Novel inhibitors of phosphatidylinositol 3-kinase

Abstract

This invention relates to the prevention and / or treatment of protein tyrosine kinase-mediated diseases, particularly phosphatidylinositol 3-kinase (PI3Ks)-mediated diseases. PI3Ks are well known as oncological targets, and several PI3K inhibitors have been developed that inhibit numerous class 1A PI3K isoforms. The development of selective inhibitors of PI3K-α may enable sufficient targeted inhibition while avoiding some of the known toxic drawbacks of pan-PI3K inhibitors. The inventors have discovered that a novel carbamoti-oil-pyrrolidine-carboxamide compound of formula (I) exhibits advantageous PI3K inhibitory activity, particularly with high selectivity for the isoform PI3K-α. In particular, this invention relates to the compound of formula (I), or deuterated or tritiated forms of the compound of formula (I), and pharmaceutically acceptable salts thereof. [Formula 1] The present invention also relates to pharmaceutical compositions containing a compound of formula (I) for use in the treatment and / or prevention of protein tyrosine kinase-mediated diseases, and to a compound of formula (I).

Description

[Technical Field]

[0001] This invention relates to a novel specific carbamoti oil-pyrrolidine-carboxamide compound, a method for synthesizing the same, and its therapeutic use.

[0002] The compounds described herein are novel phosphatidylinositol 3-kinase (PI3K) inhibitors, particularly alpha-selective phosphatidylinositol 3-kinase (PI3K alpha) inhibitors. Therefore, the compounds described herein are useful in the prevention and / or treatment of protein tyrosine kinase-mediated diseases, particularly PI3K-mediated diseases. [Background technology]

[0003] Phosphatidylinositol 3-kinases (PI3Ks) are a family of lipid kinases that phosphorylate phosphatidylinositide at the 3' position of the inositol ring. These are classified into three classes based on their substrate specificity and sequence homology.

[0004] Class I PI3K phosphorylates phosphatidylinositol-4,5-diphosphate (PIP2) downstream of either a receptor tyrosine kinase or a G protein-coupled receptor to form phosphatidylinositol-3,4,5-triphosphate (PIP3), a second messenger that transmits signals about increased cell growth, metabolism, or cell cycle progression.

[0005] Class I consists of four family members, each forming a heterodimer between a catalytic subunit p110 and a regulatory subunit. This family is further subdivided into Class IA, where isoforms p110α, p110β, and p110δ form heterodimers with the p85 family of regulatory subunits, and Class IB, where p110γ is the sole member and forms a heterodimer with either the p87 or p101 regulatory subunit.

[0006] Each isoform has been shown to have overlapping but non-redundant physiological roles. Both PI3K-α and β are universally expressed. PI3K-α plays a major role in glucose homeostasis and insulin signaling and is involved in promoting myocardial growth via the PIP3-dependent pathway. PI3K-β, on the other hand, has been shown to modulate the activity of platelet integrin αIIbβ3 in relation to platelet adhesion and aggregation. Therefore, PI3K-β is being studied as a novel treatment for thrombosis, and first-instance human trials have shown promising results. PI3K-γ and δ are more limitedly expressed and primarily confined to the hematopoietic system. They play important non-redundant roles in the immune system, and therefore both are considered immunomodulatory targets. PI3K-γ inhibition is being studied for rheumatoid arthritis and asthma, and PI3K-δ is being studied for activated PI3K-δ syndrome (APDS).

[0007] Despite its various functions, PI3K is perhaps best known as a target in oncology. The PI3K pathway is one of the most frequently dysregulated pathways in cancer.

[0008] Therefore, several PI3K inhibitors that inhibit many class 1A PI3K isoforms have been disclosed and are generally known as "pan-PI3K" inhibitors.

[0009] The development of isoform-selective inhibitors is essential to elucidating the unique function of each isoform and its corresponding therapeutic potential. Significant progress has been made, and isoform-selective inhibitors are now available for each of the four class I isoforms. These inhibitors continue to be useful in revealing important details of PI3K physiology and understanding cancer signaling.

[0010] In particular, oncogenic mutations within the gene encoding the p110α catalytic subunit, PIK3CA, are common in breast cancer, colon cancer, and endometrial cancer. Somatic missense mutations have been identified throughout the entire p110α sequence. Interestingly, approximately 80% of these mutations are concentrated in three “hotspots”: Glu542Lys, Glu545Lys, and His1047Arg.

[0011] Furthermore, the development of selective inhibitors of PI3K-α could enable sufficient targeted inhibition while avoiding some of the known toxic drawbacks of pan-PI3K inhibitors.

[0012] Therefore, several selective inhibitors of PI3K-α have been developed, such as the 2-carboxamide cycloaminourea derivative disclosed in International Publication No. 2010 / 029082.

[0013] International Publication No. 2017 / 001362 concerns cancer treatment with Taselisib®, which exhibits higher selectivity for PI3K alpha isoforms.

[0014] There is still a need to provide further compounds suitable as PI3K inhibitors for the treatment and / or prevention of proliferative diseases such as cancer.

[0015] In particular, there is a need to provide further compounds that can selectively inhibit the isoform PI3K alpha, which have advantageously higher selectivity and / or higher activity. [Prior art documents] [Patent Documents]

[0016] [Patent Document 1] International Publication No. 2010 / 029082 [Patent Document 2] International Publication No. 2017 / 001362 [Overview of the project]

[0017] The inventors discovered that the compound of formula (I), as defined below, exhibits advantageous phosphatidylinositol 3-kinase (PI3K) inhibitory activity, particularly toward isoform alpha.

[0018] Furthermore, as demonstrated in the following examples, these compounds also favorably exhibit improved selectivity for PI3K alpha with respect to beta and / or delta and / or gamma subtypes.

[0019] Therefore, the compounds of formula (I) are suitable for use in the treatment and / or prevention of protein tyrosine kinase-mediated diseases, particularly PI3K-mediated diseases, and more particularly diseases mediated by the PI3K isoform alpha.

[0020] Advantageously, the compound of formula (I) exhibits such improvements in activity and selectivity without inducing the insulin resistance problems that may be observed with some known selective PI3K-α inhibitors. In particular, the compound of formula (I) causes little to no hyperglycemia.

[0021] Furthermore, the compound of formula (I) exhibits sustained inhibitory activity against tissue-derived AKT.

[0022] Therefore, according to its first aspect, the present invention relates to a compound of formula (I) as defined below.

[0023] The present invention further relates, according to another aspect thereof, to a method for producing these compounds and to certain intermediate compounds involved in such a method, as detailed below.

[0024] The present invention, in yet another aspect thereof, relates to a pharmaceutical composition comprising a compound of formula (I) as defined below, or a deuterated or tritiated form of a compound of formula (I), or a pharmaceutically acceptable salt thereof.

[0025] The present invention further relates to a compound of formula (I) as defined below, or a deuterated or tritiated form of a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use as a pharmaceutical.

[0026] Another aspect of this disclosure relates to a compound of formula (I) as defined below, for use as a PI3K inhibitor, and more particularly as a PI3K alpha inhibitor.

[0027] The present invention further relates to a compound of formula (I) as defined below, or a deuterated or tritiated form of a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment and / or prevention of protein tyrosine kinase-mediated diseases, particularly PI3K-mediated diseases, and more particularly PI3K alpha-mediated diseases. [Brief explanation of the drawing]

[0028] [Figure 1A] This illustrates the ability of compound 5 of the present invention to improve renal lesions in the NZBWF1 / J mouse model. Urinary albumin / creatinine ratio (Ualb / Cre) (vertical coordinate, mg / mmol). Horizontal coordinate (left to right): vehicle and compound 5 (50 mg / kg). [Figure 1B] This illustrates the ability of compound 5 of the present invention to improve renal lesions in the NZBWF1 / J mouse model. Blood urea nitrogen level (BUN) (vertical coordinate, mmol / L). Horizontal coordinate (left to right): Vehicle and compound 5 (50 mg / kg). [Figure 1C] This illustrates the ability of compound 5 of the present invention to improve renal lesions in the NZBWF1 / J mouse model. Glomerular lesion scores of the kidneys (n=6 mice per group) 4 weeks after unilateral nephrectomy and subsequent treatment with vehicle or compound 5. AU: arbitrary units (vertical coordinate). Horizontal coordinate (left to right): vehicle and compound 5 (50 mg / kg). [Figure 2] This illustrates the temporal changes in insulin levels in a group of mice treated with either the vehicle or compound 5 of the present invention. Vertical coordinate: insulin (ng / mL). Horizontal coordinate: time (in hours). [Modes for carrying out the invention]

[0029] [Definition] As used herein, the term “patient” means an animal that is suffering from or may suffer from one or more of the diseases and physical conditions described herein, such as a valuable animal intended for breeding, companionship, or preservation, preferably a human or a human child.

[0030] In particular, the term "patient" as used in this application means mammals such as rodents, cats, dogs, primates, or humans, and preferably the subject is humans, but extends to birds.

[0031] Identifying patients who require treatment for the diseases and physical conditions described herein is well within the capabilities and knowledge of those skilled in the art. Veterinarians or physicians skilled in the art can readily identify patients requiring such treatment using clinical trials, physical examinations, medical / family history, or biological or diagnostic tests.

[0032] In connection with the present invention, the terms “to treat” or “to cure” as used herein mean to reverse, alleviate, inhibit the progression of, or prevent the medical condition of a patient suffering from one of the diseases described herein.

[0033] As used herein, “effective amount” means the amount of the compound of the present invention that is effective in preventing, reducing, eliminating, treating or controlling the symptoms of the diseases and physical conditions described herein. The term “control” is intended to mean all processes in which there may be a delay, interruption, blockage or cessation of the progression of the diseases and physical conditions described herein, but not necessarily the complete elimination of the symptoms of all diseases and physical conditions, and is intended to include preventive treatment.

[0034] The term "effective dose" includes both "preventive effective dose" and "therapeutic effective dose."

[0035] The term "prevent" means reducing the risk of developing a given phenomenon, namely, the disease described herein, or delaying its onset.

[0036] As used herein, the term “prevent” also includes “reduce the likelihood of occurrence” or “reduce the likelihood of recurrence.”

[0037] The term "preventive effective dose" refers to the concentration of the compound of the present invention that is effective in inhibiting, preventing, or reducing the likelihood of inflammatory diseases, diseases caused by viruses, more particularly retroviral diseases, or cancer.

[0038] Similarly, the term "therapeutic dose" means the concentration of a compound that is effective in treating the diseases described herein.

[0039] As used herein, the term "pharmaceutically acceptable" means a compound, material, excipient, composition or dosage form that, within the bounds of sound medical judgment, fits a reasonable risk-benefit ratio and is suitable for contact with human and animal tissues without excessive toxicity, irritation, allergic reactions or other problematic complications.

[0040] The term "prodrug" refers to a non-biologically active compound that can be converted in vivo to the compound of the present invention by metabolic means (e.g., hydrolysis, reduction, or oxidation). For example, the ester prodrug of the compound of the present invention can be converted in vivo to the parent molecule by hydrolysis. Suitable esters of the compound of the present invention include, for example, acetate, citrate, lactate, tartrate, malonate, oxalate, salicylate, propionate, succinate, fumarate, maleate, methylene-bis-β-hydroxynaphthoate, gentisate, isethionate, di-p-toluyl tartrate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, cyclohexylsulfamate, and quinate. An example of an ester prodrug is described in F.J. Leinweber, Drug Metab. Res., 1987, 18, 379. As used herein, references to the compounds of the present invention are intended to include any prodrug or metabolite form.

[0041] The terms "inhibit" or "block" in relation to enzymes, such as PI3K and more specifically PI3K-α, mean a reduction in enzyme activity.

[0042] As used herein, the term "PI3K" refers to phosphatidylinositol 3-kinase, and is sometimes also called PI3-kinase, PI(3)Ks, PI3Ks, or PI3K(s). PI3K enzymes are a family of enzymes involved in cellular functions, including, but not limited to, cell growth, proliferation, differentiation, motility, survival, and intracellular transport. PIK3CA is the gene that encodes the P110a protein, also called PIK3CA or PIK3C-alpha protein.

[0043] As used herein, the terms “protein tyrosine kinase-mediated disease,” “PI3K-mediated disease,” or “PI3K-α-mediated disease” mean, more specifically, diseases associated with the overexpression and / or abnormal activity of protein tyrosine kinase, PI3K, and / or PI3K-α, respectively.

[0044] "Proliferative disorders" refer to diseases resulting from abnormal growth or expansion due to the enlargement of cells. Examples of proliferative disorders include cancer, benign tumors, angiogenesis, and inflammatory diseases, including autoimmune diseases / disorders.

[0045] The term "cancer" refers to a category of diseases characterized by the development of abnormal cells that have the ability to grow uncontrollably and invade and destroy normal tissues within the body. This includes malignant and benign tumors, metastatic and non-metastatic tumors, solid and non-solid tumors, and hematological cancers, which may include, for example, leukemia, lymphoma, and myeloma; this also relates to central nervous system (CNS) cancers and non-CNS cancers. Unless otherwise stated, the term "cancer" also includes juvenile and non-juvenile cancers, recurrent and non-recurrent cancers, and cancer recurrence.

[0046] In relation to the present invention, the following terms have the following meanings: - "Halogen" is understood to mean chlorine, fluorine, bromine, or iodine, and more specifically chlorine, fluorine, or bromine, preferably fluorine. - The term "(C1~C" used in this specification x )alkyl refers to C1~C x This usually refers to a secondary or tertiary monovalent saturated, linear or branched hydrocarbon group, such as a (C1-C6) alkyl group. Examples include, but are not limited to, methyl, ethyl, propyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, and isohexyl groups. - The term "(C3~C" used in this specification x"Cycloalkyl" refers to a cyclic saturated hydrocarbon group that is saturated or partially unsaturated, and unsubstituted or substituted, containing 3 to x carbon atoms. Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0047] A "pharmaceutically acceptable salt" means a salt that, within the bounds of sound medical judgment, is suitable for use in contact with human and lower organism tissues without excessive toxicity, irritation, or allergic reactions. Pharmacologically acceptable salts include salts derived from suitable organic and inorganic acids or bases.

[0048] Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of amino groups formed using inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or by other methods known in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipine, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphor sulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxyethanesulfonate, and rh These include ctobionates, lactates, laurates, lauryl sulfates, malates, maleates, malons, methanesulfons, 2-naphthalenesulfons, nicotinates, nitrates, oleates, oxalates, palmitates, pamoates, pectates, persulfates, 3-phenylpropionates, phosphates, picrates, pivalates, propions, stearates, succinates, sulfates, tartrates, thiocyans, p-toluenesulfons, undecanoates, and valersates. Salts derived from suitable bases include alkali metals, alkaline earth metals, ammonium and N + [(C1~C4) alkyl]4- Salts are included. Typical alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium. Further pharmaceutically acceptable salts, where applicable, include non-toxic ammonium, quaternary ammonium, and amine cations formed with counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfons, and aryl sulfons.

