TWI801372B - 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

Description

Thicarbamate derivatives as A2A inhibitors and methods for use in cancer treatment

The present invention relates to novel thiamine derivatives, including their pharmaceutically acceptable salts and solvates. The compounds of the invention are inhibitors of the adenosine A2A receptor and are useful as therapeutic compounds, especially in the treatment and/or prevention of cancer.

Many mechanisms of immunosuppression in tumors are common to physiological immune regulation in normal tissues. Such immune regulation is extremely important in keeping the immune system under control to block self-reactive immune responses and prevent ongoing immune responses from causing destruction of critical tissues. Lack of physiological immune regulation often results in the overwhelming immune activation that accompanies autoimmunity. For example, CTLA-4 is a physiological mechanism that negatively regulates T cell activity by blocking co-stimulatory signaling through CD28-B7 interaction. Lack of CTLA4 causes nonspecific T cell activation, and CTLA-4-deficient mice die within weeks due to massive lymphocytic tissue infiltration. PD-1 also provides T cell inhibitory 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 strain.

In addition to cell surface transducers of immunosuppressive signals such as CTLA-4 and PD-1, immunosuppression in the tumor microenvironment involves anti-inflammatory cytokines (IL-10, TGF-β), enzymes (indoleamine-2 ,3-Dioxygenase), and specialized immune regulatory cells (regulatory T cells, suppressor cells derived from bone marrow MDSC). These immunosuppressive mechanisms play an important role in controlling immune responses in normal tissues. Because tumors utilize such physiological immunoregulatory mechanisms to protect their tissues from immune invasion, these mechanisms, intended to prevent inflammatory complications, are now a major obstacle to spontaneous cancer regression and immunological cancer therapy. The identification of mechanisms of immunosuppression in tumors points to molecular targets to restore anti-tumor immune responses. Consequently, these negative immune regulatory mechanisms, so-called immune checkpoints, have become a focus in drug discovery. Also, antibodies to PD1, PDL1, or CTLA4 have been approved as anticancer agent therapies for a number of indications, such as metastatic melanoma, non-small cell lung cancer, renal cell malignancies, Hodgkin's lymphoma, Head and neck cancer, urothelial malignancies, hepatocellular carcinoma, and as treatment of patients with solid tumors with known mismatch repair deficiency and high microsatellite instability regardless of cancer type One of two specific genetic traits.

Extracellular adenosine has been known as a suppressor of immune function. While intracellular adenosine is involved in energy metabolism, nucleic acid metabolism, and methionine cycle, extracellular adenosine plays an important role in intercellular communication. Its signals are transmitted through G protein-coupled adenosine receptors on the cell surface and it affects a variety of physiological functions, including the neurological, cardiovascular, and immune systems.

Tumors contain high levels of extracellular adenosine, suggesting that tumor cells may benefit from its immunosuppressive effects and catabolic 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 was overexpressed by a large number of tumors, all of the following tumors overexpressed intermediate or high levels of CD73 in >50% of the tumor surface by immunohistochemistry (www.proteinatlas.org): breast tumors, carcinoid tumors, cervical tumors Tumors, Colorectal Tumors, Endometrial Tumors, Gliomas, Head and Neck Tumors, Liver Tumors, Lung Tumors, Melanoma, Ovarian Tumors, Pancreatic Tumors, Prostate Tumors, Kidney Tumors, Stomach Tumors, Thyroid Tumors, Urothelial Tumors .

Of the four known types of adenosine receptors, the A2A adenosine receptor (A2AR) is the subtype that is prominently expressed on most immune cells. Stimulation of A2AR generally provides an immunosuppressive signal that inhibits the activity of: T cells (proliferation, interleukin production, cytotoxicity), NK cells (cytotoxicity), NKT cells (interleukin production, upregulation of CD40L), Macrophages/dendritic cells (antigen presentation, cytokine production), and neutrophils (oxidative burst). The presence of high levels of extracellular adenosine in tumors was found to play an important role in the evasion of antitumor immune responses. In particular, it has been demonstrated that A2AR-deficient mice can spontaneously regress inoculated tumors, whereas wild-type mice do not exhibit similar tumor regression. A2AR antagonists are also beneficial in tumor-bearing wild-type animals. Importantly, depletion of T cells and NK cells impairs tumor growth arrest by A2AR antagonists, implying improvement of anti-tumor cellular immune responses. Effector functions of T cells and NK cells are sensitive to A2AR stimulation. In addition, when activated in the presence of A2AR agonists, the effector functions of T cells are persistently impaired even after removal of the A2AR agonist. This result suggests that the adenosine-rich environment in tumors can induce T cells that are desensitized to tumor cells.

Therefore, if A2A receptors are expressed in most immune cells and especially effector immune cells such as T cells and NK cells and if A2A receptors are involved in tissues where adenosine is produced, A2A inhibitors are considered useful in all cancer indications Medium is helpful.

Therefore, there is a need for A2A inhibitors capable of restoring immune function in the tumor setting.

Adenosine is known to be an endogenous regulator of many other physiological functions. For example, at the level of the central nervous system (CNS), adenosine is known to induce sedative, anxiolytic and antiepileptic effect levels.

Therefore, A2A inhibitors have been previously developed for the treatment of depression and neurodegenerative diseases such as Parkinson's or Alzheimer's disease (Pinna A., CNS Drugs, 2014, 28, 455). One of the most advanced A2A inhibitors developed for the treatment of CNS diseases 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 were designed to cross the blood-brain barrier in order to target A2A receptors in the CNS.

Given the higher levels of adenosine present in tumors when compared to brain, much higher amounts of compound would be required to achieve the desired effect on restoration of immune function for the treatment of cancer. Therefore, to avoid deleterious side effects, A2A inhibitors should be provided that have limited, if any, CNS penetration, contrary to all previously developed A2A inhibitors.

As demonstrated in the experimental section below, applicants hereby provide novel A2A inhibitors which do not possess any significant CNS penetration and which can therefore be used in the treatment of cancer.

(I) 或其醫藥學上可接受的鹽或溶劑合物，其中R¹ 及R² 係如下文所定義。The present 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.

(Ia) 或其醫藥學上可接受的鹽或溶劑合物，其中R¹ 、R^1’ 、R^2’ 、R^3’ 、R^4’ 及R^5’ 係如下文所定義。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.

(Ia-1) 或其醫藥學上可接受的鹽或溶劑合物，其中R¹ 、R^1’ 、R^2’ 、R^3’ 、R^4’ 及R^5’ 係如式(Ia)中所定義。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 in formula (Ia) definition.

(Ia-2)

(Ia-3) 或其醫藥學上可接受的鹽或溶劑合物，其中R¹ 、R^2’ 、R^3’ 、R^4’ 及R^5’ 係如式(Ia)中所定義。According to one embodiment, the compound of formula (Ia) is 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 present invention also relates to pharmaceutical compositions comprising a compound according to the present invention or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable carrier.

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

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

The present invention further relates to compounds according to the present invention or pharmaceutically acceptable salts or solvates thereof for use as A2A inhibitors.

(A) 其中X¹ 、X² 、R^1’ 、R^2’ 、R^3’ 、R^4’ 及R^5’ 係在下文定義； 與式(B)之中間物之間偶合

其中R¹ 係如下文所定義且Y 表示鹵基、具有1至6個碳原子之烷基磺醯基氧基或具有6至10個碳原子之芳基磺醯基氧基。Also provided is a process for the manufacture of a compound of formula (Ia) or a pharmaceutically acceptable salt or solvate thereof according to the present invention, characterized in that the process 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 defined below; coupling between intermediates of formula (B)

wherein ^R is as defined below and Y represents halo, alkylsulfonyloxy having 1 to 6 carbon atoms or arylsulfonyloxy having 6 to 10 carbon atoms.

The present invention also relates to synthetic intermediates 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 " aldehydealkyl " refers to the group -alkyl-CHO, where alkyl is as defined herein.

The term " alkenyl " refers to an unsaturated hydrocarbon group, which may be straight or branched, containing 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 are vinyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl and its isomers, 2-hexene and its isomers, 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, where alkyl is as defined herein.

The term " alkyl " refers to a hydrocarbyl radical of the formula _{CnH2n +1} , where n is a number greater than or equal to 1. Typically, the alkyl groups of the present invention contain 1 to 8 carbon atoms, more preferably, the alkyl groups of the present invention contain 1 to 6 carbon atoms. Alkyl groups may be straight or branched. Suitable alkyl groups include methyl, ethylpropyl, 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 , where R ¹ is alkyl and R ² is -alkyl-NH- Alkyl, wherein alkyl is as defined in the definition.

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, where alkyl is as defined herein.

The term " alkylheteroaryl " refers to any heteroaryl group substituted with an alkyl group, where 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 " refers to the group _-SO2 -alkyl, wherein alkyl is as defined herein.

The term " alkyladenyl " refers to the group -alkyl- _SO2 -alkyl, wherein alkyl is as defined herein.

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

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

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

The term " alkyne " refers to a class of monovalent unsaturated hydrocarbon radicals in which the unsaturation results from the presence of one or more carbon-carbon triple bonds. Alkynyl groups typically and preferably have the same number of carbon atoms as described above for alkyl groups. Non-limiting examples of alkynyl 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 " alkynecarbonylalkyl " refers to the group -alkyl-(C=O)-alkyne, wherein alkyl and alkyne are as defined herein.

The term " amino " refers to the group _-NH2 .

The term " aminoalkyl " refers to the group -alkyl- _NH2 , wherein alkyl is as defined herein.

The term " aminoalkylaminocarbonyl " refers to the group -(C=O)-NH-alkyl- _NH2 , wherein alkyl is as defined herein.

The term " aminoalkylcarbonylamino " refers to the group -NH-(C=O)-alkyl- _NH2 , wherein alkyl is as defined herein.

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

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

The term " aminocarbonylalkylamino " refers to the group -NH-alkyl-(C=O) _-NH2 , wherein alkyl is as defined herein.

The term " sulfamoyl " refers to the group -SO ₂ -NH ₂ .

The term " aryl " refers to a polyunsaturated, aromatic hydrocarbon group having a single ring (i.e. phenyl) or multiple aromatic rings fused together (e.g. naphthyl), typically containing 5 to 12 atoms; Preferably 5 to 10; more preferably aryl is 5 or 6 membered aryl. Non-limiting examples of aryl include phenyl, naphthyl.

The term " carbonyl " refers to the 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 valent, saturated, or unsaturated hydrocarbon group having 1 or 2 ring structures. Cycloalkyl includes monocyclic or bicyclic hydrocarbon groups. Cycloalkyl groups may contain 3 or more carbon atoms in the ring, and in general, according to the invention contain 3 to 10, more preferably 3 to 8 carbon atoms; still more preferably cycloalkyl groups are 5 or 6-membered cycloalkyl. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.

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

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

The term "dialkylaminoalkyl" refers to the group -alkyl- ^NR1R2 , wherein ^R1 and ^{R2 are} both independently alkyl as defined herein.

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

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

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

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

The term " heteroaryl " refers to an aryl group as defined herein, wherein at least one carbon atom is replaced by a heteroatom. In other words, it refers to an aromatic monocyclic ring of 5 to 12 carbon atoms, or a ring system containing 2 rings fused together, typically containing 5 to 6 atoms; one or more of the carbon atoms being represented by oxygen , nitrogen and/or sulfur atom replacement, wherein the nitrogen and sulfur heteroatoms are optionally oxidized and the nitrogen heteroatoms are optionally quaternized. Non-limiting examples of such heteroaryl groups include: oxazolyl, thiazolyl, imidazolyl, furyl and pyrrolyl. Preferably, the heteroaryl is 5- or 6-membered heteroaryl, more preferably the 5- or 6-membered heteroaryl is furyl.

The term " heterocyclyl " refers to a non-aromatic, fully saturated or partially unsaturated cyclic group (e.g., 3 to 7 membered monocyclic ring, 7 to 11 membered bicyclic ring, or containing a total of 3 to 10 ring atoms), which There is at least one heteroatom in at least one carbon atom-containing ring. Preferably, the heterocyclic group is a 5- or 6-membered heterocyclic group. Each ring of the heterocyclic group containing heteroatoms may have 1, 2, 3 or 4 heteroatoms selected from nitrogen atoms, oxygen atoms and/or sulfur atoms, wherein the nitrogen and sulfur heteroatoms are optionally oxidized and the nitrogen heteroatoms Depending on the situation, it can be upgraded to four levels. A heterocyclyl group may be attached at any heteroatom or carbon atom where the valence of the ring or ring system permits. The rings of a polycyclic heterocycle may be fused, bridged and/or joined via one or more spiro atoms. Non-limiting exemplary heterocyclyl groups include aziridinyl, oxiranyl, thiocyclopropyl, piperidinyl, azetidinyl, 2-imidazolinyl, pyrazolidine Base, imidazolidinyl, isoxazolinyl, oxazolinyl, isoxazolinyl, thiazolidinyl, isothiazolinyl, piperidinyl, succinimide, 3H-indolyl, indole Linyl, isoindolinyl, 2H-pyrrolyl, 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolidinyl, 4H-quinazinyl, 2-oxopiperazinyl , piperazinyl, monopiperazinyl, 2-pyrazolinyl, 3-pyrazolinyl, tetrahydro-2H-pyranyl, 2H-pyranyl, 4H-pyranyl, 3,4-di Hydrogen-2H-pyranyl, oxetanyl, thietanyl, 3-dioxolyl, 1,4-dioxanyl, 2,5 -Dioxyimidazolidinyl, 2-oxo-piperidinyl, 2-oxo-pyrrolidinyl, indolinyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydrophenylsulfanyl, tetrahydroquinolinyl , tetrahydroisoquinolin-1-yl, tetrahydroisoquinolin-2-yl, tetrahydroisoquinolin-3-yl, tetrahydroisoquinolin-4-yl, thiomorpholin-4-yl, 1-oxo-1thiomorpholin-4-yl, 1-dioxo-1thiomorpholin-4-yl, 1,3-dioxolane, 1,4-oxathione Cyclohexyl (1,4-oxathianyl), 1,4-dithianyl (1,4-dithianyl), 1,3,5-trioxepanyl (1,3,5-trioxanyl) , 1H-pyrrolidinyl (1H-pyrrolizinyl), tetrahydro-1,1-dioxophenylthio, N-formylpiperazinyl, and morpholin-4-yl.

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

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 heterocyclyl is as defined herein.

The term " heterocyclylsulfonyl " refers to the group _-SO2 -heterocyclyl, wherein heterocyclyl is 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 " side oxy " refers to a =O substituent.

The term " sulfonylamino " refers to the group -NH- _SO2 .

The term " about " preceding a number means plus or minus 10% of the value of the number.

The term " administration " or variations thereof (e.g., " administering " means providing an active agent or active ingredient (e.g., an A2A inhibitor) alone or as part of a pharmaceutically acceptable composition to A patient whose condition, symptom, or disease is to be treated or prevented.

The term " _IC50 " or " half-maximal inhibitory concentration " denotes the concentration of 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 a 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 subjects of both genders and at any stage of development (ie, neonates, infants, juveniles, adolescents, adults).

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

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

The expression " pharmaceutically acceptable carrier " refers to an excipient which does not produce adverse, allergic or other adverse reactions when administered to animals, preferably humans. This includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. For human administration, preparations should meet sterility, pyrogenicity, general safety and purity standards as required by regulatory offices such as, for example, FDA offices or EMA.

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

As used herein, the terms " prevent " , " preventing " and " prevention " refer to delaying or excluding the onset of a condition or disease and/or its accompanying symptoms, preventing a patient from developing the condition or disease, or methods of reducing a patient's risk of developing 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 amide, the product of which is biotransformed in vivo to yield a biologically active drug. Prodrugs are often characterized by increased bioavailability and are readily metabolized in vivo to biologically active compounds.

The term " treating " or " treatment " refers to both therapeutic treatment and prophylactic or preventive measures; wherein the object is to prevent or slow down the targeted pathological condition or disease. Those in need of treatment include those already with the disease as well as those prone to have the disease or those in which the disease is to be prevented. A subject or mammal is successfully "treated" if, after receiving treatment according to the present invention, the subject or mammal exhibits an observable and/or measurable decrease or absence of one or more of the following "Disease or infection or condition: reduction in tumors; and/or remission to some extent for one or more of the symptoms associated with a particular disease or condition; reduced morbidity and mortality, and life Improvement of quality problems. The above parameters for assessing successful treatment and disease improvement can be readily measured by routine procedures with which physicians are familiar.

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

compound

(I) 或其醫藥學上可接受的鹽或溶劑合物，其中：R¹ 表示5或6員雜芳基或5或6員芳基，其中雜芳基或芳基視需要經一或多個選自以下各項之取代基取代：C1-C6烷基(較佳地甲基)及鹵基(較佳地氟基或氯基)；較佳地R¹ 表示5員雜芳基；更佳地R¹ 表示呋喃基；R² 表示6員芳基或6員雜芳基， 其中雜芳基或芳基視需要經一或多個選自以下各項之取代基取代：鹵基、烷基、雜環基、烷氧基、環烷氧基、雜環基氧基、羰基、烷基羰基、胺基羰基、羥基羰基、雜環基羰基、烷基亞碸、烷基磺醯基、胺基磺醯基、雜環基磺醯基、烷基碸亞胺基、羰基胺基、磺醯基胺基及烷基碸烷基； 該等取代基視需要經一或多個選自以下各項之取代基取代：側氧基、鹵基、羥基、氰基、烷基、烯基、醛、雜環基烷基、羥烷基、二羥基烷基、羥基烷基胺基烷基、胺基烷基、烷基胺基烷基、二烷基胺基烷基、(雜環基)(烷基)胺基烷基、雜環基、雜芳基、烷基雜芳基、炔烴、烷氧基、胺基、二烷基胺基、胺基烷基羰基胺基、胺基羰基烷基胺基、(胺基羰基烷基)(烷基)胺基、烯基羰基胺基、羥基羰基、烷氧基羰基、胺基羰基、胺基烷基胺基羰基、烷基胺基烷基胺基羰基、二烷基胺基烷基胺基羰基、雜環基烷基胺基羰基、(烷基胺基烷基)(烷基)胺基羰基、烷基胺基烷基羰基、二烷基胺基烷基羰基、雜環基羰基、烯基羰基、炔基羰基、烷基亞碸、烷基亞碸烷基、烷基磺醯基及烷基碸烷基； 或雜芳基或芳基視需要經兩個取代基取代，該等取代基連同其連接的原子一起形成5或6員芳基環、5或6員雜芳基環、5或6員環烷基環或5或6員雜環基環；視需要經一或多個選自以下各項之取代基取代：側氧基、鹵基、羥基、氰基、烷基、烯基、醛、雜環基烷基、羥烷基、二羥基烷基、羥基烷基胺基烷基、胺基烷基、烷基胺基烷基、二烷基胺基烷基、(雜環基)(烷基)胺基烷基、雜環基、雜芳基、烷基雜芳基、炔烴、烷氧基、胺基、二烷基胺基、胺基烷基羰基胺基、胺基羰基烷基胺基、(胺基羰基烷基)(烷基)胺基、烯基羰基胺基、羥基羰基、烷氧基羰基、胺基羰基、胺基烷基胺基羰基、烷基胺基烷基胺基羰基、二烷基胺基烷基胺基羰基、雜環基烷基胺基羰基、(烷基胺基烷基)(烷基)胺基羰基、烷基胺基烷基羰基、二烷基胺基烷基羰基、雜環基羰基、烯基羰基、炔基羰基、烷基亞碸、烷基亞碸烷基、烷基磺醯基及烷基碸烷基。The present invention therefore relates to compounds of formula I

(I) or a pharmaceutically acceptable salt or solvate thereof, wherein: R ¹ represents a 5 or 6-membered heteroaryl or a 5 or 6-membered aryl, wherein the heteroaryl or aryl is optionally modified by one or more A substituent selected from the following substituents is substituted: C1-C6 alkyl (preferably methyl) and halo (preferably fluoro or chloro); preferably R ¹ represents a 5-membered heteroaryl; more Preferably, ^R represents furyl; ^R represents 6-membered aryl or 6-membered heteroaryl, wherein the heteroaryl or aryl is optionally substituted by one or more substituents selected from the group consisting of halo, alkane radical, heterocyclyl, alkoxy, cycloalkoxy, heterocyclyloxy, carbonyl, alkylcarbonyl, aminocarbonyl, hydroxycarbonyl, heterocyclylcarbonyl, alkylene, alkylsulfonyl, Aminosulfonyl group, heterocyclylsulfonyl group, alkylimino group, carbonylamino group, sulfonylamino group and alkylsulfonyl group; these substituents are optionally selected from the following Substituent substitution of each item: 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)amino, alkenylcarbonylamino, Hydroxycarbonyl, Alkoxycarbonyl, Aminocarbonyl, Aminoalkylaminocarbonyl, Alkylaminoalkylaminocarbonyl, Dialkylaminoalkylaminocarbonyl, Heterocyclylalkylaminocarbonyl, (Alkylaminoalkyl)(alkyl)aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylene , alkylidenealkyl, alkylsulfonyl and alkylidenealkyl; or heteroaryl or aryl is optionally substituted with two substituents which, together with the atoms to which they are attached, form 5 or 6 5- or 6-membered aryl ring, 5- or 6-membered heteroaryl ring, 5- or 6-membered cycloalkyl ring, or 5- or 6-membered heterocyclyl ring; optionally substituted with one or more substituents selected from the following: Oxy, halo, hydroxy, cyano, alkyl, alkenyl, aldehyde, heterocyclylalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylamine ylalkyl, dialkylaminoalkyl, (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl, alkylheteroaryl, alkyne, alkoxy, amine, Dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, (aminocarbonylalkyl)(alkyl)amino, alkenylcarbonylamino, hydroxycarbonyl, alkoxycarbonyl, Aminocarbonyl, Aminoalkylaminocarbonyl, Alkylaminoalkylaminocarbonyl, Dialkylaminoalkylaminocarbonyl, Heterocyclylalkylaminocarbonyl, (Alkylaminoalkyl) (Alkyl)aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylene, alkylidene, Alkylsulfonyl and alkylsulfonyl.

According to one embodiment, in formula I: ^R represents a 5- or 6-membered heteroaryl or a 5- or 6-membered aryl, wherein the heteroaryl or aryl is optionally substituted by one or more substituents selected from the following Substitution: C1-C6 alkyl (preferably methyl) and halo (preferably fluoro or chloro); preferably R ¹ represents 5-membered heteroaryl; more preferably R ¹ represents furyl; R ² represents a 6-membered aryl or a 6-membered heteroaryl, wherein the heteroaryl or aryl is optionally substituted by one or more substituents selected from the following: halo, alkyl, heterocyclyl, alkoxy , cycloalkoxy, heterocyclyloxy, carbonyl, alkylcarbonyl, aminocarbonyl, hydroxycarbonyl, heterocyclylcarbonyl, alkylene, alkylsulfonyl, aminosulfonyl, heterocyclyl Sulfonyl, carbonylamino, sulfonylamino, and alkylsulfonyl; these substituents are optionally substituted with one or more substituents selected from the group consisting of hydroxyl, cyano, alkyl, alkenyl aldehyde, hydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl)(alkyl)aminoalkyl, Heterocyclyl, heteroaryl, alkylheteroaryl, alkyne, alkoxy, amino, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, (aminocarbonyl Alkyl)(alkyl)amino, alkenylcarbonylamino, hydroxycarbonyl, alkoxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylamine Alkylaminoalkylcarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkenylcarbonyl, alkyne Alkylcarbonyl, alkylenylene, alkylenalkylene, alkylsulfonyl and alkylenalkylene.

According to one embodiment, in formula I: ^R represents a 5- or 6-membered heteroaryl or a 5- or 6-membered aryl, wherein the heteroaryl or aryl is optionally substituted by one or more substituents selected from the following Substitution: C1-C6 alkyl (preferably methyl) and halo (preferably fluoro or chloro); preferably R ¹ represents 5-membered heteroaryl; more preferably R ¹ represents furyl; R ² represents a 6-membered aryl or a 6-membered heteroaryl, wherein the heteroaryl or aryl is optionally substituted by one or more substituents selected from the following: halo, alkyl, heterocyclyl, alkoxy , cycloalkoxy, heterocyclyloxy, carbonyl, alkylcarbonyl, aminocarbonyl, hydroxycarbonyl, heterocyclylcarbonyl, alkylene, alkylsulfonyl, aminosulfonyl, heterocyclyl Sulfonyl, carbonylamino and sulfonylamino; these substituents are optionally substituted with one or more substituents selected from the group consisting of hydroxyl, cyano, alkyl, alkenyl, aldehyde, hydroxyalkane radical, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl radical, alkylheteroaryl, alkyne, alkoxy, amino, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, (aminocarbonylalkyl)(alkyl )amino, alkenylcarbonylamino, hydroxycarbonyl, alkoxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl , (alkylaminoalkyl) (alkyl)aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylene Alkyl, alkylene alkylene.

或其醫藥學上可接受的鹽或溶劑合物，其中：R ¹ 表示5或6員雜芳基或5或6員芳基，其中雜芳基或芳基視需要經一或多個選自以下各項之取代基取代：C1-C6烷基(較佳地甲基)及鹵基(較佳地氟基或氯基)；較佳地R ¹ 表示5員雜芳基；更佳地R ¹ 表示呋喃基；X ¹ 及X ² 各自獨立地表示C或N；當X ¹ 為N時R ^1’ 不存在；或當X ¹ 為C時，R ^1’ 表示H、鹵基、烷基、雜環基、烷氧基、環烷氧基、雜環基氧基、羰基、烷基羰基、胺基羰基、羥基羰基、雜環基羰基、烷基亞碸、烷基磺醯基、胺基磺醯基、雜環基磺醯基、烷基碸亞胺基、羰基胺基、磺醯基胺基或烷基碸烷基；該等取代基視需要經一或多個選自以下各項之取代基取代：側氧基、鹵基、羥基、氰基、烷基、烯基、醛、雜環基烷基、羥烷基、二羥基烷基、羥基烷基胺基烷基、胺基烷基、烷基胺基烷基、二烷基胺基烷基、(雜環基)(烷基)胺基烷基、雜環基、雜芳基、烷基雜芳基、炔烴、烷氧基、胺基、二烷基胺基、胺基烷基羰基胺基、胺基羰基烷基胺基、(胺基羰基烷基)(烷基)胺基、烯基羰基胺基、羥基羰基、烷氧基羰基、胺基羰基、胺基烷基胺基羰基、烷基胺基烷基胺基羰基、二烷基胺基烷基胺基羰基、雜環基烷基 胺基羰基、(烷基胺基烷基)(烷基)胺基羰基、烷基胺基烷基羰基、二烷基胺基烷基羰基、雜環基羰基、烯基羰基、炔基羰基、烷基亞碸、烷基亞碸烷基、烷基磺醯基及烷基碸烷基；R ^2’ 表示H、鹵基、烷基、雜環基、烷氧基、環烷氧基、雜環基氧基、羰基、烷基羰基、胺基羰基、羥基羰基、雜環基羰基、烷基亞碸、烷基磺醯基、胺基磺醯基、雜環基磺醯基、烷基碸亞胺基、羰基胺基、磺醯基胺基、或烷基碸烷基；該等取代基視需要經一或多個選自以下各項之取代基取代：側氧基、鹵基、羥基、氰基、烷基、烯基、醛、雜環基烷基、羥烷基、二羥基烷基、羥基烷基胺基烷基、胺基烷基、烷基胺基烷基、二烷基胺基烷基、(雜環基)(烷基)胺基烷基、雜環基、雜芳基、烷基雜芳基、炔烴、烷氧基、胺基、二烷基胺基、胺基烷基羰基胺基、胺基羰基烷基胺基、(胺基羰基烷基)(烷基)胺基、烯基羰基胺基、羥基羰基、烷氧基羰基、胺基羰基、胺基烷基胺基羰基、烷基胺基烷基胺基羰基、二烷基胺基烷基胺基羰基、雜環基烷基胺基羰基、(烷基胺基烷基)(烷基)胺基羰基、烷基胺基烷基羰基、二烷基胺基烷基羰基、雜環基羰基、烯基羰基、炔基羰基、烷基亞碸、烷基亞碸烷基、烷基磺醯基及烷基碸烷基；或R ^1’ 及R ^2’ 連同其連接的原子一起形成5或6員芳基環、5或6員雜芳基環、5或6員環烷基環或5或6員雜 環基環；視需要經一或多個選自以下各項之取代基取代：側氧基、鹵基、羥基、氰基、烷基、烯基、醛、雜環基烷基、羥烷基、二羥基烷基、羥基烷基胺基烷基、胺基烷基、烷基胺基烷基、二烷基胺基烷基、(雜環基)(烷基)胺基烷基、雜環基、雜芳基、烷基雜芳基、炔烴、烷氧基、胺基、二烷基胺基、胺基烷基羰基胺基、胺基羰基烷基胺基、(胺基羰基烷基)(烷基)胺基、烯基羰基胺基、羥基羰基、烷氧基羰基、胺基羰基、胺基烷基胺基羰基、烷基胺基烷基胺基羰基、二烷基胺基烷基胺基羰基、雜環基烷基胺基羰基、(烷基胺基烷基)(烷基)胺基羰基、烷基胺基烷基羰基、二烷基胺基烷基羰基、雜環基羰基、烯基羰基、炔基羰基、烷基亞碸、烷基亞碸烷基、烷基磺醯基及烷基碸烷基；當X ² 為N時R ^3’ 不存在；或當X ² 為C時，R ^3’ 表示H或鹵基，較佳地H或F；R ^4’ 表示H或鹵基，較佳地H或F；且R ^5’ 表示H或鹵基，較佳地H或F。 According to a preferred embodiment, the present invention relates to the compound of formula (Ia):

