WO2022090711A1 - Composés utilisés en tant qu'inhibiteurs de cd73 - Google Patents

Composés utilisés en tant qu'inhibiteurs de cd73 Download PDF

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WO2022090711A1
WO2022090711A1 PCT/GB2021/052788 GB2021052788W WO2022090711A1 WO 2022090711 A1 WO2022090711 A1 WO 2022090711A1 GB 2021052788 W GB2021052788 W GB 2021052788W WO 2022090711 A1 WO2022090711 A1 WO 2022090711A1
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alkyl
methyl
pyridazin
pyrimidine
dione
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PCT/GB2021/052788
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Clive Mccarthy
Robert HEAP
Sarah MAJOR
Daniel Cotton
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AdoRx Therapeutics Limited
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Priority claimed from GBGB2016964.5A external-priority patent/GB202016964D0/en
Priority claimed from GBGB2104781.6A external-priority patent/GB202104781D0/en
Application filed by AdoRx Therapeutics Limited filed Critical AdoRx Therapeutics Limited
Publication of WO2022090711A1 publication Critical patent/WO2022090711A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/08—Bridged systems

Definitions

  • the present invention relates to certain compounds that function as inhibitors of the CD73, also known as 5’-nucleotidase or ecto-5’nucleotidase.
  • the present invention also relates to processes for the preparation of these compounds, to pharmaceutical compositions comprising them, and to their use in the treatment of diseases or conditions in which CD73 activity is implicated, such as, for example, cancer.
  • BACKGROUND OF THE INVENTION [0002]
  • Purinergic signalling plays a critical role in physiological processes and imbalance can lead to various pathophysiological conditions. Extracellular adenosine trisphosphate and adenosine levels are regulated by a complex network of enzymes and transporters.
  • Downstream signalling is mediated by ligand gated ion channels and via G-protein coupled receptors.
  • the cell surface protein CD39 acts at an early point in the pathway by catalyzing the hydrolysis of adenosine trisphosphate (ATP) to adenosine diphosphate (ADP) and subsequently the conversion of ADP to AMP.
  • CD73 is a cell surface ecto-5’- nucleotidase encoded by the NT5E gene. CD73 is widely expressed and is responsible for the conversion of adenosine monophosphate (AMP) to adenosine.
  • AMP adenosine monophosphate
  • Aberrant purinergic signalling is observed in a variety of disease including cancer, autoimmune disorders, inflammation, fibrosis, bleeding disorders and atherosclerosis.
  • CD73 expression levels are increased in various human tumour types including ovarian cancer, melanoma, prostate cancer, breast cancer, colon cancer, head and neck cancer, leukemia, hepatocellular carcinoma and glioblastoma [Arab and Hadjati, 2019]. High CD73 expression has been associated with poor cancer outcome [Leone and Emens, 2018; Hammami et al, 2019].
  • CD73 expression can change in response to treatment with chemotherapy and targeted therapies and is also controlled by hypoxia through activation by the transcription factor HIF1a.
  • CD73 expression on leukocyte and myeloid cells has been summarised by Roh et al (Roh et al, 2020).
  • CD73 is expressed on regulatory T cells and on exhausted or anergic T effector cells. Increased expression of CD73 is observed on myeloid derived suppressor cells in cancer patients.
  • the growth of tumours is altered in mice harbouring a deletion in the gene encoding CD73 [Yegutkin et al, 2011].
  • CD73 ablation significantly suppresses the growth of MC38 colon cancer cells, EG7 lymphoma and AT-3 mammary tumour cells and B16F10 melanoma in syngeneic models [Stagg et al, 2011].
  • hematopoetic cells e.g. regulatory T cells
  • non- hematopoetic cells such as endothelial cells.
  • tumour growth and metastasis could be reduced using a monoclonal antibody targeting CD73.
  • MEDI9447 (AstraZeneca) is a human monoclonal antibody that non-competitively inhibits CD73 function by blocking dimerization and by preventing CD73 from transitioning to a catalytically active conformation [Geoghegan J.C. et al].
  • MEDI9447 was shown to inhibit tumour growth as a single agent and in combination with anti-PD-1 antibodies in animal studies using syngeneic tumours [Hay C. M. et al 2016]. Another antibody, BMS-986179 enhances the internalisation of CD73. [0005] Small molecular weight chemical inhibitors of CD73 have also entered clinical trials including AB680 (Arcus Biosiences) and LY3475070 (Eli Lilly). AB680 is a potent, reversible inhibitor of CD73 catalytic activity [Lawson K.V. et al 2020].
  • OP-5244 (Oric Pharmaceuticals) is a sub-nanomolar CD73 inhibitor that has been shown to inhibit adenosine production from both cancer cells and T cells in vitro and reversed immunosuppression in mouse models [Du X. et al 2020]. [0006] However, there remains a need for further compounds that are potent CD73 inhibitors. In particular, there is a need for compounds that are potent and selective CD73 inhibitors. [0007] The present invention was devised with the foregoing in mind. References Allard D. et al. (2019) Immunol Lett 205; 31-39. Arab S. and Hadjait J. (2019) Immune Netw 19 (4) e23 Du, X. et al.
  • a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof as defined herein.
  • a pharmaceutical composition comprising a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in admixture with a pharmaceutically acceptable diluent or carrier.
  • a method of inhibiting CD73 in vitro or in vivo comprising contacting a cell with an effective amount of a compound or a pharmaceutically acceptable salt, hydrate or solvate thereof as defined herein.
  • a method of selectively inhibiting CD73 in vitro or in vivo comprising contacting a cell with an effective amount of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein.
  • a method of inhibiting cell proliferation comprising contacting a cell with an effective amount of a compound or a pharmaceutically acceptable salt, hydrate or solvate thereof as defined herein, or a pharmaceutical composition as defined herein.
  • the compound or pharmaceutical composition is administered in combination with one or more additional antiproliferative agents (e.g. checkpoint inhibitors and/or cytotoxic agents).
  • a method of treating a disease or disorder associated CD73 activity in a patient in need of such treatment comprising administering to said patient a therapeutically effective amount of a compound or a pharmaceutically acceptable salt, hydrate or solvate thereof as defined herein, or a pharmaceutical composition as defined herein.
  • a method of treating a proliferative disorder in a patient in need of such treatment comprising administering to said patient a therapeutically effective amount of a compound or a pharmaceutically acceptable salt, hydrate or solvate thereof as defined herein, or a pharmaceutical composition as defined herein.
  • the compound or pharmaceutical composition is administered in combination with one or more additional antiproliferative agents (e.g. checkpoint inhibitors and/or cytotoxic agents).
  • additional antiproliferative agents e.g. checkpoint inhibitors and/or cytotoxic agents.
  • a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein, for use in therapy for use in therapy.
  • a compound or a pharmaceutically acceptable salt, hydrate or solvate thereof as defined herein, or a pharmaceutical composition as defined herein, for use in the treatment of a proliferative condition is provided.
  • the compound or pharmaceutical composition is administered in combination with one or more additional antiproliferative agents (e.g. checkpoint inhibitors and/or cytotoxic agents).
  • a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein for use in the treatment of cancer In a particular embodiment, the cancer is human cancer.
  • the compound or pharmaceutical composition is administered in combination with one or more additional anticancer agents (e.g. checkpoint inhibitors and/or cytotoxic agents).
  • additional anticancer agents e.g. checkpoint inhibitors and/or cytotoxic agents.
  • a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof as defined herein for use in the treatment of a disease or disorder in which CD73 activity is implicated.
  • a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof as defined herein in the manufacture of a medicament for the treatment of a proliferative condition.
  • the compound or pharmaceutical composition is administered in combination with one or more additional antiproliferative agents (e.g. checkpoint inhibitors and/or cytotoxic agents).
  • a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof as defined herein in the manufacture of a medicament for the treatment of cancer.
  • the cancer is a human cancer.
  • the compound or pharmaceutical composition is administered in combination with one or more additional anticancer agents (e.g. checkpoint inhibitors and/or cytotoxic agents).
  • additional anticancer agents e.g. checkpoint inhibitors and/or cytotoxic agents.
  • a process for preparing a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein there is provided a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, obtainable by, or obtained by, or directly obtained by a process of preparing a compound as defined herein.
  • Treating” or “treatment” of a state, disorder or condition therefore includes: (1) preventing or delaying the appearance of clinical symptoms of the state, disorder or condition developing in a human that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition, (2) inhibiting the state, disorder or condition, i.e., arresting, reducing or delaying the development of the disease or a relapse thereof (in case of maintenance treatment) or at least one clinical or subclinical symptom thereof, or (3) relieving or attenuating the disease, i.e., causing regression of the state, disorder or condition or at least one of its clinical or subclinical symptoms.
  • a “therapeutically effective amount” means the amount of a compound that, when administered to a mammal for treating a disease, is sufficient to effect such treatment for the disease.
  • the “therapeutically effective amount” will vary depending on the compound, the disease and its severity and the age, weight, etc., of the mammal to be treated.
  • alkyl includes both straight and branched chain alkyl groups. References to individual alkyl groups such as “propyl” are specific for the straight chain version only and references to individual branched chain alkyl groups such as “isopropyl” are specific for the branched chain version only.
  • (1-6C)alkyl includes (1- 4C)alkyl, (1-3C)alkyl, propyl, isopropyl and t-butyl.
  • phenyl(1-6C)alkyl includes phenyl(1-4C)alkyl, benzyl, 1-phenylethyl and 2-phenylethyl.
  • phenyl(1-6C)alkyl includes phenyl(1-4C)alkyl, benzyl, 1-phenylethyl and 2-phenylethyl.
  • (m-nC) or "(m-nC) group” used alone or as a prefix, refers to any group having m to n carbon atoms.
  • alkylene is an alkyl, alkenyl, or alkynyl group that is positioned between and serves to connect two other chemical groups.
  • (1- 6C)alkylene means a linear saturated divalent hydrocarbon radical of one to six carbon atoms or a branched saturated divalent hydrocarbon radical of three to six carbon atoms, for example, methylene, ethylene, propylene, 2-methylpropylene, pentylene, and the like.
  • (2-6C)alkenylene means a linear divalent hydrocarbon radical of two to six carbon atoms or a branched divalent hydrocarbon radical of three to six carbon atoms, containing at least one double bond, for example, as in ethenylene, 2,4-pentadienylene, and the like.
  • (2-6C)alkynylene means a linear divalent hydrocarbon radical of two to six carbon atoms or a branched divalent hydrocarbon radical of three to six carbon atoms, containing at least one triple bond, for example, as in ethynylene, propynylene, and butynylene and the like.
  • (3-8C)cycloalkyl means a hydrocarbon ring containing from 3 to 8 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or bicyclo[2.2.1]heptyl.
  • (3-8C)cycloalkenyl means a hydrocarbon ring containing at least one double bond, for example, cyclobutenyl, cyclopentenyl, cyclohexenyl or cycloheptenyl, such as 3- cyclohexen-1-yl, or cyclooctenyl.
  • (3-8C)cycloalkyl-(1-6C)alkylene means a (3-8C)cycloalkyl group covalently attached to a (1-6C)alkylene group, both of which are defined herein.
  • halo or “halogeno” refers to fluoro, chloro, bromo and iodo.
  • heterocyclyl or “heterocycle” means a non-aromatic saturated or partially saturated monocyclic, fused, bridged, or spiro bicyclic heterocyclic ring system(s).
  • Monocyclic heterocyclic rings contain from about 3 to 12 (suitably from 3 to 7) ring atoms, with from 1 to 5 (suitably 1, 2 or 3) heteroatoms selected from nitrogen, oxygen or sulfur in the ring.
  • Bicyclic heterocycles contain from 7 to 17 member atoms, suitably 7 to 12 member atoms, in the ring.
  • Bicyclic heterocyclic(s) rings may be fused, spiro, or bridged ring systems.
  • heterocyclic groups include cyclic ethers such as oxiranyl, oxetanyl, tetrahydrofuranyl, dioxanyl, and substituted cyclic ethers.
  • Heterocycles containing nitrogen include, for example, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, tetrahydrotriazinyl, tetrahydropyrazolyl, and the like.
  • Typical sulfur containing heterocycles include tetrahydrothienyl, dihydro-1,3-dithiol, tetrahydro-2H-thiopyran, and hexahydrothiepine.
  • heterocycles include dihydrooxathiolyl, tetrahydrooxazolyl, tetrahydro-oxadiazolyl, tetrahydrodioxazolyl, tetrahydrooxathiazolyl, hexahydrotriazinyl, tetrahydrooxazinyl, morpholinyl, thiomorpholinyl, tetrahydropyrimidinyl, dioxolinyl, octahydrobenzofuranyl, octahydrobenzimidazolyl, and octahydrobenzothiazolyl.
  • the oxidized sulfur heterocycles containing SO or SO 2 groups are also included.
  • examples include the sulfoxide and sulfone forms of tetrahydrothienyl and thiomorpholinyl such as tetrahydrothiene 1,1-dioxide and thiomorpholinyl 1,1-dioxide.
  • heterocyclyl groups are saturated monocyclic 3 to 7 membered heterocyclyls containing 1, 2 or 3 heteroatoms selected from nitrogen, oxygen or sulfur, for example azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, morpholinyl, tetrahydrothienyl, tetrahydrothienyl 1,1-dioxide, thiomorpholinyl, thiomorpholinyl 1,1-dioxide, piperidinyl, homopiperidinyl, piperazinyl or homopiperazinyl.
  • any heterocycle may be linked to another group via any suitable atom, such as via a carbon or nitrogen atom.
  • reference herein to piperidino or morpholino refers to a piperidin-1- yl or morpholin-4-yl ring that is linked via the ring nitrogen.
  • bridged ring systems is meant ring systems in which two rings share more than two atoms, see for example Advanced Organic Chemistry, by Jerry March, 4 th Edition, Wiley Interscience, pages 131-133, 1992.
