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WO2018178338A1 - Dérivés de 2-oxo-thiazole en tant qu'inhibiteurs de a2a et composés destinés à être utilisés dans le traitement de cancers - Google Patents

Dérivés de 2-oxo-thiazole en tant qu'inhibiteurs de a2a et composés destinés à être utilisés dans le traitement de cancers Download PDF

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Publication number
WO2018178338A1
WO2018178338A1 PCT/EP2018/058301 EP2018058301W WO2018178338A1 WO 2018178338 A1 WO2018178338 A1 WO 2018178338A1 EP 2018058301 W EP2018058301 W EP 2018058301W WO 2018178338 A1 WO2018178338 A1 WO 2018178338A1
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WIPO (PCT)
Prior art keywords
amino
ethyl
piperazin
triazolo
pyrimidin
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PCT/EP2018/058301
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English (en)
Inventor
Stefano Crosignani
Bruno GOMES
Erica HOUTHUYS
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Iteos Belgium SA
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Iteos Therapeutics SA
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Priority claimed from ARP180100778A external-priority patent/AR111200A1/es
Priority to HRP20221039TT priority Critical patent/HRP20221039T1/hr
Priority to BR112019020421A priority patent/BR112019020421A8/pt
Priority to IL300149A priority patent/IL300149A/en
Priority to AU2018246355A priority patent/AU2018246355B2/en
Priority to ES18716193T priority patent/ES2926158T3/es
Priority to LTEPPCT/EP2018/058301T priority patent/LT3601296T/lt
Priority to CA3058260A priority patent/CA3058260A1/fr
Priority to JP2020503355A priority patent/JP7197558B2/ja
Priority to KR1020197031322A priority patent/KR102640927B1/ko
Priority to RU2019134724A priority patent/RU2822758C2/ru
Priority to PL18716193.0T priority patent/PL3601296T3/pl
Priority to EP18716193.0A priority patent/EP3601296B1/fr
Priority to MX2019011743A priority patent/MX393711B/es
Application filed by Iteos Therapeutics SA filed Critical Iteos Therapeutics SA
Priority to EP22165965.9A priority patent/EP4112623A1/fr
Priority to RS20220794A priority patent/RS63557B1/sr
Priority to CN201880034926.9A priority patent/CN110678472B/zh
Priority to CN202211658370.5A priority patent/CN115991679A/zh
Priority to CN202211706953.0A priority patent/CN115873022A/zh
Priority to DK18716193.0T priority patent/DK3601296T3/da
Priority to SI201830747T priority patent/SI3601296T1/sl
Priority to KR1020247005971A priority patent/KR20240027885A/ko
Publication of WO2018178338A1 publication Critical patent/WO2018178338A1/fr
Priority to US16/354,022 priority patent/US10995101B2/en
Priority to IL269710A priority patent/IL269710B2/en
Anticipated expiration legal-status Critical
Priority to US16/993,897 priority patent/US20210198281A1/en
Priority to US17/949,595 priority patent/US20230159564A1/en
Priority to JP2022199962A priority patent/JP2023027282A/ja
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D497/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having oxygen and sulfur atoms as the only ring hetero atoms
    • C07D497/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having oxygen and sulfur atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D497/14—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to novel thiocarbamate derivatives, including pharmaceutically acceptable salts and solvates thereof.
  • Compounds of the invention are inhibitors of adenosine A2A receptor and are useful as therapeutic compounds, particularly in the treatment and/or prevention of cancers.
  • CTLA-4 is a physiological mechanism that negatively regulates T cell activity by blocking a costimulatory signal through CD28-B7 interaction.
  • CTLA4 causes non-specific T cell activation, and CTLA-4- deficient mice die in several weeks with massive lymphocytic tissue infiltration.
  • PD-1 also provides a T cell inhibitory signal upon interaction with its ligands, PD-L1 and PD-L2. Deficiency of PD-1 in mice is known to cause various types of autoimmune disorders depending on the genetic strains.
  • immunosuppression in the tumor microenvironment involves anti-inflammatory cytokines (IL-10, TGF- ⁇ ), enzymes (indoleamine-2,3-dioxygenase), and professional immunoregulatory cells (regulatory T cells, myeloid-derived suppressor cells MDSCs).
  • cytokines IL-10, TGF- ⁇
  • enzymes indoleamine-2,3-dioxygenase
  • professional immunoregulatory cells regulatory T cells, myeloid-derived suppressor cells MDSCs.
  • Extracellular adenosine has been known as an inhibitor of immune functions. While intracellular adenosine is involved in energy metabolism, nucleic acid metabolism, and the methionine cycle, extracellular adenosine plays an important role in intercellular signaling. Its signal is transmitted by G protein-coupled adenosine receptors on the cell surface, and it affects diverse physiological functions including neurological, cardiovascular, and immunological systems.
  • Tumors contain high levels of extracellular adenosine, suggesting that tumor cells may benefit from its immunosuppressive effect and catabolic energy production (Allard et al, Curr. Opin. Pharmacol, 2016, 29, 7-16; Otta A., Frontiers in Immunology, 2016, 7: 109).
  • This high level of extracellular adenosine is probably due to overexpression of the enzyme CD73, which is responsible for production of extracellular adenosine.
  • CD73 is overexpressed by a large number of tumors, with all the following tumors expresign medium or high levels of CD73 in >50% of tumor surface by immunohistochemistry (www.proteinatlas.org): Breast, Carcinoid, Cervical, Colorectal, Endometrial, Glioma, Head and Neck, Liver, Lung, Melanoma, Ovarian, Pancreatic, Prostate, Renal, Gastric, Thyroid, Urothelial.
  • A2A adenosine receptor is the predominantly expressed subtype in most immune cells. Stimulation of A2AR generally provides an immunosuppressive signal that inhibits activities of T cells (proliferation, cytokine production, cytotoxicity), NK cells (cytotoxicity), NKT cells (cytokine production, CD40L upregulation), macrophages/dendritic cells (antigen presentation, cytokine production), and neutrophils (oxidative burst).
  • T cells proliferation, cytokine production, cytotoxicity
  • NK cells cytotoxicity
  • NKT cells cytokine production, CD40L upregulation
  • macrophages/dendritic cells antagonistigen presentation, cytokine production
  • neutrophils oxidative burst
  • A2A -deficient mice could spontaneously regress the inoculated tumor, whereas no wild-type mice showed similar tumor regression.
  • A2A antagonists were also beneficial in tumor-bearing wild-type animals.
  • depletion of T cells and NK cells impaired the retardation of tumor growth by A2A antagonists, suggesting improvement of antitumor cellular immune response.
  • Effector functions of T cells and NK cells are susceptible to A2AR stimulation.
  • the effector function of T cells is persistently impaired even after removal of A2AR agonist. This result suggests that the adenosine-rich environment in tumors may induce T cells that are anergic to the tumor cells.
  • A2A receptor is expressed in most immune cells and particularly effector immune cells such as T cells and NK cells and given that A2A receptor is engaged in tissues where adenosine is produced, it is thought that A2A inhibitors can be helpful in all the cancer indications.
  • Adenosine is known to be an endogenous modulator of a number of other physiological functions. For example, at the central nervous system (CNS) level, adenosine in known to induce sedative, anxiolotic and antiepileptic effects level.
  • CNS central nervous system
  • A2A inhibitors were previously developed for the treatment of depression and neurodegenerative diseases such as Parkinson's disease or Alzheimer's disease (Pinna A., CNS Drugs, 2014, 28, 455).
  • One of the most advanced A2A inhibitors developed 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).
  • A2A inhibitors were designed to cross the blood brain barrier, in order to target A2A receptor in the CNS. Given the higher level of adenosine in tumors when compared to the brain, much higher amounts of compounds will be needed to achieve the desired effect on immune functions restoration for treating cancers. Thus, in order to avoid deleterious side effects, one should provide A2A inhibitors which have a limited, if any, CNS penetrance, contrary to all previously developed A2A inhibitors.
  • the Applicant hereby provides new A2A inhibitors which do not have any significant CNS penetrance, and which may thus be useful in the treatment of cancers.
  • This invention thus relates to a compound of Formula (I)
  • compounds of Formula (I) areof Formula (la)
  • R 1 , R 1 , R 2 , R 3 , R 4' and R 5' are as defined below.
  • compounds of Formula (la) are of Formula (Ia-1)
  • R 1 , R 1 , R 2 , R 3 , R 4' and R 5' are as defined in Formula (la).
  • compounds of Formula (la) are of Formulae (Ia-2) or (la- 3)
  • R 1 , R 2 , R 3 , R 4' and R 5' are as defined in Formula (la).
  • the invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound according to the invention, or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable carrier.
  • the invention further relates to a medicament comprising a compound according to the invention, or a pharmaceutically acceptable salt or solvate thereof.
  • the invention also provides a compound according to the invention or a pharmaceutically acceptable salt or solvate thereof for use in the treatment and/or prevention of cancer.
  • the invention further relates to a compound according to the invention or a pharmaceutically acceptable salt or solvate thereof for use as A2A inhibitor.
  • R 1 is as defined below and Y represents halo, alkylsulfonyloxy having
  • the invention also relates to intermediates of synthesis of Formula (A).
  • aldehyde refers to a group -CHO.
  • aldehydealkyl refers to a group -alkyl-CHO wherein alkyl is as herein defined.
  • alkenyl refers to unsaturated hydrocarbyl group, which may be linear or branched, comprising one or more carbon-carbon double bonds. Suitable alkenyl groups comprise between 2 and 6 carbon atoms, preferably between 2 and 4 carbon atoms, still more preferably between 2 and 3 carbon atoms. Examples of alkenyl groups are ethenyl, 2- propenyl, 2-butenyl, 3-butenyl, 2-pentenyl and its isomers, 2-hexenyl and its isomers, 2,4- pentadienyl and the like.
  • alkoxy refers to a group -O-alkyl wherein alkyl is as herein defined.
  • alkyl refers to a hydrocarbyl radical of formula C n H 2n +i wherein n is a number greater than or equal to 1.
  • alkyl groups of this invention comprise from 1 to 8 carbon atoms, more preferably, alkyl groups of this invention comprise from 1 to 6 carbon atoms.
  • Alkyl groups may be linear or branched. Suitable alkyl groups include methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl and octyl.
  • alkylaminoalkyl refers to a group -alkyl-NH-alkyl wherein alkyl is as herein defined.
  • alkylheteroaryl refers to any heteroaryl substituted by an alkyl group wherein alkyl is as herein defined.
  • alkylsulfonyl refers to a group -SC -alkyl wherein alkyl is as herein defined.
  • alkylsulfonealkyl refers to a group -alkyl-SC -alkyl wherein alkyl is as herein defined.
  • alkylsulfoxidealkyl refers to a group -alkyl-SO-alkyl wherein alkyl is as herein defined.
  • alkyne refers to a class of monovalent unsaturated hydrocarbyl groups, wherein the unsaturation arises 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 in relation to alkyl groups.
  • Non-limiting examples of alkynyl groups are ethynyl, 2- propynyl, 2-butynyl, 3-butynyl, 2-pentynyl and its isomers, 2-hexynyl and its isomers-and the like.
  • alkynealkyl refers to a group -alkyl-alkyne wherein alkyl and alkyne are as herein defined.
  • amino refers to a group -NH 2 .
  • aminoalkyl refers to a group -alkyl-NH 2 wherein alkyl is as herein defined.
  • aminosulfonyl refers to a group -S0 2 -NH 2 .
  • aryl refers to a polyunsaturated, aromatic hydrocarbyl group having a single ring (i.e. phenyl) or multiple aromatic rings fused together (e.g. naphtyl), typically containing 5 to 12 atoms; preferably 5 to 10; more preferably the aryl is a 5- or 6-membered aryl.
  • Non- limiting examples of aryl comprise phenyl, naphthalenyl.
  • cycloalkyl refers to a cyclic alkyl group, that is to say, a monovalent, saturated, or unsaturated hydrocarbyl group having 1 or 2 cyclic structures.
  • Cycloalkyl includes monocyclic or bicyclic hydrocarbyl groups. Cycloalkyl groups may comprise 3 or more carbon atoms in the ring and generally, according to this invention comprise from 3 to 10, more preferably from 3 to 8 carbon atoms; still more preferably more preferably the cycloalkyl is a 5- or 6-membered cycloalkyl. Examples of cycloalkyl groups include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.
  • cycloalkyloxy refers to a group -O-cycloalkyl wherein cycloalkyl is as herein defined.
  • dialkylamino refers to a group -NR'R 2 wherein R 1 and R 2 are both independently alkyl group as herein defined.
  • dialkylaminoalkyl refers to a group -alkyl-NR'R 2 wherein R 1 and R 2 are both independently alkyl group, as herein defined.
  • dihydrox alkyl refers to a group alkyl is as herein defined substituted by two hydroxyl (-OH) groups.
  • halo or halogen refers to fluoro, chloro, bromo, or iodo.
  • heteroaryl refers to an aryl group as herein defined wherein at least one carbon atom is replaced with a heteroatom. In other words, it refers to 5 to 12 carbon-atom aromatic single rings or ring systems containing 2 rings which are fused together, typically containing 5 to 6 atoms; in which one or more carbon atoms is replaced by oxygen, nitrogen and/or sulfur atoms where the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatoms may optionally be quatemized.
  • Non-limiting examples of such heteroaryl include: oxazolyl, thiazolyl, imidazolyl, furanyl and pyrrolyl.
  • the heteroaryl is a 5- or 6-membered heteroaryl, more preferably the 5- or 6-membered heteroaryl is a furyl.
  • heterocyclyl refers to non-aromatic, fully saturated or partially unsaturated cyclic groups (for example, 3 to 7 member monocyclic, 7 to 11 member bicyclic, or containing a total of 3 to 10 ring atoms) which have at least one heteroatom in at least one carbon atom-containing ring.
  • the heretocyclyl is a 5- or 6-membered heretocyclyl.
  • Each ring of the heterocyclic group containing a heteroatom may have 1, 2, 3 or 4 heteroatoms selected from nitrogen atoms, oxygen atoms and/or sulfur atoms, where the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatoms may optionally be quatemized.
  • the heterocyclic group may be attached at any heteroatom or carbon atom of the ring or ring system, where valence allows.
  • the rings of multi-ring heterocycles may be fused, bridged and/or joined through one or more spiro atoms.
  • Non limiting exemplary heterocyclic groups include aziridinyl, oxiranyl, thiiranyl, piperidinyl, azetidinyl, 2-imidazolinyl, pyrazolidinyl imidazolidinyl, isoxazolinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, piperidinyl, succinimidyl, 3H- indolyl, indolinyl, isoindolinyl, 2H-pyrrolyl, 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolidinyl, 4H-
  • (heterocyclyl)(alkyl)aminoalkyl refers to a group -alkyl-NR'R 2 wherein R 1 is an alkyl group and R 2 is an heterocyclyl group, wherein alkyl and heterocyclyl are as herein defined.
  • heterocyclylalkyl refers to a group -alkyl-heterocyclyl wherein alkyl and heterocyclyl are as herein defined.
  • heterocyclyloxy to a group -O-heterocyclyl wherein heterocyclyl is as herein defined.
  • heterocyclylsulfonyl refers to a group - SC -heterocyclyl wherein heterocyclyl is as herein defined.
  • hydrox alkyl refers to a group -alkyl-OH wherein alkyl is as herein defined.
  • hydroxyalkylaminoalkyl refers to a group -alkyl-NH-alkyl-OH wherein alkyl is as herein defined.
  • sulfonylamino refers to a group -NH-SO2.
  • administration means providing the active agent or active ingredient (e.g. a A2A inhibitor), alone or as part of a pharmaceutically acceptable composition, to the patient in whom/which the condition, symptom, or disease is to be treated or prevented.
  • active agent or active ingredient e.g. a A2A inhibitor
  • IC50 or “half maximal inhibitory concentration” represent the concentration of an inhibitor that is required for 50% inhibition in vitro.
  • 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 a protein or that has a biological effect to inhibit or significantly reduce the biological activity of a protein. Consequently, an "A2A inhibitor” refers to a compound that has a biological effect to inhibit or significantly reduce or down-regulate the biological activity of A2A receptor.
  • human refers to a subject of both genders and at any stage of development (i.e. neonate, infant, juvenile, adolescent, adult).
  • patient refers to a warm-blooded animal, more preferably a human, who/which is awaiting the receipt of, or is receiving medical care or is/will be the object of a medical procedure.
  • pharmaceutically acceptable refers to the ingredients of a pharmaceutical composition are compatible with each other and not deleterious to the subject to which it is administered.
  • pharmaceutically acceptable carrier refers to an excipient that does not produce an adverse, allergic or other untoward reaction when administered to an animal, preferably a human. It includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like.
  • preparations should meet sterility, pyrogenicity, general safety and purity standards as required by regulatory offices, such as, e.g., FDA Office or EMA.
  • predrug means any compound that will be modified to form a drug species, wherein the modification may take place either inside or outside of the body, and either before or after the predrug reaches the area of the body where administration of the drug is indicated.
  • prevent refers to a method of delaying or precluding the onset of a condition or disease and/or its attendant symptoms, barring a patient from acquiring a condition or disease, or reducing a patient's risk of acquiring a condition or disease.
  • prodrug as used herein means the pharmacologically acceptable derivatives of compounds of Formula I, such as for example esters or amides, whose in vivo biotransformation product generates the biologically active drug. Prodrugs are generally characterized by increased bio-availability and are readily metabolized into biologically active compounds in vivo.
  • treating refers to both therapeutic treatment and prophylactic or preventative measures; wherein the object is to prevent or slow down the targeted pathologic 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 whom the disease is to be prevented.
  • a subject or mammal is successfully "treated” for a disease or affection or condition if, after receiving the treatment according to the present invention, the subject or mammal shows observable and/or measurable reduction in or absence of one or more of the following: reduction of tumors; and/or relief to some extent, for one or more of the symptoms associated with the specific disease or condition; reduced morbidity and mortality, and improvement in quality of life issues.
  • volumer refers to an animal, including a human.
  • a subject may be a patient, i.e., a person receiving medical attention, undergoing or having underwent a medical treatment, or monitored for the development of a disease.
  • the subject is a male. In another embodiment, the subject is a female.
  • This invention relates to com ounds of Formula I
  • R 1 represents 5- or 6-membered heteroaryl or 5- or 6-membered aryl, wherein heteroaryl or aryl groups are optionally substituted by one or more substituent selected from 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 6-membered aryl or 6-membered heteroaryl, wherein heteroaryl or aryl groups are optionally substituted by one or more substituent selected from halo, alkyl, heterocyclyl, alkoxy, cycloalkyloxy, heterocyclyloxy, carbonyl, alkylcarbonyl, aminocarbonyl, hydroxycarbonyl, heterocyclylcarbonyl, alkylsulfoxide, alkylsulfonyl, aminosulfonyl, heterocyclylsulfonyl, alkylsulfonimidoyl, carbonylamino, sulfonylamino and alkylsulfonealkyl; said substituents being optionally substituted by one or more substituent selected from oxo, halo, hydroxy, cyano, alkyl, alkenyl, aldehyde, heterocyclylalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylamin
  • heterocyclyl (alkyl)aminoalkyl, heterocyclyl, heteroaryl, alkylheteroaryl, alkyne, alkoxy, amino, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, (aminocarbonylalkyl)(alkyl)amino, alkenylcarbonylamino, hydroxycarbonyl, alkyloxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, heterocyclylalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)amino carbonyl, alkylamino alkylcarbony 1, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylsulfoxide, alky
  • heterocyclyl (alkyl)aminoalkyl, heterocyclyl, heteroaryl, alkylheteroaryl, alkyne, alkoxy, amino, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, (aminocarbonylalkyl)(alkyl)amino, alkenylcarbonylamino, hydroxycarbonyl, alkyloxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, heterocyclylalkylaminocarbonyl, (alkyl aminoalkyl)(alkyl)amino carbonyl, alkylamino alkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylalkylaminocarbonyl, (alkyl aminoalkyl)(alkyl)amino carbonyl, alkylamin
  • R 1 represents 5- or 6-membered heteroaryl or 5- or 6-membered aryl, wherein heteroaryl or aryl groups are optionally substituted by one or more substituent selected from 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 6-membered aryl or 6-membered heteroaryl, wherein heteroaryl or aryl groups are optionally substituted by one or more substituent selected from halo, alkyl, heterocyclyl, alkoxy, cycloalkyloxy, heterocyclyloxy, carbonyl, alkylcarbonyl, aminocarbonyl, hydroxycarbonyl, heterocyclylcarbonyl, alkylsulfoxide, alkylsulfonyl, aminosulfonyl, heterocyclylsulfonyl, carbonylamino,sulfonylamino and alkylsulfonealkyl; said substituents being optionally substituted by one or more substituent selected from hydroxy, cyano, alkyl, alkenyl, aldehyde, hydroxyalkyl, hydroxyalkylaminoalkyl, amino alkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl)(
  • R 1 represents 5- or 6-membered heteroaryl or 5- or 6-membered aryl, wherein heteroaryl or aryl groups are optionally substituted by one or more substituent selected from 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 6-membered aryl or 6-membered heteroaryl, wherein heteroaryl or aryl groups are optionally substituted by one or more substituent selected from halo, alkyl, heterocyclyl, alkoxy, cycloalkyloxy, heterocyclyloxy, carbonyl, alkylcarbonyl, aminocarbonyl, hydroxycarbonyl, heterocyclylcarbonyl, alkylsulfoxide, alkylsulfonyl, aminosulfonyl, heterocyclylsulfonyl, carbonylamino and sulfonylamino; said substituents being optionally substituted by one or more substituent selected from hydroxy, cyano, alkyl, alkenyl, aldehyde, hydroxyalkyl, hydroxyalkylaminoalkyl, amino alkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl)(alkyl)aminoalkyl
  • this invention relates to compounds of Formula (la):
  • R 1 represents 5- or 6-membered heteroaryl or 5- or 6-membered aryl, wherein heteroaryl or aryl groups are optionally substituted by one or more substituent selected from 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 represent each independently C or N; R 1' is absent when X 1 is N; or when X 1 is C, R 1' represents H, halo, alkyl, heterocyclyl, alkoxy, cycloalkyloxy, heterocyclyloxy, carbonyl, alkylcarbonyl, aminocarbonyl, hydroxycarbonyl, heterocyclylcarbonyl, alkylsulfoxide, alkylsulfonyl, aminosulfonyl, heterocyclylsulfonyl, alkylsulfonimidoyl, carbonylamino, sulfonylamino or alkylsulfonealkyl; said substituents being optionally substituted by one or more substituent selected from oxo, halo, hydroxy, cyano, alkyl, alkenyl, aldehyde, heterocyclylalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoal
  • heterocyclyl (alkyl)aminoalkyl, heterocyclyl, heteroaryl, alkylheteroaryl, alkyne, alkoxy, amino, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, (aminocarbonylalkyl)(alkyl)amino, alkenylcarbonylamino, hydroxycarbonyl, alkyloxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, heterocyclylalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)amino carbonyl, alkylamino alkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylsulfoxide, al
  • R 2' represents H, halo, alkyl, heterocyclyl, alkoxy, cycloalkyloxy, heterocyclyloxy, carbonyl, alkylcarbonyl, aminocarbonyl, hydroxycarbonyl, heterocyclylcarbonyl, alkylsulfoxide, alkylsulfonyl, aminosulfonyl, heterocyclylsulfonyl, alkylsulfonimidoyl, carbonylamino, sulfonylamino, or alkylsulfonealkyl; said substituents being optionally substituted by one or more substituent selected from oxo, 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, alkyloxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, heterocyclylalkylaminocarbonyl, (alkylaminoalky l)(alkyl)amino carbonyl, alkylamino alkylcarbony 1, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylsulfoxide, al
  • R 3' is absent when X 2 is N; or when X 2 is C, R 3' represents H or halo, preferably H or F;
  • R 4' represents H or halo, preferably H or F
  • R 5' represents H or halo, preferably H or F.