or a pharmaceutically acceptable salt or solvate thereof, wherein: R ¹ represents a 5 or 6-membered heteroaryl or a 5 or 6-membered aryl, wherein the heteroaryl or aryl is optionally selected from one or more The following substituents are substituted: C1-C6 alkyl (preferably methyl) and halo (preferably fluoro or chloro); preferably R represents 5- ^membered heteroaryl; more preferably R ¹ represents furyl; X ¹ and X ² each independently represent C or N; when X ¹ is N, R ^1' does not exist; or when X ¹ is C, R ^1' represents H, halo, alkyl, Heterocyclyl, alkoxy, cycloalkoxy, heterocyclyloxy, carbonyl, alkylcarbonyl, aminocarbonyl, hydroxycarbonyl, heterocyclylcarbonyl, alkylene, alkylsulfonyl, amino Sulfonyl, heterocyclic sulfonyl, alkylimino, carbonylamino, sulfonylamino or alkylsulfonyl; these substituents are optionally selected from the following one or more Substituent substitution: pendant oxygen, halo, hydroxyl, cyano, alkyl, alkenyl, aldehyde, heterocyclylalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl, amino Alkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl, alkylheteroaryl, alkyne, alkane Oxygen, Amino, Dialkylamino, Aminoalkylcarbonylamino, Aminocarbonylalkylamino, (Aminocarbonylalkyl)(Alkyl)amino, Alkenylcarbonylamino, Hydroxycarbonyl , alkoxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, heterocyclylalkylaminocarbonyl, (alk Aminoalkyl)(alkyl)aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylarkenyl, alkane Subgroup alkylidene, alkylsulfonyl and alkylsulfonyl; R ^2' represents H, halo, alkyl, heterocyclyl, alkoxy, cycloalkoxy, heterocyclyloxy, carbonyl , Alkylcarbonyl, Aminocarbonyl, Hydroxycarbonyl, Heterocyclylcarbonyl, Alkylsulfonyl, Alkylsulfonyl, Aminosulfonyl, Heterocyclylsulfonyl, Alkylimino, Carbonylamine A group, a sulfonylamino group, or an alkyl group; these substituents are optionally substituted by one or more substituents selected from the group consisting of pendant oxy, halo, hydroxyl, 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)amino, Alkenylcarbonylamino, Hydroxycarbonyl, Alkoxycarbonyl, Aminocarbonyl, Aminoalkylaminocarbonyl, Alkane Aminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, heterocyclylalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl, alkylaminoalkane Alkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylanthylene, alkylanthylenyl, alkylsulfonyl and alkylanthylenyl; 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; Need to be 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, amino, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, (aminocarbonylalkyl)(alkyl) Amino, alkenylcarbonylamino, hydroxycarbonyl, alkoxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, Heterocyclylalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkenylcarbonyl , alkynylcarbonyl, alkylidene, alkylidenealkyl, alkylsulfonyl and alkylidenealkyl; when X ² is N, R ^3' does not exist; 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 formula (Ia): R ¹ represents a 5- or 6-membered heteroaryl or a 5- or 6-membered aryl, wherein the heteroaryl or aryl is optionally selected from one or more of the following Substituent substitution: C1-C6 alkyl (preferably methyl) and halo (preferably fluoro or chloro); preferably R ¹ represents 5-membered heteroaryl; more preferably R ¹ represents furyl ; X ¹ and X ² each independently represent C or N; when X ¹ is N, R ^1' does not exist; or when X ¹ is C, R ^1' represents H, halo, alkyl, alkoxy, Heterocyclyloxy, alkylcarbonyl, carbonyl, aminocarbonyl, hydroxycarbonyl, heterocyclyl, heterocyclylcarbonyl, alkylsulfonyl, alkylsulfonyl, aminosulfonyl or heterocyclylsulfonyl These substituents are optionally substituted with one or more substituents selected from the group consisting of hydroxyl, cyano, alkyl, hydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkyl Aminoalkyl, dialkylaminoalkyl, (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl, alkylheteroaryl, alkyne, alkoxy, amino , Dialkylamino, Aminoalkylcarbonylamino, Aminocarbonylalkylamino, (Aminocarbonylalkyl)(Alkyl)amino, Hydroxycarbonyl, Alkoxycarbonyl, Aminocarbonyl, Amine Alkylaminoalkylcarbonyl, Alkylaminoalkylaminocarbonyl, Dialkylaminoalkylaminocarbonyl, (Alkylaminoalkyl)(Alkyl)aminocarbonyl, Alkylaminoalkyl Carbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkylonylene, alkylendonyl, alkylonyl; R ^2' represents H, alkoxyl, cycloalkoxyl, heterocyclyl Cyclooxy, alkylene, carbonyl, carbonylamino, aminocarbonyl or sulfonylamino; wherein alkoxy, cycloalkoxy, heterocyclyloxy, alkylidene, carbonyl, carbonyl Amino, aminocarbonyl or sulfonylamino groups are optionally substituted with one or more substituents selected from the group consisting of hydroxyl, cyano, alkyl, alkenyl, aldehyde, hydroxyalkyl, hydroxyalkylamine Alkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl, alkylheteroaryl group, alkyne, alkoxy group, amino group, dialkylamino group, aminoalkylcarbonylamino group, aminocarbonylalkylamino group, (aminocarbonylalkyl)(alkyl)amino group, alkenyl group Carbonylamino, hydroxycarbonyl, alkoxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, (alkylamino Alkyl)(alkyl)aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylidene, alkylidene Alkyl, alkylpyridyl; 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-membered heterocyclyl ring; optionally substituted with one or more substituents selected from the group consisting of hydroxy, cyano, alkyl, hydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl , alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl, alkylheteroaryl, alkyne, alkoxy , Amino, Dialkylamino, Aminoalkylcarbonylamino, Aminocarbonylalkylamino, (Aminocarbonylalkyl)(Alkyl)amino, Hydroxycarbonyl, Alkoxycarbonyl, Amino Carbonyl, Aminoalkylaminocarbonyl, Alkylaminoalkylaminocarbonyl, Dialkylaminoalkylaminocarbonyl, (Alkylaminoalkyl)(Alkyl)aminocarbonyl, Alkylamine An alkylalkylcarbonyl group, a dialkylaminoalkylcarbonyl group, a heterocyclylcarbonyl group, an alkylidene, an alkylidenealkyl 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 formula (Ia): R ¹ represents a 5- or 6-membered heteroaryl or a 5- or 6-membered aryl, wherein the heteroaryl or aryl is optionally selected from one or more of the following Substituent substitution: C1-C6 alkyl (preferably methyl) and halo (preferably fluoro or chloro); preferably R ¹ represents 5-membered heteroaryl; more preferably R ¹ represents furyl ; X ¹ and X ² each independently represent C or N; when X ¹ is N, R ^1' does not exist; or when X ¹ is C, R ^1' represents H, halo, alkyl, alkoxy, Heterocyclyloxy, alkylcarbonyl, carbonyl, aminocarbonyl, hydroxycarbonyl, heterocyclyl, heterocyclylcarbonyl, alkylsulfonyl, alkylsulfonyl, aminosulfonyl or heterocyclylsulfonyl These substituents are optionally substituted with one or more substituents selected from the group consisting of hydroxyl, cyano, alkyl, hydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkyl Aminoalkyl, dialkylaminoalkyl, (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl, alkylheteroaryl, alkyne, alkoxy, amino , Dialkylamino, Aminoalkylcarbonylamino, Aminocarbonylalkylamino, (Aminocarbonylalkyl)(Alkyl)amino, Hydroxycarbonyl, Alkoxycarbonyl, Aminocarbonyl, Amine Alkylaminoalkylcarbonyl, Alkylaminoalkylaminocarbonyl, Dialkylaminoalkylaminocarbonyl, (Alkylaminoalkyl)(Alkyl)aminocarbonyl, Alkylaminoalkyl Carbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkylenylene, alkylenalkylene; R ^2' represents H, alkoxy, cycloalkoxy, heterocyclyloxy, alkane Alkylene, carbonyl, carbonylamino, aminocarbonyl or sulfonylamino; wherein alkoxy, cycloalkoxy, heterocyclyloxy, alkylene, carbonyl, carbonylamino, aminocarbonyl Or the sulfonylamino group is optionally substituted with one or more substituents selected from the group consisting of hydroxyl, cyano, alkyl, alkenyl, aldehyde, hydroxyalkyl, hydroxyalkylaminoalkyl, amine Alkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl, alkylheteroaryl, alkyne, alkane Oxygen, Amino, Dialkylamino, Aminoalkylcarbonylamino, Aminocarbonylalkylamino, (Aminocarbonylalkyl)(Alkyl)amino, Alkenylcarbonylamino, Hydroxycarbonyl , alkoxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, (alkylaminoalkyl) (alkyl ) aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylene, alkylidene; 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, a 5 or 6 membered heterocyclyl ring; Substitution with one or more substituents selected from: hydroxyl, cyano, alkyl, hydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylamine ylalkyl, (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl, alkylheteroaryl, alkyne, alkoxy, amine, dialkylamino, amine Alkylcarbonylamino, Aminocarbonylalkylamino, (Aminocarbonylalkyl)(Alkyl)amino, Hydroxycarbonyl, Alkoxycarbonyl, Aminocarbonyl, Aminoalkylaminocarbonyl, Alkyl Aminoalkylaminocarbonyl, Dialkylaminoalkylaminocarbonyl, (Alkylaminoalkyl)(Alkyl)aminocarbonyl, Alkylaminoalkylcarbonyl, Dialkylaminoalkyl Carbonyl, heterocyclylcarbonyl, alkylene; when X ² is N, R ^3' does not exist; 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.

In a particular embodiment of the invention, R represents a 5- or 6-membered heteroaryl or a 5- or 6-membered aryl, wherein the heteroaryl or aryl ^is optionally substituted by one or more of the following substituents: 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 specific embodiment of the present invention, X1 ^and X2 ^each independently represent C or N. In ^another particular embodiment, both X1 ^and X2 represent C.

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

In another particular embodiment, when X ^is C, R ^represents H, halo, alkyl, heterocyclyl, alkoxy, cycloalkoxy, heterocyclyloxy, carbonyl, alkylcarbonyl , Aminocarbonyl, Hydroxycarbonyl, Heterocyclylcarbonyl, Alkylsulfonyl, Alkylsulfonyl, Aminosulfonyl, Heterocyclylsulfonyl, Alkylimino, Carbonylamino, Sulphonyl Amino or alkyl alkyl; these substituents are optionally substituted with one or more substituents selected from the group consisting of pendant oxy, halo, hydroxyl, cyano, alkyl, alkenyl, aldehyde , heterocyclylalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl)( Alkyl)aminoalkyl, heterocyclyl, heteroaryl, alkylheteroaryl, alkyne, alkoxy, amino, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkane Amino, (aminocarbonylalkyl)(alkyl)amino, alkenylcarbonylamino, hydroxycarbonyl, alkoxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkyl Aminocarbonyl, dialkylaminoalkylaminocarbonyl, heterocyclylalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl, alkylaminoalkylcarbonyl, dialkyl Aminoalkylcarbonyl, heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylenyl, alkylenyl, alkylsulfonyl and alkylenyl.

In a preferred embodiment, when X ¹ is C, R ^1' represents H, halo, alkyl, alkoxy, heterocyclyloxy, alkylcarbonyl, carbonyl, aminocarbonyl, hydroxycarbonyl, hetero Cyclic group, heterocyclylcarbonyl, alkylenesulfonyl, alkylsulfonyl, aminosulfonyl or heterocyclylsulfonyl; these substituents are optionally substituted by one or more of the following Substitution: hydroxy, cyano, alkyl, hydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl)(alk base) aminoalkyl, heterocyclyl, heteroaryl, alkylheteroaryl, alkyne, alkoxy, amino, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkyl Amino, (aminocarbonylalkyl)(alkyl)amino, hydroxycarbonyl, alkoxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkyl Aminoalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkylene , Alkyl alkylene.

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, alkylhetero Aryl, alkoxy, amino, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, heterocyclylalkylaminocarbonyl, (aminocarbonylalkyl)(alk )amino, hydroxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, (alkylaminoalkyl)( Alkyl)aminocarbonyl, heterocyclylcarbonyl, alkylenylene and alkylenylalkylene.

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, amino , Dialkylamino, Aminoalkylcarbonylamino, Aminocarbonylalkylamino, (Aminocarbonylalkyl)(Alkyl)amino, Hydroxycarbonyl, Aminocarbonyl, Aminoalkylamino Carbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl, heterocyclylcarbonyl, alkylene and alkyl Alkyl group.

In a particular embodiment of the present invention, R ^2' represents H, halo, alkyl, heterocyclyl, alkoxy, cycloalkoxy, heterocyclyloxy, carbonyl, alkylcarbonyl, aminocarbonyl , hydroxycarbonyl, heterocyclylcarbonyl, alkylene, alkylsulfonyl, aminosulfonyl, heterocyclylsulfonyl, alkylimino, carbonylamine, sulfonylamino, Or alkyl arganyl; these substituents are optionally substituted with one or more substituents selected from the group consisting of pendant oxy, halo, hydroxyl, cyano, alkyl, alkenyl, aldehyde, heterocycle hydroxyalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl)(alkyl) Aminoalkyl, heterocyclyl, heteroaryl, alkylheteroaryl, alkyne, alkoxy, amino, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino , (aminocarbonylalkyl) (alkyl)amino, alkenylcarbonylamino, hydroxycarbonyl, alkoxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl , dialkylaminoalkylaminocarbonyl, heterocyclylalkylaminocarbonyl, (alkylaminoalkyl) (alkyl)aminocarbonyl, alkylaminoalkylcarbonyl, dialkylamino Alkylcarbonyl, heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylidene, alkylidenealkyl, alkylsulfonyl and alkylidenealkyl.

In a preferred embodiment, R ^2' represents H, alkoxyl, cycloalkoxyl, heterocyclyloxyl, alkylenoxide, carbonyl, carbonylamino, aminocarbonyl or sulfonylamino; wherein Alkoxy, cycloalkoxy, heterocyclyloxy, alkylene, carbonyl, carbonylamino, aminocarbonyl or sulfonylamino, optionally with one or more substituents selected from the following Substitution: hydroxy, cyano, alkyl, alkenyl, aldehyde, hydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclic (Alkyl)aminoalkyl, heterocyclyl, heteroaryl, alkylheteroaryl, alkyne, alkoxyamino, dialkylamino, aminoalkylcarbonylamino, amino Carbonylalkylamino, (aminocarbonylalkyl)(alkyl)amino, alkenylcarbonylamino, hydroxycarbonyl, alkoxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylamino Alkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, Heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylindenylene, alkylindenylalkylene.

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, hydroxyl, cyano, alkyl, heterocyclylalkyl, Dihydroxyalkyl, dialkylaminoalkyl, heteroaryl, alkylheteroaryl, hydroxycarbonyl, alkoxycarbonyl, aminocarbonyl, heterocyclylalkylaminocarbonyl, alkylaminoalkyl Carbonyl, dialkylaminoalkylcarbonyl, alkylidene, alkylidenealkyl.

In preferred embodiments, the R ^2' substituent is optionally substituted with one or more substituents selected from the group consisting of hydroxyl, cyano, alkyl, dihydroxyalkyl, heteroaryl, alkylheteroaryl group, hydroxycarbonyl group, alkoxycarbonyl group, aminocarbonyl group, alkylaminoalkylcarbonyl group, dialkylaminoalkylcarbonyl group, alkylidene, alkylidenealkyl group.

In another specific embodiment of the present 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, hydroxyl, cyano, alkyl, alkenyl, aldehyde, heterocyclyl Alkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl)(alkyl)amine Alkyl, heterocyclyl, heteroaryl, alkylheteroaryl, alkyne, alkoxy, amine, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, (aminocarbonylalkyl)(alkyl)amino, alkenylcarbonylamino, hydroxycarbonyl, alkoxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl, Dialkylaminoalkylaminocarbonyl, heterocyclylalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkane Alkylcarbonyl, heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylanthylene, alkylanthylenyl, alkylsulfonyl and alkylanthylenyl.

In a preferred embodiment, R ^1' and R ^2' together with the atoms they connect form a 5 or 6 membered aryl ring, a 5 or 6 membered heteroaryl ring, a 5 or 6 membered cycloalkyl ring, a 5 or 6 membered A membered heterocyclyl 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, amino , Dialkylamino, Aminoalkylcarbonylamino, Aminocarbonylalkylamino, (Aminocarbonylalkyl)(Alkyl)amino, Hydroxycarbonyl, Alkoxycarbonyl, Aminocarbonyl, Amine Alkylaminoalkylcarbonyl, Alkylaminoalkylaminocarbonyl, Dialkylaminoalkylaminocarbonyl, (Alkylaminoalkyl)(Alkyl)aminocarbonyl, Alkylaminoalkyl Carbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkylenylene, alkylindenyl.

In a particular embodiment of the invention, R ^3' is absent when X ² is N. In another specific embodiment of the present 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.

或其醫藥學上可接受的鹽或溶劑合物，其中R ¹ 、R ^1’ 、R ^2’ 、R ^3’ 、R ^4’ 及R ^5’ 係如式(Ia)中所定義。 In one embodiment, preferred compounds of formula (Ia) are those compounds of formula (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).

或其醫藥學上可接受的鹽或溶劑合物，其中：R ¹ 及R ^3’ 係如式(Ia)中所定義；且R ^1” 表示烷基或雜環基，其經一或多個選自以下各項之基團取代：側氧基、鹵基、羥基、氰基、烷基、烯基、醛、雜環基烷基、羥烷基、二羥基烷基、羥基烷基胺基烷基、胺基烷基、烷基胺基烷基、二烷基胺基烷基、(雜環基)(烷基)胺基烷基、雜環基、雜芳基、烷基雜芳基、炔烴、烷氧基、胺基、二烷基胺基、胺基烷基羰基胺基、胺基羰基烷基胺基、(胺基羰基烷基)(烷基)胺基、烯基羰基胺基、羥基羰基、烷氧基羰基、胺基羰基、胺基烷基胺基羰基、烷基胺基烷基胺基羰基、二烷基胺基烷基胺基羰基、雜環基烷基胺基羰基、(烷基胺基烷基)(烷基)胺基羰基、烷基胺基烷基羰基、二烷基胺基烷基羰基、雜環基羰基、烯基 羰基、炔基羰基、烷基亞碸、烷基亞碸烷基、烷基磺醯基及烷基碸烷基。 In one embodiment, preferred compounds of formula (Ia-1) are those compounds of formula (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 or heterocyclic group, which is modified by one or more Substitution with a group selected from the group consisting of pendant oxy, halo, hydroxy, cyano, alkyl, alkenyl, aldehyde, heterocyclylalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylamine Alkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl, alkylheteroaryl , alkyne, alkoxy, amino, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, (aminocarbonylalkyl)(alkyl)amino, alkenylcarbonyl Amino, Hydroxycarbonyl, Alkoxycarbonyl, Aminocarbonyl, Aminoalkylaminocarbonyl, Alkylaminoalkylaminocarbonyl, Dialkylaminoalkylaminocarbonyl, Heterocyclylalkylamine Alkylcarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkane alkylidene, alkylidenealkyl, alkylsulfonyl and alkylidenealkyl.

According to one embodiment, in formula (Ia-1a): R ¹ and R ^3' are as defined in formula (Ia); and R ^1" represents an alkyl or heterocyclic group, which is selected from one or more The group substitution of the following: hydroxy, cyano, alkyl, hydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (hetero Cyclo)(alkyl)aminoalkyl, heterocyclyl, heteroaryl, alkylheteroaryl, alkyne, alkoxy, amino, dialkylamino, aminoalkylcarbonylamino, Aminocarbonylalkylamino, (aminocarbonylalkyl)(alkyl)amino, hydroxycarbonyl, alkoxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylamino Carbonyl, dialkylaminoalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl , alkylidene, alkylidene. 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 Heterocyclyl substituted with one or more groups selected from the group consisting of hydroxy, cyano, alkyl, hydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkane radical, dialkylaminoalkyl, (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl, alkylheteroaryl, alkyne, alkoxy, amino, dioxane Amino, Aminoalkylcarbonylamino, Aminocarbonylalkylamino, (Aminocarbonylalkyl)(Alkyl)amino, Hydroxycarbonyl, Alkoxycarbonyl, Aminocarbonyl, Aminoalkyl Aminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, Alkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkylene.

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, hydroxyl, cyano, alkane group, alkenyl, aldehyde, heterocyclylalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (Heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl, alkylheteroaryl, alkyne, alkoxy, amino, dialkylamino, aminoalkylcarbonylamine Aminocarbonylalkylamino, (aminocarbonylalkyl)(alkyl)amino, alkenylcarbonylamino, hydroxycarbonyl, alkoxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, Alkylaminoalkylaminocarbonyl, Dialkylaminoalkylaminocarbonyl, Heterocyclylalkylaminocarbonyl, (Alkylaminoalkyl)(Alkyl)aminocarbonyl, Alkylamino Alkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylidene, alkylidenealkyl, alkylsulfonyl and alkylidenealkyl.

In a preferred embodiment, R ^1" represents an alkyl or heterocyclic group, which is substituted by one or more groups selected from the group consisting of: hydroxyl, cyano, alkyl, hydroxyalkyl, hydroxyalkylamine Alkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl, alkylheteroaryl group, alkyne, alkoxy group, amino group, dialkylamino group, aminoalkylcarbonylamino group, aminocarbonylalkylamino group, (aminocarbonylalkyl)(alkyl)amino group, hydroxycarbonyl group , alkoxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, (alkylaminoalkyl) (alkyl ) aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkylene.

In a preferred embodiment, R ^1" represents an alkyl or heterocyclic group, which is substituted by one or more groups selected from the following: hydroxyl, heterocyclic, heteroaryl, alkylheteroaryl, Alkyne, Alkoxy, Amino, Dialkylamino, Aminoalkylcarbonylamino, Aminocarbonylalkylamino, (Aminocarbonylalkyl)(Alkyl)amino, Hydroxycarbonyl, Amine Alkylcarbonyl, Aminoalkylaminocarbonyl, Alkylaminoalkylaminocarbonyl, Dialkylaminoalkylaminocarbonyl, (Alkylaminoalkyl)(Alkyl)aminocarbonyl, Heterocycle Alkylcarbonyl, Alkyl-Arylene, Alkyl-Alkyl.

或其醫藥學上可接受的鹽或溶劑合物，其中：R ¹ 及R ^3’ 係如式(Ia)中所定義；R ^1’ 表示H或鹵基，較佳地H或F；且R ^2” 表示烷基或雜環基，其經一或多個選自以下各項之基團取代：側氧基、鹵基、羥基、氰基、烷基、烯基、醛、雜環基烷基、羥烷基、二羥基烷基、羥基烷基胺基烷基、胺基烷基、烷基胺基烷基、二烷基胺基烷基、(雜環基)(烷基)胺基烷基、雜環基、雜芳基、烷基雜芳基、炔烴、烷 氧基、胺基、二烷基胺基、胺基烷基羰基胺基、胺基羰基烷基胺基、(胺基羰基烷基)(烷基)胺基、烯基羰基胺基、羥基羰基、烷氧基羰基、胺基羰基、胺基烷基胺基羰基、烷基胺基烷基胺基羰基、二烷基胺基烷基胺基羰基、雜環基烷基胺基羰基、(烷基胺基烷基)(烷基)胺基羰基、烷基胺基烷基羰基、二烷基胺基烷基羰基、雜環基羰基、烯基羰基、炔基羰基、烷基亞碸、烷基亞碸烷基、烷基磺醯基及烷基碸烷基。 In one embodiment, preferred compounds of formula (Ia-1) are those compounds of formula (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, which is substituted by one or more groups selected from the group consisting of pendant oxy, halo, hydroxyl, cyano, alkyl, alkenyl, aldehyde, heterocyclylalkane hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl)(alkyl)amino Alkyl, heterocyclyl, heteroaryl, alkylheteroaryl, alkyne, alkoxy, amine, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, ( Aminocarbonylalkyl)(alkyl)amino, alkenylcarbonylamino, hydroxycarbonyl, alkoxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl, di Alkylaminoalkylaminocarbonyl, Heterocyclylalkylaminocarbonyl, (Alkylaminoalkyl)(Alkyl)aminocarbonyl, Alkylaminoalkylcarbonyl, Dialkylaminoalkyl Carbonyl, heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylidene, alkylidenealkyl, alkylsulfonyl and alkylidenealkyl.

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" denotes 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 group, dialkylamino group, aminoalkylcarbonylamino group, aminocarbonylalkylamino group, (aminocarbonylalkyl)(alkyl)amino group, hydroxycarbonyl group, alkoxycarbonyl group, aminocarbonyl group, Aminoalkylaminocarbonyl, Alkylaminoalkylaminocarbonyl, Dialkylaminoalkylaminocarbonyl, (Alkylaminoalkyl)(Alkyl)aminocarbonyl, Alkylaminoalkane Alkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkylenylene, alkylindenyl.

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" denotes 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 group, dialkylamino group, aminoalkylcarbonylamino group, aminocarbonylalkylamino group, (aminocarbonylalkyl)(alkyl)amino group, hydroxycarbonyl group, alkoxycarbonyl group, aminocarbonyl group, Aminoalkylaminocarbonyl, Alkylaminoalkylaminocarbonyl, Dialkylaminoalkylaminocarbonyl, (Alkylaminoalkyl)(Alkyl)aminocarbonyl, Alkylaminoalkane Alkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkylenylene.

In a particular embodiment of the invention, R ^1' represents H or halo. 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, hydroxyl, cyano, alkane group, alkenyl, aldehyde, heterocyclylalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (Heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl, alkylheteroaryl, alkyne, alkoxy, amino, dialkylamino, aminoalkylcarbonylamine Aminocarbonylalkylamino, (aminocarbonylalkyl)(alkyl)amino, alkenylcarbonylamino, hydroxycarbonyl, alkoxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, Alkylaminoalkylaminocarbonyl, Dialkylaminoalkylaminocarbonyl, Heterocyclylalkylaminocarbonyl, (Alkylaminoalkyl)(Alkyl)aminocarbonyl, Alkylamino Alkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylidene, alkylidenealkyl, alkylsulfonyl and alkylidenealkyl.

In a preferred embodiment, R2 ^" represents an alkyl or heterocyclic group, which is substituted by one or more groups selected from the group consisting of hydroxyl, cyano, alkyl, hydroxyalkyl, hydroxyalkylamine Alkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl, alkylheteroaryl group, alkyne, alkoxy group, amino group, dialkylamino group, aminoalkylcarbonylamino group, aminocarbonylalkylamino group, (aminocarbonylalkyl)(alkyl)amino group, hydroxycarbonyl group , alkoxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, (alkylaminoalkyl) (alkyl ) aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkylene.

In a preferred embodiment, R2 ^" represents an alkyl or heterocyclic group, which is substituted by one or more groups selected from the group consisting of hydroxyl, cyano, heteroaryl, alkylheteroaryl, alkyne Hydrocarbon, hydroxycarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, alkylidene, alkylidenealkyl.

In one embodiment, preferred compounds of formula (Ia-1) are those compounds of formula (Ia-1c) or (Ia-1d):

或其醫藥學上可接受的鹽或溶劑合物，其中：R ¹ 及R ^3’ 係如式(Ia)中所定義；R ^1’ 表示H或鹵基，較佳地H或F；且R ^2’ 表示H或鹵基，較佳地H或F；且R ¹ⁱ 及R ¹ⁱⁱ 各自獨立地表示氫、羥基、烷基、烯基、雜環基烷基、羥烷基、二羥基烷基、羥基烷基胺基烷基、胺基烷基、烷基胺基烷基、二烷基胺基烷基、(雜環基)(烷基)胺基烷基、雜環基、雜芳基、烷基雜芳基、炔烷基、烷氧基、胺基、二烷基胺基、胺基烷基羰基胺基、胺基羰基烷基胺基、(胺基羰基烷基)(烷基)胺基、烯基羰基胺基、羥基羰基、烷氧基羰基、胺基羰基、胺基烷基胺基羰基、烷基胺基烷基胺基羰基、二烷基胺基烷基胺基羰基、雜環基烷基胺基羰基、(烷基胺基烷基)(烷基)胺基羰基、烷基胺基烷基羰基、二烷基胺基烷基羰基、雜環基羰基、烯基羰基、炔基羰基、烷基亞碸烷基或烷基碸烷基；且R ²ⁱ 及R ²ⁱⁱ 各自獨立地表示氫、羥基、烷基、烯基、雜環基烷基、羥烷基、二羥基烷基、羥基烷基胺基烷基、胺基烷基、烷基胺基烷基、二烷基胺基烷基、(雜環基)(烷基)胺基烷基、雜環基、雜芳基、烷基雜芳基、炔烷基、烷氧基、胺基、二烷基胺基、胺基烷基羰基胺基、胺基羰 基烷基胺基、(胺基羰基烷基)(烷基)胺基、烯基羰基胺基、羥基羰基、烷氧基羰基、胺基羰基、胺基烷基胺基羰基、烷基胺基烷基胺基羰基、二烷基胺基烷基胺基羰基、雜環基烷基胺基羰基、(烷基胺基烷基)(烷基)胺基羰基、烷基胺基烷基羰基、二烷基胺基烷基羰基、雜環基羰基、烯基羰基、炔基羰基、烷基亞碸烷基或烷基碸烷基。

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 halo, preferably H or F; and R ¹ⁱ and R ¹ⁱⁱ each independently represent hydrogen, hydroxyl, alkyl, alkenyl, heterocyclylalkyl, hydroxyalkyl, dihydroxyalkyl, Hydroxyalkylaminoalkyl, Aminoalkyl, Alkylaminoalkyl, Dialkylaminoalkyl, (Heterocyclyl)(Alkyl)aminoalkyl, Heterocyclyl, Heteroaryl, Alkylheteroaryl, Alkynylalkyl, Alkoxy, Amino, Dialkylamino, Aminoalkylcarbonylamino, Aminocarbonylalkylamino, (Aminocarbonylalkyl)(Alkyl) Amino, alkenylcarbonylamino, hydroxycarbonyl, alkoxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, Heterocyclylalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkenylcarbonyl , alkynylcarbonyl, alkylenealkylene or alkylenealkyl; and R ²ⁱ and R ²ⁱⁱ each independently represent hydrogen, hydroxy, alkyl, alkenyl, heterocyclylalkyl, hydroxyalkyl, dihydroxy Alkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heterocyclyl Aryl, alkylheteroaryl, alkynylalkyl, alkoxyl, amino, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, (aminocarbonylalkyl)( Alkyl)amino, alkenylcarbonylamino, hydroxycarbonyl, alkoxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylamine Alkylcarbonyl, heterocyclylalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, Alkenylcarbonyl, alkynylcarbonyl, alkylanthylenyl or alkylanthylenyl.

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 halo, preferably H or F; R ¹ⁱ and R ¹ⁱⁱ each independently represent hydrogen, hydroxyl, alkyl, hydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl , alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl, alkylheteroaryl, alkynylalkyl, alkoxy Amine, Amino, Dialkylamino, Aminoalkylcarbonylamino, Aminocarbonylalkylamino, (Aminocarbonylalkyl)(Alkyl)amine, Hydroxycarbonyl, Alkoxycarbonyl, Amine Alkylcarbonyl, Aminoalkylaminocarbonyl, Alkylaminoalkylaminocarbonyl, Dialkylaminoalkylaminocarbonyl, (Alkylaminoalkyl)(Alkyl)aminocarbonyl, Alkyl Aminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkylendenyl, alkylendanyl; and R ²ⁱ and R ²ⁱⁱ each independently represent hydrogen, hydroxy, alkyl, Hydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, Heteroaryl, alkylheteroaryl, alkynyl, alkoxy, amino, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, (aminocarbonylalkyl) (Alkyl)amino, hydroxycarbonyl, alkoxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, (alk (aminoalkyl)(alkyl)aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkylendanyl, alkylendanyl.

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 halo, preferably H or F; R ¹ⁱ and R ¹ⁱⁱ each independently represent hydrogen, hydroxyl, alkyl, hydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl , alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl, alkylheteroaryl, alkynylalkyl, alkoxy Amine, Amino, Dialkylamino, Aminoalkylcarbonylamino, Aminocarbonylalkylamino, (Aminocarbonylalkyl)(Alkyl)amine, Hydroxycarbonyl, Alkoxycarbonyl, Amine Alkylcarbonyl, Aminoalkylaminocarbonyl, Alkylaminoalkylaminocarbonyl, Dialkylaminoalkylaminocarbonyl, (Alkylaminoalkyl)(Alkyl)aminocarbonyl, Alkyl Aminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkylendenyl, alkylendanyl; and R ²ⁱ and R ²ⁱⁱ each independently represent hydrogen, hydroxy, alkyl, Hydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, Heteroaryl, alkylheteroaryl, alkynyl, alkoxy, amino, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, (aminocarbonylalkyl) (Alkyl)amino, hydroxycarbonyl, alkoxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, (alk (aminoalkyl)(alkyl)aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkylendanyl, alkylendanyl.

In a particular embodiment of the invention, R ^1' represents H or halo. 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 present invention, R ¹ⁱ and R ¹ⁱⁱ each independently represent hydrogen, hydroxyl, alkyl, alkenyl, heterocyclylalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkane radical, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl, alkylheteroaryl, Alkynyl, alkoxy, amino, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, (aminocarbonylalkyl)(alkyl)amino, alkenylcarbonyl Amino, Hydroxycarbonyl, Alkoxycarbonyl, Aminocarbonyl, Aminoalkylaminocarbonyl, Alkylaminoalkylaminocarbonyl, Dialkylaminoalkylaminocarbonyl, Heterocyclylalkylamine Alkylcarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkane An alkylene group or an alkyl group group.

In a preferred embodiment, R ¹ⁱ and R ¹ⁱⁱ each independently represent hydrogen, hydroxyl, alkyl, hydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkyl Aminoalkyl, (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl, alkylheteroaryl, alkynyl, alkoxy, amine, dialkylamino, Aminoalkylcarbonylamino, Aminocarbonylalkylamino, (Aminocarbonylalkyl)(Alkyl)amino, Hydroxycarbonyl, Alkoxycarbonyl, Aminocarbonyl, Aminoalkylaminocarbonyl, Alkylaminoalkylaminocarbonyl, Dialkylaminoalkylaminocarbonyl, (Alkylaminoalkyl)(Alkyl)aminocarbonyl, Alkylaminoalkylcarbonyl, Dialkylamino Alkylcarbonyl, heterocyclylcarbonyl, alkylendanyl, alkylendanyl.

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

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 present invention, R ²ⁱ and R ²ⁱⁱ each independently represent hydrogen, hydroxyl, alkyl, alkenyl, heterocyclylalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkane radical, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl, alkylheteroaryl, Alkynyl, alkoxy, amino, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, (aminocarbonylalkyl)(alkyl)amino, alkenylcarbonyl Amino, Hydroxycarbonyl, Alkoxycarbonyl, Aminocarbonyl, Aminoalkylaminocarbonyl, Alkylaminoalkylaminocarbonyl, Dialkylaminoalkylaminocarbonyl, Heterocyclylalkylamine Alkylcarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkane An alkylene group or an alkyl group group.

In a preferred embodiment, R ²ⁱ and R ²ⁱⁱ each independently represent hydrogen, hydroxyl, alkyl, hydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkyl Aminoalkyl, (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl, alkylheteroaryl, alkynyl, alkoxy, amine, dialkylamino, Aminoalkylcarbonylamino, Aminocarbonylalkylamino, (Aminocarbonylalkyl)(Alkyl)amino, Hydroxycarbonyl, Alkoxycarbonyl, Aminocarbonyl, Aminoalkylaminocarbonyl, Alkylaminoalkylaminocarbonyl, Dialkylaminoalkylaminocarbonyl, (Alkylaminoalkyl)(Alkyl)aminocarbonyl, Alkylaminoalkylcarbonyl, Dialkylamino Alkylcarbonyl, heterocyclylcarbonyl, alkylenalkylene.

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.

(Ia-2)

(Ia-3) 或其醫藥學上可接受的鹽或溶劑合物，其中R¹ 、R^2’ 、R^3’ 、R^4’ 及R^5’ 係如式(Ia)中所定義。In one embodiment, preferred compounds of formula (Ia) are those compounds 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).

