Novel inhibitors of phosphatidylinositol 3-kinase

Abstract

The invention relates to prevention and / or treatment of diseases mediated by protein tyrosine kinase, in particular to diseases mediated by phosphatidylinositol 3-kinase (PI3K). PI3K is known as an oncology target, and a variety of PI3K inhibitors have been developed, which inhibit a variety of 1A class PI3K subtypes. Development of PI3K-alpha selective inhibitors may enable sufficient target inhibition while avoiding some known toxic defects of pan-PI3K inhibitors. The inventor finds that a novel thiocarbamoyl-pyrrolidine-carboxamide compound of a specific formula (I) shows excellent PI3K inhibitory activity, and especially has high selectivity for subtype PI3K alpha. In particular, the present invention relates to a compound of formula (I), or a deuterated or tritiated form of a compound of formula (I), and pharmaceutically acceptable salts thereof. The present invention also relates to a pharmaceutical composition comprising said compound of formula (I), and to the use of the compound of formula (I) for the treatment and / or prevention of protein tyrosine kinase mediated diseases. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to novel specific thiocarbamoyl-pyrrolidine-carboxamide compounds, methods for their synthesis, and their therapeutic uses.

[0002] The compounds described herein are novel phosphatidylinositol 3-kinase (PI3K) inhibitors, particularly α-selective phosphatidylinositol 3-kinase (PI3Kα) inhibitors. The compounds described herein are thus suitable for the prevention and / or treatment of protein tyrosine kinase-mediated diseases, particularly PI3K-mediated diseases. Background Art

[0003] Phosphatidylinositol 3-kinases (PI3Ks) comprise a family of lipid kinases that phosphorylate phosphatidylinositol at the 3'-position of the inositol ring. They are divided into three classes according to their substrate specificity and sequence homology.

[0004] Class I PI3Ks phosphorylate phosphatidylinositol-4,5-bisphosphate (PIP2) downstream of receptor tyrosine kinases or G-protein coupled receptors to form the second messenger phosphatidylinositol-3,4,5-trisphosphate (PIP3), which signals to increase cell growth, metabolism, and 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 and class IB. In class IA, the subtypes p110α, p110β, and p110δ form heterodimers with the p85 family of regulatory subunits, and in class IB, p110γ is the only member and forms a heterodimer with the p87 or p101 regulatory subunits.

[0006] Each subtype has been shown to have overlapping but non-redundant physiological roles. Both PI3K-α and PI3K-β are widely expressed. PI3K-α plays a key role in glucose homeostasis and insulin signaling and is involved in driving cardiac growth through PIP3-dependent pathways. In contrast, PI3K-β has been shown to regulate the activity of platelet integrin α IIb β3 in the context of platelet adhesion and aggregation. Thus, PI3K-β is being investigated as a novel thrombus treatment, and first-in-human trials have shown promising results. The expression of PI3K-γ and PI3K-δ is more restricted, mainly limited to the hematopoietic system. Both of them play important, non-redundant roles in the immune system and are thus regarded as immunomodulatory targets. PI3K-γ inhibition is being sought for rheumatoid arthritis and asthma, while PI3K-δ inhibition is used for activated PI3K-δ syndrome (APDS).

[0007] Although they have diverse functions, PI3Ks are perhaps best known as oncology targets. The PI3K pathway is one of the most frequently dysregulated pathways in cancer.

[0008] Accordingly, a variety of PI3K inhibitors have been developed that inhibit multiple class 1A PI3K isoforms and are commonly referred to as "pan-PI3K" inhibitors.

[0009] The development of isoform-selective inhibitors is crucial for revealing the unique functions of each isoform and their corresponding therapeutic potential. Significant progress has been made, and there are now isoform-selective inhibitors for each of the four class I isoforms. They continue to play a role in revealing important details of PI3K physiology and understanding cancer signaling.

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

[0011] In addition, the development of selective inhibitors of PI3K-α may enable sufficient target inhibition while avoiding some of the known toxicity drawbacks of pan-PI3K inhibitors.

[0012] Accordingly, some PI3K-α selective inhibitors have been developed, such as the 2-carbamoylcyclic hydrazide derivatives disclosed in Application WO 2010 / 029082.

[0013] Document WO 2017 / 001362 relates to treating cancer, which shows higher selectivity for the PI3Kα isoform. There remains a need to provide further compounds suitable as PI3K inhibitors for the treatment and / or prevention of proliferative diseases, such as cancer.

[0014] In particular, there is a need to provide further compounds that are capable of selectively inhibiting the PI3Kα isoform, advantageously with higher selectivity and / or higher activity.

[0015] In particular, there is a need to provide further compounds that are capable of selectively inhibiting the PI3Kα isoform, advantageously with higher selectivity and / or higher activity. Summary of the Invention

[0016] The inventors have found that the compounds of formula (I) defined below exhibit excellent phosphatidylinositol 3-kinase (PI3K) inhibitory activity, particularly against the α isoform.

[0017] In addition, as confirmed in the following examples, these compounds advantageously show higher selectivity for PI3Kα relative to the β and / or δ and / or γ isoforms.

[0018] Therefore, the compounds of formula (I) are suitable for the treatment and / or prevention of protein tyrosine kinase-mediated diseases, especially PI3K-mediated diseases, more particularly diseases mediated by the α isoform of PI3K.

[0019] Advantageously, the compounds of formula (I) exhibit such activity and higher selectivity without the problem of inducing insulin resistance, which can be observed in some known selective PI3K-α inhibitors. In particular, the compounds of formula (I) rarely or even do not cause hyperglycemia.

[0020] In addition, the compounds of formula (I) exhibit prolonged inhibitory activity against tissue-based AKT.

[0021] Thus, in its first aspect, the present invention relates to compounds of formula (I) as defined below.

[0022] In another aspect thereof, the present invention further relates to a method for preparing these compounds, as well as specific intermediate compounds involved in this method, as detailed below.

[0023] In another aspect thereof, the present invention relates to a pharmaceutical composition comprising a compound of formula (I) as defined below, or a deuterated or tritiated form of the compound of formula (I), or a pharmaceutically acceptable salt thereof.

[0024] The present invention further relates to a compound of formula (I) as defined below, or a deuterated or tritiated form of the compound of formula (I), or a pharmaceutically acceptable salt thereof for use as a medicament.

[0025] Another aspect of the present disclosure relates to a compound of formula (I) as defined below for use as a PI3K inhibitor, especially as a PI3Kα inhibitor.

[0026] The present invention further relates to a compound of formula (I) as defined below, or a deuterated or tritiated form of the compound of formula (I), or a pharmaceutically acceptable salt thereof for use in the treatment and / or prevention of the following diseases: protein tyrosine kinase-mediated diseases, especially PI3K-mediated diseases, more particularly PI3Kα-mediated diseases. Description of the Drawings

[0027] Figure 1(A to C) illustrate the ability of Compound 5 of the present invention to improve kidney injury in the NZBWF1 / J mouse model. A. Urinary albumin to creatinine ratio (Ualb / Cre) (ordinate, mg / mmol). Abscissa (from left to right): vehicle and Compound 5 (50 mg / kg). B. Blood urea nitrogen level (BUN) (ordinate, mmol / L). Abscissa (from left to right): vehicle and Compound 5 (50 mg / kg). C. Glomerular injury score of the kidneys after treatment with vehicle or Compound 5 for 4 weeks after unilateral nephrectomy (n = 6 mice per group). AU: arbitrary unit (ordinate). Abscissa (from left to right): vehicle and Compound 5 (50 mg / kg)

[0028] Figure 2 Illustrates the change of insulin over time in the mouse groups treated with vehicle or Compound 5 of the present invention. Ordinate: insulin (ng / mL). Abscissa: time (hours).

[0029] Definition

[0030] As used herein, the term "patient" refers to an animal (e.g., a valuable animal for breeding, companionship, or preservation purposes) or preferably a human or a human child that has or may have one or more of the diseases and disorders described herein.

[0031] In particular, the term "patient" as used in this application refers to a mammal, such as a rodent, cat, dog, primate, or human, preferably the subject is a human, and also extends to birds.

[0032] The identification of these patients in need of treatment for the diseases and disorders described herein is entirely within the ability and knowledge of those skilled in the art. A skilled veterinarian or physician in the art can easily identify these patients in need of such treatment by using clinical tests, physical examinations, medical history / family history, or biological and diagnostic tests.

[0033] In the context of the present invention, the term "treatment" or "therapy" as used herein refers to reversing, alleviating, inhibiting the progression of the medical condition of a patient suffering from the diseases described herein, or preventing the medical condition.

[0034] As used herein, "effective amount" refers to the amount of the compound of the present invention that can effectively prevent, alleviate, eliminate, treat, or control the symptoms of the diseases and disorders described herein. The term "control" is intended to refer to all processes in which the progression of the diseases and disorders described herein can be slowed down, disrupted, arrested, or stopped, but does not necessarily mean completely eliminating all symptoms of the diseases and disorders, and is intended to include prophylactic treatment.

[0035] The term "effective amount" includes "prophylactically effective amount" and "therapeutically effective amount".

[0036] As used herein, the term "prevention" means reducing the risk of occurrence of a specified phenomenon (i.e., the diseases described herein in the context of the present invention) or slowing its onset.

[0037] "Prevention" as used herein also includes "reducing the likelihood of occurrence" or "reducing the likelihood of recurrence".

[0038] The term "preventive effective amount" refers to the concentration of a compound of the present invention that is effective in inhibiting, preventing, reducing the likelihood of, inflammatory diseases, virus-induced diseases, and more particularly retrovirus-induced diseases, or cancer.

[0039] Similarly, the term "therapeutically effective amount" refers to the concentration of a compound that is effective in treating the diseases described herein.

[0040] The term "pharmaceutically acceptable" as used herein means that these compounds, materials, excipients, compositions or dosage forms are suitable for contact with the tissues of humans and animals within the scope of reasonable medical judgment, and without undue toxicity, irritation, allergic response, or other problematic complications, in accordance with a reasonable benefit / risk ratio.

[0041] The term "prodrug" refers to a compound that is not biologically active and can be converted in vivo, via a metabolic process (such as via hydrolysis, reduction or oxidation), into a compound of the present invention. For example, an ester prodrug of a compound of the present invention can be converted in vivo via hydrolysis into the parent molecule. Suitable esters of the compounds of the present invention are, for example: acetate, citrate, lactate, tartrate, malonate, oxalate, salicylate, propionate, succinate, fumarate, maleate, methylene-bis-β-hydroxy-naphthoate, gentisate, hydroxyethylsulfonate, di-p-toluoyl tartrate, mesylate, esylate, benzenesulfonate, p-toluenesulfonate, cyclohexylaminosulfonate and quinic acid ester. Examples of ester prodrugs are those described in F.J. Leinweber, Drug Metab. Res., 1987, 18, 379. As used herein, reference to a compound of the present invention is intended to also include any prodrug or metabolite form.

[0042] In the context of an enzyme, for example in the context of PI3K, and more particularly PI3K-α, the term "inhibition" or "inhibitory effect" means reducing the activity of the enzyme.

[0043] The term "PI3K" as used herein refers to phosphatidylinositol 3-kinase, sometimes also referred to as PI3-kinase, PI(3)K, 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 trafficking. PIK3CA is the gene encoding the p110a protein (which is also referred to as the PIK3CA or PIK3C-α protein).

[0044] As used herein, the expressions "protein tyrosine kinase-mediated disease", "PI3K-mediated disease" or "PI3K-α-mediated disease" more specifically refer to diseases related to the overexpression and / or abnormal activity of protein tyrosine kinase, PI3K and / or PI3K-α, respectively.

[0045] "Proliferative disease" refers to a disease that occurs due to abnormal growth or expansion caused by cell replication. Exemplary proliferative diseases include cancer, benign tumors, angiogenesis, inflammatory diseases (including autoimmune diseases / disorders).

[0046] The term "cancer" refers to a class of diseases characterized by the development of abnormal cells that proliferate uncontrollably and have the ability to invade and destroy normal body tissues. Cancer includes malignant tumors and benign tumors, metastatic tumors and non-metastatic tumors, solid tumors and non-solid tumors, such as blood-related cancers, and thus it can include leukemia, lymphoma and myeloma; it can also involve central nervous system (CNS) cancers and non-CNS cancers. Unless otherwise specified, the term "cancer" also encompasses juvenile cancers and non-juvenile cancers, recurrent cancers and non-recurrent cancers, and cancer relapse.

[0047] In the context of the present invention, the terms:

[0048] - "Halogen" should be understood to mean chlorine, fluorine, bromine, or iodine, particularly chlorine, fluorine, or bromine, preferably fluorine;

[0049] - "(C1-C x )alkyl" as used herein refers to C1-C x primary, secondary or tertiary monovalent saturated, straight-chain or branched hydrocarbon groups, for example: (C1-C6)alkyl. Examples include, but are not limited to: methyl, ethyl, propyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl and isohexyl, etc.;

[0050] "(C3-C x )cycloalkyl" as used herein refers to a cyclic saturated hydrocarbon group that contains 3 to x carbon atoms, is saturated or partially unsaturated, and is unsubstituted or substituted. Examples are, but are not limited to: cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

[0051] "Pharmaceutically acceptable salt" refers to a salt that, within the scope of reasonable medical judgment, is suitable for contact with the tissues of humans and lower animals without excessive toxicity, irritation, allergic reaction, etc. Pharmaceutically acceptable salts include salts derived from suitable organic and inorganic acids or bases.