  • R 1 represents 5- or 6-membered heteroaryl or 5- or 6-membered aryl, wherein heteroaryl or aryl groups are optionally substituted by one or more substituent selected from 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 represent each independently C or N;
  • R 1' is absent when X 1 is N; or when X 1 is C, R 1' represents H, halo, alkyl, alkoxy, heterocyclyloxy, alkylcarbonyl, carbonyl, aminocarbonyl, hydroxycarbonyl, heterocyclyl, heterocyclylcarbonyl, alkylsulfoxide, alkylsulfonyl, aminosulfonyl or heterocyclylsulfonyl; said substituents being optionally substituted by one or more substituent selected from hydroxy, cyano, alkyl, hydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl,
  • heterocyclyl (alkyl)aminoalkyl, heterocyclyl, heteroaryl, alkylheteroaryl, alkyne, alkoxy, amino, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, (aminocarbonylalkyl)(alkyl)amino, hydroxycarbonyl, alkyloxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl, alkylaminoalkylcarbonyl, dialkylamino alkylcarbonyl, heterocyclylcarbonyl, alkylsulfoxide, alkylsulfoxidealkyl, alkylsulfonealkyl;
  • R 2' represents H, alkoxy, cycloalkyloxy, heterocyclyloxy, alkylsulfoxide, carbonyl, carbonylamino, aminocarbonyl or sulfonylamino; wherein alkoxy, cycloalkyloxy, heterocyclyloxy, alkylsulfoxide, carbonyl, carbonylamino, aminocarbonyl or sulfonylamino are optionally substituted by one or more substituent selected from hydroxy, cyano, alkyl, alkenyl, aldehyde, hydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl, alkylheteroaryl, alkyne, alkoxy, amino, dialkylamino, aminoalkylcarbonylamino, aminocarbonylal
  • R 1' and R 2' form together with the atoms to which they are attached a 5- or 6- membered aryl ring, a 5- or 6-membered heretoaryl ring, a 5- or 6-membered cycloalkyl ring, a 5-
  • R 3' is absent when X 2 is N; or when X 2 is C, R 3' represents H or halo, preferably H or F;
  • R 4' represents H or halo, preferably H or F
  • R 5' represents H or halo, preferably H or F.
  • R 1 represents 5- or 6-membered heteroaryl or 5- or 6-membered aryl, wherein heteroaryl or aryl groups are optionally substituted by one or more substituent selected from 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 represent each independently C or N;
  • R 1' is absent when X 1 is N; or when X 1 is C, R 1' represents H, halo, alkyl, alkoxy, heterocyclyloxy, alkylcarbonyl, carbonyl, aminocarbonyl, hydroxycarbonyl, heterocyclyl, heterocyclylcarbonyl, alkylsulfoxide, alkylsulfonyl, aminosulfonyl or heterocyclylsulfonyl; said substituents being optionally substituted by one or more substituent selected from hydroxy, cyano, alkyl, hydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl,
  • heterocyclyl (alkyl)aminoalkyl, heterocyclyl, heteroaryl, alkylheteroaryl, alkyne, alkoxy, amino, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, (aminocarbonylalkyl)(alkyl)amino, hydroxycarbonyl, alkyloxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl, alkylaminoalkylcarbonyl, dialkylamino alkylcarbonyl, heterocyclylcarbonyl, alky lsulfo xide , alky lsulfo xidealky 1;
  • R 2' represents H, alkoxy, cycloalkyloxy, heterocyclyloxy, alkylsulfoxide, carbonyl, carbonylamino, aminocarbonyl or sulfonylamino; wherein alkoxy, cycloalkyloxy, heterocyclyloxy, alkylsulfoxide, carbonyl, carbonylamino, aminocarbonyl or sulfonylamino are optionally substituted by one or more substituent selected from hydroxy, cyano, alkyl, alkenyl, aldehyde, hydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl, alkylheteroaryl, alkyne, alkoxy, amino, dialkylamino, aminoalkylcarbonylamino, aminocarbonylal
  • R 1' and R 2' form together with the atoms to which they are attached a 5- or 6- membered aryl ring, a 5- or 6-membered heretoaryl ring, a 5- or 6-membered cycloalkyl ring, a 5- or 6-membered heretocyclyl
  • R 3 is absent when X 2 is N; or when X 2 is C, R 3' represents H or halo, preferably H or F;
  • R 4' represents H or halo, preferably H or F; and R 5' represents H or halo, preferably H or F.
  • R 1 represents 5- or 6-membered heteroaryl or 5- or 6-membered aryl, wherein heteroaryl or aryl groups are optionally substituted by one or more substituent selected from C1-C6 alkyl (preferably methyl) and halo (preferably fluoro or chloro).
  • R 1 represents 5-membered heteroaryl; more preferably, R 1 represents furyl.
  • X 1 and X 2 represent each independently C or N. In another specific embodiment, X 1 and X 2 both represent C.
  • R 1' is absent when X 1 is N.
  • R 1' represents H, halo, alkyl, heterocyclyl, alkoxy, cycloalkyloxy, heterocyclyloxy, carbonyl, alkylcarbonyl, aminocarbonyl, hydroxycarbonyl, heterocyclylcarbonyl, alkylsulfoxide, alkylsulfonyl, aminosulfonyl, heterocyclylsulfonyl, alkylsulfonimidoyl, carbonylamino, sulfonylamino or alkylsulfonealkyl; said substituents being optionally substituted by one or more substituent selected from oxo, halo, hydroxy, cyano, alkyl, alkenyl, aldehyde, heterocyclylalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoal
  • R 1' represents H, halo, alkyl, alkoxy, heterocyclyloxy, alkylcarbonyl, carbonyl, aminocarbonyl, hydroxycarbonyl, heterocyclyl heterocyclylcarbonyl, alkylsulfoxide, alkylsulfonyl, aminosulfonyl or heterocyclylsulfonyl; said substituents being optionally substituted by one or more substituent selected from hydroxy, cyano, alkyl, hydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl, alkylheteroaryl, alkyne, alkoxy, amino, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, (amino
  • R 1' substituents are optionally substituted by one or more substituent selected from halo, hydroxy, alkyl, heterocyclylalkyl, hydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl, alkylheteroaryl, alkoxy, amino, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, heterocyclylalkylaminocarbonyl, (aminocarbonylalkyl)(alkyl)amino, hydroxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl, (al
  • R 1' substituents are optionally substituted by one or more substituent selected from hydroxy, alkyl, hydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylamino alkyl, (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl, alkylheteroaryl, alkoxy, amino, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, (aminocarbonylalkyl)(alkyl)amino, hydroxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl, heterocyclylcarbonyl, alkylsulfoxide, alkylsulf
  • R 2' represents H, halo, alkyl, heterocyclyl, alkoxy, cycloalkyloxy, heterocyclyloxy, carbonyl, alkylcarbonyl, aminocarbonyl, hydroxycarbonyl, heterocyclylcarbonyl, alkylsulfoxide, alkylsulfonyl, aminosulfonyl, heterocyclylsulfonyl, alkylsulfonimidoyl, carbonylamino, sulfonylamino, or alkylsulfonealkyl; said substituents being optionally substituted by one or more substituent selected from oxo, halo, hydroxy, cyano, alkyl, alkenyl, aldehyde, heterocyclylalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl,
  • R 2' represents H, alkoxy, cycloalkyloxy, heterocyclyloxy, alkylsulfoxide, carbonyl, carbonylamino, aminocarbonyl or sulfonylamino; wherein alkoxy, cycloalkyloxy, heterocyclyloxy, alkylsulfoxide, carbonyl, carbonylamino, aminocarbonyl or sulfonylamino are optionally substituted by one or more substituent selected from hydroxy, cyano, alkyl, alkenyl, aldehyde, hydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl, alkylheteroaryl, alkyne, alkoxy, amino, dialkylamino, aminoalkylcarbonylamino,
  • alkylaminoalkyl (alkyl)aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alky lsulfo xide, alky lsulfo xidealky 1.
  • R 2 substituents are optionally substituted by one or more substituent selected from oxo, halo, hydroxy, cyano, alkyl, heterocyclylalkyl, dihydroxyalkyl, dialkylamino alkyl, heteroaryl, alkylheteroaryl, hydroxycarbonyl, alkyloxycarbonyl, aminocarbonyl, heterocyclylalkylaminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, alkylsulfoxide, alkylsulfonealkyl.
  • substituents selected from oxo, halo, hydroxy, cyano, alkyl, heterocyclylalkyl, dihydroxyalkyl, dialkylamino alkyl, heteroaryl, alkylheteroaryl, hydroxycarbonyl, alkyloxycarbonyl, aminocarbonyl, heterocyclylalkylaminocarbonyl, alkylaminoalkylcarbony
  • R 2 substituents are optionally substituted by one or more substituent selected from hydroxy, cyano, alkyl, dialkylaminoalkyl, heteroaryl, alkylheteroaryl, hydroxycarbonyl, alkyloxycarbonyl, aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, alkylsulfoxide, alkylsulfonealkyl.
  • R 1' and R 2' form together with the atoms to which they are attached a 5- or 6-membered aryl ring, a 5- or 6-membered heretoaryl ring, a 5- or 6-membered cycloalkyl ring or a 5- or 6-membered heretocyclyl ring; optionally substituted by one or more substituent selected from oxo, halo, hydroxy, cyano, alkyl, alkenyl, aldehyde, heterocyclylalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl, alkylheteroaryl, alkyne, alkoxy, amino, dialkylamino, aminoalkylcarbonylamino, aminocarbonyl
  • R 1' and R 2' form together with the atoms to which they are attached a 5- or 6-membered aryl ring, a 5- or 6-membered heretoaryl ring, a 5- or 6-membered cycloalkyl ring, a 5- or 6-membered heretocyclyl ring; optionally substituted by one or more substituent selected from hydroxy, cyano, alkyl, hydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl, alkylheteroaryl, alkyne, alkoxy, amino, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, (aminocarbonylalkyl)(alkyl)amino, hydroxycarbonyl, alkyloxy
  • R 3' is absent when X 2 is N. In another specific embodiment of the invention, when X 2 is C, R 3' represents H or halo. In a preferred embodiment, when X 2 is C, R 3' represents H or F.
  • R 4' represents H or halo. In a preferred embodiment, R 4' represents H or F.
  • R 5' represents H or halo. In a preferred embodiment, R 5' represents H or F.
  • preferred compounds of Formula (la) are those of Formula (la- 1):
  • R 1 , R 1 , R 2 , R 3 , R 4' and R 5' are as defined in Formula (la).
  • preferred compounds of Formula (Ia-1) are those of Formula (la).
  • R 1 and R 3 are as defined in Formula (la);
  • R 1 represents an alkyl or heterocyclyl group substituted by one or more group selected from oxo, 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, alkyloxycarbonyl, aminocarbonyl, amino alkylaminocarbonyl, alkylaminoalkylaminocarbonyl
  • R 1 and R 3' are as defined in Formula (la);
  • R 1 represents an alkyl or heterocyclyl group substituted by one or more group selected from hydroxy, cyano, alkyl, hydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl, alkylheteroaryl, alkyne, alkoxy, amino, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, (aminocarbonylalkyl)(alkyl)amino, hydroxycarbonyl, alkyloxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl, alkylaminoalky
  • R 1 and R 3 are as defined in Formula (la);
  • R 1 represents an alkyl or heterocyclyl group substituted by one or more group selected from hydroxy, cyano, alkyl, hydroxyalkyl, hydroxyalkylammoalkyl, aminoalkyl, alkylaminoalkyl, dialkylamino alkyl, (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl, alkylheteroaryl, alkyne, alkoxy, amino, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, (aminocarbonylalkyl)(alkyl)amino, hydroxycarbonyl, alkyloxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl, alkylaminoalky
  • R 1 represents an alkyl or heterocyclyl group substituted by one or more group selected from oxo, halo, hydroxy, cyano, alkyl, alkenyl, aldehyde, heterocyclylalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylammoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl, alkylheteroaryl, alkyne, alkoxy, amino, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, (aminocarbonylalkyl)(alkyl)amino, alkenylcarbonylamino, hydroxycarbonyl, alkyloxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoal
  • R 1 represents an alkyl or heterocyclyl group substituted by one or more group selected from hydroxy, cyano, alkyl, hydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl, alkylheteroaryl, alkyne, alkoxy, amino, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, (aminocarbonylalkyl)(alkyl)amino, hydroxycarbonyl, alkyloxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl, alkylaminoalky
  • R 1 represents an alkyl or heterocyclyl group substituted by one or more group selected from hydroxy, heterocyclyl, heteroaryl, alkylheteroaryl, alkyne, alkoxy, amino, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, (aminocarbonylalkyl)(alkyl)amino, hydroxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl, heterocyclylcarbonyl, alkylsulfoxide, alkylsulfonealkyl.
  • preferred compounds of Formula (Ia-1) are those of Formula (la
  • R 1 and R 3' are as defined in Formula (la);
  • R 1' represents H or halo, preferably H or F
  • R 2" represents an alkyl or heterocyclyl group substituted by one or more group selected from oxo, 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, alkyloxycarbonyl, aminocarbonyl, amino alkylaminocarbonyl, alkylaminoalkylaminocarbony
  • R 1 and R 3 are as defined in Formula (la);
  • R 1' represents H or halo, preferably H or F
  • R 2" represents an alkyl or heterocyclyl group substituted by one or more group selected from hydroxy, cyano, alkyl, hydroxyalkyl, hydroxyalkylammoalkyl, aminoalkyl, alkylaminoalkyl, dialkylamino alkyl, (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl, alkylheteroaryl, alkyne, alkoxy, amino, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, (aminocarbonylalkyl)(alkyl)amino, hydroxycarbonyl, alkyloxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl, alkylaminoal
  • R 1 and R 3' are as defined in Formula (la);
  • R 1' represents H or halo, preferably H or F
  • R 2" represents an alkyl or heterocyclyl group substituted by one or more group selected from hydroxy, cyano, alkyl, hydroxyalkyl, hydroxyalkylammoalkyl, aminoalkyl, alkylaminoalkyl, dialkylamino alkyl, (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl, alkylheteroaryl, alkyne, alkoxy, amino, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, (aminocarbonylalkyl)(alkyl)amino, hydroxycarbonyl, alkyloxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl, alkylaminoal
  • R 1' represents H or halo. In a preferred embodiment, R 1' represents H or F.
  • R 2" represents an alkyl or heterocyclyl group substituted by one or more group selected from oxo, 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, alkyloxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylamino, alkylamino,
  • R 2" represents an alkyl or heterocyclyl group substituted by one or more group selected from hydroxy, cyano, alkyl, hydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl, alkylheteroaryl, alkyne, alkoxy, amino, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, (aminocarbonylalkyl)(alkyl)amino, hydroxycarbonyl, alkyloxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl, alkylaminoal
  • R 2" represents an alkyl or heterocyclyl group substituted by one or more group selected from hydroxy, cyano, heteroaryl, alkylheteroaryl, alkyne, hydroxycarbonyl, alkyloxycarbonyl, aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, alkylsulfoxide, alkylsulfonealkyl.
  • preferred compounds of Formula (Ia-1) are those of Formula (laic) or (la- Id):
  • R 1 and R 3' are as defined in Formula (la);
  • R 1' represents H or halo, preferably H or F;
  • R 2' represents H or halo, preferably H or F;
  • R 1 ' and R 1 " represent each independently hydrogen, hydroxy, alkyl, alkenyl, heterocyclylalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylamino alkyl, (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl, alkylheteroaryl, alkynealkyl, alkoxy, amino, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, (aminocarbonylalkyl)(alkyl)amino, alkenylcarbonylamino, hydroxycarbonyl, alkyloxycarbonyl, aminocarbonyl, amino alkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, heterocyclylalkylaminocarbon
  • R 2 ' and R 2 " represent each independently hydrogen, hydroxy, alkyl, alkenyl, heterocyclylalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylamino alkyl, (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl, alkylheteroaryl, alkynealkyl, alkoxy, amino, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, (aminocarbonylalkyl)(alkyl)amino, alkenylcarbonylamino, hydroxycarbonyl, alkyloxycarbonyl, aminocarbonyl, amino alkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, heterocyclylalkylaminocarbon
  • R 1 and R 3' are as defined in Formula (la);
  • R 1' represents H or halo, preferably H or F
  • R 2' represents H or halo, preferably H or F
  • R 1 ' and R 1 " represent each independently hydrogen, hydroxy, alkyl, hydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl, alkylheteroaryl, alkynealkyl, alkoxy, amino, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, (aminocarbonylalkyl)(alkyl)amino, hydroxycarbonyl, alkyloxycarbonyl, aminocarbonyl, amino alkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)amino carbonyl, alkylaminoalkylcarbonyl, dialkylamino
  • R 1 and R 3' are as defined in Formula (la);
  • R 1' represents H or halo, preferably H or F
  • R 2' represents H or halo, preferably H or F
  • R 1 ' and R 1 " represent each independently hydrogen, hydroxy, alkyl, hydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl, alkylheteroaryl, alkynealkyl, alkoxy, amino, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, (aminocarbonylalkyl)(alkyl)amino, hydroxycarbonyl, alkyloxycarbonyl, aminocarbonyl, amino alkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)amino carbonyl, alkylaminoalkylcarbonyl, dialkylamino
  • R 2 ' and R 2 " represent each independently hydrogen, hydroxy, alkyl, hydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl, alkylheteroaryl, alkynealkyl, alkoxy, amino, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, (aminocarbonylalkyl)(alkyl)amino, hydroxycarbonyl, alkyloxycarbonyl, aminocarbonyl, amino alkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)amino carbonyl, alkylaminoalkylcarbonyl, dialkylamino
  • R 1' represents H or halo. In a preferred embodiment, R 1' represents H or F.
  • R 2' represents H or halo. In a preferred embodiment, R 2' represents H or F.
  • R 1 ' and R 1 " represent each independently hydrogen, hydroxy, alkyl, alkenyl, heterocyclylalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl, alkylheteroaryl, alkynealkyl, alkoxy, amino, dialkylamino, aminoalky lcarbony lamino , amino carbony lalky lamino ,
  • aminocarbonylalkyl (alkyl)amino, alkenylcarbonylamino, hydroxycarbonyl, alky loxy carbonyl, aminocarbonyl, amino alkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, heterocyclylalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylsulfoxidealkyl or alkylsulfonealkyl.
  • R 1 ' and R 1 " represent each independently hydrogen, hydroxy, alkyl, hydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl, alkylheteroaryl, alkynealkyl, alkoxy, amino, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, (aminocarbonylalkyl)(alkyl)amino, hydroxycarbonyl, alkyloxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl, alkylaminoalkylcarbonyl, dialkylamino
  • R 1 ' and R 1 " represent each independently hydrogen, alkyl, heterocyclylalkyl, hydroxyalkyl, hydroxyalkylaminoalkyl, amino alkyl, alkylaminoalkyl, dialkylammoalkyl, (heterocyclyl)(alkyl)aminoalkyl or heterocyclylalkylaminocarbonyl.
  • R 1 ' and R 1 " represent each independently hydrogen, alkyl, hydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylammoalkyl or(heterocyclyl)(alkyl)aminoalkyl.
  • R 2 ' and R 2 " represent each independently hydrogen, hydroxy, alkyl, alkenyl, heterocyclylalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylammoalkyl, (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl, alkylheteroaryl, alkynealkyl, alkoxy, amino, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, (aminocarbonylalkyl)(alkyl)amino, alkenylcarbonylamino, hydroxycarbonyl, alkyloxycarbonyl, aminocarbonyl, amino alkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, heterocycly
  • R 2 ' and R 2 " represent each independently hydrogen, hydroxy, alkyl, hydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylammoalkyl, (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl, alkylheteroaryl, alkynealkyl, alkoxy, amino, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, (aminocarbonylalkyl)(alkyl)amino, hydroxycarbonyl, alkyloxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl, alkylaminoalkylcarbonyl, dialkylamino
  • R 2 ' and R 2 " represent each independently hydrogen, alkyl, heterocyclylalkyl, dihydroxyalkyl, dialkylammoalkyl or heterocyclylalkylaminocarbonyl. In a preferred embodiment, R 2 ' and R 2 " represent each independently hydrogen, alkyl or dialkylaminoalkyl.