及其醫藥學上可接受的鹽及溶劑合物。In particular, preferred compounds of formula I according to the invention are those listed in Table 1 below. Table 1

and pharmaceutically acceptable salts and solvates thereof.

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

Compounds in Table 1 were named using ^{ChemBioDraw®} Ultra version 12.0 (PerkinElmer).

All references to compounds of formula I and its subformulas include reference to their enantiomers, salts, solvates, polymorphs, multicomponent complexes and liquid crystals.

Compounds of the present invention include compounds of formula I and subformulas thereof as defined above, including all polymorphs and crystal habits thereof, prodrugs and isomers (including optical, geometric and tautomers) thereof, and compounds of formula I and its subformulas. Isotope-labeled compounds of the sub-formula.

Compounds of formula I and its subformulas may contain asymmetric centers and thus exist in different stereoisomeric forms. Accordingly, the present invention includes all possible stereoisomers and not only racemates but also individual enantiomers and nonracemic mixtures thereof. When a compound is desired as a single enantiomer, such compound can be obtained by stereospecific synthesis, by isolation of the final product or any suitable intermediate, or by the corresponding counterpart as each is known in the art. obtained by a sex chromatography method. Isolation of final products, intermediates, or starting materials can be performed by any suitable method known in the art.

The compounds of the present invention may be in the form of pharmaceutically acceptable salts. Pharmaceutically acceptable salts of compounds of formula I and its sub-formulas include acid addition and base salts thereof. Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include acetate, adipate, aspartate, benzoate, benzylsulfonate, bicarbonate/carbonate, bisulfate/sulfate, borate, camphorsulfonate, citric acid salt, cyclamate, edisulphonate, esulphonate, formate, fumarate, glucoheptonate, gluconate, glucuronate, hexafluorophosphate , benzalkonium salt, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, propionate Dialate, mesylate, methylsulfate, naphthenate, 2-naphthalenesulfonate, nicotinate, nitrate, orotate, oxalate, palmitic acid, pamoate , Phosphate/Hydrogen Phosphate/Dihydrogen Phosphate, Pyroglutamate, Sucrose, Stearate, Succinate, Tannate, Tartrate, Tosylate, Trifluoroacetate and Oxygenate naphthalate. 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, trimethanolamine, 2-( Diethylamino)ethanol, ethanolamine, morpholine, 4-(2-hydroxyethyl)morpholine and zinc salts. For example, half-salts of acids and bases, hemi-sulfates and hemi-calcium salts can also be formed. Preferred pharmaceutically acceptable salts include hydrochloride/chloride, hydrobromide/bromide, bisulfate/sulfate, nitrate, citrate, and acetate.

When the compounds of the present invention contain acidic groups and basic groups, the compounds of the present invention can also form internal salts, and these compounds are within the scope of the present invention. When a compound of the invention contains a hydrogen donating heteroatom (eg NH), the invention also covers salts and/or isomers formed by transfer of this hydrogen atom to a basic group or atom within the molecule.

Pharmaceutically acceptable salts of compounds of formula I and its subformulas may be prepared by one or more of these methods: (i) by reacting a compound of formula I with the desired acid; (ii) by Reaction of a compound of formula I with a desired base; (iii) by removing an acid or base labile protecting group from a suitable precursor of a compound of formula I or by using a desired acid to convert a suitable ring such as a lactone or lactam or (iv) by converting one salt of the compound of formula I into another salt by reacting with a suitable acid or by means of a suitable ion exchange column.

All of these reactions are typically performed in solution. The salt can precipitate from solution and be collected by filtration or can be recovered by evaporation of the solvent. The degree of ionization in salt can vary from completely ionized to nearly non-ionized.

The compounds of the present invention may be administered in the form of pharmaceutically acceptable salts. The term "pharmaceutically acceptable salt" is intended to include all acceptable salts such as acetate, lactobionate, besylate, laurate, benzoate, malate, bicarbonate, butene Bisalt, bisulphate, mandelate, tartrate, mesylate, borate, methyl bromide, bromide, methyl nitrate, calcium edetate, methyl sulfate, camphor Sulfonate, mucate, carbonate, naphthalenesulfonate, chloride, nitrate, clavulanic acid, N-methylglucamine, citrate, ammonium salt, dihydrochloride, oleate , edetate, oxalate, edisylate, pamoate (emboate), ettoate, palmitate, esylate, pantothenate, fumarate Salt, Phosphate/Diphosphate, Glucoheptonate, Polygalacturonate, Gluconate, Salicylate, Glutamate, Stearate, Glycosyl-p-aminophenylarsinate , Sulphate, Hexyl Resorcinol, Hydroxynaphthoate, Hydramine, Succinate, Hydrobromide, Tannate, Hydrochloride, Tartrate, Hydroxynaphthoate, Theanate , iodide, tosylate, isothiosulfate, triethyl iodide, lactate, pannate, valerate, and the like, which can be used as dosage forms for modifying solubility or hydrolysis properties or can be used in sustained release or prodrug formulations. Depending on the specific functionality of the compounds of the present invention, pharmaceutically acceptable salts of the compounds of the present invention include those salts formed from cations such as sodium, potassium, aluminum, calcium, lithium, magnesium, and bases. Zinc, and bases such as ammonia, ethylenediamine, N-methyl-glutamine, lysine, arginine, ornithine, choline, N,N'-dibenzylethylene-diamine , chloroprocaine, diethanolamine, procaine, N-benzylphenethyl-amine, diethylamine, piperazine, ginseng (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 basic groups such as amine groups, acid salts, ie, hydrochloride, hydrobromide, acetate, pamoate, and the like can be used as dosage forms.

In addition, while the salts of the compounds of the present invention generally are pharmaceutically acceptable salts, it should be noted that the invention in its broadest sense also includes non-pharmaceutically acceptable salts, which may be used, for example, in the present invention. Isolation and/or purification of inventive compounds. For example, salts formed with optically active acids or bases may be used to form diastereoisomeric salts which may facilitate the separation of optically active isomers of compounds of Formula I above.

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

The invention also generally encompasses all pharmaceutically acceptable prodrugs and prodrugs of compounds of formula I and its subformulas.

In addition, where an alcohol group is present, pharmaceutically acceptable esters such as acetate, maleate, trimethylacetyloxymethyl, and the like can be used, as well as These esters are known in the art for modifying the solubility or hydrolysis properties suitable for use in sustained release or prodrug formulations. Manufacturing method

Compounds of formula I can be prepared in various ways using reactions known to those skilled in the art.

(Ia) 及其醫藥學上可接受的鹽及溶劑合物，其中X¹ 、X² 、R¹ 、 R^1’ 、 R^2’ 、 R^3’ 、 R^4’ 及R^5’ 係如式(Ia)中所定義； 其包含： (a1)使式(A)化合物

(A) 其中X¹ 、X² 、R^1’ 、 R^2’ 、 R^3’ 、 R^4’ 及R^5’ 係如式(Ia)中所定義； 與式(B)化合物反應

(B) 其中R¹ 係如式(Ia)中所定義；Y 表示鹵素(較佳地碘、溴或氯)、具有1-6個碳原子之烷基磺醯基氧基(較佳地甲基磺醯基氧基或三氟甲基磺醯基氧基)或具有6-10個碳原子之芳基磺醯基氧基(較佳地苯基或對甲苯基磺醯基氧基)、或熟習此項技術者已知的任何離去基團。The invention further relates to a process for the manufacture of compounds of formula (Ia):

(Ia) and its pharmaceutically acceptable salts and solvates, wherein X ¹ , X ² , R ¹ , R ^1' , R ^2' , R ^3' , R ^4' and R ^5' are represented by the formula ( As defined in Ia); It comprises: (a1) the 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); react with the compound of formula (B)

(B) wherein R ¹ is as defined in formula (Ia); Y represents halogen (preferably iodine, bromine or chlorine), an alkylsulfonyloxy group having 1-6 carbon atoms (preferably methyl sulfonyloxy or trifluoromethylsulfonyloxy) or arylsulfonyloxy having 6-10 carbon atoms (preferably phenyl or p-tolylsulfonyloxy), Or any leaving group known to those skilled in the art.

According to one embodiment, step (a1) of the method of the invention can be performed in the presence or absence of a base. In a particular embodiment, step (a1) of the method of the invention is performed 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 method of the present invention may be performed 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 present invention may be performed at a temperature ranging from 20° C. to about 180° C., with or without microwave irradiation, for a period ranging from 10 minutes to several hours, for example 10 minutes to 24 h.

步驟(b1)：5-胺基噻唑并[4,5-d]嘧啶-2,7(3H,6H)-二酮可轉化成5-胺基-7-羥基-3-(2-甲氧基乙基)-2H,3H-[1,3]噻唑并[4,5-d]嘧啶-2-酮。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 Ethyl)-2H,3H-[1,3]thiazolo[4,5-d]pyrimidin-2-one.

According to one embodiment, step (b1) can be achieved by utilizing 1-bromo-2-methoxyethane, 1-iodo-2-methoxyethane, 1-methylsulfonyl-2-methoxyethane alkane or 1-tosyl-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 in the presence of but not limited to sodium tert-butoxide, potassium tert-butoxide, NaH, CsOH, NaOH, K ₂ CO ₃ , Na ₂ CO ₃ , preferably tert-butoxide Execute in the presence of sodium alkoxide, potassium tert-butoxide or NaH base.

According to one embodiment, step (b1) of the method of the present invention may be performed 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 present invention may be performed at a temperature ranging from 20° C. to about 180° C., with or without microwave irradiation, for a period ranging from 10 minutes to several hours, for example 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 can Conversion to 5-amino-7-chloro-3-(2-methoxyethyl)-2H,3H-[1,3]thiazolo[4,5-d]pyrimidin-2-one.

According to one embodiment step (b2) may be performed 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 method of the invention may 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 present invention may be performed at a temperature ranging from 20° C. to about 180° C., with or without microwave irradiation, for a period ranging from 10 minutes to several hours, for example 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 can Conversion to a compound of formula (D) wherein R ¹ is as defined in formula (Ia) by reaction with formula (C) wherein R ¹ is as defined in formula (Ia).

According to one embodiment, step (b3) of the method of the invention may be performed in the presence of a suitable base.

According to one embodiment, step (b3) of the method of the invention can be carried out in the presence or absence of suitable solvents such as ethanol, propanol, methanol, THF, water, dioxane, or mixtures thereof, preferably performed in the presence of ethanol.

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

Step (b4): Compounds of formula (D) wherein R ¹ is as defined in formula (Ia) can be converted into compounds of formula (E) wherein R ¹ is as defined in formula (Ia).

According to one embodiment, step (b4) of the method of the invention can be performed in the presence of N,O-bis(trimethylsilyl)acetamide.

According to one embodiment, step (b4) of the method of the invention can be performed in the presence or absence of hexamethyldisilazane.

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

Step (b5): Compounds of formula (E) wherein R ¹ is as defined in formula (Ia) can be converted into compounds of formula (F) wherein R ¹ is as defined in formula (Ia).

According to one embodiment, step (b5) of the method of the invention may be performed in the presence of BBr ₃ .

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

Step (b6): Compounds of formula (F) wherein R ¹ is as defined in formula (Ia) can be converted into compounds of formula (B) wherein R ¹ and Y are as defined in formula (Ia).

According to one embodiment, step (b6) of the process of the invention can be carried out using any reagent known to a person skilled in the art for converting an alcohol into a haloalkyl or into an alkyl or aryl sulfonate, Depending on the nature of Y, such reagents as, but not limited to, tosyl chloride, methanesulfonyl chloride, trifluoromethanesulfonic acid chloride, trifluoromethanesulfonic anhydride, SOCl ₂ , SO ₂ Cl ₂ , POCl ₃ , PCl ₅ , Preferably tosyl chloride or methanesulfonyl chloride.

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

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

In general, the synthetic route for any individual compound of formula (I) will depend on the particular substituents of each molecule and on the necessary ready availability of intermediates; again, such factors are understood by those of ordinary skill.

According to another general procedure, compounds of formula I can be converted into substituted compounds of formula I using suitable interconversion techniques well known to those skilled in the art.

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

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

Several - 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 one another, they can in many cases be cleaved selectively.

The term "amine protecting group" is known in a general form and relates to a group suitable for protecting (blocking) an amine group against a chemical reaction, but which is readily removable after the desired chemical reaction has been carried out elsewhere in the molecule. Typical of such groups are inter alia unsubstituted or substituted acyl, 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, those with 1-20, especially 1-8 carbon atoms are preferred. The term "acyl" is to be construed in the broadest sense in connection with current methods. It includes acyl groups derived from aliphatic, araliphatic, aromatic or heterocyclic carboxylic or sulfonic acids and in particular alkoxycarbonyl, aryloxycarbonyl and especially aralkoxycarbonyl groups. Examples of such acyl groups are alkylyl groups such as acetyl, propionyl and butyryl; aralkylyl groups such as phenylacetyl; aryl groups such as benzoyl and tolyl; aryloxyalkyl Acyl, such as POA; Alkoxycarbonyl, such as methoxycarbonyl, ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, BOC (tertiary butoxycarbonyl) and 2-iodoethoxy carbonyl; aralkoxycarbonyl such as CBZ ("benzyloxycarbonyl"), 4-methoxybenzyloxycarbonyl and FMOC; and arylsulfonyl such as Mtr. Preferred amino protecting groups are BOC and Mtr, in addition to CBZ, Fmoc, benzyl and acetyl.

The term "hydroxyl protecting group" is likewise known in a general form and relates to a group suitable for protecting a hydroxy group against chemical reactions but which is readily removable after the desired chemical reaction has been carried out elsewhere in the molecule. Typical of such groups are the unsubstituted or substituted aryl, aralkyl or acyl groups mentioned above, but also alkyl groups. The nature and size of the hydroxy protecting group is not critical since it is again removed after the desired chemical reaction or reaction sequence, preference is given to groups with 1-20, especially 1-10 carbon atoms. Examples of hydroxyl protecting groups are especially benzyl, 4-methoxybenzyl, p-nitrophenyl, p-toluenesulfonyl, tert-butyl and acetyl, wherein benzyl and tert-butyl are especially preferred.

Compounds of formula I and related formulas are released from their functional derivatives - depending on the protecting group used - for example strong mineral acids such as hydrochloric acid, perchloric acid or sulfuric acid; strong organic carboxylic acids such as trichloroacetic acid, TFA or sulfonic acid Acids 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, for example carboxylic acids, such as acetic acid; ethers, such as tetrahydrofuran or dioxane; amides, such as DMF; halogenated hydrocarbons, such as dichloromethane; also alcohols, such as methanol, ethanol or isopropyl alcohol, and water. Mixtures of the abovementioned solvents are additionally suitable. TFA is preferably used in excess without adding another solvent, and perchloric acid is preferably used as a mixture of acetic acid and 70% perchloric acid in a ratio of 9:1. The reaction temperature for splitting is advantageously between about 0 and about 50°C, preferably between 15°C and 30°C (room temperature).

BOC, OtBu and Mtr groups can be cleaved for example preferably using TFA in dichloromethane or roughly 3 to 5N HCl in dioxane at 15-30°C and FMOC groups can be cleaved using dimethylamine , diethylamine or piperidine in DMF roughly 5 to 50% solution at 15-30 ° C split.

Hydrogenolytically removable protecting groups (e.g. release of CBZ, benzyl or amidinyl groups from their oxadiazole derivatives) can be achieved, for example, by utilizing hydrogen in catalysts (e.g., noble metal catalysts, such as palladium, advantageously in places such as carbon support) in the presence of treatment to split. Suitable solvents here are those indicated above, in particular for example alcohols such as methanol or ethanol; or amides such as DMF. The hydrogenolysis is generally carried out at a temperature between about 0 and 100° C. and a pressure between about 1 bar and 200 bar, preferably at 20-30° C. and 1-10 bar. Hydrogenolysis of the CBZ group works well eg on 5 to 10% Pd/C in methanol or using ammonium formate (replacing 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 methylene chloride; alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxin alkanes; glycol ethers, such as ethylene glycol monomethyl ether or monoethyl ether or ethylene glycol dimethyl ether (diglyme); ketones, such as acetone or butanone; amides, such as acetamide, dimethyl Acetamide, N-methylpyrrolidone (N-methylpyrrolidone; NMP) or dimethylformamide (dimethylformamide; DMF); Nitrile, such as acetonitrile; Sulfide, such as dimethylsulfoxide; DMSO); carbon disulfide; carboxylic acids, such as formic acid or acetic acid; nitro compounds, such as nitromethane or nitrobenzene; esters, such as ethyl acetate, or mixtures of such solvents.

Esters can _be hydrolyzed, for example, with HCl, _H2SO4 , or with LiOH, NaOH or KOH in water, water/THF, water/THF/ethanol or water/dioxane at temperatures between 0 and 100°C.

The free amine groups may additionally be acylated using acyl chlorides or anhydrides or alkylated using unsubstituted or substituted haloalkyl groups in a conventional manner, 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 temperatures between -60°C and +30°C.

For all conservation and deconservation methods, see Philip J. Kocienski, "Protecting Groups", Georg Thieme Verlag Stuttgart, New York, 1994 and Theodora W. Greene and Peter G. M. Wuts, "Protective Groups in Organic Synthesis", Wiley Interscience, pp. 3 edition, 1999.

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

(A-1) 及其鹽及溶劑合物，其中： 當X¹ 為N時R¹ ' 不存在；或當X¹ 為C時，R¹ ' 表示H、鹵基、烷基、雜環基、烷氧基、環烷氧基、雜環基氧基、羰基、烷基羰基、胺基羰基、羥基羰基、雜環基羰基、烷基亞碸、烷基磺醯基、胺基磺醯基、雜環基磺醯基、烷基碸亞胺基、羰基胺基、磺醯基胺基或烷基碸烷基； 該等取代基視需要經一或多個選自以下各項之取代基取代：側氧基、鹵基、羥基、氰基、烷基、烯基、醛、雜環基烷基、羥烷基、二羥基烷基、羥基烷基胺基烷基、胺基烷基、烷基胺基烷基、二烷基胺基烷基、(雜環基)(烷基)胺基烷基、雜環基、雜芳基、烷基雜芳基、炔烴、烷氧基、胺基、二烷基胺基、胺基烷基羰基胺基、胺基羰基烷基胺基、(胺基羰基烷基)(烷基)胺基、烯基羰基胺基、羥基羰基、烷氧基羰基、胺基羰基、胺基烷基胺基羰基、烷基胺基烷基胺基羰基、二烷基胺基烷基胺基羰基、雜環基烷基胺基羰基、(烷基胺基烷基)(烷基)胺基羰基、烷基胺基烷基羰基、二烷基胺基烷基羰基、雜環基羰基、烯基羰基、炔基羰基、烷基亞碸、烷基亞碸烷基、烷基磺醯基及烷基碸烷基；R² ' 表示H、鹵基、烷基、雜環基、烷氧基、環烷氧基、雜環基氧基、羰基、烷基羰基、胺基羰基、羥基羰基、雜環基羰基、烷基亞碸、烷基磺醯基、胺基磺醯基、雜環基磺醯基、烷基碸亞胺基、羰基胺基、磺醯基胺基、或烷基碸烷基； 該等取代基視需要經一或多個選自以下各項之取代基取代：側氧基、鹵基、羥基、氰基、烷基、烯基、醛、雜環基烷基、羥烷基、二羥基烷基、羥基烷基胺基烷基、胺基烷基、烷基胺基烷基、二烷基胺基烷基、(雜環基)(烷基)胺基烷基、雜環基、雜芳基、烷基雜芳基、炔烴、烷氧基、胺基、二烷基胺基、胺基烷基羰基胺基、胺基羰基烷基胺基、(胺基羰基烷基)(烷基)胺基、烯基羰基胺基、羥基羰基、烷氧基羰基、胺基羰基、胺基烷基胺基羰基、烷基胺基烷基胺基羰基、二烷基胺基烷基胺基羰基、雜環基烷基胺基羰基、(烷基胺基烷基)(烷基)胺基羰基、烷基胺基烷基羰基、二烷基胺基烷基羰基、雜環基羰基、烯基羰基、炔基羰基、烷基亞碸、烷基亞碸烷基、烷基磺醯基及烷基碸烷基； 或R¹ ' 及R² ' 連同其連接的原子一起形成5或6員芳基環、5或6員雜芳基環、5或6員環烷基環或5或6員雜環基環；視需要經一或多個選自以下各項之取代基取代：側氧基、鹵基、羥基、氰基、烷基、烯基、醛、雜環基烷基、羥烷基、二羥基烷基、羥基烷基胺基烷基、胺基烷基、烷基胺基烷基、二烷基胺基烷基、(雜環基)(烷基)胺基烷基、雜環基、雜芳基、烷基雜芳基、炔烴、烷氧基、胺基、二烷基胺基、胺基烷基羰基胺基、胺基羰基烷基胺基、(胺基羰基烷基)(烷基)胺基、烯基羰基胺基、羥基羰基、烷氧基羰基、胺基羰基、胺基烷基胺基羰基、烷基胺基烷基胺基羰基、二烷基胺基烷基胺基羰基、雜環基烷基胺基羰基、(烷基胺基烷基)(烷基)胺基羰基、烷基胺基烷基羰基、二烷基胺基烷基羰基、雜環基羰基、烯基羰基、炔基羰基、烷基亞碸、烷基亞碸烷基、烷基磺醯基及烷基碸烷基；當X ² 為N時R ^3’ 不存在；或當X ² 為C時，R ^3’ 表示H或鹵基，較佳地H或F；R ^4’ 表示H或鹵基，較佳地H或F；且R ^5’ 表示H或鹵基，較佳地H或F。 The present invention also relates to synthetic intermediates of formula (A).

(A-1) and its salts and solvates, wherein: when X ¹ is N , R ¹ ' does not exist; or when X ¹ is C, R ¹ ' represents H, halo, alkyl, heterocyclyl , Alkoxy, Cycloalkoxy, Heterocyclyloxy, Carbonyl, Alkylcarbonyl, Aminocarbonyl, Hydroxycarbonyl, Heterocyclylcarbonyl, Alkylsulfonyl, Alkylsulfonyl, Aminosulfonyl , heterocyclylsulfonyl, alkylimino, carbonylamino, sulfonylamino or alkylsulfonyl; these substituents are optionally selected from one or more substituents selected from the following Substitution: 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)amino, alkenylcarbonylamino, hydroxycarbonyl, alkoxy Alkylcarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, heterocyclylalkylaminocarbonyl, (alkylamino Alkyl)(alkyl)aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylidene, alkylidene Alkyl, alkylsulfonyl and alkylsulfonyl; R ² ' represents H, halo, alkyl, heterocyclyl, alkoxy, cycloalkoxy, heterocyclyloxy, carbonyl, alkyl Carbonyl, Aminocarbonyl, Hydroxycarbonyl, Heterocyclylcarbonyl, Alkylsulfonyl, Alkylsulfonyl, Aminosulfonyl, Heterocyclylsulfonyl, Alkylimino, Carbonylamino, Sulfonyl Acylamino group, or alkyl group; These substituents are optionally substituted by one or more substituents selected from the group consisting of pendant oxy, halo, hydroxyl, cyano, alkyl, alkenyl , aldehyde, heterocyclylalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl )(alkyl)aminoalkyl, heterocyclyl, heteroaryl, alkylheteroaryl, alkyne, alkoxy, amino, dialkylamino, aminoalkylcarbonylamino, amino Carbonylalkylamino, (aminocarbonylalkyl)(alkyl)amino, alkenylcarbonylamino, hydroxycarbonyl, alkoxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylamino Alkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, heterocyclylalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl, alkylaminoalkylcarbonyl, Dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylidene, alkylidenealkyl, alkylsulfonyl and alkylidenealkyl; 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 more 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, Amino, Dialkylamino, Aminoalkylcarbonylamino, Aminocarbonylalkylamino, (Aminocarbonylalkyl)(Alkyl)amino, Alkenylcarbonylamino, hydroxycarbonyl, alkoxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, heterocyclyl Alkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkenylcarbonyl, alkynyl Carbonyl, alkylidene, alkylidene, alkylsulfonyl, and alkylidene; when X ² is N, R ^3' does not exist; 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, 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-(methylsulfinyl) )ethoxy)phenyl)piperazine. use

The present invention further relates to the use of the compounds of the present invention or pharmaceutically acceptable salts and solvates thereof as A2A inhibitors.

Therefore, in a particularly preferred embodiment, the present invention relates to the use of compounds of formula I and sub-formulas, especially those of Table 1 above, or pharmaceutically acceptable salts and solvates thereof, as A2A inhibitors .

Accordingly, in another aspect, the present invention relates to the use of these compounds or their salts and solvates for the synthesis of pharmaceutically active ingredients such as A2A inhibitors.

According to another feature of the present 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 more preferably a human, comprising administering to the patient an effective amount of the present The compound of the invention or its pharmaceutically acceptable salt and solvate.

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

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

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

The present invention further provides the use of the compound of formula I or its pharmaceutically acceptable salt and solvate for the manufacture of a medicament for treating and/or preventing cancer.

The present invention also provides a method of delaying the onset of cancer in a patient comprising administering to a patient in need thereof a pharmaceutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt and solvate 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 may be treated using the methods of the invention include, for example, benign and malignant solid tumors and benign and malignant non-solid tumors. In particular embodiments, the cancer is selected from 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, gastric cancer, thyroid cancer and urothelial cell carcinoma. In specific embodiments, the cancer is breast cancer. In specific embodiments, the cancer is carcinoid carcinoma. In specific embodiments, the cancer is cervical cancer. In specific embodiments, the cancer is colorectal cancer. In specific embodiments, the cancer is endometrial cancer. In specific embodiments, the cancer is glioma. In specific embodiments, the cancer is head and neck cancer. In specific embodiments, the cancer is liver cancer. In a specific embodiment, the cancer is lung cancer. In specific embodiments, the cancer is melanoma. In specific embodiments, the cancer is ovarian cancer. In specific embodiments, the cancer is pancreatic cancer. In specific embodiments, the cancer is prostate cancer. In specific embodiments, the cancer is kidney cancer. In a specific embodiment, the cancer is gastric cancer. In specific embodiments, the cancer is thyroid cancer. In specific embodiments, the cancer is urothelial carcinoma.

Examples of solid tumors include, but are not limited to: biliary tract cancer, brain cancer (including glioblastoma and medulloblastoma), breast cancer, carcinoid tumor, cervical cancer, choriocarcinoma, colon cancer, colorectal cancer , endometrial cancer, esophageal cancer, gastric cancer, glioma, head and neck cancer, intraepithelial neoplasia (including Bowen's disease and Paget's disease), liver cancer, lung cancer, neuroblastoma, oral cancer (including squamous cell carcinoma), ovarian cancer (including those arising from epithelial cells, stromal cells, germ cells, and stromal cells), pancreatic cancer, prostate cancer, rectal cancer, renal cancer (including adenocarcinoma and Wilms sarcoma), 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 (seminoma, and nonseminoma, such as teratoma and choriocarcinoma), stromal tumors, germ cell tumors, thyroid cancer (including thyroid adenocarcinoma and medullary carcinoma) and urothelial cell carcinoma.

Examples of solid tumors include, but are not limited to: biliary tract cancer, brain cancer (including glioblastoma and medulloblastoma), breast cancer, carcinoid tumor, cervical cancer, choriocarcinoma, colon cancer, endometrial cancer cancer, esophageal cancer, gastric cancer, intraepithelial neoplasia (including Bowen'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, renal cancer (including adenocarcinoma and Wilms tumor), sarcomas (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 (seminoma, and cell tumors, such as teratoma and choriocarcinoma), stromal tumors, germ cell tumors, and thyroid cancer (including thyroid adenocarcinoma and medullary carcinoma).

Examples of non-solid tumors include, but are not limited to, hematological neoplasms. As used herein, hematological neoplasm is a term of art that includes lymphocytic disorders, myeloid disorders, and AIDS-associated leukemia.

Lymphocytic disorders include, but are not limited to, acute lymphocytic leukemia and chronic lymphoproliferative disorders (eg, lymphoma, myeloma, and chronic lymphocytic leukemia). Lymphoma includes, 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 present 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, Namely, scleroderma), chronic bacterial infections (such as eg 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 multiple A method of microbial sepsis comprising administering to a mammalian species in need thereof a therapeutically effective amount of a compound according to the present invention, or a pharmaceutically acceptable salt or solvate thereof.

The present invention further provides the use of a compound of formula I or a pharmaceutically acceptable salt and 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 , ie, scleroderma), chronic bacterial infections (such as, for example, Helicobacter pylori), abnormal scarring (keloids), and polymicrobial sepsis.

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

The present 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 present invention also encompasses pharmaceutical compositions which contain, as active ingredient, an additional therapeutic agent and/or active ingredient in addition to the compound of the invention, its pharmaceutically acceptable salts and solvates.

Another object of the present invention is a medicament comprising at least one compound of the present invention or pharmaceutically acceptable salts and solvates thereof as active ingredient.

According to another feature of the present invention, there is provided the use of a compound of formula I or a pharmaceutically acceptable salt and solvate thereof for the manufacture of a medicament for modulating A2A activity in a patient in need of such treatment, the modulating comprising adding to the A patient is administered an effective amount of a compound of the present invention, or a pharmaceutically acceptable salt and 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 agent, and optionally one or more additional pharmaceutically active compounds.

By way of non-limiting example, such formulations 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 patches, by implants, by suppositories, and the like. Such suitable administration forms - which may be solid, semi-solid or liquid, depending on the mode of administration - and methods and carriers, diluents and excipients for their preparation will be apparent to those skilled in the art; References to the latest edition of Remington's Pharmaceutical Sciences.

Some preferred but non-limiting examples of such formulations include lozenges, pills, powders, lozenges, capsules, cachets, elixirs, suspensions, emulsions, solutions, slurries, aerosols, ointments, Liqueurs, lotions, soft and hard gelatin capsules, suppositories, drops, sterile injectable solutions, and sterile packaged powders (which are usually reconstituted before use) for administration as a bolus and/or for continuous administration , which can be formulated using carriers, excipients, and diluents that are themselves suitable for such formulations, such as lactose, glucose, sucrose, sorbitol, mannitol, Starch, Gum Arabic, Calcium Phosphate, Alginate, Gum Tragacanth, Gelatin, Calcium Silicate, Microcrystalline Cellulose, Polyvinylpyrrolidone, Polyethylene Glycol, Cellulose, Water (Sterile), Methylcellulose , methyl and propyl hydroxybenzoates, talc, magnesium stearate, edible oils, vegetable and mineral oils, or suitable mixtures thereof. The formulation may optionally contain other substances commonly used in pharmaceutical formulations, such as lubricants, wetting agents, emulsifying and suspending agents, dispersing agents, disintegrants, bulking agents, fillers, preservatives, sweeteners, flavoring agents, flow Conditioner, release agent, etc. The compositions can also be formulated so as to provide quick, sustained or delayed release of the active compound contained therein.

The pharmaceutical formulations of the invention are preferably in unit dosage form and may be suitably packaged, for example, in boxes, shields, vials, bottles, sachets, ampoules, or any other suitable single-dose or multi-dose holders or containers (the may be appropriately marked); as appropriate, 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 this invention may be administered as a single daily dose, divided into one or more daily doses, or administered essentially continuously, for example using drip infusion . example

The invention will be better understood with reference to the following examples. These 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(trimethylsilyl)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: dimethylsulfoxide, eq.: equivalent EtOAc: ethyl acetate Esters, g: grams, h: hours, HAS: human serum albumin, HPLC: high performance liquid chromatography, HMDS: hexamethyldisilazane, L: liters, LCMS: liquid chromatography mass spectrometry LHMDS: bis Lithium (trimethylsilyl)amide, M: mol.L ^-1 , MeOH: methanol, µg: microgram, µmol: micromole, µL: microliter, mg: milligram, mL: milliliter, mmol: millimolar Ear, mM: mmol.L ^-1 , min: minute, mol: mole, N: normal concentration, N ₂ : nitrogen, ng: nanogram, nM: nmol.L ^-1 , NMP: N-methyl-2 -pyrrolidone, NMR: nuclear magnetic resonance spectroscopy, quant.: quantitative (yield), SFC: supercritical fluid chromatography, rt or RT: room temperature, tBu : tertiary butyl, TEA: triethylamine , TFA: trifluoroacetic acid, THF: tetrahydrofuran, TLC: thin layer chromatography, VTD: vacuum tray dryer. I. Chemical examples

MS data provided in the Examples described below were obtained as follows: LCMS was recorded using an Agilent 6130 or 6130B multimode (ESI+APCI). LCMS method: Column: XBridge C8 (50X4.6 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 for the multiplicity observed in NMR spectra are as follows: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broad).

