TW201839000A - Thiocarbamate derivatives as a2a inhibitors and methods for use in the treatment of cancers - Google Patents

Abstract

The present invention relates to compounds of Formula I or pharmaceutically acceptable salts or solvates thereof. The invention further relates to the use of the compounds of Formula I as A2A inhibitors. The invention also relates to the use of the compounds of Formula I for the treatment and/or prevention of cancer. The invention also relates to a process for manufacturing compounds of Formula I.

Description

Thiamine derivative as an A2A inhibitor and method for treating cancer

This invention relates to novel carbamide derivatives, including pharmaceutically acceptable salts and solvates thereof. The compounds of the invention are inhibitors of the adenosine A2A receptor and are useful as therapeutic compounds, particularly in the treatment and/or prevention of cancer.

Many immunosuppressive mechanisms in tumors are associated with physiological immune regulation in normal tissues. Such immunomodulation is extremely important in keeping the immune system under control to block the autoreactive immune response and prevent the ongoing immune response from causing damage to critical tissues. Lack of physiological immunomodulation often leads to overwhelming immune activation with autoimmune. For example, CTLA-4 is a physiological mechanism that negatively regulates T cell activity by blocking the co-signaling signal through CD28-B7 interaction. Lack of CTLA4 causes non-specific T cell activation, and CTLA-4 deficient mice die within weeks due to massive lymphocytic tissue infiltration. PD-1 also provides T cell suppression signals when interacting with its ligands PD-L1 and PD-L2. The lack of PD-1 in mice is known to cause various types of autoimmune disorders depending on the genetic line.

In addition to cell surface conductance such as CTLA-4 and PD-1 immunosuppressive signals, immunosuppression in the tumor microenvironment involves anti-inflammatory interleukins (IL-10, TGF-β), enzymes (guanamine-2). , 3-dioxygenase), and specialized immunoregulatory cells (regulatory T cells, bone marrow-derived suppressor cells MDSC). These immunosuppressive mechanisms play an important role in controlling immune responses in normal tissues. Because tumors use this physiological immunomodulatory mechanism to protect their tissues from immune attack, these mechanisms are intended to prevent inflammatory complications and are now a major obstacle to spontaneous cancer regression and immune cancer treatment. The identification of immunosuppressive mechanisms in tumors indicates that the molecular target system restores the anti-tumor immune response. Therefore, these negative immune regulation mechanisms, so-called immune checkpoints, have become the focus of drug discovery. In addition, antibodies against PD1, PDL1 or CTLA4 have been approved as anticancer agents for a large number of indications such as metastatic melanoma, non-small cell lung cancer, renal cell malignancy, Hodgkin's lymphoma, Head and neck cancer, urinary epithelial cell malignancies, hepatocellular carcinoma, and treatment of patients with solid tumors with known mismatch repair defects and high microsatellite instability (regardless of cancer type) One of two specific genetic features.

Extracellular adenosine has been referred to as an inhibitor of immune function. Although intracellular adenosine is involved in energy metabolism, nucleic acid metabolism, and methionine cycle, extracellular adenosine plays an important role in intercellular communication. The signal is transmitted by the G protein-coupled adenosine receptor on the cell surface and affects a variety of physiological functions, including neurology, cardiovascular, and immune systems.

Tumors contain high levels of extracellular adenosine, suggesting that tumor cells can benefit from their immunosuppressive effects and metabolic energy production (Allard et al, Curr. Opin. Pharmacol., 2016, 29, 7-16; Otta A., Frontiers in Immunology, 2016, 7: 109). These high levels of extracellular adenosine may be due to the overexpression of the enzyme CD73, which is responsible for the production of extracellular adenosine. CD73 is overexpressed by a large number of tumors in which all of the following tumors overexpress moderately or high-level CD73 (www.proteinatlas.org) by immunohistochemistry on >50% of tumor surfaces: breast tumors, carcinoid tumors, cervical cervix Tumor, colorectal tumor, endometrial tumor, glioma, head and neck tumor, liver tumor, lung tumor, melanoma, ovarian tumor, pancreatic tumor, prostate tumor, kidney tumor, stomach tumor, thyroid tumor, urinary epithelial tumor .

Among the four known types of adenosine receptors, the A2A adenosine receptor (A2AR) is a prominent subtype of most immune cells. A2AR stimulation usually provides an immunosuppressive signal that inhibits the activity of T cells (proliferation, interleukin production, cytotoxicity), NK cells (cytotoxicity), NKT cells (interleukin production, up-regulation of CD40L), Macrophages/dendritic cells (antigen presentation, interleukin production), and neutrophils (oxidative burst). It has been found that the presence of extracellular adenosine in tumors plays an important role in the avoidance of anti-tumor immune responses. In particular, it has been demonstrated that A2AR-deficient mice spontaneously degenerate inoculated tumors, whereas wild-type mice do not exhibit similar tumor regression. A2AR antagonists are also beneficial in wild-type animals with tumors. Importantly, depletion of T cells and NK cells impairs tumor growth by blockade of A2AR antagonists, suggesting an improvement in anti-tumor cellular immune responses. The effector functions of T cells and NK cells are sensitive to A2AR stimulation. In addition, when activated in the presence of an A2AR agonist, the effector function of T cells is continuously impaired even after removal of the A2AR agonist. This result suggests that the adenosine enrichment environment in tumors can induce T cells that are strain-deficient to tumor cells.

Thus, if the A2A receptor is expressed in most immune cells and in effector immune cells such as T cells and NK cells and if the A2A receptor is involved in the tissue in which adenosine is produced, the A2A inhibitor is considered to be available in all cancer indications. It is helpful.

Therefore, there is a need for A2A inhibitors that are capable of restoring immune function in a tumor environment.

Adenosine is known to be an endogenous regulator of many other physiological functions. For example, at the central nervous system (CNS) level, adenosine is known to induce sedation, anxiolytic, and anti-epileptic effects.

Therefore, A2A inhibitors have previously been developed for the treatment of depression and neurodegenerative diseases such as Parkinson's disease or Alzheimer's disease (Pinna A., CNS Drugs, 2014, 28, 455). One of the most advanced A2A inhibitors developed to treat CNS disease is Preladenant (Hodgson RA et al, J. Pharmacol. Exp. Ther., 2009, 330(1), 294-303; Hauser RA et al, JAMA Neurol. , 2015, 72(12), 1491-500).

However, these previously developed A2A inhibitors are designed to cross the blood-brain barrier in order to target the A2A receptor in the CNS.

If a higher level of adenosine is present in the tumor when compared to the brain, a much higher amount of compound is needed to achieve the desired effect on immune function recovery for the treatment of cancer. Therefore, to avoid deleterious side effects, A2A inhibitors should be provided which have limited (if any) CNS permeability, as opposed to all previously developed A2A inhibitors.

As indicated in the experimental section below, the Applicant accordingly provides a novel A2A inhibitor that does not have any significant CNS permeability and which can therefore be used to treat cancer.

The invention therefore relates to compounds of formula (I) (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ and R ² are as defined below.

According to one embodiment, the compound of formula (I) is of formula (Ia) (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ , R ^{1 '} , R ^{2 '} , R ^{3 '} , R ^{4 '} and R ^{5 '} are as defined below.

According to one embodiment, the compound of formula (Ia) is of formula (Ia-1) (Ia-1) or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ , R ^{1 '} , R ^{2 '} , R ^{3 '} , R ^{4 '} and R ^{5 '} are as defined in formula (Ia) definition.

According to one embodiment, the compound of formula (Ia) is of formula (Ia-2) or (Ia-3) (Ia-2) (Ia-3) or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ , R ^{2 '} , R ^{3 '} , R ^{4 '} and R ^{5 '} are as defined in formula (Ia).

The invention also relates to a pharmaceutical composition comprising a compound according to the invention, or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable carrier.

The invention further relates to an agent comprising a compound according to the invention or a pharmaceutically acceptable salt or solvate thereof.

The invention also provides a compound according to the invention or a pharmaceutically acceptable salt or solvate thereof for use in the treatment and/or prevention of cancer.

The invention further relates to a compound according to the invention or a pharmaceutically acceptable salt or solvate thereof for use as an A2A inhibitor.

Also provided is a process for the manufacture of a compound of formula (Ia) according to the invention, or a pharmaceutically acceptable salt or solvate thereof, characterized in that it comprises an amine intermediate of formula (A) (A) wherein X ¹ , X ² , R ^{1 '} , R ^{2 '} , R ^{3 '} , R ^{4 '} and R ^{5 '} are as defined below; coupling with an intermediate of formula (B) Wherein R ¹ is as defined below and Y represents a halogen group, an alkylsulfonyloxy group having 1 to 6 carbon atoms or an arylsulfonyloxy group having 6 to 10 carbon atoms.

The invention is also directed to a synthetic intermediate of formula (A). definition

In the present invention, the following terms have the following meanings:

The term " aldehyde " refers to the group -CHO.

The term " aldehyde alkyl " refers to the group -alkyl-CHO wherein alkyl is as defined herein.

The term " alkenyl " refers to an unsaturated hydrocarbon group which may be straight or branched and which contains one or more carbon-carbon double bonds. Suitable alkenyl groups contain between 2 and 6 carbon atoms, preferably between 2 and 4 carbon atoms, still more preferably between 2 and 3 carbon atoms. Examples of alkenyl groups are ethenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl and isomers thereof, 2-hexene and isomers thereof, 2,4- Pentadienyl and the like.

The term " alkenylcarbonyl " refers to the group -(C=O)-alkenyl, wherein alkenyl is as defined herein.

The term " alkenylcarbonylalkyl " refers to the group -alkyl-(C=O)-alkenyl, wherein alkyl and alkenyl are as defined herein.

The term " alkenylcarbonylamino " refers to the group -NH-(C=O)-alkenyl, wherein alkenyl is as defined herein.

The term " alkenylcarbonylaminoalkyl " refers to the group -alkyl-NH-(C=O)-alkenyl, wherein alkyl and alkenyl are as defined herein.

The term " alkoxy " refers to the group -O-alkyl, wherein alkyl is as defined herein.

The term " alkyl " refers to a hydrocarbyl radical of the formula C _n H _2n+1 wherein n is a number greater than or equal to 1. Usually, the alkyl group of the present invention contains 1 to 8 carbon atoms, and more preferably, the alkyl group of the present invention contains 1 to 6 carbon atoms. The alkyl group can be straight or branched. Suitable alkyl groups include methyl, ethyl propyl, butyl, pentyl, hexyl, heptyl and octyl.

The term " alkylaminoalkyl " refers to the group -alkyl-NH-alkyl wherein alkyl is as defined herein.

The term " alkylaminoalkylaminocarbonyl " refers to the group -(C=O)-NH-alkyl-NH-alkyl, wherein alkyl is as defined herein.

The term " ( alkylaminoalkyl )( alkyl ) aminocarbonyl " refers to the group -(C=O)-NR ¹ R ² wherein R ¹ is alkyl and R ² is -alkyl-NH- Alkyl, wherein alkyl is as defined.

The term " alkylaminoalkylcarbonyl " refers to the group -(C=O)-alkyl-NH-alkyl, wherein alkyl is as defined herein.

The term " alkylcarbonyl " refers to the group -(C=O)-alkyl, wherein alkyl is as defined herein.

The term " alkylheteroaryl " refers to any heteroaryl group substituted by an alkyl group, wherein alkyl is as defined herein.

The term " alkoxycarbonyl " refers to the group -(C=O)-O-alkyl, wherein alkyl is as defined herein.

The term "alkylsulfonyl group" means a group -SO ₂ - alkyl wherein alkyl is as defined herein based.

The term "alkyl sulfone group" means a group - alkyl -SO ₂ - alkyl wherein alkyl is as defined herein based.

The term " alkyl sulfoximine " refers to the group -S(=O)(=NH)-alkyl, wherein alkyl is as defined herein.

The term " alkyl fluorene " refers to the group -(S=O)-alkyl, wherein alkyl is as defined herein.

The term " alkylalkylene " refers to the group -alkyl-SO-alkyl wherein alkyl is as defined herein.

The term " alkyne " refers to a class of monovalent unsaturated hydrocarbon groups in which the degree of unsaturation is produced by the presence of one or more carbon-carbon triple bonds. The alkynyl group typically and preferably has the same number of carbon atoms as described above for the alkyl group. Non-limiting examples of alkynyl groups are ethynyl, 2-propynyl, 2-butynyl, 3-butynyl, 2-pentynyl and isomers thereof, 2-hexynyl and isomers thereof , and the like.

The term " alkynyl " refers to the group -alkyl-alkyne wherein alkyl and alkyne are as defined herein.

The term " alkynylcarbonyl " refers to the group -alkyl-(C=O)-alkyne, wherein alkyl and alkyne are as defined herein.

The term " amino " refers to the group -NH ₂ .

The term "aminoalkyl" means a radical - alkyl -NH _2, wherein alkyl is as defined herein based.

The term "alkyl amino carbonyl group" means a group - (C = O) -NH- group -NH _2, wherein alkyl is as defined herein based.

The term "alkyl carbonyl amino group" means a group -NH- (C = O) - alkyl -NH _2, wherein alkyl is as defined herein based.

The term "aminocarbonyl" refers to the group -(C=O)-NH ₂ .

The term " ( aminocarbonylalkyl )( alkyl ) amino " refers to the group -NR ¹ R ² wherein R ¹ is alkyl and R ² is -alkyl-(C=O)-NH ₂ group Wherein the alkyl group is as defined herein.

The term "aminocarbonyl alkyl group" means a group -NH- group _{- (C = O) -NH 2} , wherein alkyl is as defined herein based.

The term "sulfonic acyl group" means a group -SO ₂ -NH _2.

The term " aryl " refers to a polyunsaturated, aromatic hydrocarbon group having a single ring (ie, phenyl) or a plurality of fused aromatic rings (eg, naphthyl), which typically contains from 5 to 12 atoms; Preferably 5 to 10; more preferably the aryl group is a 5 or 6 membered aryl group. Non-limiting examples of aryl groups include phenyl, naphthyl.

The term "carbonyl group" means a group - (C = O) -.

The term " carbonylamino " refers to the group -NH-(C=O)-.

The term " cycloalkyl " refers to a cyclic alkyl group, that is, a monovalent, saturated, or unsaturated hydrocarbon group having one or two cyclic structures. The cycloalkyl group includes a monocyclic or bicyclic hydrocarbon group. The cycloalkyl group may contain 3 or more carbon atoms in the ring, and, in general, contains 3 to 10, more preferably 3 to 8 carbon atoms in accordance with the present invention; still more preferably the cycloalkyl group is 5 or 6 members of cycloalkyl. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.

The term " cycloalkoxy " refers to the group -O-cycloalkyl, wherein cycloalkyl is as defined herein.

The term " dialkylamino " refers to the group -NR ¹ R ² , wherein R ¹ and R ² are each independently alkyl as defined herein.

The term "dialkylaminoalkyl" refers to the group -alkyl-NR ¹ R ² wherein R ¹ and R ² are each independently alkyl as defined herein.

The term " dialkylaminoalkylaminocarbonyl " refers to the group -(C=O)-NH-alkyl-NR ¹ R ² wherein R ¹ and R ^{2 are} both alkyl as defined herein. .

The term " dialkylaminoalkylcarbonyl " refers to the group -(C=O)-alkyl-NR ¹ R ² wherein R ¹ and R ^{2 are} both alkyl as defined herein.

The term " dihydroxyalkyl " refers to a group alkyl as defined herein substituted with two hydroxy (-OH) groups.

The term " halo " or " halogen " means fluoro, chloro, bromo or iodo.

The term " heteroaryl " refers to an aryl group, as defined herein, wherein at least one carbon atom is replaced with a heteroatom. In other words, it refers to an aromatic monocyclic ring of 5 to 12 carbon atoms, or a ring system containing two rings fused together, which typically contains 5 to 6 atoms; wherein one or more carbon atoms are composed of oxygen Nitrogen and/or sulfur atom substitution, wherein nitrogen and sulfur heteroatoms may be oxidized as appropriate and the nitrogen heteroatoms may be quaternized as appropriate. Non-limiting examples of such heteroaryl groups include: oxazolyl, thiazolyl, imidazolyl, furanyl, and pyrrolyl. Preferably, the heteroaryl group is a 5 or 6 membered heteroaryl group, more preferably a 5 or 6 membered heteroaryl group is a furyl group.

The term " heterocyclyl " refers to a non-aromatic, fully saturated or partially unsaturated cyclic group (eg, a 3 to 7 membered monocyclic ring, a 7 to 11 membered bicyclic ring, or a total of 3 to 10 ring atoms), There is at least one hetero atom in at least one ring containing carbon atoms. Preferably, the heterocyclic group is a 5 or 6 membered heterocyclic group. Each ring of the heterocyclic group containing a hetero atom may have 1, 2, 3 or 4 hetero atoms selected from a nitrogen atom, an oxygen atom and/or a sulfur atom, wherein the nitrogen and sulfur hetero atom may be oxidized and a nitrogen hetero atom may be optionally used. It can be divided into four levels according to the situation. The heterocyclyl can be attached at any heteroatom or carbon atom where the valence of the ring or ring system permits. The ring of polycyclic heterocycles can be fused, bridged, and/or joined via one or more spiro atoms. Non-limiting exemplary heterocyclic groups include aziridinyl, oxiranyl, thiocyclopropane, piperidinyl, azetidinyl, 2-imidazolinyl, pyrazopyridine Base, imidazolidinyl, isoxazolinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, piperidinyl, amber quinone, 3H-fluorenyl, hydrazine Polinyl, isoindolyl, 2H-pyrrolyl, 1-pyrrolyl, 2-pyrroline, 3-pyrrolidino, pyrrolidinyl, 4H-quinazinyl, 2-sided oxypiperazinyl , piperazinyl, monopiperazinyl, 2-pyrazolyl, 3-pyrazolyl, tetrahydro-2H-piperidyl, 2H-piperidyl, 4H-pyranyl, 3,4-di Hydrogen-2H-piperidyl, oxetanyl, thietanyl, 3-dioxolane, 1,4-dioxanyl, 2,5 - Dioxazolidinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, porphyrinyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydrophenylthio, tetrahydroquinolyl , tetrahydroisoquinolin-1-yl, tetrahydroisoquinolin-2-yl, tetrahydroisoquinolin-3-yl, tetrahydroisoquinolin-4-yl, thiomorpholin-4-yl 1-oxo bridge-1 thiomorpholin-4-yl, 1-dioxo bridge-1 thiomorpholin-4-yl, 1,3-dioxolane, 1,4-oxothio 1,4-oxathianyl, 1,4-dithianyl, 1,3,5-trioxanyl 1H-pyrrolizinyl, tetrahydro-1,1-di- oxyphenylthio, N-methylmercaptopiperazinyl, and morpholin-4-yl.

The term "heterocyclic aminocarbonyl group" means a group - (C = O) -NH- alkyl - heterocyclyl, wherein the alkyl and heterocyclyl are as defined herein based.

The term " ( heterocyclyl )( alkyl ) aminoalkyl " refers to the group -alkyl-NR ¹ R ² wherein R ¹ is alkyl and R ² is heterocyclyl, wherein alkyl and heterocyclyl Is as defined herein.

The term " heterocyclylcarbonyl " refers to the group -(C=O)-heterocyclyl, wherein heterocyclyl is as defined herein.

The term " heterocyclylalkyl " refers to the group -alkyl-heterocyclyl, wherein alkyl and heterocyclyl are as defined herein.

The term " heterocyclyloxy " refers to the group -O-heterocyclyl, wherein the heterocyclyl is as defined herein.

The term "heterocyclyl sulfo acyl" means a group -SO ₂ - heterocyclyl, wherein heterocyclyl is based are as defined herein.

The term " hydroxyalkyl " refers to the group -alkyl-OH wherein alkyl is as defined herein.

The term " hydroxyalkylaminoalkyl " refers to the group -alkyl-NH-alkyl-OH wherein alkyl is as defined herein.

The term " hydroxycarbonyl " refers to the group -C(=O)-OH, wherein carbonyl is as defined herein. In other words, "hydroxycarbonyl" corresponds to a carboxylic acid group.

The term " tertiary oxy " refers to a =0 substituent.

The term "sulfonic acyl group" means the group -NH-SO _2.

The term " about " before a number means adding or subtracting 10% of the value of the number.

The term "administration (Administration)" or variants thereof (e.g., "administered (Administering)" means separately or active agent or ingredient (e.g., A2A inhibitor) as part of a pharmaceutically acceptable composition to the A patient who will be treated or prevented for its condition, symptoms, or disease.

The term " IC ₅₀ " or " half the maximum inhibitory concentration " means the concentration of the inhibitor required for 50% inhibition in vitro.

The term " inhibitor " refers to a natural or synthetic compound that has a biological effect to inhibit or significantly reduce or down-regulate the expression of a gene and/or protein that has a biological effect to inhibit or significantly reduce the biological activity of the protein. . Thus, "A2A inhibitor" refers to a compound that has a biological effect to inhibit or significantly reduce or down regulate the biological activity of the A2A receptor.

The term " human " refers to two genders and subjects at any stage of development (ie, newborn, toddler, juvenile, adolescent, adult).

The term " patient " refers to a warm-blooded animal, more preferably a human, who is awaiting receiving or receiving medical care or will be the subject of a medical procedure.

The expression " pharmaceutically acceptable " means that the components of the pharmaceutical composition are compatible with each other and are not deleterious to the subject to whom the administration is administered.

The expression " pharmaceutically acceptable carrier " means an excipient which does not cause an adverse, allergic or other untoward reaction when administered to an animal, preferably a human. It includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like. For human administration, the formulation should meet aseptic, febrile, general safety and purity standards, as required by regulatory offices such as, for example, the FDA Office or EMA.

As used herein, the term " prodrug " means any compound that will be modified to form a drug substance, wherein the modification may occur inside or outside the body, and the drug is administered to the body where the prodrug reaches the body. The area occurs before or after.

As used herein, the term "prevention (prevent)", "prevention (preventing)" and "prevention (prevention)" means to delay or exclude condition or disease and / or its attendant symptoms of the onset, hindering patients suffering from symptoms Or a disease, or a method of reducing the risk of a patient suffering from a condition or disease.

As used herein, the term " prodrug " means a pharmacologically acceptable derivative of a compound of formula I, such as, for example, an ester or a guanamine, which in vivo produces a biologically active drug. Prodrugs are typically characterized by increased bioavailability and are readily metabolized in vivo to biologically active compounds.

The term "treatment (treating)" or "treatment (treatment)" refers to both therapeutic treatment and prophylactic or preventative measures; wherein the object is to prevent or slow down the target pathological condition or disease. Those in need of treatment include those who already have the disease and those who are prone to have the disease or who will prevent the disease. A subject or mammal is successfully "treated" if, after receiving the treatment according to the present invention, the subject or mammal exhibits an observable and/or measurable reduction or absence of one or more of the following: Disease or infection or condition: reduction in tumor; and/or remission to a certain extent for one or more of the symptoms associated with a particular disease or condition; reduced morbidity and mortality, and life Improvements in quality issues. The above parameters for assessing successful treatment and disease improvement can be readily measured by routine procedures familiar to the physician.

The term " volunteer " or " subject " refers to animals, including humans. In the sense of the present invention, a subject may be a patient, that is, a person who receives medical attention, is undergoing or has undergone medical treatment, or is monitored for the development of the disease. In one embodiment, the subject is a male. In another embodiment, the subject is a female.

Compound

The invention therefore relates to a compound of formula I (I) or a pharmaceutically acceptable salt or solvate thereof, wherein: R ¹ represents 5 or 6 membered heteroaryl or 5 or 6 membered aryl, wherein the heteroaryl or aryl group is optionally subjected to one or more Substituted by a substituent selected from the group consisting of C1-C6 alkyl (preferably methyl) and halo (preferably fluoro or chloro); preferably R ¹ represents a 5-membered heteroaryl; Preferably, R ¹ represents a furyl group; R ² represents a 6-membered aryl group or a 6-membered heteroaryl group, wherein the heteroaryl group or the aryl group is optionally substituted with one or more substituents selected from the group consisting of halo, alkane , heterocyclic, alkoxy, cycloalkoxy, heterocyclyloxy, carbonyl, alkylcarbonyl, aminocarbonyl, hydroxycarbonyl, heterocyclylcarbonyl, alkyl amidino, alkylsulfonyl, An aminosulfonyl group, a heterocyclylsulfonyl group, an alkyl sulfoximine group, a carbonylamino group, a sulfonylamino group, and an alkylalkyl group; the substituents are optionally selected from one or more selected from the group consisting of Substituents for each substituent: pendant oxy, halo, hydroxy, cyano, alkyl, alkenyl, aldehyde, heterocyclylalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl, Aminoalkyl, alkylaminoalkyl, Alkylaminoalkyl, (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl, alkylheteroaryl, alkyne, alkoxy, amine, dialkylamino Aminoalkylcarbonylamino, aminocarbonylalkylamino, (aminocarbonylalkyl)(alkyl)amino, alkenylcarbonylamino, hydroxycarbonyl, alkoxycarbonyl, aminocarbonyl, amine Alkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, heterocyclylalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)amine Carbocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylhydrazine, alkylalkylene, alkylsulfonyl And an alkyl arylalkyl group; or a heteroaryl or aryl group, optionally substituted by two substituents which together with the atoms to which they are attached form a 5 or 6 membered aryl ring, a 5 or 6 membered heteroaryl ring a 5 or 6 membered cycloalkyl ring or a 5 or 6 membered heterocyclyl ring; optionally substituted with one or more substituents selected from the group consisting of pendant oxy, halo, hydroxy, cyano, alkyl Alkenyl, aldehyde, heterocyclylalkyl, hydroxy , dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl)(alkyl)aminoalkyl, hetero Cyclo, heteroaryl, alkylheteroaryl, alkyne, alkoxy, amine, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, (aminocarbonyl) (alkyl)amino, alkenylcarbonylamino, hydroxycarbonyl, alkoxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylamino Alkylaminocarbonyl, heterocyclylalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclic Alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylhydrazine, alkylalkylene, alkylsulfonyl and alkylalkyl.

According to one embodiment, in Formula I: R ¹ represents a 5 or 6 membered heteroaryl or a 5 or 6 membered aryl group, wherein the heteroaryl or aryl group is optionally subjected to one or more substituents selected from the group consisting of substituents: C1-C6 alkyl group (preferably methyl) group and the halo (preferably fluoro or chloro); preferably R ¹ represents 5 heteroaryl; more preferably R ¹ represents a furyl group; R ² represents a 6-membered aryl or 6-membered heteroaryl group, wherein the heteroaryl or aryl group is optionally substituted with one or more substituents selected from the group consisting of halo, alkyl, heterocyclic, alkoxy. , cycloalkoxy, heterocyclyloxy, carbonyl, alkylcarbonyl, aminocarbonyl, hydroxycarbonyl, heterocyclylcarbonyl, alkyl amidino, alkylsulfonyl, aminosulfonyl, heterocyclic a sulfonyl group, a carbonylamino group, a sulfonylamino group, and an alkylalkyl group; the substituents are optionally substituted with one or more substituents selected from the group consisting of a hydroxyl group, a cyano group, an alkyl group, and an alkene group. Base, aldehyde, hydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl)(alkyl)aminoalkyl, Heterocyclyl, heteroaryl, alkylheteroaryl, alkyne Alkoxy, amino, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, (aminocarbonylalkyl)(alkyl)amine, alkenylcarbonylamino, Hydroxycarbonyl, alkoxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, (alkylaminoalkyl) Alkyl)aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylhydrazine, alkylalkylene, alkane Alkylsulfonyl and alkylalkyl.

According to one embodiment, in Formula I: R ¹ represents a 5 or 6 membered heteroaryl or a 5 or 6 membered aryl group, wherein the heteroaryl or aryl group is optionally subjected to one or more substituents selected from the group consisting of substituents: C1-C6 alkyl group (preferably methyl) group and the halo (preferably fluoro or chloro); preferably R ¹ represents 5 heteroaryl; more preferably R ¹ represents a furyl group; R ² represents a 6-membered aryl or 6-membered heteroaryl group, wherein the heteroaryl or aryl group is optionally substituted with one or more substituents selected from the group consisting of halo, alkyl, heterocyclic, alkoxy. , cycloalkoxy, heterocyclyloxy, carbonyl, alkylcarbonyl, aminocarbonyl, hydroxycarbonyl, heterocyclylcarbonyl, alkyl amidino, alkylsulfonyl, aminosulfonyl, heterocyclic a sulfonyl group, a carbonylamino group and a sulfonylamino group; the substituents are optionally substituted with one or more substituents selected from the group consisting of a hydroxyl group, a cyano group, an alkyl group, an alkenyl group, an aldehyde group, and a hydroxy group. , hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl)(alkyl)aminoalkyl, heterocyclic, heteroaryl Base, alkyl heteroaryl, alkyne, alkoxy, amine , dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, (aminocarbonylalkyl)(alkyl)amine, alkenylcarbonylamino, hydroxycarbonyl, alkoxy Carbonyl group, aminocarbonyl group, aminoalkylaminocarbonyl group, alkylaminoalkylaminocarbonyl group, dialkylaminoalkylaminocarbonyl group, (alkylaminoalkyl)(alkyl)aminocarbonyl group An alkylaminoalkylcarbonyl group, a dialkylaminoalkylcarbonyl group, a heterocyclylcarbonyl group, an alkenylcarbonyl group, an alkynylcarbonyl group, an alkylarylene group, an alkylarylene group.

According to a preferred embodiment, the invention relates to a compound of formula (Ia): (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein: R ¹ represents 5 or 6 membered heteroaryl or 5 or 6 membered aryl, wherein the heteroaryl or aryl group is optionally subjected to one or more Substituted by a substituent selected from the group consisting of C1-C6 alkyl (preferably methyl) and halo (preferably fluoro or chloro); preferably R ¹ represents a 5-membered heteroaryl; Preferably, R ¹ represents a furyl group; X ¹ and X ² each independently represent C or N; when X ¹ is N, R ¹ ' is absent; or when X ¹ is C, R ¹ ' is H, halo, Alkyl, heterocyclic, alkoxy, cycloalkoxy, heterocyclyloxy, carbonyl, alkylcarbonyl, aminocarbonyl, hydroxycarbonyl, heterocyclylcarbonyl, alkyl amidino, alkylsulfonyl An aminosulfonyl group, a heterocyclylsulfonyl group, an alkyl sulfoximine group, a carbonylamino group, a sulfonylamino group or an alkylalkyl group; the substituents are optionally selected from one or more selected from Substituents for the following: pendant oxy, halo, hydroxy, cyano, alkyl, alkenyl, aldehyde, heterocyclylalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl Aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl (heterocyclyl) (alkyl)aminoalkyl, heterocyclyl, heteroaryl, alkylheteroaryl, alkyne, alkoxy, amine, dialkylamino, aminoalkylcarbonylamine Alkyl, aminocarbonylalkylamino, (aminocarbonylalkyl)(alkyl)amino, alkenylcarbonylamino, hydroxycarbonyl, alkoxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, Alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, heterocyclylalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl, alkylamino An alkylcarbonyl group, a dialkylaminoalkylcarbonyl group, a heterocyclic carbonyl group, an alkenylcarbonyl group, an alkynylcarbonyl group, an alkyl sulfonium group, an alkylalkylene group, an alkylsulfonyl group, and an alkylalkyl group; R ^{2 '} represents H, halo, alkyl, heterocyclic, alkoxy, cycloalkoxy, heterocyclyloxy, carbonyl, alkylcarbonyl, aminocarbonyl, hydroxycarbonyl, heterocyclylcarbonyl, alkane a pyridinium, an alkylsulfonyl group, an aminosulfonyl group, a heterocyclylsulfonyl group, an alkyl sulfoximine group, a carbonylamino group, a sulfonylamino group, or an alkylalkyl group; Base view needs to pass one or more selected from the following Substituent substitution: pendant oxy, halo, hydroxy, cyano, alkyl, alkenyl, aldehyde, heterocyclylalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl, amin Base, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl, alkylheteroaryl, alkyne, alkoxy Base, amine group, dialkylamino group, aminoalkylcarbonylamino group, aminocarbonylalkylalkyl group, (aminocarbonylalkyl)(alkyl)amino group, alkenylcarbonylamino group, hydroxycarbonyl group, Alkoxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, heterocyclylalkylaminocarbonyl, (alkyl Aminoalkyl)(alkyl)aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylanthracene, alkyl A fluorenylene group, an alkyl sulfonyl group, and an alkyl fluorenyl group; or R ¹ ' and R ² ' together with the atoms to which they are attached form a 5 or 6 membered aryl ring, a 5 or 6 membered heteroaryl ring, 5 Or a 6-membered cycloalkyl ring or a 5 or 6 membered heterocyclyl ring; Substituted by one or more substituents selected from the group consisting of pendant oxy, halo, hydroxy, cyano, alkyl, alkenyl, aldehyde, heterocyclylalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxy Alkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl, alkane Heteroaryl, alkyne, alkoxy, amine, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, (aminocarbonylalkyl)(alkyl)amine , alkenylcarbonylamino, hydroxycarbonyl, alkoxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, heterocyclic Alkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkenylcarbonyl, alkyne a carbonyl group, an alkyl sulfonium group, an alkyl sulfylene group, an alkyl sulfonyl group, and an alkyl fluorenyl group; R ³ ' is absent when X ² is N; or when X ² is C, R ³ ' Represents H or a halogen group, preferably H or F; R ^4' represents H or a halogen group, Preferably, H or F; and R ^{5 '} represents H or a halo group, preferably H or F.

According to one embodiment, in the formula (Ia): R ¹ represents a 5 or 6 membered heteroaryl or a 5 or 6 membered aryl group, wherein the heteroaryl or aryl group is optionally subjected to one or more selected from the group consisting of Substituents substituted: C1-C6 alkyl (preferably methyl) and halo (preferably fluoro or chloro); preferably R ¹ represents a 5-membered heteroaryl; more preferably R ¹ represents a furanyl X ¹ and X ² each independently represent C or N; R ¹ ' is absent when X ¹ is N; or when X ¹ is C, R ¹ ' represents H, halo, alkyl, alkoxy, Heterocyclyloxy, alkylcarbonyl, carbonyl, aminocarbonyl, hydroxycarbonyl, heterocyclyl, heterocyclylcarbonyl, alkyl amidino, alkylsulfonyl, aminosulfonyl or heterocyclosulfonyl The substituents are optionally substituted with one or more substituents selected from the group consisting of hydroxy, cyano, alkyl, hydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkyl Aminoalkyl, dialkylaminoalkyl, (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl, alkylheteroaryl, alkyne, alkoxy, amine , dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, (amine (Carbocarbonyl)alkyl (amino)amino, hydroxycarbonyl, alkoxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylamine Carbocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkylanthracene, alkyl amidene Alkyl, alkylalkylalkyl; R ^{2 '} represents H, alkoxy, cycloalkoxy, heterocyclyloxy, alkylanthracene, carbonyl, carbonylamino, aminocarbonyl or sulfonylamino Wherein alkoxy, cycloalkoxy, heterocyclyloxy, alkylanthracene, carbonyl, carbonylamino, aminocarbonyl or sulfonylamino is optionally one or more selected from the group consisting of Substituent substitution: hydroxy, cyano, alkyl, alkenyl, aldehyde, hydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, ( Heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl, alkylheteroaryl, alkyne, alkoxy, amine, dialkylamino, aminoalkylcarbonylamino Aminocarbonylalkylamino group (aminocarbonyl alkane) (alkyl)amino, alkenylcarbonylamino, hydroxycarbonyl, alkoxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylamino Alkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkenylcarbonyl, alkynyl a carbonyl group, an alkyl sulfonium group, an alkyl sulfylene group, an alkyl fluorenyl group; or R ¹ ' and R ² ' together with the atoms to which they are attached form a 5 or 6 membered aryl ring, a 5 or 6 membered heteroaryl group a cyclic, 5 or 6 membered cycloalkyl ring, a 5 or 6 membered heterocyclyl ring; optionally substituted with one or more substituents selected from the group consisting of hydroxy, cyano, alkyl, hydroxyalkyl, hydroxy Alkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl, alkane Heteroaryl, alkyne, alkoxy, amine, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, (aminocarbonylalkyl)(alkyl)amine , hydroxycarbonyl, alkoxycarbonyl, aminocarbonyl, aminoalkylamino Carbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl, alkylaminoalkylcarbonyl, dialkyl amino alkylcarbonyl, heterocyclylcarbonyl, alkyl sulfoxide, alkyl sulfone group; when X ² is N R ³ 'is absent; or when X ² is C, R ^3' represents H or halo Preferably, H or F; R ^{4 '} represents H or halo, preferably H or F; and R ^{5 '} represents H or halo, preferably H or F.

According to one embodiment, in the formula (Ia): R ¹ represents a 5 or 6 membered heteroaryl or a 5 or 6 membered aryl group, wherein the heteroaryl or aryl group is optionally subjected to one or more selected from the group consisting of Substituents substituted: C1-C6 alkyl (preferably methyl) and halo (preferably fluoro or chloro); preferably R ¹ represents a 5-membered heteroaryl; more preferably R ¹ represents a furanyl X ¹ and X ² each independently represent C or N; R ¹ ' is absent when X ¹ is N; or when X ¹ is C, R ¹ ' represents H, halo, alkyl, alkoxy, Heterocyclyloxy, alkylcarbonyl, carbonyl, aminocarbonyl, hydroxycarbonyl, heterocyclyl, heterocyclylcarbonyl, alkyl amidino, alkylsulfonyl, aminosulfonyl or heterocyclosulfonyl The substituents are optionally substituted with one or more substituents selected from the group consisting of hydroxy, cyano, alkyl, hydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkyl Aminoalkyl, dialkylaminoalkyl, (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl, alkylheteroaryl, alkyne, alkoxy, amine , dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, (amine (Carbocarbonyl)alkyl (amino)amino, hydroxycarbonyl, alkoxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylamine Carbocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkylanthracene, alkyl amidene Alkyl; R ^{2 '} represents H, alkoxy, cycloalkoxy, heterocyclyloxy, alkylanthracene, carbonyl, carbonylamino, aminocarbonyl or sulfonylamino; wherein alkoxy, A cycloalkoxy group, a heterocyclyloxy group, an alkylarylene group, a carbonyl group, a carbonylamino group, an aminocarbonyl group or a sulfonylamino group is optionally substituted with one or more substituents selected from the group consisting of a hydroxyl group, Cyano, alkyl, alkenyl, aldehyde, hydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl) (alkane) Aminoalkyl, heterocyclyl, heteroaryl, alkylheteroaryl, alkyne, alkoxy, amine, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkyl Amine, (aminocarbonylalkyl)(alkyl)amine , alkenylcarbonylamino, hydroxycarbonyl, alkoxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, (alkane) Alkylamino)(alkyl)aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylarylene, alkane a benzylidene group; or R ¹ ' and R ² ' together with the atoms to which they are attached form a 5 or 6 membered aryl ring, a 5 or 6 membered heteroaryl ring, a 5 or 6 membered cycloalkyl ring, 5 or 6 a heterocyclic ring; optionally substituted with one or more substituents selected from the group consisting of hydroxy, cyano, alkyl, hydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkyl Aminoalkyl, dialkylaminoalkyl, (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl, alkylheteroaryl, alkyne, alkoxy, amine , dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, (aminocarbonylalkyl)(alkyl)amine, hydroxycarbonyl, alkoxycarbonyl, aminocarbonyl, amine Alkylaminocarbonyl, alkylaminoalkylaminocarbonyl , dialkylaminoalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl , alkyl hydrazine; R ³ ' is absent when X ² is N; or when X ² is C , R ³ ' represents H or halo, preferably H or F; R ^{4 '} represents H or halo Preferably, H or F; and R ^5' represents H or a halo group, preferably H or F.

In a particular embodiment of the invention, R ¹ represents 5 or 6 membered heteroaryl or 5 or 6 membered aryl, wherein the heteroaryl or aryl is optionally substituted with one or more substituents of the following: C1-C6 alkyl (preferably methyl) and halo (preferably fluoro or chloro).

In a preferred embodiment, R ¹ represents a 5-membered heteroaryl group; more preferably, R ¹ represents a furyl group.

In a particular embodiment of the invention, X ¹ and X ² each independently represent C or N. In another particular embodiment, both X ¹ and X ² represent C.

In a particular embodiment of the invention, R ¹ ' is absent when X ¹ is N.

In another specific embodiment, when X ¹ is C, R ¹ ' represents H, halo, alkyl, heterocyclyl, alkoxy, cycloalkoxy, heterocyclyloxy, carbonyl, alkylcarbonyl , aminocarbonyl, hydroxycarbonyl, heterocyclylcarbonyl, alkyl amidino, alkylsulfonyl, aminosulfonyl, heterocyclylsulfonyl, alkyl sulfoximine, carbonylamino, sulfonium sulfonate Alkylamino or alkylalkyl; these substituents are optionally substituted with one or more substituents selected from the group consisting of pendant oxy, halo, hydroxy, cyano, alkyl, alkenyl, aldehyde ,heterocyclylalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl) ( Alkyl)aminoalkyl, heterocyclyl, heteroaryl, alkylheteroaryl, alkyne, alkoxy, amine, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkyl Amino group, (aminocarbonylalkyl)(alkyl)amino group, alkenylcarbonylamino group, hydroxycarbonyl group, alkoxycarbonyl group, aminocarbonyl group, aminoalkylaminocarbonyl group, alkylaminoalkyl group Aminocarbonyl, dialkylaminoalkylaminocarbonyl ,heterocyclylalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkenyl Carbonyl, alkynylcarbonyl, alkylhydrazine, alkylalkylene, alkylsulfonyl and alkylalkyl.

In a preferred embodiment, when X ¹ is C, R ¹ ' represents H, halo, alkyl, alkoxy, heterocyclyloxy, alkylcarbonyl, carbonyl, aminocarbonyl, hydroxycarbonyl, hetero a cycloalkyl, a heterocyclylcarbonyl, an alkylhydrazine, an alkylsulfonyl, an aminosulfonyl or a heterocyclylsulfonyl; the substituents being optionally substituted by one or more selected from the group consisting of Base substitution: hydroxy, cyano, alkyl, hydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl) (alkane) Aminoalkyl, heterocyclyl, heteroaryl, alkylheteroaryl, alkyne, alkoxy, amine, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkyl Amino, (aminocarbonylalkyl)(alkyl)amino, hydroxycarbonyl, alkoxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylcarbonyl, dialkyl Aminoalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkylanthracene , alkylarylene.

In a preferred embodiment, the R ¹ ' substituent is optionally substituted with one or more substituents selected from the group consisting of halo, hydroxy, alkyl, heterocyclylalkyl, hydroxyalkyl, hydroxyalkyl Aminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl, alkyl Aryl, alkoxy, amine, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, heterocyclylalkylaminocarbonyl, (aminocarbonylalkyl) (alkane) Amino group, hydroxycarbonyl group, aminocarbonyl group, aminoalkylaminocarbonyl group, alkylaminoalkylaminocarbonyl group, dialkylaminoalkylaminocarbonyl group, (alkylaminoalkyl group) ( Alkyl)aminocarbonyl, heterocyclylcarbonyl, alkylanthracene and alkylalkylene.

In a preferred embodiment, the R ¹ ' substituent is optionally substituted with one or more substituents selected from the group consisting of hydroxy, alkyl, hydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl. , alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl, alkylheteroaryl, alkoxy, amine , dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, (aminocarbonylalkyl)(alkyl)amino, hydroxycarbonyl, aminocarbonyl, aminoalkylamino Carbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl, heterocyclylcarbonyl, alkylanthracene and alkane Base to alkyl.

In a particular embodiment of the invention, R ² ' represents H, halo, alkyl, heterocyclyl, alkoxy, cycloalkoxy, heterocyclyloxy, carbonyl, alkylcarbonyl, aminocarbonyl , hydroxycarbonyl, heterocyclylcarbonyl, alkyl sulfonium, alkylsulfonyl, aminosulfonyl, heterocyclylsulfonyl, alkyl sulfoximine, carbonylamino, sulfonylamino, Or alkylalkylalkyl; such substituents are optionally substituted with one or more substituents selected from the group consisting of pendant oxy, halo, hydroxy, cyano, alkyl, alkenyl, aldehyde, heterocycle Alkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl) (alkyl) Aminoalkyl, heterocyclyl, heteroaryl, alkylheteroaryl, alkyne, alkoxy, amine, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino (Aminocarbonylalkyl)(alkyl)amino, alkenylcarbonylamino, hydroxycarbonyl, alkoxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl Dialkylaminoalkylamino group , heterocyclylalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkene Alkylcarbonyl, alkynylcarbonyl, alkylhydrazine, alkylalkylene, alkylsulfonyl and alkylalkyl.

In a preferred embodiment, R ² ' represents H, alkoxy, cycloalkoxy, heterocyclyloxy, alkylanthracene, carbonyl, carbonylamino, aminocarbonyl or sulfonylamino; Alkoxy, cycloalkoxy, heterocyclyloxy, alkylanthracene, carbonyl, carbonylamino, aminocarbonyl or sulfonylamino is optionally substituted with one or more substituents selected from the group consisting of Substitution: hydroxy, cyano, alkyl, alkenyl, aldehyde, hydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocycle (alkyl)aminoalkyl, heterocyclyl, heteroaryl, alkylheteroaryl, alkyne, alkoxyamino, dialkylamino, aminoalkylcarbonylamino, amine Carbonylalkylamino, (aminocarbonylalkyl)(alkyl)amino, alkenylcarbonylamino, hydroxycarbonyl, alkoxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylamino Alkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, Heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl Alkyl, alkylarylene, alkylarylene.

In a preferred embodiment, the R ² 'substituent is optionally substituted with one or more substituents selected from the group consisting of pendant oxy, halo, hydroxy, cyano, alkyl, heterocyclylalkyl, Dihydroxyalkyl, dialkylaminoalkyl, heteroaryl, alkylheteroaryl, hydroxycarbonyl, alkoxycarbonyl, aminocarbonyl, heterocyclylalkylaminocarbonyl, alkylaminoalkyl Carbonyl, dialkylaminoalkylcarbonyl, alkylanthracene, alkylalkylene.

In a preferred embodiment, the R ² 'substituent is optionally substituted with one or more substituents selected from the group consisting of hydroxy, cyano, alkyl, dihydroxyalkyl, heteroaryl, alkyl heteroaryl A hydroxycarbonyl group, an alkoxycarbonyl group, an aminocarbonyl group, an alkylaminoalkylcarbonyl group, a dialkylaminoalkylcarbonyl group, an alkylarylene group, an alkylalkylene group.

In another particular embodiment of the invention, R ¹ ' and R ² ' together with the atoms to which they are attached form a 5 or 6 membered aryl ring, a 5 or 6 membered heteroaryl ring, a 5 or 6 membered cycloalkyl ring. Or a 5 or 6 membered heterocyclyl ring; optionally substituted with one or more substituents selected from the group consisting of pendant oxy, halo, hydroxy, cyano, alkyl, alkenyl, aldehyde, heterocyclyl Alkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl)(alkyl)amine Alkyl, heterocyclic, heteroaryl, alkylheteroaryl, alkyne, alkoxy, amine, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, (aminocarbonylalkyl)(alkyl)amino, alkenylcarbonylamino, hydroxycarbonyl, alkoxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl, Dialkylaminoalkylaminocarbonyl, heterocyclylalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkane Carbocarbonyl, heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, Alkyl anthracene, alkylalkylene, alkylsulfonyl and alkylalkyl.

In a preferred embodiment, R ¹ ' and R ² ' together with the atoms to which they are attached form a 5 or 6 membered aryl ring, a 5 or 6 membered heteroaryl ring, a 5 or 6 membered cycloalkyl ring, 5 or 6 a heterocyclic ring; optionally substituted with one or more substituents selected from the group consisting of hydroxy, cyano, alkyl, hydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkyl Aminoalkyl, dialkylaminoalkyl, (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl, alkylheteroaryl, alkyne, alkoxy, amine , dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, (aminocarbonylalkyl)(alkyl)amine, hydroxycarbonyl, alkoxycarbonyl, aminocarbonyl, amine Alkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl, alkylaminoalkyl Carbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkylhydrazine, alkyldecanealkyl.

In a particular embodiment of the invention, R ³ ' is absent when X ² is N. In another particular embodiment of the invention, when X ² is C, R ³ ' represents H or halo. In a preferred embodiment, when X ² is C, R ³ ' represents H or F.

In a particular embodiment of the invention, R ⁴ ' represents H or halo. In a preferred embodiment, R ⁴ ' represents H or F.

In a particular embodiment of the invention, R ⁵ ' represents H or halo. In a preferred embodiment, R ⁵ ' represents H or F.

In one embodiment, preferred compounds of formula (Ia) are those of formula (Ia-1): (Ia-1) or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ , R ^{1 '} , R ^{2 '} , R ^{3 '} , R ^{4 '} and R ^{5 '} are as defined in formula (Ia) definition.

In one embodiment, the compounds of formula (Ia-1) are preferably those of formula (Ia-1a): (Ia-1a) or a pharmaceutically acceptable salt or solvate thereof, wherein: R ¹ and R ^{3 '} are as defined in formula (Ia); and R ^{1 '} represents an alkyl group or a heterocyclic group, Substituted by one or more groups selected from the group consisting of pendant oxy, halo, hydroxy, cyano, alkyl, alkenyl, aldehyde, heterocyclylalkyl, hydroxyalkyl, dihydroxyalkyl, Hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl, Alkylheteroaryl, alkyne, alkoxy, amine, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, (aminocarbonylalkyl)(alkyl)amine Base, alkenylcarbonylamino group, hydroxycarbonyl group, alkoxycarbonyl group, aminocarbonyl group, aminoalkylaminocarbonyl group, alkylaminoalkylaminocarbonyl group, dialkylaminoalkylaminocarbonyl group, hetero Cycloalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkenylcarbonyl, Alkynylcarbonyl, alkyl hydrazine, alkyl alkylene, alkyl sulfonate Alkyl group and a sulfone group.

According to one embodiment, in the formula (Ia-1a): R ¹ and R ^{3 '} are as defined in the formula (Ia); and R ^{1 "} represents an alkyl group or a heterocyclic group, which is selected from one or more selected from the group consisting of Substituents of the following: hydroxy, cyano, alkyl, hydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (hetero) (Alkyl)aminoalkyl, heterocyclyl, heteroaryl, alkylheteroaryl, alkyne, alkoxy, amine, dialkylamino, aminoalkylcarbonylamino, Aminocarbonylalkylamino group, (aminocarbonylalkyl)(alkyl)amino group, hydroxycarbonyl group, alkoxycarbonyl group, aminocarbonyl group, aminoalkylaminocarbonyl group, alkylaminoalkylamino group Carbonyl, dialkylaminoalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl , alkyl hydrazine, alkyl fluorenyl. According to one embodiment, in formula (Ia-1a): R ¹ and R ^{3 '} are as defined in formula (Ia); and R ^{1 ”} represents alkyl or a heterocyclic group substituted with one or more groups selected from the group consisting of hydroxy, cyano Alkyl, hydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl)(alkyl)aminoalkyl, hetero Cyclo, heteroaryl, alkylheteroaryl, alkyne, alkoxy, amine, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, (aminocarbonyl) (alkyl)amino group, hydroxycarbonyl group, alkoxycarbonyl group, aminocarbonyl group, aminoalkylaminocarbonyl group, alkylaminoalkylaminocarbonyl group, dialkylaminoalkylaminocarbonyl group, (Alkylaminoalkyl)(alkyl)aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkylanthracene.

In a particular embodiment of the invention, R ¹ " represents an alkyl or heterocyclic group substituted by one or more groups selected from the group consisting of pendant oxy, halo, hydroxy, cyano, alkane Base, alkenyl, aldehyde, heterocyclylalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl) (alkyl)aminoalkyl, heterocyclyl, heteroaryl, alkylheteroaryl, alkyne, alkoxy, amine, dialkylamino, aminoalkylcarbonylamine Alkyl, aminocarbonylalkylamino, (aminocarbonylalkyl)(alkyl)amino, alkenylcarbonylamino, hydroxycarbonyl, alkoxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, Alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, heterocyclylalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl, alkylamino Alkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylhydrazine, alkylalkylene, alkylsulfonyl and alkylalkyl.

In a preferred embodiment, R ¹ " represents an alkyl or heterocyclic group substituted with one or more groups selected from the group consisting of hydroxy, cyano, alkyl, hydroxyalkyl, hydroxyalkylamine Alkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl, alkyl heteroaryl Alkyl, alkyne, alkoxy, amine, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, (aminocarbonylalkyl)(alkyl)amine, hydroxycarbonyl , alkoxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, (alkylaminoalkyl) (alkyl An aminocarbonyl group, an alkylaminoalkylcarbonyl group, a dialkylaminoalkylcarbonyl group, a heterocyclic carbonyl group, an alkylarylene group.

In a preferred embodiment, R ¹ " represents an alkyl or heterocyclic group substituted with one or more groups selected from the group consisting of hydroxy, heterocyclic, heteroaryl, alkylheteroaryl, Alkynes, alkoxy groups, amine groups, dialkylamino groups, aminoalkylcarbonylamino groups, aminocarbonylalkylamino groups, (aminocarbonylalkyl)(alkyl)amino groups, hydroxycarbonyl groups, amines Carbocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl, heterocyclic Alkylcarbonyl, alkyl sulfonium, alkyl fluorenyl.

In one embodiment, the compounds of formula (Ia-1) are preferably those of formula (Ia-1b): (Ia-1b) or a pharmaceutically acceptable salt or solvate thereof, wherein: R ¹ and R ^{3 '} are as defined in formula (Ia); R ^{1 '} represents H or halo, preferably H Or F; and R ^2" represents an alkyl or heterocyclic group substituted by one or more groups selected from the group consisting of pendant oxy, halo, hydroxy, cyano, alkyl, alkenyl, aldehyde ,heterocyclylalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl) ( Alkyl)aminoalkyl, heterocyclyl, heteroaryl, alkylheteroaryl, alkyne, alkoxy, amine, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkyl Amino group, (aminocarbonylalkyl)(alkyl)amino group, alkenylcarbonylamino group, hydroxycarbonyl group, alkoxycarbonyl group, aminocarbonyl group, aminoalkylaminocarbonyl group, alkylaminoalkyl group Aminocarbonyl, dialkylaminoalkylaminocarbonyl, heterocyclylalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl, alkylaminoalkylcarbonyl, dioxane Alkylaminocarbonyl, heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkyl Anthracene, alkylalkylene, alkylsulfonyl and alkylalkyl.