  • preferred compounds of Formula (la) are those of Formulae (Ia- 2) or (Ia-3 :
  • R 1 , R 2 , R 3 , R 4' and R 5' are as defined in Formula (la).
  • Particularly preferred compounds of Formula I of the invention are those listed in Table 1 hereafter.
  • references to compounds of Formula I and subformulae thereof include references to enantiomers, salts, solvates, polymorphs, multi- component complexes and liquid crystals thereof.
  • the compounds of the invention include compounds of Formula I and subformulae thereof as hereinbefore defined, including all polymorphs and crystal habits thereof, prodrugs and isomers thereof (including optical, geometric and tautomeric isomers) and isotopically- labeled compounds of Formula I and subformulae thereof.
  • the compounds of Formula I and subformulae thereof may contain an asymmetric center and thus may exist as different stereoisomeric forms. Accordingly, the present invention includes all possible stereoisomers and includes not only racemic compounds but the individual enantiomers and their non-racemic mixtures as well.
  • a compound is desired as a single enantiomer, such may be obtained by stereospecific synthesis, by resolution of the final product or any convenient intermediate, or by chiral chromatographic methods as each are known in the art. Resolution of the final product, an intermediate, or a starting material may be performed by any suitable method known in the art.
  • the compounds of the invention may be in the form of pharmaceutically acceptable salts.
  • Pharmaceutically acceptable salts of the compounds of Formula I and subformulae thereof include the acid addition and base salts thereof.
  • Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include the acetate, adipate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate/sulphate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulphate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate,
  • Suitable base salts are formed from bases which form non-toxic salts. Examples include the aluminium, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine, 2- (diethylamino)ethanol, ethanolamine, morpholine, 4-(2-hydroxyethyl)morpholine and zinc salts. Hemisalts of acids and bases may also be formed, for example, hemisulphate and hemicalcium salts.
  • Preferred, pharmaceutically acceptable salts include hydrochloride/chloride, hydrobromide/bromide, bisulphate/sulphate, nitrate, citrate, and acetate.
  • the compounds of the invention may also form internal salts, and such compounds are within the scope of the invention.
  • the compounds of the invention contain a hydrogen- donating heteroatom (e.g. NH)
  • the invention also covers salts and/or isomers formed by transfer of said hydrogen atom to a basic group or atom within the molecule.
  • Pharmaceutically acceptable salts of compounds of Formula I and subformulae thereof may be prepared by one or more of these methods:
  • the salt may precipitate from solution and be collected by filtration or may be recovered by evaporation of the solvent.
  • the degree of ionization in the salt may vary from completely ionized to almost non- ionized.
  • the compounds of the present invention may be administered in the form of pharmaceutically acceptable salts.
  • pharmaceutically acceptable salt is intended to include all acceptable salts such as acetate, lactobionate, benzenesulfonate, laurate, benzoate, malate, bicarbonate, maleate, bisulfate, mandelate, bitartrate, mesylate, borate, methylbromide, bromide, methylnitrate, calcium edetate, methylsulfate, camsylate, mucate, carbonate, napsylate, chloride, nitrate, clavulanate, N- methylglucamine, citrate, ammonium salt, dihydrochloride, oleate, edetate, oxalate, edisylate, pamoate (embonate), estolate, palmitate, esylate, pantothenate, fumarate, phosphate/diphosphate, gluceptate, polygalacturonate
  • pharmaceutically acceptable salts of the compounds of this invention include those formed from cations such as sodium, potassium, aluminum, calcium, lithium, magnesium, zinc, and from bases such as ammonia, ethylenediamine, N-methyl-glutamine, lysine, arginine, ornithine, choline, ⁇ , ⁇ '-dibenzylethylene-diamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethyl-amine, diethylamine, piperazine, tris(hydroxymethyl)aminomethane, and tetramethylammonium hydroxide.
  • bases such as ammonia, ethylenediamine, N-methyl-glutamine, lysine, arginine, ornithine, choline, ⁇ , ⁇ '-dibenzylethylene-diamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethyl-amine, diethylamine, piperazine, tri
  • salts may be prepared by standard procedures, e.g. by reacting a free acid with a suitable organic or inorganic base. Where a basic group is present, such as amino, an acidic salt, i.e. hydrochloride, hydrobromide, acetate, palmoate, and the like, can be used as the dosage form.
  • an acidic salt i.e. hydrochloride, hydrobromide, acetate, palmoate, and the like
  • pharmaceutically acceptable salts are preferred, it should be noted that the invention in its broadest sense also included non-pharmaceutically acceptable salts, which may for example be used in the isolation and/or purification of the compounds of the invention.
  • salts formed with optically active acids or bases may be used to form diastereoisomeric salts that can facilitate the separation of optically active isomers of the compounds of Formula I above.
  • the compounds of the invention may be in the form of pharmaceutically acceptable solvates.
  • Pharmaceutically acceptable solvates of the compounds of Formula I and subformulae thereof contains stoichiometric or sub-stoichiometric amounts of one or more pharmaceutically acceptable solvent molecule such as ethanol or water.
  • the term "hydrate" refers to when the said solvent is water.
  • the invention also generally covers all pharmaceutically acceptable predrugs and prodrugs of the compounds of Formula I and subformulae thereof.
  • esters can be employed, e.g. acetate, maleate, pivaloyloxymethyl, and the like, and those esters known in the art for modifying solubility or hydrolysis characteristics for use as sustained release or prodrug formulations.
  • the compounds of Formula I can be prepared by different ways with reactions known to a person skilled in the art.
  • the invention further relates to a process for manufacturing of compounds of Formula (la):
  • R 1 is as defined in Formula (la);
  • Y represents an halogen (preferably iodine, bromine or chlorine), an alkylsulfonyloxy having 1-6 carbon atoms (preferably methylsulfonyloxy 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.
  • halogen preferably iodine, bromine or chlorine
  • alkylsulfonyloxy having 1-6 carbon atoms preferably methylsulfonyloxy or trifluoromethylsulfonyloxy
  • arylsulfonyloxy having 6-10 carbon atoms (preferably phenyl- or p-tolylsulfonyloxy), or any leaving group known to those skilled in the art.
  • step (al) of the process of the invention may be performed in the presence or absence of bases.
  • step (al) of the process of the invention is performed in the presence of bases selected from the group consisting of but not limited to TEA, DIPEA, Pyridine, NaOH, K 3 P0 4 , K 2 C0 3 , Na 2 C0 3 , preferably DIPEA or TEA.
  • step (al) of the process of the 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.
  • a suitable solvent such as but not limited to DMF, dioxane, THF, water or mixtures thereof, preferably in DMF.
  • step (al) of the process of the 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 a few hours, e.g. 10 minutes to 24 h.
  • step (bl) can be performed by treatment with l-bromo-2- methoyxy ethane, l-iodo-2-methoxy ethane, l-mesyl-2-methoxy ethane or l-tosyl-2- methoxy ethane, preferably l-bromo-2-methoyxy ethane.
  • step (bl) of the process of the invention may be performed in the presence or absence of bases.
  • step (bl) is performed in the presence of bases such as but not limited to sodium tert-butoxide, potassium tert-butoxide, NaH, CsOH, NaOH, K2CO3, Na 2 C03, preferably sodium tert-butoxide, potassium tert- butoxide or NaH.
  • step (bl) of the process of the invention may be performed in the presence of a suitable solvent such as but not limited to DMF, dioxane, THF, DMA, preferably in DMF.
  • step (bl) of the process of the 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 a few hours, e.g. 10 minutes to 24 h.
  • step (b2) may be performed in presence of a chlorinating agent, such as but not limited to POCb, PCI5, SOCb, preferably POCI3.
  • step (b2) of the process of the invention may be performed in the presence or absence of a suitable solvent, preferably in absence of solvents.
  • step (b2) of the process of the 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 a few hours, e.g. 10 minutes to 24 h.
  • step (b3) of the process of the invention may be performed in the presence of a suitable base.
  • step (b3) of the process of the invention may be performed in the presence or absence of a suitable solvent such as ethanol, propanol, methanol, THF, water, dioxane, or mixtures thereof, preferably in presence of ethanol.
  • step (b3) of the process of the 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 a few hours, e.g. 10 minutes to 24 h.
  • step (b4) of the process of the invention may be performed in the presence of N,0-Bis(trimethylsilyl)acetamide.
  • step (b4) of the process of the invention may be performed in the presence or absence of hexamethyldisilazane.
  • step (b4) of the process of the invention may be performed in the presence or absence of a suitable solvent, preferably in the absence of solvent.
  • step (b4) of the process of the 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 a few hours, e.g. 1 h to 96 h.
  • step (b5) of the process of the invention may be performed in the presence of BBr 3 .
  • step (b5) of the process 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.
  • step (b5) of the process of the 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 a few hours, e.g. 10 minutes to 24 h.
  • step (b6) of the process of the invention may be performed using any reagent known to those skilled in the art for the conversion of an alcohol to an alkyl halide, or to an alkyl or aryl sulfonic ester, depending on the nature of Y, such as but not limited to tosyl chloride, mesyl chloride, triflic chloride, triflic anhdydride, SOCh, SO2CI2, POCI3, PCI5, preferably tosyl chlorideor mesyl chloride.
  • any reagent known to those skilled in the art for the conversion of an alcohol to an alkyl halide, or to an alkyl or aryl sulfonic ester depending on the nature of Y, such as but not limited to tosyl chloride, mesyl chloride, triflic chloride, triflic anhdydride, SOCh, SO2CI2, POCI3, PCI5, preferably tosyl chlorideor mesyl chloride.
  • step (b6) of the process of the invention may be performed in the presence of a suitable base, such as but not limited to TEA or DIPEA.
  • step (b6) of the process 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.
  • step (b6) of the process of the 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 a few hours, e.g. 10 minutes to 24 h.
  • compounds of Formula I can be converted to alternative compounds of Formula I, employing suitable interconversion techniques well known by a person skilled in the art.
  • Compounds of the Formula I and related formulae can furthermore be obtained by liberating compounds of the Formula I from one of their functional derivatives by treatment with a solvolysing or hydrogenolysing agent.
  • Preferred starting materials for the solvolysis or hydrogenolysis are those which conform to the Formula I and related formulae, but contain corresponding protected amino and/or hydroxyl groups instead of one or more free amino and/or hydroxyl groups, preferably those which carry an amino -protecting group instead of an H atom bonded to an N atom, in particular those which carry an R*-N group, in which R* denotes an amino -protecting group, instead of an FiN group, and/or those which carry a hydroxyl-protecting group instead of the H atom of a hydroxyl group, for example those which conform to the Formula I, but carry a -COOR** group, in which R** denotes a hydroxyl-protecting group, instead of a -COOH group.
  • amino -protecting group is known in general terms and relates to groups which are suitable for protecting (blocking) an amino group against chemical reactions, but which are easy to remove after the desired chemical reaction has been carried out elsewhere in the molecule. Typical of such groups are, in particular, unsubstituted or substituted acyl, aryl, aralkoxymethyl or aralkyl groups. Since the amino -protecting groups are removed after the desired reaction (or reaction sequence), their type and size are furthermore not crucial; however, preference is given to those having 1-20, in particular 1-8, carbon atoms.
  • acyl group is to be understood in the broadest sense in connection with the present process.
  • acyl groups derived from aliphatic, araliphatic, aromatic or heterocyclic carboxylic acids or sulfonic acids, and, in particular, alkoxy-carbonyl, aryloxycarbonyl and especially aralkoxycarbonyl groups.
  • acyl groups are alkanoyl, such as acetyl, propionyl and butyryl; aralkanoyl, such as phenylacetyl; aroyl, such as benzoyl and tolyl; aryloxyalkanoyl, such as POA; alkoxycarbonyl, such as methoxy-'carbonyl, ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, BOC (tert-butoxycarbonyl) and 2- iodoethoxycarbonyl; aralkoxycarbonyl, such as CBZ ("carbobenzoxy”), 4- methoxybenzyloxycarbonyl and FMOC; and arylsulfonyl, such as Mtr.
  • Preferred amino- protecting groups are BOC and Mtr, further-more CBZ, Fmoc, benzyl and acetyl.
  • hydroxyl-protecting group is likewise known in general terms and relates to groups which are suitable for protecting a hydroxyl group against chemical reactions, but are easy to remove after the desired chemical reaction has been carried out elsewhere in the molecule. Typical of such groups are the above-mentioned unsubstituted or substituted aryl, aralkyl or acyl groups, furthermore also alkyl groups.
  • the nature and size of the hydroxyl- protecting groups are not crucial since they are removed again after the desired chemical reaction or reaction sequence; preference is given to groups having 1-20, in particular 1- 10, carbon atoms.
  • hydroxyl-protecting groups are, inter alia, benzyl, 4- methoxybenzyl, p-nitrobenzoyl, p-toluenesulfonyl, tert-butyl and acetyl, where benzyl and tert-butyl are particularly preferred.
  • the compounds of the Formula I and related formulae are liberated from their functional derivatives - depending on the protecting group used - for example strong inorganic acids, such as hydrochloric acid, perchloric acid or sulfuric acid, strong organic carboxylic acids, such as trichloroacetic acid, TFA or sulfonic acids, such as benzene- or p-toluenesulfonic acid.
  • strong inorganic acids such as hydrochloric acid, perchloric acid or sulfuric acid
  • strong organic carboxylic acids such as trichloroacetic acid, TFA or sulfonic acids, such as benzene- or p-toluenesulfonic acid.
  • 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, furthermore also alcohols, such as methanol, ethanol or isopropanol, and water. Mixtures of the above-mentioned solvents are furthermore suitable. TFA is preferably used in excess without addition of a further solvent, and perchloric acid is preferably used in the form of a mixture of acetic acid and 70% perchloric acid in the ratio 9: 1.
  • the reaction temperatures for the cleavage are advantageously between about 0 and about 50°C, preferably between 15 and 30°C (room temperature).
  • the BOC, OtBu and Mtr groups can, for example, preferably be cleaved off using TFA in dichloromethane or using approximately 3 to 5N HC1 in dioxane at 15-30°C, and the FMOC group can be cleaved off using an approximately 5 to 50% solution of dimethylamine, diethylamine or piperidine in DMF at 15-30°C.
  • Protecting groups which can be removed hydrogenolytically can be cleaved off, for example, by treatment with hydrogen in the presence of a catalyst (for example a noble-metal catalyst, such as palladium, advantageously on a support, such as carbon).
  • a catalyst for example a noble-metal catalyst, such as palladium, advantageously on a support, such as carbon.
  • Suitable solvents are those indicated above, in particular, for example, alcohols, such as methanol or ethanol, or amides, such as DMF.
  • the hydrogeno lysis is generally carried out at temperatures between about 0 and 100°C and pressures between about 1 and 200 bar, preferably at 20-30°C and 1-10 bar.
  • Hydrogeno lysis of the CBZ group succeeds well, for example, on 5 to 10% Pd/C in methanol or using ammonium formate (instead of hydrogen) on Pd/C in methanol/DMF at 20-30°C.
  • suitable inert solvents are hydrocarbons, such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons, such as trichloroethylene, 1,2- dichloroethane, tetrachloromethane, trifluoromethylbenzene, chloroform or dichloromethane; alcohols, such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane; glycol ethers, such as ethylene glycol mono
  • Esters can be hydrolyzed, for example, using HC1, H2SO4, or using LiOH, NaOH or KOH in water, water/THF, water/THF/ethanol or water/dioxane, at temperatures between 0 and 100°C.
  • Free amino groups can furthermore be acylated in a conventional manner using an acyl chloride or anhydride or alkylated using an unsubstituted or substituted alkyl halide, advantageously in an inert solvent, such as dichloromethane or THF and/or in the presence of a base, such as triethylamine or pyridine, at temperatures between -60°C and +30°C.
  • an inert solvent such as dichloromethane or THF
  • a base such as triethylamine or pyridine
  • the invention also relates to intermediates of synthesis of Formula (A)
  • R 1' is absent when X 1 is N; or when X 1 is C, R 1' represents H, halo, alkyl, heterocyclyl, alkoxy, cycloalkyloxy, heterocyclyloxy, carbonyl, alkylcarbonyl, aminocarbonyl, hydroxycarbonyl, heterocyclylcarbonyl, alkylsulfoxide, alkylsulfonyl, aminosulfonyl heterocyclylsulfonyl alkylsulfonimidoyl, carbonylamino, sulfonylamino or alkylsulfonealkyl; said substituents being optionally substituted by one or more substituent selected from oxo, halo, hydroxy, cyano, alkyl, alkenyl, aldehyde, heterocyclylalkyl, hydroxyalkyl, dihydroxyalkyl,hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl,
  • heterocyclyl (alkyl)aminoalkyl, heterocyclyl, heteroaryl, alkylheteroaryl, alkyne, alkoxy, amino, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, (aminocarbonylalkyl)(alkyl)amino, alkenylcarbonylamino, hydroxycarbonyl, alkyloxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, heterocyclylalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)amino carbonyl, alkylamino alkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylsulfoxide, al
  • R 2' represents H, halo, alkyl, heterocyclyl, alkoxy, cycloalkyloxy, heterocyclyloxy, carbonyl, alkylcarbonyl, aminocarbonyl arbonyl, heterocyclylcarbonyl, alkylsulfoxide, alkylsulfonyl, aminosulfonyl, heterocyclylsulfonyl, alkylsulfonimidoyl, carbonylamino, sulfonylamino or alkylsulfonealkyl; said substituents beingoptionally substituted by one or more substituent selected from oxo, 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, alkyloxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, heterocyclylalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)amino carbonyl, alkylamino alkylcarbony 1, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylsulfoxide, alky
  • R 3' is absent when X 2 is N; or when X 2 is C, R 3' represents H or halo, preferably H or F;
  • R 4' represents H or halo, preferably H or F; and R 5' represents H or halo, preferably H or F.
  • the intermediates of synthesis of Formula (A) used in the process of the invention are selected from the group consisting of:
  • the invention is further directed to the use of the compounds of the invention or pharmaceutically acceptable salts and solvates thereof as A2A inhibitors.
  • the invention relates to the use of compounds of Formula I and subformulae in particular those of Table 1 above, or pharmaceutically acceptable salts and solvates thereof, as A2A inhibitors.
  • the invention relates to the use of these compounds or salts and solvates thereof for the synthesis of pharmaceutical active ingredients, such as A2A inhibitors.
  • a method for modulating A2A activity in a patient, preferably a warm-blooded animal, and even more preferably a human, in need of such treatment, which comprises administering to said patient an effective amount of compound of the present invention, or a pharmaceutically acceptable salt and solvate thereof.
  • the invention relates to the use of compounds of Formula I and subformulae in particular those of Table 1 above, or pharmaceutically acceptable salts and solvates thereof, for increasing immune recognition and destruction of the cancer cells.
  • the compounds of the invention are therefore useful as medicaments, in particular for the prevention and/or treatment of cancer.
  • the invention further relates to a method for treatment or prevention of cancer, which comprises administering to a mammalian species in need thereof a therapeutically effective amount of the compound according to the invention or a pharmaceutically acceptable salt or solvate thereof.
  • the invention further provides the use of a compound of Formula I or a pharmaceutically acceptable salt and solvate thereof for the manufacture of a medicament for treating and/or preventing cancer.
  • the invention also provides for a method for delaying in patient the onset of cancer comprising the administration of a pharmaceutically effective amount of a compound of Formula I or pharmaceutically acceptable salt and solvate thereof to a patient in need thereof.
  • the patient is a warm-blooded animal, more preferably a human.
  • the cancer may be metastatic or non-metastatic.
  • the cancer may be may be familial or sporadic.
  • the cancer is selected from the group consisting of: leukemia and multiple myeloma. Additional cancers that can be treated using the methods of the invention include, for example, benign and malignant solid tumors and benign and malignant non-solid tumors.
  • the cancer is selected from breast, carcinoid, cervical, colorectal, endometrial, glioma, head and neck, liver, lung, melanoma, ovarian, pancreatic, prostate, renal, gastric, thyroid and urothelial cancers.
  • the cancer is breast cancer.
  • the cancer is carcinoid cancer. In a specific embodiment, the cancer is cervical cancer. In a specific embodiment, the cancer is colorectal cancer. In a specific embodiment, the cancer is endometrial cancer. In a specific embodiment, the cancer is glioma. In a specific embodiment, the cancer is head and neck cancer. In a specific embodiment, the cancer is liver cancer. In a specific embodiment, the cancer is lung cancer. In a specific embodiment, the cancer is melanoma. In a specific embodiment, the cancer is ovarian cancer. In a specific embodiment, the cancer is pancreatic cancer. In a specific embodiment, the cancer is prostate cancer. In a specific embodiment, the cancer is renal cancer. In a specific embodiment, the cancer is gastric cancer.
  • the cancer is thyroid cancer.
  • the cancer is urothelial cancer.
  • solid tumors include, but are not limited to: biliary tract cancer, brain cancer (including glioblastomas and medulloblastomas), breast cancer, carcinoid, cervical cancer, choriocarcinoma, colon cancer, colorectal cancer, endometrial cancer, esophageal cancer, gastric cancer, glioma, head and neck cancer, intraepithelial neoplasms (including Bowen's disease and Paget's disease), liver cancer, lung cancer, neuroblastomas, oral cancer (including squamous cell carcinoma), ovarian cancer (including those arising from 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, rhabdom
  • solid tumors include, but are not limited to: biliary tract cancer, brain cancer (including glioblastomas and medulloblastomas), breast cancer, cervical cancer, choriocarcinoma, colon cancer, endometrial cancer, esophageal cancer, gastric cancer, intraepithelial neoplasms (including Bowen's disease and Paget's disease), liver cancer, lung cancer, neuroblastomas, oral cancer (including squamous cell carcinoma), ovarian cancer (including those arising from 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, basocellular
  • non-solid tumors include but are not limited to hematological neoplasms.