  • bridged heterocyclyl ring systems examples include, aza-bicyclo[2.2.1]heptane, 2-oxa-5-azabicyclo[2.2.1]heptane, aza-bicyclo[2.2.2]octane, aza- bicyclo[3.2.1]octane and quinuclidine.
  • spiro bi-cyclic ring systems we mean that the two ring systems share one common spiro carbon atom, i.e. the heterocyclic ring is linked to a further carbocyclic or heterocyclic ring through a single common spiro carbon atom.
  • spiro ring systems examples include 6- azaspiro[3.4]octane, 2-oxa-6-azaspiro[3.4]octane, 2-azaspiro[3.3]heptanes, 2-oxa-6- azaspiro[3.3]heptanes, 7-oxa-2-azaspiro[3.5]nonane, 6-oxa-2-azaspiro[3.4]octane, 2-oxa-7- azaspiro[3.5]nonane and 2-oxa-6-azaspiro[3.5]nonane.
  • Heterocyclyl(1-6C)alkyl means a heterocyclyl group covalently attached to a (1- 6C)alkylene group, both of which are defined herein.
  • heteroaryl or “heteroaromatic” means an aromatic mono-, bi-, or polycyclic ring incorporating one or more (for example 14, particularly 1, 2 or 3) heteroatoms selected from nitrogen, oxygen or sulfur.
  • heteroaryl includes both monovalent species and divalent species. Examples of heteroaryl groups are monocyclic and bicyclic groups containing from five to twelve ring members, and more usually from five to ten ring members.
  • the heteroaryl group can be, for example, a 5- or 6-membered monocyclic ring or a 9- or 10- membered bicyclic ring, for example a bicyclic structure formed from fused five and six membered rings or two fused six membered rings.
  • Each ring may contain up to about four heteroatoms typically selected from nitrogen, sulfur and oxygen.
  • the heteroaryl ring will contain up to 3 heteroatoms, more usually up to 2, for example a single heteroatom.
  • the heteroaryl ring contains at least one ring nitrogen atom.
  • the nitrogen atoms in the heteroaryl rings can be basic, as in the case of an imidazole or pyridine, or essentially non-basic as in the case of an indole or pyrrole nitrogen.
  • the number of basic nitrogen atoms present in the heteroaryl group, including any amino group substituents of the ring, will be less than five.
  • heteroaryl examples include furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazenyl, benzofuranyl, indolyl, isoindolyl, benzothienyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, benzothiazolyl, indazolyl, purinyl, benzofurazanyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl, cinnolinyl, pteridinyl, naphthyridin
  • Heteroaryl also covers partially aromatic bi- or polycyclic ring systems wherein at least one ring is an aromatic ring and one or more of the other ring(s) is a nonaromatic, saturated or partially saturated ring, provided at least one ring contains one or more heteroatoms selected from nitrogen, oxygen or -sulfur-.
  • partially aromatic heteroaryl groups include for example, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 2-oxo-1,2,3,4-tetrahydroquinolinyl, dihydrobenzthienyl, dihydrobenzfuranyl, 2,3-dihydro-benzo[1,4]dioxinyl, benzo[1,3]dioxolyl, 2,2-dioxo-1,3-dihydro-2-benzothienyl, 4,5,6,7-tetrahydrobenzofuranyl, indolinyl, 1,2,3,4-tetrahydro-1,8-naphthyridinyl, 1,2,3,4-tetrahydropyrido[2,3-b]pyrazinyl, 3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazinyl and 6,8-dihydro-5H-[1,2,4]tri
  • Examples of five membered heteroaryl groups include but are not limited to pyrrolyl, furanyl, thienyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl and tetrazolyl groups.
  • Examples of six membered heteroaryl groups include but are not limited to pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl and triazinyl.
  • a bicyclic heteroaryl group may be, for example, a group selected from: a benzene ring fused to a 5- or 6-membered ring containing 1, 2 or 3 ring heteroatoms; a pyridine ring fused to a 5- or 6-membered ring containing 1, 2 or 3 ring heteroatoms; a pyrimidine ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; a pyrrole ring fused to a 5- or 6-membered ring containing 1, 2 or 3 ring heteroatoms; a pyrazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; a pyrazine ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; an imidazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; an oxazo
  • bicyclic heteroaryl groups containing a six membered ring fused to a five membered ring include but are not limited to benzfuranyl, benzthiophenyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzthiazolyl, benzisothiazolyl, isobenzofuranyl, indolyl, isoindolyl, indolizinyl, indolinyl, isoindolinyl, purinyl (e.g., adeninyl, guaninyl), indazolyl, benzodioxolyl and pyrazolopyridinyl groups.
  • bicyclic heteroaryl groups containing two fused six membered rings include but are not limited to quinolinyl, isoquinolinyl, chromanyl, thiochromanyl, chromenyl, isochromenyl, chromanyl, isochromanyl, benzodioxanyl, quinolizinyl, benzoxazinyl, benzodiazinyl, pyridopyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, naphthyridinyl and pteridinyl groups.
  • Heteroaryl(1-6C)alkyl means a heteroaryl group covalently attached to a (1- 6C)alkylene group, both of which are defined herein.
  • heteroaralkyl groups include pyridin-3-ylmethyl, 3-(benzofuran-2-yl)propyl, and the like.
  • aryl means a cyclic or polycyclic aromatic ring having from 5 to 12 carbon atoms.
  • aryl includes both monovalent species and divalent species.
  • Examples of aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl and the like. In particular embodiment, an aryl is phenyl.
  • aryl(1-6C)alkyl means an aryl group covalently attached to a (1-6C)alkylene group, both of which are defined herein.
  • aryl-(1-6C)alkyl groups include benzyl, phenylethyl, and the like.
  • This specification also makes use of several composite terms to describe groups comprising more than one functionality. Such terms will be understood by a person skilled in the art.
  • heterocyclyl(m-nC)alkyl comprises (m-nC)alkyl substituted by heterocyclyl.
  • optionally substituted refers to either groups, structures, or molecules that are substituted and those that are not substituted.
  • the present invention relates to compounds, or pharmaceutically acceptable salts, hydrates or solvates thereof, having the structural formula I shown below: I wherein: R 1 is selected from: (i) -NR 1A R 1B ; wherein R 1A and R 1B are each independently selected from hydrogen, (1-4C)alkyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl(1-2C)alkyl, aryl, aryl(1- 2C)alkyl, heteroaryl, heteroaryl(1-2C)alkyl, or R 1A and R 1B are linked such that, together with the nitrogen atom to which they are attached, they form a heterocyclic ring; and wherein any alkyl, aryl, heteroaryl or heterocyclyl group (formed by R 1A and R 1B ) is optionally substituted by one or more R x ; (ii) a carbon-linked heterocyclyl optionally substituted by one
  • the present invention relates to compounds, or pharmaceutically acceptable salts, hydrates or solvates thereof, having the structural formula I shown below: I wherein: R 1 is selected from: (i) -NR 1A R 1B ; wherein R 1A and R 1B are each independently selected from hydrogen, (1-4C)alkyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl(1-2C)alkyl, aryl, aryl(1- 2C)alkyl, heteroaryl, heteroaryl(1-2C)alkyl, or R 1A and R 1B are linked such that, together with the nitrogen atom to which they are attached, they form a heterocyclic ring; and wherein any alkyl, aryl, heteroaryl or heterocyclyl group (formed by R 1A and R 1B ) is optionally substituted by one or more R x ; (ii) a carbon-linked heterocyclyl optionally substituted by one or more R x ; (ii)
  • R 1 is selected from: (i) -NR 1A R 1B ; wherein R 1A and R 1B are each independently selected from hydrogen, (1-4C)alkyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl(1-2C)alkyl, aryl or aryl(1-2C)alkyl, or R 1A and R 1B are linked such that, together with the nitrogen atom to which they are attached, they form a heterocyclic ring; and wherein any alkyl, aryl or heterocyclyl group (formed by R 1A and R 1B ) is optionally substituted by one or more Rx; (ii) a carbon-linked hetero
  • R1 is selected from
  • R1 is selected from: (24) R 2 is selected from hydrogen, methyl, CF 3 , (1-2C)alkoxy, (1-2C)haloalkoxy, halo, cyano, (CH 2 ) 0-3 OR 2A , (CH 2 ) 0-3 NR 2A R 2B , (CH 2 ) 0-3 C(O)NR 2A R 2B , wherein R 2A and R 2B are independently selected from hydrogen or (1-4C)alkyl or R 2A and R 2B are linked such that, together with the N atom to which they are attached, they form a heterocyclic ring which is optionally substituted by halo, cyano, (1-4C)alkyl, (CH 2 ) q3 NR 2D R 2E , (CH 2 ) q3 OR 2D , (CH 2 ) q3 C(O)R 2D , (CH 2 ) q3 C(O)OR 2D , (CH 2 ) q3 OC(
  • R 2 is selected from hydrogen, methyl, CF 3 , (1-2C)alkoxy, (1-2C)haloalkoxy, halo, cyano, (CH 2 ) 0-3 OR 2A , (CH 2 ) 0-3 NR 2A R 2B , (CH 2 ) 0-3 C(O)NR 2A R 2B , wherein R 2A and R 2B are independently selected from hydrogen or (1-4C)alkyl or R 2A and R 2B are linked such that, together with the N atom to which they are attached, they form a 4-6 membered heterocyclic ring which is optionally substituted by halo, cyano, (1-4C)alkyl, (CH 2 ) q3 NR 2D R 2E , (CH 2 ) q3 OR 2D , (CH 2 ) q3 C(O)R 2D , (CH 2 ) q3 C(O)OR 2D , (CH 2 ) q3 OC(O)R
  • R 2 is selected from hydrogen, methyl, CF3, (1-2C)alkoxy, (1-2C)haloalkoxy, halo, cyano, (CH 2 ) 0-3 OR 2A , (CH 2 ) 0-3 NR 2A R 2B , (CH 2 ) 0-3 C(O)NR 2A R 2B , wherein R 2A and R 2B are independently selected from hydrogen or (1-4C)alkyl or R 2A and R 2B are linked such that, together with the N atom to which they are attached, they form a 4-6 membered heterocyclic ring which is optionally substituted by halo, cyano, (1-4C)alkyl, (CH 2 ) q3 NR 2D R 2E , (CH 2 ) q3 OR 2D , (CH 2 ) q3 C(O)R 2D , (CH 2 ) q3 C(O)OR 2D , (CH 2 ) q3 OC(O)R 2D
  • R 2 is selected from hydrogen, methyl, CF 3 , (1-2C)alkoxy, (1-2C)haloalkoxy, halo, cyano, (CH 2 ) 0-3 OR 2A , (CH 2 ) 0-3 NR 2A R 2B , (CH 2 ) 0-3 C(O)NR 2A R 2B , wherein R 2A and R 2B are independently selected from hydrogen or (1-4C)alkyl or R 2A and R 2B are linked such that, together with the N atom to which they are attached, they form a 4-6 membered heterocyclic ring which is optionally substituted by halo, cyano, (1-4C)alkyl, (CH 2 ) q3 NR 2D R 2E , (CH 2 ) q3 OR 2D , (CH 2 ) q3 C(O)R 2D , (CH 2 ) q3 C(O)OR 2D , (CH 2 ) q3 OC(O)R
  • R 2 is selected from hydrogen, methyl, CF3, (1-2C)alkoxy, (1-2C)haloalkoxy, halo, cyano, (CH 2 ) 0-3 OR 2A , (CH 2 ) 0-3 NR 2A R 2B , (CH 2 ) 0-3 C(O)NR 2A R 2B , wherein R 2A and R 2B are independently selected from hydrogen or (1-4C)alkyl;
  • R 2 is selected from hydrogen, methyl, CF3, methoxy, halo, cyano, CH 2 OR 2A , CH 2 NR 2A R 2B , C(O)NR 2A R 2B , wherein R 2A and R 2B are independently selected from hydrogen or (1-4C)alkyl;
  • R 2 is selected from hydrogen, methyl, CF3, methoxy, halo, cyano, CH 2 OR 2A , CH 2 NR 2A R 2B , C(O)NR 2A R 2B , wherein R 2A
  • a heteroaryl or heterocyclyl group as defined herein is a monocyclic heteroaryl or mono, bicyclic or bridged heterocyclyl group comprising one, two or three heteroatoms selected from N, O or S.
  • a heteroaryl is a 5- or 6-membered heteroaryl ring comprising one, two or three heteroatoms selected from N, O or S.
  • a heterocyclyl group is a 4-, 5-, 6-, 7- or 8-membered heterocyclyl ring comprising one, two or three heteroatoms selected from N, O or S.
  • a heterocyclyl group is a 5-, 6- or 7-membered monocyclic or bicyclic ring comprising one, two or three heteroatoms selected from N, O or S [e.g. morpholinyl (e.g.4-morpholinyl), pyridinyl, piperazinyl, homopiperazinyl or pyrrolidinonyl].
  • an aryl group is phenyl.
  • R 1 is as defined in any one of paragraphs (1) to (23) above. More suitably, R 1 is as defined in paragraph (5) or (6) above. [0067] Suitably, R 1 is as defined in any one of paragraphs (1) to (23) above.
  • R 1 is as defined in any one of paragraphs (1a), (2a), (3a), (4a), (5a), (6a), (7a), (7b), (7c) or (7d). More suitably again, R 1 is as defined in any one of paragraphs (7a) to (7d). Most suitably, R 1 is as defined in paragraph (7d), [0068] R 1 may also be as defined in paragraph (15) to (23) above. More suitably again, R 1 is as defined in any one of paragraphs (11) to (18). Most suitably, R 1 is as defined in paragraph (17) or (18), [0069] R 1 may also be as defined in any one of paragraphs (19) to (23), in particular paragraphs (21), (22) or (23).