HPLC purity is assessed by either of two methods: Method: XB0595TF; Column: XBridge C8 (50X4.6) mm, 3.5µm; The gradient of the eluent is 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), 3.0µm; the gradient of the eluent is from 10 mM ammonium acetate in water to ACN, and the flow rate is 1.0 mL/min. Method: XB0595NHC; Column: XBridge C8 (50X4.6) mm, 3.5µm; the gradient of eluent is from 10 mM ammonium bicarbonate in water to ACN, and the flow rate is 1.0 mL/min.

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

Intermediates and compounds described below were named using ^{ChemBioDraw®} Ultra version 12.0 (PerkinElmer). I.1. Synthesis of intermediate compounds Intermediate 1 : 2-(5- amino -8-( furan -2- yl )-2- oxothiazolo [ 5,4-e][1,2,4 ] triazolo [ 1,5-c] pyrimidin -3(2H) -yl ) ethyl methanesulfonate

Step 1 : 2,6- Diamino -5- thiocyanooxypyrimidin -4- ol: To a stirred solution of acetic acid (27500 mL) in a reactor at 25-30 °C under nitrogen atmosphere was added 2 , 6-Diaminopyrimidin-4-ol (500 g). Potassium thiocyanate (1586 g) was added slowly 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) in acetic acid (750 mL) was added dropwise, stirred at the same temperature for 2 h. After the reaction was complete, the reaction mixture was neutralized with 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 VTD at 70 °C for 24 hours to give the title compound (206 g, quant) as a pale yellow solid. 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-thiocyanoxypyrimidin-4-ol (step-1 ) (750 g, 4.09 mol) in THF (15 L) was added tetrabutylammonium fluoride (1 M in THF, 6750 mL) and the reaction mass was heated to 64±3°C for 24 h. After the reaction was complete, 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 (3.75 L) and sucked dry for 1 h. The wet mass was treated with water (6 L) and sodium bicarbonate (3 kg) was added. The reaction mass was stirred for 4 hours, filtered, washed with water (3.75 L) and dried in VTD for 16 h to give the title compound (580 g; 78%) as a yellow solid. 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- A hot (80 °C) mixture of alcohol (step 2; 570 g, 3.11 mol) and _NaNO2 (570 g, 8.26 mol) in water (5700 mL) was added slowly to hot concentrated HCl (11400 mL, 15 Vol) solution (80°C). The reaction mixture was stirred for 2 h and monitored for completion by HPLC. After the reaction was complete, the mixture was cooled to 15 °C and basified to pH 12 with 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 VTD to give the product (286 g, 51%) as a beige solid. 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, then cooled to 30 °C. To this reaction mixture was added 60% NaH (10.4 g, 1.1 eq) slowly and stirred for 30 min followed by addition of 1-bromo-2-methoxyethane (32.83 g, 1.1 eq). The reaction mixture was heated again to 100°C. The completion of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to RT, completely concentrated and purified by column chromatography using DCM/methanol (90:10) to give a white solid (20 g, 41 %). 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) and 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. The pH of the reaction mixture was adjusted to 7 using NaHCO ₃ and extracted with 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 such in the next step without further purification. 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- oxo -2,3- dihydrothiazolo [4,5-d] pyrimidin -7- yl ) Furan -2- carbazide: 5-amino-7-chloro-3-(2-methoxyethyl)thiazo[4,5-d]pyrimidin-2(3H)-one in ethanol ( 6.8 g, 0.026 mol) was added hydrazine furoate (4.9 g, 0.039 mol) and heated to 100 °C for 19 h in a sealed tube. The reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to RT and concentrated under reduced pressure. Petroleum ether was added to this residue to give a solid, which was filtered and used as such in the next step without further purification (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-oxo-2,3-dihydrothiazolo [4,5-d]pyrimidin-7-yl)furan-2-carbazide (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 complete, the reaction mixture was cooled to 0 °C and methanol (30 mL) was added. The precipitated solid was filtered and washed with petroleum ether to give an off-white solid (5.9 g, 87%) which was used as such in the next step without further purification. 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] pyrimidin -2(3H) -one: 5-amino-8-(furan-2-yl)-3-(2-methoxyethyl)thiazolo[5,4 -e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one (5.9 g, 0.017 mol) in anhydrous DCM (100 mL) was slowly added 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 complete, the reaction mixture was quenched with cold water (100 mL) followed by neutralization with 10% sodium bicarbonate solution, filtered and washed with water to give a pale yellow solid (3.6 g, 65%) which was used without further purification Used as such in 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- oxothiazolo [5,4-e][1,2,4] triazolo [1,5- c] pyrimidin -3(2H) -yl ) ethyl methanesulfonate: 5-amino-8-(furan-2-yl)-3-(2-hydroxyethyl)thiazolo[ 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 become clear. The reaction mass was cooled to 0 °C and TEA (3 g, 3 eq) was added followed by methanesulfonyl chloride (1.6 g, 1.3 eq). The reaction mixture was stirred at RT for 48 h. After the reaction was complete, ethyl acetate (100 mL) and water (50 mL) were added and extracted. The organic layer was dried over Na ₂ SO ₄ , filtered and evaporated to give the compound as a yellow solid (3.0 g, 67%) which was 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- oxothiazolo [5,4-e][1,2,4] triazolo [1,5 -c] pyrimidin -3(2H) -yl ) -acetaldehyde

To 5-amino-8-(furan-2-yl)-3-(2-hydroxyethyl)thiazolo[5,4-e][1,2,4]triazolo-[1,5- c] A stirred solution of pyrimidin-2(3H)-one (prepared according to the protocol described for Intermediate 1 Step 8, 3.6 g, 10.74 mmol) in THF (150 mL) was added IBX (15.04 g, 53.72 mmol) in DMSO (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 successively washed with saturated NaHCO ₃ solution and saturated brine solution. It was then dried over _{anhydrous Na2SO4} , filtered and concentrated under reduced pressure. The obtained crude residue (3.0 g, 75%) was used in the next step without further purification. LCMS 317 [M+1] ⁺ . I.2. Synthesis example 1 of the final compound : 3-(2-(4-(4-((1H - 1,2,3- triazol -4 base ) methoxy - 2fluorophenyl ) piperazine -1- yl ) ethyl )-5- amino- (8-( furan -2- yl ) thiazolo [5,4-e][1,2,4] triazolo [1,5-c] Pyrimidin -2(3 H ) -one :

Step 1 : tert-butyl 4-(2- fluoro -4- hydroxyphenyl ) piperazine -1- carboxylate (2) : 4-bromo-3-fluorophenol (10 g, 0.052 mol), tert-butyl piperazine-1-carboxylate (11.70 g, 0.063 mol), DavePhos (0.515 g, 0.001 mol) and Pd ₂ (dba) ₃ (0.958 g, 0.001 mol) were added LHMDS (115 mL of a 1.0 M solution in THF, 0.115 mol). The reaction mixture was heated at 65 °C for 24 h and monitored by TLC. The crude reaction mixture was neutralized with saturated NH ₄ Cl and extracted with ethyl acetate (2 x 100 mL). The combined organic layers were concentrated and purified by column chromatography to give the title compound (2.25 g, 14.5%) as an off-white solid. LCMS (ESI positive) m/z: Calculated: 296.15; Observed: 297.2 (M+1).

Step 2 : tert-butyl 4-(2- fluoro -4-( prop -2- yn -1- yloxy ) phenyl ) piperazine -1- carboxylate (3) : at 0°C under nitrogen A stirred suspension of sodium hydride (0.7 g, 0.0304 mol) in DMF (10 mL) was added to tert-butyl (hydroxyphenyl)piperazine-1-carboxylate (2, 4.5 g, 0.0152 mol). The reaction mixture was stirred at 0 °C for 15 min and then propyne bromide (2.71 g, 0.0228 mol) in DMF (10 mL) was added and stirred at RT for 16 h. After completion of the reaction (TLC), the reaction mixture was treated with saturated NH ₄ Cl (20 mL) and extracted with ethyl acetate. The organic layer was washed with saturated brine 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/Hexane as eluent) to give 4-(2-fluoro-4-(prop-2-yne- tert-butyl 1-yloxy)phenyl)piperazine-1-carboxylate (3.6 g, 70.8%). LCMS (ESI positive) m/z: Calculated: 334.17; Observed: 335.2 (M+1).

Step 3 : 1-(2- fluoro -4-( prop - 2 - yn -1- yloxy ) phenyl ) piperazine (4) : 4-(2-fluoro-4-(propane A stirred solution of tert-butyl-2-yn-1-yloxy)phenyl)piperazine-1-carboxylate (3, 3.6 g, 10.8 mmol) in dichloromethane (15 mL) was added dropwise to dichloromethane 4 N HCl (mL) in oxane 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 sodium bicarbonate solution, extracted with DCM and the combined organic layers were washed with brine, dried over sodium sulfate and then concentrated under reduced pressure to give 1-(2-fluoro-4-(propan-2 -Alkyn-1-yloxy)phenyl)piperazine (2.5 g, 99.2%); LCMS (ESI positive ion) m/z: Calculated: 234.12; Observed: 235.2 (M+1).

Step 4 : 5- Amino -3-(2-(4-(2- fluoro- ( prop -2yn - 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-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl methanesulfonate (0.9 g, 2.2 mmol) in N,N-dimethylformamide (15 mL) was added DIPEA (0.6 mL, 6.8 mmol) and the reaction mixture was stirred at 120 °C for 16 h. After completion of the reaction (TLC & LCMS), the reaction mass 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-2yn-1-yloxy)benzene as a brown solid Base) piperazin-1-yl) ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidine- 2(3H)-Kone (0.7 g, 57.8%); HPLC purity (XB0595TF): 92.63%; LCMS (ESI positive ion) m/z: Calculated: 534.16; Observed: 534.8 (M+1).

Step 5 : 3-(2-(4-(4-((1H-1,2,3- triazol -4yl ) methoxy - 2fluorophenyl ) 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) : At RT, 5-amino-3-(2-(4-(2-fluoro-4-(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 , 0.4 g, 0.7 mol) in DMF (4.5 mL) and MeOH (0.5 mL) was added cuprous iodide (0.030 g, 0.014 mmol). To the reaction mixture was added dropwise at 0 °C under nitrogen atmosphere Trimethylsilyl azide (0.2 mL, 1.4 mmol) was 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 the combined organic The layer was washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The product was further enriched by washing with diethyl ether and acetonitrile (50:50) to give compound 1 as a brown solid: 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 (0.115 g, 26.6%). HPLC purity (XB0595TF): 92.08%; LCMS (ESI positive 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- oxothiazolo [5,4-e][1,2,4] triazolo [1,5-c] pyrimidine -3(2H) -yl ) ethyl ) piperazin -1- yl )-3- fluorophenoxy ) methyl ) -1,3,4- oxadiazol -2(3H) -one

Step 1 : 4-(4-(2- ethoxy -2- oxoethoxy )-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-dimethylformyl A stirred solution in the amine (15 mL) was added K ₂ CO ₃ (2.76 g, 20.0 mmol) and the reaction mixture was heated at 90° 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 brine solution, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The obtained crude material was purified by column chromatography (20% EtOAc/Hexane as eluent) to give the product (1.9 g, 73.6%) as a brown liquid; LCMS (ESI positive ion) m/z: Calculated: 382.19; Observed: 383.0 (M+1).

Step 2 : 2-(3- fluoro -4-( piperazin- 1- yl ) phenoxy ) ethyl acetate (3) : to 4-(4-(2-ethoxy-2-oxoethyl An ice-cold solution of tert-butyl oxy)-2-fluorophenyl)piperazine-1-carboxylate ( 2 , 1.9 g, 5.0 mmol) in dichloromethane was added to 4 N in dioxane (15 mL) HCl and the reaction mixture was stirred at RT for 5 h. After the reaction was complete (TLC), the reaction mass was quenched with saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to give the product (1.00 g, 71.4%) as a brown liquid; LCMS (ESI positive) m/z: Calcd: 282.14; Obs: 283.1 (M+ 1).

Step 3 : 2-(4-(4-(2-(5- amino- 8-( furan -2- yl )-2- oxothiazolo [5,4-e][1,2,4 ] Triazolo [1,5-c] pyrimidin -3(2H) -yl ) ethyl ) piperazin -1- yl )-3- fluorophenoxy ) ethyl acetate (4) : to 2-(3 -Fluoro-4-(piperazin-1-yl)phenoxy)ethyl acetate (3, 1.0 g, 3.52 mmol) and 2-(5-amino-8-(furan-2-yl)-2- Oxythiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl methanesulfonate (1.12 g, 2.82 mmol ) in N,N-dimethylformamide (15 mL) was added DIPEA (1.3 g, 11.0 mmol) and 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 purified by recrystallization from diethyl ether: acetonitrile (1 : 1 ) mixture to give the title compound (0.70 g, 42.5%) as a dark brown solid ; LCMS (ESI positive) m/z: Calculated: 582.18; Observed: 583.0 (M+1).

Step 4 : 2-(4-(4-(2-(5- Amino- 8-( furan -2- yl )-2- oxothiazolo [5,4-e][1,2,4 ] Triazolo [1,5-c] pyrimidin -3(2H) -yl ) ethyl ) piperazin -1- yl )-3- fluorophenoxy ) acetylhydrazine (5) : to 2-(4 -(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]-triazolo[1 ,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3-fluorophenoxy)ethyl acetate ( 4,0.2 g, 0.34 mmol) in ethanol (20 mL) To the solution in hydrazine hydrate (50 mg, 1.0 mmol) was added and the reaction mixture was stirred at 90 °C for 16 h. After completion of the reaction (TLC & LCMS), the solvent was removed under reduced pressure and purified by recrystallization from a mixture of diethyl ether and acetonitrile to give the title compound (150 mg, 76.9%) as a white solid; LCMS (ESI positive ) m/z: Calculated: 568.18; Observed: 569.0 (M+1).

Step 5 : 5-((4-(4-(2-(5- amino- 8-( furan -2- yl )-2- oxothiazolo [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 Oxadiazol -2(3H) -one ( compound 2) : To a suspension of compound 5 (0.158 g, 0.27 mol) in 1,4-dioxane (10 mL) and DMF (1 mL) was added TEA (0.084 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 preparative HPLC purification to give the title compound 2 (21 mg, 12.7%) as a white solid; HPLC purity (XB0595TF): 95.33%; LCMS (ESI positive) 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) : Add 3-fluoro-4-iodopyridine ( 2 , 2 g, 4.48 mmol, 1 eq) in NMP (20 mL ) 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 gummy solid was triturated with diethyl ether and n-pentane to give 1-(3-fluoropyridin-4-yl)piperazine 3 (0.750 g, 92%) as a pale yellow solid. LCMS (ESI positive ion) m/z: Calculated: 181.21; Observed: 182.2 (M+1).

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 ) to a solution of piperazine (3, 0.071 g, 0.392 mmol, 1 eq) in DMF (2 mL) was added 2-(5-amino-8-(furan-2-yl)-2-oxothiazolo [4,5-e][1,2,4]triazolo[1,5-c]-pyrimidin-1(2H)-yl)ethyl methanesulfonate (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 obtained residue was diluted with water and extracted with ethyl acetate (2 x 30 mL). The combined organic phases were dried (anhydrous _Na2SO4 ), filtered and concentrated _under reduced pressure. The obtained crude product was purified by reverse phase preparative HPLC to afford the title compound 3 (0.013 g, 7%) as a brown solid. LCMS (ESI positive) m/z: Calculated: 481.51; Observed: 482 (M+1). HPLC purity (XB0595TF.M): 97.75%. Example 4: 2-(5-(4-(2-(5- amino- 8-( furan -2- yl )-2- oxothiazolo [5,4-e][1,2,4 ] triazolo [1,5-c] pyrimidin -3(2H) -yl ) ethyl ) piperazin -1- yl )-2,4 -difluorophenoxy ) 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 A solution of benzyl chloride (18 g, 105.26 mmol) in N,N-dimethylformamide (200 mL) was added K ₂ CO ₃ (39.62 g, 287.08 mmol) and the reaction mixture was heated at 90 °C for 16 h . 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 brine solution, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The obtained crude material was purified by column chromatography (5% EtOAc/Hexane as eluent) to give the product (24 g, 85%) as an off-white solid. LCMS (ESI negative ion); 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 4-(5-( benzyloxy )-2,4- difluorophenyl ) piperazine -1- carboxylic acid tert-butyl ester (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 tert-butoxide (17.06 g, 177.77 mmol) in toluene (200 mL) To the solution was added t -Bu Xphos (3.43 g, 8.08 mmol). The reaction mixture was flushed with N ₂ and Pd ₂ (dba) ₃ (3.69 g, 4.04 mmol) was added. The reaction mixture was heated at 115 °C for 16 h and after completion (TLC), the reaction mixture was cooled and filtered through celite. The filtrate was concentrated and purified by column chromatography (12-15% EtOAc/hexanes) to give the title compound (18 g, 55.14%) as a light brown oil; LCMS (ESI positive); m/z: 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 A clear solution of tert-butyl fluorophenyl)piperazine-1-carboxylate (3, 18 g, 44.55 mmol) in ethanol (180 mL) was added with 10% Pd-C (2.7 g, 15% Wt.) and The reaction mixture was stirred at RT for 5 h under _H2 atmosphere. After completion (TLC), the reaction mixture was filtered through celite and washed with methanol (500 mL). The filtrate was concentrated and triturated with diethyl ether to give the title compound (13 g, 92.6%) as an off-white solid; LCMS (ESI positive); m/z: Calculated: 314.14; Obs; 315.2 (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), and 1.49 (s, 9H).

Step 4 : 4-(5-(2- amino -2- oxoethoxy )-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- To a suspension in dimethylformamide (100 mL) was added _K2CO3 (13.14 g, 95.23 mmol) _. The reaction mixture was stirred at 90 °C for 5 h and monitored by TLC. After completion, the reaction mixture was diluted with water (100 mL) and the crude product was extracted with ethyl acetate. _The organic layer was washed with saturated brine solution, dried over anhydrous _Na2SO4 , filtered, concentrated and triturated with diethyl ether to give the title compound (9.5 g, 80.7%) as a beige solid; LCMS (ESI positive); 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-oxo An ice-cold solution of butylethoxy)-2,4-difluorophenyl)-piperazine-1-carboxylate (5, 8.0 g, 21.5 mmol) in DCM was added to 4 N in dioxane HCl (80 mL) and the reaction mixture was stirred at RT for 5 h. After the reaction was complete (TLC), the HCl salt was filtered. The salt was dissolved in methanol and neutralized using Tosic acid scavenger resin to give the free base as an off-white solid (3.5 g, 59.9%); LCMS (ESI positive ion); m/z: calcd: 271.11; observed; 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- oxothiazolo [5,4-e][1,2,4 ] Triazolo [1,5-c] pyrimidin -3(2H) -yl ) ethyl ) piperazin -1- yl )-2,4 -difluorophenoxy ) 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-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)-ethylmethanesulfonate A mixture of ester (5.88 g, 14.84 mmol) in N,N-dimethylformamide (70 mL) was added DIPEA (8.33 g, 64.57 mmol) and the reaction mixture was stirred at 120 °C for 16 h. After completion of the reaction (TLC & LCMS), the reaction mass was concentrated to half volume under reduced pressure and cooled to 0 °C. The product precipitated as a pale yellow solid. It was filtered and dried. Because of poor purity, it was suspended in DMSO (150 mL) and heated at 110 °C for 1 h and filtered hot. The filtrate was cooled to 0 °C, diluted with MeOH and then water was added slowly to facilitate 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 a light yellow solid. HPLC purity (XB_0595TF.M): 92.4%; LCMS (ESI positive ion) 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 ) 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 ) -piperazine -1- Base ) ethyl )-8-( furan -2- yl ) thiazolo [5,4-e][1,2,4] triazolo [1,5-c] pyrimidin -2(3H) -one:

Step 1 : synthetic 4-(2- fluoro -4-(2-( methylsulfanyl ) ethoxy ) phenyl ) piperazine -1- carboxylic acid tert-butyl ester (2) : to 4-(2-fluoro -4-Hydroxyphenyl)piperazine-1-carboxylic acid tert-butyl ester (1, 0.3 g, 1.102 mmol, 1 eq) and 1-chloro-2-methylhydrogensulfanyl-ethane (0.168 g, 1.519 mmol , 1 eq) in N,N-dimethylformamide (3 mL) was added K ₂ CO ₃ (0.419 g, 3.027 mmol, 2 eq) and the reaction mixture was heated at 90° 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 brine solution, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The obtained crude residue was purified by column chromatography (50% EtOAc/Hexane as eluent) to give the product (0.3 g, 53%) as an off-white solid. LCMS (ESI positive) m/z: Calculated: 370.48; Observed: 370.9 (M+). 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 4-(2- fluoro - 4- (2-( methylsulfinyl ) ethoxy ) phenyl ) piperazine -1- carboxylic acid tert-butyl ester (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 ) was added hydrogen peroxide (0.187 mL) dropwise 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 brine solution, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The obtained crude material was purified by column chromatography (80% EtOAc/Hexane as eluent) to give the product (0.29 g, 93%) as an off-white solid. LCMS (ESI positive) m/z: Calculated: 386.48; Observed: 387.9 (M+1). 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) yielded 130 mg of peak 1 ( 3 ) and 130 mg of peak 2 ( 4 ) as off-white solids, respectively. Note: Peak 1 from SFC purification was arbitrarily considered the (S) isomer and peak 2 was considered 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) The ice-cold solution was added 4M HCl in dioxane (1 mL) and the reaction 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. It was then dissolved in methanol and passed through Si-carbonate resin to give the free base 5 (0.094 g, 59%). LCMS (ESI positive) m/z: Calculated: 286.37; Observed: 287 (M+1).

Step 4 : Synthesis of (S)-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] pyrimidine -2(3H)- Ketone ( compound 5) : 2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[ 1,5-c]pyrimidin-3(2H)-yl)ethyl methanesulfonate ( 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) and extracted with ethyl acetate. The organic layer was washed with saturated brine solution, dried over anhydrous _Na2SO4 , filtered and concentrated _. The obtained crude residue was subjected to preparative HPLC purification to afford Compound 5 (5 mg) as an off-white solid. LCMS (ESI positive) m/z: Calculated: 586.66; Observed: 587.2 (M+1). 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- Ice-cooled tert-butyl fluoro-4-(2-(methylsulfinyl)ethoxy)-phenyl)piperazine-1-carboxylate ( 4 , 0.13 g) in dichloromethane (1 mL) The solution was added 4M HCl in dioxane (0.5 mL) 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 obtained crude residue was triturated with diethyl ether. It was then dissolved in methanol and passed through Si-carbonate resin to give the free base 6 (0.094 g). LCMS (ESI positive) m/z: Calculated: 286.37; Observed: 287 (M+1).

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-oxothiazolo[5,4-e][1,2,4]triazolo[1 ,5-c]pyrimidin-3(2H)-yl)ethyl methanesulfonate ( 7 , 0.11 g, 0.303 mmol, 1 eq), (R)-1-(2-fluoro-4-(2(methyl Sulfinyl)-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) and extracted with ethyl acetate. The organic layer was washed with saturated brine solution, dried over anhydrous _Na2SO4 , filtered and concentrated _. The obtained crude product was subjected to reverse phase preparative HPLC purification to afford compound 6 (3 mg) as an off-white solid. LCMS (ESI positive) m/z: Calculated: 586.66; Observed: 587.2 (M+1). 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] -pyrimidin -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] pyrimidin -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] pyrimidin -2(3H) -one

Step 1 : Synthesis of 4-(2,4- difluoro -5-(2-( methylsulfanyl ) ethoxy ) -phenyl ) piperazine -1- carboxylic acid tert-butyl ester (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-methylhydrogensulfanyl-ethyl A solution of alkane (0.264 g, 2.386 mmol, 1.5 eq) in N,N-dimethylformamide (5 mL) was added K ₂ CO ₃ (0.439 g, 3.181 mmol, 2 eq) and the reaction mixture was heated at 90 Heating at ℃ 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 brine solution, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The obtained crude material was purified by column chromatography (50% EtOAc/Hexane as eluent) to give the product ( 2 , 0.5 g, 77%) as an off-white solid. LCMS (ESI positive) m/z: Calculated: 388.47; Observed: 389 (M+1).

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) An ice-cold solution in acetic acid (10 mL) was added hydrogen peroxide (0.312 mL) dropwise 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 brine solution, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The obtained crude material was purified by column chromatography (80% EtOAc/Hexane as eluent) to give the product (0.38 g, 86%) as an off-white solid. LCMS (ESI positive) m/z: Calculated: 404.47; Observed: 348.9 (M-tert-butyl). 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 (0.38 g sample was dissolved in 5 mL 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) to yield 150 mg of peak 1 respectively as an off-white solid ( 3 , [a] _D = +50.7°, c=1.1, MeOH) and 150 mg of 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 (except for 3 and 4 Racemic mixture, 0.15 g, 0.371 mmol, 1 eq) to an ice-cold solution in dichloromethane (2 mL) was added 4M HCl in dioxane (0.5 mL) 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 obtained residue was triturated with diethyl ether to give the racemic product. It was then dissolved in methanol and passed through Si-carbonate resin to give the free base 6 (0.09 g). LCMS (ESI positive) m/z: Calculated: 304.36; Observed: 305 (M+1).

For compound 7 , step 4 : Synthesis of (R,S)-5- amino -3-(2-(4-(2,4- difluoro -5-(2-( methylsulfinyl ) ethoxy Base ) -phenyl ) -piperazin -1- yl ) ethyl )-8-( furan -2- yl ) thiazolo [5,4-e][1,2,4] triazolo [1,5 -c] -pyrimidin -2(3H) -one: to 2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2 ,4] A solution of triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl methanesulfonate (6, 105 mg, 0.265 mmol, 1.0 eq) in DMF (2 mL) was added (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 obtained crude product was purified by grace column chromatography with 5% methanol in DCM to give the desired racemic compound. It was further purified by preparative HPLC to give the title compound 7 (6 mg, purity 96%). LCMS (ESI positive) m/z: Calculated: 604.65; Observed: 605.2 (M+1). 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 ethyl acetate To an ice-cold stirred solution of the ester (3 mL) was added _SnCl4 (644 mg, 2.47 mmol). The resulting mixture was stirred at RT for 2 h. The reaction mixture was concentrated under reduced pressure. The obtained residue was triturated with cold ethyl acetate (2 x 10 mL) to give the crude product (580 mg), which was used as such in the next step. 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] -Pyrimidin -2(3H) -one was prepared according to the same procedure described for compound 7 with (+)-1-(2,4-difluoro-5-(2-(methylsulfinyl)ethoxy Base) phenyl) piperazine start to prepare. 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 chiral 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] pyrimidin -2(3H) -one was prepared with (-)-4-(2,4-difluoro-5-(2-(methylsulfinyl)ethyl) according to the same procedure described for compound 7 oxy)phenyl)-piperazine-1-carboxylate ( 3 ), leading to (-)-1-(2,4-difluoro-5-(2-(methylethylene Sulfonyl)ethoxy)phenyl)piperazine. LCMS (ESI positive) 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 chiral 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, 4-(2,4-difluoro-5-(2-(methylthio)ethoxy)phenyl)-piperazine-1-carboxylic acid tert-butyl ester (20 g, 51.48 mmol, as example 7 (prepared as described in Step 1) and urea hydroperoxide (21.78 g, 231.68 mmol) were 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, then filtered. Concentration of the filtrate afforded the crude product. It was purified by column chromatography using 50% ethyl acetate in petroleum ether to give the product (9 g, 42%) as an off-white solid. 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- Ice-cooled difluoro-5-(2-(methylsulfonyl)ethoxy)phenyl)piperazine-1-carboxylic acid tert-butyl ester (9 g, 21.40 mmol) in dichloromethane (50 mL) To the solution was added a solution of HCl in diethyl ether (50 mL). 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 obtained residue was triturated with diethyl ether to give pure product (10 g). LCMS (ESI positive ion) m/z: 321 (M+1).

Step 3 : Add 1-(2,4-difluoro-5-(2-(methylsulfonyl)ethoxy)phenyl)piperazine hydrochloride (7 g, 22.13 mmol) in anhydrous dichloroethyl A stirred suspension in alkanes (70 mL) was added triethylamine (6.259 g, 61.97 mmol) and freshly prepared 2-(5-amino-8-(furan-2-yl)-2-oxothiazolo [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 triacetyloxyborohydride (9.339 g, 44.26 mmol) was added. 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 successively washed with a saturated bicarbonate solution and a saturated brineution. It was then dried over _{anhydrous Na2SO4} , filtered and concentrated under reduced pressure. The obtained crude material was purified by column chromatography (230-400 silica gel, 5% methanol/dichloromethane as eluent) to give the product (3.2 g, 26%) as an off-white solid. 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 (1, 10 g, 0.052 mol), a mixture of tert-butyl piperazine-1-carboxylate (11.70 g, 0.063 mol), DavePhos (0.515 g, 0.001 mol) and Pd ₂ (dba) ₃ (0.958 g, 0.001 mol) was added LHMDS (115 mL of a 1.0 M solution in THF, 0.115 mol). The reaction mixture was heated at 65 °C for 24 h and monitored by TLC. The crude reaction mixture was neutralized with saturated NH ₄ Cl and extracted with ethyl acetate (2 x 100 mL). The combined organic layers were concentrated and purified by column chromatography to give the title compound (2.25 g, 14.5%) as an off-white solid. LCMS (ESI positive) m/z: Calculated: 296.15; Observed: 297.2 (M+1).

Step 2 : synthetic 4-(2- fluoro -4-(2-( methylsulfanyl ) ethoxy ) phenyl ) piperazine -1- carboxylic acid tert-butyl ester (3) : to 4-(2-fluoro -tert-butyl 4-(2-(methylthio)ethoxy)phenyl)piperazine-1-carboxylate ( 2 , 0.3 g, 1.102 mmol) and 1-chloro-2-methylhydrogensulfanyl - A mixture of ethane (0.168 g, 1.519 mmol) in N,N-dimethylformamide (3 mL) was added potassium carbonate (0.419 g, 3.027 mmol) and the reaction mixture was heated at 90 °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 combined organic layers were washed with saturated brine solution, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The obtained crude material was purified by column chromatography (50% EtOAc/Hexane as eluent) to give the product (0.3 g, 52.8%) as an off-white solid. LCMS (ESI positive) m/z: Calculated: 370.48; Observed: 370.9 (M+). 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 : synthetic 4-(2- fluoro -4-(2-( methylsulfonyl ) ethoxy ) phenyl ) -piperazine - 1- carboxylic acid tert-butyl ester (4) : to 4-[2 -Fluoro-4-(2-methylhydrogenthioethoxy)phenyl]piperazine-1-carboxylic acid tert-butyl ester ( 3 , 0.5 g, 0.001 mmol) in 1,4-dioxane (2 mL ) was added 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 and concentrated under reduced pressure. The crude product obtained was subjected to column chromatography (solvent mixture of 1% methanol in DCM as eluent) to give the product 4-(2-fluoro-4-(2-(methylsulfonyl)ethoxy yl)phenyl)piperazine-1-carboxylic acid tert-butyl ester (0.22 g, 40%). LCMS (ESI positive) m/z: Calculated: 402.48; Observed: 403.3 (M+1). 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 An ice-cold solution of sulfonylethoxy)phenyl]piperazine-1-carboxylic acid tert-butyl ester ( 4 , 0.22 g, 0.547 mmol) in dichloromethane (5 mL) was added to diethyl ether (2 mL) 2M HCl in medium 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 obtained residue was triturated with diethyl ether to obtain pure product. It was then dissolved in methanol and passed through Si-carbonate resin to give the free base 6 (0.105 g crude compound), which was used directly in the next step.

Step 5 : Synthesis of 5- amino -3-(2-(4-(2- fluoro -4-(2-( methylsulfonyl ) ethoxy ) phenyl ) -piperazin -1- yl ) ethyl Base )-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-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethylmethane A mixture of sulfonate (125 mg, 0.315 mmol) in N,N-dimethylformamide (2 mL) was added DIPEA (204 mg, 1.577 mmol) and the reaction mixture was stirred at 120 °C for 16 h. After completion of the reaction (TLC & LCMS), the reaction mass was concentrated under reduced pressure. The crude product was purified by column chromatography with 5% methanol in DCM to give the product. It was further purified by RP prep HPLC to give the title compound. LCMS (ESI positive) m/z: Calculated: 602.66; Observed: 603 (M+1). 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- methylimino ) 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 mmol) in DCM was added 3-chloroperoxybenzoic acid (6.78 g, 39.33 mmol) and the reaction mixture was stirred at RT for 16 h. After completion of the reaction (TLC), the reaction mixture was diluted with ice-cold water (30 mL) and the crude product was extracted with DCM. The organic layer was washed successively with aqueous sodium thiosulfate, 10% NaHCO ₃ , brine solution, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude product obtained was purified by column chromatography (50% EtOAc/Hexane as eluent) to afford the title product 2 (2.8 g, 85%) as an off-white solid; LCMS (ESI positive 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 )-16- thione (3) : to 1,2-difluoro-4-(methylsulfinyl) A solution of benzene ( 2 , 2.8 g, 15.89 mmol) in dichloromethane (60 mL) was dimerized by adding trifluoroacetamide (3.59 g, 31.79 mmol), magnesium oxide (2.54 g, 63.57 mmol) and rhodium diacetate (0.172 g, 0.429 mmol) and the reaction mixture was flushed with N ₂ for 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 a bed of celite, concentrated and purified by preparative column chromatography to give the title compound 3 (0.7 g, 23.0%) as an off-white solid; LCMS (ESI positive ions) 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 )-16- thione (4) : to (3,4-difluorophenyl )(imino)(methyl)-l6-thione (0.7 g, 3.66 mmol) in N,N-dimethylformamide (10 mL) was added piperazine (0.32 g, 3.66 mmol) , 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 obtained crude material was purified by preparative column chromatography to give the desired product 4 as an off-white solid. LCMS (ESI positive) m/z: Calculated: 257.33; Observed: 258.1 (M+1).