  • a hematologic neoplasm is a term of art which includes lymphoid disorders, myeloid disorders, and AIDS associated leukemias.
  • Lymphoid disorders include but are not limited to acute lymphocytic leukemia and chronic lymphoproliferative disorders (e.g., lymphomas, myelomas, and chronic lymphoid leukemias).
  • Lymphomas include, for example, Hodgkin's disease, non-Hodgkin's lymphoma lymphomas, and lymphocytic lymphomas).
  • Chronic lymphoid leukemias include, for example, T cell chronic lymphoid leukemias and B cell chronic lymphoid leukemias.
  • the invention further relates to the use of the compounds according to the invention or pharmaceutically acceptable salts or solvates thereof for the prevention and/or treatment of radiation-induced fibrosis, connective tissue diseases (such as for example Sjogren syndrome, i.e. scleroderma), chronic bacterial infection (such as for example Helicobacter Pylori), abnormal scarring (keloids) and polymicrobial sepsis.
  • connective tissue diseases such as for example Sjogren syndrome, i.e. scleroderma
  • chronic bacterial infection such as for example Helicobacter Pylori
  • abnormal scarring keloids
  • the invention further relates to a method for treatment or prevention of radiation-induced fibrosis, connective tissue diseases (such as for example Sjogren syndrome, i.e. scleroderma), chronic bacterial infection (such as for example Helicobacter Pylori), abnormal scarring (keloids) and polymicrobial sepsis, which comprises administering to a mammalian species in need thereof a therapeutically effective amount of the compound according to the invention or a pharmaceutically acceptable salt or solvate thereof.
  • connective tissue diseases such as for example Sjogren syndrome, i.e. scleroderma
  • chronic bacterial infection such as for example Helicobacter Pylori
  • abnormal scarring keloids
  • polymicrobial sepsis which comprises administering to a mammalian species in need thereof a therapeutically effective amount of the compound according to the invention or a pharmaceutically acceptable salt or solvate thereof.
  • the invention further provides the use of a compound of Formula I or a pharmaceutically acceptable salt and solvate thereof for the manufacture of a medicament for treating and/or preventing radiation-induced fibrosis, connective tissue diseases (such as for example Sjogren syndrome, i.e. scleroderma), chronic bacterial infection (such as for example Helicobacter Pylori), abnormal scarring (keloids) and polymicrobial sepsis.
  • connective tissue diseases such as for example Sjogren syndrome, i.e. scleroderma
  • chronic bacterial infection such as for example Helicobacter Pylori
  • abnormal scarring keloids
  • the invention also provides for a method for delaying in patient the onset of radiation- induced fibrosis, connective tissue diseases (such as for example Sjogren syndrome, i.e. scleroderma), chronic bacterial infection (such as for example Helicobacter Pylori), abnormal scarring (keloids) and polymicrobial sepsis, comprising the administration of a pharmaceutically effective amount of a compound of Formula I or pharmaceutically acceptable salt and solvate thereof to a patient in need thereof.
  • connective tissue diseases such as for example Sjogren syndrome, i.e. scleroderma
  • chronic bacterial infection such as for example Helicobacter Pylori
  • abnormal scarring keloids
  • polymicrobial sepsis comprising the administration of a pharmaceutically effective amount of a compound of Formula I or pharmaceutically acceptable salt and solvate thereof to a patient in need thereof.
  • compositions 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.
  • the invention also covers pharmaceutical compositions which contain, in addition to a compound of the present invention, a pharmaceutically acceptable salt and solvate thereof as active ingredient, additional therapeutic agents and/or active ingredients.
  • Another object of this invention is a medicament comprising at least one compound of the invention, or a pharmaceutically acceptable salt and solvate thereof, as active ingredient.
  • 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, which comprises administering to said patient an effective amount of compound of the present invention, or a pharmaceutically acceptable salt and solvate thereof.
  • the compounds of the invention may be formulated as a pharmaceutical preparation comprising at least one compound of the invention and at least one pharmaceutically acceptable carrier, diluent, excipient and/or adjuvant, and optionally one or more further pharmaceutically active compounds.
  • such a formulation may be in a form suitable for oral administration, for parenteral administration (such as by intravenous, intramuscular or subcutaneous injection or intravenous infusion), for topical administration (including ocular), for administration by inhalation, by a skin patch, by an implant, by a suppository, etc.
  • parenteral administration such as by intravenous, intramuscular or subcutaneous injection or intravenous infusion
  • topical administration including ocular
  • suitable administration forms - which may be solid, semi-solid or liquid, depending on the manner of administration - as well as methods and carriers, diluents and excipients for use in the preparation thereof, will be clear to the skilled person; reference is made to the latest edition of Remington's Pharmaceutical Sciences.
  • Such preparations include tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols, ointments, cremes, lotions, soft and hard gelatin capsules, suppositories, drops, sterile injectable solutions and sterile packaged powders (which are usually reconstituted prior to use) for administration as a bolus and/or for continuous administration, which may be formulated with carriers, excipients, and diluents that are suitable per se for such formulations, such as lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, polyethylene glycol, cellulose, (sterile) water, methylcellulose, methyl- and propy
  • the formulations can optionally contain other substances that are commonly used in pharmaceutical formulations, such as lubricating agents, wetting agents, emulsifying and suspending agents, dispersing agents, desintegrants, bulking agents, fillers, preserving agents, sweetening agents, flavoring agents, flow regulators, release agents, etc..
  • the compositions may also be formulated so as to provide rapid, sustained or delayed release of the active compound(s) contained therein.
  • the pharmaceutical preparations of the invention are preferably in a unit dosage form, and may be suitably packaged, for example in a box, blister, vial, bottle, sachet, ampoule or in any other suitable single-dose or multi-dose holder or container (which may be properly labeled); optionally with one or more leaflets containing product information and/or instructions for use.
  • the active compound of the invention may be administered as a single daily dose, divided over one or more daily doses, or essentially continuously, e.g. using a drip infusion.
  • FIG. 1 is a graph showing the percentage of cytokines released in peripheral blood lymphocytes, in the presence of A2a agonist CGS24680, over the concentration of compound 7 of the present invention.
  • FIG. 1A relates to whole blood cell cultures stimulated with LPS and
  • FIG. IB relates to whole blood cell cultures stimulated with anti- CD3/CD28.
  • Figure 2 is a graph showing the percentage pCREB inhibition in peripheral blood lymphocytes over the concentration of compound 4 of the present invention.
  • Figure 3 is a graph showing the percentage of cytotoxicity over the over the concentration of compounds 4 and 31 of the present invention.
  • BSA Bis(trimethylsilyl)acetamide or bovine serum albumin, depending on the context, Cpd: Compound,
  • DIPEA N,N-Diisopropylethylamine
  • HAS Human serum albumin
  • HMDS Hexamethyldisilazane
  • LHMDS Lithium bis(trimethylsilyl)amide
  • NMP N-Methyl-2-pyrrolidone
  • TFA Trifluoroacetic acid
  • VTD Vacuum tray drayer.
  • Step 2 2,5-diaminothiazolo[4,5-d]pyrimidin-7-ol: To a stirred solution of 2,6-diamino- 5-thiocyanatopyrimidin-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 24h. After the completion of the reaction, the reaction mixture was cooled to 25 ⁇ 5 °C for lh. The precipitate formed was filtered and rinsed with THF (2.25 L). The wet solid was taken up in water (6 L) and concentrated hydrochloric acid (1.5 L) was added.
  • Step 3 5-amino-7-hydroxythiazolo [4,5-d]pyrimidin-2(3H)-one: A hot (80 °C) mixture of 2,5-diaminothiazolo[4,5-d]pyrimidin-7-ol (Step 2; 570 g, 3.11 mol) and NaNC (570 g, 8.26 mol) in water (5700 mL) was slowly added to a hot solution (80 °C) of Cone. HC1 (11400 mL, 15 Vol). The reaction mixture was stirred for 2h and the completion of the reaction was monitored by HPLC. After the completion of the reaction, the mixture was cooled to 15 °C and basified to pH 12 with NaOH pellets.
  • 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 in dry DMF (600 mL) and heated to 90 °C in a sealed tube. The reaction mixture was stirred for 30 min at 90 °C, then cooled to 30 °C.
  • Step 5 5-amino-7-chloro-3-(2-methoxyethyl)thiazolo[4,5-d]pyrimidin-2(3 H)-one: 5- amino-7-hydroxy-3-(2-methoxyethyl)thiazolo[4,5-d]pyrimidin-2(3H)-one (10 g, 0.0412 mol) was treated with POCb (100 mL) and heated to 90 °C for 18h in a sealed tube. After the completion of the reaction as 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 NaHC0 3 and extracted with DCM.
  • Step 6 N'-(5-amino-3-(2-methoxyethyl)-2-oxo-2,3-dihydrothiazolo[4,5-(i] pyrimidin- 7-yl)furan-2-carbohydrazide: 5-amino-7-chloro-3-(2-methoxyethyl)thiazole [4,5- d]pyrimidin-2(3H)-one (6.8 g, 0.026 mol) in ethanol was added furoic acid hydrazide (4.9 g, 0.039 mol) and heated to 100 °C in a sealed tube for 19h. The reaction was monitored by TLC. After the completion of the reaction, the reaction mixture was cooled to RT, concentrated under reduced pressure. To this residue, Petroleum Ether was added to afford a solid which was filtered and was used as such for the next step without further purification (7.2 g, 79%).
  • LCMS 351.2 [M+l] + .
  • Step 7 5-amino-8-(furan-2-yl)-3-(2-methoxyethyl)thiazolo[5,4-e] [l,2,4]triazolo[l,5- c]py rimidin-2(3H)-one: N'-(5-amino-3-(2-methoxyethyl)-2-oxo-2,3- dihydrothiazolo[4,5-d]pyrimidin-7-yl)furan-2-carbohydrazide (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.
  • BSA 50.8 mL, 11 eq
  • HMDS 76 mL, 25 eq
  • Step 8 5-amino-8-(furan-2-yl)-3-(2-hydroxyethyl)thiazolo[5,4-e] [l,2,4]triazolo[l,5- c]p yrimidin-2(3H)-one: To a solution of 5-amino-8-(furan-2-yl)-3-(2- methoxyethyl)thiazolo[5,4-e][l,2,4]triazolo[l,5-c] pyrimidin-2(3H)-one (5.9 g, 0.017 mol) in dry DCM ( 100 mL) at -50 °C, was added BBr 3 (11.5 g, 2.6 eq) slowly and maintained for 19h at 25-30 °C.
  • Step 9 2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e] [l,2,4]triazolo[l,5-c]pyrimidin- 3(2H)-yl)ethyl methanesulfonate: 5-amino-8-(furan-2-yl)-3-(2- hydroxyethyl)thiazolo[5,4-e][l,2,4]triazolo[l,5-c]pyrimidin-2 (3H)-one (3.6 g, 0.01 lmol) was dissolved in dry DMF (95 mL) at 60 °C till the reaction mixture became clear.
  • Example 1 3-(2-(4-(4-((lH-l,2,3-triazolo-4yl)methoxy-2fluorophenyl)piperazine-l- yl)ethyl)-5-amino-(8-(furan-2-yl)thiazolo [5,4-e] [1 ,2,4] triazolo [ 1 ,5-c] pyrimidine- 2(3H)-one:
  • Step 1 tert-butyl 4-(2-fluoro-4-hydroxyphenyl)piperazine-l-carboxylate (2): To a mixture of 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) was added LHMDS (115 mL of 1.0 M solution in THF, 0.115 mol) at 0 °C under nitrogen. The reaction mixture was heated at 65 °C for 24 h and monitored by TLC.
  • Step 2 tert-butyl 4-(2-fluoro-4-(prop-2-yn-l-yloxy)phenyl)piperazine-l-carboxylate (3): To a stirred suspension of sodium hydride (0.7 g, 0.0304 mol) in DMF (10 mL) was added tert-butyl hydroxyphenyl)piperazine- 1-carboxylate (2, 4.5 g, 0.0152 mol) in DMF (20 mL) at 0°C under nitrogen. The reaction mixture was stirred for 15 min at 0°C and then propargyl bromide (2.71g, 0.0228 mol) in DMF (10 mL) was added and stirred for 16 h at RT.
  • Step 3 l-(2-fluoro-4-(prop-2-yn-l-yloxy)phenyl) piperazine (4): To a stirred solution of tert-butyl 4-(2-fluoro-4-(prop-2-yn-l-yloxy)phenyl)piperazine- 1-carboxylate (3, 3.6 g, 10.8 mmol) in dichloromethane (15 mL) at 0 °C, 4 N HC1 in dioxane (20 mL) was added dropwise and stirred at RT for 4 h. After the reaction completion (TLC), the reaction mixture was concentrated under reduced pressure.
  • Step 4 5-amino-3-(2-(4-(2-fluoro-(prop-2yn-l-yloxy)phenyl)piperazine-l-yl)ethyl)-8- (furan-2-yl)thaizolo[5,4-e] [l,2,4]triazolo[l,5-c]pyrimidine-2(3H)-one (5): To a mixture of l-(2-fluoro-4-(prop-2-yn-l-yloxy)phenyl)piperazine (4, 1 g, 4.3 mmol) and 2-(5-amino- 8-(furan-2-yl)-2-oxothiazolo[5,4-e][l,2,4]triazolo[l,5-c]pyrimidin-3(2H)-yl)ethyl methane sulfonate (0.9 g, 2.2 mmol) in N,N-Dimethylformamide (15 mL), was added DIPEA
  • Step 5 3-(2-(4-(4-((lH-l,2,3-triazolo-4yl)methoxy-2fluorophenyl)piperazine-l- yl)ethyl)-5-amino-(8-(furan-2-yl)thaizolo [5,4-e] [1 ,2,4] triazolo [ 1 ,5-c] pyrimidine- 2(3H)-one
  • Compound 1 To a stirred solution of 5-amino-3-(2-(4-(2-fluoro-4-(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, 0.4 g, 0.7 moles) in DMF (4.5 mL) and MeOH (
  • Example 2 5-((4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo [5,4- e] [l,2,4]triazolo[l,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-l-yl)-3- fluorophenoxy)methyl)-l,3,4-oxadiazol-2(3H)-one
  • Step 1 tert-butyl 4-(4-(2-ethoxy-2-oxoethoxy)-2-fluorophenyl)piperazine-l- carboxylate (2): To a stirred solution of tert-butyl 4-(2-fluoro-4- hydroxyphenyl)piperazine-l-carboxylate (1, 2 g, 6.75 mmol) and ethyl bromoacetate (1.67g, 10.0 mmol) in N,N-Dimethylformamide (15 mL), was added K2CO3 (2.76 g, 20.0 mmol) and the reaction mixture was heated at 90 °C for 16 h.
  • Step 2 ethyl 2-(3-fluoro-4-(piperazin-l-yl)phenoxy)acetate (3): To an ice cold solution oftert-butyl 4-(4-(2-ethoxy-2-oxoethoxy)-2-fluorophenyl)piperazine-l-carboxylate (2, 1.9 g, 5.0 mmol) in dichloromethane, 4 N HC1 in Dioxane (15 mL) was added and the reaction mixture was stirred at RT for 5 h. After the completion of reaction (TLC), reaction mass was quenched with saturated sodium bicarbonate solution and was extracted with ethyl acetate.
  • TLC TLC
  • Step 3 ethyl 2-(4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e] [1,2,4] triazolo[l,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-l-yl)-3-fluorophenoxy)acetate (4): To a mixture of ethyl 2-(3-fluoro-4-(piperazin-l-yl)phenoxy)acetate (3, 1.0 g, 3.52 mmol) and 2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][l,2,4]triazolo[l,5- c]pyrimidin-3(2H)-yl)ethyl methane sulfonate (1.12 g, 2.82 mmol) in N,N- Dimethylformamide (15 mL), was added DI
  • Step 4 2-(4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e] [l,2,4]triazolo [1,5- c]pyrimidin-3(2H)-yl)ethyl)piperazin-l-yl)-3-fluorophenoxy)acetohydrazide (5): To a solution of Ethyl 2-(4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][l,2,4]- triazolo[l,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-l-yl)-3-fluorophenoxy)acetate(4, 0.2 g, 0.34 mmol) in ethanol (20 mL), was added hydrazine hydrate (50 mg, 1.0 mmol) and the reaction mixture was stirred at 90
  • Step 5 5-((4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e] [l,2,4]tri-azolo [1,5- c]pyrimidin-3(2H)-yl)ethyl)piperazin-l-yl)-3-fluorophenoxy)methyl)-l,3,4-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), TEA (0.084 g, 0.83 mol) was added and the reaction mixture was stirred at 100 °C for 4 h.
  • TEA 0.084 g, 0.83 mol
  • Step 1 l-(3-fluoropyridin-4-yl)piperazine (3): To a stirred solution of 3-fluoro-4- iodopyridine (2, 2 g, 4.48 mmol, 1 eq) in NMP (20 mL), DIPEA (0.694 g, 5.38 mmol, 1.2 eq) and piperazine (1, 0.484 g, 6.72 mmol, 1.5 eq) were added at RT. The resulting mixture was stirred at 80°C for 16h. After the completion, the reaction mixture was concentrated under reduced pressure. The residue was taken in water and lyophilized.
  • Step 2 5-amino-3-(2-(4-(3-fluoropyridin-4-yl)piperazin-l-yl)ethyl)-8-(furan-2- yl)thiazolo[5,4-e] [l,2,4]triazolo[l,5-c]pyrimidin-2(3H)-one
  • Compound 3 To a solution of l-(3-fluoropyridin-4-yl)piperazine (3, 0.071 g, 0.392 mmol, 1 eq) in DMF (2 mL), 2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[4,5-e][l,2,4]triazolo[l,5-c]-pyrimidin- l(2H)-yl)ethyl methane sulfonate (4, 0.150 g, 0.392 mmol, 1.03 eq) and DIPEA (0.100 g,
  • Step 1 Preparation of l-(benzyloxy)-5-bromo-2,4-difluorobenzene (2): To a solution of 5-bromo-2,4-difluorophenol (1, 20 g, 95.69 mmol) and benzyl bromide (18 g, 105.26 mmol) in N,N-dimethylformamide (200 mL), was added K 2 C0 3 (39.62 g, 287.08 mmol) and the reaction mixture was heated at 90 °C for 16 h. After the reaction completion (TLC), the reaction mixture was diluted with water (200 mL) and extracted with ethyl acetate.
  • Step 2 Preparation of tert-butyl 4-(5-(benzyloxy)-2,4-difluorophenyl)piperazine-l- carboxylate (3): To a solution of l-(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), t-Bu Xphos (3.43 g, 8.08 mmol) were added.
  • reaction mixture was purged 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.
  • Step 3 tert-butyl 4-(2,4-difluoro-5-hydroxyphenyl)piperazine-l-carboxylate (4): To a clear solution of tert-butyl 4-(5-(benzyloxy)-2,4-difluorophenyl)piperazine-l-carboxylate (3, 18 g, 44.55 mmol) in ethanol (180 mL), 10% Pd-C (2.7 g, 15% Wt.) was added and the reaction mixture was stirred under H 2 atmosphere at RT for 5 h. After completion (TLC), the reaction mixture was filtered through celite and washed with methanol (500 mL).
  • Step 4 tert-butyl 4-(5-(2-amino-2-oxoethoxy)-2,4-difluorophenyl)piperazine-l- carboxylate (5): To a suspension of tert-butyl 4-(2,4-difluoro-5- hydroxyphenyl)piperazine-l-carboxylate (4, 10 g, 31.7 mmol) and bromoacetamide (5.25 g, 38.09 mmol) in ⁇ , ⁇ -Dimethyl formamide (100 mL), K2CO3 (13.14 g, 95.23 mmol) was added. The reaction mixture was stirred at 90 °C for 5 h and monitored by TLC.
  • Step 5 2-(2, 4-difluoro-5-(piperazin-l-yl)phenoxy)acetamide (6): To an ice cold solution of tert-butyl 4-(5-(2-amino-2-oxoethoxy)-2,4-difluorophenyl)-piperazine-l- carboxylate (5, 8.0 g, 21.5 mmol) in DCM, 4 N HCl in Dioxane (80 mL) was added and the reaction mixture was stirred at RT for 5 h. After completion of the reaction (TLC), the HCl salt was filtered.
  • Step 6 2-(5-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e] [l,2,4]triazolo [1,5- c]pyrimidin-3(2H)-yl)ethyl)piperazin-l-yl)-2,4-difluorophenoxy)acetamide
  • reaction mass was concentrated to half of the volume under reduced pressure and cooled to 0°C.
  • the product was precipitated as pale yellow solid. It was filtered and dried. As the purity was not good, it was suspended in DMSO (150 mL) and heated at 110 °C for 1 h and filtered in hot condition. The filtrate was cooled to 0 °C, diluted with MeOH and then water was added slowly to facilitate the precipitation. The mixture was stirred at RT for 1 h and filtered. The solid was washed with water and methanol to get compound 4 as light yellow solid (2.5 g, 34%).
  • Step 1 Synthesis of tert-butyl 4-(2-fluoro-4-(2-(methylthio)ethoxy)phenyl)piperazine- 1-carboxylate (2): To a solution of tert-butyl 4-(2-fluoro-4-hydroxyphenyl)piperazine-l- carboxylate (1, 0.3 g, 1.102 mmol, 1 eq) and l-chloro-2-methylsulfanyl-ethane (0.168 g, 1.519 mmol, 1 eq) in N,N-dimethylformamide (3 mL), K2CO3 (0.419 g, 3.027 mmol, 2 eq) was added and the reaction mixture was heated at 90 °C for 16 h.
  • Peak 1 from SFC purification was arbitrarily considered as (S) isomer and peak 2 was considered as (R) isomer.