[0052] Examples of pharmaceutically acceptable non-toxic acid addition salts are salts formed from the amino group with inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid, or with organic acids, such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid, or salts formed by using other methods known in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipates, alginates, ascorbates, aspartates, benzenesulfonates, benzoates, bisulfates, borates, butyrates, camphorates, camphorsulfonates, citrates, cyclopentanepropionates, digluconates, dodecyl sulfates, ethanesulfonates, formates, fumarates, glucoheptanoates, glycerophosphates, gluconates, hemisulfates, heptanoates, hexanoates, hydroiodides, 2-hydroxyethanesulfonates, lactobionates, lactates, laurates, dodecyl sulfates, malates, maleates, malonates, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oleates, oxalates, palmitates, pamoates, pectates, persulfates, 3-phenylpropionates, phosphates, picrates, pivalates, propionates, stearates, succinates, sulfates, tartrates, thiocyanates, p-toluenesulfonates, undecanoates, valerates, etc. Salts derived from appropriate bases include alkali metal salts, alkaline earth metal salts, ammonium salts, and N + [(C1-C4)alkyl]4-salts. Representative alkali metal salts or alkaline earth metal salts include sodium salts, lithium salts, potassium salts, calcium salts, magnesium salts, etc. Other pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium and amine cations formed (where appropriate) with counterions, such as halide ions, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate.

[0053] The compound of formula (I) or any of its pharmaceutically acceptable salts may form solvates or hydrates, and the present invention includes all such solvates and hydrates.

[0054] The terms "hydrate" and "solvate" only mean that the compound (I) according to the present invention can be in the form of a hydrate or a solvate, i.e., combined or associated with one or more water molecules or solvent molecules. This is only a chemical property of such compounds and is applicable to all such organic compounds.

[0055] In the context of the present invention, the compound of formula (I) as defined herein may also contain deuterium or tritium. The deuterated or tritiated forms of the compounds only mean that the hydrogen atoms (H) in these compounds can be partially or completely replaced by deuterium (D) atoms or tritium (T) atoms.

[0056] The compound of formula (I) may contain one or more asymmetric carbon atoms. They may thus exist in the form of enantiomers or diastereoisomers. These enantiomers, diastereoisomers and mixtures thereof are all encompassed within the scope of the present invention.

[0057] The compound of formula (I) can be in amorphous or crystalline form, and these forms are also covered by the scope of the present invention. Detailed embodiments

[0058] The present invention relates to a compound of formula (I), or a deuterated or tritiated form of the compound of formula (I), or a pharmaceutically acceptable salt thereof:

[0059]

[0060] Wherein:

[0061] - R1 is (C1-C6) alkyl or (C3-C6) cycloalkyl, which is unsubstituted or substituted by one or more fluorine atoms;

[0062] - R2 is selected from:

[0063] a hydrogen atom, and

[0064] (C1-C6) alkyl,

[0065] - m is 0, 1 or 2;

[0066] - When present, each R3 is independently selected from:

[0067] a fluorine atom,

[0068] (C1-C6) alkyl, which is unsubstituted or substituted by one or more halogen atoms,

[0069] (C3-C6) cycloalkyl, which is unsubstituted or substituted by one or more halogen atoms,

[0070] a hydroxyl group,

[0071] (C1-C6) alkoxy, and

[0072] - an NRR' group, where R and R' are independently selected from: a hydrogen atom and (C1-C6) alkyl,

[0073] or two R3 are connected through the same carbon atom, and two R3 together with the carbon atom to which they are attached form a (C3-C6) cycloalkyl ring, which is unsubstituted or substituted by one or more fluorine atoms; and

[0074] - R4 is selected from:

[0075] a fluorine atom,

[0076] a hydrogen atom,

[0077] (C1-C6) alkyl, which is unsubstituted or substituted by one or more halogen atoms, and

[0078] (C3-C6) cycloalkyl, which is unsubstituted or substituted by one or more halogen atoms,

[0079] or when R3 and R4 are connected by two adjacent carbon atoms, R3 and R4 together with the carbon atoms to which they are attached form a (C3-C6) cycloalkyl ring, which is unsubstituted or substituted by one or more halogen atoms.

[0080] In the compounds of formula (I), the following compounds may be mentioned, wherein R1 is a (C1-C6) alkyl group, especially a (C1-C4) alkyl group, more especially a tert-butyl group, which is unsubstituted or substituted by one or more fluorine atoms.

[0081] In one embodiment, in the compounds of formula (I), the R1 group is a tert-butyl group substituted by one to three fluorine atoms.

[0082] In another embodiment, in the compounds of formula (I), the R1 group is an unsubstituted tert-butyl group.

[0083] In the compounds of formula (I), the following compounds may be mentioned, wherein R2 is a (C1-C6) alkyl group, especially a (C1-C4) alkyl group, more especially a methyl group.

[0084] In one embodiment, the following compounds of formula (I) may be mentioned, wherein m is 0.

[0085] In another embodiment, the following compounds of formula (I) may be mentioned, wherein m is 1 or 2, especially m is 1.

[0086] In one embodiment, in the compounds of formula (I), m is 1 or 2, and each R3 is independently selected from:

[0087] a fluorine atom,

[0088] (C1-C6) alkyl, especially (C1-C4) alkyl, more especially methyl, which is unsubstituted or substituted by one or more halogen atoms,

[0089] (C3-C6) cycloalkyl, which is unsubstituted or substituted by one or more halogen atoms, especially substituted by one or more fluorine atoms;

[0090] a hydroxyl group,

[0091] (C1-C6) alkoxy, especially (C1-C4) alkoxy, more especially methoxy, and

[0092] the -NH2 group.

[0093] In one embodiment, in the compounds of formula (I), m is 1 or 2, and each R3 is independently selected from:

[0094] a fluorine atom,

[0095] (C1-C6)alkyl, especially (C1-C4)alkyl, more especially methyl, which is unsubstituted or substituted by one or more halogen atoms; for example, methyl or trifluoromethyl;

[0096] (C3-C6)cycloalkyl, which is unsubstituted or substituted by one or more halogen atoms, especially by one or more fluorine atoms;

[0097] a hydroxyl group, and

[0098] (C1-C6)alkoxy, especially (C1-C4)alkoxy, more especially methoxy.

[0099] In a specific embodiment, m is 1 or 2, and each R3 is independently selected from:

[0100] a fluorine atom,

[0101] (C1-C6)alkyl, especially (C1-C4)alkyl, more especially methyl, which is unsubstituted or substituted by one or more halogen atoms; for example, methyl or trifluoromethyl;

[0102] a hydroxyl group, and

[0103] (C1-C6)alkoxy, especially (C1-C4)alkoxy, more especially methoxy.

[0104] In another embodiment, in the compound of formula (I), m is 2, and the two R3 are connected through the same carbon atom, and the two R3 and the carbon atom to which they are connected form a (C3-C6)cycloalkyl ring, especially a cyclopropyl ring, which is unsubstituted or substituted by one or more fluorine atoms.

[0105] In the compound of formula (I), the following compounds may be mentioned, wherein R4 is selected from:

[0106] a hydrogen atom, and

[0107] (C1-C6)alkyl, especially (C1-C4)alkyl, more especially methyl, which is unsubstituted or substituted by one or more halogen atoms, especially by one or more fluorine atoms.

[0108] All of these subgroups and specific embodiments, whether alone or in combination, form part of this specification.

[0109] In one embodiment, the following compound of formula (I) may be mentioned, wherein:

[0110] -R1 is (C1-C6)alkyl or (C3-C6)cycloalkyl, which is unsubstituted or substituted by one or more fluorine atoms;

[0111] - R2 is selected from:

[0112] a hydrogen atom, and

[0113] (C1-C6) alkyl;

[0114] - m is 0, 1 or 2;

[0115] - When present, each R3 is independently selected from:

[0116] a fluorine atom,

[0117] (C1-C6) alkyl, which is unsubstituted or substituted by one or more halogen atoms,

[0118] (C3-C6) cycloalkyl, which is unsubstituted or substituted by one or more halogen atoms,

[0119] a hydroxyl group, and

[0120] (C1-C6) alkoxy,

[0121] or two R3 are connected through the same carbon atom, and two R3 and the carbon atom to which they are connected form a (C3-C6) cycloalkyl ring, which is unsubstituted or substituted by one or more fluorine atoms; and

[0122] - R4 is selected from:

[0123] a fluorine atom,

[0124] a hydrogen atom, and

[0125] (C1-C6) alkyl, which is unsubstituted or substituted by one or more halogen atoms.

[0126] In another embodiment, the following compounds of formula (I) can be mentioned, wherein:

[0127] - R1 is (C1-C6) alkyl, especially (C1-C4) alkyl, which is unsubstituted or substituted by one to three fluorine atoms; more especially tert-butyl, which is unsubstituted or substituted by one to three fluorine atoms;

[0128] - R2 is (C1-C6) alkyl, especially (C1-C4) alkyl, more especially methyl,

[0129] - m is 0, 1 or 2;

[0130] - When present, each R3 is independently selected from:

[0131] a fluorine atom,

[0132] (C1-C6) alkyl, especially (C1-C4) alkyl, more especially methyl,

[0133] hydroxy group, and

[0134] (C1-C6)alkoxy group, especially (C1-C4)alkoxy group, more especially methoxy group,

[0135] or two R3 are connected through the same carbon atom, and two R3 and the carbon atom to which they are connected form a (C3-C6)cycloalkyl ring, especially a cyclopropyl ring, which is unsubstituted or substituted by one or two fluorine atoms; and

[0136] -R4 is selected from:

[0137] hydrogen atom, and

[0138] (C1-C6)alkyl group, especially (C1-C4)alkyl group, more especially methyl group.

[0139] In another embodiment, the following compounds of formula (I) may be mentioned, wherein:

[0140] -R1 is (C1-C6)alkyl group, especially (C1-C4)alkyl group, more especially tert-butyl group, which is substituted by one to three fluorine atoms;

[0141] -R2 is (C1-C6)alkyl group, especially (C1-C4)alkyl group, more especially methyl group,

[0142] -m is 0 or 1;

[0143] -When present, R3 is selected from:

[0144] hydroxy group, and

[0145] (C1-C6)alkoxy group, especially (C1-C4)alkoxy group, more especially methoxy group,

[0146] Preferably, R3 is hydroxy group; and

[0147] -R4 is hydrogen atom.

[0148] The nomenclature of the following compounds (1) to (20) is generated according to the IUPAC rules of organic compounds based on the principles of the International Union of Pure and Applied Chemistry.

[0149] Among the compounds of formula (I), the following compounds, or deuterated or tritiated forms of the compounds of formula (I), or pharmaceutically acceptable salts thereof, may be especially mentioned:

[0150] (1) (S)-2-Thiocarbamoyl-4,4-difluoro-N-(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)thiazol-2-yl)pyrrolidine-1-carboxamide,

[0151] (2) (2S,4R)-2-Thiocarbamoyl-4-fluoro-N-(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)thiazol-2-yl)pyrrolidine-1-carboxamide,

[0152] (3) (2S,4S)-2-Thiocarbamoyl-4-fluoro-N-(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)thiazol-2-yl)pyrrolidine-1-carboxamide,

[0153] (4) (S)-6-Thiocarbamoyl-N-(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)thiazol-2-yl)-1,1-difluoro-5-azaspiro[2.4]heptane-5-carboxamide,

[0154] (5) (S)-2-Thiocarbamoyl-N-(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)thiazol-2-yl)pyrrolidine-1-carboxamide,

[0155] (6) (S)-2-Thiocarbamoyl-2-methyl-N-(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)thiazol-2-yl)pyrrolidine-1-carboxamide,

[0156] (7) (2S,4R)-2-Thiocarbamoyl-4-methoxy-N-(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)thiazol-2-yl)pyrrolidine-1-carboxamide,

[0157] (8) (2S,4S)-2-Thiocarbamoyl-4-methoxy-N-(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)thiazol-2-yl)pyrrolidine-1-carboxamide,

[0158] (9) (2S,5R)-2-Thiocarbamoyl-5-methyl-N-(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)thiazol-2-yl)pyrrolidine-1-carboxamide,

[0159] (10) (2S,5S)-2-Thiocarbamoyl-5-methyl-N-(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)thiazol-2-yl)pyrrolidine-1-carboxamide,

[0160] (11) (2S,4S)-2-Thiocarbamoyl-4-methyl-N-(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)thiazol-2-yl)pyrrolidine-1-carboxamide,

[0161] (12) (2S,4S)-2-Thiocarbamoyl-N-(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)thiazol-2-yl)-4-(trifluoromethyl)pyrrolidine-1-carboxamide,

[0162] (13) (2S,4R)-2-Thiocarbamoyl-4-hydroxy-N-(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)thiazol-2-yl)pyrrolidine-1-carboxamide,

[0163] (14) (2S,3S)-2-Thiocarbamoyl-3-hydroxy-N-(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)thiazol-2-yl)pyrrolidine-1-carboxamide,

[0164] (15) (2S,3S)-2-Thiocarbamoyl-3-methoxy-N-(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)thiazol-2-yl)pyrrolidine-1-carboxamide,

[0165] (16) (S)-6-Thiocarbamoyl-N-(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)thiazol-2-yl)-5-azaspiro[2.4]heptane-5-carboxamide,

[0166] (17) (2S,4S)-2-Thiocarbamoyl-4-hydroxy-N-(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)thiazol-2-yl)pyrrolidine-1-carboxamide;

[0167] (18) (S)-2-Thiocarbamoyl-N-(4-methyl-5-(2-tert-butyl-pyridin-4-yl)thiazol-2-yl)pyrrolidine-1-carboxamide,

[0168] (19) (2S,4S)-2-Thiocarbamoyl-4-fluoro-N-(4-methyl-5-(2-tert-butyl-pyridin-4-yl)thiazol-2-yl)pyrrolidine-1-carboxamide, and

[0169] (20) (S)-6-Thiocarbamoyl-N-(4-methyl-5-(2-tert-butyl-pyridin-4-yl)thiazol-2-yl)-5-azaspiro[2.4]heptane-5-carboxamide.

[0170] Among the foregoing compounds, the following compounds may be specifically mentioned: (5), (7), (8), (13), (14) and (17), or the deuterated or tritiated forms of the compound of formula (I), or a pharmaceutically acceptable salt thereof.

[0171] Among the foregoing compounds, the following compounds may be specifically mentioned: (5), (13), (14) and (17), especially (5), (13) and (14), or the deuterated or tritiated forms of the compound of formula (I), or a pharmaceutically acceptable salt thereof.

[0172] The compound of formula (I) can be prepared by the following method.

[0173] Unless otherwise specified, R1, R2, R3, R4 and m are as defined above.

[0174] The compound of formula (I) and other related compounds with different substituents are synthesized using the techniques and materials described below or other techniques and materials known to those skilled in the art. In addition, the solvents, temperatures and other reaction conditions presented below can be adjusted in a manner considered appropriate by those skilled in the art.

[0175] Scheme 1: Preparation of the compound of formula (I) – General method

[0176]

[0177] According to Scheme 1, in Step 3, the compound of formula (I) can be obtained by the coupling between compound II-A (wherein R4, R3 and m are as defined above) and compound II-B (wherein R1 and R2 are as defined above).

[0178] Compound II-A can be obtained from a compound in which the corresponding nitrogen atom is in a protected form (for example, compound I-A in which the nitrogen atom is protected by a tert-butyl carbamate (Boc) group) through a deprotection step 1 (for example, in an aqueous HCl solution). More specifically, Step 1 can be carried out as follows: Place compound I-A into an HCl solution with an appropriate solvent (such as ether or dioxane), and stir for several hours at room temperature (i.e., a temperature between 20 °C and 25 °C). Then remove the solvent under vacuum to obtain compound II-A, followed by the coupling step.

[0179] Compound II-B can be obtained by reacting Compound I-B with 1,1'-carbonyldiimidazole in Step 2. More specifically, Compound I-B can be dissolved in an organic solvent (such as dichloromethane), and 1,1'-carbonyldiimidazole can be added in a molar ratio ranging from 1 to 2 (especially 1.7). The reaction mixture can be stirred at a temperature ranging from 50 °C to 70 °C for 12 to 16 hours, then cooled to room temperature and filtered to obtain Compound II-B as a precipitate.

[0180] Then, at room temperature, in a polar aprotic organic solvent (such as N,N-dimethylformamide (DMF) or acetonitrile), using triethylamine (TEA), Compound II-A and Compound II-B are subjected to coupling Step 3. More specifically, Compound II-A and Compound II-B can be dissolved in DMF, for example, in a molar ratio of 1.3 / 1, and then TEA can be added in a molar ratio ranging from 2.5 to 3.5 (especially 3). The reaction mixture can be stirred at room temperature for 12 to 16 hours and treated with an aqueous solvent (such as water). The organic phase is extracted, for example, with dichloromethane, especially washed with brine, and dried, for example, with sodium sulfate. Then, the solvent can be evaporated to obtain a crude product, which can be further purified, especially by preparative HPLC (using a water / acetonitrile gradient), to obtain Compound I.

[0181] When R3 is a hydroxyl group, R3 in Compound I-A and Compound II-A is protected before the coupling step, for example, protected with a tert-butyldiphenylsilyl ether (tBDPS) protecting group. After the coupling step between the hydroxyl R3-protected Compound II-A and Compound II-B, the resulting precipitate can be subjected to hydroxyl deprotection, for example, using tetrabutylammonium fluoride (TBAF) to remove the tBDPS protecting group, and then purified by HPLC.

[0182] Intermediate Compound I-A can be prepared according to the method shown in Scheme 2.

[0183] Scheme 2: Preparation of Intermediate Compound of Formula (I-A) - General Method

[0184]

[0185] According to Scheme 2 (wherein R3, R4 and m are as defined above), in step 4, the nitrogen atom in compound A1 is first protected, for example, with a tert-butyl carbamate (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 low temperature, especially at 0 °C, a base (such as triethylamine) is added in a molar ratio ranging from 1 to 2 (such as 1.5), di-tert-butyl dicarbonate is added in a molar ratio ranging from 1 to 2 (such as 1.2), and a suitable nucleophilic catalyst (such as 4-dimethylaminopyridine (DMAP)) is added in a molar ratio ranging from 0.01 to 0.5 (such as 0.15). Then, the reaction mixture can be stirred at low temperature (such as 0 °C) for 15 to 45 minutes and then at room temperature for 8 to 15 hours. Then, the reaction can be quenched with, for example, an aqueous solution of sodium bicarbonate (NaHCO3) and extracted with a suitable solvent (such as dichloromethane). Then, the organic phase can be dried over, for example, anhydrous Na2SO4, filtered and concentrated (such as by vacuum concentration). Then, the crude product can be purified using, for example, flash chromatography to obtain compound A2.

[0186] In step 5, the carboxylic acid functional group can be converted to the corresponding amide under suitable conditions to convert compound A2 to compound A3. For example, step 5 can be carried out by activation with isobutyl chloroformate in the presence of a base (such as triethylamine) and then reaction with ammonia (preferably aqueous ammonia). Extraction with a suitable organic solvent (such as ethyl acetate), followed by filtration and drying (such as drying over anhydrous magnesium sulfate), and purification by flash chromatography gives compound A3.

[0187] In step 6, compound A3 can be converted to compound A4 by converting the amide functional group to a thioamide (such as using Lawesson's reagent).

[0188] When R3 is a hydroxyl group, R3 of compound A2 is protected before carrying out step 5, for example, with a tert-butyldiphenylsilyl ether (tBDPS) protecting group. In this case, compound I-A with the hydroxyl group R3 protected is obtained, which can undergo the coupling reaction as described in Scheme 1 above.

[0189] In a specific embodiment, compound A2 in which R3 is an alkoxy group can be obtained from compound A2 in which R3 is a hydroxyl group by converting the hydroxyl group to an alkoxy group (for example, by reaction with an alkyl iodide in tetrahydrofuran), and then step 5 is carried out.

[0190] The present invention also provides a method for preparing a compound of formula (I) as defined above, which method comprises a coupling reaction between a compound of formula (II-A) and a compound of formula (II-B),

[0191]

[0192] wherein R3, R4, m, R2 and R1 are as defined above, provided that when R3 is a hydroxyl group, R3 in compound II-A is protected prior to the coupling reaction, for example with a tert-butyldiphenylsilyl ether (tBDPS) protecting group; and deprotection is carried out after the coupling reaction;

[0193] wherein said coupling reaction is preferably carried out at room temperature using triethylamine (TEA) in a polar aprotic organic solvent such as dimethylformamide (DMF).

[0194] Prior to carrying out said coupling reaction, the step of obtaining compound II-A may optionally be carried out, wherein compound II-A is converted from a compound of formula I-A by a deprotection step, for example by aqueous HCl.

[0195]

[0196] wherein 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.

[0197] Prior to carrying out said coupling reaction, the step of obtaining compound II-B may optionally be carried out, wherein compound II-B is converted from a compound of formula I-B by reaction with 1,1'-carbonyldiimidazole, especially in an organic solvent such as dichloromethane.

[0198]

[0199] wherein R1 and R2 are as defined above.

[0200] The present invention further provides intermediate compounds of formula (I-A) and (II-A), or deuterated or tritiated forms of a compound of formula (I), and any pharmaceutically acceptable salts thereof:

[0201]

[0202] wherein R3, R4 and m are as defined above; or R3 represents a protected hydroxyl group, for example a hydroxyl group protected with a tert-butyldiphenylsilyl ether (tBDPS) protecting group.

[0203] In particular, in the intermediate compound of formula (I-A) or the intermediate compound of formula (II-A), m, R3 and R4 may have any of the specific definitions described for the compound of formula (I) above.

[0204] In one embodiment, in the intermediate compound of formula (I-A) or the intermediate compound of formula (II-A):

[0205] - m is 0, 1 or 2,

[0206] - When present, each R3 is independently selected from:

[0207] a fluorine atom,

[0208] (C1-C6)alkyl, especially (C1-C4)alkyl, more especially methyl, which is unsubstituted or substituted by one or more halogen atoms,

[0209] (C3-C6)cycloalkyl, which is unsubstituted or substituted by one or more halogen atoms,

[0210] a hydroxyl group, especially a protected hydroxyl group, such as a hydroxyl group protected with a tert-butyldiphenylsilyl ether (tBDPS) protecting group;

[0211] (C1-C6)alkoxy, especially (C1-C4)alkoxy, more especially methoxy,

[0212] - an -NH2 group,

[0213] or two R3 are connected through the same carbon atom, and two R3 together with the carbon atom to which they are connected form a (C3-C6)cycloalkyl ring, especially a cyclopropyl ring, which is unsubstituted or substituted by one or more fluorine atoms, and

[0214] - R4 is selected from:

[0215] a hydrogen atom,

[0216] (C1-C6)alkyl, especially (C1-C4)alkyl, more especially methyl, which is unsubstituted or substituted by one or more halogen atoms;

[0217] or when R3 and R4 are connected through two adjacent carbon atoms, R3 and R4 together with the carbon atoms to which they are connected form a (C3-C6)cycloalkyl ring, which is unsubstituted or substituted by one or more halogen atoms.

[0218] In one embodiment, in the intermediate compound of formula (I-A) or the intermediate compound of formula (II-A):

[0219] - m is 0, 1 or 2,

[0220] - When present, each R3 is independently selected from:

[0221] a fluorine atom,

[0222] (C1-C6)alkyl, especially (C1-C4)alkyl, more especially methyl,

[0223] a hydroxyl group, especially a protected hydroxyl group, such as a hydroxyl group protected with a tert-butyldiphenylsilyl ether (tBDPS) protecting group;

[0224] (C1-C6)alkoxy, especially (C1-C4)alkoxy, more especially methoxy,

[0225] or two R3 are connected through the same carbon atom, and two R3 and the carbon atom to which they are connected form a (C3-C6)cycloalkyl ring, especially a cyclopropyl ring, which is substituted with one or more fluorine atoms, and

[0226] -R4 is selected from:

[0227] a hydrogen atom, and

[0228] (C1-C6)alkyl, especially (C1-C4)alkyl, more especially methyl.

[0229] In another embodiment, in the intermediate compound of formula (I-A) or the intermediate compound of formula (II-A):

[0230] -m is 0 or 1;

[0231] -When present, R3 is selected from:

[0232] a hydroxyl group, and

[0233] (C1-C6)alkoxy, especially (C1-C4)alkoxy, more especially methoxy,

[0234] Preferably, R3 is a hydroxyl group; and

[0235] -R4 is a hydrogen atom.

[0236] In the intermediate compound of formula (I-A), the following compounds, or deuterated or tritiated forms of the compound of formula (I), or pharmaceutically acceptable salts thereof, may be specifically mentioned:

[0237] (21)(S)-2-thiocarbamoyl-4,4-difluoropyrrolidine-1-carboxylic acid tert-butyl ester;

[0238] (22)(2S,4R)-2-thiocarbamoyl-4-fluoropyrrolidine-1-carboxylic acid tert-butyl ester,

[0239] (23)(2S,4S)-2-thiocarbamoyl-4-fluoropyrrolidine-1-carboxylic acid tert-butyl ester,

[0240] (24) tert-Butyl (6S)-6-thiocarbamoyl-1,1-difluoro-5-azaspiro[2.4]heptane-5-carboxylate,

[0241] (25) tert-Butyl (S)-2-thiocarbamoylpyrrolidine-1-carboxylate,

[0242] (26) tert-Butyl (S)-2-thiocarbamoyl-2-methylpyrrolidine-1-carboxylate,

[0243] (27) tert-Butyl (2S,4R)-2-thiocarbamoyl-4-methoxypyrrolidine-1-carboxylate,

[0244] (28) tert-Butyl (2S,4S)-2-thiocarbamoyl-4-methoxypyrrolidine-1-carboxylate,

[0245] (29) tert-Butyl (2S,5R)-2-thiocarbamoyl-5-methylpyrrolidine-1-carboxylate,

[0246] (30) tert-Butyl (2S,5S)-2-thiocarbamoyl-5-methylpyrrolidine-1-carboxylate,

[0247] (31) tert-Butyl (2S,4S)-2-thiocarbamoyl-4-methylpyrrolidine-1-carboxylate,

[0248] (32) tert-Butyl (2S,4S)-2-thiocarbamoyl-4-(trifluoromethyl)pyrrolidine-1-carboxylate,

[0249] (33) tert-Butyl (2S,4R)-4-((tert-butyldiphenylsilyl)oxy)-2-thiocarbamoylpyrrolidine-1-carboxylate,

[0250] (34) tert-Butyl (2S,3S)-3-((tert-butyldiphenylsilyl)oxy)-2-thiocarbamoylpyrrolidine-1-carboxylate,

[0251] (35) tert-Butyl (2S,3S)-2-thiocarbamoyl-3-methoxypyrrolidine-1-carboxylate,

[0252] (36) tert-Butyl (S)-6-thiocarbamoyl-5-azaspiro[2.4]heptane-5-carboxylate, and

[0253] (37) tert-Butyl (2S,4S)-4-((tert-butyldiphenylsilyl)oxy)-2-thiocarbamoylpyrrolidine-1-carboxylate.

[0254] More particularly, the compounds according to the invention are selected from the group consisting of the following compounds, or deuterated or tritiated forms of the compounds of formula (I), or pharmaceutically acceptable salts thereof:

[0255] (21) (S)-tert-Butyl 2-thiocarbamoyl-4,4-difluoropyrrolidine-1-carboxylate;

[0256] (23) (2S,4S)-tert-Butyl 2-thiocarbamoyl-4-fluoropyrrolidine-1-carboxylate,

[0257] (24) (6S)-tert-Butyl 6-thiocarbamoyl-1,1-difluoro-5-azaspiro[2.4]heptane-5-carboxylate,

[0258] (26) (S)-tert-Butyl 2-thiocarbamoyl-2-methylpyrrolidine-1-carboxylate,

[0259] (28) (2S,4S)-tert-Butyl 2-thiocarbamoyl-4-methoxypyrrolidine-1-carboxylate,

[0260] (29) (2S,5R)-tert-Butyl 2-thiocarbamoyl-5-methylpyrrolidine-1-carboxylate,

[0261] (30) (2S,5S)-tert-Butyl 2-thiocarbamoyl-5-methylpyrrolidine-1-carboxylate,

[0262] (31) (2S,4S)-tert-Butyl 2-thiocarbamoyl-4-methylpyrrolidine-1-carboxylate,

[0263] (32) (2S,4S)-tert-Butyl 2-thiocarbamoyl-4-(trifluoromethyl)pyrrolidine-1-carboxylate,

[0264] (34) (2S,3S)-tert-Butyl 3-((tert-butyldiphenylsilyl)oxy)-2-thiocarbamoylpyrrolidine-1-carboxylate,

[0265] (35) (2S,3S)-tert-Butyl 2-thiocarbamoyl-3-methoxypyrrolidine-1-carboxylate,

[0266] (36) (S)-tert-Butyl 6-thiocarbamoyl-5-azaspiro[2.4]heptane-5-carboxylate, and

[0267] (37) (2S,4S)-tert-Butyl 4-((tert-butyldiphenylsilyl)oxy)-2-thiocarbamoylpyrrolidine-1-carboxylate.

[0268] For the intermediate compound of formula (II-B), R1 and R2 can have any of the specific definitions as in the compound of formula (I) above.

[0269] In one embodiment, in the intermediate compound of formula (II-B):

[0270] - R1 is a (C1 - C6)alkyl group, especially a (C1 - C4)alkyl group, more especially a tert-butyl group, which is unsubstituted or substituted by one or more fluorine atoms,

[0271] - R2 is selected from:

[0272] a hydrogen atom, and

[0273] (C1 - C6)alkyl group, especially a (C1 - C4)alkyl group, more especially a methyl group.

[0274] In another embodiment, in the intermediate compound of formula (III - B):

[0275] - R1 is a (C1 - C6)alkyl group, especially a (C1 - C4)alkyl group, more especially a tert-butyl group, which is unsubstituted or substituted by one to three fluorine atoms, and

[0276] - R2 is a (C1 - C6)alkyl group, especially a (C1 - C4)alkyl group, more especially a methyl group.

[0277] The intermediate compound of formula (II - B) is commercially available. One of them that can be mentioned is 4-methyl-5-[2-(2,2,2-trifluoro-1,1-dimethylethyl)-4-pyridyl]-2-thiazolamine (CAS 1357476-69-7) sold by AURUM pharmatech, 5-[2-(2,2,2-trifluoro-1,1-dimethylethyl)-4-pyridyl]-2-thiazolamine (CAS 1395492-61-1) sold by Carbosynth, and 5-[2-(1,1-dimethylethyl)-4-pyridyl]-2-thiazolamine (CAS 1395492-83-7) sold by Matrix Scientific.

[0278] The following Table 1a and Table 1b respectively contain specific compounds of formula (I) according to the present disclosure (basic chemical formula and structure) and their characterizations (specific optical rotation, 1 1H NMR and high-resolution electrospray ionization mass spectrometry HRMS-ESI).

[0279] The specific optical rotation (αD) was measured on a Perkin Elmer polarimeter (model 341) at 20 °C.

[0280] 1 1H NMR and 1313C NMR spectra were recorded on a Bruker Avance II 500 spectrometer at 500 MHz (for 1H values) or 125 MHz (for 13C values) at a temperature of 300 K. Chemical shifts (δ, in ppm) were referenced to 2.5 ppm in the solvent dimethyl sulfoxide-d6 (d6-DMSO). Coupling constants (J) are reported in Hertz.

[0281] High-resolution mass spectra were recorded on a ThermoFischer Exactive Orbitrap spectrometer.

[0282] Table 1a: Compounds (1) to Compound (20)

[0283]

[0284]

[0285]

[0286]

[0287]

[0288] Table 1b: Characterization of Compounds (1) to Compound (20)

[0289]

[0290]

[0291]

[0292] The following Table 2a and Table 2b respectively contain specific intermediate compounds of formula (I-A) according to the present disclosure (basic chemical formula and structure) and their characterization (specific optical rotation, 1 1H NMR, 13 13C NMR, and high-resolution electrospray ionization mass spectrometry HRMS-ESI).

[0293] The specific optical rotation (αD) was measured on a Perkin Elmer polarimeter (model 341) at 20 °C.

[0294] 1 1H NMR and 13 13C NMR spectra were recorded on a Bruker Avance II 500 spectrometer at 500 MHz (for 1H values) or 125 MHz (for 13C values) at a temperature of 300 K. Chemical shifts (δ, in ppm) were referenced to 2.5 ppm in the solvent dimethyl sulfoxide-d6 (d6-DMSO). Coupling constants (J) are reported in Hertz.

[0295] High-resolution mass spectra were recorded on a ThermoFischer Exactive Orbitrap spectrometer.

[0296] Table 2a: Intermediate compounds (21) to intermediate compounds (37)

[0297]

[0298]

[0299]

[0300]

[0301] Table 2b: Characterization of intermediate compounds (21) to intermediate compounds (37)

[0302]

[0303]

[0304]

[0305] All of the intermediates and compounds described below can be synthesized according to Scheme 1 and Scheme 2.

[0306] The following examples describe the preparation of some intermediate compounds and compounds of formula (I). These examples are not intended to limit the invention and are for illustrative purposes only.

[0307] In the following examples, if the source of the starting product is not indicated, it should be understood that the product is a known product.

[0308] The following abbreviations and empirical formulas are used:

[0309] NEt3 Triethylamine

[0310] DMAP 4-Dimethylaminopyridine

[0311] NaHCO3 Sodium bicarbonate

[0312] DCM Dichloromethane

[0313] Na2SO4 Sodium sulfate

[0314] EtOAc Ethyl acetate

[0315] r.t. Room temperature

[0316] MgSO4 Magnesium sulfate

[0317] THF Tetrahydrofuran

[0318] N2 Nitrogen

[0319] DMSO Dimethyl sulfoxide

[0320] KHSO4 Potassium bisulfate

[0321] TBAF Tetrabutylammonium fluoride

[0322] tBuMgCl tert-Butylmagnesium chloride

[0323] NH4OH Ammonium hydroxide

[0324] DMF N,N-Dimethylformamide

[0325] Example

[0326] Example 1: Synthesis of Intermediate Compounds 21 to 26, 29 to 32, and 36

[0327] Intermediate 26: (S)-2-Thiocarbamoyl-2-methylpyrrolidine-1-carboxylic acid tert-butyl ester

[0328] Intermediate 26 can be obtained from (S)-1-(tert-butoxycarbonyl)-2-methylpyrrolidine-2-carboxylic acid by the method described below.

[0329]

[0330] Step a: (S)-1-(tert-Butoxycarbonyl)-2-methylpyrrolidine-2-carboxylic acid

[0331] At 0 °C, to a solution of commercially available (S)-2-methylpyrrolidine-2-carboxylic acid (400 mg, 3.10 mmol, 1 equiv) in DCM (15 mL) were successively added triethylamine (648 μL, 4.65 mmol, 1.5 eq), di-tert-butyl dicarbonate (853 μL, 3.72 mmol, 1.2 equiv.), and DMAP (57 mg, 464 μmol, 0.15 equiv.). The reaction mixture was stirred at 0 °C for 30 min and at room temperature overnight. The reaction was quenched with saturated aqueous NaHCO3 (15 mL) and extracted with DCM (3 x 15 mL). The organic phase was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was separated by flash chromatography (Cyclo / EtOAc 5 / 5); (2S)-1-(tert-butoxycarbonyl)-2-methylpyrrolidine-2-carboxylic acid was obtained as a colorless oil (461 mg, 65% yield):

[0332] R f 0.60 (Cyclo / EtOAc 1 / 4); [α] D –8 (c 1.0, MeOH);1 1H NMR (500 MHz, MeOD) δ 3.61–3.39 (m, 2H, H5), 2.38–2.10 (m, 1H, H 3a ), 2.04–1.79 (m, 3H, H 3b , H4), 1.51 (d, J = 13.3 Hz, 3H, H 10 ), 1.44 (s, 3H, CH39), 1.42 (s, 6H, 2CH39). 13 13C NMR (126 MHz, MeOD) δ 178.2 (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 O4NNa calcd 252.1206, found 252.1204.

[0333] Step b: (2S)-2-Carbamoyl-2-methylpyrrolidine-1-carboxylic acid tert-butyl ester

[0334] At -10 °C and under argon, isobutyl chloroformate (458 μL, 3.51 mmol, 2.3 equiv.) and triethylamine (212 μL, 1.53 mmol, 1 equiv.) were successively added to a solution of (2S)-1-(tert-butoxycarbonyl)-2-methylpyrrolidine-2-carboxylic acid (350 mg, 1.53 mmol, 1 equiv.) in anhydrous THF (5 mL). The reaction mixture was stirred at 0 °C for 30 min. 0.75 mL of ammonia solution (28% aqueous solution) was added at -10 °C and the reaction mixture was stirred overnight at room temperature. The solvent was removed in vacuo. The residue was dissolved in AcOEt (15 mL), filtered, dried over anhydrous MgSO4 and concentrated in vacuo. The residue was separated by flash chromatography (Cyclo / AcOEt 1 / 1); (2S)-2-Carbamoyl-2-methylpyrrolidine-1-carboxylic acid tert-butyl ester was obtained as a white powder (240 mg, 60% yield):

[0335] R f 0.15 (Cyclo / AcOEt 1 / 1); [α] D –23 (c 1.0, MeOH); 1 1H NMR (500 MHz, MeOD) δ 3.59 (dt, J = 10.3, 7.0 Hz, 1H), 3.47 (dt, J H5a-H5b = 10.4, J H5a-H4= 6.4 Hz, 1H, H 5a ), 2.20 (dt, J H5b-H5a = 13.0, J H5b-H4 = 7.4 Hz, 1H, H 5a ), 2.03–1.93 (m, 1H, H 3a ), 1.96–1.85 (m, 3H, H 3b , H4), 1.53 (d, J = 16.3 Hz, 3H, CH3 10 ), 1.45 (d, J = 6.5 Hz, 9H, 3CH3). 13 C NMR (126 MHz, MeOD) δ 180.6 (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 ). HRMSESI + C 11 H 20 O3N2Na Calcd 251.1366, Found 251.1359.

[0336] Step c: (S)-tert-Butyl 2-thiocarbamoyl-2-methylpyrrolidine-1-carboxylate

[0337] Under argon, Lawesson's reagent (186 mg, 460 μmol, 0.5 equiv.) was added to a solution of (2S)-tert-butyl 2-carbamoyl-2-methylpyrrolidine-1-carboxylate (210 mg, 920 μmol, 1 equiv.) in anhydrous THF (2 mL). The reaction mixture was stirred at room temperature for 3.5 h. The solvent was removed in vacuo. The residue was separated by flash chromatography (Cyclo / AcOEt 1 / 1); Intermediate 26 was obtained as a white powder (204 mg, 91% yield). Characterization details are listed in Table 2b.

[0338] Starting from commercially available starting compounds, similar methods were carried out to obtain Intermediates 21 to 25, 29 to 32 and 36. The characterization of the obtained intermediate compounds is shown in Table 2b.

[0339] Example 2: Synthesis of Intermediate Compounds 27, 28 and 35

[0340] Intermediate 28: (2S,4S)-tert-Butyl 2-thiocarbamoyl-2-methoxypyrrolidine-1-carboxylate

[0341] Intermediate 28 can be obtained from (4S)-4-hydroxypyrrolidine-2-carboxylic acid by the method described below.

[0342]

[0343] Step a: (2S,4S)-1-(tert-Butoxycarbonyl)-4-methoxypyrrolidine-2-carboxylic acid

[0344] Place NaH (55% in mineral oil, 216 mg, 5.4 mmol, 2.5 eq) in a flame-dried two-necked round-bottom flask equipped with a stir bar, N2 inlet, and rubber septum; under N2, wash the hydride with anhydrous pentane (3 × 10 mL) to remove the oil; gently purge the resulting white solid with a stream of N2 until completely dry. After cooling the flask to -20 °C and under N2, slowly add a solution of N-Boc-cis-4-hydroxy-L-proline (500 mg, 2.0 mmol, 1 eq) in a mixture of anhydrous THF (2 mL) and DMSO (0.2 mL) via syringe. Then raise the temperature to 0 °C and stir the heterogeneous mixture for 30 min. Again cool the temperature to -20 °C and add a solution of methyl iodide (333 μL, 5.4 mmol, 2.5 eq) in THF (1.2 mL) via syringe. Finally, set the temperature at 25 °C and stir the reaction mixture until the starting material is completely consumed (TLC analysis). Subsequently, quench the reaction with water (2 mL) and adjust the pH to 4 with 10% aqueous KHSO4 (ca. 2 mL); extract the crude product with EtOAc (5 × 6 mL); wash the organic layer with brine (3 × 4 mL), dry over MgSO4, and remove the solvent in vacuo. The residue was separated by flash chromatography (DCM / MeOH 95 / 5); obtain (2S,4S)-1-(tert-Butoxycarbonyl)-4-methoxypyrrolidine-2-carboxylic acid as a white powder (400 mg, 75% yield):

[0345] R f 0.36 (DCM / MeOH 95 / 5); [α] D –63 (c 1.0, MeOH); 1 H NMR (500 MHz, MeOD) δ 4.34 - 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, CH39), 1.43 (s, 6H, 2CH39). 1313C NMR (126 MHz, MeOD) δ 175.8 (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 O5NNa Calcd for 268.1155, found 268.1152.

[0346] Step b: (2S,4S)-tert-Butyl 2-carbamoyl-4-methoxypyrrolidine-1-carboxylate

[0347] At -10 °C and under argon, isobutyl chloroformate (488 μL, 3.75 mmol, 2.3 equiv.) and triethylamine (227 μL, 1.63 mmol, 1 equiv.) were successively added to a solution of (2S,4S)-1-(tert-butoxycarbonyl)-4-methoxypyrrolidine-2-carboxylic acid (400 mg, 1.63 mmol, 1 equiv.) in anhydrous THF (2 mL). The reaction mixture was stirred at 0 °C for 30 min. 0.75 mL of ammonia (28% aqueous solution) was added at -10 °C, and the reaction mixture was stirred overnight at room temperature. The solvent was removed in vacuo. The residue was dissolved in AcOEt (15 mL), filtered, dried over anhydrous MgSO4, and concentrated in vacuo. The residue was separated by flash chromatography (Cyclo / AcOEt 1 / 1); (2S,4S)-tert-Butyl 2-carbamoyl-4-methoxypyrrolidine-1-carboxylate was obtained as a white powder (292 mg, 73% yield):

[0348] R f 0.25 (Cyclo / AcOEt 1 / 4); [α] D –22 (c 1.0, MeOH); 1 1H NMR (500 MHz, MeOD) δ 4.26–4.13 (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 = 17.6 Hz, 6H, 2CH3). 13CNMR(126MHz, MeOD) δ 178.4 (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 O4N2Na Calcd. 267.1315, Found 267.1313.

[0349] Step c: (2S,4S)-2-Thiocarbamoyl-4-methoxypyrrolidine-1-carboxylic acid tert-butyl ester

[0350] Under argon, Lawesson's reagent (231 mg, 573 μmol, 0.5 equiv.) was added to a solution of (2S,4S)-2-carbamoyl-4-methoxypyrrolidine-1-carboxylic acid tert-butyl ester (280 mg, 1.15 mmol, 1 equiv) in anhydrous THF (2 mL). The reaction mixture was stirred at room temperature for 3.5 h. The solvent was removed in vacuo. The residue was separated by flash chromatography (Cyclo / AcOEt 1 / 1); the intermediate compound 28 (219 mg, 77% yield) was obtained as a white powder. The characterization is detailed in Table 2b.

[0351] Starting from the commercially available starting compounds, similar methods were carried out to obtain intermediates 27 and 35. The characterization of the obtained intermediate compounds is shown in Table 2b.

[0352] Example 3: Synthesis of Intermediate Compounds 33, 34 and 37

[0353] Intermediate 33: (2S,4R)-4-((tert-Butyldiphenylsilyl)oxy)-2-thiocarbamoylpyrrolidine-1-carboxylic acid tert-butyl ester

[0354] Intermediate 33 can be obtained from (2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid by the method described below.

[0355]

[0356] Step (a): N-Boc-trans-4-(OtBDPS)-L-proline

[0357] At 0 °C and under argon, imidazole (775 mg, 11.4 mmol, 4.5 equiv.) and tert-butyldichlorophenylsilane (986 μL, 3.8 mmol, 1.5 equiv.) were successively added to a solution of N-Boc-trans-4-hydroxy-L-proline (585 mg, 2.53 mmol, 1 equiv.) in anhydrous DMF (7 mL). The reaction mixture was stirred at room temperature for 5 days. Water (30 mL) was added at 0 °C, and the reaction mixture was acidified to pH 2 with 1 M HCl, extracted with EtOAc (5 x 15 mL), dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The residue was separated by flash chromatography (Cyclo / EtOAc 9 / 1); N-Boc-trans-4-(OtBDPS)-L-proline was obtained as a white powder (480 mg, 69% yield):

[0358] R f 0.10 (Cyclo / EtOAc 9 / 1); [α] D –14 (c 1.0, MeOH); 1 1H NMR (500 MHz, MeOD) δ 7.71–7.59 (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 = 8.0 Hz, 1H), 3.48–3.39 (m, 1H, H 5a ), 3.31 (ddd, J H5b-H5a = 39.5, 11.3, 4.0 Hz, 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 ). 13 13C 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 (C11 ). HRMS ESI + C 26 H 36 Calculated for C<NO5NSi> 470.2357, found 470.2354.

[0359] Step (b): (2S,4R)-4-((tert-Butyldiphenylsilyl)oxy)-2-carbamoyl-1-pyrrolidinecarboxylic acid tert-butyl ester

[0360] At -10 °C and under argon, isobutyl chloroformate (446 μL, 3.4 mmol, 2.3 equiv.) and triethylamine (208 μL, 1.5 mmol, 1 equiv.) were successively added to a solution of N-Boc-trans-4-(OtBDPS)-L-proline (700 mg, 1.5 mmol, 1 equiv.) in anhydrous THF (4 mL). The reaction mixture was stirred at 0 °C for 30 min. 0.75 mL of ammonia (28% aqueous solution) was added at -10 °C and the reaction mixture was stirred overnight at room temperature. The solvent was removed in vacuo. The residue was dissolved in AcOEt (15 mL), filtered, dried over anhydrous MgSO4 and concentrated in vacuo. The residue was separated by flash chromatography (Cyclo / AcOEt 1 / 1); (2S,4R)-4-((tert-Butyldiphenylsilyl)oxy)-2-carbamoyl-1-pyrrolidinecarboxylic acid tert-butyl ester was obtained as a white powder (662 mg, 94% yield):

[0361] R f 0.35 (Cyclo / AcOEt 1 / 1); [α] D D –9 (c 1.0, MeOH); 1 1H NMR (500 MHz, MeOD) δ 1 1H NMR (500 MHz, MeOD) δ 7.67 - 7.61 (m, 4H, H aro aro ), 7.48 - 7.39 (m, 6H, H aro aro ), 4.47 - 4.44 (m, 1H, H2), 4.42 – 4.34 (m, 1H, H4), 3.53 - 3.43 (m, 1H, H 5a 5a ), 3.36 (dd, J H5b-H5a H5b-H5a = 11.4, J H5b-H4 H5b-H4 = 3.8 Hz, 1H, H 5b 5b ), 2.37 – 2.10 (m, 1H, H 3a 3a ), 1.89 (ddd, J H3b-H3a H3b-H3a = 12.9, J H3b-H4 H3b-H4 = 8.8, J H3b-H2 H3b-H2 = 4.2 Hz, 1H, H 3b 3b), 1.46 (s, 6H, 2CH39), 1.44 (s, 3H, CH39), 1.06 (s, 9H, CH3 11 ). 13 C 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 Calcd. for 469.2517, Found 469.2515.

[0362] Step (c): (2S,4R)-4-((tert-Butyldiphenylsilyl)oxy)-2-thiocarbamoyl pyrrolidine-1-carboxylic acid tert-butyl ester

[0363] Under argon, Lawesson's reagent (280 mg, 693 μmol, 0.5 equiv.) was added to a solution of (2S,4R)-4-((tert-butyldiphenylsilyl)oxy)-2-carbamoyl pyrrolidine-1-carboxylic acid tert-butyl ester (650 mg, 917 μmol, 1 equiv) in anhydrous THF (2 mL). The reaction mixture was stirred at room temperature for 3.5 h. The solvent was removed in vacuo. The residue was separated by flash chromatography (gradient DCM / MeOH 100 / 0 to 98 / 2) to afford the intermediate compound 33 (609 mg, 90% yield) as a colorless oil. The characterization is detailed in Table 2b.

[0364] Starting from the commercially available starting compounds, a similar method was carried out to obtain intermediates 34 and 37. The characterization of the obtained intermediate compounds is shown in Table 2b.

[0365] Example 4: Synthesis of Compounds 1 to 12, 15 and 16

[0366] Compound 5: (S)-2-Thiocarbamoyl-N-(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)thiazol-2-yl)pyrrolidine-1-carboxamide

[0367] 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 method described below.

[0368]

[0369] 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

[0370] 4-Methyl-5-[2-(2,2,2-trifluoro-1,1-dimethylethyl)-4-pyridinyl]-2-thiazolamine is commercially available from AURUM pharmatech.

[0371] 4-Methyl-5-[2-(2,2,2-trifluoro-1,1-dimethylethyl)-4-pyridinyl]-2-thiazolamine (2 g, 6.637 mmol) was dissolved in dichloromethane (60 mL), and 1,1'-carbonyldiimidazole (1.867 g, 11.512 mmol) was added. The reaction mixture was heated under reflux for 14 h, cooled to room temperature, and filtered. The obtained amorphous solid (2.62 g, 95% yield) was used in the next step without further purification.

[0372] Step (b): (S)-pyrrolidine-2-carbothioamide hydrochloride

[0373] Intermediate compound 25 was dissolved in a dioxane solution of HCl (4 N, 90 mL) at 0 °C and stirred at 0 °C for one hour. Subsequently, the reaction mixture was warmed to room temperature and the solvent was removed under vacuum. The white solid was triturated in diethyl ether and filtered to give (2S)-pyrrolidine-2-carbothioamide hydrochloride (5.43 g, quantitative).

[0374] Step (c): (S)-2-carbothioamido-N-(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)thiazol-2-yl)pyrrolidine-1-carboxamide

[0375] 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 (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 give a homogeneous solution. The reaction mixture was stirred at room temperature for 14 h and quenched with water (100 mL). The reaction mixture was extracted with dichloromethane (3 x 30 mL), the organic phase was washed with brine and dried over Na2SO4. The solvent was evaporated under vacuum to give a yellow oil, which was purified by reverse-phase HPLC (gradient MeCN / H2O 45 / 55 to 95 / 5 in 25 min, 90 ml.min -1 ). 300 mg of compound 5 (73%) was obtained. The characterization is detailed in Table 1b.

[0376] Using intermediate compounds 21 to 24, 26 to 32, 35 and 36, a similar method was carried out to obtain compounds 1 to 4, 6 to 12, 15 and 16. The characterization of the obtained compounds is shown in Table 1b.

[0377] Example 5: Synthesis of Compounds 13, 14 and 17

[0378] Compound 17: (2S,4S)-2-carbamothioyl-4-hydroxy-N-(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)thiazol-2-yl)pyrrolidine-1-carboxamide

[0379]

[0380] Compound 47 was obtained from intermediate compounds 37 and 4-methyl-5-[2-(2,2,2-trifluoro-1,1-dimethylethyl)-4-pyridinyl]-2-thiazolamine according to the detailed description of Example 4 above.

[0381] Compound 47 (210 mg) was dissolved in THF (5 mL), and TBAF (1 M solution in THF, 2.5 mL) was added. The solution was stirred at room temperature for 14 h, and water (45 mL) was added. The reaction mixture was extracted with dichloromethane (3 x 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 in 25 min, 90 ml.min -1 ), giving 75 mg of compound 17 (75 mg). The characterization is detailed in Table 1b.

[0382] Using intermediate compounds 33 and 34, a similar method was carried out to obtain compounds 13 and 14. The characterization of the obtained compounds is shown in Table 1b.

[0383] Example 6: Synthesis of Compounds (18), (19) and (20)

[0384] 6.1. Synthesis of 5-(2-(tert-butyl)pyridin-4-yl)-4-methylthiazol-2-amine

[0385]

[0386] Step (a): Synthesis of 2-tert-butyl-4-methylpyridine

[0387]

[0388] CuCN (dried at 140 °C for 3 h, 3.22 g, 36 mmol, 4 equiv) and anhydrous THF (90 ml) were placed in a dry and argon-purged 250 ml Schlenk flask. The mixture was cooled to -78 °C, and 72 ml of tBuMgCl (1 M THF solution, 8 equiv) was added dropwise. After the mixture was stirred at -78 °C for 20 min, 2-bromo-4-methylpyridine (1.55 g, 9 mmol, 1.0 equiv) was added. After the reaction mixture was stirred at -78 °C for 3 h, it was warmed to room temperature for 12 h. The resulting mixture was quenched with saturated aqueous NH4OH (40 ml), and the pH was adjusted to 10 with 1 M aqueous NaOH (55 ml). It was filtered through Celite, and 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 on silica gel (cyclohexane / EtOAc = 9 / 1 v / v) to obtain the corresponding product (0.66 g, 49% yield) as a yellow oil:

[0389] R f 0.35 (Cyclo / AcOEt 9 / 1); 1 1H NMR (500 MHz, DMSO) δ 8.35 (d, J = 4.9 Hz, 1H), 7.29–7.16 (m, 1H), 7.07–6.91 (m, 1H), 2.29 (s, 3H), 1.28 (s, 9H). 13 13C NMR (126 MHz, DMSO) δ 168.7, 148.5, 147.2, 122.2, 120.1, 37.5, 30.5, 21.2.

[0390] Step (b): Synthesis of 1-(2-tert-butylpyridin-4-yl)propan-2-one

[0391]

[0392] A freshly prepared solution of LDA (6.63 mmol in 4 mL of anhydrous THF, 1.5 equiv) was placed in a dry and argon-purged 25 mL three-necked flask. The mixture was cooled to -15 °C, and a solution of 2-tert-butyl-4-methylpyridine (0.66 g, 4.42 mmol, 1 equiv) in 4 mL of anhydrous THF was added dropwise. Then, after stirring the mixture at -15 °C for 30 minutes, a solution of N-methoxy-N-methylacetamide (0.524 g, 5.09 mmol, 1.15 equiv) in 3 mL of anhydrous THF was added dropwise. After stirring the reaction at -15 °C for 1 h 30, it was transferred onto a mixture of 5 mL of 1.5 M aqueous sulfuric acid and 20 mL of toluene at 0 °C. 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 x 2), and the combined organic phases were dried over MgSO4. The solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (cyclohexane / EtOAc 75 / 25 v / v) to give the corresponding product (0.5 g, 59% yield) as a yellow oil:

[0393] R f 0.22 (Cyclo / AcOEt 75 / 25); 1 H 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 C 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.

[0394] Step (c): Synthesis of 5-(2-(tert-butyl)pyridin-4-yl)-4-methylthiazol-2-amine

[0395]

[0396] To a solution of 1-(2-tert-butylpyridin-4-yl)propan-2-one (0.5 g, 2.61 mmol, 1 equiv) in 7.5 ml of anhydrous ethanol was added thiourea (0.22 g, 2.87 mmol, 1.1 equiv). 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 equiv) was added in portions. After the addition was complete, the resulting red clear solution was stirred at 40 °C for 1 h. The mixture was diluted with isopropyl acetate (10 ml) and the yellow-orange suspension was cooled to 0 °C over a period of 1.5 h. After filtration, the fine precipitate was dissolved in 50 ml of DCM / MeOH 9 / 1 v / v. The organic phase was washed with saturated aqueous NaHCO3 (25 ml x 2), saturated aqueous NaCl (25 ml x 1) and dried over MgSO4. The solvent was removed under reduced pressure and the product was used in the next step without purification (0.4 g, 62% yield).

[0397] R f 0.73 (DCM / MeOH 9 / 1); 1 H NMR (500 MHz, DMSO) δ 8.45–8.40 (m, 1H), 7.27–7.17 (m, 3H), 7.09 (dd, J = 5.2, 1.7 Hz, 1H), 2.29 (s, 3H), 1.32 (s, 9H). 13 C NMR (126 MHz, DMSO) δ 168.7, 166.7, 148.7, 146.9, 140.8, 118.8, 116.5, 115.4, 37.1, 29.9, 16.9.

[0398] 6.2. Synthesis of Compound 18

[0399] The synthesis of Compound 18 was carried out according to the method for synthesizing Compound 5 described in Example 4 above, except that 5-(2-(tert-butyl)pyridin-4-yl)-4-methylthiazol-2-amine and Intermediate 25 obtained as described above were used as starting materials to obtain Compound 18. The characterizations are detailed in Table 1b.

[0400] Using Compound D and Intermediate Compounds 23 and 36 in a similar method, Compounds 19 and 20 were obtained. The characterizations of the resulting compounds are shown in Table 1b.

[0401] Example 7: PI3K-Inhibitory Activity

[0402] The enzymatic HTRF (Homogeneous Time Resolved Fluorescence) assay was used to quantitatively determine the inhibitory activity of the compounds against human PtdIns(4,5)P 3-kinase activity.

[0403] PI3K p110a / p65a(h) was incubated in an assay buffer containing 10 μM phosphatidylinositol 4,5-bisphosphate and Mg / ATP (at the required concentrations). The reaction was initiated by adding the ATP solution. After incubation at room temperature for 30 minutes, the reaction was terminated by adding a stop solution containing EDTA and biotinylated phosphatidylinositol-3,4,5-trisphosphate. Finally, a detection buffer containing an europium-labeled anti-GST monoclonal antibody, a GST-labeled GRP1 PH domain, and streptavidin allophycocyanin was added. Subsequently, the plate was read in the time-resolved fluorescence mode, and the homogeneous time-resolved fluorescence (HTRF) signal was determined according to the formula HTRF = 10000 x (Em665nm / Em620nm).

[0404] Results

[0405] The tested compounds were classified according to their IC50 as follows:

[0406] A: IC50 activity less than or equal to 50 nM;

[0407] B: IC50 strictly greater than 50 nM and up to 200 nM;

[0408] C: IC50 strictly greater than 200 nM and up to 500 nM;

[0409] D: IC50 strictly greater than 500 nM and up to 1000 nM;

[0410] E: IC50 strictly greater than 1 μM

[0411]

[0412] Thus, it is obvious that the tested compounds of formula (I) according to the present invention are potent inhibitors of PI3K kinase, especially PI3K-α kinase. Most of the compounds further exhibit selective inhibitory activity against PI3K-α kinase relative to PI3K-β and / or PI3K-γ and / or PI3K-δ.

[0413] Therefore, the compounds of formula (I) can be used to prepare drugs, especially drugs for preventing and / or treating protein tyrosine kinase-mediated diseases, especially PI3K-mediated diseases, more especially diseases mediated by the α subtype of PI3K.

[0414] Accordingly, on the other hand, 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 any pharmaceutically acceptable salt thereof, particularly at least any one of compounds (1) to (20) for use as a medicament.

[0415] In particular, the compound of formula (I) can be used for treating and / or preventing conditions mediated by protein tyrosine kinases, particularly PI3K, especially PI3Kα.

[0416] According to another aspect thereof, the present invention thus relates to a compound of formula (I), or a deuterated or tritiated form of a compound of formula (I), or any pharmaceutically acceptable salt thereof for treating and / or preventing the following diseases: protein tyrosine kinase-mediated diseases, particularly PI3K-mediated diseases, more particularly PI3Kα-mediated diseases.

[0417] Another aspect of the present disclosure relates to the use of a compound of formula (I), or a deuterated or tritiated form of a compound of formula (I), or any pharmaceutically acceptable salt thereof for treating and / or preventing the following diseases: protein tyrosine kinase-mediated diseases, particularly PI3K-mediated diseases, more particularly PI3Kα-mediated diseases.

[0418] Another aspect of the present disclosure relates to the use of a compound of formula (I), or a deuterated or tritiated form of a compound of formula (I), or any pharmaceutically acceptable salt thereof for preparing / manufacturing a composition (such as a medicament) for treating and / or preventing protein tyrosine kinase-mediated diseases, particularly PI3K-mediated diseases, more particularly PI3Kα-mediated diseases.

[0419] A method for treating and / or preventing protein tyrosine kinase-mediated diseases, particularly PI3K-mediated diseases, more particularly PI3Kα-mediated diseases is also described.

[0420] The methods and uses as defined above may comprise administering to a subject in need a therapeutically effective amount of a compound of formula (I), or a deuterated or tritiated form of a compound of formula (I), or a pharmaceutically acceptable salt thereof; or a pharmaceutical composition comprising the same.

[0421] The protein tyrosine kinase-mediated diseases targeted by the uses and methods according to the present invention may more particularly be PI3K related Overgrowth Spectrum (PROS), proliferative diseases (particularly cancer), and inflammatory diseases (including autoimmune disorders), as detailed below.

[0422] The protein tyrosine kinase-mediated diseases targeted by the uses and methods according to the present invention may more particularly also be mitochondrial genetic diseases.

[0423] The protein tyrosine kinase-mediated diseases targeted by the uses and methods according to the present invention may more particularly be selected from the group consisting of: keloid; hypertrophic scar, including burn scar; and hyperpigmentation.

[0424] More particularly, the protein tyrosine kinase-mediated diseases, in particular phosphatidylinositol 3-kinase-mediated diseases, targeted by the uses and methods according to the present invention may be selected from the group consisting of: PI3K-related overgrowth spectrum (PROS); neurofibromatosis; mitochondrial genetic diseases; keloid; hypertrophic scar, including burn scar; hyperpigmentation; proliferative diseases, in particular cancer; inflammatory diseases, including autoimmune disorders; and glomerulonephritis; more particularly selected from the group consisting of: keloid; hypertrophic scar, including burn scar; and hyperpigmentation.

[0425] PI3K-related overgrowth spectrum

[0426] PI3K-related overgrowth spectrum is a group of diseases including, but not limited to: fibroadipose overgrowth (FAO), megalencephaly-capillary malformation (MCAP) syndrome, congenital trunk lipomatosis with asymmetric overgrowth, lymphatic, capillary, venous, and combined vascular malformations, epidermal nevus, complex regional overgrowth of bone and spine (CLOVES) syndrome, hemihyperplasia with multiple lipomas (HHML), Klippel-Trenaunay syndrome, solitary and complex venous malformations, solitary and complex lymphatic malformations, or combined complex vascular malformations (see, for example: 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 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).

[0427] Fibroadipose overgrowth (FAO) is a syndrome characterized mainly by segmental progressive overgrowth of subcutaneous, muscular, and visceral fibroadipose tissue, accompanied by skeletal overgrowth.

[0428] The main features of megalencephaly-capillary malformation (MCAP) syndrome consist of the presence of (1) megalencephaly (MEG) or hemimegalencephaly (HMEG), with neurological manifestations of hypotonia, epilepsy, and mild to severe intellectual disability; and (2) cutaneous capillary malformations, with focal or generalized somatic overgrowth.

[0429] CLOVES involves congenital, lipomatosis, overgrowth, vascular malformations, epidermal nevi, and spinal / skeletal anomalies and / or scoliosis. This syndrome is characterized by complex congenital overgrowth of lipomatous tissue (usually presenting as a truncal lipomatous mass), accompanied by vascular and lymphatic malformations.

[0430] Hemihyperplastic multiple lipomatosis (HHML) is a condition characterized by asymmetric non-progressive overgrowth, multiple lipomas, and superficial vascular malformations.

[0431] Klippel-Trenaunay syndrome is a rare congenital medical condition in which blood vessels and / or lymphatic vessels fail to form properly.

[0432] According to one aspect, the patient to be treated may have a PIK3CA mutation, in particular a PIK3CA mutation selected from the group consisting of: mutation H1047R, mutation C420R, mutation H1047L, mutation E542K, mutation E545K, and / or mutation Q546R.

[0433] Neurofibromatosis

[0434] Neurofibromatosis is a rare genetic disorder that typically causes benign tumors on or just under the skin and on nerves near the spine or along other parts of the body. There are three types of neurofibromatosis (NF): neurofibromatosis type 1 (NF1), neurofibromatosis type 2 (NF2), and schwannomatosis. Neurofibromatosis type 1 (NF1) is caused by a mutation in the NF1 gene, resulting in the production of a non-functional 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 genetic disorder. Neurofibromatosis type 2 (NF2) is caused by a mutation in the NF2 gene, resulting in neurofibromatosis type 2. NF2 is also known as the MISME syndrome, i.e., multiple inherited schwannomas, meningiomas, and ependymomas. The signs and symptoms of NF2 usually result from the development of benign, slow-growing tumors (acoustic neuromas) in both ears. These tumors are also called vestibular schwannomas, and they grow on the nerves that transmit sound and balance information from the inner ear to the brain. Schwannomatosis causes tumors to grow on the skull (cranium), spine, and peripheral nerves, but not on the nerves that transmit sound and balance information from the inner ear to the brain. For information on neurofibromatosis, reference can be made to PCT application WO2020053125.

[0435] Keloids, hypertrophic scars, and hyperpigmentation disorders

[0436] Regarding the use of PI3K inhibitors in the treatment of these diseases, reference can be made, for example, to PCT application WO2020201073. Reference can also be made to Mari W. et al. (J Am Coll Clin Wound Spec. 2016 Nov 30; 7(1-3): 1-7).

[0437] Typically, the boundaries of a scar are clear. However, in some cases, fibroblasts and myofibroblasts overproduce collagen (types I and III), leading to hypertrophic scars. These hypertrophic scars are limited to the original wound area. Importantly, in some cases, due to the overexpression of cytokines and growth factors, a large amount of extracellular matrix, especially collagen (types I and III), is generated, and the scar may grow outward from the original injured area and invade the adjacent dermal tissue. These scars are called keloids.

[0438] As used herein, the term "keloid" refers to an excessive accumulation of extracellular matrix proteins, resulting in excessive collagen formation. In genetically susceptible individuals, abnormal skin scars may appear after injury. As used herein, the term "keloid" refers to a hypertrophic scar in which dense fibrous tissue extends beyond the boundaries of the original wound or incision and usually does not resolve on its own.

[0439] As used herein, the term "hypertrophic scar" refers to the excessive growth of dense fibrous tissue resulting from abnormal wound healing. Unlike keloids, hypertrophic scars do not extend beyond the original boundaries of the wound. In addition, 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.

[0440] As used herein, the terms "hyperpigmentation disorder" or "hyperpigmented skin disorder" are used interchangeably and refer to the darkening of skin or nail areas due to increased melanin. Hyperpigmentation disorders are caused by one of two conditions: (1) the production of melanin by an abnormally high concentration of melanocytes; or (2) when 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 consisting of, and particularly consisting of: solar lentigines, melasma, freckles, senile lentigines, post-acne hyperpigmentation, and post-inflammatory hyperpigmentation.

[0441] The terms "freckle / sunspot" or "solar lentigines" are also known as sun-induced freckles or senile freckles and refer to dark (hyperpigmented) lesions caused by natural or artificial ultraviolet (UV) light. "Melasma" is also known as pregnancy-induced melasma. It is also known as the mask of pregnancy or chloasma. The pigmentation of melasma is usually symmetric and has clearly defined borders. The term "freckle" refers to flat, round spots that are usually brownish or light brown in color. Although freckles are a very common form of pigmentation, they are more common in people with lighter skin tones. The term "senile lentigines" refers to those that are brownish, brown, or black in color. Senile lentigines are oval-shaped and range in size from the size of a freckle to over 13 mm. Senile lentigines are also known as liver spots and usually appear on the face and other areas exposed to light after the age of 40. "Post-acne hyperpigmentation" refers to spots caused by acne. In some ethnic groups, they can be observed in over 60% of acne cases. In most cases, the darkly colored pigment spots are due to the overproduction of melanin in response to skin inflammation in the affected area. Without proper treatment, post-acne hyperpigmentation may take months or even years to fade. The term "post-inflammatory hyperpigmentation" refers to spots caused by skin injury or inflammation, in which case the production of pigment increases.

[0442] Cancer

[0443] The compound of formula (I) as defined above, or a deuterated or tritiated form of the compound of formula (I), or a pharmaceutically acceptable salt thereof can be used for the treatment or prevention of various cancers.

[0444] Specifically, the compound of formula (I) can be used as an anticancer agent, particularly for the treatment of cancers detailed below.

[0445] In cancer, the following cancers can be enumerated: blood-related cancers, pancreatic cancer, urinary system 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 (such as non-small cell lung cancer and small cell lung cancer), ovarian cancer, cervical cancer, gastric cancer, endometrial cancer, esophageal cancer, head and neck cancer (such as head and neck squamous cell carcinoma (HNSCC)), melanoma, neuroendocrine cancer, CNS cancer, brain cancer (such as glioma, glioblastoma, anaplastic oligodendroglioma, and anaplastic astrocytoma), bone cancer, hematological cancers (such as leukemia, lymphoma, and myeloma), soft tissue sarcoma, retinoblastoma, neuroblastoma, ascites, malignant pleural effusion, mesothelioma, Wilms tumor, trophoblastic tumor, hemangiopericytoma, Kaposi sarcoma, mucinous carcinoma, round cell carcinoma, squamous cell carcinoma, esophageal squamous cell carcinoma, oral cancer, adrenocortical carcinoma, or ACTH-producing tumor.

[0446] According to one embodiment, the following cancers can be enumerated: bladder cancer, breast cancer, lung cancer (such as non-small cell lung cancer and small cell lung cancer), ovarian cancer, cervical cancer, kidney cancer, liver cancer, head and neck cancer (such as head and neck squamous cell carcinoma (HNSCC)), sarcoma, brain cancer (such as glioma, glioblastoma, anaplastic oligodendroglioma, and anaplastic astrocytoma), or hematological cancers (such as leukemia, lymphoma, and myeloma).

[0447] According to another embodiment, the cancer can be selected from: head and neck cancer, head and neck squamous cell carcinoma, cervical squamous cell carcinoma, adult or pediatric acute lymphoblastic leukemia (ALL), adult or pediatric acute myeloid leukemia (AML), acute lymphoblastic leukemia, astrocytoma, B-cell or NK / T-cell lymphoma, cholangiocarcinoma, bladder cancer, adult brain and spinal cord tumors, pediatric brain and spinal cord tumors, anaplastic astrocytoma, breast cancer in females, breast cancer in young females, breast cancer in males, recurrent breast cancer, hereditary breast cancer, HER2-positive breast cancer, breast cancer associated with lymph node metastasis, ER-α-positive breast cancer, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), chronic myelomonocytic leukemia (CMML), epithelial ovarian cancer, epithelial ovarian cancer with metastasis, Ewing sarcoma, Ewing family of tumors, lymphoblastic leukemia (ALL), eye cancer (such as 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 of the breast, Hodgkin lymphoma, Kaposi sarcoma, leiomyosarcoma, leukemia, pediatric leukemia, pulmonary carcinoid tumor, lymphoma, cutaneous lymphoma, mantle cell lymphoma, medulloblastoma, melanoma skin cancer, malignant melanoma, neuroblastoma, glioma, non-Hodgkin lymphoma, pediatric non-Hodgkin lymphoma, non-small cell lung cancer, gefitinib-resistant non-small cell lung cancer, osteosarcoma, pulmonary metastatic osteosarcoma, or lymphoproliferation.

[0448] Lymphoproliferation or lymphoproliferative disease (LPD) refers to a heterogeneous group of diseases characterized by uncontrolled production of lymphocytes, leading to monoclonal lymphocytosis, lymphadenopathy, and bone marrow infiltration. Such diseases typically occur in immunocompromised individuals. There are two subsets of lymphocytes: T cells and B cells, which proliferate out of control, thereby triggering immunoproliferative diseases that are prone to cause immunodeficiency, immune system dysfunction, and lymphocytic dysregulation.

[0449] In a specific embodiment, the lymphoproliferative disease is a B-cell lymphoproliferative disease.

[0450] In a specific embodiment, the B-lymphocyte proliferative disease is selected from, but not limited to, the group consisting of: Hodgkin lymphoma, diffuse large B-cell lymphoma, acute lymphoblastic leukemia, lymphoid blastic phase Chrome Myeloid 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 lymphoma, hairy cell leukemia, primary central nervous system lymphoma, splenic marginal zone B-cell lymphoma, Waldenstrom macroglobulinemia / lymphoplasmacytic lymphoma, multiple myeloma, plasma cell disease, plasma cell tumor, primary mediastinal B-cell lymphoma, Hodgkin disease or Castleman Disease.

[0451] In a specific embodiment, the lymphocytic proliferative disease is a T-cell lymphocytic proliferative disease.

[0452] In a specific embodiment, the T-lymphoproliferative disease is selected from, but not limited to, the group consisting of: leukemia / lymphoma, extranodal natural killer / T-cell lymphoma, cutaneous T-cell lymphoma, enteropathy-type T-cell lymphoma, angioimmunoblastic T-cell lymphoma, anaplastic large T-cell / null cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, T-cell acute lymphoblastic leukemia, T-cell large granular lymphocytic leukemia, lymphoid blastic phase chronic myeloid leukemia, post-transplant lymphoproliferative syndrome, human T-cell leukemia virus type 1 positive (HTLV-G), adult T-cell leukemia / lymphoma (ATL), T-cell prolymphocytic leukemia (TPLL) or T-cell lymphoma, unspecified.

[0453] According to one embodiment, the patient does not exhibit clinically detectable metastases, particularly when the patient has a pre-cancerous condition, early cancer or non-metastatic cancer, or the patient exhibits clinically detectable metastases and the compound of formula (I), or a deuterated or tritiated form of the compound of formula (I), or any pharmaceutically acceptable salt thereof does not directly target the invasion of metastases.

[0454] Glomerulonephritis

[0455] Glomerulonephritis is a group of kidney diseases characterized by immune-mediated damage to the basement membrane, mesangium or capillary endothelium, which results in hematuria, proteinuria and azotemia and involves damage to the glomeruli.

[0456] The glomerulonephritis according to the present invention can be particularly proliferative or non-proliferative.

[0457] Non-proliferative glomerulonephritis is characterized by the absence of glomerular cell proliferation and typically presents with nephrotic syndrome.

[0458] Proliferative glomerulonephritis (PGN) refers to an increase in the cellularity of glomeruli due to proliferation of intrinsic glomerular cells, leukocyte infiltration, or both. This mainly occurs in the context of deposition of immunoglobulins, immune complexes, or complement components in the glomeruli. Different subtypes are described based on histological features: mesangial cell proliferation, endocapillary proliferation, diffuse proliferation, or extracapillary proliferation (also known as crescentic glomerulonephritis).

[0459] Proliferative glomerulonephritis can be caused by diseases selected from the group consisting of, but not limited to: infectious diseases (post-streptococcal glomerulonephritis, infective endocarditis, occult visceral sepsis, hepatitis B infection with vasculitis and / or cryoglobulinemia, HIV infection, hepatitis C with cryoglobulinemia, membranoproliferative glomerulonephritis), multisystem diseases (systemic lupus erythematosus, IgA nephropathy, allergic purpura purpura), systemic necrotizing vasculitis, including granulomatosis with polyangtiitis type Wegener, Goodpasture syndrome, primary mixed cryoglobulinemia, malignancies, relapsing polychondritis, rheumatoid arthritis - with vasculitis).

[0460] In a specific embodiment, proliferative glomerulonephritis is caused by systemic lupus erythematosus. The term "systemic lupus erythematosus" (SLE) as used herein refers to a systemic autoimmune disease that is thought to exhibit widespread immunoregulatory abnormalities. It is the most common type of lupus.

[0461] Proliferative glomerulonephritis can be lupus nephritis.

[0462] The term "lupus nephritis" (LN) as used herein refers to kidney inflammation caused by systemic lupus erythematosus (SLE). Up to 60% of lupus patients develop LN. When the kidneys become inflamed, they are unable to properly filter toxins, by-products, excess salt, excess fluid, and other impurities from the blood. If left uncontrolled, LN can lead to kidney failure. Even with treatment, it sometimes progresses to loss of kidney function. If both kidneys fail, LN patients may require dialysis. Eventually, LN patients may need to receive a kidney transplant. Symptoms of loss or abnormality of kidney function include increased protein content in the urine (proteinuria), the presence of foam in the subject's urine, and / or elevated blood urea nitrogen (BUN) levels.

[0463] In a specific embodiment, the subject is a person suffering from or predisposed to an infectious disease (post-streptococcal glomerulonephritis, infective endocarditis, occult visceral sepsis, hepatitis B infection with vasculitis and / or cryoglobulinemia, HIV infection, hepatitis C with cryoglobulinemia, membranoproliferative glomerulonephritis) or a multi-system disease (systemic lupus erythematosus, IgA nephropathy, allergic purpura, systemic necrotizing vasculitis, including Wegener's granulomatosis, Goodpasture's syndrome, essential mixed cryoglobulinemia, malignancy, relapsing polychondritis, rheumatoid arthritis - with vasculitis).

[0464] Mitochondrial genetic diseases

[0465] Mitochondrial genetic diseases refer to a group of clinically and genetically heterogeneous diseases caused by mitochondrial dysfunction. Mitochondrial genetic diseases are caused by mutations in mitochondrial DNA or nuclear DNA, resulting in mitochondrial dysfunction and insufficient energy production. Mitochondrial genetic diseases can particularly be selected from the group consisting of: mitochondrial cytopathy; aminoglycoside-induced deafness; chronic progressive external ophthalmoplegia; failure syndrome; Kearns-Sayre syndrome; Leber hereditary optic neuropathy; Leigh syndrome; cerebellar hypoplasia, mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS); myoclonic epilepsy and ragged-red fiber disease; maternally inherited Leigh syndrome; neurogenic weakness, ataxia and retinitis pigmentosa; Pearson syndrome; microcephaly, optic atrophy, lactic acidosis, optic nerve atrophy, spastic paraplegia, Friedreich ataxia, sideroblastic anemia and ataxia, sideroblastic anemia, encephalomyopathy, tubulopathy, ataxia, hypertrophic cardiomyopathy LS and Alpers syndrome.

[0466] The compound of formula (I) according to the present invention, or a deuterated or tritiated form of the compound of formula (I), or a pharmaceutically acceptable salt thereof may be particularly suitable for the treatment and / or prevention of phosphatidylinositol 3-kinase-related overgrowth syndrome group (PROS), particularly congenital PROS, lipoma, overgrowth, vascular malformation, epidermal nevus, spinal / skeletal abnormalities and / or Cobb's syndrome (CLOVES).

[0467] The compound of formula (I) according to the present invention, or a deuterated or tritiated form of the compound of formula (I), or a pharmaceutically acceptable salt thereof may be particularly suitable for the treatment and / or prevention of cancer, such as the cancers listed above.

[0468] The present invention also describes the use of a compound of formula (I), or a deuterated or tritiated form of a compound of formula (I), or a pharmaceutically acceptable salt thereof, for the treatment and / or prevention of cancer (such as the cancers listed above).

[0469] The compound of formula (I), or a deuterated or tritiated form of a compound of formula (I), or a pharmaceutically acceptable salt thereof, can be used in monotherapy or in combination with another therapy selected from: chemotherapy, immunotherapy, radiotherapy, surgery, ultrasound, monoclonal antibodies, anti-tumor vaccines, RNA vaccines, cancer vaccines, magnetic particles, intravascular micro-robots.

[0470] 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 anti-tumor agent, which anti-tumor agent is intended for use in patients being treated simultaneously with any one of the following therapies: chemotherapy, immunotherapy, radiotherapy, surgery, ultrasound, monoclonal antibodies, anti-tumor vaccines, RNA vaccines, cancer vaccines, magnetic particles, intravascular micro-robots.

[0471] According to another aspect thereof, the present invention relates to a medicament comprising a compound of formula (I), or a deuterated or tritiated form of a compound of formula (I), or any pharmaceutically acceptable salt thereof.

[0472] The medicament can be used, for example, for the therapeutic treatment and / or prevention of protein tyrosine kinase-mediated diseases, especially PI3K-mediated diseases, more especially PI3Kα-mediated diseases, in particular the diseases and disorders detailed above.

[0473] According to another aspect thereof, the present invention relates to a pharmaceutical composition comprising at least one 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, especially at least one of compounds (1) to (20). These pharmaceutical compositions especially comprise an effective dose of 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.

[0474] The pharmaceutical compositions according to the present invention can comprise one or more compounds of the present invention in any form as described herein.

[0475] These compounds can be administered by any route of administration, such as topically, intramuscularly, intravenously, intranasally, subcutaneously or orally, as a suppository, etc.

[0476] In one embodiment, the pharmaceutical composition according to the present invention is selected from 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.

[0477] The pharmaceutical composition of the present invention may further comprise at least one pharmaceutically acceptable excipient.

[0478] Depending on the pharmaceutical form and the desired mode of administration, the excipients are selected from the conventional excipients known to those skilled in the art. They may be selected from carriers, glidants, 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 Edition" (multiple editors, 1989 - 1998, Marcel Dekker) and "Pharmaceutical Dosage Forms and Drug Delivery Systems" (ANSEL et al., 1994, WILLIAMS & WILKINS).

[0479] The compounds of the present invention can be used in monotherapy or in combination with radiotherapy or chemotherapy. In one embodiment, the pharmaceutical composition of the present invention may further comprise at least one other chemotherapeutic agent.

[0480] Example 8: The compound of the present invention improves kidney damage in a lupus model

[0481] Compound 5 of the present invention was tested in NZBWF1 / J mice, which is a mature model showing lupus-like nephritis (Celhar, T. & Fairhurst, A.M. Modelling clinical systemic lupus erythematosus: similarities, differences and success stories. Rheumatology (Oxford) 56, i88 - i99 (2017)). NZBWF1 / J mice gradually develop immune glomerulonephritis characterized by proteinuria and renal dysfunction starting from about 25 weeks of age. Using a unilateral nephrectomy model, 12 female mice at 24 weeks of age were subjected to unilateral nephrectomy.

[0482] Since the incidence and severity of symptoms were more pronounced in females, only females were used in this study. Mice were then randomly assigned to receive vehicle (n = 6) or compound 5 (50 mg / kg / day, n = 6) orally for 4 weeks. At the end of the treatment period, the mice were sacrificed and their kidney histology was compared with samples obtained from unilateral nephrectomy.

[0483] At the time of unilateral nephrectomy, no significant differences were observed between the two groups in phenotypic characteristics, including proteinuria and kidney weight ratio. However, after sacrificing the mice, the mice treated with compound 5 showed decreased albuminuria ( Figure 1 A) and blood urea nitrogen levels ( Figure 1 B).

[0484] In addition, in NZBWF1 / J mice with unilateral nephrectomy receiving compound 5, the kidney weight ratio was significantly decreased. Histologically, compared with the mice receiving vehicle, the mice treated with compound 5 showed preserved glomeruli ( Figure 1 C). Although glomerular injury significantly worsened in vehicle-treated NZBWF1 / J mice with unilateral nephrectomy, it remained stable in the compound 5 group

[0485] Collectively, these results indicate that the compounds according to the present invention mitigate glomerulonephritis injury, especially lupus nephritis.

[0486] Example 9: The compound of the present invention causes a slight increase in blood glucose

[0487] 8-week-old C57Bl6 mice (n = 6 mice per group, 3 males and 3 females) were treated daily by oral gavage with vehicle or compound 5 (50 mg / kg) for 5 days.

[0488] On day 6, blood glucose concentrations were measured at different time points before and after dosing.

[0489] Existing compounds on the market are known to reach peak blood glucose approximately 2 hours after oral gavage, while compound 5 only caused a moderate increase in blood glucose. Ordinary one-way ANOVA multiple comparisons: significance was significant at 2 h.

[0490] Example 10: The compound of the present invention does not increase blood insulin concentration

[0491] 8-week-old C57Bl6 mice (n = 3 mice per group, 3 males) were treated daily by oral gavage with vehicle or compound 5 (50 mg / kg) for 5 days. On day 6, insulin concentrations were measured at different time points before and after dosing.

[0492] Plasma insulin levels (7 μL, repeated twice) were measured using MSD u.plex (Mesoscale, ref 1526HK).

[0493] The currently available compounds on the market are known to reach peak insulin levels approximately 4 hours after oral gavage and persist until 8 hours after dosing, while Compound 5 does not cause an increase in blood insulin concentration ( Figure 2 ).

Claims

1. A compound of formula (I), or a deuterated or tritiated form of a compound of formula (I), or a pharmaceutically acceptable salt thereof: Wherein: - R1 is (C1-C6)alkyl or (C3-C6)cycloalkyl, which is unsubstituted or substituted with one or more fluorine atoms; - R2 is selected from: a hydrogen atom, and (C1-C6)alkyl, - m is 0, 1 or 2; - When present, each R3 is independently selected from: a fluorine atom, (C1-C6)alkyl, which is unsubstituted or substituted with one or more halogen atoms, (C3-C6)cycloalkyl, which is unsubstituted or substituted with one or more halogen atoms, a hydroxyl group, (C1-C6)alkoxy, and -NRR' group, where R and R' are independently selected from a hydrogen atom and (C1-C6)alkyl, or two R3 are connected through the same carbon atom, and two R3 and the carbon atom to which they are connected form a (C3-C6)cycloalkyl ring, which is unsubstituted or substituted with one or more fluorine atoms; and - R4 is selected from: a fluorine atom, a hydrogen atom, (C1-C6)alkyl, which is unsubstituted or substituted with one or more halogen atoms, and (C3-C6)cycloalkyl, which is unsubstituted or substituted with one or more halogen atoms, or when R3 and R4 are connected through two adjacent carbon atoms, R3 and R4 and the carbon atoms to which they are connected form a (C3-C6)cycloalkyl ring, which is unsubstituted or substituted with one or more halogen atoms.

2. The compound of formula (I), or a deuterated or tritiated form of a compound of formula (I), or a pharmaceutically acceptable salt thereof according to claim 1, wherein R1 is (C1-C6)alkyl, especially (C1-C4)alkyl, more especially tert-butyl, which is unsubstituted or substituted with one or more fluorine atoms.

3. The compound of formula (I), or a deuterated or tritiated form of a compound of formula (I), or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein R2 is (C1-C6)alkyl, especially (C1-C4)alkyl, more especially methyl.

4. The compound of formula (I), or a deuterated or tritiated form of a compound of formula (I), or a pharmaceutically acceptable salt thereof according to any one of claims 1-3, wherein m is 1 or 2, and each R3 is independently selected from: a fluorine atom, (C1-C6)alkyl, especially (C1-C4)alkyl, more especially methyl, which is unsubstituted or substituted with one or more halogen atoms; for example, methyl or trifluoromethyl; a hydroxyl group, and (C1-C6)alkoxy, especially (C1-C4)alkoxy, more especially methoxy; or wherein m is 2, and two R3 are connected through the same carbon atom, and two R3 and the carbon atom to which they are connected form a (C3-C6)cycloalkyl ring, especially a cyclopropyl ring, which is unsubstituted or substituted with one or more fluorine atoms.

5. The compound of formula (I), or a deuterated or tritiated form of a compound of formula (I), or a pharmaceutically acceptable salt thereof according to any one of claims 1-4, wherein R4 is selected from: a hydrogen atom, and (C1-C6)alkyl, especially (C1-C4)alkyl, more especially methyl, which is unsubstituted or substituted by one or more halogen atoms, especially by one or more fluorine atoms.

6. The compound of formula (I) as claimed in any one of claims 1-5, or the deuterated or tritiated form of the compound of formula (I), or a pharmaceutically acceptable salt thereof, said compound being selected from the following compounds: (1) (S)-2-thiocarbamoyl-4,4-difluoro-N-(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)thiazol-2-yl)pyrrolidine-1-carboxamide, (2) (2S,4R)-2-thiocarbamoyl-4-fluoro-N-(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)thiazol-2-yl)pyrrolidine-1-carboxamide, (3) (2S,4S)-2-thiocarbamoyl-4-fluoro-N-(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)thiazol-2-yl)pyrrolidine-1-carboxamide, (4) (S)-6-thiocarbamoyl-N-(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)-1,1-difluoro-5-azaspiro[2.4]heptane-5-carboxamide, (5) (S)-2-thiocarbamoyl-N-(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)thiazol-2-yl)pyrrolidine-1-carboxamide, (6) (S)-2-thiocarbamoyl-2-methyl-N-(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)thiazol-2-yl)pyrrolidine-1-carboxamide, (7) (2S,4R)-2-thiocarbamoyl-4-methoxy-N-(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)thiazol-2-yl)pyrrolidine-1-carboxamide, (8) (2S,4S)-2-thiocarbamoyl-4-methoxy-N-(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)thiazol-2-yl)pyrrolidine-1-carboxamide, (9) (2S,5R)-2-thiocarbamoyl-5-methyl-N-(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)thiazol-2-yl)pyrrolidine-1-carboxamide, (10) (2S,5S)-2-thiocarbamoyl-5-methyl-N-(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)thiazol-2-yl)pyrrolidine-1-carboxamide, (11) (2S,4S)-2-Thiocarbamoyl-4-methyl-N-(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)thiazol-2-yl)pyrrolidine-1-carboxamide, (12) (2S,4S)-2-Thiocarbamoyl-N-(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)thiazol-2-yl)-4-(trifluoromethyl)pyrrolidine-1-carboxamide, (13) (2S,4R)-2-Thiocarbamoyl-4-hydroxy-N-(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)thiazol-2-yl)pyrrolidine-1-carboxamide, (14) (2S,3S)-2-Thiocarbamoyl-3-hydroxy-N-(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)thiazol-2-yl)pyrrolidine-1-carboxamide, (15) (2S,3S)-2-Thiocarbamoyl-3-methoxy-N-(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)thiazol-2-yl)pyrrolidine-1-carboxamide, (16) (S)-6-Thiocarbamoyl-N-(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)thiazol-2-yl)-5-azaspiro[2.4]heptane-5-carboxamide, (17) (2S,4S)-2-Thiocarbamoyl-4-hydroxy-N-(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)thiazol-2-yl)pyrrolidine-1-carboxamide, (18) (S)-2-Thiocarbamoyl-N-(4-methyl-5-(2-tert-butyl-pyridin-4-yl)thiazol-2-yl)pyrrolidine-1-carboxamide, (19) (2S,4S)-2-Thiocarbamoyl-4-fluoro-N-(4-methyl-5-(2-tert-butyl-pyridin-4-yl)thiazol-2-yl)pyrrolidine-1-carboxamide, and (20) (S)-6-Thiocarbamoyl-N-(4-methyl-5-(2-tert-butyl-pyridin-4-yl)thiazol-2-yl)-5-azaspiro[2.4]heptane-5-carboxamide.

7. A method for preparing a compound of formula (I) as defined in any one of claims 1-6, or a deuterated or tritiated form of a compound of formula (I), or a pharmaceutically acceptable salt thereof, the method comprising a coupling reaction between a compound of formula (II-A) and a compound of formula (II-B): wherein R3, R4, m, R2 and R1 are as described in any one of claims 1-5, provided that when R3 is a hydroxyl group, R3 in compound II-A is protected before the coupling reaction, for example, protected with a tert-butyldiphenylsilyl ether (tBDPS) protecting group; and deprotected after the coupling reaction; The coupling reaction is preferably carried out at room temperature using triethylamine in a polar aprotic organic solvent such as dimethylformamide; Before carrying out the coupling reaction, the step of obtaining compound II-A is optionally carried out, wherein compound II-A is obtained by a deprotection step, for example, by an aqueous HCl solution, from a compound of formula (I-A); wherein R3, R4 and m are as defined in any one of claims 1, 4 and 5, or R3 is a protected hydroxyl group, for example, a hydroxyl group protected with a tert-butyldiphenylsilyl ether (tBDPS) protecting group; Before carrying out the coupling reaction, the step of obtaining compound II-B is optionally carried out, wherein compound II-B is obtained by reacting a compound of formula (I-B) with 1,1'-carbonyldiimidazole, especially in an organic solvent such as dichloromethane; wherein R1 and R2 are as defined in any one of claims 1-3.

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

9. A pharmaceutical composition, characterized in that, The pharmaceutical composition comprises a compound of formula (I) as defined in any one of claims 1-6, or a deuterated or tritiated form of a compound of formula (I), or a pharmaceutically acceptable salt thereof.

10. A compound of formula (I) as defined in any one of claims 1-6, or a deuterated or tritiated form of a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use as a drug.

11. Use of a compound of formula (I) as claimed in any one of claims 1 - 6, or a deuterated or tritiated form of a compound of formula (I), or a pharmaceutically acceptable salt thereof, for the treatment and / or prophylaxis of a disease mediated by protein tyrosine kinase, in particular a disease mediated by phosphatidylinositol 3 - kinase, more particularly a disease mediated by the α - isoform of phosphatidylinositol 3 - kinase.

12. A compound of formula (I) as claimed in the use of claim 11, or a deuterated or tritiated form of a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein the disease mediated by protein tyrosine kinase, in particular a disease mediated by phosphatidylinositol 3 - kinase, more particularly a disease mediated by the α - isoform of phosphatidylinositol 3 - kinase is selected from the group consisting of: PI3K - related overgrowth syndrome (PROS); neurofibromatosis; mitochondrial genetic diseases; keloid; hypertrophic scar, including burn scar; hyperpigmentation; proliferative diseases, in particular cancer; inflammatory diseases, including autoimmune disorders; and glomerulonephritis; more particularly selected from the group consisting of: keloid; hypertrophic scar, including burn scar; and hyperpigmentation.

13. Use of a compound of formula (I) as defined in any one of claims 1-6, or a deuterated or tritiated form of a compound of formula (I), or a pharmaceutically acceptable salt thereof, for the treatment and / or prophylaxis of the following diseases: cancer, especially bladder cancer; Breast cancer; Lung cancer, such as non - small cell lung cancer and small cell lung cancer; ovarian cancer; cervical cancer; kidney cancer; liver cancer; head and neck cancer, such as head and neck squamous cell carcinoma; sarcoma; brain cancer, such as glioma, glioblastoma, anaplastic oligodendroglioma and anaplastic astrocytoma; or hematological cancer, such as leukemia, lymphoma and myeloma.

14. Use of a compound of formula (I) as claimed in any one of claims 1 - 6, or a deuterated or tritiated form of a compound of formula (I), or a pharmaceutically acceptable salt thereof, for the treatment and / or prophylaxis of a disease: phosphatidylinositol 3 - kinase - related overgrowth syndrome, in particular congenital PROS, lipoma, overgrowth, vascular malformation, epidermal nevus, spinal / skeletal abnormalities and / or scoliosis syndrome.

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