According to one embodiment, in formula (Ia-1b): R ¹ and R ^{3 '} are as defined in formula (Ia); R ^{1 '} represents H or halo, preferably H or F; and R ^2" Represents an alkyl or heterocyclic group substituted with one or more groups selected from the group consisting of hydroxy, cyano, alkyl, hydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkane Aminoalkyl, dialkylaminoalkyl, (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl, alkylheteroaryl, alkyne, alkoxy, amine a base, a dialkylamino group, an aminoalkylcarbonylamino group, an aminocarbonylalkylamino group, an (aminocarbonylalkyl)(alkyl)amino group, a hydroxycarbonyl group, an alkoxycarbonyl group, an aminocarbonyl group, Aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl, alkylaminoalkane Alkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkylhydrazine, alkyldecanealkyl.

According to one embodiment, in formula (Ia-1b): R ¹ and R ^{3 '} are as defined in formula (Ia); R ^{1 '} represents H or halo, preferably H or F; and R ^2" Represents an alkyl or heterocyclic group substituted with one or more groups selected from the group consisting of hydroxy, cyano, alkyl, hydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkane Aminoalkyl, dialkylaminoalkyl, (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl, alkylheteroaryl, alkyne, alkoxy, amine a base, a dialkylamino group, an aminoalkylcarbonylamino group, an aminocarbonylalkylamino group, an (aminocarbonylalkyl)(alkyl)amino group, a hydroxycarbonyl group, an alkoxycarbonyl group, an aminocarbonyl group, Aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl, alkylaminoalkane Alkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkylanthracene.

In a particular embodiment of the invention, R ¹ ' represents H or a halo group. In a preferred embodiment, R ¹ ' represents H or F.

In a particular embodiment of the invention, R ² " represents an alkyl or heterocyclic group substituted by one or more groups selected from the group consisting of pendant oxy, halo, hydroxy, cyano, alkane Base, alkenyl, aldehyde, heterocyclylalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl) (alkyl)aminoalkyl, heterocyclyl, heteroaryl, alkylheteroaryl, alkyne, alkoxy, amine, dialkylamino, aminoalkylcarbonylamine Alkyl, aminocarbonylalkylamino, (aminocarbonylalkyl)(alkyl)amino, alkenylcarbonylamino, hydroxycarbonyl, alkoxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, Alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, heterocyclylalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl, alkylamino Alkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylhydrazine, alkylalkylene, alkylsulfonyl and alkylalkyl.

In a preferred embodiment, R ² " represents an alkyl or heterocyclic group substituted with one or more groups selected from the group consisting of hydroxy, cyano, alkyl, hydroxyalkyl, hydroxyalkylamine Alkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl, alkyl heteroaryl Alkyl, alkyne, alkoxy, amine, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, (aminocarbonylalkyl)(alkyl)amine, hydroxycarbonyl , alkoxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, (alkylaminoalkyl) (alkyl An aminocarbonyl group, an alkylaminoalkylcarbonyl group, a dialkylaminoalkylcarbonyl group, a heterocyclic carbonyl group, an alkylarylene group.

In a preferred embodiment, R ² " represents an alkyl or heterocyclic group substituted with one or more groups selected from the group consisting of hydroxy, cyano, heteroaryl, alkylheteroaryl, alkyne A hydrocarbon, a hydroxycarbonyl group, an alkoxycarbonyl group, an aminocarbonyl group, an alkylaminoalkylcarbonyl group, a dialkylaminoalkylcarbonyl group, an alkylarylene group, an alkylalkylene group.

In one embodiment, the compounds of formula (Ia-1) are preferably those of formula (Ia-1c) or (Ia-1d): (Ia-1c) (Ia-1d) or a pharmaceutically acceptable salt or solvate thereof, wherein: R ¹ and R ^{3 '} are as defined in formula (Ia); R ^{1 '} represents H or halo, preferably H Or F; and R ^{2 '} represents H or a halogen group, preferably H or F; and R ¹ⁱ and R ¹ⁱⁱ each independently represent hydrogen, hydroxy, alkyl, alkenyl, heterocyclylalkyl, hydroxyalkyl, Dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl)(alkyl)aminoalkyl, heterocyclic , heteroaryl, alkylheteroaryl, alkynyl, alkoxy, amine, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, (aminocarbonylalkyl) (alkyl)amino, alkenylcarbonylamino, hydroxycarbonyl, alkoxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkane Aminocarbonyl, heterocyclylalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclic a carbonyl group, an alkenylcarbonyl group, an alkynylcarbonyl group, an alkylarylene group or an alkylalkyl group; and R ²ⁱ and R ²ⁱⁱ each independently represent hydrogen, hydroxy, alkyl, alkenyl, heterocyclylalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylamino Alkyl, dialkylaminoalkyl, (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl, alkylheteroaryl, alkynyl, alkoxy, amine, a dialkylamino group, an aminoalkylcarbonylamino group, an aminocarbonylalkylamino group, an (aminocarbonylalkyl)(alkyl)amino group, an alkenylcarbonylamino group, a hydroxycarbonyl group, an alkoxycarbonyl group, Aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, heterocyclylalkylaminocarbonyl, (alkylaminoalkyl) (Alkyl)aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylalkylene or alkylalkyl .

According to one embodiment, in formula (Ia-1c) or (Ia-1d): R ¹ and R ^{3 '} are as defined in formula (Ia); R ^{1 '} represents H or halo, preferably H or F; R ^{2 '} represents H or a halogen group, preferably H or F; R ¹ⁱ and R ¹ⁱⁱ each independently represent hydrogen, hydroxy, alkyl, hydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl , alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl, alkylheteroaryl, alkynyl, alkoxy Base, amine group, dialkylamino group, aminoalkylcarbonylamino group, aminocarbonylalkylalkyl group, (aminocarbonylalkyl)(alkyl)amino group, hydroxycarbonyl group, alkoxycarbonyl group, amine Carbocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl, alkyl An aminoalkylcarbonyl group, a dialkylaminoalkylcarbonyl group, a heterocyclylcarbonyl group, an alkylalkylene group, an alkylalkylene group; and R ²ⁱ and R ²ⁱⁱ each independently represent hydrogen, a hydroxyl group, an alkyl group, Hydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylamino Alkyl, (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl, alkylheteroaryl, alkynyl, alkoxy, amine, dialkylamino, amine Alkylcarbonylamino, aminocarbonylalkylamino, (aminocarbonylalkyl)(alkyl)amine, hydroxycarbonyl, alkoxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkyl Aminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkyl Carbonyl, heterocyclylcarbonyl, alkylalkylene, alkylalkyl.

According to one embodiment, in formula (Ia-1c) or (Ia-1d): R ¹ and R ^{3 '} are as defined in formula (Ia); R ^{1 '} represents H or halo, preferably H or F; R ^{2 '} represents H or a halogen group, preferably H or F; R ¹ⁱ and R ¹ⁱⁱ each independently represent hydrogen, hydroxy, alkyl, hydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl , alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl, alkylheteroaryl, alkynyl, alkoxy Base, amine group, dialkylamino group, aminoalkylcarbonylamino group, aminocarbonylalkylalkyl group, (aminocarbonylalkyl)(alkyl)amino group, hydroxycarbonyl group, alkoxycarbonyl group, amine Carbocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl, alkyl An aminoalkylcarbonyl group, a dialkylaminoalkylcarbonyl group, a heterocyclylcarbonyl group, an alkylalkylene group, an alkylalkylene group; and R ²ⁱ and R ²ⁱⁱ each independently represent hydrogen, a hydroxyl group, an alkyl group, Hydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylamino Alkyl, (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl, alkylheteroaryl, alkynyl, alkoxy, amine, dialkylamino, amine Alkylcarbonylamino, aminocarbonylalkylamino, (aminocarbonylalkyl)(alkyl)amine, hydroxycarbonyl, alkoxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkyl Aminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkyl Carbonyl, heterocyclylcarbonyl, alkylalkylene, alkylalkyl.

In a particular embodiment of the invention, R ¹ ' represents H or a halo group. In a preferred embodiment, R ¹ ' represents H or F.

In a particular embodiment of the invention, R ² ' represents H or halo. In a preferred embodiment, R ² ' represents H or F.

In a particular embodiment of the invention, R ¹ⁱ and R ¹ⁱⁱ each independently represent hydrogen, hydroxy, alkyl, alkenyl, heterocyclylalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkane. Base, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl, alkylheteroaryl, Alkynyl, alkoxy, amino, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, (aminocarbonylalkyl)(alkyl)amino, alkenylcarbonyl Amine, hydroxycarbonyl, alkoxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, heterocyclylalkylamine Alkylcarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkane Alkylene or alkylalkyl.

In a preferred embodiment, R ¹ⁱ and R ¹ⁱⁱ each independently represent hydrogen, hydroxy, alkyl, hydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkyl. Aminoalkyl, (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl, alkylheteroaryl, alkynyl, alkoxy, amine, dialkylamino, Aminoalkylcarbonylamino, aminocarbonylalkylamino, (aminocarbonylalkyl)(alkyl)amine, hydroxycarbonyl, alkoxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, Alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl, alkylaminoalkylcarbonyl, dialkylamino Alkylcarbonyl, heterocyclylcarbonyl, alkylalkylene, alkylalkyl.

In a preferred embodiment, R ¹ⁱ and R ¹ⁱⁱ each independently represent hydrogen, alkyl, heterocyclylalkyl, hydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl. A dialkylaminoalkyl group, a (heterocyclyl)(alkyl)aminoalkyl group or a heterocyclylalkylaminocarbonyl group.

In a preferred embodiment, R ¹ⁱ and R ¹ⁱⁱ each independently represent hydrogen, alkyl, hydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylamino. Alkyl or (heterocyclyl)(alkyl)aminoalkyl.

In a particular embodiment of the invention, R ²ⁱ and R ²ⁱⁱ each independently represent hydrogen, hydroxy, alkyl, alkenyl, heterocyclylalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkane. Base, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl, alkylheteroaryl, Alkynyl, alkoxy, amino, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, (aminocarbonylalkyl)(alkyl)amino, alkenylcarbonyl Amine, hydroxycarbonyl, alkoxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, heterocyclylalkylamine Alkylcarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkane Alkylene or alkylalkyl.

In a preferred embodiment, R ²ⁱ and R ²ⁱⁱ each independently represent hydrogen, hydroxy, alkyl, hydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkyl. Aminoalkyl, (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl, alkylheteroaryl, alkynyl, alkoxy, amine, dialkylamino, Aminoalkylcarbonylamino, aminocarbonylalkylamino, (aminocarbonylalkyl)(alkyl)amine, hydroxycarbonyl, alkoxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, Alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl, alkylaminoalkylcarbonyl, dialkylamino An alkylcarbonyl group, a heterocyclic carbonyl group, an alkylarylene group.

In a preferred embodiment, R ²ⁱ and R ²ⁱⁱ each independently represent hydrogen, alkyl, heterocyclylalkyl, dihydroxyalkyl, dialkylaminoalkyl or heterocyclylalkylaminocarbonyl. In a preferred embodiment, R ²ⁱ and R ²ⁱⁱ each independently represent hydrogen, alkyl or dialkylaminoalkyl.

In one embodiment, preferred compounds of formula (Ia) are those of formula (Ia-2) or (Ia-3): (Ia-2) (Ia-3) or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ , R ^{2 '} , R ^{3 '} , R ^{4 '} and R ^{5 '} are as defined in formula (Ia).

In particular, the preferred compounds of the formula I of the invention are those compounds listed in Table 1 below. Table 1 And pharmaceutically acceptable salts and solvates thereof.

In Table 1, the term "Cpd" means a compound.

The compounds of Table 1 were named using ChemBioDraw ^® Ultra version 12.0 (PerkinElmer).

All references to compounds of formula I and its subformula include references to mirror image isomers, salts, solvates, polymorphs, multicomponent complexes and liquid crystals.

The compounds of the present invention include compounds of formula I and its subformulae as defined above, including all polymorphs and crystal habits thereof, prodrugs and isomers thereof (including optical, geometric and tautomeric) and formula I Isotope labeled compound of the subtype.

Compounds of formula I and its subformulae may contain asymmetric centers and may therefore exist as different stereoisomeric forms. Accordingly, the invention includes all possible stereoisomers and includes not only racemic compounds but also individual mirror image isomers and their non-racemic mixtures. When a compound is desired as a single mirror image isomer, such a compound can be obtained by stereospecific synthesis, by isolation of the final product or any suitable intermediate, or by a pair of palms as known in the art. Obtained by a chromatographic method. Isolation of the final product, intermediate, or starting material can be performed by any suitable method known in the art.

The compounds of the invention may be in the form of a pharmaceutically acceptable salt. The pharmaceutically acceptable salts of the compounds of the formula I and its subformulas include the acid addition salts and base salts thereof. Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include acetate, adipate, aspartate, benzoate, benzyl sulfonate, bicarbonate/carbonate, disulfate/sulfate, borate, camphor sulfonate, citric acid Salt, cyclohexylamine sulfonate, ethanedisulfonate, ethanesulfonate, formate, fumarate, glucoheptonate, gluconate, glucuronate, hexafluorophosphate Benzene salt, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, C Diacid salt, methanesulfonate, methyl sulfate, naphthate, 2-naphthalenesulfonate, nicotinic acid salt, nitrate, orotate, oxalate, palmitic acid, pamoate , phosphate / hydrogen phosphate / dihydrogen phosphate, pyroglutamate, sucrose, stearate, succinate, citrate, tartrate, tosylate, trifluoroacetate and Naphthate. Suitable base salts are formed from bases which form non-toxic salts. Examples include aluminum, arginine, benzathine, calcium, choline, diethylamine, diethanolamine, glycine, lysine, magnesium, meglumine, ethanolamine, potassium, sodium, trimethylamine, 2-( Diethylamino)ethanol, ethanolamine, morpholine, 4-(2-hydroxyethyl)morpholine and zinc salt. It is also possible to form, for example, a half salt, a hemisulfate and a hemicalcium salt of an acid and a base. Preferred pharmaceutically acceptable salts include hydrochlorides/chlorides, hydrobromides/bromides, heavy sulfates/sulfates, nitrates, citrates, and acetates.

When the compound of the present invention contains an acidic group and a basic group, the compound of the present invention may also form an internal salt, and such compounds are within the scope of the present invention. When the compound of the present invention contains hydrogen to give a hetero atom (e.g., NH), the present invention also covers salts and/or isomers formed by transfer of the hydrogen atom to a basic group or atom in the molecule.

The pharmaceutically acceptable salts of the compounds of formula I and its subformula may be prepared by one or more of these methods: (i) by reacting a compound of formula I with a desired acid; Reacting a compound of formula I with a desired base; (iii) removing an acid or base labile protecting group from a suitable precursor of a compound of formula I or by using a desired acid such as a suitable lactone or lactam Ring-like precursor ring opening; or (iv) by converting a salt of a compound of formula I to another salt by reaction with a suitable acid or by means of a suitable ion exchange column.

All of these reactions are typically carried out in solution. The salt can be precipitated from the solution and collected by filtration or can be recovered by evaporation of the solvent. The degree of ionization in the salt can be different from being completely ionized to be almost non-ionized.

The compounds of the invention may be administered in the form of a pharmaceutically acceptable salt. The term "pharmaceutically acceptable salts" is intended to include all acceptable salts such as acetate, lactobionate, besylate, laurate, benzoate, malate, bicarbonate, butenene. Diacid salt, hydrogen sulfate, mandelate, hydrogen sulphate, methanesulfonate, borate, methyl bromide, bromide, methyl nitrate, calcium edetate, methyl sulfate, camphor Sulfonate, mucic acid salt, carbonate, naphthalene sulfonate, chloride, nitrate, clavulanic acid, N-methyl reduced glucosamine, citrate, ammonium salt, dihydrochloride, oleate , edetate, oxalate, ethanedisulfonate, pamoate (enpo acid salt), etidinate, palmitate, ethanesulfonate, pantothenate, fumaric acid Salt, phosphate/diphosphate, glucoheptonate, polygalacturonate, gluconate, salicylate, glutamate, stearate, ethanol oxime p-aminobenzoate , sulphate, hexyl resorcinol salt, basic acetate, succinamine, succinate, hydrobromide, decanoate, hydrochloride, tartrate, hydroxynaphthoic acid , tea chlorate, iodide, toluene sulfonate, isothiosulfate, triethyl iodide, lactate, citrate, valerate, and the like, which can be used for upgrading solubility or hydrolysis A characteristic dosage form or can be used for sustained release or prodrug formulations. Depending on the particular functionality of the compounds of the invention, the pharmaceutically acceptable salts of the compounds of the invention include those formed from cations and bases such as sodium, potassium, aluminum, calcium, lithium, magnesium, Zinc, and such bases as ammonia, ethylenediamine, N-methyl- branamine, lysine, arginine, auramine, choline, N, N'-dibenzylethylidene , chloroprocaine, diethanolamine, procaine, N-benzylphenethyl-amine, diethylamine, piperazine, cis (hydroxymethyl) aminomethane, and tetramethylammonium hydroxide.

These salts can be prepared by standard procedures, for example by reacting the free acid with a suitable organic or inorganic base. In the presence of a basic group such as an amine group, an acid salt, that is, a hydrochloride, a hydrobromide, an acetate, a pamoate, and the like can be used as a dosage form.

Further, although a pharmaceutically acceptable salt is generally preferred in terms of a salt of the compound of the present invention, it should be noted that the present invention also broadly includes a non-pharmaceutically acceptable salt, which may be used, for example, in the present invention. Isolation and/or purification of the compounds of the invention. For example, a salt formed using an optically active acid or base can be used to form a non-stereoisomeric salt which can aid in the isolation of the optically active isomer of the compound of formula I above.

The compounds of the invention may be in the form of a pharmaceutically acceptable solvate. Pharmaceutically acceptable solvates of the compounds of Formula I and its subformula contain stoichiometric or substoichiometric amounts of one or more pharmaceutically acceptable solvent molecules, such as ethanol or water. The term "hydrate" means the case when the solvent is water.

The invention also broadly encompasses all pharmaceutically acceptable prodrugs and prodrugs of the compounds of Formula I and its subformulae.

Further, in the presence of an alcohol group, a pharmaceutically acceptable ester such as acetate, maleate, trimethylacetoxymethyl, and the like can be used, and It is known in the art to modify such esters which are suitable for use as a soluble or hydrolyzable property of a sustained release or prodrug formulation. Production method

The compounds of formula I can be prepared in a variety of ways using reactions known to those skilled in the art.

The invention further relates to a process for the manufacture of a compound of formula (Ia): (Ia) and pharmaceutically acceptable salts and solvates thereof, wherein X ¹ , X ² , R ¹ , R ^{1 '} , R ^{2 '} , R ^{3 '} , R ^{4 '} and R ^{5 '} are as defined ( Defined in Ia); it comprises: (a1) a compound of formula (A) (A) wherein X ¹ , X ² , R ^{1 '} , R ^{2 '} , R ^{3 '} , R ^{4 '} and R ^{5 '} are as defined in formula (Ia); reacted with a compound of formula (B) (B) wherein R ¹ is as defined in formula (Ia); Y represents halogen (preferably iodine, bromine or chlorine), alkylsulfonyloxy having 1 to 6 carbon atoms (preferably A Alkylsulfonyloxy or trifluoromethylsulfonyloxy) or an arylsulfonyloxy group having 6 to 10 carbon atoms (preferably phenyl or p-tolylsulfonyloxy), Or be familiar with any leaving groups known to those skilled in the art.

According to one embodiment, step (a1) of the process of the invention can be carried out in the presence or absence of a base. In a particular embodiment, step (a1) of the method of the invention is carried out in the presence of a base selected from the group consisting of, but not limited to, TEA, DIPEA, pyridine, NaOH, K ₃ PO ₄ , K ₂ CO ₃ , Na ₂ CO ₃ , preferably DIPEA or TEA.

According to one embodiment, step (a1) of the process of the invention may be carried out in the presence of a suitable solvent such as, but not limited to, DMF, dioxane, THF, water or mixtures thereof, preferably in DMF.

According to one embodiment, step (a1) of the method of the invention can be carried out at a temperature in the range of from 20 ° C to about 180 ° C with or without microwave irradiation for a period of from 10 minutes to several hours, for example from 10 minutes to 24 h.

Compounds of formula (B) can be prepared according to the following scheme: Step (b1): 5-aminothiazolo[4,5-d]pyrimidine-2,7(3H,6H)-dione can be converted to 5-amino-7-hydroxy-3-(2-methoxy Benzyl)-2H,3H-[1,3]thiazolo[4,5-d]pyrimidin-2-one.

According to one embodiment, step (b1) can be carried out by using 1-bromo-2-methoxyethane, 1-iodo-2-methoxyethane, 1-methylsulfonyl-2-methoxy This is carried out by treatment with an alkane or 1-toluenesulfonyl-2-methoxyethane, preferably 1-bromo-2-methoxymethoxy.

According to one embodiment, step (b1) of the method of the invention can be carried out in the presence or absence of a base. In a particular embodiment, step (b1) is such as, but not limited to, sodium third butoxide, potassium third butoxide, NaH, CsOH, NaOH, K ₂ CO ₃ , Na ₂ CO ₃ , preferably third. Execution is carried out in the presence of sodium alkoxide, potassium t-butoxide or a base of NaH.

According to one embodiment, step (b1) of the process of the invention can be carried out in the presence of a suitable solvent such as, but not limited to, DMF, dioxane, THF, DMA, preferably in DMF.

According to one embodiment, step (b1) of the method of the invention can be carried out at a temperature in the range of from 20 ° C to about 180 ° C with or without microwave irradiation for a period of from 10 minutes to several hours, for example from 10 minutes to 24 h.

Step (b2): 5-amino-7-hydroxy-3-(2-methoxyethyl)-2H,3H-[1,3]thiazolo[4,5-d]pyrimidin-2-one Conversion to 5-amino-7-chloro-3-(2-methoxyethyl)-2H,3H-[1,3]thiazolo[4,5-d]pyrimidin-2-one.

Step (b2) according to one embodiment can be carried out in the presence of a chlorinating agent such as, but not limited to, POCl ₃ , PCl ₅ , SOCl ₂ , preferably POCl ₃ .

According to one embodiment, step (b2) of the process of the invention can be carried out in the presence or absence of a suitable solvent, preferably in the absence of a solvent.

According to one embodiment, step (b2) of the method of the invention can be carried out at a temperature ranging from 20 ° C to about 180 ° C with or without microwave irradiation for a period of from 10 minutes to several hours, for example from 10 minutes to 24 h.

Step (b3): 5-amino-7-chloro-3-(2-methoxyethyl)-2H,3H-[1,3]thiazolo[4,5-d]pyrimidin-2-one and wherein by the formula wherein R ¹ lines as in formula (Ia) as defined in (C) to be converted into the reaction wherein the compound (D) wherein R ¹ lines such as formula (Ia) as defined in the formula.

According to one embodiment, step (b3) of the process of the invention can be carried out in the presence of a suitable base.

According to one embodiment, step (b3) of the process of the invention may be carried out in the presence or absence of a suitable solvent such as ethanol, propanol, methanol, THF, water, dioxane, or mixtures thereof, preferably The ground is carried out in the presence of ethanol.

According to one embodiment, step (b3) of the method of the invention can be carried out at a temperature in the range of from 20 ° C to about 180 ° C with or without microwave irradiation for a period of from 10 minutes to several hours, for example from 10 minutes to 24 h.

Step (b4): wherein the compound (D) wherein R ¹ lines such as formula (Ia) as defined in the formula may be converted into compounds of the formula (E) wherein R ¹ lines as in formula (Ia) as defined above.

According to one embodiment, step (b4) of the process of the invention can be carried out in the presence of N,O-bis(trimethyldecyl)acetamide.

According to one embodiment, step (b4) of the process of the invention can be carried out in the presence or absence of hexamethyldioxane.

According to one embodiment, step (b4) of the process of the invention can be carried out in the presence or absence of a suitable solvent, preferably in the absence of a solvent.

According to one embodiment, step (b4) of the method of the invention can be carried out at a temperature in the range of from 20 ° C to about 180 ° C with or without microwave irradiation for a period of from 1 hour to several hours, for example from 1 h to 96 h.

Step (b5): wherein the compound of formula (E) wherein R ¹ lines as in formula (Ia) as defined may be converted to compounds of the formula (F) wherein R ¹ lines as in formula (Ia) as defined above.

According to one embodiment, the method of the present invention step (b5) may be performed in the presence of BBr _3.

According to one embodiment, step (b5) of the process of the invention can be carried out in the presence or absence of a suitable solvent such as DCM, THF, preferably in the presence of DCM.

According to one embodiment, step (b5) of the method of the present invention can be carried out at a temperature ranging from -20 ° C to about 50 ° C with or without microwave irradiation for a period of from 10 minutes to several hours, for example 10 minutes to 24 h.

Step (b6): wherein the compound of formula (F) wherein R1 is as defined in formula (Ia) can be converted to a compound of formula (B) wherein R1 and Y are as defined in formula (Ia).

According to one embodiment, step (b6) of the method of the present invention can be carried out using any reagent known to those skilled in the art for converting an alcohol to a halogenated alkyl group or to an alkyl or aryl sulfonate. Depending on the nature of Y, the reagents such as, but not limited to, toluenesulfonium chloride, methanesulfonate chloride, trifluoromethanesulfonate chloride, trifluoromethanesulfonic anhydride, SOCl ₂ , SO ₂ Cl ₂ , POCl ₃ , PCl ₅ , Preferably toluene sulfonium chloride or methanesulfonate chloride.

According to one embodiment, step (b6) of the method of the invention can be carried out in the presence of a suitable base such as, but not limited to, TEA or DIPEA.

According to one embodiment, step (b6) of the process of the invention can be carried out in the presence or absence of a suitable solvent such as DMF, DCM, THF, preferably in the presence of DMF.

According to one embodiment, step (b6) of the method of the present invention can be carried out at a temperature ranging from -20 ° C to about 50 ° C with or without microwave irradiation for a period of from 10 minutes to several hours, for example 10 minutes to 24 h.

In general, the synthetic route for any individual compound of formula (I) will depend on the particular substituent of each molecule and on the necessary ready availability of the intermediate; again, those skilled in the art will recognize such factors.

According to another general method, the compound of formula I can be converted to an alternative compound of formula I using a suitable interconversion technique well known to those skilled in the art.

Compounds of formula I and related formulas can additionally be obtained by treatment of a compound of formula I from one of its functional derivatives by treatment with a solvolysis or hydrogenolysis agent.

Preferred starting materials for solvolysis or hydrogenolysis are those according to formula I and related formulas, but containing corresponding protected amine groups and/or hydroxyl groups in place of one or more free amine groups and/or hydroxyl groups, Preferably, an amine-based protecting group is substituted for the H atom bonded to the N atom, in particular, the R*-N group is substituted for the HN group, wherein R* represents an amine protecting group. And/or such as a H atom having a hydroxy protecting group in place of a hydroxy group, such as those of formula I but having a -COOR** group in place of a -COOH group, wherein R** represents a hydroxy protecting group .

A plurality of - equal or different - protected amine groups and / or hydroxyl groups may also be present in the molecule of the starting material. If the protecting groups present are different from each other, they can be selectively cleaved in many cases.

The term "amino protecting group" is known in its general form and is a group which is suitable for protecting (blocking) an amine group from chemical reactions but which is easily removed after the desired chemical reaction has been carried out elsewhere in the molecule. Typical of such groups are, in particular, unsubstituted or substituted fluorenyl, aryl, aralkoxymethyl or aralkyl groups. Since the amine protecting group is removed after the desired reaction (or reaction sequence), its type and size are less critical; however, it is preferred to have 1-20, especially 1-8, carbon atoms. The term "mercapto" will be understood in the broadest sense in connection with current methods. It includes sulfhydryl groups derived from aliphatic, araliphatic, aromatic or heterocyclic carboxylic acids or sulfonic acids and in particular alkoxycarbonyl, aryloxycarbonyl and especially aralkyloxycarbonyl groups. Examples of such a mercapto group are an alkanoyl group such as an ethyl fluorenyl group, a propyl fluorenyl group and a butyl fluorenyl group; an aralkyl fluorenyl group such as a phenethyl fluorenyl group; an aryl fluorenyl group such as a benzamidine group and a tolyl group; an aryloxyalkyl group; Sulfhydryl group, such as POA; alkoxycarbonyl group, such as methoxycarbonyl, ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, BOC (third butoxycarbonyl) and 2-iodoethoxy Carbonyl; aralkyloxycarbonyl such as CBZ ("benzyloxymethyl"), 4-methoxybenzyloxycarbonyl and FMOC; and arylsulfonyl, such as Mtr. Preferred amine protecting groups are BOC and Mtr, in addition to CBZ, Fmoc, benzyl and acetamido.

The term "hydroxy protecting group" is likewise known in the general form and is a group which is suitable for protecting a hydroxy group against a chemical reaction but which is easily removed after the desired chemical reaction has taken place elsewhere in the molecule. Typical of such groups are the unsubstituted or substituted aryl, aralkyl or fluorenyl groups mentioned above, and also the alkyl groups. The nature and size of the hydroxy protecting group is not critical since it is removed again after the desired chemical reaction or reaction sequence, preferring groups having from 1 to 20, especially from 1 to 10, carbon atoms. Examples of the hydroxy protecting group are, in particular, a benzyl group, a 4-methoxybenzyl group, a p-nitrobenzoyl group, a p-toluenesulfonyl group, a tert-butyl group and an ethyl hydrazino group, wherein the benzyl group and the tert-butyl group are Especially preferred.

The compounds of formula I and related formulas are released from their functional derivatives - depending on the protecting group used - for example a strong mineral acid such as hydrochloric acid, perchloric acid or sulfuric acid; strong organic carboxylic acids such as trichloroacetic acid, TFA or sulphur An acid such as benzenesulfonic acid or p-toluenesulfonic acid. The presence of another inert solvent is possible, but not always necessary. Suitable inert solvents are preferably organic, such as carboxylic acids such as acetic acid; ethers such as tetrahydrofuran or dioxane; guanamines such as DMF; halogenated hydrocarbons such as dichloromethane; and also alcohols such as methanol, ethanol or Isopropyl alcohol, and water. Mixtures of solvents mentioned above are additionally suitable. The TFA is preferably used in excess without adding another solvent, and the perchloric acid is preferably used in the form of a mixture of acetic acid and 70% perchloric acid in a ratio of 9:1. The reaction temperature for the splitting is advantageously between about 0 and about 50 ° C, preferably between 15 ° C and 30 ° C (room temperature).

The BOC, OtBu and Mtr groups can be used, for example, preferably in TFA in dichloromethane or from about 3 to 5 N HCl in dioxane at 15-30 ° C, and the FMOC group can be used in dimethylamine. Approximately 5 to 50% of the solution of diethylamine or piperidine in DMF is split at 15-30 °C.

Hydrophilic-removable protecting groups (e.g., release of CBZ, benzyl or sulfhydryl groups from their oxadiazole derivatives) can be advantageously employed, for example, by utilizing hydrogen in a catalyst (e.g., a noble metal catalyst such as palladium). On the support of carbon, there is a treatment to split. Suitable solvents herein are those indicated above, such as, for example, an alcohol such as methanol or ethanol; or a guanamine such as DMF. Hydrogenolysis is usually carried out at a temperature between about 0 and 100 ° C and at a pressure between about 1 bar and 200 bar, preferably at 20-30 ° C and 1-10 bar. Hydrogenolysis of the CBZ group is carried out, for example, on 5 to 10% Pd/C in methanol or using ammonium formate (instead of hydrogen) on Pd/C in methanol/DMF at 20-30 °C.

Examples of suitable inert solvents are hydrocarbons such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons such as trichloroethylene, 1,2-dichloroethane, tetrachloromethane, trifluoromethylbenzene, Chloroform or dichloromethane; alcohol such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxins Alkane; glycol ether, such as ethylene glycol monomethyl ether or monoethyl ether or ethylene glycol dimethyl ether (diglyme); ketone, such as acetone or butanone; guanamine, such as acetamide, dimethyl Ethyl amide, N-methylpyrrolidone (NMP) or dimethylformamide (DMF); nitrile, such as acetonitrile; anthraquinone, such as dimethyl sulfoxide; DMSO); carbon disulfide; carboxylic acid such as formic acid or acetic acid; nitro compound such as nitromethane or nitrobenzene; ester such as ethyl acetate, or a mixture of such solvents.

The ester can be hydrolyzed, for example, using HCl, H ₂ SO ₄ , or using LiOH, NaOH or KOH in water, water/THF, water/THF/ethanol or water/dioxane at a temperature between 0 and 100 °C.

The free amine group can be additionally thiolated using mercapto chloride or anhydride in a conventional manner or alkylated using an unsubstituted or substituted halogenated alkyl group, which is advantageously in an inert solvent such as dichloromethane or THF and/or Or in the presence of a base such as triethylamine or pyridine at a temperature between -60 ° C and +30 ° C.

For all protection and deprotection methods, see Philip J. Kocienski, "Protecting Groups", Georg Thieme Verlag Stuttgart, New York, 1994 and Theodora W. Greene and Peter GM Wuts, "Protective Groups in Organic Synthesis", Wiley Interscience, 3rd edition, 1999.

The reaction schemes as described in the Examples section are illustrative only and are not to be construed as limiting the invention in any way. Synthetic intermediate

The invention is also directed to a synthetic intermediate of formula (A). (A-1) and salts and solvates thereof, wherein: R ¹ ' is absent when X ¹ is N; or when X ¹ is C, R ¹ ' is H, halo, alkyl, heterocyclic , alkoxy, cycloalkoxy, heterocyclyloxy, carbonyl, alkylcarbonyl, aminocarbonyl, hydroxycarbonyl, heterocyclylcarbonyl, alkyl fluorene, alkylsulfonyl, aminosulfonyl a heterocyclylsulfonyl group, an alkyl sulfoximine group, a carbonylamino group, a sulfonylamino group or an alkylalkyl group; the substituents may optionally have one or more substituents selected from the group consisting of Substituted: pendant oxy, halo, hydroxy, cyano, alkyl, alkenyl, aldehyde, heterocyclylalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, Alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl, alkylheteroaryl, alkyne, alkoxy, Amino, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, (aminocarbonylalkyl)(alkyl)amine, alkenylcarbonylamino, hydroxycarbonyl, alkoxy Carbocarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylamino Aminocarbonyl, dialkylaminoalkylaminocarbonyl, heterocyclylalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl, alkylaminoalkylcarbonyl, two Alkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylhydrazine, alkylalkylene, alkylsulfonyl and alkylalkyl; R ² ' represents H , halo, alkyl, heterocyclic, alkoxy, cycloalkoxy, heterocyclyloxy, carbonyl, alkylcarbonyl, aminocarbonyl, hydroxycarbonyl, heterocyclylcarbonyl, alkyl amidene, alkane Sulfosyl, aminosulfonyl, heterocyclylsulfonyl, alkyl sulfoximine, carbonylamino, sulfonylamino, or alkylalkyl; these substituents Or a plurality of substituents selected from the group consisting of pendant oxy, halo, hydroxy, cyano, alkyl, alkenyl, aldehyde, heterocyclylalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkane Aminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl, alkyl Heteroaryl, alkyne, alkoxy, amine, Alkylamino group, aminoalkylcarbonylamino group, aminocarbonylalkylamino group, (aminocarbonylalkyl)(alkyl)amino group, alkenylcarbonylamino group, hydroxycarbonyl group, alkoxycarbonyl group, amine Carbocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, heterocyclylalkylaminocarbonyl, (alkylaminoalkyl) Alkyl)aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylhydrazine, alkylalkylene, alkane Alkylsulfonyl and alkylalkylalkyl; or R ¹ ' and R ² ' together with the atoms to which they are attached form a 5 or 6 membered aryl ring, a 5 or 6 membered heteroaryl ring, a 5 or 6 membered cycloalkyl group a ring or a 5 or 6 membered heterocyclyl ring; optionally substituted with one or more substituents selected from the group consisting of pendant oxy, halo, hydroxy, cyano, alkyl, alkenyl, aldehyde, heterocycle Alkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl) (alkyl) Aminoalkyl, heterocyclic, heteroaryl, alkylheteroaryl Alkynes, alkoxy groups, amine groups, dialkylamino groups, aminoalkylcarbonylamino groups, aminocarbonylalkylamino groups, (aminocarbonylalkyl)(alkyl)amino groups, alkenylcarbonylamines , hydroxycarbonyl, alkoxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, heterocyclylalkylamino Carbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkyl Anthracene, alkylalkylene, alkylsulfonyl and alkylalkyl; R ³ ' is absent when X ² is N; or R ² ' represents H or halo when X ² is C Preferably, H or F; R ^{4 '} represents H or halo, preferably H or F; and R ^{5 '} represents H or halo, preferably H or F.

According to one embodiment, the synthetic intermediate of formula (A) used in the process of the invention is selected from the group consisting of: - 1-(4-((1H-1,2,3-triazole-5) -yl)methoxy)-2-fluorophenyl)piperazine; - 1-(2-fluoro-4-(prop-2-yn-1-yloxy)phenyl)piperazine; - 2-( 2,4-difluoro-5-(piperazin-1-yl)phenoxy)acetamide; -( S )-1-(2-fluoro-4-(2-(methylsulfinyl)) Ethoxy)phenyl)piperazine; -( R )-1-(2-fluoro-4-(2-(methylsulfinyl)ethoxy)phenyl)piperazine; - ( R ,S )-1-(2,4-difluoro-5-(2-(methylsulfinyl)ethoxy)phenyl)piperazine; -( S )-1-(2,4-difluoro- 5-(2-(methylsulfinyl)ethoxy)phenyl)piperazine; and -( R )-1-(2,4-difluoro-5-(2-(methylsulfinamide) Ethyl)phenyl)piperazine. use

The invention further relates to the use of a compound of the invention or a pharmaceutically acceptable salt or solvate thereof as an A2A inhibitor.

Thus, in a particularly preferred embodiment, the invention relates to the use of a compound of formula I and subformulae, especially those of Table 1 above, or a pharmaceutically acceptable salt or solvate thereof, as an A2A inhibitor. .

Thus, in another aspect, the invention relates to the use of such compounds, or salts and solvates thereof, for the synthesis of a pharmaceutically active ingredient such as an A2A inhibitor.

According to another feature of the invention, there is provided a method for modulating A2A activity in a patient in need of such treatment, preferably a warm-blooded animal, and even better in humans, comprising administering to the patient an effective amount of the present A compound of the invention or a pharmaceutically acceptable salt or solvate thereof.

In one embodiment, the invention relates to compounds of formula I and subformulae, especially those of Table 1 above, or pharmaceutically acceptable salts and solvates thereof, for use in increasing immune recognition and destroying cancer cells use.

The compounds of the invention are therefore useful as medicaments, especially for the prevention and/or treatment of cancer.

The invention further relates to a method for the treatment or prevention of cancer comprising administering to a mammalian species in need thereof a therapeutically effective amount of a compound according to the invention or a pharmaceutically acceptable salt or solvate thereof.

The invention further provides the use of a compound of formula I or a pharmaceutically acceptable salt or solvate thereof for the manufacture of a medicament for the treatment and/or prevention of cancer.

The invention also provides a method of delaying the onset of cancer in a patient comprising administering a pharmaceutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof, to a patient in need thereof.

Preferably, the patient is a warm-blooded animal, more preferably a human.

Various cancers are known in the art. Cancer can be metastatic or non-metastatic. Cancer can be familial or sporadic. In some embodiments, the cancer is selected from the group consisting of leukemia and multiple myeloma. Additional cancers that can be treated using the methods of the invention include, for example, benign and malignant solid tumors and benign and malignant non-solid tumors. In a specific embodiment, the cancer is selected from the group consisting of breast cancer, carcinoid carcinoma, cervical cancer, colorectal cancer, endometrial cancer, glioma, head and neck cancer, liver cancer, lung cancer, melanoma, ovarian cancer, pancreatic cancer. , prostate cancer, kidney cancer, stomach cancer, thyroid cancer and urinary epithelial cell carcinoma. In a particular embodiment, the cancer is breast cancer. In a particular embodiment, the cancer is a carcinoid tumor. In a particular embodiment, the cancer is cervical cancer. In a particular embodiment, the cancer is colorectal cancer. In a particular embodiment, the cancer is endometrial cancer. In a particular embodiment, the cancer is a glioma. In a particular embodiment, the cancer is head and neck cancer. In a particular embodiment, the cancer is liver cancer. In a particular embodiment, the cancer is lung cancer. In a particular embodiment, the cancer is melanoma. In a particular embodiment, the cancer is ovarian cancer. In a particular embodiment, the cancer is pancreatic cancer. In a particular embodiment, the cancer is prostate cancer. In a particular embodiment, the cancer is kidney cancer. In a particular embodiment, the cancer is gastric cancer. In a particular embodiment, the cancer is thyroid cancer. In a particular embodiment, the cancer is urinary epithelial cell carcinoma.

Examples of solid tumors include, but are not limited to, biliary tract cancer, brain cancer (including glioblastoma and neural tube blastoma), breast cancer, carcinoid tumor, cervical cancer, choriocarcinoma, colon cancer, colorectal cancer. , endometrial cancer, esophageal cancer, gastric cancer, glioma, head and neck cancer, intraepithelial neoplasm (including Bowenbie's disease and Paget's disease), liver cancer, lung cancer, neuroblastoma, oral cancer (including Squamous cell carcinoma), ovarian cancer (including those produced by epithelial cells, stromal cells, germ cells, and mesenchymal cells), pancreatic cancer, prostate cancer, rectal cancer, kidney cancer (including adenocarcinoma and Wilms) Tumors, sarcomas (including leiomyosarcoma, rhabdomyosarcoma, liposarcoma, fibrosarcoma, and osteosarcoma), skin cancer (including melanoma, Kaposi's sarcoma, basal cell carcinoma, and squamous cell carcinoma), including germ cell tumors Testicular cancer (sperm cell tumor, and non-sperm cell tumors, such as teratoma and choriocarcinoma), stromal tumors, germ cell tumors, thyroid cancer (including thyroid adenocarcinoma and medullary cancer), and urinary epithelial cell carcinoma.

Examples of solid tumors include, but are not limited to, biliary tract cancer, brain cancer (including glioblastoma and neural tube blastoma), breast cancer, carcinoid tumor, cervical cancer, choriocarcinoma, colon cancer, endometrium Cancer, esophageal cancer, gastric cancer, intraepithelial neoplasm (including Bowenbie's disease and Paget's disease), liver cancer, lung cancer, neuroblastoma, oral cancer (including squamous cell carcinoma), ovarian cancer (including Epithelial cells, stromal cells, germ cells, and mesenchymal cells), pancreatic cancer, prostate cancer, rectal cancer, kidney cancer (including adenocarcinoma and Wilms' tumor), sarcoma (including leiomyosarcoma, rhabdomyosarcoma) , liposarcoma, fibrosarcoma and osteosarcoma), skin cancer (including melanoma, Kaposi's sarcoma, basal cell carcinoma and squamous cell carcinoma), testicular cancer including germ cell tumors (sperm cell tumor, and non-fine Cell tumors, such as teratomas and choriocarcinomas, stromal tumors, germ cell tumors, and thyroid cancers (including thyroid adenocarcinoma and medullary carcinoma).

Examples of non-solid tumors include, but are not limited to, hematological neoplasms. As used herein, hematology and neoplasms are technical terms that include lymphoblastic disorders, bone marrow disorders, and AIDS-associated leukemia.

Lymphocytic disorders include, but are not limited to, acute lymphocytic leukemia and chronic lymphocytosis disorders (eg, lymphoma, myeloma, and chronic lymphocytic leukemia). Lymphomas include, for example, Hodgkin's disease, non-Hodgkin's lymphoma, and lymphocytic lymphoma. Chronic lymphocytic leukemia includes, for example, T cell chronic lymphocytic leukemia and B cell chronic lymphocytic leukemia.

The invention further relates to the use of a compound according to the invention, or a pharmaceutically acceptable salt or solvate thereof, for the prevention and/or treatment of radiation-induced fibrosis, connective tissue diseases such as, for example, Sjogrën syndrome, That is, scleroderma), chronic bacterial infections (such as, for example, Helicobacter pylori), abnormal scarring (keloids), and polymicrobial sepsis.

The invention further relates to the treatment or prevention of radiation-induced fibrosis, connective tissue diseases such as, for example, Sjogrën syndrome, i.e., scleroderma, chronic bacterial infections such as, for example, Helicobacter pylori, abnormal scarring (keloids), and more A method of microbial sepsis comprising administering to a mammalian species in need thereof a therapeutically effective amount of a compound according to the invention or a pharmaceutically acceptable salt or solvate thereof.

The invention further provides the use of a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof, for the manufacture of a medicament for the treatment and/or prevention of radiation-induced fibrosis, connective tissue diseases such as, for example, Sjogrën syndrome , that is, scleroderma), chronic bacterial infections (such as, for example, Helicobacter pylori), abnormal scarring (keloids), and polymicrobial sepsis.

The invention also provides methods for delaying the onset of the following in a patient: radiation-induced fibrosis, connective tissue disease (such as, for example, Sjogrën syndrome, ie, scleroderma), chronic bacterial infection (such as, for example, H. pylori) Abnormal scarring (keloids) and polymicrobial sepsis, the method comprising administering to a patient in need thereof a pharmaceutically effective amount of a compound of formula I or a pharmaceutically acceptable salt or solvate thereof. formula

The invention also provides a pharmaceutical composition comprising a compound of formula I, or a pharmaceutically acceptable salt and solvate thereof, and at least one pharmaceutically acceptable carrier, diluent, excipient, and/or adjuvant. As indicated above, the invention also encompasses pharmaceutical compositions comprising, in addition to the active compound as a compound of the invention, a pharmaceutically acceptable salt thereof and a solvate thereof, additional therapeutic agents and/or active ingredients.

Another object of the present invention is an agent comprising at least one of the compounds of the present invention or a pharmaceutically acceptable salt or solvate thereof as an active ingredient.

According to another feature of the invention, there is provided a use of a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, for the manufacture of a medicament for modulating A2A activity in a patient in need of such treatment, the modulation comprising The patient is administered an effective amount of a compound of the invention or a pharmaceutically acceptable salt or solvate thereof.

In general, for pharmaceutical use, the compounds of the invention may be formulated as pharmaceutical preparations comprising at least one compound of the invention and at least one pharmaceutically acceptable carrier, diluent, excipient and/or adjuvant And one or more additional pharmaceutically active compounds, as appropriate.

By way of non-limiting example, such a formulation may be in a form suitable for oral administration, parenteral administration (such as by intravenous, intramuscular or subcutaneous injection or intravenous infusion), topical administration (including the eye), by inhalation, by skin patch, by implant, by suppository, etc. Such suitable forms of administration - which may be solid, semi-solid or liquid, depending on the mode of administration - as well as methods for the preparation thereof and carriers, diluents and excipients, will be apparent to those skilled in the art; Reference is made to the latest version of Remington's Pharmaceutical Sciences.

Some preferred, but non-limiting examples of such formulations include troches, pills, powders, troches, capsules, cachets, elixirs, suspensions, emulsions, solutions, slurries, aerosols, ointments, Sweet spirits, lotions, soft and hard gelatin capsules, suppositories, drops, sterile injectable solutions and aseptic packaged powders (usually reconstituted prior to use) for administration as a bolus and/or for continuous administration It can be formulated with carriers, excipients, and diluents which are themselves suitable for such formulations, such carriers, excipients, and diluents such as lactose, glucose, sucrose, sorbitol, mannitol, Starch, gum arabic, calcium phosphate, alginate, tragacanth, gelatin, calcium citrate, microcrystalline cellulose, polyvinylpyrrolidone, polyethylene glycol, cellulose, (sterile) water, methyl cellulose , methyl and propyl hydroxybenzoate, talc, magnesium stearate, edible oils, vegetable oils and mineral oils or suitable mixtures thereof. Formulations may optionally contain other materials commonly used in pharmaceutical formulations, such as lubricants, wetting agents, emulsifying and suspending agents, dispersing agents, disintegrating agents, accumulating agents, fillers, preservatives, sweeteners, flavoring agents, flow rates Conditioner, mold release agent, and the like. The composition can also be formulated to provide rapid, sustained or delayed release of the active compound contained therein.

The pharmaceutical preparations of the present invention are preferably in unit dosage form and may be packaged, for example, in a cartridge, shield, vial, bottle, sachet, ampoule or any other suitable single or multiple dose holder or container (which Can be properly labeled); optionally with one or more inserts containing product information and/or instructions for use.

Depending on the condition to be prevented or treated and the route of administration, the active compounds of the invention may be administered as a single daily dose, divided into one or more daily doses, or administered essentially continuously, for example using a drip infusion. . Instance

The invention will be better understood with reference to the following examples. The examples are intended to represent specific embodiments of the invention and are not intended to limit the scope of the invention.

The following abbreviations are used: Boc: tert-butoxycarbonyl, BSA: bis(trimethyldecyl)acetamide or bovine serum albumin, depending on the context, Cpd: compound, DavePhos: 2-dicyclohexylphosphino- 2'-biphenyl, DCM: dichloromethane, DIPEA: N,N-diisopropylethylamine, DMF: dimethylformamide, DMSO: dimethyl hydrazine, eq.: equivalent EtOAc: acetic acid Ester, g: g, h: hour, HAS: human serum albumin, HPLC: high performance liquid chromatography, HMDS: hexamethyldiazepine, L: liter, LCMS: liquid chromatography mass spectrometry LHMDS: double Lithium (trimethylsulfonyl) guanamine, M: mol.L ^-1 , MeOH: methanol, μg: microgram, μmol: micromolar, μL: microliter, mg: milligram, mL: milliliter, mmol: millimolar Ear, mM: mmol.L ^-1 , min: minute, mol: molar, N: equivalent concentration, N ₂ : nitrogen, ng: Nike, nM: nmol.L ^-1 , NMP: N-methyl-2 - pyrrolidone, NMR: nuclear magnetic resonance spectroscopy, quant.: quantification (yield), SFC: supercritical fluid chromatography, rt or RT: room temperature, t Bu: tert-butyl, TEA: triethylamine , TFA: Three Acetic acid, THF: tetrahydrofuran, TLC: thin layer chromatography, VTD: vacuum tray dryer. I. Chemistry example

The MS data provided in the examples described below was obtained as follows: LCMS was recorded using Agilent 6130 or 6130B multimode (ESI+APCI). LCMS method: Column: XBridge C8 (50×4.6 mm) 5 μm; Method: A: 0.1% TFA in H ₂ O, B: 0.1% TFA in ACN, flow rate: 2.0 mL/min. Column: Zorbax extend C18 (50X4.6 mm) 5 μm; Method: A: 10 mM NH ₄ OAc in H ₂ O, B: ACN, flow rate: 1.2 mL/min. Column: Zorbax XDB C18 (50X4.6 mm) 3.5 μm; Method: A: 0.1% HCOOH in H ₂ O, B: ACN, flow rate: 1.5 mL/min. Column: XBridge C8 (50X4.6 mm) 3.5 μm; Method: A: 10 mM NH ₄ HCO ₃ in H ₂ O, B: ACN, flow rate: 1.2 mL/min.

The NMR data provided in the examples described below were obtained as follows: 1H-NMR: Bruker DPX 400 MHz. The abbreviations of the multiplicities observed in the NMR spectrum are as follows: s (single peak), d (doublet), t (triplet), q (quadruple), m (multiplet), br (broad).

HPLC purity was evaluated using either of two methods: Method: XB0595TF; Column: XBridge C8 (50X4.6) mm, 3.5 μm; gradient of the eluent from 0.1% TFA in H ₂ O to 0.1% TFA in ACN, flow rate: 2.0 mL/min. Method: AM9010A3; column: Phenomenex gemini NX-C18 (150X4.6), 3.0 μm; gradient of the eluent from 10 mM ammonium acetate in water to ACN, flow rate: 1.0 mL/min. Method: XB0595NHC; column: XBridge C8 (50X4.6) mm, 3.5 μm; gradient of the eluent from 10 mM ammonium bicarbonate in water to ACN, flow rate: 1.0 mL/min.

Solvents, reagents, and starting materials are purchased and used as received from commercial suppliers, unless otherwise stated.

The intermediates and compounds described below were named using ChemBioDraw ^® Ultra version 12.0 (PerkinElmer). I.1. Intermediate synthesis of intermediate compound 1 : 2-(5- Amino -8-( furan -2- yl )-2 - yloxythiazolo [ 5,4-e][1,2,4 ] triazolo [1,5-c] pyrimidine -3 (2H) - yl) ethyl methanesulfonate

Step 1 : 2,6 -Diamino -5 -thiocyanomethoxypyrimidin- 4- ol: Add 2 to a stirred solution of acetic acid (27500 mL) in a reactor at 25-30 ° C under a nitrogen atmosphere. , 6-Diaminopyrimidin-4-ol (500 g). Potassium thiocyanate (1586 g) was slowly added and the temperature was raised to 90 ± 5 ° C; until the reaction mass became a clear solution. Once it became a clear solution, the reaction mixture was cooled to 15 ± 5 ° C and bromine (633 g) was added dropwise to acetic acid (750 mL) and stirred at the same temperature for 2 h. After the reaction was completed, the reaction mixture was neutralized with aqueous ammonia (9000 mL) and stirred at 20 ± 5 ° C for 16 h. The formed precipitate was filtered and washed with water (2500 mL) and methanol (1000 mL). The wet material was dried in the VTD at 70 °C for 24 hours to give the title compound (206 g, qu. LCMS: 184.3 [M+1] ⁺ . ¹ H-NMR (400 MHz, DMSO-d6): δ 10.36 (s, 1H), 7.03 (s, 2H), 6.64 (brs, 2H).

Step 2 : 2,5 -Diaminothiazolo [4,5-d] pyrimidin -7- ol: to 2,6-diamino-5-thiocyanomethoxypyrimidin-4-ol (Step-1 (750 g, 4.09 mol) A solution of tetrabutylammonium fluoride (1 M in THF, 6750 mL) was added to a stirred solution of THF (15 L) and the reaction mixture was heated to 64 ± 3 ° C for 24 h. After the reaction was completed, the reaction mixture was cooled to 25 ± 5 ° C for 1 h. The formed precipitate was filtered and washed with THF (2.25 L). The wet solid was taken up in water (6 L) and concentrated hydrochloric acid (1.5 L) was added. The reaction mixture was stirred for 4 h. The reaction mixture was filtered and the solid residue was washed with water (3. The wet material was treated with water (6 L) and sodium bicarbonate (3 kg) was added. The reaction was stirred for 4 h, filtered, EtOAcjjjjjjjjjjj LCMS: 184.2 [M+1] ⁺ . ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 10.84 (s, 1H), 7.89 (s, 2H), 6.46 (s, 2H).

Step 3 : 5- Amino -7- hydroxythiazolo [4,5-d] pyrimidin -2(3H) -one: 2,5-diaminothiazolo[4,5-d]pyrimidin-7- Alcohol (Step 2; 570 g, 3.11 mol) and NaNO ₂ (570 g, 8.26 mol) in water (5700 mL) in a hot (80 ° C) mixture slowly added to the heat of concentrated HCl (11400 mL, 15 Vol) Solution (80 ° C). The reaction mixture was stirred for 2 h and the reaction was monitored by HPLC. After the reaction was completed, the mixture was cooled to 15 ° C and basified to pH 12 using NaOH pellets. The reaction mass was heated to 80 °C for 2 hours, then cooled to 35 °C and the pH was adjusted to 5-6 using concentrated hydrochloric acid. The precipitated solid was filtered, washed with water (5V) and dried in EtOAc (EtOAc) LCMS: 185.6 [M+1] ⁺ . ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 12.08 (s, 1H), 11.10 (s, 1H), 6.88 (s, 2H).