  • Step 3 Synthesis of (S)-l-(2-fluoro-4-(2-(methylsulfinyl)ethoxy)phenyl)piperazine (5): To an ice cold solution of tert-butyl (S)-4-(2-fluoro-4-(2- (methylsulfinyl)ethoxy)phenyl)-piperazine-l-carboxylate (3, 0.13 g) in dichloromethane (1 mL), 4M HC1 in dioxane (1 mL) was added 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.
  • Step 1 (R)-l-(2-fluoro-4-(2-(methylsulfinyl)ethoxy)phenyl)piperazine (6): To an ice- cold solution of tert-butyl (R)-4-(2-fluoro-4-(2-(methylsulfinyl)ethoxy)-phenyl)piperazine- 1-carboxylate (4, 0.13 g,) in dichloromethane (1 mL), 4M HC1 in dioxane (0.5 mL) was added 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 crude residue obtained was triturated with diethyl ether.
  • Step 2 (R)-5-amino-3-(2-(4-(2-fluoro-4-(2-(methylsulfinyl)ethoxy)phenyl)-piperazin- l-yl)ethyl)-8-(furan-2-yl)thiazolo [5,4-e] [1 ,2,4] triazolo [ 1 ,5-c] pyrimidin-2(3H)-one (Compound 6): A mixture of 2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4- e][l,2,4]triazolo[l,5-c]pyrimidin-3(2H)-yl)ethyl methane sulfonate (7, 0.11 g, 0.303 mmol, 1 eq), (R)-l-(2-fluoro-4-(2-(methylsulfinyl)-ethoxy)phenyl)piperazine (6, 0.094
  • Examples 7, 8a and 8b (R,S)-5-amino-3-(2-(4-(2,4-difluoro-5-(2- (methylsulfinyl)ethoxy)-phenyl)-piperazin-l-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4- e] [l,2,4]triazolo[l,5-c]-pyrimidin-2(3H)-one, (+)-5-amino-3-(2-(4-(2,4-difluoro-5-(2- (methylsulfinyl)ethoxy)phenyl)piperazin-l-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4- e] [l,2,4]triazolo[l,5-c]pyrimidin-2(3H)-one and (-)-5-amino-3-(2-(4-(2,4-difluoro-5- (2
  • Step 1 Synthesis of tert-butyl 4-(2,4-difluoro-5-(2-(methylthio)ethoxy)- phenyl)piperazine-l-carboxylate (2): To a solution of tert-butyl 4-(2,4-difluoro-5- hydroxyphenyl)piperazine-l-carboxylate (1, 0.5 g, 1.591 mmol, 1 eq) and l-chloro-2- methylsulfanyl-ethane (0.264 g, 2.386 mmol, 1.5 eq) in N,N-dimethylformamide (5 mL), K2CO3 (0.439 g, 3.181 mmol, 2 eq) was added and the reaction mixture was heated at 90 °C for 16 h.
  • Step 2 Synthesis of tert-butyl 4-(2,4-difluoro-5-(2-(methylsulfinyl)ethoxy)phenyl)- piperazine-l-carboxylate (3, 4): To an ice cold solution of tert-butyl 4-(2,4-difluoro-5-(2- (methylthio)ethoxy)-phenyl)piperazine-l-carboxylate (2, 0.5 g, 0.001 mmol, 1 eq) in acetic acid (10 mL), hydrogen peroxide (0.312 mL) was added drop wise and stirred at same temperature for 2 h.
  • Step 3 Synthesis of (R,S)-l-(2,4-difluoro-5-(2- (methylsulfinyl)ethoxy)phenyl)piperazine (5RS): To an ice cold solution of tert-butyl (R,S)-4-(2,4-difluoro-5-(2-(methylsulfinyl)ethoxy)phenyl)-piperazine-l-carboxylate (racemic mixture of 3 and 4, 0.15 g, 0.371 mmol, 1 eq) in dichloromethane (2 mL), 4M HC1 in dioxane (0.5 mL) was added and the reaction mixture was stirred at 0°C for 1 h.
  • Step 4 for Compound 7 Synthesis of (R,S)-5-amino-3-(2-(4-(2,4-difluoro-5-(2- (methylsulfinyl)ethoxy)-phenyl)-piperazin-l-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4- e] [l,2,4]triazolo[l,5-c]-pyrimidin-2(3H)-one:To a solution of 2-(5-amino-8-(furan-2-yl)- 2-oxothiazolo[5,4-e][l,2,4]triazolo[l,5-c]pyrimidin-3(2H)-yl)ethyl methane sulfonate (6, 105 mg, 0.265 mmol, 1.0 eq) in DMF (2 mL), (R)-l-(2,4-difiuoro-5-(2- (methylsulfin
  • Step 4' for Compound 8a Synthesis of (+)-5-amino-3-(2-(4-(2,4-difluoro-5-(2- (methylsulfinyl)ethoxy)-phenyl)-piperazin-l-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4- e] [l,2,4]triazolo[l,5-c]-pyrimidin-2(3H)-one was prepared according to the same procedure described for Compound 7, starting from (+)-l-(2,4-difluoro-5-(2- (methylsulfmyl)ethoxy)phenyl)piperazine.
  • Steps 3" and 4" for Compound 8b (-)-5-amino-3-(2-(4-(2,4-difluoro-5-(2- (methylsulfinyl)ethoxy)phenyl)piperazin-l-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4- e] [l,2,4]triazolo[l,5-c]pyrimidin-2(3H)-one was prepared according to the same procedure described for Compound 7, starting from (-)-4-(2,4-difluoro-5-(2- (methylsulfinyl)ethoxy)phenyl)-piperazine-l -carboxylate (3) leading by a step 3" to the (- )-l-(2,4-difluoro-5-(2-(methylsulfinyl)ethoxy)phenyl)piperazine.
  • Step 1 Synthesis of tert-butyl 4-(2,4-difluoro-5-(2-(methylsulfonyl)ethoxy)phenyl)- piperazine-l-carboxylate: In an open vial tert-butyl 4-(2,4-difluoro-5-(2- (methylthio)ethoxy)phenyl)-piperazine-l-carboxylate (20 g, 51.48 mmol, prepared as described in Example 7, Step 1) and urea hydrogen peroxide (21.78 g, 231.68 mmol) were heated to 90 °C.
  • Step 2 Synthesis of l-(2,4-difluoro-5-(2-(methylsulfonyl)ethoxy)phenyl)piperazine hydrochloride (7): To an ice cold solution of tert-butyl 4-(2,4-difluoro-5-(2- (methylsulfonyl)ethoxy)phenyl) piperazine-l-carboxylate (9 g, 21.40 mmol) in dichloromethane (50 mL) was added a solution of HC1 in in diethyl ether (50 mL). After stirring at 0°C for 0.5h, it was allowed to reach room temperature and stirred for 16h. The reaction mixture was concentrated under reduced pressure at room temperature. The residue obtained was triturated with diethyl ether to afford the pure product (10 g). LCMS (ESI positive ion) m/z: 321 (M+l).
  • Step 3 To a stirred suspension of l-(2,4-difluoro-5-(2- (methylsulfonyl)ethoxy)phenyl)piperazine hydrochloride (7 g, 22.13 mmol) in dry dichloroethane (70 mL), triethyl amine (6.259 g, 61.97 mmol) and freshly prepared 2-(5- amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][l,2,4]triazolo[l,5-c]pyrimidin-3(2H)-yl)- acetaldehyde (7 g, 22.13 mmol) were added.
  • Step 1 Synthesis of tert-butyl 4-(2-fluoro-4-hydroxyphenyl)piperazine-l-carboxylate (2): To a mixture of 4-Bromo-3-fluorophenol (1, 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) was added LHMDS (115 mL of 1.0 M solution in THF, 0.115 mol) at 0 °C under nitrogen. The reaction mixture was heated at 65 °C for 24 h and monitored by TLC.
  • Step 2 Synthesis of tert-butyl 4-(2-fluoro-4-(2-(methylthio)ethoxy)phenyl)piperazine-
  • Step 3 Synthesis of tert-butyl 4-(2-fluoro-4-(2-(methylsulfonyl)ethoxy)phenyl)- piperazine-l-carboxylate (4): To a solution of tert-butyl 4-[2-fluoro-4-(2- methylsulfanylethoxy)phenyl]piperazine-l-carboxylate (3, 0.5 g, 0.001 mmol) in 1,4- Dioxane (2 mL), Urea hydrogen peroxide (507.49 g, 0.005 mmol) was added. The mixture was heated to 85°C for 16h. After the completion of the reaction, it was concentrated under reduced pressure.
  • Step 4 Synthesis of l-(2-fluoro-4-(2-(methylsulfonyl)ethoxy)phenyl)piperazine (5): To an ice cold solution of tert-butyl 4-[2-fluoro-4-(2-methylsulfonylethoxy)phenyl] piperazine- 1-carboxylate (4, 0.22 g, 0.547 mmol) in dichloromethane (5 mL), 2M HC1 in diethyl ether (2 mL) was added and the reaction mixture was stirred at 0°C for lh. After completion (TLC), the reaction mixture was concentrated under reduced pressure at room temperature. The residue obtained was triturated with diethyl ether to afford the pure product. Then it was dissolved in methanol, passed through Si-Carbonate resin for making free base (0.105 g crude compound) directly used for the next step.
  • Step 5 Synthesis of 5-amino-3-(2-(4-(2-fluoro-4-(2-(methylsulfonyl)ethoxy)phenyl)- piperazin- l-yl)ethyl)-8-(furan-2-yl)thiazolo [5,4-e] [1 ,2,4] triazolo [ 1 ,5-c] pyrimidin-
  • Example 80 5-amino-3-(2-(4-(2-fluoro-4-(S-methylsulfonimidoyl)phenyl)piperazin- l-yl)ethyl)-8-(furan-2-yl)thiazolo
  • Step 1 Synthesis of l,2-difluoro-4-(methylsulfinyl)benzene (2): To an ice cold solution of (3,4-difluorophenyl)(methyl)sulfane (1, 3.0 g, 18.73 mmol) in DCM, was added 3- chloroperbenzoic acid (6.78 g, 39.33 mmol) and stirred the reaction mixture at RT for 16 h. After the reaction completion (TLC), the reaction mixture was diluted with ice cold water (30mL) and the crude product was extracted with DCM. Organic layer was successively washed with aqueous sodium thiosulphate, 10% NaHC0 3?
  • Step 2 Synthesis of (3,4-difluorophenyl)(imino)(methyl)-16-sulfanone (3): To a solution of l,2-difluoro-4-(methylsulfinyl)benzene (2, 2.8 g, 15.89 mmol) in dichloromethane (60 mL) was added trifluoroacetamide (3.59 g, 31.79 mmol), magnesium oxide (2.54 g, 63.57 mmol) and rhodium diacetate dimer (0.172 g, 0.429 mmol) and the reaction mixture was purged with N 2 for 2 min.
  • Step 3 Synthesis of (3-fluoro-4-(piperazin-l-yl)phenyl)(imino)(methyl)-16-sulfanone (4): To a solution of (3,4-difluorophenyl)(imino)(methyl)-16-sulfanone (0.7 g, 3.66 mmol) in N,N-Dimethylformamide (10 mL), was added Piperazine (0.32 g, 3.66 mmol),
  • Step 4 Synthesis of 5-amino-3-(2-(4-(2-fluoro-4-(S-methylsulfonimidoyl) phenyl) piperazin- l-yl)ethyl)-8-(furan-2-yl)thiazolo [5,4-e] [1 ,2,4] triazolo [ 1 ,5-c] pyrimidin-2 (3H)-one
  • Compound 80 A mixture of (3-fluoro-4-(piperazin-l-yl)phenyl) (imino)(methyl)- 16-sulfanone (4, 0.14 g, 0.545 mmol), 2-(5-amino-8-(furan-2-yl)-2- oxothiazolo [5,4-e] [1,2,4] triazolo[l,5-c] pyrimidin-3(2H)-yl)ethyl methanesulfonate (0.18 g, 0.45 mmol) and DIPE
  • Example 81 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-l-yl)-N-(2-(dimethylamino)ethyl)-2,4- difluorobenzamide
  • Step 1 Synthesis of methyl 5-amino-2,4-difluorobenzoate (2): To an ice cold solution of 5-amino-2,4-difluoro-benzoic acid (1, 0 g,0.017 mol) in methanol (20.0 mL), thionyl chloride (2.514 mL, 0.035 mol) was added. The resulting mixture was heated at 80°C for lh. Progress of the reaction was monitored by TLC. The reaction mixture was concentrated under reduced pressure. DCM and water was added to the reaction mixture. Combined organic layer was dried over sodium sulphate, concentrated under reduced pressure to afford the product methyl 5-amino-2,4-difluoro-benzoate (2.8 g, 86.0%).
  • Step 2 Synthesis of methyl 2,4-difluoro-5-(piperazin-l-yl)benzoate (3): A mixture of methyl 5-amino-2,4-difluoro-benzoate (2, 3.0 g, 0.016 mol) and 2-chloro-N-(2- chloroethyl)ethanamine hydrochloride (3.719 g, 0.021 mol) in diethylene glycol monomethyl ether (12 mL) was heated to 170°C for 2.5h. Progress of the reaction was monitored by TLC. Water was added to the reaction mixture and extracted with ethyl acetate. The organic part was discarded.
  • Step 3 Synthesis of tert-butyl 4-(2,4-difluoro-5-(methoxycarbonyl)phenyl)piperazine- 1-carboxylate (4): To an ice cold solution of methyl 2,4-difluoro-5-piperazin-l-yl- benzoate (3, 1.0 g, 0.009 mol) in DCM (10 mL), triethyl amine (1.510 mL, 0.012mol) and boc anhydride (1.278 mL, 0.006 mol) were added. The resulting mixture was stirred at room temperature for 16h. Progress of the reaction was monitored by TLC. The reaction mixture was diluted with water and extracted with ethyl acetate.
  • Step 4 Synthesis of 5-(4-(tert-butoxycarbonyl)piperazin-l-yl)-2,4-difluorobenzoic acid (5): To a stirred solution of tert-butyl 4-(2,4-difluoro-5- (methoxycarbonyl)phenyl)piperazine-l-carboxylate (4, 1.0 g, 0.003 mol) in THF : water (20 mL, 3: 1), lithium hydroxide (0.176 g, 0.004 mol) was added and reaction mixture was stirred at RT for 16h. 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.
  • Step 5 Synthesis of tert-butyl 4-(5-((2-(dimethylamino)ethyl)carbamoyl)-2,4- difluorophenyl)piperazine-l-carboxylate (6): To a stirred solution of 5-(4-(tert- butoxycarbonyl)piperazin-l-yl)-2,4-difluorobenzoic acid (5, 0.200 g, 0.0005 mol) in DCM (10 mL), Nl,Nl-dimethylethane-l,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 successively added.
  • Step 6 Synthesis of N-(2-(dimethylamino)ethyl)-2,4-difluoro-5-(piperazin-l-yl)- benzamide (7): To an ice cold solution of tert-butyl 4-(5-((2- (dimethylamino)ethyl)carbamoyl)-2,4-difluorophenyl)piperazine- 1 -carboxylate (6, 0.200 g, 0.0004 mol) in DCM (10 mL), HCl in diethyl ether solution (0.121 mL, 4M soln) was added. The resulting mixture was stirred at RT for 16h. Progress of the reaction was monitored by TLC.
  • Step 7 Synthesis of 5-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4- e] [l,2,4]triazolo-[l,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-l-yl)-N-(2- (dimethylamino)ethyl)-2,4-difluorobenzamide (Compound 81): To a stirred mixture of 2-(5-amino-8-(mran-2-yl)-2-oxothiazolo[5,4-e][l,2,4]triazolo[l,5-c]pyrimidin-3(2H)- yl)ethyl methane sulfonate (8, 120 mg, 0.0003 mol) and N-[2-(dimethylamino)ethyl]-2,4- difluoro-5-piperazin-l-yl-benz
  • Examples 83 and 84 5-amino-3-(2-(4-(2-fluoro-4-(((3R,4R)-4- hydroxytetrahydrofuran-3-yl)oxy)phenyl)piperazin-l-yl)ethyl)-8-(furan-2- yl)thiazolo[5,4-e] [l,2,4]triazolo[l,5-c]pyrimidin-2(3H)-one and 5-amino-3-(2-(4-(2- fluoro-4-(((3S,4S)-4-hydroxytetrahydrofuran-3-yl)oxy)phenyl)piperazin-l-yl)ethyl)- -(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): To a stirred solution of 3-fluoro-4- nitrophenol (1, 10 g, 0.064 mol) in ethyl acetate (140 mL), Pd/C (4.0 g, 0.038 mol) was added under nitrogen atmosphere. The reaction mixture was stirred under hydrogen bladder pressure for 16h. The progress of the reaction was monitored by TLC. The reaction mixture was filtered through Celite bed, and the filtrate was concentrated under reduced pressure to afford 4-amino-3-fluorophenol as light pink colored solid (6.9 g, 94%). LCMS (ESI positive ion); m/z: calculated: 127.12; Observed; 128.2 (M+l).
  • Step 2 Synthesis of 3-fluoro-4-(piperazin-l-yl)phenol hydrochloride (3): To a stirred solution of 4-amino-3-fluorophenol (2, 6.9 g, 0.054 mol) in sulfolane (15 mL), bis(2- chloroethyl)amine hydrochloride (13.56 g, 0.076 mol) was added. The reaction mixture was heated at 150°C for 16h. After the completion of the reaction, the reaction mixture was cooled to RT. About 30 mL of cold acetone was added and stirred at 0°C for 0.5h.
  • Step 3 Synthesis of tert-butyl 4-(2-fluoro-4-hydroxyphenyl)piperazine-l-carboxylate (4): To an ice cold stirred solution of 3-fluoro-4-(piperazin-l-yl)phenol hydrochloride (3, 3.0 g, 0.015 mol) in DMF (30 mL), triethyl amine was added till it becomes basic. Then BOC anhydride (3.0 mL, 0.041 mol) was added and the reaction was kept at 0°C for 0.5h. After the reaction completion it was diluted with ethyl acetate and water. The organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure.
  • Step 4 Synthesis of tert-butyl 4-(2-fluoro-4-((4-hydroxytetrahydrofuran-3-yl)oxy)- phenyl)piperazine-l-carboxylate (5): To a stirred solution of tert-butyl 4-(2-fluoro-4- hydroxyphenyl)piperazine-l-carboxylate (4, 1.5 g, 0.005 mol) in dioxane (25 mL), 3,6- dioxabicyclo[3.1.0]hexane (1.089 g, 0.013 mol) and cesium carbonate (2.47 g, 0.008 mol) were added. The reaction mixture was heated at 100°C for 16h.
  • Step 5 Synthesis of 4-(3-fluoro-4-(piperazin-l-yl)phenoxy)tetrahydrofuran-3-ol (6):
  • Step 6 Synthesis of 5-amino-3-(2-(4-(2-fluoro-4-(((3R,4R)-4- hydroxytetrahydrofuran-3-yl)oxy)phenyl)piperazin-l-yl)ethyl)-8-(furan-2- yl)thiazolo[5,4-e] [l,2,4]triazolo[l,5-c]-pyrimidin-2(3H)-one (Compound 83) and 5- amino-3-(2-(4-(2-fluoro-4-(((3S,4S)-4-hydroxy-tetrahydrofuran-3- yl)oxy)phenyl)piperazin- l-yl)ethyl)-8-(furan-2-yl)thiazolo [5,4-e] - [ 1,2,4] triazolo [ 1 ,5- c]pyrimidin-2(3H)-one (Compounds 84): To a stirred solution of 2-(
  • Example 88 5-amino-3-(2-(4-(2-fluoro-5-(2-hydroxyethoxy)phenyl)piperazin-l- 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)(tert-butyl)dimethylsilane (2): A mixture of 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), K2C03 (2.49 g, 0.018 mol) was heated to 70°C for 16h. Progress of the reaction was monitored by TLC. After the reaction completion, water (20 mL) was added to the reaction mixture and extracted with dichloromethane (30 mL x 2). The combined organic part was washed with saturated brine solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford the title compound (2 g, 29%), which was used as such for the next step.
  • Step 2 Synthesis of l-(5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-2-fluorophenyl)- piperazine (3): To a stirred solution of 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), NaOBu-t (412 mg) was added. The resulting mixture was degassed with nitrogen.
  • Step 3 Synthesis of 2-(4-fluoro-3-(piperazin-l-yl)phenoxy)ethan-l-ol (4): To an ice cold solution of l-(5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-2-fluorophenyl)-piperazine (3, 0.354 g, 0.0009 mol) in THF (10 mL), TBAF (0.499 mL, 4 M in THF) was added slowly. The resulting mixture was allowed to reach RT and stirred there for 16h. After reaction completion, the reaction mixture was diluted with water and ethyl acetate. The organic layer separated was dried over anhydrous sodium sulphate, concentrated under reduced pressure. The crude product obtained was purified by column chromatography to afford the title compound (0.240 g, 98.99%). LCMS (ESI positive ion) m/z: calculated: 240.28; observed: 241.2 (M+l).
  • Step 4 Synthesis of 5-amino-3-(2-(4-(2-fluoro-5-(2-hydroxyethoxy)phenyl)piperazin- l-yl)ethyl)-8-(furan-2-yl)thiazolo [5,4-e] [1 ,2,4] triazolo [ 1 ,5-c] pyrimidin-2(3H)-one
  • Compound 88 To a stirred solution of 2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4- e][l,2,4]triazolo[l,5-c]pyrimidin-3(2H)-yl)ethyl methane sulfonate (0.300 g, 0.0007 mol) in DMF (8 mL), 2-(4-fluoro-3-(piperazin-l-yl)phenoxy)ethan-l-ol (4, 0.218 g, 0.0009 mol) and DIPE
  • Example 90 5-amino-3-(2-(4-(2,4-difluoro-5-(morpholin-3- ylmethoxy)phenyl)piperazin-l-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 3-((5-(4-((benzyloxy)carbonyl)piperazin-l-yl)-2,4- difluorophenoxy)methyl)morpholine-4-carboxylate (2): To a stirred solution of benzyl 4-(2,4-difluoro-5-hydroxyphenyl)piperazine-l-carboxylate (1, 1.2 g, 2.9 mmol) and tert- butyl 3-(hydroxymethyl)morpholine-4-carboxylate (1.1 g, 4.3 mmol) in toluene (10 mL) was added triphenyl phosphine (1.8 g, 6.9 mol) followed by the drop-wise addition of DIAD (1.39 g, 6.9 mmol) at 0°C.