  • R 1A and R 1B may be as defined in any of paragraphs (1) to (13) above.
  • R 1A and R 1B are as defined in any of paragraphs (11) to (13) above.
  • R 1A and R 1B are as defined in paragraph (13) above.
  • R 2 is as defined in any one of paragraphs (24) to (37) above. More suitably, R 2 is as defined in any one of paragraphs (30) to (37) above. Most suitably, R 2 is as defined in paragraph (31), (32) or (33) above.
  • R 1 is as defined in any one of paragraphs (1), (2), (3), (4), (5), (6), (7), (8), (9), (10), (14), (20) or (22) above and R 2 has any one of the definitions herein.
  • R 1 is as defined in any one of paragraphs (1a), (2a), (3a), (4a), (5a), (6a), (7a), (7b), (7c), (7d), (11), (12), (13), (15), (16), (17), (18), (19), (21) or (23) above and R 2 has any one of the definitions herein.
  • R 1 is as defined in paragraph (1) or (1a) above and R 2 has any one of the definitions herein.
  • R 1 is as defined in paragraph (2) or (2a) above and R 2 has any one of the definitions herein.
  • R 1 is as defined in paragraph (3) or (3a) above and R 2 has any one of the definitions herein.
  • R 1 is as defined in paragraph (4) or (4a) above and R 2 has any one of the definitions herein.
  • R 1 is as defined in paragraph (5) or (5a) above and R 2 has any one of the definitions herein.
  • R 1 is as defined in paragraph (6) or (6a) above and R 2 has any one of the definitions herein.
  • R 1 is as defined in paragraph (7) or (7a) above and R 2 has any one of the definitions herein.
  • R 1 is as defined in paragraph (7b) above and R 2 has any one of the definitions herein.
  • R 1 is as defined in paragraph (7c) above and R 2 has any one of the definitions herein.
  • R 1 is as defined in paragraph (7d) above and R 2 has any one of the definitions herein.
  • R 1 is as defined in paragraph (8) above and R 2 has any one of the definitions herein.
  • R 1 is as defined in paragraph (9) above and R 2 has any one of the definitions herein.
  • R 1 is as defined in paragraph (10) above and R 2 has any one of the definitions herein.
  • R 1 is as defined in paragraph (11) above and R 2 has any one of the definitions herein.
  • R 1 is as defined in paragraph (12) above and R 2 has any one of the definitions herein.
  • R 1 is as defined in paragraph (13) above and R 2 has any one of the definitions herein.
  • R 1 is as defined in paragraph (14) above and R 2 has any one of the definitions herein.
  • R 1 is as defined in paragraph (15) above and R 2 has any one of the definitions herein.
  • R 1 is as defined in paragraph (16) above and R 2 has any one of the definitions herein.
  • R 1 is as defined in paragraph (17) above and R 2 has any one of the definitions herein.
  • R 1 is as defined in paragraph (18) above and R 2 has any one of the definitions herein.
  • R 1 is as defined in paragraph (19) above and R 2 has any one of the definitions herein.
  • R 1 is as defined in paragraph (20) above and R 2 has any one of the definitions herein.
  • R 1 is as defined in paragraph (21) above and R 2 has any one of the definitions herein.
  • R 1 is as defined in paragraph (22) above and R 2 has any one of the definitions herein.
  • R 1 is as defined in paragraph (23) above and R 2 has any one of the definitions herein.
  • R 2 is as defined in any one of paragraphs (24), (25), (26), (27), (28), (29), (30), (31), (32), (33), (34), (35), (36) or (37) above and R 1 has any one of the definitions herein. Most suitably, R 2 is as defined in any one of paragraphs (32) or (33).
  • R 2 is as defined in paragraph (24) above and R 1 has any one of the definitions herein.
  • R 2 is as defined in paragraph (25) above and R 1 has any one of the definitions herein.
  • R 2 is as defined in paragraph (26) above and R 1 has any one of the definitions herein.
  • R 2 is as defined in paragraph (27) above and R 1 has any one of the definitions herein.
  • R 2 is as defined in paragraph (28) above and R 1 has any one of the definitions herein.
  • R 2 is as defined in paragraph (29) above and R 1 has any one of the definitions herein.
  • R 2 is as defined in paragraph (30) above and R 1 has any one of the definitions herein.
  • R 2 is as defined in paragraph (31) above and R 1 has any one of the definitions herein.
  • R 2 is as defined in paragraph (32) above and R 1 has any one of the definitions herein.
  • R 2 is as defined in paragraph (33) above and R 1 has any one of the definitions herein.
  • R 2 is as defined in paragraph (34) above and R 1 has any one of the definitions herein.
  • R 1 has any one of the definitions herein.
  • R 2 is as defined in paragraph (36) above and R 1 has any one of the definitions herein.
  • R 2 is as defined in paragraph (37) above and R 1 has any one of the definitions herein.
  • the compounds have the structural formula Ia [a sub-definition of formula (I)] shown below, or a pharmaceutically acceptable salt, hydrate and/or solvate thereof: Ia wherein R 1A , R 1B and R 2 are each as defined hereinbefore.
  • R 1A is as defined in any one of paragraphs (1) to (13) above; R 1B is as defined in any one of paragraphs (1) to (13) above; and R 2 is as defined in any one of paragraphs (24) to (37) above.
  • R 1A and R 1B are as defined in any one of paragraphs (5) to (13) above; and R 2 is as defined in any one of paragraphs (24) to (37) above.
  • R 1A and R 1B are as defined in any one of paragraphs (11) to (13) above; and R 2 is as defined in any one of paragraphs (29) to (33) above.
  • R 1A and R 1B are as defined in paragraph (13) above; and R 2 is as defined in any one of paragraphs (29) to (33) above.
  • R 1A and R 1B are as defined in paragraph (5) or (5a) above; and R 2 is as defined in paragraph (28) above.
  • R 1A and R 1B are as defined in paragraph (6) or (6a) above; and R 2 is as defined in paragraph (29) above.
  • R 1A and R 1B are as defined in paragraph (7) or (7a) above; and R 2 is as defined in paragraph (30) above.
  • R 1A and R 1B are as defined in paragraph (9) above; and R 2 is as defined in paragraph (31) above.
  • R 1A and R 1B are as defined in any one of paragraphs (8) to (13) above; and R 2 is as defined in paragraph any one of paragraphs (29) to (33) above.
  • R 1A and R 1B are as defined in any one of paragraphs (11) to (13) above; and R 2 is as defined in paragraph (32) or (33) above.
  • R 1A and R 1B are as defined in paragraph (13) above; and R 2 is as defined in paragraph (33) above.
  • the compounds have the structural formula Ib [a sub-definition of formula (I)] shown below, or a pharmaceutically acceptable salt, hydrate and/or solvate thereof: Ib wherein R 1C and R 2 are each as defined hereinbefore.
  • R 1C is as defined in any one of paragraphs (1) to (8); and R 2 is as defined in any one of paragraphs (24) to (22) above.
  • R 1C is as defined in any one of paragraphs (5) to (8); and R 2 is as defined in any one of paragraphs (24) to (22) above.
  • R 1C is as defined in paragraph (5); and R 2 is as defined in paragraph (28).
  • R 1C is as defined in paragraph (6); and R 2 is as defined in paragraph (29).
  • R 1C is as defined in paragraph (7); and R 2 is as defined in paragraph (30) above.
  • R 1C is as defined in paragraph (8); and R 2 is as defined in paragraph (31) above.
  • R 1C is as defined in paragraph (18); and R 2 is as defined in paragraph (31) above.
  • the compounds have the structural formula Ic [a sub-definition of formula (I)] shown below, or a pharmaceutically acceptable salt, hydrate and/or solvate thereof: wherein R 1 is as defined hereinbefore.
  • R 1 is as defined in any one of paragraphs (1) to (23).
  • R 1 is as defined in any one of paragraphs (3) to (23). [00138] In another embodiment of the compounds of formula Ic: R 1 is as defined in any one of paragraphs (5) to (14). [00139] In another embodiment of the compounds of formula Ic: R 1 is as defined in any one of paragraphs (8) or (9). [00140] In another embodiment of the compounds of formula Ic: R 1 is as defined in paragraph (10). [00141] In another embodiment of the compounds of formula Ic: R 1 is as defined in paragraph (20).
  • R 1 is as defined in any one of paragraphs (1a), (2a), (3a), (4a), (5a), (6a), (7a), (7b), (7c) or (7d) above. [00143] In another embodiment of the compounds of formula Ic: R 1 is as defined in any one of paragraphs (7a) to (7d) above. [00144] In another embodiment of the compounds of formula Ic: R 1 is as defined in paragraph (7d) above. [00145] In another embodiment of the compounds of formula Ic: R 1 is as defined in any one of paragraphs (15) to (23) above. [00146] In another embodiment of the compounds of formula Ic: R 1 is as defined in any one of paragraphs (11) to (18) above.
  • R 1 is as defined in any one of paragraphs (19) to (23) above.
  • R 1 is as defined in any one of paragraphs (21), (22) or (23) above.
  • the compounds have the structural formula Id [a sub-definition of formula (I)] shown below, or a pharmaceutically acceptable salt, hydrate and/or solvate thereof: wherein R 1 is as defined hereinbefore.
  • R 1 is as defined in any one of paragraphs (1) to (23) and .
  • R 1 is as defined in any one of paragraphs (3) to (23). [00152] In another embodiment of the compounds of formula Id: R 1 is as defined in any one of paragraphs (5) to (14). [00153] In another embodiment of the compounds of formula Id: R 1 is as defined in any one of paragraphs (7), (8) or (9). [00154] In another embodiment of the compounds of formula Id: R 1 is as defined in any one of paragraphs (10) or (14). [00155] In another embodiment of the compounds of formula Id: R 1 is as defined in paragraph (20). [00156] In another embodiment of the compounds of formula Id: R 1 is as defined in paragraph (21).
  • R 1 is as defined in any one of paragraphs (1a), (2a), (3a), (4a), (5a), (6a), (7a), (7b), (7c) or (7d) above. [00158] In another embodiment of the compounds of formula Id: R 1 is as defined in any one of paragraphs (7a) to (7d) above. [00159] In another embodiment of the compounds of formula Id: R 1 is as defined in paragraph (7d) above. [00160] In another embodiment of the compounds of formula Id: R 1 is as defined in any one of paragraphs (15) to (23) above. [00161] In another embodiment of the compounds of formula Ic: R 1 is as defined in any one of paragraphs (11) to (18) above.
  • R 1 is as defined in any one of paragraphs (19) to (23) above.
  • R 1 is as defined in any one of paragraphs (21), (22) or (23) above.
  • the compounds have the structural formula Ie [a sub-definition of formula (I)] shown below, or a pharmaceutically acceptable salt, hydrate and/or solvate thereof: Ie wherein R 1 is as defined hereinbefore.
  • R 1 is as defined in any one of paragraphs (1) to (23).
  • R 1 is as defined in any one of paragraphs (3) to (23). [00167] In another embodiment of the compounds of formula Ie: R 1 is as defined in any one of paragraphs (5), (6) or (7). [00168] In another embodiment of the compounds of formula Ie: R 1 is as defined in any one of paragraphs (9) or (10). [00169] In another embodiment of the compounds of formula Ie: R 1 is as defined in paragraph (20). [00170] In another embodiment of the compounds of formula Ie: R 1 is as defined in paragraph (21).
  • R 1 is as defined in any one of paragraphs (1a), (2a), (3a), (4a), (5a), (6a), (7a), (7b), (7c) or (7d) above.
  • R 1 is as defined in any one of paragraphs (7a) to (7d) above.
  • R 1 is as defined in paragraph (7d) above.
  • R 1 is as defined in paragraph (7d) above.
  • R 1 is as defined in any one of paragraphs (15) to (23) above.
  • R 1 is as defined in any one of paragraphs (11) to (18) above.
  • R 1 is as defined in any one of paragraphs (19) to (23) above.
  • R 1 is as defined in any one of paragraphs (21), (22) or (23) above.
  • the compounds have the structural formula If [a sub-definition of formula (I)] shown below, or a pharmaceutically acceptable salt, hydrate and/or solvate thereof: wherein R 1 is as defined hereinbefore.
  • R 1 is as defined in any one of paragraphs (1) to (23).
  • R 1 is as defined in any one of paragraphs (1a), (2a), (3a), (4a), (5a), (6a), (7a), (7b), (7c) or (7d) above. [00186] In another embodiment of the compounds of formula If: R 1 is as defined in any one of paragraphs (7a) to (7d) above. [00187] In another embodiment of the compounds of formula If: R 1 is as defined in paragraph (7d) above. [00188] In another embodiment of the compounds of formula If: R 1 is as defined in any one of paragraphs (15) to (23) above. [00189] In another embodiment of the compounds of formula If: R 1 is as defined in any one of paragraphs (11) to (18) above.
  • R 1 is as defined in any one of paragraphs (19) to (23) above.
  • R 1 is as defined in any one of paragraphs (21), (22) or (23) above.
  • the compounds have the structural formula Ig [a sub-definition of formula (I)] shown below, or a pharmaceutically acceptable salt, hydrate and/or solvate thereof: wherein R 1A and R 1B are each as defined hereinbefore.
  • R 1A is as defined in any one of paragraphs (1) to (13); and R 1B is as defined in any one of paragraphs (1) to (13) above.
  • R 1A and R 1B are as defined in any one of paragraphs (5) to (13) above.
  • R 1A and R 1B are as defined in paragraph (5) or (5a) above.
  • R 1A and R 1B are as defined in paragraph (6) or (6a) above.
  • R 1A and R 1B are as defined in paragraph (7), (7a), (7b), (7c) or (7d) above.
  • R 1A and R 1B are as defined in any one of paragraphs (1) to (13) above.