Step 4 : 5- Amino- 3-(2 -methoxyethyl ) thiazolo [4,5-d] pyrimidine- 2,7(3H, 4H) -dione: 5-amino-7- Hydroxythiazolo[4,5-d]pyrimidin-2(3H)-one (36.2 g, 0.196 mol, 1 eq) was taken up in anhydrous DMF (600 mL) and heated to 90 ° C in a sealed tube. The reaction mixture was stirred at 90 ° C for 30 min and then cooled to 30 °C. To this reaction mixture was slowly added 60% NaH (10.4 g, 1.1 eq) and stirred for 30 min followed by 1-bromo-2-methoxyethane (32.83 g, 1.1 eq). The reaction mixture was again heated to 100 °C. The completion of the reaction was monitored by TLC. After the reaction was completed, the reaction mixture was evaporated to EtOAcjjjjjjjjjjj LCMS: 243.6 [M+1] ⁺ . ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 11.10 (s, 1H), 6.92 (brs, 2H), 3.93 (t, J = 6 Hz, 2H), 3.57 (t, J = 6 Hz, 2H), 3.23 (s, 3H).

Step 5 : 5- Amino -7- chloro- 3-(2 -methoxyethyl ) thiazolo [ 4,5-d] pyrimidin -2(3H) -one: 5-amino-7- Hydroxy-3-(2-methoxyethyl)thiazolo[4,5-d]pyrimidin-2(3H)-one (10 g, 0.0412 mol) was treated with POCl ₃ (100 mL) in a sealed tube Heat to 90 ° C for 18 h. After the completion of the reaction was monitored by TLC, the reaction mixture was concentrated and ice-cold water was added. NaHCO ₃ used the pH of the reaction mixture was adjusted to 7 and extracted using DCM. The organic layer was separated, dried over Na ₂ SO _4, filtered and concentrated to give a pale yellow solid (6.8 g, 63%), which was used as is without further purification in the next step. LCMS: 261.2 [M+1] ⁺ . ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 7.37 (s, 2H), 4.01 (t, J = 5.6 Hz, 2H), 3.62 (t, J = 5.6 Hz, 2H), 3.23 (s, 3H).

Step 6 : N'-(5- Amino- 3-(2 -methoxyethyl )-2 -yloxy -2,3 -dihydrothiazolo [4,5-d] pyrimidin -7- yl ) furan-2 card hydrazine: to 5 in ethanol and the amino-7-chloro-3- (2-methoxyethyl) thiazolo [4,5-d] pyrimidin -2 (3H) - one ( 6.8 g, 0.026 mol) yttrium ruthenate (4.9 g, 0.039 mol) was added and heated to 100 ° C in a sealed tube for 19 h. The reaction was monitored by TLC. After the reaction was completed, the reaction mixture was cooled to RT and concentrated. To the residue was added petroleum ether to give a solid, which was filtered and was taken to the next step (7.2 g, 79%). LCMS: 351.2 [M+1] ⁺ .

Step 7 : 5- Amino -8-( furan -2- yl )-3-(2 -methoxyethyl ) thiazolo [5,4-e][1,2,4] triazolo [1 , 5-c] pyrimidin -2(3H) -one: N'-(5-Amino-3-(2-methoxyethyl)-2-yloxy-2,3-dihydrothiazole [4,5-d]pyrimidin-7-yl)furan-2-carboate (7.2 g, 0.20 mol) was treated with BSA (50.8 mL, 11 eq) and HMDS (76 mL, 25 eq). The reaction mixture was heated to 127 °C for 20 h. After the reaction was completed, the reaction mixture was cooled to 0 ° C and methanol (30 mL) was added. The precipitated solid was filtered and washed with EtOAc EtOAc (EtOAc) LCMS: 333.2 [M+1] ⁺ .

Step 8 : 5- Amino -8-( furan -2- yl )-3-(2- hydroxyethyl ) thiazolo [5,4-e][1,2,4] triazolo [1,5 -c] pyrimidine -2(3H) -one: 5-amino-8-(furan-2-yl)-3-(2-methoxyethyl)thiazolo[5,4 at -50 °C -e] [1,2,4] triazolo [1,5-c] pyrimidin -2 (3H) - one (5.9 g, 0.017 mol) in dry DCM (100 mL) was slowly added in the BBr ₃ (11.5 g, 2.6 eq) and maintained at 25-30 °C for 19 h. The reaction was monitored by TLC. After the reaction was completed, the reaction mixture was purified with EtOAc EtOAc EtOAc (EtOAc) Used as is for the next step. LCMS: 319.2 [M+1] ⁺ . ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 8.31 (s, 2H), 7.95 (d, J = 0.8 Hz, 1H), 7.24 (t, J = 2.8 Hz, 1H), 6.74-6.74 ( m, 1H), 4.94 (t, J = 5.6 Hz, 1H), 4.01 (t, J = 6.4 Hz, 2H), 3.71 (t, J = 6.0 Hz, 2H).

Step 9 : 2-(5- Amino -8-( furan -2- yl )-2 - yloxythiazolo[5,4-e][1,2,4] triazolo [1,5- c] pyrimidine -3(2H) -yl ) ethylmethanesulfonate: 5-amino-8-(furan-2-yl)-3-(2-hydroxyethyl)thiazolidine at 60 ° C [ 5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one (3.6 g, 0.011 mol) was dissolved in anhydrous DMF (95 mL) until the reaction mixture It becomes clear. The reaction mass was cooled to 0.degree. C. and TEA (3 g, 3 eq) was then added, followed by the addition of methanesulfonium chloride (1.6 g, 1.3 eq). The reaction mixture was stirred at RT for 48 h. After the reaction was completed, ethyl acetate (100 mL) and water (50 mL) were added and extracted. The dried organic layer was ₂ SO ₄ Na, filtered and evaporated to give the compound as a yellow solid (3.0 g, 67%) of which is analytically pure for the next step. LCMS: 397.2 [M+1] ⁺ . ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 8.37 (s, 2H), 7.95 (s, 1H), 7.25 (d, J = 3.6 Hz, 1H), 6.74-6.74 (m, 1H), 4.56 (t, J = 5.2 Hz, 2H), 4.26 (t, J = 4.8 Hz, 2H), 3.16 (s, 3H). Intermediate 2: 2- (5-amino-8- (furan-2-yl) -2-oxo-thiazolo [5,4-e] [1,2,4] triazolo [1,5- -c] pyrimidine -3(2H) -yl ) -acetaldehyde

To 5-Amino-8-(furan-2-yl)-3-(2-hydroxyethyl)thiazolo[5,4-e][1,2,4]triazolo-[1,5- Add a IBX (15.04 g, 53.72 mmol) in DMSO to a stirred solution of pyrimidine-2(3H)-one (prepared according to the procedure described for the intermediate 1 step 8 , 3.6 g, 10.74 mmol) in THF (150 mL) Solution in (35 mL). The resulting mixture was stirred at RT for 6 h. The reaction mixture was diluted with DCM and the layers were separated. The organic layer was washed successively with a saturated NaHCO ₃ solution and a saturated brine solution. Subsequently dried over anhydrous Na ₂ SO _4, filtered and concentrated under reduced pressure. The crude residue obtained (3.0 g, 75%) was used in the next step without further purification. LCMS 317 [M+1] ⁺ . I.2. Synthesis of the final compound Example 1 : 3-(2-(4-(4-(( 1H -1 ) , 2,3 - triazol -4 -yl ) methoxy- 2- fluorophenyl ) piperazine ) -1 -yl ) ethyl )-5- amino- (8-( furan -2- yl ) thiazolo [5,4-e][1,2,4] triazolo [1,5-c] Pyrimidine -2(3 H ) -one :

Step 1 : 4-(2- Fluoro- 4 -hydroxyphenyl ) piperazine- 1- carboxylic acid tert - butyl ester (2) : 4-bromo-3-fluorophenol (10 g, under nitrogen at 0 ° C Add LHMDS (115) to a mixture of piperazine-1-carboxylic acid tert-butyl ester (11.70 g, 0.063 mol), DavePhos (0.515 g, 0.001 mol) and Pd ₂ (dba) ₃ (0.958 g, 0.001 mol) mL of 1.0 M solution in THF, 0.115 mol). The reaction mixture was heated at 65 &lt;0&gt;C for 24 h and was monitored by TLC. The crude reaction mixture was washed with saturated NH ₄ Cl and extracted with ethyl acetate and (2 x 100 mL). The combined organic layers were concentrated with EtOAc EtOAcjjjjjjj </RTI><RTIID=0.0></RTI></RTI><RTIID=0.0></RTI>

Step 2 : 4-(2- Fluoro- 4-( prop -2- yn- 1 -yloxy ) phenyl ) piperazine- 1- carboxylic acid tert - butyl ester (3) : under nitrogen at 0 ° C Add a stirred solution of sodium hydride (0.7 g, 0.0304 mol) in DMF (10 mL) (3 mL, EtOAc (EtOAc) 0.0152 mol). The reaction mixture was stirred at 0 ° C for 15 min then bromopropyne (2.71 g, 0.0228 mol) After completion of the reaction (TLC), the reaction mixture was washed with saturated NH ₄ Cl (20 mL) and extracted with ethyl acetate treatment. The organic layer was washed with saturated saline solution, dried over anhydrous Na ₂ SO _4, filtered and concentrated under reduced pressure. The crude material obtained was purified by column chromatography (40% EtOAc / hexanes eluting) to afford 4-(2-fluoro-4-(prop-2-)- T-butyl 3-methyloxy)phenyl)piperazine-1-carboxylate (3.6 g, 70.8%). </RTI><RTIID=0.0></RTI></RTI><RTIID=0.0></RTI>

Step 3 : 1-(2- Fluoro- 4-( prop -2- yn- 1 -yloxy ) phenyl ) piperazine (4) : 4-(2-fluoro-4-(propyl ) at 0 °C a stirred solution of 2-butyl-1-yloxy)phenyl)piperazine-1-carboxylic acid tert-butyl ester (3, 3.6 g, 10.8 mmol) in dichloromethane (15 mL) 4 N HCl (mL) in methylene chloride and stirred at RT for 4 h. After completion of the reaction (TLC), the reaction mixture was concentrated under reduced pressure. The salt was neutralized with a sodium bicarbonate solution, extracted with DCM, and the combined organic layer was washed with brine, dried over sodium sulfate and then evaporated - alkynyl-1-yloxy)phenyl)piperazine (2.5 g, 99.2%); mp.

Step 4 : 5- Amino- 3-(2-(4-(2- fluoro- ( prop- 2- yn- 1 -yloxy ) phenyl ) piperazin- 1 -yl ) ethyl )-8-( Furan -2- yl ) thiazolo [5,4-e][1,2,4] triazolo [1,5-c] pyrimidin -2(3H) -one (5) : to 1-(2- Fluoro-4-(prop-2-yn-1-yloxy)phenyl)piperazine (4,1 g, 4.3 mmol) and 2-(5-amino-8-(furan-2-yl)- 2-sided oxythiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethylmethanesulfonate (0.9 g, DIPEA (0.6 mL, 6.8 mmol) was added <RTI ID=0.0></RTI></RTI><RTIgt; After completion of the reaction (TLC & LCMS), the reaction mixture was concentrated under reduced pressure. The crude product was washed with a mixture of diethyl ether and acetonitrile to give 5-amino-3-(2-(4-(2-fluoro-4-(prop-2-yn-1-yloxy)benzene) as a brown solid. Piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidine- 2 (3H)-one (0.7 g, 57.8%); HPLC purity (XB0595 TF): 92.63%; LCMS (ESI ESI) m/z: Calculated: 534.16;

Step 5 : 3-(2-(4-(4-((1H-1,2,3- triazol -4 -yl ) methoxy- 2- fluorophenyl ) piperazin- 1 -yl ) ethyl )- 5- amino- (8-( furan -2- yl ) thiazolo [5,4-e][1,2,4] triazolo [1,5-c] pyrimidin -2(3H) -one ( Compound 1) : 5-amino-3-(2-(4-(2-fluoro-4-(prop-2-yn-1-yloxy)phenyl)piperazin-1-yl ) at RT Ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one (5 , 0.4 g, 0.7 mol), a cuprous iodide (0.030 g, 0.014 mmol) was added to a stirred solution of DMF (4.5 mL) and MeOH (0.5 mL). The mixture was added dropwise at 0 ° C under nitrogen atmosphere. Trimethylsulfonyl azide (0.2 mL, 1.4 mmol) and heated to 100 ° C for 16 h. After completion of the reaction (TLC), the reaction mixture was extracted with ethyl acetate (2 x 20 mL) and organic layer was washed with brine, dried over sodium sulfate and concentrated under reduced pressure by using a product with diethyl ether and washed with acetonitrile (50:50) to give further enriched compound as a brown solid of 1: 3- (2- (4- ( 4-((1H-1,2,3-triazol-4-yl)methoxy)-2-fluorophenyl)-piperazin-1-yl)ethyl)-5-amino-8-( Furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c] Piperidin -2 (3H) - one (0.115 g, 26.6%) HPLC purity (XB0595TF): 92.08%; LCMS (ESI pos. Ion) m / z: Calculated: 577.18; Observed: 578.0 (M + 1);. ¹ H-NMR (400 MHz, DMSO-d6): δ 15.12 (brs, 1H), 8.32 (brs, 2H), 7.96 (s, 2H), 7.24 (d, J = 3.2 Hz, 1H), 6.96-6.89 (m, 2H), 6.79-6.73 (m, 2H), 5.13 (s, 2H), 4.08 (t, J = 6.0 Hz, 2H), 2.86 (m, 4H), 2.72-2.63 (m, 6H). Example 2 : 5-((4-(4-(2-(5- Amino -8-( furan -2- yl )-2 - yloxythiazolo[5,4-e][1,2, 4] Triazolo [1,5-c] pyrimidin -3(2H) -yl ) ethyl ) piperazin- 1 -yl )-3- fluorophenoxy ) methyl )-1,3,4- oxa Diazol- 2(3H) -one

Step 1 : 4-(4-(2- ethoxy -2 -oxoethoxyethoxy )-2- fluorophenyl ) piperazine- 1- carboxylic acid tert- butyl ester (2) : to 4-(2) -Fluoro-4-hydroxyphenyl)piperazine-1-carboxylic acid tert-butyl ester (1, 2 g, 6.75 mmol) and ethyl bromoacetate (1.67 g, 10.0 mmol) in N,N-dimethylformamidine K ₂ CO ₃ (2.76 g, 20.0 mmol) was added to a stirred solution of EtOAc (EtOAc). After completion of the reaction (TLC), the reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate. The organic layer was washed with saturated saline solution, dried over anhydrous Na ₂ SO _4, filtered and concentrated under reduced pressure. The crude material obtained was purified by column chromatography (20%EtOAc / hexanes) Calculated: 382.19; observed: 383.0 (M + 1).

Step 2 : 2-(3- Fluoro- 4-( piperazin- 1 -yl ) phenoxy ) acetate (3) : to 4-(4-(2-ethoxy-2-oxooxy) Addition of t-butyl oxy)-2-fluorophenyl)piperazine-1-carboxylate ( 2 , 1.9 g, 5.0 mmol) in dichloromethane to 4 N in dioxane (15 mL) HCl and the reaction mixture was stirred at RT for 5 h. After completion of the reaction (TLC), the reaction mixture was purified eluted with sat. The organic layer was dried with EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj 1).

Step 3 : 2-(4-(4-(2-(5- Amino -8-( furan -2- yl )-2 - yloxythiazolo[5,4-e][1,2,4 ] triazolo [1,5-c] pyrimidine -3 (2H) - yl) ethyl) piperazin-1-yl) -3-fluorophenoxy) acetate (4): to a solution of 2- (3 -Fluoro-4-(piperazin-1-yl)phenoxy)acetate (3, 1.0 g, 3.52 mmol) and 2-(5-amino-8-(furan-2-yl)-2- Side-oxythiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethylmethanesulfonate (1.12 g, 2.82 mmol DIPEA (1.3 g, 11.0 mmol) was added <RTI ID=0.0></RTI></RTI><RTIgt; After completion of the reaction (TLC & EtOAc), EtOAc (EtOAc) LCMS (ESI ESI) m/z: Calculated: 582.18;

Step 4 : 2-(4-(4-(2-(5- Amino -8-( furan -2- yl )-2 - yloxythiazolo[5,4-e][1,2,4 ] triazolo [1,5-c] pyrimidine -3 (2H) - yl) ethyl) piperazin-1-yl) -3-fluorophenoxy) acetyl hydrazine (5): to a solution of 2- (4 -(4-(2-(5-Amino-8-(furan-2-yl)-2-yloxythiazolo[5,4-e][1,2,4]-triazolo[1 ,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3-fluorophenoxy)acetate ( 4 , 0.2 g, 0.34 mmol) in ethanol (20 mL) A solution of hydrazine hydrate (50 mg, 1.0 mmol) was added and the mixture was stirred at 90 ° C for 16 h. After the completion of the reaction (TLC & EtOAc), EtOAc (EtOAc) elut. m/z: Calculated: 568.18; observed: 569.0 (M+1).

Step 5 : 5-((4-(4-(2-(5- Amino -8-( furan -2- yl )-2 - yloxythiazolo[5,4-e][1,2, 4] Triazolo [1,5-c] pyrimidin -3(2H) -yl ) ethyl ) piperazin- 1 -yl )-3- fluorophenoxy ) methyl )-1,3,4- oxa Diazole- 2(3H) -one ( Compound 2) : Add TEA (0.084) to a suspension of compound 5 (0.158 g, 0.27 mol) in 1,4-dioxane (10 mL) and DMF (1 mL) g, 0.83 mol) and the reaction mixture was stirred at 100 ° C for 4 h. After completion of the reaction (TLC & LCMS), the solvent was removed under reduced pressure and purified by prep HPLC purified to give the title compound as a white solid of 2 (21 mg, 12.7%) ; HPLC purity (XB0595TF): 95.33%; LCMS (ESI pos. ion) m / z: calculated: 594.16; observed: 595.1 (m + 1); 1 H-NMR (400 MHz, DMSO-d6): δ 12.52 (brs, 1H), 8.32 (brs, 2H), 7.96 (d, J = 0.80 Hz, 1H), 7.25 (d, J = 3.20 Hz, 1H), 6.99-6.92 (m, 2H), 6.78 (dd, J = 2.0 & 8.8 Hz, 1H), 6.74 (dd, J = 1.6 & 3.2 Hz, 1H), 5.01 (s, 2H), 4.08 (t, J = 6.40 Hz, 2H), 2.87 (m, 4H), 2.72-2.63 (m, 6H). Example 3 : 5- Amino- 3-(2-(4-(3- fluoropyridin- 4 -yl ) piperazin- 1 -yl ) ethyl )-8-( furan -2- yl ) thiazolo [5 ,4-e][1,2,4] triazolo [1,5-c] pyrimidin -2(3H) -one

Step 1 : 1-(3- Fluoropyridin- 4 -yl ) piperazine (3) : 3-fluoro-4-iodopyridine ( 2 , 2 g, 4.48 mmol, 1 eq) in NMP (20 mL) The stirred solution was added DIPEA (0.694 g, 5.38 mmol, 1.2 eq) and piperazine ( 1 , 0.484 g, 6.72 mmol, 1.5 eq). The resulting mixture was stirred at 80 ° C for 16 h. After completion, the reaction mixture was concentrated under reduced pressure. The residue was taken up in water and lyophilized. The obtained adhesive solid was triturated with diethyl ether and n-pentane to give 1-(3-fluoropyridin-4-yl)piperazine 3 (0.750 g, 92%) as pale yellow solid. </RTI><RTIID=0.0></RTI></RTI><RTIID=0.0>

Step 2 : 5- Amino- 3-(2-(4-(3- fluoropyridin- 4 -yl ) piperazin- 1 -yl ) ethyl )-8-( furan -2- yl ) thiazolo [5 , 4-e][1,2,4] triazolo [1,5-c] pyrimidin -2(3H) -one ( Compound 3) : 1-(3-fluoropyridin-4-yl ) at RT Add 2-(5-Amino-8-(furan-2-yl)-2-oxo-oxythiazole to a solution of piperazine (3, 0.071 g, 0.392 mmol, 1 eq) in DMF (2 mL) [4,5-e][1,2,4]triazolo[1,5-c]-pyrimidin-1(2H)-yl)ethylmethanesulfonate (4, 0.150 g, 0.392 mmol, 1.03 Eq) and DIPEA (0.100 g, 0.775 mmol, 2 eq). The reaction was stirred at 80 ° C for 16 h. After completion, the reaction mixture was concentrated under reduced pressure. The residue obtained was diluted with water and extracted with ethyl acetate (2×30 mL). The combined organic phase was dried (over anhydrous Na ₂ SO _4), filtered and concentrated under reduced pressure. The obtained crude product was purified by EtOAc EtOAcjjjjj </RTI><RTIID=0.0></RTI></RTI><RTIID=0.0> HPLC purity (XB0595TF.M): 97.75%. Example 4: 2-(5-(4-(2-(5- Amino -8-( furan -2- yl )-2 - yloxythiazolo[5,4-e][1,2,4 ] triazolo [1,5-c] pyrimidine -3 (2H) - yl) ethyl) piperazin-1-yl) -2,4-difluorophenoxy) as acetamide

Step 1 : Preparation of 1-( benzyloxy )-5- bromo -2,4 -difluorobenzene (2) : to 5-bromo-2,4-difluorophenol (1, 20 g, 95.69 mmol) and bromine benzyltrimethylammonium (18 g, 105.26 mmol) in N, N- dimethylformamide (200 mL) was added in the _{K 2 CO 3 (39.62 g,} 287.08 mmol) and the reaction mixture was heated for 16 h at 90 deg.] C . After completion of the reaction (TLC), the reaction mixture was diluted with water (200 mL) and extracted with ethyl acetate. The organic layer was washed with saturated saline solution, dried over anhydrous Na ₂ SO _4, filtered and concentrated under reduced pressure. The crude material obtained was purified by column chromatography (EtOAc EtOAc EtOAc) LCMS (ESI negative); m / z: Calculated: 297.98; observed; 296.8 (M-1); 1 H-NMR (400 MHz, DMSO-d6): δ 7.60-7.67 (m, 1H), 7.55- 7.58 (m, 1H), 7.37-7.44 (m, 5H), and 5.20 (s, 2H).

Step 2 : Preparation of tert-butyl 4-(5-( benzyloxy )-2,4 -difluorophenyl ) piperazine- 1- carboxylate (3) : to 1-(benzyloxy)-5-bromo -2,4-difluorobenzene (2,24 g, 80.08 mmol), N-Boc piperazine (16.55 g, 88.88 mmol) and sodium butoxide (17.06 g, 177.77 mmol) in toluene (200 mL) The solution was added t- Bu Xphos (3.43 g, 8.08 mmol). The reaction mixture was flushed and the use of N ₂ was added _{Pd 2 (dba) 3 (3.69} g, 4.04 mmol). The reaction mixture was heated at 115 °C for 16 h and after completion (TLC), the reaction mixture was cooled and filtered thru Celite. The filtrate was concentrated and purified with EtOAc EtOAcqqqqqqqqQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQ Calculated: 404.19; observed; 405 (M+1); ¹ H-NMR (400 MHz, DMSO-d6): δ 7.34-7.38 (m, 5H), 7.26 (t, J = 11.60 Hz, 1H), 6.94 (t, J = 8.80 Hz, 1H), 5.16 (s, 2H), 3.45 (m, 4H), 2.90 (t, J = 4.8 Hz, 4H), and 1.42 (s, 9H).

Step 3 : 4-(2,4 -Difluoro -5- hydroxyphenyl ) piperazine- 1- carboxylic acid tert- butyl ester (4) : to 4-(5-(benzyloxy)-2,4-di 10% Pd-C (2.7 g, 15% Wt.) was added to a clear solution of fluorophenyl)piperazine-1-carboxylic acid tert-butyl ester (3, 18 g, 44.55 mmol) in ethanol (180 mL). the reaction mixture was stirred under an atmosphere of H ₂ at RT 5 h. After completion (TLC), the reaction mixture was filtered with EtOAc EtOAc (EtOAc) The filtrate was concentrated and purified with EtOAcqqqqqqHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH ¹ H-NMR (400 MHz, CD ₃ OD): δ 6.92 (t, J = 8.8 Hz, 1H), 6.56-6.51 (m, 2H), 3.57 (m, 4H), 2.91 (t, J = 4.80 Hz , 4H), and 1.49 (s, 9H).

Step 4 : 4-(5-(2- Amino -2 -oxoethoxyethoxy )-2,4 -difluorophenyl ) piperazine- 1- carboxylic acid tert- butyl ester (5) : to 4- (2,4-Difluoro-5-hydroxyphenyl)piperazine-1-carboxylic acid tert-butyl ester (4, 10 g, 31.7 mmol) and bromoacetamide (5.25 g, 38.09 mmol) in N,N- K ₂ CO ₃ (13.14 g, 95.23 mmol) was added to the suspension in dimethylformamide (100 mL). The reaction mixture was stirred at 90 &lt;0&gt;C for 5 h and was monitored by TLC. After completion, the reaction mixture was diluted with water (100 mL) andEtOAc The organic layer was washed with saturated brine solution, dried over anhydrous Na ₂ SO _4, filtered, concentrated and trituration with diethyl ether to afford the title compound as a light brown solid (9.5 g, 80.7%); LCMS (ESI positive ion); m /z: Calculated: 371.17; observed; 372.2 (M+1); ¹ H-NMR (400 MHz, CDCl ₃ ): δ 6.92 (t, J = 11.2 Hz, 1H), 6.92 (m, 2H), 5.66 (brs, 1H), 4.53 (s, 2H), 3.61 (t, J = 5.20 Hz, 4H), 2.98 (t, J = 4.40 Hz, 4H), and 1.51 (s, 9H).

Step 5 : 2-(2,4 -Difluoro -5-( piperazin- 1 -yl ) phenoxy ) acetamide (6) : to 4-(5-(2-amino-2- yloxy ) Addition of t-butyl butyl ethoxy)-2,4-difluorophenyl)-piperazine-1-carboxylate (5, 8.0 g, 21.5 mmol) in DCM to 4 N in dioxane HCl (80 mL) and the mixture was stirred at RT for 5 h. After completion of the reaction (TLC), the HCl salt was filtered. The salt was dissolved in methanol and neutralized with a Tosic acid-resolvent resin to give a free base (3.5 g, 59. <RTI ID=0.0></RTI></RTI><RTIgt; 272.1 (M+1); ¹ H-NMR (400 MHz, DMSO-d6): δ 7.49 (brs, 1H), 7.43 (brs, 1H), 7.25 (t, J = 11.60 Hz, 1H), 6.75 (t , J = 8.80 Hz, 1H), 4.51 (s, 2H), and 2.81-2.86 (m, 8H).

Step 6 : 2-(5-(4-(2-(5- Amino -8-( furan -2- yl )-2 - yloxythiazolo[5,4-e][1,2,4 ] triazolo [1,5-c] pyrimidine -3 (2H) - yl) ethyl) piperazin-1-yl) -2,4-difluorophenoxy) as acetamide (compound 4): to 2-(2,4-Difluoro-5-(piperazin-1-yl)phenoxy)acetamide ( 6 , 3.5 g, 12.91 mmol) and 2-(5-amino-8-(furan- 2-yl)-2-yloxythiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)-ethylmethanesulfonate DIPEA (8.33 g, 64.57 mmol) was added <RTI ID=0.0></RTI></RTI><RTIID=0.0> After completion of the reaction (TLC & LCMS), the reaction mass was concentrated under reduced pressure to half volume and cooled to 0 °C. The product precipitated as a pale yellow solid. It was filtered and dried. Because of its poor purity, it was suspended in DMSO (150 mL) and heated at 110 ° C for 1 h and filtered under hot conditions. The filtrate was cooled to 0 ° C, diluted with MeOH and then water was slowly added to promote precipitation. The mixture was stirred at RT for 1 h and filtered. The solid was washed with water and methanol to give compound 4 (2.5 g, 34%) as pale yellow solid. HPLC purity (XB_0595TF.M): 92.4%; LCMS (ESI ESI) m/z: Calculated: 571.16; observed: 572.0 (M+1); ¹ H-NMR (400 MHz, DMSO-d6): δ 8.31 (brs, 2H), 7.95 (t, J = 0.8 Hz, 1H), 7.44 (brs, 1H), 7.40 (brs, 1H), 7.27-7.21 (m, 2H), 6.76-6.72 (m, 2H) , 4.49 (s, 2H), 4.08 (t, J = 6.0 Hz, 2H), 2.90 (m, 4H), 2.71 (t, J = 6.00 Hz, 2H), and 2.63 (m, 4H). Examples 5 and 6: (S) -5- amino-3- (2- (4- (2-fluoro-4- (2- (methylsulfinyl acyl) ethoxy) phenyl) piperazine - 1- yl ) ethyl )-8-( furan -2- yl ) thiazolo [5,4-e][1,2,4] triazolo [1,5-c] pyrimidine -2(3H)- Ketone and (R)-5- amino- 3-(2-(4-(2- fluoro- 4-(2-( methylsulfinyl ) ethoxy ) phenyl ) -piperazin- 1- yl) ethyl) -8- (furan-2-yl) thiazolo [5,4-e] [1,2,4] triazolo [1,5-c] pyrimidin -2 (3H) - one:

Step 1 : Synthesis of 4-(2- fluoro- 4-(2-( methylthio ) ethoxy ) phenyl ) piperazine- 1- carboxylic acid tert- butyl ester (2) : to 4-(2-fluoro 1,4-hydroxyphenyl)piperazine-1-carboxylic acid tert-butyl ester (1, 0.3 g, 1.102 mmol, 1 eq) and 1-chloro-2-methylhydrothio-ethane (0.168 g, 1.519 mmol) , 1 eq) in N, N- dimethylformamide (3 mL) was added in the _{K 2 CO 3 (0.419 g,} 3.027 mmol, 2 eq) and the reaction mixture was heated for 16 h at 90 ℃. After completion of the reaction (TLC), the reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate. The organic layer was washed with saturated saline solution, dried over anhydrous Na ₂ SO _4, filtered and concentrated under reduced pressure. The crude residue obtained was purified by EtOAc EtOAc EtOAc (EtOAc) </RTI><RTIID=0.0></RTI><RTIID=0.0></RTI> 1H-NMR (400 MHz, DMSO-d6): δ 7.02 (m, 1H), 6.85 (m, 1H), 6.72 (m, 1H), 4.09-4.12 (m, 2H), 3.45 (d, J = 4.40 Hz, 4H), 2.80-2.86 (m, 6H), 2.14 (s, 3H), and 1.42 (s, 9H).

Step 2 : Synthesis of tert- butyl 4-(2 - fluoro- 4-(2-( methylsulfinyl ) ethoxy ) phenyl ) piperazine- 1- carboxylate (3, 4) : to 4- (2-Fluoro-4-(2-(methylthio)ethoxy)phenyl)piperazine-1-carboxylic acid tert-butyl ester (2, 0.3 g, 0.809 mmol, 1 eq) in acetic acid (10 mL Hydrogen peroxide (0.187 mL) was added dropwise to the ice-cold solution and stirred at the same temperature for 2 h. After completion of the reaction (TLC), the reaction mixture was poured into 4N NaOH solution (20 mL) and extracted with ethyl acetate. The organic layer was washed with saturated saline solution, dried over anhydrous Na ₂ SO _4, filtered and concentrated under reduced pressure. The crude material obtained was purified by EtOAc EtOAc (EtOAc:EtOAc </RTI><RTIID=0.0></RTI></RTI><RTIID=0.0></RTI> 1H-NMR (400 MHz, DMSO-d6): δ 7.02-7.04 (m, 1H), 6.88-6.92 (m, 1H), 6.75-6.78 (m, 1H), 4.28-4.35 (m, 2H), 3.45 (d, J = 4.52 Hz, 4H), 3.21-3.27 (m, 1H), 3.00-3.05 (m, 1H), 2.85-2.87 (m, 4H), 2.63 (s, 3H), and 1.41 (s, 9H).

The racemic mixture (0.29 g) was subjected to SFC (0.29 g sample dissolved in 3 mL of methanol, column-Lux A1 mobile phase: 70:30 (A:B), A = liquid CO ₂ , B = Methanol, flow rate: 0.9 mL/min; wavelength: 220 nm) was separated by palms to produce a peak of 130 mg 1 ( 3 ) and a peak of 130 mg 2 ( 4 ), respectively, in an off-white solid. Note: Peak 1 from SFC purification is arbitrarily considered to be the (S) isomer and peak 2 is considered to be the (R) isomer. Synthesis of Compound 5 :

Step 3 : Synthesis of (S)-1-(2- fluoro- 4-(2-( methylsulfinyl ) ethoxy ) phenyl ) piperazine (5) : to (S)-4-(2) -Fluoro-4-(2-(methylsulfinyl)ethoxy)phenyl)-piperazine-1-carboxylic acid tert-butyl ester ( 3 , 0.13 g) in dichloromethane (1 mL) 4M HCl (1 mL) in dioxane was added and the mixture was stirred at 0 ° C for 1 h. After completion, the reaction mixture was concentrated under reduced pressure at room temperature. The residue obtained was triturated with diethyl ether. This was then dissolved in methanol and passed through a Si-carbonate resin to give the free base 5 (0.094 g, 59%). </RTI><RTIID=0.0></RTI></RTI><RTIID=0.0>

Step 4: Synthesis of (S) -5- amino-3- (2- (4- (2-fluoro-4- (2- (methylsulfinyl acyl) ethoxy) phenyl) - piperazine - 1- yl ) ethyl )-8-( furan -2- yl ) thiazolo [5,4-e][1,2,4] triazolo [1,5-c] pyrimidine -2(3H)- Ketone ( Compound 5) : 2-(5-Amino-8-(furan-2-yl)-2-yloxythiazolo[5,4-e][1,2,4]triazolo[ 1,5-c]pyrimidin-3(2H)-yl)ethylmethanesulfonate ( 7 , 0.11 g, 0.303 mmol, 1 eq), (S)-1-(2-fluoro-4-(2) Methylsulfinyl)-ethoxy)phenyl)piperazine ( 5 , 0.094 g, 0.33 mmol, 1.1 eq) and diisopropylethylamine (0.195 g, 1.514 mmol, 5 eq) in N, N The mixture in dimethylformamide (2 mL) was stirred at 120 ° C for 16 h. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was diluted with water (10 mL) andEtOAc. The organic layer was washed with saturated brine solution, dried over anhydrous Na ₂ SO _4, filtered, and concentrated. The crude residue obtained was subjected to preparative HPLC purification to give compound 5 (5 mg) as pale white solid. </RTI><RTIID=0.0></RTI></RTI><RTIID=0.0></RTI> HPLC purity (XB0595TF.M): 91.67%. 1H-NMR (400 MHz, DMSO-d6): δ 8.32 (s, 2H), 7.95-7.96 (m, 1H), 7.24-7.25 (m, 1H), 6.93-6.98 (m, 1H), 6.85-6.89 (m, 1H), 6.73-6.74 (m, 2H), 4.25-4.30 (m, 2H), 4.09 (s, 2H), 3.22-3.27 (m, 1H), 3.02 (m, 1H), 2.87 (m , 5H), and 2.63 (m, 8H). Synthesis of compound 6 :

Step 1 : (R)-1-(2- Fluoro- 4-(2-( methylsulfinyl ) ethoxy ) phenyl ) piperazine (6) : to (R)-4-(2- Tributyl fluoro-4-(2-(methylsulfinyl)ethoxy)-phenyl)piperazine-1-carboxylate ( 4 , 0.13 g) in ice cold in dichloromethane (1 mL) 4M HCl (0.5 mL) in dioxane was added and the mixture was stirred at 0 ° C for 1 h. After completion (TLC), the reaction mixture was concentrated under reduced pressure at room temperature. The crude residue obtained was triturated with diethyl ether. This was then dissolved in methanol and passed through a Si-carbonate resin to give the free base 6 (0.094 g). </RTI><RTIID=0.0></RTI></RTI><RTIID=0.0>

Step 2 : (R)-5- Amino- 3-(2-(4-(2- fluoro- 4-(2-( methylsulfinyl ) ethoxy ) phenyl ) -piperazine- 1 - yl) ethyl) -8- (furan-2-yl) thiazolo [5,4-e] [1,2,4] triazolo [1,5-c] pyrimidin -2 (3H) - one ( Compound 6) : 2-(5-Amino-8-(furan-2-yl)-2-yloxythiazolo[5,4-e][1,2,4]triazolo[1 , 5-c] pyrimidine -3 (2H) - yl) ethyl methanesulfonate (7, 0.11 g, 0.303 mmol , 1 eq), (R) -1- (2- fluoro-4- (2 (A Isosulfonyl)-ethoxy)phenyl)piperazine ( 6 , 0.094 g, 0.33 mmol, 1.1 eq) and diisopropylethylamine (0.195 g, 1.514 mmol, 5 eq) in N,N- The mixture in dimethylformamide (2 mL) was stirred at 120 ° C for 16 h. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was diluted with water (10 mL) andEtOAc. The organic layer was washed with saturated brine solution, dried over anhydrous Na ₂ SO _4, filtered, and concentrated. The crude product obtained was purified by reverse phase preparative HPLC to give compound 6 (3 mg) as pale white solid. </RTI><RTIID=0.0></RTI></RTI><RTIID=0.0></RTI> HPLC purity (XB0595TF.M): 96.6%. 1H-NMR (400 MHz, DMSO-d6): δ 8.31 (brs, 2H), 7.95-7.95 (s, 1H), 7.24-7.25 (m, 1H), 7.00-6.88 (m, 1H), 6.85 (m , 1H), 6.71-6.74 (m, 2H), 4.25-4.31 (m, 2H), 4.08 (t, J = 6.00 Hz, 2H), 3.22-3.29 (m, 2H), 3.00-3.03 (m, 1H ), 2.86 (s, 4H), and 2.62-2.70 (m, 8H). Examples 7 , 8a and 8b : (R,S)-5- amino- 3-(2-(4-(2,4 -difluoro -5-(2-( methylsulfinyl )) ethoxy ) ) -Phenyl ) -piperazin- 1 -yl ) ethyl )-8-( furan -2- yl ) thiazolo [5,4-e][1,2,4] triazolo [1,5- c] -pyrimidine -2(3H) -one, (+)-5- amino- 3-(2-(4-(2,4 -difluoro -5-(2-( methylsulfinyl )) Ethoxy ) phenyl ) piperazin- 1 -yl ) ethyl )-8-( furan -2- yl ) thiazolo [5,4-e][1,2,4] triazolo [1,5 -c] pyrimidine -2(3H) -one and (-)-5- amino- 3-(2-(4-(2,4 -difluoro -5-(2-( methylsulfinyl )) Ethoxy ) phenyl ) piperazin- 1 -yl ) ethyl )-8-( furan -2- yl ) thiazolo [5,4-e][1,2,4] triazolo [1,5 -c] pyrimidine -2(3H) -one

Step 1 : Synthesis of tert-butyl 4-(2,4 -difluoro -5-(2-( methylthio ) ethoxy ) -phenyl ) piperazine- 1- carboxylate (2) : to 4- (2,4-Difluoro-5-hydroxyphenyl)piperazine-1-carboxylic acid tert-butyl ester ( 1 , 0.5 g, 1.591 mmol, 1 eq) and 1-chloro-2-methylhydrosulfanyl-B alkyl (0.264 g, 2.386 mmol, 1.5 eq) in N, N- dimethylformamide (5 mL) was added in the _{K 2 CO 3 (0.439 g,} 3.181 mmol, 2 eq) and the reaction mixture was 90 Heat at °C for 16 h. After completion of the reaction (TLC), the reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate. The organic layer was washed with saturated saline solution, dried over anhydrous Na ₂ SO _4, filtered and concentrated under reduced pressure. The crude material obtained by the Department column chromatography (50% EtOAc / hexanes as elution solution) to give the product as an off-white solid of (2, 0.5 g, 77% ). </RTI><RTIID=0.0></RTI></RTI><RTIID=0.0>

Step 2 : Synthesis of tert-butyl 4-(2,4 -difluoro -5-(2-( methylsulfinyl ) ethoxy ) phenyl ) -piperazine- 1- carboxylate (3, 4) : to tert-butyl 4-(2,4-difluoro-5-(2-(methylthio)ethoxy)phenyl)piperazine-1-carboxylate ( 2 , 0.5 g, 0.001 mmol, 1 Eq) Hydrogen peroxide (0.312 mL) was added dropwise to ice-cold solution in acetic acid (10 mL) and stirred at the same temperature for 2 h. After completion of the reaction (TLC), the reaction mixture was poured into 4N NaOH solution (20 mL) and extracted with ethyl acetate. The organic layer was washed with saturated saline solution, dried over anhydrous Na ₂ SO _4, filtered and concentrated under reduced pressure. The crude material was purified by EtOAc EtOAc (EtOAc:EtOAc </RTI><RTIID=0.0></RTI></RTI><RTIID=0.0> 1H-NMR (400 MHz, DMSO-d6): δ 7.24-7.32 (m, 1H), 6.89-6.94 (m, 1H), 4.39-4.45 (m, 2H), 3.47 (s, 4H), 3.05 (m , 2H), 2.94 (s, 4H), 2.64 (s, 3H), and 1.42 (s, 9H). The above racemic compound (0.38 g) was subjected to SFC (dissolving 0.38 g of sample in 5 mL of methanol, column-Lux A1 mobile phase: 70:30 (A:B), A = liquid CO ₂ , B = methanol, flow rate: 0.9 mL/min; wavelength: 220 nm) for palm separation to produce 150 mg peaks 1 ( 3 , [a] _D = +50.7°, c=1.1, MeOH), respectively, as an off-white solid. And 150 mg peak 2 ( 4 , [a] _D = -45.2 °, c = 1.1, MeOH).

Step 3 : Synthesis of (R,S)-1-(2,4 -difluoro -5-(2-( methylsulfinyl ) ethoxy ) phenyl ) piperazine (5RS) : to (R, S)-4-(2,4-difluoro-5-(2-(methylsulfinyl)ethoxy)phenyl)-piperazine-1-carboxylic acid tert-butyl ester (other than 3 and 4 ) </RTI></RTI></RTI><RTIID=0.0></RTI></RTI><RTIgt;</RTI><RTIgt;</RTI><RTIgt; After completion (TLC), the reaction mixture was concentrated under reduced pressure at room temperature. The residue obtained was triturated with diethyl ether to give a racemic product. This was then dissolved in methanol and passed through a Si-carbonate resin to give the free base 6 (0.09 g). </RTI><RTIID=0.0></RTI></RTI><RTIID=0.0>

For compound 7 , step 4 : Synthesis of (R,S)-5- amino- 3-(2-(4-(2,4 -difluoro -5-(2-( methylsulfinyl )) ethoxylate yl) - phenyl) - piperazin-1-yl) ethyl) -8- (furan-2-yl) thiazolo [5,4-e] [1,2,4] triazolo [1,5- -c] -pyrimidine -2(3H) -one: to 2-(5-amino-8-(furan-2-yl)-2-yloxythiazolo[5,4-e][1,2 , 4] Triazolo[1,5-c]pyrimidin-3(2H)-yl)ethylmethanesulfonate (6, 105 mg, 0.265 mmol, 1.0 eq) in DMF (2 mL) (R)-1-(2,4-difluoro-5-(2-(methylsulfinyl)ethoxy)phenyl)piperazine ( 5RS , 86.46 mg, 0.278 mmol) and DIPEA (170.85 mg) , 0.001 mmol, 5 eq). The reaction mass was degassed with nitrogen and heated to 120 °C for 16 h. The progress of the reaction was monitored by LCMS analysis. After completion, the reaction mixture was concentrated under reduced pressure. The crude product obtained was purified by EtOAc EtOAc (EtOAc) eluting It was further purified by preparative HPLC to give the title compound 7 (6 mg, purity 96%). </RTI><RTIID=0.0></RTI></RTI><RTIID=0.0></RTI> HPLC purity (XB0595TF.M): 96.68%. 1H-NMR (400 MHz, DMSO-d6): δ 8.31 (s, 1H), 7.50 (m, 1H), 7.27-6.97 (m, 3H), 6.83 (m, 1H), 6.73-6.74 (m, 1H) ), 4.36-4.45 (m, 2H), 4.08 (m, 2H), 3.25-3.38 (m, 2H), 3.00-3.06 (m, 2H), 2.94 (s, 3H), 2.63-2.71 (m, 2H) ), and 2.53-2.58 (m, 6H).

Step 3' : Synthesis of (+)- 1-(2,4 -difluoro -5-(2-( methylsulfinyl ) ethoxy ) phenyl ) piperazine: to (+)-4-( 2,4-Difluoro-5-(2-(methylsulfinyl)ethoxy)-phenyl)piperazine-1-carboxylic acid tert-butyl ester ( 4 , 500 mg, 1.23 mmol) in acetic acid SnCl ₄ (644 mg, 2.47 mmol) was added to the ice-cooled stirring solution in the ester (3 mL). The resulting mixture was stirred at RT for 2 h. The reaction mixture was concentrated under reduced pressure. The residue obtained was triturated with cold ethyl acetate (2 x 10 mL) to afford crude ( 580 mg) LCMS (M+H) 305.1. [a] _D = +24°, c=0.5, MeOH.

For compound 8a , step 4' : synthesis of (+)-5- amino- 3-(2-(4-(2,4 -difluoro -5-(2-( methylsulfinyl )) ethoxy ) ) -Phenyl ) -piperazin- 1 -yl ) ethyl )-8-( furan -2- yl ) thiazolo [5,4-e][1,2,4] triazolo [1,5- c] -pyrimidine -2(3H) -one is (+)-1-(2,4-difluoro-5-(2-(methylsulfinyl)) ethoxylate according to the same procedure as described for compound 7. The base)phenyl)piperazine was prepared starting. 1H-NMR (400 MHz, DMSO-d6): δ 8.31 (s, 1H), 7.50 (m, 1H), 7.27-6.97 (m, 3H), 6.83 (m, 1H), 6.73-6.74 (m, 1H) ), 4.36-4.45 (m, 2H), 4.08 (m, 2H), 3.25-3.38 (m, 2H), 3.00-3.06 (m, 2H), 2.94 (s, 3H), 2.63-2.71 (m, 2H) ), and 2.53-2.58 (m, 6H). [a] _D = +24°, c=0.1, AcOH. The absolute stereochemistry of the palm center is unknown.

For compound 8b , steps 3'' and 4'' : (-)-5- amino- 3-(2-(4-(2,4 -difluoro -5-(2-( methylsulfinyl)) ) ethoxy) phenyl) piperazin-1-yl) ethyl) -8- (furan-2-yl) thiazolo [5,4-e] [1,2,4] triazolo [1, 5-c] pyrimidine -2(3H) -one is based on the same procedure as described for compound 7 with (-)-4-(2,4-difluoro-5-(2-(methylsulfinyl)) Starting with oxy)phenyl)-piperazine-1-carboxylate ( 3 ), step 3'' to (-)-1-(2,4-difluoro-5-(2-(methyl) It is prepared by sulfonyl)ethoxy)phenyl)piperazine. LCMS (ESI pos. Ion) m / z: Calculated: 604.65; observed; 605.2 (M + 1); HPLC purity ^{(XB0595TF): 98.81%; 1} H NMR (400 MHz, DMSO-d6): δ 8.32 (brs , 1H), 7.96 (s, 1H), 7.22-7.28 (m, 2H), 6.74-6.85 (m, 2H), 6.73-6.74 (m, 1H), 4.36-4.45 (m, 2H), 4.09 (s , 2H), 3.28-3.30 (m, 1H), 3.23-3.26 (m, 1H), 3.00-3.06 (m, 4H), 2.71-2.94 (m, 3H), and 2.64 (s, 6H). [a] _D = -39°, c = 0.1, AcOH. The absolute stereochemistry of the palm center is unknown. Example 77 : 5- Amino- 3-(2-(4-(2,4 -difluoro -5-(2-( methylsulfonyl ) ethoxy ) phenyl ) piperazin- 1 -yl ) Ethyl )-8-( furan -2- yl ) thiazolo [5,4-e][1,2,4] triazolo [1,5-c] pyrimidin -2(3H) -one

Step 1 : Synthesis of tert-butyl 4-(2,4 -difluoro -5-(2-( methylsulfonyl ) ethoxy ) phenyl ) -piperazine- 1- carboxylate: in an open vial, 3-(2,4-Difluoro-5-(2-(methylthio)ethoxy)phenyl)-piperazine-1-carboxylic acid tert-butyl ester (20 g, 51.48 mmol, as in Example 7 Prepared according to step 1) and urea hydrogen peroxide (21.78 g, 231.68 mmol) heated to 90 °C. After 1 hour, the reaction mixture was allowed to reach room temperature. About 500 mL of ethyl acetate was added and stirred for 0.5 h, followed by filtration. Concentration of the filtrate gave the crude product. This was purified by column chromatography eluting with 50%EtOAcEtOAcEtOAcEtOAc LCMS (ESI positive ion) m/z: 421.

Step 2 : Synthesis of 1-(2,4 -difluoro -5-(2-( methylsulfonyl ) ethoxy ) phenyl ) piperazine hydrochloride (7) : to 4-(2,4- Dibutyl-5-(2-(methylsulfonyl)ethoxy)phenyl)piperazine-1-carboxylic acid tert-butyl ester (9 g, 21.40 mmol) in ice cold (50 mL) A solution of HCl in diethyl ether (50 mL) was added. After stirring at 0 ° C for 0.5 h, it was allowed to reach room temperature and stirred for 16 h. The reaction mixture was concentrated under reduced pressure at room temperature. The residue obtained was triturated with diethyl ether to give a pure product (10 g). LCMS (ESI positive ion) m/z: 321 (M+1).

Step 3 : To 1-(2,4-difluoro-5-(2-(methylsulfonyl)ethoxy)phenyl)piperazine hydrochloride (7 g, 22.13 mmol) in anhydrous dichloromethane A stirred suspension of the alkane (70 mL) was added triethylamine (6.259 g, 61.97 mmol) and freshly prepared 2-(5-amino-8-(furan-2-yl)-2-oxyloxythiazole. [5,4-e][1,2,4]Triazolo[1,5-c]pyrimidin-3(2H)-yl)-acetaldehyde (7 g, 22.13 mmol). After stirring at room temperature for 3 h, sodium triethoxysulfonate hydride (9.339 g, 44.26 mmol). The resulting mixture was stirred at room temperature for 24 h. After completion, the reaction mixture was diluted with dichloromethane. The separated organic layer was continuously washed with a saturated bicarbonate solution and a saturated brine solution. Subsequently dried over anhydrous Na ₂ SO _4, filtered and concentrated under reduced pressure. The crude material obtained was purified by column chromatography (230-400 EtOAc EtOAc EtOAc EtOAc LCMS (ESI positive ion) m/z: 621 (M+1). ¹ H-NMR (400 MHz, DMSO-d6): δ 8.31 (s, 2H), 7.95 (d, J = 0.92 Hz, 1H), 7.23-7.29 (m, 2H), 6.82 (t, J = 8.60 Hz , 1H), 6.73-6.74 (m, 1H), 4.40 (t, J = 5.64 Hz, 2H), 4.08 (t, J = 5.96 Hz, 2H), 3.62 (t, J = 5.44 Hz, 2H), 3.07 (s, 3H), 2.94 (s, 4H), 2.71 (t, J = 6.04 Hz, 2H), and 2.67-2.68 (m, 4H). Example 78 : 5- Amino- 3-(2-(4-(2- fluoro- 4-(2-( methylsulfonyl ) ethoxy ) phenyl ) piperazin- 1 -yl ) ethyl ) 8-(- furan -2- yl ) thiazolo [5,4-e][1,2,4] triazolo [1,5-c] pyrimidin -2(3H) -one

Step 1 : Synthesis of tert-butyl 4-(2- fluoro- 4 -hydroxyphenyl ) piperazine- 1- carboxylate (2) : 4-bromo-3-fluorophenol under nitrogen at 0 ° C (1, 10 g, 0.052 mol), a mixture of piperazine-1-carboxylic acid tert-butyl ester (11.70 g, 0.063 mol), DavePhos (0.515 g, 0.001 mol) and Pd ₂ (dba) ₃ (0.958 g, 0.001 mol) LHMDS (115 mL of a 1.0 M solution in THF, 0.115 mol). The reaction mixture was heated at 65 &lt;0&gt;C for 24 h and was monitored by TLC. The crude reaction mixture was washed with saturated NH ₄ Cl and extracted with ethyl acetate and (2 x 100 mL). The combined organic layers were concentrated with EtOAc EtOAcjjjjjjj </RTI><RTIID=0.0></RTI></RTI><RTIID=0.0></RTI>

Step 2 : Synthesis of tert- butyl 4-(2 - fluoro- 4-(2-( methylthio ) ethoxy ) phenyl ) piperazine- 1- carboxylate (3) : to 4-(2-fluoro -4-(2-(methylthio)ethoxy)phenyl)piperazine-1-carboxylic acid tert-butyl ester ( 2 , 0.3 g, 1.102 mmol) and 1-chloro-2-methylhydrosulfanyl Potassium carbonate (0.419 g, 3.027 mmol) was added to a mixture of EtOAc (EtOAc) (EtOAc) After completion of the reaction (TLC), the reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate. The combined organic layers were washed with a saturated saline solution, dried over anhydrous Na ₂ SO _4, filtered and concentrated under reduced pressure. The crude material obtained was purified by column chromatography eluting with EtOAc EtOAc EtOAc </RTI><RTIID=0.0></RTI></RTI><RTIgt; ¹ H-NMR (400 MHz, DMSO-d6): δ 7.02 (m, 1H), 6.85 (d, J = 2.80 Hz, 1H), 6.72 (d, J = 2.00 Hz, 1H), 4.09-4.12 (m , 2H), 3.45 (d, J = 4.40 Hz, 4H), 2.80-2.86 (m, 6H), 2.14 (s, 3H), and 1.42 (s, 9H).