  • reaction mixture was stirred at 110 °C for 16 h. After the reaction completion (TLC), the reaction mixture was diluted with water (20mL) and extracted with ethyl acetate. Organic layer was washed with saturated brine solution, dried over anhydrous Na 2 S0 4 , filtered and concentrated under reduced pressure. The crude obtained was purified by column chromatography (20% EtOAc/Hexane) to afford the title compound as brown liquid (1.4 g, 63.8%); LCMS (ESI positive ion) m/z: calculated: 547.25; observed: 548.1 (M+l).
  • Step 2 Synthesis of tert-butyl 3-((2,4-difluoro-5-(piperazin-l-yl)phenoxy)methyl) morpholine-4-carboxylate (3): To stirred solution of tert-butyl 3-((5-(4- ((benzyloxy)carbonyl)piperazin-l-yl)-2,4-difluorophenoxy)methyl)morpholine-4- carboxylate (0.5 g, 0.91 mmol) in EtOAc (20mL) was added 10% Pd/C (0.2 g) under nitrogen atmosphere. The reaction mixture was stirred under hydrogenation atmosphere at room temperature for 16 h. The reaction progress was monitored by TLC.
  • Step 3 Synthesis of tert-butyl 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- l-yl)-2,4- difluorophenoxy)-methyl) morpholine-4-carboxylate (4): To a stirred solution of tert- butyl 3-((2,4-difluoro-5-(piperazin- 1 -yl)phenoxy)methyl)-morpholine-4-carboxylate (3, 100 mg, 0.242 mmol) and 2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4- e][l,2,4]triazolo[l,5-c]pyrimidin-3(2H)-y
  • Step 4 Synthesis of 5-amino-3-(2-(4-(2,4-difluoro-5-(morpholin-3-ylmethoxy)- phenyl)piperazin- l-yl)ethyl)-8-(furan-2-yl)thiazolo [5,4-e] [1 ,2,4] triazolo [ 1 ,5- c]pyrimidin-2(3H)-one (Compound 90): To a stirred solution of tert-butyl 3-((3-(4-(2-(5- amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][l,2,4]triazolo[l,5-c]pyrimidin-3(2H)- yl)ethyl)piperazin-l-yl)-4,5-difluorophenoxy)-methyl)-morpholine -4-carboxylate (4, 25 mg, 0.035 mmol) in DCM (5,
  • Example 91 5-amino-3-(2-(4-(2,4-difluoro-5-(((3S,4S)-4-fluoropyrrolidin-3- yl)oxy)phenyl)piperazin- l-yl)ethyl)-8-(furan-2-yl)thiazolo [5,4-e] [1 ,2,4] triazolo [ 1 ,5- c] pyrimidin-2(3H)-one
  • Step 1 Synthesis of benzyl 4-(5-((l-(ter ⁇ butoxycarbonyl)-4-hydroxypyrrolidin-3- yl)oxy)-2,4-difluorophenyl)piperazine-l-carboxylate (2): To a suspension of benzyl 4- (2,4-difluoro-5-hydroxyphenyl)piperazine-l-carboxylate (6.0g, 17.22 mmol) and tert- butyl 6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylate (3.82 g, 20.67 mmol) in dry DMF (30mL), was added K2CO3 (7.13 g, 51.67 mmol ) and the reaction mixture was heated at 100°C for 16h. After completion of reaction (TLC), the reaction mixture was
  • Step 2 Synthesis of benzyl 4-(5-(((3S,4S)-l-(tert-butoxycarbonyl)-4-fluoropyrrolidin- 3-yl)oxy)-2,4-difluorophenyl)piperazine-l-carboxylate (3): A solution of benzyl 4-(5- ((l-(tert-butoxycarbonyl)-4-hydroxypyrrolidin-3-yl)oxy)-2,4-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 16h.
  • Step 3 Synthesis of tert-butyl (3S, 4S)-3-(2,4-difluoro-5-(piperazin-l-yl)phenoxy)-4- fluoropyrrolidine-l-carboxylate (4): A suspension of benzyl 4-(5-(((3S,4S)-l-(tert- butoxycarbonyl)-4-fluoropyrrolidin-3-yl)oxy)-2,4-difluorophenyl)piperazine-l- carboxylate (0.23 g, 0.429 mmol) in ethyl acetate (10 mL) was charged with 10% Palladium on carbon (0.049 g) and stirred under hydrogen bladder pressure for 5h at room temperature.
  • Step 4 Synthesis of tert-butyl (3R,4R)-3-(5-(4-(2-(5-amino-8-(furan-2-yl)-2- oxothiazolo [5,4-e] [l,2,4]triazolo[l,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-l-yl)-2,4- difluorophenoxy)-4-fluoropyrrolidine-l-carboxylate (5): To a solution of tert-butyl (3S, 4S)-3-(2,4-difluoro-5-(piperazin-l-yl)phenoxy)-4-fluoropyrrolidine-l-carboxylate (0.16 g, 0.399 mmol) and 2-(5-amino-8-(furan-2-yl) -2-oxothiazolo [5,4-e][l,2,4]triazolo[l,5-c
  • Step 5 Synthesis of 5-amino-3-(2-(4-(2,4-difluoro-5-(((3R,4R)-4-fluoropyrrolidin-3- yl)oxy)phenyl)piperazin- l-yl)ethyl)-8-(furan-2-yl)thiazolo [5,4-e] [1 ,2,4] triazolo [ 1 ,5- c]pyrimidin-2(3H)-one (Compound 91): To an ice cooled solution of tert-butyl (3R,4R)- 3-(5-(4-(2-(5-amino-8-(furan-2-yl)-2- oxothiazolo[5,4-e][l,2,4]triazolo[l,5-c]pyrimidin- 3(2H)-yl)ethyl)piperazin- 1 -yl)-2,4-difluorophenoxy)-4-fluoro
  • Step 1 Synthesis of (R)-2-oxopyrrolidin-3-yl methanesulfonate (6): To a stirred solution of (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 mesyl chloride (1.36 g, 1 1.9 mmol) at 0 °C. Resulting reaction mixture was stirred at RT for 2 h. After completion of the reaction, reaction mixture was quenched with NH 4 C1 solution and extracted with DCM. Organic layer was washed with saturated brine solution, dried over anhydrous Na 2 S0 4 , filtered and concentrated under reduced pressure.
  • Step 2 Synthesis of tert-butyl (S)-4-(2,4-difluoro-5-((2-oxopyrrolidin-3- yl)oxy)phenyl) piperazine-l-carboxylate (2): To a stirred solution of tert-butyl 4-(2,4- difluoro-5-hydroxyphenyl)piperazine-l-carboxylate (1, 900 mg, 2.86 mmol) in DMF (20 mL) was added K2CO3 (791 mg, 5.73 mmol) and (R)-2-oxopyrrolidin-3-yl methanesulfonate (6, 769 mg, 4.3 mmol) and heated at 80°C for 16 h.
  • Step 3 Synthesis of (S)-3-(2,4-difluoro-5-(piperazin-l-yl)phenoxy)pyrrolidin-2-one (3): To a stirred solution of tert-butyl (S)-4-(2,4-difluoro-5-((2-oxopyrrolidin-3- yl)oxy)phenyl) piperazine-l-carboxylate (2, 900 mg, 2.26 mmol) in dichloromethane (20 mL) at 0 °C, 4 N HC1 in dioxane (2.5 mL) was added dropwise and stirred at RT for 3 h. After the reaction completion (TLC), the reaction mixture was concentrated under reduced pressure.
  • the salt was dissolved in methanol and neutralized using tosic acid scavenger resin to get the free base as the off white gum (400 mg, 58.2%); LCMS (ESI positive ion) m/z: calculated: 297.13; observed: 298.1 (M+l).
  • Step 4 Synthesis of (S)-5-amino-3-(2-(4-(2,4-difluoro-5-((2-oxopyrrolidin-3-yl)oxy)- phenyl)piperazin- l-yl)ethyl)-8-(furan-2-yl)thiazolo [5,4-e] [1 ,2,4] triazolo [ 1 ,5-c] pyri- midin-2(3H)-one (Compound 95): To a stirred solution of (S)-3-(2,4-difluoro-5- (piperazin-l-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][l,2,4]triazolo[l,5-c
  • reaction mixture was stirred at 120 °C for 16h. After completion of 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 S04 and filtered.
  • Step 1 Synthesis of (S)-2-oxopyrrolidin-3-yl methanesulfonate (6): To a solution of (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 mesyl chloride (2.49 g, 0.022 mol) at 0 °C. Resulting reaction mixture was stirred at RT for 2 h. After completion of the reaction, reaction mixture was quenched with NH4CI solution and extracted with DCM.
  • Step 2 Synthesis of tert-butyl (R)-4-(2,4-difluoro-5-((2-oxopyrrolidin-3- yl)oxy)phenyl) piperazine-l-carboxylate (2): To a solution of tert-butyl 4-(2,4-difluoro- 5-hydroxyphenyl)piperazine-l-carboxylate (1, 1.5 g, 4.8 mmol) in DMF (20 mL) was added (S)-2-oxopyrrolidin-3-yl methanesulfonate (6, 1.3 g, 7.2 mmol) and K2CO3 (1.32 g, 9.6 mmol) and heated to 90 °C for 16 h.
  • reaction mixture was treated with saturated NH4CI solution and extracted with ethyl acetate. Organic layer was washed with saturated brine solution, dried over anhydrous Na 2 S04, filtered and concentrated under reduced pressure. The crude reaction mixture was purified by column chromatography to afford the title compound as pale brown solid (1.0 g 45.8%); LCMS (ESI positive ion) m/z: calculated: 397.18; observed: 398.1 (M+l).
  • Step 3 Synthesis of (R)-3-(2,4-difluoro-5-(piperazin-l-yl)phenoxy)pyrrolidin-2-one (3): To a stirred solution of tert-butyl 4-[2,4-difluoro-5-[(3R)-2-oxopyrrolidin-3- yl]oxy)phenyl] piperazine-l-carboxylate (2, 1.0 g, 2.5 mmol) in dichloromethane (15 mL) at 0 °C, 4 N HC1 in dioxane (10 mL) was added dropwise and stirred at RT for 2 h. After the reaction completion (TLC), the reaction mixture was concentrated under reduced pressure.
  • Step 4 Synthesis of (R)-5-amino-3-(2-(4-(2,4-difluoro-5-((2-oxopyrrolidin-3-yl)oxy)- phenyl)piperazin- l-yl)ethyl)-8-(furan-2-yl)thiazolo [5,4-e] [1 ,2,4] triazolo [ 1 ,5- c]pyrimidin-2(3H)-one (Compound 96): To a solution of 2-(5-amino-8-(furan-2-yl)-2- oxothiazolo[5,4-e][l,2,4]triazolo[l,5-c]pyrimidin-3(2H)-yl)ethyl methane sulfonate (300 mg, 0.76 mmol) in DMF (10 mL) was added DIPEA (0.49 g, 3.79 mmol) and (R)-3-(2,4- difluor
  • reaction mixture was stirred at 120 °C for 16 h. After completion of 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 S04 and filtered. The filtrate was concentrate under reduced pressure and purified by flash column chromatography using (3%> methanol/dichloromethane) to afford the title compound.
  • Step 1 Synthesis of tert-butyl 3-((4-(4-((benzyloxy)carbonyl)piperazin-l-yl)-3- fluorophenoxy)methyl)morpholine-4-carboxylate (2): To a stirred solution of benzyl 4- (2-fluoro-4-hydroxyphenyl)piperazine-l-carboxylate (1, 2.0 g, 6.05 mmol) in toluene (20 mL) was added tert-butyl 3-(hydroxymethyl)morpholine-4-carboxylate (2.63 g, 12.1 mmol), triphenyl phosphine (4.76 g, 12.1 mmol) and DIAD (2.45 g, 12.1 mmol) at RT.
  • reaction mixture was stirred at 120 °C in seal tube for 16 h. Reaction progress was monitored by TLC. After completion of the reaction, reaction mixture was partitioned between water and ethyl acetate and separated organic layer was washed with brine solution dried over anhydrous Na 2 S0 4 , and concentrated under vacuum to afford as a crude product.
  • Step 2 Synthesis of tert-butyl 3-((3-fluoro-4-(piperazin-l-yl)phenoxy)methyl)- morpholine-4-carboxylate (3): To a stirred solution of tert-butyl 3-((4-(4- ((benzyloxy)carbonyl)piperazin-l-yl)-3-fluorophenoxy)methyl)morpholine-4-carboxylate (2, 600 mg, 1.1 mmol) in ethyl acetate (10 mL) was added 10% Pd/C (120 mg) at RT and stirred under hydrogen atmosphere for 16 h. After completion, the reaction mixture was filtered using celite to remove the Pd/C.
  • Step 3 Synthesis of tert-butyl 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- l-yl)-3-fluorophenoxy)- methyl)-morpholine-4-carboxylate (4): To a stirred solution of 2-(5-amino-8-(furan-2- yl)-2-oxothiazolo[5,4-e][l,2,4]triazolo[l,5-c]pyrimidin-3(2H)-yl)ethyl methane sulfonate (200 mg, 0.631 mmol) and tert-butyl tert-butyl 3-((3-fluoro-4-(piperazin-l-
  • reaction progress was monitored by TLC, the reaction mixture was partitioned between water and ethyl acetate. The separated organic layer was washed with NaHC0 3 solution, brine solution, dried over anhydrous Na 2 SC"4 and concentrated under reduced pressure to afford crude product.
  • Step 4 Synthesis of 5-amino-3-(2-(4-(2-fluoro-4-(morpholin-3-ylmethoxy)phenyl)- piperazin- l-yl)ethyl)-8-(furan-2-yl)thiazolo [5,4-e] [1 ,2,4] triazolo [ 1 ,5-c] pyrimidin- 2(3H)-one (Compound 99): To a stirred solution of tert-butyl 3-((4-(4-(2-(5-amino-8- (furan-2-yl)-2-oxothiazolo[5,4-e]-[l,2,4]triazolo[l,5-c]pyrimidin-3(2H)- yl)ethyl)piperazin-l-yl)-3-fluorophenoxy)methyl) morpholine-4-carboxylate (4, 80 mg, 0.11 mmol) in DCM (5 mL) was added 2 N
  • Example 100 5-amino-3-(2-(4-(2-fluoro-4-(morpholin-2- ylmethoxy)phenyl)piperazin-l-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 2-(((methylsulfonyl)oxy)methyl)morpholine-4- carboxylate (2): To a cooled suspension of tert-butyl 2-(hydroxymethyl) morpholine-4- carboxylate (1, 5.0 g, 23.01 mmol) in dry DCM (50 mL) was added methane sulfonyl chloride drop wise (3.42 g, 29.92 mmol) and the reaction mixture was stirred at RT for 16h.
  • Step 2 Synthesis of tert-butyl 2-((4-(4-((benzyloxy)carbonyl)piperazin-l-yl)-3- fluorophenoxy)methyl)morpholine-4-carboxylate (3): To a suspension of benzyl 4-(2- fluoro-4-hydroxyphenyl) piperazine-l-carboxylate (2, 0.5 g, 1.51 mmol) and tert-butyl 2- (((methylsulfonyl)oxy)methyl)morpholine-4-carboxylate (0.53 g, 1.81 mmol) in dry DMF (10 mL) was added K2CO3 (0.63 g, 4.54 mmol ) and the reaction mixture was heated at
  • reaction mass was filtered through pad of celite and the filtrate was concentrated and purified by column chromatography (30% EtOAc/Hexane as eluent) to afford the title compound 3 as off white solid (0.35 g, 39%); LCMS (ESI positive ion) m/z: calculated: 529.61; observed: 530.3 (M+l).
  • Step 3 Synthesis of tert-butyl 2-((3-fluoro-4-(piperazin-l-yl)phenoxy)methyl) morpholine-4-carboxylate (4): A solution of of tert-butyl 2-((4-(4- ((benzyloxy)carbonyl)piperazin-l-yl)-3-fluorophenoxy) methyl) morpholine -4- carboxylate (3, 0.33 g, 0.62 mmol) in ethyl acetate (6 mL) was charged with 10% Palladium on Carbon (0.060 g) and the reaction mixture was stirred under hydrogen bladder pressure at room temperature for 16h.
  • Step 4 Synthesis of tert-butyl 2-((4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4- e] [l,2,4]triazolo[l,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-l-yl)-3-fluorophenoxy)- methyl)-orpholine-4-carboxylate (5): A mixture of 2-(5-amino-8-(furan-2-yl)-2- oxothiazolo[5,4-e][l,2,4]triazolo[l,5-c]pyrimidin-3(2H)-yl)ethyl methanesulfonate (0.16 g, 0.40 mmol), tert-butyl 2-((3-fluoro-4-(piperazin-l-yl)phenoxy)methyl) morpholine-4- carboxylate (4,
  • Step 5 Synthesis of 5-amino-3-(2-(4-(2-fluoro-4-(morpholin-2-ylmethoxy)phenyl) piperazin- l-yl)ethyl)-8-(furan-2-yl)thiazolo [5,4-e] [1 ,2,4] triazolo [ 1 ,5-c] pyrimidin- 2(3H)-one (Compound 100): To an ice cold solution of tert-butyl 2-((4-(4-(2-(5-amino-8- (furan-2-yl)-2-oxothiazolo [5,4-e] [1,2,4] triazolo[l,5-c]pyrimidin-3(2H)-yl)ethyl) piperazin- l-yl)-3-fluorophenoxy) methyl) morpholine -4-carboxylate (5, 0.04 g, 0.057 mmol) in dichloromethane (1 mL
  • Examples 101 and 102 5-amino-3-(2-(4-(2-fluoro-4-(((3R,4R)-4-fluoropyrrolidin-3- yl)oxy)phenyl)piperazin- l-yl)ethyl)-8-(furan-2-yl)thiazolo [5,4-e] [1 ,2,4] triazolo [ 1 ,5- c]pyrimidin-2(3H)-one and 5-amino-3-(2-(4-(2-fluoro-4-(((3S,4S)-4-fluoropyrrolidin- 3-yl)oxy)phenyl)piperazin- l-yl)ethyl)-8-(furan-2-yl)thiazolo [5,4-e] [1 ,2,4] triazolo [ 1 ,5- c]pyrimidin-2(3H)-one
  • Step 1 Synthesis of benzyl 4-(2-fluoro-4-hydroxyphenyl)piperazine-l-carboxylate (2): To an ice cold stirred solution of 4-bromo-3-fluorophenol (1, 15 g, 0.079 mol), benzyl piperazine-l-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), LHMDS (100 mL) was added. After addition, the reaction was allowed to reach room temperature. Then it was heated to 65°C for 24h.
  • Step 2 Synthesis of benzyl 4-(4-((l-(tert-butoxycarbonyl)-4-fluoropyrrolidin-3- yl)oxy)-2-fluorophenyl)piperazine-l-carboxylate (3): To a stirred solution of benzyl 4- (2-fluoro-4-hydroxyphenyl)piperazine-l-carboxylate (6.8g, 20.58 mmol), tert-butyl 6-oxa- 3-azabicyclo[3.1.0]hexane-3-carboxylate (4.986 g, 26.76 mmol) in 1,4-dioxane (20 mL),Cs2C03 (10.3 g, 30.88 mmol) was added.
  • Step 3 Synthesis of benzyl 4-(4-((-l-(tert-butoxycarbonyl)-4-fluoropyrrolidin-3- yl)oxy)-2-fluorophenyl)piperazine-l-carboxylate (4A & 4B): To an ice cold stirred solution of benzyl 4-(4-((l-(tert-butoxycarbonyl)-4-hydroxypyrrolidin-3-yl)oxy)-2- fluorophenyl)piperazine-l-carboxylate (3, 6 g, 11.64 mmol) in DCM (30 mL), DAST (5.816 g, 34.91 mmol) was added to the reaction mixture at -20°C.
  • Step 4 Synthesis of tert-butyl (3R,4R)-3-fluoro-4-(3-fluoro-4-(piperazin-l- yl)phenoxy)-pyrrolidine-l-carboxylate (5A): To a stirred solution of benzyl 4-(4- (((3R,4R)- 1 -(tert-butoxycarbonyl)-4-fluoropyrrolidin-3-yl)oxy)-2- fluorophenyl)piperazine-l-carboxylate (4A, 430 mg, 0.831 mmol), in ethyl acetate (10 mL), Pd/C 10%) (200 mg) was added under nitrogen atmosphere.
  • Step 5 Synthesis of tert-butyl (3R,4R)-3-(4-(4-(2-(5-amino-8-(furan-2-yl)-2- oxothiazolo-[5,4-e] [l,2,4]triazolo[l,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-l-yl)-3- fluorophenoxy)-4-fluoropyrrolidine-l-carboxylate (7A): To a stirred solution of tert- butyl (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- fluoropyr
  • Step 6 Synthesis of 5-amino-3-(2-(4-(2-fluoro-4-(((3R,4R)-4-fluoropyrrolidin-3- yl)oxy)phenyl)piperazin- l-yl)ethyl)-8-(furan-2-yl)thiazolo [5,4-e] [1 ,2,4] triazolo [1,5- c]pyrimidin-2(3H)-one (Compound 101):
  • Step 4 Synthesis of tert-butyl (3S,4S)-3-fluoro-4-(3-fluoro-4-(piperazin-l- yl)phenoxy)-pyrrolidine-l-carboxylate (5B): To a stirred solution of benzyl 4-(4- (((3S,4S)-l-(tert-butoxycarbonyl)-4-fluoropyrrolidin-3-yl)oxy)-2- fluorophenyl)piperazine-l-carboxylate (4B, 380 mg, 0.734 mmol), in ethyl acetate (10 mL), Pd/C 10% (200 mg) was added under nitrogen atmosphere.