Step 4 : Synthesis of 5- amino -3-(2-(4-(2- fluoro -4-(S- methylimino ) 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) : the (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-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethylmethane A mixture of 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 give the product as an off-white solid. title compound. LCMS (ESI positive) m/z: Calculated: 557.62; Observed: 558.1 (M+1). 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- oxothiazolo [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 benzamide

Step 1 : Synthesis of 5- amino -2,4- difluorobenzoic acid methyl ester (2) : To 5-amino-2,4-difluoro-benzoic acid ( 1 , 0 g, 0.017 mol) in methanol ( To an ice-cold solution in 20.0 mL) was added thionyl chloride (2.514 mL, 0.035 mol). 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 over sodium sulfate and concentrated under reduced pressure to give the product 5-amino-2,4-difluoro-benzoic acid methyl ester (2.8 g, 86.0%). LCMS (ESI positive ion) m/z: Calculated: 187.15; Observed: 188.2 (M+1). 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 2,4- difluoro -5-( piperazin -1- yl ) methyl 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) was heated to 170°C It took 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 over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by column chromatography to give the product (1.5 g, 29.9%). LCMS (ESI positive ion) m/z: Calculated: 256.25; Observed: 257.0 (M+1).

Step 3 : Synthesis of 4-(2,4- difluoro -5-( methoxycarbonyl ) phenyl ) piperazine -1- carboxylic acid tert-butyl ester (4) : to 2,4-difluoro-5-piper To an ice-cold solution of azin-1-yl-benzoic acid methyl ester ( 3 , 1.0 g, 0.009 mol) in DCM (10 mL) was added triethylamine (1.510 mL, 0.012 mol) and boc anhydride (1.278 mL, 0.006 mol) . 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 fractions were washed with saturated brine solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure to give the product (0.800 g, 58%). LCMS (ESI positive) m/z: Calculated: 356.37; Observed: 357.2 (M+1).

Step 4 : Synthesis of 5-(4-( tertiary butoxycarbonyl ) piperazin -1- yl )-2,4 -difluorobenzoic acid (5) : to 4-(2,4-difluoro-5- (Methoxycarbonyl) phenyl) piperazine-1-carboxylic acid tert-butyl ester ( 4 , 1.0 g, 0.003 mol) in THF:water (20 mL, 3:1) was stirred solution, lithium hydroxide ( 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. 1.5N HCl was added to make the pH acidic. The resulting solid was filtered to give 5-(4-(tert-butoxycarbonyl)piperazin-1-yl)-2,4-difluorobenzoic acid (0.800 g, 97%). LCMS (ESI negative ion) m/z: Calculated: 342.34; Observed: 341.0 (M-1).

Step 5 : synthetic 4-(5-((2-( dimethylamino ) ethyl ) aminoformyl )-2,4 -difluorophenyl ) piperazine -1- carboxylic acid tert-butyl ester (6 ) : 5-(4-(tert-butoxycarbonyl)piperazin-1-yl)-2,4-difluorobenzoic acid ( 5 , 0.200 g, 0.0005 mol) was stirred in DCM (10 mL) solution, N1,N1-dimethylethane-1,2-diamine (0.062 g, 0.0007 mol), DIPEA (0.306 mL, 0.002 mol) and T3P solution (0.438 mL, 0.001 mol) were added successively. 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 over anhydrous sodium sulfate and concentrated under reduced pressure to give the product (0.13 g, 46.4%). LCMS (ESI positive) m/z: Calculated: 412.48; Observed: 413.6 (M+1).

Step 6 : Synthetic N-(2-( dimethylamino ) ethyl )-2,4- difluoro -5-( piperazin -1- yl ) -benzamide (7) : to 4-( tert-butyl 5-((2-(dimethylamino)ethyl)carbamoyl)-2,4-difluorophenyl)piperazine-1-carboxylate ( 6 , 0.200 g, 0.0004 mol) To an ice-cold solution in DCM (10 mL) was added HCl in diethyl ether (0.121 mL, 4M solution). 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% ). LCMS (ESI positive) m/z: Calculated: 312.36; Observed: 313.2 (M+1).

Step 7 : Synthesis of 5-(4-(2-(5- amino -8-( furan -2- yl )-2- oxothiazolo [5,4-e][1,2,4] tri Azolo- [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-oxothiazolo[5,4-e][1,2,4 ]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl methanesulfonate ( 8 , 120 mg, 0.0003 mol) and N-[2-(dimethylamino)ethyl A stirred mixture of ]-2,4-difluoro-5-piperazin-1-yl-benzamide ( 7 , 113 mg, 0.00036 mol) in DMF (5 mL) was added DIPEA (0.129 mL, 0.0009 mol) . 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 obtained crude residue was purified by reverse phase preparative HPLC purification to give the product. LCMS (ESI positive) m/z: Calculated: 612.66; Observed: 613.2 (M+1). 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) - Keto and 5- amino -3-(2-(4-(2- fluoro -4-(((3S,4S)-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] pyrimidin -2 ( 3H) -one

Step 1 : Synthesis of 4- amino -3- fluorophenol (2) : Addition of 3-fluoro-4-nitrophenol ( 1 , 10 g, 0.064 mol) in ethyl acetate (140 mL) under nitrogen atmosphere The stirred solution was added with Pd/C (4.0 g, 0.038 mol). The reaction mixture was stirred under balloon pressure of hydrogen for 16 h. The progress of the reaction was monitored by TLC. The reaction mixture was filtered through a bed of celite, and the filtrate was concentrated under reduced pressure to give 4-amino-3-fluorophenol (6.9 g, 94%) as a pale pink solid. LCMS (ESI positive ion); m/z: Calculated: 127.12; Observed: 128.2 (M+1).

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 a 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 complete, the reaction mixture was cooled to RT. About 30 mL of cold acetone was added and stirred at 0 °C for 0.5 h. The resulting solid was filtered and dried to give 3-fluoro-4-(piperazin-1-yl)phenol hydrochloride (10 g, 98%) as a black solid. LCMS (ESI positive ion); m/z: Calculated: 196.23; Observed: 197.1 (M+1).

Step 3 : Synthesis of 4-(2- fluoro -4- hydroxyphenyl ) piperazine -1- carboxylic acid tert-butyl ester (4) : to 3-fluoro-4-(piperazin-1-yl) phenol hydrochloride ( 3 , 3.0 g, 0.015 mol) in DMF (30 mL) was added triethylamine until it became basic. Then BOC anhydride (3.0 mL, 0.041 mol) was added and the reaction was kept 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 sulfate and concentrated under reduced pressure. The obtained crude product was purified by column chromatography to give tert-butyl 4-(2-fluoro-4-hydroxyphenyl)piperazine-1-carboxylate (1.5 g, 86%). LCMS (ESI positive ion); m/z: Calculated: 296.34; Observed: 297.1 (M+1).

Step 4 : synthetic 4-(2- fluoro -4-((4- hydroxytetrahydrofuran -3- yl ) oxygen group ) -phenyl ) piperazine -1- carboxylic acid tert-butyl ester (5) : to 4-(2 To a stirred solution of -fluoro-4-hydroxyphenyl)piperazine-1-carboxylic acid tert-butyl ester ( 4 , 1.5 g, 0.005 mol) in dioxane (25 mL) was added 3,6-dioxabicyclo[ 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 layers were dried over anhydrous MgSO ₄ and concentrated under reduced pressure to give 4-(2-fluoro-4-((4-hydroxytetrahydrofuran-3-yl)oxy)phenyl)piperazine-1- as a brown solid. Tertiary butyl formate (0.800 g, 98%). LCMS (ESI positive ion); m/z: Calculated: 382.43; Observed: 383.1 (M+1).

Step 5 : Synthesis of 4-(3- fluoro -4-( piperazin -1- yl ) phenoxy ) tetrahydrofuran -3- alcohol (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) was added to the ice-cold solution in dioxane HCl (4M solution, 1 mL). After stirring at room temperature for 16 h, the reaction mixture was concentrated under reduced pressure. The residue was neutralized with 10% sodium bicarbonate solution and extracted with DCM. Concentration of the organic portion afforded 4-(3-fluoro-4-(piperazin-1-yl)phenoxy)tetrahydrofuran-3-ol (0.250 g, 88%). LCMS (ESI positive ion); m/z: Calculated: 282.3; Observed: 283.2 (M+).

Step 6 : Synthesis of 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) -ketone ( compound 83) and 5- amino -3-(2-(4-(2- fluoro -4-(((3S,4S)-4- hydroxyl - 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)-ketone ( compound 84 ) : to 2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4 ]Triazolo[1,5-c]pyrimidin-3(2H)-yl)-ethyl methanesulfonate ( 7 , 0.320 g, 0.00080 mol) in DMF (8 mL) was added 4-( 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 completion of the reaction, the reaction mixture was concentrated and the residue was purified by preparative HPLC purification. The pure product was then purified by chiral SFC purification to give the two isomers 5-amino-3-(2-(4-(2-fluoro-4-(((3R,4R)-4- Hydroxytetrahydrofuran-3-yl)oxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]tri Azolo[1,5-c]pyrimidin-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]pyrimidin-2(3H)-one.

First resolving enantiomer: LCMS (ESI positive); m/z: Calculated: 582.61; Observed; 583.2 (M+1). 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).

Second resolving enantiomer: LCMS (ESI positive); m/z: Calculated: 582.61; Observed: 583.2 (M+1). 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 ) ( tertiary butyl ) dimethylsilane (2) : 3-bromo-4-fluorophenol (1, 2.3 g, 0.012 mol), (2-bromoethoxy)(tert-butyl)dimethylsilane (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 to the reaction mixture and extracted with dichloromethane (30 mL x 2). The combined organic portions were washed with saturated brine solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound (2 g, 29%), which was used as such in the next step.

Step 2 : Synthesis of 1-(5-(2-(( tertiary butyldimethylsilyl ) oxy ) ethoxy )-2- fluorophenyl ) -piperazine (3) : to 2-(3 -Bromo-4-fluoro-phenoxy)ethoxy-tert-butyl-dimethyl-silane ( 2 , 1.0 g, 0.003 mol) and piperazine (499 mg, 0.006 mol) in toluene (15 mL) To the stirred solution in was added NaOBu-t (412 mg). The resulting mixture was degassed with nitrogen. Then BINAP (107 mg, 0.00017 mol) and palladium acetate (262 mg, 0.0003 mol) were added and the resulting mixture was heated to 110 °C for 16 h. After completion, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The obtained crude residue was purified by column chromatography to give the title compound (0.3 g, 29.5%). LCMS (ESI positive) m/z: Calculated: 354.54; Observed: 355.3 (M+1).

Step 3 : Synthesis of 2-(4- fluoro -3-( piperazin -1- yl ) phenoxy group ) ethan -1- alcohol (4) : to 1-(5-(2-((tertiary butyl di To an ice-cold solution of methylsilyl)oxy)ethoxy)-2-fluorophenyl)-piperazine ( 3 , 0.354 g, 0.0009 mol) in THF (10 mL) was slowly added TBAF (0.499 mL, in 4 M in THF). The resulting mixture was brought to RT and it was 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 sulfate, and concentrated under reduced pressure. The obtained crude product was purified by column chromatography to give the title compound (0.240 g, 98.99%). LCMS (ESI positive) m/z: Calculated: 240.28; Observed: 241.2 (M+1).

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-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidine-3(2H) - to a stirred solution of ethyl methanesulfonate (0.300 g, 0.0007 mol) in DMF (8 mL) was added 2-(4-fluoro-3-(piperazin-1-yl)phenoxy)ethyl- 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 the obtained crude product was purified by reverse phase preparative HPLC purification to give the title compound as an off-white solid. HPLC purity (XB_0595TF): 98.29%; LCMS (ESI positive) m/z: Calculated: 540.57; Observed: 541.0 (M+1). 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 third Butyl ester (2) : Benzyl 4-(2,4-difluoro-5-hydroxyphenyl)piperazine-1-carboxylate ( 1 , 1.2 g, 2.9 mmol) and 3-(hydroxymethyl To a stirred solution of tert-butyl morpholine-4-carboxylate (1.1 g, 4.3 mmol) in toluene (10 mL) was added triphenylphosphine (1.8 g, 6.9 mol) 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 brine 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) to give the title compound (1.4 g, 63.8%) as a brown liquid; LCMS (ESI positive) m/z: Calculated: 547.25; observed value: 548.1 (M+1).

Step 2 : Synthesis of tert-butyl 3-((2,4- difluoro -5-( piperazin -1- yl ) phenoxy ) methyl ) morpholine -4- carboxylate (3) : under nitrogen atmosphere To 3-((5-(4-((benzyloxy)carbonyl)piperazin-1-yl)-2,4-difluorophenoxy)methyl)morpholine-4-carboxylic acid tert-butyl ester ( 0.5 g, 0.91 mmol) in EtOAc (20 mL) was added with 10% Pd/C (0.2 g). The reaction mixture was stirred at room temperature under hydrogenation atmosphere for 16 h. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was filtered using celite to remove Pd/C. The combined organic layers were dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to give the title compound (280 mg, 73.5%) as a brown gummy solid; LCMS (ESI positive) m/z: calcd: 413.21; observed : 414.3 (M+1).

Step 3 : Synthesis of 3-((5-(4-(2-(5- amino -8-( furan -2- yl )-2- oxothiazolo [5,4-e][1,2 ,4] Triazolo [1,5-c] pyrimidin -3 ( 2H)-yl ) ethyl ) piperazin - 1- yl )-2,4- difluorophenoxy ) -methyl ) morpholine- 4- Tert-butyl carboxylate (4) : Add 3-((2,4-difluoro-5-(piperazin-1-yl)phenoxy)methyl)-morpholine- 4-tert-butyl carboxylate (3, 100 mg, 0.242 mmol) and 2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][ 1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl methanesulfonate (86 mg, 0.218 mmol) in N,N-dimethylformamide ( 10 mL) was added DIPEA (94 mg, 0.726 mmol) and the reaction mixture was stirred at 120 °C for 16 h. After the reaction was complete (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 brine solution, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude product was purified by prep-TLC to give the title compound (25 mg, 14.4%) as a dark brown solid; LCMS (ESI positive) m/z: Calc.: 713.26; Obs.: 714.1 (M+1).

Step 4 : Synthesis of 5- amino -3-(2-(4-(2,4- difluoro -5-( morpholin- 3- ylmethoxy ) -phenyl ) piperazin -1- yl ) ethyl Base )-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-oxothiazolo[5,4-e][1 ,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-4,5-difluorophenoxy)-methyl)- A stirred solution of tert-butyl morpholine-4-carboxylate ( 4 , 25 mg, 0.035 mmol) in DCM (5 mL) was added 4 N HCl in dioxane (1.5 mL) and the reaction mixture was stirred at RT 5 h. After completion of the reaction (TLC), the reaction mixture was concentrated under reduced pressure to give the crude product, which was washed with acetonitrile to give the title compound (16 mg, 73.3%) as a brown solid; HPLC purity (AM9010A3): 98.49%; LCMS (ESI positive ion) m/z: Calculated: 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-((1-( tert-butoxycarbonyl )-4- hydroxypyrrolidin -3- yl ) oxy )-2,4- difluorophenyl ) piperazine -1- Benzyl formate (2) : Benzyl 4-(2,4-difluoro-5-hydroxyphenyl)piperazine-1-carboxylate (6.0g, 17.22 mmol) and 6-oxa-3-azabicyclo [3.1.0] A suspension of tert-butyl hexane-3-carboxylate (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 completion of the reaction (TLC), the reaction mixture was concentrated under reduced pressure and the crude material was purified by column chromatography to give the title compound 2 (3.5 g, 36%) as a less colored liquid; LCMS (ESI positive ion ); 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-( tert-butoxycarbonyl )-4- fluoropyrrolidin -3- yl ) oxy )-2,4- difluorophenyl ) Benzyl piperazine -1- carboxylate (3) : 4-(5-((1-(3-butoxycarbonyl)-4-hydroxypyrrolidin-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 added slowly, 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 washed successively with 10% NaHCO3, water, brine, dried over _Na2SO4 , filtered and concentrated to give crude product _. The diastereomers formed were separated into peaks 1 and 2 by normal silica column chromatography. The enantiomer present in peak 1 was separated via SFC on a chiral column; 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 eluting from the chiral column was concentrated to give the title compound 3 (0.7 g, 19%) as an off-white solid; LCMS (ESI positive); m/z: Calculated: 535.56; Observed: 536.2 (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 ) : 4-(5-(((3S,4S)-1-(tertiary butoxycarbonyl)-4-fluoropyrrolidin-3-yl)oxy)-2,4-difluorophenyl) A suspension of benzyl piperazine-1-carboxylate (0.23 g, 0.429 mmol) in ethyl acetate (10 mL) was charged 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 a pad of celite and concentrated to give the title compound 4 (0.16 g, 92.8%) as a beige solid; LCMS (ESI positive ion); m/z: calculated 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- oxothiazolo [5,4-e ][1,2,4] triazolo [1,5-c] pyrimidin -3(2H) -yl ) ethyl ) piperazin -1- yl )-2,4 -difluorophenoxy )-4 -Tertiary butyl fluoropyrrolidine -1- carboxylate (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-oxothiazolo[5,4-e ][1,2,4]Triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl methanesulfonate (0.15 g, 0.39 mmol) in dry DMF (3 mL) N,N-Diisopropylethylamine (0.13 g, 0.83 mmol) was added and the reaction mixture was heated in a sealed tube at 120 °C for 16 h. After completion of the reaction (LCMS), the reaction mixture was concentrated under reduced pressure and purified by preparative HPLC to afford the title compound 5 (0.06 g, 21.4%) as an off-white solid. LCMS (ESI positive ion); m/z: Calculated: 701.73; Observed: 702.3 (M+1); 1H-NMR (400 MHz, DMSO-d6): δ 8.30 (s, 2H), 7.95 (t, 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)-Kone ( Compound 91 ) : Under nitrogen pressure, to (3R,4R)-3-(5-(4-(2-(5-amino-8-(furan-2-yl)-2- Oxythiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-2 , An ice-cold solution of tert-butyl 4-difluorophenoxy)-4-fluoropyrrolidine-1-carboxylate (0.06 g, 0.086 mmol) in dichloromethane (3 mL) was added to 2M HCl in diethyl ether ( 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, triturated with diethyl ether and dried to give the title compound 91 (0.02 g, 38.9%) as an off-white solid. LCMS (ESI positive ion); m/z: Calculated: 601.61; Observed: 602.2 (M+1); HPLC purity (XB_0595TF): 97.51%; 1H-NMR (400 MHz, DMSO-d6): 10.26 (brs , 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- oxopyrrolidin -3- yl methanesulfonate (6) : (3R)-3-hydroxypyrrolidin-2-one (5, 1.0 g , 9.9 mmol) in DCM (15 mL) was added TEA (2.0 g, 19.8 mmol) and methanesulfonyl chloride (1.36 g, 11.9 mmol). The resulting reaction mixture was stirred at RT for 2 h. After completion of the reaction, 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. The crude material was purified by column chromatography to give pure 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) : To 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-oxopyrrolidin-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 treated with saturated NH ₄ Cl solution and extracted with ethyl acetate. The organic layer was washed with saturated brine solution, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude reaction mixture was purified by column chromatography to give the title compound (900 mg, 78%); LCMS (ESI positive) m/z: Calcd: 397.18; Obs: 398.1 (M+1).

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-oxopyrrolidin-3-yl)oxy)phenyl)piperazine-1-carboxylic acid tert-butyl ester (2, 900 mg, 2.26 mmol) in dichloromethane (20 mL) was added dropwise to 4 N HCl in dioxane (2.5 mL) and 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 methanol and neutralized using tosic acid scavenger resin to give the free base as an off-white gum (400, 58.2%); LCMS (ESI positive ion) m/z: Calculated: 297.13; Observed: 298.1 (M+1).

Step 4 : Synthesis of (S)-5- amino -3-(2-(4-(2,4- difluoro -5-((2- oxopyrrolidin -3- yl ) oxy ) -benzene Base ) piperazin -1- yl ) ethyl ) -8-( furan -2- yl ) thiazolo [5,4-e][1,2,4] triazolo [1,5-c] pyrimidine- 2(3H)-Kone ( Compound 95 ) : To (S)-3-(2,4-difluoro-5-(piperazin-1-yl)phenoxy)pyrrolidin-2-one (3, 350 mg, 1.18 mmol) in DMF (10 mL) was added DIPEA (608 mg, 4.71 mmol) and 2-(5-amino-8-(furan-2-yl)-2-oxothiazolo [5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl methanesulfonate (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 reaction mixture was partitioned between water and ethyl acetate. The separated organic layer was washed with brine solution, dried over anhydrous Na ₂ SO ₄ and filtered. The filtrate was concentrated under reduced pressure and purified by flash column chromatography using (3% methanol/dichloromethane) to give the title compound (250 mg, 34.1%); HPLC purity (XB0595TF): 96.08%; LCMS (ESI normal ions) 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- oxopyrrolidin -3- yl methanesulfonate (6) : To (S)-3-hydroxypyrrolidin-2-one ( 5 , 2.0 g , 0.02 mol) in DCM (10 mL) was added triethylamine (4.0 g, 0.04 mol) and methanesulfonyl chloride (2.49 g, 0.022 mol). The resulting reaction mixture was stirred at RT for 2 h. After completion of the reaction, 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 _Na2SO4 , filtered and concentrated _under reduced pressure to give (S)-2-oxopyrrolidin-3-ylmethanesulfonate (1.4 g, 39.5%); LCMS (ESI positive ion) m/z: Calculated: 179.03; Observed: 180.1 (M+1).

Step 2 : Synthesis of (R)-4-(2,4- difluoro -5-((2 -oxopyrrolidin -3- yl ) oxy ) phenyl ) piperazine -1- carboxylic acid tert-butyl ester (2) : To 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) was added (S)-2-Oxypyrrolidin-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 treated with saturated NH ₄ Cl solution and extracted with ethyl acetate. The organic layer was washed with saturated brine solution, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude reaction mixture was purified by column chromatography to give the title compound (1.0 g 45.8%) as a beige solid; LCMS (ESI positive ion) m/z: Calcd: 397.18; Obs: 398.1 (M+ 1).

Step 3 : Synthesis of (R)-3-(2,4- difluoro -5-( piperazin -1- yl ) phenoxy ) pyrrolidin -2- one (3) : 4-[ 2,4-Difluoro-5-[(3R)-2-oxopyrrolidin-3-yl]oxy)phenyl]piperazine-1-carboxylic acid tert-butyl ester ( 2 , 1.0 g, 2.5 mmol ) in dichloromethane (15 mL) was added dropwise with 4 N HCl in dioxane (10 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 using Tosic acid scavenger resin to give the free base (600 mg 72.9%) as an off-white gum; LCMS (ESI positive ion) m/z: Calculated: 297.13; Observed: 298.2 (M+1).

Step 4 : Synthesis of (R)-5- amino -3-(2-(4-(2,4- difluoro -5-((2- oxopyrrolidin -3- yl ) oxy ) -benzene Base ) piperazin -1- yl ) ethyl ) -8-( furan -2- yl ) thiazolo [5,4-e][1,2,4] triazolo [1,5-c] pyrimidine- 2(3H)-ketone ( compound 96 ) : to 2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4 ]Triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl methanesulfonate (300 mg, 0.76 mmol) in DMF (10 mL) was added DIPEA (0.49 g, 3.79 mmol ) 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 reaction mixture was partitioned between water and ethyl acetate. The separated organic layer was washed with brine solution, dried over anhydrous Na ₂ SO ₄ and filtered. The filtrate was concentrated under reduced pressure and purified by flash column chromatography using (3% methanol/dichloromethane) to give the title compound. HPLC purity (XB0595TF): 97.73%; LCMS (ESI positive ion) 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) : To a stirred solution of benzyl 4-(2-fluoro-4-hydroxyphenyl)piperazine-1-carboxylate (1, 2.0 g, 6.05 mmol) in toluene (20 mL) at RT was added 3- (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 separated organic layer was washed with brine solution, dried over anhydrous Na ₂ SO ₄ , and concentrated in vacuo to get the crude product. The obtained crude material was purified by column chromatography (20% EtOAc/hexanes) to give 3-((4-(4-((benzyloxy)carbonyl)piperazin-1-yl)-3- Fluorophenoxy)-methyl)morpholine-4-carboxylic acid tert-butyl ester (1.0 g, 31.2%); LCMS (ESI positive ion) m/z: Calculated: 529.26; Observed: 530.1 (M+1 ).

Step 2 : synthetic 3-((3- fluoro -4-( piperazin -1- yl ) phenoxy ) methyl ) -morpholine - 4- formic acid tert-butyl ester (3) : under RT to 3- ((4-(4-((Benzyloxy)carbonyl)piperazin-1-yl)-3-fluorophenoxy)methyl)morpholine-4-carboxylic acid tert-butyl ester ( 2 , 600 mg, 1.1 A stirred solution of mmol) in ethyl acetate (10 mL) was added 10% Pd/C (120 mg) and stirred under hydrogen atmosphere for 16 h. After completion, the reaction mixture was filtered using celite to remove Pd/C. The combined organic layers were dried over _{anhydrous Na2SO4} and concentrated under reduced pressure to give 3-((3-fluoro-4-(piperazin-1-yl)phenoxy)methyl)morpholine- tert-Butyl 4-carboxylate (350 mg, 61.7%); LCMS (ESI positive ion) m/z: Calculated: 395.22; Observed: 396.1 (M+1).

Step 3 : Synthesis of 3-((4-(4-(2-(5- amino -8-( furan -2- yl )-2- oxothiazolo [5,4-e]-[1, 2,4] triazolo [1,5-c] pyrimidin -3(2H) -yl ) ethyl ) piperazin -1- yl )-3- fluorophenoxy ) -methyl ) -morpholine -4 -Tertiary butyl formate (4) : to 2-(5-amino-8-(furan-2-yl)-2-side oxythiazolo[5,4-e][1,2,4] Triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl methanesulfonate (200 mg, 0.631 mmol) and 3-((3-fluoro-4-(piperazin-1-yl )phenoxy)methyl)morpholine-4-carboxylic acid tert-butyl ester (300 mg, 0.756 mmol) in DMF (10 mL) was added DIPEA (292 mg, 2.27 mmol) and the reaction mixture was heated at 100 Stir at ℃ for 16 h. The progress of the reaction was monitored by TLC and the reaction mixture was 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 and concentrated under reduced pressure to get crude product. The crude product was purified by preparative HPLC to give pure 3-((4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5, 4-e][1,2,4]-triazolo[1,5-c]pyrimidin-3(2H)yl)ethyl)piperazin-1-yl)-3-fluorophenoxy)methyl ) tert-butyl morpholine-4-carboxylate (80 mg, 21.4%); LCMS (ESI positive ion) m/z: Calculated: 695.26; Observed: 696.1 (M+1).

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-oxothiazolo[5,4-e]-[1,2,4]tri 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) in DCM (5 mL) was added 2 N HCl in diethyl ether (2 mL) and the resulting reaction mixture was stirred at RT for 2 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain a crude compound which was purified by preparative HPLC to obtain pure 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 (15 mg, 22%); HPLC purity (XB0595TF): 95.90%; LCMS (ESI positive ion) m/z: Calculated: 595.21 ; Observed value: 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 : synthetic 2-((( methylsulfonyl ) oxy) methyl ) morpholine - 4 - formic acid tert-butyl ester (2) : to 2-(hydroxymethyl) morpholine-4-formic acid tertiary A cooled suspension of tributyl ester ( 1 , 5.0 g, 23.01 mmol) in anhydrous DCM (50 mL) was added dropwise with methanesulfonyl chloride (3.42, 29.92 mmol) 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 DCM, concentrated and purified by column chromatography (30% EtOAc/Hexane as eluent) to give a pale yellow gum The title compound 2 (6.0 g, 87%) was obtained as a solid. LCMS (ESI positive ion) m/z: Calculated: 295.35; Observed: 196.1 (M+1-100).

Step 2 : Synthesis of tert-butyl 2-((4-(4-(( benzyloxy ) carbonyl ) piperazin -1- yl )-3- fluorophenoxy ) methyl ) morpholine -4- carboxylate ( 3) : To 4-(2-fluoro-4-hydroxyphenyl)piperazine-1-carboxylic acid benzyl ester (2, 0.5 g, 1.51 mmol) and 2-(((methylsulfonyl)oxy)methanol To a suspension of tert-butyl morpholine-4-carboxylate (0.53 g, 1.81 mmol) in anhydrous DMF (10 mL) was added K ₂ CO ₃ (0.63 g, 4.54 mmol) and the reaction mixture was heated at 100°C Heat for 16 h. After completion of the reaction (TLC), the reaction mass was filtered through a pad of celite and the filtrate was concentrated and purified by column chromatography (30% EtOAc/Hexane as eluent) to give the title as an off-white solid Compound 3 (0.35 g, 39%); LCMS (ESI positive ion) m/z: Calculated: 529.61; Observed: 530.3 (M+1). 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 : synthetic 2-((3- fluoro -4-( piperazin -1- yl ) phenoxy ) methyl ) morpholine -4- formic 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 A solution in ethyl ester (6 mL) was charged 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 a pad of celite and the filtrate was concentrated under reduced pressure to give the title compound 4 (0.18 g, 65%) as a beige solid; LCMS (ESI positive 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- oxothiazolo [5,4-e][1,2 ,4] Triazolo [1,5-c] pyrimidin -3(2H) -yl ) ethyl ) piperazin -1- yl )-3- fluorophenoxy ) -methyl ) -morpholine - 4- Tertiary butyl formate (5) : 2-(5-Amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e] in a sealed tube at 120°C [1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl methanesulfonate (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 RT, diluted with water and the crude solid was filtered and purified by column chromatography (70% EtOAc/hexanes as eluent) to give the title as an off-white solid Compound 5 (0.05 g, 16.4%); LCMS (ESI positive ion) m/z: Calculated: 695.77; Observed: 696.0 (M+1). 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-oxothiazolo[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 ( 5 , 0.04 g, 0.057 mmol) in dichloromethane (1 mL) was added 2 M HCl in diethyl ether (1 mL) and the reaction mixture was stirred at RT for 2 h. After completion of the reaction (TLC), the resulting solid (HCl salt) was filtered and dried under reduced pressure to give the title compound 100 (0.014 g, 36%) as an off-white solid; HPLC purity (XB_0595TF.M): 95.72%; LCMS (ESI positive ion) m/z: Calculated: 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 ) piper Oxazin -1- yl ) ethyl )-8-( furan -2- yl ) thiazolo [5,4-e][1,2,4] triazolo [1,5-c] pyrimidine -2(3H ) -keto 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) - Keto

Step 1 : Synthesis of benzyl 4-(2- fluoro -4- hydroxyphenyl ) piperazine -1- carboxylate (2) : 4-bromo-3-fluorophenol ( 1 , 15 g, 0.079 mol), piperazine To an ice-cold stirred solution of benzyl-1-carboxylate (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) was added LHMDS ( 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 ammonium chloride solution and extracted with ethyl acetate. The combined organic layers were washed with saturated brine solution, dried over anhydrous _Na2SO4 , filtered and concentrated under reduced pressure _. The crude material obtained was purified by column chromatography (230-400 silica gel (30% EA/Pet ether as eluent)) to give the product (10.00 g, 30.1%) as an off-white solid. LCMS (ESI positive ) m/z: Calculated: 330.36; Observed: 331.1 (M+1).

Step 2 : Synthesis of benzyl 4-(4-((1-( tert-butoxycarbonyl )-4- fluoropyrrolidin -3- yl ) oxy )-2- fluorophenyl ) piperazine -1- carboxylate (3) : To 4-(2-fluoro-4-hydroxyphenyl)piperazine-1-carboxylic acid benzyl ester (6.8 g, 20.58 mmol), 6-oxa-3-azabicyclo[3.1.0]hexyl To a stirred solution of tert-butyl alkane-3-carboxylate (4.986 g, _26.76 mmol) in 1,4-dioxane (20 mL) was added _Cs2CO3 (10.3 g, 30.88 mmol). The resulting mixture was stirred at 100 °C for 16 h. It was then filtered to remove inorganics. The crude residue obtained upon concentrating the filtrate was purified by column chromatography (230-400 silica gel (30% EA/Pet ether as eluent)) to give an off-white solid (6.00 g, 56.0%). LCMS (ESI n ion) m/z: Calculated: 515.58; Observed: 516.2 (M+1).