Step 3 : Synthesis of tert- butyl 4-(2 - fluoro- 4-(2-( methylsulfonyl ) ethoxy ) phenyl ) -piperazine- 1- carboxylate (4) : to 4-[2 -Fluoro-4-(2-methylhydrothioethoxy)phenyl]piperazine-1-carboxylic acid tert-butyl ester ( 3 , 0.5 g, 0.001 mmol) in 1,4-dioxane (2 mL The solution in the solution was added with urea hydrogen peroxide (507.49 g, 0.005 mmol). The mixture was heated to 85 ° C for 16 h. After the reaction was completed, it was concentrated under reduced pressure. The residue was taken up in ethyl acetate and filtered. The filtrate was washed with water, dried over anhydrous Na ₂ SO ₄ dried, and concentrated under reduced pressure. The obtained crude product was subjected to column chromatography (solvent mixture of 1% methanol in DCM as a solvent) to give the product 4-(2-fluoro-4-(2-(methylsulfonyl) ethoxylate). Phenyl)piperazine-1-carboxylic acid tert-butyl ester (0.22 g, 40%). </RTI><RTIID=0.0></RTI><RTIID=0.0></RTI> 1H-NMR (400 MHz, DMSO-d6): δ 7.02 (brs, 1H), 6.65-6.72 (m, 2H), 4.41 (t, J = 5.60 Hz, 2H), 3.64 (s, 4H), 3.44 ( t, J = 5.20 Hz, 2H), 3.07 (s, 3H), 3.00 (s, 4H), and 1.50 (s, 9H).

Step 4 : Synthesis of 1-(2- fluoro- 4-(2-( methylsulfonyl ) ethoxy ) phenyl ) piperazine (5) : to 4-[2-fluoro-4-(2-methyl) Addition of diethyl sulfonyl ethoxy)phenyl]piperazine-1-carboxylic acid tert-butyl ester ( 4 , 0.22 g, 0.547 mmol) in dichloromethane (5 mL) 2M HCl was taken and the reaction mixture was stirred at 0 ° C for 1 h. After completion (TLC), the reaction mixture was concentrated under reduced pressure at room temperature. The residue obtained was triturated with diethyl ether to give a pure product. This was then dissolved in methanol and passed through a Si-carbonate resin to give the free base 6 (0.105 g of crude compound) which was used directly in the next step.

Step 5: Synthesis of 5-amino-3- (2- (4- (2-fluoro-4- (2- (meth sulfo acyl) ethoxy) phenyl) - piperazin-1-yl) acetate yl) -8- (furan-2-yl) thiazolo [5,4-e] [1,2,4] triazolo [1,5-c] pyrimidin -2 (3H) - one (compound 78) : to 1-[2-fluoro-4-(2-methylsulfinylethoxy)phenyl]piperazine ( 5 , 105 mg, 0.347 mmol) and 2-(5-amino-8-( Furan-2-yl)-2-yloxythiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethylmethane DIPEA (204 mg, 1.577 mmol) was added <RTI ID=0.0></RTI></RTI><RTIID=0.0></RTI></RTI><RTIgt; After completion of the reaction (TLC & LCMS), the reaction mixture was concentrated under reduced pressure. The crude product was purified by column chromatography using 5% methanol in DCM to afford product. This was further purified by RP preparative HPLC to give the title compound. </RTI><RTIID=0.0></RTI><RTIID=0.0></RTI> HPLC purity (PG_AM9010A3): 93.64%. 1H-NMR (400 MHz, DMSO-d6): δ 8.31 (brs, 2H), 7.95 (s, 1H), 7.24 (d, J = 3.20 Hz, 1H), 6.87-6.98 (m, 2H), 6.73- 6.74 (m, 2H), 4.29 (t, J = 5.60 Hz, 2H), 4.08 (t, J = 5.60 Hz, 2H), 3.58 (t, J = 5.60 Hz, 2H), 3.05 (s, 3H), 2.86 (s, 4H), and 2.68-2.72 (m, 6H). Example 80 : 5- Amino- 3-(2-(4-(2- fluoro- 4-(S -methylindenido ) phenyl ) piperazin- 1 -yl ) ethyl )-8-( Furan -2- yl ) thiazolo [5,4-e][1,2,4] triazolo [1,5-c] pyrimidin -2(3H) -one

Step 1 : Synthesis of 1,2 -difluoro- 4-( methylsulfinyl ) benzene (2) : to (3,4-difluorophenyl)(methyl)sulfane ( 1 , 3.0 g, 18.73 Methyl acetate (6.78 g, 39.33 mmol) was added in EtOAc (EtOAc)EtOAc. After completion of the reaction (TLC), the reaction mixture was diluted with ice cold water (30 mL) The organic layer was successively using aqueous sodium thiosulfate solution, 10% NaHCO _3, brine solution, dried over anhydrous Na ₂ SO _4, filtered and concentrated under reduced pressure. The crude product obtained by the Department column chromatography (50% EtOAc / hexanes as elution solution) to give the title product was an off-white solid of 2 (2.8 g, 85%) ; LCMS (ESI pos. Ion) m / z: Calculated: 176.18; observed; 177.1 (M+1); 1H-NMR (400 MHz, DMSO-d6): δ 7.83-7.79 (m, 1H), 7.73-7.66 (m, 1H), 7.60- 7.57 (m, 1H), 2.78 (s, 1H).

Step 2 : Synthesis of (3,4 -difluorophenyl )( imino )( methyl )-l6- thione (3) : to 1,2-difluoro-4-(methylsulfinyl) A solution of benzene ( 2 , 2.8 g, 15.89 mmol) in dichloromethane (60 mL) was added trifluoroacetamide (3.59 g, 31.79 mmol), magnesium oxide (2.54 g, 63.57 mmol) and the reaction mixture was (0.172 g, 0.429 mmol) using N ₂ flushed 2 min. Iodobenzene diacetate (10.23 g, 31.79 mmol) was added and the reaction mixture was stirred at RT for 16 h. After completion of the reaction (TLC), the reaction mixture was filtered through diatomaceous earth bed, concentrated and purified by preparative column chromatography to give an off-white solid of the title compound 3 (0.7 g, 23.0%) ; LCMS (ESI positive m/z: Calculated: 191.20; observed: 192.1 (M+1); 1H-NMR (400 MHz, DMSO-d6): δ 8.07-8.02 (m, 1H), 7.86-7.83 (m, 1H) ), 7.75-7.71 (m, 1H), 3.28 (s, 3H).

Step 3 : Synthesis of (3- fluoro- 4-( piperazin- 1 -yl ) phenyl )( imino )( methyl )-l6- thione (4) : to (3,4-difluorophenyl) Piperazine (0.32 g, 3.66 mmol) was added to a solution of (imino)(methyl)-l6-thione (0.7 g, 3.66 mmol) in N,N-dimethylformamide (10 mL) Potassium carbonate (1.51 g, 10.98 mmol) and the reaction mixture was heated at 100 ° C for 16 h. After completion of the reaction (TLC), the reaction mixture was diluted with water and the crude product was extracted with ethyl acetate, washed with brine, dried over Na ₂ SO _4, filtered and concentrated under reduced pressure. The crude material obtained was purified by preparative column chromatography to give the desired product 4 as an off white solid. </RTI><RTIID=0.0></RTI></RTI><RTIID=0.0></RTI>

Step 4 : Synthesis of 5- amino- 3-(2-(4-(2- fluoro- 4-(S -methylindenido ) phenyl ) piperazin- 1 -yl ) ethyl )-8- ( furan -2- yl ) thiazolo [5,4-e][1,2,4] triazolo [1,5-c] pyrimidin -2(3H) -one ( Compound 80) : (3- Fluoro-4-(piperazin-1-yl)phenyl)(imino)(methyl)-l6-thione (4, 0.14 g, 0.545 mmol), 2-(5-amino-8-( Furan-2-yl)-2-yloxythiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethylmethane A mixture of the sulfonate (0.18 g, 0.45 mmol) and DIPEA (0.176 g, 1.36 mmol) in N,N-dimethylformamide (2 mL) was stirred at 120 ° C for 16 h. After completion of the reaction (TLC), the reaction mixture was diluted with water and the crude product was extracted with ethyl acetate, washed with brine, dried over Na ₂ SO _4, filtered, concentrated and purified by preparative HPLC to afford an off-white solid of Title compound. </RTI><RTIID=0.0></RTI><RTIID=0.0></RTI> HPLC purity (XB_0595TF.M): 93.12%.; 1H-NMR (400 MHz, DMSO-d6): δ 8.31 (brs, 2H), 7.95 (s, 1H), 7.61-7.57 (m, 2H), 7.24 ( d , J = 4.8 Hz, 1H), 7.15 (t, J = 9.2Hz, 1H), 6.73-6.72 (m, 1H), 4.14 (s, 1H), 4.10 (t, J = 6.00 Hz, 2H), 3.08 (m, 4H), 3.03 (s, 3H), 2.73 (t, J = 6.00 Hz, 2H), 2.67-2.65 (m, 4H). Example 81 : 5-(4-(2-(5- Amino -8-( furan -2- yl )-2 - yloxythiazolo[5,4-e][1,2,4] triazole And [1,5-c] pyrimidin -3(2H) -yl ) ethyl ) piperazin- 1 -yl )-N-(2-( dimethylamino ) ethyl )-2,4 -difluoro Benzylamine

Step 1 : Synthesis of methyl 5- amino -2,4 -difluorobenzoate (2) : to 5-amino-2,4-difluoro-benzoic acid ( 1 , 0 g, 0.017 mol) in methanol ( Add sulfoxide (2.514 mL, 0.035 mol) to the ice-cold solution in 20.0 mL). The resulting mixture was heated at 80 ° C for 1 h. The progress of the reaction was monitored by TLC. The reaction mixture was concentrated under reduced pressure. DCM and water were added to the reaction mixture. The combined organic layers were dried with sodium sulfate and evaporated, evaporated]]]]]]] </RTI><RTIID=0.0></RTI><RTIID=0.0></RTI> 1H-NMR (400 MHz, CDCl3): δ 7.35-7.39 (m, 1H), 6.82-6.87 (m, 1H), and 3.92 (s, 3H).

Step 2 : Synthesis of methyl 2,4 -difluoro -5-( piperazin- 1 -yl ) benzoate (3) : 5-Amino-2,4-difluoro-benzoic acid methyl ester ( 2 , 3.0 g, 0.016 mol) and a mixture of 2-chloro-N-(2-chloroethyl)ethylamine hydrochloride (3.719 g, 0.021 mol) in diethylene glycol monomethyl ether (12 mL) heated to 170 ° C It lasted 2.5 hours. The progress of the reaction was monitored by TLC. Water was added to the reaction mixture and extracted with ethyl acetate. Discard the organic portion. The pH of the aqueous portion was then adjusted with sodium bicarbonate and extracted with ethyl acetate. The combined organic portions were dried with anhydrous sodium The crude product obtained was purified by column chromatography to give the product (1.5 g, 29.9%). </RTI><RTIID=0.0></RTI></RTI><RTIID=0.0></RTI>

Step 3 : Synthesis of tert-butyl 4-(2,4 -difluoro -5-( methoxycarbonyl ) phenyl ) piperazine- 1- carboxylate (4) : to 2,4-difluoro-5-peri Triethylamine (1.510 mL, 0.012 mol) and boc anhydride (1.278 mL, 0.006 mol) were added to an ice-cold solution of methyl iodide-1-yl-benzoate ( 3 , 1.0 g, 0.009 mol) in DCM (10 mL). . The resulting mixture was stirred at room temperature for 16 h. The progress of the reaction was monitored by TLC. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic portions were washed with EtOAc EtOAc (EtOAc m. </RTI><RTIID=0.0></RTI></RTI><RTIID=0.0></RTI>

Step 4 : Synthesis of 5-(4-( t-butoxycarbonyl ) piperazin- 1 -yl )-2,4 -difluorobenzoic acid (5) : to 4-(2,4-difluoro-5- a stirred solution of (methoxycarbonyl)phenyl)piperazine-1-carboxylic acid tert-butyl ester ( 4 , 1.0 g, 0.003 mol) in THF: water (20 mL, 3:1), 0.176 g, 0.004 mol) and the reaction mixture was stirred at RT for 16 h. The progress of the reaction was monitored by TLC. The reaction mixture was concentrated to remove THF. 1.5 N HCl was added to make the pH acidic. The solid formed was filtered to give 5-(4-(t-butoxycarbonyl)piperazin-1-yl)-2,4-difluorobenzoic acid (0.800 g, 97%). </RTI><RTIID=0.0></RTI></RTI><RTIID=0.0></RTI>

Step 5 : Synthesis of tert-butyl 4-(5-((2-( dimethylamino ) ethyl )) carbamoyl )-2,4 -difluorophenyl ) piperazine- 1- carboxylic acid (6) ): to a solution of 5- (4- (tert-butoxy-carbonyl) piperazin-1-yl) -2,4-difluorobenzoic acid (5, 0.200 g, 0.0005 mol ) was stirred in DCM's (10 mL) in The solution was continuously added with N1, N1-dimethylethane-1,2-diamine (0.062 g, 0.0007 mol), DIPEA (0.306 mL, 0.002 mol) and a T3P solution (0.438 mL, 0.001 mol). The resulting mixture was stirred at RT for 16 h. The progress of the reaction was monitored by TLC. Water was added to the reaction mixture and extracted with dichloromethane. The combined organic portions were dried with anhydrous sodium </RTI><RTIID=0.0></RTI></RTI><RTIID=0.0>

Step 6 : Synthesis of N-(2-( dimethylamino ) ethyl )-2,4 -difluoro -5-( piperazin- 1 -yl ) -benzamide (7) : to 4-( 3-((2-(Dimethylamino)ethyl)amine-carbazyl)-2,4-difluorophenyl)piperazine-1-carboxylic acid tert-butyl ester ( 6 , 0.200 g, 0.0004 mol) HCl (0.121 mL, 4 M solution) in diethyl ether solution was added to ice-cooled solution in DCM (10 mL). The resulting mixture was stirred at RT for 16 h. The progress of the reaction was monitored by TLC. The reaction mixture was concentrated under reduced pressure. The residue was neutralized with sodium bicarbonate and extracted with DCM. The organic portion was concentrated to give N-(2-(dimethylamino)-ethyl)-2,4-difluoro-5-(piperazin-1-yl)benzamide (0.130 g, 62.28%) ). </RTI><RTIID=0.0></RTI></RTI><RTIID=0.0>

Step 7 : Synthesis of 5-(4-(2-(5- amino -8-( furan -2- yl )-2 - yloxythiazolo[5,4-e][1,2,4] 3 Zoxa- [1,5-c] pyrimidin -3(2H) -yl ) ethyl ) piperazin- 1 -yl )-N-(2-( dimethylamino ) ethyl )-2,4- Difluorobenzamide ( Compound 81) : to 2-(5-Amino-8-(furan-2-yl)-2-yloxythiazolo[5,4-e][1,2,4 Triazolo[1,5-c]pyrimidin-3(2H)-yl)ethylmethanesulfonate ( 8 , 120 mg, 0.0003 mol) and N-[2-(dimethylamino)ethyl Add a DIPEA (0.129 mL, 0.0009 mol) to a stirred mixture of 2,4-difluoro-5-piperazin-1-yl-benzamide ( 7 , 113 mg, 0.00036 mol) in DMF (5 mL) . The resulting mixture was heated to 120 ° C for 16 h. After the reaction was completed, the reaction mixture was concentrated under reduced pressure. The crude residue obtained was purified by reverse phase preparative HPLC purification to give the product. </RTI><RTIID=0.0></RTI></RTI><RTIID=0.0></RTI> HPLC purity (XB_0595TF): 92.76%. 1H-NMR (400 MHz, DMSO-d6): δ 7.72 (s, 1H), 7.52-7.56 (m, 1H), 7.20 (s, 1H), 7.11-7.17 (m, 1H), 6.63 (t, J =2.00 Hz, 1H), 4.31 (brs, 2H), 3.91 (t, J = 7.84 Hz, 2H), 3.83 (m, 4H), 3.63 (t, J = 6.12 Hz, 3H), 2.85 (m, 5H ), and 2.56 (brs, 6H). Examples 83 and 84 : 5- amino- 3-(2-(4-(2-) fluoro -4-(((3R,4R)-4 -hydroxytetrahydrofuran- 3 -yl ) oxy ) phenyl ) piperazine -1 -yl ) ethyl )-8-( furan -2- yl ) thiazolo [5,4-e][1,2,4] triazolo [1,5-c] pyrimidine -2(3H) - one and 5-amino-3- (2- (4- (2-fluoro -4 - (((3S, 4S ) -4- hydroxy-tetrahydrofuran-3-yl) oxy) phenyl) piperazine -1 - yl) ethyl) -8- (furan-2-yl) thiazolo [5,4-e] [1,2,4] triazolo [1,5-c] pyrimidin -2 (3H) - one

Step 1: Synthesis of 4-amino-3-fluorophenol (2): Under a nitrogen atmosphere a solution of 3-fluoro-4-nitrophenol (1, 10 g, 0.064 mol ) in ethyl acetate (140 mL) in the Pd/C (4.0 g, 0.038 mol) was added to the stirred solution. The reaction mixture was stirred under a hydrogen balloon pressure for 16 h. The progress of the reaction was monitored by TLC. The reaction mixture was filtered through a pad of celite, and the filtrate was concentrated under reduced pressure to afford 4-amino-3-fluorophenol (6.9 g, 94%) as pale pale solid. </RTI><RTIID=0.0></RTI></RTI><RTIID=0.0>

Step 2 : Synthesis of 3- fluoro- 4-( piperazin- 1 -yl ) phenol hydrochloride (3) : to 4-amino-3-fluorophenol ( 2 , 6.9 g, 0.054 mol) in cyclobutane ( To the stirred solution in 15 mL) was added bis(2-chloroethyl)amine hydrochloride (13.56 g, 0.076 mol). The reaction mixture was heated at 150 ° C for 16 h. After the reaction was completed, the reaction mixture was cooled to RT. Approximately 30 mL of cold acetone was added and stirred at 0 °C for 0.5 h. The solid which formed was filtered and dried to give 3-fluoro-4-(piperazin-1-yl)phenol hydrochloride (10 g, 98%). </RTI><RTIID=0.0></RTI></RTI><RTIID=0.0>

Step 3 : Synthesis of tert-butyl 4-(2- fluoro- 4 -hydroxyphenyl ) piperazine- 1- carboxylate (4) : to 3-fluoro-4-(piperazin-1-yl)phenol hydrochloride ( 3 , 3.0 g, 0.015 mol) Triethylamine was added to the ice-cold stirred solution in DMF (30 mL) until it became basic. BOC anhydride (3.0 mL, 0.041 mol) was then added and the reaction was maintained at 0 °C for 0.5 h. After the reaction was completed, it was diluted with ethyl acetate and water. The organic layer was dried over anhydrous sodium The crude product obtained was purified by column chromatography to afford to afforded 4-(2-fluoro-4-hydroxyphenyl)piperazine-l-carboxylic acid tert-butyl ester (1.5 g, 86%). </RTI><RTIID=0.0></RTI><RTIID=0.0></RTI>

Step 4 : Synthesis of 4-(2- fluoro -4-((4- hydroxytetrahydrofuran- 3 -yl ) oxy ) -phenyl ) piperazine- 1- carboxylic acid tert- butyl ester (5) : to 4-(2) -3,6-dioxabicyclo[4,6-dioxabicyclo[4-fluorobutane] ( 3 , 1.5 g, 0.005 mol) in dioxane (25 mL) 3.1.0] Hexane (1.089 g, 0.013 mol) and cesium carbonate (2.47 g, 0.008 mol). The reaction mixture was heated at 100 ° C for 16 h. The progress of the reaction was monitored by TLC. The reaction mixture was then diluted with 10 mL of water and extracted with ethyl acetate (10 mL x 2). The combined organic layer was dried over anhydrous MgSO _4, concentrated under reduced pressure to give a brown solid 4- (2-fluoro-4 - ((4-hydroxy-tetrahydrofuran-3-yl) oxy) phenyl) piperazin-1 T-butyl formate (0.800 g, 98%). </RTI><RTIID=0.0></RTI><RTIID=0.0></RTI>

Step 5 : Synthesis of 4-(3- fluoro- 4-( piperazin- 1 -yl ) phenoxy ) tetrahydrofuran- 3- ol (6) : to 4-(2-fluoro-4-((4-hydroxytetrahydrofuran) -3-yl)oxy)-phenyl)piperazine-1-carboxylic acid tert-butyl ester ( 5 , 0.500 g, 0.001 mol) in dioxane (10 mL) in ice-cold solution added to dioxane solution HCl (4M solution, 1 mL). After stirring at room temperature for 16 h, the reaction mixture was evaporated. The residue was neutralized with a 10% aqueous sodium bicarbonate solution and extracted with DCM. Concentration of the organic portion gave 4-(3-fluoro-4-(piperazin-1-yl)phenoxy)tetrahydrofuran-3-ol (0.250 g, 88%). </RTI><RTIID=0.0></RTI></RTI><RTIID=0.0>

Step 6: Synthesis of 5-amino-3- (2- (4- (2-fluoro -4 - (((3R, 4R ) -4- hydroxy-tetrahydrofuran-3-yl) oxy) phenyl) piperazine - 1- yl ) ethyl )-8-( furan -2- yl ) thiazolo [5,4-e][1,2,4] triazolo [1,5-c] -pyrimidine -2(3H) - one (compound 83) and 5-amino-3- (2- (4- (2-fluoro -4 - (((3S, 4S ) -4- hydroxy - tetrahydrofuran-3-yl) oxy) phenyl ) piperazin-1-yl) ethyl) -8- (furan-2-yl) thiazolo [5,4-e] - [1,2,4 ] triazolo [1,5-c] pyrimidine - 2(3H) -one ( Compound 84) : to 2-(5-Amino-8-(furan-2-yl)-2-yloxythiazolo[5,4-e][1,2,4 Add a 4-(3-(5-c)pyrimidin-3(2H)-yl)-ethylmethanesulfonate ( 7 , 0.320 g, 0.00080 mol) in a stirred solution of DMF (8 mL) 3-fluoro-4-(piperazin-1-yl)phenoxy)tetrahydrofuran-3-ol (6, 0.273 g, 0.0009 mol) and N-ethyl-N-isopropylpropan-2-amine (0.218) mL, 0.002 mol). The reaction mixture was heated at 120 ° C for 16 h. After the reaction was completed, the reaction mixture was concentrated and the residue was purified by preparative HPLC. The pure product was subsequently purified by purifying the palm of the SFC to give the two isomers 5-amino-3-(2-(4-(2-fluoro-4-((3R,4R))) Hydroxytetrahydrofuran-3-yl)oxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4] Zoxao[1,5-c]pyrimidine-2(3H)-one (5.29 mg) and 5-amino-3-(2-(4-(2-)-fluoro-4-((3S,4S)-) 4-hydroxytetrahydrofuran-3-yl)oxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4 Triazolo[1,5-c]pyrimidine-2(3H)-one.

The first crystallization of the isomers: LCMS (ESI ESI); m/z: calc.: 582.21. HPLC purity (XB_0595TF): 96.23%. 1H-NMR (400 MHz, DMSO-d6): δ 8.30 (brs, 2H), 7.95 (s, 1H), 7.23 (d, J = 3.20 Hz, 1H), 6.92- 6.96 (m, 1H), 6.83-6.87 (m, 1H), 6.70-6.74 (m, 2H), 5.48 (brs, 1H), 4.58 (d, J = 4.00 Hz, 1H), 4.58 (d, J = 4.00 Hz, 1H), 4.07 (t, J= 6.40 Hz, 2H), 3.99-4.03 (m, 1H), 3.85-3.89 (m, 1H), 3.71-3.74 (m, 1H), 3.55-3.58 (m , 1H), 2.61 (s, 4H), 2.708 (m, 2H), and 2.67 (m, 4H).

The second analyzed image isomer: LCMS (ESI ESI); m/z: calc.: 58.21. HPLC purity (XB_0595TF): 93.44%. 1H-NMR (400 MHz, DMSO-d6): δ 8.31 (brs, 2H), 7.96 (s, 1H), 7.24 (d, J = 3.32 Hz, 1H), 6.94 ( t, J = 9.36 Hz, 1H), 6.83-6.87 (m, 1H), 6.70-6.74 (m, 2H), 5.46 (d, J = 3.84 Hz, 1H), 4.58 (d, J = 3.40 Hz, 1H ), 4.16 (s, 1H), 4.08 (t, J = 6.24 Hz, 2H), 4.02-4.03 (m, 1H), 3.86-3.89 (m, 1H), 3.72 (d, J = 9.96 Hz, 1H) , 3.57 (d, J = 9.60 Hz, 1H), 2.9277 (m, 4H), 2.9363 (m, 2H), and 2.7029 (s, 4H). Example 88: 5-amino-3- (2- (4- (2-fluoro-5- (2-hydroxyethoxy) phenyl) piperazin-1-yl) ethyl) -8- (furan - 2- yl) thiazolo [5,4-e] [1,2,4] triazolo [1,5-c] pyrimidin -2 (3H) - one

Step 1 : Synthesis of (2-(3- bromo- 4- fluorophenoxy ) ethoxy )( t-butyl ) dimethyloxane (2) : 3-bromo-4-fluorophenol (1, 2.3 g, 0.012 mol), (2-bromoethoxy)(t-butyl)dimethyl decane (3.74 g, 0.016 mol) in DMF (30 mL), K ₂ CO ₃ (2.49 g, 0.018 mol) The mixture was heated to 70 ° C for 16 h. The progress of the reaction was monitored by TLC. After the reaction was completed, water (20 mL) was added and the mixture was extracted with dichloromethane (30 mL x 2). The combined organic portions were washed with EtOAc EtOAc m.

Step 2 : Synthesis of 1-(5-(2-(( t-butyldimethyl)methyl ) oxy ) ethoxy )-2- fluorophenyl ) -piperazine (3) : 2-(3) -Bromo-4-fluoro-phenoxy)ethoxy-tert-butyl-dimethyl-decane ( 2 , 1.0 g, 0.003 mol) and piperazine (499 mg, 0.006 mol) in toluene (15 mL) NaOBu-t (412 mg) was added to the stirred solution. The resulting mixture was degassed with nitrogen. BINAP (107 mg, 0.00017 mol) and palladium acetate (262 mg, 0.0003 mol) were then added and the mixture was heated to 110 ° C for 16 h. After completion, the reaction mixture was filtered, and the filtrate was concentrated. The crude residue obtained was purified by column chromatography to afford the title compound (0.3 g, 29.5%). </RTI><RTIID=0.0></RTI></RTI><RTIID=0.0></RTI>

Step 3 : Synthesis of 2-(4- fluoro- 3-( piperazin- 1 -yl ) phenoxy ) ethan- 1- ol (4) : to 1-(5-(2-((t-butyl) TBAF (0.499 mL) was slowly added to an ice-cold solution of methylmercapto)oxy)ethoxy)-2-fluorophenyl)-piperazine ( 3 , 0.354 g, 0.0009 mol) in THF (10 mL) 4 M in THF. The resulting mixture was brought to RT and stirred for 16 h. After the reaction was completed, the reaction mixture was diluted with water and ethyl acetate. The separated organic layer was dried over anhydrous sodium The crude product was purified by column chromatography toiel </RTI><RTIID=0.0></RTI></RTI><RTIID=0.0>

Step 4 : Synthesis of 5- amino- 3-(2-(4-(2- fluoro -5-(2- hydroxyethoxy ) phenyl ) piperazin- 1 -yl ) ethyl )-8-( furan) -2- yl ) thiazolo [5,4-e][1,2,4] triazolo [1,5-c] pyrimidin -2(3H) -one ( Compound 88) : to 2-(5- Amino-8-(furan-2-yl)-2-yloxythiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidine-3(2H) 2-(4-Fluoro-3-(piperazin-1-yl)phenoxy)B---A solution of ethylmethanesulfonate (0.300 g, 0.0007 mol) in DMF (8 mL) 1-Alcohol ( 4 , 0.218 g, 0.0009 mol) and DIPEA (0.397 mL, 0.002 mol). The reaction mixture was heated to 120 °C for 16 h. After completion, the reaction mixture was concentrated and purified to purified crystall HPLC purity (XB_0595TF): 98.29%; LCMS (ESI ESI) m/z: Calculated: 540. 1H-NMR (400 MHz, DMSO-d6): δ 9.19 (s, 1H), 8.39-8.45 (brs, 2H), 7.97 (s, 1H), 7.11 (m, 1H), 6.75 (s, 1H), 6.59 (m, 2H), 4.86 (m, 1H), 4.32 (m, 2H), 3.95-3.98 (m, 4H), 3.68-3.70 (m, 2H), 3.63 (m, 3H), 2.94-3.00 ( m, 2H), and 3.69 (s, 2H). Example 90 : 5- Amino- 3-(2-(4-(2,4 -difluoro -5-( morpholin- 3 -ylmethoxy ) phenyl ) piperazin- 1 -yl ) ethyl ) 8-(- furan -2- yl ) thiazolo [5,4-e][1,2,4] triazolo [1,5-c] pyrimidin -2(3H) -one

Step 1 : Synthesis of 3-((5-(4-(( benzyloxy )) carbonyl ) piperazin- 1 -yl )-2,4 -difluorophenoxy ) methyl ) morpholine- 4- carboxylic acid Butyl ester (2) : Benzyl 4-(2,4-difluoro-5-hydroxyphenyl)piperazine-1-carboxylate ( 1 , 1.2 g, 2.9 mmol) and 3-(hydroxyl ) at 0 °C Add a triphenylphosphine (1.8 g, 6.9 mol) to a stirred solution of morpholine-4-carboxylic acid tert-butyl ester (1.1 g, 4.3 mmol) in toluene (10 mL) followed by dropwise addition of DIAD (1.39) g, 6.9 mmol). The reaction mixture was stirred at 110 ° C for 16 h. After completion of the reaction (TLC), the reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate. The organic layer was washed with saturated saline solution, dried over anhydrous Na ₂ SO _4, filtered and concentrated under reduced pressure. The crude material was purified by EtOAc EtOAc EtOAc (EtOAc) 547.25; observed: 548.1 (M+1).

Step 2 : Synthesis of 3-((2,4 -difluoro -5-( piperazin- 1 -yl ) phenoxy ) methyl ) morpholine- 4- carboxylic acid tert- butyl ester (3) : under nitrogen atmosphere To 3-((5-(4-((benzyloxy)carbonyl)piperazin-1-yl)-2,4-difluorophenoxy)methyl)morpholine-4-carboxylic acid tert-butyl ester ( Add 0.5% Pd/C (0.2 g) to a stirred solution of EtOAc (20 mL). The reaction mixture was stirred at room temperature under a hydrogenation atmosphere for 16 h. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was filtered using diatomaceous earth to remove Pd/C. The combined organic layer was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to afford the title compound solids sticky brown gum (280 mg, 73.5%); LCMS (ESI pos. Ion) m / z: Calculated: 413.21; observed :414.3 (M+1).

Step 3 : Synthesis of 3-((5-(4-(2-(5- amino -8-( furan -2- yl )-2 - yloxythiazolo[5,4-e][1,2 , 4] triazolo [1,5-c] pyrimidine -3 (2H) - yl) ethyl) piperazin-1-yl) -2,4-difluorophenoxy) - methyl) morpholine - 4- butylic acid tert- butyl ester (4) : 3-((2,4-difluoro-5-(piperazin-1-yl)phenoxy)methyl)-morpholine in a 50 mL sealed tube 4-butylic acid tert-butyl ester (3, 100 mg, 0.242 mmol) and 2-(5-amino-8-(furan-2-yl)-2-yloxythiazolo[5,4-e][ 1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethylmethanesulfonate (86 mg, 0.218 mmol) in N,N-dimethylformamide DIPEA (94 mg, 0.726 mmol) was added to a stirred solution of 10 mL) and the mixture was stirred at 120 ° C for 16 h. After the reaction was completed (TLC & LCMS), the solvent was removed under reduced pressure. The reaction mass was treated with water and extracted with ethyl acetate. The organic layer was washed with saturated saline solution, dried over anhydrous Na ₂ SO _4, filtered and concentrated under reduced pressure. The crude product was purified by EtOAc EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj

Step 4: Synthesis of 5-amino-3- (2- (4- (2,4-difluoro-5- (morpholin-3-ylmethoxy) - phenyl) piperazin-1-yl) acetate yl) -8- (furan-2-yl) thiazolo [5,4-e] [1,2,4] triazolo [1,5-c] pyrimidin -2 (3H) - one (compound 90) : 3-((3-(4-(2-(5-Amino-8-(furan-2-yl)-2-yloxythiazolo[5,4-e][1] at 0 °C , 2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-4,5-difluorophenoxy)-methyl)- To a stirred solution of morpholine-4-carboxylic acid tert-butyl ester ( 4 , 25 mg, 0.035 mmol) in DCM (5 mL) was added 4 N HCl (1.5 mL) in dioxane and the mixture was stirred at RT. 5 h. After the completion of the reaction (TLC), EtOAc (EtOAc): EtOAc (EtOAc) (ESI cation) m/z: calcd.: 613.20; observed: 614.1 (M+1); ¹ H-NMR (400 MHz, DMSO-d6): δ 10.33 (brs, 1H), 9.53 (brs, 2H) ), 8.41 (brs, 2H), 7.97 (s, 1H), 7.40 (t, J = 11.20 Hz, 1H), 7.26 (d, J = 3.20 Hz, 1H), 7.01 (t, J = 7.60 Hz, 1H ), 6.75-6.74 (m, 1H), 4.33-4.23 (m, 4H), 4.02-3.93 (m, 4H), 3.69-3.62 (m, 6H), 3.27 (m, 3H), 2.98 (m, 4H) ). Example 91 : 5- Amino- 3-(2-(4-(2,4 -difluoro- 5-((3S,4S)-4- fluoropyrrolidin- 3 -yl ) oxy ) phenyl ) Piperazin- 1 -yl ) ethyl )-8-( furan -2- yl ) thiazolo [5,4-e][1,2,4] triazolo [1,5-c] pyrimidine -2 ( 3H) -ketone

Step 1: Synthesis of 4- (5 - ((l- (tert-butoxy carbonyl) -4-hydroxy-pyrrolidin-3-yl) oxy) -2,4-difluorophenyl) piperazin-1 Benzyl formate (2) : Benzyl 4-(2,4-difluoro-5-hydroxyphenyl)piperazine-1-carboxylate (6.0 g, 17.22 mmol) and 6-oxa-3-azabicyclo [3.1.0] A suspension of hexane-3-carboxylic acid tert-butyl ester (3.82 g, 20.67 mmol) in anhydrous DMF (30 mL) was added K ₂ CO ₃ (7.13 g, 51.67 mmol) and the reaction mixture was Heat at 100 ° C for 16 h. After the completion of the reaction (TLC), the reaction mixture was concentrated under reduced pressure and the crude material was purified by column chromatography to afford the title compound 2 (3.5 g, 36%) m/z: calculated: 533.57; observed: 534.1 (M+1); 1H-NMR (400 MHz, DMSO-d6): δ 7.38-7.28 (m, 6H), 6.89-6.88 (m, 1H) ), 5.49-5.48 (m, 1H), 5.10-4.65 (m, 2H), 4.15 (m, 1H), 4.05-4.03 (m, 1H), 3.59-3.49 (m, 6H), 2.96-2.88 (m , 4H), 1.40 (s, 9H).

Step 2 : Synthesis of 4-(5-(((3S,4S)-1-( t-butoxycarbonyl )-4- fluoropyrrolidin- 3 -yl ) oxy )-2,4 -difluorophenyl ) piperazine-1-carboxylic acid benzyl ester (3): 4- (5 - ((l- (tert-butoxy carbonyl) -4-hydroxypyrrolidine-3-yl) oxy) -2,4- A solution of benzyl difluorophenyl)piperazine-1-carboxylate (3.5 g, 6.56 mmol) in dichloromethane (60 mL) was cooled to -70 ° C and DAST (2.11 g, 0.013 mmol) was slowly added and The reaction mixture was stirred at RT for 16 h. After completion of the reaction (TLC), the reaction mixture was diluted with water and the crude product was extracted with dichloromethane. The organic layer was successively using 10% NaHCO3, washed with water, brine, dried over Na ₂ SO _4, filtered and concentrated to give a crude product. The non-image isomers formed are separated into peak 1 and peak 2 by normal vermiculite column chromatography. The mirror image isomer present in peak 1 was separated from the palm column by SFC; Method: YMC cellulose SC_IPA; 70:30 (A:B), A = liquid CO ₂ , B = IPA, flow rate: 0.9 mL /min; Wavelength: 220 nm. The first peak was eluted to give the title compound ( 3 g) (yield: ESI): m. (M+1); 1H-NMR (400 MHz, DMSO-d6): δ 7.38-7.29 (m, 6H), 6.97-6.95 (m, 1H), 5.38-5.25 (m, 1H), 5.11-5.04 ( m, 2H), 3.84-3.79 (m, 7H), 3.22-3.16 (m, 4H), 1.42 (s, 9H).

Step 3 : Synthesis of (3S, 4S)-3-(2,4 -difluoro -5-( piperazin- 1 -yl ) phenoxy )-4- fluoropyrrolidine- 1- carboxylic acid tert - butyl ester (4 ): the 4- (5 - (((3S , 4S) -1- ( tert-butoxy carbonyl) -4-fluoro-pyrrolidin-3-yl) oxy) -2,4-difluorophenyl) The suspension of benzyl piperazine-1-carboxylate (0.23 g, 0.429 mmol) in ethyl acetate (10 mL) was loaded with 10% palladium on carbon (0.049 g) and stirred at room temperature under hydrogen balloon pressure for 5 h. . After completion of the reaction (TLC), the reaction mass was filtered through diatomaceous earth pad and concentrated to give a light brown solid of the title compound 4 (0.16 g, 92.8%) ; LCMS (ESI positive ion); m / z: Calculation Value: 401.43; observed; 402.2 (M+1); ¹ H-NMR (400 MHz, CD ₃ OD): δ 6.92 (t, J = 8.8 Hz, 1H), 6.56-6.51 (m, 2H), 3.57 (m, 4H), 2.91 (t, J = 4.80 Hz, 4H), 1.49 (s, 9H).

Step 4 : Synthesis of (3R,4R)-3-(5-(4-(2-(5- amino -8-( furan -2- yl )-2 - yloxythiazolo[5,4-e] ][1,2,4] triazolo [1,5-c] pyrimidin -3(2H) -yl ) ethyl ) piperazin- 1 -yl )-2,4 -difluorophenoxy )-4 - Fluoropyrrolidine- 1- carboxylic acid tert- butyl ester (5) : to (3S, 4S)-3-(2,4-difluoro-5-(piperazin-1-yl)phenoxy)-4- Fluoropyrrolidine-1-carboxylic acid tert-butyl ester (0.16 g, 0.399 mmol) and 2-(5-amino-8-(furan-2-yl)-2-yloxythiazolo[5,4-e a solution of [1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethylmethanesulfonate (0.15 g, 0.39 mmol) in anhydrous DMF (3 mL) N,N-Diisopropylethylamine (0.13 g, 0.83 mmol) was added and the reaction mixture was heated at 120 ° C for 16 h. After completion of the reaction (LCMS), the reaction mixture was concentrated by preparative HPLC purification to afford an off-white solid of the title compound 5 (0.06 g, 21.4%) and reduced pressure. LCMS (ESI </ RTI></RTI></RTI></RTI></RTI></RTI></RTI></RTI><RTIgt; J = 0.80 Hz, 1H), 7.30-7.23 (m, 2H), 6.88 (t, J = 8 Hz, 1H), 6.73-6.72 (m, 1H), 5.32 (s, 1H), 5.06-5.04 (m , 1H), 4.06 (t, J = 12 Hz, 2H), 3.60-3.49 (m, 4H), 2.92 (s, 4H), 2.73-2.68 (m, 2H), 2.67-2.51 (m, 4H), 1.41 (s, 9H).

Step 5 : Synthesis of 5- amino- 3-(2-(4-(2,4 -difluoro- 5-((3R,4R)-4- fluoropyrrolidin- 3 -yl ) oxy ) phenyl ) ) piperazin-1-yl) ethyl) -8- (furan-2-yl) thiazolo [5,4-e] [1,2,4] triazolo [1,5-c] pyrimidine-2 (3H) -ketone ( Compound 91) : (3R,4R)-3-(5-(4-(2-(5-Amino-8-(furan-2-yl))-2-) Sideoxythiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-2 2,4-difluorophenoxy)-4-fluoropyrrolidine-1-carboxylic acid tert-butyl ester (0.06 g, 0.086 mmol) in dichloromethane (3 mL) 3 mL). The reaction mixture was stirred at RT for 3 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, developed with diethyl ether and dried to give an off-white solid of the title compound 91 (0.02 g, 38.9%) . <RTI ID=0.0></RTI></RTI><RTIID=0.0></RTI></RTI><RTIID=0.0></RTI></RTI> , 1H), 9.83 (brs, 2H), 8.41 (brs, 2H), 7.96 (d, J = 0.30 Hz, 1H), 7.46-7.43 (m, 1H), 7.40-7.26 (m, 1H), 7.25- 7.08 (m, 1H), 6.75-6.74 (m, 1H), 5.42 (s, 1H), 5.26-5.24 (m, 1H), 4.33 (m, 2H), 3.94-3.91 (m, 2H), 3.64- 3.55 (m, 10H), 3.39-3.27 (m, 2H), 3.17-3.05 (m, 2H). Example 95 : (S)-5- Amino- 3-(2-(4-(2,4 -difluoro- 5-((2-)- oxypyrrolidin- 3 -yl ) oxy ) phenyl ) Piperazin- 1 -yl ) ethyl )-8-( furan -2- yl ) thiazolo [5,4-e][1,2,4] triazolo [1,5-c] pyrimidine -2 ( 3H) -ketone

Step 1 : Synthesis of (R)-2 -Sideoxypyrrolidin- 3 -ylmethanesulfonate (6) : (3R)-3-hydroxypyrrolidin-2-one at 5 ° C (5, 1.0 g TEA (2.0 g, 19.8 mmol) and methanesulfonium chloride (1.36 g, 11.9 mmol) were added to a stirred solution of EtOAc. The resulting reaction mixture was stirred at RT for 2 h. After the reaction was completed, the reaction mixture was quenched with NH ₄ Cl solution and extracted with DCM. The organic layer was washed with saturated saline solution, dried over anhydrous Na ₂ SO _4, filtered and concentrated under reduced pressure. The crude material was purified by column chromatography to give purified product (1,2 g, 67.0%); ¹ H-NMR (400 MHz, CDCl ₃ ): δ 5.17 (t, J = 7.96 Hz, 1H), 3.53- 3.50 (m, 1H), 3.43-3.38 (m, 1H), 3.27 (s, 3H), 2.69-2.64 (m, 1H), 2.43-2.36 (m, 1H).

Step 2 : Synthesis of (S)-4-(2,4 -difluoro- 5-((2 -oxopyrrolidin- 3 -yl ) oxy ) phenyl ) piperazine- 1- carboxylic acid tert - butyl ester (2) : a stirred solution of tert-butyl 4-(2,4-difluoro-5-hydroxyphenyl)piperazine-1-carboxylate ( 1 , 900 mg, 2.86 mmol) in DMF (20 mL) K ₂ CO ₃ (791 mg, 5.73 mmol) and (R)-2-oxoxypyrrolidin-3-ylmethanesulfonate (6, 769 mg, 4.3 mmol) were added and heated at 80 ° C for 16 h. After completion of the reaction, the reaction mixture was washed with saturated NH ₄ Cl solution and extracted with ethyl acetate treatment. The organic layer was washed with saturated saline solution, dried over anhydrous Na ₂ SO _4, filtered and concentrated under reduced pressure. The crude reaction mixture was purified by EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj

Step 3 : Synthesis of (S)-3-(2,4 -difluoro -5-( piperazin- 1 -yl ) phenoxy ) pyrrolidin -2- one (3) : at 0 ° C to (S) 4-(2,4-difluoro-5-((2-oxopyryrrolidin-3-yl)oxy)phenyl)piperazine-1-carboxylic acid tert-butyl ester (2, 900 mg, 2.26 To a stirred solution of dichloromethane (20 mL), EtOAc (EtOAc) After completion of the reaction (TLC), the reaction mixture was concentrated under reduced pressure. The salt was dissolved in methanol and neutralized with a tosic acid-resolvent resin to give a free base (400, 58.2%) as an off-white gel; LCMS (ESI ESI) m/z: Calculated: 297.13; 298.1 (M+1).

Step 4 : Synthesis of (S)-5- amino- 3-(2-(4-(2,4 -difluoro- 5-((2 -)- oxypyrrolidin- 3 -yl ) oxy ) -benzene yl) piperazin-1-yl) ethyl) -8- (furan-2-yl) thiazolo [5,4-e] [1,2,4] triazolo [1,5-c] pyrimidine - 2(3H) -one ( Compound 95) : to (S)-3-(2,4-difluoro-5-(piperazin-1-yl)phenoxy)pyrrolidin-2-one (3, 350 Methyl, 1.18 mmol) DMFEA (608 mg, 4.71 mmol) and 2-(5-amino-8-(furan-2-yl)-2-oxyloxythiazole were added to a stirred solution of DMF (10 mL) [5,4-e][1,2,4]Triazolo[1,5-c]pyrimidin-3(2H)-yl)ethylmethanesulfonate (420 mg, 1.06 mmol). The reaction mixture was stirred at 120 ° C for 16 h. After completion of the reaction (TLC & LCMS), the solvent was removed under reduced pressure and the mixture was partitioned between water and ethyl acetate. The separated organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ and filtered. The filtrate was concentrated under reduced pressure and purified by flash chromatography eluting elut elut elut elut elut elut elut elut elut m/z: Calculated: 597.17; observed: 598.0 (M+1); ¹ H-NMR (400 MHz, DMSO-d6): δ 8.31 (brs, 2H), 8.08 (s, 1H), 7.95 (s, 1H), 7.24-7.18 (m, 2H), 6.97 (t, J = 8.80 Hz, 1H), 6.74-6.73 (m, 1H), 4.92 (t, J = 7.60 Hz, 1H), 4.08 ( t, J = 6.00 Hz, 2H), 3.27-3.18 (m, 2H), 2.91 (m, 4H), 2.73-2.64 (m, 6H), 2.03-1.98 (m, 1H). Example 96 : (R)-5- Amino- 3-(2-(4-(2,4 -difluoro- 5-((2-)- oxypyrrolidin- 3 -yl ) oxy ) phenyl ) Piperazin- 1 -yl ) ethyl )-8-( furan -2- yl ) thiazolo [5,4-e][1,2,4] triazolo [1,5-c] pyrimidine -2 ( 3H) -ketone

Step 1 : Synthesis of (S)-2 -oxooxypyrrolidin- 3 -ylmethanesulfonate (6) : (S)-3-hydroxypyrrolidin-2-one at 5 ° C ( 5 , 2.0 g , 0.02 mol) of a solution in DCM (10 mL) was added triethylamine (4.0 g, 0.04 mol) and methanesulfonium chloride (2.49 g, 0.022 mol). The resulting reaction mixture was stirred at RT for 2 h. After the reaction was completed, the reaction mixture was quenched with NH ₄ Cl solution and extracted with DCM. The organic layer was washed with saturated brine solution, dried over anhydrous Na ₂ SO _4, filtered and concentrated under reduced pressure to give 2-oxo-pyrrolidin-3-yl methanesulfonate as a pale yellow liquid of (S) (1.4 g, 39.5%); LCMS (ESI ESI) m/z: Calculated: 179.

Step 2 : Synthesis of (R)-4-(2,4 -difluoro- 5-((2 -oxopyrrolidin- 3 -yl ) oxy ) phenyl ) piperazine- 1- carboxylic acid tert - butyl ester (2) : Addition of a solution of tert-butyl 4-(2,4-difluoro-5-hydroxyphenyl)piperazine-1-carboxylate ( 1 , 1.5 g, 4.8 mmol) in DMF (20 mL) (S)-2-Sideoxypyrrolidin-3-ylmethanesulfonate ( 6 , 1.3 g, 7.2 mmol) and K ₂ CO ₃ (1.32 g, 9.6 mmol) and heated to 90 ° C for 16 h. After completion of the reaction, the reaction mixture was washed with saturated NH ₄ Cl solution and extracted with ethyl acetate treatment. The organic layer was washed with saturated saline solution, dried over anhydrous Na ₂ SO _4, filtered and concentrated under reduced pressure. The crude reaction mixture was purified by EtOAcqqqqqqqqqqqqqqqqQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQ 1).

Step 3: Synthesis of (R) -3- (2,4- difluoro-5- (piperazin-1-yl) phenoxy) pyrrolidin-2-one (3): at 0 ℃ 4- [ 2,4-difluoro-5-[(3R)-2-oxooxypyrrolidin-3-yl]oxy)phenyl]piperazine-1-carboxylic acid tert-butyl ester ( 2 , 1.0 g, 2.5 mmol 4N HCl (10 mL) in dioxane was added dropwise to a stirred solution of dichloromethane (15 mL) and stirred at RT for 2 h. After completion of the reaction (TLC), the reaction mixture was concentrated under reduced pressure. The salt was dissolved in methanol and neutralized with a Tosic acid-resolvent resin to give a free base (600 mg, 72.9%) as an off-white gel; LCMS (ESI ESI) m/z: Calculated: 297.13; 298.2 (M+1).

Step 4 : Synthesis of (R)-5- amino- 3-(2-(4-(2,4 -difluoro- 5-((2 -)- oxypyrrolidin- 3 -yl ) oxy ) -benzene yl) piperazin-1-yl) ethyl) -8- (furan-2-yl) thiazolo [5,4-e] [1,2,4] triazolo [1,5-c] pyrimidine - 2(3H) -one ( Compound 96) : to 2-(5-Amino-8-(furan-2-yl)-2-yloxythiazolo[5,4-e][1,2,4 Add DIPEA (0.49 g, 3.79 mmol) to a solution of triazolo[1,5-c]pyrimidin-3(2H)-yl)ethylmethanesulfonate (300 mg, 0.76 mmol) in DMF (10 mL) And (R)-3-(2,4-difluoro-5-(piperazin-1-yl)phenoxy)pyrrolidin-2-one (337 mg, 1.14 mmol). The reaction mixture was stirred at 120 ° C for 16 h. After completion of the reaction (TLC & LCMS), the solvent was removed under reduced pressure and the mixture was partitioned between water and ethyl acetate. The separated organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ and filtered. The filtrate was concentrated under reduced pressure and purified by flash chromatography eluting HPLC purity (XB0595TF): 97.73%; LCMS (ESI ESI) m/z: Calculated: 597.17; observed: 598.0 (M+1); ¹ H-NMR (400 MHz, DMSO-d6): δ 8.32 ( Brs, 2H), 8.09 (s, 1H), 7.95 (s, 1H), 7.19-7.25 (m, 2H), 6.97 (t, J = 8.64 Hz, 1H), 6.74 (s, 1H), 4.93 (t , J = 7.56 Hz, 2H), 4.08 (t, J = 6.00 Hz, 2H), 3.18-3.26 (m, 2H), 2.91 (m, 4H), 2.64-2.73 (m, 6H), 1.98-2.03 ( m, 1H). Example 99 : 5- Amino- 3-(2-(4-(2- fluoro- 4-( morpholin- 3 -ylmethoxy ) phenyl ) piperazin- 1 -yl ) ethyl )-8- ( furan -2- yl ) thiazolo [5,4-e][1,2,4] triazolo [1,5-c] pyrimidin -2(3H) -one

Step 1 : Synthesis of 3-((4-(4-(( benzyloxy )) carbonyl ) piperazin- 1 -yl )-3- fluorophenoxy ) methyl ) morpholine- 4- carboxylic acid tert- butyl ester ( 2) : Addition of 3-benzyl 2-(2-fluoro-4-hydroxyphenyl)piperazine-1-carboxylate (1, 2.0 g, 6.05 mmol) in toluene (20 mL) at RT (Hydroxymethyl)morpholine-4-carboxylic acid tert-butyl ester (2.63 g, 12.1 mmol), triphenylphosphine (4.76 g, 12.1 mmol) and DIAD (2.45 g, 12.1 mmol). The reaction mixture was stirred at 120 ° C for 16 h in a sealed tube. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was partitioned between water and ethyl acetate and the organic layer was washed with brine solution separated, dried over anhydrous Na ₂ SO _4, and concentrated in vacuo to give the crude product. The crude material obtained was purified by column chromatography (20%EtOAc / hexane) to afford 3-((4-((benzyloxy))) Fluorylphenoxy)-methyl)morpholine-4-carboxylic acid tert-butyl ester (1.0 g, 31.2%); LCMS (ESI ESI) m/z: Calculated: 529.26; ).

Step 2 : Synthesis of 3-((3- fluoro- 4-( piperazin- 1 -yl ) phenoxy ) methyl ) -morpholine- 4- carboxylic acid tert- butyl ester (3) : 3- at RT ((4-(4-((benzyloxy)carbonyl)piperazin-1-yl)-3-fluorophenoxy)methyl)morpholine-4-carboxylic acid tert-butyl ester ( 2 , 600 mg, 1.1 Add a 10% Pd/C (120 mg) to a stirred solution of ethyl acetate (10 mL) and stirred for 16 h under hydrogen atmosphere. After completion, the reaction mixture was filtered using diatomaceous earth to remove Pd/C. The combined organic layer was dried over anhydrous Na ₂ SO _4, and concentrated under reduced pressure to give solids Adhesive 3 - ((3-fluoro-4- (piperazin-1-yl) phenoxy) methyl) morpholine - Tetrabutyl 4-formate (350 mg, 61.7%); LCMS (ESI ESI) m/z: Calculated: 395.21.

Step 3 : Synthesis of 3-((4-(4-(2-(5- amino -8-( furan -2- yl )-2 - yloxythiazolo[5,4-e]-[1, 2,4] triazolo [1,5-c] pyrimidin -3(2H) -yl ) ethyl ) piperazin- 1 -yl )-3- fluorophenoxy ) -methyl ) -morpholine -4 - tert- butyl formate (4) : to 2-(5-amino-8-(furan-2-yl)-2-yloxythiazolo[5,4-e][1,2,4] Triazolo[1,5-c]pyrimidin-3(2H)-yl)ethylmethanesulfonate (200 mg, 0.631 mmol) and 3-((3-fluoro-4-(piperazin-1-yl) Add a DIPEA (292 mg, 2.27 mmol) to a stirred solution of phenoxy)methyl)morpholine-4-carboxylic acid tert-butyl ester (300 mg, 0.756 mmol) in DMF (10 mL). Stir at °C for 16 h. The reaction mixture was monitored by TLC and partitioned between water and ethyl acetate. The separated organic layer was washed with NaHCO ₃ solution, brine solution, dried over anhydrous Na ₂ SO ₄ dried, and concentrated under reduced pressure to give the crude product. The crude product was purified by preparative HPLC to give pure 3-((4-(4-(5-amino)-8-(furan-2-yl)-2-yloxythiazole [5, 4-e][1,2,4]-triazolo[1,5-c]pyrimidin-3(2H)yl)ethyl)piperazin-1-yl)-3-fluorophenoxy)methyl ) morpholine-4-carboxylic acid tert-butyl ester (80 mg, 21.4%); LCMS (ESI ESI) m/z: calc.