  • Step 5 Synthesis of tert-butyl (3S,4S)-3-(4-(4-(4-(2-(5-amino-8-(furan-2-yl)-2- oxothiazolo-[5,4-e] [l,2,4]triazolo[l,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-l-yl)-3- fluorophenoxy)-4-fluoropyrrolidine-l-carboxylate (7B): To a stirred solution of tert- butyl (3S,4S)-3-(4-(4 2-(5-amino-8-(furan-2-yl)-2-oxothiazolo-[5,4-e][l,2,4]triazolo[l, 5- c]pyrimidin-3(2H)-yl)ethyl)piperazin- 1 -yl)-3-fluoro-phenoxy)-4-fluoropyrrol
  • Step 6 Synthesis of 5-amino-3-(2-(4-(2-fluoro-4-(((3S,4S)-4-fluoropyrrolidin-3- yl)oxy)-phenyl)piperazin- l-yl)ethyl)-8-(furan-2-yl)thiazolo [5,4-e] [1 ,2,4] triazolo [1,5- c]pyrimidin-2(3H)-one (Compound 102): To an ice cold stirred solution of tert-butyl (3S,4S)-3-(4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][l,2,4]triazolo[l,5- c]pyrimidin-3(2H)-yl)ethyl)piperazin- 1 -yl)-3-fluoro-phenoxy)-4-fluoropyrrolidine- 1 - carboxy
  • Example 111 5-amino-3-(2-(4-(2,4-difluoro-5-(((ls,4s)-l-oxidotetrahydro-2H- thiopyran-4-yl)oxy)phenyl)piperazin-l-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4- e] [1 ,2,4] triazolo [ 1 ,5-c] pyrimidin-2(3H)-one
  • Step 1 Synthesis of tetrahydro-2H-thiopyran-4-yl methane sulfonate (2):To an ice cold solution of tetrahydro-2H-thiopyran-4-ol (2.0 g, 16.94 mmol) and triethyl amine (4.26 g, 42.2 mmol) in dichloromethane (30 mL) was added wise, methane sulfonyl chloride (2.1g, 18.62 mmol) and the reaction mixture was stirred at RT for 12h. After the reaction completion 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/Hexane as eluent) to afford the title compound 2 as light brown liquid (3.1 g, 94%>). The crude was directly taken for the next step as such.
  • Step 2 Synthesis of tert-butyl 4-(2,4-difluoro-5-((tetrahydro-2H-thiopyran-4- yl)oxy)phenyl)piperazine-l-carboxylate (3): To a solution of tetrahydro-2H-thiopyran- 4-yl methanesulfonate (2, 2.25 g, 11.45 mmol) and tert-butyl 4-(2,4-difluoro-5- hydroxyphenyl)piperazine-l-carboxylate (3 g, 9.55 mmol) in N,N-dimethylformamide (10 mL), was added K2CO3 (2.69 g, 19.04 mmol) and the reaction mixture was heated at
  • Step 3 Synthesis of tert-butyl 4-(2,4-difluoro-5-((l-oxidotetrahydro-2H-thiopyran-4- yl)oxy)phenyl)piperazine-l-carboxylate (4): A solution of tert-butyl 4-(2,4-difluoro-5- (tetrahydro-2H-thiopyran-4-yl)oxy)phenyl) piperazine-l-carboxylate ( 3, 1.7 g, 4.101 mmol) in acetic acid (20 mL), was cooled to 0°C, 3 ⁇ 4(3 ⁇ 4 (30%, 2 mL) was added and the reaction mixture was stirred at the same temperature for lh.
  • 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 Na2SC"4, filtered and concentrated under reduced pressure to afford racemic product as off white solid. Yield: (1.62 g, 91.8%).
  • the isomers present in the racemic mixture were separated through SFC chiral method. The first peak eluted out (peak 1) was concentrated to afford the title compound 4 as off white solid (0.65 g, 80%); LCMS (ESI positive ion) m/z: calculated: 430.51; observed: 431.1 (M+l).
  • Step 4 Synthesis of (Is, 4s)-4-(2,4-difluoro-5-(piperazin-l-yl)phenoxy)tetrahydro-2H- thiopyran 1-oxide (5): To an ice cold solution of tert-butyl 4-(2,4-difluoro-5-(((ls,4s)-l- oxidotetrahydro-2H-thiopyran-4-yl)oxy)phenyl)piperazine-l-carboxylate (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 5h.
  • Step 5 Synthesis of 5-amino-3-(2-(4-(2,4-difluoro-5-(((ls, 4s)-l-oxidotetrahydro-2H- thiopyran-4-yl)oxy)phenyl)piperazin- l-yl)ethyl)-8-(furan-2-yl)thiazolo [5,4-e] [ 1 ,2,4] - triazolo[l,5-c] pyrimidin-2(3H)-one (Compound 111): A mixture of 2-(5-amino-8- (furan-2-yl)-2-oxothiazolo[5,4-e][l,2,4]triazolo[l,5-c]pyrimidin-3(2H)-yl)ethyl methanesulfonate (0.35 g, 0.88 mmol), (ls,4s)-4-(2,4-difluoro-5-(piperazin-l- y
  • Example 112 5-amino-3-(2-(4-(2,4-difluoro-5-(((lr,4r)-l-oxidotetrahydro-2H- thiopyran-4-yl)oxy)phenyl)piperazin-l-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4- -c] pyrimidin-2(3H)-one
  • Step 1 Synthesis of (lr, 4r)-4-(2,4-difluoro-5-(piperazin-l-yl)phenoxy)tetrahydro- 2H-thiopyran 1-oxide (2): To an ice cold solution of tert-butyl 4-(2,4-difluoro-5-(((lr,4r)- l-oxidotetrahydro-2H-thiopyran-4-yl)oxy)phenyl)piperazine-l-carboxylate (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 5h.
  • Step 2 Synthesis of 5-amino-3-(2-(4-(2,4-difluoro-5-(((lr,4r)-l-oxidotetrahydro-2H- thiopyran-4-yl)oxy)phenyl)piperazin- l-yl)ethyl)-8-(furan-2-yl)thiazolo [5,4-e] [ 1 ,2,4] - triazolo[l,5-c]pyrimidin-2(3H)-one (Compound 112): A mixture of 2-(5-amino-8- (furan-2-yl)-2-oxothiazolo[5,4-e][l,2,4]triazolo[l,5-c]pyrimidin-3(2H)-yl)ethyl methanesulfonate (0.23 g, 0.58 mmol), (lr,4r)-4-(2,4-difluoro-5-(piperazin-l- yl
  • Step 1 Synthesis of (3,4-difluorophenyl)(methyl)sulfane (2): To a stirred solution of 3,4-difiuorobenzenethiol (1, 8.0 g, 54.74 mmol) in DMF (25 mL) was added K2CO3 (9.08 g, 65.68 mmol) followed by Mel (8.5 g, 60.21 mmol) at 0°C in sealed tube and stirred at RT for 16 h. After completion (TLC), the reaction mass was poured into ice cold water and extracted with diethyl ether. Organic layer was washed with saturated brine solution, dried over anhydrous Na 2 S04, filtered and concentrated under reduced pressure to give the title compound. The crude product that was used for next step without purification (8.05 g, 88.1%).
  • Step 2 Synthesis of l,2-difluoro-4-(methylsulfinyl)benzene (3): To a stirred solution of (3,4-difluorophenyl)(methyl)sulfane (2, 8.0 g, 49.94 mmol) in DCM (120 mL) was added mCPBA (8.6 g, 49.94 mmol) at 0 °C and stirred at RT for 16 h. After completion (TLC), the reaction mass was quenched with saturated sodium bicarbonate solution and extracted with DCM. Organic layer was washed with saturated brine solution, dried over anhydrous Na 2 S0 4 , filtered and concentrated under reduced pressure. The crude obtained was purified by column chromatography to give the title compound (5.0 g, 55.6%); LCMS (ESI positive ion) m/z: calculated: 176.01; observed: 177.0 (M+l).
  • Step 3 Synthesis of tert-butyl 4-(2-fluoro-4-(methylsulfinyl)phenyl)piperazine-l- carboxylate (4, 5): To a stirred solution of tert-butyl piperazine-l-carboxylate (5.3 g, 28.38 mmol) in DMF (50 mL) at 0°C was added K 2 C0 3 (7.8 g, 56.76 mmol) followed by 1,2- difluoro-4-(methylsulfinyl)-benzene (3, 5.0 g, 28.38 mmol). The reaction mixture was stirred at 145 °C for 16 h.
  • Peak 1 from SFC purification was arbitrarily considered as (S) isomer and peak 2 was considered as (R) isomer.
  • Step 4 Synthesis of (S)-l-(2-fluoro-4-(methylsulfinyl)phenyl)piperazine (6): To a stirred solution of tert-butyl (S)-4-(2-fluoro-4-(methylsulfinyl)phenyl)piperazine-l- carboxylate (4, 800 mg, 0.292 mmol) in DCM (18 mL) was added TFA (1.3 g, 11.68 mmol) at 0 °C. The reaction mixture was stirred at RT for 3 h. After the reaction completion (TLC), the reaction mixture was concentrated under reduced pressure.
  • Examples 121 and 122 5-amino-3-(2-(4-(2-fluoro-4-(((ls,4s)-l-oxidotetrahydro-2H- thiopyran-4-yl)oxy)phenyl)piperazin-l-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4- e] [l,2,4]triazolo[l,5-c]pyrimidin-2(3H)-one and 5-amino-3-(2-(4-(2-fluoro-4-(((lr,4r)- l-oxidotetrahydro-2H-thiopyran-4-yl)oxy)phenyl)piperazin-l-yl)ethyl)-8-(furan-2- yl)thiazolo [5,4-e] [1 ,2,4] triazolo [ 1 ,5-c] pyrimidin-2(3H)-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), 5N sodium hydroxide solution (10 mL) solution was added slowly. Then sodium borohydride (0.488 g, 0.013 mol) was added portion wise. After addition, the reaction mixture was allowed to reach room temperature. After the reaction completion ( ⁇ lh), the reaction mixture was poured in to water and extracted with dichloromethane. Combined organic layer was washed with saturated brine solution, dried over anhydrous Na2S04, and concentrated under reduced pressure.
  • Step 2 Synthesis of tetrahydro-2H-thiopyran-4-yl methanesulfonate (12): To an ice cold solution of tetrahydrothiopyran-4-ol (11, 3.5 g, 0.030 mol) in dichloromethane (40 mL), triethyl amine (5.982 g, 0.059 mol) and methane sulfonyl chloride (0.727 g, 0.006 mol) were added. After 3h, the reaction mixture poured into water and extracted with dichloromethane. Combined organic layer was washed with saturated brine solution, dried over anhydrous Na 2 S0 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 tert-butyl 4-(2-fluoro-4-((tetrahydro-2H-thiopyran-4- yl)oxy)phenyl)-piperazine-l-carboxylate (2): To a solution of tert-butyl 4-(2,4-difluoro- 5-hydroxyphenyl)piperazine-l-carboxylate (1, 1.6 g, 5.399 mmol) and tetrahydrothiopyran-4-yl methane sulfonate (12, 1.272 g, 6.479 mmol) in DMF (20 mL), was added K2C03 (1.490 g, 10.80 mmol). The resulting mixture was heated to 100°C for 16h.
  • Step 4 Synthesis of tert-butyl 4-(2-fluoro-4-((l-oxidotetrahydro-2H-thiopyran-4- yl)oxy)phenyl)piperazine-l-carboxylate (3, 4): To an ice cold mixture of tert-butyl4-(2- fluoro-4-tetrahydrothiopyran-4-yloxy-phenyl)-piperazine-l-carboxylate (1.650 g, 4.161mmol,leq) in acetic acid (25 mL), hydrogen peroxide (1 mL) was added drop wise and stirred at same temperature for lh.
  • Step 5 Synthesis of (ls,4s)-4-(3-fluoro-4-(piperazin-l-yl)phenoxy)tetrahydro-2H- thiopyran 1-oxide (5): To an ice cold solution of tert-butyl 4-(2-fluoro-4-(((ls,4s)-l- oxidotetrahydro-2H-thiopyran-4-yl)oxy)phenyl)-piperazine-l-carboxylate (3, 0.5 g, 1.212 mmol) in dichloromethane (10 mL), trifluoro acetic acid (0.207 g, 0.002 mol).
  • Step 6 Synthesis of 5-amino-3-(2-(4-(2-fluoro-4-(((ls,4s)-l-oxidotetrahydro-2H- thiopyran-4-yl)oxy)phenyl)piperazin- l-yl)ethyl)-8-(furan-2-yl)thiazolo [5,4-e] [ 1 ,2,4] - triazolo-[l,5-c]pyrimidin-2(3H)-one (Compound 121): To a mixture of 2-(5-amino-8- (furan-2-yl)-2-oxothiazolo[5,4-e][l,2,4]triazolo[l,5-c]pyrimidin-3(2H)-yl)ethyl methane sulfonate (7, 0.385 g, 0.971 mmol) and (ls,4s)-4-(3-fluoro-4-(piperazin-l- y
  • Example 122 5-amino-3-(2-(4-(2-fluoro-4-(((lr,4r)-l-oxidotetrahydro-2H-thiopyran- 4-yl)oxy)phenyl)piperazin- l-yl)ethyl)-8-(furan-2-yl)thiazolo [5,4-e] [1 ,2,4] triazolo [ 1 ,5- c]pyrimidin-2(3H)-one
  • Step 5 Synthesis of (lr,4r)-4-(3-fluoro-4-(piperazin-l-yl)phenoxy)tetrahydro-2H- thiopyran 1-oxide (6): To an ice cold solution of tert-butyl 4-(2-fluoro-4-(((lr,4r)-l- oxidotetrahydro-2H-thiopyran-4-yl)oxy)phenyl)piperazine-l-carboxylate (4, 0.5 g, 1.212 mmol) in dichloromethane (10 mL), trifluoro acetic acid (0.207 g, 0.002 mol).
  • Step 6 Synthesis of 5-amino-3-(2-(4-(2-fluoro-4-(((lr,4r)-l-oxidotetrahydro-2H- thiopyran-4-yl)oxy)phenyl)piperazin- l-yl)ethyl)-8-(furan-2-yl)thiazolo [5,4-e] [ 1 ,2,4] - triazolo[l,5-c]pyrimidin-2(3H)-one (Compound 122): To a mixture of 2-(5-amino-8- (furan-2-yl)-2-oxothiazolo[5,4-e][l,2,4]triazolo[l,5-c]pyrimidin-3(2H)-yl)ethyl methane sulfonate (7, 0.235 g, 0.593 mmol) and (ls,4s)-4-(3-fluoro-4-(piperazin-l- yl)
  • Example 126 5-amino-3-(2-(4-(2-fluoro-4-(l-oxidothiomorpholino)phenyl)piperazin- l-yl)ethyl)-8-(furan-2-yl)thiazolo [5,4-e] [1 ,2,4] triazolo [ 1 ,5-c] pyrimidin-2(3H)-one
  • Step 1 Synthesis of 4-bromo-2-fluoroaniline (2): To a stirred solution of 4-bromo-2- fluoro-1 -nitrobenzene (1, 9.0 g, 13.64 mmol) and acetic acid (1 1.5 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 completion of the reaction, reaction mixture was diluted with EtOAc and filtered through celite bed.
  • Step 2 Synthesis of l-(4-bromo-2-fluorophenyl)piperazine (3): To a stirred solution of 4-bromo-2-fluoroaniline (2, 6.0 g, 31.58 mmol) in diglyme (4.8 mL) was added bis(2- chloroethyl)amine hydrogen chloride (6.7 g, 37.89 mmol) and the reaction mixture was stirred at 160° C for 16 h. After completion of the reaction (TLC), reaction mixture was cooled to RT and was treated with cold acetone. The precipitated solid was filtered and used for the next step directly (5.0 g, 61%); LCMS (ESI positive ion) m/z: calculated: 258.02; observed: 259.0 (M+l).
  • Step 3 Synthesis of tert-butyl 4-(4-bromo-2-fluorophenyl)piperazine-l-carboxylate (4): To a stirred solution of l-(4-bromo-2-fluorophenyl)piperazine (3, 4.0 g, 15.4 mmol) and TEA (3.1 g, 30.9 mmol) in DCM (30 mL) at 0 °C 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), reaction mixture was treated with water and extracted with DCM.
  • Step 4 Synthesis of tert-butyl 4-(2-fluoro-4-thiomorpholinophenyl)piperazine-l- carboxylate (5): To a stirred solution of tert-butyl 4-(4-bromo-2-fluorophenyl)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 NaO'Bu (2.34 g, 24.4 mmol) in sealed tube.
  • reaction mixture was purged 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.
  • reaction mixture was treated with water and extracted with ethyl acetate. The separated organic layer was washed with NaHC0 3 solution, brine solution, dried over anhydrous Na 2 S0 4 and concentrated under reduced pressure to afford crude product.
  • the crude product was purified by column chromatography to get the title compound (1.53 g, 33.9%); LCMS (ESI positive ion) m/z: calculated: 381.19; observed: 382.1 (M+l).
  • Step 5 Synthesis of tert-butyl 4-(2-fluoro-4-thiomorpholinophenyl)piperazine-l- carboxylate (6): To a stirred solution of tert-butyl 4-(2-fluoro-4- thiomorpholinophenyl)piperazine- 1-carboxylate (5, 1.8 g,4.7 mmol) in acetic acid (20 mL) at 0° C hydrogen peroxide (160.48 mg, 4.7 mmol) was added. The reaction mixture was stirred at RT for 16 h. After completion of the reaction (TLC), reaction mixture was treated with 10% NaOH solution (aq.) and extracted with DCM.
  • Step 6 Synthesis of 4-(3-fluoro-4-(piperazin-l-yl)phenyl)thiomorpholine 1-oxide (7): To a stirred solution of tert-butyl 4-(2-fluoro-4-(l- oxidothiomorpholino)phenyl)piperazine- 1-carboxylate (6, 1.2 g, 3.0 mmol) in DCM (15 mL) at 0° C TFA (330 mg, 9.0 mmol) was added. The reaction mixture was stirred at room temperature for 2 h. After completion of the reaction (TLC), reaction mixture was concentrated under reduced pressure.
  • Step 7 Synthesis of 5-amino-3-(2-(4-(2-fluoro-4-(l-oxidothiomorpholino)phenyl)- piperazin- l-yl)ethyl)-8-(furan-2-yl)thiazolo [5,4-e] [1 ,2,4] triazolo [ 1 ,5-c] pyrimidin- 2(3H)-one (Compound 126): To a stirred solution of l-(3-fluoro-4-(piperazin-l- 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][l,2,4]triazolo [ 1 ,5-c]pyrimidin- 1 (2H)-yl)ethyl methanesulfonate (500 mg, 1.26 mmol) and
  • Step 1 Synthesis of (S)-(2,2-dimethyl-l,3-dioxolan-4-yl)methyl methanesulfonate (7): To a stirred solution of (R)-(2,2-dimethyl-l,3-dioxolan-4-yl)methanol (6, 2.5 g, 19 mmol) in DCM (30 mL) was added triethylamine (9.6 g, 95 mmol) and methane sulfonyl chloride (4.33 g, 38 mmol) at 0 °C. The reaction mixture was allowed to stir for 3 h at 0 °C. The reaction was monitored by TLC and after completion, the reaction mixture was diluted with water and extracted with DCM.
  • Step 2 Synthesis of benzyl (R)-4-(5-((2,2-dimethyl-l,3-dioxolan-4-yl)methoxy)-2,4- difluorophenyl)piperazine-l-carboxylate (2): To a stirred solution of benzyl 4-(2,4- difluoro-5-hydroxyphenyl)piperazine-l-carboxylate (1, 1 g, 2.9 mmol) and (S)-(2,2- dimethyl-l,3-dioxolan-4-yl)methyl methanesulfonate (7, 1.15 g, 5.8 mmol) in DMF (20 mL) was added potassium carbonate (1.19 g, 8.7 mmol) and reaction mixture was heated to 90 °C for 16 h.
  • Step 3 Synthesis of (R)-l-(5-((2,2-dimethyl-l,3-dioxolan-4-yl)methoxy)-2,4-difluoro- phenyl) piperazine (3): To a stirred solution of benzyl (R)-4-(5-((2,2-dimethyl-l,3- dioxolan-4-yl)methoxy)-2,4-difluorophenyl)piperazine-l-carboxylate (2, 0.8 g, 1.73 mmol) in EtOAc (20 mL), 10%> Pd/C (0.2 g) was added under nitrogen atmosphere. The reaction mixture was stirred under H 2 atmosphere for 16 h.
  • Step 4 Synthesis of (R)-5-amino-3-(2-(4-(5-((2,2-dimethyl-l,3-dioxolan-4- yl)methoxy)-2,4-difluorophenyl)piperazin-l-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4- e] [l,2,4]triazolo[l,5-c]pyrimidin-2(3H)-one (4): To a stirred solution of (R)-l-(5-((2,2- dimethyl-l,3-dioxolan-4-yl)methoxy)-2,4-difluorophenyl) piperazine (3, 0.45 g, 1.4 mmol) and 2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][l,2,4]triazolo [l,5-c]pyrimidin-
  • Step 5 Synthesis of (S)-5-amino-3-(2-(4-(5-(2,3-dihydroxypropoxy)-2,4- difluorophenyl)-piperazin- l-yl)ethyl)-8-(furan-2-yl)thiazolo [5,4-e] [1 ,2,4] triazolo [ 1 ,5- c]pyrimidin-2(3H)-one (Compound 127): To a stirred solution 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][l,2,4]triazolo[l,5-c]pyrimidin-2(3H)-one (4, 50 mg, 0.08 m
  • Example 128 (R)-5-amino-3-(2-(4-(5-(2,3-dihydroxypropoxy)-2,4- difluorophenyl)piperazin- l-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): To a stirred solution of 2,4- difluoro-5-nitrophenol (1, 25 g, 0.143 mol) in EtOAc (200 mL), 10% Pd/C (4.55 g, 0.043 mol) was added. The reaction mixture was stirred at RT under H 2 for 16 h.