[0049] A compound of formula (I) or any pharmaceutically acceptable salt thereof may form a solvate or hydrate, and the present invention encompasses all such solvates and hydrates.

[0050] The terms "hydrate" and "solvate" simply mean that compound (I) according to the present invention may exist in the form of a hydrate or solvate, that is, it may be combined with or associated with one or more water molecules or solvent molecules. This is merely a chemical property of such compounds and is applicable to all organic compounds of this type.

[0051] In connection with the present invention, the compounds of formula (I) as defined herein may contain deuterium or tritium. The deuterated or tritiated form of the compound simply means that the hydrogen atoms (H) in these compounds can be partially or entirely replaced by deuterium (D) or tritium (T) atoms.

[0052] Compounds of formula (I) may contain one or more chiral carbon atoms. Therefore, these compounds may exist in the form of enantiomers or diastereoisomers. These enantiomers, diastereoisomers, and mixtures thereof are encompassed within the scope of the present invention.

[0053] The compounds of formula (I) may exist in amorphous or crystalline forms, and these are also included within the scope of the present invention.

[0054] [Detailed description of the invention] The present invention relates to formula (I): [ka] In the compound: - R1 is an unsubstituted (C1-C6) alkyl group or (C3-C6) cycloalkyl group, either unsubstituted or substituted with one or more fluorine atoms; - R2: ■ Hydrogen atom, and ■(C1~C6) alkyl groups, Selected from among; - m is 0, 1, or 2; - Each R3, if present, operates independently. ■Fluorine atom, ■Unsubstituted or substituted with one or more halogen atoms, (C1-C6) alkyl groups, ■Unsubstituted or substituted with one or more halogen atoms, (C3-C6) cycloalkyl groups ■Hydroxy group, ■(C1~C6)alkoxy groups, and ■ A -NRR' group in which R and R' are independently selected from a hydrogen atom and an alkyl group (C1-C6), Selected from among these, Alternatively, two R3 atoms supported by the same carbon atom may form a (C3-C6) cycloalkyl ring together with the supporting carbon atom, which may be unsubstituted or substituted with one or more fluorine atoms. - R4 is: ■Fluorine atom, ■Hydrogen atom, ■Unsubstituted or substituted with one or more halogen atoms, (C1-C6) alkyl groups, and ■Unsubstituted or substituted with one or more halogen atoms, (C3-C6) cycloalkyl groups Selected from among these, Alternatively, if R3 and R4 are supported by two adjacent carbon atoms, they form a (C3-C6) cycloalkyl ring together with the supporting carbon atoms, which may be unsubstituted or substituted with one or more halogen atoms. The present invention relates to a compound of formula (I), or a deuterated or tritiated form of a compound of formula (I), or a pharmaceutically acceptable salt thereof.

[0055] Among the compounds of formula (I), we can refer to compounds in which R1 is an unsubstituted (C1-C6) alkyl group, particularly a (C1-C4) alkyl group, and more particularly a tert-butyl group, which is substituted with one or more fluorine atoms.

[0056] In one embodiment, the R1 group in the compound of formula (I) is a tert-butyl group substituted with 1 to 3 fluorine atoms.

[0057] In another embodiment, in the compound of formula (I), the R1 group is an unsubstituted tert-butyl group.

[0058] Among the compounds of formula (I), we can refer to those in which R2 is a (C1-C6) alkyl group, particularly a (C1-C4) alkyl group, and more particularly a methyl group.

[0059] In one embodiment, a compound of formula (I) where m is 0 can be mentioned.

[0060] In another embodiment, we can refer to compounds of formula (I) where m is 1 or 2, in particular where m is 1.

[0061] In one embodiment, in the compound of formula (I), m is 1 or 2, and each R3 is independently: ■Fluorine atom, ■Unsubstituted or substituted with one or more halogen atoms, (C1-C6) alkyl groups, especially (C1-C4) alkyl groups and more especially methyl groups, ■Unsubstituted or (C3-C6) cycloalkyl groups substituted with one or more halogen atoms, particularly one or more fluorine atoms. ■Hydroxy group, ■(C1~C6) alkoxy groups, especially (C1~C4) alkoxy groups and more particularly methoxy groups, ■-NH2 group, It will be selected from among the following.

[0062] In one embodiment, in the compound of formula (I), m is 1 or 2, and each R3 is independently: ■Fluorine atom, ■Unsubstituted or substituted with one or more halogen atoms, (C1-C6) alkyl groups, especially (C1-C4) alkyl groups and more particularly methyl groups; for example, methyl groups or trifluoromethyl groups, ■Unsubstituted or (C3-C6) cycloalkyl groups substituted with one or more halogen atoms, particularly one or more fluorine atoms. ■ Hydroxyl group, and ■(C1~C6) alkoxy groups, especially (C1~C4) alkoxy groups, and more particularly methoxy groups, It will be selected from among the following.

[0063] In a particular embodiment, m is 1 or 2, and each R3 is independently: ■Fluorine atom, ■ Unsubstituted or substituted with one or more halogen atoms, (C1-C6) alkyl groups, especially (C1-C4) alkyl groups, and more particularly methyl groups: for example, methyl groups or trifluoromethyl groups; ■ Hydroxyl group, and ■(C1~C6) alkoxy groups, especially (C1~C4) alkoxy groups, and more particularly methoxy groups, It will be selected from among the following.

[0064] In another embodiment, in the compound of formula (I), m is 2, and the two R3s supported by the same carbon atom, together with the supporting carbon atom, form a (C3-C6) cycloalkyl ring, particularly a cyclopropyl ring, which is unsubstituted or substituted with one or more fluorine atoms.

[0065] Of the compounds of formula (I), R4 is: ■ Hydrogen atom, and ■Unsubstituted or one or more halogen atoms, in particular one or more substituted fluorine atoms, (C1-C6) alkyl groups, in particular (C1-C4) alkyl groups, and more particularly methyl groups, We can then discuss the compounds selected from among them.

[0066] These subgroups and specific embodiments, considered individually or in combination, constitute part of this specification.

[0067] In one embodiment, - R1 is an unsubstituted (C1-C6) alkyl group or (C3-C6) cycloalkyl group, either unsubstituted or substituted with one or more fluorine atoms; - R2: ■ Hydrogen atom, and ■(C1~C6) alkyl groups, Selected from among; - m is 0, 1, or 2; - If each R3 exists, independently, ■Fluorine atom, ■Unsubstituted or substituted with one or more halogen atoms, (C1-C6) alkyl groups, ■Unsubstituted or (C3-C6) cycloalkyl groups substituted with one or more halogen atoms, ■ Hydroxyl group, and ■(C1~C6)alkoxy groups, Will it be selected from among them? Alternatively, two R3 atoms supported by the same carbon atom may form a (C3-C6) cycloalkyl ring together with the supporting carbon atom, which may be unsubstituted or substituted with one or more fluorine atoms. - R4: ■Fluorine atom, ■ Hydrogen atom, and ■Unsubstituted or substituted with one or more halogen atoms, (C1-C6) alkyl groups, We can refer to the compound of formula (I) selected from among them.

[0068] In another embodiment, - R1 is an unsubstituted or substituted (C1-C6) alkyl group, particularly a (C1-C4) alkyl group; and more particularly, an unsubstituted or substituted (C1-C4) tert-butyl group; - R2 is a (C1-C6) alkyl group, especially a (C1-C4) alkyl group, and more particularly a methyl group. - m is 0, 1, or 2; - If each R3 exists, independently, ■Fluorine atom, ■(C1~C6) alkyl groups, especially (C1~C4) alkyl groups, and more particularly methyl groups, ■ Hydroxyl group, and ■(C1~C6) alkoxy groups, especially (C1~C4) alkoxy groups, and more particularly methoxy groups, Selected from among these, Alternatively, two R3s supported by the same carbon atom, together with the supporting carbon atom, form an unsubstituted or substituted (C3-C6) cycloalkyl ring, particularly a cyclopropyl ring; and - R4: ■ Hydrogen atom, and ■(C1~C6) alkyl groups, especially (C1~C4) alkyl groups, and more particularly methyl groups, We can refer to the compound of formula (I) selected from among them.

[0069] In another embodiment, - R1 is a (C1-C6) alkyl group, particularly a (C1-C4) alkyl group, and more particularly a tert-butyl group, substituted with 1-3 fluorine atoms; - R2 is a (C1-C6) alkyl group, especially a (C1-C4) alkyl group, and more particularly a methyl group. - m is 0 or 1; - If R3 exists, ■ Hydroxyl group, and ■(C1~C6) alkoxy groups, especially (C1~C4) alkoxy groups, and more particularly methoxy groups, Selected from among, Preferably, R3 is a hydroxyl group; and - R4 is a hydrogen atom. We can refer to the compound of formula (I).

[0070] The nomenclature for the following compounds (1) to (20) was created using IUPAC rules for organic compounds, in accordance with the principles of the International Union of Pure and Applied Chemistry.

[0071] Among the compounds of formula (I), the following compounds may be mentioned in particular, or the deuterated or tritiated forms of the compounds of formula (I), or their pharmaceutically acceptable salts: (1) (S)-2-carbamoticoil-4,4-difluoro-N-(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridine-4-yl)thiazole-2-yl)pyrrolidine-1-carboxamide, (2) (2S,4R)-2-carbamoticoyl-4-fluoro-N-(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridine-4-yl)thiazole-2-yl)pyrrolidine-1-carboxamide, (3) (2S,4S)-2-carbamotioyl-4-fluoro-N-(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridine-4-yl)thiazole-2-yl)pyrrolidine-1-carboxamide, (4) (S)-6-Carbamotioyl-N-(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropane-2-yl)pyridine-4-yl)thiazole-2-yl)-1,1-difluoro-5-azaspiro[2,4]heptan-5-carboxamide, (5) (S)-2-carbamoteoyl-N-(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridine-4-yl)thiazole-2-yl)pyrrolidine-1-carboxamide, (6) (S)-2-carbamotioyl-2-methyl-N-(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridine-4-yl)thiazole-2-yl)pyrrolidine-1-carboxamide, (7) (2S,4R)-2-carbamoticoyl-4-methoxy-N-(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropane-2-yl)pyridine-4-yl)thiazole-2-yl)pyrrolidine-1-carboxamide, (8) (2S,4S)-2-carbamotioyl-4-methoxy-N-(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridine-4-yl)thiazole-2-yl)pyrrolidine-1-carboxamide, (9) (2S,5R)-2-carbamoticoyl-5-methyl-N-(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridine-4-yl)thiazole-2-yl)pyrrolidine-1-carboxamide, (10) (2S,5S)-2-carbamoticoyl-5-methyl-N-(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropane-2-yl)pyridine-4-yl)thiazole-2-yl)pyrrolidine-1-carboxamide, (11) (2S,4S)-2-carbamoticoyl-4-methyl-N-(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropane-2-yl)pyridine-4-yl)thiazole-2-yl)pyrrolidine-1-carboxamide, (12) (2S,4S)-2-carbamoticoil-N-(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropane-2-yl)pyridine-4-yl)thiazole-2-yl)-4-(trifluoromethyl)pyrrolidine-1-carboxamide, (13) (2S,4R)-2-carbamoteoyl-4-hydroxy-N-(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropane-2-yl)pyridine-4-yl)thiazole-2-yl)pyrrolidine-1-carboxamide, (14) (2S,3S)-2-carbamoticoyl-3-hydroxy-N-(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropane-2-yl)pyridine-4-yl)thiazole-2-yl)pyrrolidine-1-carboxamide, (15) (2S,3S)-2-carbamoticoyl-3-methoxy-N-(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropane-2-yl)pyridine-4-yl)thiazole-2-yl)pyrrolidine-1-carboxamide, (16) (S)-6-Carbamotioyl-N-(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridine-4-yl)thiazole-2-yl)-5-azaspiro[2.4]heptan-5-carboxamide, (17) (2S,4S)-2-carbamoteoyl-4-hydroxy-N-(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridine-4-yl)thiazole-2-yl)pyrrolidine-1-carboxamide, (18) (S)-2-Carbamotioyl-N-(4-methyl-5-(2-tert-butylpyridine-4-yl)thiazole-2-yl)pyrrolidine-1-carboxamide, (19) (2S,4S)-2-carbamotioyl-4-fluoro-N-(4-methyl-5-(2-tert-butylpyridine-4-yl)thiazole-2-yl)pyrrolidine-1-carboxamide, and (20) (S)-6-carbamotioyl-N-(4-methyl-5-(2-tert-butylpyridine-4-yl)thiazole-2-yl)-5-azaspiro[2.4]heptan-5-carboxamide.

[0072] Among the compounds listed above, the following compounds can be particularly mentioned: (5), (7), (8), (13), (14), and (17), or the deuterated or tritiated forms of the compounds of formula (I), or their pharmaceutically acceptable salts.

[0073] Among the compounds listed above, the following compounds can be particularly mentioned: (5), (13), (14), and (17), especially (5), (13), and (14), or the deuterated or tritiated forms of the compounds of formula (I), or their pharmaceutically acceptable salts.

[0074] The compound of formula (I) can be prepared by the following process.

[0075] Unless otherwise stated, R1, R2, R3, R4, and m are as previously defined.

[0076] Compounds of formula (I) and other related compounds having different substituents are synthesized using the techniques and materials described below or known to those skilled in the art. Furthermore, the solvents, temperatures, and other reaction conditions presented below may be varied as deemed appropriate by those skilled in the art.

[0077] [Scheme 1: Preparation of the compound of formula (I) - General process] [ka]

[0078] According to Scheme 1, compound (I) can be obtained in step 3 by coupling compound II-A, in which R4, R3, and m are as defined above, with compound II-B, in which R1 and R2 are as defined above.

[0079] Compound II-A can be obtained from the corresponding compound, which has a nitrogen atom in a protected form, for example, compound IA having a nitrogen atom protected by a tert-butylcarbamate (Boc) group, by a deprotection step 1, for example, in an aqueous solution of HCl. More specifically, step 1 can be carried out by placing compound IA in an HCl solution with a suitable solvent such as ether or dioxane and stirring at room temperature (i.e., at a temperature between 20 and 25°C) for several hours. The solvent is then removed under vacuum to obtain compound II-A, which can then be subjected to the coupling step.