Step 4 : Synthesis of 5- amino- 3-(2-(4-(2- fluoro- 4-( morpholin- 3 -ylmethoxy ) phenyl ) -piperazin- 1 -yl ) ethyl )- 8-( furan -2- yl ) thiazolo [5,4-e][1,2,4] triazolo [1,5-c] pyrimidin -2(3H) -one ( compound 99) : to 3 -((4-(4-(2-(5-Amino-8-(furan-2-yl)-2-yloxythiazolo[5,4-e]-[1,2,4]3 Azolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3-fluorophenoxy)methyl)morpholine-4-carboxylic acid tert-butyl ester ( 4, 80 mg, 0.11 mmol) <RTI ID=0.0></RTI></RTI><RTIgt; After the reaction was completed, the reaction mixture was evaporated to dryness crystals crystals crystals crystalssssssssssssssss -(morpholin-3-ylmethoxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4 Triazolo[1,5-c]pyrimidin-2(3H)-one (15 mg, 22%); HPLC purity (XB0595TF): 95.90%; LCMS (ESI ESI) m/z: Calculated: 595.21. Observed: 596.1 (M+1); ¹ H-NMR (400 MHz, DMSO-d6): δ 8.31 (brs, 2H), 7.95 (m, 1H), 7.24 (dd, J = 0.80 Hz and 3.40 Hz) , 1H), 6.92 (t, J = 10.00 Hz, 1H), 6.80 (dd, J = 2.80 Hz and 14.00 Hz, 1H), 6.73 (dd, J = 2.00 Hz and 3.40 Hz, 1H), 6.67 (dd, J = 2.40 Hz and 8.80 Hz, 1H), 4.08 (t, J = 6.40 Hz, 2H), 3.81-3.74 (m, 3H), 3.67-3.64 (m, 1H), 3.34 (m, 1H), 3.18 ( t, J = 10.80 Hz, 1H), 3.01-2.98 (m, 1H), 2.85 (m, 4H), 2.77-2.67 (m, 4H), 2.63 (m, 4H). Example 100 : 5- Amino- 3-(2-(4-(2- fluoro- 4-( morpholin -2 -ylmethoxy ) phenyl ) piperazin- 1 -yl ) ethyl )-8- ( furan -2- yl ) thiazolo [5,4-e][1,2,4] triazolo [1,5-c] pyrimidin -2(3H) -one

Step 1 : Synthesis of 2-(((( methylsulfonyl ) oxy ) methyl ) morpholine- 4- carboxylic acid tert- butyl ester (2) : to 2-(hydroxymethyl)morpholine-4-carboxylic acid Methanesulfonyl chloride (3.42, 29.92 mmol) was added dropwise to a cooled suspension of tributyl ester ( 1 , 5.0 g, 23.01 mmol) elute After the completion of the reaction (TLC), the reaction mixture was diluted with water and the crude product was purified eluting with EtOAc EtOAc. The title compound 2 (6.0 g, 87%). </RTI><RTIID=0.0></RTI></RTI><RTIID=0.0></RTI>

Step 2 : Synthesis of tert-butyl 2-((4-(4-(( benzyl )) carbonyl ) piperazin- 1 -yl )-3- fluorophenoxy ) methyl ) morpholine- 4- carboxylate ( 3) : Benzyl 4-(2-fluoro-4-hydroxyphenyl)piperazine-1-carboxylate (2, 0.5 g, 1.51 mmol) and 2-(((methylsulfonyl)oxy) yl) morpholine-4-carboxylic acid tert-butyl ester (0.53 g, 1.81 mmol) in dry DMF (10 mL) was added in the suspension of _{K 2 CO 3 (0.63 g,} 4.54 mmol) and the reaction mixture was at 100 ℃ Heating for 16 h. After the completion of the reaction (TLC), the reaction was filtered through EtOAc EtOAc (EtOAc)EtOAc. Compound 3 (0.35 g, 39%): mp. 1H-NMR (400 MHz, DMSO-d6): δ 7.39-7.35 (m, 5H), 7.32-7.00 (m, 1H), 6.97-6.85 (m, 1H), 6.84-6.72 (m, 1H), 5.11 (s, 2H), 3.98-3.96 (m, 2H), 3.86-3.73 (m, 2H), 3.70-3.66 (m, 2H), 3.64-3.43 (m, 2H), 3.38-3.34 (m, 4H) , 3.32 (m, 1H), 2.89 (m, 4H).

Step 3 : Synthesis of 2-((3- fluoro- 4-( piperazin- 1 -yl ) phenoxy ) methyl ) morpholine- 4- carboxylic acid tert- butyl ester (4) : 2-((4- (4-((Benzyloxy)carbonyl)piperazin-1-yl)-3-fluorophenoxy)methyl)morpholine-4-carboxylic acid tert-butyl ester ( 3 , 0.33 g, 0.62 mmol) in acetic acid The solution in ethyl acetate (6 mL) was loaded with 10% palladium on carbon (0.060 g) and the reaction mixture was stirred under hydrogen balloon pressure for 16 h at room temperature. After completion of the reaction (TLC), the reaction mixture was filtered through diatomaceous earth pad and the filtrate was concentrated under reduced pressure to give the title compound as a light brown solid of 4 (0.18 g, 65%) ; LCMS (ESI pos. Ion) m / z: Calculated: 395.48; observed: 396.3 (M+1). 1H-NMR (400 MHz, DMSO-d6): δ 6.95 (t, J = 10.00 Hz, 1H), 6.84-6.80 (m, 1H), 6.72-6.70 (m, 1H), 3.96-3.95 (m, 2H) ), 3.92-3.83 (m, 2H), 3.74-3.67 (m, 2H), 3.65-3.64 (m, 1H), 3.33-2.99 (m, 9H), 1.42 (s, 9H).

Step 4 : Synthesis of 2-((4-(4-(2-(5- amino) -8-( furan -2- yl )-2 - yloxythiazolo[5,4-e][1,2 ,4] triazolo [1,5-c] pyrimidin -3(2H) -yl ) ethyl ) piperazin- 1 -yl )-3- fluorophenoxy ) -methyl ) -morpholin- 4- T-butyl formate (5) : 2-(5-Amino-8-(furan-2-yl)-2-yloxythiazolo[5,4-e] at 120 ° C in a sealed tube [1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethylmethanesulfonate (0.16 g, 0.40 mmol), 2-((3-fluoro-4-) (piperazin-1-yl)phenoxy)methyl)morpholine-4-carboxylic acid tert-butyl ester (4, 0.176 g, 0.444 mmol) and DIPEA (0.26 g, 2.01 mmol) in anhydrous DMF (3 mL) The mixture was heated for 16 h. After completion (TLC), the reaction mixture was cooled to EtOAc EtOAc (EtOAc m. Compound 5 (0.05 g, 16.4%); mp. 1H-NMR (400 MHz, DMSO-d6): δ 8.30 (brs, 2H), 7.95 (brs, 1H), 7.24 (s, 1H), 6.92 (m, 1H), 6.83-6.73 (m, 1H), 6.69 (d, J = 8.80 Hz, 2H), 4.08-3.95 (m, 2H), 3.85-3.83 (m, 2H), 3.70 (m, 2H), 3.43 (m, 2H), 3.33 (m, 1H) , 2.85 (m, 4H), 2.68-2.63 (m, 4H), 2.45-2.33 (m, 4H), 1.41 (s, 9H).

Step 5 : Synthesis of 5- amino- 3-(2-(4-(2- fluoro- 4-( morpholin -2 -ylmethoxy ) phenyl ) piperazin- 1 -yl ) ethyl )-8 -( furan -2- yl ) thiazolo [5,4-e][1,2,4] triazolo [1,5-c] pyrimidin -2(3H) -one ( Compound 100) : to 2- ((4-(4-(2-(5-Amino-8-(furan-2-yl)-2-yloxythiazolo[5,4-e][1,2,4]triazole [1,5-c]pyrimidine-3(2H)-yl)ethyl)piperazin-1-yl)-3-fluorophenoxy)methyl)morpholine-4-carboxylic acid tert-butyl ester ( 5 , </RTI></RTI></RTI><RTIgt;</RTI><RTIgt; After completion of the reaction (TLC), the formed solid (HCl salt) was filtered, dried under reduced pressure to afford an off-white solid of the title compound 100 (0.014 g, 36%) ; HPLC purity (XB_0595TF.M): 95.72%; LCMS (ESI positron) m/z: calcd: 595.35; observed: 596.2 (M+1); 1H-NMR (400 MHz, DMSO-d6): δ 10.11 (brs, 1H), 9.39-9.41 (m, 2H), 8.42 (brs, 2H), 7.97 (s, 1H), 7.26-7.27 (m, 1H), 7.04 (t, J = 9.64 Hz, 1H), 6.90-6.94 (m, 1H), 6.74-6.77 (m, 2H), 4.14 (t, J = 3.32 Hz, 2H), 3.99-4.03 (m, 4H), 3.91-3.94 (m, 2H), 3.78 (t, J = 12.12 Hz, 1H), 3.60- 3.61 (m, 2H), 3.30-3.48 (m, 3H), 3.271-3.198 (m, 2H), 3.17-3.00 (m, 4H). Examples 101 and 102 : 5- Amino- 3-(2-(4-(2 -)- fluoro -4-(((3R,4R)-4- fluoropyrrolidin- 3 -yl ) oxy ) phenyl ) piperidin Pyrazin- 1 -yl ) ethyl )-8-( furan -2- yl ) thiazolo [5,4-e][1,2,4] triazolo [1,5-c] pyrimidine -2 (3H ) -ketone and 5- amino- 3-(2-(4-(2- fluoro -4-((3S,4S)-4- fluoropyrrolidin- 3 -yl ) oxy ) phenyl ) piperazine -1 -yl ) ethyl )-8-( furan -2- yl ) thiazolo [5,4-e][1,2,4] triazolo [1,5-c] pyrimidine -2(3H) - one

Step 1 : Synthesis of benzyl 4-(2- fluoro- 4 -hydroxyphenyl ) piperazine- 1- carboxylate (2) : to 4-bromo-3-fluorophenol ( 1 , 15 g, 0.079 mol), piperazine LHMDS was added to the ice-cold stirred solution of benzyl acetate (20.76 g, 0.094 mol), DavePhos (3.704 g, 0.009 mol), Pd ₂ (dba) ₃ (7.186 g, 0.008 mol) in THF (100 mL). 100 mL). After the addition, the reaction was allowed to reach room temperature. It was then heated to 65 ° C for 24 h. After completion, the reaction mixture was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate. The combined organic layers were washed with a saturated saline solution, dried over anhydrous Na ₂ SO _4, filtered and concentrated under reduced pressure. The crude material obtained was purified by column chromatography (230-400 EtOAc (30% EtOAc/EtOAc) elute m/z: Calculated: 330.36; observed: 331.1 (M+1).

Step 2 : Synthesis of benzyl 4-(4-((1-( t-butoxycarbonyl )-4- fluoropyrrolidin- 3 -yl ) oxy )-2- fluorophenyl ) piperazine- 1- carboxylate (3) : Benzyl 4-(2-fluoro-4-hydroxyphenyl)piperazine-1-carboxylate (6.8 g, 20.58 mmol), 6-oxa-3-azabicyclo[3.1.0] Cs ₂ CO ₃ (10.3 g, 30.88 mmol) was added to a stirred solution of aq. The resulting mixture was stirred at 100 ° C for 16 h. It is then filtered to remove inorganics. The crude residue obtained by concentrating the filtrate was purified by column chromatography (230-400 EtOAc (30% EtOAc/EtOAc) as eluent) to give an off-white solid (6.00 g, 56.0%). Ion) m/z: Calculated: 515.58; observed: 516.2 (M+1).

Step 3 : Synthesis of 4-(4-((-1-( t-butoxycarbonyl )-4- fluoropyrrolidin- 3 -yl ) oxy )-2- fluorophenyl ) piperazine- 1- carboxylic acid benzyl Ester (4A & 4B) : 4-(4-((1-(T-butoxycarbonyl)-4-hydroxypyrrolidin-3-yl)oxy)-2-fluorophenyl ) at -20 °C The solution of benzyl piperazine-1-carboxylate (3,6 g, 11.64 mmol) in EtOAc (30 mL) was evaporated. The resulting mixture was stirred at -20 °C for 0.5 h and then stirred at RT for 16 h. After completion of the reaction, the reaction mixture was washed with saturated NaHCO ₃ solution and quenched with DCM and extracted. The combined organic layer was dried over anhydrous Na ₂ SO _4, filtered and concentrated under reduced pressure. The crude material obtained was purified by column chromatography (230-400 oxime (30% EA / hexanes as eluent) to give two fractions of the product. fraction -1 - 1.4 g, fraction - s. </ RTI><RTIID=0.0></RTI></RTI><RTIID=0.0></RTI>

The two fractions were further purified by palmitic SFC purification (0.5% DEA in IPA, YMC cellulose-SC) to give mirror image isomers 4A and 4B.

Step 4 : Synthesis of (3R,4R)-3- fluoro- 4-(3- fluoro- 4-( piperazin- 1 -yl ) phenoxy ) -pyrrolidine- 1- carboxylic acid tert- butyl ester (5A) : To 4-(4-(((3R,4R)-1-((t-butoxycarbonyl)-4-fluoropyrrolidin-3-yl)oxy)-2-fluorophenyl)pere Pd/C 10% (200 mg) was added to a stirred solution of benzyl-l-carboxylate ( 4A , 430 mg, 0.831 mmol) in ethyl acetate (10 mL). The resulting mixture was stirred at RT under a hydrogen atmosphere for 32 h. It was then filtered through a diatomaceous earth pad to remove Pd/C. The crude residue obtained when the filtrate was concentrated gave a viscous material. The crude material (0.23 g, 69.3%) was used in the next step without purification. </RTI><RTIID=0.0></RTI></RTI><RTIID=0.0></RTI>

Step 5: Synthesis of (3R, 4R) -3- (4- (4- (2- (5- amino-8- (furan-2-yl) -2-oxo-thiazolo - [5,4 e][1,2,4] triazolo [1,5-c] pyrimidin -3(2H) -yl ) ethyl ) piperazin- 1 -yl )-3- fluorophenoxy )-4- fluoro Pyrrolidine- 1- carboxylic acid tert- butyl ester (7A) : to (3R,4R)-3-(4-(4-(2-(5-amino-8-(furan-2-yl))-2- Sideoxythiazolo-[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)- 2-(5-Amino-8) was added to a stirred solution of 3-fluorophenoxy)-4-fluoropyrrolidine-1-carboxylic acid tert-butyl ester ( 5A , 100 mg, 0.261 mmol) in DCM (10 mL) -(furan-2-yl)-2-yloxythiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl) Aldehyde (82 mg, 0.261 mmol) and Et ₃ N (52 mg, 0.552 mmol). The resulting mixture was stirred at room temperature for 3 h. Then NaBH(OAc) ₃ (165 mg 0.522 mmol) was added and the mixture was stirred at room temperature for 24 h. After completion, the reaction mixture was diluted with DCM. The separated organic portion was continuously washed with a saturated bicarbonate solution and a saturated saline solution. After dried over anhydrous Na ₂ SO _4, filtered and concentrated under reduced pressure. The crude material obtained was purified by column chromatography (230-400 EtOAc (EtOAc: EtOAc EtOAc EtOAc) m/z: Calculated: 683.74; observed: 684.3 (M+1).

step 6 :synthesis 5- Amine -3-(2-(4-(2- fluorine -4-(((3R,4R)-4- Flupiridine -3- base ) Oxyl ) Phenyl ) Piperazine -1- base ) Ethyl )-8-( Furan -2- base ) Thiazol [5,4-e][1,2,4] Triazole [1,5-c] Pyrimidine -2(3H)- ketone ( Compound 101) :

To (3R,4R)-3-(4-(4-(2-(5-Amino-8-(furan-2-yl)-2-yloxythiazolo[5,4-e][1 , 2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3-fluorophenoxy)-4-fluoropyrrolidin-1 - carboxylic acid tert-butyl ester (7A, 25 mg, 0.037 mmol ) in DCM (1 mL) was stirred in the ice-cooling solution of diethyl ether was added HCl (0.073 mL). The resulting mixture was stirred at 0 ° C for 1 h. After the reaction was completed, the reaction mixture was concentrated under reduced pressure. The crude product obtained was triturated with diethyl ether to afford (yield: &lt;RTIgt;</RTI><RTIID=0.0></RTI></RTI><RTIID=0.0></RTI> HPLC purity (XB0595TF): 92.31%. 1H-NMR (400 MHz, DMSO-d6): δ 9.86 (brs, 1H), 9.69 (brs, 1H), 9.47 (brs, 1H), 8.42 (m, 2H), 7.97 (s, 1H), 7.26 ( d, J = 3.60 Hz, 1H), 7.06-7.10 (m, 2H), 6.87 (d, J = 8.40 Hz, 1H), 6.74-6.76 (m, 1H), 5.49 (m, 1H), 5.07-5.13 (m, 1H), 4.32 (brs, 2H), 3.72-3.92 (m, 2H) 3.62 (d, J = 5.20 Hz, 2H), 3.39 (t, J = 5.20 Hz, 5H), and 3.02 (brs, 5H).

Step 4 : Synthesis of (3S,4S)-3- fluoro- 4-(3- fluoro- 4-( piperazin- 1 -yl ) phenoxy ) -pyrrolidine- 1- carboxylic acid tert- butyl ester (5B) : To 4-(4-(((3S,4S)-1-((t-butoxycarbonyl)-4-fluoropyrrolidin-3-yl)oxy)-2-fluorophenyl)pere Pd/C 10% (200 mg) was added to a stirred solution of benzyl-l-carboxylate ( 4B , 380 mg, 0.734 mmol) in ethyl acetate (10 mL). The resulting mixture was stirred at RT under a hydrogen atmosphere for 32 h. It was then filtered through a diatomaceous earth pad to remove Pd/C. The crude residue obtained when the filtrate was concentrated gave a viscous material. The crude material (0.2 g, 71.04%) was used in the next step without purification. </RTI><RTIID=0.0></RTI></RTI><RTIID=0.0></RTI>

Step 5: Synthesis of (3S, 4S) -3- (4- (4- (2- (5- amino-8- (furan-2-yl) -2-oxo-thiazolo - [5,4 e][1,2,4] triazolo [1,5-c] pyrimidin -3(2H) -yl ) ethyl ) piperazin- 1 -yl )-3- fluorophenoxy )-4- fluoro Pyrrolidine- 1- carboxylic acid tert- butyl ester (7B) : to (3S,4S)-3-(4-(4-(2-(5-amino-8-(furan-2-yl))-2- Sideoxythiazolo-[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)- 2-(5-Amino-)-(3-fluoro-phenoxy)-4-fluoropyrrolidine-1-carboxylic acid tert-butyl ester ( 5B , 70 mg, 0.187 mmol) in DCM (10 mL) 8-(furan-2-yl)-2-yloxythiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl) Acetaldehyde (57 mg, 0.187 mmol) and Et ₃ N (52 mg, 0.548 mmol). The resulting mixture was stirred at room temperature for 3 h. Then NaBH(OAc) ₃ (77 mg, 0.365 mmol) was added and the mixture was stirred at room temperature for 24 h. After completion, the reaction mixture was diluted with DCM. The separated organic portion was continuously washed with a saturated bicarbonate solution and a saturated saline solution. After dried over anhydrous Na ₂ SO _4, filtered and concentrated under reduced pressure. The crude material obtained was purified by column chromatography (230-400 EtOAc (EtOAc EtOAc EtOAc EtOAc) m/z: Calculated: 683.74; observed: 684.3 (M+1).

Step 6: Synthesis of 5-amino-3- (2- (4- (2-fluoro -4 - (((3S, 4S ) -4- fluoro-pyrrolidin-3-yl) oxy) - phenyl) -piperazin l-yl) ethyl) -8- (furan-2-yl) thiazolo [5,4-e] [1,2,4] triazolo [1,5-c] pyrimidin -2 (3H ) -ketone ( Compound 102) : to (3S,4S)-3-(4-(4-(2-(5-Amino-8-(furan-2-yl)-2-yloxythiazolo[ 5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3-fluoro-phenoxy ) in the -4-fluoropyrrolidine-l-carboxylic acid tert-butyl ester (7B, 25 mg, 0.037 mmol ) in DCM (1 mL) was added diethyl ether stirred solution of the HCl (0.073 mL). The resulting mixture was stirred at 0 ° C for 1 h. After the reaction was completed, the reaction mixture was concentrated under reduced pressure. The obtained crude product was triturated with diethyl ether to afford (yield: </RTI><RTIID=0.0></RTI><RTIID=0.0></RTI> HPLC purity (XB_0595TF): 93.18%. 1H-NMR (400 MHz, DMSO-d6): δ 10.27 (brs, 1H), 9.69-9.82 (m, 2H), 8.41 (brs, 2H), 7.97 (m, 1H), 7.26-7.27 (m, 1H) ), 7.05-7.10 (m, 2H), 6.87-6.90 (m, 1H), 6.75 (t, J = 1.60 Hz, 1H), 5.49 (d, J = 4.00 Hz, 1H), 5.07-5.13 (m, 1H), 4.32 (d, J = 5.20 Hz, 2H), 3.73-3.93 (m, 2H), 3.49-3.66 (m, 2H), 3.40-3.44 (m, 3H), 3.30-3.39 (m, 2H) , 3.25-3.30 (m, 3H), and 3.07-3.10 (m, 2H). Example 111 : 5- Amino- 3-(2-(4-(2,4 -difluoro- 5-((1s,4s)-1 -oxo -tetrahydro -2H- thiopyran- 4 -yl ) Oxy ) phenyl ) piperazin- 1 -yl ) ethyl )-8-( furan -2- yl ) thiazolo [5,4-e][1,2,4] triazolo [1,5- c] pyrimidine -2(3H) -one

Step 1 : Synthesis of tetrahydro -2H- thiopyran- 4 -ylmethanesulfonate (2) : to tetrahydro-2H-thiopyran-4-ol (2.0 g, 16.94 mmol) and triethylamine (4.26 g, 42.2 mmol) </RTI></RTI><RTIID=0.0></RTI></RTI><RTIgt; After the reaction was completed, the reaction mixture was diluted with water and the crude product was extracted with dichloromethane. The organic layer was dried, concentrated and by column chromatography (20% EtOAc / hexanes as elution solution) to give the title compound as a light brown liquid of 2 (3.1 g, 94%) . The crude material was used as it is in the next step.

Step 2 : Synthesis of tert-butyl 4-(2,4 -difluoro- 5-(( tetrahydro -2H- thiopyran- 4 -yl ) oxy ) phenyl ) piperazine- 1- carboxylate (3) : To tetrahydro-2H-thiopyran-4-ylmethanesulfonate (2, 2.25 g, 11.45 mmol) and 4-(2,4-difluoro-5-hydroxyphenyl)piperazine-1-carboxylic acid K ₂ CO ₃ (2.69 g, 19.04 mmol) was added to a solution of butyl ester (3 g, 9.55 mmol) in N,N-dimethylformamide (10 mL) and the reaction mixture was heated at 100 ° C for 16 h. . After completion of the reaction (TLC), the reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate. The organic layer was Li salt solution, washed with water, dried over anhydrous ₂ SO ₄ Na, filtered and concentrated under reduced pressure to give the crude product, which system further by column chromatography (20% EtOAc / hexanes as Eluant) The title compound ( 3 g, EtOAc, m.

Step 3 : Synthesis of tert-butyl 4-(2,4 -difluoro- 5-((1 -oxotetrahydro- 2H- thiopyran- 4 -yl ) oxy ) phenyl ) piperazine- 1- carboxylate (4) : tert-butyl 4-(2,4-difluoro-5-(tetrahydro-2H-thiopyran-4-yl)oxy)phenyl)piperazine-1-carboxylate ( 3 , 1.7 g, 4.101 mmol) in acetic acid (20 mL) in the solution was cooled to 0 ℃, was added _{H 2 O 2 (30%,} 2 mL) and the reaction mixture was stirred at the same temperature for 1 h. After completion of the reaction (TLC), the reaction mixture was neutralized with a cooled 10% NaOH solution and the crude was extracted with dichloromethane. The organic layer was washed with brine, dried over anhydrous Na ₂ SO _4, filtered and concentrated under reduced pressure to afford an off-white solid than the racemic product. Yield: (1.62 g, 91.8%). The isomers present in the racemic mixture are separated by the SFC method. The first peak (peak 1 ) which was eluted was concentrated to give the title compound 4 (0.65 g, 80%): m. +1). 1H-NMR (400 MHz, DMSO-d6): 7.31 (t, J = 12 Hz, 1H), 6.97-6.93 (s, J = 8.8 Hz 1H), 4.43-4.40 (m, 1H), 3.46-3.16 ( m, 4H), 2.96-2.90 (m, 6H), 2.75-2.67 (m, 2H), 2.50-2.30 (m, 2H), 1.86-1.83 (m, 2H), 1.42 (s, 9H).

Step 4 : Synthesis of (1s, 4s)-4-(2,4 -difluoro -5-( piperazin- 1 -yl ) phenoxy ) tetrahydro -2H- thiopyran 1- oxide (5) : 4-(2,4-difluoro-5-((1s,4s)-1-oxo-tetrahydro-2H-thiopyran-4-yl)oxy)phenyl)piperazine-1-carboxylic acid To the ice-cold solution of butyl ester ( 4 , 0.48 g, 1.11 mmol) in dichloromethane (10 mL), trifluoroacetic acid (1.3 mL), and the mixture was stirred at RT for 5 h. After completion of the reaction (TLC), excess TFA was removed by evaporation and the reaction mixture was purified by tosic acid to afford title compound 5 (0.31 g, 84%) m/z: Calculated: 330.39; observed: 331.0 (M+1).

Step 5 : Synthesis of 5- amino- 3-(2-(4-(2,4 -difluoro- 5-((1s, 4s)-1 -oxo-tetrahydro -2H- thiopyran- 4 -yl) ) oxy) phenyl) piperazin-1-yl) ethyl) -8- (furan-2-yl) thiazolo [5,4-e] [1,2,4] - triazolo [1, 5-c] pyrimidine -2(3H) -one ( Compound 111) : 2-(5-Amino-8-(furan-2-yl)-2-oxooxythiazole at 120 ° C in a sealed tube And [5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethylmethanesulfonate (0.35 g, 0.88 mmol), (1 s , 4s)-4-(2,4-difluoro-5-(piperazin-1-yl)phenoxy)tetrahydro-2H-thiopyran 1-oxide (5, 0.32 g, 0.97 mmol) and DIPEA (0.34 g, 2.64 mmol) mixture in dry DMF (3 mL After completion (TLC), the reaction mixture was cooled to EtOAc EtOAc (EtOAc m. Compound 111 . </RTI><RTIID=0.0></RTI></RTI><RTIID=0.0></RTI></RTI><RTIgt;

¹ H-NMR (400 MHz, DMSO-d6): δ 8.29 (s, 2H), 7.94 (s, 1H), 7.23 (t, J = 10.72 Hz, 2H), 6.80 (t, J = 8.52 Hz, 1H ), 6.72 (t, J = 1.72 Hz, 1H), 4.36 (t, J = 9.08 Hz, 1H), 4.05 (t, J = 7.32 Hz, 2H), 2.90 (s, 6H), 2.79 (d, J = 11.56 Hz, 2H), 2.73 (d, J = 8.80 Hz, 2H), 2.69 (t, J = 9.92 Hz, 4H), 2.14 (q, J = 10.68 Hz, 2H), 1.97 (d, J = 12.84 Hz, 2H). Example 112 : 5- Amino- 3-(2-(4-(2,4 -difluoro- 5-((1r,4r)-1 -oxo-tetrahydro -2H- thiopyran- 4 -yl )) Oxy ) phenyl ) piperazin- 1 -yl ) ethyl )-8-( furan -2- yl ) thiazolo [5,4-e][1,2,4] triazolo [1,5- c] pyrimidine -2(3H) -one

Step 1 : Synthesis of (1r, 4r)-4-(2,4 -difluoro -5-( piperazin- 1 -yl ) phenoxy ) tetrahydro -2H- thiopyran 1- oxide (2) : 4-(2,4-difluoro-5-(((1r, 4r)-1-oxo-tetrahydro-2H-thiopyran-4-yl)oxy)phenyl)piperazine-1-carboxylic acid To the ice-cold solution of butyl ester ( 1 , 0.3 g, 0.697 mmol) in dichloromethane (10 mL), trifluoroacetic acid (1.3 mL), and the mixture was stirred at RT for 5 h. After completion of the reaction (TLC), excess TFA was removed by evaporation and the reaction mixture was treated by tosic acidic resin and to give an off-white solid of the title compound 2 (0.20 g, 85%) ; LCMS (ESI pos. Ion) m/z: Calculated: 330.39; observed: 331.0 (M+1).

Step 2 : Synthesis of 5- amino- 3-(2-(4-(2,4 -difluoro- 5-((1r,4r)-1 -oxo-tetrahydro -2H- thiopyran- 4 -yl) ) oxy) phenyl) piperazin-1-yl) ethyl) -8- (furan-2-yl) thiazolo [5,4-e] [1,2,4] - triazolo [1, 5-c] pyrimidine -2(3H) -one ( Compound 112) : 2-(5-Amino-8-(furan-2-yl)-2-oxooxythiazole at 120 ° C in a sealed tube And [5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethylmethanesulfonate (0.23 g, 0.58 mmol), (1r , 4r)-4-(2,4-difluoro-5-(piperazin-1-yl)phenoxy)tetrahydro-2H-thiopyran 1-oxide ( 2 , 0.21 g, 0.63 mmol) and DIPEA A mixture of (0.23 g, 1.74 mmol) in dry m. After completion (TLC), the reaction mixture was cooled to EtOAc EtOAc (EtOAc m. Compound 3 . </RTI><RTIID=0.0></RTI></RTI><RTIID=0.0></RTI></RTI><RTIID=0.0> ¹ H-NMR (400 MHz, DMSO-d6): δ 8.29 (s, 2H), 7.94 (s, 1H), 7.23 (t, J = 11.8 Hz, 2H), 6.85 (t, J = 8.64 Hz, 1H ), 6.72 (t, J = 1.72 Hz, 1H), 4.57 (s, 1H), 4.05 (t, J = 7.32 Hz, 2H), 2.93 (brs, 6H), 2.72-2.67 (m, 4H), 2.62 (s, 6H), 2.34-2.32 (m, 2H), 1.85 (d, J = 12.84 Hz, 2H). Examples 119 and 120 : (R)-5- Amino- 3-(2-(4-(2- fluoro- 4-( methylsulfinyl ) phenyl ) piperazin- 1 -yl ) ethyl ) 8-(- furan -2- yl ) thiazolo [5,4-e][1,2,4] triazolo [1,5-c] pyrimidin -2(3H) -one and (S)-5 - amino-3- (2- (4- (2-fluoro-4- (methylsulfinyl acyl) phenyl) piperazin-1-yl) ethyl) -8- (furan-2-yl) Thiazolo [5,4-e][1,2,4] triazolo [1,5-c] pyrimidin -2(3H) -one

Step 1 : Synthesis of (3,4 -difluorophenyl )( methyl ) sulfane (2) : 3,4-difluorobenzenethiol ( 1 , 8.0 g, 54.74 mmol ) at 0 ° C in a sealed tube ) in DMF (25 mL stirring) was added a solution of _{K 2 CO 3 (9.08 g,} 65.68 mmol) followed by MeI (8.5 g, 60.21 mmol) and stirred at RT 16 h. After completion (TLC), the reaction mass was poured into ice cold water and extracted with diethyl ether. The organic layer was washed with saturated saline solution, dried over anhydrous Na ₂ SO _4, filtered and concentrated under reduced pressure to give the title compound. The crude product (8.05 g, 88.1%) was used in the next step without purification.

Step 2 : Synthesis of 1,2 -difluoro- 4-( methylsulfinyl ) benzene (3) : (3,4-difluorophenyl)(methyl)sulfane at 0 ° C ( 2 , 8.0 g, 49.94 mmol) mCPBA (8.6 g, 49.94 mmol) was added to a stirred solution in DCM and stirred at RT for 16 h. After completion (TLC), the reaction was quenched with saturated aqueous sodium bicarbonate and extracted with DCM. The organic layer was washed with saturated saline solution, dried over anhydrous Na ₂ SO _4, filtered and concentrated under reduced pressure. The crude material was purified by EtOAc EtOAc EtOAc EtOAc.

Step 3 : Synthesis of tert-butyl 4-(2- fluoro- 4-( methylsulfinyl ) phenyl ) piperazine- 1- carboxylate (4, 5) : Piperazine-1- at 0 ° C K ₂ CO ₃ (7.8 g, 56.76 mmol) followed by 1,2-difluoro-4-(methyl ia) in a stirred solution of tert-butyl formate (5.3 g, 28.38 mmol) in DMF (50 mL) Sulfosyl)-benzene ( 3 , 5.0 g, 28.38 mmol). The reaction mixture was stirred at 145 ° C for 16 h. After completion (TLC), the reaction mass was quenched with water and extracted with ethyl acetate. The organic layer was washed with saturated saline solution, dried over anhydrous Na ₂ SO _4, filtered and concentrated under reduced pressure. The crude material was purified by EtOAc EtOAc EtOAc.

The racemic mixture (0.22 g) was subjected to SFC (0.22 g sample dissolved in 3 mL of methanol, column-Lux A1 mobile phase: 70:30 (A:B), A = liquid CO ₂ , B = Methanol, flow rate: 3.0 mL/min; wavelength: 220 nm) for palmar separation to produce peaks 1 ( 4 ) of 810 mg and peaks 2 ( 5 ) of 820 mg, respectively.

Note: Peak 1 from SFC purification is arbitrarily considered to be the (S) isomer and peak 2 is considered to be the (R) isomer.

Step 4 : Synthesis of (S)-1-(2- fluoro- 4-( methylsulfinyl ) phenyl ) piperazine (6) : (S)-4-(2-fluoro- at 0 °C Add a TFA (1.3 g, 11.68 mmol) to a stirred solution of 4-(methylsulfinamido)phenyl)piperazine-1-carboxylic acid tert-butyl ester ( 4 , 800 mg, 0.292 mmol) in DCM (18 mL) ). The reaction mixture was stirred at RT for 3 h. After completion of the reaction (TLC), the reaction mixture was concentrated under reduced pressure. The salt was dissolved in MeOH and EtOAc (EtOAc) EtOAc (EtOAc: EtOAc) (M+1).

Step 5 : Synthesis of (S)-5- amino- 3-(2-(4-(2- fluoro- 4-( methylsulfinyl ) phenyl ) piperazin- 1 -yl ) ethyl )- 8-( furan -2- yl ) thiazolo [5,4-e][1,2,4] triazolo [1,5-c] pyrimidin -2(3H) -one ( Compound 120) : in a sealed Add DIPEA to a stirred solution of (S)-1-(2-fluoro-4-(methylsulfinyl)phenyl)piperazine ( 6 , 200 mg, 0.825 mmol) in DMF (10 mL). (426.7 mg, 3.302 mmol) followed by 2-(5-amino-8-(furan-2-yl)-2-yloxythiazolo[5,4-e][1,2,4] Zoxao[1,5-c]pyrimidin-3(2H)-yl)ethylmethanesulfonate (294 mg, 0.743 mmol) and stirred at 120 ° C for 16 h. After completion (TLC & LCMS), the solvent was removed under reduced pressure. The reaction mass was quenched with water and extracted with ethyl acetate. The organic layer was washed with saturated saline solution, dried over anhydrous Na ₂ SO _4, filtered and concentrated under reduced pressure. The crude material was purified by EtOAc EtOAcqqqqqqqQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQ Value: 543.2 (M+1); ¹ H-NMR (400 MHz, DMSO-d6): δ 8.30 (brs, 2H), 7.95 (m, 1H), 7.48-7.39 (m, 2H), 7.24 (d, J = 3.60 Hz, 1H), 7.15 (t, J = 8.40 Hz, 1H), 6.74-6.73 (m, 1H), 4.09 (m, 2H), 3.04 (m, 4H), 2.72 (s, 3H), 2.67 (m, 4H).

Instance 119 : (S)-5- Amine -3-(2-(4-(2- fluorine -4-( Methylsulfinyl ) Phenyl ) Piperazine -1- base ) Ethyl )-8-( Furan -2- base ) Thiazol [5,4-e][1,2,4] Triazole [1,5-c] Pyrimidine -2(3H)- ketone

step 1 :synthesis (R)-1-(2- fluorine -4-( Methylsulfinyl ) Phenyl ) Piperazine (7) :

(R)-4-(2-Fluoro-4-(methylsulfinylidene)phenyl)piperazine-1-carboxylic acid tert-butyl ester ( 5 , 800 mg, 0.292 mmol) in DCM at 0 °C TFA (1.3 g, 11.68 mmol) was added to the stirred solution in (18 mL). The reaction mixture was stirred at RT for 3 h. After completion of the reaction (TLC), the reaction mixture was concentrated under reduced pressure. The salt was dissolved in MeOH and EtOAc (EtOAc) EtOAc (EtOAc: EtOAc) (M+1).

Step 2 : Synthesis of (R)-5- amino- 3-(2-(4-(2- fluoro- 4-( methylsulfinyl ) phenyl ) piperazin- 1 -yl ) ethyl )- 8-( Furan -2- yl ) thiazolo [5,4-e][1,2,4] triazolo [1,5-c] pyrimidin -2(3H) -one ( Compound 119) : in a sealed Add DIPEA to a stirred solution of (R)-1-(2-fluoro-4-(methylsulfinyl)phenyl)piperazine (7, 200 mg, 0.825 mmol) in DMF (10 mL) 426.7 mg, 3.302 mmol) followed by 2-(5-amino-8-(furan-2-yl)-2-yloxythiazolo[5,4-e][1,2,4]triazole [1,5-c]pyrimidin-3(2H)-yl)ethylmethanesulfonate (294 mg, 0.743 mmol) was stirred at 120 ° C for 16 h. After completion (TLC & LCMS), the solvent was removed under reduced pressure. The reaction mass was treated with water and extracted with ethyl acetate. The organic layer was washed with saturated saline solution, dried over anhydrous Na ₂ SO _4, filtered and concentrated under reduced pressure. The crude material was purified by EtOAc EtOAcqqqqqqqQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQ Value: 541.0 (M-1); ¹ H-NMR (400 MHz, DMSO-d6): δ 8.32 (brs, 2H), 7.96 (s, 1H), 7.49-7.40 (m, 2H), 7.25 (d, J = 3.16 Hz, 1H), 7.16 (t, J = 8.52 Hz, 1H), 6.74-6.73 (m, 1H), 4.09 (m, 2H), 3.04 (m, 4H), 2.76-2.66 (m, 9H ). Examples 121 and 122 : 5- Amino- 3-(2-(4-(2- fluoro -4-((1s,4s)-1 -oxo -tetrahydro -2H- thiopyran- 4 -yl ) oxy ) yl) phenyl) piperazin-1-yl) ethyl) -8- (furan-2-yl) thiazolo [5,4-e] [1,2,4] triazolo [1,5-c ] pyrimidin -2 (3H) - one and 5-amino-3- (2- (4- (2-fluoro -4 - (((1r, 4r ) -1- oxido tetrahydro-thiopyran -2H- - 4- yl ) oxy ) phenyl ) piperazin- 1 -yl ) ethyl )-8-( furan -2- yl ) thiazolo [5,4-e][1,2,4] triazolo [ 1,5-c] pyrimidine -2(3H) -one

Step 1 : Synthesis of tetrahydro -2H- thiopyran- 4- ol (11) : slowly added to an ice-cold solution of tetrahydrothiopyran-4-one (10, 5 g, 0.043 mol) in methanol (40 mL) 5N sodium hydroxide solution (10 mL). Sodium borohydride (0.488 g, 0.013 mol) was then added portionwise. After the addition, the reaction mixture was allowed to reach room temperature. After completion of the reaction (about 1 h), the reaction mixture was poured into water and extracted with dichloromethane. The combined organic layers were washed with a saturated saline solution, dried over anhydrous Na ₂ SO _4, and concentrated under reduced pressure. The crude product was purified by column chromatography using EtOAc EtOAc EtOAc 1H-NMR (400 MHz, DMSO-d6): δ 4.69 (d, J = 4.24 Hz, 1H), 3.41-3.47 (m, 1H), 2.65-2.70 (m, 2H), 2.50-2.54 (m, 1H) ), 2.47 (d, J = 2.76 Hz, 1H), 2.00-2.02 (m, 2H), and 1.96-1.99 (m, 2H).

Step 2 : Synthesis of tetrahydro -2H- thiopyran- 4 -ylmethanesulfonate (12) : to tetrahydrothiopyran-4-ol ( 11 , 3.5 g, 0.030 mol) in dichloromethane (40 mL) The ice-cold solution was added with triethylamine (5.982 g, 0.059 mol) and methanesulfonyl chloride (0.727 g, 0.006 mol). After 3 h, the reaction mixture was poured into water and extracted with dichloromethane. The combined organic layers were washed with a saturated saline solution, dried over anhydrous Na ₂ SO _4, and concentrated under reduced pressure. The crude residue was subjected to column chromatography using 2% methanol in DCM to elute to afford product (6 g, 98.07%).

Step 3 : Synthesis of 4-(2- fluoro -4-(( tetrahydro -2H- thiopyran- 4 -yl ) oxy ) phenyl ) -piperazine- 1- carboxylic acid tert- butyl ester (2) : to 4 -(2,4-Difluoro-5-hydroxyphenyl)piperazine-1-carboxylic acid tert-butyl ester ( 1 , 1.6 g, 5.399 mmol) and tetrahydrothiopyran-4-ylmethanesulfonate ( 12 , 1.272 g, 6.479 mmol) in DMF (20 mL) was added in the _{K 2 CO 3 (1.490 g,} 10.80 mmol). The resulting mixture was heated to 100 ° C for 16 h. After completion of the reaction (TLC), the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with a saturated saline solution, dried over anhydrous Na ₂ SO _4, filtered and concentrated under reduced pressure. The crude material obtained was purified by EtOAc EtOAc EtOAc (EtOAc) </RTI><RTIID=0.0></RTI><RTIID=0.0></RTI>

Step 4 : Synthesis of tert-butyl 4-(2- fluoro -4-((1- oxo-tetrahydro -2H- thiopyran- 4 -yl ) oxy ) phenyl ) piperazine- 1- carboxylate (3, 4) : to 3-(2-fluoro-4-tetrahydrothiopyran-4-yloxy-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (1.650 g, 4.161 mmol, 1 eq) in acetic acid Hydrogen peroxide (1 mL) was added dropwise to the ice-cold mixture (25 mL) and stirred at the same temperature for 1 h. After completion of the reaction (TLC), the reaction mixture was poured into 4N sodium hydroxide solution (20 mL) and extracted with ethyl acetate. The combined organic layers were washed with a saturated saline solution, dried over anhydrous Na ₂ SO _4, filtered and concentrated under reduced pressure. The crude material was purified by EtOAc EtOAc (EtOAc:EtOAc </RTI><RTIID=0.0></RTI><RTIID=0.0></RTI>

The racemic mixture (1.4 g) was subjected to palm separation by SFC (1.4 g sample dissolved in 10 mL of methanol), column-YMC Amylose-SA mobile phase: 70:30 (A:B), A = liquid CO ₂ , B = 0.5% DEA in methanol, flow rate: 3 mL/min; wavelength: 210 nm. The yield is 600 mg peak 1 ( 3 ) and 500 mg peak 2 ( 4 ).

Step 5 : Synthesis of (1s, 4s)-4-(3- fluoro- 4-( piperazin- 1 -yl ) phenoxy ) tetrahydro -2H- thiopyran 1- oxide (5) : to 4-( 2-fluoro-4-(((1s,4s)-1-oxo-tetrahydro-2H-thiopyran-4-yl)oxy)phenyl)-piperazine-1-carboxylic acid tert-butyl ester ( 3 , 0.5 g, 1.212 mmol) of ice-cold solution in dichloromethane (10 mL) was added trifluoroacetic acid (0.207 g, 0.002 mol). After stirring at 0 ° C for 1 h, the reaction mixture was concentrated under reduced vacuo. The residue obtained was triturated with diethyl ether. It was then dissolved in methanol and passed through a Si-carbonate resin to give a free base (0.38 g, 99.35%) which was used directly in the next step. 1H-NMR (400 MHz, DMSO-d6): δ 7.02 (d, J = 9.20 Hz, 1H), 6.90-6.98 (m, 1H), 6.76-6.79 (m, 1H), 4.40-4.43 (m, 1H) ), 3.18 (s, 1H), 3.05 (t, J = 2.40 Hz, 4H), 2.93-2.99 (m, 4H), 2.85 (t, J = 11.20 Hz, 1H), 2.79 (d, J = 2.40 Hz) , 2H), 2.12 (t, J = 10.00 Hz, 2H), and 1.96 (d, J = 12.40 Hz, 2H).

Step 6 : Synthesis of 5- amino- 3-(2-(4-(2- fluoro -4-((1s,4s)-1 -oxo-tetrahydro -2H- thiopyran- 4 -yl ) oxy ) ) phenyl) piperazin-1-yl) ethyl) -8- (furan-2-yl) thiazolo [5,4-e] [1,2,4] - triazolo - [1,5-c ] pyrimidin -2 (3H) - one (compound 121): to a solution of 2- (5-amino-8- (furan-2-yl) -2-oxo-thiazolo [5,4-e] [1, 2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethylmethanesulfonate (7, 0.385 g, 0.971 mmol) and (1s, 4s)-4-(3- Add DIPEA (0.626 g, 4.856) to a mixture of fluoro-4-(piperazin-1-yl)phenoxy)tetrahydro-2H-thiopyran 1-oxide (0.334 g, 1.068 mmol) in DMF (4 mL) Mm). The reaction mixture was stirred at 90 ° C for 16 h. After completion, the reaction mixture was diluted with water (10 mL) andEtOAc. The combined organic layers were washed with a saturated saline solution, dried over anhydrous Na ₂ SO _4, filtered, and concentrated. The crude product was purified by EtOAc EtOAc (EtOAc) </RTI><RTIID=0.0></RTI></RTI><RTIID=0.0> HPLC purity (XB_0595TF): 99.21%. 1H-NMR (400 MHz, DMSO-d6): δ 8.31 (brs, 2H), 7.95 (s, 1H), 7.24 (d, J = 3.20 Hz, 1H), 6.88-6.93 (m, 2H), 6.73- 6.77 (m, 2H), 4.59 (s, 1H), 4.08 (t, J = 5.60 Hz, 2H), 3.50 (d, J = 12.80 Hz, 2H), 2.86-2.95 (m, 6H), 2.63-2.71 (m, 6H), 2.27-2.33 (m, 2H) and 1.80-1.83 (m, 2H). Example 122 : 5- amino- 3-(2-(4-(2- fluoro -4-((1r,4r)-1 -oxo-tetrahydro -2H- thiopyran- 4 -yl ) oxy ) Phenyl ) piperazin- 1 -yl ) ethyl )-8-( furan -2- yl ) thiazolo [5,4-e][1,2,4] triazolo [1,5-c] pyrimidine -2(3H) -ketone

Step 5 : Synthesis of (1r,4r)-4-(3- fluoro- 4-( piperazin- 1 -yl ) phenoxy ) tetrahydro -2H- thiopyran 1- oxide (6) : to 4-( 2-Fluoro-4-(((1r, 4r)-1-oxo-tetrahydro-2H-thiopyran-4-yl)oxy)phenyl)-piperazine-1-carboxylic acid tert-butyl ester (4, 0.5 g, 1.212 mmol) of ice-cold solution in dichloromethane (10 mL) was added trifluoroacetic acid (0.207 g, 0.002 mol). After stirring at 0 ° C for 1 h, the reaction mixture was concentrated under reduced vacuo. The residue obtained was triturated with diethyl ether. It was then dissolved in methanol and passed through a Si-carbonate resin to give a free base (0.375 g, 98.05%) which was used directly in the next step. 1H-NMR (400 MHz, DMSO-d6): δ 7.02 (d, J = 9.20 Hz, 1H), 6.90-6.98 (m, 1H), 6.76-6.79 (m, 1H), 4.40-4.43 (m, 1H) ), 3.18 (s, 1H), 3.05 (t, J = 2.40 Hz, 4H), 2.93-2.99 (m, 4H), 2.85 (t, J = 11.20 Hz, 1H), 2.79 (d, J = 2.40 Hz) , 2H), 2.12 (t, J = 10.00 Hz, 2H), and 1.96 (d, J = 12.40 Hz, 2H).

Step 6 : Synthesis of 5- amino- 3-(2-(4-(2- fluoro -4-((1r,4r)-1 -oxo-tetrahydro -2H- thiopyran- 4 -yl ) oxy ) ) phenyl) piperazin-1-yl) ethyl) -8- (furan-2-yl) thiazolo [5,4-e] [1,2,4] - triazolo [1,5-c ] pyrimidin -2 (3H) - one (compound 122): to a solution of 2- (5-amino-8- (furan-2-yl) -2-oxo-thiazolo [5,4-e] [1, 2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethylmethanesulfonate ( 7 , 0.235 g, 0.593 mmol) and (1s, 4s)-4-(3- Add DIPEA (0.382 g, 2.964) to a mixture of fluoro-4-(piperazin-1-yl)phenoxy)tetrahydro-2H-thiopyran 1-oxide (0.204 g, 0.652 mmol) in DMF (2 mL) Mm). The reaction mixture was stirred at 90 ° C for 16 h. After completion, the reaction mixture was diluted with water (10 mL) andEtOAc. The combined organic layers were washed with a saturated saline solution, dried over anhydrous Na ₂ SO _4, filtered, and concentrated. The crude product was purified by EtOAc EtOAc (EtOAc) </RTI><RTIID=0.0></RTI></RTI><RTIID=0.0> HPLC purity (XB_0595TF): 98.46%. 1H-NMR (400 MHz, DMSO-d6): δ 8.31 (brs, 2H), 7.95 (s, 1H), 7.24 (d, J = 3.20 Hz, 1H), 6.88-6.93 (m, 2H), 6.73- 6.77 (m, 2H), 4.39 (t, J = 9.20 Hz, 1H), 4.08 (t, J = 6.00 Hz, 2H), 3.50 (d, J = 12.40 Hz, 2H), 2.72-2.95 (m, 6H) ), 2.63-2.70 (m, 6H), 2.13-2.33 (m, 2H) and 1.85-1.99 (m, 2H). Example 126 : 5- Amino- 3-(2-(4-(2- fluoro- 4-(1- oxo -hydroxymorpholinyl ) phenyl ) piperazin- 1 -yl ) ethyl )-8- ( furan -2- yl ) thiazolo [5,4-e][1,2,4] triazolo [1,5-c] pyrimidin -2(3H) -one

Step 1 : Synthesis of 4- bromo -2- fluoroaniline (2) : to 4-bromo-2-fluoro-1-nitrobenzene ( 1 , 9.0 g, 13.64 mmol) and acetic acid (11.5 g, 0.57 mol) in ethanol Iron powder (15.9 g, 0.285 mol) was added to the stirred solution in (60 mL). The reaction mixture was stirred at 80 ° C for 1 h. After the reaction was completed, the reaction mixture was diluted with EtOAc and filtered thru. The filtrate was concentrated under reduced pressure to dryness crystals crystals crystalsssssssssssssssssssssssssssssssssss .

Step 2 : Synthesis of 1-(4- bromo -2- fluorophenyl ) piperazine (3) : to 4-bromo-2-fluoroaniline ( 2 , 6.0 g, 31.58 mmol) in di-glyme (4.8 mL) The stirred solution was added bis(2-chloroethyl)amine hydrochloride (6.7 g, 37.89 mmol) and the mixture was stirred at 160 ° C for 16 h. After completion of the reaction (TLC), the reaction mixture was cooled to RT and treated with cold acetone. The precipitated solid was filtered and used directly to the next step (5,5 g, 61%);

Step 3 : Synthesis of tert-butyl 4-(4- bromo -2- fluorophenyl ) piperazine- 1- carboxylate (4) : 1-(4-bromo-2-fluorophenyl)piperidin at 0 ° C To a stirred solution of EtOAc ( 3 , 4.0 g, 15.4 mmol) The reaction mixture was stirred at RT for 2 h. After completion of the reaction (TLC), the reaction mixture was treated with water and extracted with DCM. The separated organic layer was washed with NaHCO ₃ solution, brine solution, dried over anhydrous Na ₂ SO ₄ dried, and concentrated under reduced pressure to give the crude product. The crude product was purified by EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj

Step 4 : Synthesis of tert-butyl 4-(2- fluoro- 4- thiomorpholinophenyl ) piperazine- 1- carboxylate (5) : 4-(4-bromo-2-fluoro ) in a sealed tube XPhos (530 mg, phenyl) piperazine-1-carboxylic acid tert-butyl ester ( 4 , 4.0 g, 11.1 mmol) and thiomorpholine (1.3 g, 12.3 mmol) in toluene (30 mL) 1.11 mmol) followed by NaO ^t Bu (2.34 g, 24.4 mmol). The reaction mixture was flushed and the use of N ₂ gas was added _{Pd (OAc) 2 (250 mg} , 1.11 mmol). The reaction mixture was heated at 110 ° C for 16 h. After completion of the reaction (TLC), the reaction mixture was treated with water and extracted with ethyl acetate. The separated organic layer was washed with NaHCO ₃ solution, brine solution, dried over anhydrous Na ₂ SO ₄ dried, and concentrated under reduced pressure to give the crude product. The crude product was purified by EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj

Step 5 : Synthesis of tert-butyl 4-(2- fluoro- 4- thiomorpholinophenyl ) piperazine- 1- carboxylate (6) : 4-(2-fluoro-4-sulfuric acid at 0 ° C Hydrogen peroxide (160.48 mg, 4.7 mmol) was added to a stirred solution of dimorpholinyl phenyl)piperazine-1-carboxylic acid tert-butyl ester ( 5 , 1.8 g, 4.7 mmol) in acetic acid (20 mL). The reaction mixture was stirred at RT for 16 h. After completion of the reaction (TLC), the reaction mixture was treated with a 10% NaOH solution (aq.) and extracted with DCM. The separated organic layer was washed with NaHCO ₃ solution, brine solution, dried over anhydrous Na ₂ SO ₄ dried, and concentrated under reduced pressure to give the crude product. The crude product was purified by EtOAc EtOAcjjjjjjj

Step 6 : Synthesis of 4-(3- fluoro- 4-( piperazin- 1 -yl ) phenyl ) thiomorpholine 1- oxide (7) : 4-(2-fluoro-4- ) at 0 °C Add a TFA (330 mg, 9.0) to a stirred solution of (1-oxo-bromomorpholino)phenyl)piperazine-1-carboxylic acid tert-butyl ester ( 6 , 1.2 g, 3.0 mmol) in DCM (15 mL) Mm). The reaction mixture was stirred at room temperature for 2 h. After completion of the reaction (TLC), the reaction mixture was concentrated under reduced pressure. The residue was dissolved in MeOH (EtOAc) EtOAc (EtOAc) (EtOAc) 1).