  • Step 2 Synthesis of 2,4-difluoro-5-(piperazin-l-yl)phenol (3): To a stirred solution of 5-amino-2,4-difluorophenol (2, 20 g, 0.131 mol) in sulfolane (30 mL) bis(2-chloroethyl) amine hydrogen chloride (31 g, 0.170 mol) was added. 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 chilled acetone under nitrogen atmosphere.
  • Step 3 Synthesis of benzyl 4-(2,4-difluoro-5-hydroxyphenyl)piperazine-l-carboxylate (4): To a stirred solution of 2,4-difluoro-5-(piperazin-l-yl)phenol hydrochloride (3, 25 g, 0.117 mol), in THF (250 mL) was added NaHCOs (14.7 g, 0.175 mol) and Cbz-Cl (16.66 mL, 0.117 mol) at 0 °C. The reaction mixture was stirred at RT for 16 h. The progress of the reaction was monitored by TLC.
  • Step 4 Synthesis of (R)-(2,2-dimethyl-l,3-dioxolan-4-yl)methyl methanesulfonate (10): To a stirred solution of (S)-(2,2-dimethyl-l,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 methane sulfonyl chloride (8.4 mL, 0.109 mol) at 0 °C. The reaction mixture was allowed to stir for 3 h at 0 °C.
  • Step 5 Synthesis of benzyl (S)-4-(5-((2,2-dimethyl-l,3-dioxolan-4-yl)methoxy)-2,4- difluorophenyl)piperazine-l-carboxylate (5): To a stirred solution of benzyl 4-(2,4- difluoro-5-hydroxyphenyl)piperazine-l-carboxylate (4.
  • Step 6 Synthesis of (S)-l-(5-((2,2-dimethyl-l,3-dioxolan-4-yl)methoxy)-2,4-difluoro- phenyl) piperazine (6): To a stirred solution of benzyl (S)-4-(5-((2,2-dimethyl-l,3- dioxolan-4-yl)methoxy)-2,4-difluorophenyl)piperazine-l-carboxylate (5, 13 g, 0.028 mol) in EtOAc (100 mL), 10%> Pd/C (4 g) was added under nitrogen atmosphere. The reaction mixture was stirred under H 2 atmosphere for 16 h.
  • Step 7 Synthesis of (S)-5-amino-3-(2-(4-(5-((2,2-dimethyl-l,3-dioxolan-4- yl)methoxy)-2,4-difluorophenyl)piperazin-l-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4- e] [l,2,4]triazolo[l,5-c]pyrimidin-2(3H)-one (7): To a stirred solution of (S)-l-(5-((2,2- dimethyl-l,3-dioxolan-4-yl)methoxy)-2,4-difluorophenyl)piperazine (6, 7 g, 0.021 mol) and 2-(5-amino-8-(furan-2-yl)-2-oxothiazolo-[5,4-e][l,2,4]triazolo[l,5-c]pyrimidin-
  • Step 8 Synthesis of (R)-5-amino-3-(2-(4-(5-(2,3-dihydroxypropoxy)-2,4- difluorophenyl)-piperazin- l-yl)ethyl)-8-(furan-2-yl)thiazolo [5,4-e] [1 ,2,4] triazolo [ 1 ,5- c]pyrimidin-2(3H)-one
  • Compound 128) To a stirred solution 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][l,2,4]triazolo[l,5-c]pyrimidin -2(3H)-one (7, 1.4 g, 2.
  • Example 9 5-amino-8-(furan-2-yl)-3-(2-(4-(4-(2-hydroxyethoxy)phenyl)piperazin-l- yl)ethyl)thiazolo[5,4-e] [l,2,4]triazolo[l,5-c]pyrimidin-2(3H)-one.
  • Example 10 2-(4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo [5,4- e] [l,2,4]triazolo[l,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-l-yl)phenoxy)acetic acid hydrochloride.
  • Example 11 2-(4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4- e] [l,2,4]triazolo[l,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-l-yl)phenoxy)acetamide.
  • Example 12 5-amino-3-(2-(4-(4-(2,3-dihydroxypropoxy)phenyl)piperazin-l- yl)ethyl)-8-(furan-2-yl)thiazolo [5,4-e] [1 ,2,4] triazolo [ 1 ,5-c] pyrimidin-2(3H)-one.
  • Example 13 5-amino-3-(2-(4-(4-(2-aminoethoxy)phenyl)piperazin-l-yl)ethyl)-8- (furan-2-yl)thiazolo [5,4-e] [1 ,2,4] triazolo [ 1 ,5-c] pyrimidin-2(3H)-one hydrochloride.
  • Example 14 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-l-yl)benzamide.
  • Example 15 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-l-yl)-N-methylbenzamide.
  • Example 16 5-amino-8-(furan-2-yl)-3-(2-(4-(4-(2- morpholinoethoxy)phenyl)piperazin- l-yl)ethyl)thiazolo [5,4-e] [1 ,2,4] triazolo [ 1 ,5- c]pyrimidin-2(3H)-one.
  • Example 17 5-amino-3-(2-(4-(4-(2-(dimethylamino)ethoxy)phenyl)piperazin-l- yl)ethyl)-8-(furan-2-yl)thiazolo [5,4-e] [1 ,2,4] triazolo [ 1 ,5-c] pyrimidin-2(3H)-one.
  • Example 18 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-l-yl)benzenesulfonamide.
  • Example 19 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-l-yl)-N-methylbenzenesulfonamide.
  • Example 20 5-amino-8-(furan-2-yl)-3-(2-(4-(4-(methylsulfonyl)phenyl)piperazin-l- yl)ethyl)thiazolo[5,4-e] [l,2,4]triazolo[l,5-c]pyrimidin-2(3H)-one.
  • Example 21 5-amino-8-(furan-2-yl)-3-(2-(4-(4-(methylsulfinyl)phenyl)piperazin-l- yl)ethyl)thiazolo[5,4-e] [l,2,4]triazolo[l,5-c]pyrimidin-2(3H)-one.
  • Example 22 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-l-yl)benzamide.
  • Example 23 5-amino-8-(furan-2-yl)-3-(2-(4-(3-(2-hydroxyethoxy)phenyl)piperazin- l-yl)ethyl)thiazolo[5,4-e] [l,2,4]triazolo[l,5-c]pyrimidin-2(3H)-one.
  • Example 24 5-amino-3-(2-(4-(2-fluoro-4-(2-oxo-2-(piperazin-l- yl)ethoxy)phenyl)piperazin-l-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4- e] [l,2,4]triazolo[l,5-c]pyrimidin-2(3H)-one hydrochloride.
  • Example 25 5-amino-3-(2-(4-(2-fluoro-4-(piperidin-4-ylmethoxy)phenyl)piperazin-l- yl)ethyl)-8-(furan-2-yl)thiazolo [5,4-e] [1 ,2,4] triazolo [ 1 ,5-c] pyrimidin-2(3H)-one hydrochloride.
  • Example 26 5-amino-3-(2-(4-(2-fluoro-4-(piperazine-l-carbonyl)phenyl)piperazin-l- yl)ethyl)-8-(furan-2-yl)thiazolo [5,4-e] [1 ,2,4] triazolo [ 1 ,5-c] pyrimidin-2(3H)-one hydrochloride.
  • Example 27 5-amino-3-(2-(4-(2-fluoro-4-(2-(piperazin-l-yl)ethoxy)phenyl)piperazin- l-yl)ethyl)-8-(furan-2-yl)thiazolo [5,4-e] [1 ,2,4] triazolo [ 1 ,5-c] pyrimidin-2(3H)-one hydrochloride.
  • Example 28 5-amino-3-(2-(4-(2-fluoro-4-(piperazin-l-ylsulfonyl)phenyl)piperazin-l- yl)ethyl)-8-(furan-2-yl)thiazolo [5,4-e] [1 ,2,4] triazolo [ 1 ,5-c] pyrimidin-2(3H)-one hydrochloride.
  • Example 29 5-amino-3-(2-(4-(2-fluoro-4-(methylsulfonyl)phenyl)piperazin-l- yl)ethyl)-8-(furan-2-yl)thiazolo [5,4-e] [1 ,2,4] triazolo [ 1 ,5-c] pyrimidin-2(3H)-one.
  • Example 30 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-l-yl)-N-(2-aminoethyl)-3-fluorobenzamide hydrochloride.
  • Example 31 4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e] [l,2,4]triazolo[l,5- c]pyrimidin-3(2H)-yl)ethyl)piperazin-l-yl)-3-fluoro-N-(2-
  • Example 32 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-l-yl)-N-(2-(dimethylamino)ethyl)-3- fluorobenzamide.
  • Example 33 4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e] [l,2,4]triazolo[l,5- c]pyrimidin-3(2H)-yl)ethyl)piperazin-l-yl)-3-fluoro-N-(2-hydroxyethyl)benzamide.
  • Example 34 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-l-yl)-N-(2,3-dihydroxypropyl)-3- fluorobenzamide.
  • Example 35 2-(4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo [5,4- e] [l,2,4]triazolo[l,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-l-yl)-3- fluorophenoxy)acetic acid.
  • Example 36 2-(4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4- e] [l,2,4]triazolo[l,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-l-yl)-3,5- difluorophenoxy)acetic acid.
  • Example 37 2-(4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo [5,4- e] [l,2,4]triazolo[l,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-l-yl)-3- fluorophenoxy)propanoic acid.
  • Peak 1 was arbitrarily considered as (S) isomer and peak 2 was considered as (R) isomer.
  • Example 39 2-(4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo [5,4- e] [l,2,4]triazolo[l,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-l-yl)-3-fluorophenoxy)-2- methylpropanoic acid hydrochloride.
  • Example 40 3-(4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo [5,4- e] [l,2,4]triazolo[l,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-l-yl)-3- fluorophenyl)propanoic acid.
  • Example 41 4-(4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo [5,4- e] [l,2,4]triazolo[l,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-l-yl)-3- fluorophenoxy)butanoic acid hydrochloride.
  • Example 42 2-(3-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo [5,4- e] [l,2,4]triazolo[l,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-l-yl)-2,6- difluorophenoxy)acetic acid hydrochloride.
  • Example 43 2-(5-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo [5,4- e] [l,2,4]triazolo[l,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-l-yl)-2,4- difluorophenoxy)acetic acid hydrochloride.
  • Example 44 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-l-yl)-3-fluorobenzoic acid.
  • Example 45 2-((2-(4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo [5,4- e] [l,2,4]triazolo[l,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-l-yl)-3- fluorophenoxy)ethyl)amino)acetamide hydrochloride.
  • Example 46 2-((2-(4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo [5,4- e] [l,2,4]triazolo[l,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-l-yl)-3- fluorophenoxy)ethyl)(methyl)amino)acetamide.
  • Example 47 5-amino-3-(2-(4-(2-fluoro-4-(piperidin-4-yloxy)phenyl)piperazin-l- yl)ethyl)-8-(furan-2-yl)thiazolo [5,4-e] [1 ,2,4] triazolo [ 1 ,5-c] pyrimidin-2(3H)-one hydrochloride.
  • Example 48 5-amino-3-(2-(4-(2-fluoro-4-(pyrrolidin-3-yloxy)phenyl)piperazin-l- yl)ethyl)-8-(furan-2-yl)thiazolo [5,4-e] [ 1 ,2,4] triazolo [ 1 ,5-c] pyrimidin-2(3H)-one hydrochloride.
  • Example 49 3-(2-(4-(4-((lH-l,2,4-triazol-3-yl)methoxy)-2-fluorophenyl)piperazin-l- yl)ethyl)-5-amino-8-(furan-2-yl)thiazolo [5,4-e] [1 ,2,4] triazolo [ 1 ,5-c] pyrimidin-2(3H)- one.
  • Example 50 2-(4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4- e] [l,2,4]triazolo[l,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-l-yl)-3-fluorophenoxy)-N- (2-(methylamino)ethyl)acetamide hydrochloride.
  • Example 51 2-(4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo [5,4- e] [l,2,4]triazolo[l,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-l-yl)-3-fluorophenoxy)-N- (2-(dimethylamino)ethyl)acetamide.
  • Example 52 2-(4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4- e] [l,2,4]triazolo[l,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-l-yl)-3-fluorophenoxy)-N- (2-aminoethyl)acetamide hydrochloride.
  • Example 54 2-(4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo [5,4- e] [l,2,4]triazolo[l,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-l-yl)-3- fluorophenoxy)acetamide.
  • Example 55 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-l-yl)-3-fluoro-N-methyl-N-(2-
  • Example 56 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-l-yl)-N-(2-(dimethylamino)ethyl)-3-fluoro-N- methylbenzamide.

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Abstract

La présente invention concerne des composés de formule (I) ou des sels ou solvates pharmaceutiquement acceptables de ceux-ci. L'invention concerne également l'utilisation des composés représentés par la formule (I) en tant qu'inhibiteurs de A2A. L'invention concerne également l'utilisation des composés de formule (I) pour le traitement et/ou la prévention du cancer. L'invention concerne en outre un procédé de préparation des composés de formule (I).
PCT/EP2018/058301 2017-03-30 2018-03-30 Dérivés de 2-oxo-thiazole en tant qu'inhibiteurs de a2a et composés destinés à être utilisés dans le traitement de cancers Ceased WO2018178338A1 (fr)

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CN201880034926.9A CN110678472B (zh) 2017-03-30 2018-03-30 作为a2a抑制剂的2-氧代噻唑衍生物和用于治疗癌症的化合物
EP22165965.9A EP4112623A1 (fr) 2017-03-30 2018-03-30 Dérivés de 2-oxo-thiazole en tant qu'inhibiteurs a2a et composés destinés à être utilisés dans le traitement de cancers
IL300149A IL300149A (en) 2017-03-30 2018-03-30 2-oxo-thiazole derivatives as a2a inhibitors and compounds for use in the treatment of cancers
AU2018246355A AU2018246355B2 (en) 2017-03-30 2018-03-30 2-oxo-thiazole derivatives as A2A inhibitors and compounds for use in the treatment of cancers
ES18716193T ES2926158T3 (es) 2017-03-30 2018-03-30 Derivados de 2-oxo-tiazol como inhibidores de a2a y compuestos para su uso en el tratamiento de cánceres
LTEPPCT/EP2018/058301T LT3601296T (lt) 2017-03-30 2018-03-30 2-okso-tiazolo derivatai kaip a2a inhibitoriai ir junginiai, skirti naudoti gydant vėžį
CA3058260A CA3058260A1 (fr) 2017-03-30 2018-03-30 Derives de 2-oxo-thiazole en tant qu'inhibiteurs de a2a et composes destines a etre utilises dans le traitement de cancers
JP2020503355A JP7197558B2 (ja) 2017-03-30 2018-03-30 Ａ２ａ阻害剤及び癌の治療に使用するための化合物としての２－オキソ－チアゾール誘導体
KR1020197031322A KR102640927B1 (ko) 2017-03-30 2018-03-30 A2a 억제제로서의 2-옥소-티아졸 유도체 및 암 치료에 사용하기 위한 화합물
RU2019134724A RU2822758C2 (ru) 2017-03-30 2018-03-30 Соединения формул (I) и (A), фармацевтическая композиция, лекарственное средство, применение и способ получения соединения формулы (I)
PL18716193.0T PL3601296T3 (pl) 2017-03-30 2018-03-30 Pochodne 2-okso-tiazolowe jako inhibitory i związki a2a do stosowania w leczeniu nowotworów złośliwych
EP18716193.0A EP3601296B1 (fr) 2017-03-30 2018-03-30 Dérivés 2-oxo-thiazoles comme inhibiteurs de a2a et composés pour leur utilisation dans le traitement des cancers
MX2019011743A MX393711B (es) 2017-03-30 2018-03-30 Derivados de tiocarbamato como inhibidores de a2a y metodos para su uso en el tratamiento de canceres
HRP20221039TT HRP20221039T1 (hr) 2017-03-30 2018-03-30 Derivati 2-okso-tiazola kao inhibitori a2a i spojevi za upotrebu u liječenju karcinoma
RS20220794A RS63557B1 (sr) 2017-03-30 2018-03-30 Derivati 2-okso-tiazola kao inhibitori a2a i jedinjenja za upotrebu u lečenju kancera
SI201830747T SI3601296T1 (sl) 2017-03-30 2018-03-30 2-okso-tiazolni derivati kot zaviralci A2A in spojine za uporabo pri zdravljenju raka
KR1020247005971A KR20240027885A (ko) 2017-03-30 2018-03-30 A2a 억제제로서의 2-옥소-티아졸 유도체 및 암 치료에 사용하기 위한 화합물
CN202211658370.5A CN115991679A (zh) 2017-03-30 2018-03-30 作为a2a抑制剂的2-氧代噻唑衍生物和用于治疗癌症的化合物
CN202211706953.0A CN115873022A (zh) 2017-03-30 2018-03-30 作为a2a抑制剂的2-氧代噻唑衍生物和用于治疗癌症的化合物
DK18716193.0T DK3601296T3 (da) 2017-03-30 2018-03-30 2-oxo-thiazolderivater som a2a-inhibitorer og forbindelser til anvendelse ved behandling af cancere
BR112019020421A BR112019020421A8 (pt) 2017-03-30 2018-03-30 Derivados de 2-oxo- tiazóis como inibidores de a2a e compostos para uso no tratamento de cânceres
US16/354,022 US10995101B2 (en) 2017-03-30 2019-03-14 2-oxo-thiazole derivatives as A2A inhibitors and compounds for use in the treatment of cancers
IL269710A IL269710B2 (en) 2017-03-30 2019-09-26 2-oxo-thiazole derivatives as a2a inhibitors and compounds for use in cancer therapy
US16/993,897 US20210198281A1 (en) 2017-03-30 2020-08-14 2-oxo-thiazole derivatives as a2a inhibitors and compounds for use in the treatment of cancers
US17/949,595 US20230159564A1 (en) 2017-03-30 2022-09-21 2-Oxo-Thiazole Derivatives as A2A Inhibitors and Compounds for Use in the Treatment of Cancers
JP2022199962A JP2023027282A (ja) 2017-03-30 2022-12-15 Ａ２ａ阻害剤及び癌の治療に使用するための化合物としての２－オキソ－チアゾール誘導体

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ARP180100778A AR111200A1 (es) 2017-03-30 2018-03-28 Derivados de tiocarbamato como inhibidores de a2a y métodos para usar en el tratamiento de cánceres

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US11390613B2 (en) 2017-08-20 2022-07-19 University Of Connecticut Azole analogues and methods of use thereof
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US11427594B2 (en) 2018-09-27 2022-08-30 iTeos Belgium SA Non brain penetrant A2A inhibitors and methods for use in the treatment of cancers
US20230048888A1 (en) * 2019-12-26 2023-02-16 Zhejiang Vimgreen Pharmaceuticals, Ltd. Use of triazolotriazine derivative in treatment of diseases
WO2023059817A1 (fr) 2021-10-07 2023-04-13 Iteos Belguim Sa Sel chlorhydrate d'inupadenant, compositions pharmaceutiques et leurs procédés d'utilisation
WO2024134541A1 (fr) 2022-12-20 2024-06-27 iTeos Belgium SA Composés hétérocycliques utilisés en tant qu'inhibiteurs d'ent et composés destinés à être utilisés dans le traitement de cancers
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US11390613B2 (en) 2017-08-20 2022-07-19 University Of Connecticut Azole analogues and methods of use thereof
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JP2022500496A (ja) * 2018-09-11 2022-01-04 アイテオ ベルギウム エスエー Ａ２ａ阻害剤としてのチオカルバメート誘導体、その医薬組成物、及び抗がん剤との組み合わせ
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EP4410375A3 (fr) * 2018-09-11 2024-11-06 iTeos Belgium SA Dérivés de thiocarbamate en tant qu'inhibiteurs de a2a, composition pharmaceutique de ceux-ci et combinaisons avec des agents anticancéreux
WO2020053263A1 (fr) 2018-09-11 2020-03-19 Iteos Therapeutics S.A. Dérivés de thiocarbamate en tant qu'inhibiteurs d'a2a, composition pharmaceutique associée et combinaisons avec des agents anticancéreux
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JP2022503879A (ja) * 2018-09-27 2022-01-12 アイテオ ベルギウム エスエー がん治療におけるｅｎｔファミリートランスポーター阻害剤の使用及びそのアデノシン受容体アンタゴニストとの組み合わせ
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US11254670B2 (en) 2019-01-18 2022-02-22 Nuvation Bio Inc. 1,8-naphthyridinone compounds and uses thereof
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US12410188B2 (en) 2019-07-30 2025-09-09 Xiamen Biotime Biotechnology Co., Ltd. Adenosine receptor antagonist
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WO2021018172A1 (fr) 2019-07-30 2021-02-04 杭州阿诺生物医药科技有限公司 Antagoniste du récepteur de l'adénosine
WO2021030174A1 (fr) * 2019-08-09 2021-02-18 University Of Connecticut Analogues d'itraconazole tronqués et leurs procédés d'utilisation
US12435067B2 (en) 2019-08-09 2025-10-07 University Of Connecticut Truncated itraconazole analogues and methods of use thereof
US20230048888A1 (en) * 2019-12-26 2023-02-16 Zhejiang Vimgreen Pharmaceuticals, Ltd. Use of triazolotriazine derivative in treatment of diseases
WO2021170797A1 (fr) 2020-02-26 2021-09-02 iTeos Belgium SA Dérivés de pyrimido[5,4-d]pyrimidine servant d'inhibiteurs d'ent pour le traitement de cancers, et leur combinaison avec des antagonistes du récepteur de l'adénosine
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