[0080] Compound II-B can be obtained from compound IB in step 2 by reaction with 1,1'-carbonyldiimidazole. More specifically, compound IB can be dissolved in an organic solvent such as methylene chloride, and 1,1'-carbonyldiimidazole can be added in a molar ratio of 1 to 2, particularly 1.7. The reaction mixture can be stirred at a temperature in the range of 50°C to 70°C for a duration of 12 to 16 hours, then cooled to room temperature, filtered, and compound II-B can be obtained as a precipitate.

[0081] Compounds II-A and II-B are then subjected to coupling step 3 at room temperature using triethylamine (TEA) in a polar aprotic organic solvent such as N,N-dimethylformamide (DMF) or acetonitrile. More specifically, compounds II-A and II-B can be dissolved in DMF in a molar ratio of, for example, 1.3 / 1, and then TEA can be added in a molar ratio in the range of 2.5 to 3.5, particularly 3. The reaction mixture can be stirred at room temperature for a duration of 12 to 16 hours and treated with an aqueous solvent such as water. The organic phase can be extracted, for example with methylene chloride, washed, in particular with brine, and dried, for example, over sodium sulfate. The solvent can then be evaporated to obtain the crude product, which can be further purified, in particular by preparative HPLC using a water / acetonitrile gradient, to obtain compound I.

[0082] If R3 is a hydroxyl group, R3 is protected in compounds IA and II-A before the coupling step, for example, with a tert-butyldiphenylsilyl ether (tBDPS) protecting group. After the coupling step between compound II-A with the protected hydroxyl group R3 and compound II-B, the hydroxyl group can be deprotected in the resulting precipitate and before HPLC purification, for example, using tetra-n-butylammonium fluoride (TBAF) for the tBDPS protecting group.

[0083] Intermediate compound IA can be prepared by the process shown in Scheme 2.

[0084] [Scheme 2: Preparation of the intermediate compound of formula (IA) - General process] [ka]

[0085] According to Scheme 2, where R3, R4, and m are as defined above, the nitrogen atom in compound A1 is first protected in step 4 with, for example, a tert-butylcarbamate (Boc) group. The protection step can be carried out by reacting compound A1 with di-tert-butyl dicarbonate in the presence of a base such as triethylamine. For example, compound A1 can be dissolved in a suitable solvent such as dichloromethane (DCM). Then, at a low temperature, especially at 0°C, a base such as triethylamine in a molar ratio of 1.5 is added, along with di-tert-butyl dicarbonate in a molar ratio of 1.2 in the range of 1 to 2 and a suitable nucleophile such as 4-dimethylaminopyridine (DMAP) in a molar ratio of 0.01 to 0.5 in the range of 0.15. The reaction mixture can then be stirred at a low temperature such as 0°C for a duration of 15 to 45 minutes, and then at room temperature for a duration of 8 to 15 hours. Subsequently, the reaction can be rapidly cooled using, for example, sodium bicarbonate (NaHCO3) in an aqueous solution, and extracted using a suitable solvent such as dichloromethane. Then, the organic phase can be dried on, for example, anhydrous Na2SO4, filtered, and concentrated under vacuum. Finally, the crude product can be purified using, for example, flash chromatography to obtain compound A2.

[0086] Compound A2 can be converted to compound A3 in step 5 through suitable conditions for converting the carboxylic acid functional group to the corresponding amide. For example, step 5 can be carried out by activation with isobutyl chloroformate in the presence of a base such as triethylamine, followed by a reaction with ammonia, preferably an aqueous ammonia solution. Compound A3 can be obtained by extraction with a suitable organic solvent such as ethyl acetate, followed by filtration, drying on anhydrous magnesium sulfate, and purification by flash chromatography, for example.

[0087] Compound A3 can be converted to compound A4 in step 6 by converting the amide functional group to a thioamide, for example, using Lawson's reagent.

[0088] If R3 is a hydroxyl group, R3 of compound A2 is protected with a protecting group, for example, a tert-butyldiphenylsilyl ether (tBDPS) protecting group, before proceeding to step 5. In this case, compound IA with a protected hydroxyl group R3 is obtained, which can be subjected to the coupling reaction described above in Scheme 1.

[0089] In certain embodiments, before performing step 5, the hydroxyl group can be converted to an alkoxy group, for example, by a reaction with an alkyl iodide in tetrahydrofuran, thereby obtaining compound A2 in which R3 is an alkoxy group from compound A2 in which R3 is a hydroxyl group.

[0090] In this specification, Compound of formula (II-A) and compound of formula (II-B): [ka] A method for preparing the compound of formula (I) as defined above, including a coupling reaction between the following: In the formula, R3, R4, m, R2, and R1 are defined as above, provided that if R3 is a hydroxyl group, R3 is protected in compound II-A before the coupling reaction, for example, with a tert-butyldiphenylsilyl ether (tBDPS) protecting group; and deprotection is performed after the coupling reaction. Here, the coupling reaction is preferably carried out at room temperature using triethylamine (TEA) in a polar aprotic organic solvent such as dimethylformamide (DMF). Methods are also provided.

[0091] The aforementioned coupling reaction may optionally be preceded by a step to obtain compound II-A. Here, equation (IA) [ka] The compound is converted to compound II-A by a deprotection step, for example, with an aqueous solution of HCl, where R3, R4, and m are as defined above, or R3 is a protected hydroxyl group, for example, a hydroxyl group protected with a tert-butyldiphenylsilyl ether (tBDPS) protecting group.

[0092] The aforementioned coupling reaction may optionally be preceded by a step to obtain compound II-B. Here, equation (IB) [ka] The compound is converted to compound II-B by reaction with 1,1'-carbonyldiimidazole, particularly in an organic solvent such as methylene chloride, with R1 and R2 as defined above.

[0093] Formulas (IA) and (II-A) are further described herein. [ka] Intermediate compounds of formula (I), or deuterated or tritiated forms of the compound of formula (I), or pharmaceutically acceptable salts thereof are provided, where In the formula, R3, R4, and m are as defined above; or R3 represents a protected hydroxyl group, such as a hydroxyl group protected with a tert-butyldiphenylsilyl ether (tBDPS) protecting group.

[0094] In particular, in the intermediate compounds of formula (IA) or (II-A), m, R3, and R4 may have any one of the specific definitions mentioned above for the compound of formula (I).

[0095] In one embodiment, among the intermediate compounds of formula (IA) or (II-A), - m is 0, 1, or 2; - Each R3, if present, operates independently. ■Fluorine atom, ■Unsubstituted or substituted with one or more halogen atoms, (C1-C6) alkyl groups, especially (C1-C4) alkyl groups and more especially methyl groups, ■Unsubstituted or (C3-C6) cycloalkyl groups substituted with one or more halogen atoms, ■Hydroxy groups, especially protected hydroxyl groups, such as hydroxyl groups protected with a tert-butyldiphenylsilyl ether (tBDPS) protecting group, ■(C1~C6) alkoxy groups, especially (C1~C4) alkoxy groups, and more particularly methoxy groups, ■-NH2 group, Selected from among these, Alternatively, two R3 atoms supported by the same carbon atom, together with the supporting carbon atom, form an unsubstituted or substituted (C3-C6) cycloalkyl ring, particularly a cyclopropyl ring, which is substituted with one or more fluorine atoms. - R4 is: ■Hydrogen atom, ■Unsubstituted or substituted with one or more halogen atoms, (C1-C6) alkyl groups, especially (C1-C4) alkyl groups and more especially methyl groups, Selected from among these, Alternatively, if R3 and R4 are supported by two adjacent carbon atoms, they form a (C3-C6) cycloalkyl ring together with the supporting carbon atoms, either unsubstituted or substituted with one or more halogen atoms.

[0096] In one embodiment, among the intermediate compounds of formula (IA) or (II-A), - m is 0, 1, or 2; - Each R3, if present, independently: ■Fluorine atom, ■(C1-C6) alkyl groups, especially (C1-C4) alkyl groups, and more particularly methyl groups; ■Hydroxy groups, especially protected hydroxyl groups, such as hydroxyl groups protected with a tert-butyldiphenylsilyl ether (tBDPS) protecting group; ■(C1~C6) alkoxy groups, especially (C1~C4) alkoxy groups, and more particularly methoxy groups, Selected from among these, Alternatively, two R3 atoms supported by the same carbon atom, together with the supporting carbon atom, form an unsubstituted or substituted (C3-C6) cycloalkyl ring, particularly a cyclopropyl ring, which is substituted with one or more fluorine atoms. - R4 is: ■ Hydrogen atom, and ■(C1~C6) alkyl groups, especially (C1~C4) alkyl groups, and more particularly methyl groups, It will be selected from among the following.

[0097] In another embodiment, among the intermediate compounds of formula (IA) or (II-A), - m is either 0 or 1; - R3 is present if ■ Hydroxyl group, and ■(C1~C6) alkoxy groups, especially (C1~C4) alkoxy groups, and more particularly methoxy groups, Selected from among, Preferably, R3 is a hydroxyl group, and - R4 is a hydrogen atom.

[0098] Among the intermediate compounds of formula (IA), the following compounds may be mentioned in particular, or the deuterated or tritiated forms of the compounds of formula (I), or their pharmaceutically acceptable salts: (21) tert-butyl(S)-2-carbamotioyl-4,4-difluoropyrrolidine-1-carboxylate; (22) tert-butyl(2S,4R)-2-carbamotioyl-4-fluoropyrrolidine-1-carboxylate, (23) tert-butyl(2S,4S)-2-carbamotioyl-4-fluoropyrrolidine-1-carboxylate, (24) tert-butyl(6S)-6-carbamotioyl-1,1-difluoro-5-azaspiro[2,4]heptane-5-carboxylate, (25) tert-butyl(S)-2-carbamoteoylpyrrolidine-1-carboxylate, (26) tert-butyl(S)-2-carbamoteoyl-2-methylpyrrolidine-1-carboxylate, (27) tert-butyl(2S,4R)-2-carbamoteoyl-4-methoxypyrrolidine-1-carboxylate, (28) tert-butyl(2S,4S)-2-carbamotioyl-4-methoxypyrrolidine-1-carboxylate, (29) tert-butyl(2S,5R)-2-carbamoteoyl-5-methylpyrrolidine-1-carboxylate, (30) tert-butyl(2S,5S)-2-carbamoteoyl-5-methylpyrrolidine-1-carboxylate, (31) tert-butyl(2S,4S)-2-carbamoteoyl-4-methylpyrrolidine-1-carboxylate, (32) tert-butyl(2S,4S)-2-carbamoteoyl-4-(trifluoromethyl)pyrrolidine-1-carboxylate, (33) tert-butyl(2S,4R)-4-((tert-butyldiphenylsilyl)oxy)-2-carbamyoylpyrrolidine-1-carboxylate, (34) tert-butyl(2S,3S)-3-((tert-butyldiphenylsilyl)oxy)-2-carbamoteoylpyrrolidine-1-carboxylate, (35) tert-butyl(2S,3S)-2-carbamoticoyl-3-methoxypyrrolidine-1-carboxylate, (36) tert-butyl(S)-6-carbamotioyl-5-azaspiro[2.4]heptane-5-carboxylate, and (37) tert-butyl(2S,4S)-4-((tert-butyldiphenylsilyl)oxy)-2-carbamyoylpyrrolidine-1-carboxylate.

[0099] More specifically, the compounds according to the present invention may be selected from the group consisting of the following compounds, deuterated or tritiated forms of the compounds of formula (I), or pharmaceutically acceptable salts thereof: (21) tert-butyl(S)-2-carbamotioyl-4,4-difluoropyrrolidine-1-carboxylate; (23) tert-butyl(2S,4S)-2-carbamotioyl-4-fluoropyrrolidine-1-carboxylate, (24) tert-butyl(6S)-6-carbamotioyl-1,1-difluoro-5-azaspiro[2,4]heptane-5-carboxylate, (26) tert-butyl(S)-2-carbamoteoyl-2-methylpyrrolidine-1-carboxylate, (28) tert-butyl(2S,4S)-2-carbamotioyl-4-methoxypyrrolidine-1-carboxylate, (29) tert-butyl(2S,5R)-2-carbamoteoyl-5-methylpyrrolidine-1-carboxylate, (30) tert-butyl(2S,5S)-2-carbamoteoyl-5-methylpyrrolidine-1-carboxylate, (31) tert-butyl(2S,4S)-2-carbamoteoyl-4-methylpyrrolidine-1-carboxylate, (32) tert-butyl(2S,4S)-2-carbamoteoyl-4-(trifluoromethyl)pyrrolidine-1-carboxylate, (34) tert-butyl(2S,3S)-3-((tert-butyldiphenylsilyl)oxy)-2-carbamoteoylpyrrolidine-1-carboxylate, (35) tert-butyl(2S,3S)-2-carbamoticoyl-3-methoxypyrrolidine-1-carboxylate, (36) tert-butyl(S)-6-carbamotioyl-5-azaspiro[2.4]heptane-5-carboxylate, and (37) tert-butyl(2S,4S)-4-((tert-butyldiphenylsilyl)oxy)-2-carbamyoylpyrrolidine-1-carboxylate.

[0100] With respect to the intermediate compound of formula (II-B), R1 and R2 may have any one of the specific definitions mentioned above for the compound of formula (I).

[0101] In one embodiment, in the intermediate compound of formula (II-B): - R1 is an unsubstituted or substituted (C1-C6) alkyl group, particularly a (C1-C4) alkyl group, and more particularly a tert-butyl group, substituted with one or more fluorine atoms. - R2 is: ■ Hydrogen atom, and ■(C1~C6) alkyl groups, especially (C1~C4) alkyl groups, and more particularly methyl groups, It will be selected from among the following.

[0102] In another embodiment, in the intermediate compound of formula (III-B): - R1 is an unsubstituted or substituted (C1-C6) alkyl group, particularly a (C1-C4) alkyl group, and more particularly a tert-butyl group, substituted with 1-3 fluorine atoms. - R2 is a (C1-C6) alkyl group, especially a (C1-C4) alkyl group, and more particularly a methyl group.

[0103] Intermediate compounds of formula (II-B) may be commercially available. For example, 4-methyl-5-[2-(2,2,2-trifluoro-1,1-dimethylethyl)-4-pyridinyl]-2-thiazoleamine (CAS 1357476-69-7) sold by AURUM pharmatech, 5-[2-(2,2,2-trifluoro-1,1-dimethylethyl)-4-pyridinyl]-2-thiazoleamine (CAS 1395492-61-1) sold by Carbosynth, and 5-[2-(1,1-dimethylethyl)-4-pyridinyl]-2-thiazoleamine (CAS 1395492-83-7) sold by Matrix Scientific.