  • R 1A and R 1B are as defined in any one of paragraphs (8) to (13) above.
  • R 1A and R 1B are as defined in any one of paragraphs (11) to (13) above.
  • R 1A and R 1B are as defined in paragraph (13) above.
  • the compounds have the structural formula Ih [a sub-definition of formula (I)] shown below, or a pharmaceutically acceptable salt, hydrate and/or solvate thereof: wherein R 1A and R 1B are each as defined hereinbefore.
  • R 1A is as defined in any one of paragraphs (1) to (13); and R 1B is as defined in any one of paragraphs (1) to (13) above.
  • R 1A and R 1B are as defined in any one of paragraphs (5) to (13) above.
  • R 1A and R 1B are as defined in paragraph (5) or (5a) above.
  • R 1A and R 1B are as defined in paragraph (6) or (6a) above.
  • R 1A and R 1B are as defined in paragraph (7), (7a), (7b), (7c) or (7d) above.
  • R 1A and R 1B are as defined in any one of paragraphs (1) to (13) above.
  • R 1A and R 1B are as defined in any one of paragraphs (8) to (13) above.
  • R 1A and R 1B are as defined in any one of paragraphs (11) to (13) above.
  • R 1A and R 1B are as defined in paragraph (13) above.
  • the compounds have the structural formula Ii [a sub-definition of formula (I)] shown below, or a pharmaceutically acceptable salt, hydrate and/or solvate thereof: Ii wherein: R 2 is as defined hereinbefore, each occurrence of Rx is independently as defined hereinbefore in any one of paragraphs (1) to (7), and (1a), (2a), (3a), (4a), (5a), (6a), (7a), (7b), (7c) and (7d) above); and n is selected from 0, 1, 2, 3 or 4.
  • R 2 is as defined in any one of paragraphs (29) to (33) above, each occurrence of Rx is independently as defined in any one of paragraphs (5a), (6a), (7a), (7b), (7c) and (7d) above; and n is selected from 0, 1, 2, 3 or 4.
  • R 2 is as defined in paragraph (31) to (33) above, each occurrence of R x is independently as defined in any one of paragraphs (7a), (7b), (7c) and (7d) above; and n is selected from 0, 1, 2, 3 or 4.
  • R 2 is as defined in paragraph (32) or (33) above, each occurrence of R x is independently as defined in paragraph (7d) above; and n is selected from 0, 1, 2, 3 or 4.
  • the compounds have the structural formula Ik [a sub-definition of formula (I)] shown below, or a pharmaceutically acceptable salt, hydrate and/or solvate thereof: Ik wherein each occurrence of Rx is independently as defined hereinbefore in any one of paragraphs (1) to (7), and (1a), (2a), (3a), (4a), (5a), (6a), (7a), (7b), (7c) and (7d) above); and n is selected from 0, 1, 2, 3 or 4.
  • each occurrence of R x is as defined in any one of paragraphs (5a), (6a), (7a), (7b), (7c) and (7d) above; and n is selected from 0, 1, 2, 3 or 4.
  • each occurrence of R x is independently as defined in any one of paragraphs (7a), (7b), (7c) and (7d) above; and n is selected from 0, 1, 2, 3 or 4.
  • each occurrence of R x is independently as defined in (7d) above; and n is selected from 0, 1, 2, 3 or 4.
  • the compounds have the structural formula Ij [a sub-definition of formula (I)] shown below, or a pharmaceutically acceptable salt, hydrate and/or solvate thereof: Ij wherein each occurrence of Rx is independently as defined hereinbefore in any one of paragraphs (1) to (7), and (1a), (2a), (3a), (4a), (5a), (6a), (7a), (7b), (7c) and (7d) above); and n is selected from 0, 1, 2, 3 or 4.
  • each occurrence of Rx is as defined in any one of paragraphs (5a), (6a), (7a), (7b), (7c) and (7d) above; and n is selected from 0, 1, 2, 3 or 4.
  • each occurrence of Rx is independently as defined in any one of paragraphs (7a), (7b), (7c) and (7d) above; and n is selected from 0, 1, 2, 3 or 4.
  • each occurrence of Rx is independently as defined in (7d) above; and n is selected from 0, 1, 2, 3 or 4.
  • the compounds have the structural formula Im [a sub-definition of formula (I)] shown below, or a pharmaceutically acceptable salt, hydrate and/or solvate thereof: Im wherein: R 2 is as defined hereinbefore, R x1 , Rx2, R x3 and Rx4 are each independently either hydrogen or a group Rx as defined herein (wheren Rx is a group as defined in any one of paragraphs (1) to (7), and (1a), (2a), (3a), (4a), (5a), (6a), (7a), (7b), (7c) and (7d) above).
  • R 2 is as defined in any one of paragraphs (29) to (33) above, R x1 , Rx2, R x3 and Rx4 are each independently either hydrogen or a group Rx as defined in any one of paragraphs (5a), (6a), (7a), (7b), (7c) and (7d) above.
  • R x1 , Rx2, R x3 and Rx4 are each independently either hydrogen or a group Rx as defined in any one of paragraphs (7a), (7b), (7c) and (7d) above.
  • R 2 is as defined in paragraph (32) or (33) above, R x1 and Rx2 are independently selected from hydrogen or halo; R x3 and Rx4 are independently selected from hydrogen, halo, methyl or methoxy; or one of R x3 and R x4 is hydrogen, and the other is OR 1D , wherein R 1D is heterocyclyl(1-2C)alkyl, wherein the heterocyclyl is a nitrogen linked 5- or 6- membered heterocyclyl.
  • R 2 is as defined in paragraph (32) or (33) above, R x1 and R x2 are each fluoro; R x3 and R x4 are independently selected from hydrogen, halo, methyl or methoxy; or one of R x3 and R x4 is hydrogen, and the other is OR 1D , wherein R 1D is heterocyclyl(1-2C)alkyl, wherein the heterocyclyl is a nitrogen linked 5- or 6- membered heterocyclyl.
  • R x1 , Rx2, R x3 and Rx4 are each independently either hydrogen or a group Rx as defined herein (wheren Rx is a group as defined in any one of paragraphs (1) to (7), and (1a), (2a), (3a), (4a), (5a), (6a), (7a), (7b), (7c) and (7d) above).
  • R x1 , R x2 , R x3 and R x4 are each independently either hydrogen or a group R x as defined in any one of paragraphs (5a), (6a), (7a), (7b), (7c) and (7d) above.
  • R x1 , R x2 , R x3 and R x4 are each independently either hydrogen or a group R x as defined in any one of paragraphs (7a), (7b), (7c) and (7d) above.
  • R x1 and R x2 are independently selected from hydrogen or halo; R x3 and R x4 are independently selected from hydrogen, halo, methyl or methoxy; or one of R x3 and R x4 is hydrogen, and the other is OR 1D , wherein R 1D is heterocyclyl(1-2C)alkyl, wherein the heterocyclyl is a nitrogen linked 5- or 6- membered heterocyclyl.
  • R x1 and R x2 are each fluoro; R x3 and R x4 are independently selected from hydrogen, halo, methyl or methoxy; or one of R x3 and R x4 is hydrogen, and the other is OR 1D , wherein R 1D is heterocyclyl(1-2C)alkyl, wherein the heterocyclyl is a nitrogen linked 5- or 6- membered heterocyclyl.
  • the compounds have the structural formula Io [a sub-definition of formula (I)] shown below, or a pharmaceutically acceptable salt, hydrate and/or solvate thereof: wherein: R x1 , R x2 , R x3 and R x4 are each independently either hydrogen or a group R x as defined herein (wheren R x is a group as defined in any one of paragraphs (1) to (7), and (1a), (2a), (3a), (4a), (5a), (6a), (7a), (7b), (7c) and (7d) above).
  • R x1 , R x2 , R x3 and R x4 are each independently either hydrogen or a group R x as defined in any one of paragraphs (5a), (6a), (7a), (7b), (7c) and (7d) above.
  • R x1 , R x2 , R x3 and R x4 are each independently either hydrogen or a group R x as defined in any one of paragraphs (7a), (7b), (7c) and (7d) above.
  • R x1 and R x2 are independently selected from hydrogen or halo; R x3 and R x4 are independently selected from hydrogen, halo, methyl or methoxy; or one of R x3 and R x4 is hydrogen, and the other is OR 1D , wherein R 1D is heterocyclyl(1-2C)alkyl, wherein the heterocyclyl is a nitrogen linked 5- or 6- membered heterocyclyl.
  • R x1 and R x2 are each fluoro; R x3 and R x4 are independently selected from hydrogen, halo, methyl or methoxy; or one of R x3 and R x4 is hydrogen, and the other is OR 1D , wherein R 1D is heterocyclyl(1-2C)alkyl, wherein the heterocyclyl is a nitrogen linked 5- or 6- membered heterocyclyl.
  • Particular compounds of the present invention include any of the compounds described in the example section of the present application, or a pharmaceutically acceptable salt or solvate thereof, and, in particular, any of the following: 5-(5-Pyrrolidin-1-ylpyridazin-3-yl)-1H-pyrimidine-2,4-dione; 5-[5-(Cyclopropylmethoxy)-6-methyl-pyridazin-3-yl]-1H-pyrimidine-2,4-dione; 5-(6-Methyl-5-pyrrolidin-1-yl-pyridazin-3-yl)-1H-pyrimidine-2,4-dione; 4-[4-[6-(2,4-Dioxo-1H-pyrimidin-5-yl)-3-methyl-pyridazin-4-yl]morpholin-2-yl]benzonitrile; tert-Butyl 7-[6-(2,4-dioxo-1H-pyrimidin-5-
  • Particular compounds of the present invention include any of the compounds described in the example section of the present application, or a pharmaceutically acceptable salt or solvate thereof, and, in particular, any of the following: Name 5-[5-[3-(4-fluorophenyl)-1-piperidyl]-6-methyl-pyridazin-3-yl]-1H-pyrimidine-2,4- dione; 5-(6-methyl-5-pyrrolidin-1-yl-pyridazin-3-yl)-1H-pyrimidine-2,4-dione; 5-[6-methyl-5-(1-piperidyl)pyridazin-3-yl]-1H-pyrimidine-2,4-dione; 5-[6-methyl-5-(3-methyl-1-piperidyl)pyridazin-3-yl]-1H-pyrimidine-2,4-dione; 5-[5-[(3S)-3-(4-fluorophenyl)-1-piperidyl]-6-methyl-pyri
  • the various functional groups and substituents making up the compounds of the formula (I) are typically chosen such that the molecular weight of the compound of the formula (I) does not exceed 1000. More usually, the molecular weight of the compound will be less than 900, for example less than 800, or less than 750, or less than 700, or less than 650. More preferably, the molecular weight is less than 600 and, for example, is 550 or less.
  • a suitable pharmaceutically acceptable salt of a compound of the invention is, for example, an acidaddition- salt of a compound of the invention which is sufficiently basic, for example, an acidaddition- salt with, for example, an inorganic or organic acid, for example hydrochloric, hydrobromic, sulfuric, phosphoric, trifluoroacetic, formic, citric methane sulfonate or maleic acid.
  • an inorganic or organic acid for example hydrochloric, hydrobromic, sulfuric, phosphoric, trifluoroacetic, formic, citric methane sulfonate or maleic acid.
  • a suitable pharmaceutically acceptable salt of a compound of the invention which is sufficiently acidic is an alkali metal salt, for example a sodium or potassium salt, an alkaline earth metal salt, for example a calcium or magnesium salt, an ammonium salt or a salt with an organic base which affords a pharmaceutically acceptable cation, for example a salt with methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine.
  • alkali metal salt for example a sodium or potassium salt
  • an alkaline earth metal salt for example a calcium or magnesium salt
  • an ammonium salt or a salt with an organic base which affords a pharmaceutically acceptable cation, for example a salt with methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine.
  • stereoisomers that differ in the arrangement of their atoms in space are termed “stereoisomers”.
  • stereoisomers that are not mirror images of one another are termed “diastereomers” and those that are nonsuperimposable mirror images of each other are termed “enantiomers”.
  • enantiomers When a compound has an asymmetric center-, for example, it is bonded to four different groups, a pair of enantiomers is possible.
  • An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R and S sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or -levorotatory- (i.e., as (+) or (-)-isomers respectively).
  • a chiral compound can exist as either individual enantiomer or as a mixture thereof.
  • a mixture containing equal proportions of the enantiomers is called a “racemic mixture”.
  • the compounds of this invention may possess one or more asymmetric centers; such compounds can therefore be produced as individual (R) or (S)stereoisomers or as mixtures thereof.
  • the present invention also encompasses compounds of the invention as defined herein which comprise one or more isotopic substitutions.
  • H may be in any isotopic form, including 1H, 2H(D), and 3H (T);
  • C may be in any isotopic form, including 12C, 13C, and 14C; and
  • O may be in any isotopic form, including 16O and18O; and the like.
  • certain compounds of the formula (I) may exist in solvated as well as unsolvated forms such as, for example, hydrated forms. It is to be understood that the invention encompasses all such solvated forms that possess antiproliferative activity.
  • keto-, enol-, and enolate-forms examples include keto-, enol-, and enolate-forms, as in, for example, the following tautomeric pairs: keto/enol (illustrated below), imine/enamine, amide/imino alcohol, amidine/amidine, nitroso/oxime, thioketone/enethiol, and nitro/aci-nitro.
  • keto enol enolate [00249]
  • Compounds of the formula I containing an amine function may also form N-oxides.
  • a reference herein to a compound of the formula I that contains an amine function also includes the N-oxide. Where a compound contains several amine functions, one or more than one nitrogen atom may be oxidised to form an N-oxide.
  • N-oxides are the N-oxides of a tertiary amine or a nitrogen atom of a nitrogen-containing heterocycle.