Step 3 : Synthesis of 4-(4-((-1-( tert-butoxycarbonyl )-4- fluoropyrrolidin -3- yl ) oxy )-2- fluorophenyl ) piperazine -1- carboxylic acid benzyl Esters (4A & 4B) : 4-(4-((1-(tert-butoxycarbonyl)-4-hydroxypyrrolidin-3-yl)oxy)-2-fluorophenyl at -20°C ) to an ice-cold stirred solution of benzyl piperazine-1-carboxylate (3,6 g, 11.64 mmol) in DCM (30 mL), to the reaction mixture was added DAST (5.816 g 34.91 mmol). The resulting mixture was stirred at -20 °C for 0.5 h and then at RT for 16 h. After completion of the reaction, the reaction mixture was quenched with saturated NaHCO ₃ solution and extracted with DCM. The combined organic layers were dried over _{anhydrous Na2SO4} , filtered and concentrated under reduced pressure. The obtained crude material was purified by column chromatography (230-400 silica gel (30% EA/hexane as eluent) to obtain two fractions of the product. Fraction-1-1.4 g, Fraction-2-900 mg.LCMS (ESI positive) m/z: Calculated: 517.57; Observed: 518.2 (M+1).

Both fractions were further purified by chiral SFC purification (0.5% DEA in IPA, YMC cellulose-SC) to afford enantiomers 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-(tertiary butoxycarbonyl)-4-fluoropyrrolidin-3-yl)oxy)-2-fluorophenyl)piperene under nitrogen atmosphere A stirred solution of benzyloxine-1-carboxylate ( 4A , 430 mg, 0.831 mmol) in ethyl acetate (10 mL) was added Pd/C 10% (200 mg). The resulting mixture was stirred at RT under hydrogen atmosphere for 32 h. It was then filtered through a pad of Celite to remove Pd/C. The crude residue obtained upon concentration of the filtrate gave a viscous material. The crude material (0.23 g, 69.3%) was used in the next step without purification. LCMS (ESI positive) m/z: Calculated: 383.44; Observed: 384.3 (M+1).

Step 5 : Synthesis of (3R,4R)-3-(4-(4-(2-(5- amino -8-( furan -2- yl )-2- oxothiazolo- [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- Pendant oxythiazolo-[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)- To a stirred solution of tert-butyl 3-fluorophenoxy)-4-fluoropyrrolidine-1-carboxylate ( 5A , 100 mg, 0.261 mmol) in DCM (10 mL) was added 2-(5-amino-8 -(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl Aldehyde (82 mg, 0.261 mmol) and _Et3N (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 resulting mixture was stirred at room temperature for 24 h. After completion, the reaction mixture was diluted with DCM. The separated organic portion was successively washed with saturated bicarbonate solution, saturated brine solution. After drying over anhydrous _Na2SO4 , it was filtered and concentrated under reduced _pressure . The obtained crude material was purified by column chromatography (230-400 silica gel (5% MeOH/DCM as eluent)) to give the product (0.025 g, 14.0%) as an off-white solid. LCMS (ESI positive ion) m/z: Calculated: 683.74; Observed: 684.3 (M+1).

step 6 :synthesis 5- Amino -3-(2-(4-(2- fluorine -4-(((3R,4R)-4- Flupyrrolidine -3- base ) Oxygen ) Phenyl ) Piperazine -1- base ) Ethyl )-8-( Furan -2- base ) Thiazolo [5,4-e][1,2,4] Triazolo [1,5-c] pyrimidine -2(3H)- ketone ( compound 101) :

To (3R,4R)-3-(4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1 ,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3-fluorophenoxy)-4-fluoropyrrolidine-1 - An ice-cold stirred solution of tert-butyl formate ( 7A , 25 mg, 0.037 mmol) in DCM (1 mL) was added HCl in ether (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 give the product (0.013 g, 52.75%) as an off-white solid. LCMS (ESI positive) m/z: Calculated: 583.62; Observed: 584.0 (M+1). 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-(tertiary butoxycarbonyl)-4-fluoropyrrolidin-3-yl)oxy)-2-fluorophenyl)piperene under nitrogen atmosphere A stirred solution of benzyloxine-1-carboxylate ( 4B , 380 mg, 0.734 mmol) in ethyl acetate (10 mL) was added Pd/C 10% (200 mg). The resulting mixture was stirred at RT under hydrogen atmosphere for 32 h. It was then filtered through a pad of Celite to remove Pd/C. The crude residue obtained upon concentration of the filtrate gave a viscous material. The crude material (0.2 g, 71.04%) was used in the next step without purification. LCMS (ESI positive) m/z: Calculated: 383.44; Observed: 384.3 (M+1).

Step 5 : Synthesis of (3S,4S)-3-(4-(4-(2-(5- amino -8-( furan -2- yl )-2- oxothiazolo- [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- Pendant oxythiazolo-[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)- To a stirred solution of tert-butyl 3-fluoro-phenoxy)-4-fluoropyrrolidine-1-carboxylate ( 5B , 70 mg, 0.187 mmol) in DCM (10 mL) was added 2-(5-amino- 8-(furan-2-yl)-2-oxothiazolo[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 resulting mixture was stirred at room temperature for 24 h. After completion, the reaction mixture was diluted with DCM. The separated organic portion was successively washed with saturated bicarbonate solution, saturated brine solution. After drying over _{anhydrous Na2SO4} , it was filtered and concentrated under reduced pressure. The obtained crude material was purified by column chromatography (230-400 silica gel (5% MeOH/DCM as eluent)) to give the product (0.027 g, 19.9%) as an off-white solid. LCMS (ESI positive ion) 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- fluoropyrrolidin -3- yl ) oxy ) -phenyl ) piper Oxazin -1- yl ) ethyl )-8-( furan -2- yl ) thiazolo [5,4-e][1,2,4] triazolo [1,5-c] pyrimidine -2(3H ) -ketone ( compound 102) : to (3S, 4S)-3-(4-(4-(2-(5-amino-8-(furan-2-yl)-2-side oxythiazolo[ 5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3-fluoro-phenoxy )-tert-butyl 4-fluoropyrrolidine-1-carboxylate ( 7B , 25 mg, 0.037 mmol) in DCM (1 mL) was added to an ice-cold stirred solution of HCl in ether (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 give the product (0.017 g, 69.7%) as an off-white solid. LCMS (ESI positive) m/z: Calculated: 583.62; Observed: 584.4 (M+1). 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- oxotetrahydro -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

Step 1 : Synthesis of tetrahydro -2H- thiopyran -4- yl methanesulfonate (2) : To tetrahydro-2H-thiopyran-4-ol (2.0 g, 16.94 mmol) and triethylamine (4.26 g, To an ice-cold solution of 42.2 mmol) in dichloromethane (30 mL) was added methanesulfonyl chloride (2.1 g, 18.62 mmol) gradually and the reaction mixture was stirred at RT for 12 h. After completion of the reaction, the reaction mixture was diluted with water and the crude product was extracted with dichloromethane. The organic layer was dried, concentrated and purified by column chromatography (20% EtOAc/hexanes as eluent) to give the title compound 2 (3.1 g, 94%) as a beige liquid. The crude material was taken directly as such in the next step.

Step 2 : Synthesis of tertiary butyl 4-(2,4- difluoro -5-(( tetrahydro -2H- thiopyran -4- yl ) oxy ) phenyl ) piperazine -1- carboxylate (3) : To the third A solution of butyl ester (3 g, 9.55 mmol) in N,N-dimethylformamide (10 mL) was added K ₂ CO ₃ (2.69 g, 19.04 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 (30 mL) and extracted with ethyl acetate. The organic layer was washed with brine solution, water, dried over anhydrous _Na2SO4 , filtered and concentrated _under reduced pressure to give the crude product which was further analyzed by column chromatography (20% EtOAc/Hexane as eluent) Purification gave the title compound 3 (1.7 g, 42.54%) as an off-white solid; LCMS (ESI positive) m/z: Calculated: 414.51; Observed: 415.1 (M+1).

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) was cooled to 0 °C, H ₂ O ₂ (30%, 2 mL) was added 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 cooled 10% NaOH solution and the crude product was extracted with dichloromethane. The organic layer was washed with brine, dried over anhydrous _Na2SO4 , filtered and concentrated under _reduced pressure to give the racemic product as an off-white solid. Yield: (1.62 g, 91.8%). The isomers present in the racemic mixture were separated via SFC chiral method. The eluted first peak (Peak 1 ) was concentrated to give the title compound 4 (0.65 g, 80%) as an off-white solid; LCMS (ESI positive ion) m/z: Calculated: 430.51; Observed: 431.1 (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) : to 4-(2,4-difluoro-5-(((1s,4s)-1-oxotetrahydro-2H-thiopyran-4-yl)oxy)phenyl)piperazine-1-carboxylic acid third An ice-cold solution of butyl ester ( 4 , 0.48 g, 1.11 mmol) in dichloromethane (10 mL) was added trifluoroacetic acid (1.3 mL) and the reaction 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 neutralized by tosic acid resin treatment to give the title compound 5 (0.31 g, 84%) as an off-white solid; LCMS (ESI positive ion) 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- oxotetrahydro- 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 111) : 2-(5-Amino-8-(furan-2-yl)-2-oxothiazole in a sealed tube at 120 °C [5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl methanesulfonate (0.35 g, 0.88 mmol), (1s ,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) in dry DMF (3 mL) was heated for 16 h. After completion (TLC), the reaction mixture was cooled to RT, diluted with water and the crude solid was filtered and purified by column chromatography (70% EtOAc/hexanes as eluent) to give the title as an off-white solid Compound 111 . LCMS (ESI positive ion) m/z: Calculated: 630.39; Observed: 631.1 (M+1); HPLC Purity (XB_0595TF.M): 96.25%.

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- oxotetrahydro -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

Step 1 : Synthesis of (1r, 4r)-4-(2,4- difluoro -5-( piperazin -1- yl ) phenoxy ) tetrahydro -2H- thiopyran 1- oxide (2) : to 4-(2,4-Difluoro-5-(((1r, 4r)-1-oxotetrahydro-2H-thiopyran-4-yl)oxy)phenyl)piperazine-1-carboxylic acid third An ice-cold solution of butyl ester ( 1,0.3 g, 0.697 mmol) in dichloromethane (10 mL) was added trifluoroacetic acid (1.3 mL) and the reaction 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 neutralized by tosic acid resin treatment to give the title compound 2 (0.20 g, 85%) as an off-white solid; LCMS (ESI positive 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- oxotetrahydro- 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 112) : 2-(5-Amino-8-(furan-2-yl)-2-oxothiazole in a sealed tube at 120 °C [5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl methanesulfonate (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 (0.23 g, 1.74 mmol) in dry DMF (2.5 mL) was heated for 16 h. After completion (TLC), the reaction mixture was cooled to RT, diluted with water and the crude solid was filtered and purified by column chromatography (70% EtOAc/hexanes as eluent) to give the title as an off-white solid Compound 3 . LCMS (ESI positive ion) m/z: Calculated: 630.39; Observed: 631.1 (M+1); HPLC Purity (XB_0595TF.M): 94.36%. 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 ) 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 ) in DMF (25 mL) was added K ₂ CO ₃ (9.08 g, 65.68 mmol) followed by MeI (8.5 g, 60.21 mmol) and stirred at RT for 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 brine solution, dried over anhydrous _Na2SO4 , 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 ( 2 , 8.0 g, 49.94 mmol) in DCM was added mCPBA (8.6 g, 49.94 mmol) and stirred at RT for 16 h. After completion (TLC), the reaction mass was quenched with saturated sodium bicarbonate 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. The obtained crude material was purified by column chromatography to give the title compound (5.0 g, 55.6%); LCMS (ESI positive ion) m/z: Calcd: 176.01; Obs: 177.0 (M+1).

Step 3 : Synthesis of tert-butyl 4-(2- fluoro -4-( methylsulfinyl ) phenyl ) piperazine -1- carboxylate (4,5) : to piperazine-1- To a stirred solution of tert-butyl formate (5.3 g, 28.38 mmol) in DMF (50 mL) was added K ₂ CO ₃ (7.8 g, 56.76 mmol) followed by 1,2-difluoro-4-(methylethylene (sulfonyl)-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 brine solution, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude material obtained was purified by column chromatography to give the title compound (2.2 g, 22.7%); LCMS (ESI positive) m/z: Calcd: 342.14; Obs; 343.0 (M+1).

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) to yield 810 mg of peak 1 ( 4 ) and 820 mg of peak 2 ( 5 ), respectively.

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

Step 4 : Synthesis of (S)-1-(2- fluoro -4-( methylsulfinyl ) phenyl ) piperazine (6) : to (S)-4-(2-fluoro- To a stirred solution of tert-butyl 4-(methylsulfinyl)phenyl)piperazine-1-carboxylate ( 4,800 mg, 0.292 mmol) in DCM (18 mL) was added TFA (1.3 g, 11.68 mmol ). 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 methanol and neutralized using Tosic acid scavenger resin to give the title compound as free base (510 mg, 88.2%); LCMS (ESI positive ion) m/z: Calculated: 242.09; Observed: 243.1 (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 To a stirred solution of (S)-1-(2-fluoro-4-(methylsulfinyl)phenyl)piperazine ( 6 , 200 mg, 0.825 mmol) in DMF (10 mL) was added DIPEA in a tube (426.7 mg, 3.302 mmol) followed by 2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]tri Azolo[1,5-c]pyrimidin-3(2H)-yl)ethyl methanesulfonate (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 brine solution, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude material obtained was purified by column chromatography to give the title compound (180 mg, 37.7%); HPLC purity (XB0595TF): 94.08%; LCMS (ESI positive ion) m/z: Calculated: 542.13; Observation 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).

example 119 : (S)-5- Amino -3-(2-(4-(2- fluorine -4-( Methylsulfinyl ) Phenyl ) Piperazine -1- base ) Ethyl )-8-( Furan -2- base ) Thiazolo [5,4-e][1,2,4] Triazolo [1,5-c] pyrimidine -2(3H)- ketone

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

To (R)-tert-butyl 4-(2-fluoro-4-(methylsulfinyl)phenyl)piperazine-1-carboxylate ( 5 , 800 mg, 0.292 mmol) in DCM at 0°C (18 mL) was added TFA (1.3 g, 11.68 mmol). 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 methanol and neutralized using Tosic acid scavenger resin to give the title compound as free base (510 mg, 88.8%); LCMS (ESI positive ion) m/z: Calculated: 242.09; Observed: 243.1 (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 sealed DIPEA ( 426.7 mg, 3.302 mmol) followed by 2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazole [1,5-c]pyrimidin-3(2H)-yl)ethyl methanesulfonate (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 treated with water and extracted with ethyl acetate. The organic layer was washed with saturated brine solution, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The obtained crude material was purified by column chromatography to give the title compound (120 mg, 25.1%); HPLC purity (XB0595TF): 93.75%; LCMS (ESI positive ion) m/z: Calculated: 542.13; Observation 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- oxotetrahydro -2H- thiopyran - 4- yl ) oxy Base ) 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- oxotetrahydro - 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

Step 1 : Synthesis of tetrahydro -2H- thiopyran -4- ol (11) : To an ice-cold solution of tetrahydrothiopyran-4-one (10, 5 g, 0.043 mol) in methanol (40 mL) was added slowly 5N sodium hydroxide solution (10 mL). Sodium borohydride (0.488 g, 0.013 mol) was then added in portions. 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 saturated brine solution, dried over anhydrous Na ₂ SO ₄ , and concentrated under reduced pressure. The crude product was purified by column chromatography using 5% methanol in DCM to give pure product (4 g, 51.90%). 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) : Add tetrahydrothiopyran-4-ol ( 11 , 3.5 g, 0.030 mol) in dichloromethane (40 mL) To an ice-cold solution of this was added 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 saturated brine 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 as eluent to afford the 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-yl methanesulfonate ( 12 , 1.272 g, 6.479 mmol) in DMF (20 mL) was added _K2CO3 (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 saturated brine solution, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The obtained crude material was purified by column chromatography (50% EtOAc/Hexane as eluent) to give the product (1.5 g, 69%) as an off-white solid. LCMS (ESI positive) m/z: Calculated: 396.52; Observed: 397.1 (M+1).

Step 4 : Synthesis of 4-(2- fluoro -4-((1- oxotetrahydro -2H- thiopyran -4- yl ) oxy ) phenyl ) piperazine -1- carboxylic acid tert-butyl ester (3, 4) : To 4-(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 The ice-cold mixture in (25 mL) was added hydrogen peroxide (1 mL) dropwise 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 saturated brine solution, dried over anhydrous _Na2SO4 , filtered and concentrated under reduced pressure _. The obtained crude material was purified by column chromatography (80% EtOAc/Hexane as eluent) to give the product (1.4 g, 80.7%) as an off-white solid. LCMS (ESI positive) m/z: Calculated: 412.52; Observed: 413.2 (M+1).

The racemic mixture (1.4 g) was subjected to chiral 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. Yield was 600 mg of peak 1 ( 3 ) and 500 mg of 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-oxotetrahydro-2H-thiopyran-4-yl)oxy)phenyl)-piperazine-1-carboxylic acid tert-butyl ester ( 3 , To an ice-cold solution of 0.5 g, 1.212 mmol) 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 pressure at ambient temperature. The residue obtained was triturated with diethyl ether. It was then dissolved in methanol and passed through Si-carbonate resin to give the 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- oxotetrahydro -2H- thiopyran -4- yl ) oxy ) ) Phenyl ) piperazin -1- yl ) ethyl )-8-( furan -2- yl ) thiazolo [5,4-e][1,2,4] -triazole- [1,5-c ] pyrimidin -2(3H) -one ( compound 121) : to 2-(5-amino-8-(furan-2-yl)-2-side oxythiazolo[5,4-e][1, 2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl methanesulfonate (7, 0.385 g, 0.971 mmol) and (1s,4s)-4-(3- 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) was added DIPEA (0.626 g, 4.856 mmol). The reaction mixture was stirred at 90 °C for 16 h. After completion, the reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate. The combined organic layers were washed with saturated brine solution, dried over anhydrous _Na2SO4 , filtered and concentrated _. The crude product was purified by reverse phase preparative HPLC to afford the product (0.045 g, 7.5%) as an off-white solid. LCMS (ESI positive) m/z: Calculated: 612.70; Observed: 613 (M+1). 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- oxotetrahydro -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 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-oxotetrahydro-2H-thiopyran-4-yl)oxy)phenyl)-piperazine-1-carboxylic acid tert-butyl ester (4, To an ice-cold solution of 0.5 g, 1.212 mmol) 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 pressure at ambient temperature. The residue obtained was triturated with diethyl ether. It was then dissolved in methanol and passed through Si-carbonate resin to give the 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- oxotetrahydro -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 2-(5-amino-8-(furan-2-yl)-2-side oxythiazolo[5,4-e][1, 2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl methanesulfonate ( 7 , 0.235 g, 0.593 mmol) and (1s,4s)-4-(3- 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) was added DIPEA (0.382 g, 2.964 mmol). The reaction mixture was stirred at 90 °C for 16 h. After completion, the reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate. The combined organic layers were washed with saturated brine solution, dried over anhydrous _Na2SO4 , filtered and concentrated _. The crude product was purified by reverse phase preparative HPLC to afford the product (0.031 g, 8.4%) as an off-white solid. LCMS (ESI positive) m/z: Calculated: 612.70; Observed: 613.1 (M+1). 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- oxothiomorpholinyl ) 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) : 4-bromo-2-fluoro-1-nitrobenzene ( 1 , 9.0 g, 13.64 mmol) and acetic acid (11.5 g, 0.57 mol) in ethanol (60 mL) was added iron powder (15.9 g, 0.285 mol). The reaction mixture was stirred at 80 °C for 1 h. After the reaction was complete, the reaction mixture was diluted with EtOAc and filtered through a bed of celite. The filtrate was concentrated under reduced pressure to give the crude compound and it was used directly in the next step (6.0 g, 76.5%); LCMS (ESI positive ion) m/z: Calculated: 188.96; Observed: 192.0 (M+1) .

Step 2 : Synthesis of 1-(4- bromo -2- fluorophenyl ) piperazine (3) : 4-bromo-2-fluoroaniline ( 2 , 6.0 g, 31.58 mmol) in diglyme (4.8 mL ) was added bis(2-chloroethyl)amine hydrochloride (6.7 g, 37.89 mmol) and the reaction 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 in the next step (5.0 g, 61%); LCMS (ESI positive) m/z: Calculated: 258.02; Observed: 259.0 (M+1).

Step 3 : Synthesis of 4-(4- bromo -2- fluorophenyl ) piperazine -1- carboxylic acid tert-butyl ester (4) : to 1-(4-bromo-2-fluorophenyl)piperazine at 0°C To a stirred solution of oxazine ( 3 , 4.0 g, 15.4 mmol) and TEA (3.1 g, 30.9 mmol) in DCM (30 mL) was added di-tert-butyl dicarbonate (5.04 g, 23.1 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 and concentrated under reduced pressure to get crude product. The crude product was purified by column chromatography to give the title compound (4.0 g, 72.2%); LCMS (ESI positive) m/z: Calcd: 358.07; Obs: 259.0 (M-99+1).

Step 4 : Synthesis of 4-(2- fluoro -4- thiomorpholinylphenyl ) piperazine -1- carboxylic acid tert-butyl ester (5) : to 4-(4-bromo-2-fluoro To a stirred solution of tert-butyl phenyl)piperazine-1-carboxylate ( 4 , 4.0 g, 11.1 mmol) and thiomorpholine (1.3 g, 12.3 mmol) in toluene (30 mL) was added XPhos (530 mg, 1.11 mmol) followed by ^NaOtBu (2.34 g, 24.4 mmol). The reaction mixture was flushed with N ₂ gas and Pd(OAc) ₂ (250 mg, 1.11 mmol) was added. 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 and concentrated under reduced pressure to get crude product. The crude product was purified by column chromatography to give the title compound (1.53 g, 33.9%); LCMS (ESI positive) m/z: Calcd: 381.19; Obs: 382.1 (M+1).

Step 5 : Synthesis of 4-(2- fluoro -4- thiomorpholinylphenyl ) piperazine -1- carboxylic acid tert-butyl ester (6) : to 4-(2-fluoro-4-sulfur at 0°C To a stirred solution of tert-butyl morpholinophenyl)piperazine-1-carboxylate ( 5 , 1.8 g, 4.7 mmol) in acetic acid (20 mL) was added hydrogen peroxide (160.48 mg, 4.7 mmol). The reaction mixture was stirred at RT for 16 h. After completion of the reaction (TLC), the reaction mixture was treated with 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 and concentrated under reduced pressure to get crude product. The crude product was purified by column chromatography to give the title compound (1.2 g, 62.6%); LCMS (ESI positive) m/z: Calculated: 397.18; Observed: 398.1 (M+1).

Step 6 : Synthesis of 4-(3- fluoro -4-( piperazin -1- yl ) phenyl ) thiomorpholine 1- oxide (7) : 4-(2-fluoro-4- To a stirred solution of (1-oxothiomorpholinyl)phenyl)piperazine-1-carboxylic acid tert-butyl ester ( 6 , 1.2 g, 3.0 mmol) in DCM (15 mL) was added TFA (330 mg, 9.0 mmol). 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 methanol and neutralized using Tosic acid scavenger resin to give the free base (750 mg, 82.2%); LCMS (ESI positive ion) m/z: Calculated: 297.13; Obs: 298.1 (M+ 1).

Step 7 : Synthesis of 5- amino -3-(2-(4-(2- fluoro -4-(1- oxothiomorpholinyl ) 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 To a stirred solution of -(3-fluoro-4-(piperazin-1-yl)phenyl)piperidin-4-one (350 mg, 1.26 mmol) in DMF (5 mL) was added 2-(5-amino -8-(furan-2-yl)-2-oxothiazolo[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 was concentrated under reduced pressure and recrystallized using acetonitrile and diethyl ether to obtain pure 5-amino-3-(2-(4-(2-fluoro-4-(1-oxothiomorph Linyl)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 ) (150 mg, 19%); HPLC purity (XB0595TF): 95.08%; LCMS (ESI positive ion) m/z: calculated value: 597.17; observed value: 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- dioxolane -4- yl ) methyl methanesulfonate (7) : to (R)-( To a stirred solution of 2,2-dimethyl-1,3-dioxolan-4-yl)methanol (6, 2.5 g, 19 mmol) in DCM (30 mL) was added triethylamine (9.6 g, 95 mmol) 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 upon 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 concentrated under reduced pressure to give the title compound (3.0 g, 75.4%) as a yellow gummy liquid; 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) 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) was added carbonic acid 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 _Na2SO4 , filtered and then concentrated under reduced pressure _. The crude material was purified by column chromatography (30% EtOAc/hexanes) to afford (R)-4-(5-((2,2-dimethyl-1,3-di Benzyl oxolan-4-yl)methoxy)-2,4-difluorophenyl)piperazine-1-carboxylate ( 2 ) (800 mg, 56.8%); LCMS (ESI positive ion) 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) : under nitrogen atmosphere to (R)-4-(5-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-2 , a stirred solution of benzyl 4-difluorophenyl)piperazine-1-carboxylate ( 2 , 0.8 g, 1.73 mmol) in EtOAc (20 mL) was added 10% Pd/C (0.2 g). The reaction mixture was stirred under _H2 atmosphere for 16 h. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was filtered using celite to remove Pd/C. The combined organic layers were dried over _{anhydrous Na2SO4} and concentrated under reduced pressure to give (R)-1-(5-((2,2-dimethyl-1,3-dioxolane) as a brown gum -4-yl)methoxy)-2,4-difluorophenyl)piperazine ( 3 ) (0.45 g, 76.2%); LCMS (ESI positive ion) m/z: Calculated: 328.16; Observed: 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] pyrimidin -2(3H) -one (4) : to (R)-1-(5-((2,2-dimethyl-1,3-dioxolane-4- yl)methoxy)-2,4-difluorophenyl)piperazine (3, 0.45 g, 1.4 mmol) 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)ethyl methanesulfonate (0.48 g, 1.2 mmol) in A stirred solution in N,N-dimethylformamide (6 mL) was added DIPEA (0.71 g, 5.5 mmol) and the reaction mixture was stirred at 120 °C for 16 h. After the reaction was complete (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 brine 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) and further enriched by washing with a 50% ACN/diethyl ether mixture to give (R)-5-amine as a pale yellow solid Base-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)-keto compound (4) (100 g, 13.1%); LCMS (ESI positive ion) m/z: Calculated: 628.20; Observed: 629.0 (M+1);

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-dioxolane-4 -yl)methoxy)-2,4-difluorophenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2 ,4] To a stirred solution of triazolo[1,5-c]pyrimidin-2(3H)-one ( 4 , 50 mg, 0.08 mmol) in 1,4-dioxane (4 mL) was added dioxane 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 the solvent. The crude product was recrystallized using acetonitrile to give (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 ( compound 127 ) (35 mg, 67.3%); HPLC purity (XB0595TF): 92.58%; LCMS (ESI positive ion) m/z: calculated value: 588.17; observed value: 589.2 ( 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 -difluorophenol (2) : Addition of 2,4-difluoro-5-nitrophenol ( 1 , 25 g, 0.143 mol) in EtOAc (200 mL) The stirred solution was added with 10% Pd/C (4.55 g, 0.043 mol). The reaction mixture was stirred under _H2 for 16 h at RT. After completion of the reaction (TLC), the reaction mixture was filtered by using a bed of celite, washed with EtOAc (1000 mL) and concentrated under reduced pressure to give 5-amino-2,4-difluorophenol as a beige solid (2) (20.10 g, 94.6%); LCMS (ESI positive ion) m/z: Calculated: 145.03; Observed: 146.2 (M+1).

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 ring To a stirred solution in butane (30 mL) was added bis(2-chloroethyl)amine hydrochloride (31 g, 0.170 mol). The resulting mixture was stirred at 150 °C under 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 nitrogen atmosphere. The solid material was dried under vacuum to give 2,4-difluoro-5-(piperazin-1-yl)phenol ( 3 ) (23 g, 80.3%) as an off-white solid; LCMS (ESI positive ion) m/z: Calculated: 214.09; Observed: 215.1 (M+1).

Step 3 : Synthesis of 4-(2,4- difluoro -5- hydroxyphenyl ) piperazine -1- carboxylic acid benzyl ester (4) : 2,4-difluoro-5-(piperazine- To a stirred solution of 1-yl)phenol hydrochloride (3, 25 g, 0.117 mol) in THF (250 mL) was added NaHCO ₃ (14.7 g, 0.175 mol) and Cbz-Cl (16.66 mL, 0.117 mol). 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, dried over anhydrous Na ₂ SO ₄ and then concentrated under reduced pressure. The obtained crude material was purified by column chromatography (30% EtOAc/Hexane as eluent) to give 4-(2,4-difluoro-5-hydroxyphenyl)piperazine- Benzyl 1-carboxylate (20 g, 45.8%); LCMS (ESI positive) m/z: Calculated: 348.13; Observed: 349.2 (M+1).

Step 4 : Synthesis of (R)-(2,2- dimethyl -1,3- dioxolane -4- yl ) methyl methanesulfonate (10) : at 0°C to (S)-( To a stirred solution of 2,2-dimethyl-1,3-dioxolan-4-yl)methanol ( 9 , 12 g, 0.091 mol) in DCM (100 mL) was added triethylamine (37.76 mL, 0.272 mol) and methanesulfonyl 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 upon completion, the reaction mixture was diluted with water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous _Na2SO4 , filtered and concentrated under _reduced pressure to give the title compound (21.8 g, 77.8%) as a yellow gummy liquid; LCMS (ESI positive ion) m/z: Calculated Value: 210.06; Observation: 211.0 (M+1).

Step 5 : Synthesis of (S)-4-(5-((2,2- dimethyl -1,3- dioxolan -4- yl ) methoxy )-2,4 -difluorophenyl ) Benzyl piperazine -1- carboxylate (5) : Benzyl 4-(2,4-difluoro-5-hydroxyphenyl)piperazine-1-carboxylate ( 4 , 10 g, 0.029 mmol) and (R) A stirred solution of -(2,2-dimethyl-1,3-dioxolan-4-yl)methyl methanesulfonate ( 10 , 7.2 g, 0.034 mol) in DMF (70 mL) was added with carbonic acid 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 _Na2SO4 , 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-di Benzyl oxolan-4-yl)methoxy)-2,4-difluorophenyl)piperazine-1-carboxylate (5) (13 g, 70.50%); LCMS (ESI positive ion) 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) : under nitrogen atmosphere to (S)-4-(5-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-2 , A stirred solution of benzyl 4-difluorophenyl)piperazine-1-carboxylate ( 5 , 13 g, 0.028 mol) in EtOAc (100 mL) was added 10% Pd/C (4 g). The reaction mixture was stirred under _H2 atmosphere for 16 h. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was filtered using celite to remove Pd/C. The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure to give (S)-1-(5-((2,2-dimethyl-1,3-dioxolane-4- methoxy)-2,4-difluorophenyl)piperazine ( 6 ) (8.55 g, 93.0%); LCMS (ESI positive ion) m/z: Calculated: 328.16; Observed: 329.2 (M +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] pyrimidin -2(3H) -one (7) : to (S)-1-(5-((2,2-dimethyl-1,3-dioxolane-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)ethyl methanesulfonate (7.6 g, 0.019 mol) in A stirred solution in N,N-dimethylformamide (50 mL) was added DIPEA (11.12 mL, 0.064 mol) and the reaction mixture was stirred at 120 °C for 16 h. After the reaction was complete (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 brine 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) and further enriched by washing with a 50% ACN/diethyl ether mixture to give (S)-5-amine as a pale yellow solid Base-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)-Keto compound ( 7 ) (2.6 g, 17.8%); LCMS (ESI positive ion) m/z: Calculated: 628.20; Observed; 629.2 (M+1).