[0104] Tables 1a and 1b below show the specific compounds of formula (I) relating to this disclosure (basic formula and structure) and their characterization (specific rotation, 1 This includes 1H NMR and high-resolution electrospray ionization mass spectrometry (HRMS-ESI).

[0105] Optical rotation (αD) was measured at 20°C using a Perkin Elmer polarimeter (Model 341).

[0106] 1 1H NMR and 13 ¹³C NMR spectra were recorded at 500 MHz (H-value) or 125 MHz (C-value) using a Bruker Avance II 500 spectrometer, and the chemical shift (δ, in ppm) in the solvent dimethyl sulfoxide-d6 (d6-DMSO) was referenced to 2.5 ppm at a temperature of 300 K. Coupling constants (J) are reported in Hertz.

[0107] High-resolution mass spectra were recorded using a ThermoFischer Exactive Orbitrap spectrometer.

[0108] [Table 1a-1] [Table 1a-2]

Table 1a-3

Table 1a-4

[0109]

Table 1b-1

Table 1b-2

Table 1b-3

[0110] The following Tables 2a and 2b contain the intermediate compounds (basic formula and structure) of the specific formula (I-A) according to the present disclosure and their property evaluations (specific rotation, 1 H NMR, 13 C NMR and high-resolution electrospray ionization mass spectrometry HRMS-ESI). [[ID=z39]]

[0111] The specific rotation (αD) was measured at 20 °C with a Perkin Elmer polarimeter (Model 341).

[0112] 1 H NMR and 13 C NMR spectra were recorded at 500 MHz (H values) or 125 MHz (C values) with a Bruker Avance II 500 spectrometer. The chemical shifts (δ, in ppm units) in the solvent dimethyl sulfoxide-d6 (d6-DMSO) were referenced to 2.5 ppm at a temperature of 300 K. The coupling constants (J) are reported in Hertz units.

[0113] The high-resolution mass spectra were recorded with a ThermoFischer Exactive Orbitrap spectrometer.

[0114] [Table 2a-1] [Table 2a-2] [Table 2a-3] [Table 2a-4]

[0115] [Table 2b-1] [Table 2b-2] [Table 2b-3]

[0116] All intermediates and compounds described below can be synthesized according to schemes 1 and 2.

[0117] The following examples illustrate the preparation of certain intermediate compounds and compounds of formula (I). These examples are not limiting and are merely useful for illustrating the present invention.

[0118] In the following embodiments, if the source of the starting product is not specified, it should be understood that the product is a well-known product.

[0119] The following abbreviations and formulas are used: NEt3 Triethylamine DMAP 4-dimethylaminopyridine NaHCO3 (sodium bicarbonate) DCM Dichloromethane Sodium sulfate (Na2SO4) HCl ethyl acetate rt room temperature MgSO4 Magnesium Sulfate THF (Tetrahydrofuran) N2 Nitrogen DMSO (Dimethyl Sulfoxide) KHSO4 (potassium bicarbonate) TBAF Tetra-n-butylammonium fluoride tBuMgCl tert-butylmagnesium chloride NH4OH Ammonium hydroxide DMF (Dimethylformamide). [Examples]

[0120] [Example 1: Synthesis of intermediate compounds 21-26, 29-32, and 36] [Intermediate 26]: tert-butyl(S)-2-carbamoticoil-2-methylpyrrolidine-1-carboxylate Intermediate 26 can be obtained from (S)-1-(tert-butoxycarbonyl)-2-methylpyrrolidine-2-carboxylic acid by the process described below. [ka]

[0121] Step a: (S)-1-(tert-butoxycarbonyl)-2-methylpyrrolidine-2-carboxylic acid To a solution of commercially available (S)-2-methylpyrrolidine-2-carboxylic acid (400 mg, 3.10 mmol, 1 equivalent) in DCM (15 mL), triethylamine (648 μL, 4.65 mmol, 1.5 equivalents), di-tert-butyl dicarbonate (853 μL, 3.72 mmol, 1.2 equivalents), and DMAP (57 mg, 464 μmol, 0.15 equivalents) were successively added at 0°C. The reaction mixture was stirred at 0°C for 30 minutes and then at room temperature overnight. The reaction was quenched with saturated aqueous solution of NaHCO3 (15 mL) and extracted with DCM (3 × 15 mL). The organic phase was dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. Flash chromatography of the residue (Cyclo / Â5 / 5) yielded (2S)-1-(tert-butoxycarbonyl)-2-methylpyrrolidine-2-carboxylic acid as a colorless oil (461 mg, yield 65%). R f 0.60(Cyclo / ا 1 / 4);[α] D -8(c 1.0, MeOH); 1 H NMR(500MHz,MeOD)δ3.61-3.39(m,2H,H5), 2.38-2.10(m,1H,H 3a ), 2.04-1.79(m,3H,H 3b ,H4), 1.51(d,J=13.3Hz,3H,H 10 ), 1.44(s,3H,CH 3 9 ), 1.42(s,6H,2CH 3 9 ). 13 C NMR(126MHz,MeOD)δ178.2(C6), 155.7(C7), 81.6(C8), 65.9(C2), 54.7(C5), 41.3(C3), 28.5(C9), 23.2(C4), 22.5(C 10 ) HRMS ESI + C 11 H 19 The calculated value for O4NNa is 252.1206, and the measured value is 252.1204.

[0122] Step b: tert-butyl-(2S)-2-carbamoyl-2-methylpyrrolidine-1-carboxylate To a solution of (2S)-1-(tert-butoxycarbonyl)2-methylpyrrolidine-2-carboxylic acid (350 mg, 1.53 mmol, 1 equivalent) in dry THF (5 mL), chloroformate isobutyl (458 μL, 3.51 mmol, 2.3 equivalents) and triethylamine (212 μL, 1.53 mmol, 1 equivalent) were successively added under argon at -10°C. The reaction mixture was stirred at 0°C for 30 minutes. 0.75 mL of ammonia solution (28% in water) was added at -10°C, and the reaction mixture was stirred overnight at room temperature. The solvent was removed under vacuum. The residue was dissolved in AcOEt (15 mL), filtered, dried on anhydrous MgSO4, and concentrated under vacuum. Flash chromatography of the residue (Cyclo / AcOEt 1 / 1) yielded tert-butyl-(2S)-2-carbamoyl-2-methylpyrrolidine-1-carboxylate as a white powder (240 mg, 60% yield): R f 0.15(Cyclo / AcOEt 1 / 1);[α] D -23(c 1.0,MeOH); 1 H NMR(500MHz,MeOD)δ3.59(dt,J=10.3,7.0Hz,1H), 3.47(dt,J H5a-H5b =10.4,J H5a-H4 =6.4Hz,1H,H 5a ), 2.20(dt,J H5b-H5a =13.0,J H5b-H4 =7.4Hz,1H,H 5a ), 2.03-1.93(m,1H,H 3a ), 1.96-1.85(m,3H,H 3b ,H4), 1.53(d,J=16.3Hz,3H,CH 3 10 ), 1.45(d,J=6.5Hz,9H,3CH3). 13 C NMR(126MHz,MeOD)δ180.6(C6), 155.4(C7), 81.7(C8), 67.1(C2), 42.1(C5), 41.6(C3), 28.7(C9), 23.4(C4), 22.9(C 10 ) HRMS ESI + C 11 H 20The calculated value for O3N2Na is 251.1366, and the measured value is 251.1359.

[0123] Step c: tert-butyl(S)-2-carbamoticoil-2-methylpyrrolidine-1-carboxylate To a solution of tert-butyl-(2S)-2-carbamoyl-2-methylpyrrolidine-1-carboxylate (210 mg, 920 μmol, 1 equivalent) in dry THF (2 mL), Lawson's reagent (186 mg, 460 μmol, 0.5 equivalents) was added under argon. The reaction mixture was stirred at room temperature for 3.5 hours. The solvent was removed under vacuum. Intermediate 26 was obtained as a white powder (204 mg, 91% yield) by flash chromatography of the residue (Cyclo / AcOEt 1 / 1). Characterization is detailed in Table 2b.

[0124] Similar processes were carried out starting with commercially available starting compounds to obtain intermediates 21-25, 29-32, and 36. The characterization of the obtained intermediates is shown in Table 2b.

[0125] [Example 2: Synthesis of intermediate compounds 27, 28, and 35] [Intermediate 28]: tert-butyl(2S,4S)-2-carbamotioyl-2-methoxypyrrolidine-1-carboxylate Intermediate 28 can be obtained from (4S)-4-hydroxypyrrolidine-2-carboxylic acid by the process described below. [ka]

[0126] Step a: (2S,4S)-1-(tert-butoxycarbonyl)-4-methoxypyrrolidine-2-carboxylic acid In a flame-dried, two-necked round-bottom flask equipped with a stirring rod, an N2 inlet, and a rubber diaphragm, NaH (55% of the mineral oil, 216 mg, 5.4 mmol, 2.5 equivalents) was added; the mineral oil was removed by washing away the hydride with anhydrous pentane (3 × 10 mL) under N2; the resulting white solid was gently fluxed with an N2 stream until completely dry. After cooling the flask to -20°C under N2, a solution of N-Boc-cis-4-hydroxy-L-proline (500 mg, 2.0 mmol, 1 equivalent) in a mixture of anhydrous THF (2 mL) and DMSO (0.2 mL) was slowly added by syringe. The temperature was then raised to 0°C and the heterogeneous mixture was stirred for 30 minutes. The temperature was lowered again to -20°C, and methyl iodide solution (333 μL, 5.4 mmol, 2.5 equivalents) in THF (1.2 mL) was added by syringe. Finally, the temperature was set to 25°C, and the reaction mixture was stirred until the starting materials were completely consumed (TLC analysis). The reaction was then quenched with water (2 mL), and the pH was adjusted to 4 with 10% KHSO4 aqueous solution (approximately 2 mL); the crude product was extracted with ELISA (5 × 6 mL); the organic layer was washed with brine (3 × 4 mL), dried over MgSO4, and the solvent was removed under vacuum. Flash chromatography of the residue (DCM / MeOH 95 / 5) yielded (2S,4S)-1-(tert-butoxycarbonyl)-4-methoxypyrrolidine-2-carboxylic acid as a white powder (400 mg, yield 75%). R f 0.36(DCM / MeOH 95 / 5);[α] D -63(c 1.0,MeOH); 1 H NMR(500MHz,MeOD)δ4.34-4.26(m,1H,H4), 4.0-3.95(m,1H,H2), 3.65-3.55(m,1H,H 5a ), 3.47-3.39(m,1H,H 5b ), 3.28-3.23(m,3H,H 10 ), 2.42-2.38(m,1H,H 3a ), 2.34-2.19(m,1H,H 3b ), 1.48(s,3H,CH 3 9 ), 1.43(s,6H,2CH39). 13C NMR(126MHz,MeOD)δ175.8(C6), 156.0(C7), 81.2(C4), 80.0(C8), 58.6(C2), 52.8(C 10 ), 52.0(C5), 35.9(C3), 28.5(C9). HRMS ESI + C 11 H 19 The calculated value for O5NNa is 268.1155, and the measured value is 268.1152.

[0127] Step b: tert-butyl-(2S,4S)-2-carbamoyl-4-methoxypyrrolidine-1-carboxylate To a solution of (2S,4S)-1-(tert-butoxycarbonyl)-4-methoxypyrrolidine-2-carboxylic acid (400 mg, 1.63 mmol, 1 equivalent) in dry THF (2 mL), chloroformate isobutyl (488 μL, 3.75 mmol, 2.3 equivalents) and triethylamine (227 μL, 1.63 mmol, 1 equivalent) were successively added under argon at -10°C. The reaction mixture was stirred at 0°C for 30 minutes. 0.75 mL of ammonia (28% in water) was added at -10°C, and the reaction mixture was stirred overnight at room temperature. The solvent was removed under vacuum. The residue was dissolved in AcOEt (15 mL), filtered, dried on anhydrous MgSO4, and concentrated under vacuum. Flash chromatography of the residue (Cyclo / AcOEt 1 / 1) yielded tert-butyl-(2S,4S)-2-carbamoyl-4-methoxypyrrolidine-1-carboxylate as a white powder (292 mg, yield 73%): R f 0.25(Cyclo / AcOEt 1 / 4);[α] D -22(c 1.0,MeOH); 1 H NMR(500MHz,MeOD)δ4.26-4.13(m,1H,H2), 4.0-3.97(m,1H,H 5a ), 3.59(t,J=11.5,1H,H4), 3.52-3.49(m,1H,H 5b ), 3.29(s,3H,CH3 10), 2.47-2.09(m,2H,H3), 1.48(s,3H,CH3), 1.46(d,J=17.6Hz,6H,2CH3). 13 C NMR(126MHz,MeOD)δ178.4(C6), 156.1(C7), 80.4(C4), 79.5(C8), 60.8(C2), 53.7(C 10 ), 52.8(C5), 36.7(C3), 28.6(C9), 28.6(C9). HRMS ESI + C 11 H 20 The calculated value for O4N2Na is 267.1315, and the measured value is 267.1313.

[0128] Step c: tert-butyl-(2S,4S)-2-carbamotioyl-4-methoxypyrrolidine-1-carboxylate To a solution of tert-butyl(2S,4S)-2-carbamoyl-4-methoxypyrrolidine-1-carboxylate (280 mg, 1.15 mmol, 1 equivalent) in dry THF (2 mL), Lawson's reagent (231 mg, 537 μmol, 0.5 equivalents) was added under argon. The reaction mixture was stirred at room temperature for 3.5 hours. The solvent was removed under vacuum. Intermediate compound 28 was obtained as a white powder (219 mg, yield 77%) by flash chromatography of the residue (Cyclo / AcOEt 1 / 1). Characterization is detailed in Table 2b.

[0129] To obtain intermediates 27 and 35, a similar process was carried out starting with commercially available starting compounds. The characterization of the obtained intermediates is shown in Table 2b.