  • N- Oxides can be formed by treatment of the corresponding amine with an oxidizing agent such as hydrogen peroxide or a per-acid (e.g. a peroxycarboxylic acid), see for example Advanced Organic Chemistry, by Jerry March, 4th Edition, Wiley Interscience, pages. More particularly, N-oxides can be made by the procedure of L. W. Deady (Syn.
  • the compounds of formula (I) may be administered in the form of a prodrug which is broken down in the human or animal body to release a compound of the invention.
  • a pro-drug may be used to alter the physical properties and/or the pharmacokinetic properties of a compound of the invention.
  • a pro-drug can be formed when the compound of the invention contains a suitable group or substituent to which a property-modifying group can be attached.
  • pro-drugs include in vivo cleavable ester derivatives that may be formed at a carboxy group or a hydroxy group in a compound of the formula (I) and in-vivo cleavable amide derivatives that may be formed at a carboxy group or an amino group in a compound of the formula (I).
  • the present invention includes those compounds of the formula (I) as defined hereinbefore when made available by organic synthesis and when made available within the human or animal body by way of cleavage of a pro-drug thereof.
  • the present invention includes those compounds of the formula I that are produced by organic synthetic means and also such compounds that are produced in the human or animal body by way of metabolism of a precursor compound, that is a compound of the formula (I) may be a synthetically-produced compound or a metabolically-produced compound.
  • a suitable pharmaceutically acceptable pro-drug of a compound of the formula (I) is one that is based on reasonable medical judgement as being suitable for administration to the human or animal body without undesirable pharmacological activities and without undue toxicity.
  • Various forms of pro-drug have been described, for example in the following documents :- a) Methods in Enzymology, Vol.42, p.309-396, edited by K.
  • a suitable pharmaceutically acceptable pro-drug of a compound of the formula I that possesses a carboxy group is, for example, an in vivo cleavable ester thereof.
  • An in vivo cleavable ester of a compound of the formula I containing a carboxy group is, for example, a pharmaceutically acceptable ester which is cleaved in the human or animal body to produce the parent acid.
  • Suitable pharmaceutically acceptable esters for carboxy include C1-6alkyl esters such as methyl, ethyl and tert-butyl, C1-6alkoxymethyl esters such as methoxymethyl esters, C1-6alkanoyloxymethyl esters such as pivaloyloxymethyl esters, 3-phthalidyl esters, C3-8cycloalkylcarbonyloxy- C1-6alkyl esters such as cyclopentylcarbonyloxymethyl and 1-cyclohexylcarbonyloxyethyl esters, 2-oxo-1,3-dioxolenylmethyl esters such as 5-methyl-2-oxo-1,3-dioxolen-4-ylmethyl esters and C1-6alkoxycarbonyloxy- C1-6alkyl esters such as methoxycarbonyloxymethyl and 1- methoxycarbonyloxyethyl esters.
  • C1-6alkyl esters such as methyl, ethyl and tert-but
  • a suitable pharmaceutically acceptable pro-drug of a compound of the Formula (I) that possesses a hydroxy group is, for example, an in vivo cleavable ester or ether thereof.
  • An in vivo cleavable ester or ether of a compound of the formula I containing a hydroxy group is, for example, a pharmaceutically acceptable ester or ether which is cleaved in the human or animal body to produce the parent hydroxy compound.
  • Suitable pharmaceutically acceptable ester forming groups for a hydroxy group include inorganic esters such as phosphate esters (including phosphoramidic cyclic esters).
  • ester forming groups for a hydroxy group include C1-10alkanoyl groups such as acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups, C1- 10alkoxycarbonyl groups such as ethoxycarbonyl, N,N –(C1-6)2carbamoyl, 2- dialkylaminoacetyl and 2-carboxyacetyl groups.
  • Suitable pharmaceutically acceptable ether forming groups for a hydroxy group include ⁇ -acyloxyalkyl groups such as acetoxymethyl and pivaloyloxymethyl groups.
  • a suitable pharmaceutically acceptable pro-drug of a compound of the formula (I) that possesses a carboxy group is, for example, an in vivo cleavable amide thereof, for example an amide formed with an amine such as ammonia, a C1-4alkylamine such as methylamine, a (C1-4alkyl)2amine such as dimethylamine, N-ethyl-N-methylamine or diethylamine, a C1- 4alkoxy- C2-4alkylamine such as 2-methoxyethylamine, a phenyl-C1-4alkylamine such as benzylamine and amino acids such as glycine or an ester thereof.
  • an amine such as ammonia
  • a C1-4alkylamine such as methylamine
  • a (C1-4alkyl)2amine such as dimethylamine, N-ethyl-N-methylamine or diethylamine
  • a C1- 4alkoxy- C2-4alkylamine such
  • a suitable pharmaceutically acceptable pro-drug of a compound of the formula I that possesses an amino group is, for example, an in vivo cleavable amide derivative thereof.
  • Suitable pharmaceutically acceptable amides from an amino group include, for example an amide formed with C1-10alkanoyl groups such as an acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups.
  • ring substituents on the phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N- dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl and 4-(C1-4alkyl)piperazin-1-ylmethyl.
  • the in vivo effects of a compound of the formula (I) may be exerted in part by one or more metabolites that are formed within the human or animal body after administration of a compound of the formula (I). As stated hereinbefore, the in vivo effects of a compound of the formula (I) may also be exerted by way of metabolism of a precursor compound (a pro-drug).
  • the present invention may relate to any compound or particular group of compounds defined herein by way of optional, preferred or suitable features or otherwise in terms of particular embodiments, the present invention may also relate to any compound or particular group of compounds that specifically excludes said optional, preferred or suitable features or particular embodiments.
  • the present invention excludes any individual compounds not possessing the biological activity defined herein. Synthesis [00261]
  • the compounds of the present invention can be prepared by any suitable technique known in the art. Particular processes for the preparation of the compounds of the invention are described in the Example section below.
  • protecting groups see one of the many general texts on the subject, for example, ‘Protective Groups in Organic Synthesis’ by Theodora Green (publisher: John Wiley & Sons).
  • Protecting groups may be removed by any convenient method described in the literature or known to the skilled chemist as appropriate for the removal of the protecting group in question, such methods being chosen so as to effect removal of the protecting group with the minimum disturbance of groups elsewhere in the molecule.
  • reactants include, for example, groups such as amino, carboxy or hydroxy it may be desirable to protect the group in some of the reactions mentioned herein.
  • a suitable protecting group for an amino or alkylamino group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an alkoxycarbonyl group, for example a methoxycarbonyl, ethoxycarbonyl or tbutoxycarbonyl group, an arylmethoxycarbonyl group, for example benzyloxycarbonyl, or an aroyl group, for example benzoyl.
  • the deprotection conditions for the above protecting groups necessarily vary with the choice of protecting group.
  • an acyl group such as an alkanoyl or alkoxycarbonyl group or an aroyl group may be removed by, for example, hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide.
  • a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide.
  • an acyl group such as a tertbutoxycarbonyl group may be removed, for example, by treatment with a suitable acid as hydrochloric, sulfuric or phosphoric acid or trifluoroacetic acid and an arylmethoxycarbonyl group such as a benzyloxycarbonyl group may be removed, for example, by hydrogenation over a catalyst such as palladiumoncarbon, or by treatment with a Lewis acid for example boron tris(trifluoroacetate).
  • a suitable alternative protecting group for a primary amino group is, for example, a phthaloyl group which may be removed by treatment with an alkylamine, for example dimethylaminopropylamine, or with hydrazine.
  • a suitable protecting group for a hydroxy group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an aroyl group, for example benzoyl, or an arylmethyl group, for example benzyl.
  • the deprotection conditions for the above protecting groups will necessarily vary with the choice of protecting group.
  • an acyl group such as an alkanoyl or an aroyl group may be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium, sodium hydroxide or ammonia.
  • an arylmethyl group such as a benzyl group may be removed, for example, by hydrogenation over a catalyst such as palladiumoncarbon.
  • a suitable protecting group for a carboxy group is, for example, an esterifying group, for example a methyl or an ethyl group which may be removed, for example, by hydrolysis with a base such as sodium hydroxide, or for example a tbutyl group which may be removed, for example, by treatment with an acid, for example an organic acid such as trifluoroacetic acid, or for example a benzyl group which may be removed, for example, by hydrogenation over a catalyst such as palladiumoncarbon.
  • Resins may also be used as a protecting group.
  • compositions which comprises a compound of the invention as defined hereinbefore, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in association with a pharmaceutically acceptable diluent or carrier.
  • compositions of the invention may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for example as a finely divided powder or a liquid aerosol), for administration by insufflation (for example as a finely divided powder) or for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular, intraperitoneal or intramuscular dosing or as a suppository for rectal dosing).
  • oral use for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or
  • compositions of the invention may be obtained by conventional procedures using conventional pharmaceutical excipients, well known in the art.
  • compositions intended for oral use may contain, for example, one or more colouring, sweetening, flavouring and/or preservative agents.
  • An effective amount of a compound of the present invention for use in therapy is an amount sufficient to treat or prevent a proliferative condition referred to herein, slow its progression and/or reduce the symptoms associated with the condition.
  • the amount of active ingredient that is combined with one or more excipients to produce a single dosage form will necessarily vary depending upon the individual treated and the particular route of administration.
  • a formulation intended for oral administration to humans will generally contain, for example, from 0.5 mg to 0.5 g of active agent (more suitably from 0.5 to 100 mg, for example from 1 to 30 mg) compounded with an appropriate and convenient amount of excipients which may vary from about 5 to about 98 percent by weight of the total composition.
  • active agent more suitably from 0.5 to 100 mg, for example from 1 to 30 mg
  • excipients which may vary from about 5 to about 98 percent by weight of the total composition.
  • the size of the dose for therapeutic or prophylactic purposes of a compound of the formula I will naturally vary according to the nature and severity of the conditions, the age and sex of the animal or patient and the route of administration, according to well-known principles of medicine.
  • a daily dose in the range for example, 0.1 mg/kg to 75 mg/kg body weight is received, given if required in divided doses.
  • a parenteral route is employed.
  • a dose in the range for example, 0.1 mg/kg to 30 mg/kg body weight will generally be used.
  • a dose in the range for example, 0.05 mg/kg to 25 mg/kg body weight will be used.
  • Oral administration may also be suitable, particularly in tablet form.
  • unit dosage forms will contain about 0.5 mg to 0.5 g of a compound of this invention.
  • Therapeutic Uses and Applications [00285]
  • the present invention provides compounds that function as CD73 inhibitors.
  • a method of inhibiting CD73 in vitro or in vivo comprising contacting a cell with an effective amount of a compound or a pharmaceutically acceptable salt, hydrate or solvate thereof as defined herein.
  • a method of selectively inhibiting CD73 in vitro or in vivo comprising contacting a cell with an effective amount of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein.
  • a method of inhibiting cell proliferation, in vitro or in vivo comprising contacting a cell with an effective amount of a compound or a pharmaceutically acceptable salt, hydrate or solvate thereof as defined herein, or a pharmaceutical composition as defined herein.
  • the compound or pharmaceutical composition is administered in combination with one or more additional antiproliferative agents (e.g.
  • a method of treating a disease or disorder associated CD73 activity in a patient in need of such treatment comprising administering to said patient a therapeutically effective amount of a compound or a pharmaceutically acceptable salt, hydrate or solvate thereof as defined herein, or a pharmaceutical composition as defined herein.
  • a method of treating a proliferative disorder in a patient in need of such treatment comprising administering to said patient a therapeutically effective amount of a compound or a pharmaceutically acceptable salt, hydrate or solvate thereof as defined herein, or a pharmaceutical composition as defined herein.
  • the compound or pharmaceutical composition is administered in combination with one or more additional antiproliferative agents (e.g. checkpoint inhibitors and/or cytotoxic agents).
  • a method of treating cancer in a patient in need of such treatment comprising administering to said patient a therapeutically effective amount of a compound or a pharmaceutically acceptable salt, hydrate or solvate thereof as defined herein, or a pharmaceutical composition as defined herein.
  • the compound or pharmaceutical composition is administered in combination with one or more additional anticancer agents (e.g. checkpoint inhibitors and/or cytotoxic agents).
  • additional anticancer agents e.g. checkpoint inhibitors and/or cytotoxic agents.
  • the compound or pharmaceutical composition is administered in combination with one or more additional antiproliferative agents (e.g. checkpoint inhibitors and/or cytotoxic agents).
  • additional antiproliferative agents e.g. checkpoint inhibitors and/or cytotoxic agents.
  • the cancer is human cancer.
  • the compound or pharmaceutical composition is administered in combination with one or more additional anticancer agents (e.g. checkpoint inhibitors and/or cytotoxic agents).
  • additional anticancer agents e.g. checkpoint inhibitors and/or cytotoxic agents.
  • a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof as defined herein for use as an inhibitor of CD73 activity.
  • Certain compounds of the invention are selective CD73 inhibitors.
  • a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof as defined herein in the manufacture of a medicament for the treatment of a proliferative condition.
  • the compound or pharmaceutical composition is administered in combination with one or more additional antiproliferative agents (e.g. checkpoint inhibitors and/or cytotoxic agents).
  • additional antiproliferative agents e.g. checkpoint inhibitors and/or cytotoxic agents.
  • a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof as defined herein in the manufacture of a medicament for the treatment of cancer.
  • the cancer is a human cancer.
  • the compound or pharmaceutical composition is administered in combination with one or more additional anticancer agents (e.g. checkpoint inhibitors and/or cytotoxic agents).
  • additional anticancer agents e.g. checkpoint inhibitors and/or cytotoxic agents.
  • proliferative disorder are used interchangeably herein and pertain to an unwanted or uncontrolled cellular proliferation of excessive or abnormal cells which is undesired, such as, neoplastic or hyperplastic growth, whether in vitro or in vivo.