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-dioxolane-4 -yl)methoxy)-2,4-difluorophenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2 ,4] A stirred solution of triazolo[1,5-c]pyrimidin-2(3H)-one ( 7 , 1.4 g, 2.23 mmol) in 1,4-dioxane (20 mL) was added with dioxane 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 the solvent. The crude product was recrystallized using acetonitrile to give (R)-5-amino-3-(2-(4-(5-(2,3-dihydroxypropoxy)-2,4-di Fluorophenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c] Pyrimidin-2(3H)-one ( compound 128 ) (1.2 g, 87%); HPLC purity (AM9010A3): 95.05%; LCMS (ESI positive ion) m/z: Calculated value: 588.17; Observed value: 589.2 (M +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 analogous 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] pyrimidin -2(3H) -one . LCMS (ESI positive ion) m/z: Calculated: 522.18; Observed value: 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- oxothiazolo [5,4-e][1,2,4 ] triazolo [1,5-c] pyrimidin -3(2H) -yl ) ethyl ) piperazin -1- yl ) phenoxy ) acetic acid hydrochloride . LCMS (ESI positive ion) m/z: calculated Value: 536.16; Observed value: 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- oxothiazolo [5,4-e][1,2,4 ] triazolo [1,5-c] pyrimidin -3(2H) -yl ) ethyl ) piperazin -1- yl ) phenoxy ) acetamide . LCMS (ESI positive ion) m / z : Calculated : 535.58; observed value: 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 positive ion ) m/z: Calculated : 552.19; observed value: 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- aminoethoxy ) 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 Value: 521.6; observed value; 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- oxothiazolo [5,4-e][1,2,4] triazole and [1,5-c] pyrimidin -3(2H) -yl ) ethyl ) piperazin -1- yl ) benzamide . LCMS (ESI positive 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- oxothiazolo [5,4-e][1,2,4] triazole And [1,5-c] pyrimidin -3(2H) -yl ) ethyl ) piperazin -1- yl )-N- methylbenzamide . LCMS (ESI positive ion) m / z : Calculated: 519.58; observed value; 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- morpholinoethoxy ) phenyl ) piperazin -1- yl ) ethyl base ) thiazolo [5,4-e][1,2,4] triazolo [1,5-c] pyrimidin -2(3H) -one . LCMS (ESI positive ion) m/z: Calculated: 591.24; Observed value: 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- oxothiazolo [5,4-e][1,2,4] triazole and [1,5-c] pyrimidin -3(2H) -yl ) ethyl ) piperazin -1- yl ) benzenesulfonamide . LCMS (ESI positive ion) m/z: Calculated: 541.13; Observed: 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- oxothiazolo [5,4-e][1,2,4] triazole And [1,5-c] pyrimidin -3(2H) -yl ) ethyl ) piperazin -1- yl )-N- methylbenzenesulfonamide . LCMS (ESI positive ion) m/z: Calculated: 555.15; Observed value: 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] pyrimidin -2(3H)-one . LCMS : (ESI positive ion) m / z : Calculated: 540.62; Observed value; 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 positive ion) m/z: Calculated: 524.14; Observed value: 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- oxothiazolo [5,4-e][1,2,4] triazole and [1,5-c] pyrimidin -3(2H) -yl ) ethyl ) piperazin -1- yl ) benzamide . LCMS (ESI positive 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] pyrimidin -2(3H) -one . LCMS (ESI positive ion) m/z: Calculated: 522.18; Observation value: 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)- Ketone 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: Calculated: 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-( piperazine -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 positive ion) m/z: Calculated: 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: Calculated: 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 : calculated Value: 558.61; observed value; 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- oxothiazolo [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 : Calcd: 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- oxothiazolo [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 salt . 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- oxothiazolo [5,4-e][1,2,4] triazole And [1,5-c] pyrimidin -3(2H)-yl ) ethyl ) piperazin -1- yl )-N-(2-( dimethylamino ) ethyl ) -3- fluorobenzoyl Amine . LCMS (ESI positive 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- oxothiazolo [5,4-e][1,2,4] triazole And [1,5-c] pyrimidin -3(2H)-yl ) ethyl ) piperazin - 1- yl )-3- fluoro -N-(2- hydroxyethyl ) benzamide . LCMS (ESI normal 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- oxothiazolo [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 positive 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- oxothiazolo [5,4-e][1,2,4 ] triazolo [1,5-c] pyrimidin -3(2H) -yl ) ethyl ) piperazin -1- yl )-3- fluorophenoxy ) acetic acid . LCMS (ESI positive 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- oxothiazolo [5,4-e][1,2,4 ] triazolo [1,5-c] pyrimidin -3(2H) -yl ) ethyl ) piperazin -1- yl )-3,5 -difluorophenoxy ) acetic acid . LCMS (ESI positive 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- oxothiazolo [5,4-e][1,2,4 ] triazolo [1,5-c] pyrimidin -3(2H) -yl ) ethyl ) piperazin -1- yl )-3- fluorophenoxy ) propanoic acid . LCMS (ESI positive ion) m/z : Calcd: 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- oxothiazolo [5,4-e] [1,2,4] triazolo [1,5-c] pyrimidin -3(2H) -yl ) ethyl ) piperazin -1- yl )-3- fluorophenoxy ) propionic acid and (R) -2-(4-(4-(2-(5- amino- 8-( furan- 2- yl )-2- oxothiazolo [5,4-e][1,2,4] tri Azolo [1,5-c] pyrimidin -3(2H) -yl ) ethyl ) piperazin -1- yl )-3- fluorophenoxy ) propionic acid

A racemic mixture of the product (135 mg) prepared as described for the example above was subjected to chiral separation (0.08 g sample 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 generate 13 mg of peak 1(S)-2-(4-(4-(2-(5-amino-8-(furan- 2-yl)-2-oxothiazolo[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- Base)-2-oxothiazolo[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- oxothiazolo [5,4-e][1,2, 4] Triazolo [1,5-c] pyrimidin -3(2H)-yl ) ethyl ) piperazin - 1- yl )-3- fluorophenoxy ) propanoic acid . LCMS (ESI positive ion) m/ z: Calculated: 568.17; Observed: 568.9 (M+1); HPLC Purity (XB0595TF): 95.79%; Chiral 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- oxothiazolo [5,4-e][1,2, 4] Triazolo [1,5-c] pyrimidin -3(2H)-yl ) ethyl ) piperazin - 1- yl )-3- fluorophenoxy ) propanoic acid . LCMS (ESI positive ion) m/ z: Calculated: 568.17; Observed: 569.0 (M+1); HPLC Purity (XB0595TF): 98.05%; Chiral 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- oxothiazolo [5,4-e][1,2,4 ] triazolo [1,5-c] pyrimidin -3(2H) -yl ) ethyl ) piperazin -1- yl )-3- fluorophenoxy )-2- methylpropion hydrochloride . LCMS (ESI Positive Ions) m / z : Calculated: 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- oxothiazolo [5,4-e][1,2,4 ] triazolo [1,5-c] pyrimidin -3(2H) -yl ) ethyl ) piperazin -1- yl )-3- fluorophenyl ) propanoic acid . LCMS (ESI positive 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- oxothiazolo [5,4-e][1,2,4 ] triazolo [1,5-c] pyrimidin -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): δ10.31 (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- oxothiazolo [5,4-e][1,2,4 ] triazolo [1,5-c] pyrimidin -3(2H) -yl ) ethyl ) piperazin -1- yl )-2,6- difluorophenoxy ) acetic acid hydrochloride . LCMS (ESI normal ions); m / z : Calculated: 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- oxothiazolo [5,4-e][1,2,4 ] triazolo [1,5-c] pyrimidin -3(2H) -yl ) ethyl ) piperazin -1- yl )-2,4 -difluorophenoxy ) acetic acid hydrochloride . LC-MS: (ESI positive ion); m / z : Calculated: 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- oxothiazolo [5,4-e][1,2,4] triazole And [1,5-c] pyrimidin -3(2H) -yl ) ethyl ) piperazin -1- yl )-3- fluorobenzoic acid . LCMS (ESI positive ion) m/z: Calculated: 524.14; Observation 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- oxothiazolo [5,4-e][1 ,2,4] triazolo [1,5-c] pyrimidin -3(2H)-yl ) ethyl ) piperazin - 1- yl )-3- fluorophenoxy ) ethyl ) amino ) acetyl 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- oxothiazolo [5,4-e][1 ,2,4] triazolo [1,5-c] pyrimidin -3(2H)-yl ) ethyl ) piperazin - 1- yl )-3- fluorophenoxy ) ethyl )( methyl ) amine LCMS ( ESI positive 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 positive ion) m/z: Calculated: 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 positive ion) m/z: Calculated: 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 ) ethyl Base )-5- amino -8-( furan -2- yl ) thiazolo [5,4-e][1,2,4] triazolo [1,5-c] pyrimidine -2(3H)- Ketone . LCMS (ESI positive 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- oxothiazolo [5,4-e][1,2,4 ] Triazolo [ 1,5-c] pyrimidin -3(2H)-yl ) ethyl ) piperazin -1- yl )-3- fluorophenoxy )-N-(2-( methylamino ) Ethyl ) acetamide hydrochloride . LCMS (ESI positive 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- oxothiazolo [5,4-e][1,2,4 ] triazolo [1,5-c] pyrimidin -3(2H)-yl ) ethyl ) piperazin -1- yl )-3- fluorophenoxy ) -N- (2-( dimethylamino ) ethyl ) acetamide . LCMS (ESI positive ion) m/z: calcd: 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- oxothiazolo [5,4-e][1,2,4 ] Triazolo [1,5-c] pyrimidin -3(2H) -yl ) ethyl ) piperazin -1- yl )-3- fluorophenoxy )-N-(2- aminoethyl ) ethyl Amide hydrochloride . LCMS (ESI positive 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- oxothiazolo [5,4-e][1,2,4 ] triazolo [1,5-c] pyrimidin -3(2H) -yl ) ethyl ) piperazin -1- yl )-3- fluorophenoxy ) acetamide . LCMS (ESI positive 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- oxothiazolo [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 ) benzamide hydrochloride . LCMS (ESI positive 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- oxothiazolo [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- Toluamide . LCMS (ESI positive) m/z: Calculated: 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- oxothiazolo [5,4-e][1,2, 4] Triazolo [1,5-c] pyrimidin -3(2H)-yl ) ethyl ) piperazin - 1- yl )-N-(1-( dimethylamino ) propan -2- yl ) -3- Fluorobenzamide . LCMS (ESI positive ion) m/z: Calc.: 608.24; Observation: 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- oxothiazolo [5,4-e][1,2,4 ] triazolo [1,5-c] pyrimidin -3(2H)-yl ) ethyl ) piperazin -1- yl )-3- fluorophenoxy ) -N- methyl -N-(2-( Methylamino ) ethyl ) acetamide hydrochloride . LCMS (ESI positive 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- oxothiazolo [5,4-e][1,2,4 ] triazolo [1,5-c] pyrimidin -3(2H) -yl ) ethyl ) piperazin -1- yl )-2,4- difluorophenoxy )-2- methylpropionic acid hydrochloride 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- oxothiazolo [5,4-e] [1,2,4] triazolo [1,5-c] pyrimidin -3(2H) -yl ) ethyl ) piperazin -1- yl )-2,4 -difluorophenoxy ) propionic acid and (R)-2-(5-(4-(2-(5- amino- 8-( furan -2- yl )-2- oxothiazolo [5,4-e][1,2, 4] Triazolo [1,5-c] pyrimidin -3(2H)-yl ) ethyl ) piperazin - 1- yl )-2,4 -difluorophenoxy ) propionic acid

A racemic mixture of the product (0.08 g) prepared as described for the example above was subjected to chiral separation (0.08 g sample in 10 mL ethanol), column-chiralpak AD-H, and mobile phase: n-hexane 0.1% diethylamine in alkanes:ethanol (70:30), flow rate: 1.0 mL/min; to generate 10 mg of peak 1((S)-2-(5-(4-(2-(5 -Amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidine-3(2H )-yl)ethyl)piperazin-1-yl)-2,4-difluorophenoxy)propionic acid) and 13 mg of peak 2((R)-2-(5-(4-(2- (5-Amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidine-3 (2H)-yl)ethyl)piperazin-1-yl)-2,4-difluorophenoxy)propionic acid). Note: Peak 1 was arbitrarily considered the (S) isomer and peak 2 was considered the (R) isomer.

(S)-2-(5-(4-(2-(5- amino- 8-( furan -2- yl )-2- oxothiazolo [5,4-e][1,2, 4] Triazolo [1,5-c] pyrimidin -3(2H)-yl ) ethyl ) piperazin - 1- yl )-2,4 -difluorophenoxy ) propanoic acid . LCMS (ESI positive ion ) m/z: Calculated: 586.16; Observed: 587.2 (M+1); HPLC purity (XB0595TF): 99.69 %; chiral HPLC purity: 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- oxothiazolo [5,4-e][1,2, 4] Triazolo [1,5-c] pyrimidin -3(2H)-yl ) ethyl ) piperazin - 1- yl )-2,4 -difluorophenoxy ) propanoic acid . LCMS (ESI positive ion ) m/z: Calculated: 586.16; Observed: 587.2 (M+1); HPLC purity (XB0595TF): 94.42%; Chiral 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- oxothiazolo [5,4-e][1,2,4 ] triazolo [1,5-c] pyrimidin -3(2H)-yl ) ethyl ) piperazin -1- yl )-2,4 -difluorophenoxy )-N-(2- ( methyl Amino ) ethyl ) acetamide hydrochloride . LCMS (ESI positive 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- oxothiazolo [5,4-e][1,2,4 ] triazolo [1,5-c] pyrimidin -3(2H)-yl ) ethyl ) piperazin - 1- yl )-2,4- difluorophenoxy )-N-(2-( dimethyl LCMS ( ESI positive 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- oxothiazolo [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- Methylbenzamide . LCMS (ESI positive 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- oxothiazolo [5,4-e][1,2,4 ] triazolo [1,5-c] pyrimidin -3(2H) -yl ) ethyl ) piperazin -1- yl )-2,4 -difluorophenoxy ) butanoic acid . LCMS (ESI positive ion) m/z: Calculated: 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 positive ion) m/z: Calculated: 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 Base ) piperazin -1- yl ) ethyl ) -8-( furan -2- yl ) thiazolo [5,4-e][1,2,4] triazolo [1,5-c] pyrimidine- 2(3H) -Ketone . LCMS (ESI positive 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 Base ) 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.: 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- oxothiazolo [5,4-e][1,2,4] triazole And [1,5-c] pyrimidin -3(2H)-yl ) ethyl ) piperazin - 1- yl )-3- fluoro -N-(2-( methyl ( oxygen -3- yl ) amino ) ethyl ) benzamide . LCMS (ESI positive ion) m/z: Calcd.: 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- oxothiazolo [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 ) benzamide hydrochloride . LCMS (ESI positive 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- oxothiazolo [5,4- e][1,2,4] triazolo [1,5-c] pyrimidin -3(2H) -yl ) ethyl ) piperazin -1- yl )-3- fluorophenoxy ) ethyl ) ethyl Amide hydrochloride . LCMS: (ESI positive ion); 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- oxothiazolo [ 5,4-e][1,2,4] triazolo [1,5-c] pyrimidin -3(2H) -yl ) ethyl ) piperazin -1- yl )-3- fluorophenoxy ) Ethyl )-3- methylbutanamide hydrochloride . LCMS: (ESI positive ion); m / z : Calculated: 638.72; Observed: 639.1 (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- oxothiazolo [5,4-e][1,2,4 ] triazolo [1,5-c] pyrimidin -3(2H) -yl ) ethyl ) piperazin -1- yl )-2,4 -difluorophenoxy ) ethyl 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- oxothiazolo [5,4-e][1,2,4 ] triazolo [1,5-c] pyrimidin -3(2H) -yl ) ethyl ) piperazin -1- yl )-2,4 -difluorophenoxy ) acetonitrile . LCMS (ESI positive 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 positive ion) m/z: Calculated: 463.15; Observed: 464.1 (M+ 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 positive ion) m/z: Calculated: 464.15; Observed: 465.1 (M+ 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- oxoindoline -5- 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 positive ion) m/z: calculated Value: 535.16; Observed value: 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 positive ion) m/z: Calculated: 495.54 ; Observed value: 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 positive ion) m/z: Calculated: 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: 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 positive ion) m/z: Calculated: 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 : Calculated: 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) -Ketohydrochloride . LCMS (ESI positive 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) -Keto hydrochloride . LCMS (ESI positive 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) -Ketohydrochloride . LCMS (ESI positive 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- oxothiazolo [5,4-e][1,2,4 ] Triazolo [1,5-c] pyrimidin -3(2H)-yl ) ethyl ) piperazin -1- yl )-2,4 -difluorophenoxy )-N-(2 - morpholinyl Ethyl ) acetamide . LCMS (ESI positive 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- oxothiazolo [5,4-e][1,2,4] triazole And [1,5-c] pyrimidin -3(2H)-yl ) ethyl) piperazin - 1 - yl )-2,4- difluoro -N-( morpholin -3- ylmethyl ) benzoyl Amine hydrochloride . LCMS (ESI positive 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- 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)- Ketone . LCMS (ESI positive 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- 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)- Ketone . LCMS (ESI positive 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- oxothiazolo [5,4-e][1,2,4 ] Triazolo [1,5-c] pyrimidin -3(2H) -yl ) ethyl ) piperazin -1- yl )-3- fluorophenoxy )-N-(2- morpholinoethyl ) Acetamide . LCMS (ESI positive) m/z: Calculated: 666.25; Obs: 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- oxothiazolo [5,4-e][1,2,4] triazole And [1,5-c] pyrimidin -3(2H)-yl ) ethyl ) piperazin - 1- yl )-3- fluoro -N-(2- morpholinoethyl ) benzamide . LCMS ( ESI positive ion) m/z: Calculated: 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- oxothiazolo [5,4-e][1,2,4] triazole And [1,5-c] pyrimidin -3(2H)-yl ) ethyl ) piperazin - 1- yl )-3- fluoro -N-( morpholin -3- ylmethyl ) benzamide . LCMS (ESI positive ion) m/z: Calculated: 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-( azan -3- yloxy ) phenyl ) piperazin -1- yl ) ethyl )-8-( furan -2- base ) thiazolo [5,4-e][1,2,4] triazolo [1,5-c] pyrimidin -2(3H) -one hydrochloride . LCMS (ESI positive 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] pyrimidin -2(3H) -one . LCMS (ESI 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] pyrimidin -2(3H) -one . LCMS (ESI 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- oxothiazolo [5,4-e][1,2, 4] Triazolo [1,5-c] pyrimidin -3(2H)-yl ) ethyl ) piperazin - 1- yl )-2,4- difluoro -N-(2-( methylsulfinyl (yl ) ethyl ) benzamide . LCMS (ESI positive ion) m/z: Calcd.: 631.68; Observation: 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- oxothiazolo [5,4-e][1,2, 4] Triazolo [1,5-c] pyrimidin -3(2H)-yl ) ethyl ) piperazin - 1- yl )-2,4- difluoro -N-(2-( methylsulfinyl ( Ethyl ) ethyl ) benzamide . LCMS (ESI positive 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- oxothiazolo [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-( Methylsulfinyl ) ethyl ) benzamide . LCMS (ESI positive 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- oxothiazolo [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-( Methylsulfinyl ) ethyl ) benzamide . LCMS (ESI positive 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- oxothiomorpholine -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: 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- oxothiomorpholinyl ) 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: 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- oxothiazolo [5,4-e][1,2, 4] Triazolo [1,5-c] pyrimidin -3(2H)-yl ) ethyl ) piperazin - 1- yl )-3- fluoro -N-(2-( methylsulfinyl ) ethyl base ) benzamide . LCMS (ESI positive ion) m/z: Calculated: 613.17; Obs: 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- oxothiazolo [5,4-e][1,2, 4] Triazolo [1,5-c] pyrimidin -3(2H)-yl ) ethyl ) piperazin - 1- yl )-3- fluoro -N-(2-( methylsulfinyl ) ethyl base ) benzamide . LCMS (ESI positive ion) m/z: Calc.: 613.17; Obs.: 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- oxothiomorpholine -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- oxothiazolo [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 Fluorobenzamide . LCMS (ESI positive 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- oxothiazolo [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 Fluorobenzamide . LCMS (ESI positive 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-( acrazine -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 positive ion) m/z: Calculated: 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-( azan -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 positive ion) m/z: Calculated: 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) - Ketone . LCMS (ESI positive 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. Assays for A2A Functional Activity

The following two assays aim to demonstrate that the compounds of the present invention effectively inhibit the A2A receptor by showing that the compounds of the present invention inhibit the functional activity of the A2A receptor. II.1.A. Inhibition of cAMP Production in HEK Cells

Objective . To induce cAMP production when A2A receptors are activated. The current assay therefore aims to show that cAMP production is inhibited in HEK cells in response to their exposure to compounds of the invention.

Methods . A stably transfected HEK-293 cell line with the A2A receptor was purchased from PerkinElmer® (#ES-011-C). Cells were incubated in EMEM medium (Lonza, #BE12-611F) supplemented with 10% FBS (Lonza, #DE14-801F) and 200 μg/ml G418 (Tocris, #4131) at 37°C and 5% _CO nourish. Fresh media without selection markers was added directly the day before the experiment to stop the selection pressure.

cAMP inhibition and antagonist IC50 assays were performed on white half-area 96-well plates (PerkinElmer®, #6005560) using the LANCE® Ultra cAMP Kit from PerkinElmer® (#TRF0262). Assays were performed 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) EHNA (Tocris -# 1261) and 100 µM Rolipram's HSA. Stimulation buffer b) mimics the human situation by increasing the amount of albumin present in the assay.

Compounds of the invention were diluted 100X in either buffer depending on the assay performed. A total of 1000 cells per well were pre-incubated with the compounds of the invention for 10 minutes prior to the addition of A2A agonists corresponding to EC80 (3 nM NECA in normal buffer and 5 nM NECA in HSA buffer) or 5 µM Adenosine for 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 adding 10 µl of 4X EU-cAMP tracer working solution and 10 µl of 4X ULight-anti-cAMP working solution. The TR-FRET signal was measured after 1 hour using Spectramax Paradigm (Molecular Devices).

II.1.B. 藉由人類 T 細胞恢復促炎性細胞介素之產生 Results . As demonstrated in Table 2 below, compounds of the invention inhibited cAMP production in response to stimulation of A2A-overexpressing HEK cells with A2A agonists or with adenosine under different conditions. table 2

II.1.B. Restoration of pro-inflammatory cytokine production by human T cells

Purpose . When T cells are activated, they produce pro-inflammatory cytokines. When A2A receptors are activated in T cells, the amount of cytokines produced in response to stimulation of the T cells decreases. The current assay therefore aims to show that the production of pro-inflammatory cytokines by T cells can be restored by exposure to the compounds of the invention.

Isolation of PBMC and CD3+ T cells . The venous blood of healthy volunteers was obtained through ImmuneHealth (Centre Hospitalier Universitaire Tivoli, La Louviere, Belgium), and all these healthy volunteers signed the informed consent approved by the ethics committee (FOR-UIC-BV -050-01-01 ICF_HBS_HD version 5.0). Monocytes were collected by density gradient centrifugation using SepMate-50 tubes (StemCell Technologies, Grenoble, France) and Lymphoprep (Axis-shield, Oslo, Norway) according to the manufacturer's instructions. CD3+ T cells were isolated by immunomagnetic depletion selection using the EasySep Human T Cell Isolation Kit (StemCell Technologies) following the manufacturer's instructions. CD3+ T cells were stored in heat-inactivated fetal bovine serum (hiFBS; Gibco, ThermoFisher Scientific, Merelbeke, Belgium) containing 10% DMSO in liquid nitrogen.

Human IL-2 T cell assay . Purified human CD3+ T cells were thawed and utilized in complete media supplemented with 1x non-essential amino acids (Lonza), 2% Pen/Strep (Lonza) and 1 mM sodium pyruvate (Gibco) , RPMI1640 medium (with UltraGlutamine; Lonza, Verviers, Belgium) containing 10% hiFBS was washed twice. Cells were suspended in complete medium containing 20% hiFBS or 100% heat-inactivated human serum (hiHS; Sigma-Aldrich, Diegem, Belgium). Cells were activated by 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 _A2AR 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 compounds of the invention were prepared and added to the wells. Cells were placed in a 37°C humidified tissue culture incubator with 5% _CO2 for 72 hours. After 72 hours, supernatants were 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.

II.1.C. 在人類全血中恢復促炎性細胞介素之產生 Results . Addition of the A2A-selective agonist CGS-21680 to CD3+ T cells reduced the amount of cytokines produced in response to stimulation by anti-CD3 and anti-CD28 coated microbeads. Compounds of the invention dose-dependently restored the production of the pro-inflammatory interleukin IL2 in CGS-21680-treated human T cells, with potencies indicated in Table 3 below. Table 3

II.1.C. Restoration of pro-inflammatory cytokine production in human whole blood

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

Compound 7 was dissolved in DMSO at 10 mM and then diluted with TC medium. The solutions were examined microscopically to rule out the presence of particles. Freshly prepared solutions containing Compound 7 were added to thawed TC tubes containing stimulants and, where appropriate, 1 µM CGS-21680.

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

Mediator quantification . Interleukins and chemokines released in TC supernatants were measured using human interleukin MAP A plates for Luminex assay. Analysis of the following mediators: 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, changes in the secretion of cytokines and chemokines induced by increasing doses of A2A agonists in TC supernatants were analyzed. The percent change in the concentration of soluble mediator (SM) was calculated for each stimulation condition as follows: % change = 100 x [SMTC+A2A agonist]/[SMTC-A2A agonist]. To assess the biological activity of Compound 7 , CGS-21680-supplemented TC was analyzed for Compound 7 -induced restoration of cytokine and chemokinin secretion to baseline levels (ie, TC stimulation without CGS-21680 supplementation).

Rescue of interleukin secretion was estimated by calculating percentage 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 the secretion of several cytokines and chemoactivators in whole blood cell cultures. The biological activity of two A2A agonists (CGS-21680 and NECA) was assessed on whole blood cell cultures stimulated with LPS, zymosan, SEB or anti-CD3/CD28. Both agonists dose-dependently altered the secretion of several cytokines and chemokines. This effect was reproducible across the three test donors, although the degree of variation varied between individuals.

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 and anti-inflammatory cytokines reached a plateau. Specifically, the levels of the pro-inflammatory cytokines IFNg and TNFa were reduced by more than 50%, while the levels of the anti-inflammatory cytokines IL-8 and IL-10 were doubled.

The ability of compound 7 to reverse changes in cytokine and chemokines secretion induced by CGS-21680 on whole blood cell cultures stimulated with LPS, zymosan, or anti-CD3/CD28 was assessed. As shown in Figure 1A and Figure 1B , compound 7 dose-dependently restored the changes in the secretion of cytokines and chemokines induced by CGS-21680, wherein depending on the conditions tested, at a dose of 100-1000 nM Compound achieved complete recovery. This effect was reproducible across the three test donors, although the degree of variation varied between individuals.

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

Objective . A2A receptors are known to mediate CREB phosphorylation. The current assay aims to show that the compounds of the invention potently inhibit the A2A receptor by showing that CREB phosphorylation can be inhibited by exposing human immune cells to the compounds of the invention.

Methods . Venous blood was obtained from healthy volunteers who all signed informed consent (version 5.0) approved by the Ethics Committee through ImmuneHealth (Centre Hospitalier Universitaire Tivoli, La Louviere, Belgium). Peripheral blood cells were treated with the A2AR agonists CGS-21680 or NECA (Sigma-Aldrich, Diegem, Belgium) and serial dilutions of compounds of the invention (all stock solutions used were at 10 mM in DMSO). All dilutions were prepared in RPMI1640 medium (with UltraGlutamine; Lonza, Verviers, Belgium) and cells were incubated with compounds in a 37°C humidified tissue culture incubator with 5% _CO2 . Following stimulation, cells were fixed and permeabilized, followed by intracellular staining at room temperature using a mouse anti-human pCREB antibody (clonal J151-21; BD Biosciences). Data were acquired using a LSR Fortessa flow cytometer (BD Biosciences) and analyzed using FlowJo software (FlowJo, LLC, Ashland, Oregon).

Results . It was found that the compounds of the present invention inhibit A2A-mediated phosphorylation of CREB. For example, Compound 4 exhibited an IC ₅₀ of 20 nM for activation by NECA in peripheral blood lymphocytes, as shown in FIG. 2 . II.2.B. Ex vivo regulation of pCREB in mice

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

Methods . Compound 7 was formulated in 10% DMSO, 10% solutol, 80% water pH 3 to obtain a homogeneous solution. Volumes were calculated for per oral (PO) administration of a final dose of 100 ml. BALB/cAnNCrl female mice were purchased from Charles River Laboratories. Mice were treated orally with a single dose of an A2A receptor antagonist. At specific time points, animals were anesthetized with an IP injection of 200 μl of ketamine 10%/xylazine 0.1% in PBS and blood was collected via retro-orbital bleed in EDTA tubes. Dispense 45 μl blood/well in the master block. The A2A receptor agonist NECA (Tocris) was prepared at a concentration of 3 µM in RPMI 1640 (Lonza) supplemented with medium 2% penicillin/streptomycin (Lonza) and 50 µM 2-mercaptoethanol (Sigma), and the 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 lysis/fixation buffer (BD Biosciences) to each well, mixed carefully and incubated for 10 minutes in a 37°C humidified cell culture incubator with 5% CO ₂ . Cells were pelleted by centrifugation at 600xg for 5 minutes. After washing with 1 ml of DPBS (Lonza) with Ca2+Mg2+, cells were permeabilized with 200 μl of ice-cold Perm buffer II (BD Biosciences) and incubated on ice for 30 minutes. During permeabilization, cells were transferred to 96-well U-bottom plates. 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 cells in Fc block (CD16/CD32 monoclonal antibody (93), eBioscience) containing FACS buffer; after 5 min incubation at room temperature, the antibody mixture was added and incubated at room temperature Cells were incubated for 1 hour. Cells were washed with FACS buffer and resuspended in FACS buffer for acquisition at BD Fortessa (BD Biosciences).

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

表 5. 在口服投與之後12小時的化合物8a 之活性 在CD4+ T細胞中評定CREB磷酸化

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

Table 5. Activity of Compound 8a 12 hours after oral administration in CD4+ T cells assessing CREB phosphorylation

II.3. Cytotoxicity assay

Objective . Activation of A2A receptors provides immunosuppressive signals that inhibit cytotoxicity. The current assay aims to show that the compounds of the invention potently inhibit the A2A receptor by showing that cytotoxicity can be increased by exposure to the compounds of the invention.

Methods . Cytotoxicity assays were performed to assess the antigen-specific cytotoxic activity of OT-1 CD8 cells against OVA-pulsed target cells, and the effect of compounds of the present invention on attenuating A2AR-mediated inhibition of cytotoxicity: OT1 cell line derived from C57BL/6- Spleen isolation of Tg (TcraTcrb) 1100Mjb/Crl mice (Charles River). 1 ug/ml OVA peptide ( _Ovalbumin (257 -264) Chicken (S7951-1MG), Sigma Aldrich) starter OT1 cells. On day 3, all cells were pooled and counted. For day 3 cytotoxicity assays, PancO2 (target cells) were pulsed with 1 μg/ml OVA. Target cells and non-pulsed Panc02 cells (non-target bystanders) were labeled with CFSE (C1157 (ThermoFisher)) and CellTrace™ Far Red Cell Proliferation Kit (C34564, ThermoFisher), respectively, according to the manufacturer's instructions. The stimulated OT-1 cell line was added as effector cells at a 10:1 effector to target ratio. Co-culture reactions were incubated in a 37°C humidified tissue culture incubator with 5% CO ₂ . After 24 hr, cells were washed and stained with a live/dead fixable purple dead cell stain kit (Molecular Probes, L34955). Cytotoxic killing of target cells was then measured by monitoring changes in the ratio of live target cells to non-target cells by flow cytometry (MACSQuant® Analyzer 10-Miltenyi Biotec). % Cytotoxicity was 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 the presence of effector cells Absence (% of target cells)/(% of non-target cells)*100

III. 藥物動力學實例 III.1. 在 Caco-2 細胞中測定滲透性及流出物 Results . Addition of the A2A agonist CGS-21680 to the medium resulted in a reduction in cytotoxicity which could be dose-dependently reduced by the compounds of the invention (Table 6). For compounds 4 and 31 of the present invention, this is illustrated, for example, in Figure 3 . Table 6

III. Pharmacokinetic Example III.1. Determination of Permeability and Efflux in Caco -2 Cells

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

The current assay aims to show that the compounds of the invention do not possess any significant CNS permeability by showing that they are substrates for transporters that efflux them from the brain.

Indeed, it is well known in the art that xenobiotics that are substrates for transporters such as P-glycoprotein are not effective in penetrating the blood-brain barrier, 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 thus aims to show that the compounds of the invention are substrates of this transporter present in the Caco-2 cell line and thus do not cross the blood brain barrier.

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

Preparation of working solutions . For reference compounds (fenoterol, propranolol and diguxin) and test compounds, 0.4 mM intermediate solutions were prepared by diluting 10 mM or other appropriate concentrations of DMSO stock solutions with DMSO. 2 μM dosing solutions of reference and test compounds were prepared by spiking appropriate volumes of intermediate solutions into TB with and without 1 μM Zosuquidar. The final concentration of DMSO was not 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. Cells were incubated at 37°C, 5% CO2, and relative humidity. After reaching 80-90% confluency, cells were gently dissociated using 0.05% trypsin-EDTA solution. Cells at passage 30-50 were seeded on a 96-well BD insert system (Cat #359274) at a density of 1 x ¹⁰⁵ cells/ ^cm2 and cultured for 21-28 days with media changes every 4-5 days.