[0130] [Example 3: Synthesis of intermediate compounds 33, 34, and 37] [Intermediate 33]: tert-butyl(2S,4R)-4-((tert-butyldiphenylsilyl)oxy)-2-carbamotioylpyrrolidine-1-carboxylate Intermediate 33 can be obtained from (2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid by the process described below. [ka]

[0131] Step (a): N-Boc-trans-4-(OtBDPS)-L-proline To a solution of N-Boc-trans-4-hydroxy-L-proline (585 mg, 2.53 mmol, 1 equivalent) in dry DMF (7 mL), imidazole (775 mg, 11.4 mmol, 4.5 equivalents) and tert-butylchlorodiphenylsilane (986 μL, 3.8 mmol, 1.5 equivalents) were successively added under argon at 0°C. The reaction mixture was stirred at room temperature for 5 days. 30 mL of water was added at 0°C, the reaction mixture was acidified to pH 2 with 1 M HCl, extracted with Depositphotos (5 × 15 mL), dried over anhydrous MgSO4, filtered, and concentrated under vacuum. Flash chromatography of the residue (Cyclo / Depositphotos 9 / 1) yielded N-Boc-trans-4-(OtBDPS)-L-proline as a white powder (480 mg, yield 69%). R f 0.10(Cyclo / Ե 9 / 1);[α] D -14(c 1.0,MeOH); 1 H NMR(500MHz,MeOD)δ7.71-7.59(m,4H,H aro ), 7.58-7.35(m,6H,H aro ), 4.51-4.43(m,1H,H2), 4.38(dt,J H4-H5 =23.1,J H4-H3 =8.0Hz,1H), 3.48-3.39(m,1H,H 5a ), 3.31(ddd,J H5b-H5a =39.5,11.3,4.0Hz,1H,H 5b ), 2.40-2.24(m,1H,H 3a ), 1.96-1.86(m,1H,H 3v ), 1.44(s,3H,CH39), 1.43(s,6H,2CH39), 1.06(s,9H,3CH3 11 ). 1313C NMR (126 MHz, MeOD) δ 176.4 (C6), 156.7 (C7), 137.5 (C aro ), 134.3 (C aro ), 131.5 (C aro ), 129.2 (C aro ), 82.4 (C8), 73.0 (C4), 72.5 (C2), 59.6 (C3), 55.6 (C5), 41.1 (C 10 ), 28.5 (C9), 27.3 (C 11 ). HRMS ESI + for C 26 H 36 NO5NSi, calculated value 470.2357, measured value 470.2354.

[0132] Step (b): tert-Butyl (2S,4R)-4-((tert-butyldiphenylsilyl)oxy)-2-carbamoylpyrrolidine-1-carboxylate To a solution of N-Boc-trans-4-(OtBDPS)-L-proline (700 mg, 1.5 mmol, 1 eq) in dry THF (4 mL) under argon at -10 °C, isobutyl chloroformate (446 μL, 3.4 mmol, 2.3 eq) and triethylamine (208 μL, 1.5 mmol, 1 eq) were added successively. The reaction mixture was stirred at 0 °C for 30 min. 0.75 mL of ammonia (28% in water) was added at -10 °C and the reaction mixture was stirred at room temperature overnight. The solvent was removed under vacuum. The residue was dissolved in AcOEt (15 mL), filtered, then dried over anhydrous MgSO4 and concentrated under vacuum. Flash chromatography of the residue (Cyclo / AcOEt 1 / 1); tert-Butyl (2S,4R)-4-((tert-butyldiphenylsilyl)oxy)-2-carbamoylpyrrolidine-1-carboxylate was obtained as a white powder (662 mg, 94% yield): R f 0.35 (Cyclo / AcOEt 1 / 1); [α] D -9 (c 1.0, MeOH); 1 1H NMR (500 MHz, MeOD) δ 11H NMR (500 MHz, MeOD) δ 7.67 - 7.61 (m, 4H, H aro ), 7.48 - 7.39 (m, 6H, H aro ), 4.47 - 4.44 (m, 1H, H2), 4.42 - 4.34 (m, 1H, H4), 3.53 - 3.43 (m, 1H, H 5a ), 3.36 (dd, J H5b-H5a = 11.4, J H5b-H4 = 3.8 Hz, 1H, H 5b ), 2.37 - 2.10 (m, 1H, H 3a ), 1.89 (ddd, J H3b-H3a = 12.9, J H3b-H4 = 8.8, J H3b-H2 = 4.2 Hz, 1H, H 3b ), 1.46 (s, 6H, 2CH39), 1.44 (s, 3H, CH39), 1.06 (s, 9H, CH3 11 ). 13 13C NMR (126 MHz, MeOD) δ 178.4 (C6), 156.3 (C7), 136.8 (C aro ), 134.6 (C aro ), 131.2 (C aro ), 128.6 (C aro ), 81.5 (C4), 73.1 (C8), 72.6 (C 10 ), 61.1 (C2), 56.2 (C5), 41.0 (C3), 28.8 (C9), 27.5 (C9), 19.9 (C 11 ). HRMS ESI + C 26 H 37 O4N2Si calculated value for 469.2517, measured value 469.2515.

[0133] Step (c): tert - butyl (2S,4R) - 4 - ((tert - butyldiphenylsilyl)oxy) - 2 - carbamothioylpyrrolidine - 1 - carboxylate To a solution of tert-butyl (2S,4R)-4-((tert-butyldiphenylsilyl)oxy)-2-carbamoylpyrrolidine-1-carboxylate (650 mg, 917 μmol, 1 eq) in dry THF (2 mL), Lawesson's reagent (280 mg, 693 μmol, 0.5 eq) was added under argon. The reaction mixture was stirred at room temperature for 3.5 h. The solvent was removed under vacuum. The residue was purified by flash chromatography (gradient DCM / MeOH 100 / 0 - 98 / 2) to give the intermediate compound 33 as a colorless oil (609 mg, 90% yield). Characterization is detailed in Table 2b.

[0134] To obtain intermediates 34 and 37, a similar process was carried out starting from commercially available starting compounds. The characterization of the obtained intermediate compounds is shown in Table 2b.

[0135] [Example 4: Synthesis of Compounds 1 - 12, 15 and 16] [Compound 5]: (S)-2-Carbamothioyl-N-(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)thiazol-2-yl)pyrrolidine-1-carboxamide Compound 5 can be obtained from 4-methyl-5-[2-(2,2,2-trifluoro-1,1-dimethylethyl)-4-pyridinyl]-2-thiazolamine and intermediate compound 25 by the process described below. [Chemical formula]

[0136] Step (a): N-{4-Methyl-5-[2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl]-1,3-thiazol-2-yl}-1H-imidazole-1-carboxamide 4-Methyl-5-[2-(2,2,2-trifluoro-1,1-dimethylethyl)-4-pyridinyl]-2-thiazolamine is commercially available from AURUM pharmatech.

[0137] 4-Methyl-5-[2-(2,2,2-trifluoro-1,1-dimethylethyl)-4-pyridinyl]-2-thiazolamine (2 g, 6.637 mmol) was dissolved in methylene chloride (60 mL), and 1,1'-carbonyldiimidazole (1.867 g, 11.512 mmol) was added. The reaction mixture was heated under reflux for 14 hours, cooled to room temperature, and filtered. The resulting amorphous solid (2.62 g, 95% yield) was used in the next step without further purification.

[0138] Step (b): (S)-Pyrrolidine-2-carbothioamide hydrochloride The intermediate compound 25 was dissolved in a dioxane solution of HCl (4 N, 90 mL) at 0 °C and stirred at 0 °C for 1 hour. Then, the reaction mixture was warmed to room temperature and the solvent was evaporated under vacuum. The white solid was triturated in diethyl ether and filtered to give (2S)-pyrrolidine-2-carbothioamide hydrochloride (5.43 g, quantitative).

[0139] Step (c): (S)-2-Carbamothioyl-N-(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)thiazol-2-yl)pyrrolidine-1-carboxamide N-{4-methyl-5-[2-(1,1,1-trifluoro-2-methylpropane-2-yl)pyridine-4-yl]-1,3-thiazole-2-yl}-1H-imidazole-1-carboxamide (365 mg) and (S)-pyrrolidine-2-carbothioamide hydrochloride (156 mg) were added to DMF (7 mL), and Et3N (385 μL) was added dropwise to the reaction mixture to obtain a homogeneous solution. The reaction mixture was stirred at room temperature for 14 hours and quenched with water (100 mL). The reaction mixture was extracted with dichloromethane (3 × 30 mL), the organic phase was washed with brine, and dried over Na2SO4. A yellow oil was obtained by solvent evaporation under vacuum, and this was purified by reverse-phase HPLC (gradient MeCN / H2O 25 min 45 / 55~95 / 5, 90 ml / min). 300 mg of compound 5 (73%) was obtained. The characterization is detailed in Table 1b.

[0140] Similar processes were performed using intermediate compounds 21-24, 26-32, 35, and 36 to obtain compounds 1-4, 6-12, 15, and 16. The characterization of the obtained compounds is shown in Table 1b.

[0141] [Example 5: Synthesis of Compounds 13, 14, and 17] [Compound 17]: (2S,4S)-2-carbamoticoyl-4-hydroxy-N-(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridine-4-yl)thiazole-2-yl)pyrrolidine-1-carboxamide [ka]

[0142] Compound 47 is obtained from intermediate compound 37 and 4-methyl-5-[2-(2,2,2-trifluoro-1,1-dimethylethyl)-4-pyridinyl]-2-thiazoleamine, as detailed in Example 4 above.

[0143] Compound 47 (210 mg) was dissolved in THF (5 mL), and TBAF (1 M in THF, 2.5 mL) was added. The solution was stirred at room temperature for 14 hours, and water (45 mL) was added. The reaction mixture was extracted with dichloromethane (3 × 25 mL), the organic phase was washed with brine, and dried over Na₂SO₄. The yellow oil was purified by preparative reverse-phase HPLC (gradient MeCN / H₂O, 45 / 55 to 95 / 5 over 25 minutes, 90 ml / min) to obtain 75 mg of compound 17 (75 mg). The characterization is detailed in Table 1b.

[0144] Similar processes were carried out using intermediate compounds 33 and 34 to obtain compounds 13 and 14. The characterization of the obtained compounds is shown in Table 1b.

[0145] [Example 6: Synthesis of compounds (18), (19), and (20)] 6.1 Synthesis of 5-(2-(tert-butyl)pyridine-4-yl)-4-methylthiazole-2-amine [ka]

[0146] Step (a): Synthesis of 2-tert-butyl-4-methylpyridine [ka]

[0147] CuCN (3.22 g, 36 mmol, 4 equivalents, dried at 140°C for 3 hours) and anhydrous THF (90 ml) were introduced into a 250 ml Schlenk flask that had been dried and flushed with argon. The mixture was cooled to -78°C, and 72 ml of tBuMgCl (1 M in THF, 8 equivalents) was added dropwise. The mixture was then stirred at -78°C for 20 minutes, after which 2-bromo-4-methylpyridine (1.55 g, 9 mmol, 1.0 equivalent) was added. The reaction mixture was stirred at -78°C for 3 hours, and then warmed to room temperature over 12 hours. The resulting mixture was quenched with saturated NH4OH aqueous solution (40 ml), and the pH was adjusted to 10 with 1 M NaOH aqueous solution (55 ml). After filtration through Celite, the resulting solution was extracted with Et2O (75 ml x 3). The combined organic layers were dried over MgSO4, and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography using silica gel (cyclohexane / Â1=9 / 1 v / v) to obtain the corresponding product as yellow oil (0.66 g, yield 49%). R f 0.35(Cyclo / AcOEt 9 / 1); 1 H NMR (500MHz, DMSO) δ8.35(d,J=4.9Hz,1H), 7.29-7.16(m,1H), 7.07-6.91(m,1H), 2.29(s,3H), 1.28(s,9H). 13 C NMR (126MHz, DMSO) δ168.7, 148.5, 147.2, 122.2, 120.1, 37.5, 30.5, 21.2.

[0148] Step (b): Synthesis of 1-(2-tert-butylpyridine-4-yl)propan-2-one [ka]

[0149] Into a dried and argon-flushed 25 mL three-neck flask, the freshly prepared LDA solution (6.63 mmol in 4 mL of anhydrous THF, 1.5 equivalents) was introduced. The mixture was cooled to -15 °C, and a solution of 2-tert-butyl-4-methylpyridine (0.66 g, 4.42 mmol, 1 equivalent) in 4 mL of anhydrous THF was added dropwise. Then, the mixture was stirred at -15 °C for 30 minutes, and N-methoxy-N-methylacetamide (0.524 g, 5.09 mmol, 1.15 equivalents) in 3 mL of anhydrous THF was added dropwise. After stirring the reaction at -15 °C for 1 hour 30 minutes, it was transferred to 0 °C onto a mixture of 5 mL of 1.5 M aqueous sulfuric acid and 20 mL of toluene. The biphasic mixture was vigorously stirred at 0 °C for 25 minutes. Before phase separation, the pH was adjusted to 7 using saturated aqueous NaHCO3. The aqueous phase was extracted with DCM (50 mL × 2), and the combined organic phases were dried over MgSO4. The solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (cyclohexane / EtOAc 75 / 25 v / v) to obtain the corresponding product as a yellow oil (0.5 g, 59% yield): R f 0.22 (Cyclo / AcOEt 75 / 25); 1 1H NMR (500 MHz, DMSO) δ 8.41 (dd, J = 4.9, 0.5 Hz, 1H), 7.23 (d, J = 0.5 Hz, 1H), 7.00 (dd, J = 4.9, 1.5 Hz, 1H), 3.83 (s, 2H), 2.17 (s, 3H), 1.29 (s, 9H). 13 13C NMR (126 MHz, DMSO) δ 205.4, 168.7, 148.5, 144.3, 122.8, 120.7, 49.3, 37.6, 30.5, 30.3.

[0150] Step (c): Synthesis of 5-(2-(tert-butyl)pyridin-4-yl)-4-methylthiazol-2-amine

Chemical Structure

[0151] To a solution of 1-(2-tert-butylpyridine-4-yl)propan-2-one (0.5 g, 2.61 mmol, 1 equivalent) in 7.5 ml of anhydrous ethanol, thiourea (0.22 g, 2.87 mmol, 1.1 equivalents) was added. The mixture was stirred at 40°C, and a clear mixture was obtained after 10 minutes. N-bromosuccinimide (0.47 g, 2.64 mmol, 1.01 equivalents) was added in the specified amount. After complete addition, the resulting red clear solution was stirred at 40°C for 1 hour, the mixture was diluted with isopropyl acetate (10 ml), and the yellow-orange suspension was cooled to 0°C over 1.5 hours. After filtration, the fine precipitate was solubilized in 50 ml of DCM / MeOH 9 / 1 v / v. The organic phase was washed with saturated aqueous solutions of NaHCO3 (25 ml x 2) and saturated aqueous solution of NaCl (25 ml x 1), and dried on MgSO4. The solvent was removed under reduced pressure, and the product was used in the next step without purification (0.4 g, yield 62%). R f 0.73 (DCM / MeOH 9 / 1); 1 H NMR (500MHz, DMSO) δ8.45-8.40(m,1H), 7.27-7.17(m,3H), 7.09(dd,J=5.2,1.7Hz,1H), 2.29(s,3H), 1.32(s,9H). 13 C NMR (126MHz, DMSO) δ168.7, 166.7, 148.7, 146.9, 140.8, 118.8, 116.5, 115.4, 37.1, 29.9, 16.9.