  • proliferative conditions include, but are not limited to, pre-malignant and malignant cellular proliferation, including but not limited to, malignant neoplasms and tumours, cancers, leukemias, psoriasis, bone diseases, fibroproliferative disorders (e.g., of connective tissues), and atherosclerosis. Any type of cell may be treated, including but not limited to, lung, colon, breast, ovarian, prostate, liver, pancreas, brain, and skin.
  • the anti-proliferative effects of the compounds of the present invention have particular application in the treatment of human cancers.
  • a compound of general formula (I) for use in the treatment of cancer, particularly solid tumours, for example non-small cell lung cancer, head and neck squamous cancer and urothelial cancer is also provided.
  • the invention further provides a method for the treatment of cancer, particularly solid tumours, for example non-small cell lung cancer, head and neck squamous cancer and urothelial cancer, the method comprising administering to a patient in need of such treatment an effective amount of a compound of general formula (I).
  • the patient to be treated is suitably a mammal and more suitably a human.
  • Routes of Administration [00307] The compounds of the invention or pharmaceutical compositions comprising these compounds may be administered to a subject by any convenient route of administration, whether systemically/ peripherally or topically (i.e., at the site of desired action).
  • Routes of administration include, but are not limited to, oral (e.g, by ingestion); buccal; sublingual; transdermal (including, e.g., by a patch, plaster, etc.); transmucosal (including, e.g., by a patch, plaster, etc.); intranasal (e.g., by nasal spray); ocular (e.g., by eye drops); pulmonary (e.g., by inhalation or insufflation therapy using, e.g., via an aerosol, e.g., through the mouth or nose); rectal (e.g., by suppository or enema); vaginal (e.g., by pessary); parenteral, for example, by injection, including subcutaneous, intradermal, intramuscular, intravenous, intra-arterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, sub
  • the compounds of formula I are useful for the treatment and/or prophylaxis of proliferative disorders, such as, for example, cancer.
  • a compound of formula I defined herein may be used in combination with one or more additional antiproliferative/anticancer therapies, such as, for example, chemotherapy with one or more additional antiproliferative/anticancer agents, radiotherapy and/or conventional surgery.
  • An additional antiproliferative/anticancer agent may be included in the pharmaceutical composition with a compound of formula (I) as defined herein or, alternatively, it may be administered separately, either at the same time as the compound of formula (I) or at an earlier or later time.
  • a product comprising a compound of general formula (I) and an additional agent useful in the treatment or prevention of cancer as a combined preparation for simultaneous, sequential or separate use in the treatment of cancer.
  • the present invention also provides a compound of general formula (I) in combination with one or more additional antiproliferative/anticancer agents for use in the treatment of cancer as a combined preparation for simultaneous, sequential or separate use in the treatment of treatment of cancer.
  • the combination therapy defined herein is suitable for the treatment of solid tumours for example non-small cell lung cancer, head and neck squamous cancer and urothelial cancer.
  • Suitable additional antiproliferative/anti-cancer agents that may be used in combination with a compound of formula I defined herein [either separately or as part of a combined pharmaceutical composition or a combined preparation with the compounds of general formula (I)] include: 1) other forms of cancer immunotherapy and anti-cancer chemotherapeutic agents; 2) A2b antagonists; 3) anti-PD-1 and PDL-1 antibodies including, but not limited to, pembrolizumab, nivolumab, durvalumab, avelumab and atezolizumab; and 4) anti-CTLA4 antibodies including, but not limited to, ipilimumab.
  • the compounds of of formula I defined herein are particulalrly suited to use in combination with anti-PD-1 and PDL-1 antibodies including, but not limited to, pembrolizumab, nivolumab, durvalumab, avelumab and atezolizumab.
  • the CD73 inhibitors of general formula (I) can also be used in combination with cell-based immunotherapy and cancer vaccines that include, but are not limited to CAR-T cell therapy.
  • Examples of the additional antiproliferative/anticancer chemotherapeutic agents include, but are not limited to, any one or more of the following: MEK (e.g. MEK1, MEK2, or MEK1 and MEK2) inhibitors (e.g.
  • alkylating agents e.g., cyclophosphamide, ifosfamide, chlorambucil, busulfan, melphalan, mechlorethamine, uramustine, thiotepa, nitrosoureas, nitrogen mustards (e.g., mechloroethamine, cyclophosphamide, chlorambucil, meiphalan), ethylenimine and methylmelamines (e.g., hexamethlymelamine, thiotepa), alkyl sulfon
  • alkylating agents e.g., cyclophosphamide, ifosfamide, chlorambucil, busulfan, melphalan, mechlorethamine, uramustine, thiotepa, nitrosoureas, nitrogen mustards (e.g., mechloroethamine, cyclophosphamide, chlorambucil
  • Taxol.TM i.e. paclitaxel
  • Taxotere.TM compounds comprising the taxane skeleton, Erbulozole (i.e. R- 55104), Dolastatin 10 (i.e. DLS- 10 and NSC-376128), Mivobulin isethionate (i.e. as CI-980), Vincristine, NSC-639829, Discodermolide (i.e. as NVP-XX-A-296), ABT-751 (Abbott, i.e. E- 7010), Altorhyrtins (e.g. Altorhyrtin A and Altorhyrtin C), Spongistatins (e.g.
  • Epothilones e.g. Epothilone A, Epothilone B, Epothilone C (i.e. desoxyepothilone A or dEpoA), Epothilone D (i.e.
  • Epothilone E Epothilone F
  • Epothilone B N-oxide Epothilone A N-oxide
  • 16-aza- epothilone B 21-aminoepothilone B (i.e. BMS-310705)
  • 21- hydroxyepothilone D i.e. Desoxyepothilone F and dEpoF
  • 26-fluoroepothilone i.e. NSC-654663
  • Soblidotin i.e. TZT-1027
  • Vincristine sulfate i.e.
  • LY-355703 Vitilevuamide, Tubulysin A, Canadensol, Centaureidin (i.e. NSC-106969), Oncocidin Al (i.e. BTO-956 and DF E), Fijianolide B, Laulimalide, Narcosine (also known as NSC-5366), Nascapine, Hemiasterlin, Vanadocene acetylacetonate, Monsatrol, lnanocine (i.e.
  • Eleutherobins such as Desmethyleleutherobin, Desaetyleleutherobin, lsoeleutherobin A, and ZEleutherobin
  • Caribaeoside Caribaeolin
  • Halichondrin B Diazonamide A
  • Taccalonolide A Diozostatin
  • (-)-Phenylahistin i.e.
  • NSCL-96F0357 Myoseverin B, Resverastatin phosphate sodium, steroids (e.g., dexamethasone), finasteride, aromatase inhibitors, gonadotropin-releasing hormone agonists (GnRH) such as goserelin or leuprolide, adrenocorticosteroids (e.g., prednisone), progestins (e.g., hydroxyprogesterone caproate, megestrol acetate, medroxyprogesterone acetate), estrogens (e.g., diethlystilbestrol, ethinyl estradiol), antiestrogen (e.g., tamoxifen), androgens (e.g., testosterone propionate, fluoxymesterone), antiandrogen (e.g., flutamide), immunostimulants (e.g., Bacillus Calmette-Guerin (BCG), levamisole, interleukin
  • gefitinib Iressa TM
  • erlotinib Tarceva TM
  • cetuximab ErbituxTM
  • lapatinib TykerbTM
  • panitumumab VectibixTM
  • vandetanib CaprelsaTM
  • afatinib/BIBW2992 CI-1033/canertinib, neratinib/HKI-272, CP-724714, TAK-285, AST-1306, ARRY334543, ARRY-380, AG-1478, dacomitinib/PF299804, OSI-420/desmethyl erlotinib, AZD8931, AEE788, pelitinib/EKB-569, CUDC-101, WZ8040, WZ4002, WZ3146, AG-490, XL647, PD153035,BMS-599626), sorafenib, imatinib, sunitinib,
  • the combination therapy of the present invention may be achieved by way of the simultaneous, sequential or separate dosing of the individual components of the treatment.
  • Such combination products employ the compounds of this invention within the dosage range described hereinbefore and the other pharmaceutically- active agent within its approved dosage range.
  • a combination for use in the treatment of a cancer comprising a compound of the invention as defined hereinbefore, or a pharmaceutically acceptable salt, hydrate or solvate thereof, and one or more additional antiproliferative/anticancer agents.
  • a combination for use in the treatment of a proliferative condition such as cancer (for example a cancer involving a solid tumour), comprising a compound of the invention as defined hereinbefore, or a pharmaceutically acceptable salt, hydrate or solvate thereof, and one or more additional antiproliferative/anticancer agents selected from those listed above.
  • a proliferative condition such as cancer (for example a cancer involving a solid tumour)
  • a pharmaceutically acceptable salt, hydrate or solvate thereof comprising a compound of the invention as defined hereinbefore, or a pharmaceutically acceptable salt, hydrate or solvate thereof, and one or more additional antiproliferative/anticancer agents selected from those listed above.
  • a compound of the invention or a pharmaceutically acceptable salt, hydrate or solvate thereof for use in the treatment of cancer in combination with another anti-tumour agent, optionally selected from one listed herein above.
  • a pharmaceutical composition which comprises a compound of the invention, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in combination with an anti-tumour agent (optionally selected from one listed herein above), in association with a pharmaceutically acceptable diluent or carrier.
  • an anti-tumour agent optionally selected from one listed herein above
  • LCMS analysis was carried out with a Waters Acquity UPLC system consisting of a Acquity I Class Sample Manager-FL, an Acquity I Class Binary Solvent Manager and an Acquity UPLC Column Manager.
  • UV detection was afforded with a Acquity UPLC PDA detector (scanning from 210nm to 400nm) and mass detection was afforded with a Acquity QDa detector (mass scanning from 100-1250 Da; positive and negative modes simultaneously).
  • a Waters Acquity UPLC BEH C18 column (2.1x50 mm 1.7mm) was used to achieve separation of analytes. [00325] [M+H]+ refers to mono-isotopic molecular weights.
  • NMR spectra were run on either a Bruker Ultrashield 500 MHz NMR spectrometer or a Bruker Avance II 400 MHz NMR spectrometer. Spectra were recorded at 298K and were referenced using the solvent peak. [00327]
  • Method 3A Column: Acquity UPLC BEH C182.1 x 50 mm 1.7 ⁇ m Column Temp: 40 ⁇ C Eluents: A: H 2 O, 0.1% formic acid, B: MeCN Flow Rate: 0.6 mL/min Gradient: 0.0-2.5 min 2-98% B, 2.5-3.3 min 98% B Method 3B
  • B MeCN Flow Rate: 0.6 mL/min Gradient: 0.2-2.5 min 2-98% B, 2.5-3.0 min 98% B
  • Method 5B Column: YMC-Triart C1850 x 2 mm, 5 ⁇ m.
  • Step 2 5-[5-(Cyclopropylmethoxy)-6-methyl-pyridazin-3-yl]-1H-pyrimidine-2,4-dione [00337]
  • MeOH 0.5 mL
  • 4M HCl 1,4-dioxane (0.41 mL, 1.65 mmol)
  • Example 2.1 5-[5-(Cyclobutoxy)-6-methyl-pyridazin-3-yl]-1H-pyrimidine-2,4-dione Step 1: 4-(Cyclobutoxy)-6-(2,4-dimethoxypyrimidin-5-yl)-3-methyl-pyridazine
  • the title compound was prepared from 6-chloro-4-(cyclobutoxy)-3-methyl-pyridazine (Intermediate CA) and (2,4-dimethoxypyrimidin-5-yl)boronic acid analogously to Example 2 step 1.
  • Step 2 5-[5-(Cyclobutoxy)-6-methyl-pyridazin-3-yl]-1H-pyrimidine-2,4-dione
  • the title compound was prepared from 4-(cyclobutoxy)-6-(2,4-dimethoxypyrimidin-5-yl)-3- methyl-pyridazine (step 1) and 4M HCl in 1,4-dioxane analogously to Example 2 step 2.
  • Step 2 5-[5-(Cyclopropoxy)-6-methyl-pyridazin-3-yl]-1H-pyrimidine-2,4-dione
  • the title compound was prepared from 4-(cyclopropoxy)-6-(2,4-dimethoxypyrimidin-5-yl)-3- methyl-pyridazine (step 1) and 4M HCl in 1,4-dioxane analogously to Example 2 step 2.
  • Step 2 5-(6-Methyl-5-pyrrolidin-1-yl-pyridazin-3-yl)-1H-pyrimidine-2,4-dione
  • step 1 To a solution of 2,4-dimethoxy-5-(6-methyl-5-pyrrolidin-1-yl-pyridazin-3- yl)pyrimidine (step 1) (35 mg, 0.12 mmol) in MeOH (0.4 mL), 1M HCl (1.2 mL, 1.2 mmol) was added and the reaction mixture was heated to 70 °C for 3.5 h. The resulting mixture was concentrated in vacuo and the residue was dissolved in a 1:1 mixture of MeCN: H2O (5 mL) and freeze dried overnight.
  • Example 4 4-[4-[6-(2,4-Dioxo-1H-pyrimidin-5-yl)-3-methyl-pyridazin-4-yl]morpholin-2- yl]benzonitrile [00346] DIPEA (0.18 mL, 1.05 mmol) was added to a solution of 5-(5-chloro-6-methyl- pyridazin-3-yl)-1H-pyrimidine-2,4-dione (Intermediate B) (50 mg, 0.21 mmol) and 4- morpholin-2-ylbenzonitrile hydrochloride (141 mg, 0.63 mmol) in NMP (1 mL) under an atmosphere of nitrogen. The reaction mixture was heated in a sealed vessel to 120 o C overnight.