Shipping Procedure . The TB and dosing solutions were pre-warmed to 37°C prior to shipping assays. Cell monolayers were washed twice with HBSS containing 10 mM HEPES. For the AB (apical to basal side) directional transport assay, 75 μL of dosing solution was added to the apical well. Each bottom side well was filled with 250 μLTB. For the BA (basal side to apical) directional transport assay, after filling each apical well with 75 μL of TB, 250 μL of dosing solution was added to the bottom side wells. Test compounds and digusin 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 at 2 μM in the A to B direction in the absence of zosuquidar. Incubate the plate at 37°C with 5% _CO2 and saturated humidity for 120 minutes. Time zero samples were prepared by mixing 50 μL of the initial dosing solution of the test or reference compound with 100 μL of TB and 250 μL of the quench solution (acetonitrile (ACN) or other appropriate solvent with internal standard, based on bioanalytical method development) to produce. At 120 minutes, 150 μL of solution was collected from each AB receptor well followed by the addition of 250 μL of quench solution to obtain an AB receptor sample. In addition, for the other samples (AB donor, BA donor and acceptor), 50 μL of the 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. Concentrations of test compounds in all samples were determined by LC-MS/MS and expressed as the peak area ratio of analyte to internal standard.

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

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

The effluent ratio was 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 apical-to-basal lateral directional transport, respectively value and the P _app value of the compound in the directional transport from the bottom side to the top.

III.2. 相較於血漿在腦及腦脊髓液中測定 A2A 拮抗劑之濃度 Results . Compounds were generally considered P-glycoprotein substrates when the effluent ratio had a value >3. Compounds of the invention typically have an effluent ratio >3, as demonstrated in Table 7 below. Table 7

III.2. Determination of A2A Antagonist Concentrations in Brain and Cerebrospinal Fluid Compared to Plasma

Objective . The current assay aims to show that the compounds of the present invention do not possess any significant CNS permeability by measuring the concentration of the compounds in the brain and cerebrospinal fluid (CSF) compared to plasma.

Method . 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 dosing. All animals were fed an approved rodent diet (Catalog # M01-F, SLAC Laboratory Animal Cl. Ltd., Shanghai, China) ad libitum 4 hours after dosing. Serial bleeding (approximately 30 μL of blood per time point) was performed from the submandibular or saphenous vein. These samples were transferred to pre-chilled microcentrifuge tubes containing 2 μL of K2EDTA (0.5 M) as anticoagulant and placed on wet ice for further processing. Intact brains were harvested immediately after blood collection at the design time points. At selected time points after dosing, CSF was collected from the large pool.

Within half an hour of collection, blood samples were processed to plasma by centrifugation at approximately 4°C, 3000 g for 15 min. Plasma samples were stored in polypropylene tubes, snap frozen on dry ice and kept at -70°C until LC/MS/MS analysis. Brain samples were weighed, washed in cold distilled water to remove blood, and homogenized at a 1:4 ratio (4 mL of water for 1 g of brain) using pre-cooled water. In addition, brain homogenates were kept 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, for compound 4 of the present invention, no measurable amounts were found in the brain or CSF of mice under these conditions.

III.3. 藉由移動運動檢定測定 CNS 活性 Individual and mean concentrations for Example 4 following PO administration (10 mg/kg) are provided in Table 8 below. Table 8

III.3. Determination of CNS activity by ambulatory movement assay

Objective . In addition to the immunosuppressive effects of adenosine, it is also well established that adenosine modulates neuronal function in the central nervous system through its interaction with A2AR. This interaction mediates the part of the dopamine pathway involved in movement. Prevention of this signaling in the brain by brain hyperpermeable A2AR antagonist compounds such as Preladenant (originally synthesized for the prevention of Parkinson's) has been shown to induce excessive locomotor movements in animals. This could potentially pose a problem for compounds intended for Parkinson's therapy, such as Prelandenant, ie repurposed for use in cancer immunotherapy.

The current assay aims to show that the compounds of the present invention do not possess any significant CNS activity by using the method published by Hodgson et al. (J. Pharma. And Exp. Thera. 2009). The rationale for this assay is that CGS21680, a brain-penetrating A2AR-specific adenosine analog, induces immobility (hypomobility) within minutes after subcutaneous (s.c.) injection in mice. Thus, mice treated with a brain-penetrating A2AR antagonist prior to treatment with CGS21680 will prevent hypolocomotion.

The reference brain-penetrating compound Preladenant was compared with the compounds of the invention for their effect on CGS21680-induced immobility at various per os (PO) concentrations.

Methods . Compounds were administered 30 min prior to CGS21680 and ambulatory motion was monitored over a 30 min period. Mice were scored for immobility using the scoring range described in Table 10 (Table 9).

* 在至少60-100%之小鼠中歷時30分鐘觀測到的記分，n = 3-5只小鼠/組表 10. 移動運動記分

Results . CGS21680 induced complete immobility after 30 min when administered alone at 1 mg/kg (sc). Preladenant inhibited CGS21680-induced immobilization when administered at 10 mg/kg PO, whereas the compounds of the invention failed to completely prevent immobilization when administered at equivalent doses. These data support PK data from brain and spinal fluid, demonstrating that compounds of the invention have reduced brain permeability and CNS activity compared to Preladenant. Table 9. Compounds of the Invention Have Reduced Brain Penetrant Activity

* Scores observed over 30 minutes in at least 60-100% of mice, n=3-5 mice/group Table 10. Locomotor scores

none

Figure 1 is a graph showing the percentage of released cytokines in peripheral blood lymphocytes as a function of the concentration of Compound 7 of the present invention in the presence of the A2a agonist CGS24680. Figure 1A is for whole blood cell cultures stimulated with LPS and Figure 1B is for whole blood cell cultures stimulated with anti-CD3/CD28.

Figure 2 is a graph showing the percent inhibition of pCREB in peripheral blood lymphocytes as a function of the concentration of Compound 4 of the present invention.

Figure 3 is a graph showing the percentage of cytotoxicity as a function of the concentration of compounds 4 and 31 of the present invention.

Domestic deposit information (please note in order of depositor, date, and number) None

Overseas storage information (please note in order of storage country, institution, date, number) None

Claims (22)

A compound of formula (I) or a pharmaceutically acceptable salt or hydrate thereof,

Wherein: R ¹ represents a furyl group; R ² represents a 6-membered aryl group or a 6-membered heteroaryl group, wherein the heteroaryl or aryl group is optionally substituted by one or more substituents selected from the group consisting of halo, alkane radical, heterocyclyl, alkoxy, cycloalkoxy, heterocyclyloxy, carbonyl, alkylcarbonyl, aminocarbonyl, hydroxycarbonyl, heterocyclylcarbonyl, alkylene, alkylsulfonyl, Aminosulfonyl group, heterocyclylsulfonyl group, alkylimino group, carbonylamino group, sulfonylamino group and alkylsulfonyl group; these substituents are optionally selected from the following Substituent substitution of each item: 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)amino, alkenylcarbonylamino, Hydroxycarbonyl, Alkoxycarbonyl, Aminocarbonyl, Aminoalkylaminocarbonyl, Alkylaminoalkylaminocarbonyl, Dialkylaminoalkylaminocarbonyl, Heterocyclylalkylaminocarbonyl, (Alkylaminoalkyl)(alkyl)aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylene , alkylidenealkyl, alkylsulfonyl and alkylidenealkyl; or heteroaryl or aryl are optionally substituted by two substituents which together form a 5 or 6 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, one or more substituents selected from the following Substitution: 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)amino, alkenylcarbonylamino, hydroxycarbonyl, alkoxy Alkylcarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, heterocyclylalkylaminocarbonyl, (alkylamino Alkyl)(alkyl)aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylidene, alkylidene Alkyl, alkylsulfonyl, and alkylsulfonyl. The compound as claimed in item 1 or a pharmaceutically acceptable salt or hydrate thereof, which has formula (Ia)

Or a pharmaceutically acceptable salt or hydrate 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' does not exist or when X ¹ is C, R ^1' represents H, halo, alkyl, heterocyclyl, alkoxy, cycloalkoxy, heterocyclyloxy, carbonyl, alkylcarbonyl, aminocarbonyl, Hydroxycarbonyl, heterocyclylcarbonyl, alkylene, alkylsulfonyl, aminosulfonyl, heterocyclylsulfonyl, alkylimino, carbonylamine, sulfonylamino, or alkyl These substituents are optionally substituted with one or more substituents selected from the group consisting of pendant oxy, halo, hydroxyl, cyano, alkyl, alkenyl, aldehyde, heterocyclylalkane hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl)(alkyl)amino Alkyl, heterocyclyl, heteroaryl, alkylheteroaryl, alkyne, alkoxy, amine, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, ( Aminocarbonylalkyl)(alkyl)amino, alkenylcarbonylamino, hydroxycarbonyl, alkoxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl, di Alkylaminoalkylaminocarbonyl, Heterocyclylalkylaminocarbonyl, (Alkylaminoalkyl)(Alkyl)aminocarbonyl, Alkylaminoalkylcarbonyl, Dialkylaminoalkyl Carbonyl, heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylene, alkylidene, alkylsulfonyl and alkylidene; R ^2' represents H, halo, alkyl , heterocyclyl, alkoxy, cycloalkoxy, heterocyclyloxy, carbonyl, alkylcarbonyl, aminocarbonyl, hydroxycarbonyl, heterocyclylcarbonyl, alkylene, alkylsulfonyl, amine Sulfonyl, heterocyclic sulfonyl, alkylimino, carbonylamino, sulfonylamino, or alkylsulfonyl; these substituents are optionally selected from the group consisting of one or more of the following Substituent substitution of each item: 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)amino, alkenylcarbonylamino, Hydroxycarbonyl, alkoxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, heterocyclylalkylaminocarbonyl, (Alkylaminoalkyl)(alkyl)aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylene , alkylidenealkylene, alkylsulfonyl and alkylidenealkyl; 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 hetero Aryl 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, Hydroxyalkyl, Dihydroxyalkyl, Hydroxyalkylaminoalkyl, Aminoalkyl, Alkylaminoalkyl, Dialkylamine ylalkyl, (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl, alkylheteroaryl, alkyne, alkoxy, amine, dialkylamino, amine Alkylcarbonylamino, Aminocarbonylalkylamino, (Aminocarbonylalkyl)(Alkyl)amino, Alkenylcarbonylamino, Hydroxycarbonyl, Alkoxycarbonyl, Aminocarbonyl, Aminoalkyl Aminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, heterocyclylalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl, Alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylene, alkylenealkylene, alkylsulfonyl and alkyl Aryl; when ^X is N, R ^3' is absent; or when X is C, R ^{3 '} represents H or halo; R ^4' represents H or halo; and R ^5' represents H or halo base. The compound as described in Claim 1 or Claim 2 or a pharmaceutically acceptable salt or hydrate thereof, which has the formula (Ia-1)

or a pharmaceutically acceptable salt or hydrate thereof, wherein R ¹ , R ^1' , R ^2' , R ^3' , R ^4' and R ⁵ ' are as defined in Claim 2. The compound as described in claim 3 or a pharmaceutically acceptable salt or hydrate thereof, which has the formula (Ia-1a)

or a pharmaceutically acceptable salt or hydrate thereof, wherein: R ¹ and R ^3' are as defined in claim 2; and R ^1" represents an alkyl or heterocyclic group, which is selected from one or more Substitution of the following groups: pendant oxy, halo, hydroxy, cyano, alkyl, alkenyl, aldehyde, heterocyclylalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl , aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl, alkylheteroaryl, alkyne Hydrocarbon, Alkoxy, Amino, Dialkylamino, Aminoalkylcarbonylamino, Aminocarbonylalkylamino, (Aminocarbonylalkyl)(Alkyl)amino, Alkenylcarbonylamino , hydroxycarbonyl, alkoxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, heterocyclylalkylaminocarbonyl , (alkylaminoalkyl) (alkyl)aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylene Alkyl, alkylenalkylene, alkylsulfonyl, and alkylalkyl. The compound as described in claim 3 or a pharmaceutically acceptable salt or hydrate thereof, which has the formula (Ia-1b)

or a pharmaceutically acceptable salt or hydrate thereof, wherein: R ¹ and R ^3' are as defined in claim 2; R ^1' represents H or halo; and R ^2" represents alkyl or heterocyclyl , which are substituted with one or more groups selected from the group consisting of pendant oxy, halo, hydroxy, cyano, alkyl, alkenyl, aldehyde, heterocyclylalkyl, hydroxyalkyl, dihydroxyalkane radical, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl group, alkylheteroaryl group, alkyne, alkoxy group, amino group, dialkylamino group, aminoalkylcarbonylamino group, aminocarbonylalkylamino group, (aminocarbonylalkyl)(alkyl )amino, alkenylcarbonylamino, hydroxycarbonyl, alkoxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl , Heterocyclylalkylaminocarbonyl, (Alkylaminoalkyl)(Alkyl)aminocarbonyl, Alkylaminoalkylcarbonyl, Dialkylaminoalkylcarbonyl, Heterocyclylcarbonyl, Alkenyl Carbonyl, alkynylcarbonyl, alkylidene, alkylidenealkyl, alkylsulfonyl and alkylidenealkyl. The compound as described in Claim 3 or a pharmaceutically acceptable salt or hydrate thereof, which has the formula (Ia-1c) or (Ia-1d)

or a pharmaceutically acceptable salt or hydrate thereof, wherein: R ¹ and R ^3' are as defined in Claim 2; R ^1' represents H or a halogen group; R ^2' represents H or a halogen group; R ¹ⁱ and R ⁱⁱ each independently represent hydrogen, hydroxy, alkyl, alkenyl, heterocyclylalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkane radical, dialkylaminoalkyl, (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl, alkylheteroaryl, alkynylalkyl, alkoxy, amino, di Alkylamino, Aminoalkylcarbonylamino, Aminocarbonylalkylamino, (Aminocarbonylalkyl)(Alkyl)amino, Alkenylcarbonylamino, Hydroxycarbonyl, Alkoxycarbonyl, Amine Alkylcarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, heterocyclylalkylaminocarbonyl, (alkylaminoalkyl)( Alkyl)aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylenylalkylene or alkylenylalkylene; And R ²ⁱ and R ²ⁱⁱ each independently represent hydrogen, hydroxyl, alkyl, alkenyl, heterocyclylalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkyl Aminoalkyl, Dialkylaminoalkyl, (Heterocyclyl)(Alkyl)aminoalkyl, Heterocyclyl, Heteroaryl, Alkylheteroaryl, Alkynyl, Alkoxy, Amine group, dialkylamino group, aminoalkylcarbonylamino group, aminocarbonylalkylamino group, (aminocarbonylalkyl)(alkyl)amine group, alkenylcarbonylamino group, hydroxycarbonyl group, alkoxy group Carbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, heterocyclylalkylaminocarbonyl, (alkylaminoalkane (alkyl)aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylenylalkylene or alkylenylcarbonyl alkyl. The compound as described in Claim 1 or Claim 2 or a pharmaceutically acceptable salt or hydrate thereof, which has formula (Ia-2) or (Ia-3)

or a pharmaceutically acceptable salt or hydrate thereof, wherein R ¹ , R ^2' , R ^3' , R ^4' and R ^5' are as defined in Claim 2. The compound or pharmaceutically acceptable salt or hydrate thereof as described in Claim 1, which is selected from the group consisting of: 3-(2-(4-(4-((1H-1,2 ,3-triazol-4-yl)methoxy-2fluorophenyl)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; 5-((4-(4-(2-(5-amino-8-( Furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl) Piperazin-1-yl)-3-fluorophenoxy)methyl)-1,3,4-oxadiazol-2(3H)-one; 5-amino-3-(2-(4-( 3-fluoropyridin-4-yl)piperazine-1- Base) ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one; 2-(5-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazole [1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-2,4-difluorophenoxy)acetamide; (S)-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; (R)-5-amino-3- (2-(4-(2-fluoro-4-(2-(methylsulfinyl)ethoxy)phenyl)-piperazin-1-yl)ethyl)-8-(furan-2- base)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one; (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]pyrimidin-2(3H)-one; (R)-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]pyrimidin-2(3H)-one; (S)-5-amino-3- (2-(4-(2,4-difluoro-5-(2-(methylsulfinyl)ethoxy)phenyl)piperazin-1-yl)ethyl base)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one; 5-amine Base-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]pyrimidin-2(3H)-one; 2-(4-(4-(2-(5-amino-8-(furan -2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piper oxazin-1-yl)phenoxy)acetic acid; 2-(4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4 -e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)phenoxy)acetamide; 5-amine Base-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; 5-amino-3-(2-(4-(4-(2 -Aminoethoxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[ 1,5-c]pyrimidin-2(3H)-one; 4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4 -e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)benzamide; 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)-N-methyl Benzamide; 5-amino-8-(furan-2-yl)-3-(2-(4-(4-(2-morpholinoethoxy)phenyl)piperazin-1-yl ) ethyl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one; 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; 4-(4-(2-(5-amino-8-(furan-2-yl) -2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl ) benzenesulfonamide; 4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4 ]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-N-methylbenzenesulfonamide; 5-amino-8-(furan- 2-yl)-3-(2-(4-(4-(methylsulfonyl)phenyl)piperazin-1-yl)ethyl)thiazolo[5,4-e][1,2, 4] Triazolo[1,5-c]pyrimidin-2(3H)-one; 5-amino-8-(furan-2-yl)-3-(2-(4-(4-(methyl Sulfinyl)phenyl)piperazin-1-yl)ethyl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidine-2(3H) -ketone; 3-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1 ,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)benzamide; 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] pyrimidin-2(3H)-one; 5-amino-3-(2-(4-(2-fluoro-4-(2-oxo-2-(piperazin-1-yl)ethoxy Base) 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-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; 5 -Amino-3-(2-(4-(2-fluoro-4-(piperazine-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; 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; 5-amino-3-(2-(4-(2-fluoro-4-(piper Azin-1-ylsulfonyl)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazole And[1,5-c]pyrimidine -2(3H)-one; 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; 4-(4-(2 -(5-Amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidine- 3(2H)-yl)ethyl)piperazin-1-yl)-N-(2-aminoethyl)-3-fluorobenzamide; 4-(4-(2-(5-amino -8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl ) ethyl)piperazin-1-yl)-3-fluoro-N-(2-(methylamino)ethyl)benzamide; 4-(4-(2-(5-amino-8 -(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl Base) piperazin-1-yl)-N-(2-(dimethylamino)ethyl)-3-fluorobenzamide; 4-(4-(2-(5-amino-8- (Furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl )piperazin-1-yl)-3-fluoro-N-(2-hydroxyethyl)benzamide; 4-(4-(2-(5-amino-8-(furan-2-yl) -2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl )-N-(2,3-dihydroxypropyl)-3-fluorobenzamide; 2-(4-(4-(2-(5-amino-8-(furan-2-yl)- 2-side Oxythiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3- fluorophenoxy)acetic acid; 2-(4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1 ,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3,5-difluorophenoxy)acetic acid; 2-( 4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1 ,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3-fluorophenoxy)propionic acid; (S)-2-(4-(4-(2- (5-Amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidine-3 (2H)-yl)ethyl)piperazin-1-yl)-3-fluorophenoxy)propionic acid; 2-(4-(4-(2-(5-amino-8-(furan-2 -yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazine- 1-yl)-3-fluorophenoxy)-2-methylpropionic acid; 3-(4-(4-(2-(5-amino-8-(furan-2-yl)-2-side Oxythiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3- fluorophenyl)propionic acid; 4-(4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1 ,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3-fluorophenoxy base) butanoic acid; 2-(3-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2 ,4] Triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-2,6-difluorophenoxy)acetic acid; 2-(5- (4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5 -c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-2,4-difluorophenoxy)acetic acid; 4-(4-(2-(5-amino-8 -(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl Base) piperazin-1-yl)-3-fluorobenzoic acid; 2-((2-(4-(4-(2-(5-amino-8-(furan-2-yl)-2-side Oxythiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3- fluorophenoxy)ethyl)amino)acetamide; 2-((2-(4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxo Basethiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3-fluoro Phenoxy)ethyl)(methyl)amino)acetamide; 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]pyrimidine-2 (3H)-one; 5-amino-3-(2-(4-(2-fluoro-4-(pyrrolidin-3-yloxy)phenyl)piperazin-1-yl)ethyl)- 8-(furan-2-yl)thia Azolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one; 3-(2-(4-(4-((1H- 1,2,4-triazol-3-yl)methoxy)-2-fluorophenyl)piperazin-1-yl)ethyl)-5-amino-8-(furan-2-yl)thiazole And[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one; 2-(4-(4-(2-(5-amino -8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl ) ethyl)piperazin-1-yl)-3-fluorophenoxy)-N-(2-(methylamino)ethyl)acetamide; 2-(4-(4-(2-( 5-Amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidine-3( 2H)-yl)ethyl)piperazin-1-yl)-3-fluorophenoxy)-N-(2-(dimethylamino)ethyl)acetamide; 2-(4-(4 -(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c ]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3-fluorophenoxy)-N-(2-aminoethyl)acetamide; (R)-2-( 4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1 ,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3-fluorophenoxy)propanoic acid; 2-(4-(4-(2-(5-amine Base-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidine-3(2H)- Base) ethyl) piperazin-1-yl) -3-fluorophenoxy) acetamide; 4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1 ,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3-fluoro-N-methyl-N-(2-(methylamino)ethyl)benzyl Amide; 4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[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- Toluamide; (R)-4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][ 1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-N-(1-(dimethylamino)propyl- 2-yl)-3-fluorobenzamide; 2-(4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5, 4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3-fluorophenoxy)-N -Methyl-N-(2-(methylamino)ethyl)acetamide; 2-(5-(4-(2-(5-amino-8-(furan-2-yl)-2 -Oxythiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)- 2,4-Difluorophenoxy)-2-methylpropanoic acid; (S)-2-(5-(4-(2-(5-amino-8-(furan-2-yl)-2 -Oxythiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)- 2,4-difluorophenoxy)propionic acid; (R)-2-(5-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazole And[5,4-e][1,2,4]triazolo [1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-2,4-difluorophenoxy)propionic acid; 2-(5-(4-(2 -(5-Amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidine- 3(2H)-yl)ethyl)piperazin-1-yl)-2,4-difluorophenoxy)-N-(2-(methylamino)ethyl)acetamide; 2-( 5-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1 ,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-2,4-difluorophenoxy)-N-(2-(dimethylamino)ethyl ) Acetamide; 5-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4] Triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-N-(2-(dimethylamino)ethyl)-2,4- Difluoro-N-methylbenzamide; 4-(5-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4 -e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-2,4-difluorophenoxy) Butyric acid; 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; 5 -Amino-3-(2-(4-(2-fluoro-4-((1-methyl-1H-1,2,4-triazol-3-yl)methoxy)phenyl)piperazine -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-((1-methyl-1H-1,2,4-triazole-3 -yl)methoxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[ 1,5-c]pyrimidin-2(3H)-one; 4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4 -e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3-fluoro-N-(2-( Methyl(oxo-3-yl)amino)ethyl)benzamide; 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-fluoro- N-(2-((2-hydroxyethyl)amino)ethyl)benzamide; 2-amino-N-(2-(4-(4-(2-(5-amino-8 -(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl Base) piperazin-1-yl)-3-fluorophenoxy) ethyl) acetamide; (S)-2-amino-N-(2-(4-(4-(2-(5- Amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidine-3(2H) -yl)ethyl)piperazin-1-yl)-3-fluorophenoxy)ethyl)-3-methylbutanamide; 2-(5-(4-(2-(5-amino- 8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c] Pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-2,4-difluorophenoxy)ethyl acetate; 2-(5-(4-(2-(5-amino -8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl ) ethyl)piperazin-1-yl)-2,4-difluorophenoxy)acetonitrile; 5-amino-8-(furan-2-yl)-3-(2-(4-(pyridine- 4-yl)piperazin-1-yl)ethyl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one; 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; 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; 5-amino-3-(2-(4-(2-fluoro-4-(2-(methylsulfonyl)ethyl) 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; 5-amino-3-(2-(4-(6-fluoro-2-oxoindoline-5-yl)piperazin-1-yl)ethyl base)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one; 5-amine Base-3-(2-(4-(2-fluoro-4-(S-methylimino)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl) thiophene Azolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one; 5-(4-(2-(5-amino-8 -(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl Base) piperazin-1-yl)-N-(2-(dimethylamino)ethyl)-2,4-difluorobenzamide; 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; 5-amino-3-(2-(4-(2-fluoro-4-(((3R,4R)-4- Hydroxytetrahydrofuran-3-yl)oxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]tri Azolo[1,5-c]pyrimidin-2(3H)-one; 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]pyrimidin-2(3H)-one; 5-amino-3-(2-(4-(2-fluoro-4-(2-hydroxy-2-methylpropoxy)benzene Base) piperazin-1-yl) ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidine- 2(3H)-keto; 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; 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; 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; 5-amino-3-(2-(4-(2,4-di Fluoro-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; 5-amino-3-(2-(4-(2,4-difluoro-5-(morpholine- 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; 5-amino-3-(2-(4-(2,4-difluoro-5-(((3S,4S)-4-fluoropyrrole Pyridin-3-yl)oxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazole And[1,5-c]pyrimidin-2(3H)-one; 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]pyrimidin-2(3H)-one; 5-amino-3-(2-(4-(2,4-difluoro-5-(((3R,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)- Ketone; 5-amino-3-(2-(4-(2,4-difluoro-5-(((3S,4R)-4-fluoropyrrolidin-3-yl)oxy)phenyl)piper Oxazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidine-2(3H )-ketone; (S)-5-amino-3-(2-(4-(2,4-difluoro-5-((2-oxopyrrolidin-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)-keto; (R)-5-amino-3-(2-(4-(2,4-difluoro-5-((2-oxopyrrolidin-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; 2-(5-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][ 1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-2,4-difluorophenoxy)-N-( 2-morpholinoethyl)acetamide; 5-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e] [1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-2,4-difluoro-N-(morpholine- 3-ylmethyl)benzamide; 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; 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; 5-amino-3-(2-(4-(2-fluoro-4-(( (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]pyrimidin-2(3H)-one; 5-amino-3-(2-(4-(2-fluoro-4-((( 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]pyrimidin-2(3H)-one; 5-amino-3-(2-(4-(2-fluoro-4-(((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]pyrimidin-2(3H)-one; 5-amino-3-(2-(4-(2-fluoro-4-(((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]pyrimidin-2(3H)-one; 2-(4-(4-(2-(5-amino-8-(furan-2-yl) -2-Oxythiazolo[5,4-e][1,2,4]triazolo[1,5-c] Pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3-fluorophenoxy)-N-(2-morpholinoethyl)acetamide; 4-(4-(2 -(5-Amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidine- 3(2H)-yl)ethyl)piperazin-1-yl)-3-fluoro-N-(2-morpholinoethyl)benzamide; 4-(4-(2-(5-amine Base-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidine-3(2H)- Base) ethyl)piperazin-1-yl)-3-fluoro-N-(morpholin-3-ylmethyl)benzamide; 5-amino-3-(2-(4-(4- (Azil-3-yloxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]tri Azolo[1,5-c]pyrimidin-2(3H)-one; (S)-5-amino-3-(2-(4-(2,4-difluoro-5-(methylsulfinic 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; (R)-5-amino-3-(2-(4-(2,4-difluoro-5-(methylsulfinyl)phenyl)piper Oxazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidine-2(3H )-ketone; 5-amino-3-(2-(4-(2,4-difluoro-5-(((1s,4s)-1-oxotetrahydro-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; 5-amino-3-(2-(4-(2,4-difluoro-5-(((1r,4r)-1-oxotetrahydro-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; (S)-5-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazole And[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-2,4-di Fluoro-N-(2-(methylsulfinyl)ethyl)benzamide; (R)-5-(4-(2-(5-amino-8-(furan-2-yl) -2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl )-2,4-difluoro-N-(2-(methylsulfinyl)ethyl)benzamide; (S)-5-(4-(2-(5-amino-8- (Furan-2-yl)-2-oxothiazolo[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-(methylsulfinyl)ethyl)benzamide; (R)-5-(4 -(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[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-(methylsulfinyl)ethyl)benzene Formamide; 5-amino-3-(2-(4-(2,4-difluoro-5-(1-oxothiomorpholine-4-carbonyl)phenyl)piperazin-1-yl ) ethyl) -8- (fur pyran-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one; 5-amino-3-(2 -(4-(2,4-Difluoro-5-(1-oxothiomorpholinyl)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo [5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one; (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; (S)-5-amino-3-(2-(4-(2-fluoro-4-(methyl Sulfinyl)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-amino-3-(2-(4-(2-fluoro-4-(((1s,4s)-1-oxotetrahydro-2H- Thipyran-4-yl)oxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]tri Azolo[1,5-c]pyrimidin-2(3H)-one; 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; (S)-4-(4-(2-(5-amino-8-(furan-2-yl) -2-Oxythiazolo[5,4-e][1,2,4]triazolo[1,5-c] Pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3-fluoro-N-(2-(methylsulfinyl)ethyl)benzamide; (R)-4 -(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1, 5-c] pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3-fluoro-N-(2-(methylsulfinyl)ethyl)benzamide; 5 -Amino-3-(2-(4-(2-fluoro-4-(1-oxothiomorpholine-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; 5-amino-3-(2 -(4-(2-fluoro-4-(1-oxothiomorpholinyl)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5, 4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one; (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; (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; (S)-5-(4-(2-(5-amino-8-(furan-2-yl)- 2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl) -N-(2,3-dihydroxypropyl)-2,4-difluorobenzamide; (R)-5-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]tri Azolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-N-(2,3-dihydroxypropyl)-2,4-difluorobenzyl Amide; 5-amino-3-(2-(4-(4-(acrazine-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; 5-amino-3-(2 -(4-(5-(Azines-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; (S)-5-amino-3-(2-(4-( 2,4-difluoro-5-(3-(methylsulfinyl)propoxy)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 pharmaceutically acceptable salts or hydrates thereof. The compound according to claim 1 or a pharmaceutically acceptable salt or hydrate thereof, wherein the compound is (+)-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]pyrimidin-2(3H)-one or a pharmaceutically acceptable salt or hydrate thereof. The compound as described in Claim 1 or a pharmaceutically acceptable salt or hydrate thereof, wherein the compound is (+)-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]pyrimidin-2(3H)-one or its pharmaceutically acceptable salt . The compound according to claim 1 or a pharmaceutically acceptable salt or hydrate thereof, wherein the compound is (+)-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]pyrimidin-2(3H)-one. The compound as described in Claim 1 or a pharmaceutically acceptable salt or hydrate thereof, wherein the compound is (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]pyrimidin-2(3H)-one or a pharmaceutically acceptable salt or hydrate thereof. The compound as described in Claim 1 or a pharmaceutically acceptable salt or hydrate thereof, wherein the compound is (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]pyrimidin-2(3H)-one or a pharmaceutically acceptable salt thereof. The compound as described in Claim 1 or its pharmaceutically acceptable Accepted salt or hydrate, wherein the compound is (S)-5-amino-3-(2-(4-(2,4-difluoro-5-(2-(methylsulfinyl)ethyl) 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. The compound as described in claim 1 or a pharmaceutically acceptable salt or hydrate thereof, wherein the compound is (R)-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]pyrimidin-2(3H)-one or a pharmaceutically acceptable salt thereof. The compound according to claim 1 or a pharmaceutically acceptable salt or hydrate thereof, wherein the compound is ( R , S )-5-amino-3-(2-(4-(2,4-di Fluoro-5-(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 or a pharmaceutically acceptable salt thereof. A pharmaceutical composition, which comprises the compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt or hydrate thereof, and at least one pharmaceutically acceptable carrier. A medicament comprising the compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt or hydrate thereof. A use of a compound as described in any one of Claims 1 to 16 or a pharmaceutically acceptable salt or hydrate thereof in the manufacture of a medicament for treating cancer. Use as described in claim 19, wherein the cancer is selected from breast cancer, carcinoid tumor, cervical cancer, colorectal cancer, endometrial cancer, glioma, head and neck cancer, liver cancer, lung cancer, melanoma, Ovarian cancer, pancreatic cancer, prostate cancer, kidney cancer, gastric cancer, thyroid cancer and urothelial cell carcinoma. A use of a compound as described in any one of Claims 1 to 16 or a pharmaceutically acceptable salt or hydrate thereof in the manufacture of a medicament for use as an A2A inhibitor. A method for producing a compound of formula (Ia) as described in claims 2 to 16 or a pharmaceutically acceptable salt or hydrate thereof, characterized in that the method comprises the following steps: in the middle of the amine of formula (A) thing

Wherein X ¹ , X ² , R ^1' , R ^2' , R ^3' , R ^4' and R ^5' are as defined in claim item 2; coupled with intermediates of formula (B) and

wherein R is as defined in claim ² and Y represents halo, an alkylsulfonyloxy group having 1 to 6 carbon atoms or an arylsulfonyloxy group having 6 to 10 carbon atoms.

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