory properties and / or ability to modulate NRF2 (e.g., tetracyclines, including minocycline, clindamycin, macrolide antibiotics); anti-androgen 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 or mizoribine.; 59. The compound or its pharmaceutically acceptable salt and / or solvate for use, the pharmaceutical composition for use, the use or method according to any one of claims 41 to 44, which is used in combination with other therapeutic agents selected from the group consisting of: palliative treatment, such as those selected from the group consisting of: antiemetics; drugs intended to relieve pain, such as opioids; drugs for reducing high blood uric acid levels, such as allopurinol or rasburicase; antidepressants; sedatives; antispasmodic drugs; laxatives; antidiarrheal drugs and / or antacids.

60. The compound or its pharmaceutically acceptable salt and / or solvate for use, the pharmaceutical composition for use, the use or method according to any one of claims 41 to 44, which is used in combination with other cancer treatments selected from the group consisting of: chemotherapy, targeted therapy, immunotherapy and hormone therapy.

61. The compound or its pharmaceutically acceptable salt and / or solvate for use, the pharmaceutical composition for use, the use or the method according to claim 60, wherein the chemotherapeutic agent is selected from the group consisting of: Aclarubicin, Actinomycin, Alitretinon, Altretamine, Aminopterin, Aminolevulinicacid), Amrubicin, Amsacrine, Anagrelide, arsenic trioxide, asparaginase, Atrasentan, Belotecan, Bexarotene, Bendamustine, Bleomycin, Bortezomib, Busulfan, Camptothecin, Capecitabine, Carboplatin, 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, Etoglucid, Etoposide, Floxuridine, Fludarabine, Fluorouracil; 5FU, Fotemustine, Gemcitabine, Gliadelimplants), Hydroxycarbamide, Hydroxyurea, Idarubicin, Ifosfamide, Irinotecan, Irofulven, Ixabepilone, Larotaxel, Leucovorin, Liposomal doxorubicin, Liposomal daunorubicin, Lonidamine, Lomustine, Lucanthone, Mannosulfan, Masoprocol, Melphalan, Mercaptopurine, Mesna, Methotrexate, 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, Sapacitabine, Semustine, Sitimageneceradenovec), satraplatin, streptozocin, talaporfin, tegafur-uracil, temoporfin, temozolomide, teniposide, tesetaxel, testolactone, tetranitrate, thiotepa, tiazofurin, tioguanine, tipifarnib, topotecan, trabectedin, triaziquone, triethylenemelamine, triplatin, tretinoin, treosulfan, trofosfamide, uramustine, valrubicin, verteporfin, vinblastine, vincristine, vindesine, vinflunine, vinorelbine, vorinostat, and zorubicin.

62. The compound or a pharmaceutically acceptable salt and / or solvate thereof for use, the pharmaceutical composition for use, the use or method according to claim 60, wherein the targeted therapy is selected from the group consisting of axitinib, bosutinib, cediranib, dasatinib, erlotinib, imatinib, gefitinib, lapatinib, lestaurtinib, nilotinib, masitinib, sorafenib, sunitinib, vandetanib, avasimibe, celecoxib, herceptin, rituximab, tositumomab, cetuximab, panitumumab, trastuzumab, alemtuzumab, bevacizumab, eculizumab, gemtuzumab, aflibercept, denileukin diftitox, and bexarotene.

63. A compound for use or a pharmaceutically acceptable salt and / or solvate thereof, a pharmaceutical composition for use, a use or a method according to claim 45 or claim 46, which is used in combination with the following: a gastric or pancreatic lipase inhibitor (such as orlistat); a lipid-lowering agent (such as a statin, a fibrate, niacin or a derivative thereof (such as acipimox), lecithin, a bile acid sequestrant, ezetimibe, lomitapide, phytosterol, an ω-3 supplement, a PCSK9 inhibitor); a CB-1 antagonist; a lipoxygenase inhibitor; a somostatin analogue; an insulin compound or an insulin analogue (such as human insulin, insulin lispro, insulin aspart, insulin glulisine, insulin glargine, insulin degludec); an insulin sensitizer, such as a PPAR-γ agonist, a PPAR-α agonist or a mixed PPAR-γ / α agonist (such as metformin, pioglitazone or rosiglitazone); an insulin secretagogue (such as nateglinide or repaglinide, or a sulfonylurea such as gliclazide, glimeperide, limepiride, glyburide); an SGLT2 inhibitor (such as dapagliflozin, canagliflozin or empagliflozin); a dextrin analogue (such as pramlintide); a DPPIV inhibitor (such as sitagliptin, saxagliptin, linagliptin, alogliptin or vildagliptin); a GLP-1 agonist (such as albiglutide, dulaglutide, exenatide, liraglutide, semaglutide or lixisenatide);α-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.

64. A compound or a pharmaceutically acceptable salt and / or solvate thereof for use, a pharmaceutical composition for use, a use or a method according to any one of claims 47 to 52, which is used in combination with the following: gastric or pancreatic lipase inhibitors (such as orlistat); lipid-lowering agents (such as statins, fibrates, niacin or their derivatives (such as acipimox), lecithin, bile acid sequestrants, ezetimibe, lomitapide, phytosterols, ω-3 supplements, PCSK9 inhibitors); CB-1 antagonists; lipoxygenase inhibitors; somatostatin analogs; insulin compounds or insulin analogs (such as human insulin, insulin lispro, insulin aspart, insulin glulisine, insulin glargine, insulin degludec); insulin sensitizers such as PPAR-γ agonists, PPAR-α agonists or mixed PPAR-γ / α agonists (such as metformin, pioglitazone or rosiglitazone); insulin secretagogues (such as nateglinide or repaglinide, or sulfonylureas such as gliclazide, glymidine, limigidine, glibenclamide); 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 (such as albiglutide, dulaglutide, exenatide, liraglutide, semaglutide or lixisenatide); α-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.

65. A compound selected from the group consisting of: 2-((5-methoxypyridin-2-yl)methyl)-6-((1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)thio)phthalazin-1(2H)-one; 6-((1-(difluoromethyl)-1H-pyrazol-4-yl)thio)-2-((1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)methyl)phthalazin-1(2H)-one; 6-((1-(2-((tert-Butyldimethylsilyl)oxy)ethyl)-1H-pyrazol-4-yl)thio)-2-((2,3-dihydrofuro[3,2-b]pyridin-5-yl)methyl)phthalazin-1(2H)-one; 2-((2,3-Dihydropyrazolo[5,1-b]oxazol-6-yl)methyl)-6-((1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)thio)phthalazin-1(2H)-one; 2-((2,3-Dihydropyrazolo[5,1-b]oxazol-6-yl)methyl)-6-((1-methyl-1H-pyrazol-4-yl)thio)phthalazin-1(2H)-one; and 2-((4-Chloro-5-methyl-1H-pyrazol-3-yl)methyl)-6-((1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)sulfonyl)phthalazin-1(2H)-one; or a salt thereof.

66. A process for preparing a compound of formula (Ia) as defined in any one of claims 1 to 19 or a salt thereof, such as a pharmaceutically acceptable salt and / or solvate, which comprises oxidizing a compound of formula (IIa) using an oxidizing agent such as Oxone: or a salt and / or solvate thereof; wherein R A and R B are as defined in any one of claims 1 to 19.

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