[0152] 6.2. Synthesis of Compound 18 Compound 18 was synthesized using the process described above in Example 4, except that 5-(2-(tert-butyl)pyridine-4-yl)-4-methylthiazole-2-amine and intermediate 25, obtained as described above, were used as starting materials. The characterization is detailed in Table 1b.

[0153] Similar processes were carried out using compound D and intermediate compounds 23 and 36 to obtain compounds 19 and 20. The characterization of the obtained compounds is shown in Table 1b.

[0154] [Example 7: PI3K-inhibitory activity] The inhibitory activity of compounds against human PtdIns(4,5)P3 kinase activity was quantified using an enzyme HTRF (homogeneous time-resolved fluorescence) assay.

[0155] PI3K p110a / p65a(h) is incubated in assay buffer containing 10 μM phosphatidylinositol 4,5-bisphosphate and Mg / ATP (required concentration). The reaction is initiated by adding ATP solution. After incubation at room temperature for 30 minutes, the reaction is stopped by adding a stop solution containing EDTA and biotinylated phosphatidylinositol-3,4,5-trisphosphate. Finally, a detection buffer containing europium-labeled anti-GST monoclonal antibody, GST-tagged GRP1 PH domain, and streptavidin allophycocyanin is added. The plate is then read in time-resolved fluorescence mode, and the homogeneous time-resolved fluorescence (HTRF) signal is determined according to the formula HTRF = 10000 × (Em665 nm / Em620 nm).

[0156] [result] The compounds under test were classified as follows according to their IC50 values: A: IC50 activity of 50 nM or less; B: IC50 strictly between 50nM and 200nM; C: IC50 strictly between 200nM and 500nM; D: IC50 strictly between 500nM and 1000nM; E: IC50 that is strictly over 1 μM.

[0157] [Table 3]

[0158] Therefore, it is clear that the compounds of formula (I) under test according to the present invention are potent inhibitors of PI3K kinase, and in particular PI3K-α kinase. Most of the compounds further exhibit selective inhibitory activity against PI3K-α kinase with respect to PI3K-β and / or PI3K-γ and / or PI3K-δ.

[0159] Therefore, the compound of formula (I) can be used for pharmaceuticals, particularly for the prevention and / or treatment of protein tyrosine kinase-mediated diseases, especially PI3K-mediated diseases, and more particularly for diseases mediated by the isoform alpha of PI3K.

[0160] Accordingly, another aspect of the present invention relates to a compound of formula (I) as defined above, or a deuterated or tritiated form of a compound of formula (I), or a pharmaceutically acceptable salt thereof, in particular to at least one of compounds (1) to (20), for use as a pharmaceutical.

[0161] In particular, the compound of formula (I) may be used in the treatment and / or prevention of pathologies mediated by the activation of protein tyrosine kinases, especially PI3K, and especially PI3K alpha.

[0162] Accordingly, the present invention relates, according to another aspect thereof, to a compound of formula (I) for use in the treatment and / or prevention of protein tyrosine kinase-mediated diseases, in particular PI3K-mediated diseases, more particularly PI3K alpha-mediated diseases, or to a deuterated or tritiated form of a compound of formula (I), or to any pharmaceutically acceptable salt thereof.

[0163] Another aspect of the present disclosure relates to the use of any one of the compounds of formula (I), or a deuterated or tritiated form of the compounds of formula (I), or a pharmaceutically acceptable salt thereof, for the treatment and / or prevention of protein tyrosine kinase-mediated diseases, in particular PI3K-mediated diseases, and more particularly PI3K alpha-mediated diseases.

[0164] Another aspect of the present disclosure relates to the use of any one of the compounds of formula (I), or the deuterated or tritiated forms of the compounds of formula (I), or a pharmaceutically acceptable salt thereof, for the purpose of preparing / manufacturing compositions such as medical products for the treatment and / or prevention of protein tyrosine kinase-mediated diseases, in particular PI3K-mediated diseases, and more particularly PI3K alpha-mediated diseases.

[0165] Also described are methods for treating and / or preventing protein tyrosine kinase-mediated diseases, particularly PI3K-mediated diseases, and more specifically, PI3K alpha-mediated diseases.

[0166] The methods and uses defined above may include administering to a subject in need a therapeutically effective amount of the compound of formula (I), or a deuterated or tritiated form of the compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same.

[0167] The protein tyrosine kinase-mediated diseases targeted by the uses and methods of the present invention may more particularly include PI3K-related overgrowth spectrum (PROS), proliferative disorders, especially cancer, and inflammatory diseases, including autoimmune disorders, as detailed below.

[0168] The protein tyrosine kinase-mediated diseases targeted by the uses and methods of the present invention may, more particularly, be mitochondrial gene disorders.

[0169] The protein tyrosine kinase-mediated diseases targeted by the uses and methods of the present invention may be more particularly selected from the group consisting of keloids, hypertrophic scars including burn scars, and hyperpigmentation disorders.

[0170] More particularly, the protein tyrosine kinase-mediated diseases, especially phosphatidylinositol 3-kinase-mediated diseases, targeted by the uses and methods of the present invention are selected from the group consisting of PI3K-related hypergrowth spectrum (PROS); neurofibromatosis; mitochondrial genetic disorders; keloids; hypertrophic scars, including burn scars; hyperpigmentation disorders; proliferative disorders, particularly cancer; inflammatory diseases, including autoimmune disorders; and glomerulonephritis, and more particularly from the group consisting of keloids; hypertrophic scars, including burn scars; and hyperpigmentation disorders.

[0171] [PI3K-related overgrowth spectrum] The phosphatidylinositol 3 kinase-related hypergrowth spectrum is a group of disorders that include, non-limitingly, fibroadipose hypergrowth (FAO), megacephaly-capillary malformation (MCAP) syndrome, asymmetrical hypergrowth of congenital lipomas of the trunk, lymphatic, capillary, venous, and complex vascular malformations, epidermal nevi, skeletal and spinal anomalies (CLOVES) syndrome, unilateral hypertrophic multiple lipomatosis (HHML), Klippel-Trenaunay syndrome, isolated and complex venous malformations, isolated and complex lymphatic malformations, or mixed complex vascular malformations (e.g., Venot Q. et al., Nature 2018 Jun;558(7711):540~546; Canaud G. et al., Orphanet J Rare Dis. 2021 Jul 8;16(1):306; Morin G, Canaud G., Br Med Bull. 2021 Dec See 16;140(1):36~49;Delestre F. et al., Sci Transl Med. 2021. Oct 6;13(614); and Morin G. et al., J Exp Med. 2022 Mar 7;219(3):e20212148).

[0172] Fibroadipose overgrowth (FAO) is a syndrome characterized by segmental, progressive overgrowth of subcutaneous, muscular, and visceral fibroadipose tissue, often accompanied by skeletal overgrowth.

[0173] Megalenosis-Capillary Malformation (MCAP) syndrome is characterized by (1) megalenosis (MEG) or hemimegalencephaly (HMEG) associated with neurological findings such as hypotension, seizures, and mild to severe intellectual disability; and (2) capillary malformations of the skin with focal or systemic somatic cell overgrowth.

[0174] CLOVES is associated with congenital, lipomatous, overgrowth, vascular malformations, epidermal nevi, and spinal / skeletal abnormalities and / or scoliosis. The syndrome is characterized by a combination of lipomatous tissue showing complex congenital overgrowth (typically presenting as lipomatous masses of the trunk), as well as vascular and lymphatic malformations.

[0175] Hemiplegia multiple lipomatosis (HHML) is a physical condition characterized by asymmetrical, non-progressive overgrowth, multiple lipomas, and superficial vascular malformations.

[0176] Klippel-Trenaunay syndrome is a rare congenital medical condition in which blood vessels and / or lymphatic vessels are not properly formed.

[0177] According to one embodiment, patients to be treated may have PIK3CA mutations, particularly PIK3CA mutations selected from the group including H1047R mutations, C420R mutations, H1047L mutations, E542K mutations, E545K mutations, and / or Q546R mutations.

[0178] [Neurofibromatosis] Neurofibromatosis is a rare genetic disorder that typically causes benign tumors on or just beneath the skin, within nerves near the spinal cord, and along nerves in other parts of the body. There are three types of neurofibromatosis: neurofibromatosis type 1 (NF1), neurofibromatosis type 2 (NF2), and schwann cell tumor. Neurofibromatosis type 1 (NF1) is caused by a mutation in the NF1 gene that leads to the production of a dysfunctional version of neurofibromin that cannot regulate cell growth and division. As a result, tumors such as neurofibromas can form along nerves throughout the body. NF1 is an autosomal dominant disorder. Neurofibromatosis type 2 (NF2) is caused by a mutation in the NF2 gene. NF2 is also known as MISME syndrome, for multiple hereditary schwann cell tumors, meningiomas, and ependymoma. The signs and symptoms of NF2 are usually the result of the development of benign, slowly growing tumors (acoustic neuromas) in both ears. These tumors, also called vestibular schwannomas, grow on the nerves that transmit auditory and balance information from the inner ear to the brain. Schwann cell tumors develop on the cranial nerve, spinal nerve, and peripheral nerve, but not on the nerves that transmit auditory and balance information from the inner ear to the brain. For more information on neurofibromatosis, see International Publication No. 2020 / 053125.

[0179] [Keloids, hypertrophic scars, hyperpigmentation disorders] For information regarding the use of PI3K inhibitors in the treatment of these disorders, see, for example, International Publication No. 2020 / 201073. Similarly, see Mari W. et al., (J Am Coll Clin Wound Spec. 2016 Nov 30;7(1~3):1~7).

[0180] Normally, scars have clearly defined boundaries. However, under certain conditions, fibroblasts and myofibroblasts overproduce collagen (types I and III), leading to hypertrophic scars. These hypertrophic scars are confined to the original wound area. Importantly, under certain circumstances, scars can grow outward from the original injury area and infiltrate adjacent dermal tissue due to overproduction of the extracellular matrix, particularly collagen (types I and III), caused by the overexpression of cytokines and growth factors. These scars are called keloids.

[0181] As used herein, the term "keloid" refers to the excessive accumulation of extracellular matrix proteins that lead to the over-formation of collagen. In genetically susceptible individuals, abnormal skin scarring may occur after injury. As used herein, the term "keloid scar" refers to an excessive scar in which dense fibrous tissue extends beyond the boundary of the original wound or incision and does not usually regress spontaneously.

[0182] As used herein, the term “hypertrophic scar” refers to the hypertrophic growth of dense fibrous tissue that results from abnormal wound healing. In contrast to keloids, hypertrophic scars do not extend beyond the original boundaries of the wound. Also, unlike keloids, hypertrophic scars typically reach a certain size and then stabilize or regress. Hypertrophic scars include hypertrophic burn scars, which are the most common complication of burns.

[0183] As used herein, the terms “hyperpigmentation disorder” or “skin disorder due to hyperpigmentation” are used interchangeably and refer to the darkening of areas of skin or nails caused by an increase in melanin. Hyperpigmentation is the result of one of two conditions: (1) melanin is produced due to an abnormally high concentration of melanocytes, or (2) melanocytes are overactive. Hyperpigmentation disorders can affect any part of the body, including the face, hands, and neck. Hyperpigmentation disorders are selected from the group that includes, and more specifically, the group consisting of, solar lentigines, melasma, freckles, age spots, post-acne hyperpigmentation, and post-inflammatory hyperpigmentation.

[0184] "Lentils" or "solar lentigines," also called sun-induced freckles or senile lentigines, are dark (hyperpigmented) lesions caused by natural or artificial ultraviolet (UV) light. The term "melasma" is also known as pregnancy melasma. It is also known as pregnancy mask or cloasma. In melasma, the pigmentation is generally symmetrical and has clearly defined edges. The term "freckles" usually refers to flat, circular spots that are yellowish-brown or light brown. Freckles are a very common type of hyperpigmentation, but are more common in people with lighter skin tones. The term "spots" refers to brown, reddish-brown, or black spots. Spots are oval-shaped and vary in size from the size of freckles to over 13 mm. Also called reverse spots, they tend to appear on the face or in areas exposed to sunlight after the age of 40. The term "post-acne hyperpigmentation" refers to spots caused by acne. In some ethnic groups, this may be present in over 60% of acne cases. In most cases, dark pigmented spots result from excessive melanin production in response to inflammation of the skin in the affected area. Without proper treatment, post-acne hyperpigmentation can take months or even years to gradually disappear. The term "post-inflammatory hyperpigmentation" refers to spots caused by skin damage or inflammation, in which pigment production increases.

[0185] [cancer] As defined above, the compound of formula (I), or the deuterated or tritiated form of the compound of formula (I), or a pharmaceutically acceptable salt thereof, may be useful in the treatment or prevention of various cancers.

[0186] In particular, the compound of formula (I) may be used as an anticancer agent, especially for applications in the treatment of cancer, as detailed below.

[0187] Cancers that can be classified include: blood-related cancers, pancreatic cancer, urinary tract cancers, bladder cancer, colorectal cancer, colon cancer, breast cancer, prostate cancer, kidney cancer, hepatocellular carcinoma, thyroid cancer, gallbladder cancer, kidney cancer, liver cancer, lung cancer (e.g., non-small cell lung cancer and small cell lung cancer), ovarian cancer, cervical cancer, stomach cancer, endometrial cancer, esophageal cancer, head and neck cancer (e.g., head and neck squamous cell carcinoma (HNSCC)), melanoma, neuroendocrine cancer, and central nervous system cancers. Cancers of the nervous system, brain cancers such as glioma, glioblastoma, anaplastic oligodendroglioma, anaplastic astrocytoma, bone cancer, hematological cancers such as leukemia, lymphoma, myeloma, soft tissue sarcoma, retinoblastoma, neuroblastoma, ascites, malignant pleural effusion, mesothelioma, Wilms' tumor, trophoblastic tumor, hemangiopericytoma, Kaposi's sarcoma, mucinous carcinoma, round cell carcinoma, squamous cell carcinoma, esophageal squamous cell carcinoma, oral cancer, adrenocortical carcinoma, or ACTH-producing tumors.