  • Example 5a and 5b [00353] Chiral separation of racemic 5-[5-[3-(4-fluorophenyl)-1-piperidyl]-6-methyl- pyridazin-3-yl]-1H-pyrimidine-2,4-dione (Example 5) using Supercritical Fluid Chromatography under the following conditions afforded the individual enantiomers: Column Details: Lux C3 (21.2 mm x 250 mm, 5um) Column Temperature: 40°C Flow Rate: 50 mL/min BPR: 125 BarG Detector Wavelength: 288 nm Injection Volume: 1000 ⁇ L (3.8 mg) Isocratic Conditions 25:75 MeOH : CO 2 (0.2% v/v NH 3 )
  • Example 5a 5-[5-[(3S)-3-(4-Fluorophenyl)-1-piperidyl]-6-methyl-pyridazin-3-yl]-1H- pyrimidine-2,4-dione or
  • Example 5b 5-[5-[(3S)-3-(4-Fluorophenyl)-1-piperidyl]-6-methyl-pyridazin-3-yl]-1H- pyrimidine-2,4-dione or 5-[5-[(3R)-3-(4-Fluorophenyl)-1-piperidyl]-6-methyl-pyridazin-3- yl]-1H-pyrimidine-2,4-dione
  • Step 2 5-[5-(2,9-Diazaspiro[4.5]decan-2-yl)-6-methyl-pyridazin-3-yl]-1H-pyrimidine-2,4-dione [00358] TFA (0.15 mL, 1.96 mmol) was added to tert-butyl 2-[6-(2,4-dioxo-1H- pyrimidin-5-yl)-3-methyl-pyridazin-4-yl]-2,7-diazaspiro[4.5]decane-7-carboxylate (step 1) (77 mg, 0.17 mmol) in DCM (2 mL) and the reaction mixture was stirred at room temperature for 2.5 h.
  • DIPEA (0.54 mL, 3.1mmol) was added and heating continued at 50 °C for 2 h. Additional pyrrolidine (0.22 mL, 2.59 mmol) and DIPEA (0.54 mL, 3.1mmol) were added and the mixture was heated to reflux for 17 h. Further pyrrolidine (0.22 mL, 2.59 mmol) and DIPEA (0.54 mL, 3.1 mmol) were added and heating continued at reflux for 2 h. After cooling to room temperature, the resulting suspension was filtered and washed with MeCN (3 x 2 mL).
  • Step 2 6-(2,4-Dimethoxypyrimidin-5-yl)-4-pyrrolidin-1-yl-pyridazine-3-carbonitrile
  • Step 3 6-(2,4-Dioxo-1H-pyrimidin-5-yl)-4-pyrrolidin-1-yl-pyridazine-3-carbonitrile
  • 1M HCl 3.2 mL, 3.2mmol
  • 6-(2,4- dimethoxypyrimidin-5-yl)-4-pyrrolidin-1-yl-pyridazine-3-carbonitrile step 2 (100 mg, 0.32 mmol) in MeOH (2 mL) and heated to 70 °C for 9 h.
  • the resulting mixture was allowed to cool to room temperature and concentrated in vacuo. A solid began to crystallise out and the mixture was left to stand at room temperature for 30 mins.
  • Example 7.1 6-(2,4-Dioxo-1H-pyrimidin-5-yl)-4-(3,3,4,4-tetrafluoropyrrolidin-1-yl)pyridazine-3- carbonitrile
  • Step 1 6-Chloro-4-(3,3,4,4-tetrafluoropyrrolidin-1-yl)pyridazine-3-carbonitrile
  • the title compound was prepared from 4,6-dichloropyridazine-3-carbonitrile and 3,3,4,4-tetrafluoropyrrolidine hydrochloride analogously to Example 7 step 1.
  • Step 2 6-(2,4-Dimethoxypyrimidin-5-yl)-4-(3,3,4,4-tetrafluoropyrrolidin-1-yl)pyridazine-3- carbonitrile [00371]
  • the title compound was prepared from 6-chloro-4-(3,3,4,4-tetrafluoropyrrolidin- 1-yl)pyridazine-3-carbonitrile (step 1) and (2,4-dimethoxypyrimidin-5-yl)boronic acid analogously to Example 7 step 2.
  • Step 3 6-(2,4-Dioxo-1H-pyrimidin-5-yl)-4-(3,3,4,4-tetrafluoropyrrolidin-1-yl)pyridazine-3- carbonitrile
  • step 2 The title compound was prepared from 6-(2,4-dimethoxypyrimidin-5-yl)-4- (3,3,4,4-tetrafluoropyrrolidin-1-yl)pyridazine-3-carbonitrile (step 2) and 1M HCl analogously to Example 7 step 3.
  • Step 2 2,4-Dimethoxy-5-(6-methoxy-5-pyrrolidin-1-yl-pyridazin-3-yl)pyrimidine [00376]
  • the title compound was prepared from (2,4-dimethoxypyrimidin-5-yl)boronic acid and 6-chloro-3-methoxy-4-pyrrolidin-1-yl-pyridazine (step 1) analogously to Example 7 step 2.
  • Step 3 5-(6-Methoxy-5-pyrrolidin-1-yl-pyridazin-3-yl)-1H-pyrimidine-2,4-dione [00379]
  • the title compound was prepared from 2,4-dimethoxy-5-(6-methoxy-5- pyrrolidin-1-yl-pyridazin-3-yl)pyrimidine (step 2) and 1M HCl analogously to Example 7 step 3.
  • Example 9 4-(5-Azaspiro[2.4]heptan-5-yl)-6-(2,4-dioxo-1H-pyrimidin-5-yl)pyridazine-3-carbonitrile [00382] A mixture of 4-chloro-6-(2,4-dioxo-1H-pyrimidin-5-yl)pyridazine-3-carbonitrile (Intermediate G) (40 mg, 0.16 mmol), 5-azaspiro[2.4]heptane hydrochloride (43 mg, 0.32 mmol) and DIPEA (0.14 mL, 0.80 mmol) in MeCN (1 mL) was stirred at 70 °C for 2 h. The mixture was cooled to room temperature overnight.
  • Example 9.1 4-[3-[(4-Chlorophenyl)methyl]pyrrolidin-1-yl]-6-(2,4-dioxo-1H-pyrimidin-5- yl)pyridazine-3-carbonitrile [00385] The title compound was prepared from 4-chloro-6-(2,4-dioxo-1H-pyrimidin-5- yl)pyridazine-3-carbonitrile (Intermediate G) and 3-[(4-chlorophenyl)methyl]pyrrolidine; oxalic acid analogously to Example 9.
  • Example 9.2 4-(3,3-Dimethylpyrrolidin-1-yl)-6-(2,4-dioxo-1H-pyrimidin-5-yl)pyridazine-3-carbonitrile [00388] The title compound was prepared from 4-chloro-6-(2,4-dioxo-1H-pyrimidin-5- yl)pyridazine-3-carbonitrile (Intermediate G) and 3,3-dimethylpyrrolidine hydrochloride analogously to Example 9.
  • Example 9.3 4-[2-(4-Cyanophenyl)morpholin-4-yl]-6-(2,4-dioxo-1H-pyrimidin-5-yl)pyridazine-3- carbonitrile [00391] The title compound was prepared from 4-chloro-6-(2,4-dioxo-1H-pyrimidin-5- yl)pyridazine-3-carbonitrile (Intermediate G) and 4-morpholin-2-ylbenzonitrile hydrochloride analogously to Example 9.
  • Example 9.4 4-[3-(4-Cyanophenoxy)pyrrolidin-1-yl]-6-(2,4-dioxo-1H-pyrimidin-5-yl)pyridazine-3- carbonitrile [00394] The title compound was prepared from 4-chloro-6-(2,4-dioxo-1H-pyrimidin-5- yl)pyridazine-3-carbonitrile (Intermediate G) and 4-pyrrolidin-3-yloxybenzonitrile hydrochloride (Intermediate E) analogously to Example 9.
  • Step 2 Methyl 6-(2,4-dimethoxypyrimidin-5-yl)-4-pyrrolidin-1-yl-pyridazine-3-carboxylate
  • Step 3 [6-(2,4-Dimethoxypyrimidin-5-yl)-4-pyrrolidin-1-yl-pyridazin-3-yl]methanol
  • step 2 A solution of methyl 6-(2,4-dimethoxypyrimidin-5-yl)-4-pyrrolidin-1-yl- pyridazine-3-carboxylate (step 2) (200 mg, 0.56 mmol) in THF (1.39 mL) was added to a suspension of lithium aluminium hydride (36 mg, 0.95 mmol) in THF (1.39 mL) at 0 °C and the mixture was allowed to warm to room temperature whilst stirring overnight.
  • step 2 A solution of methyl 6-(2,4-dimethoxypyrimidin-5-yl)-4-pyrrolidin-1-yl- pyridazine-3-carboxylate (step 2) (200 mg, 0.56 mmol) in THF (1.39 mL) was added to a suspension of lithium aluminiu
  • Step 4 5-[6-(Hydroxymethyl)-5-pyrrolidin-1-yl-pyridazin-3-yl]-1H-pyrimidine-2,4-dione
  • 1M HCl 2.4 mL, 2.4 mmol
  • step 3 a solution of [6-(2,4- dimethoxypyrimidin-5-yl)-4-pyrrolidin-1-yl-pyridazin-3-yl]methanol (step 3)(38 mg, 0.12 mmol) in MeOH (2.4 mL) and heated to 70 °C for 1.5 h.
  • the resulting mixture was concentrated in vacuo and re-dissolved in MeOH (5 mL).
  • Example 11 4-(6-Azaspiro[3.4]octan-6-yl)-6-(2,4-dioxo-1H-pyrimidin-5-yl)pyridazine-3-carbonitrile
  • Step 1 4-(6-Azaspiro[3.4]octan-6-yl)-6-(2,4-dimethoxypyrimidin-5-yl)pyridazine-3-carbonitrile
  • Step 2 4-(6-Azaspiro[3.4]octan-6-yl)-6-(2,4-dioxo-1H-pyrimidin-5-yl)pyridazine-3-carbonitrile
  • step 1 A stirred solution of 4-(6-azaspiro[3.4]octan-6-yl)-6-(2,4-dimethoxypyrimidin-5- yl)pyridazine-3-carbonitrile (step 1) (430 mg, 1.22 mmol) in 1M HCl (12.2 mL, 12.2 mmol) and MeOH (12.2 mL) was heated to 70 °C for 1 h. The resulting mixture was allowed to cool to room temperature and concentrated in vacuo to remove methanol.
  • Step 2 4-(2-Azaspiro[4.4]nonan-2-yl)-6-(2,4-dioxo-1H-pyrimidin-5-yl)pyridazine-3-carbonitrile
  • step 1 A mixture of 4-(2-azaspiro[4.4]nonan-2-yl)-6-(2,4-dimethoxypyrimidin-5- yl)pyridazine-3-carbonitrile (step 1) (466 mg, 1.27 mmol), 1M HCl (14 mL, 14 mmol) and MeOH (7 mL) was stirred at 70 °C for 2 h. The mixture was allowed to cool to room temperature and concentrated in vacuo to remove methanol.
  • Example 12.1 6-(2,4-Dioxo-1H-pyrimidin-5-yl)-4-(3-methoxypyrrolidin-1-yl)pyridazine-3-carbonitrile
  • Step 1 6-(2,4-Dimethoxypyrimidin-5-yl)-4-(3-methoxypyrrolidin-1-yl)pyridazine-3-carbonitrile
  • the title compound was prepared from 4-chloro-6-(2,4-dimethoxypyrimidin-5- yl)pyridazine-3-carbonitrile (Intermediate F) and 3-methoxypyrrolidine analogously to Example 12 step 1.
  • Step 2 6-(2,4-Dioxo-1H-pyrimidin-5-yl)-4-(3-methoxypyrrolidin-1-yl)pyridazine-3-carbonitrile
  • step 2 6-(2,4-Dioxo-1H-pyrimidin-5-yl)-4-(3-methoxypyrrolidin-1-yl)pyridazine-3-carbonitrile
  • Example 13 6-(2,4-Dioxo-1H-pyrimidin-5-yl)-4-[3-[2-(1-piperidyl)ethoxy]pyrrolidin-1-yl]pyridazine-3- carbonitrile [00407]
  • a suspension of 4-chloro-6-(2,4-dioxo-1H-pyrimidin-5-yl)pyridazine-3- carbonitrile (Intermediate G) 40 mg, 0.16 mmol
  • 1-(2-pyrrolidin-3-yloxyethyl)piperidine dihydrochloride 65 mg, 0.24 mmol
  • DIPEA 0.14 mL, 0.8 mmol
  • Example 14 4-(3,3-Difluoro-4,4-dimethyl-pyrrolidin-1-yl)-6-(2,4-dioxo-1H-pyrimidin-5-yl)pyridazine- 3-carbonitrile
  • Step 1 4-(3,3-Difluoro-4,4-dimethyl-pyrrolidin-1-yl)-6-(2,4-dimethoxypyrimidin-5- yl)pyridazine-3-carbonitrile
  • Step 2 4-(3,3-Difluoro-4,4-dimethyl-pyrrolidin-1-yl)-6-(2,4-dioxo-1H-pyrimidin-5- yl)pyridazine-3-carbonitrile
  • step 1 A stirred solution of 4-(3,3-difluoro-4,4-dimethyl-pyrrolidin-1-yl)-6-(2,4- dimethoxypyrimidin-5-yl)pyridazine-3-carbonitrile (step 1) (1.06 g, 2.82 mmol) in 1M HCl (28.16 mL, 28.16 mmol) and MeOH (30 mL) was heated to 70 °C for 7 h.