Step 7 : Synthesis of 5- amino- 3-(2-(4-(2- fluoro- 4-(1- oxo -hydroxymorpholinyl ) phenyl ) -piperazin- 1 -yl ) ethyl )- 8-( furan -2- yl ) thiazolo [5,4-e][1,2,4] triazolo [1,5-c] pyrimidin -2(3H) -one ( Compound 126) : to 1 2-(5-Amino group) was added to a stirred solution of (3-fluoro-4-(piperazin-1-yl)phenyl)piperidin-4-one (350 mg, 1.26 mmol) in DMF (5 mL) 8-(-furan-2-yl)-2-yloxythiazolo[4,5-e][1,2,4]triazolo[1,5-c]pyrimidin-1(2H)-yl Ethyl methanesulfonate (500 mg, 1.26 mmol) and DIPEA (815 mg, 6.31 mmol). The reaction mixture was stirred at 120 ° C for 16 h. After completion, the reaction mass is concentrated under reduced pressure and recrystallized from acetonitrile and diethyl ether to give pure 5-amino-3-(2-(4-(2-fluoro-4-(1-oxy bridge thio)? Phenyl)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]-triazolo[1,5 -c]pyrimidine-2(3H)-one ( Compound 126 ) (150 mg, 19%); HPLC purity (XB0595TF): 95.08%; LCMS (ESI ESI) m/z: Calculated: 597.17; 598.2 (M+1); ¹ H-NMR (400 MHz, DMSO-d6): δ 8.31 (brs, 2H), 7.95 (s, 1H), 7.24 (d, J = 3.2 Hz, 1H), 6.92-6.85 (m, 2H), 6.73-6.71 (m, 2H), 4.08-4.05 (m, 2H), 3.70-3.66 (m, 2H), 3.53-3.50 (m, 2H), 2.93-2.86 (m, 7H) , 2.74-2.63 (m, 7H). Example 127 : (S)-5- Amino- 3-(2-(4-(5-(2,3 -dihydroxypropoxy )-2,4 -difluorophenyl ) piperazin- 1 -yl ) ethyl) -8- (furan-2-yl) thiazolo [5,4-e] [1,2,4] triazolo [1,5-c] pyrimidin -2 (3H) - one

Step 1 : Synthesis of (S)-(2,2 -dimethyl- 1,3- dioxolan- 4 -yl ) methylmethanesulfonate (7) : (R)- at 0 °C Triethylamine (9.6 g, 95) was added to a stirred solution of 2,2-dimethyl-1,3-dioxolan-4-yl)methanol (6, 2.5 g, 19 mmol) in DCM (30 mL) Methyl) and methanesulfonyl chloride (4.33 g, 38 mmol). The reaction mixture was stirred at 0 °C for 3 h. The reaction was monitored by TLC and after completion, the reaction mixture was diluted with water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO _4, filtered and then concentrated under reduced pressure to give the title material as a yellow gum mucus of compound (3.0 g, 75.4%); 1 H-NMR (400 MHz, CDCl 3) : δ 4.39-4.43 (m, 1H), 4.25 (d, J = 5.20 Hz, 2H), 4.11-4.15 (m, 1H), 3.84-3.87 (m, 1H), 3.09-3.15 (m, 3H), 1.45 (s, 3H), 1.43 (s, 3H).

Step 2 : Synthesis of (R)-4-(5-((2,2 -dimethyl- 1,3- dioxolan- 4 -yl ) methoxy )-2,4 -difluorophenyl ) Benzyl piperazine- 1- carboxylate (2) : Benzyl 4-(2,4-difluoro-5-hydroxyphenyl)piperazine-1-carboxylate ( 1 , 1 g, 2.9 mmol) and (S) Adding carbonic acid to a stirred solution of (2,2-dimethyl-1,3-dioxolan-4-yl)methylmethanesulfonate ( 7 , 1.15 g, 5.8 mmol) in DMF (20 mL) Potassium (1.19 g, 8.7 mmol) and the reaction mixture was heated to 90 ° C for 16 h. The progress of the reaction was monitored by TLC. After completion, the reaction mass was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO _4, filtered and then concentrated under reduced pressure. The crude material was purified by column chromatography (30% EtOAc / hexane) to afford (R)-4-(5-((2,2- dimethyl- 1,3-) Benzyl oxol-4-yl)methoxy)-2,4-difluorophenyl)piperazine-1-carboxylate ( 2 ) (800 mg, 56.8%); LCMS (ESI cation) m/z : Calculated: 462.20; observed: 463.0 (M+1).

Step 3 : Synthesis of (R)-1-(5-((2,2 -dimethyl- 1,3- dioxolan- 4 -yl ) methoxy )-2,4 -difluoro - phenyl ) piperazine (3): to (R) -4- (5 under a nitrogen atmosphere - ((2,2-dimethyl-1,3-dioxolan-4-yl) methoxy) -2 Add a 10% Pd/C (0.2 g) to a stirred solution of benzyl 4-(difluorophenyl)piperazine-l-carboxylate ( 2 , 0.8 g, 1.73 mmol) in EtOAc (20 mL). The reaction mixture was stirred for 16 h under an atmosphere of H _2. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was filtered using diatomaceous earth to remove Pd/C. The combined organic layer was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to give a brown gum substances (R) -1- (5 - ( (2,2- dimethyl-1,3-dioxolane 4-yl)methoxy)-2,4-difluorophenyl)piperazine ( 3 ) (0.45 g, 76.2%); LCMS (ESI ESI) m/z: Calculated: 328.16; 329.1 (M+1).

Step 4 : Synthesis of (R)-5- amino- 3-(2-(4-(5-((2,2 -dimethyl- 1,3- dioxolan- 4 -yl ) methoxy) ) -2,4-difluorophenyl) piperazin-1-yl) ethyl) -8- (furan-2-yl) thiazolo [5,4-e] [1,2,4] triazolo [1,5-c] pyrimidine -2(3H) -one (4) : to (R)-1-(5-((2,2-dimethyl-1,3-dioxolan-4- Methoxy)-2,4-difluorophenyl)piperazine (3, 0.45 g, 1.4 mmol) and 2-(5-amino-8-(furan-2-yl)-2-sideoxy Thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethylmethanesulfonate (0.48 g, 1.2 mmol) DIPEA (0.71 g, 5.5 mmol) was added to a stirred solution of EtOAc (EtOAc)EtOAc. After the reaction was completed (TLC & LCMS), the solvent was removed under reduced pressure. The reaction mass was treated with water and extracted with ethyl acetate. The organic layer was washed with saturated saline solution, dried over anhydrous Na ₂ SO _4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (14-16% MeOH / DCM) eluting with 50% ACN / diethyl ether mixture to afford (R)-5-amine as pale yellow solid. 3-(4-(5-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-2,4-difluorophenyl) Piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidine-2 ( 3H)-keto compound (4) (100 g, 13.1%); LCMS (ESI ESI) m/z: calc.

Step 5 : Synthesis of (S)-5- amino- 3-(2-(4-(5-(2,3 -dihydroxypropoxy )-2,4 -difluorophenyl ) -piperazine- 1 - yl) ethyl) -8- (furan-2-yl) thiazolo [5,4-e] [1,2,4] triazolo [1,5-c] pyrimidin -2 (3H) - one ( Compound 127) : (R)-5-Amino-3-(2-(4-(5-((2,2-dimethyl-)-1,3-dioxolan-4 ) at 0 °C -yl)methoxy)-2,4-difluorophenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2 , 4] Trioxo[1,5-c]pyrimidin-2(3H)-one ( 4 , 50 mg, 0.08 mmol) in 1,4-dioxane (4 mL) 4 N HCl (20 mL). The reaction mixture was stirred at room temperature for 1 h. The progress of the reaction was monitored by TLC. After the reaction was completed, it was concentrated under reduced pressure to remove solvent. The crude product was recrystallized from acetonitrile to give (S)-5-amino-3-(2-(4-(5-(2)3-dihydroxypropoxy)-2,4- as a light brown solid. Difluorophenyl) piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c Pyrimidine-2(3H)-one ( Compound 127 ) (35 mg, 67.3%); HPLC purity (XB0595TF): 92.58%; LCMS (ESI ESI) m/z: Calculated: 588.17; M+1); ¹ H-NMR (400 MHz, DMSO-d6): δ 9.67 (brs, 1H), 8.42 (brs, 2H), 7.97 (s, 1H), 7.35-7.26 (m, 2H), 6.86 (t, J = 8.40 Hz, 1H), 6.75-6.74 (m, 1H), 4.31 (m, 2H), 4.09-4.05 (m, 1H), 3.97-3.92 (m, 3H), 3.77 (t, J = 5.20 Hz, 1H), 3.43 (m, 2H), 3.29 (m, 2H), 3.06-2.99 (m, 2H). Example 128 : (R)-5- Amino- 3-(2-(4-(5-(2,3 -dihydroxypropoxy )-2,4 -difluorophenyl ) piperazin- 1 -yl ) ethyl) -8- (furan-2-yl) thiazolo [5,4-e] [1,2,4] triazolo [1,5-c] pyrimidin -2 (3H) - one

Step 1: Synthesis of 5-amino-2,4-difluoro-phenol (2): To a solution of 2,4-difluoro-5-nitrophenol (1, 25 g, 0.143 mol ) in in EtOAc (200 mL) of The solution was added with 10% Pd/C (4.55 g, 0.043 mol). The reaction mixture was stirred at RT for 16 h under H _2. After the completion of the reaction (TLC), the reaction mixture was purified eluting with EtOAc EtOAc (EtOAc) (2) (20.10 g, 94.6%); LCMS (ESI ESI) m/z: calc.

Step 2 : Synthesis of 2,4 -difluoro -5-( piperazin- 1 -yl ) phenol (3) : to 5-amino-2,4-difluorophenol ( 2 , 20 g, 0.131 mol) in the ring To the stirred solution of butyl hydrazine (30 mL) was added bis(2-chloroethyl)amine hydrochloride (31 g, 0.170 mol). The resulting mixture was stirred at 150 ° C under a nitrogen atmosphere for 16 h. It was cooled to RT and acetone was added to the crude reaction mixture and stirred at 0 ° C for 1 h. After 1 h, the precipitated solid was filtered and washed with cold acetone under a nitrogen atmosphere. The solid material was dried in vacuo to give 2,4-difluoro-5-(piperazin-1-yl)phenol ( 3 ) (23 g, 80.3%) as an off-white solid; LCMS (ESI ESI) m/z: Calculated: 214.09; observed: 215.1 (M+1).

Step 3 : Synthesis of benzyl 4-(2,4 -difluoro -5- hydroxyphenyl ) piperazine- 1- carboxylate (4) : 2,4-difluoro-5-(piperazine ) at 0 °C NaHCO ₃ (14.7 g, 0.175 mol) and Cbz-Cl (16.66 mL, 0.117 mol) were added to a stirred solution of 1-phenyl) phenol hydrochloride (3, 25 g, 0.117 mol) in THF (250 mL). The reaction mixture was stirred at RT for 16 h. The progress of the reaction was monitored by TLC. The reaction mixture was extracted with ethyl acetate and the combined organic layers were washed with brine, ₂ SO ₄ and then concentrated under reduced pressure and dried over anhydrous Na. The crude material obtained was purified by column chromatography (30% EtOAc / hexanes) to afford 4-(2,4-difluoro-5-hydroxyphenyl)piperazine as a white solid. Benzyl 1-carboxylate (20 g, 45.8%); mp.

Step 4 : Synthesis of (R)-(2,2 -dimethyl- 1,3- dioxolan- 4 -yl ) methylmethanesulfonate (10) : (S)- at 0 °C Triethylamine (37.76 mL, 0.272) was added to a stirred solution of 2,2-dimethyl-1,3-dioxolan-4-yl)methanol ( 9 , 12 g, 0.091 mol) in DCM (100 mL) Mol) and methane sulfonium chloride (8.4 mL, 0.109 mol). The reaction mixture was stirred at 0 °C for 3 h. The reaction was monitored by TLC and after completion, the reaction mixture was diluted with water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO _4, filtered and then concentrated under reduced pressure to give the title material as a yellow gum mucus of compound (21.8 g, 77.8%); LCMS (ESI pos. Ion) m / z: Calculation Value: 210.06; observed: 211.0 (M+1).

Step 5: Synthesis of (S) -4- (5 - -2,4- difluorophenyl ((2,2-dimethyl-1,3-dioxolan-4-yl) methoxy)) Benzyl piperazine- 1- carboxylate (5) : Benzyl 4-(2,4-difluoro-5-hydroxyphenyl)piperazine-1-carboxylate ( 4 , 10 g, 0.029 mmol) and (R) Adding carbonic acid to a stirred solution of (2,2-dimethyl-1,3-dioxolan-4-yl)methylmethanesulfonate ( 10 , 7.2 g, 0.034 mol) in DMF (70 mL) Potassium (11.9 g, 0.086 mol), and the reaction mixture was heated to 90 ° C for 16 h. The progress of the reaction was monitored by TLC. After completion, the reaction mass was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO _4, filtered and then concentrated under reduced pressure. The crude material was purified by column chromatography (30% EtOAc / hexanes) to afford (S)-4-(5-((2,2- dimethyl- 1,3-) Benzyloxypenta-4-yl)methoxy)-2,4-difluorophenyl)piperazine-1-carboxylate (5) (13 g, 70.50%); LCMS (ESI ESI) m/z : Calculated: 462.20; observed: 463.1 (M+1).

Step 6 : Synthesis of (S)-1-(5-((2,2 -dimethyl- 1,3- dioxolan- 4 -yl ) methoxy )-2,4 -difluoro - phenyl ) piperazine (6): to (S) -4- (5 under a nitrogen atmosphere - ((2,2-dimethyl-1,3-dioxolan-4-yl) methoxy) -2 Add a 10% Pd/C (4 g) to a stirred solution of benzyl 4-(difluorophenyl)piperazine-l-carboxylate ( 5 , 13 g, 0.028 mol) in EtOAc (100 mL). The reaction mixture was stirred for 16 h under an atmosphere of H _2. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was filtered using diatomaceous earth to remove Pd/C. The combined organic layers were dried over anhydrous Na.sub.2SO.sub.sub.sub.sub.sub.sub.sub.sub.sub.sub.sub. Methoxy)-2,4-difluorophenyl)piperazine ( 6 ) (8.55 g, 93.0%); LCMS (ESI ESI) m/z: Calculated: 328.16; +1).

Step 7 : Synthesis of (S)-5- amino- 3-(2-(4-(5-((2,2 -dimethyl- 1,3- dioxolan- 4 -yl ) methoxy) -2,4 -difluorophenyl ) piperazin- 1 -yl ) ethyl )-8-( furan -2- yl ) thiazolo [5,4-e][1,2,4] triazolo [1,5-c] pyrimidine -2(3H) -one (7) : to (S)-1-(5-((2,2-dimethyl-1,3-dioxolan-4- yl) methoxy) -2,4-difluorophenyl) piperazine (6, 7 g, 0.021 mol ) and 2- (5-amino-8- (furan-2-yl) -2-oxo Thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethylmethanesulfonate (7.6 g, 0.019 mol) DIPEA (11.12 mL, 0.064 mol) was added to a stirred solution of N,N-dimethylformamide (50 mL) and the mixture was stirred at 120 ° C for 16 h. After the reaction was completed (TLC & LCMS), the solvent was removed under reduced pressure. The reaction mass was treated with water and extracted with ethyl acetate. The organic layer was washed with saturated saline solution, dried over anhydrous Na ₂ SO _4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (14-16% MeOH / DCM) eluting with 50% ACN / diethyl ether mixture to afford (S)-5-amine as pale yellow solid. 3-(4-(5-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-2,4-difluorophenyl) Piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidine-2 ( 3H)-keto compound ( 7 ) (2.6 g, 17.8%); LCMS (ESI ESI) m/z: calc.

Step 8 : Synthesis of (R)-5- amino- 3-(2-(4-(5-(2,3 -dihydroxypropoxy )-2,4 -difluorophenyl ) -piperazine- 1 - yl) ethyl) -8- (furan-2-yl) thiazolo [5,4-e] [1,2,4] triazolo [1,5-c] pyrimidin -2 (3H) - one ( Compound 128) : (S)-5-Amino-3-(2-(4-(5-((2,2-dimethyl-1,3-dioxolan-4 )) at 0 °C -yl)methoxy)-2,4-difluorophenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2 , 4] Triazolo[1,5-c]pyrimidin-2(3H)-one ( 7 , 1.4 g, 2.23 mmol) in dioxane in 1,4-dioxane (20 mL) 4 N HCl (20 mL). The reaction mixture was stirred at room temperature for 1 h. The progress of the reaction was monitored by TLC. After the reaction was completed, it was concentrated under reduced pressure to remove solvent. The crude product was recrystallized from acetonitrile to give (R)-5-amino-3-(2-(4-(5-(2,3-dihydroxypropyloxy)-2,4-di) as a white solid. Fluorophenyl) piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c] Pyrimidine-2(3H)-one ( Compound 128 ) (1.2 g, 87%); HPLC purity (AM9010A3): 95.05%; LCMS (ESI ESI) m/z: Calculated: 588.17; +1); ¹ H-NMR (400 MHz, DMSO-d6): δ 10.34 (brs, 1H), 8.40 (brs, 2H), 7.95 (s, 1H), 7.33-7.24 (m, 2H), 6.87- 6.82 (m, 1H), 6.73 (s, 1H), 4.31 (m, 2H), 4.08-4.05 (m, 1H), 3.96-3.91 (m, 3H), 3.76 (m, 1H), 3.59 (m, 2H), 3.51-3.48 (m, 2H), 3.42-3.38 (m, 2H), 3.29-3.27 (m, 2H), 3.14-3.08 (m, 2H).

The following examples were prepared according to procedures similar to those described for the examples above:

Example 9 : 5- Amino -8-( furan -2- yl )-3-(2-(4-(4-(2- hydroxyethoxy ) phenyl ) piperazin- 1 -yl ) ethyl ) Thiazolo [5,4-e][1,2,4] triazolo [1,5-c] pyrimidine -2(3H) -one . LCMS (ESI ESI) m/z: calc. Observed: 523.2 (M+1); HPLC purity (XB0595TF): 97.0%; ¹ H NMR (400 MHz, CD ₃ OD): δ 7.79 (s, 1H), 7.28 (d, J = 3.2 Hz, 1H) , 7.01 (d, J = 8.1 Hz, 2H), 6.93 (d, J = 9.2 Hz, 2H), 6.69 (dd, J = 1.6 & 3.2 Hz, 1H), 4.49 (m, 2H), 4.01 (t, J = 4.4 Hz, 2H), 3.86 (t, J = 4.4 Hz, 2H), 3.67 (m, 4H).

Example 10 : 2-(4-(4-(2-(5- Amino -8-( furan -2- yl )-2 - yloxythiazolo[5,4-e][1,2,4 .] triazolo [1,5-c] pyrimidine -3 (2H) - yl) ethyl) piperazin-1-yl) phenoxy) acetic acid hydrochloride LCMS (ESI pos. ion) m / z: calculation Value: 536.16; observed: 536.8 (M + 1); HPLC purity (XB0595TF): 93.00%; ¹ H NMR (400 MHz, DMSO-d6): δ 12.92 (brs, 1H), 9.72 (brs, 1H), 8.44 (brs, 2H), 7.97 (t, J = 0.8 Hz, 1H), 7.26 (dd, J = 0.6 & 3.2 Hz, 1H), 6.96-6.94 (m, 2H), 6.88-6.84 (m, 2H) , 6.75 (dd, J = 1.6 & 3.2 Hz, 1H), 4.60 (s, 2H), 4.32 (m, 2H), 3.92-3.90 (m, 2H), 3.72-3.69 (m, 2H), 3.27-3.24 (m, 2H), 2.92 (m, 2H).

Example 11: 2- (4- (4- (2- (5-amino-8- (furan-2-yl) -2-oxo-thiazolo [5,4-e] [1,2,4 .] triazolo [1,5-c] pyrimidine -3 (2H) - yl) ethyl) piperazin-1-yl) phenoxy) acetyl amine LCMS (ESI pos. ion) m / z: Calcd. Observed: 535.8 (M+); HPLC purity (XB0595TF): 92.65%; ¹ H NMR (400 MHz, DMSO-d6): δ 8.31 (brs, 2H), 7.94 (m, 1H), 7.44 (m) , 1H), 7.36 (m, 1H), 7.23 (d, J = 3.20 Hz, 1H), 6.85 (t, J = 4.40 Hz, 4H), 6.73 (s, 1H), 4.31 (s, 2H), 4.08 (m, 1H), 2.95 (m, 4H), 2.68 (d, J = 6.00 Hz, 2H), 2.61 (m, 3H), and 2.30 (s, 2H).

Example 12 : 5- Amino- 3-(2-(4-(4-(2,3 -dihydroxypropoxy ) phenyl ) piperazin- 1 -yl ) ethyl )-8-( furan -2 - yl) thiazolo [5,4-e] [1,2,4] triazolo [1,5-c] pyrimidin -2 (3H) - one LCMS (ESI pos. ion) m / z:. Calcd. 552.19; observed: 552.8 (M+1); HPLC purity (XB0595TF): 91.20%; ¹ H NMR (400 MHz, DMSO-d6): δ 9.7 (brs, 1H), 9.0 (brs, 1H), 8.41 (brs, 2H), 7.98 (dd, J = 0.8 & 1.6 Hz, 1H), 7.27 (m, 1H), 6.87 (m, 2H), 6.76-7.68 (m, 3H), 4.39 (m, 3H), 3.28 (m, 3H), 2.85 (m, 4H).

Example 13: 5-amino-3- (2- (4- (4- (2-amino-ethoxy) phenyl) piperazin-1-yl) ethyl) -8- (furan-2-yl .) thiazolo [5,4-e] [1,2,4] triazolo [1,5-c] pyrimidin -2 (3H) - one hydrochloride LCMS (ESI pos. ion) m / z: calculation Found: 521.6; observed; 522.2 (M + 1); HPLC purity ^{(XB0595TF): 96.52%; 1} H NMR (400 MHz, DMSO-d6): δ 8.41 (brs, 2H), 8.23 (brs, 3H), 7.96 (dd, J = 2 Hz, 1H), 7.25 (d, J = 3.2 Hz, 1H), 6.99 (d, J = 9.20 Hz, 2H), 6.93 (d, J = 2.40 Hz, 2H), 6.74 ( t, J = 1.60 Hz, 1H), 4.33 (t, J = 5.60 Hz, 2H), 4.12 (t, J = 5.20 Hz, 2H), 3.88 (d, J = 10.80 Hz, 2H), 3.69 (d, J = 12.00 Hz, 2H), 3.58 (m, 2H), and 3.14-3.20 (m, 6H).

Example 14 : 4-(4-(2-(5- Amino -8-( furan -2- yl )-2 - yloxythiazolo[5,4-e][1,2,4] triazole . and [1,5-c] pyrimidine -3 (2H) - yl) ethyl) piperazin-1-yl) benzoyl amine LCMS (ESI pos. ion) m / z: calculated: 505.56; observed; 506.2 (M + 1); HPLC purity ^{(XB0595TF): 99.08%; 1} H NMR (400 MHz, DMSO-d6): δ 8.32 (brs, 2H), 7.95 (brs, 1H), 7.73 (brs, 3H), 7.24 (brs, 1H), 6.91-7.01 (m, 3H), 6.73 (brs, 1H), 4.09 (brs, 2H), 3.19 (brs, 4H), and 2.69 (brs, 6H).

Example 15 : 4-(4-(2-(5- Amino -8-( furan -2- yl )-2 - yloxythiazolo[5,4-e][1,2,4] triazole And [1,5-c] pyrimidin -3(2H) -yl ) ethyl ) piperazin- 1 -yl )-N- methylbenzamide . LCMS (ESI ESI) m / z : Calculated: 519.58; observed; 520.8 (M+1); HPLC purity (XB0595TF): 95.07%; ¹ H NMR (400 MHz, DMSO-d6): δ 8.33 (brs, 2H), 8.13 (d, J = 4.40 Hz, 1H), 7.95 (s, 1H), 7.70 (d, J = 8.60 Hz, 2H), 7.24 (d, J = 3.32 Hz, 1H), 6.91 (d, J = 8.64 Hz, 2H), 6.73 (d, J = 1.72 Hz, 1H), 4.09 (t, J = 6.16 Hz, 2H), 3.18 (m, 4H), 2.72-2.74 (m, 5H), and 2.62-2.70 (m, 4H).

Example 16: 5-amino-8- (furan-2-yl) -3- (2- (4- (4- (2-morpholino-ethoxy) phenyl) piperazin-1-yl) acetate yl) thiazolo [5,4-e] [1,2,4] triazolo [1,5-c] pyrimidin -2 (3H) - one LCMS (ESI pos. ion) m / z:. Calcd: 591.24; observed: 592.3 (M+1); HPLC purity (XB0595TF): 99.39 %; ¹ H NMR (400 MHz, DMSO-d6): δ 8.32 (brs, 2H), 7.95 (s, 1H), 7.24 ( d, J = 3.2 Hz, 1H), 6.85-6.79 (m, 4H), 6.73-6.72 (m, 1H), 4.08 (t, J = 6.0 Hz, 2H), 3.99 (t, J = 5.6 Hz, 2H ), 3.57 (t, J = 4.0 Hz, 4H), 2.94 (m, 4H), 2.71-2.62 (m, 8H), 2.46 (m, 4H).

Example 17 : 5- Amino- 3-(2-(4-(4-(2-( dimethylamino ) ethoxy ) phenyl ) piperazin- 1 -yl ) ethyl )-8- ( Furan -2- yl ) thiazolo [5,4-e][1,2,4] triazolo [1,5-c] pyrimidin -2(3H) -one . LCMS (ESI positive ion) m/z Calculated: 549.22; observed: 549.8 (M + 1); HPLC purity (XB0595TF): 92.54%; ¹ H NMR (400 MHz, DMSO-d6): δ 8.31 (brs, 2H), 7.95 (s, 1H) ), 7.24 (d, J = 2.8 Hz, 1H), 6.85-6.79 (m, 4H), 6.73 (m, 1H), 4.08 (t, J = 6.00 Hz, 2H), 3.95 (t, J = 6.0 Hz) , 2H), 2.94 (m, 4H), 2.69 (m, 2H), 2.61 (m, 4H), 2.56 (t, J = 6.0 Hz, 2H), 2.19 (s, 6H).

Example 18 : 4-(4-(2-(5- Amino -8-( furan -2- yl )-2 - yloxythiazolo[5,4-e][1,2,4] triazole And [1,5-c] pyrimidin -3(2H) -yl ) ethyl ) piperazin- 1 -yl ) benzenesulfonamide . LCMS (ESI ESI) m/z: Calculated: 541. 542.2 (M + 1); HPLC purity ^{(XB0595TF): 90.64%; 1} H NMR (400 MHz, DMSO-d6): δ 8.31 (brs, 2H), 7.94 (d, J = 0.40 Hz, 1H), 7.60 ( d, J = 8.4 Hz, 2H), 7.23 (d, J = 3.6 Hz, 1H), 7.07-6.98 (m, 4H), 6.72 (m, 1H), 4.08 (m, 2H), 3.20 (m, 4H) ), 2.70-2.61 (m, 6H).

Example 19 : 4-(4-(2-(5- Amino -8-( furan -2- yl )-2 - yloxythiazolo[5,4-e][1,2,4] triazole And [1,5-c] pyrimidin -3(2H) -yl ) ethyl ) piperazin- 1 -yl )-N- methylbenzenesulfonamide . LCMS (ESI ESI) m/z: Calculated: 555.15; observed: 556.3 (M+1); HPLC purity (XB0595TF): 93.45%; ¹ H NMR (400 MHz, DMSO-d6): δ 8.33 (brs, 2H), 7.95 (s, 1H), 7.55 ( d, J = 8.8 Hz, 2H), 7.24 (d, J = 3.2 Hz, 1H), 7.11 (q, J = 4.80 Hz, 1H), 7.03 (d, J = 8.8 Hz, 2H), 6.73 (m, 1H), 4.10 (t, J = 5.6 Hz, 2H), 3.24 (m, 4H), 2.73-2.62 (m, 6H), 2.34 (d, J = 5.20 Hz, 3H).

Example 20 : 5- Amino -8-( furan -2- yl )-3-(2-(4-(4-( methylsulfonyl ) phenyl ) piperazin- 1 -yl ) ethyl ) thiazole And [5,4-e][1,2,4] triazolo [1,5-c] pyrimidine -2(3H) -one . LCMS: (ESI ESI) m / z : Calculated: 540.62; Observed; 541.3 (M+1); HPLC purity (XB0595TF): 98.58%; ¹ H NMR (400 MHz, DMSO-d6): δ 8.31 (brs, 2H), 7.95 (s, 1H), 7.67 (d, J = 8.80 Hz, 2H), 7.24 (d, J = 3.20 Hz, 1H), 7.05 (d, J = 8.80 Hz, 2H), 6.73 (q, J = 2.00 Hz, 1H), 4.11-4.05 (m, 2H), 3.27 (m, 4H), 3.08 (m, 3H), 2.71 (t, J = 6.00 Hz, 2H), and 2.51 (m, 4H).

Example 21 : 5- Amino -8-( furan -2- yl )-3-(2-(4-(4-( methylsulfinyl ) phenyl ) piperazin- 1 -yl ) ethyl ) Thiazolo [5,4-e][1,2,4] triazolo [1,5-c] pyrimidin -2(3H) -one . LCMS (ESI ESI) m/z: calc. Observed: 525.1; HPLC purity (XB0595TF): 98.99%; ¹ H NMR: (400 MHz, DMSO-d6): δ 8.32 (brs, 2H), 7.95 (s, 1H), 7.49 (d, J = 8.8 Hz , 2H), 7.24 (d, J = 3.2 Hz, 1H), 7.06 (d, J = 8.8 Hz, 2H), 6.73 (dd, J = 1.6 & 3.2 Hz, 1H), 4.09 (t, J = 6.0 Hz , 2H), 3.18 (m, 4H), 2.72-2.62 (m, 9H).

Example 22 : 3-(4-(2-(5- Amino -8-( furan -2- yl )-2 - yloxythiazolo[5,4-e][1,2,4] triazole . and [1,5-c] pyrimidine -3 (2H) - yl) ethyl) piperazin-1-yl) benzoyl amine LCMS (ESI pos. ion) m / z: calculated: 505.16; observed: 506.2 (M + 1); HPLC purity ^{(XB0595TF): 90.01%; 1} H NMR (400 MHz, DMSO-d6): δ 8.33 (brs, 2H), 7.95 (s, 1H), 7.89 (s, 1H), 7.38 (s, 1H), 7.26-7.23 (m, 4H), 7.05 (m, 1H), 6.73 (m, 1H), 4.10 (t, J = 6.0 Hz, 2H), 3.12 (m, 4H), 2.73 -2.63 (m, 6H).

Example 23 : 5- Amino -8-( furan -2- yl )-3-(2-(4-(3-(2- hydroxyethoxy ) phenyl ) piperazin- 1 -yl ) ethyl ) Thiazolo [5,4-e][1,2,4] triazolo [1,5-c] pyrimidine -2(3H) -one . LCMS (ESI ESI) m/z: calc. Observed: 522.8 (M+1); HPLC purity (XB0595TF): 92.67%; ¹ H NMR (400 MHz, DMSO-d6): δ 9.98 (brs, 1H), 8.43 (brs, 2H), 7.96 (t, J = 0.8 Hz, 1H), 7.26 (d, J = 0.8 Hz, 1H), 7.16 (t, J = 8.0 Hz, 1H), 6.74 (dd, J = 1.6 & 3.2 Hz, 1H), 6.57-6.52 ( m, 2H), 6.46 (dd, J = 2.0 & 8. 0 Hz, 1H), 4.31 (t, J = 5.6 Hz, 2H), 3.97-3.85 (m, 6H), 3.70 (t, J = 5.2 Hz , 2H), 3.60 (m, 2H), 3.03 (m, 2H).

Example 24: 5-amino-3- (2- (4- (2-fluoro-4- (2-oxo-2- (piperazin-1-yl) ethoxy) phenyl) piperazine - 1- yl ) ethyl )-8-( furan -2- yl ) thiazolo [5,4-e][1,2,4] triazolo [1,5-c] pyrimidine -2(3H)- . hydrochloride LCMS: (ESI positive ion) m / z: calculated: 622.68; observed; 623.2 (m + 1); HPLC purity ^{(XB0595TF): 98.01%; 1} H NMR (400 MHz, DMSO-d6 ): δ 8.90 (brs, 2H), 8.41 (brs, 2H), 7.97 (d, J = 0.80 Hz, 1H), 7.26 (t, J = 5.20 Hz, 1H), 7.00 (d, J = 8.40 Hz, 1H), 6.90 (d, J = 13.60 Hz, 1H), 6.75-6.74 (m, 2H), 4.86 (m, 2H), 4.30 (bs, 2H), 3.94 (bs, 2H), 3.64 (t, J = 4.80 Hz, 4H), 3.49 (t, J = 5.20 Hz, 2H), 3.22 (m, 4H), 3.18 (brs, 2H), 3.1 (brs, 2H), and 2.94 (brs, 2H).

Example 25 : 5- Amino- 3-(2-(4-(2- fluoro- 4-( piperidin- 4 -ylmethoxy ) phenyl ) piperazin- 1 -yl ) ethyl )-8- ( furan -2- yl ) thiazolo [5,4-e][1,2,4] triazolo [1,5-c] pyrimidin -2(3H) -one hydrochloride . LCMS (ESI positive ion m/z: calcd.: 593.23; observed: 594.2 (M+1); HPLC purity (XB0595TF): 96.25%; ¹ H NMR (400 MHz, DMSO-d6): δ 10.25 (brs, 1H), 8.85 (brs, 1H), 8.55 (brs, 1H), 8.41 (brs, 2H), 7.96 (s, 1H), 7.26 (d, J = 3.2 Hz, 1H), 7.03 (t, J = 9.60 Hz, 1H) , 6.88 (dd, J = 2.4 & 14.0 Hz, 1H), 6.74 (m, 2H), 4.32 (m, 2H), 4.06 (m, 4H), 3.62 (m, 2H), 3.39 (m, 2H), 3.28 (m, 4H), 3.05 (t, J = 12.4 Hz, 2H), 2.90 (m, 2H), 2.01 (m, 1H), 1.89 (m, 2H), 1.47 (m, 2H).

Example 26: 5-amino-3- (2- (4- (2-fluoro-4- (piperazin-1-carbonyl) phenyl) piperazin-1-yl) ethyl) -8- (furan - 2- yl ) thiazolo [5,4-e][1,2,4] triazolo [1,5-c] pyrimidin -2(3H) -one hydrochloride . LCMS (ESI positive ion) m/ z: Calculated: 592.21; observed: 592.9 (M + 1); HPLC purity (XB0595TF): 95.39%; ¹ H NMR (400 MHz, DMSO-d6): δ 10.30 (brs, 1H), 9.22 (brs, 2H), 8.42 (brs, 2H), 7.96 (s, 1H), 7.34 (dd, J = 1.6 & 12.8 Hz, 1H), 7.28 (m, 2H), 7.14 (t, J = 8.8 Hz, 1H), 6.74 (dd, J = 1.6 & 3.2 Hz, 1H), 4.33 (m, 2H), 3.96-3.88 (m, 2H), 3.17 (m, 6H), 2.32 (m, 6H).

Example 27 : 5- Amino- 3-(2-(4-(2- fluoro- 4-(2-( piperazin- 1 -yl ) ethoxy ) phenyl ) piperazin- 1 -yl ) ethyl ) -8-( furan -2- yl ) thiazolo [5,4-e][1,2,4] triazolo [1,5-c] pyrimidin -2(3H) -one hydrochloride . LCMS (ESI cation) m/z: calcd.: 608.24; observed: 609.0 (M+1); HPLC purity (XB0595TF): 91.12%; ¹ H NMR (400 MHz, DMSO-d6): δ 10.52 (brs, 1H), 9.71 (brs, 2H), 8.42 (brs, 2H), 7.97 (s, 1H), 7.26 (d, J = 3.6 Hz, 1H), 7.10-6.99 (m, 2H), 6.84-6.74 (m , 2H), 4.40 (t, J = 4.4 Hz, 2H), 4.33 (t, J = 4.8 Hz, 2H), 3.92 (m, 2H), 3.45-3.40 (m, 4H), 3.24 (m, 3H) , 3.11 (m, 3H).

Example 28 : 5- Amino- 3-(2-(4-(2- fluoro- 4-( piperazin- 1 -ylsulfonyl ) phenyl ) piperazin- 1 -yl ) ethyl )-8- ( furan -2- yl ) thiazolo [5,4-e][1,2,4] triazolo [1,5-c] pyrimidin -2(3H) -one hydrochloride . LCMS (ESI positive ion m/z: calcd.: 628.18; observed: 628.8 (M+1); HPLC purity (XB0595TF): 90.55%; ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 10.91 (brs, 1H), 9.26 (brs, 2H), 8.42 (brs, 2H), 7.96 (s, 1H), 7.64-7.54 (m, 2H), 7.3 (t, J = 8.4 Hz, 1H), 7.25 (m, 1H), 6.74 (s, 1H), 4.33 (m, 2H), 4.07 (m, 8H), 3.95 (m, 2H), 3.76 (m, 2H), 3.60 (m, 2H), 3.33 (m, 4H).

Example 29 : 5- Amino- 3-(2-(4-(2- fluoro- 4-( methylsulfonyl ) phenyl ) piperazin- 1 -yl ) ethyl )-8-( furan -2 - yl) thiazolo [5,4-e] [1,2,4] triazolo [1,5-c] pyrimidin -2 (3H) - one LCMS: (ESI positive ion) m / z: calculation Value: 558.61; observed: 559.8 (M+1); HPLC purity (XB0595TF): 97.88%; ¹ H NMR (400 MHz, DMSO-d6): δ 8.31 (brs, 2H), 7.95 (s, 1H), 7.62 (t, J = 8.40 Hz, 2H), 7.24 (d, J = 3.20 Hz, 1H), 7.16 (t, J = 8.40 Hz, 1H), 6.73 (s, 1H), 4.11-4.04 (m, 2H ), 3.18 (s, 3H), 3.12 (brs, 4H), and 2.73-2.65 (m, 6H).

Example 30 : 4-(4-(2-(5- Amino -8-( furan -2- yl )-2 - yloxythiazolo[5,4-e][1,2,4] triazole And [1,5-c] pyrimidin -3(2H) -yl ) ethyl ) piperazin- 1 -yl )-N-(2 -aminoethyl )-3- fluorobenzamide hydrochloride . LCMS: (ESI positive ion) m / z: calculated: 566.62; observed; 567.0 (m + 1); HPLC purity ^{(XB0595TF): 99.16%; 1} H NMR (400 MHz, DMSO-d6): δ 10.92 ( Brs, 1H), 8.79 (t, J = 5.60 Hz, 1H), 8.41 (brs, 2H), 8.10 (s, 3H), 7.97-7.96 (m, 1H), 7.79-7.75 (m, 2H), 7.26 -7.25 (m, 1H), 7.16 (t, J = 9.20 Hz, 1H), 6.74 (q, J = 1.60 Hz, 1H), 4.33 (t, J = 5.20 Hz, 2H), 3.94-3.92 (m, 2H), 3.69-3.66 (m, 2H), 3.59 (m, 2H), 3.53-3.49 (m, 2H), 3.26 (m, 4H), and 2.97 (m, 2H).

Example 31 : 4-(4-(2-(5- Amino -8-( furan -2- yl )-2 - yloxythiazolo[5,4-e][1,2,4] triazole And [1,5-c] pyrimidin -3(2H) -yl ) ethyl ) piperazin- 1 -yl )-3- fluoro -N-(2-( methylamino ) ethyl ) benzamide . hydrochloride LCMS: (ESI positive ion) m / z: calculated: 580.21; observed; 581.2 (m + 1); HPLC purity ^{(XB0595TF): 98.97%; 1} H NMR (400 MHz, DMSO-d6) : δ 10.81 (bs, 1H), 8.94 (brs, 2H), 8.83 (t, J = 4.80 Hz, 1H), 8.41 (br s, 2H), 7.97 (s, 1H), 7.80-7.76 (m, 2H ), 7.26 (d, J = 3.20 Hz, 1H), 7.16 (t, J = 8.80 Hz, 1H), 6.74 (q, J = 1.20 Hz, 1H), 4.33 (m, 2H), 3.93 (d, J = 9.20 Hz, 2H), 3.68 (m, 6H), 3.26 (t, J = 11.60 Hz, 4H), 3.09-3.08 (m, 2H), and 2.563 (t, J = 4.8 Hz, 3H).

Example 32 : 4-(4-(2-(5- Amino -8-( furan -2- yl )-2 - yloxythiazolo[5,4-e][1,2,4] triazole And [1,5-c] pyrimidin -3(2H) -yl ) ethyl ) piperazin- 1 -yl )-N-(2-( dimethylamino ) ethyl )-3- fluorobenzhydrazide amine LCMS (ESI pos. ion) m / z: calculated: 594.23; observed: 595.0 (m + 1); HPLC purity ^{(XB0595TF.M): 96.47%; 1} H NMR (400 MHz, DMSO-d6): δ 8.30 (m, 3H), 7.95 (d, J = 1.20 Hz, 1H), 7.62-7.57 (m, 2H), 7.24 (d, J = 3.20 Hz, 1H), 7.02 (t, J = 8.80 Hz, 1H), 6.73 (dd, J = 1.6 & 3.2 Hz, 1H), 4.09 (t, J = 6.40 Hz, 2H), 3.04 (m, 4H), 2.72 (d, J = 6.0 Hz, 2H), 2.66 ( m, 4H), 2.42 (t, J = 6.00 Hz, 2H), 2.19 (s, 6H).

Example 33 : 4-(4-(2-(5- Amino -8-( furan -2- yl )-2 - yloxythiazolo[5,4-e][1,2,4] triazole and [1,5-c] pyrimidine -3 (2H) -.-yl) ethyl) piperazin-1-yl) -3-fluoro -N- (2- hydroxyethyl) amine benzoyl LCMS (ESI positive ion) m / z: calculated: 567.18; observed: 567.8 (m + 1); HPLC purity ^{(XB0595TF): 98.37%; 1} H NMR (400 MHz, DMSO-d6): δ 8.34 (brs, 2H), 7.95 (s, 1H), 7.63 (s, 2H), 7.24 (m, 1H), 7.01-6.95 (m, 1H), 6.73 (m, 1H), 4.72 (m, 2H), 4.57 (m, 2H) , 4.09 (m, 2H), 3.48 (m, 6H), 3.03 (m, 4H).

Example 34 : 4-(4-(2-(5- Amino -8-( furan -2- yl )-2 - yloxythiazolo[5,4-e][1,2,4] triazole And [1,5-c] pyrimidin -3(2H) -yl ) ethyl ) piperazin- 1 -yl )-N-(2,3 -dihydroxypropyl )-3- fluorobenzamide . LCMS (ESI pos. ion) m / z: calculated: 597.19; observed: 597.8 (m + 1); HPLC purity ^{(XB0595TF): 95.11%; 1} H NMR (400 MHz, DMSO-d6): δ 8.36-8.31 ( m, 4H), 7.95 (s, 1H), 7.64-7.60 (m, 2H), 7.24 (d, J = 3.2 Hz, 1H), 7.02 (m, 1H), 6.73 (dd, J = 1.6 & 3.2 Hz , 1H), 4.80 (m, 1H), 4.59 (m, 2H), 4.09 (t, J = 6.0 Hz, 2H), 3.61 (m, 4H), 3.10 (m, 4H), 2.65 (m, 4H) .

Example 35 : 2-(4-(4-(2-(5- Amino -8-( furan -2- yl )-2 - yloxythiazolo[5,4-e][1,2,4 .] triazolo [1,5-c] pyrimidine -3 (2H) - yl) ethyl) piperazin-1-yl) -3-fluorophenyl) acetic acid LCMS (ESI pos. ion) m / z: Calculated: 554.15; observed: 555.0 (M+1); HPLC purity (XB0595TF): 98.30%; ¹ H NMR (400 MHz, DMSO-d6): δ 10.20 (brs, 1H), 8.42 (brs, 2H) , 7.97 (t, J = 0.8 Hz, 1H), 7.26 (d, J = 3.6 Hz, 1H), 7.03 (t, J = 9.2 Hz, 1H), 6.88 (dd, J = 2.8, 14.0 Hz, 1H) , 6.75-6.74 (m, 2H), 4.67 (s, 2H), 4.31 (m, 2H), 3.91 (m, 2H), 3.60 (m, 2H), 3.42 (m, 2H), 3.28 (q, J = 10.0 Hz, 2H), 3.05 (t, J = 12.00 Hz, 2H).

Example 36 : 2-(4-(4-(2-(5- Amino -8-( furan -2- yl )-2 - yloxythiazolo[5,4-e][1,2,4 ] triazolo [1,5-c] pyrimidine -3 (2H) -.-yl) ethyl) piperazin-1-yl) -3,5-difluorophenoxy) acetic acid LCMS (ESI pos. ion) m /z: Calculated: 572.14; observed: 572.8 (M + 1); HPLC purity (XB0595TF): 95.07%; ¹ H NMR (400 MHz, DMSO-d6): δ 9.83 (brs, 1H), 8.41 (brs , 2H), 7.97 (dd, J = 0.8 & 2.0 Hz, 1H), 7.26 (dd, J = 0.80 & 3.2 Hz, 1H), 6.78-6.74 (m, 3H), 4.72 (s, 2H), 4.31 ( m, 2H), 3.88 (m, 2H), 3.60 (m, 2H), 3.25 (m, 4H).

Example 37 : 2-(4-(4-(2-(5- Amino -8-( furan -2- yl )-2 - yloxythiazolo[5,4-e][1,2,4 ] triazolo [1,5-c] pyrimidine -3 (2H) -.-yl) ethyl) piperazin-1-yl) -3-fluorophenoxy) propanoic acid LCMS (ESI pos. ion) m / z Calculated: 568.17; observed: 568.8 (M+1); HPLC (XB0595TF): 95.55%; ¹ H NMR (400 MHz, DMSO-d6): δ 10.15 (brs, 1H), 8.41 (brs, 2H) , 7.96 (s, 1H), 7.26 (s, 1H), 7.03 (t, J = 9.60 Hz, 1H), 6.82 (d, J = 14.00 Hz, 1H), 6.74 (d, J = 1.60 Hz, 1H) , 6.67 (d, J = 8.40 Hz, 1H), 4.83 (q, J = 6.80 Hz, 1H), 4.32 (m, 2H), 3.91 (m, 2H), 3.59 (m, 2H), 3.40 (m, 2H), 3.28 (m, 2H), 3.04 (m, 2H), 1.48 (t, J = 6.4 Hz, 3H). Examples 38 and 53 : (S)-2-(4-(4-(2-(5- Amino -8-( furan -2- yl )-2 - yloxythiazolo[5,4-e] [1,2,4] triazolo [1,5-c] pyrimidin -3(2H) -yl ) ethyl ) piperazin- 1 -yl )-3- fluorophenoxy ) propanoic acid and (R) -2-(4-(4-(2-(5- Amino -8-( furan -2- yl )-2 - yloxythiazolo[5,4-e][1,2,4] 3 Zoxa [1,5-c] pyrimidin -3(2H) -yl ) ethyl ) piperazin- 1 -yl )-3- fluorophenoxy ) propanoic acid

The racemic mixture (135 mg) of the product prepared as described in the above examples was subjected to palm separation (0.08 g sample dissolved in 10 mL ethanol), Phenomenex Lux C4 mobile phase: 0.1% TFA in n-hexane : ethanol (30:70), flow rate: 1.0 mL/min; to produce 13 mg of peak 1(S)-2-(4-(4-(2-(5-amino-8-)-furan- 2-yl)-2-yloxythiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazine -1-yl)-3-fluorophenoxy)propionic acid and 13 mg of peak 2 ((R)-2-(4-(4-(2-(5-amino-8-(furan-2-) 2-yloxythiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazine-1 -yl)-3-fluorophenoxy)propionic acid). Note: Peak 1 is arbitrarily considered to be the (S) isomer and peak 2 is considered to be the (R) isomer.

(S)-2-(4-(4-(2-(5- Amino -8-( furan -2- yl )-2 - yloxythiazolo[5,4-e][1,2, 4] Triazolo [1,5-c] pyrimidin -3(2H) -yl ) ethyl ) piperazin- 1 -yl )-3- fluorophenoxy ) propionic acid . LCMS (ESI positive ion) m/ z: Calculated: 568.17; observed: 568.9 (M+1); HPLC purity (XB0595TF): 95.79%; HPLC purity: 100%; ¹ H-NMR (400 MHz, DMSO-d6): δ 13.03 (brs, 1H), 9.21 (brs, 1H), 8.41 (brs, 2H), 7.96 (s, 1H), 7.26 (s, 1H), 7.04 (m, 1H), 6.82 (m, 1H), 6.75 ( s, 1H), 6.67 (m, 1H), 4.82 (q, J = 5.2 Hz, 1H), 4.31 (m, 2H), 3.97 (m, 2H), 3.63 (m, 2H), 2.93 (m, 2H) ), 1.48 (d, J = 5.60 Hz, 3H).

(R)-2-(4-(4-(2-(5- Amino -8-( furan -2- yl )-2 - yloxythiazolo[5,4-e][1,2, 4] Triazolo [1,5-c] pyrimidin -3(2H) -yl ) ethyl ) piperazin- 1 -yl )-3- fluorophenoxy ) propionic acid . LCMS (ESI positive ion) m/ z: Calculated: 568.17; observed: 569.0 (M+1); HPLC purity (XB0595TF): 98.05%; HPLC purity: 95.46%; ¹ H-NMR (400 MHz, DMSO-d6): δ 13.03 (brs, 1H), 9.25 (brs, 1H), 8.41 (brs, 2H), 7.97 (s, 1H), 7.26 (s, 1H), 7.03 (m, 1H), 6.82 (m, 1H), 6.75 ( s, 1H), 6.67 (m, 1H), 4.82 (q, J = 6.4 Hz, 1H), 4.30 (m, 2H), 3.96 (m, 2H), 3.62 (m, 2H), 3.30 (m, 2H) ), 2.93 (m, 2H), 1.48 (d, J = 6.0 Hz, 3H).

Example 39 : 2-(4-(4-(2-(5- Amino -8-( furan -2- yl )-2 - yloxythiazolo[5,4-e][1,2,4 ] triazolo [1,5-c] pyrimidine -3 (2H) - yl) ethyl) piperazin-1-yl) -3-fluorophenoxy) -2-methylpropanoic acid hydrochloride LCMS. (ESI cation) m / z : calcd.: 582.61; observed: 582.8 (M+); HPLC purity (XB0595TF): 90.46%; ¹ H NMR (400 MHz, DMSO-d6): δ 10.9 (br s, 1H ), 8.40 (brs, 2H), 7.96 (d, J = 1.20 Hz, 1H), 7.25-7.26 (m, 1H), 7.01 (t, J = 10.00 Hz, 1H), 6.75-6.73 (m, 2H) , 6.65-6.63 (m, 1H), 4.32 (t, J = 5.60 Hz, 2H), 3.88 (d, J = 11.20 Hz, 2H), 3.57 (d, J = 4.00 Hz, 2H), 3.41 (t, J = 8.80 Hz, 2H), 3.25 (t, J = 9.60 Hz, 2H), 3.13 (t, J = 11.60 Hz, 2H), and 1.48 (s, 6H).

Example 40 : 3-(4-(4-(2-(5- Amino -8-( furan -2- yl )-2 - yloxythiazolo[5,4-e][1,2,4 .] triazolo [1,5-c] pyrimidine -3 (2H) - yl) ethyl) piperazin-1-yl) -3-fluorophenyl) propanoic acid LCMS (ESI pos. ion) m / z: Calculated: 553.18; observed: 552.9; HPLC purity (XB0595TF): 93.92%; ¹ H NMR (400 MHz, DMSO-d6): δ 9.62 (brs, 1H), 8.41 (brs, 2H), 7.96 (m, 1H), 7.25 (m, 1H), 7.10 (m, 1H), 6.99 (m, 2H), 6.74 (dd, J = 2.0 & 3.6 Hz, 1H), 4.32 (m, 2H), 3.95 (m, 2H) ), 3.28 (m, 2H), 2.99 (m, 2H), 2.32 (m, 2H).

Example 41 : 4-(4-(4-(2-(5- Amino -8-( furan -2- yl )-2 - yloxythiazolo[5,4-e][1,2,4 ] triazolo [1,5-c] pyrimidine -3 (2H) - yl) ethyl) piperazin-1-yl) -3-fluorophenoxy) butyric acid hydrochloride LCMS: (ESI positive ion. m / z : Calculated: 582.61; observed: 582.3 (M+1); HPLC purity (XB0595TF): 96.04%; ¹ H NMR (400 MHz, DMSO-d6): δ 10.31 (br s, 1H 8.41 (brs, 2H), 7.97 (d, J = 0.80 Hz, 1H), 7.26 (d, J = 3.20 Hz, 1H), 7.02 (t, J = 9.60 Hz, 1H), 6.87 (q, J = 2.40 Hz, 1H), 6.75-6.72 (m, 2H), 4.32 (m, 2H), 3.96-3.89 (m, 4H), 3.59 (m, 2H), 3.40 (d, J = 11.60 Hz, 2H), 3.28 (d, J = 10.00 Hz, 2H), 3.06-3.03 (m, 2H), 2.36 (t, J = 7.20 Hz, 2H), and 1.91 (t, J = 6.80 Hz, 2H).

Example 42 : 2-(3-(4-(2-(5- Amino -8-( furan -2- yl )-2 - yloxythiazolo[5,4-e][1,2,4 ] triazolo [1,5-c] pyrimidine -3 (2H) -.-yl) ethyl) piperazin-1-yl) -2,6-difluorophenoxy) acetic acid hydrochloride LCMS (ESI positive m / z : calcd.: 572.55; observed: 573.0 (M+1); HPLC purity (XB0595TF): 93.35%; ¹ H NMR (400 MHz, DMSO-d6): δ 10.41 (brs, 1H) , 8.42 (brs, 2H), 7.97 (t, J = 0.96 Hz, 1H), 7.27 (d, J = 4.04 Hz, 1H), 7.07 (t, J = 9.40 Hz, 1H), 6.81-6.78 (m, 1H), 6.75-6.74 (m, 1H), 4.77 (m, 2H), 4.32 (d, J = 5.20 Hz, 2H), 3.92 (d, J = 8.84 Hz, 2H), 3.60 (m, 2H), 3.46 (d, J = 12.04 Hz, 2H), 3.29 (d, J = 9.16 Hz, 2H), and 3.10 (t, J = 11.28 Hz, 2H).