[0188] According to one embodiment, the following cancers may be listed: bladder cancer, breast cancer, lung cancer, e.g., non-small cell lung cancer and small cell lung cancer, ovarian cancer, cervical cancer, kidney cancer, liver cancer, head and neck cancer, e.g., squamous cell carcinoma of the head and neck (HNSCC), sarcoma, brain cancer, e.g., glioma, glioblastoma, anaplastic oligodendroglioma, and anaplastic astrocytoma, or hematological cancers, e.g., leukemia, lymphoma, myeloma.

[0189] According to another embodiment, cancers include head and neck cancer, head and neck squamous cell carcinoma, cervical squamous cell carcinoma, acute lymphoblastic leukemia (ALL) in adults or children, acute myeloid leukemia (AML) in adults or children, acute lymphoblastic leukemia, glioa astrocytoma, B-cell or NK / T-cell lymphoma, cholangiocarcinoma, bladder cancer, brain and spinal cord tumors in adults, brain and spinal cord tumors in children, anaplastic astrocytoma, breast cancer in women, breast cancer in young women, breast cancer in men, recurrent breast cancer, hereditary breast cancer, HER2-positive breast cancer, breast cancer with lymph node metastasis, ER-alpha-positive breast cancer, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), chronic myelomonocytic leukemia (CMML), epithelial ovarian cancer, epithelial ovarian cancer with metastasis. The following may be selected from cancer, Ewing's sarcoma, Ewing's family tumors, lymphoblastic leukemia (ALL), ocular cancer, e.g., ocular melanoma and lymphoma, gestational trophoblastic disease, glioblastoma, glioblastoma multiforme (GBM), hairy cell leukemia, glioma, high-grade glioma, hepatocellular carcinoma, intrahepatic cholangiocarcinoma, invasive ductal carcinoma, Hodgkin's lymphoma, Kaposi's sarcoma, leiomyosarcoma, leukemia, childhood leukemia, pulmonary carcinoid tumors, lymphoma, cutaneous lymphoma, mantle cell lymphoma, medulloblastoma, melanoma, melanoma, malignant melanoma, neuroblastoma, neuroglioma, non-Hodgkin's lymphoma, childhood non-Hodgkin's lymphoma, non-small cell lung cancer, gefitinib-resistant non-small cell lung cancer, osteosarcoma, metastatic osteosarcoma, or lymphoproliferation.

[0190] Lymphoproliferative disorders, or lymphoproliferative disorders (LPDs), refer to a heterogeneous group of diseases characterized by uncontrolled production of lymphocytes, leading to monoclonal lymphocytosis, lymphadenopathy, and bone marrow infiltration. These diseases are more common in immunocompromised individuals. Lymphocytes consist of two subsets: T cells and B cells, which regenerate uncontrollably, leading to immunoproliferative disorders that can cause immunodeficiency, immune system dysfunction, and lymphocyte dysregulation.

[0191] In certain embodiments, the lymphoproliferative disorder is a B-cell lymphoproliferative disorder.

[0192] In certain embodiments, B lymphoproliferative disorders are selected from the group consisting of, but not limited to, Hodgkin's lymphoma, diffuse large B-cell lymphoma, acute lymphoblastic leukemia, lymphoblastic chromomeyeloid leukemia, chronic lymphocytic leukemia / small lymphocytic lymphoma, extranodal marginal zone B-cell lymphoma, mucosa-associated lymphoid tissue lymphoma, follicular lymphoma, mantle cell lymphoma, nodal marginal zone B-cell lymphoma, Burkitt's lymphoma, hairy cell leukemia, primary central nervous system lymphoma, splenic marginal zone B-cell lymphoma, Waldenstrom macroglobulinemia / lymphoplasmacytic lymphoma, multiple myeloma, formation cell disease, plasmacytoma, primary mediastinal B-cell lymphoma, Hodgkin's disease, or Kastelmann's disease.

[0193] In certain embodiments, lymphoproliferative disorder is T-cell lymphoproliferative disorder.

[0194] In certain embodiments, T lymphoproliferative disorders are selected from the group consisting of, without limitation: leukemia / lymphoma, extranodal natural killer / T-cell lymphoma, cutaneous T-cell lymphoma, enteropathy-type T-cell lymphoma, angioimmunoblastic T-cell lymphoma, anaplastic large T / null cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, T-cell acute lymphoblastic leukemia, T-cell large granular lymphocyte leukemia, lymphocytic blast-stage chromomeyeloid leukemia, post-transplant lymphoproliferative syndrome, human T-cell leukemia virus type 1 positive (HTLV-G) adult T-cell leukemia / lymphoma (ATL), T-cell prelymphocytic leukemia (TPLL), or unspecified T-cell lymphoma.

[0195] According to one embodiment, the patient does not exhibit clinically detectable metastases, in particular, the patient has a precancerous condition, early-stage cancer, or non-metastatic cancer, or the patient exhibits clinically detectable metastases, and none of the compounds of formula (I) as defined above, or the deuterated or tritiated forms of the compounds of formula (I), or any pharmaceutically acceptable salt thereof, directly target metastatic invasion.

[0196] [Glomerulonephritis] Glomerulonephritis is a group of kidney diseases characterized by immune-mediated damage to the basement membrane, mesangia, or capillary endothelium, leading to hematuria, proteinuria, and azotemia, which involve damage to the glomeruli.

[0197] The glomerulonephritis according to the present invention may be particularly proliferative or non-proliferative.

[0198] Nonproliferative glomerulonephritis is characterized by a lack of glomerular cell proliferation and typically presents as nephrotic syndrome.

[0199] Proliferative glomerulonephritis (PGN) refers to increased glomerular cellularity resulting from specific glomerular cell proliferation, leukocyte infiltration, or both. This primarily occurs under conditions of glomerular deposition of immunoglobulins, immune complexes, or complement components. Various subtypes are described based on histological features such as mesangial cell proliferation, intracapillary proliferation, diffuse proliferation, or extracapillary proliferation (also known as crescentic glomerulonephritis).

[0200] Proliferative glomerulonephritis may be caused by a selection of diseases from the group consisting of: infections (post-streptococcal glomerulonephritis, infectious endocarditis, occult visceral sepsis, hepatitis B infection (with vasculitis and / or cryoglobulinemia), HIV infection, hepatitis C with cryoglobulinemia, membranoproliferative glomerulonephritis), and multi-organ diseases (systemic lupus erythematosus, IgA nephropathy, Henoch-Schönlein purpura, systemic necrotizing vasculitis (including granulomatosis with Wegener's polyangiitis, Goodpasture syndrome, essential mixed cryoglobulinemia, malignant tumors, relapsing polychondritis, rheumatoid arthritis)).

[0201] In certain embodiments, proliferative glomerulonephritis is caused by systemic lupus erythematosus. As used herein, the term “systemic lupus erythematosus (SLE)” refers to a systemic autoimmune disease thought to manifest as widespread immunomodulatory abnormalities. This is the most common type of lupus.

[0202] Proliferative glomerulonephritis can be a form of lupus nephritis.

[0203] As used herein, the term “lupus nephritis” (LN) refers to inflammation of the kidneys caused by systemic lupus erythematosus (SLE). Up to 60% of lupus patients develop LN. When the kidneys become inflamed, they are unable to function properly to filter toxins, metabolites, excess salt, excess fluid, and other impurities from the blood. If left uncontrolled, LN can lead to kidney failure. Even with treatment, loss of kidney function can sometimes progress. If both kidneys stop functioning, LN patients may require dialysis. Ultimately, LN patients may need a kidney transplant. Symptoms of loss or abnormality of kidney function include increased urinary proteinuria, foamy urine, and / or elevated blood urea nitrogen (BUN) levels.

[0204] In certain embodiments, the subjects are individuals who have or are susceptible to an infectious disease (post-streptococcal glomerulonephritis, infectious endocarditis, occult visceral sepsis, hepatitis B infection (with vasculitis and / or cryoglobulinemia), HIV infection, hepatitis C (with cryoglobulinemia and membranoproliferative glomerulonephritis), or a multi-organ disease (systemic lupus erythematosus, IgA nephropathy, Henoch-Schönlein purpura, systemic necrotizing vasculitis (including granulomatosis with Wegener's polyangiitis, Goodpasture syndrome, essential mixed cryoglobulinemia, malignant tumors, relapsing polychondritis, and rheumatoid arthritis)).

[0205] [Mitochondrial genetic disorders] Mitochondrial genetic disorders refer to a group of clinically and genetically heterogeneous disorders resulting from mitochondrial dysfunction. Mitochondrial genetic disorders are caused by mutations in either mitochondrial DNA or nuclear DNA, which lead to mitochondrial dysfunction and improper energy production. Mitochondrial genetic disorders may be selected from the group consisting of, in particular, mitochondrial cell disorders; aminoglycoside-induced hearing loss; chronic progressive extraocular muscle palsy; depletion syndrome; Kearns-Sayre syndrome; Leber hereditary optic neuropathy; Leigh syndrome; cerebellar hypoplasia, mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like seizures (MELAS); myoclonus epilepsy and red ragged fibrillation; maternal Leigh syndrome; neurogenic hypomuscular atrophy, ataxia, and retinitis pigmentosa; Pearson syndrome; microcephaly, visual atrophy, lactic acidosis, optic nerve atrophy, spastic paraplegia, Friedreich's ataxia, sideroblastic anemia and ataxia, sideroblastic anemia, encephalomyopathy, renal tubulopathy, ataxia, hypertrophic cardiomyopathy (LS), and Alpers syndrome.

[0206] The compounds of formula (I) according to the present invention, or the deuterated or tritiated forms of the compounds of formula (I), or pharmaceutically acceptable salts thereof, are particularly suitable for use in the treatment and / or prevention of phosphatidylinositol 3 kinase-related hypergrowth spectrum (PROS), especially congenital PROS, lipidomatous, hypergrowth, vascular malformations, epidermal nevi, and spinal / skeletal abnormalities and / or scoliosis (CLOVES) syndrome.

[0207] The compounds of formula (I) according to the present invention, or deuterated or tritiated forms of the compounds of formula (I), or pharmaceutically acceptable salts thereof, are particularly suitable for use in the treatment and / or prevention of cancers, such as those listed above.

[0208] Also described herein is the use of compounds of formula (I), or deuterated or tritiated forms of compounds of formula (I), or pharmaceutically acceptable salts thereof, for the treatment and / or prevention of cancers, including the cancers listed above.

[0209] Compounds of formula (I), or deuterated or tritiated forms of compounds of formula (I), or pharmaceutically acceptable salts thereof may be used as monotherapy or in combination with other therapies selected from among chemotherapy, immunotherapy, radiotherapy, surgery, ultrasound, monoclonal antibodies, antitumor vaccines, RNA vaccines, cancer vaccines, magnetic particles, and intravascular microrobots.

[0210] Accordingly, another aspect of the present disclosure is a compound of formula (I), or a deuterated or tritiated form of a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use as an antitumor agent intended for patients also receiving treatment with any of the following: chemotherapy, immunotherapy, radiotherapy, surgery, ultrasound, monoclonal antibodies, antitumor vaccines, RNA vaccines, cancer vaccines, magnetic particles, or intravascular microrobots.

[0211] According to another aspect of the present invention, the present invention relates to a pharmaceutical product comprising a compound of formula (I), a deuterated or tritiated form of a compound of formula (I), or a pharmaceutically acceptable salt thereof.

[0212] Pharmaceuticals may be used therapeutically, for example, in the treatment and / or prevention of protein tyrosine kinase-mediated diseases, particularly PI3K-mediated diseases, more particularly PI3K-alpha-mediated diseases, and especially the diseases and physical conditions detailed above.

[0213] In another aspect, the present invention relates to a pharmaceutical composition comprising at least one compound of formula (I) as defined, or a deuterated or tritiated form of a compound of formula (I), or a pharmaceutically acceptable salt thereof, particularly at least one of compounds (1) to (20). These pharmaceutical compositions contain at least one compound of formula (I), or a deuterated or tritiated form of a compound of formula (I), or a pharmaceutically acceptable salt thereof, in a particularly effective dose.

[0214] The pharmaceutical compositions according to the present invention may contain one or more of the compounds of the present invention in any form described herein.

[0215] The compound can be administered through any mode of administration, such as topically, intramuscularly, intravenously, intranasally, subcutaneously, or orally, or as a suppository.

[0216] In one embodiment, the pharmaceutical composition according to the present invention is selected from among oral compositions; topical compositions; inhalation compositions; injectable compositions, particularly subcutaneous compositions, intramuscular compositions or intravenous compositions, suppositories, and oral, injectable or surgical sustained-release compositions.

[0217] The pharmaceutical composition of the present invention may also contain at least one pharmaceutically acceptable excipient.

[0218] The excipients are selected from common excipients known to those skilled in the art, depending on the formulation and the desired mode of administration. These may be selected from carriers, lubricants, diluents, excipients, stabilizers, and preservatives. Such additives are well known to those skilled in the art and are described in particular in "Ullmann's Encyclopedia of Industrial Chemistry, 6th Ed." (various editors, 1989-1998, Marcel Dekker) and "Pharmaceutical Dosage Forms and Drug Delivery Systems" (ANSEL et al., 1994, WILLIAMS & WILKINS).

[0219] The compounds of the present invention can be used as monotherapy or in combination with radiotherapy or chemotherapy. In one embodiment, the pharmaceutical composition of the present invention may further contain at least one other chemotherapeutic agent.

[0220] [Example 8: The compound of the present invention improves renal lesions in a lupus model] Compound 5 of the present invention was tested in the NZBWF1 / J mouse, an established model of lupus-like nephritis (Celhar, T. & Fairhurst, AM: Modeling clinical systemic lupus erythematosus: similarities, differences and success stories. Rheumatology (Oxford) 56, i88-i99 (2017)). NZBWF1 / J mice gradually develop immunogenic glomerulonephritis characterized by proteinuria and renal dysfunction, starting at approximately 25 weeks of age. Using a unilateral nephrectomy model, unilateral nephrectomy was performed on 12 female mice at 24 weeks of age.

[0221] Because the incidence and severity of symptoms are more pronounced in females, only female mice were used in this study. Mice were then randomly assigned to receive either a vehicle (n=6) or oral administration of compound 5 (50 mg / kg / day) for a duration of 4 weeks (n=6). At the end of the treatment period, the mice were sacrificed, and the histology of their kidneys was compared to samples obtained during unilateral nephrectomy.

[0222] At the time of unilateral nephrectomy, no distinguishable differences were observed between the two groups in terms of phenotypic characteristics, including proteinuria and kidney-to-body weight ratio. However, at the time of sacrifice, mice treated with compound 5 showed a significant reduction in albuminuria (Figure 1A) and serum urea nitrogen concentration (Figure 1B).