  • Step 2 tert-Butyl 3-[6-(2,4-dimethoxypyrimidin-5-yl)-3-methyl-pyridazin-4-yl]pyrrolidine-1- carboxylate [00411]
  • a mixture of tert-butyl 3-[6-(2,4-dimethoxypyrimidin-5-yl)-3-methyl-pyridazin-4- yl]-2,5-dihydropyrrole-1-carboxylate (step 1) (571 mg, 1.42 mmol) and Pd/C (10%) (162 mg, 1.42 mmol) was degassed under a flow of nitrogen and the flask was charged with MeOH (25 mL).
  • Step 3 2,4-Dimethoxy-5-(6-methyl-5-pyrrolidin-3-yl-pyridazin-3-yl)pyrimidine
  • a solution of tert-butyl 3-[6-(2,4-dimethoxypyrimidin-5-yl)-3-methyl-pyridazin-4- yl]pyrrolidine-1-carboxylate (532 mg, 1.33 mmol) in DCM (10 mL) under nitrogen was treated with TFA (1 mL, 13.06 mmol) and stirred at room temperature for 22 h. The resulting mixture was diluted with DCM (25 mL) and neutralised with saturated NaHCO3 solution (25 mL).
  • Step 4 2,4-Dimethoxy-5-[6-methyl-5-(1-methylpyrrolidin-3-yl)pyridazin-3-yl]pyrimidine
  • step 3 A stirred suspension of 2,4-dimethoxy-5-(6-methyl-5-pyrrolidin-3-yl-pyridazin- 3-yl)pyrimidine (step 3) (100 mg, 0.33 mmol) and paraformaldehyde (200 mg, 6.66 mmol) in acetic acid (10 mL) was treated with sodium triacetoxyborohydride (352 mg, 1.66 mmol) which was added in two portions 30 mins apart.
  • step 3 A stirred suspension of 2,4-dimethoxy-5-(6-methyl-5-pyrrolidin-3-yl-pyridazin- 3-yl)pyrimidine (step 3) (100 mg, 0.33 mmol) and paraformaldehyde (200 mg, 6.66 mmol) in acetic acid (10 mL) was treated with
  • Step 5 5-[6-Methyl-5-(1-methylpyrrolidin-3-yl)pyridazin-3-yl]-1H-pyrimidine-2,4-dione
  • the reaction was purged with nitrogen for 5 mins, sealed and heated to 70 ⁇ C for 20 h.
  • the resulting mixture was allowed to cool to room temperature, filtered through Celite® and washed thoroughly with EtOAc (100 mL).
  • the filtrate was concentrated in vacuo and the crude product was purified by chromatography on silica eluting with a gradient of 0-50% EtOAc in hexanes to afford the title compound as a white solid.
  • Step 2 4-Pyrrolidin-3-yloxybenzonitrile
  • tert-Butyl 3-(4-cyanophenoxy)pyrrolidine-1-carboxylate (step 1) (197 mg, 0.68 mmol) in ether (10 mL) was treated with 4N HCl in dioxane (5.0 mL, 20 mmol) and stirred at room temperature overnight. The resulting mixture was concentrated in vacuo and the residue was azeotroped twice from MeCN to afford 4-pyrrolidin-3-yloxybenzonitrile hydrochloride.
  • BIOLOGICAL EXAMPLE A CD73 Inhibition Assay Compound inhibition of human (h)CD73 (amino acids Trp27-Lys547, R&D Systems 5795-EN-500) enzymatic activity was tested via the Malachite Green Phosphate Detection Kit (R&D DY996). Experiments were performed in 20 ⁇ L Tris buffer (25 mM Tris pH 7.5, 5 mM MgCl 2 , 0.002% Tween20), with 250 pM of hCD73. Test compounds of interest were prepared in a threefold serial dilution in DMSO and added to the assay to give the appropriate final concentration, with the assay DMSO concentration being 1 %.
  • U138-MG cells from ATCC are cultured in DMEM (Gibco 31966) with 10% FBS. Cells are seeded into 96-well culture plates (5,000 cell/ well) in 100 ⁇ L of media for 24 h. Cells are washed twice with 200 ⁇ L of assay buffer (20 mM HEPES, pH 7.4; 137 mM NaCl; 5.4 mM KCl; 1.3 mM CaCl2; 4.2mM NaHCO3; 1 mg/mL glucose) to remove residual inorganic phosphate. CD73 inhibitor is added to each well in 100 ⁇ l volume and preincubated for 30 mins at 37 °C.
  • AMP substrate Sigma A1572
  • AMP substrate Sigma A1572
  • Control wells containing cells but lacking added AMP define the assay signal equivalent to 100% inhibition of CD73 activity.
  • Supernatant is removed for measurement of inorganic phosophate using the PiColorLock Gold kit (Abcam, ab 270004).
  • the IC 50 values of test compounds are determined as the inflection point of the sigmoidal concentration response curve.
  • T-cells expressing CD8 are purified from human PBMCs using CD8 Microbeads (Miltenyi Biotec 130-045-201). Cells are labelled with CFSE reagent (Fisher #10013162) in PBS/ 0.1% BSA at a final concentration of 3 ⁇ M CFSE and 1x10 6 cell/ml for 10 minutes at 370C. Cells are washed in Immunocult XF T-cell expansion medium (Stemcell Technologies #10982), incubated in fresh medium for 5 min at 370C to quench remaining unlabelled dye, then washed again and resuspended in fresh Immunocult XF medium.
  • CD73 inhibitor compounds in RPMI-1640 medium are incubated with CFSE-labelled cells at a ratio of 20 ⁇ l compound + 100 ⁇ l cells in round bottomed 96-well culture plates for 1 h at 370C. Following the inhibitor pre-incubation, add 80 ⁇ l of a mixture containing the remaining assay components prepared in Immunocult medium.
  • the mixture comprises Immunocult Human CD3/CD28/CD2 T cell activator (Stemcell Technologies #10979, final concentration 25 ⁇ l/ml), Interleukin-2 (R&D Systems 202-IL-010, final concentration 100IU/ml), EHNA (Sigma #E114- 25MG, final concentration 5 ⁇ M) and AMP (Sigma A1752 final concentration 5 or 10 ⁇ M).
  • FACS Fluorescence-activated Cell Sorting
  • BIOLOGICAL EXAMPLE D Whole Blood AMP Glo assay Blood is drawn from healthy volunteers by venepuncture and anti-coagulated with Lithium Heparin (10 IU/ml).150 ⁇ l of blood is added to U-bottom polypropylene 96-well assay plates pre-filled with 20 ⁇ l of compound dilutions prepared in RPMI also containing the Tissue Non-specific Alkaline Phosphatase inhibitor Levamisole (final assay concentration 1.5mM).
  • Control wells to define uninhibited CD73 contain DMSO in place of compound.
  • Control wells to define complete stabilization of AMP attributable to CD73 contain LY3475070 (CAS: 2375815-63-5) at 30 ⁇ M final assay concentration.
  • Compounds are pre-incubated with whole blood at 37°C for 30 minutes. Following this, AMP is added in a 30 ⁇ l volume for a final assay concentration of 10 ⁇ M, mixed, and the plates are incubated for 15 minutes at 37°C. Final DMSO concentration/well is 0.6% and final volume/well is 200 ⁇ L. After incubating with AMP, the plates are placed on ice and then centrifuged at 2000g for 10 minutes at 4°C. Plasma is removed and then diluted 1:10 with pre-chilled HBSS (Ca2+ & Mg2+ free) and kept on ice.
  • the stabilized AMP concentration in diluted plasma is measured using AMP- Glo kit (Promega), in parallel with a standard curve of known AMP concentrations, with a final volume of 40 ⁇ l in white flat bottom half-well 96-well plates (Corning). Signal is measured by Luminescence. The IC50 values of test compounds are determined as the inflection point of the sigmoidal concentration response curve.
  • R 1 is selected from: (i) -NR 1A R 1B ; wherein R 1A and R 1B are each independently selected from hydrogen, (1-4C)alkyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl(1-2C)alkyl, aryl, aryl(1- 2C)alkyl, heteroaryl, heteroaryl(1-2C)alkyl, or R 1A and R 1B are linked such that, together with the nitrogen atom to which they are attached, they form a heterocyclic ring; and wherein any alkyl, aryl, heteroaryl or heterocyclyl group (formed by R 1A and R 1B ) is optionally substituted by one or more Rx; (ii) a carbon-linked heterocyclyl optionally substituted by one or more Rx
  • R 1 is selected from: (i) -NR 1A R 1B ; wherein R 1A and R 1B are each independently selected from hydrogen, (1-4C)alkyl, (3- 6C)cycloalkyl, (3-6C)cycloalkyl(1-2C)alkyl, phenyl or phenyl(1-2C)alkyl, or R 1A and R 1B are linked such that, together with the nitrogen atom to which they are attached, they form a heterocyclic ring; and wherein any alkyl, aryl or heterocyclyl group (formed by R 1A and R 1B ) is optionally substituted by one or more R x ; (ii) a carbon-linked heteroaryl or heterocyclyl optionally substituted by one or more R x ; (iii) -O-R 1C ; wherein R 1C is selected from (1-6C)alkyl, (3-8C)cycloalkyl, (3
  • R 1 is selected from: (i) -NR 1A R 1B ; wherein R 1A and R 1B are R 1A and R 1B are linked such that, together with the nitrogen atom to which they are attached, they form a heterocyclic ring which is optionally substituted by one or more R x ; (ii) a carbon-linked heteroaryl or heterocyclyl which is optionally substituted by one or more R x ; (iii) -O-R 1C ; wherein R 1C is selected from (1-6C)alkyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl(1- 2C)alkyl,phenyl, or phenyl(1-2C)alkyl, each of which is optionally substituted by one or more R x ; R x is selected from: halo, cyano, (1-4C)alkyl, (CH 2 ) q1 NR
  • R 1 is selected from: (i) -NR 1A R 1B ; wherein R 1A and R 1B are R 1A and R 1B are linked such that, together with the nitrogen atom to which they are attached, they form a heterocyclic ring which is optionally substituted by one or more Rx; (ii) -O-R 1C ; wherein R 1C is selected from (1-6C)alkyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl(1- 2C)alkyl,phenyl, or phenyl(1-2C)alkyl, each of which is optionally substituted by one or more R x ; R x is selected from: halo, cyano, (1-4C)alkyl, (CH 2 ) q1 NR 1D R 1E , (CH 2 ) q1 OR 1D , (CH 2 ) q1 C(O)
  • R 2 is selected from hydrogen, methyl, CF 3 , methoxy, halo, cyano, CH 2 OR 2A , CH 2 NR 2A R 2B , C(O)NR 2A R 2B , wherein R 2A and R 2B are independently selected from hydrogen or (1-4C)alkyl. 7.
  • R 2 is selected from hydrogen, methyl, methoxy or cyano.
  • a compound according to any one of the preceding paragraphs, or a pharmaceutically acceptable salt thereof, wherein R 2 is methyl. 11. A compound according to any one of the preceding paragraphs, or a pharmaceutically acceptable salt thereof, wherein R 2 is methoxy. 12. A compound according to any one of the preceding paragraphs, or a pharmaceutically acceptable salt thereof, wherein R 2 is cyano. 13. A compound of the formula: Ib wherein R 1A , R 1B and R 1C are as defined in any one of paragraphs 1 to 4 and R 2 is as defined in any one of paragraphs 1 or 6 to 12; or a pharmaceutically acceptable salt thereof. 14. A compound of the formula:
  • R 1 is as defined in any one of paragraphs 1 to 5; or a pharmaceutically acceptable salt thereof.
  • a pharmaceutical composition comprising a compound according to any one of paragraphs 1 to 15, or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable diluent or carrier. 17.
  • a method of treating a proliferative disorder in a patient in need of such treatment comprising administering a therapeutically effective amount of a compound according to any one of paragraphs 1 to 15, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to paragraph 16.
  • a method of treating cancer in a patient in need of such treatment comprising administering a therapeutically effective amount of a compound according to any one of paragraphs 1 to 15, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to paragraph 16. 21.
  • a method of treating a proliferative disorder in a patient in need of such treatment comprising administering a therapeutically effective amount of a compound according to any one of paragraphs 1 to 15, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to paragraph 16 in combination with one or more additional anticancer agents.
  • the one or more additional anticancer agents is selected from: 1) other forms of cancer immunotherapy and anti-cancer chemotherapeutic agents; 2) A2b antagonists; 3) anti-PD-1 and PDL-1 antibodies (e.g. pembrolizumab, nivolumab, durvalumab, avelumab and atezolizumab); and 4) anti-CTLA4 antibodies (e.g ipilimumab).

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Abstract

La présente invention concerne des composés de formule I ci-dessous : , R1 et R2 étant chacun tels que définis dans l'invention. La présente invention concerne également des procédés de préparation de ces composés, des compositions pharmaceutiques les comprenant, ainsi que leur utilisation dans le traitement de maladies ou d'états dans lesquels l'activité de l'adénosine CD73 est impliquée, telles que, par exemple, le cancer.
PCT/GB2021/052788 2020-10-26 2021-10-26 Composés utilisés en tant qu'inhibiteurs de cd73 WO2022090711A1 (fr)

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WO2024006929A1 (fr) * 2022-07-01 2024-01-04 Gilead Sciences, Inc. Composés cd73
WO2024013206A1 (fr) * 2022-07-14 2024-01-18 F. Hoffmann-La Roche Ag Composés hétérocycliques pour le traitement du cancer

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* Cited by examiner, † Cited by third party
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WO2023201267A1 (fr) 2022-04-13 2023-10-19 Gilead Sciences, Inc. Polythérapie pour le traitement de cancers exprimant trop-2
WO2024006929A1 (fr) * 2022-07-01 2024-01-04 Gilead Sciences, Inc. Composés cd73
WO2024013206A1 (fr) * 2022-07-14 2024-01-18 F. Hoffmann-La Roche Ag Composés hétérocycliques pour le traitement du cancer

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