Example 43 : 2-(5-(4-(2-(5- Amino -8-( furan -2- yl )-2 - yloxythiazolo[5,4-e][1,2,4 .] triazolo [1,5-c] pyrimidine -3 (2H) - yl) ethyl) piperazin-1-yl) -2,4-difluorophenoxy) acetic acid hydrochloride LC-MS: (ESI positron); m / z : calcd: 572.55; observed: 573.0 (M+1); HPLC purity (XB0595TF): 96.60%; ¹ H NMR (400 MHz, DMSO-d6): δ 13.06 (brs , 1H), 10.23 (brs, 1H), 8.40 (brs, 2H), 7.96-7.96 (m, 1H), 7.33 (t, J = 11.60 Hz, 1H), 7.25 (d, J = 3.20 Hz, 1H) , 6.82 (t, J = 8.80 Hz, 1H), 6.73-6.75 (m, 1H), 4.79 (s, 2H), 4.32 (m, 2H), 3.89-3.92 (m, 2H), 3.60 (brs, 2H ), 3.49-3.46 (m, 2H), 3.30-3.27 (m, 2H), ), and 3.07 (t, J = 11.6 Hz, 2H).

Example 44 : 4-(4-(2-(5- Amino -8-( furan -2- yl )-2 - yloxythiazolo[5,4-e][1,2,4] triazole And [1,5-c] pyrimidin -3(2H) -yl ) ethyl ) piperazin- 1 -yl )-3- fluorobenzoic acid . LCMS (ESI ESI) m/z: Calculated: 524. Value: 525.0; HPLC purity (XB0595TF): 89.07%; ¹ H NMR: (400 MHz, DMSO-d6): δ 12.80 (brs, 1H), 8.30 (brs, 2H), 7.95 (dd, J = 0.8 & 1.6 Hz, 1H), 7.66 (dd, J = 2.0 & 8.4 Hz, 1H), 7.54 (dd, J = 2.0 & 14.0 Hz, 1H), 7.23 (dd, J = 0.8 & 3.2 Hz, 1H), 7.04 (t , J = 8.8 Hz, 1H), 6.73 (dd, J = 1.6 & 3.2 Hz, 1H), 4.08 (t, J = 6.0 Hz, 2H), 3.08 (m, 4H), 2.73-2.65 (m, 6H) .

Example 45 : 2-((2-(4-(4-(2-(5- Amino -8-( furan -2- yl )-2 - yloxythiazolo[5,4-e][1 ,2,4] triazolo [1,5-c] pyrimidin -3(2H) -yl ) ethyl ) piperazin- 1 -yl )-3- fluorophenoxy ) ethyl ) amino ) aminopurine amine hydrochloride LCMS: (ESI positive ion); m / z: calculated: 596.64; observed; 597.0 (m + 1); HPLC purity ^{(XB0595TF): 94.28%; 1} H NMR (400 MHz, DMSO- D6): δ 10.62 (brs, 1H), 9.12 (brs, 2H), 7.96 (t, J = 0.80 Hz, 1H), 7.92 (s, 1H), 7.58 (brs, 1H), 7.26 (d, J = 3.20 Hz, 1H), 7.07 (t, J = 9.60 Hz, 1H), 6.96 (dd, J = 2.80, 13.60 Hz, 1H), 6.81-6.78 (m, 2H), 4.33-4.32 (m, 2H), 4.24 (t, J = 5.20 Hz, 2H), 3.76-3.77 (m, 2H), 3.59 (s, 2H), 3.42-3.35 (m, 8H), and 3.118 (m, 2H).

Example 46 : 2-((2-(4-(4-(2-(5- Amino -8-( furan -2- yl )-2 - yloxythiazolo[5,4-e][1 ,2,4] triazolo [1,5-c] pyrimidin -3(2H) -yl ) ethyl ) piperazin- 1 -yl )-3- fluorophenoxy ) ethyl )( methyl ) amine .-yl) acetyl amine LCMS (ESI pos. ion) m / z: calculated: 610.22; observed: 611.0 (m + 1); HPLC purity ^{(XB0595TF): 99.25%; 1} H NMR (400 MHz, DMSO-d6 ): δ 8.30 (brs, 2H), 7.95 (d, J = 0.8 Hz, 1H), 7.24 (m, 1H), 7.16 (brs, 1H), 7.11 (brs, 1H), 6.93 (d, J = 9.6 Hz, 1H), 6.79 (dd, J = 2.8 & 14.0 Hz, 1H), 6.73 (dd, J = 1.6 & 3.2 Hz, 1H), 6.67 (m, 1H), 4.08-4.02 (m, 4H), 2.96 (s, 2H), 2.85 (m, 4H), 2.75-2.63 (m, 8H), 2.31 (s, 3H).

Example 47 : 5- Amino- 3-(2-(4-(2- fluoro- 4-( piperidin- 4 -yloxy ) phenyl ) piperazin- 1 -yl ) ethyl )-8-( Furan -2- yl ) thiazolo [5,4-e][1,2,4] triazolo [1,5-c] pyrimidin -2(3H) -one hydrochloride . LCMS (ESI cation) m/z: calcd.: 579.22; observed: 580.0 (M +1); HPLC purity (XB0595TF): 95.3%; ¹ H NMR (400 MHz, DMSO-d6): δ 10.29 (brs, 1H), 8.89 ( Brs, 2H), 8.42 (brs, 2H), 7.97 (s, 1H), 7.26 (d, J = 3.2 Hz, 1H), 7.06-6.97 (m, 2H), 6.82-6.75 (m, 2H), 4.60 (m, 1H), 4.32 (m, 2H), 3.92 (m, 2H), 3.60 (m, 2H), 3.41 (m, 2H), 3.29-3.20 (m, 4H), 3.06 (m, 4H), 2.06 (m, 2H), 1.81 (m, 2H).

Example 48 : 5- Amino- 3-(2-(4-(2- fluoro- 4-( pyrrolidin- 3 -yloxy ) phenyl ) piperazin- 1 -yl ) ethyl )-8-( Furan -2- yl ) thiazolo [5,4-e][1,2,4] triazolo [1,5-c] pyrimidin -2(3H) -one hydrochloride . LCMS (ESI cation) m/z: calcd.: 565.20; observed: 566.0 (M+1); HPLC purity (XB0595TF): 97.96%; ¹ H NMR (400 MHz, DMSO-d6): δ 10.72 (brs, 1H), 9.72 ( Brs, 1H), 9.50 (brs, 1H), 8.42 (brs, 2H), 7.97 (s, 1H), 7.26 (d, J = 3.6 Hz, 1H), 7.05 (t, J = 9.2 Hz, 1H), 6.95 (dd, J = 2.4 & 13.6 Hz, 1H), 6.80-6.74 (m, 2H), 5.10 (m, 1H), 4.33 (m, 2H), 3.90 (m, 2H), 3.59 (m, 2H) , 3.42 (m, 3H), 3.28 (m, 5H), 3.13 (m, 2H), 2.14 (m, 2H).

Example 49: 3- (2- (4- ( 4 - ((1H-1,2,4- triazol-3-yl) methoxy) -2-fluorophenyl) piperazin-1-yl) acetate yl) -5-amino-8- (furan-2-yl) thiazolo [5,4-e] [1,2,4] triazolo [1,5-c] pyrimidin -2 (3H) - ketones LCMS (ESI pos. ion) m / z: calculated: 577.17; observed: 578.2 (m + 1); HPLC purity ^{(XB0595TF): 93.44%; 1} H NMR (400 MHz, DMSO-d6): δ 14.09 (brs, 1H), 8.56 (brs, 1H), 8.31 (brs, 3H), 7.96 (s, 1H), 7.24 (d, J = 3.20 Hz, 1H), 6.96-6.90 (m, 2H), 6.79- 6.74 (m, 2H), 5.08 (s, 2H), 4.08 (t, J = 6.0 Hz, 2H), 2.86 (m, 4H), 2.72-2.68 (m, 6H).

Example 50 : 2-(4-(4-(2-(5- Amino -8-( furan -2- yl )-2 - yloxythiazolo[5,4-e][1,2,4 ] triazolo [1,5-c] pyrimidine -3 (2H) - yl) ethyl) piperazin-1-yl) -3-fluorophenoxy) -N- (2- (dimethylamino) ethyl) as acetamide hydrochloride LCMS (ESI pos. ion) m / z: calculated: 610.22; observed: 611.0 (m + 1); HPLC purity ^{(XB0595TF): 99.20%; 1} H NMR (400 MHz , DMSO-d6): δ 10.36 (brs, 1H), 8.79 (brs, 2H), 8.42 (brs, 3H), 7.97 (t, J = 0.8 Hz, 1H), 7.26 (d, J = 3.2 Hz, 1H ), 7.06 (t, J = 9.6 Hz, 1H), 6.96 (dd, J = 2.4 & 13.6 Hz, 1H), 6.80 (m, 1H), 6.74 (t, J = 1.6 Hz, 1H), 4.50 (s , 2H), 4.33 (m, 2H), 3.59 (m, 2H), 3.46-3.40 (m, 4H), 3.28 (m, 2H), 3.10-2.99 (m, 4H), 2.55 (s, 3H).

Example 51 : 2-(4-(4-(2-(5- Amino -8-( furan -2- yl )-2 - yloxythiazolo[5,4-e][1,2,4 ] triazolo [1,5-c] pyrimidine -3 (2H) - yl) ethyl) piperazin-1-yl) -3-fluorophenoxy) -N- (2- (dimethylamino .) ethyl) amine acetyl LCMS (ESI pos. ion) m / z: calculated: 624.24; observed: 625.0 (m + 1); HPLC purity ^{(XB0595TF): 97.22%; 1} H NMR (400 MHz, DMSO -d6): δ 8.31 (brs, 2H), 7.95 (m, 2H), 7.24 (d, J = 3.2 Hz, 1H), 6.94 (t, J = 9.6 Hz, 1H), 6.83 (d, J = 14.0 Hz, 1H), 6.74-6.69 (m, 2H), 4.42 (s, 2H), 4.08 (m, 2H), 3.20 (q, J = 6.4 Hz, 2H), 2.86 (m, 4H), 2.70-2.63 (m, 6H), 2.29 (t, J = 6.4 Hz, 2H), 2.13 (s, 6H).

Example 52 : 2-(4-(4-(2-(5- Amino -8-( furan -2- yl )-2 - yloxythiazolo[5,4-e][1,2,4 ] triazolo [1,5-c] pyrimidine -3 (2H) - yl) ethyl) piperazin-1-yl) -3-fluorophenoxy) -N- (2- aminoethyl) acetate . Amides hydrochloride LCMS (ESI pos. ion) m / z: calculated: 596.21; observed: 597.0 (m + 1); HPLC purity ^{(XB0595TF): 93.18%; 1} H NMR (400 MHz, DMSO-d6 ): δ 10.40 (brs, 1H), 8.39 (brs, 3H), 7.97 (m, 3H), 7.26 (dd, J = 0.8 & 3.2 Hz, 1H), 7.06 (t, J = 9.6 Hz, 1H), 6.95 (dd, J = 2.4 & 13.6 Hz, 1H), 6.81-6.78 (m, 2H), 4.49 (s, 2H), 4.32 (t, J = 5.2 Hz, 2H), 3.90 (m, 2H), 3.60 (m, 2H), 3.40 (m, 4H), 3.28 (a, J = 10.00 Hz, 2H), 3.08 (m, 2H), 2.90 (m, 2H).

Example 54 : 2-(4-(4-(2-(5- Amino -8-( furan -2- yl )-2 - yloxythiazolo[5,4-e][1,2,4 ] triazolo [1,5-c] pyrimidine -3 (2H) -.-yl) ethyl) piperazin-1-yl) -3-fluorophenoxy) as acetamide LCMS (ESI pos. ion) m / z: Calculated: 553.16; observed: 554.0 (M+1); HPLC purity (XB0595TF): 95.07%; ¹ H NMR (400 MHz, DMSO-d6): δ 9.43 (brs, 1H), 8.41 (brs, 2H), 7.97 (s, 1H), 7.52 (brs, 1H), 7.40 (brs, 1H), 7.27 (m, 1H), 7.05 (t, J = 9.20 Hz, 1H), 6.91-6.87 (m, 1H) ), 6.75 (m, 2H), 4.41 (s, 2H), 4.31 (m, 2H), 3.97 (m, 2H), 3.31 (m, 4H), 2.96 (m, 4H).

Example 55 : 4-(4-(2-(5- Amino -8-( furan -2- yl )-2 - yloxythiazolo[5,4-e][1,2,4] triazole And [1,5-c] pyrimidin -3(2H) -yl ) ethyl ) piperazin- 1 -yl )-3- fluoro -N- methyl -N-(2-( methylamino ) ethyl .) benzoyl hydrochloride LCMS (ESI pos. ion) m / z: calculated: 594.23; observed: 595.2 (m + 1); HPLC purity ^{(XB0595TF): 93.61%; 1} H NMR (400 MHz, DMSO-d6): δ 10.13 (brs, 1H), 8.63 (brs, 2H), 8.42 (brs, 2H), 7.97 (s, 1H), 7.40 (m, 1H), 7.32-7.26 (m, 2H), 7.14 (t, J = 8.80 Hz, 1H), 6.75 (dd, J = 0.8 & 3.2 Hz, 1H), 4.35 (m, 2H), 3.98 (m, 2H), 3.67 (m, 6H), 3.15 (m , 6H), 2.96 (s, 3H).

Example 56 : 4-(4-(2-(5- Amino -8-( furan -2- yl )-2 - yloxythiazolo[5,4-e][1,2,4] triazole And [1,5-c] pyrimidin -3(2H) -yl ) ethyl ) piperazin- 1 -yl )-N-(2-( dimethylamino ) ethyl )-3- fluoro -N- Methyl benzamide . LCMS (ESI ESI) m/z: Calculated: s.: 608.70; observed: 609.0 (M+1); HPLC purity (XB0595TF): 99.46%; ¹ H NMR (400 MHz, DMSO- D6): δ 8.31 (s, 2H), 7.95 (s, 1H), 7.24 (d, J = 3.36 Hz, 1H), 7.18-7.12 (m, 2H), 7.00 (t, J = 8.48 Hz, 1H) , 6.74-6.73 (m, 1H), 4.09 (t, J = 12.60 Hz, 2H), 3.37-3.30 (m, 2H), 3.01-2.93 (m, 4H), 2.91 (s, 3H), 2.73-2.62 (m, 8H), 2.22 (m, 3H), and 2.02 (m, 3H).

Example 57 : (R)-4-(4-(2-(5- Amino -8-( furan -2- yl )-2 - yloxythiazolo[5,4-e][1,2, 4] Triazolo [1,5-c] pyrimidin -3(2H) -yl ) ethyl ) piperazin- 1 -yl )-N-(1-( dimethylamino ) propan -2- yl ) . Amides -3- fluorobenzamide LCMS (ESI pos. ion) m / z: calculated: 608.24; observed: 609.3 (m + 1); HPLC purity ^{(XB0595TF): 98.79%; 1} H NMR (400 MHz, DMSO-d6): δ 8.32 (brs, 2H), 8.02 (m, 1H), 7.95 (s, 1H), 7.62-7.59 (m, 2H), 7.24 (d, J = 3.2 Hz, 1H), 7.02 ( t, J = 8.8 Hz, 1H), 6.74 (m, 1H), 4.09 (m, 3H), 3.04 (m, 4H), 2.73-2.66 (m, 6H), 2.15 (m, 6H), 1.11 (d , J = 6.4 Hz, 3H).

Example 58 : 2-(4-(4-(2-(5- Amino -8-( furan -2- yl )-2 - yloxythiazolo[5,4-e][1,2,4 ] triazolo [1,5-c] pyrimidine -3 (2H) - yl) ethyl) piperazin-1-yl) -3-fluorophenoxy) -N- methyl -N- (2- ( . methyl) ethyl) amine hydrochloride acetyl LCMS (ESI pos. ion) m / z: calculated: 624.24; observed: 625.0 (m + 1); HPLC purity (XB0595TF): 92.37%; ¹ H NMR (400 MHz, DMSO-d6): δ 10.10 (brs, 1H), 8.63 (brs, 2H), 8.41 (brs, 1H), 7.96 (dd, J = 0.8 & 1.6 Hz, 1H), 7.35 (d , J = 2.4 Hz, 1H), 7.06-6.90 (m, 2H), 6.78-6.74 (m, 2H), 4.81 (s, 2H), 4.32 (m, 2H), 3.91 (d, J = 10.80 Hz, 2H), 3.59 (m, 4H), 3.30 (m, 2H), 3.06 (m, 3H), 3.00 (s, 3H), 2.60-2.55 (m, 3H).

Example 59 : 2-(5-(4-(2-(5- Amino -8-( furan -2- yl )-2 - yloxythiazolo[5,4-e][1,2,4 ] triazolo [1,5-c] pyrimidine -3 (2H) - yl) ethyl) piperazin-1-yl) -2,4-difluorophenoxy) -2-methyl-propanoic acid salt LCMS: (ESI positive ion); m / z: calculated: 600.60; observed; 601.0 (m + 1); HPLC purity ^{(XB0595TF): 97.84%; 1} H NMR (400 MHz, DMSO-d6): δ 10.30 (brs, 1H), 8.40 (brs, 2H), 7.96 (brs, 1H), 7.34 (t, J = 11.20 Hz, 1H), 7.26 (d, J = 3.20 Hz, 1H), 6.80 (t, J = 8.40 Hz, 1H), 6.79-6.73 (m, 1H), 4.32 (m, 2H), 3.93-3.90 (m, 2H), 3.60 (t, J = 6.40 Hz, 2H), 3.46-3.43 (m , 2H), 3.30-3.28 (m, 2H), 3.03 (t, J = 11.20 Hz, 2H), and 1.45 (s, and 6H). Examples 60 and 61 : (S)-2-(5-(4-(2-(5- Amino -8-( furan -2- yl )-2 - yloxythiazolo[5,4-e] [1,2,4] triazolo [1,5-c] pyrimidin -3(2H) -yl ) ethyl ) piperazin- 1 -yl )-2,4 -difluorophenoxy ) propanoic acid and (R)-2-(5-(4-(2-(5- Amino -8-( furan -2- yl )-2 - yloxythiazolo[5,4-e][1,2, 4] Triazolo [1,5-c] pyrimidin -3(2H) -yl ) ethyl ) piperazin- 1 -yl )-2,4 -difluorophenoxy ) propionic acid

The racemic mixture (0.08 g) of the product prepared as described in the above examples was subjected to palm separation (0.08 g sample dissolved in 10 mL ethanol), column-chiralpak AD-H, and mobile phase: positive 0.1% diethylamine in the alkane: ethanol (70:30), flow rate: 1.0 mL/min; to produce a peak of 10 mg 1 ((S)-2-(5-(4-(2-(5) -amino-8-(furan-2-yl)-2-yloxythiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidine-3 (2H )-yl)ethyl)piperazin-1-yl)-2,4-difluorophenoxy)propanoic acid) and 13 mg of peak 2 ((R)-2-(5-(4-(2-) (5-Amino-8-(furan-2-yl)-2-yloxythiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidine-3 (2H)-yl)ethyl)piperazin-1-yl)-2,4-difluorophenoxy)propanoic acid). Note: Peak 1 is arbitrarily considered to be the (S) isomer and Peak 2 is considered to be the (R) isomer.

(S)-2-(5-(4-(2-(5- Amino -8-( furan -2- yl )-2 - yloxythiazolo[5,4-e][1,2, 4] Triazolo [1,5-c] pyrimidin -3(2H) -yl ) ethyl ) piperazin- 1 -yl )-2,4 -difluorophenoxy ) propionic acid . LCMS (ESI positive ion m/z: calcd.: 586.16; observed: 587.2 (M + 1); HPLC purity (XB0595TF): 99.69 %; palm purity HPLC: 100%; ¹ H NMR (400 MHz, DMSO-d6): δ 13.03 (brs, 1H), 8.29 (brs, 2H), 7.94 (s, 1H), 7.24-7.18 (m, 2H), 6.72 (m, 1H), 6.67 (t, J = 8.8 Hz, 1H), 4.90 (q, J = 6.80 Hz, 1H), 4.07 (m, 2H), 2.86 (m, 4H), 2.70-2.62 (m, 6H), 1.47 (d, J = 6.80 Hz, 3H).

(R)-2-(5-(4-(2-(5- Amino -8-( furan -2- yl )-2 - yloxythiazolo[5,4-e][1,2, 4] Triazolo [1,5-c] pyrimidin -3(2H) -yl ) ethyl ) piperazin- 1 -yl )-2,4 -difluorophenoxy ) propionic acid . LCMS (ESI positive ion m/z: Calculated: 586.16; observed: 587.2 (M+1); HPLC purity (XB0595TF): 94.42%; HPLC purity: 98.71%; ¹ H NMR (400 MHz, DMSO-d6): δ 12.98 (brs, 1H), 8.30 (brs, 2H), 7.95 (s, 1H), 7.25-7.19 (m, 2H), 6.73-6.68 (m, 2H), 4.91 (q, J = 6.40 Hz, 1H ), 4.07 (m, 2H), 2.90 (m, 4H), 2.70-2.67 (m, 6H), 1.48 (d, J = 6.40 Hz, 3H).

Example 62 : 2-(5-(4-(2-(5- Amino -8-( furan -2- yl )-2 - yloxythiazolo[5,4-e][1,2,4 ] triazolo [1,5-c] pyrimidine -3 (2H) - yl) ethyl) piperazin-1-yl) -2,4-difluorophenoxy) -N- (2- (methyl . amino) ethyl) amine hydrochloride acetyl LCMS (ESI pos. ion) m / z: calculated: 628.21; observed: 629.2 (m + 1); HPLC purity ^{(XB0595TF): 95.15%; 1} H NMR (400 MHz, DMSO-d6): δ 10.40 (brs, 1H), 8.66 (brs, 2H), 8.42 (brs, 2H), 8.33 (t, J = 6.0 Hz, 1H), 7.97 (d, J = 1.2 Hz, 1H), 7.38 (t, J = 11.60 Hz, 1H), 7.26 (m, 1H), 6.90 (t, J = 8.40 Hz, 1H), 6.75 (dd, J = 2.00 & 3.6 Hz, 1H), 4.63 (s, 2H), 4.33 (m, 2H), 3.92 (m, 2H), 3.52-3.41 (m, 6H), 3.30 (m, 2H), 3.11 (m, 2H), 3.00 (t, J = 6.0 Hz, 2H), 2.56 (s, 3H).

Example 63 : 2-(5-(4-(2-(5- Amino -8-( furan -2- yl )-2 - yloxythiazolo[5,4-e][1,2,4 ] triazolo [1,5-c] pyrimidine -3 (2H) - yl) ethyl) piperazin-1-yl) -2,4-difluorophenoxy) -N- (2- (dimethylamino .-ylamino) ethyl) amine acetyl LCMS (ESI pos. ion) m / z: calculated: 642.23; observed: 643.3 (m + 1); HPLC purity ^{(XB0595TF): 96.98%; 1} H NMR (400 MHz, DMSO-d6): δ 8.29 (brs, 2H), 7.95-7.91 (m, 2H), 7.24 (m, 2H), 6.67-6.74-6.67 (m, 2H), 4.53 (s, 2H), 4.07 (t, J = 6.40 Hz, 2H), 3.19 (q, J = 6.40 Hz, 2H), 2.88 (m, 4H), 2.71 (t, J = 6.40 Hz, 2H), 2.63 (m, 4H), 2.27 (t, J = 6.0 Hz, 2H), 2.07 (s, 6H).

Example 64 : 5-(4-(2-(5- Amino -8-( furan -2- yl )-2 - yloxythiazolo[5,4-e][1,2,4] triazole And [1,5-c] pyrimidin -3(2H) -yl ) ethyl ) piperazin- 1 -yl )-N-(2-( dimethylamino ) ethyl )-2,4 -difluoro . -N- benzoyl-methyl-amine LCMS (ESI pos. ion) m / z: calculated: 626.69; observed; 627.2 (m + 1); HPLC purity ^{(XB0595TF): 92.93%; 1} H NMR (400 MHz , DMSO-d6): δ 8.32 (m, 2H), 7.95 (s, 1H), 7.33-7.24 (m, 2H), 6.94-6.88 (m, 1H), 6.74-6.73 (m, 1H), 4.09- 4.06 (m, 2H), 3.53-3.49 (m, 1H), 3.33 (m, 1H), 2.97-2.56 (m, 13H), 2.34-2.29 (m, 5H), and 1.90 (s, 3H).

Example 65 : 4-(5-(4-(2-(5- Amino -8-( furan -2- yl )-2 - yloxythiazolo[5,4-e][1,2,4 ] triazolo [1,5-c] pyrimidine -3 (2H) - yl) ethyl) piperazin-1-yl) -2,4-fluorophenoxy) butyric acid LCMS (ESI positive ion). m/z: calcd.: 600.17; observed: 601.0 (M+1); HPLC purity (XB0595TF): 90.64%; ¹ H NMR (400 MHz, DMSO-d6): δ 9.90 (brs, 1H), 8.42 ( Brs, 2H), 7.96 (s, 1H), 7.35-7.26 (m, 2H), 6.84 (t, J = 9.60 Hz, 1H), 6.75 (dd, J = 1.6 & 3.6 Hz, 1H), 4.32 (m , 2H), 4.06 (t, J = 6.40 Hz, 2H), 3.91 (m, 2H), 3.51 (m, 2H), 3.29 (m, 2H), 3.07 (t, J = 12.00 Hz, 2H), 2.39 (m, 2H), 1.93 (t, J = 6.80 Hz, 2H).

Example 66 : 3-(2-(4-(5-((1H -tetrazol- 5- yl ) methoxy )-2,4 -difluorophenyl ) piperazin- 1 -yl ) ethyl )- 5- amino -8-( furan -2- yl ) thiazolo [5,4-e][1,2,4] triazolo [1,5-c] pyrimidin -2(3H) -one . LCMS (ESI cation) m/z: calcd.: 596.16; observed: 596.8 (M+1); HPLC purity (XB0595TF): 92.14%; ¹ H NMR (400 MHz, DMSO-d6): δ 8.32 (brs, 2H), 7.95 (s, 1H), 7.28-7.24 (m, 2H), 6.98 (t, J = 8.0 Hz, 1H), 6.73 (d, J = 1.20 Hz, 1H), 5.48 (s, 2H), 4.10 (m, 2H), 2.95 (m, 4H), 2.78-2.67 (m, 4H).

Example 67 : 5- Amino- 3-(2-(4-(2- fluoro -4-((1 -methyl- 1H-1,2,4- triazol- 3 -yl ) methoxy ) benzene ) yl) piperazin-1-yl) ethyl) -8- (furan-2-yl) thiazolo [5,4-e] [1,2,4] triazolo [1,5-c] pyrimidine - . 2 (3H) - one LCMS (ESI pos. ion) m / z: calculated: 591.63; observed; 592.8 (m + 1); HPLC purity ^{(XB0595TF): 98.87%; 1} H NMR (400 MHz, DMSO- D6): δ 8.43 (s, 1H), 8.30 (m, 2H), 7.95 (m, 1H), 7.24 (m, 1H), 7.01-6.73 (m, 4H), 4.99 (s, 2H), 4.09- 4.03 (m, 2H), 3.90 (s, 3H), 2.98-2.86 (m, 4H), and 2.72-2.67 (m, 6H).

Example 68 : 5- Amino- 3-(2-(4-(2,4 -difluoro- 5-((1 -methyl- 1H-1,2,4- triazol- 3 -yl ) methoxy ) yl) phenyl) piperazin-1-yl) ethyl) -8- (furan-2-yl) thiazolo [5,4-e] [1,2,4] triazolo [1,5-c .] pyrimidin -2 (3H) - one LCMS (ESI pos. ion) m / z: calculated: 609.62; observed; 610.2 (m + 1); HPLC purity ^{(XB0595TF): 90.03%; 1} H NMR (400 MHz , DMSO-d6): δ 8.70 (brs, 1H), 8.49 (s, 1H), 7.94 (s, 1H), 7.32-7.07 (m, 3H), 6.72 (m, 1H), 5.15 (m, 2H) , 4.35-4.31 (m, 2H), 3.91-3.86 (m, 5H), 3.69 (m, 4H), and 3.08 (m, 4H).

Example 69 : 4-(4-(2-(5- Amino -8-( furan -2- yl )-2 - yloxythiazolo[5,4-e][1,2,4] triazole And [1,5-c] pyrimidin -3(2H) -yl ) ethyl ) piperazin- 1 -yl )-3- fluoro -N-(2-( methyl ( oxaindole- 3 -yl ) amino ) .) ethyl) benzoyl-amine LCMS (ESI pos. ion) m / z: calculated: 636.24; observed: 637.3 (m + 1); HPLC purity ^{(XB0595TF): 97.10%; 1} H NMR (400 MHz, DMSO-d6): δ 8.34 (brs, 2H), 7.96 (s, 1H), 7.60 (m, 2H), 7.24 (m, 1H), 7.03 (m, 1H), 6.73 (m, 1H), 4.51 ( m, 2H), 4.37 (m, 2H), 4.09 (m, 2H), 3.55 (m, 1H), 3.05 (m, 4H), 2.68 (m, 6H), 2.11 (s, 3H).

Example 70 : 4-(4-(2-(5- Amino -8-( furan -2- yl )-2 - yloxythiazolo[5,4-e][1,2,4] triazole And [1,5-c] pyrimidin -3(2H) -yl ) ethyl ) piperazin- 1 -yl )-3- fluoro -N-(2-((2- hydroxyethyl ) amino ) ethyl .) benzoyl hydrochloride LCMS (ESI pos. ion) m / z: calculated: 610.22; observed: 611.3 (m + 1); HPLC purity ^{(XB0595TF): 96.51%; 1} H NMR (400 MHz, DMSO-d6): δ 10.25 (brs, 1H), 8.72 (brs, 3H), 8.40 (brs, 2H), 7.95 (t, J = 0.8 Hz, 1H), 7.72 (m, 2H), 7.25 (d, J = 3.2 Hz, 1H), 7.16 (t, J = 7.6 Hz, 1H), 6.73 (dd, J = 1.6 & 3.2 Hz, 1H), 5.26 (brs, 1H), 4.32 (m, 2H), 3.94 ( d, J = 10.8 Hz, 2H), 3.68-3.56 (m, 8H), 3.16-3.03 (m, 6H).

Example 71 : 2- Amino -N-(2-(4-(4-(2-(5- amino -8-( furan -2- yl )-2 - yloxythiazolo[5,4- e] [1,2,4] triazolo [1,5-c] pyrimidine -3 (2H) - yl) ethyl) piperazin-1-yl) -3-fluorophenyl) ethyl) acetate Hydramine hydrochloride . LCMS: (ESI ESI): m / z : Calculated: 596.64; observed: 597.0 (M+1); HPLC purity (XB0595TF): 94.31%; ¹ H NMR (400 MHz, DMSO -d6): δ 8.31 (brs, 1H), 8.22 (d, J = 5.20 Hz, 1H), 7.95 (t, J = 0.40 Hz, 1H), 7.24 (t, J = 0.80 Hz, 1H), 6.95- 6.91 (m, 1H), 6.81 (dd, J = 2.80, 14.00 Hz, 1H), 6.73-6.74 (m, 1H), 6.69 (dd, J = 2.00, 8.80 Hz, 1H), 5.00 (brs, 1H) , 4.08 (t, J = 6.40 Hz, 2H), 3.95 (t, J = 5.60 Hz, 2H), 3.45 (q, J = 5.60 Hz, 2H), 3.24 (brs, 2H), 2.85 (brs, 4H) , 2.70-2.67 (m, 2H), and 2.63 (m, 4H).

Example 72 : (S)-2- Amino -N-(2-(4-(4-(2-(5- amino -8-( furan -2- yl )-2 -yloxythiazolo [ 5,4-e][1,2,4] triazolo [1,5-c] pyrimidin -3(2H) -yl ) ethyl ) piperazin- 1 -yl )-3- fluorophenoxy ) Ethyl )-3 -methylbutyridamine hydrochloride . LCMS: (ESI ESI); m / z : Calculated: 638.72; observed; 69.1 (M+1); HPLC purity (AM9010A3): 98.36% ¹ H NMR (400 MHz, DMSO-d6): δ 8.44 (brs, 1H), 8.30 (brs, 2H), 7.94 (s, 1H), 7.23 (d, J = 3.20 Hz, 1H), 6.92 (t , J = 9.60 Hz, 1H), 6.80-6.73 (m, 3H), 4.05-4.08 (m, 4H), 3.56-3.53 (m, 1H), 3.41-3.40 (m, 1H), 2.84 (m, 4H ), 2.71-2.671 (m, 3H), 2.62 (m, 3H), 2.33 (m, 1H), 1.94-1.99 (m, 1H), and 0.894-0.853 (m, 6H).

Example 73 : 2-(5-(4-(2-(5- Amino -8-( furan -2- yl )-2 - yloxythiazolo[5,4-e][1,2,4 ] triazolo [1,5-c] pyrimidine -3 (2H) -.-yl) ethyl) piperazin-1-yl) -2,4-difluorophenoxy) acetate LCMS (ESI positive ion m/z: Calculated: 600.17; observed: 601.2 (M+1); HPLC purity (XB0595TF): 96.15%; ¹ H NMR (400 MHz, DMSO-d6): δ 8.31 (brs, 2H), 7.96 (s, 1H), 7.24 (m, 2H), 6.72 (m, 2H), 4.85 (s, 2H), 4.16 (q, J = 6.80 Hz, 2H), 4.08 (m, 2H), 2.89 (m, 4H), 2.71-2.63 (m, 6H), 1.19 (t, J = 6.80 Hz, 3H).

Example 74 : 2-(5-(4-(2-(5- Amino -8-( furan -2- yl )-2 - yloxythiazolo[5,4-e][1,2,4 ] triazolo [1,5-c] pyrimidine -3 (2H) -.-yl) ethyl) piperazin-1-yl) -2,4-difluorophenoxy) acetonitrile LCMS (ESI pos. ion) m /z: Calculated: 553.14; observed: 554.2 (M + 1); HPLC purity (XB0595TF): 96.92%; ¹ H NMR (400 MHz, DMSO-d6): δ 8.31 (brs, 2H), 7.95 (d , J = 0.80 Hz, 1H), 7.33 (t, J = 10.80 Hz, 1H), 7.24 (d, J = 3.2 Hz, 1H), 6.94 (t, J = 8.4 Hz, 1H), 6.73 (dd, J = 1.6 & 3.2 Hz, 1H), 5.22 (s, 2H), 4.09 (t, J = 5.6 Hz, 2H), 2.93 (m, 4H), 2.74-2.64 (m, 6H).

Example 75 : 5- Amino -8-( furan -2- yl )-3-(2-(4-( pyridin- 4 -yl ) piperazin- 1 -yl ) ethyl ) thiazolo [5,4- e][1,2,4] triazolo [1,5-c] pyrimidin -2(3H) -one . LCMS (ESI ESI) m/z: Calculated: 459.15; 1); HPLC purity (XB0595TF): 93.77%; ¹ H NMR: (400 MHz, DMSO-d6): δ 8.30 (brs, 2H), 8.13 (d, J = 6.40 Hz, 2H), 7.94 (d, J = 0.80 Hz, 1H), 7.23 (d, J = 3.60 Hz, 1H), 6.77 (d, J = 6.40 Hz, 2H), 6.72 (dd, J = 1.6 & 3.2 Hz, 1H), 4.08 (t, J = 6.00 Hz, 2H), 3.23 (m, 4H), 2.71-2.67 (m, 2H), 2.58 (m, 4H).

Example 76 : 5- Amino -8-( furan -2- yl )-3-(2-(4-( pyrimidin- 4 -yl ) piperazin- 1 -yl ) ethyl ) thiazolo [5,4- e][1,2,4] triazolo [1,5-c] pyrimidin -2(3H) -one . LCMS (ESI ESI) m/z: Calculated: 464.15; 1); HPLC purity (XB0595TF): 95.02%; ¹ H NMR: (400 MHz, DMSO-d6): δ 8.47 (s, 1H), 8.31 (brs, 2H), 8.16 (d, J = 6.40 Hz, 1H ), 7.95 (s, 1H), 7.23 (d, J = 2.8 Hz, 1H), 6.79 (dd, J = 0.8 & 6.0 Hz, 1H), 6.73 (dd, J = 1.6 & 3.2 Hz, 1H), 4.08 (t, J = 6.00 Hz, 2H), 3.53 (m, 4H), 2.69 (t, J = 6.80 Hz, 2H), 2.55 (m, 4H).

Example 79: 5-amino-3- (2- (4- (6-fluoro-2-oxo-indol-5-yl) piperazin-1-yl) ethyl) -8- (furan - 2- yl ) thiazolo [5,4-e][1,2,4] triazolo [1,5-c] pyrimidine -2(3H) -one . LCMS (ESI positive ion) m/z: Value: 535.16; observed: 536.0 (M+1); HPLC purity (XB0595TF): 82.71%; ¹ H NMR (400 MHz, DMSO-d6): δ 10.26 (s, 1H), 8.30 (brs, 2H), 7.95 (s, 1H), 7.24 (d, J = 3.60 Hz, 1H), 6.94 (d, J = 8.40 Hz, 1H), 6.73-6.74 (m, 1H), 6.60 (d, J = 12.00 Hz, 1H ), 4.08 (t, J = 5.60 Hz, 2H), 3.39 (s, 2H), 2.84 (m, 4H), 2.72-2.63 (m, 6H).

Example 82 : 5- Amino- 3-(2-(4-(5- fluoro -2 -methylpyridin- 4 -yl ) piperazin- 1 -yl ) ethyl )-8-( furan -2- yl ) thiazolo [5,4-e] [1,2,4] triazolo [1,5-c] pyrimidin -2 (3H) - one LCMS (ESI pos. ion) m / z:. Calcd: 495.54 ; observed: 496.1 (M + 1); HPLC purity (XB0595TF): 93.17%; H-NMR (400 MHz, DMSO-d6): 8.31 (brs, 2H), 8.08 (d, J = 5.60 Hz, 1H) , 7.95 (s, 1H), 7.24 (t, J = 2.40 Hz, 1H), 6.72-6.79 (m, 2H), 4.06-4.11 (m, 2H), 3.16 (t, J = 6.00 Hz, 4H), 2.68-2.72 (m, 2H), 2.62 (s, 4H), and 2.33 (s, 3H).

Example 85 : 5- Amino- 3-(2-(4-(2- fluoro- 4-(2- hydroxy -2 -methylpropoxy ) phenyl ) piperazin- 1 -yl ) ethyl )- 8-( furan -2- yl ) thiazolo [5,4-e][1,2,4] triazolo [1,5-c] pyrimidin -2(3H) -one . LCMS (ESI cation) m/z: calcd.: 568.20; observed: 569.3 (M +1); HPLC purity (XB0595TF): 92.42%; ¹ H NMR (400 MHz, DMSO-d6): δ 8.31 (brs, 2H), 7.95 ( s, 1H), 7.24 (s, 1H), 6.92 (t, J = 9.60 Hz, 1H), 6.79-6.66 (m, 3H), 4.60 (s, 1H), 4.07 (m, 2H), 3.65 (s , 2H), 2.85 (m, 4H), 2.70-2.63 (m, 6H), 1.17 (s, 6H).

Example 86 : 5- Amino- 3-(2-(4-(2- fluoro- 4-(2- hydroxypropan- 2- yl ) phenyl ) piperazin- 1 -yl ) ethyl )-8-( Furan -2- yl ) thiazolo [5,4-e][1,2,4] triazolo [1,5-c] pyrimidin -2(3H) -one . LCMS (ESI positive ion) m/z Calculated value: 538.60; observed: 539.2 (M+1); HPLC purity (XB0595TF): 94.02%; 1H-NMR (400 MHz, DMSO-d6): δ 8.31 (brs, 2H), 7.95 (s, 1H ), 7.24 (s, 1H), 7.15 (m, 2H), 6.90 (m, 1H), 6.73 (m, 1H), 4.08 (t, J = 6.00 Hz, 2H), 2.92 (brs, 4H), 2.64 -2.71 (m, 6H), and 1.38 (s, 6H).

Example 87 : 5- Amino- 3-(2-(4-(2- fluoro- 4-(3,3,3- trifluoro -2 -hydroxypropoxy ) phenyl ) piperazin- 1 -yl ) Ethyl )-8-( furan -2- yl ) thiazolo [5,4-e][1,2,4] triazolo [1,5-c] pyrimidin -2(3H) -one . LCMS ( ESI cation) m/z: calc.: 608.16; observed: 609.0 (M+1); HPLC purity (XB0595TF): 95.69%; ¹ H NMR (400 MHz, DMSO-d6): δ 8.30 (brs, 2H) ), 7.95 (dd, J = 0.8 Hz and 1.6 Hz, 1H), 7.24 (dd, J = 0.8 Hz and 3.2 Hz, 1H), 6.94 (t, J = 9.60 Hz, 1H), 6.85 (dd, J = 2.80 Hz and 14.00 Hz, 1H), 6.74-6.71 (m, 2H), 6.63 (d, J = 6.80 Hz, 1H), 4.35-4.33 (m, 1H), 4.10-3.99 (m, 4H), 2.86 ( m, 4H), 2.70 (t, J = 6.40 Hz, 2H), 2.63 (m, 4H).

Example 89 : 5- Amino- 3-(2-(4-(2,4 -difluoro -5-( morpholin -2 -ylmethoxy ) phenyl ) piperazin- 1 -yl ) ethyl ) 8-(- furan -2- yl ) thiazolo [5,4-e][1,2,4] triazolo [1,5-c] pyrimidin -2(3H) -one hydrochloride . LCMS ( ESI positive ion) m / z : calcd.: 613.64; observed: 614.2 (M + 1); HPLC purity (XB_0595TF): 96.82%; 1H-NMR (400 MHz, DMSO-d6): δ 10.95 (brs, 1H) ), 9.71 (m, 1H), 9.51-9.49 (m, 1H), 8.40 (brs, 2H), 7.96 (s, 1H), 7.36 (t, J = 11.6Hz, 1H), 7.25-7.24 (m, 1H), 6.89 (t, J = 8.4Hz, 1H), 6.74-6.73 (m, 1H), 4.33-4.31 (m, 2H), 4.18-4.11 (m, 3H), 4.01-3.79 (m, 2H) , 3.58-3.48 (m, 2H), 3.29-3.31 (m, 4H), 3.15-2.96 (m, 6H), 2.95-2.93 (m, 2H).

Example 92 : 5- Amino- 3-(2-(4-(2,4 -difluoro- 5-((3S,4S)-4- fluoropyrrolidin- 3 -yl ) oxy ) phenyl ) Piperazin- 1 -yl ) ethyl )-8-( furan -2- yl ) thiazolo [5,4-e][1,2,4] triazolo [1,5-c] pyrimidine -2 ( . 3H) - one hydrochloride LCMS (ESI pos. ion) m / z: calculated: 601.61; observed: 602.2 (m + 1); HPLC purity (XB_0595TF): 96.09% 1H- NMR (400 MHz, DMSO- D6): δ 10.50 (s, 1H), 9.92 (s, 2H), 8.40 (s, 2H), 7.96 (d, J = 0.8 Hz, 1H), 7.46 (t, J = 11.6 Hz, 1H), 7.26 -7.25 (m, 1H), 7.13-7.08 (m, 1H), 6.75-6.74 (m, 1H), 5.42 (s, 1H), 5.26-5.24 (m, 1H), 4.33(m, 2H), 3.93 -3.90 (m, 2H), 3.70-3.54 (m, 8H), 3.41-3.36 (m, 2H), 3.30-3.16 (m, 2H).

Example 93: 5- Amino- 3-(2-(4-(2,4 -difluoro- 5-((3R,4S)-4- fluoropyrrolidin- 3 -yl ) oxy ) phenyl ) Piperazin- 1 -yl ) ethyl )-8-( furan -2- yl ) thiazolo [5,4-e][1,2,4] triazolo [1,5-c] pyrimidine -2 ( . 3H) - one hydrochloride LCMS (ESI pos. ion) m / z: calculated: 601.61; observed; 602.1 (m + 1); HPLC purity ^{(XB_0595TF): 95.74%; 1} H NMR (400 MHz, DMSO -d6): δ 10.60 (s, 1H), 9.83-9.75 (m, 2H), 8.41 (s, 2H), 7.97 (s, 1H), 7.41 (t, J = 11.60 Hz, 1H), 7.26 (d , J = 3.20 Hz, 1H), 7.02 (t, J = 8.40 Hz, 1H), 6.74 (q, J = 1.60 Hz, 1H), 5.45 (m, 1H), 5.21-5.15 (m, 1H), 4.42 (s, 2H), 3.91 (d, J = 10.80 Hz, 2H), 3.69-3.64 (m, 2H), 3.61 (s, 4H), 3.38 (s, 4H), 3.16 (d, J = 8.80 Hz, 2H).

Example 94 : 5- Amino- 3-(2-(4-(2,4 -difluoro- 5-((3S,4R)-4- fluoropyrrolidin- 3 -yl ) oxy ) phenyl ) Piperazin- 1 -yl ) ethyl )-8-( furan -2- yl ) thiazolo [5,4-e][1,2,4] triazolo [1,5-c] pyrimidine -2 ( . 3H) - one hydrochloride LCMS (ESI pos. ion) m / z: calculated: 601.61; observed; 602.2 (m + 1); HPLC purity ^{(PG_AM9010.M): 91.76%; 1} H NMR (400 MHz , DMSO-d6): δ 8.31 (s, 2H), 7.95 (s, 1H), 7.26-7.23 (m, 2H), 6.83 (d, J = 8 Hz, 1H), 6.74 (d, J = 5.6 Hz , 1H), 5.24-5.15 (m, 1H), 4.73-4.71(m, 1H), 4.09 (t, J = 6 Hz, 2H), 2.91 (m, 5H), 2.73-2.63 (m, 8H), 1.92 (s, 4H).

Example 97 : 2-(5-(4-(2-(5- Amino -8-( furan -2- yl )-2 - yloxythiazolo[5,4-e][1,2,4 ] triazolo [1,5-c] pyrimidine -3 (2H) - -2,4- difluorophenoxy) ethyl) piperazin-1-yl)) -N- (2- morpholinyl ethyl) as acetamide LCMS (ESI pos. ion) m / z: calculated: 684.24; observed: 685.0 (m + 1); HPLC purity ^{(XB0595TF): 90.92%; 1} H NMR (400 MHz, DMSO- D6): δ 8.30 (brs, 2H), 7.95 (d, J = 0.80 Hz, 1H), 7.90 (d, J = 5.60 Hz, 1H), 7.29-7.18 (m, 2H), 6.76-6.70 (m, 2H), 4.55 (s, 2H), 4.08 (t, J = 6.40 Hz, 2H), 3.53 (m, 4H), 3.23 (t, J = 6.00 Hz, 2H), 2.90 (m, 4H), 2.72 ( m, 2H), 2.67 (m, 4H), 2.35 (m, 6H).

Example 98 : 5-(4-(2-(5- Amino -8-( furan -2- yl )-2 - yloxythiazolo[5,4-e][1,2,4] triazole and [1,5-c] pyrimidine -3 (2H) - yl) ethyl) piperazin-1-yl) -2,4-difluoro -N- (morpholin-3-ylmethyl) benzoyl amine hydrochloride LCMS (ESI pos. ion) m / z: calculated: 640.67; observed; 641.1 (m + 1); HPLC purity ^{(XB_0595TF): 95.86%; 1} H NMR (400 MHz, DMSO-d6) : δ 10.57 (s, 1H), 9.50 (d, J = 7.60 Hz, 1H), 9.29 (d, J = 8.00 Hz, 1H), 8.64 (s, 1H), 8.41 (s, 2H), 7.97 (s , 1H), 7.44 (m, 2H), 7.26 (d, J = 3.20 Hz, 1H), 6.75 (q , J = 1.60 Hz, 1H), 4.33 (m, 2H), 3.90 (m, 4H), 3.49 -3.57 (m, 8H), 3.11-3.33 (m, 7H).

Example 103: 5-amino-3- (2- (4- (2-fluoro -4 - (((3R, 4S ) -4- fluoro-pyrrolidin-3-yl) oxy) phenyl) piperazine - 1- yl ) ethyl )-8-( furan -2- yl ) thiazolo [5,4-e][1,2,4] triazolo [1,5-c] pyrimidine -2(3H)- ketones LCMS (ESI pos. ion) m / z: calculated: 583.62; observed: 584.2 (m + 1); HPLC purity (XB0595TF): 90.29%; 1H -NMR (400 MHz, DMSO-d6): δ 10.27 (brs, 1H), 9.69-9.82 (m, 2H), 8.41 (brs, 2H), 7.97 (m, 1H), 7.26-7.27 (m, 1H), 7.05-7.10 (m, 2H), 6.87-6.90 (m, 1H), 6.75 (t, J = 1.60 Hz, 1H), 5.49 (m, 1H), 5.07-5.13 (m, 1H), 4.32 (d, J = 5.20 Hz, 2H), 3.73-3.93 ( m, 2H), 3.49-3.66 (m, 2H), 3.40-3.44 (m, 3H), 3.30-3.39 (m, 3H), 3.25-3.30 (m, 3H), 3.07-3.10 (m, 2H).

Example 104: 5-amino-3- (2- (4- (2-fluoro -4 - (((3S, 4R ) -4- fluoro-pyrrolidin-3-yl) oxy) phenyl) piperazine - 1- yl ) ethyl )-8-( furan -2- yl ) thiazolo [5,4-e][1,2,4] triazolo [1,5-c] pyrimidine -2(3H)- ketones LCMS (ESI pos. ion) m / z: calculated: 583.62; observed: 584.2 (m + 1); HPLC purity (XB0595TF): 96.80%; 1H -NMR (400 MHz, DMSO-d6): δ 10.40 (brs, 1H), δ 9.94 (m, 2H), 8.42 (brs, 2H), 7.97 (s, 1H), 7.26 (d, J = 3.60 Hz, 1H), 7.06-7.10 (m, 2H), 6.87 (d, J = 8.40 Hz, 1H), 6.74-6.76 (m, 1H), 5.49 (d, J = 4.00 Hz, 1H), 5.07-5.13 (m, 1H), 4.32 (s, 2H), 3.90 ( m, 2H), 3.62 (d, J = 5.20 Hz, 2H), 3.39 (m, 6H), and 3.02-3.33 (brs, 4H).

Example 105 : 2-(4-(4-(2-(5- Amino -8-( furan -2- yl )-2 - yloxythiazolo[5,4-e][1,2,4 ] triazolo [1,5-c] pyrimidine -3 (2H) - yl) ethyl) piperazin-1-yl) -3-fluorophenoxy) -N- (2- morpholinoethyl) . as acetamide LCMS (ESI pos. ion) m / z: calculated: 666.25; observed: 667.0 (m + 1); HPLC purity ^{(XB0595TF): 92.35%; 1} H NMR (400 MHz, DMSO-d6): δ 8.30 (brs, 2H), 7.95-7.90 (m, 2H), 7.24 (dd, J = 0.8 Hz and 3.2 Hz, 1H), 6.94 (t, J = 10.00 Hz, 1H), 6.85-6.80 (m, 1H), 6.74-6.69 (m, 2H), 4.43 (s, 2H), 4.08 (t, J = 6.00 Hz, 2H), 3.53 (m, 4H), 3.22 (m, 2H), 2.90 (m, 4H) ), 2.72-2.63 (m, 6H), 2.37-2.34 (m, 6H).

Example 106 : 4-(4-(2-(5- Amino -8-( furan -2- yl )-2 - yloxythiazolo[5,4-e][1,2,4] triazole and [1,5-c] pyrimidine -3 (2H) -.-yl) ethyl) piperazin-1-yl) -3-fluoro -N- (2- morpholinoethyl) amine benzoyl LCMS ( ESI cation) m/z: calc.: 636.71; observed: 637.0 (M+1); HPLC purity (XB0595TF): 92.87%; 1H-NMR (400 MHz, DMSO-d6): δ 8.29-8.32 (brs , 2H), 7.95 (s, 1H), 7.59 (m, 2H), 7.24 (s, 1H), 7.02 (m, 1H), 6.73 (m, 1H), 4.07-4.10 (m, 2H), 3.55- 3.57 (m, 4H), 3.33 (m, 2H), 3.04 (m, 4H), 2.72 (m, 2H), 2.67-2.68 (m, 4H), and 2.51 (m, 6H).

Example 107 : 4-(4-(2-(5- Amino -8-( furan -2- yl )-2 - yloxythiazolo[5,4-e][1,2,4] triazole and [1,5-c] pyrimidine -3 (2H) - yl) ethyl) piperazin-1-yl) -3-fluoro -N- (morpholin-3-ylmethyl) benzoyl amine LCMS. (ESI cation) m/z: calcd.: 622.68; observed: 623.3 (M+1); HPLC purity (XB0595TF): 95.43%; 1H-NMR (400 MHz, DMSO-d6): 10.58 (brs, 1H) ), 9.52 (d, J = 8.80 Hz, 1H), 9.33 (d, J = 8.40 Hz, 1H), 8.81 (d, J = 5.20 Hz, 1H), 8.42 (brs, 2H), 7.97 (s, 1H) ), 7.75-7.79 (m, 2H), 7.26 (d, J = 3.20 Hz, 1H), 7.17 (t, J = 8.80 Hz, 1H), 6.74-6.75 (m, 1H), 4.33 (brs, 2H) , 3.86-3.96 (m, 3H), 3.71 (s, 1H), 3.58 (t, J = 11.60 Hz, 2H), 3.46-3.51 (m, 4H), 3.44 (d, J = 5.60 Hz, 1H), 3.41 (d, J = 9.60 Hz, 1H), 3.18-3.32 (m, 6H), and 3.05-3.08 (m, 1H).

Example 108 : 5- Amino- 3-(2-(4-(4-( indol- 3 -yloxy ) phenyl ) piperazin- 1 -yl ) ethyl )-8-( furan -2- yl) thiazolo [5,4-e] [1,2,4] triazolo [1,5-c] pyrimidin -2 (3H) - one hydrochloride LCMS (ESI pos. ion) m / z.: Calculated: 533.20; observed: 534.1 (M + 1); HPLC purity (XB0595TF): 88.50%; ¹ H NMR (400 MHz, DMSO-d6): δ 10.17 (brs, 1H), 9.22 (brs, 1H) , 9.09 (brs, 1H), 8.41 (brs, 2H), 7.96 (s, 1H), 7.25 (d, J = 3.56 Hz, 1H), 6.95 (d, J = 8.80 Hz, 2H), 6.80 (d, J = 8.92 Hz, 2H), 6.73 (t, J = 1.64 Hz, 1H), 4.98 (m, 1H), 4.41-4.32 (m, 4H), 3.94-3.90 (m, 4H), 3.72 (m, 2H) ), 3.24-3.21 (m, 2H), 2.97 (m, 2H).