[0223] Furthermore, NZBWF1 / J mice that underwent unilateral nephrectomy and were administered compound 5 showed a significant decrease in kidney-to-body weight ratio. From a histological perspective, mice treated with compound 5 showed glomerular preservation compared to mice treated with the vehicle (Figure 1C). On the other hand, glomerular lesions worsened significantly in NZBWF1 / J mice that underwent unilateral nephrectomy and were treated with the vehicle, while they remained stable in the compound 5 group.

[0224] Collectively, these findings indicate that the compounds according to the present invention alleviate the lesions of glomerulonephritis, particularly lupus nephritis.

[0225] [Example 9: The compound of the present invention induces a gradual rise in blood glucose levels.] Eight-week-old C57Bl6 mice (n=6 per group, 3 males and 3 females) were treated daily for five consecutive days by forced oral administration with either the vehicle or compound 5 (50 mg / kg).

[0226] On the sixth day, blood glucose levels were measured at different points in time, before and after drug administration.

[0227] While currently available compounds are known to cause a peak in blood glucose levels approximately two hours after forced oral administration, compound 5 only induced a moderate rise in blood glucose. Multiple comparisons using standard one-way ANOVA showed significant differences at two hours.

[0228] [Example 10: The compound of the present invention does not increase blood insulin concentration.] Eight-week-old C57Bl6 mice (n=3 per group, 3 males) were treated daily for 5 consecutive days by forced oral administration with either the vehicle or compound 5 (50 mg / kg). On day 6, insulin concentrations were measured at different time points before and after drug administration.

[0229] Insulin levels were measured in plasma (7 μL duplicate) using an MSD u.plex (Mesoscale, catalog number 1526HK).

[0230] While currently available compounds are known to be associated with an insulin peak approximately 4 hours after forced oral administration, which can last up to 8 hours after drug administration, compound 5 did not induce any increase in blood insulin concentration (Figure 2).

Claims

1. Equation (I): 【Chemistry 1】 In the compound: - R １ However, unsubstituted or substituted with one or more fluorine atoms, (C １ ~C ６ ) alkyl group or (C ３ ~C ６ ) is a cycloalkyl group; - R ２ but: ■ Hydrogen atom, and ■ (C １ ~C ６ ) alkyl group, Selected from among; - m is 0, 1, or 2; - each R ３ when present, are each independently ■Fluorine atom, ■Unsubstituted or substituted with one or more halogen atoms, (C １ ~C ６ ) alkyl group, ■Unsubstituted or substituted with one or more halogen atoms, (C ３ ~C ６ ) Cycloalkyl groups, ■Hydroxy group, ■ (C １ ~C ６ ) Alkoxy groups, and ■ R and R' independently form hydrogen atoms and (C １ ~C ６ ) Selected from alkyl groups, -NRR' group, Selected from among these, Alternatively, two R atoms supported by the same carbon atom ３ However, along with the carbon atoms supporting them, they are substituted with unsubstituted or one or more fluorine atoms, (C ３ ~C ６ ) Forms a cycloalkyl ring, - R ４ teeth: ■Fluorine atom, ■Hydrogen atom, ■Unsubstituted or substituted with one or more halogen atoms, (C １ ~C ６ ) alkyl groups, and, ■Unsubstituted or substituted with one or more halogen atoms, (C ３ ~C ６ ) Selected from cycloalkyl groups, Alternatively, R ３ and R ４ However, if supported by two adjacent carbon atoms, they may be supported together with the supporting carbon atoms, either unsubstituted or substituted with one or more halogen atoms, (C ３ ~C ６ ) Forms a cycloalkyl ring, A compound of formula (I), or a deuterated or tritiated form of a compound of formula (I), or a pharmaceutically acceptable salt thereof.

2. R １ However, unsubstituted or substituted with one or more fluorine atoms, (C １ ~C ６ ) Alkyl alkyl groups, especially (C １ ~C ４ A compound of formula (I) according to claim 1, wherein the alkyl group and more particularly a tert-butyl group, or a deuterated or tritiated form of a compound of formula (I), or a pharmaceutically acceptable salt thereof.

3. R ２ But (C １ ~C ６ ) Alkyl alkyl groups, especially (C １ ~C ４ A compound of formula (I) according to claim 1 or 2, wherein the alkyl group, and more particularly, a methyl group, or a deuterated or tritiated form of a compound of formula (I), or a pharmaceutically acceptable salt thereof.

4. m is 1 or 2, and each R ３ Independently: ■Fluorine atom, ■Unsubstituted or substituted with one or more halogen atoms, (C １ ~C ６ ) Alkyl alkyl groups, especially (C １ ~C ４ ) Alkyl groups, and more particularly methyl groups; for example, methyl groups or trifluoromethyl groups, ■ Hydroxyl group, and ■ (C １ ~C ６ ) Alkoxy groups, especially (C １ ~C ４ ) Alkoxy groups, and more particularly methoxy groups; Will it be selected from among them? Alternatively, m is 2, and two Rs are supported by the same carbon atom. ３ However, along with the carbon atoms supporting them, they are substituted with unsubstituted or one or more fluorine atoms, (C ３ ~C ６ A compound of formula (I) according to any one of claims 1 to 3, which forms a cycloalkyl ring, particularly a cyclopropyl ring, or a deuterated or tritiated form of a compound of formula (I), or a pharmaceutically acceptable salt thereof.

5. R ４ but: ■ Hydrogen atom, and ■Unsubstituted or one or more halogen atoms, in particular substituted with one or more fluorine atoms, (C １ ~C ６ ) Alkyl alkyl groups, especially (C １ ~C ４ ) Alkyl groups, and more particularly methyl groups, Selected from among A compound of formula (I) according to any one of claims 1 to 4, or a deuterated or tritiated form of a compound of formula (I), or a pharmaceutically acceptable salt thereof.

6. The following compounds: (1) (S)-2-carbamotioyl-4,4-difluoro-N-(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridine-4-yl)thiazole-2-yl)pyrrolidine-1-carboxamide, (2) (2S,4R)-2-carbamotioyl-4-fluoro-N-(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridine-4-yl)thiazole-2-yl)pyrrolidine-1-carboxamide, (3) (2S,4S)-2-carbamotioyl-4-fluoro-N-(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridine-4-yl)thiazole-2-yl)pyrrolidine-1-carboxamide, (4) (S)-6-carbamotioyl-N-(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropane-2-yl)pyridine-4-yl)thiazole-2-yl)-1,1-difluoro-5-azaspiro[2,4]heptan-5-carboxamide, (5) (S)-2-carbamotioyl-N-(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridine-4-yl)thiazole-2-yl)pyrrolidine-1-carboxamide, (6) (S)-2-carbamoteoyl-2-methyl-N-(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridine-4-yl)thiazole-2-yl)pyrrolidine-1-carboxamide, (7) (2S,4R)-2-carbamoteoyl-4-methoxy-N-(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridine-4-yl)thiazole-2-yl)pyrrolidine-1-carboxamide, (8) (2S,4S)-2-carbamotioyl-4-methoxy-N-(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridine-4-yl)thiazole-2-yl)pyrrolidine-1-carboxamide, (9) (2S,5R)-2-carbamoteoyl-5-methyl-N-(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropane-2-yl)pyridine-4-yl)thiazole-2-yl)pyrrolidine-1-carboxamide, (10) (2S,5S)-2-carbamoteoyl-5-methyl-N-(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropane-2-yl)pyridine-4-yl)thiazole-2-yl)pyrrolidine-1-carboxamide, (11) (2S,4S)-2-carbamoteoyl-4-methyl-N-(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropane-2-yl)pyridine-4-yl)thiazole-2-yl)pyrrolidine-1-carboxamide, (12) (2S,4S)-2-carbamotioyl-N-(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropane-2-yl)pyridine-4-yl)thiazole-2-yl)-4-(trifluoromethyl)pyrrolidine-1-carboxamide, (13) (2S,4R)-2-carbamoteoyl-4-hydroxy-N-(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropane-2-yl)pyridine-4-yl)thiazole-2-yl)pyrrolidine-1-carboxamide, (14) (2S,3S)-2-carbamoteoyl-3-hydroxy-N-(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropane-2-yl)pyridine-4-yl)thiazole-2-yl)pyrrolidine-1-carboxamide, (15) (2S,3S)-2-carbamoteoyl-3-methoxy-N-(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropane-2-yl)pyridine-4-yl)thiazole-2-yl)pyrrolidine-1-carboxamide, (16) (S)-6-carbamotioyl-N-(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropane-2-yl)pyridine-4-yl)thiazole-2-yl)-5-azaspiro[2,4]heptan-5-carboxamide, (17) (2S,4S)-2-carbamoteoyl-4-hydroxy-N-(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropane-2-yl)pyridine-4-yl)thiazole-2-yl)pyrrolidine-1-carboxamide; (18) (S)-2-carbamotioyl-N-(4-methyl-5-(2-tert-butylpyridine-4-yl)thiazole-2-yl)pyrrolidine-1-carboxamide, (19) (2S,4S)-2-carbamotioyl-4-fluoro-N-(4-methyl-5-(2-tert-butylpyridine-4-yl)thiazole-2-yl)pyrrolidine-1-carboxamide, and (20) (S)-6-carbamotioyl-N-(4-methyl-5-(2-tert-butylpyridine-4-yl)thiazole-2-yl)-5-azaspiro[2.4]heptan-5-carboxamide, A compound of formula (I) according to any one of claims 1 to 5, selected from among the above, or a deuterated or tritiated form of a compound of formula (I), or a pharmaceutically acceptable salt thereof.

7. Compound of formula (II-A) and compound of formula (II-B): 【Chemistry 2】 A method for preparing a compound of formula (I) according to any one of claims 1 to 6, or a deuterated or tritiated form of a compound of formula (I), or a pharmaceutically acceptable salt thereof, comprising a coupling reaction between the following: In the formula, R ３ , R ４ , m, R ２ and R １ R ３ If it is a hydroxyl group, then R ３ The compound II-A is protected in compound II-A with, for example, a tert-butyldiphenylsilyl ether (tBDPS) protecting group before the coupling reaction, and deprotection is performed after the coupling reaction, provided that the compound is as described in any one of claims 1 to 5. Here, the coupling reaction is preferably carried out at room temperature using triethylamine in a polar aprotic organic solvent such as dimethylformamide; The coupling reaction may optionally be preceded by a step to obtain compound II-A. Here, equation (I - A) 【Transformation 3】 The compound is R in the formula. ３ , R ４ and m is as defined in any one of claims 1, 4, and 5, or R ３ Assuming that the hydroxyl group is protected, for example, a hydroxyl group protected with a tert-butyldiphenylsilyl ether (tBDPS) protecting group, it is converted to compound II-A by a deprotection step, for example, with an aqueous solution of HCl; The coupling reaction may optionally be preceded by a step to obtain compound II-B. Here, equation (I - B) 【Chemistry 4】 The compound is R １ and R ２ As defined in any one of claims 1 to 3, the compound II-B is converted by reaction with 1,1'-carbonyldiimidazole in an organic solvent such as methylene chloride. method.

8. The following compounds: (21) tert-butyl(S)-2-carbamotioyl-4,4-difluoropyrrolidine-1-carboxylate; (23) tert-butyl(2S,4S)-2-carbamotioyl-4-fluoropyrrolidine-1-carboxylate, (24) tert-butyl(6S)-6-carbamotioyl-1,1-difluoro-5-azaspiro[2.4]heptane-5-carboxylate, (26) tert-butyl(S)-2-carbamoteoyl-2-methylpyrrolidine-1-carboxylate, (28) tert-butyl(2S,4S)-2-carbamoteoyl-4-methoxypyrrolidine-1-carboxylate, (29) tert-butyl(2S,5R)-2-carbamoteoyl-5-methylpyrrolidine-1-carboxylate, (30) tert-butyl(2S,5S)-2-carbamoteoyl-5-methylpyrrolidine-1-carboxylate, (31) tert-butyl(2S,4S)-2-carbamoteoyl-4-methylpyrrolidine-1-carboxylate, (32) tert-butyl(2S,4S)-2-carbamoteoyl-4-(trifluoromethyl)pyrrolidine-1-carboxylate, (34) tert-butyl(2S,3S)-3-((tert-butyldiphenylsilyl)oxy)-2-carbamyoylpyrrolidine-1-carboxylate, (35) tert-butyl(2S,3S)-2-carbamotioyl-3-methoxypyrrolidine-1-carboxylate, (36) tert-butyl(S)-6-carbamotioyl-5-azaspiro[2.4]heptane-5-carboxylate, and (37) tert-butyl(2S,4S)-4-((tert-butyldiphenylsilyl)oxy)-2-carbamoticoylpyrrolidine-1-carboxylate; A compound selected from among, or a deuterated or tritiated form of the compound of formula (I), or a pharmaceutically acceptable salt thereof.

9. A pharmaceutical composition characterized by comprising a compound of formula (I) according to any one of claims 1 to 6, or a deuterated or tritiated form of a compound of formula (I), or a pharmaceutically acceptable salt thereof.

10. A compound of formula (I) according to any one of claims 1 to 6, or a deuterated or tritiated form of a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use as a pharmaceutical.

11. A compound of formula (I) according to any one of claims 1 to 6, or a deuterated or tritiated form of a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment and / or prevention of protein tyrosine kinase-mediated diseases, particularly phosphatidylinositol 3-kinase-mediated diseases, and more particularly diseases mediated by the isoform α of phosphatidylinositol 3-kinase.

12. A compound of formula (I), or a deuterated or tritiated form of a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use according to claim 1

13. A compound of formula (I) according to any one of claims 1 to 6, or a deuterated or tritiated form of a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment and / or prevention of cancer, particularly bladder cancer, breast cancer, lung cancer, e.g., non-small cell lung cancer and small cell lung cancer, ovarian cancer, cervical cancer, kidney cancer, liver cancer, head and neck cancer, e.g., squamous cell carcinoma of the head and neck, sarcoma, brain cancer, e.g., glioma, glioblastoma, anaplastic oligodendroglioma and anaplastic astrocytoma, or hematological cancer, e.g., leukemia, lymphoma and myeloma.

14. A compound of formula (I) according to any one of claims 1 to 6, or a deuterated or tritiated form of a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment and / or prevention of phosphatidylinositol 3-kinase-related hypergrowth spectrum, particularly congenital prosthesia, lipomatous hypergrowth, vascular malformations, epidermal nevi and spinal / skeletal abnormalities and / or scoliosis syndrome.

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