Example 109 : (S)-5- Amino- 3-(2-(4-(2,4 -difluoro -5-( methylsulfinyl ) phenyl ) piperazin- 1 -yl ) ethyl -8-( furan -2- yl ) thiazolo [5,4-e][1,2,4] triazolo [1,5-c] pyrimidine -2(3H) -one . LCMS (ESI positive ion) m / z: calculated: 560.12; observed: 561.1 (m + 1); HPLC purity ^{(XB0595TF): 99.33%; 1} H NMR (400 MHz, DMSO-d6): δ 8.32 (brs, 2H), 7.95 (s, 1H), 7.45 (dd, J = 9.2 Hz and 12.0 Hz, 1H), 7.29-7.24 (m, 2H), 6.73 (dd, J = 1.6 Hz and 3.2 Hz, 1H), 4.08 (t, J = 8.0 Hz, 2H), 2.99 (m, 4H), 2.80 (s, 3H), 2.73-2.67 (m, 6H).

Example 110 : (R)-5- Amino- 3-(2-(4-(2,4 -difluoro -5-( methylsulfinyl ) phenyl ) piperazin- 1 -yl ) ethyl -8-( furan -2- yl ) thiazolo [5,4-e][1,2,4] triazolo [1,5-c] pyrimidine -2(3H) -one . LCMS (ESI positive ion) m / z: calculated: 560.12; observed: 561.0 (m + 1); HPLC purity ^{(XB0595TF): 98.18%; 1} H NMR (400 MHz, DMSO-d6): δ 8.32 (brs, 2H), 7.95 (s, 1H), 7.47-7.42 (dd, J = 9.2 Hz and 12.0 Hz, 1H), 7.29-7.23 (m, 2H), 6.74-6.73 (dd, J = 1.6 Hz and 3.2 Hz, 1H), 4.08 (t, J = 8.0 Hz, 2H), 2.99-2.98 (m, 4H), 2.8 (s, 3H), 2.73-2.67 (m, 6H).

Example 113 : (S)-5-(4-(2-(5- Amino -8-( furan -2- yl )-2 - yloxythiazolo[5,4-e][1,2, 4] Triazolo [1,5-c] pyrimidin -3(2H) -yl ) ethyl ) piperazin- 1 -yl )-2,4 -difluoro -N-(2-( methylsulfinone) .-yl) ethyl) benzoyl-amine LCMS (ESI pos. ion) m / z: calculated: 631.68; observed: 632.2 (m + 1); HPLC purity ^{(XB0595TF): 95.04%; 1} H-NMR (400 MHz, DMSO-d6) 8.52 (d, J = 2.00 Hz, 1H), 8.32 (brs, 2H), 7.95 (s, 1H), 7.28-7.34 (m, 1H), 7.20-7.25 (m, 2H), 6.73-6.74 (m, 1H), 4.07 (d, J = 6.40 Hz, 2H), 3.58-3.64 (m, 2H), 2.99-3.06 (m, 4H), 2.84-2.93 (m, 2H), 2.69- 2.72 (m, 2H), 2.65-2.69 (m, 4H), and 2.60 (s, 3H).

Example 114 : (R)-5-(4-(2-(5- Amino -8-( furan -2- yl )-2 - yloxythiazolo[5,4-e][1,2, 4] Triazolo [1,5-c] pyrimidin -3(2H) -yl ) ethyl ) piperazin- 1 -yl )-2,4 -difluoro -N-(2-( methylsulfinone) .-yl) ethyl) benzoyl-amine LCMS (ESI pos. ion) m / z: calculated: 631.68; observed: 632.2 (m + 1); HPLC purity ^{(XB0595TF): 96.65%; 1} H-NMR (400 MHz, DMSO-d6) δ 8.52 (d, J = 2.00 Hz, 1H), 8.32 (brs, 2H), 7.95 (s, 1H), 7.28-7.34 (m, 1H), 7.20-7.25 (m, 2H) , 6.73-6.74 (m, 1H), 4.07 (d, J = 6.40 Hz, 2H), 3.58-3.64 (m, 3H), 3.30 (m, 2H), 2.99-3.06 (m, 4H), 2.84-2.93 (m, 2H), 2.69-2.72 (m, 2H), 2.65-2.69 (m, 4H), 2.60 (s, 3H).

Example 115 : (S)-5-(4-(2-(5- Amino -8-( furan -2- yl )-2 - yloxythiazolo[5,4-e][1,2, 4] Triazolo [1,5-c] pyrimidin -3(2H) -yl ) ethyl ) piperazin- 1 -yl )-2,4 -difluoro -N- methyl -N-(2-( . acyl methylsulfinyl) ethyl) benzoyl-amine LCMS (ESI pos. ion) m / z: calculated: 645.70; observed: 646.2 (m + 1); HPLC purity (XB0595TF): 99.10%; ¹ H-NMR (400 MHz, DMSO-d6): δ 8.13 (br s, 1H), 7.85 (br s, 1H), 7.37 (t, J = 9.28 Hz, 1H), 7.01-7.10 (m, 3H), 6.64-6.66 (m, 1H), 4.17 (t, J = 9.08 Hz, 2H), 3.87 (m, 1H), 3.72-3.78 (m, 2H), 3.39-3.66 (m, 2H), 3.08-3.17 ( m, 10H), 2.89-3.01 (m, 2H), and 2.60-2.67 (m, 3H).

Example 116 : (R)-5-(4-(2-(5- Amino -8-( furan -2- yl )-2 - yloxythiazolo[5,4-e][1,2, 4] Triazolo [1,5-c] pyrimidin -3(2H) -yl ) ethyl ) piperazin- 1 -yl )-2,4 -difluoro -N- methyl -N-(2-( . acyl methylsulfinyl) ethyl) benzoyl-amine LCMS (ESI pos. ion) m / z: calculated: 645.7; observed: 646.1 (m + 1); HPLC purity (XB0595TF): 93.418%; ¹ H-NMR (400 MHz, DMSO-d6): δ 8.29 (br s, 2H), 7.94 (s, 1H), 7.22-7.32 (m, 2H), 6.95 (t, J = 7.72 Hz, 1H), 6.72 (d, J = 1.28 Hz, 1H), 4.06 (t, J = 5.92 Hz, 2H), 3.50-3.54 (m, 1H), 3.06-3.11 (m, 1H), 2.96-3.02 (m, 2H), 2.86-3.00 (m, 4H), 2.78-2.86 (m, 2H), 2.68-2.71 (m, 2H), 2.62 (s, 6H), and 2.47-2.50 (m, 2H).

Example 117 : 5- Amino- 3-(2-(4-(2,4 -difluoro -5-(1- oxo -hydroxymorpholine- 4- carbonyl ) phenyl ) piperazin- 1 -yl ) Ethyl )-8-( furan -2- yl ) thiazolo [5,4-e][1,2,4] triazolo [1,5-c] pyrimidin -2(3H) -one . LCMS ( ESI cation) m/z: calc.: 643.69; observed: 644.1 (M+1); HPLC purity (XB0595TF): 92.78%; ¹ H-NMR (400 MHz, DMSO-d6): δ 7.85-7.88 ( m, 2H), 7.38-7.44 (m, 1H), 7.18-7.22 (m, 1H), 7.04-6.98 (m, 1H), 6.81 (s, 1H), 6.65-6.71 (m, 1H), 4.35 ( Brs, 1H), 4.16 (t, J = 9.20 Hz, 2H), 3.79-4.01 (m, 1H), 3.51-3.77 (m, 3H), 3.41-3.49 (m, 4H), 3.17-3.39 (m, 2H), 2.95-3.07 (m, 4H), and 2.75-2.90 (m, 3H).

Example 118 : 5- Amino- 3-(2-(4-(2,4 -difluoro -5-(1- oxo-bromomorpholino ) phenyl ) piperazin- 1 -yl ) ethyl ) 8-(- furan -2- yl ) thiazolo [5,4-e][1,2,4] triazolo [1,5-c] pyrimidin -2(3H) -one . LCMS (ESI positive ion m/z: calcd.: 615.68; observed: 616.2 (M + 1); HPLC purity (XB0595NHC): 93.08%; ¹ H-NMR (400 MHz, DMSO-d6): δ 8.32 (brs, 2H), 7.95 (s, 1H), 7.24 (s, 1H), 7.16 (m, 1H), 6.72 (m, 2H), 4.06-4.10 (m, 2H), 3.49-3.54 (m, 2H), 3.14-3.18 ( m, 2H), 2.93-3.00 (m, 6H), 2.82-2.85 (m, 2H), 2.67-2.72 (m, 2H), and 2.50-2.63 (m, 4H).

Example 123 : (S)-4-(4-(2-(5- Amino -8-( furan -2- yl )-2 - yloxythiazolo[5,4-e][1,2, 4] Triazolo [1,5-c] pyrimidin -3(2H) -yl ) ethyl ) piperazin- 1 -yl )-3- fluoro -N-(2-( methylsulfinyl ) B .-yl) benzoyl amine LCMS (ESI pos. ion) m / z: calculated: 613.17; observed: 612.0 (m-1); HPLC purity ^{(XB0595NHC): 99.46%; 1} H NMR (400 MHz, DMSO- D6): δ 8.32 (brs, 2H), 8.09 (m, 1H), 7.95 (s, 1H), 7.58 (t, J = 8.8 Hz, 1H), 7.24 (d, J = 3.6 Hz, 1H), 6.79 -6.71 (m, 3H). 4.09 (t, J = 6.0 Hz, 2H), 3.61 (q, J = 6.0 Hz, 2H), 3.22 (m, 4H), 3.07-3.00 (m, 1H), 2.90- 2.85 (m, 1H), 2.72-2.69 (m, 2H), 2.60 (m, 7H).

Example 124 : (R)-4-(4-(2-(5- Amino -8-( furan -2- yl )-2 - yloxythiazolo[5,4-e][1,2, 4] Triazolo [1,5-c] pyrimidin -3(2H) -yl ) ethyl ) piperazin- 1 -yl )-3- fluoro -N-(2-( methylsulfinyl ) B .-yl) benzoyl amine LCMS (ESI pos. ion) m / z: calculated: 613.17; observed: 614.1 (m + 1); HPLC purity ^{(XB0595NHC): 98.08%; 1} H NMR (400 MHz, DMSO- D6): δ 8.32 (brs, 2H), 8.09 (m, 1H), 7.95 (s, 1H), 7.58 (t, J = 8.8 Hz, 1H), 7.24 (m, 1H), 6.79-6.70 (m, 3H). 4.09 (t, J = 6.0 Hz, 2H), 3.61 (q, J = 6.0 Hz, 2H), 3.22 (m, 4H), 3.05-3.00 (m, 1H), 2.90-2.85 (m, 1H) ), 2.72-2.68 (m, 2H), 2.60 (m, 7H).

Example 125 : 5- Amino- 3-(2-(4-(2- fluoro- 4-(1- oxo-bridge thiomorpholine- 4- carbonyl ) phenyl ) piperazin- 1 -yl ) ethyl ) 8-(- furan -2- yl ) thiazolo [5,4-e][1,2,4] triazolo [1,5-c] pyrimidin -2(3H) -one . LCMS (ESI positive ion m/z: Calculated: 625.17; observed: 626.0 (M + 1); HPLC purity (XB0595TF): 95.09%; ¹ H NMR (400 MHz, DMSO-d6): δ 8.30 (brs, 2H), 7.94 (s, 1H), 7.24 (m, 2H), 6.79-6.72 (m, 3H), 4.36-4.35 (m, 1H), 4.08 (t, J = 6.04 Hz, 2H), 3.78-3.62 (m, 2H ), 3.55-3.46 (m, 1H), 3.17 (m, 4H), 2.83 (m, 3H), 2.71-2.66 (m, 3H), 2.59 (m, 4H).

Example 129 : (S)-5-(4-(2-(5- Amino -8-( furan -2- yl )-2 - yloxythiazolo[5,4-e][1,2, 4] Triazolo [1,5-c] pyrimidin -3(2H) -yl ) ethyl ) piperazin- 1 -yl )-N-(2,3 -dihydroxypropyl )-2,4- di . Amides fluorobenzamide LCMS (ESI pos. ion) m / z: calculated: 615.62; observed: 616.1 (m + 1); HPLC purity ^{(XB0595NHC): 97.60%; 1} H-NMR (400 MHz, DMSO- D6): A broad peak was observed in 1H NMR.

Example 130 : (R)-5-(4-(2-(5- Amino -8-( furan -2- yl )-2 - yloxythiazolo[5,4-e][1,2, 4] Triazolo [1,5-c] pyrimidin -3(2H) -yl ) ethyl ) piperazin- 1 -yl )-N-(2,3 -dihydroxypropyl )-2,4- di . Amides fluorobenzamide LCMS (ESI pos. ion) m / z: calculated: 615.62; observed: 616.2 (m + 1); HPLC purity ^{(XB0595NHC): 95.00%; 1} H-NMR (400 MHz, DMSO- D6): δ 8.32 (brm, 2H), 8.09 (s, 1H), 7.95 (s, 1H), 7.24-7.42 (m, 3H), 6.73 (s, 1H), 4.84 (s, 1H), 4.60 ( s, 1H), 4.32 (s, 1H), 3.96-4.08 (m, 2H), 3.56 (t, J = 2.80 Hz, 2H), 3.17 (t, J = 6.04 Hz, 2H), 2.94 (s, 4H ), 2.65-2.71 (m, 6H).

Example 131: 5-amino-3- (2- (4- (4- (Ta acridine 3-yloxy) -2-fluorophenyl) piperazin-1-yl) ethyl) -8- ( Furan -2- yl ) thiazolo [5,4-e][1,2,4] triazolo [1,5-c] pyrimidin -2(3H) -one hydrochloride . LCMS (ESI cation) m/z: calcd.: 551.19; observed: 552.2 (M + 1); HPLC purity (XB0595NHC): 90.50%; ¹ H NMR (400 MHz, DMSO-d6): δ 10.33 (brs, 1H), 9.33 ( Brs, 1H), 9.21 (brs, 1H), 8.42 (brs, 2H), 7.97 (s, 1H), 7.26 (d, J = 3.2 Hz, 1H), 7.05 (t, J = 9.6 Hz, 1H), 6.87 (d, J = 13.6 Hz, 1H), 6.74-6.73 (m, 1H), 6.67 (d, J = 8.4 Hz, 1H), 5.03 (s, 1H), 4.44-4.32 (m, 4H), 3.93 (m, 4H), 3.60 (m, 2H), 3.43-3.06 (m, 6H).

Example 132 : 5- Amino- 3-(2-(4-(5-( indol- 3 -yloxy )-2,4 -difluorophenyl ) piperazin- 1 -yl ) ethyl )- 8-( furan -2- yl ) thiazolo [5,4-e][1,2,4] triazolo [1,5-c] pyrimidin -2(3H) -one . LCMS (ESI cation) m/z: calcd.: 569.18; observed: 570.0 (M-1); HPLC purity (XB0595TF): 94.68%; ¹ H NMR (400 MHz, DMSO-d6): δ 8.32 (brs, 2H), 7.95 ( s, 1H), 7.27-7.21 (m, 2H), 6.74 (s, 1H), 6.43 (t, J = 8.40 Hz, 1H), 5.01 (m, 1H), 4.07 (t, J = 5.60 Hz, 2H ), 3.71 (t, J = 7.20 Hz, 2H), 3.53-3.47 (m, 2H), 2.90 (m, 4H), 2.72-2.63 (m, 6H).

Example 133 : (S)-5- Amino- 3-(2-(4-(2,4 -difluoro -5-(3-( methylsulfinyl ) propoxy ) phenyl ) piperazine -1 -yl ) ethyl )-8-( furan -2- yl ) thiazolo [5,4-e][1,2,4] triazolo [1,5-c] pyrimidine -2(3H) - one LCMS (ESI pos. ion) m / z: calculated: 618.16; observed: 617.2 (m-1); HPLC purity ^{(XB0595NHC): 97.91%; 1} H NMR (400 MHz, DMSO-d6): δ 8.30 (brs, 2H), 7.94 (s, 1H), 7.23-7.18 (m, 2H), 6.77-6.73 (m, 2H), 4.14-4.07 (m, 4H), 2.89 (m, 5H), 2.77- 2.55 (m, 10H), 2.05 (m, 2H). II. Biological Examples II.1. Verification for A2A Functional Activity

The following two assays are intended to demonstrate that the compounds of the invention effectively inhibit the A2A receptor by demonstrating that the compounds of the invention inhibit the functional activity of the A2A receptor. II.1.A. Inhibition of cAMP production in HEK cells

Purpose . Induces cAMP production when A2A receptor is activated. The current assay is therefore intended to demonstrate that cAMP production is inhibited in HEK cells in response to its exposure to the compounds of the invention.

Methods . HEK-293 cell lines stably transfected with A2A receptor were purchased from PerkinElmer® (#ES-011-C). The cells were plated in EMEM medium (Lonza, #BE12-611F) supplemented with 10% FBS (Lonza, #DE14-801F) and 200 μg/ml of G418 (Tocris, #4131) at 37 ° C and 5% CO ₂ . to cultivate. Fresh medium without selection markers was added directly on the day before the experiment to stop the selection pressure.

cAMP inhibition and antagonist IC50 determinations were performed on a white half 96-well plate (PerkinElmer®, #6005560) using a LANCE® Ultra cAMP kit from PerkinElmer® (#TRF0262). Verification in two different stimulation buffers: a) Normal buffer with 1X HBSS (Gibco®, #141750-95), 5 mM HEPES (Lonza, #BE17-737E), 0.1% BSA and 25 μM Rolipram , and b) with 1X HBSS (Gibco®, #141750-95), 5 mM HEPES (Lonza, #BE17-737E), 2% human serum albumin (Sigma-Aldrich®-A1653), 30 μM EHNA (Tocris -# 1261) and HSA of 100 μM Rolipram. Stimulation buffer b) simulates the human condition by increasing the amount of albumin present in the assay.

The compound of the invention is diluted 100X in either buffer depending on the assay performed. A total of 1000 cells per well were pre-incubated with the compound of the invention for 10 minutes, after which the corresponding EC80 of A2A agonist (3 nM NECA in normal buffer and 5 nM NECA in HSA buffer) or 5 μM was added. Adenosine reached a total reaction time of 30 minutes. The total volume of the reaction was 20 μl (10 μl of cells, 5 μl of antagonist and 5 μl of agonist). The reaction was finally terminated by the addition of 10 μl of 4X EU-cAMP Tracker working solution and 10 μl of 4X ULight-anti-cAMP working solution. The TR-FRET signal was measured after 1 hour using a Spectramax Paradigm (Molecular Devices).

Results. As demonstrated in Table 2, the compounds of the present invention in response to overexpression of HEK cells with A2A agonist stimulation of adenosine A2A or under different conditions of suppressing the generation of cAMP. Table 2 II.1.B. Recovery of pro-inflammatory cytokines by human T cells

Purpose . When activated T cells, they produce pro-inflammatory interleukins. When the A2A receptor is activated in T cells, the amount of interleukin produced in response to stimulation by T cells is reduced. The current assay is therefore intended to demonstrate that pro-inflammatory interleukins can be restored by exposure to the compounds of the invention by the production of T cells.

PBMC and CD3+ T cells were isolated . The venous blood of healthy volunteers was obtained via ImmuneHealth (Centre Hospitalier Universitaire Tivoli, La Louviere, Belgium), all of which signed an informed consent form approved by the Ethics Committee (FOR-UIC-BV) -050-01-01 ICF_HBS_HD Version 5.0). Mononuclear cells were collected by density gradient centrifugation using a SepMate-50 tube (StemCell Technologies, Grenoble, France) and Lymphoprep (Axis-shield, Oslo, Norway) according to the manufacturer's instructions. CD3+ T cells were isolated by immunomagnetic stripping using the EasySep Human T Cell Isolation Kit (StemCell Technologies) according to the manufacturer's instructions. CD3+ T cells were stored in liquid nitrogen in heat-passivated bovine fetal serum (hiFBS; Gibco, Thermo Fisher Scientific, Merelbeke, Belgium) containing 10% DMSO.

Human IL-2 T cell assay . Purified human CD3+ T cells were thawed and supplemented with 1x non-essential amino acids (Lonza), 2% Pen/Strep (Lonza) and 1 mM sodium pyruvate (Gibco) (complete medium) The RPMI 1640 medium (with UltraGlutamine; Lonza, Verviers, Belgium) containing 10% hiFBS was washed twice. The cells were suspended in complete medium containing 20% hiFBS or 100% heat-passivated human serum (hiHS; Sigma-Aldrich, Diegem, Belgium). Cells were activated by the addition of anti-CD3 and anti-CD28 coated microbeads (Dynabeads Human T-Activator CD3/CD28; Life Technologies, Paisley, UK) suspended in complete medium containing 20% hiFBS or 100% hiHS. The selective A _2A R agonist CGS-21680 (Sigma-Aldrich; 10 mM stock solution in DMSO) was added at a final assay concentration of 0.5 or 5 mM. Serial dilutions of the compounds of the invention are prepared and added to the wells. The cells were placed in a 37 ° C humidified tissue culture incubator with 5% CO ₂ for 72 hours. After 72 hours, the supernatant was sampled and IL-2 was quantified using the IL-2 (human) AlphaLISA biotin-free detection kit (AL333F; Perkin-Elmer, Zaventem, Belgium) according to the manufacturer's instructions.

Results . The addition of the A2A selective agonist CGS-21680 to CD3+ T cells reduced the amount of interleukin produced in response to stimulation by anti-CD3 and anti-CD28 coated beads. The compounds of the invention dose-dependently restored the production of pro-inflammatory interleukin IL2 in CGS-21680-treated human T cells, with potency as indicated in Table 3 below. Table 3 II.1.C. Restoring the production of pro-inflammatory interleukins in human whole blood

Preparation of test tubes . Tubes containing selected stimulators (SEB, LPS, zymosan, anti-CD3/CD28) and TruCulture media were purchased from Myriad RBM (catalog numbers 782-001124, 782-001087, 782-001259 and 782, respectively). -001125) and A2a agonist (CGS-21680 and NECA) was added and the tube was frozen directly at -20 °C until used in cell culture experiments.

Compound 7 was dissolved in DMSO at 10 mM and then a dilution was made using TC medium. The solution was microscopically examined to rule out the presence of particles. The freshly prepared solution containing Compound 7 was added to a thawed TC tube containing a stimulating agent and, if appropriate, 1 μM CGS-21680.

Cell culture . Blood was drawn from a healthy donor (age: 20-65 years old, both genders) from the donor pool prior to testing at HOT Screen GmbH. Heparinized fresh peripheral whole blood (1 mL) from 3 healthy donors was added to the thawed TC tube and incubated for 24 hours (LPS and zymosan stimulation) or 48 hours (SEB) in a heated block at 37 °C And anti-CD3/CD28 stimulation). At the end of the incubation period, a seraplas filter was inserted to harvest the supernatant. The supernatant was carefully collected, mixed, aliquoted and frozen at -20 °C.

Mediator quantification . The interleukin and chemo-activin released in the TC supernatant were measured using a human interleukin MAP A plate for Luminex assay. The following mediators were analyzed: GM-CSF, IFNg, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-18, MCP-1 , MIP-1a, MIP-1b, TNF-a, TNF-b.

Data analysis . To assess the biological activity of CGS-21680 and NECA, the changes in interleukin and chemoactivin secretion induced by increasing the dose of the A2A agonist in the TC supernatant were analyzed. Percent change in concentration of soluble mediator (SM) was calculated for each stimulation condition as follows: % change = 100 x [SMTC + A2A agonist] / [SMTC-A2A agonist]. Compound 7 To assess the biological activity of the compound, CGS-21680 Analysis of TC in supplemented chemical activation and cytokine secretion level to baseline (i.e., no supplemental CGS-21680 to stimulate the TC) of 7 induce recovery.

The recovery of interleukin secretion was estimated by calculating the percent control for each stimulation condition of whole blood TC as follows: Control % = 100 x [SMTC + CGS + Compound 7 ] / [SMTC - CGS - Compound 7 ].

Results . LPS, zymosan, SEB, and anti-CD3/CD28 induced secretion of several interleukins and chemical activins in whole blood cell cultures. The biological activity of two A2A agonists (CGS-21680 and NECA) on whole blood cell cultures stimulated with LPS, zymosan, SEB or anti-CD3/CD28 was assessed. Both agonists dose-dependently alter the secretion of several interleukins and chemical activins. This effect is reproducible across the three test donors, although the degree of variation varies from individual to individual.

When 1 μM CGS-21680 or NECA was added to LPS or zymosan-stimulated whole blood cultures, the effect on the release of both pro-inflammatory interleukins and anti-inflammatory interleukins reached the plateau region. In particular, the levels of pro-inflammatory interleukins IFNg and TNFa were reduced by more than 50%, while the levels of anti-inflammatory interleukins IL-8 and IL-10 were doubled.

Compound 7 was assessed for its ability to reverse the changes in interleukin and chemical activin secretion induced by CGS-21680 on whole blood cell cultures stimulated with LPS, zymosan, or anti-CD3/CD28. As shown in Figure 1A and FIG. 1B, compound 7 dose-dependently restored by CGS-21680-induced cytokine secretion and activation of chemical changes, which depending on the conditions tested, to 100-1000 nM of The compound achieved complete recovery. This effect is reproducible across the three test donors, although the degree of variation varies from individual to individual.

In LPS and zymosan-stimulated whole blood TC, secretion of IFNg, TNFa, IL-8 and IL-10 was mainly affected by CGS-21680 treatment and was completely restored by 40-100 nM compound 7. II.2. PCREB II.2.A. of modulating the human immune cells pCREB

Purpose . A2A receptors are known to mediate CREB phosphorylation. The current assay aims to demonstrate that the compounds of the invention effectively inhibit the A2A receptor by demonstrating that CREB phosphorylation can be inhibited by exposing human immune cells to a compound of the invention.

Methods . Venous blood from healthy volunteers was obtained via Immune Health (Centre Hospitalier Universitaire Tivoli, La Louviere, Belgium), all of which signed an informed consent form (version 5.0) approved by the Ethics Committee. Peripheral blood cells were treated with serial dilutions of the A2AR agonist CGS-21680 or NECA (Sigma-Aldrich, Diegem, Belgium) and the compounds of the invention (all used stock solutions in 10 mM in DMSO). All dilutions lines in RPMI1640 medium (having UltraGlutamine; Lonza, Verviers, Belgium) was prepared, and the cells use a compound having a 5% CO ₂ at 37 [deg.] C humidified tissue culture of the incubator to hatch. After stimulation, the cells were fixed and permeabilized, followed by intracellular staining at room temperature using mouse anti-human pCREB antibody (pure line J151-21; BD Biosciences). Data were acquired using LSRFortessa flow cytometry (BD Biosciences) and analyzed using FlowJo software (FlowJo, LLC, Ashland, Oregon).

Results found that the compounds of the present invention A2A-mediated inhibition of phosphorylation of CREB. For example, compound 4 exhibits in peripheral blood lymphocytes activated by 20 nM NECA of the IC _50, as shown in Figure 2. II.2.B. In vitro regulation of pCREB in mice

Purpose . A2A receptors are known to mediate CREB phosphorylation. The current assay aims to demonstrate that the compounds of the invention effectively inhibit the A2A receptor by demonstrating that CREB phosphorylation can be inhibited in mice by administering the compounds of the invention to mice.

Method . Compound 7 was formulated in 10% DMSO, 10% solutol, 80% water pH 3 to obtain a homogeneous solution. The volume was calculated to give a final dose of 100 ml per oral (PO). BALB/cAnNCrl female mice were purchased from Charles River Laboratories. Mice were orally treated with a single dose of A2A receptor antagonist. At specific time points, animals were anesthetized with 200 μl of ketamine 10%/xylazine 0.1% IP injection in PBS and blood was collected via iliac bone bleeding in an EDTA tube. 45 μl of blood/well was dispensed into the main block. Preparation of A2A receptor agonist NECA (Tocris) at a concentration of 3 μM in RPMI 1640 (Lonza) supplemented with 2% penicillin/streptomycin (Lonza) and 50 μM 2-mercaptoethanol (Sigma), and 50 μl was added to the wells and incubated for 45 minutes in a 37 °C humidified cell culture incubator with 5% CO ₂ . The final concentration of DMSO in the assay was 0.125%. Cells were fixed by adding 1 ml of pre-warmed dissolution/fixation buffer (BD Biosciences) to each well, carefully mixed and incubated for 10 minutes in a humidified cell culture incubator with 5% CO ₂ at 37 °C. The cells were pelleted by centrifugation at 600 xg for 5 minutes. After washing with 1 ml of DPBS (Lonza) with Ca2+Mg2+, the cells were permeabilized with 200 μl of ice-cold Perm buffer II (BD Biosciences) and incubated on ice for 30 minutes. During permeabilization, the cells were transferred to a 96-well U-bottom plate. The cells were pelleted and washed twice with FACS buffer consisting of PBS (Lonza), 0.1% BSA (VWR), 2 mM EDTA (Ambion). FACS staining was performed by resuspending the cells in an Fc block containing FACS buffer (CD16/CD32 monoclonal antibody (93), eBioscience); after incubation at room temperature for 5 min, the antibody mixture was added and at room temperature The cells were incubated for 1 hour. Cells were washed with FACS buffer and resuspended in FACS buffer for acquisition in BD Fortessa (BD Biosciences).

Data obtained by flow cytometry were analyzed using FlowJo 10.4 software. The MFI (median fluorescence intensity) of the marker pCREB of our interest was assessed and normalized by the corresponding DMSO control (ratio) and reported graphically. Dose response data were analyzed using the GraphPad Prism 7.0 software using a non-linear regression applied to a sigmoidal dose response model. Data were acquired using LSRFortessa flow cytometry (BD Biosciences) and analyzed using FlowJo software (FlowJo, LLC, Ashland, Oregon).

Results . Compound 8a demonstrated complete inhibition of the A2A signaling pathway by CD4+ T cells at 30 minutes after po at a dose of 0.1 mg/Kg (Table 4). At a dose of 1 mg/Kg, more than 70% of A2A signaling pathway inhibition was observed 12 hours after dosing. Similar data were obtained for CD8+ T cells (Table 5). Table 4. Activity of Compound 8a 30 minutes after oral administration CREB phosphorylation was assessed in CD4+ T cells Table 5. Activity of Compound 8a 12 hours after oral administration CREB phosphorylation was assessed in CD4+ T cells II.3. Cytotoxicity assay

Purpose . Activation of the A2A receptor provides an immunosuppressive signal that inhibits cytotoxicity. The current assay is intended to demonstrate that the compounds of the invention effectively inhibit the A2A receptor by exhibiting increased cytotoxicity by exposure to a compound of the invention.

Method . A cytotoxicity assay was performed to assess the antigen-specific cytotoxic activity of OT-I CD8 cells against OVA pulsed target cells, and the effect of the compounds of the invention on cytotoxic A2AR-mediated inhibition: OT1 cell line from C57BL/6- Spleen separation of Tg (TcraTcrb) 1100 Mjb/Crl mice (Charles River). 1 ug/ml OVA peptide (ovalbumin (257) in a humidified tissue culture incubator with 5% CO ₂ at 37 ° C in the presence of 5 μM CGS-21680 (Sigma-Aldrich) and increasing concentrations of the compound of the invention -264) Chicken (S7951-1MG), Sigma Aldrich) initiated OT1 cells. On day 3, all cells were pooled and counted. For the cytotoxicity assay on day 3, Panc02 (target cells) was pulsed with 1 μg/ml OVA. Target cells and non-pulsed Panc02 cells (non-target bystanders) were labeled with CFSE (C1157 (ThermoFisher)) and CellTraceTM Far Red Cell Proliferation Kit (C34564, ThermoFisher), respectively, according to the manufacturer's instructions. The stimulated OT-1 cell line was added as an effector cell at a target ratio of 10:1 effector to target. The co-culture reaction was incubated at 37 ° C in a humidified tissue culture incubator with 5% CO ₂ . After 24 hr, the cells were washed and stained with a live/dead fixed purple dead cell staining kit (Molecular Probes, L34955). The cytotoxic killing of the target cells was then measured by monitoring the change in the ratio of live target cells to non-target cells by flow cytometry (MACSQuant® Analyzer 10-Miltenyi Biotec). The cytotoxicity % is calculated as follows: cytotoxicity % = (1-R1/R2)*100 where R1 = in the presence of effector cells (% of target cells) / (% of non-target cells) * 100 and R2 = in effector cells In the absence (% of target cells) / (% of non-target cells) * 100

Results added to the medium A2A agonist CGS-21680 leads to a reduction of cytotoxicity, the cytotoxic dose of the compound can be by the present invention dependently reduced (Table 6). For compounds 4 and 31 of the present invention, this is illustrated, for example, in Figure 3. Table 6 III. Pharmacokinetics Example III.1. Determination of permeability and effluent in Caco-2 cells

Purpose . As mentioned in the introduction, the compounds of the invention must exhibit limited (if present) CNS permeability in order to avoid the deleterious side effects that can occur if the compounds penetrate significantly into the brain.

The current assay is intended to demonstrate that the compounds of the invention do not have any significant CNS permeability by displaying the compounds of the invention as substrates for the transport of their own brains.

Indeed, it is well known in the art that heterogeneous organisms that are substrates for transports such as P-glycoproteins are not effective in penetrating blood-brain barriers and are therefore less effective in the central nervous system ( Alfred H. Schinkel, "P-Glycoprotein, a gatekeeper in the blood-brain barrier", Advanced Drug Delivery Reviews 36 (1999) 179-194).

The current assay is therefore intended to demonstrate that the compounds of the invention are substrates for such transports present in the Caco-2 cell line and therefore do not cross the blood brain barrier.

Materials . Transport buffer (TB, pH 7.4) used in the study was a Henck's buffered saline solution (HBSS, Gibco, Cat #14025-076) with a pH of 7.4 with 10 mM HEPES. Fetal bovine serum (FBS) (Corning, Cat #Corning-35-076-CV or other supplier), Minimum Essential Media (MEM) (Gibco, Cat # 41500-034) and its supplements The system was purchased from Invitrogen (Carlsbad, CA, USA). The Caco-2 cell line (Cat #HTB-37) was purchased from ATCC (Rockville, MD, USA). The organic solvent used in the study was purchased from Sigma Aldrich (St. Louis, MO, USA).

Preparation of working solution . For the reference compounds (fenofrol, propranolol and digoxin) and test compounds, a 0.4 mM intermediate solution was prepared by diluting 10 mM or other suitable concentration of DMSO stock solution with DMSO. The 2 μΜ dosing solution of the reference compound and the test compound was prepared by incorporating an appropriate volume of the intermediate solution into the TB with and without 1 μΜ Zosuquidar. The final concentration of DMSO is no more than 1% (v/v).

Caco-2 cell culture . The Caco-2 cell line was grown in MEM supplemented with 2 mM L-glutamine, 10% FBS, 100 U/mL penicillin-G, and 100 μg/mL streptomycin. The cells were incubated at 37 ° C, 5% CO 2 and relative saturation humidity. After reaching 80-90% confluence, the cells were gently fractionated using a 0.05% trypsin-EDTA solution. Cells passaged 30-50 were seeded at a density of 1 x 10 ⁵ cells/cm ² on a 96-well BD insertion system (Cat #359274), and cultured 21-28, wherein the medium was changed every 4-5 days.

Transport procedure . Pre-warm TB and dosing solution to 37 °C prior to shipping assay. The cell monolayer was washed twice with HBSS containing 10 mM HEPES. For the AB (top to bottom side) directional transport assay, 75 μL of dosing solution was added to the tip well. Fill each bottom side hole with 250 μLTB. For the BA (bottom side to tip) directional transport assay, after filling each tip well with 75 μL TB, add 250 μL of the dosing solution to the bottom side well. Test compounds and digoxin were tested in duplicate at 2 μM in both directions in the presence or absence of 1 μM zosuquidar. Atenolol and propranolol were tested in duplicate in 2 μM in the A to B direction in the absence of zosuquidar. The plates were incubated for 120 minutes at 37 ° C with 5% CO ₂ and saturated humidity. The time zero sample is prepared by mixing 50 μL of the initial dosing solution of the test compound or reference compound with 100 μL of TB and 250 μL of quenching solution (acetonitrile (ACN) or other suitable solvent with internal standard, based on bioanalytical methods). To produce. At 120 minutes, 150 μL of solution was collected from each AB acceptor well followed by the addition of 250 μL of quenching solution to obtain an AB receptor sample. In addition, for the other samples (AB donor, BA donor and acceptor), 50 μL of solution was collected from each corresponding well followed by the addition of 250 μL of quenching solution and 100 μL of TB. All samples were vortex mixed and centrifuged at 3220 g for 20 minutes. Subsequently, the supernatant was diluted with ultrapure water for LC-MS/MS analysis. The concentration of the test compound in all samples was determined by LC-MS/MS and expressed as the peak area ratio of the analyte to the internal standard.

The concentration of the sample is expressed as the peak area ratio of the analyte to the internal standard (analyte/IS).

The performance permeability coefficient (P _app ) is calculated using the following equation: P _app = V _R / (area * time) * (C _R /C ₀ ) where V _R is the volume of the solution in the receptor chamber (0.075 mL on the top side) , 0.25 mL on the side of the bottom side; the area is the surface area of the transport, that is, 0.0804 cm ² for the single-layer area; the time is the incubation time, expressed in seconds, 2 h = 2 × 3600 s; C ₀ the initial concentration in the donor chamber body; C _R is the receptor chamber of final concentration.

The effluent ratio is calculated using the following equation: Effluent ratio = P _app (AB) / P _app (BA) where P _app (AB) and P _app (BA) are the P _app of the compound in the directional transport from top to bottom, respectively. Value and P _app value of the compound in the bottom side to top directional transport.

The results when the value of the ratio of the effluent was> 3, the compound is generally considered to be based P- glycoprotein substrate. The compounds of the invention typically have an effluent ratio of > 3 as demonstrated in Table 7 below. Table 7 III.2. Determination of the concentration of A2A antagonists in brain and cerebrospinal fluid compared to plasma

Purpose . The current assay aims to demonstrate that these compounds do not have any significant CNS permeability by determining the concentration of the compounds of the invention in brain and cerebrospinal fluid (CSF) compared to plasma.

Method . Oral administration of a 1.00 mg/mL suspension (homogeneous opaque suspension) adjusted to pH 3-4 in 10% DMSO + 10% solutol + 80% water at a dose of 10 mg/kg 7- 9-week-old female Balb-c mice (obtained from SLAC Laboratory Animal Co. Ltd., Shanghai, China or SIPPR-B & K Laboratory Animal Co. Ltd., Shanghai, China).

Animals were fasted for at least 12 hours prior to administration. All animals were fed ad libitum to a qualified rodent diet (Catalog # M01-F, SLAC Laboratory Animal Cl. Ltd., Shanghai, China) 4 hours after dosing. Continuous bleeding was performed from the submandibular or saphenous vein (approximately 30 μL of blood per time point). The samples were transferred to a pre-cooled microcentrifuge tube containing 2 μL of K2EDTA (0.5 M) as an anticoagulant and placed on wet ice for further processing. Immediately after blood collection, the intact brain is harvested immediately at the design time point. CSF was collected from the large pool at selected time points after administration.

Blood samples from the blood samples were centrifuged at approximately 4 ° C, 3000 g for 15 min within half an hour of collection. Plasma samples were stored in polypropylene tubes, snap frozen on dry ice and maintained at -70 °C until LC/MS/MS analysis. Brain samples were weighed, washed in cold distilled water to remove blood, and homogenized using pre-cooled water at a ratio of 1:4 (1 g of brain using 4 mL of water). In addition, the brain homogenate was maintained at -70 °C until LC/MSMS analysis. CSF was snap frozen on dry ice and kept at -70 °C until LC/MS/MS analysis.

Results. For example, compounds of the present invention 4, in which under these conditions, in the brain or CSF of mice not measurable amount of discovery.

The individual and average concentrations of Example 4 after PO administration (10 mg/kg) are provided in Table 8 below. Table 8 III.3. Determination of CNS activity by mobile motion assay

OBJECTIVE . In addition to the adenosine immunosuppressive effect, it has also been established that adenosine regulates neuronal function via its interaction with A2AR in the central nervous system. This interaction mediates the part of the dopamine pathway involved in movement. It has been demonstrated in the brain to prevent this movement from inducing excessive movement in animals by a highly permeable A2AR antagonist compound in the brain such as Preladenant (formerly used to prevent Parkinson's disease). This can potentially cause problems for compounds intended for Parkinson's therapy, such as Prelandenant, ie for resetting purposes for cancer immunotherapy.

The current assay is intended to demonstrate that the compounds of the invention do not have any significant CNS activity by using the method disclosed by Hodgson et al. (J. Pharma. And Exp. Thera. 2009). The principle of this assay is that CGS21680, which is a brain-permeable A2AR-specific adenosine analog, induces immobility (too low moving motion) within a few minutes after subcutaneous (s.c.) injection in mice. Therefore, mice treated with a brain permeable A2AR antagonist prior to treatment with CGS21680 will prevent hypokinetic movement.

The reference brain osmotic compound Preladenant was compared to the compounds of the invention for their effect on CGS21680 induced immobility at various oral (PO) concentrations.

Method . Compounds were administered 30 min before CGS21680 and monitored for movement over a period of 30 min. Mice were scored for non-mobility using the score ranges described in Table 10 (Table 9).

Results . When administered alone at 1 mg/kg (sc), CGS21680 induced complete immobility after 30 min. Preladenant inhibits the inability to induce CGS21680 when administered at 10 mg/kg PO, while the compounds of the invention fail to completely prevent immobility when administered at equivalent doses. This data supports PK data from brain and spinal fluid to confirm that the compounds of the present invention have reduced brain permeability and CNS activity compared to Preladenant. Table 9. Compounds of the invention have reduced brain permeability activity * Scores observed over 30 minutes in at least 60-100% of mice, n = 3-5 mice/group Table 10. Mobile Motion Scores

no

FIG 1 is a show in the presence of A2a agonist CGS24680, the percentage of cytokine release in peripheral blood lymphocytes with the compounds of the present invention a concentration of 7 changes graph. Figure 1A relates to whole blood cell cultures stimulated with LPS and Figure 1B relates to whole blood cell cultures stimulated with anti-CD3/CD28.

FIG 2 is a showing of peripheral blood lymphocytes with pCREB inhibition percentage graph of the concentration of compound 4 of the present invention changes.

FIG 3 is a graph showing the percentage cytotoxicity of the compounds of the present invention with a concentration of 4 and 31 of the change.

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Claims (15)

a compound of formula (I) (I) or a pharmaceutically acceptable salt or solvate thereof, wherein: R ¹ represents a 5 or 6 membered heteroaryl group or a 5 or 6 membered aryl group, wherein the heteroaryl or aryl group is optionally subjected to one or a plurality of substituents selected from the group consisting of C1-C6 alkyl (preferably methyl) and halo (preferably fluoro or chloro); preferably R ¹ represents a 5-membered heteroaryl; More preferably R ¹ represents a furyl group; R ² represents a 6-membered aryl group or a 6-membered heteroaryl group, wherein the heteroaryl group or the aryl group is optionally substituted with one or more substituents selected from the group consisting of halo, Alkyl, heterocyclic, alkoxy, cycloalkoxy, heterocyclyloxy, carbonyl, alkylcarbonyl, aminocarbonyl, hydroxycarbonyl, heterocyclylcarbonyl, alkyl amidino, alkylsulfonyl An aminosulfonyl group, a heterocyclylsulfonyl group, an alkyl sulfoximine group, a carbonylamino group, a sulfonylamino group and an alkylalkyl group; the substituents being optionally selected from one or more Substituents for the following: pendant oxy, halo, hydroxy, cyano, alkyl, alkenyl, aldehyde, heterocyclylalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl Aminoalkyl, alkylaminoalkyl, two Alkylaminoalkyl, (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl, alkylheteroaryl, alkyne, alkoxy, amine, dialkylamino Aminoalkylcarbonylamino, aminocarbonylalkylamino, (aminocarbonylalkyl)(alkyl)amino, alkenylcarbonylamino, hydroxycarbonyl, alkoxycarbonyl, aminocarbonyl, amine Alkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, heterocyclylalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)amine Carbocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylhydrazine, alkylalkylene, alkylsulfonyl And an alkylarylalkyl group; or a heteroaryl or aryl group is optionally substituted with two substituents which, together with the atom to which they are attached, form a 5 or 6 membered aryl ring, a 5 or 6 membered heteroaryl group. a ring, a 5 or 6 membered cycloalkyl ring or a 5 or 6 membered heterocyclyl ring; optionally substituted with one or more substituents selected from the group consisting of pendant oxy, halo, hydroxy, cyano , alkyl, alkenyl, aldehyde, heterocycloalkyl Hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl)(alkyl)aminoalkyl ,heterocyclyl,heteroaryl,alkylheteroaryl,alkyne,alkoxy,amino,dialkylamino,aminoalkylcarbonylamino,aminocarbonylalkylamino,(amino) Carbonylalkyl)(alkyl)amino, alkenylcarbonylamino, hydroxycarbonyl, alkoxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkyl Aminoalkylaminocarbonyl, heterocyclylalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, Heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylhydrazine, alkylalkylene, alkylsulfonyl and alkylalkyl. The compound of claim 1, which has the formula (Ia) (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein: R ¹ is as defined in claim 1; X ¹ and X ² each independently represent C or N; when X ¹ is N, R ¹ 'absent; or when X ¹ is C, R ¹ ' represents H, halo, alkyl, heterocyclyl, alkoxy, cycloalkoxy, heterocyclyloxy, carbonyl, alkylcarbonyl, Aminocarbonyl, hydroxycarbonyl, heterocyclylcarbonyl, alkylhydrazine, alkylsulfonyl, aminosulfonyl, heterocyclylsulfonyl, alkyl sulfoximine, carbonylamino, sulfonyl Amino or alkylalkyl; these substituents are optionally substituted with one or more substituents selected from the group consisting of pendant oxy, halo, hydroxy, cyano, alkyl, alkenyl, aldehyde, Heterocyclylalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl) (alkane) Aminoalkyl, heterocyclyl, heteroaryl, alkylheteroaryl, alkyne, alkoxy, amine, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkyl Amine, (aminocarbonylalkyl)(alkyl)amino, alkenylcarbonylamino , hydroxycarbonyl, alkoxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, heterocyclylalkylaminocarbonyl (alkylaminoalkyl)(alkyl)aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkyl Anthracene, alkylalkylene, alkylsulfonyl and alkylalkyl; R ² ' represents H, halo, alkyl, heterocyclyl, alkoxy, cycloalkoxy, heterocyclooxy Base, carbonyl, alkylcarbonyl, aminocarbonyl, hydroxycarbonyl, heterocyclylcarbonyl, alkyl sulfonium, alkylsulfonyl, aminosulfonyl, heterocyclylsulfonyl, alkyl sulfimine a carbonylamino group, a sulfonylamino group, or an alkylalkyl group; the substituents are optionally substituted with one or more substituents selected from the group consisting of pendant oxy, halo, hydroxy, cyano , alkyl, alkenyl, aldehyde, heterocyclylalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkane (heterocyclyl) (alkyl Aminoalkyl, heterocyclyl, heteroaryl, alkylheteroaryl, alkyne, alkoxy, amine, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamine (Aminocarbonylalkyl)(alkyl)amino, alkenylcarbonylamino, hydroxycarbonyl, alkoxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylamino Carbonyl, dialkylaminoalkylaminocarbonyl, heterocyclylalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl, alkylaminoalkylcarbonyl, dialkylamine Alkylcarbonyl, heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylhydrazine, alkylalkylene, alkylsulfonyl and alkylalkyl; or R ¹ 'and R ² ' Together with the atoms to which they are attached form a 5 or 6 membered aryl ring, a 5 or 6 membered heteroaryl ring, a 5 or 6 membered cycloalkyl ring or a 5 or 6 membered heterocyclyl ring; Or a plurality of substituents selected from the group consisting of pendant oxy, halo, hydroxy, cyano, alkyl, alkenyl, aldehyde, heterocyclylalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkane Aminoalkyl, aminoalkyl, alkylaminoalkyl Dialkylaminoalkyl, (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl, alkylheteroaryl, alkyne, alkoxy, amine, dialkylamine Alkylaminocarbonylamino group, aminocarbonylalkylamino group, (aminocarbonylalkyl)(alkyl)amino group, alkenylcarbonylamino group, hydroxycarbonyl group, alkoxycarbonyl group, aminocarbonyl group, Aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, heterocyclylalkylaminocarbonyl, (alkylaminoalkyl)(alkyl) Aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylhydrazine, alkylalkylene, alkylsulfonate And alkylalkylalkyl; R ³ ' is absent when X ² is N; or when X ² is C, R ³ ' represents H or halo, preferably H or F; R ^{4 '} represents H or Halo, preferably H or F; and R ^{5 '} represents H or halo, preferably H or F. A compound according to claim 1 or claim 2, which has the formula (Ia-1) (Ia-1) or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ , R ^{1 '} , R ^{2 '} , R ^{3 '} , R ^{4 '} and R ^{5 '} are as defined in claim 2 . The compound of claim 3, which has the formula (Ia-1a) (Ia-1a) or a pharmaceutically acceptable salt or solvate thereof, wherein: R ¹ and R ^{3 '} are as defined in the claim 2; and R ^1" represents an alkyl group or a heterocyclic group, which is One or more groups selected from the group consisting of: pendant oxy, halo, hydroxy, cyano, alkyl, alkenyl, aldehyde, heterocyclylalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxy Alkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl, alkane Heteroaryl, alkyne, alkoxy, amine, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, (aminocarbonylalkyl)(alkyl)amine , alkenylcarbonylamino, hydroxycarbonyl, alkoxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, heterocyclic Alkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkenylcarbonyl, alkyne Carbocarbonyl, alkyl hydrazine, alkyl alkylene, alkyl sulfonate Alkyl group and a sulfone group. The compound of claim 3, which has the formula (Ia-1b) (Ia-1b) or a pharmaceutically acceptable salt or solvate thereof, wherein: R ¹ and R ^{3 '} are as defined in claim 2; R ^{1 '} represents H or a halo group, preferably H or F; and R ^2" represents an alkyl or heterocyclic group substituted by one or more groups selected from the group consisting of pendant oxy, halo, hydroxy, cyano, alkyl, alkenyl, aldehyde, Heterocyclylalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl) (alkane) Aminoalkyl, heterocyclyl, heteroaryl, alkylheteroaryl, alkyne, alkoxy, amine, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkyl Amino, (aminocarbonylalkyl)(alkyl)amino, alkenylcarbonylamino, hydroxycarbonyl, alkoxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylamine Carbocarbonyl, dialkylaminoalkylaminocarbonyl, heterocyclylalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl, alkylaminoalkylcarbonyl, dialkyl Aminoalkylcarbonyl, heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkyl Anthracene, alkylalkylene, alkylsulfonyl and alkylalkyl. A compound according to claim 3, which has the formula (Ia-1c) or (Ia-1d) (Ia-1c) (Ia-1d), or a pharmaceutically acceptable salt or solvate thereof, wherein: R ¹ and R ^{3 '} are as defined in claim 2; R ^{1 '} represents H or halo, preferably H or F; R ^{2 '} represents H or a halogen group, preferably H or F; R ¹ⁱ and R ¹ⁱⁱ each independently represent hydrogen, hydroxy, alkyl, alkenyl, heterocyclylalkyl, hydroxyalkyl, dihydroxyalkane , hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl)(alkyl)aminoalkyl, heterocyclic, heteroaryl Base, alkyl heteroaryl, alkynyl, alkoxy, amine, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, (aminocarbonylalkyl) (alkane) Amino, alkenylcarbonylamino, hydroxycarbonyl, alkoxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylamino Carbonyl, heterocyclylalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkene Carbocarbonyl, alkynylcarbonyl, alkylalkylene or alkylalkyl; and R ²ⁱ and R ²ⁱⁱ each independently represents hydrogen, hydroxy, alkyl, alkenyl, heterocyclylalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, Dialkylaminoalkyl, (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl, alkylheteroaryl, alkynyl, alkoxy, amine, dialkyl Amino, aminoalkylcarbonylamino, aminocarbonylalkylamino, (aminocarbonylalkyl)(alkyl)amino, alkenylcarbonylamino, hydroxycarbonyl, alkoxycarbonyl, aminocarbonyl Aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, heterocyclylalkylaminocarbonyl, (alkylaminoalkyl) (alkyl) Aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylalkylene or alkylalkyl. A compound according to claim 1 or claim 2, which has the formula (Ia-2) or (Ia-3) (Ia-2) (Ia-3) or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ , R ^{2 '} , R ^{3 '} , R ^{4 '} and R ^{5 '} are as defined in the claim 2. The compound of claim 1, which is selected from the group consisting of: And pharmaceutically acceptable salts or solvates thereof. A pharmaceutical composition comprising a compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable carrier. An agent, which comprises a compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt or solvate thereof. A compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment and/or prevention of cancer. The compound for use according to claim 11, wherein the cancer is selected from the group consisting of breast cancer, carcinoid carcinoma, cervical cancer, colorectal cancer, endometrial cancer, glioma, head and neck cancer, liver cancer, lung cancer, Melanoma, ovarian cancer, pancreatic cancer, prostate cancer, kidney cancer, stomach cancer, thyroid cancer, and urinary epithelial cell carcinoma. A compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt or solvate thereof, for use as an A2A inhibitor. A process for the manufacture of a compound of the formula (Ia) according to any one of claims 2 to 8 or a pharmaceutically acceptable salt or solvate thereof, characterized in that the process comprises the step of: an amine of the formula (A) Intermediate (A) wherein X ¹ , X ² , R ^{1 '} , R ^{2 '} , R ^{3 '} , R ^{4 '} and R ^{5 '} are as defined in claim 2; and are coupled with the intermediate of formula (B) Wherein R ¹ is as defined in the claim 2 and Y represents a halogen group, an alkylsulfonyloxy group having 1 to 6 carbon atoms or an arylsulfonyloxy group having 6 to 10 carbon atoms. A compound of formula (A) selected from the group consisting of: - 1-(4-((1H-1,2,3-triazol-5-yl)methoxy)-2-fluorobenzene Piperazine; 1-(2-fluoro-4-(prop-2-yn-1-yloxy)phenyl)piperazine; 2-(2,4-difluoro-5-(piperazine) -1-yl)phenoxy)acetamide;-( S )-1-(2-fluoro-4-(2-(methylsulfinyl)ethoxy)phenyl)piperazine;- R )-1-(2-fluoro-4-(2-(methylsulfinyl)ethoxy)phenyl)piperazine; -( R,S )-1-(2,4-difluoro- 5-(2-(methylsulfinyl)ethoxy)phenyl)piperazine; -( S )-1-(2,4-difluoro-5-(2-(methylsulfinyl) Ethoxy)phenyl)piperazine;-( R )-1-(2,4-difluoro-5-(2-(methylsulfinyl)ethoxy)phenyl)piperazine; Its salt